Azapine condensed ring compounds and their medical uses

Abstract

An azepine fused ring compound and its medical use. Specifically, it relates to an azepine fused ring compound represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the same, and its use as a receptor interacting protein kinase 1 (RIP1) inhibitor for treating diseases related to RIP1 activity. The definition of each substituent in general formula (I) is the same as that in the specification.

Description

Technical Field

[0001] The present invention relates to an azapine fused ring compound and its medical use. Specifically, the present invention relates to an azapine fused ring compound represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the same, and its use as a receptor interacting protein kinase 1 (RIP1) inhibitor for treating diseases related to RIP1 activity. Background Art

[0002] Apoptosis and necrosis are two ways of cell death. Passive cell death and cell necrosis caused by environmental factors play an important role in pathological and physiological processes such as inflammatory response. RIP1 is at the intersection of multiple inflammation and cell death-related signaling pathways, and participates in regulating multiple downstream signaling pathways such as TNF-activated NF-κB, apoptosis, and necrosis.

[0003] RIP1 can promote inflammatory responses by mediating the NF-κB pathway, but it is worth noting that the activation of the NF-κB pathway and TNF-induced apoptosis do not require the kinase activity of RIP1, and RIP1 kinase inhibition has no effect on TNF-induced NF-κB pathway activation. However, the kinase activity of RIP1 can also promote the occurrence and development of inflammation through multiple pathways such as cell necrosis, inflammasomes, and TNF production.

[0004] RIP1 kinase-mediated cell necrosis and inflammation: apoptotic cells can be quickly cleared by the body before the cell membrane ruptures, while necrotic cells are cleared more slowly. After the cell membrane ruptures, a large amount of dangerous contents in the cytoplasm are released and are regarded as pathogen-like substances by the body, activating many pattern recognition receptors and severely enhancing the inflammatory response. Cell necrosis is also considered to be an important factor in the rapid development and severe symptoms of related inflammatory diseases.

[0005] RIP1 kinase and inflammasomes: Like TNF-α, IL-1β is also a key pro-inflammatory factor. For example, in the development of RA, IL-1β aggravates the destruction of cartilage, bone tissue, and periarticular soft tissue by acting on synovial fibroblasts and chondrocytes. IL-1β secretion requires the assistance of two pathways: first, pathways such as TLR4 and TNF promote the expression of IL-1β / IL-18 precursors; then, the formed inflammasome platforms such as NLPR3 promote the maturation of IL-1β / IL-18 precursors. Inflammasomes are closely related to the development and progression of autoimmune diseases such as RA and psoriasis. The activation of inflammasomes depends on RIP1 and RIP3 and their kinase activity. RIP1 and RIP3 can amplify the expression of IL-1β, and this process is independent of cell necrosis.

[0006] RIP1 kinase-dependent mediation of IL-1α production: Protein tyrosine phosphatase SHP-1 plays an important role in immune signaling pathways. SHP-1 mutant mice produce a large number of inflammatory factors accompanied by inflammatory diseases such as arthritis, but the mechanism is unknown. Specific SHP-1 mutant mice can spontaneously develop severe inflammation, and the symptoms are similar to human neutrophilic dermatosis. In this model, RIP1 kinase is dependent on promoting IL-1α production, which can mediate and amplify inflammation and tissue damage, all of which are independent of inflammasomes, IL-1β and RIP3. RIP1 kinase inhibition can prevent the occurrence of related inflammation and damage, and NF-κB and ERK inhibition can alleviate RIP1-mediated inflammatory factor production. Therefore, inflammation and tissue damage in SHP-1 mutant mice depend on RIP1 kinase-mediated IL-1α production, and the mechanism is related to RIP1 kinase regulating NF-κB and ERK pathways.

[0007] RIP1 kinase-dependent mediation of TNFα production: cIAP can inhibit RIP1 activity through ubiquitination, and cIAP inhibitors such as Smac can induce TNFα production and cell death, but the mechanism is unknown. TNFα inhibition can prevent cell death induced by caspase inhibition, indicating that caspase e inhibition may induce TNFα production. RIP1 kinase inhibition can prevent cell death induced by caspase inhibition. Therefore, in the case of caspase inhibition, RIP1 may serve as an upstream mechanism for TNFα production. Recent studies have shown that RIP1 kinase can interact with EDD to induce JNK pathway activation and TNFα production. This pathway specifically corresponds to caspase inhibition, indicating that RIP1 kinase activity not only regulates cell necrosis downstream of TNFR1, but also plays an important role in mediating TNFα production.

[0008] In recent years, some genetic evidence (such as RIP1 kinase inactivation mutations) and related studies on RIP1 kinase inhibitor tool molecules (such as Nec-1) have further confirmed that RIP1 kinase plays an important role in the occurrence and development of some inflammatory and various tissue damage diseases. RIP1 kinase inactivation mutations can completely prevent multi-organ inflammatory phenotypes, especially skin inflammation; RIP1 kinase inhibition can prevent renal injury caused by ischemia-reperfusion in renal transplant animal models; RIP1 kinase inhibitor Nec-1 prevents myocardial infarction and cardiac hypoxia; RIP1 kinase inhibitor Nec-1 prevents cone cell death, dsRNA-induced retinal degeneration, and pigmentary retinitis.

[0009] Unlike RIP1 deficiency, which causes animal death, RIP1 kinase-inactivated mutant mice can survive normally and resist necrotic stimulation. Therefore, the death caused by RIP1 deficiency is not related to kinase activity. Ripk1D138N / D138N and RipkK45A / K45A kinase-inactivated mutant mice have no obvious phenotype changes, indicating that RIP1 kinase activity is a relatively safe target. In contrast, RIP3 kinase-inactivated mutant mice lose weight rapidly and die.

[0010] Given the important role that RIP1 kinase plays in the development of inflammation, RIP1 kinase inhibitors for the treatment of inflammatory diseases have received a certain amount of attention from leading global pharmaceutical companies. Among them, GSK's representative compound GSK2982772 has begun clinical phase II research; Roche also has molecules in the preclinical research stage. However, no RIP1 kinase inhibitors have been launched on the market so far, and researchers need to develop more RIP1 kinase inhibitor molecules in order to select better compounds for the treatment of related diseases and inflammation. Summary of the invention

[0011] After intensive research, the inventors have designed and synthesized a series of azapine fused ring compounds, which show inhibitory activity on receptor interacting protein kinase 1 (RIP1) and can be developed as drugs for preventing or treating diseases related to RIP1 activity.

[0012] Therefore, the object of the present invention is to provide a compound represented by general formula (I) or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

[0013]

[0014] in,

[0015] X is selected from -O-, -S(O) m -、-NR a -,-CR'R"-;

[0016] Y 1 and Y 2 Each independently selected from O or S;

[0017] Z 1 and Z 2 are each independently selected from C or N atoms;

[0018] L is selected from a single bond, -O-, -S(O) m -、-NR a -、-(CR a R b ) n -、-(CR aR b ) n O-、-(CR a R b ) n S-and-(CR a R b ) n NR a -;

[0019] Ring A is selected from aryl, heteroaryl, cycloalkyl and heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally further substituted by one or more R 9 replace;

[0020] Ring B is an aromatic ring or an aromatic heterocyclic ring, which is optionally further substituted with one or more R 8 replace;

[0021] Ring C is a nitrogen-containing heterocyclic ring, which is optionally further substituted with one or more R 7 replace;

[0022] R 1 and R 2 together with the atoms to which they are attached form a 5-membered heteroaryl, a 5-membered heterocyclyl or a 5-membered cycloalkyl, or R 2 and R 3 together with the atoms to which they are attached form a 5-membered heteroaryl, a 5-membered heterocyclyl or a 5-membered cycloalkyl, or R 3 and R 4 Together with the atoms to which they are attached, they form a 5-membered heteroaryl, a 5-membered heterocyclyl or a 5-membered cycloalkyl, wherein the 5-membered heteroaryl, the 5-membered heterocyclyl or the 5-membered cycloalkyl is optionally further substituted with one or more R 6 replace;

[0023] in:

[0024] When R 1 and R 2 When R is taken together with the atoms to which they are attached to form a 5-membered heteroaryl, a 5-membered heterocyclyl or a 5-membered cycloalkyl, 3 and R 4 Each independently selected from R 6 ;or

[0025] When R 2 and R 3 When R is taken together with the atoms to which they are attached to form a 5-membered heteroaryl, a 5-membered heterocyclyl or a 5-membered cycloalkyl, 1 and R 4 Each independently selected from R 6 ;or

[0026] When R 3 and R 4When R is taken together with the atoms to which they are attached to form a 5-membered heteroaryl, a 5-membered heterocyclyl or a 5-membered cycloalkyl, 1 and R 2 Each independently selected from R 6 ;

[0027] R 5 is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl and halocycloalkyl;

[0028] Each R 6 are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR a R b 、-C(O)R a 、-O(O)CR a 、-C(O)OR a 、-C(O)NR a R b 、-NHC(O)R a 、-S(O) m R a 、-S(O) m NR a R b 、-NHS(O) m R a and -P(O)(R a )2, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl are optionally further substituted by one or more groups selected from deuterium atoms, halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl;

[0029] Each R 7 are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR a R b 、-C(O)R a 、-O(O)CR a 、-C(O)OR a 、-C(O)NR a R b 、-NHC(O)R a 、-S(O) m R a 、-S(O) m NR a R b , and -NHS(O) m R a; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0030] Each R 8 are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR a R b 、-C(O)R a 、-O(O)CR a 、-C(O)OR a 、-C(O)NR a R b 、-NHC(O)R a 、-S(O) m R a 、-S(O) m NR a R b , and -NHS(O) m R a ; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0031] Each R 9 are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR a R b 、-C(O)R a 、-O(O)CR a 、-C(O)OR a 、-C(O)NR a R b 、-NHC(O)R a 、-S(O) m R a 、-S(O) m NR a R b , and -NHS(O) m R a; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0032] R' and R" are each independently selected from hydrogen, halogen, alkyl, haloalkyl;

[0033] R a and R b each independently selected from hydrogen, halogen, hydroxy, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, thiol, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0034] or R a and R b Together with the atoms to which they are attached, they form a cycloalkyl or heterocyclyl group, which is optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0035] m is 0, 1 or 2;

[0036] n is an integer of 0-3.

[0037] In a preferred embodiment, the compound represented by general formula (I) according to the present invention or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by general formula (II) or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0038]

[0039] in,

[0040] Ring D is selected from 5-membered heteroaryl, 5-membered heterocyclyl or 5-membered cycloalkyl, preferably imidazolyl, dihydroimidazolyl, pyrazolyl, dihydropyrazolyl, dioxolyl, thiazolyl, oxazolyl, pyrrolyl, furanyl; which is optionally further selected from halogen, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, cycloalkyl, heterocyclyl, -NR a R b 、-C(O)R a 、-O(O)CR a、-C(O)OR a 、-C(O)NR a R b 、-NHC(O)R a 、-S(O) m R a 、-S(O) m NR a R b 、-NHS(O) m R a and -P(O)(R a )2 is substituted with one or more groups;

[0041] R 1 and R 2 Each is independently selected from hydrogen, halogen, alkyl;

[0042] R a and R b each independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more groups selected from deuterium atoms, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0043] or R a and R b Together with the atoms to which they are attached, they form a cycloalkyl or heterocyclyl group, which is optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0044] m is 0, 1 or 2;

[0045] X, Y 1 , Y 2 , Z 1 , Z 2 , L, Ring A, Ring B, Ring C, R 5 As defined in general formula (I).

[0046] In another preferred embodiment, the compound of general formula (I) according to the present invention or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound of general formula (III) or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0047]

[0048] in,

[0049] Ring E is selected from 5-membered heteroaryl, 5-membered heterocyclyl or 5-membered cycloalkyl, preferably imidazolyl, dihydroimidazolyl, pyrazolyl, dihydropyrazolyl, dioxolyl, thiazolyl, oxazolyl, pyrrolyl, furanyl; which is optionally further selected from halogen, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, cycloalkyl, heterocyclyl, -NR a R b 、-C(O)R a 、-O(O)CR a 、-C(O)OR a 、-C(O)NR a R b 、-NHC(O)R a 、-S(O) m R a 、-S(O) m NR a R b 、-NHS(O) m R a and -P(O)(R a )2 is substituted with one or more groups;

[0050] R 1 and R 4 Each is independently selected from hydrogen, halogen, alkyl;

[0051] R a and R b each independently selected from hydrogen, halogen, hydroxy, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, thiol, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0052] or R a and R b Together with the atoms to which they are attached, they form a cycloalkyl or heterocyclyl group, which is optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0053] m is 0, 1 or 2;

[0054] X, Y 1 , Y 2 , Z 1 , Z2 , L, Ring A, Ring B, Ring C, R 5 As defined in general formula (I).

[0055] In another preferred embodiment, the compound of general formula (I) according to the present invention, or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound of general formula (IV), or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0056]

[0057] in:

[0058] Ring F is selected from 5-membered heteroaryl, 5-membered heterocyclyl or 5-membered cycloalkyl, preferably imidazolyl, dihydroimidazolyl, pyrazolyl, dihydropyrazolyl, dioxolyl, thiazolyl, oxazolyl, pyrrolyl, furanyl; which is optionally further selected from halogen, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, cycloalkyl, heterocyclyl, -NR a R b 、-C(O)R a 、-O(O)CR a 、-C(O)OR a 、-C(O)NR a R b 、-NHC(O)R a 、-S(O) m R a 、-S(O) m NR a R b 、-NHS(O) m R a and -P(O)(R a )2 is substituted with one or more groups;

[0059] R 3 and R 4 Each is independently selected from hydrogen, halogen, alkyl;

[0060] R a and R b each independently selected from hydrogen, halogen, hydroxy, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, thiol, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0061] or Ra and R b Together with the atoms to which they are attached, they form a cycloalkyl or heterocyclyl group, which is optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0062] m is 0, 1 or 2;

[0063] X, Y 1 , Y 2 , Z 1 , Z 2 , L, Ring A, Ring B, Ring C, R 5 As defined in general formula (I).

[0064] In a preferred embodiment, the compound represented by the general formula (II), (III) and (IV) or its meso form, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

[0065] in:

[0066] R a and R b Each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl is optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0067] or R a and R b Together with the atoms to which they are attached, they form a 5-7 membered nitrogen-containing heterocyclic group, which is optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0068] In another preferred embodiment, according to the compounds of the general formula (I), (II), (III) and (IV) of the present invention or their racemates, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, X is -O- or -S-.

[0069] In another preferred embodiment, the compounds represented by general formula (I), (II), (III) and (IV) according to the present invention or their mesomorphs, racemates, enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ring C is a 5- to 8-membered nitrogen-containing heterocyclic ring, preferably a piperidine ring, a tetrahydropyrrole ring, a piperazine ring, a dihydropyrrole ring, a tetrahydropyridine ring or a homopiperazine ring, more preferably a piperidine ring, which is optionally further substituted with one or more R 7 replace;

[0070] Each R 7 are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR a R b 、-C(O)R a 、-O(O)CR a 、-C(O)OR a 、-C(O)NR a R b 、-NHC(O)R a 、-S(O) m R a 、-S(O) m NR a R b , and -NHS(O) m R a ; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0071] in:

[0072] R a and R b each independently selected from hydrogen, halogen, hydroxy, nitro, cyano, oxo, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, thiol, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0073] or R a and R bTogether with the atoms to which they are attached, they form a cycloalkyl or heterocyclyl group, which is optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0074] m is 0, 1 or 2.

[0075] In another preferred embodiment, according to the compounds represented by general formula (I), (II), (III) and (IV) of the present invention or their mesomorphs, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ring B is a 6- to 10-membered aromatic ring or a 5- to 6-membered aromatic heterocyclic ring, preferably a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a pyrrole ring, a pyrazole ring, an imidazole ring, an oxazole ring, a thiazole ring, an isoxazole ring, an isothiazole ring, an oxadiazole ring, a thiadiazole ring, or a triazole ring, more preferably a pyrazole ring, an imidazole ring, or a triazole ring, which is optionally further replaced by one or more R 8 replace;

[0076] Each R 8 are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR a R b 、-C(O)R a 、-O(O)CR a 、-C(O)OR a 、-C(O)NR a R b 、-NHC(O)R a 、-S(O) m R a 、-S(O) m NR a R b , and -NHS(O) m R a ; wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl are optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, sulfhydryl, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; preferably R 8 is a halogen;

[0077] in:

[0078] R a and R beach independently selected from hydrogen, halogen, hydroxy, nitro, cyano, oxo, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, thiol, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0079] or R a and R b Together with the atoms to which they are attached, they form a cycloalkyl or heterocyclyl group, which is optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0080] m is 0, 1 or 2.

[0081] In another preferred embodiment, the compounds represented by general formula (I), (II), (III) and (IV) according to the present invention or their mesomorphs, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein:

[0082] Selected from:

[0083]

[0084] in,

[0085] Y 2 Selected from O or S;

[0086] Z 1 and Z 2 are each independently selected from C or N atoms;

[0087] Ring B is a 6- to 10-membered aromatic ring or a 5- to 6-membered aromatic heterocyclic ring, preferably a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a pyrrole ring, a pyrazole ring, an imidazole ring, an oxazole ring, a thiazole ring, an isoxazole ring, an isothiazole ring, an oxadiazole ring, a thiadiazole ring, or a triazole ring, more preferably a pyrazole ring, an imidazole ring, or a triazole ring, which is optionally further substituted with one or more R 8 replace;

[0088] Each R 7 Each is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy; or two adjacent R 7Together with the atoms to which they are attached, they form a heterocyclic group or a cycloalkyl group, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic group is optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl; preferably R 7 is hydrogen;

[0089] Each R 8 Each is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; p is 0, 1, 2, 3 or 4, preferably 0.

[0090] In another preferred embodiment, the compounds represented by general formula (I), (II), (III) and (IV) according to the present invention or their mesomorphs, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein:

[0091] Selected from:

[0092] Best

[0093] in,

[0094] Y 2 Selected from O or S;

[0095] Each R 8 Each is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, oxo, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl is optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; preferably R 8 is a halogen;

[0096] q is 0, 1, or 2.

[0097] In a specific embodiment, the compound represented by the general formula (I) according to the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (IA) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0098]

[0099] X, Y 1 , Y 2 , L, Ring A, R 1 , R 2 , R 3 , R 4 , R 5 , R 8 As defined in general formula (I).

[0100] In another preferred embodiment, the compounds represented by general formula (I), (IA), (II), (III) and (IV) according to the present invention or their mesomorphs, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein Y 2 is O.

[0101] In another preferred embodiment, the compounds represented by general formula (I), (IA), (II), (III) and (IV) according to the present invention or their mesomorphs, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein Y 1 is O.

[0102] In another preferred embodiment, the compounds represented by general formula (I), (IA), (II), (III) and (IV) according to the present invention or their mesomorphs, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

[0103] in,

[0104] Ring A is selected from aryl and heteroaryl, preferably phenyl, wherein the aryl or heteroaryl is optionally further substituted by one or more R 9 replace,

[0105] Each R 9Each is independently selected from hydrogen, halogen, cyano, hydroxyl, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, preferably hydrogen, halogen, alkyl and alkoxy; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.

[0106] In another preferred embodiment, the compounds represented by general formula (I), (IA), (II), (III) and (IV) according to the present invention or their mesomorphs, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

[0107] Wherein, L is selected from -NR a -and-(CR a R b ) n -, preferably -(CR a R b ) n -;

[0108] R a and R b are each independently selected from hydrogen and C 1-6 alkyl;

[0109] n is an integer from 0 to 3, preferably 1;

[0110] L is more preferably -CH2-;

[0111] In another preferred embodiment, according to the compounds of the general formula (I), (IA), (II), (III) and (IV) of the present invention, or their mesomorphs, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 5 Selected from hydrogen, C 1-6 Alkyl and halogenated C 1-6 Alkyl, preferably hydrogen and C 1-6 alkyl.

[0112] In a specific embodiment of the present invention, the compound represented by the general formula (I) according to the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, is a compound represented by the general formula (II-1) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt,

[0113]

[0114] in,

[0115] X is -O- or -S-;

[0116] Ring D is selected from 5-membered heteroaryl, 5-membered heterocyclyl or 5-membered cycloalkyl, preferably imidazolyl, dihydroimidazolyl, pyrazolyl, dihydropyrazolyl, dioxolyl, thiazolyl, oxazolyl, pyrrolyl, furanyl; which is optionally further selected from halogen, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, -C(O)OR a One or more groups are substituted;

[0117] R 1 and R 2 Each is independently selected from hydrogen, halogen, C1-C6 alkyl;

[0118] R 5 is selected from hydrogen and C1-C6 alkyl;

[0119] R 8 is selected from hydrogen and halogen;

[0120] R 9 is selected from hydrogen and halogen;

[0121] R a Selected from C1-C6 alkyl;

[0122] p is 0, 1 or 2.

[0123] In another specific embodiment of the present invention, the compound represented by the general formula (I) according to the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (III-1) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0124]

[0125] in,

[0126] X is -O- or -S-;

[0127] Ring E is selected from 5-membered heteroaryl, 5-membered heterocyclyl or 5-membered cycloalkyl, preferably imidazolyl, dihydroimidazolyl, pyrazolyl, dihydropyrazolyl, dioxolyl, thiazolyl, oxazolyl, pyrrolyl, furanyl; which is optionally further selected from halogen, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, -C(O)OR a One or more groups are substituted;

[0128] R 1 and R 4 Each is independently selected from hydrogen, halogen, C1-C6 alkyl;

[0129] R 5 is selected from hydrogen and C1-C6 alkyl;

[0130] R 8 is selected from hydrogen and halogen;

[0131] R 9 is selected from hydrogen and halogen;

[0132] R a Selected from C1-C6 alkyl;

[0133] p is 0, 1 or 2.

[0134] In another specific embodiment of the present invention, the compound represented by the general formula (I) according to the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (IV-1) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0135]

[0136] in,

[0137] X is -O- or -S-;

[0138] Ring F is selected from 5-membered heteroaryl, 5-membered heterocyclyl or 5-membered cycloalkyl, preferably imidazolyl, dihydroimidazolyl, pyrazolyl, dihydropyrazolyl, dioxolyl, thiazolyl, oxazolyl, pyrrolyl, furanyl; which is optionally further selected from halogen, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, -C(O)OR a One or more groups are substituted;

[0139] R 3 and R 4 Each is independently selected from hydrogen, halogen, C1-C6 alkyl;

[0140] R 5 is selected from hydrogen and C1-C6 alkyl;

[0141] R 8 is selected from hydrogen and halogen;

[0142] R 9 is selected from hydrogen and halogen;

[0143] R a Selected from C1-C6 alkyl;

[0144] p is 0, 1 or 2.

[0145] Typical compounds of the present invention include, but are not limited to:

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153] or its meso form, racemate, enantiomer, diastereomer, or mixture form, or its pharmaceutically acceptable salt.

[0154] The present invention further provides a method for preparing the compound represented by the general formula (IA) according to the present invention or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, which comprises the following steps:

[0155]

[0156] In the presence of a catalyst, compound IA-I undergoes an intramolecular ring-closing reaction to obtain a compound of formula (IA), wherein the catalyst is preferably trimethylaluminum;

[0157] Among them, X, Y 1 , Y 2 , L, Ring A, R 1 , R 2 , R 3 , R 4 , R 5 , R 8 As defined in formula (IA).

[0158] The present invention further provides a method for preparing the compound represented by the general formula (II-1) according to the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, which comprises the following steps:

[0159]

[0160] In the presence of a catalyst, compound II-1a undergoes an intramolecular ring-closing reaction to obtain a compound of formula (II-1), wherein the catalyst is preferably trimethylaluminum;

[0161] Among them, X, ring D, R1 , R 2 , R 5 , R 8 , R 9 , p is as defined in the general formula (II-1).

[0162] The present invention further provides a method for preparing the compound represented by the general formula (III-1) according to the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which comprises the following steps:

[0163]

[0164] In the presence of a catalyst, compound III-1a undergoes an intramolecular ring-closing reaction to obtain a compound of formula (III-1), wherein the catalyst is preferably trimethylaluminum;

[0165] Among them, X, ring E, R 1 , R 4 , R 5 , R 8 , R 9 , p is as defined in the general formula (III-1).

[0166] The present invention further provides a method for preparing the compound represented by the general formula (IV-1) according to the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, which comprises the following steps:

[0167]

[0168] In the presence of a catalyst, compound IV-1a undergoes an intramolecular ring-closing reaction to obtain a compound of formula (IV-1), wherein the catalyst is preferably trimethylaluminum;

[0169] Among them, X, ring F, R 3 , R 4 , R 5 , R 8 , R 9 , p are as defined in the general formula (IV-1).

[0170] The present invention further provides a pharmaceutical composition comprising a compound represented by the general formula (I), (IA), (II), (III), (IV), (II-1), (III-1) or (IV-1) according to the present invention or its racemate, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0171] The present invention further relates to the use of a compound represented by the general formula (I), (IA), (II), (III), (IV), (II-1), (III-1) or (IV-1) according to the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt or a pharmaceutical composition containing the same in the preparation of a receptor interacting protein kinase 1 (RIP1) inhibitor.

[0172] The present invention further relates to the use of the compound represented by the general formula (I), (IA), (II), (III), (IV), (II-1), (III-1) or (IV-1) according to the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt or pharmaceutical composition containing the same in the preparation of a drug for preventing or treating a disease associated with the activity of receptor interacting protein kinase 1, wherein the disease is preferably an inflammatory disease, an autoimmune disease or a nervous system disease, wherein the inflammatory disease and the autoimmune disease are, for example, rheumatoid arthritis, ulcerative colitis, Crohn's disease, psoriasis, retinal detachment, pigmentary retinitis, macular degeneration, pancreatitis, atopic dermatitis, spondyloarthritis, gout, juvenile idiopathic The invention relates to an autoimmune disease, such as arthritis, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, antiphospholipid syndrome, vasculitis, osteoarthritis, nonalcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune thrombocytopenic purpura, transplant rejection, solid organ ischemia-reperfusion injury, sepsis, systemic inflammatory response syndrome, allergic diseases, asthma, atopic skin diseases, multiple sclerosis, type I diabetes, orbital necrotizing granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1 converting enzyme-associated febrile syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-associated syndrome or periodontitis; the neurological disease is such as Huntington's disease, Alzheimer's disease, Parkinson's disease or amyotrophic lateral sclerosis.

[0173] The present invention further relates to a compound represented by the general formula (I), (IA), (II), (III), (IV), (II-1), (III-1) or (IV-1) according to the present invention, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt or a pharmaceutical composition containing the same, which is used as a receptor interacting protein kinase 1 (RIP1) inhibitor.

[0174] The present invention further relates to a compound represented by the general formula (I), (IA), (II), (III), (IV), (II-1), (III-1) or (IV-1) according to the present invention, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt or a pharmaceutical composition comprising the same, which is used for preventing or treating a disease associated with the activity of receptor interacting protein kinase 1, wherein the disease is preferably an inflammatory disease, an autoimmune disease or a nervous system disease, wherein the inflammatory disease and the autoimmune disease are, for example, rheumatoid arthritis, ulcerative colitis, Crohn's disease, psoriasis, retinal detachment, pigmentary retinitis, macular degeneration, pancreatitis, atopic dermatitis, spondyloarthritis, gout, juvenile idiopathic joint inflammation, leukemia, leukemia, necrosis ... Arthritis, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, antiphospholipid syndrome, vasculitis, osteoarthritis, nonalcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune thrombocytopenic purpura, transplant rejection, solid organ ischemia-reperfusion injury, sepsis, systemic inflammatory response syndrome, allergic diseases, asthma, atopic skin diseases, multiple sclerosis, type I diabetes, orbital necrotizing granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1 converting enzyme-associated febrile syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-associated syndrome or periodontitis; the nervous system disease is such as Huntington's disease, Alzheimer's disease, Parkinson's disease or amyotrophic lateral sclerosis.

[0175] The present invention further relates to a method for inhibiting receptor interacting protein kinase 1 (RIP1), which comprises administering to a patient in need thereof an effective amount of a compound represented by the general formula (I), (IA), (II), (III), (IV), (II-1), (III-1) or (IV-1) according to the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0176] The present invention further relates to a method for preventing or treating a disease associated with receptor interacting protein kinase 1 activity, comprising administering to a patient in need thereof a preventive or therapeutically effective amount of a compound represented by general formula (I), (IA), (II), (III), (IV), (II-1), (III-1) or (IV-1) according to the present invention or its racemate, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; wherein the disease is preferably an inflammatory disease, an autoimmune disease or a nervous system disease, and the inflammatory disease and autoimmune disease are, for example, rheumatoid arthritis, ulcerative colitis, Crohn's disease, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, spinal arthritis, Arthritis, gout, juvenile idiopathic arthritis, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, antiphospholipid syndrome, vasculitis, osteoarthritis, nonalcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune thrombocytopenic purpura, transplant rejection, solid organ ischemia-reperfusion injury, sepsis, systemic inflammatory response syndrome, allergic diseases, asthma, atopic skin diseases, multiple sclerosis, type I diabetes, orbital necrotizing granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1 converting enzyme-associated febrile syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-associated syndrome or periodontitis; the nervous system disease is such as Huntington's disease, Alzheimer's disease, Parkinson's disease or amyotrophic lateral sclerosis.

[0177] According to the conventional method in the field to which the present invention belongs, the compound of the general formula of the present invention can form a pharmaceutically acceptable basic addition salt with a base. The base includes an inorganic base and an organic base, and the acceptable organic base includes diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc., and the acceptable inorganic base includes aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide, etc.

