Pyridine-2(1H)-one PRMT5-MTA inhibitor, and pharmaceutical composition and use thereof

Abstract

Provided is a type of compound acting as a PRMT5-MTA inhibitor, specifically a compound represented by formula (I), a stereoisomer, a deuterate, a solvate, and a pharmaceutically acceptable salt thereof, the symbols being as defined in the text. Further provided are a pharmaceutical composition comprising the compound, and a use thereof in treating cancer.

Description

A pyridin-2(1H)-one PRMT5-MTA inhibitor, its pharmaceutical composition and its application Technical field:

[0001] The present invention belongs to the field of medicine, and specifically relates to a class of pyridin-2(1H)-one compounds, their stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, pharmaceutical compositions containing the same, and their use in preparing drugs for treating PRMT5-mediated related diseases. Background technology:

[0002] Protein arginine methyltransferases (PRMTs) methylate histones and non-histone proteins, thereby regulating biological processes such as gene transcription, signal transduction, protein stability, cell proliferation, differentiation, apoptosis, and tumor formation. Currently, 11 PRMT family members have been identified, which can be divided into types I, II, and III based on the manner in which they catalyze arginine methylation. PRMT5 belongs to type II, catalyzing symmetric dimethylation.

[0003] PRMT5 catalyzes the transfer of a methyl group from S-adenosylmethionine (SAM) to the guanidino N atom on the substrate arginine, causing symmetric dimethylation (SDMA). It plays an important role in regulating various cellular processes, such as transcription, RNA splicing, translation, and DNA damage response. PRMT5 protein is overexpressed in various cancer types, including B and T cell lymphomas, metastatic melanoma, neuroblastoma, glioblastoma, ovarian cancer, and breast cancer. Growing evidence indicates that it plays an important role in tumor development and progression. Based on this, PRMT5 inhibitors have become a hot topic in the research and development of cancer treatment drugs.

[0004] CDKN2A is a tumor suppressor gene located on human chromosome 9p21. Loss of CDKN2A occurs in approximately 10-15% of all human cancers, including 53% of glioblastomas and 26% of pancreatic cancers and other tumor types (KJ Mavrakis et al., Science 10.1126 / science.aad5944(2016)). The gene for the metabolic enzyme 5'-methylthioadenonine phosphorylase (MTAP) is also located on chromosome 9p21. Because it is very close to CDKN2A, tumors with CDKN2A gene deletion often have MTAP loss. Therefore, MTAP is also one of the most frequently mutated genes in tumors.

[0005] In 2016, a paper published in Science revealed for the first time that MTAP deficiency and PRMT5 are synthetically lethal (KJMavrakis et al., Science 10.1126 / science.aad5944(2016)). MTAP deficiency causes the accumulation of its substrate, methylthioadenosine (MTA), an analog of SAM that selectively inhibits PRMT5 activity. MTA competes with SAM to bind to PRMT5, forming a PRMT5-MTA complex. By enhancing inhibition of the PRMT5-MTA complex, PRMT5 activity can be specifically inhibited in tumor cells, while the inhibitory effect on PRMT5 activity in normal cells is weak.

[0006] A large number of PRMT5 small molecule inhibitors have been reported. Depending on whether the compounds occupy the SAM binding site, they can be divided into two categories: SAM non-competitive inhibitors and SAM competitive inhibitors. SAM non-competitive inhibitors occupy the substrate binding site and compete with the substrate, while SAM competitive inhibitors occupy the SAM binding site.

[0007] While non-competitive SAM inhibitors can effectively inhibit the growth of many cell lines in vitro, they lack tumor cell selectivity and their ability to inhibit tumor cells is independent of the MTAP status in the cells, which may lead to potential clinical toxicity. In cancer cells lacking MTAP, PRMT5-MTA inhibitors selectively affect only tumor cells, sparing healthy cells. This provides a therapeutic safety window. Therefore, designing a small molecule that synergizes with MTA to bind to PRMT5 and specifically binds to the PRMT5·MTA complex, thereby inhibiting tumor cell growth, is an effective approach to improving the selectivity of PRMT5 inhibitors.

[0008] Summary of the Invention

[0009] The present invention provides a compound represented by formula (I), its stereoisomers, deuterated substances, solvates, and pharmaceutically acceptable salts:

[0010] in,

[0011] represents any single or double bond allowed by the valence;

[0012] X1 and X2 are independently selected from NR X , S, N, CR X1 ;

[0013] R X 、R X1Each independently selected from H, halogen, -C1~C6 alkyl, deuterium-substituted -C1~C6 alkyl, halogen-substituted -C1~C6 alkyl, -C(O)-C1~C3 alkyl;

[0014] X3 is selected from N, CR 3 ;

[0015] R 3 Selected from H, halogen, -C1-C6 alkyl, -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2;

[0016] X4 is selected from N, CR 5 ;

[0017] R 7 Selected from H, halogen, -CN, -NO2, -NH2, -C1~C6 alkyl, deuterium-substituted -C1~C6 alkyl, halogen-substituted -C1~C6 alkyl;

[0018] L is selected from a bond,

[0019] n is independently selected from 0, 1, and 2;

[0020] R 1 、R 5 Each of the following groups is independently selected from hydrogen, halogen, -C1-C6 alkyl, -C2-C6 alkenyl, halogen-substituted -C1-C6 alkyl, -O-C1-C6 alkyl, 3-6-membered carbocyclic ring, 5-10-membered heteroaromatic ring, and 6-10-membered aromatic ring; wherein the carbocyclic ring, heterocyclic ring, heteroaromatic ring, and aromatic ring may be optionally substituted with one or more halogen, -C1-C3 alkyl, halogen-substituted -C1-C3 alkyl, and -O-C1-C3 alkyl;

[0021] R 4 、R 6 are independently selected from hydrogen, -C1~C6 alkyl, halogen-substituted -C1~C6 alkyl, -C0~C2 alkylene-(3-10 membered carbocyclic ring), -C0~C2 alkylene-(4-11 membered heterocyclic ring), -C0~C2 alkylene-(6-10 membered aromatic ring) or -C0~C2 alkylene-(5-10 membered heteroaromatic ring); wherein the alkyl, alkylene, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring may be optionally replaced by one or more R 41 replace;

[0022] R 41Selected from hydrogen, halogen, amino, nitro, cyano, oxo, -NH2, -C(O)NH2, -C(O)H, -C(O)OH, -C1~C6 alkyl, -C2~C6 alkenyl, -C2~C6 alkynyl, halogen-substituted -C1~C6 alkyl, halogen-substituted -C2~C6 alkenyl, halogen-substituted -C2~C6 alkynyl, -O-C1~C6 alkyl;

[0023] R 2 is selected from a 3-10 membered carbocyclic ring, a 4-11 membered heterocyclic ring, a 6-10 membered aromatic ring or a 5-10 membered heteroaromatic ring; wherein the carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring may be optionally replaced by one or more R 21 replace;

[0024] R 21 Selected from hydrogen, halogen, nitro, cyano, oxo, -NH2, -C(O)NH2, -C(O)H, -C(O)OH, -C1~C6 alkyl, -C2~C6 alkenyl, -C2~C6 alkynyl, halogen-substituted -C1~C6 alkyl, halogen-substituted -C2~C6 alkenyl, halogen-substituted -C2~C6 alkynyl, -O-C1~C6 alkyl, -O-C2~C6 alkenyl, -O-C2~C6 alkynyl, -O-halogen substituted C1~C6 alkyl, -O-halogen substituted C2~C6 alkenyl, -O-halogen substituted C2~C6 alkynyl, -O-(3-6 membered carbocyclic ring), 3-10 membered carbocyclic ring, 4-11 membered heterocyclic ring, 6-10 membered aromatic ring or 5-10 membered heteroaromatic ring; wherein the carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring may be optionally replaced by one or more R c replace;

[0025] R c Selected from hydrogen, halogen, nitro, cyano, oxo, -NH2, -C(O)NH2, -C(O)H, -C(O)OH, -C1~C6 alkyl, -C2~C6 alkenyl, -C2~C6 alkynyl, halogen-substituted-C1~C6 alkyl, halogen-substituted-C2~C6 alkenyl, halogen-substituted-C2~C6 alkynyl, -O-C1~C6 alkyl, -O-C2~C6 alkenyl, -O-C2~C6 alkynyl, -O-halogen-substituted C1~C6 alkyl, -O-halogen-substituted C2~C6 alkenyl or -O-halogen-substituted C2~C6 alkynyl.

[0026] In certain specific embodiments, the compound of formula (I), its stereoisomers, deuterated substances, solvates, and pharmaceutically acceptable salts are represented by formula (IIa) or formula (IIb):

[0027] Among them, R 1 、R 2 、R 7 、RX 、R X1 , L, X3, and X4 are as described in formula (I).

[0028] In certain specific embodiments, the compound of formula (I), its stereoisomers, deuterated forms, solvates, and pharmaceutically acceptable salts are represented by formula (IIc), formula (IId), formula (IIe), or formula (IIf):

[0029] Among them, R 1 、R 2 、R 3 、R 7 、R X 、R X1 , L, and X4 are as described in formula (I).

[0030] In certain specific embodiments, the compound represented by formula (I), its stereoisomers, deuterated substances, solvates, and pharmaceutically acceptable salts are represented by formula (Ia):

[0031] in,

[0032] represents any single or double bond allowed by the valence;

[0033] R 1 、R 2 、R 5 , X1, X2 and L are as described in formula (I).

[0034] In certain specific embodiments, the present invention relates to a compound of Formula (I), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), or Formula (IIf), stereoisomers, deuterated forms, solvates, or pharmaceutically acceptable salts thereof.

[0035] Among them, R 7 Selected from H, halogen, -CN, -NO2, -NH2, -C1~C3 alkyl, deuterium-substituted -C1~C3 alkyl, halogen-substituted -C1~C3 alkyl.

[0036] In certain specific embodiments, the present invention relates to a compound of Formula (I), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), or Formula (IIf), stereoisomers, deuterated forms, solvates, or pharmaceutically acceptable salts thereof.

[0037] Among them, R 7Selected from H, F, Cl, Br, I, -CN, -NO2, -NH2, methyl, ethyl, propyl, isopropyl, -CF3, -CH2F, -CHF2, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2D, -CH2CD3.

[0038] In certain specific embodiments, the present invention relates to a compound of Formula (I), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), or Formula (IIf), stereoisomers, deuterated forms, solvates, or pharmaceutically acceptable salts thereof.

[0039] Among them, R 3 Selected from H, halogen, -C1~C3 alkyl, -C(O)NH2, -C(O)NH(C1~C3 alkyl), -C(O)N(C1~C3 alkyl)2.

[0040] In certain specific embodiments, the present invention relates to a compound of Formula (I), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), or Formula (IIf), stereoisomers, deuterated forms, solvates, or pharmaceutically acceptable salts thereof.

[0041] Among them, R 3 Selected from H, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2.

[0042] In certain specific embodiments, the present invention relates to a compound of Formula (I), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), or Formula (IIf), stereoisomers, deuterated forms, solvates, or pharmaceutically acceptable salts thereof.

[0043] Wherein, X4 is selected from N, CR 5 ;

[0044] R 5 They are independently selected from hydrogen, halogen, -C1~C3 alkyl, -C2~C4 alkenyl, halogen-substituted -C1~C3 alkyl, -O-C1~C3 alkyl, 3-4-membered carbocyclic ring, 5-6-membered heteroaromatic ring or 6-10-membered aromatic ring; wherein the carbocyclic ring, heterocyclic ring, heteroaromatic ring and aromatic ring may be optionally substituted by one or more halogen, -C1~C3 alkyl, halogen-substituted -C1~C3 alkyl and -O-C1~C3 alkyl.

[0045] In certain specific embodiments, the present invention relates to a compound of Formula (I), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), Formula (IIf), or Formula (Ia), stereoisomers, deuterated forms, solvates, or pharmaceutically acceptable salts thereof.

[0046] Among them, R X 、R X1 Each is independently selected from H, halogen, -C1~C3 alkyl, deuterium-substituted -C1~C3 alkyl, halogen-substituted -C1~C3 alkyl, and -C(O)CH3.

[0047] In certain specific embodiments, the present invention relates to a compound of Formula (I), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), Formula (IIf), or Formula (Ia), stereoisomers, deuterated forms, solvates, or pharmaceutically acceptable salts thereof.

[0048] Among them, R X 、R X1 Each is independently selected from H, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, -CF3, -CH2F, -CHF2, -CH2CH2F, -CH2CHF2, -C(O)CH3, -CH2CF3, -CD3, -CH2D, -CH2CD3.

[0049] In certain specific embodiments, the present invention relates to a compound of Formula (I), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), Formula (IIf), or Formula (Ia), stereoisomers, deuterated forms, solvates, or pharmaceutically acceptable salts thereof.

[0050] Among them, R 1 、R 5 They are independently selected from hydrogen, halogen, -C1~C3 alkyl, -C2~C4 alkenyl, halogen-substituted -C1~C3 alkyl, -O-C1~C3 alkyl, 3-4-membered carbocyclic ring, 5-6-membered heteroaromatic ring or 6-10-membered aromatic ring; wherein the carbocyclic ring, heterocyclic ring, heteroaromatic ring and aromatic ring may be optionally substituted by one or more halogen, -C1~C3 alkyl, halogen-substituted -C1~C3 alkyl and -O-C1~C3 alkyl.

[0051] In certain specific embodiments, the compound represented by formula (I), its stereoisomers, deuterated substances, solvates, and pharmaceutically acceptable salts are represented by formula (Ia):

[0052] in,

[0053] X1 and X2 are independently selected from NH, S, N, CH;

[0054] represents any single or double bond allowed by the valence;

[0055] L is selected from a bond,

[0056] n is independently selected from 0, 1, and 2;

[0057] R 1 、R 5 are independently selected from hydrogen, halogen, -C1~C6 alkyl, halogen-substituted -C1~C6 alkyl, -C2~C6 alkenyl-O-C1~C6 alkyl, 3-6 membered carbocyclic ring, 5-10 membered heteroaromatic ring, 6-10 membered aromatic ring; wherein the carbocyclic ring, heterocyclic ring, heteroaromatic ring, aromatic ring may be optionally substituted with one or more halogen, -C1~C3 alkyl, halogen-substituted -C1~C3 alkyl, -O-C1~C3 alkyl; for example, R 1 、R 5 Each is independently selected from hydrogen, halogen, -C1~C6 alkyl, and halogen-substituted -C1~C6 alkyl;

[0058] R 4 、R 6 are independently selected from hydrogen, -C1~C6 alkyl, halogen-substituted -C1~C6 alkyl, -C0~C2 alkylene-(3-10 membered carbocyclic ring), -C0~C2 alkylene-(4-11 membered heterocyclic ring), -C0~C2 alkylene-(6-10 membered aromatic ring) or -C0~C2 alkylene-(5-10 membered heteroaromatic ring); wherein the alkyl, alkylene, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring may be optionally replaced by one or more R 41 replace;

[0059] R 41 Selected from hydrogen, halogen, amino, nitro, cyano, oxo, -NH2, -C(O)NH2, -C(O)H, -C(O)OH, -C1~C6 alkyl, -C2~C6 alkenyl, -C2~C6 alkynyl, halogen-substituted -C1~C6 alkyl, halogen-substituted -C2~C6 alkenyl, halogen-substituted -C2~C6 alkynyl, -O-C1~C6 alkyl;

[0060] R 2 is selected from a 3-10 membered carbocyclic ring, a 4-11 membered heterocyclic ring, a 6-10 membered aromatic ring or a 5-10 membered heteroaromatic ring; wherein the carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring may be optionally replaced by one or more R 21 replace;

[0061] R 21Selected from hydrogen, halogen, nitro, cyano, oxo, -NH2, -C(O)NH2, -C(O)H, -C(O)OH, -C1~C6 alkyl, -C2~C6 alkenyl, -C2~C6 alkynyl, halogen-substituted -C1~C6 alkyl, halogen-substituted -C2~C6 alkenyl, halogen-substituted -C2~C6 alkynyl, -O-C1~C6 alkyl, -O-C2~C6 alkenyl, -O-C2~C6 alkynyl, -O-halogen substituted C1~C6 alkyl, -O-halogen substituted C2~C6 alkenyl, -O-halogen substituted C2~C6 alkynyl, -O-(3-6 membered carbocyclic ring), 3-10 membered carbocyclic ring, 4-11 membered heterocyclic ring, 6-10 membered aromatic ring or 5-10 membered heteroaromatic ring; wherein the carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring may be optionally replaced by one or more R c replace;

[0062] R c Selected from hydrogen, halogen, nitro, cyano, oxo, -NH2, -C(O)NH2, -C(O)H, -C(O)OH, -C1~C6 alkyl, -C2~C6 alkenyl, -C2~C6 alkynyl, halogen-substituted-C1~C6 alkyl, halogen-substituted-C2~C6 alkenyl, halogen-substituted-C2~C6 alkynyl, -O-C1~C6 alkyl, -O-C2~C6 alkenyl, -O-C2~C6 alkynyl, -O-halogen-substituted C1~C6 alkyl, -O-halogen-substituted C2~C6 alkenyl or -O-halogen-substituted C2~C6 alkynyl.

[0063] In certain specific embodiments, the compound of formula (Ia), its stereoisomers, deuterated substances, solvates, and pharmaceutically acceptable salts are as shown in formula (Ie):

[0064] Among them, R 1 、R 2 、R 5 , L is as described in formula (Ia).

[0065] In certain specific embodiments, the compound of formula (Ia), its stereoisomers, deuterated substances, solvates, and pharmaceutically acceptable salts are represented by formula (Ib), formula (Ic), or formula (Id):

[0066] Among them, R 1 , L, R 2 As described in formula (Ia).

[0067] In certain specific embodiments, the present invention relates to a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), or Formula (IIf), stereoisomers, deuterated forms, solvates, or pharmaceutically acceptable salts thereof, wherein:

[0068] R 2 is selected from a 3-7 membered carbocyclic ring, a 4-6 membered monocyclic heterocyclic ring, a 9-11 membered fused heterocyclic ring, a 6-10 membered aromatic ring or a 5-10 membered heteroaromatic ring; wherein the carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring may be optionally replaced by one or more R 21 replace;

[0069] R 21 Selected from hydrogen, halogen, nitro, cyano, oxo, -NH2, -C(O)NH2, -C(O)H, -C(O)OH, -C1~C3 alkyl, -C2~C3 alkenyl, -C2~C3 alkynyl, halogen-substituted -C1~C3 alkyl, halogen-substituted -C2~C3 alkenyl, halogen-substituted -C2~C3 alkynyl, -O-C1~C3 alkyl, -O-C2~C3 alkenyl, -O-C2~C3 alkynyl, -O-halogen substituted C1~C3 alkyl, -O-halogen substituted C2~C3 alkenyl, -O-halogen substituted C2~C3 alkynyl, -O-(3-6 membered carbocyclic ring), 3-10 membered carbocyclic ring, 4-11 membered heterocyclic ring, 6-10 membered aromatic ring or 5-10 membered heteroaromatic ring; wherein the carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring may be optionally replaced by one or more R c replace;

[0070] R c Selected from hydrogen, halogen, nitro, cyano, oxo, -NH2, -C(O)NH2, -C(O)H, -C(O)OH, -C1~C3 alkyl, -C2~C4 alkenyl, -C2~C4 alkynyl, halogen-substituted -C1~C3 alkyl, halogen-substituted -C2~C4 alkenyl, halogen-substituted -C2~C4 alkynyl, -O-C1~C3 alkyl.

[0071] In certain specific embodiments, the present invention relates to compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), or Formula (IIf), stereoisomers, deuterated forms, solvates, or pharmaceutically acceptable salts thereof, wherein R 2 Selected from For example, selected

[0072] Among them, R 21 is selected from hydrogen, halogen, nitro, cyano, oxo, -NH2, -C(O)NH2, -C(O)H, -C(O)OH, -C1~C3 alkyl, halogen-substituted -C1~C3 alkyl, -O-C1~C3 alkyl, -O-halogen-substituted C1~C3 alkyl, -O-(3-6 membered carbocyclic ring), 3-10 membered carbocyclic ring, 4-11 membered heterocyclic ring, 6-10 membered aromatic ring or 5-10 membered heteroaromatic ring; wherein the carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring may be optionally replaced by one or more R c replace;

[0073] y = 0, 1, 2, or 3;

[0074] R c Selected from hydrogen, halogen, nitro, cyano, oxo, -NH2, -C(O)NH2, -C(O)H, -C(O)OH, -C1~C3 alkyl, -C2~C4 alkenyl, -C2~C4 alkynyl, halogen-substituted -C1~C3 alkyl, halogen-substituted -C2~C4 alkenyl, halogen-substituted -C2~C4 alkynyl, -O-C1~C3 alkyl.

[0075] In certain specific embodiments, the present invention relates to a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), or Formula (IIf), stereoisomers, deuterated forms, solvates, or pharmaceutically acceptable salts thereof, wherein:

[0076] R 21 Selected from hydrogen, halogen, -O-C1~C3 alkyl, -C1~C3 alkyl, -O-halogen substituted C1~C3 alkyl, For example, selected from hydrogen, halogen, -O-C1-C3 alkyl, -C1-C3 alkyl,

[0077] In certain specific embodiments, the present invention relates to compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), or Formula (IIf), stereoisomers, deuterated forms, solvates, or pharmaceutically acceptable salts thereof, wherein R c Selected from hydrogen, F, Cl, Br, nitro, cyano, oxo, -NH2, methyl, ethyl, isopropyl.

[0078] In certain specific embodiments, the present invention relates to a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), or Formula (IIf), stereoisomers, deuterated forms, solvates, or pharmaceutically acceptable salts thereof, wherein:

[0079] L is selected from a bond,

[0080] R 4 、R 6 are independently selected from hydrogen, -C1~C3 alkyl, halogen-substituted -C1~C3 alkyl, -C0~C1 alkylene-(3-6 membered carbocyclic ring), -C0~C1 alkylene-(4-6 membered heterocyclic ring), -C0~C1 alkylene-(6-10 membered aromatic ring), -C0~C1-(5-10 membered heteroaromatic ring); wherein the alkyl, alkylene, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring may be optionally replaced by one or more R 41 replace;

[0081] R 41 Selected from hydrogen, halogen, amino, nitro, cyano, oxo, -NH2, -C(O)NH2, -C(O)H, -C(O)OH, -C1~C3 alkyl, -C2~C3 alkenyl, -C2~C3 alkynyl, halogen-substituted -C1~C3 alkyl, halogen-substituted -C2~C6 alkenyl, halogen-substituted -C2~C6 alkynyl, -O-C1~C6 alkyl.

[0082] In certain specific embodiments, the present invention relates to compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), or Formula (IIf), stereoisomers, deuterated forms, solvates, or pharmaceutically acceptable salts thereof, wherein L is selected from a bond, Where a end and R 2 connect.

[0083] In certain specific embodiments, the present invention relates to compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), or Formula (IIf), stereoisomers, deuterated forms, solvates, or pharmaceutically acceptable salts thereof, wherein R 4 、R 6are independently selected from hydrogen, -C1~C3 alkyl, halogen-substituted -C1~C3 alkyl, 3-6-membered carbocyclic ring, -CH2-(3-6-membered carbocyclic ring), 4-6-membered heterocyclic ring, -CH2-(4-6-membered heterocyclic ring), 6-10-membered aromatic ring, -CH2-(6-10-membered aromatic ring), 5-10-membered heteroaromatic ring, -CH2-(5-10-membered heteroaromatic ring); wherein the alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring may be optionally replaced by one or more R 41 replace;

[0084] R 41 Selected from hydrogen, methyl, ethyl, isopropyl.

[0085] In certain specific embodiments, the present invention relates to compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), or Formula (IIf), stereoisomers, deuterated forms, solvates, or pharmaceutically acceptable salts thereof, wherein R 4 、R 6 are independently selected from benzene ring, -CH2-benzene ring, 5-6 membered heteroaromatic ring, -CH2-(5-6 membered heteroaromatic ring); wherein the benzene ring and heteroaromatic ring may be optionally replaced by one or more R 41 replace.

[0086] In certain specific embodiments, the present invention relates to compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), or Formula (IIf), stereoisomers, deuterated forms, solvates, or pharmaceutically acceptable salts thereof, wherein R 4 、R 6 are independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl,

[0087] In certain specific embodiments, the present invention relates to compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), or Formula (IIf), stereoisomers, deuterated forms, solvates, or pharmaceutically acceptable salts thereof, wherein L is selected from a bond,

[0088] In certain specific embodiments, the present invention relates to a compound of Formula (I), Formula (Ia), Formula (Ie), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), or Formula (IIf), stereoisomers, deuterated forms, solvates, or pharmaceutically acceptable salts thereof.

[0089] Among them, R 1 、R 5 are independently selected from hydrogen, halogen, -C1~C3 alkyl, halogen-substituted -C1~C3 alkyl, -C2~C4 alkenyl, halogen-substituted -C1~C3 alkyl, -O-C1~C3 alkyl, 3-4-membered carbocyclic ring, 5-6-membered heteroaromatic ring or 6-10-membered aromatic ring; wherein the carbocyclic ring, heterocyclic ring, heteroaromatic ring or aromatic ring may be optionally substituted with one or more halogen, -C1~C3 alkyl, halogen-substituted -C1~C3 alkyl or -O-C1~C3 alkyl; for example, R 1 、R 5 They are independently selected from hydrogen, halogen, -C1~C3 alkyl or halogen-substituted -C1~C3 alkyl.

[0090] In certain specific embodiments, the present invention relates to compounds of formula (Ib), formula (Ic) or formula (Id), stereoisomers, deuterated forms, solvates, pharmaceutically acceptable salts thereof,

[0091] Among them, R 1 Selected from hydrogen, halogen, -C1~C3 alkyl or halogen-substituted -C1~C3 alkyl.

[0092] In certain specific embodiments, the present invention relates to compounds of formula (Ib), formula (Ic) or formula (Id), stereoisomers, deuterated forms, solvates, pharmaceutically acceptable salts thereof,

[0093] where R 1 is selected from hydrogen, methyl, ethyl, Cl, Br, I, F, -CF3, -CH2F, -CHF2, -CH2CH2F, -CH2CHF2 or -CH2CF3.

[0094] In certain specific embodiments, the present invention relates to a compound of Formula (I), Formula (Ia), Formula (Ie), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), or Formula (IIf), stereoisomers, deuterated forms, solvates, or pharmaceutically acceptable salts thereof,

[0095] Among them, R 1 、R 5Each independently selected from hydrogen, methyl, ethyl, F, Cl, Br, I, -CF3, -CH2F, -CHF2, -CH2CH2F, -CH2CHF2, -CH2CF3, -Cl, -Br, -OCH3, Phenyl, For example, R 1 、R 5 Each is independently selected from hydrogen, methyl, ethyl, F, -CF3, -CH2F, -CHF2, -CH2CH2F, -CH2CHF2 or -CH2CF3.

[0096] In certain specific embodiments, the present invention relates to compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), or Formula (IIf), stereoisomers, deuterated forms, solvates, or pharmaceutically acceptable salts thereof, wherein R 21 Selected from H, F, Cl, Br, -CF3, -OCH3, -OCF3, methyl, ethyl, isopropyl,

[0097] In certain specific embodiments, the present invention relates to compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), or Formula (IIf), stereoisomers, deuterated forms, solvates, or pharmaceutically acceptable salts thereof, wherein R 2 Selected from For example, selected from

[0098] Furthermore, in certain specific embodiments, the present invention relates to compounds of formula (Ib), formula (Ic), and formula (Id), and their stereoisomers, deuterated substances, solvates, and pharmaceutically acceptable salts.

[0099] where R 1 is selected from hydrogen, halogen, -C1~C3 alkyl or halogen-substituted -C1~C3 alkyl;

[0100] L is selected from (For example, Where a end and R 2 connect);

[0101] R 4is selected from hydrogen, -C1~C3 alkyl, halogen-substituted -C1~C3 alkyl, 3-6 membered carbocyclic ring or 4-6 membered heterocyclic ring;

[0102] R 2 is selected from a 3-7 membered carbocyclic ring, a 4-10 membered heterocyclic ring, a 6-10 membered aromatic ring or a 5-10 membered heteroaromatic ring; wherein the carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring may be optionally replaced by one or more R 21 replace.

[0103] Furthermore, in certain specific embodiments, the present invention relates to compounds of formula (Ib), formula (Ic), and formula (Id), and their stereoisomers, deuterated substances, solvates, and pharmaceutically acceptable salts, wherein R 1 Selected from hydrogen, methyl, ethyl, F, Cl, Br, I, -CF3, -CH2F, -CHF2, -CH2CH2F, -CH2CHF2 or -CH2CF3;

[0104] L is selected from (For example, Where a end and R 2 connect);

[0105] R 4 is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl;

[0106] R 2 Selected from in particular

[0107] In certain specific embodiments, the present invention relates to compounds of Formula (I), Formula (Ia), Formula (Ie), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), or Formula (IIf), stereoisomers, deuterated forms, solvates, or pharmaceutically acceptable salts thereof.

[0108] in,

[0109] R 2 Selected from

[0110] Among them, R 21 Selected from hydrogen, halogen, -O-C1~C3 alkyl, -C1~C3 alkyl, -O-halogen substituted C1~C3 alkyl,

[0111] y = 0, 1, 2, or 3;

[0112] Among them, R c is selected from hydrogen, halogen, nitro, cyano, oxo, -NH2, -C(O)NH2, -C(O)H, -C(O)OH, -C1-C3 alkyl, -C2-C4 alkenyl, -C2-C4 alkynyl, halogen-substituted -C1-C3 alkyl, halogen-substituted -C2-C4 alkenyl, halogen-substituted -C2-C4 alkynyl, -O-C1-C3 alkyl (e.g., R 2 Specific selection );

[0113] L is selected from a bond, (For example, L is selected from a bond, Where a end and R 2 connect),

[0114] Among them, R 4 、R 6 are independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl,

[0115] Among them, R 41 is selected from hydrogen, halogen, methyl, ethyl, isopropyl (for example, L is specifically selected from a bond, For example, the L is specifically selected from a bond, Where a end and R 2 connect);

[0116] R 1 、R 5 are independently selected from hydrogen, halogen, -C1~C3 alkyl, -C2~C4 alkenyl, halogen-substituted -C1~C3 alkyl, -O-C1~C3 alkyl, 3-4-membered carbocyclic ring, 5-6-membered heteroaromatic ring or 6-10-membered aromatic ring; wherein the carbocyclic ring, heterocyclic ring, heteroaromatic ring or aromatic ring may be optionally substituted with one or more halogen, -C1~C3 alkyl, halogen-substituted -C1~C3 alkyl or -O-C1~C3 alkyl; for example, R 1 、R 5 Each independently selected from hydrogen, methyl, ethyl, F, Cl, Br, I, -CF3, -CH2F, -CHF2, -CH2CH2F, -CH2CHF2, -CH2CF3, -Cl, -Br, -OCH3, Phenyl,

[0117] In certain specific embodiments, the present invention relates to compounds of Formula (I), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe), or Formula (IIf), stereoisomers, deuterated forms, solvates, or pharmaceutically acceptable salts thereof.

[0118] in,

[0119] R 2 Selected from

[0120] y = 0, 1, 2, or 3;

[0121] Among them, R 21 Selected from hydrogen, halogen, -O-C1~C3 alkyl, -C1~C3 alkyl, -O-halogen substituted C1~C3 alkyl,

[0122] Among them, R c is selected from hydrogen, halogen, nitro, cyano, oxo, -NH2, -C(O)NH2, -C(O)H, -C(O)OH, -C1-C3 alkyl, -C2-C4 alkenyl, -C2-C4 alkynyl, halogen-substituted -C1-C3 alkyl, halogen-substituted -C2-C4 alkenyl, halogen-substituted -C2-C4 alkynyl, -O-C1-C3 alkyl (e.g., R 2 Specific selection );

[0123] L is selected from a bond, (For example, L is selected from a bond, Where a end and R 2 connect),

[0124] Among them, R 4 、R 6 are independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl,

[0125] Among them, R 41 is selected from hydrogen, halogen, methyl, ethyl, isopropyl (for example, L is specifically selected from a bond, For example, the L is specifically selected from a bond, Where a end and R 2 connect);

[0126] RX 、R X1 are independently selected from H, halogen, -C1~C3 alkyl, deuterium-substituted -C1~C3 alkyl, halogen-substituted -C1~C3 alkyl, -C(O)CH3; for example, R X 、R X1 Each independently selected from H, -CD3, -CH2CHF2, -Cl, -F, -CH3, -CH2F, -COCH3;

[0127] X4 respectively N, CR 5 ;

[0128] R 1 、R 5 are independently selected from hydrogen, halogen, -C1~C3 alkyl, -C2~C4 alkenyl, halogen-substituted -C1~C3 alkyl, -O-C1~C3 alkyl, 3-4-membered carbocyclic ring, 5-6-membered heteroaromatic ring or 6-10-membered aromatic ring; wherein the carbocyclic ring, heterocyclic ring, heteroaromatic ring or aromatic ring may be optionally substituted with one or more halogen, -C1~C3 alkyl, halogen-substituted -C1~C3 alkyl or -O-C1~C3 alkyl; for example, R 1 、R 5 Each independently selected from hydrogen, methyl, ethyl, F, Cl, Br, I, -CF3, -CH2F, -CHF2, -CH2CH2F, -CH2CHF2, -CH2CF3, -Cl, -Br, -OCH3, Phenyl,

[0129] R 7 is selected from H, halogen, -CN, -NO2, -NH2, -C1-C3 alkyl, deuterium-substituted -C1-C3 alkyl, halogen-substituted -C1-C3 alkyl; for example, R 7 is selected from H, methyl, ethyl, isopropyl, -Cl, -F;

[0130] R 3 Selected from H, halogen, -C1-C3 alkyl, -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2; for example, R 3 Selected from H, methyl, ethyl, isopropyl, -Cl, -F, -C(O)NHCH3.

[0131] In certain specific embodiments, the inhibitory activity of the compounds of the present application on OCI-Ly19 cells is better than that of the compounds of the prior art. For example, in certain specific embodiments, the inhibitory activity of the compounds of the present application on OCI-Ly19 cells is 1 to 10 times that of the compounds of the prior art; for example, in certain specific embodiments, the inhibitory activity of the compounds of the present application on OCI-Ly19 cells is 10 to 20 times that of the compounds of the prior art; for example, in certain specific embodiments, the inhibitory activity of the compounds of the present application on OCI-Ly19 cells is 20 to 50 times that of the compounds of the prior art; for example, in certain specific embodiments, the inhibitory activity of the compounds of the present application on OCI-Ly19 cells is 50 to 100 times that of the compounds of the prior art; for example, in certain specific embodiments, the inhibitory activity of the compounds of the present application on OCI-Ly19 cells is 100 to 150 times or better than that of the compounds of the prior art.

[0132] Furthermore, in certain specific embodiments, the compound of formula (I), its stereoisomers, deuterated substances, solvates, and pharmaceutically acceptable salts are selected from the group consisting of:

[0133] In this application, the compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (IIe) or formula (IIf) defined in the above embodiments, their stereoisomers, deuterated forms, solvates, pharmaceutically acceptable salts, and the specific compounds disclosed in the examples of this application are referred to as "compounds of the present invention."

[0134] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present invention, its stereoisomers, deuterated substances, solvates, pharmaceutically acceptable salts, and pharmaceutically acceptable carriers and / or excipients.

