Heterocyclic compound and use thereof

Abstract

The present invention relates to the field of biomedicine, and specifically relates to a heterocyclic compound represented by formula (I) and the use thereof.

Description

Heterocyclic compounds and uses thereof

[0001] This application is based on and claims priority to CN application No. 202410840648.3, filed on June 26, 2024, the disclosure of which is hereby incorporated by reference in its entirety into the present application. TECHNICAL FIELD

[0002] The present application belongs to the field of biological medicine, and specifically relates to heterocyclic compounds and applications thereof. BACKGROUND

[0003] Alzheimer's disease (AD) is a progressive neurodegenerative disease that can manifest as memory loss, impaired cognitive function, and behavioral disorders. The important pathological features of AD include intracellular neurofibrillary tangles (NFTs) caused by tau protein hyperphosphorylation and extracellular plaque deposition caused by amyloid β-protein (Aβ) aggregation. The pathogenesis of AD has not been conclusively determined, and the mainstream hypotheses include the amyloid cascade hypothesis, the tau protein hypothesis, and the neuroinflammation hypothesis. Among them, the amyloid cascade hypothesis considers that the main cause of AD is the abnormal aggregation and deposition of Aβ. The amyloid plaques formed by the aggregation of Aβ can cause damage and death of neurons, ultimately inducing AD. Based on this hypothesis, inhibiting Aβ production, reducing Aβ aggregation, and promoting Aβ clearance are considered to be the main intervention direction to slow down AD. Currently, immunotherapy targeting Aβ has been approved for marketing by the FDA, which provides strong support for the amyloid cascade hypothesis.

[0004] Aβ is a hydrolysis product of amyloid precursor protein (APP), and its production process is mainly related to β-secretase and γ-secretase. The C-terminal fragment (APP-C99) produced after APP is cleaved by β-secretase can be cleaved by γ-secretase to produce an intracellular fragment (AICD) and a transmembrane polypeptide (Aβ48 or Aβ49). Aβ48 and Aβ49 can be further cleaved by γ-secretase, thereby producing a series of Aβs of different lengths, such as Aβ38, Aβ40, and Aβ42, etc. Among them, Aβ42 is more prone to aggregation to form neurotoxic amyloid plaques than other Aβs, and is therefore considered to be one of the pathogenic factors in the occurrence and development of AD. In addition, it has also been found in clinical practice that there is a certain degree of correlation between the ratio of Aβ42 / Aβ40 in the cerebrospinal fluid and blood of AD patients and the results of PET imaging, so reducing the production of Aβ42 or adjusting the ratio of Aβ42 / Aβ40 is crucial to slow down the progression of AD.

[0005] The γ-secretase comprises four subunits: catalytic subunits PS1 (Presenilin 1) or PS2 (Presenilin 2), and regulatory subunits Pen-2 (Presenilin Enhancer 2), APH-1 (Anterior Pharynx-defective 1) and NCT (Nicastrin). Among them, Pen-2 binds to the PS1 or PS2 subunit, which can promote the assembly and activity of γ-secretase; APH-1 and NCT can stabilize the structure of γ-secretase and regulate its activity; mutations in PS1 and PS2 can change the activity of γ-secretase, leading to an increase in the production of Aβ42. Genetic evidence shows that more than half of the patients with Familial Alzheimer's Disease (FAD) carry mutations in the PS1, PS2 or APP genes, which lead to abnormal hydrolysis of APP and abnormal aggregation of Aβ. Therefore, one of the important strategies to slow down the progression of AD is to intervene in the activity of γ-secretase through drugs.

[0006] Currently, the intervention methods for γ-secretase include γ-secretase inhibitors (GSIs) and γ-secretase modulators (GSMs). Representative compounds of GSIs are Semagacestat (LY450139) and Avagacestat (BMS-708163). Such compounds failed to improve AD symptoms in clinical trials and had serious adverse reactions, so the development has been terminated. The serious adverse reactions of GSIs may be related to the inhibition of the cleavage of substrates other than APP, such as Notch.

[0007] Unlike GSIs, GSMs only modulate the activity of the γ-secretase cleavage site of APP, shifting the cleavage of APP to produce shorter Aβ (such as Aβ37 and Aβ38) instead of longer, easily aggregated Aβ (such as Aβ42 and Aβ43); at the same time, it does not affect the ε cleavage site, thereby avoiding the influence on the cleavage of other substrates such as Notch. Certain non-steroidal anti-inflammatory drugs (NSAIDs) analogs, such as Tarenflurbil, were found to be GSMs. Such compounds can specifically reduce the level of Aβ42 and the ratio of Aβ42 / Aβ40, and increase the level of Aβ38, but do not affect the processing of Notch, and have the effect of reducing neuroinflammation. However, their modulation of γ-secretase is weak, and the BBB permeability is low, so it is difficult to be clinically translated.

[0008] Another class of GSMs is non-NSAIDs, often containing a methylimidazole core, which has a stronger modulation effect on γ-secretase, can effectively reduce the level of Aβ42 and the ratio of Aβ42 / Aβ40, and increase the levels of Aβ37 and Aβ38, and does not affect Notch cleavage. A new generation of GSMs (RG6289) from Roche abandons the methylimidazole core, which can reduce the level of Aβ42 and the ratio of Aβ42 / Aβ40, and increase the levels of Aβ37 and Aβ38 in vitro and in mice, and has completed phase I clinical trials and is planned to conduct phase II clinical trials in 2024. Compared with γ-secretase inhibitors, γ-secretase modulators show better prospects for research.

[0009] Although important progress has been made in immunotherapy against Aβ, AD is a long-term progressive disease that requires continuous treatment. Therefore, developing a new generation of safe and effective γ-secretase modulators as maintenance therapy is a good strategy and is expected to bring new breakthroughs in the treatment of AD. SUMMARY

[0010] The first aspect of the present application provides a compound represented by formula (I), a pharmaceutically acceptable salt, a prodrug, a stereoisomer, a tautomer, a hydrate, a solvate, a crystal form, an isotopically labeled form or a metabolite form thereof,

[0011] wherein,

[0012] is a single bond or a double bond;

[0013] X is selected from O, S, N, NR 5 , CR 4 and CHR 4 ;

[0014] Y is selected from O, S, N, NR 5 , CR 4 and CHR 4 ;

[0015] M is selected from O and S;

[0016] T1 is selected from C(=W) and S(=W1)(=W2), W, W1 and W2 are each independently selected from O and S and NR 6 ;

[0017] L1 and L2 are each independently selected from a bond, -O-, -S-, -NR a -, -(C1-C4)alkylene-, -(C2-C4)alkenylene- and -(C2-C4)alkynylene-, said R a is selected from hydrogen, -(C1-C4)alkyl and -(C1-C4)haloalkyl;

[0018] R 1 is selected from the group consisting of hydrogen, (C6-C 14 )aryl, (5-12 membered)heteroaryl, (3-12 membered)heterocyclyl, and (C3-C 12 )cycloalkyl, said (C6-C 14 )aryl, (5-12 membered)heteroaryl, (3-12 membered)heterocyclyl, and (C3-C 12 )cycloalkyl being optionally substituted with one or more R 11 ,

[0019] R 11 is each independently selected from the group consisting of 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 , -C(=O)NR b R c , -P(=O)-R b R c , -Si[(C1-C6)alkyl]3, =O, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C1-C6)haloalkyl, -CH2R b , -(C1-C6)alkylene-OH, -(C1-C6)alkylene-NH2, -(C3-C 10 )cycloalkyl, -(C6-C 10 )aryl, (3-10 membered)heterocyclyl, and (5-12 membered)heteroaryl, said -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C1-C6)haloalkyl, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-NH2, -(C3-C 10 )cycloalkyl, -(C6-C 10)aryl, (3-10-membered)heterocyclic and (5-12-membered)heteroaryl groups may optionally be substituted by one or more groups independently selected from hydrogen, halogen, -OH, -SH, -NH2, -COOH, -(C1-C4)alkyl, -O(C1-C4)alkyl, -NH(C1-C4)alkyl and -NH[(C1-C4)alkyl]2, wherein R b and R c Each is independently selected from hydrogen, halogen, -OH, -NH2, -(C1-C6)alkyl, -O(C1-C6)alkyl, -(C1-C6)haloalkyl, -C(=O)(C1-C6)alkyl, -S(=O)2(C1-C6)alkyl, (3-10-membered)heterocyclic and (5-12-membered)heteroaryl;

[0020] 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 -C(=O)NR b R c -P(=O)-R b R c -Si[(C1-C6)alkyl]3, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)ynyl, (C6-C 14 ) aryl, (5-12 quinone) heteroaryl, (3-12 quinone) heterocyclic, (C3-C 12 )cycloalkyl and (C4-C 12 )cycloalkenyl, wherein -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)ynyl, (C6-C 14 ) aryl, (5-12 quinone) heteroaryl, (3-12 quinone) heterocyclic, (C3-C 12 )cycloalkyl and (C4-C 12)alkyl, -S(=O)2-(C1-C6)alkyl, -NH2, -NH(C1-C6)alkyl, -N[(C1-C6)alkyl]2, -COOH, -C(=O)-(C1-C6)alkyl, -C(=O)O-(C1-C6)alkyl, -C(=O)NH(C1-C6)alkyl, -P(=O)(OH)2, -P(=O)(OH)[O(C1-C6)alkyl], -P(=O)[(C1-C6)alkyl]2, -P(=O)[O(C1-C6)alkyl]2, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, (C3-C7)cycloalkyl, and (4-7 membered)heterocyclyl, said R b and R c are each independently selected from the group consisting of hydrogen, halogen, -OH, -NH2, -(C1-C6)alkyl, -O(C1-C6)alkyl, -(C1-C6)haloalkyl, -C(=O)(C1-C6)alkyl, -S(=O)2(C1-C6)alkyl, (3-9 membered)heterocyclyl, and (5-9 membered)heteroaryl;

[0021] R 3 is selected from the group consisting of 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 , -C(=O)NR b R c , -P(=O)-R b R c , -Si[(C1-C6)alkyl]3, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, (C6-C 14 )aryl, (5-12 membered)heteroaryl, (3-12 membered)heterocyclyl, and (C3-C 12)cycloalkyl, wherein -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)ynyl, (C6-C 14 ) aryl, (5-12) heteroaryl, (3-12) heterocyclic and (C3-C 12 ) cycloalkyl groups are optionally surrounded by one or more R 31 Instead, the R b and R c Each is independently selected from hydrogen, halogen, -OH, -NH2, -(C1-C6)alkyl, -O(C1-C6)alkyl, -(C1-C6)haloalkyl, -C(=O)(C1-C6)alkyl, -S(=O)2(C1-C6)alkyl, (3-10-membered)heterocyclic groups, and (5-12-membered)heteroaryl groups.

[0022] R 31 Each is independently selected from hydrogen, halogen, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)ynyl, 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 -C(=O)NR b R c -P(=O)-R b R c -Si[(C1-C6)alkyl]3, -(C1-C6)haloalkyl, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-NH2, -(C3-C9)cycloalkyl, -(C6-C 10 )aryl, (3-9)heterocyclic and (5-9)heteroaryl, wherein the (3-9)heterocyclic group is optionally substituted with one or more groups selected from hydrogen, -(C1-C4)alkyl and -C(=O)-O(C1-C4)alkyl, wherein R b and R ceach independently selected from the group consisting of hydrogen, -OH, -NH2, halogen, -(Ci-C6)alkyl, -0(Ci-C6)alkyl, -(Ci-C6)haloalkyl, -C(=0)(Ci-C6)alkyl, -C(=0)0(Ci-C6)alkyl, -S(=0)2(Ci-C6)alkyl, -Si[(Ci-C6)alkyl]3, -(Ci-C4)alkylene-Si[(Ci-C6)alkyl]3, (3-9 membered)heterocyclyl, and (5-9 membered)heteroaryl;

[0023] R 4 each independently selected from the group consisting of hydrogen, halogen, nitro, nitroso, -CN, -OH, -0-(Ci-C6)alkyl, -SH, -S(=0)-(Ci-C6)alkyl, -S(=0)2-(Ci-C6)alkyl, -NH2, -NH(Ci-C6)alkyl, -N[(Ci-C6)alkyl]2, -COOH, -C(=0)-(Ci-C6)alkyl, -C(=0)NH(Ci-C6)alkyl, -(Ci-C6)alkyl, -(Ci-C6)haloalkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(Ci-C4)alkylene-(3-12 membered)heterocyclyl, -(Ci-C4)alkylene-(C3-C 12 ) cycloalkyl, and -(Ci-C4)alkylene-NH-(6-12 membered)heterocyclyl, said -(Ci-C6)alkyl, -(Ci-C6)haloalkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(Ci-C4)alkylene-(3-12 membered)heterocyclyl, -(Ci-C4)alkylene-(C3-C 12 ) cycloalkyl, and -(Ci-C4)alkylene-NH-(6-12 membered)heterocyclyl being optionally substituted with one or more groups selected from halogen, nitro, nitroso, -CN, -OH, -SH, -NH2, -NH(Ci-C6)alkyl, -N[(Ci-C6)alkyl]2, -(Ci-C6)alkyl, and (5-9 membered)heteroaryl, said (5-9 membered)heteroaryl being optionally substituted with one or more groups selected from hydrogen, halogen, and -(Ci-C6)alkyl;

[0024] R 5 each independently selected from the group consisting of hydrogen, halogen, nitro, nitroso, -CN, -OH, -SH, -NH2, -(Ci-C6)alkyl, -(Ci-C6)haloalkyl, -0(Ci-C6)alkyl, -NH(Ci-C6)alkyl, -N[(Ci-C6)alkyl]2, and (C3-C8)cycloalkyl.

[0025] In certain embodiments, said X is selected from O, S, N, NR 5 and CR 4 , wherein R 4and R 5 as defined in any of the embodiments.

[0026] In certain embodiments, said Y is selected from O, S, N, NR 5 and CR 4 wherein R 4 and R 5 as defined in any of the embodiments.

[0027] In certain embodiments, said M is O.

[0028] In certain embodiments, said T1is selected from C(=0), C(=S) and S(=0)2.

[0029] In certain embodiments, said structural unit is selected from wherein X, Y, M, W, W1and W2are as defined in any of the embodiments.

[0030] In certain embodiments, said structural unit is selected from wherein X, Y, M, W, W1, W2and R 4 as defined in any of the embodiments.

[0031] In certain embodiments, said structural unit is selected from wherein R 4 and R 5 as defined in any of the embodiments.

[0032] In certain embodiments, said R 4each is independently selected from hydrogen, halogen, nitro, nitroso, -CN, -OH, -SH, -NH2, -COOH, -(Ci-C6)alkyl, -(Ci-C6)haloalkyl, -(Ci-C4)alkylene-(4-10 membered)heterocyclyl, -(Ci-C4)alkylene-(C3-C8)cycloalkyl, and -(Ci-C4)alkylene-NH-(6-10 membered)heterocyclyl, said -(Ci-C6)alkyl, -(Ci-C6)haloalkyl, -(Ci-C4)alkylene-(4-10 membered)heterocyclyl, -(Ci-C4)alkylene-(C3-C8 membered)cycloalkyl, and -(Ci-C4)alkylene-NH-(6-10 membered)heterocyclyl are optionally substituted with one or more groups selected from halogen, nitro, -CN, -OH, -SH, -NH2, -(Ci-C4)alkyl, and (5-6 membered)heteroaryl, said (5-6 membered)heteroaryl is optionally substituted with 1, 2, or 3 -(Ci-C4)alkyl.

[0033] In certain embodiments, said R 4 each is independently selected from hydrogen, halogen, -(Ci-C4)alkyl, -(Ci-C4)haloalkyl, -(Ci-C4)alkylene-(5-6 membered)heterocyclyl, and -(Ci-C4)alkylene-NH-(6-9 membered)heterocyclyl, said -(Ci-C4)alkyl, -(Ci-C4)haloalkyl, -(Ci-C4)alkylene-(5-6 membered)heterocyclyl, and -(Ci-C4)alkylene-NH-(6-9 membered)heterocyclyl are optionally substituted with 1, 2, 3, 4, or 5 groups selected from halogen, -OH, -NH2, -(Ci-C4)alkyl, and (5-6 membered)heteroaryl, said (5-6 membered)heteroaryl is optionally substituted with 1, 2, or 3 methyl groups.

[0034] In certain embodiments, said R 4 each is independently selected from hydrogen, -(Ci-C4)alkyl, -(Ci-C4)haloalkyl, -CH2-(5-6 membered)heterocyclyl, and -CH2-NH-(6-9 membered)heterocyclyl, said -(Ci-C4)alkyl, -(Ci-C4)haloalkyl, -CH2-(5-6 membered)heterocyclyl, and -CH2-NH-(6-9 membered)heterocyclyl are optionally substituted with 1, 2, 3, 4, or 5 groups selected from halogen, -OH, -NH2, -(Ci-C4)alkyl, and methyl-substituted (5-6 membered)heteroaryl, said (5-6 membered)heterocyclyl and (5-6 membered)heteroaryl contain 1, 2, or 3 heteroatoms selected from N and O.

[0035] In certain embodiments, said R 4each is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, halomethyl, haloethyl, halo-n-propyl, halo-i-propyl, -CH2-tetrahydropyrrolyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-morpholinyl, and -CH2-NH-3-azabicyclo[3.2.1]octanyl, said methyl, ethyl, n-propyl, i-propyl, halomethyl, haloethyl, halo-n-propyl, halo-i-propyl, -CH2-tetrahydropyrrolyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-morpholinyl, and -CH2-NH-3-azabicyclo[3.2.1]octanyl being optionally substituted with 1, 2, 3, 4, or 5 groups selected from fluoro, chloro, bromo, -OH, -NH2, methyl, imidazolyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, methylimidazolyl, methylpyrazolyl, methylpyridazinyl, methylpyrimidinyl, and methylpyrazinyl.

[0036] In certain embodiments, the R 4 each is independently selected from the group consisting of hydrogen, -CH3, -CHF2, -CH2CH3,

[0037] In certain embodiments, the R 5 each is independently selected from the group consisting of hydrogen, halogen, nitro, -CN, -OH, -SH, -NH2, -(Ci-C6)alkyl, and -(Ci-C6)haloalkyl.

[0038] In certain embodiments, the R 5 each is independently selected from the group consisting of hydrogen, halogen, -OH, -NH2, and -(Ci-C6)alkyl.

[0039] In certain embodiments, the R 5 each is independently selected from the group consisting of hydrogen and -(Ci-C4)alkyl.

[0040] In certain embodiments, the R 5 each is independently selected from the group consisting of hydrogen, methyl, ethyl, and i-propyl.

[0041] In certain embodiments, the R 5 is -CH3.

[0042] In certain embodiments, the L1is selected from the group consisting of a bond, -NR a -, -(Ci-C4)alkylene-, -(C2-C4)alkenylene-, and -(C2-C4)alkynylene-, said R a is selected from the group consisting of hydrogen, -(Ci-C4)alkyl, and -(Ci-C4)haloalkyl.

[0043] In certain embodiments, the L1is selected from the group consisting of a bond, -NR a-, -CH2-, -CH2CH2-, vinylidene, propenyne, ethynylidene, and propynylidene, wherein R a Selected from hydrogen and methyl.

[0044] In some embodiments, L1 is selected from bonds, -NH-, -CH=CH-, and

[0045] In some implementations, the R 1 Selected from hydrogen, (C 6- C 10 ) aryl, (5-10) heteroaryl, (4-10) heterocyclic and (C3-C 10 )cycloalkyl, the (C 6- C 10 ) aryl, (5-10) heteroaryl, (4-10) heterocyclic and (C3-C 10 ) cycloalkyl groups are optionally surrounded by one or more R 11 Instead, the R 11 As defined in any of the implementation schemes.

[0046] In some implementations, the R 1 The R group is selected from hydrogen, phenyl, naphthyl, (5-9 quinary) heteroaryl, and (5-9 quinary) heterocyclic groups, wherein the (5-9 quinary) heteroaryl and (5-9 quinary) heterocyclic groups contain 1, 2, or 3 heteroatoms selected from N, O, and S, wherein the N and S atoms are optionally oxidized. 1 Choose any 1, 2, 3, 4 or 5 Rs 11 Instead, the R 11 As defined in any of the implementation schemes.

[0047] In some implementations, the R 1 The alkyl group is selected from hydrogen, phenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, indolyl, benzimidazolyl, benzoxazolyl, 1,3-benzodioxonel, 2-benzozolinonel, 2-benzimidazolonel, piperidinyl, and 3-azabicyclo[3.2.1]octyl, wherein the phenyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, indolyl, benzimidazolyl, benzoxazolyl, 1,3-benzodioxonel, 2-benzozolinonel, 2-benzimidazolonel, piperidinyl, and 3-azabicyclo[3.2.1]octyl group is optionally surrounded by 1, 2, or 3 R... 11 Instead, the R 11 As defined in any of the implementation schemes.

[0048] In some implementations, the R 11 Each is independently selected from hydrogen, halogen, nitro, -CN, -OR b -SR b -NRb R c , -COOH, -C(=O)-R b , -C(=O)NR b R c , -P(=O)-R b R c , =O, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, -(C6-C 10 )aryl, (3-9 membered)heterocyclyl, and (5-9 membered)heteroaryl, said -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, -(C6-C 10 )aryl, (3-9 membered)heterocyclyl, and (5-9 membered)heteroaryl optionally substituted with 1, 2, 3, 4, or 5 groups independently 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. In certain embodiments, said R b and R c are each independently selected from hydrogen, methyl, methoxy, ethyl, and halomethyl.

[0049] In certain embodiments, said R 11 are each independently selected from hydrogen, halogen, -CN, -OH, -O-(C1-C4)alkyl, -SH, -NH2, -COOH, -C(=O)NH2, -C(=O)NH-(C1-C4)alkyl, =O, -(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 optionally substituted with 1, 2, or 3 groups selected from hydrogen, halogen, -O(C1-C4)alkyl, and -(C1-C4)alkyl.

[0050] In certain embodiments, said R 11 are each independently selected from hydrogen, -(C1-C4)alkyl, -O-(C1-C4)alkyl, -C(=O)NH2, =O, and (5-6 membered)heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, said -(C1-C4)alkyl, -O-(C1-C4)alkyl, and (5-6 membered)heteroaryl optionally substituted with 1, 2, or 3 groups selected from hydrogen, fluorine, chlorine, bromine, -CH3, -CH2CH3, and -OCH3.

[0051] In certain embodiments, the R 11 each is independently selected from the group consisting of hydrogen, -CH3, -OCH3, -C(=O)NH2, =O,

[0052] In certain embodiments, the R 1 is selected from the group consisting of hydrogen,

[0053] In certain embodiments, the L2is selected from the group consisting of a bond, -O-, -S-, -NR a - and -(C1-C4)alkylene-, said R a is selected from the group consisting of hydrogen, -(C1-C4)alkyl and -(C1-C4)haloalkyl.

[0054] In certain embodiments, the L2is selected from the group consisting of a bond, -O-, -S-, -NR a - and -(C1-C4)alkylene-, said R a is selected from the group consisting of hydrogen, methyl and halomethyl.

[0055] In certain embodiments, the L2is selected from the group consisting of a bond, -O-, -S-, -NH-, -N(CH3)-, -CH2-, -CH2CH2-, -CH(CH3)- and -CH(CH2CH3)-.

[0056] In certain embodiments, the L2is selected from the group consisting of a bond, -CH2- and -CH2CH2-.

[0057] In certain embodiments, the R 2 is selected from the group consisting of hydrogen, halogen, nitro, -CN, -OR b , -SR b , -S(=O)-R b , -S(=O)2-R b , -NR b R c , -COOH, -C(=O)-R b , -C(=O)NR b R c , -P(=O)-R b R c , -(C1-C6)alkyl, -(C6-C 10 )aryl, (5-10 membered)heteroaryl, (4-10 membered)heterocyclyl, (C3-C 10 )cycloalkyl and (C4-C 10 )cycloalkenyl, said -(C1-C6)alkyl, -(C6-C 10)aryl, (5-10 membered)heteroaryl, (4-10 membered)heterocyclyl, (C3-C 10 )Cycloalkyl and (C4-C 10 )Cycloalkenyl are optionally substituted with one or more groups selected from hydrogen, halogen, nitro, -CN, -OH, -O-(C1-C4)alkyl, -SH, -S(=O)2-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -COOH, -C(=O)-(C1-C4)alkyl, -C(=O)O(C1-C4)alkyl, -C(=O)NH(C1-C4)alkyl, -P(=O)(OH)2, -P(=O)(OH)[O(C1-C4)alkyl], -P(=O)[(C1-C4)alkyl]2, -P(=O)[O(C1-C4)alkyl]2, -(C1-C4)alkyl, -(C1-C4)haloalkyl, -(C2-C4)alkenyl, -(C2-C4)alkynyl, (C3-C7)cycloalkyl and (4-7 membered)heterocyclyl, said R b and R c are each independently selected from hydrogen, -OH, -NH2, halogen, -(C1-C4)alkyl, -(C1-C4)haloalkyl, -O(C1-C4)alkyl, -C(=O)(C1-C4)alkyl and -S(=O)2(C1-C4)alkyl.

[0058] In certain embodiments, said R 2 are selected from hydrogen, halogen, nitro, -CN, -OH, -O-(C1-C4)alkyl, -S(=O)2-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -C(=O)OH, -C(=O)(C1-C4)alkyl, -C(=O)O-(C1-C4)alkyl, -C(=O)NH-(C1-C4)alkyl, -(C1-C6)alkyl, (C3-C8)cycloalkyl, (C4-C 10 )Cycloalkenyl, (4-10 membered)heterocyclyl, (5-10 membered)heteroaryl, phenyl and naphthyl, said -(C1-C6)alkyl, (C3-C8)cycloalkyl, (C4-C 10) cycloalkenyl, (4-10 membered)heterocyclyl, (5-10 membered)heteroaryl, phenyl, and naphthyl, said (4-10 membered)heterocyclyl and (5-10 membered)heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, said N and S atoms optionally oxidized, said -(Ci-C4)alkyl, (C3-C6)cycloalkyl, (C6-Ci0)cycloalkenyl, (4-10 membered)heterocyclyl, (5-10 membered)heteroaryl, phenyl, and naphthyl optionally substituted with one or more groups selected from hydrogen, halogen, -OH, -O(Ci-C4)alkyl, -S(=O)2(Ci-C4)alkyl, -NH2, -NH(Ci-C4)alkyl, -N[(Ci-C4)alkyl]2, -C(=O)OH, -C(=O)(Ci-C4)alkyl, -C(=O)O(Ci-C4)alkyl, -P(=O)(OH)2, -P(=O)[(Ci-C4)alkyl]2, -(Ci-C4)alkyl, -(Ci-C4)haloalkyl, -(C2-C4)alkenyl, -(C2-C4)alkynyl, (C3-C6)cycloalkyl, and (4-6 membered)heterocyclyl;

[0059] In certain embodiments, said R 2 selected from hydrogen, halogen, -NH2, -C(=O)OH, -C(=O)O-(Ci-C4)alkyl, -(Ci-C4)alkyl, (C3-C6)cycloalkyl, (C6-Ci0)cycloalkenyl, (4-10 membered)heterocyclyl, (5-10 membered)heteroaryl, phenyl, and naphthyl, said (4-10 membered)heterocyclyl and (5-10 membered)heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, said N and S atoms optionally oxidized, said -(Ci-C4)alkyl, (C3-C6)cycloalkyl, (C6-Ci0)cycloalkenyl, (4-10 membered)heterocyclyl, (5-10 membered)heteroaryl, phenyl, and naphthyl optionally substituted with one or more groups selected from hydrogen, halogen, -OH, -OCH3, -OCH2CH3, -S(=O)2CH3, -S(=O)2CH2CH3, -NH2, -N(CH3)(CH2CH3), -N(CH2CH3)2, -NHCH3, -N(CH3)2, -C(=O)OH, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)OCH3, -C(=O)OCH2CH3, -P(=O)(OH)2, -P(=O)(CH3)2, -CH3, -CH2CH3, propyl, cyclopropyl, cyclobutyl, cyclopentyl, isopropyl, t-butyl, trifluoromethyl, ethynyl, and tetrahydropyrrolyl; 10 ) cycloalkenyl, (4-10 membered)heterocyclyl, (5-10 membered)heteroaryl, phenyl, and naphthyl, said (4-10 membered)heterocyclyl and (5-10 membered)heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, said N and S atoms optionally oxidized, said -(Ci-C4)alkyl, (C3-C6)cycloalkyl, (C6-Ci0)cycloalkenyl, (4-10 membered)heterocyclyl, (5-10 membered)heteroaryl, phenyl, and naphthyl optionally substituted with one or more groups selected from hydrogen, halogen, -OH, -O(Ci-C4)alkyl, -S(=O)2(Ci-C4)alkyl, -NH2, -NH(Ci-C4)alkyl, -N[(Ci-C4)alkyl]2, -C(=O)OH, -C(=O)(Ci-C4)alkyl, -C(=O)O(Ci-C4)alkyl, -P(=O)(OH)2, -P(=O)[(Ci-C4)alkyl]2, -(Ci-C4)alkyl, -(Ci-C4)haloalkyl, -(C2-C4)alkenyl, -(C2-C4)alkynyl, (C3-C6)cycloalkyl, and (4-6 membered)heterocyclyl; 10 ) cycloalkenyl, (4-10 membered)heterocyclyl, (5-10 membered)heteroaryl, phenyl, and naphthyl, said (4-10 membered)heterocyclyl and (5-10 membered)heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, said N and S atoms optionally oxidized, said -(Ci-C4)alkyl, (C3-C6)cycloalkyl, (C6-Ci0)cycloalkenyl, (4-10 membered)heterocyclyl, (5-10 membered)heteroaryl, phenyl, and naphthyl optionally substituted with one or more groups selected from hydrogen, halogen, -OH, -O(Ci-C4)alkyl, -S(=O)2(Ci-C4)alkyl, -NH2, -NH(Ci-C4)alkyl, -N[(Ci-C4)alkyl]2, -C(=O)OH, -C(=O)(Ci-C4)alkyl, -C(=O)O(Ci-C4)alkyl, -P(=O)(OH)2, -P(=O)[(Ci-C4)alkyl]2, -(Ci-C4)alkyl, -(Ci-C4)haloalkyl, -(C2-C4)alkenyl, -(C2-C4)alkynyl, (C3-C6)cycloalkyl, and (4-6 membered)heterocyclyl;

[0060] In certain embodiments, said R 2halogen, -NH2, -C(=O)OH, -C(=O)O-(Ci-C4)alkyl, -(Ci-C4)alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydropyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, piperidinyl, pyrrolyl, pyridyl, phenyl, naphthyl, pyrimidinyl, 1,3,5-triazinyl, 1,4-dioxanyl, piperazinyl, morpholinyl, thiomorpholinyl, indolyl, indazolyl, benzimidazolyl, 2,3-benzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, azaindolyl, indolinyl, benzothiazolyl, indanyl, benzothiophenyl, pyridazinyl, benzocyclobutenyl, 1,2,3,4-tetrahydronaphthyl, dihydrogestenyl, benzotriazolyl, 1,2,3-thiazol(1,5-A)pyridinyl, 2,3-naphthyridinyl, 4-azaindolazolyl, benzo[D]isothiazolyl, benzothiazolinyl, thiazolo[5,4-C]pyridinyl, benzoxazolyl, and 1,2-benzisoxazolyl groups are optionally substituted with one or more groups selected from hydrogen, fluorine, chlorine, bromine, -OCH3, -OCH2CH3, -S(=O)2CH3, -S(=O)2CH2CH3, -NH2, -NH(CH3), -N(CH3)2, -N(CH3)(CH2CH3), -N(CH2CH3)2, -C(=O)OH, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)OCH3, -C(=O)OCH2CH3, -P(=O)(OH)2, -P(=O)(CH3)2, -CH3, -CH2CH3, propyl, cyclopropyl, cyclobutyl, cyclopentyl, isopropyl, t-butyl, trifluoromethyl, ethynyl, and tetrahydropyrrolyl groups.

[0061] In certain embodiments, the R 2selected from the group consisting of hydrogen, halogen, -NH2, -C(=O)OH, -C(=O)O-(Ci-C4)alkyl, -(Ci-C4)alkyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl, pyrrolyl, pyridinyl, phenyl, indolyl, indazolyl, benzimidazolyl, 2,3-benzofuranyl, quinolinyl, indolinyl, benzothiazolyl, indanyl, and benzothiophenyl, said cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl, pyrrolyl, pyridinyl, phenyl, indolyl, indazolyl, benzimidazolyl, 2,3-benzofuranyl, quinolinyl, indolinyl, benzothiazolyl, indanyl, and benzothiophenyl being optionally substituted with one or more radicals selected from the group consisting of hydrogen, fluorine, chlorine, bromine, -OCH3, -S(=O)2CH3, -NH2, -NH(CH3), -N(CH3)2, -C(=O)OH, -C(=O)OCH3, -P(=O)(OH)2, -CH2CH3, propyl, isopropyl, cyclopropyl, tert-butyl, trifluoromethyl, ethynyl, cyclobutyl, and tetrahydropyrrolyl. 3、 -CH2CH3, propyl, isopropyl, cyclopropyl, tert-butyl, trifluoromethyl, ethynyl, cyclobutyl, and tetrahydropyrrolyl.

[0062] In certain embodiments, said R 2 selected from the group consisting of hydrogen, -NH2, -CH3, -C(=O)OH, -C(=O)OCH3,

[0063] In certain embodiments, said R 3 selected from the group consisting of hydrogen, halogen, -NH2, -C(=O)OH, -C(=O)O-(Ci-C4)alkyl, -(Ci-C4)alkyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl, pyrrolyl, pyridinyl, phenyl, indolyl, indazolyl, benzimidazolyl, 2,3-benzofuranyl, quinolinyl, indolinyl, benzothiazolyl, indanyl, and benzothiophenyl, said cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl, pyrrolyl, pyridinyl, phenyl, indolyl, indazolyl, benzimidazolyl, 2,3-benzofuranyl, quinolinyl, indolinyl, benzothiazolyl, indanyl, and benzothiophenyl being optionally substituted with one or more radicals selected from the group consisting of hydrogen, fluorine, chlorine, bromine, -OCH3, -S(=O)2CH3, -NH2, -NH(CH3), -N(CH3)2, -C(=O)OH, -C(=O)OCH3, -P(=O)(OH)2, -CH2CH3, propyl, isopropyl, cyclopropyl, tert-butyl, trifluoromethyl, ethynyl, cyclobutyl, and tetrahydropyrrolyl. b b b b b c b b c selected from the group consisting of hydrogen, halogen, -NH2, -C(=O)OH, -C(=O)O-(Ci-C4)alkyl, -(Ci-C4)alkyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl, pyrrolyl, pyridinyl, phenyl, indolyl, indazolyl, benzimidazolyl, 2,3-benzofuranyl, quinolinyl, indolinyl, benzothiazolyl, indanyl, and benzothiophenyl, said cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl, pyrrolyl, pyridinyl, phenyl, indolyl, indazolyl, benzimidazolyl, 2,3-benzofuranyl, quinolinyl, indolinyl, benzothiazolyl, indanyl, and benzothiophenyl being optionally substituted with one or more radicals selected from the group consisting of hydrogen, fluorine, chlorine, bromine, -OCH3, -S(=O)2CH3, -NH2, -NH(CH3), -N(CH3)2, -C(=O)OH, -C(=O)OCH3, -P(=O)(OH)2, -CH2CH3, propyl, isopropyl, cyclopropyl, tert-butyl, trifluoromethyl, ethynyl, cyclobutyl, and tetrahydropyrrolyl. 10 10 10 10 31 b c ​​​​​​​​​​​​​​each independently selected from the group consisting of hydrogen, -OH, -NH2, halogen, -(Ci-C6)alkyl, -0(Ci-C6)alkyl, and -(Ci-C6)haloalkyl, said R 31 as defined in any embodiment.

[0064] In certain embodiments, said R 3 selected from the group consisting of hydrogen, halogen, nitro, -CN, -OH, -0-(Ci-C4)alkyl, -S(=0)2-(Ci-C4)alkyl, -NH2, -NH(Ci-C4)alkyl, -N[(Ci-C4)alkyl]2, -COOH, -C(=0)-(Ci-C4)alkyl, -C(=0)0-(Ci-C4)alkyl, -C(=0)NH-(Ci-C4)alkyl, -(Ci-C4)alkyl, -(C2-C4)alkenyl, -(C2-C4)alkynyl, (C6-C 10 )aryl, (5-10 membered)heteroaryl, (3-8 membered)heterocyclyl, and (C3-C8)cycloalkyl, said -(Ci-C4)alkyl, -(C2-C4)alkenyl, -(C2-C4)alkynyl, (C6-C 10 )aryl, (5-10 membered)heteroaryl, (3-8 membered)heterocyclyl, and (C3-C8)cycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 R 31 , said R 31 as defined in any embodiment.

[0065] In certain embodiments, said R 3 selected from the group consisting of hydrogen, -S(=0)2-(Ci-C4)alkyl, -C(=0)-(Ci-C4)alkyl, -C(=0)0-(Ci-C4)alkyl, -(Ci-C4)alkyl, -(C2-C4)alkenyl, (C6-C 10 )aryl, (4-8 membered)heterocyclyl, and (C3-C7)cycloalkyl, said -(Ci-C4)alkyl, -(C2-C4)alkenyl, (C6-C 10 )aryl, (4-8 membered)heterocyclyl, and (C3-C7)cycloalkyl is optionally substituted with 1, 2, or 3 R 31 , said R 31 as defined in any embodiment.

[0066] In certain embodiments, said R 3selected from hydrogen, -S(=0)2-(Ci-C4)alkyl, -(Ci-C4)alkyl, -(C2-C4)alkenyl, phenyl, (4-6 membered)heterocyclyl, and (C3-C5)cycloalkyl, said (4-6 membered)heterocyclyl containing 1 or 2 heteroatoms selected from N and O, said -(Ci-C4)alkyl, -(C2-C4)alkenyl, phenyl, (4-6 membered)heterocyclyl, and (C3-C5)cycloalkyl optionally substituted with 1, 2, or 3 R 31 substituents, said R 31 substituents are as defined in any of the embodiments.

[0067] In certain embodiments, said R 3 substituents are as defined in any of the embodiments. 31 substituents, said R 31 substituents are as defined in any of the embodiments.

[0068] In certain embodiments, said R 31 are each independently selected from hydrogen, halogen, -(Ci-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, nitro, -CN, -OR b , -SR b , -S(=0)-R b , -S(=0)2-R b , -NR b R c , -NR b C(=0)-R c , -COOH, -C(=0)-R b , -C(=0)NR b R c , -P(=0)-R b R c , -Si[(Ci-C6)alkyl]3, -(Ci-C6)haloalkyl, -(Ci-C6)alkylene-OH, -(Ci-C6)alkylene-NH2, -(C3-C9)cycloalkyl, -(C6-C 10 )aryl, (3-9 membered)heterocyclyl, and (5-9 membered)heteroaryl, said (3-9 membered)heterocyclyl optionally substituted with one or more groups selected from hydrogen, -(Ci-C6)alkyl, and -C(=0)-0(Ci-C4)alkyl, said Rb and R c are each independently selected from the group consisting of hydrogen, -OH, -NH2, halogen, -(Ci-C4)alkyl, -0(Ci-C4)alkyl, -(Ci-C4)haloalkyl, -C(=0)(Ci-C4)alkyl, -C(=0)0(Ci-C4)alkyl, -Si[(Ci-C4)alkyl]3, and -(Ci-C4)alkylene-Si[(Ci-C4)alkyl]3.

[0069] In certain embodiments, the R 31 are each independently selected from the group consisting of hydrogen, halogen, -(Ci-C4)alkyl, -(C2-C4)alkenyl, -(C2-C4)alkynyl, -CN, -OH, -0-Si[(Ci-C4)alkyl]3, -0-(Ci-C4)alkylene-Si[(Ci-C4)alkyl]3, -S(=0)2-(Ci-C4)alkyl, -NH2, -NR b (Ci-C4)alkyl, -NR b C(=0)-(Ci-C4)alkyl, -NR b C(=0)-0(Ci-C4)alkyl, -COOH, -C(=0)-0(Ci-C4)alkyl, -C(=0)NR b (Ci-C4)alkyl, -P(=0)-(OR b )(OR b ), -P(=0)-[(Ci-C4)alkyl]2, -(Ci-C4)haloalkyl, -(C3-C7)cycloalkyl, phenyl, (3-7 membered)heterocyclyl, and (5-6 membered)heteroaryl, said (3-7 membered)heterocyclyl being optionally substituted with one or more -C(=0)-0(Ci-C4)alkyl, said R b are each independently selected from the group consisting of hydrogen and -(Ci-C4)alkyl.

[0070] In certain embodiments, the R 31each independently selected from the group consisting of hydrogen, halogen, -(Ci-C4)alkyl, -(C2-C4)alkenyl, -(C2-C4)alkynyl, -OH, -0-Si[(Ci-C4)alkyl]3, -0-(Ci-C4)alkylene-Si[(Ci-C4)alkyl]3, -S(=0)2-(Ci-C4)alkyl, -NH2, -NH(Ci-C4)alkyl, -N[(Ci-C4)alkyl]2, -NHC(=0)-(Ci-C4)alkyl, -NHC(=0)0(Ci-C4)alkyl, -N[(Ci-C4)alkyl]C(=0)0(Ci-C4)alkyl, -COOH, -C(=0)-0(Ci-C4)alkyl, -C(=0)NH(Ci-C4)alkyl, -P(=0)-(OH)2, -P(=0)(OH)[0(Ci-C4)alkyl], -P(=0)[0(Ci-C4)alkyl]2, -P(=0)-[(Ci-C4)alkyl]2, -(C3-C5)cycloalkyl, phenyl, (3-6 membered)heterocyclyl, and (5-6 membered)heteroaryl, said (3-6 membered)heterocyclyl and (5-6 membered)heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, said N and S atoms optionally oxidized, said (3-6 membered)heterocyclyl optionally substituted with 1 -C(=0)-OCH(CH3)3.

[0071] In certain embodiments, the R 31 each independently selected from the group consisting of hydrogen, halogen, -OH, methyl, ethyl, propyl, ethenyl, propenyl, ethynyl, propynyl, -S(=0)2CH3, -S(=0)2CH2CH3, -NH2, -NHCH3, -N(CH3)2, -NHC(=0)CH3, -NHBoc, -N(CH3)Boc, -C(=0)OH, -C(=0)OCH3, -C(=0)OCH2CH3, -C(=0)NHCH3, -C(=0)NHCH2CH3, -P(=0)(OH)2, -P(=0)(CH3)2, -P(=0)(OCH3)2, -P(=0)(OCH3)(OCH2CH3), -Boc, cyclopropyl, cyclobutyl, cyclopentyl, oxiranyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyrrolyl, tetrahydropyranyl, phenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, piperidinyl, pyrrolyl, pyridinyl, pyrimidinyl, 1,4-dioxanyl, piperazinyl, morpholinyl, thiomorpholinyl,

[0072] In certain embodiments, the R 31each independently selected from hydrogen, fluoro, chloro, -OH, methyl, ethenyl, ethynyl, -S(=0)2CH3, -NH2, -NHCH3, -N(CH3)2, -NHC(=0)CH3, -NHBoc, -N(CH3)Boc, -C(=0)OH, -C(=0)OCH3, -C(=0)OCH2CH3, -C(=0)NHCH3, -P(=0)(OH)2, -P(=0)(CH3)2, -Boc, cyclopropyl, cyclobutyl, oxiranyl, oxetanyl, azetidinyl, tetrahydropyranyl, phenyl, oxazolyl,

[0073] In certain embodiments, the R 3 is selected from hydrogen, -CH3, -CH2CH3,

[0074] In certain embodiments, the compound is selected from the structures of Formula (I-1)

[0075] wherein M, W, L1, L2, R 1 , R 2 , R 3 and R 4 are as defined in any of the embodiments.

[0076] In certain embodiments, the compound is selected from the structures of Formula (I-2)

[0077] wherein L2, R 2 , R 3 and R 4 are as defined in any of the embodiments.

[0078] In certain embodiments, the L2is selected from a bond, -0-, -S-, -NH-, and -(Ci-C4)alkylene-.

[0079] In certain embodiments, the L2is selected from a bond, -CH2-, and -CH2CH2-.

[0080] In certain embodiments, the L2is selected from a bond.

[0081] In certain embodiments, the R 2hydrogen, fluoro, chloro, bromo, -OCH3, -S(=O)2CH3, -NH2, -NH(CH3), -N(CH3)2, -C(=O)OH, -C(=O)OCH3, -P(=O)(OH)2, -P(=O)(CH3)2, -CH3, and -CH2CH3.

[0082] In certain embodiments, the R 2 hydrogen, phenyl, (9-10) membered heteroaryl, 9 membered heterocyclyl, and C9cycloalkenyl, said (9-10) membered heteroaryl and 9 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, S, said phenyl, (9-10) membered heteroaryl, 9 membered heterocyclyl, and C9cycloalkenyl optionally substituted with one or more groups selected from hydrogen, halogen, -(Ci-C4)alkyl, and -O-(Ci-C4)alkyl.

[0083] In certain embodiments, the R 2 hydrogen, phenyl, indolyl, indazolyl, benzimidazolyl, 2,3-benzofuranyl, quinolinyl, indolinyl, benzothiazolyl, indanyl, and benzothiophenyl, said phenyl, indolyl, indazolyl, benzimidazolyl, 2,3-benzofuranyl, quinolinyl, indolinyl, benzothiazolyl, indanyl, and benzothiophenyl optionally substituted with one or more groups selected from hydrogen, fluoro, chloro, bromo, -OCH3, -CH3, and -CH2CH3.

[0084] In certain embodiments, the R 2 hydrogen,

[0085] In certain embodiments, the R 2 hydrogen,

[0086] In certain embodiments, the R 3 hydrogen, -(Ci-C4)alkyl, -(C2-C4)alkenyl, phenyl, (4-6 membered)heterocyclyl containing 1 or 2 heteroatoms selected from N and O, and (C3-C5)cycloalkyl, said -(Ci-C4)alkyl, phenyl, (4-6 membered)heterocyclyl, and (C3-C5)cycloalkyl optionally substituted with 1, 2, or 3 R 31substituted, said R 31 as defined in any of the embodiments.