[0178] The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the following: sweeteners, flavoring agents, colorants and preservatives to provide pleasing and palatable pharmaceutical preparations. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for preparing tablets for mixing. These excipients may be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrants such as microcrystalline cellulose, crosslinked sodium carboxymethyl cellulose, corn starch or alginic acid; binders such as starch, gelatin, polyvinyl pyrrolidone or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release action over a longer period of time. For example, water soluble taste masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or time extending materials such as ethylcellulose, cellulose acetate butyrate may be used.

[0179] Oral preparations may also be provided in hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in soft gelatin capsules wherein the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oily vehicle such as peanut oil, liquid paraffin or olive oil.

[0180] Aqueous suspensions contain the active substance and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and gum arabic; dispersants or wetting agents, which may be naturally occurring phosphatides such as lecithin, or condensation products of alkylene oxides with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long chain fatty alcohols, for example, heptadecaethyleneoxy cetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, for example, polyethylene oxide sorbitan monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, polyethylene oxide dehydrated sorbitan monooleate. The aqueous suspension may also contain one or more preservatives, for example ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, for example sucrose, saccharin or aspartame.

[0181] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin. The oil suspension may contain a thickener such as beeswax, hard paraffin or cetyl alcohol. The above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding an antioxidant such as butylated hydroxyanisole or alpha-tocopherol.

[0182] Dispersible powders and granules suitable for preparing aqueous suspensions can provide the active ingredient and a dispersant or wetting agent, a suspending agent or one or more preservatives for mixing by adding water. Suitable dispersants or wetting agents and suspending agents are as described above. Other excipients such as sweeteners, flavoring agents and coloring agents can also be added. These compositions can be preserved by adding antioxidants such as ascorbic acid.

[0183] The pharmaceutical composition of the present invention can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof. Suitable emulsifiers can be naturally occurring phospholipids, such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, such as polyethylene oxide sorbitol monooleate. Emulsions can also contain sweeteners, flavoring agents, preservatives, and antioxidants. Syrups and elixirs prepared with sweeteners such as glycerol, propylene glycol, sorbitol, or sucrose can be used. Such preparations can also contain a demulcent, a preservative, a coloring agent, and an antioxidant.

[0184] The pharmaceutical composition of the present invention may be in the form of a sterile injectable aqueous solution. Acceptable vehicles and solvents that may be used are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then added to a mixture of water and glycerol and processed to form a microemulsion. The injection or microemulsion may be injected into the patient's bloodstream by local mass injection. Alternatively, the solution and microemulsion may be preferably administered in a manner that maintains a constant circulating concentration of the compound of the present invention. To maintain this constant concentration, a continuous intravenous drug delivery device may be used.

[0185] The pharmaceutical composition of the present invention can be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be prepared by known techniques with the above-mentioned suitable dispersants or wetting agents and suspending agents. The sterile injection preparation can also be a sterile injection solution or suspension prepared in a non-toxic parenteral acceptable diluent or solvent, such as a solution prepared in 1,3-butanediol. In addition, sterile fixed oil can be conveniently used as a solvent or suspension medium. For this purpose, any blended fixed oil including synthetic glycerol mono- or di-esters can be used. In addition, fatty acids such as oleic acid can also be used to prepare injections.

[0186] The compounds of the invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and which will dissolve in the rectum to release the drug. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycol.

[0187] It is well known to those skilled in the art that the dosage of a drug depends on a variety of factors, including but not limited to the following factors: the activity of the specific compound used, the patient's age, the patient's weight, the patient's health condition, the patient's behavior, the patient's diet, the administration time, the administration method, the excretion rate, the combination of drugs, etc. In addition, the best treatment method, such as the mode of treatment, the daily dosage of the general compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment plans.

[0188] The present invention may contain the general formula compound and its pharmaceutically acceptable salt, hydrate or solvate as an active ingredient, mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition, and prepared into a clinically acceptable dosage form. The derivatives of the present invention can be used in combination with other active ingredients, as long as they do not produce other adverse effects, such as allergic reactions. The compounds of the present invention can be used as the only active ingredient, or in combination with other drugs for treating diseases related to tyrosine kinase activity. Combination therapy is achieved by administering the individual therapeutic components simultaneously, separately or sequentially.

[0189] Detailed description of the invention

[0190] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0191] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0192] The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.

[0193] The term "alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, propynyl, butynyl, etc. Alkynyl may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.

[0194] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include spirocyclic, fused and bridged cycloalkyls.

[0195] The term "spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (called a spiral atom) between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiral atoms shared between the rings, the spirocycloalkyl is divided into a single spiral cycloalkyl, a double spiral cycloalkyl or a multi-spirocycloalkyl, preferably a single spiral cycloalkyl and a double spiral cycloalkyl. More preferably, it is a 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral cycloalkyl. Non-limiting examples of spirocycloalkyl include:

[0196]

[0197] The term "condensed cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl, preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of condensed cycloalkyls include:

[0198]

[0199] The term "bridged cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably a bicyclic, tricyclic or tetracyclic, and more preferably a bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

[0200]

[0201] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0202] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O). m(wherein m is an integer from 0 to 2) heteroatoms, but does not include -OO-, -OS- or -SS- ring parts, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably, it contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably, it contains 5 to 7 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably 1, 2, 5-oxadiazolyl, pyranyl or morpholinyl. Polycyclic heterocyclic groups include spirocyclic, fused ring and bridged heterocyclic groups.

[0203] The term "spiro heterocyclyl" refers to a polycyclic heterocyclic group in which the monocyclic rings of 5 to 20 members share one atom (called a spiro atom), wherein one or more of the ring atoms is selected from nitrogen, oxygen or S(O) m (wherein m is an integer 0 to 2) heteroatom, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of shared spiral atoms between rings, the spiral heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group. More preferably, it is a 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral heterocyclic group. Non-limiting examples of spiral heterocyclic groups include:

[0204]

[0205] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

[0206]

[0207] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system, and one or more of the ring atoms is selected from nitrogen, oxygen or S(O)m (wherein m is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0208]

[0209] The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

[0210] wait.

[0211] The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0212] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples of which include:

[0213]

[0214] The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0215] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10 members, containing 1 to 3 heteroatoms; more preferably 5 or 6 members, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidyl, thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0216]

[0217] The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0218] The term "alkoxy" refers to-O-(alkyl) and-O-(unsubstituted cycloalkyl), wherein the definition of alkyl is as described above. The non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0219] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0220] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0221] The term "hydroxy" refers to an -OH group.

[0222] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0223] The term "amino" refers to -NH2.

[0224] The term "cyano" refers to -CN.

[0225] The term "nitro" refers to -NO2.

[0226] The term "oxo" refers to =0.

[0227] The term "carboxy" refers to -C(O)OH.

[0228] The term "thiol" refers to -SH.

[0229] The term "ester group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

[0230] The term "acyl" refers to a compound containing a -C(O)R group, wherein R is alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0231] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0232] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.

[0233] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0234] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention, which are safe and effective when used in mammals and have the desired biological activity.

[0235] Synthesis method of the compound of the present invention

[0236] In order to achieve the purpose of the present invention, the present invention adopts the following synthesis scheme to prepare the compound of the present invention.

[0237] The compound represented by the general formula (IA) of the present invention is synthesized according to the following scheme 1:

[0238]

[0239] Solution 1

[0240] Step 1: In the presence of a catalyst, compound IAa is reacted with compound IAm to obtain compound IAb, wherein the catalyst is preferably triphenylphosphine and DIAD, and the protecting group is preferably Boc and Trt;

[0241] Step 2: In the presence of a catalyst, subjecting compound IAb to a hydrogenation reaction to obtain compound IAc, wherein the catalyst is preferably palladium on carbon;

[0242] Step 3: In the presence of a catalyst, subjecting compound IAc to an intramolecular ring-closure reaction to obtain compound IAd, wherein the catalyst is preferably trimethylaluminum;

[0243] Step 4: Under alkaline conditions, compound IAd is reacted with R 5 I is reacted to obtain compound IAe, wherein the alkaline condition is preferably cesium carbonate;

[0244] Step 5: Under acidic conditions, compound IAe is subjected to a deprotection reaction to obtain compound IAf, wherein the acidic conditions are preferably trifluoroacetic acid;

[0245] Step 6: Under alkaline conditions, diethyl butynedioate is reacted with a hydrazine compound IAg to obtain a compound IAh, wherein the alkaline condition is preferably potassium carbonate;

[0246] Step 7: In the presence of a catalyst, subjecting compound IAh to a Vilsmeier-Hack reaction and chlorination to obtain compound IAi, wherein the catalyst is preferably DMF and phosphorus oxychloride;

[0247] Step 8: Under alkaline conditions, compound IAi is reacted with a wittig reagent to obtain compound IAj, wherein the alkaline conditions are preferably potassium tert-butoxide;

[0248] Step 9: Under acidic conditions, subjecting compound IAj to hydrolysis to obtain compound IAk, wherein the acidic conditions are preferably hydrochloric acid;

[0249] Step 10: Under a catalyst condition, compound IAk and compound IAF are subjected to a reduction amination reaction to obtain compound IA-I, wherein the catalyst is preferably a 2-methylpyridine borane complex;

[0250] Step 11: In the presence of a catalyst, subjecting compound IA-I to an intramolecular ring-closing reaction to obtain a compound of formula (IA), wherein the catalyst is preferably trimethylaluminum;

[0251] Wherein, R is an amino protecting group, X, Y 1 , Y 2 , L, Ring A, R 1 , R 2 , R 3 , R4 , R 5 , R 8 As defined in general formula (IA); preferably, X is -O-, Y 1 , Y 2 is O, and L is -CH2-. DETAILED DESCRIPTION

[0252] The compounds of the present invention and their preparation are further understood by way of examples, which illustrate some methods of preparing or using the compounds. However, it is to be understood that these examples do not limit the present invention. Variations of the present invention now known or further developed are considered to fall within the scope of the invention described herein and claimed.

[0253] The compounds of the present invention are prepared using convenient starting materials and common preparation steps. The present invention provides typical or preferred reaction conditions, such as reaction temperature, time, solvent, pressure, and molar ratio of reactants. However, unless otherwise specified, other reaction conditions can also be adopted. The optimized conditions may change with the use of specific reactants or solvents, but in general, the reaction optimized steps and conditions can be determined.

[0254] In addition, some protecting groups may be used in the present invention to protect certain functional groups from unnecessary reactions. Protecting groups suitable for various functional groups and their protection or deprotection conditions are widely known to those skilled in the art. For example, TW Greene and GM Wuts's "Protective Groups in Organic Preparations" (3rd edition, Wiley, New York, 1999 and references therein) describes in detail the protection or deprotection of a large number of protecting groups.

[0255] The separation and purification of compounds and intermediates can be carried out by appropriate methods and steps according to specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin layer plate chromatography, preparative high performance liquid chromatography or a combination of the above methods. The specific use method can refer to the examples described in the present invention. Of course, other similar separation and purification means can also be adopted. Conventional methods (including physical constants and spectral data) can be used to characterize them.

[0256] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of (ppm) is given. NMR measurements were performed using a Brukerdps 300 nuclear magnetic spectrometer, the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS).

[0257] MS was measured using LC (Waters 2695) / MS (Quattro Premier xE) mass spectrometer (manufacturer: Waters) (Photodiode Array Detector).

[0258] The preparative liquid chromatography method used an LC6000 high performance liquid chromatograph (manufacturer: Chuangxin Tongheng), the chromatographic column was Daisogel C18 10 μm 100A (30 mm×250 mm), and the mobile phase was acetonitrile / water.

[0259] Thin layer chromatography (TLC) used Qingdao Ocean Chemical GF254 silica gel plate. The silica gel plate used in reaction monitoring thin layer chromatography adopted a specification of 0.20 mm to 0.25 mm, and the silica gel plate used in separation and purification thin layer chromatography adopted a specification of 0.5 mm.

[0260] Silica gel column chromatography uses Qingdao marine silica gel 100-200 mesh, 200-300 mesh and 300-400 mesh silica gel as the carrier.

[0261] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from online shopping malls, Beijing Coupling, Sigma, Bailingwei, Yishiming, Shanghai Shuya, Shanghai Inokai, Anaiji Chemical, Shanghai Bid, etc.

[0262] Unless otherwise specified in the examples, all reactions were carried out under a nitrogen atmosphere.

[0263] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

[0264] Reaction solvent, organic solvent or inert solvent are each expressed as the solvent used that does not participate in the reaction under the described reaction conditions, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, dichloromethane, ether, methanol, nitrogen-methylpyrrolidone (NMP), pyridine, etc. Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0265] The chemical reactions described in the present invention are generally carried out under normal pressure. The reaction temperature is between -78°C and 200°C. The reaction time and conditions are, for example, between -78°C and 200°C at one atmosphere, and are completed within about 1 to 24 hours. If the reaction is left overnight, the reaction time is generally 16 hours. In the embodiments, unless otherwise specified, the reaction temperature is room temperature, which is 20°C to 30°C.

[0266] The reaction progress in the examples was monitored by thin layer chromatography (TLC), and the developing solvent systems used in the reaction were: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system, C: acetone, and the volume ratio of the solvent was adjusted according to the polarity of the compound.

[0267] The eluent system of column chromatography and the developing solvent system of thin layer chromatography used for purifying compounds include: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and trifluoroacetic acid can also be added for adjustment.

[0268] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any method and material similar or equivalent to the described content can be applied to the method of the present invention.

[0269] Example

[0270] Example 1: Preparation of (S)-7-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-1,3,9-trimethyl-3,6,7,9-tetrahydro-1H-imidazo[4′,5′:4,5]benzo[1,2-b][1,4]oxazepine-2,8-dione (1)

[0271]

[0272] Step 1: Preparation of 5-methoxy-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (1a)

[0273] At room temperature, 4-methoxybenzene-1,2-diamine (3.00 g, 21.7 mmol) and triethylamine (3.30 g, 32.7 mmol) were added to dichloromethane (30 mL). In an ice bath, triphosgene (6.50 g, 21.9 mmol) was added, the reaction solution was warmed to room temperature and stirred for 6 hours. Water was added to the reaction solution to quench, the pH was adjusted to 8 with saturated sodium carbonate solution, EA was extracted (30 mL x 2), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: CH2Cl2 / MeOH=10:1) to obtain 2 g of the title compound as a yellow solid, with a yield of 56%.

[0274] LC-MS: m / z 165.06 [M+H] + .

[0275] Step 2: Preparation of 5-methoxy-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (1b)

[0276] 5-Methoxy-1,3-dihydro-2H-benzo[d]imidazol-2-one (1a) (2.00 g, 12.2 mmol) was dissolved in DMF (30 mL) at 0°C, and NaH (877 mg, 36.6 mmol, 60%) was added in batches. The mixture was stirred for 20 minutes, and CH3I (15.6 g, 109 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 3 hours. Water was added to the reaction mixture to quench the mixture, and the mixture was extracted with EA (100 mL x 2), washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: EA / PE = 1:100-100:1) to obtain 1.5 g of the title compound as a black solid, yield: 64.1%.

[0277] LC-MS: m / z 193.09 [M+H] + .

[0278] Step 3: Preparation of 5-methoxy-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1c)

[0279] At 0°C, 5-methoxy-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (1b) (1.50 g, 7.81 mmol) was dissolved in acetic acid (7.50 mL), HNO3 (67%, 1.50 mL) was added dropwise, and stirred for 15 minutes. The reaction solution was diluted with water (150 mL), extracted with DCM (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase DCM / MeOH = 100: 1-20: 1) to obtain 1.3 g of the title compound as a yellow solid, yield: 72%.

[0280] LC-MS: m / z 238.07 [M+H] + .

[0281] Step 4: Preparation of 5-hydroxy-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1d)

[0282] At 0°C, 5-methoxy-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1c) (1.3 g, 5.14 mmol) was dissolved in DCM (50 ml), and BBr3 (5.16 g, 20.5 mmol) was added dropwise. The reaction solution was warmed to room temperature and stirred for 1 hour. Water was added to quench the mixture, and the mixture was extracted with DCM (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1.00 g of the title compound as a yellow solid, with a yield of 87.1%.

[0283] LC-MS: m / z 224.06 [M+H] + .

[0284] Step 5: Preparation of O-(1,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-trityl-L-serine methyl ester (1e)

[0285] At room temperature, 5-hydroxy-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1d) (1.00 g, 4.48 mmol) was dissolved in 50 mL of THF, and trityl-L-serine methyl ester (2.43 g, 6.72 mmol) and triphenylphosphine ((Ph)3P) (2.35 g, 8.96 mmol) were added. Under nitrogen atmosphere and in an ice bath, DIAD (1.81 g, 8.96 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 hours. 50 mL of water was added, and the mixture was extracted with DCM (100 mL x 2), washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100:1-1:1) to obtain 2.90 g of the title compound as a yellow oil.

[0286] LC-MS: m / z 566.61 [M+H] + .

[0287] Step 6: Preparation of O-(1,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-L-serine methyl ester (1f)

[0288] Dissolve O-(1,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-trityl-L-serine methyl ester (1e) (2.90 g, 5.11 mmol) in 50 mL of DCM, add a dioxane solution of HCl (4 M, 10 mL), and stir at room temperature for 1 hour. The reaction solution is concentrated under reduced pressure, the residue is slurried with EA / PE=(1:1), filtered, and the filter cake is washed with EA / PE=(1:1) to obtain 1.4 g of the title compound as a light yellow solid.

[0289] LC-MS: m / z 324.29 [M+H] + .

[0290] Step 7: Preparation of N-(tert-butoxycarbonyl)-O-(1,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-L-serine methyl ester (1 g)

[0291] Dissolve O-(1,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-L-serine methyl ester (1f) (1.4 g, 4.36 mmol) in DCM (50 ml), add TEA (1.32 g, 13.1 mmol), and stir until the reaction solution is clear. Add (Boc)2O (1.43 g, 6.55 mmol) under ice bath, and stir at room temperature for 3 hours. Dilute with water (50 mL), extract with DCM (50 x 1), wash with saturated brine (50 mL x 1), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100:1-1:100) to obtain 1 g of the title compound as a yellow solid, yield: 60.2%.

[0292] LC-MS: m / z 424.16 [M+H] + .

[0293] Step 8: Preparation of O-(6-amino-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-(tert-butoxycarbonyl)-L-serine methyl ester (1h)

[0294] Dissolve N-(tert-butoxycarbonyl)-O-(1,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-L-serine methyl ester (1 g) (1.00 g, 2.36 mmol) in 30 mL EA, add Pd-C (260 mg, 0.236 mmol), and stir at room temperature for 2 hours under a hydrogen atmosphere. The reaction solution is filtered, and the filtrate is concentrated under reduced pressure to obtain 650 mg of the title compound as a light yellow solid, with a yield of 92.9%.

[0295] LC-MS: m / z 394.19 [M+H] + .

[0296] Step 9: Preparation of tert-butyl (S)-(1,3-dimethyl-2,8-dioxo-2,3,6,7,8,9-hexahydro-1H-imidazo[4′,5′:4,5]benzo[1,2-b][1,4]oxazepin-7-yl)carbamate (1i)

[0297] Under ice bath, compound 1h (650 mg, 1.52 mmol) was dissolved in 20 mL of chloroform. Under nitrogen atmosphere, Al(CH)3 (2.40 mL, 4.56 mmol) was added dropwise to the reaction solution and reacted at 50°C for 2 hours. DCM (50 mL) was added to dilute, methanol was added to quench, diatomaceous earth was used for suction filtration, and the filtrate was concentrated under reduced pressure to obtain 600 mg of crude product of the title compound as a light yellow solid.

[0298] LC-MS: m / z 362.16 [M+H] + .

[0299] Step 10: Preparation of tert-butyl (S)-(1,3,9-trimethyl-2,8-dioxo-2,3,6,7,8,9-hexahydro-1H-imidazo[4′,5′:4,5]benzo[1,2-b][1,4]oxazepin-7-yl)carbamate (1j)

[0300] Under ice bath, compound 1i (600 mg, 1.66 mmol) was dissolved in 10 mL DMF, CS2CO3 (809 mg, 2.28 mmol) was added, and finally CH3I (235 mg, 1.66 mmol) was added dropwise. The mixture was reacted at room temperature for 2 hours. EA (100 mL × 1) was added for dilution, and the mixture was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100: 1-1100) to obtain 320 mg of the title compound as a light yellow solid, with a yield of 51.2%.

[0301] LC-MS: m / z 376.17 [M+H] + .

[0302] Step 11: Preparation of (S)-7-amino-1,3,9-trimethyl-3,6,7,9-tetrahydro-1H-imidazo[4′,5′:4,5]benzo[1,2-b][1,4]oxazepine-2,8-dione (1k)

[0303] Compound 1j (300 mg, 0.798 mmol) was dissolved in 10 ml of DCM at room temperature, and a solution of HCl in dioxane (4 M, 5 mL) was added dropwise, and stirred at room temperature for 1 hour. Aqueous sodium bicarbonate solution was added for neutralization, and the mixture was extracted with DCM (50 mL × 1), washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 120 mg of the title compound as a yellow solid, with a yield of 55.5%.

[0304] LC-MS: m / z 276.12 [M+H] + .

[0305] Step 12: Preparation of ethyl 1-benzyl-5-hydroxy-1H-pyrazole-3-carboxylate (11)

[0306] At 0°C, diethyl butynedioate (4.4g, 25.6mmol), benzylhydrazine dihydrochloride (5g, 25.6mmol) and anhydrous potassium carbonate (8.8g, 64mmol) were added to 160mL of anhydrous ethanol and heated under reflux with stirring overnight. The reaction solution was cooled to room temperature and the reaction solution was stirred for 5 hours. 6N hydrochloric acid was added to adjust the pH value to 3. 300mL of water and 150mL of ethyl acetate were added, the organic layer was washed with 100mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was slurried with 10mL of acetonitrile and filtered to obtain 2.2g of the title compound as a yellow solid with a yield of 35%.

[0307] LC-MS: m / z 247.10 [M+H] + .

[0308] Step 13: Preparation of ethyl 1-benzyl-5-chloro-4-formyl-1H-pyrazole-3-carboxylate (1m)

[0309] At room temperature, add 1-benzyl-5-hydroxy-1H-pyrazole-3-carboxylic acid ethyl ester (0.5 g, 2.1 mmol) to DMF 0.65 mL, add phosphorus oxychloride (1.6 mL, 16 mmol) dropwise, heat to 90 ° C and stir for 4 hours. Slowly pour the reaction solution into an ice-saturated sodium bicarbonate solution, add 30 mL of ethyl acetate, wash the organic phase with 20 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase: PE / EA=10:1-5:1) to obtain 300 mg of the title compound as a white solid, with a yield of 48.9%.

[0310] LC-MS: m / z 293.06 [M+H] + .

[0311] Step 14: Preparation of ethyl 1-benzyl-5-chloro-4-(2-methoxyvinyl)-1H-pyrazole-3-carboxylate (1n)

[0312] At room temperature, (methoxymethyl)triphenylium chloride (1.6 g, 4.8 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran. At 0°C, a solution of potassium tert-butoxide (0.5 g, 4.4 mmol) dissolved in 10 mL of anhydrous tetrahydrofuran was added dropwise. After stirring for 10 minutes, a solution of 1-benzyl-5-chloro-4-formyl-1H-pyrazole-3-carboxylic acid ethyl ester (0.3 g, 1.1 mmol) in 10 mL of anhydrous tetrahydrofuran was added dropwise. After continuing to stir for 30 minutes, the mixture was warmed to room temperature and stirred overnight. 60 mL of water and 40 mL of ethyl acetate were added to the reaction solution. The organic phase was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA=5:1-2:1) to obtain 200 mg of the title compound as a yellow solid with a yield of 56.8%.

[0313] LC-MS: m / z 321.09 [M+H] + .

[0314] Step 15: Preparation of ethyl 1-benzyl-5-chloro-4-(2-oxoethyl)-1H-pyrazole-3-carboxylate (1o)

[0315] At room temperature, 1-benzyl-5-chloro-4-(2-methoxyvinyl)-1H-pyrazole-3-carboxylic acid ethyl ester (0.2 g, 0.63 mmol) was dissolved in 10 mL of THF, 2 mL of 6N hydrochloric acid was added, the temperature was raised to 60°C, and stirred for 30 minutes. The reaction solution was poured into 20 mL of saturated sodium bicarbonate solution, 30 mL of ethyl acetate was added, the organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 190 mg of the title compound as a colorless oil, with a yield of 98.6%.

[0316] LC-MS: m / z 307.08 [M+H] + .

[0317] Step 16: Preparation of (S)-1-benzyl-5-chloro-4-(2-((1,3,9-trimethyl-2,8-dioxo-2,3,6,7,8,9-hexahydro-1H-imidazo[4′,5′:4,5]benzo[1,2-b][1,4]oxazepin-7-yl)amino)ethyl)-1H-pyrazole-3-carboxylic acid ethyl ester (1p)

[0318] At room temperature, compound 1k (100 mg, 0.362 mmol) was dissolved in 5 mL of methanol, compound 1o (134 mg, 0.434 mmol) was added, acetic acid (0.5 mL) was added, and finally methyl borane (58.8 mg, 0.543 mmol) was added, and the mixture was reacted at room temperature for 1 hour. EA (50 mL × 1) was added for dilution, and the mixture was washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100: 1-1: 100) to obtain 30 mg of the title compound as a light yellow solid, with a yield of 15.0%.

[0319] LC-MS: m / z 566.20 [M+H] + .

[0320] Step 17: Preparation of (S)-7-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-1,3,9-trimethyl-3,6,7,9-tetrahydro-1H-imidazo[4′,5′:4,5]benzo[1,2-b][1,4]oxazepine-2,8-dione (1)

[0321] Under ice bath, compound 1p (30.0 mg, 0.035 mmol) was dissolved in 1 mL of chloroform. Under nitrogen atmosphere, Al(CH3)3 (0.06 mL, 0.105 mmol) was added dropwise to the reaction solution and reacted at 50°C for 2 hours. DCM (10 mL) was added to dilute, methanol was added to quench, diatomaceous earth was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by high pressure preparative liquid chromatography (chromatographic column model: XBRIDGE 3.5um 2.1×50mm, mobile phase: acetonitrile / water (0.05% formic acid), gradient: 10%-100%) to obtain 9.30 mg of the title compound as a white solid, yield: 50.2%.

[0322] LC-MS: m / z 521.16 [M+H] + .

[0323] 1 H NMR (400MHz, DMSO-d6) δ7.44-7.32 (m, 3H), 7.31-7.22 (m, 2H), 6.82 (s, 2H), 5.91-5.85 (m, 1H), 5.49-5.48 (s, 2H), 4.71-4.6 2 (m, 1H), 4.49-4.48 (m, 1H), 4.47-4.46 (m, 1H), 3.65-3.55 (m, 1H), 3.49-3.35 (m, 9H), 3.15-3.10 (m, 1H), 2.73-2.64 (m, 1H).

[0324] Example 2: Preparation of (S)-7-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-9-methyl-6,7-dihydro-[1,3]dioxol[4′5′:4,5]benzo[1,2-b][1,4]oxazepin-8(9H)-one (2)

[0325]

[0326] Step 1: Preparation of benzo[d][1,3]dioxin-5-yl acetate (2a)

[0327] Under nitrogen atmosphere, sesamol (4.00 g, 29.0 mmol) was dissolved in 50 mL of DCM. DIPEA (12.0 mL, 87.0 mmol) was added in an ice bath, and acetyl chloride (3.00 mL, 43.5 mmol) dissolved in 10 mL of DCM was added dropwise with stirring, and the mixture was warmed to room temperature and stirred for 2 h. 100 mL of water was added, and the organic layer was washed with saturated brine, dried, and the solvent was removed under reduced pressure to obtain 4 g of the title compound as a dark yellow oil with a yield of 76.7%.

[0328] LC-MS: m / z 181.04 [M+H] + .

[0329] Step 2: Preparation of 6-nitrobenzo[d][1,3]dioxin-5-yl acetate (2b)

[0330] In an ice bath, add benzo[d][1,3]dioxin-5-yl acetate (4.00 g, 24.0 mmol) to 40 mL of acetic acid, stir for 10 minutes, then slowly add nitric acid (2.80 g, 26.0 mmol) dropwise. After stirring at room temperature for 3 hours, pour the reaction solution into crushed ice, let stand for 30 minutes, filter, wash the filter cake twice, and dry to obtain 4.2 g of the title compound as a yellow solid, with a yield of 83.9%.

[0331] LC-MS: m / z 226.03 [M+H] + .

[0332] Step 3: Preparation of 6-nitrobenzo[d][1,3]dioxin-5-ol (2c)

[0333] In an ice bath, add 6-nitrobenz[d][1,3]dioxin-5-yl acetate (4.20 g, 18.7 mmol) to 40 mL of 20% sulfuric acid aqueous solution, stir for 10 minutes, then heat to 80°C and stir for 3 hours. Pour the reaction solution into crushed ice, let stand for 30 minutes, then filter, wash the filter cake twice with water, and dry to obtain 3.1 g of the title compound as a yellow solid, with a yield of 90.7%.

[0334] LC-MS: m / z 184.02 [M+H] + .

[0335] The remaining steps are the same as the preparation method of Example 1, except that 6-nitrobenzo[d][1,3]dioxin-5-ol (2c) is used instead of 5-hydroxy-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1d) in step 5 to obtain the title compound 2.

[0336] LC-MS: m / z 481.12 [M+H] + .

