Condensed heterocyclic compound, pharmaceutical composition and application thereof

Abstract

The invention provides a fused heterocyclic compound, a pharmaceutical composition and application thereof.The compound comprises a compound shown in the formula I: # imgabs0, the compound provided by the invention can be competitively combined with CLK2 in a targeted mode with ATP in a binding pocket of ATP of the CLK2, the compound shown in the formula I has an excellent CLK2 inhibiting effect, and the compound can be used as a medicine for inhibiting the CLK2. And the compound can be used for preventing and treating cancers related to CLK2 amplification or CLK2 overexpression.

Description

[0001] This application claims the priority of the prior patent application filed by the applicant with the State Intellectual Property Office of China on November 21, 2023, with patent application number 202311560206.5 and title “Condensed heterocyclic compounds, pharmaceutical compositions and their applications”; the full text of the prior application is incorporated into this application by reference. Technical Field

[0002] The present application belongs to the field of medical technology, and in particular relates to a fused heterocyclic compound and a pharmaceutical composition and application thereof. Background Art

[0003] Protein kinase is an important enzyme that catalyzes the phosphorylation of proteins. It can regulate the activity of proteins through phosphorylation, and also amplify the signal through the step-by-step phosphorylation of proteins to cause cellular responses. Protein kinase plays a key regulatory role in life processes, and abnormalities in protein kinases often lead to the occurrence of malignant diseases such as cancer. Dysregulation of protein kinase function, such as through functional genetic mutations, gene amplification, autonomous activation, and activation of chromosomal rearrangements, is closely related to the development and progression of cancer, and is involved in cancer cell transformation, growth, proliferation, and survival.

[0004] Protein phosphorylation and alternative splicing are both important links in gene expression regulation. CLKs family kinases (Cdc-like kinases) have both of the above regulatory functions. CLKs family kinases are an evolutionarily conserved dual-specificity kinase, belonging to protein kinases, and are composed of four kinase subtypes, namely CLK1, CLK2, CLK3, and CLK4. CLKs are a group of dual-specificity kinases that can autophosphorylate and can also phosphorylate substrates at serine / threonine residues. CLK2 plays an important regulatory function in many diseases. In recent years, more and more studies have focused on explaining the biological functions of CLK2, a member of this family. As a protein kinase, CLK2 is directly involved in the regulation of multiple important signaling pathways in cells. CLK2 indirectly regulates the expression of other genes by phosphorylating splicing factors, and is involved in the occurrence and development of diseases such as obesity, nervous system diseases, and malignant tumors.

[0005] One of the main functions of CLK2 is to regulate the alternative splicing (AS) of messenger RNA (mRNA) precursors through SR proteins. AS is an important regulatory mode of protein expression. More than 90% of human genes are affected by AS. The incidence of AS in malignant tumors is 30% higher than that in non-malignant tissues, and it is highly diverse, participating in the regulation of cell cycle, stress, metastasis, invasion, angiogenesis, immunosuppression and drug resistance. Various factors can lead to AS disorders, such as mutations in genes encoding splicing factors, abnormal expression and activation of splicing factors, etc. SR proteins are important splicing factors, which mainly regulate the selection of splicing sites by binding to corresponding cis-acting elements on mRNA precursors, or regulate the recognition of splicing sites through interactions between proteins. CLK2 regulates the splicing of mRNA precursors by phosphorylating a variety of SR proteins, and participates in the occurrence and development of a variety of diseases such as nervous system diseases, infections, and malignant tumors. CLK2 indirectly regulates the expression of proteins including ribosomal protein S6 kinase (S6K), Bcl-2associated transcription factor 1 (BCLAF1), and MAPK interacting serine / threonine kinase 2 (MKNK2) through AS. CLK2 inhibitors can synergize with Bcl-xL / Bcl-2 inhibitors to induce apoptosis of human ovarian cancer A2870 cells and rectal cancer HCT116 cells. Transformer 2beta homolog 1 (TRA2B1) is one of the splicing factors with pro-oncogenic effects. CLK2 can hyperphosphorylate TRA2B1, promote the formation of TRA2B1 splicing variants that do not contain exons 2 and 3, and participate in the regulation of TRA2B1 itself AS. CLK2 and Myc synergistically regulate pre-mRNA biosynthesis and splicing processing to improve the survival rate of cancer cells. Serine and arginine-rich splicing factor 1 (SRSF1) is a direct substrate of CLKs and a direct transcriptional target of Myc, which can promote breast epithelial cell transformation. CLK2 is overexpressed in breast cancer cells and tissues, and exogenous downregulation of CLK2 expression can inhibit the proliferation of Myc-amplified breast cancer cells. CLK2 overexpression can promote the proliferation of non-small cell lung cancer (BSCLC), and its mechanism of action may be related to the reduced expression of miR-573 in NSCLC.Inhibiting the activity of CLKs can reduce the expression of Wnt pathway genes and inhibit the growth of gastrointestinal tumor cells. The CLK2 / PAGE4 / HIPK1 axis is closely related to the androgen dependence of prostate cancer and may even be one of the mechanisms that induce androgen-independent lineage plasticity in prostate cancer, which is closely related to castration-resistant prostate cancer. Therefore, inhibiting the activity of CLK2 kinase is likely to be a promising method for treating cancer. Summary of the invention

[0006] The present invention provides a fused heterocyclic compound, a pharmaceutical composition and an application thereof. The compound can inhibit the activity of CLK2 protein by binding to CLK2 protein, and the compound can also indirectly regulate the expression of other genes (such as S6K, BCLAF1, MKNK2, TRA2B1, etc.) through CLK2 phosphorylation splicing factor, and participate in the occurrence and development of diseases such as obesity, nervous system diseases and malignant tumors.

[0007] In a first aspect, the present application provides a fused heterocyclic compound, the compound comprising a compound represented by Formula I or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof. The compound comprises a compound represented by Formula I:

[0008]

[0009] In formula (I):

[0010] X 1 , X 2 and X 3 are each independently selected from CH or N;

[0011] Y 1 and Y 2 Each independently selected from CR 5 or N; R 5 is selected from hydrogen, halogen, alkyl, cyano, nitro, alkynyl, alkyl or alkoxy;

[0012] M is selected from CH or N;

[0013] R 1 Selected from hydrogen;

[0014] R 2 is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkyloxy, substituted or unsubstituted 3-6 membered heterocyclyloxy, substituted or unsubstituted 3-6 membered heterocyclyl-C1-C6 alkylene-oxy, substituted or unsubstituted C3-C6 cycloalkyl-C1-C6 alkylene-oxy or R 6 R 7 N-;

[0015] Among them, R 6 , R 7 Each is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C6 alkylene, substituted or unsubstituted 3-6 membered heterocyclyl-C1-C6 alkylene; or R 6 , R 7 The N atom to which it is connected forms a substituted or unsubstituted 3-6 membered heterocyclic group which optionally contains additional O, S or N heteroatoms

[0016] R 2 The substitution is mono- or poly-substituted by a group selected from the following: hydroxyl, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyloxy, 3-6 membered heterocyclyl, C3-C6 cycloalkyl;

[0017] R 3 is selected from cyano, substituted or unsubstituted C1-C6 alkyl, C3-C6 cycloalkyl, oxo, R 8 R 9 N-;

[0018] Where R 8 , R 9 Each is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C6 alkylene, substituted or unsubstituted 3-6 membered heterocyclyl-C1-C6 alkylene; or R 8 , R 9 The N atom to which it is attached forms a substituted or unsubstituted 3-6 membered heterocyclic group which optionally additionally contains an O, S or N heteroatom;

[0019] R 3 The substitution is mono- or poly-substituted by a group selected from the following: hydroxyl, C1-C6 alkyl;

[0020] R 4 Selected from substituted or unsubstituted C2-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C6 alkylene, substituted or unsubstituted 3-6 membered heterocyclyl-C1-C6 alkylene;

[0021] R 4 The substitution is mono- or poly-substitution by groups selected from the following groups: hydroxyl, halogen, cyano, C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyloxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C1-C6 alkyl acyl.

[0022] In a second aspect, the present application provides a pharmaceutical composition comprising as an active ingredient a compound of formula I or any one of its pharmaceutically acceptable salts, stereoisomers, and deuterated compounds. The pharmaceutical composition of the present application can be used in drugs for treating diseases associated with CLK2 amplification or CLK2 overexpression.

[0023] The present application also relates to the use of the compound of formula I or its pharmaceutically acceptable salt, stereoisomer, deuterated product in the preparation of a drug for treating and / or preventing diseases associated with CLK2 amplification or CLK2 overexpression.

[0024] The present application also relates to a method for diagnosing or treating a disease associated with CLK2 amplification or overexpression, which comprises administering to a patient in need thereof a therapeutically effective amount and / or a preventive effective amount of a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, deuterated compound, or combination thereof.

[0025] The technical solution of this application has at least the following beneficial effects:

[0026] The compounds provided in the present application can competitively target and bind CLK2 with ATP in the ATP binding pocket of CLK2. The compounds shown in Formula I have excellent CLK2 inhibitory effects and can be used to prevent and treat cancers associated with CLK2 amplification or CLK2 overexpression. DETAILED DESCRIPTION

[0027] In order to better illustrate the present application and facilitate understanding of the technical solution of the present application, the present application is further described in detail below. It should be clear that the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0028] definition

[0029] The definitions of specific functional groups and chemical terms are described in more detail below. The abbreviations used herein have their conventional meanings in the chemical and biological fields. Chemical structures and chemical formulas described herein are constructed according to standard chemical valence rules known in the chemical field.

[0030] When a range of values ​​is listed, it is intended to include each number within the range. For example, "C1-C6 alkyl" is intended to include C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl.

[0031] The term "alkyl" refers to a straight or branched saturated hydrocarbon group having 1 to 10 carbon atoms. In some embodiments, the alkyl group has 1 to 6 carbon atoms. In some embodiments, the alkyl group has 1 to 5 carbon atoms. In some embodiments, the alkyl group has 1 to 4 carbon atoms. In some embodiments, the alkyl group has 1 to 3 carbon atoms. In some embodiments, the alkyl group has 1 to 2 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, 3-pentyl, pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl, and n-hexyl.

[0032] Unless otherwise specified, the term "alkylene" means a divalent group derived from an alkyl group, such as but not limited to -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-; the above definition of alkylene applies to the "alkylene" in heterocyclyl-alkylene, cycloalkyl-alkylene and other groups mentioned herein.

[0033] "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms. In some embodiments, cycloalkyl has 3 to 6 ring carbon atoms. In some embodiments, cycloalkyl has 5 to 10 ring carbon atoms. Cycloalkyl includes but is not limited to cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, cyclooctyl, cyclooctenyl, cubic alkyl, bicyclo [1.1.1] pentyl, bicyclo [2.2.2] octyl, bicyclo [2.1.1] hexyl, bicyclo [3.1.1] heptyl, cyclononyl, cyclononenyl, cyclodecyl, cyclodecenyl, octahydro-1H-indenyl, decahydronaphthyl, spiral [4.5] decyl and the like. In certain embodiments, a cycloalkyl group is a single ring (a "monocyclic cycloalkyl") or contains a fused, bridged, or spiro ring system, such as a bicyclic ring system (a "bicyclic cycloalkyl") and may be saturated or may be partially unsaturated.

[0034] "Heterocyclyl" or "heterocycle" refers to a 3-10 membered non-aromatic ring system radical having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from N, O, S. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom if valence permits. The heterocyclyl group may be a monocyclic ring ("monocyclic heterocyclyl") or a fused, bridged or spiro ring system, such as a bicyclic ring system ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. The heterocyclyl bicyclic ring system may include one or more heteroatoms in one or both rings. In some embodiments, the heterocyclyl group is a 3-8 membered non-aromatic ring system having ring carbon atoms and 1-3 ring heteroatoms, wherein each heteroatom is independently selected from N, O and S. In some embodiments, the heterocyclyl group is a 3-6 membered non-aromatic ring system having ring carbon atoms and 1-2 ring heteroatoms, wherein each heteroatom is independently selected from N, O and S. In some embodiments, the heterocyclyl group is a 4-6 membered non-aromatic ring system having ring carbon atoms and 1-2 ring heteroatoms, wherein each heteroatom is independently selected from N and O.

[0035] Examples of heterocyclic groups include, but are not limited to, aziridine, oxirane, thiirane; azetidinyl, oxetanyl, and thietanyl; tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione; dioxolanyl, oxathiolane, dithiolane, and oxazolidin-2-one; triazolinyl, oxadiazolinyl, and thiazolinyl. diazolinyl; piperidinyl, tetrahydropyranyl, dihydropyridinyl and thianyl; piperazinyl, morpholinyl, dithianyl, dioxanyl; triazinyl; azepanyl, oxepanyl and thiepanyl; azocanyl, oxepanyl and thiocanyl; indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinyl and the like; tetrahydroquinolinyl, tetrahydroisoquinolinyl and the like.

[0036] The term "halo" or "halogen" means a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom.

[0037] The term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo-C1-C6 alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, and the like.

[0038] The term "alkoxy" refers to the formula alkyl-O-, wherein alkyl is as defined herein. Alkoxy includes, but is not limited to, methoxy, ethoxy, propoxy, isopropoxy, and the like.

[0039] The term "cycloalkyloxy" means a group of the formula cycloalkyl-O- wherein cycloalkyl is as defined herein.

[0040] The term "heterocyclyloxy" refers to a radical of the formula heterocyclyl-O- wherein heterocyclyl is as defined herein.

[0041] The term "alkyl acyl" refers to the formula alkyl-C(O)-, wherein alkyl is as defined herein. Alkyl acyl includes, but is not limited to, acetyl, propionyl, or butyryl, and the like.

[0042] "Optionally substituted" unless otherwise indicated, means that the group can be unsubstituted or substituted with one or more (e.g., 0, 1, 2, 3, 4, or 5 or more) of the substituents listed for the group, wherein the substituents can be the same or different. In one embodiment, the optionally substituted group has 1 substituent. In another embodiment, the optionally substituted group has 2 substituents. In another embodiment, the optionally substituted group has 3 substituents. In another embodiment, the optionally substituted group has 4 substituents. In another embodiment, the optionally substituted group has 5 substituents.

