Pyrimidine-fused heteroaromatic compound and use thereof

Abstract

The present invention relates to the field of biomedicine, and specifically relates to a pyrimidine-fused heteroaromatic compound as shown in formula (I), and a use thereof.

Description

Pyrimidoheteroaromatic compounds and their applications

[0001] This application is based on the application with CN application number 202410214392.5 and application date February 27, 2024, and claims its priority. The disclosed content of the aforementioned application is hereby introduced into this application as a whole. Technical Field

[0002] The present invention belongs to the field of biomedicine, and specifically relates to pyrimidoheteroaromatic compounds and applications thereof. Background Art

[0003] Alzheimer's disease (AD) is the most widespread neurodegenerative disease today, highly correlated with aging. The pathogenesis of AD remains unclear, with the amyloid-β (Aβ) cascade hypothesis being the most mainstream hypothesis for its mechanism. This hypothesis posits that Aβ is central to the pathogenesis of AD, with abnormal production and deposition of Aβ in specific brain regions, forming senile plaques, a key pathological hallmark of AD. This in turn triggers neurotoxic effects, causing synaptic damage and neuronal death, ultimately leading to the development of AD.

[0004] Aβ peptides are polypeptides containing 37 to 49 amino acid residues produced by the sequential hydrolysis of amyloid precursor protein (APP) by β-secretase and γ-secretase. First, the APP extracellular domain is cleaved by β-secretase to produce the C-terminal fragment of APP (CTFβ). CTFβ is a substrate for γ-secretase. CTFβ is hydrolyzed by γ-secretase at several adjacent positions within the transmembrane domain, producing various Aβ peptides and cytoplasmic fragments, including Aβ42, which consists of 42 amino acid residues. Aβ42 is considered the main pathogenic factor in the development of AD due to its neurotoxicity. Reducing the production of Aβ, especially Aβ42, is of great value in the prevention and treatment of AD.

[0005] γ-secretase, a key enzyme in the production of Aβ, is composed of four subunits: presenilin (PS), presenilin enhancer 2 (Pen2), anterior pharynx-defective 1 (Aph-1), and nicastrin (NCT). PS is the catalytic subunit carrying the catalytic site, while NCT and Aph-1 are primarily responsible for substrate recognition and recruitment. Genetic evidence indicates that over 200 mutations in genes encoding the active γ-secretase subunit PS1 are found in patients with heritable familial Alzheimer's disease (AD). Therefore, modulating the cleavage activity of γ-secretase and reducing amyloid plaque deposition have become important therapeutic strategies for AD.

[0006] γ-secretase inhibitors (GSIs) and γ-secretase modulators (GSMs) are two major development directions for γ-secretase-targeted drugs. GSIs were an early development focus for pharmaceutical companies. These compounds inhibit γ-secretase activity but also simultaneously inhibit the cleavage of other γ-secretase substrates, including Notch protein, causing a series of toxic side effects that have slowed the clinical development of these drugs.

[0007] In recent years, the research focus in the field of AD treatment has shifted from GSIs to GSMs. Unlike GSIs, which inhibit the entire γ-secretase activity, GSMs only regulate the cleavage site of γ-secretase. These compounds (1) inhibit the production of Aβ42 or reduce the Aβ42 / Aβ40 ratio; (2) increase Aβ37 or Aβ38 short peptides; (3) do not affect the production of total Aβ or the accumulation of APP-CTF; and (4) have no cleavage effect on Notch. Currently, several GSMs have entered AD clinical trials. Tarenflurbil (Myriad Genetics & Laboratories) showed no adverse reactions related to Notch inhibition, but failed in Phase III clinical trials due to lack of efficacy. Eisai's E2212 withdrew from Phase I clinical trials due to cataracts induced by inhibition of cholesterol biosynthesis. The subsequent launch of E2212 showed better safety than E2212 in Phase I clinical trials, but it also caused adverse reactions such as diarrhea. Pfizer's PF-06648671 was well-tolerated in healthy subjects after a single dose, significantly reducing plasma Aβ40 and Aβ42 and increasing Aβ37 and Aβ38. However, trials of this small molecule were terminated in 2018 after Pfizer discontinued its neurological research and development efforts. Compared to γ-secretase inhibitors, γ-secretase modulators show greater research potential.

[0008] In addition, some studies have shown that GSMs can also be used as potential anti-tumor drugs with broad indications, such as their application in the treatment of hematological malignancies and triple-negative breast cancer (CN116808219A and Front. Immunol., 13 October 2023).

[0009] However, due to poor drug-like properties and toxic side effects, there are currently no approved drugs in the GSMs field. The development of new small molecule regulators targeting γ-secretase is of great value. Summary of the Invention

[0010] The present invention provides a series of novel small molecule γ-secretase modulators, which can be used to treat, prevent and alleviate diseases associated with β-amyloid protein deposition, especially Alzheimer's disease (AD), and can also be used to treat, prevent and alleviate diseases associated with tumors.

[0011] The first aspect of the present invention provides a compound represented by formula (I), a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystal form, isotope-labeled substance or metabolite thereof,

[0012] in,

[0013] X is selected from C(R x ) and N, the R x is selected from hydrogen, halogen, hydroxy, mercapto, -(C1-C6)alkyl, -O-(C1-C6)alkyl and (C3-C6)cycloalkyl;

[0014] Y is selected from S and O, S is optionally oxidized;

[0015] L1 and L2 are each independently selected from a bond, -O-, -O-(C1-C4)alkylene-, -(C1-C4)alkylene-O-, -S-, -S(=O)-, -S(=O)2-, -OC(=O)-, -C(=O)O-, -NR a S(=O)2-、-S(=O)2NR a -、-NR a -、-NR a -(C1-C4)alkylene-, -(C1-C4)alkylene-NR a -、-NR a C(=O)-, -C(=O)NR a -、-P(=O)R a -、-P(=O)(OR a )-, -(C1-C4)alkylene-, -(C2-C4)alkenylene- and -(C2-C4)alkynylene-, the -O-(C1-C4)alkylene-, -(C1-C4)alkylene-O-, -NR a S(=O)2-、-S(=O)2NR a -、-NR a -、-NR a -(C1-C4)alkylene-, -(C1-C4)alkylene-NR a -、-NR a C(=O)-, -C(=O)NR a -、-P(=O)R a -、-P(=O)(OR a)-, -(C1-C4)alkylene-, -(C2-C4)alkenylene- and -(C2-C4)alkynylene- are optionally substituted by one or more groups selected from hydrogen, halogen, -OH, -SH, -NH2, -COOH and -(C1-C6)alkyl, wherein R a is selected from hydrogen, -(C1-C6)alkyl and -(C1-C6)haloalkyl;

[0016] Ring A is selected from (C6-C 14 ) aryl, 5-12 membered heteroaryl, 3-12 membered heterocyclyl, and 3-12 membered cycloalkyl;

[0017] R 1 Selected from hydrogen, halogen, nitro, nitroso, -CN, -OR b 、-SR b 、-S(=O)-R b 、-S(=O)2-R b 、-S(=O)NR b R c 、-S(=O)2NR b R c 、-NR b S(=O)2R c 、-NR b R c 、-NR b C(=O)-R c 、-COOH、-C(=O)-R b 、-P(=O)-R b R c 、-C(=O)NR b R c , -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, -(C6-C 10 )aryl, 3-9 membered heterocyclyl, 5-9 membered heteroaryl, =O, -CH2R b , -(C1-C6 alkyl) OH, -(C1-C6 alkyl) NH2, sulfonic acid and -Si(C1-C3 alkyl) 3, the -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, -(C1-C6) haloalkyl, -(C3-C7) cycloalkyl, -(C6-C 10 )aryl, 3-9 membered heterocyclic group, 5-9 membered heteroaryl, -CH2R b, -(C1-C6 alkyl) OH, -(C1-C6 alkyl) NH2, sulfonic acid and -Si(C1-C3 alkyl) 3 are optionally substituted by one or more groups selected from hydrogen, halogen, -OH, -SH, -NH2, -COOH, -(C1-C6) alkyl and -O(C1-C6) alkyl, wherein R b and R c each independently selected from hydrogen, -OH, -NH2, halogen, -(C1-C6)alkyl, -O(C1-C6)alkyl, -(C1-C6)haloalkyl, -C(=O)(C1-C6)alkyl, -S(=O)2(C1-C6alkyl), -(C1-C6)alkoxy, 3-9 membered heterocyclyl and 5-9 membered heteroaryl;

[0018] Ring B is selected from (C6-C 14 ) aryl, 5-12 membered heteroaryl, 3-12 membered heterocyclyl, and 3-12 membered cycloalkyl;

[0019] R 2 Selected from hydrogen, halogen, nitro, nitroso, -CN, -OR b 、-SR b 、-S(=O)-R b 、-S(=O)2-R b 、-S(=O)NR b R c 、-S(=O)2NR b R c 、-NR b S(=O)2R c 、-NR b R c 、-NR b C(=O)-R c 、-COOH、-C(=O)-R b 、-P(=O)-R b R c 、-C(=O)NR b R c , -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, -(C6-C 10 )aryl, 3-9 membered heterocyclyl, 5-9 membered heteroaryl, =O, -CH2R b , -(C1-C6 alkyl) OH, -(C1-C6 alkyl) NH2, sulfonic acid and -Si(C1-C3 alkyl) 3, the -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, -(C1-C6) haloalkyl, -(C3-C7) cycloalkyl, -(C6-C 10)aryl, 3-9 membered heterocyclic group, 5-9 membered heteroaryl, -CH2R b , -(C1-C6 alkyl) OH, -(C1-C6 alkyl) NH2, sulfonic acid and -Si(C1-C3 alkyl) 3 are optionally substituted by one or more groups selected from hydrogen, halogen, -OH, -SH, -NH2, -COOH and -(C1-C6) alkyl, wherein R b and R c each independently selected from hydrogen, -OH, -NH2, halogen, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -C(=O)(C1-C6)alkyl, -S(=O)2(C1-C6alkyl), -O-(C1-C6)alkyl, 3-9 membered heterocyclyl and 5-9 membered heteroaryl;

[0020] R 3 is selected from the group consisting of hydrogen, halogen, nitro, -CN, -OH, -O-(C1-C6)alkyl, -SH, -S-(C1-C6)alkyl, -S(=O)-(C1-C6)alkyl, -S(=O)2-(C1-C6)alkyl, -S(=O)NH2, -S(=O)2NH2, -NH2, -NH-(C1-C6)alkyl, -N[(C1-C6)alkyl]2, -NHC(=O)H, -NHC(=O)-(C1-C6)alkyl, -COOH, -C(=O)-(C1-C6)alkyl, -C(=O)NH2, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl and -(C1-C6)haloalkyl;

[0021] m is 0, 1, 2, 3, 4, 5, 6 or 7;

[0022] n is 0, 1, 2, 3, 4, 5, 6 or 7.

[0023] In certain embodiments, when X is CR x , when Y is S, R x , L1, L2, Ring A, R 1 ,m,ring B,R 2 ,n,R 3 As defined above.

[0024] In certain embodiments, when X is CR x , when Y is 0, R x , L1, L2, Ring A, R 1 ,m,ring B,R 2 、n、R 3 As defined above.

[0025] In certain embodiments, when X is N and Y is S, L1, L2, Ring A, R 1 ,m,ring B,R2 、n、R 3 As defined above.

[0026] In certain embodiments, when X is N and Y is O, L1, L2, Ring A, R 1 ,m,ring B,R 2 、n、R 3 As defined above.

[0027] In certain embodiments, L1 and L2 are each independently selected from a bond, -O-, -O-(C1-C4)alkylene-, -(C1-C4)alkylene-O-, -S-, -NR a -、-NR a -(C1-C4)alkylene-, -(C1-C4)alkylene-NR a -、-NR a C(=O)-, -C(=O)NR a - and -(C1-C4)alkylene-, the -NR a -(C1-C4)alkylene-, -(C1-C4)alkylene-NR a - is optionally substituted by one or more groups selected from hydrogen, methyl, said R a Selected from hydrogen and -(C 1- C4) alkyl.

[0028] In certain embodiments, the R a is selected from hydrogen, methyl, ethyl and isopropyl.

[0029] In certain embodiments, L1 and L2 are each independently selected from a bond, -O-, -S-, -NH-, -N[(C1-C4)alkyl]-, -NH-(C1-C4)alkylene-, -(C1-C4)alkylene-NH-, -NHC(=O)-, -C(=O)NH- and -(C1-C4)alkylene-, and the -NH-(C1-C4)alkylene-, -(C1-C4)alkylene-NH- are optionally substituted by one or more groups selected from hydrogen and methyl.

[0030] In certain embodiments, L1 and L2 are each independently selected from a bond, -O-, -S-, -NH-, -N[(C1-C4) alkyl]-, -NH-(C1-C4) alkylene-#, #-NH-(C1-C4) alkylene-, -NHC(=O)-#, -C(=O)NH-# and -(C1-C4) alkylene-, and the -NH-(C1-C4) alkylene-# and #-NH-(C1-C4) alkylene- are optionally substituted with one or more groups selected from hydrogen and methyl, wherein the # end represents the end connected to ring A or ring B.

[0031] In certain embodiments, L1 and L2 are each independently selected from a bond, -O-, -NH-, -N(methyl)-, -N(ethyl)-, -N(isopropyl)-, -NH-methylene-#, -NH-ethylidene-#, -NHCH(methyl)-#, -NHCH(ethyl)-#, -NHC(=O)-#, -C(=O)NH-#, methylene, ethylene, and isopropylidene, wherein the # end represents the end connected to ring A or ring B.

[0032] In certain embodiments, L1 is selected from a bond, -O-, -NH-, -N(CH3)-, and -NHC(=O)-#, wherein the # end represents the end connected to ring A.

[0033] In certain embodiments, L2 is selected from a bond, -O-, -NH-, -N(CH3)-, -CH2-, -NHCH2-#, -NHC(=O)-#, and -NHCH(CH3)-#, wherein the # end represents the end connected to ring B.

[0034] In certain embodiments, the X is selected from C(R x ) and N, the R x is selected from hydrogen, halogen, hydroxy, -(C1-C6)alkyl and -O-(C1-C6)alkyl.

[0035] In certain embodiments, the X is selected from C(R x ) and N, the R x is selected from hydrogen, -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, isopropyl, methoxy and ethoxy.

[0036] In certain embodiments, the X is selected from C(R x ) and N, the R x is selected from hydrogen, -F, -Cl, hydroxyl and methyl.

[0037] In certain embodiments, the X is selected from C(R x ) and N, the R x For hydrogen.

[0038] In certain embodiments, said Y is selected from S, O, S(=O) and S(=O)2.

[0039] In certain embodiments, said Y is selected from S and O.

[0040] In certain embodiments, the ring A is selected from (C 6- C 10 )aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl and 5-10 membered cycloalkyl.

[0041] In certain embodiments, the ring A is selected from phenyl, naphthyl, 6-9 membered heteroaryl, 6-9 membered heterocyclyl and 6-9 membered cycloalkyl, wherein the 6-9 membered heteroaryl and 6-9 membered heterocyclyl contain 1, 2 or 3 heteroatoms selected from N atoms, O atoms and S atoms, and the N atoms and S atoms are optionally oxidized.

[0042] In certain embodiments, the ring A is selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, piperidinyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, and 1,3-dihydrobenzimidazol-2-onyl.

[0043] In certain embodiments, the ring A is selected from

[0044] In certain embodiments, the R 1 Selected from hydrogen, halogen, nitro, -CN, -OR b 、-SR b 、-NR b R c 、-COOH、-C(=O)-R b 、-P(=O)-R b R c 、-C(=O)NR b R c , -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, -(C6-C 10 ) aryl, 3-9 membered heterocyclic group and 5-9 membered heteroaryl, the -(C1-C6) alkyl, -(C1-C6) haloalkyl, -(C3-C7) cycloalkyl, -(C6-C 10 ) aryl, 3-9 membered heterocyclyl and 5-9 membered heteroaryl are optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, halogen, -OH, -SH, -NH2, -COOH, -O(C1-C4)alkyl and -(C1-C4)alkyl, said R b and R c Each is independently selected from hydrogen, -OH, -NH2, halogen, -(C1-C4)alkyl, -O(C1-C4)alkyl and -(C1-C4)haloalkyl.

[0045] In certain embodiments, the R b and R c Each is independently selected from hydrogen, methyl, methoxy, ethyl and halomethyl.

[0046] In certain embodiments, the R 1Selected from hydrogen, halogen, -CN, -OH, -O-(C1-C4)alkyl, -SH, -NH2, -COOH, -C(=O)NH-(C1-C4)alkyl, -(C1-C4)alkyl and 5-6 membered heteroaryl, said -O-(C1-C4)alkyl, -C(=O)NH-(C1-C4)alkyl, -(C1-C4)alkyl and 5-6 membered heteroaryl are optionally substituted by 1, 2 or 3 groups selected from hydrogen, -O(C1-C4)alkyl and -(C1-C4)alkyl.

[0047] In certain embodiments, the R 1 Selected from hydrogen, fluorine, chlorine, bromine, -CN, -OH, -O-methyl, -O-ethyl, -O-propyl, -SH, -NH2, -COOH, -C(=O)NH-CH3, -C(=O)NH-CH2CH3, methyl, ethyl, propyl, imidazolyl, pyrazolyl, pyridinyl, triazolyl and pyrrolyl, and the -O-methyl, -O-ethyl, -O-propyl, methyl, ethyl, propyl, imidazolyl, pyrazolyl, pyridinyl, triazolyl and pyrrolyl are optionally substituted with 1 or 2 groups selected from methyl and methoxy.

[0048] In certain embodiments, the R 1 Selected from hydrogen, -OCH3, In certain embodiments, m is 0, 1, 2, 3, or 4.

[0049] In certain embodiments, m is 0 or 2.

[0050] In certain embodiments, the ring B is selected from (C 6- C 10 )aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl and 5-10 membered cycloalkyl.

[0051] In certain embodiments, the ring B is selected from phenyl, naphthyl, 5-9 membered heteroaryl, 6-9 membered heterocyclyl and 6-9 membered cycloalkyl, wherein the 5-9 membered heteroaryl and 6-9 membered heterocyclyl contain 1, 2 or 3 heteroatoms selected from N atoms, O atoms and S atoms, and the N atoms and S atoms are optionally oxidized.

[0052] In certain embodiments, the ring B is selected from tetrahydropyranyl, morpholinyl, phenyl, naphthyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, piperidinyl, 3,4-dihydro-2H-pyranyl, benzoxazolyl, benzisoxazolyl, benzofuranyl, benzothiazolyl, indolyl, benzimidazolyl, 1,3-benzodioxolyl, and 2-benzoxazolone.

[0053] In certain embodiments, the ring B is selected from

[0054] In certain embodiments, the R 2 Selected from hydrogen, halogen, nitro, -CN, -OR b 、-SR b 、-NR b R c 、-COOH、-C(=O)-R b 、-P(=O)-R b R c 、-C(=O)NR b R c , -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, -(C6-C 10 ) aryl, 3-9 membered heterocyclic group and 5-9 membered heteroaryl, the -(C1-C6) alkyl, -(C1-C6) haloalkyl, -(C3-C7) cycloalkyl, -(C6-C 10 ) aryl, 3-9 membered heterocyclyl and 5-9 membered heteroaryl are optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, halogen, -OH, -SH, -NH2, -COOH and -(C1-C4)alkyl, wherein R b and R c Each is independently selected from hydrogen, -OH, -NH2, halogen, -O-(C1-C4)alkyl, -(C1-C4)alkyl and -(C1-C4)haloalkyl.

[0055] In certain embodiments, the R b and R c Each is independently selected from hydrogen, methyl, ethyl, -O-(C1-C4)alkyl and halomethyl.

[0056] In certain embodiments, the R 2 Selected from hydrogen, halogen, -CN, -OH, -O-(C1-C4)alkyl, -SH, -NH2, -COOH, -C(=O)O(C1-C4)alkyl, -(C1-C4)alkyl and 5-6 membered heteroaryl, said -O-(C1-C4)alkyl, -C(=O)O(C1-C4)alkyl, -(C1-C4)alkyl and 5-6 membered heteroaryl are optionally substituted by 1, 2 or 3 groups selected from hydrogen and -(C1-C4)alkyl.

[0057] In certain embodiments, the R 2Selected from hydrogen, fluorine, chlorine, bromine, -CN, -OH, -O-methyl, -O-ethyl, -O-propyl, -C(=O)OC(CH3)3, -SH, -NH2, -COOH, methyl, ethyl, propyl, imidazolyl, pyrazolyl and pyrrolyl, and the -O-methyl, -O-ethyl, -O-propyl, methyl, ethyl, propyl, imidazolyl, pyrazolyl and pyrrolyl are optionally substituted by 1 or 2 groups selected from hydrogen and methyl.

[0058] In certain embodiments, the R 2 Selected from hydrogen, -F, -Cl, -OCH3, -CH3, -C(=O)OC(CH3)3 and

[0059] In certain embodiments, n is 0, 1, 2, 3, or 4.

[0060] In certain embodiments, n is 0, 1 or 2.

[0061] In certain embodiments, the R 3 Selected from hydrogen, halogen, nitro, -CN, -OH, -O-(C1-C4)alkyl, -SH, -S-(C1-C6alkyl), -S(=O)-(C1-C6)alkyl, -S(=O)NH2, -NH2, -NH-(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -COOH, -C(=O)-(C1-C4)alkyl, -C(=O)NH2, -(C1-C4)alkyl and -(C1-C4)haloalkyl.

[0062] In certain embodiments, the R 3 Selected from hydrogen, halogen, -CN, -OH, -O-(C1-C4)alkyl, -SH, -S-(C1-C6alkyl), -NH2, -NH-(C1-C4)alkyl, -COOH, -(C1-C4)alkyl and -(C1-C4)haloalkyl.

[0063] In certain embodiments, the R 3 is selected from hydrogen, fluorine, chlorine, bromine, -CN, -OH, -SH, -NH2, -COOH, methyl and halomethyl.

[0064] In certain embodiments, the R 3 For hydrogen.

[0065] In certain embodiments, the compound is selected from the compound represented by formula (IA)

[0066] in,

[0067] T1, T2 and T3 are each independently selected from C(Rt ) and N, the R t is selected from hydrogen, hydroxy, -(C1-C6)alkyl and halogen,

[0068] X, Y, L1, R 1 ,m,L2,Ring B,R 2 , n and R 3 As defined in any embodiment of the present invention.

[0069] In certain embodiments, T1, T2 and T3 are each independently selected from C(R t ) and N, and at most one of T1, T2 and T3 is N, the R t is selected from hydrogen, hydroxy and methyl.

[0070] In certain embodiments, T1 is CH, T2 is CH, and T3 is N, or T1 is N, T2 is CH, and T3 is C, or T1 is CH, T2 is N, and T3 is C, or T1, T2, and T3 are all CH.

[0071] In certain embodiments, T1, T2, and T3 are all CH.

[0072] In certain embodiments, the compound is selected from the compound represented by formula (IB)

[0073] in,

[0074] Ring C is absent or is selected from 5-6 membered heteroaryl (e.g., oxazolyl, isoxazolyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl) and 5-6 membered heterocyclyl,

[0075] X, Y, L1, Ring A, R 1 ,m,L2,R 2 , n and R 3 As defined in any embodiment of the present invention.

[0076] In certain embodiments, the ring C is absent, or Selected from

[0077] In certain embodiments, Ring C is absent.

[0078] In certain embodiments, the compound is selected from the compound represented by formula (IAB)

[0079] in,

[0080] T1 is CH, T2 is CH, and T3 is N, or T1 is N, T2 is CH, and T3 is C, or T1 is CH, T2 is N, and T3 is C, or T1, T2, and T3 are all CH,

[0081] Ring C is absent or is selected from 5-6 membered heteroaryl (e.g., oxazolyl, isoxazolyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl) and 5-6 membered heterocyclyl,

[0082] X, Y, L1, R 1 ,m,L2,R 2 , n and R 3 As defined in any embodiment of the present invention.

[0083] In certain embodiments, T1, T2, and T3 are all CH.

[0084] In certain embodiments, the ring C is absent, or Selected from

[0085] In certain embodiments, Ring C is absent.

[0086] In certain embodiments, L1 is selected from a bond, -O-, -NH-, -N(CH3)-, -C(=O)NH-, and -NHC(=O)-.

[0087] In certain embodiments, L2 is selected from a bond, -O-, -NH-, -N(CH3)-, -CH2-, -C(=O)NH-, -NHC(=O)-, -NHCH(CH3)-, and -CH(CH3)NH-.

[0088] In certain embodiments, the R 1 Selected from hydrogen, -OCH3, -C(=O)NHCH2CH3,

[0089] In certain embodiments, the R 2 Selected from hydrogen, -F, -Cl, -OCH3 and

[0090] In certain embodiments, the compound is selected from the compound represented by formula (IAB-1)

[0091] in,

[0092] X, Y, L1, R 1 ,m,L2,R 2 , n and R 3As defined in any embodiment of the present invention.

[0093] In certain embodiments, L1 is selected from a bond, -O-, -NH-, -N(CH3)-, -C(=O)NH-, and -NHC(=O)-.

[0094] In certain embodiments, L2 is selected from a bond, -O-, -NH-, -N(CH3)-, -CH2-, -C(=O)NH-, -NHC(=O)-, -NHCH(CH3)-, and -CH(CH3)NH-.

[0095] In certain embodiments, the R 1 Selected from hydrogen, -OCH3,

[0096] In certain embodiments, the R 2 Selected from hydrogen, -F, -Cl, -OCH3 and

[0097] In certain embodiments, the compound is selected from the compound represented by formula (IAB-1-1)

[0098] in,

[0099] R 1a and R 1b Each as R 1 As defined, R 1a and R 1b Can be the same or different, R 2a 、R 2b and R 2c Each as R 2 As defined, R 2a 、R 2b and R 2c Can be the same or different,

[0100] X, Y, L1, R 1 , L2, R 2 and R 3 As defined in any embodiment of the present invention.

[0101] In certain embodiments, L1 is selected from a bond, -O-, -NH-, -N(CH3)-, -C(=O)NH-, and -NHC(=O)-.

[0102] In certain embodiments, L2 is selected from a bond, -O-, -NH-, -N(CH3)-, -CH2-, -C(=O)NH-, -NHC(=O)-, -NHCH(CH3)-, and -CH(CH3)NH-.

[0103] In certain embodiments, the R 1a and R 1b Each independently selected from hydrogen, -OCH3,

[0104] In certain embodiments, the R 1a Selected from hydrogen and -OCH3, R 1b Selected from hydrogen,

[0105] In certain embodiments, the R 2a 、R 2b and R 2c Each independently selected from hydrogen, -F, -Cl, -OCH3 and

[0106] In certain embodiments, the R 2a selected from hydrogen and -F, R 2b Selected from hydrogen and -OCH3, R 2c Selected from hydrogen, -F, -Cl, -OCH3 and

[0107] In certain embodiments, the compound is selected from the compound represented by formula (II),

[0108] in,

[0109] T1 is CH, T2 is N, or T1 is N, T2 is CH, or both T1 and T2 are CH,

[0110] R 1a and R 1b Each as R 1 As defined, R 1a and R 1b Can be the same or different,

[0111] X, Y, L1, R 1 , L2, Ring B, R 2 , n and R 3 As defined in any embodiment of the present invention.

[0112] In certain embodiments, said X is selected from CH and N.

[0113] In certain embodiments, said Y is selected from S and O.

[0114] In certain embodiments, said L1 is selected from a bond, -NH-, -C(=O)NH-, and -NHC(=O)-.

[0115] In certain embodiments, the L1 is selected from a bond, -NH- and -NHC(=O)-#, wherein the # terminal represents Connected end.

[0116] In certain embodiments, the R 1a and R 1b Each is independently selected from hydrogen, -O-(C1-C4)alkyl and 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with 1 or 2 methyl groups.

[0117] In certain embodiments, the R 1a and R 1b Each independently selected from hydrogen, -OCH3,

[0118] In certain embodiments, the R 1a Selected from hydrogen and -OCH3, R 1b Selected from hydrogen,

[0119] In certain embodiments, the R 1a -OCH3, R 1b Selected from

[0120] In certain embodiments, L2 is selected from a bond, -O-, -NH-, -(C1-C4)alkylene-, -N[(C1-C4)alkyl]-, -NH-(C1-C4)alkylene-, -(C1-C4)alkylene-NH-, -C(=O)NH- and -NHC(=O)-, and the -NH-(C1-C4)alkylene-, -(C1-C4)alkylene-NH- are optionally substituted by one or more groups selected from hydrogen and methyl.

[0121] In certain embodiments, L2 is selected from a bond, -O-, -NH-, -CH2-, -N(CH3)-, -NH-CH(CH3)-#, -NHCH2-#, and -NHC(=O)-#, wherein the # end represents the end connected to ring B.

[0122] In certain embodiments, the ring B is selected from (C 6- C 10 ) aryl, 5-9 membered heteroaryl and 6-9 membered heterocyclyl.

[0123] In certain embodiments, the 5-9 membered heteroaryl and 6-9 membered heterocyclyl groups contain 1, 2 or 3 heteroatoms selected from N atoms and O atoms.

[0124] In certain embodiments, the ring B is selected from phenyl, pyridyl, thiazolyl, pyrrolyl, tetrahydropyranyl, benzoxazolyl, and 1,3-benzodioxolyl.

[0125] In certain embodiments, the ring B is selected from

[0126] In certain embodiments, the R 2 is selected from hydrogen, halogen, -(C1-C6)alkyl, -O-(C1-C4)alkyl and 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with 1 or 2 methyl groups.

[0127] In certain embodiments, the R 2 Selected from hydrogen, methyl, -F, -Cl, -OCH3 and

[0128] In certain embodiments, n is 0, 1 or 2.

[0129] In certain embodiments, the R 3 For hydrogen.

[0130] In certain embodiments, the compound is selected from the compound represented by formula (III),

[0131] in,

[0132] T1 is CH or N,

[0133] T b is CH or N,

[0134] R 1a and R 1b Each as R 1 As defined, R 1a and R 1b Can be the same or different, R 2a and R 2c Such as R 2 As defined, R 2a and R 2c Can be the same or different,

[0135] X, Y, L1, R 1 、R 2 , L2 and R 3 As defined in any embodiment of the present invention.

