WO2020048347A1

WO2020048347A1 - Aminopyrimido five-membered heterocyclic compound, and intermediate thereof, preparation method therefor, pharmaceutical composition thereof and application thereof

Info

Publication number: WO2020048347A1
Application number: PCT/CN2019/102678
Authority: WO
Inventors: 王玉光; 张农; 吴添智; 吴新亮
Original assignee: 上海再极医药科技有限公司
Priority date: 2018-09-04
Filing date: 2019-08-27
Publication date: 2020-03-12
Also published as: TW202024092A; CN110872297A; CN110872297B

Abstract

Disclosed by the present invention is an aminopyrimido five-membered heterocyclic compound as represented by formula I, and an intermediate thereof, a preparation method therefor, a pharmaceutical composition thereof and an application thereof. The aminopyrimido five-membered heterocyclic compound provided by the present invention has a significant antagonistic effect on adenosine A2A receptors, and may be used as an antagonist for adenosine A2A receptors to effectively relieve or treat immune tolerance, diseases of the central nervous system, inflammatory diseases and other related diseases.

Description

Aminopyrimido five-membered heterocyclic compound, intermediate thereof, preparation method, pharmaceutical composition and application

This application claims priority from Chinese patent application 2018110226731 with a filing date of 2018/9/4. This application cites the full text of the aforementioned Chinese patent application.

Technical field

The invention relates to an aminopyrimido five-membered heterocyclic compound, an intermediate thereof, a preparation method, a pharmaceutical composition and an application thereof.

Background technique

Immune regulation is an important means for the body to maintain a stable internal environment and resist harmful external stimuli. Adenosine, as an important transmitter and modulator of the body, will increase significantly during metabolic disorders and cell damage, activate adenosine receptors to exert biological effects, and participate in the body's immune regulation. Recent studies have shown that activation of adenosine A2A receptors can play an important role in immunoregulation during many pathological processes such as ischemia, hypoxia, inflammation, trauma, and transplantation. Nuclear macrophages, neutrophils, and other immune cells have higher expression levels (Su, Y., et.al., Cancer, Immunol, Immuno Ther., 2008, 57 (11), 1611-1623.). Adenosine A2A receptor is one of the four adenosine receptors (A1, A2A, A2B, and A3) currently known. It belongs to the G protein coupled receptor family and is mainly coupled to Gs and Gα proteins. It is widely distributed in the body, and is mainly expressed in the striatum in the central nervous system. A2A receptors are also expressed in the tissues of the heart, liver, lung, and kidney (Chu YY, et al., Biol, 1996, 15 (4), 329-337.).

Recent studies have found that adenosine A2A receptor antagonists play an increasingly important role in tumor immunotherapy. Under normal circumstances, the body can rely on a complete immune mechanism to effectively monitor and reject cancerous cells, such as: in terms of cellular immunity, T lymphocytes, antibody-dependent cytotoxic cells (K cells), NK cells and macrophages against tumors The cells are killing. However, if the cancerous cells themselves or the functions of the above-mentioned immune cells change, they may escape the body's immune system and form malignant hyperplasia to form tumors. The activation of adenosine A2A receptor can promote the body's immune tolerance, and closely participate in the formation of tumor cells' "immunity escape" or "immunosuppression", creating favorable conditions for tumorigenesis and development (Desai A., et al., Mol. Pharmacol., 2005, 67 (5), 1406-1413 .; Lokshin A., et al., Cancer Res, 2006, 66 (15), 7758-7765 .; Hoskin DW, et al., Int. J Oncol., 2008, 32 (3), 527-535 .; Deaglio S., et al., J. Exp. Med., 2007, 204 (6), 1257-1265.). The development of adenosine A2A receptor antagonists can inhibit the activation of adenosine A2A receptors, thereby preventing the body from developing immune tolerance, and ultimately affecting the growth of tumor cells, which has an anti-tumor effect.

Summary of the Invention

The technical problem to be solved by the present invention is to fill the current market blank of adenosine A2A receptor antagonist drugs, thereby providing an aminopyrimido five-membered heterocyclic compound, its intermediate, preparation method, pharmaceutical composition and application. The aminopyrimido five-membered heterocyclic compound provided by the invention has obvious antagonistic effect on adenosine A2A receptor, and it can be used as adenosine A2A receptor antagonist, which can effectively alleviate or treat immune tolerance, central nervous system disease and inflammatory Related diseases.

The present invention provides a compound represented by Formula I, which is a pharmaceutically acceptable salt, deuterate, tautomer, cis-trans isomer, enantiomer, diastereomer or Prodrugs:

among them,

Stands for single or double bond;

Represents a single key;

when

When it is a single bond, W is N or CR ⁵ ; R ⁵ is H, deuterium or methyl;

when

When it is a double bond, W is C, and the double bond is Z configuration, E configuration, or a mixture of Z configuration and E configuration;

X is O, CO or NR ³ ;

Y is CO, CH ₂ or NR ⁴ ;

R ¹ is a substituted or unsubstituted C ₆ -C ₂₀ aryl group or a substituted or unsubstituted 5-10 membered heteroaryl group;

When R ¹ is a substituted C ₆ -C ₂₀ aryl group or a substituted 5-10 membered heteroaryl group, the number of substituents is one or more, and each substituent is independently halogen or C ₁ -C ₁₀ alkyl;

R ² is a substituted or unsubstituted C ₆ -C ₂₀ aryl group or a substituted or unsubstituted 5-10 membered heteroaryl group;

When R ² is a substituted C ₆ -C ₂₀ aryl group or a substituted 5-10 membered heteroaryl group, the number of substituents is one or more, and each substituent is independently halogen, C ₁ -C ₁₀ Alkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ alkyl mercapto, halogen substituted C ₁ -C ₁₀ alkyl, oxo, hydroxyl, amino,

Cyano, halogen-substituted C ₁ -C ₁₀ alkoxy or halogen-substituted C ₁ -C ₁₀ alkylmercapto; wherein R ^a and R ^{b are} each independently hydrogen or C ₁ -C ₁₀ alkyl, R ^c is C _1- C ₁₀ alkyl;

R ³ is H, C ₁ -C ₁₀ alkyl or C ₃ -C ₁₀ cycloalkyl;

R ⁴ is H, C ₁ -C ₁₀ alkyl or C ₃ -C ₁₀ cycloalkyl;

The number of heteroatoms in the 5- to 10-membered heteroaryl group is 1, 2, 3, or 4, and each heteroatom is independently O, N, or S;

And, the compound represented by Formula I does not have any of the following structures:

In a preferred embodiment of the present invention, in the compound represented by formula I:

When X is O, Y is CO or CH ₂ ;

When X is CO, Y is NR ⁴ ;

When X is NR ³ , Y is CO.

In a preferred embodiment of the present invention, in the compound represented by formula I,

Is a double bond; X is O or NR ³ , and Y is CO.

Is a double bond

X is O or NR ³ , preferably NR ³ ;

Y is CO;

R ³ is H, C ₁ -C ₁₀ alkyl or C ₃ -C ₁₀ cycloalkyl;

R ¹ is a substituted or unsubstituted 5-10 membered heteroaryl group;

When R ¹ is a substituted 5-10 membered heteroaryl group, the number of substituents is one or more, and each substituent is independently halogen or C ₁ -C ₁₀ alkyl;

R ² is a substituted or unsubstituted C ₆ -C ₂₀ aryl group;

When R ² is a substituted C ₆ -C ₂₀ aryl group, the number of substituents is one or more, and each substituent is independently halogen, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy Radical, halogen-substituted C ₁ -C ₁₀ alkyl or halogen-substituted C ₁ -C ₁₀ alkoxy;

The number of heteroatoms in the 5-10 membered heteroaryl group is 1, 2, 3 or 4, and each heteroatom is independently O, N or S.

It is a double bond, and the double bond has an E configuration.

In the compound represented by formula I, when R ³ is C ₁ -C ₁₀ alkyl, the C ₁ -C ₁₀ alkyl may be C ₁ -C ₄ alkyl, such as methyl, ethyl Propyl, isopropyl or n-propyl, such as methyl, ethyl or n-propyl, preferably methyl.

In the compound represented by formula I, when R ³ is a C ₃ -C ₁₀ cycloalkyl group, the C ₃ -C ₁₀ cycloalkyl group may be a C ₃ -C ₆ cycloalkyl group, such as a cyclo Propyl.

In the compound represented by Formula I, when R ⁴ is C ₁ -C ₁₀ alkyl, the C ₁ -C ₁₀ alkyl may be C ₁ -C ₄ alkyl, such as methyl.

In the compound represented by formula I, when R ⁴ is a C ₃ -C ₁₀ cycloalkyl group, the C ₃ -C ₁₀ cycloalkyl group may be a C ₃ -C ₆ cycloalkyl group, such as a cyclo Propyl.

In a preferred embodiment of the present invention, in the compound represented by I,

for

In a preferred embodiment of the present invention, R ⁴ is H or C ₁ -C ₁₀ alkyl.

for

In some embodiments of the present invention, in the compound represented by I,

for

In the compound represented by formula I, when R ¹ is a substituted or unsubstituted C ₆ -C ₂₀ aryl group, the C ₆ -C ₂₀ aryl group may be a C ₆ -C ₁₀ aryl group, Such as phenyl.

In the compound represented by formula I, when R ¹ is a substituted or unsubstituted 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group may be a 5-membered heteroaryl group or a 6-membered Heteroaryl is preferably a 5-membered heteroaryl. The number of heteroatoms in the 5-10 membered heteroaryl group may be one or two. Examples of the 5-membered heteroaryl group are furyl (such as furan-2-yl), thiazolyl (such as thiazol-4-yl), and pyrazolyl (such as pyrazol-3-yl). The 6-membered heteroaryl group is, for example, pyridyl (such as pyridin-2-yl).

In the compound represented by the formula I, when R ¹ is a substituted C ₆ -C ₂₀ aryl group or a substituted 5-10 membered heteroaryl group, the number of the substituents may be 1, 2, 3 or Four, such as one or two, such as one.

In the compound represented by formula I, when R ¹ is a substituted C ₆ -C ₂₀ aryl group or a substituted 5-10 membered heteroaryl group, and the substituent is halogen, the halogen may be fluorine, Chlorine, bromine or iodine, such as chlorine or bromine (for example, chlorine).

In the compound represented by Formula I, when R ¹ is a substituted C ₆ -C ₂₀ aryl group or a substituted 5-10 membered heteroaryl group, and the substituent is a C ₁ -C ₁₀ alkyl group, The C ₁ -C ₁₀ alkyl may be a C ₁ -C ₄ alkyl, such as methyl.

In the compound represented by formula I, when R ² is a substituted or unsubstituted C ₆ -C ₂₀ aryl group, the C ₆ -C ₂₀ aryl group may be a C ₆ -C ₁₀ aryl group, Such as phenyl.

In the compound represented by formula I, when R ² is a substituted or unsubstituted 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group may be a 5 membered heteroaryl group or a 6 membered member Heteroaryl, such as 6-membered heteroaryl. The number of heteroatoms in the 5-10 membered heteroaryl group may be one or two. The 6-membered heteroaryl group is, for example, pyridyl (such as pyridin-4-yl).

In the compound represented by the formula I, when R ² is a substituted C ₆ -C ₂₀ aryl group or a substituted 5-10 membered heteroaryl group, the number of substituents may be 1, 2, 3 or Four, such as one or two.

In the compound represented by Formula I, when R ² is a substituted C ₆ -C ₂₀ aryl group or a substituted 5-10 membered heteroaryl group, and the substituent is halogen, the halogen may be fluorine, Chlorine, bromine or iodine, such as fluorine or chlorine (such as fluorine).

In the compound represented by formula I, when R ² is a substituted C ₆ -C ₂₀ aryl group or a substituted 5-10 membered heteroaryl group, and the substituent is a C ₁ -C ₁₀ alkyl group, The C ₁ -C ₁₀ alkyl may be a C ₁ -C ₄ alkyl, such as methyl.

In the compound represented by formula I, when R ² is a substituted C ₆ -C ₂₀ aryl group or a substituted 5-10 membered heteroaryl group, and the substituent is a C ₁ -C ₁₀ alkoxy group, The C ₁ -C ₁₀ alkoxy group may be a C ₁ -C ₄ alkoxy group, such as a methoxy group.

In the compound represented by the formula I, when R ² is a substituted C ₆ -C ₂₀ aryl group or a substituted 5-10 membered heteroaryl group, and the substituent is a C ₁ -C ₁₀ alkylthiol group, The C ₁ -C ₁₀ alkyl mercapto group may be a C ₁ -C ₄ alkyl mercapto group, such as methyl mercapto.

In the compound represented by formula I, when R ² is a substituted C ₆ -C ₂₀ aryl group or a substituted 5-10 membered heteroaryl group, and the substituent is a halogen substituted C ₁ -C ₁₀ alkyl group the "halogen-substituted C ₁ -C ₁₀ alkyl" C ₁ -C ₁₀ alkyl group may be a C ₁ -C ₄ alkyl such as methyl. The number of halogens in the "halogen-substituted C ₁ -C ₁₀ alkyl" may be 1-5, such as 1, 2 or 3; when the number of halogens is multiple, the halogen Same or different. The halogen in the "halogen-substituted C ₁ -C ₁₀ alkyl" may be fluorine, chlorine, bromine or iodine, such as fluorine. For example, the "halogen-substituted C ₁ -C ₁₀ alkyl group" may be -CF ₃ .

In the compound represented by formula I, when R ² is a substituted C ₆ -C ₂₀ aryl group or a substituted 5-10 membered heteroaryl group, the substituent is

R ^a and R ^b may each independently be hydrogen or C ₁ -C ₃ alkyl, such as

for

In this case, R ^c may be C ₁ -C ₄ alkyl, such as methyl.

In the compound represented by formula I, when R ² is a substituted C ₆ -C ₂₀ aryl group or a substituted 5-10 membered heteroaryl group, the substituent is a halogen-substituted C ₁ -C ₁₀ alkoxy group. when the "halogen-substituted C ₁ -C ₁₀ alkoxy" are C ₁ -C ₁₀ alkoxy group may be C ₁ -C ₄ alkoxy, such as methoxy. The number of halogens in the "halogen-substituted C ₁ -C ₁₀ alkoxy group" may be 1-5, such as 1, 2 or 3; when the number of halogens is multiple, the The halogens are the same or different. The halogen in the "halogen-substituted C ₁ -C ₁₀ alkoxy group" may be fluorine, chlorine, bromine or iodine, such as fluorine. For example, the "halogen-substituted C ₁ -C ₁₀ alkoxy group" may be -OCHF ₂ or -OCF ₃ .

In the compound represented by formula I, when R ² is a substituted C ₆ -C ₂₀ aryl group or a substituted 5-10 membered heteroaryl group, and the substituent is a halogen-substituted C ₁ -C ₁₀ alkylthiol group , in the "halogen-substituted C ₁ -C ₁₀ alkylmercapto," C ₁ -C ₁₀ alkylmercapto may be C ₁ -C ₄ alkylmercapto, for example methylmercapto. The number of halogens in the "halogen-substituted C ₁ -C ₁₀ alkylthiol group" may be 1-5, such as 1, 2 or 3; when the number of halogens is multiple, the halogen Same or different. The halogen in the "halogen-substituted C ₁ -C ₁₀ alkylthiol group" may be fluorine, chlorine, bromine or iodine, such as fluorine.

In a preferred embodiment of the present invention, in the compound represented by formula I, when R ² is a substituted C ₆ -C ₂₀ aryl group or a substituted 5-10 membered heteroaryl group, the substituent may be Halogen, C ₁ -C ₁₀ alkyl, halogen substituted C ₁ -C ₁₀ alkyl, oxo,

Cyano, or halogen-substituted C ₁ -C ₁₀ alkoxy.

In a preferred embodiment of the present invention, in the compound represented by formula I, when R ² is a substituted C ₆ -C ₂₀ aryl group or a substituted 5-10 membered heteroaryl group, the substituent is fluorine , Chlorine, methyl, -CF ₃ , oxo,

Cyano, -OCHF ₂ or -OCF ₃ .

In a preferred embodiment of the present invention, in the compound represented by formula I, R ¹ may be

Preferably

More preferably

In a preferred embodiment of the present invention, in the compound represented by formula I, R ² may be

Preferably

In a preferred embodiment of the present invention, in the compound represented by formula I, R ² is preferably

Wherein R ¹³ is H or halogen (for example, fluorine or chlorine, and also fluorine), R ¹¹ , R ¹² , R ¹⁴ and R ¹⁵ are each independently H, halogen (for example, fluorine or chlorine, and also fluorine), halogen-substituted C ₁ -C ₁₀ alkyl (for example -CF ₃ ) or halogen-substituted C ₁ -C ₁₀ alkoxy (for example -OCHF ₂ or -OCF ₃ ); said halogen, "halogen-substituted C ₁ -C ₁₀ The definitions of "alkyl" and "halogen-substituted C ₁ -C ₁₀ alkoxy" are as described in "Definition of Substitution in R ² above". More preferably, at least two of R ¹¹ , R ¹² , R ¹⁴ and R ¹⁵ are H.

X is NR ³ and Y is CO;

Is a double bond

R ³ is H, C ₁ -C ₁₀ alkyl or C ₃ -C ₁₀ cycloalkyl;

R ¹ is

R ² is

The definitions of R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are as described above. Preferably, R ¹¹ , R ¹² , R ¹⁴ and R ¹⁵ are each independently H, halogen or halogen-substituted C ₁ -C ₁₀ alkyl. Preferably, R ¹² and R ¹⁴ are each independently H or halogen. Preferably, R ¹¹ is H, halogen or halogen-substituted C ₁ -C ₁₀ alkyl, and R ¹⁵ is hydrogen. Preferably, R ¹¹ is hydrogen or halogen, and R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are all hydrogen. Preferably, R ¹¹ is halogen or halogen-substituted C ₁ -C ₁₀ alkyl, and R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are all hydrogen.

X is NR ³ and Y is CO;

Is a double bond

R ³ is H, C ₁ -C ₁₀ alkyl or C ₃ -C ₁₀ cycloalkyl;

R ¹ is

R ² is

The definitions of R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are as described above. Preferably, R ¹¹ , R ¹² , R ¹⁴ and R ¹⁵ are each independently H, halogen, halogen-substituted C ₁ -C ₁₀ alkyl or halogen-substituted C ₁ -C ₁₀ alkoxy. Preferably, R ¹² and R ¹⁴ are each independently H or halogen. Preferably, R ¹¹ is H, halogen, halogen-substituted C ₁ -C ₁₀ alkyl or halogen-substituted C ₁ -C ₁₀ alkoxy, and R ¹⁵ is hydrogen. Preferably, R ¹¹ is hydrogen or halogen, and R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are all hydrogen.

X is NR ³ and Y is CO;

Is a double bond

R ³ is methyl;

R ¹ is

R ² is

X is NR ³ and Y is CO;

Is a double bond

R ³ is C ₃ -C ₁₀ cycloalkyl (such as cyclopropyl);

R ¹ is

R ² is

The definitions of R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are as described above. Preferably, R ¹¹ , R ¹² , R ¹⁴ and R ¹⁵ are each independently H, halogen, halogen-substituted C ₁ -C ₁₀ alkyl or halogen-substituted C ₁ -C ₁₀ alkoxy. Preferably, R ¹² and R ¹⁴ are each independently H or halogen. Preferably, R ¹¹ is H, halogen, halogen-substituted C ₁ -C ₁₀ alkyl or halogen-substituted C ₁ -C ₁₀ alkoxy, and R ¹⁵ is hydrogen. Preferably, R ¹¹ is hydrogen, halogen or halogen-substituted C ₁ -C ₁₀ alkoxy, and R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are all hydrogen.

Preferably, the compound represented by formula I is selected from any one of the following structures:

The present invention also provides a method for preparing a compound represented by the formula I as described above, which comprises the following steps: in an organic solvent, the compound represented by the formula IA is subjected to an affinity reaction as shown below A nuclear substitution reaction to obtain the compound represented by formula I,

among them,

X, Y, W, R ¹ and R ² have the same definitions as above. X ¹ is a halogen (for example, F, Cl, Br, or I, and also Cl) or a C ₁ -C ₄ alkyl-substituted sulfone group ( (Eg, methylsulfone).

In the method for preparing the compound represented by Formula I, the conditions of the nucleophilic substitution reaction may be the conventional conditions for such reactions in the art. The present invention is preferably as follows: the organic solvent can be a conventional organic solvent for such reactions in the art, and an ether solvent is preferred. The ether-based solvent is preferably tetrahydrofuran. The amount of the organic solvent used is not particularly limited as long as it does not affect the progress of the reaction. The amination reagent may be a conventional amination reagent for such reactions in the art, preferably ammonia water or an alcohol solution of ammonia (for example, a methanol solution of ammonia). The molar concentration of the ammonia alcohol solution is preferably 5.0 mol / L to 10.0 mol / L (for example, 7.0 mol / L). The amount of the amination reagent may not be specifically limited, as long as it does not affect the progress of the reaction, and generally, it is a conventional amount of such reactions in the art. The temperature of the nucleophilic substitution may be a temperature conventional for such reactions in the art, for example, 10 ° C-40 ° C. The progress of the nucleophilic substitution reaction can be monitored by conventional detection methods in the art (such as TLC, HPLC, GC, or HNMR, etc.), and generally the end point of the reaction is when the compound represented by Formula I-A is no longer reacted.

After the nucleophilic substitution reaction is completed, it may further include a post-processing operation. The post-processing operation may be a conventional post-processing method in the field of organic synthesis. The present invention preferably includes the following steps: the reaction solution after the nucleophilic substitution reaction is completed, after performing solid-liquid separation (preferably concentrated under reduced pressure), and purified by column chromatography (column chromatography conditions can be routinely selected according to TLC conditions) .

The invention also provides a compound represented by formula I-A:

among them,

X, Y, W, R ¹ and R ² are as defined above; X ¹ is a halogen (e.g. F, Cl, Br or I, such as Cl) or a C ₁ -C ₄ alkyl-substituted sulfone group (e.g. Methylsulfone);

In addition, the compound represented by Formula I-A does not have any of the following structures:

The compound represented by formula I-A may be selected from any one of the following structures:

The method for preparing the compound represented by Formula IA may include the following steps: In an organic solvent, the compound represented by Formula IB and an oxidant are subjected to an oxidation reaction as shown below to obtain the compound represented by Formula IA. Shown compounds, that is;

among them,

X, Y, W, R ¹ and R ² have the same definitions as above. X ² is a C ₁ -C ₄ alkyl-substituted mercapto (such as methyl mercapto), and X ¹ is C ₁ -C ₄ alkyl-substituted. Sulfone (such as methylsulfone).

In the method for preparing a compound represented by Formula I-A, the conditions of the oxidation reaction may be conventional conditions for such reactions in the art. The present invention is preferably as follows: the organic solvent may be a conventional organic solvent for such reactions in the art, and a chlorinated hydrocarbon solvent is preferred. The chlorinated hydrocarbon solvent is preferably dichloromethane. The amount of the organic solvent used is not particularly limited as long as it does not affect the progress of the reaction. The oxidant may be a conventional oxidant of this type of reaction in the art, such as m-chloroperoxybenzoic acid. The amount of the oxidizing agent may not be specifically limited, as long as it does not affect the progress of the reaction, and generally, it is a conventional amount of such reactions in the art. The temperature of the nucleophilic substitution may be a temperature conventional for such reactions in the art, for example, 10 ° C-40 ° C. The progress of the nucleophilic substitution reaction can be monitored by conventional detection methods in the art (for example, TLC, HPLC, GC, HNMR, etc.), and generally the end point of the reaction is when the compound represented by Formula I-B is no longer reacted.

The method for preparing the compound represented by Formula IB may include the following steps: in an organic solvent, reacting the compound represented by Formula IC with R ² -CHO in the presence of a base to obtain the following: The compound represented by the formula IB is sufficient;

among them,

The definitions of X, Y, R ¹ , R ² and X ² are the same as described above, W is C,

Is a double bond.

In the method for preparing a compound represented by Formula IB, the reaction conditions may be conventional conditions for reactions of this type in the field of organic synthesis. The present invention is preferably as follows: the organic solvent may be a conventional organic solvent for such reactions in the art, preferably an alcoholic solvent (such as ethanol). The amount of the organic solvent used is not particularly limited as long as it does not affect the progress of the reaction. The base may be a base conventional for this type of reaction in the art, such as DBU (1,8-diazabicycloundec-7-ene). The amount of the base is a conventional amount for such reactions in the art. The ratio of the amount of the compound represented by Formula IC to R ² -CHO may be a conventional ratio of this type of reaction in the art. The reaction temperature may be a temperature conventional for such reactions in the art, for example, 50 ° C to 90 ° C. The progress of the reaction can be monitored by conventional detection methods in the art (such as TLC, HPLC, GC or HNMR, etc.), and generally the end point of the reaction is when the compound represented by Formula IC is no longer reacted.

In the present invention, the compound represented by the formula IB prepared by the method for preparing a compound represented by the formula IB as described above is generally a mixture of the Z configuration and the E configuration. However, when the structure of the compound represented by Formula IC and R ² -CHO are changed, the following situations may occur: the content of the E configuration and the Z configuration in the product is not much different; there may be some dominant configuration, and the product The contents of the E configuration and the Z configuration are quite different. The compounds of the Z configuration and the E configuration as shown in Formula IB can be separated by conventional separation methods in the art, such as silica gel column chromatography or preparative liquid chromatography. Alternatively, the mixture of the compounds represented by formula IB in the Z configuration and the E configuration can also be directly subjected to the next step of the reaction and left for subsequent steps for separation. When the content of the E configuration and the Z configuration in the product is relatively large, a product with a less content configuration can be obtained by enlarging the reaction amount.

In addition, the compound obtained by the above method can also refer to the related methods disclosed in the examples, and further modify the peripheral position to obtain other target compounds of the present invention.

The present invention also provides a pharmaceutical composition comprising the compound represented by Formula I as described above, a pharmaceutically acceptable salt, deuterate, tautomer, cis-trans isomer, enantiomer Isomers, diastereomers or prodrugs, and pharmaceutically acceptable carriers. Preferably, in the pharmaceutical composition, the compound represented by Formula I, its pharmaceutically acceptable salt, deuterate, tautomer, cis-trans isomer, enantiomer The content of diastereomers or prodrugs is a therapeutically effective amount.

The present invention also provides a compound represented by formula I, which is a pharmaceutically acceptable salt, deuterate, tautomer, cis-trans isomer, enantiomer, diastereomer Isomers or prodrugs, or the pharmaceutical composition, for use in the preparation of adenosine A2A receptor antagonists.

The present invention also provides a method for inhibiting adenosine A2A receptor, which comprises an effective amount of said compound represented by formula I, a pharmaceutically acceptable salt thereof, a deuterate, a tautomer, A cis-trans isomer, an enantiomer, a diastereomer or a prodrug, or the pharmaceutical composition is contacted with an adenosine A2A receptor, and the contact is performed in vivo or in vitro.

The present invention also provides a compound represented by formula I, which is a pharmaceutically acceptable salt, deuterate, tautomer, cis-trans isomer, enantiomer, diastereomer Isomers or prodrugs, or the use of said pharmaceutical composition in the manufacture of a medicament for the prevention, alleviation and / or treatment of related diseases caused by adenosine A2A receptors.

The present invention also provides a method for preventing, alleviating and / or treating related diseases caused by adenosine A2A receptor, which comprises administering to a patient in need thereof a therapeutically effective amount of said compound represented by formula I , Pharmaceutically acceptable salts, deuterates, tautomers, cis-trans isomers, enantiomers, diastereomers or prodrugs thereof, or said pharmaceutical composition.

The related diseases caused by the adenosine A2A receptor include central nervous system diseases, immune tolerance diseases, and inflammatory diseases.

The present invention also provides a compound represented by formula I, which is a pharmaceutically acceptable salt, deuterate, tautomer, cis-trans isomer, enantiomer, diastereomer Isomers or prodrugs, or the use of said pharmaceutical composition in the preparation of a medicament for the prevention, alleviation and / or treatment of central nervous system diseases, immune tolerance diseases or inflammatory diseases.

The present invention also provides a method for preventing, relieving and / or treating central nervous system disease, immune tolerance disease or inflammatory disease, which comprises administering a therapeutically effective amount of said formula I to a patient in need thereof. The compound shown, its pharmaceutically acceptable salt, deuterate, tautomer, cis-trans isomer, enantiomer, diastereomer or prodrug, or said drug combination.

The central nervous system diseases include Parkinson's disease, Alzheimer's disease, depression, schizophrenia, epilepsy and Huntington's disease.

The immune tolerance diseases include organ transplant rejection and tumor. The tumors include bone marrow fibrosis, hematomas (such as leukemia, lymphoma, etc.) and solid tumors (such as kidney cancer, liver cancer, stomach cancer, lung cancer, breast cancer, prostate cancer, pancreatic cancer, thyroid cancer, ovarian cancer, glia). Blastoma, skin cancer, melanoma, etc.).

The inflammatory diseases include acute inflammatory diseases such as pneumonia, hepatitis, nephritis, myocarditis, and sepsis, and chronic inflammatory diseases such as arthritis, asthma, and atherosclerosis.

The pharmaceutical composition described in the present invention may be in a form suitable for oral administration or in the form of a sterile injectable aqueous solution, and the oral or injectable composition may be prepared according to any method known in the art for preparing a pharmaceutical composition.

The pharmaceutical composition described in the present invention can be used in combination with one or more chemotherapeutic drugs and / or targeted drugs used clinically, which can be made into a single dosage form, especially a lipid, in any suitable ratio according to the conventional methods in the art. Liposomal dosage form to treat various tumor diseases.

Unless otherwise stated, the following terms appearing in the description and claims of the present invention have the following meanings:

The term "alkyl" (including when used alone and when contained in other groups) refers to branched and straight-chain saturated aliphatic hydrocarbon groups including 1-20 carbon atoms (preferably 1-10 carbon atoms, more preferably 1- 8 carbon atoms), such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, 4,4-dimethylpentyl, 2,2,4-trimethylpentyl, undecyl, dodecyl, and various isomers thereof.

The term "cycloalkyl" (including when used alone and in other groups) refers to the inclusion of saturated or partially unsaturated (containing 1 or 2 double bonds, but none of which has a fully conjugated π-electron system) 1, 2 or 3 ring cyclic hydrocarbon groups, including monocyclic alkyl, bicycloalkyl, and tricyclic alkyl groups, which contain 3-20 ring-forming carbons, preferably 3-10 carbons, For example: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecane, cyclododecyl, cyclohexenyl and the like.

The term "aryl" (including when used alone and contained in other groups) refers to any stable monocyclic or bicyclic carbocyclic ring that can be up to 7 atoms in each ring, at least one of which is an aromatic ring. Examples of the above-mentioned aryl units include phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydroindenyl, biphenyl, phenanthryl, anthracenyl, or acenaphthyl. It can be understood that in the case where the aryl substituent is a bicyclic substituent and one of the rings is a non-aromatic ring, the connection is performed through the aromatic ring.

The term "heteroaryl" (including when used alone and contained in other groups) means a stable monocyclic or bicyclic ring of up to 7 atoms in each ring, at least one of which is an aromatic ring and contains 1, 2, 3 Or 4 heteroatoms selected from O, N and S. For example: when heteroaryl is a 5-membered heteroaryl containing 1 heteroatom, including furyl, thienyl, and pyrrolyl; when heteroaryl is a 5-membered heteroaryl containing 2 heteroatoms, including pyr Oxazolyl, thiazolyl, and oxazolyl. Heteroaryl groups within the scope of this definition include, but are not limited to: acridinyl, carbazolyl, fluorinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thienyl , Benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, Tetrahydroquinoline. As defined above for "heterocycloalkyl", "heteroaryl" should also be understood to include N-oxide derivatives of any nitrogen-containing heteroaryl. In the case where the heteroaryl substituent is a bicyclic substituent and one ring is a non-aromatic ring or does not contain a heteroatom, it can be understood that the connection is performed through an aromatic ring or a heteroatom containing a ring, respectively.