[0043] The present application provides a fused heterocyclic compound, including a compound represented by Formula I or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof:

[0044]

[0045] In formula (I):

[0046] X 1 , X 2 and X 3 are each independently selected from CH or N;

[0047] Y 1 and Y 2 Each independently selected from CR 5 or N; R 5 is selected from hydrogen, halogen, alkyl, cyano, nitro, alkynyl, alkyl or alkoxy;

[0048] M is selected from CH or N;

[0049] R 1 Selected from hydrogen;

[0050] R 2 is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkyloxy, substituted or unsubstituted 3-6 membered heterocyclyloxy, substituted or unsubstituted 3-6 membered heterocyclyl-C1-C6 alkylene-oxy, substituted or unsubstituted C3-C6 cycloalkyl-C1-C6 alkylene-oxy or R 6 R 7 N-;

[0051] Where R6 , R 7 Each is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C6 alkylene, substituted or unsubstituted 3-6 membered heterocyclyl-C1-C6 alkylene or R 6 , R 7 The N atom to which it is attached forms a substituted or unsubstituted 3-6 membered heterocyclic group which optionally additionally contains an O, S or N heteroatom;

[0052] R 2 The substitution is mono- or poly-substituted (optionally di-, tri- or tetra-substituted) by a group selected from the following: hydroxyl, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyloxy, 3-6 membered heterocyclyl, C3-C6 cycloalkyl;

[0053] R 3 is selected from cyano, substituted or unsubstituted C1-C6 alkyl, C3-C6 cycloalkyl, oxo, R 8 R 9 N-;

[0054] Where R 8 , R 9 Each is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C6 alkylene, substituted or unsubstituted 3-6 membered heterocyclyl-C1-C6 alkylene or R 8 , R 9 The N atom to which it is attached forms a substituted or unsubstituted 3-6 membered heterocyclic group which optionally additionally contains an O, S or N heteroatom;

[0055] R 3 The substitution is mono- or poly-substituted (optionally di-, tri- or tetra-substituted) by a group selected from the following: hydroxyl, C1-C6 alkyl;

[0056] R 4 Selected from substituted or unsubstituted C2-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C6 alkylene, substituted or unsubstituted 3-6 membered heterocyclyl-C1-C6 alkylene;

[0057] R 4The substitution is mono- or poly-substituted (optionally di-, tri- or tetra-substituted) by groups selected from the following: hydroxy, halogen, cyano, C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyloxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C1-C6 alkylacyl.

[0058] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer, wherein X 1 Select from N, X 2 and X 3 Selected from CH.

[0059] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer, wherein Y 1 Selected from N, Y 2 Selected from CR 5 .

[0060] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer, wherein M is selected from N.

[0061] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer, wherein R 2 is selected from substituted or unsubstituted C1-C6 alkoxy; substituted or unsubstituted C3-C6 cycloalkyloxy; substituted or unsubstituted 3-6 membered heterocyclyloxy; substituted or unsubstituted 3-6 membered heterocyclyl-C1-C6 alkylene-oxy; substituted or unsubstituted C3-C6 cycloalkyl-C1-C6 alkylene-oxy; R 6 R 7 N-, where R 6 , R 7 Each is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C6 alkylene, substituted or unsubstituted 3-6 membered heterocyclyl-C1-C6 alkylene, or R 6 , R 7 The N atom to which it is attached forms a substituted or unsubstituted 3-6 membered heterocyclic group which optionally additionally contains an O, S or N heteroatom;

[0062] R 2 The substitution is mono- or poly-substituted (optionally di-, tri- or tetra-substituted) by groups selected from the following: hydroxyl, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyloxy.

[0063] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer, wherein R 2 is selected from substituted or unsubstituted C1-C4 alkoxy; substituted or unsubstituted C3-C6 cycloalkyloxy; substituted or unsubstituted 3-6 membered heterocyclyloxy; substituted or unsubstituted 3-6 membered heterocyclyl-C1-C4 alkylene-oxy; substituted or unsubstituted C3-C6 cycloalkyl-C1-C4 alkylene-oxy; R 6 R 7 N-, where R 6 , R 7 Each is independently selected from H, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C4 alkylene, substituted or unsubstituted 3-6 membered heterocyclyl-C1-C4 alkylene, or R 6 , R 7 The N atom to which it is attached forms a substituted or unsubstituted 3-6 membered heterocyclic group which optionally additionally contains an O, S or N heteroatom;

[0064] R 2 The substitution is mono- or poly-substituted (optionally di-, tri- or tetra-substituted) by groups selected from the following: hydroxyl, halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyloxy.

[0065] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer, wherein R 2 is selected from substituted or unsubstituted C1-C4 alkoxy; substituted or unsubstituted C3-C6 cycloalkyloxy; substituted or unsubstituted 3-6 membered heterocyclyloxy; substituted or unsubstituted 3-6 membered heterocyclyl-C1-C2 alkylene-oxy; substituted or unsubstituted C3-C6 cycloalkyl-C1-C2 alkylene-oxy; R 6 R 7 N-, where R 6 , R 7 Each is independently selected from H, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C2 alkylene, substituted or unsubstituted 3-6 membered heterocyclyl-C1-C2 alkylene, or R 6 , R 7 The N atom to which it is attached forms a substituted or unsubstituted 3-6 membered heterocyclic group which optionally additionally contains an O, S or N heteroatom;

[0066] R 2The substitution is mono- or poly-substituted (optionally di-, tri- or tetra-substituted) by groups selected from the following: hydroxyl, halogen, cyano, C1-C2 alkyl, C1-C2 alkoxy, C3-C6 cycloalkyloxy.

[0067] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer, wherein R 2 is selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, butyloxy, isobutoxy, methylamino, ethylamino, isopropylamino, 2-hydroxy-ethyl-oxy, 2-methoxy-ethyl-oxy, 2-isopropoxy-ethyl-oxy, 2-cyclopropyloxy-ethyl-oxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, oxetanyl-oxy, tetrahydrofuranyl-oxy, pyrrolyl-oxy, tetrahydro-2H-pyranyl-oxy, piperidinyl-oxy, azepine Cyclobutan-1-yl, pyrrol-1-yl, piperidin-1-yl, morpholin-4-yl, cyclobutylamino, oxetanylamino, pyrrolylamino, tetrahydrofuranylamino, tetrahydrofuranyl-methylene-oxy, cyclopropyl-methylene-oxy, oxetanyl-methylene-oxy, azetidinyl-methylene-oxy, cyclopropyl-methylene-amine, cyclobutyl-methylene-amine, cyclopentyl-methylene-amine, oxetanyl-methylene-amine, tetrahydrofuran-methylene-amine; R 2 wherein the above groups are monosubstituted or polysubstituted (optionally disubstituted, trisubstituted, tetrasubstituted) by groups selected from the following: hydroxyl, F, cyano, methyl, methoxy. In some embodiments of the present disclosure, the compound represented by the general formula (I) or its pharmaceutically acceptable salt, stereoisomer, wherein R 3 is selected from cyano; substituted or unsubstituted C1-C6 alkyl; C3-C4 cycloalkyl; oxo; R 8 R 9 N-, where R 8 , R 9 Each independently selected from H, substituted or unsubstituted C1-C6 alkyl, or R 8 , R 9 The N atom to which it is attached forms a substituted or unsubstituted 3-6 membered heterocyclic group which optionally additionally contains an O, S or N heteroatom;

[0068] R 3 The substitution is mono- or poly-substituted (optionally di-, tri- or tetra-substituted) by groups selected from the following: hydroxyl, C1-C6 alkyl.

[0069] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer, wherein R 3 is selected from cyano; substituted or unsubstituted C1-C4 alkyl; C3-C6 cycloalkyl; oxo; R8 R 9 N-, where R 8 , R 9 Each independently selected from H, substituted or unsubstituted C1-C4 alkyl, or R 8 , R 9 The N atom to which it is attached forms a substituted or unsubstituted 3-6 membered heterocyclic group which optionally additionally contains an O or N heteroatom;

[0070] R 3 The substitution is mono- or poly-substituted (optionally di-, tri- or tetra-substituted) by groups selected from the following: hydroxyl, C1-C4 alkyl.

[0071] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer, wherein R 3 is selected from cyano; substituted or unsubstituted C1-C2 alkyl; C3-C4 cycloalkyl; oxo; R 8 R 9 N-, where R 8 , R 9 Each independently selected from H, substituted or unsubstituted C1-C2 alkyl, or R 8 , R 9 The N atom to which it is attached forms a substituted or unsubstituted 3-6 membered heterocyclic group which optionally additionally contains an O or N heteroatom;

[0072] R 3 The substitution is mono- or poly-substituted (optionally di-, tri- or tetra-substituted) by groups selected from the following: hydroxyl, C1-C2 alkyl.

[0073] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer, wherein R 3 Selected from the following groups: cyano, methyl, ethyl, hydroxymethyl, dimethylamino, azetidin-1-yl, 4-methyl-piperazin-1-yl.

[0074] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer, wherein R 3 In the case of being selected from oxo groups, the general formula (I) contains R 3 The group fragment is as follows:

[0075]

[0076] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer, wherein R 4Selected from substituted or unsubstituted C2-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C6 alkylene, substituted or unsubstituted 3-6 membered heterocyclyl-C1-C6 alkylene;

[0077] R 4 The substitution is mono- or poly-substituted (optionally di-, tri- or tetra-substituted) by groups selected from the following: hydroxyl, halogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkyl acyl.

[0078] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer, wherein R 4 Selected from substituted or unsubstituted C2-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C4 alkylene, substituted or unsubstituted 3-6 membered heterocyclyl-C1-C4 alkylene;

[0079] R 4 The substitution is mono- or poly-substituted (optionally di-, tri- or tetra-substituted) by groups selected from the following: hydroxy, halogen, C1-C4 alkyl, hydroxy-C1-C4 alkyl, C1-C4 alkyl acyl.

[0080] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer, wherein R 4 Selected from substituted or unsubstituted C2-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C2 alkylene, substituted or unsubstituted 3-6 membered heterocyclyl-C1-C2 alkylene;

[0081] R 4 The substitution is mono- or poly-substituted (optionally di-, tri- or tetra-substituted) by groups selected from the following: hydroxyl, halogen, C1-C4 alkyl, hydroxy-C1-C2 alkyl, C1-C2 alkyl acyl.

[0082] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer, wherein R 4R is selected from the group consisting of ethyl, 2-hydroxy-ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, cyclopropyl-methylene, cyclobutyl-methylene, cyclopentyl-methylene, cyclohexyl-methylene, tetrahydrofuranyl-methylene, tetrahydro-2H-pyran-methylene, piperidinyl-methylene, morpholinyl-methylene, azetidinyl-methylene or oxetanyl-methylene; 4 wherein the above groups are monosubstituted or polysubstituted (optionally disubstituted, trisubstituted, tetrasubstituted) by groups selected from the following: hydroxyl, F, methyl, acetyl, 2-hydroxy-ethyl.

[0083] In some embodiments, the compound of formula (I) is selected from any one of structures (1) to (3) shown below:

[0084]

[0085] The present application also provides a method for preparing the compound represented by the above formula I, including any one of the following preparation methods: It can be understood that Y in the following synthesis method 1 , Y 2 , R 1 , R 2 , R2, R3, R4 and R5 are all selected from the groups described in the compound represented by formula I of the present application. The synthetic route is as follows: (1)

[0087]

[0088]

[0089] 1. Synthesis of intermediate 4 or 5:

[0090] (1) Intermediate 1 and NH 2 R 4 The reaction gives intermediate 2, and the reaction is preferably carried out under alkaline conditions.

[0091] (2) Under reducing conditions, intermediate 2 is reduced to intermediate 3, wherein the reducing conditions are: (a) reduction by hydrogen or other reagents under the catalysis of a catalyst; (b) reduction by a reducing metal, preferably iron powder or zinc powder, under acidic conditions.

[0092] (3) Intermediate 3 contains R 3 A reagent of a group (such as trimethyl orthoacetate or trimethyl orthopropionate) is used for condensation reaction to obtain intermediate 4;

[0093] Alternatively, intermediate 3 is subjected to a cyclization reaction with carbonyldiimidazole (CDI), phosgene, triphosgene and their equivalents, and the resulting product is subjected to a chlorination reaction with phosphorus oxychloride, oxalyl chloride, dichlorothionyl, etc. to form intermediate 6; intermediate 6 can be reacted with cyanide, corresponding alcohol compounds, or amine compounds to obtain intermediate 4.

[0094] (4) intermediate 4 reacts with an organic borate or bis-boronate to obtain intermediate 5, wherein R'B represents a pinacol boron group, a dihydroxy boron group, a dialkoxy boron group, etc.; the reaction is (a) carried out in the presence of a metal catalyst such as palladium or nickel and a base, wherein intermediate 4 and bis-boronate (bis-pinacol boronate) undergo a coupling reaction; or (b) carried out in the presence of an organic lithium reagent or an organic magnesium reagent, for example, intermediate 4 reacts with n-butyl lithium (or lithium diisopropylamide) to generate a lithiated product, and then reacts with a boric ester (such as triisopropyl borate or isopropoxy pinacol borate).

[0095] 2. Synthesis of intermediate 8:

[0096] Intermediate 7 reacts with an organic borate or an organic bis-borate to obtain intermediate 8, wherein R'B represents a pinacol borate, a dihydroxy borate, a dialkoxy borate, etc.; the reaction is (a) carried out in the presence of a metal catalyst such as palladium or nickel and a base, wherein intermediate 7 and the bis-borate (bis-pinacol borate) undergo a coupling reaction; or (b) carried out in the presence of an organic lithium reagent or an organic magnesium reagent, for example, intermediate 7 reacts with n-butyl lithium (or lithium diisopropylamide) to generate a lithiated product, and then reacts with a boric ester (such as triisopropyl borate or isopropoxy pinacol borate).