[0087] In certain embodiments, said R 31 each is independently selected from hydrogen, halogen, -OH, methyl, ethyl, -S(=0)2CH3, -NH2, -NHCH3, -N(CH3)2, -NHC(=0)CH3, -NHBoc, -C(=0)OH, -C(=0)OCH3, -C(=0)OCH2CH3, -C(=0)NHCH3, -P(=0)(OH)2, -P(=0)(CH3)2, -Boc, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyrrolyl, tetrahydropyranyl, oxazolyl, phenyl,

[0088] In certain embodiments, said R 31 each is independently selected from hydrogen, halogen, -OH, methyl, ethyl, -S(=0)2CH3, -NH2, -NHCH3, -N(CH3)2, -NHC(=0)CH3, -NHBoc, -C(=0)OH, -C(=0)OCH3, -C(=0)NHCH3, -P(=0)(OH)2, -P(=0)(CH3)2, -Boc, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyrrolyl, tetrahydropyranyl, phenyl.

[0089] In certain embodiments, said R 3 is selected from hydrogen, -(Ci-C4)alkyl, -(C2-C4)alkenyl, azetidinyl, tetrahydropyranyl, and (C3-C5)cycloalkyl, said -(Ci-C4)alkyl, -(C2-C4)alkenyl, azetidinyl, tetrahydropyranyl, and (C3-C5)cycloalkyl being optionally substituted with 1, 2, or 3 R 31 substituted, said R 31 as defined in any of the embodiments.

[0090] In certain embodiments, said R 3 is selected from hydrogen, -CH3, -CH2CH3,

[0091] In certain embodiments, said R 3 is selected from hydrogen, -CH3, and

[0092] In certain embodiments, said R 3 is selected from -(Ci-C4)alkyl and -(Ci-C4)alkylene-azetidinyl.

[0093] In certain embodiments, the R 3 is selected from -CH3and

[0094] In certain embodiments, the R 4 are each independently selected from hydrogen, -(Ci-C4)alkyl, -(Ci-C4)haloalkyl, and -CH2-(5-6 membered)heterocyclyl, said -(Ci-C4)alkyl, -(Ci-C4)haloalkyl, and -CH2-(5-6 membered)heterocyclyl being optionally substituted with 1, 2, 3, 4, or 5 groups selected from halogen, -OH, -NH2, -(Ci-C4)alkyl, and methyl substituted (5-6 membered)heteroaryl, said (5-6 membered)heterocyclyl and (5-6 membered)heteroaryl containing 1, 2, or 3 heteroatoms selected from N and O.

[0095] In certain embodiments, the R 4 are each independently selected from hydrogen, -(Ci-C4)alkyl, and -(Ci-C4)haloalkyl.

[0096] In certain embodiments, the R 4 are each independently selected from methyl and halomethyl.

[0097] In certain embodiments, the R 4 is methyl.

[0098] In certain embodiments, the compound is selected from

[0099] A second aspect of the present application provides a pharmaceutical composition comprising a compound of the first aspect of the application, a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystal form, isotopically-labeled, or metabolite form thereof; said pharmaceutical composition further comprising a pharmaceutically acceptable adjuvant and / or diluent and / or carrier and / or excipient.

[0100] A third aspect of the present application provides the use of a compound of the first aspect of the application, a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystal form, isotopically-labeled, or metabolite form thereof, or a pharmaceutical composition of the second aspect of the application, for the manufacture of a medicament as a gamma-secretase modulator.

[0101] The fourth aspect of the present application provides the use of the compound, pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystal form, isotopically-labeled form or metabolite form thereof of the first aspect of the present application, or the pharmaceutical composition of the second aspect of the present application in the manufacture of a medicament for treating and / or preventing a disease related to β-amyloid deposition (e.g. Alzheimer's disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, hereditary cerebral hemorrhage with amyloidosis-Dutch type, multi-infarct dementia, dementia pugilistica, Down's syndrome, mild cognitive impairment, memory loss, stroke, glaucoma, small gliacytic disease, 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 of Alzheimer's disease, senile dementia, dementia of mixed vascular origin, dementia of degenerative origin, presenile dementia, dry age-related macular degeneration, etc.). In some embodiments, the disease related to β-amyloid deposition is Alzheimer's disease.

[0102] The fifth aspect of the present application provides the use of the compound, pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystal form, isotopically-labeled form or metabolite form thereof of the first aspect of the present application, or the pharmaceutical composition of the second aspect of the present application in the manufacture of an anti-tumor medicament, 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 lymphocytic cancer, 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, large intestine 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, small non-cleaved cell lymphoma, endemic Burkitt's lymphoma, sporadic Burkitt's lymphoma, marginal zone lymphoma, extranodal mucosa-associated lymphoid tissue lymphoma, nodal 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.

[0103] Definitions of terms

[0104] In the present application, unless otherwise specified, the scientific and technical terms used herein have the meanings commonly understood by one of ordinary skill in the art. Also, the laboratory procedures referred to herein are conventional procedures well established in the respective fields. Also, for better understanding of the present application, the definitions and explanations of the related terms are provided below.

[0105] In case the compound names used herein are not consistent with the chemical structural formulas, the chemical structural formulas shall prevail.

[0106] As used herein, the term "pharmaceutically acceptable salt" refers to (i) a salt formed between an acidic functional group (e.g., -COOH) present in the compounds provided herein and an appropriate inorganic or organic cation (base), and includes, but is not limited to, alkali metal salts such as sodium salts, potassium salts, lithium salts, and the like; alkaline earth metal salts such as calcium salts, magnesium salts, and the like; other metal salts such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts, cobalt salts, and the like; inorganic base salts such as ammonium salts; organic base salts such as tertiary octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine 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 the like; and (ii) a salt formed between a basic functional group (e.g., -NH2) present in the compounds provided herein and an appropriate inorganic or organic anion (acid), and includes, but is not limited to, hydrogen halide salts such as hydrofluoride salts, hydrochloride salts, hydrobromide salts, hydroiodide salts, and the like; inorganic acid salts such as nitrate salts, perchlorate salts, sulfate salts, phosphate salts, and the like; lower alkyl sulfonic acid salts such as methanesulfonate salts, trifluoromethanesulfonate salts, ethanesulfonate salts, and the like; aryl sulfonic acid salts such as benzenesulfonate salts, p-toluenesulfonate salts, and the like; organic acid salts such as acetate salts, malate salts, fumarate salts, succinate salts, citrate salts, tartrate salts, oxalate salts, maleate salts, and the like; amino acid salts such as glycine salts, trimethylglycine salts, arginine salts, ornithine salts, glutamic acid salts, aspartic acid salts, and the like.

[0107] As used herein, the term "prodrug" refers to compounds of the present application which can be converted in vivo after administration to a subject to the compound of the present application by, for example, oxidation, reduction, hydrolysis or the like. The prodrug itself can or can not exhibit biological activity, for example, the biological activity of the compound of Formula (I). For example, a compound of Formula (I) which includes a hydroxyl or carboxyl group can be administered as an ester which is hydrolyzed in vivo to form the hydroxyl compound or carboxyl compound. Similarly, a compound of Formula (I) which includes an amino group is acylated, alkylated or phosphorylated to form, for example, a compound which includes an Eicosanoylamino, Alaninylamino, Pivaloyloxymethylamino group. Further information on the use of prodrugs can be found in Pro-drugs as Novel Delivery Systems, Vol. 14, of the A.C.S. Symposium Series (T Higuchi and W Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association). Some examples of prodrugs in accordance with the present application include: (i) if the compound of Formula (I) contains a carboxylic acid functional group (-COOH), then included are esters thereof, for example, where (C1-C8)alkyl is substituted for the hydrogen; (ii) if the compound of Formula (I) contains an alcohol functional group (-OH), then included are ethers thereof, for example, where (C1-C6)alkanoyloxymethyl is substituted for the hydrogen; and (iii) if the compound of Formula (I) contains a primary or secondary amino functional group (-NH2or -NHR, where R is not H), then included are amides thereof, for example, where (C1-C6)alkanoyl is substituted for one or both hydrogens. In addition, certain compounds of Formula (I) can themselves act as prodrugs of other compounds of Formula (I). 10 )alkanoyl is substituted for one or both hydrogens. In addition, certain compounds of Formula (I) can themselves act as prodrugs of other compounds of Formula (I).

[0108] As used herein, the term "stereoisomer" means isomers having the same molecular formula but differing in the arrangement of atoms or groups in space. The term "stereoisomers" includes conformational isomers and configurational isomers. Configurational isomers include enantiomeric and diastereomeric isomers. The present application encompasses all possible stereoisomers of the compounds of the present application, and mixtures thereof. For example, single enantiomers, single diastereomers or mixtures of diastereomers. When the present compounds contain olefinic double bonds, unless specified otherwise, the compounds can exist as E or Z isomers, or as mixtures thereof.

[0109] As used herein, the term "tautomer" refers to isomers of functional groups that result from the rapid movement of an atom in a molecule to two positions, for example, keto-enol tautomers, imine-enamine tautomers, and the like. Compounds of the present application, if tautomers exist, can exist as single tautomers or mixtures of them, preferably as the more stable tautomer predominates.

[0110] As used herein, the term "solvate" refers to a substance formed by the association of a compound of the present application with solvent molecules. The solvent can be an organic solvent (e.g., methanol, ethanol, propanol, acetonitrile, and the like), for example, a compound of the present application can form an ethanolate with ethanol. A compound of the present application can also form a hydrate with water. The amount of solvent can be present in stoichiometric or non-stoichiometric amounts.

[0111] As used herein, the term "crystal form" refers to the crystal structure of a substance. When a substance crystallizes, the way the molecules or atoms are arranged in the crystal lattice space is different due to the influence of various factors, which makes the intramolecular or intermolecular bonding mode change, resulting in different crystal structures. A compound of the present application can exist in one crystal structure, or can exist in multiple crystal structures, i.e., has "polymorphism". A compound of the present application can exist in different crystal forms.

[0112] As used herein, the term "isotopically-labeled compound" refers to a compound in which one or more atoms are replaced by the same atom having an atomic mass or mass number different from the atomic mass or mass number that predominates in nature. Examples of isotopes suitable for inclusion in the compounds of the present application 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.

[0113] As used herein, "selected from the group consisting of" means that the groups on either side of the hyphen are directly connected, for example, A-L-B, when L is a bond, A-L-B is A-B.

[0114] As used herein, "optionally substituted" means that the group can be unsubstituted or substituted with a substituent, for example, -(C1-C6)alkyl optionally substituted with halogen means that -(C1-C6)alkyl can be unsubstituted or substituted with halogen to give haloalkyl. As used herein, unless otherwise indicated, substituents can be substituted on any reasonable site capable of forming a bond.

[0115] As used herein, the term "(C1-C6)alkyl" means a straight or branched chain saturated hydrocarbon radical containing from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms, examples of which include, but are not limited to, methyl, ethyl, propyl, n-butyl, isobutyl, isopropyl, t-butyl, n-pentyl, n-hexyl, and in the present application, preferred C1-C6 alkyl is C1-C4 alkyl. It is understood that -N[(C 1- (C1-C6)alkyl]2 means that the nitrogen atom is attached to two (C 1- (C1-C6)alkyl groups, which can be the same or different.

[0116] As used herein, the term "(C2-C6)alkenyl" means a straight or branched chain unsaturated hydrocarbon radical containing at least one carbon-carbon double bond and from 2 to 6 (e.g., 2, 3, 4, 5, or 6) carbon atoms, examples of which include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,4-hexadienyl, and in the present application, preferred C2-C6 alkenyl is C2-C4 alkenyl.

[0117] As used herein, the term "(C2-C6)alkynyl" means a straight or branched chain unsaturated hydrocarbon radical containing at least one carbon-carbon triple bond and from 2 to 6 carbon atoms, examples of which 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, 1,4-hexadiynyl, and in the present application, preferred C2-C6 alkynyl is C2-C4 alkynyl.

[0118] As used herein, the term "(C1-C6)alkylene" means a straight or branched chain saturated divalent hydrocarbon radical containing from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms, examples of which include, but are not limited to, methylene, ethylene, propylene, and in the present application, preferred (C1-C6)alkylene is (C1-C4)alkylene.

[0119] As used herein, the term "(C2-C4)alkenylene" refers to a straight or branched chain unsaturated divalent hydrocarbon radical containing at least one carbon-carbon double bond and having a carbon atom number of from 2 to 4 (e.g., 2, 3, or 4), specific examples of which include, but are not limited to: ethenylene, propenylene, butenylene, butadienylene.

[0120] As used herein, the term "(C2-C4)alkynylene" refers to a straight or branched chain unsaturated divalent hydrocarbon radical containing at least one triple bond and having a carbon atom number of from 2 to 4, specific examples of which include, but are not limited to: ethynylene, propynylene, butynylene, butadiynylene.

[0121] As used herein, the term "halogen" includes fluorine, chlorine, bromine, and iodine, preferred halogens in the present application are fluorine, chlorine, bromine.

[0122] As used herein, the term "halo" refers to a hydrogen on a group or compound being replaced by one or more halogen atoms, including perhalo and partial halo.

[0123] As used herein, the term "aryl" refers to an unsaturated carbocyclic radical having a conjugated pi-electron system, for example, (C6-C 14 )aryl groups consist of 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) carbon atoms, (C6-C 14 )aryl groups include (C6-C 10 )aryl groups. Non-limiting examples include, but are not limited to: phenyl, naphthyl, anthryl.

[0124] As used herein, the term "heteroaryl" refers to an unsaturated radical having a conjugated pi-electlectron system consisting of ring atoms, at least one (e.g., 1, 2, 3, or 4) of which is a heteroatom selected from N, O, and S, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized. For example, (5-12 membered)heteroaryl groups consist 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, and the like heteroaryl groups. The heteroaryl groups include monocyclic and polycyclic, specific examples of which include, but are not limited to: furanyl, 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, quinolinyl, isoquinolinyl.

[0125] As used herein, the term "cycloalkyl" refers to a saturated hydrocarbon group consisting of carbon atoms, such as (C3-C4) cycloalkyl groups. 12 Cycloalkyl groups refer to those composed of 3 to 12 carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12), including C3-C4. 10 ,C3-C9,C3-C8,C3-C7,C4-C 10 ,C5-C6,C3,C4,C5,C6,C7,C8,C9,C 10 Cycloalkyl groups. The cycloalkyl groups include monocyclic, bicyclic, or polycyclic rings, including spirocyclic, fused, or bridged rings, and specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0126] As used herein, the term "cycloalkenyl" refers to a partially unsaturated hydrocarbon group consisting of one or more double bonds, such as (C3-C4) carbon atoms. 12 Cycloalkenyl groups refer to groups composed of 3 to 12 carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12), including C3-C4 groups. 10 ,C3-C9,C3-C8,C3-C7,C4-C 10 ,C5-C6,C3,C4,C5,C6,C7,C8,C9,C 10 Isocyclic alkenyl groups. The cyclic alkenyl groups include monocyclic, bicyclic, or polycyclic rings, including spirocyclic, fused, or bridged rings, and specific examples include, but are not limited to, 1,3-cyclohexadienyl and indenyl.

[0127] As used herein, the term "heterocyclic group" refers to a saturated or partially unsaturated cyclic group consisting of ring atoms, wherein at least one (e.g., 1, 2, 3, 4, or 5) of the ring atoms is a heteroatom selected from N, O, and S, wherein the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms are optionally oxidized, and the carbon atom is optionally oxidized. For example, a (3-12-membered) heterocyclic group refers to a group consisting of 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) ring atoms, including 4-10-membered, 5-10-membered, 5-9-membered, 6-9-membered, 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, and other heterocyclic groups. The heterocyclic group includes monocyclic, bicyclic, or polycyclic rings, including spirocyclic, fused, or bridged rings. Specific embodiments 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-benzodioxyl, benzomorpholinyl, and 1,2,3,4-tetrahydroquinoxaline.

[0128] As used herein, the term "pharmaceutically acceptable carrier or excipient" refers to a carrier and / or excipient that is compatible, philosophically and / or physiologically, with the subject and the active ingredient, 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 adjusting agents, ionic strength enhancers, agents to maintain osmotic pressure, agents to retard absorption, diluents, antioxidants, coloring, flavoring agents, preservatives, taste masking agents, and the like. 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 hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Non-limiting examples of binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycols, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose, and hydroxypropylmethylcellulose. Non-limiting examples of diluents include lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dicalcium 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 adjusting agents include phosphate buffers. Ionic strength enhancers include, but are not limited to, sodium chloride. Agents to maintain osmotic pressure include, but are not limited to, sugars, NaCl, and the like. Agents to retard absorption include, but are not limited to, mono- and diglycerides, and gelatin. Preservatives include, but are not limited to, various antibacterial and antifungal agents such as thiomersal, 2-phenoxyethanol, parabens, chlorobutanol, phenol, sorbic acid, and the like.

[0129] As used herein, the term "prevent" refers to an approach taken to stop or delay the occurrence of a disease or disorder or a symptom in a subject. As used herein, the term "treat" refers to an approach taken to obtain a beneficial or desired clinical result. For purposes of this application, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilization (i.e., not worsening) of the state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. Moreover, "treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0130] As used herein, the term "effective amount" means an amount that is sufficient to achieve or at least partially achieve the desired effect. For example, a prophylactically effective amount is an amount that is sufficient to prevent, retard, or delay the onset of a disease; a therapeutically effective amount is an amount that is sufficient to cure or at least partially arrest the disease and its complications in an already afflicted patient. Determining such effective amounts is well within the capability of those skilled in the art. For example, an amount effective for therapeutic purposes will depend on the severity of the disease to be treated, the general state of the patient's own immune system, the general condition of the patient, e.g., the age, weight, and sex of the patient, the mode of administration of the drug, and other therapies that the patient may be undergoing, etc. DETAILED DESCRIPTION

[0131] The embodiments of the present application will be described in detail with examples, but those skilled in the art will understand that the following examples are only for illustrating the present application and should not be considered as limiting the scope of the present application. The specific conditions not mentioned in the examples are carried out according to the conventional conditions or the conditions recommended by the manufacturer. The reagents or instruments used are not specified by the manufacturer, and are all conventional products that can be obtained by purchase.

[0132] Nuclear magnetic resonance: In the following examples, the structure of the compounds is determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LCMS). The NMR chemical shifts (δ) are given in 10 -6 (ppm) units. NMR measurements are performed by a Bruker AVANCE III 500MHz nuclear magnetic instrument, and the measurement solvents are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), etc., and the internal standard is tetramethylsilane (TMS).

[0133] Analytical liquid chromatography: Analytical liquid chromatography is used for reaction system monitoring and purity analysis of important intermediates and target products. Analytical liquid chromatography system: Agilent 1260 Infinity II (equipped with 1260 Binary Pump pump, Vial Sampler injector, MCT column oven, DAD WR detector); chromatographic column: Waters XBridge BEH C18 3.5 μm, 4.6*150 mm.

[0134] Preparative liquid chromatography: Preparative liquid chromatography is used for separation and purification of small amounts of important intermediates and target products. Preparative liquid chromatography system: Agilent 1290 Infinity II (equipped with 1290 Prep Bin Pump pump, Prep ALS / FC injector / collection, 1260 VWD detector); C18 reversed-phase silica gel chromatographic column.

[0135] LC-MS system: Waters UPLC H-Class ultra-high performance liquid-QDa combination instrument; chromatographic column: Waters XBridge BEH C18 1.7 μm, 2.1*75 mm.

[0136] Liquid phase flow phase matching: acidic condition: A: 0.05% formic acid aqueous solution, B: acetonitrile; basic condition: A: 0.05% ammonia aqueous solution, B: acetonitrile; neutral condition: A: 5mM NH4HCO3 aqueous solution, B: acetonitrile. The above data is the default flow phase matching, and appropriate adjustment can be made according to the measured sample properties during specific implementation analysis test.

[0137] Fast purification system: the fast purification system is used for the rough preparation and purification of compounds in the conventional reaction system, the instrument model is Biotage Isolera One, and the normal phase column and the reverse phase column matched therewith are purchased from Santai Tech. The normal phase silica gel column commonly used has specifications of 12g, 25g, 40g, 80g, 120g and 330g, and specific parameters are as follows: 40-63 μm, The reverse phase C18 column commonly used has specifications of 40g, 80g, 120g and 330g, and specific parameters are as follows: 20-45 μm,

[0138] Thin layer chromatography: thin layer chromatography (TLC) silica gel plate is used for qualitative analysis of reaction system or separation and purification of a small amount of sample. When thin layer chromatography is used for qualitative analysis, the product used is Merck thin layer silica gel plate, and the specifications are as follows: GF 254 , 20*20 cm, glass plate, 0.25 mm coating; when thin layer chromatography is used for separation and purification, the product used is Lianyuan preparative silica gel plate, and the specifications are as follows: GF 254 , 20*20 cm, glass plate, 1 mm coating.

[0139] Chemical reagents: the known starting materials of the present application can be synthesized according to the literature, patent methods and the like known in the art, or can be purchased from chemical reagent companies such as Alfa Aesar, Acros, Sigma-Aldrich, TCI, Aikang, An'eg, Ailadin, Bailingwei (J&K), Bide, Lianyuan, Makclin, Shaoyuan (Accela), Titan (Adamas), Xinesi, Ino Kai and the like.

[0140] Abbreviations

[0141] Abbreviations of protecting groups:

[0142] Boc tert-butyloxycarbonyl

[0143] TBDPS tert-butyldiphenylsilyl

[0144] TBS tert-butyldimethylsilyl

[0145] THP 2-tetrahydropyranyl

[0146] Tos p-toluenesulfonyl

[0147] Reagent Abbreviations:

[0148] ACN acetonitrile

[0149] Boc2O di-tert-butyl dicarbonate

[0150] DCE 1,2-dichloroethane

[0151] DCM dichloromethane

[0152] DEAD diethyl azodicarboxylate

[0153] DIAD diisopropyl azodicarboxylate

[0154] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0155] DIEA N,N-diisopropylethylamine

[0156] DMAP 4-dimethylaminopyridine

[0157] DMF N,N-dimethylformamide

[0158] DMSO dimethyl sulfoxide

[0159] EA ethyl acetate

[0160] HMPA hexamethylphosphoramide

[0161] HATU N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate

[0162] NBS N-bromosuccinimide

[0163] PE petroleum ether

[0164] TBAF tetrabutylammonium fluoride

[0165] TBDPSCl tert-butyldiphenylsilyl chloride

[0166] TBSCl tert-butyldimethylsilyl chloride

[0167] TEA triethylamine

[0168] TFA trifluoroacetic acid

[0169] THF tetrahydrofuran

[0170] TPSCl 2,4,6-triisopropylbenzenesulfonyl chloride

[0171] TsCl p-toluenesulfonyl chloride

[0172] TsOH p-toluenesulfonic acid

[0173] Bpin pinacolatoboronate

[0174] General preparation route

[0175] Route one:

[0176] wherein step A is a multi-step reaction, step B is a coupling reaction, and step C is a nucleophilic reaction; A1is as defined for X herein, A2is as defined for Y herein, and A3is C or as defined for W herein, for example A1, A2, and A3are each independently selected from N, C, O, and S; R is absent or as defined for R 4 , R 5 herein, for example R is absent or is alkyl; R 3 is absent or as defined herein, for example R 3 is absent or is alkyl; L1and L2are as defined herein, for example L1and L2are each independently selected from a bond, -CH2-, and R 1 , R 2 herein.

[0177] Route two:

[0178] wherein step A is a coupling reaction, step B is a multi-step reaction, and step C is a nucleophilic reaction; L2is as defined herein, for example L2is selected from a bond, -CH2-, and R 2 as defined herein; R 3 is absent or as defined herein, for example R 3 is absent or is alkyl.

[0179] Example 1: Synthesis of compound E-1

[0180] Step A: To a solution of ethyl 2-amino-5-(3-methoxy-4-(4-methyl-1H-imidazol-1- yl)phenyl)-4-methylthiophene-3-carboxylate (160 mg, 0.431 mmol), 4-fluorophenyl isocyanate (177.18 mg, 1.292 mmol) in acetonitrile (30 mL) was added cesium carbonate (421.04 mg, 1.292 mmol) at room temperature. After the addition, the whole mixture was stirred at 90 °C for 8 hours. When the reaction was completed, it was directly filtered and concentrated, and the residue was separated by HPLC preparation. The preparation condition: Waters XBridge Prep C 18 18 (30 mm x 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-15% B; 3.5-15 min, 15%-40% B; detector, UV 254 nm. Compound E-1, 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5- methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (86.67 mg, 0.187 mmol, 43.50%) was obtained. 1 1H NMR (500 MHz, DMSO-d6) δ ppm 12.44 (s, 1H), 7.82 (d, J = 1.1 Hz, 1H), 7.47-7.49 (m, 1H), 7.34-7.37 (m, 2H), 7.29-7.32 (m, 2H), 7.24 (d, J = 2.3 Hz, 1H), 7.17 (s, 1H), 7.14 (dd, J = 8.5 and 2.3 Hz, 1H), 3.89 (s, 3H), 2.47 (s, 3H), 2.16 (s, 3H). ESI-MS m / z = 463.0 [M+H] + ; Calcu. = 462.1.

[0181] Example 2: Synthesis of compound E-2

[0182] Step A: To a solution of 1-(4-bromo-2-methoxyphenyl)-4-methyl-1H-imidazole (4000 mg, 16.871 mmol), dichlorobis(triphenylphosphine)palladium (592 mg, 0.844 mmol), copper(I) iodide (535 mg, 1.687 mmol), triethylamine (4.690 mL, 33.741 mmol) in tetrahydrofuran (80 mL) was added trimethylsilyl ethyne (1823 mg, 18.558 mmol) at room temperature. After the addition, the whole mixture was stirred at 50 °C for 3 h under nitrogen atmosphere. The reaction was concentrated under reduced pressure to give a residue. The residue was separated by silica gel column (SiO2, PE:EA = 80:20) to give the product 1-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)-4-methyl-1H-imidazole (3000 mg, 11.792 mmol, 69.90%) as colorless oil. ESI-MS m / z = 285.1 [M+H] + ; Calcu. = 284.1.

[0183] Step B: To a solution of 1-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)-4-methyl-1H- imidazole (3000 mg, 10.547 mmol) in tetrahydrofuran (60 mL) was added tetrabutylammonium fluoride (10.5 mL, 10.5 mmol, 1 M in tetrahydrofuran) at room temperature. After the addition, the whole mixture was stirred at room temperature for 6 h. When the reaction was completed, the reaction was filtered and concentrated under reduced pressure to give an oily residue, which was separated by silica gel column (SiO2, PE:EA = 80:20). The reaction gave the product 1-(4-ethynyl-2-methoxyphenyl)-4-methyl-1H-imidazole (1800 mg, 8.481 mmol, 80.40%) as brown solid. ESI-MS m / z = 213.1 [M+H] + ; Calcu. = 212.1.

[0184] Step C: To a solution of 1-(4-ethynyl-2-methoxyphenyl)-4-methyl-1H-imidazole (20 mg, 0.094 mmol), 6-bromo-3-(4-fluorophenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)- dione (33 mg, 0.094 mmol) in N,N-dimethylformamide (3 mL) was added palladium on tris(dibenzylideneacetone)dipalladium (22 mg, 0.019 mmol) at room temperature. After the addition, the whole mixture was stirred at 120 °C for overnight under nitrogen atmosphere. When the reaction was completed, the reaction was concentrated directly to give a solid residue, which was separated by preparative HPLC. The preparative condition: Welch C 18(30 mm x 250 mm, 5 μm); A: 0.05% FA; B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-25% B; 3.5-18 min, 25%-65% B; Detector, UV 254 nm. The reaction gave E-2, white solid product 3-(4-fluorophenyl)-6-((3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)ethynyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (5 mg, 0.010 mmol, 10.91%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 12.43 (s, 1H,), 7.87 (s, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.41 (d, J = 1.5 Hz, 2H), 7.34-7.39 (m, 3H), 7.28-7.34 (m, 1H), 7.26 (dd, J = 8.0 and 1.6 Hz, 1H), 3.89 (s, 3H), 2.51 (s, 3H), 2.16 (s, 3H). ESI-MS m / z = 487.2 [M+H] + ; Calcu. = 486.1.

[0185] Example 3: Synthesis of compound E-3

[0186] Step A: To a solution of 6-bromo-3-(4-fluorophenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (40 mg, 0.113 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole (28 mg, 0.113 mmol) in N,N-dimethylformamide (4 mL) was added cesium carbonate (110 mg, 0.338 mmol) and tetrakis(triphenylphosphine)palladium (39 mg, 0.034 mmol) at room temperature, then the whole mixture was warmed to 120 °C and stirred for 4 h under nitrogen protection. Then the reaction mixture was concentrated under reduced pressure to give brown crude product. The crude product was separated by HPLC prep, prep condition: Welch Xtimate C18 (30 mm x 250 mm, 5 μm); A: 0.1% formic acid in water; B: MeCN; 5 mL / min; 0-3 min, 5% B; 3-15 min, 5%-50% B; Detector, UV 254 nm. The reaction gave E-3, white solid product 6-(benzo[d]oxazol-6-yl)-3-(4-fluorophenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (11.71 mg, 0.030 mmol, 26.54%).1 H NMR (500 MHz, DMSO-d6) δ ppm 8.77 (s, 1 H), 7.7-7.9 (m, 2 H), 7.45 (dd, J=1.7, 8.2 Hz, 1 H), 7.2-7.3 (m, 4 H), 2.43 (s, 3 H). ESI-MS m / z = 393.9 [M+H] + ; Calcu. = 393.1.

[0187] Example 4: Synthesis of compound E-4

[0188] Step A: To a solution of 6-bromo-3-(4-fluorophenyl)-5-methylthieno[2,3- d]pyrimidine-2,4(lH,3H)-dione (40 mg, 0.113 mmol), 3,4- (methylenedioxy)benzeneboronic acid (23 mg, 0.136 mmol) in N,N- dimethylformamide (4 mL) was added cesium carbonate (110 mg, 0.339 mmol) and tetrakis(triphenylphosphine)palladium (39 mg, 0.034 mmol) at room temperature. The whole mixture was warmed to 120 °C and stirred under nitrogen atmosphere for 4 h. Subsequently, the reaction mixture was concentrated under reduced pressure to give a brown crude product. The crude product was subjected to HPLC preparative separation, preparative condition: Welch Xtimate C18 (30 mm x 250 mm, 5 μm); A: 0.1% formic acid in water; B: MeCN; 5 mL / min; 0-3 min, 5% B; 3-15 min, 5%-50% B; detector, UV 254 nm. This reaction gave E-4, white solid product 6-(benzo[d][l,3]dioxol-5-yl)-3-(4-fluorophenyl)-5- methylthieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (8.41 mg, 0.021 mmol, 18.58%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.77 (s, 1 H), 7.7-7.9 (m, 2 H), 7.45 (dd, J=1.7, 8.2 Hz, 1 H), 7.2-7.3 (m, 4 H), 2.43 (s, 3 H). ESI-MS m / z = 393.9 [M+H]

[0189] Example 5: Synthesis of compounds E-5 and M-7

[0190] Step A: After 6-bromo-3-(4-fluorophenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(lH,3H)- dione (900 mg, 2.534 mmol), potassium carbonate (350 mg, 2.534 mmol) were dissolved in N,N- dimethylformamide (10 mL), iodomethane (0.206 mL, 2.534 mmol) was added at room temperature, the whole mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was controlled to room temperature, then filtered through diatomite, then water (80 mL) was added, white solid precipitated, suction filtration to obtain solid crude product 6-bromo-3-(4-fluorophenyl)-l,5-dimethylthieno[2,3-d]pyrimidine-2,4(lH,3H)- dione (700 mg, 1.896 mmol, 74.82 %). ESI-MS m / z = 371.0 [M+H] + ; Calc u. = 369.9.

[0191] Step B: After 6-bromo-3-(4-fluorophenyl)-l,5-dimethylthieno[2,3-d]pyrimidine-2,4(lH,3H)- dione (150 mg, 0.406 mmol), (3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl)boronic acid (104 mg, 0.447 mmol), cesium carbonate (331 mg, 1.015 mmol) were dissolved in N,N- dimethylformamide (5 mL), tetrakis triphenylphosphine palladium (140.75 mg, 0.122 mmol) was added at room temperature, the whole mixture was stirred at 120 °C under nitrogen protection for 5 hours. After the reaction was completed, the reaction was directly concentrated to obtain solid residue, and preparative separation was carried out. Preparation condition: Welch Xtimate C 18 (30 mm x 250 mm, 5 μm); A: 0.1 % FA; B: MeCN; 40 mL / min; 0-3 min, 10 % B; 3-3.5 min, 10 %-20 % B; 3.5-18 min, 20 %-60 % B; detector, UV 254 nm. The reaction obtained E-5, white solid product 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-lH-imidazol-l- yl)phenyl)-l,5-dimethylthieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (45 mg, 0.094 mmol, 23.24 %). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.83 (d, J = 1.1 Hz, 1 H), 7.50 (d, J = 8.1 Hz, 1 H), 7.32 - 7.36 (m, 5 H), 7.26 (d, J = 1.7 Hz, 1 H), 7.16 - 7.19 (m, 2 H), 3.90 (s, 3 H), 3.51 (s, 3 H), 3.31 (s, 3 H), 2.17 (s, 3 H). ESI-MS m / z = 477.3 [M+H] + ; Calcu. = 476.1.

[0192] Example 6: Synthesis of compound E-6

[0193] Step A: To a solution of 6-bromo-3-(4-fluorophenyl)-5-methylthieno[2,3- d]pyrimidine-2,4(lH,3H)-dione (40 mg, 0.113 mmol), (2-oxo-2,3-dihydrobenzo[d]oxazol-6- yl)boronic acid (24.26 mg, 0.136 mmol) in N,N-dimethylformamide (4 mL) was added cesium carbonate (110.08 mg, 0.338 mmol) and tetrakis(triphenylphosphine)palladium (39.04 mg, 0.034 mmol) at room temperature. The whole mixture was warmed to 120 °C and stirred under nitrogen atmosphere for 4 h. Then the reaction mixture was concentrated under reduced pressure to give brown crude product. The crude product was separated by HPLC prep, prep condition: Welch Xtimate C18 (30 mm x 250 mm, 5 μm); A: 0.1% formic acid in water; B: MeCN; 5 mL / min; 0~3 min, 5% B; 3~15 min, 5%~50% B; Detector, UV 254 nm. This reaction gave E-6, white solid product 3-(4-fluorophenyl)-5-methyl-6-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)thieno[2,3- d]pyrimidine-2,4-(lH,3H)dione (3.34 mg, 0.008 mmol, 7.08%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.42 (d, J = 1.5 Hz, 1 H), 7.3 - 7.4 (m, 4 H), 7.2 - 7.2 (m, 1 H), 7.1 - 7.2 (m, 1 H), 2.39 (s, 3 H). ESI-MS m / z = 410.0 [M+H] + ; Calcu. = 409.1.

[0194] Example 7: Synthesis of compound E-7

[0195] Step A: 6-bromo-3-(4-fluorophenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(lH,3H)- dione (25 mg, 0.070 mmol), 4-pyridineboronic acid (10 mg, 0.077 mmol), tetrakis(triphenylphosphine)palladium (16 mg, 0.014 mmol), cesium carbonate (57 mg, 0.18 mmol) were sequentially dissolved in N,N-dimethylformamide (4 mL) at room temperature. The whole reaction was heated to 120 °C under helium protection. After 3 hours of stirring, the reaction was cooled to room temperature. The reaction was filtered through celite and the filtrate was directly subjected to preparative liquid chromatography. Preparative conditions: Waters XBridge Prep C18 (19 mm x 250 mm, 5 μm); A: 0.1% formic acid in water; B: MeOH; 18 mL / min; 0-3 min, 10% B; 3-15 min, 10%-80% B; 15-16 min, 80%-100% B; Detector: UV 254 nm. Lyophilization under reduced pressure gave E-7, white solid product 3-(4-fluorophenyl)-5-methyl-6-(pyridin-4-yl)-thieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (4.43 mg, 0.013 mmol, 17.81%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 12.50 (s, 1H), 8.63 (d, J = 6.0 Hz, 2H), 7.49 (dd, J = 4.5, 1.6 Hz, 2H), 7.36 - 7.27 (m, 4H), 2.52 (s, 3H). ESI-MS m / z = 354.0 [M+H] + ; Calcu. = 353.1.

[0196] Example 8: Synthesis of compound E-8

[0197] Step A: 6-bromo-3-(4-fluorophenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(lH,3H)- dione (25 mg, 0.070 mmol), 3-pyridineboronic acid (10 mg, 0.077 mmol), tetrakis triphenylphosphine palladium (16 mg, 0.014 mmol), cesium carbonate (57 mg, 0.18 mmol) were sequentially dissolved in N,N-dimethylformamide (4 mL) at room temperature. The whole reaction was heated to 120 °C under helium protection. After 3 hours of stirring, the reaction was cooled to room temperature. The reaction was filtered through celite and the filtrate was directly subjected to preparative liquid separation. Preparative conditions: Waters XBridge Prep C18 (19 mm x 250 mm, 5 μm); A: 0.1% formic acid in water; B: MeOH; 18 mL / min; 0-3 min, 10% B; 3-15 min, 10%-80% B; 15-16 min, 80%-100% B; Detector: UV 254 nm. The product was lyophilized under reduced pressure to obtain E-8, white solid, 3-(4-fluorophenyl)-5-methyl-6-(pyridin-3-yl)-thieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (1.04 mg, 0.0029 mmol, 4.18%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 12.47 (s, 1H), 8.69 (d, J = 1.9 Hz, 1H), 8.58 (dd, J = 4.8, 1.3 Hz, 1H), 7.92-7.88 (m, 1H), 7.51 (dd, J = 7.9, 4.8 Hz, 1H), 7.36-7.27 (m, 4H), 2.42 (s, 3H). ESI-MS m / z = 354.0 [M+H] + ; Calcu. = 353.1.

[0198] Example 9: Synthesis of compound E-9

[0199] Step A: 6-bromo-3-(4-fluorophenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(lH,3H)- dione (30 mg, 0.042 mmol), 5-indoleboronic acid (15 mg, 0.093 mmol), tetrakis- triphenylphosphine palladium (20 mg, 0.017 mmol), cesium carbonate (69 mg, 0.21 mmol) were sequentially dissolved in N,N-dimethylformamide (4 mL) at room temperature. The whole reaction was heated to 120 °C under helium protection. After 3 hours of stirring, the reaction was allowed to cool to room temperature. The reaction was filtered through celite and the filtrate was directly subjected to preparative liquid chromatography. Preparative conditions: Waters XBridge Prep C18 OBD (19 mm x 250 mm, 5 μm) A: 0.1% formic acid in water; B: MeOH; 18 mL / min; 0-3 min, 30% B; 3-16 min, 30%-100% B; Detector: UV 254 nm. Lyophilization under reduced pressure afforded E-9, 3-(4-fluorophenyl)-6-(lH-indol-5-yl)-5-methyl-thieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (1.44 mg, 0.0037 mmol, 4.36%) as a brown solid. 1 H NMR (500 MHz, DMSO-d6) δ ppm 12.32 (s, 1H), 11.26 (s, 1H), 7.61 (s, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.43-7.41 (m, 1H), 7.37-7.28 (m, 4H), 7.16 (dd, J = 8.4, 1.7 Hz, 1H), 6.49 (s, 1H), 2.40 (s, 3H). ESI-MS m / z = 392.0 [M+H] + ; Calcu. = 391.1.

[0200] Example 10: Synthesis of compound E-10

[0201] Step A: 6-Bromo-3-(4-fluorophenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(lH,3H)- dione (25 mg, 0.070 mmol), l-methyl-5-indoleboronic acid (14 mg, 0.077 mmol), tetrakis(triphenylphosphine)palladium (16 mg, 0.014 mmol), cesium carbonate (57 mg, 0.18 mmol) were sequentially dissolved in N,N-dimethylformamide (4 mL) and the whole reaction was heated to 120 °C under helium protection. After 3 hours of stirring at 120 °C, the reaction was allowed to cool to room temperature. The reaction was filtered over celite and the filtrate was directly subjected to preparative liquid chromatography. Preparative conditions: Welch Xtimate C18 (30 mm x 250 mm, 5 μιη); A: 0.1% formic acid in water; B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-40% B; 3.5-15 min, 40%-85% B, 15-15.5 min, 85%-100% B; Detector: UV 254 nm. Lyophilization under reduced pressure afforded E-10, white solid product 3-(4-fluorophenyl)-5-methyl-6-(l-methylindol-5-yl)-thieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (2.14 mg, 0.0053 mmol, 7.50%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 12.33 (s, 1H), 7.62 (d, J=1.3 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.41 (d, J=3.0 Hz, 1H), 7.37-7.27 (m, 4H), 7.22 (dd, J=8.4, 1.7 Hz, 1H), 6.50-6.47 (m, 1H), 3.83 (s, 3H), 2.40 (s, 3H). ESI-MS m / z = 406.0 [M+H] + ; Calcu. = 405.1.

[0202] Example 11: Synthesis of compound E-11

[0203] Step A: To a solution of 2-amino-5-(3-methoxy-4-(4-methylimidazol-l-yl)phenyl)- 4-methylthiophene-3-carboxylic acid ethyl ester (73 mg, 0.197 mmol), cesium carbonate (128.37 mg, 0.394 mmol) in acetonitrile (2 mL) was added 4- fluorobenzyl isocyanate (59.55 mg, 0.394 mmol). After the addition, the whole mixture was warmed to 90 °C and stirred for 2 hours. The reaction was filtered through celite and the filtrate was directly subjected to HPLC prep. Prep condition: Waters XBridge C18 (19 mm x 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 18 mL / min 0-3 min, 10% B; 3-18 min, 10%-100% B; Detector, UV 254 nm. This reaction gave E-11, white solid product 3-((4-fluorophenyl)methyl)-6-(3-methoxy-4-(4-methylimidazol-l-yl)phenyl)-5- methyl-thieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (15.26 mg, 0.032 mmol, 16.29%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.76 (d, J = 1.0 Hz, 1 H), 7.37 - 7.27 (m, 3 H), 7.17 - 7.10 (m, 2 H), 7.10 - 7.00 (m, 3 H), 5.00 (s, 2 H), 3.81 (s, 3 H), 2.48 (s, 3 H), 2.15 (s, 3 H). ESI-MS m / z = 477.1 [M+H] + ; Calcu. = 476.2.

[0204] Example 12: Synthesis of compounds E-12 and M-1

[0205] Step A: To a solution of ethyl 2-amino-4-methylthiophene-3-carboxylate (6.481 g, 34.987 mmol) in dichloromethane (90 mL) was added N-bromosuccinimide (6.280 g, 35.283 mmol) portionwise at 0 °C. After the addition was complete, the mixture was stirred at 0 °C for 1 h. After the reaction was complete, the reaction was diluted with dichloromethane (200 mL) and quenched by the addition of a saturated solution of sodium carbonate (100 mL) under an ice-water bath. The reaction was then partitioned between saturated brine (100 mL*2) and the organic phase was dried over anhydrous sodium sulfate. The organic phase was then concentrated under reduced pressure at room temperature to give a solid residue. The solid residue was purified by silica gel column chromatography (SiO2, PE:EA = 90:10) and concentrated under reduced pressure at 30 °C to give a brown solid product, which was stored in a freezer at -20 °C (this compound is unstable at room temperature). This reaction gave a brown solid product of ethyl 2-amino-5-bromo-4-methylthiophene-3-carboxylate (6.321 g, 23.930 mmol, 68.40 %). ESI-MS m / z = 263.8 [M+H] + ; Calcu. = 263.0.

[0206] Step B: To a 25 mL Schlenk tube was added (3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)boronic acid (2.180 g, 9.395 mmol), ethyl 2-amino-5-bromo-4- methylthiophene-3-carboxylate (2.037 g, 7.712 mmol), (1,1'-bis(diphenylphosphino) ferrocene)palladium dichloride (1.169 g, 1.598 mmol) and sodium carbonate (2.563 g, 24.182 mmol) sequentially at room temperature under argon. The system was then purged with argon for three times. Then, water (15 mL) and 1,4-dioxane (60 mL) were added under argon. Finally, the mixture was stirred at 90 °C under argon for 18 h. After the reaction was complete, the mixture was diluted with ethyl acetate (100 mL) after it was cooled to room temperature. The solid was then filtered through silica gel and washed with ethyl acetate (100 mL). The filtrate was then concentrated under reduced pressure to give a solid residue. The residue was then purified by silica gel column chromatography (SiO2, PE:EA = 0:100). This reaction gave M-1, ethyl 2-amino-5-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4- methylthiophene-3-carboxylate (1.308 g, 3.521 mmol, 37.48 %) as a brown solid. ESI-MS m / z = 372.0 [M+H] + ; Calcu. = 371.1.

[0207] Step C: To a solution of ethyl 2-amino-5-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-4-methylthiophene-3-carboxylate (60 mg, 0.162 mmol) in acetonitrile (1.0 mL) was added cesium carbonate (104 mg, 0.319 mmol) at 0 °C. Then, 4-methoxyphenyl isocyanate (26 μL, 0.200 mmol) was added dropwise to the reaction solution at 0 °C. Finally, the whole mixture was stirred at 90 °C for 5 h. After the reaction was completed, the solution was allowed to cool to room temperature, and the reaction solution was filtered through a sintered glass funnel with celite, and the solid was washed with ethyl acetate (30 mL) and methanol (30 mL), and then the resulting solution was concentrated under reduced pressure at room temperature. The resulting mixture was separated by preparative HPLC. Chromatography conditions: Waters XBridge Prep Shield RP18 OBD (19 mm x 250 mm, 5 μm), A: 0.1% FA, B: ACN; 10 mL / min; 0-3.0 min, 10% B; 3.0-3.5 min, 10%-15% B; 3.5-15 min, 15%-65%; 15-20 min, 65%-100%; B detector, UV 254 nm). This reaction gave E-12, 6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-3-(4- methoxyphenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione as a light yellow solid product (24.26 mg, 0.049 mmol, 29.04%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.78 (s, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.18 (s, 1H), 7.14 (s, 1H), 7.01 - 7.10 (m, 3H), 6.95 (br d, J = 8.9 Hz, 2H), 3.87 (s, 3H), 3.79 (s, 3H), 2.46 (s, 3H), 2.16 (s, 3H). ESI-MS m / z = 475.3 [M+H] + ; Calcu. = 474.1.

