Inhibitors Containing Tricyclic Derivatives, Methods for Their Preparation, and Uses - Patent application

Abstract

To provide a compound represented by general formula (I), its stereoisomer or its pharmaceutically acceptable salt.SOLUTION: An inhibitor containing one kind of a tricyclic derivative, a manufacturing method therefor and a pharmaceutical composition comprising the inhibitor, as well as a use thereof as a phosphoinositide 3 kinase (PI3K) inhibitor in the treatment of cancer and diseases or conditions mediated by or dependent on PI3K imbalance.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention belongs to the field of pharmaceutical synthesis, and specifically relates to a tricyclic derivative inhibitor and its preparation method and application. [Background technology]

[0002] The phosphatidylinositol 3-kinase (PI3K) protein family is broadly divided into four classes, I, II, III, and IV, and is involved in regulating multiple cellular functions, including cell growth, proliferation, differentiation, survival, and glucose metabolism. The four classes of PI3K proteins differ in structure and function, with class I PI3K being the most widely studied. This class of PI3K is further divided into four subclasses: PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ. Among these, PI3Kα exhibits activating mutations and amplifications in multiple tumors and is closely associated with tumor development and progression. Several studies have demonstrated that PI3Kβ can activate platelets and play an important role in the development and progression of diseases such as thrombosis. PI3Kδ and PI3Kγ are primarily expressed in the hematologic system and are closely associated with the immune system and inflammation, while PI3Kγ is closely associated with blood pressure regulation and smooth muscle contraction.

[0003] PI3Kα is a driving factor in tumor development, undergoing activating mutations and amplification in several tumor types. PI3Kα is a heterodimer consisting of a p110 catalytic subunit and a p85 regulatory subunit. It is activated by receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs). After activation, PI3Kα catalyzes the synthesis of phosphatidylinositol triphosphate (PIP3) from phosphatidylinositol diphosphate (PIP2). PIP3 can then activate protein kinase B (PKB, also known as AKT) and its downstream signaling pathways. Several cell growth factors, such as epidermal growth factor (EGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and insulin, can activate PI3Kα, thereby activating downstream proliferation signaling pathways in cells. Abnormal activation of PI3Kα can cause rapid cell proliferation, thereby leading to tumor development.

[0004] PI3Kα has traditionally been an important target in the research and development of oncology drugs. However, most compounds are broad-spectrum inhibitors of PI3Ks, which have resulted in relatively severe side effects in clinical studies, severely limiting the development of PI3Ks inhibitors. Previous research has shown that most side effects of broad-spectrum PI3Ks inhibitors are caused by inhibition of the PI3Kβ, PI3Kδ, and PI3Kγ subtypes. PI3Kβ plays an important role in the mechanism of side effects such as thrombocytopenia and thrombosis, while PI3Kδ inhibition can cause immune system abnormalities. Autoimmunity and infectious toxicity, such as pneumonia, hepatitis, and diarrhea / enteritis, are closely related to the inhibition of PI3Kδ targets. PI3Kγ is closely related to blood pressure regulation and smooth muscle contraction, and is the main target causing hypertension. Therefore, developing highly active and highly selective PI3Kα inhibitors would further enhance the antitumor effects of PI3Kα inhibitors and reduce or eliminate serious side effects, such as inflammation, thrombocytopenia, and hypertension, caused by the inhibition of other subtypes.

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

[0006] Although international applications WO2010029082(A1) and WO2011022439(A1) report compounds related to PI3Kα selective inhibitors, subsequent studies have revealed that these compounds all have low cellular activity, which adversely affects their antitumor efficacy in clinical settings. Therefore, there is an urgent need to develop PI3Kα selective inhibitors with high activity and selectivity. PI3Kα selective inhibitors can be used to treat multiple types of tumors with PI3Kα-activating mutations or amplifications, and have significant clinical application value.

[0007] Through research, it was found that the examples of the present invention have higher activity and selectivity against the PI3Kα enzyme, better cellular activity, better tumor inhibition rate in mouse efficacy models, and are safer. Summary of the Invention [Problem to be solved by the invention]

[0008] An object of the present invention is to provide a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: [Means for solving the problem]

[0009] Here, the structure of the compound represented by general formula (I) is as follows: [ka] (where, Q, Y, and Z each independently represent N or -CR aa Selected from Ring A is selected from a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group; R1 is hydrogen, deuterium, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, a hydroxy group, a cyano group, an enyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an oxoheterocyclic group, a thioheterocyclic group, an aryl group, a heteroaryl group, -(CH2) n1 R bb , -(CH2) n1 OR bb , -NR aa C(O)(CH2) n1 OR bb , -NR aa C(S)(CH2) n1 OR bb , -(CH2) n1 SR bb , -(CH2) n1 C(O)R bb , -(CH2) n1 C(O)OR bb , -(CH2) n1 S(O) m1 R bb , -(CH2) n1 NR bb R cc , -(CH2) n1 C(O)NR bb R cc , -(CH2) n1 NR bb C(O)R cc or -(CH2) n1 NR bb S(O) m1 R ccwherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, enyl, alkynyl, cycloalkyl, heterocyclic, oxoheterocyclic, thioheterocyclic, aryl, and heteroaryl groups may further be selected from the group consisting of deuterium, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkylhaloalkyl, halogen, substituted or unsubstituted cycloalkylamino, oxo, thio, nitro, cyano, hydroxy, substituted or unsubstituted cycloalkylenyl, substituted or unsubstituted cycloalkylalkynyl, substituted or unsubstituted cycloalkylalkoxy, substituted or unsubstituted cycloalkylhaloalkoxy, substituted or unsubstituted cycloalkylhydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH) n1 R dd , -(CH2) n1 OR dd , -(CH2) n1 SR dd , -(CH2) n1 C(O)R dd , -(CH2) n1 C(O)OR dd , -(CH2) n1 S(O) m1 R dd , -(CH2) n1 NR dd R ee , -(CH2) n1 C(O)NR dd R ee , -(CH2) n1 C(O)NHR dd , -(CH2) n1 NR dd C(O)R ee and -(CH2) n1 NR dd S(O) m1 R ee and optionally substituted by one or more substituents selected from R x and R yare each independently hydrogen, deuterium, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a mercapto group, a nitro group, a hydroxy group, a cyano group, an enyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -(CH2) n1 -, -(CH2) n1 R bb , -(CH2) n1 OR bb , -(CH2) n1 SR bb , -(CH2) n1 C(O)R bb , -(CH2) n1 C(O)OR bb , -(CH2) n1 S(O) m1 R bb , -(CH2) n1 NR bb R cc , -(CH2) n1 C(O)NR bb R cc , -(CH2) n1 NR bb C(O)R cc or -(CH2) n1 NR bb S(O) m1 R cc wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, enyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may further be selected from the group consisting of deuterium, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkylhaloalkyl, halogen, substituted or unsubstituted cycloalkylamino, mercapto, oxo, nitro, cyano, hydroxy, substituted or unsubstituted enyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkylalkoxy, substituted or unsubstituted cycloalkylhaloalkoxy, substituted or unsubstituted cycloalkylhydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH) n1 Rdd , -(CH2) n1 OR dd , -(CH2) n1 SR dd , -(CH2) n1 C(O)R dd , -(CH2) n1 C(O)OR dd , -(CH2) n1 S(O) m1 R dd , -(CH2) n1 NR dd R ee , -(CH2) n1 C(O)NR dd R ee , -(CH2) n1 C(O)NHR dd , -(CH2) n1 NR dd C(O)R ee and -(CH2) n1 NR dd S(O) m1 R ee and optionally substituted by one or more substituents selected from Or any two adjacent or non-adjacent R x are linked to form a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group can further include deuterium, a substituted or unsubstituted alkyl group, a substituted or unsubstituted haloalkyl group, a halogen atom, a substituted or unsubstituted amino group, an oxo group, a nitro group, a cyano group, a hydroxy group, a substituted or unsubstituted enyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted haloalkoxy group, a substituted or unsubstituted hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, -(CH) n1 -, -(CH2) n1 R bb , -(CH2) n1 OR bb , -(CH2) n1 SR bb , -(CH2) n1 C(O)Rbb , -(CH2) n1 C(O)OR bb , -(CH2) n1 S(O) m1 R bb , -(CH2) n1 NR bb R cc , -(CH2) n1 C(O)NR bb R cc , -(CH2) n1 NR bb C(O)R cc or -(CH2) n1 NR bb S(O) m1 R cc and optionally substituted by one or more substituents selected from Or any two adjacent or non-adjacent R y are linked to form a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group can further include deuterium, a substituted or unsubstituted alkyl group, a substituted or unsubstituted haloalkyl group, a halogen atom, a substituted or unsubstituted amino group, an oxo group, a nitro group, a cyano group, a hydroxy group, a substituted or unsubstituted enyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted haloalkoxy group, a substituted or unsubstituted hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, -(CH) n1 -, -(CH2) n1 R bb , -(CH2) n1 OR bb , -(CH2) n1 SR bb , -(CH2) n1 C(O)R bb , -(CH2) n1 C(O)OR bb , -(CH2) n1 S(O) m1 R bb , -(CH2) n1 NR bb R cc, -(CH2) n1 C(O)NR bb R cc , -(CH2) n1 NR bb C(O)R cc or -(CH2) n1 NR bb S(O) m1 R cc and optionally substituted by one or more substituents selected from R aa is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, enyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, enyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted enyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl groups; R bb , R cc , R dd and R eeare each independently selected from hydrogen, deuterium, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a hydroxyalkyl group, a haloalkoxy group, a halogen, a cyano group, a nitro group, a hydroxy group, an amino group, an enyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, The heteroaryl group may be further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl groups, halogen, hydroxy groups, substituted or unsubstituted amino groups, oxo groups, nitro groups, cyano groups, substituted or unsubstituted enyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted alkoxy groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocyclic groups, substituted or unsubstituted aryl groups, and substituted or unsubstituted heteroaryl groups; 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; m1 is 0, 1 or 2, and n1 is 0, 1, 2, 3, 4, or 5.

[0010] A preferred form is R x Ha-(CH2) n1 NR bb C(R ff R gg )C(O)R cc and R ff and R ggare each independently selected from hydrogen, deuterium, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a hydroxyalkyl group, a haloalkoxy group, a halogen, a cyano group, a nitro group, a hydroxy group, an amino group, an enyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, The heteroaryl group may be further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl groups, halogen, hydroxy groups, substituted or unsubstituted amino groups, oxo groups, nitro groups, cyano groups, substituted or unsubstituted enyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted alkoxy groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocyclic groups, substituted or unsubstituted aryl groups, and substituted or unsubstituted heteroaryl groups; n1, R bb or R cc is as shown in general formula (I).

[0011] In a more preferred embodiment, ring A is a benzene ring, and R y is hydrogen, Q and Y are N, and Z is -CR aa and R aa is hydrogen, n is 1, and R1 is [ka] If R x Ha-NHCHR ff Instead of C(O)NH2, here R ff is CH3-, cyclopropyl- or -CH2CH3, Ring A is a benzene ring, and R y is hydrogen, Q and Y are N, and Z is -CR aa and R aa is hydrogen, n is 1, and R1 is [ka] If R x Ha-NCHR ff Instead of C(O)NH2, here R ff is CH3- or cyclopropyl-, Ring A is a benzene ring, and R y is hydrogen, Q and Y are N, and Z is -CR aa and R aa is hydrogen, n is 1, and R1 is [ka] If R x Ha-NHCHR ff Instead of C(O)NH2, here R ff is cyclopropyl- or cyclobutyl-. In one preferred embodiment of the present invention, there is provided a compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound is represented by the general formula (II). [ka] (where, W is selected from oxygen or sulfur, preferably oxygen; R9 and R 10 are each independently hydrogen, deuterium, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a mercapto group, a nitro group, a hydroxy group, a cyano group, an enyl group, an alkynyl group, a cycloalkyl group, a halocycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -(CH2) n1 -, -(CH2) n1 R bb , -(CH2) n1 OR bb , -(CH2) n1 SR bb , -(CH2) n1 C(O)R bb , -(CH2) n1 C(O)OR bb , -(CH2) n1 S(O) m1 Rbb , -(CH2) n1 NR bb R cc , -(CH2) n1 C(O)NR bb R cc , -(CH2) n1 NR bb C(O)R cc or -(CH2) n1 NR bb S(O) m1 R cc wherein the alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, mercapto, oxo, nitro, cyano, hydroxy, enyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH) n1 R dd , -(CH2) n1 OR dd , -(CH2) n1 SR dd , -(CH2) n1 C(O)R dd , -(CH2) n1 C(O)OR dd , -(CH2) n1 S(O) m1 R dd , -(CH2) n1 NR dd R ee , -(CH2) n1 C(O)NR dd R ee , -(CH2) n1 C(O)NHR dd , -(CH2) n1 NR dd C(O)R ee and -(CH2) n1 NR dd S(O) m1 R ee and optionally substituted by one or more substituents selected from Or, R9 and R10 are linked to form a heterocyclic group and a heteroaryl group, wherein the heterocyclic group and the heteroaryl group can further comprise deuterium, an alkyl group, a haloalkyl group, a halogen atom, an amino group, an oxo group, a nitro group, a cyano group, a hydroxy group, an enyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, -(CH) n1 -, -(CH2) n1 R bb , -(CH2) n1 OR bb , -(CH2) n1 SR bb , -(CH2) n1 C(O)R bb , -(CH2) n1 C(O)OR bb , -(CH2) n1 S(O) m1 R bb , -(CH2) n1 NR bb R cc , -(CH2) n1 C(O)NR bb R cc , -(CH2) n1 NR bb C(O)R cc or -(CH2) n1 NR bb S(O) m1 R cc and optionally substituted by one or more substituents selected from Rings A, H, Y, Z, R 23 ~R 26 , R x , R y , n, p, q, m1 and n1 are as defined in general formula (II).

[0012] In one preferred embodiment of the present invention, there is provided a compound represented by the general formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound is represented by the general formulas (II-A) and (II-B). [ka] (where, G is selected from oxygen or sulfur; L is nitrogen, oxygen, sulfur or -CR aa Selected from Ring B is selected from heterocyclic groups or heteroaryl groups, and is preferably a thioheterocyclic group or an oxoheterocyclic group; R z is hydrogen, deuterium, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, mercapto group, nitro group, hydroxy group, cyano group, oxo group, enyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, -(CH2) n1 -, -(CH2) n1 R bb , -(CH2) n1 OR bb , -(CH2) n1 SR bb , -(CH2) n1 C(O)R bb , -(CH2) n1 C(O)OR bb , -(CH2) n1 S(O) m1 R bb , -(CH2) n1 NR bb R cc , -(CH2) n1 C(O)NR bb R cc , -(CH2) n1 NR bb C(O)R cc or -(CH2) n1 NR bb S(O) m1 R ccwherein the alkyl, haloalkyl, alkoxy, haloalkoxy, enyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, mercapto, oxo, nitro, cyano, hydroxy, enyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl-(CH). n1 R dd , -(CH2) n1 OR dd , -(CH2) n1 SR dd , -(CH2) n1 C(O)R dd , -(CH2) n1 C(O)OR dd , -(CH2) n1 S(O) m1 R dd , -(CH2) n1 NR dd R ee , -(CH2) n1 C(O)NR dd R ee , -(CH2) n1 C(O)NHR dd , -(CH2) n1 NR dd C(O)R ee and -(CH2) n1 NR dd S(O) m1 R ee and optionally substituted by one or more substituents selected from Or any two adjacent or non-adjacent R zThe groups are linked to form a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group can further include deuterium, an alkyl group, a haloalkyl group, a halogen, an amino group, an oxo group, a nitro group, a cyano group, a hydroxy group, an enyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, -(CH) n1 -, -(CH2) n1 R bb , -(CH2) n1 OR bb , -(CH2) n1 SR bb , -(CH2) n1 C(O)R bb , -(CH2) n1 C(O)OR bb , -(CH2) n1 S(O) m1 R bb , -(CH2) n1 NR bb R cc , -(CH2) n1 C(O)NR bb R cc , -(CH2) n1 NR bb C(O)R cc and -(CH2) n1 NR bb S(O) m1 R cc and optionally substituted by one or more substituents selected from R2 is present or absent, and L is nitrogen or -CR aa In the case where R2 is a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen atom, an amino group, a mercapto group, a nitro group, a hydroxy group, a cyano group, an enyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -(CH2) n1 -, -(CH2) n1 R bb , -(CH2) n1 ORbb , -(CH2) n1 SR bb , -(CH2) n1 C(O)R bb , -(CH2) n1 C(O)OR bb , -(CH2) n1 S(O) m1 R bb , -(CH2) n1 NR bb R cc , -(CH2) n1 C(O)NR bb R cc , -(CH2) n1 NR bb C(O)R cc or -(CH2) n1 NR bb S(O) m1 R cc Selected from R3 and R4 each independently represent hydrogen, deuterium, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a hydroxyalkyl group, a haloalkoxy group, a halogen, an amino group, a mercapto group, a nitro group, a hydroxy group, a cyano group, an enyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -(CH2) n1 -, -(CH2) n1 R bb , -(CH2) n1 OR bb , -(CH2) n1 SR bb , -(CH2) n1 C(O)R bb , -(CH2) n1 C(O)OR bb , -(CH2) n1 S(O) m1 R bb , -(CH2) n1 NR bb R cc , -(CH2) n1 C(O)NR bb R cc , -(CH2) n1 NR bb C(O)R cc or -(CH2) n1 NRbb S(O) m1 R cc wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, enyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, mercapto, oxo, nitro, cyano, hydroxy, enyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH) n1 R dd , -(CH2) n1 OR dd , -(CH2) n1 SR dd , -(CH2) n1 C(O)R dd , -(CH2) n1 C(O)OR dd , -(CH2) n1 S(O) m1 R dd , -(CH2) n1 NR dd R ee , -(CH2) n1 C(O)NR dd R ee , -(CH2) n1 C(O)NHR dd , -(CH2) n1 NR dd C(O)R ee and -(CH2) n1 NR dd S(O) m1 R ee and optionally substituted by one or more substituents selected from Or, the groups R2, R3, R4 and R aaAny two of these may be linked to form a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, and the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group may further include deuterium, an alkyl group, a haloalkyl group, a halogen atom, an amino group, an oxo group, a nitro group, a cyano group, a hydroxy group, an enyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, -(CH) n1 -, -(CH2) n1 R bb , -(CH2) n1 OR bb , -(CH2) n1 SR bb , -(CH2) n1 C(O)R bb , -(CH2) n1 C(O)OR bb , -(CH2) n1 S(O) m1 R bb , -(CH2) n1 NR bb R cc , -(CH2) n1 C(O)NR bb R cc , -(CH2) n1 NR bb C(O)R cc or -(CH2) n1 NR bb S(O) m1 R cc and optionally substituted by one or more substituents selected from 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; Rings A, Q, Y, Z, R bb , R cc , R dd , R ee , R x , R y , n, p, q, m1 and n1 are as defined in general formula (I).

[0013] In one preferred embodiment of the present invention, there is provided a compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound is represented by the general formula (III). [ka] (where, R5, R6 and R 14 are each independently hydrogen, deuterium, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a mercapto group, a nitro group, a hydroxy group, a cyano group, an enyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -(CH2) n1 -, -(CH2) n1 R bb , -(CH2) n1 OR bb , -(CH2) n1 SR bb , -(CH2) n1 C(O)R bb , -(CH2) n1 C(O)OR bb , -(CH2) n1 S(O) m1 R bb , -(CH2) n1 NR bb R cc , -(CH2) n1 C(O)NR bb R cc , -(CH2) n1 NR bb C(O)R cc or -(CH2) n1 NR bb S(O) m1 R ccwherein the alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally further substituted with one or more substituents selected from deuterium, alkyl, haloalkyl, halogen, amino, mercapto, oxo, nitro, cyano, hydroxy, enyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; or R5 and R6 are linked to form a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group can further be selected from the group consisting of deuterium, alkyl group, haloalkyl group, halogen, amino group, oxo group, nitro group, cyano group, hydroxy group, enyl group, alkynyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, -(CH2) n1 -, -(CH2) n1 R bb , -(CH2) n1 OR bb , -(CH2) n1 SR bb , -(CH2) n1 C(O)R bb , -(CH2) n1 C(O)OR bb , -(CH2) n1 S(O) m1 R bb , -(CH2) n1 NR bb R cc , -(CH2) n1 C(O)NR bb R cc , -(CH2) n1 NR bb C(O)R cc and -(CH2) n1 NR bb S(O) m1 R ccand optionally substituted by one or more substituents selected from Q, Y, Z, R bb , R cc , R1, R2, R y , n, p, q, m1 and n1 are as defined in general formula (I). G, m, R3 and R4 are as defined in general formula (II-A).

[0014] In one preferred embodiment of the present invention, there is provided a compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound is represented by the general formula (IV). [ka] (where, R 13 is selected from hydrogen, deuterium, an alkyl group, a deuterated alkyl group, a halogen, a cyano group, a nitro group, a haloalkyl group, a hydroxy group, an amino group, an enyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group are further substituted with one or more substituents selected from deuterium, an alkyl group, a halogen, a hydroxy group, an amino group, an oxo group, a nitro group, a cyano group, an enyl group, an alkynyl group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, and are preferably halogen, an amino group, a nitro group, a cyano group, an alkyl group, a haloalkyl group, or a cycloalkyl group; Ring B, Q, Z, G, R2~R4, R y , R z , m, n, q and t are as defined in general formula (III).

[0015] In one preferred embodiment of the present invention, there is provided a compound represented by the general formula (III), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound is represented by the general formula (III-A) or (III-B). [ka] (where, R7, R8, R 11 and R 12 are each independently hydrogen, deuterium, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a mercapto group, a nitro group, a hydroxy group, a cyano group, an enyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -(CH2) n1 -, -(CH2) n1 R bb , -(CH2) n1 OR bb , -(CH2) n1 SR bb , -(CH2) n1 C(O)R bb , -(CH2) n1 C(O)OR bb , -(CH2) n1 S(O) m1 R bb , -(CH2) n1 NR bb R cc , -(CH2) n1 C(O)NR bb R cc , -(CH2) n1 NR bb C(O)R cc and -(CH2) n1 NR bb S(O) m1 R cc wherein the alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally further substituted with one or more substituents selected from deuterium, alkyl, haloalkyl, halogen, amino, mercapto, oxo, nitro, cyano, hydroxy, enyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups; Or, the group R7, R8, R 11 and R 12any two of these are linked to form a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group are optionally further substituted by one or more substituents selected from deuterium, an alkyl group, a haloalkyl group, a halogen atom, an amino group, an oxo group, a nitro group, a cyano group, a hydroxy group, an enyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; R 9 and R 10 is represented by general formula (II), Q, Z, G, R2 to R6, R bb , R cc , R y , m, n, q, m1 and n1 are as defined in general formula (III), R 14 is represented by general formula (III-A).

[0016] In one preferred embodiment of the present invention, there is provided a compound represented by the general formula (III-A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound is represented by the general formula (V). [ka] (where, Ring B is represented by general formula (II-A), Q, Z, G, L, R2 to R8, R 11 , R 12 , R 14 , R z , m and t are as defined in general formula (III-A).

[0017] In one preferred embodiment of the present invention, there is provided a compound represented by the general formula (III-A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound is represented by the general formula (VI). [ka] (where, Ring B is represented by general formula (II-A), Q, Z, G, L, R2 to R6, R 14 , R y , R z , q, m, and t are as defined in general formula (III-A).

[0018] In one preferred embodiment of the present invention, in any of the compounds of general formula (II-A), (II-B), (IV), (V), and (VI), their stereoisomers, and pharmaceutically acceptable salts thereof, ring B is selected from the following groups: [ka]

[0019] In one preferred embodiment of the present invention, there is provided a compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound is represented by the general formula (VII). [ka] (where, R aa is selected from hydrogen, deuterium, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a hydroxyalkyl group, a haloalkoxy group, a halogen, a cyano group, a nitro group, a hydroxy group, an amino group, an enyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, hydroxyalkyl group, haloalkoxy group, enyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group may be further substituted with one or more substituents selected from deuterium, an alkyl group, a halogen, a hydroxy group, an amino group, an oxo group, a nitro group, a cyano group, an enyl group, an alkynyl group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; L, R2 to R8, R 11 , R12 , R 14 and m is as defined in general formula (V).

[0020] Preferably, the R aa , R2, R5~R8, R 11 , R 12 , and R 14 are not simultaneously hydrogen, R3 and R4 are as shown in general formula (VII).

