Oxamide compound and use thereof in pharmaceuticals

Abstract

Provided in the present invention are an oxamide compound having a structure as shown in formula (I), or a pharmaceutically acceptable salt, isotope derivative or solvate thereof, or a stereoisomer, geometric isomer or tautomer thereof, or a prodrug molecule or metabolite thereof, and a pharmaceutical composition thereof and the use thereof. The compound involved in the present invention can efficiently inhibit STAT6 phosphorylation, can be used for preparing drugs for preventing and treating inflammatory diseases, and can be used for preparing anti-tumor drugs.

Description

Oxamide compounds and their use in medicine TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and relates to oxamide compounds, a preparation method thereof and use thereof in medicine, in particular to a compound shown in formula (I) or a pharmaceutically acceptable salt, isotope derivative, solvate, stereoisomer, geometric isomer, tautomer, or a prodrug molecule, metabolite thereof, and use thereof in medicine. BACKGROUND

[0002] Transcription factors play an important role in eukaryotic gene expression by binding to specific DNA sites and regulating the transcription of almost every gene in the cell genome. It is estimated that there are more than 1600 transcription factors in the human genome, nearly 20% of which have been associated with different disease phenotypes. A variety of transcription factors have been identified to be associated with inflammatory and tumor diseases.

[0003] STAT6 is an important factor in the Jak-STAT signaling pathway, which links extracellular signals from various cytokines, hormones and growth factors to nuclear transcription machinery. Four JAK (tyrosine kinase Janus kinase) proteins (JAK1, JAK2, JAK3, TYK2) and seven STAT members (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6) have been identified in mammals. STAT proteins regulate the expression of numerous genes, including genes related to cell survival, development, differentiation, migration, apoptosis and immune response.

[0004] STAT6 is mainly stimulated by IL-4 and IL-13, and plays a very important role in type II inflammation dominated by helper T cell 2 (Th2). Therefore, it is closely related to the pathophysiology of various allergic diseases, such as atopic dermatitis, bullous pemphigoid, nodular prurigo, and chronic spontaneous urticaria, eosinophilic esophagitis and food allergy, chronic rhinosinusitis with nasal polyps (CRSwNP), chronic rhinosinusitis without nasal polyps (CRSsNP), nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD / AERD), allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), eosinophilic granulomatosis with polyangiitis (EGPA), and allergic bronchopulmonary aspergillosis, etc. The JAK-STAT6 transduction pathway can induce the polarization of tumor-associated macrophages (TAM) to M2-type TAM, and has a certain effect on the formation of immunosuppressive tumor microenvironment and the promotion of intratumoral neovascularization. In addition, STAT6 is also related to the regulation of tumor microenvironment, in addition, some forms of lymphoma, especially Hodgkin's lymphoma group, primary mediastinal and primary central nervous system lymphoma, and some follicular and T-cell lymphomas are related to the dysregulation of STAT6 pathway. Therefore, STAT6 has broad application prospects in inflammatory and tumor diseases. Because STAT6 is downstream of the JAK-STAT pathway, regulating STAT6 may be safer than JAK inhibitors.

[0005] Currently, there is no STAT6 inhibitor on the market, and targeting the STAT6 signaling pathway may provide a better treatment strategy for these diseases. SUMMARY

[0006] The technical problem to be solved by the present application is to provide a structurally novel oxalamide compound which can be used as a STAT6 inhibitor for preparing a medicament for treating STAT6-mediated diseases or disorders and related diseases or disorders.

[0007] In one aspect, the present application provides a compound of Formula (I) or a pharmaceutically acceptable salt, isotope derivative, solvate, or stereoisomer, geometric isomer, tautomer, or prodrug molecule, metabolite thereof:

[0008] wherein,

[0009] is a single or double bond;

[0010] q and t are each independently selected from 0, 1 or 2, and q and t are not simultaneously selected from 0;

[0011] p is selected from 1 or 2;

[0012] Z is selected from S, O, -S(=0)-, -S(=0)2-, -S(=0)=NH, CHR 10 , CR 9 R 10 or NR 10 ;

[0013] Y is selected from CHR 9 , CR 9 R 10 or NR 9 ;

[0014] R 1 is selected from C 6-12 aryl, 5-12 membered heteroaryl, 4-12 membered heterocyclyl, 4-12 membered cycloalkenyl, C3-C 12 cycloalkyl, C 1-4 alkylene C 6-12 aryl, or C 1-4 alkylene C 6-12 alkenylene C g aryl substituted with one or more substituents selected from R 1a , CR 2a R 1b P(O)OR 2b OR 1a , CR 2a R 1b P(O)OR 2b NHR 1a , CR 2a R 1b P(O)(OR 1c )(NH(AA)C(O)O R 1a ), CR 2a R 2c P(O)(NHR 1c )(NH(AA)C(O)OR 1a ), CR2a P(O)(NH(AA)C(O)OR 1c )(NH(AA)C(O)OR 1c ), P(O)OR 1b OR 2b 、P(O)(OR 1b )(NH(AA)C(O)OR 1c ), P(O)(NHR 2c )(NH(AA)C(O)OR 1c ) or P(O)(NH(AA)C(O)OR 1c )(NH(AA)C(O)OR 1c );

[0015] R 1a R 2a Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Hydroxyalkyl; or, R 1a and R 2a It forms C3-C6 cycloalkyl or 3-6 membered heterocyclic groups with the atoms it is attached to;

[0016] R 1b R 2b Each is independently selected from -R 1aa -R 1aa -OC(O)-R 1ab -R 1aa -C(O)OR 1ab -R 1aa -OC(O)OR 1ab -R 1aa -OR 1ab -R 1aa -SC(O)OR 1ab -R 1aa -SC(O)-R 1ab -R 1aa -OC(O)NH-R 1ab -R 1aa -OC(O)NR 1ab R 1ac -R 1aa -OC(O)-R 1ab -OR 1ac -R 1aa -OC(O)OR 1ab -OR 1ac -R 1aa -SC(O)OR 1ab -OR1ac , -R 1aa -SC(O)-R 1ab -O-R 1ac or -R 1aa -OC(O)-(NH(AA)C(O)OR 1c );

[0017] R 1aa , R 1ab , R 1ac each independently is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, or C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, 5-7 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, C 1-4 alkylene C 6-12 aryl, or C 1-4 alkylene C 2-10 heteroaryl, said 5-7 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, C 1-4 alkylene C 6-12 aryl, or C 1-4 alkylene C 2-10 heteroaryl can be optionally further substituted by one or more R h or C(O)OR h ;

[0018] R 1c , R 2c each independently is selected from hydrogen, deuterium, or C 1-6 alkyl, 5-7 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, C 1-4 alkylene C 6-12 aryl, or C 1-4 alkylene C 2-10 heteroaryl, said substituents being selected from deuterium, halogen, cyano, hydroxyl, amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy;

[0019] AA is selected from a residue of a natural or non-natural amino acid, said residue of a natural or non-natural amino acid being in an alpha or beta configuration;

[0020] R 2 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, or C 1-6 alkyl, C 1-6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfone, C 1-6 alkylthio, C 1-6 alkylamino or 4-10 membered heterocyclyl, said substituent being selected from the group consisting of deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl or C 1-4 haloalkoxy;

[0021] R 3 , R 4 are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, or C Y alkyl, C 1-6 alkenyl, C 1-6 alkoxy, C 1-6 alkylacyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfone, C 1-6 alkylthio, C 1-6 alkylamino, 4-10 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, C 1-6 alkylene C 6-12 aryl or C 1-6 alkylene C 2-10 heteroaryl;

[0022] or, R 3 and R 4 together with the atom to which they are attached form a C3-C6cycloalkyl or 3-6 membered heterocyclyl, which C3-C6cycloalkyl or 3-6 membered heterocyclyl can be optionally substituted with one or more R Y1 or R Y2 ;

[0023] R Y1 , R Y2 are each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl or C 1-4 haloalkoxy;

[0024] R 5 , R 6 are each independently selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl or C 1-6Halogenated alkyl groups;

[0025] R 7 R 8 Each is independently selected from one or more Rs. Z Replacement C 1-6 Alkyl, 5-12 membered heterocyclic, 5-12 membered cycloalkyl, C 6-12 Aryl, 5-12 heteroaryl, C 1-4 Alkylene C 6-12 Aryl or C 1-4 Alkylene C 2-10 Mixed aromatics;

[0026] Or, R 7 and R 8 Together with the atoms they are attached to, they form 4-14 membered heterocyclic groups and 5-12 membered heteroaryl groups, wherein the 4-14 membered heterocyclic groups and 5-12 membered heteroaryl groups may optionally be further bonded by one or more R groups. Z replace;

[0027] R 9 R 10 Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, or optionally influenced by one or more R groups. Y Replacement C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl acyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 Alkylamine group, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, C 1-6 Alkylene C 6-12 Aryl or C 1-6 Alkylene C 2-10 Mixed aromatics;

[0028] Or, R 9 and R 10 The atoms attached to them together form a C3-C6 cycloalkyl or a 3-6 membered heterocyclic group, wherein the C3-C6 cycloalkyl or 3-6 membered heterocyclic group may optionally be bonded by one or more R Y1 or R Y2 replace;

[0029] R Z R Y Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, imino, or optionally by one or more R groups. Qsubstituted C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfone, C 1-6 alkylthio, C 1-6 alkylamino, 4-10 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, -NR a R b , -OR a , -C(O)R a , -C(O)OR a , -NHC(O)OR a , -NHC(O)R b C(O)OR a , -NR b C(O)R a , -NR a C(O)NR b R c , -C(O)NR a R b , -S(O)R c , -S(O)2R c , -S(O)=NHR c , -S(O)NR c R d or -S(O)2NR c R d ;

[0030] R Q is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, imino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfone, C 1-6 alkylthio, C 1-6 alkylamino, 4-10 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, -NR e R f , -OR e , -C(O)R e , -C(O)OR e , -NHC(O)OR e , -NHC(O)R e-NR e C(O)OR f -NR e C(O)R f -NR g C(O)NR e R f -C(O)NR e R f -S(O)R e -S(O)2R e -S(O)=NHR e -S(O)NR e R f or -S(O)2NR e R f ;

[0031] R a R b R c R d R e R f R g R h Each C group is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, imino, or optionally substituted with one or more substituents. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 Alkylamine group, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, C 1-4 Alkylene C 6-12 Aryl or C 1-4 Alkylene C 2-10 Heteroaryl groups, wherein the substituents are selected from deuterium, halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy, phenyl, or benzyl.

[0032] In some embodiments, the compound has the structure shown in formula (II):

[0033] Among them, p, t, q, Z, Y, R 1 R 2 R 3 R 4R 5 R 6 R 7 R 8 The definition is as stated in general formula (I).

[0034] In some embodiments, the compound has a structure as shown in formula (III), (IV), (V), (VI), (VII), or (VIII):

[0035] Among them, p, Z, Y, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 The definition is as stated in general formula (I).

[0036] In some embodiments, the compound has a structure as shown in formula (IIIa), (IVa), (Va), (VIa), (VIIa), (VIIIa), (IIIb), (IVb), (Vb), (VIb), (VIIb), or (VIIIb):

[0037] Among them, Z, Y, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 The definition is as stated in general formula (I).

[0038] In some embodiments, the compound has a structure as shown in formulas (IIIa-1), (IIIa-2), (IIIa-3), (IIIa-4), (IIIa-5), (IVa-1), (IVa-2), (IVa-3), (IVa-4), (IVa-5), (IVa-6), (IVa-7), (IVa-8), (IVa-9), (IVa-10), (Va-1), (Via-1), or (IVb-1):

[0039] Among them, R 1 R 2 R 5 R 6 R 7 R 8R 9 R 10 R Y1 R Y2 The definition is as stated in general formula (I).

[0040] In some implementations, the R 2 Selected from hydrogen or hydroxyl.

[0041] In some implementations, the R 3 R 4 Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, or optionally influenced by one or more R groups. Y Replacement C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl acyl, C 3-6 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-12 Aryl, 5-12 heteroaryl, C 1-6 Alkylene C 6-12 Aryl or C 1-6 Alkylene C 2-10 Heteroaryl, the R Y Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, or imino.

[0042] In some implementations, the R 3 and R 4 The atoms to which they are attached together form a C3-C6 cycloalkyl group, wherein the C3-C6 cycloalkyl group may optionally be bonded by one or more R Y1 or R Y2 Replace; the R Y1 R Y2 Each is independently selected from deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 Halogenated alkoxy groups.

[0043] In some implementations, the R 3 R 4 Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkylene C 2-10 heteroaryl or C 1-6 Alkyl acyl group.

[0044] In some implementations, the R 9 R 10Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, or optionally influenced by one or more R groups. Y Replacement C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl acyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 Alkylamine group, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, C 1-6 Alkylene C 6-12 Aryl or C 1-6 Alkylene C 2-10 Heteroaryl; the R Y Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl or imino.

[0045] In some implementations, the R 9 R 10 Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, or optionally influenced by one or more R groups. Y Replacement C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl acyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 Alkylamine group, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, C 1-6 Alkylene C 6-12 Aryl or C 1-6 Alkylene C 2-10 Heteroaryl; the R Y Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, or imino.

[0046] In some implementations, the R 9 and R 10 The atoms attached to them together form a C3-C6 cycloalkyl or a 3-6 membered heterocyclic group, wherein the C3-C6 cycloalkyl or 3-6 membered heterocyclic group may optionally be bonded by one or more R Y1 or R Y2 Instead, the R Y1 or RY2 Each is independently selected from deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 Halogenated alkoxy groups.

[0047] In some implementations, the R 9 and R 10 Each is independently selected from hydrogen, deuterium, or optionally converted by one or more R. Y Replacement C 1-6 Alkyl, C 1-6 Alkyl acyl, 5-12 heteroaryl or C 1-6 Alkylene C 2-10 Mixed aromatic compounds.

[0048] In some implementations, the R is characterized by 9 R 10 The atoms attached to them together form a cyclopropyl group, which may optionally be converted by one or more R atoms. Y1 or R Y2 Instead, the R Y1 or R Y2 Each is independently selected from deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 Halogenated alkoxy groups.

[0049] In some implementations, the R 5 R 6 Each is independently selected from hydrogen or C. 1-6 alkyl.

[0050] In some implementations, the R 1 Selected from C that has been substituted with one or more substituent groups 6-12 aryl or 5-12 heteroaryl groups, wherein the substituent is selected from R g CR 1a R 2a P(O)OR 1b OR 2b CR 1a R 2a P(O)OR 1b NHR 2b or CR 1a R 2a P(O)(OR 1b )(NH(AA)C(O)OR 1c ).

[0051] In some implementations, the R 1 Selected from one or more substituent groups The substituent group is selected from R g CR 1a R 2a P(O)OR 1b OR 2b CR 1a R 2a P(O)OR 1b NHR 2b or CR 1a R 2a P(O)(OR 1b )(NH(AA)C(O)OR 1c ).

[0052] In some implementations, the R 1a or R 2a Each is independently selected from hydrogen, halogen, or oxo, with the halogen preferably being F or Cl.

[0053] In some implementations, the CR 1a R 2a P(O)OR 1b OR 2b CR 1a R 2a P(O)OR 1b NHR 2b or CR 1a R 2a P(O)(OR 1b )(NH(AA)C(O)OR 1c (Selected from)

[0054] In some implementations, the CR 1a R 2a P(O)OR 1b OR 2b CR 1a R 2a P(O)OR 1b NHR 2b or CR 1a R 2a P(O)(OR 1b )(NH(AA)C(O)OR 1c (Selected from)

[0055] In some implementations, the R 7 R 8 Each is independently selected from one or more Rs. Z Replacement C1-6 alkyl, 5-12 membered heterocyclyl, 5-12 membered cycloalkyl, C 6-12 aryl, 5-12 membered heteroaryl, C 1-4 alkylene C 6-12 aryl or C 1-4 alkylene C 2-10 heteroaryl;

[0056] said R Z is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, oxo, or C Q substituted C 1-6 alkyl, C 3-6 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl.

[0057] In some embodiments, said R 7 and R 8 together with the atom to which they are attached form a 4-14 membered heterocyclyl, which can be optionally substituted with one or more R Z ;

[0058] said R Z is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, oxo, or C Q substituted C 1-6 alkyl, C 3-6 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl.

[0059] In further embodiments, said R Q is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, imino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, 4-10 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, -NR e R f , -C(O)R e , -NHC(O)R e or -NR e C(O)R f , said R e , R f are each independently selected from hydrogen, deuterium or C 1-6 alkyl.

[0060] In some embodiments, said is selected from:

[0061] In some embodiments, the compound of Formula (I) is selected from the following structures, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or stereoisomer, geometric isomer, tautomer thereof, or prodrug molecule, metabolite thereof:

[0062] In another aspect, the present application provides a pharmaceutical composition containing a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (Ilia), (IVa), (Va), (Via), (Vila), (Villa), (IIIb), (IVb), (Vb), (VIb), (Vlb), (Villa), (Ilia-1), (Ilia-2), (Ilia-3), (Ilia-4), (Ilia-5), (IVa-1), (IVa-2), (IVa-3), (IVa-4), (IVa-5), (IVa-6), (IVa-7), (IVa-8), (IVa-9), (IVa-10), (Va-1), (Via-1), or (IVb-1), or a pharmaceutically acceptable salt, isotopic derivative, solvate, or stereoisomer, geometric isomer, tautomer thereof, or prodrug molecule, metabolite thereof.

[0063] In yet another aspect, the present application provides use of a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IIIa), (IVa), (Va), (Via), (Vila), (Villa), (IIIb), (IVb), (Vb), (VIb), (VIIb), (VIIIb), (IIIa-1), (IIIa-2), (IIIa-3), (IIIa-4), (IIIa-5), (IVa-1), (IVa-2), (IVa-3), (IVa-4), (IVa-5), (IVa-6), (IVa-7), (IVa-8), (IVa-9), (IVa-10), (Va-1), (Via-1), or (IVb-1) as described above, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or stereoisomer, geometric isomer, tautomer, or prodrug, metabolite thereof, or a pharmaceutical composition thereof as described above, in the manufacture of a medicament for the treatment of a STAT6-mediated disease or disorder, preferably atopic dermatitis, bullous pemphigoid, nodular prurigo, chronic spontaneous urticaria, eosinophilic esophagitis, food allergy, chronic rhinosinusitis with nasal polyps (CRSwNP), chronic rhinosinusitis without nasal polyps (CRSsNP), nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD / AERD), allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), eosinophilic granulomatosis with polyangiitis (EGPA), or allergic bronchopulmonary aspergillosis; or a tumor selected from lymphoma, solitary fibrous tumor, colon cancer, esophageal cancer, breast cancer, cholangiocarcinoma, hepatocarcinoma, renal cancer, gastric cancer, head and neck squamous carcinoma, prostate cancer, lung cancer, non-small cell lung cancer (NSCLC), acute B-lymphoblastic leukemia, bladder cancer, pancreatic cancer, osteosarcoma, myeloma, glioma, ovarian cancer, or skin cancer.

[0064] The present application also provides a method of treating a disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (Ilia), (IVa), (Va), (Via), (Vila), (Villa), (IIIb), (IVb), (Vb), (VIb), (VIIb), (VIIIb), (Ilia-1), (Ilia-2), (Ilia-3), (Ilia-4), (Ilia-5), (IVa-1), (IVa-2), (IVa-3), (IVa-4), (IVa-5), (IVa-6), (IVa-7), (IVa-8), (IVa-9), (IVa-10), (Va-1), (Via-1), or (IVb-1), or a pharmaceutically acceptable salt, isotopic derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, or a pharmaceutical composition as described above.

[0065] In some embodiments, the disease treated and / or prevented is a disease mediated by STAT6, which is a tumor or a type II inflammation related disease selected from atopic dermatitis, bullous pemphigoid, nodular prurigo, chronic spontaneous urticaria, eosinophilic esophagitis, food allergy, chronic rhino-sinusitis with nasal polyps (CRSwNP), chronic rhino-sinusitis without nasal polyps (CRSsNP), non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD / AERD), allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), eosinophilic granulomatosis with polyangiitis (EGPA), or allergic bronchopulmonary aspergillosis.

[0066] Further, the tumor is selected from lymphoma, solitary fibrous tumor, colon cancer, esophageal cancer, breast cancer, cholangiocarcinoma, hepatocarcinoma, renal cancer, gastric cancer, head and neck squamous carcinoma, prostate cancer, lung cancer, non-small cell lung cancer (NSCLC), acute B-lymphoblastic leukemia, bladder cancer, pancreatic cancer, osteosarcoma, myeloma, glioma, ovarian cancer, or skin cancer.

[0067] In some embodiments, the present application provides an intermediate compound M2, which is (3R,4S or 3S,4R)-1-((3S,6S,10aS)-6-amino-5-oxodecahydropyrrolo[l,2-a]azepine-3-carbonyl)-4-phenylpyrrolidine-3-carbonitrile, with the structure as follows:

[0068] In some embodiments, the present application provides intermediate compound M2 as a mixture of 3R,4S and 3S,4R; other similar structures in the present application are also mixtures of 3R,4S and 3S,4R, which are depicted by thick solid lines.

[0069] In some embodiments, the present application provides intermediate compound M3 or a pharmaceutically acceptable salt, isotopic derivative, solvate, or stereoisomer, geometric isomer, tautomer, or prodrug molecule thereof, which has the chemical name of (3S,6S,10aS)-6-amino-3-((R)-2-phenylmorpholine-4-carbonyl)octahydro pyrrolo[l,2-a]oxazin-5(lH)-one trifluoroacetate, and has the following structural formula:

[0070] In some embodiments, the present application provides intermediate compound M1-1 or a pharmaceutically acceptable salt, isotopic derivative, solvate, or stereoisomer, geometric isomer, tautomer, or prodrug molecule thereof:

[0071] wherein R 1a , R 2a , R 6 , R g are as described in general formula (I).

[0072] In some embodiments, the present application provides intermediate compound M1-3 or a pharmaceutically acceptable salt, isotopic derivative, solvate, or stereoisomer, geometric isomer, tautomer, or prodrug molecule thereof:

[0073] wherein R 1a , R 2a , R 5 , R 6 , R 7 , R 8 , R g , Z and Y are as described in general formula (I).

[0074] In some embodiments, the present application provides intermediate compound M1 or a pharmaceutically acceptable salt, isotopic derivative, solvate, or stereoisomer, geometric isomer, tautomer, or prodrug molecule thereof:

[0075] wherein R 1a , R 2a , R 5 , R 6 , R 7 , R 8 , Rg Z and Y are defined as in general formula (I).

[0076] In some embodiments, the present application provides an intermediate compound M4, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or stereoisomer, geometric isomer, tautomer, or prodrug molecule thereof:

[0077] Unless otherwise indicated, the general chemical terms used in the structural formulae have their usual meanings.

[0078] For example, the term "halogen" as used herein, means fluorine, chlorine, bromine or iodine, unless otherwise indicated.

[0079] In the present application, unless otherwise indicated, "alkyl" includes straight-chain or branched-chain monovalent saturated hydrocarbon groups. For example, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, and the like. Similarly, "C 1-6 " in "alkyl" means a straight-chain or branched-chain group containing 1, 2, 3, 4, 5, or 6 carbon atoms. 1-6

[0080] The term "alkylene" refers to the group resulting from removal of one hydrogen from a "alkyl" group as previously defined. For example, methylene, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH(CH3)-, -CH2CH(CH3)CH2-, and the like.

[0081] The term "alkoxy" refers to the oxygen ether form of the straight-chain or branched-chain alkyl groups previously defined, i.e., -O-alkyl.

[0082] The term "haloalkyl" refers to an alkyl group in which one or more H's have been replaced by a halogen atom.

[0083] The term "haloalkoxy" refers to the group -O-haloalkyl.

[0084] The term "oxo" or "oxo group" refers to an oxygen atom in its bivalent substituent form, which forms a carbonyl group when attached to a C, or a sulfoxide or sulfone group or N-oxide group when attached to a heteroatom.

[0085] The term "cycloalkyl" refers to a ring system having at least one ring of cyclized alkyl groups. Preferably, the "cycloalkyl" group contains from 3 to 6 carbon atoms in the ring, more preferably from 3 to 4 carbon atoms in the ring. 3-12 C 3-6 " in "cycloalkyl" means a ring system containing 3, 4, 5, or 6 carbon atoms in the ring. 3-12 ​" is intended to mean that the cycloalkyl group can have 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring-forming atoms. The cycloalkyl group can include monocyclic and polycyclic (e.g., having 2, 3, or 4 fused rings, spiro rings, bridged rings, etc.). In some embodiments, the cycloalkyl group includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, etc. The cycloalkyl group can also be fused to an aryl, heterocyclyl, or heteroaryl ring, wherein the ring that is attached to the parent structure is a cycloalkyl.

[0086] The term "alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds, such as ethenyl, propenyl, 1,3-butadienyl, cis-butenyl, trans-butenyl, and the like.

[0087] The term "alkenylene" refers to the group formed by removing one hydrogen from the "alkenyl" groups described above, such as, for example, -CH=CH-, -CH2CH=CH-, -CH2CH=CHCH2-, and the like.

[0088] The term "imino" refers to the divalent radical that is derived from the removal of two hydrogen atoms from an ammonia molecule, having the structure HN= (or -NH-). When it is attached to a hydrocarbyl group, it forms a secondary amine.

[0089] The term "alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds, such as ethynyl, propynyl, and the like.

[0090] The term "aryl", as used herein, unless otherwise indicated, means an unsubstituted or substituted, monocyclic or fused ring aromatic group including carbon ring atoms. Preferably, the aryl group is a C 6-12 More preferably, the aryl group is a C 6-10 monocyclic or bicyclic aromatic ring group. Preferably, the aryl group is phenyl, naphthyl. The aryl ring can be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring that is attached to the parent structure is an aryl ring, non-limiting examples of which include, but are not limited to, benzocyclopentyl.

[0091] The term "heteroaryl," as used herein, unless otherwise indicated, means a monocyclic or polycyclic (e.g., fused bicyclic) aromatic heterocycle having at least one heteroatom selected from N, O, and / or S, and wherein the nitrogen or sulfur heteroatoms can optionally be oxidized, and the nitrogen heteroatoms can optionally be quaternized. Preferred is a 5-14 membered heteroaryl, wherein "5-14 membered" in 5-14 membered heteroaryl means a heteroaryl group consisting of 5-14 C, N, O, or S ring-forming atoms. More preferred is a 5-10 membered heteroaryl, and even more preferred is a 5-6 membered heteroaryl. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl adenine, quinolinyl, or isoquinolinyl. The heteroaryl group can be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring that is attached to the parent structure is the heteroaryl ring.

[0092] The term "heterocyclyl" means a ring system having at least one ring alkyl or cycloalkenyl ring containing a heteroatom selected from N, O, and / or S. The heterocyclyl group can include a single ring or multiple rings (e.g., having 2, 3, or 4 fused rings, spiro rings, bridged rings, etc.). The heterocyclyl group can be attached to the remainder of the molecule via a ring carbon atom or a ring heteroatom. Preferred is a 3-14 membered heterocyclyl, wherein "3-14 membered" in 3-14 membered heterocyclyl means a heterocyclyl group consisting of 3-14 C, N, O, or S ring-forming atoms; more preferred is a 3-6 membered heterocyclyl, and even more preferred is a 5-6 membered heterocyclyl; wherein the nitrogen or sulfur heteroatoms can optionally be oxidized, and the nitrogen heteroatoms can optionally be quaternized. Examples of these heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and tetrahydrooxadiazolyl. The spiro heterocycle can be a 6-12 membered spiro heterocycle, including but not limited to: 4-azaspiro[2.4]heptane, 4-azaspiro[2.4]heptane. The heterocyclyl group also includes ring systems in which the above heterocyclyl ring is fused to one or more cycloalkyl, aryl, or heteroaryl rings, including but not limited to: indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydrobenzopyranyl, tetrahydropyrano pyridinyl.

[0093] The term "benzyl" refers to a group (C6H5CH2-) formed by removing one hydrogen atom from the methyl carbon of a benzene molecule.

[0094] The term "amino acid residue" refers to the amino acid that makes up a polypeptide after it has been combined with another amino acid, as a result of the loss of a molecule of water due to the formation of a peptide bond by a portion of the group. Thus, the unit of an amino acid in a polypeptide is referred to as an amino acid residue; i.e., the portion of the amino acid remaining after the loss of a molecule of water due to the formation of a peptide bond. For example, a glycine residue is -NH-CH2-CO-.