[0135] The present invention also provides the use of the compound of the present invention, its stereoisomers, deuterated substances, solvates, pharmaceutically acceptable salts, or pharmaceutical compositions thereof in the preparation of drugs for treating PRMT5-mediated diseases.

[0136] The present invention also provides the use of the compound of the present invention, its stereoisomers, deuterated substances, solvates, pharmaceutically acceptable salts, or pharmaceutical compositions thereof in the preparation of drugs for treating diseases mediated by MTAP gene deletion and / or MTA accumulation.

[0137] The present invention also provides the compound of the present invention, its stereoisomer, deuterated form, solvate, pharmaceutically acceptable salt, or pharmaceutical composition thereof, for use in treating PRMT5-mediated diseases.

[0138] The present invention also provides the compound of the present invention, its stereoisomer, deuterated substance, solvate, pharmaceutically acceptable salt, or pharmaceutical composition thereof, which is used for treating diseases mediated by MTAP gene deletion and / or MTA accumulation.

[0139] Furthermore, the PRMT5-mediated disease and / or the MTAP gene deletion-mediated disease is cancer.

[0140] Diseases mediated by PRMT5 or mediated by MTAP gene deficiency and / or MTA accumulation disorders as defined herein include cancer or malignant tumors. "Cancer" or "malignant tumor" refers to any of a variety of diseases characterized by abnormal, uncontrolled cell proliferation, the ability of affected cells to spread locally or to other parts of the body via the bloodstream and lymphatic system (i.e., metastasis), and any of a number of characteristic structural and / or molecular features. "Cancer cell" refers to a cell that is undergoing an early, intermediate, or advanced stage of multi-step tumor progression. The "cancer" or "malignant tumor" is selected from the group consisting of neuroma, adenocarcinoma, adrenal cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelioma, hemangioma), appendix cancer, benign monoclonal gamma disease, bile duct cancer, bladder cancer, brain cancer (e.g., meningioma, glioma, e.g., astrocytoma, oligodendroglioma, medulloblastoma), bronchial cancer, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial cancer, ependymoma, endothelial sarcoma (e.g., Kaposi's sarcoma, polyps), ulcerative colitis, myeloma, leukemia, myeloma, leukemia, necrosis factor alpha ... idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's gland carcinoma), Ewing's sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), hypereosinophilia, gallbladder cancer, stomach cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma), oral cancer (e.g., oral squamous cell carcinoma), laryngeal cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)), hematopoietic cancer (e.g., leukemias, such as acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL L), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL), hairy cell leukemia (HCL), lymphomas such as follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; and non-Hodgkin lymphomas, such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphomas (such as cutaneous T-cell lymphoma (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma);A mixture of one or more of the above leukemias / lymphomas; multiple myeloma (MM), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic tumor, immune cell amyloidosis, renal cancer (e.g., Wilms tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular carcinoma, malignant hepatocellular carcinoma), lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma, leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorders (MPD) (e.g., polycythemia vera (PV), Essential thrombocythemia (ET), idiopathic myeloid metaplasia (AMM), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES), neuroblastoma, neurofibromas (such as neurofibromatosis type 1 or type 2, schwannomatosis), neuroendocrine cancers (such as gastroenteropancreatic neuroendocrine tumors (GEP-NETs), carcinoid tumors), osteosarcoma, ovarian cancer (such as cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, penile cancer, breast cancer, pancreatic cancer, skin cancer, Hodgkin lymphoma, cancers with homozygous deletion of the methylthioadenosine phosphorylase gene, and neurofibrosarcoma.

[0141] Definition and Description

[0142] The compounds and derivatives provided herein can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0143] Definitions of terms used in the present invention: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined herein, they should be given the meaning that a person skilled in the art would give them based on the disclosure and context.

[0144] The term "halogen" herein refers to F, Cl, Br, I or isotopes thereof.

[0145] The term "alkyl" refers to a saturated straight or branched chain aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 In certain specific embodiments, the alkyl group has 1 to 12 carbon atoms (i.e., C1 to C 12 alkyl), which in certain embodiments has 1 to 6 carbon atoms (i.e., C l ~C6 alkyl).

[0146] The term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond, having from 2 to 20 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., C 2-20 The alkenyl group has, in certain specific embodiments, 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C2 to C 12 alkenyl), and in certain specific embodiments have 2 to 6 carbon atoms (ie, C2-C6 alkenyl).

[0147] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon triple bond, having from 2 to 20 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., C 2-20 Alkynyl), which in certain specific embodiments has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C2 to C 12 alkynyl), which in certain specific embodiments has 2 to 6 carbon atoms (ie, C2-C6 alkynyl).

[0148] The term "halogen-substituted alkyl" refers to a situation where one or more hydrogen atoms in an alkyl group are replaced by one or more halogen atoms (such as fluorine, chlorine, bromine, iodine, or their isotopes). The upper limit of the number of halogen substituents is equal to the sum of the number of replaceable hydrogen atoms in the alkyl group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit. Typically, an alkyl group is substituted with 1-5 halogens, or 1-3 halogens, or 1-2 halogens, or 1 halogen. When the number of halogen substituents is greater than 1, they may be the same or different halogens. Specific examples include, but are not limited to, -CF3, -CH2Cl, -CH2CF3, -CF3, etc.

[0149] The term "oxo" or "oxo group" refers to "=0" where an oxygen atom replaces two hydrogen atoms or a lone pair of electrons through a double bond.

[0150] In the present invention, the oxygen atom in "-C(O)R", "-S(O)2R", etc. is connected to the carbon atom or sulfur atom by a double bond, and the R group is connected to the carbon atom or sulfur atom by a single bond. For example, "-S(O)(NH)R" means that the oxygen atom and the nitrogen atom are connected to the sulfur atom by a double bond, and the R group is connected to the sulfur atom by a single bond.

[0151] Specific non-limiting examples of the term "-O-C1~C6 alkyl" include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyloxy and cyclobutyloxy, etc.

[0152] Non-limiting examples of the term "-O-halogen-substituted C1~C6 alkyl" include -O-halogenated C1~C6 alkyl, -O-halogenated C1~C4 alkyl or -O-halogenated C1~C2 alkyl; the upper limit of the number of halogen substituents is equal to the sum of the number of hydrogen atoms that can be substituted by the substituted group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit. In certain specific embodiments, it is 1-5 halogen substitutions, 1-3 halogen substitutions, 1-2 halogen substitutions, or 1 halogen substitution; when the number of halogen substituents is greater than 1, the halogen substitutions may be the same or different; non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, and the like.

[0153] The term "carbocycle" or "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., a monocyclic cycloalkyl) or a polycyclic all-carbon ring system (i.e., a polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 3-20-membered carbocycle or cycloalkyl). In some specific embodiments, the cycloalkyl group has 3 to 12 ring atoms (i.e., a 3-12-membered carbocycle or cycloalkyl), in some specific embodiments, 3 to 10 ring atoms (i.e., a 3-10-membered carbocycle or cycloalkyl), in some specific embodiments, 3 to 8 ring atoms (i.e., a 3-8-membered carbocycle or cycloalkyl), in some specific embodiments, 3 to 7 ring atoms (i.e., a 3-7-membered carbocycle or cycloalkyl), and in some specific embodiments, 3 to 6 ring atoms (i.e., a 3-6-membered carbocycle or cycloalkyl).

[0154] Non-limiting examples of the monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl and cyclooctyl, etc. The polycyclic cycloalkyl includes spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl.

[0155] The term "spiroalkyl" refers to a full-carbon polycyclic ring system in which the rings share a single carbon atom (called a spiro atom), which may contain one or more double bonds within the ring. The spiroalkyl group has, in certain specific embodiments, 6 to 14 ring atoms (i.e., 6 to 14-membered spiroalkyl groups), and in certain specific embodiments, 7 to 10 ring atoms (i.e., 7 to 10-membered spiroalkyl groups). Non-limiting examples include: Its connection point can be at any location.

[0156] The term "fused cycloalkyl" refers to a full-carbon polycyclic ring system in which two adjacent carbon atoms are shared between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyls and aryls, and which may contain one or more double bonds within the ring, provided that the fused ring formed is non-aromatic. The fused cycloalkyl has 6 to 14 ring atoms (i.e., 6 to 14-membered fused cycloalkyl) in certain specific embodiments, and 7 to 10 ring atoms (i.e., 7 to 10-membered fused cycloalkyl) in certain specific embodiments. Non-limiting examples include: Its connection point can be at any location.

[0157] The term "bridged cycloalkyl" refers to a full-carbon polycyclic ring system that shares two carbon atoms that are not directly connected between the rings, and may contain one or more double bonds within the ring. The bridged cycloalkyl has 6 to 14 carbon atoms (i.e., 6 to 14-membered bridged cycloalkyl) in certain specific embodiments, and 7 to 10 carbon atoms (i.e., 7 to 10-membered bridged cycloalkyl) in certain specific embodiments. The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), and in certain specific embodiments is bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl. Non-limiting examples include: Its connection point can be at any location.

[0158] The terms "heterocycle" and "heterocyclyl" refer to a saturated or non-aromatic partially saturated monocyclic heterocycle (i.e., a monocyclic heterocyclyl) or a polycyclic heterocyclic ring system (i.e., a polycyclic heterocyclyl), which contains at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides, or quaternized; the sulfur may be optionally oxoed, i.e., to form sulfoxides or sulfones). Non-limiting examples of the monocyclic heterocyclyl include: The polycyclic heterocycle also includes a heterocycle fused with one or more of a carbocycle, a heterocycle, an aryl group or a heteroaryl group to form a fused heterocycle, the attachment site of which can be located at a non-aromatic carbon atom, an aromatic carbon atom or a heteroatom. Non-limiting examples of the fused heterocycle include The polycyclic heterocyclic group also includes a spiro heterocyclic group and a bridged heterocyclic group.

[0159] The term "spirohetero" or "spiroheterocyclyl" refers to a polycyclic heterocyclic ring system in which the rings share one atom (called a spiro atom), which may contain one or more double bonds in the ring and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides, or quaternized; the sulfur may be optionally oxoed, i.e., to form sulfoxides or sulfones). Non-limiting examples include: wait.

[0160] The term "bridged hetero" or "bridged heterocyclyl" refers to a polycyclic heterocyclic ring system that shares two atoms that are not directly connected between the rings, which may contain one or more double bonds in the ring and at least one (e.g., 1, 2, 3 or 4) heteroatom selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides, or quaternized; the sulfur may be optionally oxoed, i.e., to form sulfoxides or sulfones) in the ring. Non-limiting examples include: wait.

[0161] The terms "aromatic ring" and "aryl" refer to a monocyclic all-carbon aromatic ring (i.e., a monocyclic aromatic group) or a polycyclic aromatic ring system (i.e., a polycyclic aromatic group) having a conjugated π electron system. In certain embodiments, the aryl group has 6 to 10 ring atoms (i.e., a 6- to 10-membered aromatic group). Examples of monocyclic aromatic groups include phenyl. Non-limiting examples of polycyclic aromatic groups include naphthyl, anthracenyl, phenanthrenyl, and the like.

[0162] The terms "heteroaromatic ring" and "heteroaryl" refer to a monocyclic heteroaromatic ring (i.e., a monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., a polycyclic heteroaryl) having a conjugated π electron system, which contains at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides, or quaternized; the sulfur may be optionally oxoed, i.e., to form sulfoxides or sulfones) in the ring, and the heteroaryl has 5 to 10 ring atoms (i.e., a 5- to 10-membered heteroaryl) in certain specific embodiments, and 5 or 6 ring atoms (i.e., a 5- or 6-membered heteroaryl) in certain specific embodiments. Non-limiting examples of the monocyclic heteroaryl group include: furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, pyrazinyl, pyridazinyl, etc. Non-limiting examples of the polycyclic heteroaryl group include: indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothienyl, quinazolinyl, benzothiazolyl, carbazolyl, etc.

[0163] The term "optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not. For example, "alkyl optionally substituted with F" means that the alkyl group may but need not be substituted with F, and the description includes instances where the alkyl group is substituted with F and instances where the alkyl group is not substituted with F.

[0164] The group description of the present invention Used to describe the substitution position of a group, e.g. refers to the tetrahydropyrrole ring passing through The position forms a spiral ring with other rings in the structure.

[0165] The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention that retain the biological effectiveness and properties of the free acids or free bases obtained by reacting the free acids with non-toxic inorganic or organic bases or the free bases with non-toxic inorganic or organic acids.

[0166] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein, their stereoisomers, deuterated forms, solvates, pharmaceutically acceptable salts, and other ingredients, wherein the other ingredients include physiologically / pharmaceutically acceptable carriers and / or excipients.

[0167] The term "carrier" refers to a system that does not cause significant irritation to the organism and does not eliminate the biological activity and properties of the administered compound, and can change the way the drug enters the human body and its distribution in the body, control the release rate of the drug, and deliver the drug to the target organ. Non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0168] The term "excipient" refers to a substance that is not itself a therapeutic agent but is used as a diluent, adjuvant, binder, and / or vehicle and is added to a pharmaceutical composition to improve its handling or storage properties or to allow or facilitate the formation of a compound or pharmaceutical composition into a unit dosage form for administration. As known to those skilled in the art, pharmaceutical excipients can serve a variety of functions and can be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents, and sweeteners.

[0169] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers and conformational isomers.

[0170] The term "solvate" refers to a substance formed by a compound of the present invention or a salt thereof and a stoichiometric or non-stoichiometric amount of a solvent bound to the compound or salt thereof by non-covalent forces between the molecules. When the solvent is water, the solvate is a hydrate.

[0171] The term "deuterated compound" refers to a molecule or group in which one or more hydrogen atoms are replaced by deuterium atoms, wherein the proportion of deuterium atoms is greater than the abundance of deuterium in nature. DETAILED DESCRIPTION

[0172] The present invention is further explained below with reference to specific examples, but the examples do not limit the present invention in any form.

[0173] Abbreviation Description:

[0174] PMB represents p-methoxybenzyl; Boc represents tert-butyloxycarbonyl; DMAP represents 4-dimethylaminopyridine; Na2CO3 represents sodium carbonate; THF represents tetrahydrofuran; DBU represents 1,8-diazabicyclo[5.4.0]undec-7-ene; AcOH represents acetic acid; Pd(dppf)Cl2 represents 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride; K2CO3 represents potassium carbonate; SEMCl represents 2-(trimethylsilyl)ethoxymethyl chloride; RT / rt represents room temperature; LiAlH4 represents lithium aluminum hydride; DEAD represents diethyl azodicarboxylate; PPh3 represents triphenylphosphine; NaBH(OAc)3 represents sodium triacetoxyborohydride; EDCI represents 1-(3- (2-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride); Py represents pyridine; TFAA represents trifluoroacetic anhydride; TEA represents triethylamine; DIEA represents N,N-diisopropylethylamine; t-Bubrettphos represents 2-(di-tert-butylphosphino)-3,6-dimethoxy-2',4',6'-triisopropylbiphenyl; NMP represents N-methylpyrrolidone; Pd2(dba)3 represents tris(dibenzylideneacetone)dipalladium; Xantphos represents 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; NaBH3CN represents sodium cyanoborohydride; HATU represents 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; Pd(OAc2) represents acetic acid Palladium; X-Phos represents 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; Cs2CO3 represents cesium carbonate; DIAD represents diisopropyl azodicarboxylate; MeONa represents sodium methoxide; MeOH represents methanol; KOAc represents potassium acetate; DMSO represents dimethyl sulfoxide; NaBH3CN represents sodium cyanoborohydride; HBr represents hydrobromic acid; TBAB represents tetrabutylammonium bromide; LiBr represents lithium bromide; DMAP represents 4-dimethylaminopyridine; NIS represents N-iodosuccinimide; NBS represents N-bromosuccinimide; TFA represents trifluoroacetic acid; DCM represents dichloromethane; TCFH represents N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate; NMI represents N-methylimidazole; Pd(PPh3)4 represents palladium tetrakistriphenylphosphine; K3PO4 represents potassium phosphate; CuI represents cuprous iodide; t-BuOK represents potassium tert-butoxide; DMF represents N,N-dimethylformamide; ACN represents acetonitrile; TMEDA represents tetramethylethylenediamine; n-BuLi represents n-butyllithium; m-CPBA represents m-chloroperbenzoic acid; POCl3 represents phosphorus oxychloride; DPPA represents diphenylphosphoryl azide; HOBt represents 1-hydroxybenzotriazole; Brettphos-G3-Pd represents methanesulfonate (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium;ZnBr2 represents zinc bromide; Pd(PPh3)2Cl2 represents bis(triphenylphosphine)palladium dichloride; Brettphos represents 2-(dicyclohexylphosphine)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl.

[0175] Preparation of intermediates

[0176] Preparation Example 1: Preparation of (5-(bis(4-methoxybenzyl)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)methanol

[0177] Step 1: Preparation of 3-bromo-N,N-bis[(4-methoxyphenyl)methyl]-6-methyl-5-nitropyridin-2-amine

[0178] Dissolve 3-bromo-2-chloro-6-methyl-5-nitropyridine (12 g, 47.72 mmol) and bis[(4-methoxyphenyl)methyl]amine (14.74 g, 57.26 mmol) in tetrahydrofuran (60 mL). Add sodium carbonate (6.07 g, 57.26 mmol) and react at 75°C for 16 hours. After LC-MS indicated completion of the reaction, the system was filtered, concentrated, and purified on a silica gel column to yield 11.7 g of the title compound.

[0179] MS (ESI) m / z (M+H) + =472.1.

[0180] Step 2: Preparation of ethyl 3-(6-(bis[(4-methoxyphenyl)methyl]amino)-5-bromo-3-nitropyridin-2-yl)-2-oxopropanoate

[0181] 3-Bromo-N,N-bis[(4-methoxyphenyl)methyl]-6-methyl-5-nitropyridin-2-amine (11.7 g, 24.77 mmol) was dissolved in diethyl oxalate (10.86 g, 74.31 mmol) and 1,8-diazabicycloundec-7-ene (4.53 g, 29.72 mmol) was added dropwise at 40°C. The mixture was allowed to react for 12 hours at 40°C. LC-MS indicated a small amount of starting material remaining. Water was added to the system and the mixture was extracted three times with ethyl acetate. The organic phase was concentrated and purified on a silica gel column to afford 13 g of the title compound as a pale white solid.

[0182] MS (ESI) m / z (M+H) + =572.1.

[0183] Step 3: Preparation of ethyl 5-(bis(4-methoxybenzyl)amino)-6-bromo-1H-pyrrolo[3,2-b]pyridine-2-carboxylate

[0184] Ethyl 3-(6-(bis[(4-methoxyphenyl)methyl]amino)-5-bromo-3-nitropyridin-2-yl)-2-oxopropanoate (13 g, 22.71 mmol) was dissolved in acetic acid (150 mL) and iron powder (5.07 g, 90.84 mmol) was added. The mixture was allowed to react at room temperature for 12 hours. LC-MS indicated the reaction was complete. Water was added and the mixture was extracted three times with ethyl acetate. The mixture was washed with saturated sodium bicarbonate solution. The organic phase was concentrated and purified on a silica gel column to afford 8.5 g of the title compound as an oil.

[0185] MS (ESI) m / z (M+H) + =524.1.

[0186] Step 4: Preparation of ethyl 5-(bis(4-methoxybenzyl)amino)-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylate

[0187] Ethyl 5-(bis(4-methoxybenzyl)amino)-6-bromo-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (8.5 g, 16.21 mmol) was dissolved in 1,4-dioxane (80 mL). Methylboric acid (3.88 g, 64.84 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (0.59 g, 0.81 mmol), and potassium carbonate (8.96 g, 64.84 mmol) were added sequentially. The atmosphere was purged with nitrogen three times and heated to 110°C for 12 hours. After LC-MS indicated completion of the reaction, the mixture was filtered, the filtrate was concentrated, and purified on a silica gel column to obtain 6 g of the title compound as an oil.

[0188] MS (ESI) m / z (M+H) + =460.2.

[0189] Step 5: Preparation of ethyl 5-(bis(4-methoxybenzyl)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylate

[0190] Dissolve ethyl 5-(bis(4-methoxybenzyl)amino)-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (6 g, 13.06 mmol) in tetrahydrofuran (60 mL). Add sodium hydride (0.41 g, 16.98 mmol) portionwise under ice-water bath. After stirring for 20 minutes, add 2-(trimethylsilyl)ethoxymethyl chloride (2.83 g, 16.98 mmol) and react at room temperature for 2 hours. After TLC indicated completion of the reaction, quench with water and extract three times with ethyl acetate. The organic phases were combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, and purified on a silica gel column to afford 7.5 g of the title compound as a white solid.

[0191] MS (ESI) m / z (M+H) + =590.3.

[0192] Step 6: Preparation of (5-(bis[(4-methoxyphenyl)methyl]amino)-6-methyl-1-[(2-(trimethylsilyl)ethoxy)methyl]-1H-pyrrolo[3,2-b]pyridin-2-yl)methanol

[0193] Ethyl 5-(bis(4-methoxybenzyl)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (7.5 g, 12.72 mmol) was dissolved in tetrahydrofuran (100 mL). Lithium aluminum hydride (0.72 g, 19.08 mmol) was added portionwise under an ice-water bath. The temperature was gradually warmed to room temperature and allowed to react for 1 hour. LC-MS indicated the reaction was complete. Water (1 mL) was added under an ice-water bath and stirred for 5 minutes. 15% sodium hydroxide solution (1 mL) was then added dropwise followed by water (3 mL). The mixture was stirred at room temperature for 0.5 hour, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purification on a silica gel column afforded 6.8 g of the title compound as an oil.

[0194] MS (ESI) m / z (M+H) + =548.3.

[0195] Preparation Example 2: Preparation of 1-((5-(bis(4-methoxybenzyl)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-2-carboxylic acid

[0196] Step 1: Preparation of methyl 1-((5-(bis(4-methoxybenzyl)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-2-carboxylate

[0197] (5-(Bis[(4-methoxyphenyl)methyl]amino)-6-methyl-1-[(2-(trimethylsilyl)ethoxy)methyl]-1H-pyrrolo[3,2-b]pyridin-2-yl)methanol (2 g, 3.56 mmol) and methyl 6-oxo-1,6-dihydropyridine-2-carboxylate (0.84 g, 5.47 mmol) were dissolved in tetrahydrofuran (30 mL). Triphenylphosphine (1.44 g, 5.47 mmol) was added dropwise under an ice-water bath, followed by the dropwise addition of diethyl azodicarboxylate (0.95 g, 5.47 mmol). The mixture was stirred at room temperature for 12 hours. After LC-MS indicated the reaction was complete, the reaction was quenched with water and extracted three times with ethyl acetate. The organic phases were combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, and purified on a silica gel column to afford 0.447 g of the title compound as an oil.

[0198] MS (ESI) m / z (M+H) + =683.3.

[0199] Step 2: Preparation of 1-((5-(bis(4-methoxybenzyl)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-2-carboxylic acid

[0200] Methyl 1-((5-(bis(4-methoxybenzyl)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-2-carboxylate (447 mg, 0.65 mmol) was dissolved in tetrahydrofuran (5 mL) and water (5 mL). Lithium hydroxide monohydrate (54.55 mg, 1.3 mmol) was added and the mixture was reacted at room temperature for 1 hour. After LC-MS indicated completion of the reaction, the mixture was concentrated, purified by reverse phase preparative chromatography, and lyophilized to afford 380 mg of the title compound as a white solid.

[0201] MS (ESI) m / z (M+H) + =669.3.

[0202] Preparation Example 3: Preparation of N-isopropyl-6-oxo-N-phenyl-1,6-dihydropyridine-2-carboxamide

[0203] Step 1: Preparation of N-isopropylaniline

[0204] Dissolve aniline (500.0 mg, 5.37 mmol) and propan-2-one (1559.4 mg, 26.85 mmol) in tetrahydrofuran (20 mL). Add sodium triacetoxyborohydride (2276.2 mg, 10.74 mmol) at room temperature. Allow to react for 12 hours. After TLC indicates completion, quench the reaction with water, extract several times with dichloromethane, and dry over anhydrous sodium sulfate. Concentrate the solvent to obtain the crude product, which is then purified by column chromatography (dichloromethane / methanol = 15 / 1 (v:v)) to yield 350.0 mg of the title compound as a pale yellow oil.

[0205] MS (ESI) m / z (M+H) + =136.2.

[0206] Step 2: Preparation of N-isopropyl-6-oxo-N-phenyl-1,6-dihydropyridine-2-carboxamide

[0207] Dissolve N-isopropylaniline (350.0 mg, 2.59 mmol) and 6-oxo-1,6-dihydropyridine-2-carboxylic acid (360.2 mg, 2.59 mmol) in pyridine (5 mL). Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (993.0 mg, 5.18 mmol) at room temperature. Allow to react at room temperature for 2 hours. After TLC indicates completion of the reaction, concentrate the solvent under reduced pressure to obtain a crude product, which is purified by column chromatography (dichloromethane / methanol = 10 / 1 (v:v)) to yield 300.0 mg of the title compound as a light green solid.

[0208] MS (ESI) m / z (M+H) + =257.3.

[0209] 1 H NMR (400MHz, DMSO-d6) δ11.51(s,1H),7.40–7.24(m,3H),7.26–7.10(m,3H),6.21–5.91(m,2H),4.90–4.71(m,1H),1.10(d,J=6.8Hz,6H).

[0210] Preparation Example 4: Preparation of N-methyl-6-oxo-N-phenyl-1,6-dihydropyridine-2-carboxamide

[0211] The title compound was prepared using the corresponding commercial reagents as raw materials and a preparation method similar to that of Preparation Example 3.

[0212] MS (ESI) m / z (M+H) + =229.2.

[0213] 1 H NMR (400MHz, DMSO-d6) δ11.51(s,1H),7.34(t,J=7.6Hz,2H),7.29–7.18(m,4H),6.25(d,J=9.0Hz,1H),6.08(s,1H),3.33(s,3H).

[0214] Preparation Example 5: Preparation of tert-butyl (2-(hydroxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-5-yl)carbamate

[0215] Step 1: Preparation of ethyl 5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylate

[0216] Dissolve ethyl 5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (1 g, 4.45 mmol) in tetrahydrofuran (30 mL). Add sodium hydride (0.14 g, 5.79 mmol) portionwise under an ice-water bath. Stir at this temperature for 30 minutes, then add 2-(trimethylsilyl)ethoxymethyl chloride (0.96 g, 5.79 mmol). Allow to react at room temperature for 2 hours. After TLC indicates the reaction is complete, quench with water and extract three times with ethyl acetate. The organic phases are combined and backwashed once with saturated brine, dried over anhydrous sodium sulfate, and purified on a silica gel column to afford 1.5 g of the title compound as a white solid.

[0217] MS (ESI) m / z (M+H) + =355.1.

[0218] Step 2: Preparation of ethyl 5-((tert-butoxycarbonyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylate

[0219] Ethyl 5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (500 mg, 1.1 mmol) and tert-butyl carbamate (330 mg, 2.82 mmol) were dissolved in 1,4-dioxane (20 mL). Palladium acetate (31.66 mg, 0.14 mmol), 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl (134.4 mg, 0.28 mmol), and cesium carbonate (0.92 mg, 2.82 mmol) were added, and the reaction system was incubated at 100°C for 12 hours. LC-MS indicated the reaction was complete. The system was filtered through celite, and the filtrate was concentrated to dryness. Purification on a silica gel column afforded 0.46 g of the title compound as a pale white solid.

[0220] MS (ESI) m / z (M+H) + =436.2.

[0221] Step 3: Preparation of tert-butyl (2-(hydroxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-5-yl)carbamate

[0222] Ethyl 5-((tert-butoxycarbonyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (460 mg, 1.06 mmol) was dissolved in tetrahydrofuran (40 mL). Lithium aluminum hydride (60.3 mg, 1.59 mmol) was added portionwise under ice-water bath. After stirring for 1 hour, the reaction was complete as monitored by LC-MS. Water (1 mL) was added under ice-water bath. 15% sodium hydroxide solution (1 mL) was added dropwise, followed by the gradual addition of water (3 mL) and stirring at room temperature for 0.5 hour. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purification on a silica gel column gave 320 mg of the title compound as an oil.

[0223] MS (ESI) m / z (M+H) + =294.2.

[0224] Preparation Example 6: Preparation of 1-((5-(bis(4-methoxybenzyl)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-6-bromopyridin-2(1H)-one

[0225] (5-(Bis(4-methoxybenzyl)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)methanol (1.0 g, 1.83 mmol), triphenylphosphine (718.3 mg, 2.74 mmol), and 6-bromopyridin-2(1H)-one (349.4 mg, 2.01 mmol) were dissolved in tetrahydrofuran (50 mL). Diisopropyl azodicarboxylate (553.7 mg, 2.74 mmol) was then slowly added dropwise under nitrogen protection in an ice-water bath. After the addition was complete, the reaction system was stirred at room temperature for 3 hours. LCMS indicated the reaction was complete. The reaction solution was concentrated and purified by column chromatography to obtain 350.0 mg of the title compound as a yellow gum.

[0226] MS (ESI) m / z (M+H) + =703.3.

[0227] Preparation Example 7: 4-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine

[0228] Step 1: Preparation of 5-bromo-4-methoxypyrrolo[2,1-f][1,2,4]triazine

[0229] Dissolve 5-bromo-4-chloropyrrolo[2,1-f][1,2,4]triazine (0.5 g, 2.15 mmol) in anhydrous methanol (10 mL), followed by the addition of sodium methoxide (174.3 mg, 3.23 mmol). After addition, stir the reaction at room temperature for 16 hours. LCMS indicates completion of the reaction. Add water, filter, and dry the filter cake to afford the title compound (450.0 mg, crude) as a light yellow solid.

[0230] MS (ESI) m / z (M+H) + =228.1.

[0231] Step 2: Preparation of 4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine

[0232] 5-Bromo-4-methoxypyrrolo[2,1-f][1,2,4]triazine (410.0 mg, 1.80 mmol), pinacol diboronate (730.5 mg, 2.88 mmol), and potassium acetate (705.8 mg, 7.19 mmol) were dissolved in tetrahydrofuran (14.0 mL) and dimethyl sulfoxide (2.0 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (130.5 mg, 0.18 mmol) was then added. After the addition was complete, the reaction system was heated to 80°C under a nitrogen atmosphere and stirred for 16 hours. LCMS indicated that the starting materials had reacted substantially completely. The reaction solution was concentrated and purified by column chromatography to afford 400.0 mg of the title compound as a pale yellow oil.

[0233] MS (ESI) m / z (M+H) + =276.2.

[0234] Preparation Example 8: Preparation of 6-((3,4-dihydroquinolin-1(2H)-yl)methyl)-1-(prop-2-yn-1-yl)pyridin-2(1H)-one

[0235] Step 1: Preparation of 1-((6-methoxypyridin-2-yl)methyl)-1,2,3,4-tetrahydroquinoline

[0236] To a dry round-bottom flask, add 1,2,3,4-tetrahydroquinoline (2.9 g, 21.77 mmol), 6-methoxypyridine-2-carbaldehyde (4.5 g, 32.66 mmol), and methanol (50 mL) in sequence. After stirring, sodium cyanoborohydride (2.1 g, 32.66 mmol) was slowly added at room temperature. The reaction mixture was then allowed to react for 5 hours. LC-MS monitoring revealed minimal residual starting material. The reaction was quenched with water and extracted three times with ethyl acetate. The organic phases were combined and backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was purified by column chromatography to yield 3.2 g of the title product as a yellow, viscous liquid.

[0237] MS (ESI) m / z (M+H) + =255.1.

[0238] Step 2: Preparation of 6-((3,4-dihydroquinolin-1(2H)-yl)methyl)pyridin-2(1H)-one

[0239] To a reaction tube, add 1-[(6-methoxypyridin-2-yl)methyl]-1,2,3,4-tetrahydroquinoline (1.5 g, 5.90 mmol), hydrobromic acid (5 mL, 7.45 g, 92.08 mmol), and acetic acid (10 mL). After stirring, the reaction system was placed in an 80°C oil bath for 6 hours. After completion, the reaction was quenched with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase concentrated. The crude product was purified on a silica gel column to afford 1.3 g of the title product as a light green solid.

[0240] MS (ESI) m / z (M+H) + =241.1.

[0241] Step 3: Preparation of 6-((3,4-dihydroquinolin-1(2H)-yl)methyl)-1-(prop-2-yn-1-yl)pyridin-2(1H)-one

[0242] To a reaction tube, 6-[(1,2,3,4-tetrahydroquinolin-1-yl)methyl]-1,2-dihydropyridin-2-one (600.0 mg, 2.50 mmol), potassium carbonate (1.1 g, 7.50 mmol), tetrabutylammonium bromide (890.0 g, 0.28 mmol), and lithium bromide (430.0 mg, 5.00 mmol) were added sequentially, followed by toluene (40 mL) and water (1 mL). After stirring, 3-bromopropyne (480.0 mg, 4.00 mmol) was slowly added. The reaction mixture was allowed to react at 80°C for 6 hours, and the reaction was complete as monitored by LC-MS. The reaction was quenched with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase concentrated. The crude product was purified on a silica gel column to afford 630.0 mg of the title product as a yellow solid.

[0243] MS (ESI) m / z (M+H) + =279.1.

[0244] Preparation Example 9: Preparation of tert-butyl N-(5-amino-6-iodo-3-methylpyridin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate

[0245] Step 1: Preparation of tert-butyl N-[(tert-butoxy)carbonyl]-N-(3-methyl-5-nitropyridin-2-yl)carbamate

[0246] 3-Methyl-5-nitropyridin-2-amine (9.0 g, 58.8 mmol) was dissolved in dichloromethane (100 mL). Di-tert-butyl dicarbonate (12.8 g, 58.8 mmol) and 4-dimethylaminopyridine (7.2 g, 16.0 mmol) were added sequentially in an ice-water bath. The mixture was allowed to react at room temperature for 3 hours. After TLC indicated completion of the reaction, the mixture was added dropwise to 500 mL of water in an ice-water bath. The mixture was extracted three times with ethyl acetate. The organic phases were combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1 (v:v)) to yield 20.0 g of the title compound as a white solid.

[0247] MS (ESI) m / z (M+H) + =354.1.

[0248] Step 2: Preparation of tert-butyl N-(5-amino-3-methylpyridin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate

[0249] Tert-butyl N-[(tert-butoxy)carbonyl]-N-(3-methyl-5-nitropyridin-2-yl)carbamate (20.0 g, 56.7 mmol) was dissolved in methanol (200 mL), and palladium carbon (4.0 g, 10% (W / W)) was slowly added in batches at 0°C. After the addition, the hydrogen was replaced three times, and then the reaction was carried out under a hydrogen atmosphere at room temperature for 10 hours. TLC showed that the starting material was completely consumed. The system was filtered and concentrated to obtain 18.0 g of the title compound as a colorless oil, which was used directly in the next reaction.

[0250] MS (ESI) m / z (M+H) + =324.1.

[0251] Step 3: Preparation of tert-butyl N-(5-amino-6-iodo-3-methylpyridin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate

[0252] Dissolve tert-butyl N-(5-amino-3-methylpyridin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate (18.0 g, 55.7 mmol) in N,N-dimethylformamide (100 mL). Add N-iodosuccinimide (12.5 g, 55.7 mmol) at 0°C. After addition, allow to react at room temperature for 1 hour. After TLC indicates completion of the reaction, add 1 L of water and extract five times with ethyl acetate. The combined organic phases are backwashed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is purified by column chromatography (dichloromethane / methanol = 20 / 1 (v:v)) to yield 15.0 g of the title compound as a dark green solid.

