A quinazoline derivative and uses thereof

Abstract

The present application relates to a quinazoline derivative of general formula (I) or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer, which can selectively inhibit CDK9 and / or TNIK, and has good enzymatic and cellular activity.

Description

Technical Field

[0001] This invention relates to a quinazoline derivative or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer, and its use in CDK9 and / or TNIK-mediated diseases. Background Technology

[0002] Aberrant activation of the Wnt signaling pathway has been observed in various human cancers, including colorectal cancer, pancreatic cancer, non-small cell lung cancer, and prostate cancer. Approximately 90% of colorectal cancers exhibit mutations in at least one Wnt pathway regulator, such as the adenomatous polyposis (APC) and β-catenin (CTNNB1) genes. These mutations lead to the intracellular accumulation of β-catenin and its translocation to the nucleus, stimulating the TCF4 / LEF family transcription factors to activate numerous genes involved in intestinal epithelial cell proliferation, differentiation, and death, such as MYC, CCND1, AXIN, and JUN, driving tumor development and progression. Therefore, inhibiting aberrant activation of the Wnt pathway is an effective strategy for treating colorectal cancer. In the classic Wnt pathway, the Traf2- and NCK-interacting protein kinase (TNIK) has been identified as a crucial component of the transcriptional regulatory complex of Wnt target genes. It interacts directly with TCF4 in a β-catenin-dependent manner, activating TCF4 / LEF-driven transcription of Wnt target genes through TCF4 phosphorylation, leading to Wnt signaling transduction within tumor cells. As the downstream transcriptional regulator of the Wnt pathway, TNIK plays a vital role in activating the Wnt signaling pathway and maintaining the growth of colorectal cancer cells. Inhibiting TNIK is expected to block the aberrant transduction of Wnt signaling in colorectal cancer cells, suggesting that TNIK may be a potential drug target for treating colorectal cancers with abnormal Wnt signaling pathways.

[0003] Cyclin-dependent kinase 9 (CDK9) is a serine / threonine protein kinase that typically forms a heterodimeric complex with its intracellular counterpart, cyclin cyclin, regulating cellular transcription. Increasing research indicates that CDK9 is highly expressed in various malignant tumors and is associated with poor cancer prognosis. As an important component of positive transcription elongation factor P-TEFb, the CDK9 / Cyclin T1 complex activates the transcriptional elongation of genes regulating cell proliferation, development, and stress, such as MYC, nuclear factor-κB (NF-κB), and MCL1, by specifically phosphorylating the negative elongation factor NELF, DRB sensitivity-inducing factor DSIF, and the Ser2 residue at the CTD end of RNA polymerase II (Pol II). This promotes tumorigenesis and development. Inhibiting CDK9 can block the phosphorylation activation of RNA Pol II by P-TEFb, inhibit transcriptional elongation, reduce the mRNA levels of oncogenes such as MYC in cells, and downregulate the expression of anti-apoptotic genes, thereby preventing tumor cell proliferation and inducing tumor cell apoptosis. Therefore, the specific regulatory role of CDK9 in the transcriptional process makes it one of the most promising anti-tumor targets in the CDK family.

[0004] WO2007117607 reported a quinazoline compound with a structure targeting PDK1 inhibitors, but no evidence of its inhibitory effect on CDK9 has been shown. Furthermore, drug research on CDK9 is scarce, with the vast majority being non-selective inhibitors. Common examples of non-selective CDK9 inhibitors include P276-00, SCH727965, or AT7519. Non-selective inhibitors have significant toxic side effects during use, such as neutropenia and thrombocytopenia.

[0005] Currently, there are also research reports on the Wnt transmission pathway. CN201380026183.8 discloses the use of bicyclic thiazole compounds as TNIK inhibitors, and CN201980015875.X reports the use of heterocyclic fused phenyl compounds for TNIK inhibition. However, there are few reports on the use of quinazoline derivatives as TNIK inhibitors, especially those involving selective inhibition of TNIK and / or CDK9 targets.

[0006] Therefore, developing a class of highly active inhibitors that selectively inhibit CDK9 and / or TNIK targets is an urgent technical challenge that needs to be addressed. Summary of the Invention

[0007] This invention provides a quinazoline derivative or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer, which selectively inhibits CDK9 and / or TNIK and exhibits good enzymatic and cellular activity.

[0008] This is mainly achieved through the following technical solutions.

[0009] On the one hand, the present invention relates to compounds or stereoisomers of general formula (I), pharmaceutically acceptable salts, solvates, or tautomers:

[0010]

[0011] in,

[0012] Q is selected from 5-6 aryl, 5-6 substituted aryl, 5-6 heteroaryl or 5-6 substituted heteroaryl;

[0013] The 5-6 substituted aryl group or the 5-6 substituted heteroaryl group may optionally have one or more substituents, which are optionally selected from halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, etc. -(CR5R6) m SO2R a Or SF5; R a Selected from H, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, 4-7 membered heterocyclic alkyl, aryl or heteroaryl; R b The carbon atom is selected from H, C1-C6 alkyl, C1-C6 alkoxy, cyano, C3-C7 cycloalkyl, 4-7 heterocyclic alkyl, aryl or heteroaryl; R5 or R6 is selected from C1-C3 alkyl, halogen, or optionally R5 and R6 together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl or a 4- to 6-membered heterocyclic alkyl; wherein the 3- to 5-membered cycloalkyl or the 4- to 6-membered heterocyclic alkyl may be further substituted with C1-C6 alkyl, C1-C6 alkoxy or halogen; wherein the C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, 4-7 heterocyclic alkyl, aryl or heteroaryl may be further substituted with a substituent selected from: alkyl, halogen, amino, cyano or hydroxyl;

[0014] 5-6-membered heteroaryl, 5-6-membered substituted heteroaryl, 4-7-membered heterocycloalkyl, heteroaryl or 4- to 6-membered heterocycloalkyl, having one or more heteroatoms, said heteroatoms being arbitrarily selected from N, O or S;

[0015] m is 0, 1, 2, or 3;

[0016] R 1 R 2 R 3 or R 4 Each is independently selected from H, halogen, amino, hydroxyl, cyano, haloalkyl, haloalkoxy, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C7 alkenyl or C2-C7 alkynyl;

[0017] B represents O, NH, S, or CH2;

[0018] W represents a 5-7 nucleotide saturated cycloalkyl group, wherein the 5-7 nucleotide saturated cycloalkyl group optionally has one or more substituents selected from: halogen, amino, hydroxyl, haloalkyl, C1-C6 alkyl or C1-C6 alkoxy; wherein the C1-C6 alkyl or C1-C6 alkoxy group is each optionally substituted by a substituent selected from: halogen, amino, cyano or hydroxyl.

[0019] In one aspect, the present invention relates to compounds or stereoisomers of general formula (I), pharmaceutically acceptable salts, solvates, or tautomers having formula (Ia).

[0020]

[0021] in,

[0022] X1 represents O or NR8, where R8 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, cyano, C3-C7 cycloalkyl, 4-7 membered heterocyclic alkyl, aryl or heteroaryl; C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, 4-7 membered heterocyclic alkyl, aryl or heteroaryl, further substituted by substituents selected from: alkyl, halogen, amino, cyano or hydroxyl;

[0023] X2, X3, X4 or X5 are each independently selected from N or CR9, and R9 is selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy or SF5;

[0024] R 1 R 2 R 3 or R 4 Each is independently selected from H, halogen, amino, hydroxyl, cyano, haloalkyl, haloalkoxy, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C7 alkenyl or C2-C7 alkynyl;

[0025] R5 or R6 is independently selected from C1-C3 alkyl, halogen, or, as an option, R5 and R6 together with the carbon atom to which they are attached can optionally form a 3- to 5-membered cycloalkyl or a 4- to 6-membered heterocycloalkyl; wherein the 3- to 5-membered cycloalkyl or the 4- to 6-membered heterocycloalkyl may be further substituted with C1-C6 alkyl, C1-C6 alkoxy or halogen; the C1-C6 alkyl or C1-C6 alkoxy may be further substituted with a substituent selected from: halogen, amino, cyano or hydroxyl; the heteroatom of the 4- to 6-membered heterocycloalkyl is selected from N, O or S;

[0026] R7 is selected from H, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, 4-7 membered heterocyclic alkyl, aryl or heteroaryl; wherein the C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, 4-7 membered heterocyclic alkyl, aryl or heteroaryl is further substituted by a substituent selected from: halogen, amino, cyano or hydroxyl;

[0027] B represents O, NH, S, or CH2;

[0028] Z represents halogen, amino, hydroxyl, haloalkyl, C1-C6 alkyl or C1-C6 alkoxy; C1-C6 alkyl or C1-C6 alkoxy, each of which may be substituted by a substituent selected from: halogen, amino, cyano or hydroxyl.

[0029] m is 0, 1, 2, or 3;

[0030] n is 0, 1, or 2.

[0031] In one aspect, the present invention relates to compounds or stereoisomers of general formula (I), pharmaceutically acceptable salts, solvates, or tautomers, wherein Q is a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 6-membered heteroaryl group; wherein the substituted phenyl group or the substituted 6-membered heteroaryl group has substituents each arbitrarily selected from halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, -(CR5R6) m SO2R a Or SF5; R a Selected from H, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, 4-7 membered heterocyclic alkyl, aryl or heteroaryl; R bSelected from H, C1-C6 alkyl, C1-C6 alkoxy, cyano, C3-C7 cycloalkyl, 4-7-membered heterocyclic alkyl, aryl, or heteroaryl; R5 or R6 is selected from C1-C3 alkyl, halogen, or optionally R5 and R6 together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl or a 4- to 6-membered heterocyclic alkyl; wherein the 3- to 5-membered cycloalkyl or the 4- to 6-membered heterocyclic alkyl can be further converted by C1-C6 alkyl, C1-C6 alkyl Oxide or halogen substitution; C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, 4-7 heterocyclic alkyl, aryl or heteroaryl, further substituted by a substituent selected from: halogen, amino, cyano or hydroxyl; wherein the substituted or unsubstituted 6-membered heteroaryl, 4-7-membered heterocyclic alkyl, heteroaryl or 4 to 6-membered heterocyclic alkyl has one or more heteroatoms, the heteroatoms being arbitrarily selected from N, O or S; m is 0, 1, 2 or 3.

[0032] In one aspect, the present invention relates to compounds or stereoisomers of general formula (I), pharmaceutically acceptable salts, solvates, or tautomers, wherein Q is a 6-membered heteroaryl group having the following substituted or unsubstituted structures:

[0033]

[0034] Its substituents are arbitrarily selected from halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, -(CR5R6) m SO2R a Or SF5; R a Selected from H, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, 4-7 membered heterocyclic alkyl, aryl or heteroaryl; R b The carbon atom is selected from H, C1-C6 alkyl, C1-C6 alkoxy, cyano, C3-C7 cycloalkyl, 4-7 heterocyclic alkyl, aryl or heteroaryl; R5 or R6 is selected from C1-C3 alkyl, halogen, or optionally R5 and R6 together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl or a 4- to 6-membered heterocyclic alkyl; wherein the 3- to 5-membered cycloalkyl or the 4- to 6-membered heterocyclic alkyl may be further substituted with C1-C6 alkyl, C1-C6 alkoxy or halogen; C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, 4- to 7-membered heterocyclic alkyl, aryl or heteroaryl may be further substituted with a substituent selected from: halogen, amino, cyano or hydroxyl; 4- to 7-membered heterocyclic alkyl, heteroaryl or 4- to 6-membered heterocyclic alkyl having one or more heteroatoms, wherein the heteroatoms are arbitrarily selected from N, O or S; m is 0, 1, 2 or 3.

[0035] In another aspect, the present invention relates to a compound or stereoisomer of general formula (Ia), a pharmaceutically acceptable salt, a solvate, or a tautomer, wherein X2, X3, X4, or X5 is each independently CR9, wherein R9 is selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, or SF5; or one of X2, X3, X4, and X5 is N, and the rest are CR9, wherein R9 is selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, or SF5; preferably R9 is selected from H, F, Cl, Br, CH3, or OCH3.

[0036] On the other hand, the present invention relates to compounds or stereoisomers of general formula (I), pharmaceutically acceptable salts, solvates, or tautomers, R 1 R 2 R 3 or R 4 Each is independently selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, C3-C7 cycloalkyl, C1-C6 alkyl or C1-C6 alkoxy.

[0037] In another aspect, the present invention relates to compounds or stereoisomers of general formula (I), pharmaceutically acceptable salts, solvates, or tautomers, R 1 Selected from H, F, Cl, Br, CF3, CN, CH3, OCH3 or cyclopropyl.

[0038] In another aspect, the present invention relates to compounds or stereoisomers of general formula (Ia), pharmaceutically acceptable salts, solvates, or tautomers, where Z is 4-hydroxyl and n is 1.

[0039] In another aspect, the present invention relates to compounds or stereoisomers of general formula (I) or (Ia), pharmaceutically acceptable salts, solvates, or tautomers, where m is 1.

[0040] In other respects, the present invention relates to a pharmaceutical composition comprising a compound or stereoisomer of general formula (I) or (Ia), a pharmaceutically acceptable salt, a solvate, or a tautomer, and a pharmaceutically acceptable excipient.

[0041] In other respects, the present invention relates to the use of compounds or stereoisomers of general formula (I) or (Ia), pharmaceutically acceptable salts, solvates, or tautomers, or pharmaceutical compositions thereof in the preparation of CDK9 and / or TNIK-mediated diseases.

[0042] In other respects, the present invention relates to compounds or stereoisomers of general formula (I) or (Ia), pharmaceutically acceptable salts, solvates, or tautomers, or pharmaceutical compositions wherein CDK9 and / or TNIK-mediated diseases are hyperplastic diseases.

[0043] In other respects, the present invention relates to compounds or stereoisomers of general formula (I) or (Ia), pharmaceutically acceptable salts, solvates, or tautomers, or pharmaceutical compositions wherein CDK9 and / or TNIK mediate diseases of cancer, further solid tumors and / or hematologic malignancies.

[0044] In another aspect, the present invention relates to compounds or stereoisomers of the general formula (I) or (Ia), pharmaceutically acceptable salts, solvates, or tautomers, or pharmaceutical compositions thereof, wherein CDK9 and / or TNIK-mediated cancers may be selected from breast cancer, ovarian cancer, lung cancer, gastric cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer, prostate cancer, thyroid cancer, liver cancer, acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, or neurocytoma, etc.

[0045] Furthermore, the present invention can also be achieved through the following technical solutions:

[0046] On the one hand, the present invention relates to compounds or stereoisomers of general formula (I), pharmaceutically acceptable salts, solvates, or tautomers:

[0047]

[0048] in,

[0049] Q is selected from 5-6 aryl, 5-6 substituted aryl, 5-6 heteroaryl or 5-6 substituted heteroaryl;

[0050] The 5-6 substituted aryl group or the 5-6 substituted heteroaryl group may optionally have one or more substituents, which are optionally selected from halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, etc. -(CR5R6) m SO2R a SF5, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, or 3-7 membered substituted heterocycloalkyl; wherein the 3-7 membered substituted heterocycloalkyl has substituents selected from C1-C6 alkyl, C1-C6 alkoxy, or halogen; R a Selected from H, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, 4-7 membered heterocyclic alkyl, aryl or heteroaryl; R bThe carbon atom is selected from H, C1-C6 alkyl, C1-C6 alkoxy, cyano, C3-C7 cycloalkyl, 4-7 heterocyclic alkyl, aryl or heteroaryl; R5 or R6 is selected from C1-C3 alkyl, halogen, or optionally R5 and R6 together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl or a 4- to 6-membered heterocyclic alkyl; wherein the 3- to 5-membered cycloalkyl or the 4- to 6-membered heterocyclic alkyl may be further substituted with C1-C6 alkyl, C1-C6 alkoxy or halogen; wherein the C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, 4-7 heterocyclic alkyl, aryl or heteroaryl may be further substituted with a substituent selected from: alkyl, halogen, amino, cyano or hydroxyl;

[0051] 5-6-membered heteroaryl, 5-6-membered substituted heteroaryl, 4-7-membered heterocycloalkyl, heteroaryl, 4-6-membered heterocycloalkyl, 3-7-membered heterocycloalkyl or 3-7-membered substituted heterocycloalkyl, having one or more heteroatoms, said heteroatoms being arbitrarily selected from N, O or S;

[0052] m is 0, 1, 2, or 3;

[0053] R 1 R 2 R 3 or R 4 Each of the following is independently selected from H, halogen, amino, hydroxyl, cyano, haloalkyl, haloalkoxy, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C7 alkenyl, C2-C7 alkynyl, 5-6-membered heteroaryl, 5-6-membered substituted heteroaryl, C1-C6 substituted alkyl, and 4-7-membered heterocycloalkyl; wherein the 5-6-membered substituted heteroaryl has substituents that are arbitrarily selected from halogen, amino, hydroxyl, or C1-C6 alkyl; wherein the C1-C6 substituted alkyl has substituents that are arbitrarily selected from halogen, amino, cyano, hydroxyl, or C3-C7 cycloalkyl;

[0054] B represents O, NH, S, or CH2;

[0055] W represents a 5-7 nucleotide saturated cycloalkyl group, wherein the 5-7 nucleotide saturated cycloalkyl group optionally has one or more substituents selected from: halogen, amino, hydroxyl, haloalkyl, C1-C6 alkyl or C1-C6 alkoxy; wherein the C1-C6 alkyl or C1-C6 alkoxy group is each optionally substituted by a substituent selected from: halogen, amino, cyano or hydroxyl.

[0056] In one aspect, the present invention relates to compounds or stereoisomers of general formula (I), pharmaceutically acceptable salts, solvates, or tautomers having formula (Ia).

[0057]

[0058] in,

[0059] X1 represents O or NR8, where R8 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, cyano, C3-C7 cycloalkyl, 4-7 membered heterocyclic alkyl, aryl or heteroaryl; C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, 4-7 membered heterocyclic alkyl, aryl or heteroaryl, further substituted by substituents selected from: alkyl, halogen, amino, cyano or hydroxyl;

[0060] X2, X3, X4, or X5 are each independently selected from N or CR9, and R9 is selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, SF5, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, or 3-7 membered substituted heterocycloalkyl; wherein the substituent of the 3-7 membered heterocycloalkyl is selected from C1-C6 alkyl, C1-C6 alkoxy, or halogen; wherein the 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl has one or more heteroatoms, wherein the heteroatoms are arbitrarily selected from N, O, or S;

[0061] R 1 R 2 R 3 or R 4 Each of the following is independently selected from H, halogen, amino, hydroxyl, cyano, haloalkyl, haloalkoxy, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C7 alkenyl, C2-C7 alkynyl, 5-6-membered heteroaryl, 5-6-membered substituted heteroaryl, C1-C6 substituted alkyl, or 4-7-membered heterocyclic alkyl; wherein the 5-6-membered heteroaryl, 5-6-membered substituted heteroaryl, and 4-7-membered heterocyclic alkyl have one or more heteroatoms, wherein the heteroatoms are arbitrarily selected from N, O, or S; wherein the 5-6-membered substituted heteroaryl has substituents arbitrarily selected from halogen, amino, hydroxyl, or C1-C6 alkyl; wherein the C1-C6 substituted alkyl has substituents arbitrarily selected from halogen, amino, cyano, hydroxyl, or C3-C7 cycloalkyl;

[0062] R5 or R6 is independently selected from H, C1-C3 alkyl, halogen, or optionally R5 and R6 together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl or a 4- to 6-membered heterocycloalkyl; wherein the 3- to 5-membered cycloalkyl or the 4- to 6-membered heterocycloalkyl may be further substituted with a C1-C6 alkyl, a C1-C6 alkoxy or halogen; the C1-C6 alkyl or C1-C6 alkoxy may be further substituted with a substituent selected from: halogen, amino, cyano or hydroxyl; the heteroatom of the 4- to 6-membered heterocycloalkyl is selected from N, O or S;

[0063] R7 is selected from H, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, 4-7 membered heterocyclic alkyl, aryl or heteroaryl; wherein the C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, 4-7 membered heterocyclic alkyl, aryl or heteroaryl is further substituted by a substituent selected from: halogen, amino, cyano or hydroxyl;

[0064] B represents O, NH, S, or CH2;

[0065] Z represents halogen, amino, hydroxyl, haloalkyl, C1-C6 alkyl or C1-C6 alkoxy; C1-C6 alkyl or C1-C6 alkoxy, each of which may be substituted by a substituent selected from: halogen, amino, cyano or hydroxyl.

