Fused pentacyclic benzimidazole derivative as TNF activity modulator, and preparation method therefor and use thereof

Abstract

The present invention relates to a fused pentacyclic benzimidazole derivative as a TNF activity modulator, as represented by formula (I), a preparation method therefor, a pharmaceutical composition comprising same, and a medical use thereof. The compound exhibits a strong inhibitory effect on TNF α-induced NF-κB signaling pathway activation; and the compound has excellent pharmacokinetic and pharmacodynamic properties, can be used in the treatment of TNF α-related diseases, and has a high prospect for clinical application.

Description

Fused pentacyclic benzimidazole derivatives as modulators of TNF activity and methods of making and using the same

[0001] This application claims priority to Chinese Patent Application No. 2024112330006, filed on September 4, 2024, entitled “Fused pentacyclic benzimidazole derivatives as modulators of TNF activity and methods of making and using the same” and Chinese Patent Application No. 2025104017071, filed on April 1, 2025, entitled “Fused pentacyclic benzimidazole derivatives as modulators of TNF activity and methods of making and using the same”, which are incorporated herein by reference in their entirety. TECHNICAL FIELD

[0002] The present application relates to the field of biological medicine, in particular to a fused pentacyclic benzimidazole derivative as a modulator of TNF activity, a preparation method thereof, a pharmaceutical composition comprising the same, and a medical use thereof. BACKGROUND

[0003] Tumor necrosis factor (TNF) is a protein superfamily containing TNF homology domain at the carbon terminal and forming a trimer, which can bind to the tumor necrosis factor receptor superfamily (TNFRSF) to regulate various cell functions such as immune response, inflammatory response, and cell proliferation, differentiation, and apoptosis, etc. TNF mainly includes TNFα and TNFβ. TNFα is a monocyte factor mainly produced by monocytes and macrophages. TNFβ is a lymphocyte factor mainly produced by lymphocytes. The full-length of human TNFα gene is about 2.76 kb, which is composed of 4 exons and 3 introns, and is located on the 6th and 17th chromosomes. The human TNFα protein precursor is composed of 233 amino acids, which contains a signal peptide of 76 amino acids. The mature TNFα protein is a homotrimer composed of 157 amino acids, which exists in a soluble form and a transmembrane form. Transmembrane TNFα (also known as tmTNFα) exists in a precursor form, which needs to be processed by TNFα converting enzyme (TACE) to release secreted TNFα (also known as sTNFα). Secreted TNFα can bind to type 1 receptor (TNFR1, also known as TNFRSF1A, CD120a or p55) and type 2 receptor (TNFR2, also known as TNFRSF1B, CD120b or p75), thereby producing various biological activities.

[0004] TNFα is a key cytokine of Th1 signaling pathway in the upstream initiation stage of inflammatory cascade, which induces keratinocytes and vascular endothelial cells to express intercellular cell adhesion molecule-1 (ICAM-1), and promotes the migration of activated neutrophils and T cells from epidermis to dermis. In addition, TNFα is also involved in Th17 signaling pathway, which produces IL-12 and IL-23 by interacting with dendritic cells and histiocytes, and IL-23 is involved in the process of differentiating initial T cells into Th17 cells, and then Th17 cells secrete cytokines such as IL-17A, IL-17F, IL-6, IL-22 and TNFα. In the NF-kB signaling pathway, TNFα can stimulate the phosphorylation of p65 and help it to transfer to the nucleus, thereby activating many target genes to form a positive cycle of TNFα pro-inflammatory response. In the PI3K / Akt signaling pathway, TNFα can significantly increase the phosphorylation of Akt, phosphorylate IkB and degrade it, release NF-kB into the nucleus, thereby enhancing the resistance of tumor cells to apoptosis and regulating tumor angiogenesis. In the MAPK signaling pathway, TNFα can affect the MAPK signaling pathway by regulating extracellular signal-regulated kinase (ERK), thereby promoting cell growth. In addition, TNFα can also activate Caspase-8, which activates downstream Caspase-3, Caspase-6 and Caspase-7 through a cascade amplification reaction, thereby activating the Caspase family signaling pathway and promoting tumor cell apoptosis.

[0005] Due to the important role of TNFα in biological processes such as immune response, inflammatory response, cell proliferation, differentiation and apoptosis, drugs targeting TNFα have significant effects in infectious diseases and autoimmune diseases. Currently approved TNFα drugs are all biological macromolecules, or monoclonal antibodies (such as adalimumab, golimumab and certolizumab etc.), or recombinant proteins (such as etanercept etc.), which play a role by inhibiting the binding of TNFα to its receptor. The administration of these biological macromolecule drugs targeting TNFα is by intravenous injection or subcutaneous injection, thus having certain limitations on the use environment and administration operation of the drugs. Compared with biological macromolecule drugs, small molecule drugs can be administered by oral administration and topical application, which is more convenient for patients to use drugs and improves patient compliance. Therefore, it is an urgent need in clinical practice to develop new TNFα small molecule inhibitors.

[0006] In view of this, the present application is proposed. SUMMARY

[0007] PROBLEMS TO BE SOLVED BY THE INVENTION

[0008] To solve the above problems, the present application provides a fused five-ring benzimidazole derivative shown in formula (I) as a TNF activity modulator, which can be used for treating diseases related to abnormal TNFα function.

[0009] Solution for solving the problem

[0010] The present application provides a compound shown in formula (I) or its stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative and pharmaceutically acceptable salt,

[0011] wherein,

[0012] R1is selected from -C(=O)-R3, amino, cycloalkyl and -O-R9, the amino being substituted with one or more R7, the cycloalkyl being substituted with one or more R8;

[0013] R3is selected from H, D, halogen, hydroxyl and amino, the amino being substituted with one or more R 3a ;

[0014] R 3a is selected from H, D, halogen, hydroxyl, amino, alkyl, alkoxy, aryl, heteroaryl, cycloalkyl and heterocyclyl, the amino, alkyl, alkoxy, aryl, heteroaryl, cycloalkyl and heterocyclyl being substituted with one or more R 3b ;

[0015] R 3b is selected from H, D, halogen, hydroxyl, alkyl, alkoxy, cycloalkyl, heterocyclyl and substituted or unsubstituted amino, the substitution being substituted with one or more H, D, halogen, hydroxyl, amino or alkyl;

[0016] R4is selected from substituted or unsubstituted cycloalkyl, the substitution being substituted with one or more H, D, halogen or amino;

[0017] R5and R6are each independently selected from H, D, halogen, hydroxyl, cyano and substituted or unsubstituted amino, the substitution being substituted with one or more H, D, halogen, hydroxyl or alkyl;

[0018] R7is selected from H, D, halogen, hydroxyl, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, the amino, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl being substituted with one or more R 7a ;

[0019] R 7aH, D, halogen, oxo, hydroxyl, cyano, amino, alkyl, alkoxy, cycloalkyl, and heterocyclyl, said amino, alkyl, alkoxy, cycloalkyl, and heterocyclyl being substituted with one or more R 7b substituted;

[0020] said R 7b H, D, halogen, oxo, hydroxyl, cyano, amino, alkyl, alkoxy, and cyanoalkoxy;

[0021] said R8is selected from the group consisting of H, D, halogen, hydroxyl, cyano, amino, azido, alkyl, and haloalkyl, said amino and alkyl being substituted with one or more R 8a substituted;

[0022] said R 8a H, D, halogen, oxo, hydroxyl, cyano, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, and cyanoalkoxy;

[0023] said R9is selected from the group consisting of H, D, halogen, oxo, hydroxyl, cyano, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl, said amino, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl being substituted with one or more R 9a substituted;

[0024] said R 9a H, D, halogen, oxo, hydroxyl, cyano, amino, alkyl, alkoxy, cycloalkyl, and heterocyclyl;

[0025] A, B, and E are each independently selected from the group consisting of N and CR a , said R a H, D, halogen, alkyl, hydroxyl, alkoxy, cyano, and amino;

[0026] X1, X2, X3, and X4are each independently selected from the group consisting of N and CR b , said R b H, D, halogen, alkyl, hydroxyl, alkoxy, cyano, and amino;

[0027] M and J are each independently selected from the group consisting of N and CH;

[0028] T is selected from the group consisting of cycloalkyl and heterocyclyl;

[0029] L is selected from the group consisting of methylene, O, S, and NR h , said R h H, D, halogen, hydroxyl, cyano, and alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl being substituted with one or more R 9a substituted;

[0030] W is selected from the group consisting of carbonyl, sulfone, and sulfoxide;

[0031] G is selected from the group consisting of heterocyclyl, aryl and heteroaryl;

[0032] R2 is selected from the group consisting of alkyl, alkoxy, thiol, cyano, amino and cycloalkyl, said R2 is substituted with one or more R 2a ;

[0033] said R 2a is selected from the group consisting of H, D, halogen, alkyl and haloalkyl.

[0034] Effects of the Invention

[0035] The fused five-ring benzimidazole derivative of formula (I) provided by the present application can regulate the function of TNFα, and is used for treating diseases related to abnormal function of TNFα. The compound has strong inhibitory effect on the activation of NF-κB signaling pathway induced by TNFα, and has excellent pharmacokinetic and pharmacodynamic characteristics, and can be used for treating diseases related to abnormal function of TNFα, and has high clinical application prospect. DETAILED DESCRIPTION

[0036] In order to make the technical solutions and beneficial effects of the present application more obvious and easy to understand, the following will be described in detail by way of listing specific embodiments. Unless otherwise defined, the technical and scientific terms used herein have the same meaning as the technical and scientific terms in the technical field to which the present application belongs.

[0037] In one aspect, the present application provides a compound represented by formula (I) or a stereoisomer, a tautomer, a solvate, a hydrate, a prodrug, a stable isotope derivative and a pharmaceutically acceptable salt thereof,

[0038] wherein,

[0039] R1 is selected from the group consisting of -C(=O)-R3, amino, cycloalkyl and -O-R9, said amino is substituted with one or more R7, said cycloalkyl is substituted with one or more R8;

[0040] said R3 is selected from the group consisting of H, D, halogen, hydroxyl and amino, said amino is substituted with one or more R 3a ;

[0041] said R 3a is selected from the group consisting of H, D, halogen, hydroxyl, amino, alkyl, alkoxy, aryl, heteroaryl, cycloalkyl and heterocyclyl, said amino, alkyl, alkoxy, aryl, heteroaryl, cycloalkyl and heterocyclyl is substituted with one or more R 3b ;

[0042] said R 3bselected from H, D, halogen, oxo, hydroxyl, cyano, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, and cyanoalkoxy;

[0043] R4is selected from substituted or unsubstituted cycloalkyl, the substitution being by one or more H, D, halogen, or amino;

[0044] R5and R6are each independently selected from H, D, halogen, hydroxyl, cyano, and substituted or unsubstituted amino, the substitution being by one or more H, D, halogen, hydroxyl, or alkyl;

[0045] R7is selected from H, D, halogen, hydroxyl, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl, the amino, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl being substituted by one or more R 7a ;

[0046] R 7a is selected from H, D, halogen, oxo, hydroxyl, cyano, amino, alkyl, alkoxy, cycloalkyl, and heterocyclyl, the amino, alkyl, alkoxy, cycloalkyl, and heterocyclyl being substituted by one or more R 7b ;

[0047] R 7b is selected from H, D, halogen, oxo, hydroxyl, cyano, amino, alkyl, alkoxy, and cyanoalkoxy;

[0048] R8is selected from H, D, halogen, hydroxyl, cyano, amino, azido, alkyl, and haloalkyl, the amino and alkyl being substituted by one or more R 8a ;

[0049] R 8a is selected from H, D, halogen, oxo, hydroxyl, cyano, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, and cyanoalkoxy;

[0050] R9is selected from H, D, halogen, oxo, hydroxyl, cyano, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl, the amino, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl being substituted by one or more R 9a ;

[0051] R 9a is selected from H, D, halogen, oxo, hydroxyl, cyano, amino, alkyl, alkoxy, cycloalkyl, and heterocyclyl;

[0052] A, B, and E are each independently selected from N and CR a ; aH, D, halogen, alkyl, hydroxyl, alkoxy, cyano, and amino;

[0053] X1, X2, X3, and X4are each independently selected from N and CR b , said R b is selected from H, D, halogen, alkyl, hydroxyl, alkoxy, cyano, and amino;

[0054] M and J are each independently selected from N and CH;

[0055] T is selected from cycloalkyl and heterocyclyl;

[0056] L is selected from methylene, O, S, and NR h , said R h is selected from H, D, halogen, hydroxyl, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl being substituted with one or more R 9a ;

[0057] W is selected from carbonyl, sulfone, and sulfoxide;

[0058] G is selected from heterocyclyl, aryl, and heteroaryl;

[0059] R2is selected from alkyl, alkoxy, thiol, cyano, amino, and cycloalkyl, said R2being substituted with one or more R 2a ;

[0060] said R 2a is selected from H, D, halogen, alkyl, and haloalkyl.

[0061] In certain embodiments, said A, B, and E are each independently selected from N and CR a , said R a is selected from H and halogen.

[0062] In certain embodiments, said A, B, and E are each independently selected from N and CR a , said R a is selected from H and F.

[0063] In certain embodiments, the compound has a structure according to Formula (I-1), Formula (I-2), Formula (I-3), or Formula (I-4):

[0064] wherein,

[0065] R1is selected from -C(=O)-R3, amino substituted with one or more R7, cycloalkyl substituted with one or more R8, and -O-R9;

[0066] The R3 is selected from H, D, halogens, hydroxyl groups, and amino groups, wherein the amino group is reacted with one or more R3 groups. 3a Replaced;

[0067] The R 3a Selected from H, D, halogen, hydroxyl, amino, alkyl, alkoxy, aryl, heteroaryl, cycloalkyl, and heterocyclic groups, wherein the amino, alkyl, alkoxy, aryl, heteroaryl, cycloalkyl, and heterocyclic groups are influenced by one or more R groups. 3b Replaced;

[0068] The R 3b The group is selected from H, D, halogen, hydroxyl, alkyl, alkoxy, cycloalkyl, heterocyclic and substituted or unsubstituted amino groups, wherein the substitution is by being substituted by one or more H, D, halogen, hydroxyl, amino or alkyl groups;

[0069] The R4 is selected from substituted or unsubstituted cycloalkyl groups, wherein the substitution is by being substituted by one or more H, D, halogen or amino groups;

[0070] R5 and R6 are each independently selected from H, D, halogen, hydroxyl, cyano and substituted or unsubstituted amino groups, wherein the substitution is by being substituted by one or more H, D, halogen, hydroxyl or alkyl groups;

[0071] The R7 is selected from H, D, halogen, hydroxyl, amino, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the amino, alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are influenced by one or more R7 groups. 7a Replaced;

[0072] The R 7a Selected from H, D, halogen, oxo, hydroxyl, cyano, amino, alkyl, alkoxy, cycloalkyl, and heterocyclic groups, wherein the amino, alkyl, alkoxy, cycloalkyl, and heterocyclic groups are separated by one or more R groups. 7b Replaced;

[0073] The R 7b Selected from H, D, halogen, oxo group, hydroxyl group, cyano group, amino group, alkyl group, alkoxy group and cyanoalkoxy group;

[0074] The R8 is selected from H, D, halogen, hydroxyl, cyano, amino, azide, alkyl, and haloalkyl, wherein the amino and alkyl groups are affected by one or more R groups. 8a Replaced;

[0075] The R 8a Selected from H, D, halogen, oxo group, hydroxyl group, cyano group, amino group, alkyl group, alkoxy group, cycloalkyl group, heterocyclic group and cyanoalkoxy group;

[0076] The R9 is selected from H, D, halogen, oxo, hydroxyl, cyano, amino, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the amino, alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are influenced by one or more R9 groups. 9a Replaced;

[0077] The R 9a Selected from H, D, halogen, oxo group, hydroxyl group, cyano group, amino group, alkyl group, alkoxy group, cycloalkyl group and heterocyclic group;

[0078] X1, X2, X3, and X4 are each independently selected from N and CR. b The R b Selected from H, D, halogens, alkyl, hydroxyl, alkoxy, cyano, and amino groups;

[0079] M and J are each independently selected from N and CH;

[0080] T is selected from cycloalkyl and heterocyclic groups;

[0081] L is selected from methylene, O, S, and NR. h The R h Selected from H, D, halogen, hydroxyl, cyano, alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are influenced by one or more R groups. 9a Replaced;

[0082] W is selected from carbonyl, sulfone, and sulfoxide groups;

[0083] G is selected from heterocyclic, aryl, and heteroaryl groups;

[0084] R2 is selected from alkyl, alkoxy, mercapto, cyano, amino, and cycloalkyl groups, wherein R2 is reacted with one or more R groups. 2a Replaced;

[0085] The R 2a Selected from H, D, halogens, alkyl groups and haloalkyl groups.

[0086] In some embodiments, the W is selected from carbonyl groups.

[0087] In some implementations, M and J are each independently selected from N.

[0088] In some implementations, T is selected from C. 3-8 Cycloalkyl and 3-8 membered heterocyclic groups.

[0089] In some embodiments, T is selected from 5-8 membered heterocyclic groups, which contain 1-4 heteroatoms selected from N, O and S.

[0090] In certain embodiments, T is selected from 5-6 membered heterocyclyl containing 1-2 heteroatoms selected from N.

[0091] In certain embodiments, T is selected from pyrrolidinyl and piperidinyl.

[0092] In certain embodiments, T is selected from

[0093] In certain embodiments, X1, X2, X3, and X4are each independently selected from N and CR b , R b is selected from H, D, and halogen.

[0094] In certain embodiments, X1, X2, X3, and X4are each independently selected from N and CR b , R b is selected from H.

[0095] In certain embodiments, the compound has a structure according to Formula (I-1-1), Formula (I-1-2), Formula (I-1-3), Formula (I-1-4), Formula (I-1-5), Formula (I-2-1), Formula (I-3-1), or Formula (I-4-1):

[0096] wherein,

[0097] R1is selected from -C(=0)-R3, amino, cycloalkyl, and -0-R9, said amino substituted with one or more R7, said cycloalkyl substituted with one or more R8;

[0098] R3is selected from H, D, halogen, hydroxyl, and amino, said amino substituted with one or more R 3a ;

[0099] R 3a is selected from H, D, halogen, hydroxyl, amino, alkyl, alkoxy, aryl, heteroaryl, cycloalkyl, and heterocyclyl, said amino, alkyl, alkoxy, aryl, heteroaryl, cycloalkyl, and heterocyclyl substituted with one or more R 3b ;

[0100] R 3b is selected from H, D, halogen, hydroxyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, and substituted or unsubstituted amino, said substitution with one or more H, D, halogen, hydroxyl, amino, or alkyl;

[0101] R4is selected from substituted or unsubstituted cycloalkyl, said substitution with one or more H, D, halogen, or amino;

[0102] each R5and R6is independently selected from H, D, halogen, hydroxyl, cyano, and substituted or unsubstituted amino, the substitution being by one or more H, D, halogen, hydroxyl, or alkyl;

[0103] R7is selected from H, D, halogen, hydroxyl, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl, the amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl being substituted by one or more R 7a ;

[0104] R 7a is selected from H, D, halogen, oxo, hydroxyl, cyano, amino, alkyl, alkoxy, cycloalkyl, and heterocyclyl, the amino, alkyl, alkoxy, cycloalkyl, and heterocyclyl being substituted by one or more R 7b ;

[0105] R 7b is selected from H, D, halogen, oxo, hydroxyl, cyano, amino, alkyl, alkoxy, and cyanoalkoxy;

[0106] R8is selected from H, D, halogen, hydroxyl, cyano, amino, azido, alkyl, and haloalkyl, the amino and alkyl being substituted by one or more R 8a ;

[0107] R 8a is selected from H, D, halogen, oxo, hydroxyl, cyano, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, and cyanoalkoxy;

[0108] R9is selected from H, D, halogen, oxo, hydroxyl, cyano, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl, the amino, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl being substituted by one or more R 9a ;

[0109] R 9a is selected from H, D, halogen, oxo, hydroxyl, cyano, amino, alkyl, alkoxy, cycloalkyl, and heterocyclyl;

[0110] L is selected from methylene, O, S, and NR h ; R h is selected from H, D, halogen, hydroxyl, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl being substituted by one or more R 9a ;

[0111] G is selected from heterocyclyl, aryl, and heteroaryl;

[0112] R2 is selected from alkyl, alkoxy, mercapto, cyano, amino, and cycloalkyl groups, wherein R2 is reacted with one or more R groups. 2a Replaced;

[0113] The R 2a Selected from H, D, halogens, alkyl groups and haloalkyl groups.

[0114] In some embodiments, the R3 is selected from H, D, halogens, and amino groups, wherein the amino group is reacted with one or more R groups. 3a What it replaced.

[0115] In some embodiments, R3 is selected from amino groups, and the amino group is reacted with one or more R groups. 3a What it replaced.

[0116] In some implementations, the R 3a Selected from H, D, halogen, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the amino group, C 1-6 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups are bound by one or more R 3b What it replaced.

[0117] In some implementations, the R 3a Selected from H, D, halogen, hydroxyl, amino, C 1-3 Alkyl, C 3-6 Cycloalkyl groups and 3-6 membered heterocyclic groups, wherein the 3-6 membered heterocyclic group contains 1-4 heteroatoms selected from N, O, and S, and the amino group, C 1-3 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups are separated by one or more R 3b What it replaced.

[0118] In some implementations, the R 3a Selected from H, D, C 1-3 Alkyl, C 3-5 Cycloalkyl groups and 4-5 membered heterocyclic groups, wherein the 4-5 membered heterocyclic group contains 1-2 heteroatoms selected from N, and the C 1-3 Alkyl, C 3-5 Cycloalkyl and 4-5 membered heterocyclic groups are separated by one or more R 3b What it replaced.

[0119] In some implementations, the R 3aselected from H, D, halogen, hydroxyl, cyano, C1-C6alkyl, C1-C6alkoxy, C3-C8cycloalkyl, 3-8 membered heterocyclyl, and substituted or unsubstituted amino, substituted with one or more H, D, halogen, hydroxyl, amino, or C1-C6alkyl; 3b substituted.

[0120] In certain embodiments, the R 3b selected from H, D, halogen, hydroxyl, cyano, C1-C6alkyl, C1-C6alkoxy, C3-C8cycloalkyl, 3-8 membered heterocyclyl, and substituted or unsubstituted amino, substituted with one or more H, D, halogen, hydroxyl, amino, or C1-C6alkyl; 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, and substituted or unsubstituted amino, substituted with one or more H, D, halogen, hydroxyl, amino, or C 1-6 alkyl.

[0121] In certain embodiments, the R 3b selected from H, D, halogen, hydroxyl, cyano, C1-C6alkyl, C1-C6alkoxy, C3-C8cycloalkyl, 3-8 membered heterocyclyl, and substituted or unsubstituted amino, substituted with one or more H, D, halogen, hydroxyl, amino, or C1-C6alkyl; 1-3 alkyl, C 1-3 alkoxy, and substituted or unsubstituted amino, substituted with one or more H, D, halogen, hydroxyl, amino, or C 1-3 alkyl.

[0122] In certain embodiments, the R 3b selected from H, D, halogen, hydroxyl, cyano, C1-C6alkyl, C1-C6alkoxy, C3-C8cycloalkyl, 3-8 membered heterocyclyl, and substituted or unsubstituted amino, substituted with one or more H, D, halogen, hydroxyl, amino, or C1-C6alkyl;

[0123] In certain embodiments, the R 3b selected from H, D, halogen, hydroxyl, cyano, C1-C6alkyl, C1-C6alkoxy, C3-C8cycloalkyl, 3-8 membered heterocyclyl, and substituted or unsubstituted amino, substituted with one or more H, D, halogen, hydroxyl, amino, or C1-C6alkyl;

[0124] In certain embodiments, the R4is selected from substituted or unsubstituted C 3-8 cycloalkyl, substituted with one or more H, D, halogen, or amino.

[0125] In certain embodiments, the R4is selected from substituted or unsubstituted C 3-5 cycloalkyl, substituted with one or more H, D, halogen, or amino.

[0126] In certain embodiments, the R4is selected from substituted or unsubstituted C

[0127] In certain embodiments, the R5is selected from H, D, halogen, hydroxyl, cyano, and substituted or unsubstituted amino, substituted with one or more H, D, halogen, hydroxyl, or C 1-6 alkyl.

[0128] In certain embodiments, R5is selected from H, D, and substituted or unsubstituted amino, the substitution being with one or more H, D, halogen, hydroxyl, or C 1-3 alkyl.

[0129] In certain embodiments, R5is selected from H and substituted or unsubstituted amino, the substitution being with one or more H or methyl.

[0130] In certain embodiments, R6is selected from H, D, halogen, hydroxyl, cyano, and substituted or unsubstituted amino, the substitution being with one or more H, D, halogen, hydroxyl, or C 1-6 alkyl.

[0131] In certain embodiments, R6is selected from H, D, and substituted or unsubstituted amino, the substitution being with one or more H, D, halogen, hydroxyl, or C 1-3 alkyl.

[0132] In certain embodiments, R6is selected from H and substituted or unsubstituted amino, the substitution being with one or more H or methyl.

[0133] In certain embodiments, R7is selected from H, D, halogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, the amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, is substituted with one or more R 7a .

[0134] In certain embodiments, R7is selected from H, D, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, and 5-8 membered heteroaryl, the 3-6 membered heterocyclyl and 5-8 membered heteroaryl containing 1-4 heteroatoms selected from N, O, and S, the C 1-6 alkyl, C 3-6 cycloalkyl, 5-8 membered heterocyclyl, C 6-8 aryl, and 5-8 membered heteroaryl, is substituted with one or more R 7a .

[0135] In certain embodiments, R7is selected from H, C 1-4 alkyl, C 3-6cycloalkyl, 4-6 membered heterocyclyl, C 6-7 aryl and 5-6 membered heteroaryl, said 4-6 membered heterocyclyl and 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N and O, said C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, C 6-7 aryl and 5-6 membered heteroaryl, said 4-6 membered heterocyclyl and 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N and O, said C 7a substituted.

[0136] In certain embodiments, said R7is selected from H, methyl, ethyl, n-propyl, i-propyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, pyrrolidinyl, phenyl, pyrrolyl, furanyl, oxazolyl, and pyrazolyl, said methyl, ethyl, n-propyl, i-propyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, pyrrolidinyl, phenyl, pyrrolyl, furanyl, oxazolyl, and pyrazolyl being substituted with one or more R 7a substituted.

[0137] In certain embodiments, said R 7a is selected from H, D, halogen, oxo, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, said amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, said amino, C 7b substituted.

[0138] In certain embodiments, said R 7a is selected from H, D, halogen, oxo, hydroxyl, cyano, amino, C 1-4 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl and 3-6 membered heterocyclyl, said 3-6 membered heterocyclyl containing 1-4 heteroatoms selected from N, O and S, said amino, C 1-4 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl and 3-6 membered heterocyclyl, said amino, C 7b substituted.

[0139] In certain embodiments, said R 7a is selected from H, F, oxo, hydroxyl, cyano, amino, C 1-4 alkyl, C 1-3 alkoxy, C 3-5cycloalkyl and 4-6 membered heterocyclyl containing 1-2 heteroatoms selected from N and O, said amino, C 1-4 alkyl, C 1-3 alkoxy, C 3-5 cycloalkyl and 4-6 membered heterocyclyl are substituted with one or more R 7b .

[0140] In certain embodiments, said R 7a is selected from H, F, oxo, hydroxyl, cyano, amino, methyl, sec-butyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, tetrahydrofuranyl, oxepanyl, azetidinyl, and azepanyl, said amino, methyl, sec-butyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, tetrahydrofuranyl, oxepanyl, azetidinyl, and azepanyl are substituted with one or more R 7b .

[0141] In certain embodiments, said R 7b is selected from H, D, halogen, oxo, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 cyanoalkoxy.

[0142] In certain embodiments, said R 7b is selected from H, D, halogen, oxo, hydroxyl, cyano, amino, C 1-3 alkyl, C 1-3 alkoxy, and C 1-3 cyanoalkoxy.

[0143] In certain embodiments, said R 7b is selected from H, F, oxo, hydroxyl, cyano, methyl, methoxy, ethoxy, and cyanoethoxy.

[0144] In certain embodiments, said R8is selected from H, D, halogen, hydroxyl, cyano, amino, azido, C 1-6 alkyl, and C 1-6 haloalkyl, said amino and C 1-6 alkyl are substituted with one or more R 8a .

[0145] In certain embodiments, said R8is selected from H, D, halogen, amino, azido, C 1-3 alkyl, and C 1-3 haloalkyl, said amino and C 1-3 alkyl are substituted with one or more R 8a .

[0146] In certain embodiments, said R8is selected from H, amino, azido, and trifluoroethyl, said amino substituted with one or more R 8a substituted.

[0147] In certain embodiments, said R 8a is selected from H, D, halogen, oxo, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl.

[0148] In certain embodiments, said R 8a is selected from H, D, halogen, oxo, hydroxyl, cyano, amino, C 1-4 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl containing 1-4 heteroatoms selected from N, O, and S.

[0149] In certain embodiments, said R 8a is selected from H, F, oxo, hydroxyl, cyano, amino, C 1-4 alkyl, C 1-3 alkoxy, C 3-5 cycloalkyl, and 4-6 membered heterocyclyl containing 1-2 heteroatoms selected from N and O.

[0150] In certain embodiments, said R 8a is selected from H and methyl.

[0151] In certain embodiments, said R9is selected from H, D, halogen, oxo, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl substituted with one or more R 9a substituted.

[0152] In certain embodiments, said R9is selected from H, D, C 1-3 alkyl, and C 3-6 cycloalkyl, said C 1-3 alkyl, and C 3-6 cycloalkyl substituted with one or more R 9a substituted.

[0153] In certain embodiments, said R9is selected from H, methyl, and cyclobutyl, said methyl and cyclobutyl being substituted with one or more R 9a substituted.

[0154] In certain embodiments, said R 9a is selected from H, D, halogen, oxo, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl.

[0155] In certain embodiments, said R 9a is selected from H, D, halogen, and 4-6 membered heterocyclyl, said 4-6 membered heterocyclyl containing 1-2 heteroatoms selected from N and O.

[0156] In certain embodiments, said R 9a is selected from H, F, and tetrahydrofuranyl.

[0157] In certain embodiments, said R1is selected from

[0158] In certain embodiments, said L is selected from NR h , said R h is selected from H, D, halogen, hydroxyl, cyano, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, said C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl being substituted with one or more R 9a .

[0159] In certain embodiments, said L is selected from NR h , said R h is selected from H, D, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, and 5-8 membered heteroaryl, said 3-6 membered heterocyclyl and 5-8 membered heteroaryl containing 1-4 heteroatoms selected from N, O, and S, said C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, and 5-8 membered heteroaryl being substituted with one or more R 9a .

[0160] In certain embodiments, the L is selected from NR h , and the R h is selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, C 6-7 aryl, and 5-6 membered heteroaryl, the 4-6 membered heterocyclyl and 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N and O, the C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, C 6-7 aryl, and 5-6 membered heteroaryl is substituted with one or more R 9a .

[0161] In certain embodiments, the L is selected from NR h , and the R h is selected from H, methyl, ethyl, n-propyl, i-propyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, pyrrolidinyl, phenyl, pyrrolyl, furanyl, oxazolyl, and pyrazolyl, the methyl, ethyl, n-propyl, i-propyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, pyrrolidinyl, phenyl, pyrrolyl, furanyl, oxazolyl, and pyrazolyl being substituted with one or more R 9a .

[0162] In certain embodiments, the R 9a is selected from H, D, halogen, oxo, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl.

[0163] In certain embodiments, the R 9a is selected from H, D, halogen, and 4-6 membered heterocyclyl, the 4-6 membered heterocyclyl containing 1-2 heteroatoms selected from N and O.

[0164] In certain embodiments, the R 9a is selected from H, F, and tetrahydrofuranyl.

[0165] In certain embodiments, the L is selected from NR h , and the R h is selected from H, methyl, ethyl, and i-propyl.

[0166] In certain embodiments, the G is selected from C 6-10 aryl, and 5-8 membered heteroaryl.

[0167] In certain embodiments, the G is selected from C 6-10aryl and 5-8 membered heteroaryl, said 5-8 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S.

[0168] In certain embodiments, said G is selected from phenyl and pyridyl.

[0169] In certain embodiments, said G is selected from

[0170] In certain embodiments, said R2is selected from C 1-6 alkyl, C 1-6 alkoxy, thiol, cyano, amino and C 3-8 cycloalkyl, said C 1-6 alkyl, C 1-6 alkoxy, thiol, amino and C 3-8 cycloalkyl is substituted with one or more R 2a .

[0171] In certain embodiments, said R2is selected from C 1-3 alkyl, C 1-3 alkoxy, thiol, amino and C 3-5 cycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy, thiol, cyano, amino and C 3-5 cycloalkyl is substituted with one or more R 2a .

[0172] In certain embodiments, said R2is selected from isopropyl, methoxy, thiol, cyano, amino and cyclopropyl, said isopropyl, methoxy, thiol, amino and cyclopropyl is substituted with one or more R 2a .

[0173] In certain embodiments, said R 2a is selected from H, D, halogen, C 1-6 alkyl and C 1-6 haloalkyl.

[0174] In certain embodiments, said R 2a is selected from H, D, halogen, C 1-3 alkyl and C 1-3 haloalkyl.

[0175] In certain embodiments, said R 2a is selected from H, F and difluoromethyl.

[0176] In another aspect, the present application provides a compound, or a stereoisomer, a tautomer, a solvate, a hydrate, a prodrug, a stable isotope derivative, and a pharmaceutically acceptable salt thereof, wherein said compound is any one of:

[0177] In another aspect, the present application provides a compound, or stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative, and pharmaceutically acceptable salt thereof, wherein the compound is any one of:

[0178] In another aspect, the present application also provides a pharmaceutical composition comprising the aforementioned compound, or stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative, and pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0179] In certain embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0180] In certain embodiments, the pharmaceutical composition contains 0.01% to 99.99% of the aforementioned compound, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1% to 99.9% of the aforementioned compound. In certain embodiments, the pharmaceutical composition contains 0.5% to 99.5% of the aforementioned compound. In certain embodiments, the pharmaceutical composition contains 1% to 99% of the aforementioned compound. In certain embodiments, the pharmaceutical composition contains 2% to 98% of the aforementioned compound.

