TW202024092A - Aminopyrimidine fused five-membered heterocyclic compound, intermediate thereof, and manufacturing method, pharmaceutical composition and application thereof - Google Patents

Abstract

The present invention discloses an aminopyrimidine fused five-membered heterocyclic compound as shown in Formula I, an intermediate thereof, a manufacturing method, a pharmaceutical composition, and an application thereof. The aminopyrimidine fused five-membered heterocyclic compound of the present invention has an obvious antagonistic action on an adenosine A2A receptor, and can be used as an adenosine A2A receptor antagonist, alleviate or treat immune tolerance, central nervous system diseases and inflammation, and other related diseases effectively.

Description

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

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

This application claims the priority of the Chinese patent application 2018110226731 with the filing date of 2018/9/4 and the Chinese patent application 2019107932777 with the filing date of 2019/8/27. This application quotes the full text of the aforementioned Chinese patent application.

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 be greatly increased 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 in many pathological processes such as ischemia, hypoxia, inflammation, trauma, and transplantation, the activation of adenosine A2A receptors can play an important immunomodulatory role. This may be related to A2A receptors in T cells, B cells, and single cells. Nuclear macrophages, neutrophils and other immune cells have higher expression levels (Su Y., et al., Cancer Immunol Immuno Ther., 2008, 57(11) ,1611-1623.). The adenosine A2A receptor is one of the four known adenosine receptors (A1, A2A, A2B and A3). It belongs to the family of G protein-coupled receptors and is mainly coupled with Gs and Gα proteins. It is widely distributed in the body. It is mainly expressed in the striatum in the central nervous system. A2A receptors are also expressed in peripheral tissues such as heart, liver, lung, and kidney (Chu YY, et al., Biol , 1996, 15(4) , 329-337.).

In recent years, 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. For example, in terms of cellular immunity, T lymphocytes, antibody-dependent cytotoxic cells (K cells), NK cells and macrophages are effective against tumors. All cells have killing effect. However, if the cancerous cells themselves or the above-mentioned immune cell functions are changed, they may escape the elimination of the body's immune system and malignant hyperplasia may form tumors. The activation of adenosine A2A receptor can promote the body to develop immune tolerance, and is closely involved in the formation of "immune escape" or "immune suppression" of tumor cells, creating favorable conditions for the occurrence and development of tumors (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, ultimately affecting the growth of tumor cells, and having an anti-tumor effect.

The technical problem to be solved by the present invention is to fill the current market gap 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 present invention has a significant antagonistic effect on adenosine A2A receptors, and can be used as adenosine A2A receptor antagonists to effectively alleviate or treat immune tolerance, central nervous system diseases and inflammation Diseases and other related diseases.

其中，“

”代表單鍵或雙鍵；“

”代表單鍵； 當“

”為單鍵時，W為N或CR⁵ ；R⁵ 為H、氘或甲基； 當“

”為雙鍵時，W為C，雙鍵為Z構型、E構型或Z構型和E構型的混合物； X為O、CO或NR³ ； Y為CO、CH₂ 或NR⁴ ； R¹ 為取代或未取代的C₆ -C₂₀ 芳基或取代或未取代的5-10元雜芳基； 當R¹ 為取代的C₆ -C₂₀ 芳基或取代的5-10元雜芳基時，取代基的個數為一個或多個，每個取代基獨立地為鹵素或C₁ -C₁₀ 烷基； R² 為取代或未取代的C₆ -C₂₀ 芳基或取代或未取代的5-10元雜芳基； 當R² 為取代的C₆ -C₂₀ 芳基或取代的5-10元雜芳基時，取代基的個數為一個或多個，每個取代基獨立地為鹵素、C₁ -C₁₀ 烷基、C₁ -C₁₀ 烷氧基、C₁ -C₁₀ 烷巰基、鹵素取代的C₁ -C₁₀ 烷基、氧代基、羥基、氨基、

、

、氰基、鹵素取代的C₁ -C₁₀ 烷氧基或鹵素取代的C₁ -C₁₀ 烷巰基；其中R^a 和R^b 各自獨立地為氫或C₁ -C₁₀ 烷基，R^c 為C₁ -C₁₀ 烷基； R³ 為H、C₁ -C₁₀ 烷基或C₃ -C₁₀ 環烷基； R⁴ 為H、C₁ -C₁₀ 烷基或C₃ -C₁₀ 環烷基； 所述的5-10元雜芳基中的雜原子的個數為1、2、3或4個，每個雜原子獨立地為O、N或S； 並且，如式I所示的化合物不為以下任一結構：

。The present invention provides a compound as shown in formula I, its pharmaceutically acceptable salt, deuterium, tautomer, cis-trans isomer, enantiomer, diastereomer or prodrug body:

among them,"

"Represents a single bond or a double bond;"

"Represents a single key; when"

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

When "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 In the case of an aryl group, the number of substituents is one or more, and each substituent is independently halogen or C ₁ -C ₁₀ alkyl; R ² is substituted or unsubstituted C ₆ -C ₂₀ aryl or substituted or Unsubstituted 5-10 membered heteroaryl; when R ² is substituted C ₆ -C ₂₀ aryl or substituted 5-10 membered heteroaryl, the number of substituents is one or more, and each substituted The groups are 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, halo-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 cycloalkane 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; and, as shown in formula I The compound 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 When, Y is CO.

”為雙鍵；X為O或NR³ ，Y為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.

”為雙鍵； X為O或NR³ ，優選為NR³ ； Y為CO； R³ 為H、C₁ -C₁₀ 烷基或C₃ -C₁₀ 環烷基； R¹ 為取代或未取代的5-10元雜芳基； 當R¹ 為取代的5-10元雜芳基時，取代基的個數為一個或多個，每個取代基獨立地為鹵素或C₁ -C₁₀ 烷基； R² 為取代或未取代的C₆ -C₂₀ 芳基； 當R² 為取代的C₆ -C₂₀ 芳基時，取代基的個數為一個或多個，每個取代基獨立地為鹵素、C₁ -C₁₀ 烷基、C₁ -C₁₀ 烷氧基、鹵素取代的C₁ -C₁₀ 烷基或鹵素取代的C₁ -C₁₀ 烷氧基； 所述的5-10元雜芳基中的雜原子的個數為1、2、3或4個，每個雜原子獨立地為O、N或S。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 , preferably NR ³ ; Y is CO; R ³ is H, C ₁ -C ₁₀ alkyl or C ₃ -C ₁₀ cycloalkyl; R ¹ is substituted or unsubstituted 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 alkane 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 Is halogen, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, halogen substituted C ₁ -C ₁₀ alkyl or halogen substituted C ₁ -C ₁₀ alkoxy; said 5-10 member The number of heteroatoms in the heteroaryl group is 1, 2, 3, or 4, and each heteroatom is independently O, N or S.

”為雙鍵，雙鍵為E構型。In a preferred embodiment of the present invention, in the compound represented by formula I, "

"Is a double bond, and the double bond is in the E configuration.

In the compound represented by formula I, when R ³ is a C ₁ -C ₁₀ alkyl group, the C ₁ -C ₁₀ alkyl group may be a C ₁ -C ₄ alkyl group, such as methyl, ethyl Group, 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 cycloalkyl group. Propyl.

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

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 cycloalkyl group. Propyl.

為

、

、

、

、

、

、

或

。In a preferred embodiment of the present invention, in the compound shown in I,

for

,

,

,

,

,

,

or

.

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

為

、

、

、

、

、

、

、

、

、

、

、

、

或

。In a preferred embodiment of the present invention, in the compound shown in I,

for

,

,

,

,

,

,

,

,

,

,

,

,

or

.

為

、

、

、

、

、

、

、

、

、

、

、

或

。In some aspects of the present invention, in the compound shown in I,

for

,

,

,

,

,

,

,

,

,

,

,

or

.

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 group. The heteroaryl group is preferably a 5-membered heteroaryl group. The number of heteroatoms in the 5-10 membered heteroaryl group can be one or two. The 5-membered heteroaryl group is for example furanyl (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 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 substituents can be 1, 2, 3 or 4, such as 1 or 2, such as 1.

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 halogen, the halogen may be fluorine, Chlorine, bromine or iodine, such as chlorine or bromine (e.g. 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 The C ₁ -C ₁₀ alkyl group may be a C ₁ -C ₄ alkyl group, 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 heteroaryl group. Heteroaryl groups, such as 6-membered heteroaryl groups. The number of heteroatoms in the 5-10 membered heteroaryl group can be one or two. The 6-membered heteroaryl group is for example pyridyl (such as pyridin-4-yl).

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 number of substituents can be 1, 2, 3 or 4, such as 1 or 2.

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, the halogen may be fluorine, Chlorine, bromine or iodine, such as fluorine or chlorine (for example 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 The C ₁ -C ₁₀ alkyl group may be a C ₁ -C ₄ alkyl group, 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 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 mercapto group, the The C ₁ -C ₁₀ alkyl mercapto group may be a C ₁ -C ₄ alkyl mercapto group, such as a methyl mercapto group.

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 group" can be 1-5, such as 1, 2 or 3; when there are more than one halogen, the halogen Same or different. The halogen in the "halogen-substituted C ₁ -C ₁₀ alkyl group" 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 .

時，R^a 和R^b 可以各自獨立地為氫或C₁ -C₃ 烷基，例如所述的

為

。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

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

for

.

時，所述的R^c 可以為C₁ -C₄ 烷基，例如甲基。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

When, said R ^c can be a C ₁ -C ₄ alkyl group, such as a methyl group.

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" can be 1 to 5, such as 1, 2 or 3; when the number of halogens is more than one, 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 alkyl mercapto 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 alkyl mercapto group" can be 1-5, such as 1, 2 or 3; when the number of halogens is more than one, the halogen Same or different. The halogen in the "halogen substituted C ₁ -C ₁₀ alkyl mercapto group" may be fluorine, chlorine, bromine or iodine, such as fluorine.

、

、氰基、或鹵素取代的C₁ -C₁₀ 烷氧基。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.

、

、氰基、-OCHF₂ 或-OCF₃ 。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 , Chloro, methyl, -CF ₃ , oxo,

,

, Cyano, -OCHF ₂ or -OCF ₃ .

、

、

、

、

、

或

；優選為

、

、

、

、

或

；進一步優選為

、

或

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

,

,

,

,

,

or

; Preferably

,

,

,

,

or

；More preferably

,

or

.