[0066] m is 0, 1, 2, or 3;

[0067] n is 0, 1, or 2.

[0068] In one aspect, the present invention relates to compounds or stereoisomers of general formula (I), pharmaceutically acceptable salts, solvates, or tautomers, wherein Q is a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 6-membered heteroaryl group; wherein the substituted phenyl group or the substituted 6-membered heteroaryl group has substituents each arbitrarily selected from halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, -(CR5R6) m SO2R a SF5, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, or 3-7 membered substituted heterocycloalkyl; wherein the 3-7 membered substituted heterocycloalkyl has substituents selected from C1-C6 alkyl, C1-C6 alkoxy, or halogen; R a Selected from H, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, 4-7 membered heterocyclic alkyl, aryl or heteroaryl; R bSelected from H, C1-C6 alkyl, C1-C6 alkoxy, cyano, C3-C7 cycloalkyl, 4-7-membered heterocyclic alkyl, aryl, or heteroaryl; R5 or R6 is selected from C1-C3 alkyl, halogen, or optionally R5 and R6 together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl or a 4- to 6-membered heterocyclic alkyl; wherein the 3- to 5-membered cycloalkyl or the 4- to 6-membered heterocyclic alkyl may be further substituted with C1-C6 alkyl, C1-C6 alkoxy, or halogen; C1 -C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, 4-7 heterocyclic alkyl, aryl or heteroaryl, further substituted by a substituent selected from: halogen, amino, cyano or hydroxyl; wherein the substituted or unsubstituted 6-membered heteroaryl, 3-7-membered heterocyclic alkyl, 3-7-membered substituted heterocyclic alkyl or 4-7-membered heterocyclic alkyl, heteroaryl or 4 to 6-membered heterocyclic alkyl has one or more heteroatoms, the heteroatoms being arbitrarily selected from N, O or S; m is 0, 1, 2 or 3.

[0069] In one aspect, the present invention relates to compounds or stereoisomers of general formula (I), pharmaceutically acceptable salts, solvates, or tautomers, wherein Q is a 6-membered heteroaryl group having the following substituted or unsubstituted structures:

[0070]

[0071] Its substituents are arbitrarily selected from halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, -(CR5R6) m SO2R a SF5, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl; wherein the 3-7 membered heterocycloalkyl has one or more heteroatoms, wherein the heteroatoms are arbitrarily selected from N, O or S; R a Selected from H, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, 4-7 membered heterocyclic alkyl, aryl or heteroaryl; R bThe carbon atom is selected from H, C1-C6 alkyl, C1-C6 alkoxy, cyano, C3-C7 cycloalkyl, 4-7 heterocyclic alkyl, aryl or heteroaryl; R5 or R6 is selected from C1-C3 alkyl, halogen, or optionally R5 and R6 together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl or a 4- to 6-membered heterocyclic alkyl; wherein the 3- to 5-membered cycloalkyl or the 4- to 6-membered heterocyclic alkyl may be further substituted with C1-C6 alkyl, C1-C6 alkoxy or halogen; C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, 4- to 7-membered heterocyclic alkyl, aryl or heteroaryl may be further substituted with a substituent selected from: halogen, amino, cyano or hydroxyl; 4- to 7-membered heterocyclic alkyl, heteroaryl or 4- to 6-membered heterocyclic alkyl having one or more heteroatoms, wherein the heteroatoms are arbitrarily selected from N, O or S; m is 0, 1, 2 or 3.

[0072] In another aspect, the present invention relates to compounds or stereoisomers of general formula (Ia), pharmaceutically acceptable salts, solvates, or tautomers, wherein X2, X3, X4, or X5 are each independently CR9, wherein R9 is selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, SF5, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, or 3-7 membered substituted heterocycloalkyl; wherein the 3-7 membered substituted heterocycloalkyl has a substituent selected from C1-C6 alkyl, C1-C6 alkoxy, or halogen; wherein the 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl has one or more heteroatoms, wherein the heteroatoms are optionally... The R9 is selected from N, O, or S; or one of X2, X3, X4, and X5 is N, and the rest are CR9, wherein R9 is selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, SF5, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, or 3-7 membered substituted heterocycloalkyl; wherein the substituent of the 3-7 membered heterocycloalkyl is selected from C1-C6 alkyl, C1-C6 alkoxy, or halogen; wherein the 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl has one or more heteroatoms, wherein the heteroatoms are arbitrarily selected from N, O, or S; preferably, R9 is selected from H, F, Cl, Br, CH3, OCH3,

[0073] On the other hand, the present invention relates to compounds or stereoisomers of general formula (I), pharmaceutically acceptable salts, solvates, or tautomers, R 1 R 2 R 3 or R 4Each of the following is independently selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C7 alkenyl, C2-C7 alkynyl, 5-6-membered heteroaryl, 5-6-membered substituted heteroaryl, C1-C6 substituted alkyl, or 4-7-membered heterocyclic alkyl; wherein the 5-6-membered heteroaryl, 5-6-membered substituted heteroaryl, or 4-7-membered heterocyclic alkyl has one or more heteroatoms, the heteroatoms being arbitrarily selected from N, O, or S; wherein the 5-6-membered substituted heteroaryl has substituents arbitrarily selected from halogen, amino, hydroxyl, or C1-C6 alkyl; wherein the C1-C6 substituted alkyl has substituents arbitrarily selected from halogen, amino, cyano, hydroxyl, or C3-C7 cycloalkyl.

[0074] On the other hand, the present invention relates to compounds or stereoisomers of general formula (I), pharmaceutically acceptable salts, solvates, or tautomers, R 1 The substituent is selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C7 alkenyl, C2-C7 alkynyl, C1-C6 substituted alkyl, or 6-membered heteroaryl; wherein the substituent of the C1-C6 substituted alkyl group is optionally selected from halogen, amino, cyano, hydroxyl, or C3-C7 cycloalkyl; wherein the 6-membered heteroaryl group is selected from the following substituted or unsubstituted structures:

[0075]

[0076] The 6-membered heteroaryl substituents are arbitrarily selected from CH3 and C2H6.

[0077] In another aspect, the present invention relates to compounds or stereoisomers of general formula (I), pharmaceutically acceptable salts, solvates, or tautomers, R 1 Selected from H, F, Cl, Br, CF3, CN, CH3, OCH3, cyclopropyl, CH2CN or

[0078] In another aspect, the present invention relates to compounds or stereoisomers of general formula (Ia), pharmaceutically acceptable salts, solvates, or tautomers, where Z is 4-hydroxyl and n is 1.

[0079] In another aspect, the present invention relates to compounds or stereoisomers of general formula (I) or (Ia), pharmaceutically acceptable salts, solvates, or tautomers, where m is 1.

[0080] In other respects, the present invention relates to a pharmaceutical composition comprising a compound or stereoisomer of general formula (I) or (Ia), a pharmaceutically acceptable salt, a solvate, or a tautomer, and a pharmaceutically acceptable excipient.

[0081] In other respects, the present invention relates to the use of compounds or stereoisomers of general formula (I) or (Ia), pharmaceutically acceptable salts, solvates, or tautomers, or pharmaceutical compositions thereof in the preparation of CDK9 and / or TNIK-mediated diseases.

[0082] In other respects, the present invention relates to compounds or stereoisomers of general formula (I) or (Ia), pharmaceutically acceptable salts, solvates, or tautomers, or pharmaceutical compositions wherein CDK9 and / or TNIK-mediated diseases are hyperplastic diseases.

[0083] In other respects, the present invention relates to compounds or stereoisomers of general formula (I) or (Ia), pharmaceutically acceptable salts, solvates, or tautomers, or pharmaceutical compositions wherein CDK9 and / or TNIK mediate diseases of cancer, further solid tumors and / or hematologic malignancies.

[0084] In another aspect, the present invention relates to compounds or stereoisomers of the general formula (I) or (Ia), pharmaceutically acceptable salts, solvates, or tautomers, or pharmaceutical compositions thereof, wherein CDK9 and / or TNIK-mediated cancers may be selected from breast cancer, ovarian cancer, lung cancer, gastric cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer, prostate cancer, thyroid cancer, liver cancer, acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, or neurocytoma, etc.

[0085] In addition, the present invention can also be implemented through the following technical solutions:

[0086] On the one hand, the present invention relates to compounds or stereoisomers of general formula (I), pharmaceutically acceptable salts, solvates, or tautomers:

[0087]

[0088] in,

[0089] Q is selected from 5-6 aryl, 5-6 substituted aryl, 5-6 heteroaryl or 5-6 substituted heteroaryl;

[0090] The 5-6 substituted aryl group or the 5-6 substituted heteroaryl group optionally has one or more substituents, wherein the substituents are optionally selected from halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, -(CR5R6) m SO2R aSF5, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, or 3-7 membered substituted heterocycloalkyl; wherein the 3-7 membered substituted heterocycloalkyl has substituents selected from C1-C6 alkyl, C1-C6 alkoxy, or halogen; wherein R a Selected from H, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, 4-7 membered heterocyclic alkyl, aryl or heteroaryl; wherein R b The components are selected from H, C1-C6 alkyl, C1-C6 alkoxy, cyano, C3-C7 cycloalkyl, 4-7 heterocyclic alkyl, aryl, or heteroaryl; wherein R5 or R6 is selected from H, C1-C3 alkyl, halogen, or optionally R5 and R6 together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl or a 4- to 6-membered heterocyclic alkyl; wherein the 3- to 5-membered cycloalkyl and the 4- to 6-membered heterocyclic alkyl may be further substituted with C1-C6 alkyl, C1-C6 alkoxy, or halogen; wherein the C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, 4-7 heterocyclic alkyl, aryl, or heteroaryl may be further substituted with a substituent selected from: alkyl, halogen, amino, cyano, or hydroxyl.

[0091] 5-6-membered heteroaryl, 5-6-membered substituted heteroaryl, 4-7-membered heterocycloalkyl, heteroaryl, 4- to 6-membered heterocycloalkyl or 3-7-membered heterocycloalkyl or 3-7-membered substituted heterocycloalkyl, having one or more heteroatoms, said heteroatoms being arbitrarily selected from N, O or S;

[0092] m is 0, 1, 2, or 3;

[0093] R 1 R 2 R 3 or R 4 Each of the following is independently selected from H, halogen, amino, hydroxyl, cyano, haloalkyl, haloalkoxy, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C7 alkenyl, C2-C7 alkynyl, 5-6-membered heteroaryl, 5-6-membered substituted heteroaryl, C1-C6 substituted alkyl, and 4-7-membered heterocycloalkyl; wherein the 5-6-membered substituted heteroaryl has substituents that are arbitrarily selected from halogen, amino, hydroxyl, or C1-C6 alkyl; and the C1-C6 substituted alkyl has substituents that are arbitrarily selected from halogen, amino, cyano, hydroxyl, or C3-C7 cycloalkyl.

[0094] B represents O, NH, S, or CH2;

[0095] W represents a 5-7 nucleotide saturated cycloalkyl group, wherein the 5-7 nucleotide saturated cycloalkyl group optionally has one or more substituents selected from: H, halogen, amino, hydroxyl, acetamido, haloalkyl, C1-C6 alkyl or C1-C6 alkoxy; wherein the C1-C6 alkyl or C1-C6 alkoxy group is each optionally substituted by a substituent selected from: halogen, amino, cyano or hydroxyl.

[0096] On the one hand, the present invention provides compounds or stereoisomers of general formula (I), pharmaceutically acceptable salts, solvates, or tautomers having formula (Ia).

[0097]

[0098] in,

[0099] X1 represents O or NR8, and R8 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, cyano, C3-C7 cycloalkyl, 4-7 membered heterocyclic alkyl, aryl or heteroaryl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, 4-7 membered heterocyclic alkyl, aryl or heteroaryl are further substituted by substituents selected from: alkyl, halogen, amino, cyano or hydroxyl;

[0100] X2, X3, X4, or X5 are each independently selected from N or CR9, and R9 is selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, SF5, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, or 3-7 membered substituted heterocycloalkyl; 3-7 membered substituted heterocycloalkyl, wherein the substituent is selected from C1-C6 alkyl, C1-C6 alkoxy, or halogen; 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl, having one or more heteroatoms, wherein the heteroatoms are arbitrarily selected from N, O, or S;

[0101] R 1 R 2 R 3 or R 4 Each of the following is independently selected from H, halogen, amino, hydroxyl, cyano, haloalkyl, haloalkoxy, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C7 alkenyl or C2-C7 alkynyl, 5-6-membered heteroaryl, 5-6-membered substituted heteroaryl, C1-C6 substituted alkyl or 4-7-membered heterocyclic alkyl; wherein the 5-6-membered heteroaryl, 5-6-membered substituted heteroaryl, and 4-7-membered heterocyclic alkyl have one or more heteroatoms, the heteroatoms being arbitrarily selected from N, O or S; wherein the 5-6-membered substituted heteroaryl has substituents arbitrarily selected from halogen, amino, hydroxyl or C1-C6 alkyl; and the C1-C6 substituted alkyl has substituents arbitrarily selected from halogen, amino, cyano, hydroxyl or C3-C7 cycloalkyl;

[0102] R5 or R6 is independently selected from H, C1-C3 alkyl, halogen, or optionally R5 and R6 together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl or a 4- to 6-membered heterocycloalkyl; wherein the 3- to 5-membered cycloalkyl or the 4- to 6-membered heterocycloalkyl may be further substituted with a C1-C6 alkyl, a C1-C6 alkoxy or halogen; the C1-C6 alkyl or C1-C6 alkoxy may be further substituted with a substituent selected from: halogen, amino, cyano or hydroxyl; the heteroatom of the 4- to 6-membered heterocycloalkyl is selected from N, O or S;

[0103] R7 is selected from H, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, 4-7 membered heterocyclic alkyl, aryl or heteroaryl; C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, 4-7 membered heterocyclic alkyl, aryl or heteroaryl, further substituted by a substituent selected from: halogen, amino, cyano or hydroxyl;

[0104] B represents O, NH, S, or CH2;

[0105] Z represents H, halogen, amino, hydroxyl, acetamido, haloalkyl, C1-C6 alkyl or C1-C6 alkoxy; wherein the C1-C6 alkyl or C1-C6 alkoxy is substituted by a substituent selected from: halogen, amino, cyano or hydroxyl.

[0106] r is 0, 1, 2, or 3;

[0107] m is 0, 1, 2, or 3;

[0108] n is 0, 1, or 2.

[0109] On one hand, the present invention provides compounds or stereoisomers of general formula (I), pharmaceutically acceptable salts, solvates, or tautomers, wherein Q is a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 6-membered heteroaryl group; the substituted phenyl group or the substituted 6-membered heteroaryl group has substituents each arbitrarily selected from halogens, cyano groups, amino groups, hydroxyl groups, haloalkyl groups, haloalkoxy groups, C3-C7 cycloalkyl groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, etc. -(CR5R6) m SO2R a SF5, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, or 3-7 membered substituted heterocycloalkyl; wherein the 3-7 membered substituted heterocycloalkyl has substituents selected from C1-C6 alkyl, C1-C6 alkoxy, or halogen; R a Selected from H, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, 4-7 membered heterocyclic alkyl, aryl or heteroaryl; R bSelected from H, C1-C6 alkyl, C1-C6 alkoxy, cyano, C3-C7 cycloalkyl, 4-7-membered heterocyclic alkyl, aryl, or heteroaryl; R5 or R6 is selected from H, C1-C3 alkyl, halogen, or optionally R5 and R6 together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl or a 4- to 6-membered heterocyclic alkyl; the 3- to 5-membered cycloalkyl or the 4- to 6-membered heterocyclic alkyl may be further substituted with C1-C6 alkyl, C1-C6 alkoxy, or halogen; C1- C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, 4-7 heterocyclic alkyl, aryl or heteroaryl, further substituted by a substituent selected from: halogen, amino, cyano or hydroxyl; wherein the substituted or unsubstituted 6-membered heteroaryl, 3-7-membered heterocyclic alkyl, 3-7-membered substituted heterocyclic alkyl or 4-7-membered heterocyclic alkyl, heteroaryl or 4 to 6-membered heterocyclic alkyl has one or more heteroatoms, wherein the heteroatoms are arbitrarily selected from N, O or S; wherein m is 0, 1, 2 or 3.

[0110] On the one hand, the present invention provides compounds or stereoisomers of general formula (I), pharmaceutically acceptable salts, solvates, or tautomers, wherein Q is a 6-membered heteroaryl group having the following substituted or unsubstituted structures:

[0111]

[0112] Its substituents are arbitrarily selected from halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, -(CR5R6) m SO2R a SF5, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl; wherein the 3-7 membered heterocycloalkyl has one or more heteroatoms, the heteroatoms being arbitrarily selected from N, O or S; R a Selected from H, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, 4-7 membered heterocyclic alkyl, aryl or heteroaryl; R bThe carbon atom is selected from H, C1-C6 alkyl, C1-C6 alkoxy, cyano, C3-C7 cycloalkyl, 4-7 heterocyclic alkyl, aryl or heteroaryl; R5 or R6 is selected from H, C1-C3 alkyl, halogen, or optionally R5 and R6 together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl or a 4- to 6-membered heterocyclic alkyl; wherein the 3- to 5-membered cycloalkyl or the 4- to 6-membered heterocyclic alkyl may be further substituted with C1-C6 alkyl, C1-C6 alkoxy or halogen; C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, 4- to 7-membered heterocyclic alkyl, aryl or heteroaryl may be further substituted with a substituent selected from: halogen, amino, cyano or hydroxyl; 4- to 7-membered heterocyclic alkyl, heteroaryl or 4- to 6-membered heterocyclic alkyl having one or more heteroatoms, wherein the heteroatoms are arbitrarily selected from N, O or S; m is 0, 1, 2 or 3.

[0113] On one hand, the present invention provides compounds or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers of general formula (I), wherein X2, X3, X4, or X5 are each independently CR9, wherein R9 is selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, SF5, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, or 3-7 membered substituted heterocycloalkyl; the 3-7 membered substituted heterocycloalkyl has a substituent selected from C1-C6 alkyl, C1-C6 alkoxy, or halogen; the 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl has one or more heteroatoms, the heteroatoms being arbitrarily selected The R9 group is selected from N, O, or S; or X2, X3, X4, X5, where one of them is N and the rest are CR9, wherein R9 is selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, SF5, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, or 3-7 membered substituted heterocycloalkyl; the substituent of the 3-7 membered heterocycloalkyl group is selected from C1-C6 alkyl, C1-C6 alkoxy, or halogen; the 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl group has one or more heteroatoms, the heteroatoms being arbitrarily selected from N, O, or S; preferably, R9 is selected from H, F, Cl, Br, CH3, OCH3,

[0114] On the one hand, the present invention provides compounds or stereoisomers of general formula (I), pharmaceutically acceptable salts, solvates, or tautomers, R 1 R 2 R 3 or R 4Each of the following is independently selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C7 alkenyl, C2-C7 alkynyl, 5-6-membered heteroaryl, 5-6-membered substituted heteroaryl, C1-C6 substituted alkyl, or 4-7-membered heterocyclic alkyl; 5-6-membered heteroaryl, 5-6-membered substituted heteroaryl, or 4-7-membered heterocyclic alkyl, having one or more heteroatoms, wherein the heteroatoms are arbitrarily selected from N, O, or S; 5-6-membered substituted heteroaryl, wherein the substituents are arbitrarily selected from halogen, amino, hydroxyl, or C1-C6 alkyl; C1-C6 substituted alkyl, wherein the substituents are arbitrarily selected from halogen, amino, cyano, hydroxyl, or C3-C7 cycloalkyl.