[0253] MS (ESI) m / z (M+H) + =450.1.

[0254] Preparation Example 10: Preparation of N-((5-fluoropyridin-2-yl)methyl)-6-oxo-N-phenyl-1,6-dihydropyridine-2-carboxamide

[0255] Step 1: Preparation of N-((5-fluoropyridin-2-yl)methyl)aniline

[0256] Dissolve 5-fluoropyridine-2-carboxaldehyde (500 mg, 4 mmol) and aniline (745.04 mg, 8 mmol) in methanol (10 mL). Add 3 drops of acetic acid solution and stir at room temperature for 20 minutes. Add sodium cyanoborohydride (502.72 mg, 8 mmol) in portions under an ice-water bath. Stir at room temperature for 4 hours. Completion of the reaction is monitored by LC-MS. Quench the reaction with water and extract three times with ethyl acetate. Combine the organic phases, backwash once with saturated brine, dry over anhydrous sodium sulfate, and purify on a silica gel column to obtain 650 mg of the title compound as an oil.

[0257] MS (ESI) m / z (M+H) + =203.1.

[0258] Step 2: Preparation of N-((5-fluoropyridin-2-yl)methyl)-6-oxo-N-phenyl-1,6-dihydropyridine-2-carboxamide

[0259] 6-Oxo-1,6-dihydropyridine-2-carboxylic acid (446.54 mg, 3.21 mmol) was dissolved in pyridine (20 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (738.43 mg, 3.85 mmol) and N-((5-fluoropyridin-2-yl)methyl)aniline (650 mg, 3.21 mmol) were then added sequentially. The reaction was allowed to proceed at room temperature for 12 hours. After LC-MS indicated completion of the reaction, the system was concentrated, the acid was adjusted, and reverse phase purification was performed to obtain 600 mg of the title compound as an oil.

[0260] MS (ESI) m / z (M+H) + =324.1.

[0261] Preparation Example 11: Preparation of N-benzyl-N-[(5-fluoropyridin-2-yl)methyl]-6-oxo-1-(prop-2-yn-1-yl)-1,6-dihydropyridine-2-carboxamide

[0262] Step 1: Preparation of N-benzyl-1-(5-fluoropyridin-2-yl)methanamine

[0263] To a dry round-bottom flask, 5-fluoropyridine-2-carboxaldehyde (1.0 g, 7.99 mmol), benzylamine (1.71 g, 15.98 mmol), and methanol (10 mL) were added sequentially. Sodium cyanoborohydride (1.2 g, 19.09 mmol) was slowly added at room temperature, and the reaction mixture was allowed to react at room temperature for 2 hours. LC-MS monitoring revealed a small amount of residual starting material. The reaction was quenched with water and extracted three times with ethyl acetate. The organic phases were combined and backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was purified by column chromatography to obtain 1.2 g of the title product as a yellow oil.

[0264] MS (ESI) m / z (M+H) + =217.2.

[0265] Step 2: Preparation of N-benzyl-N-[(5-fluoropyridin-2-yl)methyl]-6-oxo-1,6-dihydropyridine-2-carboxamide

[0266] To a reaction tube, 6-oxo-1,6-dihydropyridine-2-carboxylic acid (0.85 g, 6.11 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.60 g, 8.32 mmol), and pyridine (10 mL) were added sequentially. After complete addition, the mixture was stirred until uniform, and N-benzyl-1-(5-fluoropyridin-2-yl)methanamine (1.2 g, 5.55 mmol) was added dropwise. The reaction system was then left to react at room temperature for 6 hours. After completion, the reaction was quenched with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase concentrated. The crude product was purified on a silica gel column to yield 1.3 g of the title product as a yellow solid.

[0267] MS (ESI) m / z (M+H) + =338.1.

[0268] Step 3: Preparation of N-benzyl-N-[(5-fluoropyridin-2-yl)methyl]-6-oxo-1-(prop-2-yn-1-yl)-1,6-dihydropyridine-2-carboxamide

[0269] To a reaction tube, add N-benzyl-N-[(5-fluoropyridin-2-yl)methyl]-6-oxo-1,6-dihydropyridine-2-carboxamide (1.24 g, 3.68 mmol), potassium carbonate (1.53 g, 11.04 mmol), lithium bromide (0.64 g, 7.36 mmol), tetrabutylammonium bromide (0.13 g, 0.4 mmol), toluene (20 mL), and water (1 mL). After stirring, 3-bromopropyne (0.66 g, 5.52 mmol) was slowly added at room temperature. The reaction system was placed in an 80°C oil bath for 6 hours. After completion, the reaction was quenched with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase concentrated. The crude product was purified on a silica gel column to obtain 0.6 g of the title product.

[0270] MS (ESI) m / z (M+H) + =376.1.

[0271] Preparation Example 12: Preparation of tert-butyl (tert-butoxycarbonyl)(6-iodo-3-methyl-5-(2,2,2-trifluoroacetylamino)pyridin-2-yl)carbamate

[0272] Dissolve tert-butyl (5-amino-6-iodo-3-methylpyridin-2-yl)(tert-butoxycarbonyl)carbamate (4.493 g, 10 mmol) in dichloromethane (100 mL). Add trifluoroacetic anhydride (1.67 mL, 12 mmol) and triethylamine (2.78 mL, 20 mmol) at room temperature. Allow to react at room temperature for 2 hours. After TLC indicates completion of the reaction, add saturated brine to the reaction system, extract several times with dichloromethane, and dry over anhydrous sodium sulfate. Concentrate the solvent to obtain a crude product, which is purified by column chromatography to yield 5.18 g of the title compound.

[0273] MS (ESI) m / z (M+H) + =546.1.

[0274] Preparation Example 13: Preparation of (2-(4-fluorophenyl)pyrrolidin-1-yl)(6-hydroxy-4-methylpyridin-2-yl)methanone

[0275] Step 1: Preparation of (6-chloro-4-methylpyridin-2-yl)(2-(4-fluorophenyl)pyrrolidin-1-yl)methanone

[0276] 6-Chloro-4-methylpicolinic acid (550.0 mg, 3.22 mmol) was dissolved in dichloromethane (10 mL). N,N-diisopropylethylamine (830.0 mg, 6.44 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.2 g, 3.22 mmol) were added sequentially under ice-cooling conditions. Finally, 2-(4-fluorophenyl)pyrrolidine (531 mg, 3.22 mmol) was added. The mixture was allowed to react at room temperature for 4 hours. After TLC indicated the reaction was complete, 200 mL of water was added to the system. The system was extracted three times with ethyl acetate. The organic phases were combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1 (v:v)) to yield 960 mg of the title compound as a white solid.

[0277] MS (ESI) m / z (M+H) + =319.1.

[0278] Step 2: Preparation of (2-(4-fluorophenyl)pyrrolidin-1-yl)(6-hydroxy-4-methylpyridin-2-yl)methanone

[0279] (6-Chloro-4-methylpyridin-2-yl)(2-(4-fluorophenyl)pyrrolidin-1-yl)methanone (960 mg, 3.02 mmol), boric acid (276.0 mg, 4.53 mmol), palladium acetate (68.0 mg, 0.30 mmol), 2-(di-tert-butylphosphino)-3,6-dimethoxy-2',4',6'tri-isopropyl-1,1'-biphenyl (293.0 mg, 0.60 mmol), and cesium carbonate (2.0 g, 6.04 mmol) were weighed. The system was sealed and nitrogen atmosphere was applied. N-methylpyrrolidone (10 mL) was added to dissolve the solution, and the system was purged with nitrogen three times. The reaction was then incubated at 90°C for 3 hours. LCMS confirmed the complete reaction. The reaction was quenched with water, extracted with ethyl acetate, and concentrated. The crude product was separated by column chromatography (dichloromethane / methanol = 20 / 1) to afford 400 mg of the title compound as a purple-black solid.

[0280] MS (ESI) m / z (M+H) + =301.1.

[0281] Preparation Example 14: Preparation of 6-chloro-5-fluoro-2-iodopyridin-3-amine

[0282] Step 1: Preparation of tert-butyl N-(6-chloro-5-fluoropyridin-3-yl)carbamate

[0283] 5-Bromo-2-chloro-3-fluoropyridine (4.0 g, 19.01 mmol) was dissolved in 1,4-dioxane (80 mL). T-butyl carbamate (2.6 g, 22.81 mmol), tris(dibenzylideneacetone)dipalladium (1.7 g, 1.90 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (2.2 g, 3.80 mmol), and cesium carbonate (12.4 g, 38.02 mmol) were added at room temperature. After replacing the inert atmosphere, the mixture was reacted at 90°C for 8 hours. After TLC indicated completion of the reaction, saturated brine was added to the reaction system, and the mixture was extracted several times with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain a crude product, which was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1 (v:v)) to afford 2.0 g of the title compound as a pale yellow oil.

[0284] MS (ESI) m / z (M+H) + =247.7.

[0285] Step 2: Preparation of 6-chloro-5-fluoropyridin-3-amine

[0286] Dissolve tert-butyl N-(6-chloro-5-fluoropyridin-3-yl)carbamate (1.9 g, 7.70 mmol) in a solution of hydrochloric acid (0.6 g, 15.02 mmol) in 1,4-dioxane (2 mL). Allow to react at room temperature for 2 hours. After TLC indicates completion, concentrate the solvent, add sodium bicarbonate to the reaction system, adjust the mixture to neutrality, extract several times with ethyl acetate, and dry over anhydrous sodium sulfate. Concentrate the solvent to obtain a crude product, which is purified by column chromatography (dichloromethane / methanol = 10 / 1 (v:v)) to afford 1.0 g of the title compound as a pale yellow solid.

[0287] MS (ESI) m / z (M+H) + =147.5.

[0288] Step 3: Preparation of 6-chloro-5-fluoro-2-iodopyridin-3-amine

[0289] Dissolve 6-chloro-5-fluoropyridin-3-amine (1.0 g, 6.82 mmol) in N,N-dimethylformamide (10 mL). Add N-iodosuccinimide (3.1 g, 13.64 mmol) at room temperature. Allow to react at room temperature for 8 hours. After TLC indicates the reaction has terminated, add saturated brine to the reaction system, extract several times with ethyl acetate, and dry over anhydrous sodium sulfate. Concentrate the solvent to obtain a crude product, which is purified by column chromatography (dichloromethane / methanol = 15 / 1 (v:v)) to afford 0.2 g of the title compound as a pale yellow solid.

[0290] MS (ESI) m / z (M+H) + =273.5.

[0291] Preparation Example 15: Preparation of N-methyl-6-oxo-N-phenyl-1-(prop-2-yn-1-yl)-1,6-dihydropyridine-2-carboxamide

[0292] Dissolve N-methyl-6-oxo-N-phenyl-1,6-dihydropyridine-2-carboxamide (1.1 g, 4.82 mmol) in N,N-dimethylformamide (15 mL). Add 3-bromopropyne (1.2 g, 9.64 mmol) and potassium carbonate (1.4 g, 9.64 mmol) at room temperature. Allow to react at 50°C for 2 hours. After TLC indicates completion of the reaction, add saturated brine to the reaction system, extract several times with ethyl acetate, and dry over anhydrous sodium sulfate. Concentrate the solvent to obtain a crude product, which is purified by column chromatography (dichloromethane / methanol = 20 / 1 (v:v)) to afford 0.8 g of the title compound as a pale yellow oil.

[0293] MS (ESI) m / z (M+H) + =267.2.

[0294] Preparation Example 16: Preparation of 4-methyl-6-(2-phenylpyrrolidine-1-carbonyl)-1-(prop-2-yn-1-yl)pyridin-2(1H)-one

[0295] Step 1: Preparation of (6-chloro-4-methylpyridin-2-yl)(2-phenylpyrrolidin-1-yl)methanone

[0296] Dissolve 6-chloro-4-methylpicolinic acid (2.0 g, 11.70 mmol) in dichloromethane (20 mL). Add N,N-diisopropylethylamine (3.0 g, 23.40 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.4 g, 11.70 mmol), and finally 2-phenylpyrrolidine (1.7 g, 11.70 mmol) sequentially under ice-cooling conditions. Allow to react at room temperature for 4 hours. After TLC indicated completion of the reaction, add 200 mL of water, extract three times with ethyl acetate, combine the organic phases, backwash once with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1 (v:v)) to yield 2.8 g of the title compound as a white solid.

[0297] MS (ESI) m / z (M+H) + =301.1.

[0298] Step 2: Preparation of (6-hydroxy-4-methylpyridin-2-yl)(2-phenylpyrrolidin-1-yl)methanone

[0299] (6-Chloro-4-methylpyridin-2-yl)(2-phenylpyrrolidin-1-yl)methanone (1.1 g, 3.67 mmol), boric acid (341.0 mg, 5.51 mmol), palladium acetate (41.0 mg, 0.18 mmol), 2-(di-tert-butylphosphino)-3,6-dimethoxy-2',4',6'tri-isopropyl-1,1'-biphenyl (222.5 mg, 0.46 mmol), and cesium carbonate (2.4 g, 7.34 mmol) were weighed. A sealed system was placed under nitrogen protection. N-methylpyrrolidone (10 mL) was added to dissolve the mixture, and the system was purged with nitrogen three times. The reaction was then incubated at 90°C for 3 hours. LCMS confirmed the complete reaction. The reaction was quenched with water, extracted with ethyl acetate, and concentrated. The crude product was separated by column chromatography (dichloromethane / methanol = 20 / 1) to afford 530 mg of the title compound as a purple-black solid.

[0300] MS (ESI) m / z (M+H) + =283.1.

[0301] Step 3: Preparation of 4-methyl-6-(2-phenylpyrrolidine-1-carbonyl)-1-(prop-2-yn-1-yl)pyridin-2(1H)-one

[0302] (6-Hydroxy-4-methylpyridin-2-yl)(2-phenylpyrrolidin-1-yl)methanone (530.0 mg, 1.88 mmol) was dissolved in toluene (10 mL) and water (0.5 mL). Potassium carbonate (518.9 mg, 3.76 mmol), lithium bromide (323.0 g, 3.76 mmol), tetrabutylammonium bromide (66.0 mg, 0.21 mmol), and propargyl bromide (224.0 mg, 1.88 mmol) were added sequentially at room temperature. The mixture was reacted at 80°C for 8 hours. After TLC indicated completion of the reaction, 100 mL of water was added to the system. The system was extracted three times with ethyl acetate. The organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1 (v:v)) to afford 180 mg of the title compound as a yellow solid.

[0303] MS (ESI) m / z (M+H) + =321.1.

[0304] Preparation Example 17: Preparation of N-ethyl-N-(4-fluorophenyl)-6-oxo-1-(prop-2-yn-1-yl)-1,6-dihydropyridine-2-carboxamide

[0305] Step 1: Preparation of N-ethyl-4-fluoroaniline

[0306] To a dry round-bottom flask, 4-fluoroaniline (2.0 g, 18.00 mmol), acetaldehyde (1.19 g, 27 mmol), sodium cyanoborohydride (1.2 g, 19.8 mmol), and methanol (15 mL) were added sequentially. The reaction mixture was then allowed to react at room temperature for 2 hours. LC-MS monitoring revealed minimal residual starting material. The reaction was quenched with water and extracted three times with ethyl acetate. The combined organic phases were backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent removed by spin drying. The crude product was purified by column chromatography to yield 1.5 g of the title product as a yellow oil.

[0307] MS (ESI) m / z (M+H) + =140.1.

[0308] Step 2: Preparation of N-ethyl-N-(4-fluorophenyl)-6-oxo-1,6-dihydropyridine-2-carboxamide

[0309] To a reaction tube, 6-oxo-1,6-dihydropyridine-2-carboxylic acid (1.32 g, 9.48 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (2.48 g, 12.93 mmol), and pyridine (10 mL) were added sequentially. After stirring, N-ethyl-4-fluoroaniline (1.2 g, 8.62 mmol) was added dropwise. The reaction system was then allowed to react at room temperature for 6 hours. After completion, the reaction was quenched with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase concentrated. The crude product was purified on a silica gel column to yield 1.36 g of the title product as a yellow solid.

[0310] MS (ESI) m / z (M+H) + =261.1.

[0311] Step 3: Preparation of N-ethyl-N-(4-fluorophenyl)-6-oxo-1-(prop-2-yn-1-yl)-1,6-dihydropyridine-2-carboxamide

[0312] To a reaction tube, add N-ethyl-N-(4-fluorophenyl)-6-oxo-1,6-dihydropyridine-2-carboxamide (1.26 g, 4.84 mmol), potassium carbonate (2.01 g, 14.52 mmol), lithium bromide (0.84 g, 9.68 mmol), tetrabutylammonium bromide (0.17 g, 0.53 mmol), toluene (15 mL), and water (1 mL) in sequence. After stirring, slowly add 3-bromopropyne (0.86 g, 7.26 mmol) at room temperature. The reaction system is placed in an 80°C oil bath for 2 hours. After completion, the reaction is quenched with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase is concentrated. The crude product is purified on a silica gel column to yield 0.59 g of the title product.

[0313] MS (ESI) m / z (M+H) + =299.1.

[0314] Preparation Example 18: Preparation of N-(4-fluorophenyl)-N-methyl-6-oxo-1-(prop-2-yn-1-yl)-1,6-dihydropyridine-2-carboxamide

[0315] Step 1: Preparation of N-(4-fluorophenyl)-N-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide

[0316] Dissolve 6-oxo-1,6-dihydropyridine-2-carboxylic acid (1.0 g, 7.19 mmol) in pyridine (15 mL). Add 4-fluoro-N-methylaniline (0.9 g, 7.19 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.0 g, 10.79 mmol) at room temperature. Allow to react at room temperature for 8 hours. After TLC indicates completion of the reaction, concentrate the solvent, add saturated brine to the reaction system, extract several times with ethyl acetate, and dry over anhydrous sodium sulfate. Concentrate the solvent to obtain a crude product, which is purified by column chromatography (dichloromethane / methanol = 10 / 1 (v:v)) to afford 1.6 g of the title compound as a pale yellow oil.

[0317] MS (ESI) m / z (M+H) + =247.2.

[0318] Step 2: Preparation of N-(4-fluorophenyl)-N-methyl-6-oxo-1-(prop-2-yn-1-yl)-1,6-dihydropyridine-2-carboxamide

[0319] Dissolve N-(4-fluorophenyl)-N-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (1.5 g, 6.21 mmol) in N,N-dimethylformamide (20 mL). Add 3-bromopropyne (1.5 g, 12.42 mmol) and potassium carbonate (1.7 g, 12.42 mmol) at room temperature. Incubate at 50°C for 1 hour. After TLC indicates completion of the reaction, add saturated brine to the reaction system, extract several times with ethyl acetate, and dry over anhydrous sodium sulfate. Concentrate the solvent to obtain the crude product, which is then purified by column chromatography (petroleum ether / ethyl acetate = 1 / 3 (v:v)) to afford 1.5 g of the title compound as a brown oil.

[0320] MS (ESI) m / z (M+H) + =285.2.

[0321] Preparation Example 19: Preparation of 6-(3-phenylmorpholine-4-carbonyl)-1-(prop-2-yn-1-yl)pyridin-2(1H)-one

[0322] Step 1: Preparation of 6-(3-phenylmorpholine-4-carbonyl)pyridin-2(1H)-one

[0323] Dissolve 6-oxo-1,6-dihydropyridine-2-carboxylic acid (450.0 mg, 3.24 mmol) in pyridine (10 mL). Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (619.0 mg, 3.24 mmol) and 3-phenylmorpholine (528.0 mg, 3.24 mmol) sequentially. Allow to react at room temperature for 4 hours. After TLC indicates the reaction is complete, add 200 mL of water and extract three times with ethyl acetate. The organic phases are combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1 (v:v)) to yield 900 mg of the title compound as a white solid.

[0324] MS (ESI) m / z (M+H) + =285.1.

[0325] Step 2: Preparation of 6-(3-phenylmorpholine-4-carbonyl)-1-(prop-2-yn-1-yl)pyridin-2(1H)-one

[0326] 6-(3-Phenylmorpholine-4-carbonyl)pyridin-2(1H)-one (550.0 mg, 1.94 mmol) was dissolved in toluene (10 mL) and water (0.5 mL). Potassium carbonate (535.0 mg, 3.88 mmol), lithium bromide (337.0 g, 3.88 mmol), tetrabutylammonium bromide (66.0 mg, 0.21 mmol), and propargyl bromide (230.0 mg, 1.94 mmol) were added sequentially at room temperature. The mixture was allowed to react at 80°C for 8 hours. After TLC indicated completion of the reaction, 100 mL of water was added to the system. The system was extracted three times with ethyl acetate. The organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to afford 310 mg of the title compound as a yellow liquid.

[0327] MS (ESI) m / z (M+H) + =323.1.

[0328] Preparation Example 20: Preparation of N-methyl-N-(naphthalen-2-yl)-6-oxo-1-(prop-2-yn-1-yl)-1,6-dihydropyridine-2-carboxamide

[0329] Step 1: Preparation of tert-butyl N-(naphthalen-2-yl)carbamate

[0330] To a reaction tube, add 2-naphthaleneamine (2.0 g, 13.97 mmol), di-tert-butyl dicarbonate (4.57 g, 20.96 mmol), and methanol (30 mL) in sequence. Stir thoroughly and allow to react at 100°C for 3 hours. After completion, quench the reaction with water, extract three times with ethyl acetate, dry over anhydrous sodium sulfate, filter under reduced pressure, and concentrate the organic phase. The crude product is purified on a silica gel column to yield 3.0 g of the title product as an orange-red solid.

[0331] MS (ESI) m / z (M+H-56) + =188.2.

[0332] Step 2: Preparation of tert-butyl N-methyl-N-(naphthalen-2-yl)carbamate

[0333] To a reaction tube, tert-butyl N-(naphthalen-2-yl)carbamate (3.0 g, 12.33 mmol) and tetrahydrofuran (20 mL) were added sequentially. Sodium hydride (0.36 g, 14.80 mmol) was then slowly added with stirring. After uniform stirring, iodomethane (2.10 g, 14.80 mmol) was added dropwise. The reaction system was left to react at room temperature for 2 hours. After completion, the reaction was quenched with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase concentrated. The crude product was purified on a silica gel column to yield 3.0 g of the title product as an orange-red solid.

[0334] MS (ESI) m / z (M+H-56) + =202.1.

[0335] Step 3: Preparation of N-methylnaphthalene-2-amine

[0336] To a reaction tube, tert-butyl N-methyl-N-(naphthalen-2-yl)carbamate (3.0 g, 11.66 mmol), trifluoroacetic acid (7.65 g, 67.09 mmol), and dichloromethane (10 mL) were added sequentially and allowed to react at room temperature for 4 hours. After completion, the reaction was quenched with saturated sodium bicarbonate solution, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase concentrated. The crude product was purified on a silica gel column to yield 1.70 g of the title product as a red oil.

[0337] MS (ESI) m / z (M+H) + =158.1.

[0338] Step 4: Preparation of N-methyl-N-(naphthalen-2-yl)-6-oxo-1,6-dihydropyridine-2-carboxamide

[0339] To a reaction tube, 6-oxo-1,6-dihydropyridine-2-carboxylic acid (0.96 g, 6.87 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (2.93 g, 15.26 mmol), pyridine (5 mL), and dichloromethane (5 mL) were added sequentially. After stirring, N-methylnaphthalene-2-amine (1.2 g, 7.63 mmol) was added dropwise. The reaction was then allowed to react at room temperature for 4 hours. After completion, the reaction was quenched with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase concentrated. The crude product was purified on a silica gel column to yield 1.30 g of the title product as a yellow solid.

[0340] MS (ESI) m / z (M+H) + =279.2.

[0341] Step 5: Preparation of N-methyl-N-(naphthalen-2-yl)-6-oxo-1-(prop-2-yn-1-yl)-1,6-dihydropyridine-2-carboxamide

[0342] To a reaction tube, add N-methyl-N-(naphthalen-2-yl)-6-oxo-1,6-dihydropyridine-2-carboxamide (1 g, 3.59 mmol), potassium carbonate (1.49 g, 10.77 mmol), lithium bromide (0.62 g, 7.18 mmol), tetrabutylammonium bromide (0.12 g, 0.36 mmol), and N,N-dimethylformamide (15 mL). After stirring, slowly add 3-bromopropyne (0.64 g, 5.38 mmol) at room temperature. The reaction system is placed in a 65°C oil bath for 2 hours. After completion, the reaction is quenched with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase concentrated. The crude product is purified on a silica gel column to yield 0.40 g of the title product as a yellow syrup.

[0343] MS (ESI) m / z (M+H) + =317.2.

[0344] Preparation Example 21: Preparation of N-(4-fluorophenyl)-N-methyl-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-2-carboxamide

[0345] Step 1: Preparation of N-(4-fluorophenyl)-N-methyl-4-(trifluoromethyl)pyridine-2-carboxamide

[0346] 4-(Trifluoromethyl)pyridine-2-carboxylic acid (1 g, 5.23 mmol) was dissolved in pyridine (20 mL). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 g, 6.28 mmol) and 4-fluoro-N-methylaniline (0.79 g, 6.28 mmol) were added. The reaction was allowed to proceed at room temperature for 12 hours. After LC-MS indicated completion of the reaction, the system was concentrated, the acid was adjusted, and reverse phase purification was performed to obtain 1.38 g of the title compound as an oil.

[0347] MS (ESI) m / z (M+H) + =299.1.

[0348] Step 2: Preparation of 2-((4-fluorophenyl)(methyl)carbamoyl)-4-(trifluoromethyl)pyridine 1-oxide

[0349] Weigh N-(4-fluorophenyl)-N-methyl-4-(trifluoromethyl)pyridine-2-carboxamide (1.38 g, 4.63 mmol) and dissolve it in dichloromethane (20 mL). Add m-chloroperbenzoic acid (3.2 g, 18.52 mmol) under ice-cooling. Allow to react at room temperature for 12 hours. LC-MS indicates the reaction is complete. Adjust the system to alkaline with saturated sodium bicarbonate solution and extract three times with dichloromethane. The organic phase is concentrated and purified on a silica gel column to obtain 1.4 g of the crude title compound.

[0350] MS (ESI) m / z (M+H) + =315.1.

[0351] Step 3: Preparation of 6-chloro-N-(4-fluorophenyl)-N-methyl-4-(trifluoromethyl)pyridine-2-carboxamide

[0352] 2-((4-Fluorophenyl)(methyl)carbamoyl)-4-(trifluoromethyl)pyridine 1-oxide (1.4 g, 4.46 mmol) was weighed and dissolved in acetonitrile (20 mL). Phosphorus oxychloride (4.07 mL, 44.6 mmol) was added under ice-cooling. The mixture was heated to 100°C and allowed to react for 12 hours. LC-MS indicated the reaction was complete. The system was reduced to dryness and the saturated sodium bicarbonate solution was reduced. The product was extracted three times with ethyl acetate. The organic phase was concentrated and purified on a silica gel column to afford 660 mg of the title compound as a pale white solid.

[0353] MS (ESI) m / z (M+H) + =333.1.

[0354] Step 4: Preparation of N-(4-fluorophenyl)-N-methyl-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-2-carboxamide

[0355] 6-Chloro-N-(4-fluorophenyl)-N-methyl-4-(trifluoromethyl)pyridine-2-carboxamide (300 mg, 0.9 mmol) was dissolved in N-methylpyrrolidone (20 mL). Boric acid (83.47 mg, 1.35 mmol), palladium acetate (20.21 mg, 0.09 mmol), 2-(di-tert-butylphosphino)-3,6-dimethoxy-2',4',6'tri-isopropyl-1,1'-biphenyl (87.24 mg, 0.18 mmol), and cesium carbonate (586.48 mg, 1.8 mmol) were added. The atmosphere was purged with nitrogen three times and heated to 100°C for 3 hours. After LC-MS indicated the reaction was complete, the mixture was filtered, the filtrate was concentrated, and purified on a silica gel column to obtain 70 mg of the title compound as an oil.

[0356] MS (ESI) m / z (M+H) + =315.1.

[0357] Preparation Example A1: Preparation of tert-butyl N-(5-amino-6-iodo-3-methylpyridin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate

[0358] Step 1: Preparation of tert-butyl N-[(tert-butoxy)carbonyl]-N-(3-methyl-5-nitropyridin-2-yl)carbamate

[0359] 3-Methyl-5-nitropyridin-2-amine (9.0 g, 58.8 mmol) was dissolved in dichloromethane (100 mL). Di-tert-butyl dicarbonate (12.8 g, 58.8 mmol) and 4-dimethylaminopyridine (7.2 g, 16.0 mmol) were added sequentially in an ice-water bath. The mixture was allowed to react at room temperature for 3 hours. After TLC indicated completion of the reaction, the mixture was added dropwise to 500 mL of water in an ice-water bath. The mixture was extracted three times with ethyl acetate. The organic phases were combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1 (v:v)) to yield 20.0 g of the title compound as a white solid.

[0360] MS (ESI) m / z (M+H) + =354.1.

[0361] Step 2: Preparation of tert-butyl N-(5-amino-3-methylpyridin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate

[0362] Tert-butyl N-[(tert-butoxy)carbonyl]-N-(3-methyl-5-nitropyridin-2-yl)carbamate (20.0 g, 56.7 mmol) was dissolved in methanol (200 mL), and palladium carbon (4.0 g, 10% (W / W)) was slowly added in batches at 0°C. After the addition, the hydrogen was replaced three times, and then the reaction was carried out under a hydrogen atmosphere at room temperature for 10 hours. TLC showed that the starting material was completely consumed. The system was filtered and concentrated to obtain 18.0 g of an oily product, which was directly used in the next reaction.

[0363] MS (ESI) m / z (M+H) + =324.1.

[0364] Step 3: Preparation of tert-butyl N-(5-amino-6-iodo-3-methylpyridin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate

[0365] Dissolve tert-butyl N-(5-amino-3-methylpyridin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate (18.0 g, 55.7 mmol) in N,N-dimethylformamide (100 mL). Add N-iodosuccinimide (12.5 g, 55.7 mmol) at 0°C. After addition, allow to react at room temperature for 1 hour. After TLC indicates the reaction is complete, add 1 L of water and extract five times with ethyl acetate. The organic phases are combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is purified by column chromatography (dichloromethane / methanol = 20 / 1 (v:v)) to yield 15.0 g of the title compound as a solid.

[0366] MS (ESI) m / z (M+H) + =450.1.

[0367] Preparation Example A2: Preparation of tert-butyl (tert-butoxycarbonyl)(6-iodo-3-methyl-5-(2,2,2-trifluoroacetylamino)pyridin-2-yl)carbamate

[0368] Dissolve tert-butyl (5-amino-6-iodo-3-methylpyridin-2-yl)(tert-butoxycarbonyl)carbamate (4.493 g, 10 mmol) in dichloromethane (100 mL). Add trifluoroacetic anhydride (1.67 mL, 12 mmol) and triethylamine (2.78 mL, 20 mmol) at room temperature. Allow to react at room temperature for 2 hours. After TLC indicates completion of the reaction, add saturated brine to the reaction system, extract several times with dichloromethane, and dry over anhydrous sodium sulfate. Concentrate the solvent to obtain a crude product, which is purified by column chromatography to yield 5.18 g of the title product.

[0369] MS (ESI) m / z (M+H) + =546.1.

[0370] Preparation Example A3: Preparation of N-(2-chlorophenyl)-N-methyl-6-oxo-1-(prop-2-yn-1-yl)-1,6-dihydropyridine-2-carboxamide

[0371] Step 1: Preparation of 6-chloro-N-(2-chlorophenyl)-N-methylpyridine-2-carboxamide

[0372] To a reaction tube, add 2-chloro-N-methylaniline (1.0 g, 7.06 mmol), 6-chloropyridine-2-carboxylic acid (1.0 g, 6.35 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (2.03 g, 10.59 mmol), pyridine (5 mL), and dichloromethane (5 mL) in sequence; after stirring, the reaction system was left to react at room temperature for 4 hours. After completion, the reaction was quenched with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase concentrated. The crude product was purified on a silica gel column to yield 0.80 g of the title product as a yellow solid.

[0373] MS (ESI) m / z (M+H) + =281.2.

[0374] Step 2: Preparation of N-(2-chlorophenyl)-N-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide

[0375] To a reaction tube, 6-chloro-N-(2-chlorophenyl)-N-methylpyridine-2-carboxamide (720 mg, 2.56 mmol), boric acid (0.24 g, 3.84 mmol), palladium acetate (29 mg, 0.13 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl (160 mg, 0.32 mmol), and cesium carbonate (1.67 g, 5.12 mmol) were added sequentially. The nitrogen atmosphere was replaced three times, and then N-methylpyrrolidin-2-one (5 mL) was added. After stirring, the reaction was incubated at 80°C for 2 hours. After completion, the reaction was quenched with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase concentrated. The crude product was purified on a silica gel column to afford 600 mg of the title product as a pale yellow solid.

[0376] MS (ESI) m / z (M+H) + =263.1.

[0377] Step 3: Preparation of N-(2-chlorophenyl)-N-methyl-6-oxo-1-(prop-2-yn-1-yl)-1,6-dihydropyridine-2-carboxamide

[0378] To a reaction tube, add N-(2-chlorophenyl)-N-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (0.70 g, 2.66 mmol), potassium carbonate (1.10 g, 7.98 mmol), lithium bromide (0.46 g, 5.32 mmol), tetrabutylammonium bromide (0.086 g, 0.27 mmol), and N,N-dimethylformamide (10 mL) in sequence. After stirring, 3-bromopropyne (0.32 g, 2.66 mmol) was slowly added at room temperature. The reaction system was placed in an oil bath at 60°C for 2 hours. After completion, the reaction was quenched with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase concentrated. The crude product was purified on a silica gel column to yield 0.35 g of the title product as a brown oil.

[0379] MS (ESI) m / z (M+H) + =301.2.

[0380] Preparation Example A4: Preparation of tert-butyl N-((tert-butoxy)carbonyl)-N-(3-chloro-6-iodo-5-(trifluoroacetylamino)pyridin-2-yl)carbamate

[0381] Step 1: Preparation of tert-butyl N-((tert-butoxy)carbonyl)-N-(3-chloro-5-nitropyridin-2-yl)carbamate

[0382] Dissolve 3-chloro-5-nitropyridin-2-amine (3.0 g, 17.29 mmol) in dichloromethane (40 mL). Add di-tert-butyl dicarbonate (9.4 g, 43.22 mmol) and 4-dimethylaminopyridine (0.4 g, 3.46 mmol) at room temperature. Allow to react at room temperature for 8 hours. After TLC indicates completion of the reaction, add saturated brine to the reaction system, extract several times with ethyl acetate, and dry over anhydrous sodium sulfate. Concentrate the solvent to obtain a crude product, which is purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1 (v:v)) to yield 2.4 g of the title compound as a pale yellow solid.

[0383] MS (ESI) m / z (M+H) + =374.1.

[0384] Step 2: Preparation of tert-butyl N-(5-amino-3-chloropyridin-2-yl)-N-((tert-butoxy)carbonyl)carbamate

[0385] Dissolve tert-butyl N-((tert-butoxy)carbonyl)-N-(3-chloro-5-nitropyridin-2-yl)carbamate (2.0 g, 5.35 mmol) in ethanol (30 mL) and water (10 mL). Add iron powder (0.6 g, 10.7 mmol) and ammonium chloride (0.8 g, 16.05 mmol) at room temperature. After addition, react at 80°C for 3 hours. After TLC indicates completion of the reaction, filter the hot solids and concentrate the solvent to obtain the crude product, which is purified by column chromatography (dichloromethane / methanol = 15 / 1 (v:v)) to afford 1.5 g of the title compound as a pale yellow solid.