、

、

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、

或

；優選為

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

或

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

,

,

,

,

,

,

,

,

,

,

,

,

,

,

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or

; Preferably

,

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or

.

、

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、

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、

、

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、

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、

或

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

,

,

,

,

,

,

,

,

,

,

,

,

,

,

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,

,

,

,

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or

.

，其中R¹³ 為H或鹵素（例如氟或氯，又如氟），R¹¹ 、R¹² 、R¹⁴ 和R¹⁵ 各自獨立地為H、鹵素（例如氟或氯，又如氟）、鹵素取代的C₁ -C₁₀ 烷基（例如-CF₃ ）或鹵素取代的C₁ -C₁₀ 烷氧基（例如-OCHF₂ 或-OCF₃ ）；所述的鹵素、“鹵素取代的C₁ -C₁₀ 烷基”和“鹵素取代的C₁ -C₁₀ 烷氧基”的定義如“上述的R² 中的取代的定義”中所述。進一步優選地，R¹¹ 、R¹² 、R¹⁴ 和R¹⁵ 中至少有兩個為H。In a preferred embodiment of the present invention, in the compound represented by formula I, R ² is preferably

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

”為雙鍵； R³ 為H、C₁ -C₁₀ 烷基或C₃ -C₁₀ 環烷基； R¹ 為

或

； R² 為

，R¹¹ 、R¹² 、R¹³ 、R¹⁴ 和R¹⁵ 的定義如上所述。優選地，R¹¹ 、R¹² 、R¹⁴ 和R¹⁵ 各自獨立地為H、鹵素或鹵素取代的C₁ -C₁₀ 烷基。優選地，R¹² 和R¹⁴ 各自獨立地為H或鹵素。優選地，R¹¹ 為H、鹵素或鹵素取代的C₁ -C₁₀ 烷基，並且R¹⁵ 為氫。優選地，R¹¹ 為氫或鹵素，R¹² 、R¹³ 、R¹⁴ 和R¹⁵ 均為氫。優選地，R¹¹ 為鹵素或鹵素取代的C₁ -C₁₀ 烷基，R¹² 、R¹³ 、R¹⁴ 和R¹⁵ 均為氫。In a preferred embodiment of the present invention, in the compound represented by formula I, 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

or

; R ² is

, R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are as defined above. Preferably, R ¹¹ , R ¹² , R ¹⁴ and R ¹⁵ are each independently a C ₁ -C ₁₀ alkyl substituted with H, halogen or halogen. 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 a C ₁ -C ₁₀ alkyl substituted by halogen, and R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are all hydrogen.

”為雙鍵； R³ 為H、C₁ -C₁₀ 烷基或C₃ -C₁₀ 環烷基； R¹ 為

； R² 為

，R¹¹ 、R¹² 、R¹³ 、R¹⁴ 和R¹⁵ 的定義如上所述。優選地，R¹¹ 、R¹² 、R¹⁴ 和R¹⁵ 各自獨立地為H、鹵素、鹵素取代的C₁ -C₁₀ 烷基或鹵素取代的C₁ -C₁₀ 烷氧基。優選地，R¹² 和R¹⁴ 各自獨立地為H或鹵素。優選地， R¹¹ 為H、鹵素、鹵素取代的C₁ -C₁₀ 烷基或鹵素取代的C₁ -C₁₀ 烷氧基，並且R¹⁵ 為氫。優選地，R¹¹ 為氫或鹵素，R¹² 、R¹³ 、R¹⁴ 和R¹⁵ 均為氫。In a preferred embodiment of the present invention, in the compound represented by formula I, 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

, R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are as defined 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.

”為雙鍵； R³ 為甲基； R¹ 為

； R² 為

，R¹¹ 、R¹² 、R¹³ 、R¹⁴ 和R¹⁵ 的定義如上所述。優選地，R¹¹ 、R¹² 、R¹⁴ 和R¹⁵ 各自獨立地為H、鹵素、鹵素取代的C₁ -C₁₀ 烷基或鹵素取代的C₁ -C₁₀ 烷氧基。優選地，R¹² 和R¹⁴ 各自獨立地為H或鹵素。優選地， R¹¹ 為H、鹵素、鹵素取代的C₁ -C₁₀ 烷基或鹵素取代的C₁ -C₁₀ 烷氧基，並且R¹⁵ 為氫。優選地，R¹¹ 為氫或鹵素，R¹² 、R¹³ 、R¹⁴ 和R¹⁵ 均為氫。In a preferred embodiment of the present invention, in the compound represented by formula I, X is NR ³ and Y is CO;

"Is a double bond; R ³ is a methyl group; R ¹ is

; R ² is

, R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are as defined 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.

”為雙鍵； R³ 為C₃ -C₁₀ 環烷基（如環丙基）； R¹ 為

； R² 為

，R¹¹ 、R¹² 、R¹³ 、R¹⁴ 和R¹⁵ 的定義如上所述。優選地，R¹¹ 、R¹² 、R¹⁴ 和R¹⁵ 各自獨立地為H、鹵素、鹵素取代的C₁ -C₁₀ 烷基或鹵素取代的C₁ -C₁₀ 烷氧基。優選地，R¹² 和R¹⁴ 各自獨立地為H或鹵素。優選地， R¹¹ 為H、鹵素、鹵素取代的C₁ -C₁₀ 烷基或鹵素取代的C₁ -C₁₀ 烷氧基，並且R¹⁵ 為氫。優選地，R¹¹ 為氫、鹵素或鹵素取代的C₁ -C₁₀ 烷氧基，R¹² 、R¹³ 、R¹⁴ 和R¹⁵ 均為氫。In a preferred embodiment of the present invention, in the compound represented by formula I, 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

, R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are as defined 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 a C ₁ -C ₁₀ alkoxy substituted by halogen, and R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are all hydrogen.

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

.

其中，“

”、“

”、X、Y、W、R¹ 和R² 的定義均同前所述，X¹ 為鹵素（例如F、Cl、Br或I，又如Cl）或C₁ -C₄ 烷基取代的碸基（例如甲碸基）。The present invention also provides a method for preparing the compound represented by formula I as described above, which comprises the following steps: in an organic solvent, the compound represented by formula IA and an aminating reagent are subjected to nucleophilicity as shown below Substitution reaction to obtain the compound represented by formula I, that is;

among them,"

","

", X, Y, W, R ¹ and R ² have the same definitions as mentioned above, and X ¹ is halogen (for example, F, Cl, Br or I, and for example Cl) or C ₁ -C ₄ alkyl substituted alkane Base (for example, formazan base).

In the method for preparing the compound represented by formula I, the conditions for the nucleophilic substitution reaction may be conventional conditions for this type of reaction in the art. The preferred embodiments of the present invention are as follows: the organic solvent can be a conventional organic solvent for this type of reaction in the field, preferably an ether solvent. The ether solvent is preferably tetrahydrofuran. The amount of the organic solvent is not specifically limited, as long as it does not affect the progress of the reaction. The amination reagent may be a conventional amination reagent for this type of reaction 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 aminating reagent may not be specifically limited, as long as it does not affect the progress of the reaction. Generally, it is a conventional amount for this type of reaction in the art. The temperature of the nucleophilic substitution may be a conventional temperature for this type of reaction 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 the end point of the reaction is generally when the compound represented by formula I-A no longer reacts.

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

其中，“

”、“

”、X、Y、W、R¹ 和R² 的定義如前所述；X¹ 為鹵素（例如F、Cl、Br或I，又如Cl）或C₁ -C₄ 烷基取代的碸基（例如甲碸基）； 並且，所述的如式I-A所示的化合物不為以下任一結構：

。The present invention also provides a compound represented by formula IA:

among them,"

","

", X, Y, W, R ¹ and R ² are as defined above; X ¹ is halogen (for example, F, Cl, Br or I, and for example, Cl) or a C ₁ -C ₄ alkyl substituted alkyl group (For example, a methyl group); And, the compound represented by formula IA does not have any of the following structures:

.

。The compound represented by formula IA can be selected from any of the following structures:

.

其中，“

”、“

”、X、Y、W、R¹ 和R² 的定義均同前所述，X² 為C₁ -C₄ 烷基取代的巰基（如甲巰基），X¹ 為C₁ -C₄ 烷基取代的碸基（例如甲碸基）。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 oxidizing agent are subjected to the oxidation reaction shown below to prepare the compound represented by formula IA The compound shown, that is;

among them,"

","

", X, Y, W, R ¹ and R ² have the same definitions as described above, X ² is a C ₁ -C ₄ alkyl substituted mercapto group (such as methyl mercapto), and X ¹ is a C ₁ -C ₄ alkyl group. Substituted sulfonyl (for example, methylsulfonyl).

In the method for preparing the compound represented by formula I-A, the conditions of the oxidation reaction may be conventional conditions of this type of reaction in the art. The preferred embodiments of the present invention are as follows: the organic solvent can be a conventional organic solvent for this type of reaction in the field, preferably a chlorinated hydrocarbon solvent. The chlorinated hydrocarbon solvent is preferably dichloromethane. The amount of the organic solvent is not specifically limited, as long as it does not affect the progress of the reaction. The oxidizing agent may be a conventional oxidizing agent of this type of reaction in the art, such as m-chloroperoxybenzoic acid. The amount of the oxidant is not specifically limited, as long as it does not affect the progress of the reaction. Generally, it is a conventional amount for this type of reaction in the art. The temperature of the nucleophilic substitution may be a conventional temperature for this type of reaction 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 the end of the reaction is generally when the compound represented by formula I-B no longer reacts.

其中，“

”、X、Y、R¹ 、R² 和X² 的定義均同前所述，W為C，“

”為雙鍵。The method for preparing the compound represented by formula IB may include the following steps: in an organic solvent, the compound represented by formula IC and R ² -CHO are reacted as shown below in the presence of a base to obtain The compound represented by formula IB, that is;

among them,"

", X, Y, R ¹ , R ² and X ² have the same definitions as described above, W is C, "

"Is a double bond.