[0208] Example 13: Synthesis of compound E-13

[0209] Step A: To a solution of ethyl 2-amino-5-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-4-methylthiophene-3-carboxylate (91 mg, 0.245 mmol) in acetonitrile (1.0 mL) was added cesium carbonate (180 mg, 0.552 mmol) at room temperature. Then, 2,4-difluorophenyl isocyanate (69 μL, 0.578 mmol) was added dropwise to the reaction solution at 0 °C. After the addition, the whole mixture was warmed to 90 °C and stirred for 3 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate (5 mL) after the reaction solution was cooled to room temperature. Then, the reaction solution was filtered through a sintered glass funnel with celite, and the solid was washed with ethyl acetate (30 mL) and methanol (30 mL), and then the resulting solution was concentrated under reduced pressure at room temperature. The resulting mixture was separated by preparative HPLC. Chromatography conditions: Waters XBridge Prep Shield RP18 OBD (19 mm x 250 mm, 5 μm), A: 0.05% ammonia water, B: ACN; 10 mL / min; 0~3.0 min, 10% B; 3.0~3.5 min, 10%~25% B; 3.5~15 min, 25%~70%; 15~15.5 min, 70%~100%; B detector, UV 254 nm). This reaction gave E-13, white solid product 3-(2,4-difluorophenyl)-6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (24.30 mg, 0.048 mmol, 19.59%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 12.64 (br s, 1 H), 7.82 (s, 1 H), 7.52-7.59 (m, 1 H), 7.44-7.50 (m, 2 H), 7.22-7.27 (m, 2 H), 7.17 (s, 1 H), 7.15 (dd, J=8.1, 1.4 Hz, 1 H), 3.89 (s, 3 H), 2.47 (s, 3 H), 2.16 (s, 3 H). ESI-MS m / z = 481.0 [M+H] + ; Calcu. = 480.1.

[0210] Example 14: Synthesis of compound E-14

[0211] Step A: To a solution of ethyl 2-amino-5-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-4-methylthiophene-3-carboxylate (500 mg, 1.346 mmol), 1- bromo-4-fluorobenzene (283 mg, 1.615 mmol) and cesium carbonate (877 mg, 2.692 mmol) in dioxane (16 mL) was added 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (156 mg, 0.269 mmol) and tris(dibenzylideneacetone)dipalladium (123.26 mg, 0.135 mmol) at room temperature. After the addition, the whole mixture was purged with argon for 3 times, warmed to 100 °C and stirred overnight under argon protection. The reaction was cooled to room temperature, filtered through celite and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was separated by silica gel column (SiO2, PE:EA = 50:50). The reaction gave the product 2-((4-fluorophenyl)amino)-5-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-4-methylthiophene-3-carboxylic acid ethyl ester as yellow oil. ESI-MS m / z = 466.1 [M+H] + ; Calcu. = 465.1.

[0212] Step B: To a solution of 2-((4-fluorophenyl)amino)-5-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-4-methylthiophene-3-carboxylic acid ethyl ester (80 mg, 0.172 mmol) in dichloromethane (4 mL) was added chlorosulfonyl isocyanate (49 mg, 0.344 mmol) at -78 °C. After the addition, the whole mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction was concentrated under reduced pressure to give the crude product 2-(1-(4-fluorophenyl)ureido)-5-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-4-methylthiophene-3-carboxylic acid ethyl ester (150 mg, crude) as a gray solid, which was used directly in the next step.

[0213] Step C: To 2-(l-(4-fluorophenyl)carbamimidoyl)-5-(3-methoxy-4-(4-methyl- lH-imidazol-l-yl)phenyl)-4-methylthiophene-3-carboxylic acid ethyl ester (150 mg, crude) was added 6N hydrochloric acid (5 mL) at room temperature. After the addition, the whole mixture was warmed to 100 °C and stirred for 1 hour. The reaction was cooled to room temperature, then adjusted to pH 6-7 by adding ammonia water, and concentrated under reduced pressure to give a crude product. The crude product was dissolved in methanol (10 mL), filtered to remove ammonium chloride solid, and concentrated under reduced pressure to give a crude product. The crude product was sent for preparative separation, preparative conditions: Waters XSelect CSH Prep C18 (30 mm x 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. Lyophilized under reduced pressure to give E-14, 1-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (18.20 mg, 0.039 mmol, 12.84%) as a white solid product. 1 H NMR (500 MHz, DMSO-d6) δ ppm 11.56 (br s, 1 H) 7.79 (d, J=0.92 Hz, 1 H) 7.65-7.71 (m, 2 H) 7.46 (t, J=8.70 Hz, 2 H) 7.41 (d, J=8.24 Hz, 1 H) 7.13 (d, J=1.98 Hz, 2 H) 7.05-7.08 (m, 1 H) 3.84 (s, 3 H) 2.52 (s, 3 H) 2.14 (s, 3 H). ESI-MS m / z = 463.0 [M+H] + ; Calcu. MW = 462.1.

[0214] Example 15: Synthesis of compound E-15

[0215] Step A: To a solution of 6-bromo-3-(4-fluorophenyl)-5-methylthieno[2,3- d]pyrimidine-2,4(lH,3H)-dione (200 mg, 0.563 mmol), 2-(bromomethyl)tetrahydro- 2H-pyran (151 mg, 0.844 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (233 mg, 1.689 mmol) at room temperature. The whole mixture was stirred at 70 °C overnight. After the reaction was completed, the reaction mixture was filtered through celite, then water (20 mL) was added, extracted with ethyl acetate (50 mL in total) for three times, combined organic phase was washed with saturated brine once, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a solid residue. The residue was separated by TLC (SiO2, PE:EA = 75:25). The reaction gave 6-bromo-3-(4-fluorophenyl)-5-methyl-l-((tetrahydro-2H-pyran-2- yl)methyl)thieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (70 mg, 0.154 mmol, 27.42%) as a white solid. ESI-MS m / z = 455.2 [M+H] + ; Calcu. = 454.0.

[0216] Step B: To a solution of 6-bromo-3-(4-fluorophenyl)-5-methyl-l-((tetrahydro-2H- pyran-2-yl)methyl)thieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (40 mg, 0.088 mmol), (3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl)boronic acid (20 mg, 0.088 mmol), cesium carbonate (86 mg, 0.264 mmol) in N,N-dimethylformamide (8 mL) was added tetrakis(triphenylphosphine)palladium (20 mg, 0.018 mmol) at room temperature. After the addition, the whole mixture was stirred at 120 °C for 5 hours under nitrogen protection. After the reaction was completed, the reaction mixture was filtered through celite, concentrated for preparation. Preparation condition: Waters XBridge Prep C 18 18 min, 50%~80% B; Detector, UV 254 nm. The reaction gave E-15, 3-(4-fluorophenyl)-6-(3- methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl)-5-methyl-l-((tetrahydro-2H-pyran-2- yl)methyl)thieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (1.46 mg, 0.003 mmol, 2.95%) as a white solid. 1HNMR (500 MHz, DMSO-d6) δ ppm 7.82 (s, 1 H), 7.49 (d, J = 8.1 Hz, 1 H), 7.30-7.40 (m, 4 H), 7.24 (d, J = 1.5 Hz, 1 H), 7.18 (s, 1 H), 7.15 (dd, J = 7.9 and 1.5 Hz, 1 H), 4.05 (dd, J = 14.3 and 3.6 Hz, 1 H), 3.90 (s, 3 H), 3.86 (m, 1 H), 3.77-3.83 (m, 1 H), 3.70-3.77 (m, 1 H), 2.17 (s, 3 H), 1.78 (s, 1 H), 1.61-1.70 (m, 1 H), 1.42-1.48 (m, 4 H), 1.21-1.24 (m, 4 H). ESI-MS m / z = 561.4 [M+H] + ; Calcu. = 560.1.

[0217] Example 16: Synthesis of compound E-16 and M-3

[0218] Step A: To a solution of ethyl 2-amino-4-methylthiophene-3-carboxylate (5 g, 26.992 mmol), triethylamine (7.504 mL, 53.984 mmol) in tetrahydrofuran (100 mL) was added 4-fluorophenyl isocyanate (3.70 g, 26.992 mmol) at 0 °C. The whole mixture was stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure to get yellow crude product. The crude product was separated by silica gel column (Si02, PE:EA = 95:5) to get pale yellow solid product ethyl 2-(3-(4-fluorophenyl)ureidoethyl)-4-methylthiophene-3-carboxylate (7.00 g, 21.716 mmol, 80.45 %). ESI-MS m / z = 323.0 [M+H] + ; Calcu. = 322.1.

[0219] Step B: To a solution of 2-(3-(4-fluorophenyl)ureidoethyl)-4-methylthiophene-3- carboxylate (7.00 g, 21.716 mmol) in acetonitrile (100 mL) was added cesium carbonate (21 g, 65.147 mmol) at room temperature. The mixture was stirred at 90 °C for 1 h. The reaction was filtered and concentrated under reduced pressure to give the crude product as a yellow solid. The crude product was purified by column chromatography on silica gel (SiO2, DCM:MeOH = 98:2) to give the product 3-(4-fluorophenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (4.40 g, 15.925 mmol, 73.33%) as a white solid. ESI-MS m / z = 277.0 [M+H] + ; Calcu. = 276.0.

[0220] Step C: To a solution of 3-(4-fluorophenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(lH,3H)- dione (4.40 g, 15.925 mmol) in acetonitrile (100 mL) was added N-bromosuccinimide (3.40 g, 19.110 mmol) at 0 °C. The mixture was stirred at room temperature for 2 h. The reaction was filtered and concentrated under reduced pressure to give the crude product as a brown solid. The crude product was purified by column chromatography on silica gel (SiO2, DCM:MeOH = 97:3) to give the product M-3, 6-bromo-3-(4-fluorophenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (4.90 g, 13.796 mmol, 86.63%) as a brown solid. ESI-MS m / z = 357.0 [M+H] + ; Calcu. = 355.9.

[0221] Step D: To a solution of 6-bromo-3-(4-fluorophenyl)-5-methylthieno[2,3- d]pyrimidine-2,4(lH,3H)-dione (30 mg, 0.084 mmol), (3-methyl-2-oxo-2,3- dihydrobenzo[d]oxazol-6-yl)boronic acid (28 mg, 0.101 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) at room temperature, (l,l'-bis(diphenylphosphino)ferrocene)palladium dichloride (18.44 mg, 0.025 mmol) and cesium carbonate (82 mg, 0.252 mmol) were added, the whole mixture was warmed to 100 °C and stirred under nitrogen overnight. Subsequently, the mixture was concentrated under reduced pressure to give a brown crude product. The crude was subjected to HPLC prep purification, prep conditions: Welch Xtimate C18 (30 mm x 250 mm, 5 μm); A: 0.1% formic acid in water; B: MeCN; 5 mL / min; 0-3 min, 5% B; 3-15 min, 5%-50% B; Detector, UV 254 nm. The reaction E-16 gave 3-(4-fluorophenyl)-5-methyl-6-(3-methyl-2-oxo-2,3- dihydrobenzo[d]oxazol-6-yl)thieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (4.95 mg, 0.012 mmol, 14.29%) as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.46 (d, J = 0.9 Hz, 1 H), 7.3-7.3 (m, 6 H), 3.30 (br s, 3 H), 2.39 (s, 3 H). ESI-MS m / z = 424.2 [M+H] + ; Calcu. = 423.1.

[0222] Example 17: Synthesis of compound E-17

[0223] Step A: To a solution of ethyl 2-amino-5-bromo-4-methylthiophene-3-carboxylate (263 mg, 0.996 mmol) in tetrahydrofuran (5 mL) was added triethylamine (700 μL, 5.036 mmol) followed by the addition of triphosgene (119 mg, 0.401 mmol) at 0 °C. After the addition, the whole mixture was stirred at 0 °C for 1.5 h. Then, 4-fluoro-2-methoxyaniline (164 μL, 1.301 mmol) was added to the reaction mixture, which was then stirred at room temperature overnight. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (60 mL). The organic phase was then washed with saturated ammonium chloride (15 mL), saturated brine (15 mL) successively. The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a brown solid residue. The crude product, ethyl 5-bromo-2-(3-(4-fluoro-2-methoxyphenyl)ureido)-4-methylthiophene-3-carboxylate (497 mg) was used directly in the next reaction. ESI-MS m / z = 430.9 [M+H] + ; Calcu. = 430.0.

[0224] Step B: To a solution of ethyl 5-bromo-2-(3-(4-fluoro-2-methoxyphenyl)ureido)-4-methylthiophene-3-carboxylate (272 mg, 0.631 mmol) in ethanol (6 mL) was added sodium ethoxide (210 mg, 3.086 mmol) at room temperature. After the addition, the whole mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (150 mL) and washed with saturated ammonium chloride (30 mL), saturated brine (30 mL*2) successively. The organic phase was then dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give a solid product, which was crude. The crude product, 6-bromo-3-(4-fluoro-2-methoxyphenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (245 mg) was a brown solid. ESI-MS m / z = 384.8 [M+H] + ; Calcu. = 384.0.

[0225] Step C: To a 25 mL Schlenk flask, was added (3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)boronic acid (166 mg, 0.715 mmol), 6-bromo-3-(4-fluoro-2- methoxyphenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (198 mg, 0.514 mmol), (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (109 mg, 0.149 mmol) and sodium carbonate (214 mg, 2.019 mmol) sequentially at room temperature under argon atmosphere, then the system was purged with argon for 3 times. Then water (1.25 mL) and 1,4-dioxane (5 mL) were added under argon atmosphere. Finally, the mixture was stirred at 90 °C for 18 h under argon atmosphere. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (5 mL) after the reaction mixture was cooled to room temperature. Then the solid was washed with ethyl acetate (60 mL), and the resulting solution was concentrated under reduced pressure at room temperature. The resulting mixture was separated by preparative HPLC. Chromatographic conditions: Waters XSelect CSH Prep C18 OBD (30 mm x 250 mm, 5 μm), A: 0.1% FA, B: ACN; 40 mL / min; 0-3.0 min, 10% B; 3.0-3.5 min, 10%-25% B; 3.5-10 min, 25%-45%; 10-15 min, 45%-75% B; Detector, UV 254 nm). This reaction gave E-17, white solid product 3-(4-fluoro-2-methoxyphenyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (49.29 mg, 0.091 mmol, 8.31%). 1 HNMR (500 MHz, DMSO-d6) δ ppm 12.43 (br s, 1H) 7.81 (s, 1H) 7.46 (d, J = 8.1 Hz, 1H) 7.27-7.30 (m, 1H), 7.25 (s, 1H) 7.17 (s, 1H) 7.14 (dd, J = 8.0, 1.8 Hz, 1H) 7.08 (dd, J = 11.1, 2.4 Hz, 1H) 6.87 (td, J = 8.4, 2.4 Hz, 1H) 3.89 (s, 3H) 3.76 (s, 3H) 2.46 (s, 3H) 2.16 (s, 3H). ESI-MS m / z = 493.0 [M+H] + ; Calcu. = 492.1.

[0226] Example 18: Synthesis of compound E-18

[0227] Step A: Reaction feed: To a solution of ethyl 2-amino-5-(3-methoxy-4-(4-methyl- lH-imidazol-l-yl)phenyl)-4-methylthiophene-3-carboxylate (37 mg, 0.100 mmol) in acetonitrile (0.7 mL) was added cesium carbonate (65 mg, 0.199 mmol) at 0 °C. Then, 4- isocyanatobenzoic acid methyl ester (27 mg, 0.152 mmol) was added dropwise to the reaction solution at 0 °C. Finally, the whole mixture was stirred at 90 °C for 3 h. After the reaction was completed, the reaction solution was diluted with ethyl acetate (5 mL) after the solution was cooled to room temperature. Then, the reaction solution was filtered through a sintered glass funnel with celite, and the solid was washed with ethyl acetate (30 mL) and methanol (30 mL), and then the resulting solution was concentrated under reduced pressure at room temperature. The resulting mixture was separated by preparative HPLC. Chromatography conditions: Waters XBridge Prep C18 OBD (19 mm x 250 mm, 5 μm), A: 0.05% ammonia water, B: ACN; 18 mL / min; 0-3.0 min, 10% B; 3.0-3.5 min, 10%-15% B; 3.5-15 min, 15%-40%; 15-15.5 min, 40%-100%; B detector, UV 254 nm). This reaction gave E-18, methyl 4-(6-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl)-5-methyl- 2,4-dioxo-l,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzoate (4.21 mg, 0.008 mmol, 7.81%) as a light orange solid. 1 H NMR (500 MHz, DMSO-d6) δ ppm 12.51 (br s, 1 H), 8.06 (d, J = 8.5 Hz, 2 H), 7.81 (d, J = 1.1 Hz, 1 H), 7.46 (d, J = 7.9 Hz, 3 H), 7.23 (d, J = 1.8 Hz, 1 H), 7.17 (s, 1 H), 7.13 (dd, J = 8.2, 1.5 Hz, 1 H), 3.90 (s, 3 H), 3.89 (s, 3 H), 2.47 (s, 3 H), 2.16 (s, 3 H). ESI-MS m / z = 503.1 [M+H] + ; Calcu. = 502.1.

[0228] Example 19: Synthesis of compound E-19

[0229] Step A: To a solution of 2-amino-5-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)- 4-methylthiophene-3-carboxylic acid ethyl ester (95 mg, 0.256 mmol) in acetonitrile (1.5 mL) was added cesium carbonate (185 mg, 0.568 mmol) at 0 °C. Then, 4- isocyanatobenzoic acid (64 mg, 0.361 mmol) was added dropwise to the reaction mixture at 0 °C. Finally, the whole mixture was stirred at 90 °C for 18 h. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (5 mL). Then, the reaction mixture was filtered through a sintered glass funnel with celite, and the solid was washed with ethyl acetate (40 mL) and methanol (40 mL), and then the resulting solution was concentrated under reduced pressure at room temperature. The resulting mixture was separated by preparative HPLC. Chromatography conditions: Waters XBridge Prep C18 OBD (30 mm x 250 mm, 5 μm), A: 0.05% ammonia water, B: ACN; 40 mL / min; 0-3.0 min, 10% B; 3.0-3.5 min, 10%-15% B; 3.5-15 min, 15%-40%; 15-15.5 min, 40%-100%; B detector, UV 254 nm). This reaction gave 4-(6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl- 2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzoic acid methyl ester (36 mg, 0.072 mmol, 28.13%) as a light orange solid. ESI-MS m / z = 503.0 [M+H] + ; Calcu. = 502.1.

[0230] Step B: To a solution of methyl 4-(6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5- methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzoate (33 mg, 0.066 mmol) in tetrahydrofuran (1.2 mL) and ethanol (1.2 mL) was added sodium hydroxide solution (2N) (0.6 mL) at room temperature. After the addition, the whole mixture was stirred at room temperature for 3 hours. After filtration, the resulting mixture was separated by preparative HPLC. Chromatography conditions: Waters XSelect CSH Prep C18 OBD (30 mm x 250 mm, 5 μm), A: 0.1% FA, B: ACN; 40 mL / min; 0-3.5 min, 10% B; 3.5-15 min, 10%-40%; 15-15.5 min, 40%-100% B; Detector, UV 254 nm). This reaction gave E-19, 4-(6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-2,4-dioxo-1,4- dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzoic acid as a white solid product (5.82 mg, 0.012 mmol, 18.18%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.14 (s, 0.25H), 8.03 (d, J = 8.2 Hz, 2H), 7.81 (d, J = 1.2 Hz, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.38 - 7.43 (m, 2H), 7.23 (s, 1H), 7.17 (s, 1H), 7.10 - 7.15 (m, 1H), 3.89 (s, 3H), 2.47 (s, 3H), 2.16 (s, 3H). ESI-MS m / z = 489.1 [M+H] + ; Calcu. = 488.1.

[0231] Example 20: Synthesis of compound E-20

[0232] Step A: 6-bromo-3-(4-fluorophenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(lH,3H)- dione (50 mg, 0.14 mmol), 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3- dihydro-lH-benzo[d]imidazol-2-one (37 mg, 0.14 mmol), (l,l'-bis(diphenylphosphino) ferrocene)palladium dichloride (21 mg, 0.028 mmol), cesium carbonate (137 mg, 0.422 mmol) were sequentially dissolved in a mixture of 1,4-dioxane (4 mL) and water (1 mL), the whole reaction was heated to 100 °C under helium protection, after stirring overnight, it was cooled to room temperature, the reaction solution was filtered through celite, the filtrate was directly subjected to preparative liquid separation, the preparation conditions: ChromCore 120 C8 (21 mm x 250 mm, 5 μm); A: 0.1% formic acid aqueous solution; B: MeCN; 18 mL / min; 0-3 min, 30% B; 3-15 min, 30%-70% B; 15-15.5 min, 70%-100% B; detector: UV 254 nm. Freeze-drying under reduced pressure to obtain E-20, white solid product 3-(4-fluorophenyl)-5-methyl-6-(2-oxo-l,3-dihydrobenzo[d]imidazol-5-yl)- thieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (1.59 mg, 0.0039 mmol, 2.77%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 12.34 (s, 1H), 10.77 (s, 1H), 10.70 (s, 1H), 7.31 (dq, J = 17.6, 9.0 Hz, 4H), 7.01 (s, 2H), 6.95 (s, 1H), 2.38 (s, 3H). ESI-MS m / z = 409.0 [M+H] + ; Calcu. = 408.1.

[0233] Example 21: Synthesis of compound E-21

[0234] Step A: 6-bromo-3-(4-fluorophenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(lH,3H)- dione (50 mg, 0.14 mmol), l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3- dihydro-lH-benzo[d]imidazol-2-one (50 mg, 0.18 mmol), (l,l'-bis(diphenylphosphino) ferrocene)palladium dichloride (21 mg, 0.028 mmol), cesium carbonate (138 mg, 0.422 mmol) were sequentially dissolved in a mixture of 1,4-dioxane (5 mL) and water (1.25 mL) and the whole reaction was heated to 100 °C under helium protection. After stirring overnight, the reaction was allowed to cool to room temperature. The reaction was filtered over celite and the filtrate was directly subjected to preparative liquid chromatography. Preparative conditions: Welch Xtimate C18 (30 mm x 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; 15-16 min, 80-100% B; Detector: UV 254 nm. Lyophilization under reduced pressure afforded E-21, 3-(4-fluorophenyl)-5-methyl-6-(3-methyl-2-oxo-lH- benzo[d]imidazol-5-yl)-thieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (5.70 mg, 0.013 mmol, 9.58%) as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ ppm 12.36 (s, 1H), 10.94 (s, 1H), 7.36-7.27 (m, 4H), 7.18 (d, J = 8.1 Hz, 1H), 7.10 (dd, J = 8.1, 1.6 Hz, 1H), 7.00 (d, J = 1.5 Hz, 1H), 3.31 (s, 3H), 2.38 (s, 3H). ESI-MS m / z = 423.0 [M+H] + ; Calcu. = 422.1.

[0235] Example 22: Synthesis of compounds E-22 and E-28

[0236] Step A: 3-bromoprop-l-yne (4.0 g, 33.624 mmol), dimethyl sulfide (2.3 g, 37.019 mmol) were dissolved in acetonitrile (40 mL) and stirred at room temperature overnight. The reaction was filtered and the insoluble material was dried under reduced pressure to give the product dimethyl(2-propynyl)sulfonium bromide (4.7 g, 29.953 mmol, 77.19%).

[0237] Step B: Benzylamine (500 mg, 4.666 mmol), triethylamine (0.65 mL, 4.670 mmol), 3-chloro-3-oxopropanoic acid ethyl ester (703 mg, 4.670 mmol) were added successively to dichloromethane (10 mL) at room temperature. After stirring for 2 hours, water was added for washing. The organic phase was evaporated under reduced pressure to remove the solvent. The product, 3-(benzylamino)-3-oxopropanoic acid ethyl ester (730 mg, 3.299 mmol, 70.71%), was separated by column chromatography. ESI-MS m / z = 222.1 [M+H] + ; Calcu. = 221.1.

[0238] Step C: 3-(benzylamino)-3-oxopropanoic acid ethyl ester (1.0 g, 4.520 mmol), dimethyl(prop-2-ynyl)sulfonium bromide (1.23 g, 6.792 mmol), cesium carbonate (2.21 g, 6.782 mmol) were successively dissolved in N,N-dimethylformamide (40 mL). The reaction system was stirred at room temperature under argon protection overnight. The reaction solution was filtered, and the solvent was evaporated under reduced pressure. The crude product was added to water, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain the product, 2-(benzylamino)-4-methylfuran-3-carboxylic acid ethyl ester (300 mg, crude). ESI-MS m / z = 260.1 [M+H] + ; Calcu. = 259.1.

[0239] Step D: 2-(benzylamino)-4-methylfuran-3-carboxylic acid ethyl ester (300.00 mg, crude), 1-fluoro-4-isocyanobenzene (1269 mg, 9.255 mmol), cesium carbonate (754 mg, 2.314 mmol), acetonitrile (45 mL) were added successively in a microwave tube. The microwave tube was placed in a microwave reactor, and stirred at 130 °C for 1 hour. After the reaction was completed, the insoluble matter was filtered, and the filtrate was evaporated under reduced pressure. The product, 1-benzyl-3-(4-fluorophenyl)-5-methylfuro[2,3-d]pyrimidine-2,4(1H,3H)-dione (80 mg, 0.228 mmol, 19.74%), was separated by column chromatography. ESI-MS m / z = 351.2 [M+H] + ; Calcu. = 350.1.

[0240] Step E: 1 -benzyl-3-(4-fluorophenyl)-5-methylfuro[2,3-d]pyrimidine-2,4(1 H,3H)- dione (80.00 mg, 0.228 mmol) was dissolved in acetonitrile (20 mL), N-bromosuccinimide (41 mg, 0.348 mmol) was added at 0 °C, and the mixture was stirred at 0 °C for 2 h. The solvent was evaporated under reduced pressure, and the product 1 -benzyl-6-bromo-3-(4-fluorophenyl)-5-methylfuro[2,3-d]pyrimidine-2,4(1 H,3H)- dione (49 mg, 0.114 mmol, 50.00%) was isolated by column chromatography. ESI-MS m / z = 429.2 [M+H] + ,431.2 [M+H] + ; Calcu. = 428.0, 430.0.

[0241] Step F: 1 -benzyl-6-bromo-3-(4-fluorophenyl)-5-methylfuro[2,3-d]pyrimidine-2,4(1 H,3H)- dione (38 mg, 0.089 mmol), (3-methoxy-4-(4-methyl-1 H-imidazol-1 -yl)phenyl)boronic acid (31 mg, 0.134 mmol), 1,1 '-bis(diphenylphosphino)ferrocene) palladium dichloride (13 mg, 0.018 mmol), cesium carbonate (87 mmol, 0.267 mmol) were dissolved in a mixture of 1,4-dioxane (8 mL) and water (1.6 mL). The reaction system was heated to 100 °C under argon protection, and stirred for 5 h. The reaction solution was filtered, and the filtrate was evaporated under reduced pressure. The crude product was separated by preparative liquid chromatography with the following conditions: Welch Xtimate C18 (30 mm x 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 40 mL / min; 0-3 min, 30% B; 3-6 min, 30%-60% B; 6-16 min, 60%-80% B; 16-17 min, 80%-100% B; detector: UV 254 nm. The product E-28, 1 -benzyl-3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1 H-imidazol-1 - yl)phenyl)-5-methylfuro[2,3-d]pyrimidine-2,4(1 H,3H)-dione (33 mg, 0.062 mmol, 69.47%) was obtained. 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.82 (d, J = 1.2 Hz, 1 H), 7.50 (dd, J = 13.8, 7.6 Hz, 2 H), 7.43 - 7.24 (m, 9 H), 7.17 (s, 1 H), 5.30 (s, 2 H), 3.92 (s, 3 H), 2.49 (s, 3 H), 2.16 (s, 3 H). ESI-MS m / z = 537.4 [M+H]+ ; Calcu. = 536.2.

[0242] Step G: 1 -Benzyl-3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl- lH-imidazol- 1 - yl)phenyl)-5-methylfuro[2,3-d]pyrimidine-2,4(lH,3H)-dione (30 mg, 0.056 mmol), ammonium formate (39 mg, 0.618 mmol), 10% palladium on carbon (34 mg) were dissolved in methanol (4 mL), the reaction system was heated to 70 °C under argon protection, stirred for 24 hours. The reaction solution was filtered, the filtrate was evaporated under reduced pressure, the crude product was separated by preparative liquid phase, the preparation conditions: Waters XBridge Prep C18(19 mm x 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 18 mL / min; 0-3 min, 10% B; 3-3.5 min, 10% B; 3.5-15 min, 10%-40% B; 15-15.5 min, 40%-100% B; detector: UV 254 nm. The product E-22, 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl- lH-imidazol- 1 -yl)phenyl)-5-methylfuro[2,3-d]pyrimidine-2,4(lH,3H)-dione (1.06 mg, 0.002 mmol, 4.25%) was obtained. 1 H NMR (500 MHz, DMSO-d6) δ ppm 13.24 (s, 1H), 7.89 (s, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.29 (d, J = 6.8 Hz, 5H), 7.25 (dd, J = 8.3, 1.5 Hz, 1H), 7.19 (s, 1H), 3.91 (s, 3H), 2.48 (s, 3H), 2.17 (s, 3H). ESI-MS m / z = 447.3 [M+H] + ; Calcu. = 446.1.

[0243] Example 23: Synthesis of compound E-23

[0244] Step A: In tetrahydrofuran (5 mL) dissolved pyridin-4-amine (100 mg, 1.062 mmol), triethylamine (0.443 mL, 3.187 mmol), triphosgene (126 mg, 0.425 mmol) was added at 0 °C, the whole mixture was stirred at 0 °C for 1 hour. Concentration under reduced pressure to obtain brown crude product 4-isocyanate pyridine.

[0245] Step B: To a solution of ethyl 2-amino-5-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-4-methylthiophene-3-carboxylate (60 mg, 0.162 mmol), triethylamine (0.046 mL, 0.334 mmol) in tetrahydrofuran (5 mL) was added the crude product from previous step 100 mg at room temperature. The whole mixture was stirred at room temperature for 1 hour. Concentration under reduced pressure gave brown crude product ethyl 5-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4-methyl-2-(3-(pyridin-4-yl)ureido)thiophene-3-carboxylate. ESI-MS m / z = 492.2 [M+H] + ; Calcu. = 491.2.

[0246] Step C: To a solution of ethyl 5-(3-methoxy-4-(4-methyl-1H-imidazol-1- yl)phenyl)-4-methyl-2-(3-(pyridin-4-yl)ureido)thiophene-3-carboxylate from previous step was added sodium ethoxide in ethanol (10 mL) at room temperature. The whole mixture was stirred at room temperature for 3 hours. Concentration under reduced pressure gave brown crude product. The crude product was separated by HPLC prep, prep condition: Welch Xtimate C18 (30 mm x 250 mm, 5 μm); A: 0.1% formic acid in water; B: MeCN; 5 mL / min; 0-3 min, 5% B; 3-15 min, 5%-50% B; Detector, UV 254 nm. This reaction gave E-23, white solid product 6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-3-(pyridin-4-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (11.03 mg, 0.025 mmol, 15.43%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 12.59 (s, 1 H), 8.71 (d, J = 5.5 Hz, 2 H), 7.81 (s, 1 H), 7.46 (d, J = 8.1 Hz, 1 H), 7.41 (br d, J = 5.2 Hz, 2 H), 7.23 (s, 1 H), 7.17 (s, 1 H), 7.14 (dd, J = 1.4, 8.2 Hz, 1 H), 3.89 (s, 3 H), 2.47 (s, 3 H), 2.16 (s, 3 H). ESI-MS m / z = 446.1 [M+H] + ; Calcu. = 445.1.

[0247] Example 24: Synthesis of compound E-24

[0248] Step A: To a solution of pyridin-3-amine (100 mg, 1.062 mmol), triethylamine (0.443 mL, 3.187 mmol) in tetrahydrofuran (5 mL) at 0 °C, was added to the mixture triphosgene (126 mg, 0.425 mmol) and the whole mixture was stirred at 0 °C for 1 h. The mixture was concentrated under reduced pressure to give the crude product 3-isocyanate pyridine as a brown solid.

[0249] Step B: To a solution of ethyl 2-amino-5-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4- methylthiophene-3-carboxylate (60 mg, 0.162 mmol), triethylamine (0.046 mL, 0.334 mmol) in tetrahydrofuran (5 mL) at room temperature, was added the crude product 3-isocyanate pyridine from previous step (100 mg). After the addition, the whole mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure to give the crude product ethyl 5-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4-methyl-2-(3-(pyridin-3-yl)ureido)thiophene-3-carboxylate as a brown solid. ESI-MS m / z = 492.2 [M+H] + ; Calcu. = 491.2.

[0250] Step C: To the crude product ethyl 5-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4-methyl-2-(3-(pyridin-3-yl)ureido)thiophene-3-carboxylate from previous step was added sodium ethoxide in ethanol (10 mL) at room temperature. After the addition, the whole mixture was stirred at room temperature for 3 h. The mixture was then concentrated under reduced pressure to give the crude product as a brown solid. The crude product was separated by HPLC prep, prep condition: Welch Xtimate C18 (30 mm x 250 mm, 5 μm); A: 0.1% formic acid in water; B: MeCN; 5 mL / min; 0-3 min, 5% B; 3-15 min, 5%-50% B; detector, UV 254 nm. The reaction gave E-24, 6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-3-(pyridin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione as a white solid product (16.52 mg, 0.037 mmol, 22.83%). 1H NMR (500 MHz, DMSO-d6) δ ppm 12.66 (s, 1 H), 8.59 (d, J = 4.9 Hz, 1 H), 8.49 (s, 1 H), 7.81 (s, 1 H), 7.77 (br d, J = 8.2 Hz, 1 H), 7.54 (dd, J = 4.7, 7.7 Hz, 1 H), 7.46 (d, J = 8.4 Hz, 1 H), 7.23 (s, 1 H), 7.17 (s, 1 H), 7.14 (s, 1 H), 3.89 (s, 3 H), 2.47 (s, 3 H), 2.16 (s, 3 H). ESI-MS m / z = 446.1 [M+H] + ; Calcu. = 445.1.

[0251] Example 25: Synthesis of compound E-25

[0252] Step A: To a solution of 1-(4-fluorophenyl)-6-(3-methoxy-4-(4-methylimidazol-1- yl)phenyl)-5-methyl-thieno[2,3-d]pyrimidine-2,4(1 H,3H)-dione (15 mg, 0.032 mmol) and potassium carbonate (9 mg, 0.065 mmol) in N,N-dimethylformamide (5 mL) was added iodomethane (0.004 mL, 0.045 mmol) at room temperature. After stirring homogeneously, the reaction mixture was stirred at room temperature overnight. The reaction was concentrated in vacuo. The crude product was purified by preparative high performance liquid chromatography, prep conditions: YMC-Actus Triart C18 (21 mm x 250 mm, 5 μm); A: 0.1% formic acid in water; B: MeCN; 18 mL / min; 0-3 min, 30% B; 3-16 min, 50%-100% B; Detector: UV 254 nm. This reaction gave E-25, white solid product 1-(4-fluorophenyl)-6-(3-methoxy-4-(4-methylimidazol-1-yl)phenyl)-3,5-dimethyl-thieno[2,3-d]pyrimidine-2,4(1 H,3H)-dione (1.74 mg, 0.004 mmol, 11.26%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.79 (s, 1 H), 7.68 (dd, J = 8.8, 4.9 Hz, 2 H), 7.47 (t, J = 8.7 Hz, 2 H), 7.42 (d, J = 8.0 Hz, 1 H), 7.14 (s, 2 H), 7.07 (d, J = 8.0 Hz, 1 H), 3.84 (s, 3 H), 3.30 (s, 3 H), 2.55 (s, 3 H), 2.15 (s, 3 H). ESI-MS m / z = 477.6 [M+H] +; Calcu. = 476.5.

[0253] Example 26: Synthesis of compound E-26 and M-6

[0254] Step A: To a solution of 6-bromo-3-(4-fluorophenyl)-5-methylthieno[2,3- d]pyrimidine-2,4(lH,3H)-dione (500 mg, 0.704 mmol), potassium tert-butoxide (276 mg, 2.464 mmol) in dichloromethane (5 mL) was added triethyl oxonium tetrafluoroborate (294 mg, 1.549 mmol) at room temperature. After the addition, the whole mixture was purged with argon for 3 times and stirred at room temperature overnight. The reaction was concentrated under reduced pressure to give a crude product. The crude product was separated by silica gel column (Si02, PE:EA = 91:9). The reaction gave 6-bromo-l-ethyl-3-(4-fluorophenyl)-5-methylthieno[2,3- d]pyrimidine-2,4(lH,3H)-dione (50 mg, 0.130 mmol, 18.54%) as a white solid. ESI-MS m / z = 382.8 [M+H] + ; Calcu. = 476.5.

[0255] Step B: To a solution of 6-bromo-l-ethyl-3-(4-fluorophenyl)-5-methylthieno[2,3- d]pyrimidine-2,4(lH,3H)-dione (50 mg, 0.130 mmol), (3-methoxy-4-(4-methyl-lH- imidazol-l-yl)phenyl)boronic acid (45 mg, 0.196 mmol) and sodium carbonate (35 mg, 0.326 mmol) in dioxane (3.6 mL) and water (0.6 mL) was added (l,l'- bis(diphenylphosphino)ferrocene)palladium(II)chloride (9.55 mg, 0.013 mmol) at room temperature. After the addition, the whole mixture was purged with argon for 3 times, warmed to 90 °C and stirred at 90 °C overnight under argon protection. The reaction was cooled to room temperature, filtered through celite and concentrated under reduced pressure to give a crude product. The crude product was separated by prep-HPLC, prep-HPLC conditions: Waters XSelect CSH Prep C18 (30 mm x 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. Lyophilized under reduced pressure to give E-26, l-ethyl-3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-lH-imidazol-l- yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (26.62 mg, 0.054 mmol, 40.45%) as a white solid product.1 H NMR (500 MHz, CDC13-d) δ ppm 8.09 (br s, 1 H) 7.37 (d, J=8.1 Hz, 1 H) 7.23-7.26 (m, 2 H) 7.19-7.23 (m, 2 H) 7.14 (br d, J=7.8 Hz, 1 H) 7.11 (s, 1 H) 7.01 (s, 1 H) 4.09 (q, J=7.1 Hz, 2 H) 3.93 (s, 3 H) 2.58 (s, 3 H) 2.43 (s, 3 H) 1.46 (t, J=7.10 Hz, 3 H). ESI-MS m / z = 491.1 [M+H] + ; Calcu. MW = 490.1.

[0256] Example 27: Synthesis of compound E-27

[0257] Step A: To a solution of methyl 2-aminothiophene-3-carboxylate (1.50 g, 9.543 mmol) in tetrahydrofuran (10 mL) was added 4-fluorophenyl isocyanate (1.96 g, 14.314 mmol) and triethylamine (3.979 mL, 28.628 mmol) dropwise at 0 °C. After the addition, the whole mixture was slowly warmed to room temperature and stirred overnight. The reaction was concentrated under reduced pressure to give a crude product. The crude product was separated by silica gel column (Si02, PE:EA = 92:8). This reaction gave methyl 2-((((4-fluorophenyl)amino)carbonyl)amino)thiophene-3-carboxylate (1.95 g, 6.626 mmol, 69.44%) as a white solid. ESI-MS m / z = 294.8 [M+H] + ; Calcu. = 294.0.

[0258] Step B: To a solution of methyl 2-((((4-fluorophenyl)amino)carbonyl)amino)thiophene-3-carboxylate in acetonitrile (40 mL) was added cesium carbonate (3.87 g, 11.893 mmol) at room temperature. After the addition, the whole mixture was heated to 80 °C for 12 h. The reaction was cooled to room temperature, filtered and concentrated under reduced pressure to give a crude product. The crude product was separated by silica gel column (Si02, DCM:MeOH = 98:2). This reaction gave 3-(4-fluorophenyl)thieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (650 mg, 2.478 mmol, 41.68%) as an off-white solid. ESI-MS m / z = 262.8 [M+H] + ; Calcu. = 262.0.

[0259] Step C: To a solution of 3-(4-fluorophenyl)thieno[2,3-d]pyrimidine-2,4(lH,3H)- dione (150 mg, 0.572 mmol) in acetonitrile (5 mL) at -10 °C, N-bromosuccinimide (101.80 mg, 0.572 mmol) was added in two portions. After the addition, the whole mixture was stirred at -10 °C for 1 h. To the reaction was added saturated sodium bicarbonate solution (10 mL), extracted with dichloromethane and methanol mixture (8: 1) for three times (10 mL*3), combined the organic phase, washed with saturated brine once (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude 6-bromo-3-(4-fluorophenyl)thieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (80 mg, crude) as a yellow solid, which was used directly in the next step.

[0260] Step D: To a solution of 6-bromo-3-(4-fluorophenyl)thieno[2,3-d]pyrimidine-2,4(lH,3H)- dione (80 mg, 0.235 mmol), (3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl)boronic acid (82 mg, 0.352 mmol) and sodium carbonate (62 mg, 0.586 mmol) in 1,4-dioxane (4.8 mL) and water (0.6 mL) at room temperature, (l,l'-bis(diphenylphosphino)ferrocene)palladium dichloride (17 mg, 0.023 mmol) was added. After the addition, the whole mixture was purged with argon for 3 times, warmed to 95 °C and stirred overnight under argon protection. The reaction was cooled to room temperature, filtered through celite, concentrated under reduced pressure to give the crude. The crude was sent for prep separation, prep condition: Welch Xtimate C18 (30 mm x 250 mm, 5 μm); A: 0.1% formic acid in water, B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-16 min, 10%-50% B, Detector, UV 254 nm). Lyophilized under reduced pressure to give E-27, 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl)thieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (16.57 mg, 0.037 mmol, 15.11%) as a white solid product. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.84 (s, 1 H), 7.79 (s, 1 H), 7.54 (d, J = 1.68 Hz, 1 H), 7.38-7.40 (m, 1 H), 7.36 (br d, J = 5.04 Hz, 2 H), 7.31-7.34 (m, 2 H), 7.26-7.30 (m, 2 H), 7.14 (s, 1 H), 3.93 (s, 3 H), 2.16 (s, 3 H). ESI-MS m / z = 449.0 [M+H] + ; Calcu. MW = 448.1.

[0261] Example 28: Synthesis of compound E-29

[0262] Step A: 2-amino-5-(3-methoxy-4-(4-methylimidazol-l-yl)phenyl)-4-methylthiophene-3- carboxylic acid ethyl ester (180 mg, 0.49 mmol), 3,4-dihydro-2H-pyran (2038 mg, 24.23 mmol), p-toluenesulfonic acid (8 mg, 0.048 mmol) were sequentially dissolved in tetrahydrofuran (5 mL) at room temperature, the reaction was heated to 70 °C in a sealed tube, after 3 days of stirring, it was cooled to room temperature. The reaction solution was adjusted to weak alkaline with triethylamine, and then the solvent was evaporated under reduced pressure. The product was separated by preparative liquid chromatography under the following conditions: Welch Xtimate C18 (30 mm x 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-65% B; 3.5-15 min, 65%-95% B; 15-15.5 min, 95%-100% B; detector: UV 254 nm. After freeze-drying under reduced pressure, white solid product 5-(3-methoxy-4-(4-methylimidazol-l-yl)phenyl)-4-methyl-2-(3,4,5,6-tetrahydro-2H-pyran-2-ylamino)thiophene-3-carboxylic acid ethyl ester (71.00 mg, 0.16 mmol, 32.16%) was obtained. ESI-MS m / z = 456.1 [M+H] + ; Calcu. = 455.2.

[0263] Step B: To a solution of ethyl 5-(3-methoxy-4-(4-methylimidazol-l-yl)phenyl)-4- methyl-2-(3,4,5,6-tetrahydro-2H-pyran-2-ylamino)thiophene-3-carboxylate (40 mg, 0.088 mmol), 4-fluorophenyl isocyanate (120 mg, 0.88 mmol), cesium carbonate (57 mg, 0.176 mmol) in acetonitrile (8 mL) was added at room temperature. The mixture was heated to 120 °C in a microwave reactor for 0.5 h, then cooled to room temperature. The reaction mixture was filtered through celite and the filtrate was directly subjected to preparative liquid chromatography. The preparative conditions were: ChromCore BR C18 (10 mm x 250 mm, 5 μm); A: 0.1% ammonia water; B: MeCN; 18 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. The product was lyophilized under reduced pressure to give E-29, white solid, 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methylimidazol-l-yl)phenyl)-5- methyl-l-(3,4,5,6-tetrahydro-2H-pyran-2-yl)-thieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (24.07 mg, 0.044 mmol, 50.15%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.83 (d, J = 1.2 Hz, 1 H), 7.49 (d, J = 8.1 Hz, 1 H), 7.39 (dd, J = 8.9, 5.1 Hz, 2 H), 7.33 (t, J = 8.8 Hz, 2 H), 7.25 (d, J = 1.7 Hz, 1 H), 7.18 (s, 1 H), 7.15 (dd, J = 8.1, 1.8 Hz, 1 H), 5.91 (dd, J = 10.9, 2.7 Hz, 1 H), 4.18 (d, J = 11.6 Hz, 1 H), 3.90 (s, 3 H), 3.71 (t, J = 10.6 Hz, 1 H), 2.46 (s, 3 H), 2.17 (s, 3 H), 2.13 (d, J = 11.7 Hz, 1 H), 1.92 (s, 1 H), 1.80 (d, J = 12.4 Hz, 1 H), 1.65 (d, J = 7.7 Hz, 2 H), 1.56 (s, 1 H). ESI-MS m / z = 547.2 [M+H] + ; Calcu. = 546.2.

[0264] Example 29: Synthesis of compound E-30

[0265] Step A: To a solution of 1-methyl-1H-indol-5-amine (300 mg, 2.052 mmol), phenyl chloroformate (353.41 mg, 2.257 mmol) in tetrahydrofuran (5 mL) was added pyridine (0.332 mL, 4.104 mmol). After the addition, the whole mixture was stirred at room temperature for 2 hours. The reaction was concentrated and purified by column chromatography (SiO2, PE:EA = 80:20) to give the product phenyl (1-methyl-1H-indol-5-yl)carbamate (405 mg, 1.521 mmol, 74.11%). ESI-MS m / z = 266.9 [M+H] + ; Calcu.= 266.1.

