Fused heterocyclic compound as well as pharmaceutical composition and application thereof

Abstract

The present disclosure relates to a CLK2 inhibitor, and more particularly, to a fused heterocyclic compound and a pharmaceutical composition thereof, which can prevent and treat various diseases such as cancer.

Description

[0001] This application claims priority to the following prior application: Patent Application No. 2024104703955, filed on April 18, 2024, with the State Intellectual Property Office of China, and entitled "Fused Heterocyclic Compound and Pharmaceutical Composition and Application Thereof". The entire contents of this prior application are incorporated herein by reference. TECHNICAL FIELD

[0002] The present application belongs to the technical field of medicine, and specifically relates to a fused heterocyclic compound and a pharmaceutical composition and application thereof. BACKGROUND

[0003] Protein kinases are important enzymes that catalyze the phosphorylation of proteins, and they can regulate the activity of proteins through phosphorylation, and also amplify signals through step-by-step phosphorylation of proteins, thereby causing cellular responses. Protein kinases play a key regulatory role in life processes, and abnormal levels of protein kinases often lead to the occurrence of malignant diseases such as cancer. The dysfunction of protein kinases, for example, through gain-of-function genetic mutations, gene amplification, autonomous activation, and activation of chromosomal rearrangements, is closely related to cancer development and progression, and is involved in cancer cell transformation, growth, proliferation, and survival.

[0004] Protein phosphorylation and alternative splicing are both important links in the regulation of gene expression. CLKs family kinases (Cdc-like kinases) have both of the above two regulatory functions. CLKs are a group of dual-specificity kinases that can autophosphorylate and also phosphorylate substrates at serine / threonine residues. CLKs family kinases are an evolutionarily conserved dual-specificity kinase, which belongs to protein kinases and consists of 4 kinase subtypes, namely CLK1, CLK2, CLK3, and CLK4.

[0005] CLK2 plays an important regulatory function in various diseases. In recent years, more and more research has focused on elucidating the biological functions of the family member CLK2. CLK2, as a protein kinase, is directly involved in the regulation of multiple important signaling pathways in cells, and 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.

[0006] Alternative splicing (AS) of messenger RNA (mRNA) precursor regulated by SR proteins is one of the main functions of CLK2. AS is an important regulatory way 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, which is involved in the regulation of cell cycle, stress, metastasis, invasion, angiogenesis, immunosuppression and drug resistance and other aspects. Many factors can lead to AS disorder, such as mutation of 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 the corresponding cis-acting elements on the mRNA precursor, or regulate the recognition of splicing sites by the interaction between proteins.

[0007] CLK2 regulates the splicing of mRNA precursor by phosphorylating multiple SR proteins, and is involved in the occurrence and development of various diseases such as nervous system diseases, infections, and malignant tumors. CLK2 indirectly regulates the expression of proteins such as ribosomal protein S6 kinase (S6K), Bcl-2 associated 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 colorectal cancer HCT116 cells. Transformer 2 beta homolog 1 (TRA2B1) is one of the splicing factors with pro-cancer effect. 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 AS of TRA2B1 itself. CLK2 and Myc synergistically regulate the biosynthesis and splicing processing of pre-mRNA 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 transcription target of Myc, and can promote the transformation of breast epithelial cells. CLK2 is overexpressed in breast cancer cells and tissues, and exogenous down-regulation of CLK2 expression can inhibit the proliferation of Myc-amplified breast cancer cells. Overexpression of CLK2 can promote the proliferation of non-small cell lung cancer (NSCLC), and the mechanism may be related to the decrease of miR-573 expression in NSCLC. Inhibition of CLK activity can reduce the expression of Wnt pathway genes to 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 for inducing androgen-independent lineage plasticity of prostate cancer, and is closely related to castration-resistant prostate cancer. Therefore, inhibition of the activity of CLK2 kinase is likely to be a promising method for treating cancer. SUMMARY

[0008] To improve the above problems, the present disclosure provides a compound represented by the following formula (I), a stereoisomer, a racemate, a tautomer, an isotopically labeled material, a nitroxide or a pharmaceutically acceptable salt thereof,

[0009]

[0010] HET1 is selected from a 10-membered heteroaromatic ring group containing 1-3 nitrogen atoms;

[0011] HET2 is selected from a 5-10-membered heteroaromatic ring group containing 1-3 heteroatoms selected from N, O, S;

[0012] each R1 is the same or different, independently of one another, selected from H, halogen, cyano, hydroxyl, amino, the following groups which are unsubstituted or optionally substituted by one, two, three or more identical or different R a substituted alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl, -O-(CH2) p cycloalkyl, -O-(CH2) p heterocyclyl, -O-(CH2) p aryl, -O-(CH2) p heteroaryl, -NHalkyl, -N(alkyl)2, -SO2alkyl, -NH-SO2-alkyl; wherein, if n > 2, R1 are identical or different;

[0013] each R a is the same or different, independently of one another, selected from H, halogen, cyano, hydroxyl, amino, alkyl, alkoxy, -NHalkyl, -N(alkyl)2, -SO2alkyl, -SOalkyl, -SO(=N-alkyl)alkyl;

[0014] each R2 is the same or different, independently of one another, selected from H, halogen, cyano, hydroxyl, amino, the following groups which are unsubstituted or optionally substituted by one, two, three or more identical or different R b substituted alkyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl;

[0015] each R b is the same or different, independently of one another, selected from H, halogen, cyano, hydroxyl, amino;

[0016] R3 is selected from H, halogen, cyano, hydroxyl, amino, alkyl, alkoxy, alkylthio, cycloalkyl;

[0017] R4 is selected from H, halogen, cyano, hydroxyl, amino, alkyl, alkoxy, alkylthio, cycloalkyl;

[0018] R5, R6 are the same or different, independently of one another, selected from H, halogen, cyano, hydroxyl, amino, alkyl;

[0019] m, n, p are the same or different, independently of one another, selected from integers from 0 to 3.

[0020] According to an embodiment of formula (I) according to the disclosure, wherein HET1 is selected from a 10-membered heteroaromatic ring group containing 1, 2 or 3 nitrogen atoms; preferably a bicyclic heteroaromatic ring group as shown in the following formulae:

[0021]

[0022] According to an embodiment of formula (I) according to the disclosure, wherein each R1 is the same or different, independently of one another, selected from the group consisting of H, halogen, cyano, hydroxyl, amino, the following groups, which are unsubstituted or optionally substituted by one, two, three or more identical or different R a substituted C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 1-20 alkoxy, C 1-20 alkylthio, C 3-20 cycloalkyl, 3-10-membered heterocyclyl, C 6-20 aryl, 5-10-membered heteroaryl, -O-(CH2) p -C 3-20 cycloalkyl, -O-(CH2) p -3-10-membered heterocyclyl, -O-(CH2) p -C 6-20 aryl, -O-(CH2) p -5-10-membered heteroaryl, -NHC 1-20 alkyl, -N(C 1-20 alkyl)2, -SO2C 1-20 alkyl, -NH-SO2-C 1-20 alkyl; wherein, if n > 2, R1 are the same or different.

[0023] Preferably, each R1 is the same or different, independently of one another, selected from the group consisting of H, halogen, cyano, hydroxyl, amino, the following groups, which are unsubstituted or optionally substituted by one, two, three or more identical or different R a substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylthio, C 3-10 cycloalkyl, 3-10-membered heterocyclyl, C 6-10 aryl, 5-10-membered heteroaryl, -O-(CH2) p -C 3-10 cycloalkyl, -O-(CH2) p -3-10-membered heterocyclyl, -O-(CH2) p -C 6-10 aryl, -O-(CH2) p -5-10-membered heteroaryl, -NHC1-10 Alkyl, -N(C 1-10 Alkyl)2, -SO2C 1-10 Alkyl, -NH-SO2-C 1-10 alkyl.

[0024] More preferably, each R1 is the same or different and is independently selected from H, halogen, cyano, hydroxyl, amino, unsubstituted or optionally substituted by one, two, three or more same or different R a Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, -O-(CH2) p -C 3-6 Cycloalkyl, -O-(CH2) p -4-6 membered heterocyclic group, -O-(CH2) p -C 6-10 Aryl, -O-(CH2) p -5-6 membered heteroaryl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SO2C 1-6 Alkyl, -NH-SO2-C 1-6 alkyl.

[0025] According to the embodiment of formula (I) of the present disclosure, each R a The same or different, independently selected from halogen, cyano, hydroxyl, amino, C 1-20 Alkyl, C 1-20 Alkoxy, -NHC 1-20 Alkyl, -N(C 1-20 Alkyl)2, -SO2C 1-20 Alkyl, -SOC 1-20 Alkyl, -SO(=NC 1-20 Alkyl)C 1-20 Alkyl; preferably R a Selected from H, halogen, hydroxyl, C 1-10 Alkyl, C 1-10 Alkoxy, -NHC 1-10 Alkyl, -N(C 1-10 Alkyl)2, -SO2C 1-10 Alkyl, -SOC 1-10 Alkyl, -SO(=NC 1-10 Alkyl)C 1-10More preferably, R1 is selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -NHC 1-6 Alkyl, -SO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -SO(=NC 1-6 Alkyl)C 1-6 alkyl.

[0026] Most preferably, R1 is selected from H; halogen; cyano; hydroxy; amino; C optionally substituted or polysubstituted by halogen; 1-6 Alkyl; C 2-6 Alkynyl; optionally substituted with halogen, hydroxy, cyano, C 1-6 Alkoxy, -N(C 1-6 Alkyl)2, -SO2C 1-6 Alkyl and / or -SO(=NC 1-6 Alkyl)C 1-6 Alkyl mono- or poly-substituted C 1-6 Alkoxy; C 3-6 Cycloalkyl; -O-(CH2) p -4-6 membered heterocyclyl, wherein "4-6 membered heterocyclyl" is selected from tetrahydrofuranyl, pyrrolyl, N-methylpyrrolyl, morpholinyl, oxetanyl, tetrahydropyranyl, N-methylpiperidine or N-methylpiperazine; -O-(CH2) optionally substituted with hydroxyl groups or multiple substitutions p -C 3-6 Cycloalkyl, wherein "C 3-6 Cycloalkyl" is selected from cyclopropane, cyclobutane, cyclopentane; -N(C 1-6 Alkyl)2;-SO2C 1-6 Alkyl; -NH-SO2-C 1-6 alkyl.

[0027] According to the embodiment of formula (I) disclosed herein, HET2 is selected from a 5-6 membered heteroaromatic ring group containing 1, 2 or 3 heteroatoms selected from N, O and S; preferably a 5-6 membered heteroaromatic ring group containing 2-3 heteroatoms selected from N, O and S; more preferably a 5-membered heteroaromatic ring group containing 3 heteroatoms selected from N and O; particularly preferably, HET2 and R2 form a group shown in the following formula:

[0028]

[0029] According to the embodiment of formula (I) of the present disclosure, each R2 is the same or different and is independently selected from H, halogen, cyano, hydroxyl, amino, unsubstituted or optionally substituted by one, two, three or more R b Substituted with the following groups: C 1-20 Alkyl, C1-20 alkoxy, C 1-20 alkylthio, C 3-20 cycloalkyl, 3-20 membered heterocyclyl; preferably C 1-10 alkyl, C 1-10 alkoxy, C 1-10 alkylthio, C 3-10 cycloalkyl, 3-10 membered heterocyclyl; more preferably C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-6 cycloalkyl, 3-6 membered heterocyclyl.

[0030] According to an embodiment of formula (I) of the present disclosure, each substituent R b are independently of each other selected from the group consisting of H, halogen, cyano, hydroxy, amino; preferably H, halogen, cyano, hydroxy; more preferably H, halogen.

[0031] According to an embodiment of formula (I) of the present disclosure, wherein R3is selected from the group consisting of H, halogen, cyano, hydroxy, amino, C 1-20 alkyl, C 1-20 alkoxy, C 3-20 cycloalkyl; preferably H, halogen, cyano, hydroxy, amino, C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl; more preferably H, halogen, C 1-6 alkyl, C 1-6 alkoxy.

[0032] According to an embodiment of formula (I) of the present disclosure, wherein R4is selected from the group consisting of H, halogen, cyano, hydroxy, amino, C 1-20 alkyl, C 1-20 alkoxy, C 3-20 cycloalkyl; preferably H, halogen, cyano, hydroxy, amino, C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl; more preferably H, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl; most preferably H.

[0033] According to an embodiment of formula (I) of the present disclosure, wherein R5, R6are independently of each other selected from the group consisting of H, halogen, cyano, hydroxy, amino, C 1-20 alkyl; preferably, R5, R6are independently of each other selected from the group consisting of H, halogen, cyano, hydroxy, amino, C 1-10 alkyl; more preferably, R5, R6are independently selected from the group consisting of H, halogen, hydroxy, C 1-6 alkyl;

[0034] According to one embodiment of the present disclosure, m, n, p are the same or different, independently selected from 0, 1, 2 and 3.

[0035] The present disclosure also provides a compound as shown in formula (II), a stereoisomer, a racemate, a tautomer, an isotopically-labeled material, a nitroxide, or a pharmaceutically acceptable salt thereof:

[0036]

[0037] wherein HET2, R1, R2, R3, R4, R5, R6, m, n are independently defined as in formula (I) above;

[0038] X1is selected from N, CR c ;

[0039] X2is selected from N, CR d ;

[0040] X3is selected from N, CR e ;

[0041] X4is selected from N, CR f ;

[0042] wherein 1, 2 or 3 of X1, X2, X3, X4are N;

[0043] R c , R d , R e , R f are the same or different, independently selected from H, halogen, cyano, hydroxyl, amino, the following groups which are unsubstituted or optionally substituted by one, two, three or more identical or different R g alkyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy;

[0044] each R g is the same or different, independently selected from H, halogen, cyano, hydroxyl, amino, alkyl, alkoxy.

[0045] According to an embodiment of the present disclosure, formula (II), X1is selected from N, X2is selected from CR d , X3is selected from CR e , and X4is selected from CR f ; or X1and X2are selected from N, X3is selected from CR e , and X4is selected from CR f ; or X1and X3are selected from N, X2is selected from CR d , and X4is selected from CR f; or X1, X2, X3are selected from N and X4is selected from CR f ; or X1, X2, X4are selected from N and X3is selected from CR e .

[0046] According to an embodiment of the present disclosure of formula (II), R c , R d , R e , R f are identical or different, independently of one another, selected from the group consisting of H, halogen, cyano, hydroxyl, amino, unsubstituted or optionally substituted with one, two, three or more identical or different R g ; C 1-20 alkyl, C 1-20 alkoxy, C 1-20 alkylthio, C 3-20 cycloalkyl, 3- to 20-membered heterocyclyl, C 6-20 aryl, 5- to 20-membered heteroaryl, C 3-20 cycloalkyloxy, 3- to 20-membered heterocyclyloxy;

[0047] Preferably, R c , R d , R e , R f are identical or different, independently of one another, selected from the group consisting of H, halogen, cyano, hydroxyl, amino, unsubstituted or optionally substituted with one, two, three or more identical or different R g ; C 1-10 alkyl, C 1-10 alkoxy, C 1-10 alkylthio, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyloxy, 3- to 10-membered heterocyclyloxy;

[0048] More preferably, R c , R d , R e , R f are identical or different, independently of one another, selected from the group consisting of H, halogen, cyano, hydroxyl, amino, unsubstituted or optionally substituted with one, two, three or more identical or different R g ; C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-6 cycloalkyl, 4- to 6-membered heterocyclyl, C 6-10 aryl, 5- to 6-membered heteroaryl, C 3-6 cycloalkyloxy, 4- to 6-membered heterocyclyloxy;

[0049] Most preferably, R c , R d , R e , R f are identical or different, independently of each other, selected from the group consisting of H, fluorine, chlorine, bromine, cyano, hydroxyl, amino, unsubstituted or optionally substituted with one, two, three or more identical or different R g substituted with one, two, three or more identical or different R 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 3-6 cycloalkyl, 4-6 membered heterocyclyloxy;

[0050] According to an embodiment of the present disclosure of formula (II), each R g are identical or different, independently of each other, selected from the group consisting of H, halogen, cyano, hydroxyl, amino, C 1-20 alkyl, C 1-20 alkoxy; preferably, each R g are identical or different, independently of each other, selected from the group consisting of H, halogen, cyano, hydroxyl, amino, C 1-10 alkyl, C 1-10 alkoxy; more preferably, each R g are identical or different, independently of each other, selected from the group consisting of H, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy; especially preferably, each R g are identical or different, independently of each other, selected from the group consisting of H, halogen, hydroxyl, C 1-3 alkyl.

