RU2800543C2 - Inhibitor containing a tricyclic derivative, a method of its production and its use - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to a compound of formula (VI), its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from the group consisting of the following:

L is nitrogen; G is oxygen; Q is N; Z is -CR_aa; R_aa is selected from the group consisting of hydrogen and deuterium; each R^y is independently selected from the group consisting of hydrogen and deuterium; each of R₅, R₆ and R₁₄ is independently selected from the group consisting of hydrogen, deuterium and halogen; each of R₃ and R₄ is independently selected from the group consisting of hydrogen, deuterium, C_1-6 alkyl, C_1-6 deuterated alkyl and -(CH₂)_n1OR_bb, wherein each of the said C_1-6 alkyl and C_1-6 deuterated alkyl is optionally further substituted with one or more substituents selected from the group consisting of deuterium and C_1-6 alkoxy; R₂ is selected from the group consisting of hydrogen, deuterium and C_1-6 alkyl; or R₂ and R₃ are associated with the formation of a 4–6-membered heterocyclyl containing nitrogen, where the number of nitrogen atoms is equal to one or two; R^z is selected from the group consisting of hydrogen, deuterium, C_1-6 alkyl, C_1-6 deuterated alkyl and C_1-6 haloalkyl, wherein the said C_1-6 alkyl is optionally further substituted with one or more substituents selected from the group, consisting of deuterium, halogen, cyano; R_bb is selected from the group consisting of hydrogen, C_1-6 alkyl and cyano; n₁ is 0.1, 2 or 3; m is 1; t is 1; n is 1; and q is either 0, 1, 2, 3, 4, 5, or 6. The invention also relates to methods of preparing a compound of formula (VI), a pharmaceutical composition for inhibiting the activity of phosphatidylinositol-3-kinase (PI3K) based on it.

EFFECT: new compounds and a pharmaceutical composition based on them have been obtained, which can be used in medicine in the treatment of cancer and diseases or conditions mediated or dependent on PI3K imbalance.

24 cl, 4 tbl, 129 ex

Description

FIELD OF TECHNOLOGY

The present invention relates to the field of drug synthesis and, in particular, relates to a tricyclic derivative inhibitor, a process for its preparation and its use.

BACKGROUND OF THE INVENTION

The phosphatidylinositol 3-kinase (PI3K) family of proteins is divided into four types: I, II, III, and IV, and is involved in the regulation of multiple cell functions such as cell growth, proliferation, differentiation, survival, and glucose metabolism. The four types of PI3K proteins have different structures and functions, and type I PI3K is the most widely studied. This type I PI3K is divided into four subtypes: PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ. Among them, PI3Kα shows activating mutations and amplification in various tumors, and is closely related to tumor initiation and development. It is reported that PI3Kβ can activate platelets and play an important role in the development of diseases such as thrombosis. PI3Kδ and PI3Kγ are mainly expressed in the circulatory system and are closely associated with the immune system and inflammation. PI3Kγ is also strongly associated with blood pressure stability and smooth muscle contraction.

PI3Kα shows activating mutation and amplification in various tumors and is a driving factor leading to tumorigenesis. PI3Kα is a heterodimer consisting of the p110 catalytic subunit and the p85 regulatory subunit. PI3Kα is activated by receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs). Once activated, it catalyzes the formation of phosphatidylinositol 3-phosphate (PIP3) from phosphatidylinositol 2-phosphate (PIP2). 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 signaling pathways associated with with cell proliferation. Pathological activation of PI3Kα can lead to rapid cell proliferation, thereby leading to oncogenesis.

PI3Kα has always been an important target in the development of anticancer drugs. However, most of the compounds are broad-spectrum PI3K inhibitors and can cause obvious side effects in clinical studies that seriously limit further development of a PI3K inhibitor. In current studies, most of the side effects of broad-spectrum PI3K inhibitors have been found to be due to inhibition of the PI3Kβ, PI3Kδ, and PI3Kγ subtypes. PI3Kβ plays an important role in the side effects of thrombocytopenia and thrombosis. Inhibition of PI3Kδ can cause disturbances in the immune system, and autoimmune and viral infections such as pneumonia, hepatitis, and diarrhea/enteritis are closely associated with inhibition of the PI3Kδ target. PI3Kγ is closely associated with blood pressure stability and smooth muscle contraction, and is the main target for the side effect of hypertension. Therefore, it is necessary to develop a PI3Kα inhibitor with high activity and high selectivity, which can further improve the antitumor effect of the PI3Kα inhibitor and reduce or eliminate serious side effects such as various inflammations, thrombocytopenia and hypertension caused by the inhibition of other subtypes.

The PI3Kα selective inhibitor BYL-719 developed by Novartis is currently in phase III clinical trials. Takeda's PI3Kα-selective inhibitor of MLN1117 has entered phase II clinical trials. Genentech's selective inhibitor GDC-0077 is in Phase I clinical trials.

International patent applications WO2010029082 (A1) and WO2011022439 (A1) disclose compounds related to a PI3Kα selective inhibitor. However, subsequent studies show that the activity of these compounds in cells is low, which affects their clinical antitumor effect. Therefore, there is an urgent need to develop a selective PI3Kα inhibitor with high activity and high selectivity. Selective PI3Kα inhibitors can be used to treat many different tumors by activating mutation or amplification of PI3Kα and have important clinical implications.

Studies show that the compounds according to the examples of the present invention have higher activity and selectivity for the PI3Kα enzyme, better activity in cells, better tumor inhibition in a pharmacodynamic model in mice, and higher safety.

BRIEF DESCRIPTION OF THE INVENTION

The purpose of the present invention is to provide a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound of formula (I) is as follows:

Where:

each of Q, Y and Z is independently selected from the group consisting of N and -CR _aa ;

ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ₁ is selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxoheterocyclyl, thioxoheterocyclyl, aryl, heteroaryl, - (CH ₂ ) _n1 R _bb , -(CH ₂ ) _n1 OR _bb , -NR _aa C(O)(CH ₂ ) _n1 OR _bb , -NR _aa C(S)(CH ₂ ) _n1 OR _bb , -(CH ₂ ) _n1 SR _bb , -(CH ₂ ) _n1 C(O)R _bb , -(CH ₂ ) _n1 C(O)OR _bb , -(CH ₂ ) _n1 S(O) _m1 R _bb , -(CH ₂ ) _n1 NR _bb R _cc , -(CH ₂ ) _n1 C(O)NR _bb R _cc , -(CH ₂ ) _n1 NR _bb C(O)R _cc and -(CH ₂ ) _n1 NR _bb S(O) _m1 R _cc , wherein each of said alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxoheterocyclyl, thioxoheterocyclyl, aryl, and heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of deuterium, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkyl haloalkyl, halogen, substituted or unsubstituted cycloalkylamino, oxo, thioxo, nitro, cyano, hydroxy, substituted or unsubstituted cycloalkylalkenyl, substituted or unsubstituted cycloalkylalkynyl, substituted or unsubstituted cycloalkylalkoxy, substituted or unsubstituted cycloalkyl haloalkoxy, substituted or unsubstituted cycloalkylhydroxyalkyl , substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH ₂ ) _n1 R _dd , -(CH ₂ ) _n1 OR _dd , -(CH ₂ ) _n1 SR _dd , -( CH ₂ ) _n1 C(O)R _dd , -(CH ₂ ) _n1 C(O)OR _dd , -(CH ₂ ) _n1 S(O) _m1 R _dd , -(CH ₂ ) _n1 NR _dd R _ee , - (CH ₂ ) _n1 C(O)NR _dd R _ee , -(CH ₂ ) _n1 C(O)NHR _dd , -(CH ₂ ) _n1 NR _dd C(O)R _ee and -(CH ₂ ) _n1 NR _dd S(O) _m1 R _ee ;

each of R ^x and R ^y is independently selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, thiol, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl , heteroaryl, -(CH ₂ ) _n1 -, -(CH ₂ ) _n1 R _bb , -(CH ₂ ) _n1 OR _bb , -(CH ₂ ) _n1 SR _bb , -(CH ₂ ) _n1 C(O)R _bb , -(CH ₂ ) _n1 C(O)OR _bb , -(CH ₂ ) _n1 S(O) _m1 R _bb , -(CH ₂ ) _n1 NR _bb R _cc , -(CH ₂ ) _n1 C(O)NR _bb R _cc , -(CH ₂ ) _n1 NR _bb C(O)R _cc and -(CH ₂ ) _n1 NR _bb S(O) _m1 R _cc , where each of said alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally further substituted with one or more substituents selected from the group consisting of deuterium, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkyl haloalkyl, halogen, substituted or unsubstituted cycloalkylamino, thiol, oxo, nitro, cyano, hydroxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkylalkoxy, substituted or unsubstituted cycloalkylhaloalkoxy, substituted or unsubstituted cycloalkylhydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - (CH ₂ ) _n1 R _dd , -(CH ₂ ) _n1 OR _dd , -(CH ₂ ) _n1 SR _dd , -(CH ₂ ) _n1 C(O)R _dd , -(CH ₂ ) _n1 C(O)OR _dd , -(CH ₂ ) _n1 S(O) _m1 R _dd , -(CH ₂ ) _n1 NR _dd R _ee , -(CH ₂ ) _n1 C(O)NR _dd R _ee , -(CH ₂ ) _n1 C( O)NHR _dd , -(CH ₂ ) _n1 NR _dd C(O)R _ee and -(CH ₂ ) _n1 NR _dd S(O) _m1 R _ee ;

or any two adjacent or non-adjacent R ^x are linked to form a cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo, nitro, cyano, hydroxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH ₂ ) _n1 -, -(CH ₂ ) _n1 R _bb , -(CH ₂ ) _n1 OR _bb , -(CH ₂ ) _n1 SR _bb , - (CH ₂ ) _n1 C(O)R _bb , -(CH ₂ ) _n1 C(O)OR _bb , -(CH ₂ ) _n1 S(O) _m1 R _bb , -(CH ₂ ) _n1 NR _bb R _cc , -(CH ₂ ) _n1 C(O)NR _bb R _cc , -(CH ₂ ) _n1 NR _bb C(O)R _cc and -(CH ₂ ) _n1 NR _bb S(O) _m1 R _cc ;

or any two adjacent or non-adjacent R ^y are linked to form a cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo, nitro, cyano, hydroxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH ₂ ) _n1 -, -(CH ₂ ) _n1 R _bb , -(CH ₂ ) _n1 OR _bb , -(CH ₂ ) _n1 SR _bb , - (CH ₂ ) _n1 C(O)R _bb , -(CH ₂ ) _n1 C(O)OR _bb , -(CH ₂ ) _n1 S(O) _m1 R _bb , -(CH ₂ ) _n1 NR _bb R _cc , -(CH ₂ ) _n1 C(O)NR _bb R _cc , -(CH ₂ ) _n1 NR _bb C(O)R _cc and -(CH ₂ ) _n1 NR _bb S(O) _m1 R _cc ;

R _aa is selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, where each of said alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium, substituted or unsubstituted alkyl, halo, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl ;

each of R _bb , R _cc , R _dd and R _ee is independently selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl , cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of from deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

n is 0, 1, 2, or 3;

p is 0, 1, 2, 3, 4, 5, or 6;

q is 0, 1, 2, 3, 4, 5, or 6;

m ₁ is 0, 1 or 2; And

n ₁ is 0, 1, 2, 3, 4, or 5.

In a preferred embodiment, R ^x is -(CH ₂ ) _n1 NR _bb C(R _ff R _gg )C(O)R _cc ;

each of R _ff and R _gg is independently selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of said alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; And

n ₁ , R _bb and R _cc are as defined in formula (I).

In another preferred embodiment, when ring A is a benzene ring, R ^y is hydrogen, Q and Y are N, Z is -CR _aa , R _aa is hydrogen, n is 1, and R ₁ is R ^x is not -NHCHR _ff C(O)NH ₂ where R _ff is CH ₃ -, cyclopropyl- or -CH ₂ CH ₃ ;

when ring A is a benzene ring, R ^y is hydrogen, Q and Y are N, Z is -CR _aa , R _aa is hydrogen, n is 1, and R ₁ is R ^x is not -NCHR _ff C(O)NH ₂ where R _ff is CH ₃ - or cyclopropyl-; And

when ring A is a benzene ring, R ^y is hydrogen, Q and Y are N, Z is -CR _aa , R _aa is hydrogen, n is 1, and R ₁ is R ^x is not -NHCHR _ff C(O)NH ₂ where R _ff is cyclopropyl- or cyclobutyl-.

In a preferred embodiment of the present invention, there is provided a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound is as shown in formula (II):

Where:

W is selected from the group consisting of oxygen and sulfur, and preferably oxygen;

each of R ₉ and R ₁₀ is independently selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, thiol, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl , aryl, heteroaryl, -(CH ₂ ) _n1 -, -(CH ₂ ) _n1 R _bb , -(CH ₂ ) _n1 OR _bb , -(CH ₂ ) _n1 SR _bb , -(CH ₂ ) _n1 C(O) R _bb , -(CH ₂ ) _n1 C(O)OR _bb , -(CH ₂ ) _n1 S(O) _m1 R _bb , -(CH ₂ ) _n1 NR _bb R _cc , -(CH ₂ ) _n1 C(O )NR _bb R _cc , -(CH ₂ ) _n1 NR _bb C(O)R _cc and -(CH ₂ ) _n1 NR _bb S(O) _m1 R _cc , where each of said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, thiol, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl , substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH ₂ ) _n1 R _dd , -(CH ₂ ) _n1 OR _dd , -(CH ₂ ) _n1 SR _dd , -(CH ₂ ) _n1 C (O)R _dd , -(CH ₂ ) _n1 C(O)OR _dd , -(CH ₂ ) _n1 S(O) _m1 R _dd , -(CH ₂ ) _n1 NR _dd R _ee , -(CH ₂ ) _n1 C(O)NR _dd R _ee , -(CH ₂ ) _n1 C(O)NHR _dd , -(CH ₂ ) _n1 NR _dd C(O)R _ee and -(CH ₂ ) _n1 NR _dd S(O) _{m1 Re} ;

or R ₉ and R ₁₀ may be linked to form a heterocyclyl or heteroaryl, wherein said heterocyclyl or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH ₂ ) _n1 -, -(CH ₂ ) _n1 R _bb , - (CH ₂ ) _n1 OR _bb , -(CH ₂ ) _n1 SR _bb , -(CH ₂ ) _n1 C(O)R _bb , -(CH ₂ ) _n1 C(O)OR _bb , -(CH ₂ ) _n1 S (O) _m1 R _bb , -(CH ₂ ) _n1 NR _bb R _cc , -(CH ₂ ) _n1 C(O)NR _bb R _cc , -(CH ₂ ) _n1 NR _bb C(O)R _cc and -( CH ₂ ) _n1 NR _bb S(O) _m1 R _cc ; And

ring A, H, Y, Z, R ₂₃ -R ₂₆ , R ^x , R ^y , n, p, q, m ₁ and n ₁ are as defined in formula (II).

In a preferred embodiment of the present invention, there is provided a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound is shown in formula (II-A) or (II-B):

, ,

Where:

G is selected from the group consisting of oxygen and sulfur;

L is selected from the group consisting of nitrogen, oxygen, sulfur and -CR _aa ;

ring B is selected from the group consisting of heterocyclyl and heteroaryl, and preferably thioxoheterocyclyl or oxoheterocyclyl;

R ^z is selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, thiol, nitro, hydroxy, cyano, oxo, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH ₂ ) _n1 -, -(CH ₂ ) _n1 R _bb , -(CH ₂ ) _n1 OR _bb , -(CH ₂ ) _n1 SR _bb , -(CH ₂ ) _n1 C(O)R _bb , -(CH ₂ ) _n1 C(O)OR _bb , -(CH ₂ ) _n1 S(O) _m1 R _bb , -(CH ₂ ) _n1 NR _bb R _cc , -(CH ₂ ) _n1 C(O)NR _bb R _cc , -(CH ₂ ) _n1 NR _bb C(O)R _cc and -(CH ₂ ) _n1 NR _bb S(O) _m1 R _cc where each of said alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl , aryl, and heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, thiol, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted, or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH ₂ ) _n1 R _dd , -(CH ₂ ) _n1 OR _dd , -(CH ₂ ) _n1 SR _dd , -(CH ₂ ) _n1 C(O)R _dd , -(CH ₂ ) _n1 C(O)OR _dd , -(CH ₂ ) _n1 S(O) _m1 R _dd , -(CH ₂ ) _n1 NR _dd R _ee , -(CH ₂ ) _n1 C(O)NR _dd R _ee , -(CH ₂ ) _n1 C(O)NHR _dd , -(CH ₂ ) _n1 NR _dd C(O)R _ee and -(CH ₂ ) _n1 NR _dd S(O ) _m1 R _ee ;

or any two adjacent or non-adjacent R ^z may be linked to form a cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH ₂ ) _n1 -, -(CH ₂ ) _n1 R _bb , -(CH ₂ ) _n1 OR _bb , -(CH ₂ ) _n1 SR _bb , -(CH ₂ ) _n1 C(O)R _bb , -(CH ₂ ) _n1 C(O) OR _bb , -(CH ₂ ) _n1 S(O) _m1 R _bb , -(CH ₂ ) _n1 NR _bb R _cc , -(CH ₂ ) _n1 C(O)NR _bb R _cc , -(CH ₂ ) _n1 NR _bb C(O)R _cc and -(CH ₂ ) _n1 NR _bb S(O) _m1 R _cc ;

R ₂ is present or absent when L is nitrogen or -CR _aa R ₂ is selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, thiol, nitro, hydroxy, cyano , alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n1 -, -(CH ₂ ) _n1 R _bb , -(CH ₂ ) _n1 OR _bb , -(CH ₂ ) _n1 SR _bb , -( CH ₂ ) _n1 C(O)R _bb , -(CH ₂ ) _n1 C(O)OR _bb , -(CH ₂ ) _n1 S(O) _m1 R _bb , -(CH ₂ ) _n1 NR _bb R _cc , - (CH ₂ ) _n1 C(O)NR _bb R _cc , -(CH ₂ ) _n1 NR _bb C(O)R _cc and -(CH ₂ ) _n1 NR _bb S(O) _m1 R _cc ;

each of R ₃ and R ₄ is independently selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, amino, thiol, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl , aryl, heteroaryl, -(CH ₂ ) _n1 -, -(CH ₂ ) _n1 R _bb , -(CH ₂ ) _n1 OR _bb , -(CH ₂ ) _n1 SR _bb , -(CH ₂ ) _n1 C(O) R _bb , -(CH ₂ ) _n1 C(O)OR _bb , -(CH ₂ ) _n1 S(O) _m1 R _bb , -(CH ₂ ) _n1 NR _bb R _cc , -(CH ₂ ) _n1 C(O )NR _bb R _cc , -(CH ₂ ) _n1 NR _bb C(O)R _cc and -(CH ₂ ) _n1 NR _bb S(O) _m1 R _cc , where each of said alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, thiol, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl , alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH ₂ ) _n1 R _dd , -(CH ₂ ) _n1 OR _dd , -(CH ₂ ) _n1 SR _dd , -(CH ₂ ) _n1 C(O)R _dd , -(CH ₂ ) _n1 C(O)OR _dd , -(CH ₂ ) _n1 S(O) _m1 R _dd , -(CH ₂ ) _n1 NR _dd R _ee , -(CH ₂ ) _n1 C(O)NR _dd R _ee , -(CH ₂ ) _n1 C(O)NHR _dd , -(CH ₂ ) _n1 NR _dd C(O)R _ee and -( CH ₂ ) _n1 NR _dd S(O) _m1 R _ee ;

or any two of R ₂ , R ₃ , R ₄ and R _aa are linked to form cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -( CH ₂ ) _n1 -, -(CH ₂ ) _n1 R _bb , -(CH ₂ ) _n1 OR _bb , -(CH ₂ ) _n1 SR _bb , -(CH ₂ ) _n1 C(O)R _bb , -(CH ₂ ) _n1 C(O)OR _bb , -(CH ₂ ) _n1 S(O) _m1 R _bb , -(CH ₂ ) _n1 NR _bb R _cc , -(CH ₂ ) _n1 C(O)NR _bb R _cc , - (CH ₂ ) _n1 NR _bb C(O)R _cc and -(CH ₂ ) _n1 NR _bb S(O) _m1 R _cc ;

m is 0, 1, 2, 3, 4, 5, or 6;

t is 0, 1, 2, 3, 4, 5, or 6;

q is 0, 1, 2, 3, 4, 5, or 6; And

ring A, Q, Y, Z, R _bb , R _cc , R _dd , R _ee , R ^x , R ^y , n, p, q, m ₁ and n ₁ are as defined in formula (I).

In a preferred embodiment of the present invention, there is provided a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound is as shown in formula (III):

,

Where:

each of R ₅ , R ₆ and R ₁₄ is independently selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, thiol, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n1 -, -(CH ₂ ) _n1 R _bb , -(CH ₂ ) _n1 OR _bb , -(CH ₂ ) _n1 SR _bb , -(CH ₂ ) _n1 C(O )R _bb , -(CH ₂ ) _n1 C(O)OR _bb , -(CH ₂ ) _n1 S(O) _m1 R _bb , -(CH ₂ ) _n1 NR _bb R _cc , -(CH ₂ ) _n1 C( O)NR _bb R _cc , -(CH ₂ ) _n1 NR _bb C(O)R _cc and -(CH ₂ ) _n1 NR _bb S(O) _m1 R _cc , where each of said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, thiol, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

or R ₅ and R ₆ are linked to form cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH ₂ ) _n1 -, -(CH ₂ ) _n1 R _bb , -(CH ₂ ) _n1 OR _bb , -(CH ₂ ) _n1 SR _bb , -(CH ₂ ) _n1 C(O)R _bb , -(CH ₂ ) _n1 C(O)OR _bb , - (CH ₂ ) _n1 S(O) _m1 R _bb , -(CH ₂ ) _n1 NR _bb R _cc , -(CH ₂ ) _n1 C(O)NR _bb R _cc , -(CH ₂ ) _n1 NR _bb C(O )R _cc and -(CH ₂ ) _n1 NR _bb S(O) _m1 R _cc ;

Q, Y, Z, R _bb , R _cc , R ₁ , R ₂ , R ^y , n, p, q, m ₁ and n ₁ are as defined in formula (I); And

G, m, R ₃ and R ₄ are as defined in formula (II-A).

In a preferred embodiment of the present invention, there is provided a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound is as shown in formula (IV):

,

Where:

R ₁₃ is selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, halogen, cyano, nitro, haloalkyl, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, cycloalkyl, heterocyclyl , aryl and heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, halogen, hydroxy, amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, and preferably halogen, amino, nitro, cyano, alkyl, haloalkyl or cycloalkyl; And

ring B, Q, Z, G, R ₂ -R ₄ , R ^y , R ^z , m, n, q and t are as defined in formula (III).

In a preferred embodiment of the present invention, there is provided a compound of formula (III), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound is shown in formula (III-A) or (III-B):

, ,

Where:

each of R ₇ , R ₈ , R ₁₁ and R ₁₂ is independently selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, thiol, nitro, hydroxy, cyano, alkenyl, alkynyl , cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n1 -, -(CH ₂ ) _n1 R _bb , -(CH ₂ ) _n1 OR _bb , -(CH ₂ ) _n1 SR _bb , -(CH ₂ ) _n1 C(O)R _bb , -(CH ₂ ) _n1 C(O)OR _bb , -(CH ₂ ) _n1 S(O) _m1 R _bb , -(CH ₂ ) _n1 NR _bb R _cc , -(CH ₂ ) _n1 C(O)NR _bb R _cc , -(CH ₂ ) _n1 NR _bb C(O)R _cc and -(CH ₂ ) _n1 NR _bb S(O) _m1 R _cc , where each of said alkyl, haloalkyl, cycloalkyl , heterocyclyl, aryl and heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, thiol, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

or any two of R ₇ , R ₈ , R ₁₁ and R ₁₂ may be bonded to form cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from the group, consisting of deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁹ and R ¹⁰ are as defined in formula (II);

Q, Z, G, R ₂ -R ₆ , R _bb , R _cc , R ^y , m, n, q, m ₁ and n ₁ are as defined in formula (III); And

R ₁₄ is as defined in formula (III-A).