[0095] The term "alpha amino acid" means any natural (codable) and unnatural alpha-amino carboxylic acid, including their D-isomers, i.e., an alpha amino acid is one in which the amino group is attached to the carbon (also called the alpha carbon atom) that is directly attached to the carboxyl carbon.

[0096] The term "beta amino acid" means any beta-amino carboxylic acid, i.e., an amino acid in which the amino group is attached to a carbon (also called the beta carbon atom) that is separated from the carboxyl carbon by one carbon, e.g., beta-alanine, isoseric acid, and the like.

[0097] The term "alkylamino" refers to an open chain alkyl group containing a nitrogen atom, such as C1-C6 alkylamino, including but not limited to methylamino, ethylamino, isopropylamino, dimethylamino, methylethylamino, diethylamino, and the like.

[0098] The term "alkylthio" refers to a straight or branched chain alkyl group attached through a sulfur atom, i.e., -S-alkyl, such as C1-C6 alkylthio, including but not limited to methylthio, ethylthio, propylthio (including n-propylthio, isopropylthio), butylthio (including n-butylthio, isobutylthio, sec-butylthio, t-butylthio), pentylthio (including n-pentylthio, isopentylthio, neopentylthio), hexylthio (n-hexylthio, 2-methylpentylthio, 3-methylpentylthio, 2,3-dimethylbutylthio, 2,2-dimethylbutylthio), and the like. 1-6 The term "alkylthio" refers to a straight or branched chain alkyl group attached through a sulfur atom, i.e., -S-alkyl, such as C1-C6 alkylthio, including but not limited to methylthio, ethylthio, propylthio (including n-propylthio, isopropylthio), butylthio (including n-butylthio, isobutylthio, sec-butylthio, t-butylthio), pentylthio (including n-pentylthio, isopentylthio, neopentylthio), hexylthio (n-hexylthio, 2-methylpentylthio, 3-methylpentylthio, 2,3-dimethylbutylthio, 2,2-dimethylbutylthio), and the like.

[0099] The term "alkylsulfonyl" refers to a straight or branched chain alkyl group attached through a sulfonyl group, i.e., -SO2-alkyl, such as C1-C6 alkylsulfonyl, including but not limited to methylsulfonyl, ethylsulfonyl, propylsulfonyl (including n-propylsulfonyl, isopropylsulfonyl), butylsulfonyl (including n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, t-butylsulfonyl), pentylsulfonyl (including n-pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl), hexylsulfonyl (n-hexylsulfonyl, 2-methylpentylsulfonyl, 3-methylpentylsulfonyl, 2,3-dimethylbutylsulfonyl, 2,2-dimethylbutylsulfonyl), and the like. 1-6 The term "alkylsulfonyl" refers to a straight or branched chain alkyl group attached through a sulfonyl group, i.e., -SO2-alkyl, such as C1-C6 alkylsulfonyl, including but not limited to methylsulfonyl, ethylsulfonyl, propylsulfonyl (including n-propylsulfonyl, isopropylsulfonyl), butylsulfonyl (including n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, t-butylsulfonyl), pentylsulfonyl (including n-pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl), hexylsulfonyl (n-hexylsulfonyl, 2-methylpentylsulfonyl, 3-methylpentylsulfonyl, 2,3-dimethylbutylsulfonyl, 2,2-dimethylbutylsulfonyl), and the like.

[0100] The term "cyano" means a -CN group.

[0101] The term "pharmaceutically acceptable salt" means a salt prepared from a pharmaceutically acceptable non-toxic base or acid.

[0102] The term "compound" as used herein includes, but is not limited to, the following forms of the compound: free base, stereoisomers, geometric isomers, tautomers, isotopologues, pharmaceutically acceptable salts, solvates, hydrates, prodrugs (esters), and the like.

[0103] The term "compound" as used herein can be asymmetric, e.g., having one or more stereocenters. Unless otherwise specified, all stereoisomers, such as enantiomers and diastereomers, are included within the scope of the present application. Compounds of the present application containing an asymmetric carbon atom can be isolated in optically active form or racemic form. The optically active forms can be obtained by resolution of a racemic mixture or by synthesis from an optically active starting material or reagent.

[0104] The term "pharmaceutically acceptable salt" means a salt of a compound of the present application, which is discovered to have particular substituents, prepared from the compound of the present application with a relatively nontoxic acid or base. Alkali addition salts can be prepared from the neutral form of the compounds of the present application by contacting the neutral form with a sufficient amount of the desired alkali to produce the salt in pure form. Pharmaceutically acceptable alkali addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. Acid addition salts can be prepared from the neutral form of the compounds of the present application by contacting the neutral form with a sufficient amount of an acid to produce the salt in pure form. Certain specific compounds of the present application contain both basic and acidic functionalities and, thus, can be converted into either alkali or acid addition salts.

[0105] The pharmaceutically acceptable salts of the present application can be synthesized from the parent compound that contains an acidic or basic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of both.

[0106] When the compounds provided herein are acids, their corresponding salts can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, as well as salts of cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. Other pharmaceutically acceptable non-toxic organic bases from which salts can be derived include ion exchange resins as well as compounds of arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, chloroprocaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0107] When the compounds provided herein are bases, their corresponding salts can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, cyclohexanesulfamic acid, salicylic acid, 2- naphthalenesulfonic acid, saccharinic acid, trifluoroacetic acid, tartaric acid, p-toluenesulfonic acid, and the like. Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid. More preferably, formic acid and hydrochloric acid.

[0108] The term "isomers" is intended to include geometric isomers, cis / trans isomers, stereoisomers, enantiomers, optical isomers, diastereomers, and tautomers, unless otherwise indicated.

[0109] In addition to salt forms, the compounds provided herein can exist in a variety of solid and liquid forms, including crystalline and amorphous forms. In general, the crystal forms of the compounds provided herein are more desirable than the amorphous forms.

[0110] The compounds of the present application can contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds can be radiolabeled with radioactive isotopes such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14C). For example, deuterium substitution for hydrogen can afford greater metabolic stability, e.g., to a compound. All isotopologues of compounds of the present application are included within the scope of the application, whether or not radioactive.

[0111] Prodrugs of the compounds of the present application are included within the scope of the present application. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired compound. Thus, for example, any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of this application, which upon in vivo administration is capable of providing (directly or indirectly) the compound or a pharmaceutically active metabolite or residue thereof, is within the scope of this application.

[0112] The compounds of the present application can contain one or more asymmetric centers and can thus give rise to diastereomers and optical isomers. The present application includes all possible diastereomers, the racemic mixtures, the substantially pure resolved enantiomers, all possible geometric isomers, and the pharmaceutically acceptable salts thereof.

[0113] When the compounds of formula (I) exist as tautomers, the present application includes any possible tautomer and mixtures thereof, and the pharmaceutically acceptable salts thereof, unless specified otherwise.

[0114] The present application also includes all isotopic variations of the atoms occurring in the intermediates or final compounds. Isotopic variations of the atoms include those with the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0115] The term "pharmaceutical composition" means a mixture of one or more compounds of the present application, or pharmaceutically acceptable salts thereof, with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound of the present application to an organism.

[0116] In the present application, "a," "an," "the," "at least one," and "one or more" are used interchangeably. Thus, for example, a mixture comprising "a" pharmaceutically acceptable excipient can be interpreted to mean that the pharmaceutical composition includes "one or more" pharmaceutically acceptable excipients.

[0117] The term "pharmaceutically acceptable excipient" means an excipient that is not biologically or otherwise undesirable, i.e., the excipient can be administered to an organism without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained. The suitable excipient is well known to one skilled in the art, e.g., carbohydrates, waxes, water soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0118] The pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, pastes, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres, aerosols and the like.

[0119] Typical routes of administering the compounds of the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

[0120] The term "treatment" generally refers to obtaining a desired pharmacologic and / or physiologic effect. The effect can be therapeutic in terms of partially or completely stabilizing or reversing a disease and / or side effects caused by the disease. As used herein, "treatment" covers any treatment of a patient's disease, including: (a) inhibiting the disease symptoms, i.e., arresting their development; or (b) relieving the disease symptoms, i.e., causing regression of the disease or symptoms.

[0121] The term "effective amount" means the amount of a compound of the present application which (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The amount of a compound of the present application that will constitute an "effective amount" will vary depending on the compound, the disease state and its severity, the manner of administration, and the age of the mammal to be treated, but can be routinely determined by the skilled practitioner according to his own knowledge and the disclosure herein.

[0122] The term "STAT6" refers to signal transducer and activator of transcription family member 6.

[0123] Based on the STAT6 target, the present application develops a series of structurally novel compounds, and the present application first applies the oxamide parent nucleus in the development of STAT6 inhibitors. The biological experiment results show that the compound of the present application can significantly inhibit the phosphorylation of STAT6, has good physicochemical properties, excellent pharmacokinetic characteristics, and good metabolic stability between different species, low hERG inhibition rate, and has great clinical application prospect. DETAILED DESCRIPTION

[0124] In order to make the above content more clear and explicit, the technical solutions of the present application will be further illustrated by the following examples. The following examples are only used to illustrate the specific embodiments of the present application, so that those skilled in the art can understand the present application, but are not used to limit the protection scope of the present application. In the specific embodiments of the present application, the technical means or methods not specifically described are the conventional technical means or methods in the art.

[0125] Unless otherwise specified, all temperatures in the present application refer to degrees Celsius.

[0126] The following abbreviations are used in the present application:

[0127] DCM: dichloromethane; DMF: N,N-dimethylformamide; DIPEA: N,N-diisopropylethylamine; EA: ethyl acetate; LC-MS: liquid chromatography-mass spectrometry; HATU: 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; TFA: trifluoroacetic acid; Cd: cadmium powder; CuCl: cuprous chloride; LiOH: lithium hydroxide; THF: tetrahydrofuran; TMSBr: trimethylsilyl bromide; AgNO3: silver nitrate; NaOH: sodium hydroxide; CH3I: methyl iodide; NaH: sodium hydride; DMSO: dimethyl sulfoxide; LC-MS: liquid chromatography-mass spectrometry; HEPES: hydroxyethylpiperazine ethanesulfonic acid; Tween 20: Tween 20; EDTA: ethylenediaminetetraacetic acid; DTT: dithiothreitol; ddH2O: double distilled water; IPTG: isopropyl-β-D-thiogalactopyranoside; 5-FAM: 5-FAM-ApYKPFQDLI-NH2; SDS-PAGE: sodium dodecyl sulfate-polyacrylamide; PBST: phosphate buffered saline solution; PVDF membrane: polyvinylidene fluoride membrane; TBST: Tris-buffered saline containing Tween 20; FBS: fetal bovine serum; DMEM: Dulbecco's modified eagle's medium; IL-4: interleukin 4; BSA: bovine serum albumin; PBS: phosphate buffered saline solution; PMSF: phenylmethylsulfonyl fluoride.

[0128] In the examples of the present application, x mL x y: indicates that y times, each time x mL, for example, ethyl acetate (20 mL x 3) extraction, indicates that each time 20 mL of ethyl acetate is used for extraction, and the extraction is repeated 3 times; in the examples of the present application, the amount of eluent is by volume, for example, petroleum ether: ethyl acetate = 40:60 indicates that the volume ratio of the amount of petroleum ether and ethyl acetate is 40:60.

[0129] In addition, all operations involving easily oxidizable or easily hydrolyzable raw materials are carried out under nitrogen protection. Unless otherwise specified, the raw materials used in the present application are commercially available raw materials, which can be used directly without further purification.

[0130] The raw materials and intermediates for the reactions in the embodiments of the present application can be obtained by purchase or self-preparation. The raw materials and intermediates for the reactions that need to be self-prepared are prepared according to the following detailed processes.

[0131] Preparation route: preparation of key intermediate M1

[0132] Compound M1-1 and compound M1-2 undergo an amide condensation reaction under basic conditions to generate compound M1-3, and compound M1-3 is removed of the protecting group in the presence of trimethylsilyl bromide to obtain compound M1.

[0133] wherein, R 1a , R 2a , R 5 , R 6 , R 7 , R 8 , R g , Z and Y are as defined in general formula (I).

[0134] Synthesis of intermediate M2: (3R, 4S or 3S, 4R)-1-((3S, 6S, 10aS)-6-amino-5-oxodecahydropyrrolo[1, 2-a]azepine-3-carbonyl)-4-phenylpyrrolidine-3-carbonitrile

[0135] Step 1: Synthesis of tert-butyl ((3S, 6S, 10aS)-3-((3R, 4S or 3S, 4R)-3-cyano-4-phenylpyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1, 2-a]azepin-6-yl)carbamate (M2-2)

[0136] (3S,6S,10aS)-6-((tert-butoxycarbonyl)amino)-5-oxodecahydropyrrolo[l,2- a]azepine-3-carboxylic acid (M2-1, 326 mg, 1 mmol) and (3R,4S or 3S,4R)-4- phenylpyrrolidine-3-carbonitrile (206 mg, 1.2 mmol, prepared according to WO2023133336) were added into a flask, 5 mL DMF was added as solvent, cooled to 0 °C in ice bath, then keep the temperature, added HATU (570 mg, 1.5 mmol) and DIPEA (193 mg, 1.5 mmol), restore to room temperature for reaction, LC-MS showed the reaction was completed after 10 min, dissolved with 40 mL EA, washed with saturated brine (20 mL) for 3 times, dried with anhydrous sodium sulfate, concentrated under reduced pressure, passed through a reversed phase column (methanol / water = 5-95% gradient elution) to obtain the target product ((3S,6S,10aS)-3-((3R,4 or 3S,4R)-3-cyano-4-phenylpyrrolidine-l-carbonyl)-5- oxodecahydropyrrolo[l,2-a]azepin-6-yl)carbamic acid tert-butyl ester, freeze-dried to obtain M2-2 (290 mg), the yield was 60%.

[0137] LC-MS (m / z): 481.1 [M+H] + .

[0138] 1 H NMR (400 MHz, Chloroform-d) δ 7.28 - 7.44 (m, 5H), 4.94 - 5.37 (m, 1H), 4.18 - 4.72 (m, 4H), 3.97 - 4.17 (m, 2H), 3.51 - 3.82 (m, 2H), 3.09 - 3.36 (m, 1H), 1.89 - 2.20 (m, 6H), 1.54 - 1.76 (m, 5H), 1.43 (s, 9H).

[0139] Step 2: Synthesis of (3R,4S or 3S,4R)-l-((3S,6S,10aS)-6-amino-5-oxodecahydropyrrolo[l,2- a]azepine-3-carbonyl)-4-phenylpyrrolidine-3-carbonitrile (M2)

[0140] ((3S,6S,10aS)-3-((3R,4S or 3S,4R)-3-cyano-4-phenylpyrrolidine-l-carbonyl)-5- oxodecahydropyrrolo[l,2-a]azepin-6-yl)carbamic acid tert-butyl ester (M2-2, 290 mg, 0.6 mmol) was dissolved with 12 mL DCM, cooled to 0 °C in ice bath, then added 3 mL trifluoroacetic acid, restored to room temperature for reaction for 1 h, LC-MS monitoring showed the reaction was completed, the organic phase was concentrated under reduced pressure, which could be directly used in the next step of amide condensation reaction without purification.

[0141] LC-MS (m / z): 381.2 [M+H] + .

[0142] Synthesis of intermediate M3: (3S,6S,10aS)-6-amino-3-((R)-2-phenylmorpholine-4- carbonyl)octahydro pyrrolo[l,2-a]oxazin-5(lH)-one trifluoroacetate salt

[0143] Step 1: Synthesis of compound tert-butyl ((3S,6S,10aS)-5-oxo-3-((R)-2-phenylmorpholine-4- carbonyl)decahydropyrrolo[l,2-a]oxazin-6-yl)carbamate (M3-2)

[0144] Compound M2-1 (326.00 mg, 1.00 mmol) and (R)-2-phenylmorpholine (163.00 mg, 1.00 mmol) were dissolved in N,N-dimethylformamide (5 mL), the reaction solution was cooled to 0 °C, diisopropylethylamine (322.00 mg, 2.50 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl)urea hexafluorophosphate (570.00 mg, 1.50 mmol) were added successively, and the reaction was carried out at 25 °C for 30 min. After the reaction was completed by LC-MS monitoring, water (20 mL) was added, and the combined organic phase was extracted with ethyl acetate (3 times, 20 mL each time), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 40:60 as eluent) gave compound M3-2 (470.00 mg) with a yield of 99.8%.

[0145] LC-MS (m / z): 472.0 [M+H] + .

[0146] Step 2: Synthesis of compound (3S,6S,10aS)-6-amino-3-((R)-2-phenylmorpholine-4- carbonyl)octahydro pyrrolo[l,2-a]oxazin-5(lH)-one trifluoroacetate salt (M3)

[0147] Compound M3-2 (470.00 mg, 1.00 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (5 mL) was added. The reaction solution was reacted at 25 °C for 1 h. After the reaction was completed by LC-MS monitoring, it was concentrated under reduced pressure to give compound M3 (370.00 mg) with a yield of 99.7%.

[0148] LC-MS (m / z): 372.0 [M+H] + .

[0149] Synthesis of intermediate M4: (3S, 6S, 10aS)-6-amino-3-((S)-2-phenylmorpholine-4- carbonyl)octahydro pyrrolo[l,2-a]oxazin-5(lH)-one trifluoroacetate salt (M4)

[0150] Step 1: Synthesis of compound tert-butyl ((3S, 6S, 10aS)-5-oxo-3-((S)-2-phenylmorpholine-4- carbonyl)decahydropyrrolo[l,2-a]oxazin-6-yl)carbamate (M4-2)

[0151] Compound M2-1 (0.326 g, 1.00 mmol) and (S)-2-phenylmorpholine (0.163 g, 1.00 mmol) were dissolved in N,N-dimethylformamide (5 mL), the reaction solution was cooled to 0 °C, diisopropylethylamine (0.322 g, 2.50 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl)urem hexafluorophosphate (0.570 g, 1.50 mmol) were added successively, and the reaction was carried out at 25 °C for 30 min. After the reaction was completed by LC-MS monitoring, water (20 mL) was added, and the combined organic phase was extracted with ethyl acetate (20 mL x 3), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 40:60 as eluent) gave compound M4-2 (0.470 g) with a yield of 99.8%.

[0152] LC-MS (m / z): 472.0 [M+H] + .

[0153] Step 2: Synthesis of compound (3S, 6S, 10aS)-6-amino-3-((S)-2-phenylmorpholine-4- carbonyl)octahydro pyrrolo[l,2-a]oxazin-5(lH)-one trifluoroacetate salt (M4)

[0154] Compound M4-2 (0.470 g, 1.00 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (5 mL) was added. The reaction solution was reacted at 25 °C for 1 h. After the reaction was completed by LC-MS monitoring, it was concentrated under reduced pressure to give compound M4 (0.370 g) with a yield of 99.7%.

[0155] LC-MS (m / z): 472.0 [M+H] + .

[0156] Synthesis of Example 1 (((((4-(2-((3S,6S,10aS)-3-((3R,4S or 3S,4R)-3-cyano-4- phenylpyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]azepin-6-yl)amino)-2- oxoacetamido)phenyl) difluoromethyl) phosphoryl)bis(oxy))bis(methylene)bis(2,2- dimethylpropanoate) (Compound 1)

[0157] Step 1: Synthesis of compound methyl 2-((4-iodophenyl)amino)-2-oxoacetate (1-2)

[0158] Compound 1-1 (3.00 g, 13.70 mmol) was dissolved in anhydrous dichloromethane (60 mL), diisopropylethylamine (2.65 g, 20.54 mmol) was added, the reaction solution was cooled to 0 °C, oxalyl chloride monomethyl ester (2.00 g, 16.39 mmol) was added dropwise, and it was allowed to react at 25 °C for 1 hour. After the reaction was completed by LC-MS monitoring, water (50 mL) was added, and dichloromethane (3 times, 50 mL each time) was used for extraction, the combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50:50 as eluent) to obtain compound 1-2 (4.02 g), with a yield of 96.2%.

[0159] LC-MS (m / z): 306.0 [M+H] + .

[0160] Step 2: Synthesis of compound methyl 2-((4-(diethoxyphosphoryl)difluoromethyl)phenyl)amino)-2-oxoacetate (1-3)

[0161] To a 50 mL three-necked flask, cadmium powder (1.61 g, 14.38 mmol) was added, and a solution of bromofluoromethyl phosphonic acid diethyl ester (3.50 g, 13.11 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added, and the reaction was carried out at 40 °C for 2 hours. Another three-necked flask was prepared, and cuprous chloride (0.97 g, 9.80 mmol) and compound 1-2 (2.00 g, 6.56 mmol) were dissolved in anhydrous N,N-dimethylformamide (15 mL). The yellow solution in the cadmium powder flask was filtered out with a filter head and slowly injected into the second flask. The reaction was carried out at 40 °C for 16 hours. Ethyl acetate (50 mL) and water (50 mL) were added, and the mixture was filtered with diatomite. The filtrate was extracted with ethyl acetate (3 times, 50 mL each time), and the combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 40:60 as eluent) gave compound 1-3 (1.50 g) in a yield of 62.7%.

[0162] LC-MS (m / z): 366.0 [M+H] + .

[0163] Step 3: Synthesis of compound 2-((4-(diethoxyphosphoryl)difluoromethyl)phenyl)amino)-2- oxoacetic acid (1-4)

[0164] Compound 1-3 (200.00 mg, 0.55 mmol) was dissolved in tetrahydrofuran (3 mL), and a solution of lithium hydroxide (46.00 mg, 1.10 mmol) in water (3 mL) was added dropwise while cooling to 0 °C. The reaction was carried out at 0 °C for 15 minutes. When the reaction was completed by LC-MS monitoring, 1.0 M dilute hydrochloric acid was added to the reaction solution, and the pH of the aqueous phase was adjusted to be acidic. The aqueous phase was extracted with ethyl acetate (3 times, 20 mL each time), and the combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 1-4 (189.00 mg) in a yield of 97.9%.

[0165] LC-MS (m / z): 350.0 [M-H] - .

[0166] Step 4: Synthesis of compound diethyl (4-(2-(((3S,6S,10aS)-3-((3R,4S or 3S,4R)-3-cyano-4- phenylpyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]azepin-6-yl)amino)-2- oxoacetamido)phenyl) difluoromethyl) phosphonic acid diethyl ester (1-5)

[0167] Compound 1-4 (189.00 mg, 0.54 mmol) and M2 (257.00 mg, 0.54 mmol) were dissolved in a mixed solution of tetrahydrofuran (8 mL) and N,N-dimethylformamide (2 mL), the reaction solution was cooled to 0 °C, and diisopropylethylamine (209.00 mg, 1.62 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (308.00 mg, 0.81 mmol) were sequentially added. The reaction solution was allowed to react at 25 °C for 1 hour. After the completion of the reaction was confirmed by LC-MS, water (20 mL) was added, and the combined organic phase was extracted with ethyl acetate (20 mL, 3 times), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (dichloromethane:methanol = 96:4 as an eluent) gave compound 1-5 (350.00 mg) with a yield of 90.9%.

[0168] LC-MS (m / z): 714.0 [M+H] + .

[0169] Step 5: Synthesis of compound (4-(2-(((3S,6S,10aS)-3-((3R,4S or 3S,4R)-3-cyano-4- phenylpyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]azepin-6-yl)amino)-2- oxoacetylamino)phenyl)difluoromethyl)phosphonic acid (93)

[0170] Compound 1-5 (220.00 mg, 0.31 mmol) was dissolved in anhydrous dichloromethane (10 mL), and the reaction solution was cooled to 0 °C. Trimethylsilyl bromide (1.42 g, 9.30 mmol) was added dropwise, and the reaction solution was allowed to react at 25 °C for 16 hours. After the completion of the reaction was confirmed by LC-MS, the reaction solution was concentrated under reduced pressure, and a mixed solution of acetonitrile (8 mL) and water (2 mL) was added. The reaction solution was allowed to react at 25 °C for 40 minutes, concentrated under reduced pressure, and purified by reverse phase column chromatography (methanol:water = 50:50 as an eluent) to obtain compound 93 (129.00 mg) with a yield of 63.3%.

[0171] LC-MS (m / z): 658.0 [M+H] + .

[0172] Step 6: Synthesis of compound ((((4-(2-((3S,6S,10aS)-3-((3R,4S or 3S,4R)-3-cyano-4- phenylpyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]azepin-6-yl)amino)-2- oxoacetylamino)phenyl)difluoromethyl)phosphoryl)bis(oxy))bis(methylene)bis(2,2- dimethylpropanoate) (1)

[0173] Compound 93 (129.00 mg, 0.20 mmol) was dissolved in water (2 mL), the solution was cooled to 0 °C, and a solution of sodium hydroxide (15.00 mg, 0.38 mmol) in water (2 mL) was added dropwise. After the addition was completed, the pH of the solution was about 9, and silver nitrate (79.00 mg, 0.46 mmol) was added. The solution was stirred at 0 °C for 2 h. After filtration, the solid was dried under reduced pressure with an oil pump (rotary vane vacuum pump), and the dried solid was dissolved in toluene (3 mL). Iodomethyl pivalate (152.00 mg, 0.63 mmol) was added, and the solution was stirred at 25 °C for 16 h. After the reaction was completed as monitored by LC-MS, the solution was filtered and concentrated under reduced pressure. Compound 1 (10.40 mg) was obtained by HPLC purification with a yield of 5.9%.

[0174] LC-MS (m / z): 886.0 [M+H] + .

[0175] 1 H NMR (400 MHz, DMSO-d6) δ 11.1-10.9 (m, 1H), 8.81-8.67 (m, 1H), 8.10-7.93 (m, 2H), 7.58-7.27 (m, 7H), 5.75-5.62 (m, 4H), 4.86-4.68 (m, 1H), 4.59-4.45 (m, 1H), 4.41-4.18 (m, 2H), 4.15-3.94 (m, 1H), 3.94-3.74 (m, 2H), 3.74-3.60 (m, 1H), 3.60-3.44 (m, 1H), 2.37-2.17 (m, 1H), 2.10-1.48 (m, 11H), 1.15 (s, 18H).

[0176] Synthesis of (((4-(2-((3S,6S,10aS)-3-((3R,4S or 3S,4R)-3-cyano-4-phenylpyrrolidine-1- carbonyl)-5-oxodecahydropyrrolo[1,2-a]azepin-6-yl)amino)-N-methyl-2-oxoacetamido)phenyl) difluoromethyl)phosphoryl)bis(oxy))bis(methylene)bis(2,2-dimethylpropanoate) (Compound 2)

[0177] Step 1: Synthesis of methyl 2-((4-(diethoxyphosphoryl)difluoromethyl)phenyl)(methyl) amino)-2-oxoacetate (2-1)

[0178] Sodium hydride (41.00 mg, 1.02 mmol) was dissolved in N,N-dimethylformamide (5 mL), and 1-3 (250.00 mg, 0.68 mmol) in N,N-dimethylformamide (3 mL) was slowly added dropwise under ice bath conditions, and was allowed to react at 25 °C for 30 minutes. The reaction solution was cooled to 0 °C, and iodomethane (127.00 mg, 0.88 mmol) was slowly added dropwise, and was allowed to react at 25 °C for 1 hour. After the completion of the reaction was confirmed by LC-MS, water (20 mL) was added, and the combined organic phase was extracted with ethyl acetate (3 times, 20 mL each), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50:50 as eluent) to obtain compound 2-1 (200.00 mg) at a yield of 77.6%.

[0179] LC-MS (m / z): 380.0 [M+H] + .

[0180] Step 2: Synthesis of compound 2-((4-(diethoxyphosphoryl)difluoromethyl)phenyl)(methyl)amino)-2-oxoacetic acid (2-2)

[0181] Compound 2-1 (200.00 mg, 0.53 mmol) was dissolved in tetrahydrofuran (5 mL), and a lithium hydroxide monohydrate aqueous solution (45.00 mg, 1.06 mmol) in water (5 mL) was added, and was allowed to react at 25 °C for 10 minutes. After the completion of the reaction was confirmed by LC-MS, concentrated hydrochloric acid was added to the reaction solution, and the pH of the aqueous phase was adjusted to be acidic. The aqueous phase was extracted with ethyl acetate (3 times, 20 mL each), and the combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 2-2 (130.00 mg) at a yield of 67.2%.

[0182] LC-MS (m / z): 366.0 [M+H] + .

