METTL3 inhibitors

Abstract

The invention discloses an METTL3 inhibitor as shown in a general formula (I), a pharmaceutical composition and a preparation method of the METTL3 inhibitor and application of the METTL3 inhibitor to preparation of medicines for preventing and / or treating indications related to METTL3. The compound is an ideal high-activity METTL3 inhibitor and can be used for treating and / or preventing diseases including AML, myeloid leukemia and solid tumors such as hepatocellular carcinoma, colorectal cancer and prostate cancer. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry and relates to a METTL3 inhibitor, a pharmaceutical composition thereof, a preparation method thereof and use thereof in preparing, preventing and / or treating drugs for indications related to METTL3. Background Art

[0002] m 6 A (N6-methyladenosine modification) is the most common post-transcriptional modification of mRNA in the human body, and is involved in the splicing, translation, stability, structure, output, and decay of pre-mRNA (Stephanie Oerum et al 2021). RNA methylation is regulated by writers (methyltransferases), readers (RNA binding proteins), and erasers (demethylases). 6 A is completed by a multi-component writing complex in the core (AlexandR a Maldonado Lopez et al 2021). METTL3 is a key m 6 A writer, forms a heterodimer with METTL14, and is m 6 The core component of the A methyltransferase complex (MTC), of which METTL3 has a catalytic function (Hanqi Liu et al 2023). In addition, WTAP protein binds to the METTL3-METTL14 dimer, which is necessary for the correct m 6 A modification is necessary (Schwartz S, et al 2014). In addition to WTAP protein, MTC also includes other adaptor proteins such as VIRMA, RBM15, ZC3H13, etc. (Su S, et al2022).

[0003] m 6 A participates in a variety of physiological functions. 6 A can modify the function of non-coding RNA, such as miRNA. Adenosine methylation modification can affect the production, transport, processing and functional activity of miRNA targeting mRNA (Alarcon, CR, et al 2015). In addition, it can also affect the function of lncRNA (Yuan S, et al 2014). Normal m 6 The maintenance of MTC levels is crucial for cardiovascular homeostasis, and MTC dysregulation is associated with cardiovascular diseases such as hypertension, atherosclerosis, and heart failure (Li L, et al 2022). 6 A is also related to nervous system development, Alzheimer's disease, and viral infection (FR a ncesco Fiorentino, et al2023).

[0004] m6 A plays an important role in the occurrence and development of tumors. METTL3 is overexpressed in breast cancer tissues and cells. It regulates Bcl-2 protein levels, methylates EZH2 mRNA to promote EZH2 expression, and mRNAs of tumor suppressor protein LATS1. 6 A regulation to reduce its level and other mechanisms to promote the occurrence and development of tumors (Hong Wang et al 2020, Youqin Xuet al 2023, Hu S, et al 2022), and can also increase the expression of PD-1 to inhibit tumor immune surveillance (Weijun Wanet al 2022) and promote breast cancer lung metastasis by regulating the mRNA stability and translation efficiency of KRT7 (Feng Chen et al 2021).

[0005] METTL3 is also involved in the occurrence and development of colorectal cancer. High expression of METTL3 is associated with CRC metastasis and poor prognosis. The self-renewal ability of CRC cells knocked out by METTL3 is significantly reduced, and the occurrence and metastasis of CRC tumors are inhibited in the corresponding tumor model (Ting Li et al 2019). The regulatory pathways involved include immunosuppression (Huarong Chen et al2022), activation of the GLUT1-mTORC1 pathway (Huarong Chen et al 2021), and the miR-1246 / MAPK pathway (WenPeng et al 2019).

[0006] Other tumors in which METTL3 plays a tumor-promoting role include solid tumors such as glioma, gastric cancer, hepatocellular carcinoma, lung cancer, melanoma, and hematological tumors such as AML and CML. METTL3 is highly expressed in tumor tissues compared with normal tissues and is an independent prognostic factor for overall and disease-free survival in gastric cancer patients (Yoshinaga Okugawa et al 2022). High expression of METTL3 was found in AML cells and DLBCL cells. High expression of METTL3 is necessary for the proliferation of AML cells (Isaia Barbieriet al 2017).

[0007] Inhibition of METTL3 can effectively inhibit tumor growth. Literature reports that METTL3 inhibitors can be used to treat myeloid leukemia (Eliza Yankova et al 2021) and can also reduce the growth of hepatocellular carcinoma cells resistant to lenvatinib (Lina Wang et al 2023).

[0008] METTL3 inhibitors can also be used in combination with other drugs, such as BCL-2 inhibitors for AML (LinaVasiliauskaite et al), anti-PD-1 for CRC (YaaR a Ofir-Rosenfeld et al) and others. Summary of the invention

[0009] In order to address the deficiencies of the prior art, the object of the present invention is to provide a METTL3 inhibitor, a pharmaceutical composition, a preparation method thereof, and use of the inhibitor in the preparation, prevention and / or treatment of drugs for METTL3-related indications.

[0010] In one aspect, the present invention provides a compound of formula (I):

[0011]

[0012] or a deuterated substance, a stereoisomer, a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof;

[0013] in,

[0014] Ring A is a 5-15 membered heterocyclic group, preferably a 5-6 membered monocyclic heterocyclic group, a 9-10 membered bicyclic heterocyclic group or a 13-14 membered tricyclic heterocyclic group, containing heteroatoms selected from O, N, S and P, and optionally 1, 2 or 3 atoms are substituted with oxo;

[0015] L 1 for

[0016] m is selected from 0, 1, 2, 3, 4 or 5;

[0017] R 1 is oxo, or

[0018] R 1 For-ZR a ;

[0019] Z is selected from chemical bonds, C 1-3 Alkylene, -NH-C 1-3 Alkylene, -C(=O)-, -O-, -S-, -S(=O)-, -SO 2 -;

[0020] R a Selected from halogen, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NH 2 , nitro, aldehyde, -NH-C 1-3Alkyl, -N(-C 1-3 alkyl) 2 , optionally substituted 3-6 membered cycloalkyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted phenyl, optionally substituted 5-7 membered heteroaryl;

[0021] When two R 1 When two R 1 It can form an optionally substituted 3-6-membered cycloalkyl group or a 3-6-membered heterocyclic group containing 1-2 heteroatoms selected from N, O, and S with the carbon atom to which it is attached;

[0022] Ring B is an 8-10 membered heterocyclic group, preferably an 8-10 membered heteroaryl group;

[0023] n, p are selected from 0, 1, 2 or 3; R 2a , R 2b are independently selected from H, halogen, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, nitro, aldehyde, or

[0024] R 2a , R 2b Together with the carbon atom to which it is attached, it forms a 3-6 membered cycloalkyl group or a 3-6 membered heterocycloalkyl group containing 1-2 N, O, or S heteroatoms;

[0025] R 3 Selected from H, halogen, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, nitro, aldehyde groups;

[0026] L 2 Selected from C 1-3 Alkylene, halogenated C 1-3 Alkylene;

[0027] R 4 for

[0028] R 5a , R 5b Select from H or -L 3 -R 6 , L 3 Selected from chemical bonds, C 1-3 Alkylene, halogenated C 1-3 Alkylene, R 6 Selected from C 1-6 Alkyl, C 2-6alkynyl, optionally substituted phenyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 4-8 membered heterocycloalkyl, or

[0029] R 5a , R 5b Together with the N atom to which it is attached, it forms an optionally substituted 4-10 membered heterocyclic group, preferably a 4-10 membered heterocyclic alkyl group.

[0030] In some embodiments, R 1 Only for -ZR a ;

[0031] In some embodiments, when two R 1 When two R 1 Not in a ring;

[0032] In some embodiments, R 2a , R 2b It does not form a ring with the carbon atom to which it is attached;

[0033] In some embodiments, the L 2 Selected from C 1-3 Alkylene;

[0034] In some embodiments, R 5a , R 5b Select from H or -L 3 -R 6 , L 3 Selected from chemical bonds, C 1-3 Alkylene, R 6 Selected from C 1-6 Alkyl, C 2-6 alkynyl, optionally substituted phenyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 4-8 membered heterocycloalkyl, or

[0035] R 5a , R 5b Together with the attached N atom, it forms an optionally substituted 4-10 heterocycloalkyl group.

[0036] In some preferred embodiments, any hydrogen atom on the compound of formula (I) can be replaced by deuterium to form a deuterated compound. In some more preferred embodiments, the deuterated site can be R 2a , R 2b , L 2 or L 3 .

[0037] As a preference:

[0038] The ring A is selected from the following i), ii), iii):

[0039] i) The ring C is selected from a 5-7 membered heterocyclic group containing 1-3 heteroatoms selected from N, O, and S; more preferably The X 1 , X 2 Independently selected from O, S, CH 2 、S(=O) 2 , C(=O), the X 3 Selected from CH 2 , NH or chemical bond;

[0040] At this time, ring A includes

[0041] ii) The ring D is selected from a 6-8 membered heterocyclic group containing 1-3 heteroatoms selected from N, O, and S. 1 Selected from N or CH; more preferably Z 1 Selected from N or CH, Z 2 , Z 3 Independently selected from CH 2 , NH, O, S;

[0042] At this time, ring A includes

[0043] iii)

[0044]

[0045] Ring A is preferably:

[0046]

[0047] m is selected from 0, 1, 2 or 3;

[0048] R 1 is oxo, or

[0049] R 1 For-ZR a ;

[0050] Z is selected from a chemical bond, a methylene group, -NH-CH 2 -, -C(=O)-, -O-, -S-, -S(=O)-, -SO 2 -;

[0051] R a Selected from halogen, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NH 2 , nitro, aldehyde, -NH-C 1-3 Alkyl, -N(-C 1-3 alkyl) 2 , optionally 1, 2 or 3 R b Substituted: 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-7 membered heteroaryl;

[0052] R b Selected from halogen, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NH 2 , nitro, aldehyde, -NH-C 1-3 Alkyl, -N(-C 1-3 alkyl) 2 , preferably F, methyl, methoxy, amino, methylamino;

[0053] R a Preferably F, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, amino, methylamino, optionally substituted by 1, 2 or 3 R b Substituted with the following groups: Phenyl, More preferably, F, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, amino, methylamino, Phenyl,

[0054] The R 1 More preferably, F, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, amino, methylamino,

[0055] When two R 1 When two R 1 It can form an optionally substituted 3-6 membered cycloalkyl or a 3-6 membered heterocyclic group containing 1-2 heteroatoms selected from N, O, and S with the attached carbon atom, preferably cyclopropyl, cyclobutyl, oxirane, oxetanyl, and azetidinyl.

[0056] In some embodiments, the ring A is selected from group iii). In some other embodiments, the ring A may also be selected from group i) or group ii).

[0057] In some embodiments, the ring A is selected from:

[0058]

[0059]

[0060] In some embodiments, Ring A is preferably:

[0061]

[0062] In some embodiments, R a Preferably F, methyl, amino, methylamino, optionally substituted by 1, 2 or 3 R b Substituted with the following groups: Phenyl, More preferably, F, methyl, amino, methylamino, Phenyl,

[0063] In some embodiments, the R 1 More preferably, F, methyl, amino, methylamino,

[0064] In some embodiments, the two R 1 When two R 1 Not a ring.

[0065] Further preferred:

[0066] The ring A and R 1 The following structure is formed:

[0067]

[0068]

[0069] In some embodiments, the ring A and R 1 The following structure is formed:

[0070]

[0071] In some embodiments, the ring A and R 1 The following structure is formed:

[0072]

[0073] As a preference: the ring B is selected from:

[0074]

[0075] Ring B is preferably:

[0076]

[0077] n is selected from 0, 1, 2 or 3;

[0078] R 3 Selected from H, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy is preferably H, F, methyl, trifluoromethyl, difluoromethyl, methoxy, or trifluoromethoxy.

[0079] In some embodiments, the ring B is selected from:

[0080]

[0081] Ring B is preferably:

[0082]

[0083] As a preference:

[0084] L 2 Selected from methylene and ethylene;

[0085] The R 4 for

[0086] R 5a , R 5b Select from H or -L 3 -R 6 , L 3 Selected from chemical bonds, methylene, ethylene, propylene, R 6 Selected from 1, 2 or 3 R 7 Substituted with the following groups: ethynyl, isopropyl, tert-butyl, phenyl, or R 5a , R 5b The N atom to which it is attached forms an optionally 1, 2 or 3 R 7 Replaced

[0089] The R 7 Selected from halogen, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C1-3 Alkyl, halogenated C 1-3 Alkoxy, =CF 2 , Hydroxyl C 1-3 Alkyl, preferably F, hydroxy, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, =CF 2 , hydroxymethyl.

[0090] In some embodiments, R 5a , R 5b Select from H or -L 3 -R 6 , L 3 Selected from chemical bonds, methylene, ethylene, propylene, R 6 Selected from 1, 2 or 3 R 7 Substituted with the following groups: ethynyl, isopropyl, tert-butyl, phenyl, or

[0091] R 5a , R 5b The N atom to which it is attached forms an optionally 1, 2 or 3 R 7 Replaced

[0092] In some embodiments, R 5a , R 5b Select from H or -L 3 -R 6 , L 3 Selected from chemical bonds, methylene, ethylene, propylene, R 6 Selected from 1, 2 or 3 R 7 Substituted with the following groups: ethynyl, isopropyl, tert-butyl, phenyl, or

[0093] R 5a , R 5b The N atom to which it is attached forms an optionally 1, 2 or 3 R 7 Replaced

[0094] In some embodiments, the R 7 Selected from F, hydroxy, methyl, methoxy, =CF 2 , hydroxymethyl.

[0095] Further preferred:

[0096] R 4 Selected from

[0097] In some embodiments, R 4 Selected from

[0098]

[0099] R 4 Selected from

[0100] Further preferred:

[0101] The L 2 With R 4 The following structure is formed:

[0102]

[0103] As a preference, L 1 for

[0104] As a preference, n and p are 1; R 2a , R 2b , R 3 For H.

[0105] In some preferred embodiments, the compound, or its deuterated substance, stereoisomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, has the structure of formula (II):

[0106]

[0107] in,

[0108] Ring A is selected from the following:

[0109] i) The ring C is selected from a 5-7 membered heterocyclic group containing 1-3 heteroatoms selected from N, O, and S; more preferably The X 1 , X 2 Independently selected from O, S, CH 2 、S(=O) 2 , C(=O), the X 3 Selected from CH 2 , NH or chemical bond;

[0110] At this time, ring A includes

[0111] ii) The ring D is selected from a 6-8 membered heterocyclic group containing 1-3 heteroatoms selected from N, O, and S. 1 Selected from N or CH; more preferably Z 1 Selected from N or CH, Z 2 , Z 3 Independently selected from CH 2 , NH, O, S;

[0112] At this time, ring A includes

[0113] iii)

[0114] m is selected from 0, 1, 2 or 3;

[0115] R 1 is oxo, or

[0116] R 1 For-ZR a ;

[0117] Z is selected from chemical bonds, C 1-3 Alkylene, -NH-C 1-3 Alkylene, -C(=O)-, -O-, -S-, -S(=O)-, -SO 2 -, preferably methylene, -NH-CH 2 -, -C(=O)-, -SO 2 -;

[0118] R a Selected from halogen, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NH 2 , nitro, aldehyde, -NH-C 1-3 Alkyl, -N(-C 1-3 alkyl) 2 , optionally 1, 2 or 3 R b Substituted: 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-7 membered heteroaryl;

[0119] R bSelected from halogen, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NH 2 , nitro, aldehyde, -NH-C 1-3 Alkyl, -N(-C 1-3 alkyl) 2 , preferably F, methyl, methoxy, amino, methylamino;

[0120] R a Preferred are F, methyl, amino, methylamino;

[0121] When two R 1 When two R 1 It can form an optionally substituted 3-6-membered cycloalkyl group or a 3-6-membered heterocyclic group containing 1-2 heteroatoms selected from N, O, and S with the carbon atom to which it is attached;

[0122] L 1 for

[0123] Ring B is selected from:

[0124] n is selected from 0, 1, 2 or 3;

[0125] R 3 are independently selected from halogen, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy;

[0126] R 5a , R 5b Select from H or -L 3 -R 6 ; L 3 Selected from chemical bonds, C 1-3 Alkylene, halogenated C 1-3 Alkylene, preferably chemical bond, methylene, R 6 Selected from C 1-6 Alkyl, C 2-6 alkynyl, optionally substituted phenyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 4-8 membered heterocycloalkyl, preferably ethynyl, isopropyl, tert-butyl, optionally substituted by 1, 2 or 3 R 7 Substituted with the following groups: phenyl, or R 5a , R 5b Together with the N atom to which it is attached, it forms an optionally substituted 4-10 membered heterocyclic group, preferably a 4-10 membered heterocyclic alkyl group, preferably optionally substituted by 1, 2 or 3 R 7 Substituted with the following groups:

[0127] The R 7 Selected from halogen, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, =CF 2 , hydroxyl C 1-3 Alkyl, preferably F, hydroxy, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, =CF 2 , hydroxymethyl.

[0128] In some embodiments, the ring A is selected from group iii). In some other embodiments, the ring A may also be selected from group i) or group ii).

[0129] In some embodiments, when two R 1 When two R 1 Not in a ring;

[0130] In some embodiments, Ring B is selected from:

[0131] In some embodiments, L 3 Selected from chemical bonds, C 1-3 The alkylene group is preferably a chemical bond or a methylene group.

[0132] In some embodiments, R 6 Selected from C 1-6 Alkyl, C 2-6 alkynyl, optionally substituted phenyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 4-8 membered heterocycloalkyl, preferably ethynyl, isopropyl, tert-butyl, optionally substituted by 1, 2 or 3 R 7 Substituted with the following groups: phenyl, More preferably, ethynyl, isopropyl, tert-butyl, optionally substituted with 1, 2 or 3 R 7 Substituted with the following groups: phenyl,

[0133] In some embodiments, preferably R 5a, R 5b The N atom to which it is attached forms an optionally 1, 2 or 3 R 7 Substituted with the following groups:

[0134] In some embodiments, R 5a , R 5b The N atom to which it is attached forms an optionally substituted 4-10 heterocycloalkyl group, preferably optionally substituted with 1, 2 or 3 R 7 Substituted with the following groups:

[0135] In some embodiments, the R 7 Preferred are F, hydroxy, methyl, methoxy, =CF 2 , hydroxymethyl.

[0136] In some preferred embodiments, Ring A is selected from:

[0137]

[0138] Best More preferred

[0139] R 1 is oxo, or

[0140] R 1 For-ZR a ;

[0141] Z is selected from a chemical bond;

[0142] R a Selected from halogen, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy; preferably F, methyl.

[0143] In some more preferred embodiments, L 1 for

[0144] As a preference:

[0145] Ring B is selected from Best

[0146] R 3Independently selected from F, Cl, methyl, methoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy;

[0147] In some further preferred embodiments, the ring B is optionally substituted with 1, 2, or 3 F; the ring B and R 3 composition Best

[0148] As a preference: R 6 Selected from 1, 2 or 3 R 7 The following groups substituted: 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O, S, thienyl. The cycloalkyl or heterocycloalkyl may be in the form of a monocyclic, bicyclic, condensed, bridged, spirocyclic, etc.

[0149] R 6 More preferred

[0150] R 7 Selected from halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, =CF 2 , preferably F, hydroxy, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, =CF 2 , more preferably F, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy;

[0151] As a preference:

[0152] R 5a , R 5b The N atom to which it is attached preferably optionally 1, 2 or 3 R 7 The following groups substituted: 4-10 membered heterocycloalkyl containing 1-3 selected from N, O, S, 4-10 membered heterocyclic groups containing 1-3 selected from N, O, S; preferably 4-10 membered heterocycloalkyl containing 1-3 selected from N, O, S, The cycloalkyl group and heterocyclic group may be in the form of a monocyclic ring, a bicyclic ring, a condensed ring, a bridged ring, a spirocyclic ring, etc.;

[0153] More preferably R 5a , R 5b The N atom to which it is attached preferably optionally 1, 2 or 3 R 7 Substituted with the following groups:

[0154] R 7Selected from halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, =CF 2 , preferably F, hydroxy, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, =CF 2 , more preferably F, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy.

[0155] In some preferred embodiments, the compound, or its deuterated form, stereoisomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, has the structure of formula (III):

[0156]

[0157] r and q are selected from 0, 1 or 2.

[0158] In some embodiments, the above compounds may be deuterated, and the deuterated sites may be any atoms replaced by H atoms. In some more preferred embodiments, the deuterated sites are located at the C atoms or L atoms marked with "*", "**". 3 More preferably, the deuterated site is located at L 3 .

[0159]

[0160] The compounds of formula (I) include the following specific compounds, or deuterated compounds, stereoisomers, pharmaceutically acceptable salts, and pharmaceutically acceptable solvates thereof:

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171] Another aspect of the present invention provides a pharmaceutical composition, which contains any one of the above-mentioned compounds, deuterated substances, stereoisomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier thereof.

[0172] Another aspect of the present invention provides a use of any one of the above-mentioned compounds, deuterated substances, stereoisomers or pharmaceutically acceptable salts thereof, or the above-mentioned pharmaceutical composition in the preparation of drugs for treating and / or preventing METTL3-related diseases.

[0173] Preferably, the METTL3-related disease is selected from autoimmune diseases, neurological diseases, infectious diseases, and tumors.

[0174] Preferably, the METTL3-related disease is selected from AML, myeloid leukemia, solid tumors such as hepatocellular carcinoma, colorectal cancer, and prostate cancer.

[0175] The compounds provided by the present invention have strong efficacy, good pharmacokinetic properties, and low toxic side effects, and are ideal METTL3 inhibitors. The compounds provided by the present invention have better METTL3 inhibitory activity. The compounds of the present invention are ideal highly active METTL3 inhibitors and can be used to treat and / or prevent diseases including AML, myeloid leukemia, solid tumors such as hepatocellular carcinoma, colorectal cancer, and prostate cancer.

[0176] Compared with control drugs, the tricyclic compounds provided by the present invention have stronger METTL3 inhibitory activity (including kinases and cells), better pharmacokinetic properties (higher AUC and lower clearance rate), and lower toxic side effects. DETAILED DESCRIPTION

[0177] The present invention is further described in detail below in conjunction with specific embodiments, but the present invention is not limited to the following embodiments.

[0178] definition

[0179] "Optional" or "optionally" used herein means that any optional item can be selected or not selected. For example, "group A is optionally replaced by 1-3 groups B" comprises that group A is not replaced by group B, group A is replaced by 1 group B, group A is replaced by 2 groups B, and group A is replaced by 3 groups B. These four situations.

[0180] As used herein, "substituted" or "substituted" means that any one or more hydrogen atoms on any atom in a group or fragment are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable. When the substituent is "oxo" (i.e., =O), it means that two hydrogen atoms are replaced by oxygen, and when the atom replaced by oxygen is a carbon atom, a carbonyl group (C=O) is formed. Oxygen substitution does not occur on aromatic groups.

[0181] As used herein, "optionally substituted" means that it may be substituted or unsubstituted, and unless otherwise specified, the type and number of substituents may be any on the basis of chemical practicability. For example, "optionally substituted 5-6 membered heterocyclic group" means a 5-6 membered heterocyclic group that is substituted or unsubstituted by any group.

[0182] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice. In addition, combinations of substituents and / or variants thereof are permitted only if such combinations result in stable compounds.

[0183] When the number of a linking group is 0, such as -(CR a R b ) 0 -, indicating that the connecting group is a single bond / chemical bond.

[0184] When one of the variables is selected from chemical bond / single bond, it means that the two groups connected are directly connected, such as AL 1 -R 1 Medium 1 When it represents a single bond, it means that the structure is actually AR 1 .

[0185] The "chemical bond" used herein generally refers to a covalent bond between two atoms in a compound molecule formed by sharing a pair of electrons.

[0186] When a substituent is vacant, it means that the substituent does not exist. For example, when X in AX is vacant, it means that the structure is actually A. When the listed substituent does not specify which atom it is connected to the substituted group through, the substituent can be bonded through any atom of it. For example, pyridyl as a substituent can be connected to the substituted group through any carbon atom on the pyridine ring.

[0187] When the linking group is listed without specifying its direction of attachment, its direction of attachment is arbitrary. For example, ring AL1 -R 1 The connecting group L 1 -MW- can connect rings A and R in the same direction as reading from left to right. 1 AMWR 1 , you can also connect rings A and R in the opposite direction of reading from left to right 1 Composition ring AWMR 1 Combinations of linkers, substituents, and / or variations thereof are permissible only if such combinations result in stable compounds.

[0188] If there is no special description, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the connection mode of the chemical bond is non-positional and there are H atoms at the connectable sites, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds and become a group with corresponding valence. The chemical bond connecting the site to other groups can be represented by a straight solid line bond straight line. Dotted key For example, -OCH 3 The straight solid bond in the group indicates that it is connected to other groups through the oxygen atom in the group; The straight dashed bond in the group indicates that the two ends of the carbon atoms in the group are connected to other groups; The dotted lines in the figure indicate that the 1- and 4-carbon atoms in the phenyl group are connected to other groups; It means that any connectable site on the piperidine group can be connected to other groups through one chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Still includes For groups connected in this way, when one chemical bond is connected, the H at that site will be reduced by one and become a corresponding monovalent piperidine group.

[0189] Unless otherwise specified, in a cyclic group, the attachment site of the group or fragment is located on the ring connected by the dotted line. For example, Any connection site on the benzene ring of the group can be connected to other groups through one chemical bond, including at least These are 4 connection methods.

[0190] Generally, in aromatic or heteroaromatic rings, double bonds and single bonds have no limiting meaning. For example, All refer to a benzene ring or a phenyl group, wherein the double bond or Specifically refers to the large π bond delocalized in the plane of the benzene ring; When ring C is limited to a 5-membered aryl or heteroaryl group, ring B and ring C form a conjugated cyclic aryl or cyclic heteroaryl group, and its non-limiting examples include even though The left ring in the Still includes In this group, the double bond represents a large π bond delocalized on the annular aromatic ring.

[0191] The numerical intervals used herein include the endpoint values ​​and any values ​​between the endpoint values. For example, "0-3" may include 0, 1, 2 or 3, and "1-3" may include 1, 2 or 3.

[0192] The “C 1-n "Including C 1-2 , C 1-3 , ...C 1-n For example, “C 1-6 " means that the moiety has 1-6 carbon atoms, i.e., the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms. Thus, for example, "C 1-4 "Alkyl" refers to an alkyl group containing 1-4 carbon atoms, that is, the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. The numerical ranges in this article, such as "1-6", refer to each integer in the given range.

[0193] The annular atom refers to the non-hydrogen atom in the ring group that is used to form the ring. The linking atoms in are 3 carbon atoms; The atoms in the middle ring are three carbon atoms and one oxygen atom; The atoms in the middle chain are 1 N atom and 5 carbon atoms; The atoms in the middle chain are 8 carbon atoms and 1 nitrogen atom.

[0194] As used herein, "nm members" refers to the number of annular atoms in a cyclic group. For example, a "3-8 member" group refers to a group having 3-8 annular atoms in the moiety, i.e., the group contains 3 annular atoms, 4 annular atoms, 5 annular atoms, 6 annular atoms, 7 annular atoms, or 8 annular atoms. Thus, for example, a "3-8 membered cycloalkyl" refers to a saturated cyclic alkyl group containing 3-8 carbon atoms, i.e., the alkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

[0195] The term "alkyl" used herein, alone or in combination, refers to an optionally substituted straight chain or optionally substituted branched saturated aliphatic hydrocarbon. The "alkyl" herein preferably has 1-6 carbon atoms, for example 1-5 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, and the like. In the definitions of radicals herein, when the term “alkyl” appears in a numerical range, for example, “C 1-6 The term "alkyl" refers to an alkyl group which may be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, and the alkyl group herein also includes the case where no numerical range is specified. The alkyl group may be optionally substituted or unsubstituted.

[0196]

[0046] "Alkyl" as used herein in combination refers to an alkyl group attached to another group, for example, an alkyl group in an alkoxy group, and has the same definition as when used alone.

[0197] The term "alkoxy" or "-O-alkyl" as used herein, alone or in combination, is represented as "alkyl-O-". Non-limiting examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like. Alkoxy groups may be optionally substituted or unsubstituted.

[0198] The term "cycloalkyl" as used herein alone or in combination refers to a saturated monocyclic, bicyclic, fused, bridged, spirocyclic, and other carbocyclic rings. Preferably, 3-12-membered cycloalkyls are used herein, more preferably 3-10-membered cycloalkyls are used herein, and most preferably 3-8-membered cycloalkyls are used herein. Non-limiting examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like, which may be optionally substituted or unsubstituted.

[0199] The term "aryl" used herein, alone or in combination, refers to an aromatic hydrocarbon ring. The term "aryl" includes monocyclic aromatic hydrocarbons and polycyclic condensed ring (and ring) aromatic hydrocarbons, wherein all condensed ring systems (excluding any ring system that is a part of an optional substituent or formed by an optional substituent) are aromatic. Examples of aryl groups / parts include phenyl, naphthyl, anthracenyl and phenanthrenyl. Unless otherwise indicated, the term "aryl" does not include "heteroaryl".

[0200] The term "heterocyclyl" used herein alone or in combination includes alicyclic and heteroaryl groups, wherein one or more (such as one, two, three or four) of the annular atoms are heteroatoms, such as oxygen, nitrogen, sulfur atoms, etc., including monocyclic, condensed, bridged and spirocyclic rings. Examples of heterocyclic groups include heterocycloalkyl, heterocycloalkenyl and heteroaryl groups as discussed below. Preferred herein are 3-10 membered monocyclic, bicyclic or tricyclic heterocyclic groups, which may contain 1, 2 or 3 annular atoms selected from nitrogen, oxygen and / or sulfur. Non-limiting examples of "heterocyclyl" include azetidinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, imidazolidinyl, dioxolanyl, oxathiolanyl, piperidinyl, 2-oxo-piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, piperazin-2-one, dioxanyl, morpholinyl and thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, etc. The heterocyclyl group may be optionally substituted or unsubstituted.

[0201] In the definition of "heterocyclic group", "heterocyclic group" refers to a polycyclic group containing heteroatoms, which contains two or more cyclic structures and shares a pair of atoms with each other. Among them, one or more rings may contain several unsaturated bonds, or one ring may have a completely conjugated π-electron aromatic system, and the atoms in the rings are selected from nitrogen, oxygen or S(O) n (wherein n is selected from 0, 1 or 2) heteroatoms, and the remaining link atoms are carbon. It is preferably 6-12 members, more preferably 8-9 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic cyclic ring group, preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic cyclic ring group.

[0202] The term "heterocycloalkyl" used herein alone or in combination refers to a saturated monocyclic, bicyclic or polycyclic, wherein one or more (such as one, two, three or four) ring atoms are saturated heterocyclic groups of heteroatoms, which can be spirocyclic or bridged rings.Preferred herein are 3-12 membered heterocycloalkyls, more preferably 3-10 membered heterocycloalkyls, most preferably 3-8 membered heterocycloalkyls.Non-limiting examples of monocyclic heterocycloalkyls include but are not limited to propylene oxide, thiirane, aziridine, azetidine, oxetane, thiamine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, oxazolidine, thiazolidine, imidazolidine, tetrahydropyran, piperidine, dioxane, azepane.

[0203] The term "heteroaryl" as used herein, alone or in combination, refers to a 5-12 membered (preferably 5-10 membered, more preferably 5-6 membered) monocyclic, bicyclic or tricyclic ring system, wherein at least one ring is aromatic and at least one ring contains one or more heteroatoms selected from nitrogen, oxygen, and sulfur, and the heteroaryl group has one or more points of attachment to the rest of the molecule. Non-limiting examples of "heteroaryl" include furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, and the like; and also include, but are not limited to, the following bicyclic rings: benzimidazolyl, benzofuranyl, benzothienyl, indolyl, oxoindolyl, indolinyl, imidazopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, quinolyl, isoquinolyl, quinazolinyl, indazole, 1,8-naphthyridine, benzo[d]isoxazole, benzo[ d]thiazole, pyrrolo[3,2-b]pyridine, furano[3,2-b]pyridine, pyrrolo[1,2-b]pyridazine, imidazo[1,2-b]pyridazine, pyrazolo[1,5-a]pyrimidine, thiazolo[4,5-c]pyridine, thieno[3,2-b]pyridine, pyrrolo[1,2-b]pyridazine, 2,3-dihydrobenzofuran, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, benzo[d]oxazol-2(3H)-one, etc. The heteroaryl group may be optionally substituted or unsubstituted.

[0204] The term "halogen," as used herein, alone or in combination, refers to fluorine, chlorine, bromine or iodine.

[0205] The term "hydroxy," as used herein, alone or in combination, refers to -OH.

[0206] The term "cyano," as used herein, alone or in combination, refers to -CN.

[0207] As used herein, the term "substituted" or "substituted by" means that one or more hydrogens on a particular atom are replaced by a specified group (such as halogen, alkyl, etc.), and if the normal valence of the specified atom is not exceeded under the existing circumstances, the substitution results in a stable compound.

[0208] The term "pharmaceutically acceptable salt" used herein is well known to those skilled in the art.

[0209] The term "pharmaceutically acceptable" as used herein refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, that is, the substance can be administered to a subject without causing adverse biological reactions or interacting in an adverse manner with any components contained in the composition.

[0210] The term "pharmaceutical composition" as used herein refers to a biologically active compound optionally mixed with at least one pharmaceutically acceptable chemical component, including but not limited to a carrier, stabilizer, diluent, dispersant, suspending agent, thickener and / or excipient.

[0211] As used herein, the term "carrier" refers to relatively nontoxic chemical compounds or agents that facilitate the introduction of a compound into cells or tissues.

[0212] The term "stereoisomer" as used herein includes, but is not limited to, enantiomers, cis-trans isomers, and the like.

[0213] The term "enantiomer" as used herein refers to the isomerism caused by the different spatial configuration of atoms or atomic groups (groups) in compounds with the same molecular formula, and two compounds that are enantiomers are mirror images of each other and cannot overlap. The term "cis-trans isomer" as used herein generally refers to the stereoisomerism of diastereoisomers that occur in compound molecules due to the restriction factor of free rotation, which makes each group arranged in space differently. Organic molecules containing such isomers such as olefins, azo compounds, alicyclic hydrocarbons, etc. are regarded as cis-trans isomers. In the present application, cis-trans isomerism is mainly embodied in the form of alicyclic hydrocarbons. For example, in cyclohexane, cis-trans isomerism will occur when cyclohexane is replaced by two substituents, and when the two substituents are replaced on the same side of the ring, they are "cis" isomers, and on different sides, they are "trans" isomers.