In a preferred embodiment of the present invention, there is provided a compound of formula (III-A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound is shown in formula (V):

,

Where:

ring B is as defined in formula (II-A); And

Q, Z, G, L, R ₂ -R ₈ , R ₁₁ , R ₁₂ , R ₁₄ , R ^z , m and t are as defined in formula (III-A).

In a preferred embodiment of the present invention, there is provided a compound of formula (III-A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound is shown in formula (VI):

,

Where:

ring B is as defined in formula (II-A); And

Q, Z, G, L, R ₂ -R ₆ , R ₁₄ , R ^y , R ^z , q, m and t are as defined in formula (III-A).

In a preferred embodiment of the present invention, any of the compounds of formula (II-A), (II-B), (IV), (V) or (VI), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is characterized in that

Ring B is selected from the group consisting of:

, , , , , , ,

, , , , , , , , , , , , , , , , And .

In a preferred embodiment of the present invention, there is provided a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound is as shown in formula (VII):

,

Where:

R _aa is selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, where each of said alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, halogen, hydroxy, amino, oxo , nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; And

L, R ₂ -R ₈ , R ₁₁ , R ₁₂ , R ₁₄ and m are as defined in formula (V).

Preferably, when R _aa , R ₂ , R ₅ -R ₈ , R ₁₁ , R ₁₂ and R ₁₄ are not hydrogen at the same time, R ₃ and R ₄ are as defined in formula (VII).

Also preferably, when R _aa , R ₂ , R ₅ -R ₈ , R ₁₁ , R ₁₂ and R ₁₄ are simultaneously hydrogen, any two of R ₂ , R ₃ and R ₄ are linked to form cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy , hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH ₂ ) _n1 -, -(CH ₂ ) _n1 R _bb , -(CH ₂ ) _n1 OR _bb , - (CH ₂ ) _n1 SR _bb , -(CH ₂ ) _n1 C(O)R _bb , -(CH ₂ ) _n1 C(O)OR _bb , -(CH ₂ ) _n1 S(O) _m1 R _bb , -( CH ₂ ) _n1 NR _bb R _cc , -(CH ₂ ) _n1 C(O)NR _bb R _cc , -(CH ₂ ) _n1 NR _bb C(O)R _cc and -(CH ₂ ) _n1 NR _bb S(O ) _m1 R _cc .

In a preferred embodiment of the present invention, there is provided a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound is as shown in formula (VIII-A):

,

Where:

Ring B is selected from the group consisting of:

, , , , , And ;

R ₂ is selected from the group consisting of hydrogen, C _1-6 alkyl and C _1-6 haloalkyl;

each of R ₃ and R ₄ is independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy and -(CH ₂ ) _n1 OR _bb ;

or R ₃ and R ₄ are linked to form C _3-8 cycloalkyl or 3-8 membered heterocyclyl, and preferably oxetanyl;

or R ₂ and R ₃ or R ₂ and R ₄ are linked to form a 3-8 membered heterocyclyl, and preferably pyrrolidinyl or azetidinyl;

each of R ₅ , R ₆ and R ₁₄ is independently selected from the group consisting of hydrogen, halogen, cyano, C _1-6 alkyl, C _1-6 alkoxy and C _1-6 haloalkyl;

R _aa is selected from the group consisting of hydrogen, C _1-6 alkyl, halogen and cyano;

R ^z is selected from the group consisting of hydrogen, oxo, C _1-6 alkyl, C _1-6 haloalkyl and -(CH ₂ ) _n1 R _bb ;

R _bb is selected from the group consisting of hydrogen, C _1-6 alkyl, halogen and cyano; And

t is 0, 1, 2, or 3.

Preferably,

R ₂ is selected from the group consisting of hydrogen, C _1-3 alkyl and C _1-3 haloalkyl, and more preferably hydrogen, methyl, ethyl or propyl;

each of R ₃ and R ₄ is independently selected from the group consisting of hydrogen, C _1-3 alkyl, C _1-3 alkoxy and C _1-3 alkyl substituted with C _1-3 alkoxy, and more preferably hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, CH ₃ OCH ₂ - or CH ₃ CH ₂ OCH ₂ -;

or R ₃ and R ₄ are linked to form C _4-6 cycloalkyl or 4-6 membered heterocyclyl, preferably 4-6 membered heterocyclyl containing one oxygen or nitrogen atom, and more preferably oxetanyl;

R ₂ and R ₃ or R ₂ and R ₄ are linked to form a 3-8 membered heterocyclyl, preferably a 4-6 membered heterocyclyl containing nitrogen or oxygen, where the number of heteroatoms is one or two, and more preferably tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl or azetidinil;

each of R ₅ and R ₆ is independently selected from the group consisting of hydrogen, halogen, cyano, C _1-3 alkyl, C _1-3 alkoxy and C _1-3 haloalkyl, and preferably hydrogen;

R ₁₄ is selected from the group consisting of hydrogen and halogen, and preferably hydrogen, fluorine or chlorine;

R ^z is selected from the group consisting of hydrogen, halogen, oxo, C _1-3 alkyl, C _1-3 alkyl substituted with halogen and -(CH ₂ ) _n1 R _bb , preferably hydrogen, fluorine, chlorine, bromine, iodine, cyano , acetonitrile, propionitrile or C _1-3 alkyl substituted with fluorine, and more preferably fluorine, methyl, acetonitrile, -CHF ₂ , -CF ₂ CH ₃ or CHF ₂ CH ₂ -;

R _aa is selected from the group consisting of hydrogen and halogen, and preferably hydrogen;

R _bb is cyano;

n ₁ is 0, 1, 2 or 3; And

t is 0, 1, 2, or 3.

Provided that

when R _aa is hydrogen, ring B is , and all of R ₂ , R ₄ , R ₅ , R ₆ , R ₁₄ and R _aa are hydrogen, R ₃ is not -CH(CH ₃ ), cyclopropyl or CH ₃ CH ₂ -;

when R _aa is hydrogen, ring B is , and all of R ₂ , R ₃ , R ₅ , R ₆ , R ₁₄ and R _aa are hydrogen, R ₄ is not -CH(CH ₃ ), cyclopropyl or CH ₃ CH ₂ -;

when R _aa is hydrogen, ring B is , and all of R ₂ , R ₄ , R ₅ , R ₆ , R ₁₄ and R _aa are hydrogen, R ₃ is not -CH ₃ or cyclopropyl;

when R _aa is hydrogen, ring B is , and all of R ₂ , R ₃ , R ₅ , R ₆ , R ₁₄ and R _aa are hydrogen, R ₄ is not -CH ₃ or cyclopropyl;

when R _aa is hydrogen, ring B is , and all of R ₂ , R ₄ , R ₅ , R ₆ , R ₁₄ and R _aa are hydrogen, R ₃ is not cyclopropyl or cyclobutyl; And

when R _aa is hydrogen, ring B is , and all of R ₂ , R ₃ , R ₅ , R ₆ , R ₁₄ and R _aa are hydrogen, R ₄ is not cyclopropyl or cyclobutyl.

In a preferred embodiment of the present invention, there is provided a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound is as shown in formula (VIII):

,

where: ring B, R ₃ , R ₅ , R ₆ , R ₁₄ , R ^z , R _aa and t are as defined in formula (III-A); And

R ^z and t are as defined in formula (V).

In a preferred embodiment, Ring B is selected from the group consisting of

, , , , , And ;

R ₂ is selected from the group consisting of hydrogen and C _1-6 alkyl, preferably hydrogen or C _1-3 alkyl, and more preferably hydrogen, methyl, ethyl or propyl;

R ₃ is selected from the group consisting of C _1-6 alkyl, C _1-6 alkoxy and C _1-6 alkoxy substituted with alkyl, preferably C _1-3 alkyl, C _1-3 alkoxy or C _1-3 alkyl substituted with C _1-3 alkoxy, and more preferably methyl, ethyl, propyl, methoxy, ethoxy, CH ₃ OCH ₂ - or CH ₃ CH ₂ OCH ₂ -;

each of R ₅ and R ₆ is independently selected from the group consisting of hydrogen and halogen, and preferably hydrogen;

R ₁₄ is selected from the group consisting of hydrogen and halogen, and preferably hydrogen, fluorine or chlorine; And

R ^z is selected from the group consisting of hydrogen, halogen, cyano, C _1-6 alkyl and C _1-6 alkyl substituted with halogen, preferably hydrogen, fluorine, chlorine, bromine, iodine, cyano, acetonitrile, propionitrile or C _1-3 alkyl substituted with halogen, and more preferably fluorine, methyl, acetonitrile, -CHF ₂ , -CF ₂ CH ₃ or CHF ₂ CH ₂ -.

In a preferred embodiment of the present invention, there is provided a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound is as shown in formula (IX):

,

Where:

each of R ₁₅ and R ₁₆ is independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, and -(CH ₂ ) _n1 R _bb ; And

R ₂ -R ₄ , R ₆ , R ₁₄ , R _aa and R _bb are as defined in formula (VIII-A).

Preferably,

R ₂ is selected from the group consisting of hydrogen and C _1-6 alkyl, preferably hydrogen or C _1-3 alkyl, and more preferably hydrogen, methyl, ethyl or propyl;

each of R ₃ and R ₄ is independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _1-6 alkoxy and C _1-6 alkoxy substituted with alkyl, preferably hydrogen, C _1-3 alkyl, C _1-3 alkoxy or C _1-3 alkyl substituted with C _1-3 alkoxy, and more preferably hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, CH ₃ OCH ₂ - or CH ₃ CH ₂ OCH ₂ -;

R ₃ and R ₄ are linked to form C _4-6 cycloalkyl or 4-6 membered heterocyclyl, preferably 4-6 membered heterocyclyl containing one oxygen or nitrogen atom, and more preferably oxetanyl;

R ₂ and R ₃ or R ₂ and R ₄ are linked to form a 4-6 membered heterocyclyl, preferably a 4-6 membered heterocyclyl containing nitrogen or oxygen, where the number of heteroatoms is one or two, and more preferably tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl or azetidinil;

R ₆ is selected from the group consisting of hydrogen and halogen, and preferably hydrogen;

R ₁₄ is selected from the group consisting of hydrogen and halogen, and preferably hydrogen, fluorine or chlorine;

R _aa is selected from the group consisting of hydrogen and halogen, and preferably hydrogen; And

each of R ₁₅ and R ₁₆ is independently selected from the group consisting of hydrogen, halogen, cyano, C _1-6 alkyl and C _1-6 alkyl substituted with halogen, preferably hydrogen, fluorine, chlorine, bromine, iodine, cyano, acetonitrile, propionitrile or C _1-3 alkyl substituted with halogen, and more preferably hydrogen, fluorine, methyl, acetonitrile, -CHF ₂ , -CF ₂ CH ₃ or CHF ₂ CH ₂ -.

In a preferred embodiment of the present invention, there is provided a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound is as shown in formula (X):

,

Where:

each of R ₁₅ and R ₁₆ is independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, and -(CH ₂ ) _n1 R _bb ; And

R ₂ -R ₄ , R ₆ , R ₁₄ , R _aa and R _bb are as defined in formula (VIII-A).

Preferably,

R ₂ is selected from the group consisting of hydrogen and C _1-6 alkyl, preferably hydrogen or C _1-3 alkyl, and more preferably hydrogen, methyl, ethyl or propyl;

each of R ₃ and R ₄ is independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _1-6 alkoxy and C _1-6 alkoxy substituted with alkyl, preferably hydrogen, C _1-3 alkyl, C _1-3 alkoxy or C _1-3 alkyl substituted with C _1-3 alkoxy, and more preferably hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, CH ₃ OCH ₂ - or CH ₃ CH ₂ OCH ₂ -;

R ₃ and R ₄ are linked to form C _4-6 cycloalkyl or 4-6 membered heterocyclyl, preferably 4-6 membered heterocyclyl containing one oxygen or nitrogen atom, and more preferably oxetanyl;

R ₂ and R ₃ or R ₂ and R ₄ are linked to form a 4-6 membered heterocyclyl, preferably a 4-6 membered heterocyclyl containing nitrogen or oxygen, where the number of heteroatoms is one or two, and more preferably tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl or azetidinil;

R ₃ and R ₄ are linked to form C _4-6 cycloalkyl or 4-6 membered heterocyclyl, preferably 4-6 membered heterocyclyl containing one oxygen or nitrogen atom, and more preferably oxetanyl;

R ₆ is selected from the group consisting of hydrogen and halogen, and preferably hydrogen;

R ₁₄ is selected from the group consisting of hydrogen and halogen, and preferably hydrogen, fluorine or chlorine;

R _aa is selected from the group consisting of hydrogen and halogen, and preferably hydrogen; And

each of R ₁₅ and R ₁₆ is independently selected from the group consisting of hydrogen, halogen, cyano, C _1-6 alkyl and C _1-6 alkyl substituted with halogen, preferably hydrogen, fluorine, chlorine, bromine, iodine, cyano, acetonitrile, propionitrile or C _1-3 alkyl substituted with halogen, and more preferably hydrogen, fluorine, methyl, acetonitrile, -CHF ₂ , -CF ₂ CH ₃ or CHF ₂ CH ₂ -.

In a preferred embodiment of the present invention, any of the compounds of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is provided, wherein

R ₂ is present or absent, when present, R ₂ is selected from the group consisting of hydrogen, methoxy, C _1-6 alkyl and C _1-6 haloalkyl;

or R ₂ and R ₃ or R ₂ and R ₄ are linked to form a 3-8 membered heterocyclyl, and preferably pyrrolidinyl or azetidinyl;

each of R ₃ and R ₄ is independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, and 3-8 membered heterocyclyl;

or R ₃ and R ₄ are linked to form C _3-8 cycloalkyl or 3-8 membered heterocyclyl, and preferably oxetanyl;

each of R ₅ and R ₆ is independently selected from the group consisting of hydrogen, halogen, cyano, C _1-6 alkyl, C _1-6 alkoxy, and C _1-6 haloalkyl;

or R ₅ and R ₆ are linked to form C _3-8 cycloalkyl or 3-8 membered heterocyclyl, and preferably cyclobutanyl, cyclopentyl or 1,3-dioxolanyl;

R ₁₄ is selected from the group consisting of hydrogen, halogen, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy and C _3-8 cycloalkyl;

R ^y is selected from the group consisting of hydrogen, C _1-6 alkyl, halogen, C _1-6 alkoxy, C _1-6 haloalkyl and -(CH ₂ ) _n1 -, preferably hydrogen, C _1-3 alkyl or C _{1- 3} haloalkyl, and more preferably hydrogen, methyl or -(CH ₂ ) _n1 -; And

R _aa is selected from the group consisting of hydrogen, halogen, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy and C _3-8 cycloalkyl.

In a preferred embodiment, R ₂ is selected from the group consisting of hydrogen, C _1-3 alkyl, C _1-3 hydroxyalkyl and C _1-3 haloalkyl, and preferably methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, halomethyl, haloethyl or halopropyl;

each of R ₃ and R ₄ is independently selected from the group consisting of C _1-3 alkyl, C _1-3 hydroxyalkyl, C _1-3 haloalkyl and C _1-3 alkoxy, and preferably methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, halomethyl, haloethyl, halopropyl, methoxy, ethoxy or propoxy;

each of R ₅ and R ₆ is independently selected from the group consisting of hydrogen, C _1-3 alkyl, C _1-3 alkoxy and C _1-3 haloalkyl, and preferably methyl, ethyl, propyl, halomethyl, haloethyl, halopropyl, methoxy, ethoxy or propoxy;

R ₁₄ is selected from the group consisting of hydrogen, C _1-3 alkyl, C _1-3 alkoxy and C _1-3 haloalkyl, and preferably methyl, ethyl, propyl, halomethyl, haloethyl, halopropyl, methoxy, ethoxy or propoxy;

R ^y is selected from the group consisting of hydrogen, methyl and -(CH ₂ ) _n1 -; And

R _aa is selected from the group consisting of halo, cyano, C _1-3 alkyl, C _1-3 alkoxy and C _1-3 haloalkyl, and preferably methyl, ethyl, propyl, halomethyl, haloethyl, halopropyl, methoxy, ethoxy or propoxy.

In a preferred embodiment of the present invention in any of the compounds of formula (I), its stereoisomer or its pharmaceutically acceptable salt, where R ^z is selected from the group consisting of hydrogen, halogen, oxo, thioxo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and -(CH ₂ ) _n1 -, wherein each of said C _1-6 alkyl, C _1-6 alkoxy and C _1-6 haloalkyl is optionally further substituted with one or more substituents selected from the group consisting of from hydrogen, halogen, oxo, thioxo, C _1-6 alkyl, C _1-6 alkoxy and C _1-6 haloalkyl, R ^z is preferably halogen, C _1-6 alkyl, C _1-6 haloalkyl or oxo, and more preferably halo, C _1-3 alkyl, C _1-3 haloalkyl or oxo.

The present invention also relates to a process for the preparation of a compound of formula (IV), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising the following step

reacting a compound of formula (IV-1) and a compound of formula (IV-2) to give a compound of formula (IV), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof;

Where:

X is a halogen; And

ring B, Q, Z, G, L, R ₂ -R ₄ , R ^y , R ^z , q, m, n and t are as defined in formula (IV).

The present invention also relates to a process for the preparation of a compound of formula (VI), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising the following step

reacting a compound of formula (VI-1) and a compound of formula (IV-2) to give a compound of formula (VI), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof;

Where:

X is a halogen; And

ring B, Q, Z, G, L, R ₂ -R ₆ , R ₁₄ , R ^y , R ^z , q, m, n and t are as defined in formula (VI).

The present invention also relates to a process for the preparation of a compound of formula (IV), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

Where:

X is a halogen; And

ring B, Q, Z, G, L, R ₂ -R ₆ , R ^y , R ^z , q, m, n and t are as defined in formula (VI).

The present invention also relates to a process for the preparation of a compound of formula (VI), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

Where:

X ₁ and X ₂ are halogen; And

ring B, Q, Z, G, L, R ₂ -R ₆ , R ^y , R ^z , q, m, n and t are as defined in formula (VI).

The present invention also relates to a process for the preparation of a compound of formula (X), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising the following step

reacting a compound of formula (IX) and a Lawsson's reagent to give a compound of formula (IX-A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof;

Where:

R ₂ -R ₄ , R ₆ , R ₁₄ -R ₁₆ and R _aa are as defined in formula (IX).

The present invention also relates to a process for the preparation of a compound of formula (X), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising the following step

reacting a compound of formula (IX-A) with a transition metal complex and its ligand to give a compound of formula (X), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof;

Where:

the transition metal complex and its ligand are preferably a dimer of dichloro(p-cymene)ruthenium (II) and 2-bicyclohexylphosphino-2',6'-dimethoxybiphenyl; And

R ₂ -R ₄ , R ₆ , R ₁₄ -R ₁₆ and R _aa are as defined in formula (X).

The present invention further relates to a pharmaceutical composition comprising a therapeutically effective amount of any of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

The present invention further relates to the use of any of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing them, for the preparation of a PI3K regulating drug and preferably a PI3Kα inhibitory drug.

The present invention also relates to the use of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing them, for the preparation of a medicament for the treatment of cancer, bone disease, inflammatory disease, immune disease, nervous system disease, metabolic disease, diseases of the respiratory system and diseases of the heart, where the specified cancer is selected from the group consisting of breast cancer, pancreatic cancer, non-small cell lung cancer (NSCLC), thyroid cancer, seminoma, melanoma, bladder cancer, liver cancer, kidney cancer, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and colorectal cancer.

The present invention also relates to the use of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing them, for the preparation of a medicament for the treatment of cancer, bone disease, inflammatory disease, immune disease, nervous system disease, metabolic disease, diseases of the respiratory system and heart disease.

The present invention further relates to a method for preventing and/or treating cancer, comprising administering to a patient a therapeutically effective amount of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

The present invention also provides a method of treating a condition using a compound or pharmaceutical composition of the present invention, wherein said condition includes, but is not limited to, conditions associated with dysfunction of PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ kinases.

The present invention also relates to a method of treating a hyperproliferative disease in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.

In some embodiments, the method includes treating a disease such as cancer, bone disease, inflammatory disease, immune disease, nervous system disease, metabolic disease, respiratory disease, and heart disease.

In some embodiments, the method includes treating a cancer such as acute myeloid leukemia, myelodysplastic syndrome (MDS), thymus cancer, brain cancer, lung cancer (NSCLC and SCLC), squamous cell carcinoma, seminoma, melanoma, skin cancer, eye cancer, retinoblastoma , intraocular melanoma, oral and oropharyngeal cancer, bladder cancer, gastrointestinal cancer, stomach cancer, pancreatic cancer, bladder cancer, breast cancer, cervical cancer, head cancer, neck cancer, kidney cancer, kidney cancer , liver cancer, ovarian cancer, prostate cancer, endometrial cancer, colorectal cancer, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, CNS (central nervous system) cancer, PNS cancer (paraneoplastic neurological syndrome), AIDS-associated ( immunodeficiency syndrome), cancer (eg, lymphoma and Kaposi's sarcoma), and virus-induced cancer. In some embodiments, the method relates to the treatment of a non-malignant hyperproliferative disease such as skin disease (eg, psoriasis), restenosis, and benign prostatic hyperplasia (eg, benign prostatic hyperplasia (BPH)). In some embodiments, the cancer is melanoma or colorectal cancer.

The method of treatment provided herein comprises administering to a subject a therapeutically effective amount of a compound of the present invention. In one embodiment, the present invention provides a method for treating an inflammatory disease, including an autoimmune disease, in a mammal. The method includes administering to a mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof. A disease associated with one or more types of ERK dysfunction includes, but is not limited to, acute disseminated encephalomyelitis (ADEM), Addison's disease, antiphospholipid syndrome (APS), aplastic anemia, autoimmune hepatitis, celiac disease, Crohn's disease, diabetes (type 1) , Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, opso-myoclonal syndrome (OMS), optic neuritis, Orda thyroiditis, pemphigus, polyarthritis, primary biliary cirrhosis , psoriasis, rheumatoid arthritis, Little's syndrome, Takayasu's arteritis, temporal arteritis (also known as "giant cell arteritis"), autoimmune hemolytic anemia with warm antibodies, Wegener's granulomatosis, alopecia universalis, Chagas disease, chronic fatigue syndrome, autonomic dysfunction, endometriosis, suppurative hidradenitis, interstitial cystitis, neuromuscular rigidity, sarcoidosis, scleroderma, ulcerative colitis, vitiligo and vulvodynia. Other diseases include bone resorption disorder and thrombosis.

DEFINITIONS

Unless otherwise indicated, terms used in the description and claims have the following meanings:

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably alkyl containing 1 to 8 carbon atoms, more preferably alkyl containing 1 to 6 carbon atoms. carbon, and most preferably alkyl containing from 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1 -ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2.3 -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-nonyl , 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl and their various branched isomers. More preferably, the alkyl group is a lower alkyl having 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1 ,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1 ,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted. In case it is substituted, the substituent group(s) may be substituted(s) at any available connecting point. The substituent group(s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxy and alkoxycarbonyl. The alkyl according to the present invention is preferably selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl.

The term "alkylene" refers to an alkyl whose hydrogen atom is further substituted, e.g., "methylene" refers to -CH ₂ -, "ethylene" refers to -(CH ₂ ) ₂ -, "propylene" refers to -(CH ₂ ) ₃ -, "butylene" refers to -(CH ₂ ) ₄ - and the like. The term "alkenyl" refers to an alkyl, as defined above, which consists of at least two carbon atoms and at least one carbon-carbon double bond, e.g., ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like. The alkenyl group may be substituted or unsubstituted. When it is substituted, the substituent group(s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl , aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio and heterocyclylthio.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group having 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and most preferably 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 or cycloheptyl.