[0183] Step 3: Synthesis of compound diethyl (4-(2-(((3S,6S,10aS)-3-((3R,4S or 3S,4R)-3-cyano-4-phenylpyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]azepin-6-yl)amino)-N-methyl-2-oxoacetamido)phenyl)difluoromethylphosphonic acid diethyl ester (2-3)

[0184] Compound 2-2 (130.00 mg, 0.36 mmol) and M2 (137.00 mg, 0.36 mmol) were dissolved in N,N-dimethylformamide (10 mL), the reaction solution was cooled to 0 °C, diisopropylethylamine (140.00 mg, 1.08 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (205.00 mg, 0.54 mmol) were added successively, and the reaction was carried out at 25 °C for 1 h. After the reaction was completed by LC-MS monitoring, water (20 mL) was added, and the combined organic phase was extracted with ethyl acetate (3 times, 20 mL each time), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (dichloromethane:methanol = 90:10 as eluent) gave compound 2-3 (230.00 mg) with a yield of 87.9%.

[0185] LC-MS (m / z): 728.0 [M+H] + .

[0186] Step 4: Synthesis of compound (4-(2-(((3S,6S,10aS)-3-((3R,4S or 3S,4R)-3-cyano-4- phenylpyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]azepin-6-yl)amino)-N- methyl-2-oxoacetamido)phenyl)difluoromethyl)phosphonic acid (94)

[0187] Compound 2-3 (230.00 mg, 0.32 mmol) was dissolved in anhydrous dichloromethane (10 mL), the reaction solution was cooled to 0 °C, and trimethylsilyl bromide (1.47 g, 9.6 mmol) was added dropwise. The reaction solution was placed at 25 °C for 16 h. After the reaction was completed by LC-MS monitoring, the solution was concentrated under reduced pressure, a mixture of acetonitrile (8 mL) and water (2 mL) was added, the reaction solution was placed at 25 °C for 40 min, and concentrated under reduced pressure. Purification by reverse phase column chromatography (methanol:water = 80:20 as eluent) gave compound 94 (60.00 mg) with a yield of 27.9%.

[0188] LC-MS (m / z): 672.0 [M+H] + .

[0189] Step 5: Synthesis of compound ((((4-(2-((3S,6S,10aS)-3-((3R,4S or 3S,4R)-3-cyano-4- phenylpyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]azepin-6-yl)amino)-N- methyl-2-oxoacetamido)phenyl)difluoromethyl)phosphoryl)bis(oxy))bis(methylene)bis(2,2- dimethylpropanoate) (2)

[0190] Compound 94 (60.00 mg, 0.09 mmol) was dissolved in water (2 mL), the solution was cooled to 0 °C, and a solution of sodium hydroxide (6.48 mg, 0.16 mmol) in water (2 mL) was added dropwise. After the addition was completed, the pH of the solution was about 9, silver nitrate (34.00 mg, 0.20 mmol) was added, and the solution was allowed to react at 0 °C for 2 h. Filtration was performed, and the solid was collected and dried under reduced pressure using an oil pump (rotary vane vacuum pump). The dried solid was dissolved in toluene (3 mL), and iodomethyl pivalate (65.34 mg, 0.27 mmol) was added. The solution was allowed to react at 25 °C for 16 h. After the reaction was completed as monitored by LC-MS, filtration was performed, and the solution was concentrated under reduced pressure. Purification was performed by thin layer chromatography to obtain compound 2 (7.80 mg) in a yield of 9.8%.

[0191] LC-MS (m / z): 900.0 [M+H] + .

[0192] 1 H NMR (600 MHz, DMSO-d6) δ 8.85-8.70 (m, 1H), 7.65-7.28 (m, 9H), 5.68 (d, J = 22.1 Hz, 4H), 4.64-4.46 (m, 2H), 4.41-3.93 (m, 2H), 3.89-3.47 (m, 3H), 3.24 (d, J = 22.7 Hz, 4H), 2.42-2.07 (m, 2H), 1.99 (dt, J = 18.8, 7.1 Hz, 2H), 1.89-1.56 (m, 5H), 1.46 (d, J = 9.6 Hz, 2H), 1.41-1.24 (m, 1H), 1.16 (s, 18H), 1.08-0.81 (m, 1H).

[0193] Synthesis of (((4-(N-butyl-2-(((3S,6S,10aS)-3-((3R,4S or 3S,4R)-3-cyano-4- phenylpyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]azepin-6-yl)amino)-2- oxoacetamido)phenyl) difluoromethyl) phosphoryl) bis(oxy))bis(methylene) bis(2,2- dimethylpropanoate) (3)

[0194] Step 1: Synthesis of compound methyl 2-(butyl(4-(diethoxyphosphoryl)difluoromethyl) phenyl) amino)-2-oxoacetate (3-1)

[0195] Compound 1-3 (340.00 mg, 0.93 mmol) was dissolved in N,N-dimethylformamide (10 mL), potassium carbonate (386.00 mg, 2.80 mmol), tetrabutylammonium iodide (69.00 mg, 0.19 mmol) and n-butyl iodide (515.00 mg, 2.80 mmol) were added successively, and the mixture was reacted at 25 °C for 16 hours. After the reaction was completed by LC-MS monitoring, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL for three times), and the combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (dichloromethane:methanol = 98:2 as eluent) gave compound 3-1 (300.00 mg) with a yield of 76.6%.

[0196] LC-MS (m / z): 422.0 [M+H] + .

[0197] Step 2: Synthesis of compound 2-(butyl(4-(ethoxy(hydroxy)phosphoryl)difluoromethyl)phenyl)amino)-2-oxoacetic acid (3-2)

[0198] Compound 3-1 (300.00 mg, 0.71 mmol) was dissolved in tetrahydrofuran (5 mL), and an aqueous solution (5 mL) of lithium hydroxide monohydrate (60.00 mg, 1.43 mmol) was added, and the mixture was reacted at 25 °C for 10 minutes. After the reaction was completed by LC-MS monitoring, concentrated hydrochloric acid was added to the reaction solution, and the pH of the aqueous phase was adjusted to be acidic. The aqueous phase was extracted with ethyl acetate (20 mL for three times), and the combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 3-2 (178.00 mg) with a yield of 66.1%.

[0199] LC-MS (m / z): 380.0 [M+H] + .

[0200] Step 3: Synthesis of compound ethyl hydrogen(4-(N-butyl-2-(((3S,6S,10aS)-3-((3R,4S or 3S,4R)-3-cyano-4-phenylpyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]azepin-6-yl)amino)-2-oxoacetamido)phenyl)difluoromethyl)phosphonate (3-3)

[0201] Compound 3-2 (178.00 mg, 0.47 mmol) and M2 (224.00 mg, 0.47 mmol) were dissolved in a mixed solution of tetrahydrofuran (8 mL) and N,N-dimethylformamide (2 mL), the reaction solution was cooled to 0 °C, and diisopropylethylamine (363.00 mg, 2.81 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (267.00 mg, 0.70 mmol) were sequentially added, and the reaction was allowed to proceed at 25 °C for 1 hour. After the completion of the reaction was confirmed by LC-MS, water (20 mL) was added, and the combined organic phase was extracted with ethyl acetate (20 mL), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (dichloromethane:methanol = 90:10 as an eluent) gave compound 3-3 (340.00 mg) with a yield of 97.6%.

[0202] LC-MS (m / z): 742.0 [M+H] + .

[0203] Step 4: Synthesis of compound (4-(N-butyl-2-(((3S,6S,10aS)-3-((3R,4S or 3S,4R)-3-cyano-4-phenylpyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]oxazin-6-yl)amino)-2-oxoacetamido)phenyl)difluoromethyl)phosphonic acid (95)

[0204] Compound 3-3 (340.00 mg, 0.46 mmol) was dissolved in anhydrous dichloromethane (10 mL), and the reaction solution was cooled to 0 °C. Trimethylsilyl bromide (2.16 g, 14.1 mmol) was added dropwise, and the reaction was allowed to proceed at 25 °C for 16 hours. After the completion of the reaction was confirmed by LC-MS, a mixed solution of acetonitrile (8 mL) and water (2 mL) was added, and the reaction was allowed to proceed at 25 °C for 40 minutes. After concentration under reduced pressure, purification by reverse phase column chromatography (methanol:water = 80:20 as an eluent) gave compound 95 (162.00 mg) with a yield of 49.4%.

[0205] LC-MS (m / z): 714.0 [M+H] + .

[0206] Step 5: Synthesis of compound ((((4-(N-butyl-2-(((3S,6S,10aS)-3-((3R,4S or 3S,4R)-3-cyano-4-phenylpyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]oxazin-6-yl)amino)-2-oxoacetamido)phenyl)difluoromethyl)phosphoryl)bis(oxy))bis(methylene)bis(2,2-dimethylpropanoate) (3)

[0207] Compound 95 (162.00 mg, 0.23 mmol) was dissolved in water (2 mL), the solution was cooled to 0 °C, and a solution of sodium hydroxide (17.00 mg, 0.41 mmol) in water (2 mL) was added dropwise. After the addition was completed, the pH of the solution was about 9, and silver nitrate (86.00 mg, 0.51 mmol) was added. The solution was stirred at 0 °C for 2 h. After filtration, the solid was dried under reduced pressure with an oil pump (rotary vane vacuum pump), and the dried solid was dissolved in toluene (3 mL). Iodomethyl pivalate (167.00 mg, 0.69 mmol) was added, and the solution was stirred at 25 °C for 16 h. After the reaction was completed as monitored by LC-MS, the solution was filtered and concentrated under reduced pressure. Compound 3 (29.20 mg) was obtained by HPLC purification with a yield of 13.5%.

[0208] LC-MS (m / z): 942.0 [M+H] + .

[0209] 1 H NMR (600 MHz, DMSO-d6) δ 8.88-8.68 (m, 1H), 7.62-7.31 (m, 9H), 5.76-5.57 (m, 4H), 4.63-4.41 (m, 2H), 4.41-4.17 (m, 1H), 4.16-3.92 (m, 2H), 3.91-3.44 (m, 6H), 3.31-3.21 (m, 1H), 2.29-2.13 (m, 1H), 2.04-1.91 (m, 1H), 1.90-1.69 (m, 4H), 1.68-1.59 (m, 1H), 1.59-1.49 (m, 1H), 1.49-1.34 (m, 4H), 1.33-1.22 (m, 4H), 1.16 (s, 18H), 0.88-0.80 (m, 2H).

[0210] Example 4 Synthesis of ((difluoro(4-(2-oxo-2-(((3S,6S,10aS)-5-oxo-3-((R)-2-phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2-a]azepin-6-yl)amino)acetylamino)phenyl)methyl)phosphoryl)bis(oxy)bis(methylene)bis(2,2-dimethylpropanoate) (Compound 4)

[0211] Step 1: Synthesis of diethyl difluoro(4-(2-oxo-2-(((3S,6S,10aS)-5-oxo-3-((R)-2-phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2-a]azepin-6-yl)amino)acetylamino)phenyl)methyl)phosphonate (4-1)

[0212] Compound 1-4 (200.00 mg, 0.57 mmol) and M3 (257.00 mg, 0.55 mmol) were dissolved in a mixed solution of tetrahydrofuran (8 mL) and N,N-dimethylformamide (2 mL), the reaction solution was cooled to 0 °C, diisopropylethylamine (213.00 mg, 1.65 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (314.00 mg, 0.83 mmol) were added successively, and the reaction was carried out at 25 °C for 1 h. After the reaction was completed by LC-MS monitoring, water (20 mL) was added, and the combined organic phase was extracted with ethyl acetate (3 times, 20 mL each time), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (dichloromethane:methanol = 98:2 as eluent) gave compound 4-1 (350.00 mg) with a yield of 87.2%.

[0213] LC-MS (m / z): 705.0 [M+H] + .

[0214] Step 2: Synthesis of compound (difluoro(4-(2-oxo-2-(((3S,6S,10aS)-5-oxo-3-((R)-2-phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2-a]oxazin-6-yl)amino)acetylamino)phenyl)methyl)phosphonic acid (52)

[0215] Compound 4-1 (350.00 mg, 0.50 mmol) was dissolved in anhydrous dichloromethane (10 mL), the reaction solution was cooled to 0 °C, and trimethylsilyl bromide (2.30 g, 15.03 mmol) was added dropwise. The reaction was carried out at 25 °C for 16 h. After the reaction was completed by LC-MS monitoring, the solution was concentrated under reduced pressure, a mixed solution of acetonitrile (8 mL) and water (2 mL) was added, the reaction solution was placed at 25 °C for 40 min, and concentrated under reduced pressure. Purification by reverse phase column chromatography (methanol:water = 80:20 as eluent) gave compound 52 (100.00 mg) as a yellow liquid with a yield of 30.9%.

[0216] LC-MS (m / z): 649.0 [M+H] + .

[0217] Step 3: Synthesis of compound (((difluoro(4-(2-oxo-2-(((3S,6S,10aS)-5-oxo-3-((R)-2-phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2-a]oxazin-6-yl)amino)acetylamino)phenyl)methyl)phosphoryl)bis(oxy)bis(methylene)bis(2,2-dimethylpropanoate) (4)

[0218] Compound 52 (100 mg, 0.15 mmol) was dissolved in water (2 mL), the solution was cooled to 0 °C, and a solution of sodium hydroxide (11.00 mg, 0.28 mmol) in water (2 mL) was added dropwise. After the addition was completed, the pH of the solution was about 9, and silver nitrate (58.00 mg, 0.34 mmol) was added. The solution was stirred at 0 °C for 2 h. The solid was collected by filtration, dried under reduced pressure with an oil pump (rotary vane vacuum pump), and then dissolved in toluene (3 mL). Iodomethyl pivalate (112.00 mg, 0.46 mmol) was added, and the solution was stirred at 25 °C for 16 h. After the reaction was completed as monitored by LC-MS, the solution was filtered and concentrated under reduced pressure. Compound 4 (14.5 mg) was obtained by HPLC purification with a yield of 11.0%.

[0219] LC-MS (m / z): 877.0 [M+H] + .

[0220] 1 H NMR (600 MHz, DMSO-d6) δ 10.99 (d, J = 9.2 Hz, 1H), 8.71 (dd, J = 34.1, 7.0 Hz, 1H), 7.99 (t, J = 7.4 Hz, 2H), 7.56-7.48 (m, 2H), 7.46-7.27 (m, 5H), 5.75-5.58 (m, 4H), 4.95-4.71 (m, 2H), 4.60-4.25 (m, 3H), 4.21-3.96 (m, 2H), 3.56 (td, J = 11.9, 2.7 Hz, 1H), 3.16-2.80 (m, 1H), 2.66-2.59 (m, 1H), 2.33-2.12 (m, 1H), 2.11-1.97 (m, 2H), 1.94-1.46 (m, 9H), 1.15 (s, 18H).

[0221] Example 7: Synthesis of ((difluoro(4-(2-oxo-2-(((3S,6S,10aS)-5-oxo-3-((S)-2- phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2-a]azepin-6-yl)amino)acetylamino)phenyl)methyl)phosphoryl)bis(oxy)bis(methylene)bis(2,2-dimethylpropanoate) (Compound 7)

[0222] Step 1: Synthesis of compound diethyl difluoro(4-(2-oxo-2-(((3S,6S,10aS)-5-oxo-3-((S)-2- phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2-a]azepin-6-yl)amino)acetylamino)phenyl)methyl)phosphonate (7-1)

[0223] Compound 1-4 (0.242 g, 0.689 mmol) and M4 (0.257 g, 0.693 mmol) were dissolved in N,N-dimethylformamide (6 mL), the reaction solution was cooled to 0 °C, diisopropylethylamine (0.224 g, 1.73 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (0.394 g, 1.04 mmol) were added in turn, and the reaction was carried out at 25 °C for 1 h. After the reaction was completed by LC-MS monitoring, water (20 mL) was added, and the combined organic phase was extracted with ethyl acetate (20 mL x 3), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (dichloromethane:methanol = 96:4 as eluent) gave compound 7-1 (0.400 g) with a yield of 82.3%.

[0224] LC-MS (m / z): 705.0 [M+H] + .

[0225] Step 2: Synthesis of compound (difluoro(4-(2-oxo-2-(((3S,6S,10aS)-5-oxo-3-((S)-2-phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2-a]oxazin-6-yl)amino)acetylamino)phenyl)methyl)phosphonic acid (96)

[0226] Compound 7-1 (0.400 g, 0.568 mmol) was dissolved in anhydrous dichloromethane (10 mL), the reaction solution was cooled to 0 °C, and trimethylsilyl bromide (2.62 g, 17.1 mmol) was added dropwise. The reaction was carried out at 25 °C for 16 h. After the reaction was completed by LC-MS monitoring, the solution was concentrated under reduced pressure, a mixture of acetonitrile (8 mL) and water (2 mL) was added, the reaction was carried out at 25 °C for 40 min, and then concentrated under reduced pressure. Purification by reverse phase column chromatography (methanol:water = 50:50 as eluent) gave compound 96 (0.300 g) with a yield of 81.1%.

[0227] LC-MS (m / z): 649.0 [M+H] + .

[0228] Step 3: Synthesis of compound ((difluoro(4-(2-oxo-2-(((3S,6S,10aS)-5-oxo-3-((S)-2-phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2-a]oxazin-6-yl)amino)acetylamino)phenyl)methyl)phosphoryl)bis(oxy)bis(methylene)bis(2,2-dimethylpropanoate) (7)

[0229] Compound 96 (0.200 g, 0.309 mmol) was dissolved in water (4 mL), the solution was cooled to 0 °C, and a solution of sodium hydroxide (23.0 mg, 0.575 mmol) in water (2 mL) was added dropwise. After the addition was complete, the pH of the solution was about 9, and silver nitrate (0.116 g, 0.682 mmol) was added. The solution was stirred at 0 °C for 2 h. The solid was collected by filtration and dried under reduced pressure using an oil pump (rotary vane vacuum pump). The dried solid was dissolved in toluene (3 mL), and iodo-methyl-pivalate (0.225 g, 0.930 mmol) was added. The solution was stirred at 25 °C for 16 h. After the reaction was complete as monitored by LC-MS, the solution was filtered and concentrated under reduced pressure. Compound 7 (70.0 mg) was obtained by separation and purification on a thin layer chromatography plate with a yield of 25.7%.

[0230] LC-MS (m / z): 877.0 [M+H] + .

[0231] 1 H NMR (600 MHz, DMSO-d6) δ 10.97 (d, J = 20.5 Hz, 1H), 8.69 (dd, J = 68.7, 7.0 Hz, 1H), 7.98 (dd, J = 17.3, 8.4 Hz, 2H), 7.51 (t, J = 9.8 Hz, 2H), 7.44 (d, J = 7.6 Hz, 1H), 7.38 (qd, J = 8.5, 7.5, 2.9 Hz, 3H), 7.32 (td, J = 7.0, 4.3 Hz, 1H), 5.68 (ddt, J = 18.2, 11.1, 5.4 Hz, 4H), 4.98 - 4.66 (m, 2H), 4.39 (dd, J = 10.5, 2.6 Hz, 1H), 4.37 - 4.22 (m, 2H), 4.16 - 3.90 (m, 2H), 3.62 (dtd, J = 109.6, 11.9, 2.4 Hz, 1H), 3.16 (dd, J = 13.5, 10.7 Hz, 1H), 2.88 - 2.66 (m, 1H), 2.37 - 2.14 (m, 1H), 2.13 - 1.99 (m, 2H), 1.90 (qd, J = 12.0, 7.3, 6.3 Hz, 3H), 1.85 - 1.44 (m, 5H), 1.28 - 1.22 (m, 1H), 1.15 (d, J = 4.4 Hz, 18H).

[0232] Synthesis of ((di(fluoro(4-(2-oxo-2-(((5S,8S,10aR)-6-oxo-8-((R)-2- phenylmorpholine-4-carbonyl)-3-propionyldecahydropyrrolo[l,2-a][l,5] diazepin-5- yl)amino)acetylamino)phenyl)methyl)phosphoryl)bis(oxy))bis(methylene)bis(2,2- dimethylpropanoate) (Compound 22)

[0233] Synthesis of ((di(fluoro(4-(2-oxo-2-(((5S,8S,10aR)-6-oxo-8-((R)-2- phenylmorpholine-4-carbonyl)-3-propionyldecahydropyrrolo[l,2-a][l,5] diazepin-5- yl)amino)acetylamino)phenyl)methyl)phosphoryl)bis(oxy))bis(methylene)bis(2,2- dimethylpropanoate) (Compound 22)

[0234] Compound 53 (0.150 g, 0.217 mmol) was dissolved in water (4 mL), the solution was cooled to 0 °C, and an aqueous solution of sodium hydroxide (16.0 mg, 0.400 mmol) in water (2 mL) was added dropwise. After the addition was complete, the pH of the solution was about 9, and silver nitrate (82.0 mg, 0.482 mmol) was added. The solution was stirred at 0 °C for 2 h. The solid was collected by filtration and dried under reduced pressure using an oil pump (rotary vane vacuum pump). The dried solid was dissolved in toluene (3 mL), and iodomethyl pivalate (0.160 g, 0.661 mmol) was added. The solution was stirred at 25 °C for 16 h. After the reaction was complete as monitored by LC-MS, the solution was filtered and concentrated under reduced pressure. Compound 21 (32.0 mg) was obtained by purification using a preparative thin layer chromatography plate with a yield of 16.0%.

[0235] LC-MS (m / z): 920.0 [M+H] + .

[0236] Synthesis of ((di(fluoro(4-(2-oxo-2-(((5S,8S,10aR)-6-oxo-8-((R)-2- phenylmorpholine-4-carbonyl)-3-propionyldecahydropyrrolo[l,2-a][l,5] diazepin-5- yl)amino)acetylamino)phenyl)methyl)phosphoryl)bis(oxy))bis(methylene)bis(2,2- dimethylpropanoate) (Compound 22)

[0237] Step 1: Synthesis of compound ((difluoro(4-(2-oxo-2-(((5S,8S,10aR)-6-oxo-8-((R)-2- phenylmorpholine-4-carbonyl)-3-propionylhydro pyrrolo[l,2-a][l,5]diazepin-5-yl)amino)acetylamino)phenyl)methyl)phosphoryl)bis(oxy))bis(methylene)bis(2,2-dimethylpropanoate) (22)

[0238] Compound 56 (0.198 g, 0.281 mmol) was dissolved in water (2 mL), the solution was cooled to 0 °C, and an aqueous solution of sodium hydroxide was added dropwise. After the addition was completed, the pH of the solution was about 9-10, silver nitrate (0.105 g, 0.618 mmol) was added, and the mixture was stirred at 0 °C for 2 h. The solid was collected by filtration and dried under reduced pressure with an oil pump (rotary vane vacuum pump). The dried solid was dissolved in toluene (3 mL), and iodomethyl pivalate (0.205 g, 0.847 mmol) was added. The mixture was stirred at 25 °C for 16 h. After the reaction was completed by LC-MS monitoring, the mixture was filtered and concentrated under reduced pressure. Purification by thin layer chromatography plate (ethyl acetate as eluent) gave compound 22 (68.7 mg) in 26.0% yield.

[0239] LC-MS (m / z): 934.0 [M+H] + .

[0240] 1 H NMR (600 MHz, DMSO-d6) δ 11.17 (d, J = 10.9 Hz, 1H), 8.68 (dd, J = 39.6, 6.0 Hz, 1H), 8.02 (t, J = 8.2 Hz, 2H), 7.53 - 7.45 (m, 2H), 7.43 - 7.31 (m, 5H), 5.76 - 5.60 (m, 4H), 5.05 - 4.76 (m, 2H), 4.68 - 4.50 (m, 1H), 4.38 (dd, J = 11.2, 2.8 Hz, 1H), 4.31 - 4.13 (m, 2H), 4.03 (dt, J = 18.8, 9.5 Hz, 3H), 3.86 (d, J = 13.5 Hz, 1H), 3.57 (td, J = 11.7, 2.8 Hz, 1H), 3.17 - 3.05 (m, 2H), 2.92 - 2.73 (m, 2H), 2.67 (dd, J = 13.7, 10.9 Hz, 1H), 2.40 (ddd, J = 9.8, 7.1, 3.1 Hz, 1H), 2.11 - 1.86 (m, 3H), 1.78 - 1.53 (m, 2H), 1.15 (s, 18H), 1.04 (dd, J = 7.3, 4.3 Hz, 3H).

[0241] Synthesis of ((((4-(2-((5S,8S,10aR)-3-(2,2-difluoroethyl)-6-oxo-8-((R)-2- phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2-a][1,5]diazepin-5-yl)amino)-2- oxoacetylamino)phenyl)di fluoromethyl)phosphoryl)bis(oxy))bis(methylene)bis(2,2- dimethylpropanoate) (Compound 23)

[0242] Step 1: Synthesis of compound methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)- 3-(2,2-difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazepine-8-carboxylate (23-2)

[0243] Compound 22-SM (0.400 g, 1.17 mmol) was dissolved in anhydrous N,N- dimethylformamide (10 mL), triethylamine (0.238 g, 2.34 mmol) was added, the reaction was cooled to 0 °C, 2,2-difluoroethyl trifluoromethanesulfonate (0.501 g, 2.34 mmol) was added dropwise, and it was placed at 25 °C for 2 h. When the reaction was complete by LC-MS monitoring, water (50 mL) was added, and it was extracted with EA (10 mL x 3), the combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 23-2 (0.370 g) in a yield of 78.0%.

[0244] LC-MS (m / z): 406.0 [M+H] + .

[0245] Step 2: Synthesis of compound (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(2,2- difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazepine-8-carboxylic acid (23-3)

[0246] Compound 23-2 (0.370 g, 0.914 mmol) was dissolved in tetrahydrofuran (4 mL), a solution of lithium hydroxide (76.0 mg, 1.82 mmol) in water (4 mL) was added dropwise, and it was placed at room temperature for 2 h. When the reaction was complete by LC-MS monitoring, concentrated hydrochloric acid was added to the reaction, and the pH of the aqueous phase was adjusted to be acidic. The aqueous phase was extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 23-3 (0.350 g) in a yield of 98.3%.

[0247] LC-MS (m / z): 392.0 [M+H]+ .

[0248] Step 3: Synthesis of compound (5S,8S,10aR)-3-(2,2-difluoroethyl)-6-oxo-8-((R)-2- phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2-a][1,5]diazepin-5-yl)carbamic acid tert-butyl ester (23-4)

[0249] Compound 23-3 (0.350 g, 0.895 mmol) and R-2-phenylmorpholine (0.166 g, 1.02 mmol) were dissolved in N,N-dimethylformamide (5 mL), the reaction solution was cooled to 0 °C, diisopropylethylamine (0.287 g, 2.23 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (0.507 g, 1.36 mmol) were added successively, and the reaction was carried out at 25 °C for 1 h. After the reaction was completed by LC-MS monitoring, water (20 mL) was added, and the combined organic phase was extracted with ethyl acetate (20 mL x 3), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification on a silica gel column (dichloromethane:methanol = 96:4 as eluent) gave compound 23-4 (0.400 g) with a yield of 84.0%.

[0250] LC-MS (m / z): 537.0 [M+H] + .

[0251] Step 4: Synthesis of compound (5S,8S,10aR)-5-amino-3-(2,2-difluoroethyl)-8-((R)-2- phenylmorpholine-4-carbonyl)octahydro pyrrolo[1,2-a][1,5]diazepin-6(1H)-one trifluoroacetate (23-5)

[0252] Compound 23-4 (0.400 g, 0.743 mmol) was dissolved in anhydrous dichloromethane (7 mL), the reaction solution was cooled to 0 °C, and trifluoroacetic acid (1.28 g, 11.3 mmol) was added, and the reaction was carried out at 25 °C for 1 h. After the reaction was completed by LC-MS monitoring, it was concentrated under reduced pressure to give compound 23-5 (0.300 g) with a yield of 91.5%.

[0253] LC-MS (m / z): 437.0 [M+H] + .

[0254] Step 5: Synthesis of compound diethyl (4-(2-(((5S,8S,10aR)-3-(2,2- difluoroethyl)-6-oxo-8-((R)-2-phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2- a][1,5]diazepin-5-yl)amino)-2-oxoacetamido)phenyl)difluoromethyl)phosphonate (23-6)

[0255] Compound 1-4 (0.241 g, 0.688 mmol) and 23-5 (0.300 g, 0.688 mmol) were dissolved in N,N-dimethylformamide (6 mL), the reaction solution was cooled to 0 °C, diisopropylethylamine (0.224 g, 1.73 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (0.394 g, 1.04 mmol) were added in turn, and the reaction was carried out at 25 °C for 1 h. After the reaction was completed by LC-MS monitoring, water (20 mL) was added, and the combined organic phase was extracted with ethyl acetate (20 mL x 3), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (dichloromethane:methanol = 96:4 as eluent) gave compound 23-6 (0.350 g) with a yield of 66.0%.

