PARP7 inhibitors

Abstract

This invention belongs to the field of pharmaceutical technology, specifically relating to PARP7 kinase inhibitor compounds of general formula (I), pharmaceutically acceptable salts thereof or isomers thereof, pharmaceutical compositions containing said compounds, pharmaceutically acceptable salts thereof or isomers thereof, methods for preparing said compounds, pharmaceutically acceptable salts thereof or isomers thereof, and uses of said compounds, pharmaceutically acceptable salts thereof or isomers thereof.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a class of PARP7 inhibitor compounds, pharmaceutically acceptable salts thereof or isomers thereof, pharmaceutical compositions and formulations containing said compounds, pharmaceutically acceptable salts thereof or isomers thereof, methods for preparing said compounds, pharmaceutically acceptable salts thereof or isomers thereof, and uses of said compounds, pharmaceutically acceptable salts thereof or isomers thereof. Background Technology

[0002] There are many relevant targets in tumor development and progression. The poly-ADP-ribose polymerase (PARP) family is responsible for transferring single or multiple ADP ribose subunits from NAD+ to substrate targets, altering the function of target proteins, performing post-translational modifications, regulating basic processes such as cellular gene expression, protein degradation, and cellular stress, and participating in tumorigenesis. Based on the homology of catalytic domains in the human genome, the PARP family can be divided into 17 members, each of which is highly expressed in different cancers.

[0003] The PARP family can be divided into three categories based on catalytic activity. The first category belongs to PolyPARPs, which includes four members: PARP 1, PARP 2, PARP 5a, and PARP 5b. These members catalyze the transfer of multiple ADP-ribose subunits to the substrate. Several inhibitor drugs from this family are already on the market and play a role in DNA-induced damage. The second category belongs to MonoPARPs, which includes twelve members: PARP 3, PARP 4, PARP 6, PARP 7, PARP 8, PARP 9, PARP 10, PARP 11, PARP 12, PARP 14, PARP 15, and PARP 16. These members catalyze the transfer of a single ADP-ribose subunit to the substrate. The third category includes PARP 13, which has not yet been found to have catalytic activity.

[0004] TIPARP (TCDD-Inducible Poly-ADP-Ribose Polymerase) is a 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly-ADP-ribose polymerase, also known as PARP7 or ARTD14. It participates in processes such as tumorigenesis, cell proliferation, and immunosuppression. TIPARP (PARP7 or ARTD14) belongs to the monoPARP family and can transfer single ADP-ribose subunits to target proteins, altering the function of the target proteins. It is a post-translational modification and participates in the regulation of vital activities such as cell proliferation, possessing multiple cellular functions.

[0005] The aryl hydrocarbon receptor (AHR) is a transcription factor belonging to the bHLH-PAS family of transcriptional regulators. It primarily regulates developmental and physiological functions, including neurogenesis, tracheal and salivary duct formation, toxin metabolism, circadian rhythms, hypoxia response, and hormone receptor function. AHR can be activated by exogenous ligands such as environmental pollutants (TCDD), endogenous ligands such as toxic metabolites (kynurenine), and small molecules from microorganisms and food sources, exerting different biological effects in different cells. AHR activation promotes the transcriptional expression of downstream genes such as TIPARP (PARP7 or ARTD14) and CYP1A1. TIPARP can negatively regulate certain proteins by transferring a single ADP-ribose subunit. TIPARP can also be regulated by other transcription factors or signaling pathways.

[0006] In tumors or after viral infection, the amount of free cytoplasmic RNA or DNA increases. TBK1 kinase (TANK binding kinase 1) plays a key role in activating type I interferon responses and antiviral immunity in this pathway. TIPARP induces ADP-ribosylation in the kinase domain of TBK1, transforming TBK1 from a free, activated state to an inactive state. This inhibits the type I interferon response and subsequent innate immune responses, thereby suppressing T cell-mediated adaptive anti-tumor immunity and ultimately affecting the overall immune activation of the body. Inhibition of TIPARP can restore the type I interferon response and further enhance the body's immune response.

[0007] TIPARP is overexpressed in cancers such as lung cancer, esophageal cancer, ovarian cancer, head and neck cancer, and cervical cancer, especially in squamous cell carcinoma of the lung. Inhibiting TIPARP can suppress cell proliferation. Therefore, TIPARP inhibitors can not only directly inhibit tumor cell growth, but also repair type I interferon signaling, thereby relieving tumor cells from immune escape and suppressing the immune system.

[0008] Therefore, TIPARP inhibitors have great potential in treating cancer or other related diseases, and there are currently no small molecule inhibitors targeting this target on the market. Developing highly effective and low-toxicity TIPARP inhibitors is of great clinical significance. Summary of the Invention

[0009] The technical problem to be solved by this invention is to provide a novel polycyclic compound with good inhibitory activity against PARP7. Furthermore, this type of compound can be used to prevent and / or treat diseases related to PARP7 overexpression. Even further, this type of compound can be used to prevent and / or treat cancer, including carcinoma in situ and metastatic cancer.

[0010] The technical solution of the present invention is as follows:

[0011] In one aspect, the present invention provides compounds represented by the following general formula (I'), pharmaceutically acceptable salts thereof, or isomers thereof.

[0012]

[0013] in,

[0014] Ring B has a trifused ring structure; ring B is optionally substituted by 1-3 Q1 groups and also optionally substituted by 1 or more R8 groups; each Q1 group is independently selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkoxy; each R 8 Each group is independently selected from H, halogen, hydroxyl, amino, nitro, cyano, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, cyano C 1-6 Alkoxy;

[0015] L is selected from

[0016] X, X1, and X2 are each independently selected from -CH(R) 6 )-、-N(R 7 -, -O-, -S-, -C(O)-, -S(O)- or -S(O)2-;

[0017] R 1 Selected from H, halogen, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 alkoxy or halogenated C 1-6 Alkylthio;

[0018] Each R 4 Each R 4 '、 Each R 5 Each R 5 '、 Each R6 Each group is independently selected from H, halogen, hydroxyl, amino, nitro, cyano, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, cyano C 1-6 Alkoxy, 3-8 membered cycloalkyl, 3-8 membered cycloalkyl-C 1-6 Alkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclic -C 1-6 Alkyl, phenyl, phenyl-C 1-6 Alkyl, 5-7 heteroaryl or 5-7 heteroaryl-C 1-6 alkyl;

[0019] Each R 7 Selected independently from H and C respectively 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl or amino C 1-6 alkyl;

[0020] m and n are independently selected from 1, 2, 3 or 4 respectively;

[0021] virtual keys X3 is C if it is a chemical bond or not present.

[0022] In one aspect, the present invention provides compounds represented by the following general formula (I), pharmaceutically acceptable salts thereof, or isomers thereof.

[0023]

[0024] in,

[0025] L is selected from

[0026] X, X1, and X2 are each independently selected from -CH(R) 6 )-、-N(R 7 -, -O-, -S-, -C(O)-, -S(O)- or -S(O)2-;

[0027] X3 is selected from C, CH, or N;

[0028] X4 is selected from N or C(R) 8 );

[0029] R 1 Selected from H, halogen, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 alkoxy or halogenated C 1-6 Alkylthio;

[0030] R 2 R 3 and with R 2 The connected carbon atom and X3 together form an 8-11 fused-ring cycloalkyl, 8-11 fused-ring heterocyclic, 8-11 fused-ring aryl, or 8-11 fused-ring heteroaryl group, optionally substituted with 1-3 Q1 groups; each Q1 is independently selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkoxy;

[0031] Each R 4 Each R 4 '、 Each R 5 Each R 5 '、 Each R 6 Each group is independently selected from H, halogen, hydroxyl, amino, nitro, cyano, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, cyano C 1-6 Alkoxy, 3-8 membered cycloalkyl, 3-8 membered cycloalkyl-C 1-6 Alkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclic -C 1-6 Alkyl, phenyl, phenyl-C 1-6 Alkyl, 5-7 heteroaryl or 5-7 heteroaryl-C 1-6 alkyl;

[0032] Each R 7 Selected independently from H and C respectively 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C1-6 Alkyl or amino C 1-6 alkyl;

[0033] Each R 8 Each group is independently selected from H, halogen, hydroxyl, amino, nitro, cyano, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, cyano C 1-6 Alkoxy;

[0034] m and n are independently selected from 1, 2, 3 or 4 respectively;

[0035] virtual keys X3 is C if it is a chemical bond or not present.

[0036] In some implementations, R 2 R 3 and with R 2 The connected carbon atom and X3 together form an 8-11 membered fused-ring heterocyclic group or an 8-11 membered fused-ring heteroaryl group, optionally substituted with 1-3 Q1 groups; each Q1 is independently selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkyl group.

[0037] In some of the above implementations, R 2 R 3 and with R 2 The connected carbon atom and X3 together form a 9-10 membered fused-ring heterocyclic group or a 9-10 membered fused-ring heteroaryl group, optionally substituted with 1-3 Q1 groups; each Q1 is independently selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkyl group.

[0038] In some of the above implementations, R 2 R 3 and with R 2The connected carbon atom and X3 together form a 9-10 membered fused-ring heterocyclic group, optionally substituted with 1-3 Q1s, or a 9-10 membered fused-ring heteroaryl group containing at least one nitrogen atom or one oxygen atom; each Q1 is independently selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkyl group.

[0039] In some of the above implementations, R 2 R 3 and with R 2 The adjacent carbon atom and X3 together form the following groups, which can be optionally replaced by 1-3 Q1 atoms:

[0040]

[0041] Each X3, each X8, and each X9 is independently selected from CH or N;

[0042] Each X5 is independently selected from CH, C, or N;

[0043] Each X6 and each X7 are independently selected from -CH2-, -NH-, -O-, -S-, -C(O)-, -S(O)- or -S(O)2-;

[0044] Ring A is selected from 5-7 membered cycloalkyl, 5-7 membered heterocyclic, 5-7 membered aryl, or 5-7 membered heteroaryl;

[0045] Each Q1 is independently selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkyl group.

[0046] In some of the above implementations, R 2 R 3 and with R 2 The bonded carbon atom and X3 together form the following group:

[0047]

[0048] Each X3, each X8, and each X9 is independently selected from CH or N;

[0049] Each X5 is independently selected from CH, C, or N;

[0050] Each X6 and X7 is independently selected from -CH2-, -NH-, -O-, -S-, -C(O)-, -S(O)- or -S(O)2-;

[0051] Ring A is selected from 5-7 membered cycloalkyl, 5-7 membered heterocyclic, 5-7 membered aryl, or 5-7 membered heteroaryl;

[0052] Each Q1 is independently selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkoxy;

[0053] p is selected from 0, 1, 2 or 3.

[0054] In some of the above implementations, R 2 R 3 and with R 2 The bonded carbon atom and X3 together form the following group:

[0055]

[0056] Each X3, each X8, and each X9 is independently selected from CH or N;

[0057] Each X5 is independently selected from CH, C, or N;

[0058] Each X6 and X7 is independently selected from -CH2-, -NH-, -O-, -S-, -C(O)-, -S(O)- or -S(O)2-;

[0059] Ring A is selected from pyrrole, pyrazolyl, imidazolyl, furanyl, thiophene, oxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, phenyl, pyridinyl, pyrimidinyl, dihydropyrimidinyl, pyrazinyl, pyranyl, thioranyl, oxazinyl, azirzoyl, or diazirzoyl.

[0060] Each Q1 is independently selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkoxy;

[0061] p is selected from 0, 1, 2 or 3.

[0062] In some of the above implementations, R 2 R 3 and with R 2 The bonded carbon atom and X3 together form the following group:

[0063]

[0064] Ring A is selected from 5-7 membered cycloalkyl, 5-7 membered heterocyclic, 5-7 membered aryl, or 5-7 membered heteroaryl;

[0065] Each Q1 is independently selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkoxy;

[0066] X3 is selected from CH or N;

[0067] X5 is selected from CH, C, or N;

[0068] p is selected from 0, 1, 2 or 3.

[0069] In some of the above implementations, R 2 R 3 and with R 2 The bonded carbon atom and X3 together form the following group:

[0070]

[0071]

[0072] Ring A is selected from 5-7 aryl or 5-7 heteroaryl;

[0073] Each Q1 is independently selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkoxy;

[0074] p is selected from 0, 1, 2 or 3.

[0075] In some of the above embodiments, ring A is selected from pyrrole, pyrazolyl, imidazolyl, furanyl, thiophene, oxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, phenyl, pyridinyl, pyrimidinyl, dihydropyrimidinyl, pyrazinyl, pyranyl, thioranyl, oxazinyl, azirzoyl, or diazirzoyl.

[0076] In some of the above embodiments, cyclic A is selected from 5-7 N-containing heteroaryl groups.

[0077] In some of the above embodiments, ring A is selected from pyrrole, pyrazolyl, imidazolyl, oxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridyl, pyrimidinyl, dihydropyrimidinyl, pyrazinyl, pyridazinyl, oxazinyl, azirzoyl, or diazirzoyl.

[0078] In some of the above implementations, R 2 R 3 and with R 2 The bonded carbon atom and X3 together form the following group:

[0079]

[0080]

[0081]

[0082] Each Q1 is independently selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkoxy;

[0083] p is selected from 0, 1, 2 or 3.

[0084] In some of the above implementations, each R 4 Each R 4 '、 Each R 5 Each R 5 'Each is independently selected from H, hydroxyl, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-6 membered cycloalkyl, 3-6 membered cycloalkyl-C 1-6 Alkyl, 3-6 membered heterocyclic, 3-6 membered heterocyclic -C 1-6 Alkyl, phenyl, phenyl-C 1-6 Alkyl, 5-6 heteroaryl or 5-6 heteroaryl-C 1-6 alkyl.

[0085] In some of the above embodiments, L is selected from

[0086] X is selected from -Ch(R) 6 )-、-N(R 7)-、-O-、-S-;

[0087] Each R 4 Each R 4 '、 Each R 5 Each R 5 'Each is independently selected from H, hydroxyl, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-6 membered cycloalkyl, 3-6 membered cycloalkyl-C 1-6 Alkyl, 3-6 membered heterocyclic, 3-6 membered heterocyclic -C 1-6 Alkyl, phenyl, phenyl-C 1-6 Alkyl, 5-6 heteroaryl or 5-6 heteroaryl-C 1-6 alkyl;

[0088] Each R 6 Each R 7 Selected independently from H and C respectively 1-6 Alkyl or halogenated C 1-6 alkyl;

[0089] m and n are independently selected from 1, 2, or 3, respectively.

[0090] In some of the above embodiments, L is selected from

[0091] XX1, Select X from 2-C, H respectively (R unique) 6 -Stand, Ground-N Selection (R Self) 7 )--C, H-(OR-6,)-, -S--; N(R7)-, -O-, -S-, -C(O)-, -S(O)- or -S(O)2-;

[0092] X3 is selected from C, CH, or N;

[0093] X4 is selected from N or C(R) 8 );

[0094] R 1 Selected from H, halogen, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl, fluorinated C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 alkoxy or fluorinated C 1-6 Alkoxy;

[0095] Each R 4 Each R 4 '、 Each R 5 Each R 5 'Each is independently selected from H, hydroxyl, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-6 membered cycloalkyl, 3-6 membered cycloalkyl-C 1-6 Alkyl, 3-6 membered heterocyclic, 3-6 membered heterocyclic -C 1-6 Alkyl, phenyl, phenyl-C 1-6 Alkyl, 5-6 heteroaryl or 5-6 heteroaryl-C 1-6 alkyl;

[0096] Each R 6 Each R 7 Selected independently from H and C respectively 1-6 Alkyl or halogenated C 1-6 alkyl;

[0097] Each R 8 Each group is independently selected from H, halogen, hydroxyl, amino, cyano, and C. 1-6 Alkyl, fluorinated C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 alkoxy or fluorinated C 1-6 Alkoxy;

[0098] m and n are each independently selected from 1, 2, or 3;

[0099] q is selected from 1 or 2;

[0100] virtual keys X3 is C if it is a chemical bond or not present.

[0101] In some of the above embodiments, L is selected from

[0102] X is selected from -CH(R) 6 )-、-N(R 7 )-、-O-、-S-;

[0103] Each R 4 Each R 4 '、 Each R 5Each R 5 'Each is independently selected from H, hydroxyl, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-6 membered cycloalkyl, 3-6 membered cycloalkyl-C 1-6 Alkyl, 3-6 membered heterocyclic, 3-6 membered heterocyclic -C 1-6 Alkyl, phenyl, phenyl-C 1-6 Alkyl, 5-6 heteroaryl or 5-6 heteroaryl-C 1-6 alkyl;

[0104] Each R 6 Each R 7 Selected independently from H and C respectively 1-6 Alkyl or halogenated C 1-6 alkyl.

[0105] In some of the above implementations, each R 4 Each R 4 '、 Each R 5 Each R 5 'Each is independently selected from H, hydroxyl, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-6 membered saturated cycloalkyl, 3-6 membered saturated cycloalkyl-C 1-6 Alkyl, 5-6 membered saturated heterocyclic group, 5-6 membered saturated heterocyclic group -C 1-6 Alkyl, phenyl, phenyl-C 1-6 Alkyl, 5-6 heteroaryl or 5-6 heteroaryl-C 1-6 alkyl.

[0106] In some of the above implementations, each R 4 Each R 4 '、 Each R 5 Each R 5 'Each is independently selected from H, hydroxyl, amino, C 1-6 Alkyl, Halogenated C 1-6Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-6 saturated cycloalkyl, 3-6 saturated cycloalkyl-methyl, 3-6 saturated cycloalkyl-ethyl, 5-6 saturated heterocyclic, 5-6 saturated heterocyclic-methyl, 5-6 saturated heterocyclic-ethyl, phenyl, phenyl-methyl, phenyl-ethyl, 5-6 heteroaryl, 5-6 heteroaryl-methyl or 5-6 heteroaryl-ethyl.

[0107] In some of the above implementations, each R 4 Each R 4 '、 Each R 5 Each R 5 'Each is independently selected from H, hydroxyl, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkyl group.

[0108] In some of the above implementations, each R 4 Each R 4 '、 Each R 5 Each R 5 'Each is independently selected from H, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, hydroxyisopropyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, or 1,1,1-trifluoroethyl.

[0109] In some of the above embodiments, X1 and X2 are each independently selected from -CH(R) 6 )-、-N(R 7 -, -O-, -S-, -C(O)-, -S(O)- or -S(O)2-;

[0110] Each R 6 Each R7 Selected independently from H and C respectively 1-6 Alkyl or halogenated C 1-6 alkyl.

[0111] In some of the above implementations, each R 6 Each R 7 Each of the following is independently selected from H, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, and 1,1,1-trifluoroethyl.

[0112] In some of the above embodiments, X1 and X2 are each independently selected from -CH(R) 6 )-、-N(R 7 -, -O-, -S- or -C(O)-;

[0113] Each R 6 Each R 7 Each independently selected from H or C 1-6 alkyl.

[0114] In some of the above implementations, each R 6 Each R 7 Each is independently selected from H, methyl, ethyl, propyl or isopropyl.

[0115] In some of the above implementations, R 1 Selected from H, halogen, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl, fluorinated C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 alkoxy or fluorinated C 1-6 Alkyl group.

[0116] In some of the above implementations, R 1 Selected from H, halogen, hydroxyl, amino, nitro, cyano, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyanomethyl, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy.

[0117] In some of the above embodiments, X4 is selected from N or CH.

[0118] In some of the above implementations, each R 8 Each group is independently selected from H, halogen, hydroxyl, amino, cyano, and C. 1-6 Alkyl, fluorinated C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 alkoxy or fluorinated C 1-6 Alkyl group.

[0119] In some of the above implementations, each R8 Each is independently selected from H, halogen, hydroxyl, amino, cyano, methyl, ethyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyanomethyl, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy.

[0120] In some of the above implementations, q is selected from 1 or 2.

[0121] In some embodiments, the compound represented by general formula (I), its pharmaceutically acceptable salt, or an isomer thereof, wherein,

[0122] L is X is selected from -CH2-, -NH-, -O-, or -S-;

[0123] X1 is selected from -N(R) 7 -, -O-, or -S-;

[0124] X2 is selected from -CH(R) 6 - or -C(O)-;

[0125] X4 is selected from N or CH;

[0126] R 1 Selected from H, halogen, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 alkoxy or halogenated C 1-6 Alkylthio;

[0127] R 2 R 3 and with R 2 The bonded carbon atom and X3 together form the following group:

[0128]

[0129] X3 is selected from CH or N;

[0130] X5 is selected from CH, C, or N;

[0131] X6 and X7 are independently selected from -CH2-, -NH-, -O-, -S-, -C(O)-, -S(O)- or -S(O)2-, respectively;

[0132] X8 and X9 are independently selected from C(R) 9 ) or N;

[0133] Ring A is selected from phenyl or 5-6 member nitrogen-containing heteroaryl groups;

[0134] Each Q1 is independently selected from halogen, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkoxy;

[0135] R 4 R 4 '、R 6 Each group is independently selected from H, halogen, hydroxyl, amino, nitro, cyano, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkyl or cyano C 1-6 Alkoxy;

[0136] R 7 Selected from H, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl or amino C 1-6 alkyl;

[0137] Each R 8 Each group is independently selected from H, halogen, hydroxyl, amino, nitro, cyano, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, cyano C 1-6 Alkoxy;

[0138] Each R 9 Each is independently selected from hydrogen, halogen, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkoxy;

[0139] p is selected from 0, 1, or 2;

[0140] q is selected from 1 or 2.