[0136] In certain embodiments, X is selected from CH and N.

[0137] In certain embodiments, Y is selected from S and O.

[0138] In certain embodiments, L1 is selected from -NH-, -C(=O)NH-, and -NHC(=O)-.

[0139] In certain embodiments, L1 is selected from -NH- and -NHC(=O)-#, wherein the # terminal represents Connected end.

[0140] In certain embodiments, R 1a and R 1b Each is independently selected from hydrogen, -O-(C1-C4)alkyl and 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with 1 or 2 methyl groups.

[0141] In certain embodiments, R 1a and R 1b Each independently selected from hydrogen, -OCH3,

[0142] In certain embodiments, R 1a Selected from hydrogen and -OCH3, R 1b Selected from hydrogen,

[0143] In certain embodiments, R 1a -OCH3, R 1b for

[0144] In certain embodiments, L2 is selected from a bond, -O-, -NH-, and -(C1-C4)alkylene-.

[0145] In certain embodiments, L2 is selected from a bond, -O-, -NH-, and -CH2-.

[0146] In certain embodiments, R 2a and R 2c Each is independently selected from hydrogen, halogen and -O-(C1-C4)alkyl.

[0147] In certain embodiments, R 2a and R 2c Each is independently selected from hydrogen, -F, -Cl, -Br, -I and -OCH3.

[0148] In certain embodiments, R 2a selected from hydrogen and -F, R 2c is selected from hydrogen, -F, -Cl and -OCH3.

[0149] In certain embodiments, R 3 For hydrogen.

[0150] In certain embodiments, the compound, its pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystal form, isotopically labeled form or metabolite thereof, wherein,

[0151] X is C(R x ), Y is S, L1, L2, ring A, R 1 ,m,ring B,R 2 ,n,R 3 、T1、T2、T3、T b and Ring C are as defined in any embodiment of the present invention.

[0152] In certain embodiments, the R x For hydrogen.

[0153] In certain embodiments, said L1 is selected from a bond, -O-, -NH-, and -N[(C1-C4)alkyl]-.

[0154] In certain embodiments, said L1 is selected from a bond, -O-, -NH-, and -N(CH3)-.

[0155] In certain embodiments, said L2 is selected from a bond, -O-, -NH-, and -N[(C1-C4)alkyl]-.

[0156] In certain embodiments, said L2 is selected from a bond, -O-, -NH-, and -N(CH3)-.

[0157] In certain embodiments, the ring A is selected from (C 6- C 10 )aryl.

[0158] In certain embodiments, Ring A is

[0159] In certain embodiments, the R 1 is selected from hydrogen, -O-(C1-C4)alkyl and 5-6 membered heteroaryl, wherein the -O-(C1-C4)alkyl and 5-6 membered heteroaryl are optionally substituted with 1, 2 or 3 methyl groups.

[0160] In certain embodiments, the R 1 Selected from hydrogen, -O-methyl, -O-ethyl, -O-propyl, imidazolyl, pyrazolyl and pyrrolyl, wherein the -O-methyl, -O-ethyl, -O-propyl, imidazolyl, pyrazolyl and pyrrolyl are optionally substituted with 1 or 2 methyl groups.

[0161] In certain embodiments, the R 1 Selected from hydrogen, -OCH3 and

[0162] In certain embodiments, m is 0 or 2.

[0163] In certain embodiments, the ring B is selected from (C 6- C 10 ) aryl and 6-9 membered heterocyclic group.

[0164] In certain embodiments, the 6-9 membered heterocyclyl contains 1, 2 or 3 heteroatoms selected from N atoms, O atoms and S atoms.

[0165] In certain embodiments, the ring B is selected from tetrahydropyranyl, morpholinyl, phenyl, and naphthyl.

[0166] In certain embodiments, the ring B is selected from

[0167] In certain embodiments, the R 2 is selected from hydrogen, -O-(C1-C4)alkyl and 5-6 membered heteroaryl, wherein the -O-(C1-C4)alkyl and 5-6 membered heteroaryl are optionally substituted with 1, 2 or 3 methyl groups.

[0168] In certain embodiments, the R 2 Selected from hydrogen, -O-methyl, -O-ethyl, -O-propyl, imidazolyl, pyrazolyl and pyrrolyl, wherein the -O-methyl, -O-ethyl, -O-propyl, imidazolyl, pyrazolyl and pyrrolyl are optionally substituted with 1 or 2 methyl groups.

[0169] In certain embodiments, the R 2 Selected from hydrogen, -OCH3 and

[0170] In certain embodiments, n is 0 or 2.

[0171] In certain embodiments, the compound, its pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystal form, isotopically labeled form or metabolite thereof, wherein,

[0172] X is C(R x ), Y is O, L1, L2, ring A, R 1 ,m,ring B,R 2 、n、R 3 、T1、T2、T3、T b and Ring C are as defined in any embodiment of the present invention.

[0173] In certain embodiments, the R x For hydrogen.

[0174] In certain embodiments, said L1 is selected from a bond, -O-, -NH-, and -N[(C1-C4)alkyl]-.

[0175] In certain embodiments, L1 is -NH-.

[0176] In certain embodiments, said L2 is selected from a bond, -O-, -NH-, and -N[(C1-C4)alkyl]-.

[0177] In certain embodiments, said L2 is selected from a bond and -NH-.

[0178] In certain embodiments, the ring A is selected from (C 6- C 10 )aryl.

[0179] In certain embodiments, Ring A is

[0180] In certain embodiments, the R 1 is selected from hydrogen, -O-(C1-C4)alkyl and 5-6 membered heteroaryl, wherein the -O-(C1-C4)alkyl and 5-6 membered heteroaryl are optionally substituted with 1, 2 or 3 methyl groups.

[0181] In certain embodiments, the R 1 Selected from hydrogen, -O-methyl, -O-ethyl, -O-propyl, imidazolyl, pyrazolyl and pyrrolyl, wherein the -O-methyl, -O-ethyl, -O-propyl, imidazolyl, pyrazolyl and pyrrolyl are optionally substituted with 1 or 2 methyl groups.

[0182] In certain embodiments, the R 1 Selected from hydrogen, -OCH3 and

[0183] In certain embodiments, m is 0 or 2.

[0184] In certain embodiments, the ring B is selected from (C 6- C 10 )aryl.

[0185] In certain embodiments, the ring B is selected from phenyl and naphthyl.

[0186] In certain embodiments, Ring B is

[0187] In certain embodiments, the R 2 Selected from hydrogen and halogen.

[0188] In certain embodiments, the R 2 is selected from the group consisting of hydrogen, fluorine, chlorine and bromine.

[0189] In certain embodiments, the R 2 Selected from hydrogen and -Cl.

[0190] In certain embodiments, n is 1.

[0191] In certain embodiments, the compound, its pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystal form, isotopically labeled form or metabolite thereof, wherein,

[0192] X is N, Y is S, L1, L2, ring A, R 1 ,m,ring B,R 2 ,n,R 3 、T1、T2、T3、T b and Ring C are as defined in any embodiment of the present invention.

[0193] In certain embodiments, said L1 is selected from a bond, -NH-, -C(=O)NH-, and -NHC(=O)-.

[0194] In certain embodiments, L1 is selected from a bond, -NH- and -NHC(=O)-#, wherein the # end represents the end connected to ring A.

[0195] In certain embodiments, L2 is selected from a bond, -O-, -NH-, -(C1-C4)alkylene-, -N[(C1-C4)alkyl]-, -NH-(C1-C4)alkylene-, -(C1-C4)alkylene-NH-, -C(=O)NH- and -NHC(=O)-, and the -NH-(C1-C4)alkylene-, -(C1-C4)alkylene-NH- are optionally substituted by one or more groups selected from hydrogen and methyl.

[0196] In certain embodiments, L2 is selected from a bond, -O-, -NH-, -CH2-, -N(CH3)-, -NH-CH(CH3)-#, -NHCH2-#, and -NHC(=O)-#, wherein the # end represents the end connected to ring B.

[0197] In certain embodiments, the ring A is selected from (C 6- C 10 ) aryl, 5-9 membered heteroaryl and 6-9 membered heterocyclyl.

[0198] In certain embodiments, the 5-9 membered heteroaryl and 6-9 membered heterocyclyl groups contain 1, 2 or 3 heteroatoms selected from N atoms, O atoms and S atoms.

[0199] In certain embodiments, the ring A is selected from phenyl, pyridinyl, pyrimidinyl, piperidinyl, indolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, and 1,3-dihydrobenzimidazol-2-onyl.

[0200] In certain embodiments, the ring A is selected from

[0201] In certain embodiments, the R 1 is selected from hydrogen, -(C1-C6)alkyl, -O-(C1-C4)alkyl, -C(=O)NH-(C1-C4)alkyl and 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted by 1 or 2 groups selected from hydrogen, methyl and methoxy.

[0202] In certain embodiments, the R 1 Selected from hydrogen, -OCH3,

[0203] In certain embodiments, m is 0 or 2.

[0204] In certain embodiments, the ring B is selected from (C 6- C 10 ) aryl, 5-9 membered heteroaryl and 6-9 membered heterocyclyl.

[0205] In certain embodiments, the 5-9 membered heteroaryl and 6-9 membered heterocyclyl groups contain 1, 2 or 3 heteroatoms selected from N atoms and O atoms.

[0206] In certain embodiments, the ring B is selected from phenyl, pyridinyl, pyrimidinyl, oxazolyl, thiazolyl, pyrazolyl, pyrrolyl, piperidinyl, tetrahydropyranyl, 3,4-dihydro-2H-pyranyl, benzoxazolyl, 1,3-benzodioxolyl, and 2-benzoxazolonyl.

[0207] In certain embodiments, the ring B is selected from

[0208] In certain embodiments, the R 2 is selected from hydrogen, halogen, -(C1-C6)alkyl, -O-(C1-C4)alkyl, -C(=O)O(C1-C4)alkyl and 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with 1 or 2 methyl groups,

[0209] In certain embodiments, the R 2 selected from hydrogen, methyl, -F, -Cl, -OCH3, -C(=O)OC(CH3)3 and

[0210] In certain embodiments, n is 0 or 2.

[0211] In certain embodiments, the compound is selected from

[0212] The second aspect of the present invention provides a pharmaceutical composition comprising a compound according to any embodiment of the first aspect of the present invention, a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystal form, isotope-labeled substance or a metabolite thereof.

[0213] In certain embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable adjuvant and / or diluent and / or carrier and / or excipient.

[0214] The pharmaceutical compositions of the present invention can be formulated into any pharmaceutically acceptable dosage form and administered to patients in need of such treatment by oral, parenteral, rectal, pulmonary, topical, or transdermal routes. For oral administration, conventional solid preparations such as tablets, capsules, pills, and granules can be prepared; oral liquid preparations such as oral solutions, oral suspensions, and syrups can also be prepared. Suitable fillers, binders, disintegrants, lubricants, and the like can be added to oral preparations. For parenteral administration, injections can be prepared, including injection solutions, sterile powders for injection, and concentrated solutions for injection. Injections can be produced using conventional methods in the pharmaceutical field. Additives may be omitted or added depending on the properties of the drug. For rectal administration, suppositories can be prepared. For pulmonary administration, inhalants or sprays can be prepared. For topical administration, specific dosage forms and devices can be used, or creams, gels, and the like can be prepared. For transdermal administration, patches can be prepared.

[0215] The third aspect of the present invention provides the use of the compound described in any embodiment of the first aspect of the present invention, its pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystal form, isotope-labeled substance or metabolite form thereof, or the pharmaceutical composition described in any embodiment of the second aspect of the present invention in the preparation of a drug as a γ-secretase modulator.

[0216] The fourth aspect of the present invention provides a compound according to any embodiment of the first aspect of the present invention, a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystal form, isotope label or metabolite thereof, or a pharmaceutical composition according to any embodiment of the second aspect of the present invention for the preparation of a pharmaceutical composition for treating and / or preventing diseases associated with β-amyloid deposition (e.g., Alzheimer's disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, Dutch hereditary cerebral hemorrhage with amyloidosis) The invention also can be used in the treatment of diseases such as Alzheimer's disease, multiple infarct dementia, boxer's dementia, Down syndrome, mild cognitive impairment, memory loss, stroke, glaucoma, microgliosis, loss of olfactory function, brain inflammation, Aβ amyloid angiopathy, Alzheimer's disease-related neurodegeneration, Alzheimer's disease-related attention deficit symptoms, diffuse Lewy body type Alzheimer's disease, senile dementia, mixed vascular origin dementia, dementia of degenerative origin, presenile dementia, dry age-related macular degeneration, etc.

[0217] In certain embodiments, the disease associated with amyloid beta deposition is Alzheimer's disease.

[0218] The fifth aspect of the present invention provides the use of the compound according to any embodiment of the first aspect of the present invention, its pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystal form, isotope label or metabolite form thereof, or the pharmaceutical composition according to any embodiment of the second aspect of the present invention in the preparation of an anti-tumor drug, wherein the tumor includes but is not limited to: breast cancer, melanoma, meningioma, soft tissue sarcoma, salivary gland tumor, intraspinal tumor, mediastinal tumor, brain cancer, bone cancer, penile cancer, osteosarcoma, intracranial tumor, tongue cancer, maxillary sinus cancer, thyroid cancer, malignant lymphoma, multiple myeloma, pituitary adenoma, testicular tumor, non-Hodgkin's lymphoma, bladder cancer, leukemia, gastric cancer, nasopharyngeal cancer, laryngeal cancer, oral cancer, esophageal cancer, lung cancer, kidney cancer, cervical cancer, choriocarcinoma, vulvar cancer, skin cancer, Endometrial cancer, ovarian cancer, prostate cancer, pancreatic cancer, rectal cancer, colorectal cancer, Kaposi sarcoma, non-melanoma skin cancer (including squamous cell carcinoma and basal cell carcinoma), hemangioma, glioma, non-Hodgkin lymphoma (diffuse large B-cell lymphoma, B-cell non-Hodgkin lymphoma), colon cancer, liver cancer, neuroblastoma, glioblastoma, plasmacytoma, Hodgkin lymphoma, follicular lymphoma, small non-cleaved cell lymphoma, endemic Burkitt's lymphoma, sporadic Burkitt's lymphoma, marginal zone lymphoma, extranodal mucosa-associated lymphoid tissue lymphoma, nodular monocytic B-cell lymphoma, splenic lymphoma, mantle cell lymphoma, large cell lymphoma, diffuse mixed cell lymphoma, immunoblastic lymphoma, primary mediastinal B-cell lymphoma, pulmonary B-cell angiocentric lymphoma, small lymphocytic lymphoma.

[0219] The sixth aspect of the present invention provides a compound according to any embodiment of the first aspect of the present invention, a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystalline form, isotope-labeled substance or metabolite thereof, or a pharmaceutical composition according to any embodiment of the second aspect of the present invention, for use as a γ-secretase modulator.

[0220] The seventh aspect of the present invention provides a compound according to any embodiment of the first aspect of the present invention, a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystal form, isotope label or metabolite form thereof, or a pharmaceutical composition according to any embodiment of the second aspect of the present invention, for treating and / or preventing diseases associated with β-amyloid deposition (e.g., Alzheimer's disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, Dutch hereditary cerebral hemorrhage with amyloidosis, multi-infarct dementia, dementia pugilistica, Down syndrome, mild cognitive impairment, memory loss, stroke, glaucoma, microgliosis, loss of olfactory function, brain inflammation, Aβ amyloid angiopathy, neurodegeneration associated with Alzheimer's disease, attention deficit symptoms associated with Alzheimer's disease, diffuse Lewy body type Alzheimer's disease, senile dementia, mixed vascular origin dementia, dementia of degenerative origin, precocious dementia, dry age-related macular degeneration, etc.).

[0221] In certain embodiments, the disease associated with beta-amyloid deposition is Alzheimer's disease.

[0222] The eighth aspect of the present invention provides a compound according to any embodiment of the first aspect of the present invention, a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystal form, isotope label or metabolite thereof, or a pharmaceutical composition according to any embodiment of the second aspect of the present invention, for use as an anti-tumor drug, wherein the tumor includes but is not limited to: breast cancer, melanoma, meningioma, soft tissue sarcoma, salivary gland tumor, intraspinal tumor, mediastinal tumor, brain cancer, bone cancer, penile cancer, osteosarcoma, intracranial tumor, tongue cancer, maxillary sinus cancer, thyroid cancer, malignant lymphoma, multiple myeloma, pituitary adenoma, testicular tumor, non-Hodgkin's lymphoma, bladder cancer, leukemia, gastric cancer, nasopharyngeal cancer, laryngeal cancer, oral cancer, esophageal cancer, lung cancer, kidney cancer, cervical cancer, choriocarcinoma, vulvar cancer, skin cancer, Endometrial cancer, ovarian cancer, prostate cancer, pancreatic cancer, rectal cancer, colorectal cancer, Kaposi sarcoma, non-melanoma skin cancer (including squamous cell carcinoma and basal cell carcinoma), hemangioma, glioma, non-Hodgkin lymphoma (diffuse large B-cell lymphoma, B-cell non-Hodgkin lymphoma), colon cancer, liver cancer, neuroblastoma, glioblastoma, plasmacytoma, Hodgkin lymphoma, follicular lymphoma, small non-cleaved cell lymphoma, endemic Burkitt's lymphoma, sporadic Burkitt's lymphoma, marginal zone lymphoma, extranodal mucosa-associated lymphoid tissue lymphoma, nodular monocytic B-cell lymphoma, splenic lymphoma, mantle cell lymphoma, large cell lymphoma, diffuse mixed cell lymphoma, immunoblastic lymphoma, primary mediastinal B-cell lymphoma, pulmonary B-cell angiocentric lymphoma, small lymphocytic lymphoma.

[0223] The ninth aspect of the present invention provides a method for treating and / or preventing diseases associated with β-amyloid deposition, which comprises administering to an individual in need thereof an effective amount of a compound according to any embodiment of the first aspect of the present invention, a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystalline form, isotope label or metabolite thereof, or a pharmaceutical composition according to any embodiment of the second aspect of the present invention, wherein the disease associated with β-amyloid deposition is, for example, Alzheimer's disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, etc. Loss of vision, hereditary cerebral hemorrhage with amyloidosis of the Dutch type, multi-infarct dementia, dementia pugilistica, Down syndrome, mild cognitive impairment, memory loss, stroke, glaucoma, microgliosis, loss of olfactory function, brain inflammation, Aβ amyloid angiopathy, neurodegeneration associated with Alzheimer's disease, attention deficit symptoms associated with Alzheimer's disease, diffuse Lewy body type Alzheimer's disease, senile dementia, dementia of mixed vascular origin, dementia of degenerative origin, presenile dementia, dry age-related macular degeneration and other diseases.

[0224] In certain embodiments, the disease associated with beta-amyloid deposition is Alzheimer's disease.

[0225] The tenth aspect of the present invention provides a method for treating and / or preventing tumors, which comprises administering to an individual in need thereof an effective amount of the compound according to any embodiment of the first aspect of the present invention, its pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystal form, isotope label or metabolite form thereof, or the pharmaceutical composition according to any embodiment of the second aspect of the present invention, wherein the tumor includes but is not limited to: breast cancer, melanoma, meningioma, soft tissue sarcoma, salivary gland tumor, intraspinal tumor, mediastinal tumor, brain cancer, bone cancer, penile cancer, osteosarcoma, intracranial tumor, tongue cancer, maxillary sinus cancer, thyroid cancer, malignant lymphoma, multiple myeloma, pituitary adenoma, testicular tumor, non-Hodgkin's lymphoma, bladder cancer, leukemia, gastric cancer, nasopharyngeal cancer, laryngeal cancer, oral cancer, esophageal cancer, lung cancer, kidney cancer, cervical cancer, choriocarcinoma, Vulvar cancer, skin cancer, endometrial cancer, ovarian cancer, prostate cancer, pancreatic cancer, rectal cancer, colorectal cancer, Kaposi's sarcoma, non-melanoma skin cancer (including squamous cell carcinoma and basal cell carcinoma), hemangioma, glioma, non-Hodgkin's lymphoma (diffuse large B-cell lymphoma, B-cell non-Hodgkin's lymphoma), colon cancer, liver cancer, neuroblastoma, glioblastoma, plasmacytoma, Hodgkin's lymphoma, follicular lymphoma Burkitt's lymphoma, small non-cleaved cell lymphoma, endemic Burkitt's lymphoma, sporadic Burkitt's lymphoma, marginal zone lymphoma, extranodal mucosa-associated lymphoid tissue lymphoma, nodular monocytoid B-cell lymphoma, splenic lymphoma, mantle cell lymphoma, large cell lymphoma, diffuse mixed cell lymphoma, immunoblastic lymphoma, primary mediastinal B-cell lymphoma, pulmonary B-cell angiocentric lymphoma, small lymphocytic lymphoma.

[0226] Definition of terms

[0227] Unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Furthermore, the laboratory procedures described herein are conventional procedures widely used in the relevant fields. To facilitate a better understanding of the present invention, definitions and explanations of relevant terms are provided below.

[0228] When the compound name used in this article is inconsistent with the chemical structural formula, the chemical structural formula shall prevail.

[0229] As used herein, the term "pharmaceutically acceptable salt" refers to (i) a salt formed by an acidic functional group (e.g., -COOH) present in the compounds provided herein with a suitable inorganic or organic cation (base), and includes, but is not limited to, alkali metal salts, such as sodium salts, potassium salts, lithium salts, etc.; alkaline earth metal salts, such as calcium salts, magnesium salts, etc.; other metal salts, such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts, cobalt salts, etc.; inorganic base salts, such as ammonium salts; organic base salts, such as tert-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucosamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, chloroprocaine salts, procaine salts, diethanolamine salts, N-benzyl-phenethylamine salts, piperazine salts, tetramethylamine salts, tris(hydroxymethyl)aminomethane salts. and (ii) salts formed by basic functional groups (e.g., -NH2) present in the compounds provided by the present invention and appropriate inorganic or organic anions (acids), including but not limited to hydrohalides, such as hydrofluorides, hydrochlorides, hydrobromides, hydroiodides, etc.; inorganic acid salts, such as nitrates, perchlorates, sulfates, phosphates, etc.; lower alkanesulfonates, such as methanesulfonates, trifluoromethanesulfonates, ethanesulfonates, etc.; arylsulfonates, such as benzenesulfonates, p-toluenesulfonates, etc.; organic acid salts, such as acetates, malates, fumarates, succinates, citrates, tartrates, oxalates, maleates, etc.; amino acid salts, such as glycine, trimethylglycine, arginine, ornithine, glutamate, aspartate, etc.

[0230] As used herein, the term "prodrug" refers to a compound that can be converted into the compound of the present invention by reactions such as oxidation, reduction, hydrolysis, etc. in the subject's body. The prodrug itself may or may not have the biological activity of the compound of formula (I). For example, a compound of formula (I) comprising a hydroxyl or carboxyl group can be administered in the form of an ester, which is hydrolyzed in vivo to form a hydroxyl compound or a carboxyl compound. Similarly, a compound of formula (I) comprising an amino group can be acylated, alkylated, or phosphorylated to form, for example, an eicosanoylamino group, an alanylamino group, or a pivaloyloxymethylamino group for administration. Further information on the use of prodrugs can be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. EB Roche, American Pharmaceutical Association). Some examples of prodrugs according to the present invention include: (i) if the compound of formula (I) contains a carboxylic acid functional group (-COOH), then its esters include, for example, replacing hydrogen with a (C1-C8)alkyl group; (ii) if the compound of formula (I) contains an alcohol functional group (-OH), then its ethers include, for example, replacing hydrogen with a (C1-C6)alkanoyloxymethyl group; and (iii) if the compound of formula (I) contains a primary or secondary amino functional group (-NH2 or -NHR, wherein R is not H), then its amides include, for example, replacing hydrogen with a (C1-C6)alkanoyloxymethyl group. 10 )alkanoyl replaces one or two hydrogens. In addition, certain compounds of formula (I) may themselves act as prodrugs of other compounds of formula (I).

[0231] As used herein, the term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In a compound with one or more (e.g., 1, 2, 3, or 4) asymmetric centers, it can produce a racemic mixture, a single enantiomer, a diastereomeric mixture, and a single diastereoisomer. The term "stereoisomer" includes conformers and configurational isomers, wherein the configurational isomers primarily include cis-trans isomers and optical isomers. The compounds of the present invention can exist in the form of stereoisomers, and therefore encompass all possible stereoisomeric forms, and any combination or any mixture thereof. For example, a single enantiomer, a single diastereoisomer, or a mixture thereof. When the compounds of the present invention contain an olefin double bond, unless otherwise specified, it includes cis-isomers and trans-isomers, and any combination thereof.

[0232] As used herein, the term "tautomer" refers to functional group isomers resulting from the rapid movement of an atom in a molecule between two positions, such as keto-enol tautomers, imine-enamine tautomers, etc. If tautomers exist for the compounds of the present invention, they may exist in the form of a single tautomer or a mixture thereof, preferably in the form of a more stable tautomer as the main component.

[0233] As used herein, the term "solvate" refers to a substance formed by the association of a compound of the present invention with a solvent molecule. The solvent may be an organic solvent (e.g., methanol, ethanol, propanol, acetonitrile, etc.). For example, the compound of the present invention may form an ethanolate with ethanol. The compound of the present invention may also form a hydrate with water. The amount of the solvent may be present in a stoichiometric or non-stoichiometric ratio.

[0234] As used herein, the term "crystalline form" refers to the crystal structure of a substance. During crystallization, various factors may alter the intramolecular or intermolecular bonding patterns, resulting in different arrangements of molecules or atoms within the crystal lattice space, forming different crystal structures. The compounds of the present invention may exist in a single crystal structure or in multiple crystal structures, i.e., they may exhibit "polymorphism." The compounds of the present invention may exist in different crystalline forms.

[0235] As used herein, the term "isotopically labeled compound" refers to a compound in which one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant in nature. Examples of suitable isotopes for inclusion in the compounds of the present invention include, but are not limited to, hydrogen isotopes such as 2 H. 3 H; carbon isotopes such as 11 C. 13 C and 14 C; chlorine isotopes such as 36 Cl; fluorine isotopes such as 18 F; iodine isotopes such as 123 I and 125 I; Nitrogen isotopes such as 13 N and 15 N; oxygen isotopes such as 15 O. 17 O and 18 O; and sulfur isotopes such as 35 S.

[0236] As used herein, "selected from a bond" means that the groups on either side of the variable are directly linked, for example, ALB, when L is a bond, ALB is AB.

[0237] As used herein, "optionally substituted by..." means that the group may be unsubstituted or substituted by a substituent, for example, -(C1-C6)alkyl is optionally substituted by halogen, which means that -(C1-C6)alkyl may be unsubstituted or substituted by halogen to obtain a haloalkyl.

[0238] As used herein, the term "(C1-C6) alkyl" refers to a group obtained by removing one hydrogen atom from a straight-chain or branched saturated hydrocarbon group containing 1-6 (such as 1, 2, 3, 4, 5 or 6) carbon atoms, specific examples of which include but are not limited to: methyl, ethyl, propyl, n-butyl, isobutyl, isopropyl, tert-butyl, n-pentyl, n-hexyl. In the present invention, the preferred C1-C6 alkyl group is a C1-C4 alkyl group.

[0239] As used herein, the term "(C2-C6)alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon group containing at least one carbon-carbon double bond and having 2-6 carbon atoms (such as 2, 3, 4, 5 or 6). Specific examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, and 1,4-hexadienyl. In the present invention, the preferred C2-C6 alkenyl group is C2-C4 alkenyl.

[0240] As used herein, the term "(C2-C6)alkynyl" refers to a straight-chain or branched unsaturated hydrocarbon group containing at least one triple bond and having 2-6 carbon atoms. Specific examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1,3-butadiynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, and 1,4-hexadiynyl. In the present invention, the preferred C2-C6 alkynyl group is a C2-C4 alkynyl group.

[0241] As used herein, the term "(C1-C4)alkylene" refers to a straight-chain or branched saturated divalent hydrocarbon group containing 1-4 (such as 1, 2, 3 or 4) carbon atoms, specific examples of which include but are not limited to: methylene, ethylene, propylene.

[0242] As used herein, the term "(C2-C4) alkenylene" refers to a straight-chain or branched unsaturated divalent hydrocarbon group containing at least one carbon-carbon double bond and having 2-4 carbon atoms (such as 2, 3 or 4), specific examples of which include but are not limited to: vinylene, propenylene, butenylene, and butadienylene.

[0243] As used herein, the term "(C2-C4)alkynylene" refers to a straight-chain or branched unsaturated divalent hydrocarbon group containing at least one triple bond and having 2-4 carbon atoms, specific examples of which include but are not limited to: ethynylene, propynylene, butynylene, and butadiynylene.

[0244] As used herein, the term "halogen" includes fluorine, chlorine, bromine and iodine. In the present invention, preferred halogens are fluorine, chlorine and bromine.

[0245] As used herein, the term "halogenated" refers to a group or compound in which hydrogen is replaced by one or more halogen atoms, including full halogenation and partial halogenation.

[0246] As used herein, the term "aryl" refers to an unsaturated carbocyclic group having a conjugated π electron system, such as (C6-C 14 ) Aryl consists of 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) carbon atoms. Non-limiting examples include, but are not limited to, phenyl, naphthyl, and anthracenyl.

[0247] As used herein, the term "heteroaryl" refers to an unsaturated group having a conjugated π electron system, wherein at least one (e.g., 1, 2, 3, or 4) ring atom is a heteroatom, wherein the heteroatom is selected from N, O, and S, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized. For example, a 5-12 membered heteroaryl group is composed of 5 to 12 (e.g., 5, 6, 7, 8, 9, 10, 11, or 12) ring atoms, including 5-10 membered, 5-9 membered, 6-9 membered, 5-6 membered heteroaryl groups, etc. The heteroaryl groups include monocyclic and polycyclic groups, and specific examples include but are not limited to furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, quinolyl, and isoquinolyl.