[0181] In certain embodiments, the pharmaceutical composition contains 0.01% to 99.99% of the aforementioned compound, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1% to 99.9% of the aforementioned compound. In certain embodiments, the pharmaceutical composition contains 0.5% to 99.5% of the aforementioned compound. In certain embodiments, the pharmaceutical composition contains 1% to 99% of the aforementioned compound. In certain embodiments, the pharmaceutical composition contains 2% to 98% of the aforementioned compound.

[0182] All compounds and mixtures, compositions, etc. comprising the compounds of the present disclosure can be administered to an organism by any route of administration. The route of administration can be oral, intravenous, intramuscular, subcutaneous, rectal, vaginal, sublingual, nasal inhalation, buccal inhalation, ocular, and also topical or systemic transdermal.

[0183] All compounds and mixtures, compositions, etc. comprising the compounds of the present disclosure can be formulated into a single dosage unit comprising the active compound of the present disclosure together with a carrier, excipient, etc. and the dosage form can be tablets, capsules, injections, granules, powders, suppositories, pills, creams, pastes, gels, powders, oral solutions, inhalants, suspensions, dry suspensions, patches, lotions, etc. These dosage forms can contain ingredients commonly used in pharmaceutical formulations, such as diluents, absorbents, wetting agents, binders, disintegrants, coloring agents, pH adjusting agents, antioxidants, bacteriostatic agents, isotonicity adjusting agents, antiadherents, etc.

[0184] Suitable formulations for each of the above-mentioned dosage forms can be obtained from public sources, such as Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott Williams & Wilkins, 2006 and Rowe, Raymond C. Handbook of Pharmaceutical Excipients, Chicago, Pharmaceutical Press, 2005. Thus, those skilled in the art can easily prepare them.

[0185] The dosage of the compound of the present disclosure can be 0.01 to 500 mg / kg per day, preferably 1 to 100 mg / kg per day, and can be administered once or multiple times, depending on the nature, severity of the disease, the age, sex, body weight of the patient, the route of administration, etc.

[0186] In another aspect, the present application also provides the compound of the present application or its stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative, and pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, for use as a prophylactic and / or therapeutic agent for a disease associated with abnormal function of TNFα.

[0187] In certain embodiments, the disease associated with abnormal function of TNFα includes inflammatory diseases, autoimmune diseases, neurological diseases, neurodegenerative diseases, pain, cardiovascular diseases, metabolism-related diseases, ocular diseases, and tumors.

[0188] In certain embodiments, the autoimmune disease comprises systemic lupus erythematosus, psoriasis, psoriatic arthritis, vasculitis, inflammatory myopathy (including polymyositis, dermatomyositis, and inclusion body myositis), scleroderma, multiple sclerosis, systemic sclerosis, ankylosing spondylitis, rheumatoid arthritis, non-specific inflammatory arthritis, juvenile inflammatory arthritis, juvenile idiopathic arthritis (including its oligoarticular and polyarticular forms), anemia of chronic disease (ACD), Still's disease (juvenile and / or adult onset), Behcet's disease, Sjogren's syndrome, thyroiditis, Addison's disease, hemolytic or pernicious anemia, acute kidney injury (AKI; including cisplatin-induced AKI), diabetic nephropathy (DN), obstructive uropathy (including cisplatin-induced obstructive uropathy), glomerulonephritis (including Goodpasture's syndrome, immune complex-mediated glomerulonephritis, and anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis), lupus nephritis (LN), minimal change nephropathy, Graves' disease, idiopathic thrombocytopenic purpura, inflammatory bowel disease (including Crohn's disease, ulcerative colitis, indeterminate colitis, and pouchitis), pemphigus, atopic dermatitis, autoimmune hepatitis, primary biliary cirrhosis, autoimmune pneumonitis, autoimmune carditis, myasthenia gravis, spontaneous infertility, osteoporosis, osteopenia, erosive bone disease, cartilage inflammation, cartilage degeneration and / or destruction, fibrotic disorders (including various forms of liver and lung fibrosis), asthma, rhinitis, chronic obstructive pulmonary disease (COPD), respiratory distress syndrome, sepsis, fever, muscular dystrophy (including Duchenne muscular dystrophy), organ transplant rejection (including kidney allograft rejection), scleritis (including giant cell arteritis scleritis), Takayasu's arteritis, hidradenitis suppurativa, pyoderma gangrenosum, sarcoidosis, polymyalgia rheumatica, and axial spondyloarthritis; the ocular disease comprises uveitis, non-infectious anterior uveitis, dry eye, panuveitis, Behcet's disease, posterior uveitis, dry eye syndrome, Blau syndrome, intermediate uveitis, Behcet's uveitis, macular degeneration, anterior uveitis, conjunctivitis, wet macular degeneration, retinal pigmentosa, Sjogren's syndrome, retinal degeneration, ocular pain, vitreous disease.

[0189] In another aspect, the present application also provides the use of the compound of the present application or a stereoisomer, a tautomer, a solvate, a hydrate, a prodrug, a stable isotope derivative, and a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition for preventing and / or treating a disease associated with abnormal TNFα function.

[0190] In certain embodiments, the disease associated with abnormal TNFα function comprises an inflammatory disease, an autoimmune disease, a neurological disease, a neurodegenerative disease, pain, a cardiovascular disease, a metabolism-related disease, an ocular disease, and a tumor.

[0191] In certain embodiments, the autoimmune disease comprises systemic lupus erythematosus, psoriasis, psoriatic arthritis, vasculitis, inflammatory myopathy (including polymyositis, dermatomyositis, and inclusion body myositis), scleroderma, multiple sclerosis, systemic sclerosis, ankylosing spondylitis, rheumatoid arthritis, non-specific inflammatory arthritis, juvenile inflammatory arthritis, juvenile idiopathic arthritis (including its oligoarticular and polyarticular forms), anemia of chronic disease (ACD), Still's disease (juvenile and / or adult onset), Behcet's disease, Sjogren's syndrome, thyroiditis, Addison's disease, hemolytic or pernicious anemia, acute kidney injury (AKI; including cisplatin-induced AKI), diabetic nephropathy (DN), obstructive uropathy (including cisplatin-induced obstructive uropathy), glomerulonephritis (including Goodpasture's syndrome, immune complex-mediated glomerulonephritis, and anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis), lupus nephritis (LN), minimal change nephropathy, Graves' disease, idiopathic thrombocytopenic purpura, inflammatory bowel disease (including Crohn's disease, ulcerative colitis, indeterminate colitis, and pouchitis), pemphigus, atopic dermatitis, autoimmune hepatitis, primary biliary cirrhosis, autoimmune pneumonitis, autoimmune carditis, myasthenia gravis, spontaneous infertility, osteoporosis, osteopenia, erosive bone disease, cartilage inflammation, cartilage degeneration and / or destruction, fibrotic disorders (including various forms of liver and lung fibrosis), asthma, rhinitis, chronic obstructive pulmonary disease (COPD), respiratory distress syndrome, sepsis, fever, muscular dystrophy (including Duchenne muscular dystrophy), organ transplant rejection (including kidney allograft rejection), scleritis (including giant cell arteritis scleritis), Takayasu's arteritis, hidradenitis suppurativa, pyoderma gangrenosum, sarcoidosis, polymyalgia rheumatica, and axial spondyloarthritis; the ocular disease comprises uveitis, non-infectious anterior uveitis, dry eye, panuveitis, Behcet's disease, posterior uveitis, dry eye syndrome, Blau syndrome, intermediate uveitis, Behcet's uveitis, macular degeneration, anterior uveitis, conjunctivitis, wet macular degeneration, retinal pigmentosa, Sjogren's syndrome, retinal degeneration, ocular pain, vitreous disease.

[0192] In another aspect, the present application also provides the use of the compound of the present application or a stereoisomer, a tautomer, a solvate, a hydrate, a prodrug, a stable isotope derivative, and a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition in the manufacture of a medicament for preventing and / or treating a disease associated with abnormal TNFα function.

[0193] In certain embodiments, the disease associated with abnormal TNFα function comprises an inflammatory disease, an autoimmune disease, a neurological disease, a neurodegenerative disease, pain, a cardiovascular disease, a metabolism-related disease, an ocular disease, and a tumor.

[0194] In certain embodiments, the autoimmune disease comprises systemic lupus erythematosus, psoriasis, psoriatic arthritis, vasculitis, inflammatory myopathy (including polymyositis, dermatomyositis, and inclusion body myositis), scleroderma, multiple sclerosis, systemic sclerosis, ankylosing spondylitis, rheumatoid arthritis, non-specific inflammatory arthritis, juvenile inflammatory arthritis, juvenile idiopathic arthritis (including its oligoarticular and polyarticular forms), anemia of chronic disease (ACD), Still's disease (juvenile and / or adult onset), Behcet's disease, Sjogren's syndrome, thyroiditis, Addison's disease, hemolytic or pernicious anemia, acute kidney injury (AKI; including cisplatin-induced AKI), diabetic nephropathy (DN), obstructive uropathy (including cisplatin-induced obstructive uropathy), glomerulonephritis (including Goodpasture's syndrome, immune complex-mediated glomerulonephritis, and anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis), lupus nephritis (LN), minimal change nephropathy, Graves' disease, idiopathic thrombocytopenic purpura, inflammatory bowel disease (including Crohn's disease, ulcerative colitis, indeterminate colitis, and pouchitis), pemphigus, atopic dermatitis, autoimmune hepatitis, primary biliary cirrhosis, autoimmune pneumonitis, autoimmune carditis, myasthenia gravis, spontaneous infertility, osteoporosis, osteopenia, erosive bone disease, cartilage inflammation, cartilage degeneration and / or destruction, fibrotic disorders (including various forms of liver and lung fibrosis), asthma, rhinitis, chronic obstructive pulmonary disease (COPD), respiratory distress syndrome, sepsis, fever, muscular dystrophy (including Duchenne muscular dystrophy), organ transplant rejection (including kidney allograft rejection), scleritis (including giant cell arteritis scleritis), Takayasu's arteritis, hidradenitis suppurativa, pyoderma gangrenosum, sarcoidosis, polymyalgia rheumatica, and axial spondyloarthritis; the ocular disease comprises uveitis, non-infectious anterior uveitis, dry eye, panuveitis, Behcet's disease, posterior uveitis, dry eye syndrome, Blau syndrome, intermediate uveitis, Behcet's uveitis, macular degeneration, anterior uveitis, conjunctivitis, wet macular degeneration, retinal pigmentosa, Sjogren's syndrome, retinal degeneration, ocular pain, vitreous disease.

[0195] Terminology:

[0196] Unless otherwise indicated, the terms used in the specification and claims have the following meanings.

[0197] The term "alkyl" refers to saturated aliphatic hydrocarbon groups which are straight-chain or branched groups, preferably alkyl groups containing 1 to 20 carbon atoms, more preferably alkyl groups containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and even more preferably alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof, and the like. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any available attachment point with one or more substituents preferably independently optionally selected from D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0198] The term "alkylene" refers to a saturated straight or branched aliphatic hydrocarbon radical which is a residue derived from removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane, which is a straight chain or branched group comprising 1 to 20 carbon atoms, preferably containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, more preferably containing 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH2-), 1,1-ethylidene (-CH(CH3)-), 1,2-ethylidene (-CH2CH2)-, 1,1-propylidene (-CH(CH2CH3)-), 1,2-propylidene (-CH2CH(CH3)-), 1,3-propylidene (-CH2CH2CH2-), 1,4-butylidene (-CH2CH2CH2CH2-), and the like. The alkylene group can be substituted or unsubstituted, when substituted, it can be substituted at any available point of attachment with one or more substituents preferably independently optionally selected from alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo.

[0199] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring comprising 3 to 20 carbon atoms, preferably comprising 3 to 12 carbon atoms, preferably comprising 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, more preferably comprising 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spirocyclic, fused, and bridged cycloalkyl groups.

[0200] The term "spirocycloalkyl" refers to a 5- to 20-membered, polycyclic group sharing one carbon atom between rings (termed a spiro atom), which can contain one or more double bonds. Preferably 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7-, 8-, 9-, or 10-membered). Spirocycloalkyl groups are classified as mono-, bi-, or polyspirocycloalkyl groups, preferably mono- and bispirocycloalkyl groups, depending on the number of spiro atoms shared between rings. More preferably 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups include:

[0201] The term "cycloalkyl" refers to a monocyclic, saturated, all-carbon ring radical of 3 to 20 carbon atoms. Preferably, the cycloalkyl radical is a 3 to 14 membered ring, more preferably a 3 to 10 membered ring (e.g., 3, 4, 5, 6, 7, 8, 9, or 10 membered). The cycloalkyl radical can be classified as a monocyclic, spirocyclic, fused ring, or bridged ring cycloalkyl radical, preferably a monocyclic or spirocyclic, more preferably a 3 to 6 membered monocyclic or spirocyclic. Non-limiting examples of cycloalkyl radicals include:

[0202] The term "bridged cycloalkyl" refers to a 5 to 20 membered, all-carbon polycyclic radical in which any two rings share two non-adjacent carbon atoms, which can contain one or more double bonds. Preferably, the bridged cycloalkyl radical is a 6 to 14 membered ring, more preferably a 7 to 10 membered ring (e.g., 7, 8, 9, or 10 membered). The bridged cycloalkyl radical can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl radical, preferably a bicyclic, tricyclic, or tetracyclic, more preferably a bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl radicals include:

[0203] The cycloalkyl ring includes cycloalkyl (including monocyclic, spirocyclic, fused ring, and bridged ring) fused to an aryl, heteroaryl, or heterocycloalkyl ring as described above, wherein the ring that is attached to the parent structure is a cycloalkyl, non-limiting examples include etc.; preferably

[0204] The cycloalkyl radical can be substituted or unsubstituted, when substituted it can be substituted at any available point of attachment with one or more substituents preferably independently optionally selected from the group consisting of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0205] The term "alkoxy" refers to -O-(alkyl) and -O-(cycloalkyl), wherein alkyl, cycloalkyl are as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, and butoxy. The alkoxy radical can be optionally substituted or unsubstituted, when substituted it is preferably one or more of the following groups, which are independently selected from the group consisting of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0206] The term "cyanoalkoxy" refers to an alkoxy group substituted with one cyano group. Non-limiting examples of cyanoalkoxy groups include NCCH2O-, NCCH2CH2O-, CH3CH(CN)CH2O-, and the like.

[0207] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic nonaromatic cyclic substituent comprising 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen, and sulfur, which can optionally be oxidized (i.e., form a sulfoxide or sulfone), but not ring members of -O-O-, -O-S-, or -S-S-, the remainder of which are carbon. Preferably, there are 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, of which 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, there are 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8), of which 1 to 3 (e.g., 1, 2, and 3) are heteroatoms; more preferably, there are 3 to 6 ring atoms, of which 1 to 3 are heteroatoms; most preferably, there are 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclyl groups include spiro, fused, and bridged heterocyclyl groups.

[0208] The term "spiroheterocyclyl" refers to a 5- to 20-membered, monocyclic, nonaromatic polycyclic heterocyclic group sharing one atom (referred to as a spiro atom) between rings, one or more of which are heteroatoms selected from nitrogen, oxygen, and sulfur, which can optionally be oxidized (i.e., form a sulfoxide or sulfone), the remainder of which are carbon. It can contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7-, 8-, 9-, or 10-membered). Depending on the number of spiro atoms shared between rings, spiroheterocyclyl groups are classified as mono-, bi-, or polyspiroheterocyclyl groups, preferably mono- and bi- spiroheterocyclyl groups. More preferably, it is a 3 / 5-, 3 / 6-, 4 / 4-, 4 / 5-, 4 / 6-, 5 / 5-, or 5 / 6- membered monosprioheterocyclyl group. Non-limiting examples of spiroheterocyclyl groups include:

[0209] The term "fused heterocyclyl" refers to a non-aromatic polycyclic heterocyclic radical of 5 to 20 members, each ring in the system sharing an adjacent pair of atoms with other rings in the system, one or more rings can contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, which can optionally be oxidized (i.e., form a sulfoxide or sulfone), the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclyl radicals according to the number of rings comprising, preferably bicyclic or tricyclic, more preferably 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 4, 5 / 5, 5 / 6, 6 / 3, 6 / 4, 6 / 5, and 6 / 6 bicyclic fused heterocyclyl radicals. Non-limiting examples of fused heterocyclyl groups include:

[0210] The term "bridged heterocyclyl" refers to a non-aromatic polycyclic heterocyclic radical of 5 to 14 members, any two rings sharing two non-adjacent atoms, which can contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, which can optionally be oxidized (i.e., form a sulfoxide or sulfone), the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclyl radicals according to the number of rings comprising, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

[0211] The heterocyclyl ring includes fused to an aryl, heteroaryl, or cycloalkyl ring, as described above for heterocyclyl groups (including monocyclic, spiro, fused, and bridged heterocyclyl groups), wherein the ring that is attached to the parent structure is a heterocyclyl group, non-limiting examples of which include:

[0212] etc.

[0213] The heterocyclyl group can be substituted or unsubstituted, when substituted, it can be substituted at any available point of attachment, the substituents are preferably independently and optionally selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0214] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring sharing pairs of adjacent carbon atoms) groups having a conjugated pi electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes aryl rings fused to heteroaryl, heterocyclyl, or cycloalkyl rings as defined above, wherein the ring that is attached to the parent structure is the aryl ring, non-limiting examples of which include:

[0215] The aryl group can be substituted or unsubstituted, and when substituted, it can be substituted at any available point of attachment with one or more substituents, preferably independently and optionally selected from halo, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0216] The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5- to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5- or 6-membered, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, and the like. The heteroaryl ring includes heteroaryl rings fused to aryl, heterocyclyl, or cycloalkyl rings as defined above, wherein the ring that is attached to the parent structure is the heteroaryl ring, non-limiting examples of which include:

[0217] The heteroaryl group can be substituted or unsubstituted, and when substituted, it can be substituted at any available point of attachment with one or more substituents, preferably independently and optionally selected from halo, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0218] The above cycloalkyl, heterocyclyl, aryl, and heteroaryl groups include the residue derived from removal of one hydrogen atom from a ring atom of the parent ring, or the residue derived from removal of two hydrogen atoms from the same or two different ring atoms of the parent, i.e., "divalent cycloalkyl", "divalent heterocyclyl", "arylene", "heteroarylene".

[0219] The term "cycloalkyloxy" refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.

[0220] The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

[0221] The term "aryloxy" refers to aryl-O-, wherein aryl is as defined above.

[0222] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0223] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0224] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0225] The term "hydroxyl group" refers to -OH.

[0226] The term "thiol" refers to -SH.

[0227] The term "amino" refers to -NH2.

[0228] The term "cyano" refers to -CN.

[0229] The term "nitro" refers to -NO2.

[0230] The term "oxo" or "oxo" refers to "=O".

[0231] The term "carbonyl" refers to C=O.

[0232] In the chemical structure of the compound described in this invention, the bond... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations. Bond It can be It is a cis configuration. Although all the above structural formulas are shown in certain isomer forms for simplicity, the present invention can include all isomers, such as tautomers, rotatimers, geometric isomers, diastereomers, racemates, and enantiomers. In the chemical structure of the compounds described in this disclosure, the bond... No configuration was specified, i.e., key The configuration can be E-type or Z-type, or it can contain both E-type and Z-type configurations.

[0233] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of the event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0234] "Substituted" means that one or more hydrogen atoms, preferably 1 to 5, more preferably 1 to 3, of a group are independently of each other replaced with the corresponding number of substituents. Those skilled in the art are able to determine, without undue effort, what substitutions are possible or impossible (either by experiment or theory). For example, an amino group with a free hydrogen can be unstable when bound to a carbon atom with an unsaturated (e.g., olefinic) bond.

[0235] The term "pharmaceutical composition" means a mixture of one or more of the compounds described herein, or a physiologically / pharmaceutically acceptable salt or prodrug thereof, with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to an organism and to facilitate absorption of the active ingredient into the organism to thereby exert a biological activity.

[0236] The term "carrier" refers to a system that does not cause significant irritation to an organism and does not eliminate the biological activity and characteristics of the administered compound, and can change the way the drug enters the human body and its distribution in the body, control the release rate of the drug and deliver the drug to the target organ, non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0237] The term "isotopic derivative" refers to a compound that differs from the structure only in the presence of one or more isotopically enriched atoms. For example, a structure of the present disclosure with a "deuterium" or "tritium" in place of a hydrogen, or a 18 F-fluorine label 18 F isotope) in place of fluorine, or a 11 C-, 13 C-, or 14 C-enriched carbon 11 C-, 13 C-, or 14 C-carbon label; 11 C-, 13 C-, or 14Compounds in which a carbon atom is replaced by a carbon isotope) are within the scope of this disclosure. Such compounds can be useful as, for example, analytical tools or probes in biological assays, or can be used as in vivo diagnostic imaging tracers for disease, or as tracers for pharmacokinetic, pharmacodynamic, or receptor occupancy studies. Various deuterated forms of the compounds of the disclosure refer to each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom. One skilled in the art is able to synthesize deuterated forms of compounds with reference to the relevant literature. Commercially available deuterated starting materials can be used in the preparation of deuterated forms of compounds, or they can be synthesized using conventional techniques employing deuterated reagents, including but not limited to deuterated borane, trideuteroborane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide, and deuterated methyl iodide, among others. Deuterated compounds generally retain comparable activity to the non-deuterated compounds, and can achieve better metabolic stability when deuterated at certain specific sites, resulting in certain therapeutic advantages.

[0238] The term "solvate" means a physical association between a compound of this disclosure and one or more, preferably 1 to 3, solvent molecules, either organic or inorganic. This physical association can include hydrogen bonding. In certain instances, the solvate will be isolated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods for solvation are generally known in the art.

[0239] The term "prodrug" means a compound that can be converted in vivo to yield an active parent compound, for example, by hydrolysis in blood.

[0240] The term "hydrate" means a compound of this disclosure or a pharmaceutically acceptable salt thereof, in combination with water through non-covalent intermolecular forces. Common hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, and the like.

[0241] The term "pharmaceutically acceptable" means that these compounds, materials, compositions, and / or dosage forms are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio, and effective for their intended use.

[0242] The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salts" means a salt of a compound of this disclosure that is safe and effective for use in mammals, and possesses the desirable biological activity. The salts can be prepared from the final isolation and purification of the compounds, or by reacting a suitable base or acid with the appropriate group. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, as well as organic bases. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids, as well as organic acids.

[0243] The term "isomer" means any geometric isomer, tautomer, zwitterion, stereoisomer, enantiomer, or diastereomer of a compound. A compound can include one or more chiral centers and / or double bonds, and therefore exist as stereoisomers, such as double-bond isomers (i.e., geometric E / Z isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis / trans isomers). The present disclosure encompasses any and all isomers of the compounds described herein, including stereoisomerically pure forms (e.g., geometrically pure, enantiomeric pure, or diastereomeric pure) and mixtures of enantiomers and stereoisomers, such as racemates. Mixtures of enantiomers and stereoisomers of compounds and ways of resolving them into their component enantiomers or stereoisomers are well known.

[0244] The term "stereoisomer" refers to compounds which have the same chemical constitution, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric (cis / trans) isomers, atropisomers, and the like.

[0245] The term "tautomer" refers to different energy structural isomers that can interconvert via a low energy barrier. For example, prototropic tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine, lactam-lactim isomerization, pyrazolyl isomerization, and the like.

[0246] As used herein, the singular form "a", "an", and "the" include plural references unless the context clearly dictates otherwise.

[0247] When the term "about" is applied to a parameter such as pH, concentration, temperature, and the like, it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be appreciated by those skilled in the art, numbers are often given to only two significant digits when the parameter is not critical, for illustrative purposes only, and not by way of limitation.

[0248] The above terms relating to the present invention are defined, and can be further understood by those skilled in the art in conjunction with the present disclosure and the definitions of the terms, which are described further below.

[0249] The following examples are intended to illustrate but not limit the scope of the present application. The experimental methods in the following examples, unless otherwise indicated, were carried out under conventional conditions or as suggested by the manufacturer. Parts and percentages are by weight unless otherwise indicated. In the preparation schemes, the reactions were carried out in inert solvents at room temperature to the reflux temperature. The reaction time is usually 0.25 hour to 48 hours.

[0250] The synthetic processes of the present disclosure can accommodate a number of functional groups, and thus a variety of substituted starting materials can be used. These processes generally provide the desired final compound at or near the end of the overall process, although in some cases it can be necessary to further transform the compound into a pharmaceutically acceptable salt thereof.

[0251] The compounds of the present disclosure can be prepared in a number of ways based on the teachings of this disclosure using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic procedures and procedures apparent to one skilled in the art or that become apparent to the skilled artisan based on the teachings herein. Standard synthetic procedures and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B., March, J., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5thEd., John Wiley & Sons, New York, NY, 2001, incorporated herein by reference, provide one skilled in the art with a comprehensive approach to organic synthesis.

[0252] In the reaction schemes described herein, a variety of stereoisomers can be made. When a particular stereoisomer is not indicated, it is understood to mean all possible stereoisomers can be made by the reaction. One of ordinary skill in the art will recognize that the reaction can be optimized to preferentially give one isomer, or new schemes can be designed to make a single isomer. If a mixture is made, the isomers can be separated using techniques such as preparative thin layer chromatography, preparative HPLC, preparative chiral HPLC, or preparative SFC.

[0253] The LC-MS liquid chromatograph-mass spectrometer of the embodiments of the present disclosure uses Waters Corporation ACQUITY Arc or equivalent. Mass spectrometry (MS) uses an ESI source, and only indicates the molecular weight M of the parent molecule, usually reporting [M+H] or [M-H] depending on the instrument. +Further, NMR spectra were obtained using a Varian 400 MHz NMR spectrometer or equivalent equipment, and data were routinely reported in ppm using CDCl3, DMSO-d6 as the solvent, and chemical shifts. The description of various peaks is as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets). Coupling constants are expressed in Hz.

[0254] The list of abbreviations used in the experimental section is as follows: AcOK potassium acetate Boc2O di-tert-butyl dicarbonate B2pin2 pinacolatodi-boron CH3I methyl iodide CO carbon monoxide d day DBU 1,8-diazabicyclo[5,4,0]undec-7-ene DCM dichloromethane DEA diethanolamine DIEA N,N-diisopropylethylamine DMF N,N-dimethylformamide DMP dimethyl phthalate DMSO dimethyl sulfoxide DPPA diphenylphosphoryl azide Et3N triethylamine Et2O diethyl ether EtOAc ethyl acetate EtOH ethanol h hour HATU 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HCI hydrochloric acid H2O water K2CO3 potassium carbonate KHMDS potassium bis(trimethylsilyl)amide K2HPO4 potassium phosphate dibasic KOH potassium hydroxide K3PO4 potassium phosphate KOH potassium hydroxide LiAlH4 lithium aluminum hydride m-CPBA meta-chloroperoxybenzoic acid M moles per liter MeCN acetonitrile MeOH methanol Min minute NaH sodium hydride n-BuLi n-butyllithium NH3 ammonia NMP N-methylpyrrolidinone Pd(amphos)Cl2 bis[bis(tert-butyl-(4-dimethylaminophenyl)phosphine]palladium(II) chloride Pd2(dba)3 tris(dibenzylideneacetone)palladium Pd(dppf)Cl2 1,1 '-bis(diphenylphosphino)ferrocene dichloropalladium(II) Pd(OAc)2 palladium acetate PE petroleum ether P, PhMe methylbenzene PPh3 triphenylphosphine rt room temperature SnCl2 tin dichloride TFA trifluoroacetic acid THF tetrahydrofuran Ti(OEt)4 titanium tetraethoxide TLC thin layer chromatography TMSCN trimethylsilyl cyanide Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene Xphos Pd G2 chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1 '- biphenyl)[2-(2'-amino-1,1 '-biphenyl)]palladium(II) ZnI2 zinc iodide + HCy3BF4 - tricyclohexylphosphine fluoroborate PhMe methylbenzene PPh3 triphenylphosphine rt room temperature SnCl2 tin dichloride TFA trifluoroacetic acid THF tetrahydrofuran Ti(OEt)4 titanium tetraethoxide TLC thin layer chromatography TMSCN trimethylsilyl cyanide Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene Xphos Pd G2 chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1 '- biphenyl)[2-(2'-amino-1,1 '-biphenyl)]palladium(II) ZnI2 zinc iodide

[0255] Example 1 : Preparation of intermediate (7R,14R)-1 1 -chloro-1 -(difluoromethoxy)-6- methyl-6,7-dihydro-7,14-methanoben[f]benzo[4,5]imidazo[1,2-a][1,4]diazocine-5(14H)- one (INT1 )

[0256] First step:

[0257] Dissolve 2-bromo-6-hydroxybenzaldehyde (INT1 -1, 545.0 g, 2.71 mol) in acetonitrile, cool the system to -25 °C after adding 10 M potassium hydroxide solution, slowly add bromofluoromethyl phosphonic acid diethyl ester (770.3 mL, 4.34 mol), keep the reaction temperature below -20 °C, after stirring for 30 minutes, warm to 0 °C and react for 1 hour, after heating to room temperature, react for 2 hours, add saturated brine and extract with ethyl acetate, wash the organic layer with brine, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure, separate and purify by column chromatography (PE / EtOAc, 0-10%) to obtain 2-bromo-6-(difluoromethoxy)benzaldehyde) (INT1 -2, 273.7 g, yield: 40%, light yellow solid).

[0258] Second step:

[0259] INT1-2 (271.7 g, 1.08 mol) was dissolved in anhydrous tetrahydrofuran at 0 °C, S-tert-butylsulfinamide (144.0 g, 1.188 mol), potassium phosphate (687.8 g, 3.24 mol) and potassium hydrogen phosphate (564.3 g, 3.24 mol) were added, stirred at room temperature for 18 hours, filtered through diatomite and extracted with ethyl acetate, the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography (PE / EtOAc, 0-10%) to give N-{[2-bromo-6-(difluoromethoxy)phenyl]methylene}-(S)-2-methylpropane-2-sulfinamide (INT1-3, 272.6 g, yield: 71%, yellowish oil).

[0260] Third step:

[0261] Zinc powder (150 g) was added to 500 mL of 1 M aqueous hydrochloric acid solution, stirred at room temperature for 10 minutes, washed with water and acetone successively for 3 times, and the solid was dried under vacuum. The activated zinc powder (141.4 g, 2163 mmol) obtained in the above step was added with anhydrous tetrahydrofuran, heated at 80 °C for 30 minutes, and then INT1-3 (255.4 g, 721 mmol) and ethyl bromoacetate (361.2 g, 2163 mmol) were added. After stirring uniformly, it was transferred to a constant pressure dropping funnel to start dropping. After the dropping was completed, it was stirred at 80 °C for 1 hour, filtered through diatomite and extracted with ethyl acetate. The organic layer was washed with 1 M citric acid, saturated aqueous sodium bicarbonate, water and brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography (EtOAc / PE, 30-40%) to give (3R)-3-{[(S)-tert-butylsulfinyl]amino}-3-[2-bromo-6-(difluoromethoxy)phenyl]-propionic acid ethyl ester (INT1-4, 126 g, yield: 39.5%, yellow oil).

[0262] Fourth step:

[0263] INT1-4 (125 g, 2826 mmol) was added into a solution of ethyl ether: ethanol mixture (2:1), and then 4 M hydrogen chloride-1,4-dioxane solution was added. After stirring at room temperature for 1 hour, it was concentrated under reduced pressure, and then an appropriate amount of ethyl ether was added and dried to give (3R)-3-amino-3-[2-bromo-6-(difluoromethoxy)phenyl]-propionic acid ethyl ester (INT1-5) in the form of a yellow solid.

[0264] Fifth step:

[0265] Dissolve INT1-5 crude (94 g, 2780 mmol) in acetonitrile, add potassium carbonate (1152.6 g, 8340 mmol) and 4-chloro-2-fluoronitrobenzene (585.6 g, 3336 mmol), stir at 80 °C overnight, dilute with ethyl acetate and wash with water, separate the organic layer, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by column chromatography (EtOAc / PE, 0-10%) to obtain (3R)-3-(5-chloro-2-nitroanilino)-3-[2-bromo-6-(difluoromethoxy)phenyl]-propionic acid ethyl ester (INT1-6, 91.3 g, yield: 67%, yellow oil).

[0266] Sixth step:

[0267] Dissolve INT1-6 (91 g, 184.3 mmol) in tetrahydrofuran, stir well, and slowly add lithium aluminum hydride (11.2 g, 294.88 mmol) at -20 °C, replace with nitrogen for 3 times, add sodium sulfate decahydrate (182.0 g, 56.52 mmol) after TLC (PE:EA = 4:1) shows that the starting material has disappeared, stir at room temperature overnight, filter through diatomite, elute with ethyl acetate, concentrate under reduced pressure, and purify by column chromatography (EtOAc / PE, 20-30%) to obtain (3R)-3-(5-chloro-2-nitroanilino)-3-[2-bromo-6-(difluoromethoxy)phenyl]-propanol (INT1-7, 66.5 g, yield: 80%, yellow oil).

[0268] Seventh step:

[0269] Dissolve INT1-7 (66.0 g, 146.1 mmol) in dichloromethane, stir well, and slowly add Dess-Martin oxidant (62.0 g, 146.1 mmol) at 0 °C, replace with nitrogen for 3 times, add saturated sodium bicarbonate solution and saturated sodium sulfite after TLC (PE:EA = 4:1) shows that the starting material has basically disappeared, extract with dichloromethane, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain (3R)-3-(5-chloro-2-nitroanilino)-3-[2-bromo-6-(difluoromethoxy)phenyl]-propanal (INT1-8) crude in yellow oil.

[0270] Eighth step:

[0271] INT1-8 crude (71.0 g, 157.9 mmol) was dissolved in dichloromethane, zinc iodide (5.04 g, 15.79 mmol), triethylamine (1.60 g, 15.79 mmol) and trimethylsilyl cyanide (47.0 g, 473.7 mmol) were added, nitrogen purging was done for 3 times, stirred at 35 °C for 2-3 h, quenched with water, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to get (4R)-4-(5-chloro-2-nitroanilino)-4-[2-bromo-6-(difluoromethoxy)phenyl]-2- (trimethylsilyloxy)-butyronitrile (INT1-9) crude as yellow oil.