[0337] 1 H NMR (300MHz, DMSO-d6) δ8.23-8.01(m, 1H), 7.35-7.14(m, 6H), 5.96(s, 2H), 5.27(s, 2H), 4.50-4.34(m, 3H), 3.35-3.32(m, 2H), 3.21(s, 3H), 2.76-2.74(m, 1H), 2.73-2.68(m, 1H).

[0338] Example 3: Preparation of (S)-7-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-2,5-dimethyl-7,8-dihydrothiazolo[4′,5′:4,5]benzo[1,2-b][1,4]oxazepin-6(5H)-one (3)

[0339]

[0340] Step 1: Preparation of 2-bromo-4-methoxy-5-nitroaniline (3a)

[0341] At 0°C, add 2-bromo-4-methoxyaniline (5.00 g, 24.9 mmol) to concentrated sulfuric acid (25 mL), and add sodium nitrate (3.70 g, 27.3 mmol) in batches. Stir at 10°C for 10 minutes. Adjust the pH value to 9-10 with 20% sodium hydroxide solution, extract with EA, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase: PE / EA=10:1) to obtain 1.5 g of the title compound as a yellow solid, with a yield of 24.5%.

[0342] LC-MS: m / z 246.96 [M+H] + .

[0343] Step 2: Preparation of N-(2-bromo-4-methoxy-5-nitrophenyl)acetamide (3b)

[0344] Acetyl chloride (476 mg, 6.70 mmol) was added to 2-bromo-4-methoxy-5-nitroaniline (1.00 g, 4.07 mmol) and triethylamine (739 mg, 7.32 mmol) in DCM (20 mL) at 0°C. The mixture was heated to room temperature and stirred overnight. DCM was added to dilute the mixture, and the mixture was washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1.3 g of the title compound as a yellow solid, which was used directly in the next step.

[0345] LC-MS: m / z 288.97 [M+H] + .

[0346] Step 3: Preparation of 6-methoxy-2-methyl-5-nitrobenzo[d]thiazole (3c)

[0347] At room temperature, N-(2-bromo-4-methoxy-5-nitrophenyl)acetamide (1.30 g, 4.51 mmol), potassium sulfide (1.49 g, 13.5 mmol) and CuI (85.8 mg, 0.451 mmol) were dissolved in DMF (25 ml), and the reaction solution was heated to 90°C and stirred for 1 hour. The reaction solution was quenched by adding 1N HCl, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA=3:1) to obtain 800 mg of the title compound as a yellow solid, with a two-step yield of 87.9%.

[0348] LC-MS: m / z 225.03 [M+H] + .

[0349] Step 4: Preparation of 6-hydroxy-2-methyl-5-nitrobenzo[d]thiazole (3d)

[0350] At 0°C, a 1N dichloromethane solution of boron tribromide was slowly added dropwise to a DCM (10ml) solution of 6-methoxy-2-methyl-5-nitrobenzo[d]thiazole (1.2g, 5.36mmol), and the mixture was stirred at room temperature for 3h. The mixture was quenched with a saturated sodium bicarbonate solution, extracted with DCM (2 x 20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA=4:1) to obtain 650mg of the title compound as a light yellow solid oil, with a yield of 57.8%.

[0351] LC-MS: m / z 211.01 [M+H] + .

[0352] The remaining steps were the same as the preparation method of Example 1, except that 6-hydroxy-2-methyl-5-nitrobenzo[d]thiazole (3d) was used instead of 5-hydroxy-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1d) in step 5 to obtain the title compound 3.

[0353] LC-MS: m / z 508.11 [M+H] + .

[0354] 1 H NMR (400MHz, DMSO-d6) δ7.91 (s, 1H), 7.79 (s, 1H), 7.32-7.22 (m, 5H), 5.77-5.72 (m, 1H), 5.41 (s, 2H), 4.88-4.82 (m, 1H ), 4.42(t, 1H), 4.18-4.11(m, 1H), 3.66-3.63(m, 1H), 3.47(s, 3H), 2.95-2.91(m, 1H), 2.84(s, 3H), 2.77-2.68(m, 1H).

[0355] Example 4: Preparation of (S)-7-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4c]pyridin-6-yl)-5-methyl-2-morpholinyl-7,8-dihydrooxazolo[5′,4′:4,5]benzo[1,2-b][1,4]oxazepin-6(5H)-one (4)

[0356]

[0357] Step 1: Preparation of 5-methoxybenzo[d]oxazole-2-thiol (4a)

[0358] At room temperature, 2-amino-4-methoxyphenol (2.00 g, 14.4 mmol) was dissolved in 25 ml of ethanol, and carbon disulfide (3.28 g, 43.2 mmol) and potassium hydroxide (967 mg, 17.3 mmol) were added. The mixture was sealed and stirred at 90°C overnight. The pH was adjusted to weak acidity with 1 mol / L hydrochloric acid, extracted with EA (20 mL x 3), washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 2.30 g of the title compound as a purple-red solid, with a yield of 88.4%.

[0359] LC-MS: m / z 182.02 [M+H] + .

[0360] Step 2: Preparation of 5-methoxy-2-morpholinobenzo[d]oxazole (4b)

[0361] At room temperature, 5-methoxybenzo[d]oxazole-2-thiol (2.20 g, 12.2 mmol) was dissolved in 20 ml of morpholine and stirred at 100°C for 2 hours. 30 mL of water was added, extracted with EA (20 mL x 3), washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100: 1-3: 1) to obtain 1.84 g of the title compound as a reddish brown solid, yield: 77.6%.

[0362] LC-MS: m / z 235.10 [M+H] + .

[0363] Step 3: Preparation of 5-methoxy-2-morpholinyl-6-nitrobenzo[d]oxazole (4c)

[0364] At room temperature, 5-methoxy-2-morpholinylbenzo[d]oxazole (1.74 g, 7.44 mmol) was dissolved in 15 ml of glacial acetic acid. At 0°C, concentrated nitric acid (5 mL) was added and stirred at 0°C for 1 hour. The reaction solution was poured into ice water, filtered, extracted with EA (20 mL x 3), washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1.65 g of the title compound as a yellow solid, with a yield of 80.8%.

[0365] LC-MS: m / z 280.09 [M+H] + .

[0366] Step 4: Preparation of 2-morpholino-6-nitrobenzo[d]oxazol-5-ol (4d)

[0367] 5-Methoxy-2-morpholinyl-6-nitrobenzo[d]oxazole (1.56 g, 5.59 mmol) was dissolved in 20 mL of DCM, and BBr3 (1 mol / L) (11.2 mL) was added at 0°C under a nitrogen atmosphere, and stirred at 0°C for 2.5 h. Methanol was added to quench the mixture, and the mixture was extracted with DCM (20 mL x 3), washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1.53 g (crude) of the title compound as a yellow solid.

[0368] LC-MS: m / z 266.07 [M+H] + .

[0369] The remaining steps were the same as the preparation method of Example 1, except that 2-morpholinyl-6-nitrobenzo[d]oxazol-5-ol (4d) was used instead of 5-hydroxy-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1d) in step 5 to obtain the title compound 4.

[0370] LC-MS: m / z 563.17 [M+H] + .

[0371] 1 H NMR (400MHz, DMSO-d6) δ7.69 (s, 1H), 7.40-7.26 (m, 3H), 7.23-7.16 (m, 3H), 5.57 (dd, 1H), 5.43 (s, 2H), 4.78 (dd, 1H), 4.30 (dd, 1H), 4.04 (dt, 1H), 3.80-3.70 (m, 4H), 3.65-3.55 (m, 5H), 3.33 (s, 3H), 2.88-2.75 (m, 1H), 2.74-2.63 (m, 1H).

[0372] Example 5: Preparation of (S)-7-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-1,3-diisopropyl-9-methyl-3,6,7,9-tetrahydro-1H-imidazo[4′,5′:4,5]benzo[1,2-b][1,4]oxazepine-2,8-dione (5)

[0373]

[0374] The title compound 5 was prepared in the same manner as in Example 1, except that isopropyl iodide was used instead of methyl iodide in step 2.

[0375] LC-MS: m / z 577.10 [M+H] + .

[0376] 1 H NMR (400MHz, CDCl3) δ7.44 (s, 1H), 7.38-7.27 (m, 3H), 7.23 (s, 1H), 7.21-7.16 (m, 2H), 5.62-5.54 (m, 1H), 5.43 (s, 2H), 4.78 (t, 1H), 4.67-4. 53(m, 2H), 4.38-4.25(m, 1H), 4.10-4.00(m, 1H), 3.70-3.60(m, 1H), 3 .37(s, 3H), 2.87-2.75(m, 1H), 2.73-2.64(m, 1H), 1.52-1.38(m, 12H).

[0377] Example 6: Preparation of (S)-8-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-2,10-dimethyl-7,8-dihydrothiazolo[5′,4′:3,4]benzo[1,2-b][1,4]oxazepin-9(10H)-one (6)

[0378]

[0379] Step 1: Preparation of 2-methyl-6-hydroxy-7-nitrobenzothiazole (6a)

[0380] At 0°C, add 2-methyl-6-hydroxybenzothiazole (5.00 g, 30 mmol) to 30 mL of concentrated sulfuric acid. After stirring for 10 minutes, add sodium nitrate (2.45 g, 30 mmol). Warm the mixture to room temperature and continue stirring for 3 hours. Pour the reaction solution into crushed ice, let stand, filter, rinse the filter cake with water, and dry to obtain 4.20 g of the title compound as a yellow solid, with a yield of 66.7%.

[0381] LC-MS: m / z 211.34 [M+H] + .

[0382] Step 2: Preparation of N-(tert-butoxycarbonyl)-O-(2-methyl-7-nitrobenzo[d]thiazol-6-yl)-L-serine methyl ester (6b)

[0383] At room temperature, triphenylphosphine (6.30 g, 24 mmol) was dissolved in 30 mL THF. At 0°C, under a nitrogen atmosphere, DIAD (4.85 g, 24 mmol) was added dropwise thereto. After stirring for 10 minutes, L-Boc-serine methyl ester (4.38 g, 20 mmol) was added. After stirring for 10 minutes, 2-methyl-6-hydroxy-7-nitrobenzothiazole (4.20 g, 20 mmol) was added. The mixture was warmed to room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: DCM / MeOH=150:1-100:1) to obtain 1.40 g of the title compound as a light yellow solid, yield: 17.1%.

[0384] LC-MS: m / z 412.31 [M+H] + .

[0385] The remaining steps were the same as the preparation method of Example 1, except that N-(tert-butoxycarbonyl)-O-(2-methyl-7-nitrobenzo[d]thiazol-6-yl)-L-serine methyl ester (6b) was used instead of N-(tert-butoxycarbonyl)-O-(1,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-L-serine methyl ester (1g) in step 8 to obtain the title compound 6.

[0386] LC-MS: m / z 508.11 [M+H] + .

[0387] 1 HNMR (300MHz, DMSO-d6) δ7.39-7.13(m, 7H), 5.33(s, 2H), 4.82-4.72(m, 2H), 4.62-4.60(m , 1H), 3.32(s, 3H), 2.83(s, 3H), 3.78-3.55(m, 2H), 2.82-2.80(m, 1H), 2.78-2.75(m, 1H).

[0388] Example 7: Preparation of (S)-7-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-2-cyclopropyl-5-methyl-7,8-dihydrooxazolo[4′,5′:4,5]benzo[1,2-b][1,4]oxazepin-6(5H)-one (7)

[0389]

[0390]

[0391] Step 1: Preparation of N-(2-bromo-4-methoxyphenyl)cyclopropanecarboxamide (7a)

[0392] At room temperature, 2-bromo-4-methoxyaniline (5.00 g, 25.0 mmol) was dissolved in 100 ml of DCM, and DIEA (9.60 g, 75.0 mmol) was added. Under nitrogen atmosphere, cyclopropylacyl chloride (3.10 g, 29.8 mmol) was added to the reaction solution at 0°C and stirred at room temperature for 2 hours. Water was added to quench, extracted with DCM (200 mL x 3), washed with saturated brine (200 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 4:1) to obtain 6.50 g of the title compound as a colorless transparent liquid, with a yield of 96.8%.

[0393] LC-MS: m / z 270 [M+H] + .

[0394] Step 2: Preparation of 2-cyclopropyl-6-methoxybenzo[d]oxazole (7b)

[0395] N-(2-bromo-4-methoxyphenyl)cyclopropanecarboxamide (7a) (5.00 g, 1.86 mmol) was dissolved in DMF (100 mL), and Cs2CO3 (12.1 g, 37.2 mmol), CuI (180 mg, 0.930 mmol), and dipyridine (290 mg, 1.86 mmol) were added. The mixture was reacted at 120°C overnight under a nitrogen atmosphere. Water was added to quench the mixture, and the mixture was extracted with EA (100 mL x 3), washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 2.71 g of the title compound as a light yellow solid with a yield of 77.1%.

[0396] LC-MS: m / z 190 [M+H] + .

[0397] Step 3: Preparation of 2-cyclopropyl-6-methoxy-5-nitrobenzo[d]oxazole (7c)

[0398] 2-Cyclopropyl-6-methoxybenzo[d]oxazole (7b) (2.50 g, 13.2 mmol) was dissolved in TFA (24 ml). Concentrated nitric acid (8 mL) was added dropwise to the reaction solution at 0°C under nitrogen atmosphere. The mixture was stirred at 0°C for 2 hours and stirred at room temperature overnight. Water was added to quench the mixture at 0°C, and the mixture was extracted with EA (50 mL x 3), washed with saturated brine (80 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 1.5 g of the title compound as a light yellow solid with a yield of 49.6%.

[0399] LC-MS: m / z 234 [M+H] + .

[0400] Step 4: Preparation of 2-cyclopropyl-5-nitrobenzo[d]oxazol-6-ol (7d)

[0401] 2-Cyclopropyl-6-methoxy-5-nitrobenzo[d]oxazole (7c) (3.20 g, 13.6 mmol) was dissolved in DCM (50 ml). BBr3 (27.2 mL, 1 M) was added dropwise to the reaction solution at 0°C under nitrogen atmosphere, and stirred at 0°C for 2 hours. Methanol was added to quench at 0°C, extracted with DCM (60 mL x 3), washed with saturated brine (80 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 1.8 g of the title compound as a light yellow solid with a yield of 60.0%.

[0402] LC-MS: m / z 220 [M+H] + .

[0403] Step 5: Preparation of O-(2-cyclopropyl-5-nitrobenzo[d]oxazol-6-yl)-N-trityl-L-serine methyl ester (7e)

[0404] At room temperature, 2-cyclopropyl-5-nitrobenzo[d]oxazol-6-ol (7d) (2.30 g, 10.4 mmol) and methyl trityl-L-serine (5.66 g, 15.7 mmol) were dissolved in 50 mL THF. Under nitrogen atmosphere, PPh3 (5.47 g, 20.9 mmol) and DIAD (diisopropyl azodicarboxylate) (4.20 g, 20.9 mmol) were added to the reaction solution, and stirred at room temperature overnight. Water was added to quench the reaction, and the mixture was extracted with EA (50 mL x 3), washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 1:1) to obtain 8.2 g (crude) of the title compound as a yellow semi-solid.

[0405] LC-MS: m / z 564 [M+H] + .

[0406] Step 6: Preparation of O-(2-cyclopropyl-5-nitrobenzo[d]oxazol-6-yl)-L-serine methyl ester (7f) At room temperature, O-(2-cyclopropyl-5-nitrobenzo[d]oxazol-6-yl)-N-trityl-L-serine methyl ester (7e) (7.50 g, 13.3 mmol) was dissolved in 100 mL DCM, and a hydrochloric acid solution of dioxane (13.3 ml, 4 M) was added, and stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, slurried with PE:EA=5:1 (50 mL x 1), filtered, and the filter cake was collected to obtain 4.84 g of the title compound as a light yellow solid, with a yield of 75.4%.

[0407] LC-MS: m / z 464 [M+H] + .

[0408] Step 7: Preparation of N-(tert-butoxycarbonyl)-O-(2-cyclopropyl-5-nitrobenzo[d]oxazol-6-yl)-L-serine methyl ester (7 g)

[0409] At room temperature, O-(2-cyclopropyl-5-nitrobenzo[d]oxazol-6-yl)-L-serine methyl ester (7f) (4.50 g, 13.9 mmol) was dissolved in DCM (60 ml), DIEA (5.38 g, 41.7 mmol) and Boc2O (4.52 g, 20.9 mmol) were added to the reaction solution, and stirred at room temperature overnight. The mixture was diluted with water, extracted with DCM (50 mL x 3), washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 2:1) to obtain 3.6 g of the title compound as a yellow oil, with a yield of 58.6%.

[0410] LC-MS: m / z 492.4 [M+H] + .

[0411] Step 8: Preparation of O-(5-amino-2-cyclopropylbenzo[d]oxazol-6-yl)-N-(tert-butyloxycarbonyl)-L-serine methyl ester (7h)

[0412] At room temperature, N-(tert-butoxycarbonyl)-O-(2-cyclopropyl-5-nitrobenzo[d]oxazol-6-yl)-L-serine methyl ester (7 g) (3.50 g, 8.31 mmol) was dissolved in 30 mL of methanol, and aqueous Pd / C (1 g) was added to the reaction solution. The mixture was stirred overnight at room temperature under a hydrogen atmosphere. The mixture was filtered through celite, the filter cake was washed with MeOH, and the filtrate was concentrated under reduced pressure to obtain 3.2 g (crude) of the title compound as a yellow oil.

[0413] LC-MS: m / z 462.4 [M+H] + .

[0414] Step 9: Preparation of O-(5-amino-2-cyclopropylbenzo[d]oxazol-6-yl)-N-(tert-butyloxycarbonyl)-L-serine (7i)

[0415] Dissolve O-(5-amino-2-cyclopropylbenzo[d]oxazol-6-yl)-N-(tert-butoxycarbonyl)-L-serine methyl ester (7h) (3.20 g, 8.18 mmol) in THF (30 ml), add lithium hydroxide (282 mg, 12.3 mmol) and water (5 mL), stir at room temperature for 30 minutes, and concentrate under reduced pressure to obtain 3.4 g (crude) of the title compound as a black oil.

[0416] LC-MS: m / z 378 [M+H] + .

[0417] Step 10: Preparation of tert-butyl (S)-(2-cyclopropyl-6-oxo-5,6,7,8-tetrahydrooxazolo[4′,5′:4,5]benzo[1,2-b][1,4]oxazepin-7-yl)carbamate (7j)

[0418] O-(5-amino-2-cyclopropylbenzo[d]oxazol-6-yl)-N-(tert-butyloxycarbonyl)-L-serine (7i) (3.20 g, 8.48 mmol) was dissolved in 50 mL of DMF, DIEA (1.64 g, 12.8 mmol) and HATU (4.54 g, 12.8 mmol) were added, and the mixture was stirred at room temperature for 1 hour. 20 mL of water was added, EA was extracted (20 mL x 3), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100:1-1:1) to obtain 710 mg of the title compound as a light yellow solid, yield: 23.3%.

[0419] LC-MS: m / z 360 [M+H] + .

[0420] Step 11: Preparation of tert-butyl (S)-(2-cyclopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydrooxazolo[4′,5′:4,5]benzo[1,2-b][1,4]oxazepin-7-yl)carbamate (7k)

[0421] Dissolve (S)-(2-cyclopropyl-6-oxo-5,6,7,8-tetrahydrooxazolo[4′,5′:4,5]benzo[1,2-b][1,4]oxazepin-7-yl)carbamic acid tert-butyl ester (7j) (500 mg, 1.39 mmol) in DMF (10 ml), add Cs2CO3 (680 mg, 2.09 mmol) and iodomethane (197 mg, 1.39 mmol), and stir at room temperature for 2 hours. Dilute with water, extract with EA (15 mL x 3), wash with saturated brine (20 mL x 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 480 mg of the title compound as a yellow oil, with a yield of 92.6%.

[0422] LC-MS: m / z 374 [M+H] + .

[0423] Step 12: Preparation of (S)-7-amino-2-cyclopropyl-5-methyl-7,8-dihydrooxazolo[4′,5′:4,5]benzo[1,2-b][1,4]oxazepin-6(5H)-one (71)

[0424] At room temperature, tert-butyl (S)-(2-cyclopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydrooxazolo[4′,5′:4,5]benzo[1,2-b][1,4]oxazepin-7-yl)carbamate (7k) (200 mg, 0.536 mmol) was dissolved in 2 mL of DCM, and a hydrochloric acid dioxane solution (0.4 ml, 4 M) was added to the reaction solution, and stirred at room temperature for 2 hours. 10 mL of saturated NaHCO3 solution was added, and the mixture was extracted with DCM (10 mL x 3), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 140 mg of the title compound as a yellow oil (crude product).

[0425] LC-MS: m / z 274 [M+H] + .

[0426] The remaining steps are the same as the preparation method of Example 1, except that (S)-7-amino-2-cyclopropyl-5-methyl-7,8-dihydrooxazolo[4′,5′:4,5]benzo[1,2-b][1,4]oxazepine-6(5H)-one (7l) is used instead of (S)-7-amino-1,3,9-trimethyl-3,6,7,9-tetrahydro-1H-imidazo[4′,5′:4,5]benzo[1,2-b][1,4]oxazepine-2,8-dione (1k) in step 11 to obtain the title compound 7.

[0427] LC-MS: m / z 518.00 [M+H] + .

[0428] 1 H NMR (400MHz, DMSO-d6) δ7.80 (s, 1H), 7.60 (s, 1H), 7.39-7.25 (m, 3H), 7.22-7.15 (m, 2H), 5.55 (dd, J =12.0, 8.0Hz, 1H), 5.42 (s, 2H), 4.83 (dd, J = 12.0, 10.1Hz, 1H), 4.33 (dd, J = 10.0, 8.0Hz, 1H), 4.04 ( ddd, J=12.3, 7.0, 5.1Hz, 1H), 3.63 (ddd, J=12.9, 8.6, 4.8Hz, 1H), 3.38 (s, 3H), 2.80 (ddd, J=15.4, 8 .6, 5.1Hz, 1H), 2.68 (ddd, J=15.5, 6.9, 4.8Hz, 1H), 2.29 (tt, J=8.2, 4.9Hz, 1H), 1.26-1.10 (m, 4H).

[0429] Example 8: Preparation of (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-1,8-dimethyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepin-3,2-e]indazol-2-one (8)

[0430]

[0431] Step 1: Preparation of 7-nitro-1H-indazol-6-ol (8a)

[0432] At room temperature, 1H-indazol-6-ol (3.00 g, 22.4 mmol) was dissolved in 30 ml of concentrated sulfuric acid, sodium nitrate (2.10 g, 24.7 mmol) was added at 0°C, and stirred at room temperature for 2 hours. The reaction solution was poured into ice water, filtered, and the filter cake was washed with water (10 mL x 3) and dried to obtain 4.45 g (crude) of the title compound as a yellow solid.

[0433] LC-MS: m / z 180.0 [M+H] + .

[0434] Step 2: Preparation of N-(tert-butoxycarbonyl)-O-(7-nitro-1H-indazol-6-yl)-D-serine methyl ester (8b)

[0435] 7-Nitro-1H-indazol-6-ol (8a) (3.90 g, 19.6 mmol), (tert-butoxycarbonyl)-D-serine methyl ester (5.89 g, 26.9 mmol) and triphenylphosphine (11.7, 44.8 mmol) were dissolved in 200 mL of THF. DIAD (9.05 g, 44.8 mmol) was added at 0°C under a nitrogen atmosphere and stirred at room temperature overnight. 100 mL of water was added to quench the mixture, and the mixture was extracted with DCM (200 mL x 3), washed with saturated brine (200 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100:1-1:1) to obtain 9.46 g of the title compound as a yellow solid (crude product).

[0436] LC-MS: m / z 381.13 [M+H] + .

[0437] Step 3: Preparation of O-(7-amino-1H-indazol-6-yl)-N-(tert-butoxycarbonyl)-D-serine methyl ester (8c)

[0438] Dissolve N-(tert-butoxycarbonyl)-O-(7-nitro-1H-indazol-6-yl)-D-serine methyl ester (8b) (8.95 g, 23.6 mmol) in 80 mL MeOH, add aqueous palladium carbon (2.00 g), and stir overnight at room temperature under a hydrogen atmosphere. Filter, wash the filter cake with methanol (10 mL x 3), and concentrate the filtrate under reduced pressure to obtain 8.11 g of the title compound as a reddish brown solid, with a yield of 98.4%.

[0439] LC-MS: m / z 351.16 [M+H] + .

[0440] Step 4: Preparation of (S)-tert-butyl (9-oxo-7,8,9,10-tetrahydro-1H-[1,4]oxazepino[2,3-g]indazol-8-yl)carbamate (8d)

[0441] O-(7-amino-1H-indazol-6-yl)-N-(tert-butoxycarbonyl)-D-serine methyl ester (8c) (4.05 g, 11.6 mmol) was dissolved in 50 ml CHCl3. Under nitrogen atmosphere, 5 mL of trimethylaluminum solution (2 mol / L) was added to the reaction solution at 0°C and stirred overnight at 50°C. Methanol was added to quench the reaction, and the mixture was filtered. The filter cake was washed with DCM (10 mL x 3), and the filtrate was concentrated under reduced pressure to obtain 4.71 g (crude) of the title compound as a yellow solid.

[0442] LC-MS: m / z 319.13 [M+H] + .

[0443] Step 5: Preparation of tert-butyl (S)-(1,10-dimethyl-9-oxo-7,8,9,10-tetrahydro-1H-[1,4]oxazepino[2,3-g]indazol-8-yl)carbamate (8e)

[0444] Dissolve (S)-tert-butyl (9-oxo-7,8,9,10-tetrahydro-1H-[1,4]oxazepino[2,3-g]indazol-8-yl)carbamate (8d) (1.41 g, 4.44 mmol) in 60 mL of DMF, add cesium carbonate (2.89 g, 8.88 mmol), add iodomethane (1.26 g, 8.88 mmol) at 0°C, and stir at 0°C for 2 hours. Add 100 mL of water, extract with EA (100 mL x 3), wash with saturated brine (100 mL x 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 3.23 g (crude) of the title compound as a light yellow oil.

[0445] LC-MS: m / z 347.16 [M+H] + .

[0446] The remaining steps were the same as the preparation method of Example 1, except that (S)-(1,10-dimethyl-9-oxo-7,8,9,10-tetrahydro-1H-[1,4]oxazepin[2,3-g]indazol-8-yl)carbamic acid tert-butyl ester (8e) was used instead of (S)-(1,3,9-trimethyl-2,8-dioxo-2,3,6,7,8,9-hexahydro-1H-imidazo[4′,5′:4,5]benzo[1,2-b][1,4]oxazepin-7-yl)carbamic acid tert-butyl ester (1j) in step 10 to obtain the title compound 8.

[0447] LC-MS: m / z 491.15 [M+H] + .

[0448] 1H NMR (400MHz, DMSO-d6) δ: 8.49 (s, 1H), 7.70 (d, 1H), 7.39-7.26 (m, 3H), 7.19 (d, 2H), 6.96 (d, J=8.8Hz, 1H), 5.59 (dd, 1H), 5.42 (s, 2H) ), 4.91 (t, 1H), 4.43 (t, 1H), 4.20 (s, 3H), 4.14-4.00 (m, 1H), 3.74-3.58 (m, 1H), 3.47 (s, 3H), 2.90-2.76 (m, 1H), 2.75-2.64 (m, 1H).

[0449] Example 9: Preparation of (7S)-7-(2-benzyl-3-chloro)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-9-methyl-8-oxo-6,7,8,9-tetrahydro-[1,3]dioxol[4′,5′:4,5]benzo[1,2-b][1,4]oxazepine-2-carboxylic acid ethyl ester (9)

[0450]

[0451] Step 1: Preparation of 4,5-dimethoxy-2-nitrophenol (9a)

[0452] At room temperature, 4,5-dimethoxy-2-nitrobenzaldehyde (5.00 g, 23.7 mmol) was dissolved in 100 mL DCM, and m-CPBA (10.9 g, 63.4 mmol) was added at 0°C. Under nitrogen atmosphere, TFA (1.76 mL) was added at 0°C and stirred at room temperature overnight. At 0°C, saturated sodium thiosulfate solution was added to quench, filtered, and the filter cake was washed with DCM. The organic phase was washed with saturated sodium bicarbonate solution (100 mL x 1), saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in 70 mL methanol, 2 mol / L NaOH solution (30 mL) was added, and stirred at room temperature for 1 hour. 1 mol / L hydrochloric acid was used to adjust the pH to 3-4, filtered, and the filter cake was washed with methanol. The filter cake was collected and dried to obtain 3.25 g of the title compound as a yellow solid, with a yield of 69.0%.

[0453] LC-MS: m / z 200.0 [M+H] + .

[0454] Step 2: Preparation of O-(4,5-dimethoxy-2-nitrophenyl)-N-trityl-L-serine methyl ester (9b)

[0455] At room temperature, 4,5-dimethoxy-2-nitrophenol (9a) (3.25 g, 12.3 mmol), methyltrityl-L-serine (6.64 g, 18.4 mmol) and triphenylphosphine (6.45 g, 24.5 mmol) were dissolved in 150 mL of THF. Under nitrogen atmosphere, DIAD (4.95 g, 24.5 mmol) was added at 0°C and stirred overnight at room temperature. 100 mL of water was added to quench the mixture, and the mixture was extracted with EA (100 mL x 3), washed with saturated brine (150 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100:1-2:1) to obtain 13.2 g of the title compound as a yellow oil (crude product).