[0386] MS (ESI) m / z (M+H) + =344.2.

[0387] Step 3: Preparation of tert-butyl N-(5-amino-3-chloro-6-iodopyridin-2-yl)-N-((tert-butoxy)carbonyl)carbamate

[0388] Dissolve tert-butyl N-(5-amino-3-chloropyridin-2-yl)-N-((tert-butoxy)carbonyl)carbamate (1.5 g, 4.36 mmol) in N,N-dimethylformamide (10 mL). Add N-iodosuccinimide (1.08 g, 4.80 mmol) and trifluoroacetic acid (0.025 g, 0.22 mmol) at room temperature. Allow to react at room temperature for 5 hours. After TLC indicates completion of the reaction, add saturated brine to the reaction system, extract several times with ethyl acetate, and dry over anhydrous sodium sulfate. Concentrate the solvent to obtain a crude product, which is purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1 (v:v)) to afford 1.0 g of the title compound as a pale yellow solid.

[0389] MS (ESI) m / z (M+H) + =470.1.

[0390] Step 4: Preparation of tert-butyl N-((tert-butoxy)carbonyl)-N-(3-chloro-6-iodo-5-(trifluoroacetylamino)pyridin-2-yl)carbamate

[0391] Dissolve tert-butyl N-(5-amino-3-chloro-6-iodopyridin-2-yl)-N-((tert-butoxy)carbonyl)carbamate (1.0 g, 2.13 mmol) in dichloromethane (10 mL). Add triethylamine (0.4 g, 4.26 mmol) and trifluoroacetic anhydride (0.5 g, 2.34 mmol) at room temperature. Allow to react at room temperature for 1 hour. After TLC indicates completion of the reaction, add saturated brine to the reaction system, extract several times with ethyl acetate, and dry over anhydrous sodium sulfate. Concentrate the solvent to obtain the crude product, which is purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1 (v:v)) to afford 1.0 g of the title compound as a pale yellow solid.

[0392] MS (ESI) m / z (M+H) + =566.1.

[0393] Preparation Example A5: Preparation of N-(4-fluorophenyl)-N-methyl-6-oxo-1-(prop-2-yn-1-yl)-1,6-dihydropyridine-2-carboxamide

[0394] Step 1: Preparation of N-(4-fluorophenyl)-N-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide

[0395] Dissolve 6-oxo-1,6-dihydropyridine-2-carboxylic acid (1.0 g, 7.19 mmol) in pyridine (15 mL). Add 4-fluoro-N-methylaniline (0.9 g, 7.19 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.0 g, 10.79 mmol) at room temperature. Allow to react at room temperature for 8 hours. After TLC indicates completion of the reaction, concentrate the solvent, add saturated brine to the reaction system, extract several times with ethyl acetate, and dry over anhydrous sodium sulfate. Concentrate the solvent to obtain a crude product, which is purified by column chromatography (dichloromethane / methanol = 10 / 1 (v:v)) to afford 1.6 g of the title compound as a pale yellow oil.

[0396] MS (ESI) m / z (M+H) + =247.2.

[0397] Step 2: Preparation of N-(4-fluorophenyl)-N-methyl-6-oxo-1-(prop-2-yn-1-yl)-1,6-dihydropyridine-2-carboxamide

[0398] Dissolve N-(4-fluorophenyl)-N-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (1.5 g, 6.21 mmol) in N,N-dimethylformamide (20 mL). Add 3-bromopropyne (1.5 g, 12.42 mmol) and potassium carbonate (1.7 g, 12.42 mmol) at room temperature. Incubate at 50°C for 1 hour. After TLC indicates completion of the reaction, add saturated brine to the reaction system, extract several times with ethyl acetate, and dry over anhydrous sodium sulfate. Concentrate the solvent to obtain the crude product, which is then purified by column chromatography (petroleum ether / ethyl acetate = 1 / 3 (v:v)) to afford 1.5 g of the title compound as a brown oil.

[0399] MS (ESI) m / z (M+H) + =285.2.

[0400] Preparation Example A6: Preparation of (5-(bis(4-methoxybenzyl)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)methanol

[0401] Step 1: Preparation of 3-bromo-N,N-bis[(4-methoxyphenyl)methyl]-6-methyl-5-nitropyridin-2-amine

[0402] Dissolve 3-bromo-2-chloro-6-methyl-5-nitropyridine (12 g, 47.72 mmol) and bis[(4-methoxyphenyl)methyl]amine (14.74 g, 57.26 mmol) in tetrahydrofuran (60 mL). Add sodium carbonate (6.07 g, 57.26 mmol) and react at 75°C for 16 hours. After LC-MS indicated completion of the reaction, the mixture was filtered, concentrated, and purified on a silica gel column to afford 11.7 g of the title compound as an oil.

[0403] MS (ESI) m / z (M+H) + =472.1.

[0404] Step 2: Preparation of ethyl 3-(6-(bis[(4-methoxyphenyl)methyl]amino)-5-bromo-3-nitropyridin-2-yl)-2-oxopropanoate

[0405] 3-Bromo-N,N-bis[(4-methoxyphenyl)methyl]-6-methyl-5-nitropyridin-2-amine (11.7 g, 24.77 mmol) was dissolved in diethyl oxalate (10.86 g, 74.31 mmol) and 1,8-diazabicycloundec-7-ene (4.53 g, 29.72 mmol) was added dropwise at 40°C. The mixture was allowed to react for 12 hours at 40°C. LC-MS indicated a small amount of starting material remaining. Water was added to the system and the mixture was extracted three times with ethyl acetate. The organic phase was concentrated and purified on a silica gel column to afford 13 g of the title compound as a pale white solid.

[0406] MS (ESI) m / z (M+H) + =572.1.

[0407] Step 3: Preparation of ethyl 5-(bis(4-methoxybenzyl)amino)-6-bromo-1H-pyrrolo[3,2-b]pyridine-2-carboxylate

[0408] Ethyl 3-(6-(bis[(4-methoxyphenyl)methyl]amino)-5-bromo-3-nitropyridin-2-yl)-2-oxopropanoate (13 g, 22.71 mmol) was dissolved in acetic acid (150 mL) and iron powder (5.07 g, 90.84 mmol) was added. The mixture was allowed to react at room temperature for 12 hours. LC-MS indicated the reaction was complete. Water was added and the mixture was extracted three times with ethyl acetate. The mixture was washed with saturated sodium bicarbonate solution. The organic phase was concentrated and purified on a silica gel column to afford 8.5 g of the title compound as an oil.

[0409] MS (ESI) m / z (M+H) + =524.1.

[0410] Step 4: Preparation of ethyl 5-(bis(4-methoxybenzyl)amino)-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylate

[0411] Ethyl 5-(bis(4-methoxybenzyl)amino)-6-bromo-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (8.5 g, 16.21 mmol) was dissolved in 1,4-dioxane (80 mL). Methylboric acid (3.88 g, 64.84 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (0.59 g, 0.81 mmol), and potassium carbonate (8.96 g, 64.84 mmol) were added sequentially. The atmosphere was purged with nitrogen three times and heated to 110°C for 12 hours. After LC-MS indicated completion of the reaction, the mixture was filtered, the filtrate was concentrated, and purified on a silica gel column to obtain 6 g of the title compound as an oil.

[0412] MS (ESI) m / z (M+H) +=460.2.

[0413] Step 5: Preparation of ethyl 5-(bis(4-methoxybenzyl)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylate

[0414] Dissolve ethyl 5-(bis(4-methoxybenzyl)amino)-6-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (6 g, 13.06 mmol) in tetrahydrofuran (60 mL). Add sodium hydride (0.41 g, 16.98 mmol) portionwise under ice-water bath. After stirring for 20 minutes, add 2-(trimethylsilyl)ethoxymethyl chloride (2.83 g, 16.98 mmol) and react at room temperature for 2 hours. After TLC indicated completion of the reaction, quench with water and extract three times with ethyl acetate. The organic phases were combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, and purified on a silica gel column to afford 7.5 g of the title compound as a white solid.

[0415] MS (ESI) m / z (M+H) + =590.3.

[0416] Step 6: Preparation of (5-(bis[(4-methoxyphenyl)methyl]amino)-6-methyl-1-[(2-(trimethylsilyl)ethoxy)methyl]-1H-pyrrolo[3,2-b]pyridin-2-yl)methanol

[0417] Ethyl 5-(bis(4-methoxybenzyl)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (7.5 g, 12.72 mmol) was dissolved in tetrahydrofuran (100 mL). Lithium aluminum hydride (0.72 g, 19.08 mmol) was added portionwise under an ice-water bath. The temperature was gradually warmed to room temperature and the reaction was allowed to react for 1 hour. LC-MS indicated that the reaction was complete. Water (1 mL) was added under an ice-water bath and stirred for 5 minutes. 15% sodium hydroxide solution (1 mL) was added dropwise followed by water (3 mL). The mixture was stirred at room temperature for 0.5 hour, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purification on a silica gel column afforded 6.8 g of the title compound as an oil.

[0418] MS (ESI) m / z (M+H) + =548.3.

[0419] Preparation Example A7: Preparation of 3-fluoro-N-(4-fluorophenyl)-6-hydroxy-N-methylpyridine-2-carboxamide

[0420] Step 1: Preparation of 6-chloro-3-fluoro-N-(4-fluorophenyl)-N-methylpyridine-2-carboxamide

[0421] 6-Chloro-3-fluoropyridine-2-carboxylic acid (1 g, 5.7 mmol) was dissolved in pyridine (20 mL). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.31 g, 6.84 mmol) and 4-fluoro-N-methylaniline (0.86 g, 6.84 mmol) were added. After the addition was complete, the system was reacted at room temperature for 12 hours. After LC-MS indicated the reaction was complete, the system was concentrated, the acid was adjusted, and reverse phase purification was performed to obtain 1.46 g of the title compound as an oil.

[0422] MS (ESI) m / z (M+H) + =283.1.

[0423] Step 2: Preparation of 3-fluoro-N-(4-fluorophenyl)-6-hydroxy-N-methylpyridine-2-carboxamide

[0424] 6-Chloro-3-fluoro-N-(4-fluorophenyl)-N-methylpyridine-2-carboxamide (1.46 g, 5.17 mmol) was dissolved in N-methylpyrrolidone (10 mL). Boric acid (0.48 g, 7.75 mmol), palladium acetate (0.12 g, 0.52 mmol), 2-(di-tert-butylphosphino)-3,6-dimethoxy-2',4',6'tri-isopropyl-1,1'-biphenyl (0.5 g, 1.03 mmol), and cesium carbonate (3.37 g, 10.34 mmol) were added sequentially. The atmosphere was purged with nitrogen three times, and the reaction system was heated to 80°C for 12 hours. After LC-MS indicated the reaction was complete, the mixture was filtered, the filtrate was concentrated, and purified on a silica gel column to obtain 1.32 g of the title compound as an oil.

[0425] MS (ESI) m / z (M+H) + =265.1.

[0426] Preparation Example A8: Preparation of 3-methyl-N-(4-fluorophenyl)-6-hydroxy-N-methylpyridine-2-carboxamide

[0427] The title compound was prepared using a similar preparation method to that of Preparation Example A7 using corresponding commercial reagents.

[0428] MS (ESI) m / z (M+H) + =261.1.

[0429] Preparation Example A9: Preparation of N-(6-bromo-3-iodo-5-methylpyridin-2-yl)-2,2,2-trifluoroacetamide

[0430] Step 1: Preparation of 6-bromo-3-iodo-5-methylpyridin-2-amine

[0431] Dissolve 6-bromo-5-methylpyridin-2-amine (3.0 g, 16.04 mmol) in N,N-dimethylformamide (30 mL). Add N-iodosuccinimide (3.9 g, 17.64 mmol) and trifluoroacetic acid (0.09 g, 0.80 mmol) at room temperature. Allow to react at room temperature for 2 hours. After TLC indicates completion of the reaction, add saturated brine to the reaction system, extract several times with ethyl acetate, and dry over anhydrous sodium sulfate. Concentrate the solvent to obtain the crude product, which is then purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1 (v:v)) to afford 5.0 g of the title compound as a brown solid.

[0432] MS (ESI) m / z (M+H) + =312.9.

[0433] Step 2: Preparation of N-(6-bromo-3-iodo-5-methylpyridin-2-yl)-2,2,2-trifluoroacetamide

[0434] Dissolve 6-bromo-3-iodo-5-methylpyridin-2-amine (1.0 g, 3.20 mmol) in dichloromethane (10 mL). Add trifluoroacetic anhydride (1.01 g, 4.80 mmol) and triethylamine (0.65 g, 6.4 mmol) at room temperature. Allow to react at room temperature for 2 hours. After TLC indicates completion of the reaction, add saturated brine to the reaction system, extract several times with ethyl acetate, and dry over anhydrous sodium sulfate. Concentrate the solvent to obtain the crude product, which is then purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1 (v:v)) to afford 1.2 g of the title compound as a pale yellow solid.

[0435] MS (ESI) m / z (M+H) + =408.8.

[0436] Preparation Example A10: Preparation of tert-butyl N-(3-bromo-5-nitropyridin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate

[0437] 3-Bromo-5-nitropyridin-2-amine (5.0 g, 23.0 mmol) was dissolved in dichloromethane (100 mL). Di-tert-butyl dicarbonate (10.0 g, 46.0 mmol) and 4-dimethylaminopyridine (2.8 g, 23.0 mmol) were added sequentially under ice-cooling conditions. The mixture was allowed to react at room temperature for 3 hours. After TLC indicated completion of the reaction, the mixture was added dropwise to 500 mL of water under ice-cooling conditions. The mixture was extracted three times with ethyl acetate. The organic phases were combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1 (v:v)) to yield 9.0 g of the title compound as a white solid.

[0438] MS (ESI) m / z (M+H) + =418.1.

[0439] Preparation Example A11: Preparation of tert-butyl N-[(tert-butoxy)carbonyl]-N-(3-cyclopropyl-5-nitropyridin-2-yl)carbamate

[0440] tert-Butyl N-(3-bromo-5-nitropyridin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate (2.0 g, 4.8 mmol), cyclopropylboronic acid (413.0 mg, 4.8 mmol), and potassium carbonate (1.3 g, 9.6 mmol) were dissolved in dioxane / water (10.0 mL / 1.0 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (350 mg, 0.5 mmol) was added. The reaction was continued at 90°C for 1 hour. TLC indicated complete consumption of the starting material. Water (10 mL) was added and the mixture was extracted with ethyl acetate. The organic phase was backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then spin-dried to dryness. The crude product was separated by column chromatography (PE / EA = 4 / 1) to yield 1.0 g of the title compound as a yellow oil.

[0441] MS (ESI) m / z (M+H) + =380.2.

[0442] Preparation Example A12: Preparation of tert-butyl N-[(tert-butoxy)carbonyl]-N-(5-nitro-3-(prop-1-en-2-yl)pyridin-2-yl)carbamate

[0443] tert-Butyl N-(3-bromo-5-nitropyridin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate (2.0 g, 4.8 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (805.0 mg, 4.8 mmol), and potassium carbonate (1.3 g, 9.6 mmol) were dissolved in dioxane / water (10.0 mL / 1.0 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (350 mg, 0.5 mmol) was added. The system was reacted at 90°C for 1 hour. TLC indicated complete consumption of the starting material. Water (10 mL) was added, and the mixture was extracted with ethyl acetate. The organic phase was backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and spin-dried. The obtained crude product was separated by column chromatography (PE / EA=4 / 1) to obtain 1.2 g of the title compound as a yellow oil.

[0444] MS (ESI) m / z (M+H) + =380.2.

[0445] Preparation Examples A13-A15:

[0446] Using corresponding commercial reagents and a preparation method similar to that of Preparation Example A4, Preparation Examples A13-A15 can be prepared, as shown in the following table.

[0447] Preparation Example A16: Preparation of tert-butyl (5-amino-3-ethyl-6-iodopyridin-2-yl)(tert-butoxycarbonyl)carbamate

[0448] Step 1: Preparation of 3-ethyl-5-nitropyridin-2-amine

[0449] A concentrated nitric acid / sulfuric acid mixture (1.4 mL / 11 mL) was slowly added dropwise to a solution of 3-ethylpyridin-2-amine (4.0 g, 32.74 mmol) in concentrated sulfuric acid (11 mL) in an ice-water bath. After the addition was complete, the reaction system was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was diluted with water (10 mL), the pH was adjusted to 7-8 with saturated sodium bicarbonate solution, and then extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the solvent was concentrated to yield 3.5 g of crude product, which was used directly in the next reaction without further purification.

[0450] MS (ESI) m / z (M+H) + =168.1.

[0451] Step 2: Preparation of tert-butyl (tert-butoxycarbonyl)(3-ethyl-5-nitropyridin-2-yl)carbamate

[0452] Dissolve 3-ethyl-5-nitro-pyridin-2-amine (4.37 g, 26.14 mmol) in tetrahydrofuran (300 ml). Add 4-dimethylaminopyridine (10.5 g, 85.95 mmol) and di-tert-butyl dicarbonate (13.5 g, 61.93 mmol) at room temperature. Incubate the reaction system at room temperature for 2 hours. Concentrate the reaction solution, and purify the crude product by silica gel chromatography to obtain 3.50 g of the title compound as a yellow solid.

[0453] MS (ESI) m / z (M+H) + =368.4.

[0454] Step 3: Preparation of tert-butyl (5-amino-3-ethylpyridin-2-yl)(tert-butoxycarbonyl)carbamate

[0455] Dissolve tert-butyl (tert-butoxycarbonyl)(3-ethyl-5-nitropyridin-2-yl)carbamate (3.5 g, 9.53 mmol) in methanol (30 mL) and add palladium / carbon (300 mg, 2.47 mmol). After replacing the hydrogen three times, the reaction system was allowed to react under a hydrogen atmosphere at room temperature for 2 hours. After completion of the reaction, the reaction system was cooled to room temperature, filtered through celite, and the filter cake was washed with methanol. The filtrate was concentrated to obtain 3.20 g of the title compound.

[0456] MS (ESI) m / z (M+H) + =338.3.

[0457] Step 4: Preparation of tert-butyl (5-amino-3-ethyl-6-iodopyridin-2-yl)(tert-butoxycarbonyl)carbamate:

[0458] Dissolve tert-butyl (5-amino-3-ethylpyridin-2-yl)(tert-butoxycarbonyl)carbamate (3.20 g, 9.48 mmol) in N,N-dimethylformamide (15 mL). Add N-iodosuccinimide (6.3 g, 28.00 mmol) at room temperature. After addition, the reaction system was allowed to react at room temperature for 16 hours. After monitoring the reaction, the reaction solution was diluted with water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain a crude product, which was then concentrated and purified by column chromatography to obtain 2.20 g of the title compound.

[0459] MS (ESI) m / z (M+H) + =464.2.

[0460] Preparation Example A17: Preparation of 6-(6-fluoro-1,2,3,4-tetrahydroquinoline-1-carbonyl)-1-(prop-2-yn-1-yl)-1,2-dihydropyridin-2-one

[0461] Preparation Example A17 can be obtained by using corresponding commercial reagents and a preparation method similar to the above Preparation Example A5.

[0462] MS (ESI) m / z (M+H) + =311.1.

[0463] Preparation Example A18: Preparation of 6-chloro-5-fluoro-2-iodopyridin-3-amine

[0464] Step 1: Preparation of tert-butyl N-(6-chloro-5-fluoropyridin-3-yl)carbamate

[0465] 5-Bromo-2-chloro-3-fluoropyridine (4.0 g, 19.01 mmol) was dissolved in 1,4-dioxane (80 mL). T-butyl carbamate (2.6 g, 22.81 mmol), tris(dibenzylideneacetone)dipalladium (1.7 g, 1.90 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (2.2 g, 3.80 mmol), and cesium carbonate (12.4 g, 38.02 mmol) were added at room temperature. After replacing the inert atmosphere, the mixture was reacted at 90°C for 8 hours. After TLC indicated completion of the reaction, saturated brine was added to the reaction system, and the mixture was extracted several times with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain a crude product, which was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1 (v:v)) to afford 2.0 g of the title compound as a pale yellow oil.

[0466] (ESI)m / z(M+H) + =247.7.

[0467] Step 2: Preparation of 6-chloro-5-fluoropyridin-3-amine

[0468] Dissolve tert-butyl N-(6-chloro-5-fluoropyridin-3-yl)carbamate (1.9 g, 7.70 mmol) in a solution of hydrochloric acid (0.6 g, 15.02 mmol) in 1,4-dioxane (2 mL). Allow to react at room temperature for 2 hours. After TLC indicates completion, concentrate the solvent, add sodium bicarbonate to the reaction system, adjust the mixture to neutrality, extract several times with ethyl acetate, and dry over anhydrous sodium sulfate. Concentrate the solvent to obtain a crude product, which is purified by column chromatography (dichloromethane / methanol = 10 / 1 (v:v)) to afford 1.0 g of the title compound as a pale yellow solid.

[0469] MS (ESI) m / z (M+H) + =147.5.

[0470] Step 3: Preparation of 6-chloro-5-fluoro-2-iodopyridin-3-amine

[0471] Dissolve 6-chloro-5-fluoropyridin-3-amine (1.0 g, 6.82 mmol) in N,N-dimethylformamide (10 mL). Add N-iodosuccinimide (3.1 g, 13.64 mmol) at room temperature. Allow to react at room temperature for 8 hours. After TLC indicates the reaction has terminated, add saturated brine to the reaction system, extract several times with ethyl acetate, and dry over anhydrous sodium sulfate. Concentrate the solvent to obtain a crude product, which is purified by column chromatography (dichloromethane / methanol = 15 / 1 (v:v)) to afford 0.2 g of the title compound as a pale yellow solid.

[0472] MS (ESI) m / z (M+H) + =273.5.

[0473] Preparation A19: N-(6-chloro-5-fluoro-2-iodopyridin-3-yl)-2,2,2-trifluoroacetamide

[0474] Preparation Example A19 can be obtained by using a similar preparation method to the above Preparation Example A2 using corresponding commercial reagents.

[0475] MS (ESI) m / z (M+H) + =369.0.

[0476] Preparation Example A20: Preparation of N-methyl-N-(5-methylpyridin-2-yl)-6-oxo-1-(prop-2-yn-1-yl)-1,6-dihydropyridine-2-carboxamide

[0477] Step 1: Preparation of N,5-dimethylpyridin-2-amine

[0478] To the reaction flask, 5-methylpyridin-2-amine (2 g, 18.49 mmol), aqueous formaldehyde solution (0.83 g, 27.73 mmol), methanol (30 mL), and acetic acid (1 mL) were added sequentially. After the addition was complete, the reaction was stirred at room temperature for 1 hour. Sodium cyanoborohydride (3.49 g, 55.47 mmol) was slowly added and stirred until uniform. The reaction was allowed to react at room temperature for 4 hours. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase was concentrated. The crude product was purified on a silica gel column to obtain 0.54 g of the title product as a pale yellow liquid.

[0479] MS (ESI) m / z (M+H) + =123.1.

[0480] Step 2: Preparation of 6-methoxy-N-methyl-N-(5-methylpyridin-2-yl)pyridine-2-carboxamide

[0481] To a reaction tube, add N,5-dimethylpyridin-2-amine (220 mg, 1.80 mmol), 6-methoxypyridine-2-carboxylic acid (0.28 g, 1.8 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.52 g, 2.7 mmol), pyridine (4 mL), and dichloromethane (2 mL) in sequence. After stirring, the reaction system was left to react at room temperature for 4 hours. After completion, the reaction was quenched with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase concentrated. The crude product was purified on a silica gel column to yield 0.30 g of the title product as a yellow oil.

[0482] MS (ESI) m / z (M+H) + =258.2.

[0483] Step 3: Preparation of N-methyl-N-(5-methylpyridin-2-yl)-6-oxo-1,6-dihydropyridine-2-carboxamide

[0484] To the reaction flask was added 6-methoxy-N-methyl-N-(5-methylpyridin-2-yl)pyridine-2-carboxamide (290 mg, 1.13 mmol), acetic acid (4 mL), and hydrobromic acid (2 mL) in sequence, and the reaction was placed at 80 ° C for 2 hours. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate solution, followed by extraction three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting mixture was purified by silica gel column to obtain 200 mg of the title product as a yellow solid.

[0485] MS (ESI) m / z (M+H) + =244.2.

[0486] Step 4: Preparation of N-methyl-N-(5-methylpyridin-2-yl)-6-oxo-1-(prop-2-yn-1-yl)-1,6-dihydropyridine-2-carboxamide

[0487] To a reaction tube, N-methyl-N-(5-methylpyridin-2-yl)-6-oxo-1,6-dihydropyridine-2-carboxamide (0.21 g, 0.86 mmol), potassium carbonate (0.36 g, 2.58 mmol), lithium bromide (0.15 g, 1.72 mmol), tetrabutylammonium bromide (0.03 g, 0.09 mmol), and N,N-dimethylformamide (10 mL) were added sequentially. After stirring, 3-bromopropyne (0.15 g, 1.29 mmol) was slowly added at room temperature. The reaction system was then placed in a 60°C oil bath for 2 hours. After completion, the reaction was quenched with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase concentrated. The crude product was purified on a silica gel column to yield 0.15 g of the title product as a yellow solid.

[0488] MS (ESI) m / z (M+H) + =282.2.

[0489] Preparation Examples A21-A26:

[0490] Using corresponding commercial reagents and a similar preparation method to the above-mentioned Preparation Example A20, Preparation Examples A21-A26 can be prepared, as shown in the following table.

[0491] Preparation A27: Preparation of 6-chloro-2-iodo-5-methoxypyridin-3-amine

[0492] Step 1: Preparation of tert-butyl N-(6-chloro-5-methoxypyridin-3-yl)carbamate

[0493] To the reaction tube were added 5-bromo-2-chloro-3-methoxypyridine (1.5 g, 6.74 mmol), tert-butyl carbamate (1.18 g, 10.11 mmol), cesium carbonate (4.39 g, 13.48 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.29 g, 0.51 mmol), palladium acetate (0.23 g, 1.01 mmol), and 1,4-dioxane (20 mL) in sequence. After replacing nitrogen three times, the reaction was placed at 100 ° C for 3 hours. After the reaction was complete, the reaction was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting mixture was purified by silica gel column to obtain 1.30 g of the title product as a yellow solid.

[0494] MS (ESI) m / z (M-56+H) + =259.1.

[0495] Step 2: Preparation of 6-chloro-5-methoxypyridin-3-amine

[0496] To a reaction tube was added tert-butyl N-(6-chloro-5-methoxypyridin-3-yl)carbamate (1.3 g, 5.04 mmol), trifluoroacetic acid (4 mL), and dichloromethane (4 mL) in sequence, and the reaction was allowed to react at room temperature for 3 hours. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting mixture was purified by silica gel column chromatography to obtain 0.60 g of the title product as a yellow solid.

[0497] MS (ESI) m / z (M+H) + =159.1.

[0498] Step 3: Preparation of 6-chloro-2-iodo-5-methoxypyridin-3-amine

[0499] To a reaction tube, 6-chloro-5-methoxypyridin-3-amine (600 mg, 3.78 mmol), N-iodosuccinimide (0.94 g, 4.16 mmol), and N,N-dimethylformamide (5 mL) were added in sequence. After stirring evenly, the reaction was allowed to react at room temperature for 2 hours. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase was concentrated. The crude product was purified by silica gel column to obtain 833 mg of the title product as a yellow solid.

[0500] MS (ESI) m / z (M+H) + =285.1.

[0501] Preparation Example A28: Preparation of N-(5-fluoro-6-methylpyridin-2-yl)-N-methyl-6-oxo-1-(prop-2-yn-1-yl)-1,6-dihydropyridine-2-carboxamide

[0502] Step 1: Preparation of 5-fluoro-N,6-dimethylpyridin-2-amine

[0503] 5-Fluoro-6-methylpyridin-2-amine (10.0 g, 79.28 mmol), paraformaldehyde (8.1 g, 158.6 mmol), sodium methoxide (42.8 g, 792.8 mmol), and sodium borohydride (9.04 g, 237.9 mmol) were dissolved in methanol (120.0 mL). The reaction mixture was stirred at 40°C for 16 hours. LCMS indicated the reaction was complete. The reaction mixture was diluted with water, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the product was separated and purified by column chromatography to obtain 7.2 g of the title compound as an off-white solid.

[0504] MS (ESI) m / z (M+H) + =141.1.

[0505] Step 2: Preparation of N-(5-fluoro-6-methylpyridin-2-yl)-N-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide

[0506] 6-Oxo-1,6-dihydropyridine-2-carboxylic acid (7.5 g, 53.91 mmol), 5-fluoro-N,6-dimethylpyridin-2-amine (5.0 g, 35.94 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (20.49 g, 53.91 mmol), and N,N-diisopropylethylamine (11.59 g, 89.86 mmol) were dissolved in N,N-dimethylformamide (120.0 mL). The reaction mixture was stirred at room temperature for 16 hours. LCMS indicated the reaction was complete. The reaction mixture was diluted with water, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the residue was separated and purified by column chromatography to obtain 5.6 g of the title compound as a brown solid.

[0507] MS (ESI) m / z (M+H) + =262.1.

[0508] Step 3: Preparation of N-(5-fluoro-6-methylpyridin-2-yl)-N-methyl-6-oxo-1-(prop-2-yn-1-yl)-1,6-dihydropyridine-2-carboxamide

[0509] N-(5-Fluoro-6-methylpyridin-2-yl)-N-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (4.0 g, 15.31 mmol) and 3-bromopropyne (3.6 g, 30.62 mmol) were dissolved in acetonitrile (50.0 mL), followed by the addition of potassium carbonate (3.6 g, 26.02 mmol). After the addition was complete, the reaction system was stirred at 70°C for 6 hours. LCMS indicated that the starting materials had reacted substantially completely. The reaction mixture was diluted with water, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the residue was separated and purified by column chromatography to obtain 1.4 g of the target compound as a brown oil.

[0510] MS (ESI) m / z (M+H) + =300.1.

[0511] Preparation Example A29: Preparation of 6-chloro-2-iodo-5-(trifluoromethyl)pyridin-3-amine

[0512] Dissolve 6-chloro-5-(trifluoromethyl)pyridin-3-amine (1 g, 5.09 mmol) in N,N-dimethylformamide (10 mL). Add N-iodosuccinimide (1.37 g, 6.11 mmol) and trifluoroacetic acid (0.19 mL, 2.54 mmol) dropwise at room temperature. React at 80°C for 8 hours. After LC-MS indicated completion of the reaction, the system was concentrated and purified on a silica gel column to afford 1.44 g of the title compound as an oil.

[0513] MS (ESI) m / z (M+H) + =323.1.

[0514] Preparation Example A30: Preparation of 3,5-dibromo-6-methylpyrazin-2-amine

[0515] Dissolve 6-methylpyrazin-2-amine (2.0 g, 18.33 mmol) in dichloromethane (20 mL). Add N-bromosuccinimide (7.2 g, 40.33 mmol) in portions at 0°C. Allow to react at 0°C for 1 hour. After TLC indicates completion of the reaction, add saturated brine to the reaction system, extract several times with ethyl acetate, and dry over anhydrous sodium sulfate. Concentrate the solvent to obtain a crude product, which is then purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1 (v:v)) to afford 2.1 g of the title compound as a pale yellow solid.

[0516] MS (ESI) m / z (M+H) + =265.9.

[0517] Preparation Example A31: Preparation of N-(2-chloro-4-fluorophenyl)-6-hydroxy-N,3-dimethylpyridine-2-carboxamide

[0518] Step 1: Preparation of 6-chloro-N-(2-chloro-4-fluorophenyl)-3-methylpyridine-2-carboxamide

[0519] 6-Chloro-3-methylpyridine-2-carboxylic acid (1 g, 5.83 mmol) was dissolved in pyridine (20 mL). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.34 g, 7 mmol) and 2-chloro-4-fluoroaniline (1.02 g, 7 mmol) were added. The reaction was allowed to react at room temperature for 12 hours. After LC-MS indicated completion of the reaction, the system was concentrated, the acid was adjusted, and reverse phase purification was performed to obtain 1.74 g of the title compound as a white solid.

[0520] MS (ESI) m / z (M+H) + =299.1.

[0521] Step 2: Preparation of 6-chloro-N-(2-chloro-4-fluorophenyl)-N,3-dimethylpyridine-2-carboxamide

[0522] 6-Chloro-N-(2-chloro-4-fluorophenyl)-3-methylpyridine-2-carboxamide (1.82 g, 5.82 mmol) was dissolved in tetrahydrofuran (30 mL). Sodium hydride (0.35 g, 8.73 mmol) was added portionwise under ice-cooling. After the addition, the mixture was stirred for 15 minutes. Methyl iodide (0.54 mL, 8.73 mmol) was then added dropwise under ice-cooling. The mixture was gradually warmed to room temperature and stirred for 2 hours. After LC-MS indicated the reaction was complete, the mixture was quenched with ammonium chloride solution and extracted three times with ethyl acetate. The organic phase was dried and concentrated to yield 1.82 g of the title compound as an oil.

[0523] MS (ESI) m / z (M+H) + =313.1.

[0524] Step 3: Preparation of N-(2-chloro-4-fluorophenyl)-6-hydroxy-N,3-dimethylpyridine-2-carboxamide

[0525] 6-Chloro-N-(2-chloro-4-fluorophenyl)-N,3-dimethylpyridine-2-carboxamide (200 mg, 0.65 mmol) was dissolved in N-methylpyrrolidone (5 mL). Boric acid (48.23 mg, 0.78 mmol), palladium acetate (14.59 mg, 0.065 mmol), 2-(di-tert-butylphosphino)-3,6-dimethoxy-2',4',6'tri-isopropyl-1,1'-biphenyl (63.01 mg, 0.13 mmol), and cesium carbonate (423.57 mg, 1.3 mmol) were added. The atmosphere was purged with nitrogen three times and heated to 80°C for 12 hours. LC-MS indicated the presence of a small amount of starting material. The reaction was stopped, the system was filtered, and the product was purified by reverse phase chromatography to obtain 0.85 g of the title compound as an off-white solid.

[0526] MS (ESI) m / z (M+H) + =295.1.

[0527] Preparation Example A32: Preparation of N-(2-chloro-4-fluoro-3-methylphenyl)-N-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide

[0528] Preparation Example A32 can be prepared using a similar method to the above Preparation Example A31 using corresponding commercial reagents.

[0529] MS (ESI) m / z (M+H) + =295.1.

[0530] Preparation Example A33: Preparation of tert-butyl N-(5-amino-4-fluoro-6-iodo-3-methylpyridin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate

[0531] Step 1: Preparation of tert-butyl N-(4-fluoropyridin-2-yl)carbamate

[0532] To the reaction flask, 4-fluoropyridin-2-amine (2 g, 17.84 mmol), di-tert-butyl dicarbonate (5.84 g, 26.76 mmol), 4-dimethylaminopyridine (3 mg, 0.018 mmol) and dichloromethane (50 mL) were added in sequence. After stirring evenly, the reaction was allowed to react at room temperature for 2 hours. After the reaction was complete, it was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting mixture was purified by silica gel column to obtain 1.78 g of the title product as a white solid.