[0214] The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, hindered isomers and geometric (conformation) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

[0215] Unless otherwise indicated, the structure described in the present invention also includes all isomers of the structure (e.g., diastereomers, enantiomers, cis-trans isomers, steric isomers, geometric (conformation) isomer forms), for example, R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, cis-trans isomers of aliphatic cyclic hydrocarbons, steric isomers of biphenyl structures (see "Basic Organic Chemistry" (Second Edition), Volume 1, Xing Qiyi et al., p104-105); PAC, 1996, 68, 2193. (Basic terminology of stereochemistry (IUPAC Recommendations 1996, on page 2201)), (Z) and (E) conformational isomers. Therefore, single stereoisomers of the compounds of the present invention as well as enantiomeric mixtures, diastereomeric mixtures, steric isomers and geometric (conformation) isomer mixtures are all within the scope of the present invention.

[0216] In some preferred embodiments, the compound, or its deuterated substance, stereoisomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, has the structure of formula (II):

[0217]

[0218] Wherein each group is defined as described above (claims or invention content), when L 1 for When the compound has the general formula (IV):

[0219]

[0220] For the compound of general formula (IV), the following method can be generally used for synthesis:

[0221]

[0222] Intermediate A and intermediate B undergo amide condensation reaction in the presence of a condensation reagent to obtain intermediate C, intermediate C undergoes acetal deprotection reaction under acidic conditions to obtain intermediate D, and intermediate D undergoes reductive amination reaction with an amine raw material under the condition of a reducing agent to obtain a compound of the structure represented by general formula (IV).

[0223] Step 1: Synthesis of intermediate C.

[0224] Intermediate A and intermediate B undergo amide condensation reaction in the presence of a condensation reagent to obtain intermediate C. The specific reaction conditions at this time are:

[0225]

[0226] Dissolve intermediate A and intermediate B in a solvent, add a condensation reagent and a base, react at room temperature or above room temperature, and monitor the reaction by methods such as TLC or LCMS until the reaction is complete to obtain intermediate C. Among them, the solvent, condensation reagent and base can be selected from common amide condensation reaction systems. In some specific embodiments, the solvent can be selected from N, N-dimethylformamide, dichloromethane, dichloroethane, tetrahydrofuran or a combination thereof. In some specific embodiments, the condensation reagent can be HATU, HBTU, T3P, T4P, CDI, EDCI, PyBOP, trichlorophosphorus. In some specific embodiments, the base can be N, N-diisopropylethylamine, triethylamine, potassium carbonate, pyridine. Among them, when the reaction temperature is higher than room temperature, the reflux temperature of the solvent can also be selected, or slightly lower than the reflux temperature, specifically any temperature of 50-80°C.

[0227] Step 2: Synthesis of intermediate D.

[0228] Intermediate C is subjected to acetal deprotection reaction under acidic conditions to obtain intermediate D. The specific reaction conditions at this time are:

[0229]

[0230] Dissolve intermediate C in a solvent, add water and an acid reagent, react at room temperature or above room temperature, monitor the reaction by methods such as TLC or LCMS until the reaction is complete, and obtain intermediate D. Among them, the solvent and the acid reagent can be selected from common acetal deprotection reaction systems. In some specific embodiments, the solvent can be selected from tetrahydrofuran, water or a combination thereof. In some specific embodiments, the acid reagent can be acetic acid, p-toluenesulfonic acid, hydrochloric acid. Among them, when the reaction temperature is higher than room temperature, the reflux temperature of the solvent can also be selected, or slightly lower than the reflux temperature, specifically any temperature of 40-80°C.

[0231] Step 3: Synthesis of the compound with the structure shown in general formula (IV).

[0232] The intermediate D and the amine raw material are subjected to a reductive amination reaction under the condition of a reducing agent to obtain a compound of the structure shown in the general formula (IV). The specific reaction conditions at this time are:

[0233]

[0234] Dissolve the intermediate D and the amine raw material in a solvent, add an acid catalyst, and then add a reducing agent, react at room temperature or above room temperature, and monitor the reaction by methods such as TLC or LCMS until the reaction is complete to obtain a compound of the structure shown in the general formula (IV). Among them, the solvent, the acid catalyst, and the reducing agent can be selected from common reductive amination reaction systems. In some specific embodiments, the solvent can be selected from methanol, N,N-dimethylformamide, or a combination thereof. In some specific embodiments, the acid catalyst can be acetic acid. In some specific embodiments, the reducing agent can be selected from sodium cyanoborohydride, sodium acetate borohydride, and sodium borohydride. Among them, when the reaction temperature is higher than room temperature, the reflux temperature of the solvent can also be selected, or slightly lower than the reflux temperature, specifically any temperature between 40-80°C.

[0235] The present invention is further described in detail below in conjunction with specific embodiments, but the present invention is not limited to the following embodiments.

[0236] Some of the preparation conditions used in the examples are as follows:

[0237] Prep-HPLC conditions: instrument: GILSON-GX281; wavelength: 220 nm & 254 nm; column model: Waters X-bridge (30 × 100 mm, 10 μm) or Luna C18 (30 × 75 mm, 3 μm) or Luna C18 (30 × 75 mm, 3 μm); mobile phase: A: 10 mM ammonium bicarbonate or H 2 O (0.1% formic acid) or H 2 O (0.1% trifluoroacetic acid), B: acetonitrile; running time: 15 min; flow rate: 25 mL / min.

[0238] Reverse phase column purification used a C18 reverse phase silica gel column (Spherical C18, 40-60 μm, 40 g-120 g) with water / acetonitrile (95 / 5 to 30 / 70) as the mobile phase.

[0239] The synthesis steps of some intermediates in the present invention are as follows:

[0240] Intermediate 1: tert-butyl 6-(aminomethyl)-2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-1H-indole-1-carboxylate

[0241]

[0242] (1) 3-Amino-4-iodobenzonitrile

[0243] 4-iodo-3-nitrobenzonitrile (10g, 36.5mmol), iron powder (6.1g, 109.5mmol), ammonium chloride (5.9g, 109.5mmol) were dissolved in a mixture of ethanol / water (80mL / 20mL) and stirred at 80°C for 16 hours under condensation reflux conditions. The reaction solution was filtered, the filtrate was concentrated, water (50mL) was added, and the aqueous phase was extracted with ethyl acetate (30mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50mL), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 90 / 10) to obtain the title compound (4.3g, light yellow solid), yield: 48%. MS (ESI): m / z 244.9 [M+H] + .

[0244] (2) 3-Amino-4-(3,3-diethoxyprop-1-yn-1-yl)benzonitrile

[0245] 3-Amino-4-iodobenzonitrile (4.2 g, 17 mmol), bis(triphenylphosphine)palladium dichloride (119 mg, 0.17 mmol), triphenylphosphine (89 mg, 0.34 mmol), cuprous iodide (65 mg, 0.34 mmol) and triethylamine (5.2 g, 51 mmol) were added to tetrahydrofuran (40 mL) in sequence, and the mixture was stirred at room temperature for 20 minutes under nitrogen protection. Then, a solution of 3,3-diethoxyprop-1-yne (2.6 g, 20 mmol) in tetrahydrofuran (20 mL) was slowly added, and the reaction was continued to stir at room temperature for 16 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 90 / 10) to obtain the title compound (3.8 g, yellow oil), with a yield of 90%. MS (ESI): m / z 199.0 [M+H-EtOH] + .

[0246] (3) 2-(diethoxymethyl)-1H-indole-6-carbonitrile

[0247] 3-Amino-4-(3,3-diethoxyprop-1-yn-1-yl)benzonitrile (3.3 g, 13.5 mmol) was dissolved in tetrahydrofuran (30 mL), and 1 M lithium bis(trimethylsilyl)amide (27 mL, 27 mmol) was slowly added dropwise at 0°C. After the addition was completed, the reaction solution was stirred at 75°C for 4 hours under condensation reflux. Water (60 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 93 / 7) to obtain the title compound (1.6 g, white solid), yield: 58%. MS (ESI): m / z 245.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.68(s,1H),7.80(s,1H),7.69(d,J=8.0Hz,1H),7.32(d,J=8.4Hz,1H),6.57(s,1H),5.77(s,1H),3.61-3.58(m,4H),1.21-1.17(m,6H).

[0248] (4) 2-Formyl-1H-indole-6-carbonitrile

[0249] 2-(Diethoxymethyl)-1H-indole-6-carbonitrile (200 mg, 0.8 mmol) and acetic acid (0.5 mL) were added to a mixed solvent of tetrahydrofuran / water (5 mL / 0.5 mL) and stirred at room temperature for 2 hours. The reaction solution was concentrated, water (10 mL) was added, and the aqueous phase was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound (130 mg, yellow solid), yield: 94%. MS (ESI): m / z 171.0 [M+H] + .

[0250] (5) 2-(((Cyclobutylmethyl)amino)methyl)-1H-indole-6-carbonitrile

[0251] 2-Formyl-1H-indole-6-carbonitrile (250 mg, 1.5 mmol) and cyclobutylmethylamine (383 mg, 4.5 mmol) were dissolved in dichloroethane (5 mL), and the mixture was heated to 65 ° C and stirred for 1 hour. Sodium cyanoborohydride (331 mg, 5.25 mmol) was added and stirred at 65 ° C for 2 hours. The reaction solution was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 95 / 5) to obtain the title compound (200 mg, green oil), yield: 57%. MS (ESI): m / z 240.1 [M+H] + .

[0252] (6) tert-Butyl 2-(((tert-Butyloxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-cyano-1H-indole-1-carboxylate

[0253] 2-(((Cyclobutylmethyl)amino)methyl)-1H-indole-6-carbonitrile (200mg, 0.84mmol) and sodium hydride (224mg, 3.36mmol, 60%) were dissolved in tetrahydrofuran (10mL) and stirred at room temperature for 5 minutes. Di-tert-butyl dicarbonate (732mg, 3.36mmol) was added and the reaction was stirred at room temperature for 4 hours. Water (20mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (20mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 95 / 5) to give the title compound (300mg, colorless oil), yield: 82%. MS (ESI): m / z 340.1 [M+H-100] + .

[0254] (7) tert-Butyl 6-(aminomethyl)-2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-1H-indole-1-carboxylate

[0255] 2-(((tert-butyloxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-cyano-1H-indole-1-carboxylic acid tert-butyl ester (300 mg, 0.68 mmol) and Raney nickel (30 mg, 10%) were added to ammonia methanol solution (10 mL), hydrogen was replaced 3 times, and the mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. Raney nickel was removed by filtration, and the filtrate was concentrated to obtain the title compound (300 mg, green oil, containing about 10% of intermediate 2), yield: 99%. MS (ESI): m / z 444.1 [M+H] + .

[0256] Intermediate 2: tert-butyl ((6-(aminomethyl)-1H-indol-2-yl)methyl)(cyclobutylmethyl)carbamate

[0257]

[0258] 2-(((tert-Butyloxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-cyano-1H-indole-1-carboxylic acid tert-butyl ester (2.5 g, 5.7 mmol) and Raney nickel (250 mg, 10%) were added to ammonia methanol solution (50 mL), hydrogen was replaced 3 times, and the mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. Raney nickel was removed by filtration, and the filtrate was concentrated to obtain the title compound (2 g, green oil, containing about 20% of intermediate 1), yield: 99%. MS (ESI): m / z 344.1 [M+H] + .

[0259] Intermediate 3: 4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid

[0260]

[0261] Dissolve 4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid methyl ester (2g, 10mmol) in a mixed solvent of methanol / water (20mL / 4mL), add sodium hydroxide (1.2g, 30mmol), and stir at room temperature for 2 hours. The reaction solution is concentrated, diluted with water, and the pH is adjusted to acidity with dilute hydrochloric acid. Let stand for 1 hour until solids precipitate, filter, and dry the solids to obtain the title compound (1.6g, white solid), yield: 86%. MS (ESI): m / z 191.0 [M+H] + .

[0262] Intermediate 4: 9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxylic acid

[0263]

[0264] (1) 2-((6-bromo-4-iodopyridin-3-yl)oxy)ethane-1-ol

[0265] At 0°C, 2-bromo-5-fluoro-4-iodopyridine (3.7 g, 12.26 mmol), ethylene glycol (3.8 g, 61.28 mmol) and sodium tert-butoxide (1.51 g, 13.48 mmol) were dissolved in N,N-dimethylformamide (30 mL), and the mixture was heated to 80°C and stirred for 1 hour. The reaction solution was added to water (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 60 / 40) to obtain the title compound (1.0 g, pink solid), yield: 24%. MS (ESI): m / z 343.8 [M+H] + .

[0266] (2) 7-Bromo-2,3-dihydro-[1,4]dioxacyclo[2,3-c]pyridine

[0267] 2-((6-bromo-4-iodopyridin-3-yl)oxy)ethane-1-ol (1.0 g, 2.91 mmol) was dissolved in isopropanol (20 mL), and potassium tert-butoxide (490 mg, 4.36 mmol), 3,4,7,8-tetramethyl-1,10-phenanthroline (69 mg, 0.29 mmol) and cuprous iodide (34 mg, 0.17 mmol) were added. The mixture was heated to 80 °C and stirred for 1 hour. The reaction solution was added to water (20 mL), and then saturated ammonium chloride solution (10 mL) was added, and the aqueous phase was extracted with ethyl acetate (40 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 85 / 15) to obtain the title compound (400 mg, white solid), yield: 64%. MS (ESI): m / z 215.9 [M+H] + .

[0268] (3) tert-Butyl (2,3-dihydro-[1,4]dioxo[2,3-c]pyridin-7-yl)carbamate

[0269] 7-Bromo-2,3-dihydro-[1,4]dioxacyclo[2,3-c]pyridine (350 mg, 1.62 mmol) and tert-butyl carbamate (574 mg, 4.86 mmol) were dissolved in 1,4-dioxane (20 mL), and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (161 mg, 0.32 mmol), tris(dibenzylideneacetone)dipalladium (154 mg, 0.16 mmol) and cesium carbonate (1.32 g, 4.05 mmol) were added. The mixture was heated to 90°C under nitrogen protection and stirred for 16 hours. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 20) to obtain the title compound (310 mg, yellow solid), yield: 76%. MS (ESI): m / z 197.0 [M+H-56] + .

[0270] (4) 2,3-Dihydro-[1,4]dioxo[2,3-c]pyridin-7-amine

[0271] Dissolve tert-butyl (2,3-dihydro-[1,4]dioxo[2,3-c]pyridin-7-yl)carbamate (600 mg, 2.38 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (5 mL), and stir at room temperature for 12 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain the title compound (140 mg, yellow solid), yield: 39%. MS (ESI): m / z 153.0 [M+H] + .

[0272] (5) 9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxylic acid methyl ester

[0273] Dissolve 2,3-dihydro-[1,4]dioxo[2,3-c]pyridin-7-amine (100 mg, 0.66 mmol) and dimethyl butane-2-diacetate (160 mg, 0.72 mmol) in water (15 mL) and stir at room temperature for 12 hours. Ethyl acetate (30 mL) was added to the reaction solution for extraction, and the organic phase was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 90 / 10) to obtain the title compound (100 mg, yellow solid), yield: 58%. MS (ESI): m / z 263.0 [M+H] + .

[0274] (6) 9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxylic acid

[0275] 9-Oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxylic acid methyl ester (100 mg, 0.38 mmol) was dissolved in methanol / water (5 mL / 5 mL), sodium hydroxide (76 mg, 1.91 mmol) was added, and the mixture was heated to 80 ° C and stirred for 4 hours. The reaction solution was concentrated, 1M dilute hydrochloric acid was added to adjust the pH value to 5, and the aqueous phase was extracted with dichloromethane (30 mL x 3). The organic phases were combined and concentrated to give the title compound (60 mg, yellow solid), yield: 63%. MS (ESI): m / z 249.0 [M+H] + .

[0276] Intermediate 5: 8-Oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxylic acid

[0277]

[0278] (1) 2-Bromo-5-(methoxymethoxy)pyridine

[0279] Dissolve 6-bromopyridin-3-ol (4.46 g, 25.8 mmol) in anhydrous tetrahydrofuran (50 mL), add 1 M potassium bis(trimethylsilyl)amide in tetrahydrofuran solution (25.8 mL, 25.8 mmol) dropwise at 0°C, add bromo(methoxy)methane (3.87 g, 31 mmol) after 10 minutes, and react at room temperature overnight. Add saturated aqueous ammonium chloride solution (80 mL) to the reaction solution, and extract the aqueous phase with ethyl acetate (2 x 50 mL). The organic phases are combined, washed with saturated sodium chloride solution (75 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 20) to obtain the title compound (3.93 g, light yellow oil), yield: 70%. MS (ESI): m / z 217.6 [M+H] + .

[0280] (2) 2-Bromo-5-(methoxymethoxy)pyridin-4-ol

[0281] Dissolve diisopropylamine (2.67 g, 26.4 mmol) in anhydrous tetrahydrofuran (40 mL), cool to -70°C, slowly drop 2.5 M n-butyl lithium in n-hexane solution (10.6 mL, 26.5 mmol), and stir the mixture at -70°C for 30 minutes. Then slowly drop 2-bromo-5-(methoxymethoxy)pyridine (3.85 g, 17.6 mmol) in anhydrous tetrahydrofuran (15 mL), continue stirring for 1 hour, then drop triisopropyl borate (3.31 g, 17.6 mmol) in anhydrous tetrahydrofuran (15 mL). Stir the reaction solution at -70°C for 2 hours, then slowly add 30% hydrogen peroxide solution (4 g, 35.2 mmol), slowly warm to room temperature, and stir overnight. Water (50 mL) was added to the reaction solution, and the pH value was adjusted to less than 4 with 1M dilute hydrochloric acid. The aqueous phase was extracted with ethyl acetate (2 x 75 mL). The organic phases were combined, washed with saturated brine (75 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 60) to obtain the title compound (2.73 g, white solid), yield: 66%. MS (ESI): m / z 233.9 [M+H] + .

[0282] (3) 6-Bromopyridine-3,4-diol

[0283] Dissolve 2-bromo-5-(methoxymethoxy)pyridin-4-ol (2.73 g, 11.7 mmol) in 1,4-dioxane (20 mL), add water (2 mL) and 4M hydrochloric acid dioxane solution (20 mL), and heat the mixture to 60°C for 2 hours. The reaction solution is concentrated to obtain the title compound (3 g, white solid), yield: 100%. MS (ESI): m / z 189.9 [M+H] + .

[0284] (4) 6-Bromo-[1,3]dioxacyclo[4,5-c]pyridine

[0285] 6-Bromopyridine-3,4-diol (1.63 g, 8.58 mmol) was dissolved in N,N-dimethylformamide (30 mL), cesium carbonate (7.0 g, 21.5 mmol) and chloroiodomethane (3.03 g, 17.2 mmol) were added, and the mixture was heated to 60 ° C for 3 hours. The reaction solution was poured into water (70 mL), and the aqueous phase was extracted with ethyl acetate (2 x 35 mL). The organic phases were combined, washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 70 / 30) to obtain the title compound (630 mg, white solid), yield: 36.4%. MS (ESI): m / z 201.8 [M+H] +.

[0286] (5) tert-Butyl [1,3] dioxacyclo[4,5-c]pyridin-6-ylcarbamate

[0287] 6-Bromo-[1,3]dioxacyclo[4,5-c]pyridine (633 mg, 3.1 mmol) was dissolved in 1,4-dioxane (15 mL), tris(dibenzylideneacetone)dipalladium (275 mg, 0.3 mmol), tert-butyl carbamate (1.09 g, 9.3 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (247 mg, 0.6 mmol) and cesium carbonate (2.02 g, 6.2 mmol) were added, and the mixture was heated to 100°C under nitrogen protection and stirred overnight. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 70 / 30) to obtain the title compound (210 mg, white solid), yield: 28.5%. MS (ESI): m / z 183.0 [M+H-56] + .

[0288] (6) [1,3] dioxacyclo[4,5-c]pyridin-6-amine

[0289] Dissolve [1,3]dioxacyclo[4,5-c]pyridin-6-ylcarbamic acid tert-butyl ester (210 mg, 0.88 mmol) in dichloromethane (4 mL), add trifluoroacetic acid (4 mL), and stir at room temperature for 2 hours. The reaction solution is concentrated, saturated sodium bicarbonate solution (30 mL) is added, and the aqueous phase is extracted with ethyl acetate (2 x 20 mL). The organic phases are combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (105 mg, light yellow solid), yield: 87%. MS (ESI): m / z 139.0 [M+H] + .

[0290] (7) 8-Oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxylic acid methyl ester

[0291] Add [1,3]dioxacyclo[4,5-c]pyridine-6-amine (80 mg, 0.58 mmol), water (8 mL) and dimethyl butane-2-diacetate (82 mg, 0.58 mmol) to a 25 mL single-mouth bottle and stir at room temperature overnight. The reaction solution was diluted with water (10 mL), and the aqueous phase was extracted with ethyl acetate (2 x 20 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 80) to give the title compound (100 mg, pink solid), yield: 69.4%. MS (ESI): m / z 248.9 [M+H] + .

[0292] (8) 8-Oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxylic acid

[0293] Dissolve 8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxylic acid methyl ester (100 mg, 0.4 mmol) in methanol (5 mL), add sodium hydroxide (48 mg, 1.0 mmol) and water (5 mL), and react at room temperature overnight. The reaction solution was concentrated to remove methanol, and the pH value was adjusted to about 4 with 1M dilute hydrochloric acid. After standing, a solid was precipitated, filtered, and the filter cake was dried to obtain the title compound (40 mg, light yellow solid), with a yield of 42.7%. MS (ESI): m / z 235.0 [M+H] + .

[0294] Intermediate 6: tert-butyl 6-(aminomethyl)-2-(((tert-butoxycarbonyl)((3,3-difluorocyclobutyl)methyl)amino)methyl)-1H-indole-1-carboxylate

[0295]

[0296] (1) 2-((((3,3-difluorocyclobutyl)methyl)amino)methyl)-1H-indole-6-carbonitrile

[0297] 2-Formyl-1H-indole-6-carbonitrile (100 mg, 0.6 mmol, step 4 of intermediate 1) and (3,3-difluorocyclobutyl)methylamine hydrochloride (142 mg, 0.9 mmol) were dissolved in dichloroethane (5 mL), and the mixture was heated to 65 ° C and stirred for 1 hour. Sodium cyanoborohydride (132 mg, 2.1 mmol) was added and stirred at 65 ° C for 2 hours. The reaction solution was added to a saturated sodium bicarbonate solution (20 mL), and the aqueous phase was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with a saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 60) to give the title compound (65 mg, light yellow oil), yield: 40%. MS (ESI): m / z 276.0 [M+H] + .

[0298] (2) tert-Butyl 2-(((tert-Butoxycarbonyl)((3,3-difluorocyclobutyl)methyl)amino)methyl)-6-cyano-1H-indole-1-carboxylate

[0299] 2-((((3,3-difluorocyclobutyl)methyl)amino)methyl)-1H-indole-6-carbonitrile (65 mg, 0.24 mmol) was dissolved in tetrahydrofuran solution (10 mL), sodium hydride (38 mg, 0.96 mmol, 60%) was added, and the mixture was stirred at room temperature for 10 minutes. Di-tert-butyl dicarbonate (209 mg, 0.96 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was quenched with methanol (10 mL), concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 90 / 10) to give the title compound (87 mg, light yellow oil), yield: 78%. MS (ESI): m / z 498.0 [M+Na] + .

[0300] (3) tert-butyl 6-(aminomethyl)-2-(((tert-butoxycarbonyl)((3,3-difluorocyclobutyl)methyl)amino)methyl)-1H-indole-1-carboxylate

[0301] Dissolve tert-butyl 2-(((tert-butoxycarbonyl)((3,3-difluorocyclobutyl)methyl)amino)methyl)-6-cyano-1H-indole-1-carboxylate (40 mg, 0.08 mmol) in 7M ammonia methanol solution (10 mL), add Raney nickel (4 mg, 10%), replace hydrogen 3 times, and heat the mixture to 50°C and stir for 2 hours. The reaction solution was filtered to remove Raney nickel, and the filtrate was concentrated to obtain the title compound (40 mg, green oil), yield: 100%. MS (ESI): m / z 480.1 [M+H] + .

[0302] Intermediate 7: N-((2-Formyl-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0303]

[0304] (1) (2-(diethoxymethyl)-1H-indol-6-yl)methanamine

[0305] 2-(Diethoxymethyl)-1H-indole-6-carbonitrile (1.25 g, 5.1 mmol, step 3 of intermediate 1) was dissolved in 7M ammonia methanol solution (10 mL), Raney nickel (125 mg, 10%) was added, hydrogen was replaced three times, and the mixture was stirred at room temperature under a hydrogen atmosphere for 13 hours. The reaction solution was filtered to remove Raney nickel, and the filtrate was concentrated to obtain the title compound (1.27 g, green oil), yield: 100%. MS (ESI): m / z 158.0 [M+H-91] + .

[0306] (2) N-((2-(diethoxymethyl)-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0307] Intermediate 5 (130 mg, 0.55 mmol), N,N-diisopropylethylamine (359 mg, 2.78 mmol) and 1-propylphosphoric anhydride (530 mg, 0.83 mmol, 50% ethyl acetate solution) were dissolved in N,N-dimethylformamide (5 mL), (2-(diethoxymethyl)-1H-indol-6-yl)methylamine (179 mg, 0.72 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution (30 mL) and extracted with ethyl acetate (2 x 20 mL). The organic phases were combined, washed with a saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 60) to give the title compound (180 mg, white solid), yield: 69.8%. MS (ESI): m / z 465.0 [M+H] + .

[0308] (3) N-((2-Formyl-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0309] N-((2-(diethoxymethyl)-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide (100 mg, 0.22 mmol) was dissolved in tetrahydrofuran (10 mL), and water (1 mL) and glacial acetic acid (1 mL) were added. The mixture was reacted at room temperature for 2 hours. Solid precipitated in the reaction solution. The reaction solution was concentrated and diluted with water (10 mL). The precipitated solid was filtered and dried to obtain the title compound (80 mg, white solid). Yield: 95%. MS (ESI): m / z 390.9 [M+H] + .

[0310] Intermediate 8: N-((2-Formyl-1H-indol-6-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[0311]

[0312] Referring to the synthesis method of intermediate 7, intermediate 5 was replaced by intermediate 4 in step 2, and intermediate 8 (155 mg, white solid) was obtained through similar steps. MS (ESI): m / z 405.1 [M+H] + .

[0313] Intermediate 9: tert-Butyl 6-(1-aminocyclopropyl)-2-(diethoxymethyl)-1H-indole-1-carboxylate

[0314]

[0315] (1) tert-Butyl 6-cyano-2-(diethoxymethyl)-1H-indole-1-carboxylate

[0316] 2-(Diethoxymethyl)-1H-indole-6-carbonitrile (200 mg, 0.82 mmol, Intermediate 1 Step 3) was dissolved in tetrahydrofuran (15 mL), sodium hydride (98 mg, 2.4 mmol, 60%) was added, and the mixture was stirred at room temperature for half an hour. Di-tert-butyl dicarbonate (268 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature overnight. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound (280 mg, colorless oil), yield: 99%. MS (ESI): m / z 366.9 [M+Na] + .

[0317] (2) tert-Butyl 6-(1-aminocyclopropyl)-2-(diethoxymethyl)-1H-indole-1-carboxylate

[0318] Dissolve tert-butyl 6-cyano-2-(diethoxymethyl)-1H-indole-1-carboxylate (280 mg, 0.8 mmol) in ether (3 mL), replace nitrogen, add tetraisopropyl titanate (1.1 g, 4.0 mmol) at -70 ° C, and stir for 10 minutes. Then slowly add 2M tetrahydrofuran solution of ethyl magnesium bromide (2 mL, 4.0 mmol), stir at -70 ° C for 10 minutes, warm to room temperature and continue stirring for 1 hour. Add water (30 mL) to the reaction solution to quench, extract with ethyl acetate (20 mL x 3), wash with saturated sodium chloride solution (30 mL), dry with anhydrous sodium sulfate, filter and concentrate. The residue is purified by silica gel column chromatography (dichloromethane / methanol = 92 / 8) to obtain the title compound (40 mg, yellow solid), yield: 13%. MS (ESI): m / z 396.9 [M+Na] + .

[0319] Intermediate 10: 7,8-Dihydro-6H-9-oxa-2,2a,5,6-tetraazabenzo[cd]azulene-4-carboxylic acid

[0320]

[0321] (1) 4,6-Dichloro-3-iodopyrazolo[1,5-a]pyrazine

[0322] 4,6-Dichloropyrazolo[1,5-a]pyrazine (2.0 g, 10.64 mmol) and N-iodosuccinimide (2.63 g, 11.70 mmol) were dissolved in N,N-dimethylformamide (50 mL), heated to 50 ° C and stirred for 12 hours. The reaction solution was added to water (100 mL) and extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 95 / 5) to give the title compound (3.1 g, light yellow solid), yield: 93%. MS (ESI): m / z 313.7 [M+H] + .

[0323] (2) 4,6-Dichloro-3-vinylpyrazolo[1,5-a]pyrazine

[0324] 4,6-dichloro-3-iodopyrazolo[1,5-a]pyrazine (1.0 g, 3.19 mmol), vinylboronic acid pinacol ester (736 mg, 4.78 mmol), potassium carbonate (1.32 g, 9.56 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (258 mg, 0.32 mmol) were dissolved in 1,4-dioxane (19 mL) and water (1 mL), heated to 90 ° C and stirred for 12 hours under nitrogen protection. The reaction solution was added to water (50 mL) and extracted with ethyl acetate (40 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 90 / 10) to obtain the title compound (445 mg, yellow solid), yield: 65%. MS (ESI): m / z 213.9 [M+H] + .

[0325] (3) 4,6-Dichloropyrazolo[1,5-a]pyrazine-3-carboxaldehyde

[0326] Dissolve 4,6-dichloro-3-vinylpyrazolo[1,5-a]pyrazine (560 mg, 2.6 mmol) in tetrahydrofuran / water (15 mL / 5 mL), add potassium osmate dihydrate (95 mg, 0.26 mmol) at 0°C, warm to room temperature and stir for half an hour, add sodium periodate (1.7 g, 7.8 mmol), and continue stirring at room temperature overnight. Add water (20 mL) to the reaction solution and extract with ethyl acetate (20 mL x 3). The organic phases are combined, washed with saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain the title compound (300 mg, white solid), yield: 53%. MS (ESI): m / z 215.8 [M+H] + .

[0327] (4) 4,6-Dichloropyrazolo[1,5-a]pyrazin-3-ol

[0328] Dissolve 4,6-dichloropyrazolo[1,5-a]pyrazine-3-carboxaldehyde (300 mg, 1.4 mmol) and m-chloroperbenzoic acid (366 mg, 2.1 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (16 mg, 0.14 mmol) at 0°C, warm to room temperature and stir overnight. Add sodium bicarbonate aqueous solution (20 mL) to the reaction solution, and extract with dichloromethane (20 mL x 3). Combine the organic phases, concentrate, and dissolve the residue in methanol / water (10 mL / 2 mL), add potassium carbonate (386 mg, 2.8 mmol), and stir at room temperature for half an hour. Adjust the pH value of the reaction solution to neutral with 1M dilute hydrochloric acid, and extract with dichloromethane (20 mL x 3). Combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=50 / 50) to give the title compound (250 mg, yellow solid), yield: 88%. MS (ESI): m / z 203.8 [M+H] + .

[0329] (5) tert-Butyl (2-((4,6-dichloropyrazolo[1,5-a]pyrazin-3-yl)oxy)ethyl)carbamate

[0330] Dissolve 4,6-dichloropyrazolo[1,5-a]pyrazine-3-ol (80 mg, 0.39 mmol), tert-butyl (2-hydroxyethyl)carbamate (95 mg, 0.59 mmol) and triphenylphosphine (204 mg, 0.78 mmol) in tetrahydrofuran (5 mL), add diisopropyl azodicarboxylate (158 mg, 0.78 mmol) dropwise, heat to 50°C and stir to react overnight. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to obtain the title compound (120 mg, yellow solid), yield: 88%. MS (ESI): m / z 291.1 [M+H-56] + .

[0331] (6) 2-((4,6-dichloropyrazolo[1,5-a]pyrazin-3-yl)oxy)ethane-1-amine

[0332] Dissolve tert-butyl (2-((4,6-dichloropyrazolo[1,5-a]pyrazin-3-yl)oxy)ethyl)carbamate (120 mg, 0.35 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (2 mL), and stir at room temperature for 2 hours. The reaction solution is concentrated to obtain the title compound (85 mg, colorless oil), yield: 97%. MS (ESI): m / z 246.8 [M+H] + .

[0333] (7) 4-Chloro-7,8-dihydro-6H-9-oxa-2,2a,5,6-tetraazabenzo[cd]azulene

[0334] 2-((4,6-dichloropyrazolo[1,5-a]pyrazin-3-yl)oxy)ethane-1-amine (85 mg, 0.34 mmol) and N,N-diisopropylethylamine (134 mg, 1.04 mmol) were dissolved in dimethyl sulfoxide (5 mL), heated to 50 ° C and stirred overnight. The reaction solution was added to water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 75 / 25) to give the title compound (65 mg, yellow solid), yield: 90%. MS (ESI): m / z 210.9 [M+H] + .

[0335] (8) 7,8-Dihydro-6H-9-oxa-2,2a,5,6-tetraazabenzo[cd]azulene-4-carboxylic acid methyl ester

[0336] 4-Chloro-7,8-dihydro-6H-9-oxa-2,2a,5,6-tetraazabenzo[cd]azulene (65 mg, 0.3 mmol), palladium acetate (6.8 mg, 0.03 mmol) and 1,3-bis(diphenylphosphino)propane (18 mg, 0.045 mmol) were dissolved in methanol / acetonitrile (10 mL / 5 mL), triethylamine (60 mg, 0.6 mmol) was added, and the mixture was heated to 120°C in an autoclave (5 MPa, carbon monoxide atmosphere) and stirred for overnight reaction. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain the title compound (30 mg, yellow solid), yield: 42%. MS (ESI): m / z 234.9 [M+H] + .

[0337] (9) 7,8-Dihydro-6H-9-oxa-2,2a,5,6-tetraazabenzo[cd]azulene-4-carboxylic acid

[0338] Dissolve 7,8-dihydro-6H-9-oxa-2,2a,5,6-tetraazabenzo[cd]azulene-4-carboxylic acid methyl ester (30 mg, 0.13 mmol) and sodium hydroxide (8.0 mg, 0.20 mmol) in methanol / water (10 mL / 10 mL) and stir at room temperature for half an hour. The reaction solution was concentrated to remove methanol, 1M dilute hydrochloric acid was slowly added to the reaction solution, and the solid was filtered to obtain the title compound (20 mg, white solid), yield: 70%. MS (ESI): m / z 221.0 [M+H] + .