[0456] Step 3: Preparation of O-(4,5-dimethoxy-2-nitrophenyl)-L-serine methyl ester (9c)

[0457] Dissolve O-(4,5-dimethoxy-2-nitrophenyl)-N-trityl-L-serine methyl ester (9b) (13.2 g, 21.7 mmol) in 100 ml of DCM, add 4 mol / L hydrochloric acid dioxane solution (20 mL), stir at room temperature overnight, concentrate under reduced pressure, beat three times (EA / PE=3:1), filter, and dry the filter cake to obtain 3.05 g of the title compound as a light yellow solid, with a yield of 46.8%.

[0458] LC-MS: m / z 301.10 [M+H] + .

[0459] Step 4: Preparation of N-(tert-butoxycarbonyl)-O-(4,5-dimethoxy-2-nitrophenyl)-L-serine methyl ester (9d)

[0460] Dissolve O-(4,5-dimethoxy-2-nitrophenyl)-L-serine methyl ester (9c) (3.05 g, 10.2 mmol) in 50 mL of DCM, add DIEA (3.93 g, 30.5 mmol), stir at room temperature for 20 minutes, add Boc2O (3.32 g, 15.2 mmol) in batches at 0°C, stir at room temperature overnight. Add 100 mL of water, extract with DCM (50 mL x 2), wash with saturated brine (100 mL x 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 5.01 g (crude) of the title compound as a yellow oil.

[0461] LC-MS: m / z 401.15 [M+H] + .

[0462] Step 5: Preparation of O-(2-amino-4,5-dimethoxyphenyl)-N-(tert-butyloxycarbonyl)-L-serine methyl ester (9e)

[0463] Dissolve N-(tert-butoxycarbonyl)-O-(4,5-dimethoxy-2-nitrophenyl)-L-serine methyl ester (9d) (5.01 g, 12.5 mmol) in 50 ml MeOH, add aqueous palladium carbon (2.50 g), stir overnight at room temperature under hydrogen atmosphere. Filter, wash the filter cake with methanol (10 mL x 3), and concentrate the filtrate under reduced pressure to obtain 4.75 g (crude) of the title compound as a black oil.

[0464] LC-MS: m / z 371.17 [M+H] + .

[0465] Step 6: Preparation of tert-butyl (S)-(7,8-dimethoxy-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin]-3-yl)carbamate (9f)

[0466] O-(2-amino-4,5-dimethoxyphenyl)-N-(tert-butyloxycarbonyl)-L-serine methyl ester (9e) (4.75 g, 12.5 mmol) was dissolved in CHCl3 (80 ml). Under nitrogen atmosphere, trimethylaluminum solution (2.7 mL, 2 mol / L) was added to the reaction solution at 0°C and stirred at 50°C for 3 hours. Methanol was added to quench the reaction and the mixture was concentrated under reduced pressure. The residue was slurried with DCM / MeOH=5:1 (10 mL x 5), filtered, and the filtrate was collected and concentrated under reduced pressure to obtain 2.65 g of the title compound as a black oil with a yield of 62.8%.

[0467] LC-MS: m / z 339.15 [M+H] + .

[0468] Step 7: ( Preparation of tert-butyl S)-(7,8-dimethoxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin]-3-yl)carbamate (9 g)

[0469] Dissolve (S)-(7,8-dimethoxy-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine]-3-yl)carbamic acid tert-butyl ester (9f) (2.65 g, 7.84 mmol) in 35 mL DMF, add cesium carbonate (3.83 g, 11.7 mmol), and stir at room temperature for 30 min. Add iodomethane (111 g, 7.82 mmol) at 0°C, and stir at room temperature for 2 h. Add 50 mL of water, extract with EA (30 mL x 3), wash with saturated brine (30 mL x 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100:1-3:1) to obtain 650 mg of the title compound as a yellow oil, with a yield of 23.6%.

[0470] LC-MS: m / z 353.16 [M+H] + .

[0471] Step 8: Preparation of (S)-3-amino-7,8-dimethoxy-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one (9h)

[0472] Will ( S)-(7,8-dimethoxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine]-3-yl)carbamic acid tert-butyl (9g) (650mg, 1.85mmol) was dissolved in DCM (10ml), 4mol / L hydrochloric acid dioxane solution (3mL) was added to the reaction solution, and stirred at room temperature overnight. 10mL saturated sodium bicarbonate solution was added, DCM extraction (10mL x3), washed with saturated brine (15mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 380mg of the yellow semi-solid title compound, yield: 81.7%.

[0473] LC-MS: m / z 253.27 [M+H] + .

[0474] Step 9: Preparation of (S)-1-benzyl-5-chloro-4-(2-((7,8-dimethoxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)amino)ethyl)-1H-pyrazole-3-carboxylic acid ethyl ester (9i)

[0475] (S)-3-amino-7,8-dimethoxy-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one (9h) (360 mg, 1.43 mmol), 1-benzyl-5-chloro-4-formyl-1H-pyrazole-3-carboxylic acid ethyl ester (1m) (612 mg, 2.00 mmol) were dissolved in 10 mL of methanol, 1 mL of glacial acetic acid and 2-methylpyridine borane complex (214 mg, 2.00 mmol) were added, and stirred at room temperature for 2 hours. 20 mL of saturated sodium bicarbonate solution was added, extracted with DCM (10 mL x 3), washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100: 1-2: 3) to obtain 400 mg of the title compound as a reddish brown solid, with a yield of 51.6%.

[0476] LC-MS: m / z 543.19 [M+H] + .

[0477] Step 10: Preparation of (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-7,8-dimethoxy-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one (9j)

[0478] (S)-1-Benzyl-5-chloro-4-(2-((7,8-dimethoxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)amino)ethyl)-1H-pyrazole-3-carboxylic acid ethyl ester (9i) (350 mg, 0.644 mmol) was dissolved in 5 ml of toluene. Al(CH3)3 toluene solution (0.97 mL, 2 mol / L) was added at 0°C under nitrogen atmosphere, and stirred at 90°C for 3 hours. 10 mL of water was added to quench the mixture, and the mixture was extracted with EA (10 mL x 3), washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100:1-1:1) to obtain 330 mg of the title compound as a light red solid (crude product).

[0479] LC-MS: m / z 496.29 [M+H] + .

[0480] Step 11: Preparation of (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-7,8-dihydroxy-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one (9k)

[0481] At room temperature, (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-7,8-dimethoxy-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one (9j) (250 mg, 0.503 mmol) was dissolved in 6 mL of dichloromethane, and a dichloromethane solution of boron tribromide (1 M, 3 mL) was added at 0°C, and stirred at room temperature for 2 hours. Methanol was added dropwise at 0°C to quench the mixture, and the mixture was extracted with DCM (10 mL x 3), washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 270 mg (crude) of the title compound as a reddish brown solid.

[0482] Step 12: Preparation of (7S)-7-(2-benzyl-3-chloro)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-9-methyl-8-oxo-6,7,8,9-tetrahydro-[1,3]dioxol[4′,5′:4,5]benzo[1,2-b][1,4]oxazepine-2-carboxylic acid ethyl ester (9)

[0483] (S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-7,8-dihydroxy-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one (9k) (300 mg, 0.641 mmol) was dissolved in 10 ml of acetonitrile, potassium carbonate (265 mg, 1.92 mmol) and ethyl 2,2-dibromoacetate (234 mg, 0.960 mmol) were added, and the mixture was stirred at 70°C overnight. Add 10 mL of water, extract with EA (10 mL x 3), wash with saturated brine (10 mL x 3), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is separated by high pressure preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 um 100A, mobile phase: acetonitrile / water (0.05% formic acid), gradient: 30%-70%) to obtain 33 mg of the title compound as a white solid, yield: 9.32%.

[0484] LC-MS: m / z 553.0 [M+H] + .

[0485] 1 H NMR (400MHz, DMSO-d6) δ7.38-7.28 (m, 4H), 7.22-7.17 (m, 2H), 7.01 (d, J=2.1 Hz, 1H), 6.74 (d, J=6.7Hz, 1H), 5.55 (dt, J=11.9, 7.8Hz, 1H), 5.43 (s, 2H), 4. 82-4.71(m, 1H), 4.38-4.21(m, 3H), 4.08-3.96(m, 1H), 3.66-3.56(m, 1H), 3. 23(d, J=1.8Hz, 3H), 2.84-2.74(m, 1H), 2.73-2.62(m, 1H), 1.29-1.22(m, 3H).

[0486] Example 10: Preparation of (S)-8-(2-(2-fluorobenzyl)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-2,10-dimethyl-7,8-dihydrothiazolo[5′,4′:3,4]benzo[1,2-b][1,4]oxazepin-9(10H)-one (10)

[0487]

[0488] Step 1: Preparation of ethyl 1-(2-fluorobenzyl)-5-hydroxy-1H-pyrazole-3-carboxylate (10a)

[0489] At room temperature, diethyl oxalate sodium salt (10.0 g, 47.6 mmol) was dissolved in HAc (42.8 g, 714 mmol) and dioxane (100 ml), stirred at room temperature for 0.5 hours, (2-fluorophenyl)hydrazine (10.0 g, 71.4 mmol) was added, and stirred at 100°C for 2 hours. Water was added to quench, extracted with EA (200 mL x 3), washed with saturated brine (200 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 12.5 g of the title compound as a yellow semi-solid, with a yield of 44.2%.

[0490] LC-MS: m / z 265 [M+H] + .

[0491] Step 2: Preparation of ethyl 5-chloro-1-(2-fluorobenzyl)-4-formyl-1H-pyrazole-3-carboxylate (10b).

[0492] Dissolve 1-(2-fluorobenzyl)-5-hydroxy-1H-pyrazole-3-carboxylic acid ethyl ester (10a) (7.50 g, 28.4 mmol) in DMF (10.0 mL, 114 mmol), add POCl3 (24 ml, 228 mmol) at 0°C, and stir at 90°C for 2 hours. Add the reaction solution into ice water, extract with EA (100 mL x 3), wash with saturated brine (100 mL x 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 600 mg of the title compound as a light brown oil, with a yield of 6.80%.

[0493] LC-MS: m / z 311[M+H] + .

[0494] Step 3: Preparation of ethyl 5-chloro-1-(2-fluorobenzyl)-4-(2-methoxyvinyl)-1H-pyrazole-3-carboxylate (10c)

[0495] Chloro(methoxymethyl)triphenylphosphine (4.38 g, 12.8 mmol) was dissolved in THF (15 mL), and 20% EtONa solution (3.94 ml, 11.6 mmol) was slowly added at 0°C. The mixture was stirred for 0.5 hours, and a solution of 5-chloro-1-(2-fluorobenzyl)-4-formyl-1H-pyrazole-3-carboxylic acid ethyl ester (10b) (900 mg, 2.90 mmol) in THF (15 mL) was slowly added. The mixture was stirred at room temperature for 3 hours. The reaction solution was added to ice water, extracted with EA (30 mL x 3), washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 5:1) to give 600 mg of the title compound as a yellow oil. The yield was 55.0%.

[0496] LC-MS: m / z 338[M+H] + .

[0497] The remaining steps were the same as the preparation method of Example 1, except that 5-chloro-1-(2-fluorobenzyl)-4-(2-methoxyvinyl)-1H-pyrazole-3-carboxylic acid ethyl ester (10c) was used instead of 1-benzyl-5-chloro-4-(2-methoxyvinyl)-1H-pyrazole-3-carboxylic acid ethyl ester (1n), and N-(tert-butoxycarbonyl)-O-(2-methyl-7-nitrobenzo[d]thiazol-6-yl)-L-serine methyl ester (6b) was used instead of N-(tert-butoxycarbonyl)-O-(1,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-L-serine methyl ester (1g) in step 8 to obtain the title compound 10.

[0498] LC-MS: m / z 492.14 [M+H] + .

[0499] 1 H NMR (400MHz, CD3OD) δ: 7.85 (d, 1H), 7.57 (s, 1H), 7.41 (d, 1H), 7.28-7.26 (m, 1H), 7.23-7.21 (m, 1H), 7.13-7.08 (m, 2H), 5.73 (t, 1H), 5.41(s, 2H), 4.87(s, 1H), 4.43(t, 1H), 4.18-4.15(m, 1H), 3.41(s, 3H), 3.03-2.98(m, 1H), 2.86(s, 3H), 2.82-2.77(m, 2H).

[0500] Example 11: Preparation of (S)-7-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-2,2-difluoro-9-methyl-6,7-dihydro-[1,3]dioxol[4′,5′:4,5]benzo[1,2-b][1,4]oxazepin-8(9H)-one (11)

[0501]

[0502] Step 1: Preparation of 5-bromo-2,2-difluoro-6-nitrobenzo[d][1,3]dioxole (11a)

[0503] 5-Bromo-2,2-difluorobenzo[d][1,3]dioxole (5.00 g, 21.2 mmol) was added dropwise to TFA (50 mL) at 0°C, and concentrated HNO3 (2.94 g, 31.8 mmol) was added dropwise at 0°C, and stirred at room temperature for 2 hours. The reaction solution was poured into ice water, extracted with EA (200 mL x 3), washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 6:1) to obtain 3.0 g of the title compound as a yellow oil, with a yield of 50.3%.

[0504] LC-MS: m / z 281.9 [M+H] + .

[0505] Step 2: Preparation of 2,2-difluoro-6-nitrobenzo[d][1,3]dioxol-5-ol (11b)

[0506] 5-Bromo-2,2-difluoro-6-nitrobenzo[d][1,3]dioxole (11a) (4.30 g, 15.3 mmol), bipyralidin (8.53 g, 22.9 mmol), Pd(dppf)Cl2 (2.24 g, 3.06 mmol), KOAc (2.96 g, 30.3 mmol) were dissolved in dioxane (44 ml) and stirred at 80°C for 2 hours under nitrogen atmosphere. The mixture was extracted with EA (200 mL x 3), washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 8.9 g (crude) of the title compound as a black solid.

[0507] 8.9 g of the crude product was dissolved in DCM (43 mL) and MeOH (43 mL), and hydrogen peroxide (8.6 mL) was added at 0°C, and stirred at room temperature overnight. The mixture was concentrated under reduced pressure, extracted with DCM (50 mL×2), washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA=100:1) to obtain 2.5 g of the title compound as a brown solid, with a yield of 74.6%.

[0508] LC-MS: m / z 218.0 [MH] - .

[0509] Step 3: Preparation of O-(2,2-difluoro-6-nitrobenzo[d][1,3]dioxol-5-yl)-N-trityl-L-serine methyl ester (11c)

[0510] At room temperature, 2,2-difluoro-6-nitrobenzo[d][1,3]dioxol-5-ol (11b) (2.40 g, 11.0 mmol) and trityl-L-serine methyl ester (5.93 g, 16.4 mmol) were dissolved in 50 mL THF. Under nitrogen atmosphere, PPh3 (5.74 g, 21.9 mmol) and DIAD (4.43 g, 21.9 mmol) were added to the reaction solution and stirred at room temperature overnight. Water was added to dilute, extracted with EA (200 mL x 3), washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 9:1) to obtain 4.30 g of the title compound as a yellow solid with a yield of 69.8%.

[0511] LC-MS: m / z 563.2 [M+H] + .

[0512] Step 4: Preparation of O-(6-amino-2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-trityl-L-serine methyl ester (11d)

[0513] At room temperature, O-(2,2-difluoro-6-nitrobenz[d][1,3]dioxol-5-yl)-N-trityl-L-serine methyl ester (11c) (1.50 g, 2.67 mmol) was dissolved in 20 mL of EA, and aqueous Pd / C (800 mg) was added to the reaction solution. The mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. The mixture was filtered through celite, the filter cake was washed with EA, and the filtrate was concentrated under reduced pressure to obtain 1.6 g (crude) of the title compound as a black oil.

[0514] LC-MS: m / z 533.2 [M+H] + .

[0515] Step 5: Preparation of O-(6-amino-2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-trityl-L-serine (11e)

[0516] Dissolve O-(6-amino-2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-trityl-L-serine methyl ester (11d) (1.50 g, 2.82 mmol) in THF (15 ml), add lithium hydroxide (355 mg, 8.46 mmol) and water (4.2 mL), stir at 80°C for 16 hours, and concentrate under reduced pressure to obtain 2.3 g (crude) of the title compound as a black solid.

[0517] LC-MS: m / z 519.2 [M+H] + .

[0518] Step 6: Preparation of (S)-2,2-difluoro-7-(trityl)-6,7-dihydro-[1,3]dioxol[4′,5′;4,5]benzo[1,2-b][1,1,4]oxazepin-8(9H)-one (11f)

[0519] O-(6-amino-2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-trityl-L-serine (11e) (2.20 g, 4.25 mmol) was dissolved in 40 mL of DMF, and DIEA (1.64 g, 12.7 mmol) and HATU (2.42 g, 6.37 mmol) were added, and stirred at room temperature for 2 hours. 20 mL of water was added, and EA was extracted (200 mL x 3), washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 4:1) to obtain 740 mg of the title compound as a white solid, with a yield of 34.7%.

[0520] LC-MS: m / z 501.2 [M+H] + .

[0521] Step 7: Preparation of (S)-2,2-difluoro-9-methyl-7-(trityl)-6,7-dihydro-[1,3]dioxol[4′,5′;4,5]benzo[1,2-b][1,4]oxazepin-8(9H)-one (11 g)

[0522] (S)-2,2-difluoro-7-(trityl)-6,7-dihydro-[1,3]dioxol[4′,5′;4,5]benzo[1,2-b][1,1,4]oxazepin-8(9H)-one (11f) (700 mg, 1.40 mmol) was dissolved in DMF (7 ml), K2CO3 (386 mg, 2.80 mmol) and iodomethane (199 mg, 1.40 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with water, extracted with EA (50 mL x 3), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 4:1) to obtain 640 mg of the title compound as a white solid, with a yield of 88.9%.

[0523] LC-MS: m / z 515.2 [M+H] + .

[0524] Step 8: Preparation of (S)-7-amino-2,2-difluoro-9-methyl-6,7-dihydro-[1,3]dioxol[4′,5′;4,5]benzo[1,2-b][1,4]oxazepin-8(9H)-one (11h)

[0525] At room temperature, (S)-2,2-difluoro-9-methyl-7-(trityl)-6,7-dihydro-[1,3]dioxol[4′,5′;4,5]benzo[1,2-b][1,4]oxazepin-8(9H)-one (11 g) (300 mg, 0.584 mmol) was dissolved in 6 mL of DCM, TFA (200 mg, 1.75 mmol) was added to the reaction solution, and stirred at room temperature for 2 hours. 4 mL of ice water was added to quench, extracted with DCM (10 mL x 3), the pH was adjusted to weak alkalinity with 1 M NaOH solution, extracted with DCM (10 mL x 3), washed with saturated brine (4 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 160 mg of the title compound as a white solid (crude product).

[0526] LC-MS: m / z 273.1[M+H] + .

[0527] Step 9: Preparation of (S)-1-benzyl-5-chloro-4-(2-((2,2-difluoro-9-methyl-8-oxo-6,7,8,9-tetrahydro-[1,3]dioxol[4′,5′;4,5]benzo[1,2-b][1,4]oxazepin-7-yl)amino)ethyl)-1H-pyrazole-3-carboxylic acid ethyl ester (11i)

[0528] At room temperature, (S)-7-amino-2,2-difluoro-9-methyl-6,7-dihydro-[1,3]dioxol[4′,5′;4,5]benzo[1,2-b][1,4]oxazepine-8(9H)-one (11h) (160 mg, 0.588 mmol) and 1-benzyl-5-chloro-4-(2-formyl)-1H-pyrazole-3-carboxylic acid methyl ester (1m) (270 mg, 0.882 mmol) were dissolved in 5 mL of methanol. 2-Methylpyridine borane complex (94.0 mg, 0.882 mmol) was added to the reaction solution and stirred at room temperature for 16 hours. The residue was extracted with EA (20 mL x 3), washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and the residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 2:1) to obtain 110 mg of the title compound as a white solid. The yield was 33.5%.

[0529] LC-MS: m / z 563.1[M+H] + .

[0530] Step 10: Preparation of (S)-7-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-2,2-difluoro-9-methyl-6,7-dihydro-[1,3]dioxol[4′,5′;4,5]benzo[1,2-b][1,4]oxazepin-8(9H)-one (11)

[0531] At room temperature, (S)-1-benzyl-5-chloro-4-(2-((2,2-difluoro-9-methyl-8-oxo-6,7,8,9-tetrahydro-[1,3]dioxol[4′,5′;4,5]benzo[1,2-b][1,4]oxazepin-7-yl)amino)ethyl)-1H-pyrazole-3-carboxylic acid ethyl ester (11i) (90.0 mg, 0.174 mmol) was dissolved in 3 ml of chloroform. Under nitrogen atmosphere, Al(CH3)3 (0.26 mL, 2 M) was added to the reaction solution at 0°C and stirred at 50°C for 16 hours. The mixture was quenched with methanol, extracted with DCM (20 mL x 3), washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by high pressure preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 um 100A, mobile phase: acetonitrile / water, gradient: 10%-50%, 0.05% formic acid, 30 min) to give 38.0 mg of the title compound as a white solid, with a yield of 42.3%.

[0532] LC-MS: m / z 516.8 [M+H] + .

[0533] 1 H NMR (400MHz, DMSO-d6) δ7.73 (s, 1H), 7.46 (s, 1H), 7.38-7.26 (m, 3H), 7.22-7.16 (m, 2H) , 5.55 (dd, J=11.8, 8.0Hz, 1H), 5.43 (s, 2H), 4.85 (dd, J=11.9, 10.2Hz, 1H), 4.38 (dd, J= 10.1, 8.0Hz, 1H), 4.00 (ddd, J=12.3, 7.0, 5.0Hz, 1H), 3.63 (ddd, J=12.8, 8.4, 4.8Hz, 1H ), 3.28 (s, 3H), 2.80 (ddd, J=15.6, 8.4, 5.1Hz, 1H), 2.68 (ddd, J=15.6, 7.0, 4.8Hz, 1H).

[0534] Example 12: Preparation of (S)-7-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-2-(tert-butyl)-5-methyl-7,8-dihydrooxazolo[4′,5′:4,5]benzo[1,2-b][1,4]oxazepin-6(5H)-one (12)

[0535]

[0536] Step 1: Preparation of 2-bromo-4-methoxy-5-nitroaniline (12a)

[0537] At 0°C, 2-bromo-4-methoxyaniline (3.88 g, 19.3 mmol) was dissolved in 19.4 mL H2SO4, NaNO3 (1.80 g, 21.2 mmol) was added, and the mixture was stirred at 0°C for 10 minutes. The reaction was quenched with 2M NaOH ice solution (100 mL), extracted with EA (200 mL x 3), washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 5:1) to obtain 4.4 g of the title compound as a red solid, with a yield of 92.6%.

[0538] LC-MS: m / z 247.0 [M+H] + .

[0539] Step 2: Preparation of N-(2-bromo-4-methoxy-5-nitrophenyl)pivalamide (12b)

[0540] At room temperature, 2-bromo-4-methoxy-5-nitroaniline (12a) (4.20 g, 17.0 mmol) was dissolved in 42 mL of DCM, and DIEA (6.60 g, 51.2 mmol) was added. Under nitrogen protection, trimethylacetyl chloride (2.46 g, 20.4 mmol) was added to the reaction solution at 0°C, and stirred at room temperature for 16 hours. Water was added to quench, and the mixture was extracted with DCM (200 mL x 3), washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 6.1 g (crude) of the title compound as a brown solid.

[0541] LC-MS: m / z 331.0 [M+H] + .

[0542] Step 3: Preparation of 2-(tert-butyl)-6-methoxy-5-nitrobenzo[d]oxazole (12c)

[0543] N-(2-bromo-4-methoxy-5-nitrophenyl)pivalamide (12b) (5.75 g, 17.4 mmol) was dissolved in DMF (60 mL), and Cs2CO3 (11.3 g, 34.8 mmol), CuI (166 mg, 0.871 mmol), and dipyridine (272 mg, 1.74 mmol) were added. The mixture was stirred at 120°C overnight under a nitrogen atmosphere. Water was added to quench the mixture, and the mixture was extracted with EA (500 mL x 3), washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 5:1) to obtain 2.3 g of the title compound as a light yellow solid, with a two-step yield of 54.1%.

[0544] LC-MS: m / z 251.1 [M+H] + .

[0545] Step 4: Preparation of 2-(tert-butyl)-5-nitrobenzo[d]oxazol-6-ol (12d)

[0546] 2-(tert-Butyl)-6-methoxy-5-nitrobenzo[d]oxazole (12c) (2.28 g, 9.12 mmol) was dissolved in DCM (23 ml). BBr3 (1 M) (18.2 mL, 18.2 mmol) was added dropwise to the reaction solution at 0°C under nitrogen atmosphere, and stirred at 0°C for 0.5 hours. The reaction solution was added dropwise to ice water to quench, extracted with DCM (60 mL x 3), washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 5:1) to obtain 1.98 g of the title compound as a light yellow solid with a yield of 92%.

[0547] LC-MS: m / z 237.1[M+H] + .

[0548] The remaining steps were the same as the preparation method of Example 1, except that 2-(tert-butyl)-5-nitrobenzo[d]oxazol-6-ol (12d) was used instead of 5-hydroxy-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1d) in step 5 to obtain the title compound 12.

[0549] LC-MS: m / z 533.9 [M+H] + .

[0550] 1H NMR (400MHz, DMSO-d6) δ7.90 (s, 1H), 7.67 (s, 1H), 7.39-7.27 (m, 3H), 7.24-7.14 (m, 2H ), 5.57 (dd, J=12.0, 8.0Hz, 1H), 5.42 (s, 2H), 4.84 (dd, J=12.0, 10.0Hz, 1H), 4.34 (dd, J=10.0, 8.0Hz, 1H), 4.04 (ddd, J=12.0, 6.9, 5.2Hz, 1H), 3.64 (ddd, J=12.8, 8.4, 4.8Hz , 1H), 3.35 (s, 3H), 2.81 (ddd, J=15.2, 8.6, 5.2Hz, 1H), 2.74-2.63 (m, 1H), 1.44 (s, 9H).

[0551] Example 13: Preparation of (S)-8-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-3,10-dimethyl-3,7,8,10-tetrahydro-9H-imidazo[4′,5′:3,4]benzo[1,2-b][1,4]oxazepin-9-one (13)

[0552]

[0553] Step 1: Preparation of 4-methoxy-N1-methylbenzene-1,2-diamine (13a)

[0554] Dissolve 4-methoxy-N-methyl-2-nitroaniline (2.50 g, 13.7 mmol) in 35 mL of EtOH, add aqueous palladium carbon (146 mg), and stir at 50°C for 2 hours under a hydrogen atmosphere. Filter, wash the filter cake with ethanol (10 mL x 3), concentrate the filtrate under reduced pressure, and separate and purify the residue by silica gel column chromatography (mobile phase: DCM / MeOH=20:1-10:1) to obtain 2.00 g of the title compound as a reddish brown solid, yield: 99%.

[0555] LC-MS: m / z 153 [M+H] + .

[0556] Step 2: Preparation of 5-methoxy-1-methyl-1H-benzo[d]imidazole (13b)

[0557] 4-Methoxy-N1-methylbenzene-1,2-diamine (13a) (1.90 g, 12.5 mmol) was dissolved in formic acid (30 mL) at room temperature and stirred at 100°C for 2 hours in a sealed tube. The mixture was concentrated under reduced pressure and the residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 5:1-1:1) to obtain 2.10 g (crude) of the title compound as a brown solid.

[0558] LC-MS: m / z 163[M+H] + .

[0559] Step 3: Preparation of 5-methoxy-1-methyl-4-nitro-1H-benzo[d]imidazole (13c)

[0560] 5-Methoxy-1-methyl-1H-benzo[d]imidazole (13b) was dissolved in 10 ml of concentrated nitric acid and 10 ml of TFA at room temperature, and concentrated sulfuric acid (0.5 mL) was added at 0°C, and stirred at 50°C for 2 hours. The reaction solution was poured into ice water, and the pH was adjusted to 8 with saturated sodium bicarbonate solution, and extracted with EA (50 mL x 3), and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: DCM / MeOH = 20:1-10:1) to obtain 3.20 g of the title compound as a yellow solid, with a yield of 86.4%.

[0561] LC-MS: m / z 208 [M+H]+.

[0562] Step 4: Preparation of 1-methyl-4-nitro-1H-benzo[d]imidazole-5-hydroxy (13d)

[0563] 5-Methoxy-1-methyl-4-nitro-1H-benzo[d]imidazole (13c) (4.70 g, 22.7 mmol) was dissolved in 50 ml of hydrobromic acid at room temperature and stirred in a sealed tube at 100°C overnight. The pH was adjusted to 8 with saturated sodium bicarbonate solution. The aqueous phase was washed with DCM (50 mL x 3), and the aqueous phase was concentrated under reduced pressure. The filter cake was washed with DCM:MeOH=10:1, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: DCM / MeOH=20:1-10:1) to give 5.00 g (crude) of the title compound as a pale yellow solid.

[0564] LC-MS: m / z 194 [M+H] + .

[0565] The remaining steps were the same as the preparation method of Example 1, except that 1-methyl-4-nitro-1H-benzo[d]imidazole-5-hydroxy (13d) was used instead of 5-hydroxy-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazole-2-one (1d) in step 5 to obtain the title compound 13.

[0566] LC-MS: m / z 491[M+H] + .

[0567] 1 H NMR (400MHz, DMSO-d6) δ8.30 (s, 1H), 7.53 (d, 1H), 7.34-7.27 (m, 3H), 7.21-7.17 (m, 3H), 5.58 (dd, 1H), 5.42 (s, 2H), 4.88-4.8 2 (m, 1H), 4.34 (dd, 1H), 4.24-4.06 (m, 1H), 3.84 (s, 3H), 3.75-3.60 (m, 1H), 3.52 (s, 3H), 2.86-2.81 (m, 1H), 2.80-2.65 (m, 1H).