[0533] MS (ESI) m / z (M-56+H) + =157.0.

[0534] Step 2: Preparation of tert-butyl N-(4-fluoro-3-methylpyridin-2-yl)carbamate

[0535] tert-Butyl N-(4-fluoropyridin-2-yl)carbamate (1.7 g, 8.01 mmol) was added to tetrahydrofuran (15 mL), followed by N,N,N',N'-tetramethylethylenediamine (3.31 g, 19.22 mmol). The mixture was reacted at -78°C under nitrogen for 30 minutes. Then, n-butyllithium (1.54 g, 24.03 mmol) was added dropwise. The reaction was continued at -78°C for 1 hour. Methyl iodide (3.41 g, 24.03 mmol) was added dropwise and the reaction was continued for 1 hour. The mixture was then warmed to room temperature and allowed to react for 2 hours at room temperature. After completion of the reaction, the reaction system was added dropwise to saturated ammonium chloride, extracted with ethyl acetate, dried, and slurried with petroleum ether to obtain 1.70 g of the title product as a white solid.

[0536] MS (ESI) m / z (M-56+H) + =171.0.

[0537] Step 3: Preparation of 4-fluoro-3-methylpyridin-2-amine

[0538] To a reaction tube was added tert-butyl N-(4-fluoro-3-methylpyridin-2-yl)carbamate (1.6 g, 7.08 mmol), trifluoroacetic acid (3 mL), and dichloromethane (2 mL) in sequence, and the reaction was allowed to react at room temperature for 3 hours. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting mixture was purified by silica gel column to obtain 0.85 g of the title product as a light yellow solid.

[0539] MS (ESI) m / z (M+H) + =127.1.

[0540] Step 4: Preparation of 5-bromo-4-fluoro-3-methylpyridin-2-amine

[0541] To the reaction flask, 4-fluoro-3-methylpyridin-2-amine (786 mg, 6.23 mmol) and tetrahydrofuran (10 mL) were added in sequence, and then N-bromosuccinimide (1.22 g, 6.85 mmol) was slowly added under an ice-water bath. After stirring evenly, the reaction was continued at this temperature for 2 hours. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase was concentrated. The crude product was purified by silica gel column to obtain 1.1 g of the title product as a yellow solid.

[0542] MS (ESI) m / z (M+H) + =205.1.

[0543] Step 5: Preparation of tert-butyl N-(5-bromo-4-fluoro-3-methylpyridin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate

[0544] To the reaction flask, 5-bromo-4-fluoro-3-methylpyridin-2-amine (800 mg, 3.90 mmol), 4-dimethylaminopyridine (0.048 g, 0.39 mmol), and tetrahydrofuran (10 mL) were added sequentially, followed by di-tert-butyl dicarbonate (1.79 g, 8.19 mmol). After stirring, the reaction was allowed to proceed at room temperature for 2 hours. After completion, water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase was concentrated. The crude product was purified on a silica gel column to afford 875 mg of the title product as a yellow solid.

[0545] MS (ESI) m / z (M-156+H) + =251.1.

[0546] Step 6: Preparation of tert-butyl N-[(tert-butoxy)carbonyl]-N-(5-[(diphenylmethylene)amino]-4-fluoro-3-methylpyridin-2-yl)carbamate

[0547] To a reaction tube were added tert-butyl N-(5-bromo-4-fluoro-3-methylpyridin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate (870 mg, 2.15 mmol), benzophenone imine (0.47 g, 2.58 mmol), cesium carbonate (2.0 g, 6.15 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (149.28 mg, 0.26 mmol), palladium acetate (57.92 mg, 0.26 mmol), and 1,4-dioxane (10 mL) in sequence. After replacing nitrogen three times, the reaction was placed at 100 ° C for 3 hours. After the reaction was complete, it was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column to obtain 950 mg of the title compound as a brown solid.

[0548] MS (ESI) m / z (M+H) + =506.3.

[0549] Step 7: Preparation of tert-butyl N-(5-amino-4-fluoro-3-methylpyridin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate

[0550] To the reaction flask, tert-butyl N-[(tert-butoxy)carbonyl]-N-(5-[(diphenylmethylene)amino]-4-fluoro-3-methylpyridin-2-yl)carbamate (1.1 g, 2.18 mmol), sodium acetate (27.07 mg, 0.33 mmol), and hydroxylamine hydrochloride (454.46 mg, 6.54 mmol) were added sequentially. Methanol (10 mL) was then added and stirred thoroughly. The reaction was allowed to react at room temperature for 2 hours. After completion, water was added to quench the reaction, and the product was extracted three times with ethyl acetate. The product was dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase was concentrated. The crude product was purified on a silica gel column to afford 540 mg of the title compound as a pale yellow solid.

[0551] MS (ESI) m / z (M+H) + =342.2.

[0552] Step 8: Preparation of tert-butyl N-(5-amino-4-fluoro-6-iodo-3-methylpyridin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate

[0553] To a reaction tube, tert-butyl N-(5-amino-4-fluoro-3-methylpyridin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate (540 mg, 1.58 mmol), N-iodosuccinimide (0.39 g, 1.74 mmol), and N,N-dimethylformamide (10 mL) were added in sequence. After stirring evenly, the reaction was allowed to react at room temperature for 2 hours. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase was concentrated. The crude product was purified by silica gel column chromatography to obtain 560 mg of the title compound as a brown solid.

[0554] MS (ESI) m / z (M-156+H) + =312.1.

[0555] Preparation Example A34: Preparation of tert-butyl N-(5-amino-6-iodo-3,4-dimethylpyridin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate

[0556] Preparation Example A34 can be prepared using corresponding commercial reagents and a similar method to Steps 4-8 of Preparation Example A33 above.

[0557] MS (ESI) m / z (M-156+H) + =308.1.

[0558] Preparation Example A35: Preparation of 2,6-dibromo-4-chloro-5-methylpyridin-3-amine

[0559] Step 1: Preparation of 4-chloro-5-methylpyridin-3-amine

[0560] 5-Bromo-4-chloropyridin-3-amine (400.0 mg, 1.93 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (282.4 mg, 0.39 mmol), and potassium carbonate (533.4 mg, 3.86 mmol) were weighed into a reaction tube. The atmosphere was purged with nitrogen. A solution of trimethylcyclotriboroxine (484.5 mg, 3.86 mmol) in 1,4-dioxane (5 mL) and water (1 mL) were added, and the atmosphere was purged with nitrogen again. The system was heated to 80°C and reacted for 8 hours. After TLC indicated the reaction was complete, saturated brine was added to the reaction system, and the mixture was extracted several times with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain a crude product, which was purified by column chromatography (dichloromethane / ethyl acetate = 2 / 1 (v:v)) to afford 100.0 mg of the title compound as a pale yellow solid.

[0561] MS (ESI) m / z (M+H) + =143.2.

[0562] Step 3: Preparation of 2,6-dibromo-4-chloro-5-methylpyridin-3-amine

[0563] Dissolve 4-chloro-5-methylpyridin-3-amine (80.0 mg, 0.56 mmol) in tetrahydrofuran (3 mL). Add N-bromosuccinimide (219.2 mg, 1.23 mmol) under ice. After addition, slowly return the mixture to room temperature and react for 2 hours. After TLC indicates completion of the reaction, add saturated brine to the reaction system, extract several times with ethyl acetate, and dry over anhydrous sodium sulfate. Concentrate the solvent to obtain the crude product, which is purified by column chromatography (dichloromethane / ethyl acetate = 1 / 1 (v:v)) to afford 120.0 mg of the title compound as a pale yellow solid.

[0564] MS (ESI) m / z (M+H) + =298.8.

[0565] Preparation Example A36: Preparation of 5-fluoro-N-(4-fluorophenyl)-6'-hydroxy-N-methyl-[3,4'-bipyridine]-2'-carboxamide

[0566] Step 1: Preparation of 4-bromo-N-(4-fluorophenyl)-N-methylpyridine-2-carboxamide

[0567] 4-Bromopyridine-2-carboxylic acid (10 g, 49.5 mmol) was dissolved in pyridine (100 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.9 g, 59.4 mmol) and 4-fluoro-N-methylaniline (7.43 g, 59.4 mmol) were added. After the addition was complete, the system was reacted at room temperature for 12 hours. After LC-MS indicated the reaction was complete, the system was concentrated, the acid was adjusted, and reverse phase purification was performed to obtain 15.18 g of the title compound as an oil.

[0568] MS (ESI) m / z (M+H) + =309.1.

[0569] Step 2: Preparation of 4-bromo-2-((4-fluorophenyl)(methyl)carbamoyl)pyridine 1-oxide

[0570] 4-Bromo-N-(4-fluorophenyl)-N-methylpyridine-2-carboxamide (15 g, 48.52 mmol) was weighed and dissolved in dichloromethane (100 mL). m-Chloroperbenzoic acid (12.56 g, 72.78 mmol) was added under ice-cooling. After addition, the mixture was allowed to react at room temperature for 12 hours. LC-MS indicated completion of the reaction. The saturated sodium bicarbonate solution was reduced, and the mixture was extracted three times with dichloromethane. The organic phase was concentrated and purified on a silica gel column to yield 15.78 g of the title compound.

[0571] MS (ESI) m / z (M+H) + =325.1.

[0572] Step 3: Preparation of 5-fluoro-2'-((4-fluorophenyl)(methyl)carbamoyl)-[3,4'-bipyridine] 1'-oxide

[0573] 4-Bromo-2-((4-fluorophenyl)(methyl)carbamoyl)pyridine 1-oxide (500 mg, 1.54 mmol) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (343.5 mg, 1.54 mmol) were dissolved in 1,4-dioxane (20 mL) and water (2 mL). Dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (112.68 mg, 0.15 mmol) and potassium carbonate (425.69 mg, 3.08 mmol) were then added. The atmosphere was purged with nitrogen three times and the reaction was incubated at 80°C for 2 hours. LC-MS indicated the reaction was complete. The system was filtered through celite, and the filtrate was concentrated to dryness. Purification on a silica gel column afforded 520 mg of the title compound as a pale white solid.

[0574] MS (ESI) m / z (M+H) + =342.1.

[0575] Step 4: Preparation of 6'-chloro-5-fluoro-N-(4-fluorophenyl)-N-methyl-[3,4'-bipyridine]-2'-carboxamide

[0576] 5-Fluoro-2'-((4-fluorophenyl)(methyl)carbamoyl)-[3,4'-bipyridine]1'-oxide (520 mg, 1.52 mmol) was dissolved in acetonitrile (5 mL) and phosphorus oxychloride (1.39 mL, 15.2 mmol) was added under ice-cooling. After addition, the mixture was heated to 80°C and allowed to react for 12 hours. LC-MS indicated completion of the reaction. The system was concentrated, the sodium bicarbonate solution was reduced, and the mixture was extracted three times with dichloromethane. The organic phase was dried, concentrated, and purified on a silica gel column to afford 382 mg of the title compound.

[0577] MS (ESI) m / z (M+H) + =360.1.

[0578] Step 5: Preparation of 5-fluoro-N-(4-fluorophenyl)-6'-hydroxy-N-methyl-[3,4'-bipyridine]-2'-carboxamide

[0579] 6'-Chloro-5-fluoro-N-(4-fluorophenyl)-N-methyl-[3,4'-bipyridine]-2'-carboxamide (382 mg, 1.06 mmol) was dissolved in N-methylpyrrolidone (8 mL). Boric acid (98.31 mg, 1.59 mmol), palladium acetate (23.8 mg, 0.106 mmol), 2-(di-tert-butylphosphino)-3,6-dimethoxy-2',4',6'tri-isopropyl-1,1'-biphenyl (102.75 mg, 0.21 mmol), and cesium carbonate (690.74 mg, 2.12 mmol) were added. The atmosphere was purged with nitrogen three times and the system was heated to 90°C for 5 hours. LC-MS indicated a low amount of starting material, so the reaction was stopped, the system was filtered, and the product was purified by reverse phase chromatography to obtain 55 mg of the title compound as a white solid.

[0580] MS (ESI) m / z (M+H) + =342.1.

[0581] Preparation Example A37: Preparation of N-(4-fluorophenyl)-6'-hydroxy-N-methyl-5-(trifluoromethyl)-[3,4'-bipyridine]-2'-carboxamide

[0582] This preparation example can be prepared using a similar preparation method to the above-mentioned Preparation Example A36 using corresponding commercial reagents.

[0583] MS (ESI) m / z (M+H) + =392.2.

[0584] Preparation A38: N-(4-Fluorophenyl)-N-methyl-6-oxo-4-phenyl-1,6-dihydropyridine-2-carboxamide

[0585] This preparation example can be prepared using a similar preparation method to the above-mentioned Preparation Example A36 using corresponding commercial reagents.

[0586] MS (ESI) m / z (M+H) + =323.2.

[0587] Preparation Example A39: Preparation of N-(4-fluorophenyl)-N-methyl-4-(1-methylpyrazol-4-yl)-6-oxo-1-prop-2-ynylpyridine-2-carboxamide

[0588] Step 1: Preparation of N-(4-fluorophenyl)-N-methyl-4-(1-methylpyrazol-4-yl)-1-pyridin-1-ium oxide-2-carboxamide

[0589] 4-Bromo-2-((4-fluorophenyl)(methyl)carbamoyl)pyridine 1-oxide (2.0 g, 6.15 mmol) was dissolved in 1,4-dioxane (50.0 mL), and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.92 g, 9.23 mmol), tetrakistriphenylphosphine palladium (0.5 g, 0.62 mmol), and potassium phosphate (3.26 g, 15.38 mmol) were added. After the addition was complete, the reaction system was stirred at 80°C under a nitrogen atmosphere for 6 hours. LCMS showed that the starting material had been substantially reacted. The reaction solution was diluted with water, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the residue was separated and purified by column chromatography to obtain 1.54 g of the target compound as a yellow solid.

[0590] MS (ESI) m / z (M+H) + =327.1.

[0591] Step 2: Preparation of N-(4-fluorophenyl)-N-methyl-4-(1-methylpyrazol-4-yl)-6-oxo-1H-pyridine-2-carboxamide

[0592] N-(4-Fluorophenyl)-N-methyl-4-(1-methylpyrazol-4-yl)-1-pyridinium-1-oxide-2-carboxamide (1.4 g, 4.29 mmol) was dissolved in ultra-dry tetrahydrofuran (50.0 mL), followed by the slow addition of triethylamine (0.65 g, 6.44 mmol). The temperature was lowered to 0°C, and trifluoroacetic anhydride (1.35 g, 6.44 mmol) was added. After the addition was complete, the reaction system was stirred at 25°C for 16 hours. LCMS indicated that the starting material had reacted substantially completely. The reaction mixture was diluted with water, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was concentrated and purified by column chromatography to afford 1.0 g of the title compound.

[0593] MS (ESI) m / z (M+H) + =327.1.

[0594] Step 3: Preparation of N-(4-fluorophenyl)-N-methyl-4-(1-methylpyrazol-4-yl)-6-oxo-1-prop-2-ynylpyridine-2-carboxamide

[0595] N-(4-Fluorophenyl)-N-methyl-4-(1-methylpyrazol-4-yl)-6-oxo-1H-pyridine-2-carboxamide (900 mg, 2.76 mmol), 3-bromopropyne (656.2 mg, 5.52 mmol), and potassium carbonate (762.3 mg, 5.52 mmol) were dissolved in acetonitrile (50.0 mL). The reaction solution was stirred at 60°C for 6 hours. LCMS showed the reaction was complete. The reaction solution was diluted with water, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the residue was separated and purified by column chromatography to obtain 480 mg of the title compound.

[0596] MS (ESI) m / z (M+H) + =365.1.

[0597] Preparation Example A40: Preparation of 5-fluoro-6-isopropyl-N-methylpyridin-2-amine

[0598] Step 1: Preparation of 6-bromo-5-fluoropyridine-2-carbonyl azide:

[0599] 6-Bromo-5-fluoropyridine-2-carboxylic acid (10.0 g, 45.46 mmol) was dissolved in 1,4-dioxane (100.0 mL). Diphenylphosphoryl azide (16.6 g, 68.18 mmol) and triethylamine (6.9 g, 68.18 mmol) were added, and the reaction mixture was stirred at room temperature for 16 hours. LCMS indicated the reaction was complete. The reaction mixture was diluted with water, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. Concentration afforded 9.3 g of a brown solid compound, which was used directly in the next reaction.

[0600] MS (ESI) m / z (M+H) + =244.9 / 246.9.

[0601] Step 2: Preparation of tert-butyl (6-bromo-5-fluoropyridin-2-yl)carbamate

[0602] Dissolve 9.3 g of 6-bromo-5-fluoropyridine-2-carbonyl azide in 1.4-dioxane (100.0 mL). The temperature was lowered to 0°C, and tert-butyl carbamate (5.3 g, 45.5 mmol) was added. The reaction mixture was stirred at 70°C for 3 hours. LCMS indicated completion of the reaction. The reaction mixture was diluted with water, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the residue was separated and purified by column chromatography to yield 7.5 g of the title compound as a yellow solid.

[0603] MS (ESI) m / z (M+H) + =291.0 / 293.0.

[0604] Step 3: Preparation of tert-butyl (6-bromo-5-fluoropyridin-2-yl)(methyl)carbamate

[0605] Dissolve tert-butyl (6-bromo-5-fluoropyridin-2-yl)carbamate (3.0 g, 10.31 mmol) in N,N-dimethylformamide (50.0 mL). The mixture was cooled to 0°C and sodium hydride (742.0 mg, 30.92 mmol) was slowly added. After addition, the reaction system was stirred at 25°C for 0.5 hours. The temperature was again lowered to 0°C and iodomethane (2.19 g, 15.46 mmol) was added. After addition, the reaction system was stirred at 25°C for 3 hours. LCMS indicated that the starting material had reacted substantially completely. The reaction solution was diluted with water, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the residue was separated and purified by column chromatography to afford 2.5 g of the title compound as a brown oil.

[0606] MS (ESI) m / z (M-56+H) + =249.1 / 251.1.

[0607] Step 4: Preparation of tert-butyl (5-fluoro-6-(prop-1-en-2-yl)pyridin-2-yl)(methyl)carbamate

[0608] Dissolve tert-butyl (6-bromo-5-fluoropyridin-2-yl)(methyl)carbamate (2.0 g, 6.55 mmol) in 1,4-dioxane (50.0 mL) / water (5.0 mL). Then add 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.65 g, 9.83 mmol), tetrakistriphenylphosphine palladium (533.5 mg, 0.65 mmol), and potassium phosphate (3.47 g, 16.39 mmol). After the addition is complete, the reaction system is stirred at 80°C for 16 hours. LCMS indicates that the starting material has reacted substantially completely. The reaction solution is diluted with water, and the aqueous phase is extracted with ethyl acetate. The organic phases are combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the residue is separated and purified by column chromatography to obtain 1.5 g of the title compound as a brown oil.

[0609] MS (ESI) m / z (M+H) + =267.1.

[0610] Step 5: Preparation of tert-butyl (5-fluoro-6-isopropylpyridin-2-yl)(methyl)carbamate

[0611] Tert-butyl (5-fluoro-6-(prop-1-en-2-yl)pyridin-2-yl)(methyl)carbamate (1.4 g, 5.26 mmol) was dissolved in anhydrous methanol (50.0 mL), followed by the slow addition of palladium on carbon (0.14 g). After the addition was complete, the hydrogen atmosphere was replaced three times, and the reaction system was stirred under a hydrogen atmosphere at 25°C for 16 hours. LCMS indicated that the starting materials had essentially reacted completely, and the reaction solution was filtered. After concentration, the residue was separated and purified by column chromatography to afford 1.3 g of the title compound as a yellow oil.

[0612] MS (ESI) m / z (M+H) + =269.1.

[0613] Step 6: Preparation of 5-fluoro-6-isopropyl-N-methylpyridin-2-amine

[0614] Dissolve tert-butyl (5-fluoro-6-isopropylpyridin-2-yl)(methyl)carbamate (1.3 g, 4.84 mmol) in dichloromethane (50.0 mL), followed by the slow addition of trifluoroacetic acid (10 mL). After the addition is complete, stir the reaction system at 25°C for 16 hours. LCMS indicates that the starting material has reacted substantially completely. Adjust the pH to 8 with aqueous sodium bicarbonate. The aqueous phase is extracted with dichloromethane, and the combined organic phases are washed with saturated brine and dried over anhydrous sodium sulfate. The solution is concentrated and purified by column chromatography to afford 700 mg of the title compound as a yellow solid.

[0615] MS (ESI) m / z (M+H) + =169.1.

[0616] Preparation Example A41: Preparation of N-(5-fluoro-6-isopropylpyridin-2-yl)-N-methyl-6-oxo-1-(prop-2-yn-1-yl)-1,6-dihydropyridine-2-carboxamide

[0617] This preparation can be prepared using a similar preparation method to the above-mentioned Preparation A28 using corresponding commercial reagents.

[0618] MS (ESI) m / z (M+H) + =328.1.

[0619] Preparation Example A42: Preparation of N-(5-fluoro-6-methylpyridin-2-yl)-N,3-dimethyl-6-oxo-1-(prop-2-yn-1-yl)-1,6-dihydropyridine-2-carboxamide

[0620] Step 1: Preparation of 4-fluoro-N,5-dimethylpyridin-2-amine

[0621] To a reaction flask, 4-fluoro-5-methylpyridin-2-amine (1 g, 7.93 mmol), paraformaldehyde (0.48 g, 15.86 mmol), sodium methoxide (2.57 g, 47.58 mmol), and methanol (10 mL) were added sequentially. After stirring, the reaction was incubated at 40°C for 2 hours. The reaction system was then cooled to room temperature, and sodium borohydride (1.20 g, 31.72 mmol) was slowly added. After stirring, the reaction was allowed to react overnight at room temperature. After completion, water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase was concentrated. The crude product was purified on a silica gel column to obtain 1.05 g of the title product as a white solid.

[0622] MS (ESI) m / z (M+H) + =141.2.

[0623] Step 2: Preparation of 6-chloro-N-(5-fluoro-6-methylpyridin-2-yl)-N,3-dimethylpyridine-2-carboxamide

[0624] To a dry reaction tube were added 5-fluoro-N,6-dimethylpyridin-2-amine (743 mg, 5.30 mmol), 6-chloro-3-methylpyridine-2-carboxylic acid (909.37 mg, 5.3 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (2.03 g, 10.6 mmol), and dichloromethane (10 mL); the reaction mixture was allowed to react at room temperature for 2 hours. After the reaction was complete, the mixture was extracted with dichloromethane, the organic layers were combined, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase was concentrated. The crude product was purified by silica gel column to obtain 1.3 g of the title compound as a light yellow solid.

[0625] MS (ESI) m / z (M+H) + =294.1.

[0626] Step 3: Preparation of N-(5-fluoro-6-methylpyridin-2-yl)-N,3-dimethyl-6-oxo-1,6-dihydropyridine-2-carboxamide

[0627] To the reaction tube were added 6-chloro-N-(5-fluoro-6-methylpyridin-2-yl)-N,3-dimethylpyridine-2-carboxamide (1.2 g, 4.09 mmol), 2-(di-tert-butylphosphino)-3,6-dimethoxy-2',4',6'tri-isopropyl-1,1'-biphenyl (0.25 g, 0.51 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'tri-isopropyl-1,1'-biphenyl (0.25 g, 0.51 mmol), and 1,1'-dimethyl-2-thiazolinone (0.1 g, 0.2 g). Propyl-1,1′-biphenyl (0.38 g, 6.13 mmol), cesium carbonate (2.67 g, 8.18 mmol), and palladium acetate (2.67 g, 8.18 mmol) were added. After replacing the nitrogen atmosphere three times, 1,4-dioxane (8 mL) was added and stirred thoroughly. The reaction was allowed to proceed at 90°C overnight. After completion, water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase was concentrated. The crude product was purified on a silica gel column to afford 887 mg of the title compound as a light yellow solid.

[0628] MS (ESI) m / z (M+H) + =276.1.

[0629] Step 4: Preparation of N-(5-fluoro-6-methylpyridin-2-yl)-N,3-dimethyl-6-oxo-1-(prop-2-yn-1-yl)-1,6-dihydropyridine-2-carboxamide

[0630] To a reaction flask, add N-(5-fluoro-4-methylpyridin-2-yl)-N-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (800 mg, 2.91 mmol), potassium carbonate (1.21 g, 8.73 mmol), tetrabutylammonium bromide (0.094 g, 0.29 mmol), and lithium bromide (0.76 g, 8.73 mmol). After mixing, slowly add 3-bromopropyne (0.52 g, 4.37 mmol) and N,N-dimethylformamide (8 mL). The reaction is then allowed to react at 80°C overnight. After completion, the reaction is quenched with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase concentrated. The crude product is purified on a silica gel column to afford 380 mg of the title product as a pale yellow solid.

[0631] MS (ESI) m / z (M+H) + =314.2.

[0632] Preparation Example B1: Preparation of tert-butyl N-(5-amino-3-fluoro-6-iodo-2-pyridyl)-N-tert-butoxycarbonylcarbamate

[0633] Step 1: Preparation of 3-fluoro-5-nitropyridin-2-amine

[0634] Dissolve 2-chloro-3-fluoro-5-nitropyridine (5.0 g, 28.32 mmol) in 50 mL of 7 M ammonia in methanol. Heat the reaction to 50°C and stir for 16 hours. LCMS indicates completion of the reaction. Concentrate the reaction mixture to yield 4.17 g of 3-fluoro-5-nitropyridine-2-amine as a yellow solid, which is used directly in the next reaction.

[0635] MS (ESI) m / z (M+H) + =158.0.

[0636] Step 2: Preparation of tert-butyl N-(3-fluoro-5-nitro-2-pyridyl)-N-tert-butoxycarbonylcarbamate

[0637] Dissolve 3-fluoro-5-nitropyridin-2-amine (5.0 g, 38.21 mmol) in dichloromethane (40 mL). Add di-tert-butyl dicarbonate (14.39 g, 76.43 mmol) and 4-dimethylaminopyridine (7.77 g, 76.43 mmol) sequentially. Stir at room temperature for 16 hours. LCMS indicates that the starting materials are essentially reacted. Dilute the reaction solution with water, adjust the pH to 6 with dilute hydrochloric acid, and extract with dichloromethane. The combined organic phases are washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, column chromatography is performed to obtain 4.2 g of the title compound as a yellow solid.

[0638] MS (ESI) m / z (M+Na) + =380.2.

[0639] Step 3: Preparation of tert-butyl N-(5-amino-3-fluoro-2-pyridyl)-N-tert-butoxycarbonyl-carbamate

[0640] Dissolve tert-butyl N-(3-fluoro-5-nitro-2-pyridyl)-N-tert-butoxycarbonylcarbamate (4.2 g, 11.76 mmol) in a mixture of methanol (40 mL) and water (8 mL). Add ammonium chloride (3.24 g, 58.82 mmol) and iron powder (3.29 g, 58.82 mmol). After addition, stir the reaction mixture at 60°C for 2 hours. LCMS indicated that the starting material was substantially reacted. Filter the reaction mixture through celite, concentrate the filtrate, and purify it by column chromatography to obtain 3.6 g of the title compound as a brown solid.

[0641] MS (ESI) m / z (M+H) + =328.2.

[0642] Step 4: Preparation of tert-butyl N-(5-amino-3-fluoro-6-iodo-2-pyridyl)-N-tert-butoxycarbonylcarbamate

[0643] Dissolve tert-butyl N-(5-amino-3-fluoro-2-pyridyl)-N-tert-butoxycarbonyl-carbamate (3.5 g, 10.69 mmol) in acetonitrile (40 mL) and add N-iodosuccinimide (2.41 g, 10.69 mmol). After addition, stir the reaction system at 25°C for 16 hours. LCMS indicated that the starting material was substantially reacted. The reaction mixture was quenched by adding saturated sodium sulfite solution, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the product was separated and purified by column chromatography to yield 4.2 g of the title compound as a brown solid.

[0644] MS (ESI) m / z (M+Na) + =476.3.

[0645] Preparation Example B2: Preparation of tert-butyl (tert-butoxycarbonyl)(3-fluoro-6-iodo-5-(2,2,2-trifluoroacetylamino)pyridin-2-yl)carbamate

[0646] Preparation Example B2 can be obtained by using a similar preparation method to the above Preparation Example A2 using corresponding commercial reagents.

[0647] MS (ESI) m / z (M+H) + =550.2.

[0648] Preparation Example B3: Preparation of N-[(4-fluorophenyl)methyl]-N-(1-methyl-1H-pyrazol-3-yl)-6-oxo-1-(prop-2-yn-1-yl)-1,6-dihydropyridine-2-carboxamide

[0649] Step 1: Preparation of N-[(4-fluorophenyl)methyl]-1-methyl-1H-pyrazol-3-amine

[0650] To a reaction flask, 4-fluorobenzaldehyde (2 g, 16.11 mmol), 1-methyl-1H-pyrazol-3-amine (2.35 g, 24.16 mmol), and methanol (30 mL) were added sequentially. A catalytic amount of acetic acid was added dropwise and stirred thoroughly. The reaction was incubated at 40°C for 2 hours. The reaction system was then cooled to room temperature and sodium cyanoborohydride (0.029 g, 0.76 mmol) was slowly added. After stirring thoroughly, the reaction was allowed to react overnight at room temperature. After completion, the reaction was quenched with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase concentrated. The crude product was purified on a silica gel column to afford 1.5 g of the title compound as a white solid.

[0651] MS (ESI) m / z (M+H) + =206.1.

[0652] Step 2: Preparation of N-[(4-fluorophenyl)methyl]-N-(1-methyl-1H-pyrazol-3-yl)-6-oxo-1,6-dihydropyridine-2-carboxamide

[0653] To a dry reaction tube, add N-[(4-fluorophenyl)methyl]-1-methyl-1H-pyrazol-3-amine (1.5 g, 7.31 mmol), 6-oxo-1,6-dihydropyridine-2-carboxylic acid (1.02 g, 7.31 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (2.80 g, 14.62 mmol), dichloromethane (10 mL), and pyridine (2 mL). The reaction mixture was allowed to react at room temperature for 1 hour. After the reaction was complete, the mixture was extracted with dichloromethane. The organic layers were combined and dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by silica gel column to obtain 1.3 g of the title product as a yellow solid.

[0654] MS (ESI) m / z (M+H) + =327.2.

[0655] Step 3: Preparation of N-[(4-fluorophenyl)methyl]-N-(1-methyl-1H-pyrazol-3-yl)-6-oxo-1-(prop-2-yn-1-yl)-1,6-dihydropyridine-2-carboxamide

[0656] To a reaction flask, N-[(4-fluorophenyl)methyl]-N-(1-methyl-1H-pyrazol-3-yl)-6-oxo-1,6-dihydropyridine-2-carboxamide (1.27 g, 3.89 mmol), potassium carbonate (1.61 g, 11.67 mmol), tetrabutylammonium bromide (0.13 g, 0.39 mmol), lithium bromide (1.01 g, 11.67 mmol), and N,N-dimethylformamide (20 mL) were added sequentially. After mixing, 3-bromopropyne (0.69 g, 5.83 mmol) was slowly added. The reaction was then incubated at 80°C for 12 hours. After completion, the reaction was quenched with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase concentrated. The crude product was purified on a silica gel column to obtain 0.90 g of the title product as a yellow liquid.

[0657] MS (ESI) m / z (M+H) + =365.2.

[0658] Preparation Examples B4 to B9:

[0659] Using corresponding commercial reagents and a similar preparation method to the above-mentioned Preparation Examples A36 and A39, Preparation Examples B4 to B9 can be prepared, as shown in the following table.

[0660] Preparation Examples B10 to B18:

[0661] Using corresponding commercial reagents and a similar preparation method to the above-mentioned Preparation Examples A3, A5, and A7, Preparation Examples B10 to B18 can be prepared, as shown in the following table.

[0662] Preparation Example B19: Preparation of N-(4,5-difluoro-2-(1-methylcyclopropyloxy)phenyl)-N-methyl-6-oxo-1-(prop-2-yn-1-yl)-1,6-dihydropyridine-2-carboxamide

[0663] Step 1: Preparation of 1,2-difluoro-4-(1-methylcyclopropyloxy)-5-nitrobenzene

[0664] 1,2,4-Trifluoro-5-nitrobenzene (1.0 g, 5.65 mmol) was dissolved in N,N-dimethylformamide (10 mL). Cesium carbonate (1.8 g, 5.65 mmol) and 1-methylcyclopropanol (406.0 mg, 5.65 mmol) were added sequentially at room temperature. The mixture was allowed to react at 60°C for 6 hours. After TLC indicated completion of the reaction, 200 mL of water was added to the system. The mixture was extracted three times with ethyl acetate. The organic phases were combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1 (v:v)) to afford 900 mg of the title compound as a white solid.

[0665] MS (ESI) m / z (M+H) + =230.1.

[0666] Step 2: Preparation of 4,5-difluoro-2-(1-methylcyclopropyloxy)aniline

[0667] 1,2-Difluoro-4-(1-methylcyclopropyloxy)-5-nitrobenzene (900.0 mg, 3.93 mmol) was dissolved in methanol (50 mL), and palladium on carbon (180.0 mg, 10% (W / W)) was slowly added in portions at 0°C. After the addition, the system was reacted at room temperature for 6 hours. LCMS showed that the starting material was completely consumed. The system was filtered and concentrated to give 500.0 mg of the title compound as a colorless oil.

[0668] MS (ESI) m / z (M+H) + =200.2.

[0669] Step 3: Preparation of 6-chloro-N-(4,5-difluoro-2-(1-methylcyclopropyloxy)phenyl)pyridine-2-carboxamide

[0670] Dissolve 6-chloropyridine-2-carboxylic acid (394.0 mg, 2.51 mmol) in pyridine (5 mL). Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (480 mg, 2.51 mmol) and 4,5-difluoro-2-(1-methylcyclopropyloxy)aniline (500.0 mg, 2.51 mmol) sequentially under ice-cooling conditions. Allow to react overnight at room temperature. After TLC indicates the reaction is complete, add 200 mL of water and extract three times with ethyl acetate. The combined organic phases are backwashed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product is purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1 (v:v)) to yield 800 mg of the title compound as a white solid.

[0671] MS (ESI) m / z (M+H) +=339.1.

[0672] Step 4: Preparation of 6-chloro-N-(4,5-difluoro-2-(1-methylcyclopropyloxy)phenyl)-N-methylpyridine-2-carboxamide

[0673] 6-Chloro-N-(4,5-difluoro-2-(1-methylcyclopropyloxy)phenyl)pyridine-2-carboxamide (800 mg, 2.37 mmol) was dissolved in N,N-dimethylformamide (10 mL). Sodium hydroxide (142.0 mg, 3.56 mmol) was added under ice-cooling. After stirring for 10 minutes, iodomethane (505 mg, 3.56 mmol) was added and the mixture was allowed to react overnight at room temperature. LCMS and TLC analysis confirmed the complete reaction. The reaction was quenched with water, extracted with ethyl acetate, and concentrated. The crude product was separated by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to afford 600 mg of the title compound as a black oil.

[0674] MS (ESI) m / z (M+H) + =353.1.