[0339] Intermediate 11: 6,7,8,9-tetrahydro-2,2a,5,6-tetraazabenzo[cd]azulene-4-carboxylic acid

[0340]

[0341] (1) N-allyl-6-chloro-3-vinylpyrazolo[1,5-a]pyrazin-4-amine

[0342] 4,6-Dichloro-3-vinylpyrazolo[1,5-a]pyrazine (500 mg, 2.34 mmol, step 2 of intermediate 10), cesium carbonate (1.52 g, 4.67 mmol) and allylamine hydrochloride (262 mg, 2.80 mmol) were dissolved in acetonitrile (20 mL), and the mixture was heated to 70 ° C and stirred for 2 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 90 / 10) to obtain the title compound (140 mg, yellow solid), yield: 76%. MS (ESI): m / z 234.9 [M+H] + .

[0343] (2) Allyl (6-chloro-3-vinylpyrazolo[1,5-a]pyrazin-4-yl)carbamic acid tert-butyl ester

[0344] Dissolve N-allyl-6-chloro-3-vinylpyrazolo[1,5-a]pyrazine-4-amine (300 mg, 1.28 mmol) in dichloromethane (10 mL), add triethylamine (260 mg, 2.56 mmol), di-tert-butyl dicarbonate (1.39 g, 6.39 mmol) and 4-dimethylaminopyridine (15.6 mg, 0.13 mmol), and stir at room temperature for 1 hour. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 90 / 10) to obtain the title compound (250 mg, green solid), yield: 58%. MS (ESI): m / z 278.9 [M+H-56] + .

[0345] (3) tert-Butyl 4-chloro-2,2a,5,6-tetraazabenzo[cd]azulene-6(7H)-carboxylate

[0346] Allyl (6-chloro-3-vinylpyrazolo [1,5-a] pyrazin-4-yl) carbamic acid tert-butyl ester (250 mg, 0.75 mmol) and Grubbs second generation catalyst (63.4 mg, 0.07 mmol) were dissolved in dichloromethane (10 mL) and stirred at 25 ° C for 12 hours. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 85 / 15) to obtain the title compound (100 mg, yellow solid), yield: 44%. MS (ESI): m / z 328.9 [M+Na] + .

[0347] (4) 6,7-Dihydro-2,2a,5,6-tetraazabenzo[cd]azulene-4-carboxylic acid methyl ester

[0348] 4-Chloro-2,2a,5,6-tetraazabenzo[cd]azulene-6(7H)-carboxylic acid tert-butyl ester (100 mg, 0.33 mmol), palladium acetate (14.6 mg, 0.07 mmol) and 1,3-bis(diphenylphosphino)propane (21.2 mg, 0.07 mmol) were dissolved in methanol / acetonitrile (10 mL / 10 mL), triethylamine (66 mg, 0.65 mmol) was added, and the mixture was heated to 140°C in an autoclave (5 MPa, carbon monoxide atmosphere) and stirred for 72 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 60) to obtain the title compound (36 mg, yellow solid), yield: 48%. MS (ESI): m / z 230.8 [M+H] + .

[0349] (5) 6,7,8,9-Tetrahydro-2,2a,5,6-tetraazabenzo[cd]azulene-4-carboxylic acid methyl ester

[0350] Dissolve 6,7-dihydro-2,2a,5,6-tetraazabenzo[cd]azulene-4-carboxylic acid methyl ester (36 mg, 0.16 mmol) in ethyl acetate (5 mL), add 10% palladium on carbon (3.6 mg), and stir at room temperature under hydrogen atmosphere for 1 hour. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain the title compound (34 mg, yellow solid), yield: 94%. MS (ESI): m / z 232.9 [M+H] + .

[0351] (6) 6,7,8,9-Tetrahydro-2,2a,5,6-tetraazabenzo[cd]azulene-4-carboxylic acid

[0352] Dissolve 6,7,8,9-tetrahydro-2,2a,5,6-tetraazabenzo[cd]azulene-4-carboxylic acid methyl ester (34 mg, 0.15 mmol) and sodium hydroxide (8.8 mg, 0.22 mmol) in methanol / water (10 mL / 10 mL) and stir at room temperature for half an hour. The reaction solution was concentrated to remove methanol, 1M dilute hydrochloric acid was slowly added to the reaction solution, and the solid was filtered to obtain the title compound (25 mg, white solid), yield: 78%. MS (ESI): m / z 218.9 [M+H] + .

[0353] Example 1

[0354] N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)imidazo[1,2-b]pyridazine-2-carboxamide

[0355]

[0356] (1) tert-Butyl 2-(((tert-Butyloxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((imidazo[1,2-b]pyridazine-2-carboxamido)methyl)-1H-indole-1-carboxylate

[0357] Dissolve imidazo[1,2-b]pyridazine-2-carboxylic acid (16 mg, 0.10 mmol), N,N-diisopropylethylamine (71 mg, 0.55 mmol) and HATU (84 mg, 0.22 mmol) in N,N-dimethylformamide (2 mL) and stir at room temperature for 5 minutes. Add a solution of intermediate 1 (50 mg, 0.11 mmol) in N,N-dimethylformamide (1 mL) and continue stirring at room temperature for 10 minutes. Add saturated sodium bicarbonate solution (20 mL) to the reaction solution, and extract the aqueous phase with ethyl acetate (20 mL x 3). The organic phases are combined, washed with saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to obtain the title compound (60 mg, yellow oil), yield: 69%. MS (ESI): m / z 589.1 [M+H] + .

[0358] (2) N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)imidazo[1,2-b]pyridazine-2-carboxamide

[0359] Dissolve tert-butyl 2-(((tert-butyloxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((imidazo[1,2-b]pyridazine-2-carboxamido)methyl)-1H-indole-1-carboxylate (60 mg, 0.1 mmol) in dichloromethane (2 mL), add trifluoroacetic acid (0.5 mL), and stir at room temperature for 4 hours. The reaction solution was concentrated, and the crude product was diluted with N,N-dimethylformamide and purified by Prep-HPLC to give the title compound (9.3 mg, white solid), yield: 23%. MS (ESI): m / z 777.3 [2M+H] + . 1 HNMR (400 MHz, DMSO-d 6 )δ10.83(s,1H),8.90(t,J=6.0Hz,1H),8.65(s,1H),8.60(dd,J=4.4,1.6Hz,1H),8.1 5(dd,J=9.6,0.8Hz,1H),7.35(d,J=6.8Hz,1H),7.32(t,J=4.8Hz,1H),7.29(s,1H),6. 96(dd,J=8.0,1.2Hz,1H),6.19(s,1H),4.55(d,J=6.4Hz,2H),3.77(s,2H),2.51-2.5 0(m,2H),2.41-2.37(m,1H),1.98-1.94(m,2H),1.82-1.76(m,2H),1.63-1.59(m,2H).

[0360] Example 2

[0361] N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0362]

[0363] (1) Pyrazolo[1,5-a]pyrimidine-2-carboxylic acid

[0364] Dissolve pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester (150 mg, 0.85 mmol) in methanol / water (10 mL / 2 mL), add sodium hydroxide (104 mg, 2.6 mmol), and stir at room temperature for 2 hours. The reaction solution is adjusted to acidity with 1M dilute hydrochloric acid, and a solid product is precipitated. The title compound (100 mg, white solid) is obtained by filtration, with a yield of 72%. MS (ESI): m / z 164.0 [M+H] + .

[0365] (2) tert-Butyl 2-(((tert-Butyloxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((pyrazolo[1,5-a]pyrimidine-2-carboxamido)methyl)-1H-indole-1-carboxylate

[0366] Pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (29 mg, 0.18 mmol) and intermediate 1 (80 mg, 0.18 mmol) were dissolved in N,N-dimethylformamide (5 mL), 1-propylphosphoric anhydride (229 mg, 0.36 mmol, 50% ethyl acetate solution) and triethylamine (54 mg, 0.54 mmol) were added, and stirred at room temperature for 2 hours. The reaction solution was poured into water (20 mL), and the aqueous phase was extracted with ethyl acetate (2x20 mL). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to give the title compound (40 mg, yellow oil), yield: 38%. MS (ESI): m / z 589.1 [M+H] + .

[0367] (3) N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0368] Dissolve tert-butyl 2-(((tert-butyloxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((pyrazolo[1,5-a]pyrimidine-2-carboxamido)methyl)-1H-indole-1-carboxylate (40 mg, 0.07 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (3 mL), and react at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by Prep-HPLC to give the title compound (6.4 mg, white solid), yield: 25%. MS (ESI): m / z 777.2 [2M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ10.84(s,1H),9.11(d,J=6.8Hz,1H),9.00(t,J=6.0Hz,1H),8.63(dd,J=4.0,1.6Hz,1 H),7.36(d,J=8.0Hz,1H),7.30(s,1H),7.17(dd,J=7.2,4.0Hz,1H),7.10(d,J=0.8Hz,1H ),6.96(dd,J=8.0,1.2Hz,1H),6.20(s,1H),4.57(d,J=6.4Hz,2H),3.77(s,2H),2.51-2 .50(m,2H),2.43-2.35(m,1H),2.00-1.92(m,2H),1.85-1.74(m,2H),1.66-1.59(m,2H).

[0369] Example 3

[0370] N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0371]

[0372] Referring to the synthesis method of Example 1, pyrazolo[1,5-a]pyrimidine-3-carboxylic acid and intermediate 1 were used as starting materials and the title compound (12 mg, white solid) was obtained through similar steps. MS (ESI): m / z 777.3 [2M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.89(s,1H),9.30(dd,J=6.8,1.6Hz,1H),8.76(dd,J=4.0,1.6Hz,1H),8.62(s,1H) ,8.30(t,J=6.0Hz,1H),7.40(d,J=8.0Hz,1H),7.34(s,1H),7.25(dd,J=6.8,4.0Hz,1H) ,6.98(dd,J=8.0,1.2Hz,1H),6.27(s,1H),4.65(d,J=5.6Hz,2H),3.85(s,2H),2.60-2. 58(m,2H),2.45-2.41(m,1H),2.01-1.96(m,2H),1.83-1.77(m,2H),1.66-1.61(m,2H).

[0373] Example 4

[0374] N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)imidazo[1,2-b]pyridazine-7-carboxamide

[0375]

[0376] (1) 6-((tert-Butyloxycarbonyl)amino)pyridazine-4-carboxylic acid methyl ester

[0377] Dissolve 6-chloropyridazine-4-carboxylic acid methyl ester (900 mg, 5.2 mmol) in 1,4-dioxane (10 mL), add tert-butyl carbamate (1.2 g, 10.4 mmol), tris(dibenzylideneacetone)dipalladium (476 mg, 0.52 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (601 mg, 1.04 mmol) and cesium carbonate (3.4 g, 10.4 mmol). The mixture was heated to 100 ° C and stirred overnight under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain the title compound (400 mg, yellow solid), yield: 31%. MS (ESI): m / z 197.9 [M+H-56] + .

[0378] (2) 6-aminopyridazine-4-carboxylic acid methyl ester

[0379] Dissolve 6-((tert-butyloxycarbonyl)amino)pyridazine-4-carboxylic acid methyl ester (400 mg, 1.6 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (5 mL), and stir at room temperature for 1 hour. The reaction solution is concentrated, saturated sodium bicarbonate solution (20 mL) is added, and the aqueous phase is extracted with dichloromethane (10 mL x 3). The organic phases are combined and concentrated to give the title compound (242 mg, yellow oil). MS (ESI): m / z 154.0 [M+H] + .

[0380] (3) Methyl imidazo[1,2-b]pyridazine-7-carboxylate

[0381] Dissolve 6-aminopyridazine-4-carboxylic acid methyl ester (242 mg, 1.6 mmol) in ethanol / water (10 mL / 10 mL), add 2-bromo-1,1-diethoxyethane (630 mg, 3.2 mmol), add a few drops of 1M dilute hydrochloric acid to make the solution acidic, and stir at 80°C overnight. The reaction solution is concentrated and extracted with ethyl acetate (2x 20 mL). The organic phases are combined, washed with saturated sodium bicarbonate solution (20 mL) and saturated sodium chloride solution (20 mL) in turn, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound (200 mg, yellow solid), yield: 71%. MS (ESI): m / z 178.0 [M+H]+ .

[0382] (4) Imidazolo[1,2-b]pyridazine-7-carboxylic acid

[0383] Dissolve imidazo[1,2-b]pyridazine-7-carboxylic acid methyl ester (100 mg, 0.56 mmol) in methanol / water (10 mL / 2 mL), add sodium hydroxide (67.2 mg, 1.68 mmol), and react at room temperature overnight. Adjust to acidity with 1M dilute hydrochloric acid, concentrate the reaction solution, and purify the residue by reverse phase column to obtain the title compound (30 mg, white solid), yield: 33%. MS (ESI): m / z 164.0 [M+H] + .

[0384] (5) tert-Butyl 2-(((tert-Butyloxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((imidazo[1,2-b]pyridazine-7-carboxamido)methyl)-1H-indole-1-carboxylate

[0385] Referring to the synthesis method of step 2 of Example 2, using imidazo[1,2-b]pyridazine-7-carboxylic acid (30 mg, 0.18 mmol) and intermediate 1 (80 mg, 0.18 mmol) as raw materials, the title compound (35 mg, white solid) was obtained with a yield of 39%. MS (ESI): m / z 489.1 [M+H-100] + .

[0386] (6) N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)imidazo[1,2-b]pyridazine-7-carboxamide

[0387] Referring to the synthesis method of step 3 of Example 2, tert-butyl 2-(((tert-butyloxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((imidazo[1,2-b]pyridazine-7-carboxamido)methyl)-1H-indole-1-carboxylate (30 mg, 0.06 mmol) was used as a raw material to obtain the title compound (6.2 mg, white solid), yield: 31%. MS (ESI): m / z 389.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ10.85(s,1H),9.33(t,J=5.2Hz,1H),8.92(d,J=2.4Hz,1H),8.63(d,J=1.6Hz,1H ),8.44(s,1H),7.94(d,J=1.2Hz,1H),7.38(d,J=8.0Hz,1H),7.31(s,1H),6.96(dd ,J=8.0,1.2Hz,1H),6.21(s,1H),4.58(d,J=5.6Hz,2H),3.78(s,2H),2.52-2.51(m ,2H),2.45-2.36(m,1H),2.01-1.93(m,2H),1.85-1.74(m,2H),1.66-1.59(m,2H).

[0388] Example 5

[0389] N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrazine-6-carboxamide

[0390]

[0391] (1)[1,2,4]triazolo[1,5-a]pyrazine-6-carboxylic acid ethyl ester

[0392] Dissolve 6-bromo-[1,2,4]triazolo[1,5-a]pyrazine (299 mg, 1.5 mmol) in ethanol (10 mL), add [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (110 mg, 0.15 mmol) and triethylamine (455 mg, 4.5 mmol), replace carbon monoxide gas three times, and heat to 80°C under the protection of a carbon monoxide balloon and stir for 16 hours. The reaction solution is concentrated, and the residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 60) to obtain the title compound (96 mg, light yellow solid), yield: 33%. MS (ESI): m / z 192.8 [M+H] + .

[0393] (2) [1,2,4]triazolo[1,5-a]pyrazine-6-carboxylic acid

[0394] Dissolve [1,2,4]triazolo[1,5-a]pyrazine-6-carboxylic acid ethyl ester (96 mg, 0.5 mmol) in ethanol (10 mL), add water (4 mL) and sodium hydroxide (40 mg, 1 mmol), and stir at room temperature for 16 hours. The reaction solution was concentrated, and the pH value was adjusted to 3 with 1M dilute hydrochloric acid. After standing for 5 minutes, a solid was precipitated, filtered, and the filter cake was dried to obtain the title compound (57 mg, brown solid), with a yield of 69.5%. MS (ESI): m / z 187.0 [M+Na] + .

[0395] (3) tert-Butyl ((6-(([1,2,4]triazolo[1,5-a]pyrazine-6-carboxamido)methyl)-1H-indol-2-yl)methyl)(cyclobutylmethyl)carbamate

[0396] [1,2,4]triazolo[1,5-a]pyrazine-6-carboxylic acid (16.4 mg, 0.1 mmol) was dissolved in N,N-dimethylformamide (2 mL), and intermediate 2 (34 mg, 0.1 mmol), 1-propylphosphoric anhydride (127 mg, 0.2 mmol, 50% ethyl acetate solution) and triethylamine (50 mg, 0.5 mmol) were added and stirred at room temperature for 16 hours. The reaction solution was poured into water (30 mL), and the aqueous phase was extracted with ethyl acetate (2 x 20 mL). The organic phases were combined, washed with saturated brine (30 mL), anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to give the title compound (25 mg, light yellow oil), yield: 51%. MS (ESI): m / z 512.0 [M+Na] + .

[0397] (4) N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrazine-6-carboxamide

[0398] Tert-butyl ((6-(([1,2,4]triazolo[1,5-a]pyrazine-6-carboxamido)methyl)-1H-indol-2-yl)methyl)(cyclobutylmethyl)carbamate (25 mg, 0.05 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated, and the residue was dissolved in methanol (1 mL) and purified by Prep-HPLC to give the title compound (4 mg, white solid), yield: 20%. MS (ESI): m / z 779.2 [2M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ10.96(s,1H),9.46(s,2H),9.41(t,J=6.0Hz,1H),8.88(s,1H),7.43(d,J=8.0Hz,1H),7.38(s,1H),7.03(d,J=8.0Hz,1H),6. 38(s,1H),4.61(d,J=6.4Hz,2H),4.01(s,2H),2.75(d,J=6.8Hz,2H),2.61-2.60(m,1H),2.04-1.98(m,2H),1.85-1.66(m,4H).

[0399] Example 6

[0400] N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide

[0401]

[0402] Referring to the synthesis method of Example 1, [1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid and intermediate 1 were used as starting materials, and the title compound (7.2 mg, white solid) was obtained through similar steps. MS (ESI): m / z 389.1 [M+H] + . 1 HNMR (400 MHz, DMSO-d 6 )δ10.84(s,1H),9.48(s,1H),9.25(t,J=6.0Hz,1H),8.62(s,1H),8.11(dd,J=9.6Hz, 2.0Hz,1H),7.92(dd,J=9.2Hz,0.4Hz,1H),7.38(d,J=8.0Hz,1H),7.30(s,1H),6.96( dd,J=8.0Hz,1.2Hz,1H),6.20(s,1H),4.58(d,J=6.0Hz,2H),3.77(s,2H),2.62-2.51 (m,2H),2.45-2.35(m,1H),2.02-1.91(m,2H),1.85-1.72(m,2H),1.67-1.56(m,2H).

[0403] Example 7

[0404] N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)benzo[b]thiophene-3-carboxamide

[0405]

[0406] Referring to the synthesis method of Example 1, using benzo[b]thiophene-3-carboxylic acid and intermediate 1 as starting materials, the title compound (5.9 mg, white solid) was obtained through similar steps. MS (ESI): m / z 807.2 [2M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.01(s,1H),8.99(t,J=5.6Hz,1H),8.49(d,J=7.2Hz,1H),8.40(s,1H), 8.04(d,J=7.2Hz,1H),7.47-7.40(m,3H),7.33(s,1H),6.99(d,J=8.4Hz,1H ),6.28(s,1H),4.57(d,J=6.0Hz,2H),3.88(s,2H),2.61(d,J=7.2Hz,2H),2 .47-2.43(m,1H),2.01-1.94(m,2H),1.86-1.75(m,2H),1.69-1.62(m,2H).

[0407] Example 8

[0408] N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-8-morpholinoimidazolo[1,2-b]pyridazine-2-carboxamide

[0409]

[0410] (1) 8-Bromo-6-chloroimidazo[1,2-b]pyridazine-2-carboxylic acid methyl ester

[0411] 4-Bromo-6-chloropyridazine-3-amine (2.08 g, 10 mmol) was dissolved in N,N-dimethylformamide (40 mL), 3-bromo-2-oxopropanoic acid methyl ester (3.62 g, 20 mmol) was added, and the mixture was heated to 70 ° C and stirred overnight. The reaction solution was poured into water (300 mL), and the aqueous phase was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (70 mL x 2), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 60 / 40) to give the title compound (1.6 g, light yellow solid), yield: 55%. MS (ESI): m / z 289.9 [M+H] + .

[0412] (2) 6-Chloro-8-morpholinoimidazolo[1,2-b]pyridazine-2-carboxylic acid methyl ester

[0413] 8-Bromo-6-chloroimidazo[1,2-b]pyridazine-2-carboxylic acid methyl ester (1.3 g, 4.5 mmol) was dissolved in 1,4-dioxane (25 mL), and palladium acetate (102 mg, 0.45 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (260 mg, 0.45 mmol), morpholine (587 mg, 6.75 mmol) and cesium carbonate (2.93 g, 9.0 mmol) were added. The mixture was heated to 90 ° C and stirred for 16 hours under nitrogen protection. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 60 / 40) to obtain the title compound (550 mg, white solid), yield: 41.2%. MS (ESI): m / z 297.0 [M+H] + .

[0414] (3) 8-Morpholinoimidazolo[1,2-b]pyridazine-2-carboxylic acid methyl ester

[0415] Dissolve 6-chloro-8-morpholinoimidazo[1,2-b]pyridazine-2-carboxylic acid methyl ester (490 mg, 1.65 mmol) in methanol (75 mL) and ethyl acetate (75 mL), add 10% palladium carbon (200 mg), replace hydrogen three times, and react at room temperature for 16 hours under a hydrogen atmosphere. The reaction solution is filtered through diatomaceous earth, the filter cake is washed with a small amount of methanol, and the filtrate is concentrated to obtain the title compound (400 mg, white solid), yield: 92.5%. MS (ESI): m / z 263.0 [M+H] + .

[0416] (4) 8-Morpholinoimidazolo[1,2-b]pyridazine-2-carboxylic acid

[0417] Dissolve 8-morpholinoimidazo[1,2-b]pyridazine-2-carboxylic acid methyl ester (100 mg, 0.38 mmol) in methanol (5 mL), add sodium hydroxide (40 mg, 1.0 mmol) and water (5 mL), and heat to 60 ° C for 3 hours. The reaction solution was concentrated, and the pH value was adjusted to about 4 with 1M dilute hydrochloric acid. After standing, a white solid precipitated, which was filtered and dried to obtain the title compound (74 mg, white solid), with a yield of 78.5%. MS (ESI): m / z 248.8 [M+H] + .

[0418] (5) tert-Butyl 2-(((tert-Butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((8-morpholinoimidazolo[1,2-b]pyridazine-2-carboxamido)methyl)-1H-indole-1-carboxylate

[0419] 8-Morpholinoimidazolo[1,2-b]pyridazine-2-carboxylic acid (25 mg, 0.1 mmol), N,N-diisopropylethylamine (65 mg, 0.5 mmol), HATU (76 mg, 0.2 mmol) were dissolved in N,N-dimethylformamide (3 mL) and stirred at room temperature for 5 minutes. Intermediate 1 (44 mg, 0.1 mmol) was added and stirred at room temperature for 1 hour. The reaction solution was purified by reverse phase column to obtain the title compound (30 mg, yellow oil), yield: 44.6%. MS (ESI): m / z 574.1 [M+H-100] + .

[0420] (6) N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-8-morpholinoimidazolo[1,2-b]pyridazine-2-carboxamide

[0421] 2-(((tert-Butyloxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((8-morpholinoimidazolo[1,2-b]pyridazine-2-carboxamido)methyl)-1H-indole-1-carboxylic acid tert-butyl ester (30 mg, 0.045 mmol) was dissolved in trifluoroacetic acid (3 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was diluted with methanol (1 mL) and purified by Prep-HPLC to give the title compound (7.9 mg, light yellow solid) in a yield of 37.5%. MS (ESI): m / z 474.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.03(s,1H),8.92(t,J=6.4Hz,1H),8.41(s,1H),8.16(d,J=5.6Hz,1H),7.48(d ,J=8.0Hz,1H),7.38(s,1H),7.04(dd,J=8.4,1.2Hz,1H),6.42(s,1H),6.36(d,J=6 .0Hz,1H),4.59(d,J=6.8Hz,2H),4.20(s,2H),4.01-3.99(m,4H),3.79-3.77(m,4H ),2.94(d,J=7.6Hz,2H),2.61-2.58(m,1H),2.07-2.00(m,2H),1.87-1.71(m,4H).

[0422] Example 9

[0423] 2-Amino-N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)quinoline-6-carboxamide

[0424]

[0425] Referring to the synthesis method of Example 1, 2-aminoquinoline-6-carboxylic acid and intermediate 1 were used as starting materials, and the title compound (30 mg, white solid) was obtained through similar steps. MS (ESI): m / z 414.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.82(s,1H),8.95(t,J=6.0Hz,1H),8.22(d,J=2.0Hz,1H),7.97(dd,J=8.8,2.0Hz,1H),7.9 4(d,J=8.8Hz,1H),7.45(d,J=8.8Hz,1H),7.37(d,J=8.0Hz,1H),7.29(s,1H),6.96(dd,J=8.0,1 .2Hz,1H),6.80(d,J=9.2Hz,1H),6.67(s,2H),6.20(s,1H),4.56(d,J=6.0Hz,2H),3.77(s,2H), 2.52-2.51(m,2H),2.41-2.38(m,1H),1.99-1.95(m,2H),1.81-1.76(m,2H),1.64-1.59(m,2H).

[0426] Example 10

[0427] 4-(Aminomethyl)-N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1-oxo-1,2-dihydrophthalazine-6-carboxamide

[0428]

[0429] (1) 4-(((tert-Butyloxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazine-6-carboxylic acid methyl ester

[0430] Dissolve tert-butyl ((7-bromo-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (354 mg, 1.0 mmol) in methanol (50 mL), add [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (73 mg, 0.1 mmol) and triethylamine (303 mg, 3 mmol). After replacing carbon monoxide gas three times, the reaction solution was heated to 60°C under the protection of a carbon monoxide balloon for 16 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to obtain the title compound (300 mg, light reddish brown solid), yield: 90%. MS (ESI): m / z 334.0 [M+H]+ .

[0431] (2) 4-(((tert-Butyloxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazine-6-carboxylic acid

[0432] Dissolve 4-(((tert-butyloxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazine-6-carboxylic acid methyl ester (347 mg, 1.04 mmol) in methanol (10 mL), add water (10 mL) and sodium hydroxide (83 mg, 2.08 mmol), heat to 60 ° C and stir for 16 hours. The reaction solution was concentrated, and the pH value was adjusted to 4 with 1M dilute hydrochloric acid. After standing for 5 minutes, a solid precipitated, filtered, and the solid was dried to obtain the title compound (230 mg, brown solid), yield: 69%. MS (ESI): m / z 320.0 [M+H] + .

[0433] (3) tert-butyl ((6-((4-(((tert-butyloxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazine-6-carboxamido)methyl)-1H-indol-2-yl)methyl)(cyclobutylmethyl)carbamate

[0434] Referring to the synthesis method of step 3 of Example 5, 4-(((tert-butyloxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalic acid-6-carboxylic acid (96 mg, 0.3 mmol) and intermediate 2 (133 mg, 0.3 mmol) were used as raw materials to obtain the title compound (46 mg, yellow solid) with a yield of 23.8%. MS (ESI): m / z 667.2 [M+Na] + .

[0435] (4) 4-(Aminomethyl)-N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1-oxo-1,2-dihydrophthalazine-6-carboxamide

[0436] Referring to the synthesis method of step 4 of Example 5, tert-butyl ((6-((4-(((tert-butyloxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazine-6-carboxamido)methyl)-1H-indol-2-yl)methyl)(cyclobutylmethyl)carbamate (46 mg, 0.07 mmol) was used as a raw material to obtain the title compound (4.6 mg, pink solid), yield: 14.8%. MS (ESI): m / z 445.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ12.88(brs,1H),11.53(s,1H),9.45(t,J=6.0Hz,1H),8.45(s,1H),8.38- 8.32(m,2H),8.30(s,2H),7.44(d,J=8.0Hz,1H),7.35(s,1H),7.02(d,J=8. 4Hz,1H),6.36(s,1H),4.63(d,J=6.0Hz,2H),4.37(s,2H),4.00(s,2H),2.6 9(d,J=7.6Hz,2H),2.49-2.46(m,1H),2.03-1.96(m,2H),1.86-1.64(m,4H).

[0437] Embodiment 11

[0438] 1-Benzyl-N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxamide

[0439]

[0440] (1) 1-Benzyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid methyl ester

[0441] 2-Oxo-1,2-dihydropyridine-4-carboxylic acid methyl ester (500mg, 3.25mmol), (bromomethyl)benzene (840mg, 4.90mmol) and potassium carbonate (1.35g, 9.80mmol) were dissolved in N,N-dimethylformamide (30mL) and stirred at room temperature for 12 hours. The reaction solution was added to water (50mL), and the aqueous phase was extracted with ethyl acetate (50mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50mL x 3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 90 / 10) to give the title compound (750mg, light yellow solid), yield: 94%. MS (ESI): m / z 243.8 [M+H] + .

[0442] (2) 1-Benzyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid

[0443] 1-Benzyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid methyl ester (800 mg, 3.29 mmol) and lithium hydroxide (236 mg, 9.87 mmol) were dissolved in tetrahydrofuran / methanol / water (10 mL / 10 mL / 30 mL) and stirred at room temperature for 12 hours. The reaction solution was concentrated, water (100 mL) was added, the pH value was adjusted to 1 with concentrated hydrochloric acid, and the solid was collected by filtration to obtain the title compound (510 mg, white solid), yield: 68%. MS (ESI): m / z 229.6 [M+H] + .

[0444] (3) tert-Butyl 6-((1-benzyl-2-oxo-1,2-dihydropyridine-4-carboxamido)methyl)-2-(((tert-butyloxycarbonyl)(cyclobutylmethyl)amino)methyl)-1H-indole-1-carboxylate

[0445] Referring to the synthesis method of step 1 of Example 1, 1-benzyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (50 mg, 0.22 mmol) and intermediate 1 (145 mg, 0.33 mmol) were used as raw materials to obtain the title compound (46 mg, light yellow oil), yield: 70%. MS (ESI): m / z 655.0 [M+H] + .

[0446] (4) 1-Benzyl-N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxamide

[0447] Referring to the synthesis method of step 2 of Example 1, tert-butyl 6-((1-benzyl-2-oxo-1,2-dihydropyridine-4-carboxamido)methyl)-2-(((tert-butyloxycarbonyl)(cyclobutylmethyl)amino)methyl)-1H-indole-1-carboxylate (46 mg, 0.07 mmol) was used as a raw material to obtain the title compound (12.5 mg, white solid), yield: 39%. MS (ESI): m / z 455.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ10.82(s,1H),9.13(t,J=6.4Hz,1H),7.89(d,J=6.8Hz,1H),7.37-7.23(m,7H),6.91-6.87(m,2H),6.58(dd,J=8.8Hz,2.0Hz,1H),6.1 9(s,1H),5.12(s,2H),4.48(d,J=6.4Hz,2H),3.77(s,2H),2.45-2.36(m,3H),2.02-1.91(m,2H),1.86-1.74(m,2H),1.66-1.58(m,2H).

[0448] Example 12

[0449] 1-((1H-pyrazol-5-yl)methyl)-N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-6-oxo-1,6-dihydropyridazine-4-carboxamide

[0450]

[0451] Referring to the synthesis method of Example 11, 5-(bromomethyl)-1H-pyrazole-1-carboxylic acid tert-butyl ester and 6-oxo-1,6-dihydropyridazine-4-carboxylic acid methyl ester were used as starting materials, and the title compound (6.2 mg, light yellow solid) was obtained through similar steps. MS (ESI): m / z 446.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.70(s,1H),10.84(s,1H),9.34(t,J=6.0Hz,1H),8.19(d,J=2.0Hz,1H),7.63(s,1H) ,7.37(d,J=8.4Hz,1H),7.32(d,J=2.0Hz,1H),7.25(s,1H),6.91(dd,J=8.0,1.6Hz,1H),6 .20(s,1H),6.12(d,J=2.0Hz,1H),5.25(s,2H),4.51(d,J=5.6Hz,2H),3.78(s,2H),2.52- 2.51(m,2H),2.43-2.36(m,1H),2.01-1.93(m,2H),1.85-1.74(m,2H),1.66-1.59(m,2H).

[0452] Embodiment 13

[0453] N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-4-(methylamino)pyrazolo[1,5-a]pyrazine-6-carboxamide

[0454]

[0455] (1) 6-Chloro-N-methylpyrazolo[1,5-a]pyrazin-4-amine

[0456] 4,6-Dichloropyrazolo[1,5-a]pyrazine (500 mg, 2.66 mmol) was dissolved in dimethyl sulfoxide (10 mL), methylamine hydrochloride (359 mg, 5.32 mmol) and N,N-diisopropylethylamine (1.03 g, 8.0 mmol) were added, and the mixture was heated to 60°C for overnight reaction. The reaction solution was poured into water (80 mL), and the aqueous phase was extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 65 / 35) to give the title compound (400 mg, light yellow solid), yield: 82.6%. MS (ESI): m / z 183.0 [M+H] + .

[0457] (2) 4-(Methylamino)pyrazolo[1,5-a]pyrazine-6-carboxylic acid methyl ester

[0458] 6-Chloro-N-methylpyrazolo[1,5-a]pyrazine-4-amine (182 mg, 1.0 mmol) was dissolved in a mixed solvent of methanol / acetonitrile (5 mL / 5 mL), palladium acetate (23 mg, 0.1 mmol), diphenyl-1-phenylphenylphosphine (54 mg, 0.13 mmol) and triethylamine (202 mg, 2 mmol) were added, and the mixture was heated to 120°C in a high pressure reactor (23 atmospheres, carbon monoxide atmosphere) and stirred for 12 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to obtain the title compound (140 mg, light yellow solid), yield: 68%. MS (ESI): m / z 207.0 [M+H] + .

[0459] (3) 4-(Methylamino)pyrazolo[1,5-a]pyrazine-6-carboxylic acid

[0460] Dissolve 4-(Methylamino)pyrazolo[1,5-a]pyrazine-6-carboxylic acid methyl ester (103 mg, 0.5 mmol) in methanol (8 mL), add sodium hydroxide (40 mg, 1 mmol) and water (4 mL), and react at room temperature for 16 hours. The reaction solution was concentrated, and the pH value was adjusted to about 6 with 1M dilute hydrochloric acid. After standing, a white solid precipitated, which was filtered and dried to obtain the title compound (70 mg, white solid), with a yield of 73%. MS (ESI): m / z 192.8 [M+H] + .