[0256] LC-MS (m / z): 770.0 [M+H] + .

[0257] Step 6: Synthesis of compound (4-(2-(((5S,8S,10aR)-3-(2,2-difluoroethyl)-6-oxo-8-((R)-2-phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2-a][1,5]diazepin-5-yl)amino)-2-oxoacetamido)phenyl)difluoromethyl)phosphonic acid (103)

[0258] Compound 23-6 (0.350 g, 0.455 mmol) was dissolved in anhydrous dichloromethane (10 mL), the reaction solution was cooled to 0 °C, and trimethylsilyl bromide (2.10 g, 13.5 mmol) was added dropwise. The reaction was carried out at 25 °C for 16 h. After the reaction was completed by LC-MS monitoring, the solution was concentrated under reduced pressure, a mixture of acetonitrile (8 mL) and water (2 mL) was added, the reaction was carried out at 25 °C for 40 min, and then concentrated under reduced pressure. Purification by reverse phase column chromatography (methanol:water = 50:50 as eluent) gave compound 103 (0.220 g) with a yield of 68.5%.

[0259] LC-MS (m / z): 714.0 [M+H] + .

[0260] Step 7: Synthesis of compound (((((4-(2-((5S,8S,10aR)-3-(2,2-difluoroethyl)-6-oxo-8-((R)-2- phenylmorpholine-4-carbonyl)decahydropyrrolo[l,2-a][l,5]diazepin-5-yl)amino)-2- oxoacetylamino)phenyl)di fluoromethyl)phosphoryl)bis(oxy))bis(methylene)bis(2,2- dimethylpropanoate) (23)

[0261] Compound 103 (0.220 g, 0.309 mmol) was dissolved in water (4 mL), the solution was cooled to 0 °C, and an aqueous solution of sodium hydroxide (22.0 mg, 0.550 mmol) was added dropwise (2 mL). After the addition was completed, the pH of the solution was about 9, silver nitrate (0.116 g, 0.682 mmol) was added, and the mixture was stirred at 0 °C for 2 h. The solid was collected by filtration and dried under reduced pressure using an oil pump (rotary vane vacuum pump). The dried solid was dissolved in toluene (3 mL), and iodomethyl pivalate (0.225 g, 0.930 mmol) was added. The mixture was stirred at 25 °C for 16 h. After the reaction was completed by LC-MS monitoring, the mixture was filtered and concentrated under reduced pressure. Compound 23 (85.0 mg) was obtained by separation and purification on a thin layer chromatography plate with a yield of 29.1%.

[0262] LC-MS (m / z): 942.0 [M+H] + .

[0263] 1 H NMR (600 MHz, DMSO-d6) δ 11.07 (d, J = 10.3 Hz, 1H), 8.52 (dd, J = 39.7, 6.5 Hz, 1H), 8.00 (t, J = 7.9 Hz, 2H), 7.51 (dd, J = 8.8, 3.8 Hz, 2H), 7.45 (d, J = 7.7 Hz, 1H), 7.42 - 7.35 (m, 3H), 7.32 (t, J = 7.3 Hz, 1H), 6.29 - 5.95 (m, 1H), 5.75 - 5.61 (m, 4H), 4.88 (dt, J = 115.3, 8.6 Hz, 1H), 4.65 (dd, J = 85.1, 9.9 Hz, 2H), 4.37 (t, J = 9.6 Hz, 2H), 4.22 (dd, J = 64.1, 13.2 Hz, 1H), 4.03 (t, J = 14.5 Hz, 2H), 3.57 (q, J = 11.4 Hz, 1H), 3.26 - 3.09 (m, 4H), 3.09 - 3.00 (m, 1H), 2.94 - 2.59 (m, 2H), 2.43 - 2.17 (m, 1H), 2.13 - 1.66 (m, 4H), 1.54 (q, J = 14.7 Hz, 1H), 1.15 (s, 18H).

[0264] Synthesis of ((difluoro(3-fluoro-4-(2-oxo-2-(((3S,6S,10aS)-5-oxo-3-((R)-2- phenylmorpholine-4-carbonyl)decahydropyrrolo[l,2-a]oxazin-6-yl)amino)acetylamino)phenyl)methyl)phosphoryl)bis(oxy))bis(methylene)bis(2,2-dimethylpropanoate) (Compound 26)

[0265] Step 1: Synthesis of compound methyl 2-((2-fluoro-4-iodophenyl)amino)-2- oxoacetate (26-2)

[0266] Compound 26-1 (3.00 g, 12.7 mmol) was dissolved in anhydrous dichloromethane (60 mL), diisopropylethylamine (2.45 g, 19.0 mmol) was added, the reaction solution was cooled to 0 °C, oxalyl chloride monomethyl ester (1.86 g, 15.2 mmol) was added dropwise, and it was reacted at 25 °C for 1 hour. After the reaction was completed by LC-MS monitoring, water (50 mL) was added, and dichloromethane (50 mL x 3) was extracted, the combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50:50 as eluent) to obtain compound 26-2 (3.90 g), with a yield of 95.5%.

[0267] LCMS (ESI): m / z = 324.0 [M+H] + .

[0268] Step 2: Synthesis of compound methyl 2-((4-(diethoxyphosphoryl)difluoromethyl)-2- fluoro phenyl)amino)-2-oxoacetate (26-3)

[0269] To a 50 mL three-necked flask (first reaction flask), cadmium powder (1.53 g, 13.6 mmol) was added, and a solution of bromofluoromethyl phosphonic acid diethyl ester (3.31 g, 12.4 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added, and the reaction was carried out at 40 °C for 2 hours. Another three-necked flask (second reaction flask) was taken, and cuprous chloride (0.920 g, 9.28 mmol) and compound 26-2 (2.00 g, 6.19 mmol) were dissolved in anhydrous N,N-dimethylformamide (15 mL), and the reaction solution in the first reaction flask was filtered out with a filter head and slowly injected into the reaction system in the second reaction flask, and the reaction was carried out at 40 °C for 16 hours. Ethyl acetate (50 mL), water (50 mL) were added, and diatomite was filtered, and the filtrate was extracted with ethyl acetate (50 mL x 3), and the combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 40:60 as eluent) to obtain compound 26-3 (1.80 g), with a yield of 75.9%.

[0270] LC-MS (m / z): 384.0 [M+H] + .

[0271] Step 3: Synthesis of compound 2-((4-((diethoxyphosphoryl)difluoromethyl)-2- fluorophenyl)amino)-2-oxoacetic acid (26-4)

[0272] Compound 26-3 (1.80 g, 4.69 mmol) was dissolved in tetrahydrofuran (8 mL), and the reaction solution was cooled to 0 °C, and a solution of lithium hydroxide (0.394 g, 9.38 mmol) in water (8 mL) was added dropwise, and the reaction was carried out at 0 °C for 15 minutes. After the reaction was completed by LC-MS monitoring, concentrated hydrochloric acid was added to the reaction solution, and the pH of the aqueous phase was adjusted to be acidic, and the aqueous phase was extracted with ethyl acetate (20 mL x 3), and the combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 26-4 (1.23 g), with a yield of 71.0%.

[0273] LC-MS (m / z): 370.0 [M-H] + .

[0274] Step 4: Synthesis of compound di(fluoro(3-fluoro-4-(2-oxo-2-(((3S,6S,10aS)-5-oxo-3-((R)-2-phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2-a]azepin-6-yl)amino)acetylamino)phenyl)methyl)phosphonic acid diethyl ester (26-5)

[0275] Compound 26-4 (0.200 g, 0.542 mmol) and M3 (0.201 g, 0.542 mmol) were dissolved in N,N-dimethylformamide (5 mL), the reaction solution was cooled to 0 °C, diisopropylethylamine (0.174 g, 1.35 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (0.308 g, 0.811 mmol) were added in turn, and the reaction was carried out at 25 °C for 1 h. After the reaction was completed by LC-MS monitoring, water (20 mL) was added, and the combined organic phase was extracted with ethyl acetate (20 mL x 3), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (dichloromethane:methanol = 96:4 as eluent) gave compound 26-5 (0.280 g) with a yield of 71.7%.

[0276] LC-MS (m / z): 723.0 [M+H] + .

[0277] Step 5: Synthesis of compound (difluoro(3-fluoro-4-(2-oxo-2-(((3S,6S,10aS)-5-oxo-3-((R)-2-phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2-a]oxazin-6-yl)amino)acetylamino)phenyl)methyl)phosphonic acid (102)

[0278] Compound 26-5 (0.280 g, 0.388 mmol) was dissolved in anhydrous dichloromethane (10 mL), the reaction solution was cooled to 0 °C, and trimethylsilyl bromide (1.74 g, 11.4 mmol) was added dropwise. The reaction was carried out at 25 °C for 16 h. After the reaction was completed by LC-MS monitoring, it was concentrated under reduced pressure, a mixture of acetonitrile (8 mL) and water (2 mL) was added, the reaction was carried out at 25 °C for 40 min, and then concentrated under reduced pressure. Purification by reverse phase column chromatography (methanol:water = 50:50 as eluent) gave compound 102 (0.120 g) with a yield of 47.4%.

[0279] LC-MS (m / z): 667.0 [M+H] + .

[0280] Step 6: Synthesis of compound ((difluoro(3-fluoro-4-(2-oxo-2-(((3S,6S,10aS)-5-oxo-3-((R)-2-phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2-a]oxazin-6-yl)amino)acetylamino)phenyl)methyl)phosphoryl)bis(oxy))bis(methylene)bis(2,2-dimethylpropanoate) (26)

[0281] Compound 102 (0.120 g, 0.180 mmol) was dissolved in water (4 mL), the solution was cooled to 0 °C, and a solution of sodium hydroxide (13.0 mg, 0.325 mmol) in water (2 mL) was added dropwise. After the addition was completed, the pH of the solution was about 9, and silver nitrate (67.0 mg, 0.394 mmol) was added. The solution was stirred at 0 °C for 2 h. The solid was collected by filtration and dried under reduced pressure with an oil pump (rotary vane vacuum pump). The dried solid was dissolved in toluene (3 mL), and iodomethyl pivalate (0.131 g, 0.541 mmol) was added. The solution was stirred at 25 °C for 16 h. After the reaction was completed by LC-MS monitoring, the solution was filtered and concentrated under reduced pressure. Compound 26 (31.8 mg) was obtained by HPLC purification with a yield of 19.7%.

[0282] LC-MS (m / z): 895.0 [M+H] + .

[0283] 1 H NMR (600 MHz, DMSO-d6) δ 10.47 (d, J = 8.3 Hz, 1H), 8.72 (dd, J = 35.4, 7.1 Hz, 1H), 7.91 (q, J = 8.0 Hz, 1H), 7.56 - 7.24 (m, 7H), 5.72 (ddd, J = 18.2, 12.6, 5.5 Hz, 4H), 5.05 - 4.67 (m, 2H), 4.46 - 4.24 (m, 3H), 4.21 - 3.95 (m, 2H), 3.56 (t, J = 11.7 Hz, 1H), 3.17 - 2.78 (m, 1H), 2.71 - 2.55 (m, 1H), 2.35 - 2.11 (m, 1H), 2.10 - 1.97 (m, 2H), 1.96 - 1.41 (m, 8H), 1.16 (s, 18H).

[0284] Example 29: Synthesis of ((difluoro(3-methoxy-4-(2-oxo-2-(((3S,6S,10aS)-5-oxo-3-((R)-2-phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2-a]azepin-6-yl)amino)acetylamino)phenyl)methyl)phosphoryl)bis(oxy))bis(methylene)bis(2,2-dimethylpropanoate) (29)

[0285] Step 1: Synthesis of compound methyl 2-((4-iodo-2-methoxyphenyl)amino)-2-oxoacetate (29-2)

[0286] Compound 29-1 (3.00 g, 12.0 mmol) was dissolved in anhydrous dichloromethane (60 mL), diisopropylethylamine (2.33 g, 18.1 mmol) was added, the reaction solution was cooled to 0 °C, oxalyl chloride monomethyl ester (1.77 g, 14.4 mmol) was added dropwise, and it was reacted at 25 °C for 1 hour. After the reaction was completed by LC-MS monitoring, water (50 mL) was added, extracted with dichloromethane (50 mL x 3), the combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50:50 as eluent) to obtain compound 29-2 (3.90 g) with a yield of 96.7%.

[0287] LC-MS (m / z): 336.0 [M+H] + .

[0288] Step 2: Synthesis of compound methyl 2-((4-(diethoxyphosphoryl) difluoromethyl)-2- methoxyphenyl)amino)-2-oxoacetate (29-3)

[0289] Compound 29-1 (3.00 g, 12.0 mmol) was dissolved in anhydrous dichloromethane (60 mL), diisopropylethylamine (2.33 g, 18.1 mmol) was added, the reaction solution was cooled to 0 °C, oxalyl chloride monomethyl ester (1.77 g, 14.4 mmol) was added dropwise, and it was reacted at 25 °C for 1 hour. After the reaction was completed by LC-MS monitoring, water (50 mL) was added, extracted with dichloromethane (50 mL x 3), the combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50:50 as eluent) to obtain compound 29-2 (3.90 g) with a yield of 96.7%.

[0290] LC-MS (m / z): 396.0 [M+H] + .

[0291] Step 3: Synthesis of compound 2-((4-((diethoxyphosphoryl) difluoromethyl)-2- methoxyphenyl)amino)-2-oxoacetic acid (29-4)

[0292] Compound 29-3 (1.80 g, 4.55 mmol) was dissolved in tetrahydrofuran (8 mL), the reaction solution was cooled to 0 °C, and a lithium hydroxide (0.382 g, 9.10 mmol) aqueous solution (8 mL) was added dropwise, and it was reacted at 0 °C for 15 minutes. When the reaction was completed by LC-MS monitoring, 1.0 M dilute hydrochloric acid was added to the reaction solution, the pH of the aqueous phase was adjusted to be acidic, the aqueous phase was extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 29-4 (1.40 g) with a yield of 81.0%.

[0293] LC-MS (m / z): 382.0 [M+H] + .

[0294] Step 4: Synthesis of compound difluoro(3-methoxy-4-(2-oxo-2-(((3S,6S,10aS)-5-oxo-3-((R)-2-phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2-a]oxazin-6-yl)amino)acetamido)phenyl)methyl)phosphonic acid diethyl ester (29-5)

[0295] Compound 29-4 (0.200 g, 0.522 mmol) and M3 (0.193 g, 0.522 mmol) were dissolved in N,N-dimethylformamide (5 mL), diisopropylethylamine (0.168 g, 1.30 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (0.297 g, 0.782 mmol) were sequentially added to the reaction solution, which was cooled to 0 °C, and it was reacted at 25 °C for 1 hour. When the reaction was completed by LC-MS monitoring, water (20 mL) was added, extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane:methanol = 96:4 as an eluent) to obtain compound 29-5 (0.300 g) with a yield of 78.5%.

[0296] LC-MS (m / z): 735.0 [M+H] + .

[0297] Step 5: Synthesis of compound (difluoro(3-methoxy-4-(2-oxo-2-(((3S,6S,10aS)-5-oxo-3-((R)-2-phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2-a]oxazin-6-yl)amino)acetamido)phenyl)methyl)phosphonic acid (29-6)

[0298] Compound 29-5 (0.300 g, 0.409 mmol) was dissolved in anhydrous dichloromethane (10 mL), the reaction solution was cooled to 0 °C, trimethylsilyl bromide (1.84 g, 12.0 mmol) was added dropwise, and the reaction solution was allowed to react at 25 °C for 16 hours. After the reaction was completed by LC-MS monitoring, a mixed solution of acetonitrile (8 mL) and water (2 mL) was added, the reaction solution was allowed to react at 25 °C for 40 minutes, and then concentrated under reduced pressure. Purification by reverse phase column chromatography (methanol: water = 50: 50 as eluent) gave compound 29-6 (0.170 g) with a yield of 62.7%.

[0299] LC-MS (m / z): 679.0 [M+H] + .

[0300] Step 6: Synthesis of compound ((difluoro(3-methoxy-4-(2-oxo-2-(((3S,6S,10aS)-5-oxo-3-((R)-2-phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2-a]azepin-6-yl)amino)acetylamino)phenyl)methyl)phosphoryl)bis(oxy))bis(methylene)bis(2,2-dimethylpropanoate) (29)

[0301] Compound 29-6 (0.170 g, 0.251 mmol) was dissolved in water (4 mL), the reaction solution was cooled to 0 °C, and an aqueous solution of sodium hydroxide (18.0 mg, 0.450 mmol) (2 mL) was added dropwise. After the addition was completed, the pH of the solution was about 9, silver nitrate (94.0 mg, 0.553 mmol) was added, and the reaction was allowed to proceed at 0 °C for 2 hours. After filtration, the solid was dried under reduced pressure using an oil pump (rotary vane vacuum pump), and the resulting dried solid was dissolved in toluene (3 mL). lodomethyl pivalate (0.182 g, 0.744 mmol) was added, and the reaction was allowed to proceed at 25 °C for 16 hours. After the reaction was completed by LC-MS monitoring, the solution was filtered and concentrated under reduced pressure, and then purified by HPLC to obtain compound 29 (43.3 mg) with a yield of 19.1%.

[0302] LC-MS (m / z): 907.0 [M+H] + .

[0303] 1H NMR (600 MHz, DMSO-d6) δ 9.85 (d, J = 9.2 Hz, 1H), 8.81 (d, J = 34.2 Hz, 1H), 8.29 (d, J = 9.5 Hz, 1H), 7.38 (td, J = 30.6, 27.7, 14.3 Hz, 5H), 7.18 (d, J = 33.3 Hz, 2H), 5.70 (t, J = 13.6 Hz, 4H), 5.04 - 4.48 (m, 2H), 4.43 - 4.13 (m, 3H), 4.03 (s, 2H), 3.96 (s, 3H), 3.55 (d, J = 12.1 Hz, 1H), 3.12 (s, 1H), 1.91 (ddd, J = 201.3, 131.2, 83.4 Hz, 13H), 1.14 (s, 18H).

[0304] Synthesis of (difluoro(3-methoxy-4-(2-oxo-2-(((3S,6S,10aS)-5-oxo-3-((R)-2- phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2-a]oxazin-6-yl)amino)acetylamino)phenyl)methyl)phosphonic acid (52)

[0305] Synthetic procedure is described in example 4.

[0306] LC-MS (m / z): 649.0 [M+H] + .

[0307] 1 H NMR (600 MHz, DMSO-d6) δ 10.91 - 10.80 (m, 1H), 8.75 - 8.60 (m, 1H), 7.95 - 7.81 (m, 2H), 7.52 - 7.27 (m, 7H), 4.98 - 4.71 (m, 2H), 4.61 - 4.13 (m, 4H), 4.07 - 3.91 (m, 1H), 3.62 - 3.52 (m, 1H), 3.39 - 3.05 (m, 1H), 2.89 - 2.58 (m, 1H), 2.33 - 2.11 (m, 1H), 2.10 - 1.96 (m, 2H), 1.94 - 1.48 (m, 9H).

[0308] Synthesis of (4-(2-(((5S,8S,10aR)-3-acetyl-6-oxo-8-((R)-2-phenylmorpholine-4- carbonyl)decahydropyrrolo[1,2-a][1,5]diazepin-5-yl)amino)-2-oxoacetylamino)phenyl) difluoromethyl)phosphonic acid (compound 53)

[0309] Step 1: Synthesis of compound 3-benzyl-8-methyl (5S,8S,10aR)-5-((tert- butoxycarbonyl)amino)-6-oxooctahydropyrrolo[l,2-a][l,5]diazepine-3,8(4H)- dicarboxylate (53-1)

[0310] Compound 22-SM (1.40 g, 4.11 mmol) was dissolved in dioxane (10 mL), sodium bicarbonate (1.03 g, 12.3 mmol) was added, the reaction system was placed at 10 °C, benzyl chloroformate (0.907 g, 5.33 mmol) was added, white solid was precipitated, the reaction system was placed at 25 °C for 16 hours. After the reaction was completed by LC-MS monitoring, it was concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 2: 1 as eluent) to obtain compound 53-1 (1.65 g), with a yield of 84.6%.

[0311] LC-MS (m / z): 476.0 [M+H] + .

[0312] Step 2: Synthesis of compound (5S,8S,10aR)-3-((benzyloxy)carbonyl)-5-(tert- butoxycarbonyl)amino)-6-oxodecahydropyrrolo[l,2-a][l,5]diazepine-8-carboxylic acid (53-2)

[0313] Compound 53-1 (1.65 g, 3.47 mmol) was dissolved in dioxane (10 mL), lithium hydroxide (0.167 g, 6.94 mmol) aqueous solution (5 mL) was added, and it was placed at 25 °C for 1 hour. After the reaction was completed by LC-MS monitoring, it was concentrated under reduced pressure, most of the dioxane was removed, concentrated hydrochloric acid was added to the reaction solution, the pH of the aqueous phase was adjusted to 5, the aqueous phase was extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 53-2 (1.60 g) with a yield of 99.8%.

[0314] LC-MS (m / z): 462.0 [M+H] + .

[0315] Step 3: Synthesis of compound benzyl (5S,8S,10aR)-5-((tert-butoxy carbonyl) amino)-6-oxo-8-((R)-2-phenylmorpholine-4-carbonyl)octahydropyrrolo[l,2- a][l,5]diazepine-3(4H)-carboxylate (53-3)

[0316] Compound 53-2 (1.60 g, 3.47 mmol) and R-2-phenylmorpholine (0.566 g, 3.47 mmol) were dissolved in DMF (8 mL) solution, diisopropylethylamine (1.34 g, 10.4 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl) uronium hexafluorophosphate (1.58 g, 4.16 mmol) were added successively, and the reaction was carried out at 25 °C for 1 h. After the reaction was completed by LC-MS monitoring, water (20 mL) was added, and the combined organic phase was extracted with ethyl acetate (20 mL x 3), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification on a silica gel column (ethyl acetate as eluent) gave compound 53-3 (1.90 g) in a yield of 90.4%.

[0317] LC-MS (m / z): 607.0 [M+H] + .

[0318] Step 4: Synthesis of compound benzyl (5S,8S,10aR)-5-amino-6-oxo-8-((R)-2- phenylmorpholine-4-carbonyl)octahydropyrrolo[1,2-a][1,5]diazepine-3(4H)- carboxylate (53-4)

[0319] Compound 53-3 (1.70 g, 2.80 mmol) was dissolved in anhydrous dichloromethane (4 mL), and the reaction was cooled to 0 °C. Trifluoroacetic acid (4 mL) was added dropwise, and the reaction was carried out at 25 °C for 1 h. After the reaction was completed by TLC (alkaline) monitoring, it was concentrated under reduced pressure to give crude compound 53-4 (1.70 g).

[0320] LC-MS (m / z): 507.0 [M+H] + .

[0321] Step 5: Synthesis of compound benzyl (5S,8S,10aR)-5-(2-((4- (diethoxyphosphoryl)difluoromethyl)phenyl)amino)-2-oxoacetamido)-6-oxo-8-((R)-2- phenylmorpholine-4-carbonyl)octahydropyrrolo[1,2-a][1,5]diazepine-3(4H)-carboxylate (53-5)

[0322] Compound 53-4 (1.70 g, 2.80 mmol) and 1-4 (0.983 g, 2.80 mmol) were dissolved in N,N-dimethylformamide (10 mL), diisopropylethylamine (1.30 g, 10.8 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (1.27 g, 3.36 mmol) were added successively, and the mixture was allowed to react at 25 °C for 1 hour. After the reaction was completed as determined by LC-MS and TLC, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (ethyl acetate as eluent) gave compound 53-5 (1.40 g) in a yield of 59.5%.

[0323] LC-MS (m / z): 840.0 [M+H] + .

[0324] Step 6: Synthesis of compound diethyl (4-(2-oxo-2-(((5S,8S,10aR)-6-oxo-8-((R)-2- phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2-a][1,5]diazepin-5-yl)amino)acetylamino)phenyl)methyl)phosphonate (53-6)

[0325] Compound 53-5 (0.400 g, 0.477 mmol) was dissolved in THF (10 mL), and palladium-carbon (10%, 0.200 g, 0.189 mmol) was added. The mixture was replaced with hydrogen gas three times, and the reaction mixture was allowed to react at 25 °C for 16 hours under a hydrogen atmosphere. After the reaction was completed as determined by LC-MS, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 53-6 (0.290 g) in a yield of 86.3%.

[0326] Step 7: Synthesis of compound diethyl (4-(2-(((5S,8S,10aR)-3-acetyl-6-oxo-8-((R)-2- phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2-a][1,5]diazepin-5-yl)amino)-2- oxoacetamido)phenyl)methyl)phosphonate (53-7)

[0327] Compound 53-6 (0.150 g, 0.213 mmol) was dissolved in anhydrous dichloromethane (5 mL), the reaction solution was cooled to 0 °C, and triethylamine (43.0 mg, 0.426 mmol) and acetyl chloride (25.0 mg, 0.318 mmol) were added sequentially. The reaction was allowed to proceed at 25 °C for 0.5 h. When the reaction was complete, as monitored by LC-MS, the solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 96:4 as eluent) to give compound 53-7 (0.120 g) in 76.4% yield.

[0328] LC-MS (m / z): 748.0 [M+H] + .

[0329] Step 8: Synthesis of compound (4-(2-(((5S,8S,10aR)-3-acetyl-6-oxo-8-((R)-2- phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2-a][1,5]diazepin-5-yl)amino)-2- oxoacetylamino)phenyl) difluoromethyl)phosphonic acid (53)

[0330] Compound 53-7 (0.120 g, 0.161 mmol) was dissolved in anhydrous dichloromethane (5 mL), the reaction solution was cooled to 0 °C, and trimethylsilyl bromide (0.735 g, 4.80 mmol) was added dropwise. The reaction was allowed to proceed at 25 °C for 16 h. When the reaction was complete, as monitored by LC-MS, the solution was concentrated under reduced pressure, and a mixture of acetonitrile (8 mL) and water (2 mL) was added. The reaction was allowed to proceed at 25 °C for 40 min, and the solution was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (methanol:water = 50:50 as eluent) to give compound 53 (80.0 mg) in 72.1% yield.

[0331] LC-MS (m / z): 692.0 [M+H] + .

[0332] Example 54: Synthesis of ((difluoro(4-(2-(((3S,6S,10aS)-3-(indole-1-carbonyl)-5- oxodecahydropyrrolo[1,2-a]azepin-6-yl)amino)-2-oxoacetylamino)phenyl)methyl) phosphoryl)bis(oxy))bis(methylene)bis(2,2-dimethylpropanoate) (54)

[0333] Step 1: Synthesis of compound tert-butyl ((3S,6S,10aS)-3-(indole-1-carbonyl)-5- oxodecahydropyrrolo[1,2-a]azepin-6-yl)carbamate (54-1)

[0334] Compound M2-1 (0.300 g, 0.920 mmol) and indoline (0.163 g, 1.01 mmol) were dissolved in N,N-dimethylformamide (5 mL), the reaction solution was cooled to 0 °C, diisopropylethylamine (0.297 g, 2.30 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (0.525 g, 1.38 mmol) were added in turn, and the reaction was carried out at 25 °C for 30 min. After the reaction was completed by LC-MS monitoring, water (20 mL) was added, and the combined organic phase was extracted with ethyl acetate (20 mL x 3), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification on a silica gel column (petroleum ether: ethyl acetate = 40:60 as eluent) gave compound 54-1 (0.300 g) with a yield of 76.3%.

[0335] LC-MS (m / z): 428.0 [M+H] + .

[0336] Step 2: Synthesis of compound (3S,6S,10aS)-6-amino-3-(indole-1-carbonyl)octahydro pyrrolo[1,2-a]oxazin-5(1H)-one trifluoroacetate (54-2)

[0337] Compound 54-1 (0.300 g, 0.704 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1.20 g, 10.5 mmol) was added. The reaction solution was placed at 25 °C for 1 h. After the reaction was completed by LC-MS monitoring, it was concentrated under reduced pressure to give compound 54-2 (0.200 g) with a yield of 87.3%.

[0338] LC-MS (m / z): 328.0 [M+H] + .