[0248] As used herein, the term "cycloalkyl" refers to a saturated hydrocarbon group consisting of carbon atoms, for example, a (C3-C7) cycloalkyl group consisting of 3-7 (e.g., 3, 4, 5, 6, or 7) carbon atoms. The cycloalkyl group includes monocyclic, bicyclic, or polycyclic rings, including spirocyclic, cyclic, or bridged rings, and specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0249] As used herein, the term "heterocyclyl" refers to a saturated or partially unsaturated cyclic group consisting of ring atoms and at least one (e.g., 1, 2, 3, 4, or 5 heteroatoms) of which is a heteroatom, wherein the heteroatoms are selected from N, O, and S, wherein the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms are optionally oxidized, and the carbon atoms are optionally oxoed. For example, a 5-12 membered heterocyclyl refers to a group consisting of 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, and a 5-12 membered heterocyclyl includes a 5-10 membered heterocyclyl, a 5-9 membered heterocyclyl, a 6-9 membered heterocyclyl, and the like. The heterocyclic group includes a monocyclic, bicyclic or polycyclic ring, including a spirocyclic, paracyclic or bridged ring. Specific examples include but are not limited to: pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, imidazolinyl, 2,3-dihydrobenzofuranyl, 1,2,3,4-tetrahydroquinolinyl, 3,4-dihydro-1H-benzopyranyl, 1,4-benzodioxanyl, benzomorpholinyl, and 1,2,3,4-tetrahydroquinoxaline.

[0250] As used herein, the term "pharmaceutically acceptable carrier or excipient" refers to a carrier and / or excipient that is pharmacologically and / or physiologically compatible with the subject and the active ingredient, which is well known in the art (see, e.g., Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19th ed. Pennsylvania: Mack Publishing Company, 1995), and includes, but is not limited to, disintegrants, binders, surfactants, glidants, lubricants, pH adjusters, ionic strength enhancers, agents that maintain osmotic pressure, agents that delay absorption, diluents, antioxidants, colorants, flavorings, preservatives, taste-masking agents, etc. For example, non-limiting examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate. Non-limiting examples of binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinyl pyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. Non-limiting examples of diluents include lactose, mannitol, xylitol, glucose, sucrose, sorbitol, microcrystalline cellulose, starch, and dibasic calcium phosphate dihydrate. Non-limiting examples of surfactants include sodium lauryl sulfate and polysorbate 80. Non-limiting examples of glidants include silicon dioxide and talc. Non-limiting examples of lubricants include magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. Non-limiting examples of pH adjusters include phosphate buffers. Ionic strength enhancers include, but are not limited to, sodium chloride. Agents that maintain osmotic pressure include, but are not limited to, sugars, NaCl, and the like. Agents that delay absorption include, but are not limited to, monostearate and gelatin. Preservatives include, but are not limited to, various antibacterial and antifungal agents such as thimerosal, 2-phenoxyethanol, parabens, chlorobutanol, phenol, sorbic acid, and the like.

[0251] As used herein, the term "prevention" refers to the method implemented in order to prevent or delay the occurrence of disease or illness or symptom in a subject. As used herein, the term "treatment" refers to the method implemented in order to obtain beneficial or required clinical results. For the purposes of the present invention, beneficial or required clinical results include but are not limited to, alleviating symptoms, narrowing the scope of the disease, stabilizing (that is, no longer worsening) the state of the disease, delaying or slowing the development of the disease, improving or alleviating the state of the disease and alleviating symptoms (no matter in part or in whole), no matter it is detectable or undetectable. In addition, "treatment" can also refer to, compared with the expected survival (if not receiving treatment), extending the survival.

[0252] As used herein, the term "effective amount" refers to an amount sufficient to achieve, or at least partially achieve, a desired effect. For example, a prophylactic effective amount is an amount sufficient to prevent, inhibit, or delay the onset of a disease; a therapeutic effective amount is an amount sufficient to cure or at least partially inhibit the disease and its complications in a patient already suffering from the disease. Determining such an effective amount is well within the capabilities of those skilled in the art. For example, an effective amount for therapeutic use will depend on the severity of the disease to be treated, the overall state of the patient's own immune system, the patient's general condition such as age, weight, and sex, the mode of administration of the drug, and other concurrently administered treatments, among other factors. DETAILED DESCRIPTION

[0253] The embodiments of the present invention will be described in detail below with reference to the examples, but it will be understood by those skilled in the art that the following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the invention. Where specific conditions are not specified in the examples, the methods were performed according to conventional conditions or the conditions recommended by the manufacturer. Where the manufacturers of the reagents or instruments are not specified, they are all conventional products that can be obtained commercially.

[0254] Nuclear magnetic resonance imaging

[0255] In the following examples, the structures of the compounds were determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LCMS). -6 The units are given in ppm. NMR measurements were performed on a Bruker AVANCE III 500 MHz NMR instrument using deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), etc. as the solvents, and tetramethylsilane (TMS) as the internal standard.

[0256] Analytical liquid chromatography

[0257] Analytical HPLC was used to monitor the reaction system and analyze the purity of key intermediates and target products. Analytical HPLC system: Agilent 1260 Infinity II (equipped with 1260 Binary Pump, Vial Sampler, MCT Column Oven, DAD WR Detector); Column: Waters XBridge BEH C18 3.5 μm, 4.6 x 150 mm.

[0258] Preparative liquid chromatography

[0259] A small amount of important intermediates and the target product were isolated and purified using preparative HPLC. The preparative HPLC system included an Agilent 1290 Infinity II (equipped with a 1290 Prep Bin Pump, a Prep ALS / FC injector / collector, and a 1260 VWD detector) and a C18 reversed-phase silica gel column.

[0260] LC-MS

[0261] LC-MS was used for routine reaction system detection and molecular weight signal determination of the target product. LC-MS system: Waters UPLC H-Class ultra-high performance liquid chromatography coupled with QDa; chromatographic column: Waters XBridge BEH C18 1.7 μm, 2.1 x 75 mm.

[0262] Liquid mobile phase ratio

[0263] Acidic conditions: A: 0.05% formic acid in water, B: acetonitrile; Alkaline conditions: A: 0.05% ammonia in water, B: acetonitrile; Neutral conditions: A: 5 mM NH₄HCO₃ in water, B: acetonitrile. The above data are default mobile phase ratios and can be adjusted appropriately based on the properties of the sample during analysis and testing.

[0264] Rapid purification system

[0265] A rapid purification system was used for crude preparation and purification of compounds in conventional reaction systems. The instrument model was Biotage Isolera One, and the normal phase and reverse phase columns used were purchased from Santai Tech. The common specifications of normal phase silica gel columns are 12g, 25g, 40g, 80g, 120g, and 330g. The specific parameters are as follows: 40-63μm, The commonly used specifications of reversed-phase C18 columns are 40g, 80g, 120g and 330g, and the specific parameters are as follows: 20-45μm,

[0266] Thin layer chromatography

[0267] Use thin layer chromatography (TLC) silica gel plates to perform qualitative analysis of the reaction system or to separate and purify a small amount of sample. The product used for qualitative analysis by thin layer chromatography is Merck thin layer silica gel plates, with the following specifications: GF 254 , 20*20cm, glass plate, 0.25mm coating; when thin layer chromatography is used for separation and purification, that is, preparative thin layer chromatography (PTLC), the product used is a thin layer chromatography silica gel preparative plate (Shanghai Haohong Biotechnology Co., Ltd., size: 20*20cm; thickness: 0.9~1.0mm).

[0268] Chemical reagents

[0269] The known starting materials of the present invention can be synthesized by using or according to literature, patent methods, etc. known in the art, or can be purchased from chemical reagent companies such as Alfa Aesar, Acros, Sigma-Aldrich, TCI, Aikon, Anaiji, Aladdin, J&K, Bid Pharmaceuticals, Leyan, McLean, Accela, Titan (Adamas), Xiens, and Inokane.

[0270] Abbreviations

[0271] Protecting group abbreviations: Bn, benzyl, Boc, tert-butyloxycarbonyl, Cbz, benzyloxycarbonyl, MOM, methoxymethyl, PMB, p-methoxybenzyl, TBDPS, tert-butyldiphenylsilyl, TBS, tert-butyldimethylsilyl, THP, 2-tetrahydropyranyl, Tos, p-toluenesulfonyl

[0272] Reagent abbreviations: ACN acetonitrile AIBN azobisisobutyronitrile Boc2O di-tert-butyl dicarbonate BPO dibenzoyl peroxide tBuONa sodium tert-butoxide CAM ammonium molybdate cerium sulfuric acid color developer CDI N,N'-carbonyldiimidazole m-CPBA m-chloroperbenzoic acid DABCO triethylenediamine DCE 1,2-dichloroethane DCM dichloromethane DEAD diethyl azodicarboxylate DIAD diisopropyl azodicarboxylate DIBAL-H diisobutylaluminum hydride DBU 1,8-diazobisspiro[5.4.Undec-7-ene (DHP), 3,4-dihydro-2H-pyran (DIEA), N,N-diisopropylethylamine (DMAP), 4-dimethylaminopyridine (DMF), N,N-dimethylformamide (DMSO), dimethyl sulfoxide (EA), ethyl acetate (HMPA), hexamethylphosphoramide (HATU), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (LAH), lithium aluminum hydride (NBS), N-bromosuccinimide (PE), petroleum ether (PMA), phosphomolybdic acid (PyBOP), 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (TBAF), tetrabutylammonium fluoride (TBDPSCl), tert-butyldiphenylsilyl chloride (TBBSCl), tert-butyldimethylsilyl chloride (TEA), triethylamine (TFA), trifluoroacetic acid (THF), tetrahydrofuran (TPSCl), 2,4,6-triisopropylbenzenesulfonyl chloride (TsCl), p-toluenesulfonyl chloride (TsOH). Pd(PPh3)4 p-toluenesulfonate, tetrakistriphenylphosphine palladium (Xphos), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XantPhos), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (Pd2(dba)3), tris(dibenzylideneacetone)dipalladium (Pd(dppf)Cl2), (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (BINAP), 1,1'-binaphthyl-2,2'-bis(diphenylphosphino)phosphine.

[0273] Preparation formula

[0274] Route 1:

[0275] wherein X, Y, L1 and L2 are as defined herein, R4 is selected from ring B and -(C1-C6)alkyl, ring B is as defined herein, R5 is selected from ring A and -(C1-C6)alkyl, and ring A is as defined herein.

[0276] Route 2:

[0277] wherein X, L1 and L2 are as defined herein, R4 is selected from ring B and -(C1-C6)alkyl, ring B is as defined herein, R5 is selected from ring A and -(C1-C6)alkyl, and ring A is as defined herein.

[0278] Route 3:

[0279] wherein X, Y, T1, T2 and L2 are as defined in the present invention, R4 is selected from ring B and -(C1-C6)alkyl, ring B is as defined in the present invention, T4 is selected from C(R t ) and N, R t As defined in the present invention, U1, U2 and U3 are each independently selected from CH and N.

[0280] Route 4:

[0281] wherein T1, T2 and L2 are as defined in the present invention, R4 is selected from ring B and -(C1-C6)alkyl, ring B is as defined in the present invention, T4 is selected from C(R t ) and N, R t As defined in the present invention, U1, U2 and U3 are each independently selected from CH and N.

[0282] Example

[0283] Example 1: Synthesis of Compounds G-1 and M-1

[0284] Step A: To a solution of 2,4-dichlorothieno[3,2-d]pyrimidine (100 mg, 0.488 mmol), phenylboronic acid (89.19 mg, 0.731 mmol), and potassium carbonate (168.49 mg, 1.219 mmol) in toluene (5 mL) was added palladium tetrakis(triphenylphosphine) (22.54 mg, 0.020 mmol) at room temperature. After complete addition, the mixture was stirred at 100°C under nitrogen for 3 hours. The product was concentrated under reduced pressure and separated on a silica gel column (SiO2, PE:EA = 85:15) to afford M-1, 2-chloro-4-phenylthieno[3,2-d]pyrimidine (80 mg, 0.324 mmol, 66.45%) as a white solid. ESI-MS m / z = 246.8 [M+H] + ;Calcu.=246.0.

[0285] Step B: To a solution of 2-chloro-4-phenylthieno[3,2-d]pyrimidine (50 mg, 0.203 mmol), 3-methoxy-4-(4-methylimidazol-1-yl)aniline (45.31 mg, 0.223 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (5.80 mg, 0.012 mmol), and potassium phosphate (86.04 mg, 0.405 mmol) in N,N-dimethylformamide (3 mL) was added tris(dibenzylideneacetone)dipalladium (37.18 mg, 0.041 mmol) at room temperature. After addition, the mixture was stirred at 110°C under nitrogen for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was subjected to preparative HPLC separation using Waters XSelect CSHPrepC 18 (30 mm × 250 mm, 5 μm); A: 0.1% formic acid in water; B: MeCN; 18 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-25% B; 3.5-15 min, 25%-75% B; detector, UV 254 nm. This reaction yielded compound G-1, N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4-phenylthieno[3,2-d]pyrimidin-2-amine (10 mg, 0.024 mmol, 11.93%) as a white solid. 1 H NMR(500MHz,DMSO-d6)δppm 9.98(s,1H),8.44(d,J=5.3Hz,1H),8.16-8.21(m,2H),8.07(d,J=2.0Hz,1H),7.64-7.70(m,4H),7 .48-7.52(m,2H),7.27(d,J=8.5Hz,1H),7.06(d,J=0.9Hz,1H),3.84(s,3H),2.15(d,J=0.6Hz,3H). ESI-MS m / z=414.0[M+H] + ;Calcu.=413.1.

[0286] Example 2: Synthesis of Compounds G-2 and M-2

[0287] Step A: To a solution of 2,4-dichlorothieno[3,2-d]pyrimidine (240 mg, 1.170 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (200 mg, 0.984 mmol), and potassium carbonate (1360 mg, 9.840 mmol) in 1,4-dioxane (4 mL) was added a 1,4-dioxane solution (4 mL) consisting of palladium acetate (22 mg, 0.098 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (141 mg, 0.295 mmol). The mixture was stirred at 100°C for 2 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure and separated using a normal phase column (SiO2, EA:MeOH = 97:3). The reaction afforded M-2, a yellow solid product, 2-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thieno[3,2-d]pyrimidin-4-amine (122 mg, 0.328 mmol, 33.34%), ESI-MS m / z = 372.0 [M+H] + ;Calcu.=371.1.

[0288] Step B: Aniline (0.024 mL, 0.268 mmol) and trifluoroacetic acid (0.021 mL, 0.272 mmol) were added to a solution of 2-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thieno[3,2-d]pyrimidin-4-amine (50 mg, 0.134 mmol) in methanol (6 mL) at room temperature, and the mixture was stirred at 80°C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a residue, which was subjected to preparative HPLC separation using the following conditions: Waters XBridge C18 (30 mm × 250 mm, 5 μm); A: 0.1% formic acid in water; B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-15 min, 10%-60% B; detector, UV 254 nm. This reaction yielded compound G-2, a white solid product N 4 -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N 2 -phenylthieno[3,2-d]pyrimidine-2,4-diamine (37.67 mg, 0.087 mmol, 64.76%). 1H NMR (500MHz, DMSO-d6) δppm 9.65 (s, 1H), 9.20 (s, 1H), 8.13 (d, J = 5.3Hz, 1H), 7.98 (br s,1H),7.80(d,J=7.6Hz,2H),7.71(dd,J=8.5,2.0Hz,1H),7.64(d,J=2.1Hz,1H),7.33 (d,J=8.5Hz,1H),7.17-7.28(m,4H),6.90(t,J=7.3Hz,1H),3.78(s,3H),2.20(s,3H). ESI-MS m / z=429.3[M+H] + ;Calcu.=428.1.

[0289] Example 3: Synthesis of Compound G-3

[0290] Step A: To a solution of 2,4-dichlorothieno[3,2-d]pyrimidine (200 mg, 0.975 mmol) and potassium carbonate (138.06 mg, 0.999 mmol) in N,N-dimethylformamide (3 mL) was added phenol (0.087 mL, 0.975 mmol) at room temperature. After complete addition, the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, then water (20 mL) was added and extracted three times with ethyl acetate (15 mL x 3). The combined organic phases were washed once with saturated brine (20 mL), and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure and separated on a silica gel column (SiO2, PE:EA = 85:15). This reaction afforded 2-chloro-4-(phenoxy)thieno[3,2-d]pyrimidine (100 mg, 0.381 mmol, 39.03%) as a white solid. ESI-MS m / z=263.0[M+H] + ;Calcu.=262.0.

[0291] Step B: 2-chloro-4-(phenoxy)thieno[3,2-d]pyrimidine (50 mg, 0.190 mmol), 3-methoxy-4-(4-methylimidazol-1-yl)aniline (38.62 mg, 0.190 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (36.29 mg, 0.076 mmol), and potassium phosphate (131.48 mg, 0.571 mmol) were dissolved in N,N-dimethylformamide (3 mL) at room temperature. Tris(dibenzylideneacetone)dipalladium (34.86 mg, 0.038 mmol) was added. After the addition was complete, the mixture was stirred at 120°C under nitrogen for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain the crude product. The residue was subjected to HPLC preparative separation using Waters XSelect CSHPrepC 18 (30 mm × 250 mm, 5 μm); A: 0.1% formic acid in water; B: MeCN; 18 mL / min; 0-3 min, 5% B; 3-3.5 min, 5%-10% B; 3.5-15 min, 10%-80% B; detector, UV 254 nm. This reaction yielded compound G-3, N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4-phenoxythieno[3,2-d]pyrimidin-2-amine (10 mg, 0.025 mmol, 13.15%) as a white solid. 1 H NMR(500MHz,DMSO-d6)δppm 9.64(s,1H),8.33(d,J=5.3Hz,1H),7.62(s,2H),7.49-7.55(m,2H),7.42(d,J=5.3Hz,1H),7.39(d, J=7.6Hz,2H),7.35(t,J=7.4Hz,2H),7.08(d,J=8.5Hz,1H),6.99(s,1H),3.61(s,3H),2.13(s,3H). ESI-MS m / z=430.1[M+H] + ;Calcu.=429.1.

[0292] Example 4: Synthesis of Compounds G-4 and M-3

[0293] Step A: Aniline (0.091 mL, 0.999 mmol) was added to a solution of 2,4-dichlorothieno[3,2-d]pyrimidine (200 mg, 0.975 mmol) and potassium carbonate (138 mg, 0.999 mmol) in N,N-dimethylformamide (3 mL) at room temperature. After complete addition, the mixture was stirred at room temperature overnight. LCMS analysis indicated complete consumption of the starting material. The reaction mixture was filtered through celite, then water (20 mL) was added and extracted three times with ethyl acetate (15 mL x 3). The combined organic phases were washed once with saturated brine (20 mL), and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure and separated on a silica gel column (SiO2, PE:EA = 85:15). This reaction afforded M-3, 2-chloro-N-phenylthieno[3,2-d]pyrimidin-4-amine (80 mg, 0.306 mmol, 30.61%) as a yellow solid. ESI-MS m / z=261.8[M+H] + ;Calcu.=261.0.

[0294] Step B: 2-chloro-N-phenylthieno[3,2-d]pyrimidin-4-amine (60 mg, 0.183 mmol), 3-methoxy-4-(4-methylimidazol-1-yl)aniline (41.00 mg, 0.202 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (6.99 mg, 0.015 mmol), and potassium phosphate (77.85 mg, 0.367 mmol) were dissolved in N,N-dimethylformamide (5 mL) at room temperature. Tris(dibenzylideneacetone)dipalladium (6.72 mg, 0.007 mmol) was added. After the addition, the mixture was stirred for 3 hours under nitrogen protection while controlling the temperature, raising or lowering the temperature to 110°C. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain the crude product. The residue was subjected to HPLC preparative separation using Waters XSelect CSHPrepC 18 (30 mm × 250 mm, 5 μm); A: 0.1% formic acid in water; B: MeCN; 18 mL / min; 0-3 min, 5% B; 3-3.5 min, 5%-10% B; 3.5-15 min, 10%-80% B; detector, UV 254 nm, lyophilized. The reaction yielded compound G-4, a white solid product N 2 -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N 4 -phenylthieno[3,2-d]pyrimidine-2,4-diamine (10 mg, 0.023 mmol, 12.72%). 1H NMR(500MHz,DMSO-d6)δppm 9.52(s,1H,),9.33(s,1H),8.11(d,J=5.2Hz,1H),7.84(d,J=8.1Hz,2H),7.78(d,J=2.3Hz,1H),7.67(d,J=1.1Hz,1H),7.55(dd,J=9.3and 2.4Hz,1H),7.35-7.41(m,2H),7.27(d,J=5.1Hz,1H),7.17(d,J=9.3Hz,1H),7 .09-7.14(m,1H),7.03(d,J=1.2Hz,1H,),3.68(s,3H,),2.15(d,J=1.1Hz,1H). ESI-MS m / z=429.2[M+H] + ;Calcu.=428.1.

[0295] Example 5: Synthesis of Compound G-5

[0296] Step A: To a solution of 2-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thieno[3,2-d]pyrimidin-4-amine (7 mg, 0.019 mmol) in phenol (1 mL) was added sodium phenolate (10 mg, 0.086 mmol) and potassium carbonate (7 mg, 0.051 mmol) at room temperature. The mixture was then stirred at 120°C for 3 hours. The reaction mixture was directly subjected to preparative HPLC separation using the following preparative conditions: Waters XBridge C18 (30 mm × 250 mm, 5 μm); A: 0.05% aqueous ammonia; B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-15 min, 10%-70% B; detector: UV 254 nm. The reaction afforded compound G-5, a white solid product N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-2-phenoxythieno[3,2-d]pyrimidin-4-amine (3.67 mg, 0.008 mmol, 41.90%). 1H NMR(500MHz,DMSO-d6)δppm 9.97(s,1H),8.24(d,J=5.34Hz,1H),7.68(d,J=1.1Hz,1H),7.52(d,J=2.1Hz,1H),7.44(t,J=7.9Hz,3H),7.33(d,J=5 .3Hz,1H),7.25(t,J=7.5Hz,1H),7.21(d,J=7.5Hz,2H),7.11(d,J=8.5Hz,1H),7.05(s,1H),3.67(s,1H),2.14(s,3H). ESI-MS m / z=430.1[M+H] + ;Calcu.=429.1.

[0297] Example 6: Synthesis of Compound G-6

[0298] Step A: To a solution of 2-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thieno[3,2-d]pyrimidin-4-amine (45 mg, 0.121 mmol) in 1,4-dioxane (5 mL) was added phenylboronic acid (37 mg, 0.303 mmol), tetrakistriphenylphosphine palladium (42 mg, 0.036 mmol), and potassium carbonate (50 mg, 0.363 mmol) at room temperature. The mixture was then stirred at 110°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was separated by PTLC (SiO2, DCM:MeOH = 80:20). The reaction afforded compound G-6, a white solid product N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-2-phenoxythieno[3,2-d]pyrimidin-4-amine (5.01 mg, 0.010 mmol, 8.52%). 1 H NMR(500MHz,DMSO-d6)δppm 9.95(s,1H),8.43-8.47(m,2H),8.31(d,J=5.3Hz,1H),8.00(d,J=2.1Hz,1H),7.76(d,J=0.9Hz,1H),7.62(dd,J=8.5 ,2.1Hz,1H),7.58(d,J=5.3Hz,1H),7.48-7.54(m,3H),7.41(d,J=8.5Hz,1H),7.13(s,1H),3.89(s,1H),2.17(s,3H). ESI-MS m / z=414.0[M+H] + ;Calcu.=413.1.

[0299] Example 7: Synthesis of Compound G-7

[0300] Step A: To 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (30 mg, 0.081 mmol) dissolved in phenol (1.5 mL) was added sodium phenolate (47 mg, 0.402 mmol) and potassium carbonate (28 mg, 0.201 mmol) at room temperature. The mixture was then stirred at 120°C for 3 hours. The reaction mixture was directly subjected to preparative HPLC separation using the following preparative conditions: Waters XBridge C18 (30 mm × 250 mm, 5 μm); A: 0.05% aqueous ammonia; B: MeCN; 40 mL / min, 0-3 min, 30% B; 3-15 min, 30%-80% B; detector: UV 254 nm. The reaction afforded compound G-7, a white solid product N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-7-phenoxythiazolo[4,5-d]pyrimidin-5-amine (4.91 mg, 0.011 mmol, 13.58%). 1 H NMR (500MHz, DMSO-d6) δppm 9.89 (br s, 1H), 9.78 (s, 1H), 7.63 (d, J = 1.2Hz, 1H), 7.63 (d, J = 1.2Hz, 1H), 7.56 (br s,1H),7.50-7.54(m,2H),7.39-7.44(m,2H),7.34-7.39(m,2H),7.11(br d,J=8.5Hz,1H),3.60(br s,3H),7.01(s,1H),2.13(d,J=0.6Hz,3H). ESI-MS m / z=431.0[M+H] + ;Calcu.=430.0.

[0301] Example 8: Synthesis of Compounds G-8 and M-4

[0302] Step A: At room temperature and nitrogen environment, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (463 mg, 0.971 mmol) was added to 1,4-dioxane (15 mL) in which palladium acetate (100 mg, 0.445 mmol) was dissolved. The whole mixture was stirred at room temperature for 2 minutes, and 5,7-dichlorothiazolo[4,5-d]pyrimidine (563 mg, 2.746 mmol) was added. After stirring for 2 minutes, 1,4-dioxane solution (15 mL) consisting of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (500 mg, 2.460 mmol) and potassium carbonate (1360 mg, 9.840 mmol) was added. The whole mixture was stirred at 100 ° C for 2 hours. The reaction mixture was filtered through Celite, and the filtrate was collected, concentrated under reduced pressure, and separated by a normal phase column (SiO2, EA:MeOH = 96:4). This reaction afforded M-4, a yellow solid product, 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (435 mg, 1.167 mmol, 47.43%). ESI-MS m / z = 373.0 [M+H] + ;Calcu.=372.1.

[0303] Step B: At room temperature and nitrogen environment, palladium acetate (25 mg, 0.111 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (72 mg, 0.124 mmol) and cesium carbonate (240 mg, 0.737 mmol) were added to 1,4-dioxane (12 mL) dissolved with 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (150 mg, 0.402 mmol) and aniline (0.078 mL, 0.859 mmol). The whole mixture was stirred at 80 ° C for 2 hours. The reaction solution was filtered through celite, and the filtrate was collected and concentrated under reduced pressure to obtain a residue, which was subjected to HPLC preparative separation. Preparation conditions: Waters XBridge C18 (30 mm × 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-15 min, 10%-65% B; detector, UV 254 nm. The reaction yielded compound G-8, a white solid product N 5 -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N 7 -phenylthiazolo[4,5-d]pyrimidine-5,7-diamine (15.90 mg, 0.034 mmol, 8.33%). 1H NMR (500MHz, DMSO-d6) δppm9.79(s,1H),9.56(s,1H),9.53(s,1H),7.81(br d,J=7.9Hz,2H),7.70(d,J=1.7Hz,1H),7.66(d,J=1.2Hz,1H),7.59(br d,J=8.4Hz,1H),7.39(t,J=7.9Hz,2H),7.21(d,J=8.5Hz,1H),7.14(t,J=7.4Hz,1H),7.04(s,1H),3.68(s,3H),2.15(s,3H). ESI-MS m / z=429.1[M+H] + ;Calcu.=428.1.

[0304] Example 9: Synthesis of Compound G-9

[0305] Step A: To 1,4-dioxane (4 mL) in which 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (30 mg, 0.080 mmol) was dissolved, phenylboronic acid (25 mg, 0.205 mmol), tetrakistriphenylphosphine palladium (28 mg, 0.024 mmol) and potassium carbonate (33 mg, 0.239 mmol) were added at room temperature, and the whole mixture was stirred at 100°C for 3 hours. The reaction mixture was filtered through Celite, and the filtrate was collected and concentrated under reduced pressure to obtain a residue, which was then subjected to preparative HPLC separation using the following conditions: Waters XBridge C18 (30 mm × 250 mm, 5 μm); A: 0.1% formic acid in water; B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-15 min, 10%-60% B; detector, UV 254 nm. This reaction yielded compound G-9, a yellow solid product, N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-7-phenylthiazolo[4,5-d]pyrimidin-5-amine (12.73 mg, 0.030 mmol, 37.15%). 1HNMR(500MHz,DMSO-d6)δppm 10.21(s,1H)9.91(s,1H),8.15-8.19(m,2H),7.78(dd,J=7.9,1.4Hz,1H),7 .69(d,J=1.2Hz,1H),7.69(d,J=2.0Hz,1H),7.67(d,J=1.8Hz,1H),7.54(br d,J=7.5Hz,1H),7.31-7.34(m,2H),7.07(d,J=1.1Hz,1H),3.84(s,3H),2.15(d,J=0.6Hz,3H),. ESI-MS m / z=415.0[M+H] + ;Calcu.=414.1.

[0306] Example 10: Synthesis of Compound G-10

[0307] Step A: Tetrakistriphenylphosphine palladium (22 mg, 0.019 mmol) and cesium carbonate (187 mg, 0.573 mmol) were added to 1,4-dioxane (1.5 mL) and water (0.3 mL) in which 2-chloro-N-phenylthieno[3,2-d]pyrimidin-4-amine (50 mg, 0.191 mmol) and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylboronic acid (75 mg, 0.194 mmol) were dissolved at room temperature under nitrogen, and the whole mixture was stirred at 100°C for 3 hours. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined and concentrated under reduced pressure to obtain a residue, which was then subjected to preparative HPLC separation using the following conditions: Waters XBridge C18 (19 mm × 250 mm, 5 μm); A: 0.05% aqueous ammonia; B: MeCN; 18 mL / min; 0-3 min, 15% B; 3-16 min, 15%-85% B; detector, UV 254 nm. This reaction yielded compound G-10, 2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N-phenylthieno[3,2-d]pyrimidin-4-amine (16.7 mg, 0.040 mmol, 20.95%) as a white solid. 1H NMR(500MHz,DMSO-d6)δppm 9.88(s,1H),8.29(d,J=5.5Hz,1H),8.24(d,J=1.7Hz,1H),8.09(dd,J=8.2,1.68Hz,1H),7.89-7.94(m,2H),7.87(d,J=1.4Hz,1H),7.58(d,J= 5.3Hz, 1H), 7.51 (d, J = 8.2Hz, 1H), 7.44 (dd, J = 8.3, 7.6Hz, 2H), 7.22 (t, J = 1.1Hz, 1H), 7.13-7.18 (m, 1H), 3.95 (s, 3H), 2.17 (d, J = 0.8Hz, 3H). ESI-MS m / z=414.2[M+H] + ;Calcu.=413.3.

