Interferon gene stimulating factor (STING) modulators and compositions and methods thereof

Abstract

The invention provides a novel interferon gene stimulating factor (STING) regulator and a pharmaceutical composition thereof, as well as a preparation method and application of a medicament for treating various diseases and disorders such as cancer and infectious and autoimmune diseases or disorders.

Description

Technical Field of the Invention

[0001] The present invention generally relates to pharmaceuticals and therapeutic methods. Specifically, the present invention provides a novel modulator of stimulator of interferon genes (STING), a pharmaceutical composition thereof, a method for preparing the same, and its use in treating various diseases and disorders, such as cancer, infectious diseases, and autoimmune diseases. Background of the Invention

[0002] STING, also known as TMEM173-encoded interferon gene cGAMP interactor 1 (STING1), is an endoplasmic reticulum (ER)-associated signaling molecule that plays a crucial role in regulating the transcription of various host defense genes, including proinflammatory cytokines and type I interferons (IFNs) in response to abnormal DNA species or cyclic dinucleotides (CDNs) in the cellular cytosol (Ishikawa H et al., Nature. 2008, 455: 674-678; Ishikawa H et al. Nature. 2009; 461: 788-792; Burdette D et al. Nature. 2011, 478, 515-518).

[0003] STING is a 379-amino acid protein with several transmembrane regions that is expressed in various endothelial and endothelial cell types as well as hematopoietic cells, such as T cells, macrophages, and dendritic cells (DCs) (Ishikawa H et al., Nature. 2008, 455:674-678; Ishikawa H et al. Nature. 2009; 461:788-792). STING signaling is essential for protecting cells against various pathogens by stimulating the transcription of innate immune genes in response to some invading bacteria, DNA viruses or transfected DNA (Ishikawa H et al., Nature. 2008, 455: 674-678; Ishikawa H et al. Nature. 2009, 461: 788-792; Jin L et al. Mol Cell biol. 2008, 28: 5014-5026; Zhong B et al. Immunity. 2008, 29: 538-550; Woo, SR, et al. Trends Immunol. 2015, 36, 250-256; Barber, GN Trends Immunol. 2014, 35, 88-93).

[0004] Cytoplasmic DNA can trigger STING signaling after binding and activating intracellular nucleic acid sensors, including cyclic GMP-AMP synthase (cGAS), interferon-γ-induced protein 16 (IFI16), and MRE11 homolog, double-strand break repair nuclease (MRE11) (Ablasser A et al. Nature. 2013, 498:380-384; Almine J Fetal. Nat Commun. 2017; 8(1):14392; Kondo T et al. Proc Natl Acad Sci USA. 2013; 110:2969-2974). cGAS is a 522-amino acid protein that has been extensively studied among these sensors. cGAS synthesizes the intracellular second messenger 2'3'-cyclic GMP-AMP (cGAMP) in response to cytoplasmic double-stranded DNA (dsDNA) and activates the innate immune STING pathway (Sun L et al. Science. 2013; 339: 786-791; Ablasser A et al. Nature. 2013; 498: 380-384).

[0005] After binding to CDNs, STING undergoes endoplasmic reticulum (ER)-Golgi transport and tetramer formation through higher-order oligomerization, which oligomerizes and activates downstream TANK-binding kinase 1 (TBK1) and transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor-κB (NF-κB) (Shang GJ et al. Nature. 2019, 567: 389). These transcription factors are further transferred to the cell nucleus to initiate innate immune gene transcription. In addition, STING is associated with sensing abnormal cytoplasmic DNA, including ssDNA (single-stranded DNA) and dsDNA, and is associated with triggering the expression of genes related to host defense (Abe T et al. Mol Cell. 2013; 50: 5-15.). STING is then rapidly degraded to avoid problems associated with sustained cytokine production (Shu HB et al. Immunity. 2014; 41:871-873; Liu Y, et al. NEngl J Med. 2014; 371:507-518).

[0006] Activation of STING induces cytokines, such as type I IFNs, which belong to a multi-cytokine family and are involved in antiviral immunity (Zitvogel L et al. Nat Rev Immunol. 2015, 15: 405-414; Gonzalez-Navajas JM et al. Nat Rev Immunol. 2012, 12: 125-135). During viral infection, type I IFNs directly regulate T cell activation, proliferation, and survival during T cell priming and protect local T cell expansion against natural killer (NK) cell-mediated attack. Type I IFNs promote functional maturation, migration, and antigen presentation of DCs, thereby indirectly affecting T cell activation (Tough DF et al. Immunol Cell Biol. 2012, 90: 492-497; Longhi MP et al. J Exp Med. 2009, 206: 1589-1602). The STING signaling pathway can be activated in macrophages, B cells, some other white blood cells, and natural killer (NK) cells, playing a central role in various innate and adaptive immune responses (Barber GN. et al. Trends Immunol. 2014; 35:88-93; Barber GN. et al. Nat Rev Immunol. 2015; 15:760-770; Sundararaman SK et al. Immunity. 2018; 49:585-587).

[0007] As a key player in the host antiviral defense pathway, STING is responsible for combating a range of DNA and RNA viruses and bacteria (McNab F et al. Nat. Rev. Immunol. 2015, 15:87-103). Various viruses, including Herpesviridae, Flaviviridae, Coronaviridae, Papillomaviridae, Adenoviridae, Hepadnaviridae, Orthomyxoviridae, Paramyxoviridae, and Rhabdoviridae, have evolved mechanisms to target the STING pathway and evade host immune control (Holm C et al., Nat Comm., 2016, 7:10680; Wu J et al., Cell Host Microbe, 2015, 18:333-44; Liu Yet al., J Virol, 2016, 90:9406-19; Chen X et al. Protein Cell 2014, 5, 369-81; Lau L et al. Science, 2013, 350:568-71; Ding Q et al. J Hepatol, 2013, 59:52-8; Nitta S et al. Hepatology, 2013, 57:46-58; Sun L et al., J Virol, 2016, 90:9406-19; Chen X et al. Protein Cell, ...90:568-71; Ding Q et al. J Hepatol, 2013, 90:52-8; Nitta S et al. Hepatology, al.PLoS One,2012,7,e30802;Aguirre S et al.PLoS Pathog,2012,8,el002934;Ishikawa H et al.Nature,2009,vol.461:788-92). Of particular note, it has been reported that activation of the STING pathway can block infection by SARS-CoV-2, a human coronavirus that causes the global COVID-19 pandemic (Liu W,et al.Journal of Virology,2021,95(12):e00490-2). Recent studies have shown that inhibition of the STING pathway reduces severe lung inflammation in the late stage of novel coronavirus infection (Domizio D et al.Nature,2022,603,145-151), which emphasizes the contribution of STING modulators to future virus-related epidemics.

[0008] Both endogenous and radiation-induced anti-tumor T cell responses require the STING signaling pathway (Woo SR, et al. Immunity. 2014; 41:830-842; Deng L, et al. Immunity. 2014; 41:843-852). STING-deficient mice are highly susceptible to tumor development, have reduced anti-tumor T cell immunity, and exhibit diminished response to immunotherapy (Deng L et al. Immunity. 2014; 41:843-852).

[0009] STING-cGAS signaling is indispensable for the anti-tumor effect of immune checkpoint blockade. The anti-tumor ability of immune checkpoint inhibitors is eliminated in cGAS-deficient mice, indicating the importance of STING in the therapeutic effect of immune checkpoint inhibitors (Wang H et al. Proc Natl Acad Sci USA. 2017; 114: 1637-1642). In fact, STING agonists have shown to be effective against tumors that resist programmed cell death protein 1 (PD1) blockade (Fu Jetal. Sci. Transl Med. 2015, 7, 283ra52. The combination of STING agonist ADU-S100 with PD-L1 inhibitors and OX40R agonists enables the effective activation of innate immunity to support T cell initiation and delay tumor growth in HER2+ breast tumor mouse models (Foote JB et al. Cancer Immunol Res. 2017; 5: 468-479). In summary, STING activators may play an important role in anti-cancer.

[0010] Initial STING agonist small molecules were synthesized as derivatives of CDN natural ligands. However, due to poor stability, CDN-based agonist administration was limited to intratumoral delivery in preclinical studies (Corrales L. et al. Cell Rep. 2015, 11, 1108-1030; Sivick KE et al. Cell Rep. 2019, 29, 785-789) and has been successful in multiple human trials. Therefore, systemic STING activators have considerable potential as therapeutic agents for cancer and infectious diseases. The most common STING agonist is 5,6-dimethylxanthone-4-acetic acid (DMXAA), which has been studied as an experimental anticancer immunomodulator and laid the foundation for basic knowledge. (Baguley BC et al. BioDrugs. 1997; 8: 119-127). However, DMXAA specifically binds to mouse STING, which has affected successful clinical translation in human cancer patients and highlights the importance of species selectivity in drug development for human diseases (Roberts ZJ et al. J Exp Med. 2007, 204: 1559-1569). Due to poor initial efficacy and increased incidence of adverse reactions, many clinical trials of STING modulators in cancer patients have been terminated prematurely (www.clincaltrials.gov).

[0011] For cancer, infectious diseases, and other STING-dependent diseases and disorders, there is an urgent need in the field for a new type of STING modulator and treatment technology to provide patients with better clinical efficacy and reduce side effects. Summary of the Invention

[0012] The present invention is based, in part, on novel STING modulators, pharmaceutical compositions and methods of preparation thereof, and their use in treating or alleviating various diseases or disorders. Specifically, the compounds, compositions, and methods of the present invention are useful for treating diseases or disorders mediated by or associated with STING.

[0013] In one aspect, the present invention generally relates to a compound having structural formula I or structural formula II: in: Ring A is a 5-membered, 6-membered, or 7-membered substituted or unsubstituted heterocyclic ring; Ring B is a 4-membered, 5-membered, or 6-membered substituted or unsubstituted heterocyclic ring; Y1 is CR c or N; W1, W2, W3, and W4 are each independently CH or N; R 1 Selected from halogen and oxo, OH, CN, OR, CF3, C 1-6 Alkyl, C 3-6Cycloalkyl, 3- to 6-membered heterocycloalkyl, 5- to 6-membered aryl or heteroaryl, 6- to 10-membered fused, spiro or bridged bicyclic, NRR', N(R)C(=O)R, N(R)C(=O)(O)R, OC(=O)NRR', C(=O)R, C(=O)NRR', N(R)S(O)2R, S(O)2R, S(O)2NRR'; optionally, R 1 1 to 4 identical or different R a or R b Replacement; two R 1 'Together with the carbon or heteroatom to which they are attached, they may form a 4-6 membered carbocyclic or heterocyclic ring; R 2 Selected from halogen and oxo, OH, CN, OR, CF3, C 1-6 Alkyl; optionally, the C 1-6 The alkyl group is replaced by 1-2 R b Replacement; two R 2 'Together with the carbon or heteroatom to which they are attached, they may form a 4- to 6-membered carbocyclic or heterocyclic ring; R 3 is a 5- to 6-membered aromatic carbocyclic or heterocyclic ring, a 9- to 10-membered aromatic carbocyclic or heterocyclic ring; optionally, the aromatic carbocyclic or heterocyclic ring is surrounded by 1 to 4 identical or different R a replace; R 4 is S(=O)2-C 1-4 Alkenyl, S(=O)2-C 1-4 Alkyl, C(=O)-C 1-4 Alkenyl, C(=O)-C 1-4 Alkyl, C 1-4 Alkenyl, C 1-4 Alkyl, -C 1-4 Alkyl-NH2, -C 1-4 Alkyl-OH, C 1-3 Alkyl-NH-C 1-3 Alkyl, C 1-3 Alkyl-OC 1-3 Alkyl, C 1-3 Alkyl-SC 1-3 Alkyl, C 1-3 Alkyl-C(=O)-C 1-3 Alkyl, C 1-3 Alkyl-S(=O)2-C 1-3 alkyl, or a 3- to 6-membered saturated or unsaturated carbon or heterocyclic ring; optionally, R 4 1 to 4 identical or different R b replace; R and R' are each independently H, or C 1-6 Alkyl or C 3-6Cycloalkyl; optionally, R and R' together with the nitrogen to which they are attached form a 4-6 membered ring, each optionally substituted with 1-3 substituents independently selected from C 1-3 Alkyl, C 3-6 Cycloalkyl or heterocyclic ring, halogen, OH, OC 1-3 Alkyl, CN; R a OH, NRR', halogen, CN, NO2, C 1-2 Alkyl, C 1-2 Haloalkyl, -C 1-4 Alkyl-NRR', -C 1-4 Alkyl-OR, C 1-2 Alkoxy, C(=O)NRR', NRC(=O)R or C(=O)R; optionally, the alkyl, R or R' is separated by 1-3 R b Replace, or two R a 'Forming =O, or two R a 'Together with the carbon atoms to which they are bonded, they form a 3-5 membered saturated or unsaturated carbocyclic or heterocyclic ring; R b Halogen, CN, OH, C 1-2 Alkyl, C 1-2 Alkyl-OH, C 3-6 Cycloalkyl, C 1-2 Alkoxy, NRR', S(=O)2NRR', C(=O)R, 5- to 6-membered aromatic carbocyclic or heterocyclic ring, C 1-2 Alkyl-carbocyclic or C 1-2 Alkyl-heterocyclic group; optionally, the alkyl, R, R', aromatic carbocyclic ring or heterocyclic ring is separated by 1 to 4 identical or different R a Replace; or two R b 'forms =O; or two R attached to the same or adjacent carbon atoms b 'Can form a 3-membered carbon ring; R c H or C 1-2 Alkyl, optionally substituted with 1-5 halogens; m is 0 or 1, 2, or 3; n is 0 or 1, 2, or 3; p is 1, 2, or 3; q is 1, 2, or 3; or a pharmaceutically acceptable form or isotopic derivative thereof.

[0014] In one aspect, the present invention generally relates to a compound having structural formula I or structural formula II: in: Ring A is a 5-membered, 6-membered, or 7-membered substituted or unsubstituted heterocyclic ring; Ring B is a 4-membered, 5-membered, or 6-membered substituted or unsubstituted heterocyclic ring; Y1 is CH or CMe, N; W1, W2, W3, and W4 are each independently CH or N; R 1 Selected from halogen and oxo, OH, CN, OR, CF3, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, 5- to 6-membered aryl or heteroaryl, NRR', N(R)C(=O)R, N(R)C(=O)(O)R, OC(=O)NRR', C(=O)R, C(=O)NRR', N(R)S(O)2R, S(O)2R, S(O)2NRR'; optionally, R 1 1 to 4 identical or different R a or R b replace; R 2 Selected from halogen and oxo, OH, CN, OR, CF3, C 1-6 alkyl; R 3 is a 5- to 6-membered aromatic carbocyclic or heterocyclic ring, a 9- to 10-membered aromatic carbocyclic or heterocyclic ring; optionally, the aromatic carbocyclic or heterocyclic ring is surrounded by 1 to 4 identical or different R a replace; R 4 is S(=O)2-C 1-4 Alkenyl, S(=O)2-C 1-4 Alkyl, C(=O)-C 1-4 Alkenyl, C(=O)-C 1-4 Alkyl, C 1-4 Alkenyl, C 1-4 Alkyl, -C 1-4 Alkyl-NH2, -C 1-4 Alkyl-OH, C 1-3 Alkyl-NH-C 1-3 Alkyl, C 1-3 Alkyl-OC 1-3 Alkyl, C 1-3 Alkyl-SC 1-3 Alkyl, C 1-3 Alkyl-C(=O)-C 1-3 Alkyl, C 1-3 Alkyl-S(=O)2-C 1-3 alkyl, or a 3- to 6-membered saturated or unsaturated carbon or heterocyclic ring; optionally, R 4 1 to 4 identical or different R b replace; R and R' are each independently H, or C 1-6 Alkyl or C 3-6 Cycloalkyl; optionally, R and R' together with the nitrogen to which they are attached form a 4-6 membered ring, each optionally substituted with 1-3 substituents independently selected from C 1-3 Alkyl, halogen, OH, OC 1-3 Alkyl, CN; R a OH, NRR', halogen, CN, NO2, C 1-2 Alkyl, C 1-2 Haloalkyl, -C 1-4 Alkyl-NRR', -C 1-4 Alkyl-OR, C 1-2 Alkoxy, C(=O)NRR', NRC(=O)R or C(=O)R; or two R a 'Forming =O, or two R a 'Together with the carbon atoms to which they are bonded, they form a 3-5 membered saturated or unsaturated carbocyclic or heterocyclic ring; R b Halogen, CN, OH, C 1-2 Alkyl, C 1-2 Alkyl-OH, C 3-6 Cycloalkyl, C 1-2 Alkoxy, NRR', S(=O)2NRR', C(=O)R, 5- to 6-membered aromatic carbocyclic or heterocyclic ring, C 1-2 Alkyl-carbocyclic or C 1-2 Alkyl-heterocyclic group; optionally, the aromatic carbocyclic or heterocyclic ring is surrounded by 1 to 4 identical or different R a Replace; or two R b 'forms =O; or two R attached to the same or adjacent carbon atoms b 'Can form a 3-membered carbon ring; R c H or C 1-2 Alkyl, optionally substituted with 1-5 halogens; m is 0 or 1, 2, or 3; n is 0 or 1, 2, or 3; p is 1, 2, or 3; q is 1, 2, or 3; or a pharmaceutically acceptable form or isotopic derivative thereof.

[0015] In another aspect, the present invention generally relates to a compound having structural formula III: in: Ring A is a 5-membered, 6-membered, or 7-membered substituted or unsubstituted heterocyclic ring; Ring B is a 4-membered, 5-membered, or 6-membered substituted or unsubstituted heterocyclic ring; W1, W2 and W3 are each independently CH or N; R 1 Selected from halogen and oxo, OH, CN, OR, CF3, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, 5- to 6-membered aryl or heteroaryl, 6- to 10-membered fused, spiro or bridged bicyclic, NRR', N(R)C(=O)R, N(R)C(=O)(O)R, OC(=O)NRR', C(=O)R, C(=O)NRR', N(R)S(O)2R, S(O)2R, S(O)2NRR'; optionally, R 1 1 to 4 identical or different R a or R b Replacement; two R 1 'Together with the carbon or heteroatom to which they are attached, they may form a 4-6 membered carbocyclic or heterocyclic ring; R 2 Selected from halogen and oxo, OH, CN, OR, CF3, C 1-6 Alkyl; optionally, the C 1-6 The alkyl group is replaced by 1-2 R b Replacement; two R 2 'Together with the carbon or heteroatom to which they are attached, they may form a 4- to 6-membered carbocyclic or heterocyclic ring; R 3 is a 5- to 6-membered aromatic carbocyclic or heterocyclic ring, a 9- to 10-membered aromatic carbocyclic or heterocyclic ring; optionally, the aromatic carbocyclic or heterocyclic ring is surrounded by 1 to 4 identical or different R a replace; R 4 is S(=O)2-C 1-4 Alkenyl, S(=O)2-C 1-4 Alkyl, C(=O)-C 1-4 Alkenyl, C(=O)-C 1-4 Alkyl, C 1-4 Alkenyl, C 1-4 Alkyl, -C 1-4 Alkyl-NH2, -C 1-4 Alkyl-OH, C 1-3 Alkyl-NH-C 1-3 Alkyl, C 1-3 Alkyl-OC 1-3 Alkyl, C 1-3 Alkyl-SC 1-3 Alkyl, C 1-3 Alkyl-C(=O)-C 1-3 Alkyl, C 1-3 Alkyl-S(=O)2-C 1-3alkyl, or a 3- to 6-membered saturated or unsaturated carbon or heterocyclic ring; optionally, R 4 1 to 4 identical or different R b replace; R and R' are each independently H, or C 1-6 Alkyl or C 3-6 Cycloalkyl; optionally, R and R' together with the nitrogen to which they are attached form a 4-6 membered ring, each optionally substituted with 1-3 substituents independently selected from C 1-3 Alkyl, C 3-6 Cycloalkyl or heterocyclic ring, halogen, OH, OC 1-3 Alkyl, CN; R a OH, NRR', halogen, CN, NO2, C 1-2 Alkyl, C 1-2 Haloalkyl, -C 1-4 Alkyl-NRR', -C 1-4 Alkyl-OR, C 1-2 Alkoxy, C(=O)NRR', NRC(=O)R or C(=O)R; optionally, the alkyl, R or R' is separated by 1-3 R b Replace, or two R a 'Forming =O, or two R a 'Together with the carbon atoms to which they are bonded, they form a 3-5 membered saturated or unsaturated carbocyclic or heterocyclic ring; R b Halogen, CN, OH, C 1-2 Alkyl, C 1-2 Alkyl-OH, C 3-6 Cycloalkyl, C 1-2 Alkoxy, NRR', S(=O)2NRR', C(=O)R, 5- to 6-membered aromatic carbocyclic or heterocyclic ring, C 1-2 Alkyl-carbocyclic or C 1-2 Alkyl-heterocyclic group; optionally, the alkyl, R, R', aromatic carbocyclic ring or heterocyclic ring is separated by 1 to 4 identical or different R a Replace; or two R b 'forms =O; or two R attached to the same or adjacent carbon atoms b 'Can form a 3-membered carbon ring; m is 0 or 1, 2, or 3; n1 is 0 or 1, 2, 3; n2 is 0 or 1, 2, or 3; p is 1, 2, or 3; q is 1, 2, or 3; or a pharmaceutically acceptable form or isotopic derivative thereof.

[0016] In another aspect, the present invention generally relates to a compound having structural formula III: in: Ring A is a 5-membered, 6-membered, or 7-membered substituted or unsubstituted heterocyclic ring; Ring B is a 4-membered, 5-membered, or 6-membered substituted or unsubstituted heterocyclic ring; W1, W2 and W3 are each independently CH or N; R 1 Selected from halogen and oxo, OH, CN, OR, CF3, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, 5- to 6-membered aryl or heteroaryl, NRR', N(R)C(=O)R, N(R)C(=O)(O)R, OC(=O)NRR', C(=O)R, C(=O)NRR', N(R)S(O)2R, S(O)2R, S(O)2NRR'; optionally, R 1 1 to 4 identical or different R a or R b replace; R 2 Selected from halogen and oxo, OH, CN, OR, CF3, C 1-6 alkyl; R 3 is a 5- to 6-membered aromatic carbocyclic or heterocyclic ring, a 9- to 10-membered aromatic carbocyclic or heterocyclic ring; optionally, the aromatic carbocyclic or heterocyclic ring is surrounded by 1 to 4 identical or different R a replace; R 4 is S(=O)2-C 1-4 Alkenyl, S(=O)2-C 1-4 Alkyl, C(=O)-C 1-4 Alkenyl, C(=O)-C 1-4 Alkyl, C 1-4 Alkenyl, C 1-4 Alkyl, -C 1-4 Alkyl-NH2, -C 1-4 Alkyl-OH, C 1-3 Alkyl-NH-C 1-3 Alkyl, C 1-3 Alkyl-OC 1-3 Alkyl, C 1-3 Alkyl-SC 1-3 Alkyl, C 1-3 Alkyl-C(=O)-C 1-3 Alkyl, C 1-3 Alkyl-S(=O)2-C 1-3 alkyl; optionally, R 4 1 to 4 identical or different Rb replace; R and R' are each independently H, or C 1-6 Alkyl or C 3-6 Cycloalkyl; optionally, R and R' together with the nitrogen to which they are attached form a 4-6 membered ring, each optionally substituted with 1-3 substituents independently selected from C 1-3 Alkyl, halogen, OH, OC 1-3 Alkyl, CN; R a OH, NRR', halogen, CN, NO2, C 1-2 Alkyl, C 1-2 Haloalkyl, -C 1-4 Alkyl-NRR', -C 1-4 Alkyl-OR, C 1-2 Alkoxy, C(=O)NRR', NRC(=O)R or C(=O)R; or two R a 'Forming =O, or two R a 'Together with the carbon atoms to which they are bonded, they form a 3-5 membered saturated or unsaturated carbocyclic or heterocyclic ring; R b Halogen, CN, OH, C 1-2 Alkyl, C 1-2 Alkyl-OH, C 3-6 Cycloalkyl, C 1-2 Alkoxy, NRR', S(=O)2NRR', C(=O)R, 5- to 6-membered aromatic carbocyclic or heterocyclic ring, C 1-2 Alkyl-carbocyclic or C 1-2 Alkyl-heterocyclic group; optionally, the aromatic carbocyclic or heterocyclic ring is surrounded by 1 to 4 identical or different R a Replace; or two R b 'forms =O; or two R attached to the same or adjacent carbon atoms b 'Can form a 3-membered carbon ring; m is 0 or 1, 2, or 3; n1 is 0 or 1, 2, 3; n2 is 0 or 1, 2, or 3; p is 1, 2, or 3; q is 1, 2, or 3; or a pharmaceutically acceptable form or isotopic derivative thereof. In another aspect, the present invention generally relates to a pharmaceutical composition comprising a compound of Formula I, II or III or a compound disclosed herein, which is effective in treating or alleviating one or more diseases or disorders in mammals, including humans.

[0017] In another aspect, the present invention generally relates to a unit dosage form comprising a pharmaceutical composition disclosed herein.

[0018] In another aspect, the present invention generally relates to a method for treating or ameliorating a disease or disorder mediated by or associated with stimulator of interferon genes (STING), comprising administering to a subject in need thereof a pharmaceutical composition having Structural Formula I or Structural Formula II: in: Ring A is a 5-membered, 6-membered, or 7-membered substituted or unsubstituted heterocyclic ring; Ring B is a 4-membered, 5-membered, or 6-membered substituted or unsubstituted heterocyclic ring; Y1 is CR c or N; W1, W2, W3, and W4 are each independently CH or N; R 1 Selected from halogen and oxo, OH, CN, OR, CF3, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, 5- to 6-membered aryl or heteroaryl, 6- to 10-membered fused, spiro or bridged bicyclic, NRR', N(R)C(=O)R, N(R)C(=O)(O)R, OC(=O)NRR', C(=O)R, C(=O)NRR', N(R)S(O)2R, S(O)2R, S(O)2NRR'; optionally, R 1 1 to 4 identical or different R a or R b Replacement; two R 1 'Together with the carbon or heteroatom to which they are attached, they may form a 4-6 membered carbocyclic or heterocyclic ring; R 2 Selected from halogen and oxo, OH, CN, OR, CF3, C 1-6 Alkyl; optionally, the C 1-6 The alkyl group is replaced by 1-2 R b Replacement; two R 2 'Together with the carbon or heteroatom to which they are attached, they may form a 4- to 6-membered carbocyclic or heterocyclic ring; R 3 is a 5- to 6-membered aromatic carbocyclic or heterocyclic ring, a 9- to 10-membered aromatic carbocyclic or heterocyclic ring; optionally, the aromatic carbocyclic or heterocyclic ring is surrounded by 1 to 4 identical or different R a replace; R 4 is S(=O)2-C 1-4 Alkenyl, S(=O)2-C 1-4 Alkyl, C(=O)-C 1-4 Alkenyl, C(=O)-C 1-4 Alkyl, C 1-4 Alkenyl, C1-4 Alkyl, -C 1-4 Alkyl-NH2, -C 1-4 Alkyl-OH, C 1-3 Alkyl-NH-C 1-3 Alkyl, C 1-3 Alkyl-OC 1-3 Alkyl, C 1-3 Alkyl-SC 1-3 Alkyl, C 1-3 Alkyl-C(=O)-C 1-3 Alkyl, C 1-3 Alkyl-S(=O)2-C 1-3 alkyl, or a 3- to 6-membered saturated or unsaturated carbon or heterocyclic ring; optionally, R 4 1 to 4 identical or different R b replace; R and R' are each independently H, or C 1-6 Alkyl or C 3-6 Cycloalkyl; optionally, R and R' together with the nitrogen to which they are attached form a 4-6 membered ring, each optionally substituted with 1-3 substituents independently selected from C 1-3 Alkyl, C 3-6 Cycloalkyl or heterocyclic ring, halogen, OH, OC 1-3 Alkyl, CN; R a OH, NRR', halogen, CN, NO2, C 1-2 Alkyl, C 1-2 Haloalkyl, -C 1-4 Alkyl-NRR', -C 1-4 Alkyl-OR, C 1-2 Alkoxy, C(=O)NRR', NRC(=O)R or C(=O)R; optionally, the alkyl, R or R' is separated by 1-3 R b Replace, or two R a 'Forming =O, or two R a 'Together with the carbon atoms to which they are bonded, they form a 3-5 membered saturated or unsaturated carbocyclic or heterocyclic ring; R b Halogen, CN, OH, C 1-2 Alkyl, C 1-2 Alkyl-OH, C 3-6 Cycloalkyl, C 1-2 Alkoxy, NRR', S(=O)2NRR', C(=O)R, 5- to 6-membered aromatic carbocyclic or heterocyclic ring, C 1-2 Alkyl-carbocyclic or C 1-2 Alkyl-heterocyclic group; optionally, the alkyl, R, R', aromatic carbocyclic ring or heterocyclic ring is separated by 1 to 4 identical or different R aReplace; or two R b 'forms =O; or two R attached to the same or adjacent carbon atoms b 'Can form a 3-membered carbon ring; R c H or C 1-2 Alkyl, optionally substituted with 1-5 halogens; m is 0 or 1, 2, or 3; n is 0 or 1, 2, or 3; p is 1, 2, or 3; q is 1, 2, or 3; or a pharmaceutically acceptable form or isotopic derivative thereof.

[0019] In another aspect, the present invention generally relates to a method for treating or ameliorating a disease or disorder mediated by or associated with stimulator of interferon genes (STING), comprising administering to a subject in need thereof a pharmaceutical composition having structural formula III: in: Ring A is a 5-membered, 6-membered, or 7-membered substituted or unsubstituted heterocyclic ring; Ring B is a 4-membered, 5-membered, or 6-membered substituted or unsubstituted heterocyclic ring; W1, W2 and W3 are each independently CH or N; R 1 Selected from halogen and oxo, OH, CN, OR, CF3, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, 5- to 6-membered aryl or heteroaryl, 6- to 10-membered fused, spiro or bridged bicyclic, NRR', N(R)C(=O)R, N(R)C(=O)(O)R, OC(=O)NRR', C(=O)R, C(=O)NRR', N(R)S(O)2R, S(O)2R, S(O)2NRR'; optionally, R 1 1 to 4 identical or different R a or R b Replacement; two R 1 'Together with the carbon or heteroatom to which they are attached, they may form a 4-6 membered carbocyclic or heterocyclic ring; R 2 Selected from halogen and oxo, OH, CN, OR, CF3, C 1-6 Alkyl; optionally, the C 1-6 The alkyl group is replaced by 1-2 R b Replacement; two R 2 'Together with the carbon or heteroatom to which they are attached, they may form a 4- to 6-membered carbocyclic or heterocyclic ring; R 3is a 5- to 6-membered aromatic carbocyclic or heterocyclic ring, a 9- to 10-membered aromatic carbocyclic or heterocyclic ring; optionally, the aromatic carbocyclic or heterocyclic ring is surrounded by 1 to 4 identical or different R a replace; R 4 is S(=O)2-C 1-4 Alkenyl, S(=O)2-C 1-4 Alkyl, C(=O)-C 1-4 Alkenyl, C(=O)-C 1-4 Alkyl, C 1-4 Alkenyl, C 1-4 Alkyl, -C 1-4 Alkyl-NH2, -C 1-4 Alkyl-OH, C 1-3 Alkyl-NH-C 1-3 Alkyl, C 1-3 Alkyl-OC 1-3 Alkyl, C 1-3 Alkyl-SC 1-3 Alkyl, C 1-3 Alkyl-C(=O)-C 1-3 Alkyl, C 1-3 Alkyl-S(=O)2-C 1-3 alkyl, or a 3- to 6-membered saturated or unsaturated carbon or heterocyclic ring; optionally, R 4 1 to 4 identical or different R b replace; R and R' are each independently H, or C 1-6 Alkyl or C 3-6 Cycloalkyl; optionally, R and R' together with the nitrogen to which they are attached form a 4-6 membered ring, each optionally substituted with 1-3 substituents independently selected from C 1-3 Alkyl, C 3-6 Cycloalkyl or heterocyclic ring, halogen, OH, OC 1-3 Alkyl, CN; R a OH, NRR', halogen, CN, NO2, C 1-2 Alkyl, C 1-2 Haloalkyl, -C 1-4 Alkyl-NRR', -C 1-4 Alkyl-OR, C 1-2 Alkoxy, C(=O)NRR', NRC(=O)R or C(=O)R; optionally, the alkyl, R or R' is separated by 1-3 R b Replace, or two R a 'Forming =O, or two R a 'Together with the carbon atoms to which they are bonded, they form a 3-5 membered saturated or unsaturated carbocyclic or heterocyclic ring; R bHalogen, CN, OH, C 1-2 Alkyl, C 1-2 Alkyl-OH, C 3-6 Cycloalkyl, C 1-2 Alkoxy, NRR', S(=O)2NRR', C(=O)R, 5- to 6-membered aromatic carbocyclic or heterocyclic ring, C 1-2 Alkyl-carbocyclic or C 1-2 Alkyl-heterocyclic group; optionally, the alkyl, R, R', aromatic carbocyclic ring or heterocyclic ring is separated by 1 to 4 identical or different R a Replace; or two R b 'forms =O; or two R attached to the same or adjacent carbon atoms b 'Can form a 3-membered carbon ring; m is 0 or 1, 2, or 3; n1 is 0 or 1, 2, 3; n2 is 0 or 1, 2, or 3; p is 1, 2, or 3; q is 1, 2, or 3; or a pharmaceutically acceptable form or isotopic derivative thereof. definition

[0020] Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. General principles of organic chemistry, as well as specific functional moieties and reactivities, are the same as those described in Organic Chemistry (Thomas Sorrell, University Science Books, Sausalito: 2006).

[0021] As used herein, "at least" a particular value is understood to mean that value and all values ​​greater than that value.

[0022] When defining compositions and methods, the term "comprising" is intended to indicate that the compositions and methods include the recited elements, but do not exclude other elements. "Consisting essentially of," when used to define compositions and methods, shall mean excluding other elements of any essential importance to the recited purpose of the composition. For example, "consisting essentially of" refers to the use of the pharmacologically active agents specifically listed, but excludes pharmacologically active agents not specifically listed. The term "consisting essentially of" does not exclude pharmacologically inert or inert agents, such as pharmaceutically acceptable excipients, carriers, or diluents. When defining compositions and methods, "consisting of" shall mean excluding trace elements of other ingredients and essential method steps. Embodiments defined by each of these transition terms are within the scope of the present invention.

[0023] Unless otherwise expressly indicated herein, the term "about" should be understood to mean within the normal tolerance range in the art, such as within 2 standard deviations of the mean. Approximately can be understood as 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05% or 0.01% of the specified value. Unless the context clearly indicates otherwise, all numerical values ​​provided herein may be modified by the term "about".

[0024] The term "administering" as used in the present invention includes administering the compound of the present invention, its prodrug or other pharmaceutically acceptable forms to a subject by any appropriate formulation or administration route.

[0025] Unless the context clearly indicates otherwise, the terms "disease," "disorder," and "disorder" are used interchangeably.

[0026] The term "effective amount" or "therapeutically effective amount" used in the present invention refers to an amount of the compound or pharmaceutical composition described in the present invention that is sufficient to achieve the intended application effect (including but not limited to disease treatment), as shown below.

[0027] In some synthetic approaches, an "effective amount" is a dose effective to kill or inhibit the growth or spread of cancer cells, reduce the size or number of tumors, or other measure of the grade, stage, progression, or severity of cancer as detected by a method.

[0028] The term "therapeutically effective amount" depends largely on the intended mode of application, or the subject being treated and the disease state, such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of treatment, the patient's weight and age, and is readily determined by one of ordinary skill in the art. The term also applies to doses that elicit a specific response in target cells, such as, for example, a reduction in cancer cell metastasis. The specific dosage depends on the specific compound selected, the species of the subject being administered and their age / current health status or risk of disease, the dosing regimen to be followed, the severity of the disease, whether other drugs are used in combination, the timing of administration, the tissue to be administered, and the delivery system to be used to deliver the compound.

[0029] The term "optionally substituted" means that a given chemical structure (e.g., an alkyl group) can (but need not) be attached to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group can be a fully saturated alkyl chain (i.e., a pure hydrocarbon) or can be an alkyl group with substituents other than hydrogen. For example, it can be attached to a halogen atom, a hydroxyl group, or any other substituent described in the invention at any point along the chain. Therefore, the term "optionally substituted" means that a given chemical structure may contain other functional groups, but not necessarily other functional groups. Suitable substituents for use in the selective substitution of the groups are, but are not limited to, halogen, oxo, -CN, -COOH, -CH2CN, -O-C1-C6 alkyl, C1-C6 alkyl, -O-(C1-C6 alkenyl), -O(C1-C6 alkynyl), -(C1-C6 alkenyl), -C1-C6 alkynyl, -OH, -OP(O)(OH)2, -OC(O)-(C1-C6 alkyl), -C(O)C1-C6 alkyl, -OC(O)O(C1-C6 alkyl), -NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -NHC(O)(C1-C6 alkyl), -C(O)NH(C1-C6 alkyl), -S(O)2-(C1-C6 alkyl), -S(O)NH(C1-C6 alkyl), S(O)N(C1-C6 alkyl)2.

[0030] As used herein, "pharmaceutically acceptable forms" of the disclosed compounds include, but are not limited to, pharmaceutically acceptable salts, esters, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives of the disclosed compounds. In one embodiment, "pharmaceutically acceptable forms" include, but are not limited to, pharmaceutically acceptable salts, esters, isomers, prodrugs, and isotopically labeled derivatives of the disclosed compounds. In certain embodiments, "pharmaceutically acceptable forms" include, but are not limited to, pharmaceutically acceptable salts, esters, stereoisomers, prodrugs, and isotopically labeled derivatives of the disclosed compounds.

[0031] In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for contact with the tissues of a subject without producing excessive toxicity, irritation, allergic reaction, etc., within the scope of reasonable medical judgment, and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., in Pharmaceutical Science (1977) 66: 1-19, describe pharmaceutically acceptable salts in detail. Pharmaceutically acceptable salts of the compounds provided herein include those derived from appropriate inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are amino salts formed by inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by using other methods in the art, such as amino salts formed by ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonic acid, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, gluconate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, laurate, dodecylsulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, dodecanoate, valerate, and the like. In certain embodiments, organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoroacetic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0032] Salts can be prepared in situ during the isolation and purification of the disclosed compounds, or separately, for example, by reacting the free base or free acid of the parent compound with a suitable base or acid, respectively. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4Salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and primary amine cations formed by counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In certain embodiments, pharmaceutically acceptable base addition salts can be selected from ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0033] In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable ester. As used herein, "pharmaceutically acceptable esters" refer to ester compounds that are hydrolyzable in vivo, including those that readily decompose in the human body and leave the parent compound or a salt thereof. Such esters may also serve as prodrugs as defined herein. Pharmaceutically acceptable esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl esters of acidic groups including, but not limited to, carboxylic, phosphoric, phosphinic, sulfinic, sulfonic, and boric acids. Examples of esters include formates, acetates, propionates, butyrates, acrylates, and ethyl succinate. Esters may be formed from hydroxyl or carboxylic acid groups of the parent compound.

[0034] In certain embodiments, the pharmaceutically acceptable form is a "solvate" (e.g., a hydrate). As used herein, the term "solvate" refers to a compound that further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. The solvate can be a disclosed compound or a pharmaceutically acceptable salt thereof. When the solvent is water, the solvate is a "hydrate." Pharmaceutically acceptable solvates and hydrates are complexes that can include, for example, about 1 to 100, 1 to 10, 1 to 2, 3, or 4 solvent or water molecules. It should be understood that the term "compound" used herein includes compounds and solvates of compounds, and mixtures thereof.

[0035] In certain embodiments, the pharmaceutically acceptable form is a prodrug. As used herein, the term "prodrug" (or "prodrug") refers to a compound that is converted in vivo to produce a compound disclosed herein or a pharmaceutically acceptable form of the compound. The prodrug is inactive when administered to a subject, but can be converted into an active compound in vivo by hydrolysis (e.g., hydrolysis in the blood). In some cases, the prodrug has better physical and / or transport properties than the parent compound. When administered to a subject, the prodrug can increase the bioavailability of the compound (e.g., by enhancing blood absorption through oral administration), which improves the transport efficiency to the target biological compartment (e.g., the brain or lymphatic system) relative to the parent compound. Relative to the parent compound, exemplary prodrugs include derivatives of the disclosed compounds that have strong water solubility or active transport across the intestinal membrane.

[0036] Prodrug compounds often have advantages in solubility, tissue compatibility or delayed release in mammalian organisms (see, Bundgard, H., Prodrug Design (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). Regarding prodrugs, Higuchi, T. et al., Prodrugs: A Novel Drug Delivery System, ACS Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, Edward B. Roche, American Medical Association and Pergamon Press, 1987, provide discussions, both of which are fully incorporated herein by reference. Exemplary advantages of prodrugs include, but are not limited to, physical properties, such as increased water solubility at physiological pH for parenteral administration, enhanced digestive tract absorption, or enhanced stability of the drug during long-term storage compared to the parent compound.

[0037] As used herein, the term "pharmaceutically acceptable" excipient, carrier, or diluent refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that participates in the transport or delivery of the subject drug from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Examples of materials that can be used as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffered saline; and other nontoxic, compatible substances used in pharmaceutical formulations. Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate, magnesium stearate and polyethylene oxide-polypropylene oxide copolymers, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0038] As used herein, the term "subject" refers to any animal (e.g., mammal), including but not limited to humans, non-human primates, rodents, a population awaiting a specific treatment. Typically, the terms "subject" and "patient" are used interchangeably herein for human subjects.

[0039] As used herein, the terms "treating" or "managing" a disease or disorder refer to methods that alleviate, delay, or ameliorate the condition, either before or after the onset of the disease or disorder. Treatment may be directed at one or more effects or symptoms of the disease and / or underlying pathology. Treatment is intended to achieve beneficial or desired results, including but not limited to therapeutic benefit and / or prophylactic benefit. A therapeutic benefit refers to eradication or amelioration of the underlying disease being treated, such that, while the patient may still be in the disease state, improvement is observed in the patient by eliminating or ameliorating one or more physiological symptoms associated with the underlying disease. A prophylactic benefit refers to the administration of a pharmaceutical compound and / or composition to a patient at risk for developing a particular disease or a patient who, although a diagnosis has not been made, reports one or more pathophysiological symptoms of a disease. Treatment may include, but is not limited to, alleviation or complete elimination of the disease or symptom. Such alleviation or prevention may be at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100% (as measured by any standard technique) compared to an equivalent untreated control group.

[0040] The term "therapeutic effect" as used herein refers to the therapeutic benefit and / or prophylactic benefit described herein. A prophylactic effect includes delaying or eliminating the onset of a disease or disorder, delaying or eliminating the onset of symptoms of a disease or disorder, slowing, halting, or reversing the progression of a disease or disorder, or any combination thereof.

[0041] After the compounds of the present disclosure are prepared, they are preferably isolated and purified to obtain compositions containing 95% or more by weight ("substantially pure") and then used or formulated as described herein. In certain embodiments, the compounds of the present disclosure are greater than 99% pure.

[0042] Solvates and polymorphs of the compounds of the invention are also contemplated herein. Solvates of the compounds of the invention include, for example, hydrates.

[0043] As used herein, the term "independent" or "substantially independent" molecules (e.g., polypeptides or polynucleotides) are molecules that have been treated to exist at a higher concentration than naturally present or separated from their naturally occurring environment. For example, when at least 10%, 20%, 40%, 50%, 70%, 90% of the non-subject antibody components present in the natural state are removed, the subject antibody is isolated, purified, substantially independent, or substantially purified. For example, a polynucleotide or polypeptide naturally present in a living animal is not "independent", but a polynucleotide or polypeptide separated from the coexisting components of its natural state is "independent". In addition, the present invention considers that the recombinant DNA molecules contained in the vector are independent. Independent RNA molecules include in vivo or in vitro RNA replication products of DNA and RNA molecules. Independent nucleic acid molecules also include synthetically produced nucleic acid molecules. In addition, vector molecules contained in recombinant host cells are independent. Therefore, not all "independent" molecules need to be "purified".

[0044] As used herein, the term "purified" when describing a molecule refers to an increased concentration of the molecule relative to molecules with which it is associated in its natural environment or in the environment in which it is produced, discovered, or synthesized. Naturally associated molecules include proteins, nucleic acids, lipids, and sugars, but generally exclude water, buffers, and reagents added to maintain integrity or facilitate purification of the molecule. According to this definition, when other impurities are taken into account, the purity of a substance can be greater than 5%, greater than 10%, greater than 20%, greater than 30%, greater than 40%, greater than 50%, greater than 60%, greater than 70%, greater than 80%, greater than 90%, greater than 95%, greater than 98%, greater than 99%, or greater than 100%.