[0141] In some of the above embodiments, R 2 R 3 and with R 2 The bonded carbon atom and X3 together form the following group:

[0142]

[0143]

[0144] X3 is selected from CH or N; X5 is selected from CH, C or N.

[0145] In some embodiments, the compound represented by general formula (I), its pharmaceutically acceptable salt, or an isomer thereof, wherein,

[0146] L is X is selected from -O- or -S-;

[0147] X1 is selected from -N(R) 7 )-;X2 is selected from -CH(R 6 - or -C(O)-;

[0148] X4 is selected from N or CH;

[0149] R 1 Selected from H, halogen, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 alkoxy or halogenated C 1-6 Alkylthio;

[0150] R 2 R 3 and with R 2 The bonded carbon atom and X3 together form the following group:

[0151]

[0152] Ring A is selected from phenyl or 5-6 member heteroaryl groups containing 1-3 nitrogen atoms;

[0153] Q1 is selected from halogen, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkoxy;

[0154] R 4 R 4 '、R 6 Each group is independently selected from H, halogen, hydroxyl, amino, nitro, cyano, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkyl or cyano C 1-6 Alkoxy;

[0155] R 7 Selected from H, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl or amino C 1-6 alkyl;

[0156] Each R 8 Each group is independently selected from H, halogen, hydroxyl, amino, nitro, cyano, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, cyano C 1-6 Alkoxy;

[0157] Each R 9 Each is independently selected from hydrogen, halogen, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkoxy;

[0158] p is selected from 0 or 1; q is selected from 1 or 2.

[0159] In some embodiments, the compound represented by general formula (I), its pharmaceutically acceptable salt, or an isomer thereof, wherein,

[0160] L is X is selected from -O- or -S-;

[0161] X1 is selected from -N(R) 7 )-;X2 is selected from -CH(R 6 - or -C(O)-;

[0162] X4 is selected from N or CH;

[0163] R 1 Selected from H, halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, cyano C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl thiols, halogenated C 1-4 alkoxy or halogenated C 1-4 Alkylthio;

[0164] R 2 R 3 and with R 2 The bonded carbon atom and X3 together form the following group:

[0165]

[0166] Ring A is selected from phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazoleyl, or triazolyl;

[0167] Q1 is selected from halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 alkoxy or halogenated C 1-4 Alkoxy;

[0168] R 4 R 4 'Each element is independently selected from H, halogen, hydroxyl, amino, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, hydroxy C 1-4 alkoxy or amino C 1-4 Alkoxy;

[0169] R 6 For H;

[0170] R 7 Selected from H, C 1-4Alkyl, Halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl or amino C 1-4 alkyl;

[0171] Each R 8 Each is independently selected from H, halogen, hydroxyl, amino, cyano, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, cyano C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, amino C 1-4 Alkoxy, cyano C 1-4 Alkoxy;

[0172] Each R 9 Each is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 alkoxy or halogenated C 1-4 Alkoxy;

[0173] p is 1; q is selected from 1 or 2.

[0174] In some of the above embodiments, ring A is selected from phenyl, pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, or triazolyl.

[0175] In some embodiments, the compound represented by general formula (I), its pharmaceutically acceptable salt, or an isomer thereof, wherein,

[0176] L is X is selected from -O- or -S-;

[0177] X1 is selected from -N(R) 7 )-;X2 is selected from -CH(R 6 - or -C(O)-;

[0178] X4 is selected from N or CH;

[0179] R 1 Selected from H, halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, cyano C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl thiols, halogenated C 1-4 alkoxy or halogenated C1-4 Alkylthio;

[0180] R 2 R 3 and with R 2 The bonded carbon atom and X3 together form the following group:

[0181]

[0182]

[0183] Q1 is selected from halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 alkoxy or halogenated C 1-4 Alkoxy;

[0184] R 4 R 4 'Each element is independently selected from H, halogen, hydroxyl, amino, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, hydroxy C 1-4 alkoxy or amino C 1-4 Alkoxy;

[0185] R 6 For H;

[0186] R 7 Selected from H, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl or amino C 1-4 alkyl;

[0187] Each R 8 Each is independently selected from H, halogen, hydroxyl, amino, cyano, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, cyano C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, amino C 1-4 Alkoxy, cyano C1-4 Alkoxy;

[0188] Each R 9 Each is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 alkoxy or halogenated C 1-4 Alkoxy;

[0189] p is 1; q is selected from 1 or 2.

[0190] In some embodiments, the compound represented by general formula (I), its pharmaceutically acceptable salt, or an isomer thereof, wherein,

[0191] L is X is selected from -O- or -S-;

[0192] X1 is selected from -N(R) 7 )-;X2 is selected from -CH(R 6 - or -C(O)-;

[0193] X4 is selected from N or CH;

[0194] R 1 Selected from H, halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, fluorinated C 1-4 Alkyl, cyano C 1-4 Alkyl, C 1-4 alkoxy or fluorinated C 1-4 Alkoxy;

[0195] R 2 R 3 and with R 2 The bonded carbon atom and X3 together form the following group:

[0196]

[0197] Q1 is selected from halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, fluorinated C 1-4 Alkyl, C 1-4 alkoxy or fluorinated C 1-4 Alkoxy;

[0198] R 4 R 4 'Each element is independently selected from H, halogen, hydroxyl, amino, and C. 1-4 Alkyl, fluorinated C 1-4 Alkyl, C 1-4 alkoxy or fluorinated C 1-4 Alkoxy;

[0199] R6 For H;

[0200] R 7 Selected from H or C 1-4 alkyl;

[0201] Each R 8 Each is independently selected from H, halogen, hydroxyl, amino, cyano, and C. 1-4 Alkyl, fluorinated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, cyano C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 alkoxy or fluorinated C 1-4 Alkoxy;

[0202] Each R 9 Each is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, and C. 1-4 Alkyl, fluorinated C 1-4 Alkyl, C 1-4 alkoxy or fluorinated C 1-4 Alkoxy;

[0203] p is 1; q is selected from 1 or 2.

[0204] In some embodiments, the compound represented by general formula (I), its pharmaceutically acceptable salt, or an isomer thereof, wherein,

[0205] L is X is selected from -O- or -S-;

[0206] X1 is selected from -N(R) 7 )-;X2 is selected from -CH(R 6 - or -C(O)-;

[0207] X4 is selected from N or CH;

[0208] R 1 Selected from H, halogen, hydroxyl, amino, cyano, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyanomethyl, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy;

[0209] R 2 R 3 and with R 2 The bonded carbon atom and X3 together form the following group:

[0210]

[0211] Q1 is selected from halogen, hydroxyl, amino, cyano, methyl, ethyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy;

[0212] R 4 R 4 Each of the following is independently selected from H, halogen, hydroxyl, amino, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy, or trifluoromethoxy;

[0213] R 6 For H;

[0214] R 7 Selected from H, methyl, ethyl, or isopropyl;

[0215] Each R 8 Each of the following is independently selected from H, halogen, hydroxyl, amino, cyano, methyl, ethyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, hydroxymethyl, aminomethyl, cyanomethyl or methoxymethyl;

[0216] Each R 9 Each of the following is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy, or trifluoromethoxy;

[0217] p is 1; q is selected from 1 or 2.

[0218] In some of the above implementations, R 2 R 3 and with R 2 The bonded carbon atom and X3 together form the following group:

[0219]

[0220] In one aspect, the present invention provides compounds represented by general formula (II), pharmaceutically acceptable salts thereof, or isomers thereof.

[0221]

[0222] Among them, R 1 R 2 R 3 R 7 R 8 L, X 3 X 4 Q1, X, R 4 R 4’ R 5 R 5’ m, n, q, virtual keys The definition is as described in any of the preceding schemes.

[0223] In some embodiments, the compound represented by general formula (II), its pharmaceutically acceptable salt, or an isomer thereof, wherein,

[0224] L is X is selected from -O- or -S-;

[0225] X4 is selected from N or CH;

[0226] R 1 Selected from H, halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, cyano C 1-4 Alkyl, C 1-4 alkoxy or halogenated C 1-4 Alkoxy;

[0227] R 2 R 3 and with R 2 The bonded carbon atom and X3 together form the following group:

[0228]

[0229] Ring A is selected from phenyl, pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, or 1,2,4-triazolyl;

[0230] Q1 is selected from halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 alkoxy or halogenated C 1-4 Alkoxy;

[0231] R 4 R 4 'Each element is independently selected from H, halogen, hydroxyl, amino, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl or C 1-4 Alkoxy-C 1-4 alkyl;

[0232] R 7 Selected from H or C 1-4 alkyl;

[0233] R 8 Selected from H, halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 alkoxy or halogenated C 1-4 Alkoxy;

[0234] Each R 9 Each is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, and C. 1-4 Alkyl or halogenated C 1-4 Alkyl group; p = 1; q = 1.

[0235] In some of the above implementations, R 2 R 3 and with R 2 The bonded carbon atom and X3 together form the following group:

[0236]

[0237] In one aspect, the present invention provides compounds represented by general formula (III-1) or general formula (III-2), pharmaceutically acceptable salts thereof, or isomers thereof.

[0238]

[0239] Among them, R 1 R 2 R 3 R 8 X3, X4, R 5 R 5’ Q1, q, virtual key The definition is as described in any of the preceding schemes.

[0240] In one aspect, the present invention provides compounds represented by general formula (IV-1) or general formula (IV-2), pharmaceutically acceptable salts thereof, or isomers thereof.

[0241]

[0242] Among them, R 1 R 8 The definitions of X4, Q1, and q are as described in any of the previous schemes.

[0243] In one aspect, the present invention provides compounds represented by the following general formula (IV-3), pharmaceutically acceptable salts thereof, or isomers thereof.

[0244]

[0245] Among them, R 1 R 8 The definitions of X4, Q1, and q are as described in any of the previous schemes.

[0246] In some embodiments, the compound represented by general formula (IV-3), its pharmaceutically acceptable salt, or an isomer thereof, wherein,

[0247] R1 Selected from H, halogen, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 alkoxy or halogenated C 1-6 Alkylthio;

[0248] Each R 8 Each group is independently selected from H, halogen, hydroxyl, amino, nitro, cyano, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, cyano C 1-6 Alkoxy;

[0249] X4 is N;

[0250] Q1 is selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkoxy;

[0251] q is selected from 1 or 2.

[0252] In one aspect, the present invention provides compounds represented by the following general formula (IV-4), pharmaceutically acceptable salts thereof, or isomers thereof.

[0253]

[0254] Among them, R 1 R 8 R 9 The definitions of X4, Q1, p, and q are as described in any of the above schemes;

[0255] Ring A is selected from phenyl, pyridyl, pyrimidinyl, or pyrazinyl.

[0256] In one aspect, the present invention provides compounds represented by the following general formula (IV-5), pharmaceutically acceptable salts thereof, or isomers thereof.

[0257]

[0258] Among them, R 1 R 8 R 9 The definitions of X4, Q1, p, and q are as described in any of the above schemes.

[0259] In some embodiments, the compound represented by general formula (IV-5), its pharmaceutically acceptable salt, or an isomer thereof, wherein,

[0260] R 1 Selected from H, halogen, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 alkoxy or halogenated C 1-6 Alkylthio;

[0261] Each R 8 Each group is independently selected from H, halogen, hydroxyl, amino, nitro, cyano, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, cyano C 1-6 Alkoxy;

[0262] R 9 Selected from hydrogen, halogen, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, 3-6 membered cycloalkyl, or 3-6 membered heterocyclic group;

[0263] Each Q1 is independently selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkoxy;

[0264] X4 is N;

[0265] p is selected from 1 or 2;

[0266] q is selected from 1 or 2.

[0267] The various technical solutions in this invention can be combined with each other to form new technical solutions, and the new technical solutions formed are also included within the scope of this invention.

[0268] In some embodiments, the compounds represented by general formula (I'), general formula (I), general formula (II), general formula (III-1), general formula (III-2), general formula (IV-1), general formula (IV-2), general formula (IV-3), general formula (IV-4) or general formula (IV-5), their pharmaceutically acceptable salts or isomers thereof, are selected from the compounds shown in Table 1 below:

[0269] Table 1

[0270]

[0271]

[0272]

[0273]

[0274] In some embodiments, the compound represented by general formula (I), its pharmaceutically acceptable salt, or its isomer,

[0275]

[0276] Where L is X is selected from -O- or -S-;

[0277] X1 is selected from -N(R) 7 )-;

[0278] X2 is -C(O)-;

[0279] X4 is N;

[0280] R 1 Selected from H, halogen, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 alkoxy or halogenated C 1-6 Alkylthio;

[0281] R 2 R 3 and with R 2The bonded carbon atom and X3 together form the following group:

[0282]

[0283] Each Q1 is independently selected from halogen, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkoxy;

[0284] R 4 R 4 'Each group is independently selected from H, halogen, hydroxyl, amino, nitro, cyano, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkyl or cyano C 1-6 Alkoxy;

[0285] R 7 Selected from H, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl or amino C 1-6 alkyl;

[0286] Each R 8 Each group is independently selected from H, halogen, hydroxyl, amino, nitro, cyano, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, cyano C 1-6 Alkoxy;

[0287] R 9 Selected from hydrogen, halogen, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, 3-6 membered cycloalkyl, or 3-6 membered heterocyclic group;

[0288] p is selected from 0, 1, or 2;

[0289] q is selected from 1 or 2.

[0290] The present invention also provides the following compounds, their pharmaceutically acceptable salts, or isomers thereof.

[0291]

[0292]

[0293] In another aspect, the present invention also provides a pharmaceutical composition comprising the compounds of the aforementioned formulas (I'), (I), (II), (III-1), (III-2), (IV-1), (IV-2), (IV-3), (IV-4), or (IV-5), pharmaceutically acceptable salts thereof, or isomers thereof, and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition may be in any pharmaceutically acceptable dosage form. Pharmaceutically acceptable excipients are substances that are non-toxic, compatible with the active ingredient, and otherwise biologically suitable for use in organisms. The selection of a particular excipient will depend on the route of administration or the type and state of disease for the treatment of a particular patient.

[0294] In some embodiments, the above-described pharmaceutical composition can be administered to patients or subjects requiring this treatment via oral, parenteral, rectal, or pulmonary administration. For oral administration, the pharmaceutical composition can be formulated into oral preparations, such as conventional oral solid dosage forms like tablets, capsules, pills, granules, etc.; or into oral liquid preparations, such as oral solutions, oral suspensions, syrups, etc. For parenteral administration, the above-described pharmaceutical composition can also be formulated into injectable preparations, including injection solutions, sterile powders for injection, and concentrated solutions for injection. For rectal administration, the pharmaceutical composition can be formulated into suppositories, etc. For pulmonary administration, the pharmaceutical composition can be formulated into inhaled preparations, aerosols, powder inhalers, or sprays, etc.

[0295] In another aspect, the present invention also relates to the use of the compounds of the aforementioned formulas (I'), (I), (II), (III-1), (III-2), (IV-1), (IV-2), (IV-3), (IV-4), or (IV-5), pharmaceutically acceptable salts thereof, or isomers thereof, in the preparation of medicaments for the prevention and / or treatment of diseases associated with PARP7 overactivation.

[0296] In another aspect, the present invention also relates to the use of the compounds of the aforementioned formulas (I'), (I), (II), (III-1), (III-2), (IV-1), (IV-2), (IV-3), (IV-4), or (IV-5), pharmaceutically acceptable salts thereof, or isomers thereof, in the preparation of medicaments for the prevention and / or treatment of cancer, including carcinoma in situ and metastatic cancer.

[0297] Furthermore, the present invention also relates to the use of pharmaceutical compositions comprising the compounds of the aforementioned general formulas (I'), (I), (II), (III-1), (III-2), (IV-1), (IV-2), (IV-3), (IV-4), or (IV-5), pharmaceutically acceptable salts thereof, or isomers thereof, in the preparation of medicaments for the prevention and / or treatment of diseases associated with PARP7 overactivation.

[0298] Furthermore, the present invention also relates to the use of pharmaceutical compositions comprising the compounds of the aforementioned general formulas (I'), (I), (II), (III-1), (III-2), (IV-1), (IV-2), (IV-3), (IV-4), or (IV-5), pharmaceutically acceptable salts thereof, or isomers thereof, in the preparation of medicaments for the prevention and / or treatment of cancer, including carcinoma in situ and metastatic cancer.

[0299] In another aspect, the pharmaceutical composition of the present invention comprises the compounds of the aforementioned general formulas (I'), (I), (II), (III-1), (III-2), (IV-1), (IV-2), (IV-3), (IV-4), or (IV-5), their pharmaceutically acceptable salts, or isomers thereof, and may further comprise one or more second therapeutic agents selected from anticancer agents, drugs that reduce or decrease one or more side effects produced when the compounds of the present invention are used to treat a subject's disease, or drugs that enhance the efficacy of the compounds of the present invention.

[0300] In another aspect, the present invention also provides a method for treating diseases associated with PARP7 overactivation, the method comprising administering to a patient in need an effective amount of the aforementioned compound of formula (I'), formula (I), formula (II), formula (III-1), formula (III-2), formula (IV-1), formula (IV-2), formula (IV-3), formula (IV-4) or formula (IV-5), a pharmaceutically acceptable salt thereof, or an isomer thereof, the aforementioned pharmaceutical composition.

[0301] Furthermore, the present invention also provides a method for treating cancer, the method comprising administering to a patient in need an effective amount of the aforementioned compound of formula (I'), formula (I), formula (II), formula (III-1), formula (III-2), formula (IV-1), formula (IV-2), formula (IV-3), formula (IV-4) or formula (IV-5), a pharmaceutically acceptable salt thereof, or an isomer thereof, the aforementioned pharmaceutical composition.

[0302] In another aspect, the present invention also provides a kit comprising an effective amount of one or more of the aforementioned compounds of formula (I'), formula (I), formula (II), formula (III-1), formula (III-2), formula (IV-1), formula (IV-2), formula (IV-3), formula (IV-4), or formula (IV-5), pharmaceutically acceptable salts thereof, or isomers thereof.

[0303] In another aspect, the present invention also provides a kit comprising:

[0304] (a) An effective amount of one or more compounds of the preceding general formulas (I'), (I), (II), (III-1), (III-2), (IV-1), (IV-2), (IV-3), (IV-4), or (IV-5), their pharmaceutically acceptable salts, or isomers thereof.

[0305] (b) an effective amount of one or more anticancer agents.

[0306] The "anticancer agent" described in this invention refers to a drug that has a certain therapeutic effect on tumors, including but not limited to mitosis inhibitors, alkylating agents, antimetabolites, DNA chimeras, antitumor antibiotics, growth factor inhibitors, signal transduction inhibitors, cell cycle inhibitors, enzyme inhibitors, vitamin A receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modulators, hormonal drugs, angiogenesis inhibitors, cell growth inhibitors, targeted antibodies, HMG-CoA reductase inhibitors, and protein isoprenyltransferase inhibitors. The "effective dose" refers to the drug dosage that can prevent, alleviate, delay, inhibit, or cure the subject's symptoms. The dosage is related to the route of drug administration, the pharmacokinetics of the drug, the severity of the disease, and the subject's individual characteristics (gender, weight, height, age).

[0307] In this invention, unless otherwise stated, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, for a better understanding of this invention, definitions of some terms are provided below. When the definitions and interpretations of the terms provided in this invention differ from the meanings commonly understood by those skilled in the art, the definitions and interpretations provided in this invention shall prevail.

[0308] The "halogen" mentioned in this invention refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0309] The "C" described in this invention 1-6 "Alkyl" refers to a straight-chain or branched alkyl group containing 1-6 carbon atoms, including, for example, "C". 1-4 Alkyl", C 1-3 Alkyl", C 1-2 Alkyl", C 2-6 Alkyl", C 2-5 Alkyl", C 2-4 Alkyl", C 2-3 Alkyl groups, etc., specific examples include but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, etc. The "C" in this invention... 1-4 "alkyl" refers to C 1-6 Specific examples of alkyl groups containing 1-4 carbon atoms.

[0310] The "C" described in this invention 1-6 "Alkoxy" refers to "C 1-6Alkyl-O-”, the “C” 1-6 "alkyl" is as defined above. The "C" in this invention... 1-4 "Alkoxy" refers to "C 1-4 Alkyl-O-”, the “C” 1-4 "Alkyl" is as defined above.

[0311] The "C" described in this invention 1-6 "Alkylthio" refers to "C 1-6 Alkyl-S-", the "C" 1-6 "alkyl" is as defined above. The "C" in this invention... 1-4 "Alkylthio" refers to "C 1-4 Alkyl-S-", the "C" 1-4 "Alkyl" is as defined above.

[0312] The "hydroxyl C" of this invention 1-6 Alkyl, amino C 1-6 Alkyl, Halogenated C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 "alkyl" refers to C 1-6 One or more hydrogens in the alkyl group are respectively converted by one or more hydroxyl, amino, halogen, cyano or C groups. 1-6 Alkyl groups are substituted. C 1-6 Alkyl, C 1-6 Alkoxy groups are as defined above.