[0266] Step B: To a solution of ethyl 2-amino-5-[3-methoxy-4-(4-methylimidazol-1- yl)phenyl]-4-methylthiophene-3-carboxylate (60 mg, 0.162 mmol), phenyl (1- methyl-1H-indol-5-yl)carbamate (86.03 mg, 0.323 mmol) in N,N-dimethylformamide (2 mL) was added triethylamine (0.067 mL, 0.485 mmol). After the addition, the whole mixture was stirred at 70 °C overnight. The reaction was concentrated to give the product ethyl 5-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4-methyl-2-(3-(1- methyl-1H-indol-5-yl)ureido)thiophene-3-carboxylate (87.81 mg, crude). ESI-MS m / z = 544.2 [M+H] + ; Calcu.= 543.2.

[0267] Step C: To a solution of 5-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4- methyl-2-(3-(1-methyl-1H-indol-5-yl)ureido)thiophene-3-carboxylic acid ethyl ester (87 mg, 0.160 mmol) in N,N-dimethylformamide (2 mL) was added sodium ethoxide (0.400 mL, 0.800 mmol). After addition, the whole mixture was stirred at room temperature overnight. The reaction was concentrated and separated by HPLC prep. Prep condition: Waters XBridge C18 (30 mm x 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 18 mL / min 0~3 min, 10% B; 3~18 min, 10%~100% B; Detector, UV 254 nm. The reaction gave compound E-30, 6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-3-(1- methyl-1H-indol-5-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (3.47 mg, 0.007 mmol, 4.36%) as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.77 (d, J = 1.2 Hz, 1 H), 7.40 - 7.33 (m, 2 H), 7.31 (d, J = 3.0 Hz, 1 H), 7.17 - 7.11 (m, 3 H), 7.05 (dd, J = 8.1, 1.8 Hz, 1 H), 6.79 (dd, J = 8.5, 1.9 Hz, 1 H), 6.40 (d, J = 3.0 Hz, 1 H), 3.86 (s, 3 H), 3.81 (s, 3 H), 2.46 (s, 3 H), 2.16 (s, 3 H). ESI-MS m / z = 498.1 [M+H] + ; Calcu. = 497.2.

[0268] Example 30: Synthesis of compound E-31

[0269] Step A: To a solution of 5-aminoindole (260 mg, 1.967 mmol), phenyl chloroformate (338.78 mg, 2.164 mmol) in tetrahydrofuran (5 mL) was added pyridine (0.318 mL, 3.934 mmol). After addition, the whole mixture was stirred at room temperature for 2 hours. The reaction was concentrated and purified by column chromatography (Si02, PE:EA = 65:35) to give the product, (1H-indol-5-ylamino) phenyl carbonate (158 mg, 0.626 mmol, 31.84%). ESI-MS m / z = 253.1 [M+H] + ; Calcu. = 252.1.

[0270] Step B: To a solution of 2-amino-5-(3-methoxy-4-(4-methylimidazol-l-yl)phenyl)- 4-methylthiophene-3-carboxylic acid ethyl ester (80 mg, 0.215 mmol), (lH-indol-5- yl amino) formic acid phenyl ester (54.33 mg, 0.215 mmol) in N,N-dimethylformamide (2 mL) was added triethylamine (0.090 mL, 0.646 mmol). After the addition, the whole mixture was stirred at 70 °C overnight. The reaction was concentrated to give the product 2-(3-(lH-indol-5-yl)ureido)-5-(3-methoxy-4-(4-methyl-lH- imidazol-l-yl)phenyl)-4-methylthiophene-3-carboxylic acid ethyl ester (114 mg, crude). ESI-MS m / z = 530.1 [M+H] + ; Calc'u. = 529.2.

[0271] Step C: To a solution of 2-(3-(lH-indol-5-yl)ureido)-5-(3-methoxy-4-(4-methyl-lH- imidazol-l-yl)phenyl)-4-methylthiophene-3-carboxylic acid ethyl ester (114 mg, 0.215 mmol) in N,N-dimethylformamide (2 mL) was added sodium ethoxide (0.538 mL, 1.076 mmol). After the addition, the whole mixture was stirred at room temperature overnight. The reaction was concentrated and separated by HPLC prep, prep condition: Waters XBridge C18 (19 mm x 250 mm, 5 μm); A: 0.1% formic acid in water; B: MeCN; 18 mL / min 0~3 min, 10% B; 3~16 min, 10%~100% B; Detector, UV 254 nm. The reaction gave compound E-31, 3-(lH-indol-5-yl)-6-(3-methoxy-4-(4-methyl-lH-imidazol-l- yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (4.32 mg, 0.009 mmol, 4.15%) as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ ppm 12.39 (br s, 1 H), 11.22 (s, 1 H), 7.82 (d, J = 1.2 Hz, 1 H), 7.47 (d, J = 8.1 Hz, 1 H), 7.44 (d, J = 8.5 Hz, 1 H), 7.42 (dd, J = 5.4, 2.6 Hz, 2 H), 7.25 (d, J = 1.7 Hz, 1 H), 7.18 - 7.12 (m, 2 H), 6.93 (dd, J = 8.5, 1.8 Hz, 1 H), 6.47 (s, 1 H), 3.89 (s, 3 H), 2.47 (s, 3 H), 2.16 (s, 3 H). ESI-MS m / z = 484.1 [M+H]+ ; Calcu. = 483.1.

[0272] Example 31: Synthesis of compound E-32

[0273] Step A: Into a 50 mL pressure tube, was added methyl 3-amino-4-methylthiophene-2- carboxylate (1 g, 5.841 mmol), 1-fluoro-4-isocyanatobenzene (1.20 g, 8.761 mmol), triethylamine (2.436 mL, 17.522 mmol) and acetonitrile (10 mL) at room temperature. After stirring well, the reaction mixture was heated at 110 °C for 12 h. After the reaction mixture was cooled to room temperature, the reaction mixture was concentrated under vacuum. The crude product was purified by reverse phase C18 column chromatography. Column: SW-5222-080-SP (AQ); mobile phase: formic acid water / methanol; detection wavelength: 254 nm. The solvent was removed by concentration under reduced pressure to give 760 mg of product 3-(4-fluorophenyl)-7-methyl-thieno[3,2-d]pyrimidine-2,4(lH,3H)-dione (760 mg, 2.751 mmol, 47.10 %). ESI-MS m / z = 276.9 [M+H] + ; Calcu. = 276.3.

[0274] Step B: Into a 50 mL round bottom flask, was added 3-(4-fluorophenyl)-7-methyl- thieno[3,2-d]pyrimidine-2,4(lH,3H)-dione (500 mg, 1.810 mmol), bromine (376 mg, 2.353 mmol) and acetic acid (5 mL) at room temperature. After stirring well, the reaction mixture was heated at 70 °C for 2 h. After the reaction mixture was cooled to room temperature, the reaction mixture was concentrated under vacuum. The crude product was purified by reverse phase C18 column chromatography. Column: SW-5222-040-SP (AQ); mobile phase: formic acid water / methanol; detection wavelength: 254 nm. The solvent was removed by concentration under reduced pressure to give the product 6-bromo-3-(4-fluorophenyl)-7-methyl-thieno[3,2-d]pyrimidine-2,4(lH,3H)-dione (130 mg, 0.366 mmol, 20.23 %). ESI-MS m / z = 355.9 [M+H] + ; Calcu. = 276.3.

[0275] Step C: To a pressure tube of 35 mL, (3-methoxy-4-(4-methylimidazol-l- yl)phenyl)boronic acid (127 mg, 0.549 mmol), 6-bromo-3-(4-fluorophenyl)-7- methyl-thieno[3,2-d]pyrimidine-2,4(lH,3H)-dione (130 mg, 0.366 mmol), l,l'- bis(diphenylphosphino)ferrocene) palladium dichloride (90 mg, 0.110 mmol), potassium carbonate (152 mg, 1.098 mmol) and 1,4-dioxane and water (10 mL:2 mL) were added sequentially at room temperature. After stirring homogeneously, the reaction mixture was heated at 100 °C under argon overnight. After the reaction mixture was cooled to room temperature, the reaction mixture was concentrated in vacuo. The crude product was purified by preparative high performance liquid chromatography. Prep conditions: Column: Waters XBridge Prep C18 5 μm OBD (19 mm x 250 mm, 5 μm); A: 0.1% formic acid in water; B: MeCN; 18 mL / min; 0-3 min, 10% B; 3-4 min, 10%-20% B; 4-15 min, 20%-60% B; 15-16 min, 60%-100% B; Detector: UV 254 nm. The solvent was removed by concentration under reduced pressure to give the product E-32, 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methylimidazol-l- yl)phenyl)-7-methyl-thieno[3,2-d]pyrimidine-2,4(lH,3H)-dione (3.65 mg, 0.008 mmol, 2.16%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 11.94 (s, 1H), 7.85 (d, J=1.3 Hz, 1H), 7.53 (d, J=8.1 Hz, 1H), 7.40 (dd, J=8.9, 5.1 Hz, 2H), 7.36 - 7.31 (m, 3H), 7.25 (dd, J=8.1, 1.9 Hz, 1H), 7.20 (d, J=1.3 Hz, 1H), 3.91 (s, 3H), 2.36 (s, 3H), 2.17 (d, J=1.1 Hz, 3H). ESI-MS m / z = 463.5 [M+H] + Calcu. = 462.5.

[0276] Example 32: Synthesis of compound E-33

[0277] Step A: To a solution of ethyl 2-cyano-2-(4-iodo-3-methoxybenzamido)acetate (873 mg, 2.246 mmol) in dichloromethane (18 mL) was added trifluoroacetic acid (1.28 g, 11.226 mmol) at room temperature. After addition, the mixture was stirred at room temperature for 3 hours, then the reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution (30 mL), water (20 mL) was added, and the mixture was extracted with dichloromethane (50 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude ethyl 5-amino-2-(4-iodo-3-methoxyphenyl)oxazole-4-carboxylate as a yellow solid, which was used directly in the next step without further purification. ESI-MS m / z = 389.1 [M+H] + ; Calcu. = 388.0.

[0278] Step B: To a solution of ethyl 2-cyano-2-(4-iodo-3-methoxybenzamido)acetate (873 mg, 2.246 mmol) in dichloromethane (18 mL) was added trifluoroacetic acid (1.28 g, 11.226 mmol) at room temperature. After addition, the mixture was stirred at room temperature for 3 hours, then the reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution (30 mL), water (20 mL) was added, and the mixture was extracted with dichloromethane (50 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude ethyl 5-amino-2-(4-iodo-3-methoxyphenyl)oxazole-4-carboxylate as a yellow solid, which was used directly in the next step without further purification. ESI-MS m / z = 389.1 [M+H] + ; Calcu. = 388.0.

[0279] Step C: To a solution of crude ethyl 5-amino-2-(4-iodo-3-methoxyphenyl)oxazole-4- carboxylate and 1-fluoro-4-isocyanatobenzene (463 mg, 3.377 mmol) in acetonitrile (30 mL) was added cesium carbonate (1.47 g, 4.512 mmol) at room temperature. After addition, the mixture was heated to reflux for 6 hours. The reaction was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (SiO2, DCM:MeOH = 88:12) to give the product 6-(4-fluorophenyl)-2-(4-iodo-3-methoxyphenyl)oxazolo[5,4- d]pyrimidine-5,7(4H,6H)-dione (480 mg, 1.002 mmol, 29.67% yield over two steps) as a yellow solid. ESI-MS m / z = 480.1 [M+H] +; Calcu. = 479.0.

[0280] Step D: To a solution of 6-(4-fluorophenyl)-2-(4-iodo-3-methoxyphenyl)oxazolo[5,4- d]pyrimidine-5,7(4H,6H)-dione (96 mg, 0.200 mmol), 4-methyl-lH-imidazole (20 mg, 0.244 mmol) in N,N-dimethylformamide (3 mL) was added (1R,2R)-N 1 ,N 2 dimethylcyclohexane-1,2-diamine (11 mg, 0.077 mmol), cesium carbonate (130 mg, 0.399 mmol) and copper(I) iodide (8 mg, 0.042 mmol) was added. After the addition, the whole mixture was warmed to 120 °C and stirred for 7 h under nitrogen atmosphere. The reaction was directly subjected to HPLC preparation separation, preparation condition: ChromCore BR C18 (10 mm x 250 mm, 5 μm); A: 0.1% formic acid in water; B: MeCN; 5.5 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 reaction gave light yellow solid product E-33, 6-(4-fluorophenyl)-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl)oxazolo[5,4- d]pyrimidine-5,7(4H,6H)-dione (0.64 mg, 0.001 mmol, 0.50%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.43 (br s, 1 H), 7.71 (d, J = 1.4 Hz, 1 H), 7.60-7.65 (m, 2 H), 7.43 (br s, 1 H), 7.20-7.27 (m, 5 H), 3.97 (s, 3 H), 2.24 (s, 3 H). ESI-MS m / z = 434.0 [M+H] + ; Calcu. = 433.1.

[0281] Example 33: Synthesis of compound E-34

[0282] Step A: To a solution of ethyl 5-aminothiazole-4-carboxylate (521 mg, 3.026 mmol) in tetrahydrofuran (6 mL) was added triethylamine (1200 μί, 8.633 mmol) under argon. Then, 4-fluorophenyl isocyanate (514 μί, 4.499 mmol) was added to the reaction at 0 °C. The reaction was then heated at 100 °C for 18 h. After the reaction was cooled to room temperature, ethyl acetate (100 mL) was added to the reaction, followed by the extraction of the product with water (50 mL). The aqueous phase was then lyophilized to give a white solid. The white solid was slurried with ethyl acetate (100 mL) to dissolve the organic material, filtered, and the filtrate was concentrated under reduced pressure. This reaction gave a white solid product, 6-(4-fluorophenyl)thiazolo[5,4-d]pyrimidine-5,7(4H,6H)-dione (300 mg, 1.140 mmol, 37.67 %). ESI-MS m / z = 263.9 [M+H] + ; Calcu. = 263.0.

[0283] Step B: To a solution of 6-(4-fluorophenyl)thiazolo[5,4-d]pyrimidine-5,7(4H,6H)-dione (115 mg, 0.437 mmol) in N,N-dimethylformamide (2 mL) was added carbonic acid, tetrabromo-, sodium (198 mg, 0.597 mmol) and sodium tert-butoxide (211 mg, 2.196 mmol) at room temperature. After the addition was complete, the whole mixture was stirred at room temperature for 5 h. After the reaction was complete, ethyl acetate (50 mL) was added to the reaction to dilute the reaction, and then the organic phase was washed with saturated ammonium chloride solution (15 mL), saturated brine (10 mL*2) successively. The organic phase was then dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a solid product as a crude. The crude was purified by a preparative thin layer chromatography plate (PTLC) on silica gel (ethyl acetate). This reaction gave a dark brown solid product, 2-bromo-6-(4-fluorophenyl)thiazolo[5,4-d]pyrimidine-5,7(4H,6H)-dione (33 mg, 0.096 mmol, 21.96 %). ESI-MS m / z = 341.8 [M+H] + ; Calcu. = 340.9.

[0284] Step C: Into a 25 mL Schlenk flask, was added (3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)boronic acid (52 mg, 0.224 mmol), 2-bromo-6-(4- fluorophenyl)thiazolo[5,4-d]pyrimidine-5,7(4H,6H)-dione (33 mg, 0.096 mmol), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium (19 mg, 0.026 mmol) and sodium carbonate (35 mg, 0.330 mmol) sequentially at room temperature under argon atmosphere, and then the system was purged with argon for three times. Then, water (0.25 mL) and 1,4-dioxane (1.0 mL) were added under argon atmosphere. Finally, the mixture was stirred at 90 °C for 18 h under argon atmosphere. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (5 mL) after the mixture was cooled to room temperature. Then, the reaction mixture was filtered through a sintered glass funnel with celite, and the solid was washed with ethyl acetate (60 mL), and then the resulting solution was concentrated under reduced pressure at room temperature. The resulting mixture was separated by preparative HPLC. The chromatographic conditions: Waters XSelect CSH Prep C18 OBD (30 mm x 250 mm, 5 μm), A: 0.1% FA, B: ACN; 40 mL / min; 0-3.0 min, 10% B; 3.0-3.5 min, 10%-10% B; 3.5-15 min, 10%-40%; 15-15.5 min, 40%-100% B; Detector, UV 254 nm). This reaction gave E-34, white solid product 6-(4-fluorophenyl)-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiazolo[5,4-d]pyrimidine-5,7(4H,6H)-dione (2.82 mg, 0.006 mmol, 6.25%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.86 (s, 1H), 7.65 (s, 1H), 7.55-7.60 (m, 1H), 7.49-7.53 (m, 1H), 7.31 (br d, J = 9.2 Hz, 4H), 7.21 (s, 1H), 3.96 (s, 3H), 2.17 (s, 3H). ESI-MS m / z = 450.0 [M+H] + ; Calcu. = 449.1.

[0285] Example 34: Synthesis of compound E-35

[0286] Step A: To a solution of 5-amino-l-methyl-lH-imidazole-4-carboxylic acid ethyl ester (1.07 g, 6.325 mmol), cesium carbonate (4.12 g, 12.649 mmol) in acetonitrile (20 mL) was added 4-fluorophenyl isocyanate (2.60 g, 18.974 mmol). After the addition, the whole mixture was warmed to 90 °C and stirred for 2 h. The solid was removed by suction filtration and the filtrate was concentrated and purified by column chromatography (SiO2, PE:EA = 50:50) to give the product l-(4-fluorophenyl)-9-methyl-3,9-dihydro-lH-purine-2,6-dione (695 mg, 2.67 mmol, 42.23 %). ESI-MS m / z = 260.9 [M+H] + ; Calc u. = 260.1.

[0287] Step B: To a solution of l-(4-fluorophenyl)-9-methyl-3,9-dihydro-lH-purine-2,6-dione (400 mg, 1.537 mmol) in acetonitrile and N,N-dimethylformamide (10 mL, ACN:DMF = 4: 1) was added N-bromosuccinimide (273.59 mg, 1.537 mmol). After the addition, the whole mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated to give the crude product which was used directly in the next step. ESI-MS m / z = 338.8 [M+H] + ; Calc u. = 338.0.

[0288] Step C: To a solution of 8-bromo-l-(4-fluorophenyl)-9-methyl-l,2,3,6-tetrahydro purine-2,6-dione (110 mg, 0.324 mmol), (3-methoxy-4-(4-methyl-lH-imidazol-l- yl)phenyl)boronic acid (75.27 mg, 0.324 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) was added (l,l'-bis(diphenylphosphino)ferrocene)palladium dichloride (23.71 mg, 0.032 mmol) and sodium carbonate (69 mg, 0.648 mmol). After the addition, the whole mixture was warmed to 90 °C and stirred overnight. The mixture was extracted and the organic phase was concentrated. The product was purified by HPLC prep (Waters XBridge C8 (21.2 mm x 250 mm, 5 μm); A: 0.1% formic acid in water; B: MeCN; 18 mL / min 0~3 min, 10% B; 3~15.5 min, 10%~100% B; Detector, UV 254 nm). The reaction gave E-35, l-(4-fluorophenyl)-8-(3-methoxy-4-(4-methyl-lH-imidazol-l- yl)phenyl)-9-methyl-3,9-dihydro-lH-purine-2,6-dione (6.43 mg, 0.014 mmol, 4.44 %) as a white solid.1 H NMR (500 MHz, DMSO-d6) δ ppm 12.52 (br s, 1 H), 7.86 (s, 1 H), 7.55-7.51 (m, 2 H), 7.43 (d, J=8.2 Hz, 1 H), 7.33-7.17 (m, 5 H), 3.90 (s, 3 H), 3.75 (s, 3 H), 2.15 (s, 3 H). ESI-MS m / z = 447.0 [M+H] + ; Calcu.= 446.2.

[0289] Example 35: Synthesis of compound E-36

[0290] Step A: To a solution of 3-(4-fluorophenyl)-6-((3-methoxy-4-(4-methyl-1 H- imidazol-1 -yl)phenyl)ethynyl)-5-methyl-2-sulfooxy-2,3-dihydrothieno[2,3-d]pyrimidin- 4(1 H)-one (10 mg, 0.020 mmol), potassium ethyl xanthate (6 mg, 0.040 mmol) in N,N- dimethylformamide (3 mL) was added formic acid (0.002 mL, 0.040 mmol) at room temperature. After the addition, the whole mixture was stirred at 130 °C for 3 hours. When the reaction was completed, the reaction solution was directly concentrated to get a solid residue, which was subjected to preparative separation. Preparative conditions: Welch C 18 (30 mm x 250 mm, 5 μm); A: 0.05% FA; B: MeCN; 40 mL / min; 0-3.0 min, 10% B; 3.0-3.5 min, 10%-25% B 3.5-18 min, 25%-65% B; detector, UV 254 nm. The reaction gave E-36, white solid product 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1 H-imidazol-1 - yl)phenethyl)-5-methyl-2-sulfooxy-2,3-dihydrothieno[2,3-d]pyrimidin-4(1 H)-one (3 mg, 0.006 mmol, 29.88%). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.79 (d, J = 17.7 Hz, 1 H), 7.54 (d, J = 16.0 Hz, 1 H), 7.44 (s, 1 H), 7.34 (m, 1 H), 7.31 (s, 1 H), 7.12 - 7.21 (m, 4 H), 7.00 - 7.09 (m, 3 H), 6.68 - 6.79 (m, 1 H), 6.54 - 6.61 (m, 1 H), 3.88 - 3.90 (m, 2 H), 3.79 (s, 1 H), 2.54 (s, 3 H), 2.33 - 2.38 (m, 2 H), 2.15 (s, 4 H). ESI-MS m / z = 505.3 [M+H] + ; Calcu. = 504.1.

[0291] Example 36: Synthesis of compounds E-37 and E-40

[0292] Step A: To a solution of ethyl 2-amino-5-(3-methoxy-4-(4-methyl-1 H-imidazol-1 - yl)phenyl)-4-methylthiophene-3-carboxylate (500 mg, 1.346 mmol), 1 -bromo-4- fluorobenzene (283 mg, 1.615 mmol) and cesium carbonate (877 mg, 2.692 mmol) in 1,4- dioxane (16 mL) was added 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (156 mg, 0.269 mmol) and tris(dibenzylideneacetone)dipalladium (123 mg, 0.135 mmol) at room temperature. After the addition, the whole mixture was purged with argon for 3 times, warmed to 100 °C and stirred overnight under argon protection. The reaction was cooled to room temperature, filtered through celite and the filtrate was concentrated under reduced pressure to give a crude. The crude was separated by silica gel column (Si02, PE:EA = 50:50). This reaction gave the product ethyl 2-((4-fluorophenyl)amino)-5-(3-methoxy-4-(4-methyl-1 H-imidazol-1 - yl)phenyl)-4-methylthiophene-3-carboxylate (180.00 mg, 0.387 mmol, 28.72%) as yellow oil. ESI-MS m / z = 466.1 [M+H] + ; Calcu. = 465.1.

[0293] Step B: At -78°C, chlorosulfonyl isocyanate (109 mg, 0.773 mmol) was added to 4 mL of dichloromethane containing dissolved 2-((4-fluorophenyl)amino)-5-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4-methylthiophen-3-carboxylic acid ethyl ester (180 mg, 0.387 mmol). After the addition was complete, the mixture was slowly brought back to room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a gray solid crude product, 2-(1-(4-fluorophenyl)ureo)-5-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4-methylthiophen-3-carboxylic acid ethyl ester (410.20 mg, crude product), which was directly used in the next step of the reaction. ESI-MS m / z = 509.1 [M+H] + ;Calcu. = 508.1.

[0294] Step C: At room temperature, 6N hydrochloric acid (5 mL) was added to ethyl 2-(1-(4-fluorophenyl)ureo)-5-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4-methylthiophene-3-carboxylic acid (400 mg, 0.787 mmol). After the addition was complete, the mixture was heated to 100 °C and stirred for 1 hour. The reaction solution was cooled to room temperature, and then ammonia was added to adjust the pH to 6-7. The solution was concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in methanol (10 mL), filtered to remove ammonium chloride solid, and then concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in methanol (2 mL) and subjected to reversed-phase separation. The chromatographic column was a Santai SepaFlash C18 (Spherical C18, 20-45 μm). 80 g); mobile phase: water (containing 0.05% TFA) and acetonitrile; flow rate: 40 mL / min; gradient: acetonitrile from 0% to 100% over 30 min; detection wavelength: 254 nm. Lyophilization under reduced pressure yielded a white solid product, 1-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (102.30 mg, 0.221 mmol, 28.12%). ESI-MS m / z = 463.0 [M+H] + ;Calcu.MW=462.1.

[0295] Step D: To a solution of 1-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (20 mg, 0.043 mmol) in tetrahydrofuran (2 mL) was added sodium hydride (4.32 mg, 0.108 mmol) at room temperature. After addition, the whole mixture was stirred at room temperature for 20 min. To the reaction was added methyl 3-bromopropanoate (29 mg, 0.173 mmol) dropwise. After addition, the whole mixture was stirred at room temperature for 3 h. To the reaction was added water (1 mL) to quench sodium hydride and the mixture was concentrated under reduced pressure to give a crude. The crude was dissolved in methanol (2 mL) and separated by reverse phase. Column: Santai SepaFlash C18 (Spherical C18, 20-45 μm, 40 g); mobile phase: water (containing 0.05% TFA) and acetonitrile; flow rate: 40 mL / min; gradient: acetonitrile from 0% to 100% in 30 min; detection wavelength: 254 nm. The product was obtained as methyl E-37, white solid, 2-(1-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)acetate (21.00 mg, 0.039 mmol, 88.10%) after lyophilization under reduced pressure. 40g) ; mobile phase: water (containing 0.05% TFA) and acetonitrile; flow rate: 40 mL / min; gradient: acetonitrile from 0% to 100% in 30 min; detection wavelength: 254 nm. The product was obtained as methyl E-37, white solid, 2-(1-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)acetate (21.00 mg, 0.039 mmol, 88.10%) after lyophilization under reduced pressure. 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.79 (d, J=1.07 Hz, 1 H), 7.68-7.72 (m, 2 H), 7.49 (t, J=8.77 Hz, 2 H), 7.43 (d, J=8.09 Hz, 1 H), 7.14-7.18 (m, 2 H), 7.09 (dd, J=8.09, 1.83 Hz, 1 H), 4.71 (s, 2 H), 3.84 (s, 3 H), 3.71 (s, 3 H), 2.53 (s, 3 H), 2.15 (s, 3 H). ESI-MS m / z = 535.0 [M+H] + ; Calcu. = 534.1.

[0296] Step E: To a solution of methyl 2-(l-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl- lH-imidazol-l-yl)phenyl)-5-methyl-2,4-dioxo-l,4-dihydrothieno[2,3-d]pyrimidin-3(2H)- yl)acetate (15 mg, 0.028 mmol) in methanol (2 mL) was added dropwise a solution of lithium hydroxide (3.53 mg, 0.084 mmol) dissolved in water (1 mL) under ice bath. After the addition was completed, the whole mixture was slowly warmed to room temperature and stirred overnight. The reaction was neutralized with 1 N hydrochloric acid and concentrated under reduced pressure to give a crude product. The crude product was sent for preparative separation, preparative conditions: Waters XSelect C18 (30 mm x 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. Lyophilized under reduced pressure to give E-40, white solid product 2-(l-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl)-5-methyl- 2,4-dioxo-l,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)acetic acid (2.09 mg, 0.004 mmol, 13.53%). ESI-MS 1 H NMR (500 MHz, DMSO-d6) δ ppm 12.90-13.23 (m, 1 H), 7.96 (br d, J=2.9 Hz, 1 H), 7.67-7.71 (m, 2 H), 7.47-7.51 (m, 2 H), 7.45 (d, J=8.1 Hz, 1 H), 7.21 (br s, 1 H), 7.18 (d, J=1.7 Hz, 1 H), 7.12 (s, 1 H), 4.60 (s, 2 H), 3.85 (s, 3 H), 2.54 (s, 3 H), 2.17 (s, 3 H). m / z = 521.0 [M+H] + ; Calcu. = 520.1.

[0297] Example 37: Synthesis of compound E-38

[0298] Step A: To a solution of 1-(4-ethynyl-2-methoxyphenyl)-4-methyl-1H-imidazole (20 mg, 0.094 mmol), 6-bromo-3-(4-fluorophenyl)-5-methyl-2-sulfooxy-2,3-dihydrothieno[2,3- d]pyrimidin-4(lH)-one (34.98 mg, 0.094 mmol), cesium carbonate (61.40 mg, 0.188 mmol) in N,N-dimethylformamide (2 mL) was added tetrakis(triphenylphosphine)palladium (21.78 mg, 0.019 mmol) at room temperature. After the addition, the whole mixture was stirred at 120 °C under nitrogen protection overnight. When the reaction was completed, the reaction solution was directly concentrated to get a solid residue, which was subjected to preparative separation. Preparative conditions: Welch C 18 (30 mm x 250 mm, 5 μm); A: 0.05% FA; B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-25% B; 3.5-18 min, 25%-65% B; detector, UV 254 nm. The reaction gave E-38, yellow solid product 3-(4-fluorophenyl)-6-((3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)ethynyl)-5-methyl-2-sulfooxy-2,3-dihydrothieno[2,3-d]pyrimidin-4(1H)-one (5.5 mg, 0.011 mmol, 11.61%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.96 (s, 1H), 7.41-7.48 (m, 3H), 7.26-7.30 (m, 5H), 7.23 (s, 1H), 3.89 (s, 3H), 2.49 (s, 3H), 2.17 (s, 3H). ESI-MS m / z = 503.0 [M+H] + ; Calcu. = 502.1.

[0299] Example 38: Synthesis of compounds E-39 and M-5

[0300] Step A: To a solution of 4-bromo-1-iodo-2-methoxybenzene (25000 mg, 79.890 mmol), 4-methyl-1H-imidazole (7215 mg, 87.879 mmol), 8-hydroxyquinoline (1159 mg, 7.989 mmol), cesium carbonate (65074 mg, 199.725 mmol) in N,N-dimethylformamide (250 mL) was added copper iodide (2535 mg, 7.989 mmol) at room temperature. After the addition, the whole mixture was stirred at 100 °C overnight under nitrogen atmosphere. When the reaction was completed, the reaction solution was concentrated under reduced pressure to get an oily residue. The residue was separated by silica gel column (SiO2, PE:EA = 20:80), which gave the product 1-(4-bromo-2-methoxyphenyl)-4-methyl-1H-imidazole (13000 mg, 48.665 mmol, 60.92%) as a light yellow solid. ESI-MS m / z = 267.8 [M+H] + ; Calcu. = 266.0.

[0301] Step B: To a solution of 1-(4-bromo-2-methoxyphenyl)-4-methyl-1H-imidazole (3500 mg, 13.102 mmol), bis(pinacolato)diboron (3992.62 mg, 15.723 mmol), potassium acetate (3214 mg, 32.756 mmol) in 1,4-dioxane (100 mL) was added (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (1069 mg, 1.310 mmol) at room temperature. After the addition, the whole mixture was stirred at 100 °C overnight under nitrogen atmosphere. When the reaction was completed, the reaction solution was filtered and concentrated under reduced pressure to get an oily residue crude product (3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)boronic acid. ESI-MS m / z = 232.9 [M+H] + ; Calcu. = 232.1.

[0302] Step C: To a solution of 2-amino-4-methylthiophene-3-carboxylate (3500 mg, 18.894 mmol) in dichloromethane (50 mL) was added N-bromosuccinimide (3363 mg, 18.894 mmol) in portions at -10 °C. After the addition, the whole mixture was warmed to room temperature and stirred for 2 hours. When the reaction was completed, the reaction solution was controlled to room temperature and then filtered through celite, then saturated sodium carbonate solution (100 mL) was added, extracted with ethyl acetate, the combined organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get a solid residue crude product. ESI-MS m / z = 265.9 [M+H] + ; Calcu. = 264.9.

[0303] Step D: To a solution of ethyl 2-amino-5-bromo-4-methylthiophene-3-carboxylate (1000 mg, 3.786 mmol), 4-fluorophenyl isothiocyanate (695 mg, 4.543 mmol) in acetonitrile (10 mL) was added cesium carbonate (1233 mg, 3.786 mmol) at room temperature. After the addition, the whole mixture was stirred at 90 °C for 8 h. When the reaction was completed, the reaction mixture was directly concentrated to get a solid residue, which was separated by silica gel column (SiO2, DCM:MeOH = 91:9). This reaction gave M-5, 6-bromo-3-(4-fluorophenyl)-5-methyl-2-sulfooxy-2,3-dihydrothieno[2,3- d]pyrimidin-4(lH)-one (900 mg, 2.424 mmol, 64.04%) as orange-yellow solid. ESI-MS m / z = 272.8 [M+H] + Calcu. = 371.9.

[0304] Step E: To a solution of 6-bromo-3-(4-fluorophenyl)-5-methyl-2-sulfooxy-2,3- dihydrothieno[2,3-d]pyrimidin-4(lH)-one (80 mg, 0.215 mmol), (3-methoxy-4-(4-methyl- lH-imidazol-l-yl)phenyl)boronic acid (68 mg, 0.215 mmol), cesium carbonate (70 mg, 0.215 mmol) in N,N-dimethylformamide (25 mL) was added tetrakis(triphenylphosphine)palladium (249 mg, 0.215 mmol) at room temperature. After the addition, the whole mixture was stirred at 120 °C under nitrogen overnight. When the reaction was completed, the reaction mixture was directly concentrated to get a solid residue, which was separated by preparative HPLC. Preparative conditions: Welch C 18 (30 mm x 250 mm, 5 μm); A: 0.05% FA; B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-25% B; 3.5-18 min, 25%-65% B; Detector, UV 254 nm. This reaction gave E-39, 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-lH-imidazol-l- yl)phenyl)-5-methyl-2-sulfooxy-2,3-dihydrothieno[2,3-d]pyrimidin-4(lH)-one (2.73 mg, 0.006 mmol, 2.65%) as white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 13.90 (s, 1 H), 7.89 (s, 1 H), 7.49 (d, J = 8.1 Hz, 1 H), 7.31 (d, J = 6.9 Hz, 4 H), 7.27 (d, J = 1.8z, 1 H), 7.21 (s, 1 H), 7.15-7.19 (m, 1 H), 3.90 (s, 3 H), 2.48 (s, 3 H), 2.17 (s, 3 H). ESI-MS m / z = 478.9 [M+H] + ; Calcu. = 478.0.

[0305] Example 39: Synthesis of compound E-41

[0306] Step A: To a solution of 6-bromo-3-(4-fluorophenyl)-5-methyl-thieno[2,3- d]pyrimidine-2,4(lH,3H)-dione (750 mg, 2.112 mmol), potassium carbonate (875 mg, 6.335 mmol) in N,N-dimethylformamide (10.00 mL) was added ethyl bromide (0.63 mL, 8.446 mmol) at room temperature. After the addition, the whole mixture was stirred at room temperature overnight. The reaction was concentrated under reduced pressure to give a crude. The crude was separated by silica gel column (Si02, PE:EA = 85:15). This reaction gave white solid product 6-bromo-l-ethyl-3-(4-fluorophenyl)-5-methyl-thieno[2,3- d]pyrimidine-2,4(lH,3H)-dione (150 mg, 0.392 mmol, 18.56 %). ESI-MS m / z = 383.1 [M+H] + ; Calcu. = 381.9.

[0307] Step B: To a solution of 6-bromo-l-ethyl-3-(4-fluorophenyl)-5-methyl- thieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (130.00 mg, 0.339 mmol), (4-bromo-3- methoxyphenyl)boronic acid (117 mg, 0.509 mmol) in 1,4-dioxane (3.6 mL) and water (0.6 mL) was added (l,l'-bis(diphenylphosphino)ferrocene)palladium dichloride (25 mg, 0.034 mmol) at room temperature. After the addition, the whole mixture was purged with argon for 3 times, warmed to 100 °C and stirred overnight under argon protection. The reaction was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was separated by silica gel column (Si02, PE:EA = 80:20). The reaction gave white solid product 6-(4-bromo-3-methoxyphenyl)-l-ethyl-3-(4- fluorophenyl)-5-methyl-thieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (60 mg, 0.123 mmol, 36.21 %). ESI-MS m / z = 489.2 [M+H] + ; Calcu. = 488.0.

[0308] Step C: To a solution of 6-(4-bromo-3-methoxyphenyl)-l-ethyl-3-(4- fluorophenyl)-5-methyl-thieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (90 mg, 0.031 mmol), ((6-methylpyrimidin-4-yl)boronic acid (6.5 mg, 0.047 mmol) and potassium carbonate (13 mg, 0.094 mmol) in toluene (2 mL) was added tetrakis(triphenylphosphine)palladium (4 mg, 0.003 mmol) at room temperature. After the addition, the whole mixture was purged with argon for 3 times, warmed to 100 °C and stirred overnight under argon protection. The reaction was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was separated by preparative, preparative condition: Waters XSelect C18 (30 mm x 250 mm, 5 μm); A: 0.1% formic acid in water, B: MeCN; 40 mL / min; 0-3 min, 6% B; 3-15 min, 6%-50% B, Detector, UV 254 nm). Lyophilized under reduced pressure to give E-41, white solid product l-ethyl-3-(4-fluorophenyl)-6-(3-methoxy-4-(6-methylpyrimidin-4- yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (2.47 mg, 0.005 mmol, 14.40 %). 1H NMR (500 MHz, CD3OD-d4) δ ppm 9.05 (d, J = 0.9 Hz, 1 H), 8.02 (d, J = 8.4 Hz, 1 H), 7.99 (s, 1 H), 7.31 - 7.36 (m, 2 H), 7.23 - 7.28 (m, 4 H), 4.08 - 4.14 (m, 2 H), 3.99 (s, 3 H), 2.58 (d, J = 8.5 Hz, 6 H), 1.43 (t, J = 7.1 Hz, 3 H). ESI-MS m / z = 535.0 [M+H] + ; Calcu. = 534.1.

[0309] Example 40: Synthesis of compound E-42

[0310] Step A: 2-Amino-5-(3-methoxy-4-(4-methyl-1 H-imidazol-1 -yl)phenyl)-4- methylthiophene-3-carboxylic acid ethyl ester (194 mg, 0.503 mmol) and cesium carbonate (340 mg, 1.044 mmol) were dissolved in N,N-dimethylformamide (20 mL), iodomethane (74 mg, 0.522 mmol) was added at 0 °C. The reaction system was stirred at 0 °C for 2 h, then warmed to room temperature and stirred overnight. The insoluble was filtered, the filtrate was evaporated under reduced pressure, and the product 5-(3-methoxy-4-(4-methyl-1 H-imidazol-1 -yl)phenyl)-4-methyl-2-(methylamino)thiophene-3-carboxylic acid ethyl ester (30 mg, 0.078 mmol, 14.90%) was separated by column. + ; Calcu. = 385.1.

[0311] Step B: At room temperature, 5-(3-methoxy-4-(4-methyl-1 H-imidazol-1 -yl)phenyl)-4- methyl-2-(methylamino)thiophene-3-carboxylic acid ethyl ester (20 mg, 0.052 mmol), 4- isocyanatobenzoic acid methyl ester (92 mg, 0.519 mmol), cesium carbonate (34 mg, 0.104 mmol) were dissolved in acetonitrile (4 mL), and the reaction system was heated to 120 °C by microwave reactor. After stirring for 1 h, the reaction system was cooled to room temperature, the insoluble was filtered, the filtrate was evaporated under reduced pressure, and the product E-42, 4-(6-(3-methoxy-4-(4-methyl-1 H-imidazol-1 -yl)phenyl)-1,5-dimethyl-2,4-dioxo-1,4- dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzoic acid methyl ester (15.00 mg, 0.029 mmol, 55.97%) was separated by column. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.10 (d, J = 2.0 Hz, 1 H), 8.09 (d, J = 1.9 Hz, 1 H), 7.91 (d, J = 8.9 Hz, 1 H), 7.84 - 7.84 (m, J = 1.3 Hz, 1 H), 7.64 (d, J = 8.8 Hz, 3 H), 7.52 (s, 1 H), 7.50 (d, J = 1.5 Hz, 1 H), 7.48 (d, J = 1.9 Hz, 1 H), 7.28 (d, J = 1.8 Hz, 1 H), 7.18 (dd, J = 8.1, 1.7 Hz, 3 H), 3.91 (s, 6 H), 3.52 (s, 3 H), 2.18 (d, J = 0.7 Hz, 3 H). ESI-MS m / z = 517.1 [M+H] + ; Calcu. = 516.1.

[0312] Example 41 : Synthesis of compound E-43

[0313] Step A: Methyl 4-(6-(3-methoxy-4-(4-methyl-1 H-imidazol-1 -yl)phenyl)-1,5- dimethyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzoate (6 mg, 0.012 mmol) was dissolved in a mixture of tetrahydrofuran (3 mL) and ethanol (3 mL), 2M aqueous sodium hydroxide (0.23 mL) was added, and the reaction was stirred at room temperature for 2 hours until the starting material disappeared. The reaction was cooled to 0 °C, and formic acid was added dropwise to adjust the pH of the reaction to neutral. The solvent was evaporated under reduced pressure, and the product was separated by preparative liquid chromatography with the following conditions: Welch Xtimate C18 (30 mm x 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-65% B; 3.5-15 min, 65%-95% B; 15-15.5 min, 95%-100% B; detector: UV 254 nm. The product E-43, 4-(6-(3-methoxy-4-(4-methyl-1 H-imidazol-1 -yl)phenyl)-1,5-dimethyl-2,4-dioxo-1,4- dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzoic acid (1.05 mg, 0.002 mmol, 17.98%) was obtained. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.02 (d, J = 7.5 Hz, 1 H), 7.83 (s, 1 H), 7.50 (d, J = 7.7 Hz, 1 H), 7.36 (s, 2 H), 7.27 (s, 1 H), 7.17 (d, J = 8.3 Hz, 2 H), 3.90 (s, 1 H), 3.51 (s, 1 H), 2.17 (s, 1 H). ESI-MS m / z = 503.0 [M+H] + ; Calcu. = 502.1.

[0314] Example 42: Synthesis of compound E-44

[0315] Step A: To a solution of pyridin-4-amine (300 mg, 3.187 mmol), triethylamine (1.329 mL, 9.562 mmol) in tetrahydrofuran (15 mL) was added with triphosgene (378 mg, 1.275 mmol) at 0 °C. After the addition, the whole mixture was stirred at 0 °C for 1 hour. Concentration under reduced pressure gave brown crude product 4-isocyanate pyridine.

[0316] Step B: To a solution of ethyl 2-amino-5-(3-methoxy-4-(4-methyl-1 H-imidazol-1 - yl)phenyl)-4-methylthiophene-3-carboxylate (186 mg, 0.500 mmol), triethylamine (0.139 mL, 0.999 mmol) in tetrahydrofuran (15 mL) was added with the crude product 4-isocyanate pyridine (300 mg) from previous step at room temperature. After the addition, the whole mixture was stirred at room temperature for 1 hour. Concentration under reduced pressure gave brown crude product ethyl 5-(3-methoxy-4-(4-methyl-1 H-imidazol-1 -yl)phenyl)-4-methyl-2-(3-(pyridin-4- yl)ureido)thiophene-3-carboxylate. ESI-MS m / z = 492.2 [M+H] + ; Calcu. = 491.2.

[0317] Step C: To the crude 5-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4- methyl-2-(3-(pyridin-4-yl)ureido)thiophene-3-carboxylic acid ethyl ester from previous step was added sodium ethoxide in ethanol (10 mL) at room temperature. After the addition was complete, the whole mixture was stirred at room temperature for 3 hours. Subsequent concentration under reduced pressure gave a brown crude product. The crude was subjected to HPLC prep purification, prep condition: Welch Xtimate C18 (30 mm x 250 mm, 5 μm); A: 0.1% formic acid in water; B: MeCN; 5 mL / min; 0-3 min, 10% B; 3-3.5 min, 10% B; 3.5-15 min, 10%-100% B; Detector, UV 254 nm. This reaction gave 6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-3- (pyridin-4-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (15 mg, 0.034 mmol, 6.73%) as a white solid. ESI-MS m / z = 446.1 [M+H]+; Calcu.= 445.1.

[0318] Step D: To 6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-3-(pyridin-4- yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (15 mg, 0.034 mmol), potassium carbonate (13.96 mg, 0.101 mmol) in N,N-dimethylformamide (3 mL) was added iodomethane (0.003 mL, 0.034 mmol) at 0 °C. After the addition was complete, the whole mixture was stirred at room temperature for 3 hours. Subsequent concentration under reduced pressure gave a brown crude product. The crude was subjected to HPLC prep purification, prep condition: Welch Xtimate C18 (30 mm x 250 mm, 5 μm); A: 0.05% ammonia in water; B: MeCN; 5 mL / min; 0-3 min, 30% B; 3-15 min, 30%-100% B; Detector, UV 254 nm. This reaction gave E-44, 6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-1,5-dimethyl-3- (pyridin-4-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (6.09 mg, 0.013 mmol, 38.24%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.74 (d, 2 H, J=6.1 Hz), 7.83 (d, 1 H, J=1.4 Hz), 7.50 (d, 1 H, J=7.9 Hz), 7.4 - 7.4 (m, 2 H), 7.27 (d, 1 H, J=1.7 Hz), 7.2 - 7.2 (m, 2 H), 3.90 (s, 3 H), 3.52 (s, 3 H), 2.17 (d, 3 H, J=0.6 Hz). ESI-MS m / z = 460.3 [M+H] + ; Calcu. = 459.1.

[0319] Example 43: Synthesis of compound E-45

[0320] Step A: To a solution of pyridin-3-amine (300 mg, 3.187 mmol), triethylamine (1.329 mL, 9.562 mmol) in tetrahydrofuran (15 mL) was added to triphosgene (378 mg, 1.275 mmol) at 0 °C. After the addition, the whole mixture was stirred at 0 °C for 1 hour. Concentration under reduced pressure gave brown crude product 3-isocyanate pyridine.