The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group with individual rings connected via one common carbon atom (called a spiro atom), where the rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron systems. Spirocycloalkyl is preferably 6-14 membered spirocycloalkyl and more preferably 7-10 membered spirocycloalkyl. According to the number of spiroatoms common between the rings, spirocycloalkyl can be subdivided into monospirocycloalkyl, dispirocycloalkyl or polyspirocycloalkyl, and spirocycloalkyl is preferably monospirocycloalkyl or dispirocycloalkyl, and more preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/ 6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocycloalkyl. Non-limiting examples of spirocycloalkyl include:

;

and also include spirocycloalkyl wherein cycloalkyl and heterocyclyl are bonded via a single spiro atom, their non-limiting examples include:

And .

The term "fused cycloalkyl" refers to a 5-20 membered polycyclic group consisting of only carbon atoms, where each ring in the system shares an adjacent pair of carbon atoms with another ring, one or more rings may contain one or more double bonds, but neither one of the rings does not have a fully conjugated π-electron system. The fused cycloalkyl is preferably a 6-14 membered fused cycloalkyl and more preferably a 7-10 membered fused cycloalkyl. According to the number of rings it contains, the fused cycloalkyl can be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, and the fused cycloalkyl is preferably bicyclic or tricyclic fused cycloalkyl, and more preferably 5-membered/5-membered or 5-membered/6- membered bicyclic fused cycloalkyl. Non-limiting examples of fused cycloalkyl include:

.

The term "bridged cycloalkyl" refers to a 5- to 20-membered, all-carbon polycyclic group in which every two rings in the system share two unbonded carbon atoms, the rings may have one or more double bonds, but none of the rings has a fully conjugated π-electron system. The bridged cycloalkyl is preferably a 6-14 membered bridged cycloalkyl and more preferably a 7-10 membered bridged cycloalkyl. According to the number of rings it contains, bridged cycloalkyl can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, and bridged cycloalkyl is preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyl, and more preferably bicyclic or tricyclic bridged cycloalkyl. Non-limiting examples of bridged cycloalkyl include:

A cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocyclyl ring, where the ring associated with the parent structure is cycloalkyl. Non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like. Cycloalkyl may be optionally substituted or unsubstituted. When it is substituted, the substituent group(s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl , aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxy and alkoxycarbonyl.

The term "heterocyclyl" refers to a 3-20 membered saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, where one or more ring atoms are heteroatoms selected from the group consisting of N, O and S(O) _m (where m is is an integer from 0 to 2), but excluding -OO-, -OS- or -SS- in the ring, with the remaining ring atoms being carbon atoms. Preferably, the heterocyclyl has 3 to 12 ring atoms, where 1 to 4 atoms are heteroatoms; more preferably 3 to 8 ring atoms; more preferably 3 to 8 ring atoms; and most preferably 4 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclyl include oxetanyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, and preferably ox ethanyl, pyrrolidinyl, pyrrolidonil, tetrahydrofuranyl, pyrazolidinyl, morpholinyl, piperazinyl and pyranyl. Polycyclic heterocyclyl includes heterocyclyl having a spiro ring, a fused ring, or a bridged ring. A heterocyclyl containing a spiro ring, a fused ring, or a bridged ring is optionally bonded to another group via a single bond, or additionally linked to other cycloalkyl, heterocyclyl, aryl, and heteroaryl via any two or more ring atoms.

The term "spiroheterocyclyl" refers to a 3-20 membered polycyclic heterocyclyl group with individual rings connected via one common atom (called a spiro atom), where one or more ring atoms are heteroatoms selected from the group consisting of N, O and S( O) _m (where m is an integer from 0 to 2), wherein the remaining ring atoms are carbon atoms, and the rings may contain one or more double bonds, but none of the rings has a fully conjugated π electron system. Spiroheterocyclyl is preferably 6-14 membered spiroheterocyclyl and more preferably 7-10 membered spiroheterocyclyl. According to the number of spiroatoms common between the rings, spiroheterocyclyl can be classified into monospiroheterocyclyl, dispyroheterocyclyl or polyspiroheterocyclyl, and spiroheterocyclyl is preferably monospiroheterocyclyl or dispyroheterocyclyl, and more preferably 3-membered/5-membered, 4-membered/5-membered, 4-membered/ 6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl. Non-limiting examples of spiroheterocyclyl include:

The term "fused heterocyclyl" refers to a 5-20 membered polycyclic heterocyclyl group where each ring in the system shares an adjacent pair of atoms with another ring, one or more rings may contain one or more double bonds, but none of the rings has a complete conjugated π-electron system, and one or more ring atoms are heteroatoms selected from the group consisting of N, O and S(O) _m (where m is an integer from 0 to 2), and the remaining ring atoms are atoms carbon. The fused heterocyclyl is preferably a 6-14 membered fused heterocyclyl and more preferably a 7-10 membered fused heterocyclyl. According to the number of rings it contains, fused heterocyclyl can be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl, and preferably bicyclic or tricyclic fused heterocyclyl, and more preferably 3-membered/5-membered, 4-membered/5-membered or 5- membered/6-membered bicyclic fused heterocyclyl. Non-limiting examples of fused heterocyclyl include:

The term "bridged heterocyclyl" refers to a 5-14 membered polycyclic heterocyclyl group where every two rings in the system share two unbonded atoms, where the rings may have one or more double bonds, but none of the rings has a fully conjugated π-electron system, and one or more ring atoms are heteroatoms selected from the group consisting of N, O and S(O) _m (where m is an integer from 0 to 2), with the remaining ring atoms being carbon atoms. The bridged heterocyclyl is preferably a 6-14 membered bridged heterocyclyl and more preferably a 7-10 membered bridged heterocyclyl. According to the number of rings it contains, bridged heterocyclyl can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl, and bridged heterocyclyl is preferably bicyclic, tricyclic or tetracyclic bridged heterocyclyl, and more preferably bicyclic or tricyclic bridged heterocyclyl. Non-limiting examples of bridged heterocyclyl include:

.

The heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, where the ring linked to the parent structure is heterocyclyl. Non-limiting examples include:

and so on.

The heterocyclyl may be optionally substituted or unsubstituted. When it is substituted, the substituent group(s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl , aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxy and alkoxycarbonyl.

The term "aryl" refers to a 6-14-membered monocyclic or polycyclic fused ring (i.e. each ring in the system shares a pair of carbon atoms with another ring in the system), consisting of only carbon atoms, having a conjugated π electron system, preferably 6-10 membered aryl, eg phenyl and naphthyl. Aryl is more preferably phenyl. An aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, where the ring linked to the parent structure is an aryl ring. Non-limiting examples include:

, , , , , , , , , , , , , And .

Aryl may be substituted or unsubstituted. When it is substituted, the substituent group(s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl , aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy and alkoxycarbonyl.

The term "heteroaryl" refers to a 5-14 membered heteroaromatic system having 1 to 4 heteroatoms selected from the group consisting of O, S and N. Heteroaryl is preferably a 5-10 membered heteroaryl and more preferably 5- or 6 -membered heteroaryl, e.g. imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, pyrazinyl and the like, preferably triazolyl, thienyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl and thiazolyl, and more preferably triazolyl, pyrrolyl, thienyl, thiazolyl, pyridyl and pyrimidinyl. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, where the ring linked to the parent structure is a heteroaryl ring. Non-limiting examples include:

, , , , , , , And .

Heteroaryl may be optionally substituted or unsubstituted. When it is substituted, the substituent group(s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl , aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy and alkoxycarbonyl.

The term "alkoxy" refers to the group -O-(alkyl) or -O-(unsubstituted cycloalkyl), where alkyl is as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy may be optionally substituted or unsubstituted. When it is substituted, the substituent group(s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl , aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy and alkoxycarbonyl.

"Haloalkyl" refers to an alkyl group substituted with one or more halogen atoms, where alkyl is as defined above.

"Haloalkoxy" refers to an alkoxy group substituted with one or more halogen atoms, where alkoxy is as defined above.

"Hydroxyalkyl" refers to an alkyl group substituted with hydroxy group(s), where alkyl is as defined above.

"Alkenyl" refers to a chain structure alkenyl, also known as an alkene group. Alkenyl may be further substituted with another related group, e.g., alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy or alkoxycarbonyl.

"Alkynyl" refers to (CH≡C-). Alkynyl may be further substituted with another related group, for example alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, carboxy, or alkoxycarbonyl.

"Hydroxy" refers to the -OH group.

"Halogen" refers to fluorine, chlorine, bromine or iodine.

"Amino" refers to the -NH ₂ group.

"Cyano" refers to the -CN group.

"Nitro" refers to the -NO ₂ group.

"Carboxy" refers to the -C(O)OH group.

"THF" refers to tetrahydrofuran.

"EtOAc" refers to ethyl acetate.

"EA" refers to ethyl acetate.

"MeOH" refers to methanol.

"DMF" refers to N,N-dimethylformamide.

"DIPEA" refers to diisopropylethylamine.

"TFA" refers to trifluoroacetic acid.

"MeCN" refers to acetonitrile.

"DMA" refers to N,N-dimethylacetamide.

"Et ₂ O" refers to diethyl ether.

"DCE" refers to 1,2-dichloroethane.

"DIPEA" refers to N,N-diisopropylethylamine.

"NBS" refers to N-bromosuccinimide.

"NIS" refers to N-iodosuccinimide.

"Cbz-Cl" refers to benzyl chloroformate.

"Pd ₂ (dba) ₃ " refers to tris(dibenzylideneacetone) dipalladium.

"Dppf" refers to 1,1'-bisdiphenylphosphinoferrocene.

"HATU" refers to 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

"KHMDS" refers to potassium hexamethyldisilazide.

"LiHMDS" refers to lithium bis(trimethylsilyl)amide.

"MeLi" refers to methyllithium.

"n-BuLi" refers to n-butyllithium.

"NaBH(OAc) ₃ " refers to sodium triacetoxyborohydride.

"DXM" refers to dichloromethane.

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”, etc. have the same meaning, that is, X can be one or more of A, B, and C.

The hydrogen atom of the present invention may be replaced by its deuterium isotope. Any of the hydrogen atoms in the compounds of the examples of the present invention may also be replaced by a deuterium atom.

"Optional" or "optional" means that the following phenomenon or circumstance may, but need not, occur, and such description includes the situation in which the phenomenon or circumstance occurs or does not occur. For example, "heterocyclyl optionally substituted with alkyl" means that an alkyl group may, but need not, be present, and such description includes the situation where the heterocyclyl is substituted with alkyl and when the heterocyclyl is not substituted with alkyl.

"Substituted" refers to one or more hydrogen atoms in a group, preferably up to 5 and more preferably 1 to 3 hydrogen atoms, independently substituted with the appropriate number of substituents. Of course, substituents exist only in their possible chemical positions. One skilled in the art is able to determine whether or not substitution can be made through experimentation or theoretical knowledge without undue effort. For example, the combination of amino or hydroxy groups having free hydrogen atoms and carbon atoms having unsaturated bonds (such as olefins) may be unstable.

"Pharmaceutical composition" refers to a mixture of one or more of the described compounds according to the present invention or their physiologically/pharmaceutically acceptable salts or prodrugs with other chemical components and other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the introduction of the compound into the body, which facilitates the absorption of the active ingredient necessary for the manifestation of biological activity.

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

DETAILED DESCRIPTION OF THE INVENTION

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.

EXAMPLES

The structures of the compounds according to the present invention were identified using nuclear magnetic resonance (NMR) and/or liquid chromatography and tandem mass spectrometry (LC-MS). NMR shifts (δ) are given in parts per million (ppm). NMR spectra were determined on a Bruker AVANCE-400 instrument. The determination solvents were deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated methanol (CDCl ₃ ) and deuterated chloroform (CD ₃ OD) and the internal standard was tetramethylsilane (TMS).

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

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

The starting materials used in the examples of the present invention are known and commercially available, or can be synthesized by adopting or in accordance with methods known in the art.

Unless otherwise indicated, all reactions according to the present invention were carried out with continuous stirring with a magnetic stirrer in an atmosphere of dry nitrogen or argon, the solvent was dry, and the reaction temperature was in degrees Celsius.

Intermediate 1

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

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

(R)-oxiran-2-ylmethanol (3.7 g, 50.0 mmol) and (isocyanatomethyl)benzene (6.66 g, 50.0 mmol) were mixed in dichloromethane (50 ml). Under nitrogen atmosphere, the reaction solution was heated to 45° C. and stirred overnight. After cooling, 100 ml of a saturated sodium bicarbonate aqueous solution was added, followed by extraction of the reaction solution with dichloromethane (100 ml×2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was 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 (16.8 g, 60.0 mmol) were mixed in ethyl acetate (100 ml). Under a nitrogen atmosphere, the reaction solution was stirred at 85° C. for 3 hours. The reaction solution was cooled and filtered. The filtrate was concentrated under reduced pressure to give the crude product (S)-3-benzyl-4-(dihydroxymethyl)oxazolidin-2-one (4.46 g) which was immediately 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). Under a nitrogen atmosphere, DAST (6.45 g, 40.0 mmol) was added dropwise in an ice bath, and then the reaction solution was naturally warmed to room temperature and allowed to react for 3 hours. The reaction solution was slowly added dropwise to a pre-cooled saturated sodium bicarbonate aqueous solution, and then extracted with dichloromethane (200 ml×2). The organic phases were combined and concentrated under reduced pressure. The residue was subjected to column chromatography to give the title compound (S)-3-benzyl-4-(difluoromethyl)oxazolidin-2-one (1.82 g, 40% yield over two steps).

MS m/z (ESI): 228.2 [M + H] ⁺ .

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) followed by the addition of Pd(OH) ₂ /C (300 mg). Under a hydrogen atmosphere, the reaction solution was stirred 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);

MS m/z (ESI): 138.1 [M+H] ⁺ .

Intermediate 2

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

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

An aqueous solution of glyoxal (40 wt.%, 87 g, 597 mmol) was added to a solution of 4-bromo-2-hydroxybenzaldehyde (24.0 g, 119 mmol) in methanol (250 ml). On a water bath, ammonia (28 wt%, 121 g, 860 mmol) was slowly added dropwise to the reaction solution with stirring, the addition process lasted 30 minutes, and the temperature of the reaction solution was controlled so that it did not exceed 40°C . The mixture was stirred at 35°C for two days, cooled and concentrated under reduced pressure to remove the organic solvent to give the crude product 5-bromo-2-(1H-imidazol-2-yl)phenol, which was immediately 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 (ca. 29 g, 119 mmol), cesium carbonate (158 g, 485 mmol) and 1,2-dibromoethane (42 ml, 485 mmol) were mixed in DMF (250 ml), and the reaction solution was stirred at 85°C overnight. The reaction solution was cooled and diluted with more ethyl acetate. The organic phase was washed several times with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was 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, yield over two steps: 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

NIS (29.8 g, 132 mmol) was added portionwise 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) 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. The solution was washed successively with 1 M aqueous NaOH and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound 9-bromo-2,3-diiodo-5,6-dihydrobenzo[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

EtMgBr (1.0 M, THF solution, 60.9 mL, 60.9 mmol) was slowly added dropwise 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) at minus 20°C. After completion of the addition, the reaction solution was stirred at minus 15°C for 3 hours. The reaction solution was slowly warmed to room temperature, and a saturated ammonium chloride aqueous solution was added dropwise. After stirring for 15 minutes, the reaction solution was extracted several times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was subjected to column chromatography to give the title compound 9-bromo-2-iodo-5,6-dihydro-benzo[f]imidazo[1,2-d][1,4]oxazepine (12.5 g, yield over two steps : 79%).

MS m/z (ESI): 390.9 [M+H] ⁺ .

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

9-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (300 mg, 0.77 mmol), (S)-4-(difluoromethyl)oxazolidine -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 with 2-methyltetrahydrofuran (6 ml). The reaction system was purged with nitrogen three times and left to react at 78°C for 22 hours. The reaction solution was cooled to room temperature, and 15% ammonia was added. The reaction solution was stirred for 5 minutes and extracted three times with EtOAc. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. The residue was subjected to column chromatography to give the title compound (S)-3-(9-bromo-5,6-dihydro-benzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4 -(difluoromethyl)oxazolidin-2-one (186 mg, 61%).

¹ H 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

Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-6,7-dihydro-5H-benzo[b]imidazo[2,1-d ][1,5]oxazocin-10-yl)amino)propanamide

Step 1: Preparation of 10-bromo-6,7-dihydro-5H-benzo[b]imidazo[2,1-d][1,5]oxazocine

5-bromo-2-(1H-imidazol-2-yl)phenol (1.0 g, 4.2 mmol), 1,3-dibromopropane (3.2 g, 15.9 mmol) and cesium carbonate (5, 2 g, 15.9 mmol) was mixed in N,N-dimethylformamide (20 ml), and the reaction solution was stirred at room temperature for 1.5 hours. Water was added and the reaction solution was stirred for 5 minutes and extracted three times with EtOAc. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography to give the title compound 10-bromo-6,7-dihydro-5H-benzo[b]imidazo[2,1-d][1,5]oxazocine (1.1 g, 94%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.89-1.94 (m, 2H), 4.03-4.09 (m, 4H), 7.03 (d, J = 0.8 Hz, 1H), 7.28-7.33 (m, 3H), 7.95 (s, 1H);

MS m/z (ESI): 279.0 [M+H] ⁺ .

Step 2: Preparation of 10-bromo-2,3-diiodo-6,7-dihydro-5H-benzo[b]imidazo[2,1-d][1,5]oxazocine

10-bromo-6,7-dihydro-5H-benzo[b]imidazo[2,1-d][1,5]oxazocine (1.1 g, 3.96 mmol) and N-iodosuccinimide (2.5 g, 11.08 mmol) in N,N-dimethylformamide (15 ml). The reaction system was purged with nitrogen three times and stirred at 80° C. overnight. The reaction solution was cooled to room temperature, and then ice water was added to the reaction flask. The reaction solution was stirred for 5 minutes and extracted three times with EtOAc. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography to give the title compound 10-bromo-2,3-diiodo-6,7-dihydro-5H-benzo[b]imidazo[2,1-d][1,5]oxazocine (720 g, 34%).

MS m/z (ESI): 530.8 [M+H] ⁺ .

Step 3: Preparation of 10-bromo-2-iodo-6,7-dihydro-5H-benzo[b]imidazo[2,1-d][1,5]oxazocine

10-bromo-2,3-diiodo-6,7-dihydro-5H-benzo[b]imidazo[2,1-d][1,5]oxazocine (500 mg, 0.94 mmol) was dissolved in tetrahydrofuran (10 ml). The reaction system was cooled to minus 20°C and purged with nitrogen three times. Ethylmagnesium bromide (0.35 ml, 1.05 mmol) was added dropwise, and the reaction solution was left to react at minus 20° C. for 3 hours. A saturated ammonium chloride solution was added to stop the reaction, and the reaction solution was extracted with EtOAc three times. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography to give the title compound 10-bromo-2-iodo-6,7-dihydro-5H-benzo[b]imidazo[2,1-d][1,5]oxazocine (365 g, 96% ).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.87-1.96 (m, 2H), 4.00-4.11 (m, 4H), 7.30-7.37 (m, 2H ), 7.47-7.52 (m, 2H);

MS m/z (ESI): 404.9 [M+H] ⁺ .

Step 4: Preparation of (S)-3-(10-bromo-6,7-dihydro-5H-benzo[b]imidazo[2,1-d][1,5]oxazocin-2-yl)-4-( difluoromethyl)oxazolidin-2-one

10-bromo-2-iodo-6,7-dihydro-5H-benzo[b]imidazo[2,1-d][1,5]oxazocine (300mg, 0.75mmol), (S)-4- (difluoromethyl)oxazolidin-2-one (103 mg, 0.75 mmol), (1R,2R)-N ¹ ,N ² -dimethylcyclohexane-1,2-diamine (43 mg, 0.30 mmol), copper iodide ( 29 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 left to react at 100° C. for 5 hours. The reaction solution was cooled to room temperature, and 15% ammonia was added. The reaction solution was stirred for 5 minutes and extracted three times with EtOAc. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography to give the title compound (S)-3-(10-bromo-6,7-dihydro-5H-benzo[b]imidazo[2,1-d][1,5]oxazocin-2- yl)-4-(difluoromethyl)oxazolidin-2-one (187 mg, 60%).

MS m/z (ESI): 414.0 [M+H] ⁺ .

Step 5: Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-6,7-dihydro-5H-benzo[b]imidazo[2, 1-d][1,5]oxazocin-10-yl)amino)propanamide

(S)-3-(10-bromo-6,7-dihydro-5H-benzo[b]imidazo[2,1-d][1,5]oxazocin-2-yl)-4-(difluoromethyl)oxazolidin- 2-one (100 mg, 0.24 mmol), L-alanine (43 mg, 0.48 mmol), copper iodide (9 mg, 0.048 mmol) and potassium phosphate (103 mg, 0.48 mmol) were mixed with dimethyl sulfoxide (5 ml). The reaction system was purged with nitrogen three times and left to react at 100° C. for 5 hours. The reaction solution was cooled to room temperature, then ammonium chloride (78 mg, 1.45 mmol) and triethylamine (367 mg, 3.63 mmol) were added, and the reaction solution was stirred for 5 minutes. O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (830 mg, 2.18 mmol) was added and the reaction solution was stirred at room temperature for 2 hours and filtered. A saturated sodium bicarbonate aqueous solution was added to the filtrate, which was then extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to 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]oxazocin-10-yl)amino)propanamide (34 mg, 34%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.31 (d, J = 6.9 Hz, 3H), 1.82-1.96 (m, 2H), 3.71-3.82 ( m, 1H), 3.87-4.06 (m, 4H), 4.51-4.62 (m, 2H), 4.89-4.95 (m, 1H), 6.11-6, 17 (m, 2H), 6.35-6.40 (m, 1H), 6.54-6.82 (m, 1H), 7.01 (s, 1H), 7.20 (s, 1H) , 7.32 (d, J = 8.6 Hz, 1H), 7.39 (s, 1H);

MS m/z (ESI): 422.1 [M+H] ⁺ .

Example 2 and Example 3

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

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 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 concentrated under reduced pressure. Dichloromethane and water were added to the concentrate and the two phases were separated. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography to give the title compound 2-(5-bromo-2-fluorophenyl)-1H-imidazole (3.3 g, 56%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.18-7.27 (m, 2H), 7.33-7.38 (m, 1H), 7.56-7.60 (m, 1H ), 8.10-8.16 (m, 1H);

MS m/z (ESI): 241.0[M+H] ⁺ .

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

2-(5-bromo-2-fluorophenyl)-1H-imidazole (1.0 g, 4.2 mmol) was dissolved in N,N-dimethylformamide (5 ml) followed by the addition of sodium hydride (221 mg, 4.6 mmol ) in an ice water bath and stirred the reaction solution for 10 minutes. 1,2-propylene oxide (292 mg, 5.1 mmol) was added and the reaction solution was heated to 95° C. and stirred for 6 hours. The reaction solution was cooled to room temperature, and then a saturated ammonium chloride aqueous solution was added to the reaction flask. The reaction solution was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography to give the title compound 9-bromo-6-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (1.1 g, 94%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.40 (d, J = 6.4 Hz, 3H), 4.19-4.25 (m, 1H), 4.42-4.53 ( m, 2H), 6.96 (d, J = 8.7 Hz, 1H), 7.07 (s, 1H), 7.31 (s, 1H), 7.38-7.42 (m, 1H ), 8.41 (d, J = 2.5 Hz, 1H);

MS m/z (ESI): 279.0 [M+H] ⁺ .

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

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.42 (d, J = 6.4 Hz, 3H), 4.14-4.20 (m, 1H), 4.31-4.36 ( m, 1H), 4.44-4.56 (m, 1H), 6.99 (d, J = 8.7 Hz, 1H), 7.43-7.48 (m, 1H), 8.26 (d, J = 2.5 Hz, 1H);

MS m/z (ESI): 530.8 [M+H] ⁺ .

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

9-bromo-2-iodo-6-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] ⁺ .

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

(4S)-3-(9-bromo-6-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)oxazolidin- 2-he received the method described in example 1.

MS m/z (ESI): 414.0 [M+H] ⁺ .