[0021] More preferably, the R aa , R2, R5-R8, R 11 , R 12 , and R 14 are simultaneously hydrogen, any two of the groups R, R, and R may be linked to form a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group may further be selected from the group consisting of deuterium, alkyl group, haloalkyl group, halogen, amino group, oxo group, nitro group, cyano group, hydroxy group, enyl group, alkynyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, -(CH) n1 -, -(CH2) n1 R bb , -(CH2) n1 OR bb , -(CH2) n1 SR bb , -(CH2) n1 C(O)R bb , -(CH2) n1 C(O)OR bb , -(CH2) n1 S(O) m1 R bb , -(CH2) n1 NR bb R cc , -(CH2) n1 C(O)NR bb R cc , -(CH2) n1 NR bb C(O)R ccand -(CH2) n1 NR bb S(O) m1 R cc may be substituted with one or more substituents selected from:

[0022] In one preferred embodiment of the present invention, there is provided a compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound is represented by the general formula (VIII-A). [ka] (where, Ring B is selected from the following groups: [ka] R2 is hydrogen, C 1~6 Alkyl group or C 1~6 haloalkyl groups, R3 and R4 are each independently hydrogen, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkoxy group or -(CH2) n1 OR bb Selected from Or, R3 and R4 are linked to form C 3~8 forming a cycloalkyl group or a 3- to 8-membered heterocyclic group, preferably an oxatanyl group; or R2 and R3 or R2 and R4 are linked to form a 3- to 8-membered heterocyclic group, preferably a pyrrolidinyl group or an azetidinyl group; R5, R6 and R 14 are each independently hydrogen, halogen, cyano group, C 1~6 Alkyl group, C 1~6 Alkoxy group or C 1~6 haloalkyl groups, R aa is hydrogen, C 1~6 selected from alkyl groups, halogen groups, and cyano groups; R z is hydrogen, oxo group, C 1~6Alkyl group, C 1~6 Haloalkyl group or -(CH2) n1 R bb Selected from R bb is hydrogen, C 1~6 selected from an alkyl group, a halogen group, or a cyano group, and t is 0, 1, 2, or 3.

[0023] Preferably, The R2 is hydrogen, C 1~3 Alkyl group or C 1~3 haloalkyl groups, more preferably hydrogen, methyl, ethyl or propyl; R3 and R4 are each independently hydrogen, C 1~3 Alkyl group, C 1~3 Alkoxy group or C 1~3 Alkoxy-substituted C 1~3 an alkyl group, more preferably a hydrogen atom, a methyl group, an ethyl group, a propyl group, a methoxy group, an ethoxy group, CH3OCH2-, or CH3CH2OCH2-; Or, R3 and R4 are linked to form C 4~6 forming a cycloalkyl group or a 4- to 6-membered heterocyclic group, preferably a 4- to 6-membered heterocyclic group containing one oxygen or nitrogen atom, more preferably an oxatanyl group; R2 and R3, or R2 and R4, are linked to form a 3- to 8-membered heterocyclic group, preferably a 4- to 6-membered heterocyclic group containing nitrogen or oxygen (wherein the number of heteroatoms is 1 or 2), more preferably a tetrahydropyrrolyl group, a tetrahydrofuranyl group, a piperidinyl group, or an azetidinyl group; R5 and R6 each independently represent hydrogen, halogen, a cyano group, or C 1~3 Alkyl group, C 1~3 Alkoxy group or C 1~3 haloalkyl groups, preferably hydrogen; R 14 is selected from hydrogen or halogen, preferably hydrogen, fluorine or chlorine; R z is hydrogen, halogen, oxo group, C1~3 Alkyl group, halogen-substituted C 1~3 Alkyl group or -(CH2) n1 R bb Preferably, hydrogen, fluorine, chlorine, bromine, iodine, a cyano group, an acetonitrile group, a propionitrile group, or a fluorine-substituted C 1~3 an alkyl group, more preferably fluorine, a methyl group, an acetonitrile group, -CHF, -CFCH, or CHFCH-; R aa is selected from hydrogen or halogen, preferably hydrogen; R bb is selected from a cyano group, n1 is 0, 1, 2 or 3; t is 0, 1, 2 or 3.

[0024] The conditions are as follows: R aa is hydrogen and ring B is [ka] and R2, R4, R5, R6, R 14 , and R aa are both hydrogen, where R is not —CH(CH), a cyclopropyl group, or CH—CH—; R aa is hydrogen and ring B is [ka] and R2, R3, R5, R6, R 14 , and R aa are both hydrogen, then R4 is not —CH(CH3), a cyclopropyl group, or CH3CH2—; R aa is hydrogen and ring B is [ka] and R2, R4, R5, R6, R 14 , and R aaare both hydrogen, where R3 is not —CH3 or a cyclopropyl group; R aa is hydrogen and ring B is [ka] and R2, R3, R5, R6, R 14 , and R aa are both hydrogen, where R4 is not —CH3 or a cyclopropyl group; R aa is hydrogen and ring B is [ka] and R2, R4, R5, R6, R 14 , and R aa are both hydrogen, where R3 is not a cyclopropyl group or a cyclobutyl group, R aa is hydrogen and ring B is [ka] and R2, R3, R5, R6, R 14 , and R aa are both hydrogen, then R4 is not a cyclopropyl group or a cyclobutyl group.

[0025] In one preferred embodiment of the present invention, there is provided a compound represented by the general formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound is as represented by the general formula (VIII). [ka] (wherein ring B, R3, R5, R6, R 14 , R Z , R aa and t are as shown in general formula (III-A), R Z and t are as in general formula (V).

[0026] In a preferred embodiment, the ring B is [ka] Selected from R2 is hydrogen or C 1~6 alkyl group, preferably hydrogen or C 1~3 an alkyl group, more preferably a hydrogen atom, a methyl group, an ethyl group, or a propyl group; R3 is C 1~6 Alkyl group, C 1~6 Alkoxy or alkyl substituted C 1~6 Alkoxy groups, preferably C 1~3 Alkyl group, C 1~3 Alkoxy group or C 1~3 Alkoxy-substituted C 1~3 an alkyl group, more preferably a methyl group, an ethyl group, a propyl group, a methoxy group, an ethoxy group, CH3OCH2- or CH3CH2OCH2-; R5 or R6 are each independently selected from hydrogen or halogen, preferably hydrogen; R 14 is selected from hydrogen or halogen, preferably hydrogen, fluorine or chlorine; R z is hydrogen, halogen, nitrile group, C 1~6 Alkyl or halogen substituted C 1~6 alkyl group, preferably hydrogen, fluorine, chlorine, bromine, iodine, cyano group, acetonitrile group, propionitrile group or halogen-substituted C 1~3 An alkyl group is more preferably fluorine, a methyl group, an acetonitrile group, -CHF2, -CF2CH3 or CHF2CH2-.

[0027] In one preferred embodiment of the present invention, there is provided a compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound is as represented by the general formula (IX). [ka] (where, R 15 and R 16 are each independently hydrogen, C 1~6 Alkyl group, C 1~6 Haloalkyl group or -(CH2) n1 R bb Selected from R2~R4, R6, R 14 , R aa or R bb is represented by general formula (VIII-A).

[0028] Preferably, R2 is hydrogen or C 1~6 alkyl group, preferably hydrogen or C 1~3 an alkyl group, more preferably a hydrogen atom, a methyl group, an ethyl group, or a propyl group; R3 and R4 are each independently hydrogen, C 1~6 Alkyl group, C 1~6 Alkoxy or alkyl substituted C 1~6 alkoxy groups, preferably hydrogen, C 1~3 Alkyl group, C 1~3 Alkoxy group or C 1~3 Alkoxy-substituted C 1~3 an alkyl group, more preferably a hydrogen atom, a methyl group, an ethyl group, a propyl group, a methoxy group, an ethoxy group, CH3OCH2- or CH3CH2OCH2-; R3 and R4 are linked together to form C 4~6 forming a cycloalkyl group or a 4- to 6-membered heterocyclic group, preferably a 4- to 6-membered heterocyclic group containing one oxygen or nitrogen atom, more preferably an oxatanyl group; R2 and R3, or R2 and R4, are linked to form a 4- to 6-membered heterocyclic group, preferably a 4- to 6-membered heterocyclic group containing nitrogen or oxygen (wherein the number of heteroatoms is 1 or 2), more preferably a tetrahydropyrrolyl group, a tetrahydrofuranyl group, a piperidinyl group, or an azetidinyl group; R6 is selected from hydrogen or halogen, preferably hydrogen; R 14is selected from hydrogen or halogen, preferably hydrogen, fluorine or chlorine; R aa is selected from hydrogen or halogen, preferably hydrogen.

[0029] R 15 and R 16 are each independently hydrogen, halogen, a nitrile group, or C 1~6 Alkyl or halogen substituted C 1~6 alkyl group, preferably hydrogen, fluorine, chlorine, bromine, iodine, cyano group, acetonitrile group, propionitrile group or halogen-substituted C 1~3 It is preferably an alkyl group, more preferably hydrogen, fluorine, a methyl group, an acetonitrile group, -CHF2, -CF2CH3 or CHF2CH2-.

[0030] In one preferred embodiment of the present invention, there is provided a compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound is as represented by the general formula (X). [ka] (where, R 15 and R 16 are each independently hydrogen, C 1~6 Alkyl group, C 1~6 Haloalkyl group or -(CH2) n1 R bb Selected from R2~R4, R6, R 14 , R aa or R bb is represented by general formula (VIII-A).

[0031] Preferably, R2 is hydrogen or C 1~6 alkyl group, preferably hydrogen or C 1~3 an alkyl group, more preferably a hydrogen atom, a methyl group, an ethyl group, or a propyl group; R3 and R4 are each independently hydrogen, C 1~6Alkyl group, C 1~6 Alkoxy and alkyl substituted C 1~6 alkoxy groups, preferably hydrogen, C 1~3 Alkyl group, C 1~3 Alkoxy group or C 1~3 Alkoxy-substituted C 1~3 an alkyl group, more preferably a hydrogen atom, a methyl group, an ethyl group, a propyl group, a methoxy group, an ethoxy group, CH3OCH2- or CH3CH2OCH2-; R3 and R4 are linked together to form C 4~6 forming a cycloalkyl group or a 4- to 6-membered heterocyclic group, preferably a 4- to 6-membered heterocyclic group containing one oxygen or nitrogen atom, more preferably an oxatanyl group; R2 and R3, or R2 and R4, are linked to form a 4- to 6-membered heterocyclic group, preferably a 4- to 6-membered heterocyclic group containing nitrogen or oxygen (wherein the number of heteroatoms is 1 or 2), more preferably a tetrahydropyrrolyl group, a tetrahydrofuranyl group, a piperidinyl group, or an azetidinyl group; R3 and R4 are linked together to form C 4~6 forming a cycloalkyl group or a 4- to 6-membered heterocyclic group, preferably a 4- to 6-membered heterocyclic group containing one oxygen or nitrogen atom, more preferably an oxatanyl group; R6 is selected from hydrogen or halogen, preferably hydrogen; R 14 is selected from hydrogen or halogen, preferably hydrogen, fluorine or chlorine; R aa is selected from hydrogen or halogen, preferably hydrogen.

[0032] R 15 and R 16 are each independently hydrogen, halogen, a nitrile group, or C 1~6 Alkyl or halogen substituted C 1~6 alkyl group, preferably hydrogen, fluorine, chlorine, bromine, iodine, cyano group, acetonitrile group, propionitrile group or halogen-substituted C 1~3It is preferably an alkyl group, more preferably hydrogen, fluorine, a methyl group, an acetonitrile group, -CHF2, -CF2CH3 or CHF2CH2-.

[0033] In one preferred embodiment of the present invention, in any of the compounds of general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, wherein: R2 may be present or absent, and when present, may be hydrogen, a methoxy group, C 1~6 Alkyl group or C 1~6 haloalkyl groups, or R2 and R3 or R2 and R4 are linked to form a 3- to 8-membered heterocyclic group, preferably a pyrrolidinyl group or an azetidinyl group; R3 and R4 are each independently hydrogen, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 selected from an alkoxy group or a 3- to 8-membered heterocyclic group, or R3 and R4 are linked to form C 3~8 forming a cycloalkyl group or a 3- to 8-membered heterocyclic group, preferably an oxatanyl group; R5 and R6 are each independently hydrogen, halogen, cyano group, C 1~6 Alkyl group, C 1~6 Alkoxy group or C 1~6 haloalkyl groups, Or R5 and R6 are linked to form one C 3~8 forming a cycloalkyl group or a 3- to 8-membered heterocyclic group, preferably a cyclobutanyl group, a cyclopentanyl group, or a 1,3-dioxolanyl group; R 14 is hydrogen, halogen, cyano group, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkoxy group or C 3~8 cycloalkyl groups, R y is hydrogen, C 1~6 Alkyl groups, halogens, C 1~6 Alkoxy group, C 1~6 Haloalkyl groups and -(CH2) n1-, preferably hydrogen, C 1~3 Alkyl group or C 1~3 Haloalkyl groups, more preferably hydrogen, methyl groups or -(CH2) n1 - and R aa is hydrogen, halogen, cyano group, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkoxy group or C 3~8 It is selected from cycloalkyl groups.

[0034] In a preferred embodiment, R2 is hydrogen, C 1~3 Alkyl group, C 1~3 Hydroxy-substituted alkyl group or C 1~3 selected from haloalkyl groups, preferably a methyl group, an ethyl group, a propyl group, a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a halomethyl group, a haloethyl group, or a halopropyl group; R3 and R4 are each independently C 1~3 Alkyl group, C 1~3 Hydroxy-substituted alkyl groups, C 1~3 haloalkyl group or C 1~3 an alkoxy group, preferably a methyl group, an ethyl group, a propyl group, a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a halomethyl group, a haloethyl group, a halopropyl group, a methoxy group, an ethoxy group, or a propoxy group; R5 and R6 are each independently hydrogen, C 1~3 Alkyl group, C 1~3 Alkoxy group or C 1~3 selected from haloalkyl groups, preferably methyl, ethyl, propyl, halomethyl, haloethyl, halopropyl, methoxy, ethoxy, or propoxy; R 14 is hydrogen, C 1~3 Alkyl group, C 1~3 Alkoxy group or C 1~3selected from haloalkyl groups, preferably methyl, ethyl, propyl, halomethyl, haloethyl, halopropyl, methoxy, ethoxy, or propoxy; R y is hydrogen, a methyl group or -(CH2) n1 -Selected from R aa is a halogen, a cyano group, C 1~3 Alkyl group, C 1~3 Alkoxy group or C 1~3 It is selected from haloalkyl groups, and is preferably a methyl group, an ethyl group, a propyl group, a halomethyl group, a haloethyl group, a halopropyl group, a methoxy group, an ethoxy group or a propoxy group.

[0035] In one preferred embodiment of the present invention, in any of the compounds of general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, wherein R z is hydrogen, halogen, oxo group, thio group, C 1~6 Alkyl group, C 1~6 Alkoxy group, C 1~6 Haloalkyl group or -(CH2) n1 -, wherein said C 1~6 Alkyl group, C 1~6 Alkoxy groups, and C 1~6 Haloalkyl groups can further include hydrogen, halogen, oxo, thio, C 1~6 Alkyl group, C 1~6 Alkoxy groups, and C 1~6 It may be substituted by one or more substituents of haloalkyl groups, preferably halogen, C 1~6 Alkyl group, C 1~6 haloalkyl group or oxo group, more preferably halogen, C 1~3 Alkyl group, C 1~3 It is a haloalkyl group or an oxo group.

[0036] The present invention also relates to a method for preparing a compound represented by general formula (IV) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof, comprising the steps of: [ka] A step of reacting general formula (IV-1) with general formula (IV-2) to obtain a compound represented by general formula (IV) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof. (where, X is selected from halogens; Ring B, Q, Z, G, L, R2~R4, R y , R z , q, m, n, and t are as defined in general formula (IV).

[0037] The present invention also relates to a method for preparing a compound represented by general formula (VI) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof, comprising the steps of: [ka] A step of reacting general formula (VI-1) with general formula (IV-2) to obtain a compound represented by general formula (VI) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof. (where, X is selected from halogens; Ring B, Q, Z, G, L, R2~R6, R 14 , R y , R z , q, m, n, and t are as defined in general formula (VI).

[0038] The present invention also relates to a method for preparing a compound represented by general formula (IV) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof, comprising the steps of: [ka] (where, X is selected from halogens; Ring B, Q, Z, G, L, R2~R6, R y , R z , q, m, n, and t are as defined in general formula (VI).

[0039] The present invention also relates to a method for preparing a compound represented by general formula (VI) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof, comprising the steps of: [ka] (where, X1 and X2 are selected from halogens; Ring B, Q, Z, G, L, R2~R6, R y , R z , q, m, n, and t are as defined in general formula (VI).

[0040] The present invention also relates to a method for producing a compound represented by the above general formula (X) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof, which comprises the following steps: [ka] Reacting the compound of formula (IX) with Lawesson's reagent to obtain a compound of formula (IX-A) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof. (where, R2~R4, R6, R 14 ~R 16 and R aa is represented by general formula (IX).

[0041] The present invention also relates to a method for producing a compound represented by the above general formula (X) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof, which comprises the following steps: [ka] A step of reacting the compound represented by general formula (IX-A) with a transition metal complex and its ligand to obtain a compound represented by general formula (X) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof. (where, The transition metal complex and its ligand are preferably dichloro(p-cymene)ruthenium(II) dimer and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl; R2~R4, R6, R14 ~R 16 and R aa is represented by general formula (X).

[0042] The present invention further relates to pharmaceutical compositions, which comprise a therapeutically effective amount of any of the compounds of general formula (I) shown, its stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0043] The present invention further relates to the application of any of the compounds represented by the general formula (I), their stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions described above, in the manufacture of PI3K modulator pharmaceuticals, preferably, in the manufacture of PI3Kα inhibitor pharmaceuticals.

[0044] The present invention further relates to the application of the compound represented by general formula (I), its stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for treating cancer, bone disease, inflammatory disease, immune disease, nervous system disease, metabolic disease, respiratory disease, and heart disease, wherein the cancer is selected from 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.

[0045] The present invention further relates to the application of the compound represented by general formula (I), its stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicine for treating cancer, bone disease, inflammatory disease, immune disease, nervous system disease, metabolic disease, respiratory disease, and heart disease.

[0046] The present invention also relates to a method for preventing and / or treating cancer, which comprises administering to a patient a therapeutically effective amount of a compound represented by general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0047] The present invention also provides methods for treating conditions using the compounds or pharmaceutical compositions of the present invention, including, but not limited to, conditions associated with dysfunction of PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ kinases.

[0048] The present invention also relates to a method of treating a hyperproliferative disorder 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.

[0049] In some embodiments, the methods relate to the treatment of conditions such as cancer, bone diseases, inflammatory diseases, immune diseases, neurological diseases, metabolic diseases, respiratory diseases, and cardiac diseases.

[0050] In some embodiments, the methods relate to the treatment of cancer, such as acute myeloid leukemia, myelodysplastic syndromes (MDS), thymic 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, gastric cancer, stomach cancer, pancreatic cancer, bladder cancer, breast cancer, cervical cancer, head cancer, neck cancer, renal cancer, kidney cancer, liver cancer, ovarian cancer, prostate cancer, endometrial cancer, colorectal cancer, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, CNS cancer, PNS cancer, AIDS-related cancer (e.g., lymphoma and Kaposi's sarcoma), or virally induced cancer. In some embodiments, the method relates to the treatment of a non-cancerous hyperproliferative disorder, such as a disorder of the skin (e.g., psoriasis), restenosis, or benign hyperplasia of the prostate (e.g., benign prostatic hyperplasia (BPH)). In some embodiments, the cancer is melanoma or colorectal cancer.

[0051] The therapeutic methods provided herein comprise 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 inflammatory conditions, including autoimmune diseases, in a mammal. The method comprises administering to the mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof. Diseases associated with one or more types of ERK dysfunction include acute disseminated encephalomyelitis (ADEM), Addison's disease, antiphospholipid syndrome (APS), aplastic anemia, autoimmune hepatitis, celiac disease, Crohn's disease, diabetes mellitus (type 1), Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, lupus erythematosus, multiple sclerosis, myasthenia gravis, myoclonus syndrome (OMS), optic neuritis, Ord's thyroiditis, pemphigus, polyarthritis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis (also called "giant cell arteritis"), and warm autoimmune hemolytic anemia. These conditions include, but are not limited to, ticanemia, Wegener's granulomatosis, alopecia universalis, Chagas' disease, chronic fatigue syndrome, autonomic dysfunction, endometriosis, hidradenitis suppurativa, interstitial cystitis, neuromuscular rigidity, sarcoidosis, scleroderma, ulcerative colitis, vitiligo, and vulvodynia. Other conditions include bone resorption disorders and thrombosis. DETAILED DESCRIPTION OF THE INVENTION

[0052] Unless otherwise stated, terms used in the specification and claims have the following definitions.

[0053] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, s-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, Examples include 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 various branched isomers thereof.More preferred are lower alkyl groups containing 1 to 6 carbons, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, s-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, and when substituted, the substituent may be substituted on any available point of attachment, and the substituent is preferably one or more of the following groups, which are independently selected from alkyl, enyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester groups, and in the present invention are preferably methyl, ethyl, isopropyl, t-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl groups.

[0054] The term "alkylene group" refers to an alkyl group in which one hydrogen has been further substituted, for example, a "methylene group" refers to -CH-, an "ethylene group" refers to -(CH)-, a "propylene group" refers to -(CH)-, a "butylene group" refers to -(CH)-, etc. The term "enyl group" refers to an alkyl group as defined above consisting of at least two carbons and at least one carbon-carbon double bond, for example, an ethylene group, a 1-propylene group, a 2-propylene group, a 1-, 2-, or 3-butene group, etc. The enyl group may be substituted or unsubstituted, and if substituted, the substituents are preferably one or more of the following groups, independently selected from alkyl, enyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio groups.

[0055] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, where the cycloalkyl ring contains 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 groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl groups. Polycyclic cycloalkyl groups include spirocyclic, fused, and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl groups.

[0056] The term "spirocycloalkyl group" refers to a polycyclic group in which one carbon atom (called a spiro atom) is shared between 5- to 20-membered monocyclic rings, which may contain one or more double bonds, but in which none of the rings has a completely conjugated π-electron system. Preferably, it has 6 to 14 members, more preferably 7 to 10 members. Depending on the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified as monospirocycloalkyl groups, bispirocycloalkyl groups, or polyspirocycloalkyl groups, with monospirocycloalkyl groups and bispirocycloalkyl groups being preferred. More preferred are 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups include: [ka] Includes:

[0057] Also included are monospirocycloalkyl groups and spirocycloalkyl groups in which heterocycloalkyl groups share a spiro atom, non-limiting examples of which are: [ka] Includes:

[0058] The term "fused cycloalkyl group" refers to an all-carbon polycyclic group having 5 to 20 members, in which each ring in the system shares an adjacent pair of carbon atoms with another ring in the system, where one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. Preferably, it has 6 to 14 members, more preferably 7 to 10 members. Depending on the number of rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl group, preferably a bicyclic or tricyclic group, more preferably a 5-membered / 5-membered or 5-membered / 6-membered dicycloalkyl group. Non-limiting examples of fused cycloalkyl groups include: [ka] Includes:

[0059] The term "bridged cycloalkyl group" refers to an all-carbon polycyclic group having 5 to 20 members, in which any two rings share two carbon atoms that are not directly connected, and which may contain one or more double bonds, but in which no ring has a completely conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of rings, bridged cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, and are preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups are: [ka] Includes:

[0060] The cycloalkyl ring can be fused to an aryl group, a heteroaryl group, or a heterocycloalkyl ring, where the ring integrally connected to the parent structure is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthyl, and benzocycloheptyl groups. The cycloalkyl group can be substituted or unsubstituted, and if substituted, the substituents are preferably one or more of the following groups, independently selected from alkyl, enyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester groups.

[0061] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, which contains 3 to 20 ring atoms, wherein one or more of the ring atoms is nitrogen, oxygen, or S(O). m(where m is an integer of 0 to 2), with the proviso that the ring moiety -OO-, -OS-, or -SS- is not included, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms, more preferably 3 to 8 ring atoms, even more preferably 3 to 8 ring atoms, and most preferably 4 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include oxatanyl, pyrrolidinyl, pyrrolidone, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and pyranyl groups, and preferred are oxatanyl, pyrrolidinyl, pyrrolidone, tetrahydrofuranyl, pyrazolidinyl, morpholinyl, piperazinyl, and pyranyl groups. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups, which may be connected to other groups via a single bond or further cyclized to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups via any two or more atoms on the ring.

[0062] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between 3- to 20-membered monocyclic rings, where one or more ring atoms is nitrogen, oxygen, or S(O) m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. It is preferably 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of spiro atoms shared between rings, spiroheterocyclic groups can be classified as monospiroheterocyclic groups, dispiroheterocyclic groups, or polyspiroheterocyclic groups, with monospiroheterocyclic groups and dispiroheterocyclic groups being preferred. More preferred are 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocyclic groups. Non-limiting examples of spiroheterocyclic groups include: [ka] Includes:

[0063] The term "fused heterocyclic group" refers to a polycyclic heterocyclic group having 5 to 20 members, in which each ring in the system shares an adjacent pair of atoms with another ring in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated pi-electron system, and in which one or more ring atoms is nitrogen, oxygen, or S(O). m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of constituting rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, and is preferably a bicyclic or tricyclic, more preferably a 3-membered / 5-membered, 4-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups are: [ka] Includes:

[0064] The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly connected atoms, which may contain one or more double bonds, but no ring has a completely conjugated pi-electron system, and in which one or more ring atoms is nitrogen, oxygen, or S(O). m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of constituting rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, and is preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged heterocyclic groups are: [ka] Includes:

[0065] The heterocyclic group can be fused onto an aryl group, heteroaryl group, or cycloalkyl ring, where the ring integrally connected to the parent structure is a heterocyclic group, non-limiting examples of which include: [ka] Includes:

[0066] Heterocyclic groups may be substituted or unsubstituted, and if substituted, the substituents are preferably one or more of the following groups, independently selected from alkyl, enyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester groups.