[0051] The present disclosure also provides a compound as shown in formula (III), a stereoisomer, a racemate, a tautomer, an isotopically-labeled, a nitroxide or a pharmaceutically acceptable salt thereof:

[0052]

[0053] wherein R1, R2, R3, R4, R5, R6, n are independently defined as above in formula (I) or formula (II);

[0054] X1, X2, X3, X4 are independently defined as above in formula (II).

[0055] The present disclosure also provides a compound as shown in formula (IV), a stereoisomer, a racemate, a tautomer, an isotopically-labeled, a nitroxide or a pharmaceutically acceptable salt thereof:

[0056]

[0057] wherein R1, R2, R3, R4, R5, R6 independently have the definition as in formula (I), (II) or (III) above;

[0058] X1, X2, X3, X4 independently have the definition as in formula (II) or (III) above;

[0059] R', R" are the same or different, independently from each other selected from H, halogen, cyano, hydroxyl, amino, alkyl, alkoxy, alkylthio, cycloalkyl.

[0060] According to an embodiment of the present disclosure, formula (IV) wherein R', R" are the same or different, independently from each other selected from H, halogen, cyano, hydroxyl, amino, C 1-20 alkyl, C 1-20 alkoxy, C 3-20 cycloalkyl; preferably H, halogen, cyano, hydroxyl, amino, C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl; more preferably H, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl; most preferably H.

[0061] The present disclosure also provides a compound as shown in formula (V) below, a stereoisomer, a racemate, a tautomer, an isotopically-labeled, a nitroxide or a pharmaceutically acceptable salt thereof:

[0062]

[0063] wherein R1, R2, R3, R4 independently have the definition as in formula (I), (II) or (III) above;

[0064] X1, X2, X3 independently have the definition as in formula (II) or (III) above.

[0065] The present disclosure also provides a compound as shown in formula (VI) below, a stereoisomer, a racemate, a tautomer, an isotopically-labeled, a nitroxide or a pharmaceutically acceptable salt thereof:

[0066]

[0067] wherein R1, R2, R3, R4 independently have the definition as in formula (I), (II) or (III) above;

[0068] R e have the definition as in formula (II) or (III) above.

[0069] According to embodiments of the present disclosure, the present disclosure provides the above-mentioned compounds of formula (I)-(VI), stereoisomers, racemates, tautomers, isotopically-labeled, nitro-oxides or pharmaceutically acceptable salts thereof, wherein the compounds of formula (I)-(VI) are selected from the following compounds:

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084] The present disclosure also provides a method for preparing a compound of formula (I) as described above, stereoisomers, racemates, tautomers, isotopically-labeled, nitro-oxides or pharmaceutically acceptable salts thereof, wherein the method comprises one of the following schemes:

[0085] Scheme I-1

[0086]

[0087] Scheme I-2

[0088]

[0089] wherein HET1, HET2, R1, R2, R3, R4, R5, R6, m, n are independently as defined in formula (I) as described above;

[0090] Y is selected from Cl, Br, I or OTf;

[0091] R 21 is selected from alkyl, OH, alkoxy; or two R 21 together with the B atom to which they are attached form a 5-6 membered heterocyclic ring optionally substituted with alkyl; preferably, R 21 is selected from C 1-20 alkyl, OH, C 1-20 alkoxy, or two R 21 together with the B atom to which they are attached form a 5-6 membered heterocyclic ring optionally substituted with C 1-20 alkyl; more preferably, R 21 is selected from C 1-10 alkyl, OH, C 1-10 alkoxy, or two R 21 together with the B atom to which they are attached form a 5-6 membered heterocyclic ring optionally substituted with C 1-10 alkyl; especially preferably, R 21 is selected from C 1-6 alkyl, OH, C 1-6 alkoxy, or two R 21 together with the B atom to which they are attached form a 5-6 membered heterocyclic ring optionally substituted with C 1-6 alkyl; most preferably, R 21 is selected from methyl, ethyl, propyl, isopropyl, OH, methoxy, ethoxy, propoxy, isopropoxy; or two R 21 together with the B atom to which they are attached form a pinacol boron ester.

[0092] According to the embodiments of the present disclosure, in the above preparation method, the target compound is prepared by a cross-coupling reaction such as a Suzuki coupling reaction. For example, it is carried out in a suitable solvent in the presence of a metal catalyst such as palladium or nickel, optionally using a base and an additive. The suitable solvent is selected from methanol, ethanol, dimethoxyethane, N,N-dimethylformamide, dimethyl sulfoxide, dioxane, tetrahydrofuran and water, or a mixture thereof; the palladium catalyst is selected from PdCl2(dppf), Pd2(dba)3, Pd(PPh3)4, and the like; and the base is usually selected from Na2CO3, Ba(OH)2, K3PO4, Cs2CO3, K2CO3, KF, CsF, Bu4F, NaOH, and the like.

[0093] The present disclosure also provides a preparation method of a compound as shown in formula (II) above, a stereoisomer, a racemate, a tautomer, an isotopically labeled material, a nitroxide, or a pharmaceutically acceptable salt thereof, wherein the preparation method comprises one of the following schemes:

[0094] Scheme II-1

[0095]

[0096] Scheme II-2

[0097]

[0098] wherein HET2, R1, R2, R3, R4, R5, R6, m, and n are independently defined as described above in formula (II);

[0099] Y is selected from Cl, Br, I or OTf;

[0100] R 21 Selected from alkyl, OH, alkoxy; or two R 21 Together with the B atom to which it is attached, it forms a 5-6 membered heterocyclic ring which is optionally substituted by an alkyl group; preferably, R 21 Selected from C 1-20 Alkyl, OH, C 1-20 Alkoxy, or two R 21 Together with the B atom to which it is attached, it forms an optionally C 1-20 Alkyl-substituted 5-6 membered heterocyclic ring; more preferably, R 21 Selected from C 1-10 Alkyl, OH, C 1-10 Alkoxy, or two R 21 Together with the B atom to which it is attached, it forms an optionally C 1-10 Alkyl-substituted 5-6 membered heterocyclic ring; particularly preferably, R 21 Selected from C 1-6 Alkyl, OH, C 1-6 Alkoxy, or two R 21 Together with the B atom to which it is attached, it forms an optionally C 1-6 Alkyl-substituted 5-6 membered heterocyclic ring; most preferably, R 21 Selected from methyl, ethyl, propyl, isopropyl, OH, methoxy, ethoxy, propoxy, isopropoxy; or two R 21 Together with the B atom to which it is attached, it forms a pinacol boronate.

[0101] According to an embodiment of the present disclosure, in the above-mentioned preparation method, the target compound is prepared by a cross-coupling reaction such as a Suzuki coupling reaction. For example, in a suitable solvent, in the presence of a metal catalyst such as palladium or nickel, a base and an additive are optionally used. The suitable solvent is selected from methanol, ethanol, dimethoxyethane, N,N-dimethylformamide, dimethyl sulfoxide, dioxane, tetrahydrofuran and water, or a mixture thereof; the palladium catalyst is selected from PdCl2(dppf), Pd2(dba)3, Pd(PPh3)4, etc.; the base is generally selected from Na2CO3, Ba(OH)2, K3PO4, Cs2CO3, K2CO3, KF, CsF, Bu4F, NaOH, etc.

[0102] The present disclosure also provides a pharmaceutical composition comprising at least one of the compounds represented by formula (I)-(VI) described above, their stereoisomers, racemates, tautomers, isotope-labeled substances, nitrogen oxides, or pharmaceutically acceptable salts thereof.

[0103] Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0104] The present disclosure also provides the use of at least one of the compounds represented by formula (I)-(VI), their stereoisomers, racemates, tautomers, isotope-labeled substances, nitrogen oxides, or pharmaceutically acceptable salts thereof in the preparation of a medicament for treating and / or preventing diseases associated with or affected by CLK2.

[0105] The present disclosure also provides a method for preventing and / or treating diseases associated with or affected by CLK2, comprising administering to an individual in need thereof a therapeutically effective amount of at least one of the compounds represented by Formulas (I)-(VI), their stereoisomers, racemates, tautomers, isotopically labeled substances, nitrogen oxides, or pharmaceutically acceptable salts thereof.

[0106] The compounds disclosed herein have good CLK2 inhibitory activity and can be used as preventive or therapeutic agents for cancer, cancer growth inhibitors, or cancer metastasis inhibitors.

[0107] The compounds of the present disclosure can be used to inhibit the excessive (abnormal) effects of CLK2 in mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, or humans).

[0108] According to embodiments of the present disclosure, the disease associated with or affected by CLK2 is selected from, for example, a cancer [e.g., a colorectal cancer (e.g., colon cancer, rectal cancer, anal cancer, familial colorectal cancer, hereditary nonpolyposis colorectal cancer, and gastrointestinal stromal tumor), a lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, and malignant mesothelioma), a mesothelioma, a pancreatic cancer (e.g., pancreatic ductal carcinoma and pancreatic endocrine gland tumor), a pharyngeal cancer, a laryngeal cancer, an esophageal cancer, a gastric cancer (e.g., papillary adenocarcinoma, mucous adenocarcinoma, and adenosquamous carcinoma), a duodenal cancer, a small intestinal cancer, a breast cancer (e.g., invasive ductal carcinoma, non-invasive intraductal carcinoma, and inflammatory breast cancer), an ovarian cancer (e.g., ovarian epithelial cancer, extragonadal germ cell tumor, ovarian germ cell tumor, and ovarian low malignant potential tumor), a testicular tumor, a prostate cancer (e.g., hormone-dependent prostate cancer, non-hormone-dependent prostate cancer, and castration-resistant prostate cancer), a liver cancer (e.g., hepatocellular carcinoma, primary liver cancer, and extrahepatic bile duct cancer), a thyroid cancer (e.g., medullary thyroid carcinoma), a renal cancer (e.g., renal cell carcinoma (e.g., clear cell renal cell carcinoma) and metastatic cell carcinoma of the renal pelvis and ureter), a uterine cancer (e.g., cervical cancer, uterine body cancer, and uterine sarcoma), a gestational choriocarcinoma, a brain tumor (e.g., medulloblastoma, glioma, astrocytoma of the pineal body, fibrous astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, and pituitary adenoma), retinoblastoma, a skin cancer (e.g., basal cell carcinoma and malignant melanoma), a sarcoma (e.g., rhabdomyosarcoma, leiomyosarcoma, soft tissue sarcoma, and spindle cell sarcoma), a malignant bone tumor, a bladder cancer, a blood cancer (e.g., multiple myeloma, leukemia (e.g., acute myeloid leukemia), malignant lymphoma, lymphogranulomatosis, and chronic myeloproliferative disease), and an unknown primary cancer], a cancer growth inhibitor, a cancer metastasis inhibitor, a cell program death promoter, or a therapeutic agent for a precancerous lesion (e.g., myelodysplastic syndrome).

[0109] In particular, the compounds of the present disclosure can be used as a medicament for myelodysplastic syndrome, acute myeloid leukemia, multiple myeloma, or breast cancer.

[0110] The compounds of the present disclosure can be administered orally or parenterally to mammals (preferably, humans) in the form of a pharmaceutical comprising the compound of the present disclosure alone or in a mixture with a pharmacologically acceptable carrier.

[0111] Advantages

[0112] The compounds of the present disclosure exhibit good selective inhibitory activity against CLK2 and have significant advantages in terms of pharmacological effects, pharmacokinetics (e.g., absorption, distribution, metabolism, and excretion), solubility (e.g., water solubility), interactions with other drugs (e.g., drug-metabolizing enzyme inhibition), safety (e.g., acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity, and central toxicity), and stability (e.g., chemical stability and stability against enzymes).

[0113] Definitions and explanations of terms

[0114] Unless defined otherwise, all technical and scientific terms herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs.

[0115] When the numerical ranges described in the specification and claims of this application are defined as "integers", they should be understood as recording the two endpoints of the range and each integer within the range. For example, "an integer from 0 to 10" should be understood as recording each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. When the numerical range is defined as a "number", it should be understood as recording the two endpoints of the range, each integer within the range and each decimal within the range. For example, "a number from 0 to 10" should be understood as recording not only each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also at least the sum of each of these integers and 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, respectively. "More" means three or more.

[0116] It should be understood that references to the invention can be found in the literature including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4 THED. Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise indicated, conventional methods within the skill of the art are employed, such as mass spectrometry, NMR, IR and UV / Vis spectroscopy and pharmacological methods. Unless specific definitions are provided, the nomenclature utilized in connection with, and the procedures involved in, analytical chemistry, synthetic organic and medicinal chemistry, and the use of prodrugs are those well known and commonly used in the art. Standard techniques can be used for chemical synthesis, chemical analysis, pharmaceutical formulation, and delivery, and treatment of patients. For example, reagents, kits, and the like can be used according to manufacturer's instructions or according to well-known methods in the art or as described herein. The foregoing techniques and procedures can be readily implemented by the skilled artisan by reference to the descriptions contained in the numerous general and more specific references discussed above. In the present description, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds. When a substituent is described by a conventional chemical formula written from left to right, the substituent is also intended to include the chemically identical substituent obtained from right to left writing of the formula. For example, CH2O is equivalent to OCH2.

[0117] The term "halogen" includes F, CI, Br or I.

[0118] The term "alkyl" is to be understood as a straight-chained or branched saturated monovalent hydrocarbon group, for example, as representing a straight-chained or branched saturated monovalent hydrocarbon group having 1 to 20 carbon atoms (C 1-20 alkyl), preferably C 1-10 alkyl. "C 1-10 The term "alkyl" is to be understood as representing a straight-chained or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1 -methylbutyl, 1 -ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1 -dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1 -methylpentyl, 2-ethylbutyl, 1 -ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1 -dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl and the like or isomers thereof. In particular, the group has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms ("C 1-6 alkyl"), for example, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, more particularly, the group has 1, 2 or 3 carbon atoms ("C 1-3alkyl), such as methyl, ethyl, n-propyl, or i-propyl. Alkyl groups can be independently optionally substituted at each occurrence, in some embodiments, "optionally substituted alkyl" is substituted with 1, 2, 3, 4, or 5 substituents, such as 1-2, 1-3, or 1-4 substituents, selected from the group consisting of the moieties listed herein (see definition of "optionally substituted").

[0119] The term "alkenyl" is to be understood as a straight or branched chain monovalent hydrocarbon group having at least one carbon-carbon double bond, including groups having "cis" and "trans" orientations or alternatively "E" and "Z" orientations, such as a straight or branched chain monovalent hydrocarbon group having 1-20 carbon atoms, and having at least one carbon-carbon double bond (C 1-20 alkenyl), preferably C 1-10 alkenyl. "C 1-10 alkenyl" is to be understood as meaning a straight or branched chain monovalent hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms having at least one carbon-carbon double bond. The alkenyl group is, for example, ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, but-1,3-dienyl, 2-methylbut-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hex-1,3-dienyl. Alkenyl groups can be independently optionally substituted at each occurrence, in some embodiments, "optionally substituted alkenyl" is substituted with 1, 2, 3, 4, or 5 substituents, such as 1-2, 1-3, or 1-4 substituents, selected from the group consisting of the moieties listed herein (see definition of "optionally substituted").

[0120] The term "alkynyl" is to be understood as a straight or branched chain monovalent hydrocarbon group having at least one carbon-carbon triple bond, such as a straight or branched chain monovalent hydrocarbon group comprising 2 to 20 carbon atoms, and having at least one carbon-carbon triple bond (C 2-20 alkynyl), preferably C 1-10 alkynyl. "C 1-10 alkynyl" is to be understood as meaning a straight or branched chain monovalent hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms having at least one carbon-carbon triple bond. The alkenyl group is, for example, ethynyl (-C≡CH), prop-1-ynyl (-C≡CCH3), prop-2-ynyl (propargyl, -CH2C≡CH), but-1-ynyl, but-2-ynyl, and but-3-ynyl. Alkynyl groups can be independently optionally substituted at each occurrence, in some embodiments, "optionally substituted alkynyl" is substituted with 1, 2, 3, 4, or 5 substituents, such as 1-2, 1-3, or 1-4 substituents, selected from the group consisting of the moieties listed herein (see definition of "optionally substituted").

[0121] The term "cycloalkyl" is understood to mean a saturated, monovalent monocyclic or bicyclic hydrocarbon ring which can have, for example, 3 to 20 carbon atoms, preferably "C 3-10 cycloalkyl". The term "C 3-10 cycloalkyl" is understood to mean a saturated, monovalent monocyclic or bicyclic hydrocarbon ring which has 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The C 3-10 cycloalkyl group can be a monocyclic hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as a decalin ring. The cycloalkyl group can be independently in each case optionally substituted, in some embodiments, the "optionally substituted cycloalkyl" is substituted with 1, 2, 3, 4 or 5 substituents, for example 1-2, 1-3 or 1-4 substituents, the substituents being selected from the groups specified herein (see definition of "optionally substituted").