[0308] Example 11: Synthesis of Compound G-11

[0309] Step A: To paraformaldehyde (100 mg, 3.333 mmol) and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (500 mg, 2.460 mmol) dissolved in methanol (30 mL) was added sodium hydroxide (680 mg, 17.000 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour. Sodium borohydride (140 mg, 3.701 mmol) was then added, and the mixture was refluxed and stirred for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a residue, which was separated by normal phase column chromatography (SiO2, DCM:MeOH = 98:2). The reaction afforded 3-methoxy-N-methyl-4-(4-methyl-1H-imidazol-1-yl)aniline (252 mg, 1.160 mmol, 47.15%) as a yellow solid. ESI-MS m / z = 218.2 [M+H] + ;Calcu.=217.1.

[0310] Step B: Potassium phosphate (406 mg, 1.913 mmol), tris(dibenzylideneacetone)dipalladium (53 mg, 0.058 mmol) and 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (65 mg, 0.112 mmol) were added to N,N-dimethylformamide (10 mL) in which 3-methoxy-N-methyl-4-(4-methyl-1H-imidazol-1-yl)aniline (84 mg, 0.387 mmol) and 2-chloro-N-phenylthieno[3,2-d]pyrimidin-4-amine (100 mg, 0.382 mmol) were dissolved at room temperature under nitrogen atmosphere, and the whole mixture was stirred at 110°C for 24 hours. The reaction solution was filtered through celite, and the filtrate was collected and concentrated under reduced pressure to obtain a residue, which was subjected to HPLC preparative separation under the following conditions: Waters XBridge C18 (30 mm × 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-18 min, 10%-75% B; detector, UV 254 nm. This reaction yielded compound G-11, a white solid product N 2 -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N 2 -methyl-N 4 -phenylthieno[3,2-d]pyrimidine-2,4-diamine (19.74 mg, 0.042 mmol, 11.12%). 1 H NMR(500MHz,DMSO-d6)δppm 9.39(s,1H),8.06(d,J=5.3Hz,1H),7.76(d,J=1.2Hz,1H),7.64(d,J=7.6Hz,2H),7.38(d,J=8.4Hz,1H),7.26(d,J=2.3Hz,1H),7 .24(d,J=5.3Hz,1H),7.09-7.14(m,3H),7.04(dd,J=8.4,2.1Hz,1H),6.93-6.98(m,1H),3.70(s,3H),3.53(s,3H),2.19(s,3H). ESI-MS m / z=443.3[M+H] + ;Calcu.=442.2.

[0311] Example 12: Synthesis of Compounds G-12 and M-5

[0312] Step A: To a solution of 2,4-dichlorothieno[3,2-d]pyrimidine (1000 mg, 4.877 mmol) and N-methylaniline (0.528 mL, 4.877 mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate (1347.90 mg, 9.753 mmol) at room temperature. After the addition, the mixture was stirred at room temperature overnight. Upon completion of the reaction, the reaction mixture was cooled to room temperature and filtered through celite. Water (30 mL) was then added and the mixture was extracted with ethyl acetate. The combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield the crude product. The crude product was separated on a silica gel column (SiO2, PE:EA = 85:15). The reaction yielded M-5, a white solid product, 2-chloro-N-methyl-N-phenylthieno[3,2-d]pyrimidin-4-amine (700 mg, 2.539 mmol, 52.06%). ESI-MS m / z = 275.9 [M+H] + ;Calcu.=275.0.

[0313] Step B: 2-chloro-N-methyl-N-phenylthieno[3,2-d]pyrimidin-4-amine (80 mg, 0.290 mmol), 3-methoxy-4-(4-methylimidazol-1-yl)aniline (58.97 mg, 0.290 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (41.49 mg, 0.087 mmol), and potassium phosphate (153.95 mg, 0.725 mmol) were dissolved in N,N-dimethylformamide (3 mL) at room temperature. Tris(dibenzylideneacetone)dipalladium (39.85 mg, 0.044 mmol) was added. After the addition was complete, the mixture was stirred at 110°C under nitrogen for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain a residue. The residue was subjected to HPLC preparative separation using the Welch Xtimate C 18 (30 mm × 250 mm, 5 μm); A: 0.1% formic acid in water; B: MeCN; 40 mL / min; 0-3.5 min, 10% B; 3.5-15 min, 10%-50% B; detector, UV 254 nm. The reaction yielded compound G-12, a white solid product N 2 -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N 4 -methyl-N 4 -phenylthieno[3,2-d]pyrimidine-2,4-diamine (10 mg, 0.023 mmol, 7.79%). 1H NMR(500MHz,DMSO-d6)δppm 9.39(s,1H),7.96(d,J=2.3Hz,1H),7.78-7.81(m,1H),7.80(d,J=5.5Hz,1H),7.65(d,J=1.2Hz,1H),7.45-7.54(m,6H) ,7.22(d,J=8.5Hz,1H),7.08(d,J=5.5Hz,1H),7.03(t,J=1.1Hz,1H),3.82(s,3H),3.60(s,3H),2.15(d,J=0.8Hz,3H). ESI-MS m / z=443.1[M+H] + ;Calcu.=442.1.

[0314] Example 13: Synthesis of Compound G-13

[0315] Step A: 2-chloro-N-methyl-N-phenylthieno[3,2-d]pyrimidin-4-amine (80 mg, 0.290 mmol), 1-(2-methoxy-4-(methylamino)phenyl)-4-methylimidazole (63.03 mg, 0.290 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (55.32 mg, 0.116 mmol), and potassium phosphate (184.74 mg, 0.870 mmol) were dissolved in N,N-dimethylformamide (3 mL) at room temperature. Tris(dibenzylideneacetone)dipalladium (53.13 mg, 0.058 mmol) was added. After the addition was complete, the mixture was stirred at 120°C under nitrogen for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain a residue. The residue was subjected to HPLC preparative separation using the Welch Xtimate C 18 (30 mm × 250 mm, 5 μm); A: 0.1% formic acid in water; B: MeCN; 40 mL / min; 0-3.5 min, 10% B; 3.5-15 min, 10%-45% B; detector, UV 254 nm. The reaction yielded compound G-13, a white solid product N 2 -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N 2 ,N 4 -dimethyl-N 4 -phenylthieno[3,2-d]pyrimidine-2,4-diamine (8 mg, 0.018 mmol, 6.04%). 1H NMR(500MHz,DMSO-d6)δppm 7.70-7.79(m,2H),7.46-7.55(m,3H),7.40-7.45(m,2H),7.31-7.38(m,2H),7.09-7.1 5(m,2H),7.01-7.06(m,1H),3.79-3.85(m,3H),3.59(s,3H),3.41(s,3H),2.16(s,3H). ESI-MS m / z=457.1[M+H] + ;Calcu.=456.1.

[0316] Example 14: Synthesis of Compound G-14

[0317] Step A: To a solution of 2,4-dichlorothieno[3,2-d]pyrimidine (500 mg, 2.438 mmol) and 4-aminotetrahydropyran (296 mg, 2.926 mmol) in n-butanol (30 mL) was added N,N-diisopropylethylamine (472 mg, 3.652 mmol) at room temperature. After complete addition, the mixture was heated to 75°C and stirred for 5 hours. The reaction mixture was concentrated under reduced pressure to afford a crude white solid. The residue was separated on a silica gel column (SiO2, PE:EA = 10:90) to afford 2-chloro-N-(tetrahydro-2H-pyran-4-yl)thieno[3,2-d]pyrimidin-4-amine (612 mg, 2.269 mmol, 93.05%) as a white solid. ESI-MS m / z = 270.1 [M+H] + (C 11 H 13 ClN3OS); Calcu.=269.0.

[0318] Step B: To a solution of 2-chloro-N-(tetrahydro-2H-pyran-4-yl)thieno[3,2-d]pyrimidin-4-amine (200 mg, 0.741 mmol) and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (301 mg, 1.481 mmol) in 1,4-dioxane (10 mL) was added palladium acetate (17 mg, 0.076 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (46 mg, 0.074 mmol), and cesium carbonate (483 mg, 1.482 mmol) at room temperature under nitrogen. After the addition was complete, the mixture was heated to 100°C and stirred under nitrogen for 6 hours. The reaction solution was concentrated under reduced pressure to obtain a brown solid crude residue. The residue was subjected to HPLC preparative separation under the following conditions: Welch Xtimate C18 (30 mm × 250 mm, 5 μm); A: 0.1% formic acid in water, B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-3.5 min, 10% B; 3.5-15 min, 10%-50% B; 15-15.5 min, 50%-100% B; detector, UV 254 nm. Compound G-14 was obtained, a white solid product N 2 -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N 4 -(tetrahydro-2H-pyran-4-yl)thieno[3,2-d]pyrimidine-2,4-diamine (190.33 mg, 0.402 mmol, 54.27%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.17(s,1H)7.98(d,J=5.6Hz,1H)7.76(d,J=1.6Hz,1H)7.66(d,J=1.2Hz, 1H)7.60(dd,J=8.6,2.1Hz,1H)7.57(d,J=7.6Hz,1H)7.20(d,J=8.6Hz,1H) 7.17(d,J=5.6Hz,1H)7.03(s,1H)4.32-4.41(m,1H)3.91-3.97(m,2H)3.80 (s,3H)3.38-3.45(m,2H)2.15(s,3H)1.88-1.94(m,2H)1.59-1.70(m,2H). ESI-MS m / z=437.3[M+H] + ;Calcu.=436.2.

[0319] Example 15: Synthesis of Compound G-15

[0320] Step A: At room temperature and nitrogen environment, palladium acetate (13 mg, 0.058 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (38 mg, 0.066 mmol) and cesium carbonate (128 mg, 0.393 mmol) were added to 1,4-dioxane (10 mL) in which 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (80 mg, 0.215 mmol) and 4-fluoroaniline (48 mg, 0.432 mmol) were dissolved. The whole mixture was stirred at 80 ° C for 2 hours. The reaction solution was filtered through celite, and the filtrate was collected and concentrated under reduced pressure to obtain a residue, which was subjected to HPLC preparative separation. Preparation conditions: Waters XBridge C8 (21 mm × 250 mm, 5 μm); A: 0.1% formic acid in water; B: MeCN; 18 mL / min; 0-3 min, 10% B; 3-15 min, 0%-80% B; detector, UV 254 nm. The reaction yielded compound G-15, a gray solid product N 7 -(4-Fluorophenyl)-N 5 -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidine-5,7-diamine (27.03 mg, 0.056 mmol, 25.91%). 1 H NMR (500MHz, DMSO-d6) δppm 9.81 (s, 1H), 9.56 (s, 1H), 9.54 (s, 1H), 7.82 (br dd, 2H, J = 5.0, 8.7Hz), 7.68 (s, 1H), 7.66 (d, 1H, J = 1.2Hz), 7.59 (br d,1H,J=7.6Hz),7.2-7.3(m,3H),7.04(s,1H),3.70(s,3H),2.15(s,3H). ESI-MS m / z=448.0[M+H] + ;Calcu.=447.1.

[0321] Example 16: Synthesis of Compound G-16

[0322] Step A: At room temperature and nitrogen environment, palladium acetate (17 mg, 0.076 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (48 mg, 0.083 mmol) and cesium carbonate (160 mg, 0.491 mmol) were added to 1,4-dioxane (8 mL) in which 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (100 mg, 0.268 mmol) and 4-methoxyaniline (66 mg, 0.536 mmol) were dissolved. The whole mixture was stirred at 80 ° C for 2 hours. The reaction solution was filtered through celite, and the filtrate was collected and concentrated under reduced pressure to obtain a residue, which was subjected to HPLC preparative separation. Preparation conditions: Waters XBridge C18 (30 mm × 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 40 mL / min; 0-3 min, 20% B; 3-15 min, 10%-85% B; detector, UV 254 nm. The reaction yielded compound G-16, a white solid product N 5 -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N 7 -(4-methoxyphenyl)thiazolo[4,5-d]pyrimidine-5,7-diamine (11.88 mg, 0.024 mmol, 9.08%). 1 H NMR (500MHz, DMSO-d6) δppm 9.64 (s, 1H), 9.50 (s, 1H), 9.47 (s, 1H), 7.72 (s, 1H), 7.65 (d, 1H, J = 1.4Hz), 7.62 (br d, 2H, J = 8.4Hz), 7.56 (br d,1H,J=7.9Hz),7.19(d,1H,J=8.5Hz),7.03(t,1H,J=1.1Hz),6.97(d,2H,J=9.0Hz),3.78(s,3H),3.67(s,3H),2.15(d,3H,J=0.8Hz). ESI-MS m / z=460.0[M+H] + ;Calcu.=459.1.

[0323] Example 17: Synthesis of Compound G-17

[0324] Step A: To a solution of 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (100 mg, 0.268 mmol) and benzo[d][1,3]dioxolane-5-amine (73 mg, 0.533 mmol) in 1,4-dioxane (20 mL) was added palladium acetate (12 mg, 0.053 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (62 mg, 0.107 mmol), and cesium carbonate (175 mg, 0.537 mmol) at room temperature under nitrogen. After the addition was complete, the mixture was heated to 80°C and stirred under nitrogen for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a brown solid crude residue, which was then subjected to HPLC preparative separation under the following conditions: Waters XBridge Prep C18 (30 mm × 250 mm, 5 μm); A: 0.05% aqueous ammonia, B: MeCN; 40 mL / min; 0-3 min, 20% B; 3-3.5 min, 20%-50% B; 3.5-15 min, 50%-70% B; 15-16 min, 70%-100% B; detector, UV 254 nm. Compound G-17, a pale yellow solid product N 7 -(Benzo[d][1,3]dioxolane-5-amino)-N 5 -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidine-5,7-diamine (23.13 mg, 0.049 mmol, 18.24%). 1 H NMR(500MHz,DMSO-d6)δppm 9.66(br s,1H)9.51(s,1H)9.51(br s,1H)7.72(s,1H)7.65(d,J=1.2Hz,1H)7.58(d,J=7.8Hz,1H)7.45(s,1H)7.20(d,J=8.6Hz,1H )7.11(d,J=7.8Hz,1H)7.03(s,1H)6.93(d,J=8.6Hz,1H)6.05(s,2H)3.71(s,3H)2.15(s,3H). ESI-MS m / z=474.3[M+H] + ;Calcu.=473.1.

[0325] Example 18: Synthesis of Compound G-18

[0326] Step A: To a solution of 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (100 mg, 0.268 mmol) and benzo[d][1,3]dioxolane-4-amine (73 mg, 0.533 mmol) in 1,4-dioxane (20 mL) was added palladium acetate (12 mg, 0.053 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (62 mg, 0.107 mmol), and cesium carbonate (175 mg, 0.537 mmol) at room temperature under nitrogen. After the addition was complete, the mixture was heated to 80°C and stirred under nitrogen for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a brown solid crude residue, which was then subjected to HPLC preparative separation under the following conditions: Welch Xtimate C18 (30 mm × 250 mm, 5 μm); A: 0.05% aqueous ammonia, B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-40% B; 3.5-18 min, 40%-75% B; 18-20 min, 75%-100% B; detector, UV 254 nm. Compound G-18 was obtained as a pale yellow solid product N. 7 -(Benzo[d][1,3]dioxolane-4-amino)-N 5 -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5,7-amine (13.77 mg, 0.029 mmol, 10.85%). 1 H NMR(500MHz,DMSO-d6)δppm 9.76(br s,1H)9.50(s,1H)9.45(br s,1H)7.65(s,1H)7.62(d,J=1.0Hz,1H)7.50(d,J=8.2Hz,1H)7.11(d,J=8.6Hz,1H)7 .00(s,1H)6.93-6.97(m,1H)6.87-6.92(m,2H)5.94(s,2H)3.63(s,3H)2.14(s,3H). ESI-MS m / z=474.3[M+H] + ;Calcu.=473.1.

[0327] Example 19: Synthesis of Compound G-19

[0328] Step A: 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (40 mg, 0.107 mmol), 3,4-(methylenedioxy)phenylboronic acid (17.76 mg, 0.107 mmol), and potassium carbonate (14.83 mg, 0.107 mmol) dissolved in 1,4-dioxane (3 mL) and water (0.6 mL) were added at room temperature. 1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (87.62 mg, 0.107 mmol) was added. After the addition was complete, the mixture was stirred at 100°C under nitrogen for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain a residue. The residue was subjected to HPLC preparative separation using the following preparation conditions: Waters XBridge Prep C 18 (30 mm × 250 mm, 5 μm); A: 0.1% formic acid in water; B: MeCN; 40 mL / min; 0-3 min, 20% B; 3-3.5 min, 20%-50% B; 3.5-15 min, 50%-70% B; detector, UV 254 nm. This reaction yielded compound G-19, a yellow solid product, 7-(benzo[d][1,3]dihydroxy-5-yl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (10.2 mg, 0.022 mmol, 20.87%). 1 H NMR(500MHz,DMSO-d6)δppm 10.14(s,1H),9.88(s,1H),7.99(d,J=1.1Hz,1H),7.68-7.73(m,1H),7.49-7.54(m,1H),7.31(d,J=8.5 Hz, 1H), 7.22 (d, J = 8.5Hz, 1H), 7.07 (t, J = 1.1Hz, 1H), 6.20 (s, 1H), 3.84 (s, 1H), 2.15 (d, J = 0.8Hz, 1H). ESI-MS m / z=459.2[M+H] + ;Calcu.=458.1.

[0329] Example 20: Synthesis of Compound G-20

[0330] Step A: At room temperature, (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (87.62 mg, 0.107 mmol) was added to 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (40 mg, 0.107 mmol), (4-methoxyphenyl)boronic acid (17.93 mg, 0.118 mmol), and potassium carbonate (14.83 mg, 0.107 mmol) dissolved in 1,4-dioxane (3 mL) and water (0.6 mL). After the addition was complete, the mixture was stirred at 100°C under nitrogen for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain a residue. The residue was subjected to HPLC preparative separation using the following preparation conditions: Waters XBridge Prep C 18 (30 mm × 250 mm, 5 μm); A: 0.1% formic acid in water; B: MeCN; 40 mL / min; 0-3 min, 20% B; 3-3.5 min, 20%-50% B; 3.5-15 min, 50%-70% B; detector, UV 254 nm. This reaction yielded compound G-20, a yellow solid product, N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-7-(4-methoxyphenyl)thiazolo[4,5-d]pyrimidin-5-amine (10.24 mg, 0.023 mmol, 21.47%). 1 H NMR(500MHz,DMSO-d6)δppm 10.13(s,1H),9.88(s,1H),8.18(d,J=8.9Hz,2H),7.69(d,J=1.1Hz,1H),7.46-7.60 (m,3H),7.23(d,J=8.9Hz,2H),7.07(s,1H),3.89(s,3H),3.84(s,3H),2.15(s,3H). ESI-MS m / z=445.0[M+H] + ;Calcu.=444.1.

[0331] Example 21: Synthesis of Compound G-21

[0332] Step A: At room temperature, (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (87.62 mg, 0.107 mmol) was added to 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (40 mg, 0.107 mmol), (2,4-difluorophenyl)boronic acid (20.28 mg, 0.128 mmol), and potassium carbonate (14.83 mg, 0.107 mmol) dissolved in 1,4-dioxane (3 mL) and water (0.6 mL). After the addition was complete, the mixture was stirred at 100°C under nitrogen for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain a residue. The residue was subjected to HPLC preparative separation using the following preparation conditions: Waters XBridge Prep C 18 (30 mm × 250 mm, 5 μm); A: 0.1% formic acid in water; B: MeCN; 40 mL / min; 0-3 min, 20% B; 3-3.5 min, 20%-50% B; 3.5-15 min, 50%-70% B; detector, UV 254 nm. This reaction yielded compound G-21, a yellow solid product, 7-(2,4-difluorophenyl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (20.06 mg, 0.045 mmol, 41.51%). 1 H NMR(500MHz,DMSO-d6)δppm 10.28(s,1H),9.88(s,1H),7.96(d,J=1.7Hz,1H),7.69(d,J=1.4Hz,1H),7.46-7.59(m,3H),7.3 6-7.42(m,1H),7.30(d,J=8.5Hz,1H),7.06(t,J=1.1Hz,1H),3.81(s,3H),2.15(d,J=0.8Hz,3H). ESI-MS m / z=451.2[M+H] + ;Calcu.=450.1.

[0333] Example 22: Synthesis of Compound G-22

[0334] Step A: At room temperature, (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (87.62 mg, 0.107 mmol) was added to 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (40 mg, 0.107 mmol), (2-fluoro-4-methoxyphenyl)boronic acid (18.23 mg, 0.107 mmol), and potassium carbonate (14.83 mg, 0.107 mmol) dissolved in 1,4-dioxane (3 mL) and water (0.6 mL). After the addition was complete, the mixture was stirred at 100°C under nitrogen for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain a residue. The residue was subjected to HPLC preparative separation using Waters XBridge Prep C 18 (30 mm × 250 mm, 5 μm); A: 0.1% formic acid in water; B: MeCN; 40 mL / min; 0-3 min, 20% B; 3-3.5 min, 20%-50% B; 3.5-15 min, 50%-70% B; detector, UV 254 nm, lyophilized. This reaction yielded compound G-22, a yellow solid product, 7-(2-fluoro-4-methoxyphenyl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (5.28 mg, 0.011 mmol, 10.64%). 1 H NMR (500MHz, DMSO-d6) δppm 10.21(s,1H),9.85(s,1H),7.99(d,J=1.4Hz,1H),7.87(t,J=8.8Hz,1H),7.68(d,J=1.2Hz,1H),7.50(dt,J=6.7and 3.4Hz,1H),7.29(d,J=8.5Hz,1H),7.13(dd,J=13.0and 2.3Hz,1H),7.03-7.07(m,2H),3.89(s,3H),3.81(s,3H),2.15(d,J=0.6Hz,3H). ESI-MS m / z=463.0[M+H] + ;Calcu.=462.1。

[0335] Example 23: Synthesis of Compound G-23

[0336] Step A: At room temperature and nitrogen environment, palladium acetate (9 mg, 0.040 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (28 mg, 0.048 mmol) and cesium carbonate (96 mg, 0.295 mmol) were added to 1,4-dioxane (5 mL) in which 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (60 mg, 0.161 mmol) and 4-chloroaniline (42 mg, 0.329 mmol) were dissolved. The whole mixture was stirred at 80 ° C for 2 hours. The reaction solution was filtered through celite, and the filtrate was collected and concentrated under reduced pressure to obtain a residue, which was subjected to HPLC preparative separation. Preparation conditions: Waters XBridge C18 (30 mm × 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 40 mL / min; 0-3 min, 20% B; 3-15 min, 20%-85% B; detector, UV 254 nm. The reaction yielded compound G-23, a white solid product N 7 -(4-chlorophenyl)-N 5 -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidine-5,7-diamine (2.59 mg, 0.005 mmol, 3.30%). 1 H NMR (500MHz, DMSO-d6) δppm 9.90 (br s, 1H), 9.55 (br s, 2H), 7.86 (br d, 2H, J = 4.4Hz), 7.70 (s, 1H), 7.66 (d, 1H, J = 1.1Hz), 7.59 (br d,1H,J=8.7Hz),7.41(br d,2H,J=8.4Hz),7.23(d,1H,J=8.4Hz),7.04(s,1H),3.70(s,3H),2.15(s,3H). ESI-MS m / z=464.2[M+H] + ;Calcu.=463.1.

[0337] Example 24: Synthesis of Compound G-24

[0338] Step A: Palladium acetate (13 mg, 0.058 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (66 mg, 0.114 mmol), cesium carbonate (249 mg, 0.764 mmol) and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (116 mg, 0.571 mmol) were added to 1,4-dioxane (10 mL) in which 7-chloro-5-phenylthiazolo[4,5-d]pyrimidine (100 mg, 0.404 mmol) was dissolved at room temperature under nitrogen atmosphere, and the whole mixture was stirred at 80 ° C for 2 hours. The reaction mixture was filtered through Celite, and the filtrate was collected and concentrated under reduced pressure to obtain a residue, which was then subjected to preparative HPLC separation using the following conditions: Waters XBridge C18 (30 mm × 250 mm, 5 μm); A: 0.1% formic acid in water; B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-15 min, 10%-80% B; detector, UV 254 nm. This reaction yielded compound G-24, N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-phenylthiazolo[4,5-d]pyrimidin-7-amine (14.82 mg, 0.035 mmol, 8.65%) as a white solid. 1 H NMR(500MHz,DMSO-d6)δppm 10.23(s,1H),9.78(s,1H),8.4-8.5(m,2H),8.1-8.3(m,1H),7.96(d,1H,J=2.0Hz),7.77(d,1H,J=1. 2Hz),7.6-7.6(m,1H),7.5-7.6(m,2H),7.43(d,1H,J=8.5Hz),7.14(s,1H),3.90(s,3H),2.17(s,3H). ESI-MS m / z=415.2[M+H] + ;Calcu.=414.1.

[0339] Example 25: Synthesis of Compound G-25

[0340] Step A: To a solution of 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (80 mg, 0.214 mmol) and benzo[d]oxazol-6-amine (57 mg, 0.425 mmol) in 1,4-dioxane (16 mL) was added palladium acetate (10 mg, 0.044 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (50 mg, 0.087 mmol), and cesium carbonate (140 mg, 0.429 mmol) at room temperature under nitrogen. After the addition was complete, the mixture was heated to 80°C and stirred under nitrogen for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a brown solid crude residue, which was then subjected to HPLC preparative separation under the following conditions: Welch Xtimate C18 (30 mm × 250 mm, 5 μm); A: 0.05% aqueous ammonia, B: MeCN; 40 mL / min; 0-3 min, 20% B; 3-3.5 min, 20%-50% B; 3.5-15 min, 50%-65% B; 15-15.5 min, 65%-100% B; detector, UV 254 nm. Compound G-25 was obtained as a pale yellow solid product N. 7 -(Benzo[d]oxazol-6-ylamino)-N 5 -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidine-5,7-diamine (26.10 mg, 0.055 mmol, 25.85%). 1 H NMR (500MHz, DMSO-d6) δppm 10.02 (s, 1H) 9.65 (s, 1H) 9.58 (s, 1H) 8.72 (s, 1H) 8.59 (br s, 1H) 7.78 (d, J=8.5Hz, 1H) 7.71 (br s,1H)7.66-7.70(m,2H)7.61(d,J=8.2Hz,1H)7.23(d,J=8.5Hz,1H)7.04(s,1H)3.69(s,3H)2.15(s,3H). ESI-MS m / z=471.3[M+H] + ;Calcu.=470.1.

[0341] Example 26: Synthesis of Compound G-26

[0342] Step A: To a solution of 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (80 mg, 0.215 mmol) and 7-aminobenzo[d]oxazol-2(3H)-one (64 mg, 0.429 mmol) in methanol (4 mL) at room temperature was added trifluoroacetic acid (0.033 mL, 0.429 mmol). After the addition was complete, the mixture was heated to 80°C and stirred overnight. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative HPLC using the following conditions: Welch Xtimate C18 (30 mm × 250 mm, 5 μm); A: 0.1% formic acid in water, B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-20% B; 3.5-15 min, 20%-60% B; detector, UV 254 nm). The product was then lyophilized under reduced pressure to afford compound G-26, 7-((5-((3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)amino)thiazolo[4,5-d]pyrimidin-7-yl)amino)benzo[d]oxazol-2(3H)-one (9.91 mg, 0.020 mmol, 8.61%) as a white solid. 1 H NMR (500MHz, DMSO-d6) δppm 9.98 (s, 1H) 9.55 (s, 1H) 9.50 (s, 1H) 7.62 (d, J = 1.1Hz, 1H) 7.54 (br s, 1H) 7.40 (br s,1H)7.18(d,J=4.6Hz,2H)6.99-7.05(m,3H)3.61(s,3H)2.14(s,4H). ESI-MS m / z=487.0[M+H] + ;Calcu.MW=486.1.

[0343] Example 27: Synthesis of Compound G-27

[0344] Step A: To a solution of 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (100 mg, 0.268 mmol), (4-fluorophenyl)boronic acid (75 mg, 0.536 mmol), and cesium carbonate (174 mg, 0.536 mmol) in 1,4-dioxane (4.8 mL) and water (0.8 mL) was added (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (19.63 mg, 0.027 mmol) at room temperature. After the addition was complete, the mixture was evacuated with argon three times, heated to 100°C, and stirred under argon for 3 hours. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative HPLC using the following conditions: Welch Xtimate C18 (30 mm × 250 mm, 5 μm); A: 0.1% formic acid in water, B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-15% B; 3.5-15 min, 15%-60% B; UV detector, 254 nm. Freeze-dried under reduced pressure to afford compound G-27, 7-(4-fluorophenyl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (14.32 mg, 0.033 mmol, 10.27%) as a white solid. 1 H NMR(500MHz,DMSO-d6)δppm10.22(s,1H)9.91(s,1H)8.21-8.26(m,2H)7.99(d,J=1.8Hz,1H)7.69(d ,J=1.4Hz,1H)7.51-7.56(m,3H)7.31(d,J=8.5Hz,1H)7.07(s,1H)3.84(s,3H)2.15(d,J=0.6Hz,3H). ESI-MS m / z=432.9[M+H] + ;Calcu.MW=432.1.

[0345] Example 28: Synthesis of Compound G-28

[0346] Step A: To a solution of 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (100 mg, 0.268 mmol), (4-chlorophenyl)boronic acid (84 mg, 0.536 mmol), and potassium carbonate (74 mg, 0.536 mmol) in 1,4-dioxane (4.8 mL) and water (0.8 mL) was added tetrakistriphenylphosphine palladium (31.00 mg, 0.027 mmol) at room temperature. After the addition was complete, the mixture was evacuated with argon three times, heated to 100°C, and stirred under argon for 3 hours. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative HPLC using the following conditions: Welch Xtimate C18 (30 mm × 250 mm, 5 μm); A: 0.1% formic acid in water, B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-15% B; 3.5-15 min, 15%-60% B; detector, UV 254 nm. Freeze-dried under reduced pressure to afford compound G-28, 7-(4-chlorophenyl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (16.56 mg, 0.037 mmol, 13.01%) as a white solid. 1 H NMR(500MHz,DMSO-d6)δppm 10.22(s,1H)9.91(s,1H)8.21-8.26(m,2H)7.99(d,J=1.8Hz,1H)7.69(d,J=1.4Hz,1H) 7.51-7.56(m,3H)7.31(d,J=8.5Hz,1H)7.07(s,1H)3.84(s,3H)2.15(d,J=0.6Hz,3H). ESI-MS m / z=448.9[M+H] + ;Calcu.MW=448.0.