[0067] The term "aryl group" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl groups. More preferably, it is a phenyl group. The aryl ring can be fused onto a heteroaryl, heterocyclic, or cycloalkyl ring, where the ring integrally connected to the parent structure is an aryl ring, non-limiting examples of which include: [ka] Includes:

[0068] The aryl group may be substituted or unsubstituted, and if substituted, the substituents are preferably one or more of the following groups, independently selected from alkyl, enyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester groups.

[0069] The term "heteroaryl group" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered, more preferably 5- or 6-membered, such as imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidine, thiadiazole, and pyrazinyl, preferably triazolyl, thienyl, imidazolyl, pyrazolyl, pyridyl, pyrimidine, and thiazolyl, more preferably triazolyl, pyrrolyl, thienyl, thiazolyl, pyridyl, and pyrimidine. The heteroaryl ring can be fused onto an aryl group, a heterocyclic group, or a cycloalkyl ring, where the ring integrally connected to the parent structure is a heteroaryl ring, non-limiting examples of which are: [ka] Includes:

[0070] Heteroaryl groups may be substituted or unsubstituted, and if substituted, the substituents are preferably one or more of the following groups, independently selected from alkyl, enyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester groups.

[0071] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), where alkyl is as defined above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy. Alkoxy groups can be substituted or unsubstituted, and if substituted, the substituents are preferably one or more of the following groups, independently selected from alkyl, enyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester.

[0072] "Haloalkyl group" refers to an alkyl group substituted with one or more halogens, where alkyl group is as defined above.

[0073] A "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.

[0074] "Hydroxyalkyl group" refers to an alkyl group substituted with a hydroxy group, where alkyl is as defined above.

[0075] The term "enyl group" refers to an alkenyl group, also known as an olefin group, which may be further substituted with other related groups, such as alkyl groups, enyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylic acid ester groups.

[0076] The term "alkynyl group" refers to (CH≡C-), which may be further substituted with other related groups such as alkyl, enyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester groups.

[0077] "Hydroxy group" refers to an -OH radical. "Halogen" refers to fluorine, chlorine, bromine or iodine. "Amino group" refers to -NH2. The term "cyano group" refers to -CN. "Nitro group" refers to -NO2. A "carboxyl group" refers to -C(O)OH. "THF" refers to tetrahydrofuran. "EtOAc" refers to ethyl acetate. "EA" is 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. "Et2O" refers to ethyl 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. "Pd2(dba)3" refers to tris(dibenzylideneacetone)dipalladium. "Dppf" refers to 1,1'-bis(diphenylphosphino)ferrocene. "HATU" refers to O-(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. "DCM" refers to dichloromethane; The various terms "X is selected from A, B, or C," "X is selected from A, B, and C," "X is A, B, or C," "X is A, B, and C," and the like all mean the same thing, i.e., that X can be any one or more of A, B, and C.

[0078] All hydrogen atoms described in the present invention may be substituted with their isotope, deuterium, and all hydrogen atoms in the compounds of the examples of the present invention may also be substituted with deuterium atoms.

[0079] "May" or "may" means that an event or circumstance described below may occur, but need not occur, and the description includes cases where the event or circumstance occurs and cases where it does not occur. For example, "a heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may be present, but is not necessarily present, and the description includes cases where the heterocyclic group is substituted by an alkyl group and cases where the heterocyclic group is not substituted by an alkyl group.

[0080] "Substituted" means that one or more hydrogen atoms in the group, preferably at most 5, more preferably 1 to 3 hydrogen atoms, are independently replaced by a corresponding number of substituents. Obviously, substituents are only present at these possible chemical positions, and those skilled in the art can determine (through experiment or theory) possible or impossible substitutions without much effort. For example, an amino group or a hydroxy group having a free hydrogen atom may be unstable when bonded to a carbon atom having an unsaturated (e.g., ethylenic) bond.

[0081] "Pharmaceutical composition" refers to a mixture of one or more of the compounds described herein or their physiologically / pharmaceutically acceptable salts or precursor drugs with other chemical components, and other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living body, which is advantageous for the absorption of the active ingredient and further biological activity. "Pharmaceutically acceptable salts thereof" refers to salts of the compounds of the present invention, which are safe and effective when used in the mammalian body and have the desired biological activity.

[0082] The present invention will be further described below in conjunction with examples, but these examples do not limit the scope of the present invention.

[0083] Example The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 nuclear magnetic spectrometer, with deuterated dimethyl sulfoxide (DMSO-d), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents and tetramethylsilane (TMS) as the internal standard. Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1200 Infinity Series mass spectrometer, and HPLC was performed using an Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm chromatography column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C18 150 x 4.6 mm chromatography column). Thin layer chromatography silica gel plates are Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plates, with TLC specifications of 0.15mm to 0.20mm and thin layer chromatography purified products specifications of 0.4mm to 0.5mm. Column chromatography generally uses 200-300 mesh Yantai Yellow Sea silica gel as the carrier. The starting materials in the embodiments of the present invention are known and can be purchased commercially or synthesized using methods known in the art. Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in an atmosphere of dry nitrogen or argon gas, the solvents are dry solvents, and the reaction temperatures are in °C. Intermediate 1 (S)-4-(Difluoromethyl)oxazolidin-2-one [ka] First Step: Preparation of (R)-3-benzyl-4-(hydroxymethyl)oxazolidin-2-one [ka] (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) and heated to 45 °C under nitrogen gas protection and stirred overnight. After cooling, 100 mL of saturated aqueous sodium bicarbonate was added and extracted with dichloromethane (100 mL × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the title compound (R)-3-benzyl-4-(hydroxymethyl)oxazolidin-2-one (4.14 g, 40%). MS m / z (ESI): 208.2 [M+H] + . Second step: Preparation of (S)-3-benzyl-4-(dihydroxymethyl)oxazolidin-2-one [ka] (R)-3-benzyl-4-(hydroxymethyl)oxazolidin-2-one (4.14 g, 20.0 mmol) and IBX (16.8 g, 60.0 mmol) were mixed in ethyl acetate (100 mL) and stirred at 85 °C for 3 h under nitrogen gas protection. After cooling, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give 4.46 g of crude (S)-3-benzyl-4-(dihydroxymethyl)oxazolidin-2-one, which was used directly in the next step. MS m / z (ESI): 224.2 [M+H] + . Third Step: Preparation of (S)-3-benzyl-4-(difluoromethyl)oxazolidin-2-one [ka] (S)-3-benzyl-4-(dihydroxymethyl)oxazolidin-2-one (4.46 g, 20.0 mmol) was dissolved in dichloromethane (100 mL). DAST (6.45 g, 40.0 mmol) was added dropwise to the reaction mixture in an ice bath under nitrogen gas protection. The mixture was allowed to warm to room temperature and react for 3 h. The reaction mixture was slowly added dropwise to a pre-cooled saturated aqueous sodium bicarbonate solution. Extraction was performed with dichloromethane (200 mL x 2). The organic phases were combined, concentrated under reduced pressure, and then subjected to column chromatography to obtain the title compound (S)-3-benzyl-4-(difluoromethyl)oxazolidin-2-one (1.82 g, 40% yield for two steps). MS m / z (ESI): 228.2 [M+H] + . Fourth Step: Preparation of (S)-4-(difluoromethyl)oxazolidin-2-one [ka] (S)-3-Benzyl-4-(difluoromethyl)oxazolidin-2-one (1.82 g, 8 mmol) was dissolved in ethanol (100 mL), Pd(OH)2 / C (300 mg) was added, and the mixture was stirred overnight at 70 °C under a hydrogen atmosphere. After cooling and filtration, the filtrate was concentrated under reduced pressure to give the title compound (S)-4-(difluoromethyl)oxazolidin-2-one (0.88 g, 80%). 1 H NMR (400 MHz, CDCl3) δ 4.05-4.18 (m, 1H), 4.39-4.45 (m, 1H), 4.54 (t, J = 9.3 Hz, 1H), 5.78 (td, J = 55.3, 4.7 Hz, 1H), 6.07 (s, 1H); MS m / z (ESI): 138.1 [M+H] + . Intermediate 2 9-Bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine First step: Preparation of 5-bromo-2-(1H-imidazol-2-yl)phenol [ka] To a solution of 4-bromo-2-hydroxybenzaldehyde (24.0 g, 119 mmol) in methanol (250 mL) was added an aqueous solution of glyoxal (40 wt.%, 87 g, 597 mmol), and then aqueous ammonia (28 wt.%, 121 g, 860 mmol) was slowly added dropwise under stirring in a water bath. The addition was continued for 30 minutes, and the temperature of the reaction mixture was controlled so as not to exceed 40° C. The mixture was then stirred at 35° C. for 2 days, cooled, and the organic solvent was removed under reduced pressure to obtain crude 5-bromo-2-(1H-imidazol-2-yl)phenol, which was used directly in the next step. MS m / z (ESI): 239.0 [M+H] + . Second Step: Preparation of 9-Bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine [ka] Crude 5-bromo-2-(1H-imidazol-2-yl)phenol (approximately 29 g, 119 mmol), cesium carbonate (158 g, 485 mmol), and 1,2-dibromoethane (42 mL, 485 mmol) were mixed in DMF (250 mL), stirred overnight at 85°C, cooled, and diluted with a large amount of ethyl acetate. The organic phase was washed several times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to give the title compound, 9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (12.5 g, two-step yield: 38%). MS m / z (ESI): 265.0 [M+H] + . Third Step: Preparation of 9-Bromo-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine [ka] NIS (29.8 g, 132 mmol) was added batchwise to a DMF solution (150 mL) of 9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (11.7 g, 44.1 mmol) at room temperature, followed by stirring at 60°C overnight. After cooling, water was added to precipitate a solid. After filtration, the solid was dissolved in ethyl acetate, washed successively with 1 M aqueous NaOH and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound, 9-bromo-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] + . Fourth Step: Preparation of 9-Bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine [ka] EtMgBr (1.0 M THF solution, 60.9 mL, 60.9 mmol) was slowly added dropwise to a THF solution (140 mL) of 9-bromo-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (21.0 g, 40.6 mmol) at -20 °C. After the addition was complete, the mixture was stirred at -15 °C for 3 hours. The mixture was slowly warmed to room temperature, and then saturated aqueous ammonium chloride solution was added dropwise. The mixture was stirred for 15 minutes and extracted multiple times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain the title compound, 9-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (12.5 g, 79% yield). MS m / z (ESI): 390.9 [M+H] + . Fifth Step: Preparation of (S)-3-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)oxazolidin-2-one [ka] 9-Bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (300 mg, 0.77 mmol), (S)-4-(difluoromethyl)oxazolidin-2-one (105 mg, 0.77 mmol), (1R,2R)-N 1 ,N 2

[0047] Dimethylcyclohexane-1,2-diamine (43 mg, 0.30 mmol), copper acetate (27 mg, 0.15 mmol), and cesium carbonate (489 mg, 1.5 mmol) were mixed in 2-methyltetrahydrofuran (6 mL). The reaction mixture was purged with nitrogen three times and incubated at 78 °C for 22 hours. The reaction mixture was cooled to room temperature, 15% aqueous ammonia was added, 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 the organic solvent was concentrated under reduced pressure. The mixture was then purified by column chromatography to give the title compound (S)-3-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)oxazolidin-2-one (186 mg, 61%). 1 H NMR (400 MHz, CDCl3) δ 4.35-4.41 (m, 2H), 4.44-4.52 (m, 2H), 4.53-4.55 (m, 1H), 4.73-4.76 (m, 1H), 4.89-4.91 (m, 1H), 6.62-6.71 (m, 1H), 7.19-7.28 (m, 2H), 7.30 (s, 1H), 8.21 (d, J = 8.6 Hz, 1H); MS m / z (ESI): 400.1 [M+H] + .

[0084] Example 1 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-6,7-dihydro-5H-benzo[b]imidazo[2,1-d][1,5]oxazocin-10-yl)amino)propionamide [ka] First Step: Preparation of 10-Bromo-6,7-dihydro-5H-benzo[b]imidazo[2,1-d][1,5]oxazocine [ka] 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) were mixed in N,N-dimethylformamide (20 mL) and stirred at room temperature for 1.5 hours. Water was added, the mixture was stirred for 5 minutes, and the mixture was extracted three times with EtOAc. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to 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-d6) 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] + . Second Step: Preparation of 10-bromo-2,3-diiodo-6,7-dihydro-5H-benzo[b]imidazo[2,1-d][1,5]oxazocine [ka] 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) were mixed in N,N-dimethylformamide (15 mL), purged with nitrogen gas three times, and stirred overnight at 80 °C. After cooling to room temperature, ice water was added to the reaction flask, stirred for 5 minutes, and extracted three times with EtOAc. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to afford the title compound, 10-bromo-2,3-diiodo-6,7-dihydro-5H-benzo[b]imidazo[2,1-d][1,5]oxazocine (720 mg, 34%). MS m / z (ESI): 530.8 [M+H] + . Third Step: Preparation of 10-bromo-2-iodo-6,7-dihydro-5H-benzo[b]imidazo[2,1-d][1,5]oxazocine [ka] 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), cooled to -20 ° C., purged with nitrogen gas three times, ethylmagnesium bromide (0.35 mL, 1.05 mmol) was added dropwise, and the mixture was reacted at -20 ° C. for 3 hours. The mixture was quenched by adding saturated ammonium chloride, extracted three times with EtOAc, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the title compound 10-bromo-2-iodo-6,7-dihydro-5H-benzo[b]imidazo[2,1-d][1,5]oxazocine (365 mg, 96%). 1 H NMR (400 MHz,DMSO-d6) 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]+ . Fourth Step: 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 [ka] 10-Bromo-2-iodo-6,7-dihydro-5H-benzo[b]imidazo[2,1-d][1,5]oxazocine (300 mg, 0.75 mmol), (S)-4-(difluoromethyl)oxazolidin-2-one (103 mg, 0.75 mmol), (1R,2R)-N 1 ,N 2 A mixture of 1,2-dimethylcyclohexane-1,2-diamine (43 mg, 0.30 mmol), cuprous iodide (29 mg, 0.15 mmol), and potassium carbonate (205 mg, 1.5 mmol) in 1,4-dioxane (6 mL) was mixed. The reaction mixture was purged with nitrogen gas three times and incubated at 100 °C for 5 h. The mixture was cooled to room temperature, and 15% aqueous ammonia was added. The mixture was stirred for 5 min and extracted three times with EtOAc. The combined organic phases were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by 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] + . Fifth Step: Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-6,7-dihydro-5H-benzo[b]imidazo[2,1-d][1,5]oxazocin-10-yl)amino)propionamide [ka] (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), cuprous iodide (9 mg, 0.048 mmol), and potassium phosphate (103 mg, 0.48 mmol) were mixed in dimethyl sulfoxide (5 mL), and the reaction system was purged with nitrogen gas. The mixture was purged three times, reacted at 100°C for 5 hours, cooled to room temperature, and then ammonium chloride (78 mg, 1.45 mmol) and triethylamine (367 mg, 3.63 mmol) were added and stirred for 5 minutes. O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (830 mg, 2.18 mmol) was added and stirred at room temperature for 2 hours. The mixture was filtered, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the title compound (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-6,7-dihydro-5H-benzo[b]imidazo[2,1-d][1,5]oxazocin-10-yl)amino)propionamide (34 mg, 34%). 1 H NMR (400 MHz, DMSO-d6) 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] + .

[0085] Examples 2 and 3 Preparation of (S)-2-(((S)-2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-6-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide and (S)-2-(((R)-2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-6-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] First Step: Preparation of 2-(5-bromo-2-fluorophenyl)-1H-imidazole [ka] 5-Bromo-2-fluorobenzaldehyde (5.0 g, 24.6 mmol) was dissolved in isopropanol / water (25 mL / 25 mL) at room temperature, ammonium acetate (17.6 g, 221.7 mmol) was added, and glyoxal (4.5 mL, 221.7 mmol) was added dropwise. The mixture was stirred overnight. After dilution with isopropanol, the reaction mixture was filtered and concentrated under reduced pressure. The concentrate was partitioned between dichloromethane and water. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography to afford the title compound, 2-(5-bromo-2-fluorophenyl)-1H-imidazole (3.3 g, 56%). 1 H NMR (400 MHz, DMSO-d6) 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] + . Second step: Preparation of 9-bromo-6-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine [ka] 2-(5-Bromo-2-fluorophenyl)-1H-imidazole (1.0 g, 4.2 mmol) was dissolved in N,N-dimethylformamide (5 mL). The reaction mixture was cooled in an ice-water bath, and sodium hydride (221 mg, 4.6 mmol) was added to the mixture. The mixture was stirred for 10 minutes, and then 1,2-propylene oxide (292 mg, 5.1 mmol) was added. The mixture was heated to 95°C and stirred for 6 hours. After cooling to room temperature, saturated aqueous ammonium chloride was added to the reaction flask, and the mixture was extracted three times with dichloromethane. The combined organic phases were then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain 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-d6) 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] + . Third Step: Preparation of 9-bromo-2,3-diiodo-6-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine [ka] The production method of 9-bromo-2,3-diiodo-6-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine was as described in Example 1. 1H NMR (400 MHz,DMSO-d6) 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] + . Fourth step: Preparation of 9-bromo-2-iodo-6-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine [ka] The production method of 9-bromo-2-iodo-6-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine was as described in Example 1. MS m / z (ESI): 404.9 [M+H] + . Fifth Step: Preparation of (4S)-3-(9-bromo-6-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)oxazolidin-2-one [ka] The production method of (4S)-3-(9-bromo-6-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)oxazolidin-2-one was as described in Example 1. MS m / z(ESI): 414.0 [M+H] + . Sixth Step: Preparation of (S)-2-(((S)-2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-6-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide and (S)-2-(((R)-2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-6-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] (S)-2-(((S)-2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-6-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide and (S)-2-(((R)-2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-6-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide were prepared by chiral resolution with reference to Example 1. The nuclear magnetic and mass spectrometric data of the mixed pair of epimers are as follows: 1 H NMR (400 MHz, DMSO-d6) 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] + .

[0086] Example 4 Preparation of (S)-2-(((R)-2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-(((R)-2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 2 and Example 3. 1 H NMR (400 MHz, CD3OD) 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] + .

[0087] Example 5 Preparation of (S)-2-(((S)-2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-(((S)-2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was described in accordance with Examples 2 and 3. 1 H NMR (400 MHz, CD3OD) 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] + .

[0088] Example 6 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-6,6-dimethyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-6,6-dimethyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Examples 2 and 3. 1H NMR (400 MHz, DMSO-d6) 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] + .

[0089] Example 7 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,5-dimethyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,5-dimethyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 2 and Example 3. MS m / z (ESI): 436.1 [M+H] + .

[0090] Example 8 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5H-spiro[benzo[f]imidazo[1,2-d][1,4]oxazepine-6,1'-cyclopropan]-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5H-spiro[benzo[f]imidazo[1,2-d][1,4]oxazepine-6,1′-cyclopropan]-9-yl)amino)propionamide was as described in Example 2 and Example 3. MS m / z (ESI): 434.1 [M+H] + .

[0091] Example 9 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-6H-spiro[benzo[f]imidazo[1,2-d][1,4]oxazepine-5,1'-cyclopropan]-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-6H-spiro[benzo[f]imidazo[1,2-d][1,4]oxazepine-5,1′-cyclopropan]-9-yl)amino)propionamide was as described in Example 2 and Example 3. MS m / z (ESI): 434.1 [M+H] + .

[0092] Example 10 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-3-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] First Step: Preparation of 9-Bromo-3-fluoro-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine [ka] At −78° C., 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 to a solution of LDA (1.28 mL, 2.56 mmol) in tetrahydrofuran (10 mL). After the addition was completed, the mixture was stirred at −78° C. for 30 minutes, and then a solution of N-fluorobenzenesulfonamide (806 mg, 2.56 mmol) in tetrahydrofuran (9 mL) was added dropwise, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with dichloromethane (100 mL × 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then subjected to column chromatography to obtain 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-d6) δ 4.31-4.34 (m, 2H), 4.43-4.48 (m, 2H), 7.19-7.34 (m, 2H), 8.17 (d, J = 8.6 Hz, 1H); MS m / z (ESI): 408.9 [M+H] + . Second Step: Preparation of (S)-3-(9-bromo-3-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)oxazolidin-2-one [ka] 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 2Dimethylcyclohexane-1,2-diamine (35 mg, 0.24 mmol), cuprous iodide (46 mg, 0.24 mmol), and potassium phosphate (155 mg, 0.73 mmol) were mixed in dimethyl sulfoxide (10 mL) and reacted at 130 °C for 3 hours. The reaction mixture was cooled to room temperature, 15% aqueous ammonia was added, stirred for 5 minutes, and extracted three times with EtOAc. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to give the title compound (S)-3-(9-bromo-3-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)oxazolidin-2-one (21 mg, 20%). 1 H NMR (400 MHz, CDCl3) δ 4.25-4.29 (m, 1H), 4.42-4.50 (m, 2H), 4.56-4.69 (m, 4H), 6.16-6.35 (m, 1H), 7.20-7.25 (m, 2H), 8.15 (d, J = 8.4Hz, 1H); MS m / z (ESI): 417.9 [M+H] + . Third Step: Preparation of (2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-3-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-L-alanine [ka] The production method of (2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-3-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-L-alanine was as described in Example 1. MS m / z (ESI): 427.1 [M+H] + . Fourth Step: Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-3-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-3-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. 1 H NMR (400 MHz, CDCl3) δ 1.55 (d, J = 7.0 Hz, 3H), 3.70-3.87 (m, 1H), 4.21 (d, J = 3.6 Hz, 2H), 4.43 (d, J = 5.2 Hz, 2H), 4.57-4.66 (m, 2H), 5.35 (s, 1H), 6.10-6.27 (m, 2H), 6.37-6.50 (m, 2H), 8.07 (d, J = 8.6 Hz, 1H). MS m / z (ESI): 426.1 [M+H] + .

[0093] Example 11 Preparation of (S)-1-(2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-3-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-formamide [ka] The production method of (S)-1-(2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-3-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-formamide was described in Example 10. MS m / z (ESI): 452.1 [M+H] + .

[0094] Example 12 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-3-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)oxo)propionamide [ka] The production method of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-3-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)oxo)propionamide was as described in Example 10. MS m / z (ESI): 427.1 [M+H] + .

[0095] Example 13 Preparation of (S)-2-((3-fluoro-2-((S)-2-carbonyl-4-(trifluoromethyl)oxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of S)-2-((3-fluoro-2-((S)-2-carbonyl-4-(trifluoromethyl)oxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 10. MS m / z (ESI): 444.1 [M+H] + .

[0096] Example 14 Preparation of (S)-2-((3-chloro-2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((3-chloro-2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 10. 1 H NMR (400 MHz, CD3OD) δ 1.46 (d, J = 7.0 Hz, 3H), 3.80-3.86 (m, 1H), 4.29-4.32 (m, 2H), 4.43-4.46 (m, 2H), 4.57-4.67 (m, 3H), 6.07-6.31 (m, 2H), 6.43-6.46 (m, 1H), 7.98 (d, J = 8.8 Hz, 1H); MS m / z (ESI): 442.1 [M+H] + .

[0097] Example 15 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] First step: Preparation of 5-bromo-2-(5-methyl-1H-imidazol-2-yl)phenol [ka] To a solution (100 mL) of 4-bromo-2-hydroxybenzaldehyde (5 g, 119 mmol) in methanol, an aqueous solution of pyruvaldehyde (40 wt. %, 80 mL) was added, followed by slow dropwise addition of aqueous ammonia (28 wt. %, 40 g) with stirring in a water bath. The addition was continued for 30 minutes, and the temperature of the solution was controlled so as not to exceed 40° C. The reaction mixture was then stirred at 75° C. for 2 hours, cooled to room temperature, and the solid precipitated and filtered to obtain 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] + . Second step: Preparation of 9-bromo-3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine [ka] 5-Bromo-2-(5-methyl-1H-imidazol-2-yl)phenol (2.5 g, 9.8 mmol), cesium carbonate (12.2 g, 37.5 mmol), and 1,2-dibromoethane (42.0 mL, 37.5 mmol) were mixed in DMF (30 mL) and stirred overnight at 85 °C. The reaction mixture was cooled to room temperature and diluted with a large amount of ethyl acetate. The organic phase was washed multiple times with saturated brine, then dried over sodium sulfate, concentrated, and subjected to column chromatography to give the title compound, 9-bromo-3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.92 g, 33%). 1 H NMR (400 MHz, CDCl3) δ 2.25 (s, 3H), 4.12-4.29 (m, 2H), 4.40-4.53 (m, 2H), 6.94 (s, 1H), 7.14-7.18 (m, 1H), 7.20-7.22 (m, 1H), 8.37 (d, J = 8.6 Hz, 1H); MS m / z (ESI): 279.1 [M+H] + . Third step: Preparation of 9-bromo-2-iodo-3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine [ka] The production method of 9-bromo-2-iodo-3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine was as described in Example 1. MS m / z (ESI): 404.9 [M+H ]+ . Fourth Step: Preparation of (S)-3-(9-bromo-3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)oxazolidin-2-one [ka] The production method of (S)-3-(9-bromo-3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)oxazolidin-2-one was as described in Example 1. MS m / z (ESI): 414.0 [M+H] + . Fifth Step: Preparation of (2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-L-alanine [ka] The production method of (2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-L-alanine was as described in Example 1. MS m / z (ESI): 423.1 [M+H] + . Sixth Step: Synthesis of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. 1 H NMR (400 MHz, CD3OD) δ 1.37 (d, J = 7.0 Hz, 3H), 2.08 (s, 3H), 3.68-3.75 (m, 1H), 4.18-4.24 (m, 2H), 4.32-4.35 (m, 2H), 4.45-4.61 (m, 3H), 6.10 (m, 2H), 6.34 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H). MS m / z (ESI): 422.2 [M+H] + .