[0339] Step 3: Synthesis of compound diethyl difluoro(4-(2-(((3S,6S,10aS)-3-(indole-1-carbonyl)-5-oxodecahydro pyrrolo[1,2-a]oxazin-6-yl)amino)-2-oxoacetamido)phenyl)methyl)phosphonate (54-3)

[0340] Compound 1-4 (0.215 g, 0.613 mmol) and 54-2 (0.200 g, 0.613 mmol) were dissolved in N,N-dimethylformamide (6 mL), the reaction solution was cooled to 0 °C, diisopropylethylamine (0.197 g, 1.53 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (0.348 g, 0.916 mmol) were added in turn, and the reaction was carried out at 25 °C for 1 h. After the reaction was completed by LC-MS monitoring, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (dichloromethane:methanol = 96:4 as eluent) gave compound 54-3 (0.300 g) with a yield of 74.4%.

[0341] LC-MS (m / z): 661.0 [M+H] + .

[0342] Step 4: Synthesis of compound ((difluoro(4-(2-(((3S,6S,10aS)-3-(indole-1-carbonyl)-5- oxodecahydropyrrolo[1,2-a]azepin-6-yl)amino)-2-oxoacetamido)phenyl)methyl)phosphonic acid (97)

[0343] Compound 54-3 (0.300 g, 0.455 mmol) was dissolved in anhydrous dichloromethane (10 mL), the reaction solution was cooled to 0 °C, and trimethylsilyl bromide (2.06 g, 13.5 mmol) was added dropwise. The reaction was carried out at 25 °C for 16 h. After the reaction was completed by LC-MS monitoring, the solution was concentrated under reduced pressure, a mixture of acetonitrile (8 mL) and water (2 mL) was added, the reaction was carried out at 25 °C for 40 min, and then concentrated under reduced pressure. Purification by reverse phase column chromatography (methanol:water = 50:50 as eluent) gave compound 97 (0.171 g) with a yield of 62.9%.

[0344] LC-MS (m / z): 605.0 [M+H] + .

[0345] Step 5: Synthesis of compound ((difluoro(4-(2-(((3S,6S,10aS)-3-(indole-1-carbonyl)-5- oxodecahydropyrrolo[1,2-a]azepin-6-yl)amino)-2-oxoacetamido)phenyl)methyl)phosphoryl)bis(oxy))bis(methylene)bis(2,2-dimethylpropanoate) (54)

[0346] Compound 97 (0.171 g, 0.283 mmol) was dissolved in water (4 mL), the solution was cooled to 0 °C, and a solution of sodium hydroxide (20.0 mg, 0.500 mmol) in water (2 mL) was added dropwise. After the addition was completed, the pH of the solution was about 9, silver nitrate (0.105 g, 0.618 mmol) was added, and the solution was stirred at 0 °C for 2 h. The solid was collected by filtration, dried under reduced pressure with an oil pump (rotary vane vacuum pump), and then dissolved in toluene (3 mL). Iodomethyl pivalate (0.204 g, 0.843 mmol) was added, and the solution was stirred at 25 °C for 16 h. After the reaction was completed as monitored by LC-MS, the solution was filtered and concentrated under reduced pressure. Compound 54 (55.0 mg) was obtained by purification with a thin layer chromatography plate with a yield of 23.6%.

[0347] LC-MS (m / z): 833.0 [M+H] + .

[0348] 1 H NMR (600 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.71 (d, J = 7.0 Hz, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.98 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 7.4 Hz, 1H), 7.14 (t, J = 7.7 Hz, 1H), 7.01 (t, J = 7.4 Hz, 1H), 5.68 (ddd, J = 18.2, 12.6, 5.5 Hz, 4H), 4.82 (dt, J = 12.2, 6.1 Hz, 1H), 4.64 (t, J = 8.7 Hz, 1H), 4.35 (p, J = 9.2 Hz, 2H), 4.18 (td, J = 10.1, 6.5 Hz, 1H), 3.19 (q, J = 8.9 Hz, 2H), 2.37 (dt, J = 14.2, 7.4 Hz, 1H), 2.14 - 2.04 (m, 1H), 2.03 - 1.85 (m, 5H), 1.83 - 1.47 (m, 3H), 1.35 - 1.18 (m, 2H), 1.15 (s, 18H).

[0349] Example 55 Synthesis of (((difluoro(4-(2-((3S,6S,10aS)-3-(methyl(phenyl)carbamoyl)-5- oxodecahydropyrrolo[l,2-a]azepin-6-yl)amino)-2-oxoacetamido)phenyl)methyl) phosphoryl)bis(oxy)bis(methylene)bis(2,2-dimethylpropanoate) (Compound 55)

[0350] Step 1: Synthesis of compound tert-butyl ((3S,6S,10aS)-3-(methyl(phenyl)carbamoyl)- 5-oxodecahydropyrrolo[l,2-a]azepin-6-yl)carbamate (55-1)

[0351] Compound M2-1 (0.200 g, 0.613 mmol) and N-methylaniline (65.0 mg, 0.607 mmol) were dissolved in N,N-dimethylformamide (5 mL), the reaction solution was cooled to 10 °C, diisopropylethylamine (0.237 g, 1.84 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl)urea hexafluorophosphate (0.279 g, 0.734 mmol) were added successively, and the reaction was carried out at 25 °C for 30 min. After the reaction was completed by LC-MS monitoring, water (20 mL) was added, and the combined organic phase was extracted with ethyl acetate (20 mL x 3), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification on a silica gel column (petroleum ether: ethyl acetate = 40:60 as eluent) gave compound 55-1 (0.130 g) with a yield of 51.3%.

[0352] LC-MS (m / z): 416.0 [M+H] + .

[0353] Step 2: Synthesis of compound (3S,6S,10aS)-6-amino-N-methyl-5-oxo-N-phenyldecahydropyrrolo[l,2-a]azepine-3-carboxamide (55-2)

[0354] Compound 55-1 (0.130 g, 0.313 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1.50 g, 13.2 mmol) was added. The reaction solution was reacted at 25 °C for 1 h. After the reaction was completed by LC-MS monitoring, it was concentrated under reduced pressure to give compound 55-2 (0.125 g) with a yield of 97.6%.

[0355] LC-MS (m / z): 316.0 [M+H] + .

[0356] Step 3: Synthesis of compound diethyl (4-(2-(((3S,6S,10aS)-3-(methyl(phenyl)carbamoyl)- 5-oxodecahydropyrrolo[l,2-a]azepin-6-yl)amino)-2-oxoacetamido)methyl)phosphonate (55-3)

[0357] Compound 55-2 (0.125 g, 0.303 mmol) and 1-4 (0.109 g, 0.311 mmol) were dissolved in N,N-dimethylformamide (6 mL), the reaction solution was cooled to 10 °C, diisopropylethylamine (0.120 g, 0.930 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (0.140 g, 0.368 mmol) were added successively, and the reaction was carried out at 25 °C for 1 h. After the reaction was completed by LC-MS monitoring, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (EA as eluent) gave compound 55-3 (0.150 g) in a yield of 77.3%.

[0358] LC-MS (m / z): 649.0 [M+H] + .

[0359] Step 4: Synthesis of compound ((difluoro(4-(2-(((3S,6S,10aS)-3-(methyl(phenyl)carbamoyl)-5- oxodecahydropyrrolo[1,2-a]azepin-6-yl)amino)-2-oxoacetamido)phenyl)methyl)phosphonic acid (98)

[0360] Compound 55-3 (0.150 g, 0.231 mmol) was dissolved in anhydrous dichloromethane (5 mL), the reaction solution was cooled to 0 °C, and trimethylsilyl bromide (1.05 g, 6.86 mmol) was added dropwise. The reaction was carried out at 25 °C for 16 h. After the reaction was completed by LC-MS monitoring, the solution was concentrated under reduced pressure, a mixture of acetonitrile (8 mL) and water (2 mL) was added, the reaction was carried out at 25 °C for 40 min, and then concentrated under reduced pressure. Purification by reverse phase column chromatography (methanol: water = 50: 50 as eluent) gave compound 98 (55.0 mg) in a yield of 40.1%.

[0361] LC-MS (m / z): 593.0 [M+H] + .

[0362] Step 5: Synthesis of compound (((difluoro(4-(2-((3S,6S,10aS)-3-(methyl(phenyl)carbamoyl)-5- oxodecahydropyrrolo[1,2-a]azepin-6-yl)amino)-2-oxoacetamido)phenyl)methyl)phosphoryl)bis(oxy) bis(methylene)bis(2,2-dimethylpropanoate) (55)

[0363] Compound 98 (55.0 mg, 0.0929 mmol) was dissolved in water (4 mL), the solution was cooled to 0 °C, and an aqueous solution of sodium hydroxide was added dropwise. After the addition was completed, the pH of the solution was about 9, silver nitrate (34.6 mg, 0.204 mmol) was added, and the mixture was stirred at 0 °C for 2 h. The solid was collected by filtration, dried under reduced pressure with an oil pump (rotary vane vacuum pump), and then dissolved in toluene (3 mL). Iodomethyl pivalate (67.0 mg, 0.277 mmol) was added, and the mixture was stirred at 25 °C for 16 h. After the reaction was completed as monitored by LC-MS, the mixture was filtered and concentrated under reduced pressure. Compound 55 (17.9 mg) was obtained by purification on a thin layer chromatography plate with a yield of 23.7%.

[0364] LC-MS (m / z): 821.0 [M+H] + .

[0365] 1 H NMR (600 MHz, DMSO-d6) δ 1 H NMR (600 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.67 (d, J = 6.9 Hz, 1H), 7.98 (d, J = 8.5 Hz, 2H), 7.45 (ddd, J = 55.0, 20.9, 8.1 Hz, 7H), 5.68 (ddd, J = 18.3, 12.6, 5.5 Hz, 4H), 4.81 - 4.67 (m, 1H), 4.16 (d, J = 6.2 Hz, 2H), 3.16 (s, 3H), 2.03 (s, 1H), 1.96 - 1.82 (m, 5H), 1.70 (t, J = 4.2 Hz, 1H), 1.62 (s, 2H), 1.52 (t, J = 12.2 Hz, 2H), 1.27 - 1.20 (m, 1H), 1.15 (s, 18H).

[0366] Synthesis of (difluoro(4-(2-oxo-2-(((5S,8S,10aR)-6-oxo-8-((R)-2-phenylmorpholine-4- carbonyl)-3-propionylpyrrolo[1,2-a][1,5]diazepin-5-yl)amino)acetylamino)phenyl)methyl)phosphonic acid (Compound 56)

[0367] Step 1: Synthesis of methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6- oxodecahydropyrrolo[1,2-a][1,5]diazepine-8-carboxylate (56-1)

[0368] Compound 22-SM (0.200 g, 0.580 mmol) was dissolved in THF (5 mL), triethylamine (0.118 g, 1.17 mmol) was added, and propionyl chloride (65.0 mg, 0.700 mmol) was added at 0 °C. A white solid was precipitated, and the mixture was stirred at 0 °C for 1 h. After the reaction was completed by LC-MS monitoring, water (20 mL) was added, and the aqueous phase was extracted with dichloromethane (20 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (dichloromethane:methanol = 90:10 as eluent) gave compound 56-1 (0.227 g) in 98.7% yield.

[0369] LC-MS (m / z): 398.0 [M+H] + .

[0370] Step 2: Synthesis of compound (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxo-3- propionyldecahydropyrrolo[1,2-a][1,5]diazepine-8-carboxylic acid (56-2)

[0371] Compound 56-1 (0.227 g, 0.572 mmol) was dissolved in dioxane (4 mL), and a lithium hydroxide (48.0 mg, 1.15 mmol) aqueous solution (2 mL) was added. The mixture was stirred at 25 °C for 1 h. After the reaction was completed by LC-MS monitoring, most of the dioxane was removed by concentration under reduced pressure. Concentrated hydrochloric acid was added to the reaction mixture, and the aqueous phase was adjusted to pH 5. The aqueous phase was extracted with ethyl acetate (20 mL x 3), and the combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 56-2 (0.222 g) in 99.0% yield.

[0372] LC-MS (m / z): 384.0 [M+H] + .

[0373] Step 3: Synthesis of compound tert-butyl (5S,8S,10aR)-6-oxo-8-((R)-2-phenylmorpholine-4- carbonyl)-3-propionyldecahydropyrrolo[1,2-a][1,5]diazepin-5-yl)carbamate (56-3)

[0374] Compound 56-2 (0.222 g, 0.579 mmol) and (R)-2-phenylmorpholine (0.112 g, 0.687 mmol) were dissolved in N,N-dimethylformamide (3 mL), diisopropylethylamine (0.221 g, 1.71 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (0.260 g, 0.684 mmol) were added successively, and the reaction was carried out at 25 °C for 1 h. After the reaction was completed by LC-MS monitoring, water (20 mL) was added, and the combined organic phase was extracted with ethyl acetate (20 mL x 3), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification on a silica gel column (ethyl acetate as eluent) gave compound 56-3 (0.293 g) in a yield of 97.6%.

[0375] LC-MS (m / z): 529.0 [M+H] + .

[0376] Step 4: Synthesis of compound (5S,8S,10aR)-5-amino-8-((R)-2-phenylmorpholine-4-carbonyl)-3-propionylheptahydro pyrrolo[1,2-a][1,5]diazepin-6(1H)-one (56-4)

[0377] Compound 56-3 (0.293 g, 0.555 mmol) was dissolved in anhydrous dichloromethane (10 mL), and the reaction was cooled to 0 °C. Trifluoroacetic acid (2 mL) was added dropwise, and the reaction was carried out at 25 °C for 1 h. After the reaction was completed by TLC (alkaline) monitoring, it was concentrated under reduced pressure to give compound 56-4 (0.310 g, crude).

[0378] LC-MS (m / z): 429.0 [M+H] + .

[0379] Step 5: Synthesis of compound diethyl (4-(2-oxo-2-(((5S,8S,10aR)-6-oxo-8-((R)-2-phenylmorpholine-4-carbonyl)-3-propionylheptahydro pyrrolo[1,2-a][1,5]diazepin-5-yl)amino)acetamido)phenyl)methyl)phosphonate (56-5)

[0380] The above compound 56-4 crude (0.310 g) and 1-4 (0.203 g, 0.578 mmol) were dissolved in N, N-dimethylformamide (3 mL) solution, diisopropyl ethylamine (0.250 g, 1.93 mmol) and N, N, N', N'-tetramethyl-O- (7-azabenzotriazol-1-yl) urea hexafluorophosphate (0.244 g, 0.642 mmol) were added in turn, and placed at 25 °C for 1 hour. After LC-MS monitoring reaction was complete, water (20 mL) was added, extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate as eluent) to obtain compound 56-5 (0.200 g), yield 44.7%.

[0381] LC-MS (m / z): 762.0 [M+H] + .

[0382] Step 6: Synthesis of compound (difluoro(4-(2-oxo-2-(((5S,8S,10aR)-6-oxo-8-((R)-2- phenylmorpholine-4-carbonyl)-3-propionylpyrrolo[1,2-a][1,5]diazepin-5-yl)amino)acetylamino)phenyl)methyl)phosphonic acid (56)

[0383] Compound 56-5 (0.200 g, 0.263 mmol) was dissolved in anhydrous dichloromethane (10 mL), the reaction solution was cooled to 0 °C, and trimethylsilyl bromide (1.3 mL) was added dropwise, and the reaction solution was placed at 25 °C for 16 hours. After LC-MS monitoring reaction was complete, concentrated under reduced pressure, a mixture solution of acetonitrile (8 mL) and water (2 mL) was added, the reaction solution was placed at 25 °C for 40 minutes, concentrated under reduced pressure, and purified by reverse phase column chromatography ((methanol: water = 80:20 as eluent) to obtain compound 56 (0.198 g) crude.

[0384] LC-MS (m / z): 704.0 [M-H] – .

[0385] 1H NMR (600 MHz, DMSO-d6) δ 11.05 (d, J = 11.8 Hz, 1H), 8.68 (dd, J = 39.2, 6.2 Hz, 1H), 8.00 - 7.74 (m, 2H), 7.60 - 7.27 (m, 7H), 5.09 - 4.71 (m, 2H), 4.63 - 4.33 (m, 2H), 4.32 - 3.97 (m, 5H), 3.93 - 3.76 (m, 1H), 3.66 - 3.54 (m, 2H), 3.17 - 3.03 (m, 2H), 2.91 - 2.73 (m, 2H), 2.71 - 2.61 (m, 1H), 2.43 - 2.21 (m, 1H), 2.11 - 1.85 (m, 2H), 1.77 - 1.51 (m, 2H), 1.08 - 1.01 (m, 3H).

[0386] Example 57: Synthesis of ((difluoro(4-(2-(((3S,6S,10aS)-3-(morpholine-4-carbonyl)-5- oxodecahydropyrrolo[l,2-a]azepin-6-yl)amino)-2-oxoacetylamino)phenyl)methyl)phosphoryl) bis(oxy))bis(methylene) bis(2,2-dimethylpropanoate) (Compound 57)

[0387] Step 1: Synthesis of compound tert-butyl ((3S,6S,10aS)-3-(morpholine-4-carbonyl)-5- oxodecahydropyrrolo[l,2-a]azepin-6-yl)carbamate (57-1)

[0388] Compound M2-1 (0.300 g, 0.920 mmol) and morpholine (88.0 mg, 1.01 mmol) were dissolved in N,N-dimethylformamide (5 mL), the reaction solution was cooled to 0 °C, diisopropylethylamine (0.297 g, 2.30 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl)urea hexafluorophosphate (0.525 g, 1.38 mmol) were added in turn, and it was placed at 25 °C for reaction for 30 minutes. After the reaction was completed by LC-MS monitoring, water (20 mL) was added, extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 40:60 as eluent) to obtain compound 57-1 (0.350 g) with a yield of 96.2%.

[0389] LC-MS (m / z): 396.0 [M+H] + .

[0390] Step 2: Synthesis of compound (3S,6S,10aS)-6-amino-3-(morpholine-4-carbonyl) octahydropyrrolo[l,2-a]oxazin-5(lH)-one trifluoroacetate (57-2)

[0391] Compound 57-1 (0.350 g, 0.886 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (1.50 g, 13.2 mmol) was added, and the reaction was placed at 25 °C for 1 hour. After the reaction was completed by LC-MS monitoring, it was concentrated under reduced pressure to obtain compound 57-2 (0.205 g) with a yield of 78.8%.

[0392] LC-MS (m / z): 296.0 [M+H] + .

[0393] Step 3: Synthesis of compound diethyl (4-(2-(((3S,6S,10aS)-3-(morpholine-4-carbonyl)-5- oxodecahydro pyrrolo[l,2-a]oxazin-6-yl)amino)-2-oxoacetamido)phenyl)methyl) phosphonate (57-3)

[0394] Compound 1-4 (0.242 g, 0.689 mmol) and 57-2 (205.00 mg, 0.695 mmol) were dissolved in N,N-dimethylformamide (6 mL), the reaction was cooled to 0 °C, diisopropylethylamine (0.224 g, 1.73 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl)urea hexafluorophosphate (0.394 g, 1.04 mmol) were added in turn, and the reaction was placed at 25 °C for 1 hour. After the reaction was completed by LC-MS monitoring, water (20 mL) was added, and the combined organic phase was extracted with ethyl acetate (20 mL x 3), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane:methanol = 96:4 as eluent) to obtain compound 57-3 (0.400 g) with a yield of 92.2%.

[0395] LC-MS (m / z): 629.0 [M+H] + .

[0396] Step 4: Synthesis of compound (di fluor o(4-(2-(((3S,6S,10aS)-3-(morpholine-4-carbonyl)-5- oxodecahydro pyrrolo[l,2-a]oxazin-6-yl)amino)-2-oxoacetamido)phenyl)methyl) phosphonic acid (99)

[0397] Compound 57-3 (0.400 g, 0.637 mmol) was dissolved in anhydrous dichloromethane (10 mL), the reaction solution was cooled to 0 °C, trimethylsilyl bromide (2.10 g, 19.2 mmol) was added dropwise, and the reaction solution was allowed to react at 25 °C for 16 hours. After the reaction was completed by LC-MS monitoring, a mixed solution of acetonitrile (8 mL) and water (2 mL) was added, the reaction solution was allowed to react at 25 °C for 40 minutes, and then concentrated under reduced pressure. Purification by reverse phase column chromatography (methanol: water = 50: 50 as eluent) gave compound 99 (0.130 g) with a yield of 35.5%.

[0398] LC-MS (m / z): 573.0 [M+H] + .

[0399] Step 5: Synthesis of compound ((difluoro(4-(2-(((3S,6S,10aS)-3-(morpholine-4-carbonyl)-5- oxodecahydropyrrolo[l,2-a]azepin-6-yl)amino)-2-oxoacetylamino)phenyl)methyl)phosphoryl)bis(oxy))bis(methylene)bis(2,2-dimethylpropanoate) (57)

[0400] Compound 99 (0.130 g, 0.227 mmol) was dissolved in water (4 mL), and a solution of sodium hydroxide (16.6 mg, 0.415 mmol) in water (2 mL) was added dropwise while cooling to 0 °C. After the dropwise addition was completed, the pH of the solution was about 9, silver nitrate (86.0 mg, 0.506 mmol) was added, and the reaction solution was allowed to react at 0 °C for 2 hours. After filtration, the collected solid was dried under reduced pressure using an oil pump (rotary vane vacuum pump), and the obtained dried solid was dissolved in toluene (3 mL). lodomethyl pivalate (0.167 g, 0.690 mmol) was added, and the reaction solution was allowed to react at 25 °C for 16 hours. After the reaction was completed by LC-MS monitoring, the solution was filtered and concentrated under reduced pressure, and then purified by thin layer chromatography to obtain compound 57 (16.4 mg) with a yield of 9.0%.

[0401] LC-MS (m / z): 801.0 [M+H] + .

[0402] 1H NMR (600 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.69 (d, J = 7.0 Hz, 1H), 7.99 (d, J = 8.5 Hz, 2H), 7.50 (t, J = 7.2 Hz, 2H), 5.68 (ddd, J = 18.4, 12.6, 5.5 Hz, 4H), 5.41 (d, J = 10.4 Hz, 1H), 4.86 - 4.67 (m, 2H), 4.29 (dd, J = 11.8, 8.1 Hz, 1H), 3.67 (d, J = 11.4 Hz, 1H), 3.62 - 3.56 (m, 3H), 3.55 - 3.47 (m, 3H), 2.22 (dt, J = 12.0, 7.6 Hz, 1H), 2.02 (tt, J = 11.6, 8.0 Hz, 2H), 1.89 (dt, J = 12.3, 7.4 Hz, 2H), 1.84 - 1.47 (m, 7H), 1.15 (s, 18H).

[0403] Synthesis of Example 58 (((((4-(2-((3S,6S,10aS)-3-((2S,6R)-2,6-dimethylmorpholine-4- carbonyl)-5-oxodecahydropyrrolo[1,2-a]oxazin-6-yl)amino)-2-oxoacetylamino)phenyl) difluoromethyl)phosphoryl)bis(oxy))bis(methylene)bis(2,2-dimethylpropanoate) (Compound 58)

[0404] Synthesis of Step 1: Compound tert-butyl ((3S,6S,10aS)-3-((2S,6R)-2,6-dimethylmorpholine-4- carbonyl)-5-oxodecahydropyrrolo[1,2-a]oxazin-6-yl)carbamate (58-1)

[0405] Compound M2-1 (0.300 g, 0.920 mmol) and cis-2,6-dimethylmorpholine (0.116 g, 1.01 mmol) were dissolved in N,N-dimethylformamide (5 mL), the reaction solution was cooled to 0 °C, diisopropylethylamine (0.297 g, 2.30 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.525 g, 1.38 mmol) were added in turn, and it was placed at 25 °C for 30 minutes. After the reaction was completed by LC-MS monitoring, water (20 mL) was added, extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 40:60 as eluent) to obtain compound 58-1 (0.330 g), with a yield of 84.6%.

[0406] LC-MS (m / z): 424.0 [M+H] + .

[0407] Step 2: Synthesis of compound (3S,6S,10aS)-6-(l2azepinyl)-3-((2S,6R)-2,6- dimethylmorpholine-4-carbonyl)octahydropyrrolo[l,2-a]azol-5(lH)-one (58-2)

[0408] Compound 58-1 (0.330 g, 0.780 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (3 mL) was added, and the reaction was placed at 25 °C for 1 hour. After the reaction was completed by LC-MS monitoring, it was concentrated under reduced pressure to obtain crude 58-2 (0.330 g), which was directly used in the next step without purification.

[0409] LC-MS (m / z): 324.0 [M+H] + .

[0410] Step 3: Synthesis of compound diethyl (4-(2-(((3S,6S,10aS)-3-(morpholine-4- carbonyl)-5-oxodecahydropyrrolo[l,2-a]azepin-6-yl)amino)-2-oxoacetylamino)phenyl) methyl)phosphonate (58-3)

[0411] Compound 1-4 (0.270 g, 0.780 mmol) and 58-2 (0.330 g, 0.780 mmol) were dissolved in N,N-dimethylformamide (3 mL), the reaction was cooled to 10 °C, diisopropylethylamine (0.302 g, 2.34 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl)urea hexafluorophosphate (0.356 g, 0.937 mmol) were added in turn, and the reaction was placed at 25 °C for 1 hour. After the reaction was completed by LC-MS monitoring, water (20 mL) was added, and the combined organic phase was extracted with ethyl acetate (20 mL x 3), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (EA as eluent) to obtain compound 58-3 (0.190 g) with a yield of 37.1%.

[0412] LC-MS (m / z): 657.0 [M+H] + .

[0413] Step 4: Synthesis of compound (4-(2-(((3S,6S,10aS)-3-((2S,6R)-2,6-dimethylmorpholine- 4-carbonyl)-5-oxodecahydropyrrolo[l,2-a]azepin-6-yl)amino)-2-oxoacetylamino)phenyl) difluoromethyl)phosphonic acid (100)

[0414] Compound 58-3 (0.190 g, 0.290 mmol) was dissolved in anhydrous dichloromethane (1.5 mL), the reaction solution was cooled to 0 °C, and trimethylsilyl bromide (1.5 mL) was added dropwise. The reaction solution was allowed to react at 25 °C for 16 hours. After the reaction was completed by LC-MS monitoring, a mixed solution of acetonitrile (8 mL) and water (2 mL) was added, and the reaction solution was allowed to react at 25 °C for 40 minutes. After concentration under reduced pressure, purification by reverse phase column chromatography (methanol: water = 50: 50 as eluent) gave compound 100 (0.110 g) with a yield of 63.2%.

[0415] LC-MS (m / z): 601.0 [M+H] + .

[0416] Step 5: Synthesis of compound (((((4-(2-((3S,6S,10aS)-3-((2S,6R)-2,6-dimethylmorpholine-4-carbonyl)-5-oxodecahydropyrrolo[1,2-a]oxazin-6-yl)amino)-2-oxoacetylamino)phenyl) difluoromethyl) phosphoryl)oxy))bis(methylene)bis(2,2-dimethylpropanoate) (58)

[0417] Compound 100 (0.110 g, 0.183 mmol) was dissolved in water (4 mL), and the reaction solution was cooled to 0 °C. An aqueous solution of sodium hydroxide was added dropwise, and after the dropwise addition was completed, the pH of the solution was about 9. Silver nitrate (68.2 mg, 0.401 mmol) was added, and the solution was allowed to react at 0 °C for 2 hours. After filtration, the collected solid was dried under reduced pressure using an oil pump (rotary vane vacuum pump), and the obtained dried solid was dissolved in toluene (3 mL). lodomethyl pivalate (0.133 g, 0.550 mmol) was added, and the solution was allowed to react at 25 °C for 16 hours. After the reaction was completed by LC-MS monitoring, the solution was filtered and concentrated under reduced pressure. Purification by thin layer chromatography gave compound 58 (66.7 mg) with a yield of 44.5%.

[0418] LC-MS (m / z): 829.0 [M+H] + .

[0419] 1 H NMR (600 MHz, DMSO-d6) δ 1H NMR (600 MHz, DMSO-d6) δ 11.03 - 10.93 (m, 1H), 8.68 (dd, J = 19.5, 7.0 Hz, 1H), 7.99 (d, J = 8.6 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 5.75 - 5.61 (m, 4H), 4.88 - 4.66 (m, 2H), 4.35 - 4.19 (m, 2H), 3.97 (dd, J = 41.9, 13.2 Hz, 1H), 3.65 - 3.43 (m, 1H), 2.83 - 2.67 (m, 1H), 2.30 - 2.18 (m, 2H), 2.02 (td, J = 17.0, 15.4, 8.5 Hz, 2H), 1.89 (d, J = 4.7 Hz, 2H), 1.82 - 1.66 (m, 4H), 1.61 - 1.49 (m, 3H), 1.30 - 1.19 (m, 1H), 1.15 (s, 18H), 1.10 (dd, J = 11.9, 6.9 Hz, 6H).