[0272] Ninth step:

[0273] INT1-9 (74.0 g, 134.8 mmol) was dissolved in ethanol, stannous chloride (127.8 g, 674.0 mmol) was added, nitrogen purging was done for 3 times, heated at 80 °C for 3 h, cooled to room temperature, quenched with water, basified to pH 7-8 with 1 M aqueous potassium hydroxide solution, diluted with ethyl acetate, filtered through celite, organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, purified by column chromatography (EtOAc / PE, 50-100%) to get (1R)-7-chloro-1-[2-bromo-6-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2- a]benzoimidazol-3-ol (INT1-10, 34.0 g, yield: 58.7%, yellow oil).

[0274] Tenth step:

[0275] INT1-10 (34.0 g, 79.13 mmol) was dissolved in dry toluene, nitrogen purging was done for 3 times, diphenyl phosphorazide (32.7 g, 118.7 mmol), DBU (18.1 g, 118.7 mmol) were added at 0 °C, stirred at room temperature for 1 h, then stirred at 50 °C overnight, diluted with water and ethyl acetate, extracted with ethyl acetate, combined organic layer was washed with saturated aqueous ammonium chloride solution and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to get (1R)-7-chloro-1-[2-bromo-6-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2- a]benzoimidazol-3-yl azide (INT1-11) crude as light yellow solid.

[0276] Eleventh step:

[0277] INT1-11 (36.0 g, 79.18 mmol) was dissolved in tetrahydrofuran / water (4:1, 500 mL), replaced with nitrogen gas for 3 times, added with triphenylphosphine (37.4 g, 142.5 mmol), stirred at room temperature for 2 hours, diluted with water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (1R)-7-chloro-1-[2-bromo-6-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzoimidazole-3-amine (INT1-12) crude in yellow oil.

[0278] Twelfth step:

[0279] INT1-12 (34.0 g, 79.32 mmol) was dissolved in dimethyl sulfoxide, added with potassium carbonate (16.4 g, 118.98 mmol), Xantphos (6.9 g, 11.90 mmol), palladium acetate (1.4 g, 6.35 mmol), replaced with nitrogen gas for 3 times, and then carbon monoxide gas (2-3 atm) was introduced, reacted at 130°C for 14 hours, cooled to room temperature, added with acetonitrile and stirred until uniform, further added with N,N-diisopropylethylamine (9.2 g, 71.39 mmol), HATU (18.1 g, 47.59 mmol), stirred at room temperature for 30 minutes, dissolved in saturated sodium chloride solution and ethyl acetate, the aqueous layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and then separated and purified by column chromatography (MeOH / DCM, 0-5%) to obtain (7R,14R)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a]-[1,4]diazocine-5(14H)-one (INT1-13, 10.7 g, yield: 35.9%, yellowish solid) and (7S,14S)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a]-[1,4]diazocine-5(14H)-one (INT1-14, 10.5 g, yield: 35.7%, yellowish solid).

[0280] Thirteenth step:

[0281] To a solution of INT1-13 (8.0 g, 21.3 mmol) in tetrahydrofuran at -70 °C was added slowly 1.0 M KHMDS (32 mL, 32.0 mmol) solution, stirred for 0.5 h, added iodomethane (9.0 g, 63.9 mmol) slowly, room temperature overnight, quenched with saturated ammonium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the crude was isolated and purified by column chromatography (MeOH / DCM, 0-10%) to give (7R,14R)-11-chloro-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocine-5(14H)-one (INT1, 3.7 g, yield: 44.5%, yellow solid), [M+H] + = 390.

[0282] Example 2: Preparation of (7R,14R)-1-(difluoromethoxy)-11-(2-ethylaminopyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocine-5(14H)-one (Compound 1)

[0283] First step:

[0284] To a solution of 2-chloropyrimidine-5-boronic acid (474 mg, 3.0 mmol) in ethanol in a pressure tube was added 2M ethylamine tetrahydrofuran solution (4 mL) and N,N-diisopropylethylamine (774 mg, 6.0 mmol) at 70 °C for 2 h, concentrated under reduced pressure, slurried with methyl tert-butyl ether, filtered, washed with methyl tert-butyl ether to give 2-ethylaminopyrimidine-5-boronic acid (Compound 1-1, 400 mg) as a crude yellow solid.

[0285] Second step:

[0286] To a solution of INT1 (260 mg, 0.67 mmol) in 1,4-dioxane / water (10:1) were added compound 1-1 (223 mg, 1.34 mmol), tris(dibenzylideneacetone)dipalladium (61 mg, 0.067 mmol), tricyclohexylphosphonium tetrafluoroborate (57 mg, 0.15 mmol) and potassium phosphate (284 mg, 1.34 mmol) successively, replaced with nitrogen for three times, after reaction at 105 °C for 16 hours, concentrated under reduced pressure, separated by column chromatography and C18 column to obtain (7R,14R)-1-(difluoromethoxy)-11-(2- ethylaminopyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14-methanoben[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (compound 1, 22 mg, yield: 6.9%, white solid), [M+H] + = 477.

[0287] 1 H NMR (400 MHz, CD3OD) δ 8.52 (s, 2H), 8.35-8.38 (m, 1H), 7.67-7.70 (m, 2H), 7.42-7.50 (m, 3H), 7.32 (t, J = 72.8 Hz, 1H), 6.42 (d, J = 7.2 Hz, 1H), 5.20 (d, J = 7.2 Hz, 1H), 3.52-3.60 (m, 1H), 3.47 (s, 3H), 3.40-3.46 (m, 2H), 2.89 (d, J = 14 Hz, 1H), 1.24 (t, J = 7.2 Hz, 3H).

[0288] Example 3: Preparation of (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2- hydroxyethylaminopyrimidin-5-yl)-6,7-dihydro-7,14-methanoben[f]benzo[4,5]imidazo[1,2- a]diazocin-5(14H)-one (compound 2)

[0289] First step:

[0290] Intermediate INT1 (2.55 g, 6.54 mmol) was dissolved in 1,4-dioxane / water (10:1, 39.6 mL), stirred well, potassium phosphate (4.16 g, 19.62 mmol), tris(dibenzylideneacetone)dipalladium (0.48 g, 0.52 mmol), tricyclohexylphosphonium tetrafluoroborate (0.36 g, 0.98 mmol) and 2-methylthiopyrimidine-5-boronic acid (1.44 g, 8.50 mmol) were added, nitrogen was purged for 3 times, heated to 130 °C in an oil bath, stirred for 13 h, cooled to room temperature, water and ethyl acetate were added, the aqueous layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, purified by column chromatography (MeOH / DCM, 0-5%) to give (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-methylsulfanylpyrimidin-5-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a]diazocine-5(14H)-one (Compound 2-1, 276 mg, yield: 16.0%, yellow solid).

[0291] Second Step:

[0292] Compound 2-1 (276 mg, 0.58 mmol) was dissolved in dichloromethane, m-chloroperoxybenzoic acid (354 mg, 1.74 mmol, 85%) was added with stirring, nitrogen was purged for 3 times, reacted for 2 h at 25 °C, dissolved in an appropriate amount of dichloromethane, washed with saturated sodium sulfite solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-methylsulfonylpyrimidin-5-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a]diazocine-5(14H)-one (Compound 2-2, 200 mg, yield: 69.0%, yellow solid) as a crude product.

[0293] Third Step:

[0294] Compound 2-2 (200 mg, 0.40 mmol) was dissolved in acetonitrile, stirred uniformly, N,N-diisopropyl ethylamine (103 mg, 0.80 mmol), 2-(tert-butyldimethylsilyl)ethylamine (1.40 g, 8.0 mmol) were added, replaced with nitrogen for 3 times, stirred at 60℃ overnight, added with appropriate amount of water, extracted with ethyl acetate for 3 times, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated by column chromatography (MeOH / DCM, 0-7%) and prep-HPLC (ACN / H2O, 0-95%) to obtain (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-(tert-butyldimethylsilyl)hydroxyethylamino pyrimidin-5-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a]diazocine-5(14H)-one (compound 2-3, 8 mg, yield: 3.3%, yellowish solid).

[0295] Fourth step:

[0296] Compound 2-3 (8 mg, 0.013 mmol) was dissolved in acetonitrile, stirred uniformly, then 4M hydrogen chloride-1,4-dioxane solution (0.5 mL) was added, replaced with nitrogen for 3 times, stirred at room temperature for 0.5 hours, concentrated under reduced pressure, added with appropriate amount of water, extracted with ethyl acetate for 3 times, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, obtained the crude product by column chromatography (MeOH / DCM, 0-6%), and then (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-hydroxyethylamino pyrimidin-5-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a]diazocine-5(14H)-one (compound 2, 1.87 mg, yield: 28.8%, off-white solid) was obtained by slurry with appropriate amount of methyl tert-butyl ether, [M+H] + = 493.

[0297] 1 H NMR (400 MHz, CD3OD) δ 8.53 (s, 2H), 8.34-8.38 (m, 1H), 7.67-7.70 (m, 2H), 7.42-7.50 (m, 3H), 7.31 (t, J = 73.2 Hz, 1H), 6.41 (d, J = 7.2 Hz, 1H), 5.20 (d, J = 7.2 Hz, 1H), 3.74 (t, J = 5.6 Hz, 2H), 3.52-3.60 (m, 3H), 3.47 (s, 3H), 2.89 (d, J = 14 Hz, 1H).

[0298] Example 4: Preparation of (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2- methoxyethylamino-pyrimidin-5-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5] imidazo[1,2-a]diazocine-5(14H)-one (Compound 3)

[0299] Compound 2-2 (25 mg, 0.05 mmol) was dissolved in acetonitrile, stirred uniformly, N,N-diisopropyl ethylamine (13 mg, 0.10 mmol) and 2-methoxyethylamine (75 mg, 1.00 mmol) were added, replaced with nitrogen for 3 times, reacted at 60 °C for 2.5 hours, added appropriate amount of water, extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated and purified by prep-HPLC (ACN in H2O, 0-95%) and prep-TLC (DCM / MeOH = 17.5:1) to obtain (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-methoxyethylamino-pyrimidin-5-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a]diazocine-5(14H)-one (Compound 3, 2.6 mg, yield: 10.2%, yellowish solid), [M+H] + = 507.

[0300] 1 H NMR (400 MHz, CDCl3) δ 8.49 (d, J = 8 Hz, 1H), 7.81-7.83 (m, 1H), 7.57 (s, 1H), 7.42-7.47 (m, 1H), 7.32-7.35 (m, 2H), 6.95-7.00 (m, 1H), 6.87 (t, J = 73.2 Hz, 1H), 6.30 (d, J = 7.2 Hz, 1H), 5.33-5.36 (m, 1H), 5.04-5.08 (m, 1H), 3.74-3.78 (m, 2H), 3.54-3.63 (m, 2H), 3.54 (s, 3H), 3.40 (s, 3H), 2.29-2.36 (m, 1H), 2.20-2.25 (m, 1H).

[0301] Example 5: Preparation of (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-(azetidin-3- yl)amino-pyrimidin-5-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a]diazocine-5(14H)-one (Compound 4)

[0302] First step:

[0303] To a solution of 2-chloropyrimidine-5-boronic acid (474 mg, 3.0 mmol) in ethanol was added 1-tert-butoxycarbonyl-3-aminocyclobutane (775 mg, 4.5 mmol) and N,N-diisopropylethylamine (774 mg, 6.0 mmol), and reacted at 80°C for 2 hours. After concentration under reduced pressure, it was washed with methyl tert-butyl ether, filtered, and washed with methyl tert-butyl ether to obtain 2-(1-tert-butoxycarbonylazetidin-3-yl)aminopyrimidine-5-boronic acid (compound 4-1, 400 mg) as a yellow solid.

[0304] Second step:

[0305] To a solution of intermediate INT1 (300 mg, 0.77 mmol) in 1,4-dioxane / water (10:1) were sequentially added compound 4-1 (453 mg, 1.54 mmol), tris(dibenzylideneacetone)dipalladium (70 mg, 0.08 mmol), tricyclohexylphosphonium tetrafluoroborate (57 mg, 0.15 mmol), and potassium phosphate (490 mg, 2.31 mmol), and replaced with nitrogen three times, and reacted at 120°C for 16 hours. After concentration under reduced pressure, it was separated by column chromatography and C18 column to obtain (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-(1-tert-butoxycarbonylazetidin-3-yl)aminopyrimidin-5-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a]diazocin-5(14H)-one (compound 4-2, 50 mg, yield: 10.7%, yellow solid).

[0306] Third step:

[0307] Compound 4-2 (50 mg, 0.08 mmol) was added to a dichloromethane / trifluoroacetic acid (10 / 1) solution, and stirred at room temperature until the starting material disappeared. The pH was adjusted to about 7 to 8 with a saturated sodium bicarbonate solution, extracted with chloroform / isopropyl alcohol (4:1) three times, concentrated the organic phase, dissolved in a small amount of ethyl acetate, and recrystallized with methyl tert-butyl ether to obtain the product (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-(azetidin-3-yl)aminopyrimidin-5-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a]diazocin-5(14H)-one (compound 4, 4 mg, yield: 57.0%, yellow solid), [M+H] + = 504.

[0308] 1H NMR (400 MHz, CD3OD) δ 8.63 (s, 2H), 8.35-8.38 (m, 1H), 7.70-7.72 (m, 2H), 7.47-7.48 (m, 3H), 7.30 (t, J = 72.4 Hz, 1H), 6.42 (d, J = 7.2 Hz, 1H), 5.21 (d, J = 7.2 Hz, 1H), 4.84-4.92 (m, 1H), 4.35-4.41 (m, 2H), 4.25-4.30 (m, 2H), 3.55-3.59 (m, 1H), 3.48 (s, 3H), 2.90 (d, J = 14 Hz, 1H).

[0309] Example 6: Preparation of (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-(azetidin-3- yl)aminopyrimidin-5-yl)-6,7-dihydro-7,14-methanoben[f]benzo[4,5]imidazo[1,2-a] diazocine-5(14H)-one (Compound 5)

[0310] First Step:

[0311] To a solution of 2-chloropyrimidine-5-boronic acid (474 mg, 3.0 mmol) in ethanol was added tert-butyl 3-aminopyrrolidine-1-carboxylate (837 mg, 4.5 mmol) and N,N- diisopropylethylamine (774 mg, 6.0 mmol) and reacted at 60 °C for 2 hours, concentrated under reduced pressure, slurried with methyl tert-butyl ether, filtered, washed with methyl tert-butyl ether to give 2-(1-tert-butoxycarbonylazetidin-3-yl)aminopyrimidine-5-boronic acid (Compound 5-1, 400 mg) as a crude yellow solid.

[0312] Second Step:

[0313] To a solution of intermediate INT1 (220 mg, 0.56 mmol) in 1,4-dioxane / water (10:1) was added compound 5-1 (220 mg, 0.71 mmol), tris(dibenzylideneacetone)dipalladium (51 mg, 0.056 mmol), tricyclohexylphosphonium tetrafluoroborate (31 mg, 0.084 mmol), and potassium phosphate (237 mg, 1.12 mmol) sequentially, replaced with nitrogen three times, and reacted at 130 °C for 16 hours. Concentrated under reduced pressure, separated by column chromatography and C18 column to give (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-(1- tert-butoxycarbonylazetidin-3-yl)aminopyrimidin-5-yl)-6,7-dihydro-7,14- methanoben[f]benzo[4,5]imidazo[1,2-a]diazocine-5(14H)-one (Compound 5-2, 20 mg, yield: 5.8%, yellow solid).

[0314] Third step:

[0315] Compound 5-2 (20 mg, 0.032 mmol) was dissolved with 4M hydrogen chloride-1,4-dioxane solution, stirred at room temperature for 3 hours, concentrated under reduced pressure, dissolved with water, washed with ethyl acetate for several times, the aqueous phase was separated by C18 column chromatography, and freeze-dried to obtain (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-(azetidin-3-yl)aminopyrimidin-5-yl)-6,7-dihydro-7,14-methanoben[f]benzo[4,5]imidazo[1,2-a]diazocin-5(14H)-one (compound 5, 4 mg, yield: 24.1%, light yellow solid), [M+H] + = 518.

[0316] 1 H NMR (400 MHz, CD3OD) δ 8.63 (s, 2H), 8.36-8.39 (m, 1H), 7.73-7.76 (m, 2H), 7.47-7.52 (m, 3H), 7.32 (t, J = 73.2 Hz, 1H), 6.48 (d, J = 6.8 Hz, 1H), 5.30 (d, J = 7.2 Hz, 1H), 4.60-4.64 (m, 1H), 3.55-3.60 (m, 3H), 3.48 (s, 3H), 3.39-3.43 (m, 2H), 2.92-2.96 (m, 1H), 2.39-2.44 (m, 1H), 2.16-2.22 (m, 1H).

[0317] Example 7: Preparation of (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2- cyclopropylaminopyrimidin-5-yl)-6,7-dihydro-7,14-methanoben[f]benzo[4,5]imidazo[1,2-a]diazocin-5(14H)-one (compound 6)

[0318] To a solution of intermediate INT1 (400 mg, 1.02 mmol) in 1,4-dioxane / water (10:1) were added 2-(cyclopropylamino)pyrimidine-5-boronic acid (276 mg, 1.54 mmol), tris(dibenzylideneacetone)dipalladium (93 mg, 0.10 mmol), tricyclohexylphosphonium tetrafluoroborate (75 mg, 0.20 mmol) and potassium phosphate (434 mg, 2.04 mmol) successively, replaced with nitrogen for three times, reacted at 105 °C for 16 hours, concentrated under reduced pressure, separated by column chromatography and C18 column to obtain (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-cyclopropylaminopyrimidin-5-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a]diazocin-5(14H)-one (Compound 6, 22 mg, yield: 4.4%, white solid), [M+H] + = 489.

[0319] 1 H NMR (400 MHz, CD3OD) δ 8.56 (s, 2H), 8.54-8.55 (m, 1H), 7.68-7.70 (m, 2H), 7.43-7.50 (m, 3H), 7.32 (t, J = 72.4 Hz, 1H), 6.40-6.43 (m, 1H), 5.20 (d, J = 7.2 Hz, 1H), 3.48-3.58 (m, 1H), 3.47 (s, 3H), 2.89 (d, J = 14.4 Hz, 1H), 2.72-2.74 (m, 1H).

[0320] Example 8: Preparation of (7R,14R)-1-(difluoromethoxy)-11-(2-acetylamino-pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a]diazocin-5(14H)-one (Compound 7)

[0321] First step:

[0322] To a solution of intermediate INT1 (800 mg, 2.05 mmol) in 1,4-dioxane / water (10:1) were added 2-amino pyrimidine-5-boronic acid (428 mg, 3.08 mmol), tris(dibenzylideneacetone)dipalladium (188 mg, 0.21 mmol), tricyclohexylphosphonium tetrafluoroborate (151 mg, 0.41 mmol) and potassium phosphate (1307 mg, 6.16 mmol) successively, replaced with nitrogen for three times, reacted at 130 °C for 16 hours, concentrated under reduced pressure, separated by column chromatography and C18 column to obtain (7R,14R)-1-(difluoromethoxy)-11-(2-aminopyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a]diazocin-5(14H)-one (compound 7-1, 190 mg, yield: 55%, yellow solid), [M+H] + = 449.

[0323] Second step:

[0324] Compound 7-1 (63 mg, 0.14 mmol) and trichloroacetyl isocyanate (135 mg, 0.72 mmol) were dissolved in pyridine, reacted at room temperature overnight, after the disappearance of the raw material was determined by spotting, 7M ammonium methanol solution (0.1 mL) was added and the reaction was continued for 2 hours, the reaction solution was concentrated, separated by column chromatography and C18 column to obtain (7R,14R)-1-(difluoromethoxy)-11-(2-acetylamino pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a]diazocin-5(14H)-one (compound 7, 22 mg, yield: 32%, white solid), [M+H] + = 492.

[0325] 1 H NMR (400 MHz, CDCl3) δ 8.92 (br, 1H), 8.75 (s, 2H), 8.48-8.53 (m, 2H), 7.82-7.85 (m, 1H), 7.66 (s, 1H), 7.40-7.46 (m, 2H), 7.27-7.34 (m, 1H), 6.94 (t, J = 72.4 Hz, 1H), 6.31-6.33 (m, 1H), 5.37 (br, 1H), 5.04 (d, J = 6.8 Hz, 1H), 3.54 (s, 3H), 3.48-3.50 (m, 1H), 2.92 (d, J = 13.6 Hz, 1H).

[0326] Example 9: Preparation of (7R,14R)-1-(difluoromethoxy)-11-(2-N,N- dimethylacetamidopyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5] imidazo[1,2-a]diazocine-5(14H)-one (Compound 8)

[0327] Compound 7-1 (40 mg, 0.09 mmol) was dissolved in N,N-dimethylformamide, 60% sodium hydride (7.14 mg) was added at 0 °C, stirred for 0.5 hours, dimethylaminoformyl chloride (19.2 mg, 0.18 mmol) was added, and the reaction was allowed to proceed at room temperature for 4 hours. Water was added for quenching, and ethyl acetate was added for extraction. Column chromatography was performed to obtain (7R,14R)-1-(difluoromethoxy)-11-(2-N,N-dimethylacetamidopyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a]diazocine-5(14H)-one (Compound 8, 4 mg, yield: 8%, white solid), [M+H] + = 520.

[0328] 1 H NMR (400 MHz, CDCl3) δ 8.76 (s, 2H), 8.49 (d, J = 8.4 Hz, 1H), 7.83-7.85 (m, 1H), 7.66 (s, 1H), 7.42-7.45 (m, 2H), 7.31-7.34 (m, 2H), 6.85 (t, J = 72.4 Hz, 1H), 6.32-6.34 (m, 1H), 5.09 (s, 1H), 3.56 (s, 3H), 3.50-3.54 (m, 1H), 3.10 (s, 6H), 2.92 (d, J = 13.6 Hz, 1H).

[0329] Example 10: Preparation of (7R,14R)-11-(2-(cyclobutylamino)pyrimidin-5-yl)-1- (difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4] diazepin-5(14H)-one (Compound 9)

[0330] First step:

[0331] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (2.00 g, 8.32 mmol) in tert-butanol was added cyclobutylamine hydrochloride (1.20 g, 10.8 mmol) and N,N-diisopropylethylamine (3.30 g, 24.9 mmol), and the mixture was stirred at 65 °C for 4 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water. The solution was extracted with dichloromethane (3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give N-cyclobutyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (compound 9-1, 0.90 g) as a yellow solid.

[0332] Second step:

[0333] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) was added compound 9-1 (89 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol), and potassium phosphate (109 mg, 0.51 mmol) sequentially, and the mixture was stirred at 75 °C for 2 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was separated by column chromatography and C18 column to give (7R,14R)-11-(2-(cyclobutylamino)pyrimidin-5-yl)-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanoben[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (compound 9, 69 mg, yield: 44%, white solid), [M+H] + = 503.

[0334] 1 H NMR (400 MHz, CDCl3) δ 1.73-1.93 (m, 2H), 2.13-2.26 (m, 2H), 2.38-2.52 (m, 2H), 2.94 (d, J = 13.76 Hz, 1H), 3.46-3.60 (m, 4H), 4.54-4.66 (m, 1H), 5.18 (d, J = 7.00 Hz, 1H), 6.04-6.25 (m, 1H), 6.32 (d, J = 7.25 Hz, 1H), 6.69-7.11 (m, 1H), 7.31-7.39 (m, 2H), 7.44-7.50 (m, 1H), 7.88 (d, J = 8.38 Hz, 1H), 8.10-8.39 (m, 1H), 8.51 (d, J = 8.26 Hz, 1H), 8.84 (br dd, J = 7.13, 3.38 Hz, 1H), 9.80 (br dd, J = 6.13, 3.50 Hz, 1H).

[0335] Example 11: Preparation of (7R,14R)-11-(2-((cyclopropylmethyl)amino)pyrimidin-5-yl)-1- (difluoromethoxy)-6-methyl-6,7-dihydro-7,14-tetramethylbenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazepin-5(14H)-one (Compound 10)

[0336] First Step:

[0337] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (5.00 g, 20.7 mmol) in tert-butanol was added cyclopropylmethylamine (1.92 g, 27.0 mmol) and N,N- diisopropylethylamine (8.10 g, 62.3 mmol) and reacted at 65 °C for 3 hours, concentrated under reduced pressure, added appropriate amount of water, extracted with dichloromethane for 3 times, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain N-(cyclopropylmethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (Compound 10-1, 4.50 g) as a crude product in yellow solid.

[0338] Second Step:

[0339] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) was added Compound 10-1 (89 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'- biphenyl)]palladium(II) (10 mg, 0.01 mmol) and potassium phosphate (109 mg, 0.51 mmol) sequentially, replaced with nitrogen for 3 times, reacted at 75 °C for 2 hours, concentrated under reduced pressure, separated by column chromatography and C18 column to obtain (7R,14R)-11-(2-((cyclopropylmethyl)amino)pyrimidin-5-yl)-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-tetramethylbenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazepin-5(14H)-one (Compound 10, 30 mg, yield: 16%, white solid), [M+H] = 503. +

[0340] 1 ​H NMR (400 MHz, CDC13) δ 0.31-0.38 (m, 2H), 0.58-0.64 (m, 2H), 1.12-1.25 (m, 1H), 2.96 (d, J = 13.76 Hz, 1H), 3.47 (d, J = 7.25 Hz, 2H), 3.49-3.51 (m, 3H), 3.51-3.60 (m, 1H), 5.27 (d, J = 7.13 Hz, 1H), 6.35 (d, J = 7.25 Hz, 1H), 6.74-7.15 (m, 3H), 7.35-7.40 (m, 2H), 7.44-7.51 (m, 1H), 7.61 (d, J = 1.38 Hz, 1H), 7.89 (d, J = 8.50 Hz, 1H), 8.50 (dd, J = 8.25, 1.13 Hz, 1H).

[0341] Example 12: Preparation of (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-((oxetan-3- ylmethyl)amino)pyrimidin-5-yl)-6,7-dihydro-7,14-methanoben[f]benzo[4,5]imidazo[1,2- a][1,4]diazepin-5(14H)-one (Compound 11)

[0342] Compound 7-1 (250 mg, 0.55 mmol) was dissolved in N-methylpyrrolidone, 60% sodium hydride (26 mg) was added at 0 °C, stirred for 0.5 hours, 4-methylbenzenesulfonic acid (oxetan-3-yl)methyl ester (81 mg, 0.33 mmol) was added, and the reaction was carried out at room temperature for 2.5 hours. Water was added for quenching, and extraction was carried out with ethyl acetate. Pre-HPLC separation gave (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-((oxetan-3- ylmethyl)amino)pyrimidin-5-yl)-6,7-dihydro-7,14-methanoben[f]benzo[4,5]imidazo[1,2- a][1,4]diazepin-5(14H)-one (Compound 11, 53 mg, yield: 18%, yellow solid), [M+H] + = 519.

[0343] 1H NMR (400 MHz, CDC13) δ 2.91 (d, J = 13.76 Hz, 1H), 3.31 - 3.41 (m, 1H), 3.44 - 3.53 (m, 1H), 3.55 (s, 3H), 3.84 (t, J = 6.63 Hz, 2H), 4.53 (t, J = 5.94 Hz, 2H), 4.88 (t, J = 6.94 Hz, 2H), 4.99 (d, J = 7.13 Hz, 1H), 5.30 - 5.37 (m, 1H), 6.30 (d, J = 7.13 Hz, 1H), 6.64 - 7.06 (m, 1H), 7.35 (dd, J = 17.39, 8.25 Hz, 2H), 7.41 - 7.48 (m, 1H), 7.60 (s, 1H), 7.79 (d, J = 8.50 Hz, 1H), 8.52 (d, J = 8.38 Hz, 1H), 8.55 (s, 2H).

[0344] Example 13: Preparation of (7R,14R)-1-(difluoromethoxy)-11-(2-(isopropylamino)pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14-methanoben[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (Compound 12)

[0345] Compound 7-1 (100 mg, 0.22 mmol) was dissolved in N,N-dimethylformamide, 60% sodium hydride (34 mg) was added at 0 °C, stirred for 0.5 hours, 2-iodopropane (157 mg, 0.33 mmol) was added, and the reaction was allowed to proceed at room temperature for 2.5 hours. Water was added for quenching, and extraction was performed with ethyl acetate. Pre-HPLC separation gave (7R,14R)-1-(difluoromethoxy)-11-(2-(isopropylamino)pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14-methanoben[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (Compound 12, 53 mg, yield: 45%, yellow solid), [M+H] + = 491.

[0346] 1H NMR (400 MHz, CDC13) δ 1.36 (d, J = 6.63 Hz, 6H), 2.95 (d, J = 13.76 Hz, 1H), 3.50 (s, 3H), 3.52 - 3.59 (m, 1H), 4.34 (dt, J = 12.98, 6.46 Hz, 1H), 5.23 (br d, J = 7.00 Hz, 1H), 6.34 (d, J = 7.25 Hz, 1H), 6.72 - 7.13 (m, 1H), 7.32 - 7.40 (m, 2H), 7.42 - 7.51 (m, 1H), 7.60 (s, 1H), 7.88 (d, J = 8.50 Hz, 1H), 8.06 - 8.35 (m, 3H), 8.49 (d, J = 8.13 Hz, 1H).

[0347] Example 14: Preparation of (7R, 14R)-1-(difluoromethoxy)-6-methyl-11-(2-((2,2,2- trifluoroethyl)amino)pyrimidin-5-yl)-6,7-dihydro-7,14-methanoben[f]benzo[4,5]imidazo[1,2- a][1,4]diazepin-5(14H)-one (Compound 13)

[0348] First Step:

[0349] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (5.00 g, 20.7 mmol) in tert-butanol was added 2,2,2-trifluoroethylamine hydrochloride (3.70 g, 27.0 mmol) and N,N- diisopropylethylamine (8.10 g, 62.3 mmol) and reacted at 65 °C for 6 hours, concentrated under reduced pressure, added appropriate amount of water, extracted with dichloromethane 3 times, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(2,2,2- trifluoroethyl)pyrimidin-2-amine (Compound 13-1, 2.10 g) as a yellow oil crude.

[0350] Second Step:

[0351] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) were added compound 13-1 (98 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol) and potassium phosphate (109 mg, 0.51 mmol) successively, replaced with nitrogen for three times, reacted at 75 °C for 2 hours, concentrated under reduced pressure, separated by column chromatography and C18 column to obtain (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-((2,2,2- trifluoroethyl)amino)pyrimidin-5-yl)-6,7-dihydro-7,14-methanoben[f]benzo[4,5]imidazo[1,2- a][1,4]diazepin-5(14H)-one (compound 13, 5 mg, yield: 4%, white solid), [M+H] + = 531.

[0352] 1 H NMR (400 MHz, CDCl3) δ 2.81 (d, J = 13.51 Hz, 1H), 3.35-3.44 (m, 1H), 3.45 (s, 3H), 4.17 (quin, J = 8.38 Hz, 2H), 4.90 (d, J = 7.13 Hz, 1H), 5.69 (br t, J = 6.63 Hz, 1H), 6.20 (d, J = 7.13 Hz, 1H), 6.56-7.00 (m, 1H), 7.19 (d, J = 1.00 Hz, 1H), 7.26 (dd, J = 18.20, 8.32 Hz, 2H), 7.31-7.38 (m, 1H), 7.71 (d, J = 8.38 Hz, 1H), 8.42 (d, J = 8.25 Hz, 1H), 8.49 (d, J = 0.75 Hz, 2H).

[0353] Example 15: Preparation of (7R,14R)-11-(2-((3,3-difluorocyclobutyl)amino)pyrimidin-5-yl)-1- (difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanoben[f]benzo[4,5]imidazo[1,2- a][1,4]diazepin-5(14H)-one (compound 14)

[0354] First step:

[0355] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (5.00 g, 20.7 mmol) in tert-butanol was added 3,3-difluorocyclobutylamine hydrochloride (3.88 g, 27.0 mmol) and N,N-diisopropylethylamine (8.10 g, 62.3 mmol), and reacted at 65°C for 6 hours. After concentration under reduced pressure, an appropriate amount of water was added, and extracted with dichloromethane three times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain N-(3,3-difluorocyclobutyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (compound 14-1, 2.80 g) as a crude product in the form of a yellow solid.

[0356] Second step:

[0357] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) were sequentially added compound 14-1 (100 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol), and potassium phosphate (109 mg, 0.51 mmol), and replaced with nitrogen three times, and reacted at 75°C for 2 hours. After concentration under reduced pressure, column chromatography and C18 column separation were performed to obtain (7R,14R)-11-(2-((3,3-difluorocyclobutyl)amino)pyrimidin-5-yl)-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanoben[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (compound 14, 48 mg, yield: 29%, white solid), [M+H]=539. + = 539.

[0358] 1 H NMR (400 MHz, CDCl3) δ 2.65-2.82 (m, 2H), 2.95 (d, J = 13.76 Hz, 1H), 3.06-3.18 (m, 2H), 3.48-3.60 (m, 4H), 4.33-4.59 (m, 1H), 4.86 (br d, J = 3.13 Hz, 3H), 5.20 (br d, J = 7.13 Hz, 1H), 6.33 (d, J = 7.25 Hz, 1H), 6.68-7.11 (m, 1H), 7.33-7.40 (m, 2H), 7.45-7.51 (m, 1H), 7.60 (d, J = 1.13 Hz, 1H), 7.89 (d, J = 8.51 Hz, 1H), 8.52 (d, J = 8.13 Hz, 1H), 8.59 (ddd, J = 11.98, 7.04, 4.63 Hz, 1H), 9.18-9.29 (m, 1H).