[0122] The term "heterocyclyl" means a saturated or unsaturated, monovalent monocyclic or bicyclic hydrocarbon ring. The heterocyclyl of the present disclosure can be a 3-20 membered heterocyclyl, 3-10 membered heterocyclyl, or 3-6 membered heterocyclyl. The heterocyclyl can contain 1, 2, 3, 4 or 5 heteroatoms independently selected from N, O and S, or contain 1, 2 or 3 heteroatoms independently selected from N, O and S, or contain 1-2 heteroatoms independently selected from N, O and S. The heterocyclyl can be attached to the rest of the molecule through any of the carbon atoms or the nitrogen atom, if present. In particular, the heterocyclyl can include, but is not limited to: 4-membered rings, such as azetidinyl, oxetanyl; 5-membered rings, such as tetrahydrofuranyl, dioxolanyl, pyrrolyl, imidazolyl, pyrazolidinyl, pyrrolinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or 7-membered rings, such as diazepanyl. Optionally, the heterocyclyl can be benzo-fused. The heterocyclyl can be bicyclic, for example, but not limited to, 5,5 membered rings, such as hexahydrocyclopenta[c]pyrrol-2(lH)-yl ring, or 5,6 membered bicyclic rings, such as hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl ring. The ring containing a nitrogen atom can be partially unsaturated, i.e. it can contain one, two or more double bonds, for example, but not limited to, 2,5-dihydro-lH-pyrrolyl, 4H-[l,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[l,4]thiazinyl, or it can be benzo-fused, for example, but not limited to, dihydroisoquinolinyl, l,3-benzoxazolyl, l,3-benzodioxolyl. The heterocyclyl can be independently in each case optionally substituted, in some embodiments, the "optionally substituted heterocyclyl" is substituted with 1, 2, 3, 4 or 5 substituents, for example 1-2, 1-3 or 1-4 substituents. The above substituents can be selected from the groups specified herein (see definition of "optionally substituted").

[0123] The term "aryl" is to be understood to mean a monovalent aromatic, mono-, bi- or tricyclic hydrocarbon ring, for example a monovalent aromatic or partially aromatic mono-, bi- or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, preferably a "C 6-10 aryl". The term "C 6-10 aryl" is to be understood to mean a monovalent aromatic, mono-, bi- or tricyclic hydrocarbon ring having 6, 7, 8, 9, or 10 carbon atoms ("C 6-14 aryl"), in particular a ring having 6 carbon atoms ("C6aryl"), for example a phenyl group; or a biphenyl group, or a ring having 9 carbon atoms ("C 10 aryl"), for example a tetrahydronaphthyl group, a dihydronaphthyl group or a naphthyl group. The aryl group can in each case independently be optionally substituted, in some embodiments, an "optionally substituted aryl" is substituted with 1, 2, 3, 4 or 5 substituents, for example 1-2, 1-3 or 1-4 substituents, the substituents being selected from the groups specified herein (see definition of "optionally substituted").

[0124] The term "heteroaryl" is to be understood as including monovalent monocyclic, bicyclic or tricyclic aromatic ring systems with heteroatoms, e.g. 3- to 20-membered heteroaryl, 3- to 10-membered heteroaryl or 3- to 6-membered heteroaryl. The heteroaryl can contain 1 to 5 heteroatoms independently selected from N, O and S, or 1 to 3 heteroatoms independently selected from N, O and S, or 1 to 2 heteroatoms independently selected from N, O and S. The term "5- to 10-membered heteroaryl" is to be understood as including monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, or 10 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3, heteroatoms each independently selected from N, O and S and, in addition, in each case, can be benzo-fused. In particular, heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like and their benzo derivatives, e.g. benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like and their benzo derivatives, e.g. quinolinyl, quinazolinyl, isoquinolinyl and the like; or azocinyl, indolizinyl, purinyl and the like and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenoxazinyl, phenothiazinyl, phenoxazinyl and the like. The heteroaryl in each case can independently be optionally substituted, in some embodiments, "optionally substituted heteroaryl" is substituted with 1, 2, 3, 4 or 5 substituents, e.g. 1 to 2, 1 to 3 or 1 to 4 substituents, the substituents being selected from the groups specified herein (see definition of "optionally substituted").

[0125] Unless otherwise indicated, heterocyclyl, heteroaryl or heteroarylenyl includes all possible isomeric forms thereof, e.g. positional isomers. Thus, for some illustrative, non-limiting examples, pyridyl or pyridinylene includes pyrid-2-yl, pyrid-2- ylene, pyrid-3-yl, pyrid-3-ylene, pyrid-4-yl and pyrid-4-ylene; thienyl or thienylene includes thien-2-yl, thien-2-ylene, thien-3-yl and thien-3-ylene.

[0126] The above statements regarding the term "alkyl" apply equally to other terms containing "alkyl", e.g. the terms "alkoxy", "alkylthio" and the like.

[0127] The term "alkoxy" is understood to mean -O-alkyl, where alkyl is defined the same as for "alkyl" above. Alkoxy is, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and t-butoxy. Alkoxy can be independently optionally substituted in each occurrence, in some embodiments, "optionally substituted alkoxy" is substituted with 1, 2, 3, 4, or 5 substituents, for example 1-2, 1-3, or 1-4 substituents, the substituents selected from the groups specified herein (see "optionally substituted" definition).

[0128] The two alkyl groups in the term "-N(alkyl)2" can be the same or different.

[0129] Unless otherwise indicated, "optionally substituted" shall mean that the group can be unsubstituted or substituted with one or more (e.g., 0, 1, 2, 3, 4, or 5 or more, or any range derivable therein) substituents listed for that group, wherein the substituents can be the same or different. In one embodiment, an optionally substituted group has 1 substituent. In another embodiment, an optionally substituted group has 2 substituents. In another embodiment, an optionally substituted group has 3 substituents. In another embodiment, an optionally substituted group has 4 substituents. In another embodiment, an optionally substituted group has 5 substituents. "Optionally substituted" means substituted with, for example, F, Cl, Br, I, OH, SH, CN, NH2, NHCH3, N(CH3)2, NO2, N3, C(O)CH3, COOH, CO2CH3, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl, sulfonylamino, methylsulfonylamino, SO, SO2, phenyl, piperidinyl, piperazinyl, and pyrimidinyl, wherein the alkyl, phenyl, and heterocyclic moieties thereof can be optionally substituted with, for example, 1-4 substituents selected from the same list.

[0130] The term "subject" as used herein with respect to an individual refers to an individual having a disease, disorder, or condition, and the like, including mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates (such as chimpanzees and other apes and monkeys); farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-human mammals include, but are not limited to, birds and fish, and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0131] The terms "treatment" and other similar synonymous terms as used herein include alleviating, abating, or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing a cause of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a symptom caused by the disease or condition, or stopping the symptoms of the disease or condition, in addition, the term includes the purpose of preventing. The term also includes obtaining a therapeutic effect and / or prophylactic effect. The therapeutic effect refers to curing or improving the underlying disease being treated. In addition, a cure or improvement in one or more of the physiological symptoms associated with the underlying disease is a therapeutic effect, e.g., the patient observes an improvement in condition even though the patient can still be affected by the underlying disease. In terms of prophylactic effects, the compositions can be administered to a patient at risk of developing a particular disease, or to a patient who exhibits one, two, or more of the physiological symptoms of the disease, even though the patient has not yet been diagnosed with the disease.

[0132] The term "therapeutically effective amount" as used herein refers to the amount of at least one agent or compound that, when administered, is sufficient to alleviate, to some extent, one or more symptoms of the disease or condition being treated. The result can be reduction and / or alleviation of signs, symptoms, or causes of a disease or disorder, or any other desired alteration of a biological

[0133] The terms "administering" and the like, as used herein, refer to the methods by which a compound or composition is delivered to the desired site of biological action. These methods include, but are not limited to, oral routes, transduodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injections or infusion), topical, and rectal administration. Those of skill in the art are aware of suitable techniques for administering the compounds and methods described herein, such as those discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

[0134] The term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no long-term adverse effects on the general health of the subject being treated.

[0135] The term "pharmaceutically acceptable" as used herein means a material, such as a vehicle or diluent, which does not abrogate the biological activity or properties of the compounds of the present application, and is relatively nontoxic, i.e., the material can be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0136] The term "pharmaceutically acceptable salt" as used herein means a salt of a free acid and a free base of the specified compound which retains the biological effectiveness of the free acid and the free base and which is not biologically or otherwise undesirable.

[0137] The term "isotopically-labeled" as used herein means a compound of the present application having one or more atoms replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

[0138] The term "stereoisomers" as used herein means isomers that have the same molecular formula but different structures, resulting from the spatial arrangement of the atoms. Compounds of formula (I) contain asymmetric or chiral centers, and therefore, exist in different stereoisomeric forms. All stereoisomers of the compounds of formula (I), including but not limited to, diastereomeric mixtures, racemic mixtures, their separate enantiomers, and their separate diastereomers, are intended to be covered by the present application. Diastereomeric mixtures can be separated into their individual diastereomers by methods well known in the art, such as chiral-phase chromatography, and the like. The compounds of formula (I) can exist in different tautomeric forms, and the present application encompasses all tautomers. DETAILED DESCRIPTION

[0139] The technical solutions of the present application will be further described in detail below in combination with specific examples. It should be understood that the following examples are only illustratively and explainatively described and should not be interpreted as limiting the scope of protection of the present application. Any technology realized based on the above description of the present application is covered within the scope of the present application.

[0140] The starting materials and reagents used in the following examples are commercially available or can be prepared by known methods, unless otherwise stated.

[0141] The compounds 1a, 1b, etc. mentioned in the following examples refer to the compounds marked with the code in the reaction scheme in the corresponding example.

[0142] Preparation of intermediates

[0143] Intermediate 1 4-chloro-7-methoxyquinolin-6-ol

[0144]

[0145] At room temperature, DL-methionine (23 g) was added to a methanesulfonic acid solution (150 mL) of 4-chloro-6,7-dimethoxyquinoline (15 g). The mixture was heated to 120 ° C under a nitrogen atmosphere and stirred for 5 hours until the reaction was complete. After the reaction was completed, the reaction solution was slowly added dropwise to ice water. The pH value of the resulting mixture was adjusted to 9 with a saturated aqueous sodium carbonate solution. The mixture was extracted three times with ethyl acetate, and the organic phases were combined. The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed. The resulting residue was purified by column chromatography to obtain the title compound (4 g). ESI-MSm / z: 209.9 [M+H] + 。

[0146] Intermediate 2 4-chloro-5,7-difluoro-6-methoxyquinoline

[0147]

[0148] Step 1 Preparation of 5-(((3,5-difluoro-4-methoxyphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0149]

[0150] At room temperature, 3,5-difluoro-4-methoxyaniline (5.0 g) and 5-methoxymethylene-2,2-dimethyl-1,3-dioxane-4,6-dione (6.1 g) were suspended in isopropanol (80 mL). The mixture was heated and stirred at 80°C for 3 hours until the reaction was complete. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filter cake was washed with a small amount of isopropanol and collected. The filter cake was vacuum dried to obtain the title compound (8.5 g). ESI-MS m / z: 314.1 [M+H] + .

[0151] Step 2 Preparation of 5,7-difluoro-6-methoxyquinolin-4(1H)-one

[0152]

[0153] The compound obtained in Step 1 (1.5 g) and diphenyl ether (5 g) were added to a three-necked flask at room temperature. The mixture was heated to 230 °C under nitrogen atmosphere and stirred for 1 hour until the reaction was completed. After the reaction was completed, the mixture was cooled to room temperature and n-hexane was added. The mixture was stirred well and filtered, and the filter cake was washed with a small amount of n-hexane. The filter cake was collected and dried under vacuum to obtain the title compound (0.8 g). ESI-MS m / z: 212.0 [M+H] + .

[0154] Step 3 Preparation of 4-chloro-5,7-difluoro-6-methoxyquinoline

[0155]

[0156] The compound obtained in Step 2 (0.8 g) was added to toluene (10 mL) at room temperature, and phosphorus oxychloride (1.7 g) was added. The mixture was stirred at reflux overnight until the reaction was completed. After the reaction was completed, the solvent was removed, dichloromethane was added to the residue, and the reaction was quenched by adding an aqueous sodium bicarbonate solution. The mixture was stirred well and separated, and the aqueous phase was extracted with dichloromethane three times, and the organic phases were combined. The organic phase 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 the title compound (0.38 g). ESI-MS m / z: 230.0 [M+H] + .

[0157] Intermediate 3 4-chloro-6-fluoro-7-methoxyquinoline

[0158]

[0159] The preparation method was the same as that of Intermediate 2, except that the raw material 3,5-difluoro-4-methoxyaniline was replaced by 4-fluoro-3-methoxyaniline to obtain the title compound. ESI-MS m / z: 211.9 [M+H] + .

[0160] Intermediate 4 4-chloro-5-fluoro-6-methoxyquinoline

[0161]

[0162] The preparation method was the same as that of Intermediate 2, except that the raw material 3,5-difluoro-4-methoxyaniline was replaced by 4-fluoro-3-methoxyaniline to obtain the title compound. ESI-MS m / z: 211.9 [M+H] + .

[0163] Intermediate 5 4-chloro-7-fluoro-5-methoxyquinoline

[0164]

[0165] The preparation method is same as that of intermediate 2, except that the raw material 3, 5-difluoro-4-methoxy aniline is replaced by 3-fluoro-5-methoxy aniline to obtain the title compound. ESI-MS m / z: 211.9 [M+H] + .

[0166] Intermediate 6 4-chloro-6-fluoroquinolin-7-ol

[0167]

[0168] Intermediate 3 (1 g) was dissolved in 1, 2-dichloroethane at room temperature, and boron trifluoride etherate (14 mL, 1 M) was added. The mixture was refluxed under nitrogen overnight until the reaction was complete. After the reaction was completed, the reaction solution was cooled to 0°C, and methanol was added dropwise to quench the reaction. The mixture was concentrated under pressure, and ethyl acetate and water were added to the residue. After stirring well, the pH of the aqueous phase was adjusted to 6 with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted three times 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 the solvent was removed. The residue was purified by column chromatography to obtain the title compound (0.6 g). ESI-MS m / z: 198.0 [M+H] + .

[0169] Intermediate 7 4, 6-dichloro-7-methoxyquinazoline

[0170]

[0171] The preparation method is same as that of intermediate 2, except that the raw material 3, 5-difluoro-4-methoxy aniline is replaced by 4-chloro-3-methoxy aniline to obtain the title compound. ESI-MS m / z: 228.0 [M+H] + .

[0172] Intermediate 8 4-chloro-7-methoxy-6-methylquinoline

[0173]

[0174] The preparation method is same as that of intermediate 2, except that the raw material 3, 5-difluoro-4-methoxy aniline is replaced by 4-methyl-3-methoxy aniline to obtain the title compound. ESI-MS m / z: 208.0 [M+H] + .

[0175] Intermediate A1 2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(1-fluoroethyl)-1,3,4-oxadiazole

[0176]

[0177] Step 1 Preparation of 6-bromo-2-methyl-4-azabenzimidazole

[0178]

[0179] The 2,3-diamino-5-bromopyridine (100 g) was dissolved in acetic acid (1 L) at room temperature. The mixture was heated at 120 °C for 16 hours until the reaction was complete. After the reaction was complete, the solvent was removed. To the residue was added ice water and the pH was adjusted to 7-8 with saturated aqueous sodium bicarbonate solution. After stirring well, the mixture was filtered and the filter cake was washed with water until the filtrate was neutral. The solid was collected and dried under vacuum to give the title compound (107 g). ESI-MS m / z: 211.9 [M+H] + .

[0180] Step 2 Preparation of methyl 2-(6-bromo-2-methyl-lH-imidazo[4,5- b]pyridin-l-yl)acetate

[0181]

[0182] The three-necked flask containing the product from Step 1 (20.0 g) was charged with anhydrous tetrahydrofuran (200 mL) at room temperature and potassium tert-butoxide (11.1 g) was added portionwise with stirring. The mixture was stirred at 50 °C for 1 hour and then methyl 2-bromoacetate (17.4 g) was added dropwise. The mixture was stirred at 50 °C until the reaction was complete. After the reaction was complete, the mixture was cooled to 0 °C and the reaction was quenched by adding a mixture of acetic acid and water to the mixture. Then ethyl acetate and saturated aqueous sodium bicarbonate solution were added. The mixture was stirred well and filtered. The filter cake was washed with a small amount of a mixture of acetic acid and water. The solid was collected and dried under vacuum to give the title compound (14 g). ESI-MS m / z: 284.0 [M+H] + .