[0461] (4) tert-Butyl 2-(((tert-Butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((4-(methylamino)pyrazolo[1,5-a]pyrazine-6-carboxamido)methyl)-1H-indole-1-carboxylate

[0462] 4-(Methylamino)pyrazolo[1,5-a]pyrazine-6-carboxylic acid (30 mg, 0.16 mmol) was dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (148 mg, 1.15 mmol) and HATU (175 mg, 0.46 mmol) were added, and the reaction was stirred at room temperature for 5 minutes. Then, a solution of intermediate 1 (102 mg, 0.23 mmol) in N,N-dimethylformamide (1 mL) was added, and the reaction was continued to stir at room temperature for 30 minutes. Saturated sodium bicarbonate solution (10 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to obtain the title compound (75 mg, light yellow oil), yield: 77%. MS (ESI): m / z 618.1 [M+H] + .

[0463] (5) N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-4-(methylamino)pyrazolo[1,5-a]pyrazine-6-carboxamide

[0464] 2-(((tert-Butyloxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((4-(methylamino)pyrazolo[1,5-a]pyrazine-6-carboxamido)methyl)-1H-indole-1-carboxylic acid tert-butyl ester (75 mg, 0.12 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 6 hours. The reaction solution was concentrated, and the residue was diluted with N,N-dimethylformamide and purified by Prep-HPLC to give the title compound (10.4 mg, white solid), yield: 20%. MS (ESI): m / z 418.1 [M+H]+ . 1 H NMR (400 MHz, DMSO-d 6 )δ10.83(s,1H),8.85(t,J=6.4Hz,1H),8.36(d,J=0.4Hz,1H),8.02(d,J=2.4Hz,1H),7.89(q ,J=4.4Hz,1H),7.37(d,J=8.0Hz,1H),7.30(s,1H),7.01(dd,J=2.0,0.8Hz,1H),6.96(dd,J= 8.0,0.8Hz,1H),6.20(s,1H),4.59(d,J=6.4Hz,2H),3.77(s,2H),3.05(d,J=4.4Hz,3H),2.5 2-2.51(m,2H),2.41-2.35(m,1H),1.98-1.93(m,2H),1.82-1.76(m,2H),1.64-1.59(m,2H).

[0465] Embodiment 14

[0466] N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-4-((4-methoxybenzyl)amino)pyrazolo[1,5-a]pyrazine-6-carboxamide

[0467]

[0468] Referring to the synthesis method of Example 13, 4,6-dichloropyrazolo[1,5-a]pyrazine and (4-methoxyphenyl)methylamine were used as starting materials and the title compound (12.9 mg, white solid) was obtained through similar steps. MS (ESI): m / z 524.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ11.86(s,1H),8.77(t,J=6.0Hz,1H),8.38-8.35(m,2H),8.02(d,J=2.0Hz,1H),7.39(d, J=8.4Hz,1H),7.31-7.27(m,3H),7.09(dd,J=2.0,0.4Hz,1H),6.97(dd,J=8.4,1.2Hz,1H), 6.73-6.71(m,2H),6.21(s,1H),4.69(d,J=5.6Hz,2H),4.57(d,J=6.4Hz,2H),3.77(s,2H) ,3.63(s,3H),2.56-2.53(m,2H),2.43-2.35(m,1H),2.00-1.92(m,2H),1.84-1.58(m,4H).

[0469] Embodiment 15

[0470] N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-4-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrazine-6-carboxamide

[0471]

[0472] Referring to the synthesis method of Example 13, 4,6-dichloropyrazolo[1,5-a]pyrazine and pyrrolidine were used as starting materials and the title compound (4.1 mg, white solid) was obtained through similar steps. MS (ESI): m / z 458.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.83(s,1H),8.76(t,J=6.4Hz,1H),8.34(s,1H),8.05(d,J=2.4Hz,1H),7 .36(d,J=8.0Hz,1H),7.28(s,1H),7.12(d,J=2.0Hz,1H),6.95(dd,J=8.0,0. 8Hz,1H),6.19(s,1H),4.57(d,J=6.4Hz,2H),3.89-3.79(m,4H),3.77(s,2H) ,2.62-2.76(m,2H),2.43-2.35(m,1H),2.01-1.93(m,6H),1.83-1.59(m,4H).

[0473] Example 16

[0474] N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-4-morpholinylpyrazolo[1,5-a]pyrazine-6-carboxamide

[0475]

[0476] Referring to the synthesis method of Example 13, 4,6-dichloropyrazolo[1,5-a]pyrazine and morpholine were used as starting materials and the title compound (11.5 mg, white solid) was obtained through similar steps. MS (ESI): m / z 474.2 [M+H] +. 1 H NMR (400 MHz, DMSO-d 6 )δ10.88(s,1H),8.95(t,J=6.4Hz,1H),8.53(d,J=0.4Hz,1H),8.14(d,J=2.4Hz,1H),7 .39(d,J=8.4Hz,1H),7.30(s,1H),7.17(dd,J=2.4,0.8Hz,1H),6.97(dd,J=8.0,1.2Hz ,1H),6.28(s,1H),4.59(d,J=6.4Hz,2H),3.88(s,2H),3.87-3.84(m,4H),3.77-3.75( m,4H),2.62(d,J=7.2Hz,2H),2.48-2.42(m,1H),2.01-1.94(m,2H),1.84-1.62(m,4H).

[0477] Embodiment 17

[0478] N-((2-(2-(Cyclobutylamino)ethyl)-2H-indazol-6-yl)methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[0479]

[0480] (1) 2-(2-Hydroxyethyl)-2H-indazole-6-carbonitrile

[0481] 1H-indazole-6-carbonitrile (2.0 g, 14.0 mmol) was dissolved in N,N-dimethylformamide (30 mL), 2-bromo-1-ol (2.6 g, 21.0 mmol) and potassium carbonate (3.8 g, 28.0 mmol) were added, and the mixture was heated to 80 ° C for overnight reaction. The reaction solution was poured into water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to give the title compound (900 mg, yellow solid), yield: 35%. MS (ESI): m / z 188.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.55(s,1H),8.31(s,1H),7.93(d,J=8.8Hz,1H),7.28(d,J=8.4Hz,1H),5.01(t,J=5.6Hz,1H),4.54(t,J=5.2Hz,2H),3.90(t,J=5.6Hz,1H).

[0482] (2) 2-(6-(Aminomethyl)-2H-indazol-2-yl)ethan-1-ol

[0483] 2-(2-Hydroxyethyl)-2H-indazole-6-carbonitrile (300 mg, 1.6 mmol) was dissolved in ammonia methanol solution (7 M, 10 mL), Raney nickel (30 mg) was added, and the mixture was heated to 50°C under a hydrogen atmosphere for 3 hours. The reaction solution was filtered and the filtrate was concentrated to obtain the title compound (306 mg, colorless oil). MS (ESI): m / z 192.0 [M+H] + .

[0484] (3) N-((2-(2-hydroxyethyl)-2H-indazol-6-yl)methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[0485] 2-(6-(Aminomethyl)-2H-indazol-2-yl)ethane-1-ol (200 mg, 1.0 mmol) and intermediate 3 (200 mg, 1.0 mmol) were dissolved in N,N-dimethylformamide (5 mL), 1-propylphosphoric anhydride (1.3 g, 2 mmol, 50% ethyl acetate solution) and triethylamine (303 mg, 3 mmol) were added, and stirred at room temperature overnight. The reaction solution was purified by reverse phase column to obtain the title compound (270 mg, white solid), yield: 71%. MS (ESI): m / z 364.0 [M+H] + .

[0486] (4) 4-Oxo-N-((2-(2-oxoethyl)-2H-indazol-6-yl)methyl)-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[0487] Dissolve N-((2-(2-hydroxyethyl)-2H-indazol-6-yl)methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide (50 mg, 0.14 mmol) in dichloromethane (5 mL), add Dess-Martin periodinane (89 mg, 0.21 mmol), and react at room temperature for 2 hours. The reaction solution was filtered and concentrated to obtain the title compound (50 mg, yellow oil). MS (ESI): m / z 362.0 [M+H] + .

[0488] (5) N-((2-(2-(cyclobutylamino)ethyl)-2H-indazol-6-yl)methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[0489] 4-Oxo-N-((2-(2-oxoethyl)-2H-indazol-6-yl)methyl)-4H-pyrido[1,2-a]pyrimidine-2-carboxamide (50 mg, 0.14 mmol) and cyclobutylamine (30 mg, 0.42 mmol) were dissolved in methanol (5 mL), stirred at room temperature for half an hour, and then sodium cyanoborohydride (18 mg, 0.28 mmol) was added and stirred at room temperature overnight. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol=30 / 1) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (3.7 mg, colorless oil), yield: 6%. MS (ESI): m / z 417.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.35(t,J=6.0Hz,1H),9.02(d,J=6.8Hz,1H),8.30(s,1H),8.09-8.05(m,1H),7.7 9(d,J=8.8Hz,1H),7.64(d,J=8.4Hz,1H),7.49(s,1H),7.45(td,J=6.8,1.2Hz,1H), 7.04(dd,J=8.4,1.2Hz,1H),6.90(s,1H),4.58(d,J=6.0Hz,2H),4.39(t,J=6.4Hz,2 H),3.16-3.10(m,1H),2.93(t,J=6.4Hz,2H),2.08-2.02(m,2H),1.62-1.53(m,4H).

[0490] Embodiment 18

[0491] N-((2-(((cyclobutylmethyl)amino)methyl)quinazolin-7-yl)methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[0492]

[0493] (1) N-(5-bromo-2-formylphenyl)-2-chloroacetamide

[0494] Dissolve 2-amino-4-bromobenzaldehyde (1.8 g, 9.0 mmol) and triethylamine (1.8 g, 18.0 mmol) in dichloromethane (20 mL), add chloroacetyl chloride (1.5 g, 13.5 mmol) dropwise at 0 ° C, and react at room temperature for 3 hours under nitrogen protection. Pour the reaction solution into water (20 mL) and extract with dichloromethane (2 x 20 mL). The organic phases are combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain the title compound (1.9 g, yellow solid), yield: 77%. MS (ESI): m / z 275.8 [M+H] + .

[0495] (2) 7-Bromo-2-(chloromethyl)quinazoline

[0496] N-(5-bromo-2-formylphenyl)-2-chloroacetamide (1.5 g, 5.0 mmol) and ammonium acetate (2.3 g, 30.0 mmol) were dissolved in acetic acid (20 mL), and the mixture was heated to 80 ° C and stirred for 1 hour. The reaction solution was concentrated to remove acetic acid, saturated sodium bicarbonate solution (20 mL) was added, and the aqueous phase was extracted with ethyl acetate (2 x 20 mL). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound (1.3 g, yellow solid), yield: 93%. MS (ESI): m / z 256.8 [M+H] + .

[0497] (3) 1-(7-bromoquinazolin-2-yl)-N-(cyclobutylmethyl)methanamine

[0498] Dissolve 7-bromo-2-(chloromethyl)quinazoline (800 mg, 3.1 mmol) and cyclobutylmethylamine (527 mg, 6.2 mmol) in acetonitrile (20 mL), add potassium carbonate (856 mg, 6.2 mmol), and react at room temperature overnight. The reaction solution is concentrated and poured into water (20 mL), and the aqueous phase is extracted with dichloromethane (2 x 20 mL). The organic phases are combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue is purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give the title compound (480 mg, yellow oil), yield: 50%. MS (ESI): m / z 305.9 [M+H] + .

[0499] (4) (9H-fluoren-9-yl)methyl ((7-bromoquinazolin-2-yl)methyl) (cyclobutylmethyl) carbamate

[0500] 1-(7-bromoquinazolin-2-yl)-N-(cyclobutylmethyl)methylamine (100 mg, 0.33 mmol) and 9-fluorenylmethyl chloroformate (128 mg, 0.49 mmol) were dissolved in acetonitrile / water (20 mL / 2 mL), sodium carbonate (70 mg, 0.66 mmol) was added, and the reaction was allowed to proceed overnight at room temperature. The reaction solution was concentrated, water (20 mL) was added, and the aqueous phase was extracted with ethyl acetate (2 x 20 mL). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound (130 mg, yellow oil), yield: 75%. MS (ESI): m / z 528.0 [M+H] + .

[0501] (5) (9H-fluoren-9-yl)methyl ((7-(((tert-butyloxycarbonyl)amino)methyl)quinazolin-2-yl)methyl) (cyclobutylmethyl)carbamate

[0502] (9H-fluoren-9-yl)methyl((7-bromoquinazolin-2-yl)methyl)(cyclobutylmethyl)carbamate (130 mg, 0.25 mmol) and ((trifluoro-4-boryl)methyl)carbamic acid tert-butyl ester potassium salt (118 mg, 0.5 mmol) were dissolved in 1,4-dioxane / water (10 mL / 2 mL), and Pd(dppf)Cl was added. 2(18 mg, 0.025 mmol) and potassium carbonate (69 mg, 0.5 mmol), heated to 100 ° C under nitrogen protection and stirred overnight. The reaction solution was poured into water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to give the title compound (70 mg, yellow oil), yield: 49%. MS (ESI): m / z 579.0 [M+H] + .

[0503] (6) (9H-fluoren-9-yl)methyl ((7-(aminomethyl)quinazolin-2-yl)methyl) (cyclobutylmethyl)carbamate

[0504] Dissolve (9H-fluoren-9-yl)methyl((7-(((tert-butyloxycarbonyl)amino)methyl)quinazolin-2-yl)methyl)(cyclobutylmethyl)carbamate (30 mg, 0.05 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (5 mL), and stir at room temperature for 1 hour. The reaction solution is concentrated to obtain the title compound (25 mg, yellow oil). MS (ESI): m / z 479.2 [M+H] + .

[0505] (7) N-((2-(((cyclobutylmethyl)amino)methyl)quinazolin-7-yl)methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[0506] (9H-fluoren-9-yl)methyl((7-(aminomethyl)quinazolin-2-yl)methyl)(cyclobutylmethyl)carbamate (25 mg, 0.05 mmol) and intermediate 3 (10 mg, 0.05 mmol) were dissolved in N,N-dimethylformamide (5 mL), 1-propylphosphonic anhydride (64 mg, 0.1 mmol, 50% ethyl acetate solution) and triethylamine (10 mg, 0.1 mmol) were added, and stirred at room temperature overnight. The reaction solution was poured into water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by Prep-HPLC to give the title compound (1.6 mg, white solid) in a yield of 7%. MS (ESI): m / z 429.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ9.66-9.62(m,1H),9.53(s,1H),9.03(d,J=6.4Hz,1H),8.12-8.07(m ,2H),7.83-7.80(m,2H),7.70(d,J=8.8Hz,1H),7.49-7.46(m,1H),6.91 (s,1H),4.76(d,J=6.4Hz,2H),4.00(s,2H),2.61(d,J=7.2Hz,2H),2.43 -2.38(m,1H),2.01-1.97(m,2H),1.83-1.78(m,2H),1.68-1.60(m,2H).

[0507] Embodiment 19

[0508] N-((3-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[0509]

[0510] (1) 3-(((Cyclobutylmethyl)amino)methyl)-1H-indole-6-carbonitrile

[0511] 3-Formyl-1H-indole-6-carbonitrile (400 mg, 2.3 mmol) and cyclobutylmethylamine (391 mg, 4.6 mmol) were dissolved in methanol (5 mL) and stirred at room temperature for 1 hour. Sodium cyanoborohydride (290 mg, 4.6 mmol) was then added and the reaction was stirred at 40°C overnight. The reaction solution was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (100% ethyl acetate) to give the title compound (500 mg, yellow oil), yield: 89%. MS (ESI): m / z 239.8 [M+H] + .

[0512] (2) tert-Butyl 3-(((tert-Butyloxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-cyano-1H-indole-1-carboxylate

[0513] 3-(((Cyclobutylmethyl)amino)methyl)-1H-indole-6-carbonitrile (200mg, 0.84mmol) and sodium hydride (100mg, 2.52mmol, 60%) were dissolved in tetrahydrofuran (10mL) and stirred at room temperature for 5 minutes. Di-tert-butyl dicarbonate (545mg, 2.5mmol) was added and stirred at room temperature for 3 hours. Water (20mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (20mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound (100mg, yellow solid), yield: 27%. MS (ESI): m / z 440.0 [M+H] + .

[0514] (3) tert-Butyl 6-(aminomethyl)-3-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-1H-indole-1-carboxylate

[0515] Dissolve tert-butyl 3-(((tert-butyloxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-cyano-1H-indole-1-carboxylate (100 mg, 0.23 mmol) in ammonia methanol solution (10 mL, 7 M), add Raney nickel (10 mg), heat to 50°C under hydrogen atmosphere, stir and react overnight. Filter the reaction solution, and concentrate the filtrate to obtain the title compound (100 mg, yellow oil). MS (ESI): m / z 466.0 [M+Na] + .

[0516] (4) tert-Butyl 3-(((tert-Butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamido)methyl)-1H-indole-1-carboxylate

[0517] Intermediate 3 (17 mg, 0.09 mmol) was dissolved in N, N-dimethylformamide (5 mL), and N, N-diisopropylethylamine (23 mg, 0.18 mmol) and HATU (51 mg, 0.14 mmol) were added, and the mixture was stirred at room temperature for 5 minutes. 6-(aminomethyl)-3-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-1H-indole-1-carboxylic acid tert-butyl ester (40 mg, 0.09 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Water (20 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to give the title compound (20 mg, colorless oil), yield: 36%. MS (ESI): m / z 638.2 [M+Na] + .

[0518] (5) N-((3-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[0519] 3-(((tert-Butyloxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamido)methyl)-1H-indole-1-carboxylic acid tert-butyl ester (20 mg, 0.03 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (2 mL) was added, and stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was purified by Prep-HPLC to give the title compound (2.0 mg, white solid), yield: 15%. MS (ESI): m / z 416.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ10.80(s,1H),9.24(t,J=6.4Hz,1H),9.01(d,J=6.4Hz,1H),8.08-8.04(m,1H),7.78( d,J=8.8Hz,1H),7.55(d,J=8.0Hz,1H),7.45(td,J=7.2,1.6Hz,1H),7.33(s,1H),7.19(s ,1H),7.00(d,J=9.2Hz,1H),6.90(s,1H),4.58(d,J=6.0Hz,2H),3.82(s,2H),2.57(d,J= 7.2Hz,2H),2.45-2.37(m,1H),2.03-1.94(m,2H),1.82-1.76(m,2H),1.65-1.59(m,2H).

[0520] Embodiment 20

[0521] N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[0522]

[0523] (1) 2-((6-bromo-4-iodopyridin-3-yl)oxy)ethane-1-ol

[0524] At 0°C, 2-bromo-5-fluoro-4-iodopyridine (3.7 g, 12.26 mmol), ethylene glycol (3.8 g, 61.28 mmol) and sodium tert-butoxide (1.51 g, 13.48 mmol) were dissolved in N,N-dimethylformamide (30 mL), and the mixture was heated to 80°C and stirred for 1 hour. The reaction solution was added to water (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 60 / 40) to obtain the title compound (1.0 g, pink solid), yield: 24%. MS (ESI): m / z 343.8 [M+H] + .

[0525] (2) 7-Bromo-2,3-dihydro-[1,4]dioxacyclo[2,3-c]pyridine

[0526] 2-((6-bromo-4-iodopyridin-3-yl)oxy)ethane-1-ol (1.0 g, 2.91 mmol) was dissolved in isopropanol (20 mL), and potassium tert-butoxide (490 mg, 4.36 mmol), 3,4,7,8-tetramethyl-1,10-phenanthroline (69 mg, 0.29 mmol) and cuprous iodide (34 mg, 0.17 mmol) were added. The mixture was heated to 80 °C and stirred for 1 hour. The reaction solution was added to water (20 mL), and then saturated ammonium chloride solution (10 mL) was added, and the aqueous phase was extracted with ethyl acetate (40 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 85 / 15) to obtain the title compound (400 mg, white solid), yield: 22%. MS (ESI): m / z 215.9 [M+H] + .

[0527] (3) tert-Butyl (2,3-dihydro-[1,4]dioxo[2,3-c]pyridin-7-yl)carbamate

[0528] 7-Bromo-2,3-dihydro-[1,4]dioxacyclo[2,3-c]pyridine (350 mg, 1.62 mmol) and tert-butyl carbamate (574 mg, 4.86 mmol) were dissolved in 1,4-dioxane (20 mL), and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (161 mg, 0.32 mmol), tris(dibenzylideneacetone)dipalladium (154 mg, 0.16 mmol) and cesium carbonate (1.32 g, 4.05 mmol) were added. The mixture was heated to 90°C under nitrogen protection and stirred for 16 hours. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 20) to obtain the title compound (620 mg, yellow solid), yield: 76%. MS (ESI): m / z 197.0 [M+H-56] + .

[0529] (4) 2,3-Dihydro-[1,4]dioxo[2,3-c]pyridin-7-amine

[0530] Dissolve tert-butyl (2,3-dihydro-[1,4]dioxo[2,3-c]pyridin-7-yl)carbamate (600 mg, 2.38 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (5 mL), and stir at room temperature for 12 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain the title compound (140 mg, yellow solid), yield: 39%. MS (ESI): m / z 153.0 [M+H] + .

[0531] (5) 9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxylic acid methyl ester

[0532] Dissolve 2,3-dihydro-[1,4]dioxo[2,3-c]pyridin-7-amine (100 mg, 0.66 mmol) and dimethyl butane-2-diacetate (160 mg, 0.72 mmol) in water (15 mL) and stir at room temperature for 12 hours. Ethyl acetate (30 mL) was added to the reaction solution for extraction, and the organic phase was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 90 / 10) to obtain the title compound (100 mg, yellow solid), yield: 58%. MS (ESI): m / z 263.0 [M+H] + .

[0533] (6) 9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxylic acid

[0534] 9-Oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxylic acid methyl ester (100 mg, 0.38 mmol) was dissolved in methanol / water (5 mL / 5 mL), sodium hydroxide (76 mg, 1.91 mmol) was added, and the mixture was heated to 80 ° C and stirred for 4 hours. The reaction solution was concentrated, 1M dilute hydrochloric acid was added to adjust the pH value to 5, and the aqueous phase was extracted with dichloromethane (30 mL x 3). The organic phases were combined and concentrated to give the title compound (60 mg, yellow solid), yield: 63%. MS (ESI): m / z 249.0 [M+H] + .

[0535] (7) tert-Butyl 2-(((tert-Butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide)methyl)-1H-indole-1-carboxylate

[0536] Dissolve 9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxylic acid (60 mg, 0.24 mmol) in N,N-dimethylformamide (10 mL), add N,N-diisopropylethylamine (94 mg, 0.72 mmol) and HATU (185 mg, 0.48 mmol), and stir at room temperature for 5 minutes. Then add a solution of intermediate 1 (321 mg, 0.73 mmol) in N,N-dimethylformamide (5 mL), and continue stirring at room temperature for 12 hours. The reaction solution is added to a saturated sodium bicarbonate solution (10 mL), and the aqueous phase is extracted with ethyl acetate (20 mL x 3). The organic phases are combined, washed with a saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=50 / 50) to give the title compound (90 mg, yellow oil), yield: 14%. MS (ESI): m / z 574.1 [M+H-100] + .

[0537] (8) N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[0538] 2-(((tert-Butyloxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide)methyl)-1H-indole-1-carboxylic acid tert-butyl ester (90 mg, 0.04 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was added to saturated sodium bicarbonate solution (10 mL), and the aqueous phase was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The residue was diluted with N,N-dimethylformamide and purified by Prep-HPLC to give the title compound (4.0 mg, white solid) in a yield of 21%. MS (ESI): m / z 474.1 [M+H] + . 1 HNMR (400 MHz, DMSO-d 6)δ10.86(s,1H),9.05(t,J=6.0Hz,1H),8.62(s,1H),7.36(d,J=8.0Hz,1H), 7.29(s,1H),7.19(s,1H),6.94(d,J=8.0Hz,1H),6.67(s,1H),6.19(s,1H), 4.59-4.52(m,4H),4.49(d,J=6.0Hz,2H),3.76(s,2H),2.59-2.52(m,2H),2 .41-2.38(m,1H),2.01-1.95(m,2H),1.83-1.75(m,2H),1.66-1.59(m,2H).

[0539] Embodiment 21

[0540] N-((6-(((cyclobutylmethyl)amino)methyl)-1H-indol-2-yl)methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[0541]

[0542] (1) 6-Formyl-1H-indole-2-carbonitrile

[0543] Dissolve 6-bromo-1H-indole-2-carbonitrile (600 mg, 2.7 mmol) in tetrahydrofuran (5 mL), add sodium hydride (432 mg, 10.8 mmol, 60%) at 0 ° C, and stir the mixture under nitrogen protection for 15 minutes. The reaction solution was cooled to -78 ° C, and n-butyl lithium (2.7 mL, 6.75 mmol, 2.5 M) was slowly added dropwise, and the reaction was continued to stir for 20 minutes. N, N-dimethylformamide (1.18 g, 16.2 mmol) was added, and the mixture was continued to stir at -78 ° C for 2 hours. The reaction solution was warmed to room temperature, saturated ammonium chloride solution (40 mL) was added to quench the reaction, and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=80 / 20) to give the title compound (270 mg, yellow solid), yield: 58%. MS (ESI): m / z 171.0 [M+H] + . 1 H NMR (300 MHz, DMSO-d 6 )δ12.89(s,1H),10.11(s,1H),8.11(s,1H),7.88(d,J=8.4Hz,1H),7.68(dd,J=8.4,1.2Hz,1H),7.52(s,1H).

[0544] (2) 6-(((Cyclobutylmethyl)amino)methyl)-1H-indole-2-carbonitrile

[0545] 6-Formyl-1H-indole-2-carbonitrile (270 mg, 1.6 mmol) and cyclobutylmethylamine (272 mg, 3.2 mmol) were dissolved in dichloroethane (5 mL), and the mixture was stirred at 65 ° C for 1 hour. Sodium cyanoborohydride (302 mg, 4.8 mmol) was added, and the mixture was stirred at 65 ° C for 2 hours. The reaction solution was added to a saturated sodium bicarbonate solution (30 mL), and the aqueous phase was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with a saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 97 / 3) to obtain the title compound (150 mg, red oil), yield: 39%. MS (ESI): m / z 240.1 [M+H] + .

[0546] (3) tert-Butyl 6-(((tert-Butyloxycarbonyl)(cyclobutylmethyl)amino)methyl)-2-cyano-1H-indole-1-carboxylate

[0547] 6-(((Cyclobutylmethyl)amino)methyl)-1H-indole-2-carbonitrile (150mg, 0.63mmol) and sodium hydride (101mg, 2.52mmol, 60%) were dissolved in tetrahydrofuran (3mL) and stirred at room temperature for 5 minutes. Di-tert-butyl dicarbonate (549mg, 2.52mmol) was added and stirred at room temperature for 17 hours. The reaction solution was added to water (10mL), and the aqueous phase was extracted with ethyl acetate (10mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 95 / 5) to obtain the title compound (100mg, colorless oil), yield: 36%. MS (ESI): m / z 462.1 [M+Na] + .

[0548] (4) tert-Butyl 2-(aminomethyl)-6-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-1H-indole-1-carboxylate

[0549] 6-(((tert-butyloxycarbonyl)(cyclobutylmethyl)amino)methyl)-2-cyano-1H-indole-1-carboxylic acid tert-butyl ester (40 mg, 0.09 mmol) was dissolved in 7M ammonia methanol solution (10 mL), and Raney nickel (10 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere overnight. The reaction solution was filtered to remove Raney nickel, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol=10 / 1) to give the title compound (20 mg, colorless oil), yield: 36%. MS (ESI): m / z 444.3 [M+H] + .

[0550] (5) tert-Butyl 6-(((tert-Butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-2-((4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamido)methyl)-1H-indole-1-carboxylate

[0551] Tert-butyl 2-(aminomethyl)-6-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-1H-indole-1-carboxylate (15 mg, 0.03 mmol) was dissolved in N,N-dimethylformamide (5 mL), and intermediate 3 (5.7 mg, 0.03 mmol), N,N-diisopropylethylamine (7.7 mg, 0.06 mmol) and HATU (22.8 mg, 0.06 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was added to water (20 mL), and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to give the title compound (10 mg, colorless oil), yield: 48%. MS (ESI): m / z 616.3 [M+H] + .

[0552] (6) N-((6-(((cyclobutylmethyl)amino)methyl)-1H-indol-2-yl)methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[0553] Dissolve tert-butyl 6-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-2-((4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamido)methyl)-1H-indole-1-carboxylate (10 mg, 0.02 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (2 mL), and stir at room temperature for 1 hour. The reaction solution was added to sodium bicarbonate solution (20 mL), and the aqueous phase was extracted with a mixed solvent of dichloromethane / methanol. The organic phases were combined and concentrated, and the residue was purified by Prep-HPLC to give the title compound (1.7 mg, white solid), yield: 25%. MS (ESI): m / z 416.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.89(s,1H),9.19(t,J=6.0Hz,1H),9.02(d,J=6.4Hz,1H),8.10-8.05(m,1H),7 .80(d,J=8.4Hz,1H),7.46(td,J=7.2,1.2Hz,1H),7.37(d,J=8.0Hz,1H),7.30(s,1H ),6.94-6.92(m,2H),6.27(s,1H),4.65(d,J=6.4Hz,2H),3.75(s,2H),2.54-2.51( m,2H),2.44-2.39(m,1H),2.00-1.95(m,2H),1.82-1.75(m,2H),1.66-1.59(m,2H).

[0554] Embodiment 22

[0555] N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)pyrazolo[1,5-a]pyrido[2,3-e]pyrazine-8-carboxamide

[0556]

[0557] (1) 6-(((1H-pyrazol-3-yl)methyl)amino)-5-bromonicotinate

[0558] Dissolve 5-bromo-6-chloronicotinic acid methyl ester (900 mg, 3.6 mmol) and (1H-pyrazol-3-yl)methylamine (349 mg, 3.6 mmol) in N,N-dimethylformamide (10 mL), add triethylamine (727 mg, 7.2 mmol), and heat the mixture to 90°C to react overnight. The reaction solution was purified by reverse phase column to obtain the title compound (790 mg, yellow solid), yield: 71%. MS (ESI): m / z 310.9 [M+H] + .

[0559] (2) Methyl pyrazolo[1,5-a]pyrido[2,3-e]pyrazine-8-carboxylate

[0560] 6-(((1H-pyrazol-3-yl)methyl)amino)-5-bromonicotinate (600 mg, 1.9 mmol), L-proline (44 mg, 0.38 mmol) and cuprous iodide (36 mg, 0.19 mmol) were dissolved in N,N-dimethylformamide (10 mL), cesium carbonate (1.2 g, 3.8 mmol) was added, and the mixture was heated to 100 ° C for overnight reaction. The reaction solution was added to water (30 mL), and the aqueous phase was extracted with ethyl acetate (2x20 mL). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to give the title compound (100 mg, yellow solid), yield: 23%. MS (ESI): m / z 228.8 [M+H] + .

[0561] (3) Pyrazolo[1,5-a]pyrido[2,3-e]pyrazine-8-carboxylic acid

[0562] Pyrazolo[1,5-a]pyrido[2,3-e]pyrazine-8-carboxylic acid methyl ester (100 mg, 0.44 mmol) was dissolved in methanol / water (10 mL / 2 mL), sodium hydroxide (88 mg, 2.2 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction solution was adjusted to acidity with 1M dilute hydrochloric acid, and the solid was filtered to obtain the title compound (70 mg, yellow solid), yield: 75%. MS (ESI): m / z 214.8 [M+H] + .

[0563] (4) tert-Butyl 2-(((tert-Butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((pyrazolo[1,5-a]pyrido[2,3-e]pyrazine-8-carboxamido)methyl)-1H-indole-1-carboxylate

[0564] Pyrazolo[1,5-a]pyrido[2,3-e]pyrazine-8-carboxylic acid (20 mg, 0.09 mmol) and intermediate 2 (40 mg, 0.09 mmol) were dissolved in N,N-dimethylformamide (5 mL), 1-propylphosphoric anhydride (114 mg, 0.18 mmol, 50% ethyl acetate solution) and triethylamine (18 mg, 0.18 mmol) were added, and stirred at room temperature overnight. The reaction solution was poured into water (20 mL), and the aqueous phase was extracted with ethyl acetate (2 x 20 mL). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to give the title compound (20 mg, yellow oil), yield: 35%. MS (ESI): m / z 662.2 [M+Na] + .

[0565] (5) N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)pyrazolo[1,5-a]pyrido[2,3-e]pyrazine-8-carboxamide

[0566] Dissolve tert-butyl 2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((pyrazolo[1,5-a]pyrido[2,3-e]pyrazine-8-carboxamido)methyl)-1H-indole-1-carboxylate (20 mg, 0.03 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (3 mL), and react at room temperature for 2 hours. The reaction solution was poured into sodium bicarbonate solution (20 mL), and the aqueous phase was extracted with a mixed solvent of dichloromethane / methanol. The organic phases were combined and concentrated, and the residue was purified by Prep-HPLC to give the title compound (0.8 mg, yellow solid), yield: 6%. MS (ESI): m / z 440.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.86(s,1H),9.63(t,J=5.6Hz,1H),9.53(s,1H),9.34-9.32(m,2H),8.38(d, J=2.0Hz,1H),7.40(d,J=8.0Hz,1H),7.34(s,1H),7.27(d,J=2.0Hz,1H),7.00(d ,J=9.2Hz,1H),6.21(s,1H),4.63(d,J=6.0Hz,2H),3.78(s,2H),2.59-2.57(m,2 H),2.43-2.37(m,1H),2.03-1.99(m,2H),1.82-1.75(m,2H),1.64-1.59(m,2H).

[0567] Embodiment 23

[0568] N-((2-(((Cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-3-cyclopropyl-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxamide

[0569]

[0570] (1) 6-Bromo-3-cyclopropyl-[1,2,4]triazolo[4,3-a]pyrimidine

[0571] Dissolve 5-bromo-2-hydrazinopyrimidine (360 mg, 1.9 mmol) in dichloromethane (20 mL), add cyclopropylcarboxaldehyde (133 mg, 1.9 mmol), and then add two drops of glacial acetic acid, and stir at room temperature for 2 hours. After the system gradually becomes clear, add iodobenzene acetate (676 mg, 2.1 mmol) and continue to react for 2 hours. The reaction solution is concentrated, and the residue is purified by silica gel column chromatography (dichloromethane / methanol=94 / 6) to obtain the title compound (370 mg, white solid), yield: 81.5%. MS (ESI): m / z 238.9 [M+H] + .