[0098] Example 16 Preparation of (S)-1-(2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-formamide [ka] The production method of (S)-1-(2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-formamide was described in Example 15. MS m / z (ESI): 448.2 [M+H]+ .

[0099] Example 17 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)oxo)propionamide [ka] The production method of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)oxo)propionamide was as described in Example 15. MS m / z (ESI): 423.1 [M+H] + .

[0100] Example 18 Preparation of (S)-2-((3-methyl-2-((S)-2-carbonyl-4-(trifluoromethyl)oxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((3-methyl-2-((S)-2-carbonyl-4-(trifluoromethyl)oxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 15. MS m / z (ESI): 440.1 [M+H] + .

[0101] Example 19 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-3-(trifluoromethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-3-(trifluoromethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 15. MS m / z (ESI): 476.1 [M+H] + .

[0102] Example 20 Preparation of (S)-2-((3-cyano-2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((3-cyano-2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 15. MS m / z (ESI): 433.1 [M+H] + .

[0103] Example 21 Preparation of (S)-1-(3-cyano-2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-formamide [ka] The production method of (S)-1-(3-cyano-2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-formamide was described in Example 15. MS m / z (ESI): 459.2 [M+H] + .

[0104] Example 22 Preparation of (S)-2-((3-cyano-2-((S)-2-carbonyl-4-(trifluoromethyl)oxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((3-cyano-2-((S)-2-carbonyl-4-(trifluoromethyl)oxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 15. MS m / z (ESI): 451.1 [M+H] + .

[0105] Example 23 Preparation of (S)-2-((3-cyano-2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)oxo)propionamide [ka] The production method of (S)-2-((3-cyano-2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)oxo)propionamide was as described in Example 15. MS m / z (ESI): 434.1 [M+H] + .

[0106] Example 24 Preparation of (S)-2-((3-cyclopropyl-2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((3-cyclopropyl-2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 15. MS m / z (ESI): 448.2 [M+H] + .

[0107] Example 25 Preparation of (S)-2-((9-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydroimidazo[1,2-d]thieno[2,3-f][1,4]oxazepin-2-yl)amino)propionamide [ka] First step: Preparation of methyl 3-(cyanomethoxy)thiophene-2-carboxylate [ka] 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), heated to 60 °C, and reacted for 2 h. After cooling to room temperature, water (200 mL) was added to the reaction mixture, followed by extraction with EA (200 mL × 3). The combined organic phases were washed with saturated aqueous sodium chloride (200 mL × 3). The combined organic phases were concentrated under reduced pressure and subjected to column chromatography to afford the title compound, methyl 3-(cyanomethoxy)thiophene-2-carboxylate (1.58 g, 80%). Second Step: Preparation of 3,4-Dihydrothieno[2,3-f][1,4]oxazepin-5(2H)-one [ka] Methyl 3-(cyanomethoxy)thiophene-2-carboxylate (1.58 g, 8 mmol), Raney-Ni (400 mg), and aqueous ammonia (2 mL) were added to ethanol (100 mL) and the mixture was heated to reflux under a hydrogen atmosphere (50 psi) and reacted for 5 h. After cooling to room temperature and filtration, the filtrate was concentrated and 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] + . Third Step: Preparation of Methyl 2-(5-carbonyl-2,3-dihydrothieno[2,3-f][1,4]oxazepin-4(5H)-yl)acetate [ka] 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) were added to acetone (20 mL) and heated to reflux for 3 h. After cooling to room temperature, the reaction mixture was concentrated and partitioned between DCM and water. The organic phase was concentrated and purified by column chromatography to give the title compound, methyl 2-(5-carbonyl-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] + . Fourth Step: Preparation of 5,6-Dihydroimidazo[1,2-d]thieno[2,3-f][1,4]oxazepin-9(8H)-one [ka] Methyl 2-(5-carbonyl-2,3-dihydrothieno[2,3-f][1,4]oxazepin-4(5H)-yl)acetate (1.21 g, 5.02 mmol) and aqueous ammonia (5 mL) were added to t-amyl alcohol (25 mL), heated to 120 °C, and reacted for 5 h in a sealed tube. After cooling to room temperature, the reaction mixture was concentrated and partitioned between DCM and water. The organic phase was concentrated and then purified by 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] + . Fifth Step: Preparation of 9-Bromo-5,6-dihydroimidazo[1,2-d]thieno[2,3-f][1,4]oxazepine [ka] 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), and phosphorus oxybromide (2.15 g, 7.50 mmol) was added to the reaction mixture. The mixture was refluxed overnight. After cooling to room temperature, the pH was adjusted to neutral with saturated aqueous sodium bicarbonate, followed by extraction with DCM. The organic phase was concentrated and subjected to column chromatography to afford 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] + . Sixth Step: Preparation of (S)-4-(difluoromethyl)-3-(5,6-dihydroimidazo[1,2-d]thieno[2,3-f][1,4]oxazepin-9-yl)oxazolidin-2-one [ka] (S)-4-(Difluoromethyl)-3-(5,6-dihydroimidazo[1,2-d]thieno[2,3-f][1,4]oxazepin-9-yl)oxazolidin-2-one was prepared according to Example 21. MS m / z (ESI): 328.1 [M+H] + . Seventh Step: Preparation of (S)-4-(difluoromethyl)-3-(2-iodo-5,6-dihydroimidazo[1,2-d]thieno[2,3-f][1,4]oxazepin-9-yl)oxazolidin-2-one [ka] (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), and NIS (248 mg, 1.1 mmol) was added to the reaction mixture and allowed to react at room temperature overnight. The pH was adjusted to neutral with saturated aqueous sodium bicarbonate, extracted with DCM, and the organic phase was concentrated and then subjected to column chromatography to obtain 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] + . Eighth Step: Preparation of (S)-2-((9-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydroimidazo[1,2-d]thieno[2,3-f][1,4]oxazepin-2-yl)amino)propionamide [ka] (S)-2-((9-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydroimidazo[1,2-d]thieno[2,3-f][1,4]oxazepin-2-yl)amino)propionamide was prepared according to Example 1. MS m / z (ESI): 414.1 [M+H] + .

[0108] Example 26 Preparation of (S)-2-((9-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-3-fluoro-5,6-dihydroimidazo[1,2-d]thieno[2,3-f][1,4]oxazepin-2-yl)amino)propionamide [ka] (S)-2-((9-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-3-fluoro-5,6-dihydroimidazo[1,2-d]thieno[2,3-f][1,4]oxazepin-2-yl)amino)propionamide was prepared according to Example 25. MS m / z (ESI): 432.1 [M+H] + .

[0109] Example 27 Preparation of (S)-2-((9-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydroimidazo[1,2-d]thieno[2,3-f][1,4]oxazepin-2-yl)oxo)propionamide [ka] (S)-2-((9-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydroimidazo[1,2-d]thieno[2,3-f][1,4]oxazepin-2-yl)oxo)propionamide was prepared according to Example 25. MS m / z (ESI): 415.1 [M+H] + .

[0110] Example 28 Preparation of (S)-1-(9-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydroimidazo[1,2-d]thieno[2,3-f][1,4]oxazepin-2-yl)pyrrolidine-2-formamide [ka] (S)-1-(9-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydroimidazo[1,2-d]thieno[2,3-f][1,4]oxazepin-2-yl)pyrrolidine-2-formamide was prepared according to Example 25. MS m / z (ESI): 440.1 [M+H] + .

[0111] Example 29 Preparation of (S)-2-((9-((S)-2-carbonyl-4-(trifluoromethyl)oxazolidin-3-yl)-5,6-dihydroimidazo[1,2-d]thieno[2,3-f][1,4]oxazepin-2-yl)amino)propionamide [ka] (S)-2-((9-((S)-2-carbonyl-4-(trifluoromethyl)oxazolidin-3-yl)-5,6-dihydroimidazo[1,2-d]thieno[2,3-f][1,4]oxazepin-2-yl)amino)propionamide was prepared according to Example 25. MS m / z (ESI): 432.1 [M+H] + .

[0112] Example 30 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6,10,11-tetrahydrocyclobutadieno[5,6]benzo[1,2-f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] First Step: Preparation of 1-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)ethan-1-one [ka] AlCl3 (3.33 g, 25 mmol) was suspended in nitromethane (25 mL), and a solution of bicyclo[4.2.0]octa-1(6),2,4-triene (2.08 g, 20 mmol) and acetyl chloride (1.73 g, 22 mmol) in nitromethane (25 mL) was added dropwise under a N2 atmosphere in an ice bath. The mixture was allowed to warm to room temperature and react overnight. The reaction mixture was poured into 200 mL of ice water, extracted with DCM (200 mL x 2), and the combined organic phases were concentrated under reduced pressure. The title compound, 1-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)ethan-1-one (800 mg, 27%), was obtained by column chromatography. Second Step: Preparation of 1-(5-bromobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)ethan-1-one [ka] 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), and bromine (878.9 mg, 5.5 mmol) was added dropwise under a N atmosphere. The reaction mixture was then allowed to react for 3 hours at room temperature. The reaction mixture was concentrated and partitioned between DCM and saturated aqueous sodium bicarbonate. The organic phase was concentrated under reduced pressure and then subjected to column chromatography to obtain the title compound, 1-(5-bromobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)ethan-1-one (900 mg, 80%). Third Step: Preparation of 5-Bromobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl Acetic Acid Ester [ka] 1-(5-Bromobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)ethan-1-one (900 mg, 4 mmol) and m-CPBA (75%, 2.30 g, 10 mmol) were mixed in DCM (20 mL) and refluxed overnight under a N atmosphere. After cooling to room temperature, the insoluble material was filtered off, the reaction mixture was washed with saturated aqueous sodium bicarbonate, and the organic phase was concentrated under reduced pressure. Column chromatography afforded the title compound, 5-bromobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl acetate (723 mg, 75%). Fourth step: Preparation of 5-bromobicyclo[4.2.0]octa-1(6),2,4-trien-3-ol [ka] 5-Bromobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl acetate (723 mg, 3 mmol) was dissolved in methanol (20 mL), 5N aqueous sodium hydroxide (3 mL) was added, and the mixture was allowed to react overnight at room temperature. 50 mL of water was added, and the pH of the reaction mixture was adjusted to 5 with 1N hydrochloric acid. The mixture was extracted with DCM (50 mL x 2). The organic phases were combined, concentrated under reduced pressure, and then purified by column chromatography to obtain the title compound, 5-bromobicyclo[4.2.0]octa-1(6),2,4-trien-3-ol (567 mg, 95%). Fifth step: Preparation of 5-bromo-3-hydroxybicyclo[4.2.0]octa-1(6),2,4-triene-2-formaldehyde [ka] 5-Bromobicyclo[4.2.0]octa-1(6),2,4-trien-3-ol (567.2 mg, 2.85 mmol), magnesium chloride (407 mg, 4.28 mmol), and triethanolamine (1.15 g, 11.4 mmol) were added to acetonitrile (5 mL), heated to 40 °C, and reacted for 30 min. Paraformaldehyde (770 mg, 8.55 mmol) was added, and the mixture was reacted at 80 °C overnight. The mixture was cooled to room temperature, 50 mL of water was added, and the pH of the reaction mixture was adjusted to 5 with 4 N hydrochloric acid. The mixture was extracted with DCM (50 mL × 2). The organic phases were combined, concentrated under reduced pressure, and then subjected to column chromatography to obtain the title compound, 5-bromo-3-hydroxybicyclo[4.2.0]octa-1(6),2,4-trien-2-formaldehyde (517.6 mg, 80%). Sixth Step: Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6,10,11-tetrahydrocyclobutadieno[5,6]benzo[1,2-f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6,10,11-tetrahydrocyclobutadieno[5,6]benzo[1,2-f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was prepared according to Example 1. MS m / z (ESI): 434.2 [M+H] +.

[0113] Example 31 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6,10,11-tetrahydrocyclobutadieno[5,6]benzo[1,2-f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-methoxyacetamide [ka] (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6,10,11-tetrahydrocyclobutadieno[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] + .

[0114] Example 32 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6,11,12-tetrahydro-10H-imidazo[1,2-d]indeno[4,5-f][1,4]oxazepin-9-yl)amino)propionamide [ka] (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6,11,12-tetrahydro-10H-imidazo[1,2-d]indeno[4,5-f][1,4]oxazepin-9-yl)amino)propionamide was prepared according to Example 30. MS m / z (ESI): 448.1 [M+H] + .

[0115] Example 33 Preparation of (S)-2-((11-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-7,8-dihydro-[1,3]dioxazolo[4',5':5,6]benzo[1,2-f]imidazo[1,2-d][1,4]oxazepin-4-yl)amino)propionamide [ka] (S)-2-((11-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-7,8-dihydro-[1,3]dioxazolo[4',5':5,6]benzo[1,2-f]imidazo[1,2-d][1,4]oxazepin-4-yl)amino)propionamide was prepared according to Example 30. MS m / z (ESI): 452.1 [M+H] + .

[0116] Example 34 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]pyrazolo[1,5-d][1,4]oxazepin-9-yl)amino)propionamide [ka] First step: Preparation of 1-(4-bromo-2-methoxyphenyl)ethan-1-one [ka] 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) were mixed in DMF (60 mL) and stirred at room temperature for 3 hours. Water was added to precipitate a solid, which was then dried to give the title compound 1-(4-bromo-2-methoxyphenyl)ethan-1-one (5.3 g, 99%). Second step: Preparation of methyl 3-(4-bromo-2-methoxyphenyl)-3-carbonylpropionate [ka] Under nitrogen gas protection, dimethyl carbonate (2.76 mL, 32.7 mmol) was added to a suspension of NaH (1.75 g, 43.7 mmol) in THF (40 mL). The mixture was heated to 70 °C, and a THF solution (10 mL) of 1-(4-bromo-2-methoxyphenyl)ethan-1-one (2.50 g, 10.9 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at this temperature for 3 hours. After cooling, 1 M HCl solution was added to the mixture until the mixture became acidic, and the mixture was extracted multiple times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain the title compound, methyl 3-(4-bromo-2-methoxyphenyl)-3-carbonylpropionate (2.2 g, 70%). MS m / z (ESI): 227.0 [M+H] + . Third step: Preparation of 5-(4-bromo-2-methoxyphenyl)-1,2-dihydro-3H-pyrazol-3-one [ka] A solution of methyl 3-(4-bromo-2-methoxyphenyl)-3-carbonylpropionate (1.20 g, 4.18 mmol) in ethanol (50 mL) was added with hydrazine hydrate solution (80 wt.%, 3 mL) and stirred under reflux for 1 hour. After cooling, water was added to precipitate 600 mg of solid 5-(4-bromo-2-methoxyphenyl)-1,2-dihydro-3H-pyrazol-3-one. The filtrate was concentrated and subjected to column chromatography to obtain 400 mg of the title compound, 5-(4-bromo-2-methoxyphenyl)-1,2-dihydro-3H-pyrazol-3-one. The two fractions were combined to obtain the title compound (1.0 g, 89%). MS m / z (ESI): 269.0 [M+H] + . Fourth step: Preparation of 5-(4-bromo-2-hydroxyphenyl)-1,2-dihydro-3H-pyrazol-3-one [ka] 5-(4-Bromo-2-methoxyphenyl)-1,2-dihydro-3H-pyrazol-3-one (100 mg, 0.372 mmol) and a solution of BBr3 in DCM (1 M, 4 mL) were mixed and stirred at room temperature overnight. The organic solvent was removed under reduced pressure, and the crude product, 5-(4-bromo-2-hydroxyphenyl)-1,2-dihydro-3H-pyrazol-3-one, was used directly in the next step. MS m / z (ESI): 255.0 [M+H] + . Fifth Step: Preparation of 9-Bromo-5,6-dihydrobenzo[f]pyrazolo[1,5-d][1,4]oxazepin-2(3H)-one [ka] The crude product was dissolved in DMF (4 mL), and 1,2-dibromoethane (70 mg, 0.372 mmol) and potassium carbonate (515 mg, 3.72 mmol) were added in that order. The mixture was then stirred at 60° C. for 1 hour, at 75° C. for 1 hour, and at 90° C. for 1 hour. The mixture was cooled, diluted with ethyl acetate, washed several times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and 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, two-step yield: 42%). MS m / z (ESI): 281.0 [M+H] + . Sixth Step: Preparation of 9-Bromo-5,6-dihydrobenzo[f]pyrazolo[1,5-d][1,4]oxazepin-2-yl trifluoromesylate [ka] Trifluoromesylic 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) under ice-water bath, followed by stirring at room temperature for 2 hours. The organic solvent was removed under reduced pressure, and column chromatography was performed to obtain the title compound, 9-bromo-5,6-dihydrobenzo[f]pyrazolo[1,5-d][1,4]oxazepin-2-yl trifluoromesylate (42 mg, 71%). MS m / z (ESI): 412.9 [M+H] + . Seventh Step: Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]pyrazolo[1,5-d][1,4]oxazepin-9-yl)amino)propionamide [ka] (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]pyrazolo[1,5-d][1,4]oxazepin-9-yl)amino)propionamide was prepared according to Example 1. MS m / z (ESI): 408.1 [M+H] + .

[0117] Example 35 (S)-1-(2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]pyrazolo[1,5-d][1,4]oxazepin-9-yl)pyrrolidine-2-formamide [ka] The production method of (S)-1-(2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]pyrazolo[1,5-d][1,4]oxazepin-9-yl)pyrrolidine-2-formamide was described in Example 34. MS m / z (ESI): 434.2 [M+H] + .

[0118] Example 36 (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]pyrazolo[1,5-d][1,4]oxazepin-9-yl)oxo)propionamide [ka] The production method of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]pyrazolo[1,5-d][1,4]oxazepin-9-yl)oxo)propionamide was as described in Example 34. MS m / z (ESI): 409.1 [M+H] + .

[0119] Example 37 (S)-2-((2-((S)-2-carbonyl-4-(trifluoromethyl)oxazolidin-3-yl)-5,6-dihydrobenzo[f]pyrazolo[1,5-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((S)-2-carbonyl-4-(trifluoromethyl)oxazolidin-3-yl)-5,6-dihydrobenzo[f]pyrazolo[1,5-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 34. MS m / z (ESI): 426.1 [M+H] + .

[0120] Example 38 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-methylbutyramide [ka] The production method of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-methylbutyramide was as described in Example 1. 1 H NMR (400 MHz, CD3OD) δ 1.09 (t, J = 6.1 Hz, 6H), 2.13 (d, J = 7.0 Hz, 1H), 3.60 (d, J = 6.4 Hz, 1H), 4.38 (d, J = 19.3 Hz, 4H), 4.68-4.60 (m, 3H), 6.27 (s, 1H), 6.43-6.78 (m, 2H), 7.17 (s, 1H), 8.06 (d, J = 8.7 Hz, 1H); MS m / z (ESI): 436.1 [M+H] + .

[0121] Example 39 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-methoxyacetamide [ka] The production method of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-methoxyacetamide was as described in Example 1. MS m / z (ESI): 424.1 [M+H] + .

[0122] Example 40 Preparation of (R)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-fluoropropionamide [ka] The production method of (R)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-fluoropropionamide was as described in Example 1. MS m / z (ESI): 426.1 [M+H] + .

[0123] Example 41 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(oxetan-3-yl)acetamide [ka] The production method of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(oxetan-3-yl)acetamide was as described in Example 1. 1H NMR (400 MHz, CD3OD) δ 3.26-3.33 (m, 2H), 4.08 (d, J = 9.6 Hz, 1H), 4.22-4.25 (m, 2H), 4.29-4.31 (m, 2H), 4.40-4.50 (m, 5H), 4.61-4.69 (m, 1H), 6.18 (d, J = 2.2 Hz, 1H), 6.44-6.50 (m, 2H), 7.06 (s, 1H), 7.97 (d, J = 8.8 Hz, 1H); MS m / z (ESI): 450.1 [M+H] + .

[0124] Example 42 Preparation of (S)-2-((2-(4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-methylpropionamide [ka] The production method of (S)-2-((2-(4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-methylpropionamide was as described in Example 1. 1 H NMR (400 MHz, CD3OD) δ 1.50 (s, 6H), 4.31-4.36 (m, 2H), 4.38-4.43 (m, 2H), 4.61-4.65 (m, 2H), 4.95 (d, J = 10.6 Hz, 1H), 6.19 (d, J = 2.2 Hz, 1H), 6.64-6.81 (m, 2H), 7.17 (s, 1H), 8.05 (d, J = 8.8 Hz, 1H); MS m / z (ESI): 422.1 [M+H] + .

[0125] Example 43 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)(methyl)amino)propionamide [ka] The production method of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)(methyl)amino)propionamide was as described in Example 1. 1 H NMR (400 MHz, CD3OD): δ 1.40 (d, J = 6.8 Hz, 3H), 2.90 (s, 3H), 4.37-4.64 (m, 7H), 4.96 (m, 1H), 6.41 (s, 1H), 6.46-6.74 (m, 2H), 7.16 (s, 1H), 8.13 (d, J = 9.2 Hz, 1H); MS m / z (ESI): 422.1 [M+H] + .

[0126] Example 44 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanethioamide [ka] The production method of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanethioamide was as described in Example 1. MS m / z (ESI): 424.1 [M+H] + .

[0127] Example 45 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)thio)propionamide [ka] The production method of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)thio)propionamide was as described in Example 1. MS m / z (ESI): 425.1 [M+H] + .

[0128] Example 46 Preparation of (S)-3-((2-(4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)oxetane-3-formamide [ka] The production method of (S)-3-((2-(4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)oxetane-3-formamide was as described in Example 1. 1 H NMR (400 MHz, CD3OD) δ 4.35 (m, 4H), 4.63 (m, 4H), 4.90 (m, 1H), 5.10 (d, J = 8.0 Hz, 2H), 5.90 (s, 1H), 6.29 (d, J = 8.0 Hz, 1H), 6.59 (t, J = 56 Hz, 1H), 7.16 (s, 1H), 8.10 (d, J = 8.0 Hz, 1H); MS m / z (ESI): 436.1 [M+H] + .

[0129] 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 [ka] The production method 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 was as described in Example 1. 1 H NMR (400 MHz, CD3OD): 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] + .

[0130] Example 48 Preparation of (S)-1-(2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)azetidine-2-formamide [ka] The production method of (S)-1-(2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)azetidine-2-formamide was described in Example 1. 1 H NMR (400 MHz, CD3OD) δ 2.30-2.40 (m, 1H), 2.52-2.58 (m, 1H), 3.66-3.72 (m, 1H), 3.91-3.96 (m, 1H), 4.22-4.27 (m, 2H), 4.28-4.34 (m, 2H), 4.48-4.59 (m, 2H), 4.79-4.85 (m, 2H), 6.00 (d, J = 2.2 Hz, 1H), 6.20-6.22 (m, 1H), 6.37-6.65 (m, 1H), 7.08 (s, 1H), 8.06 (d, J = 8.7 Hz, 1H). MS m / z (ESI): 420.1 [M+H] + .

[0131] Example 49 Preparation of (S)-1-(2-(4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)azetidine-3-formamide [ka] The production method of (S)-1-(2-(4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)azetidine-3-formamide was described in Example 1. 1 H NMR (400 MHz, CD3OD) 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] + .

[0132] Example 50 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-thiooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((S)-4-(difluoromethyl)-2-thiooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. MS m / z (ESI): 424.1 [M+H] + .