In the method for preparing the compound represented by formula IB, the conditions of the reaction may be conventional conditions of this type of reaction in the field of organic synthesis. The preferred embodiments of the present invention are as follows: the organic solvent may be a conventional organic solvent for this type of reaction in the field, preferably an alcohol solvent (such as ethanol). The amount of the organic solvent is not specifically limited, as long as it does not affect the progress of the reaction. The base may be a conventional base for this type of reaction in the art, such as DBU (1,8-diazabicycloundec-7-ene). The dosage of the alkali is the conventional dosage for this type of reaction in the art. The ratio of the amount of the compound represented by formula IC to the amount of R ² -CHO can be a conventional ratio of this type of reaction in the art. The reaction temperature may be a temperature conventional in this type of reaction in the art, for example, 50°C-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 the end point of the reaction is generally when the compound represented by formula IC no longer reacts.

In the present invention, the compound represented by formula IB prepared by the method for preparing the compound represented by formula IB as described above is generally a mixture of Z configuration and E configuration. However, when the structure of the compound represented by formula IC and R ² -CHO changes, the following situation may occur: the content of the E configuration and the Z configuration in the product is not much different; there may be a certain dominant configuration, so that the product The content of E configuration and Z configuration is very different. The compounds of the formula IB in the Z configuration and the E configuration 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 compound represented by formula IB in the Z configuration and the E configuration can be directly subjected to the next step reaction, and left to the subsequent step for separation. When the content of the E configuration and the Z configuration in the product is quite different, a product with a smaller content configuration can be obtained by amplifying the reaction dosage.

In addition, the compounds obtained by the above methods can also refer to the related methods disclosed in the examples, and further modify the peripheral positions 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, and its pharmaceutically acceptable salts, deuterated compounds, tautomers, cis-trans isomers, enantiomers Isomers, diastereomers or prodrugs, and pharmaceutically acceptable carriers. Preferably, in the pharmaceutical composition, the compound represented by formula I, its pharmaceutically acceptable salt, deuterated product, tautomer, cis-trans isomer, enantiomer, The content of diastereomers or prodrugs is a therapeutically effective amount.

The present invention also provides an adenosine A2A receptor antagonist, which utilizes the compound represented by formula I, its pharmaceutically acceptable salt, deuterium, tautomer, cis-trans isomer, Enantiomers, diastereomers or prodrugs, or the pharmaceutical composition is prepared.

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

The present invention also provides a medicine for preventing, alleviating and/or treating related diseases caused by adenosine A2A receptor, which utilizes the compound represented by formula I, its pharmaceutically acceptable salt, deuterium Substitutes, tautomers, cis-trans isomers, enantiomers, diastereomers or prodrugs, or prepared from the said pharmaceutical composition.

The present invention also provides a method for preventing, alleviating and/or treating related diseases caused by adenosine A2A receptor, which comprises administering a therapeutically effective amount of the compound represented by formula I to a patient in need thereof, A pharmaceutically acceptable salt, deuterium, tautomer, cis-trans isomer, enantiomer, diastereomer or prodrug thereof, or the pharmaceutical composition.

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

The present invention also provides a compound represented by formula I, its pharmaceutically acceptable salt, deuterium, tautomer, cis-trans isomer, enantiomer, diastereomer The application of the body or prodrug, or the pharmaceutical composition in the preparation of a medicine for preventing, alleviating and/or treating central nervous system diseases, immune tolerance diseases or inflammatory diseases.

The present invention also provides a method for preventing, alleviating and/or treating central nervous system diseases, immune tolerance diseases or inflammatory diseases, which comprises administering to a patient in need thereof a therapeutically effective amount of the formula I The compound shown, its pharmaceutically acceptable salt, deuterated product, tautomer, cis-trans isomer, enantiomer, diastereomer or prodrug, or the pharmaceutical composition .

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

The immune tolerance diseases include organ transplant rejection and tumors. The tumors include bone marrow fibrosis, blood tumors (such as leukemia, lymphoma, etc.) and solid tumors (such as kidney cancer, liver cancer, gastric cancer, lung cancer, breast cancer, prostate cancer, pancreatic cancer, thyroid cancer, ovarian cancer, glioblastoma, etc.) Cell cancer, skin cancer, melanoma, etc.).

The inflammatory diseases include acute inflammatory diseases such as pneumonia, hepatitis, nephritis, myocarditis, 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. The oral or injectable composition can be prepared according to any method known in the art for preparing pharmaceutical compositions.

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

Unless otherwise stated, the following terms appearing in the specification and claims of the present invention have the following meanings: The term "alkyl" (including when used alone and in other groups) refers to branched and straight chain saturated aliphatic hydrocarbon groups of 1-20 carbon atoms (preferably 1-10 carbon atoms, more preferably 1- 8 carbon atoms), such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl , 4,4-dimethylpentyl, 2,2,4-trimethylpentyl, undecyl, dodecyl, and their various isomers.

The term "cycloalkyl" (including when used alone and when contained in other groups) refers to those containing saturated or partially unsaturated (containing 1 or 2 double bonds, but none of the rings have a fully conjugated π-electron system) Cyclic hydrocarbon groups with 1, 2 or 3 rings, including monocycloalkyl, bicycloalkyl and tricycloalkyl, containing 3-20 carbons that can form a ring, preferably 3-10 carbons, For example: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecane, cyclododecyl, cyclohexenyl, etc.

The term "aryl" (including when used alone and contained in other groups) refers to any stable monocyclic or bicyclic carbocyclic ring with up to 7 atoms in each ring, at least one of which is aromatic. Examples of the aforementioned aryl unit include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthracenyl, or acenaphthyl. It is 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 made through the aromatic ring.

唑基等。在此定義範圍內的雜芳基包括但不限於：吖啶基、咔唑基、

啉基、喹

啉基、吡唑基、吲哚基、苯并三唑基、呋喃基、噻吩基、苯并噻吩基、苯并呋喃基、喹啉基、異喹啉基、

唑基、異

唑基、吲哚基、吡

基、嗒

基、吡啶基、嘧啶基、吡咯基、四氫喹啉。正如以上“雜環烷基”的定義一樣，“雜芳基”還應當理解為包括任何含氮雜芳基的N-氧化物衍生物。在其中雜芳基取代基是二環取代基並且一個環是非芳香環或者不包含雜原子的情況下，可以理解，連接分別通過芳環或者通過包含環的雜原子進行。The term "heteroaryl" (including when used alone and when contained in other groups) means a stable monocyclic or bicyclic ring with up to 7 atoms in each ring, at least one of which is aromatic and contains 1, 2, 3 Or 4 heteroatoms selected from O, N and S. For example: when the heteroaryl group is a 5-membered heteroaryl group containing 1 heteroatom, it includes furyl, thienyl and pyrrolyl; when the heteroaryl group is a 5-membered heteroaryl group containing 2 heteroatoms, it includes pyridine. Azolyl, thiazolyl and

Azole and so on. Heteroaryl groups within the scope of this definition include, but are not limited to: acridinyl, carbazolyl,

Linyl, quino

Linyl, pyrazolyl, indolyl, benzotriazolyl, furyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl,

Azolyl, iso

Azolyl, indolyl, pyridine

Base, ta

Group, pyridyl, pyrimidinyl, pyrrolyl, tetrahydroquinoline. Just like the definition of "heterocycloalkyl" above, "heteroaryl" should also be understood to include any nitrogen-containing heteroaryl N-oxide derivative. 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 is understood that the connection is made through an aromatic ring or through a heteroatom containing the ring, respectively.

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

The term "oxo group" refers to a case where an oxygen atom is directly used as a substituent of a carbon atom or a nitrogen atom, for example, it forms a carbonyl group with a carbon atom, and forms a nitrogen oxide with a nitrogen atom.

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

The term "hydroxyl" 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 that is sufficient to effectively treat the diseases or conditions described herein when administered to a subject. Although the amount of the compound constituting the "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the subject to be treated, it can be determined by those skilled in the art in a conventional manner.

As used herein, when referring to a specific salt, pharmaceutical composition, composition, excipient, etc. as "pharmaceutically acceptable", it means that the salt, pharmaceutical composition, composition, excipient, etc. are generally non-toxic, safe, and suitable For use in subjects, mammalian subjects are preferred, and human subjects are more preferred.

The term "pharmaceutically acceptable salt" as used herein refers to a pharmaceutically acceptable organic or inorganic salt of the compound of the present invention. Exemplary salts include, but are not limited to: sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate , Lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate Salt (gentisinate), fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, Benzenesulfonate, p-toluenesulfonate and pamoate (i.e. 1-1-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, so that under biological conditions (in vitro or in vivo), the biologically reactive functional group can be cleaved from the compound or react in other ways to provide the The compound. Generally, the prodrug is inactive, or at least less active than the compound itself, so that the compound cannot exert its activity until the compound is cleaved from the biologically reactive functional group. The bioreactive functional group can be hydrolyzed or oxidized under biological conditions to provide the compound. For example, prodrugs may contain biohydrolyzable groups. Examples of biohydrolyzable groups include, but are not limited to, biohydrolyzable phosphates, biohydrolyzable esters, biohydrolyzable amides, biohydrolyzable carbonates, biohydrolyzable carbamates, and biohydrolyzable Of urea.

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

In the present invention, the term "deuterated substance" 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%. Deuterated compounds can generally retain the same activity as non-deuterated compounds, and when deuterated at certain specific sites, they can achieve better metabolic stability, thereby obtaining certain therapeutic advantages (such as increased in vivo half-life or reduced dosage requirements) ), so deuterated substances are preferred in some cases. The deuterated substance of the present invention can usually be prepared according to the preparation method of the present invention or the method disclosed in the examples, using appropriate deuterated reagents instead of non-deuterated reagents.

”代表單鍵，其所連接的雙鍵的構型為Z構型、E構型或它們的混合物。In the present invention, the "

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

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

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

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

The positive and progressive effects of the present invention are: The compound of the present invention has obvious antagonistic effect on adenosine A2A receptor, and can be used as adenosine A2A receptor antagonist to effectively alleviate or treat immune tolerance, central nervous system diseases, inflammatory diseases and other related diseases.

In order to make the above and other objects, features and advantages of the present invention more comprehensible, the following specific examples are given in conjunction with the accompanying drawings, which are described in detail as follows.

The present invention will be further explained by way of examples below, but the present invention is not limited to the scope of the described examples. In the following examples, the experimental methods without specific conditions are selected according to conventional methods and conditions, or according to the product specification.

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

The microwave reaction is carried out in the Explorer full-automatic microwave synthesizer produced by CEM, USA. The magnetron frequency is 2450MHz and the continuous microwave output power is 300W.