[0321] Step B: To a solution of ethyl 2-amino-5-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4- methylthiophene-3-carboxylate (186 mg, 0.500 mmol), triethylamine (0.139 mL, 0.999 mmol) in tetrahydrofuran (15 mL) was added the crude product 3-isocyanate pyridine 300 mg at room temperature. After the addition, the whole mixture was stirred at room temperature for 1 hour. Concentration under reduced pressure gave brown crude product ethyl 5-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4-methyl-2-(3-(pyridin-3- yl)ureido)thiophene-3-carboxylate. ESI-MS m / z = 492.2 [M+H] + ; Calcu. = 491.2.

[0322] Step C: At room temperature, 10 mL of sodium ethoxide in ethanol solution was added to the crude product 5-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4-methyl-2-(3-(pyridin-3-yl)ureo)thiophene-3-carboxylic acid ethyl ester from the previous step. After the addition was complete, the mixture was stirred at room temperature for 3 hours. Subsequently, the mixture was concentrated under reduced pressure to obtain a brown crude product. The crude product was then separated by HPLC under the following conditions: Welch Xtimate C18 (30 mm × 250 mm, 5 μm); A: 0.1% formic acid aqueous solution; B: MeCN; 5 mL / min; 0–3 min, 10% B; 3–3.5 min, 10% B; 3.5–15 min, 10%–100% B; detector, UV 254 nm. The reaction yielded a white solid product, 6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-3-(pyridin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (10 mg, 0.022 mmol, 4.49%). ESI-MS m / z = 446.1 [M+H] + ;Calcu. = 445.1.

[0323] Step D: At room temperature (0°C), iodomethane (0.002 mL, 0.022 mmol) was added to 2 mL of DMF containing 10 mg (10 mg, 0.022 mmol) of 6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-3-(pyridin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione and 9.31 mg (0.067 mmol) potassium carbonate. After the addition was complete, the mixture was stirred at room temperature for 3 hours. The mixture was then concentrated under reduced pressure to obtain a brown crude product. The crude product was prepared and separated by HPLC under the following conditions: Welch Xtimate C18 (30 mm × 250 mm, 5 μm); A: 0.05% ammonia; B: MeCN; 5 mL / min; 0–3 min, 30% B; 3–15 min, 30%–100% B; detector, UV 254 nm. The reaction yielded E-45, a white solid product 6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-1,5-dimethyl-3-(pyridin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (3.42 mg, 0.007 mmol, 33.22%). 1H NMR(DMSO-d6,500MHz)δppm 8.63(dd,1H,J=1.5,4.9Hz),8.52(d,1H,J=2.0Hz),7.83(d,1H,J=1.2Hz),7.8-7.8(m,1H),7.57(dd,1H,J=5.3 ,8.0Hz),7.50(d,1H,J=8.1Hz),7.27(d,1H,J=1.8Hz),7.1-7.2(m,2H),3.90(s,3H),3.53(s,3H),2.17(s,3H). ESI-MS m / z=460.3[M+H] + ;Calcu.=459.1.

[0324] Example 44: Synthesis of compound E-46

[0325] Step A: At room temperature, N,N-dimethylformamide (2 mL) containing 1-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methylthiopheno[2,3-d]pyrimidine-2,4(1H,3H)-dione (15 mg, 0.032 mmol) and potassium carbonate (11 mg, 0.081 mmol) was dissolved, and tert-butyl (3-bromopropyl)carbamate (31 mg, 0.130 mmol) was added. After the addition was complete, the mixture was stirred overnight at room temperature. The reaction solution was filtered through diatomaceous earth, and the crude product was obtained by concentration under reduced pressure. The crude product was directly subjected to reversed-phase separation using a Santai SepaFlash C18 column (Spherical C18, 20-45 μm). 80 g); mobile phase: water (containing 0.05% TFA) and acetonitrile; flow rate: 40 mL / min; gradient: acetonitrile from 0% to 100% over 30 min; detection wavelength: 254 nm. Lyophilized under reduced pressure, the product was a white solid (15.00 mg, 0.025 mmol, 76.37%) of tert-butyl 2-(1-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)ethyl)carbamate. ESI-MS m / z = 606.1 [M+H] + ;Calcu.MW=605.2.

[0326] Step B: To (2-(l-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-lH-imidazol-l- yl)phenyl)-5-methyl-2,4-dioxo-l,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)ethyl) tert- butyl carbamate (15.00 mg, 0.025 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL) at 0 °C. After the addition, the whole mixture was slowly warmed to room temperature and stirred for 1 h. The reaction was concentrated under reduced pressure to give a crude product. The crude product was sent for preparative separation, preparative condition: Waters XSelect C18 (30 mm x 250 mm, 5 μm); A: 0.1% formic acid in water, B: MeCN; 40 mL / min; 0-3 min, 8% B; 3-3.5 min, 8%-20% B; 3.5-15 min, 20%-50% B, detector, UV 254 nm. Lyophilized under reduced pressure to give E-46, white solid product 3-(2-aminoethyl)-l-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-lH- imidazol-l-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (6.81 mg, 0.013 mmol, 50.17%). ESI-MS m / z = 506.1 [M+H] + ; Calcu. = 505.1. 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.83 (br s, 3H), 7.64-7.68 (m, 2H), 7.60 (d, J = 8.1 Hz, 2H), 7.51 (t, J = 8.8 Hz, 2H), 7.22 (d, J = 1.7 Hz, 1H), 7.19 (dd, J = 8.1, 1.83 Hz, 1H), 4.20 (t, J = 5.8 Hz, 2H), 3.88 (s, 3H), 3.11-3.15 (m, 2H), 2.58 (s, 3H), 2.31 (s, 3H).

[0327] Example 45: Synthesis of compound E-47

[0328] Step A: To a solution of 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (15 mg, 0.032 mmol), potassium carbonate (27 mg, 0.195 mmol) in N,N-dimethylformamide (2 mL) was added (2-bromomethyl)dimethylamine (20 mg, 0.130 mmol) at room temperature. After the addition, the whole mixture was stirred at room temperature overnight. The reaction was filtered through celite, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was sent for preparative separation, preparative conditions: Waters XSelect C18 (30 mm x 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. Lyophilized under reduced pressure to give E-47, white solid product 1-(2-(dimethylamino)ethyl)-3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (3.20 mg, 0.006 mmol, 17.13%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.83 (d, J = 1.2 Hz, 1 H), 7.49 (d, J = 8.1 Hz, 1 H), 7.31 - 7.39 (m, 4 H), 7.26 (d, J = 1.8 Hz, 1 H), 7.15 - 7.19 (m, 2 H), 4.01 (br t, J = 6.9 Hz, 2 H), 3.90 (s, 3 H), 2.63 (t, J = 6.8 Hz, 2 H), 2.51 (br s, 3 H), 2.22 (s, 6 H), 2.17 (s, 3 H). ESI-MS m / z = 534.1 [M+H] + ; Calcu. = 533.2.

[0329] Example 46: Synthesis of compound E-48

[0330] Step A: To a solution of 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (32 mg, 0.069 mmol) in N,N-dimethylformamide (2 mL) was added potassium carbonate (19 mg, 0.137 mmol) and 3-(bromomethyl)oxetane (13 mg, 0.084 mmol) at room temperature. The whole mixture was stirred at room temperature overnight. Then the reaction was directly subjected to HPLC preparation separation. The preparation condition: Waters XBridge Prep C18 (19 mm x 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 18 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-40% B; 3.5-15 min, 40%-75% B; detector, UV 254 nm. The reaction gave E-48, white solid product 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-1-(oxetan-3-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (9.09 mg, 0.017 mmol, 24.74%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.83 (d, J = 1.1 Hz, 1 H), 7.50 (d, J = 8.1 Hz, 1 H), 7.31 - 7.38 (m, 4 H), 7.26 (d, J = 1.7 Hz, 1 H), 7.16 - 7.18 (m, 2 H), 4.66 (dd, J = 7.8, 6.3 Hz, 2 H), 4.49 (t, J = 6.3 Hz, 2 H), 4.28 (d, J = 7.2 Hz, 2 H), 3.90 (s, 3 H), 3.49 - 3.57 (m, 1 H), 2.17 (s, 3 H). ESI-MS m / z = 533.3 [M+H] + ; Calcu. = 532.2.

[0331] Example 47: Synthesis of compound E-49

[0332] Step A: To a solution of 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (20 mg, 0.043 mmol), potassium carbonate (18 mg, 0.130 mmol) in N,N-dimethylformamide (4 mL) was added bromomethylcyclobutane (0.005 mL, 0.043 mmol) at 0 °C. After the addition, the whole mixture was stirred at room temperature overnight. Then it was concentrated under reduced pressure to give brown crude product. The crude was subjected to HPLC prep for separation, prep condition: Welch Xtimate C18 (30 mm x 250 mm, 5 μm); A: 0.15% formic acid in water; B: MeCN; 5 mL / min; 0-3 min, 30% B; 3-15 min, 30%-100% B; Detector, UV 254 nm. The reaction gave E-49, white solid product 1-(cyclobutylmethyl)-3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (10.18 mg, 0.019 mmol, 44.18%). 1 H NMR (DMSO-d6, 500 MHz) δ ppm 7.83 (d, 1H, J = 1.1 Hz), 7.49 (d, 1H, J = 8.1 Hz), 7.3-7.4 (m, 4H), 7.26 (d, 1H, J = 1.7 Hz), 7.1-7.2 (m, 2H), 4.01 (d, 2H, J = 7.2 Hz), 3.90 (s, 3H), 2.8-2.9 (m, 1H), 2.17 (s, 3H), 2.0-2.1 (m, 2H), 1.8-1.9 (m, 4H). ESI-MS m / z = 531.4 [M+H] + ; Calcu. = 530.2.

[0333] Example 48: Synthesis of compound E-50

[0334] Step A: To a solution of 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (20 mg, 0.043 mmol), potassium carbonate (17.93 mg, 0.130 mmol) in DMF (4 mL) was added bromomethylcyclopropane (0.004 mL, 0.043 mmol) at 0 °C. After the addition, the whole mixture was stirred at room temperature overnight. Then it was concentrated under reduced pressure to give brown crude product. The crude was subjected to HPLC prep for separation, prep condition: Welch Xtimate C18 (30 mm x 250 mm, 5 μm); A: 0.15% formic acid in water; B: MeCN; 5 mL / min; 0-3 min, 30% B; 3-15 min, 30%-100% B; Detector, UV 254 nm. This reaction gave E-50, white solid product 1-(cyclopropylmethyl)-3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (12.26 mg, 0.024 mmol, 55.81%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.49 (d, 1 H, J = 8.1 Hz), 7.3-7.4 (m, 4 H), 7.27 (d, 1 H, J = 1.8 Hz), 7.2-7.2 (m, 2 H), 3.90 (s, 3 H), 3.88 (br d, 2 H, J = 7.0 Hz), 2.17 (s, 3 H), 1.3-1.4 (m, 1 H), 0.5-0.6 (m, 2 H), 0.5-0.5 (m, 2 H). ESI-MS m / z = 517.3 [M+H] + ; Calcu. = 516.2.

[0335] Example 49: Synthesis of compounds E-51 and E-52

[0336] Step A: To a solution of 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (40 mg, 0.086 mmol), potassium carbonate (30 mg, 0.216 mmol) in N,N-dimethylformamide (2 mL) was added tert-butyl (2-bromoethyl)carbamate (78 mg, 0.346 mmol) at room temperature. After the addition, the whole mixture was stirred at room temperature overnight. The reaction was filtered through celite and concentrated under reduced pressure to give a crude. The crude was dissolved in methanol (2 mL) and subjected to reverse phase separation, column: Santai SepaFlash C18 (Spherical C18, 20-45 μm, 40 g); mobile phase: water (with 0.05% TFA) and acetonitrile; flow rate: 40 mL / min; gradient: acetonitrile from 0% to 100% in 30 min; detection wavelength: 254 nm. Lyophilization under reduced pressure gave tert-butyl (E)-2-(3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5-methyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)- yl)ethyl)carbamate (20.00 mg, 0.033 mmol, 37.22%) as a white solid. 40g) ; mobile phase: water (with 0.05% TFA) and acetonitrile; flow rate: 40 mL / min; gradient: acetonitrile from 0% to 100% in 30 min; detection wavelength: 254 nm. Lyophilization under reduced pressure gave tert-butyl (E)-2-(3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5-methyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)- yl)ethyl)carbamate (20.00 mg, 0.033 mmol, 37.22%) as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.83 (d, J=0.9 Hz, 1 H), 7.51 (d, J=8.1 Hz, 1 H), 7.30 - 7.38 (m, 4 H), 7.20 (d, J=1.7 Hz, 1 H), 7.19 (s, 1 H), 7.12 (dd, J=8.0, 1.8 Hz, 1 H), 7.08 (t, J=6.3 Hz, 1 H), 3.94 (br t, J=5.2 Hz, 2 H), 3.89 (s, 3 H), 3.34 - 3.37 (m, 2 H), 2.47 (s, 3 H), 2.17 (s, 3 H), 1.27 (s, 9 H).

[0337] Step B: To a solution of tert-butyl (2-(3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5-methyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)ethyl) carbamate (15 mg, 0.025 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL) at 0 °C. After the addition, the whole mixture was stirred in ice bath, the temperature was slowly increased to room temperature overnight. The reaction was concentrated under reduced pressure to give the crude product. The crude product was sent for preparative separation, preparative condition: Waters XSelect C18 (30 mm x 250 mm, 5 μm); A: 0.1% formic acid in water, B: MeCN; 40 mL / min; 0-3 min, 5% B; 3-3.5 min, 5%-15% B; 3.5-15 min, 15%-50% B, detector, UV 254 nm. Lyophilized under reduced pressure to give E-52, white solid product 1-(2-aminoethyl)-3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5- methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (3.60 mg, 0.007 mmol, 28.48%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.28 (s, 1H), 7.83 (d, J = 1.1 Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.30 - 7.39 (m, 4H), 7.26 (d, J = 1.7 Hz, 1H), 7.18 (s, 1H), 7.15 - 7.18 (m, 1H), 7.16 (d, J = 1.8 Hz, 1H), 3.98 (br t, J = 6.3 Hz, 2H), 3.90 (s, 3H), 2.97 (t, J = 6.4 Hz, 2H), 2.50 (s, 3H), 2.17 (s, 3H). ESI-MS m / z = 520.4 [M+H] + ; Calcu. = 519.1.

[0338] Example 50: Synthesis of compounds E-53 and E-54

[0339] Step A: To a solution of 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (100 mg, 0.216 mmol), 1-bromo-4,4,5,5-tetramethyl-3-oxa-4-silahexane (78 mg, 0.324 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (60 mg, 0.432 mmol) at room temperature. After the addition, the whole mixture was stirred at room temperature overnight. When the reaction was completed, the reaction was cooled to room temperature, then water (20 mL) was added, extracted with ethyl acetate for three times (30 mL), combined the organic phase, washed with saturated brine once (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a solid residue. The residue was separated by silica gel column (SiO2, DCM:MeOH = 95:5). This reaction gave E-54, white solid product 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (60 mg, 0.097 mmol, 44.70%). 11 H NMR (500 MHz, DMSO-d6) δ ppm 7.83 (d, J = 1.1 Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.30 - 7.36 (m, 4H), 7.17 - 7.21 (m, 2H), 7.13 (dd, J = 8.2, 1.8 Hz, 1H), 4.06 (t, J = 5.2 Hz, 2H), 3.93 - 3.97 (m, 2H), 3.89 (s, 3H), 2.47 - 2.49 (m, 3H), 2.17 (s, 3H), 0.80 (s, 9H), 0.01 (s, 6H). ESI-MS m / z = 621.4 [M+H] + ; Calcu. = 620.1.

[0340] Step B: To a solution of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (40 mg, 0.064 mmol) in dichloromethane (5 mL) was added tetrabutylammonium fluoride tetrahydrofuran solution (0.15 mL, 0.15 mmol) at room temperature. After the addition, the whole mixture was stirred at room temperature overnight. When the reaction was completed, the reaction was filtered over celite, the filtrate was concentrated and directly subjected to HPLC prep. separation, prep. condition: Waters XBridge C18 (19 mm x 250 mm, 5 μm); A: 0.1% formic acid in water; B: MeCN; 18 mL / min 0~3 min, 5% B; 3~18 min, 5%~55% B; Detector, UV 254 nm. The reaction gave E-53, white solid product 3-(4-fluorophenyl)-1-(2-hydroxyethyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (7.28 mg, 0.014 mmol, 22.31%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.83 (s, 1 H), 7.49 (d, J = 8.1 Hz, 1 H), 7.31 - 7.38 (m, 4 H), 7.24 (d, J = 1.4 Hz, 1 H), 7.13 - 7.20 (m, 1 H), 5.05 - 5.10 (m, 1 H), 3.96 - 4.02 (m, 2 H), 3.90 (s, 3 H), 3.75 (d, J = 4.9 Hz, 2 H), 2.17 ppm (s, 3 H). ESI-MS m / z = 507.3 [M+H] + ; Calcu. = 506.2.

[0341] Example 51: Synthesis of compounds E-55 and E-56

[0342] Step A: To a solution of 6-bromo-3-(4-fluorophenyl)-5-methylthieno[2,3- d]pyrimidine-2,4(1H,3H)-dione (100 mg, 0.282 mmol), methyl bromoacetate (0.054 mL, 0.338 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (78 mg, 0.563 mmol) at room temperature. After the addition, the whole mixture was stirred at room temperature overnight. When the reaction was completed, the reaction was controlled to room temperature, then water (20 mL) was added, extracted with 30 mL ethyl acetate for three times, combined the organic phase, washed with saturated brine (20 mL) once, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get a solid residue. The residue was separated by silica gel column (Si02, DCM:MeOH = 95:5). The reaction gave methyl 2-(6-bromo-3-(4-fluorophenyl)-5-methyl-2,4-dioxo-3,4- dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)acetate (60 mg, 0.140 mmol, 49.88%) as a white solid product. ESI-MS m / z = 427.3 [M+H] + ; Calcu. = 425.9.

[0343] Step B: Under nitrogen, a mixture of methyl 2-(6-bromo-3-(4-fluorophenyl)-5- methyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)acetate (40 mg, 0.094 mmol), (3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)boronic acid (33 mg, 0.140 mmol), cesium carbonate (31 mg, 0.094 mmol) in N,N-dimethylformamide (5 mL) was added tetrakis(triphenylphosphine)palladium (108 mg, 0.094 mmol) at room temperature. After the addition, the whole mixture was stirred at 120 °C for 1 hour. When the reaction was completed, the reaction was filtered through celite, the filtrate was concentrated and directly subjected to HPLC preparation separation, the preparation condition: Waters XBridge C18 column (19 mm x 250 mm, 5 μm); A: 0.1% formic acid in water; B: MeCN; 18 mL / min 0~3 min, 5% B; 3~18 min, 5%~35% B; detector, UV 254 nm. The reaction gave E-56, white solid product 2-(3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)acetic acid (8.17 mg, 0.016 mmol, 16.76%). 18 (19 mm x 250 mm, 5 μm); A: 0.1% formic acid in water; B: MeCN; 18 mL / min 0~3 min, 5% B; 3~18 min, 5%~35% B; detector, UV 254 nm. The reaction gave E-56, white solid product 2-(3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)acetic acid (8.17 mg, 0.016 mmol, 16.76%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.82-7.84 (m, 1 H), 7.47-7.50 (m, 1 H), 7.32-7.35 (m, 4 H), 7.22-7.25 (m, 1 H), 7.17-7.20 (m, 1 H), 7.13-7.16 (m, 1 H), 4.35-4.61 (m, 2 H), 3.88-3.91 (m, 3 H), 2.15-2.18 (m, 3 H). ESI-MS m / z = 521.3 [M+H] + ; Calcu. = 520.1. The reaction gave E-55, white solid product methyl 2-(3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)acetate (1.31 mg, 0.002 mmol, 2.62%). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.83 (d, J = 1.1 Hz, 1 H), 7.49 (d, J = 8.1 Hz, 1 H), 7.33 - 7.37 (m, 4 H), 7.26 (d, J = 1.7 Hz, 1 H), 7.18 (s, 1 H), 7.15 (dd, J = 8.2, 1.8 Hz, 1 H), 4.84 (s, 2 H), 3.89 (s, 3 H), 3.74 (s, 3 H), 2.16 ppm (s, 3 H). ESI-MS m / z = 535.3 [M+H] + ; Calcu. = 534.1.

[0344] Example 52: Synthesis of compound E-57

[0345] Step A: 2-Amino-5-(3-methoxy-4-(4-methyl-1 H-imidazol-1 -yl)phenyl)-4- methylthiophene-3-carboxylic acid ethyl ester (140 mg, 0.377 mmol), 4- methoxyphenyl isocyanate (281 mg, 1.884 mmol), cesium carbonate (246 mg, 0.755 mmol) were dissolved in acetonitrile (10 mL) and the reaction was heated to 100 °C in a microwave reactor. After 0.5 h stirring the reaction was allowed to cool to room temperature, the insoluble material was filtered off and the filtrate was evaporated under reduced pressure. The product 6-(3-methoxy-4-(4-methyl-1 H-imidazol-1 -yl)phenyl)-3-(4- methoxyphenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1 H,3H)-dione (160 mg, 0.337 mmol, 89.46%) was isolated by column chromatography. ESI-MS m / z = 475.1 [M+H] + ; Calcu. = 474.1.

[0346] Step B: 6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-3-(4- methoxyphenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (20 mg, 0.042 mmol) and potassium carbonate (17 mg, 0.126 mmol) were dissolved in N,N-dimethylformamide (2 mL), iodomethane (6 mg, 0.042 mmol) was added at 0 °C. The reaction was stirred at 0 °C for 5 min, then warmed to room temperature and stirred for 2 h. The reaction was adjusted to neutral pH with acetic acid, the solvent was evaporated under reduced pressure, and the product was isolated by preparative liquid chromatography with the following conditions: Welch Xtimate C18 (30 mm x 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-65% B; 3.5-15 min, 65%-95% B; 15-15.5 min, 95%-100% B; detector: UV 254 nm. The product, E-57, 6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-3-(4-methoxyphenyl)-1,5-dimethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (2.89 mg, 0.006 mmol, 14.04%) was obtained. 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.83 (d, J=1.3 Hz, 1 H), 7.49 (d, J=8.1 Hz, 1 H), 7.26 (d, J=1.8 Hz, 1 H), 7.18 (ddd, J=10.0, 7.3, 2.0 Hz, 4 H), 7.05 - 7.00 (m, 2 H), 3.90 (s, 3 H), 3.81 (s, 3 H), 3.50 (s, 3 H), 2.17 (d, J=0.7 Hz, 3 H). ESI-MS m / z = 489.4 [M+H] + ; Calcu. = 488.2.

[0347] Example 53: Synthesis of compound E-58

[0348] Step A: To a solution of 4-(dimethyloxyphosphoryl)aniline (1 g, 5.912 mmol), phenyl chloroformate (1.02 g, 6.503 mmol) in tetrahydrofuran (20 mL) was added pyridine (1.912 mL, 23.646 mmol). After addition, the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and the residue was taken up in ethyl acetate (20 mL) and filtered to give phenyl (4-(dimethylphosphoryl)phenyl)carbamate (980 mg, 3.388 mmol, 57.31 %). ESI-MS m / z = 290.0 [M+H] + ; Calc u. = 289.1.

[0349] Step B: To a solution of ethyl 2-amino-5-[3-methoxy-4-(4-methylimidazol-l- yl)phenyl]-4-methylthiophene-3-carboxylate (300 mg, 0.806 mmol), phenyl (4- (dimethylphosphoryl)phenyl)carbamate (466.16 mg, 1.613 mmol) in N,N- dimethylformamide (5 mL) was added triethylamine (411.1 mg, 4.03 mmol). The mixture was stirred at 70 °C overnight. The reaction mixture was used directly in the next step. ESI-MS m / z = 567.1 [M+H] + ; Calc u. = 566.2.

[0350] Step C: To a solution of ethyl 2-(3-(4-(dimethylphosphoryl)phenyl)ureido)-5-(3- methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl)-4-methylthiophene-3-carboxylate (456.2 mg, 0.806 mmol) in ethanol (5 mL) was added sodium ethoxide (548.1 mg, 8.06 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated and directly separated by HPLC prep. Prep condition: Waters XBridge C8 (19 mm x 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 18 mL / min 0-3 min, 10% B; 3-15.5 min, 10%-100% B; Detector, UV 254 nm. This reaction gave E-58, 3-(4-(dimethylphosphoryl)phenyl)-6-(3-methoxy-4-(4-methyl-lH- imidazol-l-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (84 mg, 0.162 mmol, 20) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.50 (s, 1 H), 7.90-7.84 (m, 2 H), 7.81 (s, 1 H), 7.48-7.41 (m, 3 H), 7.23 (d, J=1.6 Hz, 1 H), 7.19-7.09 (m, 2 H), 3.89 (s, 3 H), 2.47 (s, 3 H), 2.16 (s, 3 H), 1.72 (s, 3 H), 1.69 (s, 3 H). ESI-MS m / z = 521.4 [M+H] + ; Calcu. = 520.1.

[0351] Example 54: Synthesis of compound E-59

[0352] Step A: 0 °C, dry round-bottom flask, 2-amino-5-(3-methoxy-4-(4-methyl-1 H- imidazol-1-yl)phenyl)-4-methylthiophene-3-carboxylic acid ethyl ester (185 mg, 0.498 mmol), dichloromethane (5 mL), pyridine (0.12 mL) and phenyl chloroformate (0.075 mL) were added successively. After all the addition, the mixture was stirred at room temperature for 18 hours. Then diluted with dichloromethane (15 mL) and water (15 mL). The organic layer was separated, the aqueous layer was extracted with dichloromethane (15 mL*3). The combined organic layers were washed with saturated sodium chloride solution (15 mL*3), dried over anhydrous sodium sulfate and rotary evaporated to get the solid crude product 5-(3-methoxy-4-(4-methyl-1 H-imidazol-1-yl)phenyl)-4-methyl-2-((phenoxycarbonyl)amino)thiophene-3-carboxylic acid ethyl ester (206 mg, crude).

[0353] Step B: Room temperature, dry round-bottom flask, 5-(3-methoxy-4-(4-methyl-1 H- imidazol-1-yl)phenyl)-4-methyl-2-((phenoxycarbonyl)amino)thiophene-3-carboxylic acid ethyl ester (201 mg, crude), N,N-dimethylformamide (3 mL), triethylamine (0.17 mL), 4-methanesulfonylaniline (210 mg, 1.228 mmol) were added successively. After all the addition, it was put into 80 °C oil bath and stirred for 3 hours, rotary evaporated to get the solid crude product 5-(3-methoxy-4-(4-methyl-1 H-imidazol-1-yl)phenyl)-4-methyl-2-(3-(4-(methylsulfonyl)phenyl)ureido)thiophene-3-carboxylic acid ethyl ester (140 mg, crude).

[0354] Step C: Into a dry pressure tube at room temperature was added 5-(3-methoxy-4-(4- methyl-1H-imidazol-1-yl)phenyl)-4-methyl-2-(3-(4-(methylsulfonyl)phenyl)ureido)thiophene- 3-carboxylate (85 mg, crude), methanol (2 mL), sodium methoxide (40 mg, 0.740 mmol) sequentially. After all the additions, the reaction was placed in a 75 °C oil bath for 3 hours, then the reaction was rotoevaporated. The crude product was directly subjected to HPLC prep for purification. Prep condition: Waters XBridge Prep C18 (30 mm x 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 18 mL / min 0-3.5 min, 10% B; 3.5-15 min, 10%-37% B, 15-15.5 min, 37%-100% B; Detector, UV 254 nm. This reaction gave E-59, 6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-3-(4- (methylsulfonyl)phenyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (32 mg, 0.061 mmol, 40.94%) as an orange-white solid product. 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.03 (d, J = 10.0 Hz, 2 H), 7.86 - 7.75 (m, 1 H), 7.59 (d, J = 10.0 Hz, 2 H), 7.51 - 7.40 (m, 1 H), 7.27 - 7.21 (m, 1 H), 7.18 - 7.10 (m, 2 H), 3.89 (s, 3 H), 3.30 (s, 3 H), 2.47 (s, 3 H), 2.16 (s, 3 H). ESI-MS m / z = 523.3 [M+H] + ; Calcu. = 522.1.

[0355] Example 55: Synthesis of compound E-60

[0356] Step A: 6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-3-(4- methoxyphenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (20 mg, 0.042 mmol) and potassium carbonate (17 mg, 0.126 mmol) were dissolved in N,N-dimethylformamide (2 mL), iodoe thane (7 mg, 0.042 mmol) was added at 0 °C. The reaction system was stirred at 0 °C for 5 min, then warmed to room temperature and stirred for 4 h. The reaction solution was adjusted to neutral pH with acetic acid, the solvent was evaporated under reduced pressure, and preparative liquid phase separation was performed under the following conditions: Welch Xtimate C18 (30 mm x 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-65% B; 3.5-15 min, 65%-95% B; 15-15.5 min, 95%-100% B; detector: UV 254 nm. The product 1-ethyl-6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-3-(4- methoxyphenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (2.37 mg, 0.005 mmol, 11.23%) was obtained. 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.83 (d, J = 1.2 Hz, 1 H), 7.49 (d, J = 8.1 Hz, 1 H), 7.27 (d, J = 1.8 Hz, 1 H), 7.19 (ddd, J = 16.1, 7.4, 2.0 Hz, 4 H), 7.04 - 7.00 (m, 2 H), 3.98 (dd, J = 14.2, 7.1 Hz, 2 H), 3.90 (s, 3 H), 3.81 (s, 3 H), 2.17 (s, 3 H), 1.35 - 1.31 (m, 5 H). ESI-MS m / z = 503.3 [M+H] + ; Calcu. = 502.2.

[0357] Example 56: Synthesis of compound E-61

[0358] Step A: To a solution of 2-amino-5-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)- 4-methylthiophene-3-carboxylic acid ethyl ester (40 mg, 0.117 mmol) in dichloromethane (5 mL) was added isocyanate sulfonyl chloride (82.90 mg, 0.586 mmol) slowly at -78 °C under argon protection. After the addition was completed, the mixture was stirred at -78 °C for 15 min under argon protection, then warmed to room temperature and stirred at room temperature for 1 h under argon protection. The reaction was cooled to 0-5 °C, then water (20 mL) was added slowly, extracted with dichloromethane twice (30 mL*2), the combined organic phase was washed with saturated aqueous sodium chloride solution once (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product as a light yellow solid. The reaction gave the crude product 5-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4-methyl-2- ureidothiophene-3-carboxylic acid ethyl ester (45 mg, crude) as a light yellow solid. ESI-MS m / z = 415.0 [M+H] + ; Calcu. = 414.1.

[0359] Step B: To 5-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4-methyl-2-ureidothiophene- 3-carboxylic acid ethyl ester (35 mg, 0.084 mmol) was added 6N aqueous hydrochloric acid solution (5 mL, 30.000 mmol) at room temperature, then the mixture was stirred at 100 °C for 20 h. The reaction was cooled to 0-5 °C, then the pH was adjusted to 9-10 with 4N aqueous sodium hydroxide solution, then extracted with ethyl acetate twice (20 mL*2), the combined organic phase was washed with saturated aqueous sodium chloride solution once (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a solid residue. The solid residue was separated by silica gel column (SiO2, DCM:MeOH = 91:9). The reaction gave the product 6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methylthieno[2,3- d]pyrimidine-2,4(1H,3H)-dione (20 mg, 0.054 mmol, 64.29%) as a light yellow solid. ESI-MS m / z = 369.2 [M+H] + ; Calcu. = 368.1.

[0360] Step C: To a solution of 6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)- 5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (15 mg, 0.041 mmol) and potassium carbonate (16.88 mg, 0.122 mmol) in N,N-dimethylformamide (3 mL) was added iodomethane (0.010 mL, 0.122 mmol) slowly at 0-5 °C, then the whole mixture was stirred at room temperature for 4 hours. The reaction was filtered through celite, the filter cake was rinsed with ethyl acetate twice (20 mL*2), the filtrate was concentrated under reduced pressure to get a solid residue. The solid residue was separated by HPLC prep, prep condition: Waters XBridge Prep C18 (19 mm x 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 18 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-35% B; 3.5-15 min, 35%-60% B; detector: UV 254 nm. The reaction gave E-61, white solid product 6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-1,3,5- trimethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.64 mg, 0.004 mmol, 10.10%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.82 (d, J = 0.61 Hz, 1 H) 7.48 (d, J = 7.93 Hz, 1 H) 7.25 (d, J = 1.37 Hz, 1 H) 7.17 (s, 1 H) 7.15 (m, 1 H) 3.89 (s, 3 H) 3.49 (s, 3 H) 3.27 (s, 3 H) 2.53 (s, 3 H) 2.16 (s, 3 H). ESI-MS m / z = 397.2 [M+H] + ; Calcu. = 396.1.

[0361] Example 57: Synthesis of compound E-62

[0362] Step A: To a solution of 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (30 mg, 0.065 mmol), potassium carbonate (36 mg, 0.259 mmol) in N,N-dimethylformamide (2 mL) was added 2-(bromomethyl)-1,3-oxazole (42 mg, 0.259 mmol) at room temperature. After addition, the whole mixture was stirred at room temperature overnight. The reaction was filtered through celite, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was sent for preparative separation, preparative conditions: Waters XSelect C18 (30 mm x 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. Lyophilized under reduced pressure to give E-62, white solid product 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-1-(oxazol-2-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (5.74 mg, 0.011 mmol, 16.28%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.16 (s, 1 H), 7.82 (s, 1 H), 7.48 (d, J = 8.1 Hz, 1 H), 7.31 - 7.41 (m, 4 H), 7.22 - 7.26 (m, 2 H), 7.17 (s, 1 H), 7.12 (dd, J = 8.1, 1.22 Hz, 1 H), 5.36 (s, 2 H), 3.88 (s, 3 H), 2.51 - 2.51 (s, 3 H), 2.16 (s, 3 H). ESI-MS m / z = 544.3 [M+H] + ; Calcu. = 543.1.

[0363] Example 58: Synthesis of compound E-63

[0364] Step A: Into a dry reaction tube was added 3-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridazine (1100 mg, 4.998 mmol), 4-bromo-l-iodo-2-methoxybenzene (1877 mg, 5.998 mmol), 1,4-dioxane (25 mL), (l,l'-bis(diphenylphosphino) ferrocene)palladium dichloride (365 mg, 0.499 mmol), potassium carbonate (1727 mg, 12.50 mmol), water (5 mL) at room temperature. After all the additions, the reaction was placed in a 90 °C oil bath for 4 h. After the solvents were removed by rotary evaporation, the residue was subjected to silica gel column separation (Si02, PE:EA = 50:50) to give the crude product 5-(4-bromo-2-methoxyphenyl)-3-methylpyridazine (1026 mg, crude) as a black solid.

[0365] Step B: Into a dry reaction tube was added 5-(4-bromo-2-methoxyphenyl)-3- methylpyridazine (1005 mg, crude), bis(pinacolato)diboron (1188 mg, 4.67 mmol), 1,4- dioxane (12.5 mL), potassium acetate (1060 mg, 10.80 mmol), (l,l'-bis(diphenylphosphino) ferrocene)palladium dichloride (395 mg, 0.540 mmol) at room temperature. After all the additions, the reaction was placed in a 100 °C oil bath for 4 h. The reaction was then filtered through a short silica gel column and eluted with ethyl acetate (60 mL). The solvents were removed by rotary evaporation to give the crude product 5-(2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)-3-methylpyridazine (805 mg, crude) as a black solid.

[0366] Step C: Into a dry reaction tube at room temperature were added 5-(2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-3-methylpyridazine (48 mg, crude), 6-bromo-l-ethyl-3-(4-fluorophenyl)-5-methylthieno[2,3- d]pyrimidine-2,4(lH,3H)-dione (38 mg, 0.099 mmol), N,N-dimethylformamide (1 mL), cesium carbonate (65 mg, 0.199 mmol), and tetrakis(triphenylphosphine)palladium (12 mg, 0.010 mmol). After all additions, the reaction was placed in a 120 °C oil bath for 1 h, then the reaction was spun down. The crude product was directly subjected to HPLC prep separation with the following conditions: Welch Xtimate C18 (30 mm x 250 mm, 5 μm); A: 0.05% ammonia; B: MeCN; 40 mL / min 0-3 min, 30% B; 3-5 min, 30%-50% B, 5-15 min, 50%-60% B, 15-20 min, 60%-70% B; detector, UV 254 nm. This reaction gave E-63, a gray solid product, l-ethyl-3-(4-fluorophenyl)-6-(3-methoxy-4-(6-methylpyridazin-4-yl)phenyl)-5- methylthieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (7.79 mg, 0.016 mmol, 15.66%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.28 (m, 1H), 7.71-7.80 (m, 1H), 7.59-7.66 (m, 1H), 7.29-7.42 (m, 4H), 7.20-7.28 (m, 2H), 4.00 (q, J = 8.3 Hz, 2H), 3.91 (s, 3H), 2.68 (s, 3H), 2.53 (s, 3H), 1.34 (t, J = 7.5 Hz, 3H). ESI-MS m / z = 503.3 [M+H] + ; Calcu. = 502.1.

[0367] Example 59: Synthesis of compounds E-64 and E-77

[0368] Step A: Into a dry reaction tube was added 1 -methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1 H-pyrazole (1040 mg, 5.000 mmol), 4-bromo-1 -iodo-2- methoxybenzene (1877 mg, 5.998 mmol), 1,4-dioxane (25 mL), (1,1 '- bis(diphenylphosphino)ferrocene)palladium dichloride (408 mg, 0.500 mmol), potassium carbonate (1727 mg, 12.50 mmol), water (5 mL) at room temperature. After all the addition, it was put into 80 °C oil bath for 14 hours. After the solvent was spun dry, the residue was subjected to silica gel column separation (SiO2, PE:EA = 50:50) to give the crude product 4-(4-bromo-2-methoxyphenyl)-1 -methyl-1 H-pyrazole (936 mg, crude) as a black solid.

[0369] Step B: Into a dry reaction tube was added 4-(4-bromo-2-methoxyphenyl)-1 -methyl-1 H- pyrazole (400 mg, 1.497 mmol), bis(pinacolato)diboron (495 mg, 1.949 mmol), 1,4- dioxane (5 mL), potassium acetate (441 mg, 4.493 mmol), (1,1 '-bis(diphenylphosphino) ferrocene)palladium dichloride (164 mg, 0.224 mmol) at room temperature. After all the addition, it was put into 100 °C oil bath for 4 hours. Then it was filtered with a short silica gel column and eluted with ethyl acetate (60 mL). After the solvent was spun dry, the residue was subjected to silica gel column separation (SiO2, PE:EA = 50:50) to give the crude product 4-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1 - methyl-1 H-pyrazole (330 mg, crude) as a black solid.

[0370] Step C: Into a dry reaction tube at room temperature were added 4-(2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-l-methyl-lH-pyrazole (47 mg, crude), 6-bromo-l-ethyl-3-(4-fluorophenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (38 mg, 0.099 mmol), N,N-dimethylformamide (1 mL), cesium carbonate (65 mg, 0.200 mmol), tetraphenylphosphonium palladium (5 mg, 0.004 mmol). After all the additions, the reaction was placed in a 120 °C oil bath for 1 hour, then the reaction was spun down. The crude product was directly subjected to HPLC prep for separation. Prep condition: Waters XBridge Prep C18 (19 mm x 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 18 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. The reaction gave white solid product E-77, l-ethyl-3-(4-fluorophenyl)-6-(4-(2-methoxyphenyl)-l-methyl-lH-pyrazol-3-yl)-5-methylthieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (3.14 mg, 0.006 mmol, 6.46%) and grey solid product E-64, l-ethyl-3-(4-fluorophenyl)-6-(3-methoxy-4-(l-methyl-lH-pyrazol-4-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (5.30 mg, 0.011 mmol, 10.91%). E-77, l-ethyl-3-(4-fluorophenyl)-6-(4-(2-methoxyphenyl)-l-methyl-lH-pyrazol-3-yl)-5-methylthieno[2,3-d]pyrimidine-2,4(lH,3H)-dione data: 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.67-7.74 (m, 1 H), 7.33-7.43 (m, 2 H), 7.27-7.33 (m, 2 H), 7.22-7.27 (m, 1 H), 7.04-7.08 (m, 1 H), 7.00-7.03 (m, 1 H), 6.85-6.90 (m, 1 H), 3.86-3.96 (m, 2 H), 3.74 (s, 3 H), 3.69 (s, 3 H), 2.06 (s, 3 H), 1.26 (t, J=7.5 Hz, 3 H). ESI-MS m / z = 491.3 [M+H] +; Calcu. = 490.1. E-64, 1 -Ethyl-3-(4-fluorophenyl)-6-(3-methoxy-4-(1 -methyl- 1 H-pyrazol-4-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1 H,3H)-dione data: 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.12 - 8.22 (m, 1 H), 7.92 - 7.97 (m, 1 H), 7.71 (d, J = 10.0 Hz, 1 H), 7.26 - 7.44 (m, 4 H), 7.01 - 7.18 (m, 2 H), 3.98 (q, J = 6.7 Hz, 2 H), 3.94 (s, 3 H), 3.89 (s, 3 H), 2.49 (s, 3 H), 1.33 (t, J = 7.5 Hz, 3 H). ESI-MS m / z = 491.3 [M+H] + ; Calcu. = 490.1.

[0371] Example 60: Synthesis of compounds E-65 and E-66

[0372] Step A: To a solution of 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1 H- imidazol-1 -yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1 H,3H)-dione (300 mg, 0.649 mmol), cesium carbonate (634 mg, 1.946 mmol) in N,N-dimethylformamide (5 mL) was added tert-butyl (2-chloroethyl)(methyl)carbamate (503 mg, 2.595 mmol) at ice bath. After the addition, the whole mixture was stirred at 150 °C in microwave for 1 h. The reaction was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure to give a crude. The crude was dissolved in methanol (5 mL) and separated by reverse phase, column: Santai SepaFlash C18 (Spherical C18, 20-45 μm, 80 g); mobile phase: water (with 0.05% TFA) and acetonitrile; flow rate: 40 mL / min; gradient: acetonitrile from 0% to 100% in 30 min; detection wavelength: 254 nm. Lyophilized under reduced pressure to give E-66, tert-butyl (2-(3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1 H-imidazol-1 -yl)phenyl)-5-methyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1 (2H)-yl)ethyl)(methyl)carbamate (25.20 mg, 0.041 mmol, 6.13%) as a white solid. ESI-MS m / z = 620.5 [M+H] 80g); mobile phase: water (with 0.05% TFA) and acetonitrile; flow rate: 40 mL / min; gradient: acetonitrile from 0% to 100% in 30 min; detection wavelength: 254 nm. Lyophilized under reduced pressure to give E-66, tert-butyl (2-(3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1 H-imidazol-1 -yl)phenyl)-5-methyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1 (2H)-yl)ethyl)(methyl)carbamate (25.20 mg, 0.041 mmol, 6.13%) as a white solid. ESI-MS m / z = 620.5 [M+H] + ; Calcu. = 490.1.1 H NMR (500 MHz, DMSO-d6) δ ppm 7.83 (s, 1 H), 7.49 - 7.53 (m, 1 H), 7.34 - 7.39 (m, 2 H), 7.30 - 7.34 (m, 1 H), 7.24 - 7.28 (m, 1 H), 7.21 (br d, J=5.5 Hz, 1 H), 7.18 (s, 1 H), 7.12 (dd, J=8.1, 1.68 Hz, 1 H), 4.03 - 4.15 (m, 2 H), 3.89 (s, 3 H), 3.57 - 3.68 (m, 2 H), 2.79 - 2.88 (m, 3 H), 2.42 - 2.46 (m, 3 H), 2.17 (d, J=0.8 Hz, 3 H), 1.17 - 1.25 (m, 9 H).

[0373] Step B: To tert-butyl (2-(3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1 H- imidazol-1 -yl)phenyl)-5-methyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1 (2H)- yl)ethyl)(methyl)carbamate (10 mg, 0.016 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL) at 0 °C. After the addition, the whole mixture was slowly returned to room temperature and stirred for 2 hours. The reaction was concentrated under reduced pressure to get the crude product. The crude product was sent for preparative separation, preparative condition: Waters XSelect C18 (30 mm x 250 mm, 5 μm); A: 0.1% formic acid in water, B: MeCN; 40 mL / min; 0-3 min, 8% B; 3-3.5 min, 8%-20% B; 3.5-15 min, 20%-50% B, detector, UV 254 nm. Lyophilized under reduced pressure to get E-65, white solid product 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1 H-imidazol-1 -yl)phenyl)-5- methyl-1 -(2-(methylamino)ethyl)thieno[2,3-d]pyrimidine-2,4(1 H,3H)-dione (3.70 mg, 0.007 mmol, 40.50%). ESI-MS m / z = 520.4 [M+H] + ; Calcu. = 519.1.

[0374] Example 61 : Synthesis of compound E-67

[0375] Step A: Into a dry reaction tube was added 6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5-methyl-3-(4-(methylsulfonyl)phenyl)thieno[2,3-d]pyrimidine- 2,4(1H,3H)-dione (26 mg, 0.048 mmol) and N,N-dimethylformamide (1 mL) at room temperature, then the reaction tube was placed in an ice water bath at 0 °C, potassium carbonate (20 mg, 0.145 mmol) and iodoethane (19 mg, 0.122 mmol) were added, after all the addition, the reaction was allowed to return to room temperature naturally. After 14 hours, the reaction was diluted with ethyl acetate (10 ml) and water (10 mL). The organic layer was separated, the aqueous layer was extracted with ethyl acetate (10 mL*3), the combined organic layers were washed with saturated sodium chloride solution (15 mL*3), dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was directly subjected to HPLC preparation separation, preparation conditions: Waters XBridge Prep C18 (19 mm x 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 18 mL / min 0~3 min, 10% B; 3~3.5 min, 10%~40% B, 3.5~15 min, 40%~80% B, 15~15.5 min, 80%~100% B; detector, UV 254 nm. The reaction gave E-67, white solid product 1-ethyl-6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-3-(4- (methylsulfonyl)phenyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.77 mg, 0.003 mmol, 6.70%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.07 (d, J = 10.0 Hz, 2 H), 7.80-7.84 (m, 1 H), 7.59-7.69 (m, 2 H), 7.50 (d, J = 10.0 Hz, 1 H), 7.24-7.32 (m, 1 H), 7.13-7.22 (m, 2 H), 4.00 (q, J = 6.7 Hz, 2 H), 3.90 (s, 3 H), 3.32 (s, 3 H), 2.49 (s, 3 H), 2.17 (s, 3 H), 1.34 (t, J = 7.5 Hz, 3 H). ESI-MS m / z = 551.3 [M+H] + ; Calcu. = 550.1.