[0675] Step 5: Preparation of N-(4,5-difluoro-2-(1-methylcyclopropyloxy)phenyl)-N-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide

[0676] 6-Chloro-N-(4,5-difluoro-2-(1-methylcyclopropyloxy)phenyl)-N-methylpyridine-2-carboxamide (600.0 mg, 1.70 mmol), boric acid (158.0 mg, 2.56 mmol), palladium acetate (38.0 mg, 0.17 mmol), 2-(di-tert-butylphosphino)-3,6-dimethoxy-2',4',6'tri-isopropyl-1,1'-biphenyl (165.0 mg, 0.34 mmol), and cesium carbonate (1.1 g, 3.40 mmol) were weighed, and the system was sealed with nitrogen for protection. After the solvent 1,4-dioxane (10 mL) was added to dissolve, the system was ventilated with nitrogen three times, and then reacted at 90°C for 3 hours. LCMS monitored the complete reaction of the raw materials. LCMS and TLC plates showed that the reaction of the starting material was complete. The system was quenched with water, extracted with ethyl acetate, and concentrated. The resulting crude product was separated by column chromatography (dichloromethane / methanol = 20 / 1) to obtain 450 mg of the title compound.

[0677] MS (ESI) m / z (M+H) + =335.1.

[0678] Step 6: Preparation of N-(4,5-difluoro-2-(1-methylcyclopropyloxy)phenyl)-N-methyl-6-oxo-1-(prop-2-yn-1-yl)-1,6-dihydropyridine-2-carboxamide

[0679] N-(4,5-difluoro-2-(1-methylcyclopropyloxy)phenyl)-N-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (450.0 mg, 1.35 mmol) was dissolved in N,N-dimethylformamide (5 mL). Cesium carbonate (438.0 mg, 1.35 mmol) and propargyl bromide (160.0 mg, 1.35 mmol) were added sequentially at room temperature. The mixture was allowed to react at room temperature for 4 hours. After TLC indicated completion of the reaction, 200 mL of water was added to the system. The system was extracted three times with ethyl acetate. The organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1 (v:v)) to obtain 200 mg of the title compound.

[0680] MS (ESI) m / z (M+H) + =373.2.

[0681] Preparation Examples B20 to B24:

[0682] Using the corresponding commercial reagents and a similar preparation method to the above Preparation Example 19, Preparation Examples B20 to B24 can be prepared, as shown in the following table.

[0683] Example 1: Preparation of 1-((5-amino-6-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-N-methyl-6-oxo-N-phenyl-1,6-dihydropyridine-2-carboxamide

[0684] Step 1: Preparation of 1-((5-(bis(4-methoxybenzyl)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-N-methyl-6-oxo-N-phenyl-1,6-dihydropyridine-2-carboxamide

[0685] 1-((5-(bis(4-methoxybenzyl)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-2-carboxylic acid (60 mg, 0.090 mmol) was dissolved in pyridine (10 mL). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (25.88 mg, 0.14 mmol) and N-methylaniline (14.47 mg, 0.14 mmol) were added. The system was allowed to react at room temperature for 12 hours. After LC-MS showed the reaction was complete, water was added to the system and the product was extracted three times with dichloromethane. The organic phase was concentrated and purified on a silica gel column to obtain 30 mg of the title compound as a white solid.

[0686] MS (ESI) m / z (M+H)+ = 758.3.

[0687] Step 2: Preparation of 1-((5-amino-6-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-N-methyl-6-oxo-N-phenyl-1,6-dihydropyridine-2-carboxamide

[0688] 1-((5-(bis(4-methoxybenzyl)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-N-methyl-6-oxo-N-phenyl-1,6-dihydropyridine-2-carboxamide (30 mg, 0.040 mmol) was dissolved in dichloromethane (3 mL). Trifluoroacetic acid (3 mL) was added dropwise under an ice-water bath, and the mixture was allowed to react at room temperature for 1.5 hours. After LC-MS indicated the reaction was complete, the system was concentrated, 7M ammonia methanol (5 mL) was added dropwise, and the reaction was heated to 50°C for 0.5 hours. LC-MS indicated the reaction was complete, the system was concentrated, and the product was purified by reverse phase preparative purification and lyophilized to obtain 3.63 mg of the title compound as a white solid.

[0689] MS (ESI) m / z (M+H) + =388.1.

[0690] 1 H NMR (400MHz, DMSO-d6) δ10.41(s,1H),7.35(s,1H),7.20–7.02(m,4H),6.68(d,J=7.3Hz,2H),6.34(d, J=9.1Hz,1H),6.09(s,1H),5.94(d,J=6.8Hz,1H),5.37(s,2H),5.12(s,2H),3.35(s,3H),2.11(s,3H).

[0691] Example 2: Preparation of 1-((5-amino-6-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-N-isopropyl-6-oxo-N-phenyl-1,6-dihydropyridine-2-carboxamide

[0692] Step 1: Preparation of 1-((5-(bis(4-methoxybenzyl)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-N-isopropyl-6-oxo-N-phenyl-1,6-dihydropyridine-2-carboxamide

[0693] N-isopropyl-6-oxo-N-phenyl-1,6-dihydropyridine-2-carboxamide (50.0 mg, 0.20 mmol), (5-(bis(4-methoxybenzyl)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)methanol (109.5 mg, 0.20 mmol), and triphenylphosphine (10.4 mg, 0.040 mmol) were dissolved in tetrahydrofuran (5 mL). Diisopropyl azodicarboxylate (10.1 mg, 0.050 mmol) was added at room temperature and allowed to react at room temperature for 12 hours. After TLC indicated the reaction was complete, water was added to quench the reaction, the mixture was extracted several times with dichloromethane, and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain a crude product, which was purified by column chromatography (dichloromethane / methanol = 10 / 1 (V:V)) to obtain 50.0 mg of the title compound as a light yellow solid.

[0694] (ESI)m / z(M+H) + =787.0.

[0695] Step 2: Preparation of 1-((5-amino-6-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-N-isopropyl-6-oxo-N-phenyl-1,6-dihydropyridine-2-carboxamide

[0696] 1-((5-(bis(4-methoxybenzyl)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-N-isopropyl-6-oxo-N-phenyl-1,6-dihydropyridine-2-carboxamide (50.0 mg, 0.064 mmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (1530.0 mg, 13.42 mmol) was added at room temperature and allowed to react at room temperature for 3 hours. After TLC indicated the reaction was complete, the mixture was concentrated under reduced pressure. Ammonia (119.2 mg, 7.00 mmol) in methanol (5 mL) was added and allowed to react at room temperature for 2 hours. After TLC indicated the reaction was complete, the mixture was concentrated under reduced pressure, separated and purified by preparative HPLC, and lyophilized to obtain 16.6 mg of the title compound as a white solid.

[0697] MS (ESI) m / z (M+H) + =416.5.

[0698] 1 H NMR (400MHz, DMSO-d6) δ10.31(s,1H),7.36(s,1H),7.22–6.99(m,5H),6.62(d,J=8.0Hz,1H),6.28(d,J=9.1Hz,1H),6. 06(s,1H),6.03(d,J=6.7Hz,1H),5.32(s,2H),5.13(s,2H),4.90(hept,J=6.9Hz,1H),2.12(s,3H),1.29–0.89(m,6H).

[0699] Example 3: Preparation of 1-((5-amino-6-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-N-((5-chloropyridin-2-yl)methyl)-N-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide

[0700] Step 1: Preparation of 1-[(5-(bis[(4-methoxyphenyl)methyl]amino)-6-methyl-1-[(2-(trimethylsilyl)ethoxy)methyl]-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl]-N-[(5-chloropyridin-2-yl)methyl]-N-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide

[0701] 1-((5-(bis(4-methoxybenzyl)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid (60 mg, 0.090 mmol) and 1-(5-chloropyridin-2-yl)-N-methylmethanamine (70.47 mg, 0.45 mmol) were dissolved in tetrahydrofuran (15 mL). N-methylimidazole (74 mg, 0.9 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (252 mg, 0.9 mmol) were added sequentially. The system was reacted at 50°C for 0.5 hour. After LC-MS showed the reaction was complete, water was added and the system was extracted three times with ethyl acetate. The organic phase was concentrated and purified on a silica gel column to obtain 52 mg of the title compound as a white solid.

[0702] MS (ESI) m / z (M+H) + =807.3.

[0703] Step 2: Preparation of 1-((5-amino-6-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-N-((5-chloropyridin-2-yl)methyl)-N-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide

[0704] 1-[(5-(bis[(4-methoxyphenyl)methyl]amino)-6-methyl-1-[(2-(trimethylsilyl)ethoxy)methyl]-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl]-N-[(5-chloropyridin-2-yl)methyl]-N-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (52 mg, 0.064 mmol) was dissolved in dichloromethane (3 mL). Trifluoroacetic acid (6 mL) was added dropwise under an ice-water bath, and the mixture was allowed to react at room temperature for 1.5 hours. After LC-MS indicated the reaction was complete, the system was concentrated, 7M ammonia methanol (10 mL) was added dropwise, and the reaction was heated to 60°C for 0.5 hours. LC-MS indicated the reaction was complete, and the system was concentrated. The product was purified by reverse phase preparative purification and lyophilized to obtain 10.77 mg of the title compound as a white solid.

[0705] MS (ESI) m / z (M+H) + =437.2.

[0706] 1H NMR (400MHz, DMSO-d6) δ10.53–10.38(m,1H),8.66–8.49(m,1H),7.89–7.75(m,1H),7.58–7.33(m,1H),7.32–7.13(m,2H),6.61–6.48(m,1H),6. 40–6.23(m,1H),6.00–5.83(m,1H),5.62–5.45(m,1H),5.15–4.92(m,3H ),4.66(s,1H),4.40–3.81(m,1H),2.88–2.62(m,3H),2.14–2.08(m,3H).

[0707] Example 4: Preparation of 1-((5-amino-6-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-6-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyridin-2(1H)-one

[0708] The title compound was prepared using a similar preparation method to that in Example 3 using corresponding commercial reagents and the product of the aforementioned preparation example as raw materials.

[0709] MS (ESI) m / z (M+H) + =414.2.

[0710] 1 H NMR (400MHz, DMSO-d6) δ10.47–10.38(m,1H),7.56–7.40(m,1H),7.28–7. 11(m,3H),7.08–6.91(m,2H),6.77–6.56(m,1H),6.39–6.22(m,1H),5.99– 5.80(m,1H),5.70–5.50(m,1H),5.11–4.87(m,4H),4.40–4.32(m,1H),3. 97–3.50(m,1H),2.72–2.62(m,2H),2.37–2.26(m,1H),2.10–1.94(m,3H).

[0711] Example 5: Preparation of 1-((5-amino-6-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-6-(1,2,3,4-tetrahydroquinoline-1-carbonyl)pyridin-2(1H)-one

[0712] The title compound was prepared using a similar preparation method to that in Example 1 using corresponding commercial reagents and the product of the aforementioned preparation example as raw materials.

[0713] MS (ESI) m / z (M+H) + =414.2.

[0714] 1 H NMR(400MHz,DMSO-d6)δ10.48(s,1H),8.08–6.78(m,5H),6.75–6.31(m,2H) ,6.18–5.24(m,4H),5.10(s,2H),4.38–4.21(m,1H),2.79–2.62(m,2H),2.19 -2.04(m,4H),1.90–1.11(m,2H).

[0715] Example 6: Preparation of 1-((5-amino-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-N-methyl-6-oxo-N-phenyl-1,6-dihydropyridine-2-carboxamide

[0716] Step 1: Preparation of tert-butyl (2-((6-(methyl(phenyl)carbamoyl)-2-oxopyridin-1(2H)-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-5-yl)carbamate

[0717] Dissolve tert-butyl (2-(hydroxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-5-yl)carbamate (0.2 g, 0.51 mmol) and N-methyl-6-oxo-N-phenyl-1,6-dihydropyridine-2-carboxamide (0.232 g, 1.02 mmol) in tetrahydrofuran (20 mL). Add triphenylphosphine (0.267 g, 1.02 mmol) under ice-water bath, followed by the dropwise addition of diethyl azodicarboxylate (0.177 g, 1.02 mmol). Stir at this temperature for 12 hours. After LC-MS indicated completion of the reaction, quench the reaction with water and extract three times with ethyl acetate. The organic phases were combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, and purified on a silica gel column to afford 0.15 g of the title compound as an oil.

[0718] MS (ESI) m / z (M+H) + =604.3.

[0719] Step 2: Preparation of 1-((5-amino-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-N-methyl-6-oxo-N-phenyl-1,6-dihydropyridine-2-carboxamide

[0720] Tert-butyl (2-((6-(methyl(phenyl)carbamoyl)-2-oxopyridin-1(2H)-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-5-yl)carbamate (150 mg, 0.25 mmol) was dissolved in dichloromethane (3 mL). Trifluoroacetic acid (6 mL) was added dropwise under an ice-water bath, and the mixture was allowed to react at room temperature for 1.5 hours. After LC-MS indicated the reaction was complete, the system was concentrated, 7M ammonia methanol (10 mL) was added dropwise, and the reaction was heated to 60°C for 0.5 hours. LC-MS indicated the reaction was complete, the system was concentrated, and the product was purified by reverse phase preparative purification and lyophilized to obtain 50 mg of the title compound as a white solid.

[0721] MS (ESI) m / z (M+H) + =374.2.

[0722] 1 H NMR (400MHz, DMSO-d6) δ10.75–10.31(m,1H),7.60–7.37(m,2H),7.29–7.02(m,4H),6. 80–6.50(m,2H),6.40–6.22(m,2H),6.10–5.94(m,2H),5.40–5.25(m,3H),3.36(s,3H).

[0723] Example 7: Preparation of 1-((5-amino-6-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-[2,2'-bipyridyl]-6(1H)-one

[0724] Step 1: Preparation of 1-((5-(bis(4-methoxybenzyl)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-[2,2'-bipyridyl]-6(1H)-one

[0725] 1-((5-(bis(4-methoxybenzyl)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-6-bromopyridin-2(1H)-one (250.0 mg, 0.36 mmol) and 2-(tributylstannyl)pyridine (143.9 mg, 0.39 mmol) were dissolved in anhydrous toluene (5.0 mL), followed by the addition of tetrakis(triphenylphosphine)palladium (41.1 mg, 0.036 mmol). After the addition was complete, the reaction system was heated to 110°C under a nitrogen atmosphere and stirred for 16 hours. LCMS indicated that the starting materials had reacted completely. The reaction solution was concentrated and purified by column chromatography to obtain 250.0 mg of the title compound as a brown gum, which was used in the next reaction.

[0726] MS (ESI) m / z (M+H) + =702.4.

[0727] Step 2: Preparation of 1-((5-amino-6-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-[2,2'-bipyridyl]-6(1H)-one

[0728] 1-((5-(bis(4-methoxybenzyl)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-[2,2'-bipyridyl]-6(1H)-one (150.0 mg, 0.21 mmol) was dissolved in trifluoroacetic acid (5.0 mL), and the reaction system was stirred at room temperature for 1 hour. LCMS showed that the starting material was completely reacted, and the reaction solution was concentrated to obtain the crude compound. The crude product was then dissolved in methanolic ammonia (10.0 mL, 7 M), and the reaction solution was stirred at 60°C for 1 hour. LCMS showed that the starting material was completely reacted. After concentration, 23.0 mg of the title compound was obtained by preparative separation as a light yellow solid.

[0729] MS (ESI) m / z (M+H) + =332.1.

[0730] 1H NMR (400MHz, DMSO-d6) δ10.37(s,1H),8.70(d,J=4.7Hz,1H),7.85(td,J=7.8,1.7Hz,1H),7.55–7.43(m,2H),7.43(d,J=7.9Hz, 1H),7.22(s,1H),6.55(dd,J=9.2,1.0Hz,1H),6.27(dd,J=6.8,1.1Hz,1H),5.42(s,2H),5.26(s,1H),5.19(s,2H),2.03(s,3H).

[0731] Example 8: Preparation of 1-[(5-amino-6-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl]-6-(1-isopropylpyrazol-4-yl)pyridin-2-one

[0732] Step 1: Preparation of 1-[[5-[bis[(4-methoxyphenyl)methyl]amino]-6-methyl-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-b]pyridin-2-yl]methyl]-6-(1-isopropylpyrazol-4-yl)pyridin-2-one

[0733] 1-[[5-[Bis[(4-methoxyphenyl)methyl]amino]-6-methyl-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-b]pyridin-2-yl]methyl]-6-bromo-pyridin-2-one (120.0 mg, 0.17 mmol), 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (40.6 mg, 0.17 mmol), and potassium phosphate (75.3 mg, 0.34 mmol) were dissolved in 1,4-dioxane (4.0 mL) and water (1.0 mL), followed by the addition of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (14.4 mg, 0.17 mmol). After the addition was complete, the reaction system was heated to 80°C under nitrogen and stirred for 16 hours. LCMS showed that the reaction of the starting material was complete. The reaction solution was concentrated and then purified by column chromatography to obtain 120.0 mg of the title compound as a light yellow solid.

[0734] MS (ESI) m / z (M+H) + =733.3.

[0735] Step 2: Preparation of 1-[(5-amino-6-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl]-6-(1-isopropylpyrazol-4-yl)pyridin-2-one

[0736] 1-[[5-[Bis[(4-methoxyphenyl)methyl]amino]-6-methyl-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-b]pyridin-2-yl]methyl]-6-(1-isopropylpyrazol-4-yl)pyridin-2-one (120.0 mg, 0.90 mmol) was dissolved in trifluoroacetic acid (3.0 mL), and the reaction system was stirred at room temperature for 1 hour. LCMS showed that the starting material was completely reacted, and the reaction solution was directly concentrated under reduced pressure to obtain the crude compound. The crude product was directly dissolved in ammonia methanol solution (2.0 mL, 7 M) and stirred at 60°C for 1 hour. LCMS showed that the starting material was completely reacted. After concentration, 13.7 mg of the title compound was obtained by preparative separation as a light yellow solid.

[0737] MS (ESI) (M+H) + =m / z 363.1.

[0738] 1 H NMR (400MHz, DMSO-d6) δ10.49(s,1H),7.87(s,1H),7.49–7.44(m,2H),7.30(s,1H),6.45(dd,J=9.1,1.3Hz,1H),6.27(dd,J= 6.9,1.4Hz,1H),5.57–5.52(m,1H),5.25(s,2H),5.19(s,2H),4.48(hept,J=6.6Hz,1H),2.10(s,3H),1.39(d,J=6.7Hz,6H).

[0739] Example 9: Preparation of 1-((5-amino-6-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-6-((3,4-dihydroquinolin-1(2H)-yl)methyl)pyridin-2(1H)-one

[0740] Step 1: Preparation of tert-butyl N-(5-amino-3-methyl-6-(3-(2-oxo-6-[(1,2,3,4-tetrahydroquinolin-1-yl)methyl]-1,2-dihydropyridin-1-yl)prop-1-yn-1-yl)pyridin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate

[0741] To the reaction flask, 1-(prop-2-yn-1-yl)-6-[(1,2,3,4-tetrahydroquinolin-1-yl)methyl]-1,2-dihydropyridin-2-one (580.0 mg, 2.08 mmol), tert-butyl N-(5-amino-6-iodo-3-methylpyridin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate (1.1 g, 2.50 mmol), tetrakistriphenylphosphine palladium (240.0 mg, 0.21 mmol), and cuprous iodide (48.0 mg, 0.25 mmol) were added sequentially. After the addition was complete, the nitrogen atmosphere was replaced three times, followed by the addition of triethylamine (12 mL) and dichloromethane (5 mL). After stirring, the reaction was allowed to react at room temperature for 2 hours. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase was concentrated. The crude product was purified by silica gel column to obtain 700.0 mg of the title product as a brown solid.

[0742] MS (ESI) m / z (M+H) + =600.4.

[0743] Step 2: Preparation of 1-((5-amino-6-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-6-((3,4-dihydroquinolin-1(2H)-yl)methyl)pyridin-2(1H)-one

[0744] To a dry reaction tube, tert-butyl N-(5-amino-3-methyl-6-(3-(2-oxo-6-[(1,2,3,4-tetrahydroquinolin-1-yl)methyl]-1,2-dihydropyridin-1-yl)prop-1-yn-1-yl)pyridin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate (40.0 mg, 0.07 mmol) and potassium tert-butoxide (15.04 mg, 0.13 mmol) were added sequentially. The nitrogen atmosphere was replaced three times, and tetrahydrofuran (1 mL) and N,N-dimethylformamide (0.3 mL) were added under nitrogen. The reaction was then placed in an oil bath at 80°C for 1 hour. After completion, the reaction was quenched with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase concentrated. The crude product was purified by Pre-HPLC and lyophilized to afford 6.2 mg of the title product as a white solid.

[0745] MS (ESI) m / z (M+H) + =400.2.

[0746] 1H NMR (400MHz, DMSO-d6) δ10.50 (s, 1H), 7.44–7.36 (m, 1H), 7.31 (s, 1H), 6.89 (d, J = 7. 2Hz,1H),6.75(t,J=7.6Hz,1H),6.46(t,J=7.3Hz,1H),6.41(d,J=9.0Hz,1H),6.12(d ,J=8.2Hz,1H),6.00(d,J=6.9Hz,1H),5.95(s,1H),5.35(s,2H),5.10(s,2H),4.55( s,2H),3.30–3.23(m,2H),2.71(t,J=5.9Hz,2H),2.11(s,3H),1.90(p,J=6.0Hz,2H).

[0747] The following examples can be prepared using corresponding commercial reagents and the products in the above preparation examples as raw materials, using preparation methods similar to those in the above examples.

[0748] The analytical data of the above described embodiment, including NMR and HPLC data, are as follows:

[0749] Example 25: Preparation of 1-[(5-amino-6-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl]-N-benzyl-N-[(5-fluoropyridin-2-yl)methyl]-6-oxo-1,6-dihydropyridine-2-carboxamide

[0750] Step 1: Preparation of tert-butyl N-(6-(3-(6-(benzyl[(5-fluoropyridin-2-yl)methyl]carbamoyl)-2-oxo-1,2-dihydropyridin-1-yl)prop-1-yn-1-yl)-3-methyl-5-(trifluoroacetylamino)pyridin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate

[0751] To a reaction tube, N-benzyl-N-[(5-fluoropyridin-2-yl)methyl]-6-oxo-1-(prop-2-yn-1-yl)-1,6-dihydropyridine-2-carboxamide (500 mg, 1.47 mmol), tert-butyl N-[(tert-butoxy)carbonyl]-N-(6-iodo-3-methyl-5-(trifluoroacetylamino)pyridin-2-yl)carbamate (0.88 g, 1.62 mmol), tetrakistriphenylphosphine palladium (170 mg, 0.15 mmol), and cuprous iodide (34 mg, 0.18 mmol) were added sequentially. After nitrogen was replaced three times, triethylamine (5 mL) and dichloromethane (5 mL) were added. After stirring, the reaction was allowed to react at room temperature for 1 hour. After completion, the reaction was quenched with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase concentrated. The crude product was purified on a silica gel column to yield 520 mg of the title product.

[0752] MS (ESI) m / z (M+H) + =793.3.

[0753] Step 2: Preparation of tert-butyl N-(2-[(6-(benzyl[(5-fluoropyridin-2-yl)methyl]carbamoyl)-2-oxo-1,2-dihydropyridin-1-yl)methyl]-6-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-N-[(tert-butoxy)carbonyl]carbamate

[0754] To a reaction tube, tert-butyl N-(6-(3-(6-(benzyl[(5-fluoropyridin-2-yl)methyl]carbamoyl)-2-oxo-1,2-dihydropyridin-1-yl)prop-1-yn-1-yl)-3-methyl-5-(trifluoroacetylamino)pyridin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate (260 mg, 0.33 mmol), bistriphenylphosphine palladium dichloride (46 mg, 0.066 mmol), and cuprous iodide (6.3 mg, 0.033 mmol) were added. The atmosphere was purged with nitrogen three times, and triethylamine (5 mL) was then added. After stirring, the reaction was incubated at 120°C for 1 hour. After completion, the reaction was quenched with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase concentrated. The crude product was used directly in the next reaction without further purification.

[0755] MS (ESI) m / z (M+H) + =697.3.

[0756] Step 3: Preparation of 1-[(5-amino-6-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl]-N-benzyl-N-[(5-fluoropyridin-2-yl)methyl]-6-oxo-1,6-dihydropyridine-2-carboxamide

[0757] To a dry reaction tube, add tert-butyl N-(2-[(6-(benzyl[(5-fluoropyridin-2-yl)methyl]carbamoyl)-2-oxo-1,2-dihydropyridin-1-yl)methyl]-6-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-N-[(tert-butoxy)carbonyl]carbamate (130 mg, 0.19 mmol) and trifluoroacetic acid (3.93 g, 34.45 mmol). The mixture was allowed to react at room temperature. After completion, water was added to quench the reaction, and the product was extracted three times with ethyl acetate. The product was dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase was concentrated. The crude product was purified by Pre-HPLC and lyophilized to afford 40 mg of the title product as a yellow solid.

[0758] MS (ESI) m / z (M+H) + =497.3.

[0759] 1 H NMR(400MHz,DMSO-d6)δ10.42–10.31(m,1H),8.58–8.42(m,1H),7.71–7.55(m,1H) ,7.51–7.38(m,1H),7.37–7.25(m,3H),7.25–7.18(m,2H),7.14–7.05(m,2H),6.57– 6.49(m,1H),6.50–6.37(m,1H),5.83–5.77(m,1H),5.41–5.26(m,1H),5.23–5.03( m,3H),4.98–4.75(m,1H),4.63–4.50(m,1H),4.44–4.15(m,2H),2.13–2.11(m,3H).

[0760] Example 27: 1-((5-amino-6-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-N-methyl-6-oxo-N-phenyl-1,6-dihydropyridine-2-carboxamide

[0761] Step 1: Preparation of 1-(3-(3-amino-6-chloro-5-fluoropyridin-2-yl)prop-2-yn-1-yl)-N-methyl-6-oxo-N-phenyl-1,6-dihydropyridine-2-carboxamide

[0762] 6-Chloro-5-fluoro-2-iodopyridin-3-amine (120.0 mg, 0.44 mmol), N-methyl-6-oxo-N-phenyl-1-(prop-2-yn-1-yl)-1,6-dihydropyridine-2-carboxamide (117.2 mg, 0.44 mmol), tetrakis(triphenylphosphine)palladium (101.7 mg, 0.088 mmol), and cuprous iodide (16.7 mg, 0.088 mmol) were weighed into a reaction tube. The inert atmosphere was replaced, and triethylamine (89.0 mg, 0.88 mmol) and dichloromethane (5 mL) were added to dissolve the mixture. The inert atmosphere was replaced again, and the mixture was allowed to react at room temperature for 1 hour. After TLC indicated the reaction was complete, saturated brine was added to the reaction system, and the mixture was extracted several times with dichloromethane and dried over anhydrous sodium sulfate. The solvent was concentrated to give a crude product, which was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1 (V:V)) to obtain the title compound as a light yellow solid.

[0763] MS (ESI) m / z (M+H) + =411.9.

[0764] Step 2: Preparation of 1-(3-(6-chloro-5-fluoro-3-(trifluoroacetylamino)pyridin-2-yl)prop-2-yn-1-yl)-N-methyl-6-oxo-N-phenyl-1,6-dihydropyridine-2-carboxamide

[0765] Dissolve 1-(3-(3-amino-6-chloro-5-fluoropyridin-2-yl)prop-2-yn-1-yl)-N-methyl-6-oxo-N-phenyl-1,6-dihydropyridine-2-carboxamide (170.0 mg, 0.41 mmol) in dichloromethane (5 mL). Add trifluoroacetic anhydride (103.3 mg, 0.49 mmol) and triethylamine (82.9 mg, 0.82 mmol) at room temperature. Allow to react at room temperature for 2 hours. After TLC indicated completion of the reaction, add saturated brine to the reaction system, extract several times with dichloromethane, and dry over anhydrous sodium sulfate. Concentrate the solvent to obtain a crude product, which is purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1 (v:v)) to afford 130.0 mg of the title compound as a pale yellow solid.

[0766] MS (ESI) m / z (M+H) + =507.8.

[0767] Step 3: Preparation of 1-((5-chloro-6-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-N-methyl-6-oxo-N-phenyl-1,6-dihydropyridine-2-carboxamide

[0768] 1-(3-(6-chloro-5-fluoro-3-(trifluoroacetylamino)pyridin-2-yl)prop-2-yn-1-yl)-N-methyl-6-oxo-N-phenyl-1,6-dihydropyridine-2-carboxamide (130.0 mg, 0.26 mmol) was dissolved in dichloromethane (3 mL). Bistriphenylphosphine palladium dichloride (36.5 mg, 0.052 mmol), cuprous iodide (9.9 mg, 0.052 mmol), and triethylamine (2.2 g, 21.64 mmol) were added at room temperature. After complete addition, the inert atmosphere was replaced and the temperature was raised to 110°C for 1 hour. After TLC indicated completion of the reaction, saturated brine was added to the reaction system, and the mixture was extracted several times with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain a crude product, which was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 2 (v:v)) to afford 100.0 mg of the title compound as a pale yellow solid.

[0769] MS (ESI) m / z (M+H) + =411.8.

[0770] Step 4: Preparation of 1-((5-chloro-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-N-methyl-6-oxo-N-phenyl-1,6-dihydropyridine-2-carboxamide

[0771] 1-((5-chloro-6-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-N-methyl-6-oxo-N-phenyl-1,6-dihydropyridine-2-carboxamide (100.0 mg, 0.24 mmol) was dissolved in tetrahydrofuran (5 mL). Sodium hydride (19.2 mg, 0.48 mmol) was added at room temperature. After reacting at room temperature for 10 minutes, 2-(trimethylsilyl)ethoxymethyl chloride (44.0 mg, 0.26 mmol) was added dropwise. The mixture was allowed to react at room temperature for 2 hours. After TLC indicated the reaction was complete, saturated aqueous ammonium chloride was added to the reaction system, and the mixture was extracted several times with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain a crude product, which was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1 (v:v)) to afford 60.0 mg of the title compound as a pale yellow solid.

[0772] MS (ESI) m / z (M+H) + =542.1.

[0773] Step 5: Preparation of tert-butyl N-(6-fluoro-2-((6-(methyl(phenyl)carbamoyl)-2-oxo-1,2-dihydropyridin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-5-yl)carbamate

[0774] 1-((5-chloro-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-N-methyl-6-oxo-N-phenyl-1,6-dihydropyridine-2-carboxamide (60.0 mg, 0.11 mmol) was dissolved in tetrahydrofuran (5 mL). t-Butyl carbamate (25.7 mg, 0.22 mmol), BrettPhos (11.8 mg, 0.022 mmol), BrettPhos-G3-Pd (19.9 mg, 0.022 mmol), and cesium carbonate (71.6 mg, 0.22 mmol) were added at room temperature. After the addition, the inert gas was replaced and the temperature was raised to 90°C for 5 hours. After TLC indicated the reaction was complete, saturated brine was added to the reaction system, and the mixture was extracted several times with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain a crude product, which was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 2 (V:V)) to obtain 40.0 mg of the title compound as a light yellow solid.

[0775] MS (ESI) m / z (M+H) + =622.7.

[0776] Step 6: Preparation of 1-((5-amino-6-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-N-methyl-6-oxo-N-phenyl-1,6-dihydropyridine-2-carboxamide

[0777] Tert-butyl N-(6-fluoro-2-((6-(methyl(phenyl)carbamoyl)-2-oxo-1,2-dihydropyridin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-5-yl)carbamate (30.0 mg, 0.048 mmol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (3.0 g, 26.84 mmol) was added and stirred at room temperature for 2 hours. After TLC indicated the reaction was complete, the solvent was removed by concentration and a solution of ammonia (0.36 g, 21.00 mmol) in methanol (3 mL) was added. The mixture was allowed to react at room temperature for 3 hours. After TLC indicated the reaction was complete, the solvent was concentrated to give a crude product, which was then separated and purified by preparative HPLC to afford 6.0 mg of the title compound as a white solid.

[0778] MS (ESI) m / z (M+H) + =392.4.

[0779] 1 H NMR (400MHz, DMSO-d6) δ10.55(s,1H),7.51–7.41(m,1H),7.21–7.05(m,4H),6.74(d,J=7.4Hz,2H) ,6.34(d,J=9.0Hz,1H),6.15(s,1H),5.96(d,J=6.6Hz,1H),5.55(s,2H),5.36(s,2H),3.37(s,3H).

[0780] Example 28: 1-((5-amino-6-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-4-methyl-6-(2-phenylpyrrolidine-1-carbonyl)pyridin-2(1H)-one

[0781] Step 1: Preparation of tert-butyl N-(5-amino-3-methyl-6-(3-(4-methyl-2-oxo-6-(2-phenylpyrrolidine-1-carbonyl)-1,2-dihydropyridin-1-yl)prop-1-yn-1-yl)pyridin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate

[0782] 4-Methyl-6-(2-phenylpyrrolidine-1-carbonyl)-1-(prop-2-yn-1-yl)pyridin-2(1H)-one (180.0 mg, 0.56 mmol), tert-butyl N-(5-amino-6-iodo-3-methylpyridin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate (252.0 mg, 0.56 mmol), tetrakistriphenylphosphine palladium (64.0 mg, 0.6 mmol), and cuprous iodide (21.0 mg, 0.11 mmol) were weighed, and triethylamine (5 mL) and dichloromethane (2 mL) were added. The system was purged with nitrogen three times and allowed to react at room temperature for 3 hours. LCMS confirmed the complete reaction. The system was quenched with water, extracted with ethyl acetate, and concentrated. The crude product was separated by column chromatography (dichloromethane / methanol = 20 / 1) to afford 150 mg of the title compound as a purple-black solid.

[0783] MS (ESI) m / z (M+H) + =642.3.

[0784] Step 2: Preparation of tert-butyl N-[(tert-butoxy)carbonyl]-N-(3-methyl-6-(3-(4-methyl-2-oxo-6-(2-phenylpyrrolidine-1-carbonyl)-1,2-dihydropyridin-1-yl)prop-1-yn-1-yl)-5-(trifluoroacetylamino)pyridin-2-yl)carbamate

[0785] tert-Butyl N-(5-amino-3-methyl-6-(3-(4-methyl-2-oxo-6-(2-phenylpyrrolidine-1-carbonyl)-1,2-dihydropyridin-1-yl)prop-1-yn-1-yl)pyridin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate (150.0 mg, 0.23 mmol) was dissolved in dichloromethane (5 mL). Triethylamine (95.7 μL, 0.728 g / mL, 0.69 mmol) and trifluoroacetic anhydride (32.0 μL, 1.511 g / mL, 0.23 mmol) were added sequentially at 0°C. After addition, the mixture was allowed to react overnight at room temperature. After TLC indicated the reaction was complete, 50 mL of water was added to the system, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1 (V:V)) to obtain 150 mg of the title compound as a black solid.

[0786] MS (ESI) m / z (M+H) + =738.3.

[0787] Step 3: Preparation of tert-butyl N-[(tert-butoxy)carbonyl]-N-(6-methyl-2-[(4-methyl-2-oxo-6-(2-phenylpyrrolidine-1-carbonyl)-1,2-dihydropyridin-1-yl)methyl]-1H-pyrrolo[3,2-b]pyridin-5-yl)carbamate

[0788] tert-Butyl N-[(tert-butoxy)carbonyl]-N-(3-methyl-6-(3-(4-methyl-2-oxo-6-(2-phenylpyrrolidine-1-carbonyl)-1,2-dihydropyridin-1-yl)prop-1-yn-1-yl)-5-(trifluoroacetamido)pyridin-2-yl)carbamate (150.0 mg, 0.23 mmol) was added to triethylamine (5 mL) and dichloromethane (1 mL). Bistriphenylphosphine palladium dichloride (32.0 mg, 0.05 mmol) and cuprous iodide (19.0 mg, 0.10 mmol) were then added. The system was purged with nitrogen three times and then reacted at 120°C for 2 hours. LCMS monitored the complete reaction. The reaction was quenched with water, extracted with ethyl acetate, and concentrated. The crude product was separated by column chromatography (dichloromethane / methanol = 20 / 1) to afford 100 mg of the title compound as a purple-black solid.