[0045] The definitions of functional groups and chemical terms are described in more detail below. The listed range values ​​are intended to include every value and subrange within the range. For example, "C 1-4 "Alkyl" means C1, C2, C3, C4, C1-3 、C 1-2 、C 2-4 、C 3-4 and C 2-3 alkyl.

[0046] As used herein, the term "alkyl" refers to a straight or branched chain group consisting solely of carbon atoms and hydrogen atoms, free of unsaturated bonds, having 1 to 10 carbon atoms (e.g., C1-10 alkyl). Herein, references such as "1 to 10" refer to each integer within a given range; for example, "1 to 10 carbon atoms" means that the alkyl group can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, up to and including 10 carbon atoms, and this definition also encompasses the term "alkyl" without specifying a numerical range. In certain embodiments, the "alkyl" group can be a C1-6 alkyl group. In certain embodiments, the alkyl group has 1 to 10, 1 to 8, 1 to 6, or 1 to 3 carbon atoms. Representative saturated straight chain alkyl groups include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and -n-hexyl; while saturated branched chain alkyl groups include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, etc. The alkyl group is attached to the parent molecular group by a single bond. Unless otherwise stated in the specification, an alkyl group may be optionally substituted with one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halogen, haloalkoxy, haloalkyl, ester, ether, thiol, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamido, sulfone, sulfonate, urea, -Si(R) a )3. -OR a 、-SR a 、-OC(O)-R a 、-N(R a )2、-C(O)R a 、-C(O)OR a 、-OC(O)N(R a )2、-C(O)N(R a )2、-N(R a )C(O)OR a 、-N(R a )C(O)R a 、-N(R a )C(O)N(Ra )2、-N(R a )C(NR a )N(R a )2、-N(R a )S(O) t N(R a )2 (wherein t is 1 or 2), -P(=O)(R a )(R a ), or -OP(=O)(OR a )2, where each R a In some embodiments, the alkyl radicals of the present invention are substituted alkyl radicals, ...

[0047] Unless otherwise specified, the term "aromatic" or "aryl" refers to a cyclic aromatic hydrocarbon group having 1-2 aromatic rings, including monocyclic or bicyclic groups, such as phenyl, biphenyl or naphthyl. In the case of containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group can be connected (such as biphenyl) or fused (such as naphthyl) at a single site. The aryl group can be optionally substituted with one or more substituents at any site, for example, 1-5 substituents. Examples of typical substituents include, but are not limited to, H, halogen, -O-C1-C6 alkyl, C1-C6 alkyl, -C1-C6 alkenyl, -OC1-C6 alkynyl, -C1-C6 alkenyl, -C1-C6 alkynyl, -OH, -OP(O)(OH)2, -OC(O)C1-C6 alkyl, -C(O)C1-C6 alkyl, -OC(O)OC1-C6 alkyl, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(O)2-C1-C6 alkyl, -S(O)NHC1-C6 alkyl, or S(O)N(C1-C6 alkyl)2. The substituents themselves may also be optionally substituted. In addition, when containing two fused rings, the aryl groups defined herein may have unsaturated or partially saturated rings fused to a fully unsaturated ring. These typical aromatic ring systems include indolyl, indenyl, tetrahydronaphthyl, and tetrahydrobenzonaphthylene.

[0048] The term "halogen" in the present invention refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0049] Unless otherwise defined, the "heteroaryl" or "heteroaromatic ring" described in the present invention refers to a monocyclic heteroaryl or a bicyclic heteroaryl. A monocyclic heteroaryl is a 5- or 6-membered ring. A 5-membered ring contains two double bonds and comprises one, two, three or four heteroatoms independently selected from N, O and S, a 6-membered ring contains three double bonds and comprises one, two, three or four heteroatoms independently selected from N, O and S, and a bicyclic heteroaromatic ring is composed of a 5- or 6-membered heteroaryl and a phenyl, a 5- or 6-membered heteroaryl and a cycloalkyl, a 5- or 6-membered heteroaryl and a cycloalkenyl, or a 5- or 6-membered heteroaryl and another 5- or 6-membered heteroaryl fused together. The nitrogen heteroatom contained in the heteroaryl may optionally be oxidized to an N-oxide or optionally protected by a nitrogen protecting group known to those skilled in the art. The heteroaryl is connected to the parent molecule through any carbon atom or any nitrogen atom within the heteroaryl. Representative examples of heteroaryl groups include, but are not limited to, benzothiophenyl, benzoxadiazolyl, coumarin, 5,6-dihydroisoquinolyl, 7,8-dihydroisoquinolyl, 5,6-dihydroquinolyl, 7,8-dihydroquinolyl, furopyridinyl, furanyl, imidazolyl, indazolyl, indolyl, isoxazolyl, isoquinolyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, pyridinium N-oxide, quinolyl, 5,6,7,7,8-tetrahydroisoquinolyl, 5,6,7,7,8-tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienopyridinyl, thienyl, triazolyl, and triazinyl.

[0050] The term "heteroaryl" or "heteroaromatic ring" group of the present invention can be substituted by 0, 1, 2, 3, 4 substituents independently selected from the following: alkenyl, alkoxy, alkoxyalkoxyalkoxyalkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, carboxyl, carboxylalkyl, cyano, cyanoalkyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxyl, hydroxyalkyl, sulfydryl, nitro ,-NZ1Z2 and (NZ1Z2)-carbonyl. Term "NZ1Z2" used in the present invention refers to that two groups Z1 and Z2 are connected to the parent molecular moiety by nitrogen-atoms. Z1 and Z2 are each independently selected from hydrogen, alkyl, alkylcarbonyl and formyl. Representative examples of NZ1Z2 include but are not limited to amino, methylamino, acetamido and acetylmethylamino.

[0051] As used herein, the term "alkoxy" refers to an -O-alkyl group.

[0052] As used herein, the terms "cycloalkyl" and "carbocyclyl" refer to monocyclic or polycyclic groups containing only carbon and hydrogen, respectively, and may be saturated or partially unsaturated. Partially unsaturated cycloalkyl groups may be referred to as "cycloalkenyl" if the carbocyclic ring contains at least one double bond, and as "cycloalkynyl" if the carbocyclic ring contains at least one triple bond. Cycloalkyl groups include groups having 3 to 13 ring atoms (i.e., C 3-13 Cycloalkyl). When appearing herein, a numerical range such as "3 to 10" refers to each integer in the given range; for example, "3 to 13 carbon atoms" means that the cycloalkyl group can be composed of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., up to and including 13 carbon atoms. The term "cycloalkyl" also includes bridged and spiro-fused ring structures that do not contain heteroatoms. The term also includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of atoms) groups. Polycyclic aromatic groups include bicyclic, tricyclic, tetracyclic, etc. In certain embodiments, "cycloalkyl" can be C 3-8 In certain embodiments, a "cycloalkyl" may be a C 3-5 Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties: C 3-6 Carbocyclic groups include, but are not limited to, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. 3-7 Examples of carbocyclic groups include norbornene (C7). 3-8 Examples of the carbocyclic group include the above-mentioned C 3-7 Carbocyclic groups and cycloheptyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, etc. 3-13 Examples of the carbocyclic group include the above-mentioned C 3-8 Unless otherwise stated in the specification, the cycloalkyl radical may be optionally substituted with one or more substituents independently comprising: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halogen, haloalkoxy, haloalkyl, ester, ether, sulfhydryl, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamido, sulfone, sulfonate, urea, -Si(R a )3. -OR a 、-SR a 、-OC(O)-R a 、-N(R a )2、-C(O)Ra 、-C(O)OR a 、-OC(O)N(R a )2、-C(O)N(R a )2、-N(R a )C(O)OR a 、-N(R a )C(O)R a 、-N(R a )C(O)N(R a )2、-N(R a )C(NR a )N(R a )2、-N(R a )S(O) t N(R a )2 (wherein t is 1 or 2), -P(=O)(R a )(R a ), or -OP(=O)(OR a )2, where each R a In some embodiments, the cycloalkenyl radical is a cycloalkyl radical, ...

[0053] As used herein, the term "heterocycloalkyl" refers to a cycloalkyl group having one or more backbone atoms selected from atoms other than carbon, such as O, N, S, P, or combinations thereof. Unless otherwise specified in the specification, the term is intended to include both substituted and unsubstituted heterocycloalkyl groups. Examples of heterocycloalkyl groups include 2-hydroxy-aziridine-1-yl, 3-oxo-1-oxetane-2-yl, 2,2-dimethyl-tetrahydrofuran-3-yl, 3-carboxy-morpholin-4-yl, 1-cyclopropyl-4-methylpiperazin-2-yl, 2-pyrrolinyl, 3-pyrrolinyl, dihydro-2H-pyranyl, 1,2,3,4-tetrahydropyridine, 3,4-dihydro-2H-[1,4]oxazine, and the like.

[0054] As used herein, the term "heterocycle", "heterocyclic ring" or "heterocyclyl" refers to a fully saturated or partially unsaturated cyclic group, such as a 3- to 7-membered monocyclic ring, a 7- to 12-membered bicyclic ring or a 10- to 15-membered tricyclic ring system, which has at least one heteroatom in at least one ring, wherein 0, 1, 2 or 3 atoms of each ring may be substituted with a substituent. Each ring of the heterocyclic group containing heteroatoms may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and / or sulfur atoms, wherein the nitrogen and sulfur heteroatoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heterocyclic group may be attached to any heteroatom or carbon atom of the ring or ring system. Detailed Description of the Invention

[0055] The present invention is based, in part, on the discovery of novel modulators of STING, pharmaceutical compositions thereof, methods for their preparation, and uses in treating various diseases and conditions, such as cancer (e.g., breast cancer, colon cancer, endometrial cancer, kidney cancer, lung cancer, melanoma, prostate cancer, thyroid cancer, and leukemia).

[0056] In one aspect, the present invention generally relates to a compound having structural formula I or structural formula II: in: Ring A is a 5-membered, 6-membered, or 7-membered substituted or unsubstituted heterocyclic ring; Ring B is a 4-membered, 5-membered, or 6-membered substituted or unsubstituted heterocyclic ring; Y1 is CR c or N; W1, W2, W3, and W4 are each independently CH or N; R 1 Selected from halogen and oxo, OH, CN, OR, CF3, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, 5- to 6-membered aryl or heteroaryl, 6- to 10-membered fused, spiro or bridged bicyclic, NRR', N(R)C(=O)R, N(R)C(=O)(O)R, OC(=O)NRR', C(=O)R, C(=O)NRR', N(R)S(O)2R, S(O)2R, S(O)2NRR'; optionally, R 1 1 to 4 identical or different R a or R b Replacement; two R 1 'Together with the carbon or heteroatom to which they are attached, they may form a 4-6 membered carbocyclic or heterocyclic ring; R 2 Selected from halogen and oxo, OH, CN, OR, CF3, C 1-6 Alkyl; optionally, the C 1-6 The alkyl group is replaced by 1-2 Rb Replacement; two R 2 'Together with the carbon or heteroatom to which they are attached, they may form a 4- to 6-membered carbocyclic or heterocyclic ring; R 3 is a 5- to 6-membered aromatic carbocyclic or heterocyclic ring, a 9- to 10-membered aromatic carbocyclic or heterocyclic ring; optionally, the aromatic carbocyclic or heterocyclic ring is surrounded by 1 to 4 identical or different R a replace; R 4 is S(=O)2-C 1-4 Alkenyl, S(=O)2-C 1-4 Alkyl, C(=O)-C 1-4 Alkenyl, C(=O)-C 1-4 Alkyl, C 1-4 Alkenyl, C 1-4 Alkyl, -C 1-4 Alkyl-NH2, -C 1-4 Alkyl-OH, C 1-3 Alkyl-NH-C 1-3 Alkyl, C 1-3 Alkyl-OC 1-3 Alkyl, C 1-3 Alkyl-SC 1-3 Alkyl, C 1-3 Alkyl-C(=O)-C 1-3 Alkyl, C 1-3 Alkyl-S(=O)2-C 1-3 alkyl, or a 3- to 6-membered saturated or unsaturated carbon or heterocyclic ring; optionally, R 4 1 to 4 identical or different R b replace; R and R' are each independently H, or C 1-6 Alkyl or C 3-6 Cycloalkyl; optionally, R and R' together with the nitrogen to which they are attached form a 4-6 membered ring, each optionally substituted with 1-3 substituents independently selected from C 1-3 Alkyl, C 3-6 Cycloalkyl or heterocyclic ring, halogen, OH, OC 1-3 Alkyl, CN; R a OH, NRR', halogen, CN, NO2, C 1-2 Alkyl, C 1-2 Haloalkyl, -C 1-4 Alkyl-NRR', -C 1-4 Alkyl-OR, C 1-2 Alkoxy, C(=O)NRR', NRC(=O)R or C(=O)R; optionally, the alkyl, R or R' is separated by 1-3 R b Replace, or two Ra 'Forming =O, or two R a 'Together with the carbon atoms to which they are bonded, they form a 3-5 membered saturated or unsaturated carbocyclic or heterocyclic ring; R b Halogen, CN, OH, C 1-2 Alkyl, C 1-2 Alkyl-OH, C 3-6 Cycloalkyl, C 1-2 Alkoxy, NRR', S(=O)2NRR', C(=O)R, 5- to 6-membered aromatic carbocyclic or heterocyclic ring, C 1-2 Alkyl-carbocyclic or C 1-2 Alkyl-heterocyclic group; optionally, the alkyl, R, R', aromatic carbocyclic ring or heterocyclic ring is separated by 1 to 4 identical or different R a Replace; or two R b 'forms =O; or two R attached to the same or adjacent carbon atoms b 'Can form a 3-membered carbon ring; R c H or C 1-2 Alkyl, optionally substituted with 1-5 halogens; m is 0 or 1, 2, or 3; n is 0 or 1, 2, or 3; p is 1, 2, or 3; q is 1, 2, or 3; or a pharmaceutically acceptable form or isotopic derivative thereof.

[0057] In certain embodiments, the compound has structural formula I.

[0058] In certain embodiments, Ring A is a substituted or unsubstituted 5- to 7-membered heterocyclic ring.

[0059] In certain embodiments, Ring A is: in: Y2 is CRR' or C=O; Y3, Y4 and Y5 are each independently selected from N, O, CRR' and C=O.

[0060] Non-limiting examples include:

[0061] In certain embodiments of formula I, W1 is CH or C-halo (such as CF), W2 is CH or C-halo (such as CF), and W3 is CR 1 .

[0062] In certain embodiments of Formula I, W1 is N, W2 is CH or C-halo (eg, CF), and W3 is CR 1 .

[0063] In certain embodiments of Structural Formula I, p is 1 and q is 1.

[0064] In certain embodiments, the compound has structural formula II.

[0065] In certain embodiments, Ring B is an aromatic ring. In certain embodiments, Ring B is not an aromatic ring. Y6 is CRR' or S,O; Y7 and Y8 are each independently selected from N, O, and CRR'.

[0066] Non-limiting examples include:

[0067] In certain embodiments of formula II, W1 is CH or C-halo (such as CF), W2 is CH or C-halo (such as CF), and W3 is CR 1 , W4 is CH or C-halo (such as CF).

[0068] In certain embodiments of formula II, W1 is N, W2 is CH or C-halo (such as CF), and W3 is CR 1 , W4 is CH or C-halo (such as CF).

[0069] In certain embodiments of Formula II, p is 1 and q is 1.

[0070] In one aspect, the present invention generally relates to a compound having structural formula III: in: Ring A is a 5-membered, 6-membered, or 7-membered substituted or unsubstituted heterocyclic ring; Ring B is a 4-membered, 5-membered, or 6-membered substituted or unsubstituted heterocyclic ring; W1, W2 and W3 are each independently CH or N; R 1 Selected from halogen and oxo, OH, CN, OR, CF3, C 1-6 Alkyl, C 3-6Cycloalkyl, 3- to 6-membered heterocycloalkyl, 5- to 6-membered aryl or heteroaryl, 6- to 10-membered fused, spiro or bridged bicyclic, NRR', N(R)C(=O)R, N(R)C(=O)(O)R, OC(=O)NRR', C(=O)R, C(=O)NRR', N(R)S(O)2R, S(O)2R, S(O)2NRR'; optionally, R 1 1 to 4 identical or different R a or R b Replacement; two R 1 'Together with the carbon or heteroatom to which they are attached, they may form a 4-6 membered carbocyclic or heterocyclic ring; R 2 Selected from halogen and oxo, OH, CN, OR, CF3, C 1-6 Alkyl; optionally, the C 1-6 The alkyl group is replaced by 1-2 R b Replacement; two R 2 'Together with the carbon or heteroatom to which they are attached, they may form a 4- to 6-membered carbocyclic or heterocyclic ring; R 3 is a 5- to 6-membered aromatic carbocyclic or heterocyclic ring, a 9- to 10-membered aromatic carbocyclic or heterocyclic ring; optionally, the aromatic carbocyclic or heterocyclic ring is surrounded by 1 to 4 identical or different R a replace; R 4 is S(=O)2-C 1-4 Alkenyl, S(=O)2-C 1-4 Alkyl, C(=O)-C 1-4 Alkenyl, C(=O)-C 1-4 Alkyl, C 1-4 Alkenyl, C 1-4 Alkyl, -C 1-4 Alkyl-NH2, -C 1-4 Alkyl-OH, C 1-3 Alkyl-NH-C 1-3 Alkyl, C 1-3 Alkyl-OC 1-3 Alkyl, C 1-3 Alkyl-SC 1-3 Alkyl, C 1-3 Alkyl-C(=O)-C 1-3 Alkyl, C 1-3 Alkyl-S(=O)2-C 1-3 alkyl, or a 3- to 6-membered saturated or unsaturated carbon or heterocyclic ring; optionally, R 4 1 to 4 identical or different R b replace; R and R' are each independently H, or C 1-6 Alkyl or C 3-6Cycloalkyl; optionally, R and R' together with the nitrogen to which they are attached form a 4-6 membered ring, each optionally substituted with 1-3 substituents independently selected from C 1-3 Alkyl, C 3-6 Cycloalkyl or heterocyclic ring, halogen, OH, OC 1-3 Alkyl, CN; R a OH, NRR', halogen, CN, NO2, C 1-2 Alkyl, C 1-2 Haloalkyl, -C 1-4 Alkyl-NRR', -C 1-4 Alkyl-OR, C 1-2 Alkoxy, C(=O)NRR', NRC(=O)R or C(=O)R; optionally, the alkyl, R or R' is separated by 1-3 R b Replace, or two R a 'Forming =O, or two R a 'Together with the carbon atoms to which they are bonded, they form a 3-5 membered saturated or unsaturated carbocyclic or heterocyclic ring; R b Halogen, CN, OH, C 1-2 Alkyl, C 1-2 Alkyl-OH, C 3-6 Cycloalkyl, C 1-2 Alkoxy, NRR', S(=O)2NRR', C(=O)R, 5- to 6-membered aromatic carbocyclic or heterocyclic ring, C 1-2 Alkyl-carbocyclic or C 1-2 Alkyl-heterocyclic group; optionally, the alkyl, R, R', aromatic carbocyclic ring or heterocyclic ring is separated by 1 to 4 identical or different R a Replace; or two R b 'forms =O; or two R attached to the same or adjacent carbon atoms b 'Can form a 3-membered carbon ring; m is 0 or 1, 2, or 3; n1 is 0 or 1, 2, 3; n2 is 0 or 1, 2, or 3; p is 1, 2, or 3; q is 1, 2, or 3; or a pharmaceutically acceptable form or isotopic derivative thereof.

[0071] In certain embodiments of formula III, W1 is CH or C-halo (such as CF), W2 is CH or C-halo (such as CF), and W3 is CR 1 .

[0072] In certain embodiments of formula III, W1 is N, W2 is CH or C-halo (eg, CF), and W3 is CR 1 .

[0073] In certain embodiments of Formula III, p is 1 and q is 1.

[0074] Non-limiting examples of Ring AB include:

[0075] In certain embodiments of structural formula I, II, or III, R 3 is a 5-membered or 6-membered substituted or unsubstituted aromatic or heteroaromatic group;

[0076] Non-limiting examples include:

[0077] In certain embodiments of structural formula I, II, or III, R 4 is a 5-membered or 6-membered substituted or unsubstituted carbocyclic or heterocyclic ring;

[0078] Non-limiting examples include:

[0079] In certain embodiments of Structural Formula I, R 2 is a substituted or unsubstituted aromatic or heteroaromatic group;

[0080] Non-limiting examples include:

[0081] In certain embodiments of Structural Formula II, R 2 is substituted or unsubstituted aromatic or heteroaromatic;

[0082] Non-limiting examples include:

[0083] Illustratively, the compounds of the present invention include, but are not limited to: or a pharmaceutically acceptable form or isotopic derivative thereof.

[0084] In certain embodiments, one or more (e.g., 1, 2, 3) hydrogen atoms in the compounds of the invention are replaced by one or more (e.g., 1, 2, 3) deuterium atoms. In certain synthetic schemes, a hydrogen atom in the compounds of the invention is replaced by a deuterium atom.

[0085] Another aspect of the present invention generally relates to a pharmaceutical composition comprising a compound described herein, which is effective in treating or reducing one or more diseases or disorders in mammals, including humans.

[0086] Another aspect of the present invention generally relates to a pharmaceutical composition comprising a compound having structural formula (I) or structural formula (II): in: Ring A is a 5-membered, 6-membered, or 7-membered substituted or unsubstituted heterocyclic ring; Ring B is a 4-membered, 5-membered, or 6-membered substituted or unsubstituted heterocyclic ring; Y1 is CR c or N; W1, W2, W3, and W4 are each independently CH or N; R 1 Selected from halogen and oxo, OH, CN, OR, CF3, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, 5- to 6-membered aryl or heteroaryl, 6- to 10-membered fused, spiro or bridged bicyclic, NRR', N(R)C(=O)R, N(R)C(=O)(O)R, OC(=O)NRR', C(=O)R, C(=O)NRR', N(R)S(O)2R, S(O)2R, S(O)2NRR'; optionally, R 1 1 to 4 identical or different R a or R b Replacement; two R 1 'Together with the carbon or heteroatom to which they are attached, they may form a 4-6 membered carbocyclic or heterocyclic ring; R 2 Selected from halogen and oxo, OH, CN, OR, CF3, C 1-6 Alkyl; optionally, the C 1-6 The alkyl group is replaced by 1-2 R b Replacement; two R 2 'Together with the carbon or heteroatom to which they are attached, they may form a 4- to 6-membered carbocyclic or heterocyclic ring; R 3 is a 5- to 6-membered aromatic carbocyclic or heterocyclic ring, a 9- to 10-membered aromatic carbocyclic or heterocyclic ring; optionally, the aromatic carbocyclic or heterocyclic ring is surrounded by 1 to 4 identical or different R a replace; R 4 is S(=O)2-C 1-4 Alkenyl, S(=O)2-C 1-4 Alkyl, C(=O)-C 1-4 Alkenyl, C(=O)-C 1-4 Alkyl, C 1-4 Alkenyl, C 1-4 Alkyl, -C 1-4 Alkyl-NH2, -C 1-4 Alkyl-OH, C 1-3 Alkyl-NH-C 1-3 Alkyl, C 1-3 Alkyl-OC 1-3 Alkyl, C 1-3 Alkyl-SC 1-3 Alkyl, C 1-3 Alkyl-C(=O)-C 1-3 Alkyl, C 1-3 Alkyl-S(=O)2-C 1-3 alkyl, or a 3- to 6-membered saturated or unsaturated carbon or heterocyclic ring; optionally, R 4 1 to 4 identical or different R b replace; R and R' are each independently H, or C 1-6 Alkyl or C 3-6 Cycloalkyl; optionally, R and R' together with the nitrogen to which they are attached form a 4-6 membered ring, each optionally substituted with 1-3 substituents independently selected from C 1-3 Alkyl, C 3-6 Cycloalkyl or heterocyclic ring, halogen, OH, OC 1-3 Alkyl, CN; R a OH, NRR', halogen, CN, NO2, C 1-2 Alkyl, C 1-2 Haloalkyl, -C 1-4 Alkyl-NRR', -C 1-4 Alkyl-OR, C 1-2 Alkoxy, C(=O)NRR', NRC(=O)R or C(=O)R; optionally, the alkyl, R or R' is separated by 1-3 R b Replace, or two R a 'Forming =O, or two R a 'Together with the carbon atoms to which they are bonded, they form a 3-5 membered saturated or unsaturated carbocyclic or heterocyclic ring; R b Halogen, CN, OH, C 1-2 Alkyl, C 1-2 Alkyl-OH, C 3-6 Cycloalkyl, C 1-2 Alkoxy, NRR', S(=O)2NRR', C(=O)R, 5- to 6-membered aromatic carbocyclic or heterocyclic ring, C 1-2 Alkyl-carbocyclic or C 1-2 Alkyl-heterocyclic group; optionally, the alkyl, R, R', aromatic carbocyclic ring or heterocyclic ring is separated by 1 to 4 identical or different R a Replace; or two R b 'forms =O; or two R attached to the same or adjacent carbon atoms b 'Can form a 3-membered carbon ring; R c H or C 1-2 Alkyl, optionally substituted with 1-5 halogens; m is 0 or 1, 2, or 3; n is 0 or 1, 2, or 3; p is 1, 2, or 3; q is 1, 2, or 3; or a pharmaceutically acceptable form or isotopic derivative thereof, effective for treating or alleviating one or more diseases or disorders in mammals (including humans), and a pharmaceutically acceptable excipient, carrier or diluent.

[0087] In another aspect, the present invention generally relates to a pharmaceutical composition comprising a compound of formula III: in: Ring A is a 5-membered, 6-membered, or 7-membered substituted or unsubstituted heterocyclic ring; Ring B is a 4-membered, 5-membered, or 6-membered substituted or unsubstituted heterocyclic ring; W1, W2 and W3 are each independently CH or N; R 1 Selected from halogen and oxo, OH, CN, OR, CF3, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, 5- to 6-membered aryl or heteroaryl, 6- to 10-membered fused, spiro or bridged bicyclic, NRR', N(R)C(=O)R, N(R)C(=O)(O)R, OC(=O)NRR', C(=O)R, C(=O)NRR', N(R)S(O)2R, S(O)2R, S(O)2NRR'; optionally, R 1 1 to 4 identical or different R a or R b Replacement; two R1 'Together with the carbon or heteroatom to which they are attached, they may form a 4-6 membered carbocyclic or heterocyclic ring; R 2 Selected from halogen and oxo, OH, CN, OR, CF3, C 1-6 Alkyl; optionally, the C 1-6 The alkyl group is replaced by 1-2 R b Replacement; two R 2 'Together with the carbon or heteroatom to which they are attached, they may form a 4- to 6-membered carbocyclic or heterocyclic ring; R 3 is a 5- to 6-membered aromatic carbocyclic or heterocyclic ring, a 9- to 10-membered aromatic carbocyclic or heterocyclic ring; optionally, the aromatic carbocyclic or heterocyclic ring is surrounded by 1 to 4 identical or different R a replace; R 4 is S(=O)2-C 1-4 Alkenyl, S(=O)2-C 1-4 Alkyl, C(=O)-C 1-4 Alkenyl, C(=O)-C 1-4 Alkyl, C 1-4 Alkenyl, C 1-4 Alkyl, -C 1-4 Alkyl-NH2, -C 1-4 Alkyl-OH, C 1-3 Alkyl-NH-C 1-3 Alkyl, C 1-3 Alkyl-OC 1-3 Alkyl, C 1-3 Alkyl-SC 1-3 Alkyl, C 1-3 Alkyl-C(=O)-C 1-3 Alkyl, C 1-3 Alkyl-S(=O)2-C 1-3 alkyl, or a 3- to 6-membered saturated or unsaturated carbon or heterocyclic ring; optionally, R 4 1 to 4 identical or different R b replace; R and R' are each independently H, or C 1-6 Alkyl or C 3-6 Cycloalkyl; optionally, R and R' together with the nitrogen to which they are attached form a 4-6 membered ring, each optionally substituted with 1-3 substituents independently selected from C 1-3 Alkyl, C 3-6 Cycloalkyl or heterocyclic ring, halogen, OH, OC 1-3 Alkyl, CN; R a OH, NRR', halogen, CN, NO2, C 1-2 Alkyl, C 1-2Haloalkyl, -C 1-4 Alkyl-NRR', -C 1-4 Alkyl-OR, C 1-2 Alkoxy, C(=O)NRR', NRC(=O)R or C(=O)R; optionally, the alkyl, R or R' is separated by 1-3 R b Replace, or two R a 'Forming =O, or two R a 'Together with the carbon atoms to which they are bonded, they form a 3-5 membered saturated or unsaturated carbocyclic or heterocyclic ring; R b Halogen, CN, OH, C 1-2 Alkyl, C 1-2 Alkyl-OH, C 3-6 Cycloalkyl, C 1-2 Alkoxy, NRR', S(=O)2NRR', C(=O)R, 5- to 6-membered aromatic carbocyclic or heterocyclic ring, C 1-2 Alkyl-carbocyclic or C 1-2 Alkyl-heterocyclic group; optionally, the alkyl, R, R', aromatic carbocyclic ring or heterocyclic ring is separated by 1 to 4 identical or different R a Replace; or two R b 'forms =O; or two R attached to the same or adjacent carbon atoms b 'Can form a 3-membered carbon ring; m is 0 or 1, 2, or 3; n1 is 0 or 1, 2, 3; n2 is 0 or 1, 2, or 3; p is 1, 2, or 3; q is 1, 2, or 3; or a pharmaceutically acceptable form or isotopic derivative thereof, effective for treating or alleviating one or more diseases or disorders in mammals (including humans).

[0088] In certain embodiments, the pharmaceutical composition is suitable for systemic administration.

[0089] In certain embodiments, the pharmaceutical composition can be used to treat or alleviate cancer.

[0090] In certain embodiments, the pharmaceutical composition can be used to treat or alleviate breast cancer, colon cancer, endometrial cancer, kidney cancer, lung cancer, melanoma, prostate cancer, thyroid cancer, or leukemia.

[0091] In certain embodiments, the pharmaceutical composition can be used to treat or alleviate infectious diseases or disorders.

[0092] In certain embodiments, the pharmaceutical composition can be used to treat or alleviate an autoimmune disease or disorder.

[0093] In certain embodiments, the pharmaceutical composition can be used to treat or slow down aging.

[0094] Another aspect of the present invention generally relates to unit dosage forms of pharmaceutical compositions comprising the compounds disclosed herein.

[0095] In certain embodiments, the unit dosage form is suitable for systemic administration.

[0096] In certain embodiments, the unit dosage form is, in fact, an injection, solution, suspension, tablet, or capsule.

[0097] In certain embodiments, the unit dosage form is suitable for intravenous administration.

[0098] In certain embodiments, the unit dosage form is a liquid dosage form.

[0099] According to another aspect of the present invention, there is provided a method for effectively treating or alleviating tumors or related diseases or disorders in mammals, including humans, comprising administering to a subject in need of treatment for a disease or disorder a pharmaceutical composition comprising a compound of formula (I) or formula (II) or a pharmaceutically acceptable form thereof or an isotopic derivative thereof: in: Ring A is a 5-membered, 6-membered, or 7-membered substituted or unsubstituted heterocyclic ring; Ring B is a 4-membered, 5-membered, or 6-membered substituted or unsubstituted heterocyclic ring; Y1 is CR c or N; W1, W2, W3, and W4 are each independently CH or N; R 1 Selected from halogen and oxo, OH, CN, OR, CF3, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, 5- to 6-membered aryl or heteroaryl, 6- to 10-membered fused, spiro or bridged bicyclic, NRR', N(R)C(=O)R, N(R)C(=O)(O)R, OC(=O)NRR', C(=O)R, C(=O)NRR', N(R)S(O)2R, S(O)2R, S(O)2NRR'; optionally, R 1 1 to 4 identical or different R a or R b Replacement; two R 1 'Together with the carbon or heteroatom to which they are attached, they may form a 4-6 membered carbocyclic or heterocyclic ring; R 2 Selected from halogen and oxo, OH, CN, OR, CF3, C 1-6 Alkyl; optionally, the C 1-6The alkyl group is replaced by 1-2 R b Replacement; two R 2 'Together with the carbon or heteroatom to which they are attached, they may form a 4- to 6-membered carbocyclic or heterocyclic ring; R 3 is a 5- to 6-membered aromatic carbocyclic or heterocyclic ring, a 9- to 10-membered aromatic carbocyclic or heterocyclic ring; optionally, the aromatic carbocyclic or heterocyclic ring is surrounded by 1 to 4 identical or different R a replace; R 4 is S(=O)2-C 1-4 Alkenyl, S(=O)2-C 1-4 Alkyl, C(=O)-C 1-4 Alkenyl, C(=O)-C 1-4 Alkyl, C 1-4 Alkenyl, C 1-4 Alkyl, -C 1-4 Alkyl-NH2, -C 1-4 Alkyl-OH, C 1-3 Alkyl-NH-C 1-3 Alkyl, C 1-3 Alkyl-OC 1-3 Alkyl, C 1-3 Alkyl-SC 1-3 Alkyl, C 1-3 Alkyl-C(=O)-C 1-3 Alkyl, C 1-3 Alkyl-S(=O)2-C 1-3 alkyl, or a 3- to 6-membered saturated or unsaturated carbon or heterocyclic ring; optionally, R 4 1 to 4 identical or different R b replace; R and R' are each independently H, or C 1-6 Alkyl or C 3-6 Cycloalkyl; optionally, R and R' together with the nitrogen to which they are attached form a 4-6 membered ring, each optionally substituted with 1-3 substituents independently selected from C 1-3 Alkyl, C 3-6 Cycloalkyl or heterocyclic ring, halogen, OH, OC 1-3 Alkyl, CN; R a OH, NRR', halogen, CN, NO2, C 1-2 Alkyl, C 1-2 Haloalkyl, -C 1-4 Alkyl-NRR', -C 1-4 Alkyl-OR, C 1-2 Alkoxy, C(=O)NRR', NRC(=O)R or C(=O)R; optionally, the alkyl, R or R' is separated by 1-3 R bReplace, or two R a 'Forming =O, or two R a 'Together with the carbon atoms to which they are bonded, they form a 3-5 membered saturated or unsaturated carbocyclic or heterocyclic ring; R b Halogen, CN, OH, C 1-2 Alkyl, C 1-2 Alkyl-OH, C 3-6 Cycloalkyl, C 1-2 Alkoxy, NRR', S(=O)2NRR', C(=O)R, 5- to 6-membered aromatic carbocyclic or heterocyclic ring, C 1-2 Alkyl-carbocyclic or C 1-2 Alkyl-heterocyclic group; optionally, the alkyl, R, R', aromatic carbocyclic ring or heterocyclic ring is separated by 1 to 4 identical or different R a Replace; or two R b 'forms =O; or two R attached to the same or adjacent carbon atoms b 'Can form a 3-membered carbon ring; R c H or C 1-2 Alkyl, optionally substituted with 1-5 halogens; m is 0 or 1, 2, or 3; n is 0 or 1, 2, or 3; p is 1, 2, or 3; q is 1, 2, or 3; or a pharmaceutically acceptable form or isotopic derivative thereof, which can effectively treat cancer or related diseases or disorders in mammals including humans.

[0100] In another aspect, the present invention generally relates to a method for treating or alleviating a disease or disorder, comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound having structural formula III: in: Ring A is a 5-membered, 6-membered, or 7-membered substituted or unsubstituted heterocyclic ring; Ring B is a 4-membered, 5-membered, or 6-membered substituted or unsubstituted heterocyclic ring; W1, W2 and W3 are each independently CH or N; R 1 Selected from halogen and oxo, OH, CN, OR, CF3, C 1-6 Alkyl, C 3-6Cycloalkyl, 3- to 6-membered heterocycloalkyl, 5- to 6-membered aryl or heteroaryl, 6- to 10-membered fused, spiro or bridged bicyclic, NRR', N(R)C(=O)R, N(R)C(=O)(O)R, OC(=O)NRR', C(=O)R, C(=O)NRR', N(R)S(O)2R, S(O)2R, S(O)2NRR'; optionally, R 1 1 to 4 identical or different R a or R b Replacement; two R 1 'Together with the carbon or heteroatom to which they are attached, they may form a 4-6 membered carbocyclic or heterocyclic ring; R 2 Selected from halogen and oxo, OH, CN, OR, CF3, C 1-6 Alkyl; optionally, the C 1-6 The alkyl group is replaced by 1-2 R b Replacement; two R 2 'Together with the carbon or heteroatom to which they are attached, they may form a 4- to 6-membered carbocyclic or heterocyclic ring; R 3 is a 5- to 6-membered aromatic carbocyclic or heterocyclic ring, a 9- to 10-membered aromatic carbocyclic or heterocyclic ring; optionally, the aromatic carbocyclic or heterocyclic ring is surrounded by 1 to 4 identical or different R a replace; R 4 is S(=O)2-C 1-4 Alkenyl, S(=O)2-C 1-4 Alkyl, C(=O)-C 1-4 Alkenyl, C(=O)-C 1-4 Alkyl, C 1-4 Alkenyl, C 1-4 Alkyl, -C 1-4 Alkyl-NH2, -C 1-4 Alkyl-OH, C 1-3 Alkyl-NH-C 1-3 Alkyl, C 1-3 Alkyl-OC 1-3 Alkyl, C 1-3 Alkyl-SC 1-3 Alkyl, C 1-3 Alkyl-C(=O)-C 1-3 Alkyl, C 1-3 Alkyl-S(=O)2-C 1-3 alkyl, or a 3- to 6-membered saturated or unsaturated carbon or heterocyclic ring; optionally, R 4 1 to 4 identical or different R b replace; R and R' are each independently H, or C 1-6 Alkyl or C 3-6Cycloalkyl; optionally, R and R' together with the nitrogen to which they are attached form a 4-6 membered ring, each optionally substituted with 1-3 substituents independently selected from C 1-3 Alkyl, C 3-6 Cycloalkyl or heterocyclic ring, halogen, OH, OC 1-3 Alkyl, CN; R a OH, NRR', halogen, CN, NO2, C 1-2 Alkyl, C 1-2 Haloalkyl, -C 1-4 Alkyl-NRR', -C 1-4 Alkyl-OR, C 1-2 Alkoxy, C(=O)NRR', NRC(=O)R or C(=O)R; optionally, the alkyl, R or R' is separated by 1-3 R b Replace, or two R a 'Forming =O, or two R a 'Together with the carbon atoms to which they are bonded, they form a 3-5 membered saturated or unsaturated carbocyclic or heterocyclic ring; R b Halogen, CN, OH, C 1-2 Alkyl, C 1-2 Alkyl-OH, C 3-6 Cycloalkyl, C 1-2 Alkoxy, NRR', S(=O)2NRR', C(=O)R, 5- to 6-membered aromatic carbocyclic or heterocyclic ring, C 1-2 Alkyl-carbocyclic or C 1-2 Alkyl-heterocyclic group; optionally, the alkyl, R, R', aromatic carbocyclic ring or heterocyclic ring is separated by 1 to 4 identical or different R a Replace; or two R b 'forms =O; or two R attached to the same or adjacent carbon atoms b 'Can form a 3-membered carbon ring; m is 0 or 1, 2, or 3; n1 is 0 or 1, 2, 3; n2 is 0 or 1, 2, or 3; p is 1, 2, or 3; q is 1, 2, or 3; or a pharmaceutically acceptable form or isotopic derivative thereof, which can effectively treat cancer or related diseases or disorders in mammals including humans.

[0101] In certain embodiments, the disease or disorder is mediated by or associated with STING.

[0102] In certain embodiments, the disease or disorder is selected from cancer and precancerous syndromes.

[0103] In certain embodiments, the disease or disorder is an infectious disease or disorder.

[0104] In certain embodiments, the disease or disorder is an autoimmune disease or disorder.

[0105] In certain embodiments, the methods of the present invention treat or slow aging.

[0106] In certain embodiments, the treatable cancer is selected from breast cancer, colon cancer, endometrial cancer, renal cancer, lung cancer, melanoma, prostate cancer, thyroid cancer, and leukemia. The compounds disclosed herein may also treat other PTEN-deficient tumors, such as brain tumors (gliomas), glioblastomas, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, colorectal cancer, Wilms' tumor, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, head and neck cancer, liver cancer, squamous cell carcinoma, ovarian cancer, pancreatic cancer, sarcoma, osteosarcoma, giant cell tumor of bone, lymphoblastic T-cell tumor, malignant lymphoma, Hodgkins lymphoma, non-Hodgkin lymphoma, lymphoblastic T-cell tumor, Burkitt lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial carcinoma, vulvar cancer, cervical cancer, kidney cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular carcinoma, gastric cancer, nasopharyngeal cancer, cheek cancer, oral cancer, gastrointestinal stromal tumor, and testicular cancer.

[0107] Another aspect of the present invention generally relates to the use of a compound disclosed herein and a pharmaceutically acceptable excipient, carrier or diluent in the preparation of a medicament for treating a disease or disorder.

[0108] In certain embodiments, the disease or disorder is cancer, or a disease or disorder associated with cancer.

[0109] In certain embodiments, the treatable cancer is selected from breast cancer, colon cancer, endometrial cancer, renal cancer, lung cancer, melanoma, prostate cancer, thyroid cancer, and leukemia.

[0110] In certain embodiments, the drug is administered orally.

[0111] In certain embodiments, the medicament is for intravenous administration.

[0112] Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. These compounds contemplated by the present invention, including cis and trans isomers, R- and S-enantiomers, diastereomers, (d)-isomers, (l)-isomers, racemic mixtures thereof, and other mixtures thereof, fall within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents, such as alkyl groups. All such isomers and mixtures thereof are encompassed by the present invention.

[0113] Mixtures of isomers containing any of a variety of isomer ratios can be used in accordance with the present invention. For example, in the case of combining only two isomers, the present invention contemplates mixtures comprising isomer ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0. One of ordinary skill in the art will readily appreciate that similar ratios are contemplated for more complex isomer mixtures.

[0114] For example, if a specific enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or using a chiral auxiliary derivative, the resulting diastereomeric mixture being separated and the auxiliary group being cleaved to provide the pure enantiomer. Alternatively, when the molecule contains a basic functional group such as an amino group, or an acidic functional group such as a carboxyl group, diastereomeric salts are formed with an appropriate optically active acid or base, followed by resolution of the formed diastereomers by fractional crystallization or chromatography methods well known in the art, thereby recovering the pure enantiomer.

[0115] Isotopically labeled compounds are also within the scope of the present disclosure. As used herein, "isotopically labeled compound" refers to a presently disclosed compound, including pharmaceutically acceptable salts and prodrugs thereof, wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature, as described herein. Examples of isotopes that may be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example 2 H. 3 H. 13 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F. 36 Cl.

[0116] The compounds disclosed herein can be used for drug and / or substrate tissue distribution analysis by isotope labeling. Tritium ( 3 H) and carbon-14 ( 14 C) to label compounds. In addition, heavier isotopes such as deuterium ( 2 H) substitution can bring some therapeutic advantages that benefit from higher metabolic stability, such as increasing half-life in vivo or reducing dosage requirements, and is therefore preferred in some cases. The isotope-labeled compounds disclosed herein, as well as pharmaceutically acceptable salts, esters and prodrugs thereof, can be prepared by methods known in the art.

[0117] In addition, heavy isotopes such as deuterium are used to replace the normally abundant hydrogen ( 1 H) may provide certain therapeutic advantages, for example, due to improved absorption, distribution, metabolism and / or excretion (ADME) properties, thereby creating a drug with better efficacy, safety and / or tolerability. 13 C replaces the usually abundant 12 C can also achieve the effect. (Refer to WO 2007 / 005643, WO 2007 / 005644, WO 2007 / 016361 and WO 2007 / 016431).

[0118] Stereoisomers (eg, cis and trans isomers) and all optical isomers (R and S enantiomers) of a disclosed compound, as well as racemates, diastereomers, and other isomer mixtures are also encompassed within the scope of the invention.

[0119] After the compounds of the present disclosure are prepared, they are preferably isolated and purified to obtain compositions containing 95% or more by weight ("substantially pure") and then used or formulated as described herein. In certain embodiments, the compounds of the present disclosure are greater than 99% pure.

[0120] Solvates and polymorphs of the compounds of the invention are also contemplated herein. Solvates of the compounds of the invention include, for example, hydrates.

[0121] Any suitable route of administration may be used, for example enteral, intravenous, subcutaneous, intramuscular, intraventricular, intracranial, intraperitoneal, rectal or oral administration. The most suitable mode of administration for a particular patient depends on the nature and severity of the condition being treated or the nature of the treatment being performed and the properties of the active compound.

[0122] The pharmaceutical composition for enteral injection comprises pharmaceutically acceptable sterile aqueous solution or non-aqueous solution, dispersion, suspension or emulsion, and is made into the sterile powder of sterile injection or dispersion before use.The suitable example of water, non-aqueous solution, diluent, solvent or carrier comprises water, ethanol, polyol (such as glycerol, propylene glycol, polyethylene glycol etc.), carboxymethyl cellulose and its suitable mixture, vegetable oil (such as olive oil), and injectable organic ester, such as ethyl oleate.By using coating material such as lecithin, use dispersant to keep the size of granule or use surfactant to keep suitable fluidity.