[0376] Example 62: Synthesis of compound E-68

[0377] Step A: To a solution of 3-(4-(dimethylphosphoryl)phenyl)-6-(3-methoxy-4-(4- methyl- lH-imidazol- 1 -yl)phenyl)-5 -methylthieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (28 mg, 0.054 mmol), cesium carbonate (35 mg, 0.108 mmol) in N,N-dimethylformamide (1 mL) was added iodoethane (16.78 mg, 0.108 mmol). After the addition, the whole mixture was stirred at room temperature for 3 hours. The reaction was filtered and concentrated, and directly separated by HPLC prep. Prep condition: Waters XBridge C18 (19 mm x 250 mm, 5 μm); A: 0.1% formic acid in water; B: MeCN; 18 mL / min 0-3 min, 30% B; 3-16 min, 30%-100% B; Detector, UV 254 nm. The reaction gave E-68, 3-(4-(dimethylphosphoryl)phenyl)-l-ethyl-6-(3-methoxy-4-(4-methyl-lH- imidazol- 1 -yl)phenyl)-5 -methylthieno[2,3-d]pyrimidine-2,4( 1 H,3H)-dione (12.39 mg, 0.023 mmol, 41.99%) as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.94-7.87 (m, 2H), 7.83 (s, 1H), 7.53-7.46 (m, 3H), 7.27 (d, J=1.8 Hz, 1H), 7.20-7.16 (m, 2H), 4.00 (q, J=7.1 Hz, 2H), 3.90 (s, 3H), 2.49 (s, 3H), 2.17 (s, 3H), 1.73 (s, 3H), 1.70 (s, 3H), 1.34 (t, J=7.1 Hz, 3H). ESI-MS m / z = 549.4 [M+H] + ; Calcu. = 548.2.

[0378] Example 63: Synthesis of compound E-69

[0379] Step A: To a solution of 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl- lH-imidazol-l-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (50 mg, 0.108 mmol), ethyl bromoacetate (22 mg, 0.130 mmol) in N,N-dimethylformamide (5 mL) was added cesium carbonate (53 mg, 0.162 mmol) at room temperature. After the addition, the whole mixture was stirred at room temperature overnight. When the reaction was complete, the reaction was filtered through celite, the filtrate was concentrated and directly subjected to HPLC preparation separation, preparation condition: Waters XBridge C 18 (19 mm x 250 mm, 5 μm); A: 0.1% formic acid in water; B: MeCN; 18 mL / min 0~3 min, 10% B; 3~18 min, 10%~70% B; detector, UV 254 nm. The reaction gave E-69, white solid product ethyl 2-(3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl)-5-methyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-l(2H)-yl)acetate (5.17 mg, 0.009 mmol, 8.72%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.83 (d, J = 1.2 Hz, 1 H), 7.49 (d, J = 8.1 Hz, 1 H), 7.33 - 7.38 (m, 4 H), 7.26 (d, J = 1.8 Hz, 1 H), 7.18 (s, 1 H), 7.15 (dd, J = 8.1, 1.8 Hz, 1 H), 4.82 (s, 2 H), 4.21 (q, J = 7.0 Hz, 2 H), 3.89 (s, 3 H), 2.16 (d, J = 0.6 Hz, 3 H), 1.23 ppm (t, J = 7.1 Hz, 3 H). ESI-MS m / z = 549.3 [M+H] + ; Calcu. = 548.1.

[0380] Example 64: Synthesis of compound E-70

[0381] Step A: To a solution of 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (32 mg, 0.07 mmol) in N,N-dimethylformamide (2 mL) was added cesium carbonate (114 mg, 0.35 mmol) and 3-bromooxetane (383 mg, 2.8 mmol) at room temperature. After the addition was complete, the reaction mixture was warmed to 80 °C and stirred for 3 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was separated by HPLC preparation. The preparation conditions: Waters XBridge Prep C18 (19 mm x 250 mm, 5 μm); A: 0.05% ammonia water; 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. The reaction gave E-70, white solid product 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-1-(oxetan-2-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (3.93 mg, 0.008 mmol, 11.43%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.83 (d, J = 1.2 Hz, 1 H), 7.50 (d, J = 8.1 Hz, 1 H), 7.38-7.41 (m, 2 H), 7.32-7.35 (m, 2 H), 7.24 (d, J = 1.7 Hz, 1 H), 7.18 (s, 1 H), 7.15 (dd, J = 8.1, 1.8 Hz, 1 H), 4.35 (dd, J = 15.6, 3.1 Hz, 1 H), 3.99 (dd, J = 15.6, 5.2 Hz, 1 H), 3.90 (s, 3 H), 3.34-3.37 (m, 1 H), 2.83 (t, J = 4.5 Hz, 1 H), 2.75 (dd, J = 4.7, 2.6 Hz, 1 H), 2.17 (s, 3 H). ESI-MS m / z = 519.4 [M+H] + ; Calcu. = 518.1.

[0382] Example 65: Synthesis of compound E-71

[0383] Step A: To a solution of 6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5- methyl-3-(tetrahydro-2H-pyran-4-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (40 mg, 0.088 mmol), potassium carbonate (37 mg, 0.265 mmol) in DMF (3 mL) was added ethyl bromide (0.010 mL, 0.133 mmol) at 0 °C. After the addition, the whole mixture was stirred at room temperature overnight. Then it was concentrated under reduced pressure to give a brown crude product. The crude was subjected to HPLC prep separation, prep condition: Welch Xtimate C18 (30 mm x 250 mm, 5 μm); A: 0.05% formic acid in water; B: MeCN; 5 mL / min; 0-3 min, 20% B; 3-3.5 min, 30%~60% B; 3.5-15 min, 60%~80% B; 15-20 min, 80%~100% B; detector, UV 254 nm. This reaction gave E-71, white solid product 1-ethyl-6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-3-(tetrahydro-2H-pyran-4-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (11.14 mg, 0.023 mmol, 26.14%). 1 H NMR (DMSO-d6, 500 MHz) δ ppm 7.82 (d, 1H, J = 1.2 Hz), 7.48 (d, 1H, J = 8.1 Hz), 7.24 (d, 1H, J = 1.8 Hz), 7.18 (t, 1H, J = 1.1 Hz), 7.14 (dd, 1H, J = 1.9, 8.0 Hz), 5.0-5.1 (m, 1H), 3.9-4.0 (m, 4H), 3.89 (s, 3H), 3.4-3.4 (m, 2H), 2.65 (dq, 2H, J = 4.6, 12.4 Hz), 2.52 (s, 3H), 2.16 (s, 3H), 1.50 (br dd, 2H, J = 2.4, 12.0 Hz), 1.29 (t, 3H, J = 7.1 Hz). ESI-MS m / z = 481.3 [M+H] + ; Calcu. = 480.2.

[0384] Example 66: Synthesis of compound E-72

[0385] Step A: To a solution of ethyl 2-amino-5-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-4-methylthiophene-3-carboxylate (80 mg, 0.215 mmol), cesium carbonate (211 mg, 0.646 mmol) in acetonitrile (10 mL) was added cyclohexyl isocyanate (0.110 mL, 0.861 mmol) at room temperature. After the addition was complete, the whole mixture was warmed to 90 °C and stirred overnight. Subsequently, the mixture was concentrated under reduced pressure to give a brown crude product. The crude product was subjected to HPLC prep separation, prep condition: Welch Xtimate C18 (30 mm x 250 mm, 5 μm); A: 0.05% formic acid in water; B: MeCN; 5 mL / min; 0-3 min, 20% B; 3-3.5 min, 30%~60% B; 3.5-15 min, 60%~80% B; 15-20 min, 80%~100% B; detector, UV 254 nm. This reaction gave E-72, white solid product 3-cyclohexyl-6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (2.63 mg, 0.006 mmol, 2.71%). 1 H NMR (DMSO-d6, 500 MHz) δ 12.0-12.4 (m, 1H), 7.80 (d, 1H, J = 1.1 Hz), 7.44 (d, 1H, J = 8.1 Hz), 7.20 (d, 1H, J = 1.8 Hz), 7.16 (s, 1H), 7.10 (dd, 1H, J = 1.8, 8.1 Hz), 4.6-4.9 (m, 1H), 3.87 (s, 3H), 2.48 (s, 3H), 2.3-2.4 (m, 4H), 2.16 (d, 3H, J = 0.6 Hz), 1.80 (br d, 2H, J = 12.8 Hz), 1.5-1.7 (m, 4H). ESI-MS m / z = 451.3 [M+H] + ; Calcu. = 450.2.

[0386] Example 67: Synthesis of compound E-73

[0387] Step A: To a solution of 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (100 mg, 0.216 mmol), cesium carbonate (211 mg, 0.649 mmol) in N,N-dimethylformamide (2 mL) was added bromocyclopropane (105 mg, 0.865 mmol) at room temperature. After the addition, the whole mixture was warmed to 100 °C and stirred overnight. The reaction was cooled to room temperature, filtered through celite and concentrated under reduced pressure to give the crude product. The crude product was subjected to preparative separation, preparative condition: Waters XSelect C18 (30 mm x 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, 100%-50% B, Detector, UV 254 nm. Lyophilized under reduced pressure to give E-73, yellow solid product 1-allyl-3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (6.56 mg, 0.013 mmol, 5.64%). 1 H NMR (500 MHz, CD3OD-d4) δ ppm 7.85 (d, J = 1.4 Hz, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.30-7.36 (m, 2H), 7.22-7.27 (m, 3H), 7.17 (dd, J = 8.1, 1.83 Hz, 1H), 7.12 (t, J = 1.1 Hz, 1H), 5.94-6.05 (m, 1H), 5.41 (dd, J = 17.2, 1.07 Hz, 1H), 5.35 (dd, J = 10.4, 0.92 Hz, 1H), 4.68 (br d, J = 5.3 Hz, 2H), 3.93 (s, 3H), 2.53 (s, 3H), 2.25 (d, J = 0.9 Hz, 3H). ESI-MS m / z = 503.3 [M+H] + ; Calcu. = 502.1.

[0388] Example 68: Synthesis of compound E-74

[0389] Step A: To a solution of 3-cyclohexyl-6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)- 5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (21 mg, 0.047 mmol), potassium carbonate (19 mg, 0.140 mmol) in N,N-dimethylformamide (4 mL) was added ethyl bromide (0.005 mL, 0.070 mmol) at 0 °C. After the addition, the whole mixture was stirred at room temperature overnight. Then it was concentrated under reduced pressure to give brown crude product. The crude was subjected to HPLC prep for separation, prep condition: Welch Xtimate C18 (30 mm x 250 mm, 5 μm); A: 0.05% formic acid in water; B: MeCN; 5 mL / min; 0-3 min, 20% B; 3-3.5 min, 30%~60% B; 3.5-15 min, 60%~80% B; 15-20 min, 80%~100% B; detector, UV 254 nm. This reaction gave E-74, white solid product 3-cyclohexyl-1-ethyl-6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5- methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (15.05 mg, 0.031 mmol, 65.96%). 1 H NMR (DMSO-d6, 500 MHz) δ ppm 7.82 (d, 1H, J = 1.2 Hz), 7.47 (d, 1H, J = 7.9 Hz), 7.24 (d, 1H, J = 1.8 Hz), 7.17 (s, 1H), 7.14 (dd, 1H, J = 1.8, 8.2 Hz), 4.7-4.8 (m, 1H), 3.9-4.0 (m, 2H), 3.88 (s, 3H), 2.3-2.4 (m, 3H), 2.16 (s, 3H), 1.81 (br d, 2H, J = 12.8 Hz), 1.5-1.7 (m, 4H), 1.28 (t, 4H, J = 7.1 Hz). ESI-MS m / z = 479.4 [M+H] + ; Calcu. = 478.2.

[0390] Example 69: Synthesis of compound E-75

[0391] Step A: To a solution of 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (100 mg, 0.216 mmol), cesium carbonate (211 mg, 0.649 mmol) in N,N-dimethylformamide (5 mL) was added bromocyclobutane (117 mg, 0.865 mmol) at room temperature. After the addition, the whole mixture was warmed to 100 °C and stirred overnight. The reaction was cooled to room temperature, filtered through celite and concentrated under reduced pressure to give the crude product. The crude product was subjected to preparative separation, preparative conditions: Waters XSelect C18 (30 mm x 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%-43% B; 3.5-15 min, 100%-50% B, Detector, UV 254 nm. Lyophilized under reduced pressure to give E-75, white solid product 1-cyclobutyl-3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (13.32 mg, 0.026 mmol, 11.69%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.83 (d, J = 1.2 Hz, 1 H), 7.49 (d, J = 8.1 Hz, 1 H), 7.30 - 7.39 (m, 4 H), 7.26 (d, J = 1.7 Hz, 1 H), 7.15 - 7.20 (m, 2 H), 4.79 (quin, J = 8.7 Hz, 1 H), 3.90 (s, 3 H), 2.85 - 2.96 (m, 2 H), 2.49 (s, 3 H), 2.34 - 2.43 (m, 2 H), 2.17 (d, J = 0.6 Hz, 3 H), 1.71 - 1.86 (m, 2 H). ESI-MS m / z = 517.4 [M+H] + ; Calcu. = 516.1.

[0392] Example 70: Synthesis of compound E-76

[0393] Step A: To a solution of tetrahydro-2H-pyran-4-amine (1.559 mL, 14.829 mmol), pyridine (3.598 mL, 44.488 mmol) in tetrahydrofuran (15 mL) was added phenyl chloroformate (2.046 mL, 16.312 mmol) at 0 °C. After the addition, the whole mixture was stirred at room temperature for 2 hours. Concentrated under reduced pressure to give a brown residue. The residue was separated by silica gel column (SiO2, PE:EA = 35:65) to give the product phenyl (tetrahydro-2H-pyran-4-yl)carbamate (2.5 g, 11.299 mmol) as a white solid. ESI-MS m / z = 222.1 [M+H] + ; Calcu.= 221.3.

[0394] Step B: To a solution of ethyl 2-amino-5-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)- 4-methylthiophene-3-carboxylate (100 mg, 0.269 mmol), TEA (0.112 mL, 0.808 mmol) in DMF (20 mL) was added phenyl (tetrahydro-2H-pyran-4-yl)carbamate (893.50 mg, 4.038 mmol) at room temperature. After the addition, the whole mixture was heated to 80 °C and stirred overnight. Concentrated under reduced pressure to give the product ethyl 5-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4-methyl-2-(3- (tetrahydro-2H-pyran-4-yl)ureido)thiophene-3-carboxylate as a brown crude. ESI-MS m / z = 499.4 [M+H] + ; Calcu.= 498.2.

[0395] Step C: To the crude 5-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4- methyl-2-(3-(tetrahydro-2H-pyran-4-yl)ureido)thiophene-3-carboxylic acid ethyl ester from previous step, sodium ethoxide in ethanol (10 mL) was added at room temperature. After the addition, the whole mixture was stirred at room temperature for 3 hours. Then it was concentrated under reduced pressure to give a brown crude product. The crude product was subjected to HPLC prep for purification, prep condition: Welch Xtimate C18 (30 mm x 250 mm, 5 μm); A: 0.1% formic acid in water; B: MeCN; 5 mL / min; 0-3 min, 10% B; 3-3.5 min, 10% B; 3.5-15 min, 10%-100% B; Detector, UV 254 nm. This reaction gave E-76, 6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5- methyl-3-(tetrahydro-2H-pyran-4-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione as a white solid product (4.03 mg, 0.009 mmol, 3.34%). 1 H NMR (DMSO-d6, 500 MHz) δ ppm 7.76 (d, 1H, J = 1.2 Hz), 7.34 (d, 1H, J = 8.1 Hz), 7.1-7.1 (m, 2H), 7.01 (dd, 1H, J = 1.8, 8.1 Hz), 5.06 (ddd, 1H, J = 4.3, 7.8, 11.9 Hz), 3.85 (s, 3H), 3.8-3.8 (m, 4H), 2.47 (s, 3H), 2.15 (s, 3H), 1.67 (m, 4H). ESI-MS m / z = 453.3 [M+H] + ; Calcu. = 452.2.

[0396] Example 71: Synthesis of compound E-78

[0397] Step A: To a solution of 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-7-methylthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (30 mg, 0.065 mmol) in dichloromethane (5 mL) was added triethyl oxonium tetrafluoroborate (25 mg, 0.130 mmol) at room temperature. After stirring homogeneously, the reaction mixture was stirred at room temperature overnight. The reaction was concentrated in vacuo. The crude product was purified by preparative high performance liquid chromatography, prep conditions: Waters XBridge Prep C18 5 μm OBD; A: 0.1% formic acid in water; B: MeCN; 18 mL / min; 0-5 min, 35% B; 5-15 min, 35%-45% B; 15-20 min, 45%-100% B; Detector: UV 254 nm. This reaction gave E-78, white solid product 1-ethyl-3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-7-methylthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (5.18 mg, 0.011 mmol, 16.28%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.51 (d, J = 1.8 Hz, 1 H), 8.41 (s, 1 H), 7.87 (s, 1 H), 7.72 (d, J = 8.2 Hz, 1 H), 7.45 (d, J = 1.8 Hz, 1 H), 7.37 (dd, J = 8.1, 1.8 Hz, 1 H), 7.29 (d, J = 7.1 Hz, 3 H), 4.25-4.21 (m, 2 H), 3.96 (s, 3 H), 2.40 (d, J = 1.1 Hz, 3 H), 2.32 (s, 3 H), 1.49 (d, J = 7.2 Hz, 3 H). ESI-MS m / z = 491.3 [M+H] + ; Calcu. = 490.1.

[0398] Example 72: Synthesis of compounds E-79 and E-80

[0399] Step A: To a solution of N-hydroxyacetimidamide (200 mg, 2.700 mmol), methyl 4-amino-2-methoxybenzoate (147 mg, 0.810 mmol) in tetrahydrofuran (10 mL), N,N-dimethylformamide (10 mL) was added sodium hydride (108 mg, 2.700 mmol) at room temperature under nitrogen protection. After addition, the whole mixture was stirred at 60 °C for 5 hours under nitrogen protection. After the reaction was completed, water 50 mL was added to precipitate, the filter cake was dried to give the crude 3-methoxy-4-(3-methyl-1,2,4-oxadiazol-5-yl)aniline (260 mg, crude). ESI-MS m / z = 206.1 [M+H] + ; Calcu. = 205.2.

[0400] Step B: To a solution of 3-methoxy-4-(3-methyl-1,2,4-oxadiazol-5-yl)aniline and isoamyl nitrite (0.098 mL, 0.731 mmol) in N,N-dimethylformamide (15 mL) was added copper bromide (327 mg, 1.462 mmol) at 0 °C. After addition, the whole mixture was stirred at 0 °C for 1 hour. After the reaction was completed, the reaction solution was controlled to room temperature and filtered through celite, then water 30 mL was added, extracted with ethyl acetate three times (20 mL*3), the combined organic phase was washed with saturated brine once (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a solid residue. The residue was separated on a silica gel column (SiO2, PE:EA = 50:50) to give the light yellow solid product 5-(4-bromo-2-methoxyphenyl)-3-methyl-1,2,4-oxadiazole (120 mg, 0.446 mmol, 61.01 %). ESI-MS m / z = 268.8 [M+H] + ; Calcu. = 267.9.

[0401] Step C: To a solution of 5-(4-bromo-2-methoxyphenyl)-3-methyl-1,2,4-oxadiazole (120 mg, 0.446 mmol), bis(pinacolato)diboron (170 mg, 0.669 mmol), potassium acetate (131 mg, 1.338 mmol) in 1,4-dioxane (20 mL) was added (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) chloride (73 mg, 0.089 mmol) at room temperature under nitrogen protection. After addition, the whole mixture was stirred at 100 °C for 4 hours under nitrogen protection. After the reaction was completed, it was directly filtered and concentrated to give the crude 5-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methyl-1,2,4-oxadiazole (100 mg, crude), which was used directly in the next step. ESI-MS m / z = 317.0 [M+H]+ ; Calcu. = 316.1.

[0402] Step D: To a solution of 5-(2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)-3-methyl-l,2,4-oxadiazole (50 mg, 0.158 mmol), 6-bromo-l-ethyl-3-(4- fluorophenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (73 mg, 0.190 mmol), cesium carbonate (103 mg, 0.316 mmol) in N,N-dimethylformamide (20 mL) was added tetrakis(triphenylphosphine)palladium (73 mg, 0.063 mmol) at room temperature under nitrogen. After the addition, the whole mixture was stirred at 110 °C for 1 hour under nitrogen. When the reaction was completed, the reaction mixture was directly concentrated to get a solid residue, which was subjected to preparative separation. Preparative condition: Welch C 18 (30 mm x 250 mm, 5 μm); A: 0.05% FA; B: MeCN; 40 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-25% B; 3.5-18 min, 25%-65% B; Detector, UV 254 nm. The reaction gave E-79, white solid product l-ethyl-3-(4-fluorophenyl)-6-(3-methoxy-4-(3-methyl-l,2,4-oxadiazol-5-yl)phenyl)-5- methylthieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (1.85 mg, 0.004 mmol, 2.38%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.09 (d, J = 8.1 Hz, 1 H), 7.36-7.40 (m, 2 H), 7.31 -7.36 (m, 3 H), 7.29 (dd, J = 8.2, 1.4 Hz, 1 H), 4.01 (s, 3 H), 3.97-4.00 (m, 2 H), 2.55 (s, 3 H), 2.43 (s, 3 H), 1.34 ppm (t, J = 7.2 Hz, 3 H). ESI-MS m / z = 493.3 [M+H] + ; Calcu. = 492.1. E-80, white solid product 4-(l-ethyl-3-(4-fluorophenyl)-5-methyl- 2,4-dioxo-l,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)-2-methoxybenzamide (2.63 mg, 0.006 mmol, 3.67%). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.89 (d, J = 8.4 Hz, 1 H), 7.69 (s, 1 H), 7.63 (s, 1 H), 7.30 - 7.40 (m, 4 H), 7.13 - 7.18 (m, 2 H), 3.97 - 4.02 (m, 2 H), 3.96 (s, 3 H), 1.33 ppm (t, J = 7.2 Hz, 3 H). ESI-MS m / z = 454.3 [M+H] + ; Calcu. = 453.2.

[0403] Example 73: Synthesis of compound E-81

[0404] Step A: To a solution of 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1 H-imidazol-1 - yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1 H,3H)-dione (100 mg, 0.216 mmol), potassium carbonate (60 mg, 0.432 mmol), 1,10-phenanthroline (39 mg, 0.216 mmol) and cyclopropylboronic acid (37 mg, 0.432 mmol) in 1,2-dichloroethane (2.00 mL) was added copper acetate (39 mg, 0.216 mmol) at room temperature. After the addition, the whole mixture was warmed to 70 °C and stirred open overnight. The reaction was cooled to room temperature, filtered through celite and concentrated under reduced pressure to give the crude product. The crude product was subjected to preparative separation, preparative conditions: Waters XSelect C18 (30 mm x 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%-38% B; 3.5-15 min, 100%-50% B, detector, UV 254 nm. Lyophilized under reduced pressure to give E-81, 1 -cyclopropyl-3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1 H-imidazol-1 - yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1 H,3H)-dione (7.92 mg, 0.016 mmol, 5.95%) as a white solid product. ESI-MS m / z = 503.3 [M+H] + ; Calcu. MW = 502.1.

[0405] Example 74: Synthesis of compound E-82

[0406] Step A: To a solution of 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (100 mg, 0.216 mmol), 1-chloro-5,5-dimethyl-2-oxa-5-silahexane (54 mg, 0.324 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (60 mg, 0.432 mmol) at room temperature. After the addition, the whole mixture was stirred at room temperature for 1 hour. When the reaction was completed, the reaction solution was directly concentrated to get a solid residue, which was subjected to preparative separation. Preparative conditions: Welch C 18 (30 mm x 250 mm, 5 μm); A: 0.05% FA; B: MeCN; 40 mL / min; 0-3 min, 10% B; 3.0-3.5 min, 10%-15% B; 3.5-18 min, 15%-65% B; detector, UV 254 nm. The reaction gave E-82, white solid product 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (5.17 mg, 0.009 mmol, 4.03%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.84 (d, J = 0.9 Hz, 1 H), 7.51 (d, J = 8.1 Hz, 1 H), 7.34 - 7.41 (m, 4 H), 7.24 (d, J = 1.5 Hz, 1 H), 7.19 (s, 1 H), 7.16 (dd, J = 8.1, 1.7 Hz, 1 H), 5.43 (s, 2 H), 3.90 (s, 3 H), 3.68 (t, J = 8.0 Hz, 2 H), 2.17 (s, 3 H), 1.24 (s, 3 H), 0.89 - 0.96 (m, 2 H), 0.00 ppm (s, 9 H). ESI-MS m / z = 593.4 [M+H] + ; Calcu. = 592.2.

[0407] Example 75: Synthesis of compounds E-83, E-96 and E-102

[0408] Step A: To a solution of 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (40 mg, 0.086 mmol), (2-bromoethyl)phosphonic acid diethyl ester (212 mg, 0.865 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (120 mg, 0.865 mmol) at room temperature. After the addition, the whole mixture was stirred at room temperature overnight. When the reaction was complete, the reaction was directly concentrated to get a solid residue, which was subjected to preparative separation. Preparative condition: Welch C 18 (30 mm x 250 mm, 5 μm); A: 0.1% FA; B: MeCN; 40 mL / min; 0-3 min, 10% B; 3.0-3.5 min, 10%-15% B; 3.5-18 min, 15%-65% B; Detector, UV 254 nm. The reaction gave E-83, white product (2-(3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)ethyl)phosphonic acid diethyl ester (20 mg, 0.032 mmol, 36.90%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.84 (s, 1 H), 7.51 (d, J = 8.1 Hz, 1 H), 7.35 (d, J = 6.7 Hz, 4 H), 7.27 (d, J = 1.4 Hz, 1 H), 7.15 - 7.21 (m, 2 H), 4.07 - 4.15 (m, 2 H), 3.99 - 4.07 (m, 4 H), 3.90 (s, 3 H), 2.26 - 2.39 (m, 2 H), 2.17 (s, 3 H), 2.02 - 2.02 (m, 6 H), 1.25 ppm (t, J = 7.0 Hz, 1 H). ESI-MS m / z = 627.3 [M+H] + ; Calcu. = 626.1.

[0409] Step B: To a solution of diethyl (2-(3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl- 1H-imidazol-1-yl)phenyl)-5-methyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)- yl)ethyl)phosphonate (10 mg, 0.016 mmol) in dichloromethane (5 mL) was added trimethylsilyl bromide (0.3 mL, 0.016 mmol) at room temperature. After the addition, the whole mixture was stirred at room temperature overnight. When the reaction was complete, the reaction was directly concentrated to get a solid residue, which was subjected to preparative separation. Preparative conditions: Welch C 18 (30 mm x 250 mm, 5 μm); A: 0.1% FA; B: MeCN; 40 mL / min; 0-3 min, 5% B; 3.0-18 min, 5%-50% B; Detector, UV 254 nm.

[0410] The reaction gave E-96, white solid product (2-(3-(4-fluorophenyl)-6-(3-methoxy-4-(4- methyl-1H-imidazol-1-yl)phenyl)-5-methyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)- yl)ethyl)ethyl phosphonate (3.13 mg, 0.005 mmol, 32.77%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.85 (s, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.32-7.37 (m, 4H), 7.26 (s, 1H), 7.15-7.21 (m, 2H), 4.01-4.09 (m, 2H), 3.90 (s, 3H), 3.83-3.87 (m, 2H), 3.62 (t, J = 7.1 Hz, 3H), 2.17 (s, 2H), 2.04-2.12 (m, 3H). ESI-MS m / z = 599.3 [M+H] + ; Calcu. = 598.1. E-102, white solid product (2-(3-(4-fluorophenyl)-6-(3-methoxy-4-(4- methyl-1H-imidazol-1-yl)phenyl)-5-methyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)- yl)ethyl)phosphonic acid (0.39 mg, 0.001 mmol, 4.29%). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.82 (s, 1 H), 7.46 (d, J = 8.7 Hz, 1 H), 7.29 - 7.36 (m, 4 H), 7.25 (d, J = 1.4 Hz, 1 H), 7.13 - 7.18 (m, 2 H), 4.87 (d, J = 4.3 Hz, 1 H), 4.60 - 4.66 (m, 1 H), 4.03 (dd, J = 1 1.1, 4.0 Hz, 2 H), 3.89 (s, 3 H), 3.62 (dd, J = 4.2, 2.3 Hz, 2 H), 2.16 ppm (s, 3 H). ESI-MS m / z = 571.3 [M+H] + ; Calcu. = 570.1.

[0411] Example 76: Synthesis of compound E-84

[0412] Step A: In a 100 mL pressure tube, 2-amino-5-(ethoxycarbonyl)-4-methylthiophene-3- carboxylate (2 g, 7.773 mmol), 1 -fluoro-4-isocyanatobenzene (1.60 g, 1 1.660 mmol), cesium carbonate (7.60 g, 23.319 mmol) and acetonitrile were added sequentially at room temperature. After stirring homogenously, the reaction mixture was heated at 100 °C with stirring overnight. After the reaction mixture was cooled to room temperature, it was concentrated in vacuo. The crude product was purified by reverse phase C18 column chromatography. Column: SW-5222-080-SP (AQ); mobile phase: formic acid water / methanol; detection wavelength: 254 nm. The solvent was removed by concentration under reduced pressure to give 450 mg of product 3-(4-fluorophenyl)-5-methyl-2,4-dioxo-1 H-thieno[2,3- d]pyrimidine-6-carboxylic acid ethyl ester (450 mg, 1.292 mmol, 16.62 %). ESI-MS m / z = 349.1 [M+H] + ; Calcu. = 348.1.

[0413] Step B: In a 100 mL round-bottom flask, 3-(4-fluorophenyl)-5-methyl-2,4-dioxo- 1H-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (450 mg, 1.292 mmol), sodium hydroxide (155 mg, 3.875 mmol), water (3 mL), and acetonitrile were added sequentially at room temperature. After stirring well, the reaction mixture was heated and stirred at 60 °C overnight. After the reaction system was cooled to room temperature, dilute hydrochloric acid was added to the reaction system until pH = 2. Filtration. The crude product was directly used in the next step. The product 3-(4-fluorophenyl)-5-methyl-2,4-dioxo-1H-thieno[2,3-d]pyrimidine-6-carboxylic acid (330 mg, 1.030 mmol, 79.76 %). ESI-MS m / z = 321.1 [M+H] + ; Calcu. = 320.0.

[0414] Step C: In a 50 mL round-bottom flask, 3-(4-fluorophenyl)-5-methyl-2,4-dioxo- 1H-thieno[2,3-d]pyrimidine-6-carboxylic acid (90 mg, 0.281 mmol), 1,2-phenylenediamine (46 mg, 0.421 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl) uronium hexafluorophosphate (160 mg, 0.421 mmol), triethylamine (0.117 mL, 0.843 mmol), and N,N-dimethylformamide were added sequentially at room temperature. After stirring well, argon protection. The reaction mixture was stirred at room temperature overnight. The reaction system was concentrated under vacuum. The crude product was purified by reverse phase C18 column chromatography. Column: SW-5222-040-SP (AQ); mobile phase: formic acid water / methanol; detection wavelength: 254 nm. Freeze-drying under reduced pressure to obtain the product N-(2-aminophenyl)-3-(4-fluorophenyl)-5-methyl-2,4-dioxo-1H-thieno[2,3-d]pyrimidine-6-carboxamide (33 mg, 0.080 mmol, 28.61 %). ESI-MS m / z = 411.3 [M+H] + ; Calcu. = 410.1.

[0415] Step D: In a 32 mL pressure tube, N-(2-aminophenyl)-3-(4-fluorophenyl)-5- methyl-2,4-dioxo-1H-thieno[2,3-d]pyrimidine-6-carboxamide (33 mg, 0.080 mmol) and acetic acid (3 mL) were added sequentially at room temperature. After stirring homogenously, the mixture was heated at 100 °C with stirring overnight. After the reaction system was cooled to room temperature, the reaction system was concentrated under vacuum. The crude product was purified by preparative high performance liquid chromatography. Preparative conditions: Waters XBridge Prep C18 5 μm OBD 19*250; A: 0.1% formic acid in water; B: MeCN; 18 mL / min; 0-3 min, 30% B; 3-13 min, 30%-100% B; Detector: UV 254 nm. Lyophilized under reduced pressure to obtain E-84, the product 3-(4-fluorophenyl)-6-(1H-benzo[d]imidazol-2-yl)-5-methyl-thieno[2,3-d]pyrimidine- 2,4(1H,3H)-dione (6.8 mg, 0.017 mmol, 21.55%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 12.52 (s, 2H), 7.63 (d, J = 7.5 Hz, 1H), 7.58-7.50 (m, 1H), 7.43-7.27 (m, 4H), 7.22 (td, J = 7.2, 1.5 Hz, 2H), 2.78 (s, 3H). ESI-MS m / z = 393.3 [M+H] + ; Calcu. = 392.1.

[0416] Example 77: Synthesis of compound E-85

[0417] Step A: In a room temperature, 4-amino-1-methyl-1H-imidazole-5-carboxylic acid ethyl ester (600 mg, 3.547 mmol) was dissolved in pyridine (5 mL, 61.820 mmol), then 4-fluorophenyl isocyanate (973 mg, 7.093 mmol) was added, then the whole mixture was stirred in a sealed tube at 100 °C for 2 hours. The reaction was cooled to room temperature, then concentrated under reduced pressure to obtain the crude product as a yellowish oil. The reaction gave the crude product 4-(3-(4-fluorophenyl)ureido)-1-methyl-1H-imidazole-5-carboxylic acid ethyl ester (1086 mg, crude) as a yellowish oil. ESI-MS m / z = 307.2 [M+H] + ; Calcu. = 306.1.

[0418] Step B: In a 100-mL round-bottom flask, 4-(3-(4-fluorophenyl)ureido)-1- methyl-1H-imidazole-5-carboxylic acid ethyl ester (1086 mg, crude) was dissolved in ethanol (60 mL) at room temperature. Sodium ethoxide (1206 mg, 17.728 mmol) was added into the flask, and then the whole mixture was stirred in a sealed tube at 120 °C for 2 h. The reaction was cooled to room temperature, and then concentrated under reduced pressure to get a solid residue. The solid residue was separated by silica gel column (SiO2, PE:EA = 85:15). The reaction gave the product 1-(4-fluorophenyl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione (820 mg, 3.151 mmol, 88.87%) as a light yellow oil. ESI-MS m / z = 261.1 [M+H] + ; Calcu. = 260.1.

[0419] Step C: In a 100-mL round-bottom flask, 1-(4-fluorophenyl)-7-methyl-3,7- dihydro-1H-purine-2,6-dione (200 mg, 0.769 mmol) was dissolved in dichloromethane (10 mL) at room temperature under argon protection. Potassium tert-butoxide (302 mg, 2.690 mmol) and triethyl oxonium tetrafluoroborate (321 mg, 1.691 mmol) were added into the flask, and then the whole mixture was stirred at room temperature under argon protection for 16 h. The reaction was cooled to 0-5 °C, and then saturated aqueous ammonium chloride was added into the flask slowly and dropwise. The mixture was stirred for 10 min, and then extracted with dichloromethane twice (30 mL*2). The combined organic phase was washed with saturated aqueous sodium chloride once (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to get a solid residue. The solid residue was separated by silica gel column (SiO2, PE:EA = 85:15). The reaction gave the product 3-ethyl-1-(4-fluorophenyl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione (130 mg, 0.451 mmol, 58.67%) as a light yellow solid. ESI-MS m / z = 289.1 [M+H] + ; Calcu. = 288.1.

[0420] Step D: To a solution of (3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)boronic acid (97 mg, 0.416 mmol) and 3-ethyl-1-(4-fluorophenyl)-7-methyl-3,7-dihydro-1H-purine- 2,6-dione (224 mg, 0.862 mmol) in N-methylpyrrolidine (8 mL) at room temperature under argon was added palladium acetate (16 mg, 0.069 mmol), copper acetate (252 mg, 1.388 mmol), copper(I) chloride (14 mg, 0.139 mmol), 2,6-dimethylbenzoquinone (94 mg, 0.694 mmol) and potassium fluoride (161 mg, 2.775 mmol) sequentially, then the whole mixture was stirred at room temperature for 10 minutes, then the whole mixture was warmed to 100 °C and stirred at 100 °C for 18 hours under argon. The reaction was cooled to room temperature, then filtered under reduced pressure through celite, the filter cake was rinsed twice with ethyl acetate (20 mL*2), the filtrate was concentrated under reduced pressure to give a yellow liquid. The yellow liquid was separated by HPLC prep, prep condition: Welch Xtimate C18 (30 mm x 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%~10% B; 3.5~15 min, 10%~60% B; Detector: UV 254 nm. This reaction gave E-85, white solid product 3-ethyl-1-(4-fluorophenyl)-8-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione (6.39 mg, 0.013 mmol, 0.92%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.90 (d, J = 1.2 Hz, 1 H), 7.59 (m, 2 H), 7.51 (m, 1 H), 7.34 (m, 4 H), 7.24 (s, 1 H), 4.10 (br d, J = 7.0 Hz, 2 H), 4.03 (s, 3 H), 3.93 (s, 3 H), 2.18 (d, J = 0.6 Hz, 3 H), 1.29 (t, J = 7.1 Hz, 3 H). ESI-MS m / z = 475.3 [M+H] + ; Calcu. = 474.2.

[0421] Example 78: Synthesis of compounds E-86 and E-87

[0422] Step A: To a solution of 1-(4-bromo-2-methoxyphenyl)-4-methyl-1H-imidazole (2000 mg, 7.487 mmol) in tetrahydrofuran (2 mL) was added n-butyllithium (3.9 mL, 9.733 mmol) dropwise at -78 °C under argon. After the addition was complete, the mixture was stirred at -78 °C for 0.5 h under argon. To the mixture was added a solution of N-methoxy-N-methylpropanamide (1316 mg, 11.230 mmol) in tetrahydrofuran (2 mL) dropwise at -78 °C under argon. After the addition was complete, the mixture was stirred at -78 °C for 0.5 h under argon and at room temperature for 1 h under argon. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution at 0-5 °C. The mixture was stirred at 0-5 °C for 10 min, then water (20 mL) was added. The mixture was extracted with ethyl acetate (40 mL*2). The combined organic phase was washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a solid residue. The solid residue was separated by silica gel column (SiO2, PE:EA = 75:25). The reaction gave 1-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)propan-1-one (840 mg, 3.439 mmol, 45.93%) as yellow oil. ESI-MS m / z = 245.1 [M+H] + ; Calcu.= 244.1.

[0423] Step B: To a solution of 1-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)propan-1-one (1280 mg, 5.240 mmol) in tetrahydrofuran (20 mL) was added copper bromide (1170 mg, 5.240 mmol) dropwise at room temperature. The mixture was stirred at 60 °C for 2 h. The reaction was cooled to room temperature, then filtered through celite. The filter cake was washed with ethyl acetate (20 mL*2). The filtrate was concentrated under reduced pressure to give a solid residue. The solid residue was separated by silica gel column (SiO2, PE:EA = 85:15). The reaction gave 2-bromo-1-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)propan-1-one (933 mg, 2.887 mmol, 55.10%) as yellow solid. ESI-MS m / z = 323.1 [M+H] + ; Calcu.= 322.0.

[0424] Step C: Under argon protection, sodium bicarbonate (970 mg, 11.547 mmol) was added to 5 mL of ethanol containing ethyl 3-amino-3-iminopropionic acid hydrochloride (962 mg, 5.774 mmol). After the addition was complete, the mixture was stirred for 20 minutes under argon protection at 0-5 °C. Then, a solution of 5 mL of ethanol containing 2-bromo-1-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)prop-1-one (933 mg, 2.887 mmol) was slowly added dropwise. The temperature was then raised to 80 °C and stirred for 4 hours under argon protection. The reaction solution was cooled to room temperature and then concentrated under reduced pressure to obtain a solid residue. The solid residue was separated by silica gel column chromatography (SiO2, DCM:MeOH = 90:10). The reaction yielded a pale yellow solid, ethyl 2-amino-5-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4-methyl-1H-pyrrole-3-carboxylate (760 mg, 2.144 mmol, 74.28%). ESI-MS m / z = 355.3 [M+H] + ;Calcu.=354.2.

[0425] Step D: At 0-5°C, iodomethane (0.060 mL, 0.734 mmol) was slowly added dropwise to N,N-dimethylformamide (8 mL) containing dissolved 2-amino-5-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (200 mg, 0.564 mmol) and cesium carbonate (368 mg, 1.128 mmol). After the addition was complete, the mixture was stirred at room temperature for 4 hours. The reaction solution was filtered under reduced pressure, and the filtrate was collected and concentrated under reduced pressure to obtain a solid residue. The solid residue was separated by silica gel column chromatography (SiO2, DCM:MeOH = 91:10). The reaction yielded a pale yellow oily product, ethyl 2-amino-5-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-1,4-dimethyl-1H-pyrrole-3-carboxylate (80 mg, 0.217 mmol, 38.48%). ESI-MS m / z = 369.3 [M+H] + ;Calcu.=368.2.

[0426] Step E: To a solution of 2-amino-5-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)- 1,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (40 mg, 0.109 mmol) in dichloromethane (1 mL) at 0-5 °C under argon, slowly added triphosgene (97 mg, 0.326 mmol), after the addition, the whole mixture was stirred at 0-5 °C under argon for 0.5 h, then to the mixture, slowly added dropwise a solution of 4-fluoroaniline (60 mg, 0.543 mmol) and N,N-diisopropylethylamine (140 mg, 1.086 mmol) in dichloromethane (1 mL) at 0-5 °C under argon, after the addition, the whole mixture was stirred at room temperature under argon for 18 h. The reaction was added to water (20 mL), extracted with dichloromethane twice (30 mL*2), the combined organic phase was washed with saturated aqueous sodium chloride solution once (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a solid residue. The solid residue was separated on a silica gel column (Si02, DCM:MeOH = 91:9). The reaction gave a light yellow solid product 2-(3-(4-fluorophenyl)ureido)-5-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-1,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (40 mg, 0.079 mmol, 72.87 %). ESI-MS m / z = 506.4 [M+H] + ; Calcu. = 505.2.

[0427] Step F: To a solution of 2-(3-(4-fluorophenyl)ureido)-5-(3-methoxy-4-(4-methyl- 1H-imidazol-1-yl)phenyl)-1,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (10 mg, 0.020 mmol) in ethanol (10 mL) was added sodium ethoxide (7 mg, 0.099 mmol) at room temperature, then the whole mixture was stirred at 60 °C for 6 hours. The reaction was directly concentrated under reduced pressure to give a solid residue. The solid residue was subjected to HPLC preparation separation, preparation condition: Waters XSelect CSH Prep C18 (30 mm x 250 mm, 5 μm); A: 0.05% ammonia water; 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. The reaction gave E-86, white solid product 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5,7-dimethyl-1,7-dihydro-2H-pyrrolo[2,3-d]pyrimidine-2,4(3H)-dione (1.20 mg, 0.002 mmol, 11.76%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.32 (m, 1H), 7.10 (m, 5H), 7.02 (s, 1H), 6.96 (m, 4H), 3.66 (s, 3H), 3.25 (s, 3H), 2.20 (s, 3H), 1.60 (s, 3H). ESI-MS m / z = 460.3 [M+H] + ; Calcu. = 459.2.

[0428] Step G: To a solution of 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5,7-dimethyl-1,7-dihydro-2H-pyrrolo[2,3-d]pyrimidine-2,4(3H)- dione (5 mg, 0.011 mmol) in dichloromethane (5 mL) was added potassium tert- butoxide (4 mg, 0.038 mmol) and triethylsilyl trifluoromethanesulfonate (6 mg, 0.033 mmol) at room temperature under argon. After the addition was complete, the mixture was stirred at room temperature under argon for 16 h. The reaction was cooled to 0-5 °C, then water (10 mL) was added slowly dropwise, and the mixture was extracted with dichloromethane (30 mL x 2). The combined organic phase was washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a solid residue. The solid residue was separated by HPLC preparation. The HPLC preparation conditions: Waters XBridge Prep Shield RP C18 (19 mm x 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 18 mL / min; 0-3 min, 30% B; 3-17 min, 30%-100% B; detector: UV 254 nm. The reaction gave E-87, white solid product 1-ethyl-3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5,7-dimethyl-1,7-dihydro-2H-pyrrolo[2,3-d]pyrimidine-2,4(3H)- dione (0.83 mg, 0.001 mmol, 13.72%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.36 (m, 1H), 7.29 (m, 4H), 7.15 (m, 3H), 6.97 (m, 1H), 4.35 (q, J = 7.0 Hz, 2H), 3.64 (s, 3H), 3.54 (s, 3H), 2.24 (d, J = 0.8 Hz, 3H), 1.69 (s, 3H), 1.15 (s, 3H). ESI-MS m / z = 488.3 [M+H] + ; Calcu. = 487.2.