[0313] The "hydroxyl C" of this invention 1-6 Alkoxy, amino C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano C 1-6 "Alkoxy" refers to "C 1-6 One or more hydrogen atoms in the "alkoxy" group are replaced by one or more hydroxyl, amino, halogen, or cyano groups.

[0314] The "hydroxyl C" of this invention 1-6 Alkylthio, amino C 1-6 Alkyl thiols, halogenated C 1-6 "Alkylthio" refers to "C 1-6 One or more hydrogen atoms in the "alkylthio" group are replaced by one or more hydroxyl, amino, or halogen groups.

[0315] The "fluorinated C" of this invention 1-6 Alkyl group, fluorinated C 1-6 "Alkoxy" refers to "C 1-6 Alkyl", C 1-6 In an alkoxy group, one or more hydrogen atoms are replaced by one or more fluorine atoms.

[0316] The "3-8 membered cycloalkyl" as described in this invention refers to a saturated or partially saturated monocyclic cyclic group containing 3-8 ring atoms and lacking aromaticity. The "3-8 membered cycloalkyl" in this invention includes "3-8 membered saturated cycloalkyl" and "3-8 membered partially saturated cycloalkyl," such as "3-6 membered cycloalkyl," "3-6 membered saturated cycloalkyl," "5-7 membered cycloalkyl," "5-7 membered saturated cycloalkyl," "5-6 membered cycloalkyl," and so on. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, or cyclohexenyl.

[0317] The "3-8 membered heterocyclic group" described in this invention refers to a saturated or partially saturated monocyclic cyclic group containing at least one (e.g., 1, 2, 3, 4, or 5) heteroatom and having 3-8 ring atoms, and which is non-aromatic. The heteroatom is a nitrogen atom, an oxygen atom, and / or a sulfur atom. Optionally, the ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure can be substituted with oxygen. The "3-8 membered heterocyclic group" described in this invention includes "3-8 membered saturated heterocyclic groups" and "3-8 membered partially saturated heterocyclic groups." Examples of the "3-8 membered heterocyclic group" include "3-6 membered heterocyclic group," "3-6 membered saturated heterocyclic group," "3-7 membered heterocyclic group," "3-7 membered saturated heterocyclic group," "5-7 membered heterocyclic group," "5-7 membered saturated heterocyclic group," "5-6 membered heterocyclic group," and "5-6 membered saturated heterocyclic group," etc. Specific examples include, but are not limited to: aziridine, 2H-aziridine, diaziridine, 3H-diazacyclopropenyl, aziridine, oxacyclopropyl, oxacyclobutyl, 1,4-dioxacyclohexyl, 1,3-dioxacyclohexyl, 1,3-dioxacyclopentyl, 1,4-dioxacyclohexadienyl, tetrahydrofuranyl, dihydropyrroleyl, tetrahydropyrroleyl, tetrahydrofuranyl, dihydropyrroleyl, tetrahydrofuranyl, dihydropyrroleyl, tetrahydrofuranyl, dihydropyrroleyl, tetrahydrofuranyl, dihydropyrroleyl, tetrahydrofuranyl, dihydropyrroleyl, tetrahydrofuranyl, dihydropyrroleyl, di ... Hydropyrazolyl, tetrahydroimidazolyl, 4,5-dihydroimidazolyl, pyrazolyl, 4,5-dihydropyrazolyl, 2,5-dihydrothiophenyl, tetrahydrothiophenyl, 4,5-dihydrothiazolyl, thiazolyl, tetrahydropyranyl, tetrahydrothiaranyl, 1,1-dioxotetrahydrothiaranyl, piperidinyl, tetrahydropyridinyl, piperidinoneyl, tetrahydropyridinoneyl, dihydropiperidinoneyl, piperazine, hexahydropyrimidinyl, morpholinyl, etc.

[0318] The "3-8 membered cycloalkyl-C" of this invention 1-6 Alkyl group, 3-8 membered heterocyclic group -C 1-6 "alkyl" refers to 3-8 membered cycloalkyl-C 1-6 Alkyl-", "3-8 membered heterocyclic-C" 1-6 Alkyl-", where "3-8 membered cycloalkyl", "3-8 membered heterocyclic", "C 1-6 "Alkyl" is as defined above.

[0319] The "8-11 membered fused-ring cycloalkyl" of this invention refers to a saturated or partially saturated, non-aromatic cyclic group containing 8-11 ring carbon atoms, formed by two or more cyclic structures sharing two adjacent atoms. One ring in the fused ring may be an aromatic ring, but the fused ring as a whole does not possess aromaticity. Examples include, but are not limited to: wait.

[0320] The "8-11 membered fused-ring heterocyclic group" described in this invention refers to a non-aromatic cyclic group containing 8-11 ring atoms, formed by two or more cyclic structures sharing two adjacent atoms, and at least one ring atom being a heteroatom. One ring in the fused ring may be aromatic, but the fused ring as a whole is not aromatic. The heteroatom is a nitrogen atom, an oxygen atom, and / or a sulfur atom. The ring atoms in the cyclic structure (e.g., carbon, nitrogen, or sulfur atoms) may optionally be oxidized. Specific examples include, but are not limited to, dihydrofuranopyridine, 3,4-dihydro-2H-pyranopyridine, 3,4-dihydro-2H-oxazinopyridine, dihydrooxazinopyrimidine, benzodihydrofuranyl, etc.

[0321] The “8-11 fused-ring aryl” mentioned in this invention refers to an unsaturated, aromatic cyclic group containing 8-11 cyclic carbon atoms formed by two or more cyclic structures sharing two adjacent atoms, including “9-10 fused-ring aryl”, and specific examples include, but are not limited to, naphthyl.

[0322] The "8-11 fused-ring heteroaryl" described in this invention refers to an unsaturated aromatic ring structure formed by two or more ring structures sharing two adjacent atoms, containing 8-11 ring atoms (at least one of which is a heteroatom, such as a nitrogen atom, oxygen atom, or sulfur atom). The ring atoms (e.g., carbon atom, nitrogen atom, or sulfur atom) in the ring structure may optionally be oxidized. This includes "9-10 fused heteroaryl", "8-9 fused heteroaryl", etc., and the fusion mode can be 5-nitrogen-containing heteroaryl with 5-6-nitrogen-containing heteroaryl, 6-nitrogen-containing heteroaryl with 5-6-nitrogen-containing heteroaryl, 5-6-aryl with 5-6 heteroaryl, etc.; specific examples include but are not limited to: pyrrolopyrrole, pyrrolofuran, pyrrolopyrimidine, pyrrolopyridine, pyrazolopyrrole, pyrazolopyrimidine, pyrazolothiophene, pyrazolooxazole, benzofuranyl, benzoisofuranyl, benzothiopheneyl, indolyl, isoindolyl, benzooxazolyl, benzimidazolyl, etc.

[0323] The "5-7-membered heteroaryl" as described in this invention refers to an aromatic monocyclic cyclic group containing 5-7 ring atoms (at least one of which is a heteroatom, such as a nitrogen atom, oxygen atom, or sulfur atom). The ring atoms (e.g., carbon atom, nitrogen atom, or sulfur atom) in the cyclic structure may optionally be oxidized. This includes, for example, "5-6-membered heteroaryl," "5-6-membered nitrogen-containing heteroaryl," and "6-membered nitrogen-containing heteroaryl," etc. The heteroatom in the "nitrogen-containing heteroaryl" contains at least one nitrogen atom; for example, it may contain only one or two nitrogen atoms, or it may contain one nitrogen atom and one or two other heteroatoms (e.g., oxygen atom and / or sulfur atom), or it may contain two nitrogen atoms and one or two other heteroatoms (e.g., oxygen atom and / or sulfur atom). Specific examples of "5-7 heteroaryl groups" include, but are not limited to, furanyl, thiopheneyl, pyrroleyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, 2-pyridoneyl, 4-pyridoneyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetraazinyl, aziridine-heptadienyl, 1,3-diazacycloheptadienyl, etc.

[0324] In this invention, "C" refers to the following structure:

[0325] In this invention, "CH" refers to the following structure:

[0326] The "CR" described in this invention 8 " refers to the following structure:

[0327] In this invention, "N" refers to the following structure:

[0328] The "each R" described in this invention 4 "This refers to multiple Rs when m is 2, 3, or 4" 4 In each R 4 Independently selected from the groups described in the above technical solutions.

[0329] The "each R" described in this invention 4 '" refers to multiple R's when m is 2, 3, or 4. 4 'In each R 4 'Independently selected from the groups described in the above technical solutions.'

[0330] The "each R" described in this invention 5 "This refers to the situation where n is 2, 3, or 4, and multiple R's are equal.5 In each R 5 Independently selected from the groups described in the above technical solutions.

[0331] The "each R" described in this invention 5 '" refers to multiple R's when n is 2, 3, or 4. 5 'In each R 5 'Independently selected from the groups described in the above technical solutions.'

[0332] The "each R" described in this invention 6 "" refers to the situation where X, X1, and X2 are all simultaneously "-CH(R)". 6 When )-”, multiple R 6 In each R 6 Independently selected from the groups described in the above technical solutions.

[0333] The "each R" described in this invention 7 "" refers to the situation where X, X1, and X2 are all simultaneously "-N(R) 7 When )-”, multiple R 7 In each R 7 Independently selected from the groups described in the above technical solutions.

[0334] The term "optionally substituted" in this invention refers to two situations: one or more hydrogen atoms on the substituted group are "substituted" or "not substituted" by one or more substituents.

[0335] The “R” described in this invention 2 R 3 and with R 2 In a group consisting of "connected carbon atoms and X3", the bond between ring A and the adjacent ring can be either a single bond or a double bond, depending primarily on the structure of ring A. For example, the group: If ring A is a saturated heterocycle, the bond between ring A and the adjacent ring is a single bond; if ring A is an aromatic ring, the bond between ring A and the adjacent ring is either a single bond or a double bond.

[0336] The "pharmaceutically acceptable salt" as described in this invention refers to a salt formed by an acidic functional group (e.g., -COOH, -OH, -SO3H, etc.) present in a compound and a suitable inorganic or organic cation (base), including salts formed with alkali metals or alkaline earth metals, ammonium salts, and salts formed with nitrogen-containing organic bases; and a salt formed by a basic functional group (e.g., -NH2, etc.) present in a compound and a suitable inorganic or organic anion (acid), including salts formed with inorganic acids or organic acids (e.g., carboxylic acids, etc.).

[0337] The term "isomer" as used in this invention refers to compounds containing one or more asymmetric centers, thus allowing them to exist as racemic mixtures and mixtures thereof, single enantiomers, mixtures of diastereomers, and single diastereomers. Compounds of this invention may have asymmetric centers, each of which independently produces two optical isomers. The scope of this invention includes all possible optical isomers and mixtures thereof. If the compounds of this invention contain an alkene double bond, unless otherwise specified, they include cis and trans isomers. Compounds of this invention may exist as tautomers (a type of functional group isomer) with different hydrogen connection points through one or more double bond shifts; for example, ketones and their enol forms are keto-enol tautomers. Compounds of this invention contain a spirocyclic structure, and due to the influence of the ring's stereochemical structure, substituents on the ring may exist on opposite sides of the ring, thus forming opposing cis and trans isomers. All tautomers and mixtures thereof are included within the scope of this invention. All enantiomers, diastereomers, racemates, mesomates, cis-trans isomers, tautomers, geometric isomers, epimers, and mixtures thereof are included within the scope of this invention.

[0338] The compounds of this invention can be prepared by enantiomer-specific synthesis or by resolution from mixtures of enantiomers to obtain individual enantiomers. Conventional resolution techniques include using various well-known chromatographic methods to separate mixtures of enantiomers of the starting material or the final product.

[0339] When the stereochemistry of a disclosed compound is determined by structural nomenclature or description, the named or described stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight relative to other stereoisomers. When a single isomer is determined by structural nomenclature or description, the described or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. Optical purity (by weight%) is the ratio of the weight of the enantiomer to the weight of the enantiomer plus the weight of its optical isomer.

[0340] Beneficial effects of the invention

[0341] 1. The compounds of the present invention, their pharmaceutically acceptable salts or isomers thereof have excellent PARP7 inhibitory activity, good pharmacokinetic properties in vivo, long duration of action and high bioavailability.

[0342] 2. The compounds of the present invention, their pharmaceutically acceptable salts or isomers thereof have good therapeutic effects on cancer and high stability in liver microsomes.

[0343] 3. The compound preparation process of this invention is simple, the drug has high purity and stable quality, and it is easy to carry out large-scale industrial production. Detailed Implementation Plan

[0344] The technical solution of the present invention will be described below with reference to specific embodiments, and the above-mentioned content of the present invention will be further explained in detail. However, it should not be construed that the scope of the above-mentioned subject matter of the present invention is limited to the following embodiments. All technologies implemented based on the above-mentioned content of the present invention fall within the scope of the present invention.

[0345] abbreviation:

[0346] DIPEA: N,N-diisopropylethylamine; DMSO: dimethyl sulfoxide; KOtBu: potassium tert-butoxide; TFA: trifluoroacetic acid; DCM: dichloromethane; HATU: N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea; TfOH: trifluoromethanesulfonic acid; DABCO: triethylenediamine; DMF: N,N-dimethylformamide; DMA: N,N-dimethylacetamide; Pd(tBu3P)2: bis(tri-tert-butylphosphine)palladium; TMSCF3: (trifluoromethyl)trimethylsilane; PhI(OAc)2: diacetic acid iodobenzene; NBS: N-bromosuccinimide; NMP: N-methylpyrrolidone; TBDPSCl: tert-butyldiphenylchlorosilane; TBAF: tetrabutylammonium fluoride; MsCl: methanesulfonyl chloride.

[0347] Preparation Example 1: Preparation of 5-((((2S)-1-(3-oxo-3-(3-(trifluoromethyl))-6a,7,9,10-tetrahydropyrazine[1,2-d]pyridinyl[3,2-b][1,4]oxazine-8(6H)yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H)-one (Compound 1)

[0348] 1. Preparation of tert-butyl 4-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylate

[0349]

[0350] 2,3-Difluoro-5-(trifluoromethyl)pyridine (3.66 g, 20.0 mmol), tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylic acid (4.6 g, 21.0 mmol), and DIPEA (4 mL, 24.0 mmol) were added to DMSO (40 mL). The reaction was carried out at 80 °C for 3.0 h under nitrogen protection. After cooling to room temperature, the reaction solution was poured into water and extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 8:1) to give the target compound (7.4 g, yield: 97.5%).

[0351] 2. Preparation of tert-butyl 3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyridino[3,2-b][1,4]oxazine-8(6H)-carboxylic acid

[0352]

[0353] 4-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (4.22 g, 8.4 mmol) and KOtBu (2.8 g, 25.2 mmol) were added to DMSO (50 mL) and reacted at 110 °C for 10 hours. The reaction solution was poured into water and extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 10:1) to obtain the target compound (630 mg, yield: 15.8%).

[0354] 3. Preparation of 3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyridino[3,2-b][1,4]oxazine

[0355]

[0356] At 16°C, TFA (3 mL) was slowly added dropwise to dichloromethane (9 mL) containing 3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyridino[3,2-b][1,4]oxazine-8(6H)-carboxylic acid tert-butyl ester (550 mg, 1.53 mmol). The reaction was carried out at 16°C for 3 hours. The reaction solution was directly evaporated under reduced pressure to obtain crude target compound (900 mg), which was used directly in the next step of the reaction without further purification.

[0357] 4. Preparation of 2-(4-methoxybenzyl)-5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0358]

[0359] (S)-3-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionic acid (200 mg, 0.46 mmol), 3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyridino[3,2-b][1,4]oxazine (182 mg, 0.7 mmol), HATU (266 mg, 0.7 mmol), and DIPEA (178 mg, 1.38 mmol) were added to dichloromethane (4 mL), and the reaction was carried out at 25 °C for 10 hours. The reaction solution was evaporated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to obtain the target compound (140 mg, yield: 45.4%).

[0360] 5. Preparation of 5-((((2S)-1-(3-oxo-3-(3-(trifluoromethyl))-6a,7,9,10,tetrahydropyrazine[1,2-d]pyridinyl[3,2-b][1,4]oxazine-8(6H)yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H)-one

[0361]

[0362] At 18°C, trifluoromethanesulfonic acid (0.1 mL) was slowly added dropwise to TFA (2 mL) containing 2-(4-methoxybenzyl)-5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyridino[3,2-b][1,4]oxazin-8(6H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (90 mg, 0.13 mmol), and the reaction was continued for 1 hour. After removing most of the TFA from the reaction solution under reduced pressure, the remaining reaction solution was diluted with ethyl acetate, and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The ethyl acetate layer was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 40:1) and medium-pressure reversed-phase column chromatography (methanol:water = 9:1) to obtain the target compound (25 mg, yield: 33.8%).

[0363] Molecular formula: C 22 H 24 F6N6O4 molecular weight: 550.5 LC-MS (M / e): 551.0 (M+H) + )

[0364] 1 H-NMR(400MHz,DMSO)δ:12.47(s,1H),8.31(s,1H),7.91(s,1H),7.55(s,1H),6.27(brs,1H),4.16-4.04(m,2H),3. 99-3.88(m,2H),3.65(m,2H),3.52(m,2H),3.48(m,4H),3.33-3.07(m,2H),2.65(m,1H),2.44(m,1H),1.42(m,3H).

[0365] Preparation Example 2: Preparation of (S)-5-((1-(3-oxo-3-(3-(trifluoromethyl)-8,9)dihydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazin-7(6H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 4)

[0366] 1. Preparation of 3-iodo-5-(trifluoromethyl)pyridine-2-amine

[0367]

[0368] 5-(trifluoromethyl)pyridine-2-amine (9.6 g, 59.2 mmol), silver sulfate (18.5 g, 59.2 mmol), and iodine (7.5 g, 29.6 mmol) were added to anhydrous ethanol (50 mL). The reaction was carried out at 25 °C for 8 h under nitrogen protection. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed with saturated sodium sulfite solution, separated, the ethyl acetate layer was washed with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give the target compound (2.8 g, yield: 16.4%).

[0369] 2. Preparation of 5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid

[0370]

[0371] 3-Iodo-5-(trifluoromethyl)pyridine-2-amine (2.7 g, 9.4 mmol), pyruvate (2.48 g, 28.2 mmol), DABCO (3.16 g, 28.2 mmol), and DMF (25 mL) were added to a 100 mL sealed tube. The reaction was carried out at 25 °C for 10 minutes under nitrogen protection. Then, Pd(OAc)₂ (2.74 g, 12.2 mmol) was added, and the reaction was continued at 110 °C for 3 hours under nitrogen protection. DMF was removed under reduced pressure. Ethyl acetate and water were added, and the mixture was separated. The ethyl acetate layer was extracted twice with 2N sodium hydroxide solution. The combined aqueous phase was adjusted to pH 3 with 12N hydrochloric acid solution, and extracted three times with ethyl acetate. The combined ethyl acetate layer was washed with water, then washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude target compound (0.6 g), which was directly used in the next reaction.

[0372] 3. Preparation of ethyl 5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

[0373]

[0374] Concentrated sulfuric acid (0.5 mL) was added to anhydrous ethanol (10 mL) containing 5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (0.6 g crude product), and the reaction was carried out at 85 °C for 16 hours. The reaction solution was directly evaporated to dryness under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain the target compound (316 mg).

[0375] 4. Preparation of ethyl 1-(cyanomethyl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

[0376]

[0377] Ethyl 5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (316 mg, 1.22 mmol) was added to 15 mL of DMF containing NaH (58 mg, 1.46 mmol) at 0 °C. After reacting for 1 hour, chloroacetonitrile (110 mg, 1.46 mmol) was added, and the reaction was continued at 0 °C for 10 minutes, followed by a reaction at 60 °C for 3 hours. The reaction solution was poured into water and extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give the target compound (295 mg, yield: 81.3%).

[0378] 5. Preparation of 3-(trifluoromethyl)-6,7,8,9-tetrahydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazine

[0379]

[0380] Ethyl 1-(cyanomethyl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (295 mg, 0.99 mmol) was added to anhydrous diethyl ether (40 mL) containing LiAlH4 (94 mg, 2.48 mmol) at 0 °C, and reacted at 40 °C for 8 hours. The reaction solution was evaporated to dryness under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane:methanol = 20:1) to give the target compound (40 mg, yield: 16.7%).

[0381] 6. Preparation of (S)-2-(4-methoxybenzyl)-5-((1-(3-oxo-3-(3-(trifluoromethyl)-8,9-dihydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazin-7(6H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0382]

[0383] A solution of 3-(trifluoromethyl)-6,7,8,9-tetrahydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazine (35 mg, 0.15 mmol), (S)-3-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionic acid (97 mg, 0.23 mmol), HATU (87 mg, 0.23 mmol), and DIPEA (58 mg, 0.45 mmol) in dichloromethane (10 mL) was reacted at 25 °C for 1 hour. The reaction solution was evaporated to dryness under reduced pressure, and the residue was purified by reverse-phase column chromatography (water:methanol = 1:1) to give the crude target compound (45 mg), which was used directly in the next reaction without further purification.