[0123] Pharmaceutical compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers, and dispersants. Antimicrobial and antifungal agents such as talc, chlorobutanol, and phenolic acid may be added to provide protection against microorganisms. It is sometimes desirable to add isotonic agents such as sugars and sodium chloride. The absorption time of injectable pharmaceuticals may be prolonged by adding agents that delay absorption, such as aluminum monostearate and gelatin.

[0124] The compounds disclosed herein can be formulated and administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals dispersed in an aqueous medium. Any liposome made from non-toxic, physiologically acceptable, metabolizable lipids can be used. Pharmaceutical compositions in liposome form may include the compounds disclosed herein, stabilizers, preservatives, excipients, and the like. Preferred lipids are natural or synthetic phospholipids and phosphatidylcholines (lecithins). Methods for forming liposomes are known in the art, for example, see Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, NY (1976), p. 33 et seq.

[0125] The compounds of the present invention can be administered to humans or other mammals in a single or multiple doses, with the total daily dose ranging from 0.0001 to 300 mg / kg body weight, more typically 1 to 300 mg / kg body weight. The dosage range is from 0.0001 to 300 mg / kg, possibly administered twice daily.

[0126] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granular dosage forms. In such solid dosage forms, the compound of the present invention or its derivative is mixed with at least one inert conventional excipient (or carrier), such as sodium citrate or dicalcium phosphate or (i) fillers or bulking agents, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, (ii) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, or acacia, (iii) humectants, such as glycerol, (iv) disintegrators, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, sodium carbonate, (v) solubilizers, such as paraffin, (vi) absorption enhancers, such as quaternary ammonium compounds, (vii) wetting agents, such as cetyl alcohol and glycerol monostearate, (viii) adsorbents, such as kaolin and bentonite, (ix) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets, and pills, a buffer may also be included in the formulation. Similar types of solid compositions can also be used as fillers in soft-fill and hard-fill gelatin capsules using excipients such as lactose or lactose and high molecular weight polyethylene glycol. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells (such as enteric coatings) and other techniques known in the art.

[0127] Liquid dosage forms for oral medications include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers. Typical examples include ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, fatty acid esters of sorbitol, or mixtures thereof. In addition to the above inert diluents, the pharmaceutical composition may also contain other agents, such as wetting agents, emulsifiers, suspending agents, sweeteners, flavorings, or fragrances.

[0128] The materials, compositions, and components disclosed herein can be used in the disclosed methods and compositions, can be used in conjunction with the disclosed methods and compositions, can be used in the preparation of products of the disclosed methods and compositions, or are products of the disclosed methods and compositions. It should be understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed, while specific reference to each of the various individual and collective combinations and permutations of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, if a method is disclosed and discussed, and modifications of a number of molecules included in that method are discussed, unless expressly stated to the contrary, every combination and permutation of that method, as well as possible modifications, are specifically contemplated. Similarly, any subset or combination of that method is also specifically contemplated and disclosed. This concept applies to all aspects of the present invention, including but not limited to steps in methods using the disclosed compositions. Therefore, if multiple additional steps can be performed, it should be understood that each of these additional steps can be performed using any specific method step or combination of method steps of the disclosed method, and any combination or subset can be performed. The above combinations should be considered to be specifically contemplated and disclosed. DETAILED DESCRIPTION

[0129] The following examples are given to illustrate the present invention and are not intended to limit the scope of the present invention in any way.

[0130] The compounds of the present invention, including those explicitly disclosed herein, can be prepared as described in the following schemes. For example, compounds of Formula (I), Formula (II), and Formula (III) can be prepared according to the following schemes, using methods known to those skilled in the art for preparing fragments and combining fragments. Although the present invention has been described in detail using preferred synthetic schemes, it should be understood by those skilled in the art that modifications, variations, and equivalent substitutions to the present invention that do not depart from the scope of the present invention are within the scope of the present invention. abbreviation abbreviation name DCE 1,2-Dichloroethane DCM dichloromethane DMSO dimethyl sulfoxide HPLC High-performance liquid chromatography LCMS Liquid chromatography-mass spectrometry MS mass spectrometer TLC Thin layer chromatography EtOAc Ethyl acetate <![CDATA[Pd2(dba)3]]> Tris(dibenzylideneacetone)dipalladium Xantphos 4,5-Bisdiphenylphosphine-9,9-dimethylxanthene 4,5-Bisdiphenylphosphine i-PrOH Isopropyl alcohol Pd / C Palladium on carbon DIPEA(DIEA) N,N-Diisopropylethylamine DMF N,N-Dimethylformamide <![CDATA[Ac2O]]> Acetoacetate NMP 1-Methyl-2-pyrrolidone UHP carbamide peroxide HATU 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate Solution 1 General steps for preparing compounds in Scheme 1 Preparation of 9,10-difluoro-3-methyl-5,6-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one (Step 1 of Solution 1)

[0131] At 0 ° C, within half an hour, 6,7-difluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.0 5,13] To a solution of tridecane-5(13),6,8,11-tetraene-11-carboxylic acid (10 g, 35.56 mmol, 1 eq) in MeOH (150 mL) was added NaBH4 (6.05 g, 160.02 mmol, 4.5 eq) in portions. The mixture was then stirred at 25 ° C for half an hour under a N2 atmosphere. TsOH.H2O (676.42 mg, 3.56 mmol, 0.1 eq) was subsequently added, and the mixture was heated at 95 ° C for 10 hours under a N2 atmosphere. LCMS showed that the reaction was nearly complete. The reaction mixture was concentrated under reduced pressure. The residue was slowly quenched with water (100 mL) at 0 ° C and extracted with EtOAc (60 mL×3). The combined organic layers were washed with brine (30 mL×1), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography ( 80g The eluent was a flash silica gel column with a gradient of 0-42% ethyl acetate / petroleum ether at 100 mL / min. The eluent was removed under reduced pressure to obtain compound 6,7-difluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8-trien-10-one (6.4 g, 26.75 mmol, 75.23% yield) as a yellow solid. 1 H NMR (DMSO-d6, 400MHz) δ7.17~7.12(m,1H), 4.29~4.23(m,2H), 3.59~3.54(m,2H), 3.33~3.31(m,1H), 2.71~2.63(m,2H), 1.16(d,J=6.4Hz,3H). 9,10-difluoro-3-methyl-7-oxo-3,5,6,7-tetrahydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6- Preparation of formaldehyde (Scheme 1, Step 2)

[0132] At 0 ° C, 6,7-difluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13] To a mixture of tridecane-5(13),6,8-triene-10-one (6.4 g, 26.75 mmol, 1 eq) in DCM (150 mL) was added NaOMe (11.27 g, 104.34 mmol, 50% purity, 3.9 eq) in portions. The mixture was stirred at 25 ° C for half an hour, and then ethyl formate (7.73 g, 104.34 mmol, 8.39 mL, 3.9 eq) was added dropwise at 25 ° C. Then, under a N2 atmosphere, the mixture was stirred at 25 ° C for 10 hours. LCMS showed that the reaction was complete. At 0 ° C, the reaction mixture was slowly poured into ice water (100 mL) and the pH was adjusted to 6 with 0.5N HCl. The organic layer was separated and the aqueous phase was extracted with DCM (100 mL×2). The combined organic layer was washed with brine (100 mL×1), dried over Na2SO4, filtered and concentrated under reduced pressure. Compound 6,7-difluoro-2-methyl-10-oxo-4-oxa-1-azatricyclic [7.3.1.0 5,13 ]Tridecane-5(13),6,8-triene-11-carbaldehyde (7 g, crude product) as a light brown oil. 1 HNMR(DMSO-d6,400MHz)δ11.54(s,1H),7.77(s,1H),7.16~7.11(m,1H),4.2 3~4.13(m,3H),3.89~3.84(m,1H),3.49~3.17(m,1H),1.19(d,J=6.4Hz,3H). 9,10-Difluoro-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carbaldehyde Preparation (Step 3 of Scheme 1)

[0133] To 6,7-difluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.0 5,13 ] To a mixture of tridecane-5(13), 6,8-triene-11-carboxaldehyde (7 g, 26.19 mmol, 1 eq) in MeOH (150 mL) was added MnO2 (11.37 g, 130.97 mmol, 5 eq). The mixture was then stirred at 25 ° C for 10 hours under a N2 atmosphere. LCMS showed that the reaction was complete. The reaction mixture was filtered through a celite pad and the filtrate was removed. The filter cake was washed with DCM (200 mL × 2). The filtrate was concentrated under reduced pressure. The residue was triturated with DCM and MeOH (v:v=1:3, 30 mL). After filtration, the filter cake was collected. Compound 6,7-difluoro-2-methyl-10-oxo-4-oxa-1-azatricyclic [7.3.1.0 5,13]Tridecane-5(13),6,8,11-tetraene-11-carbaldehyde (6.5 g, 24.51 mmol, 93.56% yield) as an off-white solid. 1 H NMR(DMSO-d6,400MHz)δ10.16(s,1H),8.65(s,1H),7.73~7.68(m,1H),4.86 ~4.65(m,1H),4.62~4.61(m,1H),4.47~4.45(m,1H),1.44(d,J=6.8Hz,3H). Preparation of (S)-tert-butyl (1-(6-nitropyridin-3-yl)piperidin-3-yl)carbamate (Step 4 in the scheme)

[0134] A mixture of tert-butyl N-(3-piperidinyl)carbamate (10.26 g, 51.23 mmol, 1.3 eq) and 5-bromo-2-nitropyridine (8 g, 39.41 mmol, 1 eq), Pd2(dba)3(1.80 g, 1.97 mmol, 0.05 eq), Xantphos (1.37 g, 2.36 mmol, 0.06 eq), Cs2CO3(17.33 g, 53.25 eq) in dioxane (120 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 115 ° C for 12 hours under N2 atmosphere. LCMS showed that the reaction was complete. The mixture was concentrated under reduced pressure. Ethyl acetate (50 mL) was added to the residue. After filtering through a diatomaceous earth pad, the filter cake was washed with ethyl acetate (70 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage; 120 The reaction mixture was purified by flash silica gel column with a gradient of 0-47% ethyl acetate / petroleum ether at 45 mL / min. The eluent was removed under reduced pressure to afford tert-butyl N-[1-(6-nitro-3-pyridinyl)-3-piperidinyl]carbamate (7.23 g, 22.43 mmol, 56.91% yield) as a yellow solid. 1 HNMR(DMSO-d6,400MHz)δ8.21(s,1H),8.13(d,J=9.2Hz,1H),7.41(d,J=6.4Hz,1H),7.01(d,J=6.8Hz,1H),3.89~3.87(m,2H),3 .46~3.37(m,1H),3.14~3.07(m,1H),3.04~3.01(m,1H),1.87~1.82(m,1H),1.78~1.73(m,1H),1.54~1.50(m,2H),1.40(s,9H). Preparation of (S)-1-(6-nitropyridin-3-yl)piperidin-3-amine (Step 5 of Scheme 1)

[0135] To a solution of tert-butyl N-[1-(6-nitro-3-pyridyl)-3-piperidinyl]carbamate (7.1 g, 22.03 mmol, 1 eq) in MeOH (7 mL) was added HCl / MeOH (4 M, 40 mL, 7.26 eq). The reaction mixture was stirred at 25 ° C for 2 hours. LCMS showed that the reaction was complete. The mixture was concentrated under reduced pressure. Compound 1-(6-nitro-3-pyridyl)piperidin-3-amine (6.8 g, 20.51 mmol, 93.10% yield, 3HCl) was obtained as a white solid. 1 H NMR(DMSO-d6,400MHz)δ8.52(s,2H),8.28(s,1H),8.16(d,J=8.8Hz,1H),7.50(d,J=9.2Hz,1H),4.12~4.09(m,1H),3.83~3.7 9(m,1H),3.44~3.39(m,1H),3.24~3.21(m,2H),2.04~2.01(m,1H),1.82~1.81(m,1H),1.74~1.70(m,1H),1.58~1.55(s,1H). 9,10-difluoro-3-methyl-6-(((S)-1-(6-nitropyridin-3-yl)piperidin-3-yl)amino)methyl)-2H- [1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one and 9-fluoro-10-methoxy-3-methyl-6-(((S)-1-(6-nitropyridine) (Scheme 1) Step 6)

[0136] 6,7-Difluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.0 5,13A solution of tridecane-5(13), 6,8,11-tetraene-11-carbaldehyde (1 g, 3.77 mmol, 1 eq), AcONa (1.55 g, 18.85 mmol, 5 eq) and (3S)-1-(6-nitro-3-pyridyl)piperidin-3-amine (1.25 g, 3.77 mmol, 1 eq, 3 HCl) was stirred at 25 ° C for 5 hours. NaBH3CN (355.41 mg, 5.66 mmol, 1.5 eq) was then added portionwise at 0 ° C, and the mixture was stirred at 25 ° C for 2 hours. LCMS and TLC showed that the reaction was complete. At 0 ° C, the reaction mixture was quenched with ice water (20 mL) and the pH was adjusted to 8 with saturated NaHCO3. Some yellow solids were formed. The solid was discarded after filtration. The filtrate was extracted with DCM and i-PrOH (v:v=3:1, 50 mL x 2). The combined organic layers were washed with brine (20 mL x 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 6,7-difluoro-2-methyl-11-[[[(3S)-1-(6-nitro-3-pyridinyl)-3-piperidinyl]amino]methyl]-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (1.9 g, crude product) as a yellow solid. 1 H NMR(DMSO-d6,400MHz)δ8.23(s,1H),8.22~8.06(m,2H),7.56(t,J=7.6Hz,1H),7.46~7.43(m,1H),4.60~4.54(m,2H ),4.47~4.40(m,1H),4.05~4.00(m,1H),3.87~3.81(m,1H),3.67~3.60(m,2H),3.17~3.14(m,1H),3.07~2.89(m,1H) ), 2.60-2.53 (m, 1H), 1.97-1.91 (m, 1H), 1.77-1.70 (m, 1H), 1.44-1.40 (m, 2H), 1.37-1.35 (m, 3H). The compound 9-fluoro-10-methoxy-3-methyl-6-((((S)-1-(6-nitropyridin-3-yl)piperidin-3-yl)amino)methyl)-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinolin-7-one (190 mg, crude product) was obtained as a yellow solid. Preparation of compounds in Scheme 1 (Step 7 of Scheme 1)

[0137] At 25 ° C, 6,7-difluoro-2-methyl-11-[[[(3S)-1-(6-nitro-3-pyridinyl)-3-piperidinyl]amino]methyl]-4-oxa-1-azatricyclo[7.3.1.0 5,13 ] A solution of tridecane-5(13),6,8,11-tetraen-10-one (901.46 umol, 1 eq) and different acetaldehydes (0.901 mmol~1.35 mmol, 1.0 eq~1.5 eq) in DCE (13 mL / mmol~22 mL / mmol) was stirred for 1~2 hours. The mixture was then cooled to 0°C and NaBH(OAc)3 (1.35 mmol~1.80 mmol, 1.5 eq~2 eq) was added portionwise at 0°C. The reaction mixture was stirred at 25°C for 5~15 hours. LCMS and TLC showed that the reaction was complete. The reaction mixture was quenched with ice water at 0°C and the pH was adjusted to 8 with saturated NaHCO3. The mixture was extracted with DCM and i-PrOH (v:v=3:1). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the desired product. Preparation of the Final Compounds in Scheme 1 (Step 8 of Scheme 1)

[0138] 6,7-difluoro-11-[[(2-methoxy-4-pyridinyl)methyl-[(3S)-1-(6-nitro-3-pyridinyl)-3-piperidinyl]amino]methyl]-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ] tridecane-5 (13), 6,8,11-tetraen-10-one (675.00 umol, 1 eq) and Pd / C (purity 10%, 20% wt) in MeOH (50 mL / mmol ~ 130 mL / mmol) were stirred for 3 hours to 5 hours. Alternatively, 11- [ [ (5-chloro-2-methoxy-4-pyridyl) methyl - [ (3S) -1- (6-nitro-3-pyridyl) -3-piperidinyl] amino] methyl] -6,7-difluoro-2-methyl-4-oxa-1-azatricyclo [7.3.1.0 5,13] To a mixture of tridecane-5(13),6,8,11-tetraene-10-one (159.48 umol, 1 eq) in MeOH (62 mL / mmol) and H2O (21 mL / mmol) were added Fe (797.40 umol, 5 eq) and NH4Cl (318.96 umol, 2 eq). The reaction mixture was stirred at 80°C for half an hour. The mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex C18 80*40mm*3um or Phenomenex C1875*30mm*3um or Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH4HCO3)-MeCN]; B%: 20%-65%, 8 minutes). The eluent was removed by freeze drying. The aqueous solution was freeze-dried to obtain the desired product. Compound 1 9,10-difluoro-6-(((2-methoxypyridin-4-yl)methyl)((S)-1-(6-nitropyridin-3-yl)piperidin-3-yl) Preparation of 2-(4-(2-(4-nitro-1-methyl)amino)methyl)-3-methyl-2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one (Step 1 of Scheme 1) 7)

[0139] 6,7-Difluoro-2-methyl-11-[[[(3S)-1-(6-nitro-3-pyridinyl)-3-piperidinyl]amino]methyl]-4-oxa-1-azatricyclo[7.3.1.0 5,13 ] A solution of tridecane-5(13), 6,8,11-tetraene-10-one (0.5 g, 901.46 umol, purity 85%, 1 eq) and 2-methoxypyridine-4-carboxaldehyde (185.43 mg, 1.35 mmol, 1.5 eq) was stirred for 1 hour. The mixture was then cooled to 0°C and NaBH(OAc)3 (382.11 mg, 1.80 mmol, 2 eq) was added portionwise at 0°C. The mixture was stirred at 25°C for 10 hours. LCMS and TLC showed that the reaction was complete. At 0°C, the reaction mixture was quenched with ice water (20 mL) and the pH was adjusted to 8 with saturated NaHCO3. The mixture was extracted with DCM and i-PrOH (v:v=3:1, 30 mL×3). The combined organic layers were washed with brine (20 mL×1), dried over Na2SO4, filtered and concentrated under reduced pressure. Compound 6,7-difluoro-11-[(2-methoxy-4-pyridinyl)methyl-[(3S)-1-(6-nitro-3-pyridinyl)-3-piperidinyl]amino]methyl]-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (0.5 g, crude product) as a yellow solid. 1H NMR(DMSO-d6,400MHz)δ8.25~8.24(m,1H),8.12~8.00(m,3H),7.56~7.50(m,1H),7.47~7 .44(m,1H),6.90~6.88(m,1H),6.73(s,1H),4.65~4.62(m,1H),4.60~4.58(m,1H),4.48~4 .23(m,2H),4.05~4.02(m,2H),3.93~3.90(m,2H),3.83(s,3H),3.77~3.67(m,2H),3.27~ 3.19(m,1H),3.04~2.91(m,1H),1.84~1.61(m,2H),1.39~1.34(m,2H),1.33~1.31(m,3H). 6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl)((2-methoxypyridin-4-yl)methyl)amino) Preparation of 2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one (Step 1 of Scheme 1) Step 8)

[0140] 6,7-difluoro-11-[[(2-methoxy-4-pyridinyl)methyl-[(3S)-1-(6-nitro-3-pyridinyl)-3-piperidinyl]amino]methyl]-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (0.4 g, 675.00 umol, 1 eq) and Pd / C (0.1 g, purity 10%) were stirred for 5 hours. LCMS and HPLC showed that the reaction was complete. The mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex C18 80*40mm*3um; mobile phase [water (NH4HCO3)-MeCN]; B%: 20%-50%, 8 minutes). The eluent was removed by freeze drying. Compound 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6,7-difluoro-2-methyl-4-oxa-1-azatricyclic [7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (186.3 mg, 326.76 mmol, 48.41% yield, 98.68% purity) was obtained as an off-white solid. 1H NMR(DMSO-d6,400MHz)δ8.08(d,J=6.8Hz,1H),7.99(d,J=5.2Hz,1H),7.61(d,J=3.2Hz,1H),7.56~7.51(m,1H),7.16~7.13 (m,1H),7.01~6.99(m,1H),6.82(s,1H),6.39~6.36(m,1H),5.37(s,2H),4.71~4.69(m,1H),4.57~4.55(m,1H),4.41~4.38( m,1H),3.77(s,3H),3.73~3.59(m,5H),3.24~3.19(m,1H),2.77~2.67(m,1H),2.62~2.56(m,1H),2.44~2.41(m,1H),1.99~1 .91(m,1H),1.79~1.74(m,1H),1.49~1.44(m,2H),1.35~1.32(m,3H).HPLC:98.68%(220nm),98.70%(254nm).MS(ESI):mass calcd.For C 30 H 32 F2N6O3562.25m / z found 563.3[M+H] + . Compound 2 6-((((S)-1-(6-Aminopyridin-3-yl)piperidin-3-yl)piperidin-3-yl was prepared according to the procedure described in Step 8 of Scheme 1. 4-(2-(2-(2-(2-(2-(2-(2-(2-(2-oxazino[2,3,4-ij]quinoline-7-yl)methyl)amino)methyl)-9,10-difluoro-3-methyl-2H-[1,4]oxazino[2,3,4-ij]quinoline-7-yl)- (3H)-Ketone

[0141] 6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl)(pyridin-4-ylmethyl)amino)methyl)-9,10-difluoro-3-methyl-2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one (27.2 mg, 50.80 umol, 16.81% yield, 99.46% purity) was obtained as a yellow solid. 1H NMR(DMSO-d6,400MHz)δ8.41(d,J=6.0Hz,2H),8.07(d,J=6.4Hz,1H),7.60(d,J=2.8Hz,1H),7.55~7.52(m,1H),7.42~7.41(m,2H),7.16~7.12 (m,1H),6.36(dd,J=3.6Hz,8.8Hz,1H),5.36(d,J=2.8Hz,2H),4.71~4.67(m,1H),4.57~4.54(m,1H),4.40(d,J=9.2Hz,1H),3.82~3.77(m,2H) ,3.68~3.62(m,1H),3.61~3.56(m,1H),3.52(d,J=10.0Hz,1H),3.24~3 .21(m,1H),2.75~2.61(m,1H),2.60~2.56(m,1H),2.41(s,1H),2.00~1 .97(m,1H),1.77~1.74(m,1H),1.50~1.39(m,2H),1.32(dd,J=4.4,6.4Hz,3H).MS:99.46%(220nm),99.69%(254nm).MS(ESI):masscalcd.For C 29 H 30 F2N6O2532.24m / z found 533.3[M+H] + . Compound 3 6-((((S)-1-(6-Aminopyridin-3-yl)piperidin-3-yl)piperidin-3-yl was prepared according to the procedure described in Step 8 of Scheme 1. 2-(2-Methylpyridin-4-yl)methyl)amino)methyl)-9,10-difluoro-3-methyl-2H-[1,4]oxazino[2,3,4- ij]quinolin-7(3H)-one

[0142] 6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl)((2-methylpyridin-4-yl)methyl)amino)methyl)-9,10-difluoro-3-methyl-2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one (28.9 mg, 52.62 umol, 17.85% yield, 99.53% purity) was obtained as a white solid. 1H NMR(DMSO-d6,400MHz)δ8.27(d,J=4.8Hz,1H),8.06(d,J=4.4Hz,1H),7.61(s,1H),7.58~7.53(m,1H),7.23~7.20(m,2H),7.14(dd,J=2. 4Hz,8.8Hz,1H),6.37(dd,J=2.8Hz,8.8Hz,1H),5.37(s,2H),4.71~4.54(m,1H),4.55(dd,J=2.0Hz,11.2Hz,1H),4.38(d,J=10.8Hz,1H) ,3.81~3.55(m,4H),3.52~3.49(m,1H),3.24~3.22(m,1H),2.78~2.73(m,1H),2.62~2.57(m,1H),2.46~2.39(m,1H),2.36(s,3H),2.02~ 1.97 (m, 1H), 1.77 ~ 1.74 (m, 1H), 1.53 ~ 1.38 (m, 2H), 1.32 (dd, J = 4.4Hz, 6.8Hz, 3H). HPLC: 99.53% (220nm), 99.56% (254nm). MS (ESI): mass calcd.ForC 30 H 32 F2N6O2546.26m / z found 547.3[M+H] + . Compound 4 6-((((S)-1-(6-Aminopyridin-3-yl)piperidin-3-yl)piperidin-3-yl was prepared according to the procedure described in Step 8 of Scheme 1. 1-Methyl-2-(5-chloro-2-methoxypyridin-4-yl)methyl)amino)methyl)-9,10-difluoro-3-methyl-2H-[1,4]oxazin- [2,3,4-ij]quinolin-7(3H)-one

[0143] Compound 4 (17.4 mg, 29.09 umol, yield 18.24%, purity 99.81%) was obtained as a light pink solid. 1HNMR(DMSO-d6,400MHz)δ8.08(d,J=6.0Hz,1H),8.04(s,1H),7.62(s,1H),7.56~7.52(m,1H),7.16~7.14(m,1H),7.10(s,1H),6.38( dd,J=3.6Hz,8.8Hz,1H),5.37(s,2H),4.62~4.61(m,1H),4.52(d,J=11.2Hz,1H),4.37~4.35(m,1H),3.83~3.73(m,2H),3.69(s,3H) ,3.66~3.64(m,2H),3.52(d,J=10.0Hz,1H),3.25~3.23(m,1H),2.82~2.80(m,1H),2.61~2.58(m,1H),2.43~2.40(s,1H),2.00~1.97 (m,1H),1.76~1.75(m,1H),1.47~1.44(m,2H),1.30(t,J=6.0Hz,3H).MS:99.81%(220nm),100.00%(254nm).MS(ESI):masscalcd.For C 30 H 31 ClF2N6O3596.21m / z found 597.2[M+H] + . Compound 5 and Compound 6 (R)-6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl)((2-methoxypyridin-4-yl)methyl)amino 1-[4-(2-(4-nitrophenyl)methyl)-9,10-difluoro-3-methyl-2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one and (S)-6- Preparation of ((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl)((2-methoxypyridine)

[0144] The 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6,7-difluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0] was purified by SFC (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 um); mobile phase: [0.1% NH3H2OEtOH]; B%: 50%-50%, 17 minutes). 5,13]Tridecane-5(13),6,8,11-tetraene-10-one (40 mg, 71.10 umol, 1 eq) was separated. The eluate was concentrated under reduced pressure. The obtained product was dissolved in MeCN (5 mL) and water (20 mL) respectively, and then freeze-dried. Compound (2R)-11-[[[(3S)-1-(6-amino-3-pyridyl)-3-piperidinyl]-[(2-methoxy-4-pyridyl)methyl]amino]methyl]-6,7-difluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (14.3 mg, 25.42 umol, yield 35.75%). 1 H NMR(DMSO-d6,400MHz)δ8.07(s,1H),7.99(d,J=5.2Hz,1H),7.61(s,1H),7.56~7.52(m,1H),7.16~7.13(m,1H),7.01 ~6.99(m,1H),6.82(s,1H),6.38~6.36(m,1H),5.36(s,2H),4.71~4.69(m,1H),4.56~4.54(m,1H),4.40~4.37(m,1H), 3.76(s,3H),3.73~3.59(m,5H),3.24~3.19(m,1H),2.70~2.67(m,1H),2.70~2.56(m,1H),2.48~2.43(m,1H),1.99~1. 91(m,1H),1.74~1.71(m,1H),1.49~1.44(m,2H),1.36~1.33(m,3H).HPLC:100%(220nm),100%(254nm).MS(ESI):mass calcd.For C 30 H 32 F2N6O3562.25m / zfound 563.3[M+H] + . Obtained compound (2S)-11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6,7-difluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (11.4 mg, 20.26 umol, 28.50% yield) was obtained as a white solid with random structure. 1H NMR(DMSO-d6,400MHz)δ8.09(s,1H),7.98(d,J=5.2Hz,1H),7.61(s,1H),7.56~7.52(m,1H),7.16~7.13(m,1H),7.01 ~6.99(m,1H),6.81(s,1H),6.39~6.36(m,1H),5.37(s,2H),4.70~4.68(m,1H),4.57~4.54(m,1H),4.40~4.37(m,1H), 3.76(s,3H),3.73~3.59(m,5H),3.24~3.19(m,1H),2.70~2.67(m,1H),2.70~2.56(m,1H),2.48~2.43(m,1H),1.99~1. 91(m,1H),1.74~1.71(m,1H),1.49~1.44(m,2H),1.33~1.31(m,3H).HPLC:100%(220nm),100%(254nm).MS(ESI):mass calcd.For C 30 H 32 F2N6O3562.25m / zfound 563.3[M+H] + . Compound 7 N-(5-((3S)-3-(((9,10-difluoro-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazinol[2,3, (4-ij]quinolin-6-yl)methyl)((2-methoxypyridin-4-yl)methyl)amino)piperidin-1-yl)pyridin-2-yl)acetamide Preparation (Step 10 of Scheme 1)

[0145] At 0 ° C, 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6,7-difluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13] A mixture of tridecane-5(13),6,8,11-tetraene-10-one (30 mg, 53.32 umol, 1 eq) and DIPEA (41.35 mg, 319.94 umol, 55.73 uL, 6 eq) was added dropwise with Ac2O (6.53 mg, 63.99 umol, 5.99 uL, 1.2 eq). The reaction mixture was stirred at 20°C under N2 for 2 hours. The reaction mixture was then stirred at 20°C under N2 for 10 hours. LCMS and HPLC showed that the reaction was complete. Purification was performed by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH4HCO3)-MeCN]; B%: 30%-60%, 8 minutes). The eluent was removed by freeze drying. The compound N-[5-[(3S)-3-[(6,7-difluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-11-yl)methyl-[(2-methoxy-4-pyridinyl)methyl]amino]-1-piperidinyl]-2-pyridinyl]acetamide (9.5 mg, 15.60 umol, yield 29.25%, purity 99.26%), as a white solid. 1 H NMR(DMSO-d6,400MHz)δ10.17(s,1H),8.10(d,J=6.4Hz,1H),8.00~7.97(m,2H),7.87(t,J=8.4Hz,1H),7.54~7.59(m ,1H),7.35(d,J=9.2Hz,1H),7.02(d,J=4.8Hz,1H),6.84(d,J=4.8Hz,1H),4.79~4.73(m,1H),4.56(d,J=10.0Hz,1H), 4.40(d,J=4.8Hz,1H),3.80~3.55(m,8H),3.31~3.28(m,1H),2.74~2.52(m,3H),2.03(s,3H),2.02~1.99(m,1H),1.77 ~1.73(m,1H),1.54~1.43(m,2H),1.35~1.31(m,3H).HPLC:99.26%(220nm),99.32%(254nm).MS(ESI):masscalcd.For C 32 H 34 F2N6O4604.26m / z found605.3[M+H] + . Compound 8 Preparation of (E)-4-(2-ethoxyvinyl)-2-methoxypyridine (Scheme 1, Step 11)

[0146] A mixture of 4-bromo-2-methoxy-pyridine (500 mg, 2.66 mmol, 1 eq), 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (632.05 mg, 3.19 mmol, 1.2 eq), KCO (1.10 g, 7.98 mmol, 3 eq) and Pd(dppf)Cl (291.87 mg, 398.89 umol, 0.15 eq) in dioxane (6 mL) and H2O (0.6 mL) was degassed and purged with N2 three times. The mixture was then stirred at 100 ° C for 16 hours under a N2 atmosphere. LCMS indicated that the reaction was complete. The reaction mixture was cooled to room temperature, filtered through a diatomaceous earth pad, and the filter cake was washed with EtOAc (30 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography ( 40g Flash silica gel column, eluting with a gradient of 0-20% ethyl acetate / petroleum ether at 75 mL / min. The eluent was concentrated in vacuo to afford 4-[(E)-2-ethoxyvinyl]-2-methoxy-pyridine (400 mg, 2.23 mmol, 83.93% yield) as a colorless oil. 1 H NMR(DMSO-d6,400MHz)δ7.95(d,J=5.6Hz,1H),7.52(d,J=13.2Hz,1H),6.92(dd,J=5.2Hz,1.2Hz,1 H), 6.65 (s, 1H), 5.76 (d, J = 12.8Hz, 1H), 3.94 (q, J = 6.8Hz, 2H), 3.80 (s, 3H), 1.25 (t, J = 7.2Hz, 3H). Preparation of 2-(2-methoxypyridin-4-yl)acetaldehyde (Scheme 1, Step 12)

[0147] To a solution of 4-[(E)-2-ethoxyvinyl]-2-methoxy-pyridine (120 mg, 669.59 umol, 1 eq) in DCM (1 mL) was added TFA (3.23 g, 28.36 mmol, 2.10 mL, 42.36 eq). The mixture was stirred at 50° C. for 16 hours. LCMS showed that 4-[(E)-2-ethoxyvinyl]-2-methoxy-pyridine was completely consumed, and a new peak with the desired mass was detected. At 0° C., H2O (1 mL) was added to quench the reaction mixture, and the pH was adjusted to 7 with saturated Na2CO3. The mixture was extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (10 mL×1), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. 2-(2-methoxy-4-pyridyl)acetaldehyde (100 mg, crude product) was obtained as a colorless oil. 1 H NMR (DMSO-d6, 400MHz) δ9.68 (s, 1H), 8.28 (d, J = 5.2Hz, 1H), 7.39 (dd, J = 5.2Hz, 1.6Hz, 1H), 7.22 (s, 1H), 3.90 (s, 3H), 3.84 (s, 2H). 9,10-difluoro-6-(((2-(2-methoxypyridin-4-yl)ethyl)((S)-1-(6-nitropyridin-3-yl)piperidin Preparation of 3-(3-pyridin-3-yl)amino)methyl)-3-methyl-2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one (Scheme 1) Step 13)

[0148] To 6,7-difluoro-2-methyl-11-[[[(3S)-1-(6-nitro-3-pyridinyl)-3-piperidinyl]amino]methyl]-4-oxa-1-azatricyclo[7.3.1.0 5,13 ] A mixture of tridecane-5(13), 6,8,11-tetraene-10-one (100 mg, 212.11 umol, 1 eq) and 2-(2-methoxy-4-pyridyl)acetaldehyde (100 mg, 661.54 umol, 3.12 eq) was added NaBH(OAc)3 (269.73 mg, 1.27 mmol, 6 eq). The reaction mixture was stirred at 20 ° C for 2 hours. LCMS showed 6,7-difluoro-2-methyl-11-[[[(3S)-1-(6-nitro-3-pyridyl)-3-piperidyl]amino]methyl]-4-oxa-1-azatricyclo[7.3.1.0 5,13]Tridecane-5(13),6,8,11-tetraene-10-one was retained, several new peaks were formed, and a new peak with the desired mass was detected. The reaction mixture was quenched by adding H2O (2 mL) at 0°C, and then extracted with DCM (5 ml × 3). The combined organic layer was washed with brine (3 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography ( 12g Flash silica gel column, eluting with 0-80% ethyl acetate / petroleum ether gradient @ 40 mL / min). The eluent was concentrated in vacuo. Compound 6, 7-difluoro-11-[[2-(2-methoxy-4-pyridinyl)ethyl-[(3S)-1-(6-nitro-3-pyridinyl)-3-piperidinyl]amino]methyl]-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (70 mg, crude product) as a yellow solid. 1 HNMR(DMSO-d6,400MHz)δ8.18(d,J=2.4Hz,1H),8.11~8.08(m,1H),7.99(d,J=5.2Hz,1H),7.87(d,J=10.0Hz,1H),7.59 ~7.53(m,1H),7.43~7.37(m,1H),6.83(d,J=5.2Hz,1H),6.64(s,1H),4.59~4.53(m,2H),4.43~4.41(m,1H),4.05~4.02 (m,3H),3.82~3.80(m,2H),3.32~3.28(m,2H),3.09~2.94(m,2H),2.91~2.87(m,1H),2.70~2.67(m,2H),2.40~2.32(m, 1H),2.19~2.15(m,1H),1.90~1.86(m,1H),1.78~1.76(m,1H),1.64~1.56(m,1H),1.49~1.47(m,1H),1.38~1.29(m,3H). 6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl)(2-(2-methoxypyridin-4-yl)ethyl)amino Preparation of 2-(4-(2-(2-(4-nitrophenyl)methyl)-9,10-difluoro-3-methyl-2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one (Scheme 1) Step 14)

[0149] To a solution of 6,7-difluoro-11-[[2-(2-methoxy-4-pyridinyl)ethyl-[(3S)-1-(6-nitro-3-pyridinyl)-3-piperidinyl]amino]methyl]-2-methyl-4-oxa-1-azatricyclo[7.3.1.05,13 ] tridecane-5 (13), 6,8,11-tetraen-10-one (70 mg, 115.39 umol, 1 eq) solution was added Fe (32.22 mg, 576.97 umol, 5 eq) and NH4Cl (12.34 mg, 230.79 umol, 2 eq). The mixture was stirred at 65 ° C for 3 hours. LCMS and HPLC showed that 6,7-difluoro-11-[[2-(2-methoxy-4-pyridyl)ethyl-[(3S)-1-(6-nitro-3-pyridyl)-3-piperidinyl]amino]methyl]-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraene-10-one was completely consumed and a main peak with the desired mass was detected. The reaction mixture was cooled to room temperature and filtered through a celite pad. The filtrate was concentrated in vacuo. Purified by preparative HPLC (column: Waters XbridgeBEH C18 100*30mm*10um; mobile phase: [water (NH4HCO3)-MeCN]; B%: 40%-60%, 8 minutes). The eluate was dried by freeze drying. Compound 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[2-(2-methoxy-4-pyridinyl)ethyl]amino]methyl]-6,7-difluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (10.9 mg, 17.84 umol, yield 15.46%, purity 94.04%). 1H NMR(DMSO-d6,400MHz)δ7.98(d,J=5.2Hz,1H),7.83(d,J=4.4Hz,1H),7.60~7.54(m,2H),7.11~7.07(m,1H),6.83(d,J= 5.2Hz,1H),6.63(s,1H),6.36(d,J=8.8Hz,1H),5.35(s,2H),4.57~4.51(m,2H),4.42(d,J=7.6Hz,1H),3.77(s,3H),3. 61(s,2H),3.26~3.20(m,2H),2.85~2.80(m,2H),2.78~2.73(m,1H),2.70~2.67(m,2H),2.44~2.38(m,2H),1.85~1.82( m,1H),1.74~1.71(m,1H),1.56~1.48(m,1H),1.34~1.31(m,4H).LCMS:94.04%(220nm),94.13%(254nm).MS(ESI):mass calcd.For C 31 H 34 F2N6O3576.27m / z found 577.4[M+H] + . Option 2 General steps for preparing compounds in Scheme 2 Preparation of compounds in Scheme 2 (Step 1 of Scheme 2)

[0150] A mixture of tert-butyl N-(3-piperidinyl)carbamate (22.67mmol, 1.3eq), 5-bromo-2-methyl(or H)-pyridine (17.44mmol, 1eq), Pd(dba) (871.98umol, 0.05eq), Xantphos (871.98umol, 0.05eq) and CsCO (23.54mmol, 1.35eq) in dioxane (3mL / mmol~4mL) was degassed and purged 3 times with N. The reaction mixture was then stirred at 100°C~115°C for 10 to 12 hours under an N atmosphere. LCMS showed that the reaction was complete. The reaction mixture was cooled to room temperature and filtered through a celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to obtain the desired product. Preparation of compounds in Scheme 2 (Step 2 of Scheme 2)

[0151] To a solution of tert-butyl N-[1-(6-methyl(or H)-3-pyridinyl)-3-piperidinyl]carbamate (3.43 mmol, 1 eq) in EtOAc (3 mL / mmol) or MeOH (3 mL / mmol) was added HCl / EtOAc (4 M, 6 mL / mmol) or HCl / MeOH (4 M, 4 mL / mmol). The reaction mixture was stirred at 20 °C for 12 hours. LC-MS showed that the reaction was complete. The mixture was concentrated under reduced pressure to give the desired product. Preparation of compounds in Scheme 2 (Step 3 of Scheme 2)

[0152] To (3S)-1-(6-methyl(or H)-3-pyridyl)piperidin-3-amine (2.00 mmol, 1 eq, 3 HCl) and 6,7-difluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.0 5,13 ] To a mixture of tridecane-5(13),6,8,11-tetraene-11-carbaldehyde (2.00 mmol, 1 eq) was added NaOAc (2.20 mmol, 1.1 eq). The mixture was stirred at 20°C for half an hour to 5 hours, and then NaBH(OAc)3 (2.99 mmol to 3.99 mmol, 1.5 eq to 2.0 eq) was added at 0°C. The mixture was stirred at 20°C for 2 hours to 6 hours. At 0°C, water was added to quench the reaction mixture, and then extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the desired product. Preparation of compounds in Scheme 2 (Step 4 of Scheme 2)

[0153] Under N2 and 20°C, 6,7-difluoro-2-methyl-11-[[[(3S)-1-(6-methyl(or H)-3-pyridinyl)-3-piperidinyl]amino]methyl]-4-oxa-1-azatricyclo[7.3.1.0 5,13] To a mixture of tridecane-5(13),6,8,11-tetraene-10-one (204.32 umol, 1 eq) and different aldehydes (224.75 umol, 1.1 eq) was added NaBH(OAc)3 (306.48 umol, 1.5 eq). The mixture was then stirred at 20°C for 10 to 20 hours. The reaction mixture was quenched with ice water at 0°C and the pH was adjusted to 8 with saturated NaHCO3. The mixture was extracted with DCM and i-PrOH (v:v=3:1). The combined organic layers were washed with brine (20 mL×1), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex C18 75*30mm*3um or Waters Xbridge Prep OBD C 18 150*40mm*10um; mobile phase: [water (NH4HCO3)-MeCN]; B%: 25%-60%, 8 minutes) and freeze-dried to remove the solvent to obtain the desired product. Preparation of (S)-tert-butyl (1-(6-methylpyridin-3-yl)piperidin-3-yl)carbamate in Scheme 2 Step 1)

[0154] By tert-butyl N-(3-piperidyl)carbamate (4.54g, 22.67mmol, 1.3eq), 5-bromo-2-methylpyridine (3g, 17.44mmol, 1eq), Pd2(dba)3(798.49mg, 871.98μm ol, 0.05eq), Xantphos (504.54mg, 871.98μm ol, 0.05eq) and Cs2CO3(7.67g, 23.54mmol, 1.35eq) mixture in dioxane (50mL) degassed and purged 3 times with N2.Then under N2 atmosphere, the mixture was stirred at 115 DEG C for 12 hours.LCMS shows that the reaction is complete.The reaction mixture is cooled to room temperature and filtered through a diatomaceous earth pad.The filtrate is concentrated under reduced pressure.The residue is purified by flash silica gel chromatography (Biotage; 40 The reaction mixture was purified by flash silica gel column with a gradient of 0-60% ethyl acetate / petroleum ether at 60 mL / min. The eluent was removed under reduced pressure to obtain tert-butyl N-[1-(6-methyl-3-pyridyl)-3-piperidinyl]carbamate (1 g, 3.43 mmol, 19.68% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ8.12(s,1H),7.22~7.19(m,1H),7.05(d,J=8.8Hz,1H),6.88(d,J=7.2Hz,1H),3.57~3.49(m,3H ),2.67~2.61(m,1H),2.53(s,1H),2.33(s,3H),1.81~1.70(m,2H),1.53~1.50(m,1H),1.40(s,9H),1.36~1.32(m,1H). Preparation of (S)-1-(6-methylpyridin-3-yl)piperidin-3-amine in Scheme 2 (Step 2 of Scheme 2)

[0155] To a solution of tert-butyl N-[1-(6-methyl-3-pyridyl)-3-piperidinyl]carbamate (1 g, 3.43 mmol, 1 eq) in EtOAc (10 mL) was added HCl / EtOAc (4 M, 56 mL, 67 eq). The mixture was stirred at 20° C. for 12 hours. LC-MS showed that the reaction was complete. The mixture was concentrated under reduced pressure. Compound (3S)-1-(6-methyl-3-pyridyl)piperidin-3-amine (1 g, 3.33 mmol, 96.92% yield, 3HCl) was obtained as a brown solid. 1 H NMR (400MHz, DMSO-d6) δ8.44(s,3H),8.29(s,1H),8.07(dd,J=2.8Hz,J=8.8Hz,1H),7.72(d,J=9.2Hz,1H),3.88~3.81(m,1H),3.63~3.59 (m,1H),3.34~3.26(m,2H),3.16~3.14(m,1H),2.60(s,3H),1.91~1.83(m,1H),1.82~1.78(m,1H),1.70~1.65(m,1H),1.60~1.57(m,1H). In Scheme 2, 9,10-difluoro-3-methyl-6-((((S)-1-(6-methylpyridin-3-yl)piperidin-3-yl)amino)methyl Preparation of 2-(4-(2-(4-nitrophenyl)-2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one (Step 3 of Scheme 2)