[0572] (2) 3-Cyclopropyl-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic acid methyl ester

[0573] 6-Bromo-3-cyclopropyl-[1,2,4]triazolo[4,3-a]pyrimidine (700 mg, 2.9 mmol) was dissolved in methanol / acetonitrile (10 mL / 10 mL), 1,3-bis(diphenylphosphino)propane (157 mg, 0.38 mmol), palladium acetate (65 mg, 0.29 mmol) and triethylamine (737 mg, 7.3 mmol) were added, and the mixture was heated to 100°C in a high pressure reactor (3 MPa, carbon monoxide atmosphere) for overnight reaction. The reaction solution was filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to obtain the title compound (130 mg, yellow solid), yield: 20%. MS (ESI): m / z 218.8 [M+H] + .

[0574] (3) 3-Cyclopropyl-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic acid

[0575] Dissolve 3-cyclopropyl-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic acid methyl ester (130 mg, 0.6 mmol) in methanol / water (10 mL / 2 mL), add sodium hydroxide (120 mg, 3 mmol), and react at room temperature overnight. The reaction solution is adjusted to acidity with 1M dilute hydrochloric acid, concentrated, and the residue is purified by reverse phase column to obtain the title compound (20 mg, white solid), yield: 16%. MS (ESI): m / z 204.8 [M+H] + .

[0576] (4) tert-Butyl 2-(((tert-Butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((3-cyclopropyl-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxamido)methyl)-1H-indole-1-carboxylate

[0577] 3-Cyclopropyl-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic acid (20 mg, 0.1 mmol) and intermediate 1 (44 mg, 0.1 mmol) were dissolved in N,N-dimethylformamide (5 mL), 1-propylphosphonic anhydride (190 mg, 0.3 mmol, 50% ethyl acetate solution) and triethylamine (20 mg, 0.2 mmol) were added, and the mixture was heated to 50 °C and stirred overnight. The reaction solution was poured into water (20 mL), and the aqueous phase was extracted with ethyl acetate (2 x 20 mL). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to give the title compound (10 mg, yellow oil), yield: 16%. MS (ESI): m / z 630.2 [M+H] + .

[0578] (5) N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-3-cyclopropyl-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxamide

[0579] 2-(((tert-Butyloxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((3-cyclopropyl-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxamido)methyl)-1H-indole-1-carboxylic acid tert-butyl ester (10 mg, 0.01 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (3 mL) was added, and the mixture was reacted at room temperature for 2 hours. Saturated sodium bicarbonate aqueous solution (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane / methanol (10 mL / 1 mL). The organic phase was concentrated, and the residue was purified by Prep-HPLC to give the title compound (1.0 mg, white solid), yield: 15%. MS (ESI): m / z 430.1 [M+H]+ . 1 H NMR (400 MHz, DMSO-d 6 )δ10.86(s,1H),9.64(d,J=2.4Hz,1H),9.27(t,J=4.8Hz,1H),9.17(d,J=2.4Hz,1H),7 .38(d,J=8.4Hz,1H),7.31(s,1H),6.97(d,J=8.0Hz,1H),6.21(s,1H),4.58(d,J=5.2H z,2H),3.78(s,2H),2.59-2.56(m,2H),2.41-2.37(m,1H),2.22-2.18(m,1H),2.03-1. 96(m,2H),1.83-1.75(m,2H),1.66-1.59(m,2H),1.14-1.10(m,2H),1.05-1.03(m,2H).

[0580] Embodiment 24

[0581] N-((2-((((3,3-difluorocyclobutyl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[0582]

[0583] (1) 2-(((tert-Butyloxycarbonyl)((3,3-difluorocyclobutyl)methyl)amino)methyl)-6-((9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamido)methyl)-1H-indole-1-carboxylic acid tert-butyl ester

[0584] Intermediate 4 (15 mg, 0.06 mmol) was dissolved in N, N-dimethylformamide (2 mL), and N, N-diisopropylethylamine (39 mg, 0.30 mmol) and HATU (46 mg, 0.12 mmol) were added, and the reaction was stirred at room temperature for 5 minutes. Then, a solution of intermediate 6 (40 mg, 0.08 mmol) in N, N-dimethylformamide (2 mL) was added, and the reaction was continued to stir at room temperature for 1 hour. The reaction solution was added to a saturated sodium bicarbonate solution (20 mL), and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with a saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 60) to obtain the title compound (17 mg, yellow oil), yield: 40%. MS (ESI): m / z 710.0 [M+H] + .

[0585] (2) N-((2-((((3,3-difluorocyclobutyl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[0586] 2-(((tert-Butyloxycarbonyl)((3,3-difluorocyclobutyl)methyl)amino)methyl)-6-((9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamido)methyl)-1H-indole-1-carboxylic acid tert-butyl ester (17 mg, 0.024 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and stirred at room temperature for 2 hours. The reaction solution was added to saturated sodium bicarbonate solution (30 mL), extracted with dichloromethane (15 mL x 3), and the organic phases were combined and concentrated. The residue was diluted with methanol and purified by Prep-HPLC to give the title compound (3.4 mg, white solid) in a yield of 28%. MS (ESI): m / z 510.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ10.86(s,1H),9.05(t,J=6.0Hz,1H),8.62(s,1H),7.37(d,J=8.0Hz,1H),7.29(s,1H),7.19(s,1H),6.95(dd,J=8.0,1.2Hz,1H),6. 67(s,1H),6.21(s,1H),4.57-4.53(m,4H),4.47-4.45(m,2H),3.80(s,2H),2.58-2.57(m,2H),2.54-2.53(m,1H),2.32-2.18(m,4H).

[0587] Embodiment 25

[0588] N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0589]

[0590] (1) tert-Butyl 2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamido)methyl)-1H-indole-1-carboxylate

[0591] Intermediate 5 (23 mg, 0.1 mmol) was dissolved in N, N-dimethylformamide (3 mL), and N, N-diisopropylethylamine (65 mg, 0.5 mmol) and HATU (76 mg, 0.2 mmol) were added. The mixture was stirred at room temperature for 5 minutes, and then intermediate 1 (44 mg, 0.1 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was purified by reverse phase column to obtain the title compound (11 mg, light yellow oil), with a yield of 16.7%. MS (ESI): m / z 660.4 [M+H] + .

[0592] (2) N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0593] 2-(((tert-Butyloxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamido)methyl)-1H-indole-1-carboxylic acid tert-butyl ester (11 mg, 0.017 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (3 mL) was added, and stirred at room temperature for 3 hours. The reaction solution was concentrated, and the residue was diluted with methanol (1 mL) and purified by Prep-HPLC to give the title compound (3.3 mg, white solid), yield: 43%. MS (ESI): m / z 460.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.86(s,1H),9.02(t,J=6.0Hz,1H),8.59(s,1H),7.36(d,J=8.0Hz,1H), 7.29(s,1H),7.14(s,1H),6.94(dd,J=8.0,1.2Hz,1H),6.73(s,1H),6.37(s ,2H),6.20(s,1H),4.54(d,J=6.4Hz,2H),3.77(s,2H),2.54-2.52(m,2H),2 .43-2.37(m,1H),2.01-1.93(m,2H),1.85-1.72(m,2H),1.66-1.59(m,2H).

[0594] Embodiment 26

[0595] N-((2-((((3,3-difluorocyclobutyl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0596]

[0597] (1) tert-Butyl 2-(((tert-butoxycarbonyl)((3,3-difluorocyclobutyl)methyl)amino)methyl)-6-((8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamido)methyl)-1H-indole-1-carboxylate

[0598] Intermediate 5 (19 mg, 0.08 mmol) was dissolved in N, N-dimethylformamide (2 mL), and N, N-diisopropylethylamine (52 mg, 0.40 mmol) and HATU (61 mg, 0.16 mmol) were added, and the reaction was stirred at room temperature for 5 minutes. Then, a solution of intermediate 6 (37 mg, 0.08 mmol) in N, N-dimethylformamide (1 mL) was added, and the stirring was continued at room temperature for 1 hour. The reaction solution was added to a saturated sodium bicarbonate solution (20 mL), and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with a saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 70) to obtain the title compound (25 mg, yellow oil), yield: 46%. MS (ESI): m / z 696.1 [M+H] + .

[0599] (2) N-((2-((((3,3-difluorocyclobutyl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0600] 2-(((tert-Butyloxycarbonyl)((3,3-difluorocyclobutyl)methyl)amino)methyl)-6-((8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamido)methyl)-1H-indole-1-carboxylic acid tert-butyl ester (25 mg, 0.036 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was added to saturated sodium bicarbonate solution (30 mL), and the aqueous phase was extracted with dichloromethane (15 mL x 3). The organic phases were combined and concentrated, and the residue was diluted with methanol (2 mL) and purified by Prep-HPLC to give the title compound (1.0 mg, light yellow solid) in a yield of 6%. MS (ESI): m / z 496.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ10.87(s,1H),9.04(t,J=6.0Hz,1H),8.59(s,1H),7.37(d,J=8.0Hz,1H),7.29(s,1H),7.14(s,1H),6.94(dd,J=8.4,1.6Hz,1 H),6.73(s,1H),6.37(s,2H),6.21(d,J=1.6Hz,1H),4.54(d,J=6.4Hz,2H),3.79(s,2H),2.58-2.56(m,3H),2.27-2.20(m,4H).

[0601] Embodiment 27

[0602] N-((2-((4,4-difluoropiperidin-1-yl)methyl)-1H-indol-6-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxacyclo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[0603]

[0604] (1) 2-((4,4-difluoropiperidin-1-yl)methyl)-1H-indole-6-carbonitrile

[0605] 2-Formyl-1H-indole-6-carbonitrile (250 mg, 1.50 mmol, step 4 of intermediate 1) and 4,4-difluoropyridine hydrochloride (591 mg, 3.75 mmol) were dissolved in dichloroethane (5 mL) and stirred at 65 ° C for 1 hour. Sodium cyanoborohydride (331 mg, 5.25 mmol) was added and the reaction was continued at 65 ° C for 2 hours. The reaction solution was added to a saturated sodium bicarbonate solution (30 mL), and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 60) to give the title compound (260 mg, light yellow solid), yield: 64%. MS (ESI): m / z 276.0 [M+H] + .

[0606] Tert-butyl (2)((2-((4,4-difluoropiperidin-1-yl)methyl)-1H-indol-6-yl)methyl)carbamate

[0607] 2-((4,4-difluoropiperidin-1-yl)methyl)-1H-indole-6-carbonitrile (130mg, 0.47mmol) was dissolved in methanol (5mL), nickel chloride hexahydrate (12mg, 0.05mmol) and sodium borohydride (133mg, 3.5mmol) were added, and di-tert-butyl dicarbonate (218mg, 1.0mmol) was added, and stirred at room temperature for 1 hour. The reaction solution was concentrated to remove methanol, and water (30mL) was added, and the aqueous phase was extracted with ethyl acetate (20mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to give the title compound (100mg, light yellow oil), yield: 56%. MS (ESI): m / z 402.0 [M+Na] + .

[0608] (3) (2-((4,4-difluoropiperidin-1-yl)methyl)-1H-indol-6-yl)methanamine

[0609] Dissolve tert-butyl ((2-((4,4-difluoropiperidin-1-yl)methyl)-1H-indol-6-yl)methyl)carbamate (50 mg, 0.13 mmol) in dichloromethane (2 mL), add trifluoroacetic acid (1 mL), and stir at room temperature for 1 hour. The reaction solution was concentrated to obtain the title compound (37 mg, brown oil), yield: 100%. MS (ESI): m / z 263.0 [M+H-NH 3 ] + .

[0610] (4) N-((2-((4,4-difluoropiperidin-1-yl)methyl)-1H-indol-6-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxacyclo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[0611] Intermediate 4 (10 mg, 0.04 mmol) and (2-((4,4-difluoropiperidin-1-yl)methyl)-1H-indol-6-yl)methanamine (11 mg, 0.04 mmol) were dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (10 mg, 0.08 mmol) and HATU (23 mg, 0.06 mmol) were added, and the reaction was stirred at room temperature overnight. The reaction solution was added to water (20 mL), and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by Prep-HPLC to give the title compound (7.2 mg, white solid), yield: 35%. MS (ESI): m / z 510.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.97(s,1H),9.07(t,J=6.0Hz,1H),8.62(s,1H),7.39(d,J=8.4Hz,1H),7.30(s,1H),7.19(s,1H),6.96(dd,J=8.4,1.2Hz,1H ),6.66(s,1H),6.25(d,J=1.2Hz,1H),4.57-4.53(m,4H),4.47-4.45(m,2H),3.67(s,2H),2.54-2.51(m,4H),1.98-1.91(m,4H).

[0612] Embodiment 28

[0613] N-((2-((((3-(difluoromethylene)cyclobutyl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[0614]

[0615] (1) 3-(Aminomethyl)-1-(difluoro(pyridin-2-ylsulfonyl)methyl)cyclobutanol

[0616] Potassium tert-butoxide (336 mg, 3.0 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to -50 ° C, tert-butyl ((3-oxocyclobutyl) methyl) carbamate (500 mg, 2.5 mmol) and 2-((difluoromethyl) sulfonyl) pyridine (483 mg, 2.5 mmol) were dissolved in tetrahydrofuran (10 mL) and added dropwise to the reaction system, and the mixture was stirred at -50 ° C for 1 hour. Saturated ammonium chloride (10 mL) and concentrated hydrochloric acid (10 mL) were added to the reaction solution, and the mixture was stirred at room temperature overnight. Saturated sodium bicarbonate solution was added to the reaction solution for neutralization, and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The aqueous phase was concentrated under reduced pressure, and the residue was purified by reverse phase column to obtain the title compound (250 mg, yellow solid), yield: 34%. MS (ESI): m / z 293.0 [M+H] + .

[0617] (2) 2-((((3-(difluoro(pyridin-2-ylsulfonyl)methyl)-3-hydroxycyclobutyl)methyl)amino)methyl)-1H-indole-6-carbonitrile

[0618] Dissolve 2-formyl-1H-indole-6-carbonitrile (150 mg, 0.88 mmol, step 4 of intermediate 1) and 3-(aminomethyl)-1-(difluoro(pyridin-2-ylsulfonyl)methyl)cyclobutanol (230 mg, 0.79 mmol) in methanol (5 mL) and stir at room temperature for 1 hour. Then add sodium cyanoborohydride (164 mg, 2.6 mmol) and stir at room temperature overnight. The reaction solution is concentrated and the residue is purified by reverse phase column to obtain the title compound (150 mg, colorless oil) with a yield of 38%. MS (ESI): m / z 447.0 [M+H] + .

[0619] (3) tert-butyl 2-(((tert-butoxycarbonyl)((3-((tert-butoxycarbonyl)oxy)-3-(difluoro(pyridin-2-ylsulfonyl)methyl)cyclobutyl)methyl)amino)methyl)-6-cyano-1H-indole-1-carboxylate

[0620] 2-((((3-(difluoro(pyridin-2-ylsulfonyl)methyl)-3-hydroxycyclobutyl)methyl)amino)methyl)-1H-indole-6-carbonitrile (150 mg, 0.34 mmol) was dissolved in tetrahydrofuran (10 mL), sodium hydride (40 mg, 1.0 mmol, 60%) was added, and the mixture was stirred at room temperature for 5 minutes. Di-tert-butyl dicarbonate (218 mg, 1.0 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction solution was added to water (20 mL), and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give the title compound (140 mg, yellow oil), yield: 56%. MS (ESI): m / z 747.0 [M+H] + .

[0621] (4) tert-butyl 6-(aminomethyl)-2-(((tert-butoxycarbonyl)((3-((tert-butoxycarbonyl)oxy)-3-(difluoro(pyridin-2-ylsulfonyl)methyl)cyclobutyl)methyl)amino)methyl)-1H-indole-1-carboxylate

[0622] 2-(((tert-butoxycarbonyl)((3-((tert-butoxycarbonyl)oxy)-3-(difluoro(pyridin-2-ylsulfonyl)methyl)cyclobutyl)methyl)amino)methyl)-6-cyano-1H-indole-1-carboxylic acid tert-butyl ester (70 mg, 0.1 mmol) was dissolved in 7M ammonia methanol solution (10 mL), Raney nickel (10 mg) was added, and the mixture was stirred at room temperature under hydrogen atmosphere for 2 hours. The reaction solution was filtered to remove Raney nickel, and the filtrate was concentrated to obtain the title compound (70 mg, yellow oil). MS (ESI): m / z 751.1 [M+H] + .

[0623] (5) 2-(((tert-butoxycarbonyl)((3-((tert-butoxycarbonyl)oxy)-3-(difluoro(pyridin-2-ylsulfonyl)methyl)cyclobutyl)methyl)amino)methyl)-6-((9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamido)methyl)-1H-indole-1-carboxylic acid tert-butyl ester

[0624] Intermediate 4 (20 mg, 0.08 mmol) and tert-butyl 6-(aminomethyl)-2-(((tert-butoxycarbonyl)((3-((tert-butoxycarbonyl)oxy)-3-(difluoro(pyridin-2-ylsulfonyl)methyl)cyclobutyl)methyl)amino)methyl)-1H-indole-1-carboxylate (60 mg, 0.08 mmol) were dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (20 mg, 0.16 mmol) and HATU (60 mg, 0.16 mmol) were added, and the reaction was continued to stir at room temperature overnight. The reaction solution was added to water (20 mL), and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give the title compound (30 mg, yellow solid), yield: 38%. MS (ESI): m / z 981.1 [M+H] + .

[0625] (6) N-((2-((((3-(difluoromethylene)cyclobutyl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[0626] 2-(((tert-butoxycarbonyl)((3-((tert-butoxycarbonyl)oxy)-3-(difluoro(pyridin-2-ylsulfonyl)methyl)cyclobutyl)methyl)amino)methyl)-6-((9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamido)methyl)-1H-indole-1-carboxylic acid tert-butyl ester (10 mg, 0.01 mmol) was dissolved in N,N-dimethylformamide (5 mL), concentrated hydrochloric acid / water (2 mL / 2 mL) and saturated aqueous ammonium chloride solution (2 mL) were added, and the mixture was heated to 80°C and stirred for overnight reaction. The reaction solution was concentrated, and the residue was purified by Prep-HPLC to give the title compound (1.1 mg, white solid), yield: 21%. MS (ESI): m / z 522.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ10.86(s,1H),9.05(t,J=5.6Hz,1H),8.62(s,1H),7.37(d,J=8.4Hz,1H),7.29(s,1H),7.19(s,1H),6.95(dd,J=8.0,1.2Hz,1H),6. 67(s,1H),6.21(s,1H),4.57-4.53(m,4H),4.47-4.45(m,2H),3.79(s,2H),2.71-2.65(m,2H),2.57-2.51(m,3H),2.36-2.30(m,2H).

[0627] Embodiment 29

[0628] N-((2-((4,4-difluoropiperidin-1-yl)methyl)-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0629]

[0630] Intermediate 5 (20 mg, 0.085 mmol) was dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (55 mg, 0.43 mmol) and HATU (65 mg, 0.17 mmol) were added, and the mixture was stirred at room temperature for 5 minutes. (2-((4,4-difluoropiperidin-1-yl)methyl)-1H-indol-6-yl)methylamine (24 mg, 0.085 mmol, step 3 of Example 27) was added, and the reaction was continued to stir at room temperature for 2 hours. The reaction solution was added to water (20 mL), and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by Prep-HPLC to give the title compound (10.1 mg, white solid), yield: 24%. MS (ESI): m / z 496.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ10.96(s,1H),9.04(t,J=6.0Hz,1H),8.59(s,1H),7.39(d,J=8.0Hz,1H),7.31(s,1H),7.14(s,1H),6.96(dd,J=8.0,1.2Hz,1 H),6.73(s,1H),6.37(s,2H),6.25(d,J=0.8Hz,1H),4.54(d,J=6.0Hz,2H),3.67(s,2H),2.63-2.50(m,4H),2.00-1.90(m,4H).

[0631] Embodiment 30

[0632] N-((2-(((Cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-2,2-difluoro-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0633]

[0634] (1) 6-Bromo-[1,3]dioxacyclo[4,5-c]pyridine-2-thione

[0635] Dissolve 6-bromopyridine-3,4-diol (1.69 g, 8.9 mmol, Intermediate 5 Step 3) in dichloromethane (50 mL), add 4-dimethylaminopyridine (2.71 g, 22.2 mmol) and thiophosgene (1.53 g, 13.4 mmol), and react at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 60 / 40) to obtain the title compound (1.1 g, light yellow solid), yield: 53.3%. MS (ESI): m / z 231.6 [M+H] + .

[0636] (2) 6-Bromo-2,2-difluoro-[1,3]dioxacyclo[4,5-c]pyridine

[0637] 6-Bromo-[1,3]dioxacyclo[4,5-c]pyridine-2-thione (1.1 g, 4.74 mmol) was dissolved in dichloromethane (40 mL), and 70% hydrogen fluoride pyridine solution (18 mL) and dibromohydantoin (4.07 g, 14.2 mmol) were added at -70 °C. The reaction solution was slowly warmed to room temperature and the reaction was continued for 2 hours. 2M sodium hydroxide solution was added to the reaction solution until the pH value was greater than 10, and a large amount of solid precipitated. The solid was filtered and the filter cake was washed with dichloromethane (20 mL). The organic phase was separated from the filtrate and the aqueous phase was extracted with dichloromethane (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (100% petroleum ether) to obtain the title compound (466 mg, light yellow liquid), with a yield of 41.3%. MS (ESI): m / z 237.6 [M+H] + .

[0638] (3) tert-Butyl (2,2-difluoro-[1,3]dioxacyclo[4,5-c]pyridin-6-yl)carbamate

[0639] 6-Bromo-2,2-difluoro-[1,3]dioxacyclo[4,5-c]pyridine (466 mg, 1.96 mmol) was dissolved in 1,4-dioxane (15 mL), tris(dibenzylideneacetone)dipalladium (183 mg, 0.2 mmol), tert-butyl carbamate (688 mg, 5.88 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (231 mg, 0.4 mmol) and cesium carbonate (1.28 g, 3.92 mmol) were added, and the mixture was heated to 100°C under nitrogen protection and stirred overnight. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 85 / 15) to obtain the title compound (301 mg, white solid), yield: 56%. MS (ESI): m / z 218.6 [M+H-56] + .

[0640] (4) 2,2-Difluoro-[1,3]dioxacyclo[4,5-c]pyridin-6-amine

[0641] Dissolve tert-butyl (2,2-difluoro-[1,3]dioxacyclo[4,5-c]pyridin-6-yl)carbamate (310 mg, 1.1 mmol) in dichloromethane (4 mL), add trifluoroacetic acid (4 mL), and react at room temperature for 2 hours. The reaction solution was spin-dried, saturated sodium bicarbonate solution (30 mL) was added, and extracted with ethyl acetate (2 x 20 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (165 mg, light yellow solid), yield: 86.2%. MS (ESI): m / z 174.6 [M+H] + .

[0642] (5) 2,2-difluoro-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxylic acid methyl ester

[0643] 2,2-Difluoro-[1,3]dioxacyclo[4,5-c]pyridin-6-amine (52 mg, 0.3 mmol), water (8 mL) and dimethyl butane-2-diacetate (51 mg, 0.36 mmol) were added to a 25 mL single-mouth bottle, and the mixture was heated to 70 °C and stirred overnight. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (2 x 20 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 70 / 30) to obtain the title compound (50 mg, pink solid), yield: 58.8%. MS (ESI): m / z 284.6 [M+H] + .

[0644] (6) 2,2-Difluoro-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyridine[1,2-a]pyrimidine-6-carboxylic acid

[0645] Dissolve 2,2-difluoro-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxylic acid methyl ester (23 mg, 0.08 mmol) in 1,2-dichloroethane (2 mL), add trimethyltin hydroxide (44 mg, 0.24 mmol), and heat the mixture to 80°C and stir overnight. The reaction solution was concentrated to obtain the title compound (30 mg, light yellow solid), yield: 100%. The crude product was directly used in the next step. MS (ESI): m / z 270.6 [M+H] + .

[0646] (7) tert-Butyl 2-(((tert-Butyloxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((2,2-difluoro-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamido)methyl)-1H-indole-1-carboxylate

[0647] 2,2-Difluoro-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyridine[1,2-a]pyrimidine-6-carboxylic acid (21.6 mg, 0.08 mmol) was dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (52 mg, 0.4 mmol) and HATU (46 mg, 0.12 mmol) were added, and the mixture was stirred at room temperature for 5 minutes. Intermediate 1 (35.5 mg, 0.08 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (2 x 15 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 70 / 30) to obtain the title compound (12 mg, yellow oil), with a yield of 25.2%. MS (ESI): m / z 696.1 [M+H] + .

[0648] (8) N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-2,2-difluoro-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0649] 2-(((tert-butyloxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((2,2-difluoro-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamido)methyl)-1H-indole-1-carboxylic acid tert-butyl ester (12 mg, 0.02 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated, and the residue was diluted with methanol (1 mL) and purified by Prep-HPLC to give the title compound (1.7 mg, white solid), yield: 17%. MS (ESI): m / z 991.1 [2M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ10.86(s,1H),9.20(s,1H),9.01(t,J=6.4Hz,1H),7.70(s,1H),7.37(d,J=8.0Hz,1H),7.30(s,1H),6.95(d,J=8.0Hz,1H),6.88(s,1H),6.2 0(s,1H),4.56(d,J=6.4Hz,2H),3.77(s,2H),2.63-2.58(m,2H),2.41- 2.35(m,1H),2.02-1.93(m,2H),1.83-1.75(m,2H),1.67-1.57(m,2H).

[0650] Embodiment 31

[0651] N-((5-(((Cyclobutylmethyl)amino)methyl)-4H-thieno[3,2-b]pyrrol-2-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[0652]

[0653] (1) N-(cyclobutylmethyl)-2-methyl-4-thieno[3,2-b]pyrrole-5-carboxamide

[0654] Dissolve 2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acid (800 mg, 4.4 mmol) and N,N'-carbonyldiimidazole (858 mg, 5.3 mmol) in N,N-dimethylformamide (15 mL) and stir at room temperature for half an hour. Add cyclobutylmethylamine (450 mg, 5.3 mmol) and stir at room temperature overnight. Add water (20 mL) to precipitate a solid product, filter and dry to obtain the title compound (1 g, yellow solid), yield: 92%. MS (ESI): m / z 249.0 [M+H] + .

[0655] (2) 1-cyclobutyl-N-((2-methyl-4H-thieno[3,2-b]pyrrol-5-yl)methyl)methanamine

[0656] Dissolve N-(cyclobutylmethyl)-2-methyl-4-thieno[3,2-b]pyrrole-5-carboxamide (1g, 4.0mmol) in 1,4-dioxane (15mL), add lithium aluminum hydride (460mg, 12.0mmol), and stir at 100°C for 3 hours. Add water (0.5mL) and then add 10% sodium hydroxide aqueous solution (0.5mL). The reaction solution is filtered through diatomaceous earth, and the filtrate is concentrated to obtain the title compound (943mg, colorless oil), yield: 100%. MS (ESI): m / z 150.0 [M+H-85] + .

[0657] (3) tert-Butyl 5-(((tert-Butyloxycarbonyl)(cyclobutylmethyl)amino)methyl)-2-methyl-4H-thieno[3,2-b]pyrrole-4-carboxylate

[0658] Dissolve 1-cyclobutyl-N-((2-methyl-4H-thieno[3,2-b]pyrrol-5-yl)methyl)methanamine (1.6 g, 6.8 mmol) and triethylamine (2 g, 20.1 mmol) in acetonitrile (20 mL), add 4-dimethylaminopyridine (83 mg, 0.68 mmol) and di-tert-butyl dicarbonate (2.9 g, 13.6 mmol), and stir overnight at room temperature. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain the title compound (1.6 g, yellow oil), yield: 55%. MS (ESI): m / z 457.0 [M+Na] + .

[0659] (4) tert-Butyl 5-(((tert-Butyloxycarbonyl)(cyclobutylmethyl)amino)methyl)-2-formyl-4H-thieno[3,2-b]pyrrole-4-carboxylate

[0660] Dissolve tert-butyl 5-(((tert-butyloxycarbonyl)(cyclobutylmethyl)amino)methyl)-2-methyl-4H-thieno[3,2-b]pyrrole-4-carboxylate (1.6 g, 3.6 mmol) and 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) (1.1 g, 4.7 mmol) in methanol / water (20 mL / 5 mL) and stir at room temperature to react overnight. Sodium bicarbonate aqueous solution (20 mL) was added to the reaction solution, and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound (370 mg, yellow oil), yield: 23%. MS (ESI): m / z 470.9 [M+Na] + .

[0661] (5) (E)-tert-butyl 5-(((tert-butyloxycarbonyl)(cyclobutylmethyl)amino)methyl)-2-((hydroxyimino)methyl)-4H-thieno[3,2-b]pyrrole-4-carboxylate

[0662] 5-(((tert-Butyloxycarbonyl)(cyclobutylmethyl)amino)methyl)-2-formyl-4H-thieno[3,2-b]pyrrole-4-carboxylic acid tert-butyl ester (370 mg, 0.8 mmol) and hydroxylamine hydrochloride (166 mg, 2.4 mmol) were dissolved in tetrahydrofuran / ethanol / water (10 mL / 2 mL / 1 mL) and stirred at room temperature overnight. Water (20 mL) was added to the reaction solution and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (350 mg, yellow solid) in a yield of 92%. MS (ESI): m / z 464.4 [M+H] + .

[0663] (6) tert-Butyl 2-(aminomethyl)-5-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-4H-thieno[3,2-b]pyrrole-4-carboxylate

[0664] (E)-5-(((tert-butyloxycarbonyl)(cyclobutylmethyl)amino)methyl)-2-((hydroxyimino)methyl)-4H-thieno[3,2-b]pyrrole-4-carboxylic acid tert-butyl ester (350 mg, 0.76 mmol) and zinc powder (35 mg) were added to acetic acid (10 mL) and stirred at room temperature overnight. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated, sodium bicarbonate aqueous solution (20 mL) was added, and the mixture was extracted with dichloromethane / methanol (20 mL x 3). The organic phases were combined and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give the title compound (140 mg, yellow oil), yield: 41%. MS (ESI): m / z 471.9 [M+Na] + .

[0665] (7) tert-Butyl 5-(((tert-Butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-2-((9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamido)methyl)-4H-thieno[3,2-b]pyrrole-4-carboxylate

[0666] Tert-butyl 2-(aminomethyl)-5-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-4H-thieno[3,2-b]pyrrole-4-carboxylate (20 mg, 0.04 mmol) and intermediate 4 (10 mg, 0.04 mmol) were dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (10 mg, 0.08 mmol) and HATU (30 mg, 0.08 mmol) were added, and stirred at room temperature overnight. Water (20 mL) was added to the reaction solution, and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to give the title compound (20 mg, yellow solid), yield: 67%. MS (ESI): m / z 680.3 [M+H] + .

[0667] (8) N-((5-(((cyclobutylmethyl)amino)methyl)-4H-thieno[3,2-b]pyrrol-2-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[0668] 5-(((tert-Butyloxycarbonyl)(cyclobutylmethyl)amino)methyl)-2-((9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamido)methyl)-4H-thieno[3,2-b]pyrrole-4-carboxylic acid tert-butyl ester (20 mg, 0.03 mmol) was dissolved in formic acid (5 mL) and stirred at 40°C overnight. The reaction solution was concentrated and the residue was purified by Prep-HPLC to give the title compound (1.2 mg, yellow solid) in a yield of 8.6%. MS (ESI): m / z 395.0 [M+H-85] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.92(s,1H),9.06(t,J=6.4Hz,1H),8.61(s,1H),7.18(s,1H),6.92(s,1H),6.65(s,1H),6.12(s,1H),4.61-4.55(m,4H),4 .47-4.45(m,2H),3.69(s,2H),2.54-2.52(m,2H),2.42-2.36(m,1H),2.03-1.94(m,2H),1.80-1.76(m,2H),1.65-1.59(m,2H).

[0669] Embodiment 32

[0670] N-((5-(((cyclobutylmethyl)amino)methyl)-4H-thieno[3,2-b]pyrrol-2-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0671]

[0672] (1) tert-Butyl 5-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-2-((8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamido)methyl)-4H-thieno[3,2-b]pyrrole-4-carboxylate

[0673] 2-(Aminomethyl)-5-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-4H-thieno[3,2-b]pyrrole-4-carboxylic acid tert-butyl ester (60 mg, 0.13 mmol, step 6 of Example 31) and intermediate 5 (30 mg, 0.13 mmol) were dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (34 mg, 0.26 mmol) and HATU (60 mg, 0.16 mmol) were added, and the reaction was stirred at room temperature overnight. Water (20 mL) was added to the reaction solution, and it was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to give the title compound (60 mg, yellow solid), yield: 68%. MS (ESI): m / z 665.9 [M+H] + .

[0674] (2) N-((5-(((cyclobutylmethyl)amino)methyl)-4H-thieno[3,2-b]pyrrol-2-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0675] 5-(((tert-Butyloxycarbonyl)(cyclobutylmethyl)amino)methyl)-2-((8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamido)methyl)-4H-thieno[3,2-b]pyrrole-4-carboxylic acid tert-butyl ester (60 mg, 0.09 mmol) was dissolved in formic acid (5 mL) and stirred at 40°C overnight. The reaction solution was concentrated and the residue was purified by Prep-HPLC to give the title compound (2.6 mg, yellow solid) in a yield of 6%. MS (ESI): m / z 381.0 [M+H-85] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.98(s,1H),9.06(t,J=6.4Hz,1H),8.59(s,1H),7.14(s,1H),6.92(s,1H),6.72(s,1H),6.38(s,2H),6.15(s,1H),4.61( d,J=6.0Hz,2H),3.73(s,2H),2.54-2.52(m,2H),2.42-2.36(m,1H),2.03-1.95(m,2H),1.83-1.76(m,2H),1.66-1.59(m,2H).

[0676] Embodiment 33

[0677] N-((2-(((Cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-4-oxo-6,11-dihydro-4H-pyrimidin[2,1-b]quinazoline-2-carboxamide

[0678]

[0679] (1) 2-((4-methoxybenzyl)amino)benzonitrile

[0680] Dissolve 2-aminobenzonitrile (30.0 g, 0.25 mol), triethylamine (51.7 g, 0.51 mol) and 4-methoxybenzyl chloride (47.7 g, 0.30 mol) in acetonitrile (300 mL), heat to 120 ° C and stir for 24 hours. Add water (300 mL) to the reaction solution and extract with ethyl acetate (500 mL x 2). The organic phases are combined, washed with saturated sodium chloride solution (500 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 93 / 7) to obtain the title compound (4.4 g, white solid), yield: 7%. MS (ESI): m / z 261.0 [M+Na] + .