[0789] MS (ESI) m / z (M+H) + =642.3.

[0790] Step 4: Preparation of 1-((5-amino-6-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-4-methyl-6-(2-phenylpyrrolidine-1-carbonyl)pyridin-2(1H)-one

[0791] Tert-butyl N-[(tert-butoxy)carbonyl]-N-(6-methyl-2-[(4-methyl-2-oxo-6-(2-phenylpyrrolidine-1-carbonyl)-1,2-dihydropyridin-1-yl)methyl]-1H-pyrrolo[3,2-b]pyridin-5-yl)carbamate (100.0 mg, 0.16 mmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (2 mL) was added sequentially at room temperature. After complete addition, the system was reacted at room temperature for 3 hours. LCMS showed complete consumption of the starting material. The system was concentrated, and the crude product was purified by Pre-HPLC and freeze-dried to afford 50 mg of the title compound as a white solid.

[0792] MS (ESI) m / z (M+H) + =442.1.

[0793] 1 H NMR(400MHz,Chloroform-d)δ9.71–9.18(m,1H),7.39–7.32(m,1H),7.29(s,1H),7.26–7.19(m,2H),6.91–6.80(m,1H),6.34–6.24(m,2H ),5.59–5.47(m,1H),5.33–5.15(m,3H),4.53(s,2H),4.10–3.83(m,2H),2.54–2.40(m,1H),2.23(s,3H),2.21(s,3H),2.17–1.65(m,4H).

[0794] The following examples can be prepared using corresponding commercial reagents and the products in the above preparation examples as raw materials, using preparation methods similar to those in the above examples.

[0795] The analytical data of the above described embodiment, including NMR and HPLC data, are as follows:

[0796] Example A1: Preparation of 1-[(5-amino-6-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl]-N-(2-chlorophenyl)-N-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide

[0797] Step 1: Preparation of tert-butyl N-[(tert-butoxy)carbonyl]-N-(6-(3-(6-[(2-chlorophenyl)(methyl)carbamoyl)-2-oxo-1,2-dihydropyridin-1-yl)prop-1-yn-1-yl)-3-methyl-5-(trifluoroacetylamino)pyridin-2-yl)carbamate

[0798] To a reaction tube, add N-(2-chlorophenyl)-N-methyl-6-oxo-1-(prop-2-yn-1-yl)-1,6-dihydropyridine-2-carboxamide (60 mg, 0.20 mmol), tert-butyl N-[(tert-butoxy)carbonyl]-N-(6-iodo-3-methyl-5-(trifluoroacetylamino)pyridin-2-yl)carbamate (87 mg, 0.16 mmol), tetrakistriphenylphosphine palladium (23 mg, 0.02 mmol), and cuprous iodide (4 mg, 0.02 mmol). After replacing the nitrogen atmosphere three times, triethylamine (1 mL) and dichloromethane (0.5 mL) were added. After stirring, the reaction was allowed to react at room temperature for 1 hour. After completion, the reaction was quenched with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase concentrated. The crude product was purified on a silica gel column to yield approximately 60 mg of the title product, which was used directly in the next step.

[0799] MS (ESI) m / z (M+H) + =718.3.

[0800] Step 2: Preparation of tert-butyl N-[(tert-butoxy)carbonyl]-N-(2-[(6-[(2-chlorophenyl)(methyl)carbamoyl]-2-oxo-1,2-dihydropyridin-1-yl)methyl]-6-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)carbamate

[0801] To a reaction tube, tert-butyl N-[(tert-butoxy)carbonyl]-N-(6-(3-(6-[(2-chlorophenyl)(methyl)carbamoyl)-2-oxo-1,2-dihydropyridin-1-yl)prop-1-yn-1-yl)-3-methyl-5-(trifluoroacetamido)pyridin-2-yl)carbamate (60 mg, 0.084 mmol), tetrakistriphenylphosphine palladium (9.7 mg, 0.0084 mmol), and cuprous iodide (1.6 mg, 0.0084 mmol) were added. The atmosphere was replaced with nitrogen three times, and triethylamine (1 mL) and dichloromethane (0.5 mL) were added. After stirring, the reaction was incubated at 120°C for 30 minutes. After completion, the reaction was quenched with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase concentrated. The crude product was purified on a silica gel column to afford 30 mg of the title compound as a brown solid.

[0802] MS (ESI) m / z (M+H) + =622.3.

[0803] Step 3: Preparation of 1-[(5-amino-6-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl]-N-(2-chlorophenyl)-N-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide

[0804] To a dry reaction tube, add tert-butyl N-[(tert-butoxy)carbonyl]-N-(2-[(6-[(2-chlorophenyl)(methyl)carbamoyl]-2-oxo-1,2-dihydropyridin-1-yl)methyl]-6-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)carbamate (30 mg, 0.048 mmol), trifluoroacetic acid (2 mL), and dichloromethane (2 mL). The mixture is allowed to react at room temperature for 1 hour. After completion, the reaction is quenched with saturated sodium bicarbonate solution, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase concentrated. The crude product is purified by Pre-HPLC and lyophilized to afford 9.7 mg of the title product as a pale yellow solid.

[0805] MS (ESI) m / z (M+H) + =422.2.

[0806] 1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),7.62–7.55(m,1H),7.52(d,J=8.0Hz,1 H),7.47–7.39(m,1H),7.36(s,1H),7.24(t,J=7.8Hz,1H),7.19(dd,J=9.2,6. 9Hz,1H),6.37(d,J=9.1Hz,1H),6.11(s,1H),5.96(d,J=6.6Hz,1H),5.57(d,J =14.8Hz,1H),5.20(d,J=14.9Hz,1H),5.13(s,2H),3.26(s,3H),2.12(s,3H).

[0807] Example A2: Preparation of 1-((5-amino-6-chloro-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-N-(4-fluorophenyl)-N-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide

[0808] The title compound was prepared using a similar preparation method to that of Example A1 using corresponding commercial reagents and the product of the aforementioned preparation example as raw materials.

[0809] MS (ESI) m / z (M+H) + =426.1.

[0810] 1 H NMR (400MHz, DMSO-d6) δ10.62(s,1H),7.69(s,1H),7.22(dd,J=9.2,6.8Hz,1H),6.97(t,J=8.5Hz,2H),6.89(dd,J=8.8, 4.9Hz, 2H), 6.36 (d, J = 9.2Hz, 1H), 6.13 (d, J = 2.0Hz, 1H), 6.03 (d, J = 6.7Hz, 1H), 5.63 (s, 2H), 5.32 (s, 2H), 3.33 (s, 3H).

[0811] Example A3: Preparation of 1-((5-amino-6-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-3-fluoro-N-(4-fluorophenyl)-N-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide

[0812] Step 1: Preparation of 1-((5-(bis(4-methoxybenzyl)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-3-fluoro-N-(4-fluorophenyl)-N-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide

[0813] (5-(Bis(4-methoxybenzyl)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)methanol (200 mg, 0.37 mmol) and 3-fluoro-N-(4-fluorophenyl)-6-hydroxy-N-methylpyridine-2-carboxamide (146.65 mg, 0.55 mmol) were dissolved in tetrahydrofuran (10 mL). Triphenylphosphine (145.57 mg, 0.55 mmol) was added under ice-cooling, followed by the slow dropwise addition of diethyl azodicarboxylate (96.65 mg, 0.55 mmol). The atmosphere was purged with nitrogen three times, and the mixture was stirred at room temperature for 12 hours. After LC-MS indicated the reaction was complete, the mixture was quenched with water and extracted three times with ethyl acetate. The organic phases were combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, and purified on a silica gel column to afford 110 mg of the title compound as an oil.

[0814] MS (ESI) m / z (M+H) + =794.4.

[0815] Step 2: Preparation of 1-((5-amino-6-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-3-fluoro-N-(4-fluorophenyl)-N-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide

[0816] 1-((5-(bis(4-methoxybenzyl)amino)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-3-fluoro-N-(4-fluorophenyl)-N-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (110 mg, 0.14 mmol) was dissolved in dichloromethane (3 mL). Trifluoroacetic acid (6 mL) was added dropwise under an ice bath, and the mixture was allowed to react at room temperature for 1.5 hours. LC-MS indicated the reaction was complete, and the system was concentrated. 7M ammonia methanol (10 mL) was added dropwise, and the reaction was allowed to react at room temperature for 1.5 hours. LC-MS indicated the reaction was complete, and the system was concentrated. The product was purified by reverse phase preparative purification, and lyophilized to afford 24.09 mg of the title compound as a white solid.

[0817] MS (ESI) m / z (M+H) + =424.1.

[0818] 1 H NMR (400MHz, DMSO-d6) δ10.41(s,1H),7.39–7.33(m,2H),7.31–7.19(m,1H),6.97(t,J=8.7Hz,2H),6.86–6.79(m,1H),6 .45(dd,J=10.1,5.5Hz,1H),6.11(d,J=2.0Hz,1H),5.36(d,J=15.0Hz,1H),5.21–5.11(m,3H),3.36(s,3H),2.11(s,3H).

[0819] Example A4: Preparation of 1-((5-amino-6-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-N-(4-fluorophenyl)-N,3-dimethyl-6-oxo-1,6-dihydropyridine-2-carboxamide

[0820] The title compound was prepared using a similar preparation method to that of Example A3 using corresponding commercial reagents and the product of the above preparation example as raw materials.

[0821] MS (ESI) m / z (M+H) + =420.2.

[0822] 1 H NMR (400MHz, DMSO-d6) δ10.52–10.19(m,1H),7.53–7.26(m,3H),7.14–6.97(m,3H),6.63–6.20(m,1 H),6.11–5.95(m,1H),5.62–5.23(m,1H),5.16–4.90(m,3H),3.48–2.67(m,3H),2.15–1.77(m,6H).

[0823] Example A5: Preparation of 1-((6-amino-5-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-N-(4-fluorophenyl)-N-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide

[0824] Step 1: Preparation of 1-(3-(6-bromo-5-methyl-2-(trifluoroacetylamino)pyridin-3-yl)prop-2-yn-1-yl)-N-(4-fluorophenyl)-N-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide

[0825] N-(6-bromo-3-iodo-5-methylpyridin-2-yl)-2,2,2-trifluoroacetamide (300.0 mg, 0.73 mmol), N-(4-fluorophenyl)-N-methyl-6-oxo-1-(prop-2-yn-1-yl)-1,6-dihydropyridine-2-carboxamide (207.5 mg, 0.73 mmol), tetrakis(triphenylphosphine)palladium (84.3 mg, 0.073 mmol), cuprous iodide (13.9 mg, 0.073 mmol), and triethylamine (147.7 mg, 1.46 mmol) were weighed into a reaction tube. After purging the atmosphere with nitrogen three times, dichloromethane (5 mL) was added and the atmosphere was purged with nitrogen again. The reaction was allowed to react at room temperature for 2 hours. After TLC indicated the reaction was complete, saturated brine was added to the reaction system, and the mixture was extracted several times with dichloromethane and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain a crude product, which was purified by column chromatography (dichloromethane / methanol = 15 / 1 (V:V)) to obtain 250.0 mg of the title compound as a light yellow solid.

[0826] MS (ESI) m / z (M+H) + =565.1.

[0827] Step 2: Preparation of 1-((6-bromo-5-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-N-(4-fluorophenyl)-N-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide

[0828] 1-(3-(6-bromo-5-methyl-2-(trifluoroacetylamino)pyridin-3-yl)prop-2-yn-1-yl)-N-(4-fluorophenyl)-N-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (200.0 mg, 0.35 mmol), cuprous iodide (6.6 mg, 0.035 mmol), and bistriphenylphosphine palladium dichloride (24.5 mg, 0.035 mmol) were weighed sequentially into a reaction tube. After purging the atmosphere with nitrogen, triethylamine (1460.0 mg, 14.43 mmol) and dichloromethane (1 mL) were added. The atmosphere was purged with nitrogen again, and the temperature was raised to 120°C for 1 hour. After TLC indicated the reaction was complete, saturated brine was added to the reaction system, and the mixture was extracted several times with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain a crude product, which was purified by column chromatography (dichloromethane / methanol = 10 / 1 (V:V)) to obtain 100.0 mg of the title compound as a light yellow solid.

[0829] MS (ESI) m / z (M+H) + =469.2.

[0830] Step 3: Preparation of tert-butyl 6-bromo-2-((6-((4-fluorophenyl)(methyl)carbamoyl)-2-oxo-1,2-dihydropyridin-1-yl)methyl)-5-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

[0831] 1-((6-Bromo-5-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-N-(4-fluorophenyl)-N-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (40.0 mg, 0.085 mmol) was dissolved in dichloromethane (2 mL). Di-tert-butyl dicarbonate (18.5 mg, 0.085 mmol), triethylamine (17.2 mg, 0.17 mmol), and 4-dimethylaminopyridine (2.0 mg, 0.017 mmol) were added at room temperature and allowed to react at room temperature for 2 hours. After TLC indicated the reaction was complete, saturated brine was added to the reaction system, and the mixture was extracted several times with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain a crude product, which was purified by column chromatography (dichloromethane / methanol = 15 / 1 (v:v)) to afford 30.0 mg of the title compound as a pale yellow solid.

[0832] MS (ESI) m / z (M+H) + =569.1.

[0833] Step 4: Preparation of tert-butyl 6-(((tert-butoxy)carbonyl)amino)-2-((6-((4-fluorophenyl)(methyl)carbamoyl)-2-oxo-1,2-dihydropyridin-1-yl)methyl)-5-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

[0834] tert-Butyl 6-bromo-2-((6-((4-fluorophenyl)(methyl)carbamoyl)-2-oxo-1,2-dihydropyridin-1-yl)methyl)-5-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (20.0 mg, 0.035 mmol), tert-butyl carbamate (8.2 mg, 0.070 mmol), BrettPhos-G3-Pd (6.3 mg, 0.0070 mmol), BrettPhos (3.7 mg, 0.0070 mmol), and cesium carbonate (22.8 mg, 0.070 mmol) were weighed into a reaction tube in sequence. After nitrogen was purged three times, tetrahydrofuran (2 mL) was added and nitrogen was purged again. The system was heated to 80°C and reacted for 3 hours. After TLC showed the reaction was complete, saturated brine was added to the reaction system, and the mixture was extracted several times with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain a crude product, which was purified by column chromatography (dichloromethane / ethyl acetate = 1 / 1 (V:V)) to obtain 10.0 mg of the title compound as a light yellow solid.

[0835] MS (ESI) m / z (M+H) + =606.2.

[0836] Step 5: Preparation of 1-((6-amino-5-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-N-(4-fluorophenyl)-N-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide

[0837] Tert-butyl 6-(((tert-butoxy)carbonyl)amino)-2-((6-((4-fluorophenyl)(methyl)carbamoyl)-2-oxo-1,2-dihydropyridin-1-yl)methyl)-5-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (10.0 mg, 0.017 mmol) was dissolved in dichloromethane (1 mL). Zinc bromide (19.1 mg, 0.085 mmol) was added at room temperature and allowed to react at room temperature for 8 hours. After TLC indicated the reaction was complete, saturated brine was added to the reaction system, and the mixture was extracted several times with dichloromethane and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain a crude product, which was separated and purified by preparative HPLC to obtain 1.45 mg of the title compound as a white solid.

[0838] MS (ESI) m / z (M+H) + =406.2.

[0839] 1H NMR (400MHz, DMSO-d6) δ10.36(s,1H),7.36(s,1H),7.20(dd,J=9.2,6.8Hz,1H),7.07–6.95(m,4H),6.30(dd,J=9 .1,1.3Hz,1H),6.05(d,J=6.7Hz,1H),6.02(d,J=2.0Hz,1H),5.40(s,2H),5.22(s,2H),3.35(s,3H),2.07(s,3H).

[0840] Example A6: Preparation of 1-((5-amino-6-bromo-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-N-(4-fluorophenyl)-N-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide

[0841] Step 1: Preparation of tert-butyl N-(5-amino-3-bromo-6-(3-(6-[(4-fluorophenyl)(methyl)carbamoyl]-2-oxo-1,2-dihydropyridin-1-yl)prop-1-yn-1-yl)pyridin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate

[0842] tert-Butyl N-(5-amino-3-bromo-6-iodopyridin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate (200.0 mg, 0.4 mmol), N-(4-fluorophenyl)-N-methyl-6-oxo-1-(prop-2-yn-1-yl)-1,6-dihydropyridine-2-carboxamide (114.0 mg, 0.4 mmol), tetrakistriphenylphosphine palladium (46.0 mg, 0.04 mmol), and cuprous iodide (15.0 mg, 0.08 mmol) were weighed into a dry reaction tube. Triethylamine (5 mL) and dichloromethane (2 mL) were added. The system was purged with nitrogen three times and allowed to react at room temperature for 3 hours. LCMS confirmed the complete reaction. The reaction was quenched with water, extracted with ethyl acetate, and concentrated. The crude product was separated by column chromatography (dichloromethane / methanol = 20 / 1) to give 210 mg of the title compound.

[0843] MS (ESI) m / z (M+H) + =670.2.

[0844] Step 2: Preparation of tert-butyl N-(3-bromo-6-(3-(6-[(4-fluorophenyl)(methyl)carbamoyl)-2-oxo-1,2-dihydropyridin-1-yl)prop-1-yn-1-yl)-5-(trifluoroacetylamino)pyridin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate

[0845] tert-Butyl N-(5-amino-3-bromo-6-(3-(6-[(4-fluorophenyl)(methyl)carbamoyl]-2-oxo-1,2-dihydropyridin-1-yl)prop-1-yn-1-yl)pyridin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate (210.0 mg, 0.3 mmol) was dissolved in dichloromethane (5 mL). Triethylamine (125.0 μL, 0.728 g / mL, 0.9 mmol) and trifluoroacetic anhydride (42.0 μL, 1.511 g / mL, 0.3 mmol) were added sequentially at 0°C. After addition, the mixture was allowed to react at room temperature overnight. After TLC indicated the reaction was complete, 10 mL of water was added to the system, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1 (V:V)) to obtain 170 mg of the title compound.

[0846] MS (ESI) m / z (M+H) + =766.2.

[0847] Step 3: Preparation of tert-butyl N-(6-bromo-2-[(6-[(4-fluorophenyl)(methyl)carbamoyl]-2-oxo-1,2-dihydropyridin-1-yl)methyl]-1H-pyrrolo[3,2-b]pyridin-5-yl)-N-[(tert-butoxy)carbonyl]carbamate

[0848] tert-Butyl N-(3-bromo-6-(3-(6-[(4-fluorophenyl)(methyl)carbamoyl)-2-oxo-1,2-dihydropyridin-1-yl)prop-1-yn-1-yl)-5-(trifluoroacetylamino)pyridin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate (170.0 mg, 0.2 mmol) was weighed into a dry reaction tube. Triethylamine (5 mL) and dichloromethane (1 mL) were added, followed by bistriphenylphosphine palladium dichloride (15.0 mg, 0.02 mmol) and cuprous iodide (8.0 mg, 0.04 mmol). The system was purged with nitrogen three times and then reacted at 120°C for 1 hour. LCMS confirmed the complete reaction. The reaction was quenched with water, extracted with ethyl acetate, and concentrated. The crude product was separated by column chromatography (dichloromethane / methanol = 20 / 1) to obtain 45 mg of the title compound.

[0849] MS (ESI) m / z (M+H) + =670.2.

[0850] Step 4: Preparation of 1-((5-amino-6-bromo-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-N-(4-fluorophenyl)-N-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide

[0851] tert-Butyl N-(6-bromo-2-[(6-[(4-fluorophenyl)(methyl)carbamoyl]-2-oxo-1,2-dihydropyridin-1-yl)methyl]-1H-pyrrolo[3,2-b]pyridin-5-yl)-N-[(tert-butoxy)carbonyl]carbamate (45.0 mg, 0.067 mmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (2 mL) was added at room temperature and the mixture was allowed to react for 3 hours. LCMS showed complete consumption of the starting material. The mixture was concentrated and the crude product was purified by Pre-HPLC and freeze-dried to afford 8.0 mg of the title compound as a white solid.

[0852] MS (ESI) m / z (M+H) + =470.1.

[0853] 1 H NMR (400MHz, DMSO-d6) δ10.62(s,1H),7.84(s,1H),7.22(dd,J=9.2,6.8Hz,1H),6.98(t,J=8.5Hz,2H),6.95–6. 85(m,2H),6.36(dd,J=9.2,1.3Hz,1H),6.12(s,1H),6.07–6.01(m,1H),5.55(s,2H),5.32(s,2H),3.33(s,3H).

[0854] Examples A7-A9:

[0855] The corresponding commercial reagents and the products of the above preparation examples were used as raw materials, and a preparation method similar to that of Example A6 was used to prepare the compounds of Examples A7-A9. The compound information is shown in the following table.

[0856] Example A10: Preparation of 1-((5-amino-6-isopropyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-N-(4-fluorophenyl)-N-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide

[0857] 1-((5-amino-6-(prop-1-en-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-N-(4-fluorophenyl)-N-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (50 mg, 0.12 mmol) was dissolved in methanol (10 mL). Palladium on carbon (8.0 mg, 10% (W / W)) was added at 0°C. After addition, the hydrogen atmosphere was replaced three times, and the reaction system was placed under a hydrogen atmosphere at room temperature for 3 hours. LCMS showed complete consumption of the starting material. The system was concentrated, and the crude product was purified by Pre-HPLC and freeze-dried to afford 3.5 mg of the title compound as a white solid.

[0858] MS (ESI) m / z (M+H) + =434.2.

[0859] 1 H NMR (400MHz, DMSO-d6) δ10.27(s,1H),7.36(s,1H),7.13(dd,J=9.2,6.8Hz,1H),6.82(t,J=8.5Hz,2H),6.77–6.68(m,2H),6.29(d,J=8 .9Hz,1H),6.01(d,J=2.0Hz,1H),6.00–5.89(m,1H),5.27(s,2H),5.10(s,2H),3.26(s,3H),2.97–2.81(m,1H),1.11(d,J=6.6Hz,6H).

[0860] Example A11: Preparation of 1-((5-amino-6-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-6-(6-fluoro-1,2,3,4-tetrahydroquinoline-1-carbonyl)pyridin-2(1H)-one

[0861] The title compound was prepared using a similar preparation method to that of Example A5 using corresponding commercial reagents and the product of the above preparation example as raw materials.

[0862] MS (ESI) m / z (M+H) + =436.2.

[0863] 1 H NMR(400MHz,DMSO-d6)δ10.63(s,1H),8.13–6.94(m,4H),6.74–6.31(m,2H),6.16–5.4 9(m,5H),5.41–5.04(m,1H),4.37–3.30(m,2H),3.12–2.65(m,2H),2.16–1.19(m,2H).

[0864] The following examples can be prepared using corresponding commercial reagents and the products in the above preparation examples as raw materials, using preparation methods similar to those in the above examples.

[0865] The analytical data of the above described embodiment, including NMR and HPLC data, are as follows:

[0866] Example A35: Preparation of 1-((1-acetyl-5-amino-6-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-N-(4-fluorophenyl)-N-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide

[0867] Step 1: Preparation of tert-butyl N-((tert-butoxy)carbonyl)-N-(6-(3-(6-((4-fluorophenyl)(methyl)carbamoyl)-2-oxo-1,2-dihydropyridin-1-yl)prop-1-yn-1-yl)-3-methyl-5-(trifluoroacetylamino)pyridin-2-yl)carbamate

[0868] tert-Butyl N-((tert-butoxy)carbonyl)-N-(6-iodo-3-methyl-5-(trifluoroacetylamino)pyridin-2-yl)carbamate (300.0 mg, 0.55 mmol), N-(4-fluorophenyl)-N-methyl-6-oxo-1-(prop-2-yn-1-yl)-1,6-dihydropyridine-2-carboxamide (156.4 mg, 0.55 mmol), tetrakistriphenylphosphine palladium (63.5 mg, 0.055 mmol), and cuprous iodide (10.5 mg, 0.055 mmol) were weighed into a reaction tube. After purging the atmosphere with nitrogen three times, triethylamine (111.3 mg, 1.10 mmol) and dichloromethane (5 mL) were added, and the atmosphere was purged with nitrogen again. After addition, the mixture was reacted at room temperature for 1 hour. After TLC indicated the reaction was complete, saturated brine was added to the reaction system, and the mixture was extracted several times with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain a crude product, which was purified by column chromatography (dichloromethane / ethyl acetate = 1 / 1 (V:V)) to obtain 350.0 mg of the title compound as a yellow-green solid.

[0869] MS (ESI) m / z (M+H) + =702.2.

[0870] Step 2: Preparation of tert-butyl N-((tert-butoxy)carbonyl)-N-(2-((6-((4-fluorophenyl)(methyl)carbamoyl)-2-oxo-1,2-dihydropyridin-1-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)carbamate

[0871] tert-Butyl N-((tert-butoxy)carbonyl)-N-(6-(3-(6-((4-fluorophenyl)(methyl)carbamoyl)-2-oxo-1,2-dihydropyridin-1-yl)prop-1-yn-1-yl)-3-methyl-5-(trifluoroacetamido)pyridin-2-yl)carbamate (350.0 mg, 0.50 mmol), bistriphenylphosphine palladium dichloride (70.1 mg, 0.10 mmol), and cuprous iodide (19.0 mg, 0.10 mmol) were weighed into a reaction tube. After purging the atmosphere with nitrogen three times, triethylamine (1.5 g, 14.43 mmol) and dichloromethane (5 mL) were added, and the atmosphere was purged with nitrogen again. The system was heated to 120°C and reacted for 1 hour. After TLC showed the reaction was complete, saturated brine was added to the reaction system, and the mixture was extracted several times with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain a crude product, which was purified by column chromatography (dichloromethane / ethyl acetate = 1 / 1 (V:V)) to obtain 280.0 mg of the title compound as a yellow solid.

[0872] MS (ESI) m / z (M+H) + =606.2.

[0873] Step 3: Preparation of tert-butyl N-(1-acetyl-2-((6-((4-fluorophenyl)(methyl)carbamoyl)-2-oxo-1,2-dihydropyridin-1-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-N-((tert-butoxy)carbonyl)carbamate

[0874] Tert-butyl N-((tert-butoxy)carbonyl)-N-(2-((6-((4-fluorophenyl)(methyl)carbamoyl)-2-oxo-1,2-dihydropyridin-1-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)carbamate (40.0 mg, 0.066 mmol) was dissolved in dichloromethane (5 mL). Triethylamine (13.4 mg, 0.13 mmol), 4-dimethylaminopyridine (1.6 mg, 0.013 mmol), and acetic anhydride (8.1 mg, 0.079 mmol) were added at room temperature. The mixture was reacted at room temperature for 8 hours. After TLC showed the reaction was complete, the solvent was concentrated, and a saturated aqueous sodium chloride solution was added to the reaction system. The mixture was extracted several times with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain a crude product, which was purified by column chromatography (dichloromethane / / ethyl acetate = 2 / 1 (V:V)) to obtain 30.0 mg of the title compound as a light yellow solid.

[0875] MS (ESI) m / z (M+H) + =648.2.

[0876] Step 4: Preparation of 1-((1-acetyl-5-amino-6-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-N-(4-fluorophenyl)-N-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide

[0877] Tert-butyl N-(1-acetyl-2-((6-((4-fluorophenyl)(methyl)carbamoyl)-2-oxo-1,2-dihydropyridin-1-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-N-((tert-butoxy)carbonyl)carbamate (20.0 mg, 0.031 mmol) was dissolved in dichloromethane (3 mL). Trifluoroacetic acid (1530.0 mg, 13.42 mmol) was added at room temperature and allowed to react at room temperature for 2 hours. After TLC indicated the reaction was complete, the solvent was concentrated, and the reaction system was added with saturated aqueous sodium bicarbonate. The mixture was extracted several times with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain a crude product, which was separated and purified by preparative HPLC to obtain 5.8 mg of the title compound as a white solid.

[0878] MS (ESI) m / z (M+H) + =448.2.

[0879] 1H NMR (400MHz, DMSO-d6) δ7.80 (s, 1H), 7.36–7.31 (m, 1H), 7.29–7.24 (m, 2H), 7.14 (t, J = 8.5Hz, 2H), 6.63 (s, 1H), 6.35(d,J=9.2Hz,1H),6.21(d,J=6.8Hz,1H),5.59(s,2H),5.40(s,2H),3.29(s,3H),2.79(s,3H),2.17(s,3H).

[0880] The following examples can be prepared using corresponding commercial reagents and the products of the aforementioned preparation examples as raw materials, using a similar preparation method to that of the above Examples 9, A1, A5, and A6.

[0881] The analytical data of the above described embodiment, including NMR and HPLC data, are as follows:

[0882] Experimental Example 1: Enzyme activity test

[0883] 1. Prepare assay buffer. Components: 20 mM Bicine (Sigma-Aldrich, Cat#B8660), 25 mM NaCl (Sigma, Cat#S7653), 2 mM DTT (Sigma, Cat#43815), 0.005% gelatin (Sigma, Cat#V900863), 0.01% Tween-20, 2.6 μM MTA (Sigma, Cat#D5011). Adjust pH to 7.6.

[0884] 2. Preparation of reference compound (MRTX9768) and test compound: MRTX9768 (MedChemExpress, HY-138684, CAS No.: 2629314-68-5) and test compound stock solutions were prepared at 10 mM. Appropriate amounts of the stock solutions were serially diluted in DMSO to the following concentrations: 99.010, 34.650, 12.380, 3.663, 1.282, 0.458, 0.136, 0.048, 0.017, and 0.005 μM, for a total of 10 concentration points.

[0885] 3. Prepare solutions containing both PRMT5 enzyme (BPS, Cat#51045) and histone H4 peptide substrate (custom-made by Gill Biochem, no external catalog number), as well as solutions containing only histone H4 peptide substrate. Prepare the enzyme-substrate solution in assay buffer with a PRMT5 enzyme concentration of 7.6 nM and a histone H4 concentration of 0.32 μM. Prepare the substrate solution in assay buffer with a histone H4 concentration of 0.32 μM, excluding PRMT5.

[0886] 4. Dilute SAM (New England Biolabs, Cat#B9003S) with Assay buffer to a concentration of 2.6 μM solution for later use.

[0887] 5. Preparation of detection solution. The detection solution consists of: LANCE Ultra Europium-anti-methyl-Histone H4 Arginine 3 (perkinelmer, Catalog No. TRF0414-M) at a concentration of 4 nM, LANCE Ultra ULigh-Streptavidin (perkinelmer, Catalog No. TRF0102-M) at a concentration of 53.3 nM, LANCE Detection Buffer (perkinelmer, Catalog No. CR97-100) at a content of 10% (volume percentage), and the remainder is ultrapure water.

[0888] 6. Add 100 nL of compound solution or blank DMSO to a 384-well plate (positive wells). Add 5 μL of enzyme-substrate solution or substrate solution, centrifuge at 1000 rpm for 30 seconds, and incubate at 25°C for 30 minutes. Then, add 5 μL of SAM solution, centrifuge at 1000 rpm for 30 seconds, and incubate at 25°C for 90 minutes. The test wells now contain: 3.8 nM PRMT5, 160 nM histone H4, 1.3 μM SAM, 1% DMSO (with varying concentrations of compound). Positive control wells contain: 3.8 nM PRMT5, 160 nM histone H4, 1.3 μM SAM, 1% DMSO (without compound). Negative control wells contain: 160 nM histone H4, 1.3 μM SAM, 1% DMSO (without compound).

[0889] 7. After incubation, add 10 μL of detection solution to all wells and incubate for 60 minutes. Then, detect in TR-FRET mode (320 / 340 nm excitation, 665 / 620 nm detection) and record the results.

[0890] 8. Result processing: Inhibition% = (1-(test well-negative well) / (positive well-negative well)) × 100.

[0891] The log value of the concentration was used as the X-axis and the percentage inhibition rate (Inhibition%) was used as the Y-axis. The log (inhibitor) vs. response-Variable slope analysis software GraphPad Prism 8 was used to fit the dose-effect curve to obtain the IC value of each compound on the enzyme activity. 50 The experimental results are shown in Table 1 below:

[0892] Table 1 IC values ​​of the compounds of the present invention for PRMT5 50 value

[0893] Note: ND means not tested

[0894] Conclusion: The above experiments show that the compounds of the present invention have excellent PRMT5 inhibitory activity.

[0895] Experimental Example 2: OCI-Ly19 (MTAP null) cell proliferation inhibition experiment

[0896] Cell plating:

[0897] 1) Remove cells from the incubator and place them on the workbench. Mix thoroughly by gently pipetting. Count cells using a CounterStar.

[0898] 2) Dilute the cells to the desired density with fresh complete medium. For OCI-Ly19 (Nanjing Kebai, Cat. No. CBP60621, MEM + 10% FBS + 1% P / S), plate at a density of 1 × 10^4 cells / well, using 100 μL / well.

[0899] 3) Use an electric pipette to draw 100 μL of cell suspension into a 96-well plate and add 200 μL of 1× PBS to the edge wells to prevent evaporation.

[0900] Formulated compound:

[0901] 1) First, the stock solution of the compound was diluted from 10 mM to 2000, 600, 200, 60, 20, 6, 2, and 0.6 μM, with a DMSO content of 100%.

[0902] 2) After thorough mixing, 2.6 μL of the above-mentioned serially diluted compound and DMSO (as a control) were taken out with an electric dispenser and added to 257.4 μL of culture medium, resulting in a 100-fold dilution and a DMSO content of 1%.

[0903] 3) After thorough mixing using a spray gun, remove the plated cells and set up two replicate wells for each compound concentration. Add 100 μL of the compound diluted in step 2 to each replicate well to achieve final compound concentrations of 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, and 0 μM. At this point, each well of the cell culture plate contains 200 μL of culture medium with a DMSO content of 0.5%.

[0904] 4) The cells were returned to the 37° C., 5% CO 2 incubator for continued culture and tested 5 days after compound treatment.

[0905] CTG test:

[0906] 1) After culturing for a specific time, remove the cells and aspirate a portion of the culture medium to leave 50 μL of culture medium in each well. Add 50 μL / well of CTG reagent (cell counting-Lite 2.0, Vazyme, DD1101-02) using a dispenser.

[0907] 2) Incubate on a shaker at room temperature for 15 minutes, and then let it equilibrate at room temperature for 15 minutes.

[0908] 3) Detection was performed using a multifunctional microplate reader.

[0909] Data Analysis:

[0910] 1) Calculate cell viability: Cell viability % = As / Ac × 100%. As: test well value (cell-containing culture medium, CTG, test compound), Ac: control well value (cell-containing culture medium, CTG, no test compound).

[0911] 2) Using the log value of compound concentration as the X-axis and cell viability (Cell viability%) as the Y-axis, a dose-effect curve was fitted to obtain the IC value of each compound for cell proliferation inhibition. 50 value.