[0359] Example 16: Preparation of (7R,14R)-1-(difluoromethoxy)-11-(2-(ethyl(methyl)amino)pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14-methanoben[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (Compound 15)

[0360] To a solution of intermediate INT1 (250 mg, 0.64 mmol) in N,N-dimethylformamide / water (5:1) was added (2-(ethyl(methyl)amino)pyrimidin-5-yl)boronic acid (145 mg, 0.80 mmol), bis[ditert-butyl-(4-dimethylaminophenyl)phosphine]palladium(II) dichloride (45 mg, 0.06 mmol) and potassium phosphate (272 mg, 1.28 mmol) sequentially, replaced with nitrogen three times, reacted at 120 °C for 2 hours, concentrated under reduced pressure, separated by column chromatography and C18 column to obtain (7R,14R)-1-(difluoromethoxy)-11-(2-(ethyl(methyl)amino)pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14-methanoben[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (Compound 15, 30 mg, yield: 9%, white solid), [M+H] + = 491.

[0361] 1 H NMR (400 MHz, CDCl3) δ 1.18-1.29 (m, 3H), 2.88 (d, J = 13.63 Hz, 1H), 3.21 (s, 3H), 3.46 (dt, J = 13.76, 7.13 Hz, 1H), 3.53 (s, 3H), 3.75 (q, J = 6.92 Hz, 2H), 4.97 (d, J = 7.00 Hz, 1H), 6.27 (d, J = 7.25 Hz, 1H), 6.63-7.04 (m, 1H), 7.33 (dd, J = 14.63, 8.38 Hz, 2H), 7.39-7.45 (m, 1H), 7.56 (s, 1H), 7.76 (d, J = 8.50 Hz, 1H), 8.50 (d, J = 8.25 Hz, 1H), 8.55 (s, 2H).

[0362] Example 17: Preparation of (7R,14R)-11-(2-((2,2-difluorocyclopropyl)methyl)amino)pyrimidin-5-yl)-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanoben[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (Compound 16)

[0363] First Step:

[0364] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (300 mg, 1.24 mmol) in tert-butanol was added 2,2-difluorocyclopropanemethanamine hydrochloride (233 mg, 1.62 mmol) and N,N-diisopropylethylamine (484 mg, 3.74 mmol) and reacted at 65 °C for 2 hours. The reaction mixture was concentrated under reduced pressure, and an appropriate amount of water was added. The mixture was extracted with dichloromethane three times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain N-(2,2-difluorocyclopropyl)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (compound 16-1, 0.20 g) as a crude yellow solid.

[0365] Second Step:

[0366] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) was added compound 16-1 (99 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol), and potassium phosphate (109 mg, 0.51 mmol) sequentially, and the mixture was replaced with nitrogen three times and reacted at 95 °C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was separated by column chromatography and C18 column chromatography to obtain (7R,14R)-11-(2-((2,2-difluorocyclopropyl)methyl)amino)pyrimidin-5-yl)-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanoben[f]benzo[4,5]imidazo[1,2-a][1,4]diazepine-5(14H) compound 16, 35 mg, yield: 24%, white solid), [M+H] = 539. +

[0367] 1 ​H NMR (400 MHz, CDC13) δ 1.15 - 1.29 (m, 1H), 1.50 (tdd, J= 11.71, 11.71, 7.72, 4.25 Hz, 1H), 2.01 - 2.12 (m, 1H), 2.85 - 2.94 (m, 1H), 3.43 - 3.52 (m, 2H), 3.53 (s, 3H), 3.79 (ddd, J= 13.98, 6.97, 2.81 Hz, 1H), 4.99 (d, J= 7.00 Hz, 1H), 5.59 (br t, J= 5.88 Hz, 1H), 6.28 (d, J= 7.13 Hz, 1H), 6.63 - 7.06 (m, 1H), 7.30 - 7.38 (m, 2H), 7.39 - 7.46 (m, 1H), 7.58 (d, J= 1.38 Hz, 1H), 7.78 (d, J= 8.50 Hz, 1H), 8.50 (dd, J= 8.25, 1.00 Hz, 1H), 8.55 (s, 2H).

[0368] Example 18: Preparation of (7R, 14R)-1-(difluoromethoxy)-11-(2-(((1- methoxycyclopropyl)methyl)amino)pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14- thieno[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (Compound 17)

[0369] First Step:

[0370] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (600 mg, 2.49 mmol) in tert-butanol was added (1-methoxycyclopropyl)methanamine hydrochloride (446 mg, 3.24 mmol) and N,N-diisopropylethylamine (967 mg, 7.48 mmol) and reacted at 65 °C for 2 hours, concentrated under reduced pressure, added appropriate amount of water, extracted with dichloromethane for 3 times, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain N-((1-methoxycyclopropyl)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (Compound 17-1, 0.72 g) as a yellow solid.

[0371] Second Step:

[0372] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) were added compound 17-1 (98 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol) and potassium phosphate (109 mg, 0.51 mmol) successively, replaced with nitrogen for three times, reacted at 95 °C for 3 hours, concentrated under reduced pressure, separated by column chromatography and C18 column to obtain (7R,14R)-1-(difluoromethoxy)-11-(2-(((1- methoxy cyclopropyl) methyl) amino) pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14- toluene[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one compound 17, 41 mg, yield: 28%, white solid), [M+H] + = 533.

[0373] 1 H NMR (400 MHz, CDCl3) δ 0.61-0.72 (m, 2H), 0.85-0.94 (m, 2H), 2.90 (d, J = 13.63 Hz, 1H), 3.37 (s, 3H), 3.44-3.53 (m, 1H), 3.54 (s, 3H), 3.66 (d, J = 5.25 Hz, 2H), 4.99 (d, J = 7.00 Hz, 1H), 5.63 (t, J = 5.13 Hz, 1H), 6.29 (d, J = 7.25 Hz, 1H), 6.63-7.09 (m, 1H), 7.31-7.39 (m, 2H), 7.42-7.46 (m, 1H), 7.59 (d, J = 1.50 Hz, 1H), 7.79 (d, J = 8.38 Hz, 1H), 8.51 (dd, J = 8.25, 1.13 Hz, 1H), 8.54 (s, 2H).

[0374] Example 19: Preparation of N-(5-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14- tetrahydro-7,14-toluenef]benzo[4,5]imidazo[1,2-a][1,4]diazepin-11-yl)pyrimidin-2-yl) cyclopropanecarboxamide (compound 18)

[0375] Compound 7-1 (100 mg, 0.22 mmol) and cyclopropanecarbonyl anhydride (266 mg, 1.72 mmol) were dissolved in N,N-dimethylformamide, N,N-diisopropyl ethylamine (58 mg, 0.44 mmol) was added and reacted at 120 °C for 12 hours. The reaction solution was separated by C18 column to obtain N-(5-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14- toluene[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-11-yl)pyrimidin-2-yl)cyclopropanecarboxamide (compound 18, 21 mg, yield: 22%, white solid), [M+H] + = 517.

[0376] 1 H NMR (400 MHz, CDCl3) δ 0.97 (dq, J = 7.60, 3.72 Hz, 2H), 1.19-1.25 (m, 2H), 2.18-2.34 (m, 1H), 2.91 (d, J = 13.63 Hz, 1H), 3.44-3.52 (m, 1H), 3.53 (s, 3H), 4.99 (d, J = 7.00 Hz, 1H), 6.30 (d, J = 7.25 Hz, 1H), 6.65-7.05 (m, 1H), 7.30-7.35 (m, 1H), 7.38-7.47 (m, 2H), 7.66 (d, J = 1.50 Hz, 1H), 7.82 (d, J = 8.50 Hz, 1H), 8.42 (s, 1H), 8.50 (dd, J = 8.19, 1.06 Hz, 1H), 8.81 (s, 2H).

[0377] Example 20: Preparation of (7R,14R)-1-(difluoromethoxy)-11-(2-(((1-fluorocyclopropyl)methyl)amino)pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14-toluenef[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (compound 19)

[0378] First step:

[0379] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (700 mg, 2.91 mmol) in tert-butanol was added (1-fluorocyclopropyl)methanamine hydrochloride (475 mg, 3.78 mmol) and N,N-diisopropylethylamine (1.12 g, 8.73 mmol), and reacted at 65°C for 2 hours, concentrated under reduced pressure, added appropriate amount of water, extracted with dichloromethane 3 times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain N-((1-fluorocyclopropyl)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (compound 19-1, 0.78 g) as a crude of yellow solid.

[0380] Second step:

[0381] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) was sequentially added compound 19-1 (94 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol), and potassium phosphate (109 mg, 0.51 mmol), replaced with nitrogen three times, and reacted at 95°C for 3 hours. The reaction mixture was concentrated under reduced pressure, separated by column chromatography and C18 column to obtain (7R,14R)-1-(difluoromethoxy)-11-(2-(((1-fluorocyclopropyl)methyl)amino)pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14-methanofuro[3,2-g]benzo[4,5]imidazo[1,2-a][1,4]oxazin-5(14H)-one (compound 19, 35 mg, yield: 24%, white solid), [M+H] + = 521.

[0382] 1H NMR (400 MHz, CDC13) δ 0.76-0.85 (m, 2H), 1.06-1.19 (m, 2H), 2.89 (d, J = 13.63 Hz, 1H), 3.43-3.51 (m, 1H), 3.53 (s, 3H), 3.87 (d, J = 5.88 Hz, 1H), 3.93 (d, J = 6.00 Hz, 1H), 4.98 (d, J = 7.13 Hz, 1H), 5.69 (br t, J = 5.57 Hz, 1H), 6.28 (d, J = 7.13 Hz, 1H), 6.58-7.11 (m, 1H), 7.29-7.33 (m, 1H), 7.34-7.38 (m, 1H), 7.39-7.46 (m, 1H), 7.58 (d, J = 1.25 Hz, 1H), 7.78 (d, J = 8.50 Hz, 1H), 8.50 (dd, J = 8.25, 1.00 Hz, 1H), 8.53 (s, 2H).

[0383] Example 21: Preparation of (7R, 14R)-11-(2-(((S)-1-cyclopropylethyl)amino)pyrimidin-5-yl)-1- (difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanofuro[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin- 5(14H)-one (Compound 20)

[0384] First Step:

[0385] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (1.00 g, 4.15 mmol) in tert-butanol was added (S)-1-cyclopropylethylamine (657 mg, 5.40 mmol) and N,N-diisopropylethylamine (1.61 g, 12.4 mmol) and reacted at 65 °C for 3 hours, concentrated under reduced pressure, added appropriate amount of water, extracted with dichloromethane for 3 times, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain (S)-N-(1-cyclopropylethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (Compound 20-1, 0.96 g) as a yellow solid.

[0386] Second Step:

[0387] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) were added compound 20-1 (93 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol) and potassium phosphate (109 mg, 0.51 mmol) successively, replaced with nitrogen for three times, reacted at 95 °C for 3 hours, concentrated under reduced pressure, separated by column chromatography and C18 column to obtain (7R,14R)-11-(2-(((S)-1-cyclopropylethyl)amino)pyrimidin-5-yl)-1- (difluoromethoxy)-6-methyl-6,7-dihydro-7,14-tetramethylbenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazepin-5(14H)-one (compound 20, 25 mg, yield: 16%, white solid), [M+H] + = 517.

[0388] 1 H NMR (400 MHz, CDCl3) δ 0.27-0.34 (m, 1H), 0.38-0.45 (m, 1H), 0.46-0.59 (m, 2H), 0.92-1.04 (m, 1H), 1.33 (d, J = 6.50 Hz, 3H), 2.89 (d, J = 13.63 Hz, 1H), 3.42-3.51 (m, 1H), 3.53 (s, 3H), 3.54-3.64 (m, 1H), 4.97 (d, J = 7.00 Hz, 1H), 5.22 (br d, J = 7.75 Hz, 1H), 6.28 (d, J = 7.13 Hz, 1H), 6.64-7.04 (m, 1H), 7.29-7.37 (m, 2H), 7.39-7.46 (m, 1H), 7.57 (d, J = 1.25 Hz, 1H), 7.77 (d, J = 8.38 Hz, 1H), 8.49 (d, J = 1.13 Hz, 1H), 8.50-8.52 (m, 2H).

[0389] Example 22: Preparation of (7R,14R)-11-(2-(((R)-1-cyclopropylethyl)amino)pyrimidin-5-yl)-1- (difluoromethoxy)-6-methyl-6,7-dihydro-7,14-tetramethylbenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazepin-5(14H)-one (compound 21)

[0390] First step:

[0391] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (1.00 g, 4.15 mmol) in tert-butanol was added (R)-1-cyclopropylethylamine (657 mg, 5.40 mmol) and N,N-diisopropylethylamine (1.61 g, 12.4 mmol), and reacted at 65°C for 3 hours, concentrated under reduced pressure, added appropriate amount of water, extracted with dichloromethane 3 times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (R)-N-(1-cyclopropylethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (compound 21-1, 0.96 g) as a yellow solid.

[0392] Second step:

[0393] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) was sequentially added compound 21-1 (93 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol), and potassium phosphate (109 mg, 0.51 mmol), replaced with nitrogen three times, and reacted at 95°C for 3 hours. The reaction mixture was concentrated under reduced pressure, separated by column chromatography and C18 column to obtain (7R,14R)-11-(2-(((R)-1-cyclopropylethyl)amino)pyrimidin-5-yl)-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanofuro[3,2-g]benzo[4,5]imidazo[1,2-a][1,4]oxazin-5(14H)-one (compound 21, 29 mg, yield: 20%, white solid), [M+H] + = 517.

[0394] 1H NMR (400 MHz, CDC13) δ 0.31 (dt, J = 9.26, 4.50 Hz, 1H), 0.38 - 0.45 (m, 1H), 0.46 - 0.59 (m, 2H), 0.93 - 1.02 (m, 1H), 1.33 (d, J = 6.50 Hz, 3H), 2.88 (d, J = 13.63 Hz, 1H), 3.42 - 3.51 (m, 1H), 3.53 (s, 3H), 3.56 - 3.64 (m, 1H), 4.97 (d, J = 7.13 Hz, 1H), 5.22 (br d, J = 7.88 Hz, 1H), 6.27 (d, J = 7.25 Hz, 1H), 6.62 - 7.06 (m, 1H), 7.33 (dd, J = 13.51, 8.25 Hz, 2H), 7.39 - 7.45 (m, 1H), 7.57 (s, 1H), 7.77 (d, J = 8.50 Hz, 1H), 8.48 - 8.53 (m, 3H).

[0395] Example 23: Preparation of (7R, 14R)-11-(2-((cyclopropylmethyl)(methyl)amino)pyrimidin-5-yl)-1- (difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanofuro[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)- one (Compound 22)

[0396] First Step:

[0397] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (1.00 g, 4.15 mmol) in tert-butanol was added (cyclopropylmethyl)methylamine (460 mg, 5.40 mmol) and N,N-diisopropylethylamine (1.61 g, 12.4 mmol) and reacted at 65 °C for 3 hours, concentrated under reduced pressure, added appropriate amount of water, extracted with dichloromethane for 3 times, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give N-(cyclopropylmethyl)-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (Compound 22-1, 0.40 g) as a yellow solid.

[0398] Second Step:

[0399] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) were added compound 21-1 (93 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol) and potassium phosphate (109 mg, 0.51 mmol) successively, replaced with nitrogen for three times, reacted at 95 °C for 3 hours, concentrated under reduced pressure, separated by column chromatography and C18 column to obtain (7R,14R)-11-(2-((cyclopropylmethyl)(methyl)amino)pyrimidin-5-yl)-1- (difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanofuro[f]benzo[4,5]imidazo[1,2- a][1,4]diazepin-5(14H)-one (compound 22, 65 mg, yield: 48%, white solid), [M+H] + = 517.

[0400] 1 H NMR (400 MHz, CDCl3) δ 0.32 (q, J = 5.04 Hz, 2H), 0.50-0.58 (m, 2H), 1.08-1.19 (m, 1H), 2.88 (d, J = 13.63 Hz, 1H), 3.28 (s, 3H), 3.42-3.51 (m, 1H), 3.53 (s, 3H), 3.61 (d, J = 6.75 Hz, 2H), 4.96 (d, J = 7.25 Hz, 1H), 6.27 (d, J = 7.25 Hz, 1H), 6.63-7.06 (m, 1H), 7.34 (dd, J = 15.51, 8.38 Hz, 2H), 7.42 (t, J = 8.13 Hz, 1H), 7.57 (s, 1H), 7.76 (d, J = 8.50 Hz, 1H), 8.50 (d, J = 8.25 Hz, 1H), 8.55 (s, 2H).

[0401] Example 24: Preparation of (7R,14R)-1-(difluoromethoxy)-11-(2-(((1- methoxycyclobutyl)methyl)amino)pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14- methanofuro[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (compound 23)

[0402] First step:

[0403] To a solution of 1-(aminomethyl)cyclobutan-1-ol (2.50 g, 24.7 mmol) in tetrahydrofuran was added di-tert-butyl dicarbonate (5.12 g, 23.40 mmol) and the reaction was stirred at 25 °C for 3 h. The reaction was concentrated under reduced pressure, ethyl acetate (50 mL) was added, followed by 0.5 M hydrochloric acid (30 mL). The organic phase was separated and washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl (1-hydroxycyclobutyl)methyl)carbamate (compound 23-1, 4.00 g) as a yellow oil.

[0404] Second Step:

[0405] To a solution of compound 23-1 (3.00 g, 14.9 mmol) in dichloromethane was added trimethyl oxonium tetrafluoroborate (3.00 g, 20.2 mmol), 1,8- diazabicyclononane (13.0 g, 61.1 mmol) and 4A molecular sieves and the reaction was stirred at 25 °C for 7 h. The reaction was filtered, the organic phase was added to water (30 mL), followed by 0.5 M hydrochloric acid (24 mL). The organic phase was separated and washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product which was purified by column chromatography (EtOAc / PE, 2-25%) to give tert-butyl (1-methoxycyclobutyl)methyl)carbamate (compound 23-2, 2.30 g) as a yellow oil.

[0406] Third Step:

[0407] Compound 23-2 (2.30 g, 10.6 mmol) was dissolved in methyl tert-butyl ether and stirred until homogeneous. 2 M hydrogen chloride in ethyl acetate (27 mL) was added and the reaction was stirred at room temperature for 0.5 h. The reaction was filtered and the filtrate was concentrated under reduced pressure. The resulting white solid was triturated with methyl tert-butyl ether to give (1-methoxycyclobutyl)methanamine hydrochloride (compound 23-3, 0.20 g) as a white solid.

[0408] Fourth Step:

[0409] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (200 mg, 0.83 mmol) in tert-butanol was added compound 23-3 (164 mg, 1.08 mmol) and N,N- diisopropylethylamine (322 mg, 2.49 mmol) and the reaction was stirred at 65 °C for 12 h. The reaction was concentrated under reduced pressure, water was added and the resulting mixture was extracted with dichloromethane (3x). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give N-((1-methoxycyclobutyl)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (compound 23-4, 0.22 g) as a white solid.

[0410] Fifth Step:

[0411] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) were added compound 23-4 (102 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol) and potassium phosphate (109 mg, 0.51 mmol) successively, replaced with nitrogen for three times, reacted at 95 °C for 3 hours, concentrated under reduced pressure, separated by column chromatography and C18 column to obtain (7R,14R)-1-(difluoromethoxy)-11-(2-(((1-methoxycyclobutyl)methyl)amino)pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14-methanofuro[3,2-g]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (compound 23, 71 mg, yield: 48%, white solid), [M+H] + = 547.

[0412] 1 H NMR (400 MHz, CDCl3) δ 1.63-1.73 (m, 2H), 1.92-2.01 (m, 2H), 2.15-2.25 (m, 2H), 2.88 (d, J = 13.63 Hz, 1H), 3.23 (s, 3H), 3.42-3.51 (m, 1H), 3.52 (s, 3H), 3.70 (d, J = 5.13 Hz, 2H), 4.97 (d, J = 7.00 Hz, 1H), 5.45 (br t, J = 4.88 Hz, 1H), 6.28 (d, J = 7.13 Hz, 1H), 6.58-7.08 (m, 1H), 7.31 (d, J = 7.75 Hz, 1H), 7.35 (dd, J = 8.44, 1.69 Hz, 1H), 7.39-7.45 (m, 1H), 7.58 (d, J = 1.38 Hz, 1H), 7.77 (d, J = 8.50 Hz, 1H), 8.49 (dd, J = 8.25, 1.13 Hz, 1H), 8.53 (s, 2H).

[0413] Example 25: Preparation of (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-((((R)- tetrahydrofuran-3-yl)methyl)amino)pyrimidin-5-yl)-6,7-dihydro-7,14-methanofuro[3,2- g]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (compound 24)

[0414] First step:

[0415] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (450 mg, 1.87 mmol) in tert-butanol was added (R)-(tetrahydrofuran-3-yl)methanamine (246 mg, 2.43 mmol) and N,N-diisopropylethylamine (726 mg, 5.61 mmol), and reacted at 65 °C for 12 hours. After concentration under reduced pressure, an appropriate amount of water was added, and extracted with dichloromethane three times. After drying over anhydrous sodium sulfate, filtration, and concentration under reduced pressure, (R)-N-((tetrahydrofuran-3-yl)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (compound 24-1, 0.60 g) was obtained as a crude product of a white solid.

[0416] Second step:

[0417] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) were sequentially added compound 24-1 (98 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol), and potassium phosphate (109 mg, 0.51 mmol), and replaced with nitrogen three times. After reacting at 95 °C for 3 hours, concentration under reduced pressure, column chromatography, and C18 column separation, (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-((((R)-tetrahydrofuran-3-yl)methyl)amino)pyrimidin-5-yl)-6,7-dihydro-7,14-methanofuro[3,2-g]benzo[4,5]imidazo[1,2-a][1,4]oxazin-5(14H)-one (compound 24, 66 mg, yield: 48%, white solid) was obtained. + = 533.

[0418] 1H NMR (400 MHz, CDC13) δ 1.73 - 1.77 (m, 1H), 2.06 - 2.18 (m, 1H), 2.59 - 2.71 (m, 1H), 2.88 (d, J = 13.57 Hz, 1H), 3.40 - 3.51 (m, 2H), 3.53 (s, 3H), 3.65 (dd, J = 8.74, 5.32 Hz, 1H), 3.74 - 3.83 (m, 1H), 3.84 - 4.00 (m, 2H), 4.97 (d, J = 7.09 Hz, 1H), 5.38 (br t, J = 5.87 Hz, 1H), 6.28 (d, J = 7.21 Hz, 1H), 6.60 - 7.07 (m, 1H), 7.29 - 7.37 (m, 2H), 7.38 - 7.47 (m, 1H), 7.57 (d, J = 1.22 Hz, 1H), 7.77 (d, J = 8.44 Hz, 1H), 8.49 (dd, J = 8.25, 1.04 Hz, 1H), 8.53 (s, 2H).

[0419] Example 26: Preparation of (7R, 14R)-1-(difluoromethoxy)-6-methyl-11-(2-((((S)- tetrahydrofuran-3-yl)methyl)amino)pyrimidin-5-yl)-6,7-dihydro-7,14- methanofuro[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (Compound 25)

[0420] First Step:

[0421] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (1.00 g, 4.15 mmol) in tert-butanol was added (S)-(tetrahydrofuran-3-yl)methanamine (547 mg, 5.40 mmol) and N,N-diisopropylethylamine (1.61 g, 12.4 mmol) and reacted at 65 °C for 12 hours. After concentration under reduced pressure, an appropriate amount of water was added, and extracted with dichloromethane 3 times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a white solid of (S)-N-((tetrahydrofuran-3-yl)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (Compound 25-1, 1.10 g) as a crude product.

[0422] Second Step:

[0423] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) were added compound 25-1 (98 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol) and potassium phosphate (109 mg, 0.51 mmol) successively, replaced with nitrogen for three times, reacted at 95 °C for 3 hours, concentrated under reduced pressure, separated by column chromatography and C18 column to obtain (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-((((S)- tetrahydrofuran-3-yl)methyl)amino)pyrimidin-5-yl)-6,7-dihydro-7,14- toluene[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (compound 25, 103 mg, yield: 76%, white solid), [M+H] + = 533.

[0424] 1 H NMR (400 MHz, CDCl3) δ 2.04-2.20 (m, 1H), 2.58-2.71 (m, 1H), 2.88 (d, J = 13.51 Hz, 1H), 3.42-3.51 (m, 2H), 3.53 (s, 3H), 3.65 (dd, J = 8.69, 5.32 Hz, 1H), 3.75-3.82 (m, 1H), 3.85-4.01 (m, 2H), 4.63-4.79 (m, 1H), 4.97 (d, J = 7.13 Hz, 1H), 5.37 (br t, J = 5.94 Hz, 1H), 6.28 (d, J = 7.13 Hz, 1H), 6.59-7.09 (m, 1H), 7.29-7.37 (m, 2H), 7.39-7.45 (m, 1H), 7.57 (d, J = 1.63 Hz, 1H), 7.77 (d, J = 8.50 Hz, 1H), 8.49 (dd, J = 8.25, 1.00 Hz, 1H), 8.53 (s, 2H).

[0425] Example 27: Preparation of (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-(((tetrahydro- 2H-pyran-4-yl)methyl)amino)pyrimidin-5-yl)-6,7-dihydro-7,14-toluene[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (compound 26)

[0426] First step:

[0427] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (1.00 g, 4.15 mmol) in tert-butyl alcohol was added (tetrahydro-2H-pyran-4-yl)methanamine (623 mg, 5.40 mmol) and N,N-diisopropylethylamine (1.61 g, 12.4 mmol), and reacted at 65°C for 8 hours. After concentration under reduced pressure, an appropriate amount of water was added, and extracted with dichloromethane three times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a white solid of N-((tetrahydro-2H-pyran-4-yl)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (compound 26-1, 0.82 g) as a crude product.

[0428] Second step:

[0429] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) were sequentially added compound 26-1 (102 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol), and potassium phosphate (109 mg, 0.51 mmol), and replaced with nitrogen three times, and reacted at 95°C for 3 hours. After concentration under reduced pressure, column chromatography and C18 column separation were performed to obtain (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrimidin-5-yl)-6,7-dihydro-7,14-methanofuro[3,2-g]benzo[4,5]imidazo[1,2-a][1,4]oxazin-5(14H)-one (compound 26, 75 mg, yield: 52%, white solid), [M+H]=547. + = 547.

[0430] 1H NMR (400 MHz, CDC13) δ 1.34 - 1.48 (m, 2H), 1.74 (br dd, J=13.02, 1.65 Hz, 2H), 1.92 (ddd, J=11.16, 7.37, 4.22 Hz, 1H), 2.89 (d, J=13.45 Hz, 1H), 3.37 - 3.51 (m, 5H), 3.53 (s, 3H), 4.01 (dd, J=11.07, 3.48 Hz, 2H), 4.97 (d, J=6.97 Hz, 1H), 5.30 (t, J=6.05 Hz, 1H), 6.28 (d, J=7.21 Hz, 1H), 6.63 - 7.07 (m, 1H), 7.29 - 7.38 (m, 2H), 7.39 - 7.46 (m, 1H), 7.57 (d, J=1.22 Hz, 1H), 7.77 (d, J=8.44 Hz, 1H), 8.50 (dd, J=8.31, 0.98 Hz, 1H), 8.52 (s, 2H).

[0431] Example 28: Preparation of (7R, 14R)-1-(difluoromethoxy)-11-(2-((3- methoxycyclobutyl)methyl)amino)pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14- methylenomorphinan-5(14H)-one (Compound 27)

[0432] First Step:

[0433] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (400 mg, 1.66 mmol) in tert-butanol was added (3-methoxycyclobutyl)methanamine (250 mg, 2.16 mmol) and N,N-diisopropyl ethylamine (645 mg, 4.99 mmol) and reacted at 65 °C for 12 hours, concentrated under reduced pressure, added appropriate amount of water, extracted with dichloromethane for 3 times, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain white solid N-((3-methoxycyclobutyl)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (Compound 27-1, 0.50 g) crude product.

[0434] Second Step:

[0435] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) were added compound 27-1 (103 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol) and potassium phosphate (109 mg, 0.51 mmol) successively, replaced with nitrogen for three times, reacted at 95 °C for 3 hours, concentrated under reduced pressure, separated by column chromatography and C18 column to obtain (7R,14R)-1-(difluoromethoxy)-11-(2-((3-methoxycyclobutyl)methyl)amino)pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14-methylenzol[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (compound 27, 88 mg, yield: 64%, white solid), [M+H] + = 547.

[0436] 1 H NMR (400 MHz, CDCl3-d) δ 2.06-2.23 (m, 4H), 2.42-2.59 (m, 1H), 2.88 (d, J = 13.63 Hz, 1H), 3.24 (s, 3H), 3.42-3.51 (m, 1H), 3.51-3.54 (m, 3H), 3.54-3.57 (m, 1H), 3.99-4.09 (m, 1H), 4.00-4.08 (m, 1H), 4.97 (d, J = 7.13 Hz, 1H), 5.26 (q, J = 5.88 Hz, 1H), 6.27 (d, J = 7.25 Hz, 1H), 6.61-7.07 (m, 1H), 7.29-7.37 (m, 2H), 7.39-7.45 (m, 1H), 7.57 (s, 1H), 7.77 (d, J = 8.51 Hz, 1H), 8.47-8.51 (m, 1H), 8.51-8.53 (m, 2H).

[0437] Example 29: Preparation of (7R,14R)-1-(difluoromethoxy)-11-(2-(((1-hydroxycyclopropyl)methyl)amino)pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14-methylenzol[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (compound 28)

[0438] First step:

[0439] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (1.00 g, 4.15 mmol) in tert-butyl alcohol was added 1-(aminomethyl)cyclopropan-1-ol (471 mg, 5.40 mmol) and N,N-diisopropylethylamine (1.61 g, 12.4 mmol), and reacted at 65°C for 8 hours. After concentration under reduced pressure, an appropriate amount of water was added, and extracted with dichloromethane 3 times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)amino)methyl)cyclopropan-1-ol (compound 28-1, 1.08 g) as a crude product of a yellow solid.

[0440] Second step:

[0441] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) was sequentially added compound 28-1 (94 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol), and potassium phosphate (109 mg, 0.51 mmol), and replaced with nitrogen three times, and reacted at 95°C for 3 hours. After concentration under reduced pressure, column chromatography and C18 column separation were performed to obtain (7R,14R)-1-(difluoromethoxy)-11-(2-(((1-hydroxycyclopropyl)methyl)amino)pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14-methanofuro[3,2-g]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (compound 28, 27 mg, yield: 20%, white solid), [M+H] + = 519.

[0442] 1 H NMR (400 MHz, CDCl3) δ 0.65-0.70 (m, 2H), 0.84-0.90 (m, 2H), 2.89 (d, J = 13.63 Hz, 1H), 3.43-3.52 (m, 1H), 3.53 (s, 3H), 3.64 (d, J = 5.75 Hz, 2H), 4.63 (br s, 1H), 4.97 (d, J = 7.13 Hz, 1H), 5.68 (br t, J = 5.75 Hz, 1H), 6.27 (d, J = 7.25 Hz, 1H), 6.58-7.13 (m, 1H), 7.29-7.36 (m, 2H), 7.39-7.46 (m, 1H), 7.56 (d, J = 1.50 Hz, 1H), 7.77 (d, J = 8.38 Hz, 1H), 8.48-8.51 (m, 1H), 8.52 (s, 2H).

[0443] Example 30: Preparation of (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-((((R)- tetrahydrofuran-2-yl)methyl)amino)pyrimidin-5-yl)-6,7-dihydro-7,14- toluene[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (Compound 29)

[0444] First Step:

[0445] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (1.00 g, 4.15 mmol) in tert-butanol was added (R)-(tetrahydrofuran-2-yl)methylamine hydrochloride (744 mg, 5.40 mmol) and N,N-diisopropylethylamine (1.61 g, 12.4 mmol), and reacted at 65 °C for 8 hours, concentrated under reduced pressure, added appropriate amount of water, extracted with dichloromethane 3 times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a white solid (R)-N-((tetrahydrofuran-2-yl)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (Compound 29-1, 0.65 g) as a crude product.

[0446] Second Step:

[0447] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) was sequentially added Compound 29-1 (98 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol), and potassium phosphate (109 mg, 0.51 mmol), replaced with nitrogen three times, and reacted at 95 °C for 3 hours. After concentration under reduced pressure, column chromatography and C18 column separation were performed to obtain (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-((((R)-tetrahydrofuran-2-yl)methyl)amino)pyrimidin-5-yl)-6,7-dihydro-7,14-toluenef]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (Compound 29, 70 mg, yield: 52%, white solid), [M+H] = 533. +

[0448] 1 ​H NMR (400 MHz, CDC13) δ 1.62 - 1.72 (m, 1H), 1.88 - 1.99 (m, 2H), 1.99 - 2.09 (m, 1H), 2.88 (d, J = 13.51 Hz, 1H), 3.42 - 3.52 (m, 2H), 3.52 (s, 3H), 3.72 (ddd, J = 13.63, 6.25, 3.63 Hz, 1H), 3.76 - 3.83 (m, 1H), 3.89 - 3.97 (m, 1H), 4.14 (dd, J = 6.94, 3.69 Hz, 1H), 4.97 (d, J = 7.00 Hz, 1H), 5.56 (br t, J = 5.63 Hz, 1H), 6.60 - 7.08 (m, 1H), 7.29 - 7.37 (m, 2H), 7.38 - 7.45 (m, 1H), 7.57 (d, J = 1.38 Hz, 1H), 7.76 (d, J = 8.38 Hz, 1H), 8.49 (dd, J = 8.19, 0.94 Hz, 1H), 8.52 (s, 2H).

[0449] Example 31: Preparation of (7R, 14R)-1-(difluoromethoxy)-6-methyl-11-(2-((((S)- tetrahydrofuran-2-yl)methyl)amino)pyrimidin-5-yl)-6,7-dihydro-7,14- methanofuro[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (Compound 30)

[0450] First Step:

[0451] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (1.00 g, 4.15 mmol) in tert-butanol was added (S)-(tetrahydrofuran-2-yl)methylamine hydrochloride (744 mg, 5.40 mmol) and N,N-diisopropylethylamine (1.61 g, 12.4 mmol) and reacted at 65 °C for 8 hours. After concentration under reduced pressure, an appropriate amount of water was added, and extracted with dichloromethane 3 times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a white solid of (S)-N-((tetrahydrofuran-2-yl)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (Compound 30-1, 0.98 g) as a crude product.

