Tricyclic heterocyclic compounds, their preparation methods and applications

Abstract

A tricyclic heterocyclic compound, its preparation, and its applications are disclosed. Specifically, a tricyclic heterocyclic compound as shown in Formula IA or a pharmaceutically acceptable salt thereof is provided. This tricyclic heterocyclic compound exhibits good inhibitory activity against poly(ADP-ribose) polymerase and can significantly inhibit the growth of NCI-H1373 human lung adenocarcinoma cells. It can be used as a drug for the treatment and / or prevention of abnormal proliferative diseases or other diseases related to the targets that this series of compounds targets; for example, cancer.

Description

[0001] This application claims priority to Chinese Patent Application No. 2021101515791, filed on February 3, 2021, and Chinese Patent Application No. 2021107681969, filed on July 7, 2021. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention relates to a tricyclic heterocyclic compound, its preparation method, and its application. Background Technology

[0003] Poly(ADP-ribosylation) polymerases (PARPs) are a family of enzymes with 17 members (S. Vyas, M. Chesarone-Cataldo, T. Todorova, YH Huang, P. Chang, A systematic analysis of the PARP protein family identifies new functions critical for cell physiology. Nat. Common 4, 2240 (2013)). These enzymes catalyze the transfer of poly(ADP) or single ADP to their target substrate proteins, and their functions include gene expression, protein degradation, and various cellular stress responses (MSCohen, P. Chang, Insights into the biogenesis, function, and regulation of ADP-ribosylation. Nat Chem Biol 14, 236-243 (2018)). The biological functions of some of these enzymes, such as PARP1 and PARP2, are well understood, but the biological functions of others are not yet fully understood. The PARP family currently has 17 members, four of which (PARP1, PARP2, PARP5A, and PARP5B) are capable of synthesizing PAR chains. Most other enzymes in the family can only construct a single ADP-ribose unit and are therefore classified as mono(ADP-ribosyl)ases (MARs). The ability of tumor cells to survive under stress is a fundamental mechanism of tumorigenesis and an emerging therapeutic approach. PARP1, a member of the PARP family, has been shown to be an effective cancer target. This is due to cellular stress responses, whether caused by gene mutations or DNA damage associated with cytotoxic chemotherapy. Six drugs are clinically approved, with several others in late development stages (A. Ohmoto, S. Yachida, Current status of poly(ADP-ribose)polymerase inhibitors and future directions. Onco Targets Ther 10, 5195-5208 (2017).

[0004] Aryl hydrocarbon receptors (AHRs) are coordination-activated transcription factors involved in regulating a variety of cellular functions, including pro-inflammatory responses and biometabolism (S. Feng, Z. Cao, X. Wang, Role of aryl hydrocarbon receptor in cancer. Biochim Biophys Acta 1836, 197-210 (2013); and B. Stockinger, P. Di Meglio, M. Gialitakis, J. H. Duarte, The aryl hydrocarbon receptor: multitasking in the immune system. Annu Rev Immunol 32, 403-432 (2014)). AHRs can be activated by a large number of ligands, including endogenous tryptophan produced by metabolism, such as kynurenine, and certain polycyclic aromatic hydrocarbons (CAOpitz et al., Anendogenous tumor-promoting ligand of the human aryl hydrocarbon receptor. Nature 478, 197-203 (2011)). Activation of the aryl hydrocarbon receptor (AHR) induces the expression of target genes, including those involved in metabolism, such as cytochrome P4501A1 and P4501B1. Activation also leads to an increase in TCDD-induced poly(ADP-ribose) polymerases (TIPARPs) of AHR target genes. For example, PARP7 acts as a negative regulator of some AHR transcriptional targets (L. MacPherson et al., Aryl hydrocarbon receptor repressor and TIPARP (ARTD14) use similar, but also distinct mechanisms to repress aryl hydrocarbon receptor signaling. Int J Mot Sci 15, 7939-7957 (2014).

[0005] PARP7 is an AHR-regulated gene and an important member of the PARP family. PARP7 can only transfer a single ADP-ribose (MAR) and belongs to the monoPARP family. The PARP catalytic domain of PARP7 contains a zinc finger motif that confers DNA binding, and a WWE domain that mediates protein-protein interactions (Ma, Q et al., Biochem 289, 499-506, 2001). Its mediated single ADP-ribosylation is a reversible post-translational modification involved in many important biological processes, such as immune cell function, transcriptional regulation, protein expression, and DNA repair. PARP7 is part of a negative feedback loop regulating AHR activity, which modulates immune function, inflammation, and stem differentiation, and plays a role in cancer. PARP7 has been shown to be overactive in tumors and plays a crucial role in cancer cell survival. More importantly, many cancer cells rely on PARP7 for intrinsic cell survival, and studies have shown that PARP7 enables cancer cells to "hide" outside the immune system; inhibiting PARP7 can effectively suppress cancer cell growth, restore interferon signaling, and suppress the "brakes" of innate and adaptive immune mechanisms. In several cancer models, PARP7 inhibitors have demonstrated durable tumor growth inhibition, effective antiproliferative activity, and interferon signaling restoration.

[0006] PARP7 can also be regulated by other transcription factors and signaling pathways, including androgen receptor (EC. Bolton et al., Cell-and gene-specific regulation of primary target genes by the androgen receptor. Genes Dev 21, 2005-2017 (2007)), platelet-derived growth factor (J. Schmahl, C.S. Raymond, P. Soriano, PDGF signaling specificity is mediated through multiple immediate early genes. Nat Genet 39, 52-60 (2007)) and hypoxia-inducible factor 1 (N. Hao et al., Xenobiotics and loss of cell adhesion drive distinct transcriptional outcomes by aryl hydrocarbon receptor signaling. Mot Pharmacol 82, 1082-1093 (2012)). PARP7 has multiple cellular functions. In the context of AHR signaling, PARP7 acts as a negative feedback mechanism to regulate the expression of P4501A1 and P4501B1 (L. MacPherson et al.). al., Aryl hydro-carbon receptor repressor and TIPARP(ARTD14) use simi-lar, but also distinct mechanisms to repress arylhydrocarbon receptor signaling. Int J Mot Sci 15, 7939-7957 (2014), and L. MacPherson et al., 2,3,7,8-Tetrachlorodibenzo-p-dioxin poly(ADP-ribose)polymerase(TIPARP, ARTD14) is a mono-ADP-ribosyltransferase and repressor ofaryl hydro-carbonreceptortransactivation. NucleicAcids Res 41, 1604-1621 (2013)).PARP7 is also described as an ADP-ribosyl liver X receptor that leads to the regulation of its transcriptional activity (C. Bindesbollet et al., TCDD-inducible poly-ADP-ribose polymerase (TIPARP / PARP7) mono-ADP-ribosylates and co-activates liver X receptors. Biochem J 473, 899-910 (2016)). During viral infection, PARP7 can bind to Sindbis virus (SINV) to promote viral RNA degradation (T. Kozaki et al., Mitochondrial damage elicits a TCDD-inducible poly(ADP-ribose)polymerase-mediated antiviral response. Proc Natl Acad Sci USA 114, 2681-2686 (2017)). Similarly, in the context of viral infection, AHR-induced PARP7 can interact with TBK1, a major kinase activated during the initiation of pathogen-associated molecular pattern pathways, leading to activation of type I interferon responses and antiviral immunity (T. Yamada et al., Constitutive aryl hydrocarbon receptor signaling constrains Type I interferon-mediated antiviral innate defense Nat Immunol 17687-604 (2016)). PARP7 has the activity to ADP-ribose-enzyme TBK1, inactivating TBK1 and thereby inhibiting the type I interferon response.

[0007] Based on the results of these viral infections, we can hypothesize that cancer cells can use aberrantly expressed and / or activated PARP7 as a mechanism to evade the host immune system through T cell-mediated anti-tumor immunity by inhibiting type I interferon. Indeed, in a recent study, PARP7 was identified as a potential tumor factor that inhibits T cell activation (D. Pan et al., A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing. Science 359, 770-775 (2018)). In mouse malignant tumor cell lines, PARP7 gene knockout increased the proliferation and activation of co-cultured T cells, suggesting that PARP7 inhibition may be a feasible strategy for activating T cell-mediated tumor killing.

[0008] Ribon Therapeutics' RBN-2397 is the first and currently the only PARP7 inhibitor in a Phase I clinical trial (NCT04053673). Preclinical data show that RBN-2397 has a potent, dose-dependent anti-tumor growth effect; more importantly, RBN-2397 induces tumor-specific adaptive immune memory (JMGozgit, et al., PARP7 negatively regulates the type I interferon response in cancer cells and its inhibition triggers antitumor immunity. Cancer Cell 2021, 39, 1214-1226). This suggests that PARP7 inhibitors may be excellent therapeutic agents for cancer. Therefore, exploring and developing PARP7 inhibitors with different molecular skeletons is of great significance. Summary of the Invention

[0009] This invention provides a tricyclic heterocyclic compound, its preparation method, and its applications. The tricyclic compound of this invention can be used as a PARP7 (poly-ADP-ribose polymerase 7) inhibitor; it can treat diseases improved by inhibiting poly(ADP-ribose) polymerase 7; and it can be used in pharmaceuticals for the prevention and / or treatment of abnormal proliferative diseases or other diseases related to targets that bind to this series of compounds; for example, cancer.

[0010] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0011] This invention provides a tricyclic heterocyclic compound as shown in Formula IA, or a pharmaceutically acceptable salt thereof.

[0012]

[0013] Where W is NH or O;

[0014] L is

[0015] R 1 R 1’ R 3 R 3’ R 5 R 5’ Independently for H and C 1-6 Alkyl or with one or more R 1a Replacement C 1-6 Alkyl; or, R 1 and R 1’ R 3 and R 3’ R 5 and R 5’ Independently, it is O; when there are multiple substituents, they may be the same or different;

[0016] R 1a Independently halogen, CN, OH;

[0017] R 2 R 4 Independent of halogen, CN, SF5, C 1-6 Alkyl, with one or more R 2a Replacement C 1-6 Alkyl, with one or more R 2b Replacement C 1-6 Alkyl-S-; when there are multiple substituents, they may be the same or different;

[0018] R 2a R 2b Halogens are independent of each other;

[0019] X is independently C(R) 3a ), C or N;

[0020] Q is independently C(R) 3a ) or N;

[0021] When Q is C(R) 3a ), C(R) 3a When the carbon atom in the ) is a chiral carbon atom, it is in the R configuration, S configuration, or a mixture thereof;

[0022] T independently represents C(R) 3b ) or N; Y independently is C(R)3c ) or N; Z independently is C(R) 3d ) or N;

[0023] R 3a R 3b R 3c R 3d Independently, H, halogen, CN, OH, NH2, C 1-6 Alkyl, with one or more R a4 Replacement C 1-6 Alkyl or C 1-6 Alkoxy;

[0024] A 1 Independently for C(R) 4a ), C(R 4b R 4c ) or C (=O);

[0025] R 4a R 4b R 4c Independently for H and C 1-6 Alkyl or with one or more R a1 Replacement C 1-6 Alkyl group; when there are multiple substituents, they may be the same or different;

[0026] When B is independently C(R) 6a ), C(R 6b R 6c When A 2 Independently for C(R) 5a ), C(R 5b R 5c ), O, S, N (R) 5d ), N or connection key;

[0027] When B is independently O, S, S(=O), S(=O)2, N, N(R) 6d When A 2 Independently for C(R) 5a ), C(R 5b R 5c ), connection key;

[0028] R 5a R 5b R 5c R 5d Independently for H and C 1-6 Alkyl, with one or more R a2 Replacement C 1-6 Alkyl, or R 5b and R 5c =0;

[0029] R6a R 6b R 6c Independent of H, halogen, C 1-6 Alkyl, with one or more R a3 Replacement C 1-6 Alkyl, C 3-6 cycloalkyl, OH, or R 6b and R 6c =0;

[0030] R 6d Independently for H and C 1-6 Alkyl, with one or more R a3 Replacement C 1-6 Alkyl, C 3-6 Cycloalkyl or -CN; when there are multiple substituents, they may be the same or different;

[0031] R a1 R a2 R a3 R a4 It can be independently deuterium, halogen, or OH;

[0032] R 7 and R 8 Independently H, C1-6 alkyl or OR 7a Replacement C 1-6 alkyl;

[0033] R 7a Selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0034] * indicates a double or single bond; * indicates that when it is a chiral carbon atom, it is an R configuration, an S configuration, or a mixture thereof.

[0035] In this invention, the definitions of certain substituents in the tricyclic heterocyclic compounds represented by Formula IA are as follows, and the definitions of substituents not mentioned are as described in any embodiment of this application (hereinafter referred to as "in one embodiment of the invention").

[0036] In one aspect of the present invention, R 7 and R 8 Independently for C 1-6 Alkyl or OR 7a Replacement C 1-6 C in alkyl 1-6 In alkyl groups, the C 1-6 The alkyl group is independently methyl, ethyl, n-propyl, or isopropyl; for example, methyl.

[0037] In one aspect of the present invention, R 7a Selected from C1-6 Alkyl and C 1-6 C in haloalkyl 1-6 In alkyl groups, the C 1-6 The alkyl group is independently methyl, ethyl, n-propyl or isopropyl.

[0038] In one aspect of the present invention, R 7a Selected from C 1-6 The halogen in the haloalkyl group is independently F, Cl, Br or I, for example F.

[0039] In one aspect of the present invention, R 7 and R 8 Independently H or methyl; for example R 7 and R 8 One of them is H, and the other is methyl.

[0040] In one aspect of the present invention, when R 8 When the attached carbon is a chiral carbon, it has an S configuration or an R configuration;

[0041] For example, the R configuration.

[0042] In one aspect of the present invention, the tricyclic heterocyclic compound or its pharmaceutically acceptable salt represented by Formula IA is a tricyclic heterocyclic compound or its pharmaceutically acceptable salt represented by Formula I'.

[0043]

[0044] Where L is

[0045] R 1 R 1’ R 3 R 3’ R 5 R 5’ Independently for H and C 1-6 Alkyl or with one or more R 1a Replacement C 1-6 Alkyl; or, R 1 and R 1’ R 3 and R 3’ R 5 and R 5’ Independently, it is O; when there are multiple substituents, they may be the same or different;

[0046] R 1a Independently halogen, CN, OH;

[0047] R 2 R 4 Independent of halogen, CN, C1-6 Alkyl, with one or more R 2a Replacement C 1-6 Alkyl, with one or more R 2b Replacement C 1-6 Alkyl-S-; when there are multiple substituents, they may be the same or different;

[0048] R 2a R 2b Halogens are independent of each other;

[0049] X is independently C(R) 3a ), C or N;

[0050] Q is independently C(R) 3a ) or N;

[0051] When Q is C(R) 3a ), C(R) 3a When the carbon atom in the ) is a chiral carbon atom, it is in the R configuration, S configuration, or a mixture thereof;

[0052] T independently represents C(R) 3b ) or N; Y independently is C(R) 3c ) or N; Z independently is C(R) 3d ) or N;

[0053] R 3a R 3b R 3c R 3d Independently, H, halogen, CN, NH2, C 1-6 Alkyl, with one or more R a4 Replacement C 1-6 Alkyl or C 1-6 Alkoxy;

[0054] A 1 Independently for C(R) 4a ), C(R 4b R 4c ) or C (=O);

[0055] R 4a R 4b R 4c Independently for H and C 1-6 Alkyl or with one or more R a1 Replacement C 1-6 Alkyl group; when there are multiple substituents, they may be the same or different;

[0056] When B is independently C(R) 6a ), C(R 6b R 6c When A 2 Independently for C(R)5a ), C(R 5b R 5c ), O, S, N (R) 5d ), N or connection key;

[0057] When B is independently O, S, S(=O), S(=O)2, N, N(R) 6d When A 2 Independently for C(R) 5a ), C(R 5b R 5c ), connection key;

[0058] R 5a R 5b R 5c R 5d Independently for H and C 1-6 Alkyl, with one or more R a2 Replacement C 1-6 Alkyl, or R 5b and R 5c =0;

[0059] R 6a R 6b R 6c Independent of H, halogen, C 1-6 Alkyl, with one or more R a3 Replacement C 1-6 Alkyl, C 3-6 cycloalkyl, OH, or R 6b and R 6c =0;

[0060] R 6d Independently for H and C 1-6 Alkyl, with one or more R a3 Replacement C 1-6 Alkyl, C 3-6 Cycloalkyl or -CN; when there are multiple substituents, they may be the same or different;

[0061] R a1 R a2 R a3 R a4 It can be independently deuterium, halogen, or OH;

[0062] * indicates a double or single bond; * indicates that when it is a chiral carbon atom, it is an R configuration, an S configuration, or a mixture thereof.

[0063] In one aspect of the present invention, the tricyclic heterocyclic compound represented by Formula IA is a tricyclic heterocyclic compound represented by Formula I.

[0064]

[0065] Among them, R 1 R 1’ R 3 R 3’ R 5 R 5’ Independently for H and C 1-6 Alkyl or with one or more R 1a Replacement C 1-6 Alkyl; or, R 1 and R 1’ R 3 and R 3’ R 5 and R 5’ Independently, it is O; when there are multiple substituents, they may be the same or different;

[0066] R 1a Independently halogen, CN, OH;

[0067] R 2 R 4 Independent of halogen, CN, C 1-6 Alkyl, with one or more R 2a Replacement C 1-6 Alkyl, with one or more R 2b Replacement C 1-6 Alkyl-S-; when there are multiple substituents, they may be the same or different;

[0068] R 2a R 2b Halogens are independent of each other;

[0069] X is independently C(R) 3a ), C (when When it is a double bond, it is... ) or N;

[0070] T independently represents C(R) 3b ) or N; Y independently is C(R) 3c ) or N; Z independently is C(R) 3d ) or N;

[0071] R 3a R 3b R 3c R 3d Independently, it can be H, halogen, CN, NH2, or C. 1-6 alkyl;

[0072] A 1 Independently for C(R) 4a )(when When it is a double bond), C(R)4b R 4c )(when (when it is a single bond) or C (=O);

[0073] R 4a R 4b R 4c Independently for H and C 1-6 Alkyl or with one or more R a1 Replacement C 1-6 Alkyl group; when there are multiple substituents, they may be the same or different;

[0074] When B is independently C(R) 6a ), C(R 6b R 6c When A 2 Independently for C(R) 5a ), C(R 5b R 5c ), O, S, N (R) 5d ), N or connection key;

[0075] When B is independently O, S, N or N(R) 6d When A 2 Independently for C(R) 5a ), C(R 5b R 5c ) or connection key;

[0076] R 5a R 5b R 5c R 5d Independently for H and C 1-6 Alkyl or with one or more R a2 Replacement C 1-6 alkyl;

[0077] R 6a R 6b R 6c Independent of H, halogen, C 1-6 Alkyl, with one or more R a3 Replacement C 1-6 Alkyl, C 3-6 cycloalkyl;

[0078] R 6d Independently for H and C 1-6 Alkyl, with one or more R a3 Replacement C 1-6 Alkyl, C 3-6 Cycloalkyl; when there are multiple substituents, they may be the same or different;

[0079] R a1 R a2R a3 Independently classified as deuterium and halogen;

[0080] * indicates a double or single bond; * indicates that when it is a chiral carbon atom, it is an R configuration, an S configuration, or a mixture thereof.

[0081] In one aspect of the present invention, R 1 R 1’ One of them is H, and the other is H and C. 1-6 Alkyl or with one or more R 1a Replacement C 1-6 alkyl;

[0082] For example, R 1 R 1’ One of them is H, and the other is either H or C. 1-6 alkyl;

[0083] Or, R 1 and R 1’ Together they form O = ;

[0084] Preferably, R 1 R 1’ For H.

[0085] In one aspect of the present invention, R 3 R 3’ One of them is H, and the other is H and C. 1-6 Alkyl or with one or more R 1a Replacement C 1-6 alkyl;

[0086] For example, R 3 R 3’ One of them is H, and the other is either H or C. 1-6 alkyl;

[0087] Or, R 3 and R 3’ Together they form O = ;

[0088] Preferably, R 3 R 3’ For H.

[0089] In one aspect of the present invention, R 5 R 5’ One of them is H, and the other is H and C. 1-6 Alkyl or with one or more R 1a Replacement C 1-6 alkyl;

[0090] For example, R 5 R 5’One of them is H, and the other is either H or C. 1-6 alkyl;

[0091] Or, R 5 and R 5’ Together they form O = ;

[0092] Preferably, R 5 R 5’ For H.

[0093] In one aspect of the present invention, R 1 R 1’ R 3 R 3’ R 5 R 5’ One of them is H, C 1-6 Alkyl or with one or more R 1a Replacement C 1-6 Alkyl groups, the rest being H;

[0094] For example, R 1 R 1’ R 3 R 3’ R 5 R 5’ One of them is H or C 1-6 Alkyl groups, the rest being H;

[0095] Or, R 1 and R 1’ R 3 and R 3’ R 5 and R 5’ One of them is O, and the rest are H;

[0096] Preferably, R 1 R 1’ R 3 R 3’ R 5 R 5’ For H.

[0097] In one aspect of the present invention, when R 1 R 1’ When the attached carbon is a chiral carbon, it has an S configuration or an R configuration;

[0098] For example, the R configuration.

[0099] In one aspect of the present invention, when R 3 R 3’ When the attached carbon is a chiral carbon, it has an S configuration or an R configuration.

[0100] In one aspect of the present invention, when R5 R 5’ When the attached carbon is a chiral carbon, it has an S configuration or an R configuration.

[0101] In one aspect of the present invention, R 2 Independently halogen, CN, or by one or more R 2a Replacement C 1-6 Alkyl, with one or more R 2b Replacement C 1-6 Alkyl-S-;

[0102] For example, halogens, by one or more R 2a Replacement C 1-6 alkyl;

[0103] For example, C substituted with one or more halogens 1-6 alkyl.

[0104] In one aspect of the present invention, R 4 Independently halogen, CN, or by one or more R 2a Replacement C 1-6 alkyl;

[0105] For example, halogens, by one or more R 2a Replacement C 1-6 alkyl;

[0106] For example, C replaced by one or more halogens 1-6 alkyl.

[0107] In one aspect of the present invention, R 2 R 4 Independently for one or more R 2a Replacement C 1-6 alkyl;

[0108] For example, -CF3.

[0109] In one embodiment of the present invention, X is independently N.

[0110] In one embodiment of the invention, T is independently N.

[0111] In one aspect of the present invention, R 3c H, CN, NH2 or C 1-6 alkyl;

[0112] For example, H.

[0113] In one embodiment of the present invention, Y is independently C(R) 3c );

[0114] For example, CH.

[0115] In one aspect of the present invention, R 3d H, halogen, CN or C 1-6 alkyl;

[0116] For example, H.

[0117] In one aspect of the invention, Z is independently C(R) 3d );

[0118] For example, CH.

[0119] In one aspect of the present invention, R 4a R 4b R 4c Independently H or C 1-6 alkyl;

[0120] For example, R 4b and R 4c One is H, and the other is H or C. 1-6 alkyl;

[0121] For example, R 4b and R 4c For H.

[0122] In one aspect of the present invention, when A 1 For C(R) 4b R 4c When the carbon is chiral carbon, its configuration is S configuration, R configuration or a mixture thereof.

[0123] In one aspect of the present invention, A 1 Independently for C(R) 4b R 4c ) or C(=O); for example, C(R) 4b R 4c ).

[0124] In one aspect of the present invention, R 5a R 5b R 5c R 5d Independently H or C 1-6 alkyl;

[0125] For example, R 5b and R 5c One is H, and the other is H or C. 1-6 alkyl;

[0126] For example, R 5b and R 5c For H.

[0127] In one aspect of the present invention, when A 2 For C(R) 5b R5c When the carbon is chiral carbon, its configuration is S configuration, R configuration or a mixture thereof.

[0128] In one aspect of the present invention, A 2 Independently for C(R) 5b R 5c ) or connection key.

[0129] In one aspect of the present invention, R 6a R 6b R 6c Independently H or halogen;

[0130] For example, R 6b R 6c H stands for H independently.

[0131] In one aspect of the present invention, R 6d Independently for H and C 1-6 Alkyl, with one or more R a3 Replacement C 1-6 Alkyl, C 3-6 cycloalkyl;

[0132] For example, H or C 1-6 alkyl.

[0133] In one embodiment of the invention, B is independently C(R) 6b R 6c ).

[0134] In one embodiment of the invention, B is independently O, S, or N(R) 6d );

[0135] For example, -O- or -S-;

[0136] For example, S.

[0137] In one aspect of the present invention, Independently

[0138] In one aspect of the present invention, when B is independently O, S, N(R) 6d When A 2 Independently for C(R) 5b R 5c ) or connection key.

[0139] In one aspect of the invention, when B is independently C(R) 6b R 6c When A 2 Independently for O, N(R) 5d ) or connection key.

[0140] In one aspect of the invention, when B is independently N(R) 6d ), R 6d Independently for C 1-6 Alkyl, with one or more R a3 Replacement C 1-6 When alkyl, A 1 Independently, it is C (=O).

[0141] In one aspect of the present invention, when both T and Z are N, A 2 Independently for O, N(R) 5d ) or C(R 5b R 5c ).

[0142] In one aspect of the present invention, Independently for -C(R) 4b R 4c )-O-、-C(R 4b R 4c )-S-、-C(R 4b R 4c )-N(R 6d )-、-C(R 4b R 4c )-C(R 6b R 6c )-, -C(=O)-O-, -C(=O)-N(R 6d )-、-C(R 4b R 4c )-S(=O)-、-C(R 4b R 4c -S(=O)2、-C(R) 4a )=C(R 6a )-.

[0143] In one aspect of the present invention, Independently -O-, -S-, -C(R) 6b R 6c )-、-N(R 6d )-、-OC(R 5b R 5c )-、-SC(R 5b R 5c )-、-N(R 6d )-C(R 5b R 5c )-、-C(R 6b R 6c )-O-、-C(R 6b R 6c )-S-、-C(R 6b R 6c )-N(R5d )-、-S(=O)-C(R 5b R 5c )-、-S(=O)2- C(R 5b R 5c )-、-OC(R 6b R 6c )-、=C(R 6a )-.

[0144] In one aspect of the present invention, when R 5a R 3b R 3c R 3d Independently for C 1-6 Alkyl or with one or more R a4 Replacement C 1-6 When alkyl, the C 1-6 Alkyl and one or more R a4 Replacement C 1-6 C in alkyl 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; for example, methyl. In one aspect of the invention, when R... 3a R 3b R 3c R 3d Independently for C 1-6 When alkoxy is present, the C 1-6 The alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy; for example, methoxy.

[0145] In one aspect of the present invention, Independently for -C(R) 4b R 4c )-O-、-C(R 4b R 4c )-S-、-C(R 4b R 4c )-N(R 6d )-、-C(R 4b R 4c )-C(R 6b R 6c )-, -C(=O)-O-, -C(=O)-N(R 6d )-;

[0146] For example, -CH2-O-, -CH2-S-, -CH2-NH-, -CH2-N(CH3)-, -CH2-N(CH2CF3)-, -CH2-CH2-, -CH2-CF2-, -C(CH3)-O-, -C(CH3)-S-, -C(=O)-NH-, -C(=O)-O-, -C(=O)-N(CD3)-, -CH2-N(cyclopropyl)-, -C(=O)-N(cyclopropyl)-;

[0147] For example, -C(R) 4b R 4c )-O-、-C(R 4b R 4c )-S-、-C(R 4b R 4c )-N(R 6d )-、-C(=O)-N(R 6d )-;

[0148] For example, -CH2-O- and -CH2-S-.

[0149] In one aspect of the present invention, Independently -O-, -S-, -C(R) 6b R 6c )-、-N(R 6d )-、-OC(R 5b R 5c )-、-SC(R 5b R 5c )-、-N(R 6d )-C(R 5b R 5c )-、-C(R 6b R 6c )-O-、-C(R 6b R 6c )-S-、-C(R 6b R 6c )-N(R 5d )-;

[0150] For example, -O-, -OC(R) 5b R 5c )-、-SC(R 5b R 5c )-、-N(R 6d )-、-N(R 6d )-C(R 5b R 5c )-;

[0151] For example, -O-, -O-CH2-, or -S-CH2-.

[0152] In one aspect of the present invention, Independently

[0153] In one aspect of the present invention, Independently for -C(R) 4b R 4c )-O-、-C(R 4b R 4c )-S-、-C(R 4b R 4c )-N(R 6d )-、-C(=O)-N(R 6d )-、-C(R 4b R 4c )-OC(R 5b R 5c )-、-C(R 4b R 4c )-SC(R 5b R 5c )-、-C(R 4b R 4c )-N(R 6d )-C(R 5b R 5c )-、-C(R 4b R 4c )-C(R 6b R 6c )-N(R 5d )-、-C(R 4b R 4c )-C(R 6b R 6c )-O-、-C(R 4b R 4c )-C(R 6b R 6c )-S-、-C(=O)-N(R 6d )-C(R 5b R 5c )-、-C(=O)-OC(R 5b R 5c )-、-C(R 4b R 4c )-C(R 6b R 6c )-;

[0154] For example -C(R) 4b R 4c )-O-、-C(R 4b R 4c )-S-、-C(R 4b R 4c )-N(R 6d)-、-C(=O)-N(R 6d )-、-C(R 4b R 4c )-OC(R 5b R 5c )-、-C(R 4b R 4c )-SC(R 5b R 5c )-、-C(R 4b R 4c )-N(R 6d )-C(R 5b R 5c )-;

[0155] For example, -C(R) 4b R 4c )-O-、-C(R 4b R 4c )-S-、-C(R 4b R 4c )-OC(R 5 6R 5c )-、-C(R 4b R 4c )-SC(R 5b R 5c )-;

[0156] Other examples include -CH2-O-, -CH2-S-, -CH2-O-CH2-, and -CH2-S-CH2-.

[0157] In one aspect of the present invention, Independently

[0158] In one aspect of the present invention, when R 1 R 1’ R 3 R 3’ R 5 R 5’ Independently for C 1-6 Alkyl or with one or more R 1a Replacement C 1-6 When alkyl, the C 1-6 Alkyl or with one or more R 1a Replacement C 1-6 C in alkyl 1-6 The alkyl group is a C1-C4 alkyl group.

[0159] For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl;

[0160] For example, methyl.

[0161] In one aspect of the present invention, when R 1a When the halogen is halogen, the halogen is F, Cl, Br, or I;

[0162] For example, F.

[0163] In one aspect of the present invention, when R 2 R 4 When it is a halogen on its own, the halogen is F, Cl, Br, or I;

[0164] For example, F.

[0165] In one aspect of the present invention, when R 2 R 4 Independently for C 1-6 Alkyl, with one or more R 2a Replacement C 1-6 Alkyl, with one or more R 2b Replacement C 1-6 When alkyl-S-, the C 1-6 Alkyl, with one or more R 2a Replacement C 1-6 Alkyl and one or more R 2b Replacement C 1-6 C in alkyl-S- 1-6 The alkyl group is a C1-C4 alkyl group.

[0166] For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl;

[0167] For example, methyl.

[0168] In one aspect of the present invention, when R 2 R 4 Independently for one or more R 2a Replacement C 1-6 Alkyl, with one or more R 2b Replacement C 1-6 When alkyl-S-, the number of substituents is 1, 2, or 3;

[0169] For example, 3.

[0170] In one aspect of the present invention, when R 2a R 2b When it is a halogen on its own, the halogen is F, Cl, Br, or I;

[0171] For example, F.

[0172] In one aspect of the present invention, when R 3a R 3b R3c R 3d When it is a halogen on its own, the halogen is F, Cl, Br, or I;

[0173] For example, F.

[0174] In one aspect of the present invention, when R 3a R 3b R 3c R 3d Independently for C 1-6 When alkyl, the C 1-6 The alkyl group is a C1-C4 alkyl group.

[0175] For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl;

[0176] For example, methyl.

[0177] In one aspect of the present invention, when R 4a R 4b R 4c Independently for C 1-6 Alkyl or with one or more R a1 Replacement C 1-6 When alkyl, the C 1-6 Alkyl and one or more R a1 Replacement C 1-6 C in alkyl 1-6 The alkyl group is a C1-C4 alkyl group.

[0178] For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl;

[0179] For example, methyl.

[0180] In one aspect of the present invention, when R 5a R 5b R 5c R 5d Independently for C 1-6 Alkyl or with one or more R a2 Replacement C 1-6 When alkyl, the C 1-6 Alkyl and one or more R a2 Replacement C 1-6 C in alkyl 1-6 The alkyl group is a C1-C4 alkyl group.

[0181] For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl;

[0182] For example, methyl.

[0183] In one aspect of the present invention, when R 6a R 6b R 6c When it is a halogen on its own, the halogen is F, Cl, Br, or I;

[0184] For example, F.

[0185] In one aspect of the present invention, when R 6a R 6b R 6c R 6d Independently for C 1-6 Alkyl, with one or more R a3 Replacement C 1-6 When alkyl, the C 1-6 Alkyl and one or more R a3 Replacement C 1-6 C in alkyl 1-6 The alkyl group is a C1-C4 alkyl group.

[0186] For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl;

[0187] For example, methyl.

[0188] In one aspect of the present invention, when R 6a R 6b R 6c R 6d Independently for C 3-6 When cycloalkyl, the C 3-6 The cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

[0189] For example, cyclopropyl.

[0190] In one aspect of the present invention, when R a1 R a2 R a3 When it is a halogen on its own, the halogen is F, Cl, Br, or I;

[0191] For example, F.

[0192] In one aspect of the present invention, R 1 R 1’ R 3 R 3’ R 5 R 5’ Independently, it can be H, methyl, HO-methyl, NC-methyl, CHF2, CF3; or, R 1 and R 1’ R 3 and R 3’ R 5and R 5’ Independently, it is O=.

[0193] In one aspect of the present invention, R 2 R 4 Independently, it is fluorine, bromine, chlorine, CN, CF3, CF3-S-.

[0194] In one embodiment of the present invention, T is independently N or CH.

[0195] In one embodiment of the invention, Q is independently N or CH.

[0196] In one embodiment of the present invention, Y is independently CH, N, C(CN), C(NH2), C(CHF2), or C(OMe).

[0197] In one embodiment of the present invention, Z is independently CH, N, C(CN), C(NH2), C(CHF2), or C(CH3).

[0198] In one aspect of the present invention, A 1 Independently, it can be CH2, C(CH3), C(=O), or CH.

[0199] In one embodiment of the present invention, B is independently CH2, CF2, O, S, NH, N(CH3), N(CD3), N(cyclopropyl), N(CH2CF3), C(CH3), C(=O), N(CN), S(=O), S(=O)2, CH(OH), N(CH2CH3), N(CH2CH2OH), CH.

[0200] In one aspect of the present invention, A 2 Independently represented by CH2, O, S, NH, N(CH3), N(cyclopropyl), CH(CH3), linking bond, C(=O).

[0201] In one aspect of the present invention, Independently

[0202] In one aspect of the present invention, Independently

[0203] In one aspect of the present invention, Independently

[0204] In one embodiment of the present invention, Y is independently CH, N, C(CN), C(NH2); for example, CH, N.

[0205] In one embodiment of the present invention, Z is independently CH, N, C(CN), C(NH2); for example, CH and N.

[0206] In one aspect of the present invention, A 1 It can be independently CH2, C(CH3) or C(=O);

[0207] In one embodiment of the present invention, B is independently CH2, CF2, O, S, NH, N(CH3), N(CD3), N(cyclopropyl), N(CH2CF3), C(CH3) or C(=O).

[0208] In one aspect of the present invention, A 2 It can be independently formed by CH2, O, S, NH, N(CH3), N(cyclopropyl), CH(CH3) or a connecting bond.

[0209] In one aspect of the present invention, Independently

[0210] In one aspect of the present invention, Independently

[0211] For example

[0212] For example

[0213] In one aspect of the present invention, Independently

[0214] In one aspect of the present invention, Independently

[0215] For example

[0216] For example

[0217] In one aspect of the present invention, Independently

[0218] In one aspect of the present invention, Independently The bond represents a mixture of R and S configurations.