[0133] Example 51 Preparation of (S)-2-((2-((R)-4-(difluoromethyl)-2-carbonylthiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] First Step: Preparation of (S)-3-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)oxazolidine-2-thione [ka] Lawesson's reagent (1.01 g, 2.5 mmol) was added to a toluene solution (10 mL) 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), and the mixture was heated at 140 ° C. for 3 hours using a microwave. After cooling to room temperature, the mixture was filtered, the filter cake was washed with EtOAc (20 mL), the filtrate was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the title compound (S)-3-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)oxazolidine-2-thione (42 mg, 40%). 1 H NMR (400 MHz, DMSO-d6) δ 4.43-4.52 (m, 4H), 4.79-4.86 (m, 2H), 5.24-5.35 (m, 1H), 6.57-6.85 (m, 1H), 7.23-7.38 (m, 2H), 8.10 (s, 1H), 8.26 (d, J = 8.6 Hz, 1H); MS m / z (ESI): 416.1 [M+H] + . Second Step: Preparation of (R)-3-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)thiazolidin-2-one [ka] Dichloro(p-cymene)ruthenium(II) dimer (14.7 mg, 0.024 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (9.7 mg, 0.024 mmol) were added to a toluene solution (1 mL) of (S)-3-(10-bromo-6,7-dihydro-5H-benzo[b]imidazo[2,1-d][1,5]oxazocin-2-yl)-4-(difluoromethyl)oxazolidine-2-thione (33 mg, 0.079 mmol), and the mixture was reacted at 110°C for 12 hours under an air atmosphere. The reaction was cooled to room temperature, diluted with EtOAc, and the organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to afford the title compound (R)-3-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)thiazolidin-2-one (26 mg, 79%). 1 H NMR (400 MHz, CDCl3) δ 3.57-3.72 (m, 2H), 4.28-4.41 (m, 2H),4.44-4.47 (m, 2H) 5.14-5.24 (m, 1H), 6.29-6.67 (m, 1H), 7.14-7.25 (m, 2H), 7.42 (s, 1H), 8.21 (d, J = 8.8 Hz, 1H); MS m / z (ESI): 416.1 [M+H] + . Third Step: Preparation of (S)-2-((2-((R)-4-(difluoromethyl)-2-carbonylthiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] (R)-3-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)thiazolidin-2-one (26 mg, 0.062 mmol), L-alanine (19.5 mg, 0.22 mmol), cuprous iodide (6 mg, 0.03 mmol), and potassium phosphate (40 mg, 0.19 mmol) were mixed in dimethyl sulfoxide (3 mL), and the reaction system was purged with nitrogen gas three times. The mixture was heated at 100°C for 12 hours, cooled to room temperature, and then ammonium chloride (20 mg, 0.37 mmol) and triethylamine (95 mg, 0.94 mmol) were added. The mixture was stirred for 5 minutes. O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (212 mg, 0.56 mmol) was added. The mixture was stirred at room temperature for 2 hours, filtered, and saturated aqueous sodium bicarbonate was added. The mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography to give the title compound (S)-2-((2-((R)-4-(difluoromethyl)-2-carbonylthiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide (15 mg, 56%). 1 H NMR (400 MHz, CD3OD) δ 1.37 (d, J = 7.2 Hz, 3H), 3.57-3.61 (m, 1H), 3.83-3.87 (m, 2H), 4.33-4.41 (m, 4H), 5.12-5.19 (m, 1H), 6.15-6.17 (m, 1H), 6.47-6.52 (m, 2H), 7.28 (s, 1H), 8.10 (d, J = 8.8 Hz, 1H); MS m / z (ESI): 424.1 [M+H] + .

[0134] Example 52 Preparation of (S)-2-((2-((S)-5-(difluoromethyl)-2-carbonylimidazolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((S)-5-(difluoromethyl)-2-carbonylimidazolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 51. MS m / z (ESI): 407.2 [M+H] + .

[0135] Example 53 Preparation of (S)-2-((2-((S)-5-(difluoromethyl)-3-methyl-2-carbonylimidazolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((S)-5-(difluoromethyl)-3-methyl-2-carbonylimidazolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 51. 1 H NMR (400 MHz, CD3OD) δ 1.46 (d, J = 7.0 Hz, 3H), 2.85 (s, 3H), 3.62-3.68 (m, 2H), 3.79-3.85 (m, 1H), 4.27-4.30 (m, 2H), 4.35-4.37 (m, 2H), 4.63-4.69 (m, 1H), 6.17 (d, J = 2.0 Hz, 1H), 6.34-6.62 (m, 2H), 7.05 (s, 1H), 8.01 (d, J = 8.8 Hz, 1H); MS m / z (ESI): 421.2 [M+H] + .

[0136] Example 54 Preparation of (S)-2-((2-((4S,5R)-4-(difluoromethyl)-5-methyl-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] First step: Preparation of methyl (4S,5R)-5-methyl-2-carbonyloxazolidine-4-carboxylate [ka] Methyl L-threonine ester hydrochloride (500 mg, 2.95 mmol) was dissolved in dichloromethane (15 mL), the mixture was cooled to 0°C in an ice-water bath, triphosgene (289 mg, 0.97 mmol) was added, and a solution of triethylamine (895 mg, 8.84 mmol) in dichloromethane (2 mL) was added dropwise. After the addition was completed, the mixture was reacted at 0°C for 1 hour, water was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the title compound, methyl (4S,5R)-5-methyl-2-carbonyloxazolidine-4-carboxylate (251 mg, 53%). MS m / z (ESI): 160.1 [M+H] + . Second step: Preparation of methyl (4S,5R)-3-benzyl-5-methyl-2-carbonyloxazolidine-4-carboxylate [ka] Methyl (4S,5R)-5-methyl-2-carbonyloxazolidine-4-carboxylate (200 mg, 1.26 mmol) was dissolved in DMF (5 mL), cooled to -15°C, NaH (60% in kerosene, 50 mg, 1.26 mmol) was added, and the mixture was stirred at this temperature for 1 hour. Benzyl bromide (322 mg, 1.89 mmol) was added, and the mixture was stirred for 2 hours. Water was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound, methyl (4S,5R)-3-benzyl-5-methyl-2-carbonyloxazolidine-4-carboxylate (260 mg, 83%). MS m / z (ESI): 250.1 [M+H] + . Third step: Preparation of (4R,5R)-3-benzyl-4-(hydroxymethyl)-5-methyloxazolidin-2-one [ka] (4S,5R)-3-benzyl-5-methyl-2-carbonyloxazolidine-4-carboxylic acid ester (260 mg, 1.0 mmol) was dissolved in methanol (5 mL), cooled to 0°C in an ice-water bath, sodium borohydride (11 mg, 3.1 mmol) was added batchwise, and the mixture was gradually warmed to room temperature and reacted for 2 hours. The reaction solution was concentrated, and the crude product was purified by column chromatography to obtain the title compound (4R,5R)-3-benzyl-4-(hydroxymethyl)-5-methyloxazolidin-2-one (180 mg, 78%). MS m / z (ESI): 222.1 [M+H] + . Fourth step: Preparation of (4S,5R)-3-benzyl-5-methyl-2-carbonyloxazolidine-4-formaldehyde [ka] (4R,5R)-3-benzyl-4-(hydroxymethyl)-5-methyloxazolidin-2-one (180 mg, 0.81 mmol) and IBX (683 mg, 2.44 mmol) were mixed in ethyl acetate (10 mL) and reacted at 85°C for 3 hours under nitrogen gas protection. After cooling, the reaction mixture was filtered and concentrated under reduced pressure to give 178 mg of crude (4S,5R)-3-benzyl-5-methyl-2-carbonyloxazolidine-4-formaldehyde, which was used directly in the next step. MS m / z (ESI): 220.2 [M+H] + . Fifth Step: Preparation of (4S,5R)-3-benzyl-4-(difluoromethyl)-5-methyloxazolidin-2-one [ka] (4S,5R)-3-benzyl-5-methyl-2-carbonyloxazolidine-4-formaldehyde (178 mg, 0.81 mmol) was dissolved in dichloromethane (10 mL) and cooled to 0 °C in an ice-water bath under nitrogen gas protection. DAST (262 mg, 1.62 mmol) was added dropwise to the reaction mixture, which was then allowed to warm to room temperature and react for 3 h. The reaction mixture was slowly added dropwise to pre-cooled saturated aqueous sodium bicarbonate solution. Extraction was performed with dichloromethane (20 mL × 2), and the organic phases were combined and dried over anhydrous sodium sulfate. The organic solvent was concentrated under reduced pressure. The mixture was then purified by column chromatography to obtain the title compound (4S,5R)-3-benzyl-4-(difluoromethyl)-5-methyloxazolidin-2-one (110 mg, 56% yield for two steps). 1 H NMR (400 MHz, CDCl3) δ 1.33 (d, J = 6.4 Hz, 3H), 3.27-3.33 (m, 1H), 4.16-4.20 (m, 1H), 4.41-4.64 (m, 1H), 4.91 (d, J = 15.0 Hz, 1H), 5.56-5.88 (m, 1H), 7.27-7.44 (m, 5H); MS m / z (ESI): 242.1 [M+H] + . Sixth Step: Preparation of (4S,5R)-4-(difluoromethyl)-5-methyloxazolidin-2-one [ka] (4S,5R)-3-benzyl-4-(difluoromethyl)-5-methyloxazolidin-2-one (110 mg, 0.46 mmol) was dissolved in mesitylene (2 mL), mesylic acid (438 mg, 4.56 mmol) was added, and the mixture was heated to 135 °C and reacted for 5 hours. The reaction mixture was cooled to room temperature and slowly added dropwise to pre-cooled saturated aqueous sodium bicarbonate solution. Extraction was performed with dichloromethane (20 mL × 2), and the organic phases were combined and dried over anhydrous sodium sulfate. The organic solvent was concentrated under reduced pressure. The mixture was then separated by column chromatography to yield 68 mg of the title compound (4S,5R)-4-(difluoromethyl)-5-methyloxazolidin-2-one crude product, which was used directly in the next step. MS m / z (ESI): 152.1 [M+H] + . Seventh Step: 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 [ka] 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 2Dimethylcyclohexane-1,2-diamine (22 mg, 0.15 mmol), cuprous iodide (14 mg, 0.08 mmol), and potassium phosphate (108 mg, 0.51 mmol) were mixed in dimethyl sulfoxide (3 mL) and reacted at 130 °C for 3 hours. The reaction mixture was cooled to room temperature, and 15% aqueous ammonia (5 mL) was added. The mixture was stirred for 5 minutes and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure. Column chromatography afforded the title compound (S)-3-(9-bromo-3-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)oxazolidin-2-one (61 mg, 57%). MS m / z (ESI): 414.2 [M+H] + . Eighth Step: Preparation of (S)-2-((2-((4S,5R)-4-(difluoromethyl)-5-methyl-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] (4S,5R)-3-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)-5-methyloxazolidin-2-one (61 mg, 0.15 mmol), L-alanine (39 mg, 0.44 mmol), cuprous iodide (14 mg, 0.07 mmol), and potassium phosphate (94 mg, 0.44 mmol) were mixed in dimethyl sulfoxide (5 mL), and the reaction system was aerated with nitrogen gas. The mixture was purged three times with ammonium chloride (47 mg, 0.88 mmol) and triethylamine (223 mg, 2.21 mmol) and stirred for 5 minutes. O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (505 mg, 1.33 mmol) was added and stirred at room temperature for 2 hours. The mixture was filtered, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The organic solvent was concentrated under reduced pressure, and then separated by column chromatography to obtain the title compound (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-6,7-dihydro-5H-benzo[b]imidazo[2,1-d][1,5]oxazocin-10-yl)amino)propionamide (33 mg, 53%). 1 H NMR (400 MHz, CD3OD) δ 1.46 (d, J = 6.8 Hz, 3H), 1.53 (d, J = 6.2 Hz, 3H), 3.79-3.85 (m, 1H), 4.32-4.39 (m, 4H), 4.46-4.55 (m, 1H), 4.93-4.95 (m, 1H), 6.17 (s, 1H), 6.39-6.72 (m, 2H), 7.14 (s, 1H), 8.03 (d, J = 8.6 Hz, 1H); MS m / z (ESI): 422.1 [M+H] + .

[0137] Example 55 Preparation of (R)-2-((2-((4S,5R)-4-(difluoromethyl)-5-methyl-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (R)-2-((2-((4S,5R)-4-(difluoromethyl)-5-methyl-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was described in Example 54. MS m / z (ESI): 422.2 [M+H] + .

[0138] Example 56 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-5,5-dimethyl-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((S)-4-(difluoromethyl)-5,5-dimethyl-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 54. MS m / z (ESI): 436.2 [M+H] + .

[0139] Example 57 Preparation of (S)-2-((2-((S)-7-(difluoromethyl)-5-carbonyl-4-oxa-6-azaspira[2.4]heptan-6-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((S)-7-(difluoromethyl)-5-carbonyl-4-oxa-6-azaspira[2.4]heptan-6-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was described in Example 54. MS m / z (ESI): 434.2 [M+H] + .

[0140] Example 58 Preparation of (S)-2-((2-((S)-8-(difluoromethyl)-6-carbonyl-2,5-dioxa-7-azaspira[3.4]octan-7-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((S)-8-(difluoromethyl)-6-carbonyl-2,5-dioxa-7-azaspira[3.4]octan-7-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 54. MS m / z (ESI): 450.2 [M+H]+.

[0141] Example 59 Preparation of (S)-2-((2-(6-carbonyl-2,7-dioxa-5-azaspira[3.4]octan-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-(6-carbonyl-2,7-dioxa-5-azaspira[3.4]octan-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. 1 H NMR (400 MHz, CD3OD) 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] + .

[0142] Example 60 Preparation of (S)-2-((2-((R)-4-(methoxymethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((R)-4-(methoxymethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. 1H NMR (400 MHz, CD3OD) 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] + .

[0143] Example 61 Preparation of (2S)-2-((2-((5S)-5-(difluoromethyl)-3-carbonyl-2-oxa-4-azabicyclo[3.1.0]hexan-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (2S)-2-((2-((5S)-5-(difluoromethyl)-3-carbonyl-2-oxa-4-azabicyclo[3.1.0]hexan-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. MS m / z (ESI): 420.1 [M+H] + .

[0144] Example 62 Preparation of (S)-2-((2-((1R,5S)-6,6-difluoro-3-carbonyl-2-oxa-4-azabicyclo[3.1.0]hexan-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((1R,5S)-6,6-difluoro-3-carbonyl-2-oxa-4-azabicyclo[3.1.0]hexan-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. MS m / z (ESI): 406.1 [M+H]+.

[0145] Example 63 Preparation of (S)-2-((2-((S)-1,1-difluoro-5-carbonyl-6-oxa-4-azaspira[2.4]heptan-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((S)-1,1-difluoro-5-carbonyl-6-oxa-4-azaspira[2.4]heptan-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. MS m / z (ESI): 420.1 [M+H] + .

[0146] Example 64 Preparation of (S)-2-((2-((S)-5-(difluoromethyl)-3-methyl-2,4-dicarbonylimidazolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((S)-5-(difluoromethyl)-3-methyl-2,4-dicarbonylimidazolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. MS m / z (ESI): 435.2 [M+H] + .

[0147] Example 65 Preparation of methyl (9-(((S)-1-amino-1-carbonylpropan-2-yl)amino)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)((S)-2,2-difluorocyclopropyl)carbamate [ka] The production method of methyl (9-(((S)-1-amino-1-carbonylpropan-2-yl)amino)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)((S)-2,2-difluorocyclopropyl)carbamate was as described in Example 1. MS m / z (ESI): 422.2 [M+H]+.

[0148] Example 66 Preparation of (S)-2-((2-(5,5-difluoro-2-carbonyl-1,3-oxapiperidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-(5,5-difluoro-2-carbonyl-1,3-oxapiperidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. 1H NMR (400 MHz, CD3OD) 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] + .

[0149] Example 67 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyl-1,3-oxapiperidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] First step: Preparation of methyl((benzyloxy)carbonyl)-L-homoserine ester [ka] To a solution of ((benzyloxy)carbonyl)-L-homoserine (1.0 g, 3.95 mmol) in N,N-dimethylformamide (6 mL), potassium carbonate (545 mg, 3.95 mmol) and methyl iodide (617 mg, 4.35 mmol) were added in that order, and the mixture was stirred at room temperature overnight. The mixture was quenched with saturated sodium bicarbonate solution, extracted with EtOAc, and the organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the title compound, methyl ((benzyloxy)carbonyl)-L-homoserine ester (920 mg, 87%). MS m / z (ESI): 268.1 [M+H] + . Second step: Preparation of methyl L-homoserine ester [ka] Methyl ((benzyloxy)carbonyl)-L-homoserine ester (920 mg, 3.4 mmol) was dissolved in methanol (10 mL), Pd / C (50 mg) was added, and the mixture was stirred overnight at room temperature under hydrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound, methyl L-homoserine ester (288 mg, 64%) as a crude product. MS m / z (ESI): 134.1 [M+H] + . Third step: Preparation of methyl (S)-2-carbonyl-1,3-oxapiperidine-4-carboxylate [ka] Methyl L-homoserine ester (288 mg, 2.2 mmol) was dissolved in dichloromethane (15 mL) and cooled to an ice bath. Triphosgene (258 mg, 0.87 mmol) was added, and a solution of triethylamine (658 mg, 6.51 mmol) dissolved in dichloromethane (2 mL) was added dropwise. After the addition was completed, the mixture was reacted in an ice bath for 1 hour, water was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give pure methyl (S)-2-carbonyl-1,3-oxapiperidine-4-carboxylate (110 mg, 32%). MS m / z (ESI): 160.1 [M+H] + . Fourth step: Preparation of methyl (S)-3-benzyl-2-carbonyl-1,3-oxapiperidine-4-carboxylate [ka] Methyl (S)-2-carbonyl-1,3-oxapiperidine-4-carboxylate (110 mg, 0.7 mmol) was dissolved in tetrahydrofuran (12 mL), cooled to an ice bath, sodium hydride (42 mg, 1.06 mmol) was added, and the mixture was stirred for 10 min. Benzyl bromide (142 mg, 0.84 mmol) was added dropwise to a solution of tetrahydrofuran (2 mL). After the addition was complete, the mixture was gradually warmed to room temperature and reacted for 2 h. Saturated ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give pure methyl (S)-3-benzyl-2-carbonyl-1,3-oxapiperidine-4-carboxylate (100 mg, 57%). MS m / z (ESI): 250.1 [M+H] + . Fifth Step: Preparation of (S)-3-benzyl-4-(hydroxymethyl)-1,3-oxapiperidin-2-one [ka] (S)-3-benzyl-2-carbonyl-1,3-oxapiperidine-4-carboxylic acid ester (100 mg, 0.4 mmol) was dissolved in methanol (5 mL), cooled to an ice bath, and sodium borohydride (30 mg, 0.8 mmol) was added batchwise. The mixture was gradually warmed to room temperature and reacted for 2 hours. The reaction mixture was concentrated, and the crude product was purified by column chromatography to give pure (S)-3-benzyl-4-(hydroxymethyl)-1,3-oxapiperidin-2-one (70 mg, 79%). MS m / z (ESI): 222.1 [M+H] + . Sixth Step: Preparation of (S)-3-benzyl-2-carbonyl-1,3-oxapiperidine-4-formaldehyde [ka] (S)-3-Benzyl-4-(hydroxymethyl)-1,3-oxapiperidine-2-one (70 mg, 0.32 mmol) and IBX (269 mg, 0.96 mmol) were mixed in ethyl acetate (5 mL) and stirred at 85° C. under nitrogen gas protection for 3 hours. After cooling, the reaction mixture was filtered and concentrated under reduced pressure to give 68 mg of crude (S)-3-benzyl-2-carbonyl-1,3-oxapiperidine-4-formaldehyde, which was used directly in the next step. MS m / z (ESI): 220.1[M+H] + . Seventh Step: Preparation of (S)-3-benzyl-4-(difluoromethyl)-1,3-oxapiperidin-2-one [ka] (S)-3-Benzyl-2-carbonyl-1,3-oxapiperidine-4-formaldehyde (68 mg, 0.31 mmol) was dissolved in dichloromethane (5 mL). DAST (100 mg, 0.62 mmol) was added dropwise to the reaction mixture in an ice bath under nitrogen gas protection. The mixture was allowed to warm to room temperature and react for 3 hours. The reaction mixture was slowly added dropwise to a pre-cooled saturated aqueous sodium bicarbonate solution. Extraction was performed with dichloromethane (10 mL × 2), and the organic phases were combined and concentrated under reduced pressure. Column chromatography was performed to obtain the title compound (S)-3-benzyl-4-(difluoromethyl)-1,3-oxapiperidin-2-one (55 mg, 73%). MS m / z (ESI): 242.1 [M+H] + . Eighth Step: Preparation of (S)-4-(difluoromethyl)-1,3-oxapiperidin-2-one [ka] (S)-3-Benzyl-4-(difluoromethyl)-1,3-oxapiperidin-2-one (55 mg, 0.23 mmol) was dissolved in ethanol (5 mL), Pd(OH)2 / C (10 mg) was added, and the mixture was stirred overnight at 70 ° C. under a hydrogen atmosphere. After cooling, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (S)-4-(difluoromethyl)-1,3-oxapiperidin-2-one (28 mg, 81%). MS m / z (ESI): 152.1 [M+H] + . [ka] The subsequent preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyl-1,3-oxapiperidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was carried out in accordance with Example 1. MS m / z (ESI): 422.2 [M+H] + .

[0150] Example 68 Preparation of (S)-2-((2-((S)-3-(difluoromethyl)-5-carbonylmorpholino)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] First step: Preparation of (S)-2-(benzylamino)-3,3-difluoropropan-1-ol [ka] To a solution of (S)-3-benzyl-4-(difluoromethyl)oxazolidin-2-one (340 mg, 1.5 mmol) in methanol (5 mL) was added 5 mol / L aqueous sodium hydroxide (1.5 mL, 7.5 mmol) at room temperature. After the addition was complete, the mixture was heated to 55 °C and stirred at this temperature for 3 hours. After cooling, the organic solvent was concentrated under reduced pressure, water was added to the reaction flask, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure to obtain the crude title compound (S)-2-(benzylamino)-3,3-difluoropropan-1-ol, which was used directly in the next step. MS m / z (ESI): 202.1 [M+H] + . Second step: Preparation of (S)-N-benzyl-2-chloro-N-(1,1-difluoro-3-hydroxypropan-2-yl)acetamide [ka] 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) under ice bath conditions. After the addition was complete, the mixture was stirred at this temperature for 2 hours. The reaction was quenched by adding water to the reaction flask and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure to obtain the crude product, the title compound (S)-N-benzyl-2-chloro-N-(1,1-difluoro-3-hydroxypropan-2-yl)acetamide, which was used directly in the next step. MS m / z (ESI): 278.1 [M+H] + . Third Step: Preparation of (S)-4-benzyl-5-(difluoromethyl)morpholin-3-one [ka] 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) under ice bath conditions. After the addition was complete, the mixture was gradually warmed to room temperature and stirred for 3 hours. The reaction was quenched by adding saturated ammonium chloride solution to the reaction flask and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure. The resulting mixture was purified by column chromatography to yield the title compound (S)-4-benzyl-5-(difluoromethyl)morpholin-3-one (240 mg, 66%). MS m / z (ESI): 242.1 [M+H] + . Fourth Step: Preparation of (S)-5-(difluoromethyl)morpholin-3-one [ka] At room temperature, (S)-4-benzyl-5-(difluoromethyl)morpholin-3-one (240 mg, 1.0 mmol) was dissolved in a solution of 0.5 mL of methanesulfonic acid and 2.5 mL of mesitylene and reacted at 135 °C for 1.5 hours using a microwave. The mixture was concentrated, saturated aqueous sodium carbonate was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure to obtain the crude title compound (S)-5-(difluoromethyl)morpholin-3-one. MS m / z (ESI): 152.1 [M+H] + . Fifth Step: Preparation of (S)-4-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-5-(difluoromethyl)morpholin-3-one [ka] 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 A mixture of 1,2-dimethylcyclohexane-1,2-diamine (38 mg, 0.27 mmol), cuprous iodide (25 mg, 0.13 mmol), and potassium carbonate (183 mg, 1.32 mmol) in 1,4-dioxane (4 mL) was prepared. The reaction mixture was purged with nitrogen three times and incubated at 125 °C for 5 h. The mixture was cooled to room temperature, and 15% aqueous ammonia (5 mL) was added. The mixture was stirred for 5 min and extracted three times with EtOAc. The combined organic phases were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure. The title compound (S)-4-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-5-(difluoromethyl)morpholin-3-one (110 mg, 40%) was obtained by column chromatography. MS m / z (ESI): 414.0 [M+H] + . Sixth Step: Preparation of (S)-2-((2-((S)-3-(difluoromethyl)-5-carbonylmorpholino)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] (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), cuprous iodide (5 mg, 0.025 mmol), and potassium phosphate (51 mg, 0.24 mmol) were mixed in dimethyl sulfoxide (3 mL), and the air in the reaction system was replaced with nitrogen gas three times. The mixture was incubated at 105°C for 2.5 hours, cooled to room temperature, and then added with ammonium chloride (39 mg, 0.73 mmol) and triethylamine (183 mg, 1.82 mmol). The mixture was stirred for 5 minutes, and then added with O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (414 mg, 1.09 mmol). The mixture was stirred at room temperature for 2 hours, filtered, and then saturated aqueous sodium bicarbonate was added. The mixture was extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure. The resulting mixture was subjected to column chromatography to afford the title compound (S)-2-((2-((S)-3-(difluoromethyl)-5-carbonylmorpholino)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide (8.6 mg, 17%). 1 H NMR (400 MHz, CD3OD) δ1.37 (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] + .