[0097] 3. Synthesis of compound of general formula (I):

[0098] Intermediate 4 and intermediate 8 are coupled to obtain the compound represented by formula (I) of the present application, or intermediate 5 and intermediate 7 are coupled to obtain the compound represented by formula (I) of the present application. The coupling reaction is prepared by a cross-coupling reaction such as a Suzuki coupling reaction. For example, in the presence of a metal catalyst such as palladium or nickel, a base and an additive are used as needed. The palladium catalyst is selected from PdCl2(dppf), Pd2(dba)3, Pd(PPh3)4, etc., and the base is usually selected from sodium carbonate, cesium carbonate, potassium carbonate, etc.

[0099] The compounds represented by formula (I) prepared according to the method represented by the above general formula include those shown in Table 1:

[0100] Table 1. Specific compounds provided in this application

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117] Preparation Example

[0118] Preparation of intermediate 1:

[0119]

[0120] Step 1: At room temperature, 1,7a-dihydro-4H-cyclopenta[d]pyrimidin-4-one (4 g) was added in batches to a toluene (200 mL) solution containing phosphorus oxychloride (15 mL), and DIEA (5 mL) was slowly added after sufficient stirring. The above mixture was fully replaced with nitrogen and heated to 100 ° C for overnight reaction until the reaction was complete. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. Dichloromethane was added to the residue, and the pH value of the above mixture was adjusted to 7 with saturated sodium bicarbonate aqueous solution. After separation, the aqueous phase was treated with dichloromethane and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate 1 (3.5 g) as a light yellow solid.

[0121] Step 2: At room temperature, dissolve the intermediate 1 (3.5 g) obtained in step 1 in anhydrous methanol (100 ml) and add DIEA (5 mL). The above mixture is reacted at room temperature overnight until the reaction is complete. After the reaction is completed, it is concentrated under reduced pressure. Ethyl acetate and water are added to the residue, and the liquids are separated after sufficient stirring. The aqueous phase is extracted with ethyl acetate and the organic phases are combined. The organic phase is washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue is purified by column chromatography to obtain intermediate 2 (3.1 g) as a yellow solid.

[0122] Step 3: At room temperature. Add NBS (8.25 g) in batches to a solution of intermediate 2 (3.1 g) obtained in step 2 in acetonitrile (100 mL). Stir the above solution at room temperature overnight until the reaction is complete. After the reaction is completed, concentrate under reduced pressure, add ethyl acetate and water to the residue, stir well and separate the liquids. Extract the aqueous phase with ethyl acetate and combine the organic phases. Wash the organic phase with water and saturated brine, dry over anhydrous sodium sulfate and concentrate under reduced pressure. The resulting residue is purified by column chromatography to obtain intermediate 3 (5.6 g) as a yellow solid.

[0123] Step 4: At room temperature, the intermediate (2g) obtained in step 3 was dissolved in anhydrous tetrahydrofuran (50ml), and the nitrogen was fully replaced and then cooled to -40°C and stirred for 20 minutes. Then isopropylmagnesium chloride-lithium chloride (3.6mL, 2M) was slowly added dropwise to the above solution. After stirring the above mixture at -40°C for 30 minutes, it was slowly warmed to room temperature and continued to react for 2h until the reaction was complete. After the reaction was completed, the above mixture was cooled to zero degrees and quenched with ice water. The above mixture was extracted with ethyl acetate and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain intermediate 4 (1.3g) as a white solid.

[0124] Step 5: At room temperature, dissolve the intermediate 4 (1.3 g) obtained in step 4 in a THF solution (50 mL), add triisopropyl borate (1.19 g), and cool the mixture to -50 ° C after fully replacing nitrogen. Slowly drop n-butyl lithium in n-hexane solution (2.7 ml, 2.5 M) into the above solution. After the addition is completed, the mixture is stirred at -50 ° C for 30 minutes and then slowly warmed to room temperature and continued to react for 2 hours until the reaction is complete. After the reaction is completed, concentrate under reduced pressure. Add n-hexane to the residue, stir well and filter, wash the filter cake with n-hexane, and vacuum dry to obtain intermediate A1 (1.5 g) as a gray powder.

[0125] Preparation of intermediate A2:

[0126]

[0127] Step 1: At room temperature, dissolve 2-nitro-3-fluoro-5-bromopyridine (1.03 g) in acetonitrile (15 mL), add 3-aminomethyl-tetrahydrofuran (567 mg) and cesium carbonate (2.97 g), and react at room temperature for 16 hours until the raw materials react completely. After the reaction is completed, ethyl acetate is added to the reaction solution, and the resulting mixture is washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The organic phase is concentrated to obtain a crude product, and the crude product is subjected to column chromatography to obtain intermediate 1 (1.16 g). LCMS [M+H] + =302.0,304.0.

[0128] Step 2: At room temperature, the intermediate 1 (1.15 g) obtained in step 1 was dissolved in acetic acid (40 mL) and reduced iron powder (1.95 g) was added. The above mixture was reacted at room temperature for 4 h until the raw material reacted completely. After the reaction was completed, the solvent was removed, ethyl acetate was added to the residue, and it was filtered after sufficient stirring. The filtrate was adjusted to a neutral pH with an aqueous sodium bicarbonate solution and then separated. The aqueous phase was extracted with ethyl acetate and the organic phases were combined. The obtained organic phase was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain a crude product, and the crude product was subjected to column chromatography to obtain intermediate 2 (850 mg) as a brown solid. LCMS [M+H] + =272.0,274.0.

[0129] Step 3: At room temperature, the intermediate 3 (640 mg) obtained in step 2 was dissolved in trimethyl orthoacetate (10 mL), trifluoroacetic acid (2 mL) was added, and the above mixture was reacted at 100 ° C for 16 h under nitrogen protection. After the reaction was completed, the solvent was removed. Ethyl acetate was added to the residue. The resulting mixture was adjusted to a neutral pH with an aqueous sodium bicarbonate solution and then separated. The aqueous phase was extracted with ethyl acetate and the organic phases were combined. The obtained organic phase was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain a crude product, and the crude product was subjected to column chromatography to obtain intermediate 3 (440 mg) as a gray solid. LCMS [M+H] + =296.0,298.0.

[0130] Step 4: Dissolve the intermediate 3 (420 mg) obtained in step 3 in 1,4-dioxane (5 mL) at room temperature, add bis-pinacol borate (435 mg), potassium acetate (360 mg) and Pd(dppf)Cl 2(104 mg). The above mixture was fully replaced with nitrogen and heated to 80°C until the reaction was complete. After the reaction was completed, ethyl acetate was added to the above mixture. The above mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed. The residue was purified by column chromatography to obtain intermediate A2 (260 mg) as a white solid. LCMS [M+H] + =344.2.

[0131] Embodiment 1:

[0132] Step 1: At room temperature, 6-bromo-2-methyl-4-azabenzimidazole (1.00g) and bromomethylcyclopropane (800mg) were dissolved in anhydrous tetrahydrofuran (50mL), and potassium hydroxide (792mg) and TBAI (1.6g) were added. The above mixture was stirred at 60°C overnight until the reaction was complete. After the reaction was complete, the solvent was removed under reduced pressure, water and ethyl acetate were added to the residue, and the liquids were separated after sufficient stirring. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate 1 (420mg).

[0133] Step 2: Dissolve the intermediate 1 (100 mg) obtained in step 1 in DME (2 ml) and H at room temperature. 2 O (0.5 ml), intermediate A1 (120 mg), cesium carbonate (195 mg) and Pd(dppf)Cl 2 (40 mg). The above mixture was fully replaced with nitrogen and heated to 100°C and stirred for 1 hour until the reaction was complete. After the reaction was completed, the mixture was cooled to room temperature, water and ethyl acetate were added to the above mixture, and the mixture was fully stirred and separated. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain Example 1 (34 mg). LCMS [M+H] + =335.1.

[0134] 1 H NMR (400 MHz, DMSO-d 6)δ(ppm):8.53(d,J=2.0Hz,1H),8.22(s,1H),8.16(d,J=2.0Hz,1H),8.06(d,J=2.8Hz,1H),7.06(d,J=2.8Hz,1 H), 4.16 (d, J = 7.2Hz, 2H), 4.00 (s, 3H), 2.64 (s, 3H), 1.35-1.28 (m, 1H), 0.56-0.52 (m, 2H), 0.47-0.43 (m, 2H).

[0135] Embodiment 2:

[0136]

[0137] Step 1: At room temperature, 6-bromo-2-methyl-4-azabenzimidazole (1.00g) and bromomethylcyclobutane (843mg) were dissolved in anhydrous tetrahydrofuran (50mL), and potassium hydroxide (792mg) and TBAI (1.6g) were added. The above mixture was stirred at 60°C overnight until the reaction was complete. After the reaction was complete, the solvent was removed under reduced pressure, water and ethyl acetate were added to the residue, and the liquids were separated after sufficient stirring. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate 1 (365mg).

[0138] Step 2: Dissolve the intermediate 1 (90 mg) obtained in step 1 in DME (2 ml) and H at room temperature. 2 O (0.5 ml), intermediate A1 (80 mg), cesium carbonate (152 mg) and Pd(dppf)Cl 2 (17 mg). After the nitrogen is fully replaced in the above mixture, it is heated to 100°C and stirred for 1 hour until the reaction is complete. After the reaction is completed, the mixture is cooled to room temperature, water and ethyl acetate are added to the above mixture, and the mixture is fully stirred and separated. The organic phase is washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue is purified by column chromatography to obtain Example 2 (18 mg). LCMS [M+H] + =349.2.

[0139] 1 H NMR (400 MHz, DMSO-d 6)δ(ppm):8.52(d,J=2.0Hz,1H),8.23(s,1H),8.16(d,J=2.0Hz,1H),8.06(d,J=2.8Hz,1H),7.07(d,J =2.8Hz,1H),4.28(d,J=7.6Hz,2H),4.01(s,3H),2.88-2.81(m,1H),2.62(s,3H),2.00-1.80(m,6H).

[0140] Embodiment 3:

[0141]

[0142] Step 1: At room temperature, 6-bromo-2-methyl-4-azabenzimidazole (1.00g) and bromomethylcyclopentane (922mg) were dissolved in anhydrous tetrahydrofuran (50mL), and potassium hydroxide (792mg) and TBAI (1.61g) were added. The above mixture was stirred at 60°C overnight until the reaction was complete. After the reaction was complete, the solvent was removed under reduced pressure. Water and ethyl acetate were added to the residue, and the liquids were separated after sufficient stirring. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate 1 (386mg).

[0143] Step 2: Dissolve the intermediate 1 (95 mg) obtained in step 1 in DME (2 mL) and H at room temperature. 2 O (0.5 mL), intermediate A1 (80 mg), cesium carbonate (152 mg) and Pd(dppf)Cl 2 (17 mg). The above mixture was fully replaced with nitrogen and heated to 100°C and stirred for 1 hour until the reaction was complete. After the reaction was completed, the mixture was cooled to room temperature, water and ethyl acetate were added to the above mixture, and the mixture was fully stirred and separated. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain Example 3 (18 mg). LCMS [M+H] + =363.2.

[0144] 1 H NMR (400 MHz, DMSO-d 6)δ(ppm):8.52(d,J=2.0Hz,1H),8.23(s,1H),8.15(d,J=2.0Hz,1H),8.06(d,J=2.8Hz,1H),7.07(d,J=2.8Hz,1H),4.20( d,J=7.8Hz,2H),3.99(s,3H),2.62(s,3H),2.47-2.39(m,1H),1.70-1.61(m,4H),1.54-1.51(m,2H),1.33-1.30(m,2H).

[0145] Embodiment 5:

[0146]

[0147] Step 1: At room temperature, 6-bromo-2-methyl-4-azabenzimidazole (1.00 g) was dissolved in tetrahydrofuran (15 mL), and 18-Crown-6 (626 mg), potassium iodide (1.57 g), potassium hydroxide (797 mg) and ethyl iodide (887 mg) were added in sequence. The above mixture was reacted at 70 ° C for 24 h until the raw materials reacted completely. The reaction solution was diluted with ethyl acetate, and the resulting mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by flash chromatography to obtain intermediate 1 (260 mg) as a yellow solid.

[0148] Step 2: At room temperature, the intermediate 1 (42 mg) obtained in step 1 and the intermediate A1 (50 mg) were dissolved in a solution of ethylene glycol dimethyl ether and water in a ratio of 4 / 1 (2.5 mL), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (10 mg) and cesium carbonate (95 mg) were added. The above mixture fully replaced N 2 After that, the mixture was heated to 100°C for 2 hours until the reaction of the raw materials was complete. After the reaction was completed, ethyl acetate was added to the reaction solution, and the resulting mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by flash chromatography to obtain Example 5 (11 mg) as a white solid. LCMS (ES, m / z): 309.2 [M+H] + .

[0149] 1 H NMR (400 MHz, DMSO-d 6)δ(ppm):8.54(d,J=2.0Hz,1H),8.23(s,1H),8.14(d,J=2.0Hz,1H),8.06(d,J=2.8Hz,1H),7 .10(d,J=2.8Hz,1H),4.31(q,J=7.2Hz,2H),4.01(s,3H),2.62(s,3H),1.36(t,J=7.2Hz,3H).

[0150] Embodiment 7:

[0151]

[0152] Step 1: At room temperature, 6-bromo-2-methyl-4-azabenzimidazole (1.00 g) was dissolved in tetrahydrofuran (15.0 mL), and 18-Crown-16 (630 mg), potassium iodide (1.57 g), potassium hydroxide (800 mg) and 2-bromoethanol (705 mg) were added in sequence. The mixture was heated to 70 ° C and the reaction was continued for 24 hours until the reaction was complete. LCMS detected that the raw material reaction was complete. After the reaction was completed, ethyl acetate was added to the mixture. The resulting mixture was washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash chromatography to obtain intermediate 1 (150 mg) as a yellow solid.