The term "alkoxy" (including when used alone and contained in other groups) means a cyclic or acyclic alkyl group having the stated number of carbon atoms connected by an oxygen bridge. Thus, "alkoxy" includes the above definitions of alkyl and cycloalkyl.

The term "oxo" refers to a case where an oxygen atom is directly substituted for a carbon atom or a nitrogen atom, for example, a carbonyl group is formed with a carbon atom, and a nitrogen oxide is formed with a nitrogen atom.

The term "halogen" means fluorine, chlorine, bromine, iodine, or astatine.

The term "hydroxy" means -OH.

The term "amino" means -NH _2.

The term "alkylmercapto" means -S-alkyl.

The term "cyano" means -CN.

The term "therapeutically effective amount" as used herein refers to an amount of a compound sufficient to effectively treat a disease or disorder described herein when administered to a subject. Although the amount of a compound that constitutes a "therapeutically effective amount" will vary depending on the compound, the disorder and its severity, and the age of the subject to be treated, it can be determined in a conventional manner by one skilled in the art.

As used herein, when referring to a "pharmaceutically acceptable" specific salt, pharmaceutical composition, composition, excipient, etc., it means that the salt, pharmaceutical composition, composition, excipient, etc. is generally non-toxic, safe, and Suitable for use by a subject, preferably a mammalian subject, and more preferably a human subject.

The term "pharmaceutically acceptable salt" as used herein refers to a pharmaceutically acceptable organic or inorganic salt of a compound of the invention. Exemplary salts include, but are not limited to: sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, hydrogen sulfate, phosphate, acid phosphate, isonicotinic acid Salt, lactate, salicylate, acid citrate, tartrate, oleate, tannin, pantothenate, tartrate, ascorbate, succinate, maleate, dragon Genisinate, fumarate, gluconate, glucuronide, gluconate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonic acid Salts, benzenesulfonates, p-toluenesulfonates and parabens (ie 1-methylene-bis (2-hydroxy-3-naphthoate)).

The term "prodrug" as used herein refers to a derivative of a compound containing a biologically reactive functional group such that under biological conditions (in vitro or in vivo), the biologically reactive functional group can be cleaved from the compound or otherwise react to provide the Mentioned compound. Generally, a prodrug is inactive, or at least less active than the compound itself, so that its activity cannot be exerted until the compound is cleaved from a biologically reactive functional group. Bioreactive functional groups can be hydrolyzed or oxidized under biological conditions to provide the compounds. For example, a prodrug may include a biohydrolyzable group. Examples of biohydrolyzable groups include, but are not limited to, biohydrolyzable phosphates, biohydrolyzable esters, biohydrolyzable amides, biohydrolyzable carbonates, biohydrolyzable carbamates, and biohydrolyzable Ureide.

Compounds of the invention may contain one or more asymmetric centers ("stereoisomers"). As used herein, the term "stereoisomers" refers to the cis- (Z) and trans-isomers (E), R- and S-enantiomers and diastereomers. These stereoisomers can be prepared by asymmetric synthesis or chiral separation (for example, separation, crystallization, thin-layer chromatography, column chromatography, gas chromatography, high-performance liquid chromatography). These stereoisomers may also be derived from diastereomers in which a mixture of enantiomers or racemates is reacted with an appropriate chiral compound, and then obtained by crystallization or any other suitable conventional method.

In the present invention, the term "deuterate" means that the abundance of deuterium in a certain (or some) hydrogen atom in a molecule is greater than its natural abundance, up to 100%. Deuterates can generally retain the activity equivalent to undeuterated compounds, and can achieve better metabolic stability when deuterated at certain sites, thereby obtaining certain therapeutic advantages (such as increased half-life in the body or reduced dose requirements) ), So deuterates are preferred in some cases. The deuterated product of the present invention can generally be prepared by using a suitable deuterated reagent instead of a non-deuterated reagent according to the preparation method described in the present invention or the method disclosed in the examples.

In the present invention, the

Represents a single bond, and the configuration of the connected double bond is the Z configuration, the E configuration, or a mixture thereof.

In the present invention, room temperature means 10-40 ° C.

On the basis of not violating common knowledge in the art, the above-mentioned various preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

The reagents and raw materials used in the present invention are all commercially available.

The positive progress effect of the present invention lies in:

The compounds of the present invention have obvious antagonistic effects on adenosine A2A receptors, and can be used as adenosine A2A receptor antagonists to effectively alleviate or treat related diseases such as immune tolerance, central nervous system diseases, and inflammatory diseases.

detailed description

The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods without specific conditions specified in the following examples were selected according to conventional methods and conditions, or according to product specifications.

The structure of the compound was determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). The nuclear magnetic resonance spectrum was obtained by Bruker Avance-500 instrument. Deuterated dimethyl sulfoxide, deuterated chloroform and deuterated methanol were used as solvents. Tetramethyl Silane (TMS) is the internal standard. Mass spectra were obtained by a liquid chromatography-mass spectrometer (LC-MS) Agilent 6110, using an ESI ion source.

The microwave reaction was performed in an Explorer full-automatic microwave synthesizer produced by CEM Corporation in the United States. The magnetron frequency was 2450 MHz and the continuous microwave output power was 300 W.

The instrument used for HPLC preparation was Gilson 281, and the preparative column used was Xbridge, 21.2x250mm C18, 10 μm.

Example 1: 2-amino-7- (2-fluorobenzyl) -4- (furan-2-yl) -5H, 7H-furan [3,4-d] pyrimidin-5-one (Compound 1)

synthetic route

Synthesis of compound 1-c

Add 2,4-dichloro-6-methyl-pyrimidine-5-carboxylic acid methyl ester (940 mg, 4.25 mmol), 2-furyltributylstannane (1.42 g, 4.0 mmol), tetrakis (triphenyl) phosphine palladium (260 mg, 0.22 mmol), and a mixture of tetrahydrofuran (30 mL) were stirred under nitrogen at 60 ° C for 16 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / dichloromethane = 3/1) to obtain 1-c (870 mg, yield: 81%) as a white solid.

LC-MS (ESI): m / z = 253 [M + H] ⁺ .

Synthesis of compound 1-b

A mixture of compound 1-c (800 mg, 3.2 mmol), selenium dioxide (880 mg, 8.0 mmol) and dioxane (20 mL) was heated at reflux for 8 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane) to obtain compound 1-b (280 mg. Yield: 33%).

LC-MS (ESI): m / z = 267 [M + H] ⁺ .

Synthesis of compound 1-a

Under a nitrogen atmosphere, a 0.5 M solution of o-fluorobenzyl zinc bromide in tetrahydrofuran (4.0 mL, 2.0 mmol) was added to a 10 ml solution of compound 1-b (267 mg, 1.0 mmol) in tetrahydrofuran. The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5/1) to obtain compound 1-a (220 mg, yield: 64%). LC-MS (ESI): m / z = 345 [M + H] ⁺ .

Synthesis of compound 1

A 7.0 M ammonia methanol solution (2 mL) was added to a tetrahydrofuran (10 mL) solution of compound 1-a (60 mg, 0.17 mmol), and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain compound 1 (35 mg, yield: 63%). LC-MS (ESI): m / z = 326 [M + H] ⁺ .

¹ H-NMR (500MHz, CDCl ₃ ) δ: 8.55 (d, 1H, J = 8.5Hz), 7.71 (d, 1H, J = 1.0Hz), 7.29-7.32 (m, 1H), 7.21-7.24 (m , 1H), 7.07-7.10 (m, 1H), 7.02-7.06 (m, 1H), 6.65 (dd, 1H, J = 3.5Hz, 1.5Hz), 5.88 (brs, 2H), 5.41 (dd, 1H, J = 8.0 Hz, 3.5 Hz), 3.57 (dd, 1H, J = 14.5 Hz, 3.5 Hz), 3.00 (dd, 1H, J = 14.5 Hz, 8.5 Hz) ppm

Example 2: 2-amino-7- (4-chloro-2-fluorobenzyl) -4- (furan-2-yl) -5H, 7H-furan [3,4-d] pyrimidin-5-one (Compound 2)

synthetic route

Synthesis of compound 2-f

Furfural (9.6g, 0.1mol), O-methylisourea sulfate (20.64g, 0.12mol) and ethyl acetoacetate (14.3g, 0.11mol) were dissolved in anhydrous N, N-dimethylformamide (200 mL), to the solution was added sodium bicarbonate (33.6 g, 0.4 mmol). The reaction mixture was heated to 70 ° C under a nitrogen atmosphere, stirred for 3 hours, and then cooled to room temperature. Saturated brine (300 mL) was added, and a large amount of yellow suspension appeared, and extracted with ethyl acetate (500 mL × 2). The organic phases were combined, washed with water (200 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and reduced pressure After concentration, the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 6-3: 1) to obtain 2-f (15.0 g, yield: 57%) as a pale yellow solid. LC-MS (ESI): m / z = 265.1 [M + H] ⁺ .

Synthesis of compound 2-e

Compound 2-f (14.0 g, 53 mmol) was dissolved in dichloromethane (200 mL), and 2,3-dichloro-5,6-dicyano-p-benzoquinone (12.0 g, 53.0 mmol) was added under stirring at room temperature. The reaction mixture was stirred overnight. The reaction mixture was filtered, and the filter cake was washed with dichloromethane (50 mL). The filtrates were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5-2: 1) to obtain pale yellow crystals 2 -e (8.5 g, yield: 61%). LC-MS (ESI): m / z = 263.0 [M + H] ⁺ .

Synthesis of compound 2-d

Compound 2-e (1.31g, 5.0mmol) was dissolved in dioxane (30mL), selenium dioxide (1.11g, 10.0mmol) and glacial acetic acid (2mL) were added at room temperature, and the mixture was heated to 120 ° C. And stirred for 10 hours. After cooling to room temperature, concentration under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 6-2: 1) to obtain 2-d (450 mg, yield: 33%) as a pink solid. LC-MS (ESI): m / z = 277.0 [M + H] ⁺ .

Synthesis of compound 2-c

To a 100 ml three-necked flask were added 2-d (140 mg, 0.5 mmol), 2-fluoro-4-chlorobenzyl bromide (450 mg, 2.0 mmol), zinc powder (130 mg, 2.0 mmol), and dry tetrahydrofuran (10 mL). The mixture was reacted at 55 ° C for 2 hours under nitrogen. After the reaction mixture was cooled to room temperature, a saturated aqueous solution of ammonium chloride (20 mL) was added. It was extracted with ethyl acetate (30 mL x 3), washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8: 1) to obtain 2-c (160 mg, yield: 86%) as a white solid product.

LC-MS (ESI): m / z = 375 [M + H] ⁺ .

Synthesis of compound 2-b

To a 100 ml single-necked flask were added 2-c (160 mg, 0.42 mmol), lithium iodide (374 mg, 2.81 mmol), and pyridine (8 mL). The mixture was refluxed under nitrogen for 5 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 30: 1) to obtain 2-b (138 mg, yield: 86%) as a white solid.

LC-MS (ESI): m / z = 361 [M + H] ⁺ .

Synthesis of compound 2-a

To a 25 ml single-necked flask was added 2-b (100 mg, 0.28 mmol) and phosphorus oxychloride (3 mL). The mixture was refluxed under nitrogen for 2 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate (20 mL), washed with ice water (20 mL) and saturated brine (20 mL), and dried over anhydrous sodium sulfate. It was concentrated under reduced pressure, and the obtained solid crude product 2-a was directly used in the next reaction.

Synthesis of compound 2

Compound 2-a was dissolved in tetrahydrofuran (5 mL), and a 7.0 M ammonia solution in methanol (2 mL, 14 mmol) was added. The mixture was stirred for 1 hour at room temperature. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 1) to obtain a pale yellow solid product 2 (15 mg, two-step yield: 14.8%.).

LC-MS (ESI): m / z = 360 [M + H] ⁺ .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ: 8.27 (d, J = 3.5 Hz, 1 H), 8.09 (s, br., 1 H), 8.03 (d, J = 1.0 Hz, 1 H), 7.94 (s , br., 1H), 7.42 (dd, J = 2.0 Hz, 10.0 Hz, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.26 (dd, J = 2.0 Hz, 8.5 Hz, 1H), 6.77 (dd, J = 2.0 Hz, 3.5 Hz, 1H), 5.53 (dd, J = 3.5 Hz, 8.5 Hz, 1H), 3.39 (dd, J = 3.5 Hz, 15.0 Hz, 1H), 3.01 (dd, J = (8.5Hz, 15.0Hz, 1H) ppm

Example 3: 4-{[2-amino-4- (furan-2-yl) -5-oxo-5H, 7H-furan [3,4-d] pyrimidin-7-yl] methyl-2 -Fluorobenzonitrile (Compound 3)

Using 2-d and 2-fluoro-4-cyanobenzyl bromide as raw materials, the synthesis method is the same as in Example 2.

LC-MS (ESI): m / z = 351 [M + H] ⁺ .

¹ H NMR (500MHz, d ₆ -DMSO) δ: 8.27 (d, J = 3.5 Hz, 1H), 8.11 (brs, 1H), 8.03 (s, 1H), 7.92 (brs, 1H), 7.89 (t, J = 7.5Hz, 1H), 7.50 (d, J = 10.0Hz, 1H), 7.34 (d, J = 8.0Hz, 1H), 6.78 (dd, J = 1.5Hz, 3.5Hz, 1H), 5.67 (dd , J = 3.5Hz, 8.5Hz, 1H), 3.45 (dd, J = 3.5Hz, 15.0Hz, 1H), 3.14 (dd, J = 8.5Hz, 15.0Hz, 1H) ppm.

Example 4: 4-{[2-amino-4- (furan-2-yl) -5-oxo-5H, 7H-furan [3,4-d] pyrimidin-7-yl] methylbenzoyl Nitrile (Compound 4)

The compound 2-d and 4-cyanobenzyl bromide were used as raw materials, and the synthesis method was the same as that in Example 2.

LC-MS (ESI): m / z = 333 [M + 1] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ ) δ: 8.51-8.49 (d, J = 2.8Hz, 1H), 7.71 (s, 1H), 7.57-7.55 (d, J = 6.8Hz, 2H), 7.38-7.26 (d, J = 6.8Hz, 2H), 6.65-6.64 (m, 1H), 5.40-5.38 (m, 1H), 3.54-3.50 (m, 1H), 3.18-3.14 (m, 1H) ppm

Example 5: 2-amino-7-benzyl-4- (furan-2-yl) -5H, 7H-furan [3,4-d] pyrimidin-5-one (compound 5)

Synthesis of compound 5-c

At room temperature, compound 2-d (450 mg, 1.63 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). To the reaction solution was added dropwise a 1.0 M solution of benzylmagnesium bromide in tetrahydrofuran (1.95 mL, 1.95 mmol) at -78 ° C under the protection of nitrogen. After the dropwise addition was complete, the cooling device was removed, the reaction system was allowed to slowly rise to room temperature, and stirring was continued for 16 hours. A saturated ammonium chloride solution (20 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with water (30 mL) and saturated brine (20 mL), and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 6-3: 1) to obtain 5-c (320 mg, yield: 61%) as a colorless viscous substance.

LC-MS (ESI): m / z = 323.0 [M + H] ⁺ .

Synthesis of compound 5

Using compound 5-c as a raw material, the steps for synthesizing compound 5 are the same as in Example 2.

LC-MS (ESI): m / z = 308.0 [M + H] ⁺ .

¹ H-NMR: (400MHz, CD ₃ OD) δ: 8.54 (d, J = 2.4Hz, 1H), 7.71 (s, 1H), 7.30-7.20 (m, 5H), 6.66-6.64 (dd, J ₁ = 2.0Hz, J ₂ = 2.8Hz, 1H), 5.87 (s, br., 2H), 5.42-5.40 (dd, J ₁ = 3.2 Hz, J ₂ = 6.0 Hz, 1H), 3.51-3.47 (dd, J ₁ = 2.4 Hz, J ₂ = 10.4 Hz, 1H), 3.14-3.09 (dd, J ₁ = 2.4 Hz, J ₂ = 11.6 Hz, 1H) ppm.

Example 6: (R) -7-Benzyl-4- (furan-2-yl) -5,7-dihydrofuran [3,4-d] pyrimidin-2-amine (Compound 6)

synthetic route

Synthesis of compound 6-f

Sodium hydride (480 mg, 12 mmol) was suspended in anhydrous tetrahydrofuran (20 mL), and (S) -3-phenyl-2-hydroxypropionic acid (1.08 g, 6 mmol) was added dropwise at 0 ° C. After the addition was completed, stirring was continued at 0 ° C for 30 minutes, and then methyl acrylate (0.74 g, 9 mmol) was added. Stirring was continued for 3 hours at room temperature, and 0.5 M hydrochloric acid (30 mL) was added to quench the reaction. Ethyl acetate (30 mL x 3) was extracted. The organic phases were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain 6-f (600 mg, yield: 43%) as a colorless liquid product.

Synthesis of compound 6-e

To a solution of compound 6-f (600 mg, 2.56 mmol) in ethanol (20 mL) was added urea (460 mg, 7.68 mmol) and 35% concentrated hydrochloric acid (0.5 mL). After heating and refluxing for 4 hours, it was cooled to room temperature and decompressed. After concentration, the residue was added with ethyl acetate (40 mL), followed by washing with water (40 mL) and saturated brine (40 mL) in this order, and drying over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 2) to obtain 6-e (320 mg, yield: 45%) as a pale yellow solid.

LC-MS (ESI): m / z = 277 [M + 1] ⁺ .

Synthesis of compound 6-d

Compound 6-e (320 mg, 1.16 mmol) was dissolved in a solution of ethanol (10 mL) and tetrahydrofuran (5 mL), and potassium tert-butoxide (190 mg, 1.70 mmol) was added. After the reaction mixture was stirred at 60 ° C for 2 hours, it was cooled to room temperature. Concentrated under reduced pressure, the residue was dissolved by adding water (6 mL), and then 1M hydrochloric acid was slowly added dropwise to pH <2, and a white solid precipitated. Filtered, and the cake was dried under vacuum to give 6-d (226 mg, yield: 80%) as a white solid.

¹ HNMR (500 MHz, DMSO-d ₆ ) δ: 11.57 (s, 1H), 11.02 (s, 1H), 7.26 to 7.29 (m, 2H), 7.19 to 7.22 (m, 3H), 5.17 to 5.20 (m, 1H), 4.56 to 4.58 (m, 1H), 4.41 to 4.44 (m, 1H), 3.13 to 3.17 (m, 1H), 2.89 to 2.93 (m, 1H) ppm.

Synthesis of compound 6-c

Compound 6-d (220 mg, 0.9 mmol) was suspended in phosphorus oxychloride (2 mL), and N, N-dimethylaniline (2 drops) was added. After the reaction mixture was stirred at 110 ° C for two hours, it was cooled to room temperature. After concentrating under reduced pressure, ethyl acetate (20 mL) was added to the residue, followed by washing with ice water (20 mL) and saturated brine (20 mL) in this order. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain 6-c (130 mg, yield: 51%) as a white solid.

LC-MS (ESI): m / z = 281 [M + 1] ⁺ .

Synthesis of compound 6-b

Compound 6-c (130 mg, 0.46 mmol) was dissolved in dry tetrahydrofuran (10 mL), and 2- (tri-n-butyl) tinylfuran (249 mg, 0.67 mmol), lithium chloride (210 mg, 5 mmol) and tetrakis ( Triphenyl) phosphine palladium (21 mg, 0.2 mmol). After stirring at 55 ° C for 6 hours under a nitrogen atmosphere, it was cooled to room temperature. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain 6-b (117 mg, yield: 81%) as a pale yellow solid.

LC-MS (ESI): m / z = 313 [M + 1] ⁺ .

Synthesis of compound 6-a

Compound 6-b (110 mg, 0.35 mmol) was dissolved in dioxane (10 mL), and p-methoxybenzylamine (141 mg, 1.0 mmol) and bis (isopropyl) ethylamine (271 mg, 2.1 mmol) were added. . After the reaction mixture was heated under reflux for 4 hours, it was cooled to room temperature. It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1 to 3: 1) to obtain 6-a (84 mg, yield: 58%) as a pale yellow solid.

LC-MS (ESI): m / z = 414 [M + 1] ⁺ .

Synthesis of compound 6

Compound 6-a (84 mg, 0.2 mmol) was added to trifluoroacetic acid (10 mL), and the reaction mixture was heated under reflux for 6 hours and then cooled to room temperature. The organic layer was concentrated under reduced pressure, and the residue was washed with a saturated aqueous sodium hydrogen carbonate solution (20 mL), and extracted with ethyl acetate (20 mL × 3). The organic phases were combined and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1 to 3: 1) to obtain 6 (30 mg, yield: 50%) as a yellow solid.

LC-MS (ESI): m / z = 294 [M + 1] ⁺ .

¹ HNMR (500 MHz, CDCl ₃ ) δ: 7.60 (s, 1H), 7.19 to 7.26 (m, 5H), 7.08 (d, J = 3.5 Hz, 1H), 6.55 to 6.57 (m, 1H), 5.35 (brs , 2H), 5.21 ～ 5.23 (m, 1H), 5.16 (d, J = 12.5Hz, 1H), 5.08 (dd, J = 12.5Hz, 2.5Hz, 1H), 3.30 (dd, J = 14Hz, 4.0Hz , 1H), 2.96 ～ 3.01 (m, 1H) ppm

Example 7: 2-amino-7- (3-chloro-4-fluorobenzyl) -4- (furan-2-yl) -5H, 7H-furan [3,4-d] pyrimidin-5-one (Compound 7)

The compound 2-d and 4-fluoro-3-chlorobenzyl bromide were used as raw materials, and the synthesis method was the same as that in Example 2.

LC-MS (ESI): m / z = 360.0 [M + H] ⁺ .

¹ H NMR: (400MHz CD ₃ OD) δ: 8.55 (d, J = 2.8 Hz, 1H), 7.73 (s, 1H), 7.34-7.32 (m, 1H), 7.17-7.13 (m, 1H), 7.05 (t, J = 6.8 Hz, 1H), 6.68-6.66 (m, 1H), 5.80 (bs, 1H), 5.37-5.35 (m, 1H), 3.46-3.41 (dd, J ₁ = 2.8Hz, J ₂ = 11.6 Hz, 1H), 3.10-3.04 (dd, J ₁ = 6.4 Hz, J ₂ = 12.0 Hz, 1H) ppm.

Example 8: 2-amino-7- (2,4-difluorobenzyl) -4- (furan-2-yl) -5H, 7H-furan [3,4-d] pyrimidin-5-one ( Compound 8)

The compound 2-d and 2,4-difluorobenzyl bromide were used as raw materials. The synthesis method was the same as that in Example 2.

LC-MS (ESI): m / z = 344.0 [M + H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ: 8.54-8.53 (d, J = 2.8Hz, 1H), 7.71 (s, 1H), 7.29-7.28 (m, 1H), 6.83-6.74 (m, 2H), 6.66-6.65 (m, 1H), 5.82 (s, 2H), 5.3-5.35 (m, 1H), 3.53-3.51 (m, 1H), 3.02-2.97 (m, 1H) ppm

Example 9: 2-amino-7- (4-chlorobenzyl) -4- (furan-2-yl) -5H, 7H-furan [3,4-d] pyrimidin-5-one (Compound 9)

The compound 2-d and 4-chlorobenzyl bromide were used as raw materials, and the synthesis method was the same as that in Example 2.

LC-MS (ESI): m / z = 342.0 [M + H] ⁺ .

¹ H NMR (400MHz CDCl ₃ ) δ: 8.53 (d, J = 3.2Hz, 1H), 7.72 (s, 1H), 7.28-7.20 (m, 4H), 6.66 (d, J = 1.6Hz, 1H), 5.80 (bs, 2H), 5.39-5.37 (m, 1H), 3.47-3.43 (dd, J ₁ = 3.2 Hz, J ₂ = 12.0 Hz, 1 H), 3.13-3.08 (dd, J ₁ = 5.2 Hz, J ₂ = 11.6 Hz, 1H) ppm

Example 10: 2-amino-7- (2-chloro-4-fluorobenzyl) -4- (furan-2-yl) -5H, 7H-furan [3,4-d] pyrimidin-5-one (Compound 10)

The compound 2-d and 4-fluoro-2-chlorobenzyl bromide were used as raw materials, and the synthesis method was the same as that in Example 2.

LC-MS (ESI): m / z = 360.0 [M + H] ⁺ .

¹ 1H NMR (400MHz, DMSO-d ₆ ) δ: 8.30 (s, 1H), 8.09-8.04 (m, 3H), 7.50-7.46 (m, 2H), 7.26-7.25 (m, 1H), 6.79 (s , 1H), 5.54-5.17 (m, 1H), 3.51-3.48 (m, 1H), 3.07-3.03 (m, 1H) ppm

Example 11: 2-amino-7- (2-chlorobenzyl) -4- (furan-2-yl) -5H, 7H-furan [3,4-d] pyrimidin-5-one (compound 11)

Synthesis of compound 11-c

The compound 2-d and 2-chlorobenzyl bromide were used as raw materials, and the synthesis method was the same as that in Example 2.

LC-MS (ESI): m / z = 342.0 [M + H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ: 8.60 (d, J = 2.4Hz, 1H), 7.71 (s, 1H), 7.43-7.39 (m, 2H), 7.28-7.24 (m, 2H), 6.68 ( d, J = 2.0 Hz, 1H), 5.86 (s, br., 2H), 5.50-5.48 (m, 1H), 3.75-3.71 (dd, J ₁ = 2.8 Hz, J ₂ = 12.0 Hz, 1H), 3.03-2.98 (dd, J ₁ = 7.6 Hz, J ₂ = 11.6 Hz, 1 H) ppm

Example 12: 2-amino-7- (4-chloro-3-fluorobenzyl) -4- (furan-2-yl) -5H, 7H-furan [3,4-d] pyrimidin-5-one (Compound 12)

The compound 2-d and 3-fluoro-4-chlorobenzyl bromide were used as raw materials, and the synthesis method was the same as that in Example 2.

LC-MS (ESI): m / z = 360.0 [M + H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ: 8.54 (d, J = 2.4Hz, 1H), 7.73 (s, 1H), 7.31-7.28 (m, 1H), 7.09-7.00 (m, 2H), 6.67- 6.66 (m, 1H), 5.88 (s, br., 2H), 5.39-5.36 (m, 1H), 3.47-3.43 (dd, J ₁ = 2.0 Hz, J ₂ = 12.0 Hz, 1H), 3.12-3.07 (dd, J ₁ = 6.0 Hz, J ₂ = 12.0 Hz, 1 H) ppm

Example 13: 2-amino-4- (furan-2-yl) -7- (4-methylsulfonylbenzyl) -5H, 7H-furan [3,4-d] pyrimidin-5-one (compound 13)

The compound 2-d and 4-methanesulfonyl benzyl bromide were used as raw materials, and the synthesis method was the same as that in Example 2.

LC-MS (ESI): m / z = 386 [M + H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 8.26-8.25 (d, J = 3.2Hz, 1H), 8.11-7.93 (m, 3H), 7.87-7.86 (d, J = 6.8Hz, 2H), 7.56-7.54 (d, J = 6.4Hz, 2H), 6.78-6.77 (m, 1H), 5.66-5.64 (m, 1H), 3.48-3.44 (m, 1H), 3.19 (s, 3H), 3.15- 3.10 (m, 1H) ppm

Example 14: 4-((2-amino-4- (furan-2-yl) -5-oxo-5H, 7H-furan [3,4-d] pyrimidin-7-yl) methylbenzyl Amide (Compound 14)

The compound 2-d and tert-butyl 4-bromomethylbenzoate were used as raw materials. The synthesis method was the same as that in Example 2.

LC-MS (ESI): m / z = 351 [M + H] ⁺ .

¹ H NMR: (400MHz, DMSO-d ₆ ) δ: 8.24 (d, J = 2.4Hz, 1H), 8.09 (s, 1H), 7.93 (s, 1H), 7.91 (s, 1H), 7.78 (d , J = 6.8Hz, 1H), 7.31 (s, 1H), 7.29 (d, J = 6.8Hz, 1H), 6.77-6.75 (q, 1H), 5.65-5.62 (q, 1H), 3.43-3.39 ( dd, J ₁ = 2.8 Hz, J ₂ = 11.6 Hz, 1H), 3.13-3.05 (dd, J ₁ = 6.0 Hz, J ₂ = 11.6 Hz, 1H) ppm

Example 15: 2-amino-4- (furan-2-yl) -7-((4- (trifluoromethyl) phenyl) methyl) -5H, 7H-furan [3,4-d] Pyrimidin-5-one (Compound 15)

The compound 2-d and 4-trifluoromethylbenzyl bromide were used as raw materials, and the synthesis method was the same as that in Example 2.

LC-MS (ESI): m / z = 376 [M + H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ: 8.51-8.50 (d, J = 2.8Hz, 1H), 7.703-7.701 (m, 1H), 7.56-7.52 (m, 2H), 7.39-7.37 (m, 2H ), 6.64-6.63 (m, 1H), 5.87 (s, 2H), 5.39-5.37 (m, 1H), 3.53-3.51 (m, 1H), 3.16-3.12 (m, 1H) ppm

Example 16: 2-amino-4- (furan-2-yl) -7-((2- (trifluoromethyl) phenyl) methyl) -5H, 7H-furan [3,4-d] Pyrimidin-5-one (Compound 16)

Synthesis of compound 16-c

The compound 2-d and 2-trifluoromethylbenzyl bromide were used as raw materials, and the synthesis method was the same as that in Example 2.

LC-MS (ESI): m / z = 376 [M + H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ: 8.59-8.58 (d, J = 2.8Hz, 1H), 7.72-7.69 (m, 2H), 7.59-7.53 (m, 2H), 7.42-7.39 (t, J = 5.6Hz, 1H), 6.67-6.66 (m, 1H), 5.82 (s, 2H), 5.35-5.33 (m, 1H), 3.77-3.74 (d, J = 12.4Hz, 1H), 2.98-2.93 ( m, 1H) ppm

Example 17: 2-amino-7-((2-chloro-6-fluorophenyl) methyl) -4- (furan-2-yl) -5H, 7H-furan [3,4-d] pyrimidine -5-one (compound 17)

The compound 2-d and 2-chloro-6-fluorobenzyl bromide were used as raw materials, and the synthesis method was the same as that in Example 2.

LC-MS (ESI): m / z = 360 [M + H] ⁺ .

¹ HNMR (400MHz, CDCl ₃ ) δ: 8.60-8.59 (d, J = 2.8Hz, 1H), 7.72 (s, 1H), 7.24-7.22 (m, 2H), 7.05-7.01 (m, 1H), 6.67 -6.45 (m, 1H), 5.82 (s, 2H), 5.44-5.43 (m, 1H), 3.53-3.49 (m, 1H), 3.27-3.22 (m, 1H) ppm

Example 18: 2-amino-7-((3-chloro-2-fluorophenyl) methyl) -4- (furan-2-yl) -5H, 7H-furan [3,4-d] pyrimidine -5-one (compound 18)

The compound 2-d and 3-chloro-2-fluorobenzyl bromide were used as raw materials, and the synthesis method was the same as that in Example 2.

LC-MS (ESI): m / z = 360 [M + H] ⁺ .

¹ 1H NMR (400MHz, CDCl ₃ ) δ: 8.55-8.51 (d, J = 2.8 Hz, 1H), 7.13 (s, 1H), 7.32-7.29 (m, 1H), 7.24-7.21 (m, 1H), 7.05-7.01 (t, J = 6.4Hz, 1H), 6.65-6.64 (m, 1H), 5.87 (s, 2H), 5.40-5.34 (m, 1H), 3.59-3.55 (m, 1H), 3.03- 2.99 (m, 1H) ppm

Example 19: 2-amino-7-((2-methylphenyl) methyl) -4- (furan-2-yl) -5H, 7H-furan [3,4-d] pyrimidine-5- Ketone (Compound 19)

The compound 2-d and 2-methylbenzyl bromide were used as raw materials, and the synthesis method was the same as that in Example 2.