The instrument used for HPLC preparation is Gilson 281, and the preparation column used is Xbridge, 21.2x250 mm 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: 2,4-Dichloro-6-methyl-pyrimidine-5-carboxylic acid methyl ester (940 mg, 4.25 mmol), 2-furyltributylstannane (1.42 g, 4.0 mmol), four A mixture of (triphenyl)phosphine palladium (260 mg, 0.22 mmol) and tetrahydrofuran (30 mL) was stirred at 60 ^{°C under} nitrogen protection 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 white solid 1-c (870 mg, yield: 81%).

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 to 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 nitrogen atmosphere, 0.5 M o-fluorobenzyl zinc bromide solution in tetrahydrofuran (4.0 mL, 2.0 mmol) was added to compound 1-b (267 mg, 1.0 mmol) in 10 mL tetrahydrofuran solution. 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 methanol solution of ammonia (2 mL) was added to a solution of compound 1-a (60 mg, 0.17 mmol) in tetrahydrofuran (10 mL) 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 (500 MHz, 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 = 8.0Hz, 3.5Hz), 3.57 (dd, 1H, J = 14.5Hz, 3.5Hz), 3.00 (dd, 1H, J = 14.5Hz, 8.5Hz) 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: Dissolve furfural (9.6 g, 0.1 mol), O-methyl isourea sulfate (20.64 g, 0.12 mol) and ethyl acetate (14.3 g, 0.11 mol) into anhydrous N, To the N-dimethylformamide (200 mL), add sodium bicarbonate (33.6 g, 0.4 mmol) to the solution. The reaction mixture was heated to 70 ^°C under the protection of nitrogen, stirred for 3 hours and then cooled to room temperature. Saturated salt water (300 mL) was added, a large amount of yellow suspended matter appeared, extracted with ethyl acetate (500 mL×2), and the organic phases were combined and washed with water (200 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate , Concentration under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 6-3:1) to obtain a pale yellow solid 2-f (15.0 g, yield: 57%). LC-MS (ESI): m/z =265.1[M+H] ⁺ .

Synthesis of compound 2-e: Dissolve compound 2-f (14.0 g, 53 mmol) in dichloromethane (200 mL), add 2,3-dichloro-5,6-dicyano pair with stirring at room temperature Benzoquinone (12.0 g, 53.0 mmol). The reaction mixture was stirred overnight. The reaction mixture was filtered, 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: Dissolve compound 2-e (1.31 g, 5.0 mmol) in dioxane (30 mL), add selenium dioxide (1.11 g, 10.0 mmol) and glacial acetic acid ( 2 mL), the mixture was heated to 120°C 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 = 6-2:1) to obtain a pink solid 2-d (450 mg, yield: 33%) . LC-MS (ESI): m/z =277.0[M+H] ⁺ .

Synthesis of compound 2-c: Add 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) to a 100 ml three-necked flask ). The mixture was reacted for 2 hours at 55°C under nitrogen protection. After the reaction mixture was cooled to room temperature, saturated ammonium chloride water (20 mL) was added. Extract with ethyl acetate (30 mL×3), wash with saturated brine (30 mL), and dry with anhydrous sodium sulfate. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain a white solid product 2-c (160 mg, yield: 86%).

LC-MS(ESI): m/z=375[M+H] ⁺ .

Synthesis of compound 2-b: Add 2-c (160 mg, 0.42 mmol), lithium iodide (374 mg, 2.81 mmol) and pyridine (8 mL) to a 100 mL single-necked flask. The mixture was refluxed for 5 hours under nitrogen protection. 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 a white solid product 2-b (138 mg, yield: 86%).

LC-MS(ESI): m/z=361[M+H] ⁺ .

Synthesis of compound 2-a: Add 2-b (100 mg, 0.28 mmol) and phosphorus oxychloride (3 mL) to a 25-mL single-mouth bottle. The mixture was refluxed for 2 hours under nitrogen protection. 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 with anhydrous sodium sulfate. Concentrated under reduced pressure, and the resulting 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 7.0 M ammonia in methanol (2 mL, 14 mmol) was added. The mixture was stirred at room temperature for 1 hour. 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, yield in two steps: 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, 1H), 8.09 (s, br., 1H), 8.03 (d, J = 1.0 Hz, 1H), 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 = 8.5 Hz, 15.0 Hz, 1H) ppm.

採用2-d和2-氟-4-氰基苄溴作為原料，合成方法同實施例2。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 (500 MHz, 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 = 7.5 Hz, 1H), 7.50 (d, J = 10.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 6.78 (dd, J = 1.5 Hz, 3.5 Hz, 1H), 5.67 ( dd, J = 3.5 Hz, 8.5 Hz, 1H), 3.45 (dd, J = 3.5 Hz, 15.0 Hz, 1H), 3.14 (dd, J = 8.5 Hz, 15.0 Hz, 1H) ppm.

。 採用化合物2-d和4-氰基苄溴作為原料，合成方法同實施例2。Example 4: 4-{[2-Amino-4-(furan-2-yl)-5-oxo-5 H ,7 H -furan [3,4- d ] pyrimidin-7-yl] methyl Benzoonitrile (Compound 4)

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

LC-MS (ESI): m/z =333[M+1] ⁺ .

¹ H-NMR (400 MHz, CDCl ₃ ) δ :8.51-8.49(d, J =2.8Hz, 1H), 7.71(s, 1H), 7.57-7.55 (d, J =6.8 Hz, 2H), 7.38- 7.26 (d, J =6.8 Hz, 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)-5 H ,7 H -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). Under the protection of nitrogen at -78°C, 1.0 M benzyl magnesium bromide in tetrahydrofuran (1.95 mL, 1.95 mmol) was added dropwise to the reaction solution. After the addition is complete, the cooling device is removed, the reaction system is slowly raised to room temperature, and stirring is continued for 16 hours. Add saturated ammonium chloride solution (20 mL), extract with ethyl acetate (50 mL×2), combine the organic phases, wash with water (30 mL) and saturated brine (20 mL), and dry with anhydrous sodium sulfate. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 6-3:1) to obtain a colorless viscous substance 5-c (320 mg, yield: 61%).

LC-MS (ESI): m/z =323.0[M+H] ⁺ .

Synthesis of compound 5: Using compound 5-c as a raw material, the procedure for synthesizing compound 5 was the same as that in Example 2.

LC-MS (ESI): m/z =308.0[M+H] ⁺ .

¹ H-NMR: (400 MHz,CD ₃ OD)δ:8.54 (d, J = 2.4 Hz, 1H), 7.71 (s, 1H), 7.30-7.20 (m, 5H), 6.66-6.64 (dd, J ₁ = 2.0 Hz, J ₂ = 2.8 Hz, 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 ] pyrimidine-2-amine (compound 6)

synthetic route:

Synthesis of compound 6-f: Suspend sodium hydride (480 mg, 12 mmol) in anhydrous tetrahydrofuran (20 mL), add ( S )-3-phenyl-2-hydroxypropionic acid (1.08 g) dropwise at 0℃ , 6 mmol). After the addition, 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 0.5M hydrochloric acid (30 mL) was added to quench the reaction. Extract with ethyl acetate (30mL×3). Combine the organic phases, wash with saturated brine (50 mL), and dry with anhydrous sodium sulfate. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the colorless liquid product 6-f (600 mg, yield: 43%).

Synthesis of compound 6-e: Add urea (460 mg, 7.68 mmol) and 35% concentrated hydrochloric acid (0.5 mL) to the ethanol (20 mL) solution of compound 6-f (600 mg, 2.56 mmol), heat and reflux for 4 hours, then cool to room temperature , Concentrate under reduced pressure, add ethyl acetate (40 mL) to the residue, then wash with water (40 mL) and saturated brine (40 mL) successively, and dry with anhydrous sodium sulfate. It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:2) to obtain a pale yellow solid product 6-e (320 mg, yield: 45%).

LC-MS(ESI): m/z=277[M+1] ⁺ .

Synthesis of compound 6-d: Compound 6-e (320 mg, 1.16 mmol) was dissolved in 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. Concentrate under reduced pressure, add water (6 mL) to the residue to dissolve, and then slowly add 1M hydrochloric acid dropwise to pH>2, a white solid precipitates. After filtration, the filter cake was vacuum dried to obtain a white solid 6-d (226 mg, yield: 80%).

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

Synthesis of compound 6-c: Suspend compound 6-d (220 mg, 0.9 mmol) in phosphorus oxychloride (2 mL) and add N,N-dimethylaniline (2 drops). After the reaction mixture was stirred at 110 ^°C for two hours, it was cooled to room temperature. Concentrate under reduced pressure, add ethyl acetate (20 mL) to the residue, and then wash with ice water (20 mL) and saturated brine (20 mL) in turn. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain white solid 6-c (130 mg, yield: 51%).

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), 2-(tri-n-butyl)stannylfuran (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 nitrogen protection, it was cooled to room temperature. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain light yellow solid 6-b (117 mg, yield: 81%).

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 di(isopropyl)ethylamine (271 mg , 2.1 mmol). The reaction mixture was heated to reflux for 4 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=10:1~3:1) to obtain light yellow solid 6-a (84 mg, yield: 58%).

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), the reaction mixture was heated to reflux for 6 hours, and then cooled to room temperature. Concentrated under reduced pressure, the residue was washed with saturated aqueous sodium bicarbonate solution (20 mL), and extracted with ethyl acetate (20 mL×3). The organic phases were combined, 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 a yellow solid 6 (30 mg, yield: 50%).

LC-MS(ESI): m/z=294[M+1] ⁺ .

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

。 採用化合物2-d和4-氟-3-氯苄溴作為原料，合成方法同實施例2。Example 7: 2-Amino-7-(3-chloro-4-fluorobenzyl)-4-(furan-2-yl)-5 H ,7 H -furan[3,4- d ]pyrimidine-5 -Ketone (Compound 7)

. Using compound 2-d and 4-fluoro-3-chlorobenzyl bromide as raw materials, the synthesis method is the same as in Example 2.

LC-MS (ESI): m/z = 360.0[M+H] ⁺ .

¹ H NMR: (400 MHz 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 =2.8 Hz, J ₂ =11.6 Hz, 1H), 3.10-3.04 (dd, J ₁ =6.4 Hz, J ₂ =12.0 Hz, 1H) ppm.