[0153] Step 2: Dissolve the intermediate 1 (41 mg) and intermediate A1 (50 mg) obtained in step 1 in a mixed solution of ethylene glycol dimethyl ether and water (v / v = 4 / 1) (2.5 mL), add cesium carbonate (97 mg) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (11 mg). The above mixture fully replaces N 2 Then heat to 100°C and react for 2 hours until the raw material reacts completely. After the reaction is completed, ethyl acetate is added to the above mixture. The resulting mixture is washed with water and saturated brine, and dried over anhydrous sodium sulfate. After the organic phase is concentrated, the residue is purified by flash chromatography Example 7 (15 mg). LCMS (ES, m / z): 325.2 [M+H] + .

[0154] 1 H NMR (400 MHz, DMSO-d 6)δ(ppm):8.52(d,J=2.0Hz,1H),8.22(s,1H),8.11(d,J=2.4Hz,1H),8.06(d,J=2.4Hz,1H),7.07(d, J=2.8Hz,1H),5.02(s,1H),4.30(t,J=5.2Hz,2H),4.02(s,3H),3.76(t,J=5.2Hz,2H),2.63(s,3H).

[0155] Embodiment 8:

[0156]

[0157] Step 1: At room temperature, 6-bromo-2-methyl-4-azabenzimidazole (1.00 g) was dissolved in tetrahydrofuran (15.0 mL), and 18-Crown-16 (630 mg), potassium iodide (1.57 g), potassium hydroxide (800 mg) and bromopropane (693 mg) were added in sequence. The mixture was heated to 70 ° C and the reaction was continued for 24 hours until the raw materials reacted completely. After the reaction was completed, ethyl acetate was added to the mixture. The resulting mixture was washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash chromatography to obtain the intermediate intermediate 1 (280 mg) as a yellow solid.

[0158] Step 2: The intermediate 1 (52 mg) and intermediate A1 (50 mg) obtained in step 1 were dissolved in a mixed solution of ethylene glycol dimethyl ether and water (v / v = 4 / 1) (2.5 mL), and cesium carbonate (97 mg) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (11 mg) were added. The mixture was fully replaced with N 2 Then heat to 100°C and react for 2h until the raw material reacts completely. After the reaction is completed, ethyl acetate is added to the above mixture. The resulting mixture is washed with water and saturated brine. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is purified by flash chromatography to obtain Example 8 (9 mg). LCMS (ES, m / z): 323.2 [M+H] + .

[0159] 1 H NMR (400 MHz, DMSO-d 6)δ(ppm):8.53(d,J=2.4Hz,1H),8.23(s,1H),8.15(d,J=2.0Hz,1H),8.06(d,J=2.8Hz,1H),7.08(d,J= 2.4Hz,1H),4.21(t,J=7.2Hz,2H),4.01(s,3H),2.62(s,3H),1.85-1.75(m,2H),0.92(t,J=7.2Hz,3H).

[0160] Embodiment 9:

[0161]

[0162] Step 1: At room temperature, 6-bromo-2-methyl-4-azabenzimidazole (1.02 g) was dissolved in tetrahydrofuran (15.0 mL), and 18-Crown-16 (635 mg), potassium iodide (1.58 g), potassium hydroxide (810 mg) and isopropyl bromide (695 mg) were added in sequence. The mixture was heated to 70 ° C and the reaction was continued for 24 hours until the raw materials reacted completely. After the reaction was completed, ethyl acetate was added to the mixture. The resulting mixture was washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash chromatography to obtain the intermediate intermediate 1 (310 mg) as a yellow solid.

[0163] Step 2: The intermediate 1 (52 mg) and intermediate A1 (50 mg) obtained in step 1 were dissolved in a mixed solution of ethylene glycol dimethyl ether and water (v / v = 4 / 1) (2.5 mL), and cesium carbonate (97 mg) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (11 mg) were added. The mixture was fully replaced with N 2 Then heat to 100°C and react for 2h until the raw material reacts completely. After the reaction is completed, ethyl acetate is added to the above mixture. The resulting mixture is washed with water and saturated brine. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is purified by flash chromatography to obtain Example 9 (18 mg). LCMS (ES, m / z): 323.2 [M+H] + .

[0164] 1 H NMR (400 MHz, DMSO-d 6)δ(ppm):8.51(d,J=2.0Hz,1H),8.27(d,J=2.0Hz,1H),8.22(s,1H),8.05(d,J=2.8Hz,1H ),7.10(d,J=2.8Hz,1H),4.83-4.76(m,1H),4.01(s,3H),2.63(s,3H),1.62-1.60(m,6H).

[0165] Embodiment 10:

[0166]

[0167] Step 1: At room temperature, 6-bromo-2-methyl-4-azabenzimidazole (1.01 g) was dissolved in tetrahydrofuran (15.0 mL), and 18-Crown-16 (632 mg), potassium iodide (1.58 g), potassium hydroxide (813 mg) and isobutyl bromide (773 mg) were added in sequence. The mixture was heated to 70 ° C and the reaction was continued for 24 hours until the raw materials reacted completely. After the reaction was completed, ethyl acetate was added to the mixture. The resulting mixture was washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash chromatography to obtain the intermediate intermediate 1 (220 mg) as a yellow solid.

[0168] Step 2: The intermediate 1 (47 mg) and intermediate A1 (51 mg) obtained in step 1 were dissolved in a mixed solution of ethylene glycol dimethyl ether and water (v / v = 4 / 1) (2.5 mL), and cesium carbonate (98 mg) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (11 mg) were added. The mixture was fully replaced with N 2 The mixture was then heated to 100°C for 2 hours until the reaction of the raw materials was complete. After the reaction was completed, ethyl acetate was added to the mixture. The resulting mixture was washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography to obtain Example 10 (14 mg). LCMS (ES, m / z): 337.2 [M+H] + .

[0169] 1 H NMR (400 MHz, DMSO-d 6)δ(ppm):8.53(d,J=2.0Hz,1H),8.23(s,1H),8.14(d,J=2.0Hz,1H),8.06(d,J=2.8Hz,1H),7.07(d,J= 2.8Hz, 1H), 4.06 (d, J = 7.6Hz, 2H), 3.99 (s, 3H), 2.61 (s, 3H), 2.24-2.18 (m, 1H), 0.94 (d, J = 6.4Hz, 6H).

[0170] Embodiment 14:

[0171]

[0172] Step 1: At room temperature, 2-fluoro-4-bromonitrobenzene (500 mg) was dissolved in acetonitrile (10.0 mL), 1-tert-butyloxycarbonyl-4-aminomethylpiperidine (586 mg) and cesium carbonate (1.49 g) were added, and the mixture was reacted at room temperature for 16 h until the raw materials reacted completely. After the reaction was completed, ethyl acetate was added to the reaction solution, and the resulting mixture was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain a crude product, and the crude product was subjected to column chromatography to obtain intermediate 1 (860 mg) as a yellow oil.

[0173] Step 2: At room temperature, the intermediate 1 (860 mg) obtained in step 1 was dissolved in acetic acid (50 mL), and reduced iron powder (1.16 g) was added. The above mixture was reacted at room temperature for 4 h until the raw material reacted completely. After the reaction was completed, the reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, and the mixture was filtered after sufficient stirring. The filtrate was adjusted to pH 7 with saturated sodium bicarbonate aqueous solution and separated. The aqueous phase was extracted with ethyl acetate and the organic phases were combined. The obtained organic phase was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain a crude product, and the crude product was subjected to column chromatography to obtain intermediate 2 (640 mg) as a brown solid.

[0174] Step 3: At room temperature, the intermediate 2 (300 mg) obtained in step 2 was dissolved in trimethyl orthoacetate (10 mL), acetic acid (2 mL) was added, and the reaction was carried out at 95 ° C for 16 h under nitrogen protection until the raw material reacted completely. After the reaction was completed, the solvent was removed under reduced pressure, and ethyl acetate was added to the residue. The pH of the obtained mixture was adjusted to neutral with saturated sodium bicarbonate aqueous solution. After separation, the aqueous phase was extracted with ethyl acetate and the organic phases were combined. The obtained organic phase was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain a crude product, and the crude product was subjected to column chromatography to obtain intermediate 3 (150 mg) as a gray solid.

[0175] Step 4: At room temperature, the intermediate 3 (460 mg) obtained in step 3 was dissolved in dichloromethane (4.0 mL), and trifluoroacetic acid (4.0 mL) was added. The above mixture was reacted at room temperature for 3 h until the raw material reacted completely. After the reaction was completed, the reaction solution was directly concentrated to obtain the crude intermediate 4 (1.16 g) as a black oil.

[0176] Step 5: At room temperature, the intermediate 4 (50 mg) obtained in step 4 and the intermediate A1 (149 mg) were dissolved in a solution of ethylene glycol dimethyl ether and water in a ratio of 4 / 1 (2.5 mL). Cesium carbonate (190 mg) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (11 mg) were added to the above mixture. The above mixture was fully replaced by N 2 The mixture was then heated to 100°C for 2 hours until the reaction of the raw materials was complete. After the reaction was completed, ethyl acetate was added to the reaction solution, and the resulting mixture was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain a crude product, which was purified by column chromatography to obtain Example 14 (8 mg). LCMS (ES, m / z): 377.2 [M+H] + .

[0177] 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm):8.18(s,1H),8.01(d,J=2.8Hz,1H),7.69(s,1H),7.52(d,J=8.4Hz, 1H),7.37(dd,J=8.4,1.6Hz,1H),6.98(d,J=2.8Hz,1H),4.06(d,J=7.6Hz,2H) ,4.00(s,3H),2.92(d,J=12.0Hz,2H),2.56(s,3H),2.54(d,J=3.2Hz,1H),2. 36(t,J=12.0Hz,2H),1.94(s,1H),1.46(d,J=12.4Hz,2H),1.24-1.15(m,2H).

[0178] Embodiment 17:

[0179]

[0180] Step 1: At room temperature, 2-fluoro-4-bromo-nitrobenzene (500 mg) was dissolved in acetonitrile (10 mL), and tert-butyl 3-(aminomethyl)piperidine-1-carboxylate hydrochloride (684 mg) and cesium carbonate (2.22 g) were added. The mixture was reacted at room temperature for 16 h until the raw materials reacted completely. After the reaction was completed, ethyl acetate was added to the reaction solution, and the resulting mixture was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain a crude product, and the crude product was subjected to column chromatography to obtain intermediate 1 (820 mg) as a yellow oil.

[0181] Step 2: At room temperature, the intermediate 2 (820 mg) obtained in step 1 was dissolved in acetic acid (50 mL), and reduced iron powder (1.12 g) was added. The above mixture was reacted at room temperature for 4 h until the raw material reacted completely. After the reaction was completed, the reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, and the mixture was filtered after sufficient stirring. The filtrate was adjusted to a neutral pH with a saturated aqueous sodium bicarbonate solution and separated. The aqueous phase was extracted with ethyl acetate and the organic phases were combined. The obtained organic phase was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain a crude product, and the crude product was subjected to column chromatography to obtain intermediate 3 (615 mg) as a brown solid.

[0182] Step 3: At room temperature, the intermediate 2 (610 mg) obtained in step 2 was dissolved in trimethyl orthoacetate (10 mL), acetic acid (2 mL) was added, and the reaction was carried out at 95 ° C for 16 h under nitrogen protection until the raw material reacted completely. After the reaction was completed, the solvent was removed under reduced pressure, and ethyl acetate was added to the residue. The pH of the obtained mixture was adjusted to neutral with saturated sodium bicarbonate aqueous solution. After separation, the aqueous phase was extracted with ethyl acetate and the organic phases were combined. The obtained organic phase was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain a crude product, and the crude product was subjected to column chromatography to obtain intermediate 3 (550 mg) as a gray solid.

[0183] Step 4: At room temperature, the intermediate 3 (540 mg) obtained in step 3 was dissolved in dichloromethane (4.0 mL), and trifluoroacetic acid (4.0 mL) was added. The above mixture was reacted at room temperature for 3 h until the raw material was completely reacted. After the reaction was completed, the reaction solution was directly concentrated to obtain the crude intermediate 4 (1.46 g) as a black oil.

[0184] Step 5: At room temperature, the intermediate 4 (176 mg) obtained in step 4 and the intermediate A1 (50 mg) were dissolved in a solution of ethylene glycol dimethyl ether and water in a ratio of 4 / 1 (2.0 mL). Cesium carbonate (436 mg) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (11 mg) were added to the above mixture. The above mixture was thoroughly replaced by N 2The mixture was then heated to 100°C for 2 hours until the reaction of the raw materials was complete. After the reaction was completed, ethyl acetate was added to the reaction solution, and the resulting mixture was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain a crude product, which was purified by column chromatography to obtain Example 17 (14 mg). LCMS (ES, m / z): 377.2 [M+H] + .

[0185] 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm):8.18(s,1H),8.01(d,J=2.8Hz,1H),7.69(s,1H),7.52(d,J=8.4Hz,1H),7.37(dd,J=8.4,1.6Hz,1H),6.98(d,J=2.8Hz ,1H),4.06(d,J=7.6Hz,2H),4.01(s,3H),2.94-2.91(m,2H),2.58(s,3H),2.55-2.36m,4H),1.96(brs,1H),1.46-1.15(m,4H).

[0186] Embodiment 18:

[0187]

[0188] Step 1: At room temperature, the intermediate 4 (450 mg, crude product) obtained in Example 17 was dissolved in acetonitrile (10 mL), and formaldehyde aqueous solution (50 mg, 37%) and sodium acetate (364 mg) were added. After the mixture was reacted at room temperature for 2 h, sodium cyanoborohydride (93 mg) was added. The mixture was reacted at room temperature for 2 h until the raw materials reacted completely. After the reaction was completed, ethyl acetate was added to the reaction solution. The resulting mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to obtain intermediate 1 (130 mg) as a white solid.