[0384] 7. (S)-5-((1-(3-oxo-3-(3-(trifluoromethyl)-8,9)dihydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazin-7(6H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0385]

[0386] At 0°C, 0.4 mL of TfOH was added dropwise to 4 mL of trifluoroacetic acid containing (S)-2-(4-methoxybenzyl)-5-((1-(3-oxo-3-(3-(trifluoromethyl)-8,9-dihydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazin-7(6H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (45 mg crude product). The reaction mixture was reacted at 0°C for 1 hour. The reaction mixture was then poured into a saturated sodium bicarbonate solution and extracted three times with dichloromethane. The dichloromethane layers were combined, and the solvent was removed under reduced pressure. The residue was purified by reverse-phase column chromatography (70% methanol / water system) and silica gel plate purification (ethyl acetate as the eluent) to obtain the target compound (25 mg, two-step yield: 32.4%).

[0387] Molecular formula: C 22 H 22 F6N6O3 molecular weight: 532.4 LC-MS (M / e): 532.9 (M+H) + )

[0388] 1 H-NMR(400MHz,DMSO)δ:12.43(s,1H),8.52(s,1H),8.32(s,1H),7.87(m,1H),6.50(m,1H),6.23(s,1H),4.99(s,1H), 4.90(s,1H),4.27(m,1H),4.19(m,1H),4.09(m,1H),3.97(m,2H),3.69(m,2H),3.47(m,2H),2.71(m,2H),1.11(m,3H).

[0389] Preparation Example 3: Preparation of (S)-5-((1-(3-(5-fluoro-3-(trifluoromethyl)-8,9-dihydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazin-7(6H)-yl)-3-oxopropoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 26)

[0390] 1. Preparation of 5-fluoro-3-(trifluoromethyl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one

[0391]

[0392] 3-(trifluoromethyl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (310 mg, 1.21 mmol), select F (425 mg, 1.2 mmol), acetonitrile (2.0 mL), and water (0.2 mL) were added to a microwave-safe tube. The reaction was carried out at 100 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 1:4) to give the target compound (35 mg, yield: 10.5%).

[0393] 2. Preparation of 5-fluoro-3-(trifluoromethyl)-6,7,8,9-tetrahydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazine

[0394]

[0395] At 0 °C, lithium aluminum hydride (20 mg, 0.52 mmol) was added to methyl tert-butyl ether (5 mL) containing 5-fluoro-3-(trifluoromethyl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (35 mg, 0.13 mmol), and the reaction was carried out at 60 °C for 4 hours. After the reaction was completed, water (0.5 mL) was added to quench the reaction, and C18 powder was directly mixed with the sample. The sample was purified by reverse-phase column chromatography (methanol:water = 4:1) to obtain the target compound (18 mg, yield: 54.2%).

[0396] 3. Preparation of (S)-5-((1-(3-(5-fluoro-3-(trifluoromethyl)-8,9-dihydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazin-7(6H)-yl)-3-oxopropoxy)propyl-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0397]

[0398] 5-Fluoro-3-(trifluoromethyl)-6,7,8,9-tetrahydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine (18 mg, 0.069 mmol), (S)-3-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl))amino)propoxy)propionic acid (46 mg, 0.11 mmol), HATU (40 mg, 0.11 mmol), and DIPEA (28 mg, 0.22 mmol) were added to dichloromethane (5 mL) and reacted at 29 °C for 1 hour. The C18 powder was directly mixed with the sample and purified by reverse-phase column chromatography (methanol:water = 4:1) to obtain the target compound (28 mg, yield: 60.1%).

[0399] 4. Preparation of (S)-5-((1-(3-(5-fluoro-3-(trifluoromethyl)-8,9-dihydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazin-7(6H)-yl)-3-oxopropoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0400]

[0401] At 0°C, 0.2 mL of TfOH was added dropwise to 2 mL of trifluoroacetic acid containing (S)-5-((1-(3-(5-fluoro-3-(trifluoromethyl)-8,9-dihydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazin-7(6H)-yl)-3-oxopropoxy)propyl-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (28 mg, 0.042 mmol). The reaction mixture was reacted at 0°C for 1 hour. The reaction mixture was poured into a saturated sodium bicarbonate solution and extracted three times with dichloromethane. The dichloromethane layers were combined, and the solvent was removed by vacuum distillation. The residue was purified by reverse-phase column chromatography (70% methanol / water system) and silica gel plate purification (ethyl acetate as the developing solvent) to obtain the target compound (12 mg, yield: 52.2%).

[0402] Molecular formula: C 22 H 21 F7N6O3 molecular weight: 550.4 LC-MS (M / e): 551.0 (M+H) + )

[0403] 1 H-NMR(400MHz,DMSO-d6)δ:12.46(s,1H),8.63(s,1H),8.47(s,1H),7.89(s,1H),6.26(brs,1 H),5.04-4.93(m,2H),4.29-4.00(m,5H),3.71(m,2H),3.64(m,2H),2.75(m,2H),1.14(m,3H).

[0404] Preparation Example 4: Preparation of (S)-5-((1-(3-(5-methyl-3-(trifluoromethyl)-8,9-dihydropyridino[3',2':4,5]pyrrolo[1,2-α]pyrazin-7(6H)-yl)-3-oxopropoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 27)

[0405] 1. Preparation of 3-methyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid

[0406]

[0407] 3-Bromo-5-(trifluoromethyl)pyridine-2-amine (1 g, 4.2 mmol), butyric acid (0.43 g, 4.2 mmol), anhydrous potassium phosphate (1.8 g, 8.4 mmol), magnesium sulfate (1 g, 8.4 mmol), glacial acetic acid (0.25 g, 4.2 mmol), and di(tri-tert-butylphosphine)palladium (0.87 g, 1.7 mmol) were added to DMA (10 mL), and the reaction was carried out at 140 °C for 5 h under nitrogen protection. The reaction solution was dissolved in ethyl acetate and extracted separately. The aqueous phase was collected, and the pH was adjusted to 5-6 with dilute hydrochloric acid. Ethyl acetate was added again, and the mixture was extracted three times. The organic phase was collected, dried, and evaporated to dryness. DCM was added until a solid precipitated. The solid was filtered, and the filter cake was dried under reduced pressure to give the target compound (330 mg, yield: 32.4%).

[0408] 2. Preparation of ethyl 2-methyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

[0409]

[0410] Concentrated sulfuric acid (0.5 mL) was added to anhydrous ethanol (10 mL) containing 3-methyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (300 mg, 1.2 mmol). The reaction was carried out at 85 °C for 16 hours. The pH of the reaction solution was adjusted to 7-8 with saturated sodium bicarbonate solution, and then ethyl acetate and water were added for three-way extraction. The organic phase was evaporated to dryness and then subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain the target compound (320 mg, yield 95.7%).

[0411] 3. Preparation of ethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-3-methyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid

[0412]

[0413] Ethyl 3-methyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (290 mg, 1.1 mmol) was dissolved in DMF (5 mL), and potassium tert-butoxide (134 mg, 1.2 mmol) was added at 0 °C and reacted for 30 min. Then, methyl tert-butyl-1,2,3-oxathiazole-3-carboxylate 2,2-dioxide (268 mg, 1.2 mmol) was added, and the reaction was carried out at 30 °C for 4 h. After the reaction was completed, ethyl acetate and water were added for liquid extraction, the organic phase was evaporated to dryness, and the target compound was obtained by forward separation (petroleum ether:ethyl acetate = 5:1) (152 mg, yield 34.4%).

[0414] 4. Preparation of ethyl 1-(2-aminoethyl)-3-methyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid hydrochloride

[0415]

[0416] Ethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-3-methyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (130 mg, 0.31 mmol) was dissolved in ethyl acetate (3 mL), and ethyl acetate hydrochloride solution (6 mL) was added. The reaction was carried out at 30 °C for 1 h. After the reaction was completed, the solution was evaporated to dryness to obtain the crude product (152 mg).

[0417] 5. Preparation of 5-methyl-3-(trifluoromethyl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one

[0418]

[0419] Ethyl 1-(2-aminoethyl)-3-methyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid hydrochloride was dissolved in methanol (5 mL), and potassium carbonate (179 mg, 1.3 mmol) was added. The mixture was reacted at 60 °C for 2 h. Ethyl acetate and water were added for three hydration extractions. The organic phase was evaporated to dryness and separated by forward separation (petroleum ether: ethyl acetate = 1:3) to obtain the target compound (150 mg).

[0420] 6. Preparation of 5-methyl-3-(trifluoromethyl)-6,7,8,9-tetrahydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazine

[0421]

[0422] 140 mg (0.52 mmol) of 5-methyl-3-(trifluoromethyl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one was dissolved in methyl tert-butyl ether (6 mL), and lithium aluminum hydride (119 mg, 3.1 mmol) was added. The reaction was carried out at 30 °C for 1 h. The reaction was quenched with water, evaporated to dryness, and separated by reverse C18 chromatography (water:methanol = 1:2) to give the target compound (20 mg, yield 14.6%).

[0423] 7. Preparation of (S)-2-(4-methoxybenzyl)-5-((1-(3-(5-methyl-3-(trifluoromethyl)-8,9-dihydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazin-7(6H)-yl)-3-oxopropoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0424]

[0425] A mixture of 5-methyl-3-(trifluoromethyl)-6,7,8,9-tetrahydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine (15 mg, 0.06 mmol), (S)-3-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionic acid (26 mg, 0.06 mmol), HATU (34 mg, 0.09 mmol), and DIPEA (23 mg, 0.18 mmol) in dichloromethane (5 mL) was reacted at 25 °C for 1 hour. The reaction mixture was evaporated to dryness under reduced pressure, and the residue was purified by normal-phase column chromatography (dichloromethane:methanol = 20:1) to give the product (20 mg, yield 52.9%).

[0426] 8. Preparation of (S)-5-((1-(3-(5-methyl-3-(trifluoromethyl)-8,9-dihydropyridino[3',2':4,5]pyrrolo[1,2-α]pyrazin-7(6H)-yl)-3-oxopropoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0427]

[0428] At 0°C, 0.5 mL of TfOH was added dropwise to 3 mL of trifluoroacetic acid containing (S)-2-(4-methoxybenzyl)-5-((1-(3-(5-methyl-3-(trifluoromethyl)-8,9-dihydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazin-7(6H)-yl)-3-oxopropoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (15 mg, 0.023 mmol). The reaction mixture was reacted at 0°C for 1 hour. The reaction mixture was then poured into a saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The solvent was removed under reduced pressure, and the residue was purified by reverse-phase column chromatography (water:methanol = 1:2) to give the target compound (3 mg, yield 24.6%).

[0429] Molecular formula: C 23 H 24 F6N6O3 molecular weight: 546.5 LC-MS (M / e): 547.2 (M+H) + )

[0430] 1 H-NMR(400MHz, CDCl3)δ:10.7(s,1H),8.5(s,1H),8.0(s,1H),7.6(s,1H),5.79(s,1H),4.8-5.0(d,2H),4 .3-4.5(d,2H),4.1(s,1H),3.8-4.0(d,4H),3.65(s,1H),3.5(s,1H),2.7(s,2H),2.3(s,3H),1.2(s,3H).

[0431] Preparation Example 5: Preparation of 5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-5a,6,8,9-tetrahydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazin-7(5H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 28)

[0432] 1. Preparation of tert-butyl 3-(trifluoromethyl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-7(6H)-carboxylic acid

[0433]

[0434] DMAP (122 mg, 1.0 mmol) was added to 14 mL of dichloromethane containing 3-(trifluoromethyl)-6,7,8,9-tetrahydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine (125 mg, 0.52 mmol) and (Boc)₂O (227 mg, 1.0 mmol), and the reaction was carried out at 30 °C for 20 hours. After the reaction was completed, the reaction solution was directly evaporated to dryness under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give the target compound (110 mg, yield: 62.1%).

[0435] 2. Preparation of tert-butyl 3-(trifluoromethyl)-5a,6,8,9-tetrahydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-7(5H)-carboxylic acid

[0436]

[0437] Sodium cyanoborohydride (90 mg, 1.4 mmol) was added in portions to acetic acid (10 mL) containing 3-(trifluoromethyl)-8,9-dihydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazine-7(6H)-carboxylic acid tert-butyl ester (100 mg, 0.29 mmol), and the reaction was carried out at 30 °C for 40 hours. After the reaction was completed, the acetic acid was removed under reduced pressure. The residue was dissolved in ethyl acetate, and the pH was adjusted to alkaline with saturated sodium bicarbonate solution. The ethyl acetate layer was directly evaporated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give the target compound (80 mg, yield: 79.5%).

[0438] 3. Preparation of 3-(trifluoromethyl)-5,5a,6,7,8,9-hexahydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine hydrochloride

[0439]

[0440] At 30°C, 4 mL of ethyl acetate solution containing hydrochloric acid was added to 4 mL of ethyl acetate containing 80 mg (0.23 mmol) of 3-(trifluoromethyl)-5a,6,8,9-tetrahydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazine-7(5H)-carboxylic acid tert-butyl ester (carboxylic acid tert-butyl ester). The reaction was carried out at 30°C for 3 h. After the reaction was completed, the reaction solution was directly evaporated to dryness under reduced pressure to obtain the crude product, which was used directly in the next reaction.

[0441] 4. Preparation of 2-(4-methoxybenzyl)-5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-5a,6,8,9-tetrahydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazin-7(5H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0442]

[0443] 3-(trifluoromethyl)-5,5a,6,7,8,9-hexahydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine hydrochloride (crude product from the previous step), (S)-3-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionic acid (148 mg, 1.14 mmol), HATU (433 mg, 1.14 mmol), and DIPEA (500 mg, 3.87 mmol) were added to dichloromethane (10 mL), and the reaction was carried out at 28 °C for 1 hour. After the reaction was completed, the product was purified by silica gel ablation (using pure ethyl acetate as the developing solvent) to obtain the target compound (45 mg, yield: 29.5%).

[0444] 5. Preparation of 5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-5a,6,8,9-tetrahydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazin-7(5H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0445]

[0446] At 0°C, 0.2 mL of TfOH was added dropwise to 2 mL of trifluoroacetic acid containing 45 mg (0.069 mmol) of 2-(4-methoxybenzyl)-5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-5a,6,8,9-tetrahydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazin-7(5H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (0.069 mmol). The reaction mixture was reacted at 0°C for 1 hour. The reaction mixture was then poured into a saturated sodium bicarbonate solution and extracted three times with dichloromethane. The dichloromethane layers were combined, and the solvent was removed under reduced pressure. The residue was purified by silica gel plate chromatography (using ethyl acetate as the eluent) and high-pressure HPLC (90% methanol / water system) to obtain the target compound (8 mg, yield: 21.8%).

[0447] Molecular formula: C 22 H 24 F6N6O3 molecular weight: 534.5 LC-MS (M / e): 535.2 (M+H) + )

[0448] 1 H-NMR(400MHz,DMSO-d6)δ:12.44(brs,1H),8.11(s,1H),7.90(s,1H),7.52(s,1H),6.24(s,1H),4.51-4.42(m,1H),4.15(m,1H),4.11-3.98( m,1H),3.92-3.85(m,1H),3.71(m,2H),3.51(m,2H),3.19-3.11(m,1H) ,2.99-2.85(m,2H),2.62-2.52(m,4H),2.01(m,1H),1.16-1.14(m,3H).

[0449] Preparation Example 6: Preparation of (S)-5-(methyl(1-(3-oxo-3-(3-(trifluoromethyl)-8,9-dihydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazine)-7(6H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H)-one (Compound 29)

[0450] 1、(S)-3-(2-(λ 2 Preparation of β-azine)propoxy)benzyl propionate hydrochloride

[0451]

[0452] At 25°C, 30 mL of ethyl acetate hydrochloride solution was added to (S)-3-(2-((tert-butoxycarbonyl)amino)propoxy)propionate (3.1 g, 9.2 mmol), and the reaction was continued for 1 hour. The reaction solution was evaporated to dryness under reduced pressure to obtain crude target compound (3.1 g), which was directly used in the next reaction step.

[0453] 2. Preparation of (S)-3-(2-(methylamino)propoxy)propionate benzyl ester

[0454]

[0455] At 25℃, in a solution containing (S)-3-(2-(λ) 2 A methanol solution (32 mL) of benzyl propoxy propionate hydrochloride (3.1 g crude, 9.2 mmol) was added to a 36% aqueous solution of formaldehyde (389 mg, 4.7 mmol), and the reaction was continued for 30 minutes. The reaction solution was evaporated to dryness under reduced pressure, and methanol (15 mL) and sodium cyanoborohydride (1.7 g, 27.6 mmol) were added. The reaction was continued for 30 minutes, the system was quenched with water, the organic phase was extracted with dichloromethane, and dried over anhydrous sodium sulfate to obtain a crude product of the target compound (2.0 g), which was directly used in the next step of the reaction.

[0456] 3. Preparation of (S)-3-(2-((tert-butoxycarbonyl)(methyl)amino)propoxy)propionate benzyl ester

[0457]

[0458] At 25 °C, di-tert-butyl dicarbonate (3.0 g, 13.7 mmol) and N,N-diisopropylethylamine (2.4 g, 18.6 mmol) were added to a dichloromethane solution (50 mL) of (S)-3-(2-(methylamino)propoxy)propanoate (2.0 g crude product, 9.2 mmol), and the reaction was continued for 16 hours. The reaction solution was evaporated to dryness under reduced pressure, the system was quenched with water, the organic phase was extracted with dichloromethane, dried over anhydrous sodium sulfate, the organic phase was evaporated to dryness under reduced pressure, the residue was purified by normal-phase column chromatography (ethyl acetate: petroleum ether = 1:5), the organic phase was evaporated to dryness under reduced pressure, and the residue was further purified by high-pressure reverse-phase column chromatography (acetonitrile: water = 3:5) to give the target compound (160 mg, three-step yield 4.7%).

[0459] 4. Preparation of (S)-3-(2-(methylamino)propoxy)propionate benzyl hydrochloride

[0460]

[0461] At 25°C, 10 mL of ethyl acetate solution containing hydrochloric acid was added to (S)-3-(2-((tert-butoxycarbonyl)(methyl)amino)propoxy)propionate (150 mg, 0.43 mmol), and the reaction was continued for 1 hour. The reaction solution was then evaporated to dryness under reduced pressure and used directly in the next reaction step.

[0462] 5. Preparation of benzyl(S)-3-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)(methyl)amino)propoxy)propionate

[0463]

[0464] At 25°C, 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazine-3(2H)-one (137 mg, 0.43 mmol) and N,N-diisopropylethylamine (278 mg, 2.2 mmol) were added to 10 mL of acetonitrile solution containing (S)-3-(2-(methylamino)propoxy)propionate hydrochloride (crude product, 0.43 mmol). The reaction was carried out at 25°C for 16 hours. The system was quenched with water, the organic phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness under reduced pressure. The residue was purified by normal-phase column chromatography (ethyl acetate: petroleum ether = 2:3). The organic phase was concentrated and evaporated to dryness to give the target compound (94 mg, yield 41.3%).

[0465] 6. Preparation of (S)-3-(2-((1-(4-methoxybenzyl)-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)(methyl)amino)propoxy)propionic acid

[0466]

[0467] At 25°C, palladium on carbon (30 mg) was added to a methanol solution (5 mL) of benzyl(S)-3-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)(methyl)amino)propoxy)propionate (94 mg, 0.18 mmol), and the reaction was carried out under a hydrogen atmosphere for 1 hour. The mixture was filtered, and the filtrate was concentrated and evaporated to dryness for use in the next step.

[0468] 7. Preparation of (S)-2-(4-methoxybenzyl)-5-(methyl(1-(3-oxo-3-(3-(trifluoromethyl)-8,9-dihydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazin-7(6H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0469]

[0470] In a solution of (S)-3-(2-((1-(4-methoxybenzyl)-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)(methyl)amino)propoxy)propionic acid (crude, 0.18 mmol) in dichloromethane (5 mL), 3-(trifluoromethyl)-6,7,8,9-tetrahydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazine (53 mg, 0.22 mmol), HATU (103 mg, 0.27 mmol), and DIEA (70 mg, 0.54 mmol) were added. The mixture was reacted at 25 °C for 1 h. The system was quenched with water, the organic phase was extracted with dichloromethane, dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness under reduced pressure. The residue was purified by normal-phase column chromatography (ethyl acetate: petroleum ether = 2:1) to give the target compound (100 mg, yield 85.2%).

[0471] 8. Preparation of (S)-5-(methyl(1-(3-oxo-3-(3-(trifluoromethyl)-8,9-dihydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazine)-7(6H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H)-one

[0472]

[0473] At 25 °C, trifluoromethanesulfonic acid (0.2 mL) was added to (S)-2-(4-methoxybenzyl)-5-(methyl(1-(3-oxo-3-(3-(trifluoromethyl)-8,9-dihydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazin-7(6H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (20 mg, 0.030 mmol) in 2 mL of trifluoroacetic acid, and the reaction was continued for 15 minutes. The system was quenched with saturated sodium bicarbonate solution, extracted with a mixed solvent of dichloromethane / methanol (10:1), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by high-pressure reversed-phase column chromatography (acetonitrile / water = 3:2) to give the target compound (3.9 mg, yield 23.8%).