[0151] Example 69 Preparation of (S)-2-((2-((S)-2-(difluoromethyl)-4-methyl-6-carbonylpiperazin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] First step: Preparation of (S)-2-(benzylamino)-3,3-difluoropropan-1-ol [ka] To a solution of (S)-3-benzyl-4-(difluoromethyl)oxazolidin-2-one (2.0 g, 8.8 mmol) in methanol (30 mL) was added 5 mol / L aqueous sodium hydroxide (8.8 mL, 44.0 mmol) at room temperature. After the addition was complete, the mixture was heated to 55 °C and stirred at this temperature for 3 hours. After cooling, the organic solvent was concentrated under reduced pressure, water was added to the reaction flask, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure to obtain the crude product, the title compound (S)-2-(benzylamino)-3,3-difluoropropan-1-ol, which was used directly in the next step. MS m / z (ESI): 202.1 [M+H] + . Second step: Preparation of (S)-N-benzyl-2-chloro-N-(1,1-difluoro-3-hydroxypropan-2-yl)acetamide [ka] A solution of chloroacetyl chloride (1.2 g, 10.6 mmol) in 5 mL of tetrahydrofuran 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) under ice-bath conditions. After the addition was complete, the mixture was stirred at this temperature for 2 hours. The reaction was quenched by adding water to the reaction flask and extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure to obtain the crude product, the title compound (S)-N-benzyl-2-chloro-N-(1,1-difluoro-3-hydroxypropan-2-yl)acetamide, which was used directly in the next step. MS m / z (ESI): 278.1 [M+H] + . Third Step: Preparation of (S)-N-benzyl-N-(1,1-difluoro-3-hydroxypropan-2-yl)-2-(methylamino)acetamide [ka] (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), reacted at room temperature for 1 hour, then heated to 60°C and reacted for 2 hours, concentrated, and purified by column chromatography to obtain pure (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] + . Fourth Step: Preparation of (S)-1-benzyl-6-(difluoromethyl)-4-methylpiperazin-2-one [ka] (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), reacted at room temperature overnight, concentrated, and purified by column chromatography to give pure (S)-1-benzyl-6-(difluoromethyl)-4-methylpiperazin-2-one (78 mg, 30%). MS m / z (ESI): 255.1 [M+H] + . Fifth Step: Preparation of (S)-6-(difluoromethyl)-4-methylpiperazin-2-one [ka] (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 and reacted at 150 °C for 1.5 hours using a microwave. The mixture was concentrated, saturated aqueous sodium carbonate was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure to obtain the crude title compound (S)-6-(difluoromethyl)-4-methylpiperazin-2-one. MS m / z (ESI): 152.1 [M+H] + . Sixth Step: Preparation of (S)-1-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-6-(difluoromethyl)-4-methylpiperazin-2-one [ka] 10-Bromo-2-iodo-6,7-dihydro-5H-benzo[b]imidazo[2,1-d][1,5]oxazocine (71 mg, 0.18 mmol), (S)-6-(difluoromethyl)-4-methylpiperazin-2-one (30 mg, 0.18 mmol), (1R,2R)-N 1 ,N 2 A mixture of 1,2-dimethylcyclohexane-1,2-diamine (7 mg, 0.04 mmol), cuprous iodide (10 mg, 0.07 mmol), and potassium carbonate (51 mg, 0.37 mmol) in 1,4-dioxane (4 mL) was prepared. The reaction mixture was purged with nitrogen three times and incubated at 125 °C for 5 hours. The mixture was cooled to room temperature, 15% aqueous ammonia was added, stirred for 5 minutes, and extracted three times with EtOAc. The combined organic phases were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure. The title compound (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, 82%) was obtained by column chromatography. MS m / z (ESI): 427.1 [M+H] + . Seventh Step: Preparation of (S)-2-((2-((S)-2-(difluoromethyl)-4-methyl-6-carbonylpiperazin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] (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), cuprous iodide (11 mg, 0.06 mmol), and potassium phosphate (191 mg, 0.9 mmol) were mixed in dimethyl sulfoxide (3 mL), and the air in the reaction system was replaced with nitrogen gas three times. The reaction was carried out at 105°C for 2 hours, cooled to room temperature, and ammonium chloride (49 mg, 0.9 mmol) and N,N-diisopropylethylamine (290 mg, 2.25 mmol) were added and stirred for 5 minutes. O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (513 mg, 1.35 mmol) was added and stirred at room temperature for 1 hour. The mixture was filtered, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure. The resulting mixture was subjected to column chromatography to obtain the title compound (S)-2-((2-((S)-2-(difluoromethyl)-4-methyl-6-carbonylpiperazin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide (4.6 mg, 7%). 1 H NMR (400 MHz, CD3OD) 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] + .

[0152] Example 70 Preparation of (S)-2-((2-((S)-2-(difluoromethyl)-6-carbonylpiperazin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((S)-2-(difluoromethyl)-6-carbonylpiperazin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 69. MS m / z (ESI): 421.2 [M+H] + .

[0153] Example 71 Preparation of (S)-2-((2-((S)-2-(difluoromethyl)-4-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((S)-2-(difluoromethyl)-4-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. MS m / z (ESI): 408.1 [M+H] + .

[0154] Example 72 Preparation of (S)-2-((2-((S)-4-(chlorodifluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((S)-4-(chlorodifluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. MS m / z (ESI): 442.1 [M+H] + .

[0155] Example 73 Preparation of (2S)-2-((2-((4S)-4-(difluoromethyl)-2-hydroxy-1,2,3-oxathiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (2S)-2-((2-((4S)-4-(difluoromethyl)-2-hydroxy-1,2,3-oxathiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. MS m / z (ESI): 428.1 [M+H] + .

[0156] Example 74 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2,2-dihydroxy-1,2,3-oxathiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((S)-4-(difluoromethyl)-2,2-dihydroxy-1,2,3-oxathiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. MS m / z (ESI): 444.1 [M+H] + .

[0157] Example 75 Preparation of (S)-2-((2-((S)-3-(difluoromethyl)-1,1-dihydroxyisothiazolidin-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((S)-3-(difluoromethyl)-1,1-dihydroxyisothiazolidin-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. MS m / z (ESI): 442.1 [M+H] + .

[0158] Example 76 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-N-hydroxypropionamide [ka] The production method of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-N-hydroxypropionamide was as described in Example 1. 1H NMR (400 MHz, CD3OD): 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] + .

[0159] Example 77 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] First step: Preparation of 4-bromo-3-fluoro-2-methoxybenzaldehyde [ka] 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, and the mixture was heated to 65°C and reacted for 2 hours. The mixture was concentrated and purified by column chromatography to give 4-bromo-3-fluoro-2-methoxybenzaldehyde (1.78 g, 85%). MS m / z (ESI): 233.0 [M+H] + . Second step: Preparation of 4-bromo-3-fluoro-2-hydroxybenzaldehyde [ka] At room temperature, 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), and the mixture was heated to 120°C and reacted for 16 hours. The reaction mixture was cooled and then concentrated under reduced pressure. Water and ethyl acetate were then added to the reaction flask to separate the layers, and the organic phase was dried over anhydrous sodium sulfate. The organic solvent was concentrated under reduced pressure, and the mixture was separated and purified by column chromatography to obtain 4-bromo-3-fluoro-2-hydroxybenzaldehyde (1.12 g, 67%). MS m / z (ESI): 219.0 [M+H] + . Third step: Preparation of 3-bromo-2-fluoro-6-(1H-imidazol-2-yl)phenol [ka] To a solution (12 mL) of 4-bromo-3-fluoro-2-hydroxybenzaldehyde (1.12 g, 5.14 mmol) in methanol, an aqueous solution of glyoxal (40 wt.%, 3.73 g, 25.7 mmol) was added, followed by slow dropwise addition of aqueous ammonia (28 wt.%, 5.14 g, 51.4 mmol) under stirring in a water bath. The addition was continued for 30 minutes, and the temperature of the reaction mixture was controlled so as not to exceed 40° C. The mixture was then stirred at 35° C. for 2 days, cooled, and the organic solvent was removed under reduced pressure. The mixture 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] + . Fourth Step: Preparation of 9-bromo-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine [ka] 3-Bromo-2-fluoro-6-(1H-imidazol-2-yl)phenol (1.31 g, 5.14 mmol), cesium carbonate (6.3 g, 19.53 mmol), and 1,2-dibromoethane (3.6 g, 19.12 mmol) were mixed in DMF (12 mL) and stirred overnight at 85 °C. The reaction mixture was cooled and diluted with ethyl acetate. The organic phase was washed several times with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound, 9-bromo-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (995 mg, 69%). MS m / z (ESI): 283.0 [M+H] + . Fifth Step: Preparation of 9-bromo-8-fluoro-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine [ka] NIS (2.23 g, 9.88 mmol) was added to a DMF solution (8 mL) of 9-bromo-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (995 mg, 3.53 mmol) at room temperature, followed by stirring at 60°C overnight. After cooling, water was added to precipitate a solid. After filtration, the solid was dissolved in ethyl acetate, washed successively with 1 M aqueous NaOH and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound, 9-bromo-8-fluoro-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (1.79 g, 94%). MS m / z (ESI): 534.7 [M+H] + . Sixth Step: Preparation of 9-bromo-8-fluoro-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine [ka] EtMgBr (1.0 M THF solution, 1.23 mL, 3.69 mmol) was slowly added dropwise to a THF solution (10 mL) 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) at -20°C. After the addition was complete, the mixture was stirred at -15°C for 3 hours. The mixture was slowly warmed to room temperature, and then saturated aqueous ammonium chloride solution was added dropwise. The mixture was stirred for 15 minutes and extracted multiple times with ethyl acetate. The organic phases were combined and washed with saturated brine, the organic phase was separated and dried over anhydrous sodium sulfate, the organic solvent was concentrated under reduced pressure, and the residue was separated by column chromatography to obtain 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] + . Seventh Step: Preparation of (S)-4-(difluoromethyl)-3-(8-fluoro-9-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)oxazolidin-2-one [ka] 9-Bromo-8-fluoro-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (300 mg, 0.74 mmol), (S)-4-(difluoromethyl)oxazolidin-2-one (102 mg, 0.74 mmol), (1R,2R)-N 1 ,N 2A mixture of 1,2-dimethylcyclohexane-1,2-diamine (42 mg, 0.30 mmol), cuprous iodide (28 mg, 0.15 mmol), and potassium carbonate (205 mg, 1.5 mmol) in 1,4-dioxane (6 mL) was mixed. The reaction mixture was purged with nitrogen gas three times and reacted at 105 °C for 5 hours. The mixture was cooled to room temperature, 15% aqueous ammonia was added, stirred for 5 minutes, and extracted three times with EtOAc. The combined organic phases were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the title compound (S)-4-(difluoromethyl)-3-(8-fluoro-9-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)oxazolidin-2-one (225 mg, 65%). MS m / z (ESI): 466.0 [M+H] + . The subsequent preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was carried out in accordance with Example 1. [ka] 1 H NMR (400 MHz, CD3OD) δ 1.50 (d, J = 7.0 Hz, 3H), 3.95-4.01 (m, 1H), 4.36 -4.41 (m, 2H), 4.47-4.53 (m, 2H), 4.57-4.67 (m, 2H), 4.93-4.98 (m, 1H), 6.37-6.42 (m, 1H), 6.44-6.73 (m, 1H), 7.20 (s, 1H),7.87-7.91 (m, 1H); MS m / z (ESI): 426.1 [M+H] + .

[0160] Example 78 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-11-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-11-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. 1 H NMR (400 MHz, CD3OD) δ 1.46 (d, J = 4.0 Hz, 3H), 3.84 (m, 1H), 4.24 (m, 2H), 4.49 (m, 2H), 4.60 (m, 3H), 6.19 (s, 1H), 6.28 (d, J = 8.0 Hz, 1H), 6.49 (t, J = 56 Hz, 1H), 7.30 (s, 1H); MS m / z (ESI): 426.1 [M+H] + .

[0161] Example 79 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-10-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-10-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. 1H NMR (400 MHz, CD3OD): δ 1.52 (d, J = 6.8 Hz, 3H), 3.86-3.96 (m, 1H), 4.30-4.42 (m, 4H), 4.60-4.69 (m, 3H), 4.91-5.00 (m, 1H), 6.19-6.25 (m, 1H), 6.46-6.76 (m, 1H), 7.18 (s, 1H), 8.04 (d, J = 13.4 Hz, 1H). MS m / z (ESI): 426.1 [M+H] + .

[0162] 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]oxazepin-2-yl)-4-(difluoromethyl)oxazolidin-2-one [ka] The production method of (S)-3-(9-(4-amino-5-methyl-1H-imidazol-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)oxazolidin-2-one was as described in Example 1. MS m / z (ESI): 417.1 [M+H] + .

[0163] Example 81 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-8-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-8-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. 1 H NMR (400 MHz, CD3OD) δ 1.51 (d, J = 6.9 Hz, 3H), 2.15 (s, 3H), 3.99-4.02 (m, 1H), 4.33-4.37 (m, 2H), 4.43-4.47 (m, 2H), 4.55-4.68 (m, 2H), 4.93-4.97 (m, 1H), 6.36 (d, J = 8.9 Hz, 1H), 6.43-6.71 (m, 1H), 7.19 (s, 1H),7.94 (d, J = 8.8 Hz, 1H); MS m / z (ESI): 422.1 [M+H] + .

[0164] Example 82 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-11-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-11-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. MS m / z (ESI): 422.1 [M+H] + .

[0165] Example 83 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-10-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-10-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. 1 H NMR (400 MHz, CD3OD): δ 1.52 (d, J = 6.9 Hz, 3H), 2.19 (s, 3H), 3.85-3.93 (m, 1H), 4.25-4.36 (m, 4H), 4.55-4.67 (m, 2H), 4.92-4.96 (m, 1H), 6.09 (s, 1H), 6.43-6.71 (m, 1H), 7.12 (s, 1H), 7.90 (s, 1H). MS m / z (ESI): 422.1 [M+H] + .

[0166] Example 84 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-8-methoxy-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-8-methoxy-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. MS m / z (ESI): 438.1 [M+H] +.

[0167] Example 85 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-11-methoxy-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-11-methoxy-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. MS m / z (ESI): 438.1 [M+H] + .

[0168] Example 86 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-10-methoxy-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-10-methoxy-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. MS m / z (ESI): 438.1 [M+H] + .

[0169] Example 87 Preparation of (S)-2-((8-cyano-2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((8-cyano-2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. MS m / z (ESI): 433.1 [M+H] + .

[0170] Example 88 Preparation of (S)-2-((11-cyano-2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((11-cyano-2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. MS m / z (ESI): 433.1 [M+H] + .

[0171] Example 89 Preparation of (S)-2-((10-cyano-2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((10-cyano-2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. MS m / z (ESI): 433.1 [M+H] + .

[0172] Example 90 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-methoxypropionamide [ka] The production method of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-methoxypropionamide was as described in Example 1. 1 H NMR (400 MHz, CD3OD) δ 3.39 (s, 3H), 3.67-3.76 (m, 2H), 3.94-3.98 (m, 1H), 4.30-4.34 (m, 2H), 4.37-4.41 (m, 2H), 4.57-4.66 (m, 2H), 4.91-4.96 (m, 1H), 6.21-6.25 (m, 1H), 6.43-6.46 (m, 1H), 6.48-6.73 (m, 1H), 7.15 (s, 1H), 8.06 (d, J = 8.8 Hz, 1H); MS m / z (ESI): 438.2 [M+H] + .

[0173] Example 91 Preparation of (2S,3R)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-methoxybutyramide [ka] The production method of (2S,3R)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-methoxybutyramide was the same as in Example 1. 1 H NMR (400 MHz, CD3OD): δ 1.23-1.27 (d, J = 6.9 Hz, 3H), 3.39 (s, 3H), 3.75-3.80 (m, 1H), 3.88-3.93 (m, 1H), 4.29-4.43 (m, 4H), 4.56-4.68 (m, 2H), 4.89-4.98 (m, 1H), 6.22-6.25 (m, 1H), 6.43-6.74 (m, 2H), 7.15 (s, 1H), 8.03-8.08 (d, J = 8.8 Hz, 1H); MS m / z (ESI): 452.2 [M+H] + .

[0174] Example 92 Preparation of (2S,3S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-methoxybutyramide [ka] The production method of (2S,3S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-methoxybutyramide was the same as in Example 1. MS m / z (ESI): 452.2 [M+H] + .

[0175] Example 93 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydroimidazo[1,2-d]pyrido[2,3-f][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydroimidazo[1,2-d]pyrido[2,3-f][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. MS m / z (ESI): 409.2 [M+H] + .

[0176] Example 94 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. MS m / z (ESI): 409.2 [M+H] + .

[0177] Example 95 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. MS m / z (ESI): 409.2 [M+H] + .

[0178] Example 96 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f][1,2,4]triazolo[1,5-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f][1,2,4]triazolo[1,5-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. MS m / z (ESI): 409.2 [M+H] + . Example 97 Preparation of (S)-2-((2-((S)-2-(difluoromethyl)-5-carbonylpyrrolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((S)-2-(difluoromethyl)-5-carbonylpyrrolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. 1 H NMR (400 MHz, DMSO-d6) δ 1.30 (d, J = 8.0 Hz, 3H), 2.20-2.45 (m, 3H), 3.31 (d, J = 8.0 Hz, 1H), 3.76 (t, J = 7.6 Hz, 1H), 4.32-4.36 (m, 4H), 4.69-4.78 (m, 1H), 6.08 (s, 1H), 6.15 (d, J = 8.0 Hz, 1H), 6.41 (d, J = 8.0 Hz, 1H), 6.66 (t, J = 56 Hz, 1H), 7.00 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.40 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H); MS m / z (ESI): 406.2 [M+H] + .

[0179] Example 98 Preparation of (S)-2-((2-((S)-7-(difluoromethyl)-2,5-dioxa-8-azaspira[3.4]octan-8-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((S)-7-(difluoromethyl)-2,5-dioxa-8-azaspira[3.4]octan-8-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. MS m / z (ESI): 436.2 [M+H] + .

[0180] 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)propionamide [ka] The production method 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)propionamide was as described in Example 1. MS m / z (ESI): 450.2 [M+H] + .

[0181] Example 100 Preparation of (S)—N-(9-((1-amino-1-carbonylpropan-2-yl)amino)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-N-(2,2-difluoroethyl)oxetane-3-formamide [ka] The production method of (S)—N-(9-((1-amino-1-carbonylpropan-2-yl)amino)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-N-(2,2-difluoroethyl)oxetane-3-formamide was described in Example 1. MS m / z (ESI): 436.2 [M+H] + . Example 101 Preparation of (S)-N-(9-(((S)-1-amino-1-carbonylpropan-2-yl)amino)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-N-(2,2-difluoroethyl)oxetane-2-formamide [ka] The production method of (S)—N-(9-(((S)-1-amino-1-carbonylpropan-2-yl)amino)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-N-(2,2-difluoroethyl)oxetane-2-formamide was described in Example 1. MS m / z (ESI): 436.2 [M+H] + .

[0182] Example 102 Preparation of (R)-N-(9-(((S)-1-amino-1-carbonylpropan-2-yl)amino)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-N-(2,2-difluoroethyl)oxetane-2-formamide [ka] The production method of (R)—N-(9-(((S)-1-amino-1-carbonylpropan-2-yl)amino)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-N-(2,2-difluoroethyl)oxetane-2-formamide was described in Example 1. MS m / z (ESI): 436.2 [M+H] + .

[0183] Example 103 Preparation of (S)-2-((2-(N-(2,2-difluoroethyl)-2-methoxyacetamido)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-(N-(2,2-difluoroethyl)-2-methoxyacetamido)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. MS m / z (ESI): 424.2 [M+H] + .

[0184] Example 104 Preparation of (S)-2-((2-((3S,5S)-5-(difluoromethyl)-3-methoxy-2-carbonylpyrrolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((3S,5S)-5-(difluoromethyl)-3-methoxy-2-carbonylpyrrolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. 1 H NMR (400 MHz, CD3OD) δ 1.46 (d, J = 7.0 Hz, 3H), 2.10-2.20 (m, 1H), 2.74-2.84 (m, 1H), 3.57 (s, 3H), 3.81 (q, J = 7.0 Hz, 1H), 4.25-4.40 (m, 5H), 4.71-4.84 (m, 1H), 6.13-6.18 (m, 1H), 6.37-6.70 (m, 2H), 7.38 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H); MS m / z (ESI): 436.2 [M+H] + .

[0185] Example 105 Preparation of (S)-2-((2-((3R,5S)-5-(difluoromethyl)-3-methoxy-2-carbonylpyrrolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((3R,5S)-5-(difluoromethyl)-3-methoxy-2-carbonylpyrrolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. MS m / z (ESI): 436.2 [M+H] + .

[0186] Example 106 Preparation of (1S,5R)-2-(2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-2-azabicyclo[3.1.0]hexane-1-formamide [ka] The production method of (1S,5R)-2-(2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-2-azabicyclo[3.1.0]hexane-1-formamide was described in Example 1. MS m / z (ESI): 446.2 [M+H] + .

[0187] Example 107 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-hydroxypropionamide [ka] The production method of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-hydroxypropionamide was as described in Example 1. 1 H NMR (400 MHz, CD3OD) δ 3.87 (s, 2H), 4.34 (d, J = 4.3 Hz, 2H), 4.37-4.43 (m, 2H), 4.62 (m, 4H), 6.23 (d, J = 2.6 Hz, 1H), 6.41-6.62 (m, 2H), 7.16 (s, 1H), 8.06 (d, J = 8.8 Hz, 1H); MS m / z (ESI): 424.1[M+H] + .

[0188] Example 108 Preparation of (S)-2-((2-((R)-4-(difluoromethyl)-2-carbonylthiazolidin-3-yl)-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] First step: Preparation of 4-bromo-3-fluoro-2-methoxybenzaldehyde [ka] 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, and the mixture was heated to 65°C and reacted for 2 hours. The mixture was concentrated and purified by column chromatography to give 4-bromo-3-fluoro-2-methoxybenzaldehyde (1.78 g, 85%). MS m / z (ESI): 233.0 [M+H] + . Second step: Preparation of 4-bromo-3-fluoro-2-hydroxybenzaldehyde [ka] At room temperature, 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), and the mixture was heated to 120°C and reacted for 16 hours. After cooling, the reaction mixture was concentrated under reduced pressure. Water and ethyl acetate were then added to the reaction flask and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure. The mixture was then separated and purified by column chromatography to obtain 4-bromo-3-fluoro-2-hydroxybenzaldehyde (1.12 g, 67%). MS m / z (ESI): 219.0 [M+H] + . Third step: Preparation of 3-bromo-2-fluoro-6-(1H-imidazol-2-yl)phenol [ka] To a solution (12 mL) of 4-bromo-3-fluoro-2-hydroxybenzaldehyde (1.12 g, 5.14 mmol) in methanol, an aqueous solution of glyoxal (40 wt.%, 3.73 g, 25.7 mmol) was added, followed by slow dropwise addition of aqueous ammonia (28 wt.%, 5.14 g, 51.4 mmol) under stirring in a water bath. The addition was continued for 30 minutes, and the temperature of the reaction mixture was controlled so as not to exceed 40° C. The mixture was then stirred at 35° C. for 2 days, cooled, and the organic solvent was removed under reduced pressure. The mixture 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] + . Fourth Step: Preparation of 9-bromo-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine [ka] 3-Bromo-2-fluoro-6-(1H-imidazol-2-yl)phenol (1.31 g, 5.14 mmol), cesium carbonate (6.3 g, 19.53 mmol), and 1,2-dibromoethane (3.6 g, 19.12 mmol) were mixed in DMF (12 mL) and stirred overnight at 85 °C. The reaction mixture was cooled and diluted with ethyl acetate. The organic phase was washed several times with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound, 9-bromo-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (995 mg, 69%). MS m / z (ESI): 283.0 [M+H] + . Fifth Step: Preparation of 9-bromo-8-fluoro-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine [ka] NIS (2.23 g, 9.88 mmol) was added to a DMF solution (8 mL) of 9-bromo-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (995 mg, 3.53 mmol) at room temperature, followed by stirring at 60°C overnight. After cooling, water was added to precipitate a solid. After filtration, the solid was dissolved in ethyl acetate, washed successively with 1 M aqueous NaOH and 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] + . Sixth Step: Preparation of 9-bromo-8-fluoro-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine [ka] EtMgBr (1.0 M THF solution, 1.23 mL, 3.69 mmol) was slowly added dropwise to a THF solution (10 mL) 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) at -20°C. After the addition was complete, the mixture was stirred at -15°C for 3 hours. The mixture was slowly warmed to room temperature, and then saturated aqueous ammonium chloride solution was added dropwise. The mixture was stirred for 15 minutes and extracted multiple times with ethyl acetate. The organic phases were combined and washed with saturated brine, the organic phase was separated and dried over anhydrous sodium sulfate, the organic solvent was concentrated under reduced pressure, and the residue was separated by column chromatography to obtain 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] + . Seventh Step: Preparation of (S)-4-(difluoromethyl)-3-(8-fluoro-9-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)oxazolidin-2-one [ka] 9-Bromo-8-fluoro-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (300 mg, 0.74 mmol), (S)-4-(difluoromethyl)oxazolidin-2-one (102 mg, 0.74 mmol), (1R,2R)-N 1 ,N 2A mixture of 1,2-dimethylcyclohexane-1,2-diamine (42 mg, 0.30 mmol), cuprous iodide (28 mg, 0.15 mmol), and potassium carbonate (205 mg, 1.5 mmol) in 1,4-dioxane (6 mL) was purged with nitrogen three times and reacted at 105 °C for 5 hours. The mixture was cooled to room temperature, and 15% aqueous ammonia was added. The mixture was stirred for 5 minutes and extracted three times with EtOAc. The combined organic phases were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the title compound (S)-4-(difluoromethyl)-3-(8-fluoro-9-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)oxazolidin-2-one (225 mg, 65%). MS m / z (ESI): 466.0 [M+H] + . Eighth Step: Preparation of (S)-4-(difluoromethyl)-3-(8-fluoro-9-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)oxazolidine-2-thione [ka] (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 a toluene solution (20 mL) Lawesson's reagent (1.92 g, 4.73 mmol) was added, and the mixture was heated to 145 ° C. and reacted for 6 hours. After cooling to room temperature, it was filtered, the filter cake was washed with EtOAc (20 mL), the filtrate was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the title compound (S)-3-(9-bromo-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)oxazolidine-2-thione (105 mg, 46%). MS m / z (ESI): 482.1[M+H] + . Ninth Step: Preparation of (R)-4-(difluoromethyl)-3-(8-fluoro-9-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)thiazolidin-2-one [ka] Dichloro(p-cymene)ruthenium(II) dimer (27 mg, 0.045 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (27 mg, 0.065 mmol) were added to a toluene solution (3 mL) of (S)-3-(9-bromo-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)oxazolidine-2-thione (105 mg, 0.22 mmol), and the mixture was allowed to react at 115°C for 16 hours under an air atmosphere. The reaction was cooled to room temperature, diluted with EtOAc, and the organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to afford the title compound (R)-4-(difluoromethyl)-3-(8-fluoro-9-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)thiazolidin-2-one (55 mg, 52%). MS m / z (ESI): 482.1 [M+H]+. Tenth Step: Preparation of (S)-2-((2-((R)-4-(difluoromethyl)-2-carbonylthiazolidin-3-yl)-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] (R)-4-(Difluoromethyl)-3-(8-fluoro-9-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)thiazolidin-2-one (40 mg, 0.083 mmol), L-alanine (15 mg, 0.17 mmol), cuprous iodide (6.3 mg, 0.033 mmol), and potassium phosphate (53 mg, 0.25 mmol) were mixed in dimethyl sulfoxide (3 mL), and the reaction system was evacuated with nitrogen gas. The atmosphere was replaced three times, and the mixture was reacted at 125°C for 1.5 hours. The mixture was then cooled to room temperature, and ammonium chloride (27 mg, 0.5 mmol) and DMAP (161 mg, 1.25 mmol) were added. The mixture was stirred for 5 minutes. O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (284 mg, 0.75 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was then filtered, and saturated aqueous sodium bicarbonate solution was added. The mixture was then extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the title compound (S)-2-((2-((R)-4-(difluoromethyl)-2-carbonylthiazolidin-3-yl)-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide (7.9 mg, 22%). 1 H NMR (400 MHz, CD3OD) δ 1.49 (d, J = 7.0 Hz, 3H), 3.54-3.60 (m, 1H),3.76-3.93 (m, 1H), 3.95-4.00 (m, 1H), 4.36-4.40 (m, 2H), 4.47-4.52 (m, 2H), 5.10-5.20 (m, 1H), 6.32-6.62 (m, 2H), 7.32 (s, 1H), 7.85-7.91 (m, 1H); MS m / z (ESI): 442.1 [M+H] + .