[0681] (2) 2-(Aminomethyl)-N-(4-methoxybenzyl)aniline

[0682] At 0°C, 2-((4-methoxybenzyl)amino)benzonitrile (4.4g, 18.46mmol) and lithium aluminum hydride (2.10g, 55.39mmol) were dissolved in tetrahydrofuran (100mL), heated to 75°C and stirred for 16 hours. The reaction solution was cooled to 0°C, water (100mL) was slowly added dropwise to the reaction solution, and ethyl acetate (200mL) was added and stirred at room temperature for 30 minutes. The reaction solution was filtered through diatomaceous earth, and the filtrate was extracted with ethyl acetate (100mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (100mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound (4.0g, yellow solid), yield: 89%. MS (ESI): m / z 226.0 [M+H-17] + .

[0683] (3) 1-(4-methoxybenzyl)-1,4-dihydroquinazolin-2-amine

[0684] 2-(Aminomethyl)-N-(4-methoxybenzyl)aniline (4.0 g, 16.51 mmol) and cyanogen bromide (2.62 g, 24.76 mmol) were dissolved in acetonitrile (50 mL) and stirred at room temperature for 4 hours under nitrogen protection. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 95 / 5) to obtain the title compound (2.07 g, yellow oil), yield: 47%. MS (ESI): m / z 268.0 [M+H] + .

[0685] (4) 11-(4-methoxybenzyl)-4-oxo-6,11-dihydro-4H-pyrimido[2,1-b]quinazoline-2-carboxylic acid methyl ester

[0686] 1-(4-methoxybenzyl)-1,4-dihydroquinazolin-2-amine (2.07 g, 7.74 mmol), dimethyl butane-2-diacetate (1.32 g, 9.29 mmol) and triethylamine (1.18 g, 11.61 mmol) were dissolved in methanol (50 mL) and stirred at 60°C for 4 hours. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 80) to obtain the title compound (600 mg, yellow solid), yield: 21%. MS (ESI): m / z 377.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ7.34-7.26(m,4H),7.20-7.15(m,2H),6.89(d,J=8.4Hz,2H),5.91(s,1H),5.33(s,2H),4.78(s,2H),3.72(s,3H),3.71(s,3H).

[0687] (5) 4-Oxo-6,11-dihydro-4H-pyrimido[2,1-b]quinazoline-2-carboxylic acid methyl ester

[0688] Dissolve 11-(4-methoxybenzyl)-4-oxo-6,11-dihydro-4H-pyrimido[2,1-b]quinazoline-2-carboxylic acid methyl ester (350 mg, 0.93 mmol) in trifluoroacetic acid (5 mL) and stir at 60°C for 1 hour. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (dichloromethane / methanol=92 / 8) to give the title compound (50 mg, yellow solid) with a yield of 21%. MS (ESI): m / z 257.9 [M+H] + .

[0689] (6) 4-Oxo-6,11-dihydro-4H-pyrimido[2,1-b]quinazoline-2-carboxylic acid

[0690] Dissolve 4-oxo-6,11-dihydro-4H-pyrimido[2,1-b]quinazoline-2-carboxylic acid methyl ester (50 mg, 0.19 mmol) in concentrated hydrochloric acid (1 mL) and stir at 80°C for 1 hour. The reaction solution was concentrated to obtain the title compound (40 mg, yellow solid) with a yield of 85%. MS (ESI): m / z 243.9 [M+H] + .

[0691] (7) tert-Butyl 2-(((tert-Butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((4-oxo-6,11-dihydro-4H-pyrimidinyl[2,1-b]quinazoline-2-carboxamido)methyl)-1H-indole-1-carboxylate

[0692] 4-Oxo-6,11-dihydro-4H-pyrimido[2,1-b]quinazoline-2-carboxylic acid (40 mg, 0.24 mmol), 1-propylphosphoric anhydride (157 mg, 0.49 mmol), intermediate 1 (88 mg, 0.20 mmol) and N,N-diisopropylethylamine (64 mg, 0.49 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred at room temperature for 12 hours. Water (20 mL) was added to the reaction solution and extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to give the title compound (5 mg, yellow solid), yield: 5%. MS (ESI): m / z 569.0 [M+H-100] + .

[0693] (8) N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-4-oxo-6,11-dihydro-4H-pyrimidin[2,1-b]quinazoline-2-carboxamide

[0694] 2-(((tert-Butyloxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((4-oxo-6,11-dihydro-4H-pyrimidin[2,1-b]quinazoline-2-carboxamido)methyl)-1H-indole-1-carboxylic acid tert-butyl ester (5 mg, 0.007 mmol) was dissolved in dichloromethane (0.5 mL), trifluoroacetic acid (0.5 mL) was added, and stirred at room temperature for 30 minutes. The reaction solution was concentrated, and the residue was diluted with N,N-dimethylformamide (2 mL) and purified by Prep-HPLC to give the title compound (1.2 mg, light yellow solid), yield: 34%. MS (ESI): m / z 469.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.18(s,1H),10.89(s,1H),7.40-7.37(m,1H),7.27-7.24(m,3H),7.19(s,1 H),7.11-7.05(m,2H),6.91(d,J=8.0Hz,1H),6.64(s,1H),6.23(s,1H),5.21(s ,0.5H),4.69(s,1.5H),4.49-4.43(m,2H),3.81-3.79(m,2H),2.60-2.58(m,2H ),2.43-2.41(m,1H),2.04-2.01(m,2H),1.84-1.76(m,2H),1.68-1.61(m,2H).

[0695] Embodiment 34

[0696] N-((2-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0697]

[0698] Intermediate 7 (30 mg, 0.064 mmol) and 1,2,3,4-tetrahydroisoquinoline (26 mg, 0.2 mmol) were dissolved in methanol (4 mL), glacial acetic acid (0.2 mL) was added, the reaction solution was heated to 50 ° C and stirred for 10 minutes, sodium cyanoborohydride (13 mg, 0.2 mmol) was added, and the reaction was continued to stir at 50 ° C overnight. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by Prep-HPLC to obtain the title compound (5.7 mg, white solid), yield: 14.6%. MS (ESI): m / z 508.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.01(s,1H),9.03(t,J=6.0Hz,1H),8.58(s,1H),7.40(d,J=8.0Hz,1H),7.30(s,1H),7.14(s,1H),7.09-7.05(m,3H),7.00-6.96(m,2 H),6.73(s,1H),6.37(s,2H),6.30(s,1H),4.54(d,J=6.4Hz,2H),3.77(s,2H),3.57(s,2H),2.83(t,J=5.6Hz,2H),2.71(t,J=5.6Hz,2H).

[0699] Embodiment 35

[0700] N-((2-((5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)methyl)-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0701]

[0702] Referring to the synthesis method of Example 34, intermediate 7 and 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine were used as starting materials and the title compound (4.9 mg, white solid) was obtained through similar steps. MS (ESI): m / z 498.1 [M+H] + . 1 HNMR (400 MHz, DMSO-d 6 )δ11.05(s,1H),9.04(t,J=6.0Hz,1H),8.58(s,1H),7.42(d,J=8.0Hz,1H),7 .31(s,1H),7.14(s,1H),7.03(d,J=0.8Hz,1H),6.97(dd,J=8.0,0.8Hz,1H),6 .81(d,J=0.8Hz,1H),6.73(s,1H),6.37(s,2H),6.32(s,1H),4.55(d,J=6.4Hz ,2H),3.95(t,J=5.2Hz,2H),3.82(s,2H),3.60(s,2H),2.84(t,J=5.6Hz,2H).

[0703] Embodiment 36

[0704] N-((2-((((3-Fluorobicyclo[1.1.1]pentan-1-yl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0705]

[0706] Intermediate 7 (20 mg, 0.05 mmol) and (3-fluorobicyclo[1.1.1]pentane-1-yl)methylamine hydrochloride (14 mg, 0.1 mmol) were dissolved in methanol (4 mL), triethylamine (0.1 mL) and glacial acetic acid (0.2 mL) were added, the reaction solution was heated to 50°C and stirred for 10 minutes, sodium cyanoborohydride (13 mg, 0.2 mmol) was added, and the reaction was continued to stir at 50°C overnight. The reaction solution became clear after overnight, filtered, and the filtrate was concentrated. The residue was purified by Prep-HPLC to obtain the title compound (6.3 mg, white solid), yield: 25%. MS (ESI): m / z 490.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ10.86(s,1H),9.02(t,J=6.0Hz,1H),8.59(s,1H),7.37(d,J=8.0Hz,1H),7.29(s,1H),7.14(s,1H),6.95(d,J=8.4H z,1H),6.73(s,1H),6.38(s,2H),6.21(s,1H),4.54(d,J=6.0Hz,2H),3.80(s,2H),2.75(s,2H),1.92(d,J=2.8Hz,6H).

[0707] Embodiment 37

[0708] N-((2-(((4,4-difluorocyclohexyl)amino)methyl)-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0709]

[0710] Referring to the synthesis method of Example 34, intermediate 7 and 4,4-difluorocyclohexane-1-amine were used as starting materials and the title compound (1.1 mg, white solid) was obtained through similar steps. MS (ESI): m / z 510.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.85(s,1H),9.02(t,J=6.0Hz,1H),8.59(s,1H),7.36(d,J=8.0Hz,1H),7.30(s,1H),7.14(s,1H),6.94(d,J=8.4Hz,1H),6.73(s,1H), 6.37(s,2H),6.22(s,1H),4.54(d,J=6.0Hz,2H),3.82(s,2H),2.58-2.55(m,1H),2.03-1.98(m,2H),1.80-1.70(m,4H),1.46-1.41(m,2H).

[0711] Embodiment 38

[0712] N-((2-(((3,3-difluorocyclopentyl)amino)methyl)-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0713]

[0714] Referring to the synthesis method of Example 36, intermediate 7 and 3,3-difluorocyclopentane-1-amine hydrochloride were used as starting materials, and similar steps were followed to obtain the title compound (13.3 mg, white solid). MS (ESI): m / z 496.0 [M+H] + . 1 HNMR (400 MHz, DMSO-d 6 )δ10.87(s,1H),9.02(t,J=6.0Hz,1H),8.59(s,1H),7.37(d,J=8.0Hz,1H),7.29(s,1H),7.14(s,1H),6.95(d,J=8.4Hz,1H),6.73(s,1H), 6.37(s,2H),6.23(s,1H),4.54(d,J=6.0Hz,2H),3.78(s,2H),3.20-3.13(m,1H),2.41-2.14(m,2H),1.99-1.84(m,3H),1.59-1.51(m,1H).

[0715] Embodiment 39

[0716] N-((2-(((3,3-difluorocyclobutyl)amino)methyl)-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0717]

[0718] Referring to the synthesis method of Example 34, intermediate 7 and 3,3-difluorocyclobutane-1-amine were used as starting materials and similar steps were followed to obtain the title compound (15.2 mg, white solid). MS (ESI): m / z 482.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.89(s,1H),9.02(t,J=6.0Hz,1H),8.59(s,1H),7.37(d,J=8.0Hz,1H),7.29(s,1H),7.14(s,1H),6.95(d,J=8.0Hz,1H),6.7 3(s,1H),6.37(s,2H),6.22(s,1H),4.54(d,J=6.4Hz,2H),3.74(s,2H),3.15-3.07(m,1H),2.72-2.63(m,2H),2.38-2.26(m,2H).

[0719] Embodiment 40

[0720] 8-Oxo-N-((2-((((1-(trifluoromethyl)cyclopropyl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0721]

[0722] Referring to the synthesis method of Example 36, intermediate 7 and (1-(trifluoromethyl)cyclopropyl)methylamine hydrochloride were used as starting materials and the title compound (12.8 mg, white solid) was obtained through similar steps. MS (ESI): m / z 514.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.84(s,1H),9.03(t,J=6.0Hz,1H),8.59(s,1H),7.37(d,J=8.4Hz,1H),7.30(s,1H),7.14(s,1H),6.95(d,J=8.0 Hz,1H),6.73(s,1H),6.37(s,2H),6.22(s,1H),4.54(d,J=6.4Hz,2H),3.80(s,2H),2.74(s,2H),0.86-0.78(m,4H).

[0723] Embodiment 41

[0724] N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0725]

[0726] (1) 2-(Chloromethyl)imidazo[1,2-a]pyridine-6-carbonitrile

[0727] 6-aminonicotinonitrile (1.19 g, 10 mmol) was dissolved in ethanol (20 mL), 1,3-dichloropropane-2-one (1.52 g, 12 mmol) was added, and the mixture was heated to 80°C and stirred overnight. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 60) to obtain the title compound (380 mg, white solid), yield: 20%. MS (ESI): m / z 192.0 [M+H] + .

[0728] (2) 2-(Aminomethyl)imidazo[1,2-a]pyridine-6-carbonitrile

[0729] Add 2-(Chloromethyl)imidazo[1,2-a]pyridine-6-carbonitrile (19 mg, 0.1 mmol) and concentrated aqueous ammonia (2 mL) into a 10 mL sealed tube, heat to 80°C and stir for 2 hours. The reaction solution was concentrated to obtain the title compound (17 mg, gray solid), yield: 100%. MS (ESI): m / z 173.1 [M+H] + .

[0730] (3) N-((6-cyanoimidazolo[1,2-a]pyridin-2-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0731] Intermediate 5 (23 mg, 0.1 mmol) and 2-(aminomethyl)imidazo[1,2-a]pyridine-6-carbonitrile (17 mg, 0.1 mmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (64 mg, 0.5 mmol) and 1-propylphosphoric anhydride (63 mg, 0.2 mmol, 50% ethyl acetate solution) were added, and stirred at room temperature for 3 hours. The reaction solution was purified by reverse phase column (acetonitrile / water = 50 / 50) to obtain the title compound (10 mg, white solid), yield: 26%. MS (ESI): m / z 389.0 [M+H] + .

[0732] (4) N-((6-Formylimidazo[1,2-a]pyridin-2-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0733] N-((6-cyanoimidazo[1,2-a]pyridin-2-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide (10 mg, 0.026 mmol), sodium hypophosphite monohydrate (22 mg, 0.21 mmol), pyridine (1 mL), glacial acetic acid (0.5 mL), water (0.5 mL) and Raney nickel (10 mg) were placed in a 10 mL sealed tube, heated to 100°C and stirred for 2 hours. The reaction solution was filtered, the filtrate was concentrated, a small amount of water was added and filtered, and the filter cake was dried to obtain the title compound (5 mg, light brown solid), yield: 49.6%. MS (ESI): m / z 392.0 [M+H] + .

[0734] (5) N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0735] N-((6-formylimidazo[1,2-a]pyridin-2-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide (5 mg, 0.013 mmol) and cyclobutylmethylamine (3 mg, 0.04 mmol) were dissolved in methanol (4 mL), glacial acetic acid (0.2 mL) was added, heated to 50 ° C and stirred for 10 minutes, sodium cyanoborohydride (4 mg, 0.05 mmol) was added, and stirring was continued at 50 ° C overnight. The reaction solution was filtered and the filtrate was concentrated. The residue was purified by Prep-HPLC to obtain the title compound (1.7 mg, white solid), yield: 29%. MS (ESI): m / z 461.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.97(t,J=6.0Hz,1H),8.60(s,1H),8.37(s,1H),7.77(s,1H),7.44(d ,J=9.6Hz,1H),7.22(d,J=9.6Hz,1H),7.19(s,1H),6.73(s,1H),6.38(s ,2H),4.59(d,J=6.0Hz,2H),3.64(s,2H),2.64-2.61(m,2H),2.42-2.37 (m,1H),2.01-1.93(m,2H),1.82-1.75(m,2H),1.65-1.57(m,2H).Example 42

[0736] N-(1-(2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)cyclopropyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0737]

[0738] (1) tert-Butyl 2-(diethoxymethyl)-6-(1-(8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamido)cyclopropyl)-1H-indole-1-carboxylate

[0739] Intermediate 9 (40 mg, 0.11 mmol) and intermediate 5 (19 mg, 0.08 mmol) were dissolved in N, N-dimethylformamide (5 mL), 1-propylphosphoric anhydride (140 mg, 0.22 mmol, 50% ethyl acetate solution) and triethylamine (56 mg, 0.55 mmol) were added, and stirred at room temperature for 1 hour. The reaction solution was added to water (50 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to give the title compound (40 mg, light yellow oil), yield: 91%. MS (ESI): m / z 591.0 [M+H] + .

[0740] (2) tert-Butyl 2-formyl-6-(1-(8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamido)cyclopropyl)-1H-indole-1-carboxylate

[0741] 2-(diethoxymethyl)-6-(1-(8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamido)cyclopropyl)-1H-indole-1-carboxylic acid tert-butyl ester (40 mg, 0.07 mmol) and acetic acid (1.5 mL) were dissolved in a tetrahydrofuran / water mixture (10 mL / 1 mL) and stirred at room temperature for 4 hours. The reaction solution was concentrated to remove tetrahydrofuran, water (30 mL) was added, and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (30 mg, yellow solid) in a yield of 86%. MS (ESI): m / z 517.0 [M+H] + .

[0742] (3) tert-Butyl 2-(((cyclobutylmethyl)amino)methyl)-6-(1-(8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamido)cyclopropyl)-1H-indole-1-carboxylate

[0743] Dissolve tert-butyl 2-formyl-6-(1-(8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamido)cyclopropyl)-1H-indole-1-carboxylate (30 mg, 0.06 mmol) and cyclobutylmethylamine (15 mg, 0.17 mmol) in dichloroethane (5 mL), heat to 65 ° C and stir for 1 hour. Then add sodium cyanoborohydride (13 mg, 0.20 mmol) and continue stirring at 65 ° C for 2 hours. The reaction solution is added to water (30 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases are combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (34 mg, yellow solid), yield: 100%. MS (ESI): m / z 585.9 [M+H] + .

[0744] (4) N-(1-(2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)cyclopropyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0745] 2-(((cyclobutylmethyl)amino)methyl)-6-(1-(8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamido)cyclopropyl)-1H-indole-1-carboxylic acid tert-butyl ester (34 mg, 0.06 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, and stirred at room temperature for 4 hours. The reaction solution was concentrated and purified by Prep-HPLC to give the title compound (3.3 mg, white solid), yield: 12%. MS (ESI): m / z 971.2 [2M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.77(s,1H),9.27(s,1H),8.59(s,1H),7.33-7.31(m,2H),7.19(s,1H),6.90(d,J=8.8Hz,1H),6.67(s,1H),6.39(s,2H),6.17(s, 1H),3.76(s,2H),2.55-2.50(m,2H),2.42-2.33(m,1H),1.96-1.92(m,2H),1.82-1.75(m,2H),1.65-1.58(m,2H),1.30-1.21(m,4H).

[0746] Embodiment 43

[0747] N-(1-(2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)cyclopropyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[0748]

[0749] Referring to the synthesis method of Example 42, intermediate 9 and intermediate 4 were used as starting materials and the title compound (4 mg, white solid) was obtained through similar steps. MS (ESI): m / z 500.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.77(s,1H),9.27(s,1H),8.61(s,1H),7.32-7.30(m,2H),7.24(s,1H) ,6.90(dd,J=8.4,1.2Hz,1H),6.60(s,1H),6.16(s,1H),4.58-4.56(m,2H) ,4.48-4.47(m,2H),3.75(s,2H),2.50-2.48(m,2H),2.40-2.36(m,1H),1. 98-1.93(m,2H),1.82-1.74(m,2H),1.65-1.58(m,2H),1.28-1.22(m,4H).

[0750] Embodiment 44

[0751] N-((2-(((Cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-7,8-dihydro-6H-9-oxa-2,2a,5,6-tetraazabenzo[cd]azulene-4-carboxamide

[0752]

[0753] (1) tert-Butyl (cyclobutylmethyl)((6-((7,8-dihydro-6H-9-oxa-2,2a,5,6-tetraazabenzo[cd]azulene-4-carboxamido)methyl)-1H-indol-2-yl)methyl)carbamate

[0754] Intermediate 10 (20 mg, 0.09 mmol) was dissolved in N, N-dimethylformamide (2 mL), and N, N-diisopropylethylamine (58 mg, 0.45 mmol) and HATU (51 mg, 0.13 mmol) were added, and the reaction was stirred at room temperature for 5 minutes. Then, a solution of intermediate 2 (46 mg, 0.13 mmol) in N, N-dimethylformamide (1 mL) was added, and the reaction was continued to stir at room temperature for 30 minutes. Saturated sodium bicarbonate solution (10 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to obtain the title compound (25 mg, light yellow oil), yield: 51%. MS (ESI): m / z 546.1 [M+H] + .

[0755] (5) N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-7,8-dihydro-6H-9-oxa-2,2a,5,6-tetraazabenzo[cd]azulene-4-carboxamide

[0756] Dissolve tert-butyl (cyclobutylmethyl)((6-((7,8-dihydro-6H-9-oxa-2,2a,5,6-tetraazabenzo[cd]azulene-4-carboxamido)methyl)-1H-indol-2-yl)methyl)carbamate (25 mg, 0.046 mmol) in dichloromethane (3 mL), add trifluoroacetic acid (1 mL), and stir at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by Prep-HPLC to give the title compound (5.5 mg, white solid), yield: 27%. MS (ESI): m / z 446.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.89(s,1H),8.28(t,J=6.4Hz,1H),8.20(s,1H),7.89(t,J=3.6Hz,1H),7.81(s, 1H),7.40(d,J=8.0Hz,1H),7.28(s,1H),6.93(dd,J=8.0,1.2Hz,1H),6.24(s,1H),4 .55(d,J=6.0Hz,2H),4.32-4.31(m,2H),3.82(s,2H),3.60-3.57(m,2H),2.56-2.55 (m,2H),2.45-2.41(m,1H),2.03-1.94(m,2H),1.84-1.75(m,2H),1.67-1.60(m,2H).

[0757] Embodiment 45

[0758] N-((2-(((Cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-6,7,8,9-tetrahydro-2,2a,5,6-tetraazabenzo[cd]azulene-4-carboxamide

[0759]

[0760] Referring to the synthesis method of Example 44, intermediate 11 and intermediate 2 were used as starting materials and the title compound (7.6 mg, white solid) was obtained through similar steps. MS (ESI): m / z 444.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.89(s,1H),8.32(s,1H),8.29(t,J=6.0Hz,1H),7.93(s,1H),7.76(t,J=4.0Hz,1 H),7.39(d,J=8.4Hz,1H),7.28(s,1H),6.93(dd,J=8.0Hz,1.2Hz,1H),6.22(s,1H),4. 55(d,J=6.0Hz,2H),3.79(s,2H),3.38-3.35(m,2H),2.88(t,J=6.0Hz,2H),2.53-2.5 2(m,2H),2.44-2.40(m,1H),2.03-1.93(m,4H),1.84-1.78(m,2H),1.66-1.58(m,2H).

[0761] Embodiment 46

[0762] N-((2-((((3-Fluorobicyclo[1.1.1]pentan-1-yl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[0763]

[0764] Referring to the synthesis method of Example 36, intermediate 8 and (3-fluorobicyclo[1.1.1]pentan-1-yl)methylamine hydrochloride were used as starting materials, and similar steps were followed to obtain the title compound (10.5 mg, white solid). MS (ESI): m / z 504.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6 )δ10.85(s,1H),9.04(t,J=6.4Hz,1H),8.62(s,1H),7.36(d,J=8.0Hz,1H),7.30(s,1H),7.19(s,1H),6.94(dd,J=8.4,1.2 Hz,1H),6.66(s,1H),6.20(s,1H),4.59-4.53(m,4H),4.47-4.45(m,2H),3.80(s,2H),2.75(s,2H),1.92(d,J=2.8Hz,6H).

[0765] Embodiment 47

[0766] N-((2-(((4,4-difluorocyclohexyl)amino)methyl)-1H-indol-6-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxacyclo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[0767]

[0768] Referring to the synthesis method of Example 34, the intermediate 8 and 4,4-difluorocyclohexane-1-amine were used as starting materials and the title compound (9.8 mg, white solid) was obtained through similar steps. MS (ESI): m / z 524.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.85(s,1H),9.04(t,J=6.4Hz,1H),8.62(s,1H),7.36(d,J=8.0Hz,1H),7.30(s,1H),7.18(s,1H),6.94(dd,J=8.0,1.6Hz,1H),6.67(s,1H) ,6.22(s,1H),4.57-4.53(m,4H),4.47-4.45(m,2H),3.82(s,2H),2.63 -2.56(m,1H),2.05-1.96(m,2H),1.84-1.70(m,4H),1.46-1.36(m,2H).

[0769] Embodiment 48

[0770] N-((2-(((3,3-difluorocyclopentyl)amino)methyl)-1H-indol-6-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[0771]

[0772] Referring to the synthesis method of Example 36, intermediate 8 and 3,3-difluorocyclopentane-1-amine hydrochloride were used as starting materials, and similar steps were followed to obtain the title compound (11.1 mg, white solid). MS (ESI): m / z 510.1 [M+H] + . 1 HNMR (400 MHz, DMSO-d 6 )δ10.87(s,1H),9.04(t,J=6.4Hz,1H),8.62(s,1H),7.37(d,J=8.4Hz,1H),7.30(s,1H),7.18(s,1H),6.95(dd,J=8.0,1.2Hz,1H),6. 67(s,1H),6.23(s,1H),4.57-4.53(m,4H),4.47-4.45(m,2H),3.79(s,2H),3.22-3.12(m,1H),2.35-2.14(m,2H),2.09-1.81(m,4H).

[0773] Embodiment 49

[0774] N-((2-(((3,3-Difluorocyclobutyl)amino)methyl)-1H-indol-6-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxacyclo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[0775]

[0776] Referring to the synthesis method of Example 34, intermediate 8 and 3,3-difluorocyclobutane-1-amine were used as starting materials and the title compound (15.5 mg, white solid) was obtained through similar steps. MS (ESI): m / z 496.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.87(s,1H),9.04(t,J=6.4Hz,1H),8.62(s,1H),7.37(d,J=8.4Hz,1H),7.30(s,1H),7.18(s,1H),6.94(dd,J=8.0,1.2Hz,1H),6. 68(s,1H),6.22(s,1H),4.57-4.52(m,4H),4.48-4.44(m,2H),3.78(s,2H),3.15-3.07(m,1H),2.72-2.63(m,2H),2.38-2.26(m,2H).

[0777] Embodiment 50

[0778] 9-Oxo-N-((2-((((1-(trifluoromethyl)cyclopropyl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[0779]

[0780] Referring to the synthesis method of Example 36, intermediate 8 and (1-(trifluoromethyl)cyclopropyl)methylamine hydrochloride were used as starting materials and the title compound (9.7 mg, white solid) was obtained through similar steps. MS (ESI): m / z 528.1 [M+H] + . 1 HNMR (400 MHz, DMSO-d 6 )δ10.84(s,1H),9.04(t,J=6.4Hz,1H),8.62(s,1H),7.37(d,J=8.0Hz,1H),7.30(s,1H),7.19(s,1H),6.95(dd,J=8.0,1 .2Hz,1H),6.67(s,1H),6.22(s,1H),4.57-4.52(m,4H),4.47-4.45(m,2H),3.80(s,2H),2.74(s,2H),0.85-0.80(m,4H).

[0781] Embodiment 51

[0782] N-((2-((((1-methylcyclobutyl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0783]

[0784] Referring to the synthesis method of Example 36, intermediate 7 and (1-methylcyclobutyl)methylamine hydrochloride were used as starting materials and the title compound (6.8 mg, white solid) was obtained through similar steps. MS (ESI): m / z 474.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ10.85(s,1H),9.02(t,J=6.4Hz,1H),8.59(s,1H),7.37(d,J=8.0Hz,1 H),7.30(s,1H),7.14(s,1H),6.95(dd,J=8.0,1.6Hz,1H),6.73(s,1H),6 .37(s,2H),6.21(s,1H),4.54(d,J=6.4Hz,2H),3.81(s,2H),2.41(s,2H ),1.86-1.79(m,3H),1.75-1.68(m,1H),1.58-1.52(m,2H),1.08(s,3H).

[0785] Embodiment 52

[0786] N-((2-((((1-methylcyclobutyl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[0787]

[0788] Referring to the synthesis method of Example 36, intermediate 8 and (1-methylcyclobutyl)methylamine hydrochloride were used as starting materials and the title compound (7.4 mg, white solid) was obtained through similar steps. MS (ESI): m / z 488.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.85(s,1H),9.03(t,J=6.4Hz,1H),8.62(s,1H),7.36(d,J=8.0Hz,1H),7.30(s,1H),7.19(s,1H),6.94(dd,J=8.0,1.2Hz,1H),6.67( s,1H),6.21(s,1H),4.57-4.53(m,4H),4.47-4.45(m,2H),3.81(s,2H),2.41(s,2H),1.88-1.68(m,4H),1.60-1.50(m,2H),1.08(s,3H).

[0789] Embodiment 53

[0790] N-((2-((((3,3-difluoro-1-methylcyclobutyl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0791]

[0792] Referring to the synthesis method of Example 36, intermediate 7 and (3,3-difluoro-1-methylcyclobutyl)methylamine hydrochloride were used as starting materials and the title compound (5.7 mg, white solid) was obtained through similar steps. MS (ESI): m / z 510.1 [M+H] + . 1 HNMR (400 MHz, DMSO-d 6 )δ10.85(s,1H),9.02(t,J=6.4Hz,1H),8.59(s,1H),7.37(d,J=8.0Hz,1 H),7.30(s,1H),7.14(s,1H),6.95(dd,J=8.0,1.6Hz,1H),6.73(s,1H),6 .37(s,2H),6.22(s,1H),4.55(d,J=6.4Hz,2H),3.83(s,2H),2.54-2.52 (m,1H),2.47(s,2H),2.45-2.42(m,1H),2.20-2.10(m,2H),1.16(s,3H).

[0793] Embodiment 54

[0794] N-((2-((((3,3-difluoro-1-methylcyclobutyl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[0795]

[0796] Referring to the synthesis method of Example 36, intermediate 8 and (3,3-difluoro-1-methylcyclobutyl)methylamine hydrochloride were used as starting materials, and similar steps were followed to obtain the title compound (6.5 mg, white solid). MS (ESI): m / z 524.1 [M+H] + . 1 HNMR (400 MHz, DMSO-d 6)δ10.84(s,1H),9.04(t,J=6.4Hz,1H),8.62(s,1H),7.36(d,J=8.0Hz,1H),7.30(s,1H),7.19(s,1H),6.94(dd,J=8.0,1.2Hz,1H) ,6.67(s,1H),6.22(s,1H),4.57-4.53(m,4H),4.47-4.45(m,2H),3.82(s,2H),2.47-2.45(m,4H),2.20-2.10(m,2H),1.16(s,3H).

[0797] Embodiment 55

[0798] N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[0799]

[0800] Referring to the synthesis method of Example 41, intermediate 4 was used to replace intermediate 5 in step 3, and the title compound (5.1 mg, white solid) was obtained through similar steps. MS (ESI): m / z 475.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.01(t,J=4.8Hz,1H),8.63(s,1H),8.42(s,1H),7.80(s,1H),7.47(d,J =10.0Hz,1H),7.24(d,J=9.6Hz,1H),7.22(s,1H),6.66(s,1H),4.60-4.56( m,4H),4.48-4.46(m,2H),3.75(brs,1H),3.30(s,2H),2.52-2.51(m,2H),2 .38-2.35(m,1H),2.02-1.95(m,2H),1.87-1.73(m,2H),1.69-1.62(m,2H).

[0801] Embodiment 56

[0802] 8-Oxo-N-((2-((((1-(trifluoromethyl)cyclobutyl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0803]

[0804] Referring to the synthesis method of Example 34, intermediate 7 and [1-(trifluoromethyl)cyclobutyl]methylamine were used as starting materials and the title compound (3.2 mg, white solid) was obtained through similar steps. MS (ESI): m / z 528.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.88(s,1H),9.03(t,J=6.0Hz,1H),8.59(s,1H),7.39(d,J=8.0Hz,1H),7.31(s,1H),7.14(s,1H),6.95(dd,J=8.0,1.2Hz,1H),6.73(s ,1H),6.37(s,2H),6.25(s,1H),4.55(d,J=6.0Hz,2H),3.87(s,2H),2.68(s,2H),2.31-2.25(m,1H),2.11-2.06(m,4H),1.89-1.81(m,2H).

[0805] Embodiment 57

[0806] 9-Oxo-N-((2-((((1-(trifluoromethyl)cyclobutyl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[0807]

[0808] Referring to the synthesis method of Example 34, intermediate 8 and [1-(trifluoromethyl)cyclobutyl]methylamine were used as starting materials and the title compound (2.5 mg, white solid) was obtained through similar steps. MS (ESI): m / z 542.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.89(s,1H),9.05(t,J=6.0Hz,1H),8.62(s,1H),7.39(d,J=7.6Hz,1H),7.31(s,1H),7.19(s,1H),6.96(d,J=8.0Hz,1H),6.67 (s,1H),6.25(s,1H),4.57-4.54(m,4H),4.47-4.45(m,2H),3.87(s,2H),2.70-2.67(m,2H),2.11-2.07(m,4H),1.90-1.83(m,2H).

[0809] Embodiment 58

[0810] 8-Oxo-N-((2-(((spiro[3.3]heptan-2-ylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0811]

[0812] (1) Spiro[3.3]heptane-2-carboxamide

[0813] Spiro[3.3]heptane-2-carboxylic acid (300 mg, 2.14 mmol) was dissolved in dichloromethane (10 mL), HATU (977 mg, 2.57 mmol), N,N-diisopropylethylamine (1.38 g, 10.7 mmol) and ammonium chloride (344 mg, 6.4 mmol) were added, and the reaction was allowed to react at room temperature overnight. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution (40 mL) and extracted with ethyl acetate (2 x 30 mL). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (300 mg, yellow oil), yield: 100%. MS (ESI): m / z 139.8 [M+H] + .

[0814] (2) Spiro[3.3]heptane-2-ylmethylamine

[0815] Spiro[3.3]heptane-2-carboxamide (100 mg, 0.72 mmol) was dissolved in tetrahydrofuran (5 mL), and lithium aluminum hydride (85 mg, 2.16 mmol) was added. The reaction solution was heated to 70°C and stirred for 2 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (15 mL), and two drops of water were added. After sufficient stirring, 5 g of anhydrous sodium sulfate was added, and the mixture was stirred for 5 minutes and filtered. The filtrate was concentrated to about 0.5 mL and used directly in the next step. The yield was 100%. MS (ESI): m / z 126.2 [M+H] + .