[0156] At 20 ° C. under N2, (3S)-1-(6-methyl-3-pyridyl)piperidin-3-amine (600 mg, 2.00 mmol, 1 eq, 3 HCl) and 6,7-difluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.0 5,13] To a mixture of tridecane-5(13),6,8,11-tetraene-11-carbaldehyde (529.27 mg, 2.00 mmol, 1 eq) was added NaOAc (180.08 mg, 2.20 mmol, 1.1 eq). The mixture was stirred at 20°C for 5 hours, and then NaBH(OAc)3 (634.44 mg, 2.99 mmol, 1.5 eq) was added at 0°C. The mixture was stirred at 20°C for 2 hours. LCMS showed that the reaction was complete. Water (30 mL) was added at 0°C to quench the reaction mixture, which was then extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (20 mL×2), dried over Na2SO4, filtered and concentrated under reduced pressure. Compound 6,7-difluoro-2-methyl-11-[[[(3S)-1-(6-methyl-3-pyridinyl)-3-piperidinyl]amino]methyl]-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (800 mg, crude product) as a brown solid. 1 H NMR (400MHz, DMSO-d6) δ8.12 (s, 1H), 7.97 (d, J = 5.2Hz, 1H), 7.60 ~ 7.55 (m, 1 H),7.21(d,J=7.2Hz,1H),7.03(d,J=8.8Hz,1H),4.65~4.55(m,3H),4.42~4. 38(m,2H),3.68~3.62(m,2H),3.47~3.44(m,1H),2.72~2.64(m,2H),2.33(s ,3H),1.91~1.80(m,1H),1.74~1.72(m,1H),1.54~1.51(m,2H),1.40(s,3H). Compound 9 In Scheme 2, 9,10-difluoro-3-methyl-6-((((S)-1-(6-methylpyridin-3-yl)piperidin-3-yl)((2-methyl Preparation of (4-(2-(2-(4-pyridin-4-yl)methyl)amino)methyl)-2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one) (Scheme 2 Step 4)

[0157] At 0°C under N2, 6,7-difluoro-2-methyl-11-[[[(3S)-1-(6-methyl-3-pyridinyl)-3-piperidinyl]amino]methyl]-4-oxa-1-azatricyclo[7.3.1.0 5,13] To a mixture of tridecane-5(13), 6,8,11-tetraen-10-one (90 mg, 204.32 umol, 1 eq) and 2-methylpyridine-4-carbaldehyde (27.23 mg, 224.75 umol, 1.1 eq) was added NaBH(OAc)3 (64.96 mg, 306.48 umol, 1.5 eq). The mixture was then stirred at 20°C for 10 hours. LCMS showed 6,7-difluoro-2-methyl-11-[[[(3S)-1-(6-methyl-3-pyridinyl)-3-piperidinyl]amino]methyl]-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one was completely consumed, and a main peak with the desired mass was detected. Water (1 mL) was added at 0°C to quench the reaction mixture, and then the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex C18 75*30mm*3um; mobile phase: [water (NH4HCO3)-MeCN]; B%: 30%-60%, 8 minutes). The solvent was removed by freeze drying. Compound 6,7-difluoro-2-methyl-11-[(2-methyl-4-pyridinyl)methyl-[(3S)-1-(6-methyl-3-pyridinyl)-3-piperidinyl]amino]methyl]-4-oxa-1-azatricyclic [7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (19.5 mg, 34.81 umol, yield 17.04%, purity 97.30%). 1 H NMR (400MHz, DMSO-d6) δ8.28(d,J=4.8Hz,1H),8.15(s,1H),8.04(s,1H),7.57~7.55(m,1H),7.24~7.19(m,3H),7.01( t,J=8.0Hz,1H),4.71~4.70(m,1H),4.56~4.54(m,1H),4.39(d,J=9.6Hz,1H),3.84~3.80(m,1H),3.74~3.71(m,2H),3 .71~3.64(m,2H),3.61~3.57(m,1H),2.79~2.76(m,2H),2.75~2.71(m,1H),2.37(s,3H),2.32(s,3H),1.99~1.95(m,1 H), 1.77~1.74 (m, 1H), 1.50~1.48 (m, 2H), 1.32 (t, J=7.2Hz, 3H). HPLC: 97.39% (220nm), 97.92% (254nm). MS (ESI): mass calcd.ForC 31 H33 F2N5O2545.26m / z found 546.3[M+H] + . Compound 10 9,10-Difluoro-3-methyl-6-((((2-methylpyrrolidone) was prepared according to the procedure described in step 4 of scheme 2 of the present application. ((S)-1-(pyridin-3-yl)piperidin-3-yl)amino)methyl)-2H-[1,4]oxazino[2,3,4-ij] Quinolin-7(3H)-one

[0158] 9,10-Difluoro-3-methyl-6-((((2-methylpyridin-4-yl)methyl)((S)-1-(pyridin-3-yl)piperidin-3-yl)amino)methyl)-2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one (14 mg, 26.14 umol, 11.15% yield, 99.24% purity) was obtained as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.30~8.27(m,2H),8.10(d,J=4.4Hz,1H),7.92(t,J=4.0Hz,1H),7.58~7.52(m,1H), 7.30~7.22(m,3H),7.17~7.13(m,1H),4.71~4.68(m,1H),4.59~4.56(m,1H),4.40~4.31(m,1H),3.97~3.93(m ,1H),3.72~3.57(m,5H),2.85~2.82(m,1H),2.73~2.63(m,2H),2.38(s,3H),2.01~1.96(m,1H),1.79~1.74(m ,1H),1.60~1.38(m,2H),1.32(d,J=6.8Hz,8.8Hz,3H).HPLC:99.24%(220nm),98.93%(254nm).MS(ESI):mass calcd.For C 30 H 31 F2N5O2531.24m / zfound 532.3[M+H] + . Compound 11 6-((((2-aminopyridin-4-yl)methyl)((S)-1-(6-methylpyridin-3-yl)piperidin-3-yl)amino)methyl Preparation of 2-(4-(2-(4-nitro-1-yl)-9,10-difluoro-3-methyl-2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one (Step 2 of Scheme 2) 5)

[0159] N-[4-[(6,7-difluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.0 5,13A solution of tert-butyl 1-[(3S)-1-(6-methyl-3-pyridyl)-3-piperidyl]amino]methyl]-2-pyridyl]carbamate (150 mg, 231.94 μmol, 1 eq) was stirred for 2 hours. LC-MS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex C 1880*40 mm*3 μm; mobile phase: [water (NH4HCO3)-MeCN]; B%: 20%-50%, 8 minutes). The solvent was removed by freeze drying. Compound 11-[(2-amino-4-pyridyl)methyl-[(3S)-1-(6-methyl-3-pyridyl)-3-piperidyl]amino]methyl]-6,7-difluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (16.6 mg, 28.26 umol, yield 12.18%, purity 93.06%). 1 H NMR (400MHz, DMSO-d6) δ8.13(s,1H),8.03(d,J=6.0Hz,1H),7.76(d,J=5.6Hz,1H),7.58~7.53(m,1H),7.20(dd,J=3.2Hz,7 .6Hz,1H),7.02(t,J=7.6Hz,1H),6.55(t,J=4.8Hz,1H),6.45(s,1H),5.75(s,2H),4.69~4.66(m,1H),4.57(d,J=4Hz,1H),4 .43~4.40(m,1H),3.79(d,J=8.8Hz,1H),3.69~3.53(m,5H),2.76~2.67(m,2H),2.63~2.56(m,1H),2.32(s,3H),2.00~1.97 (m,1H),1.78~1.75(m,1H),1.54~1.44(m,2H),1.35(t,J=6.4Hz,3H).HPLC:93.06%(220nm),98.18%(254nm).MS(ESI):mass calcd.ForC 30 H 32 F2N6O2546.26m / z found 547.3[M+H] + . Option 3 Specific steps for preparing the compounds in Scheme 3 Preparation of (S)-tert-butyl (1-(6-cyanopyridin-3-yl)piperidin-3-yl)carbamate (Step 3 of Scheme 3) 1)

[0160] By N- (3-piperidinyl) carbamic acid tert-butyl ester (1.42g, 7.10mmol, 1.3eq), 5-bromopyridine-2-carbonitrile (1g, 5.46mmol, 1eq), Pd2(dba)3 (250.19mg, 273.22umol, 0.05eq), Xantphos (189.71mg, 327.86umol, 0.06eq) and Cs2CO3 (2.40g, 7.38mmol, 1.35eq) mixture in dioxane (20mL) degassed and purged 3 times with N2. Then under N2 atmosphere, the mixture was stirred at 90 DEG C for 12 hours. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure. Ethyl acetate (50mL) was added to the residue and filtered through a diatomaceous earth pad. The filter cake was washed with ethyl acetate (70mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage; 20 The reaction mixture was purified by flash silica gel column with a gradient of 0-47% petroleum ether / ethyl acetate at 45 mL / min. The eluent was removed under reduced pressure to afford tert-butyl N-[(3S)-1-(6-cyano-3-pyridinyl)-3-piperidinyl]carbamate (0.7 g, 2.32 mmol, 42.37% yield) as a yellow solid. 1 H NMR(DMSO-d6,400MHz)δ8.37(s,1H),7.71(d,J=8.8Hz,1H),7.30(dd,J=2.8Hz,8.4Hz,1H),7.01(d,J=7.2Hz,1H),3.81(d,J=12.8Hz,2H),3.3 8~3.36(m,1H),3.01~2.99(m,1H),2.90(dd,J=9.6Hz,12.8Hz,1H),1.85~1.81(m,1H),1.75~1.73(m,1H),1.47(t,J=8.8Hz,2H),1.39(s,9H). Preparation of (S)-5-(3-aminopiperidin-1-yl)pyridinecarbonitrile (Step 2 of Scheme 3)

[0161] To a solution of tert-butyl N-[(3S)-1-(6-cyano-3-pyridyl)-3-piperidyl]carbamate (0.7 g, 2.32 mmol, 1 eq) in MeOH (2 mL) was added HCl / MeOH (4 M, 6 mL, 10.37 eq). The mixture was stirred at 20 ° C for 3 hours. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure. Compound 5-[(3S)-3-amino-1-piperidyl]pyridine-2-carbonitrile (0.7 g, thick, 3 HCl) was obtained as a yellow solid. 1 H NMR (DMSO-d6, 400MHz) δ8.48~8.42(m,3H),7.77(d,J=8.8Hz,1H),7.39(dd,J=2.8Hz,8.8Hz,1H),4.01~3.98(m,1H),3.74~3.71(m,1H) ,3.31~3.26(m,1H),3.21~3.08(m,1H),3.17~3.12(m,1H),2.02~1.99(m,1H),1.81~1.78(m,1H),1.70~1.66(m,1H),1.56~1.55(m,1H). 5-((3S)-3-(((9,10-difluoro-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazin[2,3,4- Preparation of (i)-[(1,2 ...

[0162] At 20 ° C, 5-[(3S)-3-amino-1-piperidinyl]pyridine-2-carbonitrile (0.7 g, 2.25 mmol, 1 eq, 3 HCl) and 6,7-difluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraene-11-carbaldehyde (595.72 mg, 2.25 mmol, 1 eq) solution was stirred for 1 hour. NaBH(OAc)3 (952.12 mg, 4.49 mmol, 2 eq) was then added portionwise at 0°C, and the resulting mixture was stirred at 20°C for 11 hours. LCMS showed that the reaction was nearly complete. The reaction mixture was quenched with ice water (30 mL) and then extracted with DCM (10 mL×3). The combined organic phases were washed with brine (10 mL×1), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Compound 5-[(3S)-3-[(6,7-difluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]tridec-5(13),6,8,11-tetraen-11-yl)methylamino]-1-piperidinyl]pyridine-2-carbonitrile (0.92 g, crude product) as a yellow solid. 1H NMR(DMSO-d6,400MHz)δ8.43(s,1H),8.23~8.22(m,1H),7.73(d,J=8.8Hz,1H),7.62~7 .54(m,1H),7.39~7.37(m,1H),4.69~4.56(m,2H),4.44~4.41(m,1H),4.05~4.04(m,1H ),3.96(d,J=4.8Hz,1H),3.90(s,3H),3.84~3.76(m,1H),3.07~3.05(m,1H),2.90~2.8 5(m,1H),2.00~1.99(m,1H),1.82~1.74(m,1H),1.52~1.48(m,2H),1.43~1.38(m,3H). Compound 12 5-((3S)-3-(((9,10-difluoro-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazin[2,3,4- Preparation of (ij]quinolin-6-yl)methyl)((2-methylpyridin-4-yl)methyl)amino)piperidin-1-yl)pyridinecarbonitrile (Scheme 3) Step 4)

[0163] 5-[(3S)-3-[(6,7-difluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-11-yl)methylamino]-1-piperidinyl]pyridine-2-carbonitrile (0.15 g, 332.25 umol, 1 eq) and 2-methylpyridine-4-carboxaldehyde (40.25 mg, 332.25 umol, 1 eq) solution was stirred for 1 hour. Then, NaBH(OAc)3 (140.83 mg, 664.50 umol, 2 eq) was added in batches at 0°C. The resulting mixture was stirred at 20°C for 3 hours. LCMS and HPLC showed that the reaction was complete. The mixture was quenched with ice water (1 mL) and concentrated under reduced pressure. Purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 um; mobile phase: [water (NH4HCO3)-MeCN]; B%: 30%-60%, 10 minutes). The eluent was removed by freeze drying. The compound 5-[(3S)-3-[(6,7-difluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-11-yl)methyl-[(2-methyl-4-pyridinyl)methyl]amino]-1-piperidinyl]pyridine-2-carbonitrile (16.7 mg, 28.92 umol, yield 8.71%, purity 96.40%). 1H NMR(DMSO-d6,400MHz)δ8.41(s,1H),8.28(d,J=4.8Hz,1H),8.09(s,1H),7.68(dd,J=6.8Hz,8.8Hz,1H),7.55~7.54(m,1H),7.35~7.34(m,1 H),7.24(dd,J=5.2Hz,9.2Hz,2H),4.69~4.67(m,1H),4.57~4.55(m,1H),4.40~4.37(m,1H),4.18(d,J=11.6Hz,1H),3.93(d,J=12.8Hz,1H), 3.82~3.75(m,1H),3.72~3.56(m,3H),3.09(t,J=12.0Hz,1H),2.90~2.83(m,1H),2.63~2.59(m,1H),2.38(s,3H),2.03~2.00(m,1H),1.78( d,J=12.8Hz,1H),1.69~1.64(m,1H),1.42~1.39(m,1H),1.32(dd,J=6.8Hz,11.2Hz,3H).MS:96.40%(220nm),97.44%(254nm).MS(ESI):mass calcd.ForC 31 H 30 F2N6O2556.24m / z found 557.2[M+H] + . Compound 13 5-((3S)-3-(((9,10-difluoro-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazin[2,3,4- Preparation of (2-methylpyridin-4-yl)methyl)amino)piperidin-1-yl)pyridineamide (Scheme 3) Step 5)

[0164] At 20 °, 5-[(3S)-3-[(6,7-difluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.0 5,13]Tridecane-5(13),6,8,11-tetraen-11-yl)methyl-[(2-methyl-4-pyridyl)methyl]amino]-1-piperidinyl]pyridine-2-carbonitrile (0.15 g, 269.49 umol, 1 eq) was added K2CO3 (74.49 mg, 538.98 umol, 2 eq) and UHP (0.13 g, 1.38 mmol, 5.13 eq). The reaction mixture was then stirred at 40°C for 5 hours. LCMS and HPLC showed that the reaction was complete. Water (30 mL) was added to the mixture, which was then extracted with ethyl acetate (10 mL×3). The combined organic phases were washed with saturated Na2SO3, dried over Na2SO4, filtered and concentrated in vacuo. Purification was performed by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH4HCO3)-MeCN]; B%: 30%-55%, 8 minutes). The eluent was removed by freeze drying. Compound 5-[(3S)-3-[(6,7-difluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-11-yl)methyl-[(2-methyl-4-pyridinyl)methyl]amino]-1-piperidinyl]pyridine-2-carboxamide (48.1 mg, 83.71 umol, yield 31.06%, purity 100%). 1 H NMR (DMSO-d6, 400MHz) δ8.29~8.26(m,2H),8.09(s,1H),7.78(dd,J=6.4Hz,8.8Hz,1H),7.68~7.63(m,1H),7.58~7.53(m,1H),7.38~7.3 4(m,1H),7.28~7.23(m,3H),4.71~4.68(m,1H),4.60~4.55(m,1H),4.40~4.34(m,1H),4.12(d,J=12.0Hz,1H),3.89~3.86(m,1H),3.79~3 .69(m,2H),3.66~3.54(m,2H),3.04(t,J=11.6Hz,1H),2.83~2.76(m,1H),2.70~2.64(m,1H),2.38(s,3H),2.04~2.01(m,1H),1.79(d,J= 12.8Hz,1H),1.67~1.60(m,1H),1.49~1.43(m,1H),1.32(dd,J=6.8Hz,8.4Hz,3H).MS:100.00%(220nm),100.00%(254nm).MS(ESI):mass calcd.For C31 H 32 F2N6O3574.25m / z found575.3[M+H] + . Option 4 Specific steps for preparing the compounds in Scheme 4 Preparation of (S)-tert-Butyl (1-(pyrazin-2-yl)piperidin-3-yl)carbamate (Step 1 of Scheme 4)

[0165] To a mixture of tert-butyl N-[(3S)-3-piperidinyl]carbamate (2 g, 9.99 mmol, 1 eq) and 2-chloropyrazine (1.26 g, 10.98 mmol, 982.90 uL, 1.1 eq) in DMSO (20 mL) was added Cs2CO3 (6.51 g, 19.97 mmol, 2 eq). The reaction mixture was stirred at 100 ° C for 3 hours. LCMS showed that tert-butyl N-[(3S)-3-piperidinyl]carbamate was consumed and a major peak with the desired mass was detected. The reaction mixture was cooled to 0 ° C, quenched with H2O (50 mL) at 0 ° C, and then extracted with EtOAc (40 mL×2). The combined organic layers were washed with brine (40 mL×3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography ( 25g Flash silica gel column, eluting with a gradient of 0-50% ethyl acetate / petroleum ether at 75 mL / min. The eluent was concentrated in vacuo to afford tert-butyl-(1-pyrazin-2-yl-3-piperidinyl)carbamate (1.4 g, 5.03 mmol, 50.37% yield) as a yellow solid. 1 H NMR(DMSO-d6,400MHz)δ8.27(s,1H),8.04(s,1H),7.78(s,1H),6.95(d,J=7.6Hz,1H),4.18(d,J=11.2Hz,1H),4.04(d,J=12.4Hz, 1H), 3.28~3.27(m,1H),2.96(t,J=10.4Hz,1H),2.80(t,J=12.4Hz,1H),1.84(s,1H),1.74(s,1H),1.46~1.42(m,2H),1.39(s,9H). Preparation of (S)-1-(pyrazin-2-yl)piperidin-3-amine (Scheme 4, Step 2)

[0166] To a solution of tert-butyl N-(1-pyrazine-2-yl-3-piperidinyl)carbamate (1.4 g, 5.03 mmol, 1 eq) in MeOH (2 mL) was added HCl / MeOH (4 M, 40 mL). The reaction mixture was stirred at 20° C. for 2 hours. LCMS showed that tert-butyl N-(1-pyrazine-2-yl-3-piperidinyl)carbamate was almost consumed, and a main peak with the desired mass was detected. The mixture was concentrated in vacuo. Compound (3S)-1-pyrazine-2-ylpiperidin-3-amine (1.2 g, 4.17 mmol, 82.95% yield, 3HCl) was obtained as a yellow solid. 1 H NMR(DMSO-d6,400MHz)δ8.37(s 1H),8.28(s,2H),8.13(s,1H),7.86(s,1H),4.30(d,J=10.0Hz,1H),3.96~3.90(m,1H),3.2 6~3.14(m,3H),2.04~2.00(m,1H),1.81~1.77(m,1H),1.70~1.61(m,1H),1.58~1.48(m,1H). 9,10-difluoro-3-methyl-6-((((S)-1-(pyrazin-2-yl)piperidin-3-yl)amino)methyl)-2H-[1,4- Preparation of oxazino[2,3,4-ij]quinolin-7(3H)-one (Scheme 4, Step 3)

[0167] To 6,7-difluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.0 5,13 To a mixture of tridecane-5(13), 6,8,11-tetraene-11-carbaldehyde (0.3 g, 1.13 mmol, 1 eq) and (3S)-1-pyrazin-2-ylpiperidin-3-amine (325.34 mg, 1.13 mmol, 1 eq, 3 HCl) were added NaOAc (102.07 mg, 1.24 mmol, 1.1 eq) and NaBH(OAc) 3 (359.61 mg, 1.70 mmol, 1.5 eq). The reaction mixture was stirred at 20° C. for 3 hours. LCMS indicated that the reaction was complete. At 0° C., H 2 O (15 mL) was added to quench the reaction mixture, which was then extracted with EtOAc (20 mL×3). The combined organic phase was washed with brine (10 mL×1), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. Compound 6,7-difluoro-2-methyl-11-[[[(3S)-1-pyrazin-2-yl-3-piperidinyl]amino]methyl]-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (310 mg, crude product) as a white solid. 1H NMR(DMSO-d6,400MHz)δ8.30(s,1H),8.08(d,J=5.2Hz,1H),8.04~8.01(m,1H),7.73(s,1H),7.56(dd,J=8.0Hz,10.4Hz,1H),4.62~4.57 (m,2H),4.33~4.24(m,4H),4.04~4.01(m,2H),3.94(s,1H),3.05~2.94(m,1H),2.86~2.77(m,1H),1.95~1.86(m,4H),1.38~1.36(m,3H). Compound 14 9,10-Difluoro-3-methyl-6-((((2-methylpyridin-4-yl)methyl)((S)-1-(pyrazin-2-yl)piperidin-3-yl) Preparation of 2-(4-(2-(2-(4-nitrophenyl)amino)methyl)-2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one (Step 4 of Scheme 4)

[0168] To 6,7-difluoro-2-methyl-11-[[[(3S)-1-pyrazin-2-yl-3-piperidinyl]amino]methyl]-4-oxa-1-azatricyclo[7.3.1.0 5,13 To a mixture of tridecane-5(13),6,8,11-tetraene-10-one (300 mg, 701.84 μmol, 1 eq) and 2-methylpyridine-4-carbaldehyde (127.53 mg, 1.05 mmol, 1.5 eq) was added NaBH(OAc)3 (297.50 mg, 1.40 mmol, 2 eq). The mixture was stirred at 20°C for 3 hours. LCMS indicated that the reaction was complete. At 0°C, H2O (15 mL) was added to quench the reaction mixture, which was then extracted with DCM (20 mL×3). The combined organic layers were washed with brine (15 mL×2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification was performed by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH4HCO3-MeCN]; B%: 25%-55%, 10 minutes). The eluate was dried by freeze drying. Compound 6,7-difluoro-2-methyl-11-[[(2-methyl-4-pyridinyl)methyl-[(3S)-1-pyrazin-2-yl-3-piperidinyl]amino]methyl]-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (136.8 mg, 256.86 umol, yield 36.60%, purity 100%). 11H NMR (DMSO-d6, 400 MHz) δ 8.32 (s, 1H), 8.27 (d, J = 4.8 Hz, 1H), 8.07 (s, 1H), 8.03 - 8.00 (m, 1H), 7.74 (t, J = 2.4 Hz, 1H), 7.54 (dd, J = 8.4 Hz, 10.0 Hz, 1H), 7.25 (s, 1H), 7.21 (t, J = 4.4 Hz, 1H), 4.68 - 4.65 (m, 1H), 4.57 - 4.51 (m, 2H), 4.39 - 4.35 (m, 1H), 4.26 (d, J = 12.8 Hz, 1H), 3.84 - 3.66 (m, 3H), 3.60 - 3.56 (m, 1H), 2.98 (t, J = 12.0 Hz, 1H), 2.79 (t, J = 12.8 Hz, 1H), 2.63 - 2.57 (m, 1H), 2.36 (d, J = 3.6 Hz, 3H), 2.02 (d, J = 11.2 Hz, 1H), 1.77 (d, J = 13.2 Hz, 1H), 1.70 - 1.61 (m, 1H), 1.42 - 1.38 (m, 1H), 1.32 (dd, J = 6.8 Hz, 14.8 Hz, 3H). LCMS: 100% (220 nm), 100% (254 nm). MS (ESI): mass calcd. For C 29 H 30 F2N6O2532.24 m / z found 533.3 [M + H] + . Scheme 5 Specific steps for preparing the compounds in Scheme 5 Preparation of (S)-tert-butyl carbamate (1-(6-nitropyridin-3-yl)pyrrolidin-3-yl) (Step 5) 1)

[0169] To be N- pyrrolidin-3-ylcarbamic acid tert-butyl ester (1.79g, 9.61mmol, 1.3eq) and 5-bromo-2-nitropyridine (1.5g, 7.39mmol, 1eq), Pd2(dba)3(338.33mg, 369.47μm ol, 0.05eq), Xantphos (213.78mg, 369.47μm ol, 0.05eq), Cs2CO3(3.25g, 9.98mmol, 1.35eq) degassed in dioxane (30mL), and purged 3 times with N2.Then under N2 atmosphere, the reaction mixture was stirred at 115 DEG C for 12 hours.LCMS shows that the reaction is complete. The mixture is cooled to room temperature and filtered through a diatomaceous earth pad. The filter cake is washed with ethyl acetate (100mL). The combined filtrate is concentrated under reduced pressure. The residue is purified by flash silica gel chromatography (Biotage; 40 The reaction mixture was purified by flash silica gel column with a gradient of 0-45% ethyl acetate / petroleum ether at 60 mL / min. The solvent was removed under reduced pressure to afford tert-butyl N-[1-(6-nitro-3-pyridyl)pyrrolidin-3-yl]carbamate (1.8 g, 5.84 mmol, 79.00% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ8.15(d,J=8.8Hz,1H),7.87(s,1H),7.28(d,J=6.8Hz,1H),7.05(dd,J=2.8Hz,9.2Hz,1H),4.21~4.18(m,1H),3.64(dd,J =6.4Hz,10.8Hz,1H),3.56~3.51(m,1H),3.48~3.42(m,1H),3.25(dd,J=4.4Hz,10.8Hz,1H),2.21~2.13(m,1H),1.97~1.91(m,1H),1.39(s,9H). Preparation of (S)-1-(6-nitropyridin-3-yl)pyrrolidin-3-amine (Scheme 5, Step 2)

[0170] A solution of tert-butyl N-[1-(6-nitro-3-pyridyl)pyrrolidin-3-yl]carbamate in HCl / MeOH (4M, 30 mL, 34.97 eq) was stirred at 20°C for 12 hours. LC-MS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to afford compound (3S)-1-(6-nitro-3-pyridyl)pyrrolidin-3-amine (1.8 g, crude product, 3HCl) as a brown solid. 1H NMR (400MHz, DMSO-d6) δ8.45(s,2H),8.20(d,J=9.2Hz,1H),7.92(s,1H),7.13(dd,J=2.8Hz,9.2Hz,1H),4.05~3.98 (m,1H),3.74(dd,J=1.2Hz,6.4Hz,1H),3.69~3.63(m,1H),3.57~3.53(m,2H),2.40~2.31(m,1H),2.22~2.17(m,1H). 9,10-difluoro-3-methyl-6-((((S)-1-(6-nitropyridin-3-yl)pyrrolidin-3-yl)amino)methyl)- Preparation of 2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one (Scheme 5, Step 3)

[0171] To 6,7-difluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.0 5,13 ] To a mixture of tridecane-5(13),6,8,11-tetraene-11-carbaldehyde (835.05 mg, 3.15 mmol, 1 eq) and (3S)-1-(6-nitro-3-pyridyl)pyrrolidin-3-amine (1 g, 3.15 mmol, 1 eq, 3 HCl) was added NaOAc (284.11 mg, 3.46 mmol, 1.1 eq). The reaction mixture was stirred at 20°C for half an hour, and then NaBH(OAc)3 (1.00 g, 4.72 mmol, 1.5 eq) was added at 20°C. The reaction mixture was stirred at 20°C for 6 hours. LC-MS showed that the reaction was complete. Water (50 mL) was added at 0°C to quench the reaction mixture and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 ml×2), dried over Na2SO4, filtered and concentrated under reduced pressure. Compound 6,7-difluoro-2-methyl-11-[[[(3S)-1-(6-nitro-3-pyridyl)pyrrolidin-3-yl]amino]methyl]-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (1 g, crude product) as a brown solid. 1H NMR (400MHz, DMSO-d6) δ8.15(d,J=9.2Hz,1H),8.06(s,1H),7.86(d,J=2.4Hz,1H),7 .57(dd,J=8.0Hz,10.8Hz,1H),7.03(dd,J=2.8Hz,8.8Hz,1H),4.56(d,J=11.2Hz,1H) ,4.41~4.36(m,1H),3.64~3.55(m,4H),3.47~3.45(m,2H),3.32~3.28(m,2H),3.17( d,J=3.6Hz,1H),2.17~2.11(m,1H),1.97~1.90(m1H),1.39(dd,J=6.8Hz,8.8Hz,3H). 9,10-difluoro-6-((((2-methoxypyridin-4-yl)methyl)((S)-1-(6-nitropyridin-3-yl)pyrrole Preparation of 2-(3-methyl)-2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one (Scheme 5) Step 4)

[0172] At 20 ° C under N2, 6,7-difluoro-2-methyl-11-[[[(3S)-1-(6-nitro-3-pyridyl)pyrrolidin-3-yl]amino]methyl]-4-oxa-1-azatricyclo[7.3.1.0 5,13 ] To a mixture of tridecane-5(13), 6,8,11-tetraen-10-one (200 mg, 437.23 μmol, 1 eq) and 2-methoxypyridine-4-carbaldehyde (59.96 mg, 437.23 μmol, 1 eq) was added NaBH(OAc)3 (139.00 mg, 655.84 μmol, 1.5 eq). The mixture was then stirred at 20°C for 10 hours. LC-MS showed 6,7-difluoro-2-methyl-11-[[[(3S)-1-(6-nitro-3-pyridyl)pyrrolidin-3-yl]amino]methyl]-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraene-10-one was completely consumed and a new peak with the desired m / z was detected. At 25°C, water (50 mL) was added to quench the reaction mixture and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL×2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound 6,7-difluoro-11-[(2-methoxy-4-pyridinyl)methyl-[(3S)-1-(6-nitro-3-pyridinyl)pyrrolidin-3-yl]amino]methyl]-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13]Tridecane-5(13),6,8,11-tetraen-10-one (200 mg, crude product) as a brown solid. 1 H NMR (400MHz, DMSO-d6) δ8.14~8.11(m,1H),8.08~8.04(m,1H),7.97~7.95(m,1H),7.83(d,J=2.8Hz,1 H),7.56~7.51(m,1H),7.01~6.98(m,1H),6.96~6.93(m,1H),6.79~6.76(m,1H),4.64~4.59(m,1H),4. 55~4.52(m,1H),4.49~4.48(m,1H),4.39~4.31(m,1H),3.93~3.92(m,1H),3.72(s,3H),3.68~3.66(m ,2H),3.62~3.59(m,3H),3.47~3.45(m,1H),3.39~3.37(m,1H),1.33~1.32(m,2H),1.19~1.16(m,3H). Compound 15 6-((((S)-1-(6-aminopyridin-3-yl)pyrrolidin-3-yl)((2-methoxypyridin-4-yl)methyl)amino Preparation of 2-(4-(2-(2-(4-nitrophenyl)methyl)-9,10-difluoro-3-methyl-2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one (Scheme 5) Step 5)

[0173] 6,7-Difluoro-11-[[(2-methoxy-4-pyridinyl)methyl-[(3S)-1-(6-nitro-3-pyridinyl)pyrrolidin-3-yl]amino]methyl]-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 A mixture of tridecane-5(13), 6,8,11-tetraen-10-one (200 mg, 345.68 μmol, 1 eq) and Pd / C (60 mg, purity 10%, 1 eq) was stirred for 5 hours. LC-MS and HPLC showed that 6,7-difluoro-11-[(2-methoxy-4-pyridinyl)methyl-[(3S)-1-(6-nitro-3-pyridinyl)pyrrolidin-3-yl]amino]methyl]-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13]Tridecane-5(13),6,8,11-tetraene-10-one was completely consumed and a main peak with the expected mass was detected. The reaction mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C 18150*40mm*10um; mobile phase: [water (NH4HCO3)-MeCN]; B%: 25%-55%, 8 minutes). The solvent was removed by freeze drying. The pale yellow compound 11-[[[(3S)-1-(6-amino-3-pyridyl)pyrrolidin-3-yl]-[(2-methoxy-4-pyridyl)methyl]amino]methyl]-6,7-difluoro-2-methyl-4-oxa-1-azatricyclic [7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (3.1 mg, 5.65 umol, yield 1.63%). 1 HNMR (400MHz, DMSO-d6) δ13.96~13.90(m,1H),8.46(s,1H),8.06(s,1H),7.71~7.70(m,1H),7.57~7.56(m,1 H),7.43~7.41(m,2H),7.27(s,1H),7.22~7.21(m,1H),7.01~6.99(m,1H),4.56~4.54(m,2H),4.39(s,3H),4 .32~4.18(m,3H),4.00~3.93(m,2H),3.78~3.75(m,3H),3.56~3.54(m,1H),3.50~3.46(m,1H),3.13~3.12(m ,1H),2.67~2.63(m,1H),1.47~1.43(m,3H).HPLC:98.76%(220nm),98.51%(254nm).MS(ESI):masscalcd.For C 29 H 30 F2N6O3548.23m / z found 549.3[M+H] + . Option 6 General procedures for preparing compounds in Scheme 6 Preparation of (S)-tert-Butyl Carbamate (1-(6-bromopyridin-3-yl)piperidin-3-yl) (Step 1 of Scheme 6)

[0174] A mixture of (6-bromo-3-pyridyl)boronic acid (10.08 g, 49.93 mmol, 2 eq) and 4AMS (10 g, 1.00 eq) in DCE (100 mL) was stirred at 20° C. for 5 minutes, and then tert-butyl N-[(3S)-3-piperidinyl]carbamate (5 g, 24.97 mmol, 1 eq) was added. The reaction mixture was stirred at 60° C. under O (1 atm) for 15 hours. LCMS and TLC (petroleum ether: ethyl acetate = 2:1, R f =0.4) indicated that (6-bromo-3-pyridyl)boronic acid still remained and a peak with the desired mass was formed. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography ( 80g Flash silica gel column, 0-45% ethyl acetate / petroleum ether gradient elution @ 110 mL / min. The eluent was concentrated in vacuo to afford tert-butyl N-[(3S)-1-(6-bromo-3-pyridinyl)-3-piperidinyl]carbamate (3.2 g, 8.98 mmol, 35.98% yield) as a yellow solid. 1 H NMR(DMSO-d6,400MHz)δ8.14(s,1H),7.37(d,J=8.8Hz,1H),7.28(d,J=5.6Hz,1H),6.94(d,J=7.6Hz,1H),3.64~3.57(m,2H),3.42~ 3.33(m,1H),2.75(t,J=10.8Hz,1H),2.62(t,J=10.0Hz,1H),1.99~1.87(m,1H),1.70~1.63(m,1H),1.54~1.50(m,2H),1.39(s,9H). Preparation of (S)-1-(6-bromopyridin-3-yl)piperidin-3-amine (Step 2 of Scheme 6)

[0175] A mixture of tert-butyl N-[(3S)-1-(6-bromo-3-pyridinyl)-3-piperidinyl]carbamate (1 g, 2.81 mmol, 1 eq) in HCl / MeOH (4 M, 14.03 mL, 20 eq) was stirred at 20°C for 3 hours. LCMS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to afford (3S)-1-(6-bromo-3-pyridinyl)piperidin-3-amine (0.7 g, 1.92 mmol, 68.23% yield, 3 HCl) as a yellow solid. 1H NMR(DMSO-d6,400MHz)δ8.08(s,1H),8.04(s,3H),7.45(d,J=8.4Hz,1H),7.35~7.32(m,1H),3.44~3.40 (m,2H),3.27~3.23(m,1H),3.17~2.98(m,2H),1.94~1.91(m,1H),1.80~1.76(m,1H),1.61~1.52(m,2H). 6-((((S)-1-(6-bromopyridin-3-yl)piperidin-3-yl)amino)methyl)-9,10-difluoro-3-methyl-2H- Preparation of [1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one (Scheme 6, Step 3)

[0176] A solution of 9,10-difluoro-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carbaldehyde (0.7 g, 2.64 mmol, 1 eq) and (3S)-1-(6-bromo-3-pyridyl)piperidin-3-amine (964.77 mg, 2.64 mmol, 1 eq, 3 HCl) in DCE (20 mL) was stirred at 20° C. for half an hour. The mixture was then cooled to 0° C., and NaBH(OAc) 3 (1.12 g, 5.28 mmol, 2 eq) was added portionwise at 0° C. The mixture was stirred at 20° C. for 10 hours. LCMS and TLC (ethyl acetate:methanol=6:1, R f =0.3) showed that the reaction was complete. At 0 ° C, the reaction mixture was quenched with ice water (20 mL) and the pH was adjusted to 8 with saturated NaHCO3. The mixture was extracted with DCM and i-PrOH (v:v=3:1, 30 mL×3). The combined organic layer was washed with brine (20 mL×1), dried over Na2SO4, filtered and concentrated under reduced pressure. Compound 11-[[[(3S)-1-(6-bromo-3-pyridyl)-3-piperidinyl]amino]methyl]-6,7-difluoro-2-methyl-4-oxa-1-azatricyclic [7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (1 g, 1.98 mmol, 74.97% yield) as a yellow solid. 1H NMR(DMSO-d6,400MHz)δ8.11~8.09(m,1H),8.06~8.04(m,1H),7.59~7.55(m,1 H),7.33~7.31(m,2H),4.64~4.55(m,3H),4.42~4.39(m,2H),3.79~3.75(m,1H) ),3.53~3.50(m,1H),2.80~2.74(m,1H),2.67~2.64(m,2H),1.90~1.88(m,1H) ,1.77~1.70(m,1H),1.54~1.45(m,1H),1.40~1.36(m,3H),1.34~1.25(m,1H). 6-((((S)-1-(6-bromopyridin-3-yl)piperidin-3-yl)((2-methoxypyridin-4-yl)methyl)amino)methyl Preparation of 2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one (Step 6 of Scheme 6) 4)

[0177] 11-[[[(3S)-1-(6-bromo-3-pyridinyl)-3-piperidinyl]amino]methyl]-6,7-difluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (1 g, 1.68 mmol, purity 85%, 1 eq) and 2-methoxypyridine-4-carbaldehyde (345.99 mg, 2.52 mmol, 1.5 eq) were stirred at 25°C for 1 hour. The mixture was then cooled to 0°C and NaBH(OAc)3 (712.96 mg, 3.36 mmol, 2 eq) was added portionwise at 0°C. The mixture was stirred at 20°C for 10 hours. LCMS and TLC (ethyl acetate: methanol = 8: 1, R f =0.3) showed that the reaction was almost complete. At 0 ° C, the reaction mixture was quenched with ice water (20 mL) and the pH was adjusted to 8 with saturated NaHCO 3. The mixture was extracted with DCM and i-PrOH (v:v=3:1, 30 mL×3). The combined organic layer was washed with brine (20 mL×1), dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography ( 20g Flash silica gel column, eluting with 0-10% methanol / ethyl acetate gradient @ 80 mL / min). The eluent was concentrated in vacuo. Compound 11-[[[(3S)-1-(6-bromo-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6,7-difluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13]Tridecane-5(13),6,8,11-tetraen-10-one (0.7 g, 1.12 mmol, yield 66.43%) was obtained in a light yellow color. 1 H NMR(DMSO-d6,400MHz)δ8.09(s,1H),8.05(s,1H),8.03~8.00(m,1H),7.55~7.53(m,1H),7.32~7. 29(m,2H),7.02~7.00(m,1H),6.85~6.83(m,1H),4.69~4.67(m,1H),4.56~4.55(m,1H),4.40~4.3 8(m,1H),4.01~3.82(m,2H),3.76(s,3H),3.73~3.55(m,4H),2.85~2.81(m,1H),2.70~2.65(m,2H ),1.98~1.96(m,1H),1.77~1.74(m,1H),1.54~1.42(m,1H),1.40~1.36(m,1H),1.34~1.30(m,3H). Preparation of compounds in Scheme 6 (Step 5 of Scheme 6)

[0178] Method A: 11-[[[(3S)-1-(6-bromo-3-pyridyl)-3-piperidyl]-[(2-methoxy-4-pyridyl)methyl]amino]methyl]-6,7-difluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 A mixture of tridecane-5(13),6,8,11-tetraen-10-one (111.73 μmol, 1 eq) and different amines (335.20 μmol to 558.65 μmol, 3 eq to 5 eq), Cs2CO3 (223.47 μmol to 333.71 μmol, 2 eq to 3 eq), SPhos or BrettPhos Pd G3 (16.76 μmol, 0.15 eq) was stirred for 10 hours. The mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. Purification was performed by preparative HPLC (column: Waters Xbridge PrepOBD C 18 150*40mm*10um or Waters Xbridge BEH C18 100*30mm*10um or Phenomenex C18 75*30mm*3um; mobile phase: [water (NH4HCO3)-MeCN]; B%: 25%-70%, 8 mins or 10 min) or by flash silica gel chromatography ( 12g Purify the product by flash silica gel column with 0-100% ethyl acetate / petroleum ether gradient at 45 mL / min as eluent. Freeze-dry and remove the eluent to obtain the desired product. Method B: Under N2, 11-[[[(3S)-1-(6-bromo-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6,7-difluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 A mixture of tridecane-5(13),6,8,11-tetraen-10-one (159.62 μmol, 1 eq) and different amides, CuI (79.81 μmol, 0.5 eq), N2N1-dimethylethane-1,2-diamine (31.92 μmol, 0.2 eq), and Cs2CO3 (319.24 μmol to 478.86 μmol, 2 eq to 3 eq) was stirred for 10 to 16 hours. The mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The precipitates were purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um or Waters Xbridge BEH C18 100*30mm*10um or Phenomenex C18 75*30mm*3um; mobile phase: [water (NH4HCO3)-MeCN]; B%: 25%-70%, 8 mins or 10 min) or flash silica gel chromatography ( 12g Flash silica gel column, eluting with a gradient of 0-100% ethyl acetate / petroleum ether @ 45 mL / min). The eluent was removed by freeze drying to obtain the desired product. Compound 16 Preparation of (5-((3S)-3-(((9,10-difluoro-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazin[2, 3,4-ij]quinolin-6-yl)methyl)((2-methoxypyridin-4-yl)methyl)amino)piperidin-1-yl)pyridin-2-yl)(methyl tert-Butyl)carbamate (Step 5 of Scheme 6)

[0179] A mixture of 11-[[[(3S)-1-(6-bromo-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6,7-difluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13]Tridecane-5(13),6,8,11-tetraen-10-one (100 mg, 159.62 umol, 1 eq) and tert-butyl N-methylcarbamate (83.75 mg, 638.48 umol, 4 eq), Cs2CO3 (104.01 mg, 319.24 umol, 2 eq), CuI (15.20 mg, 79.81 umol, 0.5 eq), N,N'-dimethylethane-1,2-diamine (7.04 mg, 79.81 umol, 8.59 uL, 0.5 eq) were degassed and purged with N2 for 3 times. LCMS and HPLC showed that 11-[[[(3S)-1-(6-bromo-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6,7-difluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraene-10-one was consumed and a new peak with the desired MS was detected. The reaction mixture was cooled to room temperature, filtered through celite and washed with EtOAc (10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography ( 12g Flash silica gel column, eluent: 0~100% ethyl acetate / petroleum ether gradient @45mL / min). The eluent was concentrated in vacuo. The compound tert-butyl N-[5-[(3S)-3-[(6,7-difluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.0 5,13