LC-MS (ESI): m / z = 322.0 [M + H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.57 (d, J = 1.6 Hz, 1H), 7.73 (s, 1H), 7.28-7.26 (m, 1H), 7.18-7.14 (m, 3H), 6.67 ( d, J = 1.6 Hz, 1H), 5.85 (s, br., 2H), 5.42-5.39 (m, 1H), 3.53-3.49 (dd, J ₁ = 6.8 Hz, J ₂ = 12.0 Hz, 1H), 3.07-3.02 (dd, J ₁ = 6.0 Hz, J ₂ = 18.8 Hz, 1H), 2.42 (s, 3H) ppm

Example 20: 2-amino-7-((3,5-bis (trifluoromethyl) phenyl) methyl) -4- (furan-2-yl) -5H, 7H-furan [3,4- d) pyrimidin-5-one (compound 20)

The compound 2-d and 3,5-bis (trifluoromethyl) benzyl bromide were used as raw materials. The synthesis method was the same as that in Example 2.

LC-MS (ESI): m / z = 444 [M + H] ⁺ .

¹ 1H NMR (400MHz, CDCl ₃ ) δ: 8.51-8.50 (d, J = 2.8Hz, 1H), 7.75 (m, 3H), 7.72-7.71 (m, 1H), 6.66-6.65 (m, 1H), 5.77 (s, 2H), 5.41-5.38 (m, 1H), 3.60-3.56 (m, 1H), 3.24-3.19 (m, 1H) ppm

Example 21: 2-amino-7-((4- (trifluoromethoxy) phenyl) methyl) -4- (furan-2-yl) -5H, 7H-furan [3,4-d] Pyrimidin-5-one (Compound 21)

The compound 2-d and 4-trifluoromethoxybenzyl bromide were used as raw materials, and the synthesis method was the same as that in Example 2.

LC-MS (ESI): m / z = 391.9 [M + H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ: 8.53 (d, J = 2.8 Hz, 1H), 7.72 (s, 1H), 7.32-7.28 (m, 2H), 7.14-7.12 (m, 2H), 6.66 ( d, J = 1.6 Hz, 1H), 5.80 (s, br., 2H), 5.40-5.37 (m, 1H), 3.51-3.47 (dd, J ₁ = 2.8 Hz, J ₂ = 11.6 Hz, 1H), 3.13-3.08 (dd, J ₁ = 10.0 Hz, J ₂ = 11.6 Hz, 1 H) ppm

Example 22: 2-amino-7-((2,6-difluorophenyl) methyl) -4- (furan-2-yl) -5H, 7H-furan [3,4-d] pyrimidine- 5-keto (compound 22)

The compound 2-d and 2,6-difluorobenzyl bromide were used as raw materials. The synthesis method was the same as that in Example 2.

LC-MS (ESI): m / z = 344 [M + H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ: 8.60 (d, J = 3.2Hz, 1H), 7.74 (s, 1H), 7.28-7.23 (m, 2H), 6.95-6.91 (m, 2H), 6.68- 6.67 (m, 1H), 5.85 (s, br., 2H), 5.43-5.40 (m, 1H), 3.47-3.43 (dd, J ₁ = 3.2 Hz, J ₂ = 11.2 Hz, 1H), 3.17-3.12 (dd, J ₁ = 7.6 Hz, J ₂ = 11.6 Hz, 1H) ppm

Example 23: 2-amino-7-((2- (trifluoromethoxy) phenyl) methyl) -4- (furan-2-yl) -5H, 7H-furan [3,4-d] Pyrimidin-5-one (Compound 23)

The compound 2-d and 2-trifluoromethoxybenzyl bromide were used as raw materials, and the synthesis method was the same as that in Example 2.

LC-MS (ESI): m / z = 391.9 [M + H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ: 8.57 (d, J = 2.8Hz, 1H), 7.73 (s, 1H), 7.47-7.45 (m, 1H), 7.35- 7.260 (m, 3H), 6.68- 6.67 (m, 1H), 5.84 (s, br., 2H), 5.43-5.40 (m, 1H), 3.64-3.60 (dd, J ₁ = 2.8 Hz, J ₂ = 11.6 Hz, 1H), 3.06-3.01 (dd, J ₁ = 6.8 Hz, J ₂ = 11.6 Hz, 1 H) ppm

Example 24: 2-amino-7-benzyl-4- (pyridin-2-yl) -5H, 7H-furan [3,4-d] pyrimidin-5-one (Compound 24)

synthetic route

Synthesis of compound 24-f

Dissolve 2-pyridinaldehyde (5.0 g, 46.7 mmol), O-methylisourea sulfate (9.64 g, 56.0 mmol) and ethyl acetoacetate (6.67 g, 51.3 mmol) in anhydrous N, N-dimethylformamide To formamide (100 mL), sodium bicarbonate (15.7 g, 186.8 mmmol) was added to the solution. The reaction mixture was heated to 70 ° C under a nitrogen atmosphere, stirred for 3 hours, and then cooled to room temperature. Saturated brine (200 mL) was added, and a large amount of yellow suspension appeared, and extracted with ethyl acetate (500 mL × 2). The organic phases were combined, washed with water (200 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and decompressed. It was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain 24-f (10.2 g, yield: 79%) as a white solid.

LC-MS (ESI): m / z = 276.3 [M + H] ⁺ .

Synthesis of compound 24-e

Compound 24-f (10.0 g, 36.3 mmol) was dissolved in dichloromethane (100 mL), and 2,3-dichloro-5,6-dicyano-p-benzoquinone (9.08 g, 40.0 mmol) was added under stirring at room temperature. . The reaction mixture was stirred overnight. The reaction mixture was filtered, and the filter cake was washed with dichloromethane (50 mL). The filtrates were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5-2: 1) to obtain gray crystals 24- e (6.5 g, yield: 65%). LC-MS (ESI): m / z = 274.3 [M + H] ⁺ .

Synthesis of compound 24-d

Compound 24-e (6.5g, 23.8mmol) was dissolved in dioxane (100mL), and selenium dioxide (3.96g, 35.7mmol) and glacial acetic acid (2mL) were added at room temperature. And stirred for 10 hours. After cooling to room temperature, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain 24-d (1.8 g, yield: 26%) as a pink solid.

LC-MS (ESI): m / z = 288.1 [M + H] ⁺ .

Synthesis of compound 24-c

A solution of benzylmagnesium chloride in tetrahydrofuran (1.0M, 1.5mL, 1.5mmol) was added to a solution of compound 24-d (287mg, 1.0mmol) in anhydrous tetrahydrofuran (10mL) at -78 ° C under nitrogen protection. The reaction solution Warm slowly to room temperature and stir for 16 hours. A saturated aqueous ammonium chloride solution (20 mL) was added. It was extracted with ethyl acetate (30 mL x 3), washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 6: 1) to obtain 24-c (230 mg, yield: 69%) as a gray solid product. LC-MS (ESI): m / z = 334 [M + H] ⁺ .

Synthesis of compound 24-b

To a 100 ml single-necked flask were added 24-c (310 mg, 0.93 mmol), lithium iodide (623 mg, 4.6 mmol) and pyridine (15 mL). The reaction solution was stirred at 120 ° C for 16 hours and then cooled to room temperature. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: methanol = 100-10: 1) to obtain 24-b (280 mg, yield: 94%) as a yellow solid.

LC-MS (ESI): m / z = 320 [M + 1] ⁺ .

Synthesis of compound 24-a

Compound 24-b (280 mg, 0.87 mmol) was dissolved in phosphorus oxychloride (15 mL), and the reaction solution was stirred at 120 ° C for 3 hours and then cooled to room temperature. The organic layer was concentrated under reduced pressure, the residue was added to an ice-water mixture (100 mL), and extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with water (30 mL) and saturated brine (20 mL), and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain 24-a (180 mg, yield: 62%) as a yellow solid.

LC-MS (ESI): m / z = 338 [M + 1] ⁺ .

Synthesis of compound 24

Compound 24-a (180 mg, 0.53 mmol) was dissolved in tetrahydrofuran (5 mL), and a 7.0 M ammonia methanol solution (5 mL, 35 mmol) was added at room temperature, and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was added with methanol (3 mL), ultrasonicated for one minute, and filtered. The filter cake was dried under vacuum to obtain compound 24 (45 mg, yield: 27%).

LC-MS (ESI): m / z = 319 [M + H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ: 8.86 (d, J = 3.6 Hz, 1H), 8.11 (d, J = 6.4 Hz, 1H), 7.89-7.85 (m, 1H), 7.47-7.45 (m, 1H), 7.26-7.21 (m, 5H), 5.95 (s, br., 2H), 5.49-5.47 (m, 1H), 3.54-3.50 (dd, J ₁ = 3.2 Hz, J ₂ = 11.6 Hz, 1H ), 3.19-3.14 (dd, J ₁ = 6.4 Hz, J ₂ = 12.0 Hz, 1 H) ppm

Example 25: 2-amino-4- (5-bromofuran-2-yl) -7-((2,4-difluorophenyl) methyl) -5H, 7H-furan [3,4-d] Pyrimidin-5-one (Compound 25)

synthetic route

Synthesis of compound 25

Compound 8 (60 mg, 0.17 mmol) was dissolved in N, N-dimethylformamide (15 mL), N-bromosuccinimide (47 mg, 0.26 mmol) was added, and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to high-performance liquid chromatography (mobile phase: water (10 mM ammonium bicarbonate), acetonitrile; gradient: 15% to 65% (the initial mobile phase was 15% water to 85% acetonitrile, and the end) The mobile phase was 65% water to 35% acetonitrile, where% refers to the volume percentage), and compound 25 was obtained after purification (26 mg, yield: 36.2%).

LC-MS (ESI): m / z = 423 [M + H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ: 8.49-8.48 (d, J = 2.8Hz, 1H), 7.25-7.24 (m, 1H), 6.82-6.79 (m, 2H), 6.59-6.58 (d, J = 3.2 Hz, 1H), 5.92 (s, 2H), 5.38-5.35 (m, 1H), 3.53-3.49 (m, 1H), 3.03-2.99 (m, 1H) ppm.

Example 26

2-amino-7-((2,4-difluorophenyl) methyl) -4- (5-methylfuran-2-yl) -5H, 7H-furan [3,4-d] pyrimidine- 5-keto (compound 26)

synthetic route

Synthesis of compound 26-f

Furfural (16.92 g, 153.68 mmol), O-methylisourea sulfate (26.46 g, 153.68 mmol) and ethyl acetoacetate (20 g, 153.68 mmol) were dissolved in anhydrous N, N-dimethylformamide ( 200 mL), to the solution was added sodium bicarbonate (19.37 g, 230.52 mmol). The reaction mixture was heated to 75 ° C under a nitrogen atmosphere, stirred for 16 hours, and then cooled to room temperature. Ethyl acetate (200 mL) was added to the reaction mixture, followed by washing with water (200 mL × 3) and saturated brine (200 mL), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum Ether: ethyl acetate = 10-3: 1) to obtain compound 26-f (32.38 g, yield: 75.7%).

Synthesis of compound 26-e

Compound 26-f (32.38 g, 116.35 mmol) was dissolved in dichloromethane (700 mL), and 2,3-dichloro-5,6-dicyano-p-benzoquinone (52.83 g, 232.7 mmol) was added under stirring at room temperature. . The reaction mixture was stirred for 12 hours. After the reaction mixture was filtered, the filter cake was washed with ethyl acetate (150 mL × 3), and the filtrates were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain compound 26- e (26.38 g, yield: 82.9%).

¹ H NMR (500MHz, CDCl3) δ: 7.25-7.24 (d, J = 3.5 Hz, 1H), 6.17-6.16 (d, J = 3.0 Hz, 1H), 4.44-4.39 (m, 2H), 4.03 (s , 3H), 2.47 (s, 3H), 2.36 (s, 3H), 1.39-1.37 (t, 3H) ppm

Synthesis of compound 26-d

Compound 26-e (1.0 g, 3.62 mmol) was dissolved in a mixed solution of dioxane (20 mL) and ethyl acetate (1 mL), selenium dioxide (522 mg, 4.71 mmol) was added at room temperature, and the mixture was heated. To 120 ° C and stirred for 6 hours. After cooling to room temperature, the reaction mixture was filtered, and the filter cake was washed with ethyl acetate (50 mL × 3). The filtrates were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1), Compound 26-d (561 mg, yield: 53.4%) was obtained.

¹ H NMR (500MHz, CDCl3) δ: 9.89 (s, 1H), 7.36-7.35 (d, J = 3.5Hz, 1H), 6.22-6.21 (d, J = 3.0Hz, 1H), 4.53-4.48 (q , 2H), 4.13 (s, 3H), 2.39 (s, 3H), 1.44-1.42 (t, 3H) ppm

Synthesis of compound 26-c

At room temperature, compound 26-d (642 mg, 3.1 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and zinc powder (203 mg, 3.1 mmol) and 2,4-difluorobenzyl bromide (300 mg, 1.03) were added to the reaction solution. mmol). The reaction mixture was raised to 55 ° C and stirred for 1 hour. After cooling to room temperature, a saturated ammonium chloride solution (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL × 2), and the organic phases were combined, washed with water (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain 26-c (300 mg, yield: 91%) as a white solid. LC-MS (ESI): m / z = 373 [M + 1] ⁺ .

Synthesis of compound 26-b

Compound 26-c (300 mg, 0.81 mmol) was dissolved in 1,4-dioxane (20 mL), and concentrated hydrochloric acid (0.5 mL) was added at room temperature. The reaction solution was stirred at 100 ° C for 4 hours and then cooled to room temperature. A large amount of solids were precipitated, filtered, and the filter cake was washed with water (20mL × 2). After vacuum drying, a yellow solid 26-b (200mg, yield: 70%) was obtained. . LC-MS (ESI): m / z = 359 [M + 1] ⁺ .

Synthesis of compound 26-a

Compound 26-b (200 mg, 0.56 mmol) was dissolved in phosphorus oxychloride (15 mL), N, N-dimethylaniline (0.02 mL) was added, and the reaction solution was stirred at 125 ° C for 2 hours and then cooled to room temperature. The organic layer was concentrated under reduced pressure, the residue was added to an ice-water mixture (100 mL), and extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with water (30 mL) and saturated brine (20 mL), and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain 26-a (160 mg, yield: 75.9%) as a yellow solid.

LC-MS (ESI): m / z = 377 [M + 1] ⁺ .

Synthesis of compound 26

Compound 26-a (160 mg, 0.43 mmol) was dissolved in tetrahydrofuran (15 mL), and a 7.0 M ammonia methanol solution (5 mL, 35 mmol) was added at room temperature, and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: ethyl acetate = 15: 1) to obtain compound 26 (60 mg, yield: 39%). LC-MS (ESI): m / z = 358 [M + H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ: 8.49-8.48 (d, J = 2.8Hz, 1H), 7.25-7.24 (m, 1H), 6.81-6.79 (m, 2H), 6.28-6.27 (d, J = 2.8Hz, 1H), 5.83 (s, 2H), 5.35-5.33 (m, 1H), 3.53-3.49 (m, 1H), 3.01-2.96 (m, 1H), 2.48 (s, 3H) ppm

Example 27: 2-amino-7-((2-fluorophenyl) methyl) -4- (5-methylfuran-2-yl) -5H, 7H-furan [3,4-d] pyrimidine -5-one (compound 27)

Compound 26-d and 2-fluorobenzyl bromide were used as raw materials. The synthesis method was the same as that in Example 26.

LC-MS (ESI): m / z = 340 [M + H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ: 8.49-8.48 (d, J = 2.8Hz, 1H), 7.32-7.28 (m, 1H), 7.25-7.21 (m, 1H), 7.08-7.01 (m, 2H ), 6.28-6.27 (d, J = 2.8Hz, 1H), 5.79 (s, 2H), 5.39-5.37 (m, 1H), 3.58-3.54 (m, 1H), 3.02-2.97 (m, 1H), 2.48 (s, 3H) ppm

Example 28: 2-amino-7-((2- (trifluoromethyl) phenyl) methyl) -4- (5-methylfuran-2-yl) -5H, 7H-furan [3,4 -d] pyrimidin-5-one (compound 28)

Compound 26-d and 2-trifluoromethylbenzyl bromide were used as raw materials. The synthesis method was the same as that in Example 26.

LC-MS (ESI): m / z = 390 [M + H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ: 8.54-8.53 (d, J = 2.8 Hz, 1H), 7.69-7.68 (d, J = 6.4 Hz, 1H), 7.58-7.52 (m, 2H), 7.41- 7.38 (t, J = 5.4Hz, 1H), 6.30-6.29 (m, 1H), 5.92 (s, 1H), 5.32-5.29 (m, 1H), 4.80 (s, 1H), 3.76-3.73 (m, 1H), 2.98-2.93 (m, 1H), 2.49 (s, 3H) ppm

Example 29: 2-amino-7-((2,5-difluorophenyl) methyl) -4- (5-methylfuran-2-yl) -5H, 7H-furan [3,4-d ] Pyrimidin-5-one (compound 29)

Compound 26-d and 2,5-difluorobenzyl bromide were used as raw materials. The synthesis method was the same as that in Example 26.

LC-MS (ESI): m / z = 358 [M + H] ⁺ .

¹ 1H NMR (400MHz, CDCl ₃ ) δ: 8.51-8.50 (d, J = 2.8Hz, 1H), 7.05-6.97 (m, 2H), 6.94-6.90 (m, 1H), 6.29-6.28 (d, J = 2.8Hz, 1H), 5.85 (s, 2H), 5.36-5.34 (m, 1H), 3.55-3.51 (m, 1H), 2.97-2.92 (m, 1H), 2.49 (s, 3H) ppm

Example 30: 2-amino-7-((5-chloro-2-fluorophenyl) methyl) -4- (5-methylfuran-2-yl) -5H, 7H-furan [3,4- d) pyrimidin-5-one (compound 30)

Compound 26-d and 5-chloro-2-fluorobenzyl bromide were used as raw materials. The synthesis method was the same as that in Example 26.

LC-MS (ESI): m / z = 374 [M + H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ: 8.51-8.50 (d, J = 2.8Hz, 1H), 7.32-7.29 (m, 1H), 7.22-7.19 (m, 1H), 7.01-6.97 (t, J = 7.2Hz, 1H), 6.29-6.28 (d, J = 2.8Hz, 1H), 5.82 (s, 2H), 5.35-5.33 (m, 1H), 3.53-3.49 (m, 1H), 2.95-2.90 ( m, 1H), 2.49 (s, 3H) ppm.

Example 31: 2-amino-7-((6-chloro-2-fluorophenyl) methyl) -4- (5-methylfuran-2-yl) -5H, 7H-furan [3,4- d) pyrimidin-5-one (compound 31)

The compound 26-d and 6-chloro-2-fluorobenzyl bromide were used as raw materials, and the synthesis method was the same as that in Example 26.

LC-MS (ESI): m / z = 374 [M + H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ: 8.55-8.54 (d, J = 3.2Hz, 1H), 7.23-7.21 (m, 2H), 7.04-7.00 (m, 1H), 6.29-6.28 (m, 1H ), 5.74 (s, 2H), 5.43-5.40 (m, 1H), 3.52-3.48 (m, 1H), 3.25-3.23 (m, 1H), 2.49 (s, 3H) ppm

Example 32: 2-amino-7-((4-fluoro-2- (trifluoromethyl) phenyl) methyl) -4- (5-methylfuran-2-yl) -5H, 7H-furan [3,4-d] pyrimidin-5-one (Compound 32)

Compound 26-d and 4-fluoro-2-trifluoromethylbenzyl bromide were used as raw materials. The synthesis method was the same as that in Example 26.

LC-MS (ESI): m / z = 408 [M + H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ: 8.53-8.52 (d, J = 2.4Hz, 1H), 7.58-7.55 (m, 1H), 7.42-7.39 (m, 1H), 7.26-7.23 (m, 1H ), 6.30-6.29 (d, J = 2.8Hz, 1H), 5.81 (s, 2H), 5.28-5.25 (m, 1H), 3.73-3.69 (m, 1H), 2.96-2.90 (m, 1H), 2.49 (s, 3H) ppm

Example 33: (S) -7-Benzyl-4- (furan-2-yl) -5,7-dihydrofuran [3,4-d] pyrimidin-2-amine (Compound 33)

Synthesis of compound 33-f

Sodium hydride (1.08 g, 27.0 mmol) was suspended in anhydrous tetrahydrofuran (60 mL), and (R) -3-phenyl-2-hydroxypropionic acid (3.24 g, 18.0 mmol) was added dropwise at 0 ° C. After the addition was completed, stirring was continued at 0 ° C for 30 minutes, and then methyl acrylate (2.22 g, 27.0 mmol) was added. Stirring was continued for 3 hours at room temperature, and 0.5 M hydrochloric acid (30 mL) was added to quench the reaction. Ethyl acetate (50 mL x 3) was extracted. The organic phases were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1 to 10: 1) to obtain 33-f (2.8 g, yield: 66%) as a colorless liquid product.

Synthesis of compound 33-e

To a solution of compound 33-f (2.8 g, 12.0 mmol) in ethanol (50 mL) was added urea (2.15 g, 36.0 mmol) and 35% concentrated hydrochloric acid (1.5 mL), and the mixture was heated under reflux for 4 hours, and then cooled to room temperature. After concentrating under reduced pressure, ethyl acetate (100 mL) was added to the residue, followed by washing with water (100 mL) and saturated brine (100 mL) in this order, and drying over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1 to 1: 1) to obtain 33-e (810 mg, yield: 25%) as a pale yellow solid. LC-MS (ESI): m / z = 277 [M + 1] ⁺ .

Synthesis of compound 33-d

Compound 33-e (810 mg, 2.93 mmol) was dissolved in a solution of ethanol (20 mL) and tetrahydrofuran (10 mL), and potassium tert-butoxide (493 mg, 4.4 mmol) was added. After the reaction mixture was stirred at 60 ° C for 2 hours, it was cooled to room temperature. Concentrated under reduced pressure, the residue was dissolved by adding water (15 mL), and then 1M hydrochloric acid was slowly added dropwise to pH <2, and a white solid precipitated. After filtration, the filter cake was dried under vacuum to obtain 33-d (550 mg, yield: 77%) as a white solid.

¹ HNMR (500 MHz, DMSO-d ₆ ) δ: 11.57 (s, 1H), 11.02 (s, 1H), 7.26 to 7.29 (m, 2H), 7.19 to 7.22 (m, 3H), 5.17 to 5.20 (m, 1H), 4.56 to 4.58 (m, 1H), 4.41 to 4.44 (m, 1H), 3.13 to 3.17 (m, 1H), 2.89 to 2.93 (m, 1H) ppm

Synthesis of compound 33-c

Compound 33-d (244 mg, 1.0 mmol) was suspended in phosphorus oxychloride (20 mL). After the reaction mixture was stirred at 120 ° C for 3 hours, it was cooled to room temperature. The organic layer was concentrated under reduced pressure, and the residue was added with ethyl acetate (50 mL × 2), followed by washing with ice water (20 mL) and saturated brine (20 mL) in this order. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1 to 10: 1) to obtain 33-c (260 mg, yield: 92%) as a white solid.

LC-MS (ESI): m / z = 281 [M + 1] ⁺ .

Synthesis of compound 33-b

Compound 33-c (260 mg, 0.93 mmol) was dissolved in dry tetrahydrofuran (30 mL), and 2- (tri-n-butyl) tinyl furan (364 mg, 1.02 mmol) and tetrakis (triphenyl) phosphine palladium (107.4 mg) were added. , 0.093 mmol). After stirring at 60 ° C for 16 hours under a nitrogen atmosphere, it was cooled to room temperature. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1 to 10: 1) to obtain 33-b (240 mg, yield: 83%) as a pale yellow solid.

LC-MS (ESI): m / z = 313 [M + 1] ⁺ .

Synthesis of compound 33-a

Compound 33-b (240 mg, 0.77 mmol) was dissolved in dioxane (20 mL), and 2,4-dimethoxybenzylamine (385 mg, 2.30 ml) and bis (isopropyl) ethylamine (296.7) were added. mg, 2.3 mmol). After the reaction mixture was refluxed for 4 hours, it was cooled to room temperature. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1 to 5: 1) to obtain 33-a (150 mg, yield: 44%) as a pale yellow viscous substance. LC-MS (ESI): m / z = 444 [M + 1] ⁺ .

Synthesis of compound 33

Compound 33-a (150 mg, 0.33 mmol) was added to trifluoroacetic acid (10 mL), and the reaction mixture was heated under reflux for one hour and then cooled to room temperature. The organic layer was concentrated under reduced pressure, and the residue was washed with a saturated aqueous sodium hydrogen carbonate solution (20 mL), and extracted with ethyl acetate (20 mL × 3). The organic phases were combined and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1 to 3: 1) to obtain 33 (50 mg, yield: 50%) as a white solid.

LC-MS (ESI): m / z = 294 [M + 1] ⁺ .

¹ HNMR (500 MHz, CDCl ₃ ) δ: 7.60 (s, 1H), 7.19 to 7.26 (m, 5H), 7.08 (d, J = 3.5 Hz, 1H), 6.55 to 6.57 (m, 1H), 5.35 (brs , 2H), 5.21 to 5.23 (m, 1H), 5.16 (d, J = 12.5Hz, 1H), 5.08 (dd, J = 12.5Hz, 2.5Hz, 1H), 3.30 (dd, J = 14Hz, 4.0Hz , 1H), 2.96 ～ 3.01 (m, 1H) ppm

Example 34: 2-amino-9-((2,4-difluorophenyl) methyl) -6- (furan-2-yl) -8,9-dihydro-7H-purine-8-one ( (Compound 34)

synthetic route

Synthesis of compound 34-e

Dissolve 2,4,6-trichloro-5-nitropyrimidine (454 mg, 2.0 mmol) and diisopropylethylamine (516 mg, 4.0 mmol) in anhydrous tetrahydrofuran (20 mL), and slowly add dropwise at 0 ° C. 2,4-difluorobenzylamine (300 mg, 2.1 mmol) was stirred at 0 ° C for 1 hour. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15: 1) to obtain 34-e (547 mg, yield: 82%) as a yellow solid.

Synthesis of compound 34-d

Compound 34-e (200 mg, 0.60 mmol), 2- (tri-n-butyl) tinyl furan (257 mg, 0.72 mmol), lithium chloride (50 mg, 1.2 mmol), and tetrakis (triphenyl) phosphine palladium (63 mg , 0.06 mmol) was added to dry tetrahydrofuran (10 mL). The reaction solution was stirred at 25 ° C for 18 hours under the protection of nitrogen. It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain the product 34-d (120 mg, yield: 55%) as a yellow solid.

LC-MS (ESI): m / z = 367 [M + 1] ⁺ .

Synthesis of compound 34-c

Compound 34-d (120 mg, 0.30 mmol), bis (p-methoxybenzyl) amine (168 mg, 0.65 mmol) and diisopropylethylamine (84 mg, 0.65 mmol) were added to dry tetrahydrofuran (10 mL). After the reaction mixture was reacted at 60 ° C for 5 hours, it was cooled to room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain the product 34-c (152 mg, yield: 78%) as a yellow solid.

LC-MS (ESI): m / z = 588 [M + 1] ⁺ . .

Synthesis of compound 34-b

Dissolve ammonium chloride (268mg, 5.0mmol) in water (5mL), then add zinc powder (163mg, 2.5mmol) and ethanol (10mL) in this order, and add 34-c (120mg, 0.30mmol) dropwise with stirring at 0 ° C. ) Solution in tetrahydrofuran (8 mL). After stirring at 0 ° C for 1 hour, the temperature was raised to room temperature. The reaction solution was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with ethyl acetate (20 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was passed through a silica gel column. Chromatographic purification (petroleum ether: ethyl acetate = 5: 1) gave the product 34-b (120 mg, yield: 86%) as a red solid. LC-MS (ESI): m / z = 558 [M + 1] ⁺ . .

Synthesis of compound 34-a

At 0 ° C, triphosgene (74 mg, 0.25 mmol) was added to a dry tetrahydrofuran (10 mL) solution of 34-b (120 mg, 0.21 mmol) and diisopropylethylamine (387 mg, 3.0 mmol), and stirred for 10 minutes. Warm to room temperature and continue stirring for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain 34-a (75 mg, yield: 61%) as a pink solid product. LC-MS (ESI): m / z = 584 [M + 1] ⁺ .

Synthesis of compound 34

Compound 34-a (38 mg, 0.065 mmol) was added to trifluoroacetic acid (4 mL). After the reaction mixture was stirred at 80 ° C for 5 hours, it was cooled to room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain a white solid product 34 (15 mg, yield: 67%).

LC-MS (ESI): m / z = 344 [M + 1] ⁺ .

1HNMR (500MHz, CD3OD) δ: 7.74 (s, 1H), 7.38 (s, 2H), 6.82 ～ 6.87 (m, 2H), 6.65 (s, 1H), 5.07 (s, 2H) ppm

Example 35: 2-amino-9-((2,4-difluorophenyl) methyl) -6- (furan-2-yl) -7-methyl-8,9-dihydro-7H-purine 8-one (Compound 35)

Synthesis of compound 35-a

60% of sodium hydride (8 mg, 0.2 mol) dispersed in mineral oil was suspended in dry N, N-dimethylformamide (4 mL), and 34-a ( 36 mg, 0.061 mmol) of a dry N, N-dimethylformamide (2 mL) solution, and stirring was continued for 1 hour at 0 ° C. Methyl iodide (43 mg, 0.3 mmol) was added, and the reaction was continued for 1 hour after warming to room temperature. The reaction mixture was poured into a half-saturated aqueous ammonium chloride solution (20 mL), and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain the white solid product 35-a ( 33 mg, yield: 90%)).

LC-MS (ESI): m / z = 344 [M + 1] ⁺ .

Synthesis of compound 35

Compound 35-a (33 mg, 0.055 mmol) was added to trifluoroacetic acid (4 mL). After the reaction mixture was stirred at 80 ° C for 4 hours, it was cooled to room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain a white solid product 35 (18 mg, yield: 91%).

LC-MS (ESI): m / z = 358 [M + 1] ⁺ .

1HNMR (500MHz, CD3OD) δ: 7.60 (s, 1H), 7.31 ～ 7.36 (m, 1H), 7.10 (s, 1H), 6.80 ～ 6.83 (m, 2H), 6.58 (s, 1H), 5.09 ( s, 2H), 3.58 (s, 3H) ppm

Example 36: 2-amino-7-((2- (trifluoromethoxy) phenyl) methyl) -4- (5-methylfuran-2-yl) -5H, 7H-furan [3, 4-d] pyrimidin-5-one (compound 36)

The compound 26-d and 2-trifluoromethoxybenzyl bromide were used as raw materials. The synthesis method was the same as that in Example 26.

LC-MS (ESI): m / z = 406 [M + H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ: 8.50-8.49 (d, J = 3.2Hz, 1H), 7.44-7.41 (m, 1H), 7.31-7.29 (m, 1H), 7.26-7.23 (m, 2H ), 6.28-6.27 (d, J = 2.8Hz, 1H), 5.78 (s, 2H), 5.37-5.35 (m, 1H), 3.60-3.57 (m, 1H), 3.03-2.98 (m, 1H), 2.48 (s, 3H) ppm

Example 37: 2-amino-7-((2- (trifluoromethoxy) phenyl) methyl) -4- (5-bromofuran-2-yl) -5H, 7H-furan [3,4 -d] pyrimidin-5-one (compound 37)

Synthesis of compound 37

Compound 23 (130 mg, 0.33 mmol) was dissolved in N, N-dimethylformamide (15 mL), N-bromosuccinimide (89 mg, 0.49 mmol) was added, and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography (mobile phase: water (10 mM ammonium bicarbonate), acetonitrile; gradient: 15% to 65% (the initial mobile phase was 15% water to 85% acetonitrile) The mobile phase was 65% water to 35% acetonitrile, where% refers to volume percentage), and compound 37 was obtained after purification (70 mg, yield: 45.2%).

LC-MS (ESI): m / z = 470 [M + H] ⁺ .