[0816] (3) 8-Oxo-N-((2-(((spiro[3.3]heptane-2-ylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0817] The crude product obtained in the previous step was diluted with methanol (4 mL), and intermediate 7 (19.5 mg, 0.05 mmol), glacial acetic acid (0.2 mL) and triethylamine (0.2 mL) were added. Insoluble matter was present in the reaction solution. After heating to 50°C and stirring for 10 minutes, sodium cyanoborohydride (10 mg, 0.15 mmol) was added and the reaction was continued at 50°C overnight. The reaction solution was filtered and concentrated, and the residue was purified by Prep-HPLC to obtain the title compound (5.2 mg, white solid), yield: 20%. MS (ESI): m / z 500.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.84(s,1H),9.01(t,J=6.0Hz,1H),8.59(s,1H),7.36(d,J=8.0Hz,1H),7.28(s ,1H),7.14(s,1H),6.94(d,J=8.4Hz,1H),6.73(s,1H),6.37(s,2H),6.19(s,1H),4. 54(d,J=6.0Hz,2H),3.75(s,2H),2.46-4.45(m,2H),2.22-2.18(m,1H),2.03-1.98( m,2H),1.96-1.92(m,2H),1.83-1.79(m,2H),1.76-1.70(m,2H),1.62-1.57(m,2H).

[0818] Embodiment 59

[0819] N-((2-(((Cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-6-methyl-7,8-dihydro-6H-9-oxa-2,2a,5,6-tetraazabenzo[cd]azulene-4-carboxamide

[0820]

[0821] (1) 4-Chloro-6-methyl-7,8-dihydro-6H-9-oxa-2,2a,5,6-tetraazabenzo[cd]azulene

[0822] Dissolve 4-chloro-7,8-dihydro-6H-9-oxa-2,2a,5,6-tetraazabenzo[cd]azulene (150 mg, 0.71 mmol, step 7 of intermediate 10) in tetrahydrofuran (5 mL), add sodium hydride (56 mg, 1.4 mmol), then add iodomethane (203 mg, 1.4 mmol), and stir at room temperature overnight. The reaction solution was added to water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain the title compound (40 mg, yellow solid), yield: 25%. MS (ESI): m / z 224.9 [M+H] + .

[0823] (2) 6-methyl-7,8-dihydro-6H-9-oxa-2,2a,5,6-tetraazabenzo[cd]azulene-4-carboxylic acid methyl ester

[0824] 4-Chloro-6-methyl-7,8-dihydro-6H-9-oxa-2,2a,5,6-tetraazabenzo[cd]azulene (40 mg, 0.18 mmol), palladium acetate (4 mg, 0.018 mmol) and 1,3-bis(diphenylphosphino)propane (11 mg, 0.027 mmol) were dissolved in methanol / acetonitrile (10 mL / 5 mL), triethylamine (66 mg, 0.36 mmol) was added, and the mixture was heated to 120°C in an autoclave (5 MPa, carbon monoxide atmosphere) and stirred for overnight reaction. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain the title compound (20 mg, yellow solid), yield: 45%. MS (ESI): m / z 249.1 [M+H] + .

[0825] (3) 6-Methyl-7,8-dihydro-6H-9-oxa-2,2a,5,6-tetraazabenzo[cd]azulene-4-carboxylic acid

[0826] Dissolve 6-methyl-7,8-dihydro-6H-9-oxa-2,2a,5,6-tetraazabenzo[cd]azulene-4-carboxylic acid methyl ester (20 mg, 0.08 mmol) in methanol / water (5 mL / 1 mL), add sodium hydroxide (6 mg, 0.16 mmol), and react at room temperature for 3 hours. Adjust to acidity with 1M dilute hydrochloric acid, solid precipitates, filter and dry to obtain the title compound (15 mg, white solid), yield: 83%. MS (ESI): m / z 234.9 [M+H] + .

[0827] (4) tert-butyl (cyclobutylmethyl)((6-((6-methyl-7,8-dihydro-6H-9-oxa-2,2a,5,6-tetraazabenzo[cd]azulene-4-carboxamido)methyl)-1H-indol-2-yl)methyl)carbamate

[0828] 6-Methyl-7,8-dihydro-6H-9-oxa-2,2a,5,6-tetraazabenzo[cd]azulene-4-carboxylic acid (15 mg, 0.06 mmol) and intermediate 2 (21 mg, 0.06 mmol) were dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (15 mg, 0.12 mmol) and HATU (27 mg, 0.072 mmol) were added, and the reaction was stirred at room temperature overnight. The reaction solution was added to water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to give the title compound (20 mg, yellow solid), yield: 56%. MS (ESI): m / z 560.4 [M+H] + .

[0829] (5) N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-6-methyl-7,8-dihydro-6H-9-oxa-2,2a,5,6-tetraazabenzo[cd]azulene-4-carboxamide

[0830] Dissolve tert-butyl (cyclobutylmethyl)((6-((6-methyl-7,8-dihydro-6H-9-oxa-2,2a,5,6-tetraazabenzo[cd]azulene-4-carboxamido)methyl)-1H-indol-2-yl)methyl)carbamate (20 mg, 0.04 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (3 mL), and react at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by Prep-HPLC to give the title compound (7.9 mg, white solid), yield: 49%. MS (ESI): m / z 460.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ10.84(s,1H),8.84(t,J=6.4Hz,1H),8.19(s,1H),7.81(s,1H),7.36(d,J=8.0H z,1H),7.27(s,1H),6.94(dd,J=8.0,1.2Hz,1H),6.19(s,1H),4.57(d,J=6.4Hz,2H ),4.39-4.385(m,2H),3.82-3.81(m,2H),3.76(s,2H),3.27(s,3H),2.56-2.51(m ,2H),2.42-2.37(m,1H),2.03-1.92(m,2H),1.82-1.75(m,2H),1.65-1.59(m,2H).

[0831] Embodiment 60

[0832] N-((2-(((bicyclo[3.1.0]hexan-1-ylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0833]

[0834] Referring to the synthesis method of Example 58, the first step uses bicyclo[3.1.0]hexane-1-carboxylic acid as the starting material, and similar steps are followed to obtain the title compound (15.1 mg, white solid). MS (ESI): m / z 486.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.85(s,1H),9.02(t,J=6.4Hz,1H),8.59(s,1H),7.36(d,J=8.0Hz,1H),7. 29(s,1H),7.14(s,1H),6.95(dd,J=8.0,1.2Hz,1H),6.73(s,1H),6.37(s,2H), 6.19(s,1H),4.54(d,J=6.4Hz,2H),3.79(s,2H),2.58(s,2H),1.69-1.62(m,3H ),1.61-1.51(m,2H),1.19-1.11(m,1H),1.02-0.98(m,1H),0.32-0.26(m,2H).

[0835] Embodiment 61

[0836] N-((2-(((Cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-7,8-dihydro-6,9-dioxa-2,2a,5-triazabenzo[cd]azulene-4-carboxamide

[0837]

[0838] (1) 6-Chloro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyrazolo[1,5-a]pyrazin-3-ol

[0839] 4,6-Dichloropyrazolo[1,5-a]pyrazine-3-ol (300 mg, 1.48 mmol, step 4 of intermediate 10) and sodium hydride (118 mg, 2.96 mmol) were dissolved in tetrahydrofuran (5 mL), 2-((tetrahydro-2H-pyran-2-yl)oxy)ethane-1-ol (432 mg, 2.96 mmol) was added, and the reaction was stirred at room temperature overnight. The reaction solution was added to water (20 mL), the pH was adjusted to acidic with dilute hydrochloric acid, and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give the title compound (380 mg, yellow oil), yield: 82%. MS (ESI): m / z 314.2 [M+H] + .

[0840] (2) 6-Chloro-4-(2-hydroxyethoxy)pyrazolo[1,5-a]pyrazin-3-ol

[0841] Dissolve 6-chloro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyrazolo[1,5-a]pyrazine-3-ol (380 mg, 1.2 mmol) in methanol (10 mL), add p-toluenesulfonic acid monohydrate (22.8 mg, 0.12 mmol), and stir at room temperature to react overnight. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound (200 mg, white solid), yield: 72%. MS (ESI): m / z 230.1 [M+H] + .

[0842] (3) 4-Chloro-7,8-dihydro-6,9-dioxa-2,2a,5-triazabenzo[cd]azulene

[0843] 6-Chloro-4-(2-hydroxyethoxy)pyrazolo[1,5-a]pyrazine-3-ol (200 mg, 0.87 mmol) and triphenylphosphine (681 mg, 2.6 mmol) were dissolved in tetrahydrofuran (10 mL), diisopropyl azodicarboxylate (525 mg, 2.6 mmol) was added dropwise, and the mixture was heated to 50°C and stirred for overnight reaction. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain the title compound (70 mg, white solid), yield: 38%. MS (ESI): m / z 212.0 [M+H] + .

[0844] (4) 7,8-Dihydro-6,9-dioxa-2,2a,5-triazabenzo[cd]azulene-4-carboxylic acid methyl ester

[0845] 4-Chloro-7,8-dihydro-6,9-dioxa-2,2a,5-triazabenzo[cd]azulene (70 mg, 0.33 mmol), palladium acetate (7.5 mg, 0.033 mmol) and 1,3-bis(diphenylphosphino)propane (21 mg, 0.05 mmol) were dissolved in methanol / acetonitrile (10 mL / 5 mL), triethylamine (67 mg, 0.66 mmol) was added, and the mixture was heated to 120°C in an autoclave (5 MPa, carbon monoxide atmosphere) and stirred to react overnight. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound (40 mg, white solid), yield: 51%. MS (ESI): m / z 236.0 [M+H] + .

[0846] (5) 7,8-Dihydro-6,9-dioxa-2,2a,5-triazabenzo[cd]azulene-4-carboxylic acid

[0847] Dissolve 7,8-dihydro-6,9-dioxa-2,2a,5-triazabenzo[cd]azulene-4-carboxylic acid methyl ester (40 mg, 0.17 mmol) in methanol / water (5 mL / 1 mL), add sodium hydroxide (13.6 mg, 0.34 mmol), and react at room temperature for 3 hours. Adjust the pH value to acidity with 1M dilute hydrochloric acid, filter the solid and dry to obtain the title compound (19 mg, white solid), yield: 50%. MS (ESI): m / z 222.1 [M+H] + .

[0848] (6) tert-butyl (cyclobutylmethyl)((6-((7,8-dihydro-6,9-dioxa-2,2a,5-triazabenzo[cd]azulene-4-carboxamido)methyl)-1H-indol-2-yl)methyl)carbamate

[0849] 7,8-dihydro-6,9-dioxa-2,2a,5-triazabenzo[cd]azulene-4-carboxylic acid (19 mg, 0.08 mmol) and intermediate 2 (27 mg, 0.08 mmol) were dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (21 mg, 0.16 mmol) and HATU (38 mg, 0.1 mmol) were added, and the reaction was stirred at room temperature overnight. The reaction solution was added to water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (20 mg, colorless oil), yield: 43%. MS (ESI): m / z 547.4 [M+H] + .

[0850] (7) N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-7,8-dihydro-6,9-dioxa-2,2a,5-triazabenzo[cd]azulene-4-carboxamide

[0851] Dissolve tert-butyl (cyclobutylmethyl)((6-((7,8-dihydro-6,9-dioxa-2,2a,5-triazabenzo[cd]azulene-4-carboxamido)methyl)-1H-indol-2-yl)methyl)carbamate (20 mg, 0.04 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (3 mL), and react at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by Prep-HPLC to give the title compound (4.3 mg, white solid), yield: 27%. MS (ESI): m / z 893.2 [2M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.85(s,1H),8.86(t,J=6.0Hz,1H),8.60(s,1H),8.01(s,1H),7.37(d,J= 8.4Hz,1H),7.28(s,1H),6.95(d,J=8.0Hz,1H),6.22(s,1H),4.78-4.77(m,2 H),4.59-4.58(m,2H),4.53(d,J=6.0Hz,2H),3.79(s,2H),2.62-2.59(m,2H) ,2.44-2.36(m,1H),1.98-1.96(m,2H),1.83-1.75(m,2H),1.66-1.59(m,2H).

[0852] Embodiment 62

[0853] N-((2-(((cyclobutylmethyl)amino)methyl-d 2 )-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0854]

[0855] (1) 6-Cyano-1H-indole-2-carboxylic acid

[0856] Dissolve methyl 6-cyano-1H-indole-2-carboxylate (2g, 10mmol) in methanol / water (20mL / 5mL), add sodium hydroxide (800mg, 20mmol), heat the reaction solution to 40°C and stir for 3 hours. Adjust the pH value to acidity with 1M dilute hydrochloric acid, solid precipitates, filter and dry to obtain the title compound (1.8g, white solid), yield: 97%. MS (ESI): m / z 186.9 [M+H] + .

[0857] (2) 6-Cyano-N-(cyclobutylmethyl)-1H-indole-2-carboxamide

[0858] Dissolve 6-cyano-1H-indole-2-carboxylic acid (1.8 g, 10 mmol) and N,N'-carbonyldiimidazole (1.9 g, 12 mmol) in N,N-dimethylformamide (30 mL), add cyclobutylmethylamine (1.02 g, 12 mmol), and stir the reaction at room temperature overnight. Add ethyl acetate (10 mL) to the reaction solution, solid precipitates, and filter. Add ethyl acetate (20 mL) and water (20 mL) to the filtrate, white solid precipitates, filter and dry to obtain the title compound (1.5 g, white solid), yield: 60%. MS (ESI): m / z 254.2 [M+H] + .

[0859] (3) 6-(Aminomethyl)-N-(cyclobutylmethyl)-1H-indole-2-carboxamide

[0860] Dissolve 6-cyano-N-(cyclobutylmethyl)-1H-indole-2-carboxamide (800 mg, 3.2 mmol) in 7M ammonia methanol solution (10 mL), add Raney nickel (80 mg), and heat the mixture to 40°C under a hydrogen atmosphere and stir for 3 hours. The reaction solution was filtered and the filtrate was concentrated to obtain the title compound (700 mg, white solid). MS (ESI): m / z 241.2 [M+H-NH 3 ] + .

[0861] (4) 1-(6-(aminomethyl)-1H-indol-2-yl)-N-(cyclobutylmethyl)methane-d 2 -amine

[0862] 6-(Aminomethyl)-N-(cyclobutylmethyl)-1H-indole-2-carboxamide (100 mg, 3.2 mmol) was dissolved in 1,4-dioxane (10 mL), lithium aluminum deuteride (50 mg, 1.2 mmol) was added, and the mixture was heated to 110°C and stirred overnight. The reaction solution was quenched with methanol and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain the title compound (30 mg, yellow oil), yield: 32%. MS (ESI): m / z 229.2 [M+H-NH 3 ] + .

[0863] (5) N-((2-(((cyclobutylmethyl)amino)methyl-d 2 )-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0864] 1-(6-(aminomethyl)-1H-indol-2-yl)-N-(cyclobutylmethyl)methane-d 2 -amine (30 mg, 0.12 mmol) and intermediate 5 (14 mg, 0.06 mmol) were dissolved in N, N-dimethylformamide (5 mL), and N, N-diisopropylethylamine (30 mg, 0.24 mmol) and HATU (27 mg, 0.07 mmol) were added, and the reaction was stirred at room temperature overnight. Water (20 mL) was added to the reaction solution, and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain a crude product, and then purified by Prep-HPLC to obtain the title compound (3.3 mg, white solid), yield: 12%. MS (ESI): m / z 462.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ10.87(s,1H),9.04(t,J=6.4Hz,1H),8.59(s,1H),7.37(d,J=8.0Hz,1H),7.29(s,1H),7.14(s,1H),6.94(d,J=8.0Hz,1H),6.73(s,1H),6.3 7(s,2H),6.20(s,1H),4.54(d,J=6.4Hz,2H),2.54-2.52(m,2H),2.42- 2.35(m,1H),2.01-1.93(m,2H),1.83-1.75(m,2H),1.65-1.58(m,2H).

[0865] Embodiment 63

[0866] N-((2-(((bicyclo[3.1.0]hexan-1-ylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[0867]

[0868] Referring to the synthesis method of Example 58, bicyclo[3.1.0]hexane-1-carboxylic acid was used as the starting material in the first step, and intermediate 8 was used to replace intermediate 7 in the third step. The title compound (5.5 mg, white solid) was obtained through similar steps. MS (ESI): m / z 500.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.89(s,1H),9.06(t,J=4.4Hz,1H),8.62(s,1H),7.37(d,J=7.6Hz,1H) ,7.30(s,1H),7.19(s,1H),6.95(d,J=8.0Hz,1H),6.66(s,1H),6.24(s,1H ),4.58-4.52(m,4H),4.47-4.44(m,2H),3.85(s,2H),2.75-2.64(m,2H),1 .71-1.57(m,5H),1.23-1.17(m,1H),1.07-0.98(m,1H),0.36-0.27(m,2H).

[0869] Embodiment 64 to Embodiment 70

[0870] The preparation of Examples 64 to 70 refers to the method of Example 62, using corresponding raw materials and intermediates and synthesized through similar steps.

[0871]

[0872]

[0873] Embodiment 71

[0874] N-((2-(((cyclobutylmethyl-d 2 )amino)methyl)-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0875]

[0876] (1) Cyclobutylmethane-d 2 -Amine hydrochloride

[0877] Cyclobutanamide (50 mg, 0.5 mmol) was dissolved in tetrahydrofuran (5 mL), and lithium aluminum deuteride (63 mg, 1.5 mmol) was added. The mixture was heated to 70 ° C and stirred for 2 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (5 mL), and two drops of water were added. After sufficient stirring, 5 g of anhydrous sodium sulfate was added, and the mixture was stirred for 5 minutes and filtered. 4M hydrochloric acid / dioxane solution (1 mL) was added to the filtrate, and the title compound (50 mg, white solid) was concentrated to obtain the title compound (50 mg, white solid), yield: 80%. MS (ESI): m / z 88.2 [M+H] + .

[0878] (2) N-((2-(((cyclobutylmethyl-d 2 )amino)methyl)-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0879] Cyclobutylmethane-d 2 -Amine hydrochloride (35 mg, 0.28 mmol) was dissolved in methanol (2 mL), and intermediate 7 (11 mg, 0.028 mmol), glacial acetic acid (0.2 mL) and triethylamine (0.2 mL) were added. The reaction solution was heated to 50 ° C and stirred for 10 minutes, then sodium cyanoborohydride (10 mg, 0.15 mmol) was added and continued to stir at 50 ° C overnight. The reaction solution was filtered and concentrated, and the residue was purified by Prep-HPLC to obtain the title compound (8.5 mg, white solid), yield: 65%. MS (ESI): m / z 462.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ10.86(s,1H),9.03(t,J=6.0Hz,1H),8.59(s,1H),7.37(d,J=8.0Hz,1H),7.29(s,1H),7.14(s,1H),6.94(d,J=8.0Hz,1H),6.73(s,1H), 6.38(s,2H),6.20(s,1H),4.54(d,J=6.0Hz,2H),3.76(s,2H),2.42-2.36(m,1H),2.00-1.92(m,2H),1.85-1.75(m,2H),1.65-1.59(m,2H).

[0880] Embodiment 72

[0881] N-((2-((((3-Fluorobicyclo[1.1.1]pentan-1-yl)methyl-d 2 )amino)methyl)-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0882]

[0883] Referring to the synthesis method of Example 71, the first step uses 3-fluorobicyclo[1.1.1]pentane-1-carboxamide as the starting material, and similar steps are followed to obtain the title compound (4.3 mg, white solid). MS (ESI): m / z 492.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.91(s,1H),9.06(t,J=6.0Hz,1H),8.60(s,1H),7.40(d,J=7.6Hz,1H),7.31(s,1H),7.14(s,1H),6.97(d,J =7.6Hz,1H),6.73(s,1H),6.38(s,2H),6.26(s,1H),4.55(d,J=6.0Hz,2H),3.89(s,2H),1.95(d,J=2.8Hz,6H).

[0884] Embodiment 73

[0885] N-((2-(((cyclobutylmethyl)amino)methyl)-5-fluoro-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0886]

[0887] (1) 5-amino-4-(3,3-diethoxypropyl-1-yn-1-yl)-2-fluorobenzonitrile

[0888] 5-Amino-4-bromo-2-fluorobenzonitrile (2.0 g, 9.30 mmol) and 3,3-diethoxyprop-1-yne (2.98 g, 23.25 mmol) were dissolved in triethylamine (25 mL), and bis(triphenylphosphine)palladium dichloride (330 mg, 0.47 mmol), triphenylphosphine (240 mg, 0.93 mmol) and cuprous iodide (180 mg, 0.93 mmol) were added in sequence. The mixture was heated to 80°C and stirred for 16 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 90 / 10) to obtain the title compound (2.0 g, brown oil), yield: 82%. MS (ESI): m / z 217.0 [M+H-EtOH] + .

[0889] (2) 2-(diethoxymethyl)-5-fluoro-1H-indole-6-carbonitrile

[0890] 5-Amino-4-(3,3-diethoxypropyl-1-yn-1-yl)-2-fluorobenzonitrile (2.0 g, 7.6 mmol) was dissolved in tetrahydrofuran (20 mL), and a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (15.2 mL, 15.2 mmol) was slowly added dropwise at 25°C. After the addition was completed, the mixture was heated to 75°C and stirred for 4 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 90 / 10) to obtain the title compound (700 mg, yellow solid), yield: 36%. MS (ESI): m / z 263.0 [M+H] + . 1 H NMR (300 MHz, DMSO-d 6 )δ11.82(s,1H),7.83(d,J=5.4Hz,1H),7.60(d,J=10.5Hz,1H),6.58(d,J=0.9Hz,1H),5.79(s,1H),3.65-3.58(m,4H),1.21(t,J=7.2Hz,6H).

[0891] (3) (2-(diethoxymethyl)-5-fluoro-1H-indol-6-yl)methanamine

[0892] 2-(Diethoxymethyl)-5-fluoro-1H-indole-6-carbonitrile (300 mg, 1.14 mmol) was dissolved in 7M ammonia methanol solution (20 mL), 10% Raney nickel (30 mg) was added, hydrogen was replaced 3 times, and the mixture was heated to 50°C and stirred for 16 hours. The reaction solution was filtered to remove the Raney nickel, and the filtrate was concentrated to obtain the title compound (290 mg, green oil), yield: 95%. MS (ESI): m / z 175.9 [M+H-91] + .

[0893] (4) N-((2-(diethoxymethyl)-5-fluoro-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0894] 8-Oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxylic acid (40 mg, 0.17 mmol) and (2-(diethoxymethyl)-5-fluoro-1H-indol-6-yl)methylamine (68 mg, 0.26 mmol) were dissolved in N,N-dimethylformamide (5 mL), 1-propylphosphoric anhydride in ethyl acetate (218 mg, 0.34 mmol, 50%) and N,N-diisopropylethylamine (110 mg, 0.85 mmol) were added, and stirred at room temperature for 1 hour. The reaction solution was added to saturated sodium bicarbonate solution (30 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=30 / 70) to give the title compound (25 mg, light yellow oil), yield: 61%. MS (ESI): m / z 483.0 [M+H] + .

[0895] (5) N-((5-fluoro-2-formyl-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0896] N-((2-(diethoxymethyl)-5-fluoro-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide (50 mg, 0.10 mmol) and acetic acid (1 mL) were dissolved in a tetrahydrofuran / water mixture (5 mL / 0.5 mL), and the mixture was heated to 50°C and stirred for 3 hours. The reaction solution was concentrated, diluted with ethyl acetate, filtered, and dried to obtain the title compound (32 mg, white solid), yield: 76%. MS (ESI): m / z 408.8 [M+H] + .

[0897] (6) N-((2-(((cyclobutylmethyl)amino)methyl)-5-fluoro-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0898] N-((5-fluoro-2-formyl-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide (16 mg, 0.04 mmol) and cyclobutylmethylamine (10 mg, 0.12 mmol) were dissolved in a mixed solvent of methanol / acetic acid / N,N-dimethylformamide (3 mL / 0.3 mL / 1 mL), and the mixture was heated to 50°C and stirred for 1 hour. Sodium cyanoborohydride (12 mg, 0.20 mmol) was then added and stirred at 50°C for 48 hours. The reaction solution was concentrated and the residue was purified by Prep-HPLC to obtain the title compound (6.5 mg, white solid) with a yield of 35%. MS (ESI): m / z 478.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.96(s,1H),8.99(t,J=6.0Hz,1H),8.60(s,1H),7.29(d,J=6.4Hz,1H),7.20-7.17(m,2H),6.73(s,1H),6.38(s,2H),6.22(s,1H) ,4.59(d,J=6.0Hz,2H),3.77(s,2H),2.55-2.50(m,2H),2.43-2.33(m,1H),1.98-1.92(m,2H),1.82-1.76(m,2H),1.66-1.59(m,2H).

[0899] Embodiment 74

[0900] N-((5-Fluoro-2-((((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0901]

[0902] Referring to the synthesis method of step 6 of Example 73, (3-fluorobicyclo[1.1.1]pentan-1-yl)methylamine hydrochloride was used to replace cyclobutylmethylamine, and the title compound (5.0 mg, white solid) was obtained through similar steps. MS (ESI): m / z 508.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.95(s,1H),9.00(t,J=6.0Hz,1H),8.60(s,1H),7.28(d,J=6.8Hz,1H),7.21-7.17(m,2H),6.7 3(s,1H),6.38(s,2H),6.22(s,1H),4.59(d,J=5.6Hz,2H),3.79(s,2H),2.74(s,2H),1.92(s,6H).

[0903] Embodiment 75

[0904] N-((2-(((cyclobutylmethyl)amino)methyl)-5,7-difluoro-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0905]

[0906] Referring to the synthesis method of Example 73, the first step uses 3-amino-4-bromo-2,6-difluorobenzonitrile as the starting material, and similar steps are followed to obtain the title compound (8.2 mg, white solid). MS (ESI): m / z 496.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ11.49(s,1H),8.74(t,J=5.2Hz,1H),8.58(s,1H),7.17(s,1H),7.13(d,J=10.8Hz,1H),6.69(s,1H),6.37-6.35(m,3H),4.66 (d,J=5.6Hz,2H),3.82(s,2H),2.54-2.51(m,2H),2.42-2.40(m,1H),2.01-1.97(m,2H),1.81-1.79(m,2H),1.65-1.60(m,2H).

[0907] The synthesis method of 3-amino-4-bromo-2,6-difluorobenzonitrile is as follows: 3-amino-2,6-difluorobenzonitrile (1 g, 6.5 mmol) is dissolved in dichloromethane (10 mL), N-bromosuccinimide (1.39 mg, 7.8 mmol) is added, and the mixture is stirred at room temperature for 16 hours. The reaction solution is concentrated, and the residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 97 / 3) to obtain 3-amino-4-bromo-2,6-difluorobenzonitrile (1 g, white solid), yield: 66%. MS (ESI): m / z 233.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.66(dd,J=8.8,2.0Hz,1H),5.79(brs,2H).

[0908] Embodiment 76

[0909] N-((2-((((5-Fluorothien-2-yl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[0910]

[0911] Dissolve intermediate 8 (15 mg, 0.04 mmol) and (5-fluorothiophen-2-yl)methylamine (7.30 mg, 0.06 mmol) in methanol (5 mL) and stir at 50 ° C for 1 hour. Then add sodium cyanoborohydride (6.99 mg, 0.11 mmol) and continue stirring at 50 ° C for 12 hours. The reaction solution is concentrated, and the residue is diluted with anhydrous methanol and purified by Prep-HPLC to obtain the title compound (7.7 mg, white solid), yield: 40%. MS (ESI): m / z 520.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6 )δ10.88(s,1H),9.06(t,J=6.4Hz,1H),8.62(s,1H),7.38(d,J=8.0Hz,1H),7.30(s,1H),7.19(s,1H),6.95(d,J=7.6Hz,1H),6.67(s ,1H),6.61(t,J=3.6Hz,1H),6.51-6.49(m,1H),6.24(s,1H),4.56-4.53(m,4H),4.47-4.45(m,2H),3.80(s,2H),3.74-3.73(m,2H).

[0912] Embodiment 77

[0913] N-((2-((((2-Oxabicyclo[2.1.1]hexan-1-yl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[0914]

[0915] Dissolve intermediate 8 (15 mg, 0.04 mmol) and (2-oxabicyclo[2.1.1]hexane-1-yl)methylamine hydrochloride (8.94 mg, 0.06 mmol) in methanol (5 mL) and stir at 50°C for 1 hour. Add sodium cyanoborohydride (6.99 mg, 0.11 mmol) and continue stirring at 50°C for 12 hours. The reaction solution is concentrated, diluted with anhydrous methanol, and purified by Prep-HPLC to obtain the title compound (5.0 mg, white solid), yield: 27%. MS (ESI): m / z 502.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.89(s,1H),9.04(t,J=6.4Hz,1H),8.62(s,1H),7.37(d,J=8.0Hz,1H),7.29(s,1H),7.19(s,1H),6.94(d,J=8.0Hz,1H),6.67(s,1H),6.21 (s,1H),4.57-4.53(m,4H),4.47-4.45(m,2H),3.83(s,2H),3.61(s,2H) ,2.84-2.83(m,1H),2.77(s,2H),1.76-1.69(m,2H),1.32-1.30(m,2H).

[0916] Embodiment 78

[0917] (R)-9-Oxo-N-((2-((((tetrahydrofuran-2-yl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[0918]

[0919] Referring to the synthesis method of Example 76, the title compound (9.0 mg, white solid) was obtained by similar steps using intermediate 8 and (R)-(tetrahydrofuran-2-yl)methylamine as starting materials. MS (ESI): m / z 490.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.91(s,1H),9.06(t,J=6.4Hz,1H),8.62(s,1H),7.38(d,J=8.0Hz,1H),7.30 (s,1H),7.19(s,1H),6.95(d,J=9.2Hz,1H),6.66(s,1H),6.24(s,1H),4.59-4.53 (m,4H),4.47-4.44(m,2H),3.93-3.87(m,3H),3.74-3.69(m,1H),3.62-3.57(m, 1H),2.58-2.57(m,2H),1.92-1.84(m,1H),1.81-1.73(m,2H),1.54-1.45(m,1H).

[0920] Embodiment 79

[0921] (S)-N-((2-(((oxetan-2-ylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxacyclo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[0922]

[0923] Referring to the synthesis method of Example 76, intermediate 8 and (S)-oxetane-2-ylmethylamine were used as starting materials and the title compound (9.6 mg, white solid) was obtained through similar steps. MS (ESI): m / z 476.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ10.90(s,1H),9.05(t,J=6.0Hz,1H),8.62(s,1H),7.37(d,J=7.6Hz,1H),7.29(s,1H),7.19(s,1H),6.95(dd,J=8.8Hz,1.6Hz,1H),6.67(s,1H ),6.22(s,1H),4.80-4.73(m,1H),4.57-4.53(m,4H),4.49-4.45(m,3H) ,4.40-4.33(m,1H),3.83(s,2H),2.77-2.66(m,2H),2.43-2.32(m,2H).

[0924] Embodiment 80

[0925] N-((2-((((1-methoxycyclobutyl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[0926]

[0927] (1) 1-Methoxycyclobutane-1-carboxylic acid methyl ester

[0928] 1-Hydroxycyclobutane-1-carboxylic acid (800 mg, 6.89 mmol) was dissolved in N,N-dimethylformamide (10 mL), sodium hydride (1.10 g, 27.56 mmol, 60%) was added at 0°C, and the mixture was stirred at room temperature for 2 hours. Methyl iodide (2.94 g, 20.67 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, saturated ammonium chloride solution (50 mL) was added to quench the mixture, and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound (500 mg, yellow oil), with a yield of 50%. 1 H NMR (400 MHz, DMSO-d 6 )δ3.70(s,3H),3.09(s,3H),2.37-2.30(m,2H),2.16-2.08(m,2H),1.82-1.71(m,2H).

[0929] (2) 1-Methoxycyclobutane-1-carboxamide

[0930] 1-Methoxycyclobutane-1-carboxylic acid methyl ester (300 mg, 2.08 mmol) was dissolved in 7M ammonia methanol solution (5 mL) and stirred at 60°C for 16 hours. After the reaction was completed, the reaction solution was concentrated to obtain the title compound (200 mg, white oil) with a yield of 74%. 1 H NMR (400 MHz, CDCl 3 )δ6.26(s,1H),5.28(s,1H),3.24(s,3H),2.49-2.42(m,2H),2.24-2.16(m,2H),1.95-1.82(m,2H).

[0931] (3) (1-methoxycyclobutyl)methylamine

[0932] 1-Methoxycyclobutane-1-carboxamide (50 mg, 0.39 mmol) and lithium aluminum hydride (44.04 mg, 1.16 mmol) were dissolved in tetrahydrofuran (3 mL) and stirred at 70°C for 1 hour. The reaction was completed by LCMS, and the reaction solution was concentrated to obtain the title compound (44 mg, yellow oil) with a yield of 99%. MS (ESI): m / z 116.2 [M+H] + .

[0933] (4) N-((2-((((1-methoxycyclobutyl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[0934] Intermediate 8 (7.5 mg, 0.02 mmol) and (1-methoxycyclobutyl)methylamine (10.65 mg, 0.09 mmol) were dissolved in methanol / acetic acid (3 mL / 0.3 mL) and stirred at 50°C for 1 hour. Sodium cyanoborohydride (5.81 mg, 0.09 mmol) was then added and the reaction was continued at 50°C for 16 hours. The reaction solution was concentrated and the residue was purified by Prep-HPLC to obtain the title compound (4 mg, white solid) with a yield of 43%. MS (ESI): m / z 504.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ10.93(s,1H),9.08(t,J=5.6Hz,1H),8.62(s,1H),7.37(d,J=8.4Hz,1H),7.29(s,1H),7.19(s,1H),6.95(d,J=8.4Hz,1H),6.67(s,1H),6.23 (s,1H),4.56-4.53(m,4H),4.46-4.42(m,2H),3.84(s,2H),2.99(s,3H) ,2.62(s,2H),2.00-1.92(m,2H),1.87-1.82(m,2H),1.68-1.56(m,2H).

[0935] Embodiment 81

[0936] N-((2-((5-oxa-8-azaspiro[3.5]nonan-8-yl)methyl)-1H-indol-6-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[0937]

[0938] Referring to the synthesis method of Example 76, intermediate 8 and 5-oxa-8-azaspiro[3.5]nonane were used as starting materials and similar steps were followed to obtain the title compound (6.0 mg, white solid). MS (ESI): m / z 516.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.92(s,1H),9.07(t,J=7.8Hz,1H),8.62(s,1H),7.38(d,J=8.4Hz,1H) ,7.32(s,1H),7.19(s,1H),6.96(d,J=8.8Hz,1H),6.67(s,1H),6.24(s,1H ),4.59-4.53(m,4H),4.47-4.46(m,2H),3.59(s,2H),3.51-3.48(m,2H),2 .36-2.30(m,4H),2.00-1.82(m,4H),1.75-1.64(m,1H),1.52-1.41(m,1H).