[0115] On the one hand, the present invention provides compounds or stereoisomers of general formula (I), pharmaceutically acceptable salts, solvates, or tautomers, R 1 Selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C7 alkenyl, C2-C7 alkynyl, C1-C6 substituted alkyl, or 6-membered heteroaryl; C1-C6 substituted alkyl, wherein the substituent is optionally selected from halogen, amino, cyano, hydroxyl, or C3-C7 cycloalkyl; 6-membered heteroaryl, selected from the following substituted or unsubstituted structures:

[0116]

[0117] The 6-membered heteroaryl substituents are arbitrarily selected from CH3 and C2H6.

[0118] On the one hand, the present invention provides compounds or stereoisomers of general formula (I), pharmaceutically acceptable salts, solvates, or tautomers, R 1 Selected from H, F, Cl, Br, CF3, CN, CH3, OCH3, cyclopropyl, CH2CN or

[0119] On the one hand, the present invention provides compounds or stereoisomers of general formula (I), pharmaceutically acceptable salts, solvates, or tautomers, wherein Z can be arbitrarily selected from H, acetamido, methyl, or 4-hydroxy; n is 1; and r is 0, 1, or 2.

[0120] On the one hand, the present invention provides compounds or stereoisomers of general formula (I), pharmaceutically acceptable salts, solvates, or tautomers, where m is 1.

[0121] In another aspect, the present invention provides a pharmaceutical composition comprising a compound or stereoisomer of general formula (I), a pharmaceutically acceptable salt, a solvate, or a tautomer, and a pharmaceutically acceptable excipient.

[0122] In another aspect, the present invention provides the use of a compound or stereoisomer of general formula (I), a pharmaceutically acceptable salt, a solvate, or a tautomer, or a pharmaceutical composition thereof in the preparation of CDK9 and / or TNIK-mediated diseases.

[0123] In another aspect, the present invention provides compounds or stereoisomers of general formula (I), pharmaceutically acceptable salts, solvates, or tautomers, or pharmaceutical compositions wherein CDK9 and / or TNIK-mediated diseases are hyperplastic diseases.

[0124] In another aspect, the present invention provides compounds or stereoisomers of general formula (I), pharmaceutically acceptable salts, solvates, or tautomers, or pharmaceutical compositions wherein CDK9 and / or TNIK mediate diseases of cancer, further solid tumors and / or hematologic malignancies.

[0125] In another aspect, the present invention provides compounds or stereoisomers of general formula (I), pharmaceutically acceptable salts, solvates, or tautomers, or pharmaceutical compositions, wherein the cancers mediated by CDK9 and / or TNIK are selected from breast cancer, ovarian cancer, lung cancer, gastric cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer, prostate cancer, thyroid cancer, liver cancer, acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, or neurocytoma. Detailed Implementation

[0126] Before further describing the invention, it should be understood that the invention is not limited to the specific embodiments described herein. The terminology used herein is for the purpose of describing specific embodiments only and is not intended to limit them. Furthermore, the scope of the invention is limited only by the appended claims and specification. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0127] Chemical definition

[0128] "alkyl" refers to an aliphatic hydrocarbon group, specifically a saturated hydrocarbon group. The alkyl moiety can be a straight-chain alkyl group or a branched alkyl group. Examples include C1-C6 alkyl, C1-C4 alkyl, or C1-C3 alkyl. C1-C6 alkyl refers to an alkyl group having 1 to 6 carbon atoms, such as alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of alkyl groups include (but are not limited to) methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that, based on the knowledge of the art and the teachings provided herein, will be considered equivalent to any of the foregoing examples. The alkyl group can be unsubstituted or substituted with one or more substituents, including but not limited to alkyl, alkoxy, cyano, amino, hydroxyl, carbonyl, carboxyl, aryl, heteroaryl, amino, halogen, sulfonyl, sulfinyl, phosphonyl, etc.

[0129] In this terminology, "ring" refers to any covalently closed structure, including, for example, carbocyclic rings (e.g., aryl or cycloalkyl), heterocyclic rings (e.g., heteroaryl or heterocycloalkyl), aromatic groups (e.g., aryl or heteroaryl), and non-aromatic groups (e.g., cycloalkyl or heterocycloalkyl). The ring may be optionally substituted and may be monocyclic or polycyclic. Typical polycyclic rings generally include bicyclic and tricyclic rings. The rings in this application typically have 1-20 ring atoms, for example, 1 ring atom, 2 ring atoms, 3 ring atoms, 4 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms, 9 ring atoms, 10 ring atoms, 11 ring atoms, 12 ring atoms, 13 ring atoms, 14 ring atoms, 15 ring atoms, 16 ring atoms, 17 ring atoms, 18 ring atoms, 19 ring atoms, or 20 ring atoms.

[0130] In terminology, "membered ring" refers to the number of skeletal atoms that make up the ring. Typical 5-membered rings include, for example, cyclopentyl, pyrrole, imidazole, thiazole, furan, and thiophene; typical 6-membered rings include, for example, cyclohexyl, pyridine, pyran, pyrazine, thiran, pyridazine, pyrimidine, and benzene. Among these, rings containing heteroatoms in their skeletal structure are called heterocycles; aromatic groups containing heteroatoms are called heteroaryl groups; and non-aromatic groups containing heteroatoms are called heterocyclic alkyl groups.

[0131] In this terminology, "heteroatom" refers to an atom other than carbon or hydrogen. One or more heteroatoms in the heterocycle of this application may be independently selected from O, S, N, Si, and P, but are not limited thereto.

[0132] "4-hydroxy" indicates that the hydroxyl group is located at position 4 or para position of the group.

[0133] In the terminology, "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0134] In the terminology, "cyano" refers to -CN.

[0135] In the terminology, "hydroxyl group" refers to -OH.

[0136] In the terminology, "amino" refers to -NH2.

[0137] In the terminology, "halogenated alkyl" refers to an alkyl group in which at least one hydrogen atom is replaced by a halogen atom, such as CF3, (CH2)F, CHF2, CH2Br, CH2CF3, and CH2CH2F.

[0138] In the terminology, "haloalkoxy" refers to an alkoxy group in which at least one hydrogen atom is replaced by a halogen atom, such as CH3OCH2F.

[0139] In this terminology, "cycloalkyl" refers to a cyclic hydrocarbon substituent comprising 1-3 rings that is saturated or partially unsaturated (containing one or more double bonds, but none of the rings having a fully conjugated π-electron system). It includes monocycloalkyl, bicycloalkyl, and tricycloalkyl groups, containing 3-20 ring-forming carbon atoms, preferably 3-10 carbon atoms (i.e., 3-10 membered cycloalkyl, also referred to as C3-C10 cycloalkyl), for example 3 to 8, 3 to 7, 3 to 6, or 5 to 6 carbon atoms. Preferably, the cycloalkyl group is selected from monovalent cycloalkyl groups obtained from the following rings:

[0140]

[0141] More preferably, the cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0142] "Heterocyclic alkyl" and "cycloheteroalkyl" are used interchangeably to refer to a saturated, non-aromatic monocyclic, fused, bridged, or spirocyclic group containing one or more (e.g., 1, 2, 3, or 4) heteroatoms, wherein the heteroatoms may be N, O, or S. Heterocyclic alkyl groups may be 3 to 10 members (e.g., 3, 4, 5, 6, 7, 8, 9, or 10 members, i.e., containing 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms) of monocyclic, bicyclic, or tricyclic groups. The ring structure may optionally contain up to two oxo groups on the carbon or sulfur ring member.

[0143] Typical heterocyclic alkyl groups include, but are not limited to, monovalent groups derived from the following rings:

[0144]

[0145] These heterocyclic alkyl groups can also be represented using the commonly understood structural formulas, for example...

[0146]

[0147] The preferred structure is a saturated, non-aromatic monocyclic structure containing one or more heteroatoms.

[0148] The term "aryl" refers to a monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system and 6 to 14 carbon atoms (6 to 14 members). Illustrative aryl groups include, but are not limited to, phenyl, naphthyl, and anthracene. Phenyl is preferred.

[0149] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 (e.g., 1, 2, 3, or 4) heteroatoms and 5 to 14 ring atoms (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14), wherein the heteroatoms are selected from O, S, or N. Illustrative examples of heteroaryls include entities in the form of suitable bonded portions:

[0150]

[0151] The heteroaryl group is preferably 5 to 10 membered, containing 1 to 3 heteroatoms; preferably 5 or 6 membered, containing 1 to 3 heteroatoms; more preferably 6 membered heteroaryl, such as pyridyl, pyrimidinyl, pyrazinyl, etc.

[0152] The term "alkenyl" refers to a straight-chain, branched, or cyclic hydrocarbon group containing 2 to 12 carbon atoms and having one or more double bonds. For example, C2-C7 alkenyl groups refer to those containing 2-7 carbon atoms, which can be vinyl groups with 2 carbon atoms, allyl groups with 3 carbon atoms, etc. Alkenyl groups can be terminal or non-terminated, and can be unsubstituted or substituted as described by alkyl groups or as described in the various examples provided herein. This term includes cis and trans isomers and mixtures thereof.

[0153] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group having 2 to 12 carbon atoms in the chain and having one or more triple bonds. The alkynyl group may be unsubstituted or substituted as described with respect to alkyl groups or as described in the various examples provided herein.

[0154] In compound structures, "*" indicates that the atom at that location has a chiral center; in compound structures Such as structure This indicates that compounds containing this structure can exist in either the R or S configuration.

[0155] "Substitution" refers to one or more hydrogen atoms in a group, preferably up to five (e.g., 1, 2, 3, 4, 5), more preferably 1 to 3 hydrogen atoms that can be independently replaced by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and those skilled in the art can determine (through experiment or theory) possible or impossible substitutions without much effort.

[0156] "Optionally" means that the events or circumstances described below may or may not occur, and the description includes both the possibility that the events or circumstances have occurred and the possibility that they have not occurred. For example, "wherein each hydrogen atom in the C1-C6 alkyl, 5-6 aryl, and 5-6 heteroaryl groups is optionally independently substituted by a C1-C6 alkyl group" means that the alkyl group may or may not be present on any of the C1-C6 alkyl, 5-6 aryl, and 5-6 heteroaryl groups by substituting hydrogen atoms of the alkyl group.

[0157] "Independently" means that the event or situation described below should be understood in itself with respect to other similar events or circumstances. For example, "independently" means that each hydrogen atom on a group can be substituted by another group, wherein the groups substituting for each hydrogen atom can be the same or different. Or, for example, if there are multiple groups, each of which can be selected from the group of possibilities, then using "independently" means that each group can be selected from the group of possibilities independently of any other group, and the groups selected in the case can be the same or different.

[0158] The term "stereoisomer" as used in this invention refers to the presence of a compound containing one or more asymmetric centers, which can exist as a racemic mixture and a mixture thereof, a single enantiomer, a mixture of diastereomers, and a single diastereomer. Compounds of this invention may have asymmetric centers, resulting in two optical isomers. The scope of this invention includes all possible optical isomers and mixtures thereof. If the compounds of this invention contain an olefin double bond, the scope of this invention includes cis and trans isomers unless otherwise specified. Compounds of this invention can exist as tautomers (a type of functional group isomer) having different hydrogen connection points through one or more double bond shifts; for example, a ketone and its enol form are keto-enol tautomers. All tautomers and mixtures thereof are within the scope of this invention. Enantiomers of all compounds. Diastereomers, racemates, mesomates, cis-trans isomers, tautomers, geometric isomers, epimers, and mixtures thereof are all within the scope of this invention.

[0159] The term “compounds of the present invention” is intended to cover compounds of general formula (I) as defined herein, or any preferred or specific embodiment thereof (including compounds of formula (Ia) and the example compounds), their stereoisomers, pharmaceutically acceptable salts, tautomers or solvates.

[0160] The term "pharmaceutically acceptable" means a molecular entity or composition that is approved or can be approved by the relevant authorities of each country, or is listed in a generally accepted pharmacopoeia for use in animals, and more specifically in humans, or that will not produce adverse, allergic, or other adverse reactions when administered appropriately to animals, such as humans. Specifically, such salts are non-toxic and may be addition salts of inorganic acids, organic acids, or bases.

[0161] The “pharmaceutical composition” of this invention refers to a composition comprising one or more compounds of formula (I), formula (Ia) or their stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, and a carrier or excipient generally accepted in the art for delivering a bioactive compound to an organism (e.g., a human).

[0162] The pharmaceutical compositions of the present invention can be formulated using techniques known to those skilled in the art, such as those disclosed in the 20th edition of Remington's Pharmaceutical Sciences. The pharmaceutical compositions of the present invention can be prepared by mixing the compounds of the present invention or pharmaceutically acceptable salts thereof with one or more pharmaceutically acceptable excipients. Preparation may further include the step of mixing one or more other active ingredients with the compounds of the present invention and one or more pharmaceutically acceptable excipients.

[0163] The selection of pharmaceutically acceptable excipients in this invention depends on a variety of factors, such as the route of administration and the form of the composition provided. Suitable pharmaceutically acceptable excipients are well known to those skilled in the art and described, for example, in Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia Lippincott, Williams & Wikins, 2004, and include, for example, adjuvants, diluents (e.g., glucose, lactose, or mannitol), carriers, pH adjusters, buffers, sweeteners, fillers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow aids, processing aids, colorants, flavorings, diluents, binders, and other known additives.

[0164] The pharmaceutical compositions of the present invention can be administered in a standard manner. Suitable administration methods include, for example, oral, intravenous, rectal, parenteral, topical, transdermal, ocular, nasal, buccal, or pulmonary (inhalation) administration; wherein parenteral administration includes intramuscular, intravenous, intra-arterial, intraperitoneal, or subcutaneous administration. For these purposes, the compounds of the present invention can be formulated into tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops, aerosols, dry powder injections, and sterile injectable aqueous or oily solutions or suspensions by methods known in the art. The compounds of the present invention, or pharmaceutically acceptable salts thereof, can be formulated into solutions, emulsions, suspensions, or dispersions in suitable pharmaceutical solvents or carriers, or formulated with pharmaceutically acceptable excipients, into commonly used pharmaceutically acceptable dosage forms, according to conventional methods known in the art for preparing various dosage forms.

[0165] The preventive or therapeutic dose of the compounds of this invention will vary depending on a range of factors, including the individual being treated, the severity of the condition or illness, the rate of administration, the disposal of the compound, and the prescribing physician's judgment. Generally, the effective dose is from about 0.0001 to about 5000 mg per kg of body weight per day, for example, from about 0.01 to about 1000 mg / kg / day (single or divided doses). For a 70 kg person, this would total from about 0.007 mg / day to about 7000 mg / day, for example, from about 0.7 mg / day to about 1500 mg / day. Depending on the administration method, the content or amount of the compound of the present invention in the pharmaceutical composition can be from about 0.01 mg to about 1000 mg, suitably 0.1-500 mg, preferably 0.5-300 mg, more preferably 1-150 mg, particularly preferably 1-50 mg, such as 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg, etc.; accordingly, the pharmaceutical composition of the present invention will contain 0.05 to 99% w / w (weight percentage), such as 0.05 to 80% w / w, such as 0.10 to 70% w / w, such as 0.10 to 50% w / w of the compound of the present invention, all weight percentages are based on the total composition. It should be understood that it may be necessary to use doses exceeding these limits in certain circumstances.

[0166] It should be understood that the compound structures and functional groups of the present invention conform to the rules of chemical valence bonds. Some functional groups or structures have had their connecting bonds omitted in writing. For example, in some cases, X2 / X3 / X4 / X5 in formula (Ia) are selected from N, and based on the general formula structure, X2 / X3 / X4 / X5 is =N-. Additionally, in the present invention, substituents such as =NR... b Based on the general formula structure, NR b =NR b Other groups can be understood and explained in a similar way.

[0167] The present invention also includes compounds identical to those described herein, but in which one or more atoms are labeled with isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 31P, 32P, 35S, 18F, 123I, 125I, and 36Cl, respectively.

[0168] Certain isotopically labeled compounds of this disclosure (e.g., those labeled with 3H and 14C) can be used in the analysis of compound and / or substrate tissue distribution. Tritium (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emission isotopes, such as 15O, 13N, 11C, and 18F, can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of this disclosure can generally be prepared by replacing unlabeled reagents with isotopically labeled reagents.

[0169] Furthermore, substitution with a heavier isotope (such as deuterium (i.e., 2H)) can provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirements), and may therefore be preferred in certain situations, where the deuterium substitution can be partial or complete, with partial deuterium substitution referring to at least one hydrogen being replaced by at least one deuterium.

[0170] Obviously, based on the above description of the present invention, and using common technical knowledge and methods in the field, various other modifications, substitutions, or alterations can be made without departing from the basic technical concept of the present invention.

[0171] Beneficial effects of the invention

[0172] This invention provides a class of compounds or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers with the general formula (I) structure. Studies have shown that this type of structure can effectively inhibit CDK9-mediated and / or TNIK-mediated diseases, thereby preventing or treating CDK9 and / or TNIK-mediated related diseases. Detailed Implementation

[0174] The following examples illustrate the synthesis methods of the compounds and intermediates of this invention. These examples are merely illustrative and should not be construed as limiting the scope of the invention. Unless otherwise specified, the raw materials and reagents involved in this invention are commercially available, and their specific sources do not affect the implementation of the technical solutions of this invention. The abbreviations and symbols used in the following description have the following meanings:

[0175]

[0176]

[0177] Preparation Example 1: Preparation of 3-((methylthio)methyl)aniline

[0178]

[0179] Step 1: Preparation of 1-(chloromethyl)-3-nitrobenzene

[0180]

[0181] 3-Nitrobenzyl alcohol (2.0 g) was dissolved in anhydrous dimethyl sulfoxide (50 mL), and cyanuric chloride (2.0 g) was slowly added. The reaction was carried out at room temperature for 1 hour. The reaction was confirmed to be complete by TLC. Water was added and the mixture was stirred for 5 minutes. The mixture was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to give 1.8 g of the title compound.

[0182] Step 2: Preparation of (3-nitrobenzyl)thiol

[0183]

[0184] 1-(chloromethyl)-3-nitrobenzene (1.5 g) was dissolved in ethanol (10 mL), and an aqueous solution of sodium methanethiol (20% in H2O, 3.5 mL) was slowly added dropwise at 0 °C. The reaction was allowed to proceed for 20 minutes. The reaction was confirmed to be complete by TLC. Water was added, and the mixture was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to give 1.2 g of the title compound.

[0185] Step 3: Preparation of 3-((methylthio)methyl)aniline

[0186]

[0187] (3-Nitrobenzyl)thiol (1.0 g) was dissolved in ethanol (4 mL), followed by the addition of water (1 mL), iron powder (3.5 g), and a few drops of hydrochloric acid. The mixture was refluxed for 3 hours. The reaction was confirmed to be complete by TLC. The solid was removed by filtration. The filtrate was adjusted to a weakly alkaline pH with saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to give 0.75 g of the title compound.

[0188] MS(ESI)m / z(M+H) + =154.1.

[0189] Preparation Example 2: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2-chloroquinazoline

[0190] Step 1: Preparation of 8-methoxyquinazoline-2,4(1H,3H)-dione

[0191]

[0192] 2-Amino-3-methoxybenzoic acid (20.0 g) was dissolved in N-methylpyrrolidone (100 mL), and urea (30.0 g) was slowly added. The mixture was heated at 160 °C for 6 hours. TLC and LCMS showed that the reaction was complete. Water (100 mL) was added while hot to precipitate the solid. The solid was filtered, collected, washed with petroleum ether, and dried to give 20.0 g of the title compound.

[0193] MS(ESI)m / z(M+H) + =193.1.

[0194] Step 2: Preparation of 2,4-dichloro-8-methoxyquinazoline

[0195]

[0196] 20.0 g of 8-methoxyquinazoline-2,4(1H,3H)-dione was dissolved in 100 mL of phosphorus oxychloride, and 30.0 g of N,N-dimethylaniline was added dropwise. The mixture was refluxed at 130 °C for 3 hours. TLC and LCMS showed that the reaction was complete. The reaction solution was concentrated to remove excess phosphorus oxychloride, and the residue was slowly added to an ice-water solution of saturated sodium bicarbonate. The mixture was extracted four times with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to give 15.0 g of the title compound.