[0189] Example 109 Preparation of (S)-2-((2-((R)-4-(difluoromethyl)-2-carbonylthiazolidin-3-yl)-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-methoxypropionamide [ka] (S)-2-((2-((R)-4-(difluoromethyl)-2-carbonylthiazolidin-3-yl)-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-methoxypropionamide was prepared according to Example 108. 1 H NMR (400 MHz,CD3OD) δ 3.40 (s, 3H), 3.53-3.60 (m, 1H), 3.69-3.83 (m, 3H), 4.06-4.13 (m, 1H), 4.35-4.41 (m,2H), 4.47-4.52 (m, 2H), 5.10-5.21 (m, 1H), 6.30-6.60 (m, 2H), 7.32 (s, 1H), 7.89 (d, J = 8.5 Hz, 1H); MS m / z (ESI): 472.1 [M+H] + .

[0190] Example 110 Preparation of (S)-2-((2-((R)-4-(difluoromethyl)-2-carbonylthiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-methoxypropionamide [ka] First Step: Preparation of (S)-2-((2-((R)-4-(difluoromethyl)-2-carbonylthiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-methoxypropionamide [ka] (R)-3-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)thiazolidin-2-one (26 mg, 0.062 mmol), O-methyl-L-serine (22 mg, 0.18 mmol), cuprous iodide (6.0 mg, 0.03 mmol), and potassium phosphate (40 mg, 0.19 mmol) were mixed in dimethyl sulfoxide (3 mL), and the air in the reaction system was replaced with nitrogen gas three times. The mixture was reacted at 100°C for 12 hours, cooled to room temperature, and ammonium chloride (20 mg, 0.37 mmol) and triethylamine (95 mg, 0.94 mmol) were added. The mixture was stirred for 5 minutes, and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (212 mg, 0.56 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, and saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate three times. The organic phases were combined and dried over anhydrous sodium sulfate. The organic solvent was concentrated under reduced pressure, and then separated by column chromatography to obtain the title compound (S)-2-((2-((R)-4-(difluoromethyl)-2-carbonylthiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-methoxypropionamide (13 mg, 46%). 1 H NMR (400 MHz, CD3OD) δ 3.39 (s, 3H), 3.53-3.57 (m, 1H), 3.62-3.76 (m, 3H), 3.93-3.98 (m, 1H), 4.16-4.30 (m, 4H), 5.06-5.16 (m, 1H), 6.21-6.23 (m, 1H), 6.28-6.52 (m, 2H), 7.23 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H); MS m / z (ESI): 454.1 [M+H] + .

[0191] Example 111 Preparation of (S)-1-(2-((R)-4-(difluoromethyl)-2-carbonylthiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-formamide [ka] The production method of (S)-1-(2-((R)-4-(difluoromethyl)-2-carbonylthiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-formamide was described in Example 51. 1 H NMR (400 MHz, DMSO-d6) δ 1.83-1.92 (m, 2H), 2.09-2.15 (m, 1H), 3.72-3.81 (m, 4H), 4.25-4.32 (m, 4H), 5.07-5.15 (m, 1H), 5.93-5.97 (m, 1H), 6.22-6.28 (m, 1H), 6.35-6.65 (s, 1H), 7.00 (s, 1H), 7.26 (s, 1H), 7.35 (s, 1H), 7.99 (d, J = 8.6 Hz, 1H); MS m / z (ESI): 450.1 [M+H] + .

[0192] Example 112 Preparation of (S)-2-((2-((R)-4-(difluoromethyl)-2-carbonylthiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)(methyl)amino)propionamide [ka] The production method of (S)-2-((2-((R)-4-(difluoromethyl)-2-carbonylthiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)(methyl)amino)propionamide was as described in Example 51. 1 H NMR (400 MHz, CD3OD) δ 1.40 (d, J = 7.0 Hz, 3H), 2.90 (s, 3H), 3.53-3.58 (m, 1H), 3.75-3.80 (m, 1H), 4.30-4.44 (m, 4H), 4.46-4.51 (m, 1H), 5.08-5.18 (m, 1H), 6.22-6.41 (m, 2H), 6.51-6.73 (m, 1H),7.28 (s, 1H), 8.11 (d, J = 9.0 Hz, 1H); MS m / z (ESI): 438.1[M+H] + .

[0193] Example 113 Preparation of (S)-2-((2-((R)-5-(methoxymethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((R)-5-(methoxymethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. 1 H NMR (400 MHz, CD3OD) 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] + .

[0194] Example 114 Preparation of (S)-2-((2-((R)-4-methoxy-2-carbonylpyrrolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((R)-4-methoxy-2-carbonylpyrrolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. 1 H NMR (400 MHz, CDCl3) 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] + .

[0195] Example 115 Preparation of (2S)-2-((2-(4-(cyanomethyl)-2-carbonylpyrrolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (2S)-2-((2-(4-(cyanomethyl)-2-carbonylpyrrolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. 1 H NMR (400 MHz, DMSO-d6) 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] + .

[0196] Example 116 Preparation of (2S)-2-((2-(4-cyano-2-carbonylpyrrolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (2S)-2-((2-(4-cyano-2-carbonylpyrrolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. 1H NMR (400 MHz, CD3OD) 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] + .

[0197] Example 117 Preparation of (S)-2-((2-((S)-2-(cyanomethyl)-5-carbonylpyrrolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((S)-2-(cyanomethyl)-5-carbonylpyrrolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. 1H NMR (400 MHz, DMSO-d6) 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] + .

[0198] Example 118 Preparation of (S)-2-((2-((R)-4-(cyanomethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((R)-4-(cyanomethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. 1H NMR (400 MHz, DMSO-d6) 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] + .

[0199] Example 119 Preparation of (S)-2-((2-((R)-4-(cyanomethyl)-2-carbonylthiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] The production method of (S)-2-((2-((R)-4-(cyanomethyl)-2-carbonylthiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was as described in Example 1. MS m / z (ESI): 436.2 [M+H] + .

[0200] Example 120 Preparation of (S)-2-((2-((R)-4-(cyanomethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-methoxypropionamide [ka] The production method of (S)-2-((2-((R)-4-(cyanomethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-methoxypropionamide was as described in Example 1. 1 H NMR (400 MHz, DMSO-d6) 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] + .

[0201] Example 121 Preparation of (S)-2-((2-((R)-4-(2-methoxyethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] (S)-2-((2-((R)-4-(2-methoxyethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was prepared according to Example 1. MS m / z (ESI): 416.1 [M+H] + .

[0202] Example 122 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyl-1,3-thiapiperidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyl-1,3-thiapiperidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was prepared according to Example 51. MS m / z (ESI): 438.1 [M+H] + .

[0203] Example 123 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyl-1,3-thiapiperidin-3-yl)-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyl-1,3-thiapiperidin-3-yl)-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was prepared according to Example 51. MS m / z (ESI): 456.1 [M+H]+ .

[0204] Example 124 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyl-1,3-thiapiperidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-methoxypropionamide [ka] (S)-2-((2-((S)-4-(difluoromethyl)-2-carbonyl-1,3-thiapiperidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-methoxypropionamide was prepared according to Example 51. MS m / z (ESI): 468.1 [M+H] + .

[0205] Example 125 Preparation of (S)-2-((2-((S)-3-(difluoromethyl)-5-carbonylmorpholino)-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] (S)-2-((2-((S)-3-(difluoromethyl)-5-carbonylmorpholino)-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was prepared according to Example 68. MS m / z (ESI): 440.1 [M+H] + .

[0206] Example 126 Preparation of (S)-2-((2-((S)-3-(difluoromethyl)-5-carbonylmorpholino)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-methoxypropionamide [ka] (S)-2-((2-((S)-3-(difluoromethyl)-5-carbonylmorpholino)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-methoxypropionamide was prepared according to Example 68. MS m / z (ESI): 452.1 [M+H] + .

[0207] Example 127 Preparation of (S)-2-((2-((S)-2-(difluoromethyl)-4-methyl-6-carbonylpiperazin-1-yl)-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide [ka] (S)-2-((2-((S)-2-(difluoromethyl)-4-methyl-6-carbonylpiperazin-1-yl)-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was prepared according to Example 69. MS m / z (ESI): 453.1 [M+H] + .

[0208] Example 128 Preparation of (S)-2-((2-((S)-2-(difluoromethyl)-4-methyl-6-carbonylpiperazin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-methoxypropionamide [ka] (S)-2-((2-((S)-2-(difluoromethyl)-4-methyl-6-carbonylpiperazin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-methoxypropionamide was prepared according to Example 69. MS m / z (ESI): 465.1 [M+H] + .

[0209] Example 129 Preparation of (2S,3R)-1-(2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-3-methylpyrrolidine-2-formamide [ka] (2S,3R)-1-(2-((S)-4-(difluoromethyl)-2-carbonyloxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-3-methylpyrrolidine-2-formamide was prepared according to Example 1. MS m / z (ESI): 448.1 [M+H] + .

[0210] Biological Test Evaluation The present invention will be further explained and interpreted in conjunction with the following test examples, but these examples are not intended to limit the scope of the present invention. Test Example 1: Measurement of the inhibitory effect of the compounds of the present invention on PI3Kα / β / γ / δ kinase activity

[0211] Experimental Objective: The objective of this test example is to test the inhibitory activity of the compounds of the examples against PI3K α / β / γ / δ kinase.

[0212] Experimental equipment: Centrifuge (5810R) was purchased from Eppendorf, pipettes were purchased from Eppendorf or Rainin, and the microplate reader was a full-function microplate reader with model number SynergyH1 purchased from BioTek, USA.

[0213] Experimental method: This experiment used Promega's ADP-Glo ​​lipid kinase assay (Promega #V9102). Lipid kinase PI3Kα / β / γ / δ undergoes catalytic reaction in the presence of substrates PIP2:3PS and ATP, and ADP is generated from ATP. The activity of lipid kinase is characterized by measuring the ADP content in the reaction. The half-maximal inhibitory concentration (IC) of compounds inhibiting the activity of PI3Kα / β / γ / δ kinase is also measured. 50 get.

[0214] The specific experimental procedures are as follows. Kinase reactions were performed in a white 384-well plate (Perkin Elmer #6007299). 2 μL of compound diluted with 1% DMSO in ddH2O was added to each well. 2 μL of 1% DMSO in ddH2O was added to the positive control wells. 2 μL of 0.1-2 nM PI3K kinase solution diluted with 5x kinase buffer (HEPES 250 mM, MgCl2 15 mM, NaCl 250 mM, BSA 0.05%) was then added to each well. 2 μL of 5x kinase buffer was added to the negative control wells. 4 μL of 50 μM substrate PIP2:3PS (Promega #V1701) prepared with 10x dilution buffer and ddH2O was added to each well. Finally, 2 μL of 50-100 μM ATP solution diluted with water was added to each well to initiate the reaction. After incubation at room temperature for 90-120 minutes, ADP-Glo ​​Reagent (10 mM) was added to each well. After adding 10 μL of ATP (containing MgCl2) to each well, the mixture was incubated at room temperature for 60 minutes. Excess ATP was removed during the reaction, and then 20 μL of Kinase Detection Reagent was added to each well. The mixture was incubated at room temperature for 20 minutes in the dark, and the chemiluminescence was detected using a BioTek Synergy H1 microplate reader. [Table 1]

[0215] How to process experimental data: The percentage inhibition data of the compound-treated wells was calculated from the positive control wells (DMSO control wells) and negative control wells (no kinase added). The IC was calculated by fitting the different concentrations and the corresponding percentage inhibition data to a four-parameter nonlinear logistic equation using GraphPad Prism. 50 The value was calculated.

[0216] Testing Conclusion: From the above scheme, it was found that the compounds of the examples shown in the present invention exhibit the biological activities shown in Table 1 below in the PI3K α / β / γ / δ kinase activity test.

[0217] [Table 2]

[0218] As is clear from the above data, the compounds of the Examples shown in the present invention have good activity and selectivity in terms of the activity of PI3K α / β / γ / δ kinases.

[0219] Test Example 2: Measurement of the growth inhibitory effect of the compounds of the present invention on PI3Kα mutant cancer cells

[0220] Experimental Objective: The objective of this test example is to test the growth inhibitory activity of the compounds of the examples against PI3Kα mutant cancer cells HCC1954 (H1047R), HGC-27 (E542K), and MKN1 (E545K).

[0221] Experimental equipment: the centrifuge (5702R) was purchased from Eppendorf, the carbon dioxide incubator was purchased from Thermo, the biosafety cabinet was purchased from Shanghai Boxun Company, the pipettes were purchased from Eppendorf or Rainin, and the microplate reader was a full-function microplate reader with model number SynergyH1 purchased from BioTek, USA.

[0222] Experimental Method: Cell Titer-Glo method was used to detect the growth inhibitory effect of the compounds of the examples on PI3Kα mutant cancer cell lines (HCC1954, HGC-27, and MKN1). The cell lines were cultured in RPMI 1640 medium (Gibco #22400089) containing 10% FBS (Gibco #10091148) and 1% P / S (Hyclone #SV30010) under the conditions of 37°C, 5% CO2. Before the experiment, the cells were harvested and counted, and the cell density was adjusted. The cells were seeded into a white 96-well plate (Corning #3610) at a density of 1,000-10,000 cells / well and cultured overnight in a 37°C, 5% CO2 incubator. After that, the prepared compound solutions at different concentrations were added, and the corresponding solvent controls were also set up. Subsequently, the cells were cultured at 37°C, 5% CO2. After culturing in a CO2 incubator for 48 to 96 hours, the cell plate and its contents were equilibrated to room temperature, and 20 to 100 μL of Cell Titer-Glo solution (Promega #G7573) was added to each well. After shaking to mix evenly, the plate was incubated at room temperature for 5 to 30 minutes in the dark. Chemiluminescence values ​​were then detected using a BioTek Synergy H1 microplate reader.

[0223] How to process experimental data: Percent inhibition data {% inhibition = 100 - (test compound value / solvent control value) x 100} for wells treated with example compounds was calculated from the solvent control wells in the plate. The IC was calculated by fitting the different concentrations and corresponding percentage inhibition data to a four-parameter nonlinear logistic equation using GraphPad Prism. 50 The value was calculated.

[0224] Testing Conclusion: From the above scheme, it was found that the compounds of the examples of the present invention exhibited the biological activities shown in Table 2 below in the growth inhibitory activity test against PI3Kα mutant cancer cells HCC1954 (H1047R), HGC-27 (E542K), and MKN1 (E545K).

[0225] [Table 3]

[0226] As is clear from the above data, the compounds of the examples shown in the present invention have good activity in terms of growth inhibition against PI3Kα mutant cancer cells HCC1954 (H1047R), HGC-27 (E542K), and MKN1 (E545K).

[0227] Test 3: Toxicity test using SD rats with repeated oral administration for 7 days

[0228] 3.1 Experimental Objectives The purpose of this study was to investigate the toxic reactions that may occur after repeated oral gavage administration of GDC-0077 and Example 51 to SD rats for 7 days, and to compare the differences in toxicity between GDC-0077 and Example 51.

[0229] 3.2 Experimental materials and equipment 3.2.1 Test Subjects Test Subject 1: GDC-0077 Test subject 2: Example 51 3.2.2 Solvents Name: 20% SBE-β-CD (Captisol) aqueous solution 3.2.3 Animal information Species & strain: Sprague-Dawley (SD) rats Animal grade: SPF grade Number and sex of animals: 112 rats, half male and half female. 3.2.4 Equipment The ADVIA2120 series fully automated hematology analyzer is used to count blood cells. The SYSMEX CA-500 coagulation meter is used to detect coagulation function indicators. The TBA-120FR fully automated biochemical analyzer is used to detect biochemical indicators in blood. The Easylyte Electrolyte Analyzer is used to detect electrolytes. The liquid mass spectrometry detector is model API4000, with an electrospray source (ESI) in positive ion mode, and the chromatography column model is Agilent ZORBAX XDB-C18 (3.5 μm, 2.1×50 mm) used for bioanalytical detection of plasma samples.

[0230] 3.3 Experimental method 1) In the study, 112 rats (56 rats / sex) were divided into 14 groups based on their body weight, with 70 rats used for toxicology studies (groups 1-7, 5 rats / sex / group) and 42 rats used for toxicokinetic studies (groups 8-14, 3 rats / sex / group). 2) Groups 1 and 8 were given a 20% SBE-β-CD (Captisol) aqueous solution by oral gavage to serve as the vehicle control group. 3) Animals in groups 2 and 9, 3 and 10, and 4 and 11 were administered 10, 30, and 60 mg / kg of GDC-0077 by oral gavage, respectively. 4) Animals in groups 5 and 12, 6 and 13, and 7 and 14 were orally gavaged with 10, 30, and 60 mg / kg of Example 51, respectively. 5) Animals were dosed once daily for 7 consecutive days (animals in groups 7 and 14 were dosed for 6 consecutive days). 6) The dose was 10 mL / kg in all cases. 7) During the study period, clinical observations, body weight, food intake, clinical pathological indices (blood cell count, coagulation function, and blood biochemistry), and toxicokinetics were examined. 8) All animals were euthanized on day 8 (animals in groups 7 and 14 were euthanized after administration on day 6). 9) During the study period, all animals in groups 1 to 7, group 14, and all animals that died (including animals used in toxicokinetic studies) were subjected to gross necropsy and histopathological examination of abnormal tissues, gastrointestinal tissues (e.g., colon, cecum), and immune tissues (e.g., thymus).

[0231] 3.4 Test data list 3.4.1 Dying / dead At the 60 mg / kg dose, both GDC-0077 and Example 51 caused moribundity / death in animals, while the remaining doses did not cause death / moribundity. 3.4.2 Toxicokinetics At a dose of 30 mg, the mean exposure AUC of the system after the final administration of Example 51 (male: 11,400 h*ng / mL, female: 15,900 h*ng / mL) was 2.4 to 3.8 times that of GDC-0077 at the same dose (male: 3,000 h*ng / mL, female: 6,510 h*ng / mL), and was close to the exposure after the first administration of GDC-0077 at a dose of 60 mg / kg (male: 15,400 h*ng / mL, female: 22,800 h*ng / mL). At a dose of 10 mg, the mean system exposure AUC after the final dose of Example 51 (male: 2110 h*ng / mL, female: 3170 h*ng / mL) was approximately 1.4 to 2.5 times that of GDC-0077 (male: 845 h*ng / mL, female: 2250 h*ng / mL). Thus, at the same dose, the exposure of the Example 51 system is clearly higher than that of GDC-0077. 3.4.3 Clinical observations GDC-0077: In the high-dose group, abnormal symptoms such as arching of the back, loose stools, soiling of the anus, and fluffy fur were observed. Example 51: In the medium and high dose groups, abnormal symptoms such as arching of the back, loose stools, soiling of the anus, and fluffy fur were observed. 3.4.4 Body weight and food intake GDC-0077: All animals in the intermediate and high dose groups experienced a decrease in final body weight, accompanied by some degree of decrease in food intake. Example 51: All low, medium and high dose groups experienced a decrease in final body weight with a corresponding decrease in food intake. 3.4.5 Blood Cell Count and Coagulation Function GDC-0077: Retic reduction was observed in both male and female animals in each dose group. Example 51: A decrease in Retic was observed in both male and female animals in each dose group, and an increase in Neut and a decrease in PLT were observed in male and female animals in the 30 and 60 mg / kg dose groups. 3.4.6 Blood biochemistry GDC-0077: Male animals in each dose group had elevated Glu and CHO; in the 60 mg / kg dose group, male and female animals had elevated AST and UREA, decreased A / G, and male animals had elevated ALT; and in the 30 mg / kg dose group, male and female animals had elevated AST and UREA, and female animals had elevated ALT.

[0232] Example 51: In the 60 mg / kg dose group, both male and female animals had elevated AST, Glu, and UREA; in the 30 mg / kg dose group, both male and female animals had elevated AST and UREA, and male animals had elevated Glu; and in the 10 mg / kg dose group, both male and female animals had elevated AST. 3.4.7 Pathology GDC-0077: Microscopic pathological changes mainly included: atrophy of cecal mucosal goblet cells, increased thymic chromatin-containing macrophages, and gastric mucosal erosion, bleeding, and edema. Example 51: Pathological changes under a microscope mainly include: glandular gastric mucosa bleeding, atrophy; cecal mucosa bleeding, goblet cell atrophy and colonic mucosa goblet cell atrophy; atrophy of splenic white pulp; atrophy of thymic cortex or cortex and medulla, increase in dystrophic body macrophages, etc. The primary toxic target organs of both GDC-0077 and Example 51 are gastrointestinal tissues (eg, stomach, cecum) and immune tissues (eg, thymus). 3.5 Experimental Conclusions Under the test conditions, GDC-0077 and the test subject of Example 51 were both administered orally by gavage to SD rats at doses of 10, 30, and 60 mg / kg for 7 days (once / day). The lethal dose of GDC-0077 and Example 51 was 60 mg / kg, and the maximum tolerated dose (MTD) was 30 mg / kg. At a dose of 30 mg / kg, C of Example 51 max and AUC (0-24h) was significantly higher than that of GDC-0077, and Example 51 was better tolerated than GDC-0077.

[0233] Test Example 4: In vivo efficacy test of the compounds of the present invention

[0234] 4.1 Experimental Objectives Through in vivo efficacy experiments, compounds with relatively significant efficacy and relatively small toxic side effects are screened.