[0912] Table 2 Proliferation inhibition activity of the compounds of the present invention on OCI-Ly19 cells

[0913] The test results showed that the compounds of the present application had significant anti-proliferation activity in MTAP-deficient cells. The inhibitory activity of the compounds of the present application on OCI-Ly19 cells was 10-20 times greater than that of prior art compounds; certain compounds of the present application had 20-50 times greater inhibitory activity on OCI-Ly19 cells; and certain compounds of the present application had 50-100 times greater inhibitory activity on OCI-Ly19 cells than prior art compounds.

[0914] Experimental Example 3: Liver microsome metabolic stability test

[0915] Liver microsome source information:

[0916] The test compound was prepared to 10 mM with DMSO, and 2 μL was added to 198 μL of 50% acetonitrile / 50% aqueous solution to obtain a 100 μM solution. Liver microsomes were taken and prepared to 0.5 mg / mL with PBS, and NADPH cofactor (final concentration of 1 mM) was added. The mixture was preheated at 37°C for 10 minutes. 2.5 μL of the prepared test compound was taken and added to 222.5 μL of the above preheated mixture and placed in a 37°C water bath to start the reaction. At 0.5, 15, 30 and 45 minutes, the incubated centrifuge tubes were removed and 25 μL of the incubated liver microsome suspension (containing the compound) was taken out. 5 times the volume of the stop solution was added to terminate the reaction, and the mixture was centrifuged at 3220g for 40 minutes. After taking the supernatant, the remaining compound content in the sample at each time point was detected by LC-MS / MS. After performing nonlinear linear regression on the % remaining drug dose-time, the half-life of the compound in the liver microsomes (t 1 / 2 ). Exemplary experimental results are shown in Table 3.

[0917] Table 3. Half-life of the compounds of the present invention in liver microsomes (t 1 / 2 )

[0918] The test results show that the compounds of the present invention show good in vitro metabolic stability in the in vitro human, rat and mouse liver microsome stability test (for example, in vitro rat and mouse liver microsome metabolic t 1 / 2 All were greater than 30 min, and the in vitro human liver microsome metabolism t 1 / 2 More than 60min).

[0919] Experimental Example 4: HCT116 WT Cell (Source: Nanjing Kebai) Activity Test

[0920] On Day 1, cell plating: After trypsinization, resuspend the cells in complete medium (McCoy5A with 10% FBS (ExCell Bio FBS, Cat. No. FND500; BOSTER McCoy5A, Cat. No. PYG0025) to the desired density. Mix thoroughly and plate 100 μL / well into a 96-well plate at a density of 500-1000 cells per well. Return the plate to the incubator and allow the cells to adhere and grow. On Day 2, add the test compound: Prior to compound addition, starve the cells with serum-free medium for 4 hours. Then, add complete medium containing the compound at the appropriate concentration and incubate at 37°C, 5% CO2 for 120 hours. On day 7, remove the compound-treated cells and equilibrate them to room temperature. Aspirate a portion of the culture medium from the culture plate wells, leaving 50 μL of medium in each well. Then, add 50 μL of CTG reagent (cellcounting-Lite 2.0, Vazyme, DD1101-02) to each well. Shake at room temperature for 15 minutes to fully lyse the cells. Allow to stand at room temperature for another 15 minutes, and then measure fluorescence intensity. Calculate the following formula: % Inhibition = 100 - (Signal of the test compound well - Signal of the medium-only well without cells) / (Signal of the cell-free well without compound - Signal of the medium-only well without cells) × 100.

[0921] The IC values ​​of each compound on cell activity were obtained by fitting the dose-effect curve using the analysis software GraphPad Prism 5. 50 value.

[0922] Table 4 Inhibitory activity of HCT116 WT cells

[0923] The test results show that the compounds of the present invention have weak inhibitory activity against MTAP wild-type HCT116 cells, but exhibit excellent selectivity against MTAP-deficient OCI-LY19 cells. For example, Example A16 has an inhibitory activity IC of 0. 50 The inhibitory activity against wild-type MTAP in HCT116 cells was 24 nM. 50 The selectivity is more than 150 times.

[0924] Experimental Example 5: HCT116 MTAP WT and HCT116 MTAP- / - cell proliferation inhibition experiment

[0925] The inhibitory effect of the compounds of the present invention on tumor cell proliferation was tested using two cell lines: HCT116 MTAP WT (Nanjing Kebai Biotechnology Co., Ltd., CBP60028) and HCT116 MTAP- / -.

[0926] Cell plating:

[0927] 1) HCT116 MTAP WT and HCT116 MTAP- / - cells were grown to 90% confluence in culture dishes in McCoy's 5A medium (BOSTER, Catalog No. PYG0025) containing 10% FBS (Ecocell, Catalog No. FND500), trypsinized into single cells, and the cells were counted.

[0928] 2) Dilute the cells to the desired density with fresh culture medium. The plating density for HCT116 MTAP WT cells is 120 cells / well, and the plating density for HCT116 MTAP- / - cells is 160 cells / well.

[0929] 3) Use an electric pipette to draw 100 μL of cell suspension into a 96-well plate and add 200 μL of 1× PBS to the edge wells to prevent evaporation.

[0930] Formulated compound:

[0931] 1) First, the stock solution of the compound was diluted from 10 mM to 4000, 1200, 400, 120, 40, 12, 4, and 1.2 μM, with a DMSO content of 100%.

[0932] 2) Using an electric dispenser, 1.3 μL of the compound after gradient dilution and DMSO (as a control well) were added to 258.7 μL of culture medium. The mixture was diluted 200-fold and the DMSO content was 0.5%.

[0933] 3) Using an electric dispenser, add 100 μL of each compound diluted in step 2) to the plated wells of the cells to achieve final concentrations of 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001, and 0 μM. Set up two replicates for each concentration. At this point, each well of the cell culture plate contains 200 μL of culture medium with 0.25% DMSO.

[0934] 4) The cell culture plate was returned to the 37° C., 5% CO 2 incubator and tested 10 days after compound treatment.

[0935] CTG test:

[0936] 1) After 10 days of culture, remove the cells, aspirate all the culture medium, and add 100 μL / well of pre-prepared detection solution (CTG reagent (cell counting-Lite 2.0, Vazyme, DD1101-03) and culture medium mixed in a 1:1 ratio) using a dispenser.

[0937] 2) Incubate on a shaker at room temperature for 15 minutes, and then let it equilibrate at room temperature for 15 minutes.

[0938] 3) Use a multifunctional microplate reader (BGM, FSX) was used to detect the fluorescence signal intensity.

[0939] Data Analysis:

[0940] 1) Calculate cell viability: Cell viability % = As / Ac × 100%. As: Fluorescence intensity of the test well (cell-containing culture medium, CTG, test compound), Ac: Fluorescence intensity of the control well (cell-containing culture medium, CTG, DMSO).

[0941] 2) Using the log value of compound concentration as the X-axis and cell viability (Cell viability%) as the Y-axis, a dose-effect curve was fitted to obtain the IC value of each compound for cell proliferation inhibition. 50 value.

[0942] Table 5 Proliferation inhibition activity of the compounds of the present invention on HCT116 MTAP WT and HCT116 MTAP- / - cells

[0943] The test results show that the compound of the present application has weak inhibitory activity on MTAP wild-type HCT116 cells, but significantly stronger inhibition on MTAP-deficient HCT116 cells, demonstrating good selectivity.

Claims

1. The compound represented by formula (I), its stereoisomers, deuterated substances, solvates, and pharmaceutically acceptable salts: in, represents any single or double bond allowed by the valence; X1 and X2 are independently selected from NR X , S, N, CR X1 ; R X , R X1 Each of the following is independently selected from H, halogen, -C1~C6 alkyl, deuterium-substituted -C1~C6 alkyl, halogen-substituted -C1~C6 alkyl, -C(O)-C1~C3 alkyl; X3 is selected from N, CR 3 ; R 3 Selected from H, halogen, -C1-C6 alkyl, -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2; X4 is selected from N, CR 5 ; R 7 Selected from H, halogen, -CN, -NO2, -NH2, -C1~C6 alkyl, deuterium-substituted -C1~C6 alkyl, halogen-substituted -C1~C6 alkyl; L is selected from a bond, n is independently selected from 0, 1, and 2; R 1 , R 5 Each of the following is independently selected from hydrogen, halogen, -C1-C6 alkyl, -C2-C6 alkenyl, halogen-substituted -C1-C6 alkyl, -O-C1-C6 alkyl, 3-6-membered carbocyclic ring, 5-10-membered heteroaromatic ring, and 6-10-membered aromatic ring; wherein the carbocyclic ring, heterocyclic ring, heteroaromatic ring, and aromatic ring may be optionally substituted with one or more halogen, -C1-C3 alkyl, halogen-substituted -C1-C3 alkyl, and -O-C1-C3 alkyl; R 4 , R 6 are independently selected from hydrogen, -C1-C6 alkyl, -C1-C6 alkyl substituted with halogen, -C0-C2 alkylene-(3-10-membered carbocyclic ring), -C0-C2 alkylene-(4-11-membered heterocyclic ring), -C0-C2 alkylene-(6-10-membered aromatic ring) or -C0-C2 alkylene-(5-10-membered heteroaromatic ring); wherein the alkyl, alkylene, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring may be optionally replaced by one or more R 41 replace; R 41 Selected from hydrogen, halogen, amino, nitro, cyano, oxo, -NH2, -C(O)NH2, -C(O)H, -C(O)OH, -C1~C6 alkyl, -C2~C6 alkenyl, -C2~C6 alkynyl, halogen-substituted -C1~C6 alkyl, halogen-substituted -C2~C6 alkenyl, halogen-substituted -C2~C6 alkynyl, -O-C1~C6 alkyl; R 2 is selected from a 3-10-membered carbocyclic ring, a 4-11-membered heterocyclic ring, a 6-10-membered aromatic ring or a 5-10-membered heteroaromatic ring; wherein the carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring may be optionally replaced by one or more R 21 replace; R 21 is selected from hydrogen, halogen, nitro, cyano, oxo, -NH2, -C(O)NH2, -C(O)H, -C(O)OH, -C1~C6 alkyl, -C2~C6 alkenyl, -C2~C6 alkynyl, halogen-substituted -C1~C6 alkyl, halogen-substituted -C2~C6 alkenyl, halogen-substituted -C2~C6 alkynyl, -O-C1~C6 alkyl, -O-C2~C6 alkenyl, -O-C2-C6 alkynyl, -O-halogen substituted C1-C6 alkyl, -O-halogen substituted C2-C6 alkenyl, -O-halogen substituted C2-C6 alkynyl, -O-(3-6 membered carbocyclic ring), 3-10 membered carbocyclic ring, 4-11 membered heterocyclic ring, 6-10 membered aromatic ring or 5-10 membered heteroaromatic ring; wherein the carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring may be optionally substituted with one or more R c replace; R c Selected from hydrogen, halogen, nitro, cyano, oxo, -NH2, -C(O)NH2, -C(O)H, -C(O)OH, -C1~C6 alkyl, -C2~C6 alkenyl, -C2~C6 alkynyl, halogen-substituted-C1~C6 alkyl, halogen-substituted-C2~C6 alkenyl, halogen-substituted-C2~C6 alkynyl, -O-C1~C6 alkyl, -O-C2~C6 alkenyl, -O-C2~C6 alkynyl, -O-halogen-substituted C1~C6 alkyl, -O-halogen-substituted C2~C6 alkenyl or -O-halogen-substituted C2~C6 alkynyl.

2. The compound according to claim 1, its stereoisomers, deuterated substances, solvates, and pharmaceutically acceptable salts, characterized in that: The compound of formula (I) is shown in formula (IIa) and formula (IIb): in, R 1 , R 2 , R 7 , R X , R X1 , L, X3, X4 as described in claim 1.

3. The compound according to claim 1, its stereoisomers, deuterated substances, solvates, and pharmaceutically acceptable salts, characterized in that: The compound of formula (I) is represented by formula (IIc), formula (IId), formula (IIe) or formula (IIf): in, R 1 , R 2 , R 3 , R 7 , R X , R X1 , L, X4 as described in claim 1.

4. The compound according to claim 1, its stereoisomers, deuterated substances, solvates, and pharmaceutically acceptable salts, characterized in that: The compound of formula (I) is shown in formula (Ia): in, represents any single or double bond allowed by the valence; R 1 , R 2 , R 5 , X1, X2 and L as described in claim 1.

5. The compound according to any one of claims 1 to 3, its stereoisomer, deuterated substance, solvate, pharmaceutically acceptable salt, characterized in that: R 7 Selected from H, halogen, -CN, -NO2, -NH2, -C1~C3 alkyl, deuterium-substituted -C1~C3 alkyl, halogen-substituted -C1~C3 alkyl.

6. The compound according to any one of claims 1 to 3, its stereoisomer, deuterated substance, solvate, pharmaceutically acceptable salt, characterized in that: R 3 Selected from H, halogen, -C1~C3 alkyl, -C(O)NH2, -C(O)NH(C1~C3 alkyl), -C(O)N(C1~C3 alkyl)2.

7. The compound according to any one of claims 1 to 3, its stereoisomer, deuterated substance, solvate, pharmaceutically acceptable salt, characterized in that: X4 is selected from N, CR 5 ; R 5 Selected from hydrogen, halogen, -C1~C3 alkyl, -C2~C4 alkenyl, halogen-substituted -C1~C3 alkyl, -O-C1~C3 alkyl, 3-4-membered carbocyclic ring, 5-6-membered heteroaromatic ring or 6-10-membered aromatic ring; wherein the carbocyclic ring, heterocyclic ring, heteroaromatic ring and aromatic ring may be optionally substituted by one or more halogen, -C1~C3 alkyl, halogen-substituted -C1~C3 alkyl and -O-C1~C3 alkyl.

8. The compound according to any one of claims 1 to 7, its stereoisomers, deuterated substances, solvates, and pharmaceutically acceptable salts, characterized in that: R X , R X1 Each of them is independently selected from H, halogen, -C1~C3 alkyl, deuterium-substituted -C1~C3 alkyl, halogen-substituted -C1~C3 alkyl, and -C(O)CH3.

9. The compound according to any one of claims 1 to 8, its stereoisomer, deuterated substance, solvate, pharmaceutically acceptable salt, characterized in that: R 1 , R 5 They are independently selected from hydrogen, halogen, -C1~C3 alkyl, -C2~C4 alkenyl, halogen-substituted -C1~C3 alkyl, -O-C1~C3 alkyl, 3-4-membered carbocyclic ring, 5-6-membered heteroaromatic ring or 6-10-membered aromatic ring; wherein the carbocyclic ring, heterocyclic ring, heteroaromatic ring and aromatic ring may be optionally substituted by one or more halogen, -C1~C3 alkyl, halogen-substituted -C1~C3 alkyl and -O-C1~C3 alkyl.

10. The compound according to claim 1, its stereoisomers, deuterated substances, solvates, and pharmaceutically acceptable salts, characterized in that: The compound of formula (I) is shown in formula (Ia): in, X1 and X2 are independently selected from NH, S, N, and CH; represents any single or double bond allowed by the valence; L is selected from a bond, n is independently selected from 0, 1, and 2; R 1 , R 5 are independently selected from hydrogen, halogen, -C1~C6 alkyl, halogen-substituted -C1~C6 alkyl, -C2~C6 alkenyl, -O-C1~C6 alkyl, 3-6-membered carbocyclic ring, 5-10-membered heteroaromatic ring, 6-10-membered aromatic ring; wherein the carbocyclic ring, heterocyclic ring, heteroaromatic ring, aromatic ring may be optionally substituted by one or more halogen, -C1~C3 alkyl, halogen-substituted -C1~C3 alkyl, -O-C1~C3 alkyl; for example, R 1 , R 5 Each is independently selected from hydrogen, halogen, -C1~C6 alkyl, and halogen-substituted -C1~C6 alkyl; R 4 , R 6 are independently selected from hydrogen, -C1-C6 alkyl, -C1-C6 alkyl substituted with halogen, -C0-C2 alkylene-(3-10-membered carbocyclic ring), -C0-C2 alkylene-(4-11-membered heterocyclic ring), -C0-C2 alkylene-(6-10-membered aromatic ring) or -C0-C2 alkylene-(5-10-membered heteroaromatic ring); wherein the alkyl, alkylene, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring may be optionally replaced by one or more R 41 replace; R 41 Selected from hydrogen, halogen, amino, nitro, cyano, oxo, -NH2, -C(O)NH2, -C(O)H, -C(O)OH, -C1~C6 alkyl, -C2~C6 alkenyl, -C2~C6 alkynyl, halogen-substituted -C1~C6 alkyl, halogen-substituted -C2~C6 alkenyl, halogen-substituted -C2~C6 alkynyl, -O-C1~C6 alkyl; R 2 is selected from a 3-10-membered carbocyclic ring, a 4-11-membered heterocyclic ring, a 6-10-membered aromatic ring or a 5-10-membered heteroaromatic ring; wherein the carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring may be optionally replaced by one or more R 21 replace; R 21 is selected from hydrogen, halogen, nitro, cyano, oxo, -NH2, -C(O)NH2, -C(O)H, -C(O)OH, -C1~C6 alkyl, -C2~C6 alkenyl, -C2~C6 alkynyl, halogen-substituted -C1~C6 alkyl, halogen-substituted -C2~C6 alkenyl, halogen-substituted -C2~C6 alkynyl, -O-C1~C6 alkyl, -O-C2~C6 alkenyl, -O-C2-C6 alkynyl, -O-halogen substituted C1-C6 alkyl, -O-halogen substituted C2-C6 alkenyl, -O-halogen substituted C2-C6 alkynyl, -O-(3-6 membered carbocyclic ring), 3-10 membered carbocyclic ring, 4-11 membered heterocyclic ring, 6-10 membered aromatic ring or 5-10 membered heteroaromatic ring; wherein the carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring may be optionally substituted with one or more R c replace; R c Selected from hydrogen, halogen, nitro, cyano, oxo, -NH2, -C(O)NH2, -C(O)H, -C(O)OH, -C1~C6 alkyl, -C2~C6 alkenyl, -C2~C6 alkynyl, halogen-substituted-C1~C6 alkyl, halogen-substituted-C2~C6 alkenyl, halogen-substituted-C2~C6 alkynyl, -O-C1~C6 alkyl, -O-C2~C6 alkenyl, -O-C2~C6 alkynyl, -O-halogen-substituted C1~C6 alkyl, -O-halogen-substituted C2~C6 alkenyl or -O-halogen-substituted C2~C6 alkynyl.

11. The compound according to claim 10, its stereoisomer, deuterated substance, solvate, pharmaceutically acceptable salt, characterized in that: The compound of formula (Ia) is shown in formula (Ie): Among them, R 1 , R 2 , R 5 , L as described in claim 10.

12. The compound according to claim 10, its stereoisomers, deuterated substances, solvates, and pharmaceutically acceptable salts, characterized in that: The compound (Ia) is represented by formula (Ib), formula (Ic) or formula (Id): Among them, R 1 , L, R 2 As described in claim 10.

13. The compound according to any one of claims 1 to 12, its stereoisomers, deuterated substances, solvates, and pharmaceutically acceptable salts, characterized in that: R 2 is selected from a 3-7-membered carbocyclic ring, a 4-6-membered monocyclic heterocyclic ring, a 9-11-membered fused heterocyclic ring, a 6-10-membered aromatic ring or a 5-10-membered heteroaromatic ring; wherein the carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring may be optionally replaced by one or more R 21 replace; R 21 is selected from hydrogen, halogen, nitro, cyano, oxo, -NH2, -C(O)NH2, -C(O)H, -C(O)OH, -C1~C3 alkyl, -C2~C3 alkenyl, -C2~C3 alkynyl, halogen-substituted -C1~C3 alkyl, halogen-substituted -C2~C3 alkenyl, halogen-substituted -C2~C3 alkynyl, -O-C1~C3 alkyl, -O-C2~C3 alkenyl, -O-C2-C3 alkynyl, -O-halogen substituted C1-C3 alkyl, -O-halogen substituted C2-C3 alkenyl, -O-halogen substituted C2-C3 alkynyl, -O-(3-6 membered carbocyclic ring), 3-10 membered carbocyclic ring, 4-11 membered heterocyclic ring, 6-10 membered aromatic ring or 5-10 membered heteroaromatic ring; wherein the carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring may be optionally substituted with one or more R c replace; R c Selected from hydrogen, halogen, nitro, cyano, oxo, -NH2, -C(O)NH2, -C(O)H, -C(O)OH, -C1~C3 alkyl, -C2~C4 alkenyl, -C2~C4 alkynyl, halogen-substituted-C1~C3 alkyl, halogen-substituted-C2~C4 alkenyl, halogen-substituted-C2~C4 alkynyl, -O-C1~C3 alkyl.

14. The compound according to claim 13, its stereoisomers, deuterated substances, solvates, and pharmaceutically acceptable salts, characterized in that: R 2 Selected from Among them, R 21 is selected from hydrogen, halogen, nitro, cyano, oxo, -NH2, -C(O)NH2, -C(O)H, -C(O)OH, -C1-C3 alkyl, halogen-substituted -C1-C3 alkyl, -O-C1-C3 alkyl, -O-halogen-substituted C1-C3 alkyl, -O-(3-6-membered carbocyclic ring), 3-10-membered carbocyclic ring, 4-11-membered heterocyclic ring, 6-10-membered aromatic ring or 5-10-membered heteroaromatic ring; wherein the carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring may be optionally replaced by one or more R c replace; y = 0, 1, 2 or 3; R c Selected from hydrogen, halogen, nitro, cyano, oxo, -NH2, -C(O)NH2, -C(O)H, -C(O)OH, -C1~C3 alkyl, -C2~C4 alkenyl, -C2~C4 alkynyl, halogen-substituted-C1~C3 alkyl, halogen-substituted-C2~C4 alkenyl, halogen-substituted-C2~C4 alkynyl, -O-C1~C3 alkyl.

15. The compound according to claim 14, its stereoisomers, deuterated substances, solvates, and pharmaceutically acceptable salts, characterized in that: R 21 is selected from hydrogen, halogen, -O-C1-C3 alkyl, -C1-C3 alkyl, -O-halogen substituted C1-C3 alkyl, For example, selected from hydrogen, halogen, -O-C1-C3 alkyl, -C1-C3 alkyl, 16. The compound according to any one of claims 1 to 12, its stereoisomers, deuterated substances, solvates, and pharmaceutically acceptable salts, characterized in that: L is selected from a bond, R 4 , R 6 are independently selected from hydrogen, -C1-C3 alkyl, -C1-C3 alkyl substituted with halogen, -C0-C1 alkylene-(3-6-membered carbocyclic ring), -C0-C1 alkylene-(4-6-membered heterocyclic ring), -C0-C1 alkylene-(6-10-membered aromatic ring), -C0-C1-(5-10-membered heteroaromatic ring); wherein the alkyl, alkylene, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring may be optionally substituted with one or more R 41 replace; R 41 Selected from hydrogen, halogen, amino, nitro, cyano, oxo, -NH2, -C(O)NH2, -C(O)H, -C(O)OH, -C1~C3 alkyl, -C2~C3 alkenyl, -C2~C3 alkynyl, halogen-substituted -C1~C3 alkyl, halogen-substituted -C2~C6 alkenyl, halogen-substituted -C2~C6 alkynyl, -O-C1~C6 alkyl.

17. The compound according to claim 16, its stereoisomers, deuterated substances, solvates, and pharmaceutically acceptable salts, characterized in that: R 4 , R 6 are independently selected from hydrogen, -C1-C3 alkyl, -C1-C3 alkyl substituted with halogen, 3-6-membered carbocyclic ring, -CH2-(3-6-membered carbocyclic ring), 4-6-membered heterocyclic ring, -CH2-(4-6-membered heterocyclic ring), 6-10-membered aromatic ring, -CH2-(6-10-membered aromatic ring), 5-10-membered heteroaromatic ring, -CH2-(5-10-membered heteroaromatic ring); wherein the alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring may be optionally substituted with one or more R 41 replace; R 41 Selected from hydrogen, halogen, methyl, ethyl, isopropyl.

18. The compound according to claim 17, its stereoisomers, deuterated substances, solvates, and pharmaceutically acceptable salts, characterized in that: R 4 , R 6 are independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, 19. The compound according to any one of claims 1 to 11, its stereoisomers, deuterated substances, solvates, and pharmaceutically acceptable salts, characterized in that: R 2 Selected from R 21 is selected from hydrogen, halogen, -O-C1-C3 alkyl, -C1-C3 alkyl, -O-halogen substituted C1-C3 alkyl, y = 0, 1, 2 or 3; R c is selected from hydrogen, halogen, nitro, cyano, oxo, -NH2, -C(O)NH2, -C(O)H, -C(O)OH, -C1~C3 alkyl, -C2~C4 alkenyl, -C2~C4 alkynyl, halogen-substituted -C1~C3 alkyl, halogen-substituted -C2~C4 alkenyl, halogen-substituted -C2~C4 alkynyl, -O-C1~C3 alkyl; L is selected from a bond, R 4 , R 6 are independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, R 41 is selected from hydrogen, halogen, methyl, ethyl, isopropyl; R 1 , R 5 They are independently selected from hydrogen, halogen, -C1~C3 alkyl, -C2~C4 alkenyl, halogen-substituted -C1~C3 alkyl, -O-C1~C3 alkyl, 3-4-membered carbocyclic ring, 5-6-membered heteroaromatic ring or 6-10-membered aromatic ring; wherein the carbocyclic ring, heterocyclic ring, heteroaromatic ring and aromatic ring may be optionally substituted by one or more halogen, -C1~C3 alkyl, halogen-substituted -C1~C3 alkyl and -O-C1~C3 alkyl.

20. The compound according to any one of claims 1 to 3, its stereoisomers, deuterated substances, solvates, and pharmaceutically acceptable salts, characterized in that: R 2 Selected from R 21 is selected from hydrogen, halogen, -O-C1-C3 alkyl, -C1-C3 alkyl, -O-halogen substituted C1-C3 alkyl, y = 0, 1, 2 or 3; R c Selected from hydrogen, halogen, nitro, cyano, oxo, -NH2, -C(O)NH2, -C(O)H, -C(O)OH, -C1~C3 alkyl, -C2~C4 alkenyl, -C2~C4 alkynyl, halogen-substituted -C1~C3 alkyl, halogen-substituted -C2~C4 alkenyl, halogen-substituted -C2~C4 alkynyl, -O-C1~C3 alkyl; L is selected from a bond, R 4 , R 6 are independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, R 41 is selected from hydrogen, halogen, methyl, ethyl, isopropyl; R X , R X1 are independently selected from H, halogen, -C1-C3 alkyl, deuterium-substituted -C1-C3 alkyl, halogen-substituted -C1-C3 alkyl, -C(O)CH3; X4 is selected from N, CR 5 ; R 1 , R 5 Each of the following is independently selected from hydrogen, halogen, -C1-C3 alkyl, -C2-C4 alkenyl, halogen-substituted -C1-C3 alkyl, -O-C1-C3 alkyl, 3-4-membered carbocyclic ring, 5-6-membered heteroaromatic ring or 6-10-membered aromatic ring; wherein the carbocyclic ring, heterocyclic ring, heteroaromatic ring or aromatic ring may be optionally substituted by one or more halogen, -C1-C3 alkyl, halogen-substituted -C1-C3 alkyl or -O-C1-C3 alkyl; R 7 Selected from H, halogen, -CN, -NO2, -NH2, -C1~C3 alkyl, deuterium-substituted -C1~C3 alkyl, halogen-substituted -C1~C3 alkyl; R 3 Selected from H, halogen, -C1~C3 alkyl, -C(O)NH2, -C(O)NH(C1~C3 alkyl), -C(O)N(C1~C3 alkyl)2.

21. The compound according to any one of claims 1 to 20, its stereoisomers, deuterated substances, solvates, and pharmaceutically acceptable salts, characterized in that: L is selected from a bond, 22. The compound according to any one of claims 1 to 11, its stereoisomers, deuterated substances, solvates, and pharmaceutically acceptable salts, characterized in that: R 1 , R 5 are independently selected from hydrogen, halogen, -C1-C3 alkyl, halogen-substituted -C1-C3 alkyl, -C2-C4 alkenyl, -O-C1-C3 alkyl, 3-4-membered carbocyclic ring, 5-6-membered heteroaromatic ring or 6-10-membered aromatic ring; wherein the carbocyclic ring, heterocyclic ring, heteroaromatic ring or aromatic ring may be optionally substituted by one or more halogen, -C1~C3 alkyl, -C1~C3 alkyl substituted with halogen, -O-C1~C3 alkyl; for example, R 1 , R 5 Each is independently selected from hydrogen, halogen, -C1~C3 alkyl or halogen-substituted -C1~C3 alkyl.

23. The compound according to any one of claims 1 to 11, its stereoisomers, deuterated substances, solvates, and pharmaceutically acceptable salts, characterized in that: R 1 , R 5 Each independently selected from hydrogen, methyl, ethyl, Cl, Br, I, F, -CF3, -CH2F, -CHF2, -CH2CH2F, -CH2CHF2, -CH2CF3, -Cl, -Br, -OCH3, Phenyl, For example, R 1 , R 5 Each is independently selected from hydrogen, methyl, ethyl, F, -CF3, -CH2F, -CHF2, -CH2CH2F, -CH2CHF2 or -CH2CF3.

24. The compound according to claims 1-20, its stereoisomers, deuterated substances, solvates, and pharmaceutically acceptable salts, characterized in that: R 1 Selected from hydrogen, halogen, -C1~C3 alkyl or halogen-substituted -C1~C3 alkyl.

25. The compound according to claim 24, its stereoisomers, deuterated substances, solvates, and pharmaceutically acceptable salts, characterized in that: R 1 is selected from hydrogen, methyl, ethyl, Cl, Br, I, F, -CF3, -CH2F, -CHF2, -CH2CH2F, -CH2CHF2 or -CH2CF3.

26. The compound according to any one of claims 1 to 20, its stereoisomers, deuterated substances, solvates, and pharmaceutically acceptable salts, characterized in that: R 21 Selected from H, F, Cl, Br, -CF3, -OCH3, -OCF3, methyl, ethyl, isopropyl, 27. The compound according to any one of claims 1 to 20, its stereoisomers, deuterated substances, solvates, and pharmaceutically acceptable salts, characterized in that: R 2 Selected from For example, selected from 28. The compound according to claim 12, its stereoisomers, deuterated substances, solvates, and pharmaceutically acceptable salts, characterized in that: R 1 is selected from hydrogen, halogen, -C1~C3 alkyl or halogen-substituted -C1~C3 alkyl; L is selected from R 4 is selected from hydrogen, -C1-C3 alkyl, -C1-C3 alkyl substituted with halogen, 3-6 membered carbocyclic ring or 4-6 membered heterocyclic ring; R 2 is selected from a 3-7-membered carbocyclic ring, a 4-10-membered heterocyclic ring, a 6-10-membered aromatic ring or a 5-10-membered heteroaromatic ring; wherein the carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring may be optionally replaced by one or more R 21 replace.

29. The compound according to claim 28, its stereoisomers, deuterated substances, solvates, and pharmaceutically acceptable salts, characterized in that: R 1 Selected from hydrogen, methyl, ethyl, F, Cl, Br, I, -CF3, -CH2F, -CHF2, -CH2CH2F, -CH2CHF2 or -CH2CF3; L is selected from R 4 is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl; R 2 Selected from 30. The compound according to claims 1-3, its stereoisomers, deuterated substances, solvates, and pharmaceutically acceptable salts, characterized in that: R 7 Selected from H, F, Cl, Br, I, -CN, -NO2, -NH2, methyl, ethyl, propyl, isopropyl, -CF3, -CH2F, -CHF2, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2D, -CH2CD3.

31. The compound according to claims 1-3, its stereoisomers, deuterated substances, solvates, and pharmaceutically acceptable salts, characterized in that: R 3 Selected from H, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2.

32. The compound according to claims 1-4, its stereoisomers, deuterated substances, solvates, and pharmaceutically acceptable salts, characterized in that: R X , R X1 Each is independently selected from H, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, -CF3, -CH2F, -CHF2, -CH2CH2F, -CH2CHF2, -C(O)CH3, -CH2CF3, -CD3, -CH2D, -CH2CD3.

33. The compound according to claim 1, its stereoisomers, deuterated substances, solvates, and pharmaceutically acceptable salts, characterized in that: The compound is selected from:

34. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 33, its stereoisomers, deuterated forms, solvates, pharmaceutically acceptable salts, and pharmaceutically acceptable carriers and / or excipients.

35. Use of the compound according to any one of claims 1 to 33, its stereoisomer, deuterated form, solvate, pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 34 in the preparation of a medicament for treating a PRMT5-mediated disease.

36. The use according to claim 35, characterized in that The disease mediated by PRMT5 is tumor.

37. The use according to claim 36, characterized in that The tumors are associated with MTAP gene deletion and / or MTA accumulation.

38. The use according to claim 36 or claim 37, characterized in that The tumor is selected from the group consisting of neuroma, adenocarcinoma, adrenal cancer, anal cancer, angiosarcoma, appendix cancer, benign monoclonal gamma disease, bile duct cancer, bladder cancer, brain cancer, bronchial cancer, carcinoid tumor, cervical cancer, choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer, epithelial cancer, ependymoma, endothelial sarcoma, endometrial cancer, esophageal cancer, Ewing's sarcoma, eye cancer, eosinophilia, gallbladder cancer, gastric cancer, gastrointestinal stromal tumor, head and neck cancer, oral cancer, leukemia, lymphoma, multiple myeloma, heavy chain disease, hemangioblastoma Tumor, inflammatory myofibroblastic tumor, immune cell amyloidosis, renal cancer, liver cancer, lung cancer, leiomyosarcoma, mastocytosis, myelodysplastic syndrome, mesothelioma, myeloproliferative diseases, essential thrombocythemia, idiopathic extramedullary metaplasia, chronic idiopathic myelofibrosis, hypereosinophilic syndrome, neuroblastoma, neurofibroma, neuroendocrine cancer, osteosarcoma, ovarian cancer, papillary adenocarcinoma, penile cancer, breast cancer, pancreatic cancer, skin cancer, cancer with homozygous deletion of methylthioadenosine phosphorylase gene.

39. The use according to claim 36 or claim 37, characterized in that The tumor is selected from the group consisting of lymphangiosarcoma, lymphangioendothelioma, hemangioma, meningioma, astrocytoma, oligodendroglioma, medulloblastoma, cervical adenocarcinoma, colon cancer, rectal cancer, colorectal adenocarcinoma, Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcomas, uterine cancer, uterine sarcoma, esophageal adenocarcinoma, Barrett's adenocarcinoma, intraocular melanoma, retinoblastoma, gastric adenocarcinoma, head and neck squamous cell carcinoma, oral squamous cell carcinoma, laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, acute lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic myeloid leukemia, chronic neutrophilic leukemia, follicular lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, lymph node marginal zone B cell lymphoma, splenic marginal zone B cell lymphoma, primary mediastinal B cell B cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia, immunoblastic large cell lymphoma, precursor B lymphoblastic lymphoma and primary central nervous system lymphoma, non-Hodgkin lymphoma, Hodgkin lymphoma, angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma, alpha chain disease, gamma chain disease, mu chain disease, Wilms tumor, renal cell carcinoma, hepatocellular carcinoma, bronchogenic carcinoma, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, leiomyosarcoma, systemic mastocytosis, neurofibromatosis type 1 or 2, schwannomatosis, gastroenteropancreatic neuroendocrine tumors, cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma, neurofibrosarcoma.

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