[0452] Second Step:

[0453] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) were added compound 30-1 (98 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol) and potassium phosphate (109 mg, 0.51 mmol) successively, replaced with nitrogen for three times, reacted at 95 °C for 3 hours, concentrated under reduced pressure, separated by column chromatography and C18 column to obtain (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-((((S)- tetrahydrofuran-2-yl)methyl)amino)pyrimidin-5-yl)-6,7-dihydro-7,14- methanofuro[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (compound 30, 93 mg, yield: 68%, white solid), [M+H] + = 533.

[0454] 1 H NMR (400 MHz, CDCl3) δ 1.62-1.69 (m, 1H), 1.87-1.99 (m, 2H), 2.00-2.09 (m, 1H), 2.88 (d, J = 13.45 Hz, 1H), 3.42-3.51 (m, 2H), 3.52 (s, 3H), 3.72 (ddd, J = 13.63, 6.30, 3.67 Hz, 1H), 3.76-3.83 (m, 1H), 3.89-3.96 (m, 1H), 4.14 (qd, J = 6.97, 3.67 Hz, 1H), 4.97 (d, J = 7.09 Hz, 1H), 5.56 (br t, J = 5.75 Hz, 1H), 6.27 (d, J = 7.21 Hz, 1H), 6.54-7.10 (m, 1H), 7.29-7.36 (m, 2H), 7.39-7.45 (m, 1H), 7.57 (d, J = 1.22 Hz, 1H), 7.76 (d, J = 8.44 Hz, 1H), 8.49 (dd, J = 8.25, 0.92 Hz, 1H), 8.52 (s, 2H).

[0455] Example 32: Preparation of (7R,14R)-1-(difluoromethoxy)-11-(2-((1- methoxycyclopropyl)methyl)(methyl)amino)pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14- methanofuro[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (compound 31)

[0456] First step:

[0457] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (120 mg, 0.49 mmol) in tert-butanol was added 1-(1-methoxycyclopropyl)-N-methylmethanamine hydrochloride (99 mg, 0.64 mmol) and N,N-diisopropylethylamine (193 mg, 1.49 mmol), and reacted at 65 °C for 12 hours. After concentration under reduced pressure, an appropriate amount of water was added, and extracted with dichloromethane three times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a white solid of N-((1-methoxycyclopropyl)methyl)-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (compound 31-1, 0.16 g) as a crude product.

[0458] Second step:

[0459] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) was added compound 31-1 (102 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol), and potassium phosphate (109 mg, 0.51 mmol) sequentially, and replaced with nitrogen three times, and reacted at 95 °C for 3 hours. After concentration under reduced pressure, column chromatography and C18 column separation were performed to obtain (7R,14R)-1-(difluoromethoxy)-11-(2-((1-methoxycyclopropyl)methyl)(methyl)amino)pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14- methanofuro[3,2-b]furo[2,3-d]pyrimidin-5(14H)-one (compound 31, 12 mg, white solid), [M+H]=547. + = 547.

[0460] 1 H NMR (400 MHz, CDCl3) δ 0.65-0.73 (m, 2H), 0.81-0.90 (m, 2H), 2.87 (d, J = 13.57 Hz, 1H), 3.33 (d, J = 11.37 Hz, 6H), 3.41-3.50 (m, 1H), 3.52 (s, 3H), 3.98 (s, 2H), 4.96 (d, J = 7.09 Hz, 1H), 6.27 (d, J = 7.09 Hz, 1H), 6.62-7.07 (m, 1H), 7.29-7.45 (m, 3H), 7.56 (s, 1H), 7.76 (d, J = 8.56 Hz, 1H), 8.49 (d, J = 8.07 Hz, 1H), 8.54 (s, 2H).

[0461] Example 33: Preparation of (7R, 14R)-1-(difluoromethoxy)-11-(2-(((1- ethoxycyclopropyl)methyl)amino)pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14- toluene[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (Compound 32)

[0462] First Step:

[0463] Dichloromethane (20 mL) was added to the reaction bottle, tert-butyl (1- hydroxycyclopropyl)methylcarbamate (2.0 g, 10.68 mmol) was added to the reaction bottle, followed by the addition of triethyl oxonium tetrafluoroborate (3.1 g, 16.02 mmol), 4A molecular sieves (2.0 g) and 1,8-bisdimethylamino (9.2 g, 40.72 mmol), the system was stirred at 15-25 °C for 5 hours. The reaction liquid was filtered, water (30 mL) was added, the liquid was separated, and the organic phase was concentrated to obtain a crude product, which was separated by column chromatography to obtain tert-butyl (1-ethoxycyclopropyl)methylcarbamate (Compound 32-1, 1.0 g) in the form of yellow oil.

[0464] Second Step:

[0465] Compound 32-1 (1.0 g, 4.65 mmol) was dissolved with 4M hydrogen chloride-1,4-dioxane solution, stirred at room temperature for 0.5 hours, and concentrated under reduced pressure to obtain a white solid (1-ethoxycyclopropyl)methanamine hydrochloride (Compound 32-2, 0.7 g) crude product.

[0466] Third Step:

[0467] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (200 mg, 0.83 mmol) in tert-butanol, compound 32-2 (300 mg, 1.99 mmol) and N,N-diisopropylethylamine (450 mg, 3.49 mmol) were added, and the reaction was carried out at 65 °C for 12 hours. After being concentrated under reduced pressure, an appropriate amount of water was added, dichloromethane was extracted three times, anhydrous sodium sulfate was added for drying, filtered, and concentrated under reduced pressure to obtain N-((1-ethoxycyclopropyl)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (Compound 32-3, 300 mg) in the form of red oil crude product.

[0468] Fourth Step: To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N- dimethylformamide / water (5:1) were added compound 32-3 (100 mg, 0.32 mmol), chloro(2- dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol) and potassium phosphate (109 mg, 0.51 mmol) sequentially, replaced with nitrogen for three times, reacted at 95 °C for 3 hours, concentrated under reduced pressure, separated by column chromatography and C18 column to give (7R,14R)-1-(difluoromethoxy)-11-(2-(((1- ethoxycyclopropyl)methyl)amino)pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14- toluene[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (compound 32, 16 mg, white solid), [M+H] + = 547.

[0469] 1 H NMR (400 MHz, CDCl3) δ 0.59-0.72 (m, 2H), 0.86-0.93 (m, 2H), 1.12-1.21 (m, 3H), 2.80-2.92 (m, 1H), 3.41-3.49 (m, 1H), 3.50-3.55 (m, 3H), 3.57-3.65 (m, 4H), 4.97 (d, J = 7.13 Hz, 1H), 5.55-5.78 (m, 1H), 6.23-6.36 (m, 1H), 6.61-7.09 (m, 1H), 7.30-7.37 (m, 2H), 7.39-7.46 (m, 1H), 7.50-7.64 (m, 1H), 7.69-7.91 (m, 1H), 8.43-8.63 (m, 3H).

[0470] Example 34: Preparation of (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-(methyl(((R)- tetrahydrofuran-2-yl)methyl)amino)pyrimidin-5-yl)-6,7-dihydro-7,14-toluene[f]benzo[4,5] imidazo[1,2-a][1,4]diazepin-5(14H)-one (compound 33)

[0471] First Step:

[0472] To a solution of (R)-(tetrahydrofuran-2-yl)methanamine (2.40 g, 23.76 mmol) in N,N-dimethylformamide was added di-tert-butyl dicarbonate (4.92 g, 22.57 mmol) and the reaction was stirred at 25 °C for 3 h. The reaction was concentrated under reduced pressure, ethyl acetate (50 mL) was added, followed by 0.5 M hydrochloric acid (30 mL). The organic phase was separated and washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (R)-((tetrahydrofuran-2-yl)methyl)carbamic acid tert-butyl ester (compound 33-1, 3.38 g) as a pale yellow oil.

[0473] Second step:

[0474] A solution of lithium aluminium tetrahydrofuran (34 mL, 85 mmol) was placed in a reaction flask and compound 33-1 (3.38 g, 16.81 mmol) was added slowly at -20 °C. The system was purged with nitrogen three times and then warmed to 70 °C and stirred for 2.5 h. The system was then cooled to 25 °C and water (3 mL), 15% sodium hydroxide solution (3 mL) and water (8 mL) were added sequentially. A large amount of solid precipitated and the reaction mixture was diluted with tetrahydrofuran (20 mL). The mixture was filtered and the filter cake was washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure to give (R)-N-methyl-1-(tetrahydrofuran-2-yl)methanamine (compound 33-2, 1.64 g) as a pale yellow oil.

[0475] Third step:

[0476] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (500 mg, 2.1 mmol) in tert-butanol was added compound 33-2 (312 mg, 2.7 mmol) and N,N-diisopropylethylamine (806 mg, 6.3 mmol) and the reaction was stirred at 65 °C for 12 h. The reaction was concentrated under reduced pressure, water was added and the mixture was extracted with dichloromethane (3 x). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (R)-N-methyl-N-((tetrahydrofuran-2-yl)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (compound 33-3, 650 mg) as a white solid.

[0477] Fourth step:

[0478] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) were added compound 33-3 (123 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol) and potassium phosphate (109 mg, 0.51 mmol) successively, replaced with nitrogen for three times, reacted at 95 °C for 3 hours, concentrated under reduced pressure, separated by column chromatography and C18 column to obtain (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-(methyl(((R)- tetrahydrofuran-2-yl)methyl)amino)pyrimidin-5-yl)-6,7-dihydro-7,14- methanofuro[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (compound 33, 95 mg, white solid), [M+H] + = 547.

[0479] 1 H NMR (400 MHz, CDCl3) δ 1.56-1.68 (m, 1H), 1.97-2.09 (m, 2H), 2.87 (d, J = 13.45 Hz, 1H), 3.29 (s, 3H), 3.41-3.49 (m, 1H), 3.51 (s, 3H), 3.67 (dd, J = 14.12, 7.15 Hz, 1H), 3.73-3.81 (m, 1H), 3.86-3.97 (m, 3H), 4.15-4.28 (m, 1H), 4.95 (d, J = 7.09 Hz, 1H), 6.26 (d, J = 7.21 Hz, 1H), 6.61-7.05 (m, 1H), 7.29-7.37 (m, 2H), 7.38-7.44 (m, 1H), 7.55 (d, J = 1.34 Hz, 1H), 7.75 (d, J = 8.44 Hz, 1H), 8.46-8.51 (m, 1H), 8.54 (s, 2H).

[0480] Example 35: Preparation of (7R,14R)-1-(difluoromethoxy)-11-(2-(((1- hydroxycyclobutyl)methyl)amino)pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14- methanofuro[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (compound 34)

[0481] First step:

[0482] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (7.00 g, 29.1 mmol) in tert-butanol was added 1-(aminomethyl)cyclobutan-1-ol (3.82 g, 37.8 mmol) and N,N-diisopropylethylamine (11.3 g, 87.4 mmol), and reacted at 65°C for 12 hours, concentrated under reduced pressure, added appropriate amount of water, extracted with dichloromethane 3 times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)amino)methyl)cyclobutan-1-ol (compound 34-1, 6.9 g) as a crude product of a yellow solid.

[0483] Second step:

[0484] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) was sequentially added compound 34-1 (100 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol), and potassium phosphate (109 mg, 0.51 mmol), replaced with nitrogen three times, and reacted at 95°C for 3 hours, concentrated under reduced pressure, separated by column chromatography and C18 column to obtain (7R,14R)-1-(difluoromethoxy)-11-(2-(((1-hydroxycyclobutyl)methyl)amino)pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14-methanofuro[f]benzo[4,5]imidazo[1,2-a][1,4]oxazin-5(14H)-one (compound 34, 82 mg, white solid), [M+H] + = 533.

[0485] 1 H NMR (400 MHz, CDCl3) δ 1.45-1.62 (m, 1H), 1.70-1.84 (m, 1H), 2.03-2.24 (m, 5H), 2.82-2.95 (m, 1H), 3.46 (dt, J = 13.82, 7.15 Hz, 1H), 3.52 (s, 3H), 3.66 (d, J = 5.99 Hz, 2H), 4.96 (d, J = 7.09 Hz, 2H), 5.85 (br t, J = 5.87 Hz, 1H), 6.26 (d, J = 7.09 Hz, 1H), 6.63-7.07 (m, 1H), 7.28-7.36 (m, 2H), 7.38-7.44 (m, 1H), 7.54 (d, J = 1.10 Hz, 1H), 7.76 (d, J = 8.44 Hz, 1H), 8.47 (br s, 1H), 8.49 (s, 2H).

[0486] Example 36: Preparation of (7S,14S)-1-(difluoromethoxy)-11-(2-(((1- hydroxycyclobutyl)methyl)amino)pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14- toluene[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (Compound 35)

[0487] First Step:

[0488] To a solution of INT1-14 (8.0 g, 21.3 mmol) in tetrahydrofuran at -70 °C was added 1.0 M KHMDS (32 mL, 32.0 mmol) solution slowly, stirred for 0.5 h, iodomethane (9.0 g, 63.9 mmol) was added slowly, room temperature overnight, quenched with saturated ammonium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the crude was isolated and purified by column chromatography (MeOH / DCM, 0-10%) to give (7S,14S)-11-chloro-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14- toluene[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (Compound 35-1, 3.7 g, yellow solid).

[0489] Second Step:

[0490] To a solution of Compound 35-1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) was added Compound 34-1 (100 mg, 0.32 mmol), chloro(2- dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'- biphenyl)]palladium(II) (10 mg, 0.01 mmol) and potassium phosphate (109 mg, 0.51 mmol) sequentially, replaced with nitrogen three times, reacted at 95 °C for 3 h, concentrated under reduced pressure, isolated by column chromatography and C18 column to give (7S,14S)-1-(difluoromethoxy)-11-(2-(((1- hydroxycyclobutyl)methyl)amino)pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14- toluene[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (Compound 35, 70 mg, white solid), [M+H] = 533. +

[0491] 1 ​H NMR (400 MHz, CDC13) δ 1.38-1.53 (m, 1H), 1.67-1.78 (m, 2H), 1.98-2.15 (m, 4H), 2.81 (d, J = 13.57 Hz, 1H), 3.33-3.44 (m, 1H), 3.45 (s, 3H), 3.59 (d, J = 5.99 Hz, 2H), 4.90 (d, J = 7.09 Hz, 1H), 5.65 (br t, J = 5.81 Hz, 1H), 6.20 (d, J = 7.09 Hz, 1H), 6.57-6.97 (m, 1H), 7.21-7.28 (m, 2H), 7.31-7.39 (m, 1H), 7.48 (d, J = 1.22 Hz, 1H), 7.70 (d, J = 8.44 Hz, 1H), 8.41 (s, 1H), 8.42 (s, 2H).

[0492] Example 37: Preparation of (7R, 14R)-1-(difluoromethoxy)-6-methyl-11-(5-(((S)- tetrahydrofuran-3-yl)methoxy)pyrimidin-2-yl)-6,7-dihydro-7,14-methanofuro[f]benzo[4,5] imidazo[1,2-a][1,4]diazepin-5(14H)-one (Compound 36)

[0493] First Step:

[0494] To a solution of INT1 (500 mg, 1.28 mmol) in 1,4-dioxane was added pinacol diborane (652 mg, 2.57 mmol), potassium acetate (377 mg, 3.86 mmol), tris(dibenzylideneacetone)dipalladium (117 mg, 0.13 mmol) and tricyclohexylphosphonium tetrafluoroborate (47 mg, 0.13 mmol) under nitrogen at 110 °C for 3.5 hours, cooled to room temperature, added dichloromethane and water, the organic phase was added to a thio urea resin, stirred at room temperature for 0.5 hours, filtered, the filter cake was washed with dichloromethane, concentrated under reduced pressure to give a brown solid (7R, 14R)-1-(difluoromethoxy)-6-methyl-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14-methanofuro[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (Compound 36-1, 0.6 g) crude.

[0495] Second Step:

[0496] To a solution of (R)-(tetrahydrofuran-3-yl)methanol (496 mg, 4.86 mmol) in tetrahydrofuran was added 2-bromopyrimidin-5-ol (850 mg, 4.86 mmol) and triphenylphosphine (1.53 g, 5.83 mmol) under nitrogen protection, and the mixture was stirred in an ice bath. Diisopropyl azodicarboxylate (1.18 g, 5.83 mmol) was slowly added, and the mixture was stirred in an ice bath for 1 h. The mixture was concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography to obtain (S)-2-bromo-5-(tetrahydrofuran-3-yl)methoxy)pyrimidine (compound 36-2, 0.4 g) in the form of a yellowish oil.

[0497] Step 3:

[0498] To a solution of compound 36-2 (140 mg, 0.54 mmol) in N,N-dimethylformamide / water (5:1) were sequentially added compound 36-1 (200 mg, 0.42 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (32 mg, 0.04 mmol), and potassium phosphate (176 mg, 0.84 mmol). The mixture was replaced with nitrogen three times and reacted at 95 °C for 3 h. The mixture was concentrated under reduced pressure, separated by column chromatography and C18 column to obtain (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(5-(((S)-tetrahydrofuran-3-yl)methoxy)pyrimidin-2-yl)-6,7-dihydro-7,14-methanofuro[f]benzo[4,5]imidazo[1,2-a][1,4]oxazin-5(14H)-one (compound 36, 4.4 mg, white solid), [M+H] + = 534.

[0499] 1H NMR (400 MHz, CDC13) δ 1.76 - 1.84 (m, 1H), 2.12 - 2.28 (m, 1H), 2.82 (br dd, J = 7.15, 5.93 Hz, 1H), 2.91 (d, J = 13.57 Hz, 1H), 3.50 (br dd, J = 13.63, 7.15 Hz, 1H), 3.56 (s, 3H), 3.74 - 3.88 (m, 2H), 3.93 - 4.00 (m, 2H), 4.02 - 4.14 (m, 2H), 5.01 (d, J = 7.09 Hz, 1H), 6.35 (d, J = 7.09 Hz, 1H), 6.74 - 7.17 (m, 1H), 7.33 - 7.38 (m, 1H), 7.39 - 7.45 (m, 1H), 7.79 (d, J = 8.56 Hz, 1H), 8.30 (dd, J = 8.56, 1.47 Hz, 1H), 8.48 (s, 2H), 8.50 - 8.54 (m, 2H).

[0500] Example 38: Preparation of (7R, 14R)-1-(difluoromethoxy)-6-methyl-11-(2-((((R)-5- oxopyrrolidin-2-yl)methyl)amino)pyrimidin-5-yl)-6,7-dihydro-7,14- methanofuro[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (Compound 37)

[0501] First Step:

[0502] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (350 mg, 1.45 mmol) in tert-butanol was added (R)-5-(aminomethyl)pyrrolidin-2-one hydrochloride (285 mg, 1.89 mmol) and N,N-diisopropylethylamine (564 mg, 4.36 mmol) and reacted at 65 °C for 12 hours. After concentration under reduced pressure, an appropriate amount of water was added, and extracted with dichloromethane 3 times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude of (R)-5-(((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)amino)methyl)pyrrolidin-2-one (Compound 37-1, 0.35 g) as a white solid.

[0503] Second Step:

[0504] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) were added compound 37-1 (102 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol) and potassium phosphate (109 mg, 0.51 mmol) successively, replaced with nitrogen for three times, reacted at 95 °C for 3 hours, concentrated under reduced pressure, separated by column chromatography and C18 column to obtain (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-((((R)-5-oxopyrrolidin-2-yl)methyl)amino)pyrimidin-5-yl)-6,7-dihydro-7,14-methanofuro[3,2-g]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (compound 37, 93 mg, white solid), [M+H] + = 546.

[0505] 1 H NMR (400 MHz, CDCl3) δ 1.84-1.96 (m, 1H), 2.25-2.36 (m, 1H), 2.36-2.46 (m, 2H), 2.86 (d, J = 13.63 Hz, 1H), 3.40-3.50 (m, 2H), 3.52 (s, 3H), 3.70 (ddd, J = 14.04, 6.22, 4.13 Hz, 1H), 3.95-4.07 (m, 1H), 4.95 (d, J = 7.00 Hz, 1H), 5.83 (t, J = 6.25 Hz, 1H), 6.24 (d, J = 7.13 Hz, 1H), 6.64 (s, 1H), 6.66-7.05 (m, 1H), 7.28-7.35 (m, 2H), 7.38-7.44 (m, 1H), 7.51 (d, J = 1.13 Hz, 1H), 7.76 (d, J = 8.50 Hz, 1H), 8.47 (s, 1H), 8.49 (s, 2H).

[0506] Example 39: Preparation of (7R, 14R)-1-(difluoromethoxy)-6-methyl-11-(2-((((R)-2- oxopyrrolidin-3-yl)methyl)amino)pyrimidin-5-yl)-6,7-dihydro-7,14- toluene[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one and (7R, 14R)-1- (difluoromethoxy)-6-methyl-11-(2-((((S)-2-oxopyrrolidin-3-yl)methyl)amino)pyrimidin- 5-yl)-6,7-dihydro-7,14-toluene[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (Compound 38 and Compound 39)

[0507] First Step:

[0508] To a solution of 3-(hydroxymethyl)pyrrolidin-2-one (0.80 g, 6.96 mmol) in dichloromethane was added triethylamine (1.2 mL, 8.35 mmol), p-toluenesulfonyl chloride (1.66 g, 8.35 mmol), and 4-dimethylaminopyridine (170 mg, 1.39 mmol) sequentially under nitrogen protection. The mixture was stirred at room temperature for 14 hours. Water was added to quench the reaction. The mixture was stirred and partitioned. The organic phase was collected and concentrated under reduced pressure to give a crude product. The crude product was slurried with n-heptane to give 4-methylbenzenesulfonic acid (2-oxopyrrolidin-3-yl)methyl ester (Compound 38-1, 0.6 g) as a white solid.

[0509] Second Step:

[0510] To a solution of Compound 38-1 (0.30 g, 1.1 mmol) in acetonitrile was added sodium azide (100 mg, 1.6 mmol) under nitrogen protection. The mixture was heated to 80 °C and stirred for 12 hours. Then the mixture was cooled to room temperature. The mixture was filtered. The filtrate was diluted with tetrahydrofuran to 3 mL to give a solution of 3-(azidomethyl)pyrrolidin-2-one (Compound 38-2). The solution was used directly in the next step.

[0511] Third Step:

[0512] Compound 38-2 (156 mg, 2 mL solution in tetrahydrofuran) was placed in a reaction flask under nitrogen protection. Methanol (2 mL) and palladium on carbon (10 mg, 10%) were added. The mixture was purged with nitrogen for 3 times and purged with hydrogen for 3 times. The mixture was stirred at room temperature for 1 hour. The mixture was filtered. The filter cake was washed with methanol. The filtrate was collected and concentrated to give 3-(aminomethyl)pyrrolidin-2-one (Compound 38-3, 200 mg) as a crude product.

[0513] Fourth Step:

[0514] To a solution of compound 38-3 (100 mg, 0.88 mmol) in methanol was added di-tert-butyl dicarbonate (287 mg, 1.31 mmol) and sodium bicarbonate (147 mg, 1.76 mmol), stirred at 25 °C for 1 h, concentrated under reduced pressure to get a crude, which was separated by column chromatography to get (2-oxopyrrolidin-3-yl)methyl)carbamic acid tert-butyl ester (compound 38-4, 140 mg) as yellow oil.

[0515] Fifth step:

[0516] Compound 38-4 (140 mg, 0.65 mmol) was dissolved with 4 M hydrogen chloride-1,4-dioxane solution, stirred at room temperature for 0.5 h, concentrated under reduced pressure to get 3-(aminomethyl)pyrrolidin-2-one hydrochloride (compound 38-5, 100 mg) as white solid.

[0517] Sixth step:

[0518] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (100 mg, 0.42 mmol) in tert-butanol was added compound 38-5 (100 mg, 0.42 mmol) and N,N-diisopropylethylamine (270 mg, 2.1 mmol), reacted at 65 °C for 12 h, concentrated under reduced pressure, added appropriate amount of water, extracted with dichloromethane for 3 times, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to get 3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)amino)methyl)pyrrolidin-2-one (compound 38-6, 140 mg) as white solid.

[0519] Seventh step:

[0520] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) was added compound 38-6 (100 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol) and potassium phosphate (109 mg, 0.51 mmol) in turn, replaced with nitrogen for 3 times, reacted at 95 °C for 3 h, concentrated under reduced pressure, separated by column chromatography and C18 column to get (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-(((2-oxopyrrolidin-3-yl)methyl)amino)pyrimidin-5-yl)-6,7-dihydro-7,14-methanofuro[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (compound 38-7, 28 mg) as white solid.

[0521] Eighth step:

[0522] Compound 38-7 (40 mg) was subjected to SFC resolution (Preparative method, Waters 150 Preparative SFC system, Chiral column: DAICEL Chiralpak AS 250*30 mm I.D., 10 um, A phase: Supercritical CO2, B phase: IPA:ACN = 4:1 (0.1% ammonia water), Gradient: 70% of B phase in supercritical CO2, Flow rate: 100 g / min, Pressure: 100 bar, Keep CO2 in critical superfluid state, UV detection wavelength: 220 nm) to give the first peak (Analytical method, Chiral column: Chiralpak AS-3 50*4.6 mm I.D., 3 um, A phase: Supercritical CO2, B phase: EtOH (0.05% DEA), Gradient: 60% of B phase in supercritical CO2, Flow rate: 3 mL / min, Pressure: 100 bar, Keep CO2 in critical superfluid state, UV detection wavelength: 220 nm, Retention time: 0.535 minute) as compound 38 (13 mg, white solid), [M+H] + = 546.

[0523] 1 H NMR (400 MHz, DMSO-d6) 1.83 (br dd, J = 12.76, 8.38 Hz, 1H), 2.13-2.21 (m, 1H), 2.57-2.65 (m, 2H), 2.81 (br d, J = 13.76 Hz, 1H), 3.13-3.22 (m, 2H), 3.35 (br s, 3H), 3.49 (br dd, J = 14.01, 7.00 Hz, 2H), 3.64-3.70 (m, 1H), 5.22 (d, J = 7.13 Hz, 1H), 6.27 (d, J = 7.00 Hz, 1H), 7.31 (br t, J = 6.00 Hz, 1H), 7.42-7.50 (m, 3H), 7.58 (d, J = 1.00 Hz, 1H), 7.66-7.69 (m, 2H), 8.26 (dd, J = 6.44, 2.94 Hz, 1H), 8.56 (s, 2H).

[0524] The second peak (Analytical method, Chiral column: Chiralpak AS-3 50*4.6 mm I.D., 3 um, A phase: Supercritical CO2, B phase: EtOH (0.05% DEA), Gradient: 60% of B phase in supercritical CO2, Flow rate: 3 mL / min, Pressure: 100 bar, Keep CO2 in critical superfluid state, UV detection wavelength: 220 nm, Retention time: 1.388 minute) was compound 39 (13 mg, white solid), [M+H] + = 546.

[0525] 1 H NMR (400 MHz, DMSO-d6) δ 1.78 - 1.91 (m, 1H), 2.12 - 2.24 (m, 1H), 2.56 - 2.67 (m, 2H), 2.82 (br d, J=13.63 Hz, 1H), 3.11 - 3.22 (m, 2H), 3.35 - 3.36 (m, 3H), 3.45 - 3.56 (m, 2H), 3.68 (dt, J=13.16, 5.24 Hz, 1H), 5.23 (d, J=7.00 Hz, 1H), 6.28 (d, J=7.00 Hz, 1H), 7.32 (br t, J=5.88 Hz, 1H), 7.42 - 7.51 (m, 3H), 7.58 (s, 1H), 7.66 - 7.70 (m, 2H), 8.23 - 8.33 (m, 1H), 8.56 (s, 2H).

[0526] Example 40: Preparation of (7R,14R)-11-(2-((azetidin-3-ylmethyl)amino)pyrimidin-5-yl)-1- (difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanofuro[f]benzo[4,5]imidazo[1,2-a][1,4] diazepin-5(14H)-one (Compound 40)

[0527] First Step:

[0528] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (1.00 g, 4.17 mmol) in tert-butanol was added tert-butyl 3-(aminomethyl)azetidine-1-carboxylate (1.00 g, 5.42 mmol) and N,N-diisopropylethylamine (1.61 g, 12.5 mmol) and reacted at 65 °C for 12 hours, concentrated under reduced pressure, added appropriate amount of water, extracted with dichloromethane for 3 times, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain white solid tert-butyl 3-(((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)methyl)azetidine-1-carboxylate (Compound 40-1, 1.5 g) crude product.

[0529] Second Step:

[0530] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) was added compound 40-1 (130 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol) and potassium phosphate (109 mg, 0.51 mmol) sequentially, purged with nitrogen three times, reacted at 95 °C for 3 hours, cooled to room temperature, added water and dichloromethane, separated, the organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure to give 3-(((5-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14- toluene[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-11-yl)pyrimidin-2-yl)methyl)azetidin-1- yl)carbamic acid tert-butyl ester (compound 40-2, 150 mg) as a yellow oil crude.

[0531] Third step:

[0532] Compound 40-2 (150 mg, 0.24 mmol) was dissolved in dichloromethane, trifluoroacetic acid (387 mg, 1.7 mmol) was added dropwise at room temperature and stirred for 12 hours, then a few drops of triethylamine were added to adjust the pH of the system to neutral, separated by column chromatography and C18 column chromatography to give (7R,14R)-11-(2-((azetidin-3-ylmethyl)amino)pyrimidin-5-yl)-1- (difluoromethoxy)-6-methyl-6,7-dihydro-7,14-toluenefbenzo[4,5]imidazo[1,2-a][1,4]diazepin- 5(14H)-one (compound 40, 66 mg, white solid), [M+H] + = 518.

[0533] 1 H NMR (400 MHz, DMSO-d6) δ 2.40 (br s, 1H), 2.86 (s, 1H), 3.29-3.34 (m, 1H), 3.34-3.40 (m, 3H), 3.48-3.59 (m, 1H), 3.61-3.71 (m, 1H), 4.14-4.28 (m, 1H), 4.40-4.56 (m, 1H), 5.19-5.31 (m, 1H), 6.17-6.35 (m, 1H), 7.38-7.56 (m, 1H), 7.55-7.71 (m, 1H), 7.85 (s, 1H), 8.21-8.30 (m, 1H), 8.31-8.36 (m, 1H), 8.68-8.76 (m, 1H), 9.03-9.11 (m, 1H).

[0534] Example 41: Preparation of (7R,14R)-11-(2-((((R)-1-cyclopropyl-2- hydroxyethyl)amino)pyrimidin-5-yl)-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14- toluene[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (Compound 41)

[0535] First Step:

[0536] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (450 mg, 1.87 mmol) in tert-butanol was added (R)-2-amino-2-cyclopropylethan-1-ol (247 mg, 1.43 mmol) and N,N- diisopropylethylamine (725 mg, 5.61 mmol), and reacted at 65 °C for 12 hours, concentrated under reduced pressure, added appropriate amount of water, extracted with dichloromethane for 3 times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a white solid of (R)-2-cyclopropyl-2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)amino)ethan-1-ol (Compound 41-1, 0.34 g) crude product.

[0537] Second Step:

[0538] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) was added Compound 41-1 (98 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol) and potassium phosphate (109 mg, 0.51 mmol) in sequence, replaced with nitrogen for 3 times, and reacted at 95 °C for 3 hours. Concentrated under reduced pressure, separated by column chromatography and C18 column to obtain (7R,14R)-11-(2-((((R)-1-cyclopropyl-2-hydroxyethyl)amino)pyrimidin-5-yl)-1- (difluoromethoxy)-6-methyl-6,7-dihydro-7,14-toluenef]benzo[4,5]imidazo[1,2-a][1,4]diazepin- 5(14H)-one (Compound 41, 36 mg, white solid), [M+H] = 533. +

[0539] 1 ​H NMR (400 MHz, CDC13) δ 0.43 (br d, J = 4.13 Hz, 2H), 0.55-0.71 (m, 2H), 1.04 (td, J = 8.69, 4.25 Hz, 1H), 2.88 (d, J = 13.63 Hz, 1H), 3.23-3.36 (m, 1H), 3.42-3.50 (m, 1H), 3.52 (s, 3H), 3.82 (br dd, J = 10.76, 7.13 Hz, 1H), 4.01 (br d, J = 10.51 Hz, 1H), 4.39 (br d, J = 2.50 Hz, 1H), 4.97 (d, J = 7.00 Hz, 1H), 5.56 (br d, J = 5.50 Hz, 1H), 6.26 (d, J = 7.25 Hz, 1H), 6.60-7.11 (m, 1H), 7.32 (br d, J = 8.26 Hz, 2H), 7.42 (t, J = 8.19 Hz, 1H), 7.54 (s, 1H), 7.76 (d, J = 8.51 Hz, 1H), 8.47 (s, 2H), 8.50 (s, 1H).

[0540] Example 42: Preparation of (7R,14R)-11-(2-((((S)-1-cyclopropyl-2- hydroxyethyl)amino)pyrimidin-5-yl)-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14- thieno[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (Compound 42)

[0541] First Step:

[0542] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (450 mg, 1.87 mmol) in tert-butanol was added (S)-2-amino-2-cyclopropylethan-1-ol (247 mg, 1.43 mmol) and N,N- diisopropylethylamine (725 mg, 5.61 mmol) and reacted at 65 °C for 12 hours. The reaction mixture was concentrated under reduced pressure, an appropriate amount of water was added, and the mixture was extracted with dichloromethane three times. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a white solid of (S)-2-cyclopropyl-2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)amino)ethan-1-ol (Compound 42-1, 0.34 g) as a crude product.

[0543] Second Step:

[0544] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) were added compound 42-1 (98 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol) and potassium phosphate (109 mg, 0.51 mmol) successively, replaced with nitrogen for three times, reacted at 95 °C for 3 hours, concentrated under reduced pressure, separated by column chromatography and C18 column to obtain (7R,14R)-11-(2-((((S)-1-cyclopropyl-2-hydroxyethyl)amino)pyrimidin-5-yl)-1- (difluoromethoxy)-6-methyl-6,7-dihydro-7,14-tetramethylbenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazepin-5(14H)-one (compound 42, 30 mg, white solid), [M+H] + = 533.