[0183] Step 3 Preparation of 2-(6-bromo-2-methyl-lH-imidazo[4,5- b]pyridin-l-yl)acetohydrazide

[0184]

[0185] To a solution of the product obtained in step 2 (15 g) in ethanol / water (300 mL, v / v = 10 / 1) was added hydrazine hydrate (23 mL, 80%) at room temperature. The mixture was stirred at 70 °C for 20 min, and then hydrazine hydrate (23 mL, 80%) was added. The mixture was stirred at 70 °C for 1 h until the reaction was complete. After the reaction was completed, the mixture was cooled to 0 °C and stirred for 1 h before being filtered, and the filter cake was washed with a small amount of cold ethanol. The solid was collected and dried under vacuum to give the title compound (12 g). ESI-MS m / z: 283.7 [M+H] + .

[0186] Step 4: Preparation of 2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(1- fluoroethyl)-1,3,4-oxadiazole

[0187]

[0188] To a solution of the product obtained in step 4 (12 g) in butyl acetate (330 mL) was added 2-fluoropropanoic acid (4.0 g), DIPEA (29 mL), and T3P (50 mL, 50%) at room temperature. The mixture was stirred at 50 °C for 1 h until the substrate was completely reacted. To the mixture was added T3P (25 mL, 50%), and the mixture was refluxed overnight. After the reaction was completed, the mixture was cooled to room temperature and quenched with the addition of aqueous sodium bicarbonate solution and then filtered. The filtrate 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 the solvent was removed. The residue was purified by column chromatography to give the title compound (6.5 g). ESI-MS m / z: 339.8 [M+H] + .

[0189] Intermediate A2 (1-((5-(1-Fluoroethyl)-1,3,4-oxadiazol-2-yl)methyl)-2-methyl-1H- imidazo[4,5-b]pyridin-6-yl)boronic acid

[0190]

[0191] Intermediate Al (1 g) and bis-pinacol diboron (1.1 g) were dissolved in 1,4-dioxane (10 mL) at room temperature, potassium acetate (867 mg) and Pd(dppf)Cl2(215 mg) were added. The mixture was stirred at 100 °C for 2 hours under nitrogen until the reaction was completed. After the reaction was completed, the mixture was cooled to room temperature, and water and dichloromethane were added. After the mixture was stirred well, it was separated, the aqueous phase was extracted with dichloromethane three times, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed. Methyl tert-butyl ether was added to the residue, stirred well, filtered, the filter cake was washed with methyl tert-butyl ether, and the filter cake was dried under vacuum to obtain the title compound (1 g). ESI-MS m / z: 306.1 [M+H] + .

[0192] Intermediate A3 (1-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)boronic acid

[0193]

[0194] The preparation method is the same as that of Intermediate A2, except that 2-fluoropropionic acid in step 4 of Intermediate Al is replaced by cyclopropylcarboxylic acid to prepare the title compound. ESI-MS m / z: 300.1 [M+H] + .

[0195] Intermediate A4 (1-((5-(1,1-difluoroethyl)-1,3,4-oxadiazol-2-yl)methyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)boronic acid

[0196]

[0197] The preparation method is the same as that of Intermediate A2, except that 2-fluoropropionic acid in step 4 of Intermediate Al is replaced by 2,2-difluoropropionic acid to prepare the title compound. ESI-MS m / z: 324.1 [M+H] + .

[0198] Intermediate A5 (1-((5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)methyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)boronic acid

[0199]

[0200] The preparation method is the same as that of Intermediate A2, except that 2-fluoropropionic acid in step 4 of Intermediate Al is replaced by difluoroacetic acid to prepare the title compound. ESI-MS m / z: 310.1 [M+H]+ .

[0201] Intermediate A6 (2-methyl-1-((5-methyl-1, 3, 4-oxadiazol-2-yl)methyl)-1H- imidazo[4, 5-b]pyridin-6-yl)boronic acid

[0202]

[0203] The preparation method is the same as that of Intermediate A2 except that 2-fluoropropionic acid in step 4 of Intermediate A1 is replaced by acetic acid to obtain the title compound. ESI-MS m / z: 274.1 [M+H] + .

[0204] Intermediate A7 (1-((5-ethyl-1, 3, 4-oxadiazol-2-yl)methyl)-2-methyl-1H- imidazo[4, 5-b]pyridin-6-yl)boronic acid

[0205]

[0206] The preparation method is the same as that of Intermediate A2 except that 2-fluoropropionic acid in step 4 of Intermediate A1 is replaced by propionic acid to obtain the title compound. ESI-MS m / z: 288.1 [M+H] + .

[0207] Intermediate A8 (2-methyl-1-((5-(trifluoromethyl)-1, 3, 4-oxadiazol-2-yl)methyl)-1H- imidazo[4, 5-b]pyridin-6-yl)boronic acid

[0208]

[0209] The preparation method is the same as that of Intermediate A2 except that 2-fluoropropionic acid in step 4 of Intermediate A1 is replaced by trifluoroacetic acid to obtain the title compound. ESI-MS m / z: 328.1 [M+H] + .

[0210] Example 1 2-(1-fluoroethyl)-5-((2-methyl-6-(quinolin-4-yl)-1H-imidazo[4, 5-b]pyridin-1- yl)methyl)-1, 3, 4-oxadiazole

[0211]

[0212] Intermediate Al and quinoline-4-boronic acid (71 mg) were added to 1,4-dioxane / water (3 mL, v / v = 3 / 1) containing Pd(dppf)Cl2(17 mg) and K2CO3(57 mg) at room temperature. The mixture was heated to 100 °C after being sufficiently replaced with nitrogen and stirred for 16 hours until the reaction was completed. After the reaction was completed, ethyl acetate and water were added to the mixture, which was stirred well and then separated. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed. The residue was purified by column chromatography to obtain the title compound (8.5 mg). ESI-MS m / z: 389.2 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) d (ppm): 9.21 (d, J = 4.0 Hz, 1H), 8.80-8.76 (m, 2H), 8.19 (s, 1H), 8.12-8.08 (m, 2H), 7.91-7.88 (m, 2H), 5.84-5.72 (m, 1H), 5.70 (s, 2H), 2.97 (s, 3H), 1.86-1.78 (m, 3H).

[0213] Example 2 2-((6-(6,7-dimethoxyquinolin-4-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(1-fluoroethyl)-1,3,4-oxadiazole

[0214]

[0215] Intermediate Al and quinoline-4-boronic acid (71 mg) were added to 1,4-dioxane / water (3 mL, v / v = 3 / 1) containing Pd(dppf)Cl2(17 mg) and K2CO3(57 mg) at room temperature. The mixture was heated to 100 °C after being sufficiently replaced with nitrogen and stirred for 16 hours until the reaction was completed. After the reaction was completed, ethyl acetate and water were added to the mixture, which was stirred well and then separated. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed. The residue was purified by column chromatography to obtain the title compound (8.5 mg). ESI-MS m / z: 389.2 [M+H] + 。 1HNMR (400 MHz, CDC13) δ (ppm): 8.83 (d, J = 4.4 Hz, 1H), 8.76 (s, 1H), 8.24 (s, 1H), 8.08 (s, 1H), 7.60 (d, J = 4.0 Hz, 1H), 7.23 (s, 1H), 5.86-5.67 (m, 3H), 4.14 (s, 3H), 3.92 (s, 3H), 2.93 (s, 3H), 1.85-1.78 (m, 3H).

[0216] Example 3 2-((6-(7-Fluoro-6-methoxyquinolin-4-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1- yl)methyl)-5-(1-fluoroethyl)-1,3,4-oxadiazole

[0217]

[0218] The preparation method is the same as that of Example 2 except that the raw material 4-bromo-6,7-dimethoxyquinoline is replaced by 4-chloro-6-methoxy-7-fluoroquinoline to obtain the title compound. ESI-MS m / z: 437.2 [M+H] + . 1 H NMR (400 MHz, CDC13) δ (ppm): 8.86 (d, J = 4.0 Hz, 1H), 8.60 (d, J = 4.0 Hz, 1H), 8.42 (s, 1H), 8.31 (s, 1H), 7.92 (d, J = 12.0 Hz, 1H), 7.52 (d, J = 4.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 6.03 (s, 2H), 5.93-5.90 (m, 2H), 3.80 (s, 3H), 2.71 (s, 3H), 1.74-1.66 (m, 3H).

[0219] Example 4 2-((4-(1-((5-(1-Fluoroethyl)-1,3,4-oxadiazol-2-yl)methyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-6-methoxyquinolin-7-yl)oxy)ethan-1-ol

[0220]

[0221] Step 1 Preparation of 2-((4-chloro-7-methoxyquinolin-6-yl)oxy)ethan-1-ol

[0222]

[0223] To a solution of intermediate 1 (300 mg) and 2-bromoethanol (268 mg) in DMF (3.0 mL) was added cesium carbonate (932 mg) at room temperature. The mixture was heated to 80 °C under nitrogen atmosphere for 16 hours until the reaction was completed. After the reaction was completed, ethyl acetate and water were added to the mixture, which was stirred well and then separated. The aqueous phase was extracted with ethyl acetate three times, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed. The residue was purified by column chromatography to obtain the title compound (150 mg). ESI-MS m / z: 254.1 [M+H] + 。

[0224] Step 2 Preparation of 2-((4-(1-((5-(1-fluoroethyl)-1,3,4-oxadiazol-2-yl)methyl)-2-methyl-1H- imidazo[4,5-b]pyridin-6-yl)-7-methoxyquinolin-6-yl)oxy)ethan-1-ol

[0225]

[0226] To a solution of intermediate A2 (144 mg) and 2-((4-chloro-7-methoxyquinolin-6-yl)oxy)ethan-1-ol (100 mg) in 1,4-dioxane / water (3.0 mL, v / v = 5 / 1) were added potassium phosphate (167 mg), CataCXium A Pd-G3 (29 mg) respectively at room temperature. The mixture was heated to 100 °C under nitrogen atmosphere for 16 hours until the reaction was completed. After the reaction was completed, ethyl acetate and water were added to the mixture, which was stirred well and then separated. The aqueous phase was extracted with ethyl acetate three times, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed. The residue was purified by column chromatography to obtain the title compound (150 mg). ESI-MS m / z: 479.1 [M+H] + 。 1 HNMR (400 MHz, CDCl3) δ (ppm): 8.71-8.68 (m, 2H), 8.59-8.25 (m, 1H), 7.88-7.87 (br s, 1H), 7.41-7.40 (m, 2H), 5.84-5.71 (m, 3H), 4.25 (s, 2H), 4.07-4.04 (m, 2H), 4.03 (s, 3H), 2.88 (s, 3H), 1.87-1.79 (m, 3H).

[0227] Example 5 2-(1-Fluoroethyl)-5-((6-(6-methoxy-7-((tetrahydrofuran-3-yl)oxy)quinolin-4-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-1,3,4-oxadiazole

[0228]

[0229] Step 1 Preparation of 4-chloro-6-methoxy-7-((tetrahydrofuran-3-yl)oxy)quinoline

[0230]

[0231] DIAD (710 mg) was added dropwise to a solution of intermediate 1 (300 mg) and 3-hydroxytetrahydrofuran (151 mg) and triphenylphosphine (562 mg) in anhydrous tetrahydrofuran (10 mL) at room temperature. The mixture was stirred at room temperature for 16 hours until the reaction was complete. After the reaction was completed, the solvent was removed. The residue was purified by column chromatography to give the title compound (260 mg). ESI-MS m / z: 280.0 [M+H] + .

[0232] Step 2 Preparation of 2-(1-fluoroethyl)-5-((6-(6-methoxy-7-((tetrahydrofuran-3-yl)oxy)quinolin-4-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-1,3,4-oxadiazole

[0233]

[0234] The compound obtained in step 1 (100 mg) and intermediate A2 (141 mg) were dissolved in a mixture of 1,4-dioxane / water (5 mL, v / v = 5 / 1) at room temperature, and CataCXium A Pd-G3 (25 mg) and potassium phosphate (151 mg) were added. The mixture was heated to 80 °C after being sufficiently purged with nitrogen and continuously stirred for 16 hours until the reaction was complete. After the reaction was completed, it was concentrated under reduced pressure, and the residue was purified by column chromatography to give the title compound (9.5 mg). ESI-MS m / z: 504.9 [M+H] + . 1H NMR (400 MHz, CDC13) δ (ppm): 8.77 (d, J = 4.0 Hz, 1H), 8.72 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 1.6 Hz, 1H), 7.56 (s, 1H), 7.28-7.26 (m, 1H), 7.11 (s, 1H), 5.86-5.66 (m, 1H), 5.61 (s, 2H), 5.18 (s, 1H), 4.19-4.15-4.13 (m, 2H), 4.07-3.93 (m, 2H), 3.80 (s, 3H), 2.88 (s, 3H), 2.44-2.29 (m, 2H), 1.80-1.77 (m, 3H).

[0235] Example 6 2-(1-Fluoroethyl)-5-((6-(6-methoxyquinolin-4-yl)-2-methyl-1H- imidazo[4,5-b]pyridin-1-yl)methyl)-1,3,4-oxadiazole

[0236]

[0237] The preparation method is the same as that of Example 2 except that the raw material 4-bromo-6,7-dimethoxyquinoline is replaced by 4-bromo-6-methoxyquinoline to obtain the title compound. ESI-MS m / z: 419.1 [M+H] + . 1 H NMR (400 MHz, CDC13) δ (ppm): 9.03 (d, J = 5.2 Hz, 1H), 8.82 (s, 1H), 8.52 (d, J = 9.6 Hz, 1H), 8.31 (s, 1H), 7.80 (d, J = 5.2 Hz, 1H), 7.70-7.67 (m, 1H), 7.27 (s, 1H), 5.88-5.62 (m, 2H), 5.76 (s, 2H), 3.88 (s, 3H), 2.98 (s, 3H), 1.86-1.79 (m, 3H).

[0238] Example 7 2-(1-Fluoroethyl)-5-((6-(7-methoxyquinolin-4-yl)-2-methyl-1H- imidazo[4,5-b]pyridin-1-yl)methyl)-1,3,4-oxadiazole

[0239]

[0240] The preparation method is the same as that of Example 2 except that the raw material 4-bromo-6,7-dimethoxyquinoline is replaced by 4-bromo-6-methoxyquinoline to obtain the title compound. ESI-MS m / z: 419.1 [M+H] + . 1H NMR (400 MHz, CDC13) δ (ppm): 8.79 (d, J = 4.4 Hz, 1H), 8.71 (d, J = 2.0 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.52 (s, 1H), 7.24 (d, J = 4.4 Hz, 1H), 7.07 (s, 1H), 5.79-5.66 (m, 1H), 5.60 (s, 2H), 4.43 (t, J = 5.6 Hz, 2H), 3.78 (s, 3H), 3.11 (s, 2H), 2.87 (s, 3H), 2.57 (s, 6H), 1.82-1.76 (m, 3H).

[0241] Example 8 2-((4-(1-((5-(1-Fluoroethyl)-1,3,4-oxadiazol-2-yl)methyl)-2-methyl-1H- imidazo[4,5-b]pyridin-6-yl)-6-methoxyquinolin-7-yl)oxy)-N,N-dimethylethan-1-amine

[0242]

[0243] The preparation method is the same as that of Example 5, except that the raw material 3-hydroxytetrahydrofuran is replaced by 2-(dimethylamino)ethanol to prepare the title compound. ESI-MS m / z: 505.9 [M+H] + . 1 H NMR (400 MHz, CDC13) δ (ppm): 8.79 (d, J = 4.4 Hz, 1H), 8.71 (d, J = 2.0 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.52 (s, 1H), 7.24 (d, J = 4.4 Hz, 1H), 7.07 (s, 1H), 5.79-5.66 (m, 1H), 5.60 (s, 2H), 4.43 (t, J = 5.6 Hz, 2H), 3.78 (s, 3H), 3.11 (s, 2H), 2.87 (s, 3H), 2.57 (s, 6H), 1.82-1.76 (m, 3H).