[0366] Tridecane-5(13),6,8,11-tetraen-11-yl)methyl-[(2-methoxy-4-pyridinyl)methyl]amino]-1-piperidinyl]-2-pyridinyl]-N-methylcarbamate (70 mg, 103.44 umol, 32.40% yield) was obtained as a yellow solid. This was carried out in two batches and processed together. 1H NMR(DMSO-d6,400MHz)δ8.11(d,J=5.2Hz,1H),8.00(d,J=6.0Hz,1H),7.54(t,J=8.0Hz,1H),7.46~7.38(m,1H),7.35~7.31(m ,1H),7.02(t,J=4.0Hz,1H),6.85(d,J=5.6Hz,1H),6.79~6.73(m,1H),4.70(d,J=6.8Hz,1H),4.60~4.58(m,1H),4.39(d,J=9. 6Hz,1H),3.77(s,3H),3.71~3.65(m,3H),3.60~3.52(m,2H),3.44~3.37(m,2H),3.17(d,J=3.6Hz,3H),2.86~2.77(m,1H),2. 71~2.68(m,1H),1.95~1.90(m,1H),1.79~1.76(m,1H),1.55~1.48(m,2H),1.41(d,J=2.4Hz,9H),1.33(dd,J=6.8Hz,4.0,3H). 9,10-difluoro-6-(((2-methoxypyridin-4-yl)methyl)((S)-1-(6-(methylamino)pyridin-3-yl)piperidin Preparation of 3-(3-pyridin-3-yl)amino)methyl)-3-methyl-2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one (Scheme 6) Step 6)

[0180] To tert-butyl N-[5-[(3S)-3-[(6,7-difluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-11-yl)methyl-[(2-methoxy-4-pyridyl)methyl]amino]-1-piperidinyl]-2-pyridinyl]-N-methylcarbamate (65 mg, 96.05 umol, 1 eq) was added HCl / EtOAc (4M, 5 mL, 208.23 eq). The mixture was stirred at 20°C for 4 hours. LCMS and HPLC showed that the reaction was complete. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex C18 75*30mm*3um; mobile phase: [water (NH4HCO3)-MeCN]; B%: 25%-60%, 8 minutes). The eluate was dried by freeze drying. Compound 6,7-difluoro-11-[[(2-methoxy-4-pyridinyl)methyl-[(3S)-1-[6-(methylamino)-3-pyridinyl]-3-piperidinyl]amino]methyl]-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13]Tridecane-5(13),6,8,11-tetraen-10-one (5.6 mg, 9.70 umol, yield 10.10%, purity 99.87). 1 H NMR(DMSO-d6,400MHz)δ8.08(d,J=7.2Hz,1H),7.99(d,J=5.2Hz,1H),7.69(s,1H),7.57~7.52(m,1H),7.17(d,J=9.2Hz,1H),6.99(s,1H),6.82(s,1H ),6.36(dd,J=9.2Hz,3.6Hz,1H),5.94(t,J=4.8Hz,1H),4.70(d,J=5.2Hz, 1H),4.55(d,J=11.2Hz,1H),4.39(d,J=11.2Hz,1H),3.76(s,3H),3.72~3.5 8(m,3H),3.56~3.50(m,1H),3.35~3.34(m,1H),3.25~3.22(m,1H),2.78~2 .73(m,1H),2.70~2.69(m,3H),2.59(t,J=10.8Hz,1H),2.45~2.39(m,1H),1 .97(d,J=8.4Hz,1H),1.76(d,J=11.2Hz,1H),1.54~1.38(m,2H),1.33(dd,J=6.4Hz,2.8Hz,3H).LCMS:99.87%(220nm),99.58%(254nm).MS(ESI):mass calcd.For C 31 H 34 F2N6O3576.27m / zfound577.3[M+H] + . Compound 17 9,10-difluoro-6-((((2-methoxypyridin-4-yl)methyl)((S)-1-(6-(pyrrolidin-1-yl)pyridine-3- Preparation of 3-methyl-2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one (Scheme 6) Step 5)

[0181] 6,7-difluoro-11-[[(2-methoxy-4-pyridinyl)methyl-[(3S)-1-(6-pyrrolidin-1-yl-3-pyridinyl)-3-piperidinyl] amino]methyl]-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (10.5 mg, 16.55 umol, yield 14.81%, purity 97.20%). 1H NMR(DMSO-d6,400MHz)δ8.08(d,J=8.0Hz,1H),7.99(d,J=5.2Hz,1H),7.79(t,J=3.2Hz,1H),7.56~7.51(m,1H),7.27~7. 23(m,1H),7.01~6.99(m,1H),6.82(s,1H),6.37~6.33(m,1H),4.72~4.69(m,1H),4.57~4.55(m,1H),4.41~4.38(m,1H), 3.78~3.77(m,1H),3.76(s,3H),3.73~3.53(m,4H),3.32~3.28(m,5H),2.64~2.58(m,3H),1.99~1.97(m,1H),1.92~1.91 (m,4H),1.77~1.74(m,1H),1.49~1.44(m,2H),1.35~1.32(m,3H).HPLC:97.20%(220nm),99.12%(254nm).MS(ESI):mass calcd.For C 34 H 38 F2N6O3616.30m / z found617.3[M+H] + . Compound 18 9,10-difluoro-6-((((2-methoxypyridin-4-yl)methyl)((S)-1-(6-(2-oxopyrrolidin-1-yl) pyridin-3-yl)piperidin-3-yl)amino)methyl)-3-methyl-2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one Preparation (Step 5 of Scheme 6)

[0182] 6,7-difluoro-11-[[(2-methoxy-4-pyridinyl)methyl-[(3S)-1-[6-(2-oxopyrrolidin-1-yl)-3-pyridinyl]-3-piperidinyl]amino]methyl]-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (23.5 mg, 37.07 umol, yield 23.22%, purity 99.49%). 1H NMR(DMSO-d6,400MHz)δ8.12~7.99(m,4H),7.56~7.51(m,1H),7.43~7.41(m,1H),7.03~6.99 (m,1H),6.86(s,1H),4.73~4.69(m,1H),4.58~4.55(m,1H),4.41~4.38(m,1H),3.93~3.89(m, 3H),3.77(s,3H),3.73~3.51(m,5H),2.79~2.58(m,5H),2.03~1.98(m,3H),1.79~1.75(m,1H) ,1.52~1.47(m,2H),1.35~1.32(m,3H).HPLC:99.49%(220nm),99.56%(254nm).MS(ESI):mass calcd.For C 34 H 36 F2N6O4630.28m / z found631.3[M+H] + . Compound 19 11-[[[(3S)-1-[6-(dimethylamino)-3-pyridinyl]-3-piperidinyl]-[(2-methoxy-4-pyridinyl) methyl]amino]methyl]-6,7-difluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6, Preparation of 8,11-tetraen-10-one (Step 5 of Scheme 6)

[0183] Compound 11-[[[(3S)-1-[6-(dimethylamino)-3-pyridinyl]-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6,7-difluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (1.1 mg, 1.77 umol, 2.77% yield, 94.85% purity) was obtained as a yellow solid. 1HNMR(DMSO-d6,400MHz)δ8.08(d,J=8.0Hz,1H),7.99(d,J=5.2Hz,1H),7.82 (t,J=2.4Hz,1H),7.57~7.52(m,1H),7.27~7.23(m,1H),7.01~6.99(m,1H),6 .83~6.82(m,1H),6.56(dd,J=6.0Hz,9.6Hz,1H),4.72~4.69(m,1H),4.57~4. 54(m,1H),4.39(d,J=11.2Hz,1H),3.78~3.77(m,1H),3.76(s,3H),3.72~3.7 1(m,1H),3.65(d,J=14.0Hz,1H),3.59~3.58(m,1H),3.57~3.54(m,1H),3.29 ~3.27(m,1H),2.92(s,6H),2.78~2.72(m,1H),2.68~2.65(m,1H),2.62~2.59 (m,1H),2.00~1.95(m,1H),1.78~1.75(m,1H),1.52~1.43(m,2H),1.33(d,J=5.2Hz,3H).LCMS:94.85%(220nm),96.44%(254nm).MS(ESI):masscalcd.For C 32 H 36 F2N6O3590.28m / z found 591.3[M+H] + . Compound 20 11-[[[(3S)-1-[6-(cyclopropylmethylamino)-3-pyridinyl]-3-piperidinyl]-[(2-methoxy-4-pyridinyl)- [piperidinyl)methyl]amino]methyl]-6,7-difluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5 (13) Preparation of 6,8,11-tetraen-10-one (Step 5 of Scheme 6)

[0184] 11-[[[(3S)-1-[6-(cyclopropylmethylamino)-3-pyridinyl]-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6,7-difluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (10 mg, 15.38 umol, 19.28% yield, 94.87% purity) was obtained as a white solid. 1HNMR(DMSO-d6,400MHz)δ8.08~8.07(m,1H),7.99(s,1H),7.65(s,1H),7.58~7.51(m,1H),7.21~7.11(m,1H),7.00~6.99(m,1H),6.82 (s,1H),6.42~6.40(m,1H),6.03(s,1H),4.72~4.69(m,1H),4.55(d,J=10.4Hz,1H),4.42~4.37(m,1H),3.76(s,3H),3.71~3.63(m,2H) ,3.54~3.49(m,2H),3.25~3.17(m,2H),3.03(s,2H),2.79~2.72(m,1H),2.63~2.57(m,2H),1.98~1.97(m,1H),1.77~1.75(m,1H),1.5 0~1.42(m,2H),1.33(s,3H),1.02~0.99(m,1H),0.41~0.39(m,2H),0.16(s,2H).LCMS:94.87%(220nm),99.93%(254nm).MS(ESI):mass calcd.For C 34 H 38 F2N6O3616.30m / z found 617.3[M+H] + . Compound 21 11-[[[(3S)-1-[6-[cyclopropyl(methyl)amino]-3-pyridinyl]-3-piperidinyl]-[(2-methoxy-4- pyridyl)methyl]amino]methyl]-6,7-difluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5 (13) Preparation of 6,8,11-tetraen-10-one (Step 5 of Scheme 6)

[0185] 11-[[[(3S)-1-[6-[cyclopropyl(methyl)amino]-3-pyridinyl]-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6,7-difluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (9.3 mg, 14.44 umol, yield 9.05%, purity 95.77%). 1H NMR(DMSO-d6,400MHz)δ8.10(d,J=8.4Hz,1H),8.00(d,J=5.6Hz,1H),7.85(t, J=2.8Hz,1H),7.57~7.52(m,1H),7.30~7.26(m,1H),7.01~6.99(m,1H),6.90( dd,J=7.2Hz,8.8Hz,1H),6.83(d,J=3.2Hz,1H),4.71~4.69(m,1H),4.57(d,J= 11.2Hz,1H),4.40(d,J=10.8Hz,1H),3.82(s,1H),3.76(s,3H),3.72~3.71(m,1 H),3.69~3.62(m,2H),3.60~3.54(m,2H),3.34(s,1H),2.97(d,J=2.4Hz,3H), 2.76~2.73(m,1H),2.67~2.61(m,1H),2.37~2.33(m,1H),1.99(d,J=9.6Hz,1H) ,1.78(d,J=10.8Hz,1H),1.51~1.45(m,2H),1.34(d,J=6.8Hz,3H),0.83~0.78 (m,2H),0.53~0.52(m,2H).MS:95.77%(220nm),97.99%(254nm).MS(ESI):mass calcd.For C 34 H 38 F2N6O3616.30m / z found 617.4[M+H] + . Compound 22 9,10-difluoro-6-((((2-methoxypyridin-4-yl)methyl)((S)-1-(pyridin-3-yl)piperidin-3-yl)amino Preparation of 2-(4-(2-(2-methyl-1-thiazolyl)methyl)-3-methyl-2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one (Step 5 of Scheme 6)

[0186] Compound 9,10-difluoro-6-((((2-methoxypyridin-4-yl)methyl)((S)-1-(pyridin-3-yl)piperidin-3-yl)amino)methyl)-3-methyl-2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one (3.2 mg, 5.84 umol, 3.66% yield, 100% purity) was obtained as a white solid. 1H NMR(DMSO-d6,400MHz)δ8.30(d,J=2.8Hz,1H),8.13(d,J=6.0Hz,1H),8.01(d,J=5.2Hz,1H),7.92(t,J=4.4Hz,1H),7.57~7.52(m,1H),7.30~7.27 (m,1H),7.17~7.13(m,1H),7.03(d,J=4.8Hz,1H),6.86(d,J=4.4Hz,1H) ,4.74~4.67(m,1H),4.58(d,J=11.6Hz,1H),4.41(d,J=11.6Hz,1H),3.95 ~3.92(m,1H),3.84~3.80(m,1H),3.77(s,3H),3.74(s,1H),3.72~3.70( m,1H),3.68~3.66(m,1H),3.61~3.54(m,1H),2.86~2.79(m,1H),2.77~2. 60(m,2H),2.02(d,J=10.0Hz,1H),1.79~1.76(m,1H),1.57~1.44(m,2H),1.33(t,J=8.0Hz,3H).MS:100.00%(220nm),100%(254nm).MS(ESI):mass calcd.For C 30 H 31 F2N5O3547.27m / z found 548.1[M+H] + . Option 7 General procedures for preparing compounds in Scheme 7 Preparation of compounds in Scheme 7 (Step 1 of Scheme 7)

[0187] To a mixture of 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6,7-difluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13] To tridecane-5(13),6,8,11-tetraene-10-one (710.97 umol, 1 eq) and various amines (2.13 mmol to 14.22 mmol, 3 eq to 20 eq) was added DIEA (2.13 mmol to 5.68 mmol, 3 eq to 8 eq). The mixture was stirred at 180°C to 220°C under microwave for 1 to 48 hours. The reaction mixture was quenched with ice water at 0°C and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography. The eluent was concentrated in vacuo. Alternatively, the reaction mixture was filtered, and the filtrate was directly purified by preparative HPLC (column: Waters Xbridge Prep OBD C 18 150*40mm*10um or Waters Xbridge BEH C18 100*30mm*10um or Phenomenex C18 75*30mm*3um or Phenomenex C 18 80*40mm*3um or Phenomenex Luna 80*30mm*3um; mobile phase: [water (NH4HCO3)-MeCN] or [water (HCl)-MeCN]; B%: 1%-75%, 7 minutes or 8 minutes, 10 minutes). The eluent was then lyophilized to obtain the desired product. Compound 24 2-(6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl)((2-methoxypyridin-4-yl)methyl)amino 1-(2-(2-(2-nitro-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinolin-10-yl)-2,7- Preparation of tert-butyl diazaspiro[3.5]nonane-7-carboxylate (Step 1 of Scheme 7)

[0188] To the mixture 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6,7-difluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ] tridecane-5 (13), 6,8,11-tetraene-10-one (400 mg, 710.97 umol, 1 eq) and tert-butyl 2,7-diazaspiro [3.5] nonane-7-carboxylate (482.71 mg, 2.13 mmol, 3 eq) were added DIEA (275.66 mg, 2.13 mmol, 371.51 uL, 3 eq). The mixture was stirred at 190 ° C for 1 hour under microwave. LCMS showed 11- [[ [(3S) -1- (6-amino-3-pyridinyl) -3-piperidinyl] - [(2-methoxy-4-pyridinyl) methyl] amino] methyl] -6,7-difluoro-2-methyl-4-oxa-1-azatricyclo [7.3.1.0 5,13]Tridecane-5(13),6,8,11-tetraene-10-one was consumed and a new peak with the desired mass was detected. The reaction mixture was quenched with ice water (15 mL) at 0°C and then extracted with EtOAc (15 mL×2). The combined organic layers were washed with brine (15 mL×2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography ( 12g Flash silica gel column, eluting with 0-100% ethyl acetate / petroleum ether gradient @ 40 mL / min). The eluent was concentrated in vacuo. The compound tert-butyl 2-[11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-7-fluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]tridec-5(13),6,8,11-tetraen-6-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (0.4 g, 520.21 umol, 73.17% yield) as a purple solid. 1 H NMR(DMSO-d6,400MHz)δ7.99(d,J=5.2Hz,1H),7.85(d,J=7.6Hz,1H),7.60(d,J=2.8Hz,1H),7.27(dd,J=2.4Hz,14.0Hz,1H),7.15~7.12(m,1H),6. 99(d,J=4.8Hz,1H),6.82(s,1H),6.37(dd,J=3.2Hz,8.8Hz,1H),5.37(s, 2H),4.51~4.49(m,1H),4.33(d,J=10.4Hz,1H),4.13(d,J=9.2Hz,1H),4. 02~4.00(m,4H),3.77(s,3H),3.70~3.69(m,1H),3.65~3.54(m,2H),3.51 ~3.46(m,1H),3.32~3.28(m,5H),3.24~3.22(m,1H),2.76~2.72(m,1H),2 .59~2.56(m,1H),2.42~2.37(m,1H),1.96~1.92(m,1H),1.76~1.73(m,1H) ),1.69~1.67(m,4H),1.39~1.37(m,11H),1.29(dd,J=4.8Hz,6.0Hz,3H). 6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl)((2-methoxypyridin-4-yl)methyl)amino) methyl)-9-fluoro-3-methyl-10-(2,7-diazaspiro[3.5]nonan-2-yl)-2H-[1,4]oxazino[2,3,4-ij]quinone Preparation of lin-7(3H)-one (Scheme 7, Step 2)

[0189] To the tert-butyl 2-[11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-7-fluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.0 5,13 To the solution of [1,3-dihydro-1,3-dihydro-2,7-diazaspiro[3,5 ... The filtrate was concentrated under reduced pressure to give a crude product of 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6-(2,7-diazaspiro[3.5]nonan-2-yl)-7-fluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (200 mg, crude product) was obtained as a purple solid. Purified by preparative HPLC (column: Phenomenex LunaC18 75*30mm*3um; mobile phase: [water(NH4HCO3)-MeCN]; B%: 10%-40%, 8 minutes). The eluate was directly dried by freeze drying. Compound 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6-(2,7-diazaspiro[3.5]nonan-2-yl)-7-fluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (26.1 mg, 37.84 umol, 9.70% yield, 96.962% purity) was obtained as a gray solid. 1H NMR(DMSO-d6,400MHz)δ7.99(d,J=5.2Hz,1H),7.85(d,J=7.6Hz,1H),7.60(d,J =2.8Hz,1H),7.26(dd,J=2.0Hz,13.6Hz,1H),7.15~7.12(m,1H),6.99(d,J=4.8H z,1H),6.81(s,1H),6.37(dd,J=3.2Hz,8.8Hz,1H),5.36(d,J=3.2Hz,2H),4.52 ~4.32(m,1H),4.33(d,J=10.0Hz,1H),4.13(d,J=9.2Hz,1H),3.96(d,J=2.8Hz,4 H),3.77(s,3H),3.74~3.65(m,2H),3.63~3.54(m,2H),3.51~3.46(m,1H),3.24 ~3.20(m,1H),2.76~2.71(m,1H),2.64~2.58(m,4H),2.56~2.55(m,1H),2.43~2. 37(m,1H),1.96~1.94(m,1H),1.76~1.73(m,1H),1.67~1.60(m,4H),1.49~1.37( m,2H),1.30~1.28(m,3H).LCMS:96.96%(220nm),98.37%(254nm).MS(ESI):mass calcd.ForC 37 H 45 FN8O3668.36m / z found669.5[M+H] + . Compound 25 Preparation of 4-(bromomethyl)-5-methyl-1,3-dioxol-2-one (Step 3 of Scheme 7)

[0190] To a solution of 4,5-dimethyl-1,3-dioxol-2-one (5 g, 43.82 mmol, 1 eq) in CHCl (100 mL) at 20°C under N2 was added NBS (7.80 g, 43.82 mmol, 1 eq) and AIBN (359.79 mg, 2.19 mmol, 0.05 eq). The mixture was stirred at 85°C for 16 hours. TLC (petroleum ether:ethyl acetate = 1:1, R f=0.46) showed that 4,5-dimethyl-1,3-dioxol-2-one was completely consumed and a new spot was formed. The reaction mixture was cooled to 20°C, quenched by adding water (200 mL), and then extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography ( 80g The reaction mixture was purified by flash silica gel column with a gradient of 0-50% ethyl acetate / petroleum ether at 100 mL / min. The solvent was removed under reduced pressure to obtain the compound 4-(bromomethyl)-5-methyl-1,3-dioxol-2-one (7.6 g, 39.38 mmol, 89.86% yield) as a brown oil. 1 H NMR(DMSO-d6,400MHz)δ4.68(s,2H),2.15(s,3H) 6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl)((2-methoxypyridin-4-yl)methyl)amino)- 9-fluoro-3-methyl-10-(4-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)piperazin-1-yl)-2H- Preparation of [1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one (Step 4 of Scheme 7)

[0191] To a mixture of 4-(bromomethyl)-5-methyl-1,3-dioxol-2-one (30.70 mg, 159.05 mmol, 1 eq) and 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-7-fluoro-2-methyl-6-piperazin-1-yl-4-oxa-1-azatricyclo[7.3.1.0] in MeCN (0.5 mL) at 20° C. under N 2 was added the following: 5,13] To tridecane-5(13),6,8,11-tetraen-10-one (100 mg, 159.05 umol, 1 eq) was added NaHCO3 (40.08 mg, 477.15 umol, 18.56 uL, 3 eq). The reaction mixture was stirred at 20°C for 3 hours. LC-MS showed that 4-(bromomethyl)-5-methyl-1,3-dioxol-2-one was completely consumed, and a new peak with the desired mass was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification was performed by preparative HPLC (column: Waters Xbridge BEH C 18100*30mm*10um; mobile phase: [water (NH4HCO3)-MeCN]; B%: 35%-65%, 8 minutes). The solvent was removed by freeze drying. Compound 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-7-fluoro-2-methyl-6-[4-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one. 1 H NMR (DMSO-d6, 400MHz) δ8.00~7.95 (m, 2H), 7.60 (d, J = 2.4Hz, 1H), 7.34 (dd, J = 2. 4Hz, 12.8Hz, 1H), 7.14 (dt, J=2.8Hz, 8.8Hz, 1H), 7.00 (d, J=4.8Hz, 1H), 6.81 (s, 1H), 6.39 (dd, J=3.6Hz, 8.8Hz, 1H), 5.37 (d, J=3.6Hz, 2H), 4.58~4.46 (m, 1H), 4. 43(d,J=10.0Hz,1H),4.26(dd,J=2.8Hz,=12.0Hz,1H),3.76(s,4H),3.71~3.70( m,1H),3.61~3.60(m,1H),3.58(s,1H),3.50~3.47(m,1H),3.43(s,2H),3.21(s, 4H),3.12~3.10(m,1H),2.80~2.71(m,2H),2.57~2.54(m,4H),2.43~2.38(m,1H) ,2.12(s,3H),1.97~1.93(m,1H),1.78~1.72(m,1H),1.50~1.40(m,2H),1.31(t, J=4.8Hz,3H).LCMS:100.00%(220nm),100.00%(254nm).MS(ESI):masscalcd.For C39 H 45 FN8O6740.34m / z found 741.1[M+H] + . Preparation of benzyl 7-methyl-2,7-diazaspiro[3.5]nonane-2-carboxylate (Step 5 of Scheme 7)

[0192] To a solution of 2,7-diazaspiro[3.5]nonane-2-carboxylic acid benzyl ester (0.5 g, 1.92 mmol, 1 eq) and formaldehyde (311.72 mg, 3.84 mmol, 285.98 uL, 37% purity, 2 eq) in DCM (5 mL) was added NaBH(OAc) (610.59 mg, 2.88 mmol, 1.5 eq). The reaction mixture was stirred at 20 ° C for 10 hours. LCMS showed that the reaction was complete. The reaction mixture was quenched with ice water (40 mL) and then the pH was adjusted to 7 with saturated NaHCO. The mixture was extracted with DCM (15 mL × 3). The combined organic phases were washed with brine (15 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The compound 7-methyl-2,7-diazaspiro[3.5]nonane-2-carboxylic acid benzyl ester (0.5 g, 1.82 mmol, yield 94.89%) was obtained as a colorless oil. 1 H NMR (DMSO-d6, 400MHz) δ7.39~7.31(m,5H),5.02(s,2H),3.62(d,J=2.0Hz,4H),2.21(s,4H),2.12(s,3H),1.66(t,J=5.2Hz,4H). Preparation of 7-methyl-2,7-diazaspiro[3.5]nonane (Scheme 7, Step 6)

[0193] A mixture of benzyl 7-methyl-2,7-diazaspiro[3.5]nonane-2-carboxylate (0.5 g, 1.82 mmol, 1 eq) and Pd(OH) 2( The mixture was degassed with H2 (0.01 g, 10% purity) and purged with H2 three times, and then the mixture was stirred at 50 ° C for 12 hours under an atmosphere of H2 (50 psi.). LCMS showed that the reaction was complete. The reaction mixture was filtered through a celite pad and the filter cake was washed with MeOH (60 mL). The combined filtrate was concentrated under reduced pressure. Compound 7-methyl-2,7-diazaspiro[3.5]nonane (0.25 g, crude product) was obtained as a colorless oil. 1H NMR(DMSO-d6,400MHz)δ3.61~3.58(m,1H),3.51~3.47(m,1H),3.21~3.17(m ,3H),3.19~3.15(m,3H),2.08(s,3H),2.03~1.99(m,1H),1.74~1.59(m,4H). Compound 26 1-((4-(6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl)((2-methoxypyridin-4-yl)methane 1-(4-(2-(2-nitro-3-methyl)-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinolin-10-yl) Preparation of (piperazin-1-yl)methyl)urea (Scheme 7, Step 7)

[0194] To 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-7-fluoro-2-methyl-6-piperazin-1-yl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ] A mixture of tridecane-5(13),6,8,11-tetraen-10-one (100 mg, 159.05 umol, 1 eq) was added with (HCHO)n (14.31 mg, 477.15 umol, 13.13 uL, 3 eq) and urea (14.33 mg, 238.57 umol, 12.79 uL, 1.5 eq). The mixture was stirred at 110°C for one hour. LCMS and HPLC showed that the reaction was complete. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification was performed by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH4HCO3)-MeCN]; B%: 20%-40%, 8 minutes). The eluate was dried by freeze drying. The crude product was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH4HCO3)-MeCN]; B%: 20%-40%, 8 minutes). The eluate was dried by freeze drying. The compound [4-[11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-7-fluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]tridec-5(13),6,8,11-tetraen-6-yl]piperazin-1-yl]methyl urea (1.6 mg, 2.28 umol, yield 1.43%, purity 99.80%). 1H NMR(DMSO-d6,400MHz)δ7.99(d,J=5.2Hz,1H),7.95(d,J=6.8Hz,1H),7.77(t,J=2 .8Hz,1H),7.33(dd,J=1.6Hz,12.4Hz,1H),7.22~7.19(m,1H),6.99(d,J=4.8Hz,1 H),6.81(s,1H),6.61~6.57(m,1H),6.48(dd,J=3.2Hz,9.2Hz,1H),6.40(t,J=6.0 Hz,1H),5.57(s,2H),4.57~4.55(m,1H),4.49~4.43(m,3H),4.26~4.24(m,1H),3.7 8~3.75(m,4H),3.71(m,1H),3.66~3.58(m,2H),3.55~3.51(m,1H),3.27(m,1H),3 .14~3.07(m,4H),2.79~2.77(m,4H),2.74~2.72(m,1H),2.61~2.56(m,1H),2.45~2 .39(m,1H),1.97~1.95(m,1H),1.78~1.175(m,1H),1.55~1.38(m,2H),1.31(dd,J =4.0Hz,6.4Hz,3H).LCMS:99.80%(220nm),100%(254nm).MS(ESI):masscalcd.For C 36 H 45 FN 10 O4700.36m / z found701.5[M+H] + . Preparation of tert-butyl 5,5-difluorohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Scheme 7, Step 8)

[0195] To a solution of tert-butyl 5-oxo-1,3,3a,4,6,6a-hexahydrocyclopenta[C]pyrrole-2-carboxylate (2 g, 8.88 mmol, 1 eq) in DCM (20 mL) was added dropwise DAST (7.15 g, 44.39 mmol, 5.86 mL, 5 eq) at 0°C under N2. The mixture was stirred at 20°C for 12 hours. DAST (4.29 g, 26.63 mmol, 3.52 mL, 3 eq) was then added dropwise at 0°C under N2, and stirred at 20°C for 24 hours. TLC (petroleum ether: ethyl acetate = 3:1, R f=0.56) showed that the reaction was almost complete. At 0 ° C, the mixture was quenched with ice water (50 mL) and the pH was adjusted to 7 with saturated NaHCO 3. The mixture was extracted with DCM (20 mL×3). The combined organic layer was washed with brine (20 mL×1), dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography ( 20g The reaction mixture was purified by flash silica gel column with a gradient elution of 0-24% petroleum ether / ethyl acetate at 40 mL / min. The eluent was removed under reduced pressure to obtain tert-butyl 5,5-difluoro-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxylate (1.4 g, 5.66 mmol, 63.77% yield) as a yellow solid. 1 H NMR (DMSO-d6, 400MHz) δ3.57~3.50(m,2H), 3.28~3.27(m,2H), 2.84~2.78(m,2H), 2.38~2.34(m,2H), 2.07~1.98(m,2H), 1.47(s,9H). Preparation of 5,5-difluorooctahydrocyclopenta[c]pyrrole hydrochloride (Scheme 7, Step 9)

[0196] To a solution of 5,5-difluoro-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester (0.9 g, 3.64 mmol, 1 eq) in MeOH (1 mL) was added HCl / MeOH (4 M, 9.00 mL, 9.89 eq). The mixture was stirred at 20 ° C for 1 hour. LCMS showed that the reaction was complete. The mixture was concentrated under reduced pressure and then adjusted to pH 7 with saturated NaHCO . The eluent was removed by freeze drying. The residue was washed with DCM (150 mL) and the filtrate was concentrated under reduced pressure. Compound 5,5-difluoro-2,3,3a,4,6,6a-hexahydro-1H-cyclopenta[c]pyrrole (0.56 g, crude product) was obtained as a brown solid. 1 H NMR (CDCl3, 400MHz) δ8.97~8.75(m,1H), 3.54~3.50(m,2H), 3.19~3.15(m,4H), 2.39~2.31(m,2H), 2.26~2.18(m,2H). Preparation of benzyl 5,5-difluorohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Scheme 7, Step 10)

[0197] To a solution of 5,5-difluoro-2,3,3a,4,6,6a-hexahydro-1H-cyclopenta[C]pyrrole (0.3 g, 2.04 mmol, 1 eq) in THF (2 mL) and H2O (1 mL) was added Na2CO3 (432.12 mg, 4.08 mmol, 2 eq), and then CbzCl (347.76 mg, 2.04 mmol, 289.80 uL, 1 eq) was added dropwise at 0 ° C. LCMS showed that the reaction was complete. The reaction mixture was quenched with ice water (40 mL) and then extracted with EtOAc (20 mL × 3). The combined organic layer was washed with brine (20 mL × 1), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography ( 12g The reaction mixture was purified by flash silica gel column with a gradient of 0-26% petroleum ether / ethyl acetate at 40 mL / min. The eluent was removed under reduced pressure to obtain the compound 5,5-difluoro-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxylic acid benzyl ester (0.38 g, 1.35 mmol, 66.27% yield) as a yellow oil. 1 H NMR(DMSO-d6,400MHz)δ7.37~7.31(m,5H),5.06(s,2H),3.57~3.55(m,2H), 3.26~3.23(m,2H),2.81~2.80(m,2H),2.34~2.26(m,2H),2.07~1.96(m,2H). Preparation of 5,5-difluorooctahydrocyclopenta[c]pyrrole (Step 11 of Scheme 7)

[0198] Benzyl 5,5-difluoro-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxylate (0.4 g, 1.42 mmol, 1 eq) and Pd(OH) 2( The mixture was degassed and purged with H2 (80mg, 20% purity) 3 times. Then under H2 (50psi) atmosphere, the mixture was stirred at 50 ° C for 12 hours. LCMS showed that the reaction was complete. The reaction mixture was filtered through a diatomaceous earth pad and the filter cake was washed with MeOH (200mL). The combined filtrate was concentrated under reduced pressure. Compound 5,5-difluoro-2,3,3a,4,6,6a-hexahydro-1H-cyclopenta[c]pyrrole (0.12g, 815.41umol, 57.34% yield) was obtained as a white solid. 1HNMR (MeOD, 400MHz) δ3.47~3.45(m,2H), 3.09~3.06(m,4H), 2.42~2.37(m,2H), 2.11~2.02(m,2H). Compound 27 6-((((S)-1-(6-Aminopyridin-3-yl)piperidin-3-yl)piperidin-1-yl)-1-(6-aminopyridin-3-yl)piperidin-6-yl)piperidin-1-yl)piperidin-2 ...3-yl)piperidin-1-yl)piperidin-2 3-yl)((2-methoxypyridin-4-yl)methyl)amino)methyl)-9-fluoro-3-methyl-10-morpholino-2H-[1,4]oxazin [2,3,4-ij]quinolin-7(3H)-one

[0199] 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-7-fluoro-2-methyl-6-morpholino-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (8 mg, 12.49 umol, 17.57% yield, 98.34% purity) was obtained as an off-white solid. 1 H NMR(DMSO-d6,400MHz)δ8.00~7.96(m,2H),7.60(s,1H),7.35(d,J=2.0Hz,12.4Hz,1H),7.15~7.12(m,1H),7.00~6.9 8(m,1H),6.81(s,1H),6.39~6.35(m,1H),5.37(s,2H),4.60~4.58(m,1H),4.47~4.45(m,1H),4.28~4.26(m,1H),3.76 (s,3H),3.73~3.39(m,9H),3.30~3.19(m,5H),2.70~2.67(m,1H),2.57~2.52(m,1H),2.40~2.37(m,1H),1.99~1.91(m ,1H),1.76~1.72(m,1H),1.39~1.31(m,2H),1.31~1.29(m,3H).HPLC:98.34%(220nm),98.74%(254nm).MS(ESI):mass calcd.For C 34 H 40 FN7O4629.31m / z found 630.3[M+H] + . Compound 28 6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl ...6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl)-1-(6-aminopyridin-3- ((2-methoxypyridin-4-yl)methyl)amino)methyl)-9-fluoro-3-methyl-10-(piperidin-1-yl)-2H-[1,4]oxazin- [2,3,4-ij]quinolin-7(3H)-one

[0200] 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-7-fluoro-2-methyl-6-(1-piperidinyl)-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (8.8 mg, 14.02 umol, 5.26% yield) was obtained as a white solid. 1 H NMR(DMSO-d6,400MHz)δ7.99(d,J=5.2Hz,1H),7.96(d,J=8.0Hz,1H),7.60(d,J =2.8Hz,1H),7.32(dd,J=12.4Hz,2.4Hz,1H),7.16~7.12(m,1H),6.99(d,J=5.2H z,1H),6.81(s,1H),6.37(dd,J=8.8Hz,3.6Hz,1H),5.37(d,J=3.6Hz,2H),4.59~ 4.57(m,1H),4.44(d,J=11.6Hz,1H),4.25(dd,J=12.0Hz,2.4Hz,1H),3.76(s,3H ),3.70(d,J=4.8Hz,1H),3.65~3.53(m,3H),3.50~3.46(m,1H),3.24~3.21(m,1 H),3.16~3.14(m,4H),2.77~2.70(m,1H),2.58(d,J=10.4Hz,1H),2.44~2.37(m, 1H),1.99~1.95(m,1H),1.77~1.73(m,1H),1.59~1.57(m,6H),1.49~1.39(m,2H) ,1.31(t,J=5.2Hz,3H).LCMS:100.00%(220nm),100.00%(254nm).MS(ESI):mass calcd.For C 35 H 42 FN7O3627.33m / z found 628.4[M+H] + . Compound 29 6-((((S)-1-(6-Aminopyridin-3-yl)piperidin-3-yl)piperidin-1-yl)-1-(6-aminopyridin-3-yl)piperidin-6-yl)piperidin-1-yl)piperidin-2 ...3-yl)piperidin-1-yl)piperidin-2 3-yl)((2-methoxypyridin-4-yl)methyl)amino)methyl)-9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-2H- [1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one

[0201] 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-7-fluoro-2-methyl-6-(4-methylpiperazin-1-yl)-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (13.1 mg, 20.38 umol, 14.33% yield, 100% purity) was obtained as a white solid. 1 H NMR(DMSO-d6,400MHz)δ8.02~7.97(m,2H),7.64~7.58(m,1H),7.37~7.31(m,1H),7.17~7.11(m,1H),7.02~6.97(m,1H),6.8 4~6.79(m,1H),6.40~6.35(m,1H),5.41~5.31(m,2H),4.59~4.53(m,1H),4.48~4.39(m,1H),4.30~4.20(m,1H),3.76(s,3H), 3.72~3.70(m,1H),3.62~3.58(m,2H),3.52~3.46(m,1H),3.31(s,2H),3.19(s,4H),2.80~2.60(m,3H),2.41(s,4H),2.22(s, 3H),2.01~1.92(m,1H),1.77~1.73(m,1H),1.50~1.42(m,2H),1.31(s,3H).LCMS:100%(220nm),100%(254nm).MS(ESI):mass calcd.ForC 35 H 43 FN8O3642.34m / z found643.4[M+H] + . Compound 30 6-((((S)-1-(6-Aminopyridin-3-yl)piperidin-3-yl)piperidin-1-yl)-1-(6-aminopyridin-3-yl)piperidin-6-yl)piperidin-1-yl)piperidin-2 ...3-yl)piperidin-1-yl)piperidin-2 3-yl)((2-methoxypyridin-4-yl)methyl)amino)methyl)-9-fluoro-3-methyl-10-(2-oxa-6-azaspiro[3.3] (6-heptyl)-2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one

[0202] 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-7-fluoro-2-methyl-6-(2-oxa-6-azaspiro[3.3]hept-6-yl)-4-oxa-1-azatricyclo[7.3.1.0 5,13]Tridecane-5(13),6,8,11-tetraen-10-one (17.2 mg, 26.80 umol, yield 21.54%, purity 100%), as a white solid. 1 H NMR(DMSO-d6,400MHz)δ7.99(d,J=4.8Hz,1H),7.86(d,J=7.6Hz,1H),7.59(d ,J=1.6Hz,1H),7.27(dd,J=2.4Hz,16.0Hz,1H),7.14~7.12(m,1H),6.99(d,J =1.6Hz,1H),6.81(s,1H),6.37(dd,J=3.6Hz,8.8Hz,1H),5.37~5.34(m,2H), 4.69(s,4H),4.52~4.50(m,1H),4.40(s,4H),4.35(d,J=11.6Hz,1H),4.14(d, J=10.8Hz,1H),3.77(s,3H),3.74~3.69(m,2H),3.62~3.57(m,1H),3.54~3.5 1(m,1H),3.49~3.46(m,1H),3.24~3.20(m,1H),2.76~2.71(m,1H),2.42~2.3 7(m,2H),1.96~1.92(m,1H),1.77~1.73(m,1H),1.50~1.37(m,2H),1.29(dd, J=4.8Hz, 6.4Hz, 3H).LCMS:100.00%(220nm),100.00%(254nm).MS(ESI):mass calcd.For C 35 H 40 FN7O4641.31m / z found 642.5[M+H] + . Compound 31 6-((((S)-1-(6-Aminopyridin-3-yl)piperidin-3-yl)piperidin-1-yl)-1-(6-aminopyridin-3-yl)piperidin-6-yl)piperidin-1-yl)piperidin-2 ...3-yl)piperidin-1-yl)piperidin-2 3-yl)((2-methoxypyridin-4-yl)methyl)amino)methyl)-9-fluoro-10-(4-hydroxypiperidin-1-yl)-3-methyl-2H- [1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one

[0203] Obtain 6-((((S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-7-fluoro-6-(4-hydroxy-1-piperidinyl)-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (9.2 mg, 13.77 umol, 11.07% yield, 96.34% purity) was obtained as an off-white solid. 1H NMR(DMSO-d6,400MHz)δ7.99(d,J=5.2Hz,1H),7.95(d,J=8.0Hz,1H),7.60(d,J=2.4Hz ,1H),7.32(dd,J=2.4Hz,12.4Hz,1H),7.14(dd,J=2.8Hz,9.2Hz,1H),6.99(d,J=4.8Hz, 1H),6.81(s,1H),6.37(dd,J=3.6Hz,9.2Hz,1H),5.37~5.34(m,2H),4.65(d,J=4.4Hz,1 H),4.58~4.56(m,1H),4.44(d,J=10.4Hz,1H),4.25(d,J=9.2Hz,1H),3.76(s,3H),3.71 ~3.70(m,1H),3.66~3.62(m,1H),3.61~3.60(m,1H),3.57~3.54(m,1H),3.50~3.47(m, 1H),3.30~3.27(m,1H),3.24~3.21(m,1H),3.09~3.03(m,2H),2.77~2.71(m,2H),2.60~ 2.57(m,2H),2.43~2.32(m,1H),1.97~1.94(m,1H),1.82~1.73(m,3H),1.53~1.41(m,4H) ), 1.31 (dd, J = 4.8Hz, 6.4Hz, 3H). LCMS: 96.34% (220nm), 96.65% (254nm). MS (ESI): mass calcd.For C 39 H 42 FN7O3643.33m / z found644.5[M+H] + . Compound 32 6-((((S)-1-(6-Aminopyridin-3-yl)piperidin-3-yl)piperidin-1-yl)-1-(6-aminopyridin-3-yl)piperidin-6-yl)piperidin-1-yl)piperidin-2 ...3-yl)piperidin-1-yl)piperidin-2 3-yl)((2-methoxypyridin-4-yl)methyl)amino)methyl)-10-(3,4-dimethylpiperazin-1-yl)-9-fluoro-3-methyl 2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one

[0204] 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6-(3,4-dimethylpiperazin-1-yl)-7-fluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5 ,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (10.2 mg, 15.53 umol, 12.48% yield, 100% purity) was obtained as a white solid. 1H NMR(DMSO-d6,400MHz)δ7.99(d,J=5.6Hz,1H),7.95(d,J=8.0Hz,1H),7.60(d,J=2.8H z,1H),7.33(dd,J=12.8Hz,2.4Hz,1H),7.15~7.12(m,1H),6.99(d,J=4.8Hz,1H),6.81 (s,1H),6.37(dd,J=8.8Hz,3.6Hz,1H),5.36(d,J=3.6Hz,2H),4.58~4.56(m,1H),4.44 (d,J=11.2Hz,1H),4.26(d,J=9.6Hz,1H),3.76(s,3H),3.71~3.70(m,1H),3.66~3.47( m,3H),3.27~3.20(m,2H),3.16~3.09(m,2H),2.92~2.85(m,1H),2.77~2.71(m,2H),2. 60~2.57(m,1H),2.44~2.37(m,2H),2.30~2.23(m,1H),2.21(s,3H),2.17~2.11(m,1H) ,1.97~1.94(m,1H),1.76~1.73(m,1H),1.53~1.37(m,2H),1.31(dd,J=6.4Hz,4.4Hz,3 H),0.98(d,J=6.0Hz,3H).LCMS:100%(220nm),100%(254nm).MS(ESI):masscalcd.For C 36 H 45 FN8O3656.36m / z found657.2[M+H] + . Compound 33 6-((((S)-1-(6-Aminopyridin-3-yl)piperidin-3-yl)piperidin-1-yl)-1-(6-aminopyridin-3-yl)piperidin-6-yl)piperidin-1-yl)piperidin-2 ...3-yl)piperidin-1-yl)piperidin-2 3-yl)((2-methoxypyridin-4-yl)methyl)amino)methyl)-10-(3,4-dihydroisoquinolin-2(1H)-yl)-9-fluoro-3- Methyl-2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one

[0205] 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6-(3,4-dihydro-1H-isoquinolin-2-yl)-7-fluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (23.1 mg, 34.10 umol, 19.18% yield, 99.76% purity) was obtained as an off-white solid. 1H NMR(DMSO-d6,400MHz)δ7.99(t,J=5.6Hz,2H),7.61(d,J=2.4Hz,1H),7.38(dd, J=2.4Hz,12.4Hz,1H),7.16~7.12(m,4H),7.10~7.08(m,1H),7.01~7.00(m,1H), 6.82(s,1H),6.37(dd,J=3.6Hz,8.8Hz,1H),5.37(d,J=3.2Hz,2H),4.61~4.59(m ,1H),4.45(d,J=11.6Hz,1H),4.37(s,2H),4.29(d,J=9.6Hz,1H),3.77(s,3H),3 .72(d,J=4.8Hz,1H),3.67~3.61(m,1H),3.59~3.55(m,1H),3.51~3.47(m,3H),3 .25~3.21(m,1H),2.91(t,J=6.0Hz,2H),2.78~2.71(m,1H),2.56~2.54(m,1H),2 .41~2.38(m,2H),2.00~1.93(m,1H),1.77~1.75(m,1H),1.50~1.41(m,2H),1.33 (dd, J=4.4Hz, 6.0Hz, 3H). LCMS: 99.76% (220nm), 99.74% (254nm). MS (ESI): mass calcd.ForC 39 H 42 FN7O3675.33m / z found676.5[M+H] + . Compound 34 6-((((S)-1-(6-Aminopyridin-3-yl)piperidin-3-yl)piperidin-1-yl)-1-(6-aminopyridin-3-yl)piperidin-6-yl)piperidin-1-yl)piperidin-2 ...3-yl)piperidin-1-yl)piperidin-2 3-yl)((2-methoxypyridin-4-yl)methyl)amino)methyl)-10-(3-aminopyrrolidin-1-yl)-9-fluoro-3-methyl- 2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one hydrochloride