[0429] Example 79: Synthesis of compound E-88

[0430] Step A: To a solution of 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (50 mg, 0.108 mmol), triethylamine (0.045 mL, 0.324 mmol) in dichloromethane (4 mL) was added trifluoromethylsulfonic chloride (0.020 mL, 0.216 mmol) at 0 °C. After the addition, the whole mixture was stirred at room temperature for 1 hour. Then it was concentrated under reduced pressure to give a yellow crude product. The crude product was separated by HPLC prep, prep condition: Welch Xtimate C18 (30 mm x 250 mm, 5 μm); A: 0.5% ammonium acetate in water; B: MeCN; 5 mL / min; 0-3 min, 30% B; 3-5 min, 30%-70% B; 5-15 min, 70%-80% B; 15-16 min, 80%-100% B; Detector, UV 254 nm). The reaction gave E-88, white solid product 6-(4-(2-chloro-4-methyl-1H-imidazol-1-yl)-3-methoxyphenyl)-3-(4-fluorophenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (10.29 mg, 0.021 mmol, 19.19%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 12.3-12.6 (m, 1H), 7.45 (d, J=8.1 Hz, 1H), 7.3-7.4 (m, 4H), 7.25 (d, J=1.2 Hz, 1H), 7.17 (dd, J=1.4, 8.0 Hz, 1H), 7.11 (s, 1H), 3.86 (s, 3H), 2.49 (s, 3H), 2.13 (s, 3H). ESI-MS m / z = 497.2 [M+H] + Calcu. = 496.1.

[0431] Example 80: Synthesis of compound E-89

[0432] Step A: To a solution of 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl- lH-imidazol-l-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (50 mg, 0.108 mmol) in dichloromethane (3 mL) was added triethylamine (0.045 mL, 0.326 mmol), 4-dimethylaminopyridine (4 mg, 0.033 mmol) and ethylsulfonyl chloride (21 mg, 0.163 mmol) at room temperature. The whole mixture was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure at low temperature to give a residue, which was separated by HPLC prep. Prep. conditions: Waters XBridge C18 (19 mm x 250 mm, 5 μm); A: 5 mM ammonium acetate in water; B: MeCN; 18 mL / min 0-3 min, 10% B; 3-18 min, 10%-65% B; Detector, UV 254 nm. The reaction gave E-89, white solid product l-(ethylsulfonyl)-3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-lH-imidazol-l- yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (0.46 mg, 0.001 mmol, 0.75%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.84 (s, 1 H), 7.50 (d, J = 8.2 Hz, 1 H), 7.45 - 7.49 (m, 2 H), 7.34 - 7.40 (m, 2 H), 7.25 (d, J = 1.8 Hz, 1 H), 7.19 (s, 1 H), 7.16 (dd, J = 7.9, 1.8 Hz, 1 H), 4.01 - 4.07 (m, 2 H), 3.90 (s, 3 H), 2.47 (s, 3 H), 2.17 (d, J = 0.8 Hz, 3 H), 1.41 (t, J = 7.4 Hz, 3 H). ESI-MS m / z = 555.3 [M+H] + ; Calcu. = 554.1.

[0433] Example 81 : Synthesis of compound E-90

[0434] Step A: Into a 50 mL round-bottom flask / pressure tube, was added 3-(4- fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methylthieno[2,3- d]pyrimidine-2,4(1H,3H)-dione (150 mg, 0.324 mmol), potassium carbonate (134 mg, 0.973 mmol), tert-butyl (2-bromoethyl)carbamate (145 mg, 0.649 mmol) and N,N- dimethylformamide. After stirring homogeneously, the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The crude product was purified by reverse phase C18 column chromatography. Column: SW-5222-080-SP (AQ); mobile phase: formic acid water / methanol; detection wavelength: 254 nm. Lyophilization under reduced pressure gave the product tert-butyl (2-(3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5-methyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)ethyl) carbamate (110 mg, 0.182 mmol, 56.00 %). ESI-MS m / z = 606.3 [M+H] + ; Calcu. = 605.2.

[0435] Step B: Into a 50 mL round-bottom flask, was added tert-butyl (2-(3-(4-fluorophenyl)-6- (3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-2,4-dioxo-3,4- dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)ethyl)carbamate (100 mg, 0.165 mmol), dichloromethane (2 mL) and trifluoroacetic acid (2 mL, 26.118 mmol). After stirring homogeneously, the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo. The crude product was used directly in the next step 1-(2-aminoethyl)-3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H-imidazol-1- yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (70 mg, 0.138 mmol, 83.86 %). ESI-MS m / z = 506.4 [M+H] + ; Calcu. = 505.2.

[0436] Step C: To a 50 mL round bottom flask was added 1 -(2-aminoethyl)-3-(4- fluorophenyl)-6-(3-methoxy-4-(4-methyl-1 H-imidazol-1 -yl)phenyl)-5-methylthieno[2,3- d]pyrimidine-2,4(1 H,3H)-dione (20 mg, 0.040 mmol), triethylamine (0.016 mL, 0.119 mmol), acetyl chloride (0.005 mL, 0.071 mmol) and dichloromethane at room temperature. After stirring homogenously, the reaction mixture was stirred at room temperature overnight. The reaction was concentrated in vacuo. The crude product was purified by preparative high performance liquid chromatography. Prep conditions: YMC-Actus Triart C18 (21 mm x 250 mm, 5 μm); A: 0.1% formic acid in water; B: MeCN; 18 mL / min; 0-3 min, 30% B; 3-16 min, 50% - 100% B; Detector: UV 254 nm. Lyophilization under reduced pressure afforded E-90, product N-(2-(3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1 H-imidazol-1 - yl)phenyl)-5-methyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1 (2H)-yl)ethyl)acetamide (6.17 mg, 0.011 mmol, 28.48%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.12 (t, J=6.1 Hz, 1 H), 7.83 (d, J=1.3 Hz, 1 H), 7.50 (d, J=8.1 Hz, 1 H), 7.36 - 7.32 (m, 4 H), 7.24 (d, J=1.9 Hz, 1 H), 7.18 (t, J=1.2 Hz, 1 H), 7.15 (dd, J=8.1, 1.9 Hz, 1 H), 3.98 (t, J=5.8 Hz, 2 H), 3.90 (s, 3 H), 3.45 (q, J=6.0 Hz, 2 H), 2.17 (d, J=1.0 Hz, 3 H), 1.73 (s, 3 H). ESI-MS m / z = 548.4 [M+H] + ; Calcu. = 547.2.

[0437] Example 82: Synthesis of compound E-91

[0438] Step A: Into a dry reaction tube was added 3-(4-fluorophenyl)-6-(3-methoxy-4-(4- methyl-1H-imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (116 mg, 0.251 mmol), potassium carbonate (104 mg, 0.752 mmol), 3-(bromomethyl)azetidine-1- carboxylate tert-butyl ester (250 mg, 1.000 mmol) and N,N-dimethylformamide (5 mL) at room temperature. After all the addition, the reaction was stirred at room temperature for 18 hours. Then the reaction was diluted with ethyl acetate (15 mL) and water (15 mL), the organic layer was separated, the aqueous layer was extracted with ethyl acetate (15 mL*3), the combined organic layers were washed with saturated sodium chloride solution (15 mL*3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The crude product was directly subjected to HPLC preparation separation, the preparation condition: Welch Xtimate C18 (30 mm x 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 40 mL / min 0~3 min, 10% B; 3~3.5 min, 10%~52% B, 3.5~15 min, 52%~85% B, 15~15.5 min, 85%~100% B; detector, UV 254 nm. The reaction gave E-91, white solid product 3-((3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl- 2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl)azetidine-1-carboxylate (67 mg, 0.106 mmol, 42.25%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.80-7.85 (m, 1 H), 7.50 (d, J = 10.0 Hz, 1 H), 7.31-7.40 (m, 4 H), 7.23-7.28 (m, 1 H), 7.13-7.20 (m, 2 H), 4.13-4.30 (m, 2 H), 3.88-4.01 (m, 5 H), 3.68-3.80 (m, 2 H), 3.30 (s, 3 H), 3.04-315 (m, 1 H), 2.17 (s, 3 H), 1.36 (s, 9 H). ESI-MS m / z = 632.4 [M+H] + Calcu. = 631.2.

[0439] Example 83: Synthesis of compound E-92

[0440] Step A: Into a dry reaction tube was added 3-((3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5-methyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl) methyl)azetidine-1-carboxylic acid tert-butyl ester (32 mg, 0.051 mmol), dichloromethane (5 mL) and trifluoroacetic acid (0.02 mL, 0.261 mmol) at room temperature. After all the addition, the reaction was stirred at room temperature for 4 hours, then the reaction was directly subjected to HPLC preparation separation after the reaction solution was dried. The preparation condition: Waters XBridge Prep C18 (19 mm x 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 18 mL / min 0~3 min, 30% B; 3~20 min, 30%~100% B; detector, UV 254 nm. The reaction gave E-92, white solid product 1-(azetidin-3-ylmethyl)-3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione trifluoroacetate salt, the ratio of trifluoroacetate ion was 0.87 (10.68 mg, 0.017 mmol, 33.60%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.56-8.75 (m, 1 H), 8.36-8.53 (m, 1 H), 7.51-7.59 (m, 1 H), 7.32-7.38 (m, 4 H), 7.27-7.32 (m, 1 H), 7.26-7.28 (m, 1 H), 7.14-7.22 (m, 1 H), 4.17-4.27 (m, 2 H), 3.88-4.05 (m, 7 H), 3.28-3.34 (m, 4 H), 2.21 (s, 3 H). ESI-MS m / z = 532.3 [M+H] + ; Calcu. = 531.2.

[0441] Example 84: Synthesis of compounds E-93 and M-4

[0442] Step A: To a solution of 6-bromo-3-(4-fluorophenyl)-5-methylthieno[2,3- d]pyrimidine-2,4(lH,3H)-dione (4940 mg, 13.908 mmol) and potassium carbonate (3844 mg, 27.817 mmol) in N,N-dimethylformamide (2 mL) was added iodomethane (2.0 mL, 25.035 mmol) dropwise at 0 °C, then the whole mixture was stirred at room temperature for 2 hours. The reaction was added to water (120 mL) dropwise, stirred at 0-5 °C for 30 minutes after adding, then reduced pressure filtration, the filter cake was washed with water twice (10 mL*2), the filter cake was collected, the filter cake was reduced pressure rotary evaporation to remove water to obtain the crude product of off-white solid. The reaction obtained the crude product of off-white solid 6-bromo-3-(4-fluorophenyl)-l,5-dimethylthieno[2,3- d]pyrimidine-2,4(lH,3H)-dione (4100 mg, crude). ESI-MS m / z = 369.0 [M+H] + ; Calc u. = 368.0.

[0443] Step B: To a solution of 6-bromo-3-(4-fluorophenyl)-l,5-dimethylthieno[2,3- d]pyrimidine-2,4(lH,3H)-dione (200 mg, 0.542 mmol) in tetrahydrofuran (1 mL) was added n-butyllithium (0.4 mL, 0.975 mmol) dropwise at -78 °C under argon protection, the whole mixture was stirred at -78 °C under argon protection for 30 minutes, then (lR,5S)-8-oxo-3- azabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (180 mg, 0.688 mmol) was added to the above mixture dropwise, the whole mixture was stirred at -78 °C under argon protection for 10 minutes, then slowly warmed to room temperature and stirred at room temperature for 16 hours under argon protection. The reaction was cooled to 0-5 °C, then slowly added saturated aqueous ammonium chloride solution to quench the reaction, then extracted with ethyl acetate twice (30 mL*2), the two organic phases were combined, washed with saturated aqueous sodium chloride solution once (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a solid residue. The solid residue was separated by silica gel column (SiO2, PE:EA = 65:35). The reaction obtained white solid product (lR,5S,8r)-8-(3-(4-fluorophenyl)-l,5-dimethyl-2,4-dioxo-l,2,3,4- tetrahydrothieno[2,3-d]pyrimidin-6-yl)-8-hydroxy-3-azabicyclo[3.2.1]octane-3- carboxylic acid tert-butyl ester (90 mg, 0.175 mmol, 32.22 %). ESI-MS m / z = 516.3 [M+H] +; Calcu. = 515.2.

[0444] Step C: To a solution of (1R,5S,8r)-8-(3-(4-fluorophenyl)-1,5-dimethyl-2,4-dioxo- 1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)-8-hydroxy-3-azabicyclo[3.2.1]octane-3- carboxylic acid tert-butyl ester (90 mg, 0.175 mmol) and trifluoroacetic acid (0.07 mL, 0.873 mmol) in dichloromethane (5 mL) was added triethylsilane (101 mg, 0.873 mmol) slowly at room temperature. After the addition was complete, the mixture was stirred at room temperature for 16 h. The reaction was cooled to 0-5 °C, then triethylamine (10 mL) was added and the mixture was directly concentrated under reduced pressure to give a solid residue. The solid residue was separated by silica gel column (Si02, PE:EA = 50:50). The reaction gave white solid product 6-((1R,5S,8r)-3-azabicyclo[3.2.1]octan-8-yl)-3-(4-fluorophenyl)-1,5-dimethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (50 mg, 0.125 mmol, 71.52 %). ESI-MS m / z = 400.2 [M+H] + ; Calcu. = 399.1.

[0445] Step D: To a solution of 6-((lR,5S,8r)-3-azabicyclo[3.2.1]octan-8-yl)-3-(4- fluorophenyl)-l,5-dimethylthieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (170 mg, 0.426 mmol) and (6-methylpyrimidin-4-yl)boronic acid (176 mg, 1.277 mmol) in dichloromethane (5 mL) were added copper acetate (232 mg, 1.277 mmol) and triethylamine (0.3 mL, 2.128 mmol) at room temperature, and the whole mixture was stirred at room temperature under air atmosphere for 18 h. The reaction was filtered over celite, the filtrate was concentrated under reduced pressure to give a solid residue. The solid residue was separated by HPLC prep, prep condition: Waters XBridge Prep Shield RP C18 (30 mm x 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 18 mL / min; 0-3 min, 30% B; 3-4 min, 30%-50% B; 4-14 min, 50%-60% B; detector: UV 254 nm. The reaction gave E-93, white solid product 3-(4-fluorophenyl)-l,5-dimethyl-6-((lR,5S,8r)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2. l]octan-8-yl)thieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (2.79 mg, 0.005 mmol, 1.27%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.38 (s, 1H), 7.30 (d, J = 6.9 Hz, 4H), 6.62 (s, 1H), 3.41 (s, 3H), 3.30 (m, 5H), 2.65 (br s, 2H), 2.43 (s, 3H), 2.26 (s, 3H), 1.93 (m, 2H), 1.58 (m, 2H). ESI-MS m / z = 492.3 [M+H] + ; Calcu. = 491.2.

[0446] Example 85: Synthesis of compound E-94

[0447] Step A: To a solution of 6-((lR,5S,8r)-3-azabicyclo[3.2.1]octan-8-yl)-3-(4- fluorophenyl)-l,5-dimethylthieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (30 mg, 0.075 mmol) and 3-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridazine (50 mg, 0.225 mmol) in dichloromethane (5 mL) were added copper acetate (27 mg, 0.150 mmol) and triethylamine (0.05 mL, 0.375 mmol) at room temperature, then the whole mixture was stirred at room temperature under air atmosphere for 24 hours. The reaction was filtered through celite, the filtrate was concentrated under reduced pressure to give a solid residue. The solid residue was separated by HPLC preparation, preparation condition: Waters XBridge Prep Shield RP C18 (19 mm x 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 18 mL / min; 0~3 min, 10% B; 3~3.5 min, 10%~32% B; 3.5~15 min, 32%~65% B; detector: UV 254 nm. The reaction gave E-94, white solid product 3-(4-fluorophenyl)-l,5-dimethyl-6-((lR,5S,8r)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)thieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (2.39 mg, 0.005 mmol, 6.23%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.74 (d, J = 2.9 Hz, 1 H), 7.29 (m, 4 H), 6.72 (d, J = 2.9 Hz, 1 H), 3.63 (br d, J = 11.1 Hz, 2 H), 3.38 (s, 3 H), 3.32 (br s, 1 H), 3.25 (br d, J = 10.7 Hz, 2 H), 2.69 (br s, 2 H), 2.44 (s, 3 H), 2.42 (s, 3 H), 1.97 (m, 2 H), 1.67 (br d, J = 7.6 Hz, 2 H). ESI-MS m / z = 492.3 [M+H] + ; Calcu. = 491.2.

[0448] Example 86: Synthesis of compound E-95

[0449] Step A: To a solution of 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (32 mg, 0.069 mmol) in N,N-dimethylformamide (2 mL) was added cesium carbonate (114 mg, 0.350 mmol), potassium iodide (58 mg, 0.349 mmol) and dimethylchloromethylphosphine oxide (88 mg, 0.696 mmol) at room temperature. After the addition, the mixture was warmed to 100 °C for 5 h. The reaction was directly subjected to HPLC preparation separation. The preparation condition: Waters XBridge Prep Shield RP C18 (19 mm x 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 18 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-30% B; 3.5-15 min, 30%-57% B; detector, UV 254 nm. The reaction gave E-95, white solid product 1-((dimethylphosphoryl)methyl)-3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (6.61 mg, 0.012 mmol, 17.33%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.83 (d, J = 1.4 Hz, 1 H), 7.50 (d, J = 8.1 Hz, 1 H), 7.33-7.41 (m, 2 H), 7.32-7.36 m, 2 H), 7.24 (dd, J = 1.8 Hz, 1 H), 7.18 (s, 1 H), 7.15 (dd, J = 8.1, 1.8 Hz, 1 H), 4.38 (d, J = 4.9 Hz, 2 H), 3.90 (s, 3 H), 2.17 (s, 3 H), 1.58 (s, 3 H), 1.56 (s, 3 H). ESI-MS m / z = 533.3 [M+H] + ; Calcu. = 552.1.

[0450] Example 87: Synthesis of compound E-97

[0451] To a solution of 6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-3-(1- methyl-1H-indol-5-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (100 mg, 0.201 mmol), 2-bromoethan-1-ol (38 mg, 0.304 mmol), potassium carbonate (56 mg, 0.405 mmol) in N,N-dimethylformamide (4 mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the product was separated by preparative liquid chromatography. Waters XBridge Prep C18 (19 mm x 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 10 mL / min; 0-3 min, 10% B; 3-5 min, 10%-45% B; 5-15 min, 45%-50% B; 15-20 min, 50%-100% B; Detector: UV 254 nm. The product E-97, 1-(2-hydroxyethyl)-6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-3-(1-methyl-1H-indol-5-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (6.40 mg, 0.012 mmol, 5.88%) was obtained. 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.83 (d, J = 1.3 Hz, 1 H), 7.50 (dd, J = 8.3, 6.8 Hz, 2 H), 7.42 (dd, J = 3.7, 2.6 Hz, 2 H), 7.25 (d, J = 1.8 Hz, 1 H), 7.20 - 7.15 (m, 2 H), 7.01 (dd, J = 8.6, 2.0 Hz, 1 H), 6.49 - 6.46 (m, 1 H), 5.10 (t, J = 6.0 Hz, 1 H), 4.01 (d, J = 6.0 Hz, 2 H), 3.90 (s, 3 H), 3.85 (d, J = 5.0 Hz, 3 H), 3.76 (dd, J = 11.6, 5.8 Hz, 2 H), 2.17 (d, J = 0.7 Hz, 3 H). ESI-MS m / z = 642.3 [M+H] + Calcu. = 541.2.

[0452] Example 88: Synthesis of compound E-98

[0453] Step A: 6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-3-(1- methyl-1H-indol-5-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (100 mg, 0.201 mmol), (2-bromoethoxy)(tert-butyl)dimethylsilane (72 mg, 0.301 mmol), potassium carbonate (56 mg, 0.405 mmol) were dissolved in N,N-dimethylformamide (4 mL), stirred at room temperature overnight, the solvent was evaporated under reduced pressure, preparative liquid phase separation, preparative conditions: Waters XBridge Prep C18 (19 mm x 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 10 mL / min; 0~3 min, 10% B; 3~5 min, 10%~45% B; 5~15 min, 45%~50% B; 15~20 min, 50%~100% B; detector: UV 254 nm. The product E-98, 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5-methyl-3-(1-methyl-1H-indol-5-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)- dione (48.62 mg, 0.074 mmol, 36.88%) was obtained. 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.83 (d, J = 1.3 Hz, 1 H), 7.51 (t, J = 8.2 Hz, 2 H), 7.42 (d, J = 3.1 Hz, 1 H), 7.38 (d, J = 1.9 Hz, 1 H), 7.20 (dd, J = 10.5, 1.4 Hz, 2 H), 7.13 (dd, J = 8.1, 1.8 Hz, 1 H), 6.96 (dd, J = 8.6, 1.9 Hz, 1 H), 6.48 (d, J = 2.7 Hz, 1 H), 4.07 (t, J = 5.1 Hz, 2 H), 3.96 (t, J = 5.2 Hz, 2 H), 3.88 (d, J = 5.2 Hz, 3 H), 3.85 (s, 3 H), 2.48 (s, 3 H), 2.17 (d, J = 0.6 Hz, 3 H), 0.80 (s, 9 H). ESI-MS m / z = 656.4 [M+H] + ; Calcu. = 655.3.

[0454] Example 89: Synthesis of compounds E-99 and E-100

[0455] Step A: To a solution of 6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5- methyl-3-(1-methyl-1H-indol-5-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (100 mg, 0.201 mmol) and cesium carbonate (131 mg, 0.402 mmol) in N,N-dimethylformamide (1 mL) was added dropwise (2-bromoethyl) tert-butylcarbamate (59 mg, 0.261 mmol) in N,N-dimethylformamide (1 mL) slowly at 0-5 °C, then the whole mixture was stirred at room temperature for 16 hours. The reaction was directly concentrated under reduced pressure to give a solid residue. A small amount of the solid residue was taken for HPLC prep separation, prep condition: Waters XBridge Prep Shield RP C18 (19 mm x 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 18 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-45% B; 3.5-15 min, 45%-90% B; Detector: UV 254 nm. The reaction gave E-100, white solid product (2-(6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-3-(1-methyl-1H-indol-5-yl)-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)ethyl) tert-butylcarbamate (1.26 mg, 0.002 mmol, 0.97%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.84 (d, J = 1.1 Hz, 1 H), 7.51 (d, J = 8.2 Hz, 2 H), 7.41 (d, J = 2.6 Hz, 2 H), 7.20 (m, 2 H), 7.13 (m, 2 H), 7.01 (dd, J = 8.5, 1.8 Hz, 1 H), 6.48 (d, J = 2.9 Hz, 1 H), 3.94 (br t, J = 5.1 Hz, 2 H), 3.88 (s, 3 H), 3.84 (s, 3 H), 2.47 (s, 3 H), 2.16 (s, 3 H), 1.28 (s, 9 H). ESI-MS m / z = 641.4 [M+H] + ; Calcu. = 640.3.

[0456] Step B: To a solution of tert-butyl (2-(6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-3-(1-methyl-1H-indol-5-yl)-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)ethyl)carbamate (50 mg, 0.078 mmol) in toluene (5 mL) was added trifluoroacetic acid (0.030 mL, 0.390 mmol) dropwise at room temperature, and the whole mixture was stirred at room temperature for 16 hours. The reaction was directly concentrated under reduced pressure to give a solid residue. The solid residue was separated by HPLC prep, prep condition: Waters XBridge Prep C18 (19 mm x 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 18 mL / min; 0-3 min, 30% B; 3-5 min, 30%-50% B; 5-15 min, 50%-60% B; detector: UV 254 nm. The reaction gave E-99, white solid product 1-(2-aminoethyl)-6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-3-(1-methyl-1H-indol-5-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (2.72 mg, 0.005 mmol, 5.96%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.82 (m, 1H), 7.51 (m, 3H), 7.19 (m, 3H), 6.94 (m, 2H), 6.62 (br s, 1H), 3.98 (br s, 2H), 3.87 (m, 6H), 2.99 (br d, J=6.4 Hz, 2H), 2.46 (m, 3H), 2.16 (s, 3H). ESI-MS m / z = 541.4 [M+H] + ; Calcu. = 540.2.

[0457] Example 90: Synthesis of compound E-101

[0458] Step A: At 0°C, bromoacetone (995 mg, 7.262 mmol) was added dropwise to N,N-dimethylformamide (20 mL) containing 4-(1-methyl-1H-pyrazol-4-yl)piperidine (1 g, 6.052 mmol) and potassium carbonate (1.67 g, 12.104 mmol). After the addition was complete, the mixture was brought to room temperature and stirred for 3 hours. The reaction was then quenched with water, and the product was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a brown crude product. The crude product was then subjected to HPLC for preparative separation. Preparation conditions: Welch Xtimate C18 (30 mm × 250 mm, 5 μm); A: 0.05% ammonia; B: MeCN; 5 mL / min; 0–3 min, 10% B; 3–3.5 min, 10%–35% B; 3.5–15 min, 35%–65% B; 15–15.5 min, 65%–100% B; detector, UV 254 nm. A light brown solid product, 1-(4-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl)propane-2-one (650 mg, 2.937 mmol, 48.53%), was obtained. ESI-MS m / z = 222.3 [M+H]. + ;Calcu.=221.2.

[0459] Step B: At room temperature, sulfur powder (232 mg, 0.904 mmol) and morpholine (2 g, 22.957 mmol) were added sequentially to 5 mL of ethanol containing 1-(4-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl)propane-2-one (200 mg, 0.904 mmol) and ethyl cyanoacetate (102 mg, 0.904 mmol). After the addition was complete, the mixture was heated to 60 °C and stirred overnight. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a brown crude product. The crude product was then subjected to HPLC for preparative separation. Preparation conditions: Welch Xtimate C18 (30mm × 250mm, 5μm); A: 0.05% ammonia; B: MeCN; 5mL / min; 0–3min, 10% B; 3–3.5min, 10%–35% B; 3.5–15min, 35%–65% B; 15–15.5min, 65%–100% B; detector, UV 254nm. This reaction yielded a light brown solid product, ethyl 2-amino-4-methyl-5-(4-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl)thiophene-3-carboxylate (50mg, 0.143mmol, 15.82%). ESI-MS m / z = 349.2 [M+H]. + ;Calcu.=348.2.

[0460] Step C: To a solution of ethyl 2-amino-4-methyl-5-(4-(l-methyl-lH-pyrazol-4- yl)piperidin-l-yl)thiophene-3-carboxylate (50 mg, 0.143 mmol) and cesium carbonate (140 mg, 0.430 mmol) in acetonitrile (5 mL) was added p-fluorophenyl isocyanate (59 mg, 0.430 mmol) at room temperature. After the addition was complete, the mixture was warmed to 90 °C and stirred for 1.5 h. The reaction was cooled to room temperature and concentrated under reduced pressure to give brown crude product 3-(4-fluorophenyl)-5-methyl-6-(4-(l-methyl-lH-pyrazol-4-yl)piperidin-l-yl)thieno[2,3- d]pyrimidine-2,4(lH,3H)-dione (crude). ESI-MS m / z = 440.2 [M+H] + ; Calc u. = 439.2.

[0461] Step D: To a solution of crude product 3-(4-fluorophenyl)-5-methyl-6-(4-(l-methyl-lH- pyrazol-4-yl)piperidin-l-yl)thieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (crude) and potassium carbonate (82 mg, 0.594 mmol) in N,N-dimethylformamide (5 mL) was added iodomethane (50 mg, 0.352 mmol) at 0 °C. After the addition was complete, the mixture was stirred at 0 °C for 1 h. Subsequently, the mixture was concentrated under reduced pressure to give brown crude product. The crude product was separated by HPLC prep. Prep condition: Welch Xtimate C18 (30 mm x 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 5 mL / min; 0~3 min, 10% B; 3~3.5 min, 10%~35% B; 3.5~15 min, 35%~65% B; 15~15.5 min, 65%~100% B; Detector, UV 254 nm. The reaction gave E-101, white solid product 3-(4-fluorophenyl)-l,5-dimethyl-6-(4-(l-methyl-lH-pyrazol-4-yl)piperidin-l-yl)thieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (1.52 mg, 0.003 mmol, 2.34%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.54 (s, 1 H), 7.30-7.33 (m, 5 H), 3.78 (s, 3 H), 3.44 (s, 3 H), 3.07 (d, J = 11.3 Hz, 2 H), 2.70-2.74 (m, 2 H), 2.55-2.60 (m, 1 H), 2.28 (s, 3 H), 1.94 (d, J = 11.1 Hz, 2 H), 1.68-1.72 (m, 2 H). ESI-MS m / z = 454.5 [M+H]+ ; Calcu. = 453.2.

[0462] Example 91: Synthesis of compounds E-103 and E-104

[0463] Step A: To a solution of 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (60 mg, 0.130 mmol) in N,N-dimethylformamide (2 mL) was added cesium carbonate (212 mg, 0.651 mmol), lithium iodide (87 mg, 0.650 mmol) and N-Boc-3-bromo-azetidine (920 mg, 3.897 mmol) at room temperature. After the addition, the whole mixture was warmed to 120 °C for 3 hours. Then the reaction was directly subjected to HPLC preparation separation, the preparation condition: Waters XBridge Prep Shield RP C18 (19 mm x 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 18 mL / min; 0~3 min, 10% B; 3~3.5 min, 10%~40% B; 3.5~15 min, 40%~75% B; detector, UV 254 nm. The reaction gave E-104, white solid product 3-(3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)azetidine-1-carboxylic acid tert-butyl ester (11 mg, 0.018 mmol, 13.70%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.83 (d, J = 1.2 Hz, 1 H), 7.50 (d, J = 8.1 Hz, 1 H), 7.32 - 7.39 (m, 4 H), 7.25 (d, J = 1.8 Hz, 1 H), 7.18 (s, 1 H), 7.15 (dd, J = 8.1, 1.8 Hz, 1 H), 5.11 - 5.17 (m, 1 H), 4.51 (m, 2 H), 4.18 (m, 2 H), 3.89 (s, 3 H), 2.49 (s, 3 H), 2.17 (s, 3 H), 1.37 (s, 9 H). ESI-MS m / z = 618.4 [M+H] + ; Calcu. = 617.2.

[0464] Step B: To a solution of tert-butyl 3-(3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl- 1H-imidazol-1-yl)phenyl)-5-methyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)- yl)azetidine-1-carboxylate (9 mg, 0.015 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.1 ml, 1.306 mmol) at room temperature. The whole mixture was stirred at room temperature overnight. The mixture was concentrated to dryness under reduced pressure, then subjected to HPLC preparation separation. The preparation condition: Waters XBridge Prep Shield RP C18 (19 mm x 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 18 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-40% B; 3.5-15 min, 40%-75% B; Detector, UV 254 nm. The reaction gave E-103, white solid product 1-(azetidin-3-yl)-3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.94 mg, 0.004 mmol, 24.99%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.83 (d, J = 1.2 Hz, 1 H), 7.49 (d, J = 8.1 Hz, 1 H), 7.31 - 7.38 (m, 4 H), 7.26 (d, J = 1.7 Hz, 1 H), 7.18 (s, 1 H), 7.16 (dd, J = 8.1, 1.8 Hz, 1 H), 4.99 - 5.05 (m, 1 H), 4.09 (t, J = 8.4 Hz, 2 H), 3.90 (s, 3 H), 3.70 (t, J = 8.2 Hz, 2 H), 2.49 (s, 3 H), 2.17 (s, 3 H). ESI-MS m / z = 518.3 [M+H] + ; Calcu. = 517.2.

[0465] Example 92: Synthesis of compound E-105

[0466] Step A: To a solution of 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (46 mg, 0.099 mmol) in N,N-dimethylformamide (2 mL) was added potassium carbonate (28 mg, 0.203 mmol) and benzyl bromide (20 mg, 0.117 mmol) at room temperature. After the addition, the whole mixture was stirred at room temperature for 4 hours. Then the reaction was directly subjected to HPLC preparation separation. The preparation condition: Waters XBridge Prep Shield RP C18 (19 mm x 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 18 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-40% B; 3.5-15 min, 40%-75% B; detector, UV 254 nm. The reaction gave E-105, white solid product 1-benzyl-3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (23.44 mg, 0.042 mmol, 42.84%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.80 (d, J = 1.2 Hz, 1 H), 7.43-7.46 (m, 5 H), 7.32-7.40 (m, 5 H), 7.19 (d, J = 1.8 Hz, 1 H), 7.15 (s, 1 H), 7.07 (dd, J = 8.1, 1.8 Hz, 1 H), 5.22 (s, 2 H), 3.86 (s, 3 H), 2.49 (s, 3 H), 2.15 (s, 3 H). ESI-MS m / z = 553.4 [M+H] + ; Calcu. = 552.2.

[0467] Example 93: Synthesis of compound E-106

[0468] Step A: To a solution of tert-butyl 2-(hydroxymethyl)azetidine-1 -carboxylate (1000 mg, 5.341 mmol) in dichloromethane (30 mL) was added triethylamine (2.225 mL, 16.009 mmol) and 4-dimethylaminopyridine (196 mg, 1.604 mmol) at 0 °C. The mixture was stirred at 0 °C for 5 min, then 4-methylbenzenesulfonyl chloride (1533 mg, 8.041 mmol) was added. The mixture was stirred at room temperature for 16 h. The reaction was quenched by the addition of saturated aqueous NaHC03solution (30 mL), and extracted with ethyl acetate (30 mL*3). The organic phase was combined and concentrated under reduced pressure to give a residue, which was separated by normal phase column (Si02, PE:EA = 90:10). The reaction gave tert-butyl 2-((toluene- sulfon-yloxy)methyl)azetidine-1 -carboxylate (1790 mg, 5.243 mmol, 98.17%) as a white oil. ESI-MS m / z = 242.1 [M-Boc+H] + ; Calcu.= 341.1.

[0469] Step B: To a solution of 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1 H-imidazol-1 - yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1 H,3H)-dione (20 mg, 0.043 mmol) in N,N-dimethylformamide (2 mL) was added potassium carbonate (30 mg, 0.217 mmol) and tert-butyl 2-((toluene-sulfon-yloxy)methyl)azetidine-1 -carboxylate (60 mg, 0.176 mmol) at room temperature. The mixture was stirred at 100 °C for 16 h. The reaction was filtered through celite, and the filtrate was concentrated under reduced pressure to give a residue, which was used directly in the next step. The reaction gave 1 -(azetidin-2-ylmethyl)-3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1 H- imidazol-1 -yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1 H,3H)-dione (60 mg, 0.055 mmol, 31.85%) as a yellow oil. ESI-MS m / z = 632.4 [M+H] + ; Calcu.= 631.2.

[0470] Step C: To a solution of 1-(azetidin-2-ylmethyl)-3-(4-fluorophenyl)-6-(3-methoxy-4-(4- methyl-1H-imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (60 mg, 0.055 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL, 13.059 mmol) at room temperature, then the whole mixture was stirred at room temperature for 4 hours. The reaction was concentrated under reduced pressure to give a residue, which was separated by HPLC prep, prep condition: Waters XBridge C18 (50 mm x 250 mm, 10 μm); A: 0.1% formic acid in water; B: MeOH; 18 mL / min 0~3 min, 10% B; 3~13 min, 10%~50% B; Detector, UV 254 nm. The reaction gave E-106, white solid product 1-(azetidin-2-ylmethyl)-3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (4.32 mg, 0.007 mmol, 7.52%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.83 (d, J = 1.1 Hz, 1 H), 7.47 - 7.53 (m, 1 H), 7.30 - 7.39 (m, 4 H), 7.25 (d, J = 1.8 Hz, 1 H), 7.18 (s, 1 H), 7.16 (dd, J = 8.1, 1.7 Hz, 1 H), 4.32 - 4.44 (m, 1 H), 4.03 - 4.19 (m, 2 H), 3.90 (s, 3 H), 3.54 - 3.64 (m, 1 H), 2.49 (br s, 3 H), 2.22 - 2.32 (m, 2 H), 2.17 (s, 3 H), 1.91 (s, 1 H). ESI-MS m / z = 532.3 [M+H] + ; Calcu. = 531.2.

[0471] Example 94: Synthesis of compound E-107

[0472] Step A: 6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-3-(1- methyl-1H-indol-5-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (200 mg, 0.402 mmol), (2-bromoethyl)-carbamic acid tert-butyl ester (117 mg, 0.522 mmol), cesium carbonate (262 mg, 0.804 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred at 60 °C overnight. The reaction was cooled and filtered, the filtrate was evaporated under reduced pressure and the product (tert-butyl (2-(6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-3-(1-methyl-1H-indol-5-yl)-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)ethyl)carbamate (140 mg, 0.218 mmol, 54.36%) was isolated by column chromatography. ESI-MS m / z = 641.4 [M+H] + ; Calcu. = 640.2.

[0473] Step B: tert-butyl (2-(6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-3-(1-methyl-1H-indol-5-yl)-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)ethyl)carbamate (140 mg, 0.218 mmol) was dissolved in N,N-dimethylformamide (5 mL), sodium hydride (19 mg, 0.47 mmol) was added at 0 °C and stirred for 20 minutes, iodomethane (66 mg, 0.047 mmol) was added at the same temperature and the reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched with water, the solvent was evaporated under reduced pressure and the product (tert-butyl (2-(6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-3-(1-methyl-1H-indol-5-yl)-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)ethyl)(methyl)carbamate (141 mg, 0.215 mmol, 98.62%) was isolated by column chromatography. ESI-MS m / z = 655.4 [M+H] + ; Calcu. = 654.3.

[0474] Step C: tert-Butyl (2-(6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5- methyl-3-(1-methyl-1H-indol-5-yl)-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)- yl)ethyl)(methyl)carbamate (120 mg, 0.183 mmol) was dissolved in dichloromethane (12 mL), trifluoroacetic acid (1.5 mL, 19.590 mmol) was added at room temperature and stirred for 2 hours. The reaction was cooled to 0 °C, triethylamine was added to adjust the pH of the reaction system to weak alkaline, water was added to wash, the organic phase was evaporated under reduced pressure to dry the solvent, preparative liquid phase separation, preparation conditions: Waters XBridge Prep C18 (19 mm x 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 18 mL / min; 0~3 min, 20% B; 3~3.5 min, 20%~45% B; 3.5~15 min, 45%~85% B; 15~15.5 min, 85%~100% B; detector: UV 254 nm. The product E-107, 6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-3-(1-methyl-1H-indol-5-yl)-1-(2-(methylamino)ethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.35 mg, 0.002 mmol, 1.33%) was obtained. 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.83 (s, 1H), 7.51 (d, J = 8.2 Hz, 2H), 7.44-7.41 (m, 2H), 7.26 (s, 1H), 7.18 (d, J = 10.2 Hz, 2H), 7.02 (d, J = 8.7 Hz, 1H), 6.48 (d, J = 2.9 Hz, 1H), 5.30 (s, 1H), 4.11 (dd, J = 10.5, 5.2 Hz, 5H), 3.90 (s, 3H), 3.85 (s, 3H), 2.17 (s, 3H), 1.34 (s, 3H). ESI-MS m / z = 555.4 [M+H] + ; Calcu. = 554.2.

[0475] Example 95: Synthesis of compound E-108

[0476] Step A: To a solution of 2-aminothiophene-3,4-dicarboxylic acid diethyl ester (3000 mg, 12.331 mmol) in dichloromethane (50 mL) was added N-bromosuccinimide (2430 mg, 13.652 mmol) slowly at 0 °C, then the whole mixture was stirred at room temperature for 1 hour. To the reaction, saturated aqueous sodium bicarbonate solution (30 mL) was added, extracted with ethyl acetate (30 mL*3), the organic phase was combined and concentrated under reduced pressure to get a residue, normal phase column separation (Si02, PE:EA = 90:10). The reaction gave yellow solid product 2-amino-5-bromothiophene-3,4-dicarboxylic acid diethyl ester (2600 mg, 8.070 mmol, 65.44 %). ESI-MS m / z = 322.0 [M+H] + ; Calcu. = 321.0.

[0477] Step B: To a solution of (3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)boronic acid (3052 mg, 7.771 mmol) in 1,4-dioxane (30 mL) was added PdCl2(dppf) (660 mg, 0.902 mmol), aqueous sodium carbonate solution (7.5 mL) and 2-amino-5-bromothiophene-3,4-dicarboxylic acid diethyl ester (2600 mg, 8.070 mmol) at room temperature under nitrogen, then the whole mixture was stirred at 90 °C for 16 hours, the reaction was concentrated under reduced pressure to get a residue, normal phase column separation (Si02, DCM:MeOH = 5% out product). The reaction gave brown solid product 2-amino-5-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiophene-3,4-dicarboxylic acid diethyl ester (1820 mg, 4.238 mmol, 52.51 %). ESI-MS m / z = 430.2 [M+H] + ; Calcu. = 429.1.

[0478] Step C: To a solution of 2-amino-5-(3-methoxy-4-(4-methyl-1H-imidazol-1- yl)phenyl)thiophene-3,4-dicarboxylic acid diethyl ester (1820 mg, 4.238 mmol) in acetonitrile (30 mL) was added cesium carbonate (2770 mg, 8.502 mmol) at room temperature, followed by the slow addition of 4-fluorophenyl isocyanate (873 mg, 6.367 mmol). The mixture was stirred at 90 °C for 16 h. The reaction was filtered through celite and the filtrate was concentrated under reduced pressure to give a residue, which was separated by normal phase column (Si02, DCM:MeOH = 95:5). The reaction gave 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H-imidazol-1- yl)phenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid ethyl ester (1920 mg, 3.688 mmol, 87.04%) as a yellowish solid. ESI-MS m / z = 521.3 [M+H] + ; Calcu.= 520.1.

[0479] Step D: To a solution of 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H-imidazol-1- yl)phenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid ethyl ester (1600 mg, 3.074 mmol) in tetrahydrofuran (10 mL) was added lithium triethylborohydride in tetrahydrofuran (16 mL, 16.000 mmol) slowly at 0 °C, then the mixture was stirred at room temperature for 1 h. The reaction was quenched by the addition of methanol (10 mL) and concentrated under reduced pressure to give a residue, which was separated by normal phase column (Si02, EA:MeOH = 95:5). The reaction gave 3-(4-fluorophenyl)-5-hydroxymethyl-6-(3-methoxy-4-(4-methyl-1H-imidazol-1- yl)phenyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (1400 mg, 2.926 mmol, 95.19%) as a yellow solid. ESI-MS m / z = 479.2 [M+H] + ; Calcu.= 478.1.

[0480] Step E: To a solution of 3-(4-fluorophenyl)-5-hydroxymethyl-6-(3-methoxy-4-(4- methyl- lH-imidazol- 1 -yl)phenyl)thieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (1400 mg, 2.926 mmol) in dichloromethane (30 mL) was added Dess-Martin periodinane (2387 mg, 5.628 mmol) and sodium bicarbonate (3000 mg, 35.710 mmol) at room temperature, then the whole mixture was stirred at room temperature for 4 hours. The reaction was concentrated under reduced pressure to give a residue, which was separated by normal phase column (Si02, DCM:MeOH = 90: 10). The reaction gave yellow solid product 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl)-2,4-dioxo-l,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carbaldehyde (2200 mg, 2.770 mmol, 94.69 %). ESI-MS m / z = 477.2 [M+H] + ; Calcu. = 476.1.

[0481] Step F: To a solution of 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-lH-imidazol-l- yl)phenyl)-2,4-dioxo-l,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carbaldehyde (80 mg, 0.168 mmol) in dichloromethane (2 mL) and 1,2-dichloroethane (2 mL) was added diethylamine trifluoride (350 mg, 2.171 mmol) at 0 °C, then the whole mixture was stirred at 60 °C for 4 hours. To the reaction was added saturated aqueous sodium bicarbonate solution (2 mL) to quench the reaction, which was concentrated under reduced pressure to give a residue, which was separated by HPLC prep. Prep condition: Waters XBridge C18 (19 mm x 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 18 mL / min 0~3 min, 10% B; 3~5 min, 10%~30% B; 5~15 min, 30%~50% B; Detector, UV 254 nm. The reaction gave white solid product 5-(difluoromethyl)-3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl)thieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (15 mg, 0.030 mmol, 17.92 %). ESI-MS m / z = 499.2 [M+H] + ; Calcu. = 498.1.

[0482] Step G: To a solution of 5-(difluoromethyl)-3-(4-fluorophenyl)-6-(3-methoxy-4-(4- methyl- lH-imidazol- 1 -yl)phenyl)thieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (15 mg, 0.030 mmol) in N,N-dimethylformamide (2 mL) was added potassium carbonate (9 mg, 0.065 mmol) and iodomethane (9 mg, 0.063 mmol) at room temperature, then the whole mixture was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure to give a residue, which was separated by HPLC prep. Prep. conditions: Waters XBridge C18 (30 mm x 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 18 mL / min 0~3 min, 30% B; 3~13 min, 10%~50% B; Detector, UV 254 nm. The reaction gave E-108, white solid product 5-(difluoromethyl)-3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl- lH-imidazol- 1 -yl)phenyl)- 1 -methylthieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (4.28 mg, 0.008 mmol, 27.41%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.23 (br s, 1 H), 7.59 (d, J = 8.1 Hz, 1 H), 7.31 - 7.56 (m, 7 H), 7.27 (dd, J = 8.0, 1.8 Hz, 1 H), 3.90 (s, 3 H), 3.53 (s, 3 H), 2.21 (s, 3 H). ESI-MS m / z = 513.2 [M+H] + ; Calcu. = 512.1.

[0483] Example 96: Synthesis of compound E-109

[0484] Step A: To a solution of 6-bromo-3-(4-fluorophenyl)-l,5-dimethylthieno[2,3- d]pyrimidine-2,4(lH,3H)-dione (100 mg, 0.271 mmol), 3-methoxy-4-(4-methyl-lH- imidazol-l-yl)aniline (83 mg, 0.406 mmol) in toluene (6 mL) at room temperature was added palladium acetate (12 mg, 0.054 mmol), 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (63 mg, 0.108 mmol) and cesium carbonate (265 mg, 0.813 mmol). After the addition, the whole mixture was warmed to 100 °C and stirred under nitrogen overnight. Subsequently, it was concentrated under reduced pressure to give a brown crude product. The crude was subjected to HPLC prep purification, prep condition: Welch Xtimate C18 (30 mm x 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 5 mL / min; 0-3 min, 10% B; 3-3.5 min, 10%-35% B; 3.5-15 min, 35%-70% B; 15-15.5 min, 70%-100% B; detector, UV 254 nm. This reaction gave E-109, white solid product 3-(4-fluorophenyl)-6-((3-methoxy-4-(4-methyl-lH-imidazol-l- yl)phenyl)amino)-l,5-dimethylthieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (6.01 mg, 0.012 mmol, 87.34% purity). 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.31 (br s, 1 H), 7.3-7.4 (m, 6 H), 7.24 (br d, J=9.2 Hz, 1 H), 6.53 (d, J=2.1 Hz, 1 H), 6.2-6.3 (m, 1 H), 3.75 (s, 3 H), 3.45 (s, 3 H), 2.23 (br s, 3 H), 2.22 (s, 3 H). ESI-MS m / z = 492.3 [M+H] + ; Calcu. = 491.1.