[0347] Example 29: Synthesis of Compound G-29

[0348] Step A: At room temperature and nitrogen environment, palladium acetate (10 mg, 0.045 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (38 mg, 0.066 mmol) and cesium carbonate (128 mg, 0.393 mmol) were added to 1,4-dioxane (8 mL) in which 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (80 mg, 0.215 mmol) and 2,4-difluoroaniline (55 mg, 0.426 mmol) were dissolved. The whole mixture was stirred at 80 ° C for 2 hours. The reaction solution was filtered through celite, and the filtrate was collected and concentrated under reduced pressure to obtain a residue, which was subjected to HPLC preparative separation. Preparation conditions: Waters XBridge C18 (30 mm × 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-15 min, 10%-70% B; detector, UV 254 nm. The reaction yielded compound G-29, a white solid product N 7 -(2,4-difluorophenyl)-N 5 -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidine-5,7-diamine (13.43 mg, 0.028 mmol, 13.04%). 1 H NMR(500MHz,DMSO-d6)δppm 9.70(s,1H),9.55(s,1H),9.45(s,1H),7.6-7.7(m,3H),7.4-7.5(m,2H),7. 2-7.2(m,1H),7.11(d,1H,J=8.5Hz),7.01(s,1H),3.65(s,3H),2.14(s,3H). ESI-MS m / z=466.2[M+H] + ;Calcu.=465.1.

[0349] Example 30: Synthesis of Compound G-30

[0350] Step A: To a solution of 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (40 mg, 0.107 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole (17.48 mg, 0.107 mmol), and potassium carbonate (14.83 mg, 0.107 mmol) in 1,4-dioxane (3 mL) and water (0.6 mL) was added (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (87.62 mg, 0.107 mmol) at room temperature. After the addition was complete, the mixture was stirred at 100°C under nitrogen for 2 hours. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure to yield a residue. The residue was subjected to HPLC preparative separation, preparation conditions: Waters XBridge Prep C 18 (30 mm × 250 mm, 5 μm); A: 0.1% formic acid in water; B: MeCN; 40 mL / min; 0-3 min, 20% B; 3-3.5 min, 20%-50% B; 3.5-15 min, 50%-70% B; detector, UV 254 nm. This reaction yielded compound G-30, 7-(benzo[d]oxazol-5-yl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (2.58 mg, 0.006 mmol, 5.28%) as a white solid. 1 H NMR (500MHz, DMSO-d6) δppm 10.24(s,1H),9.93(s,1H),8.95(s,1H),8.57(d,J=1.7Hz,1H),8.26(dd,J=8.5and 1.8Hz,1H),8.09(d,J=8.7Hz,1H),8.03(s,1H),7.70(d,J=1.4Hz,1H),7.51-7.5 6(m,1H),7.32(d,J=8.7Hz,1H),7.07(s,1H),3.85(s,3H),2.16(d,J=0.6Hz,3H). ESI-MS m / z=456.2[M+H] + ;Calcu.=455.1.

[0351] Example 31: Synthesis of Compound G-31

[0352] Step A: To a solution of 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (80 mg, 0.214 mmol) and (2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenylboronic acid (46 mg, 0.257 mmol) in 1,4-dioxane (3 mL) was added tetrakistriphenylphosphine palladium (49 mg, 0.042 mmol) and sodium carbonate (68 mg, 0.642 mmol) at room temperature under nitrogen. After the addition was complete, the mixture was heated to 100°C and stirred under nitrogen for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain a brown solid crude residue, which was then subjected to HPLC preparative separation using the following conditions: Welch Xtimate C18 (30 mm × 250 mm, 5 μm); A: 0.05% aqueous ammonia, B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-15% B; 3.5-15 min, 15%-45% B; 15-15.5 min, 45%-100% B; detector, UV 254 nm. Compound G-31, 5-(5-((3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)amino)thiazolo[4,5-d]pyrimidin-7-yl)benzo[d]oxazol-2(3H)-one (3.01 mg, 0.006 mmol, 2.98%), was obtained as a pale yellow solid. 1 H NMR(500MHz,DMSO-d6)δppm 10.05(s,1H)9.82(s,1H)8.06(br s,1H)7.70(d,J=1.1Hz,1H)7.58(d,J=1.8Hz,1H)7.58(d,J=1.8Hz,1H)7.53(d,J=8.4Hz,1H)7.49(dd,J=8.0,1.8Hz,1H)7.21(br s,1H)7.07(s,1H)7.01(d,J=8.0Hz,1H)3.85(s,3H)2.16(s,3H). ESI-MS m / z=472.2[M+H] + ;Calcu.=471.1.

[0353] Example 32: Synthesis of Compound G-32

[0354] Step A: To a solution of 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (80 mg, 0.214 mmol) and benzo[d]oxazol-4-amine (57 mg, 0.425 mmol) in 1,4-dioxane (16 mL) was added palladium acetate (10 mg, 0.044 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (50 mg, 0.087 mmol), and cesium carbonate (140 mg, 0.429 mmol) at room temperature under nitrogen. After the addition was complete, the mixture was heated to 80°C and stirred under nitrogen for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a brown solid crude residue, which was then subjected to HPLC preparative separation under the following conditions: Welch Xtimate C18 (30 mm × 250 mm, 5 μm); A: 0.05% aqueous ammonia, B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-30% B; 3.5-15 min, 10%-30% B; 15-15.5 min, 65%-100% B; detector, UV 254 nm. Compound G-32 was obtained, a white solid product N 7 -(Benzo[d]oxazol-4-ylamino)-N 5 -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidine-5,7-diamine (21.09 mg, 0.045 mmol, 20.90%). 1 H NMR(500MHz,DMSO-d6)δppm 10.13(br s,1H)9.54(s,1H)9.47(br s,1H)8.72(s,1H)7.66-7.71(m,2H)7.62(d,J=1.3Hz,1H)7.59(s,1H)7.50(t,J=8.1H z,1H)7.42(d,J=8.7Hz,1H)7.06(d,J=8.4Hz,1H)7.00(s,1H)3.59(s,3H)2.14(s,3H). ESI-MS m / z=471.3[M+H] + ;Calcu.=470.1.

[0355] Example 33: Synthesis of Compound G-33

[0356] Step A: To a solution of 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (80 mg, 0.215 mmol) and 6-aminobenzo[d]oxazol-2(3H)-one (64 mg, 0.429 mmol) in methanol (2 mL) at room temperature was added trifluoroacetic acid (0.049 mL, 0.644 mmol). After the addition was complete, the mixture was heated to 80°C and stirred overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative HPLC using the following conditions: Waters XSelect CSHPrep C18 (30 mm × 250 mm, 5 μm); A: 0.1% formic acid in water, B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-15% B; 3.5-15 min, 15%-30% B; detector: UV 254 nm. The product was then lyophilized under reduced pressure to afford compound G-33 as a yellow solid, 6-((5-((3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)amino)thiazolo[4,5-d]pyrimidin-7-yl)amino)benzo[d]oxazol-2(3H)-one (4.68 mg, 0.010 mmol, 4.44%). 1 H NMR(500MHz,DMSO-d6)δppm11.63(s,1H)9.86(s,1H)9.66(s,1H)9.55(s,1H)8.73-8.82(m,1H)8.00(br s,1H)7.78(s,1H)7.64(br d,J=7.9Hz,1H)7.48(s,1H)7.35-7.41(m,2H)7.11(d,J=8.4Hz,1H)3.73(s,3H)2.29(d,J=0.6Hz,3H). ESI-MS m / z=487.0[M+H] + ;Calcu.MW=486.1.

[0357] Example 34: Synthesis of Compounds G-34 and M-6

[0358] Step A: At 0-5°C under argon, slowly add oxalyl chloride (6235 mg, 49.132 mmol) dropwise to a solution of benzoic acid (5000 mg, 40.943 mmol) and N,N-dimethylformamide (0.16 mL, 2.047 mmol) in dichloromethane (50 mL). After completion of the addition, stir the mixture at 0-5°C for 2 hours. The reaction mixture was used directly in the next step without further treatment. The amount of material added in the next step was calculated based on the theoretical amount. This reaction yielded the crude compound benzoyl chloride (5755 mg, 40.943 mmol, crude).

[0359] Step B: Benzoyl chloride (49.931 mL, 40.943 mmol) in dichloromethane was slowly added dropwise to ethyl 4-aminothiazole-5-carboxylate (7050.44 mg, 40.943 mmol) and 4-dimethylaminopyridine (250.10 mg, 2.047 mmol) dissolved in pyridine (80 mL, 989.128 mmol) at 0-5°C under argon. After completion, the mixture was stirred at 25°C under argon for 16 hours. The reaction mixture was concentrated under reduced pressure to remove most of the pyridine. Water (50 mL) was then added and the mixture was extracted twice with dichloromethane (50 mL x 2). The organic phases were combined, washed once with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a solid residue. The residue was separated on a silica gel column (SiO2, DCM:MeOH = 91:9). The reaction afforded ethyl 4-benzamidothiazole-5-carboxylate (6787 mg, 24.563 mmol, 59.99% yield) as a pale yellow oil. 1 H NMR (500MHz, DMSO-d6) δppm 10.85 (s, 1H) 9.27 (s, 1H) 7.98 (m, 2H) 7.62 (m, 1H) 7.56 (m, 2H) 4.22 (m, 2H) 1.18 (t, J = 7.1Hz, 3H).

[0360] Step C: To ethyl 4-benzamidothiazole-5-carboxylate (3000 mg, 10.857 mmol) was added methanolic ammonia (7N in MeOH, 5 mL) at 25°C, and the mixture was stirred at 100°C for 5 hours. The reaction solution was concentrated under reduced pressure to obtain a solid residue. The residue was separated on a silica gel column (SiO2, DCM:MeOH = 91:9). The reaction afforded 5-phenylthiazolo[4,5-d]pyrimidin-7-ol (1500 mg, 6.543 mmol, 60.26%) as a pale yellow solid. ESI-MS m / z = 230.1 [M+H] + ;Calcu.=229.0.

[0361] Step D: At 25°C, N,N-diisopropylethylamine (2537 mg, 19.628 mmol) was added to a solution of 5-phenylthiazolo[4,5-d]pyrimidin-7-ol (1500 mg, 6.543 mmol) in phosphorus oxychloride (10 mL, 6.543 mmol). The mixture was then stirred at 80°C for 6 hours. The reaction mixture was cooled to room temperature and then slowly added dropwise to ice water (30 mL). After the addition was complete, the pH was adjusted to 9-10 with 4N aqueous sodium hydroxide at 0-5°C. The mixture was then extracted twice with ethyl acetate (50 mL x 2). The organic phases were combined, washed once with saturated aqueous sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product as a pale yellow oil. The reaction yielded M-6, a pale yellow oily crude product, 7-chloro-5-phenylthiazolo[4,5-d]pyrimidine (1200 mg, 4.845 mmol, crude product). ESI-MS m / z = 248.0 [M+H] + ;Calcu.=247.0.

[0362] Step E: To a solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzonitrile (1000 mg, 4.690 mmol) in methanol (10 mL) was added potassium hydroxide (1315.65 mg, 23.448 mmol) and water (2 mL) at 25°C. The mixture was then stirred at 70°C for 4 hours. The reaction mixture was cooled to room temperature, and water (20 mL) was added. The mixture was extracted twice with ethyl acetate (30 mL x 2). The combined organic phases were washed once with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzamide as a crude white solid (464 mg, 2.006 mmol). The crude product was used directly in the next reaction.

[0363] Step F: To 7-chloro-5-phenylthiazolo[4,5-d]pyrimidine (100 mg, 0.404 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzamide (100 mg, 0.432 mmol), and cesium carbonate (263 mg, 0.807 mmol) dissolved in 1,4-dioxane (5 mL) at 25°C was added 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (28.03 mg, 0.048 mmol) and tris(dibenzylideneacetone)dipalladium (14.79 mg, 0.016 mmol). The mixture was stirred at 120°C for 4 hours. The reaction mixture was filtered through celite, and the filtrate was collected and concentrated under reduced pressure to obtain a solid residue. The solid residue was subjected to preparative HPLC separation using the following conditions: Waters XBridge Prep Shield RP18 (19 mm × 250 mm, 5 μm); A: 0.05% aqueous ammonia; B: MeCN; 18 mL / min; 0-3 min, 10% B; 3-18 min, 10%-75% B; detector: UV 254 nm. This reaction yielded compound G-34, a pale yellow solid product: 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)-N-(5-phenylthiazolo[4,5-d]pyrimidin-7-yl)benzamide (38.28 mg, 0.086 mmol, 21.24%). 1 H NMR(500MHz,DMSO-d6)δppm 9.81(s,1H)8.54(m,2H)7.94(dd,J=11.4,1.3Hz,2H)7.84(dd,J=8.2,1.8Hz,1H)7.57(m,4H)7.27(s,1H)3.98(s,3H)2.18(s,3H). ESI-MS m / z=443.2[M+H] + ;Calcu.=442.1.

[0364] Example 35: Synthesis of Compound G-35

[0365] Step A: At room temperature and nitrogen environment, palladium acetate (13 mg, 0.058 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (38 mg, 0.066 mmol) and cesium carbonate (128 mg, 0.393 mmol) were added to 1,4-dioxane (8 mL) in which 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (80 mg, 0.215 mmol) and 2-fluoro-4-methoxyaniline (61 mg, 0.432 mmol) were dissolved. The whole mixture was stirred at 80 ° C for 2 hours. The reaction solution was filtered through celite, and the filtrate was collected and concentrated under reduced pressure to obtain a residue, which was subjected to HPLC preparative separation. Preparation conditions: Waters XBridge C18 (30 mm × 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-15 min, 10%-60% B; detector, UV 254 nm. The reaction yielded compound G-35, a yellow solid product N 7 -(2-Fluoro-4-methoxyphenyl)-N 5 -(3-methoxy-4-(4-methylimidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidine-5,7-diamine (21.54 mg, 0.042 mmol, 19.58%). 1 H NMR (500MHz, DMSO-d6) δppm 9.51 (s, 1H), 9.50 (s, 1H), 9.43 (s, 1H), 7.65 (br s, 1H), 7.63 (d, 1H, J = 1.1Hz), 7.4-7.5 (m, 2H), 7.11 (br d,1H,J=8.5Hz),7.0-7.0(m,2H),6.87(dd,1H,J=2.4,8.8Hz),3.82(s,3H),3.65(br s,3H),2.14(s,3H). ESI-MS m / z=478.3[M+H] + ;Calcu.=477.1.

[0366] Example 36: Synthesis of Compound G-36

[0367] Step A: To a solution of 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (80 mg, 0.214 mmol) and benzo[d]oxazol-5-amine (57 mg, 0.425 mmol) in 1,4-dioxane (16 mL) was added palladium acetate (10 mg, 0.044 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (50 mg, 0.087 mmol), and cesium carbonate (140 mg, 0.429 mmol) at room temperature under nitrogen. After the addition was complete, the mixture was heated to 80°C and stirred under nitrogen for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a brown solid crude residue, which was then subjected to HPLC preparative separation under the following conditions: Welch Xtimate C18 (30 mm × 250 mm, 5 μm); A: 0.05% aqueous ammonia, B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-30% B; 3.5-15 min, 30%-65% B; 15-15.5 min, 65%-100% B; detector, UV 254 nm. Compound G-36 was obtained, a white solid product N 7 -(Benzo[d]oxazol-5-ylamino)-N 5 -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5,7-amine (1.07 mg, 0.002 mmol, 1.06%). 1 H NMR(500MHz, DMSO-d6)δppm9.91(s,1H)9.58(s,1H)9.56(s,1H)8.77(s,1H)8.33(s,1H)7.79(d,J=8.8Hz,1H)7.73(dd,J=9.1 ,1.8Hz,1H)7.68(s,1H)7.65(d,J=1.1Hz,1H)7.59(d,J=9.1Hz,1H)7.19(d,J=8.8Hz,1H)7.03(s,1H)3.64(s,3H)2.15(s,3H). ESI-MS m / z=471.3[M+H] + ;Calcu.=470.1.

[0368] Example 37: Synthesis of Compound G-37

[0369] Step A: To a solution of 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (80 mg, 0.215 mmol) and 5-aminobenzo[d]oxazol-2(3H)-one (64 mg, 0.429 mmol) in methanol (2 mL) at room temperature was added trifluoroacetic acid (0.049 mL, 0.644 mmol). After the addition was complete, the mixture was heated to 80°C and stirred overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative HPLC under the following conditions: Waters XSelect C18 (30 mm × 250 mm, 5 μm); A: 0.1% formic acid in water, B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-20% B; 3.5-15 min, 20%-50% B, detector, UV 254 nm). The product was then lyophilized under reduced pressure to afford compound G-37, 5-((5-((3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)amino)thiazolo[4,5-d]pyrimidin-7-yl)amino)benzo[d]oxazol-2(3H)-one (6.28 mg, 0.013 mmol, 5.50%) as a white solid. 1 H NMR(500MHz,DMSO-d6)δppm 9.78(s,1H)9.51-9.56(m,2H)7.69(s,1H)7.65(d,J=1.2Hz,1H)7.58(s,1H)7.40-7.45(m,2 H)7.29(d,J=8.5Hz,1H)7.20(d,J=8.7Hz,1H)7.03(s,1H)3.66(s,3H)2.15(d,J=0.6Hz,3H). ESI-MS m / z=487.0[M+H] + ;Calcu.MW=486.1.

[0370] Example 38: Synthesis of Compound G-38

[0371] Step A: To a solution of 5,7-dichlorothiazolo[4,5-d]pyrimidine (60 mg, 0.291 mmol) in N,N-dimethylformamide (2.5 mL) was added a solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (60 mg, 0.295 mmol) and N,N-diisopropylethylamine (114 mg, 0.882 mmol) in N,N-dimethylformamide (2.5 mL) at room temperature under nitrogen. The mixture was then stirred at 100°C for 3 hours. The reaction mixture was directly used in the next step. ESI-MS m / z = 373.1 [M+H]+ ;Calcu.=372.1.

[0372] Step B: Aniline (0.045 mL, 0.494 mmol), palladium acetate (12 mg, 0.053 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (46 mg, 0.079 mmol), and cesium carbonate (106 mg, 0.325 mmol) were added to the reaction mixture at room temperature under nitrogen. The mixture was then stirred at 80°C for 2 hours. The reaction mixture was filtered through celite, and the filtrate was collected and concentrated under reduced pressure to obtain a residue, which was then subjected to HPLC preparative separation. Preparation conditions: Waters XBridge C18 (19 mm × 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 18 mL / min 0-3 min, 10% B; 3-18 min, 10%-60% B; detector, UV 254 nm. This reaction yielded compound G-38, a white solid product N 7 -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N 5 -phenylthiazolo[4,5-d]pyrimidine-5,7-diamine (0.61 mg, 0.001 mmol, 0.78%). 1 H NMR(500MHz,DMSO-d6)δppm 9.88(s,1H),9.57(s,1H),9.40(s,1H),7.79(d,2H,J=7.5Hz),7.73(d,1H,J=1.1Hz),7.6-7.7(m,1H),7.57(s,1H ), 7.31 (d, 1H, J = 8.5Hz), 7.26 (t, J = 7.9Hz, 2H), 7.10 (s, 1H), 6.9-7.0 (m, 1H), 3.77 (s, 3H), 2.17 (d, 3H, J = 0.8Hz). ESI-MS m / z=430.3[M+H] + ;Calcu.=429.1.

[0373] Example 39: Synthesis of Compounds G-39 and M-7

[0374] Step A: Aniline (0.088 mL, 0.971 mmol) was added to a solution of 5,7-dichlorothiazolo[4,5-d]pyrimidine (200 mg, 0.971 mmol) and potassium carbonate (268 mg, 1.941 mmol) in N,N-dimethylformamide (5 mL) at 0-5°C. The mixture was then stirred at 0-5°C for 2 hours. The reaction mixture was added to water (10 mL) and extracted twice with ethyl acetate (30 mL x 2). The combined organic phases were washed once with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield a solid residue. The solid residue was separated on a silica gel column (SiO2, PE:EA = 65:35). This reaction yielded M-7, 5-chloro-N-phenylthiazolo[4,5-d]pyrimidin-7-amine (60 mg, 0.228 mmol, 23.53%) as a yellow solid.

[0375] Step B: To a solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzonitrile (1000 mg, 4.690 mmol) in methanol (10 mL) was added potassium hydroxide (1315.65 mg, 23.448 mmol) and water (2 mL) at 25°C. The mixture was then stirred at 70°C for 4 hours. The reaction mixture was cooled to room temperature, and water (20 mL) was added. The mixture was extracted twice with ethyl acetate (30 mL x 2). The combined organic phases were washed once with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzamide as a crude white solid (464 mg, 2.006 mmol). The crude product was used directly in the next reaction.

[0376] Step C: To a dry reaction tube at room temperature, add 5-chloro-N-phenylthiazolo[4,5-d]pyrimidin-7-amine (65 mg, 0.25 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzamide (69 mg, 0.3 mmol), palladium acetate (5 mg, 0.025 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (14 mg, 0.025 mmol), potassium carbonate (69 mg, 0.5 mmol), and 1,4-dioxane (2.0 mL). After addition, place the reaction tube in an oil bath at 100°C and stir for 6 hours. The reaction solution was then filtered through celite, and the filtrate was collected and directly subjected to HPLC preparative separation using the following preparative conditions: Welch Xtimate C18 (30 mm × 250 mm, 5 μm); A: 0.05% aqueous ammonia; B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-30% B; 3.5-15 min, 30%-50% B; 15-18 min, 50%-100% B; detector: UV 254 nm. This reaction yielded compound G-39, 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)-N-(7-(phenylamino)thiazolo[4,5-d]pyrimidin-5-yl)benzamide (3.32 mg, 0.007 mmol, 2.85%) as a white solid. 1 H NMR(500MHz,DMSO-d6)δppm 9.67(s,1H)8.20-7.90(m,2H)7.89(s,1H)7.84(s,1H)7.70(d,J=8.2Hz,1H)7.53(d,J=8.2Hz,1H)7. 38-7.27(m,3H)7.24(s,1H)7.08(t,J=6.9Hz,1H)7.03-6.90(m,1H)3.96(s,3H)2.17(s,3H).ESI-MS m / z=458.0[M+H] + ;Calcu.=457.1.

[0377] Example 40: Synthesis of Compound G-40

[0378] Step A: To 5,7-dichlorothiazolo[4,5-d]pyrimidine (100 mg, 0.485 mmol) and 4-aminopyridine (46 mg, 0.489 mmol) dissolved in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (94 mg, 0.729 mmol) at room temperature. After the addition was complete, the mixture was heated to 100°C and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to yield a crude yellow solid residue, which was then subjected to HPLC preparative separation using the following conditions: Waters XSelect CSHPrep C18 (30 mm × 250 mm, 5 μm); A: 0.05% aqueous ammonia, B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-10% B; 3.5-15 min, 10%-45% B; 15-15.5 min, 45%-100% B; detector, UV 254 nm. The product, 5-chloro-N-(pyridin-4-yl)thiazolo[4,5-d]pyrimidin-7-amine, was obtained as a white solid (15 mg, 0.057 mmol, 11.72%). ESI-MS m / z = 263.9 [M+H] + ;Calcu.=263.0.

[0379] Step B: To a solution of 5-chloro-N-(pyridin-4-yl)thiazolo[4,5-d]pyrimidin-7-amine (15 mg, 0.057 mmol) and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (23 mg, 0.113 mmol) in 1,4-dioxane (3 mL) was added palladium acetate (5 mg, 0.022 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (26 mg, 0.045 mmol), and potassium carbonate (15 mg, 0.109 mmol) at room temperature under nitrogen. After the addition was complete, the mixture was heated to 100°C and stirred under nitrogen for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a brown solid crude residue, which was then subjected to HPLC preparative separation under the following conditions: Welch Xtimate C18 (30 mm × 250 mm, 5 μm); A: 0.05% aqueous ammonia, B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-20% B; 3.5-15 min, 20%-60% B; 15-15.5 min, 60%-100% B; detector, UV 254 nm. Compound G-40 was obtained, a white solid product N 5 -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N 7-(pyridin-4-yl)thiazolo[4,5-d]pyrimidine-5,7-diamine (1.51 mg, 0.004 mmol, 6.15%). 1 H NMR(500MHz,DMSO-d6)δppm 10.14(br s,1H)9.74(br s,1H)9.63(s,1H)8.47(dd,J=4.9,1.4Hz,2H)8.00(d,J=5.9Hz,2H)7.72(d,J=1.4Hz,1H)7.69( d,J=1.2Hz,1H)7.66(d,J=7.8Hz,1H)7.30(d,J=8.5Hz,1H)7.07(s,1H)3.77(s,3H)2.16(s,3H). ESI-MS m / z=431.3[M+H] + ;Calcu.=430.1.

[0380] Example 41: Synthesis of Compound G-41

[0381] Step A: To a solution of 5,7-dichlorothiazolo[4,5-d]pyrimidine (100 mg, 0.485 mmol) and 4-aminopyridine (47 mg, 0.489 mmol) in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (94 mg, 0.729 mmol) at room temperature. After complete addition, the mixture was heated to 100°C and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to yield a crude yellow solid residue, which was subjected to preparative HPLC separation using the following conditions: YMC-Actus Triart C18 (21 mm × 250 mm, 5 μm); A: 0.05% aqueous ammonia, B: MeCN; 18 mL / min; 0-3 min, 10% B; 3-15 min, 10%-50% B; 15-20 min, 50%-100% B; detector: UV 254 nm. The product 5-chloro-N-(1-methyl-1H-pyrazol-4-yl)thiazolo[4,5-d]pyrimidin-7-amine (20 mg, 0.075 mmol, 15.49%) was obtained as a white solid. ESI-MS m / z = 266.9 [M+H] + ;Calcu.=266.0.

[0382] Step B: To a solution of 5-chloro-N-(1-methyl-1H-pyrazol-4-yl)thiazolo[4,5-d]pyrimidin-7-amine (20 mg, 0.075 mmol) and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (31 mg, 0.153 mmol) in 1,4-dioxane (3 mL) was added palladium acetate (7 mg, 0.031 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (35 mg, 0.061 mmol), and potassium carbonate (21 mg, 0.152 mmol) at room temperature under nitrogen. After the addition was complete, the mixture was heated to 100°C and stirred under nitrogen for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a brown solid crude residue, which was then subjected to HPLC preparative separation under the following conditions: Waters XBridge Prep C18 (19 mm × 250 mm, 5 μm); A: 0.05% aqueous ammonia, B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-20% B; 3.5-15 min, 20%-70% B; 15-15.5 min, 70%-100% B; detector, UV 254 nm. Compound G-41 was obtained, a white solid product N 5 -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N 7 -(1-methyl-1H-pyrazol-4-yl)thiazolo[4,5-d]pyrimidine-5,7-diamine (1.94 mg, 0.004 mmol, 5.97%). 1 H NMR(500MHz,DMSO-d6)δppm 9.94(br s,1H)9.50(br s,1H)9.49(s,1H)8.24(s,1H)7.71-7.78(m,2H)7.68(d,J=0.9Hz,1H)7.63(d,J= 8.5Hz,1H)7.27(d,J=8.5Hz,1H)7.05(s,1H)3.87(s,3H)3.79(s,3H)2.15(s,3H). ESI-MS m / z=434.3[M+H] + ;Calcu.=433.1.

[0383] Example 42: Synthesis of Compound G-42

[0384] Step A: To a solution of 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (45 mg, 0.121 mmol) and 5-oxazoleethylamine hydrochloride (32 mg, 0.239 mmol) in 1,4-dioxane (6 mL) was added palladium acetate (11 mg, 0.049 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (56 mg, 0.097 mmol), and cesium carbonate (79 mg, 0.242 mmol) at room temperature under nitrogen. After the addition was complete, the mixture was heated to 80°C and stirred under nitrogen for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a brown solid crude residue, which was then subjected to HPLC preparative separation under the following conditions: Welch Xtimate C18 (30 mm × 250 mm, 5 μm); A: 0.05% aqueous ammonia, B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-20% B; 3.5-16 min, 20%-60% B; 16-16.5 min, 60%-100% B; detector, UV 254 nm. Compound G-42 was obtained, a white solid product N 5 -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N 7 -(Oxazol-3-ylmethyl)thiazolo[4,5-d]pyrimidine-5,7-diamine (1.34 mg, 0.003 mmol, 2.56%). 1 H NMR(500MHz,DMSO-d6)δppm 9.49(s,2H)8.55(t,J=5.5Hz,1H)8.32(s,1H)7.80(d,J=2.2Hz,1H)7.66(s,1H)7.52(d,J=8.8Hz ,1H)7.23(d,J=8.8Hz,1H)7.16(s,1H)7.04(s,1H)4.83(d,J=5.5Hz,2H)3.76(s,3H)2.14(s,3H). ESI-MS m / z=435.3[M+H] + ;Calcu.=434.1.

[0385] Example 43: Synthesis of Compound G-43

[0386] Step A: To 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (50 mg, 0.134 mmol) and benzamide (33 mg, 0.272 mmol) dissolved in 1,4-dioxane (4 mL) were added palladium acetate (8 mg, 0.036 mmol), XantPhos (24 mg, 0.041 mmol) and cesium carbonate (80 mg, 0.246 mmol) at room temperature under nitrogen. The whole mixture was stirred at 80°C for 2 hours. The reaction solution was filtered through celite, and the filtrate was collected and concentrated under reduced pressure to obtain a residue, which was subjected to HPLC preparative separation. Preparation conditions: Waters XBridge C18 (21 mm×250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 18 mL / min 0~3 min, 10% B; 3-15 min, 10%-75% B; detector, UV 254 nm. This reaction yielded compound G-43, a white solid product, N-(5-((3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)amino)thiazolo[4,5-d]pyrimidin-7-yl)benzamide (8.26 mg, 0.018 mmol, 13.26%). 1 H NMR(500MHz,DMSO-d6)δppm 11.36(br s,1H),9.82(br s,1H),9.66(br s,1H),8.05-8.09(m,2H),7.81(br s,1H),7.64-7.68(m,3H),7.54-7.59(m,2H),7.25(d,J=8.5Hz,1H),7.05(s,1H),3.84(s,3H),2.15(s,3H). ESI-MS m / z=458.3[M+H] + ;Calcu.=457.1.