[0219] In one aspect of the present invention, Independently

[0220] In one aspect of the present invention,

[0221] R 1 R 1’ Independently H or C 1-6 alkyl;

[0222] R 3 R 3’ R 5 R 5’ H is independent;

[0223] R 2 R 4 Independently for C substituted with one or more halogens 1-6 alkyl;

[0224] X and T are N independently;

[0225] Y is independently C(R) 3c );

[0226] Z is independently C(R) 3d ) or N;

[0227] A 1 Independently for C(R) 4b R 4c ) or C (=O);

[0228] B is independently O, S, N, or N(R) 6d A 2 Independently for C(R) 5b R 5c ) or connection key;

[0229] Indicates a single key.

[0230] In one aspect of the present invention,

[0231] R 1 R 1’ Independently, it is either H or methyl;

[0232] R 3 R 3’ R 5 R 5’ H is independent;

[0233] R 2 R 4 Independently for CF3;

[0234] X and T are N independently;

[0235] Y is independently CH;

[0236] Z can be CH or N independently;

[0237] A 1 It can be independently CH2 or C (=O);

[0238] B can be independently O, S, N, or NH, A 2 Independently CH2 or a connecting bond;

[0239] Indicates a single key.

[0240] In one aspect of the present invention,

[0241] R 1 R 1’ R 3 R 3’ R 5 R 5’ H is independent;

[0242] R 2 R 4 Independently for C substituted with one or more halogens 1-6 alkyl;

[0243] X and T are N independently;

[0244] Y is independently C(R) 3c );

[0245] Z is independently C(R) 3d );

[0246] A 1 Independently for C(R) 4b R 4c );

[0247] B can be either O or S independently;

[0248] A 2 Independently for C(R) 5b R 5c ) or connection key;

[0249] Indicates a single key.

[0250] In one aspect of the present invention,

[0251] R1 R 1’ R 3 R 3’ R 5 R 5’ H is independent;

[0252] R 2 R 4 Independently for CF3;

[0253] X and T are N independently;

[0254] Y and Z are independently CH;

[0255] A 1 Independently CH2;

[0256] B can be either O or S independently;

[0257] A 2 Independently CH2 or a connecting bond;

[0258] Indicates a single key.

[0259] In one aspect of the present invention,

[0260] Where L is

[0261] R 1 R 1’ Independently, H or R 1 and R 1’ O = ;

[0262] R 3 R 3’ Independently for H and C 1-6 Alkyl, or R 3 and R 3’ O = ;

[0263] R 5 R 5’ H is independent;

[0264] R 2 R 4 Independently halogen, CN, or C substituted with one or more halogens. 1-6 alkyl;

[0265] X is N;

[0266] T is C(R) 3b ) or N;

[0267] R 3b For H;

[0268] Y is C(R)3c );

[0269] R 3c For H, by one or more R a4 Replacement C 1-6 Alkyl or C 1-6 Alkoxy;

[0270] Z is C(R) 3d );

[0271] R 3d For H, C 1-6 Alkyl or with one or more R a4 Replacement C 1-6 alkyl;

[0272] A 1 Independently for C(R) 4a ), C(R 4b R 4c ) or C (=O);

[0273] R 4a R 4b R 4c Independently H or C 1-6 alkyl;

[0274] When B is independently O, S(=O), S(=O)2, N(R) 6d When A 2 Independently for C(R) 5a ), C(R 5b R 5c ), connection key;

[0275] When B is independently C(R) 6a ), C(R 6b R 6c When A 2 Independently for N(R) 5d ), connection key;

[0276] R 5b R 5c Independently, H or R 5b and R 5c =0;

[0277] R 5d C 1-6 alkyl;

[0278] R 6d C 1-6 Alkyl, with one or more R a3 Replacement C 1-6 Alkyl, C 3-6 cycloalkyl, CN;

[0279] R 6a For H;

[0280] R 6b R 6c Independently H, -OH, or R 6b and R 6c =0;

[0281] R a3 It is a halogen or -OH;

[0282] Indicates a single key.

[0283] In one aspect of the present invention,

[0284] Where L is

[0285] R 1 R 1’ Independently H or C 1-6 alkyl;

[0286] R 3 R 3’ R 5 R 5’ H is independent;

[0287] R 2 CN, C substituted with one or more halogens 1-6 alkyl;

[0288] R 4 C substituted by one or more halogens 1-6 alkyl;

[0289] X is N;

[0290] T is C(R) 3b ) or N; R 3b For H;

[0291] Y is independently C(R) 3c ); R 3c For H or C 1-6 alkyl;

[0292] Z is independently C(R) 3d ) or N; R 3d H, CN or C 1-6 alkyl;

[0293] A 1 Independently for C(R) 4b R 4c ) or C (=O); R 4b R 4c H is independent;

[0294] When B is independently O, S, S(=O), S(=O)2, N(R) 6d When A 2 Independently for C(R) 5b R 5c ) or connection key;

[0295] When B is independently C(R) 6b R 6c When A 2 Independently for O, N(R) 5d ) or connection key;

[0296] R 5b R 5c Independently for H and C 1-6 Alkyl, or R 5b and R 5c =0;

[0297] R 6d For H, C 1-6 Alkyl, with one or more R a3 Replacement C 1-6 Alkyl, C 3-6 cycloalkyl, CN;

[0298] R 5d For H, C 1-6 alkyl;

[0299] R 6b R 6c Independently H, -OH, or R 6b and R 6c =0;

[0300] R a3 It is either deuterium or -OH;

[0301] Indicates a single key.

[0302] In one aspect of the present invention,

[0303] Where L is

[0304] R 1 R 1’ Independently H or C 1-6 alkyl;

[0305] R 3 R 3’ R 5 R 5’ H is independent;

[0306] R 2CN, C substituted with one or more halogens 1-6 alkyl;

[0307] R 4 C substituted by one or more halogens 1-6 alkyl;

[0308] X and T are N independently;

[0309] Y is independently C(R) 3c ); R 3c For H;

[0310] Z is independently C(R) 3d ) or N; R 3d For H;

[0311] A 1 Independently for C(R) 4b R 4c ) or C (=O); R 4b R 4c H is independent;

[0312] When B is independently O, S, N(R) 6d When A 2 Independently for C(R) 5b R 5c ) or connection key;

[0313] When B is independently C(R) 6b R 6c When A 2 Independently for O, N(R) 5d ) or connection key;

[0314] When A 1 C is O, B is N(R) 6d When A 2 For connection key;

[0315] R 5b R 5c H is independent;

[0316] R 6d For H, C 1-6 Alkyl, with one or more R a3 Replacement C 1-6 Alkyl, C 3-6 cycloalkyl;

[0317] R 6b R 6c Independently H, -OH, or R 6b and R 6c =0;

[0318] R5d For H, C 1-6 alkyl;

[0319] R a3 It is deuterium;

[0320] Indicates a single key.

[0321] In one aspect of the present invention,

[0322] Where L is

[0323] R 1 R 1’ R 3 R 3’ R 5 R 5’ H is independent;

[0324] R 2 R 4 Independently for C substituted with one or more halogens 1-6 alkyl;

[0325] X and T are N independently;

[0326] Y is independently C(R) 3c ); R 3c For H;

[0327] Z is independently C(R) 3d ) or N; R 3d For H;

[0328] A 1 Independently for C(R) 4b R 4c ) or C (=O); R 4b R 4c H is independent;

[0329] When B is independently O, S, N(R) 6d When A 2 Independently for C(R) 5b R 5c ) or connection key;

[0330] When B is independently C(R) 6b R 6c When A 2 Independently for O, N(R) 5d ) or connection key;

[0331] When B is independently N(R) 6d When A 1 Independently, it is C (=O);

[0332] When A 1 C is O, B is N(R) 6d When A 2 For connection key;

[0333] When T and Z are both N, A 2 Independently for O, N(R) 5d ) or C(R 5b R 5c );

[0334] R 5b R 5c H is independent;

[0335] R 6d Independently for C 1-6 Alkyl, with one or more R a3 Replacement C 1-6 alkyl;

[0336] R 6b R 6c H is independent;

[0337] R 5d For H;

[0338] R a3 It is deuterium;

[0339] Indicates a single key.

[0340] In one aspect of the present invention, the tricyclic heterocyclic compound represented by Formula IA has any of the following structures:

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348] in, The bond represents a mixture of R and S configurations.

[0349] Therefore, throughout this specification, those skilled in the art can select the groups and substituents in the tricyclic heterocyclic compounds of Formula IA or their pharmaceutically acceptable salts to provide stable tricyclic heterocyclic compounds of Formula IA or their pharmaceutically acceptable salts, including but not limited to the compounds described in the embodiments of the present invention.

[0350] The tricyclic heterocyclic compounds of Formula IA described in this invention, or pharmaceutically acceptable salts thereof, can be synthesized by methods similar to those known in the chemical field, with steps and conditions referencing those of similar reactions in the art, particularly those described herein. Starting materials are typically derived from commercial sources, such as Aldrich, or can be readily prepared using methods known to those skilled in the art (obtainable via online databases such as SciFinder and Reaxys).

[0351] In this invention, the tricyclic heterocyclic compound represented by Formula IA can also be obtained by peripheral modification of the prepared tricyclic heterocyclic compound represented by Formula I' using conventional methods in the art.

[0352] Generally, the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are defined as shown in Formula I'. The following reaction schemes and examples are provided to further illustrate the content of the present invention.

[0353] The method for preparing the tricyclic heterocyclic compound as shown in Formula IA in this invention includes the following steps:

[0354] In a solvent, in the presence of a base and a condensing agent, the compound shown in Formula IIA is subjected to an amidation reaction with the compound shown in Formula IIIA as shown below to obtain the tricyclic heterocyclic compound shown in Formula IA.

[0355]

[0356] Among them, W, L, R 7 R 8 R 1 R 1’ R 2 R 3 R 3’ R 4 R 5 R 5’ X, T, Y, Z, A 1 B, A 2 Q The definitions of and * are as described in any of the above schemes;

[0357] X' is a leaving group, such as a halogen (e.g., Cl) or OH.

[0358] For example, when the tricyclic heterocyclic compound represented by Formula IA is a tricyclic heterocyclic compound represented by Formula I', its preparation method includes the following steps:

[0359] In a solvent, in the presence of a base and a condensing agent, the compound shown in Formula II' and the compound shown in Formula III' are subjected to an amidation reaction as shown below to obtain the tricyclic heterocyclic compound shown in Formula I'.

[0360]

[0361] L, R 1 R 1’ R 3 R 3’ R 5 R 5’ R 2 R 4 X, T, Y, Z, A 1 B, A 2 Q The definitions of X and * are as described above; X' is a leaving group, such as a halogen (e.g., Cl) or OH;

[0362] For example

[0363]

[0364] Among them, R 1 R 1’ R 3 R 3’ R 5 R 5’ R 2 R 4 X, T, Y, Z, A 1 B, A 2 Q The definitions of and * are as described above.

[0365] The conditions and procedures for the amidation reaction are conventional in this type of reaction in the art. In this invention, the following are preferred:

[0366] The solvent is DMF or dichloromethane (DCM). The base is diisopropylethylamine or K₂CO₃. The molar ratio of the base to the compound shown in Formula II is 1:1. The condensing agent is propylphosphonic anhydride (T₃P), for example, a 50% ethyl acetate solution. The molar ratio of the condensing agent to the compound shown in Formula II is 1:1.

[0367] The molar ratio of the compound shown in Formula IIA to the compound shown in Formula IIIA is 1:1. The amidation reaction is carried out under nitrogen protection. The temperature of the amidation reaction is from 0°C to 60°C.

[0368] The necessary raw materials or reagents for preparing compounds of formula IA are commercially available or can be prepared by synthetic methods known in the art. The methods described in the experimental section below can be used to prepare compounds of the present invention, either as a free base or as a salt thereof upon addition of acid. The term pharmaceutically acceptable salt refers to a pharmaceutically acceptable salt as defined herein and possesses all the pharmaceutical activities of the parent compound. Pharmaceutically acceptable salts can be prepared by adding a suitable acid to a suitable organic solvent containing an organic base, following conventional methods.

[0369] Examples of salt formation include: salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; and salts formed with organic acids, such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheponic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, or trimethylacetic acid.

[0370] Tricyclic compounds as shown in Formula IA may have one or more chiral carbon atoms, thus allowing for the isolation of optically pure isomers, such as pure enantiomers, racemates, or mixed isomers. Pure single isomers can be obtained by separation methods in the art, such as chiral crystallization into salts or separation using chiral preparative columns.

[0371] The chemicals used in the synthetic route described in this patent include solvents, reagents, catalysts, and protecting groups, deprotecting groups, and protecting groups. The above method may also include steps before or after the steps specifically described herein, where suitable protecting groups may be added or removed to obtain the target compound. Furthermore, the various synthetic steps may be performed alternately or sequentially to obtain the final target product.

[0372] This invention provides a pharmaceutical composition comprising a tricyclic heterocyclic compound of formula IA as described above, or a pharmaceutically acceptable salt thereof, and (one or more) pharmaceutical excipients. In the pharmaceutical composition, the amount of the tricyclic heterocyclic compound of formula IA or a pharmaceutically acceptable salt thereof may be a therapeutically effective amount.

[0373] This invention also provides the use of the tricyclic heterocyclic compound of Formula IA or a pharmaceutically acceptable salt thereof in the preparation of a PARP inhibitor. The PARP may be PARP7. In the described application, the PARP inhibitor can be used in mammalian organisms; it can also be used in vitro, primarily for experimental purposes, such as providing a standard or control sample for comparison, or preparing a kit according to conventional methods in the art to provide rapid detection of PARP inhibitory effects.

[0374] This invention also provides the use of the tricyclic heterocyclic compound of Formula IA or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention and / or treatment of PARP-related or PARP-mediated diseases. The PARP may be PARP7. The PARP-related or PARP-mediated diseases may include aberrant proliferative disorders or other diseases related to targets that bind to this series of compounds; the aberrant proliferative disorders include, but are not limited to, cancers such as lung cancer (e.g., squamous cell carcinoma of the lung, H1373 lung cancer), colon cancer, colorectal cancer, pancreatic cancer, kidney cancer, gastric cancer, esophageal cancer, ovarian cancer, breast cancer, cervical cancer, head and neck cancer (upper respiratory and digestive tract), bladder cancer, melanoma, fibrosarcoma, and glioblastoma. The amount of the tricyclic heterocyclic compound of Formula IA or a pharmaceutically acceptable salt thereof may be a therapeutically effective amount.

[0375] This invention also provides the use of the tricyclic heterocyclic compound of Formula IA or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, in the preparation of a medicament for the prevention and / or treatment of anomalous proliferative diseases. The anomalous proliferative diseases include, but are not limited to, cancers such as lung cancer (e.g., squamous cell carcinoma of the lung, H1373 lung cancer), colon cancer, colorectal cancer, pancreatic cancer, kidney cancer, gastric cancer, esophageal cancer, ovarian cancer, breast cancer, cervical cancer and head and neck cancer (upper respiratory and digestive tract), bladder cancer, melanoma, fibrosarcoma, and glioblastoma. The amount of the tricyclic heterocyclic compound of Formula IA or a pharmaceutically acceptable salt thereof may be a therapeutically effective amount.

[0376] Another aspect of the invention relates to a method for preventing and / or treating PARP7-related or PARP-mediated diseases, comprising administering to a patient a therapeutically effective dose of the said tricyclic heterocyclic compound as represented by Formula IA or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.

[0377] Another aspect of the present invention relates to a method for treating, preventing, and / or treating abnormal proliferative diseases, comprising administering to a patient a therapeutically effective dose of the said tricyclic heterocyclic compound as represented by Formula IA or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same; wherein the abnormal proliferative diseases include, but are not limited to, said cancers such as lung cancer (e.g., squamous cell carcinoma of the lung, H1373 lung cancer cell), colon cancer, colorectal cancer, pancreatic cancer, kidney cancer, stomach cancer, esophageal cancer, ovarian cancer, breast cancer, cervical cancer and head and neck cancer (upper respiratory and digestive tract), bladder cancer, melanoma, fibrosarcoma, and glioblastoma.

[0378] Another aspect of the invention relates to a medicament for inhibiting PARP7, comprising the tricyclic heterocyclic compound as shown in Formula IA or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.

[0379] This invention provides a tricyclic heterocyclic compound as shown in Formula I, or a pharmaceutically acceptable salt thereof.

[0380]

[0381] Among them, R 1 R 1’ R 3 R 3’ R 5 R 5’ Independently for H and C 1-6 Alkyl or with one or more R 1a Replacement C 1-6 Alkyl; or, R 1 and R 1’ R 3 and R 3’ R 5 and R 5’ Independently, it is O; when there are multiple substituents, they may be the same or different;

[0382] R 1a Independently halogen, CN, OH;

[0383] R 2 R 4 Independent of halogen, CN, C 1-6 Alkyl, with one or more R 2a Replacement C 1-6 Alkyl, with one or more R 2b Replacement C 1-6 Alkyl-S-; when there are multiple substituents, they may be the same or different;

[0384] R 2a R 2b Halogens are independent of each other;

[0385] X is independently C(R) 3a ), C (when When it is a double bond, it is... ) or N;

[0386] T independently represents C(R) 3b ) or N; Y independently is C(R) 3c ) or N; Z independently is C(R) 3d ) or N;

[0387] R 3a R 3b R 3c R 3d Independently, it can be H, halogen, CN, NH2, or C. 1-6 alkyl;

[0388] A 1 Independently for C(R) 4a )(when When it is a double bond), C(R) 4b R 4c )(when (when it is a single bond) or C (=O);

[0389] R 4a R 4b R 4c Independently for H and C 1-6 Alkyl or with one or more R a1 Replacement C 1-6 Alkyl group; when there are multiple substituents, they may be the same or different;

[0390] When B is independently C(R) 6a ), C(R 6b R 6c When A 2 Independently for C(R) 5a ), C(R 5b R 5c ), O, S, N (R) 5d ), N or connection key;

[0391] When B is independently O, S, N or N(R) 6d When A 2 Independently for C(R) 5a ), C(R 5b R 5c ) or connection key;

[0392] R 5a R 5b R 5c R 5d Independently for H and C 1-6Alkyl or with one or more R a2 Replacement C 1-6 alkyl;

[0393] R 6a R 6b R 6c Independent of H, halogen, C 1-6 Alkyl, with one or more R a3 Replacement C 1-6 Alkyl, C 3-6 cycloalkyl;

[0394] R 6d Independently for H and C 1-6 Alkyl, with one or more R a3 Replacement C 1-6 Alkyl, C 3-6 Cycloalkyl; when there are multiple substituents, they may be the same or different;

[0395] R a1 R a2 R a3 Independently classified as deuterium and halogen;

[0396] * indicates a double or single bond; * indicates that when it is a chiral carbon atom, it is an R configuration, an S configuration, or a mixture thereof.

[0397] In this invention, the definitions of certain substituents in the tricyclic heterocyclic compounds shown in Formula I are as follows, and the definitions of substituents not mentioned are as described in any of the above schemes.

[0398] In one aspect of the present invention, R 1 R 1’ One of them is H, and the other is H and C. 1-6 Alkyl or with one or more R 1a Replacement C 1-6 alkyl;

[0399] For example, R 1 R 1’ One of them is H, and the other is either H or C. 1-6 alkyl;

[0400] Or, R 1 and R 1’ Together they form O = ;

[0401] Preferably, R 1 R 1’ For H.

[0402] In one aspect of the present invention, R 3 R 3’ One of them is H, and the other is H and C.1-6 Alkyl or with one or more R 1a Replacement C 1-6 alkyl;

[0403] For example, R 3 R 3’ One of them is H, and the other is either H or C. 1-6 alkyl;

[0404] Or, R 3 and R 3’ Together they form O = ;

[0405] Preferably, R 3 R 3’ For H.

[0406] In one aspect of the present invention, R 5 R 5’ One of them is H, and the other is H and C. 1-6 Alkyl or with one or more R 1a Replacement C 1-6 alkyl;

[0407] For example, R 5 R 5’ One of them is H, and the other is either H or C. 1-6 alkyl;

[0408] Or, R 5 and R 5’ Together they form O = ;

[0409] Preferably, R 5 R 5’ For H.

[0410] In one aspect of the present invention, R 1 R 1’ R 3 R 3’ R 5 R 5’ One of them is H, C 1-6 Alkyl or with one or more R 1a Replacement C 1-6 Alkyl groups, the rest being H;

[0411] For example, R 1 R 1’ R 3 R 3’ R 5 R 5’ One of them is H or C 1-6 Alkyl groups, the rest being H;

[0412] Or, R 1 and R1’ R 3 and R 3’ R 5 and R 5’ One of them is O, and the rest are H;

[0413] Preferably, R 1 R 1’ R 3 R 3’ R 5 R 5’ For H.

[0414] In one aspect of the present invention, when R 1 R 1’ When the attached carbon is a chiral carbon, it has an S configuration or an R configuration;

[0415] For example, the R configuration.

[0416] In one aspect of the present invention, when R 3 R 3’ When the attached carbon is a chiral carbon, it has an S configuration or an R configuration.

[0417] In one aspect of the present invention, when R 5 R 5’ When the attached carbon is a chiral carbon, it has an S configuration or an R configuration.

[0418] In one aspect of the present invention, R 2 Independently halogen, CN, or by one or more R 2a Replacement C 1-6 Alkyl, with one or more R 2b Replacement C 1-6 Alkyl-S-;

[0419] For example, halogens, by one or more R 2a Replacement C 1-6 alkyl;

[0420] For example, C substituted with one or more halogens 1-6 alkyl.

[0421] In one aspect of the present invention, R 4 Independently halogen, CN, or by one or more R 2a Replacement C 1-6 alkyl;

[0422] For example, halogens, by one or more R 2a Replacement C 1-6 alkyl;

[0423] For example, C replaced by one or more halogens 1-6alkyl.

[0424] In one aspect of the present invention, R 2 R 4 Independently for one or more R 2a Replacement C 1-6 alkyl;

[0425] For example, -CF3.

[0426] In one embodiment of the present invention, X is independently N.

[0427] In one embodiment of the invention, T is independently N.

[0428] In one aspect of the present invention, R 3c H, CN, NH2 or C 1-6 alkyl;

[0429] For example, H.

[0430] In one embodiment of the present invention, Y is independently C(R) 3c );

[0431] For example, CH.

[0432] In one aspect of the present invention, R 3d H, halogen, CN or C 1-6 alkyl;

[0433] For example, H.

[0434] In one aspect of the invention, Z is independently C(R) 3d );

[0435] For example, CH.

[0436] In one aspect of the present invention, R 4a R 4b R 4c Independently H or C 1-6 alkyl;

[0437] For example, R 4b and R 4c One is H, and the other is H or C. 1-6 alkyl;

[0438] For example, R 4b and R 4c For H.

[0439] In one aspect of the present invention, when A 1 For C(R) 4b R 4c When the carbon is chiral carbon, its configuration is S configuration, R configuration or a mixture thereof.

[0440] In one aspect of the present invention, A 1 Independently for C(R) 4b R 4c ) or C(=O); for example, C(R) 4b R 4c ).

[0441] In one aspect of the present invention, R 5a R 5b R 5c R 5d Independently H or C 1-6 alkyl;

[0442] For example, R 5b and R 5c One is H, and the other is H or C. 1-6 alkyl;

[0443] For example, R 5b and R 5c For H.

[0444] In one aspect of the present invention, when A 2 For C(R) 5b R 5c When the carbon is chiral carbon, its configuration is S configuration, R configuration or a mixture thereof.

[0445] In one aspect of the present invention, A 2 Independently for C(R) 5b R 5c ) or connection key.

[0446] In one aspect of the present invention, R 6a R 6b R 6c Independently H or halogen;

[0447] For example, R 6b R 6c H stands for H independently.

[0448] In one aspect of the present invention, R 6d Independently for H and C 1-6 Alkyl, with one or more R a3 Replacement C 1-6 Alkyl, C 3-6 cycloalkyl;

[0449] For example, H or C 1-6 alkyl.

[0450] In one embodiment of the invention, B is independently C(R) 6b R 6c ).

[0451] In one embodiment of the invention, B is independently O, S, or N(R) 6d );

[0452] For example, -O- or -S-;

[0453] For example, S.

[0454] In one aspect of the present invention, Independently for -C(R) 4b R 4c )-O-、-C(R 4b R 4c )-S-、-C(R 4b R 4c )-N(R 6d )-、-C(R 4b R 4c )-C(R 6b R 6c )-, -C(=O)-O-, -C(=O)-N(R 6d )-;

[0455] For example, -CH2-O-, -CH2-S-, -CH2-NH-, -CH2-N(CH3)-, -CH2-N(CH2CF3)-, -CH2-CH2-, -CH2-CF2-, -C(CH3)-O-, -C(CH3)-S-, -C(=O)-NH-, -C(=O)-O-, -C(=O)-N(CD3)-, -CH2-N(cyclopropyl)-, -C(=O)-N(cyclopropyl)-;

[0456] For example, -C(R) 4b R 4c )-O-、-C(R 4b R 4c )-S-、-C(R 4b R 4c )-N(R 6d )-、-C(=O)-N(R 6d )-;

[0457] For example, -CH2-O- and -CH2-S-.

[0458] In one aspect of the present invention, Independently -O-, -S-, -C(R) 6b R 6c )-、-N(R 6d )-、-OC(R 5b R 5c )-、-SC(R 5b R5c )-、-N(R 6d )-C(R 5b R 5c )-、-C(R 6b R 6c )-O-、-C(R 6b R 6c )-S-、-C(R 6b R 6c )-N(R 5d )-;

[0459] For example, -O-, -OC(R) 5b R 5c )-、-SC(R 5b R 5c )-、-N(R 6d )-、-N(R 6d )-C(R 5b R 5c )-;

[0460] For example, -O-, -O-CH2-, or -S-CH2-.

[0461] In one aspect of the present invention, Independently

[0462] In one aspect of the present invention, Independently for -C(R) 4b R 4c )-O-、-C(R 4b R 4c )-S-、-C(R 4b R 4c )-N(R 6d )-、-C(=O)-N(R 6d )-、-C(R 4b R 4c )-OC(R 5b R 5c )-、-C(R 4b R 4c )-SC(R 5b R 5c )-、-C(R 4b R 4c )-N(R 6d )-C(R 5b R 5c )-、-C(R 4b R 4c )-C(R 6b R 6c )-N(R 5d )-、-C(R4b R 4c )-C(R 6b R 6c )-O-、-C(R 4b R 4c )-C(R 6b R 6c )-S-、-C(=O)-N(R 6d )-C(R 5b R 5c )-、-C(=O)-OC(R 5b R 5c )-、-C(R 4b R 4c )-C(R 6b R 6c )-;

[0463] For example -C(R) 4b R 4c )-O-、-C(R 4b R 4c )-S-、-C(R 4b R 4c )-N(R 6d )-、-C(=O)-N(R 6d )-、-C(R 4b R 4c )-OC(R 5b R 5c )-、-C(R 4b R 4c )-SC(R 5b R 5c )-、-C(R 4b R 4c )-N(R 6d )-C(R 5b R 5c )-;

[0464] For example, -C(R) 4b R 4c )-O-、-C(R 4b R 4c )-S-、-C(R 4b R 4c )-OC(R 5b R 5c )-、-C(R 4b R 4c )-SC(R 5b R 5c )-;

[0465] Other examples include -CH2-O-, -CH2-S-, -CH2-O-CH2-, and -CH2-S-CH2-.

[0466] In one aspect of the present invention, Independently

[0467] In one aspect of the present invention, when R 1 R 1’ R 3 R 3’ R 5 R 5’ Independently for C 1-6 Alkyl or with one or more R 1a Replacement C 1-6 When alkyl, the C 1-6 Alkyl or with one or more R 1a Replacement C 1-6 C in alkyl 1-6 The alkyl group is a C1-C4 alkyl group.

[0468] For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl;

[0469] For example, methyl.

[0470] In one aspect of the present invention, when R 1a When the halogen is halogen, the halogen is F, Cl, Br, or I;

[0471] For example, F.

[0472] In one aspect of the present invention, when R 2 R 4 When it is a halogen on its own, the halogen is F, Cl, Br, or I;

[0473] For example, F.

[0474] In one aspect of the present invention, when R 2 R 4 Independently for C 1-6 Alkyl, with one or more R 2a Replacement C 1-6 Alkyl, with one or more R 2b Replacement C 1-6 When alkyl-S-, the C 1-6 Alkyl, with one or more R 2a Replacement C 1-6 Alkyl and one or more R 2b Replacement C 1-6 C in alkyl-S- 1-6 The alkyl group is a C1-C4 alkyl group.

[0475] For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl;

[0476] For example, methyl.

[0477] In one aspect of the present invention, when R 2 R 4 Independently for one or more R 2a Replacement C 1-6 Alkyl, with one or more R 2b Replacement C 1-6 When alkyl-S-, the number of substituents is 1, 2, or 3;

[0478] For example, 3.

[0479] In one aspect of the present invention, when R 2a R 2b When it is a halogen on its own, the halogen is F, Cl, Br, or I;

[0480] For example, F.

[0481] In one aspect of the present invention, when R 3a R 3b R 3c R 3d When it is a halogen on its own, the halogen is F, Cl, Br, or I;

[0482] For example, F.

[0483] In one aspect of the present invention, when R 3a R 3b R 3c R 3d Independently for C 1-6 When alkyl, the C 1-6 The alkyl group is a C1-C4 alkyl group.

[0484] For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl;

[0485] For example, methyl.

[0486] In one aspect of the present invention, when R 4a R 4b R 4c Independently for C 1-6 Alkyl or with one or more R a1 Replacement C 1-6 When alkyl, the C 1-6 Alkyl and one or more R a1 Replacement C 1-6 C in alkyl 1-6The alkyl group is a C1-C4 alkyl group.

[0487] For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl;

[0488] For example, methyl.

[0489] In one aspect of the present invention, when R 5a R 5b R 5c R 5d Independently for C 1-6 Alkyl or with one or more R a2 Replacement C 1-6 When alkyl, the C 1-6 Alkyl and one or more R a2 Replacement C 1-6 C in alkyl 1-6 The alkyl group is a C1-C4 alkyl group.

[0490] For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl;

[0491] For example, methyl.

[0492] In one aspect of the present invention, when R 6a R 6b R 6c When it is a halogen on its own, the halogen is F, Cl, Br, or I;

[0493] For example, F.

[0494] In one aspect of the present invention, when R 6a R 6b R 6c R 6d Independently for C 1-6 Alkyl, with one or more R a3 Replacement C 1-6 When alkyl, the C 1-6 Alkyl and one or more R a3 Replacement C 1-6 C in alkyl 1-6 The alkyl group is a C1-C4 alkyl group.

[0495] For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl;

[0496] For example, methyl.

[0497] In one aspect of the present invention, when R 6a R 6b R 6c R6d Independently for C 3-6 When cycloalkyl, the C 3-6 The cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

[0498] For example, cyclopropyl.

[0499] In one aspect of the present invention, when R a1 R a2 R a3 When it is a halogen on its own, the halogen is F, Cl, Br, or I;

[0500] For example, F.

[0501] In one aspect of the present invention, R 1 R 1’ R 3 R 3’ R 5 R 5’ Independently, it can be H, methyl, HO-methyl, NC-methyl, CHF2, CF3; or, R 1 and R 1’ R 3 and R 3’ R 5 and R 5’ Independently, it is O=.

[0502] In one aspect of the present invention, R 2 R 4 Independently, it is fluorine, bromine, chlorine, CN, CF3, CF3-S-.

[0503] In one embodiment of the present invention, Y is independently CH, N, C(CN), C(NH2); for example, CH, N.

[0504] In one embodiment of the present invention, Z is independently CH, N, C(CN), C(NH2); for example, CH and N.

[0505] In one aspect of the present invention, A 1 It can be independently CH2, C(CH3) or C(=O);

[0506] In one embodiment of the present invention, B is independently CH2, CF2, O, S, NH, N(CH3), N(CD3), N(cyclopropyl), N(CH2CF3), C(CH3) or C(=O).

[0507] In one aspect of the present invention, A 2 It can be independently formed by CH2, O, S, NH, N(CH3), N(cyclopropyl), CH(CH3) or a connecting bond.

[0508] In one aspect of the present invention, Independently For example

[0509] In one aspect of the present invention, Independently

[0510] For example

[0511] For example

[0512] In one aspect of the present invention, Independently

[0513] For example

[0514] For example

[0515] In one aspect of the present invention,

[0516] R 1 R 1’ Independently H or C 1-6 alkyl;

[0517] R 3 R 3’ R 5 R 5’ H is independent;

[0518] R 2 R 4 Independently for C substituted with one or more halogens 1-6 alkyl;

[0519] X and T are N independently;

[0520] Y is independently C(R) 3c );

[0521] Z is independently C(R) 3d ) or N;

[0522] A 1 Independently for C(R) 4b R 4c ) or C (=O);

[0523] B is independently O, S, N, or N(R)6d A 2 Independently for C(R) 5b R 5c ) or connection key;

[0524] Indicates a single key.

[0525] In one aspect of the present invention,

[0526] R 1 R 1’ Independently, it is either H or methyl;

[0527] R 3 R 3’ R 5 R 5’ H is independent;

[0528] R 2 R 4 Independently for CF3;

[0529] X and T are N independently;

[0530] Y is independently CH;

[0531] Z can be CH or N independently;

[0532] A 1 It can be independently CH2 or C (=O);

[0533] B can be independently O, S, N, or NH, A 2 Independently CH2 or a connecting bond;

[0534] Indicates a single key.

[0535] In one aspect of the present invention,

[0536] R 1 R 1’ R 3 R 3’ R 5 R 5’ H is independent;

[0537] R 2 R 4 Independently for C substituted with one or more halogens 1-6 alkyl;

[0538] X and T are N independently;

[0539] Y is independently C(R) 3c );

[0540] Z is independently C(R)3d );

[0541] A 1 Independently for C(R) 4b R 4c );

[0542] B can be either O or S independently;

[0543] A 2 Independently for C(R) 5b R 5c ) or connection key;

[0544] Indicates a single key.

[0545] In one aspect of the present invention,

[0546] R 1 R 1’ R 3 R 3’ R 5 R 5’ H is independent;

[0547] R 2 R 4 Independently for CF3;

[0548] X and T are N independently;

[0549] Y and Z are independently CH;

[0550] A 1 Independently CH2;

[0551] B can be either O or S independently;

[0552] A 2 Independently CH2 or a connecting bond;

[0553] Indicates a single key.

[0554] In one aspect of the present invention, the tricyclic heterocyclic compound as shown in Formula I has any of the following structures:

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561] in, The bond represents a mixture of R and S configurations.

[0562] Therefore, throughout this specification, those skilled in the art can select the groups and substituents in the tricyclic heterocyclic compounds of Formula I or their pharmaceutically acceptable salts to provide stable tricyclic heterocyclic compounds of Formula I or their pharmaceutically acceptable salts, including but not limited to the compounds described in the embodiments of the present invention.

[0563] The tricyclic heterocyclic compounds of Formula I or their pharmaceutically acceptable salts described herein can be synthesized by methods similar to those known in the chemical field, with steps and conditions referencing those of similar reactions in the art, particularly those described herein. Starting materials are typically derived from commercial sources, such as Aldrich, or can be readily prepared using methods known to those skilled in the art (obtainable via online databases such as SciFinder and Reaxys).

[0564] In this invention, the tricyclic heterocyclic compound shown in Formula I can also be obtained by peripheral modification of the prepared tricyclic heterocyclic compound shown in Formula I using conventional methods in the art.

[0565] Generally, the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are defined as shown in Formula I. The following reaction schemes and examples are provided to further illustrate the content of the present invention.

[0566] The method for preparing the tricyclic heterocyclic compound as shown in Formula I in this invention includes the following steps:

[0567] In a solvent, in the presence of a base and a condensing agent, the compound shown in Formula II is subjected to an amidation reaction with the compound shown in Formula III as shown below to obtain the tricyclic heterocyclic compound shown in Formula I.

[0568]

[0569] Among them, R 1 R 1’ R 3 R 3’ R 5 R 5’ R 2 R 4 X, T, Y, Z, A 1 B, A2 The definitions of and * are as described above.