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

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

NMR and mass spectrometric data of the mixed pair of epimers are as follows:

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.24-1.41 (m, 6H), 3.65-3.77 (m, 1H), 4.01-4.13 (m, 1H ), 4.35-4.41 (m, 2H), 4.55-4.65 (m, 2H), 4.91-4.97 (m, 1H), 5.69 (d, J = 7 .0 Hz, 1H), 6.50-6.53 (m, 1H), 6.61-6.94 (m, 1H), 6.76-6.81 (m, 1H), 6.97 ( s, 1H), 7.29 (s, 1H), 7.33 (s, 2H);

MS m/z (ESI): 422.1 [M+H] ⁺ .

Example 4

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

(S)-2-(((R)-2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5-methyl-5,6-dihydrobenzo[f]imidazo[1, 2-d][1,4]oxazepin-9-yl)amino)propanamide in the manner described in Example 2 and Example 3.

¹ H NMR (400 MHz, CD ₃ OD) δ 1.47 (t, J = 7.4 Hz, 6H), 3.78-3.87 (m, 1H), 4.16-4.23 (m , 1H), 4.40-4.45 (m, 1H), 4.55-4.65 (m, 3H), 4.91-4.97 (m, 1H), 6.17-6.21 (m, 1H), 6.41-6.45 (m, 1H), 6.43-6.73 (m, 1H), 7.20 (s, 1H), 8.06-8.09 (m , 1H);

MS m/z (ESI): 422.1 [M+H] ⁺ .

Example 5

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

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

¹ H NMR (400 MHz, CD ₃ OD) δ 1.47 (t, J = 7.4 Hz, 6H), 3.78-3.87 (m, 1H), 4.16-4.23 (m , 1H), 4.40-4.45 (m, 1H), 4.55-4.65 (m, 3H), 4.91-4.97 (m, 1H), 6.17-6.21 (m, 1H), 6.41-6.45 (m, 1H), 6.43-6.73 (m, 1H), 7.20 (s, 1H), 8.06-8.09 (m , 1H);

MS m/z (ESI): 422.1 [M+H] ⁺ .

Example 6

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

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.26-1.33 (m, 9H), 3.69-3.75 (m, 1H), 3.90-3.98 (m, 2H ), 4.55-4.63 (m, 2H), 4.90-5.00 (m, 1H), 5.78 (d, J = 7.1 Hz, 1H), 6.54-6, 58 (m, 1H), 6.78-6.83 (m, 1H), 6.55-6.86 (m, 1H), 6.94 (d, J = 2.8 Hz, 1H), 6 .98 (s, 1H), 7.35 (s, 1H), 7.39 (s, 1H);

MS m/z (ESI): 436.1 [M+H] ⁺ .

Example 7

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

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

MS m/z (ESI): 436.1 [M+H] ⁺ .

Example 8

Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5H-spiro[benzo[f]imidazo[1,2-d][1, 4]oxazepine-6,1'-cyclopropan]-9-yl)amino)propanamide

(S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5H-spiro[benzo[f]imidazo[1,2-d][1,4 ]oxazepine-6,1'-cyclopropan]-9-yl)amino)propanamide was prepared by the method described in Example 2 and Example 3.

MS m/z (ESI): 434.1 [M+H] ⁺ .

Example 9

Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-6H-spiro[benzo[f]imidazo[1,2-d][1, 4]oxazepine-5,1'-cyclopropan]-9-yl)amino)propanamide

(S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-6H-spiro[benzo[f]imidazo[1,2-d][1,4 ]oxazepine-5,1'-cyclopropan]-9-yl)amino)propanamide was obtained by the method described in example 2 and example 3.

MS m/z (ESI): 434.1 [M+H] ⁺ .

Example 10

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)propanamide

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 9-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (500 mg, 1.28 mmol) in tetrahydrofuran (10 ml) was added dropwise solution of LDA (1.28 ml, 2.56 mmol) in tetrahydrofuran (10 ml) at minus 78°C. After completion of the addition, the reaction solution was stirred at minus 78°C for 30 minutes. A solution of N-fluorobenzenesulfonamide (806 mg, 2.56 mmol) in tetrahydrofuran (9 ml) was added dropwise, and the reaction solution was stirred at minus 78° C. for 30 minutes. The reaction was stopped with a saturated ammonium chloride aqueous solution, and the reaction solution was extracted with dichloromethane (100 ml×2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was 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-dihydro-benzo[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), iodide copper (46 mg, 0.24 mmol) and potassium phosphate (155 mg, 0.73 mmol) were mixed with dimethyl sulfoxide (10 ml) and the reaction solution was left to react at 130° C. for 3 hours. The reaction solution was cooled to room temperature, and 15% ammonia was added. The reaction solution was stirred for 5 minutes and extracted three times with EtOAc. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography to give the title compound (S)-3-(9-bromo-3-fluoro-5,6-dihydro-benzo[f]imidazo[1,2-d][1,4]oxazepine-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

(2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-3-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine- 9-yl)-L-alanine was obtained by the method described in example 1.

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)propanamide

(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)propanamide was prepared by the method described in Example 1.

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 11

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

(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 10.

MS m/z (ESI): 452.1 [M+H] ⁺ .

Example 12

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)oxy)propanamide

(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)oxy)propanamide was prepared as described in Example 10.

MS m/z (ESI): 427.1 [M+H] ⁺ .

Example 13

Preparation of (S)-2-((3-fluoro-2-((S)-2-oxo-4-(trifluoromethyl)oxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)amino)propanamide

(S)-2-((3-fluoro-2-((S)-2-oxo-4-(trifluoromethyl)oxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d ][1,4]oxazepin-9-yl)amino)propanamide was obtained by the method described in example 10.

MS m/z (ESI): 444.1 [M+H] ⁺ .

Example 14

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

(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)propanamide was prepared as described in Example 10.

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 15

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

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

An aqueous solution of pyruvaldehyde (40 wt.%, 80 ml) was added to a solution of 4-bromo-2-hydroxybenzaldehyde (5 g, 119 mmol) in methanol (100 ml). In a water bath, ammonia (28 mass%, 40 g) was slowly added dropwise to the reaction solution with stirring, the addition process lasted 30 minutes, and the temperature of the reaction solution was controlled so that it did not exceed 40°C. The reaction solution was stirred at 75°C for 2 hours, then cooled to room temperature to precipitate a solid, which was filtered off 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) was mixed in DMF (30 ml) and the reaction solution was stirred at 85° C. overnight. The reaction solution was cooled to room temperature and diluted with more ethyl acetate. The organic phase was washed several times with saturated brine, dried over sodium sulfate and concentrated. The residue was 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] ⁺ .

Step 3: Preparation of 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] ⁺ .

Step 4: Preparation of (S)-3-(9-bromo-3-methyl-5,6-dihydro-benzo[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-he received 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 obtained by the method described in example 1.

MS m/z (ESI): 423.1 [M+H] ⁺ .

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

(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)propanamide was obtained 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 16

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

(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 obtained by the method described in example 15.

MS m/z (ESI): 448.2 [M+H] ⁺ .

Example 17

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

(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)oxy)propanamide was obtained by the method described in example 15.

MS m/z (ESI): 423.1 [M+H] ⁺ .

Example 18

Preparation of (S)-2-((3-methyl-2-((S)-2-oxo-4-(trifluoromethyl)oxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)amino)propanamide

(S)-2-((3-methyl-2-((S)-2-oxo-4-(trifluoromethyl)oxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d ][1,4]oxazepin-9-yl)amino)propanamide was prepared as described in Example 15.

MS m/z (ESI): 440.1 [M+H] ⁺ .

Example 19

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

(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)propanamide was prepared as described in Example 15.

MS m/z (ESI): 476.1 [M+H] ⁺ .

Example 20

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

(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)propanamide was prepared as described in Example 15.

MS m/z (ESI): 433.1 [M+H] ⁺ .

Example 21

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

(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 15.

MS m/z (ESI): 459.2 [M+H] ⁺ .

Example 22

Preparation of (S)-2-((3-cyano-2-((S)-2-oxo-4-(trifluoromethyl)oxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)amino)propanamide

(S)-2-((3-cyano-2-((S)-2-oxo-4-(trifluoromethyl)oxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d ][1,4]oxazepin-9-yl)amino)propanamide was prepared as described in Example 15.

MS m/z (ESI): 451.1 [M+H] ⁺ .

Example 23

Preparation of (S)-2-((3-cyano-2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d ][1,4]oxazepin-9-yl)oxy)propanamide

((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)oxy)propanamide was obtained by the method described in example 15.

MS m/z (ESI): 434.1 [M+H] ⁺ .

Example 24

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

(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)propanamide was prepared as described in Example 15.

MS m/z (ESI): 448.2 [M+H] ⁺ .

Example 25

Preparation of (S)-2-((9-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydroimidazo[1,2-d]thieno[2,3-f ][1,4]oxazepin-2-yl)amino)propanamide

Step 1: Preparation of methyl 3-(cyanomethoxy)thiophene-2-carboxylate

Methyl 3-hydroxythiophene-2-carboxylate (1.58 g, 10 mmol), bromoacetonitrile (2.4 g, 20 mmol) and cesium carbonate (9.77 g, 30 mmol) were added to DMF (40 ml). The reaction solution was heated to 60°C and left to react for 2 hours. The reaction solution was cooled to room temperature, water (200 ml) was added, and the reaction solution EA (200 ml×3) was extracted. The organic phases were combined and washed with saturated aqueous sodium chloride solution (200 ml×3). The organic phases were collected and concentrated under reduced pressure. The residue was subjected to column chromatography to give the title compound methyl 3-(cyanomethoxy)thiophene-2-carboxylate (1.58 g, 80%).

Step 2: Preparation of 3,4-dihydrothieno[2,3-f][1,4]oxazepin-5(2H)-one

Methyl 3-(cyanomethoxy)thiophene-2-carboxylate (1.58 g, 8 mmol), Raney nickel (400 mg) and ammonia (2 ml) were added to ethanol (100 ml). Under a hydrogen atmosphere (50 psi (psi)) the reaction solution was heated to reflux and allowed to react for 5 hours. The reaction solution was cooled to room temperature and filtered, and the filtrate was concentrated. The residue was subjected to column chromatography to give the title compound 3,4-dihydrothieno[2,3-f][1,4]oxazepin-5(2H)-one (1 g, 74%).

MS m/z (ESI): 170.2 [M+H] ⁺ .

Step 3: Preparation of methyl 2-(5-oxo-2,3-dihydrothieno[2,3-f][1,4]oxazepin-4(5H)-yl)acetate

3,4-dihydrothieno[2,3-f][1,4]oxazepin-5(2H)-one (1 g, 5.91 mmol), methyl bromoacetate (1.09 g, 7.09 mmol) and potassium carbonate (1.63 g, 11.8 mmol) was added to acetone (20 ml). The reaction solution was heated to reflux and allowed to react for 3 hours. The reaction solution was cooled to room temperature and concentrated. DCM and water were added to the concentrate and the two phases were separated. The organic phase was concentrated and the residue subjected to column chromatography to give the title compound methyl 2-(5-oxo-2,3-dihydrothieno[2,3-f][1,4]oxazepin-4(5H)-yl)acetate (1.21 g, 85%).

MS m/z (ESI): 242.2 [M+H] ⁺ .

Step 4: Preparation of 5,6-dihydroimidazo[1,2-d]thieno[2,3-f][1,4]oxazepin-9(8H)-one

Methyl 2-(5-oxo-2,3-dihydrothieno[2,3-f][1,4]oxazepin-4(5H)-yl)acetate (1.21 g, 5.02 mmol) and ammonia ( 5 ml) was added to tert-amyl alcohol (25 ml). The reaction solution was heated to 120°C and left to react for 5 hours in a sealed tube. The reaction solution was cooled to room temperature and concentrated. DCM and water were added to the concentrate and the two phases were separated. The organic phase was concentrated and the residue subjected to column chromatography to give the title compound 5,6-dihydroimidazo[1,2-d]thieno[2,3-f][1,4]oxazepin-9(8H)-one (521 mg, 50%).

MS m/z (ESI): 209.2 [M+H] ⁺ .

Step 5: Preparation of 9-bromo-5,6-dihydroimidazo[1,2-d]thieno[2,3-f][1,4]oxazepine

5,6-dihydroimidazo[1,2-d]thieno[2,3-f][1,4]oxazepin-9(8H)-one (521 mg, 2.50 mmol) was dissolved in 1,2-dichloroethane ( 15 ml) followed by the addition of phosphorus oxybromide (2.15 g, 7.50 mmol). The reaction solution was heated to reflux and allowed to react overnight. The reaction solution was cooled to room temperature and its pH was adjusted to neutral with a saturated sodium bicarbonate aqueous solution. The reaction solution was extracted with DCM and the organic phase was concentrated. The residue was subjected to column chromatography to give the title compound 9-bromo-5,6-dihydroimidazo[1,2-d]thieno[2,3-f][1,4]oxazepine (407 mg, 60%).

MS m/z (ESI): 271.1 [M+H] ⁺ .

Step 6: Preparation of (S)-4-(difluoromethyl)-3-(5,6-dihydroimidazo[1,2-d]thieno[2,3-f][1,4]oxazepin-9-yl)oxazolidin- 2-she

(S)-4-(difluoromethyl)-3-(5,6-dihydroimidazo[1,2-d]thieno[2,3-f][1,4]oxazepin-9-yl)oxazolidin-2-one was obtained according to example 21.

MS m/z (ESI): 328.1 [M+H] ⁺ .

Step 7: Preparation of (S)-4-(difluoromethyl)-3-(2-iodo-5,6-dihydroimidazo[1,2-d]thieno[2,3-f][1,4]oxazepine-9- yl)oxazolidin-2-one

(S)-4-(difluoromethyl)-3-(5,6-dihydroimidazo[1,2-d]thieno[2,3-f][1,4]oxazepin-9-yl)oxazolidin-2-one ( 327 mg, 1.0 mmol) was dissolved in dichloromethane (5 ml) and acetic acid (5 ml) followed by the addition of NIS (248 mg, 1.1 mmol). The reaction solution was allowed to react at room temperature overnight. The pH of the reaction solution was adjusted to neutral with a saturated sodium bicarbonate aqueous solution. The reaction solution was extracted with DCM and the organic phase was concentrated. The residue was subjected to column chromatography to give the title compound (S)-4-(difluoromethyl)-3-(2-iodo-5,6-dihydroimidazo[1,2-d]thieno[2,3-f][1, 4]oxazepin-9-yl)oxazolidin-2-one (363 mg, 80%).

MS m/z (ESI): 454.1 [M+H] ⁺ .

Step 8: Preparation of (S)-2-((9-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydroimidazo[1,2-d]thieno[2, 3-f][1,4]oxazepin-2-yl)amino)propanamide

(S)-2-((9-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydroimidazo[1,2-d]thieno[2,3-f] [1,4]oxazepin-2-yl)amino)propanamide was obtained according to example 1.

MS m/z (ESI): 414.1 [M+H] ⁺ .

Example 26

Preparation of (S)-2-((9-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-3-fluoro-5,6-dihydroimidazo[1,2-d]thieno[2 ,3-f][1,4]oxazepin-2-yl)amino)propanamide

(S)-2-((9-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-3-fluoro-5,6-dihydroimidazo[1,2-d]thieno[2, 3-f][1,4]oxazepin-2-yl)amino)propanamide was prepared according to Example 25.

MS m/z (ESI): 432.1 [M+H] ⁺ .

Example 27

Preparation of (S)-2-((9-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydroimidazo[1,2-d]thieno[2,3-f ][1,4]oxazepin-2-yl)oxy)propanamide

(S)-2-((9-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydroimidazo[1,2-d]thieno[2,3-f] [1,4]oxazepin-2-yl)oxy)propanamide was prepared according to example 25.

MS m/z (ESI): 415.1 [M+H] ⁺ .

Example 28

Preparation of (S)-1-(9-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydroimidazo[1,2-d]thieno[2,3-f] [1,4]oxazepin-2-yl)pyrrolidine-2-carboxamide

(S)-1-(9-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydroimidazo[1,2-d]thieno[2,3-f][ 1,4]oxazepin-2-yl)pyrrolidine-2-carboxamide was prepared according to Example 25.

MS m/z (ESI): 440.1 [M+H] ⁺ .

Example 29

Preparation of (S)-2-((9-((S)-2-oxo-4-(trifluoromethyl)oxazolidin-3-yl)-5,6-dihydroimidazo[1,2-d]thieno[2,3- f][1,4]oxazepin-2-yl)amino)propanamide

(S)-2-((9-((S)-2-oxo-4-(trifluoromethyl)oxazolidin-3-yl)-5,6-dihydroimidazo[1,2-d]thieno[2,3-f ][1,4]oxazepin-2-yl)amino)propanamide was prepared according to example 25.

MS m/z (ESI): 432.1 [M+H] ⁺ .

Example 30

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

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

AlCl ₃ (3.33 g, 25 mmol) was suspended in nitromethane (25 ml) followed by the dropwise addition of 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) in an ice bath under N ₂ atmosphere. The reaction solution was warmed naturally to room temperature and left to react overnight. The reaction solution was added to 200 ml of ice water and extracted with DCM (200 ml×2). The organic phases were combined and concentrated under reduced pressure. The residue was subjected to column chromatography to give the title compound 1-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)ethan-1-one (800 mg, 27%).

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

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

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

1-(5-bromobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)ethan-1-one (900 mg, 4 mmol) and m-CPBA (75%, 2, 30 g, 10 mmol) was mixed in DCM (20 ml). Under N ₂ atmosphere, the reaction solution was heated to reflux and left to react overnight. The reaction solution was cooled to room temperature and filtered to remove insoluble matter. The reaction solution was washed with a saturated sodium bicarbonate aqueous solution, and the organic phase was concentrated under reduced pressure. The residue was subjected to column chromatography to give the title compound 5-bromobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl acetate (723 mg, 75%).

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

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

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

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

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

(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)propanamide was prepared according to Example 1.

MS m/z (ESI): 434.2 [M+H] ⁺ .

Example 31

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

(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 according to example 30.

MS m/z (ESI): 450.1 [M+H] ⁺ .

Example 32

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

(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)propanamide was prepared according to Example 30.

MS m/z (ESI): 448.1 [M+H] ⁺ .

Example 33

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

(S)-2-((11-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-7,8-dihydro-[1,3]dioxolo[4',5':5 ,6]benzo[1,2-f]imidazo[1,2-d][1,4]oxazepin-4-yl)amino)propanamide was prepared according to Example 30.

MS m/z (ESI): 452.1 [M+H] ⁺ .

Example 34

Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]pyrazolo[1,5-d][1, 4]oxazepin-9-yl)amino)propanamide

Step 1: Preparation of 1-(4-bromo-2-methoxyphenyl)ethan-1-one

1-(4-bromo-2-hydroxyphenyl)ethan-1-one (5.00 g, 23.3 mmol), potassium carbonate (4.82 g, 35.0 mmol) and methyl iodide (2.94 ml, 46 .5 mmol) was mixed in DMF (60 ml), and the reaction solution was stirred at room temperature for 3 hours. A solid was precipitated by adding water to the reaction solution and dried to give the title compound 1-(4-bromo-2-methoxyphenyl)ethan-1-one (5.3 g, 99%).

Step 2: Preparation of methyl 3-(4-bromo-2-methoxyphenyl)-3-oxopropanoate

Under nitrogen atmosphere, to a suspension of NaH (1.75 g, 43.7 mmol) in THF (40 ml) was added dimethyl carbonate (2.76 ml, 32.7 mmol). The reaction solution was heated to 70°C, after which a solution of 1-(4-bromo-2-methoxyphenyl)ethan-1-one (2.50 g, 10.9 mmol) in THF (10 ml) was slowly added dropwise. After completion of the addition, the reaction solution was stirred at 70° C. for 3 hours. The reaction solution was cooled and 1 M HCl was added to acidify the system. The reaction solution was extracted several times with ethyl acetate. The organic fractions were combined, dried over anhydrous sodium sulfate and concentrated. The residue was subjected to column chromatography to give the title compound methyl 3-(4-bromo-2-methoxyphenyl)-3-oxopropanoate (2.2 g, 70%).

MS m/z (ESI): 227.0 [M+H] ⁺ .

Step 3: Preparation of 5-(4-bromo-2-methoxyphenyl)-1,2-dihydro-3H-pyrazol-3-one

A solution of hydrazine hydrate (80 wt%, 3 ml) was added to a solution of methyl 3-(4-bromo-2-methoxyphenyl)-3-oxopropanoate (1.20 g, 4.18 mmol) in ethanol (50 ml). The reaction solution was stirred at the boil under reflux for 1 hour. The reaction solution was cooled, and water was added to precipitate solid 5-(4-bromo-2-methoxyphenyl)-1,2-dihydro-3H-pyrazol-3-one (600 mg). The filtrate was concentrated, and the residue was subjected to column chromatography to give the title compound 5-(4-bromo-2-methoxyphenyl)-1,2-dihydro-3H-pyrazol-3-one (400 mg). After combining the two substances, a total of 1.0 g of the title compound 5-(4-bromo-2-methoxyphenyl)-1,2-dihydro-3H-pyrazol-3-one (89%) was obtained.

MS m/z (ESI): 269.0 [M+H] ⁺ .

Step 4: Preparation of 5-(4-bromo-2-hydroxyphenyl)-1,2-dihydro-3H-pyrazol-3-one

5-(4-bromo-2-methoxyphenyl)-1,2-dihydro-3H-pyrazol-3-one (100 mg, 0.372 mmol) was mixed with a solution of BBr ₃ in DCM (1 M, 4 ml) and the reaction solution was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to remove the organic solvent and obtain the crude product 5-(4-bromo-2-hydroxyphenyl)-1,2-dihydro-3H-pyrazol-3-one, which was immediately used in the next step.

MS m/z (ESI): 255.0 [M+H] ⁺ .

Step 5: Preparation of 9-bromo-5,6-dihydrobenzo[f]pyrazolo[1,5-d][1,4]oxazepin-2(3H)-one

The crude product from the above step was dissolved in DMF (4 ml) followed by the sequential addition of 1,2-dibromoethane (70 mg, 0.372 mmol) and potassium carbonate (515 mg, 3.72 mmol). The reaction solution was stirred at 60°C for 1 hour, stirred at 75°C for 1 hour, and stirred at 90°C for 1 hour. The reaction solution was cooled, diluted with ethyl acetate, washed several times with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to column chromatography to give the title compound 9-bromo-5,6-dihydrobenzo[f]pyrazolo[1,5-d][1,4]oxazepin-2(3H)-one (44 mg, yield for two stages: 42%).

MS m/z (ESI): 281.0 [M+H] ⁺ .

Step 6: Preparation of 9-bromo-5,6-dihydrobenzo[f]pyrazolo[1,5-d][1,4]oxazepin-2-yl-trifluoromethanesulfonate

Trifluoromethanesulfonic anhydride (48 mg, 0.171 mmol) was added dropwise to a solution of 9-bromo-5,6-dihydrobenzo[f]pyrazolo[1,5-d][1,4]oxazepin-2(3H)-one (40 mg , 0.142 mmol) in pyridine (1 ml) in an ice water bath. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to remove the organic solvent. The residue was subjected to column chromatography to give the title compound 9-bromo-5,6-dihydro-benzo[f]pyrazolo[1,5-d][1,4]oxazepin-2-yl-trifluoromethanesulfonate (42 mg, 71%).

MS m/z (ESI): 412.9 [M+H] ⁺ .

Step 7: Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]pyrazolo[1,5-d] [1,4]oxazepin-9-yl)amino)propanamide

(S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]pyrazolo[1,5-d][1,4 ]oxazepin-9-yl)amino)propanamide was obtained according to example 1.

MS m/z (ESI): 408.1 [M+H] ⁺ .

Example 35

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

(S)-1-(2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]pyrazolo[1,5-d][1,4] oxazepin-9-yl)pyrrolidine-2-carboxamide was obtained by the method described in example 34.

MS m/z (ESI): 434.2 [M+H] ⁺ .

Example 36

(S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]pyrazolo[1,5-d][1,4 ]oxazepin-9-yl)oxy)propanamide

(S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]pyrazolo[1,5-d][1,4 ]oxazepin-9-yl)oxy)propanamide was obtained by the method described in example 34.

MS m/z (ESI): 409.1 [M+H] ⁺ .