[0244] Example 9 2-(1-Fluoroethyl)-5-((6-(6-methoxy-7-(((S)-tetrahydrofuran-3-yl)oxy)quinolin-4-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-1,3,4-oxadiazole

[0245]

[0246] The preparation method is the same as that of Example 5, except that the raw material 3-hydroxytetrahydrofuran is replaced by (3R)-oxolane-3-ol to prepare the title compound. ESI-MS m / z: 504.9 [M+H] + .1 H NMR (400 MHz, CDC13) δ (ppm): 8.77 (d, J = 4.4 Hz, 1H), 8.71 (d, J = 2.0 Hz, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.50 (s, 1H), 7.25 (d, J = 4.4 Hz, 1H), 7.09 (s, 1H), 5.79-5.68 (m, 1H), 5.61 (s, 2H), 5.17 (s, 1H), 4.14 (dd, J = 8.4, 6.4 Hz, 2H), 4.07-4.04 (m, 1H), 3.96-3.92 (m, 1H), 3.80 (s, 3H), 2.87 (s, 3H), 2.51-2.17 (m, 2H), 1.82-1.76 (m, 3H).

[0247] Example 10 2-(1-Fluoroethyl)-5-((6-(6-methoxy-7-(((R)-1-methylpyrrolidin-3-yl)oxy)quinolin-4-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-1,3,4-oxadiazole

[0248]

[0249] The preparation method is the same as that of Example 5 except that the raw material 3-hydroxytetrahydrofuran is replaced by (3S)-1-methylpyrrolidin-3-ol to prepare the title compound. ESI-MS m / z: 517.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.75 (d, J = 4.4 Hz, 1H), 8.58 (d, J = 2.0 Hz, 1H), 8.39 (d, J = 2.0 Hz, 1H), 7.40 (s, 1H), 7.37 (d, J = 4.4 Hz, 1H), 7.16 (s, 1H), 6.09-5.87 (m, 1H), 6.04 (s, 2H), 5.14 (s, 1H), 3.69 (s, 3H), 3.04-2.77 (m, 3H), 2.70 (s, 3H), 2.47-2.39 (m, 2H), 2.33 (s, 3H), 1.97-1.82 (m, 1H), 1.72-1.66 (m, 3H).

[0250] Example 11 2-(1-Fluoroethyl)-5-((6-(7-methoxy-6-(((R)-1-methylpyrrolidin-3-yl)oxy)quinolin-4-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-1,3,4-oxadiazole

[0251]

[0252] Step 1 Preparation of (R)-4-chloro-7-methoxy-6-((1-methylpyrrolidin-3- yl)oxy)quinoline

[0253]

[0254] DIAD (145 mg) was added dropwise to a solution of 4-chloro-7-methoxyquinolin-6-ol (100 mg), (3S)-1-methylpyrrolidin-3-ol (58 mg) and triphenylphosphine (188 mg) in anhydrous tetrahydrofuran (5 mL) at room temperature. The mixture was stirred at room temperature for 2 hours until the reaction was completed. After the reaction was completed, it was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the title compound (120 mg). ESI-MS m / z: 292.9 [M+H] + .

[0255] Step 2 Preparation of 2-(1-fluoroethyl)-5-((6-(7-methoxy-6-(((R)-1- methylpyrrolidin-3-yl)oxy)quinolin-4-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1- yl)methyl)-1,3,4-oxadiazole

[0256]

[0257] To a solution of the product obtained in Step 1 (120 mg) and Intermediate A2 (138 mg) in a mixture of 1,4-dioxane / water (6 mL, v / v = 5 / 1) was added potassium phosphate (174 mg) and CataCXium A Pd-G3 (30 mg) at room temperature. After the mixture was sufficiently purged with nitrogen, it was continuously stirred at 80°C for 16 hours until the reaction was completed. After the reaction was completed, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by a preparative plate to obtain the title compound (31.2 mg). ESI-MS m / z: 518.1 [M+H] + . 1 HNMR (400 MHz, CDCl3) δ (ppm): 8.82 (d, J = 4.4 Hz, 1H), 8.67 (d, J = 2.0 Hz, 1H), 7.97 (s, 1H), 7.55 (s, 1H), 7.16 (s, 1H), 5.90-5.84 (m, 2H), 5.63 (s, 2H), 5.06 (s, 1H), 4.03 (s, 3H), 3.10 (s, 3H), 2.88 (s, 3H), 2.74 (s, 3H), 2.30-2.22 (m, 3H), 1.84-1.78 (m, 3H).

[0258] Example 12 4-(2-((4-(1-((5-(1-Fluoroethyl)-1,3,4-oxadiazol-2-yl)methyl)-2-methyl-1H- imidazo[4,5-b]pyridin-6-yl)-6-methoxyquinolin-7-yl)oxy)ethyl)morpholine

[0259]

[0260] The preparation method is the same as that of Example 5 except that 2-(morpholin-4- yl)ethanol is used instead of 3-hydroxytetrahydrofuran to obtain the title compound. ESI-MS m / z: 547.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.75 (d, J = 4.4 Hz, 1H), 8.58 (d, J = 2.0 Hz, 1H), 8.39 (d, J = 2.0 Hz, 1H), 7.52 (s, 1H), 7.37 (d, J = 4.4 Hz, 1H), 7.16 (s, 1H), 6.12-5.86 (m, 3H), 4.30 (s, 2H), 3.70 (s, 3H), 3.60 (s, 4H), 2.79 (s, 2H), 2.70 (s, 3H), 2.57-2.51 (m, 4H), 1.74-1.66 (m, 3H).

[0261] Example 13 2-((6-(5,7-Difluoro-6-methoxyquinolin-4-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1- yl)methyl)-5-(1-fluoroethyl)-1,3,4-oxadiazole

[0262]

[0263] The preparation method is the same as that of Example 2 except that intermediate 2 is used instead of 4-bromo-6,7-dimethoxyquinoline to obtain the title compound. ESI-MS m / z: 455.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.95 (d, J = 4.4 Hz, 1H), 8.49 (t, J = 2.0 Hz, 1H), 8.23 (t, J = 2.4 Hz, 1H), 7.90 (dd, J = 11.6, 2.0 Hz, 1H), 7.49 (d, J = 4.4 Hz, 1H), 6.03 (q, J = 6.4 Hz, 1H), 5.97 (s, 2H), 3.95 (s, 3H), 2.69 (s, 3H), 1.69 (dd, J = 24.4, 6.4 Hz, 3H).

[0264] Example 14 2-((6-(6-fluoro-7-methoxyquinolin-4-yl)-2-methyl-1H-imidazo[4,5- b]pyridin-1-yl)methyl)-5-(1-fluoroethyl)-1,3,4-oxadiazole

[0265]

[0266] The preparation method is the same as that of Example 2 except that the raw material 4-bromo-6,7-dimethoxyquinoline is replaced by intermediate 3 to obtain the title compound. ESI-MS m / z: 437.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d (ppm): 8.91 (d, J = 4.0 Hz, 1H), 8.53 (s, 1H), 8.31 (d, J = 4.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 12.0 Hz, 1H), 7.47 (d, J = 4.0 Hz, 1H), 6.05-6.00 (m, 2H), 5.93-5.88 (m, 1H), 4.05 (s, 3H), 2.71 (s, 3H), 1.73-1.65 (m, 3H).

[0267] Example 15 2-((4-(1-((5-(1-fluoroethyl)-1,3,4-oxadiazol-2-yl)methyl)-2-methyl-1H- imidazo[4,5-b]pyridin-6-yl)-7-methoxyquinolin-6-yl)oxy)ethan-1-ol

[0268]

[0269] Step 1 Preparation of 2-((4-chloro-7-methoxyquinolin-6-yl)oxy)ethan-1-ol

[0270]

[0271] To a solution of intermediate 1 (300 mg) and 2-bromoethanol (268 mg) in DMF (3.0 mL) was added cesium carbonate (932 mg) at room temperature. The mixture was stirred at 80 °C for 16 hours until the reaction was completed. After the reaction was completed, water and ethyl acetate were added to the mixture, which was stirred well and then separated. The aqueous phase was extracted with ethyl acetate three times, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed. The residue was purified by column chromatography to obtain the title compound (150 mg). ESI-MS m / z: 254.1 [M+H] + .

[0272] Step 2 Preparation of 2-((4-(l-((5-(l-fluoroethyl)-l,3,4-oxadiazol-2-yl)methyl)-2- methyl-lH-imidazo[4,5-b]pyridin-6-yl)-7-methoxyquinolin-6-yl)oxy)ethan-l-ol

[0273]

[0274] The compound (100 mg) obtained in Step 1 and Intermediate A2 (144 mg) were dissolved in a mixed solution of 1,4-dioxane / water (3 mL, v / v = 5 / 1) at room temperature, and CataCXium A Pd-G3 (29 mg) and potassium phosphate (167 mg) were added. After the mixture was sufficiently purged with nitrogen, it was continuously stirred at 80 °C until the reaction was completed. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by reverse phase chromatography to obtain the title compound (2.8 mg). ESI-MS m / z: 479.1 [M+H] + . 1 HNMR (400MHz, CDC13) δ (ppm): 8.71-8.68 (m, 2H), 7.88-7.87 (m, 1H), 7.41-7.40 (m, 2H), 5.84-5.71 (m, 3H), 4.25 (s, 2H), 4.07-4.04 (m, 2H), 4.03 (s, 3H), 2.88 (s, 3H), 1.87-1.79 (m, 3H).

[0275] Example 16 2-((6-(5-Fluoro-6-methoxyquinolin-4-yl)-2-methyl-lH-imidazo[4,5-b]pyridin-l- yl)methyl)-5-(l-fluoroethyl)-l,3,4-oxadiazole

[0276]

[0277] The preparation method was the same as that of Example 2, except that the raw material 4-bromo-6,7-dimethoxyquinoline was replaced by Intermediate 4 to obtain the title compound. ESI-MS m / z: 436.9 [M+H] + .1H NMR (400MHz, CDC13) δ (ppm): 8.87 (d, J = 4.4 Hz, 1H), 8.70 (s, 1H), 7.97 (s, 1H), 7.93 (d, J = 11.6 Hz, 1H), 7.37 (d, J = 4.4 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 5.82-5.67 (m, 1H), 5.62 (s, 2H), 3.85 (s, 3H), 2.88 (s, 3H), 1.85-1.77 (m, 3H).

[0278] Example 17 2-((6-(7-(2,2-difluoroethoxy)-6-methoxyquinolin-4-yl)-2-methyl-1H- imidazo[4,5-b]pyridin-1-yl)methyl)-5-(1-fluoroethyl)-1,3,4-oxadiazole

[0279]

[0280] The preparation method is the same as that of Example 4, except that the raw material 2-bromoethanol is replaced by 1,1-difluoro-2-iodoethane, to obtain the title compound. ESI-MS m / z: 499.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.79 (d, J = 4.4 Hz, 1H), 8.70 (d, J = 2.0 Hz, 1H), 7.96 (s, 1H), 7.63 (s, 1H), 7.31 (d, J = 4.0 Hz, 1H), 7.12 (s, 1H), 6.43-6.07 (m, 1H), 5.88-5.65 (m, 1H), 5.61 (s, 2H), 4.44-4.38 (m, 2H), 3.81 (s, 3H), 2.88 (s, 3H), 1.82-1.75 (m, 3H).

[0281] Example 18 2-(1-fluoroethyl)-5-((6-(6-methoxy-7-(2,2,2-trifluoroethoxy)quinolin-4-yl)- 2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-1,3,4-oxadiazole

[0282]

[0283] The preparation method is the same as that of Example 4, except that the raw material 2-bromoethanol is replaced by 1,1,1-trifluoro-2-iodoethane, to obtain the title compound. ESI-MS m / z: 517.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.79 (d, J = 4.4 Hz, 1H), 8.70 (d, J = 2.0 Hz, 1H), 7.96 (s, 1H), 7.63 (s, 1H), 7.31 (d, J = 4.0 Hz, 1H), 7.12 (s, 1H), 6.43-6.07 (m, 1H), 5.88-5.65 (m, 1H), 5.61 (s, 2H), 4.44-4.38 (m, 2H), 3.81 (s, 3H), 2.88 (s, 3H), 1.82-1.75 (m, 3H).

[0284] Example 19 2-((6-(7-fluoro-5-methoxyquinolin-4-yl)-2-methyl-1H-imidazo[4,5- b]pyridin-1-yl)methyl)-5-(1-fluoroethyl)-1,3,4-oxadiazole

[0285]

[0286] The preparation method is the same as that of Example 2 except that the raw material 4-bromo-6,7-dimethoxyquinoline is replaced by intermediate 5 to obtain the title compound. ESI-MS m / z: 437.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) d (ppm): 8.90 (d, J = 4.4 Hz, 1H), 8.50 (s, 1H), 7.74 (s, 1H), 7.59-7.56 (m, 1H), 7.22 (s, 1H), 6.70-6.67 (m, 1H), 5.81-5.66 (m, 1H), 5.58-5.56 (m, 2H), 3.47 (s, 3H), 2.86 (s, 3H), 1.84-1.76 (m, 3H).

[0287] Example 20 1-((4-(1-((5-(1-fluoroethyl)-1,3,4-oxadiazol-2-yl)methyl)-2-methyl-1H- imidazo[4,5-b]pyridin-6-yl)-6-methoxyquinolin-7-yl)oxy)-2-methylpropan-2-ol

[0288]

[0289] Step 1 Preparation of 1-((4-chloro-6-methoxyquinolin-7-yl)oxy)-2-methyl-2- propanol

[0290]

[0291] To a solution of 4-chloro-6-methoxyquinolin-7-ol (50 mg) in DMF (3.0 mL) was added 2,2-dimethyloxirane (344 mg) and cesium carbonate (155 mg) at room temperature. The above mixture was continuously stirred at 80 °C for 16 hours until the reaction was completed. After the reaction was completed, the solvent was removed, and the residue was purified by column chromatography to obtain the title compound (55 mg). ESI-MS m / z: 282.0 [M+H] + .

[0292] Step 2 Preparation of 1-((4-(1-((5-(1-fluoroethyl)-1,3,4-oxadiazol-2-yl)methyl)-2- methyl-1H-imidazo[4,5-b]pyridin-6-yl)-6-methoxyquinolin-7-yl)oxy)-2-methylpropan-2- ol

[0293]

[0294] The compound (55 mg) obtained in Step 1 and intermediate A2 (76 mg) were dissolved in a mixed solution of 1,4-dioxane / water (6.0 mL, v / v = 5 / 1) at room temperature and potassium phosphate (83 mg) and CataCXium A Pd-G3 (14 mg) were added. After the mixture was sufficiently purged with nitrogen, it was continuously stirred at 80 °C for 16 hours until the reaction was completed. After the reaction was completed, it was filtered and the filtrate was concentrated. The residue was purified by column chromatography to obtain the title compound (20.7 mg). ESI-MS m / z: 507.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) d (ppm): 8.77-8.75 (m, 1H), 8.71-8.70 (m, 1H), 7.96 (s, 1H), 7.59 (s, 1H), 7.27 (s, 1H), 7.08 (s, 1H), 5.80-5.67 (m, 1H), 5.61 (s, 2H), 4.02 (s, 2H), 3.79 (s, 3H), 2.87 (s, 3H), 1.84-1.75 (m, 3H), 1.40 (s, 6H).

[0295] Example 21 2-(1-Fluoroethyl)-5-((6-(6-methoxy-7-(oxetan-3-yloxy)quinolin-4-yl)-2-methyl- 1H-imidazo[4,5-b]pyridin-1-yl)methyl)-1,3,4-oxadiazole

[0296]

[0297] The preparation method was the same as that of Example 4, except that the raw material 2-bromoethanol was replaced by 3-iodooxetane to obtain the title compound. ESI-MS m / z: 491.0 [M+H] + . 1H NMR (400 MHz, CDCI3) δ (ppm): 8.77 (d, J = 4.8 Hz, 1 H), 8.71 (s, 1 H), 7.98 (s, 1 H), 7.38 (s, 2 H), 7.18 (s, 1 H), 5.82-5.70 (m, 1 H), 5.67 (s, 2 H), 5.49-5.46 (m, 1 H), 5.14 (t, J = 6.8 Hz, 2 H), 4.92-4.89 (m, 2 H), 3.87 (s, 3 H), 2.89 (s, 3 H), 1.85-1.77 (m, 3 H).

[0298] Example 22 2-(1-Fluoroethyl)-5-((6-(6-methoxy-7-((tetrahydro-2H-pyran-4-yl)oxy)quinolin-4-yl)-2-methyl-1 H-imidazo[4,5-b]pyridin-1 -yl)methyl)-1,3,4-oxadiazole

[0299]

[0300] The preparation method is the same as that of Example 5 except that 3-hydroxytetrahydrofuran is replaced by tetrahydropyran-4-ol to obtain the title compound. ESI-MS m / z: 519.0 [M+H] + . 1 H NMR (400 MHz, CDCI3) δ (ppm): 8.74-8.72 (m, 2 H), 7.96 (s, 1 H), 7.32 (s, 1 H), 7.26 (s, 1 H), 7.13 (s, 1 H), 5.81-5.67 (m, 1 H), 5.60 (s, 2 H), 4.80 (s, 1 H), 4.04-4.03 (m, 2 H), 3.82 (s, 3 H), 3.63-3.61 (m, 2 H), 2.88 (s, 3 H), 2.21-2.19 (m, 2 H), 1.95-1.93 (m, 2 H), 1.84-1.76 (m, 3 H).