[0570] The conditions and procedures for the amidation reaction are conventional in this type of reaction in the art. In this invention, the following are preferred:

[0571] The solvent is DMF or dichloromethane (DCM). The base is diisopropylethylamine or K₂CO₃. The molar ratio of the base to the compound shown in Formula II is 1:1. The condensing agent is propylphosphonic anhydride (T₃P), for example, a 50% ethyl acetate solution. The molar ratio of the condensing agent to the compound shown in Formula II is 1:1.

[0572] The molar ratio of the compound shown in Formula II to the compound shown in Formula III is 1:1. The amidation reaction is carried out under nitrogen protection. The temperature of the amidation reaction is from 0°C to 60°C.

[0573] The necessary raw materials or reagents for preparing compounds of formula I are commercially available or can be prepared by synthetic methods known in the art. The methods described in the experimental section below can be used to prepare compounds of the present invention, either as a free base or as a salt thereof upon addition of acid. The term pharmaceutically acceptable salt refers to a pharmaceutically acceptable salt as defined herein and possesses all the pharmaceutical activities of the parent compound. Pharmaceutically acceptable salts can be prepared by adding a suitable acid to a suitable organic solvent containing an organic base, following conventional methods.

[0574] Examples of salt formation include: salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; and salts formed with organic acids, such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheponic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, or trimethylacetic acid.

[0575] Tricyclic compounds as shown in Formula I may have one or more chiral carbon atoms, thus allowing for the isolation of optically pure isomers, such as pure enantiomers, racemates, or mixed isomers. Pure single isomers can be obtained by separation methods in the art, such as chiral crystallization into salts or separation using chiral preparative columns.

[0576] The chemicals used in the synthetic route described in this patent include solvents, reagents, catalysts, and protecting groups, deprotecting groups, and protecting groups. The above method may also include steps before or after the steps specifically described herein, where suitable protecting groups may be added or removed to obtain the target compound. Furthermore, the various synthetic steps may be performed alternately or sequentially to obtain the final target product.

[0577] This invention provides a pharmaceutical composition comprising a tricyclic heterocyclic compound of Formula I as described above, or a pharmaceutically acceptable salt thereof, and (one or more) pharmaceutical excipients. In the pharmaceutical composition, the amount of the tricyclic heterocyclic compound of Formula I or a pharmaceutically acceptable salt thereof may be a therapeutically effective amount.

[0578] This invention also provides the use of the tricyclic heterocyclic compound of Formula I or a pharmaceutically acceptable salt thereof in the preparation of a PARP inhibitor. The PARP may be PARP7. In the described application, the PARP inhibitor can be used in mammalian organisms; it can also be used in vitro, primarily for experimental purposes, such as providing a standard or control sample for comparison, or preparing a kit according to conventional methods in the art to provide rapid detection of PARP inhibitory effects.

[0579] This invention also provides the use of the tricyclic heterocyclic compound of Formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention and / or treatment of PARP-related or PARP-mediated diseases. The PARP may be PARP7. The PARP-related or PARP-mediated diseases may include aberrant proliferative disorders or other diseases related to targets targeted by this series of compounds; the aberrant proliferative disorders include, but are not limited to, cancers such as lung cancer (e.g., squamous cell carcinoma of the lung, H1373 lung cancer), colon cancer, colorectal cancer, pancreatic cancer, kidney cancer, gastric cancer, esophageal cancer, ovarian cancer, breast cancer, cervical cancer, head and neck cancer (upper respiratory and digestive tract), bladder cancer, melanoma, fibrosarcoma, and glioblastoma. The amount of the tricyclic heterocyclic compound of Formula I or a pharmaceutically acceptable salt thereof may be a therapeutically effective amount.

[0580] This invention also provides the use of the tricyclic heterocyclic compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for the prevention and / or treatment of anomalous proliferative diseases. The anomalous proliferative diseases include, but are not limited to, cancers such as lung cancer (e.g., squamous cell carcinoma of the lung, H1373 lung cancer), colon cancer, colorectal cancer, pancreatic cancer, kidney cancer, stomach cancer, esophageal cancer, ovarian cancer, breast cancer, cervical cancer, and head and neck cancer (upper respiratory and digestive tract), bladder cancer, melanoma, fibrosarcoma, and glioblastoma. The amount of the tricyclic heterocyclic compound of Formula I or a pharmaceutically acceptable salt thereof may be a therapeutically effective amount.

[0581] Another aspect of the invention relates to a method for preventing and / or treating PARP7-related or PARP-mediated diseases, comprising administering to a patient a therapeutically effective dose of the said tricyclic heterocyclic compound as shown in Formula I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.

[0582] Another aspect of the present invention relates to a method for treating, preventing, and / or treating abnormal proliferative diseases, comprising administering to a patient a therapeutically effective dose of the said tricyclic heterocyclic compound as represented by Formula I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same; wherein the abnormal proliferative diseases include, but are not limited to, said cancers such as lung cancer (e.g., squamous cell carcinoma of the lung, H1373 lung cancer cell), colon cancer, colorectal cancer, pancreatic cancer, kidney cancer, stomach cancer, esophageal cancer, ovarian cancer, breast cancer, cervical cancer and head and neck cancer (upper respiratory and digestive tract), bladder cancer, melanoma, fibrosarcoma, and glioblastoma.

[0583] Another aspect of the invention relates to a medicament for inhibiting PARP7, comprising the tricyclic heterocyclic compound as shown in Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0584] The compounds of the present invention can be administered locally or systemically, for example, for enteral administration, such as rectal or oral administration, or for parenteral administration to mammals (especially humans). The compounds of the present invention can also be administered parenterally, for example, by inhalation, injection or infusion, such as via intravenous, intra-arterial, intra-bone, intramuscular, intracerebral, extraventricular, intrasynovial, intrasternal, intrathecal, intralesional, intralesional, intracranial, intratumoral, intradermal, and subcutaneous injection or infusion.

[0585] The effective amount of the compound, pharmaceutical composition, or drug described in this invention depends on the species, weight, age, individual condition, individual pharmacokinetic parameters, the disease to be treated, and the route of administration of the mammal.

[0586] The effective amount of the compounds, pharmaceutical compositions, or drugs described in this invention can be easily determined by routine experiments. The most effective and convenient route of administration and the most appropriate formulation can also be determined by routine experiments.

[0587] The pharmaceutical excipients described herein may be those widely used in the pharmaceutical manufacturing field. Excipients primarily serve to provide a safe, stable, and functional pharmaceutical composition, and may also provide methods for enabling the active ingredient to dissolve at a desired rate after administration to a subject, or to promote the effective absorption of the active ingredient after administration to a subject. The pharmaceutical excipients may be inert fillers, or provide a function such as stabilizing the overall pH of the composition or preventing the degradation of the active ingredient. The pharmaceutical excipients may include one or more of the following: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesion agents, flow aids, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

[0588] Substances that can be used as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicates, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl cellulose. Sodium thiosulfate, ethyl cellulose and cellulose acetate; gum powder; 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 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 salts; Ringer's solution; ethanol, phosphate buffer solution, and other non-toxic and suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings and spices, preservatives and antioxidants.

[0589] The pharmaceutical compositions of the present invention can be prepared using any method known to those skilled in the art, based on the disclosure. For example, conventional mixing, dissolving, granulation, emulsification, grinding, encapsulation, embedding, or lyophilization processes.

[0590] Pharmaceutical dosage forms of the compounds of this invention can be provided in the form of immediate-release, controlled-release, sustained-release, or targeted drug delivery systems. Common dosage forms include solutions and suspensions, (micro)emulsions, ointments, gels and patches, liposomes, tablets, sugar-coated pills, soft-shell or hard-shell capsules, suppositories, ovules, implants, amorphous or crystalline powders, aerosols, and lyophilized formulations. Depending on the route of administration used, special devices may be required to administer or deliver the drug, such as syringes and needles, inhalers, pumps, injection pens, applicators, or special flasks. Pharmaceutical dosage forms often consist of the drug, excipients, and a container / sealing system. One or more excipients (also known as inactive ingredients) may be added to the compounds of this invention to improve or facilitate the manufacture, stability, administration, and safety of the drug, and to provide a method for obtaining the desired drug release profile. Therefore, the type of excipient added to the drug can be determined by various factors, such as the physical and chemical properties of the drug, the route of administration, and the preparation steps. Pharmaceutical excipients exist in this field and include those listed in various pharmacopoeias. (See the United States Pharmacopeia (USP), Japanese Pharmacopoeia (JP), European Pharmacopoeia (EP), and British Pharmacopoeia (BP); publications of the Center for Drug Evaluation and Research (CEDR) of the US Food and Drug Administration (www.fda.gov), such as the Inactive Ingredient Guide (1996); and the Handbook of Pharmaceutical Additives (2002, Synapse Information Resources, Inc., Endicott NY; etc.)).

[0591] The pharmaceutical dosage forms of the compounds of this invention can be manufactured by any method well known in the art, such as conventional mixing, sieving, dissolving, melting, granulation, manufacturing of sugar-coated pills, tableting, suspension, extrusion, spray drying, grinding, emulsification, (nano / micron) encapsulation, packaging, or lyophilization processes. As described above, the compositions of this invention may include one or more physiologically acceptable inactive ingredients that facilitate the processing of the active molecules into formulations for pharmaceutical use.

[0592] The pharmaceutical compositions of the present invention can be administered topically or systemically, for example, for enteral administration, such as rectal or oral administration, or for parenteral administration to mammals (especially humans), and comprise a therapeutically effective amount of the active ingredient as a compound according to the invention or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient, such as a pharmaceutically acceptable carrier. The therapeutically effective amount of the active ingredient is as defined in the context and depends on the mammalian species, weight, age, individual condition, individual pharmacokinetic parameters, the disease to be treated, and the route of administration. For enteral administration, such as oral administration, the compounds of the present invention can be formulated into a wide variety of dosage forms.

[0593] The pharmaceutical composition and dosage form may contain one or more compounds of the present invention, or one or more pharmaceutically acceptable salts thereof, as the active ingredient. The pharmaceutically acceptable carrier may be solid or liquid. Solid formulations include powders, tablets, pills, lozenges, capsules, suppositories, and dispersible granules. The solid carrier may also be one or more substances serving as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, preservative, tablet disintegrant, or encapsulating material. In powders, the carrier is typically a finely ground solid, which is a mixture with the finely ground active ingredient. In tablets, the active ingredient is typically mixed with a carrier having the necessary binding capacity in a suitable proportion and compacted to the desired shape and size. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, methylcellulose, sodium carboxymethyl cellulose, low-melting-point waxes, cocoa butter, etc. Formulations of the active compound may include encapsulating materials as carriers, providing capsules in which the active ingredient, with or without a carrier, is surrounded by a carrier bound to it.

[0594] Other forms suitable for oral administration include liquid formulations, including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid formulations intended to be converted into a liquid form shortly before use. Emulsions can be prepared in solutions, such as aqueous solutions of propylene glycol, or may contain emulsifiers such as lecithin, sorbitan monooleate, or gum arabic. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavorings, stabilizers, and thickeners. Aqueous suspensions can be prepared by dispersing finely particulate active ingredients in water using binders such as natural or synthetic gums, resins, methylcellulose, carboxymethylcellulose, and other commonly used suspending agents. Solid formulations include solutions, suspensions, and emulsions, which, in addition to the active ingredient, may contain colorants, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

[0595] Exemplary combinations for rectal administration include suppositories that may contain, for example, suitable non-irritating excipients such as cocoa butter, synthetic glycerides, or polyethylene glycol, which are solid at room temperature but melt and / or dissolve in the rectal lumen to release the drug.

[0596] The compounds of the present invention can also be administered parenterally, for example by inhalation, injection or infusion, such as via intravenous, intra-arterial, intra-bone, intramuscular, intracerebral, extraventricular, intrasynovial, intrasternal, intrathecal, intrasheath, intralesional, intracranial, intratumoral, intradermal and subcutaneous injection or infusion.

[0597] Therefore, for parenteral administration, the pharmaceutical compositions of the present invention can be in the form of sterile injectable or infusionable formulations, for example, as sterile aqueous or oily suspensions. These suspensions can be formulated using suitable dispersants or wetting agents (e.g., Tween 80) and suspending agents according to techniques known in the art. Sterile injectable or infusionable formulations can also be sterile injectable or infusionable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents. For example, the pharmaceutical composition can be a solution in 1,3-butanediol. Other examples of acceptable media and solvents that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, mannitol, water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile non-volatile oils are commonly used as solvents or suspension media. Any mild non-volatile oil can be used for this purpose, including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives can be used to prepare injections, as can natural, pharmaceutically acceptable oils such as olive oil or castor oil, particularly their polyoxyethylated forms. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants. Solutions intended for parenteral use may also include suitable stabilizers and, if necessary, buffering agents. Suitable stabilizers include antioxidants, such as sodium bisulfate, sodium sulfite, or ascorbic acid, citric acid, and their salts, and sodium EDTA, alone or in combination. Parenteral solutions may also contain preservatives, such as benzalkonium chloride, p-hydroxybenzoic acid, or propylparaben, and chlorobutanol.

[0598] For inhalation or nasal administration, suitable pharmaceutical formulations may be particles, aerosols, powders, mists, or droplets, for example, with an average size of about 10 micrometers in diameter or less. For example, compositions for inhalation in solution form may be prepared in saline, using benzyl alcohol or other suitable preservatives, absorption enhancers to improve bioavailability, fluorocarbons, and / or other solubilizers or dispersants known in the art.

[0599] The pharmaceutical compositions of the present invention can also be administered topically to the skin or mucous membranes. For topical application, the pharmaceutical compositions may be, for example, lotions, gels, pastes, tinctures, transdermal patches, or gels for transmucosal delivery.

[0600] The pharmaceutical compositions may be formulated as suitable ointment preparations comprising an active ingredient suspended or dissolved in a carrier. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsified waxes, and water. Alternatively, the pharmaceutical compositions may be formulated as suitable lotions or emulsions comprising an active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water. The pharmaceutical compositions of the present invention may also be applied topically to the lower intestine in rectal suppository formulations or suitable enema formulations. Suitable pharmaceutical excipients (such as carriers) and methods for preparing pharmaceutical dosage forms are described in standard reference textbooks in the field of pharmaceutical formulations (Remington's Pharmaceutical Sciences, Mack Publishing Company).

[0601] The effective therapeutic dose can be estimated first using various methods well known in the art. The initial dose for animal studies can be based on the effective concentration established in cell culture assays. The appropriate dose range for individual humans can be determined, for example, using data obtained from animal studies and cell culture assays. In some embodiments, the compounds of the present invention can be prepared as oral formulations.

[0602] The effective amount or therapeutically effective dose of a drug (such as the compounds of this invention) refers to the amount of the drug or compound that causes improvement in individual symptoms or prolongs survival. The toxicity and therapeutic efficacy of the molecule can be determined in cell cultures or laboratory animals using standard pharmaceutical procedures, such as by measuring LD50. 50 (Dose that causes 50% lethality in the population) and ED 50 (The dose effective for 50% of the population). The dose ratio of toxicity to therapeutic effect is the therapeutic index, which can be expressed as LD50. 50 / ED 50 Drugs exhibiting a high therapeutic index are preferred.

[0603] An effective or therapeutically effective dose is the amount of a compound or pharmaceutical composition that will elicit a biological or medical response in a tissue, system, animal, or human that is being sought by researchers, veterinarians, physicians, or other clinicians. The dosage is preferably within the range of minimal or no toxicity. 50 The dosage may vary within the range of circulating concentrations. The dosage may vary within this range depending on the dosage form and / or route of administration. The appropriate formulation, route of administration, dosage, and dosing interval should be selected based on methods known in the art, taking into account the specific circumstances of the individual.

[0604] Dosage and intervals can be individually adjusted to provide a plasma level sufficient to achieve the desired effect; this is known as the minimum effective concentration (MEC). The MEC will vary from compound to compound but can be estimated, for example, from in vitro data and animal studies. The dose required to achieve the MEC will depend on individual characteristics and route of administration. In cases of local administration or selective uptake, the effective local concentration of the drug may be independent of plasma concentration.

[0605] The amount of medication or composition administered may vary depending on various factors, including the individual’s sex, age and weight, the severity of the illness, the method of administration and the prescribing physician’s judgment.

[0606] When needed, the compositions of the present invention can be provided using packaging or dispensing devices containing one or more unit dosage forms (containing the active ingredient). For example, the packaging or device may comprise metal or plastic foil (such as foam packaging) or glass and a rubber stopper, as in vials. The packaging or dispensing device may be accompanied by instructions for use. Compositions of the compounds of the present invention formulated in a compatible pharmaceutical carrier can also be prepared, placed in a suitable container, and labeled for the treatment of a specified condition.

[0607] Unless otherwise specified, all technical and scientific terms used herein have the standard meaning in the field to which the claimed subject matter pertains. Where multiple definitions exist for a term, the definition herein shall prevail.

[0608] Group definition

[0609] Unless otherwise stated, the following definitions shall apply as used herein. For the purposes of this invention, chemical elements are consistent with the CAS edition of the periodic table and the *Handbook of Chemistry and Physics*, 75th edition, 1994. Furthermore, general principles of organic chemistry can be found in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry” by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0610] In this specification, groups and their substituents may be selected by those skilled in the art to provide stable structural moieties and compounds. When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left.

[0611] Certain chemical groups defined herein are preceded by simplified symbols to indicate the total number of carbon atoms present in the group. For example, C1-C6 alkyl refers to an alkyl group having a total of 1, 2, 3, 4, 5, or 6 carbon atoms as defined below. The total number of carbon atoms in the simplified symbols does not include carbons that may be present in substituents of the group.

[0612] In this paper, the numerical ranges defined in the substituents, such as 0 to 4, 1-4, 1 to 3, etc., indicate the integers within that range, such as 1-6 being 1, 2, 3, 4, 5, 6.

[0613] Except as otherwise specified, when used in the specification and claims of this application, the following terms shall have the following meanings.

[0614] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0615] The term "substituted" refers to the substitution of one or more hydrogen atoms on a particular atom by a substituent, including deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable.

[0616] Generally, the term "substituted" indicates that one or more hydrogen atoms in a given structure are substituted by a specific substituent. Further, when the group is substituted by more than one of the substituents, the substituents are independent of each other; that is, the more than one substituent can be different or the same. Unless otherwise indicated, a substituent can be substituted at each substituted position of the substituted group. When more than one position in a given structural formula can be substituted by one or more substituents selected from a specific group, the substituents can be substituted at the same or different positions.

[0617] In various parts of this specification, the substituents of the compounds disclosed herein are disclosed according to the type or range of groups. In particular, this invention includes every independent secondary combination of the various members of these group types and ranges. For example, the terms "C1-C6 alkyl" or "C..." 1-6 "alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl; "C" 1-4"Alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl (i.e. propyl, including n-propyl and isopropyl), and C4 alkyl (i.e. butyl, including n-butyl, isobutyl, sec-butyl, and tert-butyl).

[0618] The term "halogen" is selected from F, Cl, Br or I, especially F or Cl.

[0619] In this application, as part of a group or other group, the term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 12 carbon atoms, preferably a straight-chain or branched alkyl group containing 1 to 6 carbon atoms. General formula C n H 2n+1 The term "C1-C6 alkyl" refers to an alkyl moiety containing 1, 2, 3, 4, 5, or 6 carbon atoms. In one embodiment, "alkyl" refers to a C1-C6 alkyl. In another embodiment, "alkyl" refers to a C1-C4 alkyl.

[0620] Lower alkyl groups containing 1 to 6 carbon atoms, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc.

[0621] In this application, unless otherwise specified, the term "cycloalkyl" as a group or part of other groups refers to a saturated monocyclic, polycyclic, or bridged carbocyclic substituent consisting only of carbon and hydrogen atoms, and which may be connected to the rest of the molecule via a single bond through any suitable carbon atom; when polycyclic, it may be a fused or spirocyclic system (i.e., the two geminal hydrogens on the carbon atom are replaced by alkylene groups) of either a bridged or spirocyclic system. The cycloalkyl substituent may be connected to the central molecule via any suitable carbon atom. In some embodiments, C3-C6 cycloalkyl groups include cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), and cyclohexyl (C6). In some embodiments, C3-C6 cycloalkyl groups may be connected to the central molecule via a single bond through any suitable carbon atom. 10 Examples of cycloalkyl groups include the aforementioned C3-C6 cycloalkyl groups along with cycloheptyl (C7), cyclooctyl (C8), cyclononyl (C9), and cyclodecyl (C1). 10 ).

[0622] The terms “part,” “structural part,” “chemical part,” “group,” and “chemical group” used in this article refer to specific segments or functional groups within a molecule. A chemical part is generally considered to be a chemical entity embedded in or attached to a molecule.

[0623] When a listed substituent does not specify which atom it is attached to in a compound included but not specifically mentioned in the general chemical formula, such a substituent may be bonded to any of its atoms. Combinations of substituents and / or their variants are permitted only if such combinations produce stable compounds.

[0624] Linking substituents are described in various parts of this invention. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it should be understood that "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

[0625] In some specific structures, when an alkyl group is clearly indicated as a linking group, then the alkyl group represents a linked alkylene group. For example, the C1-C6 alkyl in the group “halogenated-C1-C6 alkyl” should be understood as C1-C6 alkylene.

[0626] The term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated straight-chain or branched hydrocarbon group. Examples of alkylene groups include methylene (-CH2-), ethylene {including -CH2CH2- or -CH(CH3)-}, isopropylene {including -CH(CH3)CH2- or -C(CH3)2-}, and so on.

[0627] Unless otherwise specified, all technical and scientific terms used herein have the standard meaning in the field to which the claimed subject matter pertains. Where multiple definitions exist for a term, the definition herein shall prevail.

[0628] It should be understood that the singular forms used in this invention, such as "a," include plural references unless otherwise specified. Furthermore, the term "comprising" is an open-ended limitation, not a closed one; that is, it includes the contents specified in this invention but does not exclude other aspects.

[0629] Unless otherwise stated, this invention employs traditional methods of mass spectrometry and elemental analysis, and the steps and conditions can be referred to conventional operating procedures and conditions in the field.

[0630] Unless otherwise specified, this invention employs standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, organic synthetic chemistry, and optics. In some cases, standard techniques are used for chemical synthesis, chemical analysis, and performance testing of light-emitting devices.

[0631] Furthermore, it should be noted that, unless otherwise explicitly stated, the descriptive phrase "...independently" used in this invention should be interpreted broadly, meaning that the described entities are independent of each other and can independently be the same or different specific functional groups. More specifically, the descriptive phrase "...independently" can mean either that the specific options expressed by the same symbol in different functional groups do not affect each other, or that the specific options expressed by the same symbol in the same functional group do not affect each other.

[0632] Those skilled in the art will understand that, according to the conventions used in the art, the structural formulas of the descriptive groups described in this application... This refers to the fact that the corresponding group is connected to other fragments or groups in the compound through this site.

[0633] "Pharmaceutical acceptable" means that the conditions under which a combination of drugs can be prepared are generally safe and non-toxic and not biologically or otherwise desirable, and include acceptable conditions for veterinary and human use.

[0634] The term "excipient" refers to a pharmaceutically acceptable chemical substance, such as a reagent known to a person of ordinary skill in the pharmaceutical field for assisting in the administration of a medicine. It is a compound that can be used to prepare a drug component, is generally safe, non-toxic, and biologically or otherwise undesirable, and includes excipients acceptable for both veterinary and human drugs. Common excipients include binders, surfactants, diluents, disintegrants, and lubricants.

[0635] The term "effective therapeutic dose" refers to the amount of compound used that is sufficient to achieve therapeutic effect when administered to a subject to treat a disease state. The "effective therapeutic dose" will vary depending on the compound, the disease state being treated, the severity of the disease, the subject's age and relative health, the route and method of administration, and the judgment of the attending physician or veterinarian.

[0636] As used in this patent, "treatment" or "under treatment" refers to obtaining beneficial or desired results, including clinical outcomes. Beneficial or desired clinical outcomes include, but are not limited to, the reduction or improvement of one or more symptoms or conditions, a decrease in disease severity, stabilization of the disease state (e.g., no worsening), prevention of disease spread, delay or slowing of disease progression, improvement or remission of the disease state, and partial or complete recovery, whether detectable or undetectable. The term may also refer to extended survival, compared to expected survival without treatment.

[0637] The term mammal refers to humans or any mammal, such as primates, farm animals, pet animals, or laboratory animals. Examples of these animals include monkeys, cows, sheep, horses, pigs, dogs, cats, rabbits, mice, and rats. Humans are preferred among mammals.

[0638] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0639] The reagents and raw materials used in this invention are all commercially available.

[0640] The positive and progressive effects of this invention are as follows: tricyclic compounds can be used as PARP7 (poly-ADP-ribose polymerase 7) inhibitors; they can treat diseases that are improved by inhibiting poly(ADP-ribose) polymerase; and they can be used in the preparation of drugs for the prevention and / or treatment of abnormal proliferative diseases or other diseases related to targets that are targeted by this series of compounds. Detailed Implementation

[0641] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0642] Oxazepin; PMB: 4-methoxybenzyl; T3P: propylphosphoanhydride.

[0643] Synthesis of intermediates

[0644] Intermediate 1: Synthesis of (S)-3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionic acid

[0645]

[0646] Step 1: Synthesis of 5-{[(2S)-1-hydroxypropyl-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridin-3-one (2)

[0647] (2S)-2-aminoprop-1-ol (0.236 g, 3.14 mmol) and 5-chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (1 g, 3.14 mmol) were dissolved in ethanol (10 mL), and triethylamine (0.952 g, 9.42 mmol) was added. The reaction mixture was stirred at 60 °C for 12 hours. The reaction solution was concentrated to dryness after cooling. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 40:60) to obtain the yellow oily target product (2) 5-{[(2S)-1-hydroxypropyl-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (2) (0.8 g, 2.239 mmol, yield: 71%), LCMS: MS(ESI) m / z: 358 [M+H] + .

[0648] Step 2: Synthesis of methyl 3-[(2S)-2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl}amino)propoxy]propionate (3)

[0649] Compound 5-{[(2S)-1-hydroxypropyl-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (0.63 g, 1.4 mmol) and methyl acrylate (0.362 g, 4.2 mmol) were dissolved in acetonitrile (5 mL), and then cesium carbonate (1.37 g, 4.2 mmol) was added. The mixture was stirred at room temperature for 3 hours, the solid was removed by filtration, and the filtrate was concentrated to obtain the crude product. After purification by silica gel column chromatography (petroleum ether:ethyl acetate = 70:30), the target product, methyl 3-[(2S)-2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl}amino)propoxy]propionate (3) (400 mg, 0.902 mmol, yield: 64%), was obtained. LCMS: MS(ESI) m / z: 444 [M+H] + .

[0650] Step 3: Synthesis of methyl 3-[(2S)-2-{[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino}propoxy]propionate (4)

[0651] Methyl 3-[(2S)-2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl}amino)propoxy]propionate (0.5 g, 1.128 mmol) was dissolved in dichloromethane (5 mL), followed by the addition of trifluoroacetic acid (0.2 mL) and trifluoromethanesulfonic acid (0.1 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, saturated sodium bicarbonate solution was added to the chilled reaction solution to adjust the pH to 8. Ethyl acetate (20 mL) was added, and the extract was dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:80) to give the white oily target product methyl 3-[(2S)-2-{[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino}propoxy]propionate (4) (0.2 g, 0.693 mmol, yield: 83%). LCMS: MS(ESI) m / z: 324 [M+H] + .

[0652] Step 4: Synthesis of 3-[(2S)-2-{[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino}propoxy]propionic acid (intermediate 1)

[0653] Methyl 3-[(2S)-2-{[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino}propoxy]propionate (1 g, 3.093 mmol) was dissolved in methanol (5 mL) and water (5 mL), and then lithium hydroxide (0.15 g, 3.712 mmol) was added. The reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was introduced into ice water (50 mL) and the pH was adjusted to 3. The mixture was extracted with ethyl acetate (20 mL). The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:90) to give the white oily target product 3-[(2S)-2-{[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino}propoxy]propionate (intermediate 1) (0.8 g, 2.587 mmol, yield: 83%). LCMS: MS (ESI) m / z: 310 [M+H] + .

[0654] Intermediate 2: Synthesis of 2-hydroxy-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionic acid

[0655]

[0656] Step 1: Synthesis of ethyl 3-((S)-2-((tert-butoxycarbonyl)amino)propoxy)-2-hydroxypropionate

[0657] (S)-2-(tert-Butoxycarbonylamino)-1-propanol (10.00 g, 57.1 mmol) and ethyl ethylene oxide-2-carboxylate (6.62 g, 57.1 mmol) were dissolved in ethyl acetate (200 mL), and then magnesium perchlorate (19.12 g, 85.65 mmol) was added. The reaction was carried out at 60 °C for 3 days. After the reaction was completed, the mixture was cooled to room temperature, poured into water (200 mL), and extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 80:20) to give ethyl 3-((S)-2-((tert-Butoxycarbonyl)amino)propoxy)-2-hydroxypropanoate (9.98 g, 34.2 mmol, yield 59%) as a yellow oil. LCMS(ESI) m / z: 292 [M+H] +

[0658] Step 2: Synthesis of ethyl 3-((S)-2-aminopropoxy)-2-hydroxypropanoate

[0659] Ethyl 3-((S)-2-((tert-butoxycarbonyl)amino)propoxy)-2-hydroxypropanoate (9.98 g, 34.2 mmol) was dissolved in an ice-cold (0 °C) solution of 1,4-dioxane (4 mol / L, 30 mL) of hydrogen chloride. The mixture was slowly heated to room temperature and stirred for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was diluted with water (20 mL), the pH was adjusted to 8–9 with sodium bicarbonate, and then extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 80:20) to give ethyl 3-((S)-2-aminopropoxy)-2-hydroxypropanoate (4.99 g, 26.0 mmol, yield 76%) as a yellow solid. LCMS (ESI) m / z: 192 [M+H] +

[0660] Step 3: Synthesis of ethyl 2-hydroxy-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionate

[0661] Ethyl 3-((S)-2-aminopropoxy)-2-hydroxypropanoate (4.99 g, 26.0 mmol) and 5-chloro-4-(trifluoromethyl)-2-(2-(trimethylsilyl)ethoxy)methyl)pyridazine-3(2H)-one (8.53 g, 26.0 mmol) were dissolved in ethanol (20 mL), and then triethylamine (5.25 g, 52.0 mmol) was added. The reaction was carried out at 60 °C for 2 h. After the reaction was completed, the mixture was cooled to room temperature, poured into water (50 mL), and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration. The filtrate was concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 70:30) to give ethyl 2-hydroxy-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionate (1.40 g, 2.9 mmol, yield 11%), as a yellow oil. LCMS (ESI) m / z: 484 [M+H] +

[0662] Step 4: Synthesis of 2-hydroxy-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionic acid

[0663] In a mixed solution of methanol (5.0 mL) and water (1.0 mL), ethyl 2-hydroxy-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionate (1.40 g, 2.9 mmol) and lithium hydroxide monohydrate (121 mg, 2.9 mmol) were added. The mixture was stirred at 0 °C for 3 hours. After the reaction was complete, the pH was adjusted to 6 with 1 mol / L hydrochloric acid. Extracted with ethyl acetate (20 mL x 2), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 60:40) to give 2-hydroxy-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionic acid (400 mg, 0.88 mmol, yield: 30%) as a yellow oil. LCMS (ESI) m / z: 456 [M+H] +

[0664] Synthesis of Intermediate 3, and Intermediates 3-100 and 3-200: Ethyl 2-hydroxy-3-((S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionate (Intermediate 3), (S)-2-hydroxy-3-((S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionate (Intermediate 3-100) and (R)-2-hydroxy-3-((S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionate (Intermediate 3-200)

[0665]

[0666] The synthesis of ethyl 2-hydroxy-3-((S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionate (intermediate 3) was similar to that of intermediate 2. Intermediate 3 (2.00 g, 4.23 mmol) was separated by chiral high-performance liquid chromatography (column: CHIRAL PAK IC Cellulose-SB, 2*25 cm, 5 μm; mobile phase A: methyl tert-butyl ether (0.1% diethylamine); mobile phase B: ethanol; flow rate: 20 mL / min; elution gradient: mobile phase B increased from 0% to 20% over 25 minutes; detection wavelength: 220 nm) to obtain (S)-2-hydroxy-3-((S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionate. Ethyl hydropyridazine-4-yl)amino)propoxy)propionate (400 mg, 1.072 mmol, 20% yield) is a pale yellow oil and (R)-2-hydroxy-3-((S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)propoxy)propionate (300 mg, 0.804 mmol, 15% yield) is a pale yellow oil.

[0667] Forehead peak (intermediate 3-100): (S)-2-hydroxy-3-((S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)propoxy)ethyl propionate

[0668] LCMS (ESI): 421 [M+H] +

[0669] Chiral chromatography: Column: CHIRALPAK IC-34.6*50mm, 3µm; Mobile phase A: n-hexane (0.1% diethylamine), Mobile phase B: ethanol; Mobile phase A: Mobile phase B = 80:20; Flow rate: 1.0 mL / min; Temperature: 25°C; Wavelength: 220 / 254 nm; Retention time: 4.65 min.

[0670] Post-peak (intermediate 3-200): (R)-2-hydroxy-3-((S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)propoxy)ethyl propionate

[0671] LCMS (ESI): 421 [M+H] +

[0672] Chiral chromatography: Column: CHIRALPAK IC-34.6*50mm, 3µm; Mobile phase A: n-hexane (0.1% diethylamine), Mobile phase B: ethanol; Mobile phase A: Mobile phase B = 80:20; Flow rate: 1.0 mL / min; Temperature: 25°C; Wavelength: 220 / 254 nm; Retention time: 5.76 min.

[0673] The stereochemistry of the alcohol in the foreground and background peaks can be arbitrarily specified. Others are similar.

[0674] Intermediate 4: Synthesis of 2-fluoro-3-((S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)propoxy)propionic acid

[0675]

[0676] Step 1: Synthesis of ethyl 2-fluoro-3-((S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)propoxy)propionate

[0677] Ethyl 2-hydroxy-3-((S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionate (intermediate 3, 1.02 g, 2.11 mmol) was dissolved in dichloromethane (30 mL). The system temperature was lowered to -40 °C, and then diethylaminotrifluoride (1.71 g, 10.55 mmol) was diluted in dichloromethane (10 mL) and added dropwise to the reaction solution. The mixture was slowly heated to room temperature and the reaction was continued for 12 hours. After the reaction was completed, the mixture was slowly poured into a saturated sodium bicarbonate solution, extracted with dichloromethane (30 mL × 3), the organic phases were combined and washed with saturated brine, and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration. The filtrate was concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 80:20) to give ethyl 2-fluoro-3-((S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionate (300 mg, 0.63 mmol, yield 30%), as a yellow oil. LCMS (ESI): 476 [M+H] +

[0678] Step 2: Synthesis of 2-fluoro-3-((S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)propoxy)propionic acid

[0679] Ethyl 2-fluoro-3-((S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionate (300 mg, 0.63 mmol) was dissolved in a mixture of methanol (5 mL) and water (1 mL), followed by the addition of potassium carbonate (174 mg, 1.26 mol). The mixture was reacted at room temperature for 3 hours. After the reaction was complete, the pH was adjusted to 5 with 1 mol / L dilute hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration. The filtrate was concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 30:70) to give 2-fluoro-3-((S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionic acid (200 mg, 0.45 mmol, yield 71%), as a yellow oil. LCMS (ESI): 448 [M+H] +

[0680] Synthesis of Intermediate 5: 8-Benzyl-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthidium-5-one

[0681]

[0682] Step 1: Synthesis of 4-benzyl-2-(2-methoxy-2-oxoethyl)piperazine-1-carboxylic acid tert-butyl ester

[0683] Methyl 2-(4-benzylpiperazin-2-yl)acetate (5.00 g, 20.14 mmol) and sodium bicarbonate (3.38 g, 40.27 mmol) were added to a mixture of dichloromethane (50 mL) and water (10 mL) along with di-tert-butyl dicarbonate (6.77 g, 30.20 mmol). The mixture was stirred at room temperature for 2 hours. The product was then poured into water (10 mL) and extracted with dichloromethane (10 mL × 2). The extract was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The product was purified by column chromatography (petroleum ether / ethyl acetate = 80:20) to give a pale yellow oily target product (3.01 g, 32 mmol, yield: 60%). LCMS: MS (ESI) m / z: 349 [M+H] + .