Example 37

(S)-2-((2-((S)-2-oxo-4-(trifluoromethyl)oxazolidin-3-yl)-5,6-dihydrobenzo[f]pyrazolo[1,5-d][1, 4]oxazepin-9-yl)amino)propanamide

((S)-2-((2-((S)-2-oxo-4-(trifluoromethyl)oxazolidin-3-yl)-5,6-dihydrobenzo[f]pyrazolo[1,5-d][1 ,4]oxazepin-9-yl)amino)propanamide was obtained by the method described in example 34.

MS m/z (ESI): 426.1 [M+H] ⁺ .

Example 38

Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1, 4]oxazepin-9-yl)-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)-3-methylbutanamide was obtained 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 39

Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1, 4]oxazepin-9-yl)-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)-2-methoxyacetamide was obtained by the method described in example 1.

MS m/z (ESI): 424.1 [M+H] ⁺ .

Example 40

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

(R)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4 ]oxazepin-9-yl)-3-fluoropropanamide was obtained by the method described in example 1.

MS m/z (ESI): 426.1 [M+H] ⁺ .

Example 41

Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1, 4]oxazepin-9-yl)-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)-2-(oxetan-3-yl)acetamide was obtained 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 42

Preparation of (S)-2-((2-(4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine- 9-yl)-2-methylpropanamide

(S)-2-((2-(4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9 -yl)-2-methylpropanamide was obtained 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=10.6Hz, 1H), 6.19(d, J=2.2Hz, 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 43

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

(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)propanamide was obtained 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);

MS m/z (ESI): 422.1 [M+H] ⁺ .

Example 44

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

(S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4 ]oxazepin-9-yl)amino)propanthioamide was obtained by the method described in example 1.

MS m/z (ESI): 424.1 [M+H] ⁺ .

Example 45

Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1, 4]oxazepin-9-yl)thio)propanamide

(S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4 ]oxazepin-9-yl)thio)propanamide was obtained by the method described in example 1.

MS m/z (ESI): 425.1 [M+H] ⁺ .

Example 46

Preparation of (S)-3-((2-(4-difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-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 obtained 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 47

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

(S)-3-(9-(((3-aminooxetan-3-yl)methyl)amino)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2- yl)-4-(difluoromethyl)oxazolidin-2-one was obtained by the method described in example 1.

¹ H NMR (400 MHz, CD ₃ OD): δ 3.35 (s, 2H), 4.24 (d, J = 4.7 Hz, 2H), 4.30 (d, J = 4.7 Hz , 2H), 4.41 (d, J = 6.4 Hz, 2H), 4.45-4.60 (m, 5H), 6.22 (d, J = 2.3 Hz, 1H), 6 .27-6.71 (m, 2H), 7.05 (s, 1H), 7.94 (d, J = 8.8 Hz, 1H);

MS m/z (ESI): 422.1 [M+H] ⁺ .

Example 48

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

(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 obtained 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 49

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

(S)-1-(2-(4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9- yl)azetidine-3-carboxamide was obtained by the method described in example 1.

¹ H NMR (400 MHz, CD ₃ OD) δ 3.42-3.49 (m, 1H), 3.87 (t, J = 6.7 Hz, 2H), 3.98 (t, J = 7 .9 Hz, 2H), 4.23-4.27(m, 2H), 4.29-4.33(m, 2H), 4.50-4.58(m, 3H), 5.97( d, J = 2.2 Hz, 1H), 6.17-6.20 (m, 1H), 6.36-6.64 (m, 1H), 7.07 (s, 1H), 8.02 (d, J = 8.7 Hz, 1H);

MS m/z (ESI): 420.1 [M+H] ⁺ .

Example 50

Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-thioxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1, 4]oxazepin-9-yl)amino)propanamide

(S)-2-((2-((S)-4-(difluoromethyl)-2-thioxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4 ]oxazepin-9-yl)amino)propanamide was obtained by the method described in example 1.

MS m/z (ESI): 424.1 [M+H] ⁺ .

Example 51

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

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

Lawson's reagent (1.01 g, 2.5 mmol) was added to a solution of (S)-3-(10-bromo-6,7-dihydro-5H-benzo[b]imidazo[2,1-d][1, 5]oxazocin-2-yl)-4-(difluoromethyl)oxazolidin-2-one (100 mg, 0.25 mmol) in toluene (10 ml). The reaction solution was left to react in a microwave oven at 140°C for 3 hours. The reaction solution was cooled to room temperature and filtered, and the filter cake was washed with EtOAc (20 ml). The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography to give the title compound (S)-3-(9-bromo-5,6-dihydro-benzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4 -(difluoromethyl)oxazolidin-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);

MS m/z (ESI): 416.1 [M+H] ⁺ .

Step 2: Preparation of (R)-3-(9-bromo-5,6-dihydro-benzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)thiazolidine- 2-she

To a solution of (S)-3-(10-bromo-6,7-dihydro-5H-benzo[b]imidazo[2,1-d][1,5]oxazepin-2-yl)-4-(difluoromethyl) oxazolidin-2-thione (33 mg, 0.079 mmol) in toluene (1 ml) dimer of dichloro(p-cymene)ruthenium (II) (14.7 mg, 0.024 mmol) and 2-biscyclohexylphosphino-2',6'- dimethoxybiphenyl (9.7 mg, 0.024 mmol). The reaction solution was reacted in air at 110° C. for 12 hours. The reaction solution was cooled to room temperature and diluted with EtOAc. The organic phases were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography to give the title compound (R)-3-(9-bromo-5,6-dihydro-benzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4 -(difluoromethyl)thiazolidin-2-one (26 mg, 79%).

¹ H 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);

MS m/z (ESI): 416.1 [M+H] ⁺ .

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

(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 left to react at 100° C. for 12 hours. The reaction solution was cooled to room temperature, ammonium chloride (20 mg, 0.37 mmol) and triethylamine (95 mg, 0.94 mmol) were added, and the reaction solution was stirred for 5 minutes. O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (212 mg, 0.56 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was filtered, and a saturated sodium bicarbonate aqueous solution was added to the filtrate, which was then extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to 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)propanamide (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 52

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

(S)-2-((2-((S)-5-(difluoromethyl)-2-oxoimidazolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4 ]oxazepin-9-yl)amino)propanamide was prepared by the method described in Example 51.

MS m/z (ESI): 407.2 [M+H] ⁺ .

Example 53

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

(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)propanamide was prepared by the method described in Example 51.

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, 8Hz, 1H);

MS m/z (ESI): 421.2 [M+H] ⁺ .

Example 54

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

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

MS m/z (ESI): 160.1 [M+H] ⁺ .

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 minus 15°C. NaH (60% in kerosene, 50 mg, 1.26 mmol) was added and the reaction solution was stirred at minus 15° C. for 1 hour. Benzyl bromide (322 mg, 1.89 mmol) was added and the reaction solution was stirred for 2 hours. Water was added to stop the reaction, and the reaction solution was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the organic solvent. The resulting 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] ⁺ .

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

Methyl-(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 a bath with ice water. Sodium borohydride (11 mg, 3.1 mmol) was added in portions, the reaction solution was gradually warmed to room temperature and left to react for 2 hours. The reaction solution was concentrated, and the resulting 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

(4R,5R)-3-benzyl-4-(hydroxymethyl)-5-methyloxazolidin-2-one (180 mg, 0.81 mmol) and IBX (683 mg, 2.44 mmol) were mixed in ethyl acetate (10 ml) . Under a nitrogen atmosphere, the reaction solution was left to react at 85°C for 3 hours. The reaction solution was cooled and filtered. The filtrate was concentrated under reduced pressure to give the crude product (4S,5R)-3-benzyl-5-methyl-2-oxooxazolidine-4-carbaldehyde (178 mg) which was immediately 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-oxooxazolidin-4-carbaldehyde (178 mg, 0.81 mmol) was dissolved in dichloromethane (10 ml). Under nitrogen, the solution was cooled to 0° C. in an ice water bath and DAST (262 mg, 1.62 mmol) was added dropwise. The reaction solution was naturally warmed to room temperature and allowed to react for 3 hours. The reaction solution was slowly added dropwise to a pre-cooled saturated sodium bicarbonate aqueous solution, and then extracted with dichloromethane (20 ml×2). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the organic solvent. The residue was subjected to column chromatography to give the title compound (4S,5R)-3-benzyl-4-(difluoromethyl)-5-methyloxazolidin-2-one (110 mg, yield for two steps: 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 left to react for 5 hours. After cooling to room temperature, the reaction solution was slowly added dropwise to a pre-cooled saturated aqueous sodium bicarbonate solution, and then extracted with dichloromethane (20 ml×2). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the organic solvent. The residue was subjected to column chromatography to give the crude title compound (4S,5R)-4-(difluoromethyl)-5-methyloxazolidin-2-one (68 mg), which was immediately used in the next step.

MS m/z (ESI): 152.1 [M+H] ⁺ .

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

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 with dimethyl sulfoxide (3 ml), and the reaction solution was left to react at 130° C. for 3 hours. The reaction solution was cooled to room temperature, and 15% ammonia (5 ml) was added. The reaction solution was stirred for 5 minutes and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the organic solvent. The residue was subjected to column chromatography to give the title compound (S)-3-(9-bromo-3-fluoro-5,6-dihydro-benzo[f]imidazo[1,2-d][1,4]oxazepine-2- yl)-4-(difluoromethyl)oxazolidin-2-one (61 mg, 57%).

MS m/z (ESI): 414.2 [M+H] ⁺ .

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

(4S,5R)-3-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)-5-methyloxazolidine -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) mixed with dimethyl sulfoxide (5 ml). The reaction system was purged with nitrogen three times and left to react at 100° C. for 5 hours. The reaction solution was cooled to room temperature, then ammonium chloride (47 mg, 0.88 mmol) and triethylamine (223 mg, 2.21 mmol) were added, and the reaction solution was stirred for 5 minutes. O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (505 mg, 1.33 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was filtered, and a saturated sodium bicarbonate aqueous solution was added to the filtrate, which was then extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the organic solvent. The residue was subjected to 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]oxazocin-10-yl)amino)propanamide (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 55

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

(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)propanamide was prepared as described in Example 54.

MS m/z (ESI): 422.2 [M+H] ⁺ .

Example 56

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

(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)propanamide was prepared as described in Example 54.

MS m/z (ESI): 436.2 [M+H] ⁺ .

Example 57

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

(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)propanamide was prepared as described in Example 54.

MS m/z (ESI): 434.2 [M+H] ⁺ .

Example 58

Preparation of (S)-2-((2-((S)-8-(difluoromethyl)-6-oxo-2,5-dioxa-7-azaspiro[3,4]octan-7-yl)-5.6 -dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide

(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)propanamide was prepared by the method described in Example 54.

MS m/z (ESI): 450.2 [M+H]+.

Example 59

Preparation of (S)-2-((2-(6-oxo-2,7-dioxa-5-azaspiro[3,4]octan-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2 -d][1,4]oxazepin-9-yl)amino)propanamide

(S)-2-((2-(6-oxo-2,7-dioxa-5-azaspiro[3,4]octan-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)amino)propanamide was obtained by the method described in example 1.

¹ H NMR (400 MHz, CD ₃ OD) δ 1.37 (d, J = 7.0 Hz, 3H), 3.69-3.77 (m, 1H), 4.27-4.38 (m , 4H), 4.62 (d, J = 7.4 Hz, 2H), 4.70 (s, 2H), 5.12 (d, J = 7.4 Hz, 2H), 6.10 (d , J = 2.3 Hz, 1H), 6.33-6.38 (m, 1H), 7.18 (s, 1H), 7.96 (d, J = 8.8 Hz, 1H);

MS m/z (ESI): 400.2 [M+H] ⁺ .

Example 60

Preparation of (S)-2-((2-((R)-4-(methoxymethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1, 4]oxazepin-9-yl)amino)propanamide

(S)-2-((2-((R)-4-(methoxymethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4 ]oxazepin-9-yl)amino)propanamide was obtained by the method described in example 1.

¹ H NMR (400 MHz, CD ₃ OD) δ 1.46 (d, J = 7.0 Hz, 3H), 3.34 (s, 3H), 3.57-3.62 (m, 1H), 3.77-3.85(m, 2H), 4.31-4.35(m, 2H), 4.37-4.41(m, 2H), 4.42-4.45(m, 1H ), 4.53-4.55 (m, 1H), 4.63-4.69 (m, 1H), 6.16-6.19 (m, 1H), 6.40-6.45 (m , 1H), 7.12 (s, 1H), 8.01 (d, J = 8.8 Hz, 1H);

MS m/z (ESI): 402.2 [M+H] ⁺ .

Example 61

Preparation of (2S)-2-((2-((5S)-5-(difluoromethyl)-3-oxo-2-oxa-4-azabicyclo[3.1.0]hexan-4-yl)-5,6-dihydrobenzo [f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide

(2S)-2-((2-((5S)-5-(difluoromethyl)-3-oxo-2-oxa-4-azabicyclo[3.1.0]hexan-4-yl)-5,6-dihydrobenzo[ f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide was prepared by the method described in Example 1.

MS m/z (ESI): 420.1 [M+H] ⁺ .

Example 62

Preparation of (S)-2-((2-((1R,5S)-6,6-difluoro-3-oxo-2-oxa-4-azabicyclo[3.1.0]hexan-4-yl)-5.6 -dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide

(S)-2-((2-((1R,5S)-6,6-difluoro-3-oxo-2-oxa-4-azabicyclo[3.1.0]hexan-4-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide was prepared by the method described in Example 1.

MS m/z (ESI): 406.1 [M+H]+.

Example 63

Preparation of (S)-2-((2-((S)-1,1-difluoro-5-oxo-6-oxa-4-azaspiro[2,4]heptan-4-yl)-5,6-dihydrobenzo [f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide

(S)-2-((2-((S)-1,1-difluoro-5-oxo-6-oxa-4-azaspiro[2,4]heptan-4-yl)-5,6-dihydrobenzo[ f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide was prepared by the method described in Example 1.

MS m/z (ESI): 420.1 [M+H] ⁺ .

Example 64

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

(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)propanamide was obtained by the method described in example 1.

MS m/z (ESI): 435.2 [M+H] ⁺ .

Example 65

Preparation of methyl-(9-(((S)-1-amino-1-oxopropan-2-yl)amino)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin- 2-yl)((S)-2,2-difluorocyclopropyl)carbamate

Methyl-(9-(((S)-1-amino-1-oxopropan-2-yl)amino)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2 -yl)((S)-2,2-difluorocyclopropyl)carbamate was obtained by the method described in example 1.

MS m/z (ESI): 422.2 [M+H]+.

Example 66

Preparation of (S)-2-((2-(5,5-difluoro-2-oxo-1,3-oxazinan-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][ 1,4]oxazepin-9-yl)amino)propanamide

((S)-2-((2-(5,5-difluoro-2-oxo-1,3-oxazinan-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][ 1,4]oxazepin-9-yl)amino)propanamide was obtained by the method described in example 1.

¹ H NMR (400 MHz, CD ₃ OD) δ 1.37 (d, J = 7.0 Hz, 3H), 3.70-3.75 (m, 1H), 4.21-4.25 (m , 2H), 4.26-4.32 (m, 3H), 4.44-4.52 (m, 3H), 6.08 (d, J = 2.2 Hz, 1H), 6.36- 6.33 (m, 1H), 7.13 (s, 1H), 7.96 (d, J = 8.8 Hz, 1H);

MS m/z (ESI): 408.1 [M+H] ⁺ .

Example 67

Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxo-1,3-oxazinan-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2 -d][1,4]oxazepin-9-yl)amino)propanamide

Step 1: Preparation of methyl-((benzyloxy)carbonyl)-L-homoserinate

Potassium carbonate (545 mg, 3.95 mmol) and methyl iodide (617 mg, 4.35 mmol) were added successively to a solution of ((benzyloxy)carbonyl)-L-homoserine (1.0 g, 3.95 mmol) in N, N-dimethylformamide (6 ml), and the reaction solution was stirred at room temperature overnight. Saturated sodium bicarbonate solution was added to stop the reaction, and the reaction solution was extracted with EtOAc. The organic phases were collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography to give the title compound methyl-((benzyloxy)carbonyl)-L-homoserinate (920 mg, 87%).

MS m/z (ESI): 268.1 [M+H] ⁺ .

Stage 2: Obtaining methyl-L-homoserinate

Methyl-((benzyloxy)carbonyl)-L-homoserinate (920 mg, 3.4 mmol) was dissolved in methanol (10 ml) followed by the addition of Pd/C (50 mg). Under a hydrogen atmosphere, the reaction solution was stirred at room temperature overnight. The reaction solution was filtered and concentrated under reduced pressure to give crude methyl-L-homoserinate title compound (288 mg, 64%).

MS m/z (ESI): 134.1 [M+H] ⁺ .

Step 3: Preparation of methyl-(S)-2-oxo-1,3-oxazinan-4-carboxylate

Methyl-L-homoserinate (288 mg, 2.2 mmol) was dissolved in dichloromethane (15 ml) and the resulting solution was cooled in an ice bath. Triphosgene (258 mg, 0.87 mmol) was added, then a solution of triethylamine (658 mg, 6.51 mmol) in dichloromethane (2 ml) was added dropwise. After completion of the addition, the reaction solution was left to react in an ice bath for 1 hour. Water was added and the reaction solution was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by column chromatography to give the pure product methyl (S)-2-oxo-1,3-oxazinan-4-carboxylate (110 mg, 32%).

MS m/z (ESI): 160.1 [M+H] ⁺ .

Step 4: Preparation of methyl-(S)-3-benzyl-2-oxo-1,3-oxazinan-4-carboxylate

Methyl (S)-2-oxo-1,3-oxazinan-4-carboxylate (110 mg, 0.7 mmol) was dissolved in tetrahydrofuran (12 ml) and the resulting solution was cooled in an ice bath. Sodium hydride (42 mg, 1.06 mmol) was added and the reaction solution was stirred for 10 minutes, then a solution of benzyl bromide (142 mg, 0.84 mmol) in tetrahydrofuran (2 ml) was added dropwise. After completion of the addition, the reaction solution was gradually warmed to room temperature and allowed to react for 2 hours. A saturated ammonium chloride solution was added, and the reaction solution was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by column chromatography to give the pure product methyl-(S)-3-benzyl-2-oxo-1,3-oxazinane-4-carboxylate (100 mg, 57%).

MS m/z (ESI): 250.1 [M+H] ⁺ .

Step 5: Preparation of (S)-3-benzyl-4-(hydroxymethyl)-1,3-oxazinan-2-one

Methyl-(S)-3-benzyl-2-oxo-1,3-oxazinan-4-carboxylate (100 mg, 0.4 mmol) was dissolved in methanol (5 ml) and the resulting solution was cooled in an ice bath. Sodium borohydride (30 mg, 0.8 mmol) was added in portions and the reaction solution was gradually warmed to room temperature and allowed to react for 2 hours. The reaction solution was concentrated, and the resulting crude product was purified by column chromatography to give pure product (S)-3-benzyl-4-(hydroxymethyl)-1,3-oxazinan-2-one (70 mg, 79%).

MS m/z (ESI): 222.1 [M+H] ⁺ .

Step 6: Preparation of (S)-3-benzyl-2-oxo-1,3-oxazinan-4-carbaldehyde

(S)-3-benzyl-4-(hydroxymethyl)-1,3-oxazinan-2-one (70 mg, 0.32 mmol) and IBX (269 mg, 0.96 mmol) were mixed in ethyl acetate (5 ml) . Under a nitrogen atmosphere, the reaction solution was stirred at 85° C. for 3 hours. The reaction solution was cooled and filtered. The filtrate was concentrated under reduced pressure to give the crude product (S)-3-benzyl-2-oxo-1,3-oxazinan-4-carbaldehyde (68 mg), which was immediately used in the next step.

MS m/z (ESI): 220.1[M+H] ⁺ .

Step 7: Preparation of (S)-3-benzyl-4-(difluoromethyl)-1,3-oxazinan-2-one

(S)-3-benzyl-2-oxo-1,3-oxazinan-4-carbaldehyde (68 mg, 0.31 mmol) was dissolved in dichloromethane (5 ml). Under nitrogen atmosphere, DAST (100 mg, 0.62 mmol) was added dropwise to the reaction solution in an ice bath. The reaction solution was naturally warmed to room temperature and allowed to react for 3 hours. The reaction solution was slowly added dropwise to a pre-cooled saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (10 ml×2). The organic phases were combined and concentrated under reduced pressure. The residue was subjected to column chromatography to give the title compound (S)-3-benzyl-4-(difluoromethyl)-1,3-oxazinan-2-one (55 mg, 73%).

MS m/z (ESI): 242.1 [M+H] ⁺ .

Step 8: Preparation of (S)-4-(difluoromethyl)-1,3-oxazinan-2-one

(S)-3-benzyl-4-(difluoromethyl)-1,3-oxazinan-2-one (55 mg, 0.23 mmol) was dissolved in ethanol (5 ml) followed by the addition of Pd(OH) ₂ /C ( 10 mg). Under a hydrogen atmosphere, the reaction solution was stirred 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)-1,3-oxazinan-2-one (28 mg, 81%).

MS m/z (ESI): 152.1 [M+H] ⁺ .

(S)-2-((2-((S)-4-(difluoromethyl)-2-oxo-1,3-oxazinan-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)amino)propanamide was obtained by the method described in example 1.

MS m/z (ESI): 422.2 [M+H] ⁺ .

Example 68

Preparation of (S)-2-((2-((S)-3-(difluoromethyl)-5-oxomorpholino)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine- 9-yl)amino)propanamide

Step 1: Preparation of (S)-2-(benzylamino)-3,3-difluoropropan-1-ol

5 mol/l aqueous sodium hydroxide solution (1.5 ml, 7.5 mmol) was added to a solution of (S)-3-benzyl-4-(difluoromethyl)oxazolidin-2-one (340 mg, 1.5 mmol) in methanol (5 ml) at room temperature. After completion of the addition, the reaction solution was heated to 55°C and stirred at this temperature for 3 hours. The reaction solution was cooled and concentrated under reduced pressure to remove the organic solvent. Water was added to the reaction flask, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent to give the crude title compound (S)-2-(benzylamino)-3,3-difluoropropan-1-ol, which was used immediately on next stage.

MS m/z (ESI): 202.1 [M+H] ⁺ .

Step 2: Preparation of (S)-N-benzyl-2-chloro-N-(1,1-difluoro-3-hydroxypropan-2-yl)acetamide

A solution of chloroacetyl chloride (186 mg, 1.65 mmol) in tetrahydrofuran (2 ml) was added dropwise to a solution of (S)-2-(benzylamino)-3,3-difluoropropan-1-ol (301 mg, 1.5 mmol) and triethylamine (379 mg, 3.75 mmol) in tetrahydrofuran (10 ml) in an ice bath. After completion of the addition, the reaction solution was stirred at this temperature for 2 hours. Water was added to the reaction flask to stop the reaction, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent to give the crude title compound (S)-N-benzyl-2-chloro-N-(1,1-difluoro-3-hydroxypropane- 2-yl)acetamide, which was immediately used in the next step.

MS m/z (ESI): 278.1 [M+H] ⁺ .

Step 3: Preparation of (S)-4-benzyl-5-(difluoromethyl)morpholin-3-one

Sodium hydride (72 mg, 1.8 mmol) was added to a solution of (S)-N-benzyl-2-chloro-N-(1,1-difluoro-3-hydroxypropan-2-yl)acetamide (415 mg, 1. 5 mmol) in tetrahydrofuran (8 ml) in an ice bath. After completion of the addition, the reaction solution was gradually warmed to room temperature and stirred for 3 hours. A saturated ammonium chloride solution was added to the reaction flask to stop the reaction, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the organic solvent. The residue was subjected to column chromatography to give the title compound (S)-4-benzyl-5-(difluoromethyl)morpholin-3-one (240 mg, 66%).

MS m/z (ESI): 242.1 [M+H] ⁺ .

Step 4: Preparation of (S)-5-(difluoromethyl)morpholin-3-one

(S)-4-benzyl-5-(difluoromethyl)morpholin-3-one (240 mg, 1.0 mmol) was dissolved in a solution of methanesulfonic acid (0.5 ml) and mesitylene (2.5 ml) at room temperature. The reaction solution was left to react in a microwave oven at 135°C for 1.5 hours. The reaction solution was concentrated, a saturated sodium carbonate aqueous solution was added, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent to give the crude title compound (S)-5-(difluoromethyl)morpholin-3-one.