[0387] Example 44: Synthesis of Compound G-44

[0388] Step A: To a solution of 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (40 mg, 0.107 mmol) and 3-aminopyridine (20 mg, 0.213 mmol) in 1,4-dioxane (8 mL) was added palladium acetate (10 mg, 0.044 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (50 mg, 0.087 mmol), and potassium carbonate (30 mg, 0.217 mmol) at room temperature under nitrogen. After the addition was complete, the mixture was heated to 80°C and stirred under nitrogen for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a brown solid crude residue, which was then subjected to HPLC preparative separation under the following conditions: Welch Xtimate C18 (30 mm × 250 mm, 5 μm); A: 0.05% aqueous ammonia, B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-20% B; 3.5-19 min, 20%-60% B; 19-19.5 min, 60%-100% B; detector, UV 254 nm. Compound G-44 was obtained, a white solid product N 5 -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N 7 -(pyridin-3-yl)thiazolo[4,5-d]pyrimidine-5,7-diamine (16.68 mg, 0.039 mmol, 36.13%). 1 H NMR(500MHz,DMSO-d6)δppm 9.96(br s,1H),9.63(br s,1H),9.60(s,1H),9.06(d,J=2.0Hz,1H),8.29-8.34(m,2H),7.70(s,1H),7.67(d,J=1.2Hz,1H),7.60(d ,J=8.4Hz,1H),7.42(dd,J=8.1,4.8Hz,1H),7.24(d,J=8.4Hz,1H),7.05(s,1H),3.71(s,3H),2.15(s,3H). ESI-MS m / z=431.3[M+H] + (C 21 H 19 N8OS);Calcu.=430.1.

[0389] Example 45: Synthesis of Compound G-45

[0390] Step A: At room temperature and under nitrogen protection, 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (25 mg, 0.040 mmol), potassium carbonate (28 mg, 0.203 mmol) and palladium acetate (9 mg, 0.040 mmol) were added to 1,4-dioxane (4 mL) in which 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (37 mg, 0.099 mmol) and thiazol-5-amine (20 mg, 0.200 mmol) were dissolved. After the addition was complete, the mixture was heated to 90 ° C and stirred under nitrogen protection for 3 hours. The reaction solution was then subjected to HPLC preparative separation using the following conditions: Waters XBridge Prep C18 (19 mm × 250 mm, 5 μm); A: 0.05% ammonia; B: MeCN; 18 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-35% B; 3.5-15 min, 35%-70% B; detector, UV 254 nm. This reaction yielded compound G-45, a pale yellow solid product N 5 -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N 7 -(thiazol-5-yl)thiazolo[4,5-d]pyrimidine-5,7-diamine (0.41 mg, 0.001 mmol, 1.01%). 1 H NMR(500MHz,DMSO-d6)δppm 9.54(s,1H),8.68(s,1H),7.92(s,1H),7.75(s,1H),7.68-7.69(m,2H),7.27(d,J=8.5Hz,1H),7.20(br s,1H),7.06(s,1H),6.66(br s,1H),3.78(s,3H),2.15(s,3H). ESI-MS m / z=437.0[M+H] + ;Calcu.=436.1.

[0391] Example 46: Synthesis of Compound G-46

[0392] Step A: At 25 ° C, 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (173.35 mg, 0.300 mmol) and tris(dibenzylideneacetone)dipalladium (91.44 mg, 0.100 mmol) were added to 1,4-dioxane (20 mL) in which tert-butyl piperidin-4-ylcarbamate (1000 mg, 4.993 mmol), 4-bromo-2-methoxypyridine (1000 mg, 5.319 mmol) and cesium carbonate (4880.46 mg, 14.979 mmol) were dissolved. Then, the whole mixture was stirred under argon at 90 ° C for 16 hours. The reaction mixture was cooled to room temperature and then filtered through celite. The filtrate was collected and added with water (30 mL). The mixture was extracted twice with ethyl acetate (30 mL x 2). The organic phases were combined, washed once with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a solid residue. The solid residue was separated on a silica gel column (SiO2, PE:EA = 85:15). The reaction yielded a light yellow solid product, tert-butyl (1-(2-methoxypyridin-4-yl)piperidin-4-yl)carbamate (1400 mg, 4.554 mmol, 91.22%). ESI-MS m / z = 308.1 [M+H] + ;Calcu.=307.2.

[0393] Step B: At 25°C, trifluoroacetic acid (0.996 mL, 13.013 mmol) was added to tert-butyl (1-(2-methoxypyridin-4-yl)piperidin-4-yl)carbamate (400 mg, 1.301 mmol) dissolved in toluene (3 mL). The mixture was then stirred at 25°C for 1 hour. The reaction mixture was cooled to 0-5°C and adjusted to pH 12 with 4N aqueous sodium hydroxide solution. Water (20 mL) was then added. The mixture was extracted twice with ethyl acetate (25 mL x 2). The combined organic phases were washed once with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield a pale yellow solid crude product. This reaction yielded a pale yellow crude product, 1-(2-methoxypyridin-4-yl)piperidin-4-amine (253 mg, 1.221 mmol, crude product). ESI-MS m / z = 208.0 [M+H] + ;Calcu.=207.1.

[0394] Step C: To a solution of 5-chloro-N-phenylthiazolo[4,5-d]pyrimidin-7-amine (60 mg, 0.228 mmol) and 1-(2-methoxypyridin-4-yl)piperidin-4-amine (142.02 mg, 0.685 mmol) in isopropanol (5 mL) at 25°C was added N,N-diisopropylethylamine (295.19 mg, 2.284 mmol). The mixture was then stirred in a microwave oven at 180°C for 1.5 hours. The reaction mixture was concentrated under reduced pressure to obtain a solid residue. The solid residue was subjected to preparative HPLC separation using the following preparative conditions: Waters XBridge C18 (30 mm × 250 mm, 5 μm); A: 0.05% ammonia; B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-15 min, 10%-75% B; detector: UV 254 nm. The reaction yielded compound G-46, a pale yellow solid product N 5 -(1-(2-methoxypyridin-4-yl)piperidin-4-yl)-N 7 -phenylthiazolo[4,5-d]pyrimidine-5,7-diamine (5.77 mg, 0.013 mmol, 5.83%). 1 H NMR (500MHz, DMSO-d6) δppm9.43(m,2H),7.85(br d,J=7.9Hz,2H),7.78(d,J=6.1Hz,1H),7.34(br t,J=7.5Hz,2H),7.06(t,J=7.40Hz,1H),6.88(m,1H),6.58(dd,J=6.2,2.2Hz,1H),6.14(d,J=2.1Hz,1H),3.91(br d,J=13.1Hz,2H),3.77(s,3H),2.95(br t,J=11.8Hz,2H),1.96(br d,J=10.8Hz,2H),1.49(br d,J=10.2Hz,2H). ESI-MS m / z=434.3[M+H] + ;Calcu.=433.2.

[0395] Example 47: Synthesis of Compound G-47

[0396] To a solution of 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (60 mg, 0.161 mmol) and 1-phenylethan-1-amine (40 mg, 0.330 mmol) dissolved in 1,4-dioxane (4 mL) were added palladium acetate (9 mg, 0.040 mmol), 1,1'-bis(diphenylphosphino)ferrocene (28 mg, 0.050 mmol), and potassium carbonate (45 mg, 0.326 mmol) at room temperature under nitrogen. The mixture was stirred at 80°C for 1 hour. The reaction solution was filtered through celite, and the filtrate was collected and concentrated under reduced pressure to obtain a residue, which was subjected to preparative HPLC separation under the following conditions: Waters XBridge C18 (19 mm × 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 18 mL / min. 0~3min, 10% B; 3~18min, 10%~70% B; detector, UV 254nm. The reaction yielded compound G-47, a white solid product N 5 -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N 7 -(1-phenylethyl)thiazolo[4,5-d]pyrimidine-5,7-diamine (0.23 mg, 0.418 μmol, 0.26%). 1 H NMR(500MHz,DMSO-d6)δppm 9.47(s,1H),9.35(s,1H),7.61-7.67(m,2H),7.48-7.53(m,1H),7.45(d,J= 7.6Hz,2H),7.34(t,J=7.6Hz,3H),7.18-7.24(m,3H),7.03(s,1H),6.66(br s,1H),5.55-5.60(m,1H),3.75(s,3H),2.15(s,3H),1.57(d,J=7.0Hz,3H). ESI-MS m / z=458.3[M+H] + ;Calcu.=457.2.

[0397] Example 48: Synthesis of Compound G-48

[0398] Step A: 4-Bromo-2-methoxyaniline (5000 mg, 24.746 mmol) was added to concentrated hydrochloric acid (59 mL) at -20°C. The mixture was then stirred at -20°C for 10 minutes. A 2.5 mL aqueous solution of sodium nitrite (1792 mg, 25.984 mmol) was slowly added dropwise to the mixture. After complete addition, the mixture was stirred at -20°C for 15 minutes, then transferred to 0°C and stirred for 20 minutes. The temperature was then further lowered to -20°C, and the above mixture was slowly added dropwise to a solution of tin dichloride (17830 mg, 94.036 mmol) in concentrated hydrochloric acid (59 mL, 708.000 mmol). After complete addition, the mixture was stirred at -20°C for 10 minutes, then brought to room temperature and stirred for 40 minutes. Upon completion of the reaction, the pH was adjusted to approximately 8-9 with 2N aqueous sodium hydroxide solution, and ethyl acetate (100 mL) was added to the reaction solution. Filter through celite, rinse the filter cake twice with ethyl acetate (50 mL x 2), collect the filtrate, and after separation, collect the organic phase. The aqueous phase is further extracted once with ethyl acetate (50 mL). The two organic phases are combined, washed once with saturated sodium chloride solution (100 mL), and dried over anhydrous sodium sulfate. The filtrate is concentrated under reduced pressure to obtain a crude yellow oil. This reaction yields the crude product (4-bromo-2-methoxyphenyl)hydrazine (3700 mg, 17.045 mmol, crude) as a yellow oil.

[0399] Step B: 1-(Methylsulfanyl)ethane-1-imine hydroiodide (1050 mg, 4.837 mmol) was added to (4-bromo-2-methoxyphenyl)hydrazine (1000 mg, 4.607 mmol) dissolved in methanol (8 mL) at 25°C. The mixture was stirred at 25°C for 30 minutes. The mixture was then concentrated under reduced pressure to remove the methanol, yielding a solid residue. Toluene (7 mL), trimethyl orthoformate (3.13 mL, 28.505 mmol), and pyridine (6.25 mL, 77.276 mmol) were then added sequentially at 25°C. After the additions were complete, the mixture was heated to 100°C and stirred at 100°C for 16 hours. The reaction mixture was then concentrated under reduced pressure to yield a solid residue. The solid residue was separated on a silica gel column (SiO2, DCM:MeOH = 91:9). The reaction yielded a pale yellow solid product, 1-(4-bromo-2-methoxyphenyl)-3-methyl-1H-1,2,4-triazole (930 mg, 3.469 mmol, 75.30%). ESI-MS m / z = 267.8 [M+H] + ;Calcu.=267.0.

[0400] Step C: To a solution of 1-(4-bromo-2-methoxyphenyl)-3-methyl-1H-1,2,4-triazole (500 mg, 1.865 mmol) in N-methylpyrrolidone (3 mL) at 25°C, add aqueous ammonia (3 mL, 0.373 mmol) and cuprous oxide (54.12 mg, 0.373 mmol). The mixture is then stirred at 110°C in a sealed tube for 5 hours. The reaction mixture is cooled to room temperature and filtered through celite. The filter cake is rinsed twice with methanol (10 mL x 2). The filtrate is collected and concentrated under reduced pressure to remove most of the methanol, yielding a mixed solution (6 mL) containing the product. The resulting mixed solution is directly used for preparative separation. This reaction yields 3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (274 mg, 1.342 mmol, 71.94%) as a light brown oil. ESI-MS m / z=205.0[M+H] + ;Calcu.=204.1.

[0401] Step D: At room temperature and argon environment, palladium acetate (54.96 mg, 0.245 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (233 mg, 0.490 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred for 2 minutes (the color changed from yellow to brown), followed by the addition of 5,7-dichlorothiazolyl[4,5-d]pyrimidine (276.12 mg, 1.347 mmol), stirred for 2 minutes, and then 3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (250 mg, 1.224 mmol) and potassium carbonate (1692 mg, 12.241 mmol) dissolved in 1,4-dioxane (5 mL) were added dropwise, and the whole mixture was heated to 100 ° C and stirred at 100 ° C under argon environment for 2.5 hours. The reaction mixture was filtered through Celite, and the filtrate was collected and concentrated under reduced pressure to obtain a solid residue. The residue was separated on a silica gel column (SiO2, DCM:MeOH = 90:10). The reaction yielded 7-chloro-N-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (45 mg, 0.120 mmol, 9.83%) as a yellow oil. ESI-MS m / z = 373.9 [M+H] + ;Calcu.=373.1.

[0402] Step E: To 7-chloro-N-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (20 mg, 0.054 mmol) and aniline (0.010 mL, 0.107 mmol) dissolved in 1,4-dioxane (5 mL) was added potassium carbonate (14.93 mg, 0.108 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (9.29 mg, 0.016 mmol), and palladium acetate (1.20 mg, 0.005 mmol) in sequence at room temperature. The mixture was then stirred at 80°C under argon for 2 hours. The reaction mixture was filtered through celite, and the filtrate was collected and concentrated under reduced pressure to obtain a solid residue. The solid residue was subjected to HPLC preparative separation under the following conditions: YMC-Actus Triart C18 (20 mm × 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 18 mL / min; 0-14 min, 30%-100% B; detector: UV 254 nm. The reaction yielded compound G-48, a pale yellow solid product N 5 -(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N 7 Phenylthiazolo[4,5-d]pyrimidine-5,7-diamine (1.39 mg, 0.003 mmol, 5.51%). 1 H NMR(500MHz,DMSO-d6)δppm 9.81(s,1H),9.61(s,1H),9.56(s,1H),8.65(s,1H),7.81(br d,J=8.1Hz,2H),7.76(s,1H),7.62(m,1H),7.40(dd,J=15.1,8.2Hz,3H),7.15(s,1H),3.71(s,3H),2.33(s,3H). ESI-MS m / z=431.0[M+H] + ;Calcu.=430.1.

[0403] Step F: At 0°C, iodomethane (16 mL, 199.654 mmol) was slowly added dropwise to thioacetamide (5000 mg, 66.551 mmol) dissolved in acetone (100 mL). The mixture was then stirred at room temperature for 20 hours. Upon completion of the reaction, the reaction solution was directly concentrated under reduced pressure to obtain a yellow solid. Ethyl acetate (50 mL) was then added and stirred for 20 minutes. The solid was then filtered under reduced pressure. The resulting filter cake was rinsed three times with ethyl acetate (10 mL x 3). The filter cake was collected and concentrated under reduced pressure to obtain a white solid product. This reaction yielded 1-(methylsulfanyl)ethane-1-imine hydroiodide (14000 mg, 64.495 mmol, crude) as a white solid. 1 H NMR (500MHz, DMSO-d6) δppm 11.56 (br s, 2H), 2.68 (s, 3H), 2.58 (s, 3H).

[0404] Example 49: Synthesis of Compound G-49

[0405] Step A: To a solution of 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (80 mg, 0.215 mmol) and benzylamine (0.070 mL, 0.644 mmol) in dioxane (20 mL) was added palladium acetate (10 mg, 0.045 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (50 mg, 0.086 mmol), and potassium carbonate (59 mg, 0.427 mmol) at room temperature under nitrogen. After the addition was complete, the mixture was heated to 80°C and stirred under nitrogen for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a brown solid crude residue. The residue was subjected to HPLC preparative separation under the following conditions: YMC-Actus Triart C18 (20 mm × 250 mm, 5 μm); A: 0.05% aqueous ammonia, B: MeCN; 18 mL / min; 0-3 min, 50% B; 3-18 min, 50%-60% B; 18-19 min, 60%-100% B; detector, UV 254 nm. Compound G-49 was obtained as a pale yellow solid product N 7 -Benzyl-N 5 -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidine-5,7-diamine (3.48 mg, 0.008 mmol, 3.57%). 1H NMR(500MHz,DMSO-d6)δppm9.48(s,1H),9.44(br s,1H),8.57(t,J=5.8Hz,1H),7.78(d,J=1.9Hz,1H),7.63(d,J=1.0Hz,1H),7.45(d,J=8.0Hz,1H),7.39(d,J=7.2Hz,2H),7.34(d d,J=8.0,7.2Hz,2H),7.25(t,J=7.4Hz,1H),7.17(d,J=8.6Hz,1H),7.01(s,1H),4.80(d,J=5.8Hz,2H),3.67(s,3H),2.13(s,3H). ESI-MS m / z=444.3[M+H] + ;Calcu.=443.2.

[0406] Example 50: Synthesis of Compound G-50

[0407] Step A: To a solution of 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (80 mg, 0.215 mmol) and potassium benzyltrifluoroborate (85 mg, 0.429 mmol) in toluene (15 mL) at room temperature under nitrogen was added palladium acetate (19 mg, 0.085 mmol), triphenylphosphine (45 mg, 0.172 mmol), potassium carbonate (89 mg, 0.644 mmol), and water (3 mL). After the addition was complete, the mixture was heated to 100°C and stirred under nitrogen overnight. The reaction mixture was concentrated under reduced pressure to obtain a brown solid crude residue, which was then subjected to HPLC preparative separation using the following conditions: Welch Xtimate C18 (30 mm × 250 mm, 5 μm); A: 0.05% aqueous ammonia, B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-50% B; 3.5-15 min, 50%-80% B; 15-15.5 min, 80%-100% B; detector, UV 254 nm. Compound G-50, 7-benzyl-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (6.09 mg, 0.012 mmol, 5.59%), was obtained as a pale yellow solid. 1H NMR(500MHz,DMSO-d6)δppm 10.11(br s,1H),9.69(s,1H),7.88(d,J=2.2Hz,1H),7.68(d,J=1.2Hz,1H),7.53(dd,J=8.6,1.6Hz,1H),7.33-7.4 0(m,4H),7.28-7.31(m,1H),7.27(d,J=8.6Hz,1H),7.05(s,1H),4.37(s,2H),3.79(s,3H),2.15(s,3H). ESI-MS m / z=429.3[M+H] + ;Calcu.=428.1.

[0408] Example 51: Synthesis of Compound G-51

[0409] Step A: To a solution of 2,4-dichlorofuro[3,2-d]pyrimidine (378 mg, 2.000 mmol) and 4-chlorophenylboronic acid (344 mg, 2.200 mmol) in N,N-dimethylformamide (5 mL) and water (0.5 mL) was added triethylamine (0.56 mL, 4.028 mmol) and bistriphenylphosphine palladium dichloride (140 mg, 0.2 mmol) at room temperature under nitrogen protection. After the addition, the mixture was heated to 80°C and stirred under nitrogen protection for 4 hours. The reaction mixture was cooled to room temperature, and then water (15 mL) was added. The mixture was extracted three times with ethyl acetate (15 mL x 3). The organic phases were combined, washed once with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated on a silica gel column (SiO2, PE:EA = 90:10). The reaction afforded a yellow solid product, 2-chloro-4-(4-chlorophenyl)furo[3,2-d]pyrimidine (170 mg, 0.641 mmol, 32.06%). ESI-MS m / z = 264.8 [M+H] + ;Calcu.=264.0.

[0410] Step B: At room temperature and nitrogen protection, potassium carbonate (55 mg, 0.398 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (35 mg, 0.060 mmol) and palladium acetate (13.5 mg, 0.060 mmol) were added to 1,4-dioxane (4 mL) in which 2-chloro-4-(4-chlorophenyl)furo[3,2-d]pyrimidine (53 mg, 0.200 mmol) and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (49 mg, 0.241 mmol) were dissolved. After the addition was complete, the mixture was heated to 100 ° C and stirred under nitrogen protection for 4 hours. The reaction solution was directly subjected to HPLC preparative separation using the following preparative conditions: Waters XBridge Prep Shield RP18 (19 mm × 250 mm, 5 μm); A: 0.05% aqueous ammonia; B: MeCN; 18 mL / min; 0-3 min, 20% B; 3-3.5 min, 20%-55% B; 3.5-15 min, 55%-95% B; detector, UV 254 nm. This reaction yielded compound G-51, 4-(4-chlorophenyl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)furo[3,2-d]pyrimidin-2-amine (29.34 mg, 0.068 mmol, 33.05%), as a yellow solid. 1 H NMR(500MHz,DMSO-d6)δppm 9.86(s,1H),8.51(d,J=2.3Hz,1H),8.42-8.47(m,2H),7.94(d,J=2.1Hz,1H),7.72-7.80(m,2H),7.67(d,J=1.2Hz,1 H),7.48(dd,J=8.5,2.1Hz,1H),7.27(d,J=8.5Hz,1H),7.12(d,J=2.3Hz,1H),7.05(s,1H),3.84(s,3H),2.15(s,3H). ESI-MS m / z=432.0[M+H] + ;Calcu.=431.1.

[0411] Example 52: Synthesis of Compound G-52

[0412] Step A: To a solution of 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (60 mg, 0.161 mmol) in methanol (2 mL) was added N-methylaniline (0.036 mL, 0.336 mmol) and trifluoroacetic acid (0.036 mL, 0.474 mmol) at room temperature. The mixture was then stirred at 80°C for 4 hours. The reaction solution was concentrated under reduced pressure to obtain a residue, which was subjected to preparative HPLC separation using the following conditions: Waters XBridge C18 (30 mm × 250 mm, 5 μm); A: 0.05% aqueous ammonia; B: MeCN; 18 mL / min; 0-3 min, 10% B; 3-15 min, 10%-80% B; detector, UV 254 nm. This reaction yielded compound G-52, a white solid product N 5 -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N 7 -methyl-N 7 -phenylthiazolo[4,5-d]pyrimidine-5,7-diamine (33.83 mg, 0.069 mmol, 42.73%). 1 H NMR(500MHz,DMSO-d6)δppm 9.62(s,1H),9.24(s,1H),7.92(d,J=2.1Hz,1H),7.67(d,J=1.1Hz,1H),7.53-7.59(m,3H),7 .47-7.53(m,3H),7.25(d,J=8.5Hz,1H),7.05(s,1H),3.82(s,3H),3.62(s,3H),2.15(s,3H). ESI-MS m / z=444.3[M+H] + ;Calcu.=443.2.

[0413] Example 53: Synthesis of Compound G-53

[0414] Step A: To a solution of 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (50 mg, 0.134 mmol) and tetrahydro-2H-pyran-4-amine (45 mg, 0.445 mmol) in isopropanol (6 mL) was added N,N-diisopropylethylamine (165 mg, 1.277 mmol) at room temperature. The mixture was then stirred in a microwave reactor at 180°C for 0.5 h. The reaction solution was concentrated under reduced pressure to obtain a residue, which was subjected to HPLC preparative separation under the following conditions: Waters XBridge C18 (19 mm × 250 mm, 5 μm); A: 0.05% ammonia; B: MeCN; 18 mL / min, 0-3 min, 10% B; 3-15 min, 10%-70% B; detector, UV 254 nm. The reaction yielded compound G-53, a white solid product N 5 -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N 7 -(tetrahydro-2H-pyran-4-yl)thiazolo[4,5-d]pyrimidine-5,7-diamine (27.99 mg, 0.055 mmol, 41.20%). 1 H NMR(500MHz,DMSO-d6)δppm 9.46(s,1H),9.39(s,1H),7.88(d,J=7.5Hz,1H),7.69(s,1H),7.62-7.67(m,2H),7.24(d,J=8.7Hz,1H), 7.04(s,1H),4.29-4.39(m,1H),3.90-3.98(m,2H),3.80(s,3H),3.37-3.45(m,2H),2.15(s,3H),1.93(br dd, J=12.4, 2.4Hz, 2H), 1.61 (qd, J=12.0, 4.3Hz, 2H). ESI-MS m / z=438.3[M+H] + ;Calcu.=437.2.

[0415] Example 54: Synthesis of Compound G-54

[0416] Step A: At -20°C under argon, trimethylsilyl azide (5478 mg, 47.551 mmol) was slowly added dropwise to a solution of 3,4-dihydro-2H-pyran (2.037 mL, 23.776 mmol) and iodosobenzene (6335 mg, 28.531 mmol) in dichloromethane (30 mL). The mixture was then stirred at -20°C for 0.5 hours. The reaction solution was added to water (30 mL) and extracted once with dichloromethane (30 mL). The organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the crude product 4-azido-3,4-dihydro-2H-pyran (2975 mg, 23.775 mmol, crude) as a pale yellow oil.

[0417] Step B: To a solution of 4-azido-3,4-dihydro-2H-pyran (2975 mg, 23.775 mmol) in tetrahydrofuran (50 mL) at 0°C, slowly add lithium aluminum hydride (451 mg, 11.888 mmol) in portions. After complete addition, the mixture is stirred at room temperature for 2 hours. The reaction mixture is cooled to 0°C, and then water, 10% aqueous sodium hydroxide solution, and water are added in a 1:1:3 volume ratio. Stir for 30 minutes, filter through celite, collect the filtrate, and concentrate under reduced pressure to obtain a solid residue. The solid residue is separated on a silica gel column (SiO2, DCM:MeOH = 88:12). This reaction yields 3,4-dihydro-2H-pyran-4-amine (1000 mg, 10.088 mmol, 42.43%) as a yellow oil. 1 H NMR (500MHz, DMSO-d6) δppm 7.89 (m, 2H), 6.64 (d, J = 6.26Hz, 1H), 4.75 (dd, J = 6.0, 3.7Hz, 1H), 4.04 (m, 2H), 3.44 (br s, 1H), 2.06 (m, 1H), 1.87 (m, 1H).

[0418] Step C: To a solution of 3,4-dihydro-2H-pyran-4-amine (50 mg, 0.504 mmol) and 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (30 mg, 0.080 mmol) in isopropanol (3 mL) at room temperature was added N,N-diisopropylethylamine (652 mg, 5.044 mmol). The mixture was then stirred in a microwave at 180°C for 0.5 h. The reaction mixture was then concentrated under reduced pressure to obtain a solid residue. The solid residue was subjected to HPLC preparative separation under the following conditions: Waters XBridge Prep Shield RP18 (19 mm × 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 18 mL / min; 0-3 min, 10% B; 3-15 min, 10%-70% B; detector: UV 254 nm. The reaction yielded compound G-54, a pale yellow solid product N 7 -(3,4-dihydro-2H-pyran-4-yl)-N 5 -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidine-5,7-diamine (2.58 mg, 0.005 mmol, 0.99%). 1 H NMR(500MHz,DMSO-d6)δppm 9.45(s,2H),8.12(d,J=7.2Hz,1H),7.84(s,1H),7.65(s,1H),7.49(m,1H),7.23(d,J=8.7Hz,1H),7.03(s,1H),6.58(dd,J=6.0,1 .1Hz,1H),4.89(m,1H),4.86(m,1H),4.06(m,2H),3.80(s,3H),3.30(m,1H),2.14(s,3H)2.09(td,J=8.7,5.3Hz,1H),1.97(m,1H). ESI-MS m / z=436.0[M+H] + ;Calcu.=435.1.

[0419] Example 55: Synthesis of Compound G-55

[0420] To 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (50 mg, 0.134 mmol) and (1-methyl-1H-pyrazol-4-yl)methanamine (30 mg, 0.270 mmol) dissolved in 1,4-dioxane (4 mL) were added palladium acetate (5 mg, 0.022 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (25 mg, 0.040 mmol) and potassium carbonate (38 mg, 0.275 mmol) at room temperature under nitrogen atmosphere, and the whole mixture was stirred at 80 ° C for 1 hour. The reaction solution was filtered through celite, and the filtrate was collected and concentrated under reduced pressure at low temperature to obtain a residue, which was then subjected to HPLC preparative separation. Preparation conditions: Waters XBridge C18 (19 mm × 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 18 mL / min; 0-3 min, 10% B; 3-15 min, 10%-70% B; detector, UV 254 nm. This reaction yielded compound G-55, a white solid product N 5 -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N 7 -((1-methyl-1H-pyrazol-4-yl)methyl)thiazolo[4,5-d]pyrimidine-5,7-diamine (7.98 mg, 0.017 mmol, 12.62%). 1 H NMR (500MHz, DMSO-d6) δppm 9.46 (s, 1H), 9.45 (s, 1H), 8.34 (t, J = 5.5Hz, 1H), 7.89 (d, J = 2.1Hz, 1H), 7.66 (s, 1H), 7.65 (d, J = 1.2Hz, 1H), 7.50 (br d,J=8.7Hz,1H),7.44(s,1H),7.22(d,J=8.5Hz,1H),7.03(t,J=1.1Hz,1H ), 4.58 (d, J = 5.5Hz, 2H), 3.78 (s, 3H), 3.74 (s, 3H), 2.14 (d, J = 0.8Hz, 3H). ESI-MS m / z=448.3[M+H] + ;Calcu.=447.2.