[0189] Step 2: At room temperature, the intermediate 1 (57 mg) and intermediate A1 (50 mg) obtained in step 1 were dissolved in a mixed solution of ethylene glycol dimethyl ether and water (2.5 mL, v / v = 4 / 1), and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (11 mg) and cesium carbonate (95 mg) were added. The above mixture fully replaced N 2 The mixture was then heated to 100°C for 2 hours until the reaction of the raw materials was complete. After the reaction was completed, ethyl acetate was added to the reaction solution. The resulting mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to obtain Example 18 (12 mg). LCMS (ESI, m / z): 391.2 [M+H]+ .

[0190] 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm):8.18(s,1H),8.01(d,J=2.8Hz,1H),7.71(d,J=1.6Hz,1H),7.53(d,J=8.4Hz,1H),7.38-7.36(m,1H),7.00(d,J=2.8Hz,1H),4 .19-4.04(m,2H),4.02(s,3H),2.55(s,3H),2.44(brs,1H),2.21-2.18(m,1H),2.10(s,3H),2.04-1.96(m,1H),1.83-1.78(m,1H),1.66 -1.54(m,2H),1.45-1.42(m,

[0191] 1H), 1.17-1.14 (m, 2H).

[0192] Embodiment 19:

[0193]

[0194] Step 1: At room temperature, dissolve 6-bromo-2-methyl-4-azabenzimidazole (1.00 g) in tetrahydrofuran (15.0 mL), and add tetrabutylammonium iodide (175 mg), potassium iodide (798 mg), potassium hydroxide (175 mg) and 2-(bromomethyl)tetrahydropyran (1.44 g) in sequence. Heat the above mixture to 70 ° C and continue the reaction for 24 hours. After LCMS detection of the complete reaction of the raw materials, the reaction solution is diluted with ethyl acetate. The resulting mixture is washed with water and saturated brine. The organic phase is dried over anhydrous sodium sulfate and concentrated. The crude product is purified by flash chromatography to obtain a yellow solid intermediate 1 (270 mg).

[0195] Step 2: Dissolve the intermediate 2 (270 mg), intermediate A1 (267 mg), cesium carbonate (513 mg) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (58 mg) obtained in step 1 in a mixed solution of ethylene glycol dimethyl ether and water (v / v=4 / 1) (12.5 mL). After the mixture is fully replaced with N2, it is heated to 100°C and reacted for 2 hours. LCMS detected that the raw material reacted completely. The reaction solution was extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After the organic phase was concentrated, the residue was purified by flash chromatography to obtain Example 19 (91 mg). LCMS (ES, m / z): 379.2 [M+H] + .

[0196] 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm):8.53(d,J=2.0Hz,1H),8.24(s,1H),8.13(d,J=2.0Hz,1H),8.04(d,J=2.8Hz,1H),7.07(d,J=2.8Hz,1H),4.32-4.19(m,2H),4.0 3(s,3H),3.84-3.80(m,1H),3.68-3.59(m,1H),3.28-3.20(m,1H),2.61(s,3H),1.79-1.74(m,2H),1.52-1.36(m,3H),1.32-1.20(m,1H).

[0197] Embodiment 20:

[0198]

[0199] Step 1: At room temperature, 2-nitro-3-fluoro-5-bromopyridine (500 mg) was dissolved in acetonitrile (15 mL), 4-(aminomethyl)piperidine-1-carboxylic acid tert-butyl ester (584.5 mg) and cesium carbonate (1.481 g) were added, and the reaction was carried out at room temperature for 16 hours until the raw materials reacted completely. After the reaction was completed, ethyl acetate was added to the reaction solution, and the resulting mixture was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain a crude product, and the crude product was subjected to column chromatography to obtain intermediate 1 (850 mg).

[0200] Step 2: At room temperature, the intermediate 1 (850 mg) obtained in step 1 was dissolved in acetic acid (20 mL), and reduced iron powder (918 mg) was added. The above mixture was reacted at room temperature for 4 hours until the raw material reacted completely. After the reaction was completed, the solvent was removed, ethyl acetate was added to the residue, and it was filtered after sufficient stirring. The filtrate was adjusted to a neutral pH with an aqueous sodium bicarbonate solution and then separated. The aqueous phase was extracted with ethyl acetate and the organic phases were combined. The obtained organic phase was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain a crude product, and the crude product was subjected to column chromatography to obtain intermediate 2 (640 mg) as a brown solid.

[0201] Step 3: At room temperature, the intermediate 3 (640 mg) obtained in step 2 was dissolved in trimethyl orthoacetate (10 mL), trifluoroacetic acid (2 mL) was added, and the above mixture was reacted at 100 ° C for 16 h under nitrogen protection. After the reaction was completed, the solvent was removed. Ethyl acetate was added to the residue. The resulting mixture was adjusted to a neutral pH with an aqueous sodium bicarbonate solution and then separated. The aqueous phase was extracted with ethyl acetate and the organic phases were combined. The obtained organic phase was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain a crude product, and the crude product was subjected to column chromatography to obtain intermediate 3 (410 mg) as a gray solid.

[0202] Step 4: At room temperature, the intermediate 3 (460 mg) obtained in step 3 was dissolved in dichloromethane (4.0 mL), trifluoroacetic acid (4.0 mL) was added, and the mixture was reacted at room temperature for 3 h until the reaction of the raw materials was complete. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude black oily intermediate 4 (560 mg) as a crude product. This intermediate was used directly in the next step without further purification.

[0203] Step 5: At room temperature, the intermediate 4 (149) obtained in step 4 and the intermediate A1 (50 mg) were dissolved in a solution of ethylene glycol dimethyl ether and water in a ratio of 4 / 1 (2.0 mL). Cesium carbonate (190 mg) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (11 mg) were added to the above mixture. The above mixture was stirred for 1 h after fully replacing N 2 After that, the mixture was heated to 100°C for 2 hours until the reaction of the raw materials was complete. After the reaction was completed, ethyl acetate was added to the reaction solution. The resulting mixture was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain a crude product, which was subjected to column chromatography to obtain Example 20 (9 mg). LCMS (ES, m / z): 378.2 [M+H] + .

[0204] 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm):8.52(d,J=2.0Hz,1H),8.24(s,1H),8.15(d,J=2.0Hz,1H),8.06(d,J=2.8Hz,1H),7.08(d,J=2.8Hz,1H),4.12( d,J=7.6Hz,2H),4.00(s,4H),2.92(s,2H),2.60(s,3H),2.36(s,2H),1.96(s,1H),1.47-1.43(m,2H),1.26-1.16(m,2H).

[0205] Embodiment 21:

[0206]

[0207] Step 1: Dissolve 2-nitro-3-fluoro-5-bromopyridine (300 mg) and cesium carbonate (889 mg) in acetonitrile (10.0 mL) at room temperature, and add (1-methyl-4-piperidinyl-)methylamine (210 mg). The mixture is reacted at room temperature for 16 hours until the reaction of the raw materials is complete as detected by LCMS. The reaction solution is diluted with ethyl acetate, and the organic phase is washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue is purified by column chromatography to obtain intermediate 1 (420 mg) as a yellow oil.

[0208] Step 2: At room temperature, the intermediate 1 (420 mg) obtained in step 1 was dissolved in acetic acid (20 mL), and reduced iron powder (715 mg) was added. The above mixture was stirred and reacted at room temperature for 4 h until the raw material reacted completely. After the reaction was completed, the filtrate was filtered and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the pH was adjusted to 9-10 with saturated sodium bicarbonate aqueous solution. After separation, the aqueous phase was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to obtain intermediate 2 (250 mg) as a reddish brown solid.

[0209] Step 3: At room temperature, the intermediate 2 (250 mg) obtained in step 2 was dissolved in trimethyl orthoacetate (10 mL), and trifluoroacetic acid (2 mL) was added. The mixture was fully replaced with nitrogen and heated to 95 ° C and continued to react for 16 h until the raw material reacted completely. After the reaction was completed, it was concentrated under reduced pressure. The remaining residue was dissolved in ethyl acetate and the pH value was adjusted to 7-8 with saturated sodium bicarbonate aqueous solution. After separation, the aqueous phase was extracted with ethyl acetate and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography to obtain intermediate 3 (130 mg) as a gray solid.

[0210] Step 4: At room temperature, the intermediate 3 (50 mg) obtained in step 3 and the intermediate A1 (56 mg) were dissolved in a solution of ethylene glycol dimethyl ether and water in a ratio of 4 / 1 (2.5 mL), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (11 mg) and cesium carbonate (95 mg) were added. After the above mixture fully replaced N2, it was heated to 100°C and reacted for 2 hours until the raw material reacted completely. The reaction solution was diluted with ethyl acetate, and the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to obtain Example 21 (3 mg). LCMS (ES, m / z): 392.2 [M+H] + .

[0211] 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm):8.52(d,J=2.0Hz,1H),8.24(s,1H),8.16(d,J=2.0Hz,1H),8.07(d,J=2.8Hz,1H),7.08(d,J=2.8Hz,1H),4.14(d, J=7.6Hz,2H),4.00(s,3H),2.76(d,J=11.2Hz,2H),2.60(s,3H),2.12(s,2H),1.76(t,J=11.6Hz,3H),1.52-1.32(m,4H)).

[0212] Embodiment 22:

[0213]

[0214] Step 1: Dissolve 2-nitro-3-fluoro-5-bromopyridine (300 mg) and cesium carbonate (890 mg) in acetonitrile (10 mL) at room temperature, and add 4-methylmorpholine-2-methylamine (213 mg). The mixture is reacted at room temperature for 16 hours until the raw materials react completely. After the reaction is completed, ethyl acetate is added to the reaction solution. The resulting mixture is washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue is purified by column chromatography to obtain intermediate 1 (540 mg) as a yellow oil.

[0215] Step 2: At room temperature, the intermediate 1 (540 mg) obtained in step 1 was dissolved in acetic acid (20 mL), and reduced iron powder (921 mg) was added. The above mixture was stirred and reacted at room temperature for 4 h until the raw material reacted completely. After the reaction was completed, the filtrate was filtered and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the pH was adjusted to 9-10 with saturated sodium bicarbonate aqueous solution. After separation, the aqueous phase was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to obtain intermediate 2 (420 mg) as a reddish brown solid.

[0216] Step 3: At room temperature, the intermediate 2 (420 mg) obtained in step 2 was dissolved in trimethyl orthoacetate (10 mL), and trifluoroacetic acid (2 mL) was added. The mixture was fully replaced with nitrogen and heated to 95 ° C and continued to react for 16 hours until the raw material reacted completely. After the reaction was completed, it was concentrated under reduced pressure. The remaining residue was dissolved in ethyl acetate and the pH value was adjusted to 7-8 with saturated sodium bicarbonate aqueous solution. After separation, the aqueous phase was extracted with ethyl acetate and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography to obtain intermediate 3 (260 mg) as a gray solid.

[0217] Step 4: At room temperature, the intermediate 3 (47 mg) obtained in step 3 and the intermediate A1 (51 mg) were dissolved in a solution of ethylene glycol dimethyl ether and water in a ratio of 4 / 1 (2.5 mL), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (11 mg) and cesium carbonate (95 mg) were added. The above mixture fully replaced N 2 The mixture was then heated to 100°C for 2 h until the reaction of the raw materials was complete. The reaction solution was diluted with ethyl acetate, and the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to obtain Example 22 (12 mg). LCMS (ES, m / z): 394.2 [M+H] + .

[0218] 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm):8.52(d,J=2.0Hz,1H),8.23(s,1H),8.16(d,J=2.4Hz,1H),8.04(d, J=2.8Hz,1H),7.08(d,J=2.8Hz,1H),4.35-4.24(m,2H),4.04(s,3H),3.83-3 .81(m,1H),3.77-3.73(m,1H),3.43-3.37(m,2H),2.90-2.87(m,1H),2.61(s ,3H),2.59-2.56(m,1H),2.19(s,3H),2.01-1.96(m,1H),1.85-1.80(m,1H).

[0219] Embodiment 23:

[0220]

[0221] Step 1: At room temperature, the intermediate 4 (350 mg) obtained in step 4 of the synthesis method of Example 21 and tert-butyldimethylsilyl acetaldehyde (298 mg) were dissolved in dichloromethane (5.0 mL), and sodium triacetoxyborohydride (725 mg) was added. The above mixture was reacted at room temperature for 2 hours until the raw materials reacted completely. After the reaction was completed, dichloromethane was added to the above mixture, and the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain intermediate 1 (290 mg) as a colorless oil.

[0222] Step 2: At room temperature, the intermediate 1 (290 mg) obtained in step 1 was dissolved in a mixture of methanol (4 mL) and water (2 mL), potassium fluoride (72 mg) was added, and the mixture was reacted at room temperature for 16 h until the raw material reacted completely. After the reaction was completed, the solvent was removed under reduced pressure, and ethyl acetate was added to the residue. The ethyl acetate phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to obtain intermediate 2 (160 mg) as a white solid.

[0223] Step 3: At room temperature, the intermediate 2 (51 mg) obtained in step 2 and the intermediate A1 (50 mg) were dissolved in a solution of ethylene glycol dimethyl ether and water in a ratio of 4 / 1 (2.5 mL), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (11 mg) and cesium carbonate (95 mg) were added. The above mixture fully replaced N 2 Then heat to 100°C and react for 2h until the raw material reacts completely. After the reaction is completed, ethyl acetate is added to the reaction solution. The resulting mixture is washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The organic phase is concentrated to obtain a crude product, which is subjected to column chromatography to obtain Example 23 (10 mg). LCMS (ES, m / z): 421.2 [M+H] + .

[0224] 1 H NMR (400 MHz, DMSO-d 6)δ(ppm):8.18(s,1H),8.01(d,J=2.8Hz,1H),7.71(d,J=1.6Hz,1H),7.53(d,J=8.4Hz,1H),7.38(dd, J=8.4,1.6Hz,1H),7.00(d,J=2.8Hz,1H),4.30(s,1H),4.18-4.12(m,1H),4.07-4.04(m,1H),4.03(s, 3H),3.42(t,J=6.4Hz,2H),2.68-2.63(m,2H),2.55(s,3H),2.35-2.31(m,2H),2.17(s,1H),2.10-2.0 6(m,2H),1.92(t,J=10.4Hz,1H),1.64-1.60(m,1H),1.56-1.52(d,J=13.6Hz,1H),1.42-1.39(m,1H),

[0225] 1.13–1.11 (m, 1H).