[0420] Synthesis of ((((4-(2-((5S,8S,10aR)-8-((2S,6R)-2,6-dimethylmorpholine-4-carbonyl)-3-(5- methylbenzo[d]isoxazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazepin-5-yl)amino)- 2-oxoacetylamino)phenyl)di fluoromethyl)phosphoryl)bis(oxy))bis(methylene)bis(2,2- dimethylpropanoate) (Compound 59)

[0421] Step 1: Synthesis of methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(5- methylbenzo[d]isoxazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazepine-8- carboxylate (59-2)

[0422] Compound 22-SM (0.250 g, 0.733 mmol) and 5-methylbenzo[d]isoxazole-3- carboxylic acid (168.00 mg, 0.949 mmol) were dissolved in anhydrous dichloromethane (10 mL), the reaction solution was cooled to 0 °C, 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.211 g, 1.10 mmol) and 1-hydroxybenzotriazole (0.109 g, 0.807 mmol) were added, and it was placed at 25 °C for 2 hours. After the reaction was completed by LC-MS monitoring, water (50 mL) was added, and it was extracted with DCM (10 mL x 3), the combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 59-2 (0.350 g) with a yield of 95.6%.

[0423] LC-MS (m / z): 501.0 [M+H] + .

[0424] Step 2: Synthesis of compound ((5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3- (5-methylbenzo[d]isoxazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazepine-8- carboxylic acid (59-3)

[0425] Compound 59-2 (0.350 g, 0.700 mmol) was dissolved in tetrahydrofuran (4 mL), the reaction solution was cooled to 0 °C, and an aqueous solution (4 mL) of lithium hydroxide (59.0 mg, 1.40 mmol) was added dropwise, and it was placed at room temperature for 2 hours. After the reaction was completed by LC-MS monitoring, 1.0 M dilute hydrochloric acid was added to the reaction solution, and the aqueous phase was adjusted to be acidic, and the aqueous phase was extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 59-3 (0.330 g) with a yield of 96.7%.

[0426] LC-MS (m / z): 487.0 [M+H] + .

[0427] Step 3: Synthesis of compound tert-butyl ((5S,8S,10aR)-8-((2S,6R)-2,6-dimethylmorpholine-4- carbonyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazepin- 5-yl)carbamate (59-4)

[0428] Compound 59-3 (0.330 g, 0.679 mmol) and cis-2,6-dimethylmorpholine (94.0 mg, 0.817 mmol) were dissolved in N,N-dimethylformamide (5 mL), the reaction solution was cooled to 0 °C, diisopropylethylamine (0.220 g, 1.70 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (0.388 g, 1.02 mmol) were added successively, and the mixture was allowed to react at 25 °C for 1 hour. After the reaction was completed by LC-MS monitoring, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification on a silica gel column (dichloromethane:methanol = 96:4 as eluent) gave compound 59-4 (0.380 g) with a yield of 95.7%.

[0429] LC-MS (m / z): 584.0 [M-H] + .

[0430] Step 4: Synthesis of compound (5S,8S,10aR)-5-amino-8-((2S,6R)-2,6-dimethylmorphine-4-carbonyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)octahydro pyrrolo[1,2-a][1,5]diazepin-6(1H)-one trifluoroacetate (59-5)

[0431] Compound 59-4 (0.380 g, 0.652 mmol) was dissolved in anhydrous dichloromethane (7 mL), the reaction solution was cooled to 0 °C, and trifluoroacetic acid (1.11 g, 9.75 mmol) was added, and the mixture was allowed to react at 25 °C for 1 hour. After the reaction was completed by LC-MS monitoring, the mixture was concentrated under reduced pressure to give compound 59-5 (0.300 g) with a yield of 95.2%.

[0432] LC-MS (m / z): 484.0 [M+H] + .

[0433] Step 5: Synthesis of compound diethyl (4-(2-(((5S,8S,10aR)-8-((2S,6R)-2,6-dimethylmorphine-4-carbonyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6-oxo-decahydro pyrrolo[1,2-a][1,5]diazepin-5-yl)amino)-2-oxoacetamido)phenyl) difluoromethyl)phosphonate (59-6)

[0434] Compound 1-4 (0.218 g, 0.621 mmol) and 59-5 (0.300 g, 0.621 mmol) were dissolved in N,N-dimethylformamide (6 mL), the reaction solution was cooled to 0 °C, and diisopropylethylamine (0.200 g, 1.55 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.354 g, 0.932 mmol) were sequentially added, and the reaction was allowed to proceed at 25 °C for 1 hour. After the reaction was confirmed to be complete by LC-MS, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (dichloromethane:methanol = 96:4 as eluent) gave compound 59-6 (0.400 g) in 79.1% yield.

[0435] LC-MS (m / z): 817.0 [M+H] + .

[0436] Step 6: Synthesis of compound (4-(2-(((5S,8S,10aR)-8-((2S,6R)-2,6-dimethylmorpholine-4-carbonyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazepin-5-yl)amino)-2-oxoacetamido)phenyl)difluoromethyl)phosphonic acid (101)

[0437] Compound 59-6 (0.400 g, 0.490 mmol) was dissolved in anhydrous dichloromethane (10 mL), and the reaction solution was cooled to 0 °C. Trimethylsilyl bromide (2.25 g, 14.7 mmol) was added dropwise, and the reaction was allowed to proceed at 25 °C for 16 hours. After the reaction was confirmed to be complete by LC-MS, the reaction solution was concentrated under reduced pressure, and a mixture of acetonitrile (8 mL) and water (2 mL) was added. The reaction was allowed to proceed at 25 °C for 40 minutes, and then concentrated under reduced pressure. Purification by reverse phase column chromatography (methanol:water = 50:50 as eluent) gave compound 101 (0.250 g) in 67.0% yield.

[0438] LC-MS (m / z): 761.0 [M+H] + .

[0439] Step 7: Synthesis of compound ((((4-(2-((5S,8S,10aR)-8-((2S,6R)-2,6-dimethylmorpholine-4-carbonyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazepin-5-yl)amino)-2-oxoacetamido)phenyl)difluoromethyl)phosphoryl)bis(oxy))bis(methylene)bis(2,2-dimethylpropanoate) (59)

[0440] Compound 101 (0.150 g, 0.197 mmol) was dissolved in water (4 mL), the reaction solution was cooled to 0 °C, and a solution of sodium hydroxide (14.0 mg, 0.350 mmol) in water (2 mL) was added dropwise. After the addition was completed, the pH of the solution was about 9, and silver nitrate (75.0 mg, 0.441 mmol) was added, and the solution was reacted at 0 °C for 2 hours. Filtration was performed, and the solid was dried under reduced pressure with an oil pump (rotary vane vacuum pump). The obtained dried solid was dissolved in toluene (3 mL), and iodomethyl pivalate (0.145 g, 0.599 mmol) was added, and the solution was reacted at 25 °C for 16 hours. After the reaction was completed as monitored by LC-MS, filtration was performed, and concentration was performed under reduced pressure, and purification was performed by preparative thin layer chromatography plate to obtain compound 59 (18.2 mg) at a yield of 9.2%.

[0441] LC-MS (m / z): 989.0 [M+H] + .

[0442] 1 H NMR (600 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.94 (dd, J = 21.0, 6.8 Hz, 1H), 8.05 - 7.94 (m, 2H), 7.83 (d, J = 5.8 Hz, 1H), 7.74 - 7.69 (m, 1H), 7.52 (dd, J = 24.7, 8.7 Hz, 3H), 5.68 (ddt, J = 18.3, 12.3, 5.4 Hz, 4H), 4.97 (d, J = 23.2 Hz, 1H), 4.88 (dt, J = 17.4, 8.2 Hz, 1H), 4.74 (q, J = 8.4, 7.6 Hz, 1H), 4.43 (d, J = 9.2 Hz, 2H), 4.22 - 4.06 (m, 2H), 3.94 (td, J = 33.5, 31.8, 20.4 Hz, 3H), 3.65 - 3.37 (m, 1H), 2.73 (dq, J = 25.7, 13.1, 12.6 Hz, 1H), 2.45 (s, 3H), 2.39 - 2.15 (m, 3H), 2.14 - 1.92 (m, 3H), 1.79 (dd, J = 24.6, 13.0 Hz, 1H), 1.16 (s, 6H), 1.14 (s, 18H).

[0443] Synthesis of (((4-(2-((5S,8S,10aR)-3-acetyl-6-oxo-8-((R)-2-phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2-a][1,5]diazepin-5-yl)amino)-2-oxoacetylamino)phenyl) difluoromethyl)phosphoryl)bis(oxygen))bis(methylene)diisopropyl bis(carbonate) (Compound 61)

[0444] Step 1: Synthesis of compound 3-benzyl-8-methyl (5S,8S,10aR)-5-((tert- butoxycarbonyl)amino)-6-oxooctahydropyrrolo[l,2-a][l,5]diazepine-3,8(4H)- dicarboxylate (61-1)

[0445] Compound 22-SM (1.40 g, 4.11 mmol) was dissolved in dioxane (10 mL), sodium bicarbonate (1.03 g, 12.3 mmol) was added, the reaction system was placed at 10 °C, benzyl chloroformate (0.907 g, 5.33 mmol) was added, white solid was precipitated, the reaction system was placed at 25 °C for 16 hours. After the reaction was completed by LC-MS monitoring, it was concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 2: 1 as eluent) to obtain compound 61-1 (1.65 g), with a yield of 84.6%.

[0446] LC-MS (m / z): 476.0 [M+H] + .

[0447] Step 2: Synthesis of compound (5S,8S,10aR)-3-((benzyloxy)carbonyl)-5-(tert- butoxycarbonyl)amino)-6-oxodecahydropyrrolo[l,2-a][l,5]diazepine-8-carboxylic acid (61-2)

[0448] Compound 61-1 (1.65 g, 3.47 mmol) was dissolved in dioxane (10 mL), lithium hydroxide (0.167 g, 6.94 mmol) aqueous solution (5 mL) was added, and it was placed at 25 °C for 1 hour. After the reaction was completed by LC-MS monitoring, most of the dioxane was removed by concentration under reduced pressure, concentrated hydrochloric acid was added to the reaction solution, the pH of the aqueous phase was adjusted to 5, the aqueous phase was extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 61-2 (1.60 g) with a yield of 99.8%.

[0449] LC-MS (m / z): 462.0 [M+H] + .

[0450] Step 3: Synthesis of compound benzyl (5S,8S,10aR)-5-((tert- butoxycarbonyl)amino)-6-oxo-8-((R)-2-phenylmorpholine-4-carbonyl)octahydropyrrolo[l,2- a][l,5]diazepine-3(4H)-carboxylate (61-3)

[0451] Compound 61-2 (1.60 g, 3.47 mmol) and R-2-phenylmorpholine (0.566 g, 3.47 mmol) were dissolved in DMF (8 mL) solution, diisopropylethylamine (1.34 g, 10.4 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl) uronium hexafluorophosphate (1.58 g, 4.16 mmol) were added successively, and the reaction was carried out at 25 °C for 1 h. After the reaction was completed by LC-MS monitoring, water (20 mL) was added, and the combined organic phase was extracted with ethyl acetate (20 mL x 3), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification on a silica gel column (ethyl acetate as eluent) gave compound 61-3 (1.90 g) in a yield of 90.4%.

[0452] LC-MS (m / z): 607.0 [M+H] + .

[0453] Step 4: Synthesis of compound benzyl (5S,8S,10aR)-5-amino-6-oxo-8-((R)-2- phenylmorpholine-4-carbonyl)octahydropyrrolo[1,2-a][1,5]diazepine-3(4H)- carboxylate (61-4)

[0454] Compound 61-3 (1.70 g, 2.80 mmol) was dissolved in anhydrous dichloromethane (4 mL), and the reaction was cooled to 0 °C. Trifluoroacetic acid (4 mL) was added dropwise, and the reaction was carried out at 25 °C for 1 h. After the reaction was completed by TLC (alkaline) monitoring, it was concentrated under reduced pressure to give crude compound 61-4 (1.70 g).

[0455] LC-MS (m / z): 507.0 [M+H] + .

[0456] Step 5: Synthesis of compound benzyl (5S,8S,10aR)-5-(2-((4- (diethoxyphosphoryl)difluoromethyl)phenyl)amino)-2-oxoacetamido)-6-oxo-8-((R)-2- phenylmorpholine-4-carbonyl)octahydropyrrolo[1,2-a][1,5]diazepine-3(4H)- carboxylate (61-5)

[0457] Compound 61-4 (1.70 g, 2.80 mmol) and 1-4 (0.983 g, 2.80 mmol) were dissolved in N,N-dimethylformamide (10 mL), diisopropylethylamine (1.30 g, 10.8 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (1.27 g, 3.36 mmol) were added successively, and the mixture was allowed to react at 25 °C for 1 h. After the reaction was completed as determined by LC-MS and TLC, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification on a silica gel column (ethyl acetate as eluent) gave compound 61-5 (1.40 g) in a yield of 59.5%.

[0458] LC-MS (m / z): 840.0 [M+H] + .

[0459] Step 6: Synthesis of compound difluoro(4-(2-oxo-2-(((5S,8S,10aR)-6-oxo-8-((R)-2- phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2-a][1,5]diazepin-5-yl)amino)acetylamino)phenyl)methyl)phosphonic acid diethyl ester (61-6)

[0460] Compound 61-5 (0.400 g, 0.477 mmol) was dissolved in THF (10 mL), and palladium-carbon (10%, 0.200 g, 0.189 mmol) was added. The mixture was replaced with hydrogen gas three times, and the reaction mixture was allowed to react at 25 °C for 16 h under a hydrogen atmosphere. After the reaction was completed as determined by LC-MS, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 61-6 (0.290 g) in a yield of 86.3%.

[0461] Step 7: Synthesis of compound difluoro(4-(2-(((5S,8S,10aR)-3-acetyl-6-oxo-8-((R)-2- phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2-a][1,5]diazepin-5-yl)amino)-2- oxoacetylamino)phenyl)methyl)phosphonic acid diethyl ester (61-7)

[0462] Compound 61-6 (0.150 g, 0.213 mmol) was dissolved in anhydrous dichloromethane (5 mL), the reaction solution was cooled to 0 °C, and triethylamine (43.0 mg, 0.426 mmol) and acetyl chloride (25.0 mg, 0.318 mmol) were added successively. The reaction was allowed to proceed at 25 °C for 0.5 h. After the reaction was completed by LC-MS monitoring, it was concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane:methanol = 96:4 as eluent) to obtain compound 61-7 (0.120 g) with a yield of 76.4%.

[0463] LC-MS (m / z): 748.0 [M+H] + .

[0464] Step 8: Synthesis of compound (4-(2-(((5S,8S,10aR)-3-acetyl-6-oxo-8-((R)-2- phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2-a][1,5]diazepin-5-yl)amino)-2- oxoacetamido)phenyl)difluoromethyl)phosphonic acid (53)

[0465] Compound 61-7 (0.120 g, 0.161 mmol) was dissolved in anhydrous dichloromethane (5 mL), the reaction solution was cooled to 0 °C, and trimethylsilyl bromide (0.735 g, 4.80 mmol) was added dropwise. The reaction was allowed to proceed at 25 °C for 16 h. After the reaction was completed by LC-MS monitoring, it was concentrated under reduced pressure, a mixture of acetonitrile (8 mL) and water (2 mL) was added, and the reaction was allowed to proceed at 25 °C for 40 min. It was concentrated under reduced pressure and purified by reverse phase column chromatography (methanol:water = 50:50 as eluent) to obtain compound 53 (80.0 mg) with a yield of 72.1%.

[0466] LC-MS (m / z): 692.0 [M+H] + .

[0467] Step 9: Synthesis of compound ((((4-(2-((5S,8S,10aR)-3-acetyl-6-oxo-8-((R)-2- phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2-a][1,5]diazepin-5-yl)amino)-2- oxoacetamido)phenyl)difluoromethyl)phosphoryl)bis(oxygen))bis(methylene)diisopropyl bis(carbonate) (61)

[0468] Compound 53 (80.0 mg, 0.116 mmol) was dissolved in water (4 mL), the solution was cooled to 0 °C, and a solution of sodium hydroxide (9.00 mg, 0.225 mmol) in water (2 mL) was added dropwise. After the addition was completed, the pH of the solution was about 9, and silver nitrate (45.0 mg, 0.265 mmol) was added. The solution was stirred at 0 °C for 2 h. The solid was collected by filtration, dried under reduced pressure with an oil pump (rotary vane vacuum pump), and dissolved in toluene (3 mL). lodomethyl pivalate (87.0 mg, 0.360 mmol) was added, and the solution was stirred at 25 °C for 16 h. After the reaction was completed by LC-MS monitoring, the solution was filtered and concentrated under reduced pressure. Compound 61 (6.80 mg) was obtained by purification with a preparative thin layer chromatography plate, and the yield was 6.1%.

[0469] LC-MS (m / z): 924.0 [M+H] + .

[0470] 1 H NMR (600 MHz, DMSO-d6) δ 11.17 (d, J = 10.8 Hz, 1H), 8.66 (dd, J = 38.3, 6.3 Hz, 1H), 8.03 (t, J = 8.2 Hz, 2H), 7.53 - 7.44 (m, 3H), 7.39 (dt, J = 10.3, 7.6 Hz, 3H), 7.33 (dt, J = 9.5, 4.4 Hz, 1H), 5.73 - 5.62 (m, 4H), 5.05 - 4.52 (m, 5H), 4.44 - 4.23 (m, 3H), 4.19 - 3.96 (m, 3H), 3.84 (d, J = 13.6 Hz, 1H), 3.66 - 3.49 (m, 1H), 3.43 - 3.33 (m, 1H), 3.12 (dt, J = 25.3, 12.8 Hz, 1H), 2.92 - 2.59 (m, 1H), 2.41 (ddd, J = 16.6, 8.3, 5.3 Hz, 1H), 2.28 (d, J = 5.7 Hz, 3H), 2.12 - 1.97 (m, 1H), 1.97 - 1.85 (m, 1H), 1.69 (ddd, J = 39.7, 11.6, 6.6 Hz, 2H), 1.56 (dd, J = 27.9, 13.4 Hz, 1H), 1.26 (d, J = 6.2 Hz, 12H).

[0471] Synthesis of ((difluoro(4-(2-oxo-2-(((5S,8S,10aR)-6-oxo-8-((R)-2-phenylmorpholine-4- carbonyl)-3-propionylhydro-pyrrolo[1,2-a][1,5]diazepin-5-yl)amino)acetylamino)phenyl)methyl) phosphoryl)bis(oxy))bis(methylene)diisopropyl bis(carbonate) (Compound 62)

[0472] Step 1: Synthesis of compound diethyl (4-(2-oxo-2-(((5S,8S,10aR)-6-oxo-8-((R)-2- phenylmorpholine-4-carbonyl)-3-propionylhydro pyrrolo[l,2-a][l,5]diazepin-5-yl)amino)acetylamino)phenyl)methyl)phosphonate (62-1)

[0473] Compound 61-6 (0.150 g, 0.213 mmol) was dissolved in anhydrous dichloromethane (5 mL), the reaction solution was cooled to 0 °C, triethylamine (43.0 mg, 0.426 mmol) and propionyl chloride (30.0 mg, 0.323 mmol) were added successively, and the reaction was carried out at 25 °C for 0.5 h. After the reaction was completed by LC-MS monitoring, it was concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane:methanol = 96:4 as eluent) to obtain compound 62-1 (0.120 g) with a yield of 75.0%.

[0474] LC-MS (m / z): 762.0 [M+H] + .

[0475] Step 2: Synthesis of compound (diethyl (4-(2-oxo-2-(((5S,8S,10aR)-6-oxo-8-((R)-2- phenylmorpholine-4-carbonyl)-3-propionylpyrrolo[l,2-a][l,5]diazepin-5-yl)amino)acetylamino)phenyl)methyl)phosphonate (56)

[0476] Compound 62-1 (0.120 g, 0.158 mmol) was dissolved in anhydrous dichloromethane (5 mL), the reaction solution was cooled to 0 °C, and trimethylsilyl bromide (0.735 mg, 4.80 mmol) was added dropwise, and the reaction was carried out at 25 °C for 16 h. After the reaction was completed by LC-MS monitoring, it was concentrated under reduced pressure, a mixed solution of acetonitrile (8 mL) and water (2 mL) was added, the reaction solution was placed at 25 °C for 40 min, and concentrated under reduced pressure. Purification by reverse phase column chromatography (methanol:water = 50:50 as eluent) gave compound 56 (80.0 mg) with a yield of 71.0%.

[0477] LC-MS (m / z): 706.0 [M+H] + .

[0478] Step 3: Synthesis of compound ((difluoro(4-(2-oxo-2-(((5S,8S,10aR)-6-oxo-8-((R)-2- phenylmorpholine-4-carbonyl)-3-propionylhydro-pyrrolo[l,2-a][l,5]diazepin-5-yl)amino)acetylamino)phenyl)methyl)phosphoryl)bis(oxy))bis(methylene)diisopropyl bis(carbonate) (62)

[0479] Compound 56 (80.0 mg, 0.113 mmol) was dissolved in water (4 mL), the solution was cooled to 0 °C, and a solution of sodium hydroxide (8.00 mg, 0.200 mmol) in water (2 mL) was added dropwise. After the addition was completed, the pH of the solution was about 9, and silver nitrate (41.0 mg, 0.241 mmol) was added. The solution was stirred at 0 °C for 2 h. The solid was collected by filtration and dried under reduced pressure using an oil pump (rotary vane vacuum pump). The dried solid was dissolved in toluene (3 mL), and iodomethyl pivalate (80.0 mg, 0.331 mmol) was added. The solution was stirred at 25 °C for 16 h. After the reaction was completed as monitored by LC-MS, the solution was filtered and concentrated under reduced pressure. Compound 62 (5.10 mg) was obtained by separation and purification on a thin layer chromatography plate with a yield of 5.0%.

[0480] LC-MS (m / z): 938.0 [M+H] + .

[0481] 1H NMR (600 MHz, DMSO-d6) δ 11.17 (d, J = 10.6 Hz, 1H), 8.68 (dd, J = 39.7, 6.2 Hz, 1H), 8.03 (t, J = 8.0 Hz, 2H), 7.53 - 7.48 (m, 2H), 7.46 (d, J = 7.7 Hz, 1H), 7.39 (dt, J = 14.6, 7.5 Hz, 3H), 7.33 (dt, J = 8.6, 4.1 Hz, 1H), 5.68 (dq, J = 13.0, 5.7 Hz, 4H), 5.36 - 4.96 (m, 1H), 4.82 (tt, J = 14.6, 7.3 Hz, 3H), 4.58 (d, J = 10.6 Hz, 1H), 4.38 (d, J = 11.3 Hz, 1H), 4.21 (dd, J = 72.6, 12.9 Hz, 2H), 4.10 - 3.95 (m, 3H), 3.86 (d, J = 13.6 Hz, 1H), 3.58 (q, J = 11.8 Hz, 1H), 3.11 (dt, J = 35.6, 13.2 Hz, 1H), 2.93 - 2.73 (m, 1H), 2.72 - 2.59 (m, 1H), 2.45 - 2.16 (m, 1H), 2.11 - 1.84 (m, 2H), 1.73 (dd, J = 11.6, 7.2 Hz, 1H), 1.70 - 1.41 (m, 1H), 1.33 (d, J = 32.3 Hz, 1H), 1.26 (d, J = 6.3 Hz, 12H), 1.23 (s, 1H), 1.04 (qd, J = 8.1, 7.6, 5.1 Hz, 3H), 0.85 (t, J = 6.9 Hz, 1H).

[0482] Synthesis of ((difluoro(4-(2-oxo-2-(((3S,6S,10aS)-5-oxo-3-((R)-2-phenylmorpholine-4- carbonyl)decahydropyrrolo[1,2-a]azepin-6-yl)amino)acetamido)phenyl)methyl)phosphoryl)bis(oxy))bis(methylene)diisopropyl bis(carbonate) (Compound 65)

[0483] Synthesis of ((difluoro(4-(2-oxo-2-(((3S,6S,10aS)-5-oxo-3-((R)-2-phenylmorpholine-4- carbonyl)decahydropyrrolo[1,2-a]azepin-6-yl)amino)acetamido)phenyl)methyl)phosphoryl)bis(oxy))bis(methylene)diisopropyl bis(carbonate) (65)

[0484] Compound 52 (0.162 g, 0.250 mmol) was dissolved in water (4 mL), the solution was cooled to 0 °C, and a solution of sodium hydroxide (18.0 mg, 0.450 mmol) in water (2 mL) was added dropwise. After the addition was completed, the pH of the solution was about 9, and silver nitrate (93.5 mg, 0.550 mmol) was added. The solution was stirred at 0 °C for 2 h. The solid was collected by filtration and dried under reduced pressure using an oil pump (rotary vane vacuum pump). The dried solid was dissolved in toluene (4 mL), and iodomethyl isopropyl carbonate (0.183 g, 0.756 mmol) was added. The solution was stirred at 25 °C for 16 h. When the reaction was complete by LC-MS monitoring, the solution was filtered and concentrated under reduced pressure. Compound 65 (55.0 mg) was obtained by separation and purification on a thin layer chromatography plate with a yield of 25.0%.

[0485] LC-MS (m / z): 881.0 [M+H] + .

[0486] 1H NMR (600 MHz, DMSO-d6) δ 11.01 (d, J = 9.3 Hz, 1H), 8.71 (dd, J = 34.1, 7.0 Hz, 1H), 8.00 (t, J = 7.4 Hz, 2H), 7.50 (dd, J = 8.7, 3.1 Hz, 2H), 7.39 (ddt, J = 20.4, 13.2, 7.3 Hz, 4H), 7.32 (td, J = 7.0, 3.8 Hz, 1H), 5.68 (dq, J = 13.0, 5.8 Hz, 4H), 4.92 (t, J = 8.5 Hz, 1H), 4.82 (dhept, J = 13.2, 6.2 Hz, 3H), 4.75 (t, J = 8.8 Hz, 1H), 4.60 - 4.52 (m, 1H), 4.40 - 4.34 (m, 1H), 4.29 (t, J = 11.3 Hz, 1H), 4.16 (d, J = 13.3 Hz, 1H), 4.03 (t, J = 13.8 Hz, 2H), 3.56 (td, J = 11.8, 2.7 Hz, 1H), 3.35 (d, J = 12.4 Hz, 1H), 3.13 (dd, J = 13.5, 10.6 Hz, 1H), 2.85 (td, J = 12.9, 3.6 Hz, 1H), 2.63 (dd, J = 12.7, 10.2 Hz, 1H), 2.31 (dd, J = 11.9, 7.2 Hz, 1H), 2.22 - 2.12 (m, 1H), 2.02 (dd, J = 35.2, 8.3 Hz, 1H), 1.89 (dt, J = 12.2, 8.2 Hz, 2H), 1.81 (t, J = 12.6 Hz, 1H), 1.71 (ddd, J = 37.4, 14.7, 7.2 Hz, 1H), 1.64 - 1.45 (m, 1H), 1.26 (d, J = 6.2 Hz, 12H).

[0487] Synthesis of ((difluoro(4-(2-oxo-2-(((3S,6S,10aS)-5-oxo-3-((R)-2-phenylmorpholine-4- carbonyl)decahydropyrrolo[1,2-a]azepin-6-yl)amino)acetylamino)phenyl)methyl)(hydroxy) phosphoryl)oxy)methyl neopentanoate (67) and its ammonium salt

[0488] Synthesis of compound ((difluoro(4-(2-oxo-2-(((3S,6S,10aS)-5-oxo-3-((R)-2-phenylmorpholine-4- carbonyl)decahydropyrrolo[1,2-a]azepin-6-yl)amino)acetylamino)phenyl)methyl)(hydroxy) phosphoryl)oxy)methyl neopentanoate (67)

[0489] Compound 4 (25.0 mg, 28.5 μmol) was dissolved in methanol (3 mL) and reacted at 25 °C for 36 h. When the reaction was completed by LC-MS monitoring, compound 67 was obtained by concentration under reduced pressure.

[0490] LC-MS (m / z): 763.0 [M+H] + .

[0491] Step 2: Synthesis of compound ((difluoro(4-(2-oxo-2-(((3S,6S,10aS)-5-oxo-3-((R)-2- phenylmorpholine-4-carbonyl)decahydropyrrolo[l,2-a]azepin-6-yl)amino)acetylamino)phenyl)methyl)(hydroxy)phosphoryl)oxy)methyl neopentanoate ammonium salt

[0492] Compound 67 was separated and purified by preparative HPLC to obtain ammonium salt of compound 67 (9.0 mg) with a yield of 41.5%. Preparative method: C18 column was used with mobile phase of 10 mmol / L ammonium bicarbonate aqueous solution (A) and acetonitrile (B). Gradient elution, 0 to 10 min (15%→100%) of B phase volume content, 10.01 to 15 min (100%), 15:01 min to 20 min (100%→15%), flow rate 15 mL / min.