[0939] Embodiment 82

[0940] N-((2-((((5-Fluorothien-2-yl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0941]

[0942] Intermediate 7 (15 mg, 0.04 mmol), (5-fluorothiophen-2-yl)methylamine hydrochloride (6.7 mg, 0.04 mmol) and acetic acid (0.1 mL) were dissolved in methanol / N,N-dimethylformamide (5 mL / 1 mL) and stirred at room temperature for 0.5 hours. Sodium cyanoborohydride (5 mg, 0.08 mmol) was then added and stirred at 50°C overnight. The reaction solution was concentrated and the residue was purified by Prep-HPLC to obtain the title compound (5.3 mg, yellow solid) with a yield of 28%. MS (ESI): m / z 506.0 [M+H] + . 1 HNMR (400 MHz, DMSO-d 6 )δ10.89(s,1H),9.06(t,J=6.0Hz,1H),8.59(s,1H),7.39(d,J=8.0Hz,1H),7.30(s,1H),7.14(s,1H),6.96(dd,J=8.0,1.2Hz,1H),6.73 (s,1H),6.61(t,J=3.6Hz,1H),6.52-6.50(m,1H),6.38(s,2H),6.24(s,1H),4.55(d,J=6.4Hz,2H),3.81(s,2H),3.74(d,J=2.4Hz,2H).

[0943] Embodiment 83

[0944] N-((2-((((1-methoxycyclobutyl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0945]

[0946] Referring to the synthesis method of Example 80, in step 4, intermediate 7 and (1-methoxycyclobutyl)methylamine were used as raw materials, and the title compound (8.3 mg, white solid) was obtained through similar steps. MS (ESI): m / z 490.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6 )δ10.91(s,1H),9.04(t,J=6.0Hz,1H),8.59(s,1H),7.38(d,J=8.0Hz,1H),7 .29(s,1H),7.14(s,1H),6.95(dd,J=8.0,1.6Hz,1H),6.73(s,1H),6.38(s,2H ),6.23(s,1H),4.54(d,J=6.4Hz,2H),3.84(s,2H),2.99(s,3H),2.63(s,2H) ,2.00-1.92(m,2H),1.88-1.82(m,2H),1.67-1.59(m,1H),1.49-1.41(m,1H).

[0947] Embodiment 84

[0948] N-((2-((((2-Oxabicyclo[2.1.1]hexan-1-yl)methyl)amino)methyl)-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0949]

[0950] Intermediate 7 (15 mg, 0.04 mmol), (2-oxabicyclo[2.1.1]hexane-1-yl)methylamine hydrochloride (6.0 mg, 0.04 mmol) and acetic acid (0.1 mL) were dissolved in methanol / N,N-dimethylformamide (5 mL / 1 mL) and stirred at room temperature for 0.5 hours. Sodium cyanoborohydride (5 mg, 0.08 mmol) was then added and stirred at 50°C overnight. The reaction solution was concentrated and the residue was purified by Prep-HPLC to obtain the title compound (4.3 mg, white solid) with a yield of 23%. MS (ESI): m / z 488.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ10.91(s,1H),9.05(t,J=6.4Hz,1H),8.59(s,1H),7.38(d,J=8.0Hz,1H ),7.29(s,1H),7.15(s,1H),6.95(dd,J=8.0,1.2Hz,1H),6.73(s,1H),6. 38(s,2H),6.22(s,1H),4.54(d,J=6.0Hz,2H),3.83(s,2H),3.61(s,2H), 2.83(t,J=2.8Hz,1H),2.77(s,2H),1.72-1.70(m,2H),1.33-1.30(m,2H).

[0951] Embodiment 85

[0952] N-((2-(((cyclobutylmethyl)amino)methyl)-5-fluoro-1H-indol-6-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[0953]

[0954] (1) N-((2-(diethoxymethyl)-5-fluoro-1H-indol-6-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[0955] Referring to the synthesis method of step 4 of Example 73, intermediate 4 (50 mg, 0.2 mmol) and (2-(diethoxymethyl)-5-fluoro-1H-indol-6-yl)methanamine (80 mg, 0.3 mmol) were used as raw materials, and similar steps were followed to obtain the title compound (60 mg, yellow oil), yield: 60%. MS (ESI): m / z 519.0 [M+Na] + .

[0956] (2) N-((5-fluoro-2-formyl-1H-indol-6-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[0957] Referring to the synthesis method of step 5 of Example 73, N-((2-(diethoxymethyl)-5-fluoro-1H-indol-6-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide (60 mg, 0.12 mmol) was used as the starting material, and the title compound (50 mg, white solid) was obtained through similar steps. The yield was 98%. MS (ESI): m / z 422.8 [M+H] + .

[0958] (3) N-((2-(((cyclobutylmethyl)amino)methyl)-5-fluoro-1H-indol-6-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[0959] N-((5-fluoro-2-formyl-1H-indol-6-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide (25 mg, 0.06 mmol) and cyclobutylmethylamine (15 mg, 0.18 mmol) were dissolved in methanol / acetic acid / N,N-dimethylformamide (3 mL / 0.3 mL / 1.5 mL) and stirred at 50°C for 1 hour. Sodium cyanoborohydride (19 mg, 0.30 mmol) was added and the reaction was continued at 50°C for 16 hours. The reaction solution was concentrated and the residue was purified by Prep-HPLC to obtain the title compound (13.3 mg, white solid) with a yield of 46%. MS (ESI): m / z 492.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.95(s,1H),9.01(t,J=6.4Hz,1H),8.62(s,1H),7.28(d,J=6.8Hz,1H),7.22(s,1H),7.18(d,J=11.2Hz,1H),6.66(s,1H),6.21(s,1H),4.5 9-4.56(m,4H),4.48-4.46(m,2H),3.76(s,2H),2.49-2.46(m,2H),2.40 -2.34(m,1H),2.00-1.92(m,2H),1.82-1.75(m,2H),1.65-1.58(m,2H).

[0960] Embodiment 86

[0961] N-((2-((((2-Oxabicyclo[2.1.1]hexan-1-yl)methyl)amino)methyl)-5-fluoro-1H-indol-6-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[0962]

[0963] Referring to the synthesis method of step 3 of Example 85, N-((5-fluoro-2-formyl-1H-indol-6-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide and 2-oxabicyclo[2.1.1]hex-1-ylmethylamine hydrochloride were used as raw materials and the title compound (8.6 mg, white solid) was obtained through similar steps. MS (ESI): m / z 520.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.94(s,1H),8.94(t,J=6.4Hz,1H),8.52(s,1H),7.20(d,J=6.4Hz,1H),7.12-7.10(m,2H),6.57(s,1H),6.17(s,1H),4.50-4. 46(m,4H),4.38-4.36(m,2H),3.76(s,2H),3.52(s,2H),2.74(t,J=3.2Hz,1H),2.70(s,2H),1.64-1.59(m,2H),1.23-1.22(m,2H).

[0964] Embodiment 87

[0965] N-((2-((((2-Oxabicyclo[2.1.1]hexan-1-yl)methyl)amino)methyl)-5-fluoro-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0966]

[0967] Referring to the synthesis method of step 6 of Example 73, 2-oxabicyclo[2.1.1]hex-1-ylmethylamine hydrochloride was used to replace cyclobutylmethylamine, and the title compound (11.8 mg, white solid) was obtained through similar steps. MS (ESI): m / z 506.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6 )δ10.98(s,1H),8.99(t,J=6.0Hz,1H),8.60(s,1H),7.29(d,J=6.4Hz,1H),7.20(d,J=11.2Hz,1H),7.17(s,1H),6.73(s,1H),6.38(s,2H),6 .24(s,1H),4.59(d,J=6.0Hz,2H),3.83-3.82(m,2H),3.61(s,2H),2.8 3(t,J=3.2Hz,1H),2.77(s,2H),1.72-1.69(m,2H),1.32-1.31(m,2H).

[0968] Embodiment 88

[0969] N-((2-(((cyclobutylmethyl-d 2 )amino)methyl)-5-fluoro-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0970]

[0971] Referring to the synthesis method of step 6 of Example 73, cyclobutylmethane-d 2 -amine hydrochloride (Example 71, step 1) was used to replace cyclobutylmethylamine, and the title compound (43.0 mg, white solid) was obtained through similar steps. MS (ESI): m / z 480.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.20(s,1H),9.04(t,J=6.0Hz,1H),8.60(s,1H),7.31(d,J=5.6Hz,1H),7.23(d,J=11.2Hz,1H),7.17(s,1H),6.73(s,1H),6.38( s,2H),6.31(s,1H),4.59(d,J=6.0Hz,2H),3.89(s,2H),2.45-2.43(m,1H),1.99-1.96(m,2H),1.83-1.75(m,2H),1.66-1.62(m,2H).

[0972] Embodiment 89

[0973] N-((5-Fluoro-2-((((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl-d 2)amino)methyl)-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[0974]

[0975] Referring to the synthesis method of step 6 of Example 73, (3-fluorobicyclo[1.1.1]pentan-1-yl)methane-d 2 -amine (Example 72) was used to replace cyclobutylmethylamine, and the title compound (9.5 mg, white solid) was obtained through similar steps. MS (ESI): m / z 510.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.96(s,1H),9.01(t,J=6.4Hz,1H),8.60(s,1H),7.28(d,J=6.4Hz,1H),7.21-7.17(m,2H), 6.73(s,1H),6.38(s,2H),6.23(s,1H),4.59(d,J=6.0Hz,2H),3.79(s,2H),1.92-1.91(m,6H).

[0976] Embodiment 90

[0977] N-((2-(((cyclobutylmethyl-d 2 )amino)methyl)-5-fluoro-1H-indol-6-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[0978]

[0979] Referring to the synthesis method of step 3 of Example 85, N-((5-fluoro-2-formyl-1H-indol-6-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide and cyclobutylmethane-d 2 -amine hydrochloride (Step 1 of Example 71) was used as the starting material, and the title compound (3.5 mg, white solid) was obtained through similar steps. MS (ESI): m / z 494.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ10.95(s,1H),9.01(t,J=5.6Hz,1H),8.63(s,1H),7.28(d,J=6.4Hz,1H),7.22-7.17(m,2H),6.66(s,1H),6.21(s,1H),4.5 9-4.58(m,4H),4.48-4.46(m,2H),3.76(s,2H),2.39-2.36(m,1H),1.99-1.93(m,2H),1.81-1.74(m,2H),1.63-1.58(m,2H).

[0980] Embodiment 91

[0981] N-((2-((((2-oxabicyclo[2.1.1]hexan-1-yl)methyl-d 2 )amino)methyl)-1H-indol-6-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[0982]

[0983] Referring to the synthesis method of Example 77, intermediate 8 and (2-oxabicyclo[2.1.1]hexane-1-yl)methane-d 2 -amine as the starting material, the title compound (11.7 mg, white solid) was obtained through similar steps. MS (ESI): m / z 504.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.91(s,1H),9.04(t,J=6.4Hz,1H),8.62(s,1H),7.37(d,J=8.0Hz,1H),7.29(s,1H),7.19(s,1H),6.95(d,J=7.6Hz,1H),6.67(s,1H), 6.21(s,1H),4.57-4.53(m,4H),4.47-4.45(m,2H),3.82(s,2H),3.61(s,2H),2.83(t,J=2.8Hz,1H),1.71-1.68(m,2H),1.33-1.29(m,2H).

[0984] (2-Oxabicyclo[2.1.1]hexan-1-yl)methane-d 2 -The synthesis of amine is as follows:

[0985] (1) 1-(Iodomethyl)-2-oxabicyclo[2.1.1]hexane

[0986] (3-Methylenecyclobutyl)methanol (2.0 g, 20.38 mmol), sodium bicarbonate (5.14 g, 61.13 mmol) and iodine (10.34 g, 40.76 mmol) were added to a mixed solution of methyl tert-butyl ether and water (100 mL, 1:1), and stirred at 25°C for 16 hours. Methyl tert-butyl ether and water (300 mL, 1:1) were added to the reaction solution, and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 95 / 5) to obtain the title compound (3.5 g, yellow oil), with a yield of 77%. MS (ESI): m / z 225.0 [M+H] + .

[0987] (2) Methyl (2-oxabicyclo[2.1.1]hexan-1-yl)acetate

[0988] 1-(Iodomethyl)-2-oxabicyclo[2.1.1]hexane (1.5 g, 6.7 mmol) and potassium acetate (1.97 g, 20.09 mmol) were dissolved in dimethyl sulfoxide (50 mL) and stirred at 90°C for 16 hours. Ethyl acetate and water (200 mL, 1:1) were added for extraction, and the organic phase was concentrated under reduced pressure to obtain the title compound (1.1 g, yellow oil), yield: 100%. MS (ESI): m / z 157.0 [M+H] + .

[0989] (3) (2-Oxabicyclo[2.1.1]hexan-1-yl)methanol

[0990] Dissolve (2-oxabicyclo[2.1.1]hex-1-yl)acetic acid methyl ester (1.1 g, 7.04 mmol) and sodium ethoxide (958 mg, 14.09 mmol) in anhydrous ethanol (50 mL) and stir at 25°C for 12 hours. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to obtain the title compound (450 mg, yellow oil) with a yield of 56%. MS (ESI): m / z 137.0 [M+Na] + .

[0991] (4) 2-Oxabicyclo[2.1.1]hexane-1-carboxylic acid

[0992] (2-Oxabicyclo[2.1.1]hex-1-yl)methanol (450 mg, 3.94 mmol), 2,2,6,6-tetramethylpiperidinoxide (924 mg, 5.91 mmol) and iodophenyldiacetic acid (1.9 g, 5.91 mmol) were added to a mixed solution of acetonitrile and water (30 mL, 2:1) and stirred at 25°C for 12 hours. The reaction solution was concentrated, ethyl acetate and water (100 mL, 1:1) were added, and the aqueous phase was freeze-dried to obtain the title compound (400 mg, yellow oil), with a yield of 79%. MS (ESI): m / z 129.0 [M+H] + .

[0993] (5) N-Benzyl-2-oxabicyclo[2.1.1]hexane-1-carboxamide

[0994] 2-Oxabicyclo[2.1.1]hexane-1-carboxylic acid (400 mg, 3.12 mmol), benzylamine (1.0 g, 9.37 mmol), 1-hydroxybenzotriazole (633 mg, 4.68 mmol), 1-(3-dimethylaminopropyl)-3.ethylcarbodiimide hydrochloride (898 mg, 4.68 mmol) and N,N-diisopropylethylamine (2.03 g, 15.16 mmol) were dissolved in N,N-dimethylformamide (50 mL) and stirred at 25°C for 16 hours. The reaction solution was extracted three times with ethyl acetate and water (100 mL, 1:1), the organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 65 / 35) to obtain the title compound (270 mg, yellow solid), yield: 40%. MS (ESI): m / z 218.0 [M+H] + .

[0995] (6) N-Benzyl-1-(2-oxabicyclo[2.1.1]hexan-1-yl)methane 2 -amine

[0996] N-Benzyl-2-oxabicyclo[2.1.1]hexane-1-carboxamide (230 mg, 1.06 mmol) and lithium aluminum hydride deuteride (133 mg, 3.18 mmol) were added to 1,4-dioxane (20 mL) and stirred at 100°C for 12 hours. Ethyl acetate and water (50 mL, 1:1) were added to the reaction solution at 0°C and stirred vigorously for 0.5 hours. The mixture was then filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the extract was separated, the organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 60) to obtain the title compound (110 mg, colorless oil), yield: 51%. MS (ESI): m / z 206.1 [M+H] + .

[0997] (7) (2-Oxabicyclo[2.1.1]hexane-1-yl)methane-d 2 -amine

[0998] N-benzyl-1-(2-oxabicyclo[2.1.1]hexan-1-yl)methane 2 -amine (30 mg, 0.15 mmol) and palladium carbon (6 mg, 20% w / w) were added to anhydrous methanol (5 mL) and stirred at 50°C for 12 hours. The reaction solution was filtered to obtain a crude methanol solution of the title compound (5 mL, white liquid), with a yield of 100%. MS (ESI): m / z 116.0 [M+H] + .

[0999] Embodiment 92

[1000] N-((2-((((2-oxabicyclo[2.1.1]hexan-1-yl)methyl-d 2 )amino)methyl)-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[1001]

[1002] Referring to the synthesis method of Example 84, intermediate 7 and (2-oxabicyclo[2.1.1]hexane-1-yl)methane-d 2 -amine as the starting material, the title compound (10.5 mg, white solid) was obtained through similar steps. MS (ESI): m / z 490.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.89(s,1H),9.03(t,J=6.0Hz,1H),8.60(s,1H),7.37(d,J=8.4Hz,1H),7.29(s,1H),7.14(s,1H),6.94(d,J=8.0Hz,1H),6.73(s,1H ),6.37(s,2H),6.21(s,1H),4.57-4.53(m,2H),3.82(s,2H),3.61(s,2H),2.83(t,J=3.2Hz,1H),1.71-1.69(m,2H),1.32-1.30(m,2H).

[1003] Embodiment 93

[1004] N-((2-((((2-oxabicyclo[2.1.1]hexan-1-yl)methyl-d 2)amino)methyl)-5-fluoro-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide

[1005]

[1006] Referring to the synthesis method of Example 84, N-((5-fluoro-2-formyl-1H-indol-6-yl)methyl)-8-oxo-8H-[1,3]dioxacyclo[4',5':4,5]pyrido[1,2-a]pyrimidine-6-carboxamide (Step 5 of Example 73) and (2-oxabicyclo[2.1.1]hexan-1-yl)methane-d 2 -amine was used as the starting material, and the title compound (5.0 mg, white solid) was obtained through similar steps. MS (ESI): m / z 508.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.98(s,1H),8.99(t,J=6.0Hz,1H),8.60(s,1H),7.28(d,J=6.4Hz,1H),7.21-7.13(m,2H),6.73(s,1H),6.38(s,2H),6 .23(s,1H),4.58(d,J=6.0Hz,2H),3.81(s,2H),3.61(s,2H),2.83(t,J=3.2Hz,1H),1.71-1.69(m,2H),1.31-1.30(m,2H).

[1007] Embodiment 94

[1008] N-((5-Fluoro-2-((((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl-d 2 )amino)methyl)-1H-indol-6-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxa[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[1009]

[1010] Referring to the synthesis method of step 3 of Example 85, N-((5-fluoro-2-formyl-1H-indol-6-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxo[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide and (3-fluorobicyclo[1.1.1]pentan-1-yl)methane-d 2-amine as the starting material, the title compound (2.4 mg, white solid) was obtained through similar steps. MS (ESI): m / z 524.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.99(s,1H),9.02(t,J=6.4Hz,1H),8.63(s,1H),8.43(s,2H),7.28(d,J=6.4Hz,1H),7.22(s,1H),7.19(d,J= 11.2Hz,1H),6.66(s,1H),6.22(s,1H),4.59-4.56(m,4H),4.48-4.47(m,2H),3.79(s,2H),1.92(d,J=2.8Hz,6H).

[1011] Embodiment 95

[1012] N-((2-((((3-Fluorobicyclo[1.1.1]pentan-1-yl)methyl-d 2 )amino)methyl)-1H-indol-6-yl)methyl)-9-oxo-2,3-dihydro-9H-[1,4]dioxa[2',3':4,5]pyrido[1,2-a]pyrimidine-7-carboxamide

[1013]

[1014] Referring to the synthesis method of Example 77, intermediate 8 and (3-fluorobicyclo[1.1.1]pentane-1-yl)methane-d 2 -amine as the starting material, the title compound (21.3 mg, white solid) was obtained through similar steps. MS (ESI): m / z 506.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.87(s,1H),9.06(t,J=6.0Hz,1H),8.61(s,1H),7.37(d,J=8.0Hz,1H),7.29(s,1H),7.19(s,1H),6.95(d,J= 8.0Hz,1H),6.67(s,1H),6.20(s,1H),4.56-4.53(m,4H),4.47-4.46(m,2H),3.80(s,2H),1.92(d,J=2.8Hz,6H).

[1015] The control drug STC-15 used in the present invention is prepared according to the method of Example 2 of patent WO2021111124. Test Example 1: METTL3 / 14 methyltransferase activity test

[1016] The final starting concentration of the compound was 10uM, and 3-fold gradient dilution was performed for a total of 10 concentrations. 100nL of compound was transferred to a 384-well plate and centrifuged at 1000RPM. 2.5μL of METTL3 / 14 (active motif, Cat No.31570) was added to the test well and incubated at 25°C for 10min. 2.5μL of METTL3-Biotin & SAM (GenScript) was added to the test well and incubated at 25°C for 60min. 2.5μL of YTHDF1 (active motif, Cat No.31608) was added to the test well and centrifuged at 1000RPM. 2.5μL of Streptavidin-Tb (Perkin Elmer Cat No.61SATLB) & Flag-mede (Perkin Elmer CatNo.61FG2DLA) was added to the test well and centrifuged at 1000RPM. Incubated at 25°C for 60min. The HTRF was measured using a plate reader. The results of each compound are shown in Table 1, where A+ represents <10 nM, A represents 10-100 nM, B represents 100-1000 nM, and C represents >1000 nM.

[1017] Table 1

[1018]

[1019]

[1020] Test Example 2: Kasumi-1 cell inhibitory activity

[1021] The compound to be tested was dissolved in DMSO to prepare a solution with a final concentration of 250×. The starting concentration was 10μM, and the solution was diluted 3 times for a total of ten concentration points. 4μL of the compound solution was added to 96μL of the cell culture medium to dilute it to 10× the final concentration. On the first day, Kasumi-1 cells (purchased from Precedo) were suspended in the cell culture medium at an ideal density, 90μL of the cell suspension was added to a 96-well plate, and 10μL of the 10× compound solution was added for incubation. The final DMSO concentration in each well was 0.4%. 37℃, 5% CO 2 Incubate for 5 days. After 5 days, place the test plate at room temperature before measurement and add 50 μL Reagent (purchased from Promega, catalog number G7573), mixed on a shaker for 2 minutes to lyse the cells, incubated at room temperature for 10 minutes to stabilize the fluorescent signal, recorded the luminescence value using Paradigm, and fitted the reaction-concentration curve using Graphpad Prism 8.0 to calculate the IC 50The results of each compound are shown in Table 2, where A represents <100 nM, B represents 100-1000 nM, and C represents >1000 nM.

[1022] Calculation formula: Inhibition rate (Inh%) = 100-(RLU compound-RLU blank) / (RLU control-RLU blank)*100%

[1023] Table 2

[1024]

[1025]

[1026] Test Example 3: Pharmacokinetic Test in Rat

[1027] 3.1 Experimental animals: Male SD rats, weighing 190-230 g, 3 rats / compound

[1028] 3.2 Experimental design: All animals were fasted overnight (10-14 hours) the day before administration and fed 4 hours after administration. Intravenous administration, drug solvent: 5% DMA + 5% Solutol + 90% Saline (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline), dosage: 2 mg / kg, administration concentration: 1 mg / mL. Blood was collected from the jugular vein at 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, and 24h after administration. About 0.25mL of blood was collected from each sample, anticoagulated with EDTA-K2, placed on ice after collection, and centrifuged within 1h to separate plasma (6000g, 3min, 2-8℃). Plasma samples were stored in a -80℃ refrigerator before analysis.

[1029] 3.3 Result analysis: The collected samples were tested using the LC-MS / MS method. The blood drug concentration data at different time points were used to calculate the pharmacokinetic parameters using Phoenix WinNonlin 8.2.0 to obtain the in vivo clearance rate CL and AUC 0-t The average value of .

[1030] Table 3 CL and AUC of test compounds injected intravenously in rats

[1031] Test compound CL(mL / kg / min) <![CDATA[AUC 0-t (mg / mL)]]> STC-15 40.3 808 Embodiment 24 15.3 2179 Embodiment 25 22.7 1459 Embodiment 73 23.0 1443 Embodiment 88 19.1 1713 Embodiment 89 28.1 1214 Embodiment 94 28.5 1125

Claims

1. A compound of formula (I): or a deuterated substance, a stereoisomer, a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof; in, Ring A is a 5-15 membered heterocyclic group, preferably a 5-6 membered monocyclic heterocyclic group, a 9-10 membered bicyclic heterocyclic group or a 13-14 membered tricyclic heterocyclic group, containing heteroatoms selected from O, N, S and P, and optionally 1, 2 or 3 atoms are substituted with oxo; L1 is m is selected from 0, 1, 2, 3, 4 or 5; R1 is oxo, or R1 is -ZR a ; Z is selected from chemical bonds, C 1-3 Alkylene, -NH-C 1-3 Alkylene, -C(=O)-, -O-, -S-, -S(=O)-, -SO2-; R a Selected from halogen, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NH2, nitro, aldehyde, -NH-C 1-3 Alkyl, -N(-C 1-3 alkyl)2, optionally substituted 3-6 membered cycloalkyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted phenyl, optionally substituted 5-7 membered heteroaryl; When two R1s are simultaneously substituted on the same carbon atom of ring A, the two R1s can form an optionally substituted 3-6-membered cycloalkyl or a 3-6-membered heterocyclic group containing 1-2 heteroatoms selected from N, O, and S with the carbon atom to which they are attached; Ring B is an 8-10 membered heterocyclic group, preferably an 8-10 membered heteroaryl group; n, p are selected from 0, 1, 2 or 3; R 2a , R 2b are independently selected from H, halogen, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, nitro, aldehyde, or R 2a , R 2b Together with the carbon atom to which it is attached, it forms a 3-6 membered cycloalkyl group or a 3-6 membered heterocycloalkyl group containing 1-2 N, O, or S heteroatoms; R3 is selected from H, halogen, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, nitro, aldehyde groups; L2 is selected from C 1-3 Alkylene, halogenated C 1-3 Alkylene; R4 is R 5a , R 5b is selected from H or -L3-R6, L3 is selected from a chemical bond, C 1-3 Alkylene, halogenated C 1-3 Alkylene, R6 is selected from C 1-6 Alkyl, C 2-6 alkynyl, optionally substituted phenyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 4-8 membered heterocycloalkyl, or R 5a , R 5b Together with the N atom to which it is attached, it forms an optionally substituted 4-10 membered heterocyclic group, preferably a 4-10 membered heterocyclic alkyl group.

2. The compound according to claim 1, or its deuterated form, stereoisomer, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate, characterized in that: The ring A is selected from the following: i) The ring C is selected from a 5-7 membered heterocyclic group containing 1-3 heteroatoms selected from N, O, and S; more preferably The X1 and X2 are independently selected from O, S, CH2, S(=O)2, C(=O), and the X3 is selected from CH2, NH or a chemical bond; ii) The ring D is selected from a 6-8 membered heterocyclic group containing 1-3 heteroatoms selected from N, O, and S, and Z1 is selected from N or CH; more preferably Z1 is selected from N or CH, Z2 and Z3 are independently selected from CH2, NH, O, S; iii) Ring A is preferably: m is selected from 0, 1, 2 or 3; R1 is oxo, or R1 is -ZR a ; Z is selected from a chemical bond, a methylene group, -NH-CH2-, -C(=O)-, -O-, -S-, -S(=O)-, -SO2-; R a Selected from halogen, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NH2, nitro, aldehyde, -NH-C 1-3 Alkyl, -N(-C 1-3 alkyl)2, optionally substituted by 1, 2 or 3 R b Substituted: 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-7 membered heteroaryl; R b Selected from halogen, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NH2, nitro, aldehyde, -NH-C 1-3 Alkyl, -N(-C 1-3 Alkyl) 2, preferably F, methyl, methoxy, amino, methylamino; R a Preferably F, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, amino, methylamino, optionally substituted by 1, 2 or 3 R b Substituted with the following groups: Phenyl, More preferably, F, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, amino, methylamino, Phenyl, The R1 is more preferably F, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, amino, methylamino, When two R1s are simultaneously substituted on the same carbon atom of ring A, the two R1s can form with the carbon atom to which they are connected an optionally substituted 3-6 membered cycloalkyl group or a 3-6 membered heterocyclic group containing 1-2 heteroatoms selected from N, O, and S, preferably a cyclopropyl, cyclobutyl, oxirane, oxetanyl, and azetidinyl group.

3. The compound according to claim 2, or its deuterated form, stereoisomer, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate, characterized in that: The ring A and R1 form the following structure:

4. The compound according to claim 1, or its deuterated form, stereoisomer, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate, characterized in that: The ring B is selected from: Ring B is preferably: n is selected from 0, 1, 2 or 3; R3 is selected from H, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy is preferably H, F, methyl, trifluoromethyl, difluoromethyl, methoxy, or trifluoromethoxy.

5. The compound according to claim 1, or its deuterated form, stereoisomer, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate, characterized in that: L2 is selected from methylene and ethylene; The R4 is R 5a , R 5b is selected from H or -L3-R6, L3 is selected from a chemical bond, methylene, ethylene, propylene, R6 is selected from the following groups optionally substituted by 1, 2 or 3 R7: ethynyl, isopropyl, tert-butyl, phenyl, or R 5a , R 5b Together with the N atom to which it is attached, it forms a group optionally substituted with 1, 2 or 3 R7 The R7 is selected from halogen, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, =CF2, hydroxyl C 1-3 Alkyl, preferably F, hydroxy, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, =CF2, hydroxymethyl.

6. The compound according to claim 5, or its deuterated form, stereoisomer, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate, characterized in that: R4 is selected from 7. The compound according to claim 5, or its deuterated form, stereoisomer, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate, characterized in that: The L2 and R4 form the following structure:

8. The compound according to claim 1, or its deuterated form, stereoisomer, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate, characterized in that: L1 is 9. The compound according to claim 1, or its deuterated form, stereoisomer, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate, characterized in that: n, p are 1; R 2a , R 2b , R3 is H.

10. The compound according to claim 1, or its deuterated substance, stereoisomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, characterized in that: It has the structure of formula (II): in, Ring A is selected from the following: i) The ring C is selected from a 5-7 membered heterocyclic group containing 1-3 heteroatoms selected from N, O, and S; more preferably The X1 and X2 are independently selected from O, S, CH2, S(=O)2, C(=O), and the X3 is selected from CH2, NH or a chemical bond; ii) The ring D is selected from a 6-8 membered heterocyclic group containing 1-3 heteroatoms selected from N, O, and S, and Z1 is selected from N or CH; more preferably Z1 is selected from N or CH, Z2 and Z3 are independently selected from CH2, NH, O, S; m is selected from 0, 1, 2 or 3; R1 is oxo, or R1 is -ZR a ; Z is selected from chemical bonds, C 1-3 Alkylene, -NH-C 1-3 Alkylene, -C(=O)-, -O-, -S-, -S(=O)-, -SO2-, preferably methylene, -NH-CH2-, -C(=O)-, -SO2-; R a Selected from halogen, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NH2, nitro, aldehyde, -NH-C 1-3 Alkyl, -N(-C 1-3 alkyl)2, optionally substituted by 1, 2 or 3 R b Substituted: 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-7 membered heteroaryl; R b Selected from halogen, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NH2, nitro, aldehyde, -NH-C 1-3 Alkyl, -N(-C 1-3 Alkyl) 2, preferably F, methyl, methoxy, amino, methylamino; R a Preferred are F, methyl, amino, methylamino; When two R1s are simultaneously substituted on the same carbon atom of ring A, the two R1s can form an optionally substituted 3-6-membered cycloalkyl or a 3-6-membered heterocyclic group containing 1-2 heteroatoms selected from N, O, and S with the carbon atom to which they are attached; L1 is Ring B is selected from: n is selected from 0, 1, 2 or 3; R3 is independently selected from halogen, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy; R 5a , R 5b is selected from H or -L3-R6; L3 is selected from a chemical bond, C 1-3 Alkylene, halogenated C 1-3 Alkylene, preferably chemical bond, methylene, R6 is selected from C 1-6 Alkyl, C 2-6 alkynyl, optionally substituted phenyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 4-8 membered heterocycloalkyl, preferably ethynyl, isopropyl, tert-butyl, optionally substituted by 1, 2 or 3 R7: phenyl, or R 5a , R 5b Together with the N atom to which it is attached, it forms an optionally substituted 4-10 membered heterocyclic group, preferably a 4-10 membered heterocyclic alkyl group, preferably the following group optionally substituted by 1, 2 or 3 R7: The R7 is selected from halogen, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, =CF2, hydroxyl C 1-3 Alkyl, preferably F, hydroxy, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, =CF2, hydroxymethyl.

11. The compound according to claim 10, or its deuterated substance, stereoisomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, characterized in that: Ring A is selected from: Best More preferred R1 is oxo, or R1 is -ZR a ; Z is selected from a chemical bond; R a Selected from halogen, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy; preferably F, methyl.

12. The compound according to claim 10 or 11, or a deuterated substance, stereoisomer, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate thereof, characterized in that: L1 is More preferably: Ring B is selected from Best R3 is independently selected from F, Cl, methyl, methoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy; more preferably: R6 is selected from the following groups optionally substituted by 1, 2 or 3 R7: 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O, S, thienyl; preferably R7 is selected from halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, =CF2, preferably F, hydroxy, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, =CF2, more preferably F, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy; or more preferably: R 5a , R 5b The N atom to which it is connected forms the following groups which are preferably optionally substituted by 1, 2 or 3 R7: 4-10 membered heterocycloalkyl containing 1-3 selected from N, O, S, 4-10 membered heterocyclyl containing 1-3 selected from N, O, S; preferably 4-10 membered heterocycloalkyl containing 1-3 selected from N, O, S, More preferred R7 is selected from halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, =CF2, preferably F, hydroxy, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, =CF2, more preferably F, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy.

13. The compound according to claim 10, or its deuterated substance, stereoisomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, characterized in that: It has the structure of formula (III): r and q are selected from 0, 1 or 2.

14. The compound according to claim 10, or its deuterated form, stereoisomer, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate, characterized in that: The deuterated site is located at the C atom marked with "*", "**" or L3; more preferably, the deuterated site is located at L3.

15. The compound according to claim 1, or its deuterated substance, stereoisomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, characterized in that: Includes the following compounds:

16. A pharmaceutical composition comprising the compound according to any one of claims 1 to 15, its deuterated substance, stereoisomer or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier thereof.

17. Use of the compound according to any one of claims 1 to 15, its deuterated product, stereoisomer or pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 16 in the preparation of a medicament for treating and / or preventing a disease associated with METTL3.

18. The use according to claim 17, characterized in that: The METTL3-related disease is selected from autoimmune diseases, neurological diseases, infectious diseases, and tumors.

19. The use according to claim 18, characterized in that: The METTL3-related disease is selected from AML, myeloid leukemia, solid tumors such as hepatocellular carcinoma, colorectal cancer, and prostate cancer.

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