。 採用化合物2-d和2,4-二氟苄溴作為原料，合成方法同實施例2。Example 8: 2-Amino-7-(2,4-difluorobenzyl)-4-(furan-2-yl)-5 H ,7 H -furan [3,4- d ] pyrimidine-5- Ketone (Compound 8)

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

LC-MS (ESI): m/z = 344.0[M+H] ⁺ .

¹ H NMR (400 MHz, 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.

。 採用化合物2-d和4-氯苄溴作為原料，合成方法同實施例2。Example 9: 2-Amino-7-(4-chlorobenzyl)-4-(furan-2-yl)-5 H ,7 H -furan [3,4- d ] pyrimidin-5-one (compound 9)

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

LC-MS (ESI): m/z = 342.0[M+H] ⁺ .

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

。 採用化合物2-d和4-氟-2-氯苄溴作為原料，合成方法同實施例2。Example 10: 2-Amino-7-(2-chloro-4-fluorobenzyl)-4-(furan-2-yl)-5 H ,7 H -furan [3,4- d ] pyrimidine-5 -Ketone (Compound 10)

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

LC-MS (ESI): m/z = 360.0[M+H] ⁺ .

¹ 1H NMR (400 MHz, 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)-5 H ,7 H -furan [3,4- d ] pyrimidin-5-one (compound 11)

Synthesis of compound 11-c: Using compound 2-d and 2-chlorobenzyl bromide as raw materials, the synthesis method is the same as that in Example 2.

LC-MS (ESI): m/z = 342.0[M+H] ⁺ .

¹ H NMR(400 MHz,CDCl ₃ )δ:8.60 (d, J =2.4 Hz, 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, 1H) ppm.

。 採用化合物2-d和3-氟-4-氯苄溴作為原料，合成方法同實施例2。Example 12: 2-Amino-7-(4-chloro-3-fluorobenzyl)-4-(furan-2-yl)-5 H ,7 H -furan[3,4- d ]pyrimidine-5 -Ketone (Compound 12)

. Using compound 2-d and 3-fluoro-4-chlorobenzyl bromide as raw materials, the synthesis method is the same as in Example 2.

LC-MS (ESI): m/z = 360.0[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ )δ: 8.54 (d, J =2.4 Hz, 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, 1H) ppm.

。 採用化合物2-d和4-甲磺醯基苄溴作為原料，合成方法同實施例2。Example 13: 2-Amino-4-(furan-2-yl)-7-(4-methanesulfonylbenzyl)-5 H ,7 H -furan[3,4- d ]pyrimidine-5- Ketone (Compound 13)

. Using compound 2-d and 4-methanesulfonyl benzyl bromide as raw materials, the synthesis method is the same as in Example 2.

LC-MS (ESI): m/z = 386[M+H] ⁺ .

¹ H NMR (400 MHz, 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.

。 採用化合物2-d 和4-溴甲基苯甲酸第三丁酯作為原料，合成方法同實施例2。Example 14: 4-((2-Amino-4-(furan-2-yl)-5-oxo-5 H ,7 H -furan [3,4- d ] pyrimidin-7-yl) methyl Benzamide (Compound 14 )

. Using compound 2-d and tert-butyl 4-bromomethyl benzoate as raw materials, the synthesis method is the same as in Example 2.

LC-MS (ESI): m/z =351 [M+H] ⁺ .

¹ H NMR: (400 MHz,DMSO- d ₆ ) δ: 8.24 (d, J = 2.4 Hz, 1H), 8.09 (s, 1H), 7.93 (s, 1H), 7.91 (s, 1H), 7.78 ( d, J = 6.8 Hz, 1H), 7.31 (s, 1H), 7.29 (d, J = 6.8 Hz, 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.

。 採用化合物2-d和4-三氟甲基苄溴作為原料，合成方法同實施例2。Example 15: 2-Amino-4-(furan-2-yl)-7-((4-(trifluoromethyl)phenyl)methyl)-5 H ,7 H -furan [3,4- d ] Pyrimidine-5-one (Compound 15 )

. Using compound 2-d and 4-trifluoromethylbenzyl bromide as raw materials, the synthesis method is the same as that in Example 2.

LC-MS (ESI): m/z = 376[M+H] ⁺ .

¹ H NMR (400 MHz, 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)-5 H ,7 H -furan [3,4- d ] Pyrimidine-5-one (Compound 16)

Synthesis of compound 16-c: Using compound 2-d and 2-trifluoromethylbenzyl bromide as raw materials, the synthesis method is the same as in Example 2.

LC-MS (ESI): m/z = 376[M+H] ⁺ .

¹ H NMR (400 MHz, 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 =5.6 Hz, 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.

。 採用化合物2-d和2-氯-6-氟苄溴作為原料，合成方法同實施例2。Example 17: 2-Amino-7-((2-chloro-6-fluorophenyl)methyl)-4-(furan-2-yl)-5 H ,7 H -furan [3,4- d ] Pyrimidine-5-one (Compound 17)

. Using compound 2-d and 2-chloro-6-fluorobenzyl bromide as raw materials, the synthesis method is the same as 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.

。 採用化合物2-d和3-氯-2-氟苄溴作為原料，合成方法同實施例2。Example 18: 2-Amino-7-((3-chloro-2-fluorophenyl)methyl)-4-(furan-2-yl)-5 H ,7 H -furan [3,4- d ] Pyridin-5-one (Compound 18)

. Using compound 2-d and 3-chloro-2-fluorobenzyl bromide as raw materials, the synthesis method is the same as in Example 2.

LC-MS (ESI): m/z = 360[M+H] ⁺ .

¹ 1H NMR (400 MHz, CDCl ₃ ) δ:8.55-8.51(d, J =2.8Hz,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.

。 採用化合物2-d和2-甲基苄溴作為原料，合成方法同實施例2。Example 19: 2-Amino-7-((2-methylphenyl)methyl)-4-(furan-2-yl)-5 H ,7 H -furan [3,4- d ] pyrimidine- 5-ketone (Compound 19)

. Using compound 2-d and 2-methylbenzyl bromide as raw materials, the synthesis method is the same as 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.

。 採用化合物2-d和3,5-二（三氟甲基）苄溴作為原料，合成方法同實施例2。Example 20: 2-Amino-7-((3,5-bis(trifluoromethyl)phenyl)methyl)-4-(furan-2-yl)-5 H ,7 H -furan [3, 4- d ]pyrimidin-5-one (Compound 20)

. Using compound 2-d and 3,5-bis(trifluoromethyl)benzyl bromide as raw materials, the synthesis method is the same as in Example 2.

LC-MS (ESI): m/z =444[M+H] ⁺ .

¹ 1H NMR (400 MHz, 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.

。 採用化合物2-d和4-三氟甲氧基苄溴作為原料，合成方法同實施例2。Example 21: 2-Amino-7-((4-(trifluoromethoxy)phenyl)methyl)-4-(furan-2-yl)-5 H ,7 H -furan [3,4- d ]Pyrimidine-5-one (Compound 21)

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

LC-MS (ESI): m/z = 391.9[M+H] ⁺ .

¹ H NMR (400 MHz, 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, 1H) ppm.

。 採用化合物2-d和2,6-二氟苄溴作為原料，合成方法同實施例2。Example 22: 2-Amino-7-((2,6-difluorophenyl)methyl)-4-(furan-2-yl)-5 H ,7 H -furan[3,4- d ]o Pyrimidine-5-one (Compound 22)

. Using compound 2-d and 2,6-difluorobenzyl bromide as raw materials, the synthesis method is the same as in Example 2.

LC-MS (ESI): m/z = 344[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ )δ: 8.60 (d, J = 3.2 Hz, 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.

。 採用化合物2-d和2-三氟甲氧基苄溴作為原料，合成方法同實施例2。Example 23: 2-Amino-7-((2-(trifluoromethoxy)phenyl)methyl)-4-(furan-2-yl)-5 H ,7 H -furan [3,4- d ]Pyrimidine-5-one (Compound 23)

. Using compound 2-d and 2-trifluoromethoxybenzyl bromide as raw materials, the synthesis method is the same as that in Example 2.

LC-MS (ESI): m/z = 391.9[M+H] ⁺ .

¹ H NMR (400 MHz,CDCl ₃ )δ: 8.57 (d, J =2.8 Hz, 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, 1H) ppm.

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

synthetic route:

Synthesis of compound 24-f: Dissolve 2-pyridinecarboxaldehyde (5.0 g, 46.7 mmol), O-methylisourea sulfate (9.64 g, 56.0 mmol) and ethyl acetylacetate (6.67 g, 51.3 mmol) into anhydrous N,N-dimethyl Add sodium bicarbonate (15.7 g, 186.8 mmol) to the methamide (100 mL). The reaction mixture was heated to 70°C under the protection of nitrogen, stirred for 3 hours and then cooled to room temperature. Saturated brine (200 mL) was added, a large amount of yellow suspended matter appeared, extracted with ethyl acetate (500 mL×2), the organic phases were combined and 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 = 10:1) to obtain a white solid 24-f (10.2 g, yield: 79%).

LC-MS (ESI): m/z =276.3[M+H] ⁺ .

Synthesis of compound 24-e: Dissolve compound 24-f (10.0 g, 36.3 mmol) in dichloromethane (100 mL), add 2,3-dichloro-5,6-dicyano pair with stirring at room temperature Benzoquinone (9.08 g, 40.0 mmol). The reaction mixture was stirred overnight. The reaction mixture was filtered, 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: Dissolve compound 24-e (6.5 g, 23.8 mmol) in dioxane (100 mL), add selenium dioxide (3.96 g, 35.7 mmol) and glacial acetic acid ( 2 mL), the mixture was heated to 120°C 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 a pink solid 24-d (1.8 g, yield: 26%).

LC-MS (ESI): m/z =288.1[M+H] ⁺ .

Synthesis of compound 24-c: Add a tetrahydrofuran solution of benzylmagnesium chloride (1.0 M, 1.5 mL, 1.5 mmol) to compound 24-d (287 mg, 1.0 mmol) in anhydrous tetrahydrofuran (10 mL) In the solution, the reaction solution was slowly raised to room temperature and stirred for 16 hours. Add saturated aqueous ammonium chloride solution (20 mL). Extract with ethyl acetate (30 mL×3), wash with saturated brine (30 mL), and dry with anhydrous sodium sulfate. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain the gray solid product 24-c (230 mg, yield: 69%). LC-MS(ESI): m/z = 334[M+H] ⁺ .