[0226] Embodiment 31;

[0227]

[0228] Step 1: At room temperature, add tert-butyl 3-aminoazetidine-1-carboxylate (470 mg) and potassium carbonate (624 mg) to an acetonitrile solution (20 mL) in which 5-bromo-3-fluoro-2-nitropyridine (500 mg) is dissolved. The above mixture is stirred at room temperature for 2 hours until the reaction is complete. After the reaction is completed, ethyl acetate is added to the above mixture. The resulting mixture is washed with water and saturated brine, and the solvent is removed after drying over anhydrous sodium sulfate. The residue is purified by column chromatography to obtain intermediate 1 (740 mg) as a yellow solid. LCMS (ES, m / z): 373,375 [M+H] + .

[0229] Step 2: At room temperature, the intermediate 1 (740 mg) obtained in step 1 was dissolved in acetic acid (10 mL), and reduced iron powder (550 mg) was added. The mixture was stirred at room temperature for 4 hours until the reaction was complete. After the reaction was completed, the solvent was removed under reduced pressure, ethyl acetate was added to the residue, and the mixture was filtered after sufficient stirring. The filtrate was adjusted to a neutral pH value with a saturated sodium bicarbonate aqueous solution, and the liquids were separated after sufficient stirring. The filtrate was extracted with ethyl acetate and the organic phases were combined. The organic phase was washed with water and saturated brine, and the solvent was removed after drying over anhydrous sodium sulfate. The residue was purified by column chromatography to obtain intermediate 2 (500 mg). LCMS (ES, m / z): 343, 345 [M+H] + .

[0230] Step 3: At room temperature, the intermediate 2 (500 mg) obtained in step 2 was dissolved in acetic acid (10 mL). The above mixture was refluxed overnight under nitrogen protection. After the reaction was completed by LCMS monitoring, the reaction solution was brought to room temperature. The solvent was removed under reduced pressure. Water and ethyl acetate were added to the residue, and the pH value of the mixture was adjusted to neutral with saturated sodium bicarbonate aqueous solution, and the liquids were separated. The organic phase was washed with water and brine, and the solvent was removed after drying over anhydrous sodium sulfate. The residue was purified by column chromatography to obtain intermediate 3 (300 mg) as a light yellow solid. LCMS (ES, m / z): 309,311 [M+H] + .

[0231] Step 4: At room temperature, the intermediate 3 (100 mg) obtained in step 3 was dissolved in a mixture of DME and water (5 mL, v / v = 4 / 1), and intermediate A1 (120 mg), dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium (II) (35 mg) and cesium carbonate (211 mg) were added. The above mixture was fully replaced with nitrogen and heated to 110°C for 2 hours until the reaction was complete. After the reaction was completed, the mixture was brought to room temperature and ethyl acetate was added to the above mixture. The above mixture was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed. The residue was purified by column chromatography to obtain Example 31 (10 mg). LCMS (ES, m / z): 378 [M+H] + .

[0232] 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm):8.58(d,J=2.0Hz,1H),8.23(d,J=6.0Hz,1H),8.14(d,J=2.0Hz,1H),8.08(dd,J=4.7,2.8Hz,1H),7.12(dd ,J=7.2,2.8Hz,1H),5.51-5.42(m,1H),4.72–4.65(m,H),4.49-4.32(m,2H),4.02(s,3H),2.63(s,3H),1.85(s,3H).

[0233] Embodiment 32:

[0234]

[0235] Step 1: At room temperature, add tert-butyl 3-aminopyrrolidine-1-carboxylate (505 mg) and potassium carbonate (624 mg) to an acetonitrile solution (20 mL) containing 5-bromo-3-fluoro-2-nitropyridine (500 mg). The above mixture is stirred at room temperature for 2 hours until the reaction is complete. After the reaction is completed, ethyl acetate is added to the above mixture. The resulting mixture is washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent is removed. The residue is purified by column chromatography to obtain intermediate 1 (830 mg) as a yellow solid. LCMS (ES, m / z): 387,389 [M+H] + .

[0236] Step 2: At room temperature, the intermediate 1 (830 mg) obtained in step 1 was dissolved in acetic acid (10 mL), and reduced iron powder (650 mg) was added. The mixture was stirred at room temperature for 4 hours until the reaction was complete. After the reaction was completed, the solvent was removed under reduced pressure, ethyl acetate was added to the residue, and the mixture was filtered after sufficient stirring. The filtrate was adjusted to a neutral pH value with a saturated sodium bicarbonate aqueous solution, and the liquids were separated after sufficient stirring. The filtrate was extracted with ethyl acetate and the organic phases were combined. The organic phase was washed with water and saturated brine, and the solvent was removed after drying over anhydrous sodium sulfate. The residue was purified by column chromatography to obtain intermediate 2 (600 mg). LCMS (ES, m / z): 357, 359 [M+H] + .

[0237] Step 3: At room temperature, the intermediate 2 (600 mg) obtained in step 2 was dissolved in acetic acid (10 mL). The above mixture was refluxed overnight under nitrogen protection. After the reaction was completed by LCMS monitoring, the reaction solution was brought to room temperature. The solvent was removed under reduced pressure. Water and ethyl acetate were added to the residue, and the pH value of the mixture was adjusted to neutral with saturated sodium bicarbonate aqueous solution and then separated. The organic phase was washed with water and brine, and the solvent was removed after drying over anhydrous sodium sulfate. The residue was purified by column chromatography to obtain intermediate 3 (300 mg) as a light yellow solid. LCMS (ES, m / z): 323,325 [M+H] + .

[0238] Step 4: At room temperature, the intermediate 3 (100 mg) obtained in step 3 was dissolved in a mixture of DME and water (5 mL, v / v = 4 / 1), and intermediate A1 (110 mg), dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium (II) (30 mg) and cesium carbonate (171 mg) were added. The above mixture was fully replaced with nitrogen and heated to 110°C for 2 hours until the reaction was complete. After the reaction was completed, the mixture was brought to room temperature and ethyl acetate was added to the above mixture. The above mixture was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed. The residue was purified by column chromatography to obtain Example 32 (25 mg). LCMS (ES, m / z): 392 [M+H] + .

[0239] 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm):8.53(t,J=2.0Hz,1H),8.23(dd,J=8.0,2.0Hz,1H),8.11(d,J=2.0Hz,1H),8.05(d,J=2.8Hz,1H),7.08(t,J=2.8Hz,1H),5. 29-5.21(m,1H),4.11-4.01(m,1H),3.99(s,3H),3.83-3.56(m,2H),3.42-3.35(m,1H),2.68(s,3H),2.47-2.31(m,1H),1.97(s,3H).

[0240] Embodiment 34:

[0241]

[0242] Step 1: At room temperature, dissolve 5-bromo-3-fluoro-2-nitropyridine (350 mg) and oxetane-3-amine (150 mg) in acetonitrile (10 mL), and add potassium carbonate (437 mg). The above mixture is stirred at room temperature for 2 hours until the reaction is complete. After the reaction is completed, ethyl acetate is added to the above mixture, and the resulting mixture is washed with water and saturated brine, and the solvent is removed after drying over anhydrous sodium sulfate. The resulting residue is purified by column chromatography to obtain intermediate 1 (400 mg) as a yellow solid. LCMS (ES, m / z): 274, 276 [M+H] + .

[0243] Step 2: At room temperature, the intermediate 1 (400 mg) obtained in step 1 was dissolved in acetic acid (5 mL), and reduced iron powder (400 mg) was added. The above mixture was stirred at room temperature for 4 hours until the reaction was complete. After the reaction was completed, the solvent was removed under reduced pressure. Ethyl acetate was added to the residue, and it was filtered after sufficient stirring. The filtrate was washed with saturated aqueous sodium bicarbonate solution, water and saturated brine, and the solvent was removed after drying over anhydrous sodium sulfate. The obtained residue was purified by column chromatography to obtain intermediate 2 (340 mg). LCMS (ES, m / z): 244, 246 [M+H] + .

[0244] Step 3: At room temperature, the intermediate 2 (340 mg) obtained in step 2 was dissolved in trimethyl orthoacetate (5 mL), and trifluoroacetic acid (0.2 mL) was added. The above mixture was heated to 70°C for 4 hours until the reaction was complete. After the reaction was completed, the solvent was removed under reduced pressure. Ethyl acetate and water were added to the residue, and the pH value of the mixture was adjusted to neutral with saturated sodium bicarbonate aqueous solution. The liquids were separated, the filtrate was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, and the solvent was removed after drying over anhydrous sodium sulfate. The obtained residue was purified by column chromatography to obtain intermediate 3 (100 mg) as a light yellow solid. LCMS (ES, m / z): 268,270 [M+H] + .

[0245] Step 4: At room temperature, the intermediate 3 (100 mg) obtained in step 3 was dissolved in a mixed solution of dimethyl ether and water (5 mL, v / v = 4 / 1), and intermediate A1 (153 mg), dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium (II) (40 mg) and cesium carbonate (243 mg) were added. After the nitrogen was fully replaced, the above mixture was heated to 110°C for 2 hours until the reaction was complete. After the reaction was completed, the reaction solution was brought to room temperature, and ethyl acetate was added to the above mixture. The obtained mixture was washed with water and saturated brine, and the solvent was removed after drying over anhydrous sodium sulfate. The obtained residue was purified by column chromatography to obtain Example 34 (34 mg). LCMS (ES, m / z): 337 [M+H] + .

[0246] 1 H NMR (400 MHz, DMSO-d 6)δ(ppm):8.62(d,J=2.0Hz,1H),8.54(d,J=2.0Hz,1H),8.23(s,1H),8.08(d,J=2.8Hz,1H ), 7.16 (d, J = 2.8Hz, 1H), 5.76-5.70 (m, 1H), 5.17-5.07 (m, 4H), 4.03 (s, 3H), 2.59 (s, 3H).

[0247] CLK2 enzymatic inhibitory activity

[0248] 1.1 Compound preparation

[0249] Table 2. Solvents and concentrations of test compounds and control compounds

[0250] mixture Solvents concentration Control compound Dimethyl sulfoxide (DMSO) 50mmol / L Test compound Dimethyl sulfoxide (DMSO) 10mmol / L or 5mmol / L

[0251] 1) Prepare 2× ATP / substrate solution and 2× kinase solution using kinase reaction buffer;

[0252] 2) Use Echo 655 to transfer 40 nL of the above control compound and test compound dilution to the 384 detection plate; after centrifugation, add 2 μL of 2× kinase solution to the 384 detection plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 10 minutes;

[0253] 3) Add 2 μL of 2× substrate and ATP solution to the 384 assay plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 60 minutes;

[0254] 4) Transfer 4 μL ADP-Glo ​​to the 384 assay plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 40 minutes;

[0255] 5) Transfer 8 μL of the detection solution to a 384-well plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 40 minutes;

[0256] 6) Read the luminescence signal using a multifunctional microplate reader.

[0257] 1.2 Data Analysis

[0258] GraphPad Prism 8 software was used for analysis. The reading value of the negative control (1% DMSO well) was set as 0% inhibition rate, and the reading value of the positive control (highest concentration well of the control compound) was set as 100% inhibition rate. After calculating the inhibition rate, the IC values ​​of the control compound and the test compound were obtained using the nonlinear fitting formula of the software. 50 value (half inhibitory concentration).

[0259]

[0260] The average of the values ​​of the positive control wells; The mean of the values ​​of the negative control wells;

[0261] Appendix: The following is the software nonlinear fitting formula used to calculate the IC of the compound 50 (half inhibitory concentration)

[0262] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope));

[0263] X: log value of compound concentration;

[0264] Y: compound inhibition rate (%inh);

[0265] Z' factor calculation equation: Z' = 1-3 (SDmin + SDmax) / (AVEmax - AVEmin)

[0266] Where: Min is the positive control Data value, Max is the negative control DMSO Data value. SD is the standard error, and AVE is the average value. The test results are shown in Table 3.

[0267] Table 3. IC values ​​of some compounds for inhibiting CLK2 enzymatic activity 50 value

[0268] Example <![CDATA[IC 50 (nM)]]> Example <![CDATA[IC 50 (nM)]]> 1 1.16 30 1.37 2 1.01 31 13.12 3 0.71 32 5.69 4 0.50 33 3.27 6 1.35 34 3.01 7 1.12 35 1.39 8 1.66 36 3.62 19 1.37 38 4.22 19a 1.41 40 2.46 19b 1.22 43 3.51 25 2.81 44 1.13 26 2.46 46 12.32 27 3.09 47 1.67 28 1.20 48 15.88 29 1.36

[0269] The reagent information used in the experiment is shown in Table 4:

[0270] Table 4. Information on reagents used in the experiment

[0271] Material supplier Part Number Hepes Thermo Fisher 15630080 Brij35 Millipore 1018940100 EGTA Sigma E3889 <![CDATA[MgCl 2 ]]> Sigma M1028 ADP-Glo ​​Kinase Assay Promega V9103 DTT MCE HY-15917 DMSO Sigma D4540 ATP Promega V915B CLK2 SignalChem C58-11G-100 S6K Genscript PE9826 TG003 MCE HY-15338

[0272] The present application also provides a pharmaceutical composition, which comprises a compound of formula I as an active ingredient, and may also be any one of an enantiomer, a diastereomer, a pharmaceutically salt, a solvent compound, and a pharmaceutically acceptable carrier of the compound of formula I. It is understood that the compound of formula I of the present application is used as an active reaction substance, and conventional design can be performed on the basis thereof, so that the designed compound can still maintain the efficacy of the compound of formula I.

[0273] The pharmaceutical composition of the present application can be used in drugs for treating diseases related to CLK2 amplification or overexpression.