[0493] LC-MS (m / z): 763.0 [M+H] + .

[0494] 1H NMR (600 MHz, DMSO-d6) δ 10.78 (d, J = 9.4 Hz, 1H), 8.67 (dd, J = 33.6, 7.1 Hz, 1H), 7.81 (t, J = 7.6 Hz, 2H), 7.48 (dd, J = 8.9, 3.3 Hz, 2H), 7.45 - 7.28 (m, 5H), 7.10 (t, J = 51.0 Hz, 4H), 5.38 (d, J = 10.6 Hz, 2H), 5.02 - 4.68 (m, 2H), 4.57 (d, J = 10.4 Hz, 1H), 4.36 (t, J = 12.8 Hz, 1H), 4.29 (t, J = 10.7 Hz, 1H), 4.17 (d, J = 13.4 Hz, 1H), 4.03 (t, J = 12.3 Hz, 2H), 3.56 (t, J = 12.2 Hz, 1H), 3.12 (dd, J = 13.5, 10.5 Hz, 1H), 2.99 - 2.79 (m, 1H), 2.72 - 2.55 (m, 1H), 2.30 (d, J = 10.1 Hz, 1H), 2.22 - 1.96 (m, 3H), 1.96 - 1.78 (m, 3H), 1.77 - 1.45 (m, 3H), 1.14 (s, 9H).

[0495] Synthesis of ((4-(2-(((5S,8S,10aR)-3-acetyl-6-oxo-8-((R)-2-phenylmorpholine-4- carbonyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-2-oxoacetylamino)phenyl) difluoromethyl)(hydroxy)phosphoryl)oxy)methyl neopentanoate (Compound 68) and its ammonium salt

[0496] Synthesis of ((4-(2-(((5S,8S,10aR)-3-acetyl-6-oxo-8-((R)-2-phenylmorpholine-4- carbonyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-2-oxoacetylamino)phenyl) difluoromethyl)(hydroxy)phosphoryl)oxy)methyl neopentanoate (Compound 68) and its ammonium salt

[0497] Compound 21 (32.0 mg, 34.8 μmol) was dissolved in methanol (3 mL) and reacted at 25 °C for 36 h. When the reaction was completed by LC-MS monitoring, it was concentrated under reduced pressure to give Compound 68.

[0498] LC-MS (m / z): 806.0 [M+H] + .

[0499] Step 2: Synthesis of (((4-(2-(((5S,8S,10aR)-3-acetyl-6-oxo-8-((R)-2- phenylmorpholine-4-carbonyl)decahydropyrrolo[l,2-a][l,5]diazepin-5-yl)amino)-2- oxoacetylamino)phenyl) difluoromethyl)(hydroxy)phosphoryl)oxy)methyl neopentanoate ammonium salt

[0500] Compound 68 was purified by HPLC to give ammonium salt of compound 68 (12.0 mg) with a yield of 42.9%. Preparation method: C18 column was used with mobile phase of 10 mmol / L ammonium bicarbonate aqueous solution (A) and acetonitrile (B). Gradient elution, 0 to 10 min (15%→100%), 10.01 to 15 min (100%), 15:01 min to 20 min (100%→15%) with respect to volume content of B phase, flow rate 15 mL / min.

[0501] LC-MS (m / z): 806.0 [M+H] + .

[0502] 1 H NMR (600 MHz, DMSO-d6) δ 10.96 (d, J = 11.9 Hz, 1H), 8.65 (dd, J = 39.2, 6.3 Hz, 1H), 7.84 (t, J = 7.9 Hz, 2H), 7.52 - 7.45 (m, 3H), 7.43 - 7.35 (m, 3H), 7.35 - 7.30 (m, 1H), 7.10 (t, J = 51.0 Hz, 4H), 5.38 (d, J = 10.5 Hz, 2H), 5.09 - 4.73 (m, 2H), 4.68 - 4.23 (m, 4H), 4.21 - 3.95 (m, 3H), 3.90 - 3.77 (m, 1H), 3.58 (dt, J = 21.1, 12.0 Hz, 1H), 3.11 (ddd, J = 25.6, 14.4, 10.7 Hz, 2H), 2.97 - 2.62 (m, 1H), 2.46 - 2.31 (m, 1H), 2.28 (d, J = 5.9 Hz, 3H), 2.14 - 1.98 (m, 2H), 1.97 - 1.85 (m, 1H), 1.78 - 1.45 (m, 2H), 1.14 (s, 9H).

[0503] Example 69 Synthesis of (((difluoro(4-(2-oxo-2-(((5S,8S,10aR)-6-oxo-8-((R)-2- phenylmorpholine-4-carbonyl)-3-propionoyldecahydropyrrolo[l,2-a][l,5]diazepin-5- yl)amino)acetylamino)phenyl)methyl)(hydroxy)phosphoryl)oxy)methyl neopentanoate (Compound 69) and its ammonium salt

[0504] Step 1: Synthesis of (((difluoro(4-(2-oxo-2-(((5S,8S,10aR)-6-oxo-8-((R)-2- phenylmorpholine-4-carbonyl)-3-propionyldecahydropyrrolo[l,2-a][l,5]diazepin-5- yl)amino)acetylamino)phenyl)methyl)(hydroxy)phosphoryl)oxy)methyl neopentanoate (69)

[0505] Compound 22 (82.0 mg, 87.9 μmol) was dissolved in methanol (2 mL) and reacted at 25 °C for 48 h. The reaction was monitored by LC-MS and concentrated under reduced pressure to give compound 69.

[0506] LC-MS (m / z): 820.0 [M+H] + .

[0507] Step 2: Synthesis of (((difluoro(4-(2-oxo-2-(((5S,8S,10aR)-6-oxo-8-((R)-2- phenylmorpholine-4-carbonyl)-3-propionyldecahydropyrrolo[l,2-a][l,5]diazepin-5- yl)amino)acetylamino)phenyl)methyl)(hydroxy)phosphoryl)oxy)methyl neopentanoate ammonium salt

[0508] Compound 69 was separated and purified by preparative HPLC to give the ammonium salt of compound 69 (21.1 mg) with a yield of 29.3%.

[0509] LC-MS (m / z): 820.0 [M+H] + .

[0510] 1H NMR (600 MHz, DMSO-d6) δ 10.97 (d, J = 11.8 Hz, 1H), 8.67 (dd, J = 40.3, 6.2 Hz, 1H), 7.84 (t, J = 7.8 Hz, 2H), 7.56 - 7.43 (m, 3H), 7.38 (dq, J = 15.7, 8.0 Hz, 3H), 7.32 (t, J = 7.3 Hz, 1H), 7.10 (t, J = 51.0 Hz, 4H), 5.38 (d, J = 10.4 Hz, 2H), 5.05 - 4.75 (m, 2H), 4.48 (dd, J = 128.3, 11.1 Hz, 2H), 4.21 (dd, J = 72.4, 13.2 Hz, 2H), 4.03 (dd, J = 19.3, 11.9 Hz, 3H), 3.85 (d, J = 13.5 Hz, 1H), 3.61 - 3.53 (m, 1H), 3.10 (dq, J = 26.2, 12.3 Hz, 2H), 2.90 - 2.63 (m, 2H), 2.58 - 2.52 (m, 1H), 2.43 - 2.24 (m, 1H), 2.11 - 1.79 (m, 3H), 1.72 (dd, J = 11.9, 7.2 Hz, 1H), 1.66 - 1.54 (m, 1H), 1.14 (s, 9H), 1.05 (dt, J = 11.0, 5.6 Hz, 3H).

[0511] Synthesis of compound (4-(2-(((3S,6S,10aS)-3-((3R,4S or 3S,4R)-3-cyano-4- phenylpyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]azepin-6-yl)amino)-2- oxoacetamido)phenyl)difluoromethyl)phosphonic acid (Compound 93)

[0512] The synthesis method can be found in Example 1.

[0513] LC-MS (m / z): 658.0 [M+H] + .

[0514] Synthesis of compound (4-(2-(((3S,6S,10aS)-3-((3R,4S or 3S,4R)-3-cyano-4- phenylpyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]azepin-6-yl)amino)-N- methyl-2-oxoacetamido)phenyl)difluoromethyl)phosphonic acid (94)

[0515] The synthesis method can be found in Example 2.

[0516] LC-MS (m / z): 672.0 [M+H] + .

[0517] Synthesis of Example 95 (4-(N-butyl-2-(((3S,6S,10aS)-3-((3R,4S or 3S,4R)-3- cyano-4-phenylpyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]azepin-6-yl)amino)- 2-oxoacetamido)phenyl)difluoromethyl)phosphonic acid (95)

[0518] Synthetic procedure was described in Example 3.

[0519] LC-MS (m / z): 714.0 [M+H] + .

[0520] Synthesis of Example 96 (Difluoro(4-(2-oxo-2-(((3S,6S,10aS)-5-oxo-3-((S)-2- phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2-a]azepin-6-yl)amino)acetamido)phenyl) methyl)phosphonic acid (96)

[0521] Synthetic procedure was described in Example 7.

[0522] LC-MS (m / z): 649.0 [M+H] + .

[0523] Synthesis of Example 97 ((Difluoro(4-(2-(((3S,6S,10aS)-3-(indole-1-carbonyl)-5- oxodecahydropyrrolo[1,2-a]azepin-6-yl)amino)-2-oxoacetamido)phenyl)methyl)phosphonic acid (97)

[0524] Synthetic procedure was described in Example 54.

[0525] LC-MS (m / z): 605.0 [M+H] + .

[0526] Synthesis of Example 98 ((Difluoro(4-(2-(((3S,6S,10aS)-3-(methyl(phenyl)carbamoyl)- 5-oxodecahydropyrrolo[1,2-a]azepin-6-yl)amino)-2-oxoacetamido)phenyl)methyl)phosphonic acid (98)

[0527] Synthetic procedure was described in Example 55.

[0528] LC-MS (m / z): 593.0 [M+H] + .

[0529] Synthesis of (difluoro(4-(2-(((3S,6S,10aS)-3-(morpholine-4-carbonyl)-5- oxodecahydropyrrolo[l,2-a]azepin-6-yl)amino)-2-oxoacetamido)phenyl)methyl) phosphonic acid (99)

[0530] Synthetic procedure is same as example 57.

[0531] LC-MS (m / z): 573.0 [M+H] + .

[0532] Synthesis of (4-(2-(((3S,6S,10aS)-3-((2S,6R)-2,6-dimethylmorpholine-4-carbonyl)- 5-oxodecahydropyrrolo[l,2-a]azepin-6-yl)amino)-2-oxoacetamido)phenyl) difluoromethyl)phosphonic acid (100)

[0533] Synthetic procedure is same as example 58.

[0534] LC-MS (m / z): 601.0 [M+H] + .

[0535] Synthesis of (4-(2-(((5S,8S,10aR)-8-((2S,6R)-2,6-dimethylmorpholine-4-carbonyl)- 3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5] diazepin-5- yl)amino)-2-oxoacetamido)phenyl)difluoromethyl)phosphonic acid (101)

[0536] Synthetic procedure is same as example 59.

[0537] LC-MS (m / z): 761.0 [M+H] + .

[0538] Synthesis of (difluoro(3-fluoro-4-(2-oxo-2-(((3S,6S,10aS)-5-oxo-3-((R)-2- phenylmorpholine-4-carbonyl)decahydropyrrolo[l,2-a]azepin-6-yl)amino)acetamido) phenyl)methyl)phosphonic acid (102)

[0539] Synthetic procedure is same as example 26.

[0540] LC-MS (m / z): 667.0 [M+H] + .

[0541] Synthesis of Example 103 (4-(2-(((5S,8S,10aR)-3-(2,2-difluoroethyl)-6-oxo-8-((R)-2- phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2-a][1,5]diazepin-5-yl)amino)-2- oxoacetylamino)phenyl)difluoromethyl)phosphonic acid (103)

[0542] Synthetic procedure was described in Example 23.

[0543] LC-MS (m / z): 714.0 [M+H] + .

[0544] Synthesis of Example 121 (Difluoro(5-(2-oxo-2-(((3S,6S,10aS)-5-oxo-3-((R)-2- phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2-a]azepin-6-yl)amino)acetylamino)thiophen- 3-yl)methyl)phosphonic acid (121)

[0545] Step 1: Synthesis of compound methyl 2-((4-((diethoxyphosphoryl)difluoromethyl)thiophen-2- yl)amino)-2-oxoacetate (121-1)

[0546] Compound 121-SM (1.50 g, 5.20 mmol) was dissolved in anhydrous dichloromethane (30 mL), diisopropylethylamine (0.80 g, 6.20 mmol) was added, the reaction solution was cooled to 0 °C, oxalyl chloride monomethyl ester (0.96 g, 7.89 mmol) was added dropwise, and it was placed at 25 °C for 1 hour. After the reaction was completed by LC-MS monitoring, the reaction was quenched with water (20 mL), the aqueous phase was extracted with dichloromethane (30 mL x 3), the combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50:50 as eluent) to obtain compound 121-1 (1.40 g) with a yield of 73.9%.

[0547] LC-MS (m / z): 372.0 [M+H] + .

[0548] Step 2: Synthesis of compound 2-((4-((diethoxyphosphoryl)difluoromethyl)thiophen-2- yl)amino)-2-oxoacetic acid (121-2)

[0549] Compound 121-1 (1.20 g, 3.23 mmol) was dissolved in tetrahydrofuran (10 mL), the reaction solution was cooled to 0 °C, and a lithium hydroxide (0.34 g, 8.08 mmol) aqueous solution (10 mL) was added dropwise, and the reaction solution was reacted at 0 °C for 30 minutes. After the reaction was completed by LC-MS monitoring, a 1.0 M hydrochloric acid aqueous solution was added to the reaction solution, the pH of the aqueous phase was adjusted to be acidic, and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 121-2 (830.0 mg) with a yield of 55.3%

[0550] LC-MS (m / z): 356.0 [M-H] - .

[0551] Step 3: Synthesis of compound difluoro(5-(2-oxo-2-(((3S,6S,10aS)-5-oxo-3-((R)-2- phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2-a]azepin-6-yl)amino)acetamido)thiophen-3- yl)methyl)phosphonic acid diethyl ester (121-3)

[0552] Compound 121-2 (0.83 g, 2.32 mmol) and (3S,6S,10aS)-6-amino-3-((R)-2-phenylmorpholine-4- carbonyl)octahydro pyrrolo[1,2-a]oxazol-5(1H)-one (0.86 g, 2.32 mmol) were dissolved in N,N- dimethylformamide (40 mL), and diisopropylethylamine (1.00 g, 4.48 mmol) and N,N,N',N'-tetramethyl-O- (7-azabenzotriazol-1-yl)urea hexafluorophosphate (1.02 g, 2.68 mmol) were sequentially added at 0 °C. The reaction solution was reacted at 25 °C for 1 hour. After the reaction was completed by LC-MS monitoring, the reaction was quenched by adding water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA as eluent) to obtain compound 121-3 (882.0 mg) with a yield of 55.0%.

[0553] LC-MS (m / z): 709.0 [M-H] - .

[0554] Step 4: Synthesis of compound difluoro(5-(2-oxo-2-(((3S,6S,10aS)-5-oxo-3-((R)-2- phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2-a]azepin-6-yl)amino)acetamido)thiophen-3- yl)methyl)phosphonic acid (121)

[0555] Compound 121-3 (0.31 g, 4.36 mmol) was dissolved in anhydrous dichloromethane (3 mL), trimethylsilyl bromide (3 mL) was added, and the reaction solution was allowed to react at 25°C for 8 hours. After the reaction was completed by LC-MS monitoring, a mixed solution of acetonitrile (4 mL) and water (1 mL) was added, the reaction solution was allowed to react at 25°C for 20 minutes, and then concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (methanol: water = 80:20 as eluent) to obtain compound 121 (195.0 mg) at a yield of 68.4%.

[0556] LC-MS (m / z): 655.0 [M+H] + .

[0557] 1 H NMR (600 MHz, DMSO-d6) δ 12.23 (d, J = 10.3 Hz, 1H), 8.69 (dd, J = 32.2, 7.1 Hz, 1H), 7.48 - 7.29 (m, 6H), 7.25 - 7.18 (m, 1H), 4.96 - 4.72 (m, 2H), 4.59 - 4.24 (m, 3H), 4.21 - 3.95 (m, 2H), 3.62 - 3.52 (m, 1H), 3.16 - 3.09 (m, 1H), 2.90 - 2.58 (m, 1H), 2.33 - 2.13 (m, 1H), 2.10 - 1.96 (m, 2H), 1.94 - 1.47 (m, 9H).

[0558] Synthesis of compound 122 (((difluoro(5-(2-oxo-2-(((3S,6S,10aS)-5-oxo-3-((R)-2- phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2-a]azepin-6-yl)amino)acetamido)thiophen-3- yl)methyl)phosphoryl)bis(oxy)bis(methylene)bis(2,2-dimethylpropanoate) (122)

[0559] Synthesis of compound 122 (((difluoro(5-(2-oxo-2-(((3S,6S,10aS)-5-oxo-3-((R)-2- phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2-a]azepin-6-yl)amino)acetamido)thiophen-3- yl)methyl)phosphoryl)bis(oxy)bis(methylene)bis(2,2-dimethylpropanoate) (122)

[0560] Compound 121 (0.16 g, 0.25 mmol) was suspended in water (2 mL), and a solution of sodium hydroxide (19.6 mg, 0.49 mmol) in water (2 mL) was added dropwise at 0 °C. After the addition was completed, the pH of the aqueous phase was about 10, and then silver nitrate (124.9 mg, 0.73 mmol) was added. The reaction solution was placed at 0 °C for 2 h. Filtration was performed, and the filter cake was dried under reduced pressure with an oil pump (rotary vane vacuum pump). The obtained dried solid was dissolved in acetonitrile (10 mL), and iodomethyl pivalate (592.9 mg, 2.45 mmol) was added. The reaction solution was placed at 25 °C for 16 h. After the reaction was completed, filtration was performed, and the residue was concentrated under reduced pressure. Purification was performed by silica gel column chromatography (ethyl acetate: petroleum ether = 2:1 as eluent) to obtain compound 122 (38.5 mg) with a yield of 17.4%.

[0561] LC-MS (m / z): 883.0 [M+H] + .

[0562] 1 H NMR (600 MHz, DMSO-d6) δ 12.35 (d, J = 10.4 Hz, 1H), 8.74 (dd, J = 34.1, 7.0 Hz, 1H), 7.51 (s, 1H), 7.40 (ddd, J = 17.3, 15.2, 7.3 Hz, 4H), 7.32 (dp, J = 7.3, 5.1, 3.4 Hz, 1H), 7.19 (dd, J = 6.4, 1.8 Hz, 1H), 5.69 (td, J = 14.9, 5.6 Hz, 4H), 4.95 - 4.83 (m, 1H), 4.82 - 4.52 (m, 2H), 4.40 - 4.24 (m, 3H), 4.19 - 3.98 (m, 2H), 3.56 (t, J = 11.4 Hz, 1H), 3.16 - 2.80 (m, 1H), 2.23 (dd, J = 86.7, 10.1 Hz, 1H), 2.10 - 2.00 (m, 2H), 1.91 - 1.85 (m, 2H), 1.80 (t, J = 13.2 Hz, 1H), 1.70 (ddt, J = 32.6, 21.8, 11.3 Hz, 3H), 1.62 - 1.51 (m, 3H), 1.15 (s, 18H).

[0563] Synthesis of Example 123 (difluoro(5-(2-oxo-2-(((5S,8S,10aR)-6-oxo-8-((R)-2-phenylmorpholine-4-carbonyl)-3- propanoyldecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)acetamido)thiophen-3-yl)methyl)phosphonic acid (123)

[0564] Step 1: Synthesis of diethyl (difluoro(5-(2-oxo-2-(((5S,8S,10aR)-6-oxo-8-((R)-2- phenylmorpholine-4-carbonyl)-3-propionyldecahydropyrrolo[l,2-a][l,5]diazocin-5- yl)amino)acetylamino)thiophen-3-yl)methyl)phosphonate (123-1)

[0565] Compound 121-2 (0.22 g, 0.62 mmol) and 56-3 (0.26 g, 0.62 mmol) were dissolved in N,N-dimethylformamide (5 mL), diisopropylethylamine (0.16 g, 1.24 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl)urea hexafluorophosphate (0.28 g, 0.74 mmol) were added successively at 0 °C, and the reaction solution was placed at 25 °C for 1 hour. After the reaction was completed by LC-MS monitoring, water (10 mL) was added, and the combined organic phase was extracted with ethyl acetate (10 mL x 3), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA as eluent) to obtain compound 123-1 (60.0 mg) with a yield of 12.6%.

[0566] LC-MS (m / z): 768.0.0 [M+H] + .

[0567] Step 2: Synthesis of (difluoro(5-(2-oxo-2-(((5S,8S,10aR)-6-oxo-8-((R)-2- phenylmorpholine-4-carbonyl)-3-propionyldecahydropyrrolo[l,2-a][l,5]diazocin-5- yl)amino)acetylamino)thiophen-3-yl)methyl)phosphonic acid (123)

[0568] Compound 123-1 (60.0 mg, 0.078 mmol) was dissolved in anhydrous dichloromethane (2 mL), and trimethylsilyl bromide (1 mL) was added. The reaction solution was placed at 25 °C for 8 hours. After the reaction was completed by LC-MS monitoring, a mixture of acetonitrile (3 mL) and water (1 mL) was added, the reaction solution was placed at 25 °C for 20 minutes, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (methanol: water = 80:20 as eluent) to obtain compound 123 (22.0 mg) with a yield of 39.6%.

[0569] LC-MS (m / z): 712.0 [M+H] + .

[0570] 1H NMR (600 MHz, DMSO-d6) δ 12.39 (d, J = 12.8 Hz, 1H), 8.61 (dd, J = 41.1, 6.3 Hz, 1H), 7.49 - 7.44 (m, 1H), 7.42 - 7.35 (m, 3H), 7.35 - 7.30 (m, 2H), 7.28 - 7.21 (m, 1H), 5.06 - 4.77 (m, 2H), 4.64 - 4.32 (m, 2H), 4.32 - 4.11 (m, 2H), 4.08 - 3.79 (m, 4H), 3.65 - 3.53 (m, 2H), 3.18 - 2.99 (m, 2H), 2.91 - 2.63 (m, 2H), 2.44 - 2.20 (m, 1H), 2.10 - 1.84 (m, 3H), 1.77 - 1.48 (m, 2H), 1.10 - 0.99 (m, 3H).

[0571] Synthesis of Example 124 (((difluoro(5-(2-oxo-2-(((5S,8S,10aR)-6-oxo-8-((R)-2- phenylmorpholine-4-carbonyl)-3-propionyldecahydropyrrolo[1,2-a][1,5]diazocin-5- yl)amino)acetylamino)thiophen-3-yl)methyl)phosphoryl)bis(oxy))bis(methylene) bis(2,2- dimethylpropanoate) (124)

[0572] Compound 123 (20.0 mg, 0.028 mmol) was suspended in water (1 mL), the solution was cooled to 0 °C, and an aqueous solution of sodium hydroxide (2.8 mg, 0.07 mmol) was added dropwise. After the addition was completed, the pH of the solution was about 10, and silver nitrate (17.9 mg, 0.11 mmol) was then added. The reaction was carried out at 0 °C for 2 hours. After the reaction was completed, the solid was collected by filtration and dried by an oil pump (rotary vane vacuum pump). The obtained dry solid was suspended in toluene (1 mL), and iodomethyl pivalate (85.1 mg, 0.35 mmol) was added. The reaction was carried out at 25 °C for 16 hours. After the reaction was completed, the solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 2:1) to obtain compound 124 (3.1 mg) with a yield of 11.8%.

[0573] LC-MS (m / z): 940.0 [M+H] + .

[0574] 1H NMR (600 MHz, DMSO-d6) δ 12.62 - 12.25 (m, 1H), 8.62 (dd, J = 42.8, 6.3 Hz, 1H), 7.59 - 7.17 (m, 7H), 5.76 - 5.62 (m, 4H), 5.04 - 4.74 (m, 2H), 4.62 - 4.33 (m, 2H), 4.30 - 4.07 (m, 2H), 4.08 - 3.78 (m, 4H), 3.64 - 3.49 (m, 1H), 3.20 - 2.84 (m, 2H), 2.80 - 2.60 (m, 2H), 2.12 - 1.86 (m, 4H), 1.77 - 1.52 (m, 3H), 1.15 (s, 18H), 1.08 - 1.00 (m, 3H).

[0575] Biological activity test

[0576] Test 1, fluorescence polarization screening experiment of the compound of the application

[0577] 1. Main reagent consumables

[0578] 2. Reagent preparation

[0579] 1) Prepare the test buffer according to the following table (10 mL system):

[0580] 2) Prepare the working concentration of each component using the test buffer according to the following table (final system: 50 μL): “—” means no relevant data.

[0581] 3) This experiment uses STAT6 protein expression plasmid pT7-TrxA-6xHis-STAT6 (human source), uses Rosetta (DE3) strain, 0.2 mM IPTG concentration, 16°C, 20h induction of protein expression, and the purified STAT6 protein is obtained by Ni NTA Beads kit protein purification.

[0582] 3. Fluorescence polarization activity detection

[0583] 1) Compound dilution: 2 μL of 10 mM compound storage solution + 198 μL of DMSO to obtain 100 μM compound dilution, then 30 μL of 100 μM compound dilution + 60 μL of DMSO is sequentially diluted by 3 times to obtain 8 concentrations, then 5 μL of the gradient concentration of the test compound is added to the 96-well black plate, and two negative controls (DMSO final concentration 10%) are set.

[0584] 2) Compound incubation with protein: Then add 30 μL test buffer and 10 μL 2.5 μM STAT6 protein to the 96-well black plate, centrifuge at 1000 rpm for 1 min at room temperature, and then incubate at 25°C for 45 min with shaking.

[0585] 3) Substrate reaction: Add 5 μL 125 nM substrate 5-FAM-ApYKPFQDLI-NH2 to the 96-well black plate, centrifuge at 1000 rpm for 1 min at room temperature, and then incubate at 25°C for 30 min with shaking in the dark.

[0586] 4) Transfer the reaction system in the 96-well black plate to a 384-well black plate at 20 μL per well, detect the absorbance values at 485 / 535 nm by an enzyme marker, and calculate the fluorescence polarization mP value by software.

[0587] 5) Data processing: Take the group containing only 5-FAM substrate (without STAT6 protein) as the negative control, take the value of the DMSO control group as the positive control, calculate the inhibition of the compound on the binding of STAT6 and 5-FAM-ApYKPFQDLI-NH2 by the formula "inhibition rate (%) = (1-(experimental group value-negative control group value) / (positive control group value-negative control group value))*100%", and then use Graphpad prism8 software to fit to obtain the IC value of the compound. 50

[0588] Table 1 is the fluorescence polarization experiment result of the STAT6 protein of the compound of the present application.

[0589] Table 1 is the fluorescence polarization experiment result of the compound of the present application

[0590] Test Example 2 p-STAT6 experiment of STAT6 inhibitor

[0591] (1) Cells

[0592] (2) Reagents and consumables

[0593] (3) Compound preparation

[0594] Take an appropriate amount of the compound to be tested, dissolve it in DMSO to 10 mM. Take an appropriate amount of 10 mM test compound mother liquor and dilute it with DMSO to obtain a compound stock solution (2, 0.5, 0.125, 0.03125, 0.008, 0.002, 0.0005, 0.00012, 0.00003 μM).

[0595] (4) Experimental method

[0596] ​BEAS-2B cells were plated at a density of 70%-80%, 2*10 5 Cells were cultured in DMEM medium (containing 2% FBS) overnight. Cells in the administration group were respectively given different concentrations of drugs (final concentration 2, 0.5, 0.125, 0.03125, 0.008, 0.002, 0.0005, 0.00012, 0.00003 μM) for 3 h of pretreatment, and the same volume of DMSO was added to the blank group and the IL-4 single-drug group. After 3 h of pretreatment, 2 ng / ml of IL-4 was added to each well except the blank group, and the cells were harvested after 30 min of treatment. The supernatant was discarded, washed with PBS once, and 50 μL of RIPA lysis buffer (containing a mixture of protease inhibitors, PMSF, and 1.5x protein loading buffer) was added to each well. The cell lysate was boiled at 100°C for 5 min and stored at -20°C.