[0474] Molecular formula: C 23 H 24 F6N6O3 molecular weight: 546.5 LC-MS (M / e): 547.2 (M+H) + )

[0475] 1H-NMR(400MHz, CDCl3)δ:10.35-10.15(m,1H),8.55-8.52(m,1H),8.11(s,1H),7.76(m,1H),6.39(s,1H),5.02(s,1H),4.90(s,1H) ),4.38-4.25(m,2H),4.10-3.90(m,1H),3.85-3.75(m,2H),3.65-3.40(m,4H),2.91(s,3H),3.65-3.55(m,2H),1.40-1.20(m,3H).

[0476] Preparation Example 7: Preparation of (S)-4-(trifluoromethyl)-5-((1-(3-(3-(trifluoromethyl)-8,9-dihydropyridino[3',2':4,5]pyrrolo[1,2-a])pyrazin-7(6H)-yl)propoxy)propyl-2-yl)amino)pyridazin-3(2H)-one (compound 30)

[0477] 1. Preparation of (S)-5-((1-(3-hydroxypropoxy)propyl-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazine-3(2H)-one

[0478]

[0479] (S)-3-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)benzyl propionate (450 mg, 0.87 mmol) was dissolved in ethanol (10 mL), and sodium borohydride (131 mg, 3.5 mmol) and calcium chloride (384 mg, 3.5 mmol) were added. The reaction mixture was reacted at 25 °C for 4 h. The reaction solution was evaporated to dryness under reduced pressure, and the residue was purified by column chromatography (PE / EA = 0-70%) to give the target compound (320 mg, yield 88.9%).

[0480] 2. (S)-3-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4-yl)amino)propoxy)propanal

[0481]

[0482] (S)-5-((1-(3-hydroxypropoxy)propyl-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazine-3(2H)-one (160 mg, 0.38 mmol) was dissolved in dichloromethane (10 mL), and DMP (245 mg, 0.58 mmol) was added. The reaction mixture was reacted at 25 °C for 4 h. The reaction solution was evaporated to dryness under reduced pressure, and the residue was purified by column chromatography (PE / EA = 0-70%) to give the target compound (140 mg, yield 87.9%).

[0483] 3. (S)-2-(4-methoxybenzyl)-4-(trifluoromethyl)-5-((1-(3-(3-(trifluoromethyl)-8,9-dihydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazin-7(6H)-yl)propoxy)propyl-2-yl)amino)pyridazin-3(2H)-one

[0484]

[0485] (S)-3-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanal (140 mg, 0.34 mmol) was dissolved in dichloromethane (5 mL), and 3-(trifluoromethyl)-6,7,8,9-tetrahydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazine (82 mg, 0.34 mmol), sodium triacetoxyborohydride (143 mg, 0.68 mmol), and acetic acid (42 mg, 0.68 mmol) were added. The mixture was reacted at 25 °C for 1 h. The reaction solution was washed with water and extracted with dichloromethane to obtain the target compound (120 mg), which was used directly in the next step.

[0486] 4, (S)-4-(trifluoromethyl)-5-((1-(3-(3-(trifluoromethyl)-8,9-dihydropyridino[3',2':4,5]pyrrolo[1,2-a])pyrazin-7(6H)-yl)propoxy)propyl-2-yl)amino)pyridazin-3(2H)-one

[0487]

[0488] At 25°C, 0.5 mL of TfOH was added to (S)-2-(4-methoxybenzyl)-4-(trifluoromethyl)-5-((1-(3-(3-(trifluoromethyl)-8,9-dihydropyridino[3',2':4,5])pyrrolo[1,2-a]pyrazin-7(6H)-yl)propoxy)propyl-2-yl)amino)pyridazin-3(2H)-one (110 mg, 0.17 mmol) in trifluoroacetic acid, and the reaction was carried out at 25°C for 15 minutes. The reaction solution was poured into a saturated sodium bicarbonate solution, extracted three times with dichloromethane, and the dichloromethane layers were combined. The solvent was removed under reduced pressure, and the residue was purified by reverse-phase column chromatography (50% acetonitrile / water system) to give the target compound (7 mg, yield 6.8%).

[0489] Molecular formula: C 22 H 24 F6N6O2 molecular weight: 518.5 LC-MS (M / e): 519.2 (M+H) + )

[0490] 1 H-NMR(400MHz,DMSO-d6)δ:12.45(s,1H),8.49(s,1H),8.29(s,1H),7.94(s,1H),6.39(s,1H),6.27-6.30(m,1H),4.14- 4.17(m,3H),3.77(s,2H),3.54-3.48(m,4H),3.48-3.41(m,2H)2.90-2.87(m,2H),1.70-1.74(m,2H),1.11-1.22(m,3H).

[0491] Preparation Example 8: Preparation of (S)-5-((1-(3-oxo-3-(8-(trifluoromethyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 31)

[0492] 1. Preparation of ethyl 5-(trifluoromethyl)-1H-indole-2-carboxylic acid

[0493]

[0494] Concentrated sulfuric acid (0.5 mL) was added to anhydrous ethanol (15 mL) containing 5-(trifluoromethyl)-1H-indole-2-carboxylic acid (500 mg, 2.2 mmol). The reaction was carried out at 85 °C for 16 hours. The pH of the reaction solution was adjusted to 7-8 with saturated sodium bicarbonate solution, and then ethyl acetate and water were added for three-way extraction. The organic phase was evaporated to dryness and then subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 6:1) to obtain the target compound (540 mg, yield 96.2%).

[0495] 2. Preparation of ethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-5-(trifluoromethyl)-1H-indole-2-carboxylic acid

[0496]

[0497] Ethyl 5-(trifluoromethyl)-1H-indole-2-carboxylate (524 mg, 2.0 mmol) was dissolved in DMF (15 mL), and potassium tert-butoxide (336 g, 3.0 mmol) was added at 0°C and reacted for 30 minutes. Then, methyl tert-butyl-1,2,3-oxathiazole-3-carboxylate 2,2-dioxide (580 mg, 2.6 mmol) was added, and the reaction was carried out at 25°C for 1 hour. After the reaction was completed, ethyl acetate and water were added for liquid extraction, the organic phase was evaporated to dryness, and the product was obtained by forward separation (PE:EA = 3:1) (780 mg, yield 95.6%).

[0498] 3. Preparation of ethyl 1-(2-aminoethyl)-5-(trifluoromethyl)-1H-indole-2-carboxylic acid hydrochloride

[0499]

[0500] Ethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-5-(trifluoromethyl)-1H-indole-2-carboxylic acid (780 mg, 1.9 mmol) was dissolved in EA (6 mL), and ethyl acetate hydrochloride solution (30 mL) was added. The reaction was carried out at 25 °C for 1 h. After the reaction was completed, the solution was evaporated to dryness and used directly for the next reaction.

[0501] 4. Preparation of 8-(trifluoromethyl)-3,4-dihydropyrazino[1,2-a]indole-1(2H)-one

[0502]

[0503] Ethyl 1-(2-aminoethyl)-5-(trifluoromethyl)-1H-indole-2-carboxylic acid hydrochloride was dissolved in methanol (20 mL), and potassium carbonate (787 mg, 5.7 mmol) was added. The mixture was reacted at 50 °C for 2 h. EA was added and the mixture was extracted three times with water. The organic phase was evaporated to dryness and separated by forward separation (EA = 100%) to obtain the target compound (470 mg, two-step yield: 94.9%).

[0504] 5. Preparation of 8-(trifluoromethyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole

[0505]

[0506] 200 mg (0.79 mmol) of 8-(trifluoromethyl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one was dissolved in methyl tert-butyl ether (10 mL), and lithium aluminum hydride (180 mg, 4.7 mmol) was added. The reaction was carried out at 60 °C for 4 h. The mixture was quenched with water, evaporated to dryness, and separated by reverse C18 chromatography (water:methanol = 1:4) to give the target compound (140 mg, yield 74.1%).

[0507] 6. Preparation of (S)-2-(4-methoxybenzyl)-5-((1-(3-oxo-3-(8-(trifluoromethyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0508]

[0509] 8-(trifluoromethyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole (73 mg, 0.30 mmol), (S)-3-(2-(((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionic acid (142 mg, 0.33 mmol), HATU (171 mg, 0.45 mmol), and DIPEA (116 mg, 0.90 mmol) were added to dichloromethane (10 mL), and the reaction was carried out at 25 °C for 30 min. The system was quenched with water, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by forward evaporation (ethyl acetate: petroleum ether = 7:3) to give the target compound (130 mg, yield 65.6%).

[0510] 7. Preparation of (S)-5-((1-(3-oxo-3-(8-(trifluoromethyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0511]

[0512] At 25°C, 0.5 mL of TfOH was added dropwise to (S)-2-(4-methoxybenzyl)-5-((1-(3-oxo-3-(8-(trifluoromethyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (130 mg, 0.20 mmol) in 2 mL of trifluoroacetic acid, and the reaction was carried out at 25°C for 15 minutes. The reaction solution was poured into a saturated sodium bicarbonate solution and extracted three times with dichloromethane. The dichloromethane layers were combined, the solvent was removed under reduced pressure, and the residue was purified by normal-phase column chromatography (ethyl acetate: petroleum ether = 9:13) to give the target compound (11.2 mg, yield 10.6%).

[0513] Molecular formula: C 23 H 23 F6N5O3 molecular weight: 531.5 LC-MS (M / e): 532.2 (M+H) + )

[0514] 1 H-NMR(400MHz,DMSO-d6)δ:12.48(s,1H),7.91-7.88(m,2H),7.60(d,J=8.0Hz,1H),7.40(d,J=8.0Hz,1H),6.49(s,1H),6.35- 6.26(m,1H),4.96-4.88(m,2H),4.30-3.90(m,5H),3.80-3.65(m,2H),3.55-3.40(m,2H),2.80-2.5(m,2H),1.20-1.05(m,3H).

[0515] Preparation Example 9: Preparation of (S)-5-((1-(3-oxo-3-(8-(trifluoromethyl)-3,4-dihydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazin-7(6H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 32) 1. Preparation of 4-methyl-5-nitro-2-(trifluoromethyl)pyridine

[0516]

[0517] 2-Bromo-4-methyl-5-nitropyridine (10 g, 46.1 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (13.3 g, 69.2 mmol), and cuprous iodide (8.8 g, 46.2 mmol) were added to N,N-dimethylformamide (100 mL). The reaction was carried out at 115 °C for 16 h under nitrogen protection. The system was quenched with aqueous ammonium chloride solution, ammonia was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 24:1) to give the target compound (5.2 g, yield: 54.8%).

[0518] 2. Preparation of ethyl 5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

[0519]

[0520] Diethyl oxalate (8.3 g, 56.8 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (4.4 g, 28.9 mmol) were added to 4-methyl-5-nitro-2-(trifluoromethyl)pyridine (2.5 g, 12.1 mmol). The mixture was stirred at 25 °C for 4 hours, concentrated to dryness, and then acetic acid (50 mL) was added. The mixture was heated to 60 °C, and iron powder (1.4 g, 25.1 mmol) was added. The temperature was then raised to 70 °C and the reaction was carried out for 16 hours. The system was quenched with water, filtered, and the filter cake was washed three times with water. The filter cake was then dissolved in ethyl acetate, filtered, and the filtrate was concentrated to dryness to obtain the crude target compound (2.9 g), which was directly used in the next reaction.

[0521] 3. Preparation of ethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

[0522]

[0523] Ethyl 5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (2.9 g, 11.2 mmol) was dissolved in DMF (80 mL), and potassium tert-butoxide (1.9 g, 17.0 mmol) was added at 0°C. The reaction was allowed to proceed for 30 minutes, followed by the addition of methyl tert-butyl-1,2,3-oxathiazole-3-carboxylate 2,2-dioxide (3.2 g, 14.3 mmol), and the reaction was allowed to proceed at 25°C for 1 h. After the reaction was complete, ethyl acetate and water were added for liquefaction extraction, the organic phase was evaporated to dryness, and the solution was separated by normal-phase column chromatography (petroleum ether: ethyl acetate = 3:1) to give the target compound (2.9 g, two-step yield 59.6%).

[0524] 4. Preparation of ethyl 1-(2-aminoethyl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid hydrochloride

[0525]

[0526] Ethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (1.0 g, 2.5 mmol) was dissolved in ethyl acetate (5 mL), and ethyl acetate hydrochloride solution (20 mL) was added. The reaction was carried out at 25 °C for 1 h. After the reaction was completed, the solution was evaporated to dryness, and the product was used directly in the next reaction step.

[0527] 5. Preparation of 8-(trifluoromethyl)-3,4-dihydropyrido[4',3':4,5]pyrrolo[1,2-a]pyrazin-1(2H)-one

[0528]

[0529] Ethyl 1-(2-aminoethyl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid hydrochloride was dissolved in methanol (20 mL), and potassium carbonate (1.0 g, 7.2 mmol) was added. The mixture was reacted at 25 °C for 16 h. Ethyl acetate and water were added, and the mixture was extracted three times by separation. The organic phase was evaporated to dryness and separated by normal-phase column chromatography (dichloromethane:methanol = 10:1) to give the target compound (590 mg, two-step yield: 92.8%).

[0530] 6. Preparation of 8-(trifluoromethyl)-1,2,3,4-tetrahydropyridino[4',3':4,5]pyrrolo[1,2-a]pyrazine

[0531]

[0532] 8-(trifluoromethyl)-3,4-dihydropyrido[4',3':4,5]pyrrolo[1,2-a]pyrazin-1(2H)-one (100 mg, 0.39 mmol) was dissolved in methyl tert-butyl ether (10 mL), and lithium aluminum hydride (89 mg, 2.3 mmol) was added. The reaction was carried out at 25 °C for 4 h. The mixture was quenched with water, evaporated to dryness, and separated by reverse-phase C18 chromatography (water:methanol = 1:1) to give the target compound (30 mg, yield 31.7%).

[0533] 7. Preparation of (S)-2-(4-methoxybenzyl)-5-((1-(3-oxo-3-(8-(trifluoromethyl)-3,4-dihydropyridino[4',3':4,5]pyrrolo[1,2-a]pyrazin-2(1H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0534]

[0535] 8-(trifluoromethyl)-1,2,3,4-tetrahydropyrido[4',3':4,5]pyrrolo[1,2-a]pyrazine (30 mg, 0.12 mmol), (S)-3-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionic acid (52 mg, 0.12 mmol), HATU (68 mg, 0.18 mmol), and DIPEA (47 mg, 0.36 mmol) were added to dichloromethane (10 mL), and the reaction was carried out at 25 °C for 30 min. The reaction solution was evaporated to dryness under reduced pressure, and the residue was purified by TLC (ethyl acetate = 100%) to give the target compound (30 mg, yield 38.6%).

[0536] 8. (S)-5-((1-(3-oxo-3-(8-(trifluoromethyl)-3,4-dihydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazin-7(6H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0537]

[0538] At 25°C, TfOH (0.2 mL) was added dropwise to a solution of trifluoroacetic acid (2 mL) containing ((S)-2-(4-methoxybenzyl)-5-((1-(3-oxo-3-(8-(trifluoromethyl)-3,4-dihydropyridino[4',3':4,5]pyrrolo[1,2-a]pyrazin-2(1H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (30 mg, 0.046 mmol). The reaction was carried out at 25°C for 15 minutes. The reaction solution was poured into a saturated sodium bicarbonate solution and extracted three times with dichloromethane. The dichloromethane layers were combined, and the solvent was removed under reduced pressure. The residue was purified by silica gel preparative plate (ethyl acetate as the developing solvent) and reverse-phase column purification (50% acetonitrile / water system) to obtain the target compound (4.4 mg, yield 18.0%).

[0539] Molecular formula: C 22 H 22 F6N6O3 molecular weight: 532.4 LC-MS (M / e): 532.9 (M+H) + )

[0540] 1H-NMR(400MHz,CD3OD)δ:8.82-8.80(m,1H),7.99-7.87(m,2H),6.60(s,1H),5.11(s,1H),5.06-4.95(m,2H),4. 44-4.37(m,3H),4.20-4.05(m,3H),3.86-3.82(m,2H),3.70-3.50(m,2H),2.84-2.81(m,2H),1.31-1.16(m,3H).

[0541] Preparation Example 10: Preparation of (S)-5-((1-(3-oxo-3-(2-(trifluoromethyl)-6,7-dihydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazin-8(9H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 33)

[0542] 1. Preparation of 2-iodo-6-(trifluoromethyl)pyridine-3-amine

[0543]

[0544] 6-(trifluoromethyl)pyridine-3-amine (9.0 g, 55.5 mmol), Ag₂SO₄ (17.3 g, 55.5 mmol), and iodine (28.2 g, 111.1 mmol) were added to ethanol (100 mL). The reaction was carried out at 25 °C for 2 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to give the target compound (13.0 g, yield: 81.3%).

[0545] 2. Preparation of 5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid

[0546]

[0547] 2-Iodo-6-(trifluoromethyl)pyridine-3-amine (6.0 g, 20.8 mmol) was dissolved in DMF (100 mL), and palladium acetate (2.4 g, 10.4 mmol), pyruvate (5.5 g, 62.5 mmol), and triethylenediamine (7.0 g, 62.5 mmol) were added. The mixture was stirred at 130 °C for 4 hours, cooled, and the reaction solution was quenched with 1 M NaOH aq. Extracted with ethyl acetate. The organic phase was discarded, and the pH of the aqueous phase was adjusted to 1 with 1 M HCl aq. Extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude target compound (3.2 g), which was directly used in the next step.

[0548] Preparation of ethyl 3,5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylate

[0549]

[0550] 5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (3.0 g, 13.0 mmol) was dissolved in EtOH (20 mL), and concentrated sulfuric acid (1 mL) was added. After the reaction was completed, the mixture was extracted with ethyl acetate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to give the target compound (2.1 g, yield: 62.4%).

[0551] 4. Preparation of ethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylate

[0552]

[0553] Ethyl 5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (2.4 g, 9.3 mmol) was dissolved in DMF (20 mL), and potassium tert-butoxide (1.6 g, 13.9 mmol) was added at 0°C and reacted for 30 min. Then, methyl tert-butyl-1,2,3-oxathiazole-3-carboxylate 2,2-dioxide (2.5 g, 11.1 mmol) was added, and the reaction was carried out at 25°C for 1 h. After the reaction was completed, EA was added and water was extracted and separated. The organic phase was evaporated to dryness and separated by normal-phase column chromatography (PE:EA = 3:1) to obtain the target compound (2.4 g, yield 71.3%).

[0554] 5. Preparation of ethyl 1-(2-aminoethyl)-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid hydrochloride

[0555]

[0556] Ethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (2.2 g, 5.5 mmol) was dissolved in EA (5 mL), and ethyl acetate hydrochloride solution (20 mL) was added. The reaction was carried out at 25 °C for 1 h. After the reaction was completed, the crude target compound was obtained by rotary evaporation and used directly in the next reaction.

[0557] Preparation of 6,2-(trifluoromethyl)-7,8-dihydropyrido[2',3':4,5]pyrrolo[1,2-a]pyrazin-9(6H)-one

[0558]

[0559] 1-(2-aminoethyl)-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester hydrochloride (1.2 g, 3.6 mmol) was dissolved in methanol (20 mL), and potassium carbonate (1.4 g, 10.7 mmol) was added. The mixture was reacted at 25 °C for 2 h. EA was added and the mixture was extracted three times with water. The organic phase was evaporated to dryness and separated by normal-phase column chromatography (PE:EA = 0-70%) to obtain the target compound (240 mg, two-step yield: 26.4%).

[0560] 7. Preparation of 2-(trifluoromethyl)-6,7,8,9-tetrahydropyridino[2',3':4,5]pyrrolo[1,2-a]pyrazine

[0561]

[0562] 2-(trifluoromethyl)-7,8-dihydropyrido[2',3':4,5]pyrrolo[1,2-a]pyrazin-9(6H)-one (104 mg, 0.41 mmol) was dissolved in methyl tert-butyl ether (10 mL), and lithium aluminum hydride (77 mg, 2.0 mmol) was added. The reaction was carried out at 25 °C for 6 h. The mixture was quenched with water, evaporated to dryness, and separated by reverse-phase C18 chromatography (water:methanol = 0-70%) to give the target compound (42 mg, yield 42.7%).

[0563] 8. Preparation of (S)-2-(4-methoxybenzyl)-5-((1-(3-oxo-3-(2-(trifluoromethyl)-6,7-dihydropyridino[2',3':4,5]pyrrolo[1,2-a]pyrazin-8(9H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0564]

[0565] 2-(trifluoromethyl)-6,7,8,9-tetrahydropyrido[2',3':4,5]pyrrolo[1,2-a]pyrazine (30 mg, 0.12 mmol), (S)-3-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionic acid (57 mg, 0.13 mmol), HATU (57 mg, 0.15 mmol), and DIPEA (48 mg, 0.37 mmol) were added to dichloromethane (10 mL) and reacted at 25 °C for 30 min. The reaction solution was evaporated to dryness under reduced pressure, and the residue was purified by TLC (ethyl acetate = 100%) to give the target compound (40 mg, yield 49.3%).