[0274] The pharmaceutical composition disclosed in the present application may contain one or more excipients in addition to the above-mentioned active compound, including fillers, excipients, disintegrants, binders and wetting agents, etc. Depending on the administration method, the composition of the present application may contain 10% to 90% by weight of the compound represented by the above formula I.

[0275] The pharmaceutical composition of the present application is in the form of an oral preparation or an injection, wherein the oral preparation may be a capsule, tablet, etc., and the injection may be an intravenous injection, an intramuscular injection, or a subcutaneous injection, etc., and the present application does not limit this.

[0276] The pharmaceutical composition of the present application can be used to treat diseases including cancers associated with CLK2 amplification or overexpression, including at least one of breast cancer, triple-negative breast cancer, acute myeloid leukemia, lung adenocarcinoma, blood tumors, digestive system tumors, reproductive system tumors, nervous system tumors or head and neck cancer.

[0277] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention. Although the present application is disclosed as above with preferred embodiments, it is not intended to limit the claims. Any person skilled in the art may make several possible changes and modifications without departing from the concept of the present application. Therefore, the scope of protection of the present application shall be based on the scope defined by the claims of the present application.

Claims

1. A fused heterocyclic compound, characterized in that: The compound includes a compound represented by Formula I or a pharmaceutically acceptable salt, stereoisomer, or tritiated compound thereof: In formula (I): X1, X2 and X3 are each independently selected from CH or N; Y1 and Y2 are each independently selected from CH, C-R5 or N; R5 is selected from hydrogen, halogen, alkyl, cyano, nitro, alkynyl, alkyl or alkoxy; M is selected from CH or N; R1 is selected from hydrogen; R2 is selected from substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 3-6-membered heterocyclyloxy, substituted or unsubstituted 3-6-membered heterocyclyl-C1-C6 alkylene-oxy, substituted or unsubstituted C3-C6 cycloalkyl-C1-C6 alkylene-oxy, or R6R7N-; said R6, R7 are each independently selected from hydrogen, substituted or unsubstituted C3-C6 cycloalkyl-C1-C6 alkylene, substituted or unsubstituted 3-6-membered heterocyclyl-C1-C6 alkylene; or R6, R7 and the N atom to which they are connected form a substituted or unsubstituted 3-6-membered heterocyclyl, and the heteroatom in the 3-6-membered heterocyclyl is selected from O, S or N; R3 is selected from cyano, substituted or unsubstituted C1-C6 alkyl, C3-C6 cycloalkyl, oxo, R8R9N-; wherein R8 and R9 are each independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C6 alkylene, substituted or unsubstituted 3-6 membered heterocyclyl-C1-C6 alkylene; or R8, R9 and the N atom to which they are connected form a substituted or unsubstituted 3-6 membered heterocyclyl, wherein the heteroatom in the 3-6 membered heterocyclyl is selected from O, S or N; R4 is selected from substituted or unsubstituted C2-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted C3-C6 cycloalkyl-C1-C6 alkylene, substituted or unsubstituted 3-6 membered heterocyclyl-C1-C6 alkylene.

2. The compound according to claim 1, characterized in that The compound of formula (I) is selected from any one of the structures (1) to (3) shown below:

3. The compound according to claim 1, characterized in that The compound includes any one of the following: 1-cyclopropylmethyl-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazine-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine; 1-cyclobutylmethyl-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine; 1-Cyclopentylmethyl-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine; 1-cyclohexylmethyl-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine; 1-ethyl-6-(4-methoxypyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine; 1-cyclopropyl-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine; 2-(6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)ethan-1-ol; 6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-propyl-1H-imidazo[4,5-b]pyridine; 1-isopropyl-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine; 1-isobutyl-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine; 6-(4-methoxypyrrolo[2,1-f][1,2,4]triazine-5-yl)-2-methyl-1-(tetrahydrofuran-2-yl)methyl)-1H-imidazo[4,5-b]pyridine; 6-(4-methoxypyrrolo[2,1-f][1,2,4]triazine-5-yl)-2-methyl-1-(tetrahydrofuran-3-yl)methyl)-1H-imidazo[4,5-b]pyridine; (R)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-(tetrahydrofuran-3-yl)methyl)-1H-imidazo[4,5-b]pyridine; (S)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-(tetrahydrofuran-3-yl)methyl)-1H-imidazo[4,5-b]pyridine; 6-(4-methoxypyrrolo[2,1-f][1,2,4]triazine-5-yl)-2-methyl-1-(tetrahydro-2H-pyran-3-yl)methyl)-1H-imidazo[4,5-b]pyridine; 4-methoxy-5-(2-methyl-1-(piperidin-4-ylmethyl)-1H-benzo[d]imidazol-6-yl)pyrrolo[2,1-f][1,2,4]triazine; 4-methoxy-5-(2-methyl-1-(1-methylpiperidin-4-yl)methyl)-1H-benzimidazol-6-yl)pyrrolo[2,1-F][1,2,4]triazine; 2-(6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-benzimidazol-1-ylmethyl)-4-methylmorpholine; 4-methoxy-5-(2-methyl-1-(piperidin-3-ylmethyl)-1H-benzimidazol-6-yl)pyrrolo[2,1-F][1,2,4]triazine; 4-methoxy-5-(2-methyl-1-(1-methylpiperidin-3-yl)methyl)-1H-benzimidazol-6-yl)pyrrolo[2,1-F][1,2,4]triazine; 6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-(tetrahydro-2H-pyran-2-yl)methyl)-1H-imidazo[4,5-b]pyridine; S-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-(tetrahydro-2H-pyran-2-yl)methyl)-1H-imidazo[4,5-b]pyridine; R-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-(tetrahydro-2H-pyran-2-yl)methyl)-1H-imidazo[4,5-b]pyridine; 6-(4-methoxypyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methyl-1-(piperidin-4-ylmethyl)-1H-imidazo[4,5-b]pyridine; 6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-(1-methylpiperidin-4-yl)methyl)-1H-imidazo[4,5-b]pyridine; 2-(6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine-1-yl)methyl)-4-methylmorpholine; 2-(4-((6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-benzo[d]imidazol-1-yl)methyl)piperidin-1-yl)ethan-1-ol; 2-(3-(6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-benzimidazol-1-ylmethyl)piperidin-1-yl)ethyl-1-ol; 6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-(piperidin-3-ylmethyl)-1H-imidazo[4,5-b]pyridine; 6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-(piperidin-2-ylmethyl)-1H-imidazo[4,5-b]pyridine; 2-(3-(6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)piperidin-1-yl)ethyl-1-ol; 6-(4-methoxypyrrolo[2,1-f][1,2,4]triazine-5-yl)-2-methyl-1-(1-methylpiperidin-3-yl)methyl)-1H-imidazo[4,5-b]pyridine; 1-cyclobutyl-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazine-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine; 1-cyclopentyl-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine; 1-(3-(6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)azetidin-1-yl)ethan-1-one; 1-(3-(6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)pyrrolidin-1-yl)ethan-1-one; 6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-tetrahydrofuran-3-yl)-1H-imidazo[4,5-b]pyridine; 6-(4-methoxypyrrolo[2,1-f][1,2,4]triazine-5-yl)-2-methyl-1-oxetan-3-yl)-1H-imidazo[4,5-b]pyridine; (1R,4R)-4-(6-(4-methoxypyrrolo[2,1-f][1,2,4]triazine-5-yl)-2-methylimidazo[4,5-b]pyridin-1-yl)cyclohexane-1-ol; 4-(6-methoxypyrrolo[2,1-f][1,2,4]triazine-5-yl)-2-methylimidazo[4,5-b]pyridin-1-yl)-1-methylcyclohexane-1-ol; 3-(6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)cyclohexane-1-ol; (1s,3s)-3-(6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methylimidazo[4,5-b]pyridin-1-yl)-1-methylcyclobutan-1-ol; 1-(4,4-difluorocyclohexyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine; 1-(3,3-difluorocyclopentyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methylimidazo[4,5-b]pyridine; 6-(4-methoxypyrrolo[2,1-f][1,2,4]triazine-5-yl)-2-methyl-1-(tetrahydro-2H-pyran-3-yl)-1H-imidazo[4,5-b]pyridine; 6-(4-methoxypyrrolo[2,1-f][1,2,4]triazine-5-yl)-2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-b]pyridine; 1-(3,3-difluorocyclobutyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazine-5-yl)-2-methylimidazo[4,5-b]pyridine; 3-(6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)cyclopentan-1-ol; 1-cyclohexyl-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine; 4-(6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)piperidin-4-ol; 3-(6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)cyclobutane-1-ol; 2-(4-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)piperidin-1-yl)ethyl-1-ol; 6-(4-methoxypyrrolo[1,2-b]pyridazin-5-yl)-2-methyl-1-(oxetan-3-ylmethyl)-1H-imidazo[4,5-b]pyridine; 1-(azetidin-3-ylmethyl)-6-(4-methoxypyrrolo[1,2-b]pyridazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine; 6-(4-methoxypyrrolo[1,2-b]pyridazin-5-yl)-2-methyl-1-((1-methylazetidin-3-yl)methyl)-1H-imidazo[4,5-b]pyridine; 6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-1-(tetrahydrofuran-2-yl)methyl)-1,3-dihydroimidazo[4,5-b]pyridin-2-one; 6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-1-(tetrahydrofuran-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-2-carbonitrile; 6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N,N-dimethyl-1-(tetrahydrofuran-2-yl)methyl)-1H-imidazo[4,5-b]pyridin-2-amine; 2-(azetidin-1-yl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazine-5-yl)-1-(tetrahydrofuran-2-yl)methyl)-1H-imidazo[4,5-b]pyridine; 6-(4-methoxypyrrolo[2,1-f][1,2,4]triazine-5-yl)-1-(tetrahydrofuran-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-2-methanol; 6-(4-methoxypyrrolo[2,1-f][1,2,4]triazine-5-yl)-2-(4-methylpiperazin-1-yl)-1-(tetrahydrofuran-2-yl)methyl)-1H-imidazo[4,5-b]pyridine; 2-ethyl-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-1-(tetrahydrofuran-2-yl)methyl)-1H-imidazo[4,5-b]pyridine; 2-isopropyl-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-1-(tetrahydrofuran-2-yl)methyl)-1H-imidazo[4,5-b]pyridine b]pyridine; 2-cyclopropyl-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-1-(tetrahydrofuran-2-yl)methyl)-1H-imidazo[4,5-b]pyridine; 1-cyclopropyl-6-(4-ethoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine; 1-cyclopropyl-6-(4-isopropoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine; 1-cyclopropyl-2-methyl-6-(4-propoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-1H-imidazo[4,5-b]pyridine; 2-(5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrrolo[2,1-f][1,2,4]triazine-4-oxy)ethan-1-ol; 1-cyclopropyl-6-(4-(2-methoxyethoxy)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methylimidazo[4,5-b]pyridine; 1-cyclopropyl-6-(4-(2-isopropoxyethoxy)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methylimidazo[4,5-b]pyridine; 6-(4-(2-cyclopropyloxyethoxy)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-1-cyclopropyl-2-methylimidazo[4,5-b]pyridine; 1-cyclopropyl-6-(4-isobutoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine; 1-cyclopropyl-6-(4-(2-fluoropropoxy)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine; 1-cyclopropyl-6-(4-(2,2-difluoropropoxy)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methylimidazo[4,5-b]pyridine; 1-cyclopropyl-2-methyl-6-(4-(2,2,2-trifluoroethoxy)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-1H-imidazo[4,5-b]pyridine; 6-(4-cyclopropyloxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridine; 6-(4-cyclobutyloxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridine; 1-Cyclopropyl-2-methyl-6-(4-oxetane-3-oxocyclohexyloxy)pyrrolo[2,1-f][1,2,4]triazine-5-yl)-1H-imidazo[4,5-b]pyridine; 1-Cyclopropyl-6-(4-(3,3-difluorocyclobutyloxy)pyrrolo[2,1-f][1,2,4]triazine-5-yl)-2-methylimidazo[4,5-b]pyridine; 6-(4-(cyclopentyloxy)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-1-cyclopropyl-2-methylimidazo[4,5-b]pyridine; 1-cyclopropyl-2-methyl-6-(4-(tetrahydrofuran-3-oxy)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-1H-imidazo[4,5-b]pyridine; 1-cyclopropyl-2-methyl-6-(4-((1-methylpyrrolidin-3-yl)oxy)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-1H-imidazo[4,5-b]pyridine; 1-Cyclopropyl-6-(4-((3,3-difluorocyclopentyl)oxy)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine; 1-Cyclopropyl-6-(4-(4,4-difluorocyclohexyl)oxy)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine 5-b]pyridine; 1-cyclopropyl-2-methyl-6-(4-(tetrahydrofuran-3-yl)methoxy)pyrrolo[2,1-f][1,2,4]triazine-5-yl)-1H-imidazo[4,5-b]pyridine; 6-(4-cyclohexyloxy)pyrrolo[2,1-f][1,2,4]triazine-5-yl)-1-cyclopropyl-2-methylimidazo[4,5-b]pyridine; 1-cyclopropyl-2-methyl-6-(4-(tetrahydro-2H-pyran-3-oxy)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-1H-imidazo[4,5-b]pyridine; 1-cyclopropyl-2-methyl-6-(4-(tetrahydro-2H-pyran-4-oxy)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-1H-imidazo[4,5-b]pyridine; 1-Cyclopropyl-2-methyl-6-(4-((1-methylpiperidin-3-yl)oxy)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-1H-imidazo[4,5-b]pyridine; 1-Cyclopropyl-2-methyl-6-(4-(1-methylpiperidin-4-yl)oxy)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-1H-imidazo[4,5-b]pyridine; 1-Cyclopropyl-6-(4-(3,3-difluorocyclohexyl)oxy)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine; 1-Cyclopropyl-6-(4-((4-fluorocyclohexyl)oxy)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine; 1-Cyclopropyl-6-(4-(3-fluorocyclobutyloxy)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methylimidazo[4,5-b]pyridine; 3-(5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrrolo[2,1-f][1,2,4]triazine-4-oxy)cyclobutane-1-ol; 3-(5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrrolo[2,1-f][1,2,4]triazine-4-oxy)-1-methylcyclobutane-1-ol; 1-Cyclopropyl-6-(4-(3-fluoro-3-methylcyclobutyloxy)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methylimidazo[4,5-b]pyridine; 1-cyclopropyl-6-(4-(3-methoxycyclobutyloxy)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methylimidazo[4,5-b]pyridine; 3-(5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrrolo[2,1-f][1,2,4]triazine-4-oxy)cyclobutane-1-carbonitrile; 1-cyclopropyl-6-(4-(cyclopropylmethoxy)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine; 1-Cyclopropyl-2-methyl-6-(4-oxetan-3-ylmethoxy)pyrrolo[2,1-f][1,2,4]triazine-5-yl)-1H-imidazo[4,5-b]pyridine; 1-Cyclopropyl-6-(4-((3-fluorooxetan-3-yl)methoxy)pyrrolo[2,1-f][1,2,4]triazine-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine; 3-((5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrrolo[2,1-f][1,2,4]triazine-4-oxy)methyl)oxetan-3-ol; 1-cyclopropyl-2-methyl-6-(4-((1-methylazetidin-3-yl)methoxy)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-1H-imidazo[4,5-b]pyridine; 1-cyclopropyl-6-(4-(3-fluoro-1-methylazetidin-3-yl)methoxy)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine; 6-(4-(azetidin-1-yl)pyrrolo[2,1-f][1,2,4]triazine-5-yl)-1-cyclopropyl-2-methylimidazo[4,5-b]pyridine; 1-cyclopropyl-6-(4-(3,3-dimethylazetidin-1-yl)pyrrolo[2,1-f][1,2,4]triazine-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine; 1-Cyclopropyl-2-methyl-6-(4-(3-methylazetidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-1H-imidazo[4,5-b]pyridine; 1-Cyclopropyl-6-(4-(3,3-difluoroazetidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine; 1-Cyclopropyl-6-(4-(3-fluoroazetidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine; 1-(5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-methylazetidin-3-ol; 1-(5-(1-cyclopropyl-2-methylimidazo[4,5-b]pyridin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)azetidin-3-ol; 1-cyclopropyl-6-(4-(3-fluoropyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine; 1-Cyclopropyl-6-(4-(3-fluoro-3-methylpyrrolidin-1-yl)pyrrolo[2,1-F][1,2,4]triazine-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine; 1-Cyclopropyl-2-methyl-6-(4-(pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazine-5-yl)-1H-imidazo[4,5-b]pyridine; 1-cyclopropyl-2-methyl-6-(4-(3-methylpyrrolidin-1-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-1H-imidazo[4,5-b]pyridine; 1-Cyclopropyl-6-(4-(3,3-dimethylpyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine; 1-(5-(1-cyclopropyl-2-methylimidazo[4,5-b]pyridin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)pyrrolidin-3-ol; 1-(5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-methylpyrrolidin-3-ol; 1-cyclopropyl-6-(4-(3,3-difluoropyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine; 1-cyclopropyl-6-(4-(3-methoxypyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine; 1-cyclopropyl-2-methyl-6-(4-(piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-1H-imidazo[4,5-b]pyridine; 4-(5-(1-cyclopropyl-2-methylimidazo[4,5-b]pyridin-6-yl)pyrrolo[2,1-F][1,2,4]triazin-4-yl)morpholine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-ethylpyrrolo[2,1-f][1,2,4]triazine-4-amine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-isopropylpyrrolo[2,1-f][1,2,4]triazine-4-amine; N-cyclopropyl-5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-cyclopropylmethylpyrrolo[2,1-f][1,2,4]triazin-4-amine; N-cyclobutyl-5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-oxetan-3-yl)pyrrolo[2,1-f][1,2,4]triazine-4-amine; N-cyclopentyl-5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-tetrahydrofuran-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine; N-cyclobutylmethyl-5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-oxetan-3-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine; N-cyclopentylmethyl-5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)pyrrolo[2,1-f][1,2,4]triazine-4-amine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-(tetrahydrofuran-3-yl)methyl)pyrrolo[2,1-F][1,2,4]triazin-4-amine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-(tetrahydrofuran-2-yl)methyl)pyrrolo[2,1-F][1,2,4]triazin-4-amine; 5-(1-cyclopentyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-4-methoxy-N-methylpyrrolo[2,1-f][1,2,4]triazin-2-amine; 4-methoxy-N-methyl-5-(2-methyl-1-(tetrahydrofuran-3-yl)methyl)-1H-imidazo[4,5-b]pyridin-6-yl)pyrrolo[2,1-F][1,2,4]triazin-2-amine; N-ethyl-4-methoxy-5-(2-methyl-1-(tetrahydrofuran-3-yl)methyl)-1H-imidazo[4,5-b]pyridin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine; N-isopropyl-4-methoxy-5-(2-methyl-1-(tetrahydrofuran-3-yl)methyl)-1H-imidazo[4,5-b]pyridin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine; 4-methoxy-5-(2-methyl-1-(tetrahydrofuran-3-yl)methyl)-1H-imidazo[4,5-b]pyridin-6-yl)-N-pyrazol-4-ylpyrrolo[2,1-f][1,2,4]triazin-2-amine; 4-methoxy-5-(2-methyl-1-(tetrahydrofuran-3-methyl)-1H-imidazo[4,5-b]pyridin-6-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine; 4-methoxy-5-(2-methyl-1-(tetrahydrofuran-3-methyl)-1H-imidazo[4,5-b]pyridin-6-yl)-N-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine; 4-methoxy-5-(2-methyl-1-(tetrahydrofuran-3-methyl)-1H-imidazo[4,5-b]pyridin-6-yl)-N-phenylpyrrolo[2,1-f][1,2,4]triazin-2-amine; 4-methoxy-5-(2-methyl-1-tetrahydrofuran-3-methyl)-1H-imidazo[4,5-b]pyridin-6-yl)-N-pyridin-2-ylpyrrolo[2,1-f][1,2,4]triazin-2-amine; 4-methoxy-5-(2-methyl-1-(tetrahydrofuran-3-methyl)-1H-imidazo[4,5-b]pyridin-6-yl)-N-pyridin-3-ylpyrrolo[2,1-f][1,2,4]triazin-2-amine; 4-methoxy-5-(2-methyl-1-(tetrahydrofuran-3-yl)methyl)-1H-imidazo[4,5-b]pyridin-6-yl)-N-pyridin-4-ylpyrrolo[2,1-f][1,2,4]triazin-2-amine; 4-methoxy-5-(2-methyl-1-tetrahydrofuran-3-methyl)-1H-imidazo[4,5-b]pyridin-6-yl)-N-(4-pyrimidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine; 4-methoxy-5-(2-methyl-1-tetrahydrofuran-3-methyl)-1H-imidazo[4,5-b]pyridin-6-yl)-N-pyrimidin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine; 4-methoxy-5-(2-methyl-1-(tetrahydrofuran-3-ylmethyl)-1H-imidazo[4,5-b]pyridin-6-yl)-N-pyridazin-4-ylpyrrolo[2,1-f][1,2,4]triazin-2-amine; 4-methoxy-5-(2-methyl-1-(tetrahydrofuran-3-ylmethyl)-1H-imidazo[4,5-b]pyridin-6-yl)-N-pyrazin-2-ylpyrrolo[2,1-f][1,2,4]triazin-2-amine; N-(1-ethylpyrazol-4-yl)-4-methoxy-5-(2-methyl-1-(tetrahydrofuran-3-methyl)-1H-imidazo[4,5-b]pyridin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine; N-(1-cyclopropylmethyl)-1H-pyrazol-4-yl)-4-methoxy-5-(2-methyl-1-(tetrahydrofuran-3-yl)methyl)-1H-imidazo[4,5-b]pyridin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine; N-(1-isobutyl-1H-pyrazol-4-yl)-4-methoxy-5-(2-methyl-1-(tetrahydrofuran-3-ylmethyl)-1H-imidazo[4,5-b]pyridin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine; N-(1-isopropylpyrazol-4-yl)-4-methoxy-5-(2-methyl-1-(tetrahydrofuran-3-methyl)-1H-imidazo[4,5-b]pyridin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine; N-(1-cyclopropylpyrazol-4-yl)-4-methoxy-5-(2-methyl-1-(tetrahydrofuran-3-ylmethyl)-1H-imidazo[4,5-b]pyridin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine; 4-methoxy-5-(2-methyl-1-(tetrahydrofuran-3-ylmethyl)-1H-imidazo[4,5-b]pyridin-6-yl)-N-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-(1-methylpyrazol-4-yl)-4-(pyrrolidin-1-yl)pyrrolo[2,1-F][1,2,4]triazin-2-amine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-(1-methylpyrazol-4-yl)-4-(3-methylpyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-4-(3,3-dimethylpyrrolidin-1-yl)-N-(1-methylpyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine; 1-(5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-2-(1-methylpyrazol-4-amino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)pyrrolidin-3-ol; 1-(5-(1-cyclopropyl-2-methylimidazo[4,5-b]pyridin-6-yl)-2-(1-methylpyrazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-methylpyrrolidin-3-ol; 4-cyclobutoxy-5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-(1-methylpyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-(1-methyl-1H-pyrazol-4-yl)-4-oxetane-3-oxacyclohexyloxy)pyrrolo[2,1-f][1,2,4]triazin-2-amine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-(1-methyl-1H-pyrazol-4-yl)-4-(1-methylazetidin-3-yl)oxy)pyrrolo[2,1-F][1,2,4]triazin-2-amine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-4-(3,3-difluorocyclobutyloxy)-N-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-4-(cyclopropylmethoxy)-N-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-(1-methyl-1H-pyrazol-4-yl)-4-(oxetan-3-ylmethoxy)pyrrolo[2,1-F][1,2,4]triazin-2-amine; 4-Cyclopentylmethoxy-5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-(1-methylpyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-(1-methyl-1H-pyrazol-4-yl)-4-(tetrahydrofuran-2-yl)methoxy)pyrrolo[2,1-f][1,2,4]triazin-2-amine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-(1-methyl-1H-pyrazol-4-yl)-4-(tetrahydrofuran-3-yl)methoxy)pyrrolo[2,1-f][1,2,4]triazin-2-amine; 4-Cyclopentyloxy-5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-(1-methylpyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-(1-methyl-1H-pyrazol-4-yl)-4-(tetrahydrofuran-3-yl)oxy)pyrrolo[2,1-F][1,2,4]triazin-2-amine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-(1-methylpyrazol-4-yl)-4-(1-methylpyrrolidin-3-yl)oxy)pyrrolo[2,1-f][1,2,4]triazin-2-amine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-4-(3,3-difluorocyclopentyl)oxy)-N-(1-methylpyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine; 4-cyclohexyloxy-5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-(1-methylpyrazol-4-yl)-4-(tetrahydro-2H-pyran-3-yl)oxy)pyrrolo[2,1-f][1,2,4]triazin-2-amine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-(1-methyl-1H-pyrazol-4-yl)-4-(tetrahydro-2H-pyran-4-yl)oxy)pyrrolo[2,1-f][1,2,4]triazin-2-amine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-(1-methylpyrazol-4-yl)-4-(1-methylpiperidin-3-yl)oxy)pyrrolo[2,1-F][1,2,4]triazin-2-amine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-(1-methylpyrazol-4-yl)-4-(1-methylpiperidin-4-yl)oxy)pyrrolo[2,1-F][1,2,4]triazin-2-amine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-(1-methylpyrazol-4-yl)-4-(1-methylpiperidin-4-yl)oxy)pyrrolo[2,1-F][1,2,4]triazin-2-amine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-4-(3,3-dimethylazetidin-1-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2,4]triazin-2-amine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-(1-methyl-1H-pyrazol-4-yl)-4-(3-methylazetidin-1-yl)pyrrolo[2,1-F][1,2,4]triazin-2-amine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-4-(3,3-difluoroazetidin-1-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2,4]triazin-2-amine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-4-(3-fluoroazetidin-1-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine; 1-(5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-2-(1-methylpyrazol-4-amino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-methylazetidin-3-ol; 1-(5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-2-(1-methylpyrazol-4-amino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)azetidin-3-ol; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-4-(3-fluoropyrrolidin-1-yl)-N-(1-methylpyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-4-(3-fluoro-3-methylpyrrolidin-1-yl)-N-(1-methylpyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-(1-methyl-1H-pyrazol-4-yl)-4-(piperidin-1-yl)pyrrolo[4,5-b]pyridin-6-yl] [2,1-F][1,2,4]triazine-2-amine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-(1-methyl-1H-pyrazol-4-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-2-amine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-(1-methylpyrazol-4-yl)-4-(4-methylpiperazin-1-yl)pyrrolo[2,1-F][1,2,4]triazin-2-amine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-4-methyl-N-(1-methylpyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-4-ethyl-N-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine; 4-cyclopropyl-5-(1-cyclopropyl-2-methylimidazo[4,5-b]pyridin-6-yl)-N-(1-methylpyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine; 5-(1-cyclopropyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-4-isopropyl-N-(1-methylpyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine.

4. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises any one of the compound represented by formula (I) according to any one of claims 1 to 3, the enantiomer, diastereomer, pharmaceutical salt, solvent compound and pharmaceutically acceptable carrier of the compound represented by formula (I).

5. Use of the compound according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 4 in the preparation of a medicament for treating diseases associated with CLK2 amplification or CLK2 overexpression.

6. The use according to claim 5, characterized in that: The diseases associated with CLK2 amplification or CLK2 overexpression include at least one of breast cancer, triple-negative breast cancer, acute myeloid leukemia, lung adenocarcinoma, blood tumors, digestive system tumors, reproductive system tumors, nervous system tumors or head and neck cancer.

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