[0597] An equal amount of protein sample and protein molecular weight marker was loaded into the SDS-PAGE gel hole, and electrophoresis was performed at 100 V. After electrophoresis, the membrane was transferred at a constant current of 300 mA. After the transfer was completed, the PVDF membrane was taken out and blocked with 5% skim milk PBST solution at room temperature for 1 h. After blocking, the corresponding primary antibody solution (primary antibody dilution ratio 1:1000, 5% BSA+PBST) was added, and incubated slowly at 4°C overnight. After incubation, the membrane was washed with PBST 4 times, each for 5 min. The secondary antibody solution (secondary antibody dilution ratio 1:2000, 5% skim milk+PBST) was added, and incubated at room temperature for 1 h. The membrane was washed with PBST 4 times, each for 5 min, and developed and exposed according to the method provided by the ECL chemiluminescence detection kit. ImagJ software was used to analyze the gray value of the developed results, and the inhibition rate and IC 50 .

[0598] The inhibition rate was calculated as follows:

[0599] Inhibition rate (%) = 100 - (gray value of administration group - gray value of blank group) / (gray value of IL-4 single-drug group - gray value of blank group) x 100%

[0600] Table 2 shows the results of the inhibition of STAT6 phosphorylation in cells by the test compounds.

[0601] Table 2. Inhibition of pSTAT6 activity in cells by compounds of the present application

[0602] As can be seen from the data in Table 2, compound 4 can strongly inhibit the phosphorylation of STAT6.

[0603] Test Example 3: p-STAT6 detection experiment in BEAS-2B cells

[0604] (1) Cells: refer to Test Example 2;

[0605] (2) Reagents and Consumables: Refer to Test Example 2;

[0606] (3) Compound Preparation

[0607] Take the appropriate amount of test compound, dissolved in DMSO to 10 mM to obtain the compound stock solution.

[0608] (4) Experimental Method

[0609] BEAS-2B cells were plated when the cell density was 70%-80%, 2*10 5 Cells were cultured in DMEM medium (containing 2% FBS) overnight. The cells in the drug administration group were pre-treated with different concentrations of drugs for 3h, and the same volume of DMSO was added to the blank group and the IL-4 single drug group. After 3h of pre-treatment, 2ng / ml of IL-4 was added to each well except the blank group, and the cells were harvested after 30min of treatment. Discard the supernatant, rinse with PBS once, add 50μL RIPA lysis buffer (containing protease inhibitor cocktail, PMSF, 1.5x protein loading buffer) to each well, and boil the cell lysate at 100℃ for 5min and store at -20℃.

[0610] An equal amount of protein sample and protein molecular weight marker was loaded into the SDS-PAGE gel hole, and electrophoresis was performed at 100V. After electrophoresis, the membrane was transferred at a constant current of 300mA. After the transfer was completed, the PVDF membrane was taken out and sealed with 5% skim milk PBST solution at room temperature for 1h. After blocking, the corresponding primary antibody solution was added (primary antibody dilution ratio 1:1000, 5% BSA+PBST), and incubated slowly at 4℃ overnight. After incubation, wash the membrane with PBST 4 times, 5min each time. Add secondary antibody solution (secondary antibody dilution ratio 1:2000, 5% skim milk+PBST), incubate at room temperature for 1h, wash the membrane with PBST 4 times, 5min each time, and develop and expose according to the method provided by the ECL chemiluminescence detection kit. The ImagJ software was used to analyze the gray value of the developed results, and the inhibition rate and IC 50 .

[0611] The inhibition rate was calculated as follows:

[0612] Inhibition rate (%) = 100 - (gray value of drug administration group - gray value of blank group) / (gray value of IL-4 single drug group - gray value of blank group) x 100%, and the results are shown in Table 3:

[0613] Table 3. Inhibition rate of compounds at different concentrations on pSTAT6 in BEAS-2B cells A: indicates that the concentration of the test compound is 2 μM; B: indicates that the concentration of the test compound is 1 μM; C: indicates that the concentration of the test compound is 0.25 μM; D: indicates that the concentration of the test compound is 0.125 μM; E: indicates that the concentration of the test compound is 0.1 μM.

[0614] Test Example 4 p-STAT6 detection experiment in PBMC cells

[0615] The compounds of the present application are prepared according to the methods of the examples.

[0616] (1) Cells

[0617] (2) Reagents and consumables: refer to Test Example 2;

[0618] (3) Compound preparation

[0619] An appropriate amount of the test compound was dissolved in DMSO to 10 mM. An appropriate amount of 10 mM test compound stock solution was diluted with DMSO to obtain a compound stock solution (1, 0.333, 0.111, 0.037, 0.0123, 0.004 mM) by 3-fold gradient dilution.

[0620] (4) Experimental method

[0621] After the PBMC cells were resuscitated, plating was performed, and 1*10 6 cells per well in a 24-well plate were cultured in PRIM-1640 (containing 2% FBS) for 2 h. The cells in the drug administration groups were respectively given different concentrations of drugs (final concentration 1, 0.333, 0.111, 0.037, 0.0123, 0.004 μM) for 3 h of pretreatment, and the same volume of DMSO was added to the blank group and the IL-4 single drug group. After 3 h of pretreatment, 2 ng / ml of IL-4 was added to each well except the blank group, and the cells were harvested after 10 min of treatment. 50 μL of RIPA lysis buffer (containing protease inhibitor cocktail, PMSF, 1.5x protein loading buffer) was added to each well, and the cell lysate was boiled at 100°C for 5 min and stored at -20°C.

[0622] Equal amounts of protein sample and protein molecular weight marker were loaded into the wells of SDS-PAGE gel, and electrophoresis was performed at 100 V. After electrophoresis, the membrane was transferred at a constant current of 300 mA. After the transfer was completed, the PVDF membrane was removed and blocked with 5% skim milk in PBST at room temperature for 1 h. After blocking, the corresponding primary antibody solution was added (primary antibody dilution ratio 1:1000, 5% BSA+PBST), and incubated slowly at 4°C overnight. After incubation, the membrane was washed with PBST 4 times, each for 5 min. Secondary antibody solution was added (secondary antibody dilution ratio 1:2000, 5% skim milk+PBST), and incubated at room temperature for 1 h. The membrane was washed with PBST 4 times, each for 5 min, and developed and exposed according to the method provided by the ECL chemiluminescence detection kit. ImagJ software was used to analyze the gray value of the developed results, and the inhibition rate and IC 50 .

[0623] The inhibition rate was calculated as follows:

[0624] The inhibition rate (%) = 100 - (gray value of the administration group - gray value of the blank group) / (gray value of the IL-4 single drug group - gray value of the blank group) x 100%, and the results are shown in Table 4:

[0625] Table 4. Inhibition of PBMC cell pSTAT6 activity by compounds

[0626] Test Example 5 WB experiment for testing BEAS-2B cell p-STAT3 method

[0627] The compounds of the present application were prepared according to the methods of the examples

[0628] (1) Cells

[0629] (2) Reagents and consumables

[0630] The remaining reagents and consumables refer to Test Example 2.

[0631] (3) Compound preparation

[0632] An appropriate amount of the test compound was dissolved in DMSO to 10 mM. An appropriate amount of 10 mM test compound stock solution was diluted with DMSO to obtain a compound stock solution (10, 2.5, 0.625, 0.156 mM) in 4-fold gradient.

[0633] (4) Experimental method

[0634] BEAS-2B cells were plated when the cell density was 70%-80%, 2*10 5Cells were cultured in DMEM medium (containing 2% FBS) overnight. Cells in the administration group were respectively administered with different concentrations of drugs (final concentration 10, 2.5, 0.625, 0.156 μM) for 3 h of pre-treatment, and the same volume of DMSO was added to the blank group and the IL-6 single-drug group. After 3 h of pre-treatment, 10 ng / ml of IL-6 was added to each well except the blank group, and the cells were harvested after 60 min of treatment. The supernatant was discarded, and the cells were washed with PBS once. 50 μL of RIPA lysis buffer (containing a mixture of protease inhibitors, PMSF, and 1.5x protein loading buffer) was added to each well, and the cell lysate was boiled at 100°C for 5 min and stored at -20°C.

[0635] Equal amounts of protein samples and protein molecular weight markers were loaded into the wells of an SDS-PAGE gel, and electrophoresis was performed at 100 V. After electrophoresis, the membrane was transferred at a constant current of 300 mA. After the transfer was completed, the PVDF membrane was removed, and 5% skim milk in PBST was used for room temperature blocking for 1 h. After blocking, the corresponding primary antibody solution was added (primary antibody dilution ratio 1:1000, 5% BSA+PBST), and the solution was slowly shaken at 4°C overnight. After incubation, the membrane was washed with PBST 4 times, each time for 5 min. The secondary antibody solution was added (secondary antibody dilution ratio 1:2000, 5% skim milk+PBST), and the solution was incubated at room temperature for 1 h. The membrane was washed with PBST 4 times, each time for 5 min. The ECL chemiluminescence detection kit was used for development and exposure according to the method provided by the kit. ImagJ software was used to analyze the gray value of the developed results, and the inhibition rate and IC 50 .

[0636] The inhibition rate was calculated as follows:

[0637] The inhibition rate (%) = 100 - (gray value of the administration group - gray value of the blank group) / (gray value of the IL-6 single-drug group - gray value of the blank group) x 100%, and the results are shown in Table 5:

[0638] Table 5. Inhibition of pSTAT3 activity of BEAS-2B cells by the compound

[0639] The results show that compound 4 does not inhibit the pSTAT3 level in BEAS-2B cells, and has high selectivity.

[0640] Test Example 6 Inhibition of the human hERG ion channel by the compound of the present application

[0641] The effect of the compound on the hERG ion channel was tested on HEK293 cells stably expressing the hERG ion channel. The cells were transferred to a perfusion chamber and perfused with extracellular fluid. The intracellular fluid (mM) was: K Aspartate, 130; MgCl2, 5; EGTA 5; HEPES, 10; Tris-ATP 4; pH 7.2 (KOH titration). The intracellular fluid was stored in small batches at -80°C, and thawed on the day of the experiment. The electrodes were pulled with a PC-10 (Narishige). Whole-cell patch-clamp recording, noise was filtered with one-fifth of the sampling frequency. The cells were clamped at -80 mV, then depolarized to 40 mV with a 4-second square wave, and then hyperpolarized to -40 mV with a 2-second square wave to obtain the hERG tail current. This procedure was repeated every 20 seconds. The maximum current induced by the second square wave was detected, and after it was stable, the test compound was perfused using a perfusion system using its own gravity, and at least one cell was tested for each concentration. When the response was stable, the change in current size before and after the use of the compound was compared to calculate the blocking effect of the compound. The data were collected and analyzed with pCLAMP 10 (Molecular Devices), and the results were reviewed by the experimenter. The results of the inhibition of the human hERG ion channel by the compounds of the present application are shown in the following table:

[0642] Table 6. Inhibition rate of the human hERG ion channel by the compounds of the present application

[0643] From the data in Table 6, it can be seen that the representative compounds of the present application have no significant inhibition of the human hERG ion channel at high concentrations, which can to some extent reflect that the compounds of the present application have lower cardiotoxicity, and have a positive significance for drug safety evaluation.

[0644] Test Example 7 Rat Pharmacokinetic Characteristic Investigation

[0645] Main reagent materials:

[0646] SPF level male SD rats, 3 in each group, were given a single gavage of 3.7 mg / kg of compound 4, and blood was collected at the specified time points, the plasma was separated and stored in a -80°C refrigerator for standby. The test plasma sample was thawed at room temperature, vortexed (2500 rpm, 1 min), 30.0 μL of the plasma sample was taken into a 1.5 mL centrifuge tube, 6.00 μL of the internal standard (ramelteon, 500.0 ng / mL) was added, 1000 μL of methanol was added, vortexed (2500 rpm, 1 min), centrifuged (17000 g, 4°C) for 10 min, 180 μL of the supernatant was taken into a 96-well plate, sealed, and subjected to LC-MS / MS analysis, the injection amount was 1.00 μL. Compound 4 and compound 52 were detected at the same time. The experimental data are shown in the following table:

[0647] Table 7 In vivo pharmacokinetic parameters of compounds (p.o.) “-” indicates that the corresponding value cannot be calculated.

[0648] As can be seen from the data in Table 7, the compound 4 of the present application is rapidly decomposed into the active metabolite 52 after oral administration, has good plasma exposure, and shows excellent oral administration potential.

[0649] Test Example 8 In vitro metabolic stability

[0650] Main reagent materials:

[0651] Incubation system:

[0652] Experimental method:

[0653] 1 μM of the test substance and positive control testosterone were incubated with microsomes under the condition of NADPH for 60 min, and a negative control group (the test substance was incubated with microsomes under the condition of no any coenzyme for 60 min) was set; samples were taken at 0 min and 60 min, 300 μL of pre-cooled methanol solution containing internal standard (ramelteon: 1.000 ng / mL) was added, vortexed (2500 rpm, 1 min), centrifuged (4700 rpm, 4℃) for 10 min, 50.0 μL of supernatant + 200 μL of pure water was taken to a 96-well plate, vortexed (1000 rpm, 10 min), sealed, and subjected to LC-MS / MS analysis. The parent remaining amount of the test substance or probe substrate was detected by LC-MS / MS, the metabolic stability of the test substance was represented by the percentage of the parent remaining amount of the test substance at each time point relative to the parent amount before incubation (0 min), and the data was calculated according to the following formula: Parent remaining, % of 0 min = T x parent amount / T0 parent amount x 100; T x : any incubation time point; T0: 0 min incubation time point. The test results are shown in Table 8 below.

[0654] Table 8 In vitro metabolic stability results of compounds

[0655] As can be seen from the data in Table 8, the compound of the present application has good in vitro metabolic stability, and the species difference is small.

Claims

1. An oxamide compound having a structure shown in Formula (I) or a pharmaceutically acceptable salt, isotopic derivative, solvate, or stereoisomer, geometric isomer, tautomer, or prodrug molecule, metabolite thereof: ###0001### Formula (I) ​ wherein, is a single or double bond; q and t are each independently selected from 0, 1 or 2, and q and t are not simultaneously selected from 0; p is selected from 1 or 2; Z is selected from S, O, -S(=0)-, -S(=0)2-, -S(=0)=NH, CHR 10 , CR 9 R 10 or NR 10 ; Y is selected from CHR 9 , CR 9 R 10 or NR 9 ; R 1 Selected from C that has been substituted with one or more substituent groups 6-12 Aryl, 5-12 membered heteroaryl, 4-12 membered heterocyclic, 4-12 membered cycloalkenyl, C3-C 12 cycloalkyl, C 1-4 Alkylene C 6-12 Aryl, or C 1-4 imide C 6-12 aryl, wherein the substituent is selected from R g CR 1a R 2a P(O)OR 1b OR 2b CR 1a R 2a P(O)OR 1b NHR 2b CR 1a R 2a P(O)(OR 1b )(NH(AA)C(O)OR 1c ), CR 1a R 2a P(O)(NHR 2c )(NH(AA)C(O)OR 1c ), CR 1a R 2a P(O)(NH(AA)C(O)OR 1c )(NH(AA)C(O)OR 1c ), P(O)OR 1b OR 2b 、P(O)(OR 1b )(NH(AA)C(O)OR 1c ), P(O)(NHR 2c )(NH(AA)C(O)OR 1c ) or P(O)(NH(AA)C(O)OR 1c )(NH(AA)C(O)OR 1c ); R 1a , R 2a are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, C 1-4 alkyl, C 1-4 haloalkyl, or C 1-4 hydroxyalkyl; or, R 1a and R 2a form, with the atom to which they are attached, a C3-C6cycloalkyl or 3-6 membered heterocyclyl; R 1b , R 2b each independently is selected from -R 1aa , -R 1aa -OC(O)-R 1ab , -R 1aa -C(O)O-R 1ab , -R 1aa -OC(O)O-R 1ab , -R 1aa -O-R 1ab , -R 1aa -SC(O)O-R 1ab , -R 1aa -SC(O)-R 1ab , -R 1aa -OC(O)NH-R 1ab , -R 1aa -OC(O)NR 1ab R 1ac , -R 1aa -OC(O)-R 1ab -O-R 1ac , -R 1aa -OC(O)O-R 1ab -O-R 1ac , -R 1aa -SC(O)O-R 1ab -O-R 1ac , -R 1aa -SC(O)-R 1ab -O-R 1ac or -R 1aa -OC(O)-(NH(AA)C(O)OR 1c ); R 1aa , R 1ab , R 1ac are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, 5-7 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, C 1-4 alkylene C 6-12 aryl, or C 1-4 alkylene C 2-10 heteroaryl, said 5-7 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, C 1-4 alkylene C 6-12 aryl, or C 1-4 alkylene C 2-10 heteroaryl can be optionally further substituted by one or more R h or C(O)OR h ; R 1c , R 2c are each independently selected from hydrogen, deuterium, or C 1-6 alkyl, 5-7 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, C 1-4 alkylene C 6-12 aryl, or C 1-4 alkylene C 2-10 heteroaryl, said substituent groups being selected from deuterium, halogen, cyano, hydroxyl, amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy; AA is selected from a residue of a natural or unnatural amino acid in an alpha or beta configuration; R 2 selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, or C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfone, C 1-6 alkylthio, C 1-6 alkylamino, or 4-10 membered heterocyclyl, said substituent groups being selected from deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, or C 1-4 haloalkoxy; R 3 R 4 Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, or optionally influenced by one or more R groups. Y Replacement C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl acyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 Alkylamine group, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, C 1-6 Alkylene C 6-12 Aryl or C 1-6 Alkylene C 2-10 Mixed aromatics; or R 3 and R 4 and the atom to which they are attached together form a C3-C6cycloalkyl or 3-6 membered heterocyclyl, which can be optionally substituted with one or more R Y1 or R Y2 substituents; R Y1 , R Y2 each independently is selected from deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, or C 1-4 haloalkoxy; R 5 , R 6 each independently is selected from hydrogen, deuterium, C 1-6 alkyl or C 1-6 haloalkyl; R 7 R 8 Each is independently selected from one or more Rs. Z Replacement C 1-6 Alkyl, 5-12 membered heterocyclic, 5-12 membered cycloalkyl, C 6-12 Aryl, 5-12 heteroaryl, C 1-4 Alkylene C 6-12 Aryl or C 1-4 Alkylene C 2-10 Mixed aromatics; or R 7 and R 8 and the atom to which they are attached together form a 4-14 membered heterocyclyl, 5-12 membered heteroaryl, which is optionally further substituted by one or more R Z substituents; R 9 R 10 Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, or optionally influenced by one or more R groups. Y Replacement C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl acyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 Alkylamine group, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, C 1-6 Alkylene C 6-12 Aryl or C 1-6 Alkylene C 2-10 Mixed aromatics; or R 9 and R 10 and the atom to which they are attached together form a C3-C6cycloalkyl or 3-6 membered heterocyclyl, which can be optionally substituted with one or more R Y1 or R Y2 substituents; R Z R Y Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, imino, or optionally by one or more R groups. Q Replacement C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 Alkylamine group, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, -NR a R b -OR a -C(O)R a -C(O)OR a -NHC(O)OR a -NR b C(O)OR a -NR b C(O)R a -NR a C(O)NR b R c -C(O)NR a R b -S(O)R c -S(O)2R c -S(O)=NHR c -S(O)NR c R d or -S(O)2NR c R d ; R Q selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, imino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfone, C 1-6 alkylthio, C 1-6 alkylamino, 4-10 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, -NR e R f , -OR e , -C(O)R e , -C(O)OR e , -NHC(O)OR e , -NHC(O)R e , -NR e C(O)OR f , -NR e C(O)R f , -NR g C(O)NR e R f , -C(O)NR e R f , -S(O)R e , -S(O)2R e , -S(O)=NHR e , -S(O)NR e R f , or -S(O)2NR e R f ; R a , R b , R c , R d , R e , R f , R g , R h are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, imino, or C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfone, C 1-6 alkylthio, C 1-6 alkylamino, 4-10 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, C 1-4 alkylene C 6-12 aryl, or C 1-4 alkylene C 2-10 heteroaryl, said substituent being optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, phenyl, or benzyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, The compound has the following formula (II): wherein p, t, q, Z, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are as defined in claim 1.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, characterized in that, The compounds have the following formula (III), (IV), (V), (VI), (VII) or (VIII): wherein p, Z, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are as defined in claim 1.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, The compounds have the following formula (IIIa), (IVa), (Va), (VIa), (VIIa), (VIIIa), (IIIb), (IVb), (Vb), (VIb), (VIIb) or (VIIIb): wherein Z, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are as defined in claim 1.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, The compounds have the structure of formula (IIIa-1), (IIIa-2), (IIIa-3), (IIIa-4), (IIIa-5), (IVa-1), (IVa-2), (IVa-3), (IVa-4), (IVa-5), (IVa-6), (IVa-7), (IVa-8), (IVa-9), (IVa-10), (Va-1), (Via-1), or (IVb-1): wherein R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R Y1 , R Y2 are as defined in claim 1.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, said R 2 is selected from hydrogen or hydroxyl.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, The R 3 R 4 Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, or optionally influenced by one or more R groups. Y Replacement C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl acyl, C 3-6 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-12 Aryl, 5-12 heteroaryl, C 1-6 Alkylene C 6-12 Aryl or C 1-6 Alkylene C 2-10 Heteroaryl, the R Y Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, or imino.

8. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, R 3 and R 4 together with the atom to which they are attached form a C3-C6cycloalkyl group, which can optionally be substituted with one or more R Y1 or R Y2 ; each R Y1 , R Y2 is independently selected from deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, or C 1-4 haloalkoxy.

9. The compound of claim 7, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, R 3 , R 4 are each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkylene C 2-10 heteroaryl, or C 1-6 alkyl acyl.

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, The R 9 R 10 Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, or optionally influenced by one or more R groups. Y Replacement C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl acyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 Alkylamine group, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, C 1-6 Alkylene C 6-12 Aryl or C 1-6 Alkylene C 2-10 Heteroaryl; the R Y Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl or imino.

11. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, The R 9 R 10 Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, or optionally influenced by one or more R groups. Y Replacement C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl acyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 Alkylamine group, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, C 1-6 Alkylene C 6-12 Aryl or C 1-6 Alkylene C 2-10 Heteroaryl; the R Y Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, or imino.

12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, The R 9 and R 10 The atoms attached to them together form a C3-C6 cycloalkyl or a 3-6 membered heterocyclic group, wherein the C3-C6 cycloalkyl or 3-6 membered heterocyclic group may optionally be bonded by one or more R Y1 Or R Y2 Instead, the R Y1 Or R Y2 Each is independently selected from deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 Halogenated alkoxy groups.

13. The compound of claim 12, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein The R 9 R 10 The atoms attached to them together form a cyclopropyl group, which may optionally be converted by one or more R atoms. Y1 Or R Y2 Instead, the R Y1 Or R Y2 Each is independently selected from deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 Halogenated alkoxy groups.

14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, R 5 , R 6 each independently is selected from hydrogen or C 1-6 alkyl.

15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, R 1 C1-C6alkyl substituted with one or more substituents selected from the group consisting of 6-12 aryl or 5-12 membered heteroaryl, said substituents being selected from the group consisting of R g , CR 1a R 2a P(O)OR 1b OR 2b , CR 1a R 2a P(O)OR 1b NHR 2b or CR 1a R 2a P(O)(OR 1b )(NH(AA)C(O)OR 1c ).

16. The compound of claim 15, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, R 1 substituted by one or more substituents selected from the group consisting of R g , CR 1a R 2a P(O)OR 1b OR 2b , CR 1a R 2a P(O)OR 1b NHR 2b or CR 1a R 2a P(O)(OR 1b )(NH(AA)C(O)OR 1c ).

17. The compound of claim 16, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, said R 1a or R 2a each independently is selected from hydrogen, halogen, or oxo, said halogen preferably being F or Cl.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, CR 1a R 2a P(O)OR 1b OR 2b , CR 1a R 2a P(O)OR 1b NHR 2b or CR 1a R 2a P(O)(OR 1b )(NH(AA)C(O)OR 1c ) is selected from 19. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, said CR 1a R 2a P(O)OR 1b OR 2b , CR 1a R 2a P(O)OR 1b NHR 2b or CR 1a R 2a P(O)(OR 1b )(NH(AA)C(O)OR 1c ) is selected from 20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, The R 7 R 8 Each is independently selected from one or more Rs. Z Replacement C 1-6 Alkyl, 5-12 membered heterocyclic, 5-12 membered cycloalkyl, C 6-12 Aryl, 5-12 heteroaryl, C 1-4 Alkylene C 6-12 Aryl or C 1-4 Alkylene C 2-10 Mixed aromatics; said R Z is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, oxo, or optionally substituted C Q substituted C 1-6 alkyl, C 3-6 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, or 5-12 membered heteroaryl.

21. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, said R 7 and R 8 and the atoms to which they are attached together form a 4-14 membered heterocyclyl group, which can be optionally substituted with one or more R Z substituents; The R Z Independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, oxo, or optionally influenced by one or more R groups. Q Replacement C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups.

22. The compound of claim 20 or 21, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, said R Q is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, imino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, 4-10 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, -NR e R f , -C(O)R e , -NHC(O)R e or -NR e C(O)R f , said R e , R f are each independently selected from hydrogen, deuterium, or C 1-6 alkyl.

23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, The selected from:

24. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, The compound is selected from the following structural compounds:

25. A pharmaceutical composition comprising, the pharmaceutical composition contains a therapeutically effective amount of a compound of any one of claims 1-24, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or stereoisomer, geometric isomer, tautomer, or prodrug molecule, metabolite thereof.

26. Use of a compound of any one of claims 1-24, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or stereoisomer, geometric isomer, tautomer, or prodrug molecule, metabolite thereof, or a pharmaceutical composition of claim 25, for the manufacture of a medicament for the treatment of a STAT6-mediated disease or disorder and related diseases or disorders, the STAT6-mediated disease or disorder being a tumor or a type II inflammation related disease selected from atopic dermatitis, bullous pemphigoid, nodular prurigo, chronic spontaneous urticaria, eosinophilic esophagitis, food allergy, chronic rhinosinusitis with nasal polyps (CRSwNP), chronic rhinosinusitis without nasal polyps (CRSsNP), nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD / AERD), allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), eosinophilic granulomatosis with polyangiitis (EGPA), or allergic bronchopulmonary aspergillosis; the tumor being selected from lymphoma, solitary fibrous tumor, colon cancer, esophageal cancer, breast cancer, cholangiocarcinoma, hepatocarcinoma, renal cancer, gastric cancer, head and neck squamous carcinoma, prostate cancer, lung cancer, non-small cell lung cancer (NSCLC), acute B-lymphoblastic leukemia, bladder cancer, pancreatic cancer, osteosarcoma, myeloma, glioma, ovarian cancer, or skin cancer.

27. A method of treating and / or preventing a disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-24, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or stereoisomer, geometric isomer, tautomer, or prodrug molecule, metabolite thereof, or a pharmaceutical composition of claim 25.

28. The method of claim 27, wherein, The disease to be treated and / or prevented is a disease mediated by STAT6, which is a tumor or a type II inflammation-related disease selected from atopic dermatitis, bullous pemphigoid, nodular prurigo, chronic spontaneous urticaria, eosinophilic esophagitis, food allergy, chronic rhino-sinusitis with nasal polyps (CRSwNP), chronic rhino-sinusitis without nasal polyps (CRSsNP), non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD / AERD), allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), eosinophilic granulomatosis with polyangiitis (EGPA), or allergic bronchopulmonary aspergillosis; and the tumor is selected from lymphoma, solitary fibrous tumor, colon cancer, esophageal cancer, breast cancer, cholangiocarcinoma, hepatocarcinoma, renal cancer, gastric cancer, head and neck squamous carcinoma, prostate cancer, lung cancer, non-small cell lung cancer (NSCLC), acute B-lymphoblastic leukemia, bladder cancer, pancreatic cancer, osteosarcoma, myeloma, glioma, ovarian cancer, or skin cancer.

29. An intermediate compound M1-1, M1-3, or M1, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or stereoisomer, geometric isomer, tautomer, or prodrug molecule thereof: wherein R 1a , R 2a , R 5 , R 6 , R 7 , R 8 , R g , Z and Y are as defined in claim 1.

30. An intermediate compound M3 or M4, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or stereoisomer, geometric isomer, tautomer, or prodrug molecule thereof:

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