¹ 1H NMR (400MHz, CDCl ₃ ) δ: 8.50-8.49 (d, J = 3.2Hz, 1H), 7.43-7.41 (m, 1H), 7.31-7.29 (m, 1H), 7.24-7.23 (m, 2H ), 8.59-8.58 (d, J = 3.2Hz, 1H), 5.85 (s, 2H), 5.40-5.38 (m, 1H), 3.61-3.57 (m, 1H), 3.04-2.99 (m, 1H) ppm

Example 38: 2-amino-7-((2-fluorophenyl) methenyl) -4- (furan-2-yl) -6-methyl-5H, 6H, 7H-pyrrole [3,4- d) pyrimidin-5-one (compound 38)

Synthesis of compound 38-f

Sodium bicarbonate (21.2 g, 200 mmol) was added to furfural (9.60 g, 100 mmol), S-methylisothiourea sulfate (20.7 g, 150 mmol) and ethyl acetoacetate (13.0 g, 100 mmol) in N, N- In dimethylformyl (80 mL). After the reaction mixture was stirred at 80 ° C for 6 hours, it was cooled to room temperature. The organic layer was concentrated under reduced pressure, and the residue was added with water (100 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15: 1) to obtain 38-f (5.7 g, yield: 20%) as a yellow solid product. LC-MS (ESI): m / z = 281 [M + H] ⁺ .

Synthesis of compound 38-e

In an ice water bath, 2,3-dichloro-5,6-dicyano-p-benzoquinone (6.0 g, 26.4 mmol) was added portionwise to compound 38-f (5.60 g, 20.0 mmol) in dichloromethane (100 mL). The solution was warmed to room temperature and stirred for 8 hours. Filter and filter cake was washed with dichloromethane (100 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 12: 1) to obtain the product 38-e (4.10 g, yield: 74%) as a yellow solid.

LC-MS (ESI): m / z = 279 [M + H] ⁺ .

Synthesis of compound 38-d

Compound 38-e (1.40 g, 5.0 mmol) was dissolved in 1,4-dioxane (60 mL), and selenium dioxide (715 mg, 6.5 mmol) and glacial acetic acid (1.5 mL) were added. After the reaction solution was refluxed for 8 hours, it was cooled to room temperature. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (60 mL). It was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1 to 15: 1) to obtain 38-d (0.98 g, yield: 70%) as a yellow solid.

LC-MS (ESI): m / z = 293 [M + H] ⁺ .

Synthesis of compound 38-c

Methylamine hydrochloride (680 mg, 10.0 mmol) and sodium acetate (820 mg, 10.0 mmol) were added to methanol (30 mL). After the mixture was stirred at room temperature for 1 hour, the ice-water bath was cooled to 5 ° C, and then compound 38-d (980 mg, 3.35 mmol) and dichloromethane (30 mL) were added. After stirring for 30 minutes, sodium cyanoborohydride (315 mg, 5.0 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for 16 hours. It was concentrated under reduced pressure, and the residue was diluted with water (100 mL), and extracted with dichloromethane (50 mL × 2). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain the product 38-c (560 mg, yield: 64%) as a white solid.

LC-MS (ESI): m / z = 262 [M + H] ⁺ .

Synthesis of compound 38-b

1,8-Diazabicycloundec-7-ene (60 mg, 0.4 mmol) was added to the compound 38-c (261 mg, 1.0 mmol) and o-fluorobenzaldehyde (248 mg, 2.0 mmol) in dioxane (20 mL) solution. The mixture was refluxed under nitrogen for 16 hours, and then cooled to room temperature. It was concentrated under reduced pressure, and the residue was washed with ethyl acetate (20 mL × 3), and filtered to obtain 38-b (153 mg, yield: 41%) as a brown solid. This product did not require further purification. LC-MS (ESI): m / z = 368 [M + H] ⁺ .

Synthesis of compound 38-a

80% m-chloroperoxybenzoic acid (114 mg, 0.52 mmol) was added to a dichloromethane (20 mL) solution of compound 38-b (60 mg, 0.16 mmol), and stirred at room temperature for 16 hours. The reaction was quenched by the addition of a saturated sodium thiosulfate solution (3 mL). Water (20 mL) was added and extracted with dichloromethane (20 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 1) to obtain 38-a (40 mg, yield: 62%) as a pale yellow solid.

Synthesis of compound 38

7N ammonia in methanol (2 mL, 14 mmol) was added to a solution of compound 38-a (40 mg, 0.10 mmol) in tetrahydrofuran (5 mL). The mixture was stirred for 1 hour at room temperature. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 3) to obtain 38 (17 mg, yield: 50.4%) as a white solid.

LC-MS (ESI): m / z = 337 [M + H] ⁺ .

¹ H NMR (500 MHz, CDCl ₃ ) δ: 8.65 (d, J = 8.0 Hz, 1H), 8.05 to 8.08 (m, 1H), 7.68 to 7.69 (m, 1H), 7.29 to 7.34 (m, 1H), 7.13 ～ 7.16 (m, 1H), 7.07 ～ 7.11 (m, 1H), 6.63 (dd, J = 4.0Hz, 2.0Hz, 1H), 6.48 (s, 1H), 5.40 (brs, 2H), 3.37 (s , 3H) ppm

Example 39

2-amino-7-((2- (difluoromethoxy) phenyl) methyl) -4- (5-methylfuran-2-yl) -5H, 7H-furan [3,4-d] Pyrimidin-5-one (Compound 39)

The compound 26-d and 2-difluoromethoxybenzyl bromide were used as raw materials, and the synthesis method was the same as that in Example 26.

LC-MS (ESI): m / z = 388 [M + H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ: 8.48-8.47 (d, J = 3.2Hz, 1H), 7.34-7.22 (m, 1H), 7.28-7.24 (m, 1H), 7.16-7.09 (m, 2H ), 6.72-6.42 (3 × s, 1H), 6.28-6.27 (d, J = 2.8Hz, 1H), 5.83 (s, 2H), 5.39-5.37 (m, 1H), 3.61-3.57 (m, 1H ), 3.05-3.00 (m, 1H), 2.48 (s, 3H) ppm

Example 40: 2-amino-9-((2-fluorophenyl) methyl) -6- (furan-2-yl) -7-methyl-8,9-dihydro-7H-purine-8- Ketone (Compound 40)

Using 2-fluorobenzylamine as a raw material, the synthesis method was the same as that in Example 34.

LC-MS (ESI): m / z = 326 [M + 1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 7.81 (s, 1H), 7.32-7.29 (m, 1H), 7.23-7.11 (m, 5H), 6.67-6.66 (m, 1H), 6.24 (s , 2H), 4.98 (s, 2H) ppm.

Example 41: 2-amino-9-((2-fluorophenyl) methyl) -6- (furan-2-yl) -7-methyl-8,9-dihydro-7H-purine-8- Ketone (Compound 41)

Synthesis of compound 41-a

60% of sodium hydride (15 mg, 0.56 mol) dispersed in mineral oil was suspended in dry N, N-dimethylformamide (10 mL), and 40-a ( 210 mg, 0.37 mmol) of a dry N, N-dimethylformamide (10 mL) solution, and stirring was continued at 0 ° C for 1 hour. Methyl iodide (106 mg, 0.74 mmol) was added, and the reaction was continued for 1 hour after warming to room temperature. The reaction mixture was poured into a half-saturated aqueous ammonium chloride solution (20 mL), and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain 41-a as a white solid product ( 120 mg, yield: 55.9%)).

LC-MS (ESI): m / z = 580 [M + 1] ⁺ .

Synthesis of compound 41

Compound 41-a (120 mg, 0.21 mmol) was added to trifluoroacetic acid (4 mL). After the reaction mixture was stirred at 85 ° C for 2 hours, it was cooled to room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain a white solid product 41 (8 mg, yield: 11.2%).

LC-MS (ESI): m / z = 340 [M + 1] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ: 7.60-7.59 (m, 1H), 7.27-7.28 (m, 1H), 7.25-7.24 (m, 1H), 7.10-7.04 (m, 3H), 6.59-6.58 (m, 1H), 5.15 (s, 2H), 4.78 (s, 2H), 3.58 (s, 3H) ppm

Example 42: 2-amino-7-((2,4-difluorophenyl) methyl) -7-deuter-4- (5-methylfuran-2-yl) -5H, 7H-furan [3 , 4-d] pyrimidin-5-one (Compound 42)

Synthesis of compound 42-b

At room temperature, bis (p-methoxybenzyl) amine (215.8 mg, 0.84 mmol) and diisopropylethylamine (271 mg, 2.1 mmol) were added to dioxane of compound 26-a (300 mg, 0.79 mmol). (20 mL) solution. The reaction solution was raised to 110 ° C and stirred for 4 hours, and then cooled to room temperature. The reaction was quenched by the addition of a saturated ammonium chloride solution (20 mL). It was extracted with ethyl acetate (50 mL × 2), and the organic phases were combined, washed with water (30 mL) and saturated brine (20 mL), and dried over anhydrous sodium sulfate. It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1-10: 1) to obtain 42-b (320 mg, yield: 77%) as a yellow solid.

LC-MS (ESI): m / z = 398 [M + 1] ⁺ .

Synthesis of compound 42-a

Deuterium water (5 mL) and a 1 M solution of deuterated sodium hydroxide (4 mL) were added to a solution of compound 42-b (260 mg, 0.43 mmol) in tetrahydrofuran (8 mL). The reaction solution was stirred at room temperature for 16 hours, water (10 mL) was added, and the mixture was extracted with ethyl acetate (2 × 20 mL). The organic phases were combined, washed with water (10 mL) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. Concentrated under reduced pressure to give 42-a (200 mg, yield: 76%) as a pale yellow solid, which was obtained without further purification.

LC-MS (ESI): m / z = 599 [M + 1] ⁺ .

Synthesis of compound 42

Compound 42-a (200 mg, 0.33 mmol) was dissolved in dichloromethane (30 ml), and 2,3-dichloro-5,6-dicyano-p-benzoquinone (227 mg, 1.0) was added to the reaction solution with stirring at room temperature. mmol), and stirring was continued at room temperature for 3 days. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to high performance liquid chromatography (mobile phase: water (10 mM ammonium bicarbonate), acetonitrile; gradient: 40% -70% (the initial mobile phase was 40% water-60%). At the end, the mobile phase was 70% water to 30% acetonitrile, where% refers to volume percentage). After purification, an off-white solid 42 (22 mg, yield: 19%) was obtained.

LC-MS (ESI): m / z = 359 [M + 1] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ: 8.51 (d, J = 2.8Hz, 1H), 7.30-7.26 (m, 1H), 6.84-6.78 (m, 2H), 6.30 (d, J = 2.4Hz, 1H), 5.85 (bs, 2H), 3.52 (d, J ₁ = 11.6 Hz, 1H), 3.00 (d, J = 12.0 Hz, 1H), 2.50 (s, 3H) ppm

Example 43: 2-amino-7-((2-fluorophenyl) methyl) -7-methyl-4- (5-methylfuran-2-yl) -5H, 7H-furan [3,4 -d] pyrimidin-5-one (compound 43)

Synthesis of compound 43-c

Compound 27-c (190 mg, 0.53 mmol) was dissolved in tetrahydrofuran (15 mL), the reaction solution was lowered to -78 ° C, and a 1M hexamethyldisilazyl potassium solution (0.80 mL, 0.80 mmol), and after stirring for 30 minutes, iodomethane (225.7 mg, 1.59 mmol) was added dropwise. Stirring was continued at this temperature for 1 hour, then gradually raised to room temperature, and stirring was continued for 16 hours. The reaction was quenched with a saturated aqueous ammonium chloride solution (50 mL). It was extracted with ethyl acetate (50 mL × 2), and the organic phases were combined, washed with water (30 mL) and saturated brine (20 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 43-c (210 mg) as a yellow solid, which was obtained without further purification.

LC-MS (ESI): m / z = 369 [M + 1] ⁺ .

Synthesis of compound 43-b

Compound 43-c (210 mg) was dissolved in dioxane (25 mL), and concentrated hydrochloric acid (1.0 mL) was added to the reaction solution at room temperature. After the reaction solution was stirred at 110 ° C for 4 hours, it was cooled to room temperature. The reaction solution was concentrated under reduced pressure, and the residue was added with methanol (20 mL) to obtain a suspension, which was filtered to obtain 43-b (200 mg) as a pink solid. This product did not require further purification. LC-MS (ESI): m / z = 355 [M + 1] ⁺ . Synthesis of compound 43-a

Compound 43-b (300 mg) was dissolved in phosphorus oxychloride (20 mL), and the reaction solution was stirred at 110 ° C for 3 hours, and then cooled to room temperature. The reaction solution was concentrated under reduced pressure, the residue was added to an ice-water mixture (50 mL), and extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with water (30 mL) and saturated brine (20 mL), and anhydrous sodium sulfate. dry. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1-10: 1) to obtain 43-b (150 mg, yield: 50%) as a pale yellow solid. LC-MS (ESI): m / z = 411 [M + 1] ⁺ .

Synthesis of compound 43

Compound 43-a (150 mg, 0.40 mmol) was dissolved in tetrahydrofuran (10 mL), and a 7M ammonia methanol solution (5 mL) was added to the reaction solution at room temperature, and stirring was continued for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography (mobile phase: water (10 mM ammonium bicarbonate), acetonitrile; gradient: 40% -70% (the initial mobile phase was 40% water-60% acetonitrile, and the end) The mobile phase was 70% water to 30% acetonitrile, where% refers to the volume percentage). After purification, an off-white solid 43 (50 mg, yield: 35%) was obtained.

LC-MS (ESI): m / z = 454 [M + 1] ⁺ .

¹ H NMR: (400MHz, CDCl ₃ ) δ: 8.46 (d, J = 2.8 Hz, 1H), 7.74 (s, 1H), 7.24-7.16 (m, 2H), 7.03-6.95 (m, 2H), 6.27 -6.26 (dd, J ₁ = 0.8 Hz, J ₂ = 2.8 Hz, 1H), 5.84 (bs, 2H), 3.40 (d, J = 11.6 Hz, 1H), 3.16 (d, J = 11.2 Hz, 1H) , 2.48 (s, 3H), 1.65 (s, 3H) ppm

Example 44: 2-amino-7-((2-fluorophenyl) methyl) -4- (furan-2-yl) -6-methyl-5H, 6H, 7H-pyrrole [3,4-d ] Pyrimidin-5-one (Compound 44)

Synthesis of compound 44-b

A solution of compound 38-a (74 mg, 0.2 mmol) in tetrahydrofuran (4 mL) was added dropwise to a mixture of ammonium chloride (214 mg, 4.0 mmol) in water (5 mL), zinc powder (130 mg, 2.0 mmol), and ethanol (10 mL). in. After stirring for 4 hours, it was concentrated under reduced pressure, and the residue was diluted with water (20 mL). Extracted with ethyl acetate (20 mL), the organic phase was washed with saturated brine (20 mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain 44-b (55 mg , Yield: 74%). LC-MS (ESI): m / z = 370 [M + 1] ⁺ .

Synthesis of compound 44-a

M-80% chloroperoxybenzoic acid (57 mg, 0.26 mmol) was added to a solution of compound 44-a (30 mg, 0.08 mmol) in dichloromethane (10 mL), and the mixture was stirred at room temperature for 16 hours. The reaction was quenched by the addition of a saturated sodium thiosulfate solution (3 mL). Water (20 mL) was added and extracted with dichloromethane (20 mL x 3). The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 1) to obtain 44-a (28 mg, yield: 87%) as a pale yellow solid.

Synthesis of compound 44

7N ammonia in methanol (2 mL, 14 mmol) was added to a solution of compound 44-a (28 mg, 0.07 mmol) in tetrahydrofuran (5 mL). The mixture was stirred at room temperature for 1 hour. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 3) to obtain 44 (16 mg, yield: 68%) as a white solid.

LC-MS (ESI): m / z = 339 [M + 1] ⁺ .

¹ H NMR (500MHz, CDCl ₃ ) δ: 8.64 (d, J = 8.5 Hz, 1H), 7.65 (d, J = 1.0 Hz, 1H), 7.15 to 7.19 (m, 1H), 6.94 to 7.04 (m, 3H), 6.58 (dd, J = 3.5Hz, 2.0Hz, 1H), 5.61 (brs, 2H), 4.53 (t, J = 5.5Hz, 1H), 3.47 to 3.50 (m, 1H), 3.14 to 3.18 ( m, 1H), 3.00 (s, 3H) ppm

Example 45: 2-amino-7-((2-trifluoromethoxyphenyl) methyl) -4- (furan-2-yl) -6-methyl-5H, 6H, 7H-pyrrole [3 , 4-d] pyrimidin-5-one (Compound 45)

The compound 38-c and o-trifluoromethoxybenzaldehyde were used as raw materials. The synthesis method was the same as that in Example 38.

LC-MS (ESI): m / z = 403 [M + H] ⁺ . .

¹ H NMR (400MHz, CDCl ₃ ) δ: 8.64-8.63 (m, 1H), 7.71-7.70 (m, 1H), 7.42-7.39 (m, 1H), 7.36-7.32 (m, 3H), 7.08 (s , 1H), 6.65-6.64 (m, 1H), 5.61 (s, 2H), 2.98 (s, 3H) ppm

Example 46: 2-amino-7-((2,4-difluorophenyl) methenyl) -4- (furan-2-yl) -6-methyl-5H, 6H, 7H-pyrrole [3 , 4-d] pyrimidin-5-one (compound 46)

Compound 38-c and 2,4-difluorobenzaldehyde were used as raw materials. The synthesis method was the same as that in Example 38.

LC-MS (ESI): m / z = 355 [M + H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ: 8.65-8.64 (m, 1H), 8.10-8.05 (m, 1H), 7.71-7.69 (m, 1H), 6.92-6.83 (m, 2H), 6.65-6.63 (m, 1H), 6.39 (s, 1H), 5.37 (s, 2H), 3.36 (s, 3H) ppm

Example 47: 2-amino-7-((2,4-difluorophenyl) methyl) -4- (furan-2-yl) -6-methyl-5H, 6H, 7H-pyrrole [3, 4- d] pyrimidin-5-one (compound 47)

Synthesis of compound 47

At 0 ° C, a solution of compound 46 (160 mg, 0.45 mmol) in tetrahydrofuran (10 mL) and zinc powder (294 mg, 4.5 mmol) were added to a mixed solution of ammonium chloride (481 mg, 8.9 mmol) water (2 mL) and ethanol (2 mL). in. After stirring for 1 hour, the temperature was raised to room temperature. Dilute with water (20 mL), extract with dichloromethane (20 mL), wash the organic phase with saturated brine (20 mL), and concentrate under reduced pressure. The residue is subjected to high performance liquid chromatography (mobile phase: water (10 mM ammonium bicarbonate), Acetonitrile; gradient: 30% -60% (the initial mobile phase is 30% water-70% acetonitrile, and the mobile phase at the end is 60% water-40% acetonitrile, where% refers to volume percentage), after purification, 47 (8mg , Yield: 4.9%).

LC-MS (ESI): m / z = 357 [M + 1] ⁺ .

1H NMR (400MHz, CDCl ₃ ) δ: 8.64-8.63 (d, J = 3.2Hz, 1H), 7.65-7.64 (d, J = 1.2Hz, 1H), 6.98-6.93 (m, 1H), 6.77-6.67 (m, 2H), 6.59-6.58 (m, 1H), 5.35 (s, 2H), 4.49-4.78 (t, J = 4.0Hz, 1H), 3.43-3.39 (m, 1H), 3.21-3.17 (m , 1H), 3.04 (s, 3H) ppm

Example 48: 2-amino-7-((2,4-difluorophenyl) methenyl) -4- (5-methylfuran-2-yl) -6-methyl-5H, 6H, 7H -Pyrrole [3,4-d] pyrimidin-5-one (compound 48)

Synthesis of compound 48-f

Sodium bicarbonate (33.6 g, 400 mmol) was added to 5-methylfurfural (11.0 g, 100 mmol), S-methylisothiourea sulfate (16.68 g, 60 mmol) and ethyl acetoacetate (14.3 g, 110 mmol). N, N-dimethylformyl (200 mL). After the reaction mixture was stirred at 70 ° C for 3 hours, it was cooled to room temperature. Concentrated under reduced pressure, the residue was added with water (100 mL) and extracted with ethyl acetate (500 mL × 2). The combined organic phases were washed with water (200 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 6: 1-3: 1) to obtain 48-f (10.0 g, yield: 34%) as a pale yellow solid.

LC-MS (ESI): m / z = 295 [M + H] ⁺ .

Synthesis of compound 48-e

In an ice water bath, 2,3-dichloro-5,6-dicyano-p-benzoquinone (9.26 g, 40.8 mmol) was added portionwise to a solution of compound 48-f (10.0 g, 34 mmol) in dichloromethane (300 mL). The reaction solution was warmed to room temperature and stirred for 16 hours. Filter and wash the filter cake with dichloromethane (50 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 6: 1-3: 1) to obtain 48-e (5.10 g, yield: 52%) as a yellow viscous substance.

LC-MS (ESI): m / z = 293 [M + H] ⁺ .

Synthesis of compound 48-d

Compound 48-e (5.10 g, 5.0 mmol) was dissolved in 1,4-dioxane (60 mL), and selenium dioxide (3.7 g, 33.4 mmol) and glacial acetic acid (1.5 mL) were added. After the reaction solution was refluxed for 8 hours, it was cooled to room temperature. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (60 mL). Filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 6: 1-2: 1) to obtain 48-d (4.0 g, yield: 58%) as a yellow solid.

LC-MS (ESI): m / z = 307 [M + H] ⁺ .

Synthesis of compound 48-c

Methylamine hydrochloride (1.76 g, 26.1 mmol) and sodium acetate (3.56 g, 26.1 mmol) were added to methanol (30 mL). After the mixture was stirred at room temperature for 1 hour, the ice-water bath was cooled to 0 ° C, and then compound 48-d (2.0 g, 6.5 mmol) and dichloromethane (10 mL) were added. After stirring for 30 minutes, sodium cyanoborohydride (0.61 g, 9.8 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for another 12 hours. It was concentrated under reduced pressure, the residue was diluted with water (100 mL), and extracted with dichloromethane (50 mL × 2). The combined organic phases were washed with water (100 mL) and saturated brine (100 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain 48-c (1.38 g, yield: 75%) as a yellow solid. LC-MS (ESI): m / z = 276 [M + H] ⁺ .

Synthesis of compound 48-b

1,8-Diazabicycloundec-7-ene (105 mg, 0.69 mmol) was added to compounds 48-c (589 mg, 4.15 mmol) and 2,4-difluorobenzaldehyde (380 mg, 1.38 mmol) Of dioxane (15 mL). The mixture was refluxed under nitrogen for 12 hours, and then cooled to room temperature. It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain 48-b (270 mg, yield: 50%) as a yellow solid. LC-MS (ESI): m / z = 400 [M + H] ⁺ .

Synthesis of compound 48-a

80% m-chloroperoxybenzoic acid (427 mg, 2.71 mmol) was added to a dichloromethane (10 mL) solution of compound 48-b (270 mg, 0.67 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction was quenched by the addition of a saturated sodium thiosulfate solution (10 mL). Water (20 mL) was added, and dichloromethane (20 mL × 3) was extracted. The combined organic phases were washed with water (, 20 mL) and saturated brine (20 mL), and concentrated under reduced pressure to give 48-a (40 mg, yield: 62 as a yellow solid). %), This product was used without further purification. LC-MS (ESI): m / z = 432 [M + H] ⁺ .

Synthesis of compound 48

7N ammonia in methanol (2 mL, 14 mmol) was added to a solution of compound 48-a (400 mg, 0.93 mmol) in tetrahydrofuran (10 mL). The mixture was stirred for 1 hour at room temperature. Concentrated under reduced pressure, the residue was added with methanol (10 mL) to produce a solid, filtered, the filter cake was washed with methanol (3 mL), and the compound 48 (284 mg, yield: 80.1%) was obtained after vacuum drying.

LC-MS (ESI): m / z = 369 [M + H] ⁺ . .

¹ H NMR (400MHz, CDCl ₃ ) δ: 8.59-8.58 (m, 1H), 8.13-8.08 (m, 1H), 6.90-6.82 (m, 2H), 6.37 (s, 1H), 6.26-6.25 (m , 1H), 5.35 (s, 2H), 3.34 (s, 3H), 2.47 (s, 3H) ppm

Example 49: 2-amino-7-((2,4-difluorophenyl) methyl) -4- (5-methylfuran-2-yl) -6-methyl-5H, 6H, 7H- Pyrrole [3,4-d] pyrimidin-5-one (Compound 49)

Synthesis of compound 49

At 0 ° C, a solution of compound 48 (258 mg, 0.7 mmol) in tetrahydrofuran (10 mL) and zinc powder (458 mg, 7.1 mmol) were added to a mixed solution of ammonium chloride (760 mg, 14 mmol) water (3 mL) and ethanol (3 mL). . After stirring for 1 hour, the temperature was raised to room temperature. Dilute with water (20 mL), extract with dichloromethane (20 mL), wash the organic phase with saturated brine (20 mL), concentrate under reduced pressure, and purify the residue on a silica gel thin layer chromatography preparation plate (petroleum ether: ethyl acetate = 2 : 1) to obtain 49 (18 mg, yield: 6.9%).

LC-MS (ESI): m / z = 371 [M + 1] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ: 8.58-8.57 (d, J = 2.8Hz, 1H), 6.96-6.91 (m, 1H), 6.75-6.1 (m, 1H), 6.68-6.65 (m, 1H ), 6.21-6.20 (m, 1H), 5.59 (s, 2H), 4.47-4.45 (t, J = 4.0Hz, 1H), 3.42-3.38 (m, 1H), 3.19-3.15 (m, 1H), 3.02 (s, 3H), 2.45 (s, 3H) ppm

Example 50: 2-amino-7-((2-fluorophenyl) methenyl) -4- (5-methylfuran-2-yl) -6-methyl-5H, 6H, 7H-pyrrole [ 3,4-d] pyrimidin-5-one (compound 50)

Compound 48-c and 2-fluorobenzaldehyde were used as raw materials. The synthesis method was the same as that in Example 48.

LC-MS (ESI): m / z = 351 [M + H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ: 8.60-8.59 (d, J = 2.8Hz, 1H), 8.11-8.08 (m, 1H), 7.34-7.32 (m, 1H), 7.16-7.07 (m, 2H ), 6.47 (s, 1H), 6.27-6.26 (m, 1H), 5.35 (s, 2H), 3.36 (s, 3H), 2.48 (s, 3H) ppm.

Example 51: 2-amino-7-((2- (trifluoromethyl) phenyl) methenyl) -4- (5-methylfuran-2-yl) -6-methyl-5H, 6H , 7H-pyrrole [3,4-d] pyrimidin-5-one (Compound 51)

Compound 48-c and 2-trifluoromethylbenzaldehyde were used as raw materials. The synthesis method was the same as that in Example 48.

LC-MS (ESI): m / z = 401 [M + H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ: 8.58-8.57 (d, J = 2.8Hz, 1H), 7.82-7.81 (d, J = 6.4Hz, 1H), 7.70-7.69 (d, J = 6.0Hz, 1H), 7.52-7.49 (d, J = 6.0Hz, 1H), 7.44-7.41 (t, J = 6.0Hz, 1H), 6.60-6.59 (m, 1H), 6.26-6.25 (m, 1H), 5.23 (s, 2H), 3.34 (s, 3H), 2.48 (s, 3H) ppm

Example 52: 2-amino-7-((2- (trifluoromethoxy) phenyl) methenyl) -4- (5-methylfuran-2-yl) -6-methyl-5H, 6H, 7H-pyrrole [3,4-d] pyrimidin-5-one (Compound 52)

Compound 48-c and 2-trifluoromethoxybenzaldehyde were used as raw materials. The synthesis method was the same as that in Example 48.

LC-MS (ESI): m / z = 417 [M + H] ⁺ .

¹ H NMR: (400MHz, CDCl ₃ ) δ: 8.61 (d, J = 2.4Hz, 1H), 8.11-8.09 (m, 1H), 7.39-7.36 (m, 1H), 7.31-7.28 (m, 2H) , 6.48 (s, 1H), 6.28 (d, J = 2.8 Hz, 1H), 5.41 (bs, 2H), 3.36 (s, 3H), 2.50 (s, 3H) ppm

Example 53: 2-amino-7-((2- (trifluoromethoxy) phenyl) methyl) -4- (5-methylfuran-2-yl) -6-methyl-5H, 6H , 7H-pyrrole [3,4-d] pyrimidin-5-one (Compound 53)

At 0 ° C, a solution of compound 52 (124.8 mg, 0.3 mmol) in tetrahydrofuran (10 mL) and zinc powder (195 mg, 3.0 mmol) was added to a mixture of ammonium chloride (321 mg, 6.0 mmol) water (3 mL) and ethanol (3 mL). In solution. After stirring for 1 hour, the temperature was raised to room temperature. Dilute with water (20 mL), extract with dichloromethane (20 mL), wash the organic phase with saturated brine (20 mL), and concentrate under reduced pressure. The residue is subjected to high performance liquid chromatography (mobile phase: water (10 mM ammonium bicarbonate), Acetonitrile; gradient: 45% -75% (the initial mobile phase is 45% water-55% acetonitrile, and the mobile phase at the end is 75% water-25% acetonitrile, where% refers to volume percentage), and a white solid 53 is obtained after purification (30 mg, yield: 24%). LC-MS (ESI): m / z = 419 [M + 1] ⁺ .

¹ H NMR: (400MHz, CD ₃ OD) δ: 8.34 (d, J = 2.8Hz, 1H), 7.29-7.17 (m, 4H), 6.28-6.27 (m, 1H), 4.66 (t, J = 4.0 Hz, 1H), 3.56-3.52 (m, 1H), 3.33-3.28 (m, 1H), 2.99 (s, 3H), 2.43 (s, 3H) ppm

Example 54: 2-amino-7-((2- (trifluoromethyl) phenyl) methyl) -4- (5-methylfuran-2-yl) -6-methyl-5H, 6H, 7H-pyrrole [3,4-d] pyrimidin-5-one (Compound 54)

At 0 ° C, a solution of compound 51 (100 mg, 0.25 mmol) in tetrahydrofuran (10 mL) and zinc powder (163 mg, 2.5 mmol) were added to a mixed solution of ammonium chloride (268 mg, 5.0 mmol) water (3 mL) and ethanol (3 mL). in. After stirring for 1 hour, the temperature was raised to room temperature. Dilute with water (20 mL), extract with dichloromethane (20 mL), wash the organic phase with saturated brine (20 mL), concentrate under reduced pressure, and purify the residue on a silica gel thin-layer chromatography preparation plate (petroleum ether: ethyl acetate = 2 : 1) to obtain 54 (22 mg, yield: 21.8%).

LC-MS (ESI): m / z = 403 [M + 1] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ: 8.66-8.65 (d, J = 2.8Hz, 1H), 7.69-7.68 (d, J = 6Hz, 1H), 7.51-7.48 (m, 1H), 7.42-7.36 (m, 2H), 6.24-6.23 (m, 1H), 5.56 (s, 2H), 4.51-4.48 (m, 1H), 3.49-3.45 (m, 1H), 3.19-3.15 (m, 1H), 2.74 (s, 3H), 2.45 (s, 3H) ppm

Example 55: 2-amino-7-((2-fluorophenyl) methyl) -4- (5-methylfuran-2-yl) -6-methyl-5H, 6H, 7H-pyrrole [3 , 4-d] pyrimidin-5-one (compound 55)

At 0 ° C, a solution of compound 50 (100 mg, 0.4 mmol) in tetrahydrofuran (10 mL) and zinc powder (262 mg, 4.0 mmol) were added to a mixed solution of ammonium chloride (428 mg, 8.0 mmol) water (3 mL) and ethanol (3 mL). in. After stirring for 1 hour, the temperature was raised to room temperature. Dilute with water (20 mL), extract with dichloromethane (20 mL), wash the organic phase with saturated brine (20 mL), concentrate under reduced pressure, and purify the residue on a silica gel thin-layer chromatography preparation plate (petroleum ether: ethyl acetate = 2 : 1) to obtain 55 (15 mg, yield: 10.5%).