[0206] 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6-(3-aminopyrrolidin-1-yl)-7-fluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (4.4 mg, 6.61 umol, 9.64% yield, 100% purity, HCl) as a yellow solid. 1H NMR (DMSO-d6, 400MHz) δ14.15~14.00(m,1H),8.45~8.39(m,4H),8.09(s,1H),7.97~7.95(m,1H),7.67~7.62(m,1H), 7.75~7.52(m,1H),7.39~7.35(m,2H),7.18~7.15(m,1H),7.02~7.00(m,1H),4.47~4.20(m,7H),3.88~3.86(m,2H),3 .81(s,3H),3.79~3.77(m,2H),3.21~3.14(m,3H),3.07~3.02(m,1H),2.69~2.58(m,3H),2.12~2.06(m,1H),2.04~1. 97(m,1H),1.94~1.91(m,2H),1.57~1.52(m,1H),1.45~1.43(m,3H).HPLC:100%(220nm),100%(254nm).MS(ESI):mass calcd.For C 34 H 41 FN8O3628.33m / zfound629.4[M+H] + . Compound 35 6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl ...6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl)-1-(6-aminopyridin-3- ((2-methoxypyridin-4-yl)methyl)amino)-10-((3S,5R)-3,5-dimethylpiperazin-1-yl)-9-fluoro-3-methyl- 2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one

[0207] 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-7-fluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (17 mg, 25.88 umol, 14.56% yield) was obtained as a light yellow solid. 1H NMR(DMSO-d6,400MHz)δ8.00(d,J=5.6Hz,1H),7.96(d,J=8.0Hz,1H),7.61(d,J=2.8Hz, 1H),7.34(dd,J=2.4Hz,12.8Hz,1H),7.15~7.13(m,1H),7.00(d,J=4.8Hz,1H),6.81(s,1 H), 6.38 (dd, J=3.6Hz, 8.8Hz, 1H), 5.37 (d, J=3.2Hz, 2H), 4.57~4.56 (m, 1H), 4.45 (d, J= 10.4Hz,1H),4.25~4.23(m,1H),3.76(s,3H),3.75(s,1H),3.70(d,J=4.4Hz,1H),3.61~3 .60(m,1H),3.59~3.57(m,2H),3.47(s,1H),3.26~3.18(m,1H),3.06(d,J=10.8Hz,2H), 2.86~2.84(m,2H),2.76~2.69(m,1H),2.66(d,J=7.2Hz,1H),2.57(t,J=11.6Hz,1H),2.4 0~2.36(m,1H),2.01~1.94(m,2H),1.80~1.74(m,1H),1.43~1.36(m,2H),1.31(dd,J=4. 4Hz, 6.4Hz, 3H), 0.95 (d, J=6.0Hz, 6H).MS: 99.16% (220nm), 100% (254nm).MS (ESI): mass calcd.For C 36 H 45 FN8O3656.36m / z found657.5[M+H] + . Compound 36 6-((((S)-1-(6-Aminopyridin-3-yl)piperidin-3-yl)piperidin-1-yl)-1-(6-aminopyridin-3-yl)piperidin-6-yl)piperidin-1-yl)piperidin-2 ...3-yl)piperidin-1-yl)piperidin-2 3-yl)((2-methoxypyridin-4-yl)methyl)amino)methyl)-9-fluoro-3-methyl-10-(4-morpholinopyridin-1-yl)- 2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one

[0208] 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-7-fluoro-2-methyl-6-(4-morpholino-1-piperidinyl)-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (12.7 mg, 17.79 umol, 14.29% yield, 99.83% purity) was obtained as an off-white solid. 1H NMR(DMSO-d6,400MHz)δ7.99(d,J=5.2Hz,1H),7.96(d,J=8.0Hz,1H),7.60(d,J=2 .0Hz,1H),7.33(dd,J=2.0Hz,14.4Hz,1H),7.14(dt,J=8.8Hz,2.8Hz,1H),6.99(d ,J=4.4Hz,1H),6.81(s,1H),6.37(dd,J=3.6Hz,8.8Hz,1H),5.36(d,J=3.2Hz,2H) ,4.60~4.54(m,1H),4.44(d,J=10.8Hz,1H),4.25(d,J=9.6Hz,1H),3.76(s,3H),3. 70(d,J=4.4Hz,1H),3.66~3.63(m,1H),3.59~3.58(m,4H),3.50~3.47(m,1H),3.2 5~3.21(m,1H),3.13~3.06(m,2H),2.74~2.70(m,3H),2.60~2.57(m,4H),2.43~2.3 7(m,3H),2.33~2.28(m,2H),1.97~1.94(m,1H),1.82~1.74(m,3H),1.54~1.41(m, 4H), 1.31 (d, J = 3.2Hz, 3H). LCMS: 99.83% (220nm), 100.00% (254nm). MS (ESI): mass calcd.ForC 39 H 49 FN8O4712.39m / z found713.5[M+H] + . Compound 37 6-((((S)-1-(6-Aminopyridin-3-yl)piperidin-3-yl)piperidin-1-yl)-1-(6-aminopyridin-3-yl)piperidin-6-yl)piperidin-1-yl)piperidin-2 ...3-yl)piperidin-1-yl)piperidin-2 3-yl)((2-methoxypyridin-4-yl)methyl)amino)methyl)-9-fluoro-3-methyl-10-(2-methylpiperidin-1-yl)-2H- [1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one

[0209] 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-7-fluoro-2-methyl-6-(2-methyl-1-piperidinyl)-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (10.7 mg, 16.10 umol, yield 6.04%, purity 96.573%), as a light pink solid. 1H NMR(DMSO-d6,400MHz)δ7.99(d,J=5.2Hz,2H),7.61(d,J=2.4Hz,1H),7.33(dd,J =1.2Hz,11.2Hz,1H),7.16~7.12(m,1H),6.99(d,J=4.4Hz,1H),6.81(s,1H),6.3 7(dd,J=3.2Hz,9.2Hz,1H),5.36(d,J=3.2Hz,2H),4.62~4.59(m,1H),4.47(d,J= 11.6Hz,1H),4.25(d,J=11.6Hz,1H),3.76(s,3H),3.71~3.70(m,1H),3.66~3.55( m,3H),3.51~3.48(m,1H),3.37~3.34(m,1H),3.25~3.21(m,1H),3.06~2.98(m,2 H),2.78~2.72(m,1H),2.61~2.58(m,1H),2.41~2.38(m,1H),1.98~1.95(m,1H), 1.76~1.71(m,3H),1.60~1.56(m,2H),1.49~1.41(m,3H),1.31~1.29(m,4H),0.8 5(dd,J=2.8Hz,6.0Hz,3H).LCMS:96.57%(220nm),96.67%(254nm).MS(ESI):mass calcd.For C 36 H 44 FN7O3641.35m / z found642.5[M+H] + . Compound 38 6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl ...6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl)-1-(6-aminopyridin-3- ((2-methoxypyridin-4-yl)methyl)amino)methyl)-9-fluoro-10-(3-hydroxyazetidin-1-yl)-3-methyl- 2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one

[0210] 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-7-fluoro-6-(3-hydroxyazetidin-1-yl)-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (14.9 mg, 23.74 umol, 8.67% yield, 98.08% purity) was obtained as a yellow solid. 1H NMR(DMSO-d6,400MHz)δ7.99(d,J=5.2Hz,1H),7.86(d,J=7.6Hz,1H),7.60(d,J =2.8Hz,1H),7.27(dd,J=2.0Hz,13.6Hz,1H),7.14(dt,J=2.4Hz,8.4Hz,1H),6.9 9(d,J=5.2Hz,1H),6.81(s,1H),6.37(dd,J=3.2Hz,8.8Hz,1H),5.36(d,J=2.8Hz ,2H),4.52~4.50(m,1H),4.45(s,3H),4.34(d,J=10.8Hz,1H),4.14(d,J=9.6Hz, 1H),3.95~3.94(m,2H),3.77(s,3H),3.70~3.69(m,1H),3.65~3.61(m,1H),3.58 ~3.57(m,1H),3.55(s,1H),3.51~3.47(m,2H),3.24~3.21(m,1H),2.54(s,1H),2 .43~2.37(m,2H),1.96~1.94(m,1H),1.77~1.73(m,1H),1.50~1.40(m,2H),1.29 (dd, J=4.8Hz, 6.0Hz, 3H).LCMS:98.08%(220nm),99.10%(254nm).MS(ESI):mass calcd.ForC 33 H 38 FN7O4615.30m / z found616.5[M+H] + . Compound 39 6-((((S)-1-(6-Aminopyridin-3-yl)piperidin-3-yl)piperidin-1-yl)-1-(6-aminopyridin-3-yl)piperidin-6-yl)piperidin-1-yl)piperidin-2 ...3-yl)piperidin-1-yl)piperidin-2 3-yl)((2-methoxypyridin-4-yl)methyl)amino)methyl)-9-fluoro-3-methyl-10-(piperazin-1-yl)-2H-[1,4] Oxazino[2,3,4-ij]quinolin-7(3H)-one

[0211] 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-7-fluoro-2-methyl-6-piperazin-1-yl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (33 mg, 52.16 umol, yield 29.35%, purity 99.38%), as a white solid. 1HNMR(DMSO-d6,400MHz)δ8.00~7.95(m,2H),7.60(d,J=2.4Hz,1H),7.34(dd, J=2.4Hz,12.8Hz,1H),7.15~7.12(m,1H),6.99(d,J=4.8Hz,1H),6.81(s,1H), 6.37(dd,J=3.6Hz,8.8Hz,1H),5.37(d,J=2.8Hz,2H),4.58~4.57(m,1H),4.44 (d,J=10.4Hz,1H),4.26(d,J=9.6Hz,1H),3.76(s,3H),3.71~3.70(m,1H),3.6 6~3.54(m,2H),3.50~3.47(m,1H),3.35~3.30(m,1H),3.25~3.21(m,1H),3.17 ~3.13(m,4H),2.84~2.82(m,4H),2.77~2.71(m,1H),2.60~2.55(m,1H),2.43~ 2.37(m,1H),1.97~1.94(m,1H),1.77~1.73(m,1H),1.49~1.37(m,2H),1.31(d d, J=4.8Hz, 6.0Hz, 3H). LCMS: 99.38% (220nm), 99.55% (254nm). MS (ESI): mass calcd.For C 34 H 41 FN8O3628.33m / z found629.5[M+H] + . Compound 40 6-((((S)-1-(6-Aminopyridin-3-yl)piperidin-3-yl)piperidin-1-yl)-1-(6-aminopyridin-3-yl)piperidin-6-yl)piperidin-1-yl)piperidin-2 ...3-yl)piperidin-1-yl)piperidin-2 3-yl)((2-methoxypyridin-4-yl)methyl)amino)methyl)-9-fluoro-3-methyl-10-(3-methylpiperazin-1-yl)-2H- [1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one

[0212] 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-7-fluoro-2-methyl-6-(3-methylpiperazin-1-yl)-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (48 mg, 74.40 umol, 13.95% yield, 99.63% purity) was obtained as a white solid. 1H NMR(DMSO-d6,400MHz)δ8.00~7.95(m,2H),7.60(d,J=2.8Hz,1H),7.33(dd,J=2.4 Hz,12.8Hz,1H),7.14(dt,J=2.4Hz,9.2Hz,1H),6.99(d,J=5.2Hz,1H),6.81(s,1H) ,6.37(dd,J=3.6Hz,8.8Hz,1H),5.37(d,J=3.2Hz,2H),4.58~4.56(m,1H),4.44(d, J=11.2Hz,1H),4.25(d,J=10.8Hz,1H),3.76~3.75(m,3H),3.71~3.69(m,1H),3.66 ~3.60(m,1H),3.57~3.54(m,1H),3.50~3.47(m,1H),3.24~3.21(m,1H),3.09~3.07 (m,3H),2.86~2.67(m,5H),2.60~2.54(m,1H),2.43~2.37(m,2H),2.17~1.95(m,1H) ),1.97~1.95(m,1H),1.77~1.73(m,1H),1.49~1.37(m,2H),1.31(dd,J=5.2Hz,6.4 Hz, 3H), 0.94 (d, J = 5.6Hz, 3H). LCMS: 99.63% (220nm), 100% (254nm). MS (ESI): mass calcd.ForC 35 H 43 FN8O3642.34m / z found643.5[M+H] + . Compound 41 6-((((S)-1-(6-Aminopyridin-3-yl)piperidin-3-yl)piperidin-1-yl)-1-(6-aminopyridin-3-yl)piperidin-6-yl)piperidin-1-yl)piperidin-2 ...3-yl)piperidin-1-yl)piperidin-2 3-yl)((2-methoxypyridin-4-yl)methyl)amino)methyl)-9-fluoro-3-methyl-10-(2-methylpiperazin-1-yl)-2H- [1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one

[0213] 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-7-fluoro-2-methyl-6-(2-methylpiperazin-1-yl)-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (1.3 mg, 2.02 umol, yield 3.79e-1%, purity 99.11%) was obtained as an off-white solid. 1H NMR(DMSO-d6,400MHz)δ8.00~7.97(m,2H),7.60(d,J=2.8Hz,1H),7.21(dd,J=2.0Hz,8 .4Hz,1H),7.14(d,J=7.6Hz,1H),7.00(d,J=4.8Hz,1H),6.82(s,1H),6.37(dd,J=3.6H z,9.2Hz,1H),5.36(d,J=3.2Hz,2H),4.63~4.60(m,1H),4.47(d,J=10.8Hz,1H),4.31( d,J=10.0Hz,1H),3.80~3.77(m,4H),3.71~3.70(m,1H),3.66~3.61(m,1H),3.58~3.54 (m,1H),3.50~3.48(m,1H),3.24~3.17(m,4H),2.95~2.92(m,1H),2.88~2.83(m,2H),2 .77~2.72(m,1H),2.61~2.55(m,2H),2.43~2.38(m,1H),2.31~2.24(m,1H),1.98~1.95 (m,1H),1.77~1.74(m,1H),1.50~1.38(m,2H),1.32(dd,J=4.8Hz,6.4Hz,3H),1.01(dd ,J=3.2Hz,6.0Hz,3H).LCMS:99.11%(220nm),99.72%(254nm).MS(ESI):masscalcd.For C 35 H 43 FN8O3642.34m / z found643.5[M+H] + . Compound 42 6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl ...6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl)-1-(6-aminopyridin-3- ((2-methoxypyridin-4-yl)methyl)amino)methyl)-9-fluoro-3-methyl-10-(3-(methylamino)piperidin-1-yl)- 2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one hydrochloride

[0214] 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-7-fluoro-2-methyl-6-[3-(methylamino)-1-piperidinyl]-4-oxa-1-azatricyclo[7.3.1.0 5 ,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (24.3 mg, 33.85 umol, 9.52% yield, 96.56% purity, HCl) as a light yellow solid. 1H NMR (DMSO-d6, 400MHz) δ14.19~14.10(m,1H),9.31~9.20(m,2H),8.52~8.48(m,1H),8.11(t,J=4.8Hz,1H),7.99~7.95(m,1H), 7.55~7.52(m,1H),7.42~7.37(m,2H),7.20(d,J=6.8Hz,1H),7.00(dd,J=7.2Hz,9.6Hz,1H),4.49~4.44(m,3H),4.32~4.21(m,4 H),3.77(d,J=2.8Hz,3H),3.59~3.55(m,1H),3.41~3.34(m,2H),3.24~3.11(m,4H),3.08~3.06(m,2H),2.63~2.54(m,5H),2.1 3~2.09(m,1H),1.90~1.83(m,3H),1.67~1.53(m,3H),1.46~1.44(m,3H).LCMS:96.56%(220nm),96.68%(254nm).MS(ESI):mass calcd.For C 36 H 45 FN8O3656.36m / z found 657.5[M+H] + . Compound 43 6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl ...6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl)-1-(6-aminopyridin-3- ((2-methoxypyridin-4-yl)methyl)amino)methyl)-9-fluoro-3-methyl-10-(methyl(piperidin-3-yl)amino)-2H- [1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one hydrochloride

[0215] 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-7-fluoro-2-methyl-6-[methyl(3-piperidinyl)amino]-4-oxa-1-azatricyclo[7.3.1.0 5 ,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (3.6 mg, 5.18 umol, 1.46% yield, 99.75% purity, HCl) as a light yellow solid. 1H NMR (DMSO-d6, 400MHz) δ10.19~10.11(m,1H),9.75~9.71(m,1H),9.22~9.07(m,2H),8.46(s,1H),8.22(d,J=5.2Hz,1H),7.96(dd,J=2.4Hz,10 .0Hz,1H),7.48~7.45(m,2H),7.30(d,J=5.2Hz,1H),7.18~7.14(m,2H) ,4.63~4.61(m,1H),4.54~4.49(m,1H),4.40(s,2H),4.37~4.32(m,1H) ,4.27~4.24(m,2H),3.87(s,3H),3.84~3.83(m,1H),3.58~3.53(m,2H) ,3.27~3.19(m,4H),3.08~3.03(m,2H),2.75~2.67(m,1H),2.58~2.55( m,3H),2.11~2.07(m,2H),1.92~1.81(m,3H),1.67~1.56(m,3H),1.43(d,J=6.4Hz,3H).LCMS:99.75%(220nm),99.80%(254nm).MS(ESI):mass calcd.ForC 36 H 45 FN8O3656.36m / z found 657.5[M+H] + . Compound 44 6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl ...piperidin-3-yl)piperidin-3-yl)piperidin ((2-methoxypyridin-4-yl)methyl)amino)methyl)-9-fluoro-10-(3-hydroxy-1-oxa-8-azaspiro[4.5]decane- 8-yl)-3-methyl-2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one

[0216] 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-7-fluoro-6-(3-hydroxy-1-oxa-8-azaspiro[4.5]decan-8-yl)-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (35.4 mg, 47.89 umol, 12.55% yield, 94.69% purity) as a yellow solid. 1H NMR (DMSO-d6, 400MHz) δ8.00~7.94(m,2H),7.60(d,J=2.8Hz,1H),7.33(dd,J=2.4Hz,12. 4Hz,1H),7.14(dt,J=2.8Hz,8.8Hz,1H),6.99(d,J=4.8Hz,1H),6.81(s,1H),6.37(dd,J= 3.6Hz,8.8Hz,1H),5.36(d,J=3.6Hz,2H),4.86(d,J=3.6Hz,1H),4.57(dd,J=2.0Hz,6.8H z,1H),4.44(d,J=10.0Hz,1H),4.35~4.33(m,1H),4.25(d,J=9.2Hz,1H),3.82(dd,J=4.8H z,9.2Hz,1H),3.76(s,4H),3.71~3.63(m,2H),3.61~3.54(m,3H),3.50~3.47(m,1H),3.2 3~3.21(m,1H),3.05(dd,J=5.6Hz,11.6Hz,2H),2.77~2.71(m,1H),2.60~2.54(m,1H),2. 43~2.37(m,1H),1.97~1.88(m,2H),1.81~1.72(m,4H),1.63~1.61(m,2H),1.49~1.38(m, 2H), 1.31 (dd, J = 4.8Hz, 6.4Hz, 3H). LCMS: 94.69% (220nm), 98.36% (254nm). MS (ESI): mass calcd.For C 38 H 46 FN7O5699.35m / zfound700.5[M+H] + . Compound 45 6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl ...6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl)-1-(6-aminopyridin-3- ((2-methoxypyridin-4-yl)methyl)amino)methyl)-9-fluoro-3-methyl-10-(7-methyl-2,7-diazaspiro[3.5] Nonan-2-yl)-2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one

[0217] 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-7-fluoro-2-methyl-6-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (20.3 mg, 29.31 umol, 16.49% yield, 98.59% purity) was obtained as a white solid.1 H NMR(DMSO-d6,400MHz)δ8.00(d,J=5.6Hz,1H),7.87(dd,J=8.0Hz,12.4Hz,1H),7.60(s,1H),7.32~7.25(m,1H),7.15(d,J=8.8Hz,1H),7.00~6.99(m ,1H),6.82(s,1H),6.38(dd,J=3.2Hz,8.8Hz,1H),5.37~5.32(m,2H),4.5 4~4.49(m,1H),4.41~4.33(m,1H),4.20~4.12(m,1H),3.97(d,J=3.2Hz,2H ),3.77(d,J=1.6Hz,3H),3.71~3.66(m,2H),3.60~3.47(m,5H),3.24~3.2 1(m,1H),2.75~2.74(m,1H),3.30(s,4H),2.41~2.36(m,2H),2.23(s,3H), 1.97~1.94(s,1H),1.88~1.82(m,1H),1.74(s,4H),1.53~1.40(m,2H),1.3 1(q,J=11.2Hz,3H).LCMS:98.59%(220nm),99.03%(254nm).MS(ESI):mass calcd.For C 38 H 47 FN8O3682.38m / z found683.5[M+H] + . Compound 46 6-((((S)-1-(6-Aminopyridin-3-yl)piperidin-3-yl)piperidin-1-yl)-1-(6-aminopyridin-3-yl)piperidin-6-yl)piperidin-1-yl)piperidin-2 ...3-yl)piperidin-1-yl)piperidin-2 3-yl)((2-methoxypyridin-4-yl)methyl)amino)methyl)-10-(5,5-difluorohexahydrocyclopenta[c]pyrrole-2 (1H)-yl)-9-fluoro-3-methyl-2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one

[0218] 6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl)((2-methoxypyridin-4-yl)methyl)amino)-10-(5,5-difluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-9-fluoro-3-methyl-2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one (1.1 mg, 1.50 umol, 1.69% yield, 94.18% purity) was obtained as a light yellow solid. 1HNMR(DMSO-d6,400MHz)δ8.00(d,J=5.2Hz,1H),7.95(d,J=8.0Hz,1H),7.61~7.60(m,1H),7.37~7.30(m,1H),7.15~7.13(m,1H),7.00~6.97 (m,1H),6.81(s,1H),6.36(dd,J=3.2Hz,8.8Hz,1H),5.41~5.29(m,2H),4.57~4.55(m,1H),4.45(d,J=10.8Hz,1H),4.24(d,J=10.4Hz,1H),3 .76(s,3H),3.71~3.69(m,1H),3.67~3.62(m,1H),3.61~3.57(m,1H), 3.54~3.46(m,3H),3.24~3.21(m,2H),2.78~2.72(m,3H),2.41~2.37(m ,4H),2.02~1.95(m,4H),1.77~1.74(m,1H),1.50~1.41(m,3H),1.31(d,J=6.4Hz,3H).LCMS:94.18%(220nm),99.76%(254nm).MS(ESI):mass calcd.For C 37 H 42 F3N7O3689.33m / zfound 690.5[M+H] + . Option 8 General procedures for preparing compounds in Scheme 8 Preparation of compounds in Scheme 8 (Step 1 of Scheme 8)

[0219] A mixture of ethyl 3-oxo-3-(2,3,4,5 or 2,3,5,6-tetrafluorophenyl)propanoate (11.36 mmol, 1 eq), AcO (28.39 mmol, 2.66 mL, 2.50 eq) and triethyl orthoformate (17.03 mmol, 1.50 eq) was stirred at 130°C to 135°C for 2 hours. The mixture was concentrated under reduced pressure. To the residue in EtOH (1.6 mL / mmol to 2.8 mL / mmol) at 0°C, various amines (11.24 mmol, 1 eq) were very slowly added dropwise. The mixture was then stirred at 0°C for half an hour to 3 hours. The mixture was concentrated under reduced pressure to give the desired product. Preparation of compounds in Scheme 8 (Step 2 of Scheme 8)

[0220] To a solution of various hydroxypropylamino groups (10.02 mmol, 1 eq) in DMF (3 mL / mmol to 5 mL / mmol) at 20°C was added KCO (30.06 mmol, 3 eq). The mixture was then stirred at 80-140°C for 1-16 hours. The mixture was cooled to room temperature and poured into ice water at 0°C. Some solid formed. The solid was collected by filtration to yield the desired product. Preparation of compounds in Scheme 8 (Step 3 of Scheme 8)

[0221] To a solution of various esters (7.76 mmol, 1 eq) in H2O (1.1 mL / mmol to 1.3 mL / mmol) and AcOH (155.21 mmol, 20 eq) at 20°C was added concentrated H2SO4 (19.40 mmol, 2.5 eq). The mixture was then stirred at 80°C for 2 to 16 hours. The mixture was cooled to room temperature and then poured into ice water at 0°C. Some solid formed. The solid was collected by filtration. Preparation of compounds in Scheme 8 (Step 4 of Scheme 8)

[0222] To a solution of different carboxylic acids (7.47 mmol, 1 eq) in MeOH (3 mL / mmol to 5 mL / mmol) was added NaBH4 (33.60 mmol, 4.5 eq) in portions over half an hour at 0°C. Under an N2 atmosphere, the mixture was stirred at 20°C for 1 to 2 hours. TsOH.H2O (746.77 umol, 0.1 eq) was then added and the mixture was heated at 95°C under an N2 atmosphere for 10 hours. The reaction mixture was concentrated under reduced pressure. The residue was slowly quenched with water at 0°C and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was used in the next step without further purification or by flash silica gel chromatography ( 12g or 20g or 40g Flash silica gel column, eluent: 0-25% or 0-42% gradient of ethyl acetate / petroleum ether @ 30 mL / min or 80 mL / min). The eluent was removed under reduced pressure to obtain the desired product. Preparation of compounds in Scheme 8 (Step 5 of Scheme 8)

[0223] To a mixture of different ketones (4.60 mmol, 1 eq) in DCM (2.5 mL / mmol to 6.5 mL / mmol) was added NaOMe (17.93 mmol, 3.9 eq) in portions at 0°C. The mixture was stirred at 20°C for 1 hour, and then ethyl formate (17.93 mmol, 3.9 eq) was added dropwise at 20°C. Subsequently, under an N2 atmosphere, the mixture was stirred at 20°C for 5 to 16 hours. The reaction mixture was slowly poured into ice water at 0°C and the pH was adjusted to 6 with 0.5N HCl. The organic layer was separated and the aqueous phase was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the desired product. Preparation of compounds in Scheme 8 (Step 6 of Scheme 8)

[0224] To a mixture of unsaturated formaldehyde (4.49 mmol, 1 eq) in MeOH (3 mL / mmol to 7 mL / mmol) was added MnO2 (22.45 mmol, 5 eq). The mixture was then stirred at 20°C under a N2 atmosphere for 10 to 16 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The filter cake was washed with DCM. The combined filtrates were concentrated under reduced pressure to give the desired product. Preparation of compounds in Scheme 8 (Step 7 of Scheme 8)

[0225] At 20°C, solutions of various saturated formaldehydes (754.11 μmol, 1 eq) and (3S)-N-[(2-methoxy-4-pyridinyl)methyl]-1-(6-nitro-3-pyridinyl)piperidin-3-amine (754.11 μmol, 1 eq) in DCM (6 mL / mmol to 9 mL / mmol) or DCE (6 mL / mmol to 9 mL / mmol) were stirred for 1 hour. The mixture was then cooled to 0°C, and NaBH(OAc) (980.35 μmol to 1.13 mmol, 1.3 eq to 1.5 eq) was added portionwise at 0°C. The mixture was stirred at 20°C for 10 to 16 hours. The mixture was quenched with ice water at 0°C, and the pH was adjusted to 8 with saturated NaHCO. The mixture was extracted with DCM and i-PrOH (v:v = 3:1). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the desired product. Preparation of compounds in Scheme 8 (Step 8 of Scheme 8)

[0226] Under H2 (15 psi), a mixture of different nitro compounds (506.25 μmol, 1 eq) and Pd / C (0.1 g, 10% purity) in MeOH (20 mL / mmol to 60 mL / mmol) was stirred at 20°C for 1 to 5 hours. The mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm or Waters Xbridge BEH C18 100*30 mm*10 μm or Phenomenex C18 75*30 mm*3 μm or Phenomenex C 18 80*40 mm*3 μm or Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water(NH4HCO3)-MeCN] or [water(HCl)-MeCN]; B%: 1%-75%, 7 min or 8 min or 10 min). Freeze-drying and removal of the solvent afforded the desired product. Compound 47 Preparation of ethyl (Z)-3-((3-hydroxypropyl)amino)-2-(2,3,4,5-tetrafluorobenzoyl)acrylate (Scheme 8) Step 1)

[0227] A mixture of ethyl 3-oxo-3-(2,3,4,5-tetrafluorophenyl)propanoate (3 g, 11.36 mmol, 1 eq) and Ac2O (2.90 g, 28.39 mmol, 2.66 mL, 2.50 eq) and triethyl orthoformate (2.52 g, 17.03 mmol, 2.83 mL, 1.50 eq) was stirred at 135°C for 2 hours. The mixture was concentrated under reduced pressure. To the residue in ethanol (20 mL) was added 3-aminopropan-1-ol (844.36 mg, 11.24 mmol, 866.90 uL, 1 eq) very slowly at 0°C. The mixture was then stirred at 0°C for 2 hours. LCMS and TLC (petroleum ether: ethyl acetate = 1: 1, R f =0.05) indicated that the reaction was almost complete. The mixture was concentrated under reduced pressure to obtain ethyl (Z)-3-(3-hydroxypropylamino)-2-(2,3,4,5-tetrafluorobenzoyl)prop-2-enoate (3.8 g, 10.88 mmol, 96.78% yield) as a light yellow solid. 1H NMR(DMSO-d6,400MHz)δ11.02(s,1H),8.16~8.11(m,1H),6.99~6.97(m,1H),4.09(q,J=6.4Hz ,2H),3.82(t,J=6.0Hz,2H),3.65(t,J=6.4Hz,2H),2.02~1.91(m,2H),1.11(t,J=6.4Hz,3H). 10,11-Difluoro-8-oxo-2,3,4,8-tetrahydro-[1,4]oxazepino[2,3,4-ij]quinoline-7-carboxylic acid Preparation of esters (Scheme 8, step 2)

[0228] To a solution of ethyl (E)-3-(3-hydroxypropylamino)-2-(2,3,4,5-tetrafluorobenzoyl)prop-2-enoate (3.50 g, 10.02 mmol, 1 eq) in DMF (50 mL) was added KCO (4.15 g, 30.06 mmol, 3 eq) at 20°C. The mixture was then stirred at 80°C for 10 hours. LCMS and TLC (petroleum ether: ethyl acetate = 0:1, R f =0.1) shows that the reaction is almost complete. The mixture is cooled to room temperature and poured into ice water (100mL) at 0°C. Some solids are formed. The solid is collected after filtration. At 0°C, the filtrate is adjusted to pH=7 with 2N HCl and extracted with EtOAc (40mL×3). The combined organic layers are washed with brine (20mL×3), dried over Na2SO4, filtered and concentrated under reduced pressure. Compound 10,11-difluoro-8-oxo-2,3,4,8-tetrahydro-[1,4]oxaza[2,3,4-ij]quinoline-7-carboxylic acid ethyl ester (2.4g, 7.76mmol, 77.44% yield) is obtained as a light yellow solid. 1 H NMR(DMSO-d6,400MHz)δ8.64(s,1H),7.76(dd,J=8.4Hz,2.0Hz,1H),4.57(t,J=6.0Hz,2H ),4.48(t,J=6.8Hz,2H),4.22(q,J=7.2Hz,2H),2.42~2.38(m,2H),1.28(t,J=6.8Hz,3H). 10,11-difluoro-8-oxo-2,3,4,8-tetrahydro-[1,4]oxaza[2,3,4-ij]quinoline-7-carboxylic acid Preparation (Step 3 of Scheme 8)

[0229] At 20 ° C, to a solution of 10,11-difluoro-8-oxo-2,3,4,8-tetrahydro-[1,4]oxaza[2,3,4-ij]quinoline-7-carboxylic acid ethyl ester (2.4, 7.76 mmol, 1 eq) in H2O (10 mL) and AcOH (9.32 g, 155.21 mmol, 8.88 mL, 20 eq) was added concentrated H2SO4 (1.90 g, 19.40 mmol, 1.03 mL, 2.5 eq). The mixture was then stirred at 80 ° C for 10 hours. LCMS showed that the reaction was complete. The mixture was cooled to room temperature and then poured into ice water (20 mL) at 0 ° C. Some solids were formed. The solids were collected after filtration. Compound 7,8-difluoro-4-oxo-10-oxa-1-azatricyclo[7.4.1.0 5 ,14 ]Tetradeca-2,5,7,9(14)-tetraene-3-carboxylic acid (2.1 g, 7.47 mmol, 96.23% yield) as a light yellow solid. 1 HNMR (DMSO-d6, 400MHz) δ9.01 (s, 1H), 7.95 (dd, J = 8.0Hz, 2.0Hz, 1H), 4.75 (t, J = 6.0Hz, 2H), 4.51 (t, J = 7.2Hz, 2H), 2.47~2.43 (m, 2H). Preparation of 10,11-difluoro-3,4,6,7-tetrahydro-[1,4]oxaza[2,3,4-ij]quinolin-8(2H)-one (Step 4 of Solution 8)

[0230] 7,8-difluoro-4-oxo-10-oxa-1-azatricyclo[7.4.1.0 5,14 ] To a solution of tetradecane-2,5,7,9(14)-tetraene-3-carboxylic acid (2.1 g, 7.47 mmol, 1 eq) was added NaBH4 (1.27 g, 33.60 mmol, 4.5 eq) in portions. The mixture was stirred at 20°C for 1 hour under N2 atmosphere. TsOH.H2O (142.05 mg, 746.77 mmol, 0.1 eq) was then added, and the mixture was heated at 95°C for 10 hours under N2 atmosphere. LCMS and TLC (petroleum ether: ethyl acetate = 1: 1, R f =0.6) showed that the reaction was almost complete. The reaction mixture was concentrated under reduced pressure. The residue was slowly quenched with water (20 mL) at 0 ° C and extracted with EtOAc (30 mL × 3). The combined organic layer was washed with brine (20 mL × 1), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography ( 20g Flash silica gel column, 0~42% gradient ethyl acetate / petroleum ether elution @80mL / min). The eluent was removed under reduced pressure. Compound 7,8-difluoro-10-oxa-1-azatricyclic [7.4.1.0 5,14 ]Tetradeca-5,7,9(14)-trien-4-one (1.2 g, 5.02 mmol, 67.17% yield) was obtained as a yellow oil. 1 H NMR (DMSO-d6, 400MHz) δ7.30 (dd, J=8.8Hz, 2.0Hz, 1H), 4.31 (t, J=6.4Hz, 2H), 3.51~3.44 (m, 4H), 2.60 (t, J=7.2Hz, 2H), 2.13~2.10 (m, 2H). 10,11-Difluoro-8-oxo-2,3,4,6,7,8-hexahydro-[1,4]oxaza[2,3,4-ij]quinoline-7-carboxylic acid Preparation of aldehydes (Scheme 8, Step 5)

[0231] At 0 °C, 7,8-difluoro-10-oxa-1-azatricyclo[7.4.1.0 5,14 ] To a mixture of tetradecane-5,7,9(14)-triene-4-one (1.1 g, 4.60 mmol, 1 eq) was added NaOMe (1.94 g, 17.93 mmol, 50% purity, 3.9 eq) in portions. The mixture was stirred at 20°C for 1 hour, and then ethyl formate (1.33 g, 17.93 mmol, 1.44 mL, 3.9 eq) was added dropwise at 20°C. The mixture was then stirred at 20°C for 5 hours under a N2 atmosphere. LCMS and TLC (petroleum ether: ethyl acetate = 3: 1, R f =0.4) showed that the reaction was almost complete. The reaction mixture was slowly poured into ice water (20 mL) at 0 ° C and the pH was adjusted to 6 with 0.5N HCl. The organic layer was separated and the aqueous phase was extracted with DCM (20 mL × 2). The combined organic layer was washed with brine (15 mL × 1), dried over Na2SO4, filtered and concentrated under reduced pressure. Compound 7,8-difluoro-4-oxo-10-oxa-1-azatricyclic [7.4.1.0 5,14 ]Tetradeca-5,7,9(14)-triene-3-carbaldehyde (1.1 g, 4.12 mmol, 89.52% yield) was obtained as a light brown oil. 1 H NMR (DMSO-d6, 400MHz) δ7.76~7.74(m,1H),7.32(t,J=8.8Hz,1H),4.24(t,J=6.4Hz,2H),3.50~3.43(m,4H),2.10(t,J=6.0Hz,2H). 10,11-difluoro-8-oxo-2,3,4,8-tetrahydro-[1,4]oxaza[2,3,4-ij]quinoline-7-carbaldehyde Preparation (Step 6 of Scheme 8)

[0232] To 7,8-difluoro-4-oxo-10-oxa-1-azatricyclo[7.4.1.0 5,14 ] To a mixture of fourteen carbon-5,7,9 (14) -triene-3-carbaldehyde (1.2 g, 4.49 mmol, 1 eq) was added MnO2 (1.95 g, 22.45 mmol, 5 eq). The mixture was then stirred at 20 ° C for 10 hours under a N2 atmosphere. LCMS showed that the reaction was complete. The reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure. The filter cake was washed with DCM (100 mL × 2). The filtrate was concentrated under reduced pressure. Compound 7,8-difluoro-4-oxo-10-oxa-1-azatricyclic [7.4.1.0 5,14 ]Tetradeca-2,5,7,9(14)-tetraene-3-carbaldehyde (0.6 g, 2.26 mmol, 50.38% yield) as an off-white solid. 1 H NMR (DMSO-d6, 400MHz) δ10.33~10.19(m,1H),8.75~8.61(m,1H),7.87(s,1H),4.83~4.53(m,4H),2.53~2.43(m,2H). (S)-10,11-difluoro-7-((((2-methoxypyridin-4-yl)methyl)(1-(6-nitropyridin-3-yl)piperidin- Preparation of 3-amino)methyl)-3,4-dihydro-[1,4]oxazepino[2,3,4-ij]quinolin-8(2H)-one (Scheme 8) Step 7)

[0233] 7,8-difluoro-4-oxo-10-oxa-1-azatricyclo[7.4.1.0 5,14 ]Tetradecane-2,5,7,9(14)-tetraene-3-carbaldehyde (0.2 g, 754.11 μmol, 1 eq) and (3S)-N-[(2-methoxy-4-pyridyl)methyl]-1-(6-nitro-3-pyridyl)piperidin-3-amine (258.95 mg, 755 eq) solution was stirred for 1 hour. The mixture was then cooled to 0°C and NaBH(OAc)3 (207.77 mg, 980.35 μmol, 1.3 eq) was added in portions at 0°C. The mixture was stirred at 20°C for 10 hours. LCMS and TLC (ethyl acetate: methanol = 10: 1, R f=0.3) showed that the reaction was almost complete. The mixture was quenched with ice water (10 mL) at 0 ° C and the pH was adjusted to 8 with saturated NaHCO3. The mixture was extracted with DCM and i-PrOH (v:v=3:1, 10 mL×3). The combined organic layer was washed with brine (10 mL×1), dried over Na2SO4, filtered and concentrated under reduced pressure. Compound 7,8-difluoro-3-[[(2-methoxy-4-pyridyl)methyl-[(3S)-1-(6-nitro-3-pyridyl)-3-piperidinyl]amino]methyl]-10-oxa-1-azatricyclic [7.4.1.0 5,14 ]Tetradecan-2,5,7,9(14)-tetraen-4-one (0.3 g, 506.25 umol, 67.13% yield) as a yellow solid. 1 H NMR(DMSO-d6,400MHz)δ8.24(s,1H),8.08(d,J=7.2Hz,1H),7.99~7.96(m,2H),7.66(dd,J=8.8Hz,2.0Hz ,1H),7.44(d,J=9.6Hz,1H),7.00(d,J=5.2Hz,1H),6.82(s,1H),4.58~4.26(m,6H),3.78~3.76(m,2H),3. 75(s,3H),3.68~3.64(m,1H),3.53~3.51(m,1H),3.16(t,J=7.2Hz,1H),2.96(t,J=6.8Hz,1H),2.55~2.5 3(m,1H),2.49~2.34(m,2H),2.01~1.96(m,1H),1.77~1.72(m,1H),1.70~1.63(m,1H),1.44~1.35(m,1H). (S)-7-(((1-(6-aminopyridin-3-yl)piperidin-3-yl)((2-methoxypyridin-4-yl)methyl)amino) Preparation of 1,4-dihydro-1,1-difluoro-3,4-dihydro-[1,4]oxazepino[2,3,4-ij]quinolin-8(2H)-one (Scheme 8) Step 8)

[0234] 7,8-difluoro-3-[[(2-methoxy-4-pyridinyl)methyl-[(3S)-1-(6-nitro-3-pyridinyl)-3-piperidinyl]amino]methyl]-10-oxa-1-azatricyclo[7.4.1.0 5 ,14]Tetradecane-2,5,7,9(14)-tetraen-4-one (0.3 g, 506.25 umol, 1 eq) and Pd / C (0.1 g, purity 10%) were stirred at 20°C for 4 hours. LCMS and HPLC showed that the reaction was complete. The mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex C18 80*40mm*3um; mobile phase: [water (NH4HCO3)-MeCN]; B%: 25%-45%, 8 minutes). The solvent was removed by freeze drying. The compound 3-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-7,8-difluoro-10-oxa-1-azatricyclic [7.4.1.0 5,14 ]Tetradeca-2,5,7,9(14)-tetraen-4-one (23.1 mg, 41.06 umol, yield 8.11%, purity 100%), as a white solid. 1 H NMR (DMSO-d6, 400MHz) δ7.97~7.95(m,2H),7.68(dd,J=8.4Hz,2.0Hz,1H),7.61(d,J=2.8Hz,1H),7.14(dd,J=8.8Hz,2.8Hz,1 H),6.96(d,J=6.8Hz,1H),6.77(s,1H),6.37(d,J=8.8Hz,1H),5.36(s,2H),4.46(t,J=7.2Hz,2H),4.42(t,J=7.2Hz,2H),3.7 5(s,3H),3.70(s,2H),3.58(d,J=14.4Hz,2H),3.32~3.30(m,1H),3.27~3.21(m,1H),2.67~2.58(m,1H),2.53~2.51(m,1H),2 .49~2.35(m,3H),1.98~1.95(m,1H),1.77~1.74(m,1H),1.55~1.42(m,2H).HPLC:100%(220nm),100%(254nm).MS(ESI):mass calcd.For C 30 H 32 F2N6O3562.25m / z found 563.3[M+H] + . Compound 48 (S)-6-(((1-(6-aminopyridin-3-yl)piperidin-3-yl)piperidin-6-yl)-piperidin-1-yl)-1-[4-(6-aminopyridin-3-yl)piperidin-1-yl] ...piperidin-2-yl]piperidin-3-yl]piperidin 3-yl)((2-methoxypyridin-4-yl)methyl)amino)methyl)-9,10-difluoro-3,3-dimethyl-2H-[1,4]oxazin [2,3,4-ij]quinolin-7(3H)-one

[0235] 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6,7-difluoro-2,2-dimethyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (88.4 mg, 152.90 umol, yield 24.41%, purity 99.734%), as a white solid. 1 HNMR(DMSO-d6,400MHz)δ8.09(s,1H),7.99(d,J=5.2Hz,1H),7.60~7.55(m,2H),7.14(dd,J=8.8Hz,2.8Hz,1H),6.96(d ,J=5.6Hz,1H),6.79(s,1H),6.37(d,J=8.8Hz,1H),5.37(s,2H),4.30(s,2H),3.76~3.75(m,5H),3.66~3.63(m,2H),3. 48~3.45(m,1H),3.24~3.21(m,1H),2.82~2.76(m,1H),2.61~2.56(m,1H),2.45~2.39(m,1H),1.96~1.94(m,1H),1.78~ 1.75(m,1H),1.52~1.49(m,1H),1.46(s,6H),1.43~1.42(m,1H).LCMS:99.73%(220nm),99.65%(254nm).MS(ESI):mass calcd.For C 31 H 34 F2N6O3576.27m / z found 577.4[M+H] + . Compound 49 (S)-6-(((1-(6-aminopyridin-3-yl)piperidin-3-yl)piperidin-6-yl)-piperidin-1-yl)-1-[4-(6-aminopyridin-3-yl)piperidin-1-yl] ...piperidin-2-yl]piperidin-3-yl]piperidin 3-yl)((2-methoxypyridin-4-yl)methyl)amino)methyl)-9,10-difluorospiro[[1,4]oxazino[2,3,4-ij]quin ... [2,1'-cyclobutane]-7(3H)-one