Synthesis of compound 24-b: Add 24-c (310 mg, 0.93 mmol), lithium iodide (623 mg, 4.6 mmol), and pyridine (15 mL) to a 100 mL single-neck bottle. The reaction solution was stirred at 120°C for 16 hours and then cooled to room temperature. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: methanol = 100-10:1) to obtain a yellow solid 24-b (280 mg, yield: 94%).

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. Concentrate under reduced pressure, add the residue to ice-water mixture (100 mL), extract with ethyl acetate (50 mL×2), combine the organic phases and wash with water (30 mL) and saturated brine (20 mL), anhydrous sulfuric acid Sodium is dry. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30:1) to obtain a yellow solid 24-a (180 mg, yield: 62%).

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

LC-MS (ESI): m/z = 319[M+H] ⁺ .

¹ H NMR (400 MHz, 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, 1H) ppm.

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

synthetic route:

Synthesis of compound 25: Compound 8 (60mg, 0.17mmol) was dissolved in N,N-dimethylformamide (15 mL), N-bromosuccinimidyl (47mg, 0.26 mmol) was added, and the reaction solution was stirred at room temperature 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%-65% (initial mobile phase was 15% water-85% acetonitrile, At the end, the mobile phase was 65% water-35% acetonitrile, where% refers to volume percentage), and compound 25 (26 mg, yield: 36.2%) was obtained after purification.

LC-MS (ESI): m/z = 423 [M+H] ⁺ .

¹ H NMR (400 MHz, 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 = 3.2Hz, 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)-5 H ,7 H -furan [3,4 -d ] Pyrimidine-5-one (Compound 26 ).

synthetic route:

Synthesis of compound 26-f: Dissolve furfural (16.92 g, 153.68 mmol), O-methyl isourea sulfate (26.46 g, 153.68 mmol) and ethyl acetylacetate (20 g, 153.68 mmol) into anhydrous N,N-dimethylformamide To the amine (200 mL), add sodium bicarbonate (19.37 g, 230.52 mmol) to the solution. The reaction mixture was heated to 75°C under the protection of nitrogen, stirred for 16 hours and then cooled to room temperature. Ethyl acetate (200 mL) was added to the reaction mixture, washed with water (200 mL×3) and saturated brine (200 mL) successively, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and 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-dicyanoquinone (52.83 g, 232.7 mmol). 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), 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 = 3.5Hz, 1H), 6.17-6.16 (d, J = 3.0Hz,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: Dissolve compound 26-e (1.0 g, 3.62 mmol) in a mixed solution of dioxane (20 mL) and ethyl acetate (1 mL), and add selenium dioxide (522 mg, 4.71 mmol) at room temperature , The mixture was heated to 120°C and stirred for 6 hours. After cooling to room temperature, the reaction mixture was filtered, 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) ) To obtain compound 26-d (561 mg, yield: 53.4%).

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 were added to the reaction solution. -Difluorobenzyl bromide (300 mg, 1.03 mmol). The reaction mixture was raised to 55°C and stirred for 1 hour. After cooling to room temperature, saturated ammonium chloride solution (20 mL) was added to quench the reaction. It 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 with anhydrous sodium sulfate. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain white solid 26-c (300 mg, yield: 91%). 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 solid precipitated out. Filtered. The filter cake was washed with water (20 mL×2). After vacuum drying, a yellow solid 26-b (200 mg, yield: 70%). 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, the reaction solution was stirred at 125°C for 2 hours and then cooled to Room temperature. Concentrate under reduced pressure, add the residue to ice-water mixture (100 mL), extract with ethyl acetate (50 mL×2), combine the organic phases and wash with water (30 mL) and saturated brine (20 mL), anhydrous sulfuric acid Sodium is dry. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain a yellow solid 26-a (160 mg, yield: 75.9%).

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), 7.0 M methanol solution of ammonia (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 (400 MHz, 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.

。 採用化合物26-d和2-氟苄溴作為原料，合成方法同實施例26。Example 27: 2-Amino-7-((2-fluorophenyl)methyl)-4-(5-methylfuran-2-yl)-5 H ,7 H -furan [3,4- d ] Pyridin-5-one (Compound 27 )

. Using compound 26-d and 2-fluorobenzyl bromide 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 (400 MHz, 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.

。 採用化合物26-d 和2-三氟甲基苄溴作為原料，合成方法同實施例26。Example 28: 2-Amino-7-((2-(trifluoromethyl)phenyl)methyl)-4-(5-methylfuran-2-yl)-5 H ,7 H -furan [3 ,4- d ] Pyrimidine-5-one (Compound 28 )

. Using compound 26-d and 2-trifluoromethylbenzyl bromide as raw materials, the synthesis method is the same as that in Example 26.

LC-MS (ESI): m/z = 390[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.54-8.53(d, J =2.8Hz, 1H), 7.69-7.68(d, J =6.4Hz, 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.

。 採用化合物26-d和2,5-二氟苄溴作為原料，合成方法同實施例26。Example 29: 2-Amino-7-((2,5-difluorophenyl)methyl)-4-(5-methylfuran-2-yl)-5 H ,7 H -furan [3,4 -d ] Pyrimidine-5-one (Compound 29)

. Using compound 26-d and 2,5-difluorobenzyl bromide as raw materials, the synthesis method is the same as that in Example 26.

LC-MS (ESI): m/z = 358[M+H] ⁺ .

¹ 1H NMR (400 MHz, 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.

。 採用化合物26-d和5-氯-2-氟苄溴作為原料，合成方法同實施例26。Example 30: 2-Amino-7-((5-chloro-2-fluorophenyl)methyl)-4-(5-methylfuran-2-yl)-5 H ,7 H -furan [3, 4- d ]pyrimidin-5-one (Compound 30)

. Using compound 26-d and 5-chloro-2-fluorobenzyl bromide 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 (400 MHz, 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.

。 採用化合物26-d和6-氯-2-氟苄溴作為原料，合成方法同實施例26。Example 31: 2-Amino-7-((6-chloro-2-fluorophenyl)methyl)-4-(5-methylfuran-2-yl)-5 H ,7 H -furan [3, 4- d ]pyrimidin-5-one (Compound 31)

. Using compound 26-d and 6-chloro-2-fluorobenzyl bromide 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 (400 MHz, 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.

。 採用化合物26-d和4-氟-2-三氟甲基苄溴作為原料，合成方法同實施例26。Example 32: 2-Amino-7-((4-fluoro-2-(trifluoromethyl)phenyl)methyl)-4-(5-methylfuran-2-yl)-5 H , 7 H -Furan[3,4- d ]pyrimidin-5-one (Compound 32)

. Using compound 26-d and 4-fluoro-2-trifluoromethylbenzyl bromide as raw materials, the synthesis method is the same as that in Example 26.

LC-MS (ESI): m/z =408[M+H] ⁺ .

¹ H NMR (400 MHz, 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 ] pyrimidine-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) was added dropwise at 0 ^℃ , 18.0 mmol). After the addition, stirring was continued for 30 minutes at 0°C, and then methyl acrylate (2.22 g, 27.0 mmol) was added. Stirring was continued for 3 hours at room temperature, and 0.5M hydrochloric acid (30 mL) was added to quench the reaction. Extract with ethyl acetate (50 mL×3). Combine the organic phases, wash with saturated brine (50 mL), and dry with anhydrous sodium sulfate. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1-10:1) to obtain the colorless liquid product 33-f (2.8 g, yield: 66%).

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), heated to reflux for reaction After 4 hours, cool to room temperature, concentrate under reduced pressure, add ethyl acetate (100 mL) to the residue, and then wash with water (100 mL) and saturated brine (100 mL), and dry with anhydrous sodium sulfate. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1~ 1:1) to obtain a pale yellow solid product 33-e (810 mg, yield: 25%). LC-MS (ESI): m/z = 277 [M+1] ⁺ .

Synthesis of compound 33-d: Compound 33-e (810 mg, 2.93 mmol) was dissolved in 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. Concentrate under reduced pressure, add water (15 mL) to the residue to dissolve, then slowly add 1M hydrochloric acid dropwise to pH>2, a white solid precipitates. After filtration, the filter cake was vacuum dried to obtain a white solid 33-d (550 mg, yield: 77%).

¹ HNMR(500MHz, DMSO- d ₆ ) δ: 11.57 (s, 1H), 11.02 (s, 1H), 7.26~7.29 (m, 2H), 7.19~7.22 (m, 3H), 5.17~5.20 (m, 1H), 4.56~4.58 (m, 1H), 4.41~4.44 (m, 1H), 3.13~3.17 (m, 1H), 2.89~2.93 (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. Concentrate under reduced pressure, add ethyl acetate (50 mL×2) to the residue, and then wash with ice water (20 mL) and saturated brine (20 mL) in turn. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=20:1-10:1) to obtain a white solid 33-c (260 mg, yield: 92%).

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)stannylfuran (364 mg, 1.02 mmol) and tetrakis(triphenyl)phosphine palladium ( 107.4 mg, 0.093 mmol). After stirring at 60°C for 16 hours under nitrogen protection, it was cooled to room temperature. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1 ~ 10:1) to obtain a pale yellow solid 33-b (240 mg, yield: 83%).

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 mg, 2.3 mmol). The reaction mixture was heated to reflux for 4 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=10:1~5:1) to obtain a pale yellow viscous substance 33-a (150 mg, yield: 44%). 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), the reaction mixture was heated to reflux for hours, and then cooled to room temperature. Concentrated under reduced pressure, the residue was washed with saturated aqueous sodium bicarbonate solution (20 mL), and extracted with ethyl acetate (20 mL×3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1~3:1) to obtain a white solid 33 (50 mg, yield: 50%).

LC-MS (ESI): m/z = 294 [M+1] ⁺ .

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

Example 34: 2-Amino-9-((2,4-difluorophenyl)methyl)-6-(furan-2-yl)-8,9-dihydro-7 H -purin-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), slowly at 0℃ 2,4-Difluorobenzylamine (300 mg, 2.1 mmol) was added dropwise, and the mixture was stirred at 0°C for 1 hour. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15:1) to obtain a yellow solid product 34-e (547 mg, yield: 82%).

Synthesis of compound 34-d: Compound 34-e (200 mg, 0.60 mmol), 2-(tri-n-butyl) tin 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. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a yellow solid product 34-d (120mg, yield: 55%).