LC-MS (ESI): m / z = 353 [M + 1] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.58-8.57 (d, J = 2.8 Hz, 1H), 7.17-7.13 (m, 1H), 7.01-6.92 (m, 3H), 6.20-6.19 (m, 1H ), 5.45 (s, 2H), 4.51-4.48 (m, 1H), 3.49-3.45 (m, 1H), 3.17-3.13 (m, 1H), 2.98 (s, 3H), 2.45 (s, 3H) ppm

Example 56: 2-amino-7-((2- (trifluoromethyl) -4-fluorophenyl) methenyl) -4- (5-methylfuran-2-yl) -6-methyl -5H, 6H, 7H-pyrrole [3,4-d] pyrimidin-5-one (Compound 56)

Synthesis of compound 56-b

A solution of compound 48-c (275 mg, 1.0 mmol) in anhydrous tetrahydrofuran (20 mL) was added dropwise to 1M potassium hexamethyldisilazylamine (1.5 mL, 1.5 mmol) in tetrahydrofuran at -78 ° C under nitrogen protection. In the solution, after stirring for 1 hour, a solution of 2-trifluoromethoxy-4-fluorobenzaldehyde (384 mg, 2.0 mmol) in anhydrous tetrahydrofuran (20 mL) was added dropwise, and stirring was continued for 1 hour. After slowly warming to room temperature, the reaction solution was slowly added dropwise to a saturated ammonium chloride (50 mL) solution, and then extracted with ethyl acetate (50 mL × 2). The organic phase was washed with saturated brine (50 mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1-15: 1) to obtain 56-b (180 mg, yield) as a yellow solid. Rate: 40%). LC-MS (ESI): m / z = 450 [M + H] ⁺ .

Synthesis of compound 56-a

80% m-chloroperoxybenzoic acid (150 mg, 0.86 mmol) was added to a solution of compound 56-b (130 mg, 0.29 mmol) in dichloromethane (30 mL), and the mixture was stirred at room temperature for 1 hour. The reaction was quenched by the addition of a saturated sodium thiosulfate solution (10 mL). Water (30 mL) was added, and dichloromethane (30 mL × 2) was extracted. The combined organic phases were washed with water (30 mL) and saturated brine (30 mL), and concentrated under reduced pressure to give 56-a (150 mg, yield: 99%) as a yellow solid. ), This product was used without further purification. LC-MS (ESI): m / z = 482 [M + H] ⁺ .

Synthesis of compound 56

7N ammonia in methanol (5 mL, 35 mmol) was added to a solution of compound 56-a (150 mg, 0.31 mmol) in tetrahydrofuran (15 mL). The mixture was stirred for 1 hour at room temperature. Concentrated under reduced pressure, the residue was added with methanol (6 mL) to produce a solid, filtered, the filter cake was washed with methanol (6 mL), and the compound 56 (50 mg, yield: 39%) was obtained after vacuum drying.

LC-MS (ESI): m / z = 419 [M + H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ: 8.60 (d, J = 3.2Hz, 1H), 7.84-7.81 (m, 1H), 7.44-7.41 (m, 1H), 7.25-7.21 (m, 2H), 6.53 (s, 1H), 6.28 (d, J = 2.4Hz, 1H), 5.26 (bs, 2H), 3.35 (s, 3H), 2.50 (s, 3H) ppm

Example 57: 2-amino-7-((2- (trifluoromethyl) -4-fluorophenyl) methyl) -4- (5-methylfuran-2-yl) -6-methyl- 5H, 6H, 7H-pyrrole [3,4-d] pyrimidin-5-one (Compound 57)

Synthesis of compound 57

At 0 ° C, a solution of compound 56 (130 mg, 0.31 mmol) in tetrahydrofuran (10 mL) and zinc powder (201.5 mg, 3.1 mmol) were added to ammonium chloride (331.7 mg, 6.2 mmol) water (4 mL) and ethanol (4 mL). In mixed solution. After stirring for 1 hour, the temperature was raised to room temperature. Dilute with water (20 mL), extract with dichloromethane (50 mL), wash the organic phase with saturated brine (20 mL), and concentrate under reduced pressure. The residue is subjected to high performance liquid chromatography (mobile phase: water (10 mM ammonium bicarbonate), Acetonitrile; gradient: 45% -75% (the initial mobile phase is 45% water-55% acetonitrile, and the mobile phase at the end is 75% water-25% acetonitrile, where% refers to volume percentage), after purification, 57 (13mg Yield: 11%). LC-MS (ESI): m / z = 421 [M + 1] ⁺ .

Example 58: 4-((2-amino-6-methyl-4- (5-methylfuran-2-yl) -5-carbonyl-5H-pyrrole [3,4-d] pyrimidine-7 ( 6H) -Subunit) methyl) -N-pyridine oxide (compound 58)

Compound 48-c and 4-pyridinaldehyde were used as raw materials. The synthesis method was the same as that in Example 48.

LC-MS (ESI): m / z = 350 [M + H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ: 8.58-8.57 (d, J = 2.8Hz, 1H), 8.18-8.16 (d, J = 5.6Hz, 2H), 7.94-7.92 (d, J = 5.6Hz, 2H), 6.28-6.27 (m, 1H), 6.20 (s, 1H), 5.52 (s, 2H), 3.33 (s, 3H), 2.49 (s, 3H) ppm.

Example 59: 2-amino-6-methyl-4- (5-methylfuran-2-yl) -7- (pyridin-4-ylmethyl) -6,7-dihydro-5-carbonyl- 5H-pyrrole [3,4-d] pyrimidine (Compound 59)

Synthesis of compound 59

At 0 ° C, a solution of compound 58 (70 mg, 0.2 mmol) in tetrahydrofuran (10 mL) and zinc powder (131 mg, 2.0 mmol) were added to a mixed solution of ammonium chloride (215 mg, 4.0 mmol) water (2 mL) and ethanol (2 mL). in. After stirring for 1 hour, the temperature was raised to room temperature. Dilute with water (10 mL), extract with dichloromethane (10 mL), wash the organic phase with saturated brine (10 mL), concentrate under reduced pressure, and purify the residue on a silica gel thin-layer chromatography preparation plate (petroleum ether: ethyl acetate = 2 : 1) to obtain 59 (7 mg, yield: 10.4%).

LC-MS (ESI): m / z = 336 [M + 1] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ: 8.54-8.53 (d, J = 3.6Hz, 1H), 8.41-8.39 (d, J = 5.6Hz, 2H), 6.96-6.94 (d, J = 6.0Hz, 2H), 6.20-6.19 (m, 1H), 5.47 (s, 2H), 4.52-4.48 (m, 1H), 3.33-3.31 (m, 1H), 3.26-3.25 (m, 1H), 3.05 (s, 3H), 2.44 (s, 3H) ppm

Example 60: 2-amino-6- (5-methylfuran-2-yl) -9- (2- (trifluoromethyl) phenyl) -8 (9H) -carbonyl-7H-purine (Compound 60 )

Synthesis of compound 60-e

2,4,6-trichloro-5-nitropyrimidine (400 mg, 1.76 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and 2-trifluoromethylfluorobenzylamine (308 mg, 1.76) was slowly added dropwise at 0 ° C. mmol), and stirred at 0 ° C for 1 hour. It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain 60-e (470 mg, yield: 73%) as a yellow solid.

LC-MS (ESI): m / z = 367 [M + 1] ⁺ .

Synthesis of compound 60-d

Compound 60-e (500 mg, 1.37 mmol), 2- (tri-n-butyl) tinyl furan (210 mg, 1.67 mmol), anhydrous potassium phosphate (890 mg, 4.2 mmol), and 1,1'-bisdiphenyl Phosphinoferrocene palladium dichloride (160 mg, 0.2 mmol) was added to dry tetrahydrofuran (10 mL). The reaction solution was stirred at 80 ° C. for 18 hours under the protection of nitrogen, and then cooled to room temperature. It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain 60-d (120 mg, yield: 21%) as a yellow solid product.

LC-MS (ESI): m / z = 413 [M + 1] ⁺ .

Synthesis of compound 60-c

Compound 60-d (120 mg, 0.29 mmol), bis (p-methoxybenzyl) amine (224 mg, 0.87 mmol) was added to dry tetrahydrofuran (10 mL). After the reaction mixture was reacted at 50 ° C for 5 hours, it was cooled to room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain 360-c (120 mg, yield: 65%) as a yellow solid product.

LC-MS (ESI): m / z = 634 [M + 1] ⁺ .

Synthesis of compound 60-b

Add ammonium chloride (40 mg, 0.75 mmol), zinc powder (50 mg, 0.75 mmol), and ethanol (3 mL) to the compound 60-c (120 mg, 0.19 mmol) in water (3 mL) and In ethanol (3 mL). The temperature was raised to 80 ° C, and the mixture was cooled to room temperature after being stirred for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow solid 60-b. (98 mg, yield: 85%), this product was used without further purification.

LC-MS (ESI): m / z = 630 [M + 1] ⁺ .

Synthesis of compound 60-a

At 0 ° C, triphosgene (24 mg, 0.08 mmol) was added to a solution of 60-b (98 mg, 0.16 mmol) and triethylamine (50 mg, 0.48 mmol) in dry tetrahydrofuran (5 mL), and the mixture was stirred for 10 minutes and raised to Stirring was continued for 3 hours at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was diluted with water (5 mL), filtered, and the filter cake was dried under vacuum to obtain a light brown solid 60-a (98 mg, yield: 96%). This product did not require further purification.

LC-MS (ESI): m / z = 630 [M + 1] ⁺ .

Synthesis of compound 60

Compound 60-a (98 mg, 0.16 mmol) was added to trifluoroacetic acid (5 mL). After the reaction mixture was stirred at 80 ° C for 2 hours, it was cooled to room temperature. The reaction solution was concentrated under reduced pressure, and the residue was added with saturated potassium carbonate solution (30 mL) and dichloromethane (50 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel thin-layer chromatography preparation plate (two Methyl chloride: methanol = 10: 1) to obtain 60 (15 mg, yield: 25%) as a pale yellow solid. LC-MS (ESI): m / z = 390 [M + 1] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 11.3 (br, 1H), 7.80 (d, J = 8 Hz, 1H), 7.61 (m, 1H), 7.51 (m, 1H), 7.13 (m, 1H), 7.06 (m, 1H), 6.36 (s, 1H), 5.12 (s, 2H), 2.43 (s, 3H) ppm

Example 61: 2-amino-7-methyl-6- (5-methylfuran-2-yl) -9- (2- (trifluoromethyl) phenyl) -8 (9H) -carbonyl-7H -Purine (compound 61)

Synthesis of compound 61-f

2,4,6-trichloro-5-nitropyrimidine (500 mg, 2.19 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and 2-trifluoromethyl-4-fluorobenzylamine ( 423 mg, 2.19 mmol), and stirred at 0 ° C for 1 hour. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1) to obtain 61-f (470 mg, yield: 58%) as a yellow solid. LC-MS (ESI): m / z = 385 [M + 1] ⁺ .

Synthesis of compound 61-e

Compound 61-f (470 mg, 1.22 mmol), 2- (tri-n-butyl) tinyl-5-methyl-furan (123 mg, 0.98 mmol), potassium phosphate (780 mg, 3.67 mmol), and tetrakis (triphenyl) ) Phosphine palladium (50 mg, 0.05 mmol) was added to dry toluene (20 mL). The reaction solution was stirred at 80 ° C. for 12 hours under the protection of nitrogen, and then cooled to room temperature. The solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1) to obtain 61-e (160 mg, yield: 30%) as a yellow solid.

LC-MS (ESI): m / z = 431 [M + 1] ⁺ .

Synthesis of compound 61-d

Compound 61-e (160 mg, 0.37 mmol), bis (p-methoxybenzyl) amine (192 mg, 0.74 mmol), and diisopropylethylamine (58 mg, 0.45 mmol) were added to dry tetrahydrofuran (10 mL). After the reaction mixture was reacted at 60 ° C for 5 hours, it was cooled to room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15: 1) to obtain 61-d (175 mg, yield: 72%) as a yellow solid.

LC-MS (ESI): m / z = 652 [M + 1] ⁺ .

Synthesis of compound 61-c

Dissolve ammonium chloride (268mg, 5.0mmol) in water (3mL), then add zinc powder (171mg, 2.6mmol) and ethanol (3mL) in this order, and add 61-d (170mg, 0.26mmol) dropwise with stirring at 0 ° C. ) Solution in tetrahydrofuran (10 mL). After stirring at 0 ° C for 1 hour, the temperature was raised to room temperature. The reaction solution was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with ethyl acetate (20 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was passed through a silica gel column. Purification by chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain 61-c (116 mg, yield: 72%) as a black oil.

LC-MS (ESI): m / z = 622 [M + 1] ⁺ .

Synthesis of compound 61-b

At 0 ° C, triphosgene (63 mg, 0.21 mmol) was added to a solution of 34-b (110 mg, 0.17 mmol) and diisopropylethylamine (0.5 mL, 2.65 mmol) in dry tetrahydrofuran (15 mL) and stirred for 10 minutes After warming to room temperature, stirring was continued for 2 hours. The reaction solution was concentrated under reduced pressure to obtain 61-b (137 mg, yield: 61%) as a yellow oil, which was obtained without further purification.

LC-MS (ESI): m / z = 648 [M + 1] ⁺ .

Synthesis of compound 61-a

60% of sodium hydride (8 mg, 0.2 mol) dispersed in mineral oil was suspended in dry N, N-dimethylformamide (4 mL), and 61-b ( 137 mg, 0.21 mmol) of a dry N, N-dimethylformamide (10 mL) solution, and stirring was continued at 0 ° C for 30 minutes. Methyl iodide (60 mg, 0.42 mmol) was added, and the reaction was continued for 12 hours after warming to room temperature. The reaction mixture was poured into a half-saturated aqueous ammonium chloride solution (20 mL), and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 61-a (150 mg) as a yellow solid, which was obtained without further purification.

LC-MS (ESI): m / z = 662 [M + 1] ⁺ .

Synthesis of compound 61

Compound 61-a (150 mg, 0.23 mmol) was added to trifluoroacetic acid (3 mL). After the reaction mixture was stirred at 85 ° C for 2 hours, it was cooled to room temperature. The reaction solution was concentrated under reduced pressure, and the residue was subjected to high-performance liquid chromatography (mobile phase: water (10 mM ammonium bicarbonate), acetonitrile; gradient: 30% -60% (the initial mobile phase was 30% water-70% acetonitrile, and the end) The mobile phase was 60% water to 40% acetonitrile, where% refers to volume percentage). After purification, a white solid product 61 (26 mg, yield: 26.8%) was obtained. LC-MS (ESI): m / z = 422 [ M + 1] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ: 7.42-7.40 (m, 1H), 7.16-7.11 (m, 1H), 7.08-7.04 (m, 2H), 6.21-6.19 (m, 1H), 5.26 (m , 2H), 4.73 (s, 2H), 3.65 (s, 3H), 2.43 (s, 3H) ppm

Example 62: (E) -2-amino-7- (2-fluorophenylmethenyl) -4- (5-methylfuran-2-yl) -6-ethyl-5H, 6H, 7H- Pyrrole [3,4-d] pyrimidin-5-one (Compound 62)

Synthesis of compound 62-f

Sodium bicarbonate (33.6 g, 400 mmol) was added to 5-methylfurfural (11.0 g, 100 mmol), S-methylisothiourea sulfate (16.68 g, 60 mmol) and ethyl acetoacetate (14.3 g, 110 mmol). N, N-dimethylformamide (200 mL). After the reaction mixture was stirred at 70 ° C for 3 hours, it was cooled to room temperature. Concentrated under reduced pressure, the residue was added with water (100 mL) and extracted with ethyl acetate (500 mL × 2). The combined organic phases were washed with water (200 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 6: 1-3: 1) to obtain 62-f (10.0 g, yield: 34%) as a pale yellow solid. LC-MS (ESI): m / z = 295 [M + H] ⁺ .

Synthesis of compound 62-e

In an ice water bath, 2,3-dichloro-5,6-dicyano-p-benzoquinone (9.26 g, 40.8 mmol) was added portionwise to a solution of compound 62-f (10.0 g, 34 mmol) in dichloromethane (300 mL). The reaction solution was warmed to room temperature and stirred for 16 hours. Filter and wash the filter cake with dichloromethane (50 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 6: 1-3: 1) to obtain 62-e (5.10 g, yield: 52%) as a yellow viscous substance. LC-MS (ESI): m / z = 293 [M + H] ⁺ .

Synthesis of compound 62-d

Compound 62-e (5.10 g, 5.0 mmol) was dissolved in 1,4-dioxane (60 mL), and selenium dioxide (3.7 g, 33.4 mmol) and glacial acetic acid (1.5 mL) were added. After the reaction solution was refluxed for 8 hours, it was cooled to room temperature. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (60 mL). Filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 6: 1-2: 1) to obtain 62-d (4.0 g, yield: 58%) as a yellow solid. LC-MS (ESI): m / z = 307 [M + H] ⁺ .

Synthesis of compound 62-c

Ethylamine hydrochloride (1.06 g, 13.07 mmol) and sodium acetate (1.18 g, 13.07 mmol) were added to methanol (30 mL). After the mixture was stirred at room temperature for 1 hour, the ice-water bath was cooled to 0 ° C, and then compound 62-d (1.0 g, 3.27 mmol) and dichloromethane (10 mL) were added. After stirring for 30 minutes, sodium cyanoborohydride (0.31 g, 4.9 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for another 12 hours. It was concentrated under reduced pressure, the residue was diluted with water (100 mL), and extracted with dichloromethane (50 mL × 2). The combined organic phases were washed with water (100 mL) and saturated brine (100 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain 62-c (350 mg, yield: 37%) as a yellow solid. LC-MS (ESI): m / z = 290 [M + H] ⁺ .

Synthesis of compound 62-b

1,8-Diazabicycloundec-7-ene (92 mg, 0.61 mmol) was added to the dioxin of compound 62-c (350 mg, 1.21 mmol) and 2-fluorobenzaldehyde (451 mg, 3.63 mmol) Hexacyclic (15 mL) solution. The mixture was refluxed under nitrogen for 12 hours, and then cooled to room temperature. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain 62-b (202 mg, yield: 42%) as a yellow solid. LC-MS (ESI): m / z = 396 [M + H] ⁺ .

Synthesis of compound 62-a

80% m-chloroperoxybenzoic acid (350 mg, 2.03 mmol) was added to a dichloromethane (10 mL) solution of compound 62-b (202 mg, 0.51 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction was quenched by the addition of a saturated sodium thiosulfate solution (10 mL). Water (20 mL) was added, and dichloromethane (20 mL × 3) was extracted. The combined organic phases were washed with water (20 mL) and saturated brine (20 mL), and concentrated under reduced pressure to give 62-a (150 mg, yield: 68%) as a yellow solid. ), This product was used without further purification. LC-MS (ESI): m / z = 428 [M + H] ⁺ .

Synthesis of compound 62

7N ammonia in methanol (2 mL, 14 mmol) was added to a solution of compound 62-a (150 mg, 0.35 mmol) in tetrahydrofuran (10 mL). The mixture was stirred for 1 hour at room temperature. Concentrated under reduced pressure, the residue was added with methanol (10 mL) to produce a solid, filtered, the filter cake was washed with methanol (3 mL), and the compound 62 (135 mg, yield: 91%) was obtained after vacuum drying. LC-MS (ESI): m / z = 365 [M + H] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ ) δ: 8.61-8.60 (d, J = 2.8Hz, 1H), 8.08-8.05 (m, 1H), 7.32-7.30 (m, 1H), 7.16-7.13 (m, 1H), 7.11-7.07 (m, 1H), 6.49 (s, 1H), 6.28-6.27 (m, 1H), 5.32 (s, 2H), 3.96-3.91 (m, 2H), 2.48 (s, 3H) , 1.34-1.31 (m, 3H) ppm

Example 63: (E) -2-amino-7- (2- (trifluoromethyl) phenylmethenyl) -4- (5-methylfuran-2-yl) -6-ethyl-5H , 6H, 7H-pyrrole [3,4-d] pyrimidin-5-one (Compound 63)

Synthesis of compound 63-b

1,8-Diazabicycloundec-7-ene (116 mg, 0.76 mmol) was added to compound 63-c (440 mg, 1.52 mmol) and 2- (trifluoromethyl) benzaldehyde (795 mg, 4.56 mmol) in dioxane (15 mL). The mixture was refluxed under nitrogen for 12 hours, and then cooled to room temperature. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain 63-b (450 mg, yield: 66%) as a yellow solid. LC-MS (ESI): m / z = 446 [M + H] ⁺ .

Synthesis of compound 63-a

80% m-chloroperoxybenzoic acid (698 mg, 4.04 mmol) was added to a methylene chloride (10 mL) solution of compound 63-b (450 mg, 1.01 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction was quenched by the addition of a saturated sodium thiosulfate solution (10 mL). Water (20 mL) was added, and dichloromethane (20 mL x 3) was extracted. The combined organic phases were washed with water (20 mL) and saturated brine (20 mL), and concentrated under reduced pressure to give 63-a (500 mg) as a yellow solid. This product did not require further purification. LC-MS (ESI): m / z = 478 [M + H] ⁺ .

Synthesis of compound 63

7N ammonia in methanol (5 mL, 35 mmol) was added to a solution of compound 63-a (500 mg, 1.05 mmol) in tetrahydrofuran (10 mL). The mixture was stirred for 1 hour at room temperature. Concentrated under reduced pressure, the residue was added with methanol (10 mL) to produce a solid, filtered, the filter cake was washed with methanol (5 mL), and the compound 63 (207 mg, yield: 49%) was obtained after vacuum drying. LC-MS (ESI): m / z = 415 [M + H] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ ) δ: 8.59-8.58 (d, J = 2.8Hz, 1H), 7.81-7.79 (d, J = 6.0Hz, 1H), 7.71-7.69 (d, J = 6.4Hz , 1H), 7.50-7.48 (m, 1H), 7.44-7.42 (m, 1H), 6.63 (s, 1H), 6.26-6.25 (m, 1H), 5.23 (s, 2H), 3.91-3.90 (m , 2H), 2.46 (s, 3H), 1.34-1.31 (m, 3H) ppm.

Example 64: (E) -2-amino-4- (5-methylfuran-2-yl) -7- (2- (trifluoromethyl) phenylmethenyl) -6,7-dihydro -5H-pyrrole [3,4-d] pyrimidin-5-one (Compound 64)

Synthesis of compound 64-d

Dissolve 2,4-dimethoxybenzylamine (1.67 g, 10.0 mmol) and compound 62-d (1.53 g, 5.0 mmol), sodium acetate (1.78 g, 13.07 mmol) in methanol (20 mL) and dichloromethane To a mixed solvent (50 mL), acetic acid (600 mg, 10.0 mmol) was slowly added dropwise. After the mixture was stirred at room temperature for 2 hours, sodium cyanoborohydride (472.5 mg, 7.5 mmol) was added in portions, and the reaction mixture was stirred for another 12 hours. It was concentrated under reduced pressure, the residue was diluted with water (50 mL), and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed with water (100 mL) and saturated brine (100 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1-5: 1) to obtain 64-d (1.2 g, yield: 58%) as a yellow solid. LC-MS (ESI): m / z = 412 [M + H] ⁺ .

Synthesis of compound 64-c

A solution of compound 64-d (206 mg, 0.5 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise to a 1.0 M solution of potassium hexamethyldisilazide in tetrahydrofuran (0.6 mL, 0.6 mmol) at -78 ° C under a nitrogen atmosphere. )in. After stirring for 1 hour, a solution of 2- (trifluoromethyl) benzaldehyde (87 mg, 0.5 mmol) in anhydrous tetrahydrofuran (5 mL) was added dropwise, and stirring was continued for 1 hour. The reaction solution was slowly warmed to room temperature, and the reaction was quenched by the addition of a saturated ammonium chloride solution (50 mL), and then extracted with ethyl acetate (50 mL × 3). The organic phase was washed with water (50 mL) and saturated brine (50 mL). It was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1-1: 1) to obtain 64-c (120 mg, yield: 42) as a pale yellow solid. %). LC-MS (ESI): m / z = 568 [M + H] ⁺ .

Synthesis of compound 64-b

Compound 64-c (120 mg, 0.21 mmol) was dissolved in trifluoroacetic acid (10 mL), and the reaction solution was stirred at 75 ° C for 3 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (100 mL), and then washed sequentially with a saturated sodium bicarbonate solution (20 mL), water (20 mL) and saturated brine (20 mL). The organic phase It was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 64-b (120 mg) as a yellow solid, which was obtained without further purification. LC-MS (ESI): m / z = 418 [M + H] ⁺ .

Synthesis of compound 64-a

80% m-chloroperoxybenzoic acid (103.5 mg, 0.6 mmol) was added to a dichloromethane (10 mL) solution of compound 64-b (120 mg), and the mixture was stirred at room temperature for 2 hours. The reaction was quenched by the addition of a saturated sodium thiosulfate solution (10 mL). Water (20 mL) was added, and dichloromethane (20 mL × 3) was extracted. The combined organic phases were washed with water (20 mL) and saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1-3: 1) to obtain 64-a (36 mg, yield: 40%) as a yellow solid. LC-MS (ESI): m / z = 450 [M + H] ⁺ .

Synthesis of compound 64

7N ammonia in methanol (1 mL, 7 mmol) was added to a solution of compound 64-a (36 mg, 0.08 mmol) in tetrahydrofuran (6 mL). The mixture was stirred for 1 hour at room temperature. Concentrated under reduced pressure, the residue was added with methanol (3 mL) to produce a solid, filtered, the filter cake was washed with methanol (1 mL), and the compound 64 (11 mg, yield: 35%) was obtained after vacuum drying. LC-MS (ESI): m / z = 387 [M + H] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ ) δ: 10.48 (s, 1H), 8.46 (d, J = 2.4Hz, 1H), 8.20 (d, J = 6.0Hz, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.65-7.74 (m, 3H), 6.95 (bs, 1H), 6.66 (s, 1H), 6.39 (d, J = 2.4 Hz, 1H), 2.39 (s, 3H) ppm.

Example 65: (E) -2-amino-6-cyclopropyl-7- (2-fluorophenylmethenyl) -4- (5-methylfuran-2-yl) -6,7-di Hydrogen-5H-pyrrole [3,4-d] pyrimidin-5-one (compound 65)

Synthesis of compound 65-c

Acetic acid (1.06 g, 16.6 mmol) was slowly added dropwise to a mixed solvent of cyclopropylamine (950 mg, 16.6 mmol) and compound 62-d (1.7 g, 5.55 mmol) in methanol (10 mL) and dichloromethane (30 mL). The mixture was stirred at room temperature for 2 hours, and sodium cyanoborohydride (520 mg, 8.25 mmol) was added in portions. The reaction mixture was stirred at room temperature for 12 hours. The reaction solution was diluted with water (100 mL), and extracted with dichloromethane (50 mL × 3). The combined organic phases were washed with water (100 mL) and saturated brine (100 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 200: 1-20: 1) to obtain 65-c (1.5 g, yield: 89%) as a white solid. LC-MS (ESI): m / z = 302 [M + H] ⁺ .

Synthesis of compound 65-b

1,8-Diazabicycloundec-7-ene (375 mg, 2.5 mmol) was added to two compounds of 65-c (500 mg, 1.67 mmol) and 2-fluorobenzaldehyde (310 mg, 2, 5 mmol). Of oxane (10 mL). The mixture was refluxed under nitrogen for 12 hours, and then cooled to room temperature. It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain 65-b (320 mg, yield: 47%) as a yellow solid. LC-MS (ESI): m / z = 408 [M + H] ⁺ .

Synthesis of compound 65-a

80% m-chloroperoxybenzoic acid (405 mg, 2.0 mmol) was added to a dichloromethane (10 mL) solution of compound 65-b (320 mg, 0.78 mmol), and stirred at room temperature for 1 hour. The reaction was quenched by the addition of a saturated sodium thiosulfate solution (10 mL). Water (20 mL) was added, and dichloromethane (20 mL × 3) was extracted. The combined organic phases were washed with water (20 mL) and saturated brine (20 mL), and concentrated under reduced pressure to obtain 65-a (130 mg, yield: 38%) as a yellow solid. ), This product was used without further purification. LC-MS (ESI): m / z = 428 [M + H] ⁺ .

Synthesis of compound 65

7N ammonia in methanol (3 mL, 21 mmol) was added to a solution of compound 65-a (130 mg, 0.29 mmol) in tetrahydrofuran (15 mL). The mixture was stirred for 1 hour at room temperature. Concentrated under reduced pressure, the residue was added with methanol (6 mL) to produce a solid, ultrasonically ultrasonicated for one minute, filtered, the filter cake was washed with methanol (3 mL), and the compound 65 (84 mg, yield: 75%) was obtained after vacuum drying.

LC-MS (ESI): m / z = 377 [M + H] ⁺ .

¹ H-NMR (500MHz, CDCl ₃ ) δ: 8.58 (d, J = 3 Hz, 1H), 8.07 (m, 1H), 7.28 (m, 1H), 6.95 (s, 1H), 6.25 (m, 1H) , 5.20 (br, 2H), 2.67 (m, 1H), 2.47 (s, 3H), 1.17 (m, 2H), 1.04 (m, 2H) ppm.

Example 66: (E) -2-amino-7- (4-fluoro-2- (trifluoromethyl) phenylmethenyl) -4- (5-methylfuran-2-yl) -6, 7-Dihydro-5H-pyrrole [3,4-d] pyrimidin-5-one (Compound 66)

Synthesis of compound 66-c

A solution of compound 64-d (411 mg, 1.0 mmol) in anhydrous tetrahydrofuran (15 mL) was added dropwise to a 1.0 M solution of potassium hexamethyldisilazide in tetrahydrofuran (1.0 mL, 1.0 mmol) at -78 ° C under a nitrogen atmosphere. )in. After stirring for 1 hour, a solution of 2- (trifluoromethyl) -4-fluorobenzaldehyde (192 mg, 1.0 mmol) in anhydrous tetrahydrofuran (5 mL) was added dropwise, and stirring was continued for 1 hour. The reaction solution was slowly warmed to room temperature, and the reaction was quenched by adding saturated ammonium chloride solution (50 mL), and then extracted with ethyl acetate (50 mL × 3). The organic phase was washed with water (50 mL) and saturated brine (50 mL), It was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1-1: 1) to obtain 66-c (150 mg, yield: 25) as a pale yellow solid. %). LC-MS (ESI): m / z = 586 [M + H] ⁺ .

Synthesis of compound 66-b

Compound 66-c (150 mg, 0.25 mmol) was dissolved in trifluoroacetic acid (10 mL), and the reaction solution was stirred at 75 ° C for 3 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (100 mL), and then washed sequentially with a saturated sodium bicarbonate solution (20 mL), water (20 mL) and saturated brine (20 mL). The organic phase It was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 66-b (100 mg) as a yellow solid, which was obtained without further purification. LC-MS (ESI): m / z = 436 [M + H] ⁺ .

Synthesis of compound 66-a

80% m-chloroperoxybenzoic acid (103.5 mg, 0.6 mmol) was added to a dichloromethane (10 mL) solution of compound 66-b (100 mg), and the mixture was stirred at room temperature for 2 hours. The reaction was quenched by the addition of a saturated sodium thiosulfate solution (10 mL). Water (20 mL) was added, and dichloromethane (20 mL × 3) was extracted. The combined organic phases were washed with water (20 mL) and saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1-3: 1) to obtain 66-a (50 mg, yield: 50%) as a yellow solid. LC-MS (ESI): m / z = 468 [M + H] ⁺ .

Synthesis of compound 66

7N ammonia in methanol (1 mL, 7 mmol) was added to a solution of compound 66-a (50 mg, 0.1 mmol) in tetrahydrofuran (6 mL). The mixture was stirred for 1 hour at room temperature. Concentrated under reduced pressure, the residue was added with methanol (3 mL) to produce a solid, filtered, the filter cake was washed with methanol (1 mL), and the compound 66 (3 mg, yield: 6.9%) was obtained after vacuum drying.