[0236] 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6,7-difluoro-spiro[4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraene-3,1'-cyclobutane]-10-one (25 mg, 40.33 umol, 10.85% yield, 94.13% purity) was obtained as a light yellow solid. 1HNMR(DMSO-d6,400MHz)δ7.99(d,J=5.6Hz,2H),7.60(d,J=2.8Hz,1H),7.52(dd,J=8.0Hz,10.8Hz,1H),7.14(dd,J=3.2Hz,8.8Hz,1H) ,6.99(d,J=5.6Hz,1H),6.80(s,1H),6.37(d,J=8.8Hz,1H),5.37(s,2H),4.37(d,J=3.2Hz,2H),3.76(s,3H),3.72(s,2H),3.61(d,J=8 .4Hz,2H),3.50~3.47(m,1H),3.25~3.20(m,1H),2.79~2.73(m,1H),2.61~2.58(m,1H),2.41~2.38(m,2H),2.29~2.25(m,2H),2.12~2 .07(m,2H),1.98~1.96(m,2H),1.77~1.74(m,1H),1.53~1.41(m,2H).LCMS:94.13%(220nm),99.37%(254nm).MS(ESI):masscalcd.For C 32 H 34 F2N6O3588.27m / z found 589.4[M+H] + . Compound 50 (S)-6-(((1-(6-aminopyridin-3-yl)piperidin-3-yl)piperidin-6-yl)-piperidin-1-yl)-1-[4-(6-aminopyridin-3-yl)piperidin-1-yl] ...piperidin-2-yl]piperidin-3-yl]piperidin 3-yl)((2-methoxypyridin-4-yl)methyl)amino)methyl)-9,10-difluoro-2,2-dimethyl-2H-[1,4]oxazin [2,3,4-ij]quinolin-7(3H)-one

[0237] 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6,7-difluoro-3,3-dimethyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (123.9 mg, 213.99 umol, 32.45% yield, 99.59% purity) was obtained as a light yellow solid. 1HNMR(DMSO-d6,400MHz)δ7.97(d,J=5.2Hz,1H),7.91(s,1H),7.60(d,J=2.8Hz,1H),7.51(dd,J=8.0Hz,10.8Hz,1H),7.13(dd,J=2.8Hz,8 .8Hz,1H),6.97(d,J=5.2Hz,1H),6.77(s,1H),6.38(d,J=8.4Hz,1H),5.37~5.35(m,2H),4.20~4.12(m,2H),3.75(s,3H),3.72(s,2H),3. 66~3.61(m,2H),3.46(d,J=9.6Hz,1H),3.24(d,J=11.6Hz,1H),2.79~2.73(m,1H),2.58(t,J=10.8Hz,1H),2.41(t,J=11.6Hz,1H),2.00( d, J=10.4Hz, 1H), 1.77 (d, J=12.8Hz, 1H), 1.51~1.43 (m, 2H), 1.38 (d, J=2.8Hz, 6H). LCMS: 99.59% (220nm), 99.61% (254nm). MS (ESI): mass calcd.For C 31 H 34 F2N6O3576.27m / z found 577.4[M+H] + . Compound 51 6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl)piperidin-6-yl)-1-(6-aminopyridin-3-yl)piperidin-1-yl)piperidin-6-ylpiperidin-1-ylpiperidin-2-ylpiperidin-3 ...3-ylpiperidin- 3-yl)((2-methoxypyridin-4-yl)methyl)amino)methyl)-9,10-difluoro-2-methyl-2H-[1,4]oxazin[2,3, 4-ij]quinolin-7(3H)-one

[0238] 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6,7-difluoro-3-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (94.2 mg, 156.02 umol, yield 23.11%, purity 93.18%), as a yellow solid. 1H NMR(DMSO-d6,400MHz)δ8.00(d,J=5.2Hz,1H),7.92(s,1H),7.61(s,1H),7.52(dd,J=8.4Hz,10.8Hz,1H),7.13(dd,J=2.8Hz,9.2Hz,1H),7 .00(d,J=5.2Hz,1H),6.79(s,1H),6.39(d,J=8.8Hz,1H),5.36~5.34(m,2H),4.61~4.57(m,1H),4.51~4.46(m,1H),3.99~3.93(m,1H),3.82 ~3.81(m,1H),3.80(s,3H),3.72(s,1H),3.72~3.60(m,2H),3.49(d,J=11.2Hz,1H),3.25(d,J=11.6Hz,1H),2.77~2.72(m,1H),2.60~2.59 (m,1H),2.41~2.38(m,1H),1.97~1.95(m,1H),1.76~1.73(m,1H),1.48~1.40(m,5H).LCMS:93.18%(220nm),95.64%(254nm).MS(ESI):mass calcd.For C 30 H 32 F2N6O3562.25m / z found 563.4[M+H] + . Compound 52 6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl ...6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl)-1-(6-aminopyridin-3- ((2-methoxypyridin-4-yl)methyl)amino)methyl)-8,9-difluoro-3-methyl-2H-[1,4]oxazino[2,3,4-ij] Quinolin-7(3H)-one

[0239] 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-7,8-difluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (143.4 mg, 252.53 umol, 37.41% yield, 99.077% purity) was obtained as an off-white solid. 1HNMR(DMSO-d6,400MHz)δ7.99~7.96(m,2H),7.61(d,J=2.4Hz,1H),7.41(dd,J=11.6Hz,6.8Hz,1H),7.15(dd,J=8.4Hz,2.4Hz,1H),6.99(d,J=5 .2Hz,1H),6.81(s,1H),6.38(dd,J=9.2Hz,3.2Hz,1H),5.37~5.34(m,2H),4.62~4.60(m,1H),4.39(d,J=10.8Hz,1H),4.25(d,J=9.2Hz,1H),3.7 5(s,3H),3.72~3.71(m,2H),3.67~3.54(m,2H),3.53~3.50(m,1H),2.2 5~2.22(m,1H),2.76~2.73(m,1H),2.61~2.55(m,1H),2.44~2.39(m,1H) ,1.99~1.96(m,1H),1.78~1.75(m,1H),1.54~1.39(m,2H),1.29(dd,J=6.4Hz,4.8Hz,3H).HPLC:99.08%(220nm),98.83%(254nm).MS(ESI):mass calcd.For C 30 H 32 F2N6O3562.25m / z found 563.4[M+H] + . Compound 53 6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl ...6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl)-1-(6-aminopyridin-3- ((2-methoxypyridin-4-yl)methyl)amino)methyl)-9,10-difluoro-3-isopropyl-2H-[1,4]oxazino[2,3,4- ij]quinolin-7(3H)-one

[0240] 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6,7-difluoro-2-isopropyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one 136.8 mg, 228.50 umol, yield 19.70%, purity 98.66%), as a light yellow solid. 1HNMR(DMSO-d6,400MHz)δ8.01(d,J=5.6Hz,1H),7.60(dd,J=3.2Hz,9.6Hz,1H),7.55(dd,J=8.4Hz,10.0Hz,1H),7.14~7.12(m,1H),7.0.3~7.01(m,1H),6. 84(s,1H),6.37(dd,J=4.8Hz,8.8Hz,1H),5.37(d,J=5.2Hz,2H),4.88(d,J=1 2.0Hz,1H),4.30~4.30(m,2H),3.78~3.74(m,5H),3.65(d,J=13.6Hz,1H),3.5 2(t,J=14.0Hz,2H),3.24~3.20(m,1H),2.76~2.70(m,1H),2.59(t,J=10.8Hz ,1H),2.45~2.37(m,1H),3.62~3.61(m,1H),2.00~1.91(m,2H),1.75~1.74(m ,1H),1.48~1.41(m,2H),0.99(dd,J=6.8Hz,12.0Hz,3H),0.74(dd,J=6.8Hz,11.2Hz,3H).LCMS:98.66%(220nm),99.01%(254nm).MS(ESI):masscalcd.For C 32 H 36 F2N6O3590.28m / z found591.4[M+H] + . Option 9 Specific steps for preparing the compounds in Scheme 9 Compound 54 (3S)-3-(((9,10-Difluoro-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline (6-(Methyl)-1-piperidin-6-yl)methyl)amino)piperidin- Preparation of tert-butyl 1-carboxylate (Step 1 of Scheme 9)

[0241] At 25℃, N 2下 , to 6,7-difluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.0 5,13] To a mixture of tridecane-5 (13), 6,8,11-tetraene-11-carbaldehyde (1.5 g, 5.66 mmol, 1 eq) and tert-butyl (3S)-3-aminopiperidine-1-carboxylate (1.25 g, 6.22 mmol, 1.1 eq) in DCE (15 mL) was added NaBH (OAc) 3 (1.80 g, 8.48 mmol, 1.5 eq). The mixture was stirred at 25 ° C for 3 hours. LCMS showed 6,7-difluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraene-11-carbaldehyde was completely consumed and a main peak with the desired mass was detected. At 25°C, water (50 mL) was added to quench the reaction mixture, which was then extracted with EtOAc (40 mL×3). The combined organic layers were washed with brine (30 mL×2), dried over Na2SO4, filtered and concentrated under reduced pressure. Compound (3S)-3-[(6,7-difluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]tridec-5(13),6,8,11-tetraen-11-yl)methylamino]piperidine-1-carboxylic acid tert-butyl ester (2.5 g, crude product) was obtained as a brown solid. 1 H NMR(DMSO-d6,400MHz)δ8.07(d,J=5.2Hz,1H),7.58(dd,J=10.4Hz,4.4Hz,1H),4.64(s,1H),4.57(d,J=11.6Hz,1H),4.40(d,J=10.8 Hz,1H),3.90(s,1H),3.71(s,1H),3.69(s,1H),3.39~3.29(m,2H),2.88~2.82(m,2H),1.40~1.38(m,4H),1.37(s,9H),1.30(s,3H). (3S)-3-(((9,10-difluoro-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline Preparation of tert-butyl ((2-methoxypyridin-6-yl)methyl)((2-methoxypyridin-4-yl)methyl)amino)piperidine-1-carboxylate (Step 1 of Scheme 9) Step 2)

[0242] At 25 ° C, under N2, (3S)-3-[(6,7-difluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.0 5,13To a mixture of tert-butyl 1-[(1-tridecane-5(13),6,8,11-tetraen-11-yl)methylamino]piperidine-1-carboxylate (2.5 g, 5.56 mmol, 1 eq) and 2-methoxypyridine-4-carbaldehyde (762.73 mg, 5.56 mmol, 1 eq) in DCE (25 mL) was added NaBH(OAc)3 (1.77 g, 8.34 mmol, 1.5 eq). The mixture was then stirred at 25 ° C for 4 hours. LCMS showed that (3S)-3-[(6,7-difluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.0 5,13 ] tridecane-5 (13), 6,8,11-tetraene-11-yl) methylamino] piperidine-1-carboxylic acid tert-butyl ester was completely consumed and a new peak with the desired mass was detected. The reaction mixture was quenched by adding water (50 mL) at 25 ° C and extracted with DCM (30 mL × 3). The combined organic layer was washed with brine (30 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The compound tert-butyl (3S) -3- [(6,7-difluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo [7.3.1.0 5,13 ]tridec-5(13),6,8,11-tetraen-11-yl)methyl-[(2-methoxy-4-pyridinyl)methyl]amino]piperidine-1-carboxylate (3.1 g, crude product) was obtained as a brown solid. 1 H NMR(DMSO-d6,400MHz)δ8.07(d,J=5.6Hz,1H),8.01(d,J=4.4Hz,1H),7.54(t,J=8.4Hz,1H) ,6.94(d,J=5.2Hz,1H),6.76(s,1H),4.66(t,J=6.8Hz,1H),4.55(d,J=10.8Hz,1H),4.38(d ,J=11.6Hz,1H),3.91(d,J=11.2Hz,1H),3.80(s,2H),3.75(s,3H),3.70(s,2H),3.60(s,2H ),2.67~2.57(m,2H),1.67(d,J=12.0Hz,2H),1.54~1.45(m,2H),1.37(s,3H),1.34(s,9H). 9,10-difluoro-6-((((2-methoxypyridin-4-yl)methyl)((S)-piperidin-3-yl)amino)methyl)-3-methyl Preparation of 2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one (Step 3 of Scheme 9)

[0243] At 20 ° C, (3S)-3-[(6,7-difluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.0 5 ,13] tridecane-5 (13), 6,8,11-tetraene-11-yl) methyl-[(2-methoxy-4-pyridyl) methyl] amino] piperidine-1-carboxylic acid tert-butyl ester (3.1 g, 5.43 mmol, 1 eq) in HCl / MeOH (4 M, 30 mL) was stirred for 2 hours. LC-MS showed that the reaction was complete. The mixture was concentrated under reduced pressure and then adjusted to pH 7 with saturated NaHCO3. The aqueous phase was freeze-dried. Compound 6,7-difluoro-11-[[(2-methoxy-4-pyridyl) methyl-[(3S)-3-piperidinyl] amino] methyl]-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (1.5 g, crude product) as a brown oil. 1 HNMR(DMSO-d6,400MHz)δ8.15(t,J=3.2Hz,1H),7.62~7.60(m,1H),7.35(dd,J=5.6Hz,11.2Hz, 1H),7.24(d,J=8.0Hz,1H),7.03(d,J=5.6Hz,1H),4.66~4.61(m,1H),4.57~4.55(m,2H),4.39(d ,J=13.6Hz,2H),4.31~4.09(m,2H),3.91(s,3H),2.82(s,2H),3.66~3.56(m,1H),3.37~3.10(m ,1H),3.21~3.20(m,1H),1.99~1.90(m,2H),1.76~1.59(m,2H),1.46(dd,J=14.4Hz,6.8Hz,3H). Preparation of 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine (method Step 4 of Case 9)

[0244] To a solution of 5-bromo-1H-pyrazolo[3,4-b]pyridine (2 g, 10.10 mmol, 1 eq) in THF (18 mL) and DMF (2 mL) was added NaH (403.96 mg, 20.20 mmol, 60% purity, 2 eq) in portions at 0°C. SEM-Cl (2.18 g, 13.12 mmol, 2.32 mL, 1.3 eq) was then slowly added dropwise at 0°C. LCMS showed that the reaction was complete. The reaction mixture was slowly poured into ice water (50 mL) at 0°C and then extracted with EtOAc (15 mL×3). The combined organic phases were washed with brine (10 mL×1), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography ( 20g Flash silica gel column, 0-37% petroleum ether / ethyl acetate gradient elution @ 60 mL / min. The eluent was removed under reduced pressure to obtain the compound 2-[(5-bromopyrazolo[3,4-b]pyridin-1-yl)methoxy]ethyl-trimethylsilane (0.73 g, 2.22 mmol, 21.97% yield) as a white solid. 1 H NMR(CDCl3,400MHz)δ8.66(d,J=2.4Hz,1H),8.61(s,1H),8.58(d,J=2.4Hz,1 H),5.77(s,2H),3.64(t,J=8.0Hz,2H),0.87(t,J=8.0Hz,2H),-0.06(s,9H). 9,10-difluoro-6-((((2-methoxypyridin-4-yl)methyl)((S)-1-(1-((2-(trimethylsilyl) (ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)piperidin-3-yl)amino)methyl)-3-methyl-2H-[1,4]oxadiazole Preparation of azino[2,3,4-ij]quinolin-7(3H)-one (Step 5 of Scheme 9)

[0245] A mixture of 6,7-difluoro-11-[[(2-methoxy-4-pyridinyl)methyl-[(3S)-3-piperidinyl]amino]ethyl]2-ethyl 4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13), 6,8,11-tetraen-10-one (322.48 mg, 685.39 umol, 1.5 eq) and 2-[(5-bromopyrazolo[3,4-b]pyridin-1-yl)methoxy]ethyl-trimethylsilane (150 mg, 456.93 umol, 1 eq), Pd2(dba)3 (41.84 mg, 45.69 umol, 0.1 eq), JohnPhos (27.27 mg, 91.39 umol, 0.2 eq), t-BuONa (87.82 mg, 913.86 umol, 2 eq) were degassed and purged with N2 3 times, and then the mixture was stirred at 80°C under N2 atmosphere for 12 hours. LCMS showed about 12% of 6,7-difluoro-11-[[(2-methoxy-4-pyridinyl)methyl-[(3S)-3-piperidinyl]amino]methyl]-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one. LC-MS showed several new peaks and about 20% of the desired product was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage; 40 Flash silica gel column, 0-5% ethyl acetate / methanol gradient elution @ 40 mL / min). The eluent was removed under reduced pressure. Compound 6,7-difluoro-11-[[(2-methoxy-4-pyridinyl)methyl-[(3S)-1-[1-2-trimethylsilyloxymethyl]pyrazolo[3,4-b]pyridin-5-yl]-3-piperidinyl]amino]methyl]-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (260 mg, 362.18 umol, 39.63% yield) was obtained as a brown solid. 1 H NMR(CDCl3,400MHz)δ8.61(d,J=2.0Hz,1H),8.31(d,J=5.6Hz,1H),8.14(d,J=11.6Hz,1H),8.01(d,J=5.2Hz, 1H),7.57~7.51(m,1H),7.37~7.36(m,1H),7.04~7.03(m,1H),6.87~6.86(m,1H),5.66(s,2H),4.73~4.69(m, 1H),4.58~4.55(m,1H),4.42~4.39(m,1H),3.86~3.58(m,12H),2.83~2.82(m,1H),2.74~2.67(m,1H),2.04~2 .00(m,1H),1.85~1.81(m,1H),1.62~1.47(m,2H),1.33(t,J=6.4Hz,3H),0.86(t,J=8.0Hz,2H),-0.06(s,9H). 6-((((S)-1-(1H-pyrazolo[3,4-b]pyridin-5-yl)piperidin-3-yl)((2-methoxypyridin-4-yl) Preparation of 2-(4-(2-methyl)amino)methyl)-9,10-difluoro-3-methyl-2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one (Step 6 of Solution 9)

[0246] To 6,7-difluoro-11-[[(2-methoxy-4-pyridinyl)methyl-[(3S)-1-[1-(2-trimethylmethoxyethoxymethyl)pyrazolo[3,4-b]pyridin-5-yl]-3-piperidinyl]amino]methyl]-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13] HCl / EtOAc (4M, 8 mL) was added to a solution of tridecane-5(13),6,8,11-tetraen-10-one (0.25 g, 348.25 umol, 1 eq). The mixture was stirred at 20°C for 4 hours. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (2 mL) and NH3.H2O (0.01 mL), and then concentrated under reduced pressure to obtain 0.22 g of residue. It was purified twice by preparative HPLC (column: Phenomenex C18 75*30 mm*3 um; mobile phase: [water (NH4HCO3)-MeCN]; B%: 30%-50%, 8 minutes) and (column: Waters Xbridge BEH C18 100*30 mm*10 um; mobile phase: [water (NH4HCO3)-MeCN]; B%: 40%-50%, 8 min). The eluent was removed by freeze drying. Compound 6,7-difluoro-11-[[(2-methoxy-4-pyridinyl)methyl-[(3S)-1-(1H-pyrazolo[3,4-b]pyridin-5-yl)-3-piperidinyl]amino]methyl]-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (7.4 mg, 12.59 umol, 3.62% yield, 100% purity) was obtained as a white solid. 1 H NMR(DMSO-d6,400MHz)δ13.35(m,1H),8.43(d,J=2.4Hz,1H),8.13(d,J=12.0Hz,1H),8.01(d,J=9.2Hz,1H),7.95(d,J=6.4Hz,1H),7.62 ~7.52(m,2H),7.03~7.02(m,1H),6.86(d,J=2.4Hz,1H),4.74~4.68(m,1H),4.57(d,J=11.2Hz,1H),4.40~4.37(m,1H),3.86~3.79(m,1H ),3.76(s,3H),3.75(d,J=5.6Hz,1H),3.71~3.57(m,2H),3.53~3.51(m,1H),3.37~3.33(m,1H),2.89~2.72(m,2H),2.62~2.57(m,1H),2 .03~1.97(m,1H),1.84~1.81(m,1H),1.58~1.47(m,2H),1.33(dd,J=4.4Hz,6.4Hz,3H).LCMS:100%(220nm),100%(254nm).MS(ESI):mass calcd.For C 31 H31 F2N7O3587.25m / z found 588.3[M+H] + . Plan 10 General procedures for preparing compounds in Scheme 10 Compound 55 10-Azido-9-fluoro-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6- Preparation of Carboxylic Acids (Scheme 10, Step 1)

[0247] At 35 ° C, under N2, 6,7-difluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.0 5,13 ] To a solution of tridecane-5(13),6,8,11-tetraene-11-carboxylic acid (25 g, 88.90 mmol, 1 eq) in DMSO (200 mL) was added NaN3 (8.10 g, 124.60 mmol, 1.4 eq) in portions. The mixture was then stirred at 70 ° C for 15 hours. LCMS showed that the reaction was nearly complete. The mixture was cooled to 20 ° C and slowly poured into ice water (800 mL). Some precipitate was formed. The solid was collected after filtration, washed with water (800 mL), and then concentrated under reduced pressure at 35 ° C. Compound 6-azido-7-fluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraene-11-carboxylic acid (25 g, 82.17 mmol, 92.43% yield) as an off-white solid. 1 H NMR (DMSO-d6, 400MHz) δ14.95 (s, 1H), 9.00 (s, 1H), 7.70 (d, J = 10.8Hz, 1H), 4. 98~4.96(m,1H),4.70~4.67(m,1H),4.50~4.46(m,1H),1.46(d,J=6.8Hz,3H). 10-amino-9-fluoro-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic Preparation of acid (step 2 of scheme 10)

[0248] Under argon, 6-azido-7-fluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.0 5,13] A solution of tridecane-5(13),6,8,11-tetraene-11-carboxylic acid (20 g, 65.74 mmol, 1 eq) in DMF (500 mL) was added Pd / C (5 g, purity 10%). The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at H2 (30 psi) and 60°C for 10 hours. Three batches were carried out and processed together. LCMS and HPLC showed that the reaction was nearly complete. The reaction mixture was cooled to room temperature, filtered through celite, and washed with DMF (1000 mL) and MeOH (500 mL). The filtrate was concentrated under reduced pressure. The crude product was triturated with MeOH (200 mL) at 20°C for 10 minutes. Compound 6-amino-7-fluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraene-11-carboxylic acid (49 g, 176.11 mmol, 89.30% yield) as a gray solid. 1 H NMR (DMSO-d6, 400MHz) δ15.61 (s, 1H), 8.87 (s, 1H), 7.55 (d, J = 11.6Hz, 1H), 6.24 (s, 2H), 4.91~4.86(m,1H), 4.55~4.52(m,1H), 4.35~4.32(m,1H), 1.45(d,J=6.8Hz,3H). 10-Bromo-9-fluoro-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Preparation of (Scheme 10, step 3)

[0249] HBr (465.29 g, 2.30 mol, 312.27 mL, 40% purity, 40 eq) was cooled to 0 ° C and 6-amino-7-fluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.0 5,13 ] tridecane-5(13),6,8,11-tetraene-11-carboxylic acid (16 g, 57.51 mmol, 1 eq). Then, a solution of NaNO2 (4.76 g, 69.01 mmol, 1.2 eq) in H2O (9 mL) was added dropwise at 0-50°C over half an hour. Under N2 atmosphere, the mixture was stirred at 0°C for half an hour. LCMS showed 6-amino-7-fluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.0 5,13]Tridecane-5(13),6,8,11-tetraene-11-carboxylic acid was consumed, and LCMS detected about 59% of P1 and about 33% of by-products (NH2 converted to H, MS=264, also containing 282, which is the di-F acid substance from the above two steps, confirmed by FNMR). The mixture was slowly poured into ice water (1 L). Some precipitate was formed. The solid was collected after filtration, washed with water (100 mL), and then concentrated under reduced pressure. The filtrate was adjusted to pH 7 with 2NNaOH and removed. The obtained solid was distributed in H2O (150 mL) and the pH was adjusted to 7-8 with saturated NaHCO3. The solid was collected after filtration. The obtained solid was distributed in H2O (150 mL) and the pH was adjusted to 4 with 1N HCl. The solid was collected after filtration and concentration under reduced pressure. The resultant was triturated with MeCN (100 mL) for half an hour. The solid was collected after filtration and concentration under reduced pressure. The compound 6-bromo-7-fluoro-2-methyl-10-oxo-4-oxa-1-azatricyclic [7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraene-11-carboxylic acid (19.5 g, 57.00 mmol, 99.12% yield) as a light yellow solid. 1 H NMR (DMSO-d6, 400MHz) δ9.08 (s, 1H), 7.77 (d, J = 8.8Hz, 1H), 5.03 ~ 5.01 (m, 2H), 4.75 ~ 4.72 (m, 1H), 4.54 ~ 4.51 (m, 1H), 1.47 (d, J = 6.8Hz, 3H). Preparation of 10-bromo-9-fluoro-3-methyl-5,6-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one Preparation (Step 4 of Scheme 10)

[0250] At 0 ° C, 6-bromo-7-fluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.0 5,13 ] To a solution of tridecane-5(13),6,8,11-tetraene-11-carboxylic acid (13 g, 38.00 mmol, 1 eq) in ethanol (200 mL) was added NaBH4 (21.2 g, 560.37 mmol, 14.75 eq) in portions. The mixture was stirred at 20° C. for 2 hours under N2 atmosphere. TsOH.H2O (722.81 mg, 3.80 mmol, 0.1 eq) was then added, and the mixture was stirred at 85° C. for 10 hours under N2 atmosphere. LCMS and TLC (petroleum ether:ethyl acetate=2:1, R f = 0.50) showed that about 50% of 6-bromo-7-fluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.0 5,13]Tridecane-5(13),6,8,11-tetraene-11-carboxylic acid residue, about 30% of 6-bromo-7-fluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8-triene-10-one was formed. The reaction mixture was concentrated under reduced pressure. The residue was slowly quenched with water (300 mL) at 0°C and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (50 mL×1), dried over Na2SO4, filtered and concentrated under reduced pressure. Three batches were processed and purified together. The residue was purified by flash silica gel chromatography (Biotage 220 g SepaFlash flash silica gel column, 0-69% gradient ethyl acetate / petroleum ether eluent @ 150 mL / min). The eluent was removed under reduced pressure. The compound 6-bromo-7-fluoro-2-methyl-4-oxa-1-azatricyclic [7.3.1.0 5,13 ]Tridecane-5(13),6,8-trien-10-one (22 g, 73.30 mmol, 64.30% yield) as a yellow solid. 1 H NMR(DMSO-d6,400MHz)δ7.11(d,J=7.2Hz,1H),4.31~4.27(m,2H),3.58~3.54(m, 2H),3.33~3.32(m,1H),2.73~2.70(m,1H),2.65~2.64(m,1H),1.19~1.15(m,3H). 10-Bromo-9-fluoro-3-methyl-7-oxo-3,5,6,7-tetrahydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6- Preparation of formaldehyde (Step 5 of Scheme 10)

[0251] To a mixture of NaOMe (15.44 g, 285.88 mmol, 3.9 eq) in DCM (400 mL) was added ethyl formate (21.18 g, 285.88 mmol, 22.99 mL, 3.9 eq) at 20°C. 6-Bromo-7-fluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13]Tridecane-5(13),6,8-triene-10-one (22g, 73.30mmol, 1eq). Under N2 atmosphere, the mixture was stirred at 20°C for 10 hours. LCMS and TLC (petroleum ether: ethyl acetate = 2: 1, Rf = 0.5) showed that the reaction was complete. The reaction mixture was slowly poured into ice water (300mL) at 0°C and the pH was adjusted to 6 with 0.5N HCl. The organic layer was separated and extracted with DCM (400mL×2). The combined organic layer was washed with brine (200mL×1), dried over Na2SO4, filtered and concentrated under reduced pressure. Compound 6-bromo-7-fluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8-triene-11-carbaldehyde (23 g, 70.09 mmol, 95.62% yield) as a brown solid. 1 H NMR (DMSO-d6, 400MHz) δ11.76 (s, 1H), 7.84 (m, 1H), 7.14 (d, J = 5.2Hz, 1H), 4.26~4.25 (m,1H),4.21~4.17(m,2H),3.90~3.87(m,1H),3.51~3.50(m,1H),1.21~1.15(m,3H). 10-Bromo-9-fluoro-6-((((2-methoxypyridin-4-yl)methyl)((S)-1-(6-nitropyridin-3-yl)piperidin- Preparation of 3-methyl-2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one (Step 10 of Scheme 10) Step 6)

[0252] 6-Bromo-7-fluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.0 5,13A solution of tridecane-5(13),6,8-triene-11-carbaldehyde (6.21 g, 18.93 mmol, 1.3 eq) and (3S)-N-[(2-methoxy-4-pyridyl)methyl]-1-(6-nitro-3-pyridyl)piperidin-3-amine (5 g, 14.56 mmol, 1 eq) and AcOH (1.31 g, 21.84 mmol, 1.25 mL, 1.5 eq) was stirred for 3 hours. The mixture was then cooled to 0°C and NaBH(OAc)3 (4.01 g, 18.93 mmol, 1.3 eq) was added portionwise at 0°C. The reaction mixture was stirred at 20°C for 10 hours. LCMS, HPLC and TLC (ethyl acetate:methanol=10:1, Rf=0.10) showed that (3S)-N-[(2-methoxy-4-pyridyl)methyl]-1-(6-nitro-3-pyridyl)piperidin-3-amine remained, and about 11% of 6-bromo-7-fluoro-11-[(2-methoxy-4-pyridyl)methyl-[(3S)-1-(6-nitro-3-pyridyl)-3-piperidinyl]amino]methyl]-2-methyl-4-oxo- ...2-methoxy-4-pyridyl)methyl- 1-azatricyclo[7.3.1.05,13]tridecane-5(13),6,8-triene-10-one and about 10% of 6-bromo-7-fluoro-11-[(2-methoxy-4-pyridinyl)methyl-[(3S)-1-(6-nitro-3-pyridinyl)-3-piperidinyl]amino]methyl]-2-methyl-4-oxa-1-azatricyclo[7.3.1.05,13]tridecane-5(13),6,8,11-tetraene-10-one. The mixture was quenched with ice water (50 mL) at 0°C and the pH was adjusted to 8 with saturated NaHCO3. The mixture was extracted with DCM and i-PrOH (volume to volume = 3:1, 50 mL×2). The combined organic layers were washed with brine (30 mL×1), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification was performed by preparative HPLC (column: Xtimate C18 10 μm 250 mm × 80 mm; mobile phase: [column: Xtimate C18 10 μm 250 mm * 80 mm; mobile phase: [water (NH4HCO3)-MeCN]; B%: 45%-85%, 34 minutes). The eluent was removed under reduced pressure. Compound 6-bromo-7-fluoro-11-[[(2-methoxy-4-pyridinyl)methyl-[(3S)-1-(6-nitro-3-pyridinyl)-3-piperidinyl]amino]methyl]-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13]Tridecane-5(13),6,8-triene-10-one (2.5 g, 3.81 mmol, 26.19% yield) was obtained as an orange solid. The compound 6-bromo-7-fluoro-11-[[(2-methoxy-4-pyridinyl)methyl-[(3S)-1-(6-nitro-3-pyridinyl)-3-piperidinyl]amino]methyl]-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (0.45 g, 688.60 umol, 4.73% yield) was obtained as an orange solid. 2 g of (3S)-N-[(2-methoxy-4-pyridyl)methyl]-1-(6-nitro-3-pyridyl)piperidin-3-amine was also obtained as a yellow solid. 6-Bromo-7-fluoro-11-[(2-methoxy-4-pyridyl)methyl-[(3S)-1-(6-nitro-3-pyridyl)-3-piperidinyl]amino]methyl]-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (0.45 g, 688.60 umol, 4.73% yield) as an orange solid. 1 H NMR(DMSO-d6,400MHz)δ8.26~8.25(m,1H),8.11~8.08(m,2H),8.01~7.99(m,1H),7.51 ~7.48(m,2H),7.03~7.02(m,1H),6.87(d,J=10.0Hz,1H),4.61~4.21(m,5H),3.85~3.83 (m,1H),3.76(s,3H),3.73~3.57(m,3H),3.31~3.17(m,1H),2.98~2.96(m,1H),2.68~2. 67(m,1H),1.77~1.75(m,1H),1.74~1.73(m,1H),1.43~1.37(m,1H),1.34~1.16(m,4H). 6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl)((2-methoxypyridin-4-yl)methyl)amino) Preparation of 1-methyl)-10-bromo-9-fluoro-3-methyl-2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one (Scheme 10) Step 7)

[0253] A mixture of 6-bromo-7-fluoro-11-[[(2-methoxy-4-pyridinyl)methyl-[(3S)-1-(6-nitro-3-pyridinyl)-3-piperidinyl]amino]methyl]-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13]Tridecane-5(13),6,8,11-tetraen-10-one (0.65 g, 994.65 umol, 1 eq) and PtO2 (53.14 mg, 198.93 umol, purity 85%, 0.2 eq) were stirred for 1 hour. The mixture was then stirred at 20°C under H2 (14.6 psi) for 1.5 hours. LCMS and HPLC, TLC (ethyl acetate: methanol = 5: 1, R f =0.1) showed that the reaction was complete. The mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography ( 12g Flash silica gel column, 0-18% gradient methanol / ethyl acetate eluent @ 40 mL / min). The eluent was removed under reduced pressure. Compound 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6-bromo-7-fluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (0.51 g, 817.94 umol, yield 82.23%). 1 H NMR(DMSO-d6,400MHz)δ8.08(d,J=7.2Hz,1H),7.99(d,J=5.6Hz,1H),7.61(d,J=3.2Hz,1H),7.51(dd,J=2.4Hz,9.2Hz,1H),7.1 4~7.13(m,1H),7.01~6.99(m,1H),6.82~6.81(m,1H),6.39~6.36(m,1H),5.38(s,2H),4.71~4.68(m,1H),4.61~4.59(m,1H),4.4 4~4.41(m,1H),3.76(s,3H),3.75~3.59(m,5H),3.32~3.19(m,1H),2.70~2.67(m,1H),2.61~2.56(m,1H),2.50~2.41(m,1H),1. 99~1.91(m,1H),1.75~1.74(m,1H),1.49~1.44(m,2H),1.35~1.32(m,3H).LCMS:92.04%(220nm),93.43%(254nm).MS(ESI):mass calcd.For C 30 H 32 BrFN6O3622.17m / z found 623.3[M+H] + . Preparation of compounds in Scheme 10 (Step 8 of Scheme 10)

[0254] Method A: To a mixture of DMF (10 mL / mmol to 13 mL / mmol) and H2O (1 mL / mmol to 1.3 mL / mmol) was added 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6-bromo-7-fluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraene-10-one (80.19 umol, 1 eq) was added with different boric acids or boric acid esters (120.28 umol to 240.57 umol, 1.5 eq to 3 eq) and Pd(PPh3)4 (8.02 umol, 0.1 eq) and NaHCO3 (320.76 umol, 4 eq). The reaction mixture was degassed and purged with N2 three times. The mixture was then stirred at 130°C under a microwave and N2 atmosphere for 20 minutes to half an hour. The reaction mixture was cooled to room temperature and filtered through a celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex C18 75*30mm*3um or Waters Xbridge Prep OBD C18 150*40mm*10um or Waters Xbridge BEHC18 100*30mm*10um; mobile phase: [water (NH4HCO3)-MeCN]; B%: 20%-65%, 8 minutes). The eluent was removed by freeze drying to obtain the desired product.

[0255] Method B: different boronic acids or boronic esters (48.11umol~96.22umol, 1.5eq~3.0eq), 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6-bromo-7-fluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13]A mixture of tridecane-5(13),6,8,11-tetraen-10-one (32.08umol, 1eq) or Pd(dppf)Cl2 (1.60umol~3.20umol, 0.05eq~0.1eq), Na2CO3 (96.23umol, 3eq), K2CO3 (96.23umol, 3eq) in dioxane (3mL / mmol~10mL / mmol) and H2O (0.3mL / mmol~1.0mL / mmol) was degassed and purged with N2 3 times, and then the mixture was stirred at 80℃~90℃ under N2 atmosphere for 3 hours to 4 hours. LC-MS and HPLC showed about 15% of 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6-bromo-7-fluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (20 mg, 32.08 μmol, 1 eq) remained, and about 32% of the desired product was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex C18 75*30 mm*3 μm or Waters Xbridge Prep OBD C18 150*40 mm*10 μm or Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (NH4HCO3)-MeCN]; B%: 20%-65%, 8 minutes). Method C: To 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6-bromo-7-fluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ] To a solution of tridecane-5(13),6,8,11-tetraene-10-one (320.76umol, 1eq) in toluene (10mL) were added Pd(OAc)2 (16.04umol, 0.05eq) and Xantphos (32.08umol, 0.1eq) and t-BuONa (641.52umol, 2eq). The mixture was stirred at 120°C for 2 hours. The reaction mixture was filtered through a celite pad and the filter cake was washed with MeOH (10mL×3). The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C 18150*40mm*10um; mobile phase: [water (NH4HCO3)-MeCN]; B%: 25%-45%, 8 minutes). The solvent was removed by freeze drying to obtain the desired product. Compound 56 6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl)((2-methoxypyridin-4-yl)methyl)amino) Preparation of 9-fluoro-3-methyl-10-(pyridin-4-yl)-2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one (Step 8 of Solution 10)

[0256] To a mixture of DMF (1 mL) and H2O (0.1 mL) was added 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6-bromo-7-fluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ] Tridecane-5 (13), 6,8,11-tetraene-10-one (50 mg, 80.19 umol, 1 eq) was added 4-pyridine boronic acid (29.57 mg, 240.57 umol, 3 eq) and Pd (PPh 3 ) 4 (9.27 mg, 8.02 umol, 0.1 eq) and NaHCO 3 (26.95 mg, 320.76 umol, 12.48 uL, 4 eq). The reaction mixture was degassed and purged with N 2 3 times. Then, under microwave and N 2 atmosphere, the mixture was stirred at 130 ℃ for half an hour. LCMS and HPLC showed that the reaction was complete. The reaction mixture was cooled to room temperature and filtered through a celite pad. The filtrate was concentrated under reduced pressure. Purification was performed by preparative HPLC (column: Waters Xbridge Prep OBD C18150*40mm*10um; mobile phase: [water (NH4HCO3)-MeCN]; B%: 25%-50%, 8 minutes). The eluent was removed by freeze drying. Compound 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-7-fluoro-2-methyl-6-(4-pyridinyl)-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (16.2 mg, 25.89 umol, 32.29% yield, 99.36% purity) was obtained as a white solid. 1H NMR(DMSO-d6,400MHz)δ8.71(d,J=6.0Hz,2H),8.09(d,J=8.0Hz,1H),8.01(d,J=5.2Hz,1H),7.61(d,J=2.8Hz,1H),7.52~7.50(m,3 H),7.16~7.14(m,1H),7.02~7.00(m,1H),6.83(s,1H),6.39~6.36(m,1H),5.37(s,2H),4.68~4.66(m,1H),4.44~4.42(m,1H),4.36~ 4.33(m,1H),3.77(s,3H),3.74~3.36(m,5H),3.24~3.19(m,1H),2.77~2.67(m,1H),2.63~2.60(m,1H),2.45~2.42(m,1H),1.99~1.9 1(m,1H),1.79~1.74(m,1H),1.48~1.45(m,2H),1.35~1.32(m,3H).LCMS:99.36%(220nm),99.57%(254nm).MS(ESI):masscalcd.For C 35 H 36 FN7O3621.29m / z found 622.4[M+H] + . Compound 57 6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl ...6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl)-1-(6-aminopyridin-3- ((2-methoxypyridin-4-yl)methyl)amino)methyl)-9-fluoro-3,10-dimethyl-2H-[1,4]oxazino[2,3,4-ij] Quinolin-7(3H)-one

[0257] Method A: Obtain 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-7-fluoro-2,6-dimethyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (5.9 mg, 10.16 umol, 12.67% yield, 96.21% purity) was obtained as a white solid. 1H NMR(DMSO-d6,400MHz)δ8.02~7.98(m,2H),7.60(d,J=2.8Hz,1H),7.35(dd,J=2.4Hz,10.0Hz,1H),7.15~7.13(m,1H),6.99~6.98(m,1H),6.8 1(s,1H),6.37(dd,J=3.6Hz,8.8Hz,1H),5.37(s,2H),4.63~4.61(m,1H),4.51~4.48(m,1H),4.32~4.29(m,1H),3.75(s,3H),3.71~3.65(m,2H) ),3.63~3.54(m,2H),3.51~3.48(m,1H),3.23~3.21(m,1H),2.77~2.73 (m,1H),2.60~2.55(m,1H),2.43~2.37(m,1H),2.21(d,J=1.6Hz,3H),1 .98~1.95(m,1H),1.76~1.73(m,1H),1.49~1.38(m,2H),1.30(dd,J=4.8Hz,6.8Hz,3H).LCMS:96.21%(220nm),98.51%(254nm).MS(ESI):mass calcd.For C 31 H 35 FN6O3558.28m / z found559.4[M+H] + . Compound 58 6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl ...6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl)-1-(6-aminopyridin-3- ((2-methoxypyridin-4-yl)methyl)amino)-10-(3,6-dihydro-2H-thiopyran-4-yl)-9-fluoro-3-methyl-2H-[1, 4]Oxazino[2,3,4-ij]quinolin-7(3H)-one

[0258] Method A: Obtain 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6-(3,6-dihydro-2H-thiopyran-4-yl)-7-fluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (2 mg, 3.08 umol, 35.61% yield, 98.94% purity) was obtained as an off-white solid. 1H NMR(DMSO-d6,400MHz)δ8.04(d,J=2.8Hz,1H),8.00(d,J=2.8Hz,1H),7.61(d,J=2 .8Hz,1H),7.38(dd,J=2.4Hz,10.0Hz,1H),7.16~7.12(m,1H),7.00~6.99(m,1H), 6.81(s,1H),6.37(dd,J=3.6Hz,8.8Hz,1H),5.92(s,1H),5.36(d,J=2.8Hz,2H),4 .63~4.60(m,1H),4.47~4.44(m,1H),4.30~4.27(m,1H),3.75(s,3H),3.72~3.66( m,2H),3.63~3.57(m,2H),3.51~3.48(m,1H),3.33~3.30(m,2H),3.24~3.21(m,1H ),2.82(t,J=5.6Hz,2H),2.79~2.72(m,1H),2.61~2.56(m,1H),2.46~2.44(m,2H) ,2.41~2.37(m,1H),2.01~1.93(m,1H),1.77~1.74(m,1H),1.53~1.38(m,2H),1.3 1(dd,J=4.8Hz,6.4Hz,3H).LCMS:98.94%(220nm),98.22%(254nm).MS(ESI):mass calcd.ForC 35 H 39 FN6O3S 642.28m / z found 643.4[M+H] + . Compound 59 6-((((S)-1-(6-Aminopyridin-3-yl)piperidin-3-yl)piperidin-6-yl)piperidin-1-yl)piperidin-1-yl)piperidin-2-yl)piperidin-3 ... pyridin-3-yl)((2-methoxypyridin-4-yl)methyl)amino)methyl)-10-(1-cyclopropyl-1,2,3,6-tetrahydropyridine-4- 1-Hydroxy-9-fluoro-3-methyl-2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one

[0259] Method B: Obtain 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6-(1-cyclopropyl-3,6-dihydro-2H-pyridin-4-yl)-7-fluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (2.4 mg, 3.50 umol, 10.90% yield, 97% purity) was obtained as a light yellow solid. 1H NMR(DMSO-d6,400MHz)δ8.05~8.00(m,2H),7.62(s,1H),7.38(dd,J=2.4Hz,10.0Hz,1H),7.16~7.14(m,1H),7.01~7.00(s,1H),6.82(s,1H),6.39 ~6.37(m,1H),5.75(s,1H),5.38~5.34(m,2H),4.63~4.61(m,1H),4.47(d ,J=10.8Hz,1H),4.29(d,J=10.0Hz,1H),3.77(s,3H),3.72~3.49(m,5H), 3.23~3.22(m,3H),2.81(t,J=5.2Hz,2H),2.76~2.73(m,1H),2.60~2.59 (m,1H),2.42~2.41(m,1H),2.32~2.31(m,2H),1.98~1.96(m,1H),1.77~1 .75(m,2H),1.50~1.42(m,2H),1.31(t,J=6.0Hz,3H),0.47~0.46(m,2H),0.40~0.39(m,2H).LCMS:97.00%(220nm),98.43%(254nm).MS(ESI):mass calcd.For C 38 H 44 FN7O3665.35m / z found666.5[M+H] + . Compound 60 6-((((S)-1-(6-Aminopyridin-3-yl)piperidin-3-yl)piperidin-6-yl)piperidin-1-yl)piperidin-1-yl)piperidin-2-yl)piperidin-3 ... pyridin-3-yl)((2-methoxypyridin-4-yl)methyl)amino)methyl)-9-fluoro-3-methyl-10-(2-oxopiperidin-1-yl)- 2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one