[0545] 1 H NMR (400 MHz, CDCl3) δ 0.43 (br d, J = 4.63 Hz, 2H), 0.63 (br dd, J = 12.82, 8.19 Hz, 3H), 0.95-1.13 (m, 1H), 2.88 (d, J = 13.63 Hz, 1H), 3.22-3.37 (m, 1H), 3.48 (br dd, J = 13.76, 7.13 Hz, 1H), 3.52 (s, 3H), 3.83 (br dd, J = 7.07, 3.94 Hz, 1H), 3.96-4.05 (m, 1H), 4.40 (br dd, J = 6.50, 4.25 Hz, 1H), 4.97 (d, J = 7.13 Hz, 1H), 5.57 (br d, J = 5.63 Hz, 1H), 6.26 (d, J = 7.13 Hz, 1H), 6.58-7.12 (m, 1H), 7.29-7.36 (m, 2H), 7.42 (t, J = 8.19 Hz, 1H), 7.54 (d, J = 1.13 Hz, 1H), 7.76 (d, J = 8.38 Hz, 1H), 8.48 (s, 2H), 8.50 (br s, 1H).

[0546] Example 43: Preparation of (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-(oxetan-3- ylamino)pyrimidin-5-yl)-6,7-dihydro-7,14-tetramethylbenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazepin-5(14H)-one (compound 43)

[0547] First Step:

[0548] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (500 mg, 2.07 mmol) in tert-butanol was added oxetan-3-amine (198 mg, 2.70 mmol) and N,N- diisopropylethylamine (806 mg, 6.23 mmol) and reacted at 65 °C for 12 hours. After concentration under reduced pressure, an appropriate amount of water was added, extracted with dichloromethane three times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow solid of N-(oxetan-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (compound 43-1, 0.34 g) as a crude product.

[0549] Second Step:

[0550] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) were sequentially added compound 43-1 (89 mg, 0.32 mmol), chloro(2- dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol), and potassium phosphate (109 mg, 0.51 mmol), replaced with nitrogen three times, and reacted at 95 °C for 3 hours. After concentration under reduced pressure, column chromatography and C18 column separation were performed to obtain (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-(oxetan-3-ylamino)pyrimidin-5-yl)-6,7-dihydro-7,14- methanofuro[f]benzo[4,5]imidazo[1,2-a][1,4]oxazin-5(14H)-one (compound 43, 102 mg, white solid), [M+H] + = 505.

[0551] 1 H NMR (400 MHz, CDCl3) δ 2.89 (d, J = 13.63 Hz, 1H), 3.41-3.51 (m, 1H), 3.53 (s, 3H), 4.64 (t, J = 6.38 Hz, 2H), 4.97 (d, J = 7.13 Hz, 1H), 5.04 (t, J = 6.88 Hz, 2H), 5.15-5.25 (m, 1H), 5.88 (br d, J = 7.13 Hz, 1H), 6.28 (d, J = 7.13 Hz, 1H), 6.63-7.07 (m, 1H), 7.28-7.38 (m, 2H), 7.39-7.46 (m, 1H), 7.57 (d, J = 1.25 Hz, 1H), 7.78 (d, J = 8.50 Hz, 1H), 8.49 (dd, J = 8.25, 0.88 Hz, 1H), 8.54 (s, 2H).

[0552] Example 44: Preparation of (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-((((R)-2- oxocyclopentyl)methyl)amino)pyrimidin-5-yl)-6,7-dihydro-7,14- toluene[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one and (7R,14R)-1- (difluoromethoxy)-6-methyl-11-(2-((((S)-2-oxocyclopentyl)methyl)amino)pyrimidin- 5-yl)-6,7-dihydro-7,14-toluene[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (Compound 44 and Compound 45)

[0553] First Step:

[0554] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (400 mg, 1.67 mmol) in tert-butanol was added 2-(aminomethyl)cyclopentan-1-ol hydrochloride (250 mg, 2.17 mmol) and N,N-diisopropylethylamine (645 mg, 5.00 mmol), and reacted at 65 °C for 12 hours. After concentration under reduced pressure, an appropriate amount of water was added, and extracted with dichloromethane three times. After drying over anhydrous sodium sulfate, filtration, and concentration under reduced pressure, 2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)amino)methyl)cyclopentan-1-ol (Compound 44-1, 0.47 g) was obtained as a crude yellow solid.

[0555] Second Step:

[0556] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) was added Compound 44-1 (102 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'- biphenyl)]palladium(II) (10 mg, 0.01 mmol), and potassium phosphate (109 mg, 0.51 mmol) sequentially, and replaced with nitrogen three times. After reacting at 95 °C for 3 hours, the reaction mixture was cooled to room temperature, and water and dichloromethane were added. After drying the organic phase over anhydrous sodium sulfate, concentration under reduced pressure, and purification by column chromatography (dichloromethane / methanol, 100:0 to 90:10), (7R,14R)-1-(difluoromethoxy)-11-(2-((2- hydroxycyclopentyl)methyl)amino)pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14- toluene[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (Compound 44-2, 150 mg) was obtained as a crude yellow oil.

[0557] Third Step:

[0558] Compound 44-2 (150 mg, 0.27 mmol) was dissolved in dichloromethane, Dess-Martin Oxidizing reagent (349 mg, 0.41 mmol) was added in three portions at room temperature and stirred for 1.5 hours, then saturated aqueous sodium bicarbonate solution and saturated aqueous sodium thiosulfate solution were added, the organic phase was separated, dried and concentrated to give a crude product, which was separated by column chromatography and C18 column chromatography to give white solid (7R, 14R)-1-(difluoromethoxy)-6-methyl-11-(2-(((2-oxocyclopentyl)methyl)amino)pyrimidin-5-yl)-6,7-dihydro-7,14-methanofuro[3,2-g]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (compound 44-3, 36 mg).

[0559] Fourth step:

[0560] Compound 44-3 (36 mg) was subjected to SFC separation (preparative method, Waters 150 preparative SFC system, Chiral column: DAICEL Chiralpak AS 250*30 mm I.D., 10 um, A phase: supercritical CO2, B phase: EtOH:ACN = 7:3 (neutral), gradient: 30% of B phase in supercritical CO2, flow rate: 150 g / min, pressure: 100 bar, keep CO2 in critical superfluid state, UV detection wavelength: 220 nm), the first peak obtained (analytical method, Chiral column: Chiralpak AS-3 50*4.6 mm I.D., 3 um, A phase: supercritical CO2, B phase: ETOH:ACN = 4:1 (0.05% DEA), gradient: 20% to 60% of B phase in supercritical CO2, flow rate: 3 mL / min, pressure: 100 bar, keep CO2 in critical superfluid state, UV detection wavelength: 220 nm, retention time: 0.998 min) was compound 44 (9 mg, white solid), [M+H] + = 545.

[0561] 1H NMR (400 MHz, CDC13) δ 1.65 - 1.75 (m, 1H), 1.82 - 1.93 (m, 1H), 2.00 - 2.12 (m, 1H), 2.13 - 2.24 (m, 1H), 2.24 - 2.42 (m, 1H), 2.44 - 2.55 (m, 1H), 2.82 - 2.97 (m, 1H), 3.42 - 3.51 (m, 1H), 3.52 (s, 3H), 3.62 - 3.79 (m, 2H), 4.97 (d, J = 7.09 Hz, 1H), 5.73 (br t, J = 6.17 Hz, 1H), 6.27 (d, J = 7.21 Hz, 1H), 6.62 - 7.07 (m, 1H), 7.29 - 7.37 (m, 2H), 7.38 - 7.45 (m, 1H), 7.57 (d, J = 1.22 Hz, 1H), 7.76 (d, J = 8.44 Hz, 1H), 8.49 (d, J = 8.19 Hz, 1H), 8.52 (s, 2H).

[0562] The second peak obtained (analytical method, chiral column: Chiralpak AS-3 50*4.6 mm I.D., 3um, A phase: Supercritical CO2, B phase: ETOH:ACN = 4:1 (0.05% DEA), gradient: 20% to 60% of B phase in supercritical CO2, flow rate: 3 mL / min, pressure: 100 bar, keeping CO2 in critical superfluid state, UV detection wavelength: 220 nm, retention time: 1.132 min) was compound 45 (25 mg, white solid), [M+H] + = 545.

[0563] 1H NMR (400 MHz, CDC13) δ 1.65 - 1.77 (m, 1H), 1.78 - 1.87 (m, 1H), 2.03 - 2.09 (m, 1H), 2.18 (dt, J = 18.80, 9.37 Hz, 1H), 2.26 - 2.40 (m, 2H), 2.49 (br dd, J = 10.03, 7.70 Hz, 1H), 2.88 (d, J = 13.57 Hz, 1H), 3.41 - 3.51 (m, 1H), 3.52 (s, 3H), 3.63 - 3.78 (m, 2H), 4.97 (br d, J = 7.09 Hz, 1H), 5.80 (br t, J = 5.99 Hz, 1H), 6.27 (d, J = 7.09 Hz, 1H), 6.59 - 7.11 (m, 1H), 7.29 - 7.37 (m, 2H), 7.38 - 7.45 (m, 1H), 7.56 (d, J = 0.98 Hz, 1H), 7.76 (d, J = 8.44 Hz, 1H), 8.45 - 8.50 (m, 1H), 8.51 (s, 2H).

[0564] Example 45: Preparation of (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-(((R)-3,3,3- trifluoro-2-hydroxypropyl)amino)pyrimidin-5-yl)-6,7-dihydro-7,14-methanofuro[f]benzo[4,5] imidazo[1,2-a][1,4]diazepin-5(14H)-one and (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-(((S)-3,3,3- trifluoro-2-hydroxypropyl)amino)pyrimidin-5-yl)-6,7-dihydro-7,14-methanofuro[f]benzo[4,5] imidazo[1,2-a][1,4]diazepin-5(14H)-one (Compound 46 and Compound 47)

[0565] First Step:

[0566] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (400 mg, 1.67 mmol) in tert-butanol was added 3-amino-1,1,1-trifluoropropan-2-ol hydrochloride (280 mg, 2.17 mmol) and N,N-diisopropylethylamine (645 mg, 5.00 mmol) and reacted at 65 °C for 12 hours. After concentration under reduced pressure, an appropriate amount of water was added, and extracted with dichloromethane 3 times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1,1,1-trifluoro-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)amino)propan-2-ol (Compound 46-1, 0.45 g) as a crude product in the form of a white solid.

[0567] Second Step:

[0568] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) were added compound 46-1 (103 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol) and potassium phosphate (109 mg, 0.51 mmol) successively, replaced with nitrogen for three times, reacted at 95 °C for 3 hours, concentrated under reduced pressure, separated by column chromatography and C18 column to give (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-((3,3,3-trifluoro-2- hydroxypropyl)amino)pyrimidin-5-yl)-6,7-dihydro-7,14-methanofuro[f]benzo[4,5] imidazo[1,2-a][1,4]oxazin-5(14H)-one (compound 46-2, 35 mg) as a white solid.

[0569] Third step:

[0570] Compound 46-2 (35 mg) was subjected to SFC separation (preparative method, Waters 150 preparative SFC system, Chiral column: DAICEL Chiralcel OJ 250*30 mm I.D., 10 um, A phase: supercritical CO2, B phase: MeOH (0.1% ammonia water), gradient: 20% B phase in supercritical CO2, flow rate: 150 g / min, pressure: 100 bar, keep CO2 in critical superfluid state, UV detection wavelength: 220 nm) to give the first peak (analytical method, Chiral column: Chiralcel OJ-3 50*4.6 mm I.D., 3 um, A phase: supercritical CO2, B phase: MeOH (0.1% DEA), gradient: B phase in supercritical CO2 from 5% to 25%, flow rate: 3 mL / min, pressure: 100 bar, keep CO2 in critical superfluid state, UV detection wavelength: 220 nm, retention time: 1.923 minutes) as compound 46 (5 mg, white solid), [M+H] + = 561.

[0571] 1H NMR (400 MHz, CDC13) δ 2.89 (d, J = 13.57 Hz, 1H), 3.40 - 3.59 (m, 4H), 3.66 - 3.98 (m, 2H), 4.18 - 4.32 (m, 1H), 4.98 (d, J = 7.09 Hz, 1H), 5.71 (br t, J = 5.99 Hz, 1H), 6.27 (d, J = 7.21 Hz, 1H), 6.58 - 7.08 (m, 1H), 7.32 (dt, J = 8.31, 1.77 Hz, 2H), 7.40 - 7.47 (m, 1H), 7.55 (d, J = 1.22 Hz, 1H), 7.77 (d, J = 8.44 Hz, 1H), 8.46 - 8.59 (m, 3H).

[0572] The second peak obtained (analytical method, chiral column: Chiralcel OJ-3 50*4.6 mm I.D., 3um, A phase: supercritical CO2, B phase: MeOH (0.1% DEA), gradient: B phase from 5% to 25% in supercritical CO2, flow rate: 3 mL / min, pressure: 100 bar, keeping CO2 in the critical superfluid state, UV detection wavelength: 220 nm, retention time: 2.014 min) was compound 47 (12 mg, white solid), [M+H] + = 561.

[0573] 1 H NMR (400 MHz, CDC13) δ 2.89 (d, J = 13.57 Hz, 1H), 3.40 - 3.59 (m, 4H), 3.66 - 3.98 (m, 2H), 4.18 - 4.32 (m, 1H), 4.98 (d, J = 7.09 Hz, 1H), 5.71 (br t, J = 5.99 Hz, 1H), 6.27 (d, J = 7.21 Hz, 1H), 6.58 - 7.08 (m, 1H), 7.32 (dt, J = 8.31, 1.77 Hz, 2H), 7.40 - 7.47 (m, 1H), 7.55 (d, J = 1.22 Hz, 1H), 7.77 (d, J = 8.44 Hz, 1H), 8.46 - 8.59 (m, 3H).

[0574] Example 46: Preparation of (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-((((R)-3- methyltetrahydrofuran-3-yl)methyl)amino)pyrimidin-5-yl)-6,7-dihydro-7,14- toluene[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one and (7R,14R)-1- (difluoromethoxy)-6-methyl-11-(2-((((S)-3-methyltetrahydrofuran-3- yl)methyl)amino)pyrimidin-5-yl)-6,7-dihydro-7,14-toluene[f]benzo[4,5]imidazo[1,2- a][1,4]diazepin-5(14H)-one (Compounds 48 and 49)

[0575] First Step:

[0576] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (200 mg, 0.83 mmol) in tert-butanol was added (3-methyltetrahydrofuran-3-yl)methanamine (145 mg, 1.09 mmol) and N,N-diisopropylethylamine (430 mg, 2.50 mmol), and reacted at 65 °C for 12 h, concentrated under reduced pressure, added appropriate amount of water, extracted with dichloromethane for 3 times, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give yellow solid N-((3-methyltetrahydrofuran-3-yl)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (Compound 48-1, 0.21 g) crude.

[0577] Second Step:

[0578] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) was added Compound 48-1 (98 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'- biphenyl)]palladium(II) (10 mg, 0.01 mmol) and potassium phosphate (109 mg, 0.51 mmol) successively, replaced with nitrogen for 3 times, reacted at 95 °C for 3 h, concentrated under reduced pressure, separated by column chromatography and C18 column to give white solid (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-(((3-methyltetrahydrofuran-3- yl)methyl)amino)pyrimidin-5-yl)-6,7-dihydro-7,14-toluene[f]benzo[4,5]imidazo[1,2- a][1,4]diazepin-5(14H)-one (Compound 48-2, 70 mg).

[0579] Third Step:

[0580] Compound 48-2 (70 mg) was subjected to SFC resolution (Preparative method, Waters 150 Preparative SFC system, Chiral column: DAICEL Chiralcel OD 250 x 30 mm I.D., 10 um, A phase: Supercritical CO2, B phase: EtOH (0.1% ammonia), Gradient: 62.5% of B phase in supercritical CO2, Flow rate: 120 g / min, Pressure: 100 bar, Keep CO2 in critical superfluid state, UV detection wavelength: 220 nm) to give the first peak (Analytical method, Chiral column: Chiralcel OD-3 50 x 4.6 mm I.D., 3 um, A phase: Supercritical CO2, B phase: EtOH (0.05% DEA), Gradient: B phase from 10% to 60% in supercritical CO2, Flow rate: 3 mL / min, Pressure: 100 bar, Keep CO2 in critical superfluid state, UV detection wavelength: 220 nm, Retention time: 1.666 min) as compound 48 (25 mg, white solid), [M+H] + = 547.

[0581] 1 H NMR (400 MHz, CDC13) δ 1.21 (s, 3 H), 1.95 (dt, J = 12.23, 7.71 Hz, 1 H), 2.89 (d, J = 13.51 Hz, 1 H), 3.43 - 3.51 (m, 2 H), 3.51 - 3.60 (m, 5 H), 3.76 (d, J = 8.63 Hz, 1 H), 3.86 - 4.04 (m, 2 H), 4.97 (d, J = 7.13 Hz, 1 H), 5.41 (br t, J = 5.88 Hz, 1 H), 6.28 (d, J = 7.13 Hz, 1 H), 6.84 (t, J = 72.85 Hz, 1 H), 7.29 - 7.45 (m, 3 H), 7.57 (s, 1 H), 7.77 (d, J = 8.50 Hz, 1 H), 8.52 (s, 3 H).

[0582] The second peak (Analytical method, Chiral column: Chiralcel OD-3 50 x 4.6 mm I.D., 3 um, A phase: Supercritical CO2, B phase: EtOH (0.05% DEA), Gradient: B phase from 10% to 60% in supercritical CO2, Flow rate: 3 mL / min, Pressure: 100 bar, Keep CO2 in critical superfluid state, UV detection wavelength: 220 nm, Retention time: 2.031 min) was compound 49 (32 mg, white solid), [M+H] + = 547.

[0583] 1H NMR (400 MHz, CDC13) δ 1.21 (s, 3H), 1.92-2.02 (m, 1H), 2.89 (d, J = 13.63 Hz, 1H), 3.44-3.59 (m, 7H), 3.76 (d, J = 8.50 Hz, 1H), 3.87-4.03 (m, 2H), 4.97 (br d, J = 7.00 Hz, 1H), 5.41 (br t, J = 5.44 Hz, 1H), 6.28 (d, J = 7.00 Hz, 1H), 6.62-7.03 (m, 1H), 7.33 (br dd, J = 16.26, 8.25 Hz, 2H), 7.39-7.46 (m, 1H), 7.58 (s, 1H), 7.77 (d, J = 8.50 Hz, 1H), 8.45-8.58 (m, 3H).

[0584] Example 47: Preparation of 1-(((5-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14- toluene[f]benzo[4,5]imidazo[1,2-a][1,4]oxazepin-11-yl)pyrimidin-2-yl)amino)methyl)cyclopropane-1- carbonitrile (Compound 50)

[0585] First step:

[0586] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (350 mg, 1.45 mmol) in tert-butanol was added 1-(aminomethyl)cyclopropane-1-carbonitrile hydrochloride (250 mg, 1.89 mmol) and N,N-diisopropylethylamine (564 mg, 4.35 mmol) and reacted at 65 °C for 12 hours, concentrated under reduced pressure, added appropriate amount of water, extracted with dichloromethane for 3 times, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain white solid 1-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)amino)methyl)cyclopropane-1- carbonitrile (Compound 50-1, 0.30 g) crude product.

[0587] Second step:

[0588] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) were added compound 43-1 (49 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol) and potassium phosphate (109 mg, 0.51 mmol) successively, replaced with nitrogen for three times, reacted at 95 °C for 3 hours, concentrated under reduced pressure, separated by column chromatography and C18 column to obtain 1-(((5-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14- toluene[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-11-yl)pyrimidin-2-yl)amino)methyl)cyclopropane-1- carboxylic acid (compound 50, 12 mg, white solid), [M+H] + = 528.

[0589] 1 H NMR (400 MHz, CDCl3) δ 1.13-1.19 (m, 2H), 1.26-1.33 (m, 2H), 2.83-2.93 (m, 1H), 3.42-3.51 (m, 1H), 3.52-3.56 (m, 3H), 3.66-3.75 (m, 2H), 4.92-5.03 (m, 1H), 5.66-5.85 (m, 1H), 6.28 (d, J = 7.13 Hz, 1H), 6.59-7.12 (m, 1H), 7.28-7.37 (m, 2H), 7.39-7.45 (m, 1H), 7.58 (d, J = 1.25 Hz, 1H), 7.78 (d, J = 8.50 Hz, 1H), 8.49 (dd, J = 8.19, 1.19 Hz, 1H), 8.54 (s, 2H).

[0590] Example 48: Preparation of 1-(((5-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-toluene[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-11-yl)pyrimidin-2-yl)amino)methyl)cyclobutane-1-carboxylic acid (compound 51)

[0591] First step:

[0592] To a solution of 1-(hydroxymethyl)cyclobutane-1-carbonitrile (0.50 g, 4.50 mmol) in dichloromethane was added triethylamine (0.91 g, 9.00 mmol), N,N-diisopropylethylamine (0.24 g, 9.00 mmol), and methylsulfonyl chloride (620 mg, 5.40 mmol) sequentially under nitrogen protection. The mixture was stirred at room temperature for 1 h. The reaction was quenched by adding the mixture into water. Dichloromethane was added. The organic phase was collected and concentrated under reduced pressure to give methyl 1-(cyanocyclobutyl)methyl sulfonate (compound 51-1, 0.7 g) as a crude product.

[0593] Second Step:

[0594] To a solution of compound 51-1 (0.35 g, 1.85 mmol) in acetonitrile was added sodium azide (210 mg, 3.23 mmol) under nitrogen protection. The mixture was heated to 115 °C and stirred for 12 h. The mixture was then cooled to room temperature. The mixture was filtered. The filtrate was diluted with 2-methyltetrahydrofuran to 2 mL to give a solution of 1-(azidomethyl)cyclobutane-1-carbonitrile (compound 51-2). The solution was used directly in the next step.

[0595] Third Step:

[0596] Compound 51-2 (252 mg, 2 mL of 2-methyltetrahydrofuran solution) was placed in a reaction flask under nitrogen protection. Palladium on carbon (25 mg, 10%) was added. The mixture was purged with nitrogen for 3 times and hydrogen for 3 times. The mixture was stirred at room temperature for 12 h. The mixture was filtered. The filter cake was washed with 2-methyltetrahydrofuran. The filtrate was collected and concentrated to give 1-(aminomethyl)cyclobutane-1-carbonitrile (compound 51-3, 200 mg) as a crude product in yellow oil.

[0597] Fourth Step:

[0598] To a solution of compound 51-3 (200 mg, 1.82 mmol) in tert-butanol was added 5-bromo-2-chloropyrimidine (264 mg, 1.36 mmol) and N,N-diisopropylethylamine (235 mg, 5.46 mmol) under nitrogen protection. The mixture was stirred at 65 °C for 12 h. The mixture was concentrated under reduced pressure. Water was added. The mixture was extracted with dichloromethane for 3 times. The mixture was dried over anhydrous sodium sulfate. The mixture was filtered. The crude product was concentrated under reduced pressure. The crude product was separated by a C18 column to give 1-(((5-bromopyrimidin-2-yl)amino)methyl)cyclobutane-1-carbonitrile (compound 51-4, 44 mg) as a white solid.

[0599] Fifth Step:

[0600] To a solution of compound 51-4 (44 mg, 0.17 mmol) in N,N-dimethylformamide / water (5:1) were added compound 36-1 (49 mg, 0.13 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol) and potassium phosphate (56 mg, 0.26 mmol) successively, replaced with nitrogen for three times, reacted at 95 °C for 3 hours, concentrated under reduced pressure, separated by column chromatography and C18 column to obtain 1-(((5-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14- toluene[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-11-yl)pyrimidin-2-yl)amino)methyl)cyclobutane-1- carbonitrile (compound 51, 13 mg, white solid), [M+H] + = 542.

[0601] 1 H NMR (400 MHz, CDCl3) δ 2.19 (ddd, J = 9.08, 6.08, 2.81 Hz, 2H), 2.26-2.34 (m, 2H), 2.47-2.65 (m, 2H), 2.90 (d, J = 13.69 Hz, 1H), 3.44-3.52 (m, 1H), 3.54 (s, 3H), 3.95 (d, J = 6.60 Hz, 2H), 4.99 (d, J = 6.97 Hz, 1H), 5.54 (br s, 1H), 6.29 (d, J = 7.21 Hz, 1H), 6.62-7.09 (m, 1H), 7.30-7.39 (m, 2H), 7.40-7.47 (m, 1H), 7.59 (d, J = 1.10 Hz, 1H), 7.79 (d, J = 8.56 Hz, 1H), 8.50 (d, J = 8.19 Hz, 1H), 8.55 (s, 2H).

[0602] Example 49: Preparation of (7R,14R)-11-(2-(((S)-1-cyclopropyl-2-methoxyethyl)amino)pyrimidin-5-yl)-1- (difluoromethoxy)-6-methyl-6,7-dihydro-7,14-toluenefbenzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (compound 52)

[0603] First step:

[0604] To a solution of (S)-2-amino-2-cyclopropylethanol hydrochloride (1.00 g, 7.30 mmol) in tetrahydrofuran was added di-tert-butyl dicarbonate (1.75 g, 8.03 mmol), sodium bicarbonate (1.75 g, 18.2 mmol) and water (5 mL), and stirred at 25 °C for 12 hours. Ethyl acetate (50 mL) was added, the organic phase was separated, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (S)-(1-cyclopropyl-2-hydroxyethyl)carbamic acid tert-butyl ester (compound 52-1, 1.50 g) as a yellow oil.

[0605] Second Step:

[0606] To a reaction flask was added dichloromethane (15 mL), and then compound 52-1 (1.50 g, 0.75 mmol), followed by trimethyl oxonium tetrafluoroborate (1.65 g, 1.12 mmol), 4A molecular sieves (1.50 g) and 1,8-bisdimethylamino (6.4 g, 3.00 mmol). The system was stirred at 15-25 °C for 4 hours. The reaction solution was filtered, water (30 mL) was added, the liquid was separated, and the organic phase was concentrated to give a crude product. The crude product was separated by column chromatography to give (S)-(1-cyclopropyl-2-methoxyethyl)carbamic acid tert-butyl ester (compound 52-2, 1.6 g) as a yellow oil.

[0607] Third Step:

[0608] Compound 52-2 (1.6 g, 7.44 mmol) was dissolved in 4M hydrogen chloride-1,4-dioxane solution, and stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure to give (S)-1-cyclopropyl-2-methoxyethan-1-amine hydrochloride (compound 52-3, 1.4 g) as a crude product.

[0609] Fourth Step:

[0610] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (1.40 g, 5.81 mmol) in tert-butyl alcohol was added compound 52-3 (1.35 g, 8.72 mmol) and N,N-diisopropylethylamine (4.50 g, 34.9 mmol), and stirred at 65 °C for 12 hours. The solution was concentrated under reduced pressure, an appropriate amount of water was added, and dichloromethane was added three times. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (S)-N-(1-cyclopropyl-2-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (compound 52-4, 1.6 g) as a crude product.

[0611] Fifth Step:

[0612] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) were added compound 52-4 (99 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol) and potassium phosphate (109 mg, 0.51 mmol) successively, replaced with nitrogen for three times, reacted at 95 °C for 3 hours, concentrated under reduced pressure, separated by column chromatography and C18 column to obtain (7R,14R)-11-(2-(((S)-1-cyclopropyl-2-methoxyethyl)amino)pyrimidin-5-yl)-1- (difluoromethoxy)-6-methyl-6,7-dihydro-7,14-tetramethylbenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazepin-5(14H)-one (compound 52, 54 mg, white solid), [M+H] + = 547.

[0613] 1 H NMR (400 MHz, CDCl3) δ 0.22-0.41 (m, 1H), 0.45-0.58 (m, 3H), 1.04-1.19 (m, 1H), 2.88 (d, J = 13.26 Hz, 1H), 3.41 (d, J = 1.50 Hz, 3H), 3.44-3.49 (m, 1H), 3.53 (d, J = 1.25 Hz, 3H), 3.59-3.63 (m, 2H), 3.66-3.71 (m, 1H), 4.97 (br d, J = 7.25 Hz, 1H), 5.48 (br d, J = 8.63 Hz, 1H), 6.27 (d, J = 6.75 Hz, 1H), 6.57-7.06 (m, 1H), 7.33 (br dd, J = 12.01, 8.38 Hz, 2H), 7.42 (td, J = 8.19, 1.38 Hz, 1H), 7.52-7.63 (m, 1H), 7.71-7.84 (m, 1H), 8.47-8.56 (m, 3H).

[0614] Example 50: Preparation of (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-(((R)-3,3,3- trifluoro-2-methoxypropyl)amino)pyrimidin-5-yl)-6,7-dihydro-7,14- toluene[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one and (7R,14R)-1- (difluoromethoxy)-6-methyl-11-(2-(((S)-3,3,3-trifluoro-2-methoxypropyl)amino)pyrimidin- 5-yl)-6,7-dihydro-7,14-toluene[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (Compound 53 and Compound 54)

[0615] First Step:

[0616] To a solution of 3-amino-1,1,1-trifluoropropan-2-ol (5.00 g, 38.76 mmol) in methanol was added di-tert-butyl dicarbonate (8.03 g, 36.82 mmol) and stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give tert-butyl (3,3,3-trifluoro-2-hydroxypropyl)carbamate (Compound 53-1, 8.80 g) as a white solid.

[0617] Second Step:

[0618] To a reaction flask was added dichloromethane (15 mL), then Compound 53-1 (2.00 g, 8.73 mmol), followed by trimethylsulfoxonium tetrafluoroborate (1.93 g, 13.1 mmol), 4A molecular sieves (2.00 g) and 1,8-bisdimethylamino (5.61 g, 26.2 mmol). The reaction mixture was stirred at 15-25 °C for 3 h. The reaction mixture was filtered, water (30 mL) was added, the organic phase was separated and concentrated to give a crude product. The crude product was separated by column chromatography to give tert-butyl (3,3,3-trifluoro-2-methoxypropyl)carbamate (Compound 53-2, 1.3 g) as a yellow oil.

[0619] Third Step:

[0620] Compound 53-2 (1.3 g, 5.35 mmol) was dissolved in 4 M hydrogen chloride-1,4-dioxane solution and stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give 3,3,3-trifluoro-2-methoxypropan-1-amine hydrochloride (Compound 53-3, 1.1 g) as a crude product.

[0621] Fourth Step:

[0622] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (1.20 g, 5.00 mmol) in tert-butyl alcohol was added compound 53-3 (1.10 g, 6.50 mmol) and N,N-diisopropylethylamine (3.20 g, 25.0 mmol), and reacted at 65°C for 12 hours. After concentration under reduced pressure, an appropriate amount of water was added, and extracted with dichloromethane three times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow solid of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(3,3,3-trifluoro-2-methoxypropyl)pyrimidin-2-amine (compound 53-4, 1.5 g) as a crude product.

[0623] Fifth step:

[0624] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) was sequentially added compound 53-4 (107 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol), and potassium phosphate (109 mg, 0.51 mmol), and replaced with nitrogen three times, and reacted at 95°C for 3 hours. After concentration under reduced pressure, column chromatography and C18 column separation were performed to obtain a white solid of (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-((3,3,3-trifluoro-2-methoxypropyl)amino)pyrimidin-5-yl)-6,7-dihydro-7,14-methylenzol[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (compound 53-5, 40 mg).

[0625] Sixth step:

[0626] Compound 53-5 (40 mg) was subjected to SFC resolution (Preparative method, Waters 80Q preparative SFC system, Chiral column: DAICEL Chiralpak AD 250*30 mm I.D., 10 um, A phase: Supercritical CO2, B phase: IPA (0.1% ammonia water), Gradient: 40% of B phase in supercritical CO2, Flow rate: 70 g / min, Pressure: 100 bar, Keep CO2 in critical superfluid state, UV detection wavelength: 220 nm) to give the first peak (Analytical method, Chiral column: Chiralpak AD-3 50*4.6 mm I.D., 3 um, A phase: Supercritical CO2, B phase: IPA (0.05% DEA), Gradient: B phase in supercritical CO2 from 20% to 60%, Flow rate: 3 mL / min, Pressure: 100 bar, Keep CO2 in critical superfluid state, UV detection wavelength: 220 nm, Retention time: 1.158 min) as compound 53 (12 mg, white solid), [M+H] + = 575.

[0627] 1 H NMR (400 MHz, CDC13) δ 2.89 (d, J = 13.57 Hz, 1H), 3.43 - 3.56 (m, 5H), 3.62 (s, 3H), 3.85 (ddd, J = 8.28, 6.33, 3.85 Hz, 1H), 4.06 (ddd, J = 14.15, 7.67, 3.85 Hz, 1H), 4.98 (d, J = 7.09 Hz, 1H), 5.53 (br dd, J = 7.21, 5.38 Hz, 1H), 6.28 (d, J = 7.21 Hz, 1H), 6.59 - 7.06 (m, 1H), 7.29 - 7.39 (m, 2H), 7.40 - 7.49 (m, 1H), 7.59 (d, J = 1.22 Hz, 1H), 7.78 (d, J = 8.44 Hz, 1H), 8.41 - 8.61 (m, 3H).

[0628] The second peak (Analytical method, Chiral column: Chiralpak AD-3 50*4.6 mm I.D., 3 um, A phase: Supercritical CO2, B phase: IPA (0.05% DEA), Gradient: B phase in supercritical CO2 from 20% to 60%, Flow rate: 3 mL / min, Pressure: 100 bar, Keep CO2 in critical superfluid state, UV detection wavelength: 220 nm, Retention time: 1.288 min) was compound 54 (13 mg, white solid), [M+H] + = 575.

[0629] 1H NMR (400 MHz, CDC13) δ 2.89 (d, J = 13.57 Hz, 1H), 3.45 - 3.56 (m, 5H), 3.62 (s, 3H), 3.79 - 3.90 (m, 1H), 4.05 (ddd, J = 14.21, 7.67, 3.91 Hz, 1H), 4.98 (d, J = 7.09 Hz, 1H), 5.52 (br dd, J = 7.15, 5.32 Hz, 1H), 6.28 (d, J = 7.21 Hz, 1H), 6.61 - 7.07 (m, 1H), 7.29 - 7.38 (m, 2H), 7.40 - 7.48 (m, 1H), 7.59 (d, J = 1.34 Hz, 1H), 7.78 (d, J = 8.56 Hz, 1H), 8.47 - 8.60 (m, 3H).