[0485] Example 97: Synthesis of compound E-110

[0486] Step A: To a solution of 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (100 mg, 0.216 mmol) in N,N-dimethylformamide (3 mL) was added potassium carbonate (90 mg, 0.651 mmol) and 2-bromo-N-methylacetamide (99 mg, 0.651 mmol) at room temperature, then the whole mixture was stirred at 60 °C for 2 hours. The reaction was concentrated under reduced pressure to give a residue, which was separated by HPLC preparation, preparation condition: Waters XBridge C18 (30 mm x 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 40 mL / min 0~3 min, 10% B; 3~4 min, 10%~35% B; 4~15 min, 35%~75% B; detector, UV 254 nm. The reaction gave E-110, white solid product 2-(3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)-N-methylacetamide (32.07 mg, 0.060 mmol, 27.79%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.29 (q, J=4.6 Hz, 1 H), 7.83 (d, J=1.2 Hz, 1 H), 7.49 (d, J=7.9 Hz, 1 H), 7.35 (d, J=6.7 Hz, 4 H), 7.24 (d, J=1.8 Hz, 1 H), 7.18 (s, 1 H), 7.15 (dd, J=8.1, 1.8 Hz, 1 H), 4.56 (s, 2 H), 3.89 (s, 3 H), 2.64 (d, J=4.6 Hz, 3 H), 2.51 (s, 3 H), 2.16 (s, 3 H). ESI-MS m / z = 534.3 [M+H] + ; Calcu. = 533.2.

[0487] Example 98: Synthesis of compound E-111

[0488] Step A: To a solution of 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H- imidazol-1-yl)phenyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (30 mg, 0.065 mmol) in acetonitrile (2 mL) was added potassium carbonate (90 mg, 0.651 mmol) and 1-bromo-2-(methylsulfonyl)ethane (243 mg, 1.299 mmol) at room temperature. After the addition was complete, the mixture was warmed to 80 °C for 7 h. The mixture was filtered and washed with a small amount of methanol. The filtrate was concentrated to dryness under reduced pressure. The residue was then subjected to HPLC prep. Prep condition: Waters XBridge Prep C18 (19 mm x 250 mm, 5 μm); A: 0.05% ammonia water; B: MeCN; 18 mL / min, 0-3 min, 20% B; 3-3.5 min, 20%-40% B; 3.5-15 min, 40%-70% B; Detector, UV 254 nm. This reaction gave E-111, white solid product 3-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-1-(2-(methylsulfonyl)ethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (4.05 mg, 0.007 mmol, 10.96%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.84 (d, J = 1.4 Hz, 1 H), 7.51 (d, J = 8.1 Hz, 1 H), 7.30 - 7.39 (m, 4 H), 7.28 (d, J = 1.8 Hz, 1 H), 7.17 - 7.19 (m, 2 H), 4.37 (t, J = 7.2 Hz, 2 H), 3.90 (s, 3 H), 3.65 (t, J = 7.2 Hz, 2 H), 3.14 (s, 3 H), 2.17 (s, 3 H). ESI-MS m / z = 569.3 [M+H] + ; Calcu. = 568.1.

[0489] Example 99: Synthesis of compound E-112

[0490] Step A: To a solution of 6-((lR,5S,8r)-3-azabicyclo[3.2.1]octan-8-yl)-3-(4- fluorophenyl)-l,5-dimethylthieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (90 mg, 0.225 mmol) and l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (70 mg, 0.338 mmol) in dichloromethane (5 mL) were added copper acetate (82 mg, 0.451 mmol) and triethylamine (0.16 mL, 1.126 mmol) at room temperature, then the whole mixture was stirred at room temperature under air atmosphere for 96 hours. The reaction was filtered over celite, the filtrate was concentrated under reduced pressure to give a solid residue. The solid residue was separated by HPLC prep, prep condition: Waters XBridge Prep Shield RP C18 (...

Claims

1. The compound of formula (I), its pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystal form, isotope label, or metabolite form thereof, in, It can be a single bond or a double bond; X is selected from O, S, N, NR 5 CR 4 and CHR 4 ; Y is selected from O, S, N, NR 5 CR 4 and CHR 4 ; M is selected from O and S; T1 is selected from C (=W) and S (=W1)(=W2), and W, W1 and W2 are each independently selected from O and S; L1 and L2 are each independently selected from -O-, -S-, and -NR. a -, -(C1-C4)alkylene-, -(C2-C4)alkenylene- and -(C2-C4)ynylene-, wherein R a Selected from hydrogen, -(C1-C4)alkyl, and -(C1-C4)haloalkyl; R 1 Selected from hydrogen, (C6-C) 14 ) aryl, (5-12) heteroaryl, (3-12) heterocyclic and (C3-C 12 )cycloalkyl, the (C6-C 14 ) aryl, (5-12) heteroaryl, (3-12) heterocyclic and (C3-C 12 ) cycloalkyl groups are optionally surrounded by one or more R 11 replace, R 11 Each is independently 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 -C(=O)NR b R c -P(=O)-R b R c -Si[(C1-C6)alkyl]3, =O, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)ynyl, -(C1-C6)haloalkyl, -CH2R b -(C1-C6)alkylene-OH, -(C1-C6)alkylene-NH2, -(C3-C 10 )cycloalkyl, -(C6-C 10 aryl, (3-10) heterocyclic and (5-12) heteroaryl, wherein -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)ynyl, -(C1-C6)haloalkyl, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-NH2, -(C3-C 10 )cycloalkyl, -(C6-C 10 )aryl, (3-10-membered)heterocyclic and (5-12-membered)heteroaryl groups may optionally be substituted by one or more groups independently selected from hydrogen, halogen, -OH, -SH, -NH2, -COOH, -(C1-C4)alkyl, -O(C1-C4)alkyl, -NH(C1-C4)alkyl and -NH[(C1-C4)alkyl]2, wherein R b and R c Each is independently selected from hydrogen, halogen, -OH, -NH2, -(C1-C6)alkyl, -O(C1-C6)alkyl, -(C1-C6)haloalkyl, -C(=O)(C1-C6)alkyl, -S(=O)2(C1-C6)alkyl, (3-10-membered)heterocyclic and (5-12-membered)heteroaryl; 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 -C(=O)NR b R c -P(=O)-R b R c -Si[(C1-C6)alkyl]3, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)ynyl, (C6-C 14 ) aryl, (5-12 quinone) heteroaryl, (3-12 quinone) heterocyclic, (C3-C 12 )cycloalkyl and (C4-C 12 )cycloalkenyl, wherein -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)ynyl, (C6-C 14 ) aryl, (5-12 quinone) heteroaryl, (3-12 quinone) heterocyclic, (C3-C 12 )cycloalkyl and (C4-C 12 The cycloalkenyl group is optionally surrounded by one or more elements selected from hydrogen, halogen, nitro, nitroso, -CN, -OH, -O-(C1-C6)alkyl, -SH, -S(=O)2-(C1-C6)alkyl, -NH2, -NH(C1-C6)alkyl, -N[(C1-C6)alkyl]2, -COOH, -C(=O)-(C1-C6)alkyl, -C(=O)O-(C1-C6)alkyl, -C(=O)NH(C1- C6) alkyl, -P(=O)(OH)2, -P(=O)(OH)[O(C1-C6)alkyl], -P(=O)[(C1-C6)alkyl]2, -P(=O][O(C1-C6)alkyl]2, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C2-C6)alkenyl, -(C2-C6)ynyl, (C3-C7)cycloalkyl and (4-7) heterocyclic groups are substituted, wherein R b and R c Each is independently selected from hydrogen, halogen, -OH, -NH2, -(C1-C6)alkyl, -O(C1-C6)alkyl, -(C1-C6)haloalkyl, -C(=O)(C1-C6)alkyl, -S(=O)2(C1-C6)alkyl, (3-9-membered)heterocyclic groups, and (5-9-membered)heteroaryl groups. R 3 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 -C(=O)NR b R c -P(=O)-R b R c -Si[(C1-C6)alkyl]3, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)ynyl, (C6-C 14 ) aryl, (5-12) heteroaryl, (3-12) heterocyclic and (C3-C 12 )cycloalkyl, wherein -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)ynyl, (C6-C 14 ) aryl, (5-12) heteroaryl, (3-12) heterocyclic and (C3-C 12 ) cycloalkyl groups are optionally surrounded by one or more R 31 Instead, the R b and R c Each is independently selected from hydrogen, halogen, -OH, -NH2, -(C1-C6)alkyl, -O(C1-C6)alkyl, -(C1-C6)haloalkyl, -C(=O)(C1-C6)alkyl, -S(=O)2(C1-C6)alkyl, (3-10-membered)heterocyclic groups, and (5-12-membered)heteroaryl groups. R 31 Each is independently selected from hydrogen, halogen, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)ynyl, 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 -C(=O)NR b R c -P(=O)-R b R c -Si[(C1-C6)alkyl]3, -(C1-C6)haloalkyl, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-NH2, -(C3-C9)cycloalkyl, -(C6-C 10 )aryl, (3-9)heterocyclic and (5-9)heteroaryl, wherein the (3-9)heterocyclic group is optionally substituted with one or more groups selected from hydrogen, -(C1-C4)alkyl and -C(=O)-O(C1-C4)alkyl, wherein R b and R c Each is independently selected from hydrogen, -OH, -NH2, halogen, -(C1-C6)alkyl, -O(C1-C6)alkyl, -(C1-C6)haloalkyl, -C(=O)(C1-C6)alkyl, -C(=O)O(C1-C6)alkyl, -S(=O)2(C1-C6)alkyl, -Si[(C1-C6)alkyl]3, -(C1-C4)alkylene-Si[(C1-C6)alkyl]3, (3-9-membered)heterocyclic groups and (5-9-membered)heteroaryl groups; R 4 Each is independently selected from hydrogen, halogen, nitro, nitroso, -CN, -OH, -O-(C1-C6)alkyl, -SH, -S(=O)-(C1-C6)alkyl, -S(=O)2-(C1-C6)alkyl, -NH2, -NH(C1-C6)alkyl, -N[(C1-C6)alkyl]2, -COOH, -C(=O)-(C1-C6)alkyl, -C(=O)NH(C1-C6)alkyl, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C2-C6)alkenyl, -(C2-C6)ynyl, -(C1-C4)alkylene-(3-12-membered)heterocyclic, -(C1-C4)alkylene-(C3-C 12 )cycloalkyl and -(C1-C4)alkylene-NH-(6-12-membered)heterocyclic groups, wherein -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C2-C6)alkenyl, -(C2-C6)ynyl, -(C1-C4)alkylene-(3-12-membered)heterocyclic groups, -(C1-C4)alkylene-(C3-C 12 The cycloalkyl and -(C1-C4)alkylene-NH-(6-12-membered) heterocyclic groups are optionally substituted with one or more groups selected from halogen, nitro, nitroso, -CN, -OH, -SH, -NH2, -NH(C1-C6)alkyl, -N[(C1-C6)alkyl]2, -(C1-C6)alkyl and (5-9-membered) heteroaryl groups, wherein the (5-9-membered) heteroaryl groups are optionally substituted with one or more groups selected from hydrogen, halogen and -(C1-C6)alkyl; R 5 Each is independently selected from hydrogen, halogen, nitro, nitroso, -CN, -OH, -SH, -NH2, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -O(C1-C6)alkyl, -NH(C1-C6)alkyl, -N[(C1-C6)alkyl]2 and (C3-C8)cycloalkyl.

2. The compound of claim 1, its pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystal form, isotope label, or metabolite form thereof, wherein, X is selected from O, S, N, NR 5 and CR 4 , where R 4 and R 5 As defined in claim 1 or this claim; Y is selected from O, S, N, NR 5 and CR 4 , where R 4 and R 5 As defined in claim 1 or this claim; M is O; T1 is selected from C(=O), C(=S) and S(=O)2; Structural unit Selected from Wherein X, Y, M, W, W1, and W2 are as defined in claim 1 or this claim. Preferably, structural unit Selected from Among them, X, Y, M, W, W1, W2, and R 4 As defined in claim 1 or this claim, Preferably, structural unit Selected from Where R 4 and R 5 As defined in claim 1 or this claim, R 4 Each is independently selected from hydrogen, halogen, nitro, nitroso, -CN, -OH, -SH, -NH2, -COOH, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C1-C4)alkylene-(4-10-membered)heterocyclic, -(C1-C4)alkylene-(C3-C8)cycloalkyl, and -(C1-C4)alkylene-NH-(6-10-membered)heterocyclic, wherein the -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C1-C4)alkylene-(4-10-membered) heterocyclic groups, -(C1-C4)alkylene-(C3-C8-membered)cycloalkyl groups, and -(C1-C4)alkylene-NH-(6-10-membered) heterocyclic groups are optionally substituted with one or more groups selected from halogens, nitro groups, -CN, -OH, -SH, -NH2, -(C1-C4)alkyl groups, and (5-6-membered) heteroaryl groups, wherein the (5-6-membered) heteroaryl groups are optionally substituted with one, two, or three -(C1-C4)alkyl groups. Preferably, R 4 Each group is independently selected from hydrogen, halogen, -(C1-C4)alkyl, -(C1-C4)haloalkyl, -(C1-C4)alkylene-(5-6-membered) heterocyclic group, and -(C1-C4)alkylene-NH-(6-9-membered) heterocyclic group, wherein the -(C1-C4)alkyl, -(C1-C4)haloalkyl, -(C1-C4)alkylene-(5-6-membered) heterocyclic group, and -(C1-C4)alkylene-NH-(6-9-membered) heterocyclic group are optionally substituted with 1, 2, 3, 4, or 5 groups selected from halogen, -OH, -NH2, -(C1-C4)alkyl, and (5-6-membered) heteroaryl groups, wherein the (5-6-membered) heteroaryl group is optionally substituted with 1, 2, or 3 methyl groups. Preferably, R 4 Each group is independently selected from hydrogen, -(C1-C4)alkyl, -(C1-C4)haloalkyl, -CH2-(5-6-membered)heterocyclic, and -CH2-NH-(6-9-membered)heterocyclic groups, wherein the -(C1-C4)alkyl, -(C1-C4)haloalkyl, -CH2-(5-6-membered)heterocyclic, and -CH2-NH-(6-9-membered)heterocyclic groups are optionally substituted with 1, 2, 3, 4, or 5 (5-6-membered)heteroaryl groups selected from halogens, -OH, -NH2, -(C1-C4)alkyl, and methyl, and wherein the (5-6-membered)heterocyclic and (5-6-membered)heteroaryl groups contain 1, 2, or 3 heteroatoms selected from N and O. Preferably, R 4 Each of the following is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, halomethyl, haloethyl, halon-propyl, haloisopropyl, -CH2-tetrahydropyrrolyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-morpholinyl and -CH2-NH-3-azabicyclo[3.2.1]octyl, wherein the methyl, ethyl, n-propyl, isopropyl, halomethyl, haloethyl, halon-propyl, haloisopropyl The propyl, -CH2-tetrahydropyrrolyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-morpholinyl, and -CH2-NH-3-azabicyclo[3.2.1]octyl groups are optionally substituted with 1, 2, 3, 4, or 5 groups selected from fluorine, chlorine, bromine, -OH, -NH2, methyl, imidazole, pyrazole, pyridazine, pyrimidine, pyrazine, methylimidazolium, methylpyrazole, methylpyridazine, methylpyrimidine, and methylpyrazine groups. Preferably, R 4 Each is independently selected from hydrogen, -CH3, -CHF2, -CH2CH3, R 5 Each is independently selected from hydrogen, halogen, nitro, -CN, -OH, -SH, -NH2, -(C1-C6)alkyl, and -(C1-C6)haloalkyl. Preferably, R 5 Each is independently selected from hydrogen, halogen, -OH, -NH2, and -(C1-C6)alkyl. Preferably, R 5 Each is independently selected from hydrogen and -(C1-C4)alkyl groups. Preferably, R 5 Each is independently selected from hydrogen, methyl, ethyl, and isopropyl, preferably, R 5 It is -CH3.

3. The compound of claim 1 or 2, its pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystal form, isotope label, or metabolite form thereof, wherein, L1 is selected from the key, -NR a -, -(C1-C4)alkylene-, -(C2-C4)alkenylene- and -(C2-C4)ynylene-, wherein R a Selected from hydrogen, -(C1-C4)alkyl, and -(C1-C4)haloalkyl; Preferably, L1 is selected from bond, -NR a -, -CH2-, -CH2CH2-, vinylidene, propenyne, ethynylidene, and propynylidene, wherein R a Selected from hydrogen and methyl; Preferably, L1 is selected from bonds, -NH-, -CH=CH- and 4. The compound according to any one of claims 1 to 3, its pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystal form, isotope label, or metabolite form thereof, wherein, R 1 Selected from hydrogen, (C 6- C 10 ) aryl, (5-10) heteroaryl, (4-10) heterocyclic and (C3-C 10 )cycloalkyl, the (C 6- C 10 ) aryl, (5-10) heteroaryl, (4-10) heterocyclic and (C3-C 10 ) cycloalkyl groups are optionally surrounded by one or more R 11 Instead, the R 11 As defined in claim 1 or this claim; Preferably, R 1 The R group is selected from hydrogen, phenyl, naphthyl, (5-9 quinary) heteroaryl, and (5-9 quinary) heterocyclic groups, wherein the (5-9 quinary) heteroaryl and (5-9 quinary) heterocyclic groups contain 1, 2, or 3 heteroatoms selected from N, O, and S, wherein the N and S atoms are optionally oxidized. 1 Choose any 1, 2, 3, 4 or 5 Rs 11 Instead, the R 11 As defined in claim 1 or this claim; Preferably, R 1 The alkyl group is selected from hydrogen, phenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, indolyl, benzimidazolyl, benzoxazolyl, 1,3-benzodioxonel, 2-benzozolinonel, 2-benzimidazolonel, piperidinyl, and 3-azabicyclo[3.2.1]octyl, wherein the phenyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, indolyl, benzimidazolyl, benzoxazolyl, 1,3-benzodioxonel, 2-benzozolinonel, 2-benzimidazolonel, piperidinyl, and 3-azabicyclo[3.2.1]octyl group is optionally surrounded by 1, 2, or 3 R... 11 Instead, the R 11 As defined in claim 1 or this claim; R 11 Each is independently selected from hydrogen, halogen, nitro, -CN, -OR b -SR b -NR b R c -COOH, -C(=O)-R b -C(=O)NR b R c -P(=O)-R b R c =O, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, -(C6-C 10 aryl, (3-9 quinary)heterocyclic and (5-9 quinary)heteroaryl, wherein the -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, -(C6-C 10 The aryl, (3-9 quinary)heterocyclic, and (5-9 quinary)heteroaryl groups are optionally substituted by 1, 2, 3, 4, or 5 groups independently selected from hydrogen, halogen, -OH, -SH, -NH2, -COOH, -O(C1-C4)alkyl, and -(C1-C4)alkyl groups, wherein 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, preferably, R b and R c Each is independently selected from hydrogen, methyl, methoxy, ethyl, and halomethyl. Preferably, R 11 Each group is independently selected from hydrogen, halogen, -CN, -OH, -O-(C1-C4)alkyl, -SH, -NH2, -COOH, -C(=O)NH2, -C(=O)NH-(C1-C4)alkyl, =O, -(C1-C4)alkyl, and (5-6-membered) heteroaryl groups, wherein the -O-(C1-C4)alkyl, -C(=O)NH-(C1-C4)alkyl, -(C1-C4)alkyl, and (5-6-membered) heteroaryl groups are optionally substituted by 1, 2, or 3 groups selected from hydrogen, halogen, -O(C1-C4)alkyl, and -(C1-C4)alkyl. Preferably, R 11 Each of the following groups is independently selected from hydrogen, -(C1-C4)alkyl, -O-(C1-C4)alkyl, -C(=O)NH2, =O, and (5-6-membered)heteroaryl, wherein the (5-6-membered)heteroaryl contains 1, 2, or 3 heteroatoms selected from N, O, and S, and the -(C1-C4)alkyl, -O-(C1-C4)alkyl, and (5-6-membered)heteroaryl groups are optionally substituted by 1, 2, or 3 groups selected from hydrogen, fluorine, chlorine, bromine, -CH3, -CH2CH3, and -OCH3. Preferably, R 11 Each is independently selected from hydrogen, -CH3, -OCH3, -C(=O)NH2, =O, Preferably, R 1 Selected from hydrogen, 5. The compound according to any one of claims 1 to 4, its pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystal form, isotope label, or metabolite form thereof, wherein, L2 is selected from -key, -O-, -S-, -NR a - and -(C1-C4)alkylene-, the R a Selected from hydrogen, -(C1-C4)alkyl, and -(C1-C4)haloalkyl; Preferably, L2 is selected from bond, -O-, -S-, -NR. a - and -(C1-C4)alkylene-, the R a Selected from hydrogen, methyl, and halomethyl; Preferably, L2 is selected from the following: -O-, -S-, -NH-, -N(CH3)-, -CH2-, -CH2CH2-, -CH(CH3)-, and -CH(CH2CH3)-. Preferably, L2 is selected from bond, -CH2- and -CH2CH2-.

6. The compound according to any one of claims 1 to 5, its pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystal form, isotope label, or metabolite form thereof, wherein, R 2 Selected from hydrogen, halogen, nitro, -CN, -OR b -SR b -S(=O)-R b -S(=O)2-R b -NR b R c -COOH, -C(=O)-R b -C(=O)NR b R c -P(=O)-R b R c -(C1-C6)alkyl, -(C6-C 10 )Aryl, (5-10 yuan)heteroaryl, (4-10 yuan)heterocyclic, (C3-C 10 )cycloalkyl and (C4-C 10 )cycloalkenyl, the -(C1-C6)alkyl, -(C6-C 10 )Aryl, (5-10 yuan)heteroaryl, (4-10 yuan)heterocyclic, (C3-C 10 )cycloalkyl and (C4-C 10 The cycloalkenyl group is optionally surrounded by one or more elements selected from hydrogen, halogen, nitro, -CN, -OH, -O-(C1-C4)alkyl, -SH, -S(=O)2-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -COOH, -C(=O)-(C1-C4)alkyl, -C(=O)O(C1-C4)alkyl, -C(=O)NH(C1-C4)alkyl, etc. The R group is substituted with alkyl, -P(=O)(OH)2, -P(=O)(OH)[O(C1-C4)alkyl], -P(=O)[(C1-C4)alkyl]2, -P(=O)[O(C1-C4)alkyl]2, -(C1-C4)alkyl, -(C1-C4)haloalkyl, -(C2-C4)alkenyl, -(C2-C4)ynyl, (C3-C7)cycloalkyl and (4-7)heterocyclic groups, wherein the R group is substituted with alkyl, -P(=O)(OH)2, -P(=O)(OH)[O(C1-C4)alkyl], -(C2-C4)alkenyl, -(C2-C4)ynyl, (C3-C7)cycloalkyl and (4-7)heterocyclic groups. b and R c Each is independently selected from hydrogen, -OH, -NH2, halogen, -(C1-C4)alkyl, -(C1-C4)haloalkyl, -O(C1-C4)alkyl, -C(=O)(C1-C4)alkyl and -S(=O)2(C1-C4)alkyl; Preferably, R 2 Selected from hydrogen, halogen, nitro, -CN, -OH, -O-(C1-C4)alkyl, -S(=O)2-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -C(=O)OH, -C(=O)(C1-C4)alkyl, -C(=O)O-(C1-C4)alkyl, -C(=O)NH-(C1-C4)alkyl, -(C1-C6)alkyl, (C3-C8)cycloalkyl, (C4-C 10 Cycloalkenyl, (4-10) heterocyclic, (5-10) heteroaryl, phenyl and naphthyl, wherein -(C1-C6)alkyl, (C3-C8)cycloalkyl, (C4-C6)cycloalkyl, (C4-C6)cycloalkyl, (C5 ... 10 The cycloalkenyl, (4-10) heterocyclic, (5-10) heteroaryl, phenyl and naphthyl groups may be optionally substituted with one or more groups selected from hydrogen, halogen, -OH, -O(C1-C4)alkyl, -S(=O)2(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -C(=O)OH, -C(=O)(C1-C4)alkyl, -C(=O)O(C1-C4)alkyl, -P(=O)(OH)2, -P(=O)[(C1-C4)alkyl]2, -(C1-C4)alkyl, -(C1-C4)haloalkyl, -(C2-C4)alkenyl, -(C2-C4)ynyl, (C3-C6)cycloalkyl and (4-6) heterocyclic groups; Preferably, R 2 Selected from hydrogen, halogens, -NH2, -C(=O)OH, -C(=O)O-(C1-C4)alkyl, -(C1-C4)alkyl, (C3-C6)cycloalkyl, (C6-C 10 )cycloalkenyl, (4-10-membered) heterocyclic, (5-10-membered) heteroaryl, phenyl and naphthyl, wherein the (4-10-membered) heterocyclic and (5-10-membered) heteroaryl contain 1, 2 or 3 heteroatoms selected from N, O and S, wherein the N and S atoms are optionally oxidized, wherein the -(C1-C4)alkyl, (C3-C6)cycloalkyl, (C6-C 10 The cycloalkenyl, (4-10) heterocyclic, (5-10) heteroaryl, phenyl, and naphthyl groups are optionally substituted with one or more groups selected from hydrogen, halogen, -OH, -OCH3, -OCH2CH3, -S(=O)2CH3, -S(=O)2CH2CH3, -NH2, -N(CH3)(CH2CH3), -N(CH2CH3)2, -NHCH3, -N(CH3)2, -C(=O)OH, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)OCH3, -C(=O)OCH2CH3, -P(=O)(OH)2, -P(=O)(CH3)2, -CH3, -CH2CH3, propyl, cyclopropyl, cyclobutyl, cyclopentyl, isopropyl, tert-butyl, trifluoromethyl, ethynyl, and tetrahydropyrrolyl groups; Preferably, R 2 Selected from hydrogen, halogen, -NH2, -C(=O)OH, -C(=O)O-(C1-C4)alkyl, -(C1-C4)alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, azacyclobutyl, tetrahydrofuranyl, tetrahydrothiophene, tetrahydropyranyl, tetrahydropyrroleyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, piperidinyl, pyrroleyl, pyridinyl, phenyl, naphthyl, pyrimidinyl, 1,3,5-triazinyl, 1,4-dioxanecyclol, piperazinyl, morpholinyl, thiomorpholinyl, indoleyl, indazoleyl, benzimidazolyl, 2,3-benzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, azaindoleyl, indoleyl The following groups are listed: benzothiazolyl, indanthenyl, benzothiopheneyl, pyridazinyl, benzocyclobutenyl, 1,2,3,4-tetrahydronaphthyl, dihydroprogesteroneyl, benzotriazolyl, 1,2,3-thiazolyl(1,5-A)pyridinyl, 2,3-diazanaphthyl, 4-azainzolyl, benzo[D]isothiazolyl, benzothiazolinyl, thiazo[5,4-C]pyridinyl, benzooxazolyl, and 1,2-benzonisooxazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, azacyclobutyl, tetrahydrofuranyl, tetrahydrothiapheneyl, tetrahydropyranyl, tetrahydropyrroleyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, piperidinyl, pyrroleyl, pyridinyl, phenyl, naphthyl, Pyrimidinyl, 1,3,5-triazinyl, 1,4-dioxaneyl, piperazinyl, morpholinyl, thiomorpholinyl, indoleyl, indazoleyl, benzimidazolyl, 2,3-benzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxolinyl, azaindolyl, indololinyl, benzothiazolyl, indanyl, benzothiaphenyl, pyridazinyl, benzocyclobutenyl, 1,2,3,4-tetrahydronaphthyl, dihydroprogesteroneyl, benzotriazolyl, 1,2,3-thiazolyl(1,5-A)pyridyl, 2,3-diazanaphthyl, 4-azainazolyl, benzo[D]isothiazolyl, benzothiazolinyl, thiazo[5,4-C]pyridyl, benzoxazolyl, and 1,2-benzoxazolyl may be selected by one or more of these groups. Substitution of groups from hydrogen, fluorine, chlorine, bromine, -OCH3, -OCH2CH3, -S(=O)2CH3, -S(=O)2CH2CH3, -NH2, -NH(CH3), -N(CH3)2, -N(CH3)(CH2CH3), -N(CH2CH3)2, -C(=O)OH, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)OCH3, -C(=O)OCH2CH3, -P(=O)(OH)2, -P(=O)(CH3)2, -CH3, -CH2CH3, propyl, cyclopropyl, cyclobutyl, cyclopentyl, isopropyl, tert-butyl, trifluoromethyl, ethynyl, and tetrahydropyrrolyl groups; Preferably, R 2 Selected from hydrogen, halogen, -NH2, -C(=O)OH, -C(=O)O-(C1-C4)alkyl, -(C1-C4)alkyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrroleyl, piperidinyl, pyrroleyl, pyridinyl, phenyl, indolyl, indazoleyl, benzimidazolyl, 2,3-benzofuranyl, quinolinyl, indololinyl, benzothiazolyl, indenyl, and benzothiaphenyl, wherein the cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrroleyl, piperidinyl, pyrroleyl, pyridinyl, phenyl, indolyl, indazoleyl, benzothiaphenyl The imidazolyl, 2,3-benzofuranyl, quinolinyl, indololinyl, benzothiazolyl, indanyl, and benzothiophene groups may be optionally substituted with one or more groups selected from hydrogen, fluorine, chlorine, bromine, -OCH3, -S(=O)2CH3, -NH2, -NH(CH3), -N(CH3)2, -C(=O)OH, -C(=O)OCH3, -P(=O)(OH)2, -P(=O)(CH3)2, -CH3, -CH2CH3, propyl, isopropyl, cyclopropyl, tert-butyl, trifluoromethyl, ethynyl, cyclobutyl, and tetrahydropyrrolyl groups; Preferably, R 2 Selected from hydrogen, -NH2, -CH3, -C(=O)OH, -C(=O)OCH3, 7. The compound according to any one of claims 1 to 6, its pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystal form, isotope label, or metabolite form thereof, wherein, R 3 Selected from hydrogen, halogen, nitro, -CN, -OR b -SR b -S(=O)-R b -S(=O)2-R b -NR b R c -COOH, -C(=O)-R b -C(=O)NR b R c -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)ynyl, (C6-C 10 ) aryl, (5-12) heteroaryl, (4-10) heterocyclic and (C3-C 10 )cycloalkyl, wherein -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)ynyl, (C6-C 10 ) aryl, (5-12) heteroaryl, (4-10) heterocyclic and (C3-C 10 ) cycloalkyl groups are optionally surrounded by one or more R 31 Instead, the R b and R c Each is independently selected from hydrogen, -OH, -NH2, halogen, -(C1-C6)alkyl, -O(C1-C6)alkyl, and -(C1-C6)haloalkyl, wherein R 31 As defined in claim 1 or this claim, Preferably, R 3 Selected from hydrogen, halogen, nitro, -CN, -OH, -O-(C1-C4)alkyl, -S(=O)2-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -COOH, -C(=O)-(C1-C4)alkyl, -C(=O)O-(C1-C4)alkyl, -C(=O)NH-(C1-C4)alkyl, -(C1-C4)alkyl, -(C2-C4)alkenyl, -(C2-C4)ynyl, (C6-C 10 aryl, (5-10 quinary)heteroaryl, (3-8 quinary)heterocyclic and (C3-C8)cycloalkyl, wherein -(C1-C4)alkyl, -(C2-C4)alkenyl, -(C2-C4)ynyl, (C6-C 10 aryl, (5-10 quinone) heteroaryl, (3-8 quinone) heterocyclic and (C3-C8) cycloalkyl groups are optionally surrounded by 1, 2, 3, 4 or 5 R groups. 31 Instead, the R 31 As defined in claim 1 or this claim; Preferably, R 3 Selected from hydrogen, -S(=O)2-(C1-C4)alkyl, -C(=O)-(C1-C4)alkyl, -C(=O)O-(C1-C4)alkyl, -(C1-C4)alkyl, -(C2-C4)alkenyl, (C6-C 10 aryl, (4-8) heterocyclic and (C3-C7) cycloalkyl, wherein -(C1-C4) alkyl, -(C2-C4) alkenyl, (C6-C 10 aryl, (4-8 quinone) heterocyclic and (C3-C7) cycloalkyl groups are optionally bounded by 1, 2 or 3 R groups. 31 Instead, the R 31 As defined in claim 1 or this claim; Preferably, R 3 The group is selected from hydrogen, -S(=O)2-(C1-C4)alkyl, -(C1-C4)alkyl, -(C2-C4)alkenyl, phenyl, (4-6-membered)heterocyclic and (C3-C5)cycloalkyl, wherein the (4-6-membered)heterocyclic contains one or two heteroatoms selected from N and O, and the -(C1-C4)alkyl, -(C2-C4)alkenyl, phenyl, (4-6-membered)heterocyclic and (C3-C5)cycloalkyl are optionally surrounded by one, two or three R atoms. 31 Instead, the R 31 As defined in claim 1 or this claim; Preferably, R 3 Selected from hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, propenyl, -S(=O)2CH2CH3, cyclopropyl, cyclobutyl, oxetyl, azirone, tetrahydropyranyl, and phenyl, wherein -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, propenyl, -S(=O)2CH2CH3, cyclopropyl, cyclobutyl, oxetyl, azirone, tetrahydropyranyl, and phenyl are optionally surrounded by 1, 2, or 3 R's. 31 Instead, the R 31 As defined in claim 1 or this claim; R 31 Each is independently selected from hydrogen, halogen, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)ynyl, nitro, -CN, -OR b -SR b -S(=O)-R b -S(=O)2-R b -NR b R c -NR b C(=O)-R c -COOH, -C(=O)-R b -C(=O)NR b R c -P(=O)-R b R c -Si[(C1-C6)alkyl]3, -(C1-C6)haloalkyl, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-NH2, -(C3-C9)cycloalkyl, -(C6-C 10 )aryl, (3-9)heterocyclic and (5-9)heteroaryl, wherein the (3-9)heterocyclic group is optionally substituted with one or more groups selected from hydrogen, -(C1-C6)alkyl and -C(=O)-O(C1-C4)alkyl, wherein R b and R c Each is independently selected from hydrogen, -OH, -NH2, halogen, -(C1-C4)alkyl, -O(C1-C4)alkyl, -(C1-C4)haloalkyl, -C(=O)(C1-C4)alkyl, -C(=O)O(C1-C4)alkyl, -Si[(C1-C4)alkyl]3 and -(C1-C4)alkylene-Si[(C1-C4)alkyl]3; Preferably, R 31 Each is independently selected from hydrogen, halogen, -(C1-C4)alkyl, -(C2-C4)alkenyl, -(C2-C4)ynyl, -CN, -OH, -O-Si[(C1-C4)alkyl]3, -O-(C1-C4)alkylene-Si[(C1-C4)alkyl]3, -S(=O)2-(C1-C4)alkyl, -NH2, -NR b (C1-C4)alkyl, -NR b C(=O)-(C1-C4)alkyl, -NR b C(=O)-O(C1-C4)alkyl, -COOH, -C(=O)-O(C1-C4)alkyl, -C(=O)NR b (C1-C4)alkyl, -P(=O)-(OR) b (OR) b ), -P(=O)-[(C1-C4)alkyl]2, -(C1-C4)haloalkyl, -(C3-C7)cycloalkyl, phenyl, (3-7-membered)heterocyclic and (5-6-membered)heteroaryl, wherein the (3-7-membered)heterocyclic is optionally substituted with one or more -C(=O)-O(C1-C4)alkyl, wherein R b Each is independently selected from hydrogen and -(C1-C4)alkyl; Preferably, R 31 Each is independently selected from hydrogen, halogen, -(C1-C4)alkyl, -(C2-C4)alkenyl, -(C2-C4)alkynyl, -OH, -O-Si[(C1-C4)alkyl]3, -O-(C1-C4)alkylene-Si[(C1-C4)alkyl]3, -S(=O)2-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -NHC(=O)-(C1-C4)alkyl, -NHC(=O)O(C1-C4)alkyl, -N[(C1-C4)alkyl]C(=O)O(C1-C4)alkyl, -COOH, -C(=O)-O( C1-C4)alkyl, -C(=O)NH(C1-C4)alkyl, -P(=O)-(OH)2, -P(=O)(OH)[O(C1-C4)alkyl], -P(=O)[O(C1-C4)alkyl]2, -P(=O)-[(C1-C4)alkyl]2, -(C3-C5)cycloalkyl, phenyl, (3-6-membered)heterocyclic and (5-6-membered)heteroaryl, wherein the (3-6-membered)heterocyclic and (5-6-membered)heteroaryl contain 1, 2 or 3 heteroatoms selected from N, O and S, wherein the N and S atoms are optionally oxidized, and the (3-6-membered)heterocyclic is optionally substituted with one -C(=O)-OCH(CH3)3; Preferably, R 31 Each is independently selected from hydrogen, halogen, -OH, methyl, ethyl, propyl, vinyl, propenyl, ethynyl, propynyl, -S(=O)2CH3, -S(=O)2CH2CH3, -NH2, -NHCH3, -N(CH3)2, -NHC(=O)CH3, -NHBoc, -N(CH3)Boc, -C(=O)OH, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)NHCH3, -C(=O)NHCH2CH3, -P(=O)(OH)2, -P(=O)(CH3)2, -P(=O)(OCH3)2, -P(=O)(OCH3)(OCH2CH3), -Boc, cyclopropyl, cyclobutyl, cyclopentyl, epoxyethyl, oxacyclobutyl, azacyclobutyl, tetrahydrofuranyl, tetrahydrothiophene, tetrahydropyrrolyl, tetrahydropyranyl, phenyl, oxazolyl, pyrazolyl, imidazolyl, isoxazolyl, piperidinyl, pyrrolyl, pyridinyl, pyrimidinyl, 1,4-dioxanecyclol, piperazine, morpholinyl, thiomorpholinyl Preferably, R 31 Each is independently selected from hydrogen, fluorine, chlorine, -OH, methyl, vinyl, ethynyl, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, -NHC(=O)CH3, -NHBoc, -N(CH3)Boc, -C(=O)OH, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)NHCH3, -P(=O)(OH)2, -P(=O)(CH3)2, -Boc, cyclopropyl, epoxyethyl, cyclobutyl, oxacyclobutyl, aziridine, tetrahydropyranyl, phenyl, oxazolyl, Preferably, R 3 Selected from hydrogen, -CH3, -CH2CH3, 8. The compound according to any one of claims 1 to 7, its pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystal form, isotope label, or metabolite form thereof, wherein, The compound is selected from the structure of formula (I-1). Among them, M, W, L1, L2, R 1 R 2 R 3 and R 4 As defined in any one of claims 1-7; Preferably, the compound is selected from the structure of formula (I-2). Among them, L2, R 2 R 3 and R 4 As defined in any one of claims 1-7; Preferably, L2 is selected from bonds, -O-, -S-, -NH- and -(C1-C4)alkylene-; Preferably, L2 is selected from bond, -CH2- and -CH2CH2-; Preferably, L2 is selected from the bond; Preferably, R 2 The group is selected from hydrogen, piperidinyl, pyrrolyl, pyridinyl, phenyl, indolyl, indazole, benzimidazolyl, 2,3-benzofuranyl, quinolinyl, indololinyl, benzothiazolyl, indanyl, and benzothiaphenyl, wherein the piperidinyl, pyrrolyl, pyridinyl, phenyl, indolyl, indazole, benzimidazolyl, 2,3-benzofuranyl, quinolinyl, indololinyl, benzothiazolyl, indanyl, and benzothiaphenyl are optionally substituted with one or more groups selected from hydrogen, fluorine, chlorine, bromine, -OCH3, -S(=O)2CH3, -NH2, -NH(CH3), -N(CH3)2, -C(=O)OH, -C(=O)OCH3, -P(=O)(OH)2, -P(=O)(CH3)2, -CH3, and -CH2CH3; Preferably, R 2 The group is selected from hydrogen, phenyl, (9-10)-membered heteroaryl, 9-membered heterocyclic and C9 cycloalkenyl, wherein the (9-10)-membered heteroaryl and 9-membered heterocyclic contain 1, 2 or 3 heteroatoms selected from N, O, S, and wherein the phenyl, (9-10)-membered heteroaryl, 9-membered heterocyclic and C9 cycloalkenyl are optionally substituted by one or more groups selected from hydrogen, halogen, -(C1-C4)alkyl and -O-(C1-C4)alkyl; Preferably, R 2 The group is selected from hydrogen, phenyl, indolyl, indazole, benzimidazolyl, 2,3-benzofuranyl, quinolinyl, indololinyl, benzothiazolyl, indanyl, and benzothiaphenyl, wherein the phenyl, indolyl, indazole, benzimidazolyl, 2,3-benzofuranyl, quinolinyl, indololinyl, benzothiazolyl, indanyl, and benzothiaphenyl are optionally substituted by one or more groups selected from hydrogen, fluorine, chlorine, bromine, -OCH3, -CH3, and -CH2CH3; Preferably, R 2 Selected from hydrogen, Preferably, R 2 Selected from Preferably, R 3 The group is selected from hydrogen, -(C1-C4)alkyl, -(C2-C4)alkenyl, phenyl, (4-6-membered)heterocyclic and (C3-C5)cycloalkyl, wherein the (4-6-membered)heterocyclic contains one or two heteroatoms selected from N and O, and the -(C1-C4)alkyl, phenyl, (4-6-membered)heterocyclic and (C3-C5)cycloalkyl are optionally surrounded by one, two or three R atoms. 31 Instead, the R 31 As defined in any one of claims 1-7 or as defined in this claim; Preferably, R 31 Each is independently selected from hydrogen, halogen, -OH, methyl, ethyl, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, -NHC(=O)CH3, -NHBoc, -C(=O)OH, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)NHCH3, -P(=O)(OH)2, -P(=O)(CH3)2, -Boc, cyclopropyl, cyclobutyl, cyclopentyl, epoxyethyl, oxacyclobutyl, aziridine, tetrahydrofuranyl, tetrahydrothiophene, tetrahydropyrrolyl, tetrahydropyranyl, oxazolyl, phenyl. Preferably, R 31 Each is independently selected from hydrogen, halogen, -OH, methyl, ethyl, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, -NHC(=O)CH3, -NHBoc, -C(=O)OH, -C(=O)OCH3, -C(=O)NHCH3, -P(=O)(OH)2, -P(=O)(CH3)2, -Boc, cyclopropyl, cyclobutyl, cyclopentyl, oxacyclobutyl, aziridine, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyrrolyl, tetrahydropyranyl, phenyl; Preferably, R 3 The group is selected from hydrogen, -(C1-C4)alkyl, -(C2-C4)alkenyl, aziridine, tetrahydropyranyl, and (C3-C5)cycloalkyl, wherein the -(C1-C4)alkyl, -(C2-C4)alkenyl, aziridine, tetrahydropyranyl, and (C3-C5)cycloalkyl are optionally surrounded by 1, 2, or 3 R's. 31 Instead, the R 31 As defined in any one of claims 1-7 or as defined in this claim; Preferably, R 3 Selected from hydrogen, -CH3, -CH2CH3, Preferably, R 3 Selected from hydrogen, -CH3 and Preferably, R 3 Selected from -(C1-C4)alkyl and -(C1-C4)alkylene-azacyclobutyl; Preferably, R 3 Selected from -CH3 and Preferably, R 4 Each of the groups is independently selected from hydrogen, -(C1-C4)alkyl, -(C1-C4)haloalkyl, and -CH2-(5-6-membered)heterocyclic groups, wherein the -(C1-C4)alkyl, -(C1-C4)haloalkyl, and -CH2-(5-6-membered)heterocyclic groups are optionally substituted with 1, 2, 3, 4, or 5 groups of (5-6-membered)heteroaryl groups selected from halogen, -OH, -NH2, -(C1-C4)alkyl, and methyl, and wherein the (5-6-membered)heterocyclic groups and (5-6-membered)heteroaryl groups contain 1, 2, or 3 heteroatoms selected from N and O; Preferably, R 4 Each is independently selected from hydrogen, -(C1-C4)alkyl, and -(C1-C4)haloalkyl; Preferably, R 4 Each is independently selected from methyl and halomethyl groups; Preferably, R 4 It is a methyl group.

9. The compound of any one of claims 1 to 8, its pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystal form, isotope label, or metabolite form thereof, wherein, The compound is selected from 10. A pharmaceutical composition comprising any one of the compounds of claims 1-9, a pharmaceutically acceptable salt thereof, a prodrug, a stereoisomer, a tautomer, a hydrate, a solvate, a crystal form, an isotope label, 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 of any one of claims 1-9, its pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, hydrate, solvate, crystal form, isotope label, or metabolite form thereof, or the pharmaceutical composition of claim 10, in the preparation of a medicament as a γ-secretase regulator; or, Use in the preparation of medicaments for the treatment and / or prevention of diseases associated with β-amyloid deposition (e.g., Alzheimer's disease, cerebral amyloid angiopathy, cochlear synapse disease, hearing loss, Dutch hemorrhage with amyloidosis, multiple infarct dementia, boxer's dementia, Down syndrome, mild cognitive impairment, memory loss, stroke, glaucoma, microglia, anosmia, brain inflammation, Aβ-amyloid angiopathy, neurodegeneration associated with Alzheimer's disease, attention deficit symptoms associated with Alzheimer's disease, diffuse Levy-body type Alzheimer's disease, senile dementia, mixed vascular dementia, degenerative dementia, early-onset Alzheimer's disease, dry age-related macular degeneration, etc.), preferably, wherein the disease associated with β-amyloid deposition is Alzheimer's disease; or, Used in the preparation of antitumor drugs, the tumors including but not limited to: breast cancer, melanoma, meningioma, soft tissue sarcoma, salivary gland tumors, spinal canal tumors, mediastinal tumors, brain cancer, bone cancer, penile cancer, osteosarcoma, intracranial tumors, tongue cancer, maxillary sinus cancer, thyroid cancer, malignant lymphoma, multiple myeloma, pituitary adenoma, testicular tumors, non-Hodgkin's lymphoma, bladder cancer, leukemia, gastric cancer, nasopharyngeal carcinoma, 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, and non-melanoma skin cancer (including squamous cell carcinoma and basal cell carcinoma). Cancer, 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.

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