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 reacting the reaction mixture 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 yellow solid product 34-c (152 mg, yield: 78%).

LC-MS(ESI): m/z= 588 [M+1] ⁺ .

Synthesis of compound 34-b: Dissolve ammonium chloride (268 mg, 5.0 mmol) in water (5 mL), then add zinc powder (163 mg, 2.5 mmol) and ethanol (10 mL) in sequence, and stir at 0°C Add a solution of 34-c (120 mg, 0.30 mmol) in tetrahydrofuran (8 mL) dropwise. After stirring for 1 hour at 0°C, 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 concentrated under reduced pressure. Purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1), a red solid product 34-b (120 mg, yield: 86%.) 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 34-b (120 mg, 0.21 mmol) and diisopropylethylamine (387 mg, 3.0 mmol) in dry tetrahydrofuran ( 10 mL) in the solution, stir for 10 minutes and then rise 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 a pink solid product 34-a (75 mg, yield: 61%). 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] ⁺ .

¹ H NMR (500 MHz, 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-7 H- Purine-8-one (Compound 35)

Synthesis of compound 35-a: Suspend 60% of sodium hydride (8 mg, 0.2mol) dispersed in mineral oil in dry N,N-dimethylformamide (4 mL), and add 34 dropwise to the suspension under nitrogen protection at 0°C -a (36 mg, 0.061 mmol) in dry N,N-dimethylformamide (2 mL) and continue stirring at 0°C for 1 hour. Add methyl iodide (43 mg, 0.3 mmol), warm to room temperature and continue the reaction for 1 hour. 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 a 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] ⁺ .

1H NMR (500 MHz, 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.

。 採用化合物26-d和2-三氟甲氧基苄溴作為原料，合成方法同實施例26。Example 36: 2-Amino-7-((2-(trifluoromethoxy)phenyl)methyl)-4-(5-methylfuran-2-yl)-5 H ,7 H -furan [ 3,4- d ] Pyrimidine-5-one (Compound 36 )

. Using compound 26-d and 2-trifluoromethoxybenzyl bromide as raw materials, the synthesis method is the same as that in Example 26.

LC-MS (ESI): m/z =406[M+H] ⁺ .

¹ H NMR (400 MHz, 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)-5 H ,7 H -furan [3 ,4- d ] Pyrimidine-5-one (Compound 37)

Synthesis of compound 37: Dissolve compound 23 (130 mg, 0.33 mmol) in N,N-dimethylformamide (15 mL), add N-bromosuccinimide (89 mg, 0.49 mmol), 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%-65% (initial mobile phase was 15% water-85% acetonitrile, At the end, the mobile phase was 65% water-35% acetonitrile, where% refers to volume percentage), and compound 37 (70 mg, yield: 45.2%) was obtained after purification.

LC-MS (ESI): m/z = 470 [M+H] ⁺ .

¹ 1H NMR (400 MHz, 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)methylenyl)-4-(furan-2-yl)-6-methyl-5 H , 6 H , 7 H -pyrrole [3 ,4- d ]Pyrimidine-5-one (Compound 38)

Synthesis of compound 38-f: Add sodium bicarbonate (21.2 g, 200 mmol) to furfural (9.60 g, 100 mmol), S-methyl isothiourea sulfate (20.7 g, 150 mmol) and ethyl acetylacetate (13.0 g, 100 mmol) in a solution of N,N-dimethylformaldehyde (80 mL). After the reaction mixture was stirred at 80°C for 6 hours, it was cooled to room temperature. Concentrate under reduced pressure, add water (100 mL) to the residue, extract with ethyl acetate (40 mL×3), wash the combined organic phase with saturated brine (100 mL), and dry with anhydrous sodium sulfate. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15:1) to obtain the yellow solid product 38-f (5.7 g, yield: 20%). LC-MS (ESI): m/z = 281 [M+H] ⁺ .

Synthesis of compound 38-e: Under an ice-water bath, 2,3-dichloro-5,6-dicyano-p-benzoquinone (6.0g, 26.4mmol) was added to compound 38-f (5.60g, 20.0 mmol) in dichloromethane (100 mL ) In the solution, the reaction solution was raised to room temperature and stirred for 8 hours. Filter and wash the filter cake 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 yellow solid product 38-e (4.10 g, yield: 74%).

LC-MS (ESI): m/z = 279 [M+H] ⁺ .

Synthesis of compound 38-d: Compound 38-e (1.40g, 5.0 mmol) was dissolved in 1,4-dioxane (60 mL), 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). Filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1-15:1) to obtain a yellow solid 38-d (0.98 g, yield: 70%).

LC-MS (ESI): m/z = 293 [M+H] ⁺ .

Synthesis of compound 38-c: Add methylamine hydrochloride (680 mg, 10.0 mmol) and sodium acetate (820 mg, 10.0 mmol) to methanol (30 mL). After the mixture was stirred at room temperature for 1 hour, it was cooled to 5°C in an ice-water bath, 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 raised to room temperature and stirring continued for 16 hours. Concentrate under reduced pressure, dilute the residue with water (100 mL), and extract 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 a white solid product 38-c (560 mg, yield: 64%).

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 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 for 16 hours under nitrogen protection, and then cooled to room temperature. Concentrated under reduced pressure, and the residue was washed with ethyl acetate (20 mL×3) and filtered to obtain a brown solid 38-b (153 mg, yield: 41%). This product does 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 the 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 adding saturated sodium thiosulfate solution (3 mL). Add water (20 mL) and extract with dichloromethane (20 mL×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 light yellow solid 38-a (40 mg, yield: 62%).

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

LC-MS (ESI): m/z = 337 [M+H] ⁺ .

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

。 採用化合物26-d和2-二氟甲氧基苄溴作為原料，合成方法同實施例26。Example 39: 2-Amino-7-((2-(difluoromethoxy)phenyl)methyl)-4-(5-methylfuran-2-yl)-5 H ,7 H -furan [ 3,4- d ] Pyrimidine-5-one (Compound 39)

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

LC-MS (ESI): m/z =388[M+H] ⁺ .

¹ H NMR (400 MHz, 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.

。 採用2-氟苄胺作為原料，合成方法同實施例34。Example 40: 2-Amino-9-((2-fluorophenyl)methyl)-6-(furan-2-yl)-7-methyl-8,9-dihydro-7 H -purine-8 -Ketone (Compound 40)

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

LC-MS(ESI): m/z= 326 [M+1] ⁺ .

¹ H NMR (400 MHz, 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-7 H -purine-8 -Ketone (Compound 41)

Synthesis of compound 41-a: Suspend 60% sodium hydride (15 mg, 0.56 mol) dispersed in mineral oil in dry N,N-dimethylformamide (10 mL), and add 40 drops to the suspension at 0°C under nitrogen protection -a (210 mg, 0.37 mmol) in dry N,N-dimethylformamide (10 mL) solution, and continue stirring at 0°C for 1 hour. Add methyl iodide (106 mg, 0.74 mmol), warm up to room temperature and continue the reaction for 1 hour. 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 a white solid product 41-a ( 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 stirring the reaction mixture 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 (400 MHz, 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-deuterium-4-(5-methylfuran-2-yl)-5 H ,7 H -furan [3,4- d ] Pyrimidine-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 the compound 26-a (300 mg, 0.79 mmol) Dioxane (20mL) 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 adding saturated ammonium chloride solution (20 mL). Extract with ethyl acetate (50 mL×2), combine the organic phases, wash with water (30 mL) and saturated brine (20 mL), and dry with anhydrous sodium sulfate. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1-10:1) to obtain a yellow solid 42-b (320 mg, yield: 77%).

LC-MS(ESI): m/z= 398 [M+1] ⁺ .

Synthesis of compound 42-a: Add deuterium water (5 mL) and 1M deuterated sodium hydroxide solution (4 mL) to the 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 extracted with ethyl acetate (2×20 mL). The organic phases were combined and washed with water (10 mL) and saturated brine (10 mL). Anhydrous sulfuric acid Sodium is dry. Concentrated under reduced pressure to obtain 42-a (200 mg, yield: 76%) as a pale yellow solid, which did not require 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-dicyanoquinone was added to the reaction solution under stirring at room temperature ( 227 mg, 1.0 mmol), and continue to stir at room temperature for 3 days. The reaction mixture was filtered, the filtrate 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% (initial mobile phase was 40% water-60 % Acetonitrile, the mobile phase is 70% water-30% acetonitrile at the end, where% refers to the volume percentage). After purification, an off-white solid 42 (22 mg, yield: 19%) is obtained.

LC-MS(ESI): m/z= 359 [M+1] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.51 (d, J = 2.8 Hz, 1H), 7.30-7.26 (m, 1H), 6.84-6.78 (m, 2H), 6.30 (d, J = 2.4 Hz , 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)-5 H ,7 H -furan [3 ,4- d ] Pyrimidine-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 reduced to -78°C, and 1 M potassium hexamethyldisilazide solution was added dropwise ( 0.80 mL, 0.80 mmol). After stirring for 30 minutes, iodomethane (225.7 mg, 1.59 mmol) was added dropwise. Continue stirring at this temperature for 1 hour, then gradually rise to room temperature and continue stirring for 16 hours. The reaction was quenched with saturated aqueous ammonium chloride (50 mL). Extract with ethyl acetate (50 mL×2), combine the organic phases, wash with water (30 mL) and saturated brine (20 mL), and dry with anhydrous sodium sulfate. Concentration under reduced pressure gave 43-c (210 mg) as a yellow solid, which did not require 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 a pink solid 43-b (200 mg). This product does 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 ice-water mixture (50 mL), extracted with ethyl acetate (50 mL×2), the organic phases were combined and washed with water (30 mL) and saturated brine (20 mL). Dry with anhydrous sodium sulfate. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30:1-10:1) to obtain a pale yellow solid 43-b (150 mg, yield: 50%). LC-MS(ESI): m/z= 411 [M+1] ⁺ .

Synthesis of compound 43: Dissolve compound 43-a (150 mg, 0.40 mmol) in tetrahydrofuran (10 mL), add 7 M methanolic ammonia solution (5 mL) to the reaction solution at room temperature, and continue stirring for 2 hour. 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% (initial mobile phase was 40% water-60% acetonitrile, At the end, the mobile phase is 70% water-30% acetonitrile, where% refers to volume percentage), and an off-white solid 43 (50 mg, yield: 35%) is obtained after purification.