[0630] Example 51: Preparation of (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-((5- oxopyrrolidin-3-yl)amino)pyrimidin-5-yl)-6,7-dihydro-7,14-methanofuro[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (Compound 55)

[0631] First Step:

[0632] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (0.50 g, 2.08 mmol) in tert-butanol was added 4-aminopyrrolidin-2-one hydrochloride (0.37 g, 2.71 mmol) and N,N-diisopropylethylamine (0.80 g, 6.25 mmol) and reacted at 65 °C for 24 hours, concentrated under reduced pressure, added appropriate amount of water, extracted with dichloromethane 3 times, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain white solid 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)amino)pyrrolidin-2-one (Compound 55-1, 109 mg) crude.

[0633] Second Step:

[0634] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) were added compound 55-1 (105 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol) and potassium phosphate (109 mg, 0.51 mmol) successively, replaced with nitrogen for three times, reacted at 95 °C for 3 hours, concentrated under reduced pressure, separated by column chromatography and C18 column to obtain (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-((5-oxopyrrolidin-3-yl)amino)pyrimidin-5-yl)-6,7-dihydro-7,14- methanofuro[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (compound 55, 82 mg, white solid), [M+H] + = 532.

[0635] 1 H NMR (400 MHz, CDCl3) δ 2.30 (dd, J = 17.18, 5.20 Hz, 1H), 2.72-2.85 (m, 2H), 3.28-3.35 (m, 1H), 3.36-3.44 (m, 1H), 3.45-3.48 (m, 3H), 3.78-3.85 (m, 1H), 4.70-4.81 (m, 1H), 4.88-4.94 (m, 1H), 5.53 (br d, J = 6.97 Hz, 1H), 5.63-5.70 (m, 1H), 6.16-6.26 (m, 1H), 6.56-6.99 (m, 1H), 7.21-7.31 (m, 2H), 7.32-7.39 (m, 1H), 7.49-7.53 (m, 1H), 7.67-7.75 (m, 1H), 8.40-8.45 (m, 1H), 8.46-8.50 (m, 2H).

[0636] Example 52: Preparation of (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-(2-oxopyrrolidin-3-yl)amino)pyrimidin-5-yl)-6,7-dihydro-7,14-methanofuro[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (compound 56)

[0637] First step:

[0638] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (0.50 g, 2.08 mmol) in tert-butanol was added 3-amino pyrrolidin-2-one hydrochloride (0.37 g, 2.71 mmol) and N,N-diisopropyl ethyl amine (0.80 g, 6.25 mmol) and reacted at 65 °C for 24 h, concentrated under reduced pressure, added appropriate amount of water, extracted with dichloromethane 3 times, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)amino)pyrrolidin-2-one (compound 56-1, 0.4 g) as a crude white solid.

[0639] Second step:

[0640] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) was added compound 56-1 (105 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol) and potassium phosphate (109 mg, 0.51 mmol) sequentially, replaced with nitrogen three times, reacted at 95 °C for 3 h, concentrated under reduced pressure, separated by column chromatography and C18 column to obtain (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-(2-oxopyrrolidin-3-yl)amino)pyrimidin-5-yl)-6,7-dihydro-7,14- thieno[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (compound 56, 82 mg, white solid), [M+H] + = 532.

[0641] 1 H NMR (400 MHz, CDCl3) δ 0.71-0.88 (m, 1H), 1.90-2.11 (m, 1H), 2.72-2.89 (m, 2H), 3.34-3.40 (m, 2H), 3.45 (s, 3H), 4.49-4.64 (m, 1H), 4.90 (d, J = 7.09 Hz, 1H), 5.81 (br d, J = 5.87 Hz, 1H), 6.10 (br s, 1H), 6.19 (d, J = 7.09 Hz, 1H), 6.56-7.00 (m, 1H), 7.26 (br dd, J = 16.63, 8.31 Hz, 2H), 7.31-7.38 (m, 1H), 7.48 (s, 1H), 7.70 (d, J = 8.44 Hz, 1H), 8.42 (d, J = 8.07 Hz, 1H), 8.47 (s, 2H).

[0642] Example 53: Preparation of (R)-2-cyclopropyl-2-((5-((7R,14R)-1-(difluoromethoxy)-6- methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanofuro[f]benzo[4,5]imidazo[1,2-a][1,4] diazepin-11-yl)pyrimidin-2-yl)amino)acetamide and (S)-2-cyclopropyl-2-((5-((7R,14R)- 1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanofuro[f]benzo[4,5] imidazo[1,2-a][1,4]diazepin-11-yl)pyrimidin-2-yl)amino)acetamide (Compound 57 and Compound 58)

[0643] First Step:

[0644] To a solution of sodium cyanide (7.17 g, 142.8 mmol) in methanol was added ammonia water (17.3 mL, 128.6 mmol, 28%), water (40 mL) and cyclopropanecarboxaldehyde (10.0 g, 142.8 mmol) under nitrogen protection, followed by the addition of methanol (30 mL), dichloromethane (30 mL) and ammonium chloride (7.64 g, 142.8 mmol), and the mixture was stirred at 25 °C for 12 hours. Dichloromethane was added, the mixture was separated, and the organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in methyl tert-butyl ether, and 2M hydrochloric acid in 1,4-dioxane was added dropwise slowly. A solid was precipitated, and the mixture was stirred at room temperature for 0.5 hours. The solid was collected by filtration, and the filter cake was washed with methyl tert-butyl ether. The filter cake was collected and concentrated to obtain 2-amino-2-cyclopropylacetonitrile hydrochloride (Compound 57-1, 6.00 g) as a crude product.

[0645] Second Step:

[0646] To a solution of Compound 57-1 (3.00 g, 22.73 mmol) in dichloromethane was added di-tert-butyl dicarbonate (5.95 g, 27.27 mmol) and triethylamine (4.60 g, 45.46 mmol) under nitrogen protection, and the mixture was stirred at 25 °C for 12 hours. Water was added, the mixture was separated, and the organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography to obtain tert-butyl (cyano(cyclopropyl)methyl)carbamate (Compound 57-2, 4.40 g).

[0647] Third Step:

[0648] Dimethyl sulfoxide (20 mL) was added into a reaction flask under nitrogen protection, compound 57-2 (4.40 g, 22.45 mmol) was added into the reaction flask, followed by addition of potassium carbonate (3.10 g, 22.45 mmol) and hydrogen peroxide (6.37 g, 56.12 mmol), the system was stirred at 15-25 °C for 1 h. The reaction solution was poured into water (80 mL), a solid was precipitated, filtration was performed, the filter cake was collected, and the filter cake was concentrated to obtain (2-amino-1-cyclopropyl-2-oxoethyl) carbamic acid tert-butyl ester (compound 57-3, 3.5 g) as a crude product.

[0649] Fourth step:

[0650] Compound 57-3 (3.50 g, 16.35 mmol) was dissolved with 4 M hydrogen chloride-1,4-dioxane solution, and stirred at room temperature for 12 h, and concentrated under reduced pressure to obtain 2-amino-2-cyclopropylacetamide hydrochloride (compound 57-4, 2.7 g) as a crude product of white solid.

[0651] Fifth step:

[0652] To a solution of 5-bromo-2-chloropyrimidine (2.90 g, 15.10 mmol) in tert-butyl alcohol was added compound 57-4 (2.70 g, 18.12 mmol) and N,N-diisopropylethylamine (11.6 g, 90.62 mmol), and the mixture was reacted at 65 °C for 12 h, concentrated under reduced pressure, and then ethyl acetate (20 mL) and water (20 mL) were added, stirred, a solid was precipitated, filtration was performed, the filter cake was collected, and the filter cake was concentrated to obtain 2-((5-bromopyrimidin-2-yl)amino)-2-cyclopropylacetamide (compound 57-5, 0.4 g) as a crude product of white solid.

[0653] Sixth step:

[0654] To a solution of compound 57-5 (300 mg, 1.11 mmol) in N,N-dimethylformamide / water (5:1) were added compound 36-1 (600 mg, 1.23 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (98 mg, 0.10 mmol) and potassium phosphate (530 mg, 2.47 mmol) in sequence, the system was replaced with nitrogen for three times, and the mixture was reacted at 95 °C for 3 h, concentrated under reduced pressure, separated by column chromatography and C18 column to obtain 2-cyclopropyl-2-((5-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14- toluene [f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-11-yl)pyrimidin-2-yl)amino)acetamide (compound 57-6, 120 mg) as a white solid.

[0655] Seventh step:

[0656] Compound 57-6 (120 mg) was subjected to SFC resolution (Preparative method, Waters 150 preparative SFC system, Chiral column: DAICEL Chiralpak IH 250*30 mm I.D., 10 um, A phase: Supercritical CO2, B phase: EtOH (0.1% ammonia water), Gradient: 75% of B phase in supercritical CO2, Flow rate: 100 g / min, Pressure: 100 bar, Keep CO2 in critical superfluid state, UV detection wavelength: 220 nm) to give the first peak (Analytical method, Chiral column: Chiralpak IH-3 50*4.6 mm I.D., 3 um, A phase: Supercritical CO2, B phase: EtOH (0.05% DEA), Gradient: B phase in supercritical CO2 from 20% to 60%, Flow rate: 3 mL / min, Pressure: 100 bar, Keep CO2 in critical superfluid state, UV detection wavelength: 220 nm, Retention time: 1.654 min) as compound 57 (35 mg, white solid), [M+H] + = 546.

[0657] 1 H NMR (400 MHz, CDC13) δ 0.48 - 0.78 (m, 4 H), 1.26 - 1.32 (m, 1 H), 2.89 (d, J = 13.57 Hz, 1 H), 3.41 - 3.60 (m, 4 H), 3.80 (dd, J = 9.11, 5.69 Hz, 1 H), 4.97 (d, J = 7.09 Hz, 1 H), 5.42 (br d, J = 0.98 Hz, 1 H), 5.76 (br s, 1 H), 6.27 (d, J = 7.21 Hz, 2 H), 6.56 - 7.10 (m, 1 H), 7.30 - 7.35 (m, 2 H), 7.39 - 7.47 (m, 1 H), 7.57 (s, 1 H), 7.78 (d, J = 8.44 Hz, 1 H), 8.39 - 8.64 (m, 3 H).

[0658] The second peak (Analytical method, Chiral column: Chiralpak IH-3 50*4.6 mm I.D., 3 um, A phase: Supercritical CO2, B phase: EtOH (0.05% DEA), Gradient: B phase in supercritical CO2 from 20% to 60%, Flow rate: 3 mL / min, Pressure: 100 bar, Keep CO2 in critical superfluid state, UV detection wavelength: 220 nm, Retention time: 2.251 min) was compound 58 (38 mg, white solid), [M+H] + = 546.

[0659] 1 H NMR (400 MHz, CDC13) δ 0.43 - 0.85 (m, 4 H), 1.27 - 1.39 (m, 1 H), 2.02 (s, 1 H), 2.89 (d, J = 13.57 Hz, 1 H), 3.39 - 3.60 (m, 4 H), 3.80 (dd, J = 9.05, 5.75 Hz, 1 H), 4.98 (d, J = 7.09 Hz, 1 H), 5.39 (br s, 1 H), 5.76 (d, J = 5.75 Hz, 1 H), 6.16 - 6.40 (m, 2 H), 6.57 - 7.08 (m, 1 H), 7.30 - 7.37 (m, 2 H), 7.39 - 7.47 (m, 1 H), 7.57 (d, J = 1.22 Hz, 1 H), 7.78 (d, J = 8.44 Hz, 1 H), 8.39 - 8.65 (m, 3 H).

[0660] Example 54: Preparation of (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-((((S)-5- oxopyrrolidin-2-yl)methyl)amino)pyrimidin-5-yl)-6,7-dihydro-7,14-methanofuro[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (Compound 59)

[0661] First Step:

[0662] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (250 mg, 1.04 mmol) in tert-butanol was added (S)-5-(aminomethyl)pyrrolidin-2-one (204 mg, 1.35 mmol) and N,N-diisopropylethylamine (403 mg, 3.12 mmol) and reacted at 65 °C for 7 hours. After cooling to room temperature, a large amount of solid was precipitated, which was filtered, the filter cake was washed with water, the filter cake was collected and dried to give (S)-5-(((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)amino)methyl)pyrrolidin-2-one (Compound 59-1, 0.30 g) as a white solid.

[0663] Second Step:

[0664] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) were added compound 59-1 (108 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol) and potassium phosphate (109 mg, 0.51 mmol) successively, replaced with nitrogen for three times, reacted at 95 °C for 3 hours, concentrated under reduced pressure, separated by column chromatography and C18 column to obtain ((7R,14R)-1-(difluoromethoxy)-6-methyl-11-(2-((((S)-5-oxopyrrolidin-2-yl)methyl)amino)pyrimidin-5-yl)-6,7-dihydro-7,14- methanofuro[3,2-b]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (compound 59, 112 mg, white solid), [M+H] + = 546.

[0665] 1 H NMR (400 MHz, CDCl3) δ 1.76-1.89 (m, 1H), 2.17-2.28 (m, 1H), 2.29-2.36 (m, 2H), 2.80 (d, J = 13.45 Hz, 1H), 3.35-3.43 (m, 2H), 3.45 (s, 3H), 3.56-3.65 (m, 1H), 3.93 (br dd, J = 6.72, 4.40 Hz, 1H), 4.89 (d, J = 7.09 Hz, 1H), 5.65 (t, J = 6.24 Hz, 1H), 6.18 (d, J = 7.21 Hz, 1H), 6.39 (s, 1H), 6.51-7.01 (m, 1H), 7.21-7.27 (m, 2H), 7.30-7.38 (m, 1H), 7.47 (d, J = 1.34 Hz, 1H), 7.69 (d, J = 8.44 Hz, 1H), 8.41 (s, 1H), 8.43 (s, 2H).

[0666] Example 55: Preparation of (7R,14R)-11-(2-(((3,3-difluoro-1-hydroxycyclobutyl)methyl)amino)pyrimidin-5-yl)-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14- methanofuro[3,2-b]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (compound 60)

[0667] First step:

[0668] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (270 mg, 1.12 mmol) in tert-butanol was added 1-(aminomethyl)-3,3-difluorocyclobutan-1-ol (253 mg, 1.46 mmol) and N,N-diisopropylethylamine (435 mg, 3.38 mmol) and reacted at 65 °C for 12 hours, after cooling to room temperature, dichloromethane (10 mL) and water (30 mL) were added, the organic phase was separated, the organic phase was washed with water and concentrated to obtain 3,3-difluoro-1-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)amino)methyl)cycloban-1-ol (compound 60-1, 0.35 g) as a crude product.

[0669] Second step:

[0670] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) was added compound 60-1 (109 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol) and potassium phosphate (109 mg, 0.51 mmol) sequentially, replaced with nitrogen three times, reacted at 95 °C for 3 hours, concentrated under reduced pressure, separated by column chromatography and C18 column to obtain (7R,14R)-11-(2-(((3,3-difluoro-1-hydroxycyclobutyl)methyl)amino)pyrimidin-5-yl)-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14- thieno[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (compound 60, 80 mg, white solid), [M+H] + = 569.

[0671] 1 H NMR (400 MHz, CDCl3) δ 2.63-2.86 (m, 4H), 2.90 (d, J = 13.57 Hz, 1H), 3.44-3.53 (m, 1H), 3.54 (s, 3H), 3.73 (d, J = 5.87 Hz, 2H), 4.99 (d, J = 7.09 Hz, 1H), 5.98 (t, J = 5.87 Hz, 1H), 6.29 (d, J = 7.21 Hz, 1H), 6.47 (s, 1H), 6.64-7.12 (m, 1H), 7.30-7.38 (m, 2H), 7.40-7.50 (m, 1H), 7.57 (d, J = 1.34 Hz, 1H), 7.79 (d, J = 8.44 Hz, 1H), 8.50 (d, J = 1.10 Hz, 1H), 8.52 (s, 2H).

[0672] Example 56: Preparation of (7R, 14R)-1-(difluoromethoxy)-11-(2-((((S)-3- hydroxytetrahydrofuran-3-yl)methyl)amino)pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14- toluene[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one and (7R, 14R)-1- (difluoromethoxy)-11-(2-((((R)-3-hydroxytetrahydrofuran-3-yl)methyl)amino)pyrimidin- 5-yl)-6-methyl-6,7-dihydro-7,14-toluene[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)- one (Compound 61 and Compound 62)

[0673] First step:

[0674] Under nitrogen protection, to a solution of dihydrofuran-3(2H)-one (6.00 g, 69.77 mmol) in tetrahydrofuran was added trimethylsilyl cyanide (9.84 g, 97.67 mmol) and boron trifluoride etherate solution (10.38 g, 69.77 mmol) under ice bath, and the reaction was carried out at 25 °C for 12 hours. The reaction solution was poured into saturated aqueous sodium bicarbonate solution (100 mL), and ethyl acetate (100 mL) was added. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography to obtain (3-hydroxytetrahydrofuran-3-carbonitrile (Compound 61-1, 2.60 g) as yellow oil.

[0675] Second step:

[0676] Under nitrogen protection, to a solution of Compound 61-1 (2.60 g, 23.00 mmol) in tetrahydrofuran was added lithium aluminum hydride (11 mL, 27.61 mmol) under ice bath. The system was stirred at 0-10 °C for 1 hour. Water (1.5 mL), 15% aqueous sodium hydroxide solution (1.5 mL) and water (4.5 mL) were slowly added. The system was stirred at room temperature for 1 hour. The system was filtered through diatomite. The filter cake was dried with anhydrous sodium sulfate and concentrated to obtain 3-(aminomethyl)tetrahydrofuran-3-ol (Compound 61-2, 1.0 g) as yellow oil.

[0677] Third step:

[0678] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (1.75 g, 7.29 mmol) in tert-butanol was added compound 61-2 (1.00 g, 8.75 mmol) and N,N-diisopropylethylamine (3.76 g, 29.17 mmol) and reacted at 65 °C for 12 hours, after cooling to room temperature, dichloromethane (10 mL) and water (30 mL) were added, the organic phase was separated, the organic phase was washed with water and concentrated to obtain a yellow solid, 3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)amino)methyl)tetrahydrofuran-3-ol (compound 61-3, 0.75 g) as a crude product.

[0679] Fourth step:

[0680] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) was added compound 61-3 (107 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol) and potassium phosphate (109 mg, 0.51 mmol) sequentially, replaced with nitrogen three times, reacted at 95 °C for 3 hours, concentrated under reduced pressure, separated by column chromatography and C18 column to obtain a white solid, (7R,14R)-1-(difluoromethoxy)-11-(2-((3-hydroxytetrahydrofuran-3-yl)methyl)amino)pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14- toluene [f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (compound 61-4, 140 mg).

[0681] Fifth step:

[0682] Compound 61-4 (140 mg) was subjected to SFC resolution (Preparative method, Waters 80Q preparative SFC system, Chiral column: DAICEL Chiralpak AD 250*30 mm I.D., 10 um, A phase: Supercritical CO2, B phase: IPA (0.1% ammonia water), Gradient: 50% of B phase in supercritical CO2, Flow rate: 70 g / min, Pressure: 100 bar, Keep CO2 in critical superfluid state, UV detection wavelength: 220 nm) to give the first peak (Analytical method, Chiral column: Chiralpak AD-3 50*4.6 mm I.D., 3 um, A phase: Supercritical CO2, B phase: IPA (0.05% DEA), Gradient: B phase in supercritical CO2 from 20% to 60%, Flow rate: 3 mL / min, Pressure: 100 bar, Keep CO2 in critical superfluid state, UV detection wavelength: 220 nm, Retention time: 1.660 min) as compound 61 (60 mg, white solid), [M+H] + = 549.

[0683] 1 H NMR (400 MHz, CDC13) δ 2.02 - 2.14 (m, 2H), 2.89 (d, J=13.57 Hz, 1H), 3.42 - 3.57 (m, 4H), 3.66 - 3.76 (m, 3H), 3.84 (d, J=9.29 Hz, 1H), 3.91 - 4.10 (m, 2H), 4.98 (br d, J=7.09 Hz, 1H), 5.81 (br s, 1H), 6.28 (d, J=7.09 Hz, 1H), 6.62 - 7.10 (m, 1H), 7.30 - 7.37 (m, 2H), 7.39 - 7.48 (m, 1H), 7.57 (s, 1H), 7.78 (d, J=8.44 Hz, 1H), 8.42 - 8.60 (m, 3H).

[0684] The second peak (Analytical method, Chiral column: Chiralpak AD-3 50*4.6 mm I.D., 3 um, A phase: Supercritical CO2, B phase: IPA (0.05% DEA), Gradient: B phase in supercritical CO2 from 20% to 60%, Flow rate: 3 mL / min, Pressure: 100 bar, Keep CO2 in critical superfluid state, UV detection wavelength: 220 nm, Retention time: 1.853 min) was obtained as compound 62 (58 mg, white solid), [M+H] + = 549.

[0685] 1H NMR (400 MHz, CDC13) δ 2.01 - 2.13 (m, 2H), 2.89 (br d, J = 13.45 Hz, 1H), 3.43 - 3.55 (m, 4H), 3.68 - 3.75 (m, 3H), 3.84 (d, J = 9.29 Hz, 1H), 3.93 - 4.10 (m, 2H), 4.98 (br d, J = 5.87 Hz, 1H), 5.81 (br s, 1H), 6.28 (br d, J = 6.72 Hz, 1H), 6.64 - 7.08 (m, 1H), 7.33 (br t, J = 8.74 Hz, 2H), 7.39 - 7.46 (m, 1H), 7.57 (s, 1H), 7.79 (br d, J = 8.31 Hz, 1H), 8.45 - 8.58 (m, 3H).

[0686] Example 57: Preparation of (7R,14R)-11-(2-(((R)-3,3-difluoro-2- hydroxypropyl)amino)pyrimidin-5-yl)-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14- toluene[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one and (7R,14R)-11-(2-(((S)-3,3- difluoro-2-hydroxypropyl)amino)pyrimidin-5-yl)-1-(difluoromethoxy)-6-methyl-6,7- dihydro-7,14-toluene[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (Compound 63 and Compound 64)

[0687] First Step:

[0688] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (0.31 g, 1.29 mmol) in tert-butanol was added 3-amino-1,1-difluoropropan-2-ol (247 mg, 2.22 mmol) and N,N- diisopropylethylamine (0.50 g, 3.87 mmol) and reacted at 65 °C for 12 hours, after cooling to room temperature, dichloromethane (10 mL) and water (30 mL) were added, the organic phase was separated, the organic phase was washed with water and concentrated to give 1,1-difluoro-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)amino)propan-2-ol (Compound 63-1, 0.22 g) as a crude white solid.

[0689] Second Step:

[0690] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) were added compound 63-1 (110 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol) and potassium phosphate (109 mg, 0.51 mmol) successively, replaced with nitrogen for three times, reacted at 95 °C for 3 hours, concentrated under reduced pressure, separated by column chromatography and C18 column to give (7R,14R)-11-(2-((3,3-difluoro-2-hydroxypropyl)amino)pyrimidin-5-yl)-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanofuro[3,2-g]benzo[4,5]imidazo[1,2-a][1,4]diazepin-5(14H)-one (compound 63-2, 90 mg) as a white solid.

[0691] Third step:

[0692] Compound 63-2 (90 mg) was subjected to SFC separation (Preparative method, Waters 150 preparative SFC system, Chiral column: DAICEL Chiralpak OJ 250*30mm I.D., 10um, A phase: supercritical CO2, B phase: MeOH (0.1% ammonia water), gradient: 20% B phase in supercritical CO2, flow rate: 150 g / min, pressure: 100 bar, keep CO2 in critical superfluid state, UV detection wavelength: 220 nm). The first peak (Analytical method, Chiral column: Chiralpak OJ-3 50*4.6mm I.D., 3um, A phase: supercritical CO2, B phase: MeOH (0.05% DEA), gradient: B phase in supercritical CO2 from 5% to 20%, flow rate: 3 mL / min, pressure: 100 bar, keep CO2 in critical superfluid state, UV detection wavelength: 220 nm, retention time: 3.216 minutes) was compound 63 (17 mg, white solid), [M+H] + = 543.

[0693] 1H NMR (400 MHz, CDC13) δ 2.82 (d, J = 13.82 Hz, 1H), 3.36 (s, 3H), 3.37 - 3.42 (m, 1H), 3.46 - 3.61 (m, 2H), 3.93 (br d, J = 5.50 Hz, 1H), 5.23 (d, J = 7.09 Hz, 1H), 5.75 (s, 1H), 5.81 - 6.13 (m, 1H), 6.27 (d, J = 7.09 Hz, 1H), 7.31 (t, J = 5.93 Hz, 1H), 7.43 - 7.52 (m, 3H), 7.58 (d, J = 1.34 Hz, 1H), 7.64 - 7.89 (m, 2H), 8.27 (dd, J = 6.48, 2.93 Hz, 1H), 8.58 (s, 2H).

[0694] The second peak obtained (analytical method, chiral column: Chiralpak OJ-3 50*4.6 mm I.D., 3um, A phase: supercritical CO2, B phase: MeOH (0.05% DEA), gradient: B phase from 5% to 20% in supercritical CO2, flow rate: 3 mL / min, pressure: 100 bar, keeping CO2 in the critical superfluid state, UV detection wavelength: 220 nm, retention time: 3.308 min) was compound 64 (20 mg, white solid), [M+H] + = 543.

[0695] 1 H NMR (400 MHz, CDC13) δ 2.88 (d, J = 13.57 Hz, 1H), 3.42 - 3.50 (m, 1H), 3.52 (s, 3H), 3.61 - 3.71 (m, 1H), 3.86 (br dd, J = 14.67, 4.52 Hz, 1H), 3.96 - 4.12 (m, 1H), 4.97 (d, J = 7.09 Hz, 1H), 5.67 - 5.98 (m, 1H), 6.01 (br t, J = 5.87 Hz, 1H), 6.12 (br s, 1H), 6.25 (d, J = 7.21 Hz, 1H), 6.64 - 7.07 (m, 1H), 7.30 (d, J = 8.19 Hz, 2H), 7.37 - 7.45 (m, 1H), 7.53 (d, J = 0.86 Hz, 1H), 7.75 (d, J = 8.44 Hz, 1H), 8.47 (s, 1H), 8.49 (s, 2H).

[0696] Example 58: Preparation of 2-((5-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo- 5,6,7,14-tetrahydro-7,14-methanof[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-11-yl)pyrimidin- 2-yl)amino)acetamide (Compound 65)

[0697] First Step:

[0698] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (0.50 g, 2.08 mmol) in tert-butanol was added 2-aminoacetamide (0.20 g, 2.71 mmol) and N,N- diisopropylethylamine (0.81 g, 6.25 mmol) and reacted at 65 °C for 12 hours, after cooling to room temperature, dichloromethane (10 mL) and water (30 mL) were added, the organic phase was separated, the organic phase was washed with water and concentrated to give a yellow solid (2-(2-amino-2-oxoethyl)amino)pyrimidin-5-yl)boronic acid (Compound 65-1, 0.20 g) as a crude product.

[0699] Second Step:

[0700] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) was added Compound 65-1 (76 mg, 0.32 mmol), chloro(2- dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol) and potassium phosphate (109 mg, 0.51 mmol) sequentially, replaced with nitrogen three times, reacted at 95 °C for 3 hours, concentrated under reduced pressure, separated by column chromatography and C18 column to give 2-((5-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14- tetrahydro-7,14-methanof[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-11-yl)pyrimidin-2-yl)amino)acetamide (Compound 65, 8 mg, white solid), [M+H] + = 506.

[0701] 1H NMR (400 MHz, DMSO-d6) δ 2.82 (d, J = 13.76 Hz, 1H), 3.35 (br s, 3H), 3.50 (dt, J = 13.95, 7.04 Hz, 1H), 3.86 (d, J = 6.25 Hz, 2H), 5.22 (d, J = 7.13 Hz, 1H), 6.27 (d, J = 7.13 Hz, 1H), 6.99 (br s, 1H), 7.30 - 7.38 (m, 2H), 7.44 (dd, J = 8.50, 1.63 Hz, 1H), 7.47 - 7.50 (m, 2H), 7.58 (d, J = 1.25 Hz, 1H), 7.67 - 7.69 (m, 1H), 8.16 - 8.33 (m, 1H), 8.56 (s, 2H).

[0702] Example 59: Preparation of 2-((5-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14- tetrahydro-7,14-methanofuro[3,2-i]benzo[4,5]imidazo[1,2-a][1,4]diazepin-11-yl)pyrimidin-2- yl)amino)-N,N-dimethylacetamide (Compound 66)

[0703] First Step:

[0704] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (0.50 g, 2.08 mmol) in t-butanol was added 2-amino-N,N-dimethylacetamide (0.27 g, 2.71 mmol) and N,N- diisopropylethylamine (0.81 g, 6.25 mmol) and reacted at 65 °C for 12 hours. After cooling to room temperature, dichloromethane (10 mL) and water (30 mL) were added and the organic phase was separated. The organic phase was washed with water and concentrated to give a yellow solid (2-(2-(dimethylamino)-2-oxoethyl)amino)pyrimidin-5-yl)boronic acid (Compound 66-1, 0.40 g) as a crude product.

[0705] Second Step:

[0706] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) were added compound 66-1 (118 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol) and potassium phosphate (109 mg, 0.51 mmol) successively, replaced with nitrogen for three times, reacted at 95 °C for 3 hours, concentrated under reduced pressure, separated by column chromatography and C18 column to give 2-((5-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14- toluene[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-11-yl)pyrimidin-2-yl)amino)-N,N- dimethylacetamide (compound 66, 66 mg, white solid), [M+H] + = 534.

[0707] 1 H NMR (400 MHz, CDCl3) δ 2.89 (d, J = 13.63 Hz, 1H), 3.07 (d, J = 11.63 Hz, 6H), 3.42-3.58 (m, 4H), 4.25 (d, J = 4.38 Hz, 2H), 4.97 (d, J = 7.13 Hz, 1H), 6.21-6.34 (m, 2H), 6.61-7.07 (m, 1H), 7.30-7.45 (m, 3H), 7.58 (d, J = 0.88 Hz, 1H), 7.78 (d, J = 8.38 Hz, 1H), 8.43-8.58 (m, 3H).

[0708] Example 60 Preparation of (7R,14R)-11-(2-((cyclobutylmethyl)amino)pyrimidin-5-yl)-1- (difluoromethoxy)-6-methyl-6,7-dihydro-7,14-toluenefbenzo[4,5]imidazo[1,2- a][1,4]diazepin-5(14H)-one (compound 67)

[0709] First step:

[0710] To a solution of 2-chloropyrimidine-5-boronic acid pinacol ester (0.50 g, 2.08 mmol) in tert-butanol was added cyclobutylmethylamine (0.24 g, 2.71 mmol) and N,N-diisopropylethylamine (0.81 g, 6.25 mmol) and reacted at 65 °C for 12 hours. After cooling to room temperature, dichloromethane (10 mL) and water (30 mL) were added and the organic phase was separated. The organic phase was washed with water and concentrated to give N-(cyclobutylmethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (compound 67-1, 0.30 g) as a yellowish solid.

[0711] Second step:

[0712] To a solution of intermediate INT1 (100 mg, 0.25 mmol) in N,N-dimethylformamide / water (5:1) was added compound 67-1 (97 mg, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10 mg, 0.01 mmol) and potassium phosphate (109 mg, 0.51 mmol) sequentially, and the mixture was purged with nitrogen three times and reacted at 95 °C for 3 hours. After concentration under reduced pressure, column chromatography and C18 column separation were performed to give 2-((5-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14- toluene[f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-11-yl)pyrimidin-2-yl)amino)-N,N-dimethylacetamide (compound 67, 51 mg, white solid), [M+H] + = 517.

[0713] 1 H NMR (400 MHz, CDCl3) δ 1.72-1.85 (m, 3H), 1.87-2.00 (m, 2H), 2.07-2.19 (m, 2H), 2.54-2.72 (m, 1H), 2.88 (d, J = 13.57 Hz, 1H), 3.42-3.51 (m, 2H), 3.52 (s, 3H), 4.96 (d, J = 7.09 Hz, 1H), 5.19 (br t, J = 5.56 Hz, 1H), 6.27 (d, J = 7.21 Hz, 1H), 6.60-7.06 (m, 1H), 7.29-7.37 (m, 2H), 7.39-7.45 (m, 1H), 7.57 (d, J = 1.47 Hz, 1H), 7.77 (d, J = 8.56 Hz, 1H), 8.49 (dd, J = 8.19, 0.98 Hz, 1H), 8.52 (s, 2H).

[0714] Example 1: Inhibition of TNFα-induced NF-κB signaling pathway activation by compounds

[0715] Pre-warm Trypsin-EDTA solution (Solarbio, Cat#T1300) and test medium (500 mL DMEM (1X) + GlutaMax (Gibco, Cat#10566-016), 50 mL fetal bovine serum (Gibco, Cat#10091-148), 5 mL penicillin-streptomycin mixture (Solarbio, Cat#P1400)) to 37°C, rinse HEK-Blue TM TNFα cells (Invivogen, Cat#hkb-tnfdmyd) 2 times, add 5 mL trypsin-EDTA solution, gently shake the cell culture bottle, and place it in a 37°C incubator until most of the cells are detached. Immediately add double the volume of test medium, centrifuge for 5 minutes, resuspend the cell pellet in 10 mL of pre-warmed test medium, take 20 μL of cell suspension and load it into a cell counting plate, insert it into a cell counter (Invitrogen, C10281) to record the cell density.