[0301] Example 23 2-Cyclopropyl-5-((6-(6-fluoro-7-methoxyquinolin-4-yl)-2-methyl-1 H-imidazo[4,5-b]pyridin-1 -yl)methyl)-1,3,4-oxadiazole

[0302]

[0303] The preparation method is the same as that of Example 14 except that intermediate A2 is replaced by intermediate A3 to obtain the title compound. ESI-MS m / z: 431.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) d (ppm): 8.91 (d, J = 4.4 Hz, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.29 (d, J = 2.0 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 12.8 Hz, 1H), 7.47 (d, J = 4.4 Hz, 1H), 5.91 (s, 2H), 4.06 (s, 3H), 2.70 (s, 3H), 2.23-2.16 (m, 1H), 1.13-1.08 (m, 2H), 0.97-0.93 (m, 2H).

[0304] Example 24 2-(1,1-difluoroethyl)-5-((6-(6-fluoro-7-methoxyquinolin-4-yl)-2-methyl-1H- imidazo[4,5-b]pyridin-1-yl)methyl)-1,3,4-oxadiazole

[0305]

[0306] The preparation method is the same as that of Example 14, except that intermediate A2 is replaced by intermediate A4 to prepare the title compound. ESI-MS m / z: 455.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d (ppm): 8.91 (d, J = 4.4 Hz, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.29 (d, J = 2.0 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 12.4 Hz, 1H), 7.47 (d, J = 4.4 Hz, 1H), 6.06 (s, 2H), 4.05 (s, 3H), 2.71 (s, 3H), 2.13 (t, J = 19.6 Hz, 3H).

[0307] Example 25 2-(difluoromethyl)-5-(((6-(6-fluoro-7-methoxyquinolin-4-yl)-2-methyl-1H- imidazo[4,5-b]pyridin-1-yl)methyl)-1,3,4-oxadiazole

[0308]

[0309] The preparation method is the same as that of Example 14, except that intermediate A2 is replaced by intermediate A5 to prepare the title compound. ESI-MS m / z: 441.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) d (ppm): 8.91 (d, J = 4.4 Hz, 1H), 8.54 (d, J = 2.0 Hz, 1H), 8.32 (d, J = 2.0 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.61-7.58 (m, 1H), 7.47-7.45 (m, 1H), 6.08 (s, 2H), 4.05 (s, 3H), 2.71 (s, 3H).

[0310] Example 26 2-((6-(6-fluoro-7-methoxyquinolin-4-yl)-2-methyl-1H-imidazo[4,5- b]pyridin-1-yl)methyl)-5-methyl-1,3,4-oxadiazole

[0311]

[0312] The preparation method is the same as that of Example 14 except that intermediate A2 is replaced by intermediate A6 to prepare the title compound. ESI-MS m / z: 405.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d (ppm): 8.91 (d, J = 4.4 Hz, 1H), 8.54 (d, J = 2.0 Hz, 1H), 8.32 (d, J = 2.0 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.61-7.58 (m, 1H), 7.47-7.45 (m, 1H), 6.08 (s, 2H), 4.05 (s, 3H), 2.71 (s, 3H).

[0313] Example 27 2-ethyl-5-((6-(6-fluoro-7-methoxyquinolin-4-yl)-2-methyl-1H-imidazo[4,5- b]pyridin-1-yl)methyl)-1,3,4-oxadiazole

[0314]

[0315] The preparation method is the same as that of Example 14 except that intermediate A2 is replaced by intermediate A7 to prepare the title compound. ESI-MS m / z: 419.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) d (ppm): 8.91 (d, J = 4.4 Hz, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 12.8 Hz, 1H), 7.47 (d, J = 3.6 Hz, 1H), 5.94 (s, 2H), 4.05 (s, 3H), 2.85 - 2.79 (m, 2H), 2.70 (s, 3H), 1.23 - 1.19 (m, 3H).

[0316] Example 28 2-((6-(6-fluoro-7-methoxyquinolin-4-yl)-2-methyl-1H-imidazo[4,5- b]pyridin-1-yl)methyl)-5-(trifluoromethyl)-1,3,4-oxadiazole

[0317]

[0318] The preparation method is the same as that of Example 14 except that intermediate A2 is replaced by intermediate A8 to prepare the title compound. ESI-MS m / z: 459.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d (ppm): 8.90 (d, J = 4.4 Hz, 1H), 8.54 (d, J = 2.0 Hz, 1H), 8.31 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 12.4 Hz, 1H), 7.46 (d, J = 4.4 Hz, 1H), 6.08 (s, 2H), 4.05 (s, 3H), 2.72 (s, 3H).

[0319] Example 29 2-((6-(6-fluoro-7-(2-(pyrrolidin-1-yl)ethoxy)quinolin-4-yl)-2-methyl-1H- imidazo[4,5-b]pyridin-1-yl)methyl)-5-(1-fluoroethyl)-1,3,4-oxadiazole

[0320]

[0321] The preparation method is the same as that of Example 5 except that 3-hydroxytetrahydrofuran in Example 5 step 1 is replaced by N-(2-hydroxyethyl)-pyrrolidine and intermediate 1 is replaced by intermediate 6 to prepare the title compound. ESI-MS m / z: 520.2 [M+H] + . 1 H NMR (400 MHz, DMSO- d6)δ(ppm):8.90(d,J=4.0Hz,1H),8.53(s,1H),8.31(d,J=4.0Hz,1H),7.74(d,J=8.0Hz,1H),7.60(d,J=12.0Hz,1H),7.46(d,J=4.0 Hz,1H),6.05-6.00(m,2H),5.93-5.88(m,1H),4.39-4.36(m,2H),2.94-2.92(m,2H),2.71(s,3H),2.59(s,4H),1.73-1.67(m,6H).

[0322] Example 30 4-(2-((6-fluoro-4-(1-((5-(1-fluoroethyl)-1,3,4-oxadiazol-2-yl)methyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)quinolin-7-yl)oxy)ethyl)morpholine

[0323]

[0324] The preparation method is the same as that of Example 29, except that the starting material N-(2-hydroxyethyl)-pyrrolidine is replaced with N-(2-hydroxyethyl)-morpholine to obtain the title compound. ESI-MS m / z: 536.2 [M+H] + . 1 H NMR (400 MHz, DMSO- d6 )δ(ppm):8.90(d,J=4.0Hz,1H),8.53(s,1H),8.30(s,1H),7.76(d,J=12.0Hz,1H),7.60(d,J=12.0Hz,1H),7.46(d,J=4.0Hz,1H) ,6.05-6.00(m,2H),5.93-5.88(m,1H),4.41-4.38(m,2H),3.60-3.54(m,6H),2.83-2.80(m,2H),2.71(s,3H),1.73-1.65(m,3H).

[0325] Example 31 2-(1-fluoroethyl)-5-((6-(6-methoxy-7-(oxetan-3-ylmethoxy)quinolin-4-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-1,3,4-oxadiazole

[0326]

[0327] The preparation method is the same as that of Example 5, except that the raw material 3-hydroxytetrahydrofuran is replaced by oxetan-3-ylmethanol, to obtain the title compound. ESI-MS m / z: 505.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.77 (d, J = 4.0 Hz, 1H), 8.71 (s, 1H), 7.96 (s, 1H), 7.29 (s, 1H), 7.11 (s, 1H), 5.80-5.67 (m, 1H), 5.60 (s, 2H), 4.93-4.91 (m, 2H), 4.62-4.60 (m, 2H), 4.49 (d, J = 8.0 Hz, 2H), 3.80 (s, 3H), 3.63-3.59 (m, 1H), 2.87 (s, 3H), 1.83-1.76 (m, 3H).

[0328] Example 32 2-(1-Fluoroethyl)-5-((6-(6-methoxy-7-((1-methylpiperidin-4-yl)oxy)quinolin-4-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-1,3,4-oxadiazole

[0329]

[0330] The preparation method is the same as that of Example 5, except that the raw material 3-hydroxytetrahydrofuran is replaced by 1-methyl-4-piperidinol, to obtain the title compound. ESI-MS m / z: 532.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.78 (d, J = 4.0 Hz, 1H), 8.70 (s, 1H), 7.91 (s, 1H), 7.53 (s, 1H), 7.24 (s, 1H), 7.09 (s, 1H), 5.80-5.67 (s, 1H), 5.58 (s, 2H), 4.79 (s, 1H), 3.77 (s, 3H), 3.13-3.10 (m, 2H), 3.03 (s, 2H), 2.87 (s, 3H), 2.65 (s, 3H), 2.41-2.39 (m, 2H), 2.24-2.20 (m, 2H), 1.82-1.76 (m, 3H).

[0331] Example 33 2-((6-(7-Ethoxy-6-methoxyquinolin-4-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(1-fluoroethyl)-1,3,4-oxadiazole

[0332]

[0333] The preparation method is same as that of Example 4 except that the raw material 2-bromoethanol is replaced by iodoethane to make the title compound. ESI-MS m / z: 463.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.85 (s, 1H), 8.80 (s, 1H), 8.27 (s, 1H), 7.91 (s, 1H), 7.63 (s, 1H), 7.22 (s, 1H), 5.83-5.70 (m, 4H), 4.40-4.34 (m, 2H), 3.91 (s, 3H), 2.97 (s, 3H), 1.85-1.77 (m, 3H), 1.61-1.57 (m, 3H).

[0334] Example 34 4-(1-((5-(1-Fluoroethyl)-1,3,4-oxadiazol-2-yl)methyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-7-methoxyquinoline-6-carbonitrile

[0335]

[0336] The preparation method is same as that of Example 2 except that the raw material 4-bromo-6,7-dimethoxyquinoline is replaced by 4-chloro-7-methoxyquinoline-6-carbonitrile to make the title compound. ESI-MS m / z: 444.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ (ppm): 9.11 (d, J = 4.0 Hz, 1H), 8.70 (s, 1H), 8.21 (s, 1H), 8.04 (s, 1H), 7.60 (d, J = 4.0 Hz, 1H), 5.84-5.72 (m, 1H), 5.69 (s, 2H), 4.18 (s, 3H), 2.96 (s, 3H), 2.34 (s, 3H), 1.84-1.78 (m, 3H).

[0337] Example 35 2-((6-(6-Cyclopropyl-7-methoxyquinolin-4-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(1-fluoroethyl)-1,3,4-oxadiazole

[0338]

[0339] Step 1 Preparation of 4-chloro-6-cyclopropyl-7-methoxyquinoline

[0340]

[0341] Step 1 Preparation of 6-bromo-4-chloro-7-methoxyquinoline + .

[0342] Step 2 Preparation of 2-((6-(6-cyclopropyl-7-methoxyquinolin-4-yl)-2-methyl-1H- imidazo[4,5-b]pyridin-1-yl)methyl)-5-(1-fluoroethyl)-1,3,4-oxadiazole

[0343]

[0344] Step 1 Preparation of 6-bromo-4-chloro-7-methoxyquinoline + . 1 HNMR (400 MHz, CDC13) δ (ppm): 8.83 (d, J = 4.0 Hz, 1H), 8.66 (s, 1H), 7.93-7.90 (m, 2H), 7.41-7.37 (m, 2H), 5.81-5.67 (m, 1H), 5.62 (s, 2H), 4.11 (s, 3H), 2.89 (s, 3H), 2.25-2.23 (m, 1H), 1.82-1.75 (m, 3H), 1.00-0.97 (m, 2H), 0.61-0.57 (m, 2H).

[0345] Example 36 2-((4-(1-((5-(1-fluoroethyl)-1,3,4-oxadiazol-2-yl)methyl)-2-methyl-1H- imidazo[4,5-b]pyridin-6-yl)quinolin-7-yl)(methyl)amino)ethan-1-ol

[0346]

[0347] Step 1 Preparation of 2-((4-chloroquinolin-7-yl)(methyl)amino)ethan-1-ol

[0348]

[0349] To a solution of 7-bromo-4-chloroquinoline (500 mg) and 2-(methylamino)ethan-1-ol (230 mg) in dioxane (5 mL) was added RuPhos (192 mg), Pd2(dba)3(94 mg) and cesium carbonate (2 g) at room temperature. The mixture was heated to 80 °C after purging with nitrogen and stirred overnight until the reaction was completed. After the reaction was completed, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give the target product (160 mg). ESI-MS m / z: 237.1 [M+H] + .

[0350] Step 2 Preparation of 2-((4-(1-((5-(1-fluoroethyl)-1,3,4-oxadiazol-2-yl)methyl)-2-methyl-1H- imidazo[4,5-b]pyridin-6-yl)quinolin-7-yl)(methyl)amino)ethan-1-ol

[0351]

[0352] To a solution of the compound obtained in Step 1 (80 mg) and Intermediate A2 (104 mg) in a mixture of 1,4-dioxane / water (6 mL, v / v = 5 / 1) was added potassium phosphate (195 mg) and CataCXium A Pd-G3 (20 mg) at room temperature. The mixture was heated to 80 °C after purging with nitrogen and stirred for 16 hours until the reaction was completed. After the reaction was completed, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative plate to give the title compound (14.3 mg). ESI-MS m / z: 462.0 [M+H] + . 1 HNMR (400 MHz, CDC13) δ (ppm): 8.75 (d, J = 8.0 Hz, 1H), 8.67 (s, 1H), 8.41 (s, 1H), 7.98 (d, J = 12 Hz, 1H), 7.62-7.60 (m, 1H), 7.55-7.53 (m, 1H), 7.09 (s, 1H), 6.01 (s, 2H), 5.93-5.79 (m, 1H), 3.87-3.79 (m, 4H), 3.31 (s, 3H), 2.86 (s, 3H), 1.82-1.75 (m, 3H).

[0353] Example 37 2-((6-(7-(difluoromethoxy)-6-methoxyquinolin-4-yl)-2-methyl-1H- imidazo[4,5-b]pyridin-1-yl)methyl)-5-(1-fluoroethyl)-1,3,4-oxadiazole

[0354]

[0355] Step 1 Preparation of 4-chloro-7-difluoromethoxy-6-methoxyquinolin-7-ol

[0356]

[0357] The compound (56 mg) obtained in Step 1 and Intermediate A2 (84 mg) were dissolved in a mixture of 1,4-dioxane / water (6 mL, v / v = 5 / 1) at room temperature, and potassium phosphate (99 mg) and CataCXium A Pd-G3 (16 mg) were added. The mixture was heated to 80 °C after being sufficiently purged with nitrogen and continuously stirred for 16 hours until the reaction was completed. After the reaction was completed, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative plate to obtain the title compound (7.8 mg). ESI-MS m / z: 485.0 [M+H] + .

[0358] Step 2 2-((6-(7-(difluoromethoxy)-6-methoxyquinolin-4-yl)-2-methyl-1H-imidazo[4,5- b]pyridin-1-yl)methyl)-5-(1-fluoroethyl)-1,3,4-oxadiazole

[0359]

[0360] The compound (56 mg) obtained in Step 1 and Intermediate A2 (84 mg) were dissolved in a mixture of 1,4-dioxane / water (6 mL, v / v = 5 / 1) at room temperature, and potassium phosphate (99 mg) and CataCXium A Pd-G3 (16 mg) were added. The mixture was heated to 80 °C after being sufficiently purged with nitrogen and continuously stirred for 16 hours until the reaction was completed. After the reaction was completed, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative plate to obtain the title compound (7.8 mg). ESI-MS m / z: 485.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) d (ppm): 8.87 (d, J = 4.4 Hz, 1H), 8.70 (s, 1H), 7.96 (s, 2H), 7.37 (d, J = 4.4 Hz, 1H), 7.20 (s, 1H), 6.76 (t, J = 73.6 Hz, 1H), 5.80-5.66 (m, 1H), 5.61 (s, 2H), 3.83 (s, 3H), 2.88 (s, 3H), 1.84-1.77 (m, 3H).

[0361] Example 38 2-((6-fluoro-4-(1-((5-(1-fluoroethyl)-1,3,4-oxadiazol-2-yl)methyl)-2-methyl-1H- imidazo[4,5-b]pyridin-6-yl)quinolin-7-yl)oxy)ethan-1-ol

[0362]

[0363] The preparation method is the same as that of Example 4, except that the raw material intermediate 1 is replaced by intermediate 3, to obtain the title compound. ESI-MS m / z: 467.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.86 (d, J = 4.0 Hz, 1H), 8.62 (s, 1H), 7.60 (s, 1H), 7.32-7.30 (m, 1H), 7.29 (d, J = 4.0 Hz, 1H), 5.82-5.65 (m, 1H), 5.61 (s, 2H), 4.34-4.31 (m, 2H), 4.11-4.09 (m, 2H), 2.87 (s, 3H), 1.82-1.75 (m, 3H).