LC-MS (ESI): m / z = 405 [M + H] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ ) δ: 10.53 (s, 1H), 8.45 (d, J = 3.2Hz, 1H), 7.89-7.86 (m, 2H), 7.72-7.59 (m, 4H), 6.81 (bs, 1H), 6.41 (d, J = 2.0 Hz, 1H), 2.40 (s, 3H) ppm.

Example 67: (E) -2-amino-7- (2-fluorophenylmethenyl) -6-methyl-4- (1-methyl-1H-pyrazol-3-yl) -6, 7-Dihydro-5H-pyrrole [3,4-d] pyrimidin-5-one (Compound 67)

Synthesis of compound 67-f

Add sodium bicarbonate (15.2g, 181.6mmol) to 1-methylpyrazole-3-carboxaldehyde (5.0g, 45.4mmol), S-methylisothiourea sulfate (7.58g, 27.2mmol) and ethyl acetoacetate Ester (6.49 g, 49.4 mmol) in a solution of N, N-dimethylformamide (100 mL). After the reaction mixture was stirred at 70 ° C for 3 hours, it was cooled to room temperature. Concentrated under reduced pressure, the residue was added with water (100 mL) and extracted with ethyl acetate (500 mL × 2). The combined organic phases were washed with water (200 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1-1: 1) to obtain 67-f (3.9 g, yield: 30%) as an off-white solid. LC-MS (ESI): m / z = 295 [M + H] ⁺ .

Synthesis of compound 67-e

In an ice water bath, 2,3-dichloro-5,6-dicyano-p-benzoquinone (4.51 g, 19.8 mmol) was added portionwise to compound 67-f (3.9 g, 13.2 mmol) in dichloromethane (200 mL). The solution was warmed to room temperature and stirred for 16 hours. Filter and wash the filter cake with dichloromethane (50 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 6: 1-3: 1) to obtain 67-e (3.0 g, yield: 77%) as a white solid. LC-MS (ESI): m / z = 293 [M + H] ⁺ .

Synthesis of compound 67-d

Compound 67-e (3.0 g, 10.27 mmol) was dissolved in 1,4-dioxane (60 mL), and selenium dioxide (1.71 g, 15.41 mmol) and glacial acetic acid (1.0 mL) were added. After the reaction solution was refluxed for 8 hours, it was cooled to room temperature. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (60 mL). Filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1-1: 1) to obtain 67-d (1.0 g, yield: 32%) as a white solid. LC-MS (ESI): m / z = 307 [M + H] ⁺ .

Synthesis of compound 67-c

Methylamine hydrochloride (882 mg, 13.0 mmol) and sodium acetate (1.76 g, 13.0 mmol) were added to methanol (50 mL). After the mixture was stirred at room temperature for 1 hour, the ice-water bath was cooled to 0 ° C, and then compound 67-d (1.0 g, 3.26 mmol) and dichloromethane (50 mL) were added. After stirring for 30 minutes, sodium cyanoborohydride (368 mg, 4.89 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for another 12 hours. It was concentrated under reduced pressure, the residue was diluted with water (100 mL), and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed with water (100 mL) and saturated brine (100 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1-2: 1) to obtain 67-c (750 mg, yield: 84%) as a yellow solid. LC-MS (ESI): m / z = 276 [M + H] ⁺ .

Synthesis of compound 67-b

1,8-Diazabicycloundec-7-ene (76 mg, 0.5 mmol) was added to the dioxin of compound 67-c (275 mg, 1.0 mmol) and 2-fluorobenzaldehyde (500 mg, 2.6 mmol) Hexacyclic (20 mL) solution. The mixture was refluxed under nitrogen for 12 hours, and then cooled to room temperature. It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15: 1-10: 1) to obtain 67-b (230 mg, yield: 60%) as a yellow solid. LC-MS (ESI): m / z = 382 [M + H] ⁺ .

Synthesis of compound 67-a

80% m-chloroperoxybenzoic acid (310 mg, 1.8 mmol) was added to a solution of compound 67-b (230 mg, 0.6 mmol) in dichloromethane (10 mL), and the mixture was stirred at room temperature for 1 hour. The reaction was quenched by the addition of a saturated sodium thiosulfate solution (10 mL). Water (20 mL) was added, and dichloromethane (20 mL × 3) was extracted. The combined organic phases were washed with water (20 mL) and saturated brine (20 mL), and concentrated under reduced pressure to give a yellow solid. This solid was added to N, N-dimethylformamide (10 mL), ultrasonically filtered for 1 minute, the filter cake was washed with methanol (10 mL), and the product 67-a (150 mg, yield: 60 was obtained after vacuum drying). %), This product was used without further purification.

LC-MS (ESI): m / z = 414 [M + H] ⁺ .

Synthesis of compound 67

7N ammonia in methanol (0.15 mL, 1.05 mmol) was added to a solution of compound 67-a (150 mg, 0.36 mmol) in tetrahydrofuran (15 mL). The mixture was stirred for 1 hour at room temperature. Concentrated under reduced pressure, the residue was added with methanol (6 mL), and a solid was formed. After 1 minute of ultrasonication and filtration, the filter cake was washed with methanol (3 mL) and dried under vacuum to obtain a yellow solid 67 (22 mg, yield: 18%). LC-MS (ESI): m / z = 351 [M + H] ⁺ .

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 8.39 (t, J = 7.5 Hz, 1H), 7.80 (s, 1H), 7.60 (s, 1H), 7.39-7.36 (m, 1H), 7.25 -7.14 (m, 2H), 6.50 (s, 1H), 3.94 (s, 3H), 3.25 (s, 3H) ppm.

Example 68: (E) -2-amino-7- (2-fluoro-4- (trifluoromethyl) phenylmethenyl) -4- (5-methylfuran-2-yl) furan [3 , 4-d] pyrimidin-5 (7H) -one (Compound 68)

Synthesis of compound 68-d

Compound 62-d (1.53 g, 5.0 mmol) was dissolved in a mixed solution of methanol (5 mL) and tetrahydrofuran (30 mL), cooled to 0 ° C in an ice water bath, and sodium borohydride (209 mg, 5.5 mmol) was added in portions. The reaction solution was slowly warmed to room temperature, and stirring was continued for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was added with water (30 mL) and ethyl acetate (100 mL). The organic phase was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1-1: 1) to obtain 68-d (1.1 g, yield: 84%) as a yellow solid. LC-MS (ESI): m / z = 263 [M + H] ⁺ .

Synthesis of compound 68-c

1,8-Diazabicycloundec-7-ene (304 mg, 2.0 mmol) was added to compound 68-d (524 mg, 2.0 mmol) and 2-fluoro-4- (trifluoromethyl) benzaldehyde (384 mg, 2.6 mmol) in a solution of dioxane (20 mL). The mixture was stirred at 120 ° C for 3 hours under a nitrogen atmosphere, and then cooled to room temperature. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 25: 1-10: 1) to obtain 68-c (550 mg, yield: 60%) as a pink solid. LC-MS (ESI): m / z = 455 [M + H] ⁺ .

Synthesis of compound 68-b

Compound 68-c (550 mg, 1.2 mmol) and p-toluenesulfonic acid (414 mg, 2.4 mmol) were added to anhydrous toluene (30 mL). The reaction solution was stirred at 120 ° C for 6 hours, and then cooled to room temperature. It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 12: 1-5: 1) to obtain 68-b (450 mg, yield: 86%) as a pale yellow solid. LC-MS (ESI): m / z = 437 [M + H] ⁺ .

Synthesis of compound 68-a

80% m-chloroperoxybenzoic acid (517 mg, 3.0 mmol) was added to a dichloromethane (30 mL) solution of compound 68-b (450 mg, 1.0 mmol), and stirred at room temperature for 3 hours. The reaction was quenched by the addition of a saturated sodium thiosulfate solution (30 mL). Water (50 mL) was added, and dichloromethane (50 mL × 3) was extracted. The combined organic phases were washed with water (30 mL) and saturated brine (30 mL), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate) Ester = 5: 1-1: 1) to obtain 68-a (170 mg, yield: 36%) as a yellow solid. LC-MS (ESI): m / z = 446 [M + H] ⁺ .

Synthesis of compound 68

7N ammonia in methanol (0.35 mL, 2.25 mmol) was added to a solution of compound 68-a (120 mg, 0.25 mmol) in tetrahydrofuran (10 mL). The mixture was stirred at room temperature for 2 hours. Concentrated under reduced pressure, the residue was added with methanol (6 mL) to produce a solid. After 1 minute of ultrasonication and filtering, the filter cake was washed with methanol (3 mL) and dried under vacuum to obtain 68 (25 mg, yield: 25%) as a yellow solid. LC-MS (ESI): m / z = 404 [M + H] ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 8.32-8.29 (m, 2H), 8.20 (d, J = 2.4Hz, 1H), 8.08 (s, 1H), 7.81-7.75 (m, 2H) , 6.81 (s, 1H), 6.48 (d, J = 1.6 Hz, 1H), 2.42 (s, 3H) ppm.

Example 69: (E) -2-amino-4- (5-chlorofuran-2-yl) -7- (2-fluorophenylmethenyl) -6-methyl-6,7-dihydro- 5H-pyrrole [3,4-d] pyrimidin-5-one (Compound 69)

Synthesis of compound 69-f

Sodium bicarbonate (8.5g, 80mmol) was added to 2-chloro-5-furanaldehyde (5.2g, 40mmol), S-methylisothiourea sulfate (8.3g, 60mmol) and ethyl acetoacetate (5.2g, 40 mmol) in a solution of N, N-dimethylformyl (40 mL). After the reaction mixture was stirred at 80 ° C for 6 hours, it was cooled to room temperature. Concentrated under reduced pressure, the residue was added with water (100 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with water (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15: 1) to obtain an off-white solid 69-f (3.3 g, yield: 27%). LC-MS (ESI): m / z = 315 [M + H] ⁺ .

Synthesis of compound 69-e

In an ice-water bath, 2,3-dichloro-5,6-dicyano-p-benzoquinone (3.0 g, 13.2 mmol) was added portionwise to a solution of compound 69-f (3.14 g, 10 mmol) in dichloromethane (100 mL). The reaction solution was warmed to room temperature and stirred for 16 hours. Filter and wash the filter cake with dichloromethane (50 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 12: 1) to obtain 69-e (2.44 g, yield: 78%) as a yellow solid. LC-MS (ESI): m / z = 313 [M + H] ⁺ .

Synthesis of compound 69-d

Compound 69-e (2.4 g, 7.7 mmol) was dissolved in 1,4-dioxane (40 mL), and selenium dioxide (1.0 g, 9.1 mmol) and glacial acetic acid (2.0 mL) were added. After the reaction solution was refluxed for 8 hours, it was cooled to room temperature. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (60 mL). Filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8: 1-5: 1) to obtain 69-d (1.63 g, yield: 65%) as a yellow solid. LC-MS (ESI): m / z = 327 [M + H] ⁺ .

Synthesis of compound 69-c

Methylamine hydrochloride (938 mg, 13.8 mmol) and sodium acetate (1.13 g, 13.8 mmol) were added to methanol (40 mL). After the mixture was stirred at room temperature for 1 hour, the ice-water bath was cooled to 0 ° C, and then compound 69-d (1.5 g, 4.6 mmol) and dichloromethane (40 mL) were added. After stirring for 30 minutes, sodium cyanoborohydride (434 mg, 6.9 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for 16 hours. It was concentrated under reduced pressure, the residue was diluted with water (100 mL), and extracted with dichloromethane (60 mL × 2). The combined organic phases were washed with water (100 mL) and saturated brine (100 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain 69-c (840 mg, yield: 62%) as a yellow solid. LC-MS (ESI): m / z = 296 [M + H] ⁺ .

Synthesis of compound 69-b

1,8-Diazabicycloundec-7-ene (304 mg, 2.0 mmol) was added to the dioxin of compound 69-c (295 mg, 1.0 mmol) and 2-fluorobenzaldehyde (248 mg, 2.0 mmol) Hexacyclic (20 mL) solution. The mixture was refluxed under nitrogen for 12 hours, and then cooled to room temperature. It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1-10: 1) to obtain 69-b (250 mg, yield: 62%) as a yellow solid. LC-MS (ESI): m / z = 402 [M + H] ⁺ .

Synthesis of compound 69-a

80% m-chloroperoxybenzoic acid (322 mg, 1.87 mmol) was added to a dichloromethane (30 mL) solution of compound 69-b (250 mg, 0.62 mmol), and stirred at room temperature for 1 hour. The reaction was quenched by the addition of a saturated sodium thiosulfate solution (10 mL). Water (20 mL) was added, and dichloromethane (20 mL × 3) was extracted. The combined organic phases were washed with water (20 mL) and saturated brine (20 mL), and concentrated under reduced pressure to give a yellow solid. This solid was added to methanol (10 mL), ultrasonically filtered for 1 minute, the filter cake was washed with methanol (3 mL), and the product 69-a (250 mg, yield: 92%) was obtained after vacuum drying. This product did not require further purification. . LC-MS (ESI): m / z = 434 [M + H] ⁺ .

Synthesis of compound 69

7N ammonia in methanol (0.5 mL, 3.5 mmol) was added to a solution of compound 69-a (86.5 mg, 0.2 mmol) in tetrahydrofuran (10 mL). The mixture was stirred for 1 hour at room temperature. Concentrated under reduced pressure, the residue was added with methanol (6 mL) to produce a solid. After 1 minute of ultrasonication and filtration, the filter cake was washed with methanol (3 mL) and dried under vacuum to obtain a yellow solid 69 (22 mg, yield: 29%).

LC-MS (ESI): m / z = 371 [M + H] ⁺ .

¹ H-NMR (400MHz DMSO-d ₆ ) δ: 8.54 (s, 1H), 8.53-8.35 (m, 1H), 7.75-7.65 (bs, 1H), 7.41-7.37 (m, 1H), 7.30-7.21 (m, 3H), 6.81 (s, 1H), 7.55 (s, 1H), 3.26 (s, 3H) ppm.

Example 70: (E) -2-amino-4- (5-chlorofuran-2-yl) -7- (2- (trifluoromethyl) phenylmethenyl) -6-methyl-6, 7-Dihydro-5H-pyrrole [3,4-d] pyrimidin-5-one (Compound 70)

synthetic route

Synthesis of compound 70-b

1,8-Diazabicycloundec-7-ene (205 mg, 1.35 mmol) was added to compound 69-c (200 mg, 0.68 mmol) and 2- (trifluoromethyl) benzaldehyde (235 mg, 1.35 mmol) in dioxane (20 mL). The mixture was refluxed under nitrogen for 12 hours, and then cooled to room temperature. It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1-10: 1) to obtain 70-b (250 mg, yield: 67%) as a yellow solid. LC-MS (ESI): m / z = 452 [M + H] ⁺ .

Synthesis of compound 70-a

80% m-chloroperoxybenzoic acid (287 mg, 1.66 mmol) was added to a solution of compound 70-b (250 mg, 0.55 mmol) in dichloromethane (30 mL), and the mixture was stirred at room temperature for 1 hour. The reaction was quenched by the addition of a saturated sodium thiosulfate solution (10 mL). Water (20 mL) was added, and dichloromethane (20 mL × 3) was extracted. The combined organic phases were washed with water (20 mL) and saturated brine (20 mL), and concentrated under reduced pressure to give a yellow solid. This solid was added to methanol (10 mL), ultrasonically filtered for 1 minute, the filter cake was washed with methanol (3 mL), and the product 70-a (150 mg, yield: 56%) was obtained after vacuum drying. This product did not require further purification. . LC-MS (ESI): m / z = 484 [M + H] ⁺ .

Synthesis of compound 70

7N ammonia in methanol (1.0 mL, 7 mmol) was added to a solution of compound 70-a (150 mg, 0.32 mmol) in tetrahydrofuran (10 mL). The mixture was stirred for 1 hour at room temperature. Concentrated under reduced pressure, the residue was added with methanol (6 mL), and a solid was formed. After 1 minute of ultrasonication and filtration, the filter cake was washed with methanol (3 mL) and dried under vacuum to obtain 70 (100 mg, yield: 76%) as a yellow solid.

LC-MS (ESI): m / z = 421 [M + H] ⁺ .

¹ H-NMR (400MHz DMSO-d ₆ ) δ: 8.54 (s, 1H), 8.38-8.35 (m, 1H), 7.85-7.65 (bs, 1H), 7.40-7.37 (m, 1H), 7.30-7.21 (m, 3H), 6.81 (s, 1H), 7.55 (s, 1H), 3.26 (s, 3H) ppm.

Example 71: (E) -2-amino-6-cyclopropyl-4- (1-methyl-1H-pyrazol-3-yl) -7- (2- (trifluoromethoxy) phenyl (Methenyl) -6,7-dihydro-5H-pyrrole [3,4-d] pyrimidin-5-one (Compound 71)

Synthesis of compound 71-c

Acetic acid (1.06 g, 16.6 mmol) was slowly added dropwise to a mixed solvent of cyclopropylamine (950 mg, 16.6 mmol) and compound 67-d (1.7 g, 5.55 mmol) in methanol (10 mL) and dichloromethane (30 mL). The mixture was stirred at room temperature for 2 hours, and sodium cyanoborohydride (520 mg, 8.25 mmol) was added in portions. The reaction mixture was stirred at room temperature for 12 hours. The reaction solution was diluted with water (100 mL), and extracted with dichloromethane (50 mL × 3). The combined organic phases were washed with water (100 mL) and saturated brine (100 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 200: 1-20: 1) to obtain 71-c (1.5 g, yield: 89%) as a white solid. LC-MS (ESI): m / z = 302 [M + H] ⁺ .

Synthesis of compound 71-b

1,8-Diazabicycloundec-7-ene (304 mg, 2.0 mmol) was added to compound 71-c (300 mg, 1.0 mmol) and 2- (trifluoromethoxy) benzaldehyde (380 mg, 2.0 mmol) in dioxane (20 mL). The mixture was refluxed under nitrogen for 12 hours, and then cooled to room temperature. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15: 1-10: 1) to obtain 71-b (300 mg, yield: 64%) as a yellow solid. LC-MS (ESI): m / z = 474 [M + H] ⁺ .

Synthesis of compound 71-a

80% m-chloroperoxybenzoic acid (383 mg, 2.21 mmol) was added to a dichloromethane (10 mL) solution of compound 71-b (300 mg, 0.63 mmol), and stirred at room temperature for 1 hour. The reaction was quenched by the addition of a saturated sodium thiosulfate solution (10 mL). Water (20 mL) was added, and dichloromethane (20 mL × 3) was extracted. The combined organic phases were washed with water (20 mL) and saturated brine (20 mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate). Ester = 10: 1-2: 1) gave 71-a (300 mg, yield: 93%) as a yellow solid. LC-MS (ESI): m / z = 506 [M + H] ⁺ .

Synthesis of compound 71

7N ammonia in methanol (0.43 mL, 3.01 mmol) was added to a solution of compound 71-a (300 mg, 0.59 mmol) in tetrahydrofuran (15 mL). The mixture was stirred for 1 hour at room temperature. Concentrated under reduced pressure, the residue was added with methanol (6 mL) to produce a solid. After 1 minute of ultrasonication and filtering, the filter cake was washed with methanol (3 mL) and dried under vacuum to obtain a yellow solid 71 (90 mg, yield: 66%).

LC-MS (ESI): m / z = 443 [M + H] ⁺ .

¹ H-NMR: (400MHz, DMSO-d ₆ ) δ: 8.96 (s, 1H), 8.59-8.57 (m, 1H), 8.35 (s, 1H), 7.49-7.39 (m, 3H), 7.23-7.15 (bs, 2H), 6.93 (s, 1H), 3.96 (s, 3H), 2.67-2.63 (m, 1H), 1.11-1.07 (m, 2H), 0.91-0.89 (m, 2H) ppm.

Example 72: (E) -2-amino-6-ethyl-4- (1-methyl-1H-pyrazol-3-yl) -7- (2- (trifluoromethoxy) phenylmethyl) Alkenyl) -6,7-dihydro-5H-pyrrole [3,4-d] pyrimidin-5-one (Compound 72)

Synthesis of compound 72-c

Ethylamine hydrochloride (972 mg, 12.0 mmol) and sodium acetate (984 mg, 12.0 mmol) were added to methanol (50 mL). After the mixture was stirred at room temperature for 0.5 hours, the ice-water bath was cooled to 0 ° C, and then compound 67-d (1.1 g, 3.0 mmol) and dichloromethane (30 mL) were added. After stirring for 30 minutes, sodium cyanoborohydride (283.5 mg, 4.5 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for another 12 hours. It was concentrated under reduced pressure, the residue was diluted with water (100 mL), and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed with water (100 mL) and saturated brine (100 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1-1: 1) to obtain 72-c (650 mg, yield: 75%) as a yellow solid. LC-MS (ESI): m / z = 290 [M + H] ⁺ .

Synthesis of compound 72-b

1,8-Diazabicycloundec-7-ene (152 mg, 1.0 mmol) was added to compound 72-c (145 mg, 0.5 mmol) and 2- (trifluoromethoxy) benzaldehyde (190 mg, 1.0 mmol) in absolute ethanol (15 mL). The mixture was refluxed under nitrogen for 12 hours, and then cooled to room temperature. The solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15: 1-10: 1) to obtain 72-b (125 mg, yield: 54%) as a yellow solid. LC-MS (ESI): m / z = 462 [M + H] ⁺ .

Synthesis of compound 72-a

80% m-chloroperoxybenzoic acid (120 mg, 0.81 mmol) was added to a dichloromethane (15 mL) solution of compound 72-b (125 mg, 0.27 mmol), and stirred at room temperature for 1 hour. The reaction was quenched by the addition of a saturated sodium thiosulfate solution (10 mL). Water (20 mL) was added, and dichloromethane (20 mL × 3) was extracted. The combined organic phases were washed with water (20 mL) and saturated brine (20 mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate). Ester = 3: 1-1: 1) gave 72-a (90 mg, yield: 68%) as a yellow solid. LC-MS (ESI): m / z = 494 [M + H] ⁺ .

Synthesis of compound 72

7N ammonia in methanol (0.5 mL, 3.5 mmol) was added to a solution of compound 72-a (90 mg, 0.18 mmol) in tetrahydrofuran (15 mL). The mixture was stirred for 1 hour at room temperature. Concentrated under reduced pressure, the residue was added with methanol (6 mL) to produce a solid. After 1 minute of ultrasonication and filtering, the filter cake was washed with methanol (3 mL) and dried under vacuum to obtain a yellow solid 72 (48 mg, yield: 62%).

LC-MS (ESI): m / z = 431 [M + H] ⁺ .

¹ H-NMR: (400MHz, DMSO-d ₆ ) δ: 8.38 (s, 1H), 8.33 (d, J = 6.4Hz, 1H), 7.49-7.38 (m, 3H), 7.37-7.00 (bs, 2H ), 6.54 (s, 1H), 3.95 (s, 3H), 3.88-3.84 (q, J ₁ = 6.4 Hz, J ₂ = 11.6 Hz, 2 H), 1.19 (t, J = 6.4 Hz, 3 H) ppm.

Example 73: (E) -2-amino-6-cyclopropyl-4- (1-methyl-1H-pyrazol-3-yl) -7- (2-fluorophenylmethenyl) -6 , 7-dihydro-5H-pyrrole [3,4-d] pyrimidin-5-one (Compound 73)

Synthesis of compound 73-b

1,8-Diazabicycloundec-7-ene (152 mg, 1.0 mmol) was added to compound 71-c (150 mg, 0.5 mmol) and 2-fluorobenzaldehyde (124 mg, 1.0 mmol) in anhydrous In ethanol (10 mL). The mixture was refluxed under nitrogen for 12 hours, and then cooled to room temperature. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15: 1-10: 1) to obtain 73-b (145 mg, yield: 71%) as a yellow solid. LC-MS (ESI): m / z = 408 [M + H] ⁺ .

Synthesis of compound 73-a

80% m-chloroperoxybenzoic acid (181 mg, 1.0 mmol) was added to a dichloromethane (15 mL) solution of compound 73-b (145 mg, 0.35 mmol), and stirred at room temperature for 1 hour. The reaction was quenched by the addition of a saturated sodium thiosulfate solution (10 mL). Water (20 mL) was added, and dichloromethane (20 mL × 3) was extracted. The combined organic phases were washed with water (20 mL) and saturated brine (20 mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate). Ester = 5: 1-1: 1) gave 73-a (150 mg, yield: 96%) as a yellow solid. LC-MS (ESI): m / z = 440 [M + H] ⁺ .

Synthesis of compound 73

7N ammonia in methanol (0.32 mL, 2.24 mmol) was added to a solution of compound 73-a (100 mg, 0.22 mmol) in tetrahydrofuran (15 mL). The mixture was stirred for 1 hour at room temperature. Concentrated under reduced pressure, methanol (6 mL) was added to the residue to produce a solid, and the mixture was filtered by ultrasonication for 1 minute. The filter cake was washed with methanol (3 mL) and dried under vacuum to obtain a yellow solid 73 (50 mg, yield: 60%).

LC-MS (ESI): m / z = 377 [M + H] ⁺ .

¹ H-NMR: (400MHz, DMSO-d ₆ ) δ: 8.97 (s, 1H), 8.51-8.48 (m, 1H), 8.36 (s, 1H), 7.37-7.35 (m, 1H), 7.25-7.18 (m, 2H), 6.90 (s, 1H), 3.93 (s, 3H), 2.67-2.63 (m, 1H), 1.11-1.07 (m, 2H), 0.91-0.89 (m, 2H) ppm.

Example 74: (E) -2-amino-6-cyclopropyl-4- (1-methyl-1H-pyrazol-3-yl) -7- (2- (trifluoromethyl) phenylmethyl) Alkenyl) -6,7-dihydro-5H-pyrrole [3,4-d] pyrimidin-5-one (Compound 74)

Synthesis of compound 74-b

1,8-Diazabicycloundec-7-ene (152 mg, 1.0 mmol) was added to compound 71-c (150 mg, 0.5 mmol) and 2- (trifluoromethyl) benzaldehyde (174 mg, 1.0 mmol) in absolute ethanol (10 mL). The mixture was refluxed for 4 hours under the protection of nitrogen, cooled to room temperature, solids were formed, filtered, and the filter cake was dried under vacuum to obtain 74-b (150 mg, yield: 66%) as a yellow solid. This compound did not require further purification. LC-MS (ESI): m / z = 458 [M + H] ⁺ .

Synthesis of compound 74-a

80% m-chloroperoxybenzoic acid (170 mg, 0.98 mmol) was added to a solution of compound 74-b (150 mg, 0.33 mmol) in dichloromethane (15 mL), and the mixture was stirred at room temperature for 1 hour. The reaction was quenched by the addition of a saturated sodium thiosulfate solution (10 mL). Water (20 mL) was added, and dichloromethane (20 mL × 3) was extracted. The combined organic phases were washed with water (20 mL) and saturated brine (20 mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate). Ester = 5: 1-1: 1) gave 74-a (140 mg, yield: 87%) as a yellow solid. LC-MS (ESI): m / z = 490 [M + H] ⁺ .

Synthesis of compound 74

7N ammonia in methanol (0.4 mL, 2.8 mmol) was added to a solution of compound 74-a (140 mg, 0.28 mmol) in tetrahydrofuran (15 mL). The mixture was stirred for 1 hour at room temperature. Concentrated under reduced pressure, the residue was added with methanol (6 mL), and a solid was formed. After 1 minute of ultrasonication and filtering, the filter cake was washed with methanol (3 mL) and dried under vacuum to obtain 74 (45 mg, yield: 38%) as a yellow solid.

LC-MS (ESI): m / z = 427 [M + H] ⁺ .

¹ H-NMR: (400MHz, DMSO-d ₆ ) δ: 8.95 (s, 1H), 8.33 (s, 1H), 8.05 (d, J = 6.0Hz, 1H), 7.76 (d, J = 6.4Hz, 1H), 7.66-7.62 (m, 1H), 7.55-7.51 (m, 1H), 7.30-6.98 (m, 3H), 3.94 (s, 3H), 2.66-2.63 (m, 1H), 1.11-1.06 ( m, 2H), 0.92-0.88 (m, 2H) ppm.

Example 75: (E) -2-amino-6-ethyl-4- (1-methyl-1H-pyrazol-3-yl) -7- (2-fluorophenylmethenyl) -6, 7-dihydro-5H-pyrrole [3,4-d] pyrimidin-5-one (compound 75)

Synthesis of compound 75-b

1,8-Diazabicycloundec-7-ene (304 mg, 2.0 mmol) was added to anhydrous compound 72-c (289 mg, 1.0 mmol) and 2-fluorobenzaldehyde (248 mg, 2.0 mmol). In ethanol (20 mL). The mixture was refluxed under nitrogen protection for 5 hours, cooled to room temperature, solids were formed, filtered, the filter cake was washed with ethanol (5 mL), and dried in vacuo to obtain 75-b (268 mg, yield: 67%) as a yellow solid. The compound was used without further purification. LC-MS (ESI): m / z = 390 [M + H] ⁺ .

Synthesis of compound 75-a

80% m-chloroperoxybenzoic acid (196.6 mg, 1.14 mmol) was added to a solution of compound 75-b (150 mg, 0.38 mmol) in dichloromethane (20 mL), and the mixture was stirred at room temperature for 1 hour. The reaction was quenched by the addition of a saturated sodium thiosulfate solution (10 mL). Water (20 mL) was added, and dichloromethane (20 mL × 3) was extracted. The combined organic phases were washed with water (20 mL) and saturated brine (20 mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate). Ester = 5: 1-2: 1) to give 75-a (140 mg, yield: 86%) as a white solid. LC-MS (ESI): m / z = 428 [M + H] ⁺ .

Synthesis of compound 75

7N ammonia in methanol (0.5 mL, 3.5 mmol) was added to a solution of compound 75-a (140 mg, 0.32 mmol) in tetrahydrofuran (15 mL). The mixture was stirred for 1 hour at room temperature. Concentrated under reduced pressure, the residue was added with methanol (10 mL), and a solid was formed. After 1 minute of ultrasonication and filtration, the filter cake was washed with methanol (3 mL) and dried under vacuum to obtain 75 (85 mg, yield: 71%) as a yellow solid.

LC-MS (ESI): m / z = 365 [M + H] ⁺ .

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 8.99 (s, 1H), 8.38 (s, 1H), 8.34-8.30 (m, 1H), 7.39-7.36 (m, 1H), 7.26-7.20 ( m, 4H), 6.56 (s, 1H), 3.94 (s, 3H), 3.89-3.85 (q, J = 6.0, Hz, 2H), 1.20 (t, J = 6.0 Hz, 3H) ppm.

Example 76: (E) -2-amino-6-ethyl-4- (1-methyl-1H-pyrazol-3-yl) -7- (2- (trifluoromethyl) phenylmethene ) -6,7-dihydro-5H-pyrrole [3,4-d] pyrimidin-5-one (Compound 76)

Synthesis of compound 76-b

1,8-Diazabicycloundec-7-ene (152 mg, 1.0 mmol) was added to compound 72-c (145 mg, 0.5 mmol) and 2- (trifluoromethyl) benzaldehyde (174 mg, 1.0 mmol) in absolute ethanol (20 mL). The mixture was refluxed under nitrogen protection for 5 hours, cooled to room temperature, solids were formed, filtered, the filter cake was washed with ethanol (5 mL), and dried in vacuo to obtain 76-b (90 mg, yield: 40%) as a yellow solid. The compound was used without further purification. LC-MS (ESI): m / z = 446 [M + H] ⁺ .

Synthesis of compound 76-a

80% m-chloroperoxybenzoic acid (172.5 mg, 1.0 mmol) was added to a solution of compound 76-b (90 mg, 0.2 mmol) in dichloromethane (15 mL), and the mixture was stirred at room temperature for 1 hour. The reaction was quenched by the addition of a saturated sodium thiosulfate solution (10 mL). Water (20 mL) was added, and dichloromethane (20 mL × 3) was extracted. The combined organic phases were washed with water (20 mL) and saturated brine (20 mL), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate Ester = 5: 1-2: 1) to give 76-a as a white solid (90 mg, yield: 95%). LC-MS (ESI): m / z = 478 [M + H] ⁺ .