[0197] MS(ESI)m / z(M+H) + =229.0.

[0198] Step 3: Preparation of 2-chloro-8-methoxyquinazoline

[0199]

[0200] 15.0 g of 2,4-dichloro-8-methoxyquinazoline was dissolved in 200 mL of ethyl acetate. 16.5 mL of N,N-diisopropylethylamine was added dropwise, followed by 1.5 g of palladium on carbon. The mixture was purged with hydrogen three times and reacted at room temperature for 1 hour. TLC and LCMS showed that the reaction was complete. Excess palladium on carbon was removed by filtration. The filtrate was collected, concentrated, and the crude product was purified by column chromatography to give 8.0 g of the title compound.

[0201] MS(ESI)m / z(M+H) + =195.0.

[0202] Step 4: Preparation of 2-chloro-8-hydroxyquinazoline

[0203]

[0204] Under an ice-water bath and nitrogen atmosphere, 8.0 g of 2-chloro-8-methoxyquinazoline was dissolved in 80 mL of dichloromethane, and 40 mL of boron tribromide was slowly added. The mixture was then allowed to react overnight at room temperature. TLC and LCMS showed that the reaction was complete. The reaction solution was quenched with water, extracted four times with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to give 4.3 g of the title compound.

[0205] MS(ESI)m / z(M+H) + =181.0.

[0206] Step 5: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2-chloroquinazoline

[0207]

[0208] Under a nitrogen atmosphere, triphenylphosphine (10.4 g) was dissolved in tetrahydrofuran (150 mL), and diisopropyl azodicarbonate (7.9 g) was added dropwise. Under nitrogen protection, 2-chloro-8-hydroxyquinazoline (4.3 g) and trans-4-((tert-butyldimethylsilyl)oxy)cyclohexanol (6 g) were dissolved in tetrahydrofuran solution (150 mL). The two reaction solutions were then mixed and reacted for half an hour. TLC and LCMS showed that the reaction was complete. The reaction system was concentrated, and the crude product was purified by column chromatography to give 4.0 g of the title compound.

[0209] MS(ESI)m / z(M+H) + =393.2.

[0210] Preparation Example 3: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((methylthio)methyl)phenyl)quinazolin-2-amine)

[0211]

[0212] 3-((methylthio)methyl)aniline (0.5 g), 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2-chloroquinazoline (1.3 g), and cesium carbonate (1.1 g) were dissolved in isopropanol (10 mL) and reacted in a microwave oven at 90 °C for 30 minutes. The reaction was confirmed to be complete by TLC. The solid was removed by filtration, the filter cake was washed with ethyl acetate, the organic phases were combined, concentrated, and the crude product was purified by column chromatography to give 0.9 g of the title compound.

[0213] MS(ESI)m / z(M+H) + =510.3.

[0214] Preparation Example 4: Preparation of 7-bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2-chloroquinazoline

[0215]

[0216] Step 1: Preparation of 7-bromo-2-chloroquinazoline-8-ol

[0217]

[0218] 2-Chloroquinazoline-8-ol (3.0 g) was dissolved in chloroform (150 mL). Under ice bath conditions, diisopropylamine (6 mL) and N-bromosuccinimide (3.1 g) were slowly added, and the reaction was allowed to proceed for 2 hours. TLC and LCMS showed the reaction was complete. The reaction solution was concentrated to remove excess chloroform, and water (50 mL) was added. The mixture was extracted four times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography. The resulting solid was washed with petroleum ether and dried to give 3.5 g of the title compound.

[0219] MS(ESI)m / z(M+H) + =258.9, 260.9.

[0220] Step 2: Preparation of 7-bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2-chloroquinazoline

[0221]

[0222] Under an inert gas atmosphere, triphenylphosphine (10.2 g) was dissolved in anhydrous tetrahydrofuran (150 mL), and diisopropyl azodicarbonate (7.9 g) was slowly added. Under nitrogen protection, 7-bromo-2-chloroquinazoline-8-ol (4.0 g) and trans-4-((tert-butyldimethylsilyl)oxy)cyclohexanol (6.0 g) were dissolved in tetrahydrofuran. The two reaction solutions were then mixed, and the reaction was allowed to proceed for 30 minutes. TLC and LCMS showed that the reaction was complete. The reaction system was concentrated, and the crude product was purified by column chromatography to give 5.0 g of the title compound.

[0223] MS(ESI)m / z(M+H) + =471.1, 473.1.

[0224] Preparation Example 5: Preparation of 7-bromo-8-(cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((methylthio)methyl)phenyl)quinazolin-2-amine

[0225]

[0226] The compound of this preparation example was prepared by a method similar to that described in Preparation Example 3 above.

[0227] MS(ESI)m / z(M+H) + =588.2, 590.2.

[0228] Preparation Example 6: Preparation of 4-chloro-3-((methylthio)methyl)aniline

[0229]

[0230] Step 1: Preparation of 2-(bromomethyl)-1-chloro-4-nitrobenzene

[0231]

[0232] (2-Chloro-5-nitrophenyl)methanol (1.20 g) was dissolved in dichloromethane (15 mL). Triphenylphosphine (2.17 g) and N-bromosuccinimide (1.48 g) were added separately at 0 °C, and the mixture was allowed to react at room temperature for 1 hour. The reaction solution was quenched with water (30 mL), extracted with dichloromethane (2 x 30 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 1.2 g of the title compound. The crude product was used directly in the next reaction without purification.

[0233] Step 2: Preparation of (2-chloro-5-nitrobenzyl)(methyl)thion

[0234]

[0235] 1.20 g of 2-(bromomethyl)-1-chloro-4-nitrobenzene was dissolved in 20 mL of tetrahydrofuran, and 5 mL of 20% sodium methanethiol aqueous solution was added dropwise at -20 °C. The reaction was allowed to proceed overnight. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 935 mg of the title compound.

[0236] Step 3: Preparation of 4-chloro-3-((methylthio)methyl)aniline

[0237]

[0238] (2-chloro-5-nitrobenzyl)(methyl)thion (930 mg) was dissolved in ethanol / water (16 mL, 3:1), iron powder (721 mg) and ammonium chloride (708 mg) were added, and the mixture was heated at 50 °C for 1 hour. The reaction was complete as indicated by TLC. Insoluble matter was removed by filtration, the filtrate was collected, concentrated to remove the solvent, and the crude product was purified by column chromatography to give 590 mg of the title compound.

[0239] MS(ESI)m / z(M+H) + =188.2.

[0240] Preparation Example 7: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(4-chloro-3-((methylthio)methyl)phenyl)quinazolin-2-amine)

[0241]

[0242] The compound of this preparation example was prepared by a method similar to that described in Preparation Example 3 above.

[0243] MS(ESI)m / z(M+H) + =544.2.

[0244] Preparation Example 8: Preparation of 3-fluoro-5-((methylthio)methyl)aniline

[0245]

[0246] The compound of this preparation example was prepared by a method similar to that described in Preparation Example 6 above.

[0247] MS(ESI)m / z(M+H) + =172.1.

[0248] Preparation Example 9: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-fluoro-5-((methylthio)methyl)phenyl)quinazolin-2-amine)

[0249]

[0250] The compound of this preparation example was prepared by a method similar to that described in Preparation Example 3 above.

[0251] MS(ESI)m / z(M+H) + =528.2.

[0252] Preparation Example 10: Preparation of 7-bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-fluoro-5-((methylthio)methyl)phenyl)quinazolin-2-amine)

[0253]

[0254] The compound of this preparation example was prepared by a method similar to that described in Preparation Example 3 above.

[0255] MS(ESI)m / z(M+H) + =606.2,608.2.

[0256] Preparation Example 11: Preparation of 7-bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(4-chloro-3-((methylthio)methyl)phenyl)quinazolin-2-amine)

[0257]

[0258] The compound of this preparation example was prepared by a method similar to that described in Preparation Example 3 above.

[0259] MS(ESI)m / z(M+H) + =622.1,624.1.

[0260] Preparation Example 12: Preparation of 2-chloro-8-fluoro-7-(trifluoromethyl)quinazoline

[0261]

[0262] Step 1: Preparation of 2-(2,3-difluorophenyl)-1,3-dioxolane

[0263]

[0264] 14.2 g of 2,3-difluorobenzaldehyde was dissolved in 100 mL of toluene, and 9.3 g of ethylene glycol and 1.90 g of p-toluenesulfonic acid were added. The mixture was refluxed for three hours. TLC showed that the reaction proceeds were complete. The reaction solution was cooled to room temperature, and 100 mL of saturated ammonium bicarbonate aqueous solution was added. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to give 17.2 g of the title compound.

[0265] Step 2: Preparation of 2-(2,3-difluoro-4-iodophenyl)-1,3-dioxolane

[0266]

[0267] 5.6 g of 2-(2,3-difluorophenyl)-1,3-dioxolane was dissolved in 50 mL of anhydrous tetrahydrofuran. The mixture was stirred at -78 °C under anhydrous and oxygen-free nitrogen protection. 25 mL of 2M diisopropylaminolithium was slowly added dropwise. After the addition was complete, the mixture was heated to -50 °C and stirred for 1 hour. Then, 11.4 g of elemental iodine was added. The mixture was allowed to react at room temperature overnight. LC-MS showed that the reaction was complete. The reaction was quenched with a suitable amount of saturated sodium thiosulfate solution, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to give 7.7 g of the title compound.

[0268] Step 3: Preparation of 2,3-difluoro-4-iodobenzaldehyde

[0269]

[0270] 3.1 g of 2-(2,3-difluoro-4-iodophenyl)-1,3-dioxolane was dissolved in a mixed solution of hydrochloric acid (10 mL, 2N) and tetrahydrofuran (10 mL), and the reaction was carried out at room temperature for 2 hours. TLC analysis showed no residual starting material. The reaction mixture was concentrated to remove some of the reaction solution, diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated brine, and the organic phase was collected. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2.5 g of crude product, which was used directly in the next reaction without purification.

[0271] Step 4: Preparation of 8-fluoro-7-iodoquinazolin-2-amine

[0272]

[0273] 2,3-Difluoro-4-iodobenzaldehyde (2.5 g), guanidine carbonate (2.0 g), and N,N-diisopropylethylamine (2.4 g) were dissolved in N-methylpyrrolidone (20 mL), and reacted at 140 °C for 2 hours. LC-MS analysis showed no residual starting material. After the reaction solution cooled, ice water was slowly added until no new solid was formed. The reaction solution was filtered, the solid was collected, dried, and 1.9 g of crude product was obtained, which was used directly in the next reaction without purification.

[0274] MS(ESI)m / z(M+H) + =289.9.

[0275] Step 5: Preparation of 2-chloro-8-fluoro-7-iodoquinazoline

[0276]

[0277] 3.1 g of 8-fluoro-7-iodoquinazolin-2-amine and 2.2 g of tetrabutylammonium chloride were dissolved in a mixture of dichloromethane (15 mL) and N,N-dimethylformamide (1.5 mL). The mixture was stirred thoroughly at room temperature, and 2.9 g of trimethylchlorosilane was slowly added. After stirring for 20 minutes, 2.1 g of tert-butyl nitrite was added, and the reaction was continued for 3 hours. TLC showed no residual starting material. The pH of the reaction mixture was adjusted to approximately 10 by adding saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to give 1.0 g of the title compound.

[0278] MS(ESI)m / z(M+H) + =308.9.

[0279] Step 6: Preparation of 2-chloro-8-fluoro-7-(trifluoromethyl)quinazoline

[0280]

[0281] 2-Chloro-8-fluoro-7-iodoquinazoline (1.0 g), methyl fluorosulfonyl difluoroacetate (1.3 g), and cuprous iodide (0.74 g) were dissolved in N,N-dimethylformamide (15 mL). The mixture was reacted at 80 °C for 3 hours under anhydrous and oxygen-free nitrogen protection. LC-MS analysis showed no residual starting material. The reaction mixture was filtered, and the filtrate was collected, diluted with ethyl acetate, washed with saturated brine, and the organic phase was collected. The solution was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to give 0.35 g of the title compound.

[0282] MS(ESI)m / z(M+H) + =251.0.

[0283] Preparation Example 13: Preparation of 8-(((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-(((methylthio)methyl)phenyl)-7-(trifluoromethyl)quinazolin-2-amine)

[0284]

[0285] Step 1: Preparation of 8-fluoro-N-(3-((methylthio)methyl)phenyl)-7-(trifluoromethyl)quinazoline-2-amine

[0286]

[0287] 2-Chloro-8-fluoro-7-(trifluoromethyl)quinazoline (330 mg), 3-((methylthio)methyl)aniline (200 mg), palladium acetate (30 mg), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (130 mg), and cesium carbonate (860 mg) were dissolved in 1,4-dioxane (15 mL). The mixture was heated at 80 °C for 2 hours under anhydrous and oxygen-free nitrogen protection. LC-MS analysis showed no residual starting material. The mixture was filtered, the filtrate was collected, concentrated, and the crude product was purified by column chromatography to obtain 300 mg of the title compound.

[0288] MS(ESI)m / z(M+H) + =368.0.

[0289] Step 2: Preparation of 8-(((cis-4-hydroxycyclohexyl)oxy)-N-(3-(((methylthio)methyl)phenyl)-7-(trifluoromethyl)quinazolin-2-amine

[0290]

[0291] 8-Fluoro-N-(3-((methylthio)methyl)phenyl)-7-(trifluoromethyl)quinazolin-2-amine (100 mg), cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl-1-ol (62 mg), and sodium tert-butoxide (52 mg) were dissolved in N,N-dimethylformamide (15 mL), and the mixture was heated at 120 °C for 2 hours. LC-MS analysis showed no residual starting material. The reaction was quenched with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 120 mg of crude product, which was used directly in the next reaction without purification.

[0292] MS(ESI)m / z(M+H) + =464.1.

[0293] Step 3: Preparation of 8-(((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-(((methylthio)methyl)phenyl)-7-(trifluoromethyl)quinazolin-2-amine)

[0294]

[0295] 8-(((cis-4-hydroxycyclohexyl)oxy)-N-(3-(((methylthio)methyl)phenyl)-7-(trifluoromethyl)quinazolin-2-amine (120 mg), 1-methyl-1H-imidazolium (64 mg), and tert-butyldimethylchlorosilane (120 mg) were dissolved in dichloromethane (5 mL) and reacted at 40 °C for 3 hours. LCMS showed no residual starting material. The reaction was quenched with water, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by preparative TLC to give 60 mg of the title compound.

[0296] MS(ESI)m / z(M+H) + =578.3.

[0297] Preparation Example 14: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2,7-dichloroquinazoline

[0298] Step 1: Preparation of 4-chloro-2-fluoro-3-methoxybenzaldehyde

[0299]

[0300] 4.8 g of 1-chloro-3-fluoro-2-methoxybenzene was dissolved in 50 mL of anhydrous tetrahydrofuran, purged three times with argon, and a solution of n-butyllithium in n-hexane (15.6 mL, 2.5 M) was added dropwise at -78 °C, with stirring for 30 minutes. 10 mL of anhydrous N,N-dimethylformamide was added, and the mixture was allowed to react at room temperature for 1 hour. TLC monitoring showed no reactants remaining. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 5.9 g of the title compound.

[0301] Step 2: Preparation of 7-chloro-8-methoxyquinazoline-2-amine

[0302]

[0303] 5.9 g of 4-chloro-2-fluoro-3-methoxybenzaldehyde and 6.78 g of guanidine carbonate were dissolved in 15 mL of N,N-dimethylacetamide, and the mixture was heated at 140 °C for 2 hours. TLC showed no reactants remaining. After cooling the reaction mixture to room temperature, 100 mL of water was added, and the mixture was stirred for 30 minutes. The precipitated solid was collected, washed with water, and dried to give 3.2 g of the title compound. The crude product was used directly in the next reaction without further purification.

[0304] MS(ESI)m / z(M+H) + =210.0.

[0305] Step 3: Preparation of 2,7-dichloro-8-methoxyquinazoline

[0306]

[0307] 7-Chloro-8-methoxyquinazoline-2-amine (1.0 g) was dissolved in a mixed solvent of N,N-dimethylformamide / dichloromethane (12 mL, 1:5), and tetrabutylammonium chloride (1.3 g), trimethylchlorosilane (2.1 g), and tert-butyl nitrite (1.5 g) were added. The system was heated at 50 °C for 1 hour. TLC showed no reactants remaining. The reaction solution was quenched with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to give 254 mg of the title compound.

[0308] MS(ESI)m / z(M+H) + =229.1.

[0309] Step 4: Preparation of 2,7-dichloroquinazoline-8-ol

[0310]

[0311] 2,7-Dichloro-8-methoxyquinazoline (690 mg) was dissolved in dry dichloromethane (20 mL), and a dichloromethane solution of boron tribromide (9 mL, 1 M) was added dropwise at 0 °C. The mixture was then allowed to react overnight at room temperature. TLC showed that the starting material had completely reacted. The reaction solution was washed with saturated sodium bicarbonate aqueous solution (10 mL) and saturated brine (10 mL), respectively. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give 600 mg of the title compound.

[0312] MS(ESI)m / z(M+H) + =215.1.

[0313] Step 5: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2,7-dichloroquinazoline

[0314]

[0315] Triphenylphosphine (732 mg) was dissolved in anhydrous tetrahydrofuran (15 mL), and diisopropyl azodicarbonate (564 mg) was added dropwise at 0 °C. After the addition was complete, the mixture was stirred for 15 minutes. Subsequently, trans-4-((tert-butyldimethylsilyl)oxy)cyclohexane-1-ol (643 mg) and 2,7-dichloroquinazoline-8-ol (400 mg) were added separately, and the reaction mixture was moved to room temperature and reacted for 1 hour. TLC showed that the starting material had reacted completely. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to give 450 mg of the title compound.

[0316] MS(ESI)m / z(M+H) + =427.1.

[0317] Preparation Example 15: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-chloro-N-(3-((methylthio)methyl)phenyl)quinazolin-2-amine)

[0318]

[0319] The compound of this preparation example was prepared by a method similar to that described in Preparation Example 3 above.

[0320] MS(ESI)m / z(M+H) + =544.1.

[0321] Preparation Example 16: Preparation of 2-((methylthio)methyl)pyridine-4-amine

[0322]

[0323] Step 1: Preparation of 2-(bromomethyl)-4-chloropyridine

[0324]

[0325] (4-chloropyridin-2-yl)methanol (1.4 g) was dissolved in dichloromethane (20 mL), and triphenylphosphine (3.9 g) and N-bromosuccinimide (2.7 g) were added separately at 0 °C. The reaction mixture was reacted at room temperature for 1 hour. The reaction solution was quenched with water, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2.01 g of crude product, which was used directly in the next reaction without further purification.

[0326] MS(ESI)m / z(M+H) + =206.1

[0327] Step 2: Preparation of 4-chloro-2-((methylthio)methyl)pyridine

[0328]

[0329] 2-(bromomethyl)-4-chloropyridine (2.0 g) was dissolved in tetrahydrofuran (20 mL), and 20% sodium methanethiol aqueous solution (5 mL) was added dropwise at -20 °C. The reaction was allowed to proceed overnight. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to give 0.95 g of the title compound.

[0330] MS(ESI)m / z(M+H) + =174.1.

[0331] Step 3: Preparation of tert-butyl (2-((methylthio)methyl)pyridin-4-yl)carbamate

[0332]

[0333] 4-Chloro-2-((methylthio)methyl)pyridine (70 mg) and tert-butyl carbamate (940 mg) were dissolved in 1,4-dioxane (10 mL), and cesium carbonate (2.6 g), tribenzyl acetone dipalladium (194 mg), and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (384 mg) were added, respectively. The mixture was purged three times with argon gas, and reacted at 90 °C for 5 hours. The reaction solution was cooled to room temperature, the insoluble matter was filtered off, the filtrate was collected, concentrated, and the crude product was purified by column chromatography to obtain 500 mg of the title compound.