[0364] Example 39 2-((4-(1-((5-(1-fluoroethyl)-1,3,4-oxadiazol-2-yl)methyl)-2-methyl-1H- imidazo[4,5-b]pyridin-6-yl)quinolin-7-yl)oxy)ethan-1-ol

[0365]

[0366] The preparation method is the same as that of Example 4, except that the raw material intermediate 1 is replaced by 4-chloro-7-hydroxyquinoline, to obtain the title compound. ESI-MS m / z: 449.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.90 (d, J = 4.0 Hz, 1H), 8.67 (s, 1H), 7.94 (s, 1H), 7.79-7.77 (d, J = 8.0 Hz, 1H), 7.64 (s, 1H), 7.32-7.30 (d, J = 4.0 Hz, 1H), 7.24 (s, 1H), 5.80-5.67 (m, 1H), 5.62 (s, 2H), 4.32-4.30 (m, 2H), 4.09-4.07 (m, 2H), 2.88 (s, 3H), 1.84-1.77 (m, 3H).

[0367] Example 40 2-((6-(6-fluoro-7-methoxy-3-methylquinolin-4-yl)-2-methyl-1H- imidazo[4,5-b]pyridin-1-yl)methyl)-5-(1-fluoroethyl)-1,3,4-oxadiazole

[0368]

[0369] Step 1 Preparation of (Z)-diethyl 2-((4-fluoro-3-methoxyphenyl)imino)-3- methylbutanedioate

[0370]

[0371] At room temperature, 3-methoxy-4-fluoroaniline (1 g) was dissolved in toluene (20 mL), diethyl 2-methyl-3-oxosuccinate (1.5 g) and p-toluenesulfonic acid (120 mg) were added. The mixture was stirred at reflux overnight until the reaction was complete. After the reaction was completed, the solvent was removed, and ethyl acetate and saturated aqueous sodium bicarbonate were added to the residue, which was stirred well and then separated. The aqueous phase was extracted with ethyl acetate three times, and the organic phase was combined. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed to obtain the title compound (2.2 g). ESI-MS m / z: 326.1 [M+H] + .

[0372] Step 2 Preparation of ethyl 6-fluoro-4-hydroxy-7-methoxy-3-methylquinoline-2- carboxylate

[0373]

[0374] At room temperature, the compound obtained in Step 1 (2.1 g) and diphenyl ether (10 g) were added to a reaction flask. The mixture was stirred at 230°C for 1 hour until the reaction was complete. After the reaction was completed, the reaction liquid was cooled to room temperature and n-hexane was added. The mixture was filtered after stirring well, and the filter cake was washed with a small amount of n-hexane. The solid was collected and dried under vacuum to obtain the title compound (1.5 g). ESI-MS m / z: 280.1 [M+H] + .

[0375] Step 3 Preparation of 6-fluoro-4-hydroxy-7-methoxy-3-methylquinoline-2- carboxylic acid

[0376]

[0377] The compound obtained in Step 2 (1.5 g) was dissolved in tetrahydrofuran (30 mL) at room temperature, and an aqueous sodium hydroxide solution (5 mL, 15%) was added. The mixture was stirred at room temperature overnight until the reaction was complete. After the reaction was completed, the reaction was quenched with an aqueous hydrochloric acid solution (6 M), and the pH of the mixture was adjusted to 4. The mixture was extracted with ethyl acetate three times, and the organic phase was combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed to obtain the title compound (1.4 g) as a crude product.

[0378] Step 4 Preparation of 6-fluoro-7-methoxy-3-methylquinolin-4-ol

[0379]

[0380] The compound obtained in Step 3 (300 mg) and diphenyl ether (3 g) were added to a reaction flask at room temperature. The mixture was stirred at 230°C for 1 hour until the reaction was complete. After the reaction was completed, the reaction solution was cooled to room temperature and n-hexane was added. The mixture was filtered after being sufficiently stirred, and the filter cake was washed with a small amount of n-hexane. The solid was collected and dried under vacuum to obtain the title compound (90 mg). ESI-MS m / z: 208.1 [M+H] + .

[0381] Step 5 Preparation of 4-chloro-6-fluoro-7-methoxy-3-methylquinoline

[0382]

[0383] The compound obtained in Step 4 (90 mg) was dissolved in acetonitrile (5 mL) at room temperature, and phosphorus oxychloride (200 mg) was added. The mixture was refluxed overnight under nitrogen protection until the reaction was complete. After the reaction was complete, the solvent was removed, and ethyl acetate was added to the residue, and the pH of the mixture was adjusted to 8 with a saturated aqueous sodium bicarbonate solution. The mixture was sufficiently stirred and then separated into water and organic phases, and the organic phase was extracted with ethyl acetate three times and the organic phases were combined. The organic phase 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 the title compound (57 mg). ESI-MS m / z: 226.0 [M+H] + .

[0384] Step 6 Preparation of 2-((6-(6-fluoro-7-methoxy-3-methylquinolin-4-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(1-fluoroethyl)-1,3,4-oxadiazole

[0385]

[0386] The compound (57 mg) obtained in Step 1 and intermediate A2 (85 mg) were dissolved in a mixture of 1,4-dioxane / water (6 mL, v / v = 5 / 1) at room temperature, potassium phosphate (102 mg) and CataCXium A Pd-G3 (17 mg) were added. After the mixture was sufficiently purged with nitrogen, it was heated to 80°C and stirred for 16 hours until the reaction was completed. After the reaction was completed, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative plate to obtain the title compound (29.5 mg). ESI-MS m / z: 451.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.78 (s, 1H), 8.43 (s, 1H), 7.71 (s, 2H), 7.02-7.69 (m, 1H), 5.79-5.65 (m, 1H), 5.58 (s, 2H), 4.06 (s, 3H), 2.88 (s, 3H), 2.26 (s, 3H), 1.80-1.74 (m, 3H).

[0387] Example 41 2-((6-(6-Fluoro-7-(2-fluoro-2-methylpropoxy)quinolin-4-yl)-2-methyl-1H- imidazo[4,5-b]pyridin-1-yl)methyl)-5-(1-fluoroethyl)-1,3,4-oxadiazole

[0388]

[0389] The preparation method was the same as that of Example 38, except that the raw material 2-bromoethanol was replaced by 1-bromo-2-fluoro-2-methylpropane, to obtain the title compound. ESI-MS m / z: 497.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.82 (d, J = 4.0 Hz, 1H), 8.53 (s, 1H), 8.26 (d, J = 4.0 Hz, 1H), 7.61-7.45 (m, 3H), 5.94 (s, 2H), 5.86-5.73 (m, 1H), 4.27 (s, 1H), 4.22 (s, 1H), 2.79 (s, 3H), 1.76-1.69 (m, 3H), 1.54 (s, 3H), 1.49 (s, 3H).

[0390] Example 42 2-((6-(6-Fluoro-7-(2-methoxyethoxy)quinolin-4-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(1-fluoroethyl)-1,3,4-oxadiazole

[0391]

[0392] The preparation method is same as that of Example 38, except that the raw material 2-bromoethanol is replaced by 2-bromoethyl methyl ether, to give the title compound. ESI-MS m / z: 481.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.87 (d, J = 8.0 Hz, 1H), 8.65 (d, J = 4.0 Hz, 1H), 7.89 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.48-7.45 (m, 1H), 7.33 (d, J = 4.0 Hz, 1H), 5.78-5.65 (m, 1H), 5.61 (s, 2H), 4.39-4.37 (m, 2H), 3.86-3.84 (m, 2H), 3.48 (s, 3H), 2.86 (s, 3H), 1.82-1.75 (m, 3H).

[0393] Example 43 2-((6-(7-(2,2-difluoroethoxy)-6-fluoroquinolin-4-yl)-2-methyl-1H- imidazo[4,5-b]pyridin-1-yl)methyl)-5-(1-fluoroethyl)-1,3,4-oxadiazole

[0394]

[0395] The preparation method is same as that of Example 38, except that the raw material 2-bromoethanol is replaced by 1,1-difluoro-2-iodoethane, to give the title compound. ESI-MS m / z: 487.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.87 (d, J = 8.0 Hz, 1H), 8.65 (d, J = 4.0 Hz, 1H), 7.89 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.48-7.45 (m, 1H), 7.33 (d, J = 4.0 Hz, 1H), 5.78-5.65 (m, 1H), 5.61 (s, 2H), 4.39-4.37 (m, 2H), 3.86-3.84 (m, 2H), 3.48 (s, 3H), 2.86 (s, 3H), 1.82-1.75 (m, 3H).

[0396] Example 44 2-((6-(6-fluoro-7-((tetrahydrofuran-3-yl)methoxy)quinolin-4-yl)-2-methyl- 1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(1-fluoroethyl)-1,3,4-oxadiazole

[0397]

[0398] The preparation method is same as that of Example 29 except that the raw material N-(2-hydroxyethyl)-pyrrolidine is replaced by 3-tetrahydrofuranmethanol to obtain the title compound. ESI-MS m / z: 507.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.94 (s, 1H), 8.70 (s, 1H), 8.20 (s, 1H), 7.99 (s, 1H), 7.62-7.60 (m, 2H), 5.83-5.69 (m, 1H), 5.58 (s, 2H), 4.34-4.24 (m, 2H), 3.98-3.96 (m, 2H), 3.86-3.78 (m, 2H), 2.92 (s, 3H), 2.88-2.84 (m, 1H), 2.22-2.18 (m, 1H), 1.86-1.78 (m, 4H).

[0399] Example 45 2-(1-Fluoroethyl)-5-((2-methyl-6-(7-(trifluoromethyl)quinolin-4-yl)-1H- imidazo[4,5-b]pyridin-1-yl)methyl)-1,3,4-oxadiazole

[0400]

[0401] The preparation method is same as that of Example 2 except that the raw material 4-bromo-6,7-dimethoxyquinoline is replaced by 4-chloro-7-trifluoromethylquinoline to obtain the title compound. ESI-MS m / z: 457.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ (ppm): 9.12 (s, 1H), 8.71 (s, 1H), 8.64 (s, 1H), 8.08-7.99 (m, 2H), 7.77-7.75 (m, 1H), 7.61 (s, 1H), 5.85-5.68 (m, 1H), 5.64 (s, 2H), 2.91 (s, 3H), 1.86-1.78 (m, 3H).

[0402] Example 46 2-(1-Fluoroethyl)-5-((6-(7-methoxy-6-methylquinolin-4-yl)-2-methyl-1H- imidazo[4,5-b]pyridin-1-yl)methyl)-1,3,4-oxadiazole

[0403]

[0404] The preparation method is the same as that of Example 2 except that the raw material 4-bromo-6,7-dimethoxyquinoline is replaced by intermediate 8 to give the title compound. ESI-MS m / z: 433.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.82 (d, J = 4.0 Hz, 1H), 8.69 (s, 1H), 7.95 (s, 1H), 7.63 (s, 1H), 7.32 (s, 1H), 5.81-5.67 (m, 1H), 5.61 (s, 2H), 4.06 (s, 3H), 2.88 (s, 3H), 2.34 (s, 3H), 1.83-1.76 (m, 3H).

[0405] Example 47 2-((6-(7-ethoxy-6-fluoroquinolin-4-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(1-fluoroethyl)-1,3,4-oxadiazole

[0406]

[0407] The preparation method is the same as that of Example 38 except that the raw material 2-bromoethanol is replaced by iodoethane to give the title compound. ESI-MS m / z: 451.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.86 (d, J = 4.0 Hz, 1H), 8.67 (s, 1H), 7.92 (s, 1H), 7.55-7.50 (m, 1H), 7.40 (s, 1H), 7.24 (s, 1H), 5.81-5.67 (m, 1H), 5.61 (s, 2H), 4.37-4.32 (m, 2H), 2.88 (s, 3H), 1.83-1.76 (m, 3H), 1.58-1.55 (m, 3H).

[0408] Example 48 2-(1-fluoroethyl)-5-((2-methyl-6-(7-(trifluoromethoxy)quinolin-4-yl)-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-1,3,4-oxadiazole

[0409]

[0410] The preparation method is the same as that of Example 2 except that the raw material 4-bromo-6,7-dimethoxyquinoline is replaced by 4-chloro-7-(trifluoromethoxy)quinoline to give the title compound. ESI-MS m / z: 473.1 [M+H] + . 1H NMR (400 MHz, CDC13) δ (ppm): 9.02 (d, J = 4.0 Hz, 1H), 8.60 (s, 1H), 8.32 (s, 1H), 8.10-8.08 (m, 1H), 8.00 (s, 1H), 7.65 (s, 1H), 7.57-7.55 (m, 1H), 5.97 (s, 2H), 5.90-5.77 (m, 1H), 2.82 (s, 3H), 1.79-1.72 (m, 3H).

[0411] Example 49 1-((6-Fluoro-4-(1-((5-(1-fluoroethyl)-1,3,4-oxadiazol-2-yl)methyl)-2-methyl-1H- imidazo[4,5-b]pyridin-6-yl)quinolin-7-yl)oxy)-2-methyl-2-propanol

[0412]

[0413] The preparation method is the same as that of Example 20, except that the raw material intermediate 1 is replaced by intermediate 6 to prepare the title compound. ESI-MS m / z: 495.1 [M+H] + . 1 H NMR (400 MHz, CDC13) δ (ppm): 8.85 (d, J = 8.0 Hz, 1H), 8.56 (s, 1H), 8.28 (s, 1H), 7.61-7.47 (m, 3H), 5.97 (s, 2H), 5.89-5.75 (m, 1H), 4.06 (s, 3H), 2.81 (s, 3H), 1.77-1.71 (m, 3H), 1.40 (s, 6H).

[0414] Example 50 2-((6-(6-Fluoro-7-(2,2,2-trifluoroethoxy)quinolin-4-yl)-2-methyl-1H-imidazo[4,5- b]pyridin-1-yl)methyl)-5-(1-fluoroethyl)-1,3,4-oxadiazole

[0415]

[0416] The preparation method is the same as that of Example 38, except that the raw material 2-bromoethanol is replaced by 2-iodo-1,1,1-trifluoroethane to prepare the title compound. ESI-MS m / z: 505.1 [M+H] + . 1H NMR (400 MHz, CDCI3) δ (ppm): 8.86 (d, J = 4.0 Hz, 1 H), 8.67 (s, 1 H), 7.92 (s, 1 H), 7.55-7.50 (m, 1 H), 7.40 (s, 1 H), 7.24 (s, 1 H), 5.81 -5.67 (m, 1 H), 5.61 (s, 2 H), 4.37-4.32 (m, 2 H), 2.88 (s, 3 H), 1.83-1.76 (m, 3 H), 1.58-1.55 (m, 3 H).

[0417] Example 51 2-((6-(6,7-dimethoxyquinazolin-4-yl)-2-methyl-1 H-imidazo[4,5- b]pyridin-1 -yl)methyl)-5-(1 -fluoroethyl)-1,3,4-oxadiazole

[0418]

[0419] The preparation method is the same as that of Example 2, except that the raw material 4-bromo-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-dimethoxyquinazoline, to obtain the title compound. ESI-MS m / z: 450.1 [M+H] + . 1 H NMR (400 MHz, CDCI3) δ (ppm): 9.22 (s, 1 H), 8.98 (d, J = 4.0 Hz, 1 H), 8.28 (d, J = 4.0 Hz, 1 H), 7.43 (s, 1 H), 7.34 (s, 1 H), 5.81 -5.67 (m, 1 H), 5.64 (s, 2 H), 4.11 (s, 3 H), 3.92 (s, 3 H), 2.88 (s, 3 H), 1.85-1.78 (m, 3 H).

[0420] Example 52 2-(1 -fluoroethyl)-5-((6-(7-methoxyquinazolin-4-yl)-2-methyl-1 H- imidazo[4,5-b]pyridin-1 -yl)methyl)-1,3,4-oxadiazole

[0421]

[0422] The preparation method is the same as that of Example 2, except that the raw material 4-bromo-6,7-dimethoxyquinoline is replaced by 4-chloro-6,7-dimethoxyquinazoline, to obtain the title compound. ESI-MS m / z: 450.1 [M+H] + . 1H NMR (400 MHz, CDCI3) δ (ppm): 9.34 (s, 1 H), 9.00 (s, 1 H), 8.59 (s, 1 H), 8.19 (d, J = 8.0 Hz, 1 H), 7.76 (s, 1 H), 7.46-7.44 (m, 1 H), 5.83-5.69 (m, 3 H), 4.11 (s, 3 H), 2.95 (s, 3 H), 1.85-1.78 (m, 3 H).