[0568] Example 14: Preparation of (S)-7-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-1,5,7,8-tetrahydro-6H-[1,4]oxazepino[3,2-f]indazol-6-one (14)

[0569]

[0570] Step 1: Preparation of 6-fluoro-5-nitro-1H-indazole (14a)

[0571] 6-Fluoro-1H-indazole (10.0 g, 73.5 mmol) was dissolved in concentrated H2SO4 (100 ml) at 0°C. NaNO3 (7.40 g, 87.6 mmol) was added to the reaction solution at 0°C under nitrogen atmosphere and stirred at 0°C for 1 hour. Water (500 mL) was added at 0°C to quench the mixture, and the mixture was extracted with EA (300 mL x 3), washed with saturated brine (600 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 2:1) to obtain 3.4 g of the title compound as a light yellow solid with a yield of 25.7%.

[0572] LC-MS: m / z 182 [M+H] + .

[0573] Step 2: Preparation of 6-fluoro-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (14b)

[0574] 6-Fluoro-5-nitro-1H-indazole (14a) (3.10 g, 17.1 mmol) was dissolved in THF (30 mL), and NaH (1.03 g, 25.7 mmol) was added at 0°C. The mixture was stirred at 0°C for 0.5 h under nitrogen atmosphere. SEM-Cl (3.41 g, 20.5 mmol) was added dropwise at 0°C. The mixture was stirred at room temperature overnight, quenched with water (100 mL), extracted with EA (100 mL x 3), washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA=3:1) to give 3.81 g of the title compound as a light yellow solid in a yield of 70.8%.

[0575] LC-MS: m / z 312 [M+H] + .

[0576] Step 3: Preparation of 5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-ol (14c)

[0577] At room temperature, (tert-butyloxycarbonyl)-L-serine (659 mg, 3.22 mmol) was dissolved in DMF (10 ml). Under nitrogen atmosphere, NaH (258 mg, 6.44 mmol) was added dropwise to the reaction solution at 0°C. The mixture was stirred at 0°C for 0.5 hours. 6-Fluoro-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (14b) (500 mg, 1.61 mmol) was added in batches and stirred at room temperature overnight. Water (30 mL) was added at 0°C to quench the mixture, and the mixture was extracted with EA (30 mL x 3), washed with saturated brine (60 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 210 mg of the title compound as a light yellow solid with a yield of 42.1%.

[0578] LC-MS: m / z 310 [M+H] + .

[0579] Step 4: Preparation of O-(5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)-N-trityl-L-serine methyl ester (14d)

[0580] At room temperature, 5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-ol (14c) (230 mg, 0.744 mmol) and trityl-L-serine methyl ester (403 mg, 1.16 mmol) were dissolved in 4 mL of THF. Under a nitrogen atmosphere, PPh3 (390 mg, 1.48 mmol) and DIAD (300 mg, 1.48 mmol) were added and stirred at room temperature overnight. Water (20 mL) was added to quench the mixture, and the mixture was extracted with EA (30 mL x 3), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 800 mg of the title compound as a yellow semi-solid (crude product).

[0581] LC-MS: m / z 653 [M+H] + .

[0582] Step 5: Preparation of O-(5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)-N-trityl-L-serine methyl ester (14e)

[0583] At room temperature, O-(5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)-N-trityl-L-serine methyl ester (500 mg, 0.765 mmol) was dissolved in 10 mL of methanol, and aqueous Pd / C (250 mg) was added to the reaction solution. The mixture was stirred overnight at room temperature under a hydrogen atmosphere. The mixture was filtered through celite, the filter cake was washed with MeOH, and the filtrate was concentrated under reduced pressure to obtain 460 mg (crude) of the title compound as a yellow oil.

[0584] LC-MS: m / z 623[M+H] + .

[0585] Step 6: Preparation of O-(5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)-N-trityl-L-serine (14f)

[0586] O-(5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)-N-trityl-L-serine methyl ester (14e) (200 mg, 0.320 mmol) was dissolved in EtOH (3 ml), and lithium hydroxide (21.0 mg, 0.963 mmol) and water (0.5 mL) were added. The mixture was stirred at 80°C for 2 hours and concentrated under reduced pressure to give 320 mg (crude) of the title compound as a black oil.

[0587] LC-MS: m / z 609 [M+H]+ .

[0588] Step 7: Preparation of (S)-1-((2-(trimethylsilyl)ethoxy)methyl)-7-(tritylamino)-1,5,7,8-tetrahydro-6H-[1,4]oxazepino[3,2-f]indazol-(5H)-one (14 g)

[0589] O-(5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)-N-trityl-L-serine (1.00 g, 1.64 mmol) was dissolved in 10 mL of DMF, DIEA (367 mg, 2.47 mmol) and HATU (937 mg, 2.47 mmol) were added, and the mixture was stirred at room temperature for 1 hour. 10 mL of water was added, EA was extracted (20 mL x 3), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100:1-1:1) to obtain 560 mg of the title compound as a light yellow solid, with a yield of 58.7%.

[0590] LC-MS: m / z 591[M+H] + .

[0591] Step 8: Preparation of (S)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-7-(tritylamino)-1,5,7,8-tetrahydro-6H-[1,4]oxazepino[3,2-f]indazol-6-one (14h)

[0592] (S)-1-((2-(Trimethylsilyl)ethoxy)methyl)-7-(tritylamino)-1,5,7,8-tetrahydro-6H-[1,4]oxazepino[3,2-f]indazol-(5H)-one (14 g) (600 mg, 1.02 mmol) was dissolved in DMF (10 ml), and Cs2CO3 (663 mg, 2.04 mmol) and iodomethane (217 mg, 1.53 mmol) were added, and stirred at room temperature for 2 hours. 20 mL of water was added for dilution, EA was extracted (20 mL x 3), and saturated brine was washed (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 540 mg of the title compound as a yellow oil, with a yield of 87.2%.

[0593] LC-MS: m / z 605 [M+H] + .

[0594] Step 9: Preparation of (S)-7-amino-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5,7,8-tetrahydro-6H-[1,4]oxazepino[3,2-f]indazol-6-one (14i)

[0595] At room temperature, (S)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-7-(tritylamino)-1,5,7,8-tetrahydro-6H-[1,4]oxazepine[3,2-f]indazol-6-one (310 mg, 0.513 mmol) was dissolved in 5 mL DCM. A 4 mol / L hydrochloric acid dioxane solution (0.4 ml) was added to the reaction solution and stirred at room temperature for 2 hours. 50 mL of saturated NaHCO3 solution was added, extracted with DCM (30 mL x 3), washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 140 mg of the title compound as a yellow oil (crude product).

[0596] LC-MS: m / z 363[M+H] + .

[0597] Step 10: Preparation of (S)-1-benzyl-5-chloro-4-(2-((5-methyl-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydro-1H-[1,4]oxazepino[3,2-f]indazol-7-yl)amino)ethyl)-1H-pyrazole-3-carboxylic acid ethyl ester (14j)

[0598] At room temperature, (S)-7-amino-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5,7,8-tetrahydro-6H-[1,4]oxazepino[3,2-f]indazol-6-one (14i) (120 mg, 0.330 mmol) and 1-benzyl-5-chloro-4-formyl-1H-pyrazole-3-carboxylic acid ethyl ester (1m) (122 mg, 0.398 mmol) were dissolved in 3 mL of methanol. 2-Methylpyridineborane (53.0 mg, 0.496 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. 5 mL of saturated NaHCO3 solution was added, extracted with DCM (10 mL x 3), washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 1:1) to obtain 140 mg of the title compound as a light yellow oil. The yield was 65.1%.

[0599] LC-MS: m / z 653 [M+H] + .

[0600] Step 11: Preparation of (S)-7-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5,7,8-tetrahydro-6H-[1,4]oxazepino[3,2-f]indazol-6-one (14k)

[0601] Compound 14j (110 mg, 0.168 mmol) was dissolved in 3 ml of chloroform at room temperature, and Al(CH3)3 solution (0.253 ml, 2 M) was added to the reaction solution at 0°C under nitrogen atmosphere, and stirred at 50°C for 3 hours. The mixture was quenched by adding saturated sodium bicarbonate solution (1 mL), stirred for half an hour, filtered, and the filter cake was washed with DCM (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 100 mg of the crude title compound as an off-white solid.

[0602] LC-MS: m / z 607 [M+H] + .

[0603] Step 12: Preparation of (S)-7-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-1,5,7,8-tetrahydro-6H-[1,4]oxazepino[3,2-f]indazol-6-one (14)

[0604] At room temperature, (S)-7-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5,7,8-tetrahydro-6H-[1,4]oxazepino[3,2-f]indazol-6-one (14k) (110 mg, 0.181 mmol) was dissolved in 4 mol / L hydrochloric acid dioxane solution (3 ml), stirred at 25° C. for 12 hours under nitrogen atmosphere, concentrated under reduced pressure, added with aqueous ammonia (6 mL), stirred for 2 hours, concentrated under reduced pressure, and the residue was separated by high pressure preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 um 100A, mobile phase: acetonitrile / water, gradient: 10%-50%, 0.05% formic acid) to obtain 15 mg of the title compound as an off-white solid, with a yield of 17.4%.

[0605] LC-MS: m / z 476.9 [M+H] + .

[0606] 1H NMR (400MHz, DMSO-d6) δ13.18 (s, 1H), 8.11 (s, 1H), 7.89 (s, 1H), 7.40-7.25 (m, 4H), 7.18 (d, J = 7.0Hz, 2H), 5.59 (dd, J = 11.9, 7.9Hz, 1H), 5.42 (s , 2H), 4.86-4.76 (m, 1H), 4.36-4.27 (m, 1H), 4.05 (dt, J=12.1, 5.6Hz, 1H ), 3.69-3.58(m, 1H), 3.36(s, 3H), 2.87-2.75(m, 1H), 2.74-2.64(m, 1H).

[0607] Example 15: Preparation of (S)-7-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-2-cyclopropyl-9-methyl-6,7-dihydrooxazolo[5′,4′:4,5]benzo[1,2-b][1,4]oxazepin-8(9H)-one (15)

[0608]

[0609] Step 1: Preparation of N-(2-bromo-5-methoxyphenyl)cyclopropanecarboxamide (15a)

[0610] At room temperature, 2-bromo-5-methoxyaniline (5.00 g, 25.0 mmol) was dissolved in 100 ml of DCM, and DIEA (9.60 g, 75.0 mmol) was added. Under nitrogen atmosphere, cyclopropylacyl chloride (3.10 g, 29.8 mmol) was added to the reaction solution at 0°C, and stirred at room temperature for 2 hours. Water was added to quench, extracted with DCM (200 mL x 3), washed with saturated brine (200 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 4:1) to obtain 6.3 g of the title compound as a colorless transparent liquid, with a yield of 94.2%.

[0611] LC-MS: m / z 270 [M+H] + .

[0612] Step 2: Preparation of 2-cyclopropyl-5-methoxybenzo[d]oxazole (15b)

[0613] N-(2-bromo-5-methoxyphenyl)cyclopropanecarboxamide (15a) (5.00 g, 1.86 mmol) was dissolved in DMF (100 mL), and Cs2CO3 (12.1 g, 37.2 mmol), CuI (180 mg, 0.930 mmol), and dipyridine (290 mg, 1.86 mmol) were added. The mixture was stirred at 120°C overnight under a nitrogen atmosphere. Water was added to quench the mixture, and the mixture was extracted with EA (100 mL x 3), washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 2.4 g of the title compound as a light yellow solid with a yield of 75.1%.

[0614] LC-MS: m / z 190 [M+H] + .

[0615] Step 3: Preparation of 2-cyclopropyl-5-methoxy-6-nitrobenzo[d]oxazole (15c)

[0616] 2-Cyclopropyl-5-methoxybenzo[d]oxazole (15b) (2.50 g, 13.2 mmol) was dissolved in TFA (24 ml). Concentrated HNO3 (8 mL) was added dropwise to the reaction solution at 0°C under nitrogen atmosphere. The mixture was stirred at 0°C for 2 hours and at room temperature overnight. The mixture was quenched with water at 0°C, extracted with EA (50 mL x 3), washed with saturated brine (80 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 1.5 g of the title compound as a light yellow solid with a yield of 49.6%.

[0617] LC-MS: m / z 234 [M+H] + .

[0618] Step 4: Preparation of 2-cyclopropyl-6-nitrobenzo[d]oxazol-5-ol (15d)

[0619] 2-Cyclopropyl-5-methoxy-6-nitrobenzo[d]oxazole (15c) (3.20 g, 13.6 mmol) was dissolved in DCM (50 ml). BBr3 solution (27.2 mL, 1 M) was added dropwise to the reaction solution at 0°C under nitrogen atmosphere, and stirred at 0°C for 2 hours. Methanol was added to quench at 0°C, extracted with DCM (60 mL x 3), washed with saturated brine (80 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 1.8 g of the title compound as a light yellow solid with a yield of 60.0%.

[0620] LC-MS: m / z 220 [M+H] + .

[0621] Step 5: Preparation of O-(2-cyclopropyl-6-nitrobenzo[d]oxazol-5-yl)-N-trityl-L-serine methyl ester (15e)

[0622] At room temperature, 2-cyclopropyl-6-nitrobenzo[d]oxazol-5-ol (15d) (2.30 g, 10.4 mmol) and trityl-L-serine methyl ester (5.66 g, 15.7 mmol) were dissolved in 50 mL THF. Under nitrogen atmosphere, PPh3 (5.47 g, 20.9 mmol) and DIAD (4.20 g, 20.9 mmol) were added to the reaction solution, and stirred at room temperature overnight. The mixture was diluted with water, extracted with EA (50 mL x 3), washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 1:1) to obtain 7.8 g (crude) of the title compound as a yellow semi-solid.

[0623] LC-MS: m / z 564 [M+H] + .

[0624] Step 6: Preparation of O-(2-cyclopropyl-6-nitrobenzo[d]oxazol-5-yl)-L-serine methyl ester (15f)

[0625] At room temperature, O-(2-cyclopropyl-6-nitrobenzo[d]oxazol-5-yl)-N-trityl-L-serine methyl ester (15e) (7.50 g, 13.3 mmol) was dissolved in 100 mL of DCM, dioxane hydrochloride (13.3 ml) was added to the reaction solution, and stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, slurried with PE:EA=5:1, filtered, and the filter cake was collected to obtain 3.65 g of the title compound as a light yellow solid, with a yield of 65.4%.

[0626] LC-MS: m / z 322 [M+H] + .

[0627] Step 7: Preparation of N-(tert-butoxycarbonyl)-O-(2-cyclopropyl-6-nitrobenzo[d]oxazol-5-yl)-L-serine methyl ester (15 g)

[0628] At room temperature, O-(2-cyclopropyl-6-nitrobenzo[d]oxazol-5-yl)-L-serine methyl ester (15f) (2.25 g, 7.00 mmol) was dissolved in DCM (30 ml), DIEA (2.70 g, 20.7 mmol) and Boc2O (2.26 g, 10.9 mmol) were added to the reaction solution, and stirred at room temperature overnight. The mixture was diluted with water, extracted with DCM (30 mL x 3), washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 2:1) to obtain 1.6 g of the title compound as a yellow oil, with a yield of 53.2%.

[0629] LC-MS: m / z 422[M+H] + .

[0630] Step 8: Preparation of O-(6-amino-2-cyclopropylbenzo[d]oxazol-5-yl)-N-(tert-butyloxycarbonyl)-L-serine methyl ester (15h)

[0631] At room temperature, N-(tert-butoxycarbonyl)-O-(2-cyclopropyl-6-nitrobenzo[d]oxazol-5-yl)-L-serine methyl ester (15 g) (1.50 g, 3.05 mmol) was dissolved in 20 mL of methanol, and aqueous Pd / C (1.00 g) was added to the reaction solution. The mixture was stirred overnight at room temperature under a hydrogen atmosphere. The mixture was filtered through celite, the filter cake was washed with MeOH, and the filtrate was concentrated under reduced pressure to obtain 1.6 g (crude) of the title compound as a yellow oil.

[0632] LC-MS: m / z 392[M+H] + .

[0633] Step 9: Preparation of O-(6-amino-2-cyclopropylbenzo[d]oxazol-5-yl)-N-(tert-butyloxycarbonyl)-L-serine (15i)

[0634] Dissolve O-(6-amino-2-cyclopropylbenzo[d]oxazol-5-yl)-N-(tert-butoxycarbonyl)-L-serine methyl ester (15h) (1.60 g, 4.08 mmol) in THF (30 ml), add lithium hydroxide (141 mg, 6.12 mmol) and water (5 mL), stir at room temperature for 30 minutes, and concentrate under reduced pressure to obtain 1.9 g (crude) of the title compound as a black oil.

[0635] LC-MS: m / z 378 [M+H] + .

[0636] Step 10: Preparation of tert-butyl (S)-(2-cyclopropyl-8-oxo-6,7,8,9-tetrahydrooxazolo[5′,4′:4,5]benzo[1,2-b][1,4]oxazepin-7-yl)carbamate (15j)

[0637] O-(6-amino-2-cyclopropylbenzo[d]oxazol-5-yl)-N-(tert-butyloxycarbonyl)-L-serine (15i) (1.80 g, 4.76 mmol) was dissolved in 30 mL of DMF, DIEA (1.84 g, 14.3 mmol) and HATU (4.54 g, 12.8 mmol) were added, and the mixture was stirred at room temperature for 1 hour. 20 mL of water was added, EA was extracted (20 mL x 3), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100:1-1:1) to obtain 360 mg of the title compound as a light yellow solid, yield: 26.2%.

[0638] LC-MS: m / z 360 [M+H] + .

[0639] Step 11: Preparation of tert-butyl (S)-(2-cyclopropyl-9-methyl-8-oxo-6,7,8,9-tetrahydrooxazolo[5′,4′:4,5]benzo[1,2-b][1,4]oxazepin-7-yl)carbamate (15k)

[0640] Dissolve (S)-(2-cyclopropyl-8-oxo-6,7,8,9-tetrahydrooxazolo[5′,4′:4,5]benzo[1,2-b][1,4]oxazepin-7-yl)carbamic acid tert-butyl ester (15j) (300 mg, 0.830 mmol) in DMF (10 ml), add Cs2CO3 (408 mg, 1.25 mmol) and iodomethane (139 mg, 0.996 mmol), and stir at room temperature for 2 hours. Dilute with water, extract with EA (15 mL x 3), wash with saturated sodium chloride (20 mL x 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase PE / EA=3:1) to obtain 260 mg of the title compound as a yellow oil, with a yield of 83.8%.

[0641] LC-MS: m / z 374 [M+H] + .

[0642] Step 12: Preparation of (S)-7-amino-2-cyclopropyl-9-methyl-6,7-dihydrooxazolo[5′,4′:4,5]benzo[1,2-b][1,4]oxazepin-8(9H)-one (151)

[0643] At room temperature, tert-butyl (S)-(2-cyclopropyl-9-methyl-8-oxo-6,7,8,9-tetrahydrooxazolo[5′,4′:4,5]benzo[1,2-b][1,4]oxazepin-7-yl)carbamate (15k) (200 mg, 0.536 mmol) was dissolved in 2 mL of DCM, and a 4 mol / L hydrochloric acid dioxane solution (4 ml) was added to the reaction solution, and stirred at room temperature for 2 hours. 10 mL of saturated NaHCO3 solution was added, and the mixture was extracted with DCM (10 mL x 3), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 150 mg of the title compound as a yellow oil (crude product).

[0644] LC-MS: m / z 274 [M+H] + .

[0645] The remaining steps were the same as the preparation method of Example 1, except that (S)-7-amino-2-cyclopropyl-9-methyl-6,7-dihydrooxazolo[5′,4′:4,5]benzo[1,2-b][1,4]oxazepine-8(9H)-one (15l) was used instead of (S)-7-amino-1,3,9-trimethyl-3,6,7,9-tetrahydro-1H-imidazo[4′,5′:4,5]benzo[1,2-b][1,4]oxazepine-2,8-dione (1k) in step 11 to obtain the title compound 15.

[0646] LC-MS: m / z 518.0 [M+H] + .

[0647] 1 H NMR (400MHz, DMSO-d6) δ7.89 (s, 1H), 7.49 (s, 1H), 7.37-7.29 (m, 3H), 7.21-7.16 (m, 2H), 5.5 5 (dd, J=11.9, 8.1Hz, 1H), 5.42 (s, 2H), 4.82 (dd, J=11.9, 10.1Hz, 1H), 4.33 (dd, J=10.1, 8.1H z, 1H), 4.03 (ddd, J=12.3, 7.0, 5.1Hz, 1H), 3.64 (ddd, J=12.8, 8.5, 4.8Hz, 1H), 3.38 (s, 3H), 2.80 (ddd, J=15.5, 8.5, 5.0Hz, 1H), 2.75-2.62 (m, 1H), 2.34-2.26 (m, 1H), 1.25-1.19 (m, 4H).

[0648] Example 16: Preparation of (S)-7-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-2-(tert-butyl)-9-methyl-6,7-dihydrooxazolo[5′,4′:4,5]benzo[1,2-b][1,4]oxazepin-8(9H)-one (16)

[0649]

[0650] Step 1: Preparation of N-(2-bromo-5-methoxyphenyl)pivalamide (16a)

[0651] At room temperature, 2-bromo-5-methoxyaniline (5.00 g, 25.0 mmol) was dissolved in 100 ml of DCM, and DIEA (9.60 g, 75.0 mmol) was added. Under nitrogen atmosphere, trimethylacetyl chloride (3.58 g, 29.8 mmol) was added to the reaction solution at 0°C, and stirred at room temperature for 2 hours. Water was added to quench, extracted with DCM (200 mL x 3), washed with saturated brine (200 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 4:1) to obtain 6.1 g of the title compound as a colorless transparent oil, with a yield of 85.9%.

[0652] LC-MS: m / z 286 [M+H] + .

[0653] Step 2: Preparation of 2-(tert-butyl)-5-methoxybenzo[d]oxazole (16b)

[0654] N-(2-bromo-5-methoxyphenyl)pivalamide (16a) (5.00 g, 17.5 mmol) was dissolved in DMF (100 mL), and Cs2CO3 (11.4 g, 35.1 mmol), CuI (333 mg, 1.75 mmol), and dipyridine (546 mg, 3.50 mmol) were added. The mixture was stirred at 120°C overnight under a nitrogen atmosphere. Water was added to quench the mixture, and the mixture was extracted with EA (100 mL x 3), washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 2.1 g of the title compound as a light yellow solid with a yield of 58.3%.

[0655] LC-MS: m / z 206 [M+H] + .

[0656] Step 3: Preparation of 2-(tert-butyl)-5-methoxy-6-nitrobenzo[d]oxazole (16c)

[0657] 2-(tert-Butyl)-5-methoxybenzo[d]oxazole (16b) (2.00 g, 9.71 mmol) was dissolved in TFA (20 ml). Concentrated HNO3 (7 mL) was added dropwise at 0°C under nitrogen atmosphere. The mixture was stirred at 0°C for 2 hours and at room temperature overnight. Water was added to quench the mixture at 0°C, and the mixture was extracted with EA (50 mL x 3), washed with saturated brine (80 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 1.3 g of the title compound as a light yellow solid with a yield of 54.2%.

[0658] LC-MS: m / z 251[M+H] + .

[0659] Step 4: Preparation of 2-(tert-butyl)-6-nitrobenzo[d]oxazol-5-ol (16d)

[0660] 2-(tert-Butyl)-5-methoxy-6-nitrobenzo[d]oxazole (16c) (1.20 g, 4.78 mmol) was dissolved in DCM (50 ml), and BBr3 (9.6 mL, 1 M) was added dropwise at 0°C under nitrogen atmosphere, and stirred at 0°C for 2 hours. Methanol was added at 0°C to quench, and the mixture was extracted with DCM (60 mL x 3), washed with saturated brine (80 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 840 mg of the title compound as a light yellow solid, with a yield of 86%.

[0661] LC-MS: m / z 237[M+H] + .

[0662] The remaining steps were the same as the preparation method of Example 1, except that 2-cyclopropyl-6-nitrobenzo[d]oxazol-5-ol (16d) was used instead of 5-hydroxy-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1d) in step 5 to obtain the title compound 16.

[0663] LC-MS: m / z 534.0 [M+H] + .

[0664] 1H NMR (400MHz, DMSO-d6) δ7.96 (s, 1H), 7.59 (s, 1H), 7.38-7.26 (m, 3H), 7.22-7.15 (m, 2H), 5.56 (dd, J=11.9, 8.1Hz, 1H), 5.42 (s, 2H), 4.83 (dd, J=11.9, 10.1Hz, 1H), 4.33 (dd, J=10. 1, 8.1Hz, 1H), 4.04 (dt, J=12.3, 5.9Hz, 1H), 3.65 (ddd, J=12.8, 8.4, 4.8Hz, 1H), 3.35 (s, 3H), 2.81 (ddd, J=13.8, 8.5, 5.1Hz, 1H), 2.68 (ddd, J=15.6, 6.9, 4.8Hz, 1H), 1.45 (s, 9H).

[0665] Example 17: Preparation of (S)-7-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-2-cyclopropyl-5,10-dimethyl-7,8-dihydrooxazolo[4′,5′:4,5]benzo[1,2-b][1,4]oxazepin-6(5H)-one (17)

[0666]

[0667] Step 1: Preparation of 2-bromo-4-methoxy-3-methyl-1-nitrobenzene (17a)

[0668] 1-Bromo-3-methoxy-2-methylbenzene (15.00 g, 75.0 mmol) was dissolved in TFA (150 ml). HNO3 (50 mL) was added dropwise to the reaction solution at 0°C under nitrogen atmosphere. The mixture was stirred at 0°C for 2 hours and at room temperature overnight. Water was added to quench the mixture at 0°C, and the mixture was extracted with EA (200 mL x 3), washed with saturated brine (80 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 10.6 g of a crude product.

[0669] LC-MS: m / z 246 [M+H] + .

[0670] Step 2: Preparation of 2-bromo-4-methoxy-3-methylaniline (17b)

[0671] 2-Bromo-4-methoxy-3-methyl-1-nitrobenzene (17a) (10.0 g, 0.0408 mmol) was dissolved in THF / H2O (100 mL / 100 mL), NH4Cl (11.1 g, 0.204 mmol) was added, zinc powder (13.3 g, 0.204 mmol) was added at 0°C, and stirred at room temperature overnight. Water (200 mL) was added to quench, EA was extracted (200 mL x 3), washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 8.2 g of the title compound as a light yellow solid, with a yield of 77%.

[0672] LC-MS: m / z 216 [M+H] + .

[0673] Step 3: Preparation of N-(2-bromo-4-methoxy-3-methylphenyl)cyclopropanecarboxamide (17c)

[0674] At room temperature, 2-bromo-4-methoxy-3-methylaniline (17b) (5.00 g, 23.1 mmol) was dissolved in 100 ml of DCM, and DIEA (8.95 g, 69.4 mmol) was added. Under nitrogen atmosphere, cyclopropylacetyl chloride (3.61 g, 34.7 mmol) was added to the reaction solution at 0°C and stirred at room temperature for 2 hours. Water (100 mL) was added to quench the mixture, and the mixture was extracted with DCM (200 mL x 3), washed with saturated brine (200 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 4:1) to obtain 5.6 g of the title compound as a white solid, with a yield of 85.9%.

[0675] LC-MS: m / z 284 [M+H] + .

[0676] Step 4: Preparation of 2-cyclopropyl-6-methoxy-7-methylbenzo[d]oxazole (17d)

[0677] N-(2-bromo-4-methoxy-3-methylphenyl)cyclopropanecarboxamide (17c) (5.20 g, 18.3 mmol) was dissolved in DMF (100 mL), and Cs2CO3 (11.9 g, 36.6 mmol), CuI (340 mg, 1.83 mmol), and dipyridine (570 mg, 3.66 mmol) were added. The mixture was stirred at 120°C overnight under a nitrogen atmosphere. Water (200 mL) was added to quench the mixture, and the mixture was extracted with EA (100 mL x 3), washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 1.8 g of the title compound as a light yellow solid with a yield of 48.6%.

[0678] LC-MS: m / z 204 [M+H] + .

[0679] Step 5: Preparation of 2-cyclopropyl-6-methoxy-7-methyl-5-nitrobenzo[d]oxazole (17e)

[0680] 2-Cyclopropyl-6-methoxy-7-methylbenzo[d]oxazole (17d) (1.50 g, 7.39 mmol) was dissolved in TFA (15 ml). HNO3 (5 mL) was added dropwise to the reaction solution at 0°C under nitrogen atmosphere. The mixture was stirred at 0°C for 2 hours and at room temperature overnight. Water (30 mL) was added to quench the mixture at 0°C, and the mixture was extracted with EA (30 mL x 3), washed with saturated brine (60 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 1.1 g of the title compound as a light yellow solid with a yield of 61.1%.

[0681] LC-MS: m / z 249 [M+H] + .

[0682] Step 6: Preparation of 2-cyclopropyl-7-methyl-5-nitrobenzo[d]oxazol-6-ol (17f)

[0683] 2-Cyclopropyl-6-methoxy-7-methyl-5-nitrobenzo[d]oxazole (17e) (1.00 g, 4.03 mmol) was dissolved in DCM (15 ml). BBr3 (8.1 mL, 1 M) was added dropwise to the reaction solution at 0°C under nitrogen atmosphere. The mixture was stirred at 0°C for 2 hours, quenched by adding methanol at 0°C, extracted with DCM (60 mL x 3), washed with saturated brine (80 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA=3:1) to give 720 mg of the title compound as a light yellow solid in a yield of 76.6%.