[0334] MS(ESI)m / z(M+H) + =255.1.

[0335] Step 4: Preparation of 2-((methylthio)methyl)pyridine-4-amine

[0336]

[0337] 500 mg of 2-((methylthio)methyl)pyridin-4-yl)carbamate tert-butyl ester was dissolved in 10 mL of hydrogen chloride / 1,4-dioxane solution and reacted at 40 °C for 1 hour. The solvent was removed by concentration under reduced pressure, and the crude product was purified by reversed-phase column chromatography to give 120 mg of the title compound.

[0338] MS(ESI)m / z(M+H) + =155.1.

[0339] Preparation Example 17: Preparation of 7-bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(2-((methylthio)methyl)pyridin-4-yl)quinazolin-2-amine

[0340]

[0341] Under a nitrogen atmosphere, 2-((methylthio)methyl)pyridine-4-amine (20 mg), 7-bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2-chloroquinazoline (50 mg), (±)-2,2′-bis(diphenylphosphine)-1,1′-binaphthyl (35 mg), tris(dibenzylideneacetone)dipalladium (25 mg), and cesium carbonate (70 mg) were dissolved in toluene (50 mL), and the mixture was heated at 90 °C for 6 hours. After cooling to room temperature, the solids were removed by filtration, the filter cake was washed with ethyl acetate, the organic phases were combined, concentrated, and the crude product was separated by silica gel column chromatography to give 15 mg of the title compound.

[0342] MS(ESI)m / z(M+H) + =589.2,591.2.

[0343] Preparation Example 18: Preparation of 4-((methylthio)methyl)pyridine-2-amine

[0344]

[0345] Step 1: Preparation of (2-nitropyridin-4-yl)methanol

[0346]

[0347] Under a nitrogen atmosphere, 2-nitroisonicotinic acid (2.0 g) was dissolved in tetrahydrofuran (100 mL), and borane solution (40 mL) was slowly added. The reaction was allowed to proceed for 12 hours. TLC and LCMS showed that the reaction was complete. Water (50 mL) was added, and the mixture was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography, and the resulting solid was washed with petroleum ether and dried to give 1.7 g of the title compound.

[0348] MS(ESI)m / z(M+H) + =155.0.

[0349] The compound of this preparation example was prepared by following a similar method to that in Preparation Example 1.

[0350] MS(ESI)m / z(M+H) + =155.1.

[0351] Preparation Example 19: Preparation of 7-bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(4-((methylthio)methyl)pyridin-2-yl)quinazolin-2-amine)

[0352]

[0353] MS(ESI)m / z(M+H) +=589.2,591.2.

[0354] The compound of this preparation example was prepared by following a similar method to that in Preparation Example 17.

[0355] Preparation Example 20: Preparation of 8-(((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-cyclopropyl-N-(3-(((methylthio)methyl)phenyl)quinazolin-2-amine)

[0356]

[0357] Under a nitrogen atmosphere, 7-bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-(((methylthio)methyl)phenyl)quinazolin-2-amine) (200 mg), cyclopropylboronic acid (80 mg), 2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl (70 mg), tris(dibenzylacetone)dipalladium (70 mg), and potassium phosphate (210 mg) were dissolved in toluene (50 mL), and the mixture was heated at 90 °C for 1 hour. After cooling to room temperature, the solids were removed by filtration, the filter cake was washed with ethyl acetate, the organic phases were combined, concentrated, and the crude product was purified by preparative HPLC to give 45 mg of the title compound.

[0358] MS(ESI)m / z(M+H) + =550.2.

[0359] Preparation Example 21: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-chloro-N-(2-((methylthio)methyl)pyridin-4-yl)quinazolin-2-amine)

[0360]

[0361] 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2,7-dichloroquinazoline (220 mg), 2-((methylthio)methyl)pyridin-4-amine (94 mg), cesium carbonate (332 mg), tris(dibenzylacetone)palladium (23 mg), and 2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl (40 mg) were dissolved in toluene (7 mL). After purging three times with argon, the system was reacted at 90 °C for 5 hours. TLC showed that the starting materials had reacted completely. The reaction solution was cooled to room temperature, insoluble matter was filtered off, the filtrate was collected, concentrated, and the crude product was purified by column chromatography to give 170 mg of the title compound.

[0362] MS(ESI)m / z(M+H) + =545.1.

[0363] Preparation Example 22: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-chloro-N-(4-((methylthio)methyl)pyridin-2-yl)quinazolin-2-amine)

[0364]

[0365] MS(ESI)m / z(M+H) + =545.1.

[0366] The compound of this preparation example was prepared by following a similar method to that in Preparation Example 17.

[0367] Preparation Example 23: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-methyl-N-(3-((methylthio)methyl)phenyl)quinazolin-2-amine)

[0368]

[0369] 7-Bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((methylthio)methyl)phenyl)quinazolin-2-amine (117.73 mg), potassium methyltrifluoroborate (35.46 mg), cesium carbonate (189.51 mg), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (7.17 mg) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). The mixture was purged with nitrogen three times, and the reaction was carried out at 100 °C for 10 hours. LC-MS monitoring showed that the reaction was complete. The reaction solution was concentrated, and the crude product was purified by column chromatography to obtain 120 mg of the title compound.

[0370] MS(ESI)m / z(M+H) + =524.3.

[0371] Preparation Example 24: Preparation of trans-4-((tert-butyldimethylsilyl)oxy)cyclohexyl-1-ol

[0372]

[0373] Trans-1,4-cyclohexanediol (5.0 g) was dissolved in dichloromethane (100 mL), and N-methylimidazole (2.0 g) and tert-butyldimethylchlorosilane (5.3 g) were slowly added. The reaction was carried out at room temperature for 2 hours. TLC and LCMS showed that the reaction was complete. The mixture was extracted four times with water and dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to give 6.0 g of the title compound.

[0374] Preparation Example 25: Preparation of 7-cyano-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((methylthio)methyl)phenyl)quinazolin-2-amine)

[0375]

[0376] Under inert gas protection, 7-bromo-8-(cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((methylthio)methyl)phenyl)quinazolin-2-amine (200 mg) was dissolved in N,N-dimethylformamide (20 mL), and 2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl (120 mg), tris(dibenzylacetone)dipalladium (93 mg), and zinc cyanide (197 mg) were added. The mixture was heated at 90 °C for 3 hours. TLC and LCMS showed that the reaction was complete. The reaction solution was extracted four times with water and dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography. The resulting solid was washed with petroleum ether and dried to give 100 mg of the title compound.

[0377] MS(ESI)m / z(M+H) + =535.3.

[0378] Preparation Example 26: Preparation of 5-((methylthio)methyl)pyridine-3-amine

[0379]

[0380] Step 1: Preparation of methyl 5-((tert-Butoxycarbonyl)amino)nicotinic acid

[0381]

[0382] 5-Aminonicotinic acid methyl ester (7.0 g) was dissolved in dichloromethane (50 mL), and triethylamine (13.0 mL), 4-dimethylaminopyridine (560 mg), and di-tert-butyl dicarbonate (12.0 g) were added sequentially at room temperature, and the reaction was continued at room temperature. After stirring for 24 hours, the solvent was directly removed, and the title compound (9.2 g) was obtained by silica gel column chromatography.

[0383] MS(ESI)m / z(M+H) + =253.1.

[0384] Step 2: Preparation of tert-butyl (5-(hydroxymethyl)pyridin-3-yl)carbamate

[0385]

[0386] 5-((tert-Butoxycarbonyl)amino)nicotinic acid methyl ester (9.0 g) was dissolved in methanol (100 mL), and sodium borohydride (5.4 g) was slowly added at 0 °C, followed by continued reaction at room temperature. After 2 hours, the reaction was checked by LCMS to confirm complete reaction. The reaction was quenched by adding water and saturated sodium bicarbonate solution, extracted with dichloromethane, combined, dried, filtered, and the solvent was removed under reduced pressure to give the title compound (6.8 g).

[0387] MS(ESI)m / z(M+H) + =225.1.

[0388] Step 3: Preparation of tert-butyl (5-(chloromethyl)pyridin-3-yl)carbamate

[0389]

[0390] 6.0 g of tert-butyl (5-(hydroxymethyl)pyridin-3-yl)carbamate was dissolved in 100 mL of anhydrous dimethyl sulfoxide, and 6.0 g of cyanuric chloride was slowly added. The reaction was carried out at room temperature for 1 hour. The reaction was confirmed to be complete by TLC. Water was added and the mixture was stirred for 5 minutes. The mixture was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to give 4.5 g of the title compound.

[0391] MS(ESI)m / z(M+H) + =243.1.

[0392] Step 4: Preparation of tert-butyl (5-((methylthio)methyl)pyridin-3-yl)carbamate

[0393]

[0394] 4.0 g of tert-butyl (5-(chloromethyl)pyridin-3-yl)carbamate was dissolved in ethanol (20 mL), and an aqueous solution of sodium methanethiol (20% in H2O, 5.9 mL) was slowly added dropwise at 0 °C. The reaction was allowed to proceed for 20 minutes. TLC was used to confirm the complete reaction. Water was added, and the mixture was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to give 3.2 g of the title compound.

[0395] MS(ESI)m / z(M+H) + =255.1.

[0396] Step 5: Preparation of 5-((methylthio)methyl)pyridine-3-amine

[0397]

[0398] 3.0 g of tert-butyl (5-((methylthio)methyl)pyridin-3-yl)carbamate was dissolved in dioxane hydrochloride solution (4 M, 30 mL) at room temperature, and then heated to 60 °C. After 1 hour, the reaction was confirmed to be complete by LCMS. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and then subjected to reverse column chromatography to give the title compound (1.5 g).

[0399] MS(ESI)m / z(M+H) + =155.1.

[0400] Preparation Example 27: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-chloro-N-(5-(((methylthio)methyl)pyridin-3-yl)quinazolin-2-amine)

[0401]

[0402] 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2,7-dichloroquinazoline (220 mg), 5-((methylthio)methyl)pyridin-3-amine (160 mg), cesium carbonate (340 mg), tris(dibenzylacetone)palladium (80 mg), and 2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl (61 mg) were dissolved in toluene (30 mL). After purging with argon three times, the system was reacted at 90 °C for 5 hours. TLC showed that the starting material had reacted completely. The reaction solution was cooled to room temperature, insoluble matter was filtered off, the filtrate was collected, concentrated, and the crude product was purified by column chromatography to give 170 mg of the title compound.

[0403] MS(ESI)m / z(M+H) + =545.2.

[0404] Preparation Example 28: Preparation of 4-(4-methylpiperazin-1-yl)-3-((methylthio)methyl)aniline

[0405]

[0406] Step 1: Preparation of (2-(4-methylpiperazin-1-yl)-5-nitrophenyl)methanol

[0407]

[0408] 2-Fluoro-5-nitrobenzyl alcohol (2.0 g) and N-methylpiperazine (3.5 g) were placed in a microwave tube and reacted at 100 °C. After 2 hours, the reaction was monitored by LCMS until complete. Water and a saturated sodium bicarbonate aqueous solution were added and stirred for 10 minutes. The mixture was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (1.5 g).

[0409] MS(ESI)m / z(M+H) + =252.1.

[0410] Step 2: Preparation of 1-(2-(bromomethyl)-4-nitrophenyl)-4-methylpiperazine

[0411]

[0412] The title compound was prepared by a method similar to that used in Preparation Example 6.

[0413] MS(ESI)m / z(M+H) + =314.0,316.0.

[0414] Step 3: Preparation of 1-methyl-4-(2-((methylthio)methyl)-4-nitrophenyl)piperazine

[0415]

[0416] The title compound was prepared by a method similar to that used in Preparation Example 6.

[0417] MS(ESI)m / z(M+H) + =282.1.

[0418] Step 4: Preparation of 4-(4-methylpiperazin-1-yl)-3-((methylthio)methyl)aniline

[0419]

[0420] 1-Methyl-4-(2-((methylthio)methyl)-4-nitrophenyl)piperazine (510 mg) was dissolved in acetic acid (5 mL) at room temperature, then zinc powder (500 mg) was added and the reaction was carried out at room temperature. After 15 minutes, the reaction was monitored by LCMS until complete. After filtration to remove excess solid, the solvent was dried under reduced pressure to obtain a crude solid product. The crude solid product was dissolved in dichloromethane, and the solution was adjusted to alkalinity with saturated sodium bicarbonate aqueous solution. The organic phase was separated, and the aqueous phase was extracted multiple times with dichloromethane. The extracts were combined, dried, filtered, and concentrated under reduced pressure to obtain the title compound (350 mg).

[0421] MS(ESI)m / z(M+H) + =282.1.

[0422] Preparation Example 29: Preparation of 7-bromo-8-(cis-4-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(4-(4-methylpiperazin-1-yl)-3-((methylthio)methyl)phenyl)quinazolin-2-amine

[0423]

[0424] The compound of this preparation example was prepared by following a similar method to that in Preparation Example 3.

[0425] MS(ESI)m / z(M+H) + =686.2,688.2.

[0426] Preparation Example 30: Preparation of 2-amino-6-fluoro-3-methoxybenzoic acid

[0427]

[0428] Step 1: Preparation of 3,6-difluoro-2-nitrobenzoic acid

[0429]

[0430] 10.0 g of 2,5-difluorobenzoic acid was placed in a round-bottom flask, and concentrated sulfuric acid (30 mL) was added under ice bath conditions. Then, a mixture of concentrated sulfuric acid (9 mL) and concentrated nitric acid (9 mL) was slowly added, and stirring was continued at room temperature for 12 hours. After the reaction was monitored by TLC until complete, water was added, followed by multiple extractions with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture of the title compounds (10.0 g).

[0431] Step 2: Preparation of methyl 3,6-difluoro-2-nitrobenzene

[0432]

[0433] A mixture of 21.0 g of 3,6-difluoro-2-nitrobenzoic acid was dissolved in 200 mL of dry dichloromethane under nitrogen atmosphere. Diisopropylethylamine (30.0 g) was added at 0 °C, followed by trimethoxyonium tetrafluoroborate (18.5 g), and the reaction was continued at room temperature for 10 hours. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain the title compound (9.0 g).

[0434] Step 3: Preparation of methyl 6-fluoro-3-methoxy-2-nitrobenzoate

[0435]

[0436] Methyl 3,6-difluoro-2-nitrobenzene (8.5 g) was dissolved in dry methanol (50 mL) under nitrogen protection. Sodium methoxide (3.2 g) was slowly added, and the reaction was continued at room temperature. After 12 hours, the reaction was monitored by TLC until it was complete. The reaction was quenched by adding saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain the title compound (7.0 g).

[0437] Step 4: Preparation of 6-fluoro-3-methoxy-2-nitrobenzoic acid

[0438]

[0439] Methyl 6-fluoro-3-methoxy-2-nitrobenzene (6.0 g) was dissolved in tetrahydrofuran (50 mL), followed by the addition of sodium hydroxide (1.6 g) and the reaction continued at room temperature. After 2 hours, the reaction was monitored by TLC until complete. Water was added, and the pH was adjusted to <3 with hydrochloric acid. The mixture was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (4.5 g). Step 5: Preparation of 2-amino-6-fluoro-3-methoxybenzoic acid

[0440]

[0441] 4.0 g of 6-fluoro-3-methoxy-2-nitrobenzoic acid was dissolved in 100 mL of ethanol / water (3:1), and 50.0 g of iron powder and 20.0 g of ammonium chloride were added. The mixture was heated at 90 °C for 1 hour. The reaction was completed by TLC. The insoluble matter was removed by filtration, and the filtrate was collected and concentrated to remove the solvent, yielding 2.8 g of the title compound.

[0442] MS(ESI)m / z(M+H) + =186.0.

[0443] Preparation Example 31: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2,7-dichloro-5-fluoroquinazoline

[0444]

[0445] Step 1: Preparation of 5-fluoro-8-methoxyquinazoline-2,4(1H,3H)-dione

[0446]

[0447] 2-Amino-6-fluoro-3-methoxybenzoic acid (20.0 g) was uniformly mixed with urea (30.0 g) and heated at 160 °C for 6 hours. TLC and LCMS showed that the reaction was complete. Water (100 mL) was added while hot to precipitate the solid. The solid was filtered, collected, washed with petroleum ether, and dried to give 18.0 g of the title compound.

[0448] MS(ESI)m / z(M+H) + =211.0.

[0449] Step 2: Preparation of 2,4-dichloro-5-fluoro-8-methoxyquinazoline

[0450]

[0451] 18.0 g of 5-fluoro-8-methoxyquinazoline-2,4(1H,3H)-dione was dissolved in 100 mL of phosphorus oxychloride, and 30.0 g of N,N-dimethylaniline was added dropwise. The mixture was refluxed at 130 °C for 3 hours. TLC and LCMS showed that the reaction was complete. The reaction solution was concentrated to remove excess phosphorus oxychloride, and the residue was slowly added to an ice-water solution of saturated sodium bicarbonate. The mixture was extracted four times with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to give 14.0 g of the title compound.

[0452] MS(ESI)m / z(M+H) + =247.0.

[0453] Step 3: Preparation of 2-chloro-5-fluoro-8-methoxyquinazoline

[0454]

[0455] 2,4-Dichloro-5-fluoro-8-methoxyquinazoline (13.5 g), tetraphenylphosphine palladium (13.5 g), and tri-n-butyltin hydrogen (18.2 g) were placed in a round-bottom flask. Under nitrogen protection, anhydrous tetrahydrofuran (50 mL) was added, and the reaction was continued at room temperature. After 24 hours, the reaction was monitored by TLC until it was complete. The solvent was removed by direct concentration, and the solution was purified by silica gel column chromatography to obtain the title compound (11.3 g).

[0456] MS(ESI)m / z(M+H) + =213.0.

[0457] Step 4: Preparation of 2-chloro-5-fluoroquinazoline-8-ol

[0458]

[0459] 2-Chloro-5-fluoro-8-methoxyquinazoline (2.0 g) was dissolved in dry dichloromethane (10 mL) under nitrogen atmosphere, and boron tribromide (1 M in CH2Cl2, 15 mL) was slowly added. The mixture was allowed to react overnight at room temperature. TLC and LCMS showed that the reaction was complete. The reaction solution was quenched with water, and the pH was adjusted to >9 with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to give 1.5 g of the title compound.

[0460] MS(ESI)m / z(M+H) + =199.0.

[0461] Step 5: Preparation of 2,7-dichloro-5-fluoroquinazoline-8-ol

[0462]

[0463] 1.3 g of 2-chloro-5-fluoroquinazoline-8-ol was dissolved in 10 mL of dry dichloromethane. 92 mg of aluminum trichloride and 1.1 g of N-chlorosuccinimide were added sequentially, and the reaction was continued at room temperature. After 24 hours, the reaction was monitored by LCMS until complete. The reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to give 0.96 g of the title compound.

[0464] MS(ESI)m / z(M+H) + =233.0.

[0465] Step 6: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2,7-dichloro-5-fluoroquinazoline)

[0466]

[0467] The compound of this preparation example was prepared by a method similar to that described in Preparation Example 2 above.

[0468] MS(ESI)m / z(M+H) + =445.1.

[0469] Preparation Example 32: Preparation of 3-((methylsulfinyl)methyl)aniline

[0470]

[0471] Step 1: Preparation of (3-bromophenyl)methanol

[0472]

[0473] 3-Bromobenzaldehyde (6.8 g) was dissolved in methanol (100 mL), and sodium borohydride (1.8 g) was added at room temperature, followed by stirring at room temperature. The reaction was monitored by TLC until complete. Saturated sodium bicarbonate aqueous solution was added and stirred for 10 minutes. The mixture was extracted with dichloromethane, combined, dried, filtered, and the solvent was removed under reduced pressure to obtain the title compound (6.7 g).

[0474] Step 2: Preparation of 1-bromo-3-(bromomethyl)benzene

[0475]

[0476] (3-Bromophenyl)methanol (10.0 g) was dissolved in dichloromethane (150 mL), and phosphorus tribromide (8.7 g) was slowly added while the reaction continued at room temperature under ice bath conditions. After the reaction was monitored by TLC, saturated sodium bicarbonate aqueous solution was slowly added to adjust the solution to alkalinity. The solution was extracted with dichloromethane, combined, dried, filtered, and the solvent was removed under reduced pressure. The title compound (11.5 g) was obtained by silica gel column chromatography.