[0260] Method C: Compound 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-7-fluoro-2-methyl-6-[(1S)-2-oxo-1-piperidinyl]-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (23.1 mg, 35.83 umol, 22.34% yield, 99.53% purity) was obtained as an off-white solid. 1H NMR(DMSO-d6,400MHz)δ8.08(d,J=8.0Hz,1H),8.01(d,J=5.2Hz,1H),7.61(d,J=2.4Hz,1H),7.45(d,J=10.4Hz,1H),7.14~7.11(m,1H),7.01~6.99(m ,1H),6.83(d,J=3.2Hz,1H),6.36(t,J=9.2Hz,1H),5.37~5.35(m,2H),4.6 7~4.66(m,1H),4.52~4.50(m,1H),4.38~4.35(m,1H),3.77(s,3H),3.72~3. 67(m,2H),3.64~3.56(m,3H),3.51~3.48(m,1H),3.43~3.37(m,1H),3.25~ 3.21(m,1H),2.78~2.75(m,1H),2.62~2.59(m,1H),2.45~2.42(m,3H),1.9 8~1.96(m,1H),1.88~1.87(m,4H),1.78~1.74(m,1H),1.46~1.44(m,2H),1 .29(d,J=5.6Hz,3H).LCMS:99.53%(220nm),98.64%(254nm).MS(ESI):mass calcd.For C 35 H 40 FN7O4641.31m / z found642.5[M+H] + . Compound 61 6-((((S)-1-(6-Aminopyridin-3-yl)piperidin-3-yl)piperidin-6-yl)piperidin-1-yl)piperidin-1-yl)piperidin-2-yl)piperidin-3 ... pyridin-3-yl)((2-methoxypyridin-4-yl)methyl)amino)methyl)-9-fluoro-3-methyl-10-(2-oxopiperidin-1-yl)- 2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one

[0261] Method C: Compound 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-7-fluoro-2-methyl-6-[(1S)-2-oxo-1-piperidinyl]-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (23 mg, 35.56 umol, yield 22.17%, purity 99.22%), as a light yellow solid. 1H NMR(DMSO-d6,400MHz)δ8.09(s,1H),8.01(d,J=4.8Hz,1H),7.61(s,1H),7.46(d,J=10.0Hz,1H),7.15(dd,J=2.4Hz,8.4Hz,1H),7.01~7.00(m,1H), 6.83(s,1H),6.37(d,J=8.4Hz,1H),5.37(s,2H),4.66~4.64(m,1H),4.51 ~4.48(m,1H),4.29~4.27(m,1H),3.77(s,3H),3.72~3.70(m,2H),3.66~3. 62(m,1H),3.60~3.56(m,2H),3.56~3.48(m,1H),3.43~3.40(m,2H),3.24 ~3.21(m,1H),2.77~2.71(m,1H),2.57~2.56(m,1H),2.45~2.42(m,3H),1. 98~1.96(m,1H),1.88~1.86(m,4H),1.76~1.74(m,1H),1.50~1.39(m,2H) ,1.33~1.29(m,3H).LCMS:99.22%(220nm),98.36%(254nm).MS(ESI):mass calcd.For C 35 H 40 FN7O4641.31m / z found642.5[M+H] + . Compound 62 6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl)((2-methoxypyridin-4-yl)methyl)amino) Preparation of 1,4-oxazino[2,3,4-ij]quinolin-7(3H)-one (methoxy)-10-(benzyloxy)-9-fluoro-3-methyl-2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one (methoxy)-1,4-oxazino[2,3,4-ij]quinolin-7(3H)-one Step 9 of Case 10)

[0262] To a solution of BnOH (76.88 mg, 710.97 μmol, 73.93 μL, 2 eq) in NMP (1 mL) was added NaH (28.44 mg, 710.97 μmol, 60% purity, 2 eq) at 0°C. The mixture was stirred at 0°C for half an hour. 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6,7-difluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13] A solution of tridecane-5(13),6,8,11-tetraene-10-one (0.2 g, 355.49 umol, 1 eq) in NMP (2 mL). The reaction mixture was stirred at 0 ° C for 1 hour. LCMS and HPLC showed that the reaction was complete. The reaction mixture was quenched by slowly adding ice water (5 mL) at 0 ° C, and then extracted with EtOAc (10 mL × 2). The combined organic layer was washed with brine (5 ml × 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex C18 75*30mm*3um; mobile phase: [water (NH4HCO3)-MeCN]; B%: 35%-65%, 8 minutes). The eluate was dried by freeze drying. Compound 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6-benzyloxy-7-fluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (3.8 mg, 5.62 umol, 1.58% yield, 96.25% purity) was obtained as a light yellow solid. 1 H NMR(DMSO-d6,400MHz)δ8.01~7.98(m,2H),7.61(d,J=2.8Hz,1H),7.44~7.42(m,2H),7.40~7.30(m,4H),7.16~7.12(m,1H),7.00~6.99(m,1H),6 .82(s,1H),6.37(dd,J=2.8Hz,8.8Hz,1H),5.37(d,J=3.2Hz,2H),5.21( s,2H),4.64~4.62(m,1H),4.51~4.48(m,1H),4.28~4.25(m,1H),3.89~3. 79(m,1H),3.76(s,3H),3.71~3.70(m,1H),3.66~3.57(m,2H),3.54~3.4 8(m,1H),3.24~3.21(m,1H),2.77~2.71(m,1H),2.60~2.55(m,1H),2.43 ~2.37(m,1H),1.98~1.95(m,1H),1.77~1.74(m,1H),1.53~1.38(m,2H),1.31~1.29(m,3H).LCMS:96.25%(220nm),96.50%(254nm).MS(ESI):mass calcd.For C 37 H 39FN6O4650.30m / z found 651.5[M+H] + . Compound 63 6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl)((2-methoxypyridin-4-yl)methyl)amino) Preparation of 2-(3H)-1-methyl)-9-fluoro-10-hydroxy-3-methyl-2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one (Scheme 10 Step 10)

[0263] To 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6-benzyloxy-7-fluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ] To a solution of tridecane-5(13),6,8,11-tetraene-10-one (80 mg, 122.94 umol, 1 eq) was added Pd / C (10 mg, purity 10%). The suspension was degassed under vacuum and purged with H2 several times. The reaction mixture was stirred under H2 (15 psi) at 20°C for 3 hours. LCMS and HPLC showed 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6-benzyloxy-7-fluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one was almost consumed, and a main peak with the desired mass was detected. The reaction mixture was filtered through a celite pad, and the filter cake was washed with MeOH (50 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex C18 75*30mm*3um; mobile phase: [water (NH4HCO3)-MeCN]; B%: 10%-40%, 8 minutes). The eluate was dried by freeze drying. Compound 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-7-fluoro-6-hydroxy-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (8.5 mg, 15.05 umol, 12.24% yield, 99.25% purity) was obtained as a white solid. 11H NMR (DMSO-d6, 400 MHz) δ 10.30~10.22 (m, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.94 (d, J = 2.4 Hz, 1H), 7.60 (d, J = 2.8 Hz, 1H), 7.36 (dd, J = 3.6 Hz, 8.8 Hz, 1H), 7.16~7.12 (m, 1H), 7.00 (d, J = 4.8 Hz, 1H), 6.82 (s, 1H), 6.37 (dd, J = 3.6 Hz, 8.8 Hz, 1H), 5.36 (d, J = 2.8 Hz, 2H), 4.60~4.58 (m, 1H), 4.44 (d, J = 10.0 Hz, 1H), 4.25 (d, J = 10.8 Hz, 1H), 3.​​​​​​​​​​​​​​​A mixture of tert-butyl-[2-(6-chloro-3-pyridyl)ethoxy]-dimethylsilane (0.5 g, 1.84 mmol, 1 eq), trimethyl(trimethylstannyl)stannane (0.99 g, 3.02 mmol, 626.58 uL, 1.64 eq) and Pd(PPh 3 ) 4 (212.53 mg, 183.92 umol, 0.1 eq) in dioxane (5 mL) was degassed and purged with N 2 three times, and then the mixture was stirred at 90° C. under a N 2 atmosphere for 10 hours. LCMS showed approximately 18% of tert-butyl-[2-(6-chloro-3-pyridyl)ethoxy]-dimethylsilane remaining. LCMS showed several new peaks and approximately 31% of the desired compound was detected. The reaction mixture was filtered through a pad of celite and the filter cake was washed with EtOAc (10 mL). Water (40 mL) was added to the filtrate and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography ( 12g The reaction mixture was purified by flash silica gel column with a gradient elution of 0-10% petroleum ether / ethyl acetate at 40 mL / min. The eluent was removed under reduced pressure to obtain tert-butyl-dimethyl-[2-(6-trimethylstannyl-3-pyridyl)ethoxy]silane (0.4 g, crude product) as a yellow oil. 1 H NMR(DMSO-d6,400MHz)δ8.60~8.61(m,1H),7.56~7.53(m,1H),7.25~7.23(m,1H) ),3.83~3.80(m,2H),2.83~2.77(m,2H),0.86(s,18H),-0.03(t,J=6.4Hz,6H). 6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl)((2-methoxypyridin-4-yl)methyl)amino) methyl)-10-(5-(2-((tert-butyldimethylsilyl)oxy)ethyl)pyridin-2-yl)-9-fluoro-3-methyl-2H-[1, 4] Preparation of oxazino[2,3,4-ij]quinolin-7(3H)-one (Step 12 of Scheme 10)

[0265] Tert-butyl-dimethyl-[2-(6-trimethyltin-3-pyridyl)ethoxy]silane (96.28 mg, 240.57 umol, 5 eq) and 11-[[[(3S)-1-(6-amino-3-pyridyl)-3-piperidyl]-[(2-methoxy-4-pyridyl)methyl]amino]methyl]-6-bromo-7-fluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13A mixture of tridecane-5(13),6,8,11-tetraen-10-one (30 mg, 48.11 umol, 1 eq) and Pd(PPh3)4 (1.67 mg, 1.44 umol, 0.03 eq) in dioxane (0.5 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 90°C for 11 hours under N2 atmosphere. LC-MS and HPLC showed that the residual 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6-bromo-7-fluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one. LCMS showed several new peaks, and a small peak with the desired mass was detected. The mixture was concentrated under reduced pressure. Purification was performed by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH4HCO3)-MeCN]; B%: 60%-90%, 8 minutes). The eluate was concentrated under reduced pressure. The residue was further purified by preparative TLC (silica, ethyl acetate: methanol = 8:1). Compound 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6-[5-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-2-pyridinyl]-7-fluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (8 mg, crude product) as a yellow solid. MS (ESI): mass calcd.For C 43 H 54 FN7O4Si779.40m / z found 780.1[M+H] + . 6-((((S)-1-(6-aminopyridin-3-yl)piperidin-3-yl)((2-methoxypyridin-4-yl)methyl)amino)- 9-Fluoro-10-(5-(2-hydroxyethyl)pyridin-2-yl)-3-methyl-2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one Preparation of (Scheme 10, Step 13)

[0266] To 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-6-[5-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-2-pyridinyl]-7-fluoro-2-methyl-4-oxa-1-azatricyclo[7.3.1.0 5,13] To a solution of tridecane-5(13),6,8,11-tetraen-10-one (8 mg, 10.26 μmol, 1 eq) was added HCl / MeOH (4 M, 1 mL). The mixture was stirred at 20°C for 1 hour. TLC (ethyl acetate: methanol = 0:1, R f =0) showed that the reaction was complete. The mixture was concentrated under reduced pressure. Water (2 mL) was added to the residue, and the pH was adjusted to 7 with saturated NaHCO3. The mixture was extracted with ethyl acetate (7 mL×3). The combined organic layer was washed with brine (7 mL×1), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (silica, ethyl acetate: methanol = 0: 1). Compound 11-[[[(3S)-1-(6-amino-3-pyridinyl)-3-piperidinyl]-[(2-methoxy-4-pyridinyl)methyl]amino]methyl]-7-fluoro-6-[5-(2-hydroxyethyl)-2-pyridinyl]-2-methyl-4-oxa-1-azatricyclic [7.3.1.0 5,13 ]Tridecane-5(13),6,8,11-tetraen-10-one (2.1 mg, 2.97 umol, yield 28.95%, purity 94.13%), as a white solid. 1 H NMR (DMSO-d6, 400MHz) δ8.56~8.54(m,1H),8.10~8.08(m,1H),8.01(d,J=5.2Hz,1H),7.77(dd,J=2.4,8.0Hz,1H),7.62~7.61(m,1H),7.49~7.45(m ,2H),7.17~7.14(m,1H),7.02~7.00(m,1H),6.84~6.83(m,1H),6.39~6.3 6(m,1H),5.39~5.36(m,2H),4.70~4.64(m,1H),4.40~4.37(m,1H),4.31~4 .28(m,1H),3.77(s,3H),3.74~3.51(m,6H),3.36~3.35(m,2H),3.26~3.2 1(m,1H),2.80(t,J=6.8Hz,2H),2.75~2.72(m,1H),2.64~2.56(m,1H),2. 45~2.41(m,1H),2.01~1.97(m,1H),1.79~1.75(m,1H),1.51~1.41(m,2H) ,1.33~1.31(m,3H).LCMS:94.13%(220nm),99.21%(254nm).MS(ESI):mass calcd.For C 37 H 40FN7O4665.31m / z found666.5[M+H] + . Plan 11 General procedures for preparing compounds in Scheme 11 Preparation of 3-[(2-bromoethyl)oxy]-1,2-difluoro-4-nitrobenzene (Step 1 of Scheme 11)

[0267] To a mixture of 2,3-difluoro-6-nitrophenol (5 g, 28.57 mmol) and KCO (11.85 g, 85.71 mmol) in DMF (50 mL) was added BrCHCHBr (15 mL, 171.34 mmol). The reaction mixture was stirred at 100°C for 3 hours. TLC (PE:EA=10:1) indicated the reaction was complete. The reaction mixture was cooled to 25°C and poured into HO. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (SiO, PE:EA=25:1) to give 3-[(2-bromoethyl)oxy]-1,2-difluoro-4-nitrobenzene (3.90 g, 38.75%) as a yellow oil. 1 H NMR (DMSO-d6, 400MHz) δ: 7.88-7.95 (m, 1H), 7.40-7.53 (m, 1H), 4.58 (t, J = 5.4Hz, 2H), 3.79 (t, J = 5.4Hz, 2H). Preparation of 2-[(2-bromoethyl)oxy]-3,4-difluoroaniline (Step 2 of Scheme 11)

[0268] To a solution of 3-[(2-bromoethyl)oxy]-1,2-difluoro-4-nitrobenzene (3.0 g, 10.68 mmol) in MeOH (15 mL) was added Pd / C (0.60 g) under a hydrogen atmosphere. The reaction mixture was stirred at room temperature for 3 hours. LC-MS showed that 3-[(2-bromoethyl)oxy]-1,2-difluoro-4-nitrobenzene was consumed, and a major peak with the desired mass was detected. The reaction mixture was filtered. The filtrate was diluted with MeOH (30 mL). The organic layer was concentrated in vacuo. The residue was diluted with DCM (20 mL). The mixture was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (SiO2, PE:EA=15:1) to give 2-[(2-bromoethyl)oxy]-3,4-difluoroaniline (1.87 g, 70%) as a brown oil. MS(ESI):mass calcd.ForC8H8BrF2NO 250.98m / z found251.9[M+H]+ . Preparation of 7,8-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (Scheme 11, Step 3)

[0269] To a solution of 2-[(2-bromoethyl)oxy]-3,4-difluoroaniline (500 mg, 1.98 mmol) in DMF (3 mL) was added potassium carbonate (822.42 mg, 5.95 mmol). The reaction mixture was stirred at 100°C for 1 hour. LC-MS showed that 2-[(2-bromoethyl)oxy]-3,4-difluoroaniline was consumed and a major peak with the desired mass was detected. The reaction mixture was cooled to 25°C and poured into ice water. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to afford 7,8-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (270 mg, 79.4%) as a brown solid. MS (ESI): mass calcd. For C8H7F2NO 171.15 m / z found 172.1 [M+H] + . Preparation of ethyl 9,10-difluoro-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate Preparation (Step 4 of Scheme 11)

[0270] A mixture of 7,8-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (364 mg, 2.13 mmol) and EMME (0.43 mL, 2.13 mmol) was stirred at 135° C. for 2 hours. PPE (2.0 grams) was added to the mixture. The reaction mixture was stirred at 145° C. for 1.5 hours. LCMS showed that the reaction was complete. The reaction mixture was cooled to 25° C. and poured into ice water. The mixture was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give ethyl 9,10-difluoro-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate (430 mg, 68.47%) as a yellow solid. MS (ESI): mass calcd. For C 14 H 11 F2NO4295.07m / z found296.0[M+H] + . Preparation of 9,10-difluoro-7-oxo-2,3-dihydro[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid (Scheme Step 5 of 11)

[0271] To a solution of ethyl 9,10-difluoro-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate (430 mg, 1.46 mmol) in THF / MeOH / H2O (3 mL / 0.4 mL / 1.5 mL) was added NaOH (120 mg, 3 mmol). The reaction mixture was stirred at 60°C for 30 minutes. LC-MS showed that ethyl 9,10-difluoro-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate was consumed. The reaction mixture was cooled to 25°C and poured into H2O. The mixture was adjusted to pH = 6 with 2N HCl. The mixture was filtered. The filter cake was dried to give 9,10-difluoro-7-oxo-2,3-dihydro[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid (267 mg, 68.6%) as a yellow solid. MS (ESI): mass calcd. For C 12 H7F2NO4267.03m / z found268.0[M+H] + . Preparation of 9,10-difluoro-3,5,6,7-tetrahydro-2H-[1,4]oxazino[2,3,4-ij]quinolin-7-one (Scheme 11) Step 6)

[0272] To a solution of 9,10-difluoro-7-oxo-2,3-dihydro[1,4]oxazino[2,3,4-1]quinoline-6-carboxylic acid (217 mg, 0.81 mmol) in MeOH (1 mL) was added NaBH4 (122.90 mg, 3.25 mmol) in portions at 0°C under N2. The reaction mixture was stirred at 25°C for 1 hour. TsOH (3.09 mg, 0.02 mmol) was added to the reaction mixture. The reaction mixture was stirred at 62°C overnight. LC-MS showed that 9,10-difluoro-7-oxo-2,3-dihydro[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid was consumed. The reaction mixture was cooled to 25°C and poured into ice water. The mixture was adjusted to pH = 7 with 2N HCl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2, PE:EA=3:1) to give 9,10-difluoro-3,5,6,7-tetrahydro-2H-[1,4]oxazino[2,3,4-ij]quinolin-7-one (128 mg, 69.9%) as a yellow solid. MS (ESI): mass calcd. For C 11 H9F2NO2225.06m / zfound226.0[M+H] + . Preparation of 9,10-difluoro-7-oxo-2,3,6,7-tetrahydro-5H-[1,4]oxazino[2,3,4-ij]quinoline-6-carbaldehyde Preparation (Step 7 of Scheme 11)

[0273] To a mixture of 9,10-difluoro-3,5,6,7-tetrahydro-2H-[1,4]oxazino[2,3,4-ij]quinolin-7-one (1.79 g, 7.96 mmol) and MeONa (2.6 mL, 30.23 mmol) in DCM (10 mL) was added HCO₂Et (168.43 mg, 31.82 mmol). The reaction mixture was stirred at 25° C. for 1 minute. LC-MS showed that 9,10-difluoro-3,5,6,7-tetrahydro-2H-[1,4]oxazino[2,3,4-ij]quinolin-7-one was consumed. The reaction mixture was poured into ice water. The reaction mixture was adjusted to pH 6 with 2N HCl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 9,10-difluoro-7-oxo-2,3,6,7-tetrahydro-5H-[1,4]oxazino[2,3,4-ij]quinoline-6-carbaldehyde (1.965 g, 97.6%) as a yellow solid. MS (ESI): mass calcd. For C 12 H9F2NO3253.06m / z found254.0[M+H] + . Preparation of 9,10-difluoro-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carbaldehyde (Step 8 of Solution 11)

[0274] To a solution of 9,10-difluoro-7-oxo-2,3,6,7-tetrahydro-5H-[1,4]oxazino[2,3,4-ij]quinoline-6-carbaldehyde (1.965 g, 7.77 mmol) in MeOH (10 mL) was added MnO (1.012 g, 11.65 mmol). The reaction mixture was stirred at 25° C. overnight. LC-MS showed that 9,10-difluoro-7-oxo-2,3,6,7-tetrahydro-5H-[1,4]oxazino[2,3,4-ij]quinoline-6-carbaldehyde was consumed. The reaction mixture was diluted with DCM / MeOH, filtered and concentrated. The crude product was purified by column chromatography (SiO2, DCM: MeOH = 10: 1) to give 9,10-difluoro-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carbaldehyde (1.008 g, 51.7%) as a yellow solid. MS (ESI): mass calcd. For C 12 H7F2NO3251.04m / zfound252.0[M+H] + . (S)-9,10-difluoro-6-(((1-(6-nitropyridin-3-yl)piperidin-3-yl)amino)methyl)-2,3-dihydro- Preparation of 7H-[1,4]oxazino[2,3,4-ij]quinolin-7-one (Scheme 11, Step 9)

[0275] To a mixture of 9,10-difluoro-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carbaldehyde (300 mg, 1.20 mmol) and NaOAc (98 mg, 1.20 mmol) in DCM / MeOH (3 mL / 3 mL) was added (S)-1-(6-nitropyridin-3-yl)piperidin-3-amine (265 mg, 1.20 mmol). The reaction mixture was stirred at 25° C. for 1 hour. NaBH3CN (300 mg, 4.78 mmol) was added portionwise to the reaction mixture at 0° C. The reaction mixture was stirred at 25° C. for 2 hours. LC-MS showed that 9,10-difluoro-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carbaldehyde was consumed. The reaction mixture was poured into ice water. The mixture was then extracted with DCM / MeOH. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (SiO2, DCM:MeOH=20:1) to give (S)-9,10-difluoro-6-(((1-(6-nitropyridin-3-yl)piperidin-3-yl)amino)methyl)-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinolin-7-one (546 mg, 99.6%) as a yellow solid. MS (ESI): mass calcd. For C 22 H 21 F2N5O4457.16m / z found458.1[M+H] + . Compound 65 (S)-9,10-difluoro-6-((((2-methoxypyridin-4-yl)methyl)(1-(6-nitropyridin-3-yl)piperidin- Preparation of 3-(3-yl)amino)methyl)-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinolin-7-one (Step 11 of Scheme 11) 10)

[0276] To a solution of (S)-9,10-difluoro-6-(((6-nitropyridin-3-yl)piperidin-3-yl)amino)methyl)-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinolin-7-one (379 mg, 0.83 mmol) in DCE (4 mL) was added 2-methoxyisonicotinaldehyde (341 mg, 2.49 mmol). The reaction mixture was stirred at 25° C. for 1 hour. NaBH(AcO) (527 mg, 2.49 mmol) was added portionwise to the mixture at 0° C. The reaction mixture was stirred at 25° C. for 2 hours. LC-MS showed that (S)-9,10-difluoro-6-(((1-(6-nitropyridin-3-yl)piperidin-3-yl)amino)methyl)-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinolin-7-one was consumed. The reaction mixture was poured into ice water and extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (SiO2, DCM:MeOH=15:1) to give (S)-9,10-difluoro-6-((((2-methoxypyridin-4-yl)methyl)(1-(6-nitropyridin-3-yl)piperidin-3-yl)amino)methyl)-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinolin-7-one (365 mg, 76.2%) as a yellow solid. MS (ESI): mass calcd. For C 29 H 28 F2N6O5578.21m / z found 579.3[M+H] + . Compound 66 (S)-6-(((1-(6-aminopyridin-3-yl)piperidin-3-yl)((2-methoxypyridin-4-yl)methyl)amino) Preparation of 2-(4-(2-methyl)-9,10-difluoro-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinolin-7-one (Step 11 of Scheme 11) 11)

[0277] To (S)-9,10-difluoro-6-((((2-methoxypyridin-4-yl)methyl)(1-(6-nitropyridin-3-yl)piperidin-3-yl)amino)methyl)-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinolin-7-one (100 mg, 0.17 mmol) and C (20 mg), FeCl 3(To a mixture of (S)-9,10-difluoro-6-((((2-methoxypyridin-4-yl)methyl)(1-(6-nitropyridin-3-yl)piperidin-3-yl)amino)methyl)-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinolin-7-one was added NH2·NH2·H2O (0.02 mL, 0.34 mmol). The reaction mixture was stirred at 80°C for 1.5 hours. LC-MS showed that (S)-9,10-difluoro-6-((((2-methoxypyridin-4-yl)methyl)(1-(6-nitropyridin-3-yl)piperidin-3-yl)amino)methyl)-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinolin-7-one was consumed. The reaction mixture was diluted with ethyl acetate, filtered and concentrated. The crude product was purified by column chromatography (SiO2, DCM:MeOH=15:1) to give (S)-6-(((1-(6-aminopyridin-3-yl)piperidin-3-yl)((2-methoxypyridin-4-yl)methyl)amino)methyl)-9,10-difluoro-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinolin-7-one (20 mg, 21.09%) as a yellow solid. MS (ESI): mass calcd. For C 29 H 30 F2N6O3548.23m / z found 549.3[M+H] + . 1 H NMR(DMSO-d6,400MHz)δ:8.00(d,J=5.3Hz,1H),7.94-7.98(m,1H),7.61(d,J=2.8Hz,1H),7.47-7.58 (m,1H),7.15(dd,J=8.9,2.9Hz,1H),6.93-7.06(m,1H),6.80(s,1H),6.39(d,J=8.8Hz,1H),5.38(br s,2H),4.58(br t,J=4.4Hz,2H),4.35(br t,J=4.4Hz,2H),3.77(s,3H),3.70-3.74(m,1H),3.46-3.68(m,4H),3.24(br d,J=11.4Hz,1H),2.70-2.81(m,1H),2.49-2.53(m,1H),2.35-2.47(m,1H),1.90-2.00(m,1H),1.70-1.78(m,1H),1.38-1.55(m,2H). Plan 12 General procedures for preparing compounds in Scheme 12 Preparation of 2-methylpropan-2-yl{[(3S)-1-(6-nitropyridin-3-yl)hexahydropyridin-3-yl]amino}formate Preparation (Step 1 of Scheme 12)

[0278] Under a N₂ atmosphere, a mixture of 5-bromo-2-nitropyridine (4.72 g, 23.4 mmol), 2-methylpropan-2-yl {[(3S)-hexahydropyridin-3-yl]amino}carboxylate (3.6 g, 17.97 mmol), Pd₂(dba)₃ (518 mg, 0.9 mmol), Cs₂CO₃ (7.92 g, 24.3 mmol), and [5-(diphenylphosphino)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphine (625 mg, 1.08 mmol) in dioxane (80 mL) was stirred at 115° C. for 16 hours. The resulting mixture was poured into ice water and extracted with EA. The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by flash column with EA / PE to give 2-methylpropan-2-yl{[(3S)-1-(6-nitropyridin-3-yl)hexahydropyridin-3-yl]amino}carboxylate (2.9 g, 9.00 mmol) as a yellow solid. MS (ESI): mass calcd. For C 15 H 22 N4O4322.2m / z found 323.2[M+H] + . Preparation of (3S)-1-(6-nitropyridin-3-yl)hexahydropyridin-3-amine (Step 2 of Scheme 12)

[0279] To a solution of 2-methylpropan-2-yl {[(3S)-1-(6-nitropyridine-3-yl)hexahydropyridine-3-yl]amino}formate (2.8 g, 8.69 mmol) in DCM (20 mL) was added HCl (26.06 mL, 52.11 mmol) at 0 ° C. Under a nitrogen atmosphere, HCl (26.06 mL, 52.11 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum and diluted with water. The mixture was alkalized to pH = 8-9 with Na2CO3. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column (eluting with MeOH / DCM) to give (3S)-1-(6-nitropyridine-3-yl)hexahydropyridine-3-amine (1.6 g, 7.20 mmol, 82.88%) as a yellow solid. MS (ESI): mass calcd. For C 10 H 14 N4O2 222.1m / z found 223.1[M+H] + . 1H NMR(DMSO-d6)δ:8.17-8.26(m,1H),8.12(br d,J=9.3Hz,1H),7.42(br dd,J=9.3,2.6Hz,1H),3.86-3.98(m,2H),2.96-3.10(m,1H),2.66-2.83(m,2H),1.69-1.93(m,3H),1.21-1.66(m,3H) Preparation of ethyl (E)-3-(6-amino-2,3-difluorophenyl)acrylate (Scheme 12, Step 3)

[0280] A mixture of ethyl acrylate (14.5 g, 144.9 mmol), 2-bromo-3,4-difluoroaniline (25 g, 120.8 mmol), tri(2-methylphenyl)phosphine (3.66 g, 12.02 mmol), Pd(OAc)2 (2.7 g, 12.1 mmol), and TEA (49.98 mL, 360.56 mmol) in DMF (300 mL) was stirred at 130°C for 16 hours. The resulting mixture was poured into ice water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with EA / PE) to give ethyl (E)-3-(6-amino-2,3-difluorophenyl)acrylate (13 g, 57.22 mmol, 47.61%) as a yellow solid. MS (ESI): mass calcd. For C 11 H 11 F2NO2227.1m / z found228.1[M+H] + . Preparation of ethyl 3-(6-amino-2,3-difluorophenyl)propanoate (Step 4 of Scheme 12)

[0281] A mixture of (E)-3-(6-amino-2,3-difluorophenyl)ethyl acrylate (13g, 57.3mmol) and Pd / C (2.6g) in MeOH (60mL) was stirred at room temperature under a hydrogen atmosphere for 16 hours. The mixture was filtered and concentrated. The residue was purified by flash column (eluting with EA / PE) to obtain 3-(6-amino-2,3-difluorophenyl)ethyl propionate (11.5g, 50.22mmol), which was a white solid. MS (ESI): mass calcd. For C 11 H 13 F2NO2229.1m / z found230.1[M+H] + . Preparation of 5,6-difluoro-3,4-dihydroquinolin-2(1H)-one (Scheme 12, Step 5)

[0282] A mixture of ethyl 3-(6-amino-2,3-difluorophenyl)propanoate (7 g, 30.54 mmol) and TEA (6.17 g, 61.07 mmol) in MeOH (50 mL) was stirred at 60° C. under a nitrogen atmosphere for 16 hours. The resulting mixture was concentrated under vacuum to give 5,6-difluoro-3,4-dihydroquinolin-2(1H)-one (5 g, 27.30 mmol, 89.39%) as a white solid. MS (ESI): mass calcd. For C9H7F2NO 183.0 m / z found 184.0 [M+H] + . Preparation of 8,9-difluoro-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid ethyl ester (Step 6 of Solution 12)

[0283] Under nitrogen atmosphere, a solution of 5,6-difluoro-3,4-dihydroquinolin-2(1H)-one (9.6 g, 52.41 mmol) and LiAlH4 (4.97 g, 131.03 mmol) in THF (3 mL) was stirred at room temperature for 2 hours. The resulting mixture was poured into ice water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by FC using EA / PE to give 5,6-difluoro-1,2,3,4-tetrahydroquinoline (8 g, 47.29 mmol, 90.22%) as a yellow solid. MS (ESI): mass calcd. For C9H9F2N 169.1 m / z found 170.1 [M+H] + . Preparation of 5,6-difluoro-1,2,3,4-tetrahydroquinoline (Scheme 12, Step 7)

[0284] A mixture of 5,6-difluoro-1,2,3,4-tetrahydroquinoline (8 g, 47.29 mmol) and ethyl 3-ethoxy-2-(ethoxycarbonyl)prop-2-enoate (11.36 mL, 56.75 mmol) was stirred at 130° C. for 1 hour under a nitrogen atmosphere. Then, oxo-λ5-phosphinediol (38.77 g, 472.90 mmol) was added. The reaction mixture was stirred at 130° C. for 2 hours under a nitrogen atmosphere. The resulting mixture was poured into ice water. The mixture was filtered. The resulting filter cake was collected to give ethyl 8,9-difluoro-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylate (11 g, 37.51 mmol, 79.32%) as a gray solid. MS (ESI): mass calcd. For C 15 H 13F2NO3293.1m / z found294.1[M+H] + . Preparation of 8,9-difluoro-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid (Scheme Step 8 of 12

[0285] A mixture of ethyl 8,9-difluoro-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylate (11 g, 37.51 mmol) and sodium hydroxide (4.50 g, 112.52 mmol) in MeOH (30 mL) and THF (30 mL) was stirred at 50° C. under a nitrogen atmosphere for 1 hour. The resulting mixture was poured into ice water. The mixture was acidified to pH=2 with HCl. The resulting mixture was extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated under vacuum to give 8,9-difluoro-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid (9.5 g, 35.82 mmol, 95.50%) as a gray solid. MS (ESI): mass calcd. For C 13 H9F2NO3265.1m / z found266.1[M+H] + . 1 H NMR(DMSO-d6)δ:14.99(br s,1H),8.97(s,1H),8.10(br t,J=9.3Hz,1H),4.44(br s,2H),3.04(br s,2H),2.17(br s,2H) Preparation of 8,9-difluoro-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-1-one (Step 12 of Scheme 12) Step 9)

[0286] At 0°C and under a nitrogen atmosphere, NaBH4 (1.66 mL, 45.25 mmol) was added to a solution of 8,9-difluoro-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid (4 g, 15.08 mmol) in MeOH (20 mL). The resulting solution was stirred at room temperature for 1 hour. 4-Methylbenzenesulfonic acid (260 mg, 1.51 mmol) was added to the mixture. The reaction mixture was stirred at 63°C for 16 hours. The mixture was poured into ice water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column (eluted with EA / PE) to give 8,9-difluoro-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-1-one (2.7 g, 12.10 mmol, 80.20%) as a yellow oil. MS (ESI): mass calcd. For C 12 H 11 F2NO 223.1m / z found224.1[M+H] + . Preparation of 8,9-difluoro-1-oxo-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carbaldehyde (Step 10 of Solution 12)

[0287] At room temperature and N2 atmosphere, sodium methoxide (2.61g, 48.38mmol) and ethyl formate (3.90mL, 48.38mmol) were added to a solution of 8,9-difluoro-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinoline-1-one (2.7g, 12.10mmol) in DCM (3mL). The resulting mixture was stirred at room temperature for 10 minutes. The mixture was filtered. The filter cake was collected to give 8,9-difluoro-1-oxo-2,3,6,7-tetrahydro-1H,5H-p...

Claims

1. A compound, characterized in that Having structural formula I or structural formula II: in: Ring A is a 5-membered, 6-membered, or 7-membered substituted or unsubstituted heterocyclic ring; Ring B is a 4-membered, 5-membered, or 6-membered substituted or unsubstituted heterocyclic ring; Y1 is CR c or N; W1, W2, W3, and W4 are each independently CH or N; R 1 Selected from halogen and oxo, OH, CN, OR, CF3, C 1-6 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aryl or heteroaryl, 6-10 membered fused, spiro or bridged bicyclic, NRR', N(R)C(=O)R, N(R)C(=O)(O)R, OC(=O)NRR', C(=O)R, C(=O)NRR', N(R)S(O)2R, S(O)2R, S(O)2NRR'; optionally, R 1 1 to 4 identical or different R a or R b Replacement; two R 1 'Together with the carbon or heteroatom to which they are attached, they can form a 4-6 membered carbocyclic or heterocyclic ring; R 2 Selected from halogen and oxo, OH, CN, OR, CF3, C 1-6 Alkyl; Optionally, the C 1-6 The alkyl group is replaced by 1-2 R b Replacement; two R 2 'Together with the carbon or heteroatom to which they are attached, they may form a 4- to 6-membered carbocyclic or heterocyclic ring; R 3 is a 5- to 6-membered aromatic carbocyclic or heterocyclic ring, a 9- to 10-membered aromatic carbocyclic or heterocyclic ring; optionally, the aromatic carbocyclic or heterocyclic ring is surrounded by 1 to 4 identical or different R a replace; R 4 It is S(=O)2-C 1-4 Alkenyl, S(=O)2-C 1-4 Alkyl, C(=O)-C 1-4 Alkenyl, C(=O)-C 1-4 Alkyl, C 1-4 Alkenyl, C 1-4 Alkyl, -C 1-4 Alkyl-NH2, -C 1-4 Alkyl-OH, C 1-3 Alkyl-NH-C 1-3 Alkyl, C 1-3 Alkyl-OC 1-3 Alkyl, C 1-3 Alkyl-SC 1-3 Alkyl, C 1-3 Alkyl-C(=O)-C 1-3 Alkyl, C 1-3 Alkyl-S(=O)2-C 1-3 alkyl, or a 3- to 6-membered saturated or unsaturated carbon or heterocyclic ring; optionally, R 4 1 to 4 identical or different R b replace; R and R' are each independently H, or C 1-6 Alkyl or C 3-6 Cycloalkyl; optionally, R and R' together with the nitrogen to which they are attached form a 4-6 membered ring, each optionally substituted with 1-3 substituents independently selected from C 1-3 Alkyl, C 3-6 Cycloalkyl or heterocyclic ring, halogen, OH, OC 1-3 Alkyl, CN; R a OH, NRR', halogen, CN, NO2, C 1-2 Alkyl, C 1-2 Haloalkyl, -C 1-4 Alkyl-NRR', -C 1-4 Alkyl-OR, C 1-2 alkoxy, C(=O)NRR', NRC(=O)R or C(=O)R; optionally, the alkyl, R or R' is substituted by 1-3 R b Replace, or two R a 'Form = O, or two R a 'Together with the carbon atoms to which they are bonded, they form a 3-5 membered saturated or unsaturated carbocyclic or heterocyclic ring; R b Halogen, CN, OH, C 1-2 Alkyl, C 1-2 Alkyl-OH, C 3-6 Cycloalkyl, C 1-2 Alkoxy, NRR', S(=O)2NRR', C(=O)R, 5- to 6-membered aromatic carbocyclic or heterocyclic ring, C 1-2 Alkyl-Carbocyclic or C 1-2 Alkyl-heterocyclic group; optionally, the alkyl, R, R', aromatic carbocyclic ring or heterocyclic ring is 1 to 4 identical or different R a Replace; or two R b 'forms =O; or two R attached to the same or adjacent carbon atoms b 'Can form a 3-membered carbon ring; R c H or C 1-2 Alkyl, optionally substituted with 1-5 halogens; m is 0 or 1, 2, or 3; n is 0 or 1, 2, or 3; p is 1, 2, or 3; q is 1, 2, or 3; or a pharmaceutically acceptable form or isotopic derivative thereof.

2. The compound according to claim 1, characterized in that It has structural formula I.

3. The compound according to claim 2, characterized in that Ring A is selected from: in: Y2 is CRR' or C=O Y3, Y4 and Y5 are each independently selected from N, O, S, CRR' and C=O.

4. The compound according to any one of claims 1 to 3, characterized in that Ring A is selected from:

5. The compound according to claim 1, characterized in that It has structural formula II.

6. The compound according to claim 1 or 5, characterized in that Ring B is selected from: in: Y6 is CRR' or S, O; Y7 and Y8 are each independently N, O, or CRR'.

7. The compound according to any one of claims 1 or 5-6, characterized in that Ring B is selected from:

8. A compound, characterized in that Has structural formula III: in: Ring A is a 5-membered, 6-membered, or 7-membered substituted or unsubstituted heterocyclic ring; Ring B is a 4-membered, 5-membered, or 6-membered substituted or unsubstituted heterocyclic ring; W1, W2 and W3 are each independently CH or N; R 1 Selected from halogen and oxo, OH, CN, OR, CF3, C 1-6 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aryl or heteroaryl, 6-10 membered fused, spiro or bridged bicyclic, NRR', N(R)C(=O)R, N(R)C(=O)(O)R, OC(=O)NRR', C(=O)R, C(=O)NRR', N(R)S(O)2R, S(O)2R, S(O)2NRR'; optionally, R 1 1 to 4 identical or different R a or R b Replacement; two R 1 'Together with the carbon or heteroatom to which they are attached, they can form a 4-6 membered carbocyclic or heterocyclic ring; R 2 Selected from halogen and oxo, OH, CN, OR, CF3, C 1-6 Alkyl; Optionally, the C 1-6 The alkyl group is replaced by 1-2 R b Replacement; two R 2 'Together with the carbon or heteroatom to which they are attached, they may form a 4- to 6-membered carbocyclic or heterocyclic ring; R 3 is a 5- to 6-membered aromatic carbocyclic or heterocyclic ring, a 9- to 10-membered aromatic carbocyclic or heterocyclic ring; optionally, the aromatic carbocyclic or heterocyclic ring is surrounded by 1 to 4 identical or different R a replace; R 4 It is S(=O)2-C 1-4 Alkenyl, S(=O)2-C 1-4 Alkyl, C(=O)-C 1-4 Alkenyl, C(=O)-C 1-4 Alkyl, C 1-4 Alkenyl, C 1-4 Alkyl, -C 1-4 Alkyl-NH2, -C 1-4 Alkyl-OH, C 1-3 Alkyl-NH-C 1-3 Alkyl, C 1-3 Alkyl-OC 1-3 Alkyl, C 1-3 Alkyl-SC 1-3 Alkyl, C 1-3 Alkyl-C(=O)-C 1-3 Alkyl, C 1-3 Alkyl-S(=O)2-C 1-3 alkyl, or a 3- to 6-membered saturated or unsaturated carbon or heterocyclic ring; optionally, R 4 1 to 4 identical or different R b replace; R and R' are each independently H, or C 1-6 Alkyl or C 3-6 Cycloalkyl; optionally, R and R' together with the nitrogen to which they are attached form a 4-6 membered ring, each optionally substituted by 1-3 substituents independently selected from C 1-3 Alkyl, C 3-6 Cycloalkyl or heterocyclic ring, halogen, OH, OC 1-3 Alkyl, CN; R a OH, NRR', halogen, CN, NO2, C 1-2 Alkyl, C 1-2 Haloalkyl, -C 1-4 Alkyl-NRR', -C 1-4 Alkyl-OR, C 1-2 alkoxy, C(=O)NRR', NRC(=O)R or C(=O)R; optionally, the alkyl, R or R' is substituted by 1-3 R b Replace, or two R a 'Form = O, or two R a 'Together with the carbon atoms to which they are bonded, they form a 3-5 membered saturated or unsaturated carbocyclic or heterocyclic ring; R b Halogen, CN, OH, C 1-2 Alkyl, C 1-2 Alkyl-OH, C 3-6 Cycloalkyl, C 1-2 Alkoxy, NRR', S(=O)2NRR', C(=O)R, 5- to 6-membered aromatic carbocyclic or heterocyclic ring, C 1-2 Alkyl-Carbocyclic or C 1-2 Alkyl-heterocyclic group; optionally, the alkyl, R, R', aromatic carbocyclic ring or heterocyclic ring is 1 to 4 identical or different R a Replace; or two R b 'forms =O; or two R attached to the same or adjacent carbon atoms b 'Can form a 3-membered carbon ring; m is 0 or 1, 2, or 3; n1 is 0 or 1, 2, 3; n2 is 0 or 1, 2, or 3; p is 1, 2, or 3; q is 1, 2, or 3; or a pharmaceutically acceptable form or isotopic derivative thereof.

9. The compound according to claim 8, characterized in that Ring AB is selected from:

10. The compound according to any one of claims 1 to 9, characterized in that R 3 is a 5-membered or 6-membered substituted or unsubstituted aromatic or heteroaromatic group.

11. The compound according to any one of claims 1 to 10, characterized in that R 3 The structure is selected from the following:

12. A compound, characterized in that Selected from the following groups:

13. The compound according to any one of claims 1 to 12, characterized in that Having one or more hydrogen atoms replaced by deuterium atoms.

14. The compound according to claim 13, characterized in that Has one hydrogen atom replaced by a deuterium atom.

15. A pharmaceutical composition, characterized in that The pharmaceutical composition comprising the compound according to any one of claims 1 to 14 is effective in treating or alleviating one or more diseases or disorders in mammals (including humans).

16. A unit dosage form, characterized in that Comprising the pharmaceutical composition of claim 15.

17. The unit dosage form according to claim 16, characterized in that The unit dosage form is injection, solution, suspension, tablet or capsule.

18. A method for treating or alleviating a disease or disorder, characterized in that: It comprises administering to a subject in need thereof a pharmaceutical composition comprising a compound according to any one of claims 1 to 14.

19. The method according to claim 18, characterized in that The disease or disorder is mediated by or associated with stimulator of interferon genes (STING).

20. The method according to claim 19, characterized in that The disease or disorder is selected from cancer and precancerous syndromes.

21. The method according to claim 19, characterized in that The disease or disorder is an infectious disease or disorder.

22. The method according to claim 19, characterized in that The disease or disorder is an autoimmune disease or disorder.

23. A method for treating or delaying aging, characterized in that: The method comprises administering a pharmaceutical composition to a subject in need thereof, wherein the pharmaceutical composition comprises a compound according to any one of claims 1 to 14.

24. The method according to any one of claims 18 to 23, characterized in that The mode of administration is systemic administration.

25. Use of a compound according to any one of claims 1 to 14 in the preparation of a medicament for treating a disease or disorder.

26. The use according to claim 25, characterized in that The disease or disorder is selected from cancer, infectious and autoimmune diseases or disorders.

27. Use of a compound according to any one of claims 1 to 14 in the preparation of a drug for treating or delaying aging.

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