Synthesis of compound 76

7N ammonia in methanol (0.3 mL, 2.1 mmol) was added to a solution of compound 76-a (90 mg, 0.19 mmol) in tetrahydrofuran (15 mL). The mixture was stirred for 1 hour at room temperature. Concentrated under reduced pressure, the residue was added with methanol (6 mL) to produce a solid. After 1 minute of ultrasonication and filtration, the filter cake was washed with methanol (3 mL) and dried under vacuum to obtain 76 (55 mg, yield: 70%) as a yellow solid.

LC-MS (ESI): m / z = 415 [M + H] ⁺ .

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 8.96 (s, 1H), 8.36 (s, 1H), 7.93 (d, J = 1.6Hz, 1H), 7.76 (d, J = 1.6Hz, 1H ), 7.65-7.62 (m, 1H), 7.55-7.52 (m, 1H), 7.30-6.50 (m, 3H), 3.94 (s, 3H), 3.86-3.82 (q, J = 6.4Hz, 2H), 1.20 (t, J = 6.4Hz, 3H) ppm.

Example 77: (E) -2-amino-6-cyclopropyl-4- (1-methyl-1H-pyrazol-3-yl) -7- (2,4-difluorophenylmethenyl) ) -6,7-dihydro-5H-pyrrole [3,4-d] pyrimidin-5-one (Compound 77)

Synthesis of compound 77-b

1,8-Diazabicycloundec-7-ene (152 mg, 1.0 mmol) was added to compound 71-c (150 mg, 0.5 mmol) and 2,4-difluorobenzaldehyde (142 mg, 1.0 mmol) Of absolute ethanol (15 mL). The mixture was refluxed for 4 hours under the protection of nitrogen, cooled to room temperature, solids were formed, filtered, and the filter cake was dried under vacuum to obtain 77-b (180 mg, yield: 85%) as a yellow solid. This compound did not require further purification. LC-MS (ESI): m / z = 426 [M + H] ⁺ .

Synthesis of compound 77-a

80% m-chloroperoxybenzoic acid (219 mg, 1.27 mmol) was added to a solution of compound 77-b (180 mg, 0.42 mmol) in dichloromethane (20 mL), and the mixture was stirred at room temperature for 3 hours. The reaction was quenched by the addition of a saturated sodium thiosulfate solution (10 mL). Water (20 mL) was added, and dichloromethane (20 mL × 3) was extracted. The combined organic phases were washed with water (20 mL) and saturated brine (20 mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate). Ester = 5: 1-1: 1) gave 77-a as a yellow solid (140 mg, yield: 73%). LC-MS (ESI): m / z = 458 [M + H] ⁺ .

Synthesis of compound 77

7N ammonia in methanol (0.4 mL, 2.8 mmol) was added to a solution of compound 77-a (140 mg, 0.3 mmol) in tetrahydrofuran (15 mL). The mixture was stirred for 1 hour at room temperature. Concentrated under reduced pressure, and the residue was added with methanol (6 mL) to produce a solid. After 1 minute of ultrasonication and filtering, the filter cake was washed with methanol (3 mL) and dried under vacuum to obtain 77 (45 mg, yield: 38%) as a yellow solid.

LC-MS (ESI): m / z = 395 [M + H] ⁺ .

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 8.97 (s, 1H), 8.59-8.54 (m, 1H), 8.35 (s, 1H), 7.28-7.07 (m, 4H), 6.81 (s, 1H), 3.94 (s, 3H), 2.67-2.64 (m, 1H), 1.11-1.07 (m, 2H), 0.92-0.89 (m, 2H) ppm.

Example 78: (E) -2-amino-6-cyclopropyl-4- (1-methyl-1H-pyrazol-3-yl) -7- (4-fluoro-2- (trifluoromethyl) ) Phenylmethenyl) -6,7-dihydro-5H-pyrrole [3,4-d] pyrimidin-5-one (Compound 78)

Synthesis of compound 78-b

1,8-Diazabicycloundec-7-ene (152 mg, 1.0 mmol) was added to compound 71-c (150 mg, 0.5 mmol) and 2-trifluoromethyl-4-fluorobenzaldehyde (192 mg , 1.0 mmol) in a solution of absolute ethanol (30 mL). The mixture was refluxed under nitrogen protection for 4 hours, cooled to room temperature, solids were formed, filtered, and the filter cake was dried under vacuum to obtain 78-b (175 mg, yield: 73%) as a yellow solid. This compound did not require further purification. LC-MS (ESI): m / z = 476 [M + H] ⁺ .

Synthesis of compound 78-a

80% m-chloroperoxybenzoic acid (217 mg, 1.26 mmol) was added to a dichloromethane (30 mL) solution of compound 78-b (200 mg, 0.42 mmol), and stirred at room temperature for 3 hours. The reaction was quenched by the addition of a saturated sodium thiosulfate solution (10 mL). Water (20 mL) was added, and dichloromethane (20 mL × 3) was extracted. The combined organic phases were washed with water (20 mL) and saturated brine (20 mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate). Ester = 5: 1-1: 1) gave 78-a (150 mg, yield: 70%) as a yellow solid. LC-MS (ESI): m / z = 508 [M + H] ⁺ .

Synthesis of compound 78

7N ammonia in methanol (0.4 mL, 2.8 mmol) was added to a solution of compound 78-a (150 mg, 0.3 mmol) in tetrahydrofuran (15 mL). The mixture was stirred for 1 hour at room temperature. Concentrated under reduced pressure, the residue was added with methanol (6 mL) to produce a solid. After 1 minute of ultrasonication and filtering, the filter cake was washed with methanol (3 mL) and dried under vacuum to obtain a yellow solid 78 (95 mg, yield: 72%).

LC-MS (ESI): m / z = 445 [M + H] ⁺ .

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 8.94 (s, 1H), 8.35 (s, 1H), 8.07-8.04 (m, 1H), 7.64-7.62 (m, 1H), 7.50-7.46 ( m, 1H), 7.45-6.75 (m, 3H), 3.94 (s, 3H), 2.66-2.62 (m, 1H), 1.10-1.076 (m, 2H), 0.91-0.88 (m, 2H) ppm.

Example 79: (E) -2-amino-6-methyl-4- (1-methyl-1H-pyrazol-3-yl) -7-phenylmethenyl-6,7-dihydro- 5H-pyrrole [3,4-d] pyrimidin-5-one (Compound 79)

Synthesis of compound 79-b

1,8-Diazabicycloundec-7-ene (231 mg, 1.52 mmol) was added to 1,67-c of compound 67-c (210 mg, 0.76 mmol) and benzaldehyde (161 mg, 1.52 mmol) Of oxane (20 mL). The mixture was refluxed under nitrogen protection for 12 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15: 1-5: 1) to obtain 79-b (80mg) as a yellow solid. Yield: 29%). This compound was used without further purification. LC-MS (ESI): m / z = 364 [M + H] ⁺ .

Synthesis of compound 79-a

80% m-chloroperoxybenzoic acid (113 mg, 0.66 mmol) was added to a dichloromethane (20 mL) solution of compound 79-b (80 mg, 0.22 mmol), and stirred at room temperature for 3 hours. The reaction was quenched by the addition of a saturated sodium thiosulfate solution (10 mL). Water (20 mL) was added, and dichloromethane (20 mL × 3) was extracted. The combined organic phases were washed with water (20 mL) and saturated brine (20 mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate). Ester = 10: 1-2: 1) gave 79-a as a yellow solid (70 mg, yield: 80%). LC-MS (ESI): m / z = 396 [M + H] ⁺ .

Synthesis of compound 79

7N ammonia in methanol (0.2 mL, 1.4 mmol) was added to a solution of compound 79-a (70 mg, 0.17 mmol) in tetrahydrofuran (20 mL). The mixture was stirred for 1 hour at room temperature. Concentrated under reduced pressure, and the residue was added with methanol (6 mL) to produce a solid. After 1 minute of ultrasonication and filtration, the filter cake was washed with methanol (3 mL) and dried under vacuum to obtain 79 (16 mg, yield: 27%) as a yellow solid.

LC-MS (ESI): m / z = 333 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.99 (s, 1H), 8.40 (s, 1H), 8.28 (d, J = 6.4 Hz, 1H), 7.43-7.30 (m, 5H), 6.61 (s, 1H), 3.94 (s, 3H), 3.28 (s, 3H) ppm.

Example 80

(E) -2-amino-6-cyclopropyl-4- (1-methyl-1H-pyrazol-3-yl) -7-phenylmethenyl-6,7-dihydro-5H-pyrrole [3,4-d] pyrimidin-5-one (Compound 80)

(Z) -2-amino-6-cyclopropyl-4- (1-methyl-1H-pyrazol-3-yl) -7-phenylmethenyl-6,7-dihydro-5H-pyrrole [3,4-d] pyrimidin-5-one (Compound 81)

Synthesis of compound 80-b

1,8-Diazabicycloundec-7-ene (152 mg, 1.0 mmol) was added to compound 71-c (150 mg, 0.5 mmol) and benzaldehyde (53 mg, 0.5 mmol) in absolute ethanol (10 mL) ) In solution. The mixture was refluxed under nitrogen protection for 4 hours, cooled to room temperature, solids were formed, filtered, and the filter cake was dried under vacuum to obtain 80-b (110 mg, yield: 56%) as a yellow solid. This compound did not require further purification. LC-MS (ESI): m / z = 390 [M + H] ⁺ .

Synthesis of compound 80-a

80% m-chloroperoxybenzoic acid (217 mg, 1.26 mmol) was added to a dichloromethane (20 mL) solution of compound 80-b (110 mg, 0.28 mmol), and stirred at room temperature for 3 hours. The reaction was quenched by the addition of a saturated sodium thiosulfate solution (10 mL). Water (20 mL) was added, and dichloromethane (20 mL × 3) was extracted. The combined organic phases were washed with water (20 mL) and saturated brine (20 mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate). Ester = 5: 1-1: 1) 80-a (110 mg, yield: 94%) was obtained as a yellow solid. LC-MS (ESI): m / z = 422 [M + H] ⁺ .

Synthesis of compounds 80 and 81

7N ammonia in methanol (0.74 mL, 5.18 mmol) was added to a solution of compound 80-a (110 mg, 0.26 mmol) in tetrahydrofuran (20 mL). The mixture was stirred at room temperature for 3 hours. Concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (mobile phase: water (10 mM ammonium bicarbonate + ammonia), acetonitrile; gradient: 35% -45% (the initial mobile phase was 35% water-65% acetonitrile, At the end, the mobile phase was 45% water to 55% acetonitrile, where% refers to volume percentage)) to obtain 80 as a yellow solid (26 mg, yield: 28%) and 81 as a yellow solid (25 mg, yield: 27%). LC-MS (ESI): m / z = 359 [M + H] ⁺ .

Compound 80:

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 9.00 (s, 1H), 8.36 (s, 1H), 8.25 (d, J = 6.0 Hz, 1H), 7.43-7.40 (m, 2H), 7.34 -7.28 (m, 3H), 6.93 (s, 1H), 3.94 (s, 3H), 2.66-2.63 (m, 1H), 1.14-1.10 (m, 2H), 0.92-0.89 (m, 2H) ppm.

Compound 81:

¹ H-NMR: (400MHz DMSO-d ₆ ) δ: 8.98 (s, 1H), 8.37 (s, 1H), 7.52 (d, J = 6.0Hz, 1H), 7.40-7.30 (m, 5H), 7.02 (s, 1H), 3.95 (s, 3H), 2.72-2.69 (m, 1H), 0.44-0.40 (m, 2H), 0.33-0.29 (m, 2H) ppm.

Example 81: (E) -2-amino-6-methyl-4- (2-methylthiazol-4-yl) -7- (2-fluorophenylmethenyl) -6,7-dihydro -5H-pyrrole [3,4-d] pyrimidin-5-one (Compound 82)

Synthesis of compound 82-f

Sodium bicarbonate (6.6 g, 78.7 mmol) was added to 2-methylthiazole-4-carbaldehyde (5.0 g, 39.4 mmol), S-methylisothiourea sulfate (8.3 g, 59.1 mmol) and ethyl acetoacetate (5.12 g, 39.4 mmol) of N, N-dimethylformyl (60 mL). After the reaction mixture was stirred at 70 ° C for 3 hours, it was cooled to room temperature. Water (500 mL) was added, and a yellow solid precipitated, filtered, and the filter cake was washed with water (200 mL) and dried in vacuo to give compound 82-f (3.5 g, yield: 29%). LC-MS (ESI): m / z = 312 [M + H] ⁺ .

Synthesis of compound 82-e

In an ice water bath, 2,3-dichloro-5,6-dicyano-p-benzoquinone (3.4 g, 14.86 mmol) was added portionwise to compound 82-f (3.5 g, 11.25 mmol) in dichloromethane (200 mL). The solution was warmed to room temperature and stirred for 16 hours. Filter and wash the filter cake with dichloromethane (50 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain 82-e (2.6 g, yield: 74%) as a yellow viscous substance. LC-MS (ESI): m / z = 310 [M + H] ⁺ .

Synthesis of compound 82-d

Compound 82-e (1.4 g, 12.62 mmol) was dissolved in 1,4-dioxane (30 mL), and selenium dioxide (3.7 g, 33.4 mmol) and glacial acetic acid (3 mL) were added. After the reaction solution was refluxed for 18 hours, it was cooled to room temperature. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (60 mL). Filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain 82-d (1.2 g, yield: 44%) as a pale yellow solid. LC-MS (ESI): m / z = 399 [M + H] ⁺ .

Synthesis of compound 82-c

Methylamine hydrochloride (1.1 g, 14.86 mmol) and sodium acetate (1.22 g, 14.86 mmol) were added to methanol (20 mL). After the mixture was stirred at room temperature for 30 minutes, the ice-water bath was cooled to 0 ° C, and then compound 82-d (1.2 g, 3.72 mmol) and dichloromethane (20 mL) were added. After stirring for 30 minutes, sodium cyanoborohydride (360 mg, 5.58 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for another 12 hours. The solution was concentrated under reduced pressure, and the residue was diluted with water (50 mL), and extracted with dichloromethane (50 mL × 2). The combined organic phases were washed with water (100 mL) and saturated brine (100 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 1) to obtain 82-c (556 mg, yield: 51.4%) as a yellow solid. LC-MS (ESI): m / z = 293 [M + H] ⁺ .

Synthesis of compound 82-b

1,8-Diazabicycloundec-7-ene (207 mg, 1.36 mmol) was added to anhydrous compound 82-c (200 mg, 0.68 mmol) and 2-fluorobenzaldehyde (127 mg, 1.03 mmol). In ethanol (5 mL). The mixture was refluxed for 12 hours under the protection of nitrogen, cooled to room temperature, and continued to stir for 3 hours. Solids were formed, filtered, and the filter cake was dried under vacuum to obtain 82-b (173 mg, yield: 64%) as a yellow solid. LC-MS (ESI): m / z = 399 [M + H] ⁺ .

Synthesis of compound 82-a

80% m-chloroperoxybenzoic acid (273 mg, 1.58 mmol) was added to a dichloromethane (50 mL) solution of compound 82-b (210 mg, 0.53 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction was quenched by the addition of a saturated sodium thiosulfate solution (20 mL). Water (50 mL) was added, and dichloromethane (50 mL x 3) was extracted. The combined organic phases were washed with water (50 mL) and saturated brine (50 mL), concentrated under reduced pressure, and the residue was washed with ethyl acetate (10 mL). The solid was subjected to vacuum Drying gave yellow compound 82-a (210 mg, yield: 93%). This product did not require further purification. LC-MS (ESI): m / z = 431 [M + H] ⁺ .

Synthesis of compound 82

7N ammonia in methanol (3 mL, 21 mmol) was added to a solution of compound 82-a (210 mg, 0.49 mmol) in tetrahydrofuran (15 mL). The mixture was stirred for 1 hour at room temperature. Concentrated under reduced pressure, the residue was added with methanol (6 mL) to produce a solid, filtered, the filter cake was washed with methanol (3 mL), and the compound 82 (28 mg, yield: 16%) was obtained after vacuum drying.

LC-MS (ESI): m / z = 367 [M + H] ⁺ .

¹ H-NMR (500MHz, DMSO-d ₆ ) δ: 9.09 (s, 1H), 8.37 (m, 1H), 7.39 (m, 1H), 7.24 (m, 3H), 6.55 (s, 1H), 3.28 (s, 3H), 3.72 (s, 3H) ppm

Example 82: (E) -2-amino-6-methyl-4- (5-methylfuran-2-yl) -7- (3-fluorophenylmethenyl) -6,7-dihydro -5H-pyrrole [3,4-d] pyrimidin-5-one (Compound 83)

Synthesis of compound 83-c

Methylamine hydrochloride (1.76 g, 26.0 mmol) and sodium acetate (3.56 g, 26.0 mmol) were added to methanol (50 mL). After the mixture was stirred at room temperature for 30 minutes, the ice-water bath was cooled to 0 ° C, and then compound 62-d (2.0 g, 6.5 mmol) and dichloromethane (10 mL) were added. After stirring for 1 hour, sodium cyanoborohydride (615 mg, 9.7 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for another 12 hours. It was concentrated under reduced pressure, the residue was diluted with water (100 mL), and extracted with dichloromethane (50 mL × 2). The combined organic phases were washed with water (100 mL) and saturated brine (100 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1-2: 1) to obtain 83-c (1.5 g, yield: 84%) as a pink solid. LC-MS (ESI): m / z = 276 [M + H] ⁺ .

Synthesis of compound 83-b

1,8-Diazabicycloundec-7-ene (304 mg, 2.0 mmol) was added to anhydrous 83-c (275 mg, 1.0 mmol) and 3-fluorobenzaldehyde (248 mg, 2.0 mmol). In ethanol (30 mL). The mixture was stirred at 80 ° C for 4 hours under the protection of nitrogen, cooled to room temperature, solids were formed, filtered, the filter cake was washed with water (10 mL), and dried in vacuo to obtain 83-b (300 mg, yield: 78%) as a yellow solid. . LC-MS (ESI): m / z = 382 [M + H] ⁺ .

Synthesis of compound 83-a

80% m-chloroperoxybenzoic acid (407 mg, 2.36 mmol) was added to a dichloromethane (30 mL) solution of compound 83-b (300 mg, 0.78 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction was quenched by the addition of a saturated sodium thiosulfate solution (10 mL). Water (20 mL) was added, and dichloromethane (20 mL × 3) was extracted. The combined organic phases were washed with water (20 mL) and saturated brine (20 mL), and concentrated under reduced pressure to give 83-a (290 mg, yield: 80%) as a yellow solid. ), This product was used without further purification. LC-MS (ESI): m / z = 414 [M + H] ⁺ .

Synthesis of compound 83

7N ammonia in methanol (0.5 mL, 3.5 mmol) was added to a solution of compound 83-a (150 mg, 0.36 mmol) in tetrahydrofuran (25 mL). The mixture was stirred at room temperature for 3 hours. Concentrated under reduced pressure, the residue was added with methanol (10 mL) to produce a solid, filtered, the filter cake was washed with methanol (3 mL), and the compound 83 (70 mg, yield: 55%) was obtained after vacuum drying.

LC-MS (ESI): m / z = 351 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.47 (s, 1H), 8.14 (d, J = 6.0 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.80-7.17 (m , 3H), 7.16-7.12 (m, 1H), 6.61 (s, 1H), 6.40 (s, 1H), 3.26 (s, 3H), 2.40 (s, 3H) ppm.

Example 83: (E) -2-amino-6-propyl-4- (5-methylfuran-2-yl) -7-phenylmethenyl-6,7-dihydro-5H-pyrrole [ 3,4-d] pyrimidin-5-one (compound 84)

Synthesis of compound 84-c

N-propylamine (1.76 g, 26.0 mmol), acetic acid (1.66 g, 26.0 mmol) were added to methanol (10 mL) and dichloromethane (50 mL). After the mixture was stirred at room temperature for 30 minutes, the ice-water bath was cooled to 0 ° C, and then compound 62-d (2.0 g, 6.5 mmol) and dichloromethane (10 mL) were added. After stirring for 1 hour, sodium cyanoborohydride (614 mg, 9.7 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for another 12 hours. It was concentrated under reduced pressure, the residue was diluted with water (50 mL), and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed with water (100 mL) and saturated brine (100 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1-3: 1) to obtain 84-c (1.5 g, yield: 75%) as a pink solid. LC-MS (ESI): m / z = 304 [M + H] ⁺ .

Synthesis of compound 84-b

1,8-Diazabicycloundec-7-ene (304 mg, 2.0 mmol) was added to compound 84-c (303 mg, 1.0 mmol) and benzaldehyde (212 mg, 2.0 mmol) in absolute ethanol (30 mL) ) In solution. The mixture was stirred at 80 ° C under nitrogen protection for 4 hours, and then cooled to room temperature, solids were formed, filtered, the filter cake was washed with water (10 mL), and dried under vacuum to obtain 84-b (350 mg, yield: 89%) as a yellow solid. . LC-MS (ESI): m / z = 392 [M + H] ⁺ .

Synthesis of compound 84-a

80% m-chloroperoxybenzoic acid (463 mg, 2.68 mmol) was added to a solution of compound 84-b (350 mg, 0.89 mmol) in dichloromethane (30 mL), and the mixture was stirred at room temperature for 3 hours. The reaction was quenched by the addition of a saturated sodium thiosulfate solution (20 mL). Water (50 mL) was added, and dichloromethane (50 mL × 3) was extracted. The combined organic phases were washed with water (20 mL) and saturated brine (20 mL), and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: Ethyl acetate = 10: 1-3: 1) to obtain 84-a (300 mg, yield: 79%) as a yellow solid. LC-MS (ESI): m / z = 424 [M + H] ⁺ .

Synthesis of compound 84

7N ammonia in methanol (0.43 mL, 3.01 mmol) was added to a solution of compound 84-a (126 mg, 0.3 mmol) in tetrahydrofuran (20 mL). The mixture was stirred at room temperature for 3 hours. Concentrated under reduced pressure, the residue was added with methanol (10 mL) to produce a solid, filtered, the filter cake was washed with methanol (3 mL), and the compound 84 (70 mg, yield: 65%) was obtained after vacuum drying.

LC-MS (ESI): m / z = 361 [M + H] ⁺ .

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 8.50 (s, 1H), 8.24-8.22 (m, 2H), 7.60-7.30 (m, 5H), 6.65 (s, 1H), 6.40-6.39 ( m, 1H), 3.81-3.80 (m, 2H), 3.24 (s, 3H), 1.66-1.61 (m, 2H), 0.92 (t, J = 6.0 Hz, 3H) ppm.

Example 84: (E) -2-amino-6-cyclopropyl-4- (5-methylfuran-2-yl) -7-phenylmethenyl-6,7-dihydro-5H-pyrrole [3,4-d] pyrimidin-5-one (Compound 85)

Synthesis of compounds 85-b and 86-b

1,8-Diazabicycloundec-7-ene (304 mg, 2.0 mmol) was added to compound 65-c (301 mg, 1.0 mmol) and benzaldehyde (212 mg, 2.0 mmol) in absolute ethanol (30 mL) ) In solution. The mixture was stirred at 80 ° C for 4 hours under the protection of nitrogen, cooled to room temperature, solids were formed, filtered, the filter cake was washed with ethanol (5 mL), and dried in vacuo to obtain a yellow solid 85-b (130 mg, yield: 33%). ). The filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (mobile phase: water (10 mM ammonium bicarbonate + ammonia), acetonitrile; gradient: 85% -95% (the initial mobile phase was 85% water-15% acetonitrile) At the end, the mobile phase was 95% water-5% acetonitrile, where% means volume percentage)), to obtain 86-b (180 mg, yield: 46%) as a yellow solid. LC-MS (ESI): m / z = 390 [M + H] ⁺ .

Synthesis of compound 85-a

80% m-chloroperoxybenzoic acid (159.6 mg, 0.92 mmol) was added to a dichloromethane (20 mL) solution of compound 85-b (120 mg, 0.3 mmol), and stirred at room temperature for 3 hours. The reaction was quenched by the addition of a saturated sodium thiosulfate solution (20 mL). Water (50 mL) was added, and dichloromethane (50 mL × 3) was extracted. The combined organic phases were washed with water (20 mL) and saturated brine (20 mL), and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: Ethyl acetate = 10: 1-3: 1) to obtain 85-a (85 mg, yield: 65%) as a yellow solid. LC-MS (ESI): m / z = 422 [M + H] ⁺ .

Synthesis of compound 85

7N ammonia in methanol (0.28 mL, 1.96 mmol) was added to a solution of compound 85-a (85 mg, 0.2 mmol) in tetrahydrofuran (20 mL). The mixture was stirred at room temperature for 3 hours. Concentrated under reduced pressure, the residue was added with methanol (5 mL) to produce a solid, filtered, the filter cake was washed with methanol (2 mL), and the compound 85 (30 mg, yield: 42%) was obtained after vacuum drying.

LC-MS (ESI): m / z = 359 [M + H] ⁺ .

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 9.00 (s, 1H), 8.36 (s, 1H), 8.26-8.24 (m, 2H), 7.43-7.40 (m, 2H), 7.34-7.28 ( m, 3H), 6.93 (s, 1H), 3.94 (s, 3H), 2.66-2.63 (m, 1H), 1.13-1.11 (m, 2H), 0.92-0.90 (m, 2H) ppm.

Example 85: (Z) -2-amino-6-cyclopropyl-4- (5-methylfuran-2-yl) -7-phenylmethenyl-6,7-dihydro-5H-pyrrole [3,4-d] pyrimidin-5-one (Compound 86)

Synthesis of compound 86-a

80% m-chloroperoxybenzoic acid (239.4 mg, 1.38 mmol) was added to a dichloromethane (20 mL) solution of compound 86-b (180 mg, 0.46 mmol), and stirred at room temperature for 3 hours. The reaction was quenched by the addition of a saturated sodium thiosulfate solution (20 mL). Water (50 mL) was added, and dichloromethane (50 mL × 3) was extracted. The combined organic phases were washed with water (20 mL) and saturated brine (20 mL), and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: Ethyl acetate = 10: 1-3: 1) to obtain 86-a (50 mg, yield: 25%) as a yellow solid. LC-MS (ESI): m / z = 422 [M + H] ⁺ .

Synthesis of compound 86

7N ammonia in methanol (0.3 mL, 2.1 mmol) was added to a solution of compound 86-a (50 mg, 0.12 mmol) in tetrahydrofuran (30 mL). The mixture was stirred at room temperature for 3 hours. Concentrated under reduced pressure, the residue was added with methanol (5 mL) to produce a solid, filtered, the filter cake was washed with methanol (2 mL), and the compound 86 (26 mg, yield: 62%) was obtained after vacuum drying.

LC-MS (ESI): m / z = 359 [M + H] ⁺ .

¹ H-NMR (400MHz DMSO-d ₆ ) δ: 8.99 (s, 1H), 8.37 (s, 1H), 7.53-7.51 (m, 2H), 7.41-7.30 (m, 5H), 7.02 (s, 1H ), 3.95 (s, 3H), 2.73-2.70 (m, 1H), 0.42-0.40 (m, 2H), 0.33-0.30 (m, 2H) ppm.

Example 86: (E) -2-amino-7-phenylmethenyl-6-isopropyl-4- (5-methylfuran-2-yl) -6,7-dihydro-5H-pyrrole [3,4-d] pyrimidin-5-one (Compound 87)

Synthesis of compound 87-c

Compound 62-d (1.22 g, 4.0 mmol) and isopropylamine (708 mg, 12.0 mmol) were dissolved in anhydrous methanol / dichloromethane (10 mL / 50 mL), and acetic acid (768 mg, 12.0 mmol) was slowly added dropwise to the solution. . The reaction mixture was stirred under nitrogen at room temperature for 2 hours. To the reaction solution was added sodium cyanoborohydride (378 mg, 6.0 mmol) in portions, and the mixture was reacted at room temperature overnight. Water (50 mL) was added to quench the reaction, and the target was extracted with DCM (150 ml). The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1-1: 1) to obtain 87-c (700 mg, yield: 58%) as a yellow solid.

LC-MS (ESI): m / z = 304.1 [M + H] ⁺ .

Synthesis of compound 87-b

Compound 87-c (700 mg, 2.31 mmol) and benzaldehyde (490.0 mg, 4.62 mmol) were dissolved in absolute ethanol (50 mL), and 1,8-diazabicycloundec-7- was added to the solution. Ene (702.2 mg, 4.62 mmol). The reaction mixture was stirred at 85 ° C for 16 hours under the protection of nitrogen, and allowed to stand at room temperature. The suspension mixture was filtered to obtain 87-b (510 mg, yield: 56%) as a yellow solid.

LC-MS (ESI): m / z = 392.2 [M + H] ⁺ .

Synthesis of compound 87-a

Compound 87-b (510 mg, 1.30 mmol) was dissolved in DCM (50 ml), m-CPBA (448.5 mg, 2.60 mmol) was added to the solution, and the resulting mixture was stirred at room temperature for 3 hours. In an ice water bath, a saturated sodium sulfite solution was added to quench the reaction, and the mixture was extracted with DCM (100 ml). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1-1: 1) to obtain 87-a (300 mg, yield: 83%) as a yellow solid.

LC-MS (ESI): m / z = 424.1 [M + H] ⁺ .

Synthesis of compound 87

Compound 87-a (60 mg, 0.14 mmol) was dissolved in THF (20 ml), and a methanol solution of ammonia (0.40 ml) was added to the reaction solution at zero temperature, and stirring was continued at room temperature for 4 hours. It was concentrated under reduced pressure, methanol (4 ml) was added to the residue, and the mixture was subjected to ultrasonic treatment for one minute. The insoluble matter was filtered and dried to obtain 87 (22 mg, yield: 44%) as a yellow solid.

LC-MS (ESI): m / z = 361.3 [M + H] ⁺ .

¹ H NMR: (400MHz, DMSO-d ₆ ) δ: 8.47 (s, 1H), 8.11 (s, 1H), 8.09 (m, 1H), 7.60-7.30 (m, 5H), 6.78 (s, 1H) , 6.39 (m, 1H), 4.68 (bs, 1H), 2.43 (s, 3H), 1.56 (d, J = 4.8Hz, 3H), 1.50 (d, J = 1.2Hz, 3H) ppm

Example 87: (E) -2-Amino-7-phenylmethenyl-6-isopropyl-4- (1-methyl-1-hydro-pyrazol-3-yl) -6,7- Dihydro-5H-pyrrole [3,4-d] pyrimidin-5-one (Compound 88)

Synthesis of compound 88-c

Compound 67-d (1.53 g, 5.0 mmol) and isopropylamine (590 mg, 10.0 mmol) were dissolved in anhydrous methanol / dichloromethane (10 mL / 50 mL), and acetic acid (600 mg, 10.0 mmol) was slowly added dropwise to the solution. . The reaction mixture was stirred under nitrogen and room temperature for 2 hours. To the reaction solution was added sodium cyanoborohydride (472.5 mg, 7.5 mmol) in portions, and the mixture was stirred at room temperature overnight. Water was added (50 mL) to quench the reaction, and the target was extracted with DCM (150 ml). The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1-1: 1) to obtain 88-c (1.1 g, yield: 73%) as a white solid.

LC-MS (ESI): m / z = 304.2 [M + H] ⁺ .

Synthesis of compound 88-b

Intermediate 88-c (303 mg, 1.0 mmol) and benzaldehyde (212 mg, 2.0 mmol) were dissolved in absolute ethanol (20 mL), and 1,8-diazabicycloundec-7- was added to the solution. Ene (456 mg, 3.0 mmol). The reaction mixture was stirred at 80 ° C for 16 hours under a nitrogen blanket. After standing at room temperature, the suspension mixture was filtered to obtain 88-b (170 mg, yield: 43%) as a yellow solid.

LC-MS (ESI): m / z = 392.2 [M + H] ⁺ .