[0477] Step 3: Preparation of 1-bromo-3-((methylthio)methyl)benzene

[0478]

[0479] 1-Bromo-3-(bromomethyl)benzene (11.5 g) was dissolved in tetrahydrofuran (120 mL), and sodium methanethiol aqueous solution (20% in H2O, 21.4 mL) was slowly added under ice bath temperature while stirring at room temperature. After 30 minutes, the reaction was monitored by TLC until complete. Saturated sodium bicarbonate aqueous solution was added, and the mixture was extracted with dichloromethane, combined, dried, filtered, and the solvent was removed under reduced pressure. The title compound (7.4 g) was obtained by silica gel column chromatography.

[0480] Step 4: Preparation of 1-bromo-3-((methylsulfinyl)methyl)benzene

[0481]

[0482] 1-Bromo-3-((methylthio)methyl)benzene (7.4 g) was dissolved in acetonitrile (150 mL), and ferric chloride (166 mg) was added at room temperature. The mixture was stirred for 10 minutes, followed by the addition of periodic acid (8.2 g) and the reaction was continued at room temperature. After the reaction was monitored by TLC until complete, the reaction was quenched by adding sodium thiosulfate aqueous solution. The mixture was extracted with dichloromethane, combined, dried, filtered, and the solvent was removed under reduced pressure. The title compound (3.9 g) was obtained by silica gel column chromatography.

[0483] Step 5: Preparation of tert-butyl (3-((methylsulfinyl)methyl)phenyl)carbamate

[0484]

[0485] 1-Bromo-3-((methylsulfinyl)methyl)benzene (200 mg), 2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl (120 mg), tris(dibenzylacetone)palladium (78 mg), cesium carbonate (830 mg), and tert-butyl carbamate (200 mg) were dissolved in 1,4-Dioxane (20 mL) under nitrogen protection, and then reacted at 100 °C. After 6 hours, the reaction was monitored by LCMS until complete. The solvent was removed by direct concentration, and the title compound (120 mg) was obtained by silica gel column chromatography.

[0486] MS(ESI)m / z(M+H) + =270.1.

[0487] Step 6: Preparation of 3-((methylsulfinyl)methyl)aniline

[0488]

[0489] 100 mg of tert-butyl (3-((methylsulfinyl)methyl)phenyl)carbamate was dissolved in 10 mL of dichloromethane, and then 3.5 mL of trifluoroacetic acid was added at room temperature, and the reaction was continued at room temperature. After 2 hours, the reaction was monitored by LCMS until complete, and the solvent was directly removed to obtain the crude product. The crude product was dissolved in dichloromethane, and the aqueous layer was adjusted to alkalinity with saturated sodium bicarbonate solution. The organic phase was separated, the aqueous phase was extracted with dichloromethane, combined, dried, filtered, and the solvent was removed under reduced pressure. The title compound (50 mg) was obtained by silica gel column chromatography.

[0490] MS(ESI)m / z(M+H) + =170.1.

[0491] Preparation Example 33: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-chloro-5-fluoro-N-(3-(((methylsulfinyl)methyl)phenyl)quinazolin-2-amine)

[0492]

[0493] The compound of this preparation example was prepared by a method similar to that described in Preparation Example 3 above.

[0494] MS(ESI)m / z(M+H) + =578.2.

[0495] Preparation Example 34: Preparation of 2-fluoro-5-((methylthio)methyl)aniline

[0496]

[0497] The compound of this preparation example was prepared by a method similar to that described in Preparation Example 6 above.

[0498] MS(ESI)m / z(M+H) + =172.0.

[0499] Preparation Example 35: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-chloro-N-(2-fluoro-5-((methylthio)methyl)phenyl)quinazolin-2-amine)

[0500]

[0501] The compound of this preparation example was prepared by a method similar to that described in Preparation Example 3 above.

[0502] MS(ESI)m / z(M+H) + =562.1.

[0503] Preparation Example 36: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-(1-methyl-1H-pyrazol-4-yl)-N-(3-((methylsulfinyl)methyl)phenyl)quinazolin-2-amine)

[0504]

[0505] Step 1: Preparation of 7-bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((methylsulfinyl)methyl)phenyl)quinazolin-2-amine)

[0506]

[0507] The compound of this preparation example was prepared by a method similar to that described in Preparation Example 3 above.

[0508] MS(ESI)m / z(M+H) + =604.2,606.2.

[0509] Step 2: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-(1-methyl-1H-pyrazol-4-yl)-N-(3-((methylsulfinyl)methyl)phenyl)quinazolin-2-amine)

[0510]

[0511] At room temperature, 7-bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((methylsulfinyl)methyl)phenyl)quinazolin-2-amine (131 mg), 1-methyl-4-(tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-pyrazole (68 mg), tetraphenylphosphine palladium (25 mg), and sodium carbonate (69 mg) were placed in a round-bottom flask. Under nitrogen protection, 1,4-dioxane (10 mL) and water (2 mL) were added. The mixture was heated to 100 °C and reacted for 3 h. LC-MS showed that the reaction was complete. After concentration under reduced pressure, column chromatography was used to separate the title compound (60 mg).

[0512] MS(ESI)m / z(M+H) + =606.3.

[0513] Preparation Example 37: Preparation of 6-bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2-chloroquinazoline

[0514]

[0515] Step 1: Preparation of 2-amino-5-bromo-3-methoxybenzoic acid

[0516]

[0517] 5.0 g of 2-amino-3-methoxybenzoic acid was dissolved in 60 mL of methanol. 5.6 g of N-bromosuccinimide was slowly added under ice bath conditions. After the addition was complete, the mixture was stirred overnight at room temperature. The reaction was monitored by LCMS until complete. The reaction solution was then slowly added dropwise to ice water, resulting in the precipitation of a solid. The solid was then filtered, washed with dichloromethane, and dried to obtain the title compound (6.0 g).

[0518] MS(ESI)m / z(M+H) + =246.0, 248.0.

[0519] Step 2: Preparation of (2-amino-5-bromo-3-methoxyphenyl)methanol

[0520]

[0521] Under ice bath conditions, 6.0 g of 2-amino-5-bromo-3-methoxybenzoic acid was dissolved in 60 mL of tetrahydrofuran, followed by the addition of a borane-tetrahydrofuran complex (1 M, 125 mL). After the addition was complete, the reaction mixture was heated to 50 °C and reacted overnight. The reaction was monitored by LCMS until the starting material was completely reacted. The mixture was then cooled to 0 °C, quenched with 50 mL of MeOH, and concentrated to 25 mL. The residue was diluted with 200 mL of sodium carbonate aqueous solution and extracted with ethyl acetate. The organic layers were separated, collected, and dried over anhydrous Na₂SO₄. The residue was filtered and concentrated to give the title compound (4.5 g).

[0522] MS(ESI)m / z(M+H) + =232.0, 234.0.

[0523] Step 3: Preparation of 2-amino-5-bromo-3-methoxybenzaldehyde

[0524]

[0525] (2-Amino-5-bromo-3-methoxyphenyl)methanol (5.0 g) was dissolved in dichloromethane (150 mL), followed by the addition of manganese dioxide (9.1 g). After the addition was complete, the reaction was allowed to proceed overnight at room temperature. After the reaction was completed as monitored by LCMS, the reaction solution was filtered, the filtrate was collected, and concentrated under reduced pressure to obtain the title compound (1.52 g).

[0526] MS(ESI)m / z(M+H) + =230.0, 232.0.

[0527] Step 4: Preparation of 6-bromo-8-methoxyquinazoline-2(1H)-one

[0528]

[0529] 2-Amino-5-bromo-3-methoxybenzaldehyde (2.8 g) was dissolved in N-methylpyrrolidone (80 mL), followed by the addition of urea (3.5 g) and reaction at 180 °C for 5 hours. The reaction was monitored by LCMS until complete. The reaction solution was cooled to 100 °C, and water was slowly added, resulting in the precipitation of a solid. The solid was filtered, washed with water, and dried to obtain the title compound (2.5 g).

[0530] MS(ESI)m / z(M+H) + =255.0, 257.0.

[0531] Step 5: Preparation of 6-bromo-2-chloro-8-methoxyquinazoline

[0532]

[0533] 6-Bromo-8-methoxyquinazoline-2(1H)-one (2.0 g) was dissolved in phosphorus oxychloride (7.0 mL) under ice bath conditions, and then the mixture was heated to 120 °C and reacted for 2 hours. The reaction was then monitored by LCMS until the reactants were fully reacted. The reaction solution was cooled to room temperature, concentrated to remove excess phosphorus oxychloride, and the residue was slowly added to an ice-water solution of saturated sodium bicarbonate. The mixture was extracted four times with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to obtain the title compound (0.9 g).

[0534] MS(ESI)m / z(M+H) + =273.0, 275.0.

[0535] The remaining steps were performed using a method similar to that described in Preparation Example 2 above to prepare the compound of this preparation example.

[0536] MS(ESI)m / z(M+H) + =471.1, 473.1.

[0537] Preparation Example 38: Preparation of 6-bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((methylthio)methyl)phenyl)quinazolin-2-amine)

[0538]

[0539] The compound of this preparation example was prepared by a method similar to that described in Preparation Example 3 above.

[0540] MS(ESI)m / z(M+H) + =588.2, 590.2.

[0541] Preparation Example 39: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2-chloro-7-fluoroquinazoline

[0542]

[0543] The compound of this preparation example was prepared by a method similar to that described in Preparation Example 14 above.

[0544] MS(ESI)m / z(M+H) + =411.2.

[0545] Preparation Example 40: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-fluoro-N-(2-((methylthio)methyl)pyridin-4-yl)quinazolin-2-amine)

[0546]

[0547] The compound of this preparation example was prepared by a method similar to that described in Preparation Example 21 above.

[0548] MS(ESI)m / z(M+H) + =529.2.

[0549] Preparation Example 41: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-fluoro-N-(3-((methylthio)methyl)phenyl)quinazolin-2-amine)

[0550]

[0551] 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2-chloro-7-fluoroquinazoline (330 mg), 3-((methylthio)methyl)aniline (140 mg), palladium acetate (22 mg), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (81 mg), and cesium carbonate (550 mg) were dissolved in 1,4-dioxane (40 mL). The mixture was heated at 90 °C for 2 hours under anhydrous and oxygen-free nitrogen protection. LC-MS analysis showed no residual starting material. The mixture was filtered, the filtrate was collected, concentrated, and the crude product was purified by column chromatography to obtain the title compound (310 mg).

[0552] MS(ESI)m / z(M+H) + =528.2.

[0553] Preparation Example 42: Preparation of 4-amino-2-((methylthio)methyl)benzonitrile

[0554]

[0555] Step 1: Preparation of 2-(bromomethyl)-4-nitrobenzene

[0556]

[0557] 1.62 g of 2-methyl-4-nitrobenzyl nitrile was dissolved in 30 mL of carbon tetrachloride. 3.65 g of bromosuccinimide and 330 mg of azobisisobutyronitrile were added separately. The reaction mixture was refluxed overnight under a nitrogen atmosphere, and TLC analysis showed no residual starting material. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated and dissolved in 30 mL of tetrahydrofuran. Then, 1.65 mL of N,N-diisopropylethylamine and 1.78 g of diethyl phosphite were added under ice bath conditions, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated and purified by column chromatography to obtain the title compound (1.90 g).

[0558] The compound of this preparation example was prepared by following a similar method to that described in Preparation Example 1 above.

[0559] MS(ESI)m / z(M+H) + =179.1.

[0560] Preparation Example 43: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-chloro-N-(4-cyano-3-((methylthio)methyl)phenyl)quinazolin-2-amine)

[0561]

[0562] The compound of this preparation example was prepared by a method similar to that described in Preparation Example 41 above.

[0563] MS(ESI)m / z(M+H) + =569.2.

[0564] Preparation Example 44: Preparation of 6-((methylthio)methyl)pyridine-2-amine

[0565]

[0566] Step 1: Preparation of methyl 6-((tert-Butoxycarbonyl)amino)pyridinecarboxylate

[0567]

[0568] The title compound was prepared by a method similar to that described in Preparation Example 26 above.

[0569] MS(ESI)m / z(M+H) + =253.1.

[0570] Step 2: Preparation of tert-butyl (6-(hydroxymethyl)pyridin-2-yl)carbamate

[0571]

[0572] The title compound was prepared by a method similar to that described in Preparation Example 26 above.

[0573] MS(ESI)m / z(M+H) + =225.1.

[0574] Step 3: Preparation of tert-butyl (6-(bromomethyl)pyridin-2-yl)carbamate

[0575]

[0576] The title compound was prepared by a method similar to that described in Preparation Example 16 above.

[0577] MS(ESI)m / z(M+H) + =287.0, 289.0.

[0578] The compound of this preparation example was prepared by following a similar method to that described in Preparation Example 26 above.

[0579] MS(ESI)m / z(M+H) + =155.1.

[0580] Preparation Example 45: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-chloro-N-(6-(((methylthio)methyl)pyridin-2-yl)quinazolin-2-amine)

[0581]

[0582] The compound of this preparation example was prepared by a method similar to that described in Preparation Example 21 above.

[0583] MS(ESI)m / z(M+H) + =545.2.

[0584] Preparation Example 46: Preparation of 3-((methylthio)methyl)-4-morpholinoaniline

[0585]

[0586] The compound of this preparation example was prepared by a method similar to that described in Preparation Example 28 above.

[0587] MS(ESI)m / z(M+H) + =239.1.

[0588] Preparation Example 47: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-chloro-N-(3-((methylthio)methyl)-4-morpholinophenyl)quinazolin-2-amine)

[0589]

[0590] The compound of this preparation example was prepared by a method similar to that described in Preparation Example 41 above.

[0591] MS(ESI)m / z(M+H) + =629.2.

[0592] Preparation Example 48: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(2-((methylthio)methyl)pyridin-4-yl)-7-(trifluoromethyl)quinazolin-2-amine)

[0593]

[0594] Step 1: Preparation of 8-fluoro-N-(2-((methylthio)methyl)pyridin-4-yl)-7-(trifluoromethyl)quinazoline-2-amine

[0595]

[0596] The compound of this title was prepared by a method similar to that described in Preparation Example 21 above.

[0597] MS(ESI)m / z(M+H) + =369.1.

[0598] Step 2: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(2-((methylthio)methyl)pyridin-4-yl)-7-(trifluoromethyl)quinazolin-2-amine)

[0599]

[0600] 8-Fluoro-N-(2-((methylthio)methyl)pyridin-4-yl)-7-(trifluoromethyl)quinazolin-2-amine (100 mg), cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl-1-ol (62 mg), and sodium tert-butoxide (52 mg) were dissolved in tetrahydrofuran (15 mL) and reacted at room temperature for 5 hours. LC-MS analysis showed no residual starting material. The reaction was quenched with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give the title compound (80 mg).

[0601] MS(ESI)m / z(M+H) + =579.2.

[0602] Preparation Example 49: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2,5,7-trichloroquinazoline

[0603] Step 1: Preparation of 2,5,7-trichloroquinazoline-8-ol

[0604]

[0605] The starting material 2-chloroquinazoline-8-ol (100 mg) was dissolved in tetrahydrofuran (3 mL), followed by the addition of 1,3-dichloro-5,5-dimethylhydantoin (27 mg). After the addition was complete, the reaction system was placed at 65 °C for 2 hours. Subsequently, the reaction was monitored by LCMS to indicate completion. The reaction solution was directly concentrated, and the compound in question (95 mg) was separated by silica gel column chromatography.

[0606] MS(ESI)m / z(M+H) + =248.9, 250.9.

[0607] The compound of the preparation example was prepared by following a similar method to that described in Preparation Example 2 above.

[0608] MS(ESI)m / z(M+H) + =461.1, 463.1.

[0609] Preparation Example 50: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-5,7-dichloro-N-(3-((methylthio)methyl)phenyl)quinazolin-2-amine)

[0610]

[0611] The compound of this preparation example was prepared by a method similar to that described in Preparation Example 3 above.

[0612] MS(ESI)m / z(M+H) + =578.1.

[0613] Preparation Example 51: Preparation of 3-(2-(methanesulfonyl)propane-2-yl)aniline

[0614]

[0615] Step 1: Preparation of 1-bromo-3-((methylsulfonyl)methyl)benzene

[0616]

[0617] In an ice-water bath, 1.9 g of m-chloroperoxybenzoic acid was added to a 100 mL solution of 2.0 g of 1-bromo-3-((methylsulfinyl)methyl)benzene in ethyl acetate, and the reaction was allowed to proceed naturally overnight. TLC showed that there was a starting material remaining. After dilution with water, the solution was extracted with ethyl acetate, concentrated, and purified by silica gel column chromatography to give the title compound (740 mg).

[0618] Step 2: Preparation of 1-bromo-3-(2-(methanesulfonyl)propane-2-yl)benzene

[0619]

[0620] Sodium hydride (240 mg) was added to a tetrahydrofuran (30 mL) solution of 1-bromo-3-((methanesulfonyl)methyl)benzene (390 mg) in an ice-water bath. The mixture was stirred for 5 minutes, then iodomethane (2.2 g) was added, and the reaction was allowed to proceed naturally overnight. TLC showed a good reaction. The reaction was quenched with an aqueous sodium bicarbonate solution, and the mixture was extracted with dichloromethane. The extracts were combined, dried, and concentrated to give the title compound (200 mg).

[0621] The compound of this preparation example was prepared by following a similar method to that described in Preparation Example 32 above.

[0622] MS(ESI)m / z(M+H) + =214.1.

[0623] Preparation Example 52: Preparation of 7-bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-(2-(methanesulfonyl)propane-2-yl)phenyl)quinazolin-2-amine

[0624]

[0625] The compound of this preparation example was prepared by a method similar to that described in Preparation Example 3 above.

[0626] MS(ESI)m / z(M+H) + =648.2, 650.2.

[0627] Preparation Example 53: Preparation of N-(cis-4-((2,7-dichloroquinoline-8-yl)oxy)cyclohexyl)acetamide

[0628]

[0629] Under nitrogen protection, 1.1 g of 2,7-dichloroquinazoline-8-ol was dissolved in 25 mL of tetrahydrofuran, and 1.2 g of N-(trans-4-hydroxycyclohexyl)acetamide was added. Separately, 4.1 g of triphenylphosphine was dissolved in 10 mL of tetrahydrofuran. Under nitrogen protection, 3.2 g of diisopropyl azodicarbonate was added, and the mixture was then added to the above reaction solution. The reaction was carried out at room temperature for 20 minutes. After LC-MS showed complete reaction, the solution was directly concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound (170 mg).

[0630] MS(ESI)m / z(M+H) + =354.1.

[0631] Preparation Example 54: Preparation of 8-((cis-4-(acetamido)cyclohexyl)oxy)-7-chloro-N-(2-((methylthio)methyl)pyridin-4-yl)-quinazolin-2-amine

[0632]

[0633] N-(cis-4-((2,7-dichloroquinoline-8-yl)oxy)cyclohexyl)acetamide (150 mg) was dissolved in toluene (10 mL), and 2-((methylthio)methyl)pyridin-4-amine (97 mg), cesium carbonate (274 mg), Pd2(dba)3 (38 mg), and dppf (23 mg) were added. The system was purged with nitrogen three times, and the reaction was carried out at 90 °C for 5 h under a nitrogen atmosphere. After the reaction was confirmed to be complete by LCMS, the mixture was directly concentrated under reduced pressure, and the crude product was purified by column chromatography to give the title compound (80 mg).

[0634] MS(ESI)m / z(M+H) + =472.1.

[0635] Preparation Example 55: Preparation of 2,7-dichloro-8-(cyclohexyloxy)quinazoline

[0636]

[0637] The compound of this preparation example was prepared by a method similar to that described in Preparation Example 53 above.

[0638] MS(ESI)m / z(M+H) + =297.1.