MS m/z (ESI): 152.1 [M+H] ⁺ .

Step 5: Preparation of (S)-4-(9-bromo-5,6-dihydro-benzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-5-(difluoromethyl)morpholine- 3-she

10-bromo-2-iodo-6,7-dihydro-5H-benzo[b]imidazo[2,1-d][1,5]oxazocine (258 mg, 0.66 mmol), (S)-5- (difluoromethyl)morpholin-3-one (100 mg, 0.66 mmol), (1R,2R)-N ¹ ,N ² -dimethylcyclohexane-1,2-diamine (38 mg, 0.27 mmol), copper iodide ( 25 mg, 0.13 mmol) and potassium carbonate (183 mg, 1.32 mmol) were mixed in 1,4-dioxane (4 ml). The reaction system was purged with nitrogen three times and left to react at 125° C. for 5 hours. The reaction solution was cooled to room temperature, 15% ammonia (5 ml) was added and the reaction solution was stirred for 5 minutes and extracted with EtOAc three times. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. The residue was subjected to column chromatography to give the title compound (S)-4-(9-bromo-5,6-dihydro-benzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-5 -(difluoromethyl)morpholin-3-one (110 mg, 40%).

MS m/z (ESI): 414.0 [M+H] ⁺ .

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

(S)-4-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-5-(difluoromethyl)morpholin-3-one ( 50 mg, 0.12 mmol), L-alanine (22 mg, 0.24 mmol), copper iodide (5 mg, 0.025 mmol) and potassium phosphate (51 mg, 0.24 mmol) were mixed in dimethyl sulfoxide (3 ml) . The reaction system was purged with nitrogen three times and left to react at 105° C. for 2.5 hours. The reaction solution was cooled to room temperature, then ammonium chloride (39 mg, 0.73 mmol) and triethylamine (183 mg, 1.82 mmol) were added, and the reaction solution was stirred for 5 minutes. O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (414 mg, 1.09 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was filtered, and a saturated sodium bicarbonate aqueous solution was added to the filtrate, which was then extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the organic solvent. The residue was subjected to column chromatography to give the title compound (S)-2-((2-((S)-3-(difluoromethyl)-5-oxomorpholino)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)amino)propanamide (8.6 mg, 17%).

¹ H NMR (400 MHz, CD ₃ OD) δ 1.37 (d, J = 7.0 Hz, 3H), 3.75-3.77 (m, 1H), 3.92-3.97 (m , 1H), 4.19-4.21 (m, 1H), 4.22-4.25 (m, 2H), 4.28-4.33 (m, 3H), 4.45-4.53 (m, 2H), 6.06-6.10 (m, 1H), 6.22-6.37 (m, 2H), 7.26 (s, 1H), 7.95 (d, J = 8 .8 Hz, 1H);

MS m/z (ESI): 422.1 [M+H] ⁺ .

Example 69

Preparation of (S)-2-((2-((S)-2-(difluoromethyl)-4-methyl-6-oxopiperazin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d ][1,4]oxazepin-9-yl)amino)propanamide

Step 1: Preparation of (S)-2-(benzylamino)-3,3-difluoropropan-1-ol

5 mol/l aqueous sodium hydroxide solution (8.8 ml, 44.0 mmol) was added to a solution of (S)-3-benzyl-4-(difluoromethyl)oxazolidin-2-one (2.0 g, 8.8 mmol ) in methanol (30 ml) at room temperature. After completion of the addition, the reaction solution was heated to 55°C and stirred at this temperature for 3 hours. The reaction solution was cooled and concentrated under reduced pressure to remove the organic solvent. Water was added to the reaction flask, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent to give the crude title compound (S)-2-(benzylamino)-3,3-difluoropropan-1-ol, which was used immediately on next stage.

MS m/z (ESI): 202.1 [M+H] ⁺ .

Step 2: Preparation of (S)-N-benzyl-2-chloro-N-(1,1-difluoro-3-hydroxypropan-2-yl)acetamide

A solution of chloroacetyl chloride (1.2 g, 10.6 mmol) in tetrahydrofuran (5 ml) was added dropwise to a solution of (S)-2-(benzylamino)-3,3-difluoropropan-1-ol (1.8 g, 8 .8 mmol) and triethylamine (1.8 g, 17.6 mmol) in tetrahydrofuran (30 ml) in an ice bath. After completion of the addition, the reaction solution was stirred at this temperature for 2 hours. Water was added to the reaction flask to stop the reaction, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent to give the crude title compound (S)-N-benzyl-2-chloro-N-(1,1-difluoro-3-hydroxypropane- 2-yl)acetamide, which was immediately used in the next step.

MS m/z (ESI): 278.1 [M+H] ⁺ .

Step 3: Preparation of (S)-N-benzyl-N-(1,1-difluoro-3-hydroxypropan-2-yl)-2-(methylamino)acetamide

(S)-N-benzyl-2-chloro-N-(1,1-difluoro-3-hydroxypropan-2-yl)acetamide (1.9 g, 6.9 mmol), methylamine hydrochloride (2.3 g, 34.5 mmol) and triethylamine (4.2 g, 41.4 mmol) were dissolved in tetrahydrofuran (25 ml). The reaction solution was subjected to interaction at room temperature for 1 hour, heated to 60°C and left to react for 2 hours. The reaction solution was concentrated, and the resulting residue was purified by column chromatography to give pure product (S)-N-benzyl-N-(1,1-difluoro-3-hydroxypropan-2-yl)-2-(methylamino)acetamide (1 .0 g, 53%).

MS m/z (ESI): 273.1 [M+H] ⁺ .

Step 4: Preparation of (S)-1-benzyl-6-(difluoromethyl)-4-methylpiperazin-2-one

(S)-N-benzyl-N-(1,1-difluoro-3-hydroxypropan-2-yl)-2-(methylamino)acetamide (272 mg, 1.0 mmol), triphenylphosphorus (341 mg, 1.3 mmol), diisopropyl azodicarboxylate (263 mg, 1.3 mmol) and N,N-diisopropylethylamine (194 mg, 1.5 mmol) were dissolved in tetrahydrofuran (12 ml) and left to react at room temperature overnight. The reaction solution was concentrated, and the resulting residue was purified by column chromatography to give pure product (S)-1-benzyl-6-(difluoromethyl)-4-methylpiperazin-2-one (78 mg, 30%).

MS m/z (ESI): 255.1 [M+H] ⁺ .

Step 5: Preparation of (S)-6-(difluoromethyl)-4-methylpiperazin-2-one

(S)-1-benzyl-6-(difluoromethyl)-4-methylpiperazin-2-one (70 mg, 0.28 mmol) was dissolved in 0.5 ml of methanesulfonic acid at room temperature. The reaction solution was allowed to react in a microwave oven at 150° C. for 1.5 hours. The reaction solution was concentrated, a saturated sodium carbonate aqueous solution was added, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent to give the crude title compound (S)-6-(difluoromethyl)-4-methylpiperazin-2-one.

MS m/z (ESI): 152.1 [M+H] ⁺ .

Step 6: Preparation of (S)-1-(9-bromo-5,6-dihydro-benzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-6-(difluoromethyl)-4 -methylpiperazin-2-one

10-bromo-2-iodo-6,7-dihydro-5H-benzo[b]imidazo[2,1-d][1,5]oxazocine (71 mg, 0.18 mmol), (S)-6- (diformethyl)-4-methylpiperazin-2-one (30 mg, 0.18 mmol), (1R,2R)-N ¹ ,N ² -dimethylcyclohexan-1,2-diamine (7 mg, 0.04 mmol), copper iodide (10 mg, 0.07 mmol) and potassium carbonate (51 mg, 0.37 mmol) were mixed in 1,4-dioxane (4 ml). The reaction system was purged with nitrogen three times and left to react at 125°C for 5 hours. The reaction solution was cooled to room temperature, and 15% ammonia was added. The reaction solution was stirred for 5 minutes and extracted three times with EtOAc. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. The residue was subjected to column chromatography to give the title compound (S)-1-(9-bromo-5,6-dihydro-benzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-6 -(difluoromethyl)-4-methylpiperazin-2-one (63 mg, 82%).

MS m/z (ESI): 427.1 [M+H] ⁺ .

Step 7: Preparation of (S)-2-((2-((S)-2-(difluoromethyl)-4-methyl-6-oxopiperazin-1-yl)-5,6-dihydrobenzo[f]imidazo[1, 2-d][1,4]oxazepin-9-yl)amino)propanamide

(S)-1-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-6-(difluoromethyl)-4-methylpiperazin-2 -one (63 mg, 0.15 mmol), L-alanine (53 mg, 0.6 mmol), copper iodide (11 mg, 0.06 mmol) and potassium phosphate (191 mg, 0.9 mmol) were mixed with dimethyl sulfoxide (3 ml). The reaction system was purged with nitrogen three times and left to react at 105° C. for 2 hours. The reaction solution was cooled to room temperature, ammonium chloride (49 mg, 0.9 mmol) and N,N-diisopropylethylamine (290 mg, 2.25 mmol) were added, and the reaction solution was stirred for 5 minutes. O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (513 mg, 1.35 mmol) was added, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was filtered, and a saturated sodium bicarbonate aqueous solution was added to the filtrate, which was then extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the organic solvent. The residue was subjected to column chromatography to give the title compound (S)-2-((2-((S)-2-(difluoromethyl)-4-methyl-6-oxopiperazin-1-yl)-5,6-dihydrobenzo[ f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide (4.6 mg, 7%).

¹ H NMR (400 MHz, CD ₃ OD) δ = 1.46 (d, J = 7.0, 3H), 2.36 (s, 3H), 2.76-2.81 (m, 1H), 3.02 (s, 1H), 3.15-3.21 (m, 1H), 3.50-3.55 (m, 1H), 3.79-3.85 (m, 1H), 4, 30-4.35(m, 2H), 4.38-4.42(m, 2H), 4.72-4.79(m, 1H), 6.07-6.36(m, 1H), 6.15-6.19 (m, 1H), 6.40-6.46 (m, 1H), 7.26 (s, 1H), 8.02 (d, J = 8.8, 1H);

MS m/z (ESI): 435.1 [M+H] ⁺ .

Example 70

Preparation of (S)-2-((2-((S)-2-(difluoromethyl)-6-oxopiperazin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1, 4]oxazepin-9-yl)amino)propanamide

(S)-2-((2-((S)-2-(difluoromethyl)-6-oxopiperazin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4 ]oxazepin-9-yl)amino)propanamide was prepared by the method described in Example 69.

MS m/z (ESI): 421.2 [M+H] ⁺ .

Example 71

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

(S)-2-((2-((S)-2-(difluoromethyl)-4-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4 ]oxazepin-9-yl)amino)propanamide was obtained by the method described in example 1.

MS m/z (ESI): 408.1 [M+H] ⁺ .

Example 72

Preparation of (S)-2-((2-((S)-4-(chlorodifluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1, 4]oxazepin-9-yl)amino)propanamide

(S)-2-((2-((S)-4-(chlorodifluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4 ]oxazepin-9-yl)amino)propanamide was obtained by the method described in example 1.

MS m/z (ESI): 442.1 [M+H] ⁺ .

Example 73

Preparation of (2S)-2-((2-((4S)-4-(difluoromethyl)-2-oxido-1,2,3-oxathiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1 ,2-d][1,4]oxazepin-9-yl)amino)propanamide

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

MS m/z (ESI): 428.1 [M+H] ⁺ .

Example 74

Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2,2-dioxido-1,2,3-oxathiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo [1,2-d][1,4]oxazepin-9-yl)amino)propanamide

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

MS m/z (ESI): 444.1 [M+H] ⁺ .

Example 75

Preparation of (S)-2-((2-((S)-3-(difluoromethyl)-1,1-dioxyisothiazolidin-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][ 1,4]oxazepin-9-yl)amino)propanamide

(S)-2-((2-((S)-3-(difluoromethyl)-1,1-dioxyisothiazolidin-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1 ,4]oxazepin-9-yl)amino)propanamide was obtained by the method described in example 1.

MS m/z (ESI): 442.1 [M+H] ⁺ .

Example 76

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

(S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4 ]oxazepin-9-yl)amino)-N-hydroxypropanamide was obtained by the method described in example 1.

¹ H NMR (400 MHz, CD ₃ OD): δ 1.45 (d, J = 6.9 Hz, 3H), 3.79-3.94 (m, 1H), 4.31-4.41 ( m, 4H), 4.50-4.70 (m, 3H), 6.18-6.22 (m, 1H), 6.42-6.73 (m, 2H), 7.15 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H);

MS m/z (ESI): 424.1 [M+H] ⁺ .

Example 77

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

Stage 1: Obtaining 4-bromo-3-fluoro-2-methoxybenzaldehyde

Sodium methoxide (733 mg, 13.56 mmol) was added to a solution of 4-bromo-2,3-difluorobenzaldehyde (2.0 g, 9.05 mmol) in methanol (25 ml) at room temperature. The reaction solution was heated to 65°C and left to react for 2 hours. The reaction solution was concentrated, and the resulting residue was purified by column chromatography to obtain 4-bromo-3-fluoro-2-methoxybenzaldehyde (1.78 g, 85%).

MS m/z (ESI): 233.0 [M+H] ⁺ .

Stage 2: Obtaining 4-bromo-3-fluoro-2-hydroxybenzaldehyde

Hydrobromic acid (8.7 ml, 48%) was added to a solution of 4-bromo-3-fluoro-2-methoxybenzaldehyde (1.78 g, 7.67 mmol) in acetic acid (15 ml) at room temperature. The reaction solution was heated to 120°C and left to react for 16 hours. The reaction solution was cooled and concentrated under reduced pressure. 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 and concentrated under reduced pressure to remove the organic solvent. The resulting residue was purified 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

An aqueous solution of glyoxal (40 wt.%, 3.73 g, 25.7 mmol) was added to a solution of 4-bromo-3-fluoro-2-hydroxybenzaldehyde (1.12 g, 5.14 mmol) in methanol (12 ml) . In a water bath, ammonia (28 wt%, 5.14 g, 51.4 mmol) was slowly added dropwise to the reaction solution with stirring, the addition process lasted 30 minutes, and the temperature of the reaction solution was controlled so that it did not exceed 40°C. The mixture was stirred at 35°C for two days, cooled and concentrated under reduced pressure to remove the organic solvent. The resulting residue was 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] ⁺ .

Step 4: Preparation of 9-bromo-8-fluoro-5,6-dihydro-benzo[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) was 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, dried over sodium sulfate and concentrated under reduced pressure to remove the organic solvent. The resulting residue was purified by column chromatography to give the title compound 9-bromo-8-fluoro-5,6-dihydro-benzo[f]imidazo[1,2-d][1,4]oxazepine (995 mg, 69%) .

MS m/z (ESI): 283.0 [M+H] ⁺ .

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

NIS (2.23 g, 9.88 mmol) was added 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) 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. The solution was washed successively with 1 M NaOH aqueous 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] ⁺ .

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

EtMgBr (1.0 M, solution in THF, 1.23 ml, 3.69 mmol) was slowly added dropwise 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) at minus 20°C. After completion of the addition, the reaction solution was stirred at minus 15°C for 3 hours. The reaction solution was slowly warmed to room temperature, a saturated ammonium chloride aqueous solution was added dropwise, and the reaction solution was stirred for 15 minutes. The reaction solution was extracted several times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure to remove the organic solvent. The residue was 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] ⁺ .

Step 7: Preparation of (S)-4-(difluoromethyl)-3-(8-fluoro-9-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-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 with 1,4-dioxane (6 ml). The reaction system was purged with nitrogen three times and reacted at 105° C. for 5 hours. The reaction solution was cooled to room temperature, and 15% ammonia was added. The solution was stirred for 5 minutes and extracted three times with EtOAc. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography to give the title compound (S)-4-(difluoromethyl)-3-(8-fluoro-9-iodo-5,6-dihydro-benzo[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)propanamide was 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 78

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

(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)propanamide was prepared by the method described in Example 1.

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 79

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

(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)propanamide was prepared by the method described in Example 1.

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 80

Preparation of (S)-3-(9-(4-amino-5-methyl-1H-imidazol-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine -2-yl)-4-(difluoromethyl)oxazolidin-2-one

(S)-3-(9-(4-amino-5-methyl-1H-imidazol-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine- 2-yl)-4-(difluoromethyl)oxazolidin-2-one was obtained by the method described in example 1.

MS m/z (ESI): 417.1 [M+H] ⁺ .

Example 81

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

(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)propanamide was prepared by the method described in Example 1.

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, 8Hz, 1H);

MS m/z (ESI): 422.1 [M+H] ⁺ .

Example 82

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

(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)propanamide was prepared by the method described in Example 1.

MS m/z (ESI): 422.1 [M+H] ⁺ .

Example 83

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

(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)propanamide was prepared by the method described in Example 1.

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);

MS m/z (ESI): 422.1 [M+H] ⁺ .

Example 84

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

(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)propanamide was prepared by the method described in Example 1.

MS m/z (ESI): 438.1 [M+H] ⁺ .

Example 85

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

(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)propanamide was prepared by the method described in Example 1.

MS m/z (ESI): 438.1 [M+H] ⁺ .

Example 86

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

(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)propanamide was prepared by the method described in Example 1.

MS m/z (ESI): 438.1 [M+H] ⁺ .

Example 87

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

(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)propanamide was prepared by the method described in Example 1.

MS m/z (ESI): 433.1 [M+H] ⁺ .

Example 88

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

(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)propanamide was prepared by the method described in Example 1.

MS m/z (ESI): 433.1 [M+H] ⁺ .

Example 89

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

(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)propanamide was prepared by the method described in Example 1.

MS m/z (ESI): 433.1 [M+H] ⁺ .

Example 90

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

(S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4 ]oxazepin-9-yl)-3-methoxypropanamide was obtained 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);

MS m/z (ESI): 438.2 [M+H] ⁺ .

Example 91

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

(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 obtained 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);

MS m/z (ESI): 452.2 [M+H] ⁺ .

Example 92

Preparation of (2S,3S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][ 1,4]oxazepin-9-yl)-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)-3-methoxybutanamide was obtained by the method described in example 1.

MS m/z (ESI): 452.2 [M+H] ⁺ .

Example 93

Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydroimidazo[1,2-d]pyrido[2,3-f ][1,4]oxazepin-9-yl)amino)propanamide

(S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydroimidazo[1,2-d]pyrido[2,3-f] [1,4]oxazepin-9-yl)amino)propanamide was prepared by the method described in Example 1.

MS m/z (ESI): 409.2 [M+H] ⁺ .

Example 94

Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f ][1,4]oxazepin-9-yl)amino)propanamide

(S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f] [1,4]oxazepin-9-yl)amino)propanamide was prepared by the method described in Example 1.

MS m/z (ESI): 409.2 [M+H] ⁺ .

Example 95

Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f ][1,4]oxazepin-9-yl)amino)propanamide

(S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f] [1,4]oxazepin-9-yl)amino)propanamide was prepared by the method described in Example 1.

MS m/z (ESI): 409.2 [M+H] ⁺ .

Example 96

Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f][1,2,4]triazolo[1, 5-d][1,4]oxazepin-9-yl)amino)propanamide

(S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f][1.2.4]triazolo[1.5 -d][1,4]oxazepin-9-yl)amino)propanamide was obtained by the method described in example 1.

MS m/z (ESI): 409.2 [M+H] ⁺ .

Example 97

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

(S)-2-((2-((S)-2-(difluoromethyl)-5-oxopyrrolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4 ]oxazepin-9-yl)amino)propanamide was obtained 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);

MS m/z (ESI): 406.2 [M+H] ⁺ .

Example 98

Preparation of (S)-2-((2-((S)-7-(difluoromethyl)-2,5-dioxa-8-azaspiro[3,4]octan-8-yl)-5,6-dihydrobenzo[f ]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide

(S)-2-((2-((S)-7-(difluoromethyl)-2,5-dioxa-8-azaspiro[3,4]octan-8-yl)-5,6-dihydrobenzo[f] imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide was prepared by the method described in Example 1.

MS m/z (ESI): 436.2 [M+H] ⁺ .

Example 99

Preparation of (S)-2-((2-(N-((S)-2,2-difluoro-1-(oxetan-3-yl)ethyl)acetamido)-5,6-dihydrobenzo[f]imidazo[1 ,2-d][1,4]oxazepin-9-yl)amino)propanamide

(S)-2-((2-(N-((S)-2,2-difluoro-1-(oxetan-3-yl)ethyl)acetamido)-5,6-dihydrobenzo[f]imidazo[1, 2-d][1,4]oxazepin-9-yl)amino)propanamide was prepared by the method described in Example 1.

MS m/z (ESI): 450.2 [M+H] ⁺ .

Example 100

Preparation of (S)-N-(9-((1-amino-1-oxopropan-2-yl)amino)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin- 2-yl)-N-(2,2-difluoroethyl)oxetan-3-carboxamide

(S)-N-(9-((1-amino-1-oxopropan-2-yl)amino)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2 -yl)-N-(2,2-difluoroethyl)oxetan-3-carboxamide was obtained by the method described in example 1.

MS m/z (ESI): 436.2 [M+H] ⁺ .

Example 101

Preparation of (S)-N-(9-(((S)-1-amino-1-oxopropan-2-yl)amino)-5,6-dihydrobenzo[f]imidazo[1,2-d][1, 4]oxazepin-2-yl)-N-(2,2-difluoroethyl)oxetan-2-carboxamide

(S)-N-(9-(((S)-1-amino-1-oxopropan-2-yl)amino)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4 ]oxazepin-2-yl)-N-(2,2-difluoroethyl)oxetan-2-carboxamide was obtained by the method described in example 1.

MS m/z (ESI): 436.2 [M+H] ⁺ .

Example 102

Preparation of (R)-N-(9-(((S)-1-amino-1-oxopropan-2-yl)amino)-5,6-dihydrobenzo[f]imidazo[1,2-d][1, 4]oxazepin-2-yl)-N-(2,2-difluoroethyl)oxetan-2-carboxamide

(R)-N-(9-(((S)-1-amino-1-oxopropan-2-yl)amino)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4 ]oxazepin-2-yl)-N-(2,2-difluoroethyl)oxetan-2-carboxamide was obtained by the method described in example 1.

MS m/z (ESI): 436.2 [M+H] ⁺ .

Example 103

Preparation of (S)-2-((2-(N-(2,2-difluoroethyl)-2-methoxyacetamido)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine- 9-yl)amino)propanamide

(S)-2-((2-(N-(2,2-difluoroethyl)-2-methoxyacetamido)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9 -yl)amino)propanamide was obtained by the method described in example 1.

MS m/z (ESI): 424.2 [M+H] ⁺ .

Example 104

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

(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)propanamide was obtained 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, 8Hz, 1H);

MS m/z (ESI): 436.2 [M+H] ⁺ .

Example 105

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

(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)propanamide was prepared by the method described in Example 1.

MS m/z (ESI): 436.2 [M+H] ⁺ .

Example 106

Preparation of (1S,5R)-2-(2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1 ,4]oxazepin-9-yl)-2-azabicyclo[3.1.0]hexane-1-carboxamide

(1S,5R)-2-(2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1, 4]oxazepin-9-yl)-2-azabicyclo[3.1.0]hexane-1-carboxamide was obtained by the method described in example 1.

MS m/z (ESI): 446.2 [M+H] ⁺ .

Example 107

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

(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-hydroxypropanamide was obtained 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);

MS m/z (ESI): 424.1[M+H] ⁺ .

Example 108

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

Stage 1: Obtaining 4-bromo-3-fluoro-2-methoxybenzaldehyde

Sodium methoxide (733 mg, 13.56 mmol) was added to a solution of 4-bromo-2,3-difluorobenzaldehyde (2.0 g, 9.05 mmol) in methanol (25 ml) at room temperature. The reaction solution was heated to 65°C and left to react for 2 hours. The reaction solution was concentrated, and the resulting residue was purified by column chromatography to obtain 4-bromo-3-fluoro-2-methoxybenzaldehyde (1.78 g, 85%).