[0235] 4.2 Main experimental equipment and materials 4.2.1 Equipment: 1. Biosafety Cabinet (BSC-1300II A2, Shanghai Boxun Industrial Co., Ltd. Medical Equipment Factory) 2. Clean bench (CJ-2F, Suzhou Feng Experimental Animal Equipment Co., Ltd.) 3. CO2 incubator (Thermo-311) 4. Centrifuge (Centrifuge 5702R, Eppendorf) 5. Fully automated cell counter (Countess II, Life) 6. Pipette (10-20 μL, Eppendorf) 7. Microscope (TS2, Nikon) 8. Vernier caliper (CD-6"AX, Sanpo Co., Ltd., Japan) 9. Cell culture flasks (T75 / T225, Corning) 10. Electronic balance (CPA2202S, Sartorius) 4.2.2 Reagents: 1. RPMI-1640 medium (22400-089, Gibco) 2. Fetal bovine serum (FBS) (10091-148, Gibco) 3. 0.25% trypsin (25200-056, Gibco) 4. Penicillin-streptomycin double antibody (15140-122, Gibco) 5. Phosphate buffer solution (PBS) (10010-023, Gibco) 6. Matrigel Matrix (356234, Corning) 4.2.3 Animals: BALB / c nude mice, 6-8 weeks old, female, purchased from Shanghai Xipuer-Bikai Laboratory Animal Co., Ltd. 4.3 Experimental steps 4.3.1 Cell culture and cell suspension production a. One HCC1954 cell line was selected from the cell bank and resuscitated using RPMI-1640 medium (RPMI-1640 + 10% FBS + 1% SP). The resuscitated cells were placed in a cell culture flask (the cell type, date, name of the cultivator, etc. were clearly written on the flask wall) and cultured in a CO2 incubator (the incubator temperature was 37°C and the CO2 concentration was 5%). b) After the cells covered 80-90% of the bottom of the culture flask, they were passaged. After passage, the cells were placed in a CO2 incubator and continued to be cultured. This process was repeated until the cell number met the in vivo therapeutic efficacy needs. c. The cultured cells were collected and counted using an automated cell counter. Based on the counting results, the cells were resuspended in PBS and Matrigel to form a cell suspension (density 5 × 10 7 / mL) and store in an icebox for use. 4.3.2 Cell inoculation a, Before inoculation, nude mice were marked with disposable ear tags compatible with both rats and mice. b, At the time of inoculation, the cell suspension was mixed uniformly, and 0.1–1 mL of cell suspension was drawn up using a 1 mL syringe, air bubbles were expelled, and then the syringe was placed on an ice bag for use. c) The nude mouse was held in place with the left hand, and the area on the right side of the back near the right shoulder (inoculation site) was disinfected with 75% alcohol. After 30 seconds, inoculation began. d) Test nude mice were inoculated in turn (0.1 mL of cell suspension was inoculated per mouse). 4.3.3 Tumor measurement, grouping, and administration of tumor-bearing mice a) Tumors were measured 14 to 18 days after inoculation according to tumor growth status, and tumor size was calculated. Tumor volume calculation: Tumor volume (mm 3 ) = length (mm) x width (mm) x width (mm) / 2 b, Tumor-bearing mice were randomly assigned to groups according to their body weight and tumor size. c. Depending on the grouping results, the test drug (administration method: oral administration; administration dose: 10 mg / kg; administration volume: 10 mL / kg; administration frequency: once / day; administration cycle: 21 days; solvent: 0.5% CMC / 1% polysorbate 80) was started. d, Tumors were measured and weighed twice a week after test drug administration. e, After the experiment was completed, the animals were euthanized. f. Data is processed using software such as Excel. Calculation of compound tumor inhibition rate TGI (%): When tumor does not decrease, TGI (%) = [(1-(mean tumor volume at the end of administration of a certain treatment group - mean tumor volume at the beginning of administration of this treatment group)) / (mean tumor volume at the end of treatment of solvent control group - mean tumor volume at the beginning of treatment of solvent control group)] × 100%. When tumor decreases, TGI (%) = [1-(mean tumor volume at the end of administration of a certain treatment group - mean tumor volume at the beginning of administration of this treatment group) / mean tumor volume at the beginning of administration of this treatment group] × 100%. 4.4 The test data is shown in Table 3 below. [Table 4] 4.5 Experimental results As can be seen from the above results, the above compounds of the present patent have relatively good tumor inhibition rates.

[0236] Test Example 5: Pharmacokinetic PK experiment of the compound of the present invention in mice In the present invention, the pharmacokinetic test of the compounds of the examples in mice was preferably carried out using Balb / c male mice (Shanghai Jieshijie Laboratory Animal Co., Ltd.). □Administration method: Single oral gavage. □Dosage: 5 milligrams / 10 milliliters / kilogram of body weight. □ Formulation of the preparation: 0.5% CMC-Na was dissolved by ultrasonication to prepare a clear solution or a uniform suspension. □Sampling points: 0.5, 1, 2, 4, 6, 8 and 24 hours after administration. □Sample processing: 1) 0.1 mL of blood was collected from the orbit, placed in a K2-EDTA test tube, and centrifuged at room temperature at 1000-3000 xg for 5-20 minutes to separate the plasma, which was then stored at -80°C. 2) 160 uL of acetonitrile was added to 40 uL of plasma sample to precipitate, and after mixing, the sample was centrifuged at 500 to 2000 × g for 5 to 20 minutes. 3) 100 uL of the treated supernatant solution was taken and subjected to LC / MS / MS analysis to analyze the concentration of the example to be measured. LC-MS / MS analysis: Liquid phase conditions: Shimadzu LC-20AD pump ●Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer Chromatography column: phenomenex Gemiu 5 um C 18 50×4.6mm ●Mobile phase: Liquid A is a 0.1% formic acid aqueous solution, and liquid B is acetonitrile. ●Flow rate: 0.8mL / min Elution time: 0 to 4 minutes gradient elution □Pharmacokinetics: The main parameters were calculated using WinNonlin 6.1, and the results of the pharmacokinetic experiments in mice are shown in Table 4 below.

[0237] [Table 5]

[0238] The results of the pharmacokinetic experiments in mice shown in the table indicate that the compounds of the examples of the present invention exhibit good metabolic properties, and both the plasma exposure amount AUC and the maximum blood concentration Cmax were good.

Claims

1. A compound of formula (II-A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 (where, Q is N; Z is -CR aa ; G is selected from the group consisting of oxygen and sulfur; L is nitrogen; Ring A is phenyl; Ring B is 【Chemistry 2】 and R ｘ and R ｙ are each independently hydrogen, deuterium, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a mercapto group, a nitro group, a hydroxy group, a cyano group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -(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 wherein the alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group each further include deuterium, cycloalkylalkyl group, cycloalkylhaloalkyl group, halogen, cycloalkylamino group, mercapto group, oxo group, nitro group, cyano group, hydroxy group, alkenyl group, alkynyl group, cycloalkylalkoxy group, cycloalkylhaloalkoxy group, cycloalkylhydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, -(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 and optionally substituted with one or more substituents selected from the group consisting of: Or any two adjacent or non-adjacent R ｘ are linked to form a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group may further comprise deuterium, an alkyl group, a haloalkyl group, a halogen, an amino group, an oxo group, a nitro group, a cyano group, a hydroxy group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -(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 optionally substituted with one or more substituents selected from the group consisting of: Or any two adjacent or non-adjacent R ｙ are linked to form a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group may further comprise deuterium, an alkyl group, a haloalkyl group, a halogen, an amino group, an oxo group, a nitro group, a cyano group, a hydroxy group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -(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 optionally substituted with one or more substituents selected from the group consisting of: R ｚ represents hydrogen, deuterium, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a mercapto group, a nitro group, a hydroxy group, a cyano group, an oxo group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -(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 wherein the alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group each further include deuterium, alkyl group, haloalkyl group, halogen, amino group, mercapto group, oxo group, nitro group, cyano group, hydroxy group, alkenyl group, alkynyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, -(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 and optionally substituted with one or more substituents selected from the group consisting of: Or any two adjacent or non-adjacent R ｚ can be linked to form a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group can further include deuterium, an alkyl group, a haloalkyl group, a halogen, an amino group, an oxo group, a nitro group, a cyano group, a hydroxy group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -(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 optionally substituted with one or more substituents selected from the group consisting of: R ２ is present or absent, and L is nitrogen or -CR ａａ If R ２ represents hydrogen, deuterium, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a mercapto group, a nitro group, a hydroxy group, a cyano group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -(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 selected from the group consisting of R ３ and R ４ are each independently hydrogen, deuterium, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a hydroxyalkyl group, a haloalkoxy group, a halogen, an amino group, a mercapto group, a nitro group, a hydroxy group, a cyano group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -(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 wherein the alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group each further include deuterium, alkyl group, haloalkyl group, halogen, amino group, mercapto group, oxo group, nitro group, cyano group, hydroxy group, alkenyl group, alkynyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, -(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 and optionally substituted with one or more substituents selected from the group consisting of: Or, R ２ , R ３ , R ４ and R ａａ Any two of the groups are linked to form a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, and the cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group may further comprise deuterium, an alkyl group, a haloalkyl group, a halogen atom, an amino group, an oxo group, a nitro group, a cyano group, a hydroxy group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -(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 optionally substituted with one or more substituents selected from the group consisting of: R ａａ is selected from the group consisting of hydrogen, deuterium, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a hydroxyalkyl group, a haloalkoxy group, a halogen, a cyano group, a nitro group, a hydroxy group, an amino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, hydroxyalkyl group, haloalkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are each optionally further substituted with one or more substituents selected from the group consisting of deuterium, an alkyl group, a halogen, a hydroxy group, an amino group, an oxo group, a nitro group, cyano group, an alkenyl group, alkynyl group, alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group; R ｂｂ , R ｃｃ , R ｄｄ and R ｅｅ are each independently selected from the group consisting of hydrogen, deuterium, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a hydroxyalkyl group, a haloalkoxy group, a halogen atom, a cyano group, a nitro group, a hydroxy group, an amino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, and wherein the alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, hydroxyalkyl group, haloalkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are each optionally further substituted with one or more substituents selected from the group consisting of deuterium, an alkyl group, a halogen atom, a hydroxy group, an amino group, an oxo group, a nitro group, cyano group, an alkenyl group, alkynyl group, alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group; Alkyl refers to a saturated aliphatic hydrocarbon group that is a straight-chain or branched group containing 1 to 20 carbon atoms; Cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent having from 3 to 20 carbon atoms; Heterocycle refers to a 3- to 20-membered saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group in which one or more ring atoms is a heteroatom selected from the group consisting of N and O, with the proviso that the ring does not contain -O-O-, -O-S-, or -S-S-, and the remaining ring atoms are carbon atoms; Aryl refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic ring having a conjugated π-electron system; Heteroaryl refers to a 5-14 membered heteroaromatic system having 1-4 heteroatoms selected from the group consisting of O, S and N; Alkoxy refers to an —O-(alkyl) or —O-(unsubstituted cycloalkyl) group; Haloalkyl refers to an alkyl group substituted with one or more halogens; Haloalkoxy refers to an alkoxy group substituted with one or more halogens; Hydroxyalkyl refers to an alkyl group substituted with hydroxy; n is 1, p is 0, 1, 2, 3, 4, 5 or 6; m １ is 0, 1 or 2, n １ is 0, 1, 2, 3, 4 or 5, 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.

2. The compound of formula (II-A) according to claim 1, its stereoisomer, or a pharmaceutically acceptable salt thereof, further characterized in that it is as shown in formula (V) or (VI) or (VIII): 【Transformation 3】 (where, R ５ , R ６ and R １４ are each independently hydrogen, deuterium, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a mercapto group, a nitro group, a hydroxy group, a cyano group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -(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 wherein the alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are each optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl group, haloalkyl group, halogen, amino group, mercapto group, oxo group, nitro group, cyano group, hydroxy group, alkenyl group, alkynyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group; Or, R ５ and R ６ are linked to form a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group may further comprise deuterium, an alkyl group, a haloalkyl group, a halogen, an amino group, an oxo group, a nitro group, a cyano group, a hydroxy group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -(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 optionally substituted with one or more substituents selected from the group consisting of: R ７ , R ８ , R １１ and R １２ are each independently hydrogen, deuterium, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a mercapto group, a nitro group, a hydroxy group, a cyano group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -(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 wherein the alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are each optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl group, haloalkyl group, halogen, amino group, mercapto group, oxo group, nitro group, cyano group, hydroxy group, alkenyl group, alkynyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group; Or, R ７ , R ８ , R １１ and R １２ Any two of the groups may be linked to form a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, and the cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group may be further substituted with one or more substituents selected from the group consisting of deuterium, an alkyl group, a haloalkyl group, a halogen, an amino group, an oxo group, a nitro group, a cyano group, a hydroxy group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group.

3. The compound of formula (II-A) according to claim 1, its stereoisomer, or a pharmaceutically acceptable salt thereof, further characterized in that it is as shown in formula (VIII-A): 【Chemistry 4】 (where, Ring B is 【Transformation 5】 and R ２ is hydrogen, C １～６ Alkyl group and C １～６ haloalkyl groups; R ３ and R ４ are each independently hydrogen, C １～６ Alkyl group, C １～６ Haloalkyl group, C １～６ Alkoxy groups and -(CH ２ ) ｎ１ OR ｂｂ selected from the group consisting of Or, R ３ and R ４ are concatenated to form C ３～８ forming a cycloalkyl group or a 3- to 8-membered heterocycle, Or, R ２ and R ３ or R ２ and R ４ are linked to form a 3- to 8-membered heterocycle, R ５ , R ６ and R １４ are each independently hydrogen, halogen, a cyano group, C １～６ Alkyl group, C １～６ Alkoxy group and C １～６ haloalkyl groups; R ａａ is hydrogen, C １～６ selected from the group consisting of alkyl groups, halogens, and cyano groups; R ｚ is hydrogen, an oxo group, C １～６ Alkyl group, C １～６ Haloalkyl groups and -(CH ２ ) ｎ１ R ｂｂ selected from the group consisting of R ｂｂ is hydrogen, C １～６ selected from the group consisting of alkyl groups, halogens, and cyano groups; t is 0, 1, 2 or 3.

4. R ３ and R ４ The compound of formula (II-A) according to claim 3, its stereoisomer, or a pharmaceutically acceptable salt thereof, characterized in that:

5. R ２ and R ３ or R ２ and R ４ The compound of formula (II-A) according to claim 3, its stereoisomer, or a pharmaceutically acceptable salt thereof, characterized in that: are linked to form pyrrolidinyl or azetidinyl.

6. R ２ But hydrogen, C １～３ Alkyl group and C １～３ haloalkyl groups; R ３ and R ４ are each independently hydrogen, C １～３ Alkyl group, C １～３ Alkoxy groups, and C １～３ C substituted by alkoxy １～３ alkyl groups, Or, R ３ and R ４ But it is connected to C ４～６ forming a cycloalkyl group or a 4- to 6-membered heterocyclic group, R ２ and R ３ or R ２ and R ４ are linked to form a 4- to 6-membered heterocyclic group, R ５ and R ６ are each independently hydrogen, halogen, cyano group, C １～３ Alkyl group, C １～３ Alkoxy group and C １～３ haloalkyl groups; R １４ is selected from the group consisting of hydrogen and halogen; R ｚ is hydrogen, halogen, oxo group, C １～３ alkyl groups, halogen-substituted C １～３ Alkyl groups, and -(CH ２ ) ｎ１ R ｂｂ selected from the group consisting of R ａａ is selected from the group consisting of hydrogen and halogen; R ｂｂ But it is cyano, n １ is 0, 1, 2 or 3, t is 0, 1, 2 or 3 The compound of formula (II-A) according to claim 3, its stereoisomer, or a pharmaceutically acceptable salt thereof.

7. R ２ is hydrogen, a methyl group, an ethyl group, or a propyl group; and / or R ３ and R ４ are each independently hydrogen, a methyl group, an ethyl group, a propyl group, a methoxy group, an ethoxy group, or a CH ３ OCH ２ - or CH ３ CH ２ OCH ２ -; or R ３ and R ４ are linked to form a 4-6 membered heterocyclic group containing one oxygen or nitrogen; or R ２ and R ３ or R ２ and R ４ are linked to form a nitrogen- or oxygen-containing 4- to 6-membered heterocyclic group, wherein the number of heteroatoms is 1 or 2; and / or R ５ and R ６ are each independently hydrogen; and / or R １４ is hydrogen, fluorine or chlorine; and / or R ｚ is a C substituted with hydrogen, fluorine, chlorine, bromine, iodine, a cyano group, an acetonitrile group, a propionitrile group, or fluorine; １～３ is an alkyl group; and / or R ａａ is hydrogen 7. The compound of formula (II-A) according to claim 6, its stereoisomer, or a pharmaceutically acceptable salt thereof.

8. R ３ and R ４ are linked to form an oxetanyl; or R ２ and R ３ or R ２ and R ４ are linked to form pyrrolidinyl, tetrahydrofuranyl, piperidinyl, or azetidinyl; and / or R ｚ fluorine, methyl group, acetonitrile group, -CHF ２ , -CF ２ CH ３ or CHF ２ CH ２ - is 7. The compound of formula (II-A) according to claim 6, its stereoisomer, or a pharmaceutically acceptable salt thereof.

9. When the compound is of formula (VIII): Ring B is 【Transformation 6】 and R ２ is hydrogen and C １～６ alkyl groups, R ３ But C １～６ Alkyl group, C １～６ C substituted with alkoxy and alkyl groups １～６ alkoxy groups, R ５ and R ６ are each independently selected from the group consisting of hydrogen and halogen; R １４ is selected from the group consisting of hydrogen and halogen; R ｚ is hydrogen, halogen, cyano group, C １～６ C substituted with alkyl groups and halogens １～６ Selected from the group consisting of alkyl groups 3. The compound of formula (II-A) according to claim 2, its stereoisomer, or a pharmaceutically acceptable salt thereof.

10. R ２ is hydrogen or C １～３ is an alkyl group, and / or R ３ But C １～３ Alkyl group, C １～３ Alkoxy group, or C １～３ C substituted by alkoxy １～３ is an alkyl group, and / or R ５ and R ６ are each independently hydrogen, and / or R １４ is hydrogen, fluorine or chlorine, and / or R ｚ is substituted by hydrogen, fluorine, chlorine, bromine, iodine, a cyano group, an acetonitrile group, a propionitrile group, or a halogen; １～３ is an alkyl group 10. The compound of formula (II-A) according to claim 9, its stereoisomer, or a pharmaceutically acceptable salt thereof.

11. R ２ is hydrogen, a methyl group, an ethyl group, or a propyl group, and / or R ３ However, methyl, ethyl, propyl, methoxy, ethoxy, CH ３ OCH ２ - or CH ３ CH ２ OCH ２ - and and / or R ｚ fluorine, methyl group, acetonitrile group, -CHF ２ , -CF ２ CH ３ or CHF ２ CH ２ - is 10. The compound of formula (II-A) according to claim 9, its stereoisomer, or a pharmaceutically acceptable salt thereof.

12. The compound of formula (II-A) according to claim 1, its stereoisomer, or a pharmaceutically acceptable salt thereof, further characterized in that it is as shown in formula (X): 【Transformation 7】 (where, R １５ and R １６ are each independently hydrogen, C １～６ Alkyl group, C １～６ Haloalkyl groups and -(CH ２ ) ｎ１ R ｂｂ selected from the group consisting of R ２ ~R ４ , R ６ , R １４ , R ａａ , R ｂｂ and n1 are as defined in claim 3.

13. R ２ is present or absent, and if present, R ２ is hydrogen, a methoxy group, C １～６ Alkyl group and C １～６ haloalkyl groups; Or, R ２ and R ３ or R ２ and R ４ are linked to form a 3- to 8-membered heterocyclic group, R ３ and R ４ are each independently hydrogen, C １～６ Alkyl group, C １～６ Haloalkyl group, C １～６ selected from the group consisting of alkoxy groups and 3- to 8-membered heterocyclic groups, or R ３ and R ４ But it is connected to C ３～８ forming a cycloalkyl group or a 3- to 8-membered heterocyclic group, R ５ and R ６ are each independently hydrogen, halogen, cyano group, C １～６ Alkyl group, C １～６ Alkoxy group and C １～６ haloalkyl groups; Or, R ５ and R ６ But it is connected to C ３～８ forming a cycloalkyl group or a 3- to 8-membered heterocyclic group, R １４ is hydrogen, halogen, cyano group, C １～６ Alkyl group, C １～６ Haloalkyl group, C １～６ Alkoxy group and C ３～８ cycloalkyl groups, R ｙ But hydrogen, C １～６ Alkyl group, halogen, C １～６ Alkoxy group, C １～６ Haloalkyl groups and -(CH ２ ) ｎ１ - selected from the group consisting of R ａａ is hydrogen, halogen, cyano group, C １～６ Alkyl group, C １～６ Haloalkyl group, C １～６ Alkoxy group and C ３～８ cycloalkyl groups A compound of formula (II-A) according to any one of claims 1 to 12, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

14. R ２ and R ３ or R ２ and R ４ are linked to form a pyrrolidinyl or azetidinyl group; or R ３ and R ４ are linked to form an oxetanyl group, and / or R ５ and R ６ are linked to form a cyclobutanyl group, a cyclopentyl group, or a 1,3-dioxolanyl group, and / or R ｙ But hydrogen, C １～３ Alkyl group or C １～３ is a haloalkyl group 14. The compound of formula (II-A) according to claim 13, its stereoisomer, or a pharmaceutically acceptable salt thereof.

15. R ｙ is hydrogen, a methyl group or -(CH ２ ) ｎ１ - is 14. The compound of formula (II-A) according to claim 13, its stereoisomer, or a pharmaceutically acceptable salt thereof.

16. R ２ But hydrogen, C １～３ Alkyl group, C １～３ Hydroxyalkyl group and C １～３ haloalkyl groups; R ３ and R ４ However, each independently, C １～３ Alkyl group, C １～３ Hydroxyalkyl group, C １～３ Haloalkyl groups and C １～３ alkoxy groups, R ５ and R ６ are each independently hydrogen, C １～３ Alkyl group, C １～３ Alkoxy group and C １～３ haloalkyl groups; R １４ But hydrogen, C １～３ Alkyl group, C １～３ Alkoxy group and C １～３ haloalkyl groups; R ｙ is hydrogen, methyl group and -(CH ２ ) ｎ１ - selected from the group consisting of R ａａ is halogen, cyano group, C １～３ Alkyl group, C １～３ Alkoxy group and C １～３ haloalkyl groups A compound of formula (II-A) according to any one of claims 1 to 12, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

17. R ２ is a methyl group, an ethyl group, a propyl group, a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a halomethyl group, a haloethyl group, or a halopropyl group, and / or R ３ and R ４ are each independently a methyl group, an ethyl group, a propyl group, a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a halomethyl group, a haloethyl group, a halopropyl group, a methoxy group, an ethoxy group, or a propoxy group; and / or R ５ and R ６ are each independently a methyl group, an ethyl group, a propyl group, a halomethyl group, a haloethyl group, a halopropyl group, a methoxy group, an ethoxy group, or a propoxy group; and / or R １４ is a methyl group, an ethyl group, a propyl group, a halomethyl group, a haloethyl group, a halopropyl group, a methoxy group, an ethoxy group, or a propoxy group; and / or R ａａ is a methyl group, an ethyl group, a propyl group, a halomethyl group, a haloethyl group, a halopropyl group, a methoxy group, an ethoxy group, or a propoxy group 17. The compound of formula (II-A) according to claim 16, its stereoisomer, or a pharmaceutically acceptable salt thereof.

18. R ｚ is hydrogen, halogen, oxo group, thioxo group, C １～６ Alkyl group, C １～６ Alkoxy group, C １～６ Haloalkyl groups and -(CH ２ ) ｎ１ -, wherein said C １～６ Alkyl group, C １～６ Alkoxy groups, and C １～６ Each haloalkyl group may further include hydrogen, halogen, oxo, thioxo, C １～６ Alkyl group, C １～６ Alkoxy groups, and C １～６ may be substituted by one or more substituents selected from the group consisting of haloalkyl groups A compound of formula (II-A) according to any one of claims 1 to 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

19. R ｚ But halogen, C １～６ Alkyl group, C １～６ haloalkyl group or oxo group 19. The compound of formula (II-A) according to claim 18, its stereoisomer, or a pharmaceutically acceptable salt thereof.

20. R ｚ But halogen, C １～３ Alkyl group, C １～３ haloalkyl group or oxo group 19. The compound of formula (II-A) according to claim 18, its stereoisomer, or a pharmaceutically acceptable salt thereof.

21. The compound of formula (II-A) according to claim 1, its stereoisomer, or a pharmaceutically acceptable salt thereof, characterized in that the structure of the compound is as follows: 【Transformation 8】

22. A method for preparing a compound of formula (VI), its stereoisomer, or a pharmaceutically acceptable salt thereof, comprising the steps of: 【Chemistry 9】 Reacting a compound of formula (VI-1) and a compound of formula (IV-2) to obtain a compound of formula (VI), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. (where, X is a halogen; 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 claim 2.

23. A method for preparing a compound of formula (IX-A), its stereoisomer, or a pharmaceutically acceptable salt thereof, comprising the steps of: 【Chemistry 10】 reacting a compound of formula (IX) with Lawesson's reagent to obtain 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 is as defined in claim 12.

24. A method for preparing a compound of formula (X), its stereoisomer, or a pharmaceutically acceptable salt thereof, comprising the steps of: 【Chemistry 11】 reacting the compound of formula (IX-A) with a transition metal complex and its ligand to obtain a compound of formula (X), its stereoisomer, or a pharmaceutically acceptable salt thereof. (where, R ２ ~R ４ , R ６ , R １４ ~R １６ and R ａａ is as defined in claim 12.

25. 25. The method for preparing the compound of formula (X), its stereoisomer, or its pharmaceutically acceptable salt according to claim 24, characterized in that the transition metal complex and the ligand thereof are dichloro(p-cymene)ruthenium(II) dimer and 2-bicyclohexylphosphino-2',6'-dimethoxybiphenyl.

26. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (II-A) according to any one of claims 1 to 21, its stereoisomer, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

27. Use of the compound of formula (II-A) according to any one of claims 1 to 21, its stereoisomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 26, in the manufacture of a PI3K inhibitor pharmaceutical.

28. 28. Use of the compound of formula (II-A), its stereoisomer, or its pharmaceutically acceptable salt according to claim 27, characterized in that the PI3K inhibitor pharmaceutical is a PI3Kα inhibitor pharmaceutical.

29. Use of the compound of formula (II-A) according to any one of claims 1 to 21, its stereoisomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 26, in the manufacture of a medicament for treating cancer, bone diseases, inflammatory diseases, immune diseases, nervous system diseases, metabolic diseases, respiratory diseases, and heart diseases.

30. 30. The use of the compound or pharmaceutical composition of claim 29, wherein the cancer is selected from the group consisting of breast cancer, pancreatic cancer, non-small cell lung cancer, thyroid cancer, seminoma, melanoma, bladder cancer, liver cancer, kidney cancer, myelodysplastic syndrome, acute myeloid leukemia, and colorectal cancer.

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