[0684] Step 2: Synthesis of 2-(4-benzyl-1-(tert-butoxycarbonyl)piperazin-2-yl)acetic acid

[0685] A mixture of 4-benzyl-2-(2-methoxy-2-oxoethyl)piperazine-1-carboxylic acid tert-butyl ester (1.00 g, 2.87 mmol) and lithium hydroxide (0.23 g, 5.74 mmol) in tetrahydrofuran (10 mL) and water (2 mL) was stirred at room temperature for 2 hours, then poured into water (10 mL), the pH was adjusted to 3 with formic acid, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate and then filtered and evaporated to dryness to give a white solid target product (0.60 g, 3.61 mmol, yield: 63%). LCMS: MS (ESI) m / z: 335 [M+H]+.

[0686] Step 3: Synthesis of tert-butyl 4-benzyl-2-(2-(methoxy(methyl)amino)-2-oxoethyl)piperazine-1-carboxylic acid

[0687] A solution of 2-(4-benzyl-1-(tert-butoxycarbonyl)piperazin-2-yl)acetic acid (1.00 g, 2.99 mmol), N,O-dimethylhydroxylamine hydrochloride (0.29 g, 2.99 mmol), 1-ethyl-3-(3-dimethylpropylamine)carbodiimide (1.14 g, 5.98 mmol), 1-hydroxybenzotriazole (1.90 g, 8.97 mmol), and N,N-diisopropylethylenediamine (1.93 g, 14.95 mmol) in dichloromethane (10 mL) was stirred at room temperature for 12 hours, then poured into water (10 mL), extracted with dichloromethane (10 mL), dried over anhydrous sodium sulfate, concentrated by filtration, and purified by column chromatography (petroleum ether:ethyl acetate = 50:50) to give a white oily target product (0.80 g, 2.1 mmol, yield: 71%). LCMS: MS(ESI) m / z: 378 [M+H] + .

[0688] Step 4: Synthesis of tert-butyl 4-benzyl-2-(2-(2-chloro-5-(trifluoromethyl)pyridin-3-yl)-2-oxoethyl)piperazine-1-carboxylic acid

[0689] 4-Benzyl-2-(2-(methoxy(methyl)amino)-2-oxoethyl)piperazine-1-carboxylic acid tert-butyl ester (1.00 g, 2.65 mmol) was added to a mixture in diethyl ether (50 mL) at -78 °C, followed by the addition of n-butyllithium (2.65 mL, 5.30 mmol, 2.5 mol / L n-hexane solution), and then 3-bromo-2-chloro-5-(trifluoromethyl)pyridine (0.69 g, 2.65 mmol). The mixture was stirred for 1 hour, then poured into saturated ammonium chloride (100 mL), and extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Purification was performed by column chromatography (petroleum ether:ethyl acetate = 75:15) to give the target product (0.80 g, 1.61 mmol, yield: 61%) as a red oil. LCMS: MS (ESI) m / z: 498 [M+H] + .

[0690] Step 5: Synthesis of 2-(4-benzylpiperazin-2-yl)-1-(2-chloro-5-(trifluoromethyl)pyridin-3-yl)ethyl-1-one

[0691] A mixture of 4-benzyl-2-(2-(2-chloro-5-(trifluoromethyl)pyridin-3-yl)-2-oxoethyl)piperazine-1-carboxylic acid tert-butyl ester (3.00 g, 6.02 mmol) in hydrochloric acid / dioxane (10 mL) was stirred at room temperature for 2 hours. The mixture was then concentrated to give the target product as a yellow oil (1.80 g, 4.51 mmol, yield: 75%). LCMS: MS(ESI) m / z: 398 [M+H]+ .

[0692] Step 6: Synthesis of 8-benzyl-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthidin-5-one

[0693] A mixture of 2-(4-benzylpiperazin-2-yl)-1-(2-chloro-5-(trifluoromethyl)pyridin-3-yl)ethyl-1-one (0.50 g, 1.26 mmol) and potassium carbonate (0.35 g, 2.51 mmol) in DMF (5 mL) was stirred at 80 °C for 2 hours, then poured into water (10 mL), extracted with ethyl acetate (10 mL × 2), dried over anhydrous sodium sulfate, concentrated by filtration, and purified by column chromatography (petroleum ether:ethyl acetate = 70:30) to give a yellow oily target product (0.22 g, 1.5 mmol, yield: 60%). LCMS: MS (ESI) m / z: 362 [M+H] + .

[0694] Synthesis of Intermediates 6 and 7: 3-((S)-1-hydroxyprop-2-yl)oxy)-1-((R)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxazacycloheptane-9(7H)-yl)prop-1-one (Intermediate 6) and 3-((S)-2-hydroxypropoxy)-1-((R)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxazacycloheptane-9(7H)-yl)prop-1-one (Intermediate 7)

[0695]

[0696] Step 1: Synthesis of (R)-1-(3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxazacycloheptane-9(7H)-yl)prop-2-en-1-one

[0697] (R)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxazacycloheptane (its synthesis is shown in Example 5, 3.50 g, 12.8 mmol) was added to dichloromethane (50 mL), followed by the addition of triethylamine (3.33 g, 25.6 mmol) and acrylic anhydride (1.92 g, 15.36 mmol). The mixture was stirred at -40 °C for 2 hours. After the reaction was complete, the mixture was poured into water (50 mL). Extracted with dichloromethane (25 mL x 2), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 40:60) to give (R)-1-(3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxazacycloheptan-9(7H)-yl)prop-2-en-1-one (1.71 g, 5.2 mmol, yield 41%), as a yellow oil. LCMS (ESI): 328 [M+H]+

[0698] Step 2: Synthesis of 3-((S)-1-hydroxyprop-2-yl)oxy)-1-((R)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxazacycloheptane-9(7H)-yl)prop-1-one (intermediate 6) and 3-((S)-2-hydroxypropoxy)-1-((R)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxazacycloheptane-9(7H)-yl)prop-1-one (intermediate 7)

[0699] (R)-1-(3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxazacycloheptan-9(7H)-yl)prop-2-en-1-one (1.01 g, 3.05 mmol) and cesium carbonate (1.98 g, 6.1 mmol) were added to acetonitrile (30.00 mL). The mixture was stirred at 75 °C for 7 hours. After the reaction was complete, the mixture was concentrated under reduced pressure and added to water (20 mL). It was extracted with ethyl acetate (15 mL * 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by reversed-phase chromatography (acetonitrile:water = 50:50) to give 3-(( S)-1-hydroxypropoxy)-1-((R)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxazacycloheptane-9(7H)-yl)prop-1-one (250 mg, 0.62 mmol, 20% yield), as a yellow oil and 3-((S)-2-hydroxypropoxy)-1-((R)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxazacycloheptane-9(7H)-yl)prop-1-one (500 mg, 1.24 mmol, 40% yield), as a yellow oil.

[0700] Forepeak (intermediate 6): 3-((S)-1-hydroxypropyl-2-yl)oxy)-1-((R)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxazacycloheptane-9(7H)-yl)prop-1-one

[0701] LCMS(ESI): 404[M+H]+

[0702] HNMR (400MHz, DMSO-d6): δppm 8.49-8.31(m, 1H), 7.81-7.71(m, 1H), 4.92-4.75(m, 1H), 4.61-4.41(m, 2H), 4.23-3.81(m, 2H), 3.92-3.83(m, 2H), 3.81-3.72(m, 2H), 3.70-3.62(m, 2H), 3.62-3.33(m, 3H), 3.22-3.14(m, 3H), 2.73-2.55(m, 2H), 1.11-0.92(m, 3H).

[0703] Later peak (intermediate 7): 3-((S)-2-hydroxypropoxy)-1-((R)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxazacycloheptane-9(7H)-yl)prop-1-one

[0704] LCMS(ESI): 404[M+H]+

[0705] HNMR (400MHz, DMSO-d6): δppm 8.49-8.31(m, 1H), 7.81-7.65(m, 1H), 4.92-4.81(m, 1H), 4.61-4.41(m, 2H), 4.15-4.01(m, 2H), 4.01-3.92(m, 2H), 3.81-3.72(m, 2H), 3.70-3.62(m, 2H), 3.62-3.33(m, 3H), 3.22-3.14(m, 3H), 2.73-2.55(m, 2H), 1.11-0.92(m, 3H).

[0706] Synthesis of Intermediates 8 and 9: (S)-5,5-difluoro-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthidine intermediate 8 and (R)-5,5-difluoro-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthidine intermediate 9

[0707]

[0708] Step 1: Synthesis of 8-benzyl-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydrospirocyclic [pyrazine[1,2-a][1,8]naphthidine-5,2′-[1,3]dithiopentane]

[0709] Compound 8-benzyl-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazine[1,2-a][1,8]naphthidin-5-one (intermediate 5, 2.80 g, 7.75 mmol) was dissolved in 40 mL of dichloromethane, and ethylenedithiol (2.19 g, 23.25 mmol, 1.96 mL) and trifluoride diethyl ether complex (3.30 g, 23.3 mmol) were added. The reaction solution was reacted at 25 °C for 24 hours. LC-MS showed that the starting material was not completely consumed. Ethylenedithiol (2.19 g, 23.25 mmol, 1.96 mL) and trifluoride diethyl ether complex (3.30 g, 23.3 mmol) were then added to the reaction solution, and the reaction solution was reacted at 25 °C for another 24 hours. LC-MS showed that the starting material had completely reacted. Add 40 mL of dichloromethane and 80 mL of 15% sodium hydroxide aqueous solution to the reaction mixture. Extract, collect the organic phase, wash with saturated brine, dry with anhydrous sodium sulfate, and filter. Concentrate the filtrate to obtain the crude product, which is purified by column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give the product 8-benzyl-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydrospirocyclic [pyrazine[1,2-a][1,8]naphthidine-5,2′-[1,3]dithiopentane] (2.30 g, yield: 67.8%), as a yellow solid. MS (ESI): m / z = 438.1 [M+H]+

[0710] Step 2: Synthesis of 8-benzyl-5,5-difluoro-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthidine

[0711] N-iodosuccinimide (2.37 g, 10.5 mmol) was suspended in 20 mL of dichloromethane and cooled to -60 °C. A hydrogen fluoride-pyridine complex (2.98 g, 21.0 mmol, 70%) was added under nitrogen protection, and the reaction was carried out at -60 °C for 1 hour. 8-Benzyl-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydrospirocyclic [pyrazine[1,2-a][1,8]naphthidine-5,2′-[1,3]dithiopentane (2.30 g, 5.26 mmol) was dissolved in 20 mL of dichloromethane and added to the above reaction solution at -60 °C. The reaction was carried out at -60 °C for 1 hour. LC-MS showed that the starting material was completely consumed and the product was formed. Add 150 mL of dichloromethane to the reaction mixture, wash with saturated sodium sulfite and sodium carbonate solutions, collect the organic phase, dry with anhydrous sodium sulfate, filter, concentrate the filtrate to obtain the crude product, and purify the crude product by column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain 8-benzyl-5,5-difluoro-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthidine (900.0 mg, yield: 44.7%), as a pale yellow solid. MS (ESI): m / z = 384.1 [M+H]+

[0712] Step 3: Synthesis of (S)-5,5-difluoro-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthidine and (R)-5,5-difluoro-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthidine

[0713] Compound 8-benzyl-5,5-difluoro-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthidine (900.0 mg, 2.35 mmol) was dissolved in 10 mL of dichloromethane and cooled to 0 °C. Chloroethyl 1-chloroformate (503.5 mg, 3.52 mmol) was added under nitrogen protection. The reaction was carried out at 55 °C for 3 hours. TLC showed that most of the starting material had reacted and new products were formed. The reaction solution was concentrated to obtain a yellow oil, which was dissolved in 8 mL of methanol and reacted at 70 °C for 1 hour. LC-MS was used to detect product formation. The reaction solution was concentrated to obtain a crude product, which was purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain the final product (235.0 mg). The combined products (total 500.9 mg) were separated by chiral chromatography (chiral column: DAICL CHIRALPAK). AD (250mm*30mm, 10um); mobile phase A: CO2, mobile phase B: Ethanol (0.1% NH3H2O); mobile phase A: mobile phase B was kept at 20%; flow rate: 80 mL / min; temperature: 38°C; wavelength: 220 / 254 nm) yielded product (S)-5,5-difluoro-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthidine (194.2 mg), a pale yellow solid, and product (R)-5,5-difluoro-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthidine (196.6 mg), a pale yellow solid.

[0714] MS(ESI): m / z = 294.1 [M+H] + .

[0715] 1 H NMR (400MHz, CHLOROFORM-d) δ8.46 (s, 1H), 7.94 (s, 1H), 4.83-4.76 (m, 1H), 3.48 (br t, J=11.4Hz, 1H), 3.23-3.14 (m, 2H), 2.90-2.75 (m, 2H), 2.67 (t, J=10.9Hz, 1H), 2.46-2.35 (m, 1H), 2.17-2.01 (m, 1H).

[0716] Forepeak (Intermediate 8): Chiral chromatography: Column: ChiralPak AD-3, 150 × 4.6 mm ID, 3 μm; Mobile phase A: CO2, Mobile phase B: Ethanol (0.05% DEA); Mobile phase A: Mobile phase B = 5% to 40% over 4.5 min; then hold 5% B for 1.5 min; Flow rate: 2.5 mL / min; Temperature: 40 °C; Wavelength: 220 / 254 nm; Retention time: 1.94 min.

[0717] Post-peak (intermediate 9): Chiral chromatography: Column: ChiralPak AD-3, 150 × 4.6 mm ID, 3 μm; Mobile phase A: CO2, Mobile phase B: Ethanol (0.05% DEA); Mobile phase A: Mobile phase B = 5% to 40% over 4.5 min; then hold at 5% B for 1.5 min; Flow rate: 2.5 mL / min; Temperature: 40 °C; Wavelength: 220 / 254 nm; Retention time: 2.61 min.

[0718] The stereochemistry of the forepeak and backpeak peaks is arbitrarily specified.

[0719] Intermediate 10: Synthesis of tert-butyl(R)-3-(acetoxymethyl)-4-(4-iodo-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid ester

[0720]

[0721] Step 1: Synthesis of tert-butyl(R)-3-(hydroxymethyl)-4-(4-iodo-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid ester

[0722] 13.00 g (60.11 mmol) of tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylic acid ester was added to N,N-dimethylformamide (260.00 mL). Then, 2-chloro-4-iodo-5-(trifluoromethyl)pyridine (22.18 g, 72.13 mmol) was added, followed by potassium carbonate (16.61 g, 120.22 mmol). The mixture was stirred at 100°C for 4 hours. After the reaction was complete, the system was cooled to room temperature, and the reaction solution was poured into water (500 mL). Extraction was then performed with ethyl acetate (100 mL x 3). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (ethyl acetate:petroleum ether = 40:60) to give tert-butyl(R)-3-(hydroxymethyl)-4-(4-iodo-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid ester (6.50 g, 13.34 mmol, 22% yield), as a yellow solid. LCMS (ESI) m / z: 488 [M+H] + .

[0723] Step 2: Synthesis of tert-butyl(R)-3-(acetoxymethyl)-4-(4-iodo-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid ester

[0724] 6.00 g (12.31 mmol) of tert-butyl(R)-3-(hydroxymethyl)-4-(4-iodo-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid ester was added to dichloromethane (120.00 mL), followed by triethylamine (1.93 g (24.63 mmol). The mixture was cooled to 0°C in an ice-water bath, and then acetyl chloride (1.50 g (14.78 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was quenched in ice water (100 mL), then extracted with dichloromethane (100 mL * 2), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the crude product was purified by column chromatography (ethyl acetate:petroleum ether = 40:60) to give tert-butyl(R)-3-(acetoxymethyl)-4-(4-iodo-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid ester (4.00 g, 7.56 mmol, 61% yield), as a yellow solid. LCMS (ESI) m / z: 530 [M + H]+. Specific Implementation

[0726] Example 1: Synthesis of 5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazine[1,2-d]pyridin[3,2-b][1,4]oxazine-8(6H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H)-one (Compound 1)

[0727]

[0728] Step 1: Synthesis of (3R)-4-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (1-2)

[0729] The mixture of (3R)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (1.0 g, 4.624 mmol) and 2,3-difluoro-5-(trifluoromethyl)pyridine (0.85 g, 4.624 mmol) was dissolved in DMF (2 mL), and then K2CO3 (0.263 g, 4.624 mmol) was added. The mixture was heated to 80 °C and stirred for 12 hours under nitrogen protection. After cooling, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, water (30 mL) was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 85:15) to give a white solid target product (600 mg, 0.319 mmol, yield: 70%). LCMS: MS (ESI) m / z: 380 [M+H] + .

[0730] Step 2: Synthesis of (10R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazine[1,2-d]pyridine[3,2-b][1,4]oxazine-8(6H)-tert-butyl formate (1-3)

[0731] (3R)-4-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (500 mg, 1.318 mmol) was dissolved in DMF (5 mL), and then potassium tert-butoxide (443 mg, 3.95 mmol) was added. The mixture was heated to 80 °C and stirred for 12 hours under nitrogen protection. After cooling, the mixture was extracted three times with 10 mL of ice water and ethyl acetate (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 75:25) to give the target product as a white solid (400 mg, 1.113 mmol, 84.45%). LCMS: MS (ESI) m / z: 360 [M+H] + .

[0732] Step 3: Synthesis of (R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyridino[3,2-b][1,4]oxazine (1-4)

[0733] (10R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazine[1,2-d]pyridine[3,2-b][1,4]oxazine-8(6H)-carboxylic acid tert-butyl ester (500 mg, 1.391 mmol) was dissolved in dichloromethane (5 mL), followed by the addition of trifluoroacetic acid (3 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was diluted with water (30 mL), and the pH was adjusted to 8-9 with sodium bicarbonate. The product was extracted three times with dichloromethane (20 mL × 3). The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 15:85) to give the target product as a white solid (300 mg, 1.157 mmol, yield: 83%). LCMS: MS(ESI) m / z: 260 [M+H] + .

[0734] Step 4: Synthesis of 5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazine[1,2-d]pyridin[3,2-b][1,4]oxazine-8(6H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H)-one (Compound 1)

[0735] 3-[(2S)-2-{[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino}propoxy]propionic acid (100 mg, 0.323 mmol) (intermediate 1) and (R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyridino[3,2-b][1,4]oxazine (83.83 mg, 0.323 mmol) (1-4) were dissolved in dichloromethane (1.0 mL), and then diisopropylethylamine (0.053 mL, 0.323 mmol) and T3P (102.89 mg, 0.323 mmol, 50% ethyl acetate solution) were added. After stirring the reaction mixture at room temperature for 2 hours, the reaction solution was poured into ice water (20 mL). The aqueous phase was extracted three times with ethyl acetate (10 mL × 3). The organic phases were combined, aerated with anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by preparative liquid chromatography (column: XBridge Prep OBD C18, 30 × 150 mm 5 μm, mobile phase A: water (with 10 mol / L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 mL / min, elution gradient: mobile phase B increased from 20% to 52% within 8 minutes, detection wavelength: 220 nm, retention time: 7.28 min) to obtain the white solid target product (50 mg, 0.091 mmol, yield: 28.09%).

[0736] 1H NMR (400MHz, DMSO-d6) δ (ppm): 12.45 (s, 1H), 8.07 (s, 1H), 7.91 (s, 1H), 7.29 (d, J=2.2Hz, 1H), 6.27-6.26 (m, 1H), 4.48-4.38 (m, 3H), 4.17-4.13 (m, 1H), 4.05-3.9 5(m, 2H), 3.69-3.67(m, 2H), 3.51-3.48(d, J=5.5Hz, 2H), 3.20-3.09(m, 1H), 2.91 -2.84 (m, 1H), 2.81-2.69 (m, 1H), 2.68-2.57 (m, 3H), 1.16-1.14 (d, J=6.5Hz, 3H). LCMS:MS(ESI)m / z:551.00[M+H] + .

[0737] Example 2: Synthesis of 5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazine[1,2-d]pyridin[3,2-b][1,4]oxazine-8(6H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H)-one (compound 2)

[0738]

[0739] The synthesis method was the same as in Example 1, except that (3S)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester was used instead of (3R)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester in the first step reaction. The crude product of compound 2 was purified by preparative liquid chromatography (column: XBridge Prep OBD C18, 30×150mm 5um, mobile phase A: water (with 10 mol / L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 mL / min, elution gradient: mobile phase B increased from 20% to 52% within 8 minutes, detection wavelength: 220 nm, retention time: 7.28 min) to obtain a white solid target product (50 mg, 0.091 mmol, yield: 23.00%).

[0740] 1HNMR (400MHz, DMSO-d6) δ (ppm): 12.46 (s, 1H), 8.07 (s, 1H), 7.91 (s, 1H), 7.29-7.28 (d, J = 2.1Hz, 1H), 6.28-6.25(m, 1H), 4.51-4.38(m, 3H), 4.18-4.13(m, 1H), 4.05-3.95(m, 2H), 3.73-3.64(m, 2H), 3.49- 3.48(d, J=5.5Hz, 2H), 3.17-3.11(m, 1H), 3.01-2.85(m, 1H), 2.79-2.71( m, 1H), 2.68-2.62 (m, 2H), 2.45-2.41 (m, 1H), 1.16-1.14 (d, J=6.5Hz, 3H). LCMS:MS(ESI)m / z:551.00[M+H] + .

[0741] Example 3: Synthesis of (R)-9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazine[2,1-c]pyridine[2,3-e][1,4]oxazin-5-one (compound 3)

[0742]

[0743] Step 1: Synthesis of (R)-5-oxo-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridine[2,3-e][1,4]oxazoline-9(7H)-carboxylic acid tert-butyl ester (3-2)

[0744] 2-Chloro-5-trifluoromethylpyridine-3-carboxylate (100 mg, 0.417 mmol) (3-1) and (3R)-3-hydroxymethyl-piperidine-1-carboxylate tert-butyl ester (91 mg, 0.417 mmol) were dissolved in DMF (2 mL), and potassium carbonate (115 mg, 0.84 mmol) was added. The reaction mixture was stirred at 80 °C for 12 hours. After cooling, the solid was removed by filtration, and the filtrate was concentrated to dryness. Water (50 mL) was added to the crude product, and it was extracted three times with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 54:46) to give the target product (120 mg, 0.310 mmol, yield: 74%) as a white solid. LCMS: MS (ESI) m / z: 388 [M+H] + .

[0745] Step 2: Synthesis of (R)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyridine[2,3-e][1,4]oxazine-5-one (3-3)

[0746] (R)-5-oxo-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridine[2,3-e][1,4]oxazoline-9(7H)-carboxylic acid tert-butyl ester (3-2) (500 mg, 1.29 mmol) was dissolved in ice-cold (0 °C) 1,4-dioxane hydrochloride solution (4 M) (5 mL). The reaction mixture was slowly heated to room temperature and stirred for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was diluted with water (30 mL), the pH was adjusted to 8-9 with sodium bicarbonate, and the product was extracted three times with dichloromethane (20 mL × 3). The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 15:85) to give the target product as a white solid (250 mg, 0.87 mmol, yield: 67%). LCMS: MS(ESI) m / z: 288 [M+H] + .

[0747] Step 3: Synthesis of (R)-9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazine[2,1-c]pyridine[2,3-e][1,4]oxazin-5-one (compound 3)

[0748] 3-[(2S)-2-{[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino}propoxy]propionic acid (108 mg, 0.348 mmol) (intermediate 1) and compound (S)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyridino[3,2-b][1,4]oxazine (100 mg, 0.348 mmol) (3-3) were dissolved in dichloromethane (2.0 mL), and then diisopropylethylamine (90 mg, 0.696 mmol) and T3P (112 mg, 0.418 mmol, 50% ethyl acetate solution) were added. After stirring the reaction mixture at room temperature for 2 hours, the reaction solution was poured into ice water (20 mL). The aqueous phase was extracted three times with ethyl acetate (10 mL × 3). The organic phases were combined, aerated with anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by preparative liquid chromatography (column: XBridge Prep OBD C18, 30 × 150 mm 5 μm, mobile phase A: water (with 10 mol / L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 mL / min, elution gradient: mobile phase B increased from 20% to 52% within 8 minutes, detection wavelength: 220 nm, retention time: 6.95 min) to obtain the target product as a white solid (52 mg, 0.090 mmol, yield: 25.01%).

[0749] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 12.45 (s, 1H), 8.75 (s, 1H), 8.14 (d, J=2.2Hz, 1H), 7. 92(s, 1H), 6.28-6.26(m, 1H), 4.67-4.63(m, 1H), 4.54-4.48(m, 1H), 4.47-4.33(m, 2H ), 4.19-4.11(m, 1H), 4.04-3.91(m, 1H), 3.78-3.65(m, 3H), 3.50-3.49(d, J=2.2Hz, 2H), 3.25-3.16(m, 1H), 3.13-2.95(m, 1H), 2.83-2.56(m, 3H), 1.15(d, J=6.5Hz, 3H). LCMS: MS(ESI)m / z: 579.05[M+H] + .

[0750] Example 4: Synthesis of (S)-9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazine[2,1-c]pyridine[2,3-e][1,4]oxazin-5-one (compound 4)

[0751]

[0752] The synthesis method was the same as in Example 3, except that (3S)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester was used instead of (3R)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester in the first step reaction. The crude product of compound 4 was purified by high performance liquid chromatography (column: XBridge Prep OBD C18, 30×150mm 5um, mobile phase A: water (with 10 mol / L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 mL / min, elution gradient: mobile phase B increased from 20% to 52% within 8 minutes, detection wavelength: 220 nm, retention time: 7.13 min). After purification, a white solid target product (20 mg, 0.035 mmol, yield: 53%) was obtained.

[0753] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 12.45 (s, 1H), 8.75 (s, 1H), 8.14 (d, J = 2.5Hz, 1H), 7.92(s, 1H), 6.34-6.20(m, 1H), 4.67-4.63(m, 1H), 4.53-4.50(m, 1H), 4.43-4.33( m, 2H), 4.17-4.13 (m, 1H), 4.04-3.91 (m, 1H), 3.80-3.67 (m, 3H), 3.50-3.49 (m, 2H ), 3.22-3.16 (m, 1H), 3.08-2.95 (m, 1H), 2.81-2.62 (m, 3H), 1.16 (d, J=6.4Hz, 3H). LCMS: MS(ESI)m / z: 579.15[M+H] + .

[0754] Example 5: Synthesis of 5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridin[2,3-e][1,4]oxapine-9(7H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H)-one (compound 5)

[0755]

[0756] Step 1: Synthesis of (R)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridine[2,3-e][1,4]oxazoline-9(7H)-carboxylic acid tert-butyl ester (5-1)

[0757] (R)-5-oxo-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridine[2,3-e][1,4]oxazoline-9(7H)-carboxylic acid tert-butyl ester (3-2) (500 mg, 1.29 mmol) was dissolved in tetrahydrofuran (5 mL). After cooling to 0 °C, sodium borohydride solid (50 mg, 1.295 mmol) was added, followed by dropwise addition of boron trifluoride-ethyl ether complex (185 mg, 1.292 mmol) under stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was poured into ice water (10 mL), and extracted three times with aqueous dichloromethane (20 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 25:75) to give the target product as a white solid (120 mg, 0.321 mmol, yield: 24%). LCMS: MS (ESI) m / z: 374 [M+H] + .

[0758] Step 2: Synthesis of (R)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazine[2,1-c]pyridine[2,3-e][1,4]oxazolidine(5-2)

[0759] (R)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridine[2,3-e][1,4]oxazoline-9(7H)-carboxylic acid tert-butyl ester (5-1) (100 mg, 0.268 mmol) was dissolved in ice-cold (0 °C) 1,4-dioxane hydrochloride solution (4 M, 5 mL), and the mixture was slowly heated to room temperature with stirring for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, the crude product was diluted with water (30 mL), the pH was adjusted to 8-9 with sodium bicarbonate, and the product was extracted three times with dichloromethane (20 mL × 3). The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 34:66) to give the target product as a white solid (70 mg, 0.256 mmol, yield: 95%). LCMS: MS(ESI) m / z: 274 [M+H] + .

[0760] Step 3: Synthesis of 5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridin[2,3-e][1,4]oxapine-9(7H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 5)

[0761] 3-[(2S)-2-{[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino}propoxy]propionic acid (10 mg, 0.032 mmol) (intermediate 1) and compound (R)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazin[2,1-c]-pyridine[2,3-e][1,4]oxazopine (5-2) (8.84 mg, 0.032 mmol) were dissolved in dichloromethane (2 mL), followed by the sequential addition of diisopropylethylamine (10 mg, 0.064 mmol) and T3P (21 mg, 0.064 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by high performance liquid chromatography (column: XBridge Prep OBD C18, 30×150mm, 5um; mobile phase A: water (10mmol / L sodium bicarbonate), mobile phase B: acetonitrile; flow rate: 60mL / min; gradient: mobile phase B increased from 20% to 52% within 8 minutes; detection wavelength: 220nm; retention time: 6.85 minutes) to obtain a white solid target product (11mg, 0.019mmol, yield: 59%).

[0762] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 12.45 (s, 1H), 8.42-8.38 (m, 1H), 7.91-7.90 (d, J=5.1Hz, 1H), 7.81-7.77(m, 1H), 6.26-6.25(m, 1H), 4.94-4.86(m, 1H), 4.55-4.49(m, 1H), 4.14(brs, 1H), 4.02- 3.77 (m, 5H), 3.75-3.57 (m, 5H), 3.56-3.41 (m, 3H), 2.62-2.54 (m, 2H), 1.16-1.13 (t, J=6.3Hz, 3H). LCMS: MS(ESI)m / z: 565.10[M+H] + .

[0763] Example 6: Synthesis of 5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridin[2,3-e][1,4]oxapine-9(7H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H)-one (compound 6)

[0764]

[0765] The synthetic route is the same as in Example 5, except that (S)-5-oxo-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridine[2,3-e][1,4]oxazoline-9(7H)-tert-butyl carboxylate (6-1) is used instead of the starting material (R)-5-oxo-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridine[2,3-e][1,4]oxazoline-9(7H)-tert-butyl carboxylate (3-2) in the first step reaction. The crude product of compound 6 was purified by high performance liquid chromatography (column: XBridgePrep OBD C18, 30×150mm, 5um; mobile phase A: water (10mmol / L sodium bicarbonate), mobile phase B: acetonitrile; flow rate: 60mL / min; gradient: mobile phase B increased from 20% to 52% within 8 minutes; detection wavelength: 220nm; retention time: 6.90 minutes) to obtain a white solid target product (11mg, 0.019mmol, yield: 59%).

[0766] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 12.45 (s, 1H), 8.42-8.39 (m, 1H), 7.91 (s, 1H), 7.81-7.77 (m, 1H), 6.28-6.25 (m, 1H), 4.94-4.8 6 (m, 1H), 4.54-4.49 (m, 1H), 4.19-4.11 (m, 1H), 4.05-3.64 (m, 10H), 3.56-3.41 (m, 3H), 2.56-2.52 (m, 2H), 1.16-1.14 (m, 3H). LCMS:MS(ESI)m / z:565.00[M+H] + .

[0767] Example 7: Synthesis of (R)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridin[3,2-e]pyrazine-6(6aH)-one (compound 7)

[0768]

[0769] Step 1: Synthesis of (R)-4-(tert-Butoxycarbonyl)-1-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazin-2-carboxylic acid (7-2)

[0770] (R)-4-(tert-Butoxycarbonyl)piperazin-2-carboxylic acid (7-1) (0.50 g, 2.17 mmol) and 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (7-2) (0.49 g, 2.17 mmol) were dissolved in methanol (5 mL), and then diisopropylethylamine (0.65 g, 4.34 mmol) was added. The reaction was stirred overnight at room temperature. The reaction solution was concentrated, diluted with water, and extracted three times with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration and dried. The filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 35:65) to give the target product as a yellow solid (0.90 g, 2.17 mmol, yield: 99%). LCMS: MS (ESI) m / z: 421 [M+H] + .

[0771] Step 2: Synthesis of (R)-6-oxy-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazine[1,2-a]pyridine[3,2-e]pyrazine-8-carboxylic acid tert-butyl ester (7-3)

[0772] (R)-4-(tert-butoxycarbonyl)-1-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazin-2-carboxylic acid (7-2) (0.20 g, 0.48 mmol) was dissolved in ethanol (10.00 mL), and solid ammonium chloride (0.25 g, 4.76 mmol) and iron powder (0.27 g, 4.76 mmol) were added. The reaction mixture was heated to 70 °C and stirred for 3 hours. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure and evaporated to dryness to give a black crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 65:35) to give a yellow solid target product (80 mg, 0.215 mmol, yield: 42%). LCMS: MS (ESI) m / z: 373 [M+H] + .

[0773] Step 3: Synthesis of (R)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazinee[1,2-a]pyridine[3,2-e]pyrazine-6(6aH)-one (7-4)

[0774] (R)-6-oxy-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazine[1,2-a]pyridine[3,2-e]pyrazine-8-carboxylic acid tert-butyl ester (7-3) (0.08 g, 0.215 mmol) was dissolved in hydrogen chloride to give a 1,4-dioxane solution (2.00 mL, 4 M). The reaction mixture was stirred at room temperature for 0.5 hours until the reaction was complete. The reaction solution was concentrated under reduced pressure, and water (10 mL) was added to the crude product. The pH was adjusted to 8-9 with saturated sodium bicarbonate aqueous solution, and the mixture was extracted three times with ethyl acetate (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:90) to give the yellow target product (51 mg, 0.18 mmol, yield: 84%). LCMS: MS(ESI) m / z: 273 [M+H] + .

[0775] Step 4: Synthesis of (R)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridin[3,2-e]pyrazine-6(6aH)-one (Compound 7)

[0776] (R)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazinee[1,2-a]pyridin[3,2-e]pyrazine-6(6aH)-one (7-4) (146.72 mg, 0.54 mmol) and (S)-3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionic acid (intermediate 1) (200.00 mg, 0.65 mmol) were dissolved in dichloromethane (10.00 mL), and diisopropylethylamine (348.27 mg, 2.69 mmol) and T3P (1028.91 mg, 1.62 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (100 mL), and the organic phase was washed three times with water (30 mL × 3), and then washed once with saturated brine. The organic phase was dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product. This crude product was then purified by high-performance liquid chromatography (HPLC) (column: YMC-Actus Triart C18, 30 mm x 150 mm, 5 μm; mobile phase A: water (with 0.05% trifluoroacetic acid); mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: mobile phase B increased from 5% to 45% within 8 minutes; detection wavelength: 220 nm; retention time: 7.05 min) to obtain a white solid target product (59.61 mg, yield: 19%). 1H NMR (400MHz, DMSO-d6) δ (ppm): 12.44 (s, 1H), 10.99-10.93 (m, 1H), 8.13 (s, 1H) , 7.91 (s, 1H), 7.16 (d, J=2.2Hz, 1H), 6.28-6.27 (m, 1H), 4.83-4.47 (m, 2H), 4.2 4-4.14(m, 2H), 4.09-3.97(m, 1H), 3.75-3.68(m, 2H), 3.52-3.45(m, 2H), 3.25- 3.06 (m, 1H), 2.82-2.74 (m, 1H), 2.68-2.60 (m, 2H), 1.16-1.15 (d, J=6.5Hz, 3H). LCMS: MS(ESI)m / z: 564.10[M+H] + .