[0684] LC-MS: m / z 235 [M+H] + .

[0685] The remaining steps were the same as the preparation method of Example 1, except that 2-cyclopropyl-6-nitrobenzo[d]oxazol-5-ol (17e) was used instead of 5-hydroxy-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazole-2-one (1d) in step 5 to obtain the title compound 17.

[0686] LC-MS: m / z 532.2 [M+H] + .

[0687] 1 H NMR (400MHz, DMSO-d6) δ7.62 (s, 1H), 7.42-7.27 (m, 3H), 7.27-7.11 (m, 2H), 5.58-5.48 (m, 1H), 5.42 (s, 2H), 4.83 (dd, J=11.9, 10.1Hz, 1H), 4.36 (dd, J=10.1, 8.1Hz, 1H), 4.04 (ddd, J=12.4, 7.2, 5.1Hz, 1H), 3.64 (ddd, J=12.8, 8.4, 4.7Hz, 1H), 3.33 (s, 3H), 2.81 (ddd, J=15 .4, 8.3, 4.9Hz, 1H), 2.74-2.63(m, 1H), 2.40(s, 3H), 2.35-2.24(m, 1H), 1.27-1.10(m, 4H).

[0688] Example 18: Preparation of (S)-7-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-2-cyclopropyl-5,10-dimethyl-7,8-dihydrothiazolo[4′,5′:4,5]benzo[1,2-b][1,4]oxazepin-6(5H)-one (18)

[0689]

[0690] Step 1: Preparation of N-(2-bromo-4-methoxy-3-methylphenyl)cyclopropanethioamide (18a)

[0691] N-(2-bromo-4-methoxy-3-methylphenyl)cyclopropanecarboxamide (3.20 g, 11.3 mmol) was dissolved in toluene (50 ml). Lawesson's reagent (9.13 g, 22.6 mmol) was added to the reaction solution at 0°C under nitrogen atmosphere, and stirred at 80°C for 2 hours. The mixture was filtered at room temperature, and the filter cake was washed with toluene (10 mL x 3). The organic phases were combined, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA=3:1) to obtain 2.8 g of the title compound as a light yellow solid with a yield of 82%.

[0692] LC-MS: m / z 300 [M+H] + .

[0693] Step 2: Preparation of 2-cyclopropyl-6-methoxy-7-methylbenzo[d]thiazole (18b)

[0694] N-(2-bromo-4-methoxy-3-methylphenyl)cyclopropanethioamide (18a) (2.50 g, 8.36 mmol) was dissolved in DMF (30 mL), and Cs2CO3 (5.45 g, 16.7 mmol), CuI (79.4 mg, 0.418 mmol), and dipyridine (130 mg, 0.836 mmol) were added. The mixture was stirred at 25°C overnight under a nitrogen atmosphere. Water (100 mL) was added to quench the mixture, and the mixture was extracted with EA (100 mL x 3), washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 1.23 g of the title compound as a light yellow solid with a yield of 68.2%.

[0695] LC-MS: m / z 220 [M+H] + .

[0696] Step 3: Preparation of 2-cyclopropyl-6-methoxy-7-methyl-5-nitrobenzo[d]thiazole (18c)

[0697] 2-Cyclopropyl-6-methoxy-7-methylbenzo[d]thiazole (18b) (1.10 g, 5.02 mmol) was dissolved in TFA (9 ml) at room temperature. HNO3 (3 mL) was added dropwise to the reaction solution at 0°C under nitrogen atmosphere. The mixture was stirred at 0°C for 2 hours and at room temperature overnight. Water (30 mL) was added at 0°C to quench the mixture, and the mixture was extracted with EA (30 mL x 3), washed with saturated brine (60 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 800 mg of the title compound as a light yellow solid in a yield of 61.1%.

[0698] LC-MS: m / z 265 [M+H] + .

[0699] Step 4: Preparation of 2-cyclopropyl-7-methyl-5-nitrobenzo[d]thiazol-6-ol (18d)

[0700] 2-Cyclopropyl-6-methoxy-7-methyl-5-nitrobenzo[d]thiazole (18c) (700 mg, 2.65 mmol) was dissolved in DCM (15 ml). BBr3 (10.6 mL, 1 M) was added dropwise to the reaction solution at 0°C under nitrogen atmosphere, and stirred at 0°C for 0.5 hours. Methanol (40 mL) was added at 0°C to quench the mixture, and the mixture was extracted with DCM (50 mL x 3), washed with saturated brine (80 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 210 mg of the title compound as a light yellow solid with a yield of 32.8%.

[0701] LC-MS: m / z 251[M+H] + .

[0702] The remaining steps were the same as the preparation method of Example 1, except that 2-cyclopropyl-7-methyl-5-nitrobenzo[d]thiazol-6-ol (18d) was used instead of 5-hydroxy-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1d) in step 5 to obtain the title compound 18.

[0703] LC-MS: m / z 548.2 [M+H] + .

[0704] 1H NMR (400MHz, DMSO-d6) δ7.88 (s, 1H), 7.44-7.24 (m, 3H), 7.23-7.15 (m, 2H), 5.54 (dd, J=11.9, 8.0Hz, 1H), 5.4 2 (s, 2H), 4.85 (dd, J=11.9, 10.1Hz, 1H), 4.38 (dd, J=10.0, 8.0Hz, 1H), 4.04 (ddd, J=12.4, 7.1, 5.0Hz, 1H), 3. 64 (ddd, J=12.8, 8.3, 4.8Hz, 1H), 3.36 (s, 3H), 2.81 (ddd, J=15.4, 8.4, 5.0Hz, 1H), 2.68 (ddd, J=15.6, 7.2, 4. 9Hz, 1H), 2.55 (dt, J=6.7, 4.1Hz, 1H), 2.44 (s, 3H), 1.25 (dt, J=7.6, 3.0Hz, 2H), 1.15 (dt, J=4.7, 3.1Hz, 2H).

[0705] Example 19: Preparation of (S)-7-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-2-(tert-butyl)-5,10-dimethyl-7,8-dihydrooxazolo[4′,5′:4,5]benzo[1,2-b][1,4]oxazepin-6(5H)-one (19)

[0706]

[0707] Step 1: Preparation of N-(2-bromo-4-methoxy-3-methylphenyl)pivalamide (19a)

[0708] At room temperature, 2-bromo-4-methoxy-3-methylaniline (17b) (7.40 g, 34.4 mmol) was dissolved in 100 ml of DCM, and DIEA (13.0 g, 103 mmol) was added. Under nitrogen atmosphere, pivaloyl chloride (6.19 g, 51.6 mmol) was added to the reaction solution at 0°C and stirred at room temperature for 2 hours. Water (100 mL) was added to quench the mixture, and the mixture was extracted with DCM (200 mL x 3), washed with saturated brine (200 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 4:1) to obtain 7.9 g of the title compound as a white solid with a yield of 78.6%.

[0709] LC-MS: m / z 300 [M+H] + .

[0710] Step 2: Preparation of 2-tert-butyl-6-methoxy-7-methylbenzo[d]oxazole (19b)

[0711] N-(2-bromo-4-methoxy-3-methylphenyl)pivalamide (19a) (1.00 g, 3.30 mmol) was dissolved in DMF (10 mL), and Cs2CO3 (2.18 g, 6.68 mmol), CuI (30.0 mg, 0.165 mmol), and dipyridine (50.0 mg, 0.330 mmol) were added. The mixture was stirred at 120°C overnight under a nitrogen atmosphere. Water (20 mL) was added to quench the mixture, and the mixture was extracted with EA (20 mL x 3), washed with saturated brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 550 mg of the title compound as a light yellow solid with a yield of 75.3%.

[0712] LC-MS: m / z 220 [M+H] + .

[0713] Step 3: Preparation of 2-tert-butyl-6-methoxy-7-methyl-5-nitrobenzo[d]oxazole (19c)

[0714] 2-tert-Butyl-6-methoxy-7-methylbenzo[d]oxazole (19b) (1.50 g, 6.85 mmol) was dissolved in TFA (15 ml). Concentrated HNO3 (5 mL) was added dropwise to the reaction solution at 0°C under nitrogen atmosphere. The mixture was stirred at 0°C for 2 hours and at room temperature overnight. Water (30 mL) was added at 0°C to quench the mixture. The mixture was extracted with EA (30 mL x 3), washed with saturated brine (60 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 3:1) to obtain 900 mg of the title compound as a light yellow solid with a yield of 51.1%.

[0715] LC-MS: m / z 265 [M+H] + .

[0716] Step 4: Preparation of 2-tert-butyl-7-methyl-5-nitrobenzo[d]oxazol-6-ol (19d)

[0717] 2-tert-Butyl-6-methoxy-7-methyl-5-nitrobenzo[d]oxazole (19c) (1.00 g, 3.79 mmol) was dissolved in DCM (15 ml). BBr3 (7.6 mL, 1 M) was added dropwise to the reaction solution at 0°C under nitrogen atmosphere, and stirred at 0°C for 2 hours. Methanol was added to quench at 0°C, extracted with DCM (60 mL x 3), washed with saturated brine (80 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 640 mg of the title compound as a light yellow solid, with a yield of 67.3%.

[0718] LC-MS: m / z 251[M+H] + .

[0719] The remaining steps were the same as the preparation method of Example 1, except that 2-tert-butyl-7-methyl-5-nitrobenzo[d]oxazol-6-ol (19d) was used instead of 5-hydroxy-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1d) in step 5 to obtain the title compound 19.

[0720] LC-MS: m / z 548.2 [M+H] + .

[0721] 1 H NMR (400MHz, DMSO-d6) δ7.71 (s, 1H), 7.39-7.28 (m, 3H), 7.23-7.13 (m, 2H), 5.54 (dd, J=11 .9, 8.1Hz, 1H), 5.42 (s, 2H), 4.83 (dd, J=11.9, 10.1Hz, 1H), 4.38 (dd, J=10.1, 8.1Hz, 1H), 4 .05 (ddd, J=12.4, 7.1, 5.1Hz, 1H), 3.64 (ddd, J=12.8, 8.5, 4.7Hz, 1H), 3.34 (s, 3H), 2.81 (d dd, J=15.3, 8.3, 5.0Hz, 1H), 2.68 (ddd, J=15.6, 7.0, 4.7Hz, 1H), 2.42 (s, 3H), 1.45 (s, 9H).

[0722] Example 20: Preparation of (S)-7-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-2-cyclopropyl-9-methyl-6,7-dihydrothiazolo[5′,4′:4,5]benzo[1,2-b][1,4]oxazepin-8(9H)-one (20)

[0723]

[0724] Step 1: Preparation of N-(2-bromo-4-methoxyphenyl)cyclopropanethioamide (20a)

[0725] N-(2-bromo-4-methoxyphenyl)cyclopropanecarboxamide (7a) (6.10 g, 22.6 mmol) was dissolved in toluene (100 ml). Lawesson's reagent (18.4 g, 45.3 mmol) was added to the reaction solution at 0°C under nitrogen atmosphere, and stirred at 80°C for 2 hours. The mixture was filtered at room temperature, and the filter cake was washed with toluene (20 mL x 3). The organic phases were combined, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 5.8 g of the title compound as a light yellow solid with a yield of 81.4%.

[0726] LC-MS: m / z 286 [M+H] + .

[0727] Step 2: Preparation of 2-cyclopropyl-6-methoxybenzo[d]thiazole (20b)

[0728] N-(2-bromo-4-methoxyphenyl)cyclopropanethioamide (20a) (5.40 g, 18.9 mmol) was dissolved in DMF (60 mL), and Cs2CO3 (12.4 g, 37.9 mmol), CuI (180 mg, 0.945 mmol), and dipyridine (295 mg, 1.89 mmol) were added. The mixture was stirred at 25°C overnight under a nitrogen atmosphere. Water (100 mL) was added to quench the mixture, and the mixture was extracted with EA (100 mL x 3), washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 3.20 g of the title compound as a light yellow solid with a yield of 82.1%.

[0729] LC-MS: m / z 206 [M+H] + .

[0730] Step 3: Preparation of 2-cyclopropyl-6-methoxy-5-nitrobenzo[d]thiazole (20c)

[0731] 2-Cyclopropyl-6-methoxybenzo[d]thiazole (20b) (3.20 g, 15.6 mmol) was dissolved in TFA (30 ml) at room temperature. Concentrated HNO3 (10 mL) was added dropwise to the reaction solution at 0°C under nitrogen atmosphere. The mixture was stirred at 0°C for 2 hours and at room temperature overnight. Water (50 mL) was added at 0°C to quench the mixture, and the mixture was extracted with EA (50 mL x 3), washed with saturated brine (60 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 800 mg of the title compound as a light yellow solid in a yield of 20.5%.

[0732] LC-MS: m / z 251[M+H] + .

[0733] Step 4: Preparation of 2-cyclopropyl-5-nitrobenzo[d]thiazol-6-ol (20d)

[0734] 2-Cyclopropyl-6-methoxy-5-nitrobenzo[d]thiazole (20c) (700 mg, 2.80 mmol) was dissolved in DCM (15 ml). BBr3 (11.2 mL, 1 M) was added dropwise to the reaction solution at 0°C under nitrogen atmosphere, and stirred at 0°C for 0.5 hours. Water (40 mL) was added at 0°C to quench the mixture, and the mixture was extracted with DCM (50 mL x 3), washed with saturated brine (80 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 420 mg of the title compound as a light yellow solid with a yield of 63.3%.

[0735] LC-MS: m / z 237[M+H] + .

[0736] The remaining steps were the same as the preparation method of Example 1, except that 2-cyclopropyl-5-nitrobenzo[d]thiazol-6-ol (20d) was used instead of 5-hydroxy-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1d) in step 5 to obtain the title compound 20.

[0737] LC-MS: m / z 534.1[M+H] + .

[0738] 1H NMR (400MHz, DMSO-d6) δ8.01 (s, 1H), 7.92 (s, 1H), 7.43-7.27 (m, 3H), 7.19 (dd, J=6.9, 1.8Hz, 2H), 5.58 (dd , J=11.9, 7.9Hz, 1H), 5.42 (s, 2H), 4.85 (dd, J=12.0, 10.1Hz, 1H), 4.34 (dd, J=10.1, 7.9Hz, 1H), 4.04 (ddd, J=12.2, 6.9, 5.0Hz, 1H), 3.64 (ddd, J=12.9, 8.6, 4.8Hz, 1H), 3.37 (s, 3H), 2.81 (ddd, J=15.5, 8.6, 5.0Hz, 1 H), 2.68 (ddd, J=15.7, 7.0, 4.8Hz, 1H), 2.61-2.57 (m, 1H), 1.24 (dt, J=8.0, 3.3Hz, 2H), 1.19-1.10 (m, 2H).

[0739] Example 21: Preparation of (S)-7-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-2-cyclopropyl-9-methyl-6,7-dihydrothiazolo[5′,4′:4,5]benzo[1,2-b][1,4]oxazepin-8(9H)-one (21)

[0740]

[0741] Step 1: Preparation of N-(2-bromo-5-methoxyphenyl)cyclopropanethioamide (21a)

[0742] N-(2-bromo-5-methoxyphenyl)cyclopropanecarboxamide (15a) (6.10 g, 22.6 mmol) was dissolved in toluene (100 ml). Lawesson's reagent (18.4 g, 45.3 mmol) was added to the reaction solution at 0°C under nitrogen atmosphere, and stirred at 80°C for 2 hours. The mixture was filtered at room temperature, and the filter cake was washed with toluene (20 mL x 3). The organic phases were combined, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 5.8 g of the title compound as a light yellow solid with a yield of 81.4%.

[0743] LC-MS: m / z 286 [M+H] + .

[0744] Step 2: Preparation of 2-cyclopropyl-5-methoxybenzo[d]thiazole (21b)

[0745] N-(2-bromo-5-methoxyphenyl)cyclopropanethioamide (21a) (5.40 g, 18.9 mmol) was dissolved in DMF (60 mL), and Cs2CO3 (12.4 g, 37.9 mmol), CuI (180 mg, 0.945 mmol), and dipyridine (295 mg, 1.89 mmol) were added. The mixture was stirred at 25°C overnight under a nitrogen atmosphere. Water (100 mL) was added to quench the mixture, and the mixture was extracted with EA (100 mL x 3), washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 3.20 g of the title compound as a light yellow solid with a yield of 82.1%.

[0746] LC-MS: m / z 206 [M+H] + .

[0747] Step 3: Preparation of 2-cyclopropyl-5-methoxy-6-nitrobenzo[d]thiazole (21c)

[0748] 2-Cyclopropyl-5-methoxybenzo[d]thiazole (21b) (3.20 g, 15.6 mmol) was dissolved in TFA (30 ml) at room temperature. Concentrated HNO3 (10 mL) was added dropwise to the reaction solution at 0°C under nitrogen atmosphere. The mixture was stirred at 0°C for 2 hours and at room temperature overnight. Water (50 mL) was added at 0°C to quench the mixture, and the mixture was extracted with EA (50 mL x 3), washed with saturated brine (60 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 800 mg of the title compound as a light yellow solid in a yield of 20.5%.

[0749] LC-MS: m / z 251[M+H] + .

[0750] Step 4: Preparation of 2-cyclopropyl-6-nitrobenzo[d]thiazol-5-ol (21d)

[0751] 2-Cyclopropyl-5-methoxy-6-nitrobenzo[d]thiazole (21c) (700 mg, 2.80 mmol) was dissolved in DCM (15 ml). BBr3 solution (11.2 mL, 1 M) was added dropwise to the reaction solution at 0°C under nitrogen atmosphere, and stirred at 0°C for 0.5 hours. Water (40 mL) was added at 0°C to quench the mixture, and the mixture was extracted with DCM (50 mL x 3), washed with saturated brine (80 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 420 mg of the title compound as a light yellow solid with a yield of 63.3%.

[0752] LC-MS: m / z 237[M+H] + .

[0753] The remaining steps were the same as the preparation method of Example 1, except that 2-cyclopropyl-6-nitrobenzo[d]thiazol-5-ol (21d) was used instead of 5-hydroxy-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1d) in step 5 to obtain the title compound 21.

[0754] LC-MS: m / z 534.1[M+H] + .

[0755] 1 H NMR (400MHz, DMSO-d6) δ8.19 (s, 1H), 7.70 (s, 1H), 7.39-7.25 (m, 3H), 7.22-7.15 (m, 2H), 5.56 (dd, J=12.0, 8.0Hz, 1H), 5.42 (s, 2H), 4.85 (dd, J=12.0, 10.1Hz, 1H), 4.36 (dd, J=10.1, 8.0Hz, 1H), 4.0 3 (ddd, J=12.2, 7.0, 5.0Hz, 1H), 3.65 (ddd, J=12.8, 8.5, 4.8Hz, 1H), 3.35 (s, 3H), 2.81 (ddd, J=15. 4, 8.5, 5.0Hz, 1H), 2.74-2.64 (m, 1H), 2.54 (s, 1H), 1.30-1.21 (m, 2H), 1.15 (tq, J=6.9, 4.7Hz, 2H).

[0756] Example 22: Preparation of (S)-7-(3-chloro-2-(2-fluorobenzyl)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-2-cyclopropyl-5-methyl-7,8-dihydrooxazolo[4′,5′:4,5]benzo[1,2-b][1,4]oxazepin-6(5H)-one (22)

[0757]

[0758] Step 1: Preparation of (S)-5-chloro-4-(2-((2-cyclopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydrooxazolo[4′,5′:4,5]benzo[1,2-b][1,4]oxazepin-7-yl)amino)ethyl)-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylic acid ethyl ester (22a)

[0759] At room temperature, (S)-7-amino-2-cyclopropyl-5-methyl-7,8-dihydrooxazolo[4′,5′:4,5]benzo[1,2-b][1,4]oxazepin-6(5H)-one (7l) (80.0 mg, 0.310 mmol), ethyl 5-chloro-1-(2-fluorobenzyl)-4-(2-oxoethyl)-1H-pyrazole-3-carboxylate (10d) (145 mg, 0.450 mmol) and tetraethyl titanate (106 mg, 0.470 mmol) were dissolved in THF (8 mL), stirred at room temperature for 1 hour, methanol (4 mL) and sodium cyanoborohydride (38.9 mg, 0.620 mmol) were added, and the mixture was stirred at room temperature for 5 hours. 10 mL of saturated sodium bicarbonate solution was added, extracted with EA (30 mL x 3), washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by high pressure preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 um 100A, mobile phase: acetonitrile / water, gradient: 10%-50%, 0.05% formic acid, 30 min) to give 20.0 mg of the title compound as an off-white solid, with a yield of 11.1%.

[0760] LC-MS: m / z 582[M+H] + .

[0761] Step 2: Preparation of (S)-7-(3-chloro-2-(2-fluorobenzyl)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-2-cyclopropyl-5-methyl-7,8-dihydrooxazolo[4′,5′:4,5]benzo[1,2-b][1,4]oxazepin-6(5H)-one (22)

[0762] At 0°C, (S)-5-chloro-4-(2-((2-cyclopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydrooxazolo[4′,5′:4,5]benzo[1,2-b][1,4]oxazepin-7-yl)amino)ethyl)-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylic acid ethyl ester (22a) (20.0 mg, 0.0340 mmol) was dissolved in 1 ml of chloroform. Under nitrogen atmosphere, Al(CH3)3 (0.09 ml, 2 M) was added to the reaction solution and stirred at 50°C for 3 hours. The mixture was quenched with water, extracted with EA (10 mL x 3), washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by high pressure preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 um 100A, mobile phase: acetonitrile / water, gradient: 10%-50%, 0.05% formic acid, 30 min) to give 15 mg of the title compound as an off-white solid, in a yield of 55.5%.

[0763] LC-MS: m / z 536.0 [M+H] + .

[0764] 1 H NMR (400MHz, DMSO-d6) δ7.80 (s, 1H), 7.60 (s, 1H), 7.39-7.37 (m, 1H), 7.25-7.12 (m, 3H), 5.57-5.52 (m, 1H), 5.47 (s, 2H), 4.86-4.8 0 (m, 1H), 4.35-4.30 (m, 1H), 4.03 (m, 1H), 3.64-3.62 (m, 1H), 3.34 (s, 3H), 2.77-2.71 (m, 2H), 2.29-2.21 (m, 1H), 1.23-1.14 (m, 4H).

[0765] Example 23: Preparation of (S)-7-(3-chloro-2-(2-fluorobenzyl)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-2-cyclopropyl-9-methyl-6,7-dihydrooxazolo[5′,4′:4,5]benzo[1,2-b][1,4]oxazepin-8(9H)-one (23)

[0766]

[0767] Step 1: Preparation of (S)-5-chloro-4-(2-((2-cyclopropyl-9-methyl-8-oxo-6,7,8,9-tetrahydrooxazolo[5′,4′:4,5]benzo[1,2-b][1,4]oxazepin-7-yl)amino)ethyl)-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylic acid ethyl ester (23a)

[0768] At room temperature, (S)-7-amino-2-cyclopropyl-9-methyl-6,7-dihydrooxazolo[5′,4′:4,5]benzo[1,2-b][1,4]oxazepin-8(9H)-one (15l) (92.0 mg, 0.360 mmol), ethyl 5-chloro-1-(2-fluorobenzyl)-4-(2-oxoethyl)-1H-pyrazole-3-carboxylate (10d) (127 mg, 0.390 mmol) and tetraethyl titanate (123 mg, 0.540 mmol) were dissolved in THF (5 mL), stirred at room temperature for 2 hours, methanol (2.5 mL) and sodium cyanoborohydride (45.2 mg, 0.720 mmol) were added, and the mixture was stirred at room temperature overnight. 10 mL of saturated sodium bicarbonate solution was added, extracted with EA (30 mL x 3), washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by high pressure preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 um 100A, mobile phase: acetonitrile / water, gradient: 10%-50%, 0.05% formic acid, 30 min) to give 120 mg of the title compound as an off-white solid, with a yield of 52.4%.

[0769] LC-MS: m / z 582[M+H] + .

[0770] Step 2: Preparation of (S)-7-(3-chloro-2-(2-fluorobenzyl)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-2-cyclopropyl-9-methyl-6,7-dihydrooxazolo[5′,4′:4,5]benzo[1,2-b][1,4]oxazepin-8(9H)-one (23)

[0771] At 0°C, (S)-5-chloro-4-(2-((2-cyclopropyl-9-methyl-8-oxo-6,7,8,9-tetrahydrooxazolo[5′,4′:4,5]benzo[1,2-b][1,4]oxazepin-7-yl)amino)ethyl)-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylic acid ethyl ester (23a) (100 mg, 0.170 mmol) was dissolved in 1 ml of chloroform. Under nitrogen atmosphere, Al(CH3)3 (0.27 ml, 2 M) was added to the reaction solution and stirred at 50°C for 2 hours. The mixture was quenched with water, extracted with EA (10 mL x 3), washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by high pressure preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 um 100A, mobile phase: acetonitrile / water, gradient: 10%-50%, 0.05% formic acid, 30 min) to give 30.0 mg of the title compound as an off-white solid, with a yield of 27.3%.

[0772] LC-MS: m / z 536.0 [M+H] + .

[0773] 1 H NMR (400MHz, DMSO-d6) δ7.88 (s, 1H), 7.49 (s, 1H), 7.36 (s, 1H), 7.23-7.10 (m, 3H), 5 .57-5.52(m, 1H), 5.47(s, 2H), 4.84-4.79(m, 1H), 4.35-4.30(dd, J=10.0, 8.2Hz, 1H) , 4.04-4.00 (dt, J=12.2, 5.9Hz, 1H), 3.67-3.61 (m, 1H), 3.34 (s, 3H), 2.78-2.77 (m, 1H), 2.72-2.65 (m, 1H), 2.33-2.26 (ddd, J=13.0, 8.2, 4.9Hz, 1H), 1.22-1.13 (m, 4H).

[0774] Example 24: Preparation of (S)-7-(3-chloro-2-(3,5-difluorobenzyl)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-2-cyclopropyl-5-methyl-7,8-dihydrooxazolo[4′,5′:4,5]benzo[1,2-b][1,4]oxazepin-6(5H)-one (24)

[0775]

[0776]

[0777] Step 1: Preparation of tert-butyl (E)-2-(3,5-difluorobenzylidene)hydrazine-1-carboxylate (24a)

[0778] At room temperature, 3,5-difluorobenzaldehyde (10.0 g, 70.4 mmol) was dissolved in DCM (100 ml), tert-butyl hydrazinecarboxylate (9.29 g, 70.4 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to obtain 18.0 g of the title compound as an off-white solid, with a yield of 98.5%.

[0779] LC-MS: m / z 257 [M+H] + .

[0780] Step 2: Preparation of tert-butyl 2-(3,5-difluorobenzyl)hydrazine-1-carboxylate (24b)

[0781] Tert-butyl (E)-2-(3,5-difluorobenzylidene)hydrazine-1-carboxylate (24a) (5.00 g, 19.5 mmol) was dissolved in EtOH (30 mL), and aqueous Pd / C (2.07 g) was added at room temperature. The mixture was stirred at 50°C overnight under a hydrogen atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 5:1) to obtain 4.90 g of the title compound as an off-white solid, with a yield of 97.4%.

[0782] LC-MS: m / z 259 [M+H] + .

[0783] Step 3: Preparation of (3,5-difluorobenzyl)hydrazine (24c)

[0784] Tert-butyl 2-(3,5-difluorobenzyl)hydrazine-1-carboxylate (24b) (5.00 g, 19.4 mmol) was dissolved in MeOH (25 mL), concentrated hydrochloric acid (8 ml) was added at room temperature, and stirred at 40°C overnight. The pH was adjusted to 10 with saturated sodium bicarbonate solution, extracted with EA (50 mL x 3), washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 5:1) to obtain 1.60 g of the title compound as a yellow oil, with a yield of 53.3%.

[0785] Step 4: Preparation of ethyl 1-(3,5-difluorobenzyl)-5-hydroxy-1H-pyrazole-3-carboxylate (24d)

[0786] At room temperature, diethyl oxalate sodium salt (8.77 g, 41.8 mmol) was dissolved in HAc (34.2 g, 570 mmol) and dioxane (180 ml), stirred at room temperature for 0.5 hours, (3,5-difluorobenzyl)hydrazine (24c) (6.00 g, 38.0 mmol) was added, and stirred at 100°C for 2 hours. Water was added to quench, extracted with EA (200 mL x 3), washed with saturated brine (200 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 5.50 g of the title compound as a yellow semi-solid, with a yield of 51.4%.

[0787] LC-MS: m / z 283[M+H] + .

[0788] Step 5: Preparation of 5-chloro-1-(3,5-difluorobenzyl)-4-formyl-1H-pyrazole-3-carboxylic acid ethyl ester (24e) 1-(3,5-difluorobenzyl)-5-hydroxy-1H-pyrazole-3-carboxylic acid ethyl ester (24d) (1.00 g, 3.55 mmol) was dissolved in DMF (2.8 mL, 28.4 mmol), POCl3 (5.6 ml, 56.8 mmol) was added at 0°C, and stirred at 90°C overnight. The reaction solution was poured into ice water, the pH was adjusted to 10 with saturated sodium bicarbonate, extracted with EA (30 mL x 3), washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 1:1) to obtain 590 mg of the title compound as a yellow semi-solid, yield: 50.6%.

[0789] LC-MS: m / z 329 [M+H] + .