[0639] Preparation Example 56: Preparation of 7-chloro-8-(cyclohexyloxy)-N-(2-((methylthio)methyl)pyridin-4-yl)quinazolin-2-amine

[0640]

[0641] The compound of this preparation example was prepared by a method similar to that described in Preparation Example 54 above.

[0642] MS(ESI)m / z(M+H) + =415.2.

[0643] Preparation Example 57: Preparation of 7-cyano-8-(cyclohexyloxy)-N-(2-((methylthio)methyl)pyridin-4-yl)quinazolin-2-amine

[0644] Step 1: Preparation of 7-bromo-2-chloro-8-(cyclohexyloxy)quinazoline

[0645]

[0646] The title compound was prepared by a method similar to that described in Preparation Example 53 above.

[0647] MS(ESI)m / z(M+H) + =341.0, 343.0.

[0648] Step 2: Preparation of 7-bromo-8-(cyclohexyloxy)-N-(2-((methylthio)methyl)pyridin-4-yl)quinazolin-2-amine

[0649]

[0650] The title compound was prepared by a method similar to that described in Preparation Example 54 above.

[0651] MS(ESI)m / z(M+H) + =459.1, 461.1.

[0652] Step 3: Preparation of 7-cyano-8-(cyclohexyloxy)-N-(2-((methylthio)methyl)pyridin-4-yl)quinazoline-2-amine

[0653]

[0654] The compound of this preparation example was prepared by a method similar to that described in Preparation Example 25 above.

[0655] MS(ESI)m / z(M+H) + =406.2.

[0656] Example 1: Preparation of (racemic)-8-((cis-4-hydroxycyclohexyl)oxy)-N-(3-((S-methylsulfonylimino)methyl)phenyl)quinazolin-2-amine

[0657]

[0658] Step 1: Preparation of (racemic)-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((S-methylsulfonylimino)methyl)phenyl)quinazolin-2-amine

[0659]

[0660] 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((methylthio)methyl)phenyl)quinazolin-2-amine (50 mg) was dissolved in methanol (10 mL), and then ammonium carbamate (18 mg) and iodobenzene acetate (70 mg) were added sequentially. The reaction was carried out at room temperature for 20 minutes. The reaction was confirmed to be complete by TLC. The solution was concentrated under reduced pressure, and the crude product was purified by column chromatography to give 30 mg of the title compound.

[0661] MS(ESI)m / z(M+H) + =541.3.

[0662] Step 2: Preparation of (racemic)-8-((cis-4-hydroxycyclohexyl)oxy)-N-(3-((S-methylsulfonylimino)methyl)phenyl)quinazolin-2-amine

[0663]

[0664] (Raceous)-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((S-methylsulfonylimino)methyl)phenyl)quinazolin-2-amine (20 mg) was dissolved in dichloromethane (5 mL), and hydrochloric acid (0.1 mL, 4 M in dioxane) was added. The reaction was carried out at room temperature for 10 minutes. The reaction was confirmed to be complete by TLC. The solution was concentrated under reduced pressure, and the crude product was purified by preparative HPLC to obtain 10 mg of the title compound.

[0665] MS(ESI)m / z(M+H) + =427.1.

[0666] 1 H NMR (400MHz, DMSO-d6) δ9.93 (s, 1H), 9.26 (s, 1H), 8.49 (d, J = 8.4Hz, 1H), 7.8 2(s,1H),7.48–7.46(m,1H),7.39–7.34(m,2H),7.30–7.26(m,1H),7.05–7.0 3(m,1H),4.73(s,1H),4.62(d,J=3.6Hz,1H),4.34(q,J=13.2Hz,2H),3.66–3 .62(m,1H),3.55(s,1H),2.84(s,3H),2.02–1.96(m,2H),1.82–1.62(m,6H).

[0667] Example 7: Preparation of 7-bromo-8-((cis-4-hydroxycyclohexyl)oxy)-N-(3-((S-methylsulfonyl)methyl)phenyl)quinazolin-2-amine

[0668]

[0669] Step 1: Preparation of 7-bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((methylsulfonyl)methyl)phenyl)quinazolin-2-amine)

[0670]

[0671] 50 mg of 7-bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((methylthio)methyl)phenyl)quinazolin-2-amine) was dissolved in 5 mL of dichloromethane, and 68 mg of m-chloroperoxybenzoic acid was added. The reaction was carried out at room temperature for 3 hours. LC-MS showed that the starting material had completely reacted. The reaction solution was concentrated, and the crude product was purified by preparative TLC to give 20 mg of the title compound.

[0672] MS(ESI)m / z(M+H) + =620.1,622.1.

[0673] Step 2: Preparation of 7-bromo-8-((cis-4-hydroxycyclohexyl)oxy)-N-(3-((S-methylsulfonyl)methyl)phenyl)quinazolin-2-amine

[0674]

[0675] 20 mg of 7-bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-(((methanesulfonyl)methyl)phenyl)quinazolin-2-amine) was dissolved in a mixed solvent of 5 mL of 1,4-dioxane and 1 mL of hydrochloric acid. The reaction was carried out at room temperature for 30 minutes. LC-MS analysis showed no residual starting material. The reaction solution was concentrated, and the crude product was purified by preparative HPLC to obtain 2 mg of the title compound.

[0676] MS(ESI)m / z(M+H) + =506.1,508.1.

[0677] 1H NMR(400MHz,DMSO-d6)δ10.11(s,1H),9.33(s,1H),8.36–8.19(m,1H),7.66 (t,J=1.9Hz,1H),7.57(d,J=2.0Hz,2H),7.36(t,J=7.9Hz,1H),7.11–7.06(m ,1H),5.13–5.06(m,1H),4.52–4.42(m,3H),3.68–3.59(m,1H),2.96(s,3H), 2.06–1.92(m,2H),1.82–1.73(m,2H),1.71–1.60(m,2H),1.46–1.38(m,2H).

[0678] Example 13: Preparation of enantiomer A of 8-((cis-4-hydroxycyclohexyl)oxy)-7-chloro-N-(2-((methanesulfonylimino)methyl)pyridin-4-yl)quinazolin-2-amine

[0679]

[0680] Step 1: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-chloro-N-(2-((methanesulfonylimino)methyl)pyridin-4-yl)quinazoline-2-amine (isomers 13-1 and 13-2)

[0681]

[0682] 170 mg of 8-(cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-chloro-N-(2-((methylthio)methyl)pyridin-4-yl)quinazolin-2-amine was dissolved in methanol (5 mL), and ammonium carbamate (60 mg) and iodophenyl diacetic acid (200 mg) were added. The mixture was reacted at room temperature for 30 minutes. TLC showed that the reaction proceeds were complete. The reaction solution was quenched with 10 mL of 5% sodium thiosulfate aqueous solution, extracted with ethyl acetate (3 x 15 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to obtain 60 mg of the title compound. The title compound was separated into enantiomers by chiral preparative HPLC.

[0683] MS(ESI)m / z(M+H) + =576.2.

[0684]

[0685] Step 2: Preparation of enantiomer A of 8-((cis-4-hydroxycyclohexyl)oxy)-7-chloro-N-(2-((methanesulfonylimino)methyl)pyridin-4-yl)quinazolin-2-amine

[0686]

[0687] 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-chloro-N-(2-((methanesulfonylimino)methyl)pyridin-4-yl)quinazolin-2-amine (10 mg, isomer 13-1) was dissolved in 1,4-dioxane (1 mL), and hydrogen chloride / 1,4-dioxane (4 M, 5 mL) was added. The reaction was carried out at room temperature for 30 minutes. LC-MS showed no starting material remaining. The solvent was removed by concentration under reduced pressure, and the crude product was purified by reversed-phase column chromatography to give 4 mg of the title compound.

[0688] MS(ESI)m / z(M+H) + =462.1.

[0689] 1 H NMR (400MHz, DMSO-d6) δ10.59 (s, 1H), 9.44 (s, 1H), 8.42 (d, J = 5.6Hz, 1H), 8.26 (dd ,J=5.7,2.0Hz,1H),7.79–7.70(m,2H),7.54(d,J=8.6Hz,1H),5.04–4.95(m,1H),4 .52(d,J=3.3Hz,1H),4.45(s,2H),3.79(s,1H),3.68–3.60(m,1H),2.96(s,3H),2. 03(q,J=10.8,9.4Hz,2H),1.81–1.74(m,2H),1.74–1.67(m,2H),1.51–1.41(m,2H).

[0690] Example 14: Preparation of enantiomer B of 8-((cis-4-hydroxycyclohexyl)oxy)-7-chloro-N-(2-((methanesulfonylimino)methyl)pyridin-4-yl)quinazolin-2-amine

[0691]

[0692] 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-chloro-N-(2-((methanesulfonylimino)methyl)pyridin-4-yl)quinazolin-2-amine (10 mg, isomer 13-2) was dissolved in 1,4-dioxane (1 mL), and hydrogen chloride / 1,4-dioxane (4 M, 5 mL) was added. The mixture was reacted at room temperature for 30 minutes. LC-MS showed no starting material remaining. The solvent was removed by concentration under reduced pressure, and the crude product was purified by reversed-phase column chromatography to give 4 mg of the title compound.

[0693] MS(ESI)m / z(M+H) +=462.1.

[0694] 1 H NMR (400MHz, DMSO-d6) δ10.59(s,1H),9.44(s,1H),8.42(d,J=5.7Hz,1H),8.26( dd,J=5.7,2.0Hz,1H),7.79–7.70(m,2H),7.54(d,J=8.6Hz,1H),5.04–4.95(m,1 H),4.52(d,J=3.3Hz,1H),4.45(s,2H),3.79(s,1H),3.68–3.60(m,1H),2.96(s, 3H),2.09–1.96(m,2H),1.84–1.74(m,2H),1.74–1.64(m,2H),1.51–1.41(m,2H).

[0695] Example 21: Preparation of 8-((cis-4-hydroxycyclohexyl)oxy)-N-(3-((methanesulfonyl)methyl)phenyl)-7-vinylquinazoline-2-amine

[0696]

[0697]

[0698] Step 1: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((methylsulfonyl)methyl)phenyl)-7-vinylquinazoline-2-amine)

[0699]

[0700] 7-Bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-(((methanesulfonyl)methyl)phenyl)quinazolin-2-amine (50 mg), 2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl (10 mg), tris(dibenzylacetone)dipalladium (11 mg), lithium chloride (10 mg), and tributylvinyltin (38 mg) were placed in a round-bottom flask. Under nitrogen protection, anhydrous toluene (20 mL) was added, and the reaction was carried out at 90 °C. After the reaction was monitored by LCMS until complete, the mixture was cooled to room temperature, the solid was removed by filtration, the filtrate was concentrated under reduced pressure, and the title compound (30 mg) was obtained by silica gel column chromatography.

[0701] MS(ESI)m / z(M+H) + =568.2.

[0702] Step 2: Preparation of 8-((cis-4-hydroxycyclohexyl)oxy)-N-(3-((methanesulfonyl)methyl)phenyl)-7-vinylquinazoline-2-amine

[0703]

[0704] 30 mg of 8-(cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-(((methylsulfonyl)methyl)phenyl)-7-vinylquinazoline-2-amine) was dissolved in 10 mL of dichloromethane at room temperature. Hydrogen chloride / 1,4-dioxane (4 M, 0.2 mL) was added, and the mixture was reacted at room temperature for 30 minutes. LC-MS showed no starting material remaining. The solvent was removed by concentration under reduced pressure, and the crude product was purified by reversed-phase column chromatography to give 18 mg of the title compound.

[0705] MS(ESI)m / z(M+H) + =454.1.

[0706] 1 H NMR (400MHz, DMSO-d6) δ9.99 (s, 1H), 9.25 (s, 1H), 8.35 (d, J = 8.0Hz, 1H), 7.65–7. 59(m,3H),7.36–7.29(m,2H),7.04(d,J=7.6Hz,1H),6.02(dd,J=18.0,1.2Hz,1H) ,5.49(d,J=11.2Hz,1H),4.95–4.92(m,1H),4.48(d,J=3.6Hz,1H),4.44(s,2H),3 .62(s,1H),2.95(s,3H),1.94–1.86(m,2H),1.69–1.63(m,4H),1.42–1.36(m,2H).

[0707] Example 26: Preparation of (racemic)-8-((cis-4-hydroxycyclohexyl)oxy)-N-(3-((methanesulfonylimino)methyl)phenyl)-7-vinylquinazoline-2-amine

[0708]

[0709] Step 1: Preparation of (racemic)-7-bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((S-methylsulfonylimino)methyl)phenyl)quinazolin-2-amine

[0710]

[0711] The title compound was prepared using a method similar to that described in Example 1 above.

[0712] MS(ESI)m / z(M+H) + =619.1, 621.1.

[0713] The compound of this embodiment was prepared by following a similar method to that in Example 21 above.

[0714] MS(ESI)m / z(M+H) + =453.2.

[0715] 1 H NMR (400MHz, DMSO-d6) δ9.94 (s, 1H), 9.25 (s, 1H), 8.31 (d, J = 8.0Hz, 1H), 7.65–7.59 (m ,3H),7.37–7.30(m,2H),7.07(d,J=8.0Hz,1H),6.02(d,J=18.0Hz,1H),5.49(d,J=11.6 Hz,1H),4.94(t,J=8.0Hz,1H),4.48(d,J=3.2Hz,1H),4.34(q,J=13.2Hz,2H),3.63(s,1 H),3.59(s,1H),2.83(s,3H),1.94–1.87(m,2H),1.68–1.64(m,4H),1.42–1.35(m,2H).

[0716] Example 27: Preparation of 8-((cis-4-hydroxycyclohexyl)oxy)-7-ethynyl-N-(3-(((methanesulfonyl)methyl)phenyl)quinazolin-2-amine)

[0717]

[0718]

[0719] Step 1: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-carboxaldehyde-N-(3-(((methylsulfonyl)methyl)phenyl)quinazolin-2-amine)

[0720]

[0721] At room temperature, potassium osmium tetroxide dihydrate (22 mg) and sodium periodate (250 mg) were added to a mixed solution of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-(((methanesulfonyl)methyl)phenyl)-7-vinylquinazoline-2-amine (330 mg)) in acetone (20 mL) and water (20 mL), and the reaction was allowed to proceed for half an hour at room temperature. LC-MS showed a good reaction. The reaction was quenched with water and an aqueous solution of sodium thiosulfate. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was obtained. Column chromatography purification yielded the title compound (150 mg).

[0722] MS(ESI)m / z(M+H) + =570.2.

[0723] Step 2: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-ethynyl-N-(3-(((methylsulfonyl)methyl)phenyl)quinazolin-2-amine)

[0724]

[0725] At room temperature, dimethyl 1-diazo-2-oxopropyl)phosphonate (100 mg) and potassium carbonate (110 mg) were added to a methanol (50 mL) solution of 140 mg of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-carboxy-N-(3-(((methanesulfonyl)methyl)phenyl)quinazolin-2-amine)

[0726] MS(ESI)m / z(M+H) + =566.2.

[0727] Step 3: Preparation of 8-((cis-4-hydroxycyclohexyl)oxy)-7-ethynyl-N-(3-(((methanesulfonyl)methyl)phenyl)quinazolin-2-amine)

[0728]

[0729] In an ice-water bath, a solution of 1,4-dioxane (4M, 0.5 mL) of HCl was added to a dichloromethane (5 mL) solution of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-ethynyl-N-(3-((methanesulfonyl)methyl)phenyl)quinazolin-2-amine (30 mg),) and the reaction was allowed to proceed naturally for approximately 30 minutes. After the reaction was confirmed to be complete by LC-MS, the solvent was removed by direct concentration under reduced pressure, and the solution was then subjected to reverse preparative column chromatography to obtain the title compound (12 mg).

[0730] MS(ESI)m / z(M+H) + =452.2.

[0731] 1 H NMR (400MHz, DMSO-d6) δ10.08(s,1H),9.31(s,1H),8.29(d,J=8.0Hz,1H),7.67(s ,1H),7.60(d,J=8.4Hz,1H),7.37–7.33(m,2H),7.06(d,J=7.6Hz,1H),5.02–4.98( m,1H),4.57(s,1H),4.47(d,J=3.2Hz,1H),4.45(s,2H),3.62–3.60(m,1H),2.95(s ,3H),2.03–1.95(m,2H),1.83–1.77(m,2H),1.67–1.62(m,2H),1.45–1.40(m,2H).

[0732] Example 29: Preparation of 2-(8-((cis-4-hydroxycyclohexyl)oxy)-2-((3-(((methanesulfonyl)methyl)phenyl)amino)quinazolin-7-yl)acetonitrile

[0733]

[0734] Step 1: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-(isoxazol-4-yl)-N-(3-(((methylsulfonyl)methyl)phenyl)quinazolin-2-amine)

[0735]

[0736] At room temperature, 7-bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((methanesulfonyl)methyl)phenyl)quinazolin-2-amine (322 mg), pinacol 4-isoxazoleborate (202 mg), potassium fluoride (91 mg), palladium dichloride bis(triphenylphosphine) chloride (50 mg), DMSO (20 mL), and water (3 mL) were added to a single-necked flask. After purging with nitrogen, the mixture was heated to 110 °C and reacted for 2 h. LC-MS showed a good reaction, and direct reversed-phase column chromatography yielded the title compound (153 mg).

[0737] MS(ESI)m / z(M+H) + =609.3.

[0738] Step 2: Preparation of 2-(8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2-((3-(((methylsulfonyl)methyl)phenyl)amino)quinazolin-7-yl)acetonitrile)

[0739]

[0740] Potassium fluoride (57 mg) was added to a mixture of methanol (10 mL) and water (10 mL) of 60 mg of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-(isoxazol-4-yl)-N-(3-(((methanesulfonyl)methyl)phenyl)quinazolin-2-amine) at room temperature, and the mixture was heated to 90 °C and reacted for 1 h. LC-MS showed that the reaction was complete. After concentration under reduced pressure, water and ethyl acetate were added to separate the organic phases. The aqueous phase was extracted with dichloromethane, the organic phases were combined, dried, filtered, concentrated, and purified by column chromatography to give the title compound (47 mg).

[0741] MS(ESI)m / z(M+H) + =581.3.

[0742] Step 3: Preparation of 2-(8-((cis-4-hydroxycyclohexyl)oxy)-2-((3-((methanesulfonyl)methyl)phenyl)amino)quinazolin-7-yl)acetonitrile

[0743]

[0744] At room temperature, 47 mg of 2-(8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2-((3-(((methanesulfonyl)methyl)phenyl)amino)quinazolin-7-yl)acetonitrile was dissolved in 10 mL of dichloromethane, and 0.5 mL of HCl (4 min 1,4-Dioxane) was added at room temperature. After 10 min, the reaction was monitored by LCMS until complete, and the solution was adjusted to alkalinity by adding saturated sodium bicarbonate aqueous solution. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, dried, filtered, concentrated, and purified by reverse-phase preparative column chromatography to obtain the title compound (8 mg).

[0745] MS(ESI)m / z(M+H) + =467.2.

[0746] 1 H NMR(400MHz,DMSO-d6)δ10.04(s,1H),9.31(s,1H),8.30(d,J=8.0Hz,1H),7 .68(d,J=8.0Hz,1H),7.58(s,1H),7.39–7.33(m,2H),7.07(d,J=7.6Hz,1H), 5.13–5.08(m,1H),4.52(d,J=3.2Hz,1H),4.44(s,2H),4.12(s,2H),3.64(s ,1H),2.95(s,3H),1.98–1.88(m,2H),1.68–1.65(m,4H),1.43–1.38(m,2H).

[0747] Example 45: Preparation of 7-bromo-8-((cis-4-hydroxycyclohexyl)oxy)-N-(3-(2-(methanesulfonyl)propane-2-yl)phenyl)quinazolin-2-amine

[0748]

[0749] Hydrochloric acid (4 M in Dioxane, 0.2 mL) was added to a solution of 7-bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-(2-(2-(methanesulfonyl)propane-2-yl)phenyl)quinazolin-2-amine (46 mg)) in dichloromethane (10 mL) in an ice-water bath, and the reaction was allowed to proceed naturally with the temperature rise. LC-MS showed a good reaction. The solvent was removed directly under reduced pressure, and the compound was purified by reverse-phase HPLC to give the title compound (10 mg).