[0716] Take 2 μL of human recombinant TNFα protein (R&D, Cat#210-TA-020 / CF) and dilute it to 480 pg / mL with test medium. Add 10,000 HEK-Blue TM TNFα cells, 10 μL of diluted TNFα solution and different concentrations of compounds (starting concentration 10 μM, 3-fold dilution, 10 points), incubate in an incubator for 24 hours (37°C, 5% carbon dioxide), centrifuge for 5 minutes (1000 rpm), transfer the supernatant to a new 384-well plate, add 45 μL of QUANTI-Blue solution (Invivogen, Cat#rep-qbs3) to each well, and after gentle centrifugation, incubate in a 37°C incubator for 1 hour. Measure OD260 with EnSight TM Multifunctional Enzyme Labeling Instrument (PerkinElmer, HH34000000) to determine SEAP levels, calculate the percentage inhibition rate, and use GraphPad Prism 9.5.0 to fit IC50 values.

[0717] The inhibition rate is calculated as follows:

[0718] Inhibition rate = [OD260 (blank control) - OD260 (compound)] / OD260 (blank control) * 100%

[0719] Table 1 Inhibitory activity of exemplary compounds of the present application on TNFα-induced NF-κB signaling pathway

[0720] As shown in Table 1, the exemplary compounds of the present application have significant inhibitory activity on TNFα-induced NF-κB signaling pathway, wherein the inhibitory effect of compounds 9-17, 19-21, 23-34, 37-39, 41-54, 57, 58, 60, 63, 64 and 67 is the best.

[0721] Example 2: Inhibition of hERG K + Channel inhibition assay

[0722] Experimental platform: electrophysiological manual patch clamp system

[0723] Cell line: human embryonic kidney (HEK293) cell line stably expressing hERG potassium channel

[0724] Experimental method: Place the cell-seeded glass slide in the cell recording groove, insert the glass electrode filled with intracellular solution into the amplifier probe, connect it to the patch clamp amplifier (EPC10), and then detect the intracellular resistance. The intracellular resistance should be 2-5 MΩ. Under the microscope, pick up a single cell for whole-cell recording, and the high resistance seal between the cell and the glass electrode should be >1000 MΩ. After completing the seal, set the amplifier sampling frequency to 20 kHz, the filter frequency to 10 kHz, and the clamping voltage to -90 mV. Repeat the Ikr (hERG) stimulation program with a 10-second stimulation interval to induce hERG tail current: change the clamping voltage from -90 mV to -80 mV, and the time course is 500 ms to detect the leakage current. Apply a 4.8-second depolarization voltage to depolarize the membrane potential from -80 mV to +30 mV, and then instantaneously apply a 5.2-second repolarization voltage to reduce the membrane potential to -50 mV to remove channel inactivation, thereby inducing hERG tail current. The peak value of the tail current is the size of the hERG current. After starting current recording, perfuse blank extracellular solution and continue recording for 120 seconds. After the current is stable, perfuse the test compound at concentrations from low to high. Each dosing concentration needs to be perfused after the current is stable again before perfusing the next concentration (≥3 minutes). Each compound needs to be tested in at least 2 cells (n≥2).

[0725] Data analysis: Data is output by PatchMaster software.

[0726] 1) After perfusing blank solvent or compound gradient solution, 5 consecutive current values obtained after stabilization are averaged, and the average values are taken as "tail current size 空白 " and "tail current size 化合物 ", respectively.

[0727] The percentage of current inhibition was calculated by the following formula:

[0728] 2) The standard deviation range of two groups of data is less than 15 (SD < 15)

[0729] 3) The dose-effect curve is fitted by Graphpad Prism 8.0 software and the IC is calculated 50 The value, the fitting formula is as follows:

[0730] Wherein, X is the Log value of the concentration of the test compound, Y is the percentage inhibition rate under the corresponding concentration, Top is the end-point inhibition rate of the fitting curve, Bottom is the starting-point inhibition rate of the fitting curve, and Hill is the slope of the curve.

[0731] Table 2 Inhibition activity of exemplary compounds of the present application on hERG K + channel

[0732] As shown in Table 2, some exemplary compounds of the present application have no significant inhibition activity on hERG K + channel, and have good safety.

[0733] Example 3: Pharmacokinetic evaluation of the compound in mice

[0734] The compound was dissolved in a solvent containing 5% DMSO, 45% PEG400 and 50% pure water to prepare 0.4 mg / mL and 1.0 mg / mL compound solutions or suspensions for use. After adaptive feeding, 7-9 week old male ICR mice (Zhejiang Vantong Lihua Experimental Animal Technology Co., Ltd.) were randomly divided into groups of 3, and intravenously injected with 5 mL / kg of the aforementioned prepared 0.4 mg / mL compound solution (compound dose of 2 mg / kg) or orally gavaged with 10 mL / kg of the aforementioned prepared 1.0 mg / mL compound solution or suspension (compound dose of 10 mg / kg). Blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours (a total of 8 time points) after administration, centrifuged and the plasma was collected. 10 μL of blood sample was added with 2 μL of methanol and 200 μL of methanol-acetonitrile solution containing an internal standard (1:1, v / v), stirred and centrifuged for 15 minutes (4500 rpm), and the supernatant was detected for drug concentration by LC-MS / MS (AB Sciex Triple Quad 5500+). The chromatographic column used was C18 2.6 μm (50 mm*2.10 mm) Column; mobile phase A was 0.1% formic acid, 5 mM ammonium acetate aqueous solution; mobile phase B was 0.1% formic acid, acetonitrile solution; column temperature was room temperature, injection volume was 1 μL, gradient elution conditions were shown in Table 2; mass spectrometry used electrospray ionization source, ionization mode was positive ion selective reaction monitoring.

[0735] Table 3 Gradient elution conditions in pharmacokinetic experiment

[0736] Table 4 Pharmacokinetic experiment results of exemplary compounds in the application

[0737] Some exemplary compounds in the application have good injection and oral pharmacokinetic properties in mice.

[0738] It should be understood that the above examples are exemplary and are not intended to encompass all possible embodiments encompassed by the claims. Various modifications and alterations can also be made on the basis of the above examples without departing from the scope of the present disclosure. Similarly, any combination of the technical features of the above examples can also be made to form additional embodiments of the application that can not have been explicitly described. Therefore, the above examples only express several embodiments of the application and do not limit the protection scope of the patent of the application.

Claims

A compound of Formula (I) or a stereoisomer, a tautomer, a solvate, a hydrate, a prodrug, a stable isotope derivative, and a pharmaceutically acceptable salt thereof, wherein, R1is selected from -C(=0)-R3, amino, cycloalkyl and -O-R9, said amino being substituted with one or more R7, said cycloalkyl being substituted with one or more R8; R3is selected from H, D, halogen, hydroxyl, and amino, the amino being substituted with one or more R 3a substituted; The R 3a Selected from H, D, halogen, hydroxyl, amino, alkyl, alkoxy, aryl, heteroaryl, cycloalkyl, and heterocyclic groups, wherein the amino, alkyl, alkoxy, aryl, heteroaryl, cycloalkyl, and heterocyclic groups are influenced by one or more R groups. 3b Replaced; said R 3b selected from H, D, halogen, hydroxyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, and substituted or unsubstituted amino, the substitution being with one or more H, D, halogen, hydroxyl, amino, or alkyl; said R4 is selected from substituted or unsubstituted cycloalkyl, said substitution being with one or more H, D, halogen or amino; said R5 and R6 are each independently selected from H, D, halogen, hydroxyl, cyano and substituted or unsubstituted amino, said substitution being with one or more H, D, halogen, hydroxyl or alkyl; R7is selected from H, D, halogen, hydroxyl, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl, said amino, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl being substituted with one or more R 7a substituted; The R 7a Selected from H, D, halogen, oxo, hydroxyl, cyano, amino, alkyl, alkoxy, cycloalkyl, and heterocyclic groups, wherein the amino, alkyl, alkoxy, cycloalkyl, and heterocyclic groups are separated by one or more R groups. 7b Replaced; said R 7b selected from H, D, halogen, oxo, hydroxyl, cyano, amino, alkyl, alkoxy, and cyanoalkoxy; R8is selected from H, D, halogen, hydroxyl, cyano, amino, azido, alkyl, and haloalkyl, said amino and alkyl groups being substituted with one or more R 8a substituted; said R 8a selected from H, D, halogen, oxo, hydroxyl, cyano, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, and cyanoalkoxy; said R9is selected from the group consisting of H, D, halogen, oxo, hydroxyl, cyano, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl, said amino, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl being substituted with one or more R 9a substituted; said R 9a selected from H, D, halogen, oxo, hydroxyl, cyano, amino, alkyl, alkoxy, cycloalkyl, and heterocyclyl; A, B and E are each independently selected from N and CR a , said R a is selected from H, D, halogen, alkyl, hydroxyl, alkoxy, cyano and amino; X1, X2, X3and X4are each independently selected from N and CR b , said R b is selected from H, D, halogen, alkyl, hydroxyl, alkoxy, cyano and amino; M and J are each independently selected from N and CH; T is selected from cycloalkyl and heterocyclyl; L is selected from the group consisting of methylene, O, S, and NR h , said R h is selected from the group consisting of H, D, halogen, hydroxyl, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl being substituted with one or more R 9a ; W is selected from carbonyl, sulfone and sulfoxide; G is selected from heterocyclyl, aryl and heteroaryl; R2is selected from the group consisting of alkyl, alkoxy, thio, cyano, amino, and cycloalkyl, said R2being substituted by one or more R 2a substituted; said R 2a is selected from H, D, halogen, alkyl, and haloalkyl. The compound represented by formula (I) or its stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative and pharmaceutically acceptable salt according to claim 1, characterized in that, A, B, and E are each independently selected from N and CR. a The R a Selected from H and halogens; Preferably, A, B and E are each independently selected from N and CR a , R a is selected from H and F. The compound represented by formula (I) or a stereoisomer, a tautomer, a solvate, a hydrate, a prodrug, a stable isotope derivative, and a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that, The compounds have a structure according to Formula (I-1), Formula (I-2), Formula (I-3), or Formula (I-4): wherein, said R1, R2, X1, X2, X3, X4, M, J, T, L, W and G are as defined in claim 1 or 2. The compound represented by formula (I) or its stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative and pharmaceutically acceptable salt according to any one of claims 1-3, characterized in that, said W is selected from carbonyl. The compound represented by formula (I) or its stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative and pharmaceutically acceptable salt according to any one of claims 1-4, characterized in that, said M and J are each independently selected from N. The compound represented by formula (I) or its stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative and pharmaceutically acceptable salt according to any one of claims 1-5, characterized in that, said T is selected from C 3-8 cycloalkyl and 3-8 membered heterocyclyl; preferably from 5-8 membered heterocyclyl containing 1-4 heteroatoms selected from N, O and S; more preferably from 5-6 membered heterocyclyl containing 1-2 heteroatoms selected from N; more preferably from pyrrolidinyl and piperidinyl; most preferably from The compound represented by formula (I) or its stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative and pharmaceutically acceptable salt according to any one of claims 1-6, characterized in that, each of said X1, X2, X3and X4is independently selected from N and CR b , said R b is selected from H, D and halogen; Preferably, said X1, X2, X3and X4are each independently selected from N and CR b , said R b is selected from H. The compound represented by Formula (I) or a stereoisomer, a tautomer, a solvate, a hydrate, a prodrug, a stable isotope derivative, and a pharmaceutically acceptable salt thereof according to any one of claims 1-7, characterized in that, The compounds have the structure of Formula (I-1-1), Formula (I-1-2), Formula (I-1-3), Formula (I-1-4), Formula (I-1-5), Formula (I-2-1), Formula (I-3-1), or Formula (I-4-1): wherein, said R1, R2, L and G are as defined in any one of claims 1-7. The compound represented by formula (I) or its stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative and pharmaceutically acceptable salt according to any one of claims 1-8, characterized in that, R3is selected from H, D, halogen, and amino substituted with one or more R 3a R3is selected from H, D, halogen, and amino substituted with one or more R 3a R3is selected from H, D, halogen, and amino substituted with one or more R The compound represented by formula (I) or its stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative and pharmaceutically acceptable salt according to any one of claims 1-9, characterized in that, The R 3a Selected from H, D, halogen, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the amino group, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups are bound by one or more R 3b Replaced by; preferably from H, D, halogen, hydroxyl, amino, C 1-3 Alkyl, C 3-6 Cycloalkyl groups and 3-6 membered heterocyclic groups, wherein the 3-6 membered heterocyclic group contains 1-4 heteroatoms selected from N, O, and S, and the amino group, C 1-3 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups are separated by one or more R 3b Replaced by; more preferably from H, D, C 1-3 Alkyl, C 3-5 Cycloalkyl groups and 4-5 membered heterocyclic groups, wherein the 4-5 membered heterocyclic group contains 1-2 heteroatoms selected from N, and the C 1-3 Alkyl, C 3-5 Cycloalkyl and 4-5 membered heterocyclic groups are separated by one or more R 3b The substituted compounds are preferably selected from H, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, aziridine, and pyrrolidinyl, wherein the methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, aziridine, and pyrrolidinyl compounds are replaced by one or more R... 3b What it replaced. The compound represented by formula (I) or its stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative and pharmaceutically acceptable salt according to any one of claims 1-10, characterized in that, The R 3b Selected from H, D, halogens, hydroxyl groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic groups, and substituted or unsubstituted amino groups, wherein the substitution is by one or more H, D, halogen, hydroxyl, amino, or C groups. 1-6 Alkyl groups are substituted; preferably from H, D, halogens, hydroxyl groups, and C. 1-3 Alkyl, C 1-3 Alkyl groups and substituted or unsubstituted amino groups, wherein the substitution is caused by one or more H, D, halogen, hydroxyl, amino, or C groups. 1-3 Alkyl groups are substituted; more preferably from H and substituted or unsubstituted amino groups, wherein the substitution is by one or more H, D, halogen, hydroxyl, amino or methyl groups; preferably selected from H and substituted or unsubstituted amino groups, wherein the substitution is by one or more H or methyl groups. The compound represented by formula (I) or its stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative and pharmaceutically acceptable salt according to any one of claims 1-11, characterized in that, The compound represented by formula (I) or its stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative and pharmaceutically acceptable salt according to any one of claims 1-12, characterized in that, said R4is selected from the group consisting of substituted or unsubstituted C 3-8 cycloalkyl, said substitution being by one or more H, D, halogen or amino; preferably selected from the group consisting of substituted or unsubstituted C 3-5 cycloalkyl, said substitution being by one or more H, D, halogen or amino; more preferably selected from the group consisting of substituted or unsubstituted cyclopropyl and cyclobutyl, said substitution being by one or more H or amino. The compound represented by formula (I) or a stereoisomer, a tautomer, a solvate, a hydrate, a prodrug, a stable isotope derivative and a pharmaceutically acceptable salt thereof according to any one of claims 1-12, wherein R5is selected from H, D, halogen, hydroxyl, cyano, and substituted or unsubstituted amino, substituted with one or more H, D, halogen, hydroxyl, or C 1-6 alkyl; preferably selected from H, D, and substituted or unsubstituted amino, substituted with one or more H, D, halogen, hydroxyl, or C 1-3 alkyl; more preferably selected from H and substituted or unsubstituted amino, substituted with one or more H or methyl. The compound represented by formula (I) or a stereoisomer, a tautomer, a solvate, a hydrate, a prodrug, a stable isotope derivative and a pharmaceutically acceptable salt thereof according to any one of claims 1-13, wherein said R6is selected from the group consisting of H, D, halogen, hydroxyl, cyano, and substituted or unsubstituted amino, said substitution with one or more H, D, halogen, hydroxyl, or C 1-6 alkyl; preferably selected from the group consisting of H, D, and substituted or unsubstituted amino, said substitution with one or more H, D, halogen, hydroxyl, or C 1-3 alkyl; more preferably selected from the group consisting of H and substituted or unsubstituted amino, said substitution with one or more H or methyl. The compound represented by formula (I) or a stereoisomer, a tautomer, a solvate, a hydrate, a prodrug, a stable isotope derivative and a pharmaceutically acceptable salt thereof according to any one of claims 1-14, wherein The R7 is selected from H, D, halogen, hydroxyl, amino, C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the amino group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are affected by one or more R 7a Replaced by; preferably from H, D, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl and 5-8-membered heteroaryl groups, wherein the 3-6-membered heterocyclic group and the 5-8-membered heteroaryl group contain 1-4 heteroatoms selected from N, O and S, and the C 1-6 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl and 5-8 membered heteroaryl groups are affected by one or more R groups. 7a Replaced; more preferably from H, C 1-4 Alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclic, C 6-7 Aryl and 5-6-membered heteroaryl groups, wherein the 4-6-membered heterocyclic group and the 5-6-membered heteroaryl group contain 1-2 heteroatoms selected from N and O, and the C 1-4 Alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclic, C 6-7 Aryl and 5-6 membered heteroaryl groups are affected by one or more R groups. 7a The substituted group is preferably H, methyl, ethyl, n-propyl, isopropyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, oxacyclobutyl, aziridine, pyrrolyl, phenyl, pyrrolyl, furanyl, oxazolyl, and pyrazole, wherein the methyl, ethyl, n-propyl, isopropyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, oxacyclobutyl, aziridine, pyrrolyl, phenyl, pyrrolyl, furanyl, oxazolyl, and pyrazole are replaced by one or more R 7a What it replaced. The compound represented by formula (I) or a stereoisomer, a tautomer, a solvate, a hydrate, a prodrug, a stable isotope derivative and a pharmaceutically acceptable salt thereof according to any one of claims 1-15, wherein said R 7a selected from H, D, halogen, oxo, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, said amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl are substituted by one or more R 7b selected from H, D, halogen, oxo, hydroxyl, cyano, amino, C 1-4 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl and 3-6 membered heterocyclyl, said 3-6 membered heterocyclyl containing 1-4 heteroatoms selected from N, O and S, said amino, C 1-4 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl and 3-6 membered heterocyclyl are substituted by one or more R 7b selected from H, F, oxo, hydroxyl, cyano, amino, C 1-4 alkyl, C 1-3 alkoxy, C 3-5 cycloalkyl and 4-6 membered heterocyclyl, said 4-6 membered heterocyclyl containing 1-2 heteroatoms selected from N and O, said amino, C 1-4 alkyl, C 1-3 alkoxy, C 3-5 cycloalkyl and 4-6 membered heterocyclyl are substituted by one or more R 7b selected from H, F, oxo, hydroxyl, cyano, amino, methyl, sec-butyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, tetrahydrofuranyl, oxanyl, azetidinyl and azepanyl, said amino, methyl, sec-butyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, tetrahydrofuranyl, oxanyl, azetidinyl and azepanyl are substituted by one or more R 7b . The compound represented by formula (I) or a stereoisomer, a tautomer, a solvate, a hydrate, a prodrug, a stable isotope derivative and a pharmaceutically acceptable salt thereof according to any one of claims 1-16, wherein said R 7b is selected from the group consisting of H, D, halogen, oxo, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 cyanoalkoxy; preferably from the group consisting of H, D, halogen, oxo, hydroxyl, cyano, amino, C 1-3 alkyl, C 1-3 alkoxy and C 1-3 cyanoalkoxy; more preferably from the group consisting of H, F, oxo, hydroxyl, cyano, methyl, methoxy, ethoxy and cyanoethoxy. The compound represented by formula (I) or a stereoisomer, a tautomer, a solvate, a hydrate, a prodrug, a stable isotope derivative and a pharmaceutically acceptable salt thereof according to any one of claims 1-17, wherein R8is selected from the group consisting of H, D, halogen, hydroxyl, cyano, amino, azido, C 1-6 alkyl and C 1-6 haloalkyl, said amino and C 1-6 alkyl are substituted by one or more R 8a ; preferably from the group consisting of H, D, halogen, amino, azido, C 1-3 alkyl and C 1-3 haloalkyl, said amino and C 1-3 alkyl are substituted by one or more R 8a ; more preferably from the group consisting of H, amino, azido and trifluoroethyl, said amino is substituted by one or more R 8a ; The R 8a Selected from H, D, halogen, oxo group, hydroxyl group, cyano group, amino group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups; preferably from H, D, halogen, oxo, hydroxyl, cyano, amino, C 1-4 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl groups and 3-6 membered heterocyclic groups, wherein the 3-6 membered heterocyclic groups contain 1-4 heteroatoms selected from N, O, and S; more preferably from H, F, oxo groups, hydroxyl groups, cyano groups, amino groups, and C. 1-4 Alkyl, C 1-3 Alkoxy, C 3-5 Cycloalkyl groups and 4-6-membered heterocyclic groups, wherein the 4-6-membered heterocyclic groups contain 1-2 heteroatoms selected from N and O; preferably selected from H and methyl groups. The compound represented by formula (I) or a stereoisomer, a tautomer, a solvate, a hydrate, a prodrug, a stable isotope derivative and a pharmaceutically acceptable salt thereof according to any one of claims 1-18, wherein said R9is selected from the group consisting of H, D, halogen, oxo, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are substituted with one or more R 9a ; preferably selected from the group consisting of H, D, C 1-3 alkyl and C 3-6 cycloalkyl, said C 1-3 alkyl and C 3-6 cycloalkyl are substituted with one or more R 9a ; more preferably selected from the group consisting of H, methyl and cyclobutyl, said methyl and cyclobutyl are substituted with one or more R 9a . The compound represented by formula (I) or a stereoisomer, a tautomer, a solvate, a hydrate, a prodrug, a stable isotope derivative and a pharmaceutically acceptable salt thereof according to any one of claims 1-19, wherein said R 9a selected from H, D, halogen, oxo, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl; preferably selected from H, D, halogen and 4-6 membered heterocyclyl containing 1-2 heteroatoms selected from N and O; more preferably selected from H, F and tetrahydrofuranyl. The compound represented by formula (I) or a stereoisomer, a tautomer, a solvate, a hydrate, a prodrug, a stable isotope derivative and a pharmaceutically acceptable salt thereof according to any one of claims 1-20, wherein said R1 is selected from The compound represented by formula (I) or a stereoisomer, a tautomer, a solvate, a hydrate, a prodrug, a stable isotope derivative and a pharmaceutically acceptable salt thereof according to any one of claims 1-21, wherein L is selected from NR h R h is selected from H, D, halogen, hydroxyl, cyano, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, said C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are substituted with one or more R 9a ; preferably from H, D, halogen, hydroxyl, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl and 5-8 membered heteroaryl, said 3-6 membered heterocyclyl and 5-8 membered heteroaryl contain 1-4 heteroatoms selected from N, O and S, said C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl and 5-8 membered heteroaryl are substituted with one or more R 9a ; more preferably from H, C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, C 6-7 aryl and 5-6 membered heteroaryl, said 4-6 membered heterocyclyl and 5-6 membered heteroaryl contain 1-2 heteroatoms selected from N and O, said C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, C 6-7 aryl and 5-6 membered heteroaryl are substituted with one or more R 9a ; further more preferably from H, methyl, ethyl, n-propyl, i-propyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetanyl, pyrrolidinyl, phenyl, pyrrolyl, furanyl, oxazolyl and pyrazolyl, said methyl, ethyl, n-propyl, i-propyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetanyl, pyrrolidinyl, phenyl, pyrrolyl, furanyl, oxazolyl and pyrazolyl are substituted with one or more R 9a . The compound represented by formula (I) or a stereoisomer, a tautomer, a solvate, a hydrate, a prodrug, a stable isotope derivative and a pharmaceutically acceptable salt thereof according to any one of claims 1-22, wherein G is selected from C 6-10 aryl and 5-8 membered heteroaryl; preferably selected from C 6-8 aryl and 5-8 membered heteroaryl, the 5-8 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S; more preferably selected from phenyl and pyridyl; most preferably selected from The compound represented by formula (I) or a stereoisomer, a tautomer, a solvate, a hydrate, a prodrug, a stable isotope derivative and a pharmaceutically acceptable salt thereof according to any one of claims 1-23, wherein R2is selected from C 1-6 alkyl, C 1-6 alkoxy, thio, cyano, amino and C 3-8 cycloalkyl, C 1-6 alkyl, C 1-6 alkoxy, thio, cyano, amino and C 3-8 cycloalkyl is substituted by one or more R 2a ; preferably from C 1-3 alkyl, C 1-3 alkoxy, thio, cyano, amino and C 3-5 cycloalkyl, C 1-3 alkyl, C 1-3 alkoxy, thio, cyano, amino and C 3-5 cycloalkyl is substituted by one or more R 2a ; more preferably from isopropyl, methoxy, thio, cyano, amino and cyclopropyl, which isopropyl, methoxy, thio, cyano, amino and cyclopropyl is substituted by one or more R 2a . The compound of Formula (I) or a stereoisomer, a tautomer, a solvate, a hydrate, a prodrug, a stable isotope derivative, and a pharmaceutically acceptable salt thereof according to any one of claims 1-24, wherein R is selected from H, D, halogen, C 2a alkyl and C 1-6 alkyl and C 1-6 haloalkyl; preferably from H, D, halogen, C 1-3 alkyl and C 1-3 haloalkyl; more preferably from H, F and difluoromethyl. A compound or its stereoisomers, tautomers, solvates, hydrates, prodrugs, stable isotopic derivatives, and pharmaceutically acceptable salts thereof, characterized in that, The compound is any one of: A compound or its stereoisomers, tautomers, solvates, hydrates, prodrugs, stable isotopic derivatives, and pharmaceutically acceptable salts thereof, characterized in that, The compound is any one of: A pharmaceutical composition comprising a compound according to any one of claims 1-27, or a stereoisomer, a tautomer, a solvate, a hydrate, a prodrug, a stable isotope derivative, and a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients. The compound according to any one of claims 1-27, or a stereoisomer, a tautomer, a solvate, a hydrate, a prodrug, a stable isotope derivative, and a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 28, for use as a prophylactic and / or therapeutic agent for a disease associated with abnormal TNFα function; Preferably, the disease associated with abnormal TNFα function comprises an inflammatory disease, an autoimmune disease, a neurological disease, a neurodegenerative disease, pain, a cardiovascular disease, a metabolism-related disease, an ocular disease, and a tumor; Preferably, the disease associated with abnormal TNFα function comprises an inflammatory disease, an autoimmune disease, a neurological disease, a neurodegenerative disease, pain, a cardiovascular disease, a metabolism-related disease, an ocular disease, and a tumor; Preferably, the autoimmune diseases include systemic lupus erythematosus, psoriasis, psoriatic arthritis, vasculitis, inflammatory myopathy (including polymyositis, dermatomyositis and inclusion body myositis), scleroderma, multiple sclerosis, systemic sclerosis, ankylosing spondylitis, rheumatoid arthritis, non-specific inflammatory arthritis, juvenile inflammatory arthritis, juvenile idiopathic arthritis (including its oligoarticular and polyarticular forms), anemia of chronic disease (ACD), Still's disease (juvenile and / or adult onset), Behcet's disease, Sjogren's syndrome, thyroiditis, Addison's disease, hemolytic or pernicious anemia, acute kidney injury (AKI; including cisplatin-induced AKI), diabetic nephropathy (DN), obstructive uropathy (including cisplatin-induced obstructive uropathy), glomerulonephritis (including Goodpasture's syndrome, immune complex-mediated glomerulonephritis and anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis), lupus nephritis (LN), minimal change nephropathy, Graves' disease, idiopathic thrombocytopenic purpura, inflammatory bowel disease (including Crohn's disease, ulcerative colitis, indeterminate colitis and pouchitis), pemphigus, atopic dermatitis, autoimmune hepatitis, primary biliary cirrhosis, autoimmune pneumonitis, autoimmune carditis, myasthenia gravis, spontaneous infertility, osteoporosis, osteopenia, erosive bone disease, cartilage inflammation, cartilage degeneration and / or destruction, fibrotic disorders (including various forms of liver and lung fibrosis), asthma, rhinitis, chronic obstructive pulmonary disease (COPD), respiratory distress syndrome, sepsis, fever, muscular dystrophy (including Duchenne muscular dystrophy), organ transplant rejection (including kidney allograft rejection), scleritis (including giant cell arteritis scleritis), Takayasu's arteritis, hidradenitis suppurativa, pyoderma gangrenosum, sarcoidosis, polymyalgia rheumatica and axial spondyloarthritis; the ocular diseases include uveitis, non-infectious anterior uveitis, dry eye, panuveitis, Behcet's disease, posterior uveitis, dry eye syndrome, Blau syndrome, intermediate uveitis, Behcet's uveitis, macular degeneration, anterior uveitis, conjunctivitis, wet macular degeneration, retinal pigmentosa, Sjogren's syndrome, retinal degeneration, ocular pain, vitreous disease. The compound according to any one of claims 1-27 or a stereoisomer, a tautomer, a solvate, a hydrate, a prodrug, a stable isotope derivative, and a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 28 for use as a prophylactic and / or therapeutic agent for diseases associated with abnormal TNFα function; Preferably, the diseases associated with abnormal TNFα function include inflammatory diseases, autoimmune diseases, neurological diseases, neurodegenerative diseases, pain, cardiovascular diseases, metabolism-related diseases, ocular diseases and tumors; Preferably, the diseases associated with abnormal TNFα function include inflammatory diseases, autoimmune diseases, neurological diseases, neurodegenerative diseases, pain, cardiovascular diseases, metabolism-related diseases, ocular diseases and tumors; Preferably, the autoimmune diseases include systemic lupus erythematosus, psoriasis, psoriatic arthritis, vasculitis, inflammatory myopathy (including polymyositis, dermatomyositis and inclusion body myositis), scleroderma, multiple sclerosis, systemic sclerosis, ankylosing spondylitis, rheumatoid arthritis, non-specific inflammatory arthritis, juvenile inflammatory arthritis, juvenile idiopathic arthritis (including its oligoarticular and polyarticular forms), anemia of chronic disease (ACD), Still's disease (juvenile and / or adult onset), Behcet's disease, Sjogren's syndrome, thyroiditis, Addison's disease, hemolytic or pernicious anemia, acute kidney injury (AKI; including cisplatin-induced AKI), diabetic nephropathy (DN), obstructive uropathy (including cisplatin-induced obstructive uropathy), glomerulonephritis (including Goodpasture's syndrome, immune complex-mediated glomerulonephritis and anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis), lupus nephritis (LN), minimal change nephropathy, Graves' disease, idiopathic thrombocytopenic purpura, inflammatory bowel disease (including Crohn's disease, ulcerative colitis, indeterminate colitis and pouchitis), pemphigus, atopic dermatitis, autoimmune hepatitis, primary biliary cirrhosis, autoimmune pneumonitis, autoimmune carditis, myasthenia gravis, spontaneous infertility, osteoporosis, osteopenia, erosive bone disease, cartilage inflammation, cartilage degeneration and / or destruction, fibrotic disorders (including various forms of liver and lung fibrosis), asthma, rhinitis, chronic obstructive pulmonary disease (COPD), respiratory distress syndrome, sepsis, fever, muscular dystrophy (including Duchenne muscular dystrophy), organ transplant rejection (including kidney allograft rejection), scleritis (including giant cell arteritis scleritis), Takayasu's arteritis, hidradenitis suppurativa, pyoderma gangrenosum, sarcoidosis, polymyalgia rheumatica and axial spondyloarthritis; the ocular diseases include uveitis, non-infectious anterior uveitis, dry eye, panuveitis, Behcet's disease, posterior uveitis, dry eye syndrome, Blau syndrome, intermediate uveitis, Behcet's uveitis, macular degeneration, anterior uveitis, conjunctivitis, wet macular degeneration, retinal pigmentosa, Sjogren's syndrome, retinal degeneration, ocular pain, vitreous disease. Use of a compound according to any one of claims 1-27, or a stereoisomer, a tautomer, a solvate, a hydrate, a prodrug, a stable isotope derivative, and a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 28, for the manufacture of a medicament for the prevention and / or treatment of a disease associated with abnormal TNFα function; Preferably, the disease associated with abnormal TNFα function includes an inflammatory disease, an autoimmune disease, a neurological disease, a neurodegenerative disease, pain, a cardiovascular disease, a metabolism-related disease, an ocular disease and a tumor; Preferably, the disease associated with abnormal TNFα function includes an inflammatory disease, an autoimmune disease, a neurological disease, a neurodegenerative disease, pain, a cardiovascular disease, a metabolism-related disease, an ocular disease and a tumor; Preferably, the autoimmune disease comprises systemic lupus erythematosus, psoriasis, psoriatic arthritis, vasculitis, inflammatory myopathy (including polymyositis, dermatomyositis and inclusion body myositis), scleroderma, multiple sclerosis, systemic sclerosis, ankylosing spondylitis, rheumatoid arthritis, non-specific inflammatory arthritis, juvenile inflammatory arthritis, juvenile idiopathic arthritis (including its oligoarticular and polyarticular forms), anemia of chronic disease (ACD), Still's disease (juvenile and / or adult onset), Behcet's disease, Sjogren's syndrome, thyroiditis, Addison's disease, hemolytic or pernicious anemia, acute kidney injury (AKI; including cisplatin-induced AKI), diabetic nephropathy (DN), obstructive uropathy (including cisplatin-induced obstructive uropathy), glomerulonephritis (including Goodpasture's syndrome, immune complex-mediated glomerulonephritis and anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis), lupus nephritis (LN), minimal change nephropathy, Graves' disease, idiopathic thrombocytopenic purpura, inflammatory bowel disease (including Crohn's disease, ulcerative colitis, indeterminate colitis and pouchitis), pemphigus, atopic dermatitis, autoimmune hepatitis, primary biliary cirrhosis, autoimmune pneumonitis, autoimmune carditis, myasthenia gravis, spontaneous infertility, osteoporosis, osteopenia, erosive bone disease, cartilage inflammation, cartilage degeneration and / or destruction, fibrotic disorders (including various forms of liver and lung fibrosis), asthma, rhinitis, chronic obstructive pulmonary disease (COPD), respiratory distress syndrome, sepsis, fever, muscular dystrophy (including Duchenne muscular dystrophy), organ transplant rejection (including kidney allograft rejection), scleritis (including giant cell arteritis scleritis), Takayasu's arteritis, hidradenitis suppurativa, pyoderma gangrenosum, sarcoidosis, polymyalgia rheumatica and axial spondyloarthritis; the ocular disease comprises uveitis, non-infectious anterior uveitis, dry eye, panuveitis, Behcet's disease, posterior uveitis, dry eye syndrome, Blau syndrome, intermediate uveitis, Behcet's uveitis, macular degeneration, anterior uveitis, conjunctivitis, wet macular degeneration, retinal pigmentosa, Sjogren's syndrome, retinal degeneration, ocular pain, vitreous disease.

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