[0421] Example 56: Synthesis of Compound G-56

[0422] Step A: To a dry reaction tube at room temperature, add 5-chloro-N-phenylthiazolo[4,5-d]pyrimidin-7-amine (53 mg, 0.202 mmol), 5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-amine (82 mg, 0.402 mmol), tris(dibenzylideneacetone)dipalladium (18 mg, 0.020 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (19 mg, 0.040 mmol), potassium carbonate (83 mg, 0.601 mmol), and 1,4-dioxane (2.0 mL) in sequence. After addition, place the reaction tube in an oil bath at 100°C and stir for 3 hours. The reaction solution was then filtered through diatomaceous earth, and the filtrate was collected and directly subjected to HPLC preparative separation. The preparation conditions were: Waters XBridge (19mm×250mm, 5μm); A: 0.05% ammonia water; B: MeCN; 18mL / min; 0-3min, 20% B; 3-3.5min, 20%-45% B, 3.5-15min, 45%-85% B, 15-15.5min, 85%-100% B; detector, UV 254nm. The reaction yielded compound G-56, an orange-white solid product N 5 -(5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl)-N 7 Phenylthiazolo[4,5-d]pyrimidine-5,7-diamine (5.56 mg, 0.013 mmol, 6.44%). 1 H NMR(500MHz,DMSO-d6)δppm 9.87(s,1H),9.73(s,1H),9.58(s,1H),8.51(s,1H),8.24(s,1H),8.09(s,1H),7.79(d,J =7.8Hz,2H),7.46-7.36(m,3H),7.16(t,J=7.4Hz,1H),3.77(s,3H),2.17(s,3H).ESI-MS m / z=431.3[M+H] + ;Calcu.=430.1.

[0423] Example 57: Synthesis of Compound G-57

[0424] Step A: To a solution of 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (80 mg, 0.215 mmol) and 2-aminooxazole (40 mg, 0.476 mmol) in 1,4-dioxane (20 mL) was added palladium acetate (10 mg, 0.045 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (50 mg, 0.086 mmol), and potassium carbonate (59 mg, 0.427 mmol) at room temperature under nitrogen. After the addition was complete, the mixture was heated to 80°C and stirred under nitrogen for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a brown solid crude residue, which was then subjected to HPLC preparative separation under the following conditions: Welch Xtimate C18 (30 mm × 250 mm, 5 μm); A: 0.05% aqueous ammonia, B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-30% B; 3.5-15 min, 30%-48% B; 15-17 min, 48%-100% B; detector, UV 254 nm. Compound G-57 was obtained, a white solid product N 5 -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N 7 -(oxazol-2-yl)thiazolo[4,5-d]pyrimidine-5,7-diamine (54.37 mg, 0.129 mmol, 54.11%). 1 H NMR(500MHz,DMSO-d6)δppm 9.17(s,1H),8.81(br s,1H),8.01(d,J=1.6Hz,1H),7.69(dd,J=8.3,1.6Hz,1H),7.60(d,J=1.2Hz,1H),7.4 2(s,1H),7.09(d,J=8.3Hz,1H),6.99(s,1H),6.83(s,1H),3.75(s,3H),2.14(s,3H). ESI-MS m / z=421.0[M+H] + ;Calcu.=420.1.

[0425] Example 58: Synthesis of Compound G-58

[0426] Step A: To 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (80 mg, 0.215 mmol) and oxazole-2-carboxamine hydrochloride (57 mg, 0.424 mmol) dissolved in 1,4-dioxane (20 mL) at room temperature under nitrogen was added palladium acetate (20 mg, 0.089 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (100 mg, 0.173 mmol), and cesium carbonate (210 mg, 0.645 mmol). After the addition was complete, the mixture was heated to 80°C and stirred under nitrogen for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a brown solid crude residue, which was then subjected to HPLC preparative separation under the following conditions: Waters XBridge Prep C18 (19 mm × 250 mm, 5 μm); A: 0.05% aqueous ammonia, B: MeCN; 18 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-15% B; 3.5-15 min, 15%-55% B; 15-15.5 min, 55%-100% B; detector, UV 254 nm. Compound G-58 was obtained, a white solid product N 5 -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N 7 -(Oxazol-2-ylmethyl)thiazolo[4,5-d]pyrimidine-5,7-diamine (0.80 mg, 0.002 mmol, 0.84%). 1 H NMR(500MHz,DMSO-d6)δppm 9.51(s,1H),9.47(br s,1H),8.69(t,J=5.6Hz,1H),8.07(s,1H),7.74(d,J=1.4Hz,1H),7.65(s,1H),7.44(d,J=8 .6Hz,1H),7.15-7.20(m,2H),7.02(s,1H),4.89(d,J=5.6Hz,2H),3.76(s,3H),2.14(s,3H). ESI-MS m / z=435.3[M+H] + ;Calcu.=434.1.

[0427] Example 59: Synthesis of Compound G-59

[0428] Step A: To a solution of 2,4-dichlorofuro[3,2-d]pyrimidine (378 mg, 2.000 mmol) and 4-chloroaniline (255 mg, 1.999 mmol) in N,N-dimethylformamide (4 mL) at room temperature was added diisopropylethylamine (0.7 mL, 4.019 mmol). After complete addition, the mixture was heated to 100°C and stirred for 6 hours. The mixture was concentrated under reduced pressure, and the resulting residue was separated on a silica gel column (SiO2, PE:EA = 80:20). The reaction afforded 2-chloro-N-(4-chlorophenyl)furo[3,2-d]pyrimidin-4-amine (390 mg, 1.392 mmol, 69.65%) as a yellow solid. ESI-MS m / z = 280.0 [M+H] + ;Calcu.=279.0.

[0429] Step B: At room temperature and nitrogen protection, potassium carbonate (55 mg, 0.398 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (35 mg, 0.060 mmol) and palladium acetate (13.5 mg, 0.060 mmol) were added to 1,4-dioxane (4 mL) in which 2-chloro-N-(4-chlorophenyl)furo[3,2-d]pyrimidin-4-amine (56 mg, 0.200 mmol) and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (49 mg, 0.241 mmol) were dissolved. After the addition was complete, the mixture was heated to 100 ° C and stirred under nitrogen protection for 6 hours. The reaction solution was directly subjected to HPLC preparative separation under the following conditions: Welch Xtimate C18 (30 mm × 250 mm, 5 μm); A: 0.05% ammonia; B: MeCN; 18 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-40% B; 3.5-15 min, 40%-80% B; detector, UV 254 nm. This reaction yielded compound G-59, a white solid product N 4 -(4-chlorophenyl)-N 2 -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)furo[3,2-d]pyrimidine-2,4-diamine (38.82 mg, 0.087 mmol, 43.50%). 1H NMR(500MHz,DMSO-d6)δppm 9.93(s,1H),9.32(s,1H),8.24(d,J=2.1Hz,1H),7.97-8.00(m,2H),7.67(d,J=2.1Hz,1H),7.65(d,J=1.2Hz,1H),7.59(dd, J=8.6,2.1Hz,1H),7.37-7.40(m,2H),7.21(d,J=8.7Hz,1H),7.03(s,1H),6.92(d,J=2.0Hz,1H),3.73(s,3H),2.15(s,3H). ESI-MS m / z=447.3[M+H] + ;Calcu.=446.1.

[0430] Example 60: Synthesis of Compounds G-60 and G-61

[0431] Step A: To a solution of 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (10 mg, 0.027 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (18 mg, 0.090 mmol) in isopropanol (2 mL) was added N,N-diisopropylethylamine (33 mg, 0.255 mmol) at room temperature. The mixture was then stirred in a microwave reactor at 180°C for 0.5 h. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was then subjected to preparative HPLC separation using the following conditions: Waters XBridge C18 (19 mm × 250 mm, 5 μm); A: 0.05% ammonia; B: MeCN; 18 mL / min; 0-3 min, 20% B; 3-15 min, 20%-75% B; detector: UV 254 nm. The reaction afforded compound G-60, a yellow solid product, tert-butyl 4-((5-((3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)amino)thiazolo[4,5-d]pyrimidin-7-yl)amino)piperidine-1-carboxylate (2.56 mg, 0.005 mmol, 17.56%). 1H NMR(500MHz,DMSO-d6)δppm 9.46(s,1H),9.40(s,1H),7.82(d,J=7.5Hz,1H),7.62-7.70(m,3H),7.25(d,J=8.5Hz,1H),7.04(s,1H),4.24-4.35(m,1H),4.00(br dd,J=7.3,1.8Hz,2H),3.80(s,3H),2.74-2.98(m,2H),2.15(s,3H),1.96(br d,J=10.5Hz,2H),1.43-1.49(m,2H),1.42(s,9H). ESI-MS m / z=537.2[M+H] + ;Calcu.=536.2.

[0432] Step B: To a solution of tert-butyl 4-((5-((3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)amino)thiazolo[4,5-d]pyrimidin-7-yl)amino)piperidine-1-carboxylate (10 mg, 0.027 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL, 13.059 mmol) at room temperature, and the entire mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a residue, which was subjected to HPLC preparative separation under the following conditions: Waters XBridge C18 (19 mm × 250 mm, 5 μm); A: 0.05% aqueous ammonia; B: MeCN; 18 mL / min; 0-3 min, 10% B; 3-15 min, 20%-50% B; detector, UV 254 nm. This reaction yielded compound G-61, a white solid product N 5 -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N 7 -(piperidin-4-yl)thiazolo[4,5-d]pyrimidine-5,7-diamine (10.30 mg, 0.022 mmol, 23.32%). 1H NMR(500MHz,DMSO-d6)δppm 9.45(s,1H),9.35(s,1H),7.84(d,J=7.6Hz,1H),7.69(s,1H),7.64-7.67(m,2H ),7.22(d,J=8.5Hz,1H),7.04(s,1H),4.08-4.24(m,1H),3.80(s,3H),3.01(br d,J=12.2Hz,2H),2.52-2.60(m,2H),2.15(s,3H),1.90(br d,J=11.7Hz,2H),1.88(s,1H),1.45(qd,J=11.9,3.8Hz,2H). ESI-MS m / z=437.2[M+H] + ;Calcu.=436.2.

[0433] Example 61: Synthesis of Compound G-62

[0434] Step A: To 1-methyl-1H-pyrrol-3-amine hydrochloride dissolved in isopropanol (3 mL) was added N,N-diisopropylethylamine (165 mg, 1.277 mmol) at room temperature. The mixture was stirred at room temperature for 0.5 h, and 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (50 mg, 0.134 mmol) was added. The mixture was stirred in a microwave reactor at 180° C. for 0.5 h. The reaction solution was concentrated under reduced pressure to obtain a residue, which was subjected to HPLC preparative separation under the following conditions: Waters XBridge C18 (19 mm×250 mm, 5 μm); A: 0.05% ammonia; B: MeCN; 18 mL / min; 0-3 min, 10% B; 3-18 min, 10%-65% B; detector, UV 254 nm. The reaction yielded compound G-62, a white solid product N 5 -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N 7 -(1-methyl-1H-pyrrol-3-yl)thiazolo[4,5-d]pyrimidine-5,7-diamine (2.96 mg, 0.006 mmol, 4.66%). 1H NMR (500MHz, DMSO-d6) δppm9.71(br s,1H),9.32-9.50(m,2H),7.73-7.85(m,1H),7.66(d,J=1.2Hz,1H),7.60(br d,J=7.9Hz,1H),7.44(br s,1H),7.24(br d,J=8.5Hz,1H),7.04(s,1H),6.57-6.74(m,1H),6.15(br dd,J=9.1,6.5Hz,1H),3.78(br s, 3H), 3.64 (s, 3H), 2.15 (d, J = 0.6Hz, 3H). ESI-MS m / z=433.1[M+H] + ;Calcu.=432.2.

[0435] Example 62: Synthesis of Compound G-63

[0436] Step A: At room temperature and nitrogen environment, tris(dibenzylideneacetone)dipalladium (20 mg, 0.022 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (30 mg, 0.063 mmol) and cesium carbonate (130 mg, 0.399 mmol) were added to N,N-dimethylformamide (3 mL) in which 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (50 mg, 0.134 mmol) and pyrimidin-5-amine (40 mg, 0.421 mmol) were dissolved. The whole mixture was stirred at 80 ° C for 2 hours. The reaction solution was filtered through celite, and the filtrate was collected and concentrated under reduced pressure to obtain a residue, which was subjected to HPLC preparative separation. Preparation conditions: Waters XBridge C18 (19 mm × 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 18 mL / min; 0-3 min, 10% B; 3-18 min, 10%-65% B; detector, UV 254 nm. The reaction yielded compound G-63, a white solid product N 5 -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N 7 -(pyrimidin-5-yl)thiazolo[4,5-d]pyrimidine-5,7-diamine (18.44 mg, 0.041 mmol, 30.84%). 1H NMR (500MHz, DMSO-d6) δppm10.16(s,1H),9.78(s,1H),9.64(s,1H),9.41(s,2H),8.93(s,1H),7.72(br d,J=7.0Hz,2H),7.64(br d,J=8.2Hz,1H),7.28(d,J=8.5Hz,1H),7.07(s,1H),3.77(s,3H),2.16(s,3H). ESI-MS m / z=432.3[M+H] + ;Calcu.=431.1.

[0437] Example 63: Synthesis of Compound G-64

[0438] Step A: At room temperature and nitrogen environment, tris(dibenzylideneacetone)dipalladium (20 mg, 0.022 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (30 mg, 0.063 mmol) and cesium carbonate (130 mg, 0.399 mmol) were added to 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (50 mg, 0.134 mmol) and pyrimidin-2-amine (12.74 mg, 0.134 mmol) dissolved in N,N-dimethylformamide (5 mL). The mixture was stirred at 80 ° C for 2 hours. The reaction solution was filtered through celite and the filtrate was collected and concentrated under reduced pressure to obtain a residue, which was subjected to HPLC preparative separation. Preparation conditions: Waters XBridge C18 (19 mm × 250 mm, 5 μm); A: 0.05% ammonia water; B: 0.05% ammonia in MeCN; 18 mL / min; 0-5 min, 40% B; 5-15 min, 40%-60% B; detector, UV 254 nm. The reaction yielded compound G-64, a white solid product N 5 -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N 7 -(pyrimidin-2-yl)thiazolo[4,5-d]pyrimidine-5,7-diamine (13.65 mg, 0.029 mmol, 21.42%). 1H NMR (500MHz, DMSO-d6) δppm 9.40-9.57(m,1H),8.62(br d,J=3.2Hz,2H),7.75(br s,2H),7.64(s,1H),7.18(br d,J=8.4Hz,1H),7.02(s,2H),3.74(br s,3H),2.15(s,3H). ESI-MS m / z=432.2[M+H] + ;Calcu.=431.1.

[0439] Example 64: Synthesis of Compound G-65

[0440] Step A: To a dry reaction tube at room temperature, 6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-amine (245 mg, 1.200 mmol), 1,4-dioxane (2.5 mL), and triethylborane (1.0 mL, 1.0 M in THF, 1.000 mmol) were added sequentially. The mixture was stirred at room temperature for 15 minutes. 1,4-dioxane (5.0 mL), 5,7-dichlorothiazo[4,5-d]pyrimidine (206 mg, 1.000 mmol), tris(dibenzylideneacetone)dipalladium (45 mg, 0.049 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (95 mg, 0.199 mmol), and potassium carbonate (276 mg, 1.997 mmol) were then added. After addition, the reaction mixture was stirred in a 110°C oil bath for 3 hours, then dried by rotary evaporation. The crude product was directly subjected to HPLC preparative separation using the following conditions: Welch Xtimate C18 (30 mm × 250 mm, 5 μm); A: 0.1% formic acid in water; B: MeCN; 40 mL / min; 0-3.5 min, 10% B; 3.5-15 min, 10%-50% B; 15-15.5 min, 50%-100% B; detector, UV 254 nm. This reaction yielded 7-chloro-N-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)thiazolo[4,5-d]pyrimidin-5-amine (56 mg, 0.150 mmol, 14.98%) as a white solid. ESI-MS m / z = 374.1 [M+H] + ;Calcu.=373.1.

[0441] Step B: At room temperature, add 7-chloro-N-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)thiazolo[4,5-d]pyrimidin-5-amine (37 mg, 0.099 mmol), methanol (3 mL), trifluoroacetic acid (60 mg, 0.526 mmol), and p-chloroaniline (25 mg, 0.196 mmol) to a dry pressure-resistant reaction tube. After addition, stir in an 80°C oil bath for 2 hours, then spin dry the reaction mixture. The crude product was directly subjected to HPLC preparative separation under the following conditions: Welch Xtimate C18 (30 mm × 250 mm, 5 μm); A: 0.05% aqueous ammonia; B: MeCN; 18 mL / min; 0-3.5 min, 10% B; 3.5-15 min, 10%-40% B; 15-18 min, 40%-100% B; detector, UV 254 nm. This reaction yielded compound G-65, a white solid product N 7 -(4-chlorophenyl)-N 5 -(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)thiazolo[4,5-d]pyrimidine-5,7-diamine (0.28 mg, 0.001 mmol, 0.60%). 1 H NMR(500MHz,DMSO-d6)δppm 9.97(s,1H),9.75(br s,1H),9.59(s,1H),8.52(br s,1H),8.23(br s,1H),8.10(s,1H),7.86(d,J=8.1Hz,2H),7.42(m,3H),3.81(s,3H),2.17(s,3H). ESI-MS m / z=465.3[M+H] + ;Calcu.=464.1.

[0442] Example 65: Synthesis of Compound G-66

[0443] Step A: To a solution of 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (80 mg, 0.215 mmol) and 2-aminopyridine (40 mg, 0.425 mmol) in 1,4-dioxane (20 mL) was added palladium acetate (20 mg, 0.089 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (100 mg, 0.173 mmol), and potassium carbonate (59 mg, 0.427 mmol) at room temperature under nitrogen. After the addition was complete, the mixture was heated to 80°C and stirred under nitrogen for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a brown solid crude residue, which was then subjected to HPLC preparative separation under the following conditions: Waters XBridge Prep C18 (30 mm × 250 mm, 5 μm); A: 0.05% aqueous ammonia, B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-35% B; 3.5-15 min, 35%-75% B; 15-15.5 min, 75%-100% B; detector, UV 254 nm. Compound G-66 was obtained, a white solid product N 5 -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N 7 -(pyridin-2-yl)thiazolo[4,5-d]pyrimidine-5,7-diamine (34.79 mg, 0.076 mmol, 35.55%). 1 H NMR(500MHz,DMSO-d6)δppm 10.56(br s,1H),9.63(s,1H),9.57(s,1H),8.37-8.40(m,1H),8.19(d,J=8.0Hz,1H),7.81-7.86(m,1H),7.71(d,J=2.1Hz,1H),7.68(d,J=1 .2Hz,1H),7.66(dd,J=8.6,2.1Hz,1H),7.26(d,J=8.6Hz,1H),7.12-7.16(m,1H),7.06(t,J=1.2Hz,1H),3.77(s,3H),2.15(s,3H). ESI-MS m / z=431.3[M+H] + ;Calcu.=430.1.

[0444] Example 66: Synthesis of Compound G-67

[0445] Step A: To 7-chloro-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[4,5-d]pyrimidin-5-amine (80 mg, 0.215 mmol) and oxazole-4-methylamine hydrochloride (57 mg, 0.424 mmol) dissolved in 1,4-dioxane (20 mL) at room temperature under nitrogen was added palladium acetate (20 mg, 0.089 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (100 mg, 0.173 mmol), and cesium carbonate (210 mg, 0.645 mmol). After the addition was complete, the mixture was heated to 80°C and stirred under nitrogen for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a brown solid crude residue, which was then subjected to HPLC preparative separation under the following conditions: Waters XSelect CSHPrep C18 (30 mm × 250 mm, 5 μm); A: 0.05% aqueous ammonia, B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-30% B; 3.5-15 min, 30%-70% B; 15-15.5 min, 70%-100% B; detector, UV 254 nm. Compound G-67 was obtained, a white solid product N 5 -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N 7 -(oxazol-4-ylmethyl)thiazolo[4,5-d]pyrimidine-5,7-diamine (1.88 mg, 0.004 mmol, 2.01%). 1 H NMR(500MHz,DMSO-d6)δppm 9.47(s,1H),9.46(br s,1H),8.50(t,J=5.5Hz,1H),8.35(s,1H),8.07(s,1H),7.82(d,J=2.2Hz,1H),7.65(d,J=1.0Hz,1H),7. 49(d,J=8.4Hz,1H),7.21(d,J=8.4Hz,1H),7.03(s,1H),4.66(d,J=5.5Hz,2H),3.75(s,3H),2.14(s,3H). ESI-MS m / z=435.3[M+H] + ;Calcu.=434.1.

[0446] Test Example 1: γ-Secretase Modulator Activity Evaluation Experiment 1

[0447] Objective: To evaluate the γ-secretase modulating activity of test compounds using the HEK293 APP in vitro model.

[0448] Background: HEK293 APP cells are derived from the human embryonic kidney HEK293 cell line and express the Swedish mutant human amyloid precursor protein gene (APPswe). Amyloid precursor protein (APP) is a protein expressed in multiple tissues and concentrated in neuronal synapses. APP can be cleaved by α-, β-, and γ-secretases. The sequential action of β- and γ-secretases results in the production of Aβ. ELISA is used to measure the Aβ level produced by cleavage of the APP-C99 peptide by γ-secretase modulators, thereby evaluating the γ-secretase-modulating activity of test compounds.

[0449] Materials and methods

[0450] 1. Cell line: HEK293 APP (Cyagen), culture conditions: DMEM, 10% (v / v) FBS, Penicillin-Streptomycin, 5% CO2, 37°C.

[0451] 2 Reagents: DMEM (ThermoFisher, 11995-073), FBS (Gibco, 10091148), 0.25% Trypsin-EDTA (1X) (Gibco, 25200-114); DPBS (Shanghai Yuanpei, B210KJ), Penicillin-Streptomycin (ThermoFisher, 15140122), Human β Amyloid (1-42) ELISA Kit Wako (FujiFilm Wako Chemicals, 296-64401), E 2012 (MCE, HY-10016).

[0452] 3 Instruments: microplate reader (BIOTOK, SNERGY H1), CO2 incubator (THERMO, STERI-CYCLEI160), cell counter (Invitrogen, Countess3), micro desktop vacuum pump (Qilin Bell, GL-802B), low-speed centrifuge (Eppendorf, 5804).

[0453] 4 Methods:

[0454] Step 1: Cell plating

[0455] (1) Discard the culture medium in the T75 culture flask, add 8.0 mL of preheated DPBS, and gently shake the culture flask to rinse the cells once.

[0456] (2) After discarding DPBS, add 1.0 mL of trypsin (0.25%) to the T75 culture flask, gently shake the culture flask to allow it to infiltrate all cells, and place it in the incubator for digestion for 1 to 2 minutes.

[0457] (3) Add serum-containing culture medium to terminate digestion, collect the cell suspension, centrifuge at 1000 rpm at room temperature for 5 minutes, and discard the supernatant.

[0458] (4) Add fresh culture medium, pipette to mix the cells, and then count them using a Countess3 cell counter.

[0459] (5) Dilute the cells to a density of 2.5*10 5 cells / mL, 100 μL of diluted cell suspension was inoculated into a 96-well plate, i.e. 2.5*10 4 cells / well.

[0460] (6) Place the 96-well plate in an incubator and incubate overnight (5% CO2, 37°C).

[0461] Step 2: Compound treatment

[0462] (1) The test compound was prepared into a 30 mM or 10 mM stock solution in DMSO;

[0463] (2) Preparation of compound working solution:

[0464] a)IC 50 Test: The test compound was diluted from 30 mM or 10 mM to 30 μM using culture medium, and then diluted 3-fold using culture medium containing 0.1% DMSO, for a total of 8 concentration gradients. DMSO was used as a negative control.

[0465] b) Inhibition rate test: dilute the test compound from 30 mM or 10 mM to 5 mM with DMSO, and then dilute the test compound from 5 mM to 5 μM with culture medium, for a total of 1 concentration. DMSO serves as a negative control, and E 2012 serves as a positive control.

[0466] (3) Use a micro-tabletop vacuum pump to gently remove the supernatant from the 96-well cell plate, and add 100 μL of the diluted compound to the 96-well cell plate.

[0467] IC 50 In the assay, the final concentrations of the test compounds were 30,000, 10,000, 3,333, 1,111, 370, 123, 41, and 14 nM.

[0468] In the inhibition rate test, the final concentration of the test compound and the control compound was 5000 nM.

[0469] (4) Place the 96-well plate in a 5% CO2, 37°C incubator and incubate for 24 hours.

[0470] Step 3: ELISA test

[0471] (1) Experimental preparation: Take out the dilution buffer, standard and ELISA plate from the ELISA kit and restore them to room temperature.

[0472] (2) Prepare and dilute Aβ peptide standard according to the kit instructions.

[0473] (3) Pretreat the cell culture supernatant according to experimental requirements.

[0474] (4) Take 100 μL of standard or cell supernatant sample and add it to the balanced ELISA plate. Collect the culture supernatant in the remaining cell plate and store it at -80°C.

[0475] (5) Seal the ELISA plate with sealing film to prevent evaporation and contamination, and incubate at 4°C overnight.

[0476] (6) Washing: Discard the liquid in the wells and add 350 μL of 1× Wash Buffer to each well. Leave for 30 seconds and then discard the liquid in the wells. Repeat 5 times and blot dry on filter paper for the last time.

[0477] (7) Add detection antibody: Add 100 μL of 1× HRP-conjugated Antibody (ready-to-use) to each well, cover with sealing film, and incubate at 4°C for 1 hour.

[0478] (8) Washing: Discard the liquid in the wells and add 350 μL of 1× Wash Buffer to each well. Leave for 30 seconds and then discard the liquid in the wells. Repeat 5 times and blot dry on filter paper for the last time.

[0479] (9) Color development: Add 100 μL of TMB solution to each well and incubate at room temperature in the dark for 30 minutes.

[0480] (10) Termination of reaction: Add 100 μL Stop Solution to each well to terminate the reaction.

[0481] (11) Plate reading: Within 10 minutes after termination, detect the light absorption of Aβ42 at 450 nm using an enzyme reader.

[0482] (12) Data analysis: The raw data were calculated using GraphPad Prism 10 software based on the curve fitting of each compound concentration and the corresponding response value. 50 value or calculate the inhibition rate.

[0483] The experimental results are shown in Tables 1 and 2 below.

[0484] Table 1

[0485] Table 2

[0486] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to preferred embodiments, ordinary technicians in the field should understand that the specific implementation methods of the present invention can still be modified or some technical features can be replaced by equivalents without departing from the spirit of the technical solutions of the present invention. They should all be included in the scope of the technical solutions claimed for protection by the present invention.

Claims

1. A compound of formula (I), a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystal form, isotope-labeled substance, or metabolite thereof, in, X is selected from C(R x ) and N, the R x is selected from hydrogen, halogen, hydroxy, mercapto, -(C1-C6)alkyl, -O-(C1-C6)alkyl and (C3-C6)cycloalkyl; Y is selected from S and O, S is optionally oxidized; L1 and L2 are each independently selected from a bond, -O-, -O-(C1-C4)alkylene-, -(C1-C4)alkylene-O-, -S-, -S(=O)-, -S(=O)2-, -OC(=O)-, -C(=O)O-, -NR a S(=O)2-、-S(=O)2NR a -、-NR a -、-NR a -(C1-C4)alkylene-, -(C1-C4)alkylene-NR a -、-NR a C(=O)-, -C(=O)NR a -、-P(=O)R a -、-P(=O)(OR a )-, -(C1-C4)alkylene-, -(C2-C4)alkenylene- and -(C2-C4)alkynylene-, the -O-(C1-C4)alkylene-, -(C1-C4)alkylene-O-, -NR a S(=O)2-、-S(=O)2NR a -、-NR a -、-NR a -(C1-C4)alkylene-, -(C1-C4)alkylene-NR a -、-NR a C(=O)-, -C(=O)NR a -、-P(=O)R a -、-P(=O)(OR a )-, -(C1-C4)alkylene-, -(C2-C4)alkenylene- and -(C2-C4)alkynylene- are optionally substituted by one or more groups selected from hydrogen, halogen, -OH, -SH, -NH2, -COOH and -(C1-C6)alkyl, wherein R a is selected from hydrogen, -(C1-C6)alkyl and -(C1-C6)haloalkyl; Ring A is selected from (C6-C 14 ) aryl, 5-12 membered heteroaryl, 3-12 membered heterocyclyl, and 3-12 membered cycloalkyl; R 1 Selected from hydrogen, halogen, nitro, nitroso, -CN, -OR b 、-SR b 、-S(=O)-R b 、-S(=O)2-R b 、-S(=O)NR b R c 、-S(=O)2NR b R c 、-NR b S(=O)2R c 、-NR b R c 、-NR b C(=O)-R c 、-COOH、-C(=O)-R b 、-P(=O)-R b R c 、-C(=O)NR b R c , -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, -(C6-C 10 )aryl, 3-9 membered heterocyclyl, 5-9 membered heteroaryl, =O, -CH2R b , -(C1-C6 alkyl) OH, -(C1-C6 alkyl) NH2, sulfonic acid and -Si(C1-C3 alkyl) 3, the -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, -(C1-C6) haloalkyl, -(C3-C7) cycloalkyl, -(C6-C 10 )aryl, 3-9 membered heterocyclic group, 5-9 membered heteroaryl, -CH2R b , -(C1-C6 alkyl) OH, -(C1-C6 alkyl) NH2, sulfonic acid and -Si(C1-C3 alkyl) 3 are optionally substituted by one or more groups selected from hydrogen, halogen, -OH, -SH, -NH2, -COOH, -(C1-C6) alkyl and -O(C1-C6) alkyl, wherein R b and R c each independently selected from hydrogen, -OH, -NH2, halogen, -(C1-C6)alkyl, -O(C1-C6)alkyl, -(C1-C6)haloalkyl, -C(=O)(C1-C6)alkyl, -S(=O)2(C1-C6alkyl), -(C1-C6)alkoxy, 3-9 membered heterocyclyl and 5-9 membered heteroaryl; Ring B is selected from (C6-C 14 ) aryl, 5-12 membered heteroaryl, 3-12 membered heterocyclyl, and 3-12 membered cycloalkyl; R 2 Selected from hydrogen, halogen, nitro, nitroso, -CN, -OR b 、-SR b 、-S(=O)-R b 、-S(=O)2-R b 、-S(=O)NR b R c 、-S(=O)2NR b R c 、-NR b S(=O)2R c 、-NR b R c 、-NR b C(=O)-R c 、-COOH、-C(=O)-R b 、-P(=O)-R b R c 、-C(=O)NR b R c , -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, -(C6-C 10 )aryl, 3-9 membered heterocyclyl, 5-9 membered heteroaryl, =O, -CH2R b , -(C1-C6 alkyl) OH, -(C1-C6 alkyl) NH2, sulfonic acid and -Si(C1-C3 alkyl) 3, the -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, -(C1-C6) haloalkyl, -(C3-C7) cycloalkyl, -(C6-C 10 )aryl, 3-9 membered heterocyclic group, 5-9 membered heteroaryl, -CH2R b , -(C1-C6 alkyl) OH, -(C1-C6 alkyl) NH2, sulfonic acid and -Si(C1-C3 alkyl) 3 are optionally substituted by one or more groups selected from hydrogen, halogen, -OH, -SH, -NH2, -COOH and -(C1-C6) alkyl, wherein R b and R c each independently selected from hydrogen, -OH, -NH2, halogen, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -C(=O)(C1-C6)alkyl, -S(=O)2(C1-C6alkyl), -O-(C1-C6)alkyl, 3-9 membered heterocyclyl and 5-9 membered heteroaryl; R 3 is selected from the group consisting of hydrogen, halogen, nitro, -CN, -OH, -O-(C1-C6)alkyl, -SH, -S-(C1-C6)alkyl, -S(=O)-(C1-C6)alkyl, -S(=O)2-(C1-C6)alkyl, -S(=O)NH2, -S(=O)2NH2, -NH2, -NH-(C1-C6)alkyl, -N[(C1-C6)alkyl]2, -NHC(=O)H, -NHC(=O)-(C1-C6)alkyl, -COOH, -C(=O)-(C1-C6)alkyl, -C(=O)NH2, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl and -(C1-C6)haloalkyl; m is 0, 1, 2, 3, 4, 5, 6 or 7; n is 0, 1, 2, 3, 4, 5, 6 or 7.