[0750] MS(ESI)m / z(M+H) + =534.1, 536.1.

[0751] 1 H NMR (400MHz, DMSO-d6) δ10.03(s,1H),9.32(s,1H),8.42(d,J=9.2Hz,1H),7.74(s,1H),7.58–7.53(m,2H),7.36(t,J=8.0Hz,1H),7.28(d,J=8.0 Hz,1H),5.08–5.04(m,1H),4.46(s,1H),3.63(s,1H),2.72(s,3H),2.01 –1.93(m,2H),1.77–1.72(m,8H),1.67–1.63(m,2H),1.43–1.37(m,2H).

[0752] Example 46: Preparation of (racemic)-8-((cis-4-(acetamido)cyclohexyl)oxy)-7-chloro-N-(2-((S-methylsulfonylimino)methyl)pyridin-4-yl)quinazolin-2-amine

[0753]

[0754]

[0755] 80 mg of 8-((cis-4-(acetamido)cyclohexyl)oxy)-7-chloro-N-(2-((methylthio)methyl)pyridin-4-yl)-quinazolin-2-amine was dissolved in methanol (20 mL), and ammonium carbamate (20 mg) and PIDA (130 mg) were added. The reaction was carried out at room temperature for 30 minutes. LCMS showed that a product was formed, but a large amount of starting material remained. The mixture was concentrated under reduced pressure, and the crude product was purified by preparative chromatography. Finally, the title compound (5 mg) was purified by reversed-phase preparative HPLC.

[0756] MS(ESI)m / z(M+H) + =503.2.

[0757] 1 H NMR (400MHz, DMSO-d6) δ10.54(s,1H),9.43(s,1H),8.43(d,J=5.6Hz,1H),8.2 0–8.19(m,1H),7.85(d,J=7.2Hz,1H),7.73(d,J=8.4Hz,1H),7.65(s,1H),7.5 2(d,J=8.4Hz,1H),5.15(s,1H),4.43(s,2H),3.78(s,1H),3.64(s,1H),2.94( s,3H),2.01–1.98(m,2H),1.81(s,5H),1.73–1.70(m,2H),1.57–1.55(m,2H).

[0758] Example 49: Preparation of 7-chloro-8-((4-hydroxy-4-methylcyclohexyl)oxy)-N-(3-(((methylsulfonyl)methyl)phenyl)quinazolin-2-amine

[0759]

[0760] Step 1: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-chloro-N-(3-(((methylsulfonyl)methyl)phenyl)quinazolin-2-amine)

[0761]

[0762] The title compound was prepared using a method similar to that described in Example 7 above.

[0763] MS(ESI)m / z(M+H) + =576.2.

[0764] Step 2: Preparation of 8-((cis-4-hydroxycyclohexyl)oxy)-7-chloro-N-(3-((methanesulfonyl)methyl)phenyl)quinazolin-2-amine

[0765]

[0766] The title compound was prepared using a method similar to that described in Example 7 above.

[0767] MS(ESI)m / z(M+H) + =462.1.

[0768] Step 3: Preparation of 4-((7-chloro-2-((3-(((methylsulfonyl)methyl)phenyl)amino)quinazolin-8-yl)oxy)cyclohexane-1-one

[0769]

[0770] 8-((cis-4-hydroxycyclohexyl)oxy)-7-chloro-N-(3-(((methanesulfonyl)methyl)phenyl)quinazolin-2-amine) (50 mg) was dissolved in dichloromethane (15 mL), and Dys-Martin reagent (47 mg) and sodium bicarbonate (20 mg) were added. The reaction was carried out at room temperature for 2 hours. The reaction was confirmed to be complete by TLC. The reaction was quenched by adding aqueous sodium thiosulfate and saturated sodium bicarbonate solution. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The samples were combined, dried, filtered, and concentrated. The crude product was purified by column chromatography to give the title compound (30 mg).

[0771] MS(ESI)m / z(M+H) + =460.1.

[0772] Step 4: Preparation of 7-chloro-8-((4-hydroxy-4-methylcyclohexyl)oxy)-N-(3-(((methanesulfonyl)methyl)phenyl)quinazolin-2-amine

[0773]

[0774] Under inert gas protection, 30 mg of 4-((7-chloro-2-((3-(((methanesulfonyl)methyl)phenyl)amino)quinazolin-8-yl)oxy)cyclohexane-1-one was dissolved in 10 mL of THF. Then, 1 mL of magnesium methyl bromide (3 min THF) was added at room temperature, and the reaction was continued at room temperature for 2 hours. The reaction was confirmed to be complete by TLC. The reaction was quenched with saturated sodium bicarbonate solution. The solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Subsequent preparative HPLC purification yielded the title compounds, namely compound A (5 mg) as the first peak and compound B (5 mg) as the last peak.

[0775] Compound A: MS(ESI) m / z(M+H) + =476.1.

[0776] 1 H NMR (400MHz, DMSO-d6) δ10.15 (s, 1H), 9.33 (s, 1H), 8.40 (d, J = 8.4Hz, 1H), 7. 68–7.66(m,2H),7.43(d,J=8.4Hz,1H),7.35(t,J=8.0Hz,1H),7.09(d,J=8.0H z,1H),4.86–4.79(m,1H),4.47(s,2H),4.15(s,1H),2.97(s,3H),2.05–1.96( m,3H),1.79–1.75(m,2H),1.63–1.60(m,2H),1.24–1.20(m,1H),1.07(s,3H).

[0777] Compound B: MS(ESI) m / z(M+H) + =476.1.

[0778] 1H NMR (400MHz, DMSO-d6) δ10.12(s,1H),9.33(s,1H),8.27(d,J=8.4Hz,1H),7.67–7.63(m,2H),7.42(d,J=8.4Hz,1H),7.37(t,J=8.0Hz,1H),7.1 0(d,J=8.0Hz,1H),5.21(s,1H),4.46(s,2H),4.15(s,1H),2.96(s,3H) ,1.91–1.86(m,2H),1.80–1.70(m,4H),1.38–1.33(m,2H),1.17(s,3H).

[0779] Starting materials were prepared using a method similar to that described in the foregoing preparation examples, and the compounds in the examples listed in the table below were prepared using a method similar to that described in the foregoing examples:

[0780]

[0781]

[0782]

[0783]

[0784]

[0785]

[0786]

[0787]

[0788]

[0789]

[0790]

[0791]

[0792]

[0793]

[0794] Biological experiments

[0795] Test Example 1: TNIK Enzymatic Activity Test

[0796] The IC50 of the test compound for TNIK was determined using the ADP-Glo ​​Kinase Assay method.50 value.

[0797] The specific steps are as follows: The initial concentration of the compound for testing is 1 μM, and it is serially diluted 3-fold to obtain 10 concentration points. Take 50 nL of each of the 10 different concentrations of the test compound solution and add them to a 384-well plate for later use. Prepare a 1.25 ng / μL TNIK enzyme (Signalchem, catalog number #T27-11G-10) solution using enzyme buffer (40 mM Tris, 20 mM MgCl2, 0.1 mg / mL BSA, 50 μM DTT). Add 2.5 μL of TNIK enzyme solution to each well of the test compound at different concentrations; add 2.5 μL of enzyme buffer to the negative control well; and add 2.5 μL of STS (MCE, catalog number HY-15141) to the positive control well. After vortexing and mixing, incubate at room temperature for 10 minutes. Prepare a reaction mixture (containing 0.2 mg / mL MBP and 40 μM ATP) using enzyme buffer. Add 2.5 μL of the reaction mixture to each of the positive control well, test compound well, and negative control well, vortex to mix, and incubate at room temperature for 120 minutes. Then add 4 μL of ADP-Glo ​​(Promega, catalog number #V9102) and incubate at room temperature for 40 minutes. Finally, add 8 μL of enzyme assay reagent and incubate at room temperature for 40 minutes. Use an Envision 2104 multi-label Reader (PerkinElmer, catalog number #Oct-04) to read the Luminescence signal and process the data.

[0798] Calculation formula:

[0799] %Inhibition = 100 - (Signal compound - Signal positive control well) / (Signal negative control well - Signal positive control well) × 100

[0800] Using the concentration log value as the X-axis and the percentage inhibition rate (%Inhibition) as the Y-axis, dose-response curves were fitted using the dose response-variable slope function of GraphPad Prism 6 to obtain the IC50 values ​​of each compound on enzyme activity.

[0801] TNIK enzyme activity data

[0802] 1 11.73 2 23.75 3 37.37 4 75.09 5 25.04 6 15.16 7 9.95 8 31.67 9 39.10 10 38.67 12 7.88 13 84.53 14 73.45 16 60.32 17 83.41 18 19.68 19 7.01 20 24.61

[0803] Test Example 2: CDK9 / CycT1 Enzymatic Activity Assay

[0804] The IC50 of the test compound to CDK9 / CycT1 was determined using the Mobility Shift Assay method. 50value.

[0805] The specific steps are as follows: The initial concentration of the compound for testing is 1 μM, and it is serially diluted 3-fold to obtain 10 concentration points. Take 250 nL of each concentration of the test compound solution and add it to a 384-well plate. Prepare a 12.5 nM CDK9 kinase (Carna, catalog number #04-110) solution using enzyme buffer (20 mM HEPES, 0.01% Triton, pH 7.5), and add 10 μL of CDK9 kinase solution to each well containing a different concentration of the test compound. Add 10 μL of enzyme buffer to the negative control well, centrifuge at 1000 rpm for 30 seconds, vortex to mix, and incubate at room temperature for 10 minutes. Prepare a reaction mixture (containing 26.67 μM ATP, 16.67 mM MgCl2, and 5 μM Peptide CTD3) using enzyme buffer, and add 15 μL of the reaction mixture to each well containing the test compound and the negative control well. Start the reaction, centrifuge at 1000 rpm for 30 seconds, vortex to mix, and incubate at room temperature for 120 minutes. Then add 30 μL of BIOMOL Green reaction termination solution. TM Stop the kinase reaction with Reagent (Enzo Lifesciences, catalog number BML-AK111-1000), centrifuge at 1000 rpm for 30 seconds, and vortex to mix. Read the conversion rate using a microplate reader (Perkin Elmer, model Caliper EZ Reader II) and process the data.

[0806] Calculation formula:

[0807] %Inhibition = (Conversion% Positive Control Wells - Conversion% Test Compound Wells) / (Conversion% Positive Control Wells - Conversion% Negative Control Wells) × 100

[0808] Using the log value of concentration as the X-axis and the percentage inhibition rate (%Inhibition) as the Y-axis, the dose-response curve was fitted using the log(inhibitor) vs. response-variable slope of the analysis software GraphPad Prism 5 to obtain the IC50 value of each compound on enzyme activity.

[0809] CDK9 enzyme activity data

[0810] 1 68 2 1.3 3 17.9 4 12.5 5 1.8 6 1.3 7 1.63 8 1.12 9 1.1 10 1.21 11 5.39 12 1.07 13 1.10 14 1.23 16 1.12 17 1.39 18 0.84 19 1.45 20 1.46 21 0.8 22 2.0 24 0.77 26 0.96 27 1.2 28 0.85 29 0.36 32 0.53 33 0.34 34 0.50 35 1.7 36 1.22 37 0.99 38 0.68 40 1.49 41 0.98 42 0.76 43 63.1 45 3.76 46 1.42 47 1.08 48 0.87 49 1.31(A) / 1.46(B)

[0811] Test Example 3: HCT116 Cell Activity Inhibition Test (Source: Nanjing Kebai Biotechnology Co., Ltd.)

[0812] The IC50 of the test compound on the inhibition of HCT116 cell proliferation was detected using the CellTiter-Glo luminescent live cell assay system. 50 value.

[0813] The specific steps are as follows: On the first day, cells in the logarithmic growth phase were digested with trypsin and resuspended to a suitable density in McCoy's 5A medium (Sigma, M9309) containing 10% FBS (PAN, catalog number ST30-3302). After thorough mixing, 100 μL of the mixture was added to each well of a 96-well plate, with a cell density of 3000–5000 cells per well. The plates were then incubated overnight at 37°C in a 5% CO2 incubator to allow the cells to adhere. On the second day, the test compound was diluted from a 10 mM stock solution to 2 mM with DMSO, and then serially diluted 3.33-fold and 3-fold to eight concentration points (200×). Subsequently, the compound was diluted to 2× with complete medium, and 100 μL of complete medium containing 2× of the compound was added to each well of a 96-well plate (to make the initial test concentration 10 μM and DMSO content 0.5%). The plates were incubated at 37°C in a 5% CO2 incubator for 3 days. On day 5, after the compound-treated cells were equilibrated to room temperature, 50 μL of supernatant was collected from each well. Then, 50 μL of CellTiter-Glo (Promega, catalog number #G7571) reagent was added, and the cells were shaken at room temperature for 5 minutes to allow for complete cell lysis. After incubation for another 5 minutes, the cells were read using a microplate reader (BMG, model number 1). FSX is used to detect the Luminescence signal and process the data.

[0814] Calculation formula:

[0815] % cell viability = Signal compound / Signal negative control × 100.

[0816] Using the log value of concentration as the X-axis and %cell viability as the Y-axis, the dose-response curve was fitted and the IC was calculated using the log(inhibitor) vs. dose response-variable slope (four parameters) method in the analysis software GraphPadPrism 8. 50 value.

[0817] HCT116 cell viability data

[0818] 1 148.4 2 15.15 3 262.4 4 273.8 5 31.24 6 20.8 7 14.2 8 16.09 9 16.5 10 21.7 11 643.7 12 73.5 13 41.3 14 32.97 16 39 17 10.2 18 1.9 19 40.8 20 22.8 21 12.3 22 174.2 24 36 26 34.6 27 32.8 28 36.6 29 30.4 30 556.5 31 206.3 32 137.6 33 41.7 34 45.7 35 39.3 36 45.9 37 12.3 38 12.1 40 139.6 41 10.2 42 38.9 45 632.4 46 405.5 47 42.4 48 2.7 49 41.6(A) / 45.5(B)

Claims

1. Compounds or stereoisomers of general formula (I), pharmaceutically acceptable salts, or tautomers: in, Q is selected from 5-6 aryl, 5-6 substituted aryl, 5-6 heteroaryl or 5-6 substituted heteroaryl; Each of the 5-6 substituted aryl or 5-6 substituted heteroaryl groups optionally has one or more substituents, wherein the substituents are arbitrarily selected from halogens, cyano groups, etc. -(CR5R6) m SO2R a The R a Selected from H, C1-C6 alkyl; the R b The R5 and R6 are selected from H; the R5 and R6 are selected from H and C1-C3 alkyl groups. The 5-6 substituted heteroaryl group or the 5-6 substituted heteroaryl group has one or more heteroatoms, which are arbitrarily selected from N and O. The m is 1; R 1 R 2 R 3 or R 4 Each of the following groups is independently selected from H, halogen, amino, hydroxyl, cyano, C1-C6 haloalkoxy, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C7 alkenyl, C2-C7 alkynyl, 5-6-membered heteroaryl, 5-6-membered substituted heteroaryl, and C1-C6 substituted alkyl; the substituents of the 5-6-membered substituted heteroaryl are optionally selected from C1-C6 alkyl; the substituents of the C1-C6 substituted alkyl are optionally selected from halogen, amino, and cyano. B represents O; W represents a 5-7 nucleotide saturated cycloalkyl group, wherein the 5-7 nucleotide saturated cycloalkyl group optionally has one or more substituents selected from: H, halogen, amino, hydroxyl, acetamido, C1-C6 haloalkyl, C1-C6 alkyl.

2. Compounds or stereoisomers of general formula (Ia), pharmaceutically acceptable salts, or tautomers: (him) in, X1 represents O or NR8, where R8 is selected from H; X 2、 X3, X4, or X5 are each independently selected from N or CR9, wherein R9 is selected from H, halogen, cyano, 3-7 membered heterocyclic alkyl, The 3-7 membered heterocyclic alkyl group has one or more heteroatoms, which are arbitrarily selected from N and O. R 1 R 2 R 3 or R 4 Each of the following is independently selected from H, halogen, cyano, C1-C6 haloalkyl, C3-C7 cycloalkyl, C1-C6 alkyl, C2-C7 alkenyl or C2-C7 ynyl, 5-6-membered heteroaryl, 5-6-membered substituted heteroaryl, and C1-C6 substituted alkyl; the 5-6-membered heteroaryl and 5-6-membered substituted heteroaryl have one or more heteroatoms, the heteroatoms being arbitrarily selected from N, O or S; the 5-6-membered substituted heteroaryl has substituents arbitrarily selected from C1-C6 alkyl; the C1-C6 substituted alkyl has substituents arbitrarily selected from cyano; R5 and R6 are each independently selected from H and C1-C3 alkyl groups; R7 is selected from H and C1-C6 alkyl groups; B represents O; Z represents H, halogen, amino, hydroxyl, acetamido, C1-C6 haloalkyl, and C1-C6 alkyl. r is 0, 1, or 2; m is 1; n is 1.

3. The compound or stereoisomer, pharmaceutically acceptable salt, or tautomer according to claim 1, wherein Q is a 6-membered heteroaryl group having the following substituted structures: The substituents are arbitrarily selected from halogens, cyano groups, etc. -(CR5R6) m SO2R a The R a Selected from H, C1-C6 alkyl; the R b The components are selected from H; R5 and R6 are selected from H and C1-C3 alkyl groups.

4. The compound or stereoisomer, pharmaceutically acceptable salt, or tautomer according to claim 2, wherein X 2、 X3, X4, or X5 are each independently CR9, wherein R9 is selected from H, cyano, F, Cl, Br, .

5. The compound or stereoisomer, pharmaceutically acceptable salt, or tautomer according to any one of claims 1-4, R 1 R 2 R 3 or R 4 Each of the following is independently selected from H, halogen, cyano, C1-C6 haloalkyl, C3-C7 cycloalkyl, C1-C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, 5-6-membered heteroaryl, 5-6-membered substituted heteroaryl, and C1-C6 substituted alkyl; the 5-6-membered heteroaryl and 5-6-membered substituted heteroaryl have one or more heteroatoms, the heteroatoms being arbitrarily selected from N, O, or S; the 5-6-membered substituted heteroaryl has substituents arbitrarily selected from C1-C6 alkyl; the C1-C6 substituted alkyl has substituents arbitrarily selected from cyano.

6. The compound or stereoisomer, pharmaceutically acceptable salt, or tautomer according to claim 5, R 1 Selected from H, F, Cl, Br, CF3, CN, CH3, cyclopropyl, CH2CN or .

7. The compound or stereoisomer, pharmaceutically acceptable salt or tautomer as described in claim 2, wherein Z may be selected from H, acetamido, methyl or 4-hydroxy; n is 1; r is 0, 1 or 2.

8. A compound or stereoisomer, pharmaceutically acceptable salt, or tautomer, characterized in that... It has the following structure: 。 9. A pharmaceutical composition comprising the compound or stereoisomer of any one of claims 1-8, a pharmaceutically acceptable salt or tautomer, and a pharmaceutically acceptable excipient.

10. Use of the compound or stereoisomer, pharmaceutically acceptable salt or tautomer of any one of claims 1-8, or the pharmaceutical composition of claim 9 in the preparation of a medicament for treating CDK9 and / or TNIK-mediated diseases.

11. The use according to claim 10, wherein the CDK9 and / or TNIK-mediated disease is a hyperplastic disease.

12. The use according to any one of claims 10 or 11, wherein the CDK9 and / or TNIK-mediated disease is cancer.

13. The use according to claim 12, wherein the CDK9 and / or TNIK-mediated disease is a solid tumor and / or hematologic malignancy.

14. The use according to claim 13, wherein the CDK9 and / or TNIK-mediated cancers are selected from breast cancer, ovarian cancer, lung cancer, gastric cancer, pancreatic cancer, colorectal cancer, prostate cancer, thyroid cancer, liver cancer, acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, or neurocytoma.

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