[0777] Example 8: Synthesis of (S)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazin[1,2-a]pyridin[3,2-e]pyrazin-6(6aH)-one (compound 8)

[0778]

[0779] The synthesis procedure was the same as that of compound 7, except that (S)-4-(tert-butyloxycarbonyl)piperazine-2-carboxylic acid was used instead of (R)-4-(tert-butyloxycarbonyl)piperazine-2-carboxylic acid (7-1). The crude product of compound 8 was purified by high performance liquid chromatography (column: YMC-Actus Triart C18, 30 mm X 150 mm, 5 μm; mobile phase A: water (with 0.05% trifluoroacetic acid); mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: mobile phase B increased from 5% to 45% within 8 minutes; detection wavelength: 220 nm; retention time: 7.05 min) to obtain a white solid target product (75.78 mg, yield: 24%).

[0780] 1H NMR (400MHz, DMSO-d6) δ (ppm): 12.45-12.43 (d, J=7.4Hz, 1H), 10.98-10.92 (m, 1H), 8 .13(s, 1H), 7.91-7.89(m, 1H), 7.16(s, 1H), 6.27-6.26(m, 1H), 4.83-4.49(m, 2H), 4. 25-4.13 (m, 2H), 4.07-3.99 (m, 1H), 3.73-3.68 (m, 2H), 3.50-3.49 (d, J=5.5Hz, 2H), 3 .26-3.07 (m, 1H), 2.85-2.76 (m, 1H), 2.72-2.60 (m, 3H), 1.16-1.15 (d, J=6.5Hz, 3H). LCMS: MS(ESI)m / z: 564.10[M+H] + .

[0781] Example 9: Synthesis of 5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyridino[3,2-e]pyrazin-8-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 9)

[0782]

[0783] Step 1: Synthesis of (S)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyridino[3,2-e]pyrazin-8-carboxylic acid tert-butyl ester (9-1)

[0784] (R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyridino[3,2-e]pyrazin-8-carboxylic acid tert-butyl ester (0.12 g, 0.32 mmol) was dissolved in tetrahydrofuran (1 ml), and boron trifluoride diethyl ether (0.07 g, 0.48 mmol) and sodium borohydride (0.02 g, 0.48 mmol) were added. The reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction mixture was quenched dropwise in a saturated sodium bicarbonate aqueous solution cooled to 0°C while stirring. The mixture was extracted three times with ethyl ester and water, washed with saturated sodium chloride aqueous solution, and the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under low pressure to give the target product as a yellow solid (0.12 g, yield: 100%). LCMS: MS(ESI) m / z: 359 [M+H] + .

[0785] Step 2: Synthesis of (R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a]pyridino[3,2-e]pyrazine (9-2)

[0786] (S)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyridino[3,2-e]pyrazino-8-carboxylic acid tert-butyl ester (0.15 g, 0.42 mmol) was dissolved in 1,4-dioxane (2 mL), and a 4 mol / L solution of dioxane hydrochloride (2 mL) was added. The reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the solution was evaporated to dryness under low pressure to give a yellow solid target product (0.22 g, yield: 204%). LCMS: MS(ESI) m / z: 259 [M+H] + .

[0787] Step 3: Synthesis of 5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyridino[3,2-e]pyrazin-8-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 9)

[0788] (R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a]pyridino[3,2-e]pyrazine (9-2) (0.08 g, 0.32 mmol) was dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (0.42 g, 3.23 mmol), (S)-3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyrazino-4-)amino)propoxy)propionic acid ethyl ester (intermediate 1) (0.10 g, 0.32 mmol), and 1-propylphosphoric anhydride (0.51 g, 1.62 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was extracted three times with water and ethyl acetate. The organic phase was washed once with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The crude product was purified by high performance liquid chromatography (HPLC) (column: Xselect CSH OBD Column, 30*150mm5um, mobile phase A: water (with 10 mol / L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 mL / min, elution gradient: mobile phase B increased from 5% to 50% within 8 minutes, detection wavelength: 220 nm, retention time: 8.07 min) to obtain a white solid target product (0.05 g, yield: 27%). 1H NMR (400MHz, DMSO-d6) δ (ppm): 12.46 (s, 1H), 7.92 (s, 1H), 7.71 (s, 1H), 6.80 (d, J=2 .1Hz, 1H), 6.32-6.18 (m,, 2H), 4.55-4.43 (m, 2H), 4.15 (t, J=7.2Hz, 1H), 4.09-3.90 (m, 1H), 3.73-3.64 (m, 2H), 3.49 (d, J=5.6Hz, 3H), 3.32-3.21 (m, 1H), 3.15-3.02 (m, 1H), 2.84-2.77(m, 1H), 2.68-2.60(m, 3H), 2.48-2.36(m, 1H), 1.16(d, J=6.5Hz, 3H). LCMS: MS(ESI)m / z: 550.10[M+H] + .

[0789] Example 10: Synthesis of 5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydropyrazine[1,2-a]pyridine[3,2-f][1,4]diazaphen-9(5H)-yl)propoxy)propanol-2-yl)amino)-4-(trifluoromethyl)piperazine-3(2H)-one (Compound 10)

[0790]

[0791] Step 1: Synthesis of 1-phenyl-4-(tert-butoxycarbonyl)(S)-2-((2-chloro-5-(trifluoromethyl)nicotinamide isophthalic acid)methyl)piperazine-1,4-dicarboxylic acid (10-3)

[0792] 1-Phenyl-4-(tert-butyl)(R)-2-(aminomethyl)piperazine-1,4-dimethyl ester (10⁻¹) (1 g, 2.85 mmol) and 2-chloro-5-trifluoromethylpyridine-3-carboxylic acid (10⁻²) (0.624 g, 2.85 mmol) were dissolved in dichloromethane (10 mL), followed by the addition of diisopropylethylamine (0.735 g, 5.7 mmol) and T3P (3.648 g, 5.7 mmol, 50% ethyl acetate solution). The reaction mixture was stirred at room temperature for 2 hours, then poured into ice water (20 mL). The aqueous phase was extracted three times with ethyl acetate (10 mL × 3). The organic phases were combined, aerated with anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and the filtrate was evaporated to dryness to give the crude product. The crude product was purified by column chromatography to give the target product as a white solid (2.224 g, 4 mmol, yield: 70%). LCMS: MS (ESI) m / z: 557 [M+H] + .

[0793] Step 2: Synthesis of (R)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazine[1,2-a]pyridine[3,2-f][1,4]diazazo-5(6H)-one(10-4)

[0794] 1-Phenyl 4-(tert-Butoxycarbonyl)(S)-2-((2-chloro-5-(trifluoromethyl)nicotinamide isophthalic acid)methyl)piperazine-1,4-dicarboxylic acid (10⁻³) (2.224 g, 4 mmol) was dissolved in concentrated hydrochloric acid (10 mL). The reaction mixture was stirred at 50 °C for 2 hours. The reaction solution was then poured into sodium carbonate ice water (20 mL). The aqueous phase was extracted three times with ethyl acetate (10 mL × 3). The organic phases were combined, and anhydrous sodium sulfate was removed by filtration. The filtrate was evaporated to dryness to obtain the crude product. After purification by silica gel column chromatography, the target product (0.803 g, 2.8 mmol, yield: 70%) was obtained as a white solid. LCMS: MS(ESI) m / z: 287 [M+H] + .

[0795] Step 3: Synthesis of tert-butoxycarbonyl-(R)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazine[1,2-a]pyridine[3,2-f][1,4]diazazo-5(6H)-one(10-5)

[0796] (R)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazine[1,2-a]pyridine[3,2-f][1,4]diazaphen-5(6H)-one (10⁻⁴) (1.00 g, 3.4 mmol) was dissolved in dichloromethane (10 mL). Triethylamine (0.68 g, 6.8 mmol) and (Boc)₂O (1.5 g, 6.8 mmol) were added to the reaction system. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was then poured into water (20 mL). The aqueous phase was extracted three times with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered to remove anhydrous sodium sulfate. The filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to give the target product as a white solid (0.921 g, 2.38 mmol, yield: 70%). LCMS: MS(ESI) m / z: 387 [M+H] + .

[0797] Step 4: Synthesis of (S)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydropyrazine[1,2-a]pyridine[3,2-f][1,4]diazazo-9(5H)-carboxylic acid tert-butyl ester (10-6).

[0798] Dissolve (tert-butoxycarbonyl-(R)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazine[1,2-a]pyridine[3,2-f][1,4]diazaphen-5(6H)-one (10⁻⁵) (500 mg, 1.29 mmol) in tetrahydrofuran (5 mL), cool to 0 °C, add sodium borohydride solid (50 mg, 1.295 mmol), and add boron trifluoride-ethyl ether complex (185 mL) dropwise under stirring. (g, 1.292 mmol). After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was poured into ice water (10 ml), and extracted three times with aqueous dichloromethane (20 ml × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, and the crude product was purified by silica gel column chromatography to give the target product as a white solid (120 mg, 0.321 mmol, yield: 24%). LCMS: MS (ESI) m / z: 373 [M+H] + .

[0799] Step 5: Synthesis of (S)-3-(trifluoromethyl)-7a,8,10,11-hexahydropyrazine[1,2-a]pyridine[3,2-f][1,4]piperazine-6,9(5H,7H)-benzyl dicarboxylate tert-butyl ester (10-7)

[0800] The mixture (S)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydropyrazine[1,2-a]pyridine[3,2-f][1,4]diazaphen-9(5H)-carboxylic acid tert-butyl ester (10⁻⁶) (0.5 g, 1.31 mmol) and benzyloxycarbonyl chloride (0.24 g, 1.31 mmol) were dissolved in dichloromethane (10 mL), and then triethylamine (0.262 g, 2.62 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After cooling, the reaction solution was concentrated to dryness. The crude product was purified by silica gel column chromatography to give the target product as a yellow oil (0.532 g, 1.05 mmol, yield: 80%). LCMS: MS(ESI) m / z: 507 [M+H] + .

[0801] Step 6: Synthesis of (R)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazine[1,2-a]pyridine[3,2-f][1,4]piperazine-6(5H)-benzyl formate (10-8)

[0802] 6-Phenyl-9-(tert-butyl)(S)-3-(trifluoromethyl)-7a,8,10,11-hexahydropyrazine[1,2-a]pyridine[3,2-f][1,4]piperazine-6,9(5H,7H)-dicarboxylic acid (10⁻⁷) (500 mg, 0.986 mmol) was dissolved in dichloromethane (5 mL), followed by the addition of trifluoroacetic acid (3 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was diluted with water (30 mL), and the pH was adjusted to 8–9 with sodium bicarbonate. The product was extracted three times with dichloromethane (20 mL × 3). The extracts were combined and evaporated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the target product as a white solid (300 mg, 1.157 mmol, yield: 83%). LCMS: MS(ESI) m / z: 407 [M+H] + .

[0803] Step 7: Synthesis of (R)-9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-hexahydropyrazin-4-yl)amino)propoxy)propanol)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazin[1,2-a]pyridine[3,2-f][1,4]piperazine-6(5H)-benzyl formate (10-9)

[0804] Intermediate 13-[(2S)-2-{[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino}propoxy]propionic acid (100 mg, 0.323 mmol) and (R)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazine[1,2-a]pyridine[3,2-f][1,4]piperazine-6(5H)-carboxylic acid benzyl ester (83.83 mg, 0.323 mmol) were dissolved in dichloromethane (1.0 mL), and then diisopropylethylamine (0.053 mL, 0.323 mmol) and T3P (102.89 mg, 0.323 mmol, 50% ethyl acetate solution) were added. After stirring the reaction mixture at room temperature for 2 hours, the reaction solution was poured into ice water (20 mL). The aqueous phase was extracted three times with ethyl acetate (10 mL × 3). The organic phases were combined, and anhydrous sodium sulfate was removed by filtration. The filtrate was evaporated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain the target product (80 mg, 1.157 mmol, yield: 70%). LCMS: MS (ESI) m / z: 697 [M+H] + .

[0805] Step 8: Synthesis of 5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydropyrazine[1,2-a]pyridine[3,2-f][1,4]diazaphen-9(5H)-yl)propoxy)propanol-2-yl)amino)-4-(trifluoromethyl)piperazine-3(2H)-one (Compound 10)

[0806] (R)-9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-hexahydropyrazin-4-yl)amino)propoxy)propanol)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazin[1,2-a]pyridine[3,2-f][1,4]piperazine-6(5H)-carboxylic acid benzyl ester (10-9) (80 mg, 1.157 mmol) was dissolved in dichloromethane (1.0 mL), and then palladium dichloride (0.5 mg, 0.01 mmol), triethylamine (2231.4 mg, 2.314 mmol) and triethylsilyl (268.21 mg, 2.314 mmol) were added. After stirring the reaction mixture at room temperature for 2 hours, the reaction solution was poured into ice water (20 mL). The aqueous phase was extracted three times with ethyl acetate (10 mL × 3). The organic phases were combined, aerated with anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by preparative liquid chromatography (column: XBridge Prep OBD C18, 30 × 150 mm 5 μm, mobile phase A: water (with 10 mol / L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 mL / min, elution gradient: mobile phase B increased from 20% to 52% within 8 minutes, detection wavelength: 220 nm, retention time: 7.12 min) to obtain the white solid target product (50 mg, 0.091 mmol, yield: 28.09%).

[0807] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 12.45 (s, 1H), 8.31-8.28 (m, 1H), 7.91 (s, 1H), 7.61 (s, 1H), 6.27-6.26 (m, 1H), 4.12-4.06 (m, 2H), 4.01-3.91 ( m, 1H), 3.88-3.80 (m, 2H), 3.79-3.67 (m, 6H), 3.63-3.51 (m, 2H), 3.50- 3.44(m,2H), 2.99-2.91(m,1H), 2.89-2.81(m,2H), 1.18-1.10(m,3H). LCMS: MS(ESI)m / z: 564.15[M+H] + .

[0808] Example 11: Synthesis of (S)-9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-4-yl)amino)propoxy)propanol)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazine[1,2-a]pyridine[3,2-f][1,4]diazaphen-6(5H)-nitrile (compound 11)

[0809]

[0810] Compound 105-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydropyrazine[1,2-a]pyridin[3,2-f][1,4]diazaphen-9(5H)-yl)propoxy)propanol-2-yl)amino)-4-(trifluoromethyl)piperazine-3(2H)-one (80 mg, 1.157 mmol) was dissolved in N,N-dimethylformamide (1.0 mL), followed by the addition of potassium carbonate (321 mg, 2.314 mmol) and cyanogen bromide (115.7 mg, 1.157 mmol). After stirring the reaction mixture at room temperature for 2 hours, the reaction solution was poured into ice water (20 mL). The aqueous phase was extracted three times with ethyl acetate (10 mL × 3). The organic phases were combined, aerated with anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and the filtrate was evaporated to dryness to give the crude product. The crude product was purified by reverse-phase preparative liquid chromatography (column: XBridge Prep OBDC18, 30×150mm 5um, mobile phase A: water (with 10 mol / L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 mL / min, elution gradient: mobile phase B increased from 20% to 52% within 8 minutes, detection wavelength: 220 nm, retention time: 7.09 min) to obtain a white solid target product (50 mg, 0.091 mmol, yield: 28.09%). 1 H NMR (400MHz, DMSO-d6) δ (ppm): 12.46 (s, 1H), 8.44-8.41 (m, 1H), 7.91-7.90 (m, 1H) ,7.86-7.83(m,1H),6.28-6.26(m,1H),4.76-4.67(m,1H),4.40-4.35(m,1H),4.32- 4.22(m,1H),4.20-4.05(m,1H),3.93-3.78(m,3H),3.75-3.62(m,5H),3.58-3.51( m, 1H), 3.50-3.45 (m, 2H), 3.44-3.36 (m, 2H), 2.57-2.54 (m, 1H), 1.16-1.12 (m, 3H). LCMS: MS(ESI)m / z: 589.25[M+H] + .

[0811] Example 12: Synthesis of 5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]thiazin-9(7H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 12)

[0812]

[0813] Step 1: Synthesis of 1-benzyl4-(tert-butyl)(R)-2-(mercaptomethyl)piperazine-1,4-dicarboxylate (12-2)

[0814] 1-Benzyl-4-(tert-butyl)(R)-2-(acetylthio)methyl)piperazine-1,4-dicarboxylate (1) (700.00 mg, 1.71 mmol) was dissolved in ethanol (1.00 mL), and 4 mol / L sodium hydroxide aqueous solution (685.42 mg, 17.14 mmol) was added. The reaction was carried out at room temperature for 2 hours. After the reaction was complete, the ethanol was removed by rotary evaporation under low pressure, water was added, and the mixture was extracted three times with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The crude product was obtained by rotary evaporation and purified by silica gel column chromatography to give the target product (400.00 mg, yield: 64%). LCMS: MS(ESI) m / z: 367 [M+H] + .

[0815] Step 2: Synthesis of 1-benzyl-4-(tert-butyl)(R)-2-((((2-chloro-5-(trifluoromethyl)pyridin-3-yl)methyl)thio)methyl)piperazine-1,4-dicarboxylate (12-4)

[0816] 1-Benzyl-4-(tert-butyl)(R)-2-(mercaptomethyl)piperazine-1,4-dicarboxylate (400.00 mg, 1.09 mmol) was dissolved in ethanol (10.00 mL), and 2-chloro-3-(chloromethyl)-5-(trifluoromethyl)pyridine (426.80 mg, 1.86 mmol) was added. The reaction was stirred at room temperature for 2 hours. After the reaction was complete, the ethanol was removed by rotary evaporation under reduced pressure, the mixture was diluted with water, extracted three times with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to give the target product as a yellow solid (256.00 mg, yield: 42%). LCMS: MS(ESI) m / z: 560 [M+H] + .

[0817] Step 3: Synthesis of (R)-2-((((2-chloro-5-(trifluoromethyl)pyridin-3-yl)methyl)thio)methyl)piperazine(12-5)

[0818] 1-Benzyl-4-(tert-butyl)(R)-2-((((2-chloro-5-(trifluoromethyl)pyridin-3-yl)methyl)thio)methyl)piperazine-1,4-dicarboxylate (190.00 mg, 0.34 mmol) was dissolved in hydrochloric acid (4.00 mL). The reaction was stirred at room temperature for 0.5 hours. After the reaction was complete, the product was evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give the target product as a yellow solid (220.00 mg, yield: 200%). LCMS: MS (ESI) m / z: 326 [M+H] + .

[0819] Step 4: Synthesis of (R)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]thiazoline(12-6)

[0820] (R)-2-((((2-chloro-5-(trifluoromethyl)pyridin-3-yl)methyl)thio)methyl)piperazine (210.00 mg, 0.64 mmol) was dissolved in DMF (4.00 mL), and potassium carbonate (178.18 mg, 1.29 mmol) was added. The reaction was stirred at 100 °C for two hours. After the reaction was complete, the mixture was diluted with water, extracted three times with ethyl acetate in the aqueous phase, and the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to give a yellow solid target product (160.00 mg, yield: 86%). LCMS: MS(ESI) m / z: 290 [M+H] + .

[0821] Step 5: Synthesis of 5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]thiazin-9(7H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 12)

[0822] (R)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]thiazoline (12-6) (0.07 g, 0.22 mmol) was dissolved in dichloromethane (2.00 mL), followed by the addition of nitrogen, N-diisopropylethylamine (0.29 g, 2.25 mmol), intermediate 1(S)-3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionic acid (0.07 g, 0.22 mmol), and 1-propylphosphonic anhydride (0.71 g, 1.12 mmol). The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was quenched with water, extracted three times with dichloromethane, washed with saturated water and hydrochloric acid, dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and then the solvent was removed by rotary evaporation to obtain the crude product. After purification by preparative liquid chromatography (column: Xselect CSH OBD Column, 30*150mm 5um, mobile phase A: water (with 10 mol / L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 mL / min, elution gradient: mobile phase B increased from 5% to 42% within 8 minutes, detection wavelength: 220 nm, retention time: 7.78 min), a white solid target product (10 mg, yield: 5%) was obtained.

[0823] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 12.45 (s, 1H), 8.35-8.30 (m, 1H), 7.91 (s, 1H) ,7.75-7.70(m,1H),6.30-6.25(m,1H),4.36-4.23(m,1H),4.20-4.09(m,1H) , 3.95-3.85(m, 1H), 3.83-3.76(m, 1H), 3.72-3.61(m, 6H), 3.50-3.41(m, 2H) , 3.01-2.90 (m, 2H), 2.87-2.78 (m, 2H), 2.59-2.56 (m, 2H), 1.19-1.12 (m, 3H). LCMS: MS(ESI)m / z: 581.10[M+H] + .

[0824] Example 13: Synthesis of 5-(((S)-1-(3-(S)-5-methyl-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyridino[3,2-e]pyrazin-8-yl)-3-oxopropoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 13)

[0825]

[0826] Step 1: Synthesis of (R)-4-(tert-butoxycarbonyl)-1-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazin-2-carboxylic acid (13-3)

[0827] (R)-4-(tert-butoxycarbonyl)piperazin-2-carboxylic acid (1.00 g, 4.34 mmol) was dissolved in methanol (10.00 mL), and triethylamine (1.30 g, 8.69 mmol) and 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (1.18 g, 5.21 mmol) were added. The reaction was stirred overnight at room temperature. After the reaction was complete, the mixture was extracted three times with ethyl ester and water, washed with saturated brine, and dried over anhydrous sodium sulfate. The crude product was evaporated to dryness under low pressure and purified by medium-pressure column chromatography to give a white solid of the target product (0.96 g, yield: 53%). LCMS: MS(ESI) m / z: 421 [M+H] + .

[0828] Step 2: Synthesis of (R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyridino[3,2-e]pyrazino-8-carboxylic acid tert-butyl ester (13-4)

[0829] (R)-4-(tert-butoxycarbonyl)-1-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazin-2-carboxylic acid (0.96 g, 2.28 mmol) was dissolved in ethanol (50.00 mL), and ammonium chloride (1.22 g, 22.84 mmol) and iron powder (1.28 g, 22.84 mmol) were added. The reaction was stirred at 70 °C for 2 hours. After the reaction was complete, the reaction solution was quenched with water, extracted three times with dichloroisocyanuric acid, and the crude product was purified by silica gel column chromatography to give a yellow solid target product (0.30 g, yield: 35%). LCMS: MS(ESI) m / z: 373 [M+H] + .

[0830] Step 3: Synthesis of (R)-5-methyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyridino[3,2-e]pyrazino-8-carboxylic acid tert-butyl ester (13-5)

[0831] (R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyridino[3,2-e]pyrazin-8-carboxylic acid tert-butyl ester (0.20 g, 0.54 mmol) was dissolved in tetrahydrofuran (20.00 mL), and cesium carbonate (0.26 g, 0.81 mmol) and iodomethane (0.11 g, 0.81 mmol) were added. The reaction was stirred at room temperature for 2 hours. The reaction solution was quenched with water, extracted three times with ethyl ester, and the organic phase was dried and then evaporated under reduced pressure to give a brown oily crude product (0.40 g, yield: 193%). LCMS: MS(ESI) m / z: 387 [M+H] + .

[0832] Step 4: Synthesis of (S)-5-methyl-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyridino[3,2-e]pyrazino-8-carboxylic acid tert-butyl ester (13-6)

[0833] (R)-5-methyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyridino[3,2-e]pyrazin-8-carboxylic acid tert-butyl ester (0.40 g, 1.04 mmol) was dissolved in tetrahydrofuran (20.00 mL) and cooled to 0 °C. Boron trifluoride diethyl ether (1.67 mL, 0.00 mmol) and sodium borohydride (0.40 g, 0.00 mmol) were added to the solution, and the reaction was stirred at room temperature for 0.5 h. The reaction solution was quenched with water, extracted three times with ethyl ester, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow oily crude product (0.30 g, yield: 78%). LCMS: MS(ESI) m / z: 373 [M+H] + .

[0834] Step 5: Synthesis of (R)-5-methyl-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a]pyridino[3,2-e]pyrazine (13-7)

[0835] (S)-5-methyl-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyridino[3,2-e]pyrazin-8-carboxylic acid tert-butyl ester (0.30 g, 0.81 mmol) was dissolved in dioxane (5.00 mL), and a dioxane solution of 4 mol / L hydrochloric acid (5.00 mL, 20.00 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 0.5 hours. The dioxane was removed by rotary evaporation under reduced pressure to give a crude product (0.38 g, yield: 173%), a bright pink solid. LCMS: MS(ESI) m / z: 273 [M+H]+ .

[0836] Step 6: Synthesis of 5-(((S)-1-(3-(S)-5-methyl-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyridino[3,2-e]pyrazin-8-yl)-3-oxopropoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 13)

[0837] (R)-5-methyl-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a]pyridino[3,2-e]pyrazine (13-7) (73.37 mg, 0.27 mmol) was dissolved in dichloromethane (7 mL), followed by the addition of DIEA (348.27 mg, 2.69 mmol), (S)-3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionic acid (intermediate 1) (100.00 mg, 0.32 mmol), and 1-propylphosphoric anhydride (428.71 mg, 1.35 mmol). The reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the mixture was quenched with water, extracted three times with dichloromethane, and the combined organic phases were washed with saturated water and hydrochloric acid, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain the crude product. After high-performance reversed-phase purification (column: XBridge Prep OBD C18, 30×150mm 5µm, mobile phase A: water (with 10 mol / L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 mL / min, elution gradient: mobile phase B increased from 20% to 60% within 8 minutes, detection wavelength: 220 nm, retention time: 6.4 min), a white solid target product (32.06 mg, yield: 21%) was obtained.

[0838] 1H NMR (400MHz, DMSO-d6) δ (ppm): 12.45 (s, 1H), 7.91 (s, 1H), 7.77 (s, 1H), 6.75 (s, 1H), 6.3 2-6.22(m, 1H), 4.59-4.56(m, 1H), 4.44-4.42(m, 1H), 4.20-4.11(m, 1H), 4.03-3.96(m, 1H ), 3.73-3.65(m, 2H), 3.53-3.48(m, 2H), 3.42-3.37(m, 1H), 3.17-3.00(m, 2H), 2.91-2.72 (m, 4H), 2.71-2.65 (m, 1H), 2.62-2.58 (m, 2H), 2.438-2.42 (m, 1H), 1.16 (d, J=6.5Hz, 3H). LCMS: MS(ESI)m / z: 564.10[M+H] + .

[0839] Example 14: Synthesis of 5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazine[1,2-d]pyridin[3,2-b][1,4]oxazine-8(6H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H)-one (compound 14)

[0840]

[0841] Step 1: Synthesis of tert-butyl (3R)-4-5-(trifluoromethyl)pyridin-2-yl]-3-(hydroxymethyl)pyrazine-1-carboxylate (14-2)

[0842] The mixture of (3R)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (1.0 g, 4.624 mmol) and 2-dichloro-5-(trifluoromethyl)pyrazine (14-1) (0.85 g, 4.624 mmol) was dissolved in DMF (20 mL), and potassium carbonate (0.263 g, 4.624 mmol) was added. The mixture was stirred at 60 °C for 12 hours under nitrogen protection. After cooling, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Water (30 mL) was added, and the mixture was extracted with ethyl acetate. The residue was dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and the crude product was purified by silica gel column chromatography to give a white solid target product (800 mg, 3.25 mmol, yield: 70%). LCMS: MS(ESI) m / z: 363 [M+H] + .

[0843] Step 2: Synthesis of tert-butyl 3R-4-[3-chloro-5-(trifluoromethyl)pyrazin-2-yl]-3-(hydroxymethyl)piperazine-1-carboxylate (14-3)

[0844] (3R)-4-5-(trifluoromethyl)pyrazin-2-yl]-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (14-2) (0.6 g, 1.65 mmol) and N-chlorosuccinimide (0.447 g, 2.4 mmol) were dissolved in N,N-dimethylformamide (5 mL). The reaction mixture was heated to 60 °C and stirred for 3 hours. After the reaction was complete, the solid was removed by filtration, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the target product as a yellow oil (260 mg, 0.962 mmol, yield: 64%). LCMS: MS(ESI) m / z: 397 [M+H] + .

[0845] Step 3: Synthesis of (10R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazine[1,2-d]piperazine[3,2-b][1,4]oxazine-8(6H)-tert-butyl formate (14-4).

[0846] 3R-4-[3-chloro-5-(trifluoromethyl)pyrazin-2-yl]-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (14-3) (500 mg, 1.318 mmol) was dissolved in DMF (5 mL), and potassium carbonate (443 mg, 3.95 mmol) was added. The mixture was heated to 80 °C and stirred for 12 hours under nitrogen protection. After cooling, 10 mL of ice water was added, and the mixture was extracted three times with ethyl acetate (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, and the crude product was purified by silica gel column chromatography to give the target product (300 mg, 1.113 mmol, 60%) as a white solid. LCMS: MS (ESI) m / z: 361 [M+H] + .

[0847] Step 4: Synthesis of (10R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazine[1,2-d]piperazine[3,2-b][1,4]oxazine-8(6H)-formic acid (14-5)

[0848] (10R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazine[1,2-d]piperazine[3,2-b][1,4]oxazine-8(6H)-tert-butyl formate (14-5) (500 mg, 1.391 mmol) was dissolved in dioxane hydrochloride (6 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was diluted with water (30 mL), the pH was adjusted to 8-9 with sodium bicarbonate, and the product was extracted three times with dichloromethane (20 mL × 3). The crude product was purified by silica gel column chromatography to obtain the target product as a white solid (300 mg, 1.157 mmol, yield: 83%). LCMS: MS(ESI) m / z: 261 [M+H] + .

[0849] Step 5: Synthesis of 5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazine[1,2-d]pyridin[3,2-b][1,4]oxazine-8(6H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H)-one (Compound 14)

[0850] 3-[(2S)-2-{[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino}propoxy]propionic acid (intermediate 1) (120 mg, 0.387 mmol) and (R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]piperazino[3,2-b][1,4]oxazine (14-5) (95 mg, 0.387 mmol) were dissolved in DCM (3.0 mL), and then diisopropylethylamine (0.053 mL, 0.387 mmol) and T3P (102.89 mg, 0.387 mmol, 50% ethyl acetate solution) were added. After stirring the reaction mixture at room temperature for 2 hours, the reaction solution was poured into ice water (20 mL). The aqueous phase was extracted three times with ethyl acetate (10 mL × 3). The organic phases were combined, aerated with anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by preparative liquid chromatography (column: XBridge Prep OBD C18, 30 × 150 mm 5 μm, mobile phase A: water (with 10 mol / L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 mL / min, elution gradient: mobile phase B increased from 20% to 52% within 8 minutes, detection wavelength: 220 nm, retention time: 7.03 min) to obtain the white solid target product (50 mg, 0.091 mmol, yield: 28.09%).

[0851] 1H NMR (400MHz, DMSO-d6) δ (ppm): 12.45 (s, 1H), 8.17 (s, 1H), 7.91 (s, 1H), 6.28-6.265 (m, 1H), 4.63-4.56(m, 1H), 4.51-4.46(m, 1H), 4.45-4.35(m, 1H), 4.24-4.12(m, 2H), 4.11- 4.01 (m, 1H), 3.75-3.61 (m, 3H), 3.49-3.48 (m, 2H), 3.01-2.89 (m, 2H), 2.77-2.68 (m, 1H ), 2.65-2.60 (m, 2H), 1.62-1.43 (m, 1H), 1.16-1.14 (d, J=6.5Hz, 3H), 0.96-0.92 (m, 1H). LCMS: MS(ESI)m / z: 552.15[M+H] + .

[0852] Example 15: Synthesis of 5-(((2S)-1-(3-(((7aR)-6-oxo-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]thiazin-9(7H)-yl)-3-oxopropoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 15)

[0853]

[0854] Step 1: Synthesis of (7aR)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6-oxo5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]thiazoline (15-1)

[0855] (R)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]thiazoline (12-6) (0.08 g, 0.28 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. Then, m-chloroperoxybenzoic acid (0.05 g, 0.28 mmol) was added. The reaction was stirred at 0 °C for 0.5 h. After the reaction was complete, the mixture was quenched with water, extracted three times with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and the filtrate was evaporated under reduced pressure to give a yellow solid crude product (0.07 g, yield: 78%). LCMS: MS(ESI) m / z: 306 [M+H] + .

[0856] Step 2: Synthesis of 5-(((2S)-1-(3-(((7aR)-6-oxo-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]thiazin-9(7H)-yl)-3-oxopropoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 15)

[0857] (R)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]thiazolin-5-one (15-1) (0.06 g, 0.20 mmol) and (S)-3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionic acid (intermediate 1) (0.06 g, 0.20 mmol) were dissolved in dichloromethane (2.00 mL), followed by the addition of DIEA (0.25 g, 1.97 mmol) and 1-propylphosphoric anhydride (0.31 g, 0.98 mmol). The reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the mixture was quenched with water, extracted three times with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and the filtrate was evaporated under reduced pressure to obtain a crude solid. The crude product was purified by reversed-phase high-performance liquid chromatography (RP-HPLC) (column: Xselect CSH OBD Column, 30*150mm 5µm, mobile phase A: water (with 10 mol / L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 mL / min, elution gradient: mobile phase B increased from 5% to 42% within 8 minutes, detection wavelength: 220 nm, retention time: 7.78 min) to obtain a white solid target product (0.01 g, yield: 5%).

[0858] 1H NMR (400MHz, DMSO-d6) δ (ppm): 12.44 (s, 1H), 8.55-8.50 (m, 1H), 8.05-7.95 (m, 1H), 7.92 (s , 1H), 6.35-6.25(m, 1H), 4.39-4.32(m, 1H), 4.26-4.20(m, 1H), 4.18-4.11(m, 2H), 4.11-4. 05 (m, 1H), 3.98-3.92 (m, 1H), 3.91-3.84 (m, 1H), 3.77-3.74 (m, 1H), 3.71-3.65 (m, 3H), 3.6 2-3.58 (m, 1H), 3.50-3.47 (m, 2H), 2.92-2.81 (m, 2H), 2.60-2.58 (m, 2H), 1.19-1.10 (m, 3H). LCMS: MS(ESI)m / z: 597.10[M+H] + .

[0859] Example 16: Synthesis of (R)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-12H-pyrazino[2,1-c]pyridino[2,3-f][1,4]oxazepine-12-one (compound 16)

[0860]

[0861] Step 1: Synthesis of (R)-4-(3-chloro-5-(trifluoromethyl)methylpyridinyl)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (16-2)

[0862] 3-Chloro-5-(trifluoromethyl)pyridinecarboxylic acid (16-1) (1.56 g, 6.94 mmol) and (R)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (1.00 g, 4.62 mmol) were dissolved in dichloromethane (20 mL), followed by the addition of DIEA (1.79 g, 13.87 mmol), 1-hydroxybenzotriazole (0.94 g, 6.94 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.33 g, 6.94 mmol). The reaction mixture was stirred at room temperature for one hour. After the reaction was complete, the mixture was quenched with water, extracted three times with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and the filtrate was evaporated under reduced pressure to give a white solid crude product (1.20 g, yield: 61%). LCMS: MS(ESI) m / z: 424 [M+H] + .

[0863] Step 2: (R)-12-oxo-3-(trifluoromethyl)-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyridino[2,3-f][1,4]oxaza-8(6H)-carboxylic acid tert-butyl ester (16-3)

[0864] (R)-4-(3-chloro-5-(trifluoromethyl)methylpyridinyl)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (16-2) (1.00 g, 2.36 mmol) was dissolved in dimethyl sulfoxide (15 mL), and potassium carbonate (0.98 g, 7.08 mmol) was added. The reaction mixture was stirred at 100 °C for 2 hours. After the reaction was complete, the mixture was cooled, quenched with water, extracted three times with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, and the filtrate was evaporated to dryness under reduced pressure to give a yellow solid crude product (0.42 g, yield: 46%). LCMS: MS(ESI) m / z: 388 [M+H] + .

[0865] Step 3: Synthesis of (R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-12H-pyrazino[2,1-c]pyridino[2,3-f][1,4]oxazepine-12-one (16-4)

[0866] (R)-12-oxo-3-(trifluoromethyl)-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyridino[2,3-f][1,4]oxaza-8(6H)-carboxylic acid tert-butyl ester (16-3) (0.15 g, 0.39 mmol) was dissolved in 1,4-dioxane (1.5 mL), followed by the addition of dioxane hydrochloride solution (4 M, 1.50 mL, 6 mmol). The reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was evaporated to dryness under reduced pressure to give a yellow solid crude product (0.23 g, yield: 207%). LCMS: MS(ESI) m / z: 288 [M+H] + .