[0566] 9. (S)-5-((1-(3-oxo-3-(2-(trifluoromethyl)-6,7-dihydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazin-8(9H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0567]

[0568] At 25 °C, (S)-2-(4-methoxybenzyl)-5-((1-(3-oxo-3-(2-(trifluoromethyl)-6,7-dihydropyridino[2',3':4,5]pyrrolo[1,2-a]pyrazin-8(9H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (30 mg, 0.046 mmol) was dissolved in trifluoroacetic acid (3 mL), and TfOH (0.3 mL) was added. The reaction mixture was reacted at 25 °C for 15 minutes. The reaction mixture was poured into a saturated sodium bicarbonate solution and extracted three times with dichloromethane. The dichloromethane layers were combined, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase column chromatography (50% acetonitrile / water system) to give the target compound (22 mg, yield 89.9%).

[0569] Molecular formula: C 22 H 22 F6N6O3 molecular weight: 532.4 LC-MS (M / e): 532.9 (M+H) + )

[0570] 1 H-NMR(400MHz,CD3OD)δ:8.82-8.80(m,1H),7.99-7.87(m,2H),6.60(s,1H),5.11(s,1H) ,5.06-4.95(m,2H),4.44-4.37(m,3H),4.20-4.05(m,3H),3.86-3.82(m,2H),3.70-3.50 (m,2H),2.84-2.81(m,2H),1.31-1.16(m,3H).

[0571] Preparation Example 11: Preparation of (S)-5-((1-(3-(5-ethyl-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrolo[1,2-a]pyrazin-7(6H)-yl)-3-oxopropoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 36)

[0572] 1. Preparation of 3-ethyl-5-(trifluoromethyl)-1H-pyrrole[2,3-b]pyridine-2-carboxylic acid

[0573]

[0574] Under N2 protection, DMA (40 mL) containing 3-bromo-5-(trifluoromethyl)pyridine-2-amine (1.0 g, 4.1 mmol), Pd(tBu3P)2 (2.1 g, 4.1 mmol), pentylene acid (1.4 g, 12.1 mmol), potassium phosphate (2.6 g, 12.2 mmol), magnesium sulfate (2.5 g, 20.8 mmol), and acetic acid (738 mg, 12.3 mmol) was reacted at 140 °C for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was poured into water. The mixture was extracted three times with ethyl acetate, and the combined ethyl acetate layers were washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (water:methanol = 1:5) to give the target compound (710 mg, yield: 66.1%).

[0575] 2. Preparation of ethyl 3-ethyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

[0576]

[0577] The reaction mixture, containing 710 mg (2.7 mmol) of 3-ethyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid and 2 mL of concentrated sulfuric acid in 10 mL of anhydrous ethanol, was reacted at 80 °C for 8 hours. After the reaction was complete, most of the solvent was removed under reduced pressure. The remaining reaction mixture was diluted with ethyl acetate, and the pH was adjusted to approximately 8 with saturated sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate, and the combined ethyl acetate layers were washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (water:methanol = 1:6) to give the target compound (400 mg, yield: 50.9%).

[0578] 3. Preparation of ethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-3-ethyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid

[0579]

[0580] At 0°C, potassium tert-butoxide (191 mg, 1.7 mmol) was added in portions to 20 mL of DMF containing ethyl 3-ethyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ester (400 mg, 1.4 mmol). After stirring for 30 minutes, tert-butyl 1,2,3-oxathiazolidin-3-carboxylic acid ester 2,2-dioxide (335 mg, 1.5 mmol) was added, and the reaction was carried out at 30°C for 1 hour. After the reaction was completed, the reaction solution was poured into water and extracted three times with ethyl acetate. The ethyl acetate layers were combined, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give the target compound (445 mg, yield: 74.2%).

[0581] 4. Preparation of ethyl 1-(2-aminoethyl)-3-ethyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid hydrochloride

[0582]

[0583] At 30°C, 4 mL of ethyl hydrochloride solution was added to 4 mL of ethyl acetate containing 150 mg (0.35 mmol) of 1-(2-((tert-butoxycarbonyl)amino)ethyl)-3-ethyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester (30°C) and reacted at 30°C for 3 h. After the reaction was complete, the reaction solution was directly evaporated to dryness under reduced pressure to obtain the crude product, which was then used directly in the next reaction.

[0584] 5. Preparation of 5-ethyl-3-(trifluoromethyl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one

[0585]

[0586] After dissolving the crude product from the previous step in methanol (5 mL), potassium carbonate (276 mg, 2.0 mmol) was added, and the reaction was carried out at 30 °C for 2 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase column chromatography (methanol:water = 4:1) to give the target compound (98 mg, combined yield of the two steps: 99.0%).

[0587] 6. Preparation of 5-ethyl-3-(trifluoromethyl)-6,7,8,9-tetrahydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazine

[0588]

[0589] At 0 °C, lithium aluminum hydride (53 mg, 1.4 mmol) was added to methyl tert-butyl ether (10 mL) containing 5-ethyl-3-(trifluoromethyl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (98 mg, 0.35 mmol), and the reaction was carried out at 60 °C for 8 hours. After the reaction was completed, water (0.5 mL) was added to quench the reaction, and C18 powder was directly mixed with the sample. The mixture was purified by reverse-phase column chromatography (methanol:water = 2:1) to obtain the target compound (60 mg, yield: 64.4%).

[0590] 7. Preparation of (S)-5-((1-(3-(5-ethyl-3-(trifluoromethyl)-8,9-dihydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazin-7(6H)-yl)-3-oxopropoxy)propyl-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0591]

[0592] A mixture of 5-ethyl-3-(trifluoromethyl)-6,7,8,9-tetrahydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine (60 mg, 0.22 mmol), (S)-3-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionic acid (112 mg, 0.26 mmol), HATU (125 mg, 0.33 mmol), and DIPEA (85 mg, 0.66 mmol) in dichloromethane (10 mL) was reacted at 29 °C for 1 hour. The mixture was then directly mixed with C18 powder and purified by reverse-phase column chromatography (methanol:water = 4:1) to obtain the crude target compound (110 mg).

[0593] 8. Preparation of (S)-5-((1-(3-(5-ethyl-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrolo[1,2-a]pyrazin-7(6H)-yl)-3-oxopropoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0594]

[0595] At 0°C, 0.4 mL of TfOH was added dropwise to 4 mL of trifluoroacetic acid containing (S)-5-((1-(3-(5-ethyl-3-(trifluoromethyl)-8,9-dihydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazin-7(6H)-yl)-3-oxopropoxy)propyl-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (110 mg crude product). The reaction mixture was reacted at 0°C for 1 hour. The reaction mixture was then poured into a saturated sodium bicarbonate solution and extracted three times with dichloromethane. The dichloromethane layers were combined, and the solvent was removed under reduced pressure. The residue was purified by reverse-phase column chromatography (70% methanol / water system) and silica gel plate purification (ethyl acetate as the eluent) to obtain the target compound (40 mg, combined yield of two steps: 32.0%).

[0596] Molecular formula: C 24 H 26 F6N6O3 molecular weight: 560.5 LC-MS (M / e): 561.3 (M+H) + )

[0597] 1 H-NMR(400MHz,DMSO)δ:12.45(s,1H),8.52(s,1H),8.35(s,1H),7.90(s,1H),6.23(brs,1H),4.95-4.87(m,2H),4.26 (m,1H),4.19-4.05(m,2H),3.98(m,2H),3.72(m,2H),3.50(m,2H),2.73(m,4H),1.23-1.18(m,3H),1.16-0.86(m,3H).

[0598] Preparation Example 12: Preparation of 5-(((S)-1-(3-(((R)-9-methyl-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazin-7(6H)-yl)-3-oxopropoxy)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 45)

[0599] 1. Preparation of (R)-1-(1-((tert-butoxycarbonyl)amino)propane-2-yl)-5-(trifluoromethyl)-1H-pyrrole[2,3-b]pyridine-2-carboxylic acid ethyl ester

[0600]

[0601] Ethyl 5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (1.0 g, 3.9 mmol) was dissolved in DMF (10 mL), and potassium tert-butoxide (652 mg, 5.8 mmol) was added at 25 °C and reacted for 30 min. Then, tert-butyl(S)-5-methyl-1,2,3-oxothiazolidin-3-carboxylate 2,2-dioxide (919 mg, 3.9 mmol) was added, and the reaction was carried out at 25 °C for 2 h. After the reaction was completed, EA and water were added for liquid extraction, the organic phase was evaporated to dryness, and the target compound was obtained by normal phase column chromatography (PE:EA = 0-30%) (910 mg, yield 56.7%).

[0602] 2. Preparation of (R)-1-(1-aminopropane-2-yl)-5-(trifluoromethyl)-1H-pyrrole[2,3-b]pyridine-2-carboxylic acid ethyl ester

[0603]

[0604] Ethyl (R)-1-(1-((tert-butoxycarbonyl)amino)propane-2-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (910 mg, 2.2 mmol) was added to ethyl acetate hydrochloride solution (20 mL), and the reaction was carried out at 25 °C for 2 h. After the reaction was completed, the solution was evaporated to dryness to obtain the target compound (750 mg).

[0605] 3. Preparation of (R)-9-methyl-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazin-6(7H)-one

[0606]

[0607] Ethyl (R)-1-(1-aminopropane-2-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (750 mg, 2.1 mmol) was dissolved in methanol (10 mL), and potassium carbonate (890 mg, 6.4 mmol) was added. The mixture was reacted at 25 °C for 2 h. DCM was added and the mixture was extracted three times with water. The organic phase was evaporated to dryness to give the target compound (500 mg, yield 86.9%).

[0608] 4. Preparation of (R)-9-methyl-3-(trifluoromethyl)-6,7,8,9-tetrahydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine

[0609]

[0610] (R)-9-methyl-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazin-6(7H)-one (500 mg, 1.9 mmol) was dissolved in THF (5 mL), and lithium aluminum hydride (212 mg, 5.6 mmol) was added. The reaction was carried out at 25 °C for 1 h. The reaction was quenched with water and evaporated to dryness to give the target compound (400 mg, yield 84.4%).

[0611] 5. Preparation of 2-(4-methoxybenzyl)-5-(((S)-1-(3-(((R)-9-methyl-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazin-7(6H)-yl)-3-oxopropoxy)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0612]

[0613] A solution of acetonitrile (5 mL) containing (R)-9-methyl-3-(trifluoromethyl)-6,7,8,9-tetrahydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine (100 mg, 0.39 mmol), (S)-3-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionic acid (168 mg, 0.39 mmol), HATU (447 mg, 0.24 mmol), and DIPEA (151 mg, 1.2 mmol) was reacted at 25 °C for 4 hours. After the reaction was complete, the target compound (70 mg, yield: 26.7%) was obtained by silica gel column chromatography (PE:EA = 0-100%).

[0614] 6. Preparation of 5-(((S)-1-(3-(((R)-9-methyl-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazin-7(6H)-yl)-3-oxopropoxy)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0615]

[0616] TfOH (0.5 mL) was added dropwise to trifluoroacetic acid (5 mL) containing 2-(4-methoxybenzyl)-5-(((S)-1-(3-(((R)-9-methyl-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazin-7(6H)-yl)-3-oxopropoxy)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (70 mg, 0.10 mmol), and the reaction was carried out at 25 °C for 0.5 h. The reaction solution was poured into a saturated sodium bicarbonate solution and extracted three times with dichloromethane and isopropanol. The dichloromethane layers were combined, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA = 0-100%) to give the target compound (51 mg, yield: 88.9%).

[0617] Molecular formula: C 23 H 24 F6N6O3 molecular weight: 546.5 LC-MS (M / e): 547.2 (M+H) + )

[0618] 1 H-NMR(400MHz,CD3Cl)δ:11.15(s,1H),8.54(s,1H),8.10(s,1H),7.67-7.64(m,1H),6.36(s,1H),5.81(s,1H),5.58-5.54(m,1H),5.0 0(s,1H),4.81-4.73(m,1H),4.52-4.41(m,1H),3.90-3.82(m,3H),3.72-3.68(m,2H),3.39-3.36(m,1H),2.82-2.73(m,2H),1.55-1.48 (m,3H),1.35-1.22(m,3H).

[0619] Preparation Example 13: Preparation of 5-(((S)-1-(3-(((R)-5-ethyl-9-methyl-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazin-7(6H)-yl)-3-oxypropoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 47)

[0620] 1. (R)-1-(1-((tert-butyloxycarbonyl)-λ 2 Preparation of ethyl pyrrolo[2,3-b]pyridine-2-carboxylic acid (-nitro)propane-2-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid

[0621]

[0622] Ethyl 5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (5 g, crude) was dissolved in DMF (50 mL). Potassium tert-butoxide (3.3 g, 29.1 mmol) was added at 0 °C. After 0.5 h, tert-butyl(S)-5-methyl-1,2,3-oxothiazolidin-3-carboxylate 2,2-dioxide (4.6 g, 19.4 mmol) was added. The reaction was carried out at 25 °C for 4 h. The reaction was detected by LCMS and the reaction solution was quenched with water. The solution was extracted with EA, the organic phase was evaporated to dryness, and the target compound (4.9 g) was obtained by silica gel column chromatography (EA:PE = 1:4).

[0623] 2. Preparation of (R)-1-(1-aminopropane-2-yl)-5-(trifluoromethyl)-1H-pyrrole[2,3-b]pyridine-2-carboxylic acid ethyl ester hydrochloride

[0624]

[0625] (R)-1-(1-((tert-Butoxycarbonyl)-λ 2 Preparation of ethyl pyrrolo[2,3-b]pyridine-2-carboxylate (4.9 g, 11.8 mmol) was dissolved in HCl / dioxane (4 M) solution (100 mL) and reacted at 25 °C for 4 h. The reaction was completed by LCMS. The reaction solution was evaporated to dryness and used directly for the next step of the reaction.

[0626] 3. Preparation of (R)-9-methyl-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazin-6(7H)-one

[0627]

[0628] (R)-1-(1-aminopropan-2-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester hydrochloride (crude product, 11.8 mmol) was dissolved in methanol (100 mL), potassium carbonate (6.5 g, 47.2 mmol) was added, and the reaction was carried out at 25 °C for 4 h. The reaction was detected by LCMS to be complete. The reaction solution was evaporated to dryness, diluted with dichloromethane, washed with water, and the organic phase was evaporated to dryness to give the target compound (2.8 g, yield 88.1%).

[0629] 4. Preparation of (R)-9-methyl-3-(trifluoromethyl)-6,7,8,9-tetrahydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine

[0630]

[0631] (R)-9-methyl-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazin-6(7H)-one (2.7 g, 10.0 mmol) was dissolved in methyl tert-butyl ether (50 mL), and the reaction was carried out at 0 °C with the addition of lithium aluminum hydride (1.5 g, 40.0 mmol). The reaction was detected by LCMS and quenched with water and 15% sodium hydroxide aqueous solution. The mixture was filtered, and the filtrate was evaporated to dryness to give the target compound (2.5 g, yield 98.0%).

[0632] 5. tert-Butyl(R)-9-methyl-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine-7(6H)-carboxylate

[0633]

[0634] (R)-9-methyl-3-(trifluoromethyl)-6,7,8,9-tetrahydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine (2.4 g, 9.40 mmol) was dissolved in dichloromethane (40 mL), and (Boc)2O (3.1 g, 14.1 mmol) and triethylamine (1.9 g, 18.8 mmol) were added. The reaction was carried out at 25 °C for 2 h. After the reaction was completed, the reaction solution was evaporated to dryness, and the target compound (3 g, yield 89.8%) was separated by silica gel column chromatography (EA:PE = 1:4).

[0635] 6. tert-Butyl(R)-5-bromo-9-methyl-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine-7(6H)-carboxylate

[0636]

[0637] 2.9 g (8.16 mmol) of tert-butyl(R)-9-methyl-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine-7(6H)-carboxylate was dissolved in DMF (50 mL), and NBS (1.9 g (10.6 mmol) was added. The reaction was carried out at 25 °C for 2 h. After the reaction was completed by LCMS, water was added to quench the reaction, and the mixture was filtered. The filter cake was separated by silica gel column chromatography (EA:PE = 1:4) to obtain the target compound (2.8 g, yield 79.0%).

[0638] 7. Preparation of tert-butyl(R)-9-methyl-3-(trifluoromethyl)-5-vinyl-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine-7(6H)-carboxylate

[0639]

[0640] To a solution of tert-butyl(R)-5-bromo-9-methyl-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine-7(6H)-carboxylate (1.6 g, 3.68 mmol) in dioxane (40 mL), vinylboronic acid pinacol ester (1.7 g, 11.0 mmol), tetrakis(triphenylphosphine)palladium (855 mg, 0.74 mmol), potassium carbonate (1.5 g, 11.0 mmol), and water (10 mL) were added. The reaction was carried out at 90 °C for 16 h. The reaction was detected by LCMS to be complete. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was evaporated to dryness. The target compound (820 mg, yield 58.4%) was obtained by silica gel column chromatography (EA:PE = 1:3).

[0641] 8. Preparation of tert-butyl(R)-5-ethyl-9-methyl-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine-7(6H)-carboxylate

[0642]

[0643] Palladium on carbon (790 mg) was added to a methanol (10 mL) solution of tert-butyl(R)-9-methyl-3-(trifluoromethyl)-5-vinyl-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine-7(6H)-carboxylate (790 mg, 2.07 mmol). The mixture was stirred at 25 °C for 4 h. After the reaction was completed, the mixture was filtered through diatomaceous earth and the reaction solution was evaporated to dryness to obtain the target compound (740 mg, yield: 93.2%).

[0644] 9. Preparation of (R)-5-ethyl-9-methyl-3-(trifluoromethyl)-6,7,8,9-tetrahydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine trifluoroacetate

[0645]

[0646] Trifluoroacetic acid (4 mL) was added dropwise to a solution of tert-butyl(R)-5-ethyl-9-methyl-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine-7(6H)-carboxylate (740 mg, 1.9 mmol) in dichloromethane (8 mL). The mixture was stirred at 25 °C for 2 h. After the reaction was completed, the reaction solution was evaporated to dryness to obtain crude product (1.3 g), which was directly used in the next step of the reaction.

[0647] 10. Preparation of 5-(((S)-1-(3-(((R)-5-ethyl-9-methyl-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazin-7(6H)-yl)-3-oxypropoxy)propyl-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0648]

[0649] To a solution of 5-ethyl-9-methyl-3-(trifluoromethyl)-6,7,8,9-tetrahydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine trifluoroacetate (1.25 g, crude, 1.83 mmol) in dichloromethane (20 mL), add (S)-3-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionic acid (749 mg, 1.74 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 1.0 g, 2.63 mmol), and N,N-diisopropylethylamine (946 mg, 7.32 mmol). Stir at 25 °C for 1 h. After the reaction is complete, evaporate the reaction mixture to dryness. The target compound (750 mg, yield: 60.0%) was separated by silica gel column chromatography (EA:PE = 4:1).

[0650] 11. Preparation of 5-(((S)-1-(3-(((R)-5-ethyl-9-methyl-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazin-7(6H)-yl)-3-oxypropoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0651]

[0652] Trifluoromethanesulfonic acid (2 mL) was added dropwise to a solution of 5-(((S)-1-(3-(((R)-5-ethyl-9-methyl-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazin-7(6H)-yl)-3-oxypropoxy)propyl-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (700 mg, 1.0 mmol) in 10 mL of trifluoroacetic acid. The reaction was carried out at 25 °C for 1 h. After removing most of the TFA from the reaction solution under reduced pressure, the remaining reaction solution was diluted with ethyl acetate, and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The ethyl acetate layer was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 1:10) and medium-pressure reversed-phase column chromatography (methanol:water = 0-80%) to give the target compound (314 mg, yield: 54.0%).

[0653] Molecular formula: C 25 H 28 F6N6O3 molecular weight: 574.2 LC-MS (M / e): 575.2 (M+H) + )

[0654] 1 H-NMR(400MHz, CDCl3)δ:12.43(s,1H),8.51(s,1H),8.32(s,1H),7.82-7.90(m,H),6.25(s,1H),5.10-5.30(m,1H),4.75-4.85(m,1H) ,4.35-4.50(m,1H),4.00-4.20(m,2H),3.60-3.78(m,3H),3.40-3.50(m,2H),2.60-2.81(m,4H),1.25-1.35(m,3H),1.05-1.24(m,6H).

[0655] Preparation Example 14: Preparation of 5-(((S)-1-(3-(((R)-5,9-dimethyl-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazin-7(6H)-yl)-3-oxopropoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 49)

[0656] 1. Preparation of tert-butyl(R)-5,9-dimethyl-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine-7(6H)-carboxylate

[0657]

[0658] To a solution of tert-butyl(R)-5-bromo-9-methyl-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine-7(6H)-carboxylate (800 mg, 1.84 mmol) in 1,4-dioxane (20 mL), methylboronic acid (661 mg, 11.04 mmol), tetrakis(triphenylphosphine)palladium (427 mg, 0.37 mmol), potassium carbonate (1.0 g, 7.36 mmol), and water (4 mL) were added. The reaction was carried out at 100 °C for 16 h. The reaction was detected by LCMS and quenched with water. The product was extracted with ethyl acetate, the organic phase was evaporated to dryness, and the product was separated by silica gel column chromatography (EA:PE = 1:4) to obtain 280 mg of product (yield 41.3%).