MS m/z (ESI): 233.0 [M+H] ⁺ .

Stage 2: Obtaining 4-bromo-3-fluoro-2-hydroxybenzaldehyde

Hydrobromic acid (8.7 ml, 48%) was added to a solution of 4-bromo-3-fluoro-2-methoxybenzaldehyde (1.78 g, 7.67 mmol) in acetic acid (15 ml) at room temperature. The reaction solution was heated to 120°C and left to react for 16 hours. The reaction solution was cooled and concentrated under reduced pressure. 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 and concentrated under reduced pressure to remove the organic solvent. This was subjected to 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

An aqueous solution of glyoxal (40 wt.%, 3.73 g, 25.7 mmol) was added to a solution of 4-bromo-3-fluoro-2-hydroxybenzaldehyde (1.12 g, 5.14 mmol) in methanol (12 ml) . On a water bath, ammonia (28 wt%, 5.14 g, 51.4 mmol) was slowly added dropwise to the reaction solution with stirring, the addition process lasted 30 minutes, and the temperature of the reaction solution was controlled so that it did not exceed 40°C. The mixture was stirred at 35°C for two days, cooled and concentrated under reduced pressure to remove the organic solvent. The resulting residue was 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] ⁺ .

Step 4: Preparation of 9-bromo-8-fluoro-5,6-dihydro-benzo[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) was 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, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. The resulting residue was purified by column chromatography to give the title compound 9-bromo-8-fluoro-5,6-dihydro-benzo[f]imidazo[1,2-d][1,4]oxazepine (995 mg, 69%) .

MS m/z (ESI): 283.0 [M+H] ⁺ .

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

NIS (2.23 g, 9.88 mmol) was added 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) 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. The solution was washed successively with 1 M NaOH aqueous 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] ⁺ .

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

EtMgBr (1.0 M, solution in THF, 1.23 ml, 3.69 mmol) was slowly added dropwise 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) at minus 20°C. After completion of the addition, the reaction solution was stirred at minus 15°C for 3 hours. The reaction solution was slowly warmed to room temperature, and a saturated ammonium chloride aqueous solution was added dropwise. The reaction solution was stirred for 15 minutes and extracted several times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the organic solvent. The residue was 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] ⁺ .

Step 7: Preparation of (S)-4-(difluoromethyl)-3-(8-fluoro-9-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-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 with 1,4-dioxane (6 ml). The reaction system was purged with nitrogen three times and reacted at 105° C. for 5 hours. The reaction solution was cooled to room temperature, and 15% ammonia was added. The reaction solution was stirred for 5 minutes and extracted three times with EtOAc. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography to give the title compound (S)-4-(difluoromethyl)-3-(8-fluoro-9-iodo-5,6-dihydro-benzo[f]imidazo[1,2-d][1, 4]oxazepin-2-yl)oxazolidin-2-one (225 mg, 65%).

MS m/z (ESI): 466.0 [M+H] ⁺ .

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

Lawson's reagent (1.92 g, 4.73 mmol) was added to a solution of (S)-4-(difluoromethyl)-3-(8-fluoro-9-iodo-5,6-dihydrobenzo[f]imidazo[1,2 -d][1,4]oxazepin-2-yl)oxazolidin-2-one (220 mg, 0.47 mmol) in toluene (20 ml). The reaction solution was heated to 145°C and left to react for 6 hours. The reaction solution was cooled to room temperature and filtered, and the filter cake was washed with EtOAc (20 ml). The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography to give the title compound (S)-4-(difluoromethyl)-3-(8-fluoro-9-iodo-5,6-dihydro-benzo[f]imidazo[1,2-d][1, 4]oxazepin-2-yl)oxazolidin-2-thione (105 mg, 46%).

MS m/z (ESI): 482.1[M+H] ⁺ .

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

Dichloro(p-cymene)ruthenium(II) dimer (27 mg, 0.045 mmol) and 2-bicyclohexylphosphino-2',6'-dimethoxybiphenyl (27 mg, 0.065 mmol) were added to a solution of (S)-3-(9-bromo -8-fluoro-5,6-dihydro-benzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-difluoromethyl)oxazolidin-2-thione (105 mg, 0.22 mmol ) in toluene (3 ml). The reaction solution was left to react in air at 115°C for 16 hours. The reaction solution was cooled to room temperature and diluted with EtOAc. The organic phases were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography to give the title compound (R)-4-(difluoromethyl)-3-(8-fluoro-9-iodo-5,6-dihydro-benzo[f]imidazo[1,2-d][1, 4]oxazepin-2-yl)thiazolidin-2-one (55 mg, 52%).

MS m/z (ESI): 482.1 [M+H]+.

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

(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 with dimethyl sulfoxide (3 ml). The reaction system was purged with nitrogen three times and left to react at 125° C. for 1.5 hours. The reaction solution was cooled to room temperature, ammonium chloride (27 mg, 0.5 mmol) and DMAP (161 mg, 1.25 mmol) were added, and the reaction solution was stirred for 5 minutes. O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (284 mg, 0.75 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was filtered, and a saturated sodium bicarbonate aqueous solution was added to the filtrate, which was then extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography to give the title compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-8-fluoro-5,6-dihydrobenzo[ f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide (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);

MS m/z (ESI): 442.1 [M+H] ⁺ .

Example 109

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

(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)-3-methoxypropanamide was prepared according to example 108.

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);

MS m/z (ESI): 472.1 [M+H] ⁺ .

Example 110

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

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

(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 left to react at 100° C. for 12 hours. The reaction solution was cooled to room temperature, ammonium chloride (20 mg, 0.37 mmol) and triethylamine (95 mg, 0.94 mmol) were added, and the reaction solution was stirred for 5 minutes. O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (212 mg, 0.56 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was filtered, and a saturated sodium bicarbonate aqueous solution was added to the filtrate, which was then extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the organic solvent. The residue was subjected to 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-methoxypropanamide (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);

MS m/z (ESI): 454.1 [M+H] ⁺ .

Example 111

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

(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 obtained by the method described in example 51.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.83-1.92 (m, 2H), 2.09-2.15 (m, 1H), 3.72-3.81 (m, 4H ), 4.25-4.32 (m, 4H), 5.07-5.15 (m, 1H), 5.93-5.97 (m, 1H), 6.22-6.28 (m , 1H), 6.35-6.65 (s, 1H), 7.00 (s, 1H), 7.26 (s, 1H), 7.35 (s, 1H), 7.99 (d, J = 8.6 Hz, 1H);

MS m/z (ESI): 450.1 [M+H] ⁺ .

Example 112

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

(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)propanamide was prepared by the method described in Example 51.

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);

MS m/z (ESI): 438.1[M+H] ⁺ .

Example 113

Preparation of (S)-2-((2-((R)-5-(methoxymethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1, 4]oxazepin-9-yl)amino)propanamide

(S)-2-((2-((R)-5-(methoxymethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4 ]oxazepin-9-yl)amino)propanamide was obtained by the method described in example 1.

¹ H NMR (400 MHz, CD ₃ OD) δ 1.48 (d, J = 7.0 Hz, 3H), 3.44 (s, 3H), 3.59-3.72 (m, 2H), 3.83 (q, J = 7.0 Hz, 1H), 3.95-4.02 (m, 6.5 Hz, 1H), 4.20 (t, J = 9.3 Hz, 1H), 4.28-4.33(m, 2H), 4.35-4.42(m, 2H), 4.81-4.86(m, 1H), 6.17-6.21(m, 1H ), 6.43 (dd, J = 8.8, 2.3 Hz, 1H), 7.12 (s, 1H), 8.01 (d, J = 8.8 Hz, 1H);

MS m/z (ESI): 402.2 [M+H] ⁺ .

Example 114

Preparation of (S)-2-((2-((R)-4-methoxy-2-oxopyrrolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4] oxazepin-9-yl)amino)propanamide

(S)-2-((2-((R)-4-methoxy-2-oxopyrrolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine -9-yl)amino)propanamide was obtained by the method described in example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.52 (d, J = 6.9 Hz, 3H), 2.57-2.67 (m, 1H), 2.78-2.88 (m, 1H), 3.40 (s, 3H), 3.79-3.88 (m, 1H), 4.10-4.43 (m, 7H), 6.19 (s, 1H), 6.42 (d, J = 8.8 Hz, 1H), 7.32 (s, 1H), 8.16 (d, J = 8.7 Hz, 1H);

MS m/z (ESI): 386.2 [M+H] ⁺ .

Example 115

Preparation of (2S)-2-((2-(4-(cyanomethyl)-2-oxopyrrolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine- 9-yl)amino)propanamide

(2S)-2-((2-(4-(cyanomethyl)-2-oxopyrrolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9 -yl)amino)propanamide was obtained by the method described in example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.30 (d, J = 6.9 Hz, 3H), 2.29 (dd, J = 16.9, 6.2 Hz, 1H), 2 .70 (dd, J = 16.5, 8.0 Hz, 1H), 2.77-2.88 (m, 3H), 3.64 (dd, J = 10.8, 4.4 Hz, 1H ), 3.76 (dt, J = 13.7, 6.9 Hz, 1H), 4.13 (dd, J = 10.6, 7.1 Hz, 1H), 4.33 (dd, J = 8.5, 5.8 Hz, 4H), 6.08 (d, J = 2.0 Hz, 1H), 6.12 (d, J = 7.0 Hz, 1H), 6.40 (dd, J = 8.8, 2.2 Hz, 1H), 6.99 (d, J = 0.7 Hz, 1H), 7.37 (s, 2H), 7.99 (d, J = 8.8 Hz, 1H);

MS m/z (ESI): 395.1 [M+H] ⁺ .

Example 116

Preparation of (2S)-2-((2-(4cyano-2-oxopyrrolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl) amino)propanamide

(2S)-2-((2-(4-cyano-2-oxopyrrolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl )amino)propanamide was obtained by the method described in example 1.

¹ H NMR (400 MHz, CD ₃ OD) δ 1.49 (d, J = 7.0 Hz, 3H), 2.88 (dd, J = 17.0, 6.7 Hz, 1H), 3, 01 (dd, J = 17.0, 9.3 Hz, 1H), 3.64-3.76 (m, 1H), 3.83 (q, J = 7.1 Hz, 1H), 4.25 (dd, J = 10.8, 5.9 Hz, 1H), 4.30-4.46 (m, 5H), 6.19 (d, J = 1.8 Hz, 1H), 6.44 ( dd, J = 8.8, 2.3 Hz, 1H), 7.38 (s, 1H), 7.75 (s, 1H), 8.06 (d, J = 8.8 Hz, 1H);

MS m/z (ESI): 381.1 [M+H] ⁺ .

Example 117

Preparation of (S)-2-((2-((S)-2-(cyanomethyl)-5-oxopyrrolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1, 4]oxazepin-9-yl)amino)propanamide

(S)-2-((2-((S)-2-(cyanomethyl)-5-oxopyrrolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4 ]oxazepin-9-yl)amino)propanamide was obtained by the method described in example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.30 (d, J = 6.8 Hz, 3H), 1.99 (t, J = 10.8 Hz, 1H), 2.42 (dd , J = 22.2, 12.2 Hz, 3H), 2.62-2.71 (m, 1H), 3.13 (dd, J = 16.8, 2.8 Hz, 1H), 3, 69-3.80 (m, 1H), 4.17-4.48 (m, 4H), 4.53-4.66 (m, 1H), 6.08 (d, J = 1.7 Hz, 1H), 6.15 (d, J = 7.0 Hz, 1H), 6.40 (dd, J = 8.8, 1.8 Hz, 1H), 7.01 (s, 1H), 7, 38 (s, 1H), 7.41 (s, 1H), 7.98 (d, J = 8.9 Hz, 1H);

MS m/z (ESI): 395.2 [M+H] ⁺ .

Example 118

Preparation of (S)-2-((2-((R)-4-(cyanomethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1, 4]oxazepin-9-yl)amino)propanamide

(S)-2-((2-((R)-4-(cyanomethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4 ]oxazepin-9-yl)amino)propanamide was obtained by the method described in example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.30 (d, J = 6.9 Hz, 3H), 3.14 (dd, J = 17.1, 2.4 Hz, 1H), 3 .45 (dd, J = 17.1, 5.0 Hz, 1H), 3.72-3.80 (m, 1H), 4.33 (ddd, J = 13.3, 8.4, 4, 7 Hz, 5H), 4.66 (t, J = 8.9 Hz, 1H), 4.77 (dt, J = 8.4, 4.9 Hz, 1H), 6.08 (d, J = 2.1 Hz, 1H), 6.17 (d, J = 7.0 Hz, 1H), 6.40 (dd, J = 8.8, 2.2 Hz, 1H), 7.02 (s, 1H), 7.20 (s, 1H), 7.39 (d, J = 1.0 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H);

MS m/z (ESI): 397.1 [M+H] ⁺ .

Example 119

Preparation of (S)-2-((2-((R)-4-(cyanomethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1, 4]oxazepin-9-yl)amino)propanamide

(S)-2-((2-((R)-4-(cyanomethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4 ]oxazepin-9-yl)amino)propanamide was obtained by the method described in example 1.

MS m/z (ESI): 436.2 [M+H] ⁺ .

Example 120

Preparation of (S)-2-((2-((R)-4-(cyanomethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1, 4]oxazepin-9-yl)amino)-3-methoxypropanamide

(S)-2-((2-((R)-4-(cyanomethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4 ]oxazepin-9-yl)amino)-3-methoxypropanamide was obtained by the method described in example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.14 (dd, J = 17.6, 2.8 Hz, 1H), 3.28 (s, 3H), 3.46 (dd, J = 17.3, 4.4 Hz, 1H), 3.56 (d, J = 5.3 Hz, 2H), 3.92-4.01 (m, 1H), 4.24-4.48 (m , 5H), 4.66 (t, J = 9.0 Hz, 1H), 4.74-4.81 (m, 1H), 6.09-6.21 (m, 2H), 6.46 ( dd, J = 8.7, 1.7 Hz, 1H), 7.16 (s, 1H), 7.20 (s, 1H), 7.46 (s, 1H), 7.99 (d, J = 8.8 Hz, 1H);

MS m/z (ESI): 427.1 [M+H] ⁺ .

Example 121

Preparation of (S)-2-((2-((R)-4-(2-methoxyethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][ 1,4]oxazepin-9-yl)amino)propanamide

(S)-2-((2-((R)-4-(2-methoxyethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1 ,4]oxazepin-9-yl)amino)propanamide was obtained according to example 1.

MS m/z (ESI): 416.1 [M+H] ⁺ .

Example 122

Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxo-1,3-thiazinan-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2 -d][1,4]oxazepin-9-yl)amino)propanamide

(S)-2-((2-((S)-4-(thiazinan)-2-oxo-1,3-oxazinan-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)amino)propanamide was prepared according to Example 51.

MS m/z (ESI): 438.1 [M+H] ⁺ .

Example 123

Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxo-1,3-thiazinan-3-yl)-8-fluoro-5,6-dihydrobenzo[f]imidazo [1,2-d][1,4]oxazepin-9-yl)amino)propanamide

(S)-2-((2-((S)-4-(difluoromethyl)-2-oxo-1,3-thiazinan-3-yl)-8-fluoro-5,6-dihydrobenzo[f]imidazo[ 1,2-d][1,4]oxazepin-9-yl)amino)propanamide was prepared according to Example 51.

MS m/z (ESI): 456.1 [M+H] ⁺ .

Example 124

Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxo-1,3-thiazinan-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2 -d][1,4]oxazepin-9-yl)amino)-3-methoxypropanamide

(S)-2-((2-((S)-4-(difluoromethyl)-2-oxo-1,3-thiazinan-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)amino)-3-methoxypropanamide was prepared according to Example 51.

MS m/z (ESI): 468.1 [M+H] ⁺ .

Example 125

Preparation of (S)-2-((2-((S)-3-(difluoromethyl)-5-oxomorpholino)-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1, 4]oxazepin-9-yl)amino)propanamide

((S)-2-((2-((S)-3-(difluoromethyl)-5-oxomorpholino)-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1, 4]oxazepin-9-yl)amino)propanamide was prepared according to example 68.

MS m/z (ESI): 440.1 [M+H] ⁺ .

Example 126

Preparation of (S)-2-((2-((S)-3-(difluoromethyl)-5-oxomorpholino)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine- 9-yl)amino)3-methoxypropanamide

(S)-2-((2-((S)-3-(difluoromethyl)-5-oxomorpholino)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9 -yl)amino)3-methoxypropanamide was prepared according to Example 68.

MS m/z (ESI): 452.1 [M+H] ⁺ .

Example 127

Preparation of (S)-2-((2-((S)-2-(difluoromethyl)-4-methyl-6-oxopiperazin-1-yl)-8-fluoro-5,6-dihydrobenzo[f]imidazo[1 ,2-d][1,4]oxazepin-9-yl)amino)propanamide

(S)-2-((2-((S)-2-(difluoromethyl)-4-methyl-6-oxopiperazin-1-yl)-8-fluoro-5,6-dihydrobenzo[f]imidazo[1, 2-d][1,4]oxazepin-9-yl)amino)propanamide was prepared according to Example 69.

MS m/z (ESI): 453.1 [M+H] ⁺ .

Example 128

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

(S)-2-((2-((S)-2-(difluoromethyl)-4-methyl-6-oxopiperazin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d] [1,4]oxazepin-9-yl)amino)-3-methoxypropanamide was prepared according to Example 69.

MS m/z (ESI): 465.1 [M+H] ⁺ .

Example 129

Preparation of (2S,3R)-1-(2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1 ,4]oxazepin-9-yl)-3-methylpyrrolidin-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-methylpyrrolidin-2-carboxamide was obtained according to example 1.

MS m/z (ESI): 448.1 [M+H] ⁺ .

Biological analysis and evaluation

The present invention is further described below in conjunction with the following test cases, which are not intended to limit the scope of the present invention.

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

Purpose of experiment: The purpose of this test example is to determine the inhibitory effect of the compounds according to the examples on the activity of the kinase PI3Kα/β/γ/δ.

Experimental equipment: centrifuge (5810R, purchased from Eppendorf), pipette (purchased from Eppendorf or Rainin), and microplate reader (Model: SynergyH1 full featured microplate reader, purchased from BioTek, USA).

Experimental Procedure: Promega ADP-Glo lipid kinase assay method (Promega No. V9102) was used in this experiment. Lipid kinase PI3Kα/β/γ/δ catalyzed the formation of ADP from ATP in the presence of the substrate PIP2:3PS and ATP. Lipid kinase activity was characterized by measuring the ADP content in the reaction, and thus the semi-inhibitory IC ₅₀ concentration of the compound was obtained in relation to the inhibition of PI3Kα/β/γ/δ kinase activity.

The specific process of the experiment is as follows:

The kinase reaction was performed in a white 384-well plate (Perkin Elmer No. 6007299). To each well was added 2 μl of compound solution of various concentrations, diluted with ddH ₂ O containing 1% DMSO. 2 μl of ddH ₂ O containing 1% DMSO was added to the positive control well. 2 μl of a 0.1-2 nM PI3K kinase solution diluted 5× with kinase buffer (HEPES 250 mM, MgCl ₂ 15 mM, NaCl 250 mM, BSA 0.05%) was added to each well. 2 μl of 5x kinase buffer was added to the negative control well. 4 μl of 50 μM PIP2 substrate: 3PS (Promega # V1701) prepared with 10× dilution buffer and ddH ₂ O was added to all wells. Finally, 2 μl of a 50-100 μM ATP solution diluted with water was added to start the reaction. After reaction at room temperature for 90-120 minutes, 10 μl of ADP-Glo reagent (containing 10 mM MgCl ₂ ) was added to each well and reacted at room temperature for 60 minutes to remove excess ATP in the reaction. 20 μl of kinase detection reagent was added to each well and reacted at room temperature in the dark for 20 minutes. The chemiluminescence value was measured using a BioTek Synergy H1 microplate reader.

Enzyme
Name vendor code Concentration of enzymatic reaction Enzyme reaction time ATP concentration PI3Kα Promega #V1721 0.1 nM 120 min 50 µM PI3Kβ Carna No. 11-102 0.4 nM 90 min 100 µM PI3Kγ Thermofisher No. PV4786 0.4 nM 120 min 50 µM PI3Kδ Carna No. 11-103 0.1 nM 90 min 100 µM

Experimental data processing technique:

Percent inhibition data for a compound treated well was calculated using a positive control well (DMSO control wells) and a negative control well (no kinase addition) on the plate {% degree of inhibition = 100 - [(test compound value - negative control value) ] / (value for positive control - value for negative control) × 100}. The IC ₅₀ value was calculated by fitting the data for various concentrations and corresponding percentage inhibition levels with a four-parameter non-linear logic equation using a GraphPad prism.

Experiment results:

According to the above scheme, the compounds according to the examples of the present invention in the PI3Kα/β/γ/δ kinase activity test showed the biological activities shown in Table 1.

Table 1

Example PI3Kα, PI3Kβ, PI3Kγ, PI3Kδ, Selectivity for PI3Kα versus PI3Kβ Selectivity for PI3Kα versus PI3Kγ Selectivity for PI3Kα versus PI3Kδ IC ₅₀ (nM) IC ₅₀ (nM) IC ₅₀ (nM) IC ₅₀ (nM) Example 10 7.9 Over 10000 1788 1398 Over 1266 226 177 Example 38 4 1432 447 410 358 112 103 Example 43 0.86 283 557 25 329 648 29 Example 51 0.2 168 90 49 840 450 245 Example 53 5 6190 402 373 1238 80 75 Example 54 1.2 1799 481 336 1499 401 280 Example 55 1.7 1872 363 213 1101 214 125 Example 66 9.3 4574 2076 653 492 223 70 Example 68 0.38 198 79 24 521 208 63 Example 69 2.1 3179 332 142 1514 158 68 Example 77 5.2 924 450 306 178 87 59 Example 78 5.2 2786 510 459 536 98 88 Example 97 2.1 1649 510 190 785 243 90 Example 108 2.4 472 247 194 197 103 81 Example 109 6.8 1069 1154 348 157 170 51 Example 110 1 754 376 139 754 376 139 Example 111 2.9 1227 736 125 423 254 43 Example 112 2.2 523 478 69 238 217 31 Example 117 2.5 1948 505 280 779 202 112 Example 118 1.3 190 74 50 146 57 38 Example 119 2.4 407 116 71 170 48 thirty Example 120 4.7 988 530 200 210 113 43

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

Test Example 2 Determination of Proliferation Inhibiting Effect of Compounds According to Examples of the Present Invention on PI3Kα Mutant Cancer Cells

Purpose of Experiment: The purpose of this test example is to determine the proliferation inhibition activity of the compounds of the examples against PI3Kα mutant cancer cells HCC1954 (H1047R), HGC-27 (E542K) and MKN1 (E545K).

Experiment equipment: centrifuge (5702R, purchased from Eppendorf), carbon dioxide incubator (purchased from Thermo), biological safety cabinet (purchased from Shanghai Boxun Company), pipette (purchased from Eppendorf or Rainin), and microplate reader (model: full-featured SynergyH1 microplate reader, purchased from BioTek, USA).

Experimental Procedure: The proliferation inhibiting effect of the compounds of the examples on PI3Kα mutant cancer cell lines HCC1954, HGC-27 and MKN1 was determined by the Cell Titer-Glo method. Cell lines were cultured in RPMI 1640 medium (Gibco no. 22400089) containing 10% FBS (Gibco no. 10091148) and 1% P/S (Hyclone no. SV30010) at 37°C and 5% CO ₂ . Before the experiment, the cells were collected and counted, and then the cell density was adjusted. Cells were inoculated into a white 96-well plate (Corning No. 3610) at a density of 1000 to 10,000 cells/well and incubated in an incubator at 37° C., 5% CO ₂ overnight. A solution of the compound of various concentrations was added and at the same time an appropriate vehicle control was established. The cell plate was additionally incubated in an incubator at 37°C, 5% CO ₂ for 48-96 hours. The cell plate and its contents were equilibrated to room temperature. 20 to 100 µl of Cell Titer-Glo solution (Promega No. G7573) was added to each well, the plate was shaken well and incubated at room temperature in the dark for 5-30 minutes. The chemiluminescence value was measured using a BioTek Synergy H1 microplate reader.