[0790] Step 6: Preparation of (E)-ethyl 5-chloro-1-(3,5-difluorobenzyl)-4-(2-methoxyvinyl)-1H-pyrazole-3-carboxylate (24f)

[0791] Dissolve chloro(methoxymethyl)triphenylphosphine (1.38 g, 4.02 mmol) in THF (5 mL), add t-BuOK (408 mg, 3.64 mmol) in THF (2 mL) at 0°C, and stir for 0.5 hours. Slowly add 5-chloro-1-(3,5-difluorobenzyl)-4-formyl-1H-pyrazole-3-carboxylic acid ethyl ester (24e) (300 mg, 0.910 mmol) in THF (2 mL), and stir at room temperature overnight. Add the reaction solution into ice water, extract with EA (30 mL x 3), wash with saturated brine (100 mL x 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 350 mg of the title compound as a yellow oil, with a yield of 67.1%.

[0792] LC-MS: m / z 357 [M+H] + .

[0793] Step 7: Preparation of ethyl 5-chloro-1-(3,5-difluorobenzyl)-4-(2-oxoethyl)-1H-pyrazole-3-carboxylate (24 g)

[0794] Ethyl (E)-5-chloro-1-(3,5-difluorobenzyl)-4-(2-methoxyvinyl)-1H-pyrazole-3-carboxylate (24f) (350 mg, 0.980 mmol) was dissolved in THF (5 ml), and hydrochloric acid (6 M) (8.2 mL, 49.2 mmol) was added dropwise, and stirred at 60°C for 1 hour. At 0°C, the pH was adjusted to 10 with 2 mol / L NaOH solution, extracted with EA (10 mL x 3), washed with saturated brine (30 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 409 mg (crude) of the title compound as a yellow oil.

[0795] LC-MS: m / z 343 [M+H] + .

[0796] Step 8: Preparation of (S)-5-chloro-4-(2-((2-cyclopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydrooxazolo[4′,5′:4,5]benzo[1,2-b][1,4]oxazepin-7-yl)amino)ethyl)-1-(3,5-difluorobenzyl)-1H-pyrazole-3-carboxylic acid ethyl ester (24h)

[0797] At room temperature, (S)-7-amino-2-cyclopropyl-5-methyl-7,8-dihydrooxazolo[4′,5′:4,5]benzo[1,2-b][1,4]oxazepin-6(5H)-one (7l) (138 mg, 0.530 mmol), ethyl 5-chloro-1-(3,5-difluorobenzyl)-4-(2-oxoethyl)-1H-pyrazole-3-carboxylate (24 g) (200 mg, 0.580 mmol) and tetraethyl titanate (181 mg, 0.800 mmol) were dissolved in THF (10 mL), stirred at room temperature for 0.5 hour, methanol (5 mL) and sodium cyanoborohydride (66.6 mg, 1.06 mmol) were added, and the mixture was stirred at room temperature overnight. 10 mL of saturated sodium bicarbonate solution was added, extracted with EA (30 mL x 3), washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by high pressure preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 um 100A, mobile phase: acetonitrile / water, gradient: 10%-50%, 0.05% formic acid, 30 min) to give 200 mg of the title compound as an off-white solid, with a yield of 63.1%.

[0798] LC-MS: m / z 600[M+H] + .

[0799] Step 9: Preparation of (S)-7-(3-chloro-2-(3,5-difluorobenzyl)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-2-cyclopropyl-5-methyl-7,8-dihydrooxazolo[4′,5′:4,5]benzo[1,2-b][1,4]oxazepin-6(5H)-one (24)

[0800] At 0°C, (S)-5-chloro-4-(2-((2-cyclopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydrooxazolo[4′,5′:4,5]benzo[1,2-b][1,4]oxazepin-7-yl)amino)ethyl)-1-(3,5-difluorobenzyl)-1H-pyrazole-3-carboxylic acid ethyl ester (24h) (180 mg, 0.300 mmol) was dissolved in 2 ml of chloroform. Under nitrogen atmosphere, Al(CH3)3 (0.45 ml, 2 M) was added to the reaction solution and stirred at 50°C for 3 hours. The mixture was quenched with water, extracted with EA (10 mL x 3), washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by high pressure preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 um 100A, mobile phase: acetonitrile / water, gradient: 10%-50%, 0.05% formic acid, 30 min) to give 61.3 mg of the title compound as an off-white solid, in a yield of 37.3%.

[0801] LC-MS: m / z 554 [M+H] + .

[0802] 1 H NMR (400MHz, DMSO-d6) δ7.80 (s, 1H), 7.60 (s, 1H), 7.21 (tt, J=9.4, 2.3Hz, 1H), 6.85-6.77 (m , 2H), 5.59-5.54 (dd, J=11.9, 8.0Hz, 1H), 5.48 (s, 2H), 4.87-4.82 (m, 1H), 4.37-4.32 (m, 1H) , 4.09-4.02 (m, 1H), 3.67-3.62 (m, 1H), 3.35 (s, 3H), 2.80 (ddd, J=13.7, 8.6, 5.0Hz, 1H), 2.7 3-2.66 (dt, J=11.6, 4.9Hz, 1H), 2.33-2.26 (ddd, J=12.9, 8.2, 5.0Hz, 1H), 1.23-1.13 (m, 4H).

[0803] Example 25: Preparation of (S)-7-(3-chloro-2-(4-fluorobenzyl)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-2-cyclopropyl-5-methyl-7,8-dihydrooxazolo[4′,5′:4,5]benzo[1,2-b][1,4]oxazepin-6(5H)-one (25)

[0804]

[0805] Step 1: Preparation of ethyl 1-(4-fluorobenzyl)-5-hydroxy-1H-pyrazole-3-carboxylate (25a)

[0806] At room temperature, diethyl oxalate sodium salt (6.56 g, 31.2 mmol) was dissolved in HAc (10 mL) and dioxane (80 ml), stirred at room temperature for 0.5 hours, (4-fluorobenzyl) hydrazine hydrochloride (5.00 g, 28.4 mmol) was added, and stirred at 100°C for 2 hours. Water was added to quench, extracted with EA (200 mL x 3), washed with saturated brine (200 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 3.49 g of the title compound as a yellow semi-solid, with a yield of 46.1%.

[0807] LC-MS: m / z 265 [M+H] + .

[0808] Step 2: Preparation of 5-chloro-1-(4-fluorobenzyl)-4-formyl-1H-pyrazole-3-carboxylic acid ethyl ester (25b)

[0809] Ethyl 1-(4-fluorobenzyl)-5-hydroxy-1H-pyrazole-3-carboxylate (25a) (3.00 g, 11.4 mmol) was dissolved in DMF (9 mL), POCl3 (18 ml) was added at 0°C, and the mixture was stirred at 90°C overnight. The reaction solution was added to ice water, the pH was adjusted to 10 with saturated sodium bicarbonate, extracted with EA (30 mL x 3), washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 1:1) to obtain 1.7 g of the title compound as a yellow semisolid with a yield of 48.1%.

[0810] LC-MS: m / z 311[M+H] + .

[0811] Step 3: Preparation of ethyl 5-chloro-1-(4-fluorobenzyl)-4-(2-methoxyvinyl)-1H-pyrazole-3-carboxylate (25c)

[0812] Dissolve chloro(methoxymethyl)triphenylphosphine (7.30 g, 21.3 mmol) in THF (20 mL), add t-BuOK (2.17 g, 19.4 mmol) in THF (5 mL) at 0°C, and stir for 0.5 hours. Slowly add 5-chloro-1-(4-fluorobenzyl)-4-formyl-1H-pyrazole-3-carboxylic acid ethyl ester (25b) (1.50 g, 4.84 mmol) in THF (5 mL), and stir at room temperature overnight. Add the reaction solution into ice water, extract with EA (30 mL x 3), wash with saturated brine (100 mL x 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 500 mg of the title compound as a yellow oil, yield: 30.4%.

[0813] LC-MS: m / z 339[M+H] + .

[0814] Step 4: Preparation of ethyl 5-chloro-1-(4-fluorobenzyl)-4-(2-oxoethyl)-1H-pyrazole-3-carboxylate (25d)

[0815] Ethyl (E)-5-chloro-1-(4-fluorobenzyl)-4-(2-methoxyvinyl)-1H-pyrazole-3-carboxylate (25c) (500 mg, 1.48 mmol) was dissolved in THF (5 ml), and hydrochloric acid (8 mL, 6 M) was added dropwise, and stirred at 60°C for 1 hour. At 0°C, the pH was adjusted to 10 with 2 mol / L NaOH solution, extracted with EA (10 mL x 3), washed with saturated brine (30 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 600 mg (crude) of the title compound as a yellow oil.

[0816] LC-MS: m / z 325 [M+H] + .

[0817] Step 5: Preparation of (S)-5-chloro-4-(2-((2-cyclopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydrooxazolo[4′,5′:4,5]benzo[1,2-b][1,4]oxazepin-7-yl)amino)ethyl)-1-(4-fluorobenzyl)-1H-pyrazole-3-carboxylic acid ethyl ester (25e)

[0818] At room temperature, (S)-7-amino-2-cyclopropyl-5-methyl-7,8-dihydrooxazolo[4′,5′:4,5]benzo[1,2-b][1,4]oxazepin-6(5H)-one (71) (92.0 mg, 0.360 mmol), ethyl 5-chloro-1-(4-fluorobenzyl)-4-(2-oxoethyl)-1H-pyrazole-3-carboxylate (25d) (127 mg, 0.390 mmol) and tetraethyl titanate (123 mg, 0.540 mmol) were dissolved in THF (5 mL), stirred at room temperature for 2 hours, methanol (2.5 mL) and sodium cyanoborohydride (45.2 mg, 0.720 mmol) were added, and the mixture was stirred at room temperature overnight. 10 mL of saturated sodium bicarbonate solution was added, extracted with EA (30 mL x 3), washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by high pressure preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 um 100A, mobile phase: acetonitrile / water, gradient: 10%-50%, 0.05% formic acid, 30 min) to give 120 mg of the title compound as an off-white solid, with a yield of 52.4%.

[0819] LC-MS: m / z 582[M+H] + .

[0820] Step 6: Preparation of (S)-7-(3-chloro-2-(4-fluorobenzyl)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-2-cyclopropyl-5-methyl-7,8-dihydrooxazolo[4′,5′:4,5]benzo[1,2-b][1,4]oxazepin-6(5H)-one (25)

[0821] At 0°C, (S)-5-chloro-4-(2-((2-cyclopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydrooxazolo[4′,5′:4,5]benzo[1,2-b][1,4]oxazepin-7-yl)amino)ethyl)-1-(4-fluorobenzyl)-1H-pyrazole-3-carboxylic acid ethyl ester (25e) (60.0 mg, 0.103 mmol) was dissolved in 2 ml of chloroform. Under nitrogen atmosphere, Al(CH3)3 (0.15 ml, 2 M) was added to the reaction solution and stirred at 50°C for 2 hours. The mixture was quenched with water, extracted with EA (10 mL x 3), washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by high pressure preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 um 100A, mobile phase: acetonitrile / water, gradient: 10%-50%, 0.05% formic acid, 30 min) to give 59.0 mg of the title compound as an off-white solid, with a yield of 91.6%.

[0822] LC-MS: m / z 536.0 [M+H] + .

[0823] 1 H NMR (400MHz, DMSO-d6) δ7.80 (s, 1H), 7.60 (s, 1H), 7.26-7.16 (m, 4H), 5.56 (dd, J =11.9, 8.0, 1H), 5.42 (s, 2H), 4.84 (dd, J = 11.7, 10.3, 1H), 4.34 (dd, J = 10.0, 8.1H z, 1H), 4.04 (dt, J=12.2, 5.3Hz, 1H), 3.65-3.60 (m, 1H), 3.34 (s, 3H), 2.79-2.77 ( m, 1H), 2.70-2.64 (m, 1H), 2.29 (ddd, J=12.9, 8.2, 4.9Hz, 1H), 1.23-1.13 (m, 4H).

[0824] Example 26: Preparation of (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-1,7-dimethyl-1,3,4,7-tetrahydro-2H-[1,4]thiazepino[3,2-f]indol-2-one (26)

[0825]

[0826] Step 1: Preparation of 6-fluoro-5-nitroindoline-2,3-dione (26a)

[0827] At 0°C, 6-fluoroindoline-2,3-dione (10.0 g, 60.6 mmol) was dissolved in concentrated H28O4 (100 ml). Under nitrogen atmosphere, NaNO3 (6.18 g, 72.7 mmol) was added to the reaction solution at 0°C and stirred at 0°C for 1 hour. The reaction solution was poured into ice water, extracted with EA (300 mL x 3), washed with saturated brine (600 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 6.8 g (crude) of the title compound as a light yellow solid.

[0828] LC-MS: m / z 211[M+H] + .

[0829] Step 2: Preparation of 6-fluoro-5-nitro-1H-indole (26b)

[0830] 6-Fluoro-5-nitroindoline-2,3-dione (26a) (2.00 g, 9.52 mmol) was dissolved in THF (30 ml). Borane tetrahydrofuran solution (28.6 mL, 28.6 mmol) was added to the reaction solution at 0°C under nitrogen atmosphere, and stirred at room temperature for 4 hours. Water (50 mL) was added at 0°C to quench the mixture, and the mixture was extracted with EA (100 mL x 3), washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 1.1 g (crude) of the title compound as a pale yellow solid.

[0831] LC-MS: m / z 181[M+H] + .

[0832] Step 3: Preparation of 6-fluoro-1-methyl-5-nitro-1H-indole (26c)

[0833] 6-Fluoro-5-nitro-1H-indole (26b) (500 mg, 2.78 mmol) was dissolved in DMF (10 ml) at 0°C. Cs2CO3 (1.36 g, 4.17 mmol) was added to the reaction solution at 0°C under nitrogen atmosphere. CH3I was added at 0°C and stirred at room temperature for 12 hours. Water (50 mL) was added at 0°C to quench the mixture, and the mixture was extracted with EA (30 mL x 3), washed with saturated brine (60 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 450 mg of the title compound as a light yellow solid, with a yield of 84.9%.

[0834] LC-MS: m / z 195 [M+H] + .

[0835] Step 4: Preparation of N-(tert-butyloxycarbonyl)-S-(1-methyl-5-nitro-1H-indol-6-yl)-L-cysteine ​​(26d)

[0836] 6-Fluoro-1-methyl-5-nitro-1H-indole (26c) (250 mg, 1.28 mmol) was dissolved in DMF (10 mL), and Cs2CO3 (2.50 g, 7.73 mmol) and (tert-butyloxycarbonyl)-L-cysteine ​​(849 mg, 3.84 mmol) were added at 0°C, and stirred at 80°C for 12 hours. Water (50 mL) was added at 0°C to quench the mixture, and the mixture was extracted with EA (30 mL x 3), washed with saturated brine (60 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 450 mg (crude) of the title compound as a pale yellow solid.

[0837] LC-MS: m / z 396 [M+H] + .

[0838] Step 5: Preparation of (S)-(5-amino-1-methyl-1H-indol-6-yl)-N-(tert-butyloxycarbonyl)-L-cysteine ​​(26e)

[0839] At room temperature, N-(tert-butyloxycarbonyl)-S-(1-methyl-5-nitro-1H-indol-6-yl)-L-cysteine ​​(26d) (450 mg, 9.03 mmol) was dissolved in 10 mL of methanol, aqueous Pd / C (100 mg) was added to the reaction solution, and stirred at room temperature overnight under a hydrogen atmosphere. The mixture was filtered through celite, the filter cake was washed with MeOH, and the filtrate was concentrated under reduced pressure to obtain 460 mg (crude) of the title compound as a yellow oil.

[0840] LC-MS: m / z 366[M+H] + .

[0841] The remaining steps were the same as the preparation method of Example 7, except that (S)-(5-amino-1-methyl-1H-indol-6-yl)-N-(tert-butoxycarbonyl)-L-cysteine ​​(26e) was used instead of O-(5-amino-2-cyclopropylbenzo[d]oxazol-6-yl)-N-(tert-butoxycarbonyl)-L-serine (7i) in step 9 to obtain the title compound 26.

[0842] LC-MS: m / z 506.1[M+H] + .

[0843] 1H NMR (400MHz, DMSO-d6) δ8.42 (s, 1H), 7.73 (s, 1H), 7.66 (s, 1H), 7.43 (d, 1H), 7.29-7.24 (m, 3H), 7.11-7.09 (m, 2H), 6.45 (s, 1H), 5.3 4(br, 2H), 5.25-5.20(m, 1H), 4.12-4.06(m, 1H), 3.77(s, 3H), 3.62-3.56(m, 1H), 3.45-3.39(m, 1H), 3.35(s, 3H), 2.73-2.57(m, 2H).

[0844] Example 27: Preparation of (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-1-methyl-3,4-dihydrobenzofurano[6,5-b][1,4]oxazepin-2(1H)-one (27)

[0845]

[0846] Step 1: Preparation of 1-(4-fluoro-2-hydroxy-5-nitrophenyl)ethan-1-one (27a)

[0847] 1-(4-Fluoro-2-hydroxyphenyl)ethane-1-one (10.0 g, 64.9 mmol) was dissolved in concentrated H28O4 (100 ml) at 0°C. NaNO3 (7.40 g, 87.6 mmol) was added to the reaction solution at 0°C under nitrogen atmosphere and stirred at 0°C for 1 hour. Water (500 mL) was added at 0°C to quench the mixture, and the mixture was extracted with EA (300 mL x 3), washed with saturated brine (600 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 7.2 g of the title compound as a light yellow solid with a yield of 55.3%.

[0848] LC-MS: m / z 200 [M+H] + .

[0849] Step 2: Preparation of 2-bromo-1-(4-fluoro-2-hydroxy-5-nitrophenyl)ethan-1-one (27b)

[0850] 1-(4-Fluoro-2-hydroxy-5-nitrophenyl)ethane-1-one (27a) (3.80 g, 19.1 mmol) was dissolved in EtOH (50 mL), and CuBr2 (8.86 g, 40.1 mmol) was added at 0°C. The mixture was stirred at 70°C for 2 hours under a nitrogen atmosphere. Water (100 mL) was added to quench the mixture, and the mixture was extracted with EA (100 mL x 3), washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 4.50 g of the title compound as a light yellow solid with a yield of 83.2%.

[0851] LC-MS: m / z 278 [M+H] + .

[0852] Step 3: Preparation of 6-fluoro-5-nitrobenzofuran-3(2H)-one (27c)

[0853] 2-Bromo-1-(4-fluoro-2-hydroxy-5-nitrophenyl)ethan-1-one (27b) (2.50 g, 9.03 mmol) was dissolved in THF (30 ml) at room temperature. DIEA (1.39 g, 10.8 mmol) was added dropwise to the reaction solution at 0°C under nitrogen atmosphere, and stirred at room temperature overnight. Water (30 mL) was added at 0°C to quench the mixture, and the mixture was extracted with EA (30 mL x 3), washed with saturated brine (60 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 1.32 g of the title compound as a light yellow solid with a yield of 72.2%.

[0854] LC-MS: m / z 198 [M+H] + .

[0855] Step 4: Preparation of 6-fluoro-5-nitro-2,3-dihydrobenzofuran-3-ol (27d)

[0856] At room temperature, 6-fluoro-5-nitrobenzofuran-3(2H)-one (27c) (200 mg, 1.01 mmol) was dissolved in THF (4 mL). Under nitrogen atmosphere, NaBH4 (115 mg, 3.03 mmol) was added to the reaction solution at 0°C and stirred at room temperature for 1 hour. Water (5 mL) was added to dilute the mixture, and the mixture was extracted with EA (30 mL x 3), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 150 mg (crude) of the yellow title compound.

[0857] LC-MS: m / z 200 [M+H] + .

[0858] Step 5: Preparation of 6-fluoro-5-nitrobenzofuran (27e)

[0859] At room temperature, 6-fluoro-5-nitro-2,3-dihydrobenzofuran-3-ol (27d) (1.60 g, 8.04 mmol) was dissolved in ACN (20 mL). Under nitrogen atmosphere, 4N hydrochloric acid (5 mL) was added to the reaction solution at 0°C and stirred at 60°C for 5 h. Water (30 mL) was added to dilute the mixture, and the mixture was extracted with EA (30 mL x 3), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100:1-4:1) to obtain 720 mg of the yellow title compound, with a yield of 49.8%.

[0860] LC-MS: m / z 182 [M+H] + .

[0861] Step 6: Preparation of 5-nitrobenzofuran-6-ol (27f)

[0862] At room temperature, (tert-butyloxycarbonyl)-L-serine (906 mg, 4.42 mmol) was dissolved in DMF (10 ml). Under nitrogen atmosphere, NaH (354 mg, 8.84 mmol) was added dropwise to the reaction solution at 0°C. The mixture was stirred at 0°C for 0.5 hours. 6-Fluoro-5-nitrobenzofuran (27e) (400 mg, 2.21 mmol) was added in batches and stirred at room temperature overnight. Water (30 mL) was added at 0°C to quench the mixture. The mixture was extracted with EA (30 mL x 3), washed with saturated brine (60 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 210 mg of the title compound as a light yellow solid with a yield of 42.1%.

[0863] LC-MS: m / z 180 [M+H] + .

[0864] Step 7: Preparation of O-(5-nitrobenzofuran-6-yl)-N-triphenyl-L-serine methyl ester (27 g)

[0865] At room temperature, 5-nitrobenzofuran-6-ol (27f) (250 mg, 1.39 mmol) and methyl trityl-L-serine (756 mg, 2.09 mmol) were dissolved in 10 mL THF. Under nitrogen atmosphere, PPh3 (728 mg, 2.78 mmol) and DIAD (561 mg, 2.78 mmol) were added to the reaction solution, and stirred at room temperature overnight. Water (10 mL) was added to dilute, extracted with EA (30 mL x 3), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 1.20 g (crude) of the title compound as a yellow semi-solid.

[0866] LC-MS: m / z 523 [M+H] + .

[0867] The remaining steps are the same as the preparation method of Example 1, except that O-(5-nitrobenzofuran-6-yl)-N-triphenyl-L-serine methyl ester (27 g) is used instead of O-(1,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-trityl-L-serine methyl ester (1e) in step 5 to obtain the title compound 27.

[0868] LC-MS: m / z 477.1[M+H] + .

[0869] 1 H NMR (400MHz, DMSO-d6) δ8.07 (d, J=2.2Hz, 1H), 7.79 (s, 1H), 7.56 (s, 1H), 7.42-7.26 (m, 3H), 7.25- 7.14 (m, 2H), 7.00 (d, J=2.2Hz, 1H), 5.57 (dd, J=12.0, 8.0Hz, 1H), 5.42 (s, 2H), 4.83 (dd, J=12.0, 10 .1Hz, 1H), 4.33 (dd, J=10.1, 8.0Hz, 1H), 4.05 (ddd, J=12.3, 7.0, 5.1Hz, 1H), 3.64 (ddd, J=12.9, 8. 6, 4.8Hz, 1H), 3.35 (s, 3H), 2.81 (ddd, J=15.4, 8.5, 5.0Hz, 1H), 2.68 (ddd, J=15.5, 7.0, 4.8Hz, 1H).

[0870] Example 28: Preparation of (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-1-methyl-3,4-dihydrobenzofurano[6,5-b][1,4]thiazepin-2(1H)-one (28)

[0871]

[0872] Step 1: Preparation of N-(tert-butoxycarbonyl)-S-(5-nitrobenzofuran-6-yl)-L-cysteine ​​(28a)

[0873] At room temperature, (tert-butyloxycarbonyl)-L-cysteine ​​(732 mg, 3.31 mmol) was dissolved in DMF (10 mL). Under nitrogen atmosphere, Cs2CO3 (2.16 g, 6.64 mmol) and 6-fluoro-5-nitrobenzofuran (27e) (300 mg, 1.66 mmol) were added to the reaction solution, and stirred at 80°C overnight. Water (30 mL) was added to dilute, and the mixture was extracted with EA (30 mL x 3), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 620 mg of the yellow title compound (crude product).

[0874] LC-MS: m / z 383[M+H] + .

[0875] Step 2: Preparation of (S)-(5-aminobenzofuran-6-yl)-N-(tert-butoxycarbonyl)-L-cysteine ​​(28b)

[0876] At room temperature, N-(tert-butoxycarbonyl)-S-(5-nitrobenzofuran-6-yl)-L-cysteine ​​(28a) (550 mg, 1.44 mmol) was dissolved in 10 mL of methanol, and aqueous Pd / C (250 mg) was added to the reaction solution. The mixture was stirred overnight at room temperature under a hydrogen atmosphere. The mixture was filtered through celite, the filter cake was washed with MeOH, and the filtrate was concentrated under reduced pressure to obtain 460 mg (crude) of the title compound as a yellow oil.

[0877] LC-MS: m / z 353 [M+H] + .

[0878] The remaining steps were the same as the preparation method of Example 7, except that S-(5-aminobenzofuran-6-yl)-N-(tert-butoxycarbonyl)-L-cysteine ​​(28b) was used instead of O-(5-amino-2-cyclopropylbenzo[d]oxazol-6-yl)-N-(tert-butoxycarbonyl)-L-serine (7i) in step 9 to obtain the title compound 28.

[0879] LC-MS: m / z 473.1[M+H] + .

[0880] 1 H NMR (400MHz, DMSO-d6) δ8.16 (d, J=2.2Hz, 1H), 7.96 (s, 1H), 7.89 (s, 1H), 7.32 (ddd, J=1 3.3, 7.9, 6.2Hz, 3H), 7.20-7.14 (m, 2H), 7.07 (d, J=2.2Hz, 1H), 5.41 (s, 2H), 5.25 (dd, J= 12.5, 6.9Hz, 1H), 4.12 (ddd, J=12.5, 7.3, 5.1Hz, 1H), 3.67 (ddd, J=12.8, 8.0, 5.1Hz, 1H ), 3.57 (t, J=11.9Hz, 1H), 3.39 (dd, J=11.3, 7.0Hz, 1H), 3.32 (s, 3H), 2.81-2.64 (m, 2H).

[0881] Example 29: Preparation of (S)-7-(3-chloro-2-(3,5-difluorobenzyl)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-2-cyclopropyl-9-methyl-6,7-dihydrooxazolo[5′,4′:4,5]benzo[1,2-b][1,4]oxazepin-8(9H)-one (29)

[0882]

[0883] Step 1: Preparation of (S)-5-chloro-4-(2-((2-cyclopropyl-9-methyl-8-oxo-6,7,8,9-tetrahydrooxazolo[5′,4′:4,5]benzo[1,2-b][1,4]oxazepin-7-yl)amino)ethyl)-1-(3,5-difluorobenzyl)-1H-pyrazole-3-carboxylic acid ethyl ester (29a)

[0884] At room temperature, (S)-7-amino-2-cyclopropyl-9-methyl-6,7-dihydrooxazolo[5′,4′:4,5]benzo[1,2-b][1,4]oxazepine-8(9H)-one (151) (70.0 mg, 0.256 mmol) and 5-chloro-1-(3,5-difluorobenzyl)-4-(2-oxoethyl)-1H-pyrazole-3-carboxylic acid ethyl ester (24 g) (131 mg, 0.384 mmol) were dissolved in 1 mL of methanol. 2-Methylpyridineborane (38.0 mg, 0.358 mmol) was added to the reaction solution and stirred at room temperature overnight. 5 mL of saturated NaHCO3 solution was added, extracted with DCM (10 mL x 3), washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and the residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 1:1) to obtain 90 mg of the title compound as a light yellow oil. Yield: 58.7%.

[0885] LC-MS: m / z 600.1[M+H] + .

[0886] Step 2: Preparation of (S)-7-(3-chloro-2-(3,5-difluorobenzyl)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-2-cyclopropyl-9-methyl-6,7-dihydrooxazolo[5′,4′:4,5]benzo[1,2-b][1,4]oxazepin-8(9H)-one (29)

[0887] At room temperature, (S)-5-chloro-4-(2-((2-cyclopropyl-9-methyl-8-oxo-6,7,8,9-tetrahydrooxazolo[5′,4′:4,5]benzo[1,2-b][1,4]oxazepin-7-yl)amino)ethyl)-1-(3,5-difluorobenzyl)-1H-pyrazole-3-carboxylic acid ethyl ester (29a) (70.0 mg, 0.116 mmol) was dissolved in 2 ml of chloroform. Under nitrogen atmosphere, Al(CH3)3 (0.18 ml, 2 M) was added to the reaction solution at 0°C and stirred at 50°C for 3 hours. The mixture was quenched with saturated sodium bicarbonate solution, filtered through celite, extracted with DCM (10 mL x 3), washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by high pressure preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 um 100A, mobile phase: acetonitrile / water, gradient: 10%-50%, 0.05% formic acid, 30 min) to give 7.9 mg of the title compound as an off-white solid, in a yield of 12.8%.

[0888] LC-MS: m / z 554 [M+H] +.

[0889] 1 H NMR (400MHz, DMSO-d6) δ7.89 (s, 1H), 7.50 (s, 1H), 7.21 (tt, J=9.4, 2.4Hz, 1H), 6.96-6.82 (m, 2 H), 5.56 (dd, J=11.9, 8.1Hz, 1H), 5.48 (s, 2H), 4.82 (dd, J=11.9, 10.1Hz, 1H), 4.34 (dd, J=10.1, 8.0Hz, 1H), 4.04 (ddd, J=12.2, 7.0, 5.1Hz, 1H), 3.65 (ddd, J=12.8, 8.7, 4.8Hz, 1H), 3.34 (s, 3H ), 2.82 (ddd, J=15.5, 8.6, 5.1Hz, 1H), 2.73-2.63 (m, 1H), 2.34-2.23 (m, 1H), 1.28-1.15 (m, 4H).