[0867] Step 4: Synthesis of (R)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-12H-pyrazino[2,1-c]pyrido[2,3-f][1,4]oxazepine-12-one (Compound 16)

[0868] (R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-12H-pyrazino[2,1-c]pyridino[2,3-f][1,4]oxazepine-12-one (16-4) (0.08 g, 0.27 mmol) was dissolved in dichloromethane (7.00 mL), followed by the addition of DIEA (0.35 g, 2.69 mmol), (S)-3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionic acid (0.10 g, 0.32 mmol), and 1-propylphosphoric anhydride (0.43 g, 1.35 mmol). The reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the mixture was quenched with water, extracted three times with dichloromethane, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, and the filtrate was evaporated under reduced pressure to obtain the crude product. The crude product was purified by reversed-phase high-performance liquid chromatography (RP-HPLC) (column: YMC-Actus Triart C18, 30 mm x 150 mm, 5 μm; mobile phase A: water (with 10 mol / L ammonium bicarbonate); mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: mobile phase B increased from 10% to 52% within 8 minutes; detection wavelength: 220 nm; retention time: 7.02 min) to obtain the target product as a white solid (0.05 g, yield: 32%).

[0869] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 12.43 (s, 1H), 8.88 (s, 1H), 8.07 (s, 1H), 7.91-7.90 (m, 1H), 6.30-6.20 (m, 1H), 4.43-4.20 (m, 2H), 4. 20-4.04 (m, 2H), 4.04-3.73 (m, 4H), 3.73-3.60 (m, 3H), 3.58-3.52 (m, 1H), 3.15-3.46 (m, 2H), 2.63-2.55 (m, 2H), 1.21-1.09 (m, 3H). LCMS: MS (ESI) m / z: 579.10 [M+H].

[0870] Example 17: Synthesis of (S)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-12H-pyrazino[2,1-c]pyridino[2,3-f][1,4]oxazepine-12-one (compound 17)

[0871]

[0872] The synthesis steps are the same as those for compound 16, except that (S)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl ester is used instead of (R)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl ester in the first step reaction.

[0873] The crude product was purified by reversed-phase high-performance liquid chromatography (RP-HPLC) (column: YMC-Actus Triart C18, 30 mm x 150 mm, 5 μm; mobile phase A: water (with 10 mol / L ammonium bicarbonate); mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: mobile phase B increased from 10% to 52% within 8 min; detection wavelength: 220 nm; retention time: 7.02 min) to obtain a white solid target product (0.03 g, yield: 29%).

[0874] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 12.46 (s, 1H), 8.88 (s, 1H), 8.08-8.06 (m, 1H), 7.92-7.90 (m, 1H), 6.30-6.27 (m, 1H), 4.42-4.18 (m, 2H) , 4.18-4.02(m, 2H), 4.01-3.73(m, 4H), 3.73-3.60(m, 3H), 3.58-3.52(m, 1H), 3.15-3.46(m, 2H), 2.63-2.55(m, 2H), 1.21-1.09(m, 3H). LCMS: MS(ESI)m / z: 579.05[M+H] + .

[0875] Example 18: Synthesis of 5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[2,3-f][1,4]oxazepine-8(6H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 18)

[0876]

[0877] Step 1: Synthesis of (R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyridino[2,3-f][1,4]oxaza-8(6H)-carboxylic acid tert-butyl ester (18-1)

[0878] (R)-12-oxo-3-(trifluoromethyl)-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyridino[2,3-f][1,4]oxaza-8(6H)-carboxylic acid tert-butyl ester (16-3) (0.15 g, 0.39 mmol) was dissolved in tetrahydrofuran (3.00 mL). The solution was cooled to 0 °C, and boron trifluoride diethyl ether (1.65 g, 11.62 mmol) and sodium borohydride (0.37 g, 9.68 mmol) were added. The reaction was stirred at 0 °C for two hours. After the reaction was complete, the solution was quenched with water, extracted three times with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, and the filtrate was evaporated under reduced pressure to give a white solid crude product (0.23 g, yield: 157%). LCMS: MS(ESI) m / z: 374 [M+H] + .

[0879] Step 2: Synthesis of (R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-12H-pyrazine[2,1-c]pyrido[2,3-f][1,4]oxazapyro-12-one (18-2)

[0880] (R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyridino[2,3-f][1,4]oxaza-8(6H)-carboxylic acid tert-butyl ester (18-1) (0.23 g, 0.61 mmol) was dissolved in dioxane (5.00 mL), and dioxane hydrochloride solution (4 M, 5.00 mL, 20.00 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 h. After the reaction was complete, the mixture was evaporated to dryness under reduced pressure to give a yellow solid crude product (0.25 g, yield: 150%). LCMS: MS(ESI) m / z: 274 [M+H] + .

[0881] Step 3: Synthesis of 5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[2,3-f][1,4]oxazepine-8(6H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 18)

[0882] (R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-12H-pyrazine[2,1-c]pyrido[2,3-f][1,4]oxazapyro-12-one (18-2) (0.1 g, 1 eq) was dissolved in dichloromethane (1 ml), and N,N-diisopropylethylamine (0.24 g, 1.83 mmol), (S)-3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionic acid (intermediate 1) (0.113 g, 1.0 eq) and 1-propylphosphoric anhydride (0.23 g, 0.73 mmol) were added. The reaction was stirred at room temperature for 0.5 h. After the reaction was complete, the mixture was quenched with water, extracted three times with dichloromethane, washed with saturated brine and dried over anhydrous sodium sulfate, and then evaporated to dryness under low pressure. The crude product was purified by preparative liquid chromatography under the following conditions: column: YMC-AcmsTriart C18, 30 mm x 150 mm, 5 μm; mobile phase A: water (with 10 mol / L ammonium bicarbonate); mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: mobile phase B increased from 20% to 75% within 8 minutes; detection wavelength: 220 nm; retention time: 7.58 min. After purification, the target product 5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[2,3-f][1,4]oxazepine-8(6H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (0.03 g, yield: 12%). 1 HNMR (400MHz, DMSO-d6) δ (ppm): 12.46 (s, 1H), 8.57 (s, 1H), 7.91 (d, J = 4.4Hz, 1H) ,7.77(s,1H),6.30-6.20(m,1H),4.46-4.31(m,1H),4.22-3.95(m,3H),3.91-3.7 8(m, 2H), 3.78-3.60(m, 3H), 3.52-3.43(m, 2H), 3.24-2.97(m, 1H), 2.92-2.77(m, 2H), 2.74-2.63(m, 2H), 2.59-2.57(m, 1H), 2.44-2.39(m, 1H), 1.21-1.10(m, 3H). LCMS: MS(ESI)m / z: 565.10[M+H] + .

[0883] Example 19: Synthesis of 5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[2,3-f][1,4]oxazepine-8(6H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 19)

[0884]

[0885] The synthesis steps are the same as those for compound 18, except that (S)-12-oxo-3-(trifluoromethyl)-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyridino[2,3-f][1,4]oxaza-8(6H)-carboxylic acid tert-butyl ester is used instead of (R)-12-oxo-3-(trifluoromethyl)-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyridino[2,3-f][1,4]oxaza-8(6H)-carboxylic acid tert-butyl ester in the first step reaction. The crude product was purified by reversed-phase high-performance liquid chromatography (RP-HPLC) (column: YMC-Actus Triart C18, 30 mm x 150 mm, 5 μm; mobile phase A: water (with 10 mol / L ammonium bicarbonate); mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: mobile phase B increased from 20% to 75% within 8 minutes; detection wavelength: 220 nm; retention time: 7.58 min) to obtain a white solid target product (0.02 g, yield: 18%).

[0886] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 12.47 (s, 1H), 8.57 (s, 1H), 7.91 (d, J = 4.4Hz, 1H), 7.77 (s, 1H), 6.30-6.20 (m, 1H), 4.46-4.31 (m, 1H), 4.18-4.0 2(m, 3H), 3.99-3.75(m, 4H), 3.72-3.60(m, 3H), 3.52-3.43(m, 2H), 3.05 -2.97 (m, 1H), 2.92-2.77 (m, 3H), 2.74-2.69 (m, 1H), 1.21-1.10 (m, 3H). LCMS: MS(ESI)m / z: 565.10[M+H] + .

[0887] Example 20: Synthesis of (R)-9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-fluoro-7,7a,8,9,10,11-hexahydro-5H-pyrazine[2,1-c]pyridine[2,3-e][1,4]oxazin-5-one (compound 20)

[0888]

[0889] Step 1: Synthesis of (R)-5-oxo-3-fluoro-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridine[2,3-e][1,4]oxazoline-9(7H)-carboxylic acid tert-butyl ester (20-2)

[0890] (3R)-3-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (900 mg, 4.17 mmol) and methyl 2-fluoro-5-chloropyridine-3-carboxylate (1 g, 4.17 mmol) (20-1) were dissolved in DMF (20 mL), and potassium carbonate (1.5 g, 8.4 mmol) was added. The reaction mixture was stirred at 80 °C for 16 hours. After cooling, the solid was removed by filtration, and the filtrate was concentrated to dryness. Water (100 mL) was added to the crude product, and the mixture was extracted three times with ethyl acetate (100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, and the anhydrous sodium sulfate was removed by filtration. The crude product was purified by silica gel column chromatography after drying to give the target product as a white solid (1.2 g, 3.1 mmol, yield: 60%). LCMS: MS(ESI) m / z: 338 [M+H] + .

[0891] Step 2: Synthesis of (R)-3-fluoro-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridine[2,3-e][1,4]oxazoline-9(7H)-carboxylic acid tert-butyl ester (20-3).

[0892] (R)-5-oxo-3-fluoro-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridine[2,3-e][1,4]oxazoline-9(7H)-carboxylic acid tert-butyl ester (20-2) (1 g, 2.6 mmol) was dissolved in tetrahydrofuran (8 mL). After cooling to 0 °C, sodium borohydride solid (100 mg, 2.6 mmol) was added, followed by dropwise addition of boron trifluoride-ethyl ether complex (370 mg, 2.6 mmol) under stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water (10 mL), and extracted three times with aqueous dichloromethane (20 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, and the crude product was purified by silica gel column chromatography to give the target product as a white solid (480 mg, 0.64 mmol, yield: 50%). LCMS: MS(ESI) m / z: 324 [M+H] + .

[0893] Step 3: Synthesis of (R)-3-fluoro-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyridine[2,3-e][1,4]oxazine-5-one (20-4)

[0894] (R)-5-oxo-3-fluoro-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridine[2,3-e][1,4]oxazoline-9(7H)-carboxylic acid tert-butyl ester (20-3) (1 g, 2.6 mmol) was dissolved in 1,4-dioxane hydrogen chloride solution (4 M, 5 mL) and stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, the crude product was diluted with water (30 mL), the pH was adjusted to 8-9 with sodium bicarbonate, and the product was extracted three times with dichloromethane (20 mL × 3). The crude product was purified by silica gel column chromatography to obtain a white solid target product (500 mg, 1.80 mmol, yield: 60%). LCMS: MS(ESI) m / z: 224 [M+H] + .

[0895] Step 4: Synthesis of (R)-9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-fluoro-7,7a,8,9,10,11-hexahydro-5H-pyrazine[2,1-c]pyridine[2,3-e][1,4]oxazin-5-one (Compound 20)

[0896] 3-[(2S)-2-{[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino}propoxy]propionic acid (intermediate 1) (100 mg, 0.348 mmol) and (S)-3-fluoro-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyridino[3,2-b][1,4]oxazine (20-4) (100 mg, 0.348 mmol) were dissolved in dichloromethane (2.0 mL), and then diisopropylethylamine (100 mg, 0.696 mmol) and 1-propylphosphonic anhydride (120 mg, 0.418 mmol, 50% ethyl acetate solution) were added. After stirring the reaction mixture at room temperature for 2 hours, the reaction solution was poured into ice water (20 mL). The aqueous phase was extracted three times with ethyl acetate (10 mL × 3). The organic phases were combined, aerated with anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by reversed-phase high-performance liquid chromatography (RP-HPLC) (column: XBridge Prep OBD C18, 30 × 150 mm 5 μm, mobile phase A: water (with 10 mol / L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 mL / min, elution gradient: mobile phase B increased from 20% to 52% within 8 minutes, detection wavelength: 220 nm, retention time: 6.21 min) to obtain the white solid target product (52 mg, 0.090 mmol, yield: 25.01%).

[0897] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 12.41 (s, 1H), 8.12 (s, 1H), 8.07 (d, J=2.2Hz, 11), 7 .90 (d, J=2.2Hz, 1H), 7.72-7.70 (m, 1H), 6.28-6.23 (m, 1H), 4.38-4.22 (m, 1H), 4.19 -3.89(m, 2H), 3.80-3.62(m, 6H), 3.53-3.45(m, 2H), 3.25-3.12(m, 1H), 2.95-2.83( m, 1H), 2.83-2.70 (m, 2H), 2.65-2.57 (m, 2H). 2.38-2.26 (m, 1H), 1.20-1.09 (m, 3H). LCMS: MS(ESI)m / z: 515.15[M+H] + .

[0898] Example 21: Synthesis of (R)-9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-chloro-7,7a,8,9,10,11-hexahydro-5H-pyrazine[2,1-c]pyridine[2,3-e][1,4]oxazin-5-one (compound 21)

[0899]

[0900] The synthesis method is the same as in Example 20. The crude product was purified by reversed-phase high-performance liquid chromatography (RP-HPLC) (column: XBridge Prep OBDC18, 30×150mm 5um, mobile phase A: water (with 10 mol / L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 mL / min, elution gradient: mobile phase B increased from 20% to 52% within 8 minutes, detection wavelength: 220 nm, retention time: 6-10 min) to obtain the white solid target product (R)-9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-chloro-7,7a,8,9,10,11-hexahydro-5H-pyrazine[2,1-c]pyridine[2,3-e][1,4]oxazin-5-one (compound 21) (52 mg, 0.090 mmol, yield: 25.01%).

[0901] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 12.41 (brs, 1H), 8.12 (s, 1H), 7.90 (d, J=2.2Hz, 1H), 7.86 (s , 1H), 6.28-6.22(m, 1H), 4.42-4.27(m, 1H), 4.19-4.11(m, 1H), 4.11-3.95(m, 1H), 3.80-3. 68(m, 4H), 3.68-3.63(m, 2H), 3.50-3.46(m, 2H), 3.25-3.16(m, 1H), 2.95-2.82(m, 1H), 2.8 1-2.79 (m, 1H), 2.78-2.70 (m, 1H), 2.62-2.58 (m, 2H). 2.31-2.22 (m, 1H), 1.18-1.13 (m, 3H). LCMS: MS(ESI)m / z: 531.10[M+H] + .

[0902] Example 22: Synthesis of 5-(((S)-1-(3-(((R)-6,6-dioxa-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]thiazin-9(7H)-yl)-3-oxopropoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 22)

[0903]

[0904] 5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]thiazin-9(7H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 12) (125.00 mg, 0.22 mmol) was dissolved in methanol (25.00 mL) and cooled to 0 °C. Then, m-chloroperoxybenzoic acid (74.31 mg, 0.43 mmol) was added. The reaction was stirred at 0 °C for 1 hour. After the reaction was complete, methanol was removed by rotary evaporation under reduced pressure. The crude product was purified by reversed-phase high-performance liquid chromatography (RP-HPLC) (column: Xselect CSH OBD Column 30*150mm5um, mobile phase A: water (with 10 mol / L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 mL / min, elution gradient: mobile phase B increased from 10% to 55% within 8 minutes, detection wavelength: 220 nm, retention time: 7.27 min) to obtain a white solid target product (1.22 mg, yield: 1%).

[0905] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 12.46 (s, 1H), 8.55-8.50 (m, 1H), 8.05-7.95 (m, 1H), 7.92 (s, 1H), 6.35-6.25 (m, 1H), 5.17-5.03 (m, 1H), 4.57-4. 48(m,1H),4.36-4.28(m,1H),4.18-4.09(m,1H),4.01-3.84(m,2H),3.7 5-3.55(m, 8H), 3.52-3.44(m, 3H), 2.60-2.58(m, 1H), 1.18-1.12(m, 3H). LCMS: MS(ESI)m / z: 613.15[M+H] + .

[0906] Example 23: Synthesis of 5-(((S)-1-(3-((S)-6-methyl-3-(trifluoromethyl)-6,7,7a,8,10,11-octahydropyrazino[1,2-a]pyridin[3,2-f][1,4]diazazyl-9(5H)-yl)-3-propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 23)

[0907]

[0908] Step 1: Synthesis of (S)-6-methyl-3-(trifluoromethyl)-6,7,7a,8,9,10,11-octahydropyrazino[1,2-a]pyridine[3,2-f][1,4]diazine-9(5H)-carboxylic acid tert-butyl ester (23-1)

[0909] (S)-3-(trifluoromethyl)-6,7,7a,8,10,11-octahydropyrazino[1,2-a]pyridine[3,2-f][1,4]diazine-9(5H)-carboxylic acid tert-butyl ester (10⁻⁶) (10⁻⁶) (10⁻⁷ mg, 0.27 mmol) was dissolved in methanol (2 mL). After cooling to 0 °C, sodium borohydride acetate solid (114 mg, 0.54 mmol) was added, and 30% formaldehyde aqueous solution (135 mg, 1.35 mmol) was added dropwise under stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was poured into ice water (10 mL), and extracted three times with aqueous dichloromethane (20 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, and the crude product was concentrated under reduced pressure to obtain a white solid target product (65 mg, 0.321 mmol, yield: 58%) after purification by silica gel column chromatography. LCMS: MS(ESI) m / z: 387 [M+H] + .

[0910] Step 2: Synthesis of (R)-6-methyl-3-(trifluoromethyl)-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-a]pyridine[3,2-f][1,4]diazazolide (23-2)

[0911] (S)-6-methyl-3-(trifluoromethyl)-6,7,7a,8,9,10,11-octahydropyrazino[1,2-a]pyridine[3,2-f][1,4]diazinate-9(5H)-carboxylic acid tert-butyl ester (23-1) (65 mg, 0.168 mmol) was dissolved in ice-cold (0 °C) 1,4-dioxane hydrochloride solution (4 M, 5 mL), and the mixture was slowly heated to room temperature with stirring for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, the crude product was diluted with water (30 mL), the pH was adjusted to 8-9 with sodium bicarbonate, and the product was extracted three times with dichloromethane (20 mL × 3). The crude product was purified by silica gel column chromatography to obtain the target product as a white solid (40 mg, 0.139 mmol, yield: 89%). LCMS: MS(ESI) m / z: 287 [M+H] + .

[0912] Step 3: Synthesis of 5-(((S)-1-(3-(((S)-6-methyl-3-(trifluoromethyl)-6,7,7a,8,10,11-octahydropyrazino[1,2-a]pyridine[3,2-f][1,4]diazazyl-9(5H)-yl)-3-propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 23)

[0913] 3-[(2S)-2-{[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino}propoxy]propionic acid (intermediate 1) (43 mg, 0.139 mmol) and (R)-6-methyl-3-(trifluoromethyl)-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-a]pyridine[3,2-f][1,4]diazazolide (23-2) (40 mg, 0.139 mmol) were dissolved in dichloromethane (1.0 mL), and then diisopropylethylamine (0.023 mL, 0.139 mmol) and T3P (44.20 mg, 0.139 mmol, 50% ethyl acetate solution) were added. After stirring the reaction mixture at room temperature for 2 hours, the reaction solution was poured into ice water (20 mL). The aqueous phase was extracted three times with ethyl acetate (10 mL × 3). The organic phases were combined, and anhydrous sodium sulfate was removed by filtration. The filtrate was evaporated to dryness to obtain the crude product. After purification by reversed-phase high-performance liquid chromatography (column: XBridge Prep OBD C18, 30 × 150 mm 5 μm, mobile phase A: water (with 10 mol / L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 mL / min, elution gradient: mobile phase B increased from 20% to 52% within 8 minutes, detection wavelength: 220 nm, retention time: 7.28 min), a white solid target product (1.2 mg, 0.002 mmol, yield: 1.5%) was obtained. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 12.47 (s, 1H), 8.36 (d, J = 8.0Hz, 1H), 7.91 (d, J = 4.0Hz, 1H), 7.73 (s, 1H), 6.34-6.29 (m, 1H), 4.19-4.11 (m, 1H), 3.9 7-3.81(m, 4H), 3.77-3.67(m, 4H), 3.61-3.53(m, 2H), 3.49(d, J=4.0Hz, 2 H), 2.77-2.74(m, 2H), 2.68-2.55(m, 3H), 2.32(s, 3H), 1.16-1.13(m, 3H). LCMS: MS(ESI)m / z: 578.20[M+H] + .

[0914] Example 24: Synthesis of 5-(((S)-1-(3-(((6aR,9R)-9-methyl-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)-3-oxopropoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 24)

[0915]

[0916] Step 1: Synthesis of (2R,5R)-4-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (24-2)

[0917] 2,3-Difluoro-5-(trifluoromethyl)pyridine (24-1) (0.40 g, 2.17 mmol) and (2R,5R)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (0.50 g, 2.17 mmol) were dissolved in DMF (25.00 mL), and DIEA (0.56 g, 4.34 mmol) was added. The reaction mixture was stirred at 50 °C for 3 hours. After the reaction was complete, the solution was quenched with water, extracted three times with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and concentrated under reduced pressure to give a yellow oily crude product (0.72 g, yield: 84%). LCMS: MS(ESI) m / z: 394 [M+H] + .

[0918] Step 2: Synthesis of (6aR,9R)-9-methyl-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyridino[3,2-b][1,4]oxazine-8(6H)-carboxylic acid tert-butyl ester (24-3).

[0919] (2R,5R)-4-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-5-(hydroxymethyl)-2-methylpiperazin-1-carboxylic acid tert-butyl ester (24-2) (0.50 g, 1.27 mmol) was dissolved in DMF (10.00 mL), and potassium tert-butoxide (0.29 g, 2.54 mmol) was added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the solution was quenched with water, extracted three times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to give the target product as a yellow oil (0.48 g, yield: 101%). LCMS: MS(ESI) m / z: 374 [M+H] + .

[0920] Step 3: Synthesis of (6aR,9R)-9-methyl-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyridino[3,2-b][1,4]oxazine (24-4).

[0921] (6aR,9R)-9-methyl-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyridino[3,2-b][1,4]oxazine-8(6H)-carboxylic acid tert-butyl ester (24-3) (0.34 g, 0.91 mmol) was dissolved in dioxane (5.00 mL), and a solution of dioxane hydrogen chloride at 4 mol / L (5.00 mL, 20.00 mmol) was added. The reaction was stirred at room temperature for half an hour. After the reaction was complete, the solution was concentrated under reduced pressure to give a yellow solid target product (0.35 g, yield: 141%). LCMS: MS(ESI) m / z: 274 [M+H] + .

[0922] Step 4: Synthesis of 5-(((S)-1-(3-(((6aR,9R)-9-methyl-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)-3-oxopropoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 22)

[0923] (6aR,9R)-9-methyl-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyridino[3,2-b][1,4]oxazine (24-4) and (S)-3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionic acid (intermediate 1) (88.37 mg, 0.32 mmol) were dissolved in dichloromethane (10.00 mL), and DIEA (417.93 mg, 3.23 mmol), (100.00 mg, 0.32 mmol) and 1-propylphosphoric anhydride (1028.91 mg, 1.62 mmol) were added. The reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the mixture was quenched with water, extracted three times with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and the filtrate was concentrated to obtain the crude product. The crude product was purified by reversed-phase high-performance liquid chromatography (RP-HPLC) (column: XBridge Prep OBD C18 Column, 30*150mm, 5μm; mobile phase A: water (with 10 mol / L ammonium bicarbonate); mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: mobile phase B increased from 20% to 60% within 8 minutes; detection wavelength: 220 nm; retention time: 7.48 min) to obtain the white solid target product (31.98 mg, yield: 18%).

[0924] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 12.46 (s, 1H), 8.09-7.96 (m, 1H), 7.96-7.83 (m, 1H), 7.30-7.16 (m, 1H), 6.26-6.19 (m, 1H), 4.48- 4.17(m, 3H), 4.17-3.92(m, 2H), 3.87-3.47(m, 6H), 3.47-3.37(m, 2H), 2.62-2.55(m, 1H), 2.46-2.38(m, 1H), 1.23-1.02(m, 6H). LCMS: MS(ESI)m / z: 565.15[M+H] + .

[0925] Example 25: Synthesis of 5-(((S)-1-(3-(((6aR,9R)-9-methyl-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)-3-oxopropoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 25)

[0926]

[0927] The synthesis method was the same as in Example 20. The crude product of compound 25 was purified by reversed-phase high-performance liquid chromatography (column: XBridgePrep OBD C18 Column, 30*150mm, 5μm, mobile phase A: water (with 10 mol / L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 mL / min, elution gradient: mobile phase B increased from 20% to 60% within 8 minutes, detection wavelength: 220 nm, retention time: 7.48 min) to obtain a white solid target product (0.06 g, yield: 31%).

[0928] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 12.46 (m, 1H), 8.43 (s, 1H), 8.00-7.73 (m, 2H), 6.28 (s, 1H), 5.00-4.89 (m, 1H), 4.39-4.28 (m, 1H), 4.26-3.94 ( m, 4H), 3.94-3.77 (m, 2H), 3.77-3.62 (m, 3H), 3.62-3.55 (m, 1H), 3.52- 3.41 (m, 3H), 2.69-2.59 (m, 1H), 2.48-2.40 (m, 1H), 1.26-1.04 (m, 6H). LCMS: MS(ESI)m / z: 579.15[M+H] + .

[0929] Example 26: Synthesis of 3-oxo-5-((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxazopin-9(7H)-yl)propoxy)propyl-2-yl)amino)-2,3-dihydropyridazine-4-carboxynitrile (Compound 26)

[0930]

[0931] Step 1: Synthesis of 2-(4-methoxybenzyl)-3-oxo-5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxazopin-9(7H)-yl)propoxy)propyl-2-yl)amino)-2,3-dihydropyridazin-4-carboxynitrile (26-1)

[0932] Add 5-chloro-2-(4-methoxybenzyl)-3-oxo-2,3-dihydropyridazine-4-carboxylonitrile (52 mg, 0.19 mmol) to a DMF solution (5 mL) of a mixture of 3-((S)-2-aminopropoxy)-1-((R)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxazopin-9(7H)-yl)prop-1-one (77 mg, 0.19 mmol) and potassium carbonate (52 mg, 0.38 mmol), and stir at 80 °C for 2 h. The reaction mixture was then diluted with ethyl acetate (10 mL × 2) and water (10 mL). Extraction was performed, and the organic phases were combined and washed with saturated brine (10 mL × 2). After drying with anhydrous sodium sulfate, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude target product, 2-(4-methoxybenzyl)-3-oxo-5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxazopin-9(7H)-yl)propoxy)propyl-2-yl)amino)-2,3-dihydropyridazine-4-carboxynitrile (15 mg, 0.02 mmol, yield: 18%). The crude product was used directly in the next reaction without purification. LCMS: MS(ESI) m / z: 642 [M+H] + .

[0933] Step 2: Synthesis of 3-oxo-5-((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxazopin-9(7H)-yl)propoxy)propyl-2-yl)amino)-2,3-dihydropyridazin-4-carboxynitrile (Compound 26)

[0934] Add p-toluenesulfonic acid (12 mg, 0.06 mmol) and trifluoroacetic acid (8 mg, 0.06 mmol) to a solution of 2-(4-methoxybenzyl)-3-oxo-5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxazopin-9(7H)-yl)propoxy)propyl-2-yl)amino)-2,3-dihydropyridazin-4-carboxynitrile (15 mg, 0.02 mmol) in dichloromethane (1 mL) and stir at room temperature for 10 min. The reaction solution was extracted with dichloromethane (10 mL × 2) and water (10 mL), washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The solution was then subjected to high pressure (column: XBridge Prep OBD C18, 30 × 150 mm 5 μm, mobile phase A: water (with 10 mol / L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 mL / min, elution gradient: mobile phase B increased from 10% to 50% within 8 min, detection wavelength: 220 nm, retention time: 8.6 min) to obtain a white solid target product (6.41 mg, 0.01 mmol, yield: 52%).

[0935] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 12.46 (brs, 1H), 8.50-8.40 (m, 1H), 8.35-7.10 (m, 3H), 4.95-4.85 (m, 1H), 4.58-4.48 (m, 1H), 4.48- 4.08 (m, 1H), 4.08-3.91 (m, 2H), 3.91-3.58 (m, 7H), 3.55-3.40 (m, 3H), 3.32-3.22 (m, 1H), 2.62-2.56 (m, 2H), 1.17 (d, J=4.2Hz, 3H). LCMS: MS(ESI)m / z: 522.30[M+H] + .

[0936] Example 27: Synthesis of (7aR)-5-methyl-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]thiazoline (Compound 27)

[0937]

[0938] Step 1: Synthesis of 2-chloro-5-(trifluoromethyl)nicotinaldehyde (27-2)

[0939] 3-Bromo-2-chloro-5-(trifluoromethyl)pyridine (9 g, 35 mmol) was dissolved in tetrahydrofuran (50 mL). Butyllithium (15.4 mL, 38.5 mmol, 2.5 mol / L n-hexane solution) was added dropwise to the mixture at -65 °C. The mixture was stirred at -65 °C for 1 hour under nitrogen protection. Then, DMF (5.1 g, 70 mmol) was added dropwise at -65 °C, and the mixture was stirred at the same temperature for 1 hour. After the reaction was complete, the mixture was quenched with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and the filtrate was evaporated to dryness. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:90) to give a brown oily target product (6 g, 29 mmol, yield: 80%), LCMS (ESI) m / z: 210 [M+H]. + .

[0940] Step 2: Synthesis of 1-(2-chloro-5-(trifluoromethyl)pyridin-3-yl)ethyl-1-ol (27-3)

[0941] 2-Chloro-5-(trifluoromethyl)nicotinaldehyde (6 g, 29 mmol) was dissolved in tetrahydrofuran (70 mL), and methylmagnesium bromide (29 mL, 29 mmol, 1 mol / L diethyl ether solution) was added dropwise to the mixture. The mixture was stirred at 0 °C under nitrogen protection for 1 hour. After the reaction was complete, the mixture was extracted with brine (100 mL) and ethyl acetate (50 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and the filtrate was evaporated to dryness. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 40:60) to give the target product (4 g, 18 mmol, yield: 62%), LCMS (ESI) m / z: 226 [M+H). + .

[0942] Step 3: Synthesis of 2-chloro-3-(1-chloroethyl)-5-(trifluoromethyl)pyridine (27-4)

[0943] 1-(2-chloro-5-(trifluoromethyl)pyridin-3-yl)ethyl-1-ol (1.3 g, 5.8 mmol) was dissolved in phosphorus oxychloride (100 mL). The mixture was heated to 60 °C and stirred overnight under nitrogen protection. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was separated, and the aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and the filtrate was evaporated to dryness. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 50:50) to give the target product (0.9 g, 3.7 mmol, yield: 63%) as a yellow solid. LCMS (ESI) m / z: 244 [M+H] + .

[0944] Step 4: Synthesis of 1-benzyl 4-(2R)-2-((1-(2-chloro-5-(trifluoromethyl)pyridin-3-yl)ethyl)thio)methyl)piperazine-1,4-dicarboxylic acid tert-butyl ester (27-5)

[0945] 2-Chloro-3-(1-chloroethyl)-5-(trifluoromethyl)pyridine (0.9 g, 3.7 mmol) and 1-benzyl-4-(R)-2-(mercaptomethyl)piperazine-1,4-dicarboxylic acid tert-butyl ester (1.35 g, 3.9 mmol) were dissolved in DMF (20 mL), and potassium carbonate (1.16 g, 8 mmol) was added. The mixture was stirred at room temperature under nitrogen protection for 1 hour. After the reaction was complete, the mixture was filtered, and water (40 mL) was added. The mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, and the anhydrous sodium sulfate was removed by filtration. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 40:60) to give a yellow oily target product (820 mg, 1.4 mmol, yield: 37%), LCMS (ESI) m / z: 574 [M+H]. + .

[0946] Step 5: Synthesis of (2R)-2-((1-(2-chloro-5-(trifluoromethyl)pyridin-3-yl)ethyl)thio)methyl)piperazine (27-6)

[0947] 1-Benzyl 4-(2R)-2-((1-(2-chloro-5-(trifluoromethyl)pyridin-3-yl)ethyl)thio)methyl)piperazine-1,4-dicarboxylic acid tert-butyl ester (820 mg, 1.4 mmol) was dissolved in concentrated hydrochloric acid (10 mL). The mixture was heated to 50 °C and stirred for 3 hours under nitrogen protection. After the reaction was complete, the mixture was evaporated to dryness. The crude product was purified by column chromatography (acetonitrile:water = 50:50) to give the target product (300 mg, 0.88 mmol, yield: 62%), LCMS: (ESI) m / z: 340 [M+H].+ .

[0948] Step 6: Synthesis of (7aR)-5-methyl-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]thiazoline (27-7)

[0949] (2R)-2-((1-(2-chloro-5-(trifluoromethyl)pyridin-3-yl)ethyl)thio)methyl)piperazine (600 mg, 0.88 mmol) and triethylamine (100 mg, 1.76 mmol) were dissolved in DMF (10 mL). The mixture was heated to 100 °C and stirred for 3 hours under nitrogen protection. After cooling, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, and the anhydrous sodium sulfate was removed by filtration. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 50:50) to give a yellow oily target product (50 mg, 0.16 mmol, yield: 18%). LCMS: (ESI) m / z: 304 [M+H] + .

[0950] Step 7: Synthesis of 5-((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]thiazin-8(6H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 27)

[0951] 3-[(2S)-2-{[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino}propoxy]propionic acid (50 mg, 0.16 mmol) and (7aR)-5-methyl-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]thiazoline (50 mg, 0.16 mmol) were dissolved in dichloromethane (5.0 mL), and then diisopropylethylamine (61 mg, 0.48 mmol) and T3P (153 mg, 0.24 mmol, 50% ethyl acetate solution) were added. After stirring the reaction mixture at room temperature for 2 hours, the reaction solution was poured into ice water (20 mL). The aqueous phase was extracted three times with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by preparative liquid chromatography (column: YMC-Actus Triart C18, 30 × 150 mm, 5 μm; mobile phase A: water (with 10 mol / L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 mL / min, elution gradient: mobile phase B increased from 25% to 60% within 8 min, detection wavelength: 220 nm, retention time: 9.12 min) to obtain the white solid target product (2.29 mg, 0.004 mmol, yield: 2.5%).

[0952] 1 H NMR (400MHz, DMSO-d6,) δ (ppm): 12.32 (brs, 1H), 8.62-8.49 (m, 1H), 7.96-7.80 (m, 2H), 6.29-6.27 ( m, 1H), 4.56-4.47 (m, 1H), 4.40-4.21 (m, 1H), 4.15-4.07 (m, 1H), 4.01-3.89 (m, 1H), 3.82-3.64 (m, 3H ), 3.62-3.53(m, 1H), 3.52-3.50(m, 2H), 3.45-3.40(m, 1H), 3.26-3.23(m, 1H), 3.17-3.12(m, 1H), 3. 07-3.02 (m, 1H), 2.86-2.78 (m, 1H), 2.63-2.57 (m, 2H), 1.57 (d, J=6.0Hz, 3H), 1.16 (d, J=6.4Hz, 3H). LCMS: MS(ESI)m / z: 595.25[M+H] + .

[0953] Example 28: 5-(((S)-1-(3-(((7R,7AR)-7-methyl-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxazopin-9(7H)-yl)-3-oxopropoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 28)

[0954]

[0955] Step 1: Synthesis of (R)-1-(benzyloxy)carbonyl)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (28-2)

[0956] (R)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (5 g, 22 mmol) and sodium bicarbonate (3.7 g, 44 mmol) were dissolved in acetone (50 mL) and water (50 mL). Benzyl chloroformate (4.5 g, 26.4 mmol) was added dropwise to the mixture. The mixture was stirred at room temperature under nitrogen protection for 3 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove the anhydrous sodium sulfate, and the filtrate was evaporated to dryness. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 50:50) to give a yellow oily target product (4.5 g, 12.4 mmol, yield: 56%), LCMS: (ESI) m / z: 365 [M+H]. + .