[0423] Example 53 2-(1-Fluoroethyl)-5-((6-(7-methoxy-1,6-naphthyridin-4-yl)-2-methyl- 1 H-imidazo[4,5-b]pyridin-1 -yl)methyl)-1,3,4-oxadiazole

[0424]

[0425] The preparation method is the same as that of Example 2, except that the raw material 4-bromo-6,7-dimethoxyquinoline is replaced by 4-chloro-7-methoxy-1,6-naphthyridine, to obtain the title compound. ESI-MS m / z: 420.1 [M+H] + . 1 H NMR (400 MHz, CDCI3) δ (ppm): 9.34 (s, 1 H), 9.00 (s, 1 H), 8.59 (s, 1 H), 8.19 (d, J = 8.0 Hz, 1 H), 7.76 (s, 1 H), 7.46-7.44 (m, 1 H), 5.83-5.69 (m, 3 H), 4.11 (s, 3 H), 2.95 (s, 3 H), 1.85-1.78 (m, 3 H).

[0426] Example 54 2-((6-(6-chloro-7-methoxyquinolin-4-yl)-2-methyl-1 H-imidazo[4,5- b]pyridin-1 -yl)methyl)-5-(1 -fluoroethyl)-1,3,4-oxadiazole

[0427]

[0428] The preparation method is the same as that of Example 2, except that the raw material 4-bromo-6,7-dimethoxyquinoline is replaced by intermediate 7, to obtain the title compound. ESI-MS m / z: 453.1 [M+H] + . 1H NMR (400 MHz, CDC13) δ (ppm): 8.87 (d, J = 4.0 Hz, 1H), 8.55 (s, 1H), 8.27 (s, 1H), 7.87 (s, 1H), 7.58 (s, 1H), 7.46 (d, J = 4.0 Hz, 1H), 5.97 (s, 2H), 5.88-5.75 (m, 1H), 4.08 (s, 3H), 2.81 (s, 3H), 1.78-1.71 (m, 3H).

[0429] Test Example 1: Evaluation of in vitro kinase activity of compounds

[0430] 1.1 Preparation of compounds

[0431] Table 2. Solvents and concentrations of test compounds and control compounds

[0432] Compounds Solvents Concentrations Control compounds Dimethyl sulfoxide (DMSO) 50 mmol / L Test compounds Dimethyl sulfoxide (DMSO) 10 mmol / L or 5 mmol / L

[0433] 1) Prepare 2x ATP / substrate solution and 2x kinase solution with kinase reaction buffer;

[0434] 2) Transfer 40 μL of the above control compound and test compound compound dilutions into 384 assay plates with Echo 655; after centrifugation, add 2 μL of 2x kinase solution to 384 assay plates, centrifuge at 1000 rpm for 1 min, incubate at 25°C for 10 min;

[0435] 3) Add 2 μL of 2x substrate and ATP solution to 384 assay plates, centrifuge at 1000 rpm for 1 min, incubate at 25°C for 60 min;

[0436] 4) Transfer 4 μL of ADP-Glo to 384 assay plates, centrifuge at 1000 rpm for 1 min, incubate at 25°C for 40 min;

[0437] 5) Transfer 8 μL of detection solution to 384 assay plates, centrifuge at 1000 rpm for 1 min, incubate at 25°C for 40 min;

[0438] 6) Read luminescence signal using a multifunctional microplate reader.

[0439] 1.2 Data analysis

[0440] Use GraphPad Prism 8 software for analysis, set the reading value of negative control (1% DMSO well) as 0% inhibition rate, and set the reading value of positive control (control compound highest concentration well) as 100% inhibition rate, calculate the inhibition rate, and then use the software nonlinear fitting formula to obtain the IC 50 value (half maximal inhibitory concentration) of the control compound and the test compound.

[0441]

[0442] Average of the values of the positive control wells; Average of the values of the negative control wells;

[0443] Appendix: The following software nonlinear fitting formula is used to calculate the IC of the compounds 50 (half maximal inhibitory concentration)

[0444] Y = Bottom + (Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope));

[0445] X: compound concentration log value;

[0446] Y: compound inhibition rate (%inh);

[0447] Z' factor calculation equation: Z' = 1-3(SDmin+SDmax) / (AVEmax-AVEmin)

[0448] 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.

[0449] Table 3. IC of some compounds for inhibiting CLK2 enzymatic activity 50 value

[0450]

[0451]

[0452] From the above experimental results, it can be seen that the compounds of the present disclosure have good inhibitory activity on CLK2

[0453] The reagent information used in the experiment is shown in Table 4:

[0454] Table 4. Reagent information used in the experiment

[0455] Materials Supplier Catalogue number Hepes Thermo Fisher 15630080 Brij 35 Millipore 1018940100 EGTA Sigma E3889 MgCl2 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

[0456] Test Example 2: In vivo pharmacokinetic study in rats

[0457] 1.1 Instruments: High performance liquid chromatograph: SHIMADZU LC-30AD, mass spectrometer: AB SCIEX mass spectrometer TripleQuad 5500, all the data measured were calculated and processed by Microsoft Excel, and the related pharmacokinetic parameters were calculated by WinNonlin software. The main obtained kinetic parameters Tmax T 1 / 2, C max ,AUC 0-24h ,AUC inf Column: XSelect Hss T3 2.5 pm (2.1 x 50 mm) Column XP, column temperature 40 °C, mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile, flow rate 0.60 mL / min, gradient elution, elution gradient 0.30 min: 5% B; 1.00 min: 98% B; 1.48 min: 98% B; 1.51 min: 5% B; 2.00 min: stop. Injection volume: 1 pL.

[0458] 1.2 Animals: SD male rats, three animals, body weight range 180-300 g, purchased and acclimatized for two days in the experimental animal center before use, fasted for 12 hours before dosing and 4 hours after dosing, free access to water during the experiment. Blood samples were taken at the scheduled time points after gavage of the rats.

[0459] 1.3 Vehicle: 10% DMSO / 30% PEG400 / 30% H2O. Preparation of gavage solution: the compound was accurately weighed, after adding the vehicle, ultrasonic for 5 minutes at room temperature to completely dissolve the drug, and prepared into a 0.5 mg / mL solution.

[0460] Blood was taken at 0.083 h, 0.25 h, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 7.0 h and 24 h after gavage, blood collection method: 0.2 mL of jugular vein blood was collected, anticoagulant: EDTA-K2, the collected blood samples were transferred to microcentrifuge tubes containing anticoagulant, and the plasma was separated after centrifugation at 4 °C, 4000 g for 5 min. All the collected plasma samples were stored at -75 ± 15 °C until analysis.

[0461] The compound was accurately weighed to prepare standard curve working solution and quality control working solution of different concentrations, blank plasma was added, plasma standard curve and quality control sample were prepared, and LC / MS / MS analysis was carried out after pretreatment by protein precipitation method, and then the concentration of the above plasma compound was tested. All the measured data were collected and processed by related software, and the pharmacokinetic parameter calculation was carried out by Winnonlin software. The kinetic parameters of some representative compounds are shown in Table 9.

[0462] Table 5. Pharmacokinetic parameters of some compounds of the examples in rats

[0463]

[0464] According to the data in Table 5, pharmacokinetic studies in rats show that the fused heterocyclic compounds of the present application are rapidly absorbed in the gastrointestinal tract and have good oral bioavailability.

[0465] The above has exemplarily explained the embodiments of the present disclosure. However, the protection scope of the present application is not limited to the above specific embodiments. Any modification, equivalent replacement, improvement, etc. made by those skilled in the art within the spirit and principle of the present disclosure shall be included in the protection scope of the claims of the present application.

Claims

1. A compound of formula (I), a stereoisomer, a racemate, a tautomer, an isotopically-labeled form, a nitroxide, or a pharmaceutically acceptable salt thereof, ###0001### (I) wherein HET1 is selected from a 10-membered heteroaromatic ring group containing 1-3 nitrogen atoms; HET2 is selected from a 5-10-membered heteroaromatic ring group containing 1-3 heteroatoms selected from N, O, S; R1, R2 are the same or different, independently selected from H, halogen, cyano, hydroxyl, amino, alkyl, alkoxy, alkylthio, cycloalkyl; R3 is selected from H, halogen, cyano, hydroxyl, amino, alkyl, alkoxy, alkylthio, cycloalkyl; R4 is selected from H, halogen, cyano, hydroxyl, amino, alkyl, alkoxy, alkylthio, cycloalkyl; R5, R6 are the same or different, independently selected from H, halogen, cyano, hydroxyl, amino, alkyl; m, n, p are the same or different, independently selected from an integer of 0-3. wherein, 2. The compound of claim 1, a stereoisomer, a racemate, a tautomer, an isotopically-labeled form, a nitroxide, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from a compound of formula (II): ###0002### (II) wherein HET2, R1, R2, R3, R4, R5, R6, m, n are independently defined as in claim 1; wherein 1, 2 or 3 of X1, X2, X3, X4 are N.

3. The compound of claim 1, a stereoisomer, a racemate, a tautomer, an isotopically-labeled form, a nitroxide, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from a compound of formula (III): ###0003### (III) wherein R1, R2, R3, R4, R5, R6, n are independently defined as in claim 1 or 2; X1, X2, X3, X4 are independently defined as in claim 2. each R1is the same or different, independently of one another, selected from the group consisting of H, halogen, cyano, hydroxyl, amino, unsubstituted or optionally substituted with one, two, three or more identical or different R a the following groups, which are substituted: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl, -O-(CH2) p - cycloalkyl, -O-(CH2) p - heterocyclyl, -O-(CH2) p - aryl, -O-(CH2) p - heteroaryl, -NHalkyl, -N(alkyl)2, -SO2alkyl, -NH-SO2-alkyl; wherein, if n > 2, R1is the same or different; Every R a are the same or different and are independently selected from H, halogen, cyano, hydroxy, amino, alkyl, alkoxy, -NHalkyl, -N(alkyl)2, -SO2alkyl, -SOalkyl, -SO(=N-alkyl)alkyl; each R2is the same or different, independently of one another, selected from the group consisting of H, halogen, cyano, hydroxyl, amino, unsubstituted or optionally substituted with one, two, three or more R b substituted alkyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl; Every R b The same or different, independently selected from H, halogen, cyano, hydroxyl, amino; 4. The compound of claim 1, a stereoisomer, a racemate, a tautomer, an isotopically-labeled form, a nitroxide, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from a compound of formula (IV): ###0004### (IV) wherein R1, R2, R3, R4, R5, R6 are independently defined as in any one of claims 1-3; X1, X2, X3, X4 are independently defined as in claim 2 or 3; R', R" are the same or different, independently selected from H, halogen, cyano, hydroxyl, amino, alkyl, alkoxy, alkylthio, cycloalkyl.

5. The compound of claim 1, a stereoisomer, a racemate, a tautomer, an isotopically-labeled form, a nitroxide, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from a compound of formula (V): ###0005### (V) wherein R1, R2, R3, R4 are independently defined as in any one of claims 1-3; X1, X2, X3 are independently defined as in claim 2 or 3.

6. The compound of claim 1, a stereoisomer, a racemate, a tautomer, an isotopically-labeled form, a nitroxide, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from a compound of formula (VI): ###0006### (VI) wherein R1, R2, R3, R4 are independently defined as in any one of claims 1-3. ​ ​ wherein ​ X1is selected from N, CR c ; X2is selected from N, CR d ; X3is selected from N, CR e ; X4is selected from N, CR f ; ​ R c , R d , R e , R f are identical or different and independently of each other selected from the group consisting of H, halogen, cyano, hydroxyl, amino, unsubstituted or optionally with one, two, three or more identical or different R g substituted from the group consisting of alkyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy; each R is independently selected from H, halogen, cyano, hydroxyl, amino, alkyl, alkoxy; and g are the same or different, independently of one another, selected from H, halogen, cyano, hydroxyl, amino, alkyl, alkoxy. ​ wherein ​ ​ ​ wherein ​ ​ ​ ​ wherein, ​ ​ ​ wherein, ​ R e having the meaning as defined in claim 2 or 3.

7. The compound, stereoisomer, racemate, tautomer, isotopically labeled, nitroxide or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of Formula (I) is selected from the group consisting of:

8. A process for preparing a compound, stereoisomer, racemate, tautomer, isotopically labeled, nitroxide or pharmaceutically acceptable salt thereof according to any one of claims 1-7, wherein the process comprises one of the following schemes: Scheme I-1 Scheme I-2 wherein, HET1, HET2, R1, R2, R3, R4, R5, R6, m, n are independently defined as in any one of claims 1-7; Y is selected from the group consisting of Cl, Br, I or OTf; R 21 is selected from alkyl, OH, alkoxy; or two R 21 together with the B atom to which they are attached form a 5-6 membered heterocyclic ring which is optionally substituted with alkyl; preferably, R 21 is selected from C 1-20 alkyl, OH, C 1-20 alkoxy, or two R 21 together with the B atom to which they are attached form a 5-6 membered heterocyclic ring which is optionally substituted with C 1-20 alkyl; more preferably, R 21 is selected from C 1-10 alkyl, OH, C 1-10 alkoxy, or two R 21 together with the B atom to which they are attached form a 5-6 membered heterocyclic ring which is optionally substituted with C 1-10 alkyl; especially preferably, R 21 is selected from C 1-6 alkyl, OH, C 1-6 alkoxy, or two R 21 together with the B atom to which they are attached form a 5-6 membered heterocyclic ring which is optionally substituted with C 1-6 alkyl; most preferably, R 21 is selected from methyl, ethyl, propyl, isopropyl, OH, methoxy, ethoxy, propoxy, isopropoxy; or two R 21 together with the B atom to which they are attached form a pinacol boron ester.

9. A pharmaceutical composition, wherein the pharmaceutical composition comprises at least one of the compounds, stereoisomers, racemates, tautomers, isotopically labeled, nitroxide or pharmaceutically acceptable salt thereof according to any one of claims 1-7.

10. A method of preventing and / or treating a disease associated with or affected by CLK2, comprising administering to an individual in need thereof a therapeutically effective amount of at least one of the compounds, stereoisomers, racemates, tautomers, isotopically labeled, nitroxide or pharmaceutically acceptable salt thereof of Formula (I)-(VI). Preferably, the disease associated with or affected by CLK2 is selected from, for example, a cancer [e.g., colorectal cancer (e.g., colon cancer, rectal cancer, anal cancer, familial colorectal cancer, hereditary nonpolyposis colorectal cancer, and gastrointestinal stromal tumor), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, and malignant mesothelioma), mesothelioma, pancreatic cancer (e.g., pancreatic ductal carcinoma and pancreatic endocrine gland neoplasm), pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer (e.g., papillary adenocarcinoma, mucous adenocarcinoma, and adenosquamous carcinoma), duodenal cancer, small intestinal cancer, breast cancer (e.g., invasive ductal carcinoma, non-invasive intraductal carcinoma, and inflammatory breast cancer), ovarian cancer (e.g., ovarian epithelial cancer, extragonadal germ cell tumor, ovarian germ cell tumor, and ovarian low malignant potential tumor), testicular tumor, prostate cancer (e.g., hormone-dependent prostate cancer, non-hormone-dependent prostate cancer, and castration-resistant prostate cancer), liver cancer (e.g., hepatocellular carcinoma, primary liver cancer, and extrahepatic bile duct cancer), thyroid cancer (e.g., medullary thyroid carcinoma), renal cancer (e.g., renal cell carcinoma (e.g., clear cell renal cell carcinoma) and metastatic cell carcinoma of the renal pelvis and ureter), uterine cancer (e.g., cervical cancer, uterine body cancer, and uterine sarcoma), gestational choriocarcinoma, brain tumor (e.g., medulloblastoma, glioma, pineal astrocytoma, fibrous astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, and pituitary adenoma), retinoblastoma, skin cancer (e.g., basal cell carcinoma and malignant melanoma), sarcoma (e.g., rhabdomyosarcoma, leiomyosarcoma, soft tissue sarcoma, and spindle cell sarcoma), malignant bone tumor, bladder cancer, blood cancer (e.g., multiple myeloma, leukemia (e.g., acute myelogenous leukemia), malignant lymphoma, lymphogranulomatosis, and chronic myeloproliferative disease), and unknown primary cancer], a cancer growth inhibitor, a cancer metastasis inhibitor, a cell program death promoter, or a therapeutic agent for a precancerous lesion (e.g., myelodysplastic syndrome).

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