Experimental data processing technique:

Percent inhibition data for a well treated with the compounds of the Examples was calculated using the vehicle control well on the plate {% degree of inhibition = 100 - (test compound value/vehicle control value) × 100}. The IC ₅₀ value was calculated by fitting the data for various concentrations and corresponding percentage inhibition levels with a four-parameter non-linear logic equation using a GraphPad prism.

Experiment results:

According to the above scheme, the compounds according to the examples of the present invention in the test of inhibition of proliferation of PI3Kα mutant cancer cells HCC1954 (H1047R), HGC-27 (E542K) and MKN1 (E545K) showed the biological activities shown in table 2.

table 2

Example HCC1954 (H1047R) IC ₅₀ (nM) MKN1 (E545K) IC ₅₀ (nM) HGC-27(E542K) IC ₅₀ (nM) Example 38 204 615 417 Example 43 112 214 169 Example 48 205 399 396 Example 51 21 60 40 Example 54 79 84 93 Example 55 160 508 325 Example 68 70 113 111 Example 69 601 584 433 Example 77 226 653 499 Example 90 222 368 531 Example 97 184 268 186 Example 108 98 118 233 Example 109 243 426 455 Example 110 57 109 137 Example 111 40 66 77 Example 112 29 42 32 Example 118 140 398 371 Example 119 134 304 358

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

Test Example 3 Toxicity Test of 7-Day Repeated Intragastric Administration in SD Rats

3.1 Purpose of the experiment

The purpose of this study is to investigate the possible toxicity of GDC-0077 and Example 51 in SD (Sprague-Dawley) rats after 7 days of repeated intragastric administration, and to compare the differences in toxicity between GDC-0077 and Example 51.

3.2 Materials and equipment for the experiment

3.2.1 Test compound

Test Compound 1: GDC-0077

Test Compound 2: Example Compound 51

3.2.2 Media

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

3.2.3 Animal information

Types and Lines: Sprague Dawley Rats (SD)

Animal class: free from specific pathogenic microflora (SPF class)

Number and sex of animals: 112 rats, half male and half female

3.2.4 Equipment

The ADVIA®2120 automated blood analyzer that was used to count blood cells;

Coagulometer SYSMEX CA-500, which was used to determine the indicators of coagulation function;

Automatic biochemical analyzer TBA-120FR, which was used to determine the biochemical parameters of blood;

The Easylyte Electrolyte Analyzer, which was used to determine electrolytes; And

Liquid chromatography - mass spectrometry (detector: API4000, electrospray source (ESI) in positive ion mode, column: Agilent ZORBAX XDB-C18 (3.5 µm, 2.1×50 µm)), which was used for biological analysis of the plasma sample .

3.3 Experimental procedure

1) In the experiment, 112 rats (56 rats/sex) were divided into 14 groups according to sex and body weight, of which 70 rats were used for toxicology study (groups 1 to 7, 5 rats/sex/group) and 42 rats were used for toxicological study (groups 8 to 14, 3 rats/gender/group).

2) As a vehicle control group, the animals in groups 1 and 8 were intragastrically injected with a 20% aqueous solution of SBE-β-CD (Captisol).

3) Animals in groups 2 and 9, 3 and 10 and 4 and 11 were intragastrically injected with GDC-0077 at doses of 10, 30 and 60 mg/kg, respectively.

4) Animals in groups 5 and 12, 6 and 13 and 7 and 14 were intragastrically injected with the compound of example 51 at doses of 10, 30 and 60 mg/kg, respectively.

5) Animals were administered once a day for 7 consecutive days (animals from groups 7 and 14 were administered for 6 consecutive days).

6) The injection volume was 10 ml/kg.

7) During the experiment, such parameters as clinical observations, body weight, food intake, clinical and pathological parameters (general blood count, coagulation function, blood biochemistry), toxicokinetics, etc. were studied.

8) All animals were sacrificed on day 8 (animals in groups 7 and 14 were sacrificed after administration on day 6).

9) During the experiment, a pathological examination of animals in groups 1 to 7, animals in group 14 and dead animals (including animals participating in the toxicokinetic study) was performed, and histopathological examination of pathological tissues, tissues of the gastrointestinal tract (such as colon and caecum) and immune tissues (such as the thymus).

3.4 List of test data

3.4.1 Near death/death

In the case of GDC-0077 or Example 51 at 60 mg/kg, mortal/dead animals were observed. In the case of other doses, dead animals/animals were not observed in the near-mortem state.

3.4.2 Toxicokinetics

At a dose of 30 mg/kg, the mean systemic exposure of the AUC of the compound of example 51 after the last administration (male: 11400 h*ng/ml, female: 15900 h*ng/ml) was approximately 2.4-3.8 times higher than GDC-0077 at the same dose (male: 3000 h*ng/mL, female: 6510 h*ng/mL) and similar to GDC-0077 at 60 mg/kg after the first injection (male: 15400 h*ng/mL, females: 22800 h * ng / ml).

At a dose of 10 mg/kg, the average systemic exposure AUC (area under the curve) of the compound of example 51 after the last injection (male: 2110 h*ng/ml, female: 3170 h*ng/ml) was approximately 1.4-2.5 times higher than GDC-0077 (male: 845 h*ng/mL, female: 2250 h*ng/mL).

Therefore, the systemic exposure of Example 51 was significantly higher than that of GDC-0077 at the same dose.

3.4.3 Clinical observations

GDC-0077: In the high dose group, pathological symptoms such as arched back, loose stools, perianal contamination, and fluffy hair were observed.

Compound of Example 51: In the medium and high dose groups, pathological symptoms such as arched back, loose stools, perianal fouling, and fluffy hair were observed.

3.4.4 Body weight and food intake

GDC-0077: In the medium and high dose groups, the final body weight of all animals decreased, and their food intake also decreased over the same period.

Compound of Example 51: In the low, medium and high dose groups, the final body weight decreased and the corresponding food intake also decreased.

3.4.5 Blood cell count and clotting function

GDC-0077: In each dosing group, reticulocytes decreased in both males and females.

Compound of Example 51: In each dosing group, reticulocytes decreased in both males and females; and in the 30 mg/kg group and the 60 mg/kg group, neutrophils and platelets decreased in both males and females.

3.4.6 Blood biochemistry

GDC-0077: In each dose group, glucose and cholesterol increased in male animals; in the 60 mg/kg group, AST (aspartate aminotransferase) and urea increased in both males and females, A/G (albumin globulin index) decreased in both males and females, and ALT (alanine aminotransferase) increased in males; and in the 30 mg/kg group, AST and urea increased in both males and females, and ALT increased in females.

Compound of Example 51: In the 60 mg/kg group, AST, glucose and urea increased in both males and females; in the 30 mg/kg group, AST and urea increased in both males and females, and glucose increased in males; and in the 10 mg/kg group, AST increased in both males and females.

3.4.7 Pathological anatomy

GDC-0077: Pathological changes under the microscope mainly included atrophy of goblet cells in the caecal mucosa, an increase in staining macrophage bodies in the thymus, and erosion, bleeding, and swelling of the gastric mucosa.

Compound of Example 51 Pathological changes under the microscope mainly included bleeding and atrophy of the glandular tissue of the gastric mucosa; bleeding of the mucous membrane of the cecum, atrophy of goblet cells, atrophy of goblet cells of the mucous membrane of the colon; atrophy of the white pulp of the spleen; and atrophy of the cortex or cortex and medulla of the thymus, an increase in the number of macrophage staining bodies, and the like.

The primary target organs for toxicity of GDC-0077 and Example 51 are gastrointestinal tissues (such as the stomach and caecum) and immune tissues (such as the thymus).

3.5 Conclusion after the experiment

During this experiment, the test compound GDC-0077 and the compound of example 51 were administered intragastrically to SD rats for 7 days at a dose of 10, 30 and 60 mg/kg (once a day). The lethal dose of GDC-0077 and Example 51 is 60 mg/kg and the maximum tolerated dose (MTD) is 30 mg/kg. At 30 mg/kg, C _max and AUC _{(0-24 h)} of Example 51 are significantly higher than GDC-0077. Thus, the tolerability of the compound of example 51 is better than that of GDC-0077.

Test Example 4 Efficacy Test of Compounds According to Examples of the Present Invention in vivo

4.1 Purpose of the experiment

The goal is to select compounds with significant potency and fewer toxic and side effects using an in vivo potency test.

4.2 Basic equipment and materials for the experiment

4.2.1 Equipment:

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

2. Super Clean Work Table (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. Pipette (10-20 µl, Eppendorf)

7. Microscope (TS2, Nikon)

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

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

10.Electronic scales (CPA2202S, Sartorius)

4.2.2 Reagents:

1. RPMI-1640 environment (22400-089, Gibco)

2. Fetal bovine serum (FBS) (10091-148, Gibco)

3.0.25% trypsin (25200-056, Gibco)

4. Dual antibiotics penicillin-streptomycin (15140-122, Gibco)

5. Sodium phosphate buffer (PBS) (10010-023, Gibco)

6. Matrigel Matrix (356234, Corning)

4.2.3 Animal:

BALB/c nude mice, 6 to 8 weeks old, male, purchased from Shanghai Sippr-BK laboratory animal Co. Ltd.

4.3 Experiment process

4.3.1 Cell culture and preparation of cell suspension

a. HCC1954 cells were taken from a cell bank and resuscitated in RPMI-1640 medium (RPMI-1640 + 10% FBS + 1% SP). Resuscitated cells were placed in a cell culture flask (cell type, date, operator name, etc. were marked on the side of the flask) and cultured in a CO ₂ incubator (incubator temperature was 37°C and CO ₂ concentration was 5%) .

b. The passage was carried out after the cells covered 80 to 90% of the bottom of the culture flask. After the passage, the cells continued to be cultured in a CO ₂ incubator. This process was repeated until the number of cells met the requirements for the in vivo efficacy test.

c. Cultured cells were collected and counted using an automatic cell counter. The cells were resuspended in PBS and matrigel according to the results of counting to obtain a cell suspension (density: 5×10 ⁷ /ml) which was placed in a refrigerator for later use.

4.3.2 Cell inoculation

a. Before inoculation, nude mice were labeled with disposable universal rat and mouse ear tags.

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

c. The naked mouse was held with the left hand. A site on the right side of the back next to the right shoulder of a nude mouse (inoculation site) was disinfected with 75% alcohol and inoculated 30 seconds later.

d. Test nude mice were sequentially subjected to inoculation (each mouse was inoculated with 0.1 ml of cell suspension).

4.3.3 Tumor Volume Measurement, Grouping and Administration to Tumor Mice

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

Calculation of tumor volume: tumor volume (mm ³ ) = length (mm) × width (mm) × width (mm)/2

b. According to body weight and tumor size, tumor-bearing mice were randomized into groups.

c. According to the grouping results, the test compounds were administered (method of administration: 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 (carboxymethyl cellulose)/1% Tween 80).

d. Tumor volume and body weight were measured twice a week after the start of administration of the test compounds.

e. After the end of the experiment, the animals were sacrificed.

f. The data was processed using software such as Excel. Calculation of the degree of tumor growth inhibition TGI (%) of the compound: when the tumor did not regress, TGI (%) = [(1-(average tumor volume in the treatment group at the end of the introduction - the average tumor volume of the treatment group at the beginning of the administration)) / (average volume tumors in the vehicle control group at the end of treatment - the average tumor volume in the vehicle control group at the beginning of treatment)]×100%. When the tumor regressed, TGI (%) = [1-(mean tumor volume in the treatment group at the end of the administration - the average tumor volume in the treatment group at the beginning of the administration)/mean tumor volume in the treatment group at the beginning of the administration]×100%.

4.4 Test data are presented in Table 3:

Table 3

Groups Number of animals Days of administration (days) Degree of tumor growth inhibition Control 5 21 - Example 51 5 19 132% Example 54 5 21 120% Example 68 5 21 78% Example 108 5 21 96% Example 110 5 21 98%

4.5 Results of the experiment

From the above results, it can be seen that the above compounds according to the present application showed a good degree of inhibition of tumor growth.

Test Example 5 Pharmacokinetic (PK) Assay of Compounds According to Examples of the Present Invention in Mice

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

- Method of administration: single intragastric administration.

- Administered dose: 5 mg/10 ml/kg (body weight).

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

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

-Process example:

1) 0.1 ml of blood was taken from the ophthalmic vein, placed in a tube with K ₂ -EDTA (ethylenediaminetetraacetic acid) and centrifuged for 5 to 20 minutes at room temperature at 1000-3000×g to separate the plasma, which was then stored at minus 80 °C

2) 160 μl of acetonitrile was added to 40 μl of the plasma sample for precipitation, and then the mixture was centrifuged for 5-20 minutes at 500-2000×g.

3) 100 μl of the treated supernatant was taken and analyzed by LC/MS/MS analysis to determine the concentration of the test compound.

LC-MS/MS analysis:

- Liquid chromatography conditions: Shimadzu LC-20AD pump

- Mass Spectrometry Conditions: AB Sciex API 4000 Mass Spectrometer

- Chromatographic column: phenomenex Gemiu 5 µm C ₁₈ 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: 0-4 minutes gradient elution

Pharmacokinetics:

The main parameters were calculated using WinNonlin 6.1. The results of the pharmacokinetic analysis experiment in mice are shown in Table 4 below:

Table 4

Example No. Pharmacokinetic analysis (5 mg/kg) Time to reach maximum concentration Plasma concentration Area under the curve Area under the curve Half-life Average hold time t _max (h) _Cmax (ng/ml) AUC _0-t (ng/ml×h) AUC _0-∞ (ng/ml×h) t _1/2 (h) MRT(h) 43 0.5 2060 3442 3499 1.0 1.8 51 0.5 1057 2185 2274 1.6 2.2 53 0.5 1088 1283 1289 0.8 1.2 54 1.0 832 1560 1615 1.8 2.0 68 0.5 641 1321 1339 1.6 1.8 77 0.5 2300 4089 4116 1.2 1.7 90 0.5 1287 2072 2086 1.0 1.6 108 0.5 1227 4238 4241 2.0 3.4 110 0.5 4020 13703 13712 2.8 3.7 111 0.5 466 1742 1744 2.8 3.9

From the results of the pharmacokinetic analysis 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 plasma AUC levels and the maximum plasma concentration C _max were good.

Claims (115)

1. The compound of formula (VI), its stereoisomer or its pharmaceutically acceptable salt: Where: Ring B is selected from the group consisting of: L is nitrogen; G is oxygen; Q is N; Z is -CR _aa ; R _aa is selected from the group consisting of hydrogen and deuterium; each R ^y is independently selected from the group consisting of hydrogen and deuterium; each of R ₅ , R ₆ and R ₁₄ is independently selected from the group consisting of hydrogen, deuterium and halogen; each of R ₃ and R ₄ is independently selected from the group consisting of hydrogen, deuterium, C _1-6 alkyl, C _1-6 deuterated alkyl and -(CH ₂ ) _n1 OR _bb , wherein each of said C _1-6 alkyl and C _1-6 deuterated alkyl is optionally further substituted with one or more substituents selected from the group consisting of deuterium and C _1-6 alkoxy; R ₂ is selected from the group consisting of hydrogen, deuterium and C _1-6 alkyl; or R ₂ and R ₃ are associated with the formation of a 4-6-membered heterocyclyl containing nitrogen, where the number of nitrogen atoms is equal to one or two; R ^z is selected from the group consisting of hydrogen, deuterium, C _1-6 alkyl, C _1-6 deuterated alkyl and C _1-6 haloalkyl, wherein said C _1-6 alkyl is optionally further substituted with one or more substituents selected from the group, consisting of deuterium, halogen, cyano; R _bb is selected from the group consisting of hydrogen, C _1-6 alkyl and cyano; n ₁ is 0, 1, 2 or 3; m is 1; t is 1; n is 1; And q is 0, 1, 2, 3, 4, 5, or 6. 2. A compound of formula (VI), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that it is further as shown in formula (VIII-A): Where: Ring B is selected from the group consisting of: R ₂ is selected from the group consisting of hydrogen and C _1-6 alkyl; each of R ₃ and R ₄ is independently selected from the group consisting of hydrogen, C _1-6 alkyl and -(CH ₂ ) _n1 OR _bb ; or R ₂ and R ₃ are associated with the formation of a 4-6-membered heterocyclyl containing nitrogen, where the number of nitrogen atoms is equal to one or two; each of R ₅ , R ₆ and R ₁₄ is independently selected from the group consisting of hydrogen, halogen; R _aa is hydrogen; R ^z is selected from the group consisting of hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, and -(CH ₂ ) _n1 R _bb ; R _bb is selected from the group consisting of hydrogen, C _1-6 alkyl and cyano; n ₁ is 0, 1, 2 or 3; And t is equal to 1. 3. A compound of formula (VI), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that R ₂ and R ₃ are linked to form pyrrolidinyl or azetidinyl. 4. The compound of formula (VI), its stereoisomer or its pharmaceutically acceptable salt according to claim 2, characterized in that R ₂ is selected from the group consisting of hydrogen and C _1-3 alkyl; each of R ₃ and R ₄ is independently selected from the group consisting of hydrogen, C _1-3 alkyl and C _1-3 alkyl substituted with C _1-3 alkoxy; or R ₂ and R ₃ are associated with the formation of a 4-6-membered heterocyclyl containing nitrogen, where the number of nitrogen atoms is equal to one or two; each of R ₅ and R ₆ is independently selected from the group consisting of hydrogen and halogen; R ₁₄ is selected from the group consisting of hydrogen, fluorine and chlorine; R ^z is selected from the group consisting of hydrogen, C _1-3 alkyl, C _1-3 alkyl substituted with halogen, and -(CH ₂ ) _n1 R _bb ; R _aa is hydrogen; R _bb is cyano; n ₁ is 0, 1, 2 or 3; And t is equal to 1. 5. The compound of formula (VI), its stereoisomer or its pharmaceutically acceptable salt according to claim 4, characterized in that R ₂ is selected from the group consisting of hydrogen and methyl; each of R ₃ and R ₄ is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, CH ₃ OCH ₂ - and CH ₃ CH ₂ OCH ₂ -; R ₂ and R ₃ are associated with the formation of pyrrolidinyl, piperidinyl or azetidinyl; R ^z is selected from the group consisting of hydrogen, acetonitrile, propionitrile and C _1-3 alkyl substituted with fluorine. 6. The compound of formula (VI), its stereoisomer or its pharmaceutically acceptable salt according to claim 4 or 5, characterized in that R ^z is selected from the group consisting of acetonitrile, -CHF ₂ , -CF ₂ CH ₃ and CHF ₂ CH ₂ -. 7. A compound of formula (VI), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that it is further as shown in formula (VIII): Where: ring B, R ₃ , R ₅ , R ₆ , R ₁₄ , R ^z , R _aa and t are as defined in paragraph 1. 8. A compound of formula (VI), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 7, characterized in that ring B is selected from the group consisting of R ₂ is hydrogen; R ₃ is selected from the group consisting of C _1-3 alkyl and C _1-3 alkyl substituted with C _1-3 alkoxy; each of R ₅ and R ₆ is independently selected from the group consisting of hydrogen and halogen; R ₁₄ is selected from the group consisting of hydrogen, fluorine and chlorine; R ^z is selected from the group consisting of hydrogen, C _1-6 alkyl and C _1-6 alkyl substituted with halogen. 9. The compound of formula (VI), its stereoisomer or its pharmaceutically acceptable salt according to claim 7, characterized in that R ₃ is selected from the group consisting of methyl, ethyl, propyl, CH ₃ OCH ₂ - and CH ₃ CH ₂ OCH ₂ -; each of R ₅ and R ₆ is independently selected from the group consisting of hydrogen and halogen; R ^z is selected from the group consisting of hydrogen, acetonitrile, propionitrile and C _1-3 alkyl substituted with halogen. 10. The compound of formula (VI), its stereoisomer or its pharmaceutically acceptable salt according to claim 7, characterized in that R ^z is selected from the group consisting of methyl, acetonitrile, -CHF ₂ , -CF ₂ CH ₃ and CHF ₂ CH ₂ -. 11. A compound of formula (VI), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that it is further as shown in formula (X): Where: R ₁₅ is selected from the group consisting of hydrogen, C _1-6 alkyl, C _1-6 haloalkyl and -(CH ₂ ) _n1 R _bb ; R ₁₆ is hydrogen; R ₂ -R ₄ , R ₆ , R ₁₄ , n ₁ , R _aa and R _bb are as defined in paragraph 2. 12. The compound of formula (VI), its stereoisomer or its pharmaceutically acceptable salt according to claim 11, characterized in that R ₂ is selected from the group consisting of hydrogen and C _1-6 alkyl; or R ₂ and R ₃ are associated with the formation of a 4-6-membered heterocyclyl containing nitrogen, where the number of nitrogen atoms is equal to one or two; each of R ₃ and R ₄ is independently selected from the group consisting of hydrogen and C _1-3 alkyl; each of R ₅ and R ₆ is independently selected from the group consisting of hydrogen and halogen; R ₁₄ is selected from the group consisting of hydrogen and halogen; R _aa is hydrogen. 13. A compound of formula (VI), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 12, characterized in that R ₂ and R ₃ are linked to form pyrrolidinyl or azetidinyl. 14. The compound of formula (VI), its stereoisomer or its pharmaceutically acceptable salt according to claim 12, characterized in that R ₂ is selected from the group consisting of hydrogen and C _1-3 alkyl; each of R ₃ and R ₄ is independently selected from the group consisting of methyl, ethyl and propyl; R ₅ and R ₆ are hydrogen; R ₁₄ is hydrogen. 15. A compound of formula (VI), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, 2 or 7, characterized in that R ^z is C _1-3 alkyl or C _1-3 haloalkyl. 16. The compound of formula (VI), its stereoisomer or its pharmaceutically acceptable salt according to claim 1, characterized in that the structure of the compound is as follows: 17. A process for the preparation of a compound of formula (VI), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that it comprises the following step reacting a compound of formula (VI-1) and a compound of formula (IV-2) to give a compound of formula (VI), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; Where: X is halogen; And ring B, Q, Z, G, L, R ₂ -R ₆ , R ₁₄ , R ^y , R ^z , q, m, n and t are as defined in paragraph 1. 18. A process for the preparation of a compound of formula (X), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that it comprises the following steps reacting a compound of formula (IX) and a Lawsson reagent to give a compound of formula (IX-A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and reacting a compound of formula (IX-A) with a transition metal complex and its ligand to give a compound of formula (X) , its stereoisomer or its pharmaceutically acceptable salt; Where: R ₂ -R ₄ , R ₆ , R ₁₄ -R ₁₆ and R _aa are as defined in paragraph 11. 19. A process for the preparation of a compound of formula (X), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that it comprises the following step reacting a compound of formula (IX-A) with a transition metal complex and its ligand to give a compound of formula (X), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; Where: R ₂ -R ₄ , R ₆ , R ₁₄ -R ₁₆ and R _aa are as defined in paragraph 11. 20. The method according to claim 19, characterized in that the transition metal complex and its ligand are a dimer of dichloro(p-cymene)ruthenium (II) and 2-bicyclohexylphosphino-2',6'-dimethoxybiphenyl. 21. Pharmaceutical composition for inhibiting the activity of phosphatidylinositol-3-kinase (PI3K), containing a therapeutically effective amount of a compound of formula (VI), its stereoisomer or its pharmaceutically acceptable salt according to any one of paragraphs. 1-16 and one or more pharmaceutically acceptable carriers, diluents or excipients. 22. The use of a compound of formula (VI), its stereoisomer or its pharmaceutically acceptable salt according to any one of paragraphs. 1-16 or a pharmaceutical composition according to claim 21 for the preparation of a PI3K inhibitor drug. 23. Use according to claim 22, characterized in that the PI3K inhibitor drug is a P13Kα inhibitor drug. 24. The use of a compound of formula (VI), its stereoisomer or its pharmaceutically acceptable salt according to any one of paragraphs. 1-16 or a pharmaceutical composition according to claim 21 for the preparation of a medicament for the treatment of cancer, bone disease, inflammatory disease, immune disease, nervous system disease, metabolic disease, respiratory system disease, and heart disease mediated by PI3K activity, 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.