[0659] 2. Preparation of (R)-5,9-dimethyl-3-(trifluoromethyl)-6,7,8,9-tetrahydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine trifluoroacetate

[0660]

[0661] Add 2 mL of trifluoroacetic acid dropwise to a solution of tert-butyl(R)-5,9-dimethyl-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine-7(6H)-carboxylate (280 mg, 0.76 mmol) in 10 mL of dichloromethane. Stir at 25 °C for 2 h. After the reaction is complete, evaporate the reaction solution to obtain the crude product, which can be used directly in the next step of the reaction.

[0662] 3. Preparation of 5-(((S)-1-(3-(((R)-5,9-dimethyl-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazin-7(6H)-yl)-3-oxopropoxy)propyl-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0663]

[0664] To a solution of (R)-5,9-dimethyl-3-(trifluoromethyl)-6,7,8,9-tetrahydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine trifluoroacetate (crude) in dichloromethane (10 mL), N,N-diisopropylethylamine (393 mg, 3.04 mmol), (S)-3-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionic acid (326 mg, 0.76 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 578 mg, 1.52 mmol) were added. The mixture was stirred at 25 °C for 1 h. After the reaction was complete, the mixture was quenched with water, extracted with DCM, and the organic phase was evaporated to dryness. The product was separated by silica gel column chromatography (EA:PE = 9:1) (300 mg, two-step yield: 57.9%).

[0665] 4. Preparation of 5-(((S)-1-(3-(((R)-5,9-dimethyl-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazin-7(6H)-yl)-3-oxopropoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0666]

[0667] Trifluoromethanesulfonic acid (1 mL) was added dropwise to a solution of 5-(((S)-1-(3-(((R)-5,9-dimethyl-3-(trifluoromethyl)-8,9-dihydropyridine[3',2'4,5]pyrrole[1,2-a]pyrazin-7(6H)-yl)-3-oxopropoxy)propyl-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (300 mg, 0.44 mmol) in trifluoroacetic acid (TFA, 8 mL). The reaction was carried out at 25 °C for 1 h. After removing most of the TFA from the reaction solution under reduced pressure, the remaining reaction solution was diluted with dichloromethane, and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The organic phase was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (methanol:dichloromethane = 1:20) to obtain the target compound (133 mg, yield: 53.9%).

[0668] Molecular formula: C 24 H 26 F6N6O3 molecular weight: 560.5 LC-MS (M / e): 561.0 (M+H) + )

[0669] 1H-NMR(400MHz,DMSO)δ:12.42(s,1H),8.51(s,1H),8.30(s,1H),7.88-7.84(m,1H),6.24(s,1H),5.10-5.30(m,1H),4.80-4.90(m,1H),4. 30-4.70(m,1H),4.00-4.20(m,2H),3.62-3.82(m,3H),3.40–3.50(m, 2H),2.60-2.80(m,2H),2.21(s,3H),1.20–1.40(m,3H),1.10(s,3H).

[0670] Preparation Example 15: Preparation of (S)-5-((1-(3-oxo-3-(5-(tetrahydro-2H-pyran-4-yl)-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazin-7(6H)-yl)propoxy)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 56)

[0671] 1. Preparation of tert-butyl 5-bromo-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine-7(6H)-carboxylic acid

[0672]

[0673] 1.2 g (3.5 mmol) of 3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine-7(6H)-carboxylic acid tert-butyl ester was dissolved in DMF (35 mL), and NBS (814 mg, 10.6 mmol) was added. The reaction was carried out at 25 °C for 2 h. After the reaction was completed as detected by LCMS, water was added to quench the reaction, the organic phase was extracted with ethyl acetate, dried and concentrated, and then subjected to silica gel column chromatography (EA:PE = 1:9) to give the target compound (1.0 g, yield 66.7%).

[0674] 2. Preparation of tert-butyl 5-(3,6-dihydro-2H-pyran-4-yl)-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine-7(6H)-carboxylic acid ester

[0675]

[0676] In a mixture of 5-bromo-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine-7(6H)-carboxylic acid tert-butyl ester (900 mg, 2.1 mmol) in dioxane (40 mL) and water (8 mL), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (1.3 g, 6.2 mmol), tetrakis(triphenylphosphine)palladium (485 mg, 0.42 mmol), and potassium carbonate (871 mg, 6.3 mmol) were added. The reaction was carried out under nitrogen protection at 100 °C for 3 h. The reaction was detected by LCMS to indicate completion. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was evaporated to dryness. The target compound (850 mg, yield 93.7%) was obtained by silica gel column chromatography (EA:PE = 1:5).

[0677] 3. Preparation of tert-butyl 5-(tetrahydro-2H-pyran-4-yl)-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine-7(6H)-carboxylic acid ester

[0678]

[0679] Palladium on carbon (1.3 g) was added to a methanol (25 mL) solution of tert-butyl 5-(3,6-dihydro-2H-pyran-4-yl)-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine-7(6H)-carboxylic acid ester (850 mg, 2.0 mmol). The mixture was stirred at 30 °C for 2 h. After the reaction was completed, the mixture was filtered through diatomaceous earth, the filtrate was evaporated to dryness, and the target compound (750 mg, yield 87.8%) was separated by silica gel column chromatography (EA:PE = 1:6).

[0680] 4. Preparation of 5-(tetrahydro-2H-pyran-4-yl)-3-(trifluoromethyl)-6,7,8,9-tetrahydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine trifluoroacetate

[0681]

[0682] Trifluoroacetic acid (13 mL) was added dropwise to a solution of tert-butyl 5-(tetrahydro-2H-pyran-4-yl)-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine-7(6H)-carboxylic acid ester (750 mg, 1.8 mmol) in dichloromethane (4 mL). The mixture was stirred at 25 °C for 1 h. After the reaction was completed, the reaction solution was evaporated to dryness, and the crude product was directly used for the next step of the reaction.

[0683] 5. Preparation of (S)-2-(4-methoxybenzyl)-5-((1-(3-oxy-3-(5-(tetrahydro-2H-pyran-4-yl)-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazin-7(6H)-yl)propoxy)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0684]

[0685] To a solution of 5-(tetrahydro-2H-pyran-4-yl)-3-(trifluoromethyl)-6,7,8,9-tetrahydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine trifluoroacetate (crude, 1.8 mmol) in dichloromethane (30 mL), add (S)-3-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionic acid (773 mg, 1.8 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.0 g, 2.6 mmol), and N,N-diisopropylethylamine (930 mg, 7.2 mmol). Stir at 25 °C for 1 h. The system was quenched with water, extracted with dichloromethane, the organic phase was evaporated to dryness, and the target compound (650 mg, yield (two steps) 50%) was obtained by silica gel column chromatography (EA = 100%).

[0686] 6. Preparation of (S)-5-((1-(3-oxo-3-(5-(tetrahydro-2H-pyran-4-yl)-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazin-7(6H)-yl)propoxy)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0687]

[0688] Trifluoromethanesulfonic acid (1 mL) was added dropwise to a solution of (S)-2-(4-methoxybenzyl)-5-((1-(3-oxy-3-(5-(tetrahydro-2H-pyran-4-yl)-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazin-7(6H)-yl)propoxy)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (620 mg, 0.84 mmol) in trifluoroacetic acid (8 mL). The reaction was carried out at 25 °C for 15 min. After removing most of the TFA from the reaction solution under reduced pressure, the remaining reaction solution was diluted with dichloromethane, adjusted to alkalinity with saturated sodium bicarbonate solution, and the organic phase was extracted with dichloromethane. The solution was concentrated, and the residue was subjected to silica gel column chromatography (methanol:dichloromethane = 1:10) to give the target compound (306 mg, yield: 59.0%).

[0689] Molecular formula: C 27 H 30 F6N6O4 molecular weight: 616.6 LC-MS (M / e): 617.2 (M+H) + )

[0690] 1 H-NMR(400MHz,DMSO)δ:12.43(s,1H),8.57(s,1H),8.35(s,1H),7.90(s,1H),6.25(s,1H),5.05-4.90(m,2H),4.30-4.10(m,4H) ,4.08-3.90(m,4H),3.80-3.65(m,2H),3.60-3.42(m,4H),2.85-2.70(m,2H),2.10-1.90(m,2H),1.75-1.60(m,2H),1.25(s,3H).

[0691] Preparation Example 16: Preparation of (S)-5-((1-(3-(5-cyclopropyl-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazin-7(6H)-yl)-3-oxopropoxy)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 57)

[0692] 1. Preparation of tert-butyl 5-bromo-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine-7(6H)-carboxylic acid

[0693]

[0694] To a solution of 3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine-7(6H)-carboxylic acid tert-butyl ester (2.5 g, 7.3 mmol) in N,N-dimethylformamide (30 mL), N-bromosuccinimide (NBS, 1.6 g, 8.8 mmol) was added. The reaction was carried out at 70 °C for 1 h. After the reaction was completed, the reaction was quenched with water, and the reaction solution was extracted with ethyl acetate. The collected organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 6:1) to obtain the target compound (1.6 g, yield 52.1%).

[0695] 2. Preparation of tert-butyl 5-cyclopropyl-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine-7(6H)-carboxylic acid

[0696]

[0697] To a solution of 5-bromo-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine-7(6H)-carboxylic acid tert-butyl ester (722 mg, 1.7 mmol) in 1,4-dioxane (20 mL), cyclopropylboronic acid (728 mg, 8.5 mmol), tetrakis(triphenylphosphine)palladium (196 mg, 0.17 mmol), potassium carbonate (705 mg, 5.1 mmol), and water (5 mL) were added. The mixture was stirred at 100 °C for 12 h. After the reaction was complete, the reaction solution was evaporated to dryness and purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 6:1) to obtain the target compound (92 mg, yield 14.1%).

[0698] 3. Preparation of 5-cyclopropyl-3-(trifluoromethyl)-6,7,8,9-tetrahydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine

[0699]

[0700] Trifluoroacetic acid (2 mL) was added dropwise to a solution of 5-cyclopropyl-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine-7(6H)-carboxylic acid tert-butyl ester (92 mg, 0.24 mmol) in dichloromethane (5 mL). The mixture was stirred at 20 °C for 3 h. After the reaction was completed, the reaction solution was evaporated to dryness to obtain crude product (125 mg), which was directly used in the next step of the reaction.

[0701] 4. Preparation of (S)-5-((1-(3-(5-cyclopropyl-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazin-7(6H)-yl)-3-oxopropoxy)propane-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0702]

[0703] To a solution of 5-cyclopropyl-3-(trifluoromethyl)-6,7,8,9-tetrahydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazine (125 mg, crude) in dichloromethane (4 mL), add (S)-3-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionic acid (94 mg, 0.22 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 91 mg, 0.24 mmol), and N,N-diisopropylethylamine (62 mg, 0.48 mmol). Stir at 25 °C for 12 h. After the reaction is complete, evaporate the reaction mixture to dryness. Column chromatography (SiO2, dichloromethane:methanol = 15:1) yielded crude product (250 mg), which was directly used in the next reaction.

[0704] 5. (S)-5-((1-(3-(5-cyclopropyl-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazin-7(6H)-yl)-3-oxopropoxy)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0705]

[0706] Add 0.1 mL of trifluoromethanesulfonic acid dropwise to a solution of (S)-5-((1-(3-(5-cyclopropyl-3-(trifluoromethyl)-8,9-dihydropyridine[3',2':4,5]pyrrole[1,2-a]pyrazin-7(6H)-yl)-3-oxopropoxy)propane-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (250 mg, crude) in trifluoroacetic acid (2 mL). React at 20 °C for 2 h. After removing most of the TFA from the reaction solution under reduced pressure, the remaining reaction solution was diluted with ethyl acetate, and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The ethyl acetate layer was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) and medium-pressure reversed-phase column chromatography (methanol:water = 9:1) to obtain the target compound (20 mg, yield: 14.6%).

[0707] Molecular formula: C 25 H 26 F6N6O3 molecular weight: 572.2 LC-MS (M / e): 573.2 (M+H) + )

[0708] 1 H-NMR (400MHz, CDCl3) δ: 10.65 (brs, 1H), 8.51 (d, J = 10.0Hz, 1H), 8.17 (s, 1 H),7.66(s,1H),5.82(s,1H),5.05(s,1H),4.95(s,1H),4.43-4.25(m,2H),4 .21-4.05(m,1H),3.98-3.79(m,4H),3.73-3.58(m,1H),3.58-3.40(m,1H), 2.81-2.68(m,2H),1.88-1.68(m,1H),1.38-1.20(m,3H),0.83-0.69(m,2H).

[0709] Preparation Example 17: Preparation of (s)-5-((1-(3-oxo-3-(3-(trifluoromethyl)-9,10-dihydroimidazol[2,1-a][2,6]naphthidin-8(7H)-yl)propoxy)propane-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H)-one (compound 7)

[0710] 1. Preparation of 8-benzyl-7,8,9,10-tetrahydroimidazole[2,1-a][2,6]naphthidine

[0711]

[0712] 2-Bromo-1,1-dimethoxyethane (5.5 g, 32.7 mmol) was dissolved in ethanol (230 mL), and dilute HCl (1 M, 200 mL, 200 mmol) was added. The mixture was reacted at 90 °C for 1 h, cooled to 25 °C, and the pH was adjusted to 7-8 with saturated NaHCO3 solution. 6-Benzyl-5,6,7,8-tetrahydro-2,6-diazanaphthyl-1-amine (4.7 g, 20 mmol) was added, and the mixture was reacted at 90 °C for 2 h. After the reaction was complete, the mixture was evaporated to dryness and separated by forward preparative chromatography (DCM:MeOH = 20:1) to give the target compound (3.1 g, yield 60%).

[0713] 2. Preparation of 8-benzyl-3-(trifluoromethyl)-7,8,9,10-tetrahydroimidazole[2,1-a][2,6]naphthidine

[0714]

[0715] 8-Benzyl-7,8,9,10-tetrahydroimidazole[2,1-a][2,6]naphthidine (2.6 g, 10 mmol) was dissolved in acetonitrile (130 mL), and TMSCF3 (5.7 g, 40 mmol), PhI(OAc)2 (6.4 g, 20 mmol), and CsF (6.1 g, 40 mmol) were added. After the addition was complete, the mixture was reacted at 30 °C for 4 h. After the reaction was complete, the mixture was filtered, and the filtrate was evaporated to dryness. The crude product was obtained by forward preparative separation (PE:EA = 3:1), and then by reverse C18 preparative separation (water:methanol = 1:2) to obtain crude product (200 mg).

[0716] 3. Preparation of 3-(trifluoromethyl)-7,8,9,10-tetrahydroimidazole[2,1-a][2,6]naphthidine

[0717]

[0718] 200 mg of crude 8-benzyl-3-(trifluoromethyl)-7,8,9,10-tetrahydroimidazole[2,1-a][2,6]naphthidine was dissolved in methanol (5 mL), and Pd / C (20 mg) was added. The mixture was reacted under H2 for 2 h. After the reaction was complete, the mixture was filtered, and the filtrate was evaporated to dryness. The filtrate was then separated by reverse C18 chromatography (water:methanol = 1:2) to obtain crude product (35 mg).

[0719] 4. Preparation of (s)-2-(4-methoxybenzyl)-5-((1-(3-oxo-3-(3-(trifluoromethyl)-9,10-dihydroimidazol[2,1-a][2,6]naphthid-8(7H)-yl)propoxy)propane-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H)-one

[0720]

[0721] 3-(trifluoromethyl)-7,8,9,10-tetrahydroimidazole[2,1-a][2,6]naphthidine (35 mg crude) was dissolved in DCM (3 mL), and (S)-3-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionic acid (62 mg, 0.15 mmol), HATU (83 mg, 0.2 mmol), and DIEA (56 mg, 0.4 mmol) were added. The mixture was reacted at 30 °C for 1 h. After the reaction was complete, the solution was evaporated to dryness and then separated by forward preparative chromatography (PE:EA = 1:1) to obtain crude product (40 mg).

[0722] 5. Preparation of (s)-5-((1-(3-oxo-3-(3-(trifluoromethyl)-9,10-dihydroimidazol[2,1-a][2,6]naphthidin-8(7H)-yl)propoxy)propane-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H)-one

[0723]

[0724] The crude product from the previous step was dissolved in TFA (3 mL), and trifluoromethanesulfonic acid (0.3 mL) was added dropwise at 0 °C. The reaction was carried out at 30 °C for 30 min. After the reaction was completed, the product was poured into a saturated NaHCO3 solution, and EA and water were added for three liquid-liquid extractions. The organic phase was evaporated to dryness, and the target compound (10 mg) was obtained by reverse separation (water:methanol = 1:1).

[0725] Molecular formula: C 22 H 22 F6N6O3 molecular weight: 532.4 LC-MS (M / e): 533.1 (M+H) + )

[0726] 1 H-NMR (400MHz, DMSO) δ: 12.43 (s, 1H), 8.35-8.39 (t, 1H), 8.10 (s, 1H), 7.88-7.90 (d, J = 8Hz, 1H), 7.00-7.07 (t, 1H), 6.25 (s, 1H),4.60-4.70(m,2H),4.20(s,1H),3.60-3.80(m,4H),3.50(m,2H),2.85-3.11(m,2H),2.60-2.70(m,2H),1.05-1.2(m,3H).

[0727] Preparation Example 18: Preparation of 5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-5a,6,8,9-tetrahydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazin-7(5H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 28-1)

[0728] 1. Preparation of 2-(benzyloxy)-3-bromo-5-(trifluoromethyl)pyridine

[0729]

[0730] 3-Bromo-2-chloro-5-(trifluoromethyl)pyridine (20 g, 77 mmol) was dissolved in NMP (200 mL), and benzyl alcohol (9.9 g, 92 mmol) and cesium carbonate (75.1 g, 230 mmol) were added. The mixture was then placed at 90 °C and reacted for 16 h. The reaction was detected by LCMS and the temperature was lowered to 25 °C. The reaction solution was poured into water (1.4 L) to precipitate the solid. The solid was filtered, and the filter cake was dried to obtain the target compound (19.5 g, yield 76.8%).

[0731] 2. Preparation of methyl (S)-3-(2-(benzyloxy)-5-(trifluoromethyl)pyridin-3-yl)-2-((tert-butoxycarbonyl)amino)propionate

[0732]

[0733] Zinc powder (11.9 g, 181 mmol) was added to N,N-dimethylformamide (50 mL), purged three times with nitrogen, and then a DMF (5 mL) solution of iodine (3.2 g, 13 mmol) was added. The mixture was reacted at 25 °C for 10 min. Then, a DMF (20 mL) solution of (R)-2-((tert-butoxycarbonyl)amino)-3-iodopropionate methyl ester (19.9 g, 60 mmol) and a DMF (5 mL) solution of iodine (3.2 g, 13 mmol) were added, and the mixture was reacted at 25 °C for 3 min. At 0 min, a DMF (20 mL) solution of 2-(benzyloxy)-3-bromo-5-(trifluoromethyl)pyridine (10.0 g, 30 mmol) and bis(triphenylphosphine)-palladium dichloride (1.1 g, 1.5 mmol) was added. The mixture was reacted at 120 °C for 2 h. The reaction was detected by LCMS. The solvent was evaporated to 100 mL, filtered, and the filter cake was dissolved and concentrated with dichloromethane and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:5) to give the target compound (2.5 g, yield 18.2%).

[0734] 3. Preparation of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(2-hydroxy-5-(trifluoromethyl)pyridin-3-yl)propionate

[0735]

[0736] Methyl (S)-3-(2-(benzyloxy)-5-(trifluoromethyl)pyridin-3-yl)-2-((tert-butoxycarbonyl)amino)propionate (2.7 g, 6 mmol) was dissolved in dichloromethane (16 mL) and methanol (4 mL), and wet palladium on carbon (270 mg) was added. The mixture was purged with nitrogen three times and hydrogen three times. The reaction system was reacted at 25 °C for 3 h. The reaction was confirmed by LCMS. The reaction solution was filtered, and the organic phase was dried by rotary evaporation to obtain the target compound (2.1 g, yield 95.5%).

[0737] 4. Methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(5-(trifluoromethyl)-2-(((trifluoromethyl)sulfonyl)oxy)pyridin-3-yl)propionate

[0738]

[0739] Methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(2-hydroxy-5-(trifluoromethyl)pyridin-3-yl)propionate (2.1 g, 6 mmol) was dissolved in dichloromethane (20 mL), and pyridine (1.8 g, 23 mmol) was added at 0 °C. Trifluoromethanesulfonic anhydride (2.4 g, 8.6 mmol) was added dropwise at 0 °C. The reaction was carried out for 3 h. After the reaction was completed as detected by LCMS, the reaction solution was concentrated, and the pH was adjusted to alkaline with saturated sodium bicarbonate solution. The aqueous phase was extracted once with DCM, and the organic phases were combined and concentrated to obtain the target compound (2.6 g, yield 90.3%).

[0740] 5. Preparation of methyl (S)-2-amino-3-(2-chloro-5-(trifluoromethyl)pyridin-3-yl)propionate

[0741]

[0742] Methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(5-(trifluoromethyl)-2-(((trifluoromethyl)sulfonyl)oxy)pyridin-3-yl)propionate (2.6 g, 5.2 mmol) was dissolved in EA (20 mL), and HCl / EA solution (4 N, 10 mL) was added dropwise. The mixture was placed at 20 °C and reacted for 18 h. The reaction solution was concentrated and evaporated to dryness, and dichloromethane (20 mL) was added. The pH was adjusted to 8 with saturated sodium bicarbonate solution. The organic phase was washed with water and concentrated to obtain the target product (crude product, 1.8 g, directly used in the next reaction).