Synthesis of compound 88-a

Compound 88-b (160 mg, 0.41 mmol) was dissolved in DCM (20 ml), m-CPBA (141.1 mg, 0.82 mmol) was added to the solution, and the resulting mixture was stirred at room temperature for about 6 hours. In an ice-water bath, a saturated sodium sulfite solution was added to quench the reaction, and the mixture was extracted with DCM (50 ml). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1-1: 1) to obtain 88-a (80 mg, yield: 46%) as a yellow solid.

LC-MS (ESI): m / z = 424.2 [M + H] ⁺ .

Synthesis of compound 88

Compound 88-a (80 mg, 0.19 mmol) was dissolved in THF (20 ml), and a methanol solution (0.54 ml) of ammonia was added to the reaction solution at 0 ° C, and stirring was continued at room temperature for 4 hours. It was concentrated under reduced pressure, methanol (4 ml) was added to the residue, and the mixture was treated with ultrasound for one minute. The insoluble matter was filtered and dried to obtain 88 (16 mg, yield: 24%) as a yellow solid.

LC-MS (ESI): m / z = 361.2 [M + H] ⁺ .

¹ H NMR: (400MHz DMSO-d ₆ ) δ: 8.10 (s, 1H), 8.09 (s, 1H), 7.78 (s, 1H), 7.58 (s, 1H), 7.46-7.29 (m, 5H), 6.78 (s, 1H), 4.69-4.66 (m, 1H), 3.95 (s, 3H), 1.50 (d, J = 6.4Hz, 3H), 1.33 (d, J = 5.2Hz, 3H) ppm

Example 88: (E) -2-amino-7- (2-fluorophenylmethenyl) -6-isopropyl-4- (1-methyl-1-hydro-pyrazol-3-yl) -6,7-dihydro-5H-pyrrole [3,4-d] pyrimidin-5-one (Compound 89)

Synthesis of compound 89-b

The intermediate 88-c (303 mg, 1.0 mmol) and o-fluorobenzaldehyde (248 mg, 2.0 mmol) were dissolved in absolute ethanol (20 mL), and 1,8-diazabicycloundecyl- was added to the solution. 7-ene (456 mg, 3.0 mmol). The reaction mixture was stirred at 80 ° C for 24 hours under a nitrogen blanket. After returning to room temperature, the suspension mixture was filtered to obtain 89-b (250 mg, yield: 61%) as a yellow solid.

LC-MS (ESI): m / z = 410.2 [M + H] ⁺ .

Synthesis of compound 89-a

Compound 89-b (250 mg, 0.61 mmol) was dissolved in DCM (20 ml), m-CPBA (316.3 mg, 1.83 mmol) was added to the solution, and the resulting mixture was stirred at room temperature for about 6 hours. In an ice-water bath, a saturated sodium sulfite solution was added to quench the reaction, and the mixture was extracted with DCM (50 ml). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1-1: 1) to obtain 89-a (250 mg, yield: 92%) as a yellow solid.

LC-MS (ESI): m / z = 442.1 [M + H] ⁺ .

Synthesis of compound 89

Compound 89-a (250 mg, 0.56 mmol) was dissolved in THF (40 ml), a methanol solution of ammonia (0.80 ml) was added to the reaction solution at 0 ° C, and stirring was continued at room temperature for 4 hours. It was concentrated under reduced pressure, methanol (6 ml) was added, and ultrasonic treatment was performed for one minute. The insoluble matter was filtered and dried to obtain 89 (28 mg, yield: 13%) as a yellow solid.

LC-MS (ESI): m / z = 379.2 [M + H] ⁺ .

¹ H NMR: (400MHz DMSO-d ₆ ) δ: 7.94 (d, J = 6.0 Hz, 1H), 7.83-7.78 (m, 2H), 7.56-7.11 (m, 5H), 6.77 (s, 1H), 3.96-3.93 (m, 1H), 3.94 (s, 3H), 1.50 (s, 3H), 1.48 (s, 3H) ppm

Example 89: (E) -2-amino-7- (3-fluorophenylmethenyl) -6-methyl-4- (1-methyl-1-hydro-pyrazol-3-yl)- 6,7-dihydro-5H-pyrrole [3,4-d] pyrimidin-5-one (Compound 90)

Synthesis of compound 90-b

67-c (275 mg, 1.0 mmol) and m-fluorobenzaldehyde (248 mg, 2.0 mmol) were dissolved in absolute ethanol (20 mL), and 1,8-diazabicycloundec-7- was added to the solution. Ene (456 mg, 2.0 mmol). The reaction mixture was stirred at 80 ° C for 24 hours under a nitrogen blanket. After returning to room temperature, the suspension mixture was filtered to obtain 90-b (260 mg, yield: 68%) as a yellow solid.

LC-MS (ESI): m / z = 382.2 [M + H] ⁺ .

Synthesis of compound 90-a

Compound 90-b (260 mg, 0.68 mmol) was dissolved in DCM (30 ml), m-CPBA (353.1 mg, 2.04 mmol) was added to the solution, and the resulting mixture was stirred at room temperature for 6 hours. In an ice-water bath, a saturated sodium sulfite solution was added to quench the reaction, and the mixture was extracted with DCM (50 ml). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1-1: 1) to obtain 90-b (250 mg, yield: 89%) as a yellow solid.

LC-MS (ESI): m / z = 414.2 [M + H] ⁺ .

Synthesis of compound 90

Compound 90-a (250 mg, 0.60 mmol) was dissolved in THF (30 ml), and a methanol solution of ammonia (0.86 ml) was added to the reaction solution at zero temperature, and stirring was continued at room temperature for 4 hours. Concentrated under reduced pressure, the residue was added with methanol (6 ml), and treated with ultrasound for one minute. The insoluble matter was filtered and dried to obtain 90 (22 mg, yield: 11%) as a yellow solid.

LC-MS (ESI): m / z = 351.2 [M + H] ⁺ .

¹ H NMR: (400MHz DMSO-d ₆ ) δ: 8.12 (d, J = 6.0 Hz, 1H), 7.98 (d, J = 13.2 Hz, 1H), 779 (s, 1H), 7.65-7.20 (m, 4H), 7015 (d, J = 6.0Hz, 1H), 6.60 (s, 1H), 3.94 (s, 3H), 3.25 (s, 3H).

Example 90: (E) -2-amino-6-methyl-4- (1-methyl-1-hydro-pyrazol-3-yl) -7- (3- (trifluoromethyl) phenyl (Menyl) -6,7-dihydro-5H-pyrrole [3,4-d] pyrimidin-5-one (Compound 91)

Synthesis of compound 91-b

Intermediate 67-c (138 mg, 0.5 mmol) and 3- (trifluoromethyl) benzaldehyde (174 mg, 1.0 mmol) were dissolved in ethanol (20 mL), and 1,8-diazabicycline was added to the solution. Undec-7-ene (152 mg, 1.0 mmol). The reaction mixture was stirred at 80 ° C for 24 hours under a nitrogen blanket. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1-1: 1) to obtain 91-b (150 mg, yield: 70%) as a yellow solid.

LC-MS (ESI): m / z = 432.2 [M + H] ⁺ .

Synthesis of compound 91-a

Compound 91-b (125 mg, 0.29 mmol) was dissolved in DCM (30 ml), m-CPBA (150 mg, 0.87 mmol) was added to the solution, and the resulting mixture was stirred at room temperature for 4 hours. In an ice water bath, a saturated sodium sulfite solution was added to quench the reaction, and the mixture was extracted with DCM (100 ml). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1-2: 1) to obtain 91-a (120 mg, 79%) as a yellow solid.

LC-MS (ESI): m / z = 464.2 [M + H] ⁺ .

Synthesis of compound 91

Compound 91-a (120 mg, 0.26 mmol) was dissolved in THF (30 ml), a methanol solution of ammonia (0.37 ml) was added to the reaction solution at 0 ° C, and stirring was continued at room temperature for 4 hours. Concentrated under reduced pressure, the residue was added with methanol (6 ml), and treated with ultrasound for one minute. The insoluble matter was filtered and dried to obtain 91 (45 mg, yield: 44%) as a yellow solid.

LC-MS (ESI): m / z = 401.2 [M + H] ⁺ .

¹ H NMR: (400MHz DMSO-d ₆ ) δ: 8.80 (d, J = 4.8 Hz, 1H), 8.20 (d, J = 10.8 Hz, 1H), 7.80-7.54 (m, 5H), 7.07-6.99 ( bs, 1H), 6.71 (d, J = 10.8 Hz, 1H), 3.94 (s, 3H), 3.21 (s, 3H) ppm

Effect Example 1

IC ₅₀ evaluation experiment on the binding affinity of compound 1-61 to human adenosine A2A receptor

Reagent preparation

1) Detection buffer: 50 mM Tris-HCl pH 7.4, 10 mM MgCl2, 1 mM EDTA, 1 μg / mL Adenosine Deaminase, stored at 4 ° C until use.

2) Washing solution: 50mM Tris-HCl pH 7.4, 154mM NaCl, stored at 4 ℃ for later use.

3) 0.5% PEI solution: 0.5 g of PEI was dissolved in 100 mL of ddH2O, and stored at 4 ° C until use.

2. Operating steps

1) Add Compound: Add 250nL of compound to Opti-plate with Echo550, and seal the sealing film.

2) Membrane dilution: Add 20U A2A membrane, 0.75uCi [3H] -CGS 21680 (final 25nM) to 1mL detection buffer, mix well, add 50uL to Opti-plate.

3) Incubation: Incubate the above mixture at 25 ° C for 90 minutes.

4) Prepare the pre-filter plate: add 100uL 0.5% PEI solution to the UNIFILTER-96GF / B filter plate, and soak it at 4 ° C for 90 minutes.

5) Filtering:

a. Cell Harvester transfer 500uL cleaning solution / air cleaning UNIFILTER-96GF / B filter 2 times.

b. Suspend the mixed system in Opti-plate and transfer to UNIFILTER-96GF / B filter plate.

c. 500uL cleaning solution / air cleaning UNIFILTER-96GF / B filter 9 times.

d. Incubate at 55 ° C for 10 minutes.

3. Reading

Add 40uL ULTIMA GOLD scintillation solution to each well, and TopCount reads the CPM (count per minute) value.

Experimental results

The results of the compound 1-61 of the present invention on the human adenosine A2A receptor binding affinity according to the above experiments are shown in Table 1:

Table 1: Compound _50- IC50 values of human adenosine A2A receptor binding affinity

化合物Compound	IC ₅₀(nM) IC ₅₀ (nM)	化合物Compound	IC ₅₀(nM) IC ₅₀ (nM)
11	14.714.7	22	39.339.3

33	159159	44	249249
55	4040	66	157.3157.3
77	n.d.n.d.	88	10.710.7
99	n.d.n.d.	1010	114.4114.4
1111	32.132.1	1212	99.899.8
1313	152152	1414	218.2218.2
1515	274274	1616	15.715.7
1717	29.229.2	1818	73.773.7
1919	31.131.1	2020	298.9298.9
21twenty one	105.8105.8	22twenty two	47.347.3
23twenty three	3.93.9	24twenty four	917.8917.8
2525	18.618.6	2626	32.132.1
2727	21twenty one	2828	11.211.2
2929	252.3252.3	3030	9494
3131	38.438.4	3232	19.919.9
3333	274.8274.8	3434	39.239.2
3535	30.130.1	3636	28.128.1
3737	67.467.4	3838	6.16.1
3939	127.7127.7	4040	106.3106.3
4141	43.543.5	4242	87.487.4
4343	992.4992.4	4444	64.664.6
4545	11.611.6	4646	8.78.7
4747	16.416.4	4848	13.213.2
4949	32.132.1	5050	7.37.3
5151	4.74.7	5252	3.63.6
5353	56.256.2	5454	34.734.7
5555	29.329.3	5656	3.43.4
5757	152.1152.1	5858	21twenty one
5959	178.7178.7	6060	176.9176.9
6161	212.8212.8	Zh	Zh

n.d .: Not tested.

Effect Example 2: Compound 50-91 on human adenosine A2A receptor binding affinity IC ₅₀ evaluation experiment

Experimental steps

1: Prepare the compound to be tested

1) Centrifuge the compound master plate (1500 rpm, 1 minute);

2) Transfer nano-liter sonic pipetting system from the compound mother board to 50 nanoliters to the reaction board;

2: Preparation of buffer membrane, preparation of dagger suspension

1) Add DMSO to the assay buffer, 1% of the final DMSO concentration;

2) The homogenized A2A receptor membrane is connected to a 1 ml syringe five times with a 26 gauge needle (to avoid air bubbles);

3) Mix the buffer, A2A receptor membrane and ADA, and leave at room temperature for 15 minutes;

4) Add SPA dagger and mix with A2A receptor membrane;

3: Prepare radioisotope buffer

4: Mixed reaction reagent

1) Add 20 microliters of radioactive buffer solution to the reaction plate;

2) Add 30 microliters of membrane and dagger suspension to the reaction plate;

3) Seal the plate and incubate for 1 hour at room temperature with vigorous mixing and shaking;

4) Allow the dagger to settle for 4-5 minutes before reading;

5) Use Microbeta to read the plate;

5: Processing data

Experimental results: The results of the compounds 62-91 of the present invention on human adenosine A2A receptor binding affinity according to the above experiments are shown in Table 2:

Table 2: 62-91 Compound binding affinity IC ₅₀ values for human adenosine A2A receptor

化合物Compound	IC ₅₀(nM) IC ₅₀ (nM)	化合物Compound	IC ₅₀(nM) IC ₅₀ (nM)
6262	15.215.2	6363	8.98.9
6464	13.513.5	6565	5.15.1
6666	22.422.4	6767	8.68.6
6969	13.613.6	7070	14.414.4
7171	34.834.8	7272	71.371.3
7373	13.113.1	7474	103.3103.3
7575	99.199.1	7676	239.3239.3

77	64.9	78	106.1
79	37.8	80	36.7
81	117.2	82	33.1
83	9	87	55.8
88	36.4	89	36.1
90	13.9	91	21.8

.

Claims

A compound represented by Formula I, a pharmaceutically acceptable salt, deuterate, tautomer, cis-trans isomer, enantiomer, diastereomer or prodrug;

among them,
Stands for single or double bond;
Represents a single key;

when
When it is a single bond, W is N or CR 5 ; R 5 is H, deuterium or methyl;

when
When it is a double bond, W is C, and the double bond is in the Z configuration, the E configuration, or a mixture thereof;

X is O, CO or NR 3 ;

Y is CO, CH 2 or NR 4 ;

R 1 is a substituted or unsubstituted C 6 -C 20 aryl group or a substituted or unsubstituted 5-10 membered heteroaryl group;

When R 1 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, the number of substituents is one or more, and each substituent is independently halogen or C 1 -C 10 alkyl;

R 2 is a substituted or unsubstituted C 6 -C 20 aryl group or a substituted or unsubstituted 5-10 membered heteroaryl group;

When R 2 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, the number of substituents is one or more, and each substituent is independently halogen, C 1 -C 10 Alkyl, C 1 -C 10 alkoxy, C 1 -C 10 alkyl mercapto, halogen substituted C 1 -C 10 alkyl, oxo, hydroxyl, amino,
Cyano, halogen-substituted C 1 -C 10 alkoxy or halogen-substituted C 1 -C 10 alkylmercapto; wherein R a and R b are each independently hydrogen or C 1 -C 10 alkyl, R c is C 1- C 10 alkyl;

R 3 is H, C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl;

R 4 is H, C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl;

The number of heteroatoms in the 5- to 10-membered heteroaryl group is 1, 2, 3, or 4, and each heteroatom is independently O, N, or S;

And, the compound represented by Formula I does not have any of the following structures:
The compound of formula I according to claim 1, which is a pharmaceutically acceptable salt, deuterate, tautomer, cis-trans isomer, enantiomer, diastereomer Or a prodrug, characterized in that when X is O, Y is CO or CH 2 ; when X is CO, Y is NR 4 ; when X is NR 3 , Y is CO;

And / or, when R 3 is C 1 -C 10 alkyl, the C 1 -C 10 alkyl is C 1 -C 4 alkyl;

And / or, when R 3 is C 3 -C 10 cycloalkyl, the C 3 -C 10 cycloalkyl is C 3 -C 6 cycloalkyl;

And / or, when R 4 is C 1 -C 10 alkyl, the C 1 -C 10 alkyl is C 1 -C 4 alkyl;

And / or, when R 4 is C 3 -C 10 cycloalkyl, the C 3 -C 10 cycloalkyl is C 3 -C 6 cycloalkyl;

And / or, when R 1 is a substituted or unsubstituted C 6 -C 20 aryl group, the C 6 -C 20 aryl group is a C 6 -C 10 aryl group;

And / or, when R 1 is a substituted or unsubstituted 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group is a 5-membered heteroaryl group or a 6-membered heteroaryl group, preferably a 5-membered heteroaryl group Aryl;

And / or, when R 1 is a substituted or unsubstituted 5-10 membered heteroaryl group, the number of heteroatoms in the 5-10 membered heteroaryl group is 1 or 2;

And / or, when R 1 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, the number of substituents is 1, 2, 3, or 4;

And / or, when R 1 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group and the substituent is halogen, the halogen is fluorine, chlorine, bromine or iodine;

And / or, when R 1 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, and the substituent is a C 1 -C 10 alkyl group, the C 1 -C 10 alkyl group Is C 1 -C 4 alkyl;

And / or, when R 2 is a substituted or unsubstituted C 6 -C 20 aryl group, the C 6 -C 20 aryl group is a C 6 -C 10 aryl group;

And / or, when R 2 is a substituted or unsubstituted 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group is a 5 membered heteroaryl group or a 6 membered heteroaryl group, such as a 6 membered heteroaryl group base;

And / or, when R 2 is a substituted or unsubstituted 5-10 membered heteroaryl group, the number of heteroatoms in the 5-10 membered heteroaryl group is 1 or 2;

And / or, when R 2 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, the number of substituents is 1, 2, 3, or 4;

And / or, when R 2 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group and the substituent is halogen, the halogen is fluorine, chlorine, bromine or iodine;

And / or, when R 2 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, and the substituent is a C 1 -C 10 alkyl group, the C 1 -C 10 alkyl group Is C 1 -C 4 alkyl;

And / or, when R 2 is substituted C 6 -C 20 aryl or substituted 5-10 membered heteroaryl, and the substituent is C 1 -C 10 alkoxy, the C 1 -C 10 alkane Oxy is C 1 -C 4 alkoxy;

And / or, when R 2 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, and the substituent is a C 1 -C 10 alkylthiol group, the C 1 -C 10 alkylthiol group C 1 -C 4 alkyl mercapto;

And / or, when R 2 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, and the substituent is a halogen-substituted C 1 -C 10 alkyl group, the "halogen-substituted C 1 -C 10 alkyl "C 1 -C 10 alkyl is C 1 -C 4 alkyl;

And / or, when R 2 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, and the substituent is a halogen-substituted C 1 -C 10 alkyl group, the "halogen-substituted The number of halogens in the "C 1 -C 10 alkyl group" is 1-5, and when there are multiple halogens, the halogens are the same or different;

And / or, when R 2 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, and the substituent is a halogen-substituted C 1 -C 10 alkyl group, the "halogen-substituted The halogen in "C 1 -C 10 alkyl" is fluorine, chlorine, bromine or iodine;

And / or, when R 2 is a substituted C 6 -C 20 aryl or a substituted 5-10 membered heteroaryl, the substituent is
R a and R b are each independently hydrogen or C 1 -C 3 alkyl;

And / or, when R 2 is a substituted C 6 -C 20 aryl or a substituted 5-10 membered heteroaryl, the substituent is
When R c is C 1 -C 4 alkyl;

And / or, when R 2 is substituted C 6 -C 20 aryl or substituted 5-10 membered heteroaryl, and the substituent is halogen substituted C 1 -C 10 alkoxy, the "halogen substituted C 1 -C 10 alkoxy in "C 1 -C 10 alkoxy" is C 1 -C 4 alkoxy;

And / or, when R 2 is substituted C 6 -C 20 aryl or substituted 5-10 membered heteroaryl, and the substituent is halogen substituted C 1 -C 10 alkoxy, the "halogen substituted The number of halogens in the "C 1 -C 10 alkoxy" is 1-5, and when there are multiple halogens, the halogens are the same or different;

And / or, when R 2 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, and the substituent is a halogen-substituted C 1 -C 10 alkoxy group, the "halogen-substituted The halogen in "C 1 -C 10 alkoxy" is fluorine, chlorine, bromine or iodine;

And / or, when R 2 is a substituted C 6 -C 20 aryl or a substituted 5-10 membered heteroaryl, and the substituent is a halogen-substituted C 1 -C 10 alkylthiol, the "halogen-substituted C 1 -C 10 alkylmercapto in "C 1 -C 10 alkylmercapto" is C 1 -C 4 alkylmercapto;

And / or, when R 2 is a substituted C 6 -C 20 aryl or a substituted 5-10 membered heteroaryl, and the substituent is a halogen-substituted C 1 -C 10 alkylthiol, the "halogen-substituted The number of halogens in "C 1 -C 10 alkylmercapto" is 1-5, and when there are multiple halogens, the halogens are the same or different;

And / or, when R 2 is a substituted C 6 -C 20 aryl or a substituted 5-10 membered heteroaryl, and the substituent is a halogen-substituted C 1 -C 10 alkylthiol, the "halogen-substituted The halogen in "C 1 -C 10 alkylmercapto" is fluorine, chlorine, bromine or iodine.
The compound represented by formula I according to claim 2, which is a pharmaceutically acceptable salt, deuterate, tautomer, cis-trans isomer, enantiomer, diastereomer Or a prodrug, characterized in that when R 3 is C 1 -C 4 alkyl, the C 1 -C 4 alkyl is methyl, ethyl, isopropyl or n-propyl;

And / or, when R 3 is C 3 -C 6 cycloalkyl, the C 3 -C 6 cycloalkyl is cyclopropyl;

And / or, when R 4 is C 1 -C 4 alkyl, the C 1 -C 4 alkyl is methyl;

And / or, when R 4 is C 3 -C 6 cycloalkyl, the C 3 -C 6 cycloalkyl is cyclopropyl;

And / or, when R 1 is a substituted or unsubstituted C 6 -C 10 aryl, the C 6 -C 10 aryl is phenyl;

And / or, when R 1 is a substituted or unsubstituted 5-10 membered heteroaryl group, and the 5-10 membered heteroaryl group is a 5-membered heteroaryl group, the 5-membered heteroaryl group is a furyl group , Thiazolyl or pyrazolyl;

And / or, when R 1 is a substituted or unsubstituted 5-10 membered heteroaryl group, and the 5-10 membered heteroaryl group is a 6 membered heteroaryl group, the 6 membered heteroaryl group is a pyridyl group ;

And / or, when R 1 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, the number of the substituents is one or two;

And / or, when R 1 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, and the substituent is halogen, the halogen is chlorine or bromine;

And / or, when R 1 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, and the substituent is a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group Is methyl

And / or, when R 2 is a substituted or unsubstituted C 6 -C 10 aryl, the C 6 -C 10 aryl is phenyl;

And / or, when R 2 is a substituted or unsubstituted 5-10 membered heteroaryl group, and the 5-10 membered heteroaryl group is a 6 membered heteroaryl group, the 6 membered heteroaryl group is a pyridyl group ;

And / or, when R 2 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, the number of the substituents is one or two;

And / or, when R 2 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, and the substituent is halogen, the halogen is fluorine or chlorine;

And / or, when R 2 is a substituted C 6 -C 20 aryl or a substituted 5-10 membered heteroaryl, and the substituent is C 1 -C 4 alkyl, the C 1 -C 4 alkyl Is methyl

And / or, when R 2 is a substituted C 6 -C 20 aryl or a substituted 5-10 membered heteroaryl, and the substituent is C 1 -C 4 alkoxy, the C 1 -C 4 alkane Oxy is methoxy;

And / or, when R 2 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, and the substituent is a C 1 -C 4 alkyl mercapto group, the C 1 -C 4 alkyl mercapto group Methylmercapto

And / or, when R 2 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, and the substituent is a halogen-substituted C 1 -C 4 alkyl group, the "halogen-substituted C 1 -C 4 alkyl "C 1 -C 4 alkyl is methyl;

And / or, when R 2 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, and the substituent is a halogen-substituted C 1 -C 10 alkyl group, the "halogen-substituted The number of halogens in the "C 1 -C 10 alkyl group" is 1, 2 or 3;

And / or, when R 2 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, and the substituent is a halogen-substituted C 1 -C 10 alkyl group, the "halogen-substituted The halogen in "C 1 -C 10 alkyl" is fluorine;

And / or, when R 2 is a substituted C 6 -C 20 aryl or a substituted 5-10 membered heteroaryl, the substituent is
When the
for

And / or, when R 2 is a substituted C 6 -C 20 aryl or a substituted 5-10 membered heteroaryl, the substituent is
When R c is methyl;

And / or, when R 2 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, and the substituent is a halogen substituted C 1 -C 4 alkoxy group, the "halogen substituted C 1 -C 4 alkoxy in "C 1 -C 4 alkoxy" is methoxy;

And / or, when R 2 is substituted C 6 -C 20 aryl or substituted 5-10 membered heteroaryl, and the substituent is halogen substituted C 1 -C 10 alkoxy, the "halogen substituted The number of halogens in the "C 1 -C 10 alkoxy group" is 1, 2 or 3;

And / or, when R 2 is substituted C 6 -C 20 aryl or substituted 5-10 membered heteroaryl, and the substituent is halogen substituted C 1 -C 10 alkoxy, the "halogen substituted "C 1 -C 10 alkoxy" is halogen;

And / or, when R 2 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, and the substituent is a halogen-substituted C 1 -C 4 alkylthio group, the "halogen-substituted C 1 -C 4 alkylmercapto in C 1 -C 4 alkylmercapto is methyl mercapto;

And / or, when R 2 is a substituted C 6 -C 20 aryl or a substituted 5-10 membered heteroaryl, and the substituent is a halogen-substituted C 1 -C 10 alkylthiol, the "halogen-substituted The number of halogens in the "C 1 -C 10 alkylthiol group" is 1, 2 or 3;

And / or, when R 2 is a substituted C 6 -C 20 aryl or a substituted 5-10 membered heteroaryl, and the substituent is a halogen-substituted C 1 -C 10 alkylthiol, the "halogen-substituted The halogen in "C 1 -C 10 alkylmercapto" is fluorine.
The compound of formula I according to claim 3, wherein the pharmaceutically acceptable salt, deuterate, tautomer, cis-trans isomer, enantiomer, diastereomer Or a prodrug, characterized in that R 3 is methyl;

And / or, when R 1 is a substituted or unsubstituted 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group is a 5-membered heteroaryl group, and the 5-membered heteroaryl group is a furyl group , The furyl group is furan-2-yl;

And / or, when R 1 is a substituted or unsubstituted 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group is a 5-membered heteroaryl group, and the 5-membered heteroaryl group is a thiazolyl group , The thiazolyl group is thiazol-4-yl;

And / or, when R 1 is a substituted or unsubstituted 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group is a 5-membered heteroaryl group, and the 5-membered heteroaryl group is a pyrazolyl group When the pyrazolyl is pyrazol-3-yl;

And / or, when R 1 is a substituted or unsubstituted 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group is a 6 membered heteroaryl group, and the 6 membered heteroaryl group is a pyridyl group , Said pyridyl is pyridin-2-yl;

And / or, when R 1 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, the number of substituents is one;

And / or, when R 1 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, and the substituent is halogen, the halogen is chlorine;

And / or, when R 2 is a substituted or unsubstituted 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group is a 6 membered heteroaryl group, and the 6 membered heteroaryl group is a pyridyl group , Said pyridyl is pyridin-4-yl;

And / or, when R 2 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, and the substituent is halogen, the halogen is fluorine;

And / or, when R 2 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, and the substituent is a halogen-substituted C 1 -C 4 alkyl group, the "halogen-substituted C 1 -C 4 alkyl "is -CF 3 ;

And / or, when R 2 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, and the substituent is a halogen substituted C 1 -C 4 alkoxy group, the "halogen substituted C 1 -C 4 alkoxy "is -OCHF 2 or -OCF 3 ;

and / or,
Is a double bond, X is O or NR 3 , and Y is CO.
The compound of formula I according to claim 1, which is a pharmaceutically acceptable salt, deuterate, tautomer, cis-trans isomer, enantiomer, diastereomer Or a prodrug, characterized in that: in the compound represented by I,
for

And / or, R 4 is H or C 1 -C 10 alkyl;

And / or when R 2 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, the substituent is halogen, C 1 -C 10 alkyl, halogen substituted C 1 -C 10 Alkyl, oxo,
Cyano, or halogen-substituted C 1 -C 10 alkoxy.
The compound of formula I according to claim 1, which is a pharmaceutically acceptable salt, deuterate, tautomer, cis-trans isomer, enantiomer, diastereomer Or a prodrug, characterized in that: in the compound represented by I,
for

And / or, R 1 is
Preferably

And / or, R 2 is
The compound of formula I according to claim 1, which is a pharmaceutically acceptable salt, deuterate, tautomer, cis-trans isomer, enantiomer, diastereomer Or a prodrug, which is characterized by:
Is a double bond

X is O or NR 3 ;

Y is CO;

R 3 is H, C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl;

R 1 is a substituted or unsubstituted 5-10 membered heteroaryl group;

When R 1 is a substituted 5-10 membered heteroaryl group, the number of substituents is one or more, and each substituent is independently halogen or C 1 -C 10 alkyl;

R 2 is a substituted or unsubstituted C 6 -C 20 aryl group;

When R 2 is a substituted C 6 -C 20 aryl group, the number of substituents is one or more, and each substituent is independently halogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy Radical, halogen-substituted C 1 -C 10 alkyl or halogen-substituted C 1 -C 10 alkoxy;

The number of heteroatoms in the 5-10 membered heteroaryl group is 1, 2, 3 or 4, and each heteroatom is independently O, N or S.
The compound of formula I according to claim 1, which is a pharmaceutically acceptable salt, deuterate, tautomer, cis-trans isomer, enantiomer, diastereomer Or a prodrug, characterized in that the compound represented by formula I is selected from any one of the following structures:
A method for preparing a compound represented by formula I according to any one of claims 1 to 8, characterized in that it comprises the steps of: in an organic solvent, combining the compound represented by formula IA with an amine The chemical reagent is subjected to a nucleophilic substitution reaction as shown below to obtain the compound represented by Formula I;

among them,
X, Y, W, R 1 and R 2 are as defined in claim 1, and X 1 is a halogen or a C 1 -C 4 alkyl-substituted sulfone group.
A compound represented by Formula I-A:

among them,
X, Y, W, R 1 and R 2 are as defined in any one of claims 1 to 8, and X 1 is a halogen or a C 1 -C 4 alkyl substituted sulfone group;

In addition, the compound represented by Formula I-A does not have any of the following structures:
The compound represented by formula I-A according to claim 10, wherein it is any one of the following structures:
A pharmaceutical composition comprising the compound represented by formula I according to any one of claims 1 to 8, its pharmaceutically acceptable salt, deuterate, tautomer, cis-trans isomer Isomers, enantiomers, diastereomers or prodrugs, and pharmaceutically acceptable carriers.
A compound represented by formula I according to any one of claims 1 to 8, which is a pharmaceutically acceptable salt, deuterate, tautomer, cis-trans isomer, enantiomer Isomers, diastereomers or prodrugs, or the pharmaceutical composition according to claim 12, for use in the preparation of adenosine A2A receptor antagonists.
A compound represented by formula I according to any one of claims 1 to 8, which is a pharmaceutically acceptable salt, deuterate, tautomer, cis-trans isomer, enantiomer Use of a pharmaceutical composition, a diastereomer or a prodrug, or a pharmaceutical composition according to claim 12 in the manufacture of a medicament for the prevention, alleviation and / or treatment of related diseases caused by adenosine A2A receptors .
The application according to claim 14, wherein the related diseases caused by adenosine A2A receptors are one or more of central nervous system diseases, immune tolerance diseases and inflammatory diseases.