[0890] Example 30: Preparation of (S)-7-(3-chloro-2-(4-fluorobenzyl)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-2-cyclopropyl-9-methyl-6,7-dihydrooxazolo[5′,4′:4,5]benzo[1,2-b][1,4]oxazepin-8(9H)-one (30)

[0891]

[0892] Step 1: Preparation of (S)-5-chloro-4-(2-((2-cyclopropyl-9-methyl-8-oxo-6,7,8,9-tetrahydrooxazolo[5′,4′:4,5]benzo[1,2-b][1,4]oxazepin-7-yl)amino)ethyl)-1-(4-fluorobenzyl)-1H-pyrazole-3-carboxylic acid ethyl ester (30a)

[0893] At room temperature, (S)-7-amino-2-cyclopropyl-9-methyl-6,7-dihydrooxazolo[5′,4′:4,5]benzo[1,2-b][1,4]oxazepin-8(9H)-one (15l) (30.0 mg, 0.110 mmol), ethyl 5-chloro-1-(4-fluorobenzyl)-4-(2-oxoethyl)-1H-pyrazole-3-carboxylate (25d) (39.2 mg, 0.120 mmol) and tetraethyl titanate (37.6 mg, 0.174 mmol) were dissolved in THF (1 mL), stirred at room temperature for 1 hour, methanol (0.2 mL) and sodium cyanoborohydride (13.8 mg, 0.220 mmol) were added, and the mixture was stirred at room temperature overnight. 10 mL of saturated sodium bicarbonate solution was added, extracted with EA (15 mL x 3), washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by high pressure preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 um 100A, mobile phase: acetonitrile / water, gradient: 10%-50%, 0.05% formic acid, 30 min) to give 10.0 mg of the title compound as an off-white solid, with a yield of 15.6%.

[0894] LC-MS: m / z 582[M+H] + .

[0895] Step 2: Preparation of (S)-7-(3-chloro-2-(4-fluorobenzyl)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-2-cyclopropyl-9-methyl-6,7-dihydrooxazolo[5′,4′:4,5]benzo[1,2-b][1,4]oxazepin-8(9H)-one (30)

[0896] At 0°C, (S)-5-chloro-4-(2-((2-cyclopropyl-9-methyl-8-oxo-6,7,8,9-tetrahydrooxazolo[5′,4′:4,5]benzo[1,2-b][1,4]oxazepin-7-yl)amino)ethyl)-1-(4-fluorobenzyl)-1H-pyrazole-3-carboxylic acid ethyl ester (30a) (10.0 mg, 0.0170 mmol) was dissolved in 1 ml of chloroform. Under nitrogen atmosphere, Al(CH3)3 (0.03 ml, 2 M) was added to the reaction solution and stirred at 50°C for 2 hours. The mixture was quenched with water, extracted with DCM (10 mL x 3), washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by high pressure preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 um 100A, mobile phase: acetonitrile / water, gradient: 10%-50%, 0.05% formic acid, 30 min) to give 1 mg of the title compound as an off-white solid in a yield of 10.8%.

[0897] LC-MS: m / z 536.1[M+H] + .

[0898] 1 H NMR (400MHz, DMSO-d6) δ7.89 (s, 1H), 7.49 (s, 1H), 7.25-7.18 (m, 4H), 5.57-5.52 (m, 1H), 5.42 (s, 2H), 4.84-4.79 (m, 1H), 4.33-4.29 (m, 1H), 4.06 -3.99(m, 1H), 3.65-3.60(m, 1H), 3.33(s, 3H), 2.81-2.76(m, 1H), 2.70-2 .64 (m, 1H), 2.33-2.26 (ddd, J=13.1, 6.2, 3.5Hz, 1H), 1.24-1.15 (m, 4H).

[0899] Example 31: Preparation of (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-1-methyl-1,3,4,7-tetrahydro-2H-[1,4]oxazepine[3,2-f]indol-2-one (31)

[0900]

[0901] Step 1: Preparation of 6-fluoro-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (31a)

[0902] 6-Fluoro-5-nitro-1H-indole (26b) (2.00 g, 10.6 mmol) was dissolved in THF (30 mL), and NaH (630 mg, 15.7 mmol) was added at 0°C. The mixture was stirred at 0°C for 0.5 hours under nitrogen atmosphere, and SEM-Cl (2.12 g, 12.8 mmol) was added dropwise to the reaction solution at 0°C. Water (50 mL) was added to quench the mixture, and the mixture was extracted with EA (50 mL x 3), washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase PE / EA = 3:1) to obtain 2.20 g of the title compound as a light yellow solid, with a yield of 63.9%.

[0903] LC-MS: m / z 311[M+H] + .

[0904] The remaining steps were the same as the preparation method of Example 14, except that 6-fluoro-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (31a) was used instead of 6-fluoro-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (14b) in step 2 to obtain the title compound 31.

[0905] LC-MS: m / z 476.1[M+H] + .

[0906] 1 H NMR (400MHz, DMSO-d6) δ11.2 (s, 1H), 7.64 (s, 1H), 7.42 (s, 1H), 7.38-7.18 (m, 6H), 6.47 (s, 1H), 5.63-5.58 (m, 1H), 5.42 (s, 2H), 4.77-4.72 (m, 1H), 4.29-4.25 (m, 1H), 4.10-4.05 (m, 1H), 3.65-3.60 (m, 1H), 3.33 (s, 3H), 2.81-2.76 (m, 1H), 2.70-2.64 (m, 1H).

[0907] Biological experiments

[0908] Test Example 1: Analysis of the Inhibitory Activity of the Compounds of the Present Invention on U937 Cell Necrosis in Vitro

[0909] Receptor interacting protein kinase 1 (RIP1) activation can induce necrosis of human monocytic leukemia U937 cells. Therefore, the activity of the compounds of the present invention was tested by in vitro cell necrosis assay using human monocytic leukemia U937 cells (CBP60277, CoBioer).

[0910] ATP adenosine triphosphate participates in a variety of enzymatic reactions in the body and is an indicator of living cell metabolism. Its content directly reflects the number and state of cells. Add the corresponding volume of CellTiter-Glo to the cell culture medium. TM Reagent (Promega), measure the luminescence value, the luminescence value is proportional to the amount of ATP, and ATP is positively correlated with the number of living cells. Cell viability is determined by detecting the ATP content.

[0911] Test method:

[0912] a. Cells were cultured in RPMI 1640 medium (31800-500, Solarbio) supplemented with 10% fetal bovine serum (10099141, Gibco), 100 U / mL penicillin and 100 μg / mL streptomycin (15140122, Invitrogen). 5 The cells / mL were suspended in RPMI 1640 medium supplemented with 1% fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin. The cell suspension was added to a 384-well plate (3570, Corning), 35 μL per well, i.e., 17,500 U937 cells / well.

[0913] b. Dilute 10mM QVD (Q-VD-OPh) (Cat. No.: 551476, EMD Millipore Corp) stock solution (QVD is dissolved in 100% DMSO to prepare a 10mM stock solution) 40 times to 250μM with RPMI1640 culture medium containing 1% fetal bovine serum, 100U / mL penicillin, and 100μg / mL streptomycin. Take 5μL of QVD and add it to the corresponding cell wells. The final reaction system is 50μL, and the final concentration of QVD is 25μM.

[0914] c. A 10 mM stock solution of the compound of the present invention was used as the starting concentration (the compound of the present invention was dissolved in 100% DMSO to prepare a 10 mM stock solution), and dilution was performed in a 96-well dilution plate (249944, Nunc) at a ratio of 1:3. The gradient concentration of the compound was 10000 μM, 3333.33 μM, 1111.11 μM, 370.37 μM, 123.46 μM, 41.15 μM, 13.72 μM, 4.57 μM, and 0 μM.

[0915] d. The above compounds diluted in 100% DMSO were diluted 100 times with RPMI 1640 medium containing 1% fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin.

[0916] e. Take 5 μL of the diluted compound in step d and add it to the cells in a 384-well plate. The final concentrations of the compound are 10000 nM, 3333.33 nM, 1111.11 nM, 370.37 nM, 123.46 nM, 41.15 nM, 13.72 nM, 4.57 nM, and 0 nM.

[0917] f. Incubate in a 37°C, 5% CO2 incubator for 30 minutes.

[0918] g. After culture, dilute the TNFα (PHC3016, Gibco) stock solution (TNFα is dissolved in sterile water to prepare a 100 μg / mL stock solution) 100 times to 1 μg / mL with RPMI 1640 medium containing 1% fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin. Take 5 μL of TNFα and add it to the corresponding cell wells. The final reaction system is 50 μL, and the final concentration of TNFα is 100 ng / mL.

[0919] h. Place the cell culture plate in an incubator at 37°C, 5% CO2 and culture overnight.

[0920] i. Take out the cells from the 384-well plate and equilibrate at room temperature for 30 minutes.

[0921] j. Add 30 μL CellTiter-Glo to each test well. TM Reagents, vortex to mix, and incubate at room temperature for 10 minutes.

[0922] k. Detect chemiluminescent signal using Cytation 3.

[0923] Using GraphPad Prism 5 software, the IC of the compound was obtained using the following nonlinear fitting formula: 50 :

[0924] Y=Bottom+(Top-Bottom) / (1+10^((Log IC 50 -X)×Hillslope)),

[0925] Among them, X is the logarithmic value of the compound concentration, Y is the efficacy of the compound in inhibiting cell necrosis; Top and Bottom are the Y values ​​of the highest and lowest plateaus of the curve; Hillslope is the Hill constant.

[0926] The activity of the compounds of the present invention in inhibiting U937 cell necrosis is shown in Table 1 below.

[0927] In Table 1, A refers to the IC of the compound for inhibiting cell necrosis. 50 <10nM; B means 10nM<IC 50 <100nM; C means 100nM<IC50 <500nM; D refers to IC 50 >500nM.

[0928] Table 1 IC of the compounds of the present invention for inhibiting U937 cell necrosis 50 value

[0929]

[0930]

[0931] Conclusion: The compounds of the present invention can effectively inhibit U937 cell necrosis.

[0932] Test Example 2: Analysis of the in vitro inhibitory activity of the compounds of the present invention on L929 cell necrosis

[0933] The effects of the compounds of the present invention can be tested by in vitro cell necrosis assay using L929 cells (Nanjing Kebai).

[0934] ATP adenosine triphosphate participates in a variety of enzymatic reactions in the body and is an indicator of living cell metabolism. Its content directly reflects the number and state of cells. Add the corresponding volume of CellTiter-Glo to the cell culture medium. TM Reagent (Promega), measure the luminescence value, the luminescence value is proportional to the amount of ATP, and ATP is positively correlated with the number of living cells. Cell viability is determined by detecting the ATP content.

[0935] Test method:

[0936] a. Cells were cultured in MEM medium (11095-080, Invitrogen) supplemented with 10% fetal bovine serum (10099141, Gibco), 100 U / mL penicillin and 100 μg / mL streptomycin (15140122, Invitrogen). 4 The cells / mL were suspended in MEM medium supplemented with 1% fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin. The cell suspension was added to a 384-well plate (3570, Corning), 35 μL per well, i.e., 1750 L929 cells / well.

[0937] b. A 30 mM stock solution of the compound of the present invention was used as the starting concentration (the compound of the present invention was dissolved in 100% DMSO to prepare a 30 mM stock solution) and diluted in a 96-well dilution plate (249944, Nunc) at a ratio of 1:3. The gradient concentration of the compound was 30000 μM, 10000 μM, 3333.33 μM, 1111.11 μM, 370.37 μM, 123.46 μM, 41.15 μM, 13.72 μM, 4.57 μM, and 0 μM.

[0938] c. The above compounds diluted in 100% DMSO were diluted 100 times with MEM medium containing 1% fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin.

[0939] d. Take 5 μL of the diluted compound in step c and add it to the cells in a 384-well plate. The total reaction system is 50 μL. The final concentrations of the compounds are 30000 nM, 10000 nM, 3333.33 nM, 1111.11 nM, 370.37 nM, 123.46 nM, 41.15 nM, 13.72 nM, 4.57 nM, and 0 nM.

[0940] e. Incubate in a 37°C, 5% CO2 incubator for 30 minutes.

[0941] f. Dilute 10 mM QVD (551476, EMD) stock solution (QVD is dissolved in 100% DMSO to prepare a 10 mM stock solution) 40 times to 250 μM with MEM medium containing 1% fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin.

[0942] g. Dilute the mTNFα (50349-MNAE, Sino Biological) stock solution (TNFα was dissolved in sterile water to prepare a 590 μg / mL stock solution) 590 times to 1 μg / mL with MEM medium containing 1% fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin.

[0943] h. Mix the intermediate diluted QVD and mTNFα at a ratio of 1:1.

[0944] i. Take 10 μl of the mixture of QVD and mTNFα and add it to the corresponding cell wells. The final reaction system is 50 μl, the final concentration of QVD is 25 μM, and the final concentration of mTNFα is 100 ng / mL.

[0945] j. Place the cell culture plate in an incubator at 37°C and 5% CO2 for 48 hours.

[0946] k. Take out the cells from the 384-well plate and equilibrate at room temperature for 30 minutes.

[0947] l. Add 30 μL CellTiter-Glo to each test well TM Reagents, vortex to mix, and incubate at room temperature for 10 minutes.

[0948] m. Detect chemiluminescent signal using Cytation 3.

[0949] Using GraphPad Prism 5 software, the IC of the compound was obtained using the following nonlinear fitting formula: 50 :

[0950] Y=Bottom+(Top-Bottom) / (1+10^((Log IC 50 -X)×Hillslope)),

[0951] Among them, X is the logarithmic value of the compound concentration, Y is the efficacy of the compound in inhibiting cell necrosis; Top and Bottom are the Y values ​​of the highest and lowest plateaus of the curve; Hillslope is the Hill constant.

[0952] The activity of the compounds of the present invention in inhibiting L929 cell necrosis is shown in Table 2 below.

[0953] In Table 2, A refers to the IC of the compound for inhibiting cell necrosis. 50 <50nM; B means 50nM<IC 50 <100nM; C means 100nM<IC 50 <500nM; D refers to IC 50 >500nM.

[0954] Table 2 IC of the compounds of the present invention for inhibiting L929 cell necrosis 50 value

[0955]

[0956]

[0957] Conclusion: The compounds of the present invention can inhibit L929 cell necrosis.

[0958] Test Example 3: Liver microsomal stability test of the compound of the present invention

[0959] Metabolic stability incubation was performed with 400 μL of human, mouse and rat liver microsomes (452117, corning; 452701, corning; 452501, corning). The final concentration of liver microsomes in the system was 0.5 mg / mL, the final concentration of NADPH (2646-7H, solarbio) was 1 mM, and the final concentration of the test compound was 2 μM. 2 μM verapamil hydrochloride (100223-200102, China Pharmaceutical and Biological Products Identification Institute) was used as a positive control. At 0, 15, 30, 45, and 60 minutes, 50 μL of the reaction sample was taken out, and 200 μL of acetonitrile containing a final concentration of 200 nM labetalol (100484-201001, China Pharmaceutical and Biological Products Identification Institute) was added to terminate the reaction. After the sample is mixed, centrifuge at 10000rpm for 10 minutes, take 100μL of supernatant and add 100μL of ultrapure water to mix, and use for HPLC-MS / MS analysis. The metabolic stability of the compound is calculated by measuring the relative reduction of the compound. The natural logarithm of the remaining percentage of the compound and the incubation time are used to draw a curve to obtain the slope k and the in vitro half-life T 1 / 2 =-(0.693 / k).

[0960] The metabolic stabilities of the compounds of the present invention in human, mouse and rat liver microsomes are shown in Table 3 below.

[0961] Table 3 Metabolic stability of the compounds of the present invention in human, mouse and rat liver microsomes

[0962]

[0963] Conclusion: The compounds of the present invention have good stability in human, mouse and rat liver microsomes.

[0964] Test Example 4: Hepatocyte metabolic stability test of the compound of the present invention

[0965] Human, mouse, and rat primary hepatocytes (HPCH10, xenotech; M005052, Bioreclamation IVT; M00005, Bioreclamation IVT) were incubated with compounds at a cell density of 1.0 × 10 6Cells / mL. Hepatocytes inactivated by boiling for 5 minutes were used as negative controls. 198 μL of the suspension of live cells or inactivated cells was transferred to a 96-well deep-well plate, and the deep-well plate was placed on a vortexer and preheated in an incubator for 10 minutes. 2 μL of 100 μM test substance or verapamil hydrochloride (100223-200102, China Pharmaceutical and Biological Products Identification Institute) was added to each well to start the reaction, and the final concentration of the compound was 1 μM. The deep-well plate was placed back on the incubator vortexer. At 0, 15, 30, 60, 90, and 120 minutes, 25 μL of the suspension was taken and 150 μL of acetonitrile containing 500 nM labetalol (100484-201001, China Pharmaceutical and Biological Products Identification Institute) was added to terminate the reaction. Vortex for 10 minutes, centrifuge at 3220g, 4°C for 30 minutes, transfer 100 μL of supernatant to the sample plate, add 100 μL of pure water and mix well, and use for UPLC-MS / MS analysis. The metabolic stability of the compound is calculated by measuring the relative reduction of the compound. The natural logarithm of the remaining percentage of the compound and the incubation time are used to draw a curve to obtain the slope k and the in vitro half-life T 1 / 2 =-(0.693 / k).

[0966] The metabolic stability of the compounds of the present invention in human, mouse and rat hepatocytes is shown in Table 4 below.

[0967] Table 4 Metabolic stability of the compounds of the present invention in human, mouse and rat hepatocytes

[0968]

[0969] Conclusion: The compounds of the present invention have good stability in human, mouse and rat hepatocytes.

[0970] Experimental Example 5: Pharmacokinetic evaluation of the compounds of the present invention in ICR mice

[0971] Male 7-week-old ICR mice (Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.) were orally administered with 2 mg / kg of the compound of the present invention, with a compound concentration of 0.2 mg / mL. Blood was collected from the canthal venous plexus at 0, 0.167, 0.25, 0.50, 1.00, 2.00, 4.00, 6.00, 8.00 and 24.00 h before and after administration, respectively. The blood was anticoagulated with sodium heparin, centrifuged at 3500 rpm for 10 minutes at 4°C, and plasma was obtained and stored at -80°C until testing. 10 μL of plasma sample was added to 100 μL of acetonitrile working solution containing 5 ng / mL verapamil (100223-200102, China Pharmaceutical and Biological Products Identification Institute), vortexed vigorously for 5 minutes, and centrifuged at 4000 rpm for 10 minutes at 4°C. Take 50 μL of the supernatant, add 200 μL of acetonitrile and mix well, centrifuge at 4000 rpm for 10 min at 4°C, take the supernatant, place it in a 96-well injection plate, and analyze the blood drug concentration by LC / MS (Waters, Waters UPLC IClass, TQ-S micro), and analyze the pharmacokinetic parameters by MassLynx V4.2SCN977 data processing software.

[0972] The pharmacokinetic experimental data of the compound of the present invention after oral administration are shown in Table 5 below.

[0973] In the table, A refers to the AUC of the compound. 0-t (μg / L*h)<500; B means 500<AUC 0-t (μg / L*h)<1000; C means 1000<AUC 0-t (μg / L*h)<5000; D means 5000<AUC 0-t (μg / L*h)<10000. a refers to the half-life of the compound 1h<T 1 / 2Z <2h, b refers to the half-life of the compound 2h<T 1 / 2Z <3h, c refers to the half-life of the compound 3h<T 1 / 2Z .

[0974] Table 5 Pharmacokinetic parameters of the compounds of the present invention after single oral administration to male ICR mice

[0975]

[0976] Conclusion: The compounds of the present invention have good pharmacokinetic properties in mice.

[0977] Test Example 6: Blood-brain barrier permeability test of the compound of the present invention in C57BL / 6J mice

[0978] The compound of the present invention was orally administered to male 6-week-old C57BL / 6 mice (Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.). Blood and brain tissue of mice were collected at 0, 0.25, 1.00 and 4.00 h before and after administration. Before taking brain tissue, 10 mL of normal saline was perfused from the left ventricle of the mouse. The blood sample was anticoagulated with sodium heparin, centrifuged at 4°C, 3500 rpm for 10 minutes, and plasma was obtained and stored at -80°C until testing. The brain tissue was weighed and transferred to an EP tube. Normal saline was added according to the weight of the brain tissue to homogenize (brain weight: normal saline volume = 1:2), and the whole process was carried out at low temperature. Accurately measure 50 μL of brain tissue homogenate sample, transfer to a 1.5 mL EP tube, add 400 μL of acetonitrile working solution containing 5 ng / mL verapamil hydrochloride (100223-200102, China Pharmaceutical and Biological Products Identification Institute), vortex vigorously shake for 1 min, and centrifuge at 16000 rpm for 10 min. Take the supernatant, filter with a 0.22 μm organic membrane (AS081320-T, Agela Technologies), and add it to the injection vial for testing. The blood drug concentration and brain tissue drug concentration were analyzed by LC / MS (Waters, Waters UPLC I Class, TQ-S micro).

[0979] The blood-brain barrier permeability of the compounds of the present invention after oral administration is shown in Table 6.

[0980] In the table, A refers to a compound having Cb / Cp<0.3; B refers to a compound having Cb / Cp>0.3.

[0981] Table 6 Blood-brain barrier permeability of the compounds of the present invention after single oral administration to male C57BL / 6J mice

[0982]

[0983]

[0984] Note: C b (ng / g): drug concentration in brain tissue, C p (ng / mL): drug concentration in plasma.

[0985] Conclusion: The compounds of the present invention can penetrate the blood-brain barrier of mice.

[0986] Test Example 7: Safety test of the compounds of the present invention acting on hERG potassium ion channels

[0987] The effects of compounds on hERG potassium channel currents were tested using a manual patch clamp method.

[0988] Test method:

[0989] a. Cell Preparation

[0990] HEK293 cell line stably expressing hERG ion channel (K1236, Invitrogen) was cultured at 5×10 5 The cells were cultured at a density of 1.54 μg / mL in a 6-cm dish and induced for 48 h by adding 1 μg / mL doxycycline (D9891, Sigma). The cells were then digested and seeded on glass slides for subsequent manual patch clamp experiments.

[0991] b. Solution preparation

[0992] Extracellular solution (in mM): 132 NaCl, 4 KCl, 3 CaCl2, 0.5 MgCl2, 11.1 glucose and 10 HEPES, pH adjusted to 7.35 with NaOH.

[0993] Intracellular solution (in mM): 140 KCl, 2 MgCl2, 10 EGTA, 5 ATP-Mg and 10 HEPES, pH adjusted to 7.35 with KOH.

[0994] c. Preparation of test compound solution

[0995] The test compound was dissolved in DMSO and prepared into a stock solution with a final concentration of 3.33 mM. The test compound was diluted 333.33 times with extracellular fluid to prepare a 10 μM working solution. The content of DMSO in the working solution was 0.3%.

[0996] d. Electrophysiological Recording Process

[0997] Place the small glass slide containing HEK293 cells in the culture dish in the perfusion tank of the microscope operation table, and slowly bring the electrode close to the cell under an inverted microscope. When it is close to the cell, switch to a ×40 objective lens for observation. Use the micromanipulator to fine-tune the gear to gradually bring the electrode close to the surface of the cell. Apply negative pressure to form a seal with a resistance higher than 1GΩ between the electrode tip and the cell membrane, and compensate for the instantaneous capacitive current Cfast in the voltage clamp mode. Then repeatedly apply short negative pressure to break the membrane, and finally form a whole-cell recording mode. Under the condition that the membrane potential is clamped at -60mV, the slow capacitive current Cfast is compensated. slow, the cell membrane capacitance (Cm) and the input membrane resistance (Ra) were compensated respectively. After the cells stabilized, the clamping voltage was changed to -90mV, the sampling frequency was set to 50kHz, and the filtering frequency was 10kHz. The leakage current was detected under the conditions of a clamping voltage of -80mV and a time course of 500ms. A 4.8-second depolarization command voltage was applied to depolarize the membrane potential from -80mV to +30mV, and then a 5.2-second repolarization voltage was applied instantaneously to reduce the membrane potential to -50mV to remove channel inactivation, so that the hERG tail current could be observed. First, the hERG current measured in normal extracellular fluid was used as the detection baseline. After the hERG current remained stable for at least 5 minutes, the ALA 8-channel gravity dosing system was used to perfuse the solution containing the compound to be tested around the cells. After each perfusion, wait for about 5 minutes to allow the compound to fully act on the cells and record the hERG current synchronously. After the recorded current tends to be stable, the last 5 hERG current values ​​are recorded, and the average value is taken as the final current value at a specific concentration.

[0998] Tail current suppression rate = (1-tail current size 化合物 / Tail current size 空白 )×100%

[0999] The safety test results of the compounds of the present invention on hERG alpha ion channel are shown in Table 7 below.

[1000] In the table, A means that the inhibition rate of the compound on the hERG potassium ion channel current is less than 35%; B means that the inhibition rate of the compound on the hERG potassium ion channel current is greater than 35%.

[1001] Table 7 Inhibition of hERG alpha ion channel current by the compounds of the present invention

[1002] Example Inhibition rate, 10 μM 11 B 15 A 21 A 23 A 29 A

[1003] Conclusion: The compounds of the present invention have weak inhibitory effects on hERG potassium channel current and have a low risk of cardiac toxicity.

[1004] Test Example 8: Efficacy of the compounds of the present invention in the systemic inflammatory response syndrome model

[1005] The efficacy of the compound in mice was evaluated using the TNFα-driven systemic inflammatory response syndrome model. The experimental design included a model group, a low-dose group (3 mg / kg) of the test compound, and a high-dose group (10 mg / kg) of the test compound. After the test compound was dissolved in DMSO, a hydroxypropyl β-cyclodextrin solution was added to prepare a compound solution with a concentration of 0.3 mg / mL and 1 mg / mL, wherein the final concentration of DMSO was 3% and the final concentration of hydroxypropyl β-cyclodextrin was 20%. Male 6-week-old C57BL / 6 mice (Beijing Weitonglihua Experimental Animal Technology Co., Ltd.) were orally administered with vehicle (3% DMSO, 20% hydroxypropyl β-cyclodextrin solution) or test compounds. Fifteen minutes later, each mouse was intravenously injected with 20 μg TNFα (50349-MNAE, sinobiological). The body temperature loss of mice was measured by rectal probe with a high-precision thermometer (AZ8856, Taiwan Hengxin). The body temperature of mice was measured at 1, 2, 3, 4, 5, 6 and 24 hours after intravenous injection of TNFα, and the inhibition rate of body temperature drop of mice at 6 hours was calculated.

[1006] Inhibition rate % = 1-(temperature drop value of the model group-temperature drop value of the test compound group) / temperature drop value of the model group.

[1007] Table 8 The efficacy of the compounds of the present invention in inhibiting the decrease in body temperature of mice in the systemic inflammatory response syndrome model

[1008]

[1009]

[1010] Conclusion: The compounds of the present invention can inhibit the decrease in body temperature of mice in the systemic inflammatory response syndrome model.

Claims

1. A compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof, in, X is -O-; Ring E is oxazolyl; which is further substituted by C3-C6 cycloalkyl; R 1 and R 4 are each independently selected from hydrogen; R 5 Selected from C1-C6 alkyl; R 8 is selected from halogen; R 9 is selected from hydrogen and halogen; p is 0, 1 or 2.

2. The compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from:

3. A compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof, in, X is -O-; Ring E is selected from dioxolyl; which is optionally further substituted by one or more groups selected from halogen; R 1 and R 4 are each independently selected from hydrogen; R 5 Selected from C1-C6 alkyl; R 8 is selected from halogen; R 9 Selected from hydrogen; p is 0.

4. The compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof according to claim 3, wherein the compound is:

5. A method for preparing a compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof, comprising the following steps: In the presence of a catalyst, compound III-1a undergoes an intramolecular ring-closing reaction to obtain a compound of formula (III-1); Among them, X, ring E, R 1 , R 4 , R 5 , R 8 , R 9 , p as defined in claim 1. The preparation method according to claim 5 , wherein the catalyst is trimethylaluminum.

7. A pharmaceutical composition comprising a compound represented by the general formula (III-1) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

8. Use of the compound represented by the general formula (III-1) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 7 in the preparation of a receptor interacting protein kinase 1 (RIP1) inhibitor.

9. Use of a compound represented by the general formula (III-1) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7, in the preparation of a medicament for preventing or treating a disease associated with receptor interacting protein kinase 1 activity, wherein the disease is selected from inflammatory diseases, autoimmune diseases or nervous system diseases.

10. The use according to claim 9, wherein the inflammatory disease and autoimmune disease are rheumatoid arthritis, ulcerative colitis, Crohn's disease, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, spondyloarthritis, gout, juvenile idiopathic arthritis, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, antiphospholipid syndrome, vasculitis, osteoarthritis, nonalcoholic fatty liver disease, autoimmune hepatobiliary disease, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune The present invention relates to autoimmune thrombocytopenic purpura, transplant rejection, solid organ ischemia-reperfusion injury, sepsis, systemic inflammatory response syndrome, allergic diseases, asthma, atopic skin diseases, multiple sclerosis, type I diabetes, orbital necrotizing granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1 converting enzyme associated febrile syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-associated syndrome or periodontitis; the nervous system disease is Huntington's disease, Alzheimer's disease, Parkinson's disease or amyotrophic lateral sclerosis.

11. The use according to claim 9, wherein the inflammatory disease and autoimmune disease are atopic dermatitis or autoimmune hepatitis.

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