[0957] Step 2: Synthesis of 1-benzyl4-(R)-2-(methoxy(methyl)carbamoyl)piperazine-1,4-dicarboxylic acid tert-butyl ester (28-3)

[0958] (R)-1-(benzyloxy)carbonyl)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (4.5 g, 12.4 mmol) was dissolved in dichloromethane (70 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.6 g, 18.6 mmol), N,N-diisopropylethylamine (4.8 g, 37.2 mmol), 1-hydroxybenzotriazole (2.5 g, 18.6 mmol), and dimethylhydroxylamine hydrochloride (2.4 g, 24.8 mmol) were added to the mixture. The mixture was stirred at room temperature under nitrogen protection for 3 hours. After the reaction was complete, water (70 mL) was added, and the mixture was extracted with dichloromethane (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove the anhydrous sodium sulfate, and the filtrate was evaporated to dryness. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 50:50) to give a yellow oily target product (3 g, 7.4 mmol, yield: 59%). LCMS: (ESI) m / z: 408 [M+H]+ .

[0959] Step 3: Synthesis of 1-benzyl4-(R)-2-acetylpiperazine-1,4-dicarboxylic acid tert-butyl ester (28-4)

[0960] 1-Benzyl4-(R)-2-(methoxy(methyl)carbamoyl)piperazine-1,4-dicarboxylic acid tert-butyl ester (3 g, 7.4 mmol) was dissolved in tetrahydrofuran (30 mL), and methyl magnesium bromide (7.4 mL, 14.8 mmol, 2 mol / L diethyl ether solution) was added dropwise to the mixture. The mixture was stirred at 0 °C under nitrogen protection for 1 hour. After the reaction was completed, brine (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and the filtrate was evaporated to dryness. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 40:60) to give the target product (1.8 g, 5 mmol, yield: 67%) as a yellow oil. LCMS: (ESI) m / z: 363 [M+H] + .

[0961] Step 4: Synthesis of 1-benzyl 4-(R)-2-(S)-1-hydroxyethyl)piperazine-1,4-dicarboxylic acid tert-butyl ester (28-5)

[0962] 1-Benzyl 4-(R)-2-(S)-1-hydroxyethyl)piperazine-1,4-dicarboxylic acid tert-butyl ester (1.8 g, 5 mmol) was dissolved in tetrahydrofuran (20 mL) and ethanol (20 mL), and sodium borohydride solid (570 mg, 15 mmol) was added to the mixture. The mixture was stirred at 0 °C under nitrogen protection for 3 hours. After the reaction was completed, brine (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and the crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 40:60) to give a yellow oily target product (1.4 g, 3.8 mmol, yield: 75%), LCMS: (ESI) m / z: 365 [M+H). + .

[0963] Step 5: Synthesis of 1-benzyl 4-(R)-2-(R)-1-(2-chloro-5-(trifluoromethyl)pyridin-3-yl)methoxy)ethyl)piperazine-1,4-dicarboxylic acid tert-butyl ester (28-6)

[0964] 2-Chloro-5-(trifluoromethyl)nicotinic acid (1.7 g, 7.6 mmol) was dissolved in dichloromethane (20 mL), and oxaloyl chloride (1.4 g, 11.4 mmol) was added dropwise to the mixture. The mixture was stirred at room temperature under nitrogen protection for 1 hour. After the reaction was complete, the mixture was directly evaporated to dryness, dissolved in dichloromethane (1 mL), and added dropwise to a mixture of 1-benzyl-4-(R)-2-(S)-1-hydroxyethyl)piperazine-1,4-dicarboxylic acid tert-butyl ester (1.4 g, 3.8 mmol) and triethylamine (1.9 g, 19 mmol) in dichloromethane (20 mL). The mixture was reacted at room temperature for 2 hours. After the reaction was complete, brine (30 mL) was added, and the mixture was extracted with dichloromethane (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove the anhydrous sodium sulfate, and the filtrate was evaporated to dryness. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 50:50) to give a yellow oily target product (1.1 g, 2 mmol, yield: 50%). LCMS: (ESI) m / z: 572 [M+H] + .

[0965] Step 6: Synthesis of (R)-2-(R)-1-(2-chloro-5-(trifluoromethyl)pyridin-3-yl)methoxy)ethyl)piperazine (28-7)

[0966] 1-Benzyl 4-(R)-2-(R)-1-(2-chloro-5-(trifluoromethyl)pyridin-3-yl)methoxy)ethyl)piperazine-1,4-dicarboxylic acid tert-butyl ester (1.1 g, 2 mmol) was dissolved in concentrated hydrochloric acid (38%, 10 mL), and the mixture was slowly heated to 50 °C and stirred for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, the crude product was diluted with water (30 mL), the pH was adjusted to 8-9 with sodium bicarbonate, and the mixture was extracted three times with dichloromethane (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and the filtrate was evaporated to dryness. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 50:50) to give the target product as a yellow solid (500 mg, 1.5 mmol, yield: 77%). LCMS: (ESI) m / z: 338 [M+H] + .

[0967] Step 7: Synthesis of (R)-3-((R)-1-((2-chloro-5-(trifluoromethyl)nicotinyl)oxy)ethyl)piperazine-1-carboxylic acid tert-butyl ester (28-8)

[0968] (R)-2-(R)-1-(2-chloro-5-(trifluoromethyl)pyridin-3-yl)methoxy)ethyl)piperazine (500 mg, 1.5 mmol) and triethylamine (300 mg, 3 mmol) were dissolved in dichloromethane (10 mL), and di-tert-butyl dicarbonate (492 mg, 1.5 mmol) was added dropwise to the mixture. The mixture was stirred at room temperature under nitrogen protection for 3 hours. After the reaction was completed, brine (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and the crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 50:50) to give a yellow oily target product (430 mg, 0.98 mmol, yield: 65%), LCMS: (ESI) m / z: 438 [M+H]. + .

[0969] Step 8: Synthesis of (7R,7AR)-7-methyl-5-oxo-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxaza-9(7H)-carboxylic acid tert-butyl ester (28-9)

[0970] (R)-3-((R)-1-((2-chloro-5-(trifluoromethyl)nicotinyl)oxy)ethyl)piperazine-1-carboxylic acid tert-butyl ester (430 mg, 0.98 mmol) was dissolved in DMF (5 mL), and potassium carbonate (270 mg, 1.96 mmol) was added. The mixture was heated to 100 °C and stirred for 12 hours under nitrogen protection. After cooling, 30 mL of ice water was added, and the mixture was extracted three times with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, and the crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 70:30) to give a yellow oily target product (200 mg, 0.5 mmol, yield: 51%). LCMS: (ESI) m / z: 402 [M+H] + .

[0971] Step 9: Synthesis of (7R,7AR)-7-methyl-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxaza-9(7H)-carboxylic acid tert-butyl ester (28-10)

[0972] (7R,7AR)-7-methyl-5-oxo-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxaza-9(7H)-carboxylic acid tert-butyl ester (200 mg, 0.5 mmol) was dissolved in tetrahydrofuran (10 mL). After cooling to 0 °C, sodium borohydride solid (38 mg, 1 mmol) and boron trifluoride diethyl ether (0.4 mL) were added, and the mixture was stirred for 1 hour. After the reaction was completed, the reaction solution was poured into ice water (10 mL), and the aqueous phase was extracted three times with ethyl acetate (15 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 50:50) after rotary evaporation to give a yellow oily target product (40 mg, 0.1 mmol, yield: 20%). LCMS: (ESI) m / z: 388 [M+H] + .

[0973] Step 10: Synthesis of (7R,7aR)-7-methyl-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxazo-5-one (28-11)

[0974] (7R,7AR)-7-methyl-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxazapyro-9(7H)-carboxylic acid tert-butyl ester (40 mg, 0.1 mmol) was dissolved in ice-cold (0 °C) 1,4-dioxane hydrochloride solution (4 M, 1 mL), and the mixture was slowly heated to room temperature with stirring for 4 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, the crude product was diluted with water (30 mL), the pH was adjusted to 8-9 with sodium bicarbonate, and the mixture was extracted three times with dichloromethane (20 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 40:60) after drying to give the target product as a yellow solid (20 mg, 0.069 mmol, yield: 66%). LCMS: (ESI) m / z: 288 [M+H] + .

[0975] Step 11: Synthesis of 5-(((S)-1-(3-(((7R,7AR)-7-methyl-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxazopin-9(7H)-yl)-3-oxopropoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 28)

[0976] (7R,7aR)-7-methyl-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxazopine (20 mg, 0.069 mmol) and (S)-3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionic acid (21 mg, 0.069 mmol) were dissolved in dichloromethane (1.0 mL), and then diisopropylethylamine (27 mg, 0.207 mmol) and propyl phosphate tricyclic anhydride solution (66 mg, 0.104 mmol, 50% ethyl acetate solution) were added. After stirring the reaction mixture at room temperature for 2 hours, the reaction solution was poured into ice water (20 mL). The aqueous phase was extracted three times with ethyl acetate (10 mL × 3). The organic phases were combined, aerated with anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by preparative liquid chromatography (column: XBridge Prep OBD C18, 30 × 150 mm 5 μm, mobile phase A: water (with 10 mol / L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 mL / min, elution gradient: mobile phase B increased from 10% to 50% within 8 min, detection wavelength: 220 nm, retention time: 7.53 min) to obtain the target product as a white solid (1.28 mg, 0.002 mmol, yield 1.25%).

[0977] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 12.45 (brs, 1H), 8.50 (s, 1H), 8.18-8.10 (m, 1H), 7.92-7.84 (m, 1H), 6.31-6.21 (m, 1H), 4.11-4.04 (m, 3H), 4.01-3.88 (m, 2H), 3.74-3.59 (m, 3H), 3.49-3.40 (m, 4H), 3.14-2.92 (m, 1H), 2.84-2.60 (m, 4H), 1.42 (d, J=6.4Hz, 3H), 1.16-1.12 (m, 3H). LCMS: MS(ESI)m / z: 579.35[M+H] + .

[0978] Example 29: Synthesis of 5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxazopin-9-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 29)

[0979]

[0980] Step 1: Synthesis of (S)-4-(benzyl(2-methoxy-2-oxoethyl)amino)-3-(tert-butoxycarbonyl)amino)-4-oxobutyrate methyl ester (29-2)

[0981] (S)-2-(tert-Butoxycarbonyl)amino)-4-methoxy-4-oxobutyric acid (10 g, 0.04 mol) and benzylglycine methyl ester (10.8 g, 0.06 mol) were dissolved in 200 mL of dichloromethane in a flask. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (11.5 g, 0.06 mol), 1-hydroxybenzotriazole (8.1 g, 0.06 mol), and N,N-diisopropylethylamine (15.5 g, 0.12 mol) were added, and the mixture was reacted at room temperature for 2 hours. After the reaction was complete, water (200 mL) was added to quench the reaction. The mixture was separated, and the aqueous phase was extracted with dichloromethane (100 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:90) to obtain the target product, a yellow oil (8 g, 0.02 mol, yield: 72%). LCMS: MS (ESI) m / z: 409 [M+H] + .

[0982] Step 2: Synthesis of (S)-2-(4-benzyl-3,6-dioxoperazin-2-yl)methyl acetate (29-3)

[0983] Methyl (S)-4-(benzyl(2-methoxy-2-oxoethyl)amino)-3-(tert-butoxycarbonyl)amino)-4-oxobutyrate (8 g, 0.02 mol) was dissolved in trifluoroacetic acid. The mixture was stirred at room temperature for 1 hour, concentrated under reduced pressure, and then ammonia-methanol (50 mL) solution was added. The mixture was stirred at room temperature for 3 hours, and then concentrated to give a yellow oily target product (4.1 g, 0.014 mol, yield: 80%). LCMS: MS(ESI) m / z: 277 [M+H] + .

[0984] Step 3: Synthesis of (S)-2-(4-benzylpiperazin-2-yl)ethyl-1-ol (29-4)

[0985] In a 50 mL round-bottom flask, methyl (S)-2-(4-benzyl-3,6-dioxopiperazin-2-yl)acetate (4.1 g, 0.014 mol) dissolved in tetrahydrofuran (100 mL) was added. Lithium aluminum hydride (14 mL, 0.028 mol, 2 mol / L tetrahydrofuran solution) was added at 0 °C. The mixture was stirred overnight at room temperature. Sodium sulfate decahydrate was added, and the mixture was stirred for 30 min. The mixture was filtered, and the filtrate was evaporated to dryness to obtain a yellow solid crude product. This crude product was purified by high-performance liquid chromatography (HPLC) (column: XBridge Prep OBD C18, 30 × 150 mm). The target product (1.2 g, 5.4 mmol, yield: 36%) was obtained as a yellow solid (5 μm, mobile phase A: water (with 10 mol / L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 mL / min, elution gradient: mobile phase B increased from 5% to 30% within 8 min, detection wavelength: 220 nm, retention time: 7.37 min). LCMS: MS (ESI) m / z: 221 [M+H] + .

[0986] Step 4: Synthesis of (S)-2-(4-benzyl-1-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)piperazin-2-yl)ethyl-1-ol (29-5)

[0987] (S)-2-(4-benzylpiperazin-2-yl)ethyl-1-ol (600 mg, 2.5 mmol) was dissolved in DMF (12 mL) in a reaction flask, and 2,3-difluoro-5-(trifluoromethyl)pyridine (915 mg, 5 mmol) and potassium carbonate (690 mg, 5 mmol) were added. The mixture was stirred overnight at 80 °C, cooled, and extracted with ethyl acetate (50 mL × 2) and water (25 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 3:1) to give the target product (300 mg, 0.78 mmol, yield: 34%) as a yellow oil. LCMS: MS (ESI) m / z: 384 [M+H] + .

[0988] Step 5: Synthesis of (S)-9-benzyl-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxazopine (29-6)

[0989] (S)-2-(4-benzyl-1-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)piperazin-2-yl)ethyl-1-ol (300 mg, 0.78 mmol) was dissolved in DMF (6 mL), and potassium tert-butoxide (175 mg, 1.56 mmol) was added. The mixture was stirred at 100 °C for 3 hours, cooled, and extracted with ethyl acetate (20 mL × 2) and water (10 mL). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give a yellow oily target product (260 mg, 0.71 mmol, yield: 91%). LCMS: MS (ESI) m / z: 364 [M+H] + .

[0990] Step 6: Synthesis of (S)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxazone (29-7)

[0991] (S)-9-benzyl-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxazopine (260 mg, 0.72 mmol) was dissolved in acetic acid (20 mL), and anhydrous palladium on carbon (50 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. After the reaction was complete, the mixture was filtered, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by high performance liquid chromatography (column: XBridge Prep OBD C18, 30 × 150 mm). 5 μm, mobile phase A: water (with 10 mol / L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 mL / min, elution gradient: mobile phase B increased from 5% to 40% within 8 min, detection wavelength: 220 nm, retention time: 8.27 min) After purification, a colorless oily target product (110 mg, 0.4 mmol, yield: 56%) was obtained. LCMS: MS (ESI) m / z: 274 [M+H] + .

[0992] Step 7: Synthesis of 5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxazopin-9-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 29)

[0993] Dissolve (S)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxazone (55 mg, 0.2 mmol) in dichloromethane (2 mL), add 50% ethyl acetate solution of propyl phosphate tricyclic anhydride (190.8 mg, 0.3 mmol), N,N-diisopropylethylamine (77.4 mg, 0.6 mmol), and (S)-3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionic acid (62 mg, 0.2 mmol). The mixture was stirred at room temperature for 1 hour, then extracted with dichloromethane (10 mL × 2) and water (5 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The filtrate was then purified by high performance liquid chromatography (column: XBridge Prep OBD C18, 30 × 150 mm 5 μm, mobile phase A: water (with 10 mol / L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 mL / min, elution gradient: mobile phase B increased from 20% to 58% within 8 min, detection wavelength: 220 nm, retention time: 7.57 min) to obtain a white solid target product (26.82 mg, 0.047 mmol, yield: 23%).

[0994] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 12.45 (brs, 1H), 8.23-8.08 (m, 1H), 8.02-7.83 (m, 1H), 7.39-7.32 (m, 1H) ), 6.32-6.22(m, 1H), 4.36-4.20(m, 2H), 4.19-4.07(m, 1H), 4.07-3.95(m, 1H), 3.90-3.76(m, 2H), 3.75- 3.62(m, 4H), 3.62-3.37(m, 4H), 2.59-2.53(m, 2H), 2.18-2.01(m, 1H), 1.97-1.83(m, 1H), 1.20-1.03(m, 3H). LCMS: MS(ESI)m / z: 565.20[M+H] + .

[0995] Example 30: Synthesis of (s)-5-cyclopropyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyridino[3,2-e]pyrazin-6(6aH)-one (Compound 30)

[0996]

[0997] Step 1: Synthesis of (S)-4-(tert-butoxycarbonyl)-1-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-2-carboxylic acid (30-2)

[0998] (S)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (2.00 g, 8.69 mmol) was added to a methanol (20 mL) solution, followed by the addition of 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (1.96 g, 8.69 mmol) and TEA (1.75 g, 17.38 mmol). The mixture was stirred at room temperature for 16 hours. The resulting mixture was concentrated under reduced pressure to obtain a brown solid crude product, (S)-4-(tert-butoxycarbonyl)-1-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-2-carboxylic acid (4.00 g). The crude product was used directly in the next reaction without further purification. LCMS: MS (ESI) m / z: 421 [M+H] + .

[0999] Step 2: Synthesis of (S)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2]pyridino[3,2]pyrazine-8-carboxylic acid tert-butyl ester (30-3).

[1000] (S)-4-(tert-butoxycarbonyl)-1-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazin-2-carboxylic acid (2.00 g, 4.76 mmol) was added to an ethanol (40 mL) solution, followed by iron powder (2.67 g, 47.60 mmol) and ammonium chloride (2.52 g, 47.60 mmol). The mixture was stirred at 75 °C for 2 hours. The mixture was filtered, and the filtrate was extracted with water (100 mL) and ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated sodium chloride solution, and the ethyl acetate layer was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 30:70) to give the target product (S)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2]pyridino[3,2]pyrazine-8-carboxylic acid tert-butyl ester (0.40 g, 1.08 mmol, yield: 22.6%). LCMS: MS(ESI) m / z: 373 [M+H] + .

[1001] Step 3: Synthesis of (S)-5-cyclopropyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyridino[3,2-e]pyrazine-8-carboxylic acid tert-butyl ester (30-4).

[1002] (S)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyridino[3,2-e]pyrazino-8-carboxylic acid tert-butyl ester (300 mg, 0.80 mmol) was added to a solution of dimethylformamide (20 mL), followed by the addition of cyclopropylboronic acid (138 mg, 1.60 mmol) and Cu(OAc)₂ (9.9 mg, 0.05 mmol). The mixture was stirred at 60 °C for 120 hours. Water (40 mL) was added to the mixture, followed by extraction with ethyl acetate (20 mL × 3). The organic layer was collected and dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 30:70) to give the target product as a white solid (149 mg, 0.36 mmol, yield: 45%). LCMS: MS(ESI)m / z: 413|M+H] + .

[1003] Step 4: Synthesis of (S)-5-cyclopropyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyridino[3,2-e]pyrazino-6(6aH)-one (30-5)

[1004] (S)-5-cyclopropyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyridino[3,2-e]pyrazino-8-carboxylic acid tert-butyl ester (150 mg, 0.36 mmol) was added to a mixed solution of trifluoroacetic acid (2 mL) and dichloromethane (5 mL). The mixture was stirred at room temperature for 2 hours, and the reaction solution was concentrated to dryness under reduced pressure. Water (20 mL) was added to the residue, and the pH was adjusted to 8-9 with a saturated aqueous solution of sodium bicarbonate. The aqueous phase was extracted with ethyl acetate (10 mL × 3), and the organic layer was dried over anhydrous Na₂SO₄. The Na₂SO₄ was removed by filtration, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 30:70) to obtain the target product (100 mg, 0.32 mmol, yield: 88%) as a wine-red solid. LCMS: MS(ESI) m / z: 313 [M+H] + .

[1005] Step 5: Synthesis of (S)-5-cyclopropyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one (Compound 30)

[1006] (S)-5-cyclopropyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyridino[3,2-e]pyrazino-6(6aH)-one (35 mg, 0.11 mmol) was dissolved in a sample vial containing 2 mL of dichloromethane. Then, (S)-3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionic acid (35 mg, 0.11 mmol), propylphosphonic anhydride (214.90 mg, 0.33 mmol), and N,N-diisopropylethylamine (72.10 mg, 0.56 mmol) were added. The mixture was stirred at room temperature for 1 hour, then water (5 mL) was added, and the mixture was extracted with dichloromethane (5 mL × 3). The organic layer was collected, dried over sodium sulfate, and concentrated to give the crude product. The crude product was purified by high performance liquid chromatography (HPLC). The chromatographic column was YMC-Acms Triart C18, 30×150 mm, 5 μm; mobile phase A: water (10 mmol / L ammonium bicarbonate); mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 25% B to 60% B for 8 min; wavelength: 220 nm; retention time: 7.85 min. The target product (7.75 mg, 0.0132 mmol, yield: 12%) was obtained as a white solid.

[1007] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 12.53 (s, 1H), 8.22 (s, 1H), 7.99-7.82 (m, 1H), 7.66 (s , 1H), 6.40-6.18(m, 1H), 4.90-4.77(m, 1H), 4.57-4.22(m, 2H), 4.19-3.99(m, 2H), 3. 73-3.64(m, 2H), 3.52-3.48(m, 2H), 3.21-3.08(m, 1H), 2.85-2.74(m, 2H), 2.69-2.62 (m, 3H), 1.29-1.14 (m, 4H), 1.14-1.05 (m, 1H), 0.86-0.72 (m, 1H), 0.55-0.40 (m, 1H). LCMS: MS(ESI)m / z: 604.05[M+H] + .

[1008] Example 31: Synthesis of 5-(((S)-1-(3-(R)-2-methyl-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxazopin-9(7H)-yl)-3-oxopropoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 31)

[1009]

[1010] Step 1: Synthesis of 2-chloro-3-(methoxycarbonyl)-5-(trifluoromethyl)pyridine-1-oxide (31-2)

[1011] Hydrogen peroxide (5 mL) was added to a TFA (10 mL) solution of methyl 2-chloro-5-(trifluoromethyl)nicotinic acid (5 g, 20 mmol). The mixture was stirred at 70 °C for 1 h, then poured into water (5 mL). The mixture was extracted three times with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered to remove sodium sulfate. The filtrate was concentrated to dryness under reduced pressure. The remaining crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 80:20) to obtain a white solid target product (2.5 g, 1.2 mmol, yield: 60%). LCMS: (ESI) m / z: 256 [M+H] + .

[1012] Step 2: Synthesis of methyl 2,6-dichloro-5-(trifluoromethyl)nicotinic acid (31-3)

[1013] A mixture of 2-chloro-3-(methoxycarbonyl)-5-(trifluoromethyl)pyridine 1-oxide (2.5 g, 20 mmol) and phosphorus oxychloride (10 mL) was stirred at 100 °C for 2 h. The reaction solution was concentrated under reduced pressure to remove excess phosphorus oxychloride. The residue was dissolved in dry ethyl acetate, mixed with silica gel (6 g), and concentrated to dryness under reduced pressure. The dry sample was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 70:30) to give a yellow oily target product (1.5 g, 12 mmol, yield: 60%), LCMS: (ESI) m / z: 274 [M+H]. + .

[1014] Step 3: Synthesis of (R)-4-(6-chloro-3-(methoxycarbonyl)-5-(trifluoromethyl)pyridin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (31-4)

[1015] N,N-diisopropylethylamine (0.5 g, 7.2 mmol) was added to a mixture of methyl 2,6-dichloro-5-(trifluoromethyl)nicotinate (1 g, 3.64 mmol) and (R)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (0.78 g, 3.6 mmol) in acetonitrile (10 mL). The mixture was stirred at room temperature for 12 h. The reaction mixture was poured into water (20 mL) and extracted twice with ethyl acetate (10 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove sodium sulfate, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 30:70) to give the target product as a white solid (1 g, 3.64 mmol, yield: 70%). LCMS: (ESI) m / z: 454 [M+H] + .

[1016] Step 4: Synthesis of (R)-2-chloro-5-oxo-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxaza-9(7H)-carboxylic acid tert-butyl ester (31-5)

[1017] A mixture of (R)-4-(6-chloro-3-(methoxycarbonyl)-5-(trifluoromethyl)pyridin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (1 g, 2.2 mmol) and N,N-diisopropylethylamine (0.5 g, 4.4 mmol) in acetonitrile (10 mL) was stirred at 80 °C for 12 h. The solution was then poured into water (10 mL) and extracted with ethyl acetate (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 74:26) to give the target product as a white solid (0.75 g, 1.8 mmol, yield: 80%). LCMS: (ESI) m / z: 422 [M+H] + .

[1018] Step 5: Synthesis of (R)-2-methyl-5-oxo-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxaza-9(7H)-carboxylic acid tert-butyl ester (31-6)

[1019] (R)-2-chloro-5-oxo-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxaza-9(7H)-carboxylic acid tert-butyl ester (0.1 g, 0.23 mmol) and methylboronic acid (0.02 g, 0.35 mmol) were added to dioxane (1 mL), followed by tetra(triphenylphosphine)palladium (0.054 g, 0.023 mmol). The mixture of 1) and cesium carbonate (0.154 g, 0.46 mmol) was stirred at 100 °C for 2 h, then filtered. The filtrate was poured into water (2 mL) and extracted with ethyl acetate (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered to remove ammonium sulfate, and the filtrate was concentrated. The remaining crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50:50) to obtain the target product (0.08 g, 0.23 mmol, yield: 100%). LCMS: (ESI) m / z: 557 [M+H] + .

[1020] Step 6: Synthesis of (R)-2-methyl-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxazopine-9(7H)-carboxylic acid tert-butyl ester (31-7)

[1021] To a solution of (R)-2-methyl-5-oxo-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxaza-9(7H)-carboxylic acid tert-butyl ester (0.08 g, 0.2 mol) in tetrahydrofuran (5 mL), boron trifluoride diethyl ether solution (2 mL) and sodium borohydride (0.036 g, 1 mmol) were added. The mixture was stirred at room temperature for 2 h. The mixture was then poured into water (20 mL) and extracted with ethyl acetate (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate and filtered to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the target product (0.077 g, 0.2 mmol, yield: 40%). LCMS: (ESI) m / z: 287 [M+H] + .

[1022] Step 7: Synthesis of (R)-2-methyl-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxazazeptazoline(31-8)

[1023] (R)-2-methyl-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxaza-9(7H)-carboxylic acid tert-butyl ester (0.8 g, 2.06 mmol) was added to hydrochloric acid / dioxane (2 mL). The mixture was stirred at room temperature for 2 h, and then concentrated to give the target product as a white solid (0.5 g, 2.06 mmol, yield: 70%). LCMS: (ESI) m / z: 387 [M+H] + .

[1024] Step 8: Synthesis of 5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydropyrazine[1,2-a]pyridine[3,2-f][1,4]diazaphen-9(5H)-yl)propoxy)propanol-2-yl)amino)-4-(trifluoromethyl)piperazine-3(2H)-one (Compound 31)

[1025] (R)-2-methyl-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxazopine (50 mg, 0.13 mmol) and (S)-3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionic acid (53 mg, 0.13 mmol) in a solution in DCM (2 mL) were mixed with propylphosphonic anhydride (158.64 mg, 0.65 mmol) and N,N-diisopropylethylamine (67.3 mg, 0.52 mmol). The mixture was stirred at room temperature for 2 h. The mixture was poured into water (5 mL) and extracted with dichloromethane (5 mL × 2). The organic phase was dried over anhydrous sodium sulfate, concentrated by filtration, and separated by preparative high performance liquid chromatography (column: XBridge Prep). OBD C18, 30×150mm 5um, mobile phase A: water (with 10mol / L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60mL / min, elution gradient: mobile phase B increased from 20% to 52% within 8min, detection wavelength: 220nm, retention time: 7.67min) yielded a white solid target product (2.32mg, 0.091mmol, yield: 30%).

[1026] 1H NMR (400MHz, DMSO-d6) δ (ppm): 12.45 (s, 1H), 7.95-7.90 (m, 1H), 7.70-7.68 (m, 1H), 6.28 (s, 1H), 4.90-4.80 (m, 1H), 4.52-4.42 (m, 1H) , 4.18-4.11(m, 1H), 4.08-3.93(m, 2H), 3.93-3.80(m, 3H), 3.80-3.52(m, 8H), 3.49-3.45(m, 2H), 2.46-2.45(m, 3H), 1.18-1.12(m, 3H). LCMS: MS(ESI)m / z: 579.25[M+H] + .

[1027] Example 32: Synthesis of 5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,8]naphthidin-8-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 32)

[1028]

[1029] Step 1: Synthesis of 8-benzyl-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthidine (32-1)

[1030] Intermediate 5 of 8-benzyl-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthidin-5-one (0.10 g, 0.28 mmol), hydrazine hydrate (0.02 g, 0.55 mmol), and potassium hydroxide (0.03 g, 0.55 mmol) were added to diethylene glycol (5 mL). The mixture was stirred at 160 °C for 2 hours. The mixture was then poured into water (2 mL) and extracted with ethyl acetate (3 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered to remove sodium sulfate, and the filtrate was concentrated under reduced pressure to give the target product (0.05 g, 0.14 mmol, yield: 52%) as a yellow oil. LCMS: MS(ESI) m / z: 358 [M+H] + .

[1031] Step 2: Synthesis of 3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthidine (32-2)

[1032] A mixture of 8-benzyl-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthidine (0.12 g, 0.08 mmol) and palladium / carbon (0.01 g, 0.02 mmol) in acetic acid (2 mL) was stirred at room temperature for 2 hours under a hydrogen atmosphere. The mixture was then filtered and concentrated. The residue was purified by column chromatography (acetonitrile:water = 30:70) to give the target product (0.05 g, 0.05 mmol, yield: 68%) as a yellow oil. LCMS: MS (ESI) m / z: 258 [M+H] + .

[1033] Step 3: Synthesis of 5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,8]naphthidin-8-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 32)

[1034] 3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthidine (50 mg, 0.19 mmol) and (S)-3-(2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionic acid intermediate 1 (60.10 mg, 0.19 mmol) were added to a solution of dichloromethane (2 mL), followed by the addition of propylphosphonic anhydride (127.50 mg, 0.39 mmol) and N,N-diisopropyldiamine (75.22 mg, 0.58 mmol). The mixture was stirred at room temperature for 2 h, then poured into water (2 mL) and extracted with ethyl acetate (3 mL × 2). The organic phase was dried over anhydrous sodium sulfate, concentrated by filtration, and purified by preparative high performance liquid chromatography (column: XBridge). C18 column, 30×150mm, 5μm; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: acetonitrile; flow rate: 60mL / min; gradient: 8min 30%B to 60%B, 60%B; wavelength: 220nm; retention time: 6.45min) yielded a white solid target product (50mg, 0.08mmol, yield: 47%).

[1035] 1H NMR (400MHz, DMSO-d6) δ (ppm): 12.45 (s, 1H), 8.24 (s, 1H), 7.91 (s, 1H), 7.53 (s, 1H), 6.27 (s, 1 H), 4.71-4.68(m, 1H), 4.43-4.36(m, 1H), 4.16-4.10(m, 1H), 4.00-3.95(m, 1H), 3.71-3.63(m, 2H), 3.52-3.49(m, 2H), 3.15-3.09(m, 1H), 2.93-2.84(m, 1H), 2.82-2.74(m, 4H), 2.62-2.58(m , 2H), 2.11-2.06 (m, 1H), 1.69-1.52 (m, 1H), 1.22-1.11 (m, 3H). LCMS: MS (ESI) m / z: 549.20 [M+H] + .

[1036] Example 33: Synthesis of (S)-5-cyclopropyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyridino[3,2-e]pyrazin-6(6aH)-one (Compound 33)

[1037]

[1038] Step 1: Synthesis of (S)-5-methyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyridino[3,2-e]pyrazin-8-carboxylic acid tert-butyl ester (33-1)

[1039] (S)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]-pyridino[3,2-e]pyrazin-8-carboxylic acid tert-butyl ester (200 mg, 0.54 mmol) was added to a solution of tetrahydrofuran (5 mL). The mixture was cooled to 0 °C, and sodium hydrogen (26 mg, 0.64 mmol) was added. The mixture was stirred at room temperature for 1 hour, and then cooled to 0 °C. Iodomethane (113.60 mg, 0.80 mmol) was slowly added to the mixture, and the reaction was carried out at room temperature for 1 hour. The reaction solution was quenched with ice water (10 mL), extracted with EA (10 mL × 3), the organic layer was collected and dried over anhydrous sodium sulfate, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography to give a colorless oily target product (100 mg, 0.26 mmol, yield: 48%). LCMS: MS(ESI) m / z: 387 [M+H] +.

[1040] Step 2: Synthesis of (S)-5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyridino[3,2-e]pyrazino-6(6aH)-one (33-2)

[1041] (s)-5-methyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyridino[3,2-e]pyrazino-8-carboxylic acid tert-butyl ester (90 mg, 0.23 mmol) was added to a hydrochloric acid / dioxane (5 mL) solution. The mixture was stirred at room temperature for 1 hour, dried under reduced pressure, and concentrated to obtain an orange solid crude product (80 mg, yield: 100%). The crude product was used directly in the next reaction without purification. LCMS: MS(ESI) m / z: 287 [M+H] + .

[1042] Step 3: Synthesis of (S)-5-methyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one (Compound 33)

[1043] Dissolve (S)-5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyridino[3,2-e]pyrazino-6(6aH)-one (80 mg, 0.27 mmol) in dichloromethane (1 mL), then add (S)-3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionic acid (85.84 mg, 0.27 mmol), propylphosphonic anhydride (355.84 mg, 0.54 mmol) and N,N-diisopropylethylamine (180.40 mg, 1.36 mmol). The mixture was stirred at room temperature for 1 hour, then water (5 mL) was added to the reaction solution, followed by extraction with dichloromethane (5 mL × 3). The organic layer was collected, dried with sodium sulfate, and the sodium sulfate was filtered off. The filtrate was concentrated to obtain the product. The crude product was purified by high performance liquid chromatography (HPLC) (column: Xsele CSH C18 OBD column 30 × 150 mm 5 μm; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 15% B to 55% B, 55% B for 8 min; wavelength: 220 nm; RT1 (minimum): 7.82) to obtain the target product as a yellow solid (22.90 mg, 0.039 mmol, yield: 14.4%).

[1044] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 12.434 (s, 1H), 8.206 (s, 1H), 7.99-7.80 (m, 1H), 7.56-7.39 (m, 1H), 6.39-6.21 (m, 1H), 4.59-4.43 (m, 2H) , 4.33-3.98(m, 3H), 3.78-.3.63(m, 2H), 3.57-3.46(m, 3H), 3.32-3.31(m, 3H), 3.19-3.05(m, 1H), 2.89-2.68(m, 2H), 1.21-1.12(m, 3H). LCMS: MS(ESI)m / z: 578.05[M+H] + .

[1045] Example 34: Synthesis of propionamide 5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydrodipyrazino[2,3-b:1',2'-d][1,4]oxazin-8(6H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 34)

[1046]

[1047] Step 1: Synthesis of (S)-3-(hydroxymethyl)-4-(5-(trifluoromethyl)pyrazin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (34-2)

[1048] 2-Chloro-5-(trifluoromethyl)pyrazine (1.00 g, 5.50 mmol) was dissolved in dimethylformamide (20 mL), followed by the addition of (S)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (1.42 g, 6.59 mmol) and potassium carbonate (1.52 g, 10.99 mmol). The mixture was stirred at 60 °C for 12 hours. Water (50 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (50 mL × 3). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was then passed through a silica gel column (petroleum ether:ethyl acetate = 60:40) to give the target product (0.47 g, 1.29 mmol, yield: 23%) as an orange oil. LCMS: MS (ESI) m / z: 363 [M+H] + .