2. The compound of claim 1, its pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystal form, isotope-labeled substance or metabolite thereof, wherein: L1 and L2 are each independently selected from a bond, -O-, -O-(C1-C4)alkylene-, -(C1-C4)alkylene-O-, -S-, -NR a -、-NR a -(C1-C4)alkylene-, -(C1-C4)alkylene-NR a -、-NR a C(=O)-, -C(=O)NR a - and -(C1-C4)alkylene-, the -NR a -(C1-C4)alkylene-, -(C1-C4)alkylene-NR a - is optionally substituted by one or more groups selected from hydrogen, methyl, said R a is selected from hydrogen and -(C1-C4)alkyl, preferably R a is selected from hydrogen, methyl, ethyl and isopropyl; Preferably, L1 and L2 are each independently selected from a bond, -O-, -S-, -NH-, -N[(C1-C4)alkyl]-, -NH-(C1-C4)alkylene-, -(C1-C4)alkylene-NH-, -NHC(=O)-, -C(=O)NH- and -(C1-C4)alkylene-, wherein the -NH-(C1-C4)alkylene- and -(C1-C4)alkylene-NH- are optionally substituted by one or more groups selected from hydrogen, methyl, Preferably, L1 and L2 are each independently selected from a bond, -O-, -S-, -NH-, -N[(C1-C4) alkyl]-, -NH-(C1-C4) alkylene-#, #-NH-(C1-C4) alkylene-, -NHC(=O)-#, -C(=O)NH-# and -(C1-C4) alkylene-, wherein the -NH-(C1-C4) alkylene-# and #-NH-(C1-C4) alkylene- are optionally substituted with one or more groups selected from hydrogen and methyl, wherein the # end represents the end connected to ring A or ring B, Preferably, L1 and L2 are each independently selected from a bond, -O-, -NH-, -N(methyl)-, -N(ethyl)-, -N(isopropyl)-, -NH-methylene-#, -NH-ethylidene-#, -NHCH(methyl)-#, -NHCH(ethyl)-#, -NHC(=O)-#, -C(=O)NH-#, methylene, ethylene and isopropylidene, wherein the # end represents the end connected to ring A or ring B; Preferably, L1 is selected from a bond, -O-, -NH-, -N(CH3)- and -NHC(=O)-#, wherein the # end represents the end connected to ring A; Preferably, L2 is selected from a bond, -O-, -NH-, -N(CH3)-, -CH2-, -NHCH2-#, -NHC(=O)-# and -NHCH(CH3)-#, wherein the # end represents the end connected to ring B.

3. The compound according to claim 1 or 2, its pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystal form, isotope-labeled substance or metabolite thereof, wherein: X is selected from C(R x ) and N, the R x is selected from hydrogen, halogen, hydroxy, -(C1-C6)alkyl and -O-(C1-C6)alkyl, Preferably, X is selected from C(R x ) and N, the R x is selected from hydrogen, -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, isopropyl, methoxy and ethoxy, Preferably, X is selected from C(R x ) and N, the R x is selected from hydrogen, -F, -Cl, hydroxyl and methyl, Preferably, X is selected from C(R x ) and N, the R x is hydrogen; Y is selected from S, O, S(=O) and S(=O)2; Preferably, Y is selected from S and O.

4. The compound according to any one of claims 1 to 3, its pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystal form, isotope-labeled substance or metabolite thereof, wherein: Ring A is selected from (C6-C 10 ) aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl and 5-10 membered cycloalkyl, Preferably, ring A is selected from phenyl, naphthyl, 6-9 membered heteroaryl, 6-9 membered heterocyclyl and 6-9 membered cycloalkyl, wherein the 6-9 membered heteroaryl and 6-9 membered heterocyclyl contain 1, 2 or 3 heteroatoms selected from N atoms, O atoms and S atoms, and the N atoms and S atoms are optionally oxidized, Preferably, ring A is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, piperidinyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl and 1,3-dihydrobenzimidazol-2-one, Preferably, ring A is selected from R 1 Selected from hydrogen, halogen, nitro, -CN, -OR b 、-SR b 、-NR b R c 、-COOH、-C(=O)-R b 、-P(=O)-R b R c 、-C(=O)NR b R c , -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, -(C6-C 10 ) aryl, 3-9 membered heterocyclic group and 5-9 membered heteroaryl, the -(C1-C6) alkyl, -(C1-C6) haloalkyl, -(C3-C7) cycloalkyl, -(C6-C 10 ) aryl, 3-9 membered heterocyclyl and 5-9 membered heteroaryl are optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, halogen, -OH, -SH, -NH2, -COOH, -O(C1-C4)alkyl and -(C1-C4)alkyl, said R b and R c are each independently selected from hydrogen, -OH, -NH2, halogen, -(C1-C4)alkyl, -O(C1-C4)alkyl and -(C1-C4)haloalkyl, preferably, R b and R c are each independently selected from hydrogen, methyl, methoxy, ethyl and halomethyl, Preferably, R 1 is selected from hydrogen, halogen, -CN, -OH, -O-(C1-C4)alkyl, -SH, -NH2, -COOH, -C(=O)NH-(C1-C4)alkyl, -(C1-C4)alkyl and 5-6-membered heteroaryl, wherein the -O-(C1-C4)alkyl, -C(=O)NH-(C1-C4)alkyl, -(C1-C4)alkyl and 5-6-membered heteroaryl are optionally substituted by 1, 2 or 3 groups selected from hydrogen, -O(C1-C4)alkyl and -(C1-C4)alkyl, Preferably, R 1 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, -CN, -OH, -O-methyl, -O-ethyl, -O-propyl, -SH, -NH2, -COOH, -C(=O)NH-CH3, -C(=O)NH-CH2CH3, methyl, ethyl, propyl, imidazolyl, pyrazolyl, pyridinyl, triazolyl and pyrrolyl, wherein the -O-methyl, -O-ethyl, -O-propyl, methyl, ethyl, propyl, imidazolyl, pyrazolyl, pyridinyl, triazolyl and pyrrolyl groups are optionally substituted by 1 or 2 groups selected from the group consisting of methyl and methoxy, Preferably, R 1 Selected from hydrogen, -OCH3, m is 0, 1, 2, 3 or 4, Preferably, m is 0 or 2.

5. The compound according to any one of claims 1 to 4, its pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystal form, isotope-labeled substance or metabolite thereof, wherein: Ring B is selected from (C6-C 10 ) aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl and 5-10 membered cycloalkyl, Preferably, ring B is selected from phenyl, naphthyl, 5-9 membered heteroaryl, 6-9 membered heterocyclyl and 6-9 membered cycloalkyl, wherein the 5-9 membered heteroaryl and 6-9 membered heterocyclyl contain 1, 2 or 3 heteroatoms selected from N atoms, O atoms and S atoms, and the N atoms and S atoms are optionally oxidized, Preferably, ring B is selected from tetrahydropyranyl, morpholinyl, phenyl, naphthyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, piperidinyl, 3,4-dihydro-2H-pyranyl, benzoxazolyl, benzisoxazolyl, benzofuranyl, benzothiazolyl, indolyl, benzimidazolyl, 1,3-benzodioxolyl and 2-benzoxazolonyl, Preferably, ring B is selected from R 2 Selected from hydrogen, halogen, nitro, -CN, -OR b 、-SR b 、-NR b R c 、-COOH、-C(=O)-R b 、-P(=O)-R b R c 、-C(=O)NR b R c , -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, -(C6-C 10 ) aryl, 3-9 membered heterocyclic group and 5-9 membered heteroaryl, the -(C1-C6) alkyl, -(C1-C6) haloalkyl, -(C3-C7) cycloalkyl, -(C6-C 10 ) aryl, 3-9 membered heterocyclyl and 5-9 membered heteroaryl are optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, halogen, -OH, -SH, -NH2, -COOH and -(C1-C4)alkyl, wherein R b and R c are each independently selected from hydrogen, -OH, -NH2, halogen, -O-(C1-C4)alkyl, -(C1-C4)alkyl and -(C1-C4)haloalkyl, preferably, R b and R c are each independently selected from hydrogen, methyl, ethyl, -O-(C1-C4)alkyl and halomethyl, Preferably, R 2 is selected from hydrogen, halogen, -CN, -OH, -O-(C1-C4)alkyl, -SH, -NH2, -COOH, -C(=O)O(C1-C4)alkyl, -(C1-C4)alkyl and 5-6-membered heteroaryl, wherein the -O-(C1-C4)alkyl, -C(=O)O(C1-C4)alkyl, -(C1-C4)alkyl and 5-6-membered heteroaryl are optionally substituted by 1, 2 or 3 groups selected from hydrogen and -(C1-C4)alkyl, Preferably, R 2 is selected from hydrogen, fluorine, chlorine, bromine, -CN, -OH, -O-methyl, -O-ethyl, -O-propyl, -C(=O)OC(CH3)3, -SH, -NH2, -COOH, methyl, ethyl, propyl, imidazolyl, pyrazolyl and pyrrolyl, wherein the -O-methyl, -O-ethyl, -O-propyl, methyl, ethyl, propyl, imidazolyl, pyrazolyl and pyrrolyl are optionally substituted by 1 or 2 groups selected from hydrogen, methyl, Preferably, R 2 Selected from hydrogen, -F, -Cl, -OCH3, -CH3, -C(=O)OC(CH3)3 and n is 0, 1, 2, 3 or 4, Preferably, n is 0, 1 or 2.

6. The compound according to any one of claims 1 to 5, its pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystal form, isotope-labeled substance or metabolite thereof, wherein: R 3 is selected from hydrogen, halogen, nitro, -CN, -OH, -O-(C1-C4)alkyl, -SH, -S-(C1-C6)alkyl), -S(=O)-(C1-C6)alkyl, -S(=O)NH2, -NH2, -NH-(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -COOH, -C(=O)-(C1-C4)alkyl, -C(=O)NH2, -(C1-C4)alkyl and -(C1-C4)haloalkyl, Preferably, R 3 is selected from hydrogen, halogen, -CN, -OH, -O-(C1-C4)alkyl, -SH, -S-(C1-C6alkyl), -NH2, -NH-(C1-C4)alkyl, -COOH, -(C1-C4)alkyl and -(C1-C4)haloalkyl, Preferably, R 3 is selected from hydrogen, fluorine, chlorine, bromine, -CN, -OH, -SH, -NH2, -COOH, methyl and halomethyl, Preferably, R 3 For hydrogen.

7. The compound of claims 1-6, its pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystal form, isotope-labeled substance or metabolite thereof, wherein: The compound is selected from 1) Compound represented by formula (IA) in, T1, T2 and T3 are each independently selected from C(R t ) and N, the R t is selected from hydrogen, hydroxy, -(C1-C6)alkyl and halogen, Preferably, T1, T2 and T3 are each independently selected from C(R t ) and N, and at most one of T1, T2 and T3 is N, the R t is selected from hydrogen, hydroxy and methyl, Preferably, T1 is CH, T2 is CH, and T3 is N, or T1 is N, T2 is CH, and T3 is C, or T1 is CH, T2 is N, and T3 is C, or T1, T2, and T3 are all CH, Preferably, T1, T2 and T3 are all CH; X, Y, L1, R 1 ,m,L2,Ring B,R 2 , n and R 3 As defined in any one of claims 1 to 6; or, 2) Compound represented by formula (IB) in, Ring C is absent or is selected from 5-6 membered heteroaryl (e.g., oxazolyl, isoxazolyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl) and 5-6 membered heterocyclyl, Preferably, Ring C is absent, or Selected from Preferably, ring C is absent; X, Y, L1, Ring A, R 1 ,m,L2,R 2 , n and R 3 As defined in any one of claims 1 to 6; Preferably, the compound is selected from the compound represented by formula (IAB) in, T1 is CH, T2 is CH, and T3 is N, or T1 is N, T2 is CH, and T3 is C, or T1 is CH, T2 is N, and T3 is C, or T1, T2, and T3 are all CH, Preferably, T1, T2 and T3 are all CH; Ring C is absent or is selected from 5-6 membered heteroaryl (e.g., oxazolyl, isoxazolyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl) and 5-6 membered heterocyclyl, Preferably, Ring C is absent, or Selected from Preferably, ring C is absent; X, Y, L1, R 1 ,m,L2,R 2 , n and R 3 As defined in any one of claims 1 to 6; Preferably, L1 is selected from a bond, -O-, -NH-, -N(CH3)-, -C(=O)NH- and -NHC(=O)-; Preferably, L2 is selected from a bond, -O-, -NH-, -N(CH3)-, -CH2-, -C(=O)NH-, -NHC(=O)-, -NHCH(CH3)- and -CH(CH3)NH-; Preferably, R 1 Selected from hydrogen, -OCH3, -C(=O)NHCH2CH3, Preferably, R 2 Selected from hydrogen, -F, -Cl, -OCH3 and More preferably, the compound is selected from the compound represented by formula (IAB-1) in, X, Y, L1, R 1 ,m,L2,R 2 , n and R 3 As defined in any one of claims 1 to 6; Preferably, L1 is selected from a bond, -O-, -NH-, -N(CH3)-, -C(=O)NH- and -NHC(=O)-; Preferably, L2 is selected from a bond, -O-, -NH-, -N(CH3)-, -CH2-, -C(=O)NH-, -NHC(=O)-, -NHCH(CH3)- and -CH(CH3)NH-; Preferably, R 1 Selected from hydrogen, -OCH3, Preferably, R 2 Selected from hydrogen, -F, -Cl, -OCH3 and Still more preferably, the compound is selected from the compound represented by formula (IAB-1-1) in, R 1a and R 1b Each as R 1 As defined, R 1a and R 1b Can be the same or different, R 2a 、R 2b and R 2c Each as R 2 As defined, R 2a 、R 2b and R 2c Can be the same or different, X, Y, L1, R 1 , L2, R 2 and R 3 As defined in any one of claims 1 to 6; Preferably, L1 is selected from a bond, -O-, -NH-, -N(CH3)-, -C(=O)NH- and -NHC(=O)-; Preferably, L2 is selected from a bond, -O-, -NH-, -N(CH3)-, -CH2-, -C(=O)NH-, -NHC(=O)-, -NHCH(CH3)- and -CH(CH3)NH-; Preferably, R 1a and R 1b Each independently selected from hydrogen, -OCH3, Preferably, R 1a Selected from hydrogen and -OCH3, R 1b Selected from hydrogen, Preferably, R 2a 、R 2b and R 2c Each independently selected from hydrogen, -F, -Cl, -OCH3 and Preferably, R 2a selected from hydrogen and -F, R 2b Selected from hydrogen and -OCH3, R 2c Selected from hydrogen, -F, -Cl, -OCH3 and or, 3) a compound represented by formula (II), in, T1 is CH, T2 is N, or T1 is N, T2 is CH, or both T1 and T2 are CH, R 1a and R 1b Each as R 1 As defined, R 1a and R 1b Can be the same or different, X, Y, L1, R 1 , L2, Ring B, R 2 , n and R 3 As defined in any one of claims 1 to 6; Preferably, X is selected from CH and N; Preferably, Y is selected from S and O; Preferably, L1 is selected from a bond, -NH-, -C(=O)NH- and -NHC(=O)-, preferably L1 is selected from a bond, -NH- and -NHC(=O)-#, wherein the # terminal represents connected end; Preferably, R 1a and R 1b Each is independently selected from hydrogen, -O-(C1-C4)alkyl and 5-6 membered heteroaryl, said 5-6 membered heteroaryl being optionally substituted with 1 or 2 methyl groups, preferably R 1a and R 1b Each independently selected from hydrogen, -OCH3, Preferably, R 1a Selected from hydrogen and -OCH3, R 1b Selected from hydrogen, More preferably, R 1a -OCH3, R 1b Selected from Preferably, L2 is selected from a bond, -O-, -NH-, -(C1-C4)alkylene-, -N[(C1-C4)alkyl]-, -NH-(C1-C4)alkylene-, -(C1-C4)alkylene-NH-, -C(=O)NH- and -NHC(=O)-, wherein the -NH-(C1-C4)alkylene- and -(C1-C4)alkylene-NH- are optionally substituted with one or more groups selected from hydrogen and methyl. Preferably, L2 is selected from a bond, -O-, -NH-, -CH2-, -N(CH3)-, -NH-CH(CH3)-#, -NHCH2-# and -NHC(=O)-#, wherein the # end represents the end connected to ring B, Preferably, ring B is selected from (C6-C 10 ) aryl, 5-9 membered heteroaryl and 6-9 membered heterocyclic group, preferably the 5-9 membered heteroaryl and 6-9 membered heterocyclic group contain 1, 2 or 3 heteroatoms, and the heteroatoms are selected from N atoms and O atoms, preferably ring B is selected from phenyl, pyridyl, thiazolyl, pyrrolyl, tetrahydropyranyl, benzoxazolyl and 1,3-benzodioxolane, preferably ring B is selected from Preferably, R 2 is selected from hydrogen, halogen, -(C1-C6)alkyl, -O-(C1-C4)alkyl and 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with 1 or 2 methyl groups, preferably R 2 Selected from hydrogen, methyl, -F, -Cl, -OCH3 and Preferably, n is 0, 1 or 2; Preferably, R 3 is hydrogen; 4) a compound represented by formula (III), in, T1 is CH or N, T b is CH or N, R 1a and R 1b Each as R 1 As defined, R 1a and R 1b Can be the same or different, R 2a and R 2c Such as R 2 As defined, R 2a and R 2c Can be the same or different, X, Y, L1, R 1 、R 2 , L2 and R 3 As defined in any one of claims 1 to 6; Preferably, X is selected from CH and N; Preferably, Y is selected from S and O; Preferably, L1 is selected from -NH-, -C(=O)NH- and -NHC(=O)-, preferably L1 is selected from -NH- and -NHC(=O)-#, wherein the # end represents connected end; Preferably, R 1a and R 1b are each independently selected from hydrogen, -O-(C1-C4)alkyl and 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted by 1 or 2 methyl groups. Preferably, R 1a and R 1b Each independently selected from hydrogen, -OCH3, Preferably, R 1a Selected from hydrogen and -OCH3, R 1b Selected from hydrogen, More preferably, R 1a -OCH3, R 1b for Preferably, L2 is selected from a bond, -O-, -NH- and -(C1-C4)alkylene-, preferably L2 is selected from a bond, -O-, -NH- and -CH2-, Preferably, R 2a and R 2c are each independently selected from hydrogen, halogen and -O-(C1-C4)alkyl, Preferably, R 2a and R 2c Each independently selected from hydrogen, -F, -Cl, -Br, -I and -OCH3, preferably, R 2a selected from hydrogen and -F, R 2c is selected from hydrogen, -F, -Cl and -OCH3; Preferably, R 3 For hydrogen.

8. The compound according to any one of claims 1 to 7, its pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystal form, isotope-labeled substance or metabolite thereof, wherein: X is C(R x ), Y is S, L1, L2, ring A, R 1 ,m,ring B,R 2 、n、R 3 、T1、T2、T3、T b and Ring C is as defined in any one of claims 1 to 7, Preferably, R x For hydrogen, Preferably, L1 is selected from a bond, -O-, -NH- and -N[(C1-C4)alkyl]-, preferably L1 is selected from a bond, -O-, -NH- and -N(CH3)-, Preferably, L2 is selected from a bond, -O-, -NH- and -N[(C1-C4)alkyl]-, preferably L2 is selected from a bond, -O-, -NH- and -N(CH3)-, Preferably, ring A is selected from (C6-C 10 ) aryl, preferably ring A is Preferably, R 1 is selected from hydrogen, -O-(C1-C4)alkyl and 5-6 membered heteroaryl, wherein the -O-(C1-C4)alkyl and 5-6 membered heteroaryl are optionally substituted with 1, 2 or 3 methyl groups, preferably R 1 is selected from hydrogen, -O-methyl, -O-ethyl, -O-propyl, imidazolyl, pyrazolyl and pyrrolyl, wherein the -O-methyl, -O-ethyl, -O-propyl, imidazolyl, pyrazolyl and pyrrolyl are optionally substituted with 1 or 2 methyl groups, preferably R 1 Selected from hydrogen, -OCH3 and Preferably, m is 0 or 2, Preferably, ring B is selected from (C6-C 10 ) aryl and 6-9 membered heterocyclic group, preferably the 6-9 membered heterocyclic group contains 1, 2 or 3 heteroatoms, the heteroatoms are selected from N atoms, O atoms and S atoms, preferably ring B is selected from tetrahydropyranyl, morpholinyl, phenyl and naphthyl, preferably ring B is selected from Preferably, R 2 is selected from hydrogen, -O-(C1-C4)alkyl and 5-6 membered heteroaryl, wherein the -O-(C1-C4)alkyl and 5-6 membered heteroaryl are optionally substituted with 1, 2 or 3 methyl groups, preferably R 2 is selected from hydrogen, -O-methyl, -O-ethyl, -O-propyl, imidazolyl, pyrazolyl and pyrrolyl, wherein the -O-methyl, -O-ethyl, -O-propyl, imidazolyl, pyrazolyl and pyrrolyl are optionally substituted with 1 or 2 methyl groups, preferably R 2 Selected from hydrogen, -OCH3 and Preferably, n is 0 or 2; or, X is C(R x ), Y is O, L1, L2, ring A, R 1 ,m,ring B,R 2 、n、R 3 、T1、T2、T3、T b and Ring C is as defined in any one of claims 1 to 7, Preferably, R x For hydrogen, Preferably, L1 is selected from a bond, -O-, -NH- and -N[(C1-C4)alkyl]-, preferably L1 is -NH-, Preferably, L2 is selected from a bond, -O-, -NH- and -N[(C1-C4)alkyl]-, preferably L2 is selected from a bond and -NH-, Preferably, ring A is selected from (C6-C 10 ) aryl, preferably ring A is Preferably, R 1 is selected from hydrogen, -O-(C1-C4)alkyl and 5-6 membered heteroaryl, wherein the -O-(C1-C4)alkyl and 5-6 membered heteroaryl are optionally substituted with 1, 2 or 3 methyl groups, preferably R 1 is selected from hydrogen, -O-methyl, -O-ethyl, -O-propyl, imidazolyl, pyrazolyl and pyrrolyl, wherein the -O-methyl, -O-ethyl, -O-propyl, imidazolyl, pyrazolyl and pyrrolyl are optionally substituted with 1 or 2 methyl groups, preferably R 1 Selected from hydrogen, -OCH3 and Preferably, m is 0 or 2, Preferably, ring B is selected from (C6-C 10 ) aryl, preferably ring B is selected from phenyl and naphthyl, preferably ring B is Preferably, R 2 Selected from hydrogen and halogen, preferably R 2 is selected from hydrogen, fluorine, chlorine and bromine, preferably R 2 selected from hydrogen and -Cl, Preferably, n is 1; or, X is N, Y is S, L1, L2, ring A, R 1 ,m,ring B,R 2 、n、R 3 、T1、T2、T3、T b and Ring C is as defined in any one of claims 1 to 7, Preferably, L1 is selected from a bond, -NH-, -C(=O)NH- and -NHC(=O)-, preferably L1 is selected from a bond, -NH- and -NHC(=O)-#, wherein the # end represents the end connected to ring A, Preferably, L2 is selected from a bond, -O-, -NH-, -(C1-C4)alkylene-, -N[(C1-C4)alkyl]-, -NH-(C1-C4)alkylene-, -(C1-C4)alkylene-NH-, -C(=O)NH- and -NHC(=O)-, wherein the -NH-(C1-C4)alkylene- and -(C1-C4)alkylene-NH- are optionally substituted with one or more groups selected from hydrogen and methyl. Preferably, L2 is selected from a bond, -O-, -NH-, -CH2-, -N(CH3)-, -NH-CH(CH3)-#, -NHCH2-# and -NHC(=O)-#, wherein the # end represents the end connected to ring B, Preferably, ring A is selected from (C6-C 10 ) aryl, 5-9 membered heteroaryl and 6-9 membered heterocyclic group, preferably the 5-9 membered heteroaryl and 6-9 membered heterocyclic group contain 1, 2 or 3 heteroatoms, and the heteroatoms are selected from N atoms, O atoms and S atoms, preferably, ring A is selected from phenyl, pyridyl, pyrimidinyl, piperidinyl, indolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl and 1,3-dihydrobenzimidazol-2-one, preferably ring A is selected from Preferably, R 1 is selected from hydrogen, -(C1-C6)alkyl, -O-(C1-C4)alkyl, -C(=O)NH-(C1-C4)alkyl and 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted by 1 or 2 groups selected from hydrogen, methyl and methoxy, preferably R 1 Selected from hydrogen, -OCH3, Preferably, m is 0 or 2, Preferably, ring B is selected from (C6-C 10 ) aryl, 5-9 membered heteroaryl and 6-9 membered heterocyclic group, preferably the 5-9 membered heteroaryl and 6-9 membered heterocyclic group contain 1, 2 or 3 heteroatoms, and the heteroatoms are selected from N atoms and O atoms, preferably ring B is selected from phenyl, pyridyl, pyrimidinyl, oxazolyl, thiazolyl, pyrazolyl, pyrrolyl, piperidinyl, tetrahydropyranyl, 3,4-dihydro-2H-pyranyl, benzoxazolyl, 1,3-benzodioxolyl and 2-benzoxazolonyl, preferably ring B is selected from Preferably, R 2 is selected from hydrogen, halogen, -(C1-C6)alkyl, -O-(C1-C4)alkyl, -C(=O)O(C1-C4)alkyl and 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with 1 or 2 methyl groups, preferably R 2 Selected from hydrogen, methyl, -F, -Cl, -OCH3, -C(=O)OC(CH3)3 and Preferably, n is 0 or 2.

9. The compound according to any one of claims 1 to 8, its pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystal form, isotope-labeled substance or metabolite thereof, wherein: The compound is selected from 10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystal form, isotope-labeled substance, or a metabolite thereof; the pharmaceutical composition further comprising a pharmaceutically acceptable adjuvant and / or diluent and / or carrier and / or excipient.

11. Use of the compound according to any one of claims 1 to 9, its pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystal form, isotope-labeled substance or metabolite thereof, or the pharmaceutical composition according to claim 10 in the preparation of a medicament as a γ-secretase modulator; or Use in the preparation of a medicament for treating and / or preventing diseases associated with β-amyloid deposition (e.g., Alzheimer's disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, Dutch hereditary cerebral hemorrhage with amyloidosis, multi-infarct dementia, pugilistic dementia, Down syndrome, mild cognitive impairment, memory loss, stroke, glaucoma, microgliosis, loss of olfactory function, brain inflammation, Aβ amyloid angiopathy, Alzheimer's disease-related neurodegeneration, Alzheimer's disease-related attention deficit symptoms, diffuse Lewy body type Alzheimer's disease, senile dementia, mixed vascular origin dementia, dementia of degenerative origin, presenile dementia, dry age-related macular degeneration, etc.), preferably, the disease associated with β-amyloid deposition is Alzheimer's disease; or The invention is used in the preparation of anti-tumor drugs, wherein the tumors include but are not limited to: breast cancer, melanoma, meningioma, soft tissue sarcoma, salivary gland tumor, intraspinal tumor, mediastinal tumor, brain cancer, bone cancer, penile cancer, osteosarcoma, intracranial tumor, tongue cancer, maxillary sinus cancer, thyroid cancer, malignant lymphoma, multiple myeloma, pituitary adenoma, testicular tumor, non-Hodgkin's lymphoma, bladder cancer, leukemia, gastric cancer, nasopharyngeal cancer, laryngeal cancer, oral cancer, esophageal cancer, lung cancer, kidney cancer, cervical cancer, choriocarcinoma, vulvar cancer, skin cancer, endometrial cancer, ovarian cancer, prostate cancer, pancreatic cancer, rectal cancer, colorectal cancer, Kaposi's sarcoma, non-melanoma skin cancer (including squamous cell carcinoma and basal cell carcinoma), carcinoma), hemangioma, glioma, non-Hodgkin lymphoma (diffuse large B-cell lymphoma, B-cell non-Hodgkin lymphoma), colon cancer, liver cancer, neuroblastoma, glioblastoma, plasmacytoma, Hodgkin lymphoma, follicular lymphoma, small non-cleaved cell lymphoma, endemic Burkitt's lymphoma, sporadic Burkitt's lymphoma, marginal zone lymphoma, extranodal mucosa-associated lymphoid tissue lymphoma, nodular monocytic-like B-cell lymphoma, splenic lymphoma, mantle cell lymphoma, large cell lymphoma, diffuse mixed cell lymphoma, immunoblastic lymphoma, primary mediastinal B-cell lymphoma, pulmonary B-cell angiocentric lymphoma, small lymphocytic lymphoma.

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