[0743] 6. Preparation of (S)-5-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid methyl ester

[0744]

[0745] Methyl (S)-2-amino-3-(2-chloro-5-(trifluoromethyl)pyridin-3-yl)propionate (1.8 g, crude product from the previous step), DIPEA (4.1 g, 31.8 mmol), and DMSO (6 mL) were added to a microwave-safe tube and reacted at 140 °C for 1 hour. After the reaction was complete, the reaction was extinguished by water extraction, followed by extraction three times with ethyl acetate. The combined ethyl acetate layers were washed with water and saturated sodium chloride solution, and the organic phase was removed under reduced pressure. The residue was subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give the target compound (800 mg, two-step yield: 62.5%).

[0746] 7. Preparation of (S)-(5-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-2-yl)methanol

[0747]

[0748] Sodium borohydride (500 mg, 13.2 mmol) was added to 40 mL of anhydrous ethanol containing (S)-5-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid methyl ester (650 mg, 2.64 mmol), and the reaction was carried out at 20 °C for 3 h under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give the target compound (550 mg, yield: 95.5%).

[0749] 8. Preparation of (S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine

[0750]

[0751] TBDPSCl (1.0 g, 3.6 mmol) was added to dichloromethane (30 mL) containing (S)-(5-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-2-yl)methanol (550 mg, 2.5 mmol) and imidazole (511 mg, 7.5 mmol), and the reaction was carried out at 20 °C for 1 h under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give the target compound (720 mg, yield: 62.6%).

[0752] 9. Preparation of (S)-2-(2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)tert-butyl acetate

[0753]

[0754] At 0°C, sodium hydride (300 mg, 7.5 mmol) was added to 20 mL of DMF containing (S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (700 mg, 1.5 mmol). After reacting for 5 minutes, tert-butyl bromoacetate (429 mg, 2.2 mmol) was added, and the reaction was continued for another 30 minutes. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with water and saturated sodium chloride solution, and the organic phase was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain the target compound (810 mg, yield: 92.6%).

[0755] 10. Preparation of (S)-2-(2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)ethane-1-ol

[0756]

[0757] Sodium borohydride (265 mg, 7.0 mmol) was added to anhydrous ethanol (40 mL) containing (S)-2-(2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)acetate (800 mg, 1.4 mmol) and anhydrous calcium chloride (777 mg, 7.0 mmol). The reaction was carried out at 20 °C for 15 h under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was directly purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain the target compound (500 mg, yield: 71.2%).

[0758] 11. Preparation of (S)-2-(2-(hydroxymethyl)-5-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)ethanol-1-ol

[0759]

[0760] TBAF (2.3 mL, 2.3 mmol) was added to THF (5 mL) containing (S)-2-(2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)ethane-1-ol (230 mg, 0.46 mmol), and the reaction was carried out at 20 °C for 15 h under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was directly purified by silica gel plate chromatography (dichloromethane:methanol = 10:1) to obtain the target compound (120 mg, yield: 99.6%).

[0761] 12. Preparation of (S)-(1-(2-((methanesulfonyl)oxy)ethyl)-5-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl sulfonate

[0762]

[0763] At 0°C, MsCl (79 mg, 0.69 mmol) was added to 5 mL of dichloromethane containing (S)-2-(2-(hydroxymethyl)-5-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)ethanol-1-ol (60 mg, 0.23 mmol) and triethylamine (121 mg, 1.2 mmol), and the reaction was continued for 20 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was directly purified by silica gel plate chromatography (petroleum ether: ethyl acetate = 1:1) to give the target compound (70 mg, yield: 73.1%).

[0764] 13. Preparation of (S)-3-(trifluoromethyl)-5,5a,6,7,8,9-hexahydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine

[0765]

[0766] Methyl (S)-(1-(2-((methanesulfonyl)oxy)ethyl)-5-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-2-yl)methanesulfonate (70 mg, 0.17 mmol), ammonia (4 mL), and acetonitrile (2 mL) were added to a sealed tube, and the mixture was reacted at 90 °C for 2 hours. After the reaction was complete, the reaction mixture was extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target product (40 mg, yield: 98.3%).

[0767] 14. Preparation of 2-(4-methoxybenzyl)-5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-5a,6,8,9-tetrahydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazin-7(5H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0768]

[0769] A mixture of (S)-3-(trifluoromethyl)-5,5a,6,7,8,9-hexahydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine (40 mg, 0.16 mmol), (S)-3-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionic acid (69 mg, 0.16 mmol), HATU (91 mg, 0.24 mmol), and DIPEA (62 mg, 0.48 mmol) in dichloromethane (2 mL) was reacted at 25 °C for 1 hour. After the reaction was complete, the reaction solution was evaporated to dryness under reduced pressure, and the residue was purified by silica gel agar plate chromatography (ethyl acetate as the developing solvent) to give the target compound (65 mg, yield: 60.4%).

[0770] 15. Preparation of 5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-5a,6,8,9-tetrahydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazin-7(5H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0771]

[0772] At 0°C, 0.2 mL of TfOH was added dropwise to 2 mL of trifluoroacetic acid containing 65 mg (0.10 mmol) of 2-(4-methoxybenzyl)-5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-5a,6,8,9-tetrahydropyridino[3',2':4,5]pyrrolo[1,2-a]pyrazin-7(5H)-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (65 mg, 0.10 mmol). The reaction mixture was reacted at 0°C for 0.5 hours. The reaction mixture was then poured into a saturated sodium bicarbonate solution and extracted three times with dichloromethane. The dichloromethane layers were combined, the solvent was removed under reduced pressure, and the residue was purified by silica gel plate preparation (using ethyl acetate as the developing solvent) to obtain the target compound (25 mg, yield: 47.1%).

[0773] Molecular formula: C 22 H 24 F6N6O3 molecular weight: 534.5 LC-MS (M / e): 535.2 (M+H) + )

[0774] 1H-NMR(400MHz,DMSO)δ:12.43(brs,1H),8.09(s,1H),7.90(s,1H),7.50(s,1H),6.24(m,1H),4.51-4.42(m,1H),4.15(m,1H),4.11-3 .98(m,2H),3.92-3.85(m,1H),3.71(m,3H),3.51(m,2H),3.19-3.11(m,1H),2.99-2.85(m,2H),2.62-2.52(m,3H),1.16-1.14(m,3H).

[0775] The compounds shown in the following table were prepared using the same or similar methods as those used in the preparation examples above:

[0776]

[0777]

[0778] Experimental protocol

[0779] The following provides exemplary experimental schemes for some compounds of the present invention to demonstrate the beneficial activity and technical effects of the compounds. However, it should be understood that the following experimental schemes are merely examples of the content of the present invention and not limitations on the scope of the present invention.

[0780] Experimental Example 1: In vitro enzymatic activity of the compounds of the present invention

[0781] Test substances: The compounds in Table 1 of this invention, whose structural formulas and preparation methods are given in the preparation examples of this invention;

[0782] Compound A was prepared using existing techniques, and its structure is as follows;

[0783]

[0784] The abbreviations used in the following experiments have the following meanings:

[0785] DMSO: Dimethyl sulfoxide;

[0786] PBS: Phosphate Buffered Salt;

[0787] PBST: Phosphate buffer containing Tween 20;

[0788] HRP: Horseradish peroxidase

[0789] Experimental methods: The compounds were enzymatically evaluated in vitro on PARP7 using the PARP7 chemiluminescence method from BPS Bioscience.

[0790] Experimental steps:

[0791] 1. Reagent preparation

[0792] 1.1 Histone solution: Dilute the 5× histone mixture with PBS to prepare a 1× working solution;

[0793] 1.2 Major Mixture: Prepare the major mixture by diluting 10×PARP buffer and 10×PARP mixture with water;

[0794] 1.3 PARP7 enzyme: Prepare PARP7 enzyme working solution using 1×PARP buffer;

[0795] 1.4 Streptavidin-HRP solution: Dilute 50× streptavidin-HRP with blocking buffer to prepare 1× working solution;

[0796] 1.5 Detection solution: Mix substrate A solution and substrate B solution in a 1:1 ratio, prepare fresh before use, and mix on ice.

[0797] 2. Preparation of test compounds:

[0798] 2.1 Prepare a drug solution with a final concentration of 1000 times: Take an appropriate amount of 10mM drug stock solution, first dilute it 10 times with DMSO to 1mM, and then serially dilute it 10 times with DMSO to obtain 6 drug concentrations.

[0799] 2.2 Prepare drug solutions with a final concentration 10 times by diluting the serially diluted drug-DMSO solutions 100 times with ultrapure water. The final concentrations of the test compounds in the system are 1000, 100, 10, 1, 0.1, and 0.01 nM.

[0800] 3. Experimental Procedure:

[0801] 3.1 Coat 96-well plates with 50 μl histone working solution per well and incubate overnight at 4°C;

[0802] 3.2 Washing: Wash 3 times with 200μl PBST per well, then gently tap and shake dry;

[0803] 3.3 Blocking: 200 μl blocking buffer solution 3 / well, incubate at room temperature for 60 minutes;

[0804] 3.4 Washing: Wash 3 times with 200μl PBST per well, then gently tap and shake dry;

[0805] 3.5 Add the main mixture: 25 μl / well (2.5 μl 10×PARP buffer + 2.5 μl 10×PARP mixture + 20 μl water);

[0806] Add reagents: 5 μl of the test compound per well; add 5 μl of 0.1% DMSO to the positive control and blank wells;

[0807] Add enzyme: Add 20 μl of PARP7 enzyme to the positive control wells and test compound wells, and add 20 μl of 1×PARP buffer to the blank wells. Incubate at room temperature for 1 hour.

[0808] 3.6 Washing: Wash 3 times with 200μl PBST per well, then gently tap and shake dry;

[0809] 3.7 Add 50 μl of streptavidin-HRP solution to each well and incubate at room temperature for 30 minutes;

[0810] 3.8 Washing: Wash 3 times with 200μl PBST per well, then gently tap and shake dry;

[0811] 3.9 Detection: Add 100 μl / well of detection solution and immediately detect the chemiluminescence value.

[0812] 4. Data Processing

[0813] Nonlinear S-curve regression is used to fit the data to obtain a curve, and the relative IC is calculated from this curve. 50 value.

[0814] Activity (%) = (Test sample well reading - Blank well reading) / (Mean positive control well reading - Blank well reading) × 100%

[0815] Experimental results

[0816] Table 2. In vitro enzyme inhibitory activity of the compounds of the present invention.

[0817]

[0818] Experimental conclusions

[0819] The compounds listed in Table 1 of this invention exhibit good inhibitory activity against PARP7, with an IC50 value of [missing information]. 50 The values ​​are all less than 1 μM, where the IC50 of the test represents the compound. 50 The values ​​were all less than 100 nM, indicating good inhibitory activity.

[0820] Experimental Example 2: Inhibition of cell activity by the compounds of the present invention in vitro

[0821] Test substances: The compounds in Table 1 of this invention, whose structural formulas and preparation methods are given in the preparation examples of this invention;

[0822] Compound A was prepared using existing techniques, and its structure is as follows;

[0823]

[0824] The abbreviations used in the following experiments have the following meanings:

[0825] DMSO: Dimethyl sulfoxide;

[0826] GI50 The compound concentration corresponding to 50% cell growth inhibition

[0827] Experimental method: using The Luminescent method was used to evaluate the inhibitory effect of the compound on cell proliferation in NCI-H1373 cells in vitro.

[0828] Experimental steps:

[0829] 1. Prepare the test compound:

[0830] Preparation of stock solution for test compound: Prepare a 10mM stock solution using 100% DMSO.

[0831] Preparation of serial dilution solutions for the test compound: Take 10 mM of the test compound stock solution and perform a 3-fold serial dilution with DMSO. Take 2 μL of the compound diluted with DMSO and add it to 198 μL of culture medium containing 10% FBS to prepare 10-fold test solutions. The highest concentration of the test solution is 100 μM, and the concentration of DMSO is 1%, for a total of 8 concentration gradients.

[0832] 2. Experimental Procedure

[0833] 2.1 Trypsin digest NCI-H1373 cells that have grown to 80% confluence, and collect the cells by centrifugation. Resuspend the cells in complete culture medium, count and adjust the seeding of 96-well plates, seeding 4000 cells / well / 90μL, and incubate in a 37℃ cell culture incubator;

[0834] 2.2 After 24 hours of incubation, CTG detection was performed on the day 0 (D0) plate.

[0835] 2.3 Simultaneously, add 10 μL of 10 times the test substance of different concentrations to each well of the drug-addition plate, with 2-3 replicates for each concentration. After incubation at 37°C for 6 days (D6), perform CTG detection.

[0836] 3. CTG detection

[0837] 3.1 Place the culture plate at room temperature in advance.

[0838] 3.2 Add 60 μL of CTG solution to each well and keep out of the light.

[0839] 3.3 Vibrate on a fixed-track shaker for 2 minutes to induce cell lysis.

[0840] 3.4 Place the cell plate at room temperature for a total of 20 minutes.

[0841] 3.5 Read the fluorescence value using a multi-functional microplate reader.

[0842] 4. Data Processing

[0843] Nonlinear S-curve regression is used to fit the data to obtain the dose-response curve, and the absolute GI is calculated from it. 50 value.

[0844] Cell growth (%) = (D6 test sample well reading - mean D0 reading) / (D6 solvent control well reading - mean D0 reading) × 100%

[0845] Experimental results and conclusions:

[0846] Table 3. In vitro cellular inhibitory activity of the compounds of the present invention.

[0847]

[0848] Table 4. In vitro cellular inhibitory activity of the compounds of the present invention.

[0849] Test object <![CDATA[GI 50 (nM)]]>

[0850] H1373 cells Compound 36 59 Compound A 43

[0851] Table 5. In vitro cellular inhibitory activity of the compounds of the present invention.

[0852]

[0853] Table 6. In vitro cellular inhibitory activity of the compounds of the present invention.

[0854]

[0855] Tests showed that the compounds in Table 1 of this invention have a good inhibitory effect on the proliferation of NCI-H1373 cells, and some of the compounds inhibited the proliferation of NCI-H1373 cells by GI. 50 The value is less than 100 nM.

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein, X1is selected from N or CH; X2is selected from N or CH; X3is selected from N or CH; X4is selected from N or CH; ring A is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, or triazolyl; p is 1; q is selected from 1 or 2.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, X1is selected from N or CH; X2is selected from N or CH; X3is selected from N or CH; X4is selected from N or CH; p is 1; q is selected from 1 or 2. L is X is selected from -O- or -S-; X1is selected from -N(R 7 )-; X2is selected from -C(O)-; 3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein, X1is selected from N or CH; X2is selected from N or CH; X3is selected from N or CH; X4is selected from N or CH; p is 1; q is selected from 1 or 2. R 1 selected from H, halogen, hydroxyl, amino, cyano, C 1-4 alkyl, haloC 1-4 alkyl, cyanoC 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, haloC 1-4 alkoxy or haloC 1-4 alkylthio; R 2 , R 3 and the carbon atom to which R 2 is attached, X3together form a group of the following formula:

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein, X1is selected from N or CH; X2is selected from N or CH; X3is selected from N or CH; X4is selected from N or CH; Q1is selected from halogen, hydroxyl, amino, cyano, methyl, ethyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy; p is 1; q is selected from 1 or 2. Q1is selected from halogen, hydroxy, amino, cyano, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy or haloC 1-4 alkoxy; R 4 , R 4 are each independently selected from the group consisting of H, halogen, hydroxyl, amino, C 1-4 alkyl, haloC 1-4 alkyl, hydroxyC 1-4 alkyl, aminoC 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, hydroxyC 1-4 alkoxy, or aminoC 1-4 alkoxy; R 7 selected from H, C 1-4 alkyl, haloC 1-4 alkyl, hydroxyC 1-4 alkyl or aminoC 1-4 alkyl; each R is independently selected from H, halo, hydroxyl, amino, cyano, C 8 each R is independently selected from H, halo, hydroxyl, amino, cyano, C 1-4 each R is independently selected from H, halo, hydroxyl, amino, cyano, C 1-4 each R is independently selected from H, halo, hydroxyl, amino, cyano, C 1-4 each R is independently selected from H, halo, hydroxyl, amino, cyano, C 1-4 each R is independently selected from H, halo, hydroxyl, amino, cyano, C 1-4 each R is independently selected from H, halo, hydroxyl, amino, cyano, C 1-4 each R is independently selected from H, halo, hydroxyl, amino, cyano, C 1-4 each R is independently selected from H, halo, hydroxyl, amino, cyano, C 1-4 each R is independently selected from H, halo, hydroxyl, amino, cyano, C 1-4 each R is independently selected from H, halo, hydroxyl, amino, cyano, C 1-4 each R is independently selected from H, halo, hydroxyl, amino, cyano, C 1-4 each R is independently selected from H, halo, hydroxyl, amino, cyano, C 1-4 each R is independently selected from H, halo, hydroxyl, amino, cyano, C 5. A compound selected from the following or a pharmaceutically acceptable salt thereof:

6. A compound selected from the following or a pharmaceutically acceptable salt thereof: L is X is selected from -O- or -S-; X1is selected from -N(R 7 )-; X2is selected from -C(O)-; 7. A pharmaceutical composition comprising a compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. R 1 selected from H, halogen, hydroxyl, amino, cyano, C 1-4 alkyl, haloC 1-4 alkyl, cyanoC 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, haloC 1-4 alkoxy or haloC 1-4 alkylthio; R 2 , R 3 and the carbon atom to which R 2 is attached, X3together form a group of the formula: Q1is selected from halogen, hydroxy, amino, cyano, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy or haloC 1-4 alkoxy; R 4 , R 4 are each independently selected from the group consisting of H, halogen, hydroxyl, amino, C 1-4 alkyl, haloC 1-4 alkyl, hydroxyC 1-4 alkyl, aminoC 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, hydroxyC 1-4 alkoxy, or aminoC 1-4 alkoxy; R 7 selected from H, C 1-4 alkyl, haloC 1-4 alkyl, hydroxyC 1-4 alkyl or aminoC 1-4 alkyl; Each R 8 Each is independently selected from H, halogen, hydroxyl, amino, cyano, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, cyano C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, amino C 1-4 Alkoxy, cyano C 1-4 Alkoxy; 8. The pharmaceutical composition of claim 7, further comprising one or more second therapeutically active agents selected from an anti-cancer agent, an agent that reduces or diminishes one or more side effects of the compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof when used to treat a disease in a subject, or an agent that enhances the efficacy of the compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof.

9. Use of a compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof, the pharmaceutical composition of claim 7 or 8, for the manufacture of a medicament for the prevention and / or treatment of a disease associated with over-activation of PARP7, selected from lung cancer, esophageal cancer, ovarian cancer, head and neck cancer, or cervical cancer. L is X is selected from -O-; X1is selected from -N(R 7 )-; X2is selected from -C(O)-; 10. A kit comprising an effective amount of one or more compounds of any one of claims 1-6 or a pharmaceutically acceptable salt thereof. R 1 selected from H, halogen, hydroxyl, amino, cyano, C 1-4 alkyl, fluoroC 1-4 alkyl, cyanoC 1-4 alkyl, C 1-4 alkoxy or fluoroC 1-4 alkoxy; R 2 , R 3 and the carbon atom to which R 2 is attached, X3together form a group of the formula: Q1is selected from halogen, hydroxy, amino, cyano, C 1-4 alkyl, fluoroC 1-4 alkyl, C 1-4 alkoxy or fluoroC 1-4 alkoxy; R 4 , R 4 ' are each independently selected from H, halogen, hydroxyl, amino, C 1-4 alkyl, fluoroC 1-4 alkyl, C 1-4 alkoxy or fluoroC 1-4 alkoxy; R 7 selected from H or C 1-4 alkyl; each R is independently selected from H, halo, hydroxy, amino, cyano, C 8 is independently selected from H, halo, hydroxy, amino, cyano, C 1-4 alkyl, fluoroC 1-4 alkyl, hydroxyC 1-4 alkyl, aminoC 1-4 alkyl, cyanoC 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkoxy or fluoroC 1-4 alkoxy; 11. The kit of claim 10, further comprising an effective amount of one or more anti-cancer agents. ​ L is X is selected from -O-; X1is selected from -N(R 7 )-; X2is selected from -C(O)-; ​ R 1 selected from H, halogen, hydroxyl, amino, cyano, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyanomethyl, methoxy, ethoxy, fluoromethoxy, difluoromethoxy, or trifluoromethoxy; R 2 , R 3 and the carbon atom to which R 2 is attached, X3together form a group of the formula: ​ R 4 , R 4 are each independently selected from H, halogen, hydroxyl, amino, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy, or trifluoromethoxy; R 7 is selected from H, methyl, ethyl or isopropyl; Each R 8 Each of the following is independently selected from H, halogen, hydroxyl, amino, cyano, methyl, ethyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, hydroxymethyl, aminomethyl, cyanomethyl or methoxymethyl; ​ ​ ​ ​ ​ ​ ​ ​

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