[1049] Step 2: Synthesis of (S)-4-(3-chloro-5-(trifluoromethyl)pyrazin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (34-3)

[1050] (S)-4-(3-chloro-5-(trifluoromethyl)pyrazin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (460 mg, 1.27 mmol) was added to a solution of dimethylformamide (10 mL), followed by N-chlorosuccinimide (254 mg, 1.90 mmol). The mixture was stirred at 50 °C for 16 hours. After the reaction was complete, water (100 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL × 3). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was then passed through a silica gel column (petroleum ether:ethyl acetate = 30:70) to give the target product (102 mg, 0.26 mmol, yield: 20%). LCMS: MS (ESI) m / z: 397 [M+H] + .

[1051] Step 3: Synthesis of (S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydrodipyrazino[2,3-b:1',2'-d][1,4]oxazine-8(6H)-carboxylic acid tert-butyl ester (34-4).

[1052] (S)-4-(3-chloro-5-(trifluoromethyl)pyrazin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.25 mmol) was added to dimethylformamide (2 mL), followed by potassium carbonate (70 mg, 0.50 mmol). The mixture was stirred at room temperature for 2 hours, then water (5 mL) was added to the reaction solution, followed by extraction with ethyl acetate (5 mL × 3). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was then passed through a silica gel column (petroleum ether:ethyl acetate = 65:35) to obtain the colorless oily target product (S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydrodipyrazino[2,3-b:1',2'-d][1,4]oxazine-8(6H)-carboxylic acid tert-butyl ester (60 mg, 0.17 mmol, yield: 66%). LCMS: MS(ESI) m / z: 361 [M+H] + .

[1053] Step 4: Synthesis of (S)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydrodipyrazine[2,3-b:1',2'-d][1,4]oxazine (34-5)

[1054] (S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydrodipyrazino[2,3-b:1',2'-d][1,4]oxazine-8(6H)-carboxylic acid tert-butyl ester (50 mg, 0.13 mmol) was dissolved in dioxane hydrochloride (5 mL). The mixture was stirred at room temperature for 2 hours. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (20 mL × 2). The mixture was washed with saturated sodium chloride solution. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give a colorless oily crude product (50 mg, yield: 100%). This crude product was used directly in the next reaction without further purification. LCMS: MS(ESI) m / z: 261 [M+H] + .

[1055] Step 5: Synthesis of propionamide 5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydrodipyrazino[2,3-b:1',2'-d][1,4]oxazin-8(6H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 34)

[1056] (S)-3-(trifluoromethyl)-6,6a7,8,9,10-hexahydrodipyrazino[2,3-b:1',2'-d][1,4]oxazine (50 mg, 0.19 mmol) was added to a solution of dichloromethane (5 mL), followed by a mixture of (S)-3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionic acid (59 mg, 0.19 mmol), propylphosphonic anhydride (351.12 mg, 0.57 mmol), and N,N-diisopropylethylamine (72.96 mg, 0.57 mmol). The mixture was stirred at room temperature for 2 hours. Water (10 mL) was then added to the reaction mixture, and the mixture was extracted with dichloromethane (5 mL × 3). The organic layer was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by high-performance liquid chromatography (HPLC) using a Xsele CSH column. OBD column 30×150mm, 5um; mobile phase A: water (10mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60mL / min; gradient: 10%B to 60%B for 8min; wavelength: 220nm; retention time: 7.17min) to give a white solid target product (6.38mg, 0.01mmol, yield: 6%).

[1057] 1H NMR (400MHz, DMSO-d6) δ (ppm): 12.53 (s, 1H), 8.17 (s, 1H), 8.01-7.78 (m, 1H) , 6.41-6.12(m, 1H), 4.69-4.55(m, 1H), 4.55-4.45(m, 1H), 4.45-4.33(m, 1H) , 4.28-4.13(m, 2H), 4.13-4.01(m, 1H), 3.73-3.65(m, 2H), 3.58-3.46(m, 3H) , 3.25-3.12(m, 1H), 2.98-2.82(m, 2H), 2.65-2.61(m, 2H), 1.22-1.09(m, 3H). LCMS: MS(ESI)m / z: 552.05[M+H] + .

[1058] Example 35: 5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydropyrazino[1,2-d]pyridino[3,2-b][1,4]diazaphen-9(5H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 35)

[1059]

[1060] Step 1: Synthesis of methyl 2-(4-benzyl-1-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazin-2-yl)acetate (35-2)

[1061] 2-(4-benzylpiperazin-2-yl)methyl acetate (3.00 g, 12.09 mmol) was added to dimethylformamide (60 mL). Then, 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (2.72 g, 12.09 mmol) and potassium carbonate (3.33 g, 24.18 mmol) were added. The mixture was stirred at 60 °C for 13 hours. After the reaction was complete, water (100 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL × 3). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (EA:PE = 30:60) to obtain the yellow oily target product (4.00 g, 9.13 mmol, yield: 75.51%). LCMS: MS (ESI) m / z: 438 [M+H] + .

[1062] Step 2: Synthesis of methyl 2-(1-(3-amino-5-(trifluoromethyl)pyridin-2-yl)-4-benzylpiperazin-2-yl)acetate (35-3)

[1063] 2-(4-benzyl-1-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazin-2-yl)methyl acetate (3.80 g, 8.67 mmol) was added to ethanol (80 mL, 0.00 mmol), followed by the addition of iron powder (7.28 g, 130.05 mmol) and ammonium chloride (6.89 g, 130.05 mmol). The mixture was stirred at 80 °C for 2 hours. The reaction solution was filtered through a Buchner funnel, and the filtrate was dried under reduced pressure. The filtrate was then dissolved in water (100 mL) and extracted with ethyl acetate (50 mL × 3). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was eluted onto a silica gel column (EA:PE = 20:80) to give the target product (2.40 g, 5.86 mmol, yield: 69%) as a yellow oil. LCMS: MS(ESI) m / z: 409 [M+H] + .

[1064] Step 3: Synthesis of 9-benzyl-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyridino[3,2-b][1,4]diaza-6(5H)-one (35-4)

[1065] Methyl 2-(1-(3-amino-5-(trifluoromethyl)pyridin-2-yl)-4-benzylpiperazin-2-yl)acetate (2.40 g, 5.88 mmol) was added to a solution of tetrahydrofuran (80 mL). Potassium tert-butoxide (1.31 g, 11.76 mmol) was then added to the reaction solution. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (100 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL × 3). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was added to a silica gel column (EA:PE = 30:70) and eluted to give the target product (1.50 g, 4.8 mmol, yield: 68%) as a white solid. LCMS: MS (ESI) m / z: 309 [M+H] + .

[1066] Step 4: Synthesis of (S)-5-cyclopropyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyridino[3,2-e]pyrazino-6(6aH)-one (35-5)

[1067] 9-Benzyl-3(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyridino[3,2-b][1,4]diaza-6(5H)-one (1.20 g, 3.19 mmol) was added to a solution of tetrahydrofuran (20 mL). Boron trifluoride (2 mL) and sodium borohydride (1.20 g, 31.90 mmol) were then added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, it was quenched with ice water (40 mL), then extracted with ethyl acetate (20 mL × 3). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was eluted onto a silica gel column (EA:PE = 30:70) to give the target product as a yellow solid (0.30 g, 1.02 mmol, yield: 26%). LCMS: MS (ESI) m / z: 295 [M+H] + .

[1068] Step 5: Synthesis of (S)-9-benzyl-3-(trifluoromethyl)-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyridino[3,2-b][1,4]diazazolide (35-6)

[1069] 9-Benzyl-3-(trifluoromethyl)-5,6,7,7a,8,9,10,11-octahydropyridano[1,2-d]pyridano[3,2-b][1,4]diazazolide (0.30 g, 1.02 mmol) was resolved by chiral high-performance liquid chromatography (column: CHIRALPAK IG-3, 4.6 × 50 mm 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 20 mL / min; gradient: from 10% B to 10% B over 12.5 min; wavelength: 220 / 254 nm; retention time 1: 9.1 min, retention time 2: 11.3 min) to (S)-9-benzyl-3-(trifluoromethyl)-5,6,7,7a,8,9,10,11-octahydropyridano[1,2-d]pyridano [3,2-b][1,4]diazazolide (35-6, 120 mg, 0.40 mmol, yield: 40%), a white solid; and (R)-9-benzyl-3-(trifluoromethyl)-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyridino[3,2-b][1,4]diazazolide (36-1, 120 mg, 0.40 mmol, yield: 40%), a white solid.

[1070] Forehead peak: (S)-9-benzyl-3-(trifluoromethyl)-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyridino[3,2-b][1,4]diazepine

[1071] LCMS: MS(ESI) m / z: 363 [M+H] + .

[1072] Chiral HPLC: CHIRALPAK IG-3 4.6*50mm, 3µm; Mobile phase A: (0.1% ethylenediamine) n-hexane, Mobile phase B: ethanol; Mobile phase A: Mobile phase B = 90:10; Flow rate: 1 mL / min; Temperature: 25°C; Retention time: 2.17 min.

[1073] Post-peak: (R)-9-benzyl-3-(trifluoromethyl)-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyridino[3,2-b][1,4]diazepine

[1074] LCMS: MS(ESI) m / z: 363 [M+H] + .

[1075] Chiral HPLC: CHIRALPAK IG-3 4.6*50mm, 3µm; Mobile phase A: (0.1% ethylenediamine) n-hexane, Mobile phase B: ethanol; Mobile phase A: Mobile phase B = 90:10; Flow rate: 1 mL / min; Temperature: 25°C; Retention time: 2.51 min.

[1076] Step 6: Synthesis of (S)-3-(trifluoromethyl)-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyridino[3,2-b][1,4]diazazolide (35-7)

[1077] Palladium / carbon (11 mg) was added to a solution of (S)-9-benzyl-3-(trifluoromethyl)-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyridino[3,2-b][1,4]diazazopyridine (110 mg, 0.33 mmol) in glacial acetic acid (5 mL). The mixture was stirred at room temperature under H2 atmosphere for 16 hours. The reaction solution was filtered through a Buchner funnel, and the filter cake was washed with methanol (10 mL × 2). The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was added to a silica gel column (EA:PE = 20:80) and eluted to give a yellow oily target product (40 mg, 0.15 mmol, yield: 49%). LCMS: MS (ESI) m / z: 273 [M+H] + .

[1078] Step 7: Synthesis of 5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydropyrazino[1,2-d]pyridino[3,2-b][1,4]diazaphen-9(5H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 35)

[1079] (S)-3-(trifluoromethyl)-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyridino[3,2-b][1,4]diazazolide (38 mg, 0.14 mmol) was added to a solution of dimethylformamide (1 mL, 12.86 mmol), followed by (S)-3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy) (38 mg, 0.12 mmol), propylphosphonic anhydride (200 mg, 1.20 mmol), and N,N-diisopropylethylamine (0.27 mg, 1.55 mmol). The mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (10 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (5 mL × 2). The solution was washed with saturated sodium chloride solution. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by preparative high performance liquid chromatography (XBridge preparative OBD C18 column, 30×150 mm, 5 μm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 10% B to 54% B for 10 min; wavelength: 220 nm; retention time: 9.22 min) to obtain a white solid target product (5 mg, 0.01 mmol, yield: 6%).

[1080] LCMS: MS(ESI)m / z: 564.10[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm): 12.44 (s, 1H), 7.89 (s, 1H), 7.80-7.77 (m, 1H), 6. 98(s, 1H), 6.27-6.23(s, 1H), 5.77-5.75(m, 1H), 4.19-4.09(m, 1H), 3.90-3.82( m, 1H), 3.77-3.64 (m, 4H), 3.60-3.53 (m, 2H), 3.50-3.41 (m, 5H), 3.20-3.15 (m, 1 H), 2.58-2.54(m, 2H), 1.94-1.79(m, 1H), 1.72-1.61(m, 1H), 1.25-1.09(m, 3H).

[1081] Example 365-(((R)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydropyrazino[1,2-d]pyridino[3,2-b][1,4]diazaphen-9(5H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 36)

[1082]

[1083] Step 1: Synthesis of (R)-3-(trifluoromethyl)-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyridino[3,2-b][1,4]diazazolide(36-2)

[1084] Palladium / carbon (11 mg) was added to a solution of (R)-9-benzyl-3-(trifluoromethyl)-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyridino[3,2-b][1,4]diazaphene 36-1 (110 mg, 0.33 mmol) in glacial acetic acid (5 mL). The mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The reaction solution was filtered through a Buchner funnel, and the filter cake was washed with methanol (5 mL × 2). The filtrate was concentrated under reduced pressure to give a crude product. The crude product was eluted onto a silica gel column (ethyl acetate:petroleum ether = 20:80) to give a yellow oily target product (80 mg, 0.29 mmol, yield: 49%). LCMS: MS (ESI) m / z: 273 [M+H] + .

[1085] Step 2: Synthesis of 5-(((R)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydropyrazino[1,2-d]pyridino[3,2-b][1,4]diazaphen-9(5H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2)-one (compound 36)

[1086] (R)-3-(trifluoromethyl)-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyridino[3,2-b][1,4]diazazolide (78 mg, 0.28 mmol) was added to a solution of N,N-dimethylformamide (5 mL), followed by (S)-3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)(intermediate 1, 88.60 mg, 0.28 mmol), propylphosphonic anhydride (363 mg, 2.8 mmol), and N,N-diisopropylethylamine (184 mg, 1.40 mmol). The mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (5 mL) was added to the mixture, and the mixture was then extracted with ethyl acetate (5 mL × 2). The mixture was washed with saturated sodium chloride solution. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (HPLC) using an XBridge preparative OBDC18 column (30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 10% B to 54% B for 10 min; wavelength: 220 nm; retention time: 9.22 min) to obtain a solid white target product (7.79 mg, 0.01 mmol, yield: 9.29%).

[1087] LCMS: MS(ESI)m / z: 564.10[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm): 12.54 (s, 1H), 8.02-7.85 (m, 1H), 7.790 (s, 1H), 6. 39-6.12(m, 1H), 5.88-5.62(m, 1H), 4.28-3.99(m, 1H), 3.91-3.83(m, 1H), 3.82-3. 62(m, 4H), 3.61-3.51(m, 2H), 3.51-3.45(m, 3H), 3.45-3.37(m, 1H), 3.30-3.12(m , 2H), 2.58-2.52(m, 2H), 2.06-1.74(m, 1H), 1.74-1.51(m, 1H), 1.28-1.10(m, 3H).

[1088] Example 378 Synthesis of 3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthidium-5-one (Compound 37)

[1089]

[1090] Step 1: Synthesis of 3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthidin-5-one (37-1)

[1091] A mixture of 8-benzyl-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthidine-5-imine intermediate 5 (1.00 g, 2.77 mmol) and palladium / carbon (0.10 g) in acetic acid (10 mL) was stirred at room temperature under hydrogen for 2 h, then filtered and concentrated. The residue was subjected to column chromatography (acetonitrile:water = 30:70) to give the target product (0.52 g, 1.91 mmol, yield: 69%) as a yellow oil. LCMS: MS (ESI) m / z: 272 [M+H] + .

[1092] Step 2: Synthesis of 8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthidium-5-one (compound 37)

[1093] To a solution of 3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthidin-5-one (0.05 g, 0.18 mmol) and (S)-3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionic acid (intermediate 1, 0.06 g, 0.18 mmol) in dichloromethane (3 mL), propylphosphonic anhydride (0.28 g, 0.92 mmol) and N,N-diisopropylethylenediamine (0.12 g, 0.92 mmol) were added. The mixture was stirred at room temperature for 2 hours, then poured into water (10 mL), extracted with dichloromethane (10 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The purified solution was purified by preparative high-performance liquid chromatography (HPLC) (column: XBridgePrep OBD). C18 column, 30×150mm, 5μm; mobile phase A: water (10mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60mL / min; gradient: 25%B to 55%B for 8min; wavelength: 220nm; retention time: 6.73min) yielded a white solid target product (8.12mg, 0.01mmol, yield 8%).

[1094] LCMS: MS(ESI)m / z: 563.05[M+H] + . 1H NMR (400MHz, DMSO-d6) δ (ppm): 12.46 (s, 1H), 8.75 (s, 1H), 8.13-8.12 (d, J = 2.6Hz, 1H), 7.91(s, 1H), 6.28(s, 1H), 4.68-4.58(m, 1H), 4.54-4.47(m, 1H), 4.19-4.04(m , 2H), 3.78-3.65 (m, 3H), 3.48 (d, J=5.6Hz, 2H), 3.26-3.21 (m, 1H), 3.13-3.05 (m, 1 H), 2.96-2.90 (m, 1H), 2.85-2.82 (m, 2H), 2.64-2.62 (m, 2H), 1.15 (d, 3H, J=6.4Hz).

[1095] Example 38: Synthesis of 5-(((2S)-1-(3-(5-hydroxy-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,8]naphthidin-8-yl)-3-oxopropoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 38)

[1096]

[1097] 8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthidium-5-one (compound 37, 50 mg, 0.09 mmol) was mixed with sodium borohydride (7.11 mg, 0.18 mmol) in a methanol (1 mL) mixture. The mixture was stirred at room temperature for 2 hours, then poured into water (10 mL), extracted with dichloromethane (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated the filtrate, and purified the residue by preparative high performance liquid chromatography (column: XBridge). C18 column, 30×150mm, 5µm; mobile phase A: water (10mol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60mL / min; gradient: 10min 10% B to 35% B; 220nm; retention time 9-10min) yielded a white solid target product (4.55mg, 0.008mmol, yield: 8%).

[1098] LCMS: MS(ESI)m / z: 565.20[M+H] + . 1H NMR (400MHz, DMSO-d6) δ (ppm): 12.45 (s, 1H), 8.29 (s, 1H), 7.94-7.89 (m, 1H), 7.71-7.69 (m, 1H), 6.2 8-6.27(m, 1H), 5.80-5.78(m, 1H), 4.71-4.63(m, 2H), 4.49-4.42(m, 1H), 4.19-4.11(m, 1H), 4.09-3. 99(m, 1H), 3.72-3.68(m, 2H), 3.52-3.49(m, 2H), 3.21-3.11(m, 1H), 3.01-2.87(m, 1H), 2.88-2.79(m , 1H), 2.76-2.71(m, 1H), 2.63-2.61(m, 2H), 2.32-2.18(m, 1H), 1.62-1.46(m, 1H), 1.17-1.12(m, 3H).

[1099] Example 39: Synthesis of (s)-5-(methyl-D3)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyridino[3,2-e]pyrazino-6(6aH)-one (Compound 39)

[1100]

[1101] Step 1: Synthesis of (S)-5-(methyl-D3)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyridino[3,2-e]pyrazin-8-carboxylic acid tert-butyl ester (39-1)

[1102] (S)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyridino[3,2-e]pyrazino-8-carboxylic acid tert-butyl ester 30-3 (500 mg, 1.3 mmol) was dissolved in tetrahydrofuran (10 mL). Sodium hydride (60%, 100 mg, 2.6 mmol) was added at 0 °C. The mixture was stirred at room temperature for 1 hour. Deuterated iodomethane (0.16 mL, 2.6 mmol) was added. After reacting for 2 hours, ammonium chloride aqueous solution (20 mL) was added to quench the reaction. After extraction with ethyl acetate (40 mL × 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness and purified by silica gel column chromatograp...

Claims

1. A tricyclic heterocyclic compound or a pharmaceutically acceptable salt thereof, characterized in that, The tricyclic heterocyclic compounds are tricyclic heterocyclic compounds as shown in Formula I; Among them, R 1 R 1’ R 3 R 3’ R 5 R 5’ Independently for H and C 1-6 Alkyl or with one or more R 1a Replacement C 1-6 Alkyl group; when there are multiple substituents, they may be the same or different; R 1a Independently halogen, CN, OH; R 2 R 4 Independent of halogen, CN, C 1-6 Alkyl, with one or more R 2a Replacement C 1-6 Alkyl, with one or more R 2b Replacement C 1-6 Alkyl-S-; when there are multiple substituents, they may be the same or different; R 2a R 2b Halogens are independent of each other; X is N independently; T independently represents C(R) 3b ) or N; Y independently is C(R) 3c ) or N; Z independently is C(R) 3d ) or N; R 3b R 3c R 3d Independently H, halogen, CN, NH2 or C 1-6 alkyl; Indicates a single bond, A 1 Independently for C(R) 4b R 4c ) or C (=O); R 4a R 4b R 4c Independently for H and C 1-6 Alkyl or with one or more R a1 Replacement C 1-6 Alkyl group; when there are multiple substituents, they may be the same or different; When B is independently C(R) 6b R 6c When A 2 Independently for C(R) 5b R 5c ), O, S, N (R) 5d ) or connection key; When B is independently O, S, or N(R) 6d When A 2 Independently for C(R) 5a ), C(R 5b R 5c ) or connection key; R 5a R 5b R 5c R 5d Independently for H and C 1-6 Alkyl or with one or more R a2 Replacement C 1-6 alkyl; R 6a R 6b R 6c Independent of H, halogen, C 1-6 Alkyl, with one or more R a3 Replacement C 1-6 Alkyl, C 3-6 cycloalkyl; R 6d Independently for H and C 1-6 Alkyl, with one or more R a3 Replacement C 1-6 Alkyl, C 3-6 Cycloalkyl; when there are multiple substituents, they may be the same or different; R a1 R a2 R a3 Independently classified as deuterium and halogen; Or, when A 1 Independently for C(R) 4a When B is independently C(R), 6a ), A 2 Independently used as a connector key; A 1 B Indicates a double bond, the rest * indicates a single bond, and * indicates that when it is a chiral carbon atom, it is an R configuration, an S configuration, or a mixture thereof.

2. The tricyclic heterocyclic compound or a pharmaceutically acceptable salt thereof as described in claim 1, characterized in that, R 1 R 1’ One of them is H, and the other is either H or C. 1-6 alkyl; Or, R 3 R 3’ One of them is H, and the other is either H or C. 1-6 alkyl; Or, R 5 R 5’ One of them is H, and the other is either H or C. 1-6 alkyl; Or, when R 1 R 1’ When the attached carbon is a chiral carbon, it has an S configuration or an R configuration; Or, when R 3 R 3’ When the attached carbon is a chiral carbon, it has an S configuration or an R configuration; Or, when R 5 R 5’ When the attached carbon is a chiral carbon, it has an S configuration or an R configuration; Or, R 2 Independently halogen, CN, or by one or more R 2a Replacement C 1-6 Alkyl, with one or more R 2b Replacement C 1-6 Alkyl-S-; Or, R 4 Independently halogen, CN, or by one or more R 2a Replacement C 1-6 alkyl; Or, T is independently N; Or, R 3c H, CN, NH2 or C 1-6 alkyl; Or, R 3d H, halogen, CN or C 1-6 alkyl; Or, Z independently is C(R) 3d ) or N; Or, R 4a R 4b R 4c Independently H or C 1-6 alkyl; Or, when A 1 For C(R) 4b R 4c When the carbon is chiral carbon, its configuration is S configuration, R configuration or a mixture thereof; Or, R 5a R 5b R 5c R 5d Independently H or C 1-6 alkyl; Or, when A 2 For C(R) 5b R 5c When the carbon is chiral carbon, its configuration is S configuration, R configuration or a mixture thereof; Or, A 2 Independently for C(R) 5b R 5c ) or connection key; Or, R 6a R 6b R 6c Independently H or halogen; Or, R 6d Independently for H and C 1-6 Alkyl, with one or more R a3 Replacement C 1-6 Alkyl, C 3-6 cycloalkyl; or, Independently for -C(R) 4b R 4c )-O-、-C(R 4b R 4c )-S-、-C(R 4b R 4c )-N(R 6d )-、-C(R 4b R 4c )-C(R 6b R 6c )-, -C(=O)-O-, -C(=O)-N(R 6d )-; or, independently -O-, -S-, -C(R 6b R 6c )-, -N(R 6d )-, -O-C(R 5b R 5c )-, -S-C(R 5b R 5c )-, -N(R 6d )-C(R 5b R 5c )-, -C(R 6b R 6c )-O-, -C(R 6b R 6c )-S-, -C(R 6b R 6c )-N(R 5d )-; or, Independently or, Independently 3. The tricyclic heterocyclic compound or a pharmaceutically acceptable salt thereof as described in claim 1, characterized in that, When R 1 R 1’ When the attached carbon is a chiral carbon, it has the R configuration; Or, R 2 Independently halogenated, by one or more R 2a Replacement C 1-6 alkyl; Or, R 4 Independently halogenated, by one or more R 2a Replacement C 1-6 alkyl; Or, R 3c For H; Or, R 3d For H; Or, R 4b and R 4c One is H, and the other is H or C. 1-6 alkyl; Or, A 1 Independently for C(R) 4b R 4c ); Or, R 5b and R 5c One is H, and the other is H or C. 1-6 alkyl; Or, R 6b R 6c H is independent; Or, R 6d Independently H or C 1-6 alkyl; Alternatively, B can be independently -O-, -S-, or N(R). 6d ); or, Independently for -C(R) 4b R 4c )-O-、-C(R 4b R 4c )-S-、-C(R 4b R 4c )-N(R 6d )-、-C(=O)-N(R 6d )-; or, Independently -O-, -OC(R) 5b R 5c )-、-SC(R 5b R 5c )-、-N(R 6d )-、-N(R 6d )-C(R 5b R 5c )-.

4. The tricyclic heterocyclic compound or a pharmaceutically acceptable salt thereof as described in claim 1, characterized in that, R 1 R 1’ R 3 R 3’ R 5 R 5’ One of them is H, C 1-6 Alkyl or with one or more R 1a Replacement C 1-6 Alkyl groups, the rest being H; Or, when R 1 R 1’ R 3 R 3’ R 5 R 5’ Independently for C 1-6 Alkyl or with one or more R 1a Replacement C 1-6 When alkyl, the C 1-6 Alkyl or with one or more R 1a Replacement C 1-6 C in alkyl 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; Or, when R 1a When the halogen is halogen, the halogen is F, Cl, Br, or I; Or, when R 2 R 4 When it is a halogen on its own, the halogen is F, Cl, Br, or I; Or, when R 2 R 4 Independently for C 1-6 Alkyl, with one or more R 2a Replacement C 1-6 Alkyl, with one or more R 2b Replacement C 1-6 When alkyl-S-, the C 1-6 Alkyl, with one or more R 2a Replacement C 1-6 Alkyl and one or more R 2b Replacement C 1-6 C in alkyl-S- 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; or, when R 2 R 4 Independently for one or more R 2a Replacement C 1-6 Alkyl, with one or more R 2b Replacement C 1-6 When alkyl-S-, the number of substituents is 1, 2, or 3; Or, when R 2a R 2b When it is a halogen on its own, the halogen is F, Cl, Br, or I; Or, when R 3b R 3c R 3d When it is a halogen on its own, the halogen is F, Cl, Br, or I; Or, when R 3b R 3c R 3d Independently for C 1-6 When alkyl, the C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; Or, when R 4a R 4b R 4c Independently for C 1-6 Alkyl or with one or more R a1 Replacement C 1-6 When alkyl, the C 1-6 Alkyl and one or more R a1 Replacement C 1-6 C in alkyl 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; Or, when R 5a R 5b R 5c R 5d Independently for C 1-6 Alkyl or with one or more R a2 Replacement C 1-6 When alkyl, the C 1-6 Alkyl and one or more R a2 Replacement C 1-6 C in alkyl 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; Or, when R 6a R 6b R 6c When it is a halogen on its own, the halogen is F, Cl, Br, or I; Or, when R 6a R 6b R 6c R 6d Independently for C 1-6 Alkyl, with one or more R a3 Replacement C 1-6 When alkyl, the C 1-6 Alkyl and one or more R a3 Replacement C 1-6 C in alkyl 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; Or, when R 6a R 6b R 6c R 6d Independently for C 3-6 When cycloalkyl, the C 3-6 The cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; Or, when R a1 R a2 R a3 When it is a halogen on its own, the halogen is F, Cl, Br, or I.

5. The tricyclic heterocyclic compound or a pharmaceutically acceptable salt thereof as described in claim 4, characterized in that, R 1 R 1’ R 3 R 3’ R 5 R 5’ For H; Or, when R 1 R 1’ R 3 R 3’ R 5 R 5’ Independently for C 1-6 Alkyl or with one or more R 1a Replacement C 1-6 When alkyl, the C 1-6 Alkyl or with one or more R 1a Replacement C 1-6 C in alkyl 1-6 The alkyl group is methyl; Or, when R 1a When the halogen is halogen, the halogen is F; Or, when R 2 R 4 When it is a halogen on its own, the halogen is F; Or, when R 2 R 4 Independently for C 1-6 Alkyl, with one or more R 2a Replacement C 1-6 Alkyl, with one or more R 2b Replacement C 1-6 When alkyl-S-, the C 1-6 Alkyl, with one or more R 2a Replacement C 1-6 Alkyl and one or more R 2b Replacement C 1-6 C in alkyl-S- 1-6 The alkyl group is methyl; Or, when R 2a R 2b When it is a halogen on its own, the halogen is F; Or, when R 3b R 3c R 3d When it is a halogen on its own, the halogen is F; Or, when R 3b R 3c R 3d Independently for C 1-6 When alkyl, the C 1-6 The alkyl group is methyl; Or, when R 4a R 4b R 4c Independently for C 1-6 Alkyl or with one or more R a1 Replacement C 1-6 When alkyl, the C 1-6 Alkyl and one or more R a1 Replacement C 1-6 C in alkyl 1-6 The alkyl group is methyl; Or, when R 5a R 5b R 5c R 5d Independently for C 1-6 Alkyl or with one or more R a2 Replacement C 1-6 When alkyl, the C 1-6 Alkyl and one or more R a2 Replacement C 1-6 C in alkyl 1-6 The alkyl group is methyl; Or, when R 6a R 6b R 6c When it is a halogen on its own, the halogen is F; Or, when R 6a R 6b R 6c R 6d Independently for C 1-6 Alkyl, with one or more R a3 Replacement C 1-6 When alkyl, the C 1-6 Alkyl and one or more R a3 Replacement C 1-6 C in alkyl 1-6 The alkyl group is methyl or ethyl; Or, when R 6a R 6b R 6c R 6d Independently for C 3-6 When cycloalkyl, the C 3-6 The cycloalkyl group is cyclopropyl; Or, when R a1 R a2 R a3 When it is a halogen on its own, the halogen is F.

6. The tricyclic heterocyclic compound or a pharmaceutically acceptable salt thereof as described in claim 1, characterized in that, R 1 R 1’ R 3 R 3’ R 5 R 5’ Independently, it is H, methyl, HO-methyl, NC-methyl, CHF2, CF3; Or, R 2 R 4 Independently fluorine, bromine, chlorine, CN, CF3, CF3-S-; Alternatively, Y can be independently CH, N, C(CN), or C(NH2); Alternatively, Z can be independently CH, N, C(CN), or C(NH2); Or, A 1 It can be independently CH2, C(CH3) or C(=O); Alternatively, B can be independently CH2, CF2, O, S, NH, N(CH3), N(CD3), N(cyclopropyl), N(CH2CF3), C(CH3), or C(=O); Or, A 2 Independently formed by CH2, O, S, NH, N(CH3), N(cyclopropyl), CH(CH3) or connecting bonds; or, Independently or, Independently or, Independently 7. The tricyclic heterocyclic compound or a pharmaceutically acceptable salt thereof as described in claim 6, characterized in that, Independently or, Independently or, Independently 8. The tricyclic heterocyclic compound or a pharmaceutically acceptable salt thereof as described in claim 1, characterized in that, R 1 R 1’ Independently H or C 1-6 alkyl; R 3 R 3’ R 5 R 5’ H is independent; R 2 R 4 Independently for C substituted with one or more halogens 1-6 alkyl; X and T are N independently; Y is independently C(R) 3c ); Z is independently C(R) 3d ) or N; A 1 Independently for C(R) 4b R 4c ) or C (=O); B is independently O, S, or N(R) 6d ), A 2 Independently for C(R) 5b R 5c ) or connection key; Indicates a single key.

9. The tricyclic heterocyclic compound or a pharmaceutically acceptable salt thereof as described in claim 1, characterized in that, R 1 R 1’ Independently, it is either H or methyl; R 3 R 3’ R 5 R 5’ H is independent; R 2 R 4 Independently for CF3; X and T are N independently; Y is independently CH; Z can be CH or N independently; A 1 It can be independently CH2 or C (=O); B is independently O, S, or NH, A 2 Independently CH2 or a connecting bond; Indicates a single key.

10. The tricyclic heterocyclic compound of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, R 1 R 1’ R 3 R 3’ R 5 R 5’ H is independent; R 2 R 4 Independently for C substituted with one or more halogens 1-6 alkyl; X and T are N independently; Y is independently C(R) 3c ); Z is independently C(R) 3d ); A 1 Independently for C(R) 4b R 4c ); B can be either O or S independently; A 2 Independently for C(R) 5b R 5c ) or connection key; Indicates a single key.

11. The tricyclic heterocyclic compound or a pharmaceutically acceptable salt thereof as described in claim 1, characterized in that, R 1 R 1’ R 3 R 3’ R 5 R 5’ H is independent; R 2 R 4 Independently for CF3; X and T are N independently; Y and Z are independently CH; A 1 Independently CH2; B can be either O or S independently; A 2 Independently CH2 or a connecting bond; Indicates a single key.

12. A tricyclic heterocyclic compound or a pharmaceutically acceptable salt thereof, characterized in that, The tricyclic heterocyclic compound has any of the following structures: in, The bond represents a mixture of R and S configurations.

13. A method for preparing a tricyclic heterocyclic compound as described in any one of claims 1-12, characterized in that, It includes the following steps: In a solvent, in the presence of a base and a condensing agent, the compound shown in Formula II is subjected to an amidation reaction with the compound shown in Formula III as shown below to obtain the tricyclic heterocyclic compound shown in Formula I. Among them, R 1 R 1’ R 3 R 3’ R 5 R 5’ R 2 R 4 X, T, Y, Z, A 1 B, A 2 , The definitions of * and are as described in any one of claims 1-12.

14. The preparation method according to claim 13, characterized in that, The solvents are DMF and dichloromethane; Alternatively, the base may be diisopropylethylamine or K2CO3; Alternatively, the molar ratio of the base to the compound shown in Formula II is 1:1; Alternatively, the condensing agent is propylphosphonic anhydride; Alternatively, the condensing agent may be used in a 50% ethyl acetate solution; Alternatively, the molar ratio of the condensing agent to the compound shown in Formula II is 1:1; Alternatively, the molar ratio of the compound shown in Formula II to the compound shown in Formula III is 1:1; Alternatively, the amidation reaction is carried out under nitrogen protection; Alternatively, the temperature of the amidation reaction is from 0°C to 60°C.

15. A pharmaceutical composition comprising a tricyclic heterocyclic compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-12, and a pharmaceutical excipient.

16. The use of a tricyclic heterocyclic compound as described in any one of claims 1-12 or a pharmaceutically acceptable salt thereof in the preparation of a PARP inhibitor; The PARP mentioned is PARP7.

17. The use of a tricyclic heterocyclic compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-12 in the preparation of a medicament; said medicament for the prevention and / or treatment of PARP-related or PARP-mediated diseases; said PARP being PARP7.

18. The application as described in claim 17, characterized in that, The diseases associated with or mediated by PARP are abnormal proliferative diseases; these abnormal proliferative diseases include lung cancer, colon cancer, colorectal cancer, pancreatic cancer, kidney cancer, stomach cancer, esophageal cancer, ovarian cancer, breast cancer, cervical cancer, head and neck cancer, bladder cancer, melanoma, fibrosarcoma, and glioblastoma.

19. The use of a tricyclic heterocyclic compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-12 in the preparation of a medicament; said medicament for the prevention and / or treatment of abnormal proliferative diseases; said abnormal proliferative diseases being lung cancer, colon cancer, colorectal cancer, pancreatic cancer, kidney cancer, gastric cancer, esophageal cancer, ovarian cancer, breast cancer, cervical cancer, head and neck cancer, bladder cancer, melanoma, fibrosarcoma, and glioblastoma.

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