LC-MS(ESI): m/z= 454 [M+1] ⁺ .

¹ H NMR: (400 MHz, 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-5 H , 6 H , 7 H -pyrrole [3, 4- d ]pyrimidin-5-one (Compound 44)

Synthesis of compound 44-b: Add a solution of compound 38-a (74 mg, 0.2 mmol) in tetrahydrofuran (4 mL) dropwise to ammonium chloride (214 mg, 4.0 mmol) in water (5 mL), zinc powder (130 mg, 2.0 mmol) and ethanol (10 mL). 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 (55mg, yield: 74%). LC-MS(ESI): m/z= 370 [M+1] ⁺ .

Synthesis of compound 44-a: 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 stirred at room temperature for 16 hours. The reaction was quenched by adding saturated sodium thiosulfate solution (3 mL). Add water (20 mL) and extract with dichloromethane (20 mL×3). Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain light yellow solid 44-a (28 mg, yield: 87%).

Synthesis of compound 44: A methanol solution of 7N ammonia (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. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:3) to obtain a white solid 44 (16 mg, yield: 68%).

LC-MS (ESI): m/z = 339 [M+1] ⁺ .

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

。 採用化合物38-c和鄰三氟甲氧基苯甲醛作為原料，合成方法同實施例38。Example 45: 2-Amino-7-((2-trifluoromethoxyphenyl)methyl)-4-(furan-2-yl)-6-methyl-5 H , 6 H , 7 H- Pyrrole[3,4- d ]pyrimidin-5-one (Compound 45)

. Using compound 38-c and o-trifluoromethoxybenzaldehyde as raw materials, the synthesis method is the same as that in Example 38.

LC-MS (ESI): m/z = 403 [M+H] ⁺ .

¹ H NMR (400 MHz, 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.

採用化合物38-c和2,4-二氟苯甲醛作為原料，合成方法同實施例38。Example 46: 2-Amino-7-((2,4-difluorophenyl)methylenyl)-4-(furan-2-yl)-6-methyl-5 H , 6 H , 7 H- Pyrrole[3,4- d ]pyrimidin-5-one (Compound 46)

Using compound 38-c and 2,4-difluorobenzaldehyde as raw materials, the synthesis method is the same as that in Example 38.

LC-MS (ESI): m/z = 355 [M+H] ⁺ .

¹ H NMR (400 MHz, 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-5 H , 6 H , 7 H -pyrrole [3,4- d ] Pyrimidine-5-one (Compound 47)

Synthesis of compound 47: At 0℃, add compound 46 (160 mg, 0.45 mmol) in tetrahydrofuran (10 mL) and zinc powder (294 mg, 4.5 mmol) to ammonium chloride (481 mg, 8.9 mmol) in water (2 mL) and ethanol ( 2 mL) of the mixed solution. After stirring for 1 hour, it was warmed 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 carbonic acid) Hydrogen ammonium), acetonitrile; gradient: 30%-60% (the initial mobile phase is 30% water-70% acetonitrile, the mobile phase is 60% water-40% acetonitrile at the end, where% refers to volume percentage), after purification Obtained 47 (8 mg, yield: 4.9%).

LC-MS(ESI): m/z= 357 [M+1] ⁺ .

¹ H NMR (400 MHz, 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)methylenyl)-4-(5-methylfuran-2-yl)-6-methyl-5 H ,6 H ,7 H -pyrrole[3,4- d ]pyrimidin-5-one (Compound 48)

Synthesis of compound 48-f: Add sodium bicarbonate (33.6g, 400 mmol) to 5-methylfurfural (11.0 g, 100 mmol), S-methylisothiourea sulfate (16.68g, 60 mmol) and ethyl acetylacetate (14.3g) , 110 mmol) in N,N-dimethylformaldehyde (200 mL) solution. After the reaction mixture was stirred at 70°C for 3 hours, it was cooled to room temperature. Concentrate under reduced pressure, add water (100 mL) to the residue, extract with ethyl acetate (500 mL×2), wash the combined organic phase with water (200 mL) and saturated brine (100 mL), and dry with 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 a pale yellow solid 48-f (10.0g, yield: 34%).

LC-MS (ESI): m/z = 295 [M+H] ⁺ .

Synthesis of compound 48-e: Under ice water bath, add 2,3-dichloro-5,6-dicyanoquinone (9.26g, 40.8mmol) to compound 48-f (10.0g, 34mmol) in dichloromethane (300 mL ) In the solution, the reaction solution was raised 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 a yellow viscous product 48-e (5.10g, yield: 52%).

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). Filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate = 6:1-2:1) to obtain a yellow solid 48-d (4.0 g, yield: 58%).

LC-MS (ESI): m/z = 307 [M+H] ⁺ .

Synthesis of compound 48-c: Add methylamine hydrochloride (1.76 g, 26.1 mmol) and sodium acetate (3.56 g, 26.1 mmol) to methanol (30 mL). After the mixture was stirred at room temperature for 1 hour, it was cooled to 0°C in an ice-water bath, 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 raised to room temperature and stirring continued for 12 hours. Concentrate under reduced pressure, dilute the residue with water (100 mL), extract with dichloromethane (50 mL×2), and wash the combined organic phase 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 a yellow solid 4 8-c (1.38 g, yield: 75%). 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 compound 48-c (589 mg, 4.15 mmol) and 2,4-difluoro Benzaldehyde (380 mg, 1.38 mmol) in dioxane (15 mL) solution. After the mixture was refluxed for 12 hours under the protection of nitrogen, it was cooled to room temperature. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a yellow solid 48-b (270 mg, yield: 50%). 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 solution of compound 48-b (270 mg, 0.67 mmol) in dichloromethane (10 mL), and stirred at room temperature for 1 hour. The reaction was quenched by adding saturated sodium thiosulfate solution (10 mL). Add water (20 mL), extract with dichloromethane (20 mL×3), wash the combined organic phase with water (20 mL) and saturated brine (20 mL), and concentrate under reduced pressure to obtain a yellow solid 48-a (40 mg , Yield: 62%), this product does not require further purification. LC-MS (ESI): m/z = 432 [M+H] ⁺ .

Synthesis of compound 48 Add 7N ammonia in methanol (2 mL, 14 mmol) to compound 48-a (400 mg, 0.93 mmol) in tetrahydrofuran (10 mL). The mixture was stirred at room temperature for 1 hour. Concentrate under reduced pressure, add methanol (10 mL) to the residue to form a solid, filter, wash the filter cake with methanol (3 mL), and dry under vacuum to obtain compound 48 (284 mg, yield: 80.1%).

LC-MS (ESI): m/z = 369 [M+H] ⁺ .

¹ H NMR (400 MHz, 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-5 H ,6 H , 7 H -pyrrole[3,4- d ]pyrimidin-5-one (compound 49)

Synthesis of compound 49: At 0℃, add compound 48 (258 mg, 0.7 mmol) in tetrahydrofuran (10 mL) solution and zinc powder (458 mg, 7.1 mmol) to ammonium chloride (760 mg, 14 mmol) water (3 mL) and ethanol ( 3 mL) of the mixed solution. After stirring for 1 hour, it was warmed 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 by silica gel thin layer chromatography (petroleum ether: ethyl acetate) Ester = 2:1) to obtain 49 (18 mg, yield: 6.9%).

LC-MS(ESI): m/z= 371 [M+1] ⁺ .

¹ H NMR (400 MHz, 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.

。 採用化合物48-c和2-氟苯甲醛作為原料，合成方法同實施例48。Example 50: 2-Amino-7-((2-fluorophenyl)methylenyl)-4-(5-methylfuran-2-yl)-6-methyl-5 H , 6 H , 7 H -Pyrrole [3,4- d ] pyrimidin-5-one (compound 50)

. Using compound 48-c and 2-fluorobenzaldehyde as raw materials, the synthesis method is the same as that in Example 48.

LC-MS (ESI): m/z = 351 [M+H] ⁺ .

¹ H NMR (400 MHz, 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.

。 採用化合物48-c和2-三氟甲基苯甲醛作為原料，合成方法同實施例48。Example 51: 2-Amino-7-((2-(trifluoromethyl)phenyl)methenyl)-4-(5-methylfuran-2-yl)-6-methyl- 5H , 6 H ,7 H -pyrrole [3,4- d ] pyrimidin-5-one (compound 51)

. Using compound 48-c and 2-trifluoromethylbenzaldehyde as raw materials, the synthesis method is the same as that in Example 48.

LC-MS (ESI): m/z = 401 [M+H] ⁺ .

¹ H NMR (400 MHz, 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.

。 採用化合物48-c和2-三氟甲氧基苯甲醛作為原料，合成方法同實施例48。Example 52: 2-Amino-7-((2-(trifluoromethoxy)phenyl)methenyl)-4-(5-methylfuran-2-yl)-6-methyl-5 H ,6 H ,7 H -pyrrole[3,4- d ]pyrimidin-5-one (Compound 52)

. Using compound 48-c and 2-trifluoromethoxybenzaldehyde as raw materials, the synthesis method is the same as that in Example 48.

LC-MS (ESI): m/z = 417 [M+H] ⁺ .

¹ H NMR: (400 MHz, CDCl ₃ )δ: 8.61 (d, J = 2.4 Hz, 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-5 H , 6 H ,7 H -pyrrole [3,4- d ] pyrimidin-5-one (compound 53)

At 0℃, add compound 52 (124.8 mg, 0.3 mmol) in tetrahydrofuran (10 mL) and zinc powder (195 mg, 3.0 mmol) to ammonium chloride (321 mg, 6.0 mmol) in water (3 mL) and ethanol ( 3 mL) of the mixed solution. After stirring for 1 hour, it was warmed 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 carbonic acid) Ammonium hydrogen), acetonitrile; gradient: 45%-75% (the initial mobile phase is 45% water-55% acetonitrile, the mobile phase is 75% water-25% acetonitrile at the end, where% refers to volume percentage), after purification A white solid 53 (30 mg, yield: 24%) was obtained. LC-MS (ESI): m/z= 419 [M+1] ⁺ .

¹ H NMR: (400 MHz, CD ₃ OD)δ: 8.34 (d, J = 2.8 Hz, 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 ,6 H ,7 H -pyrrole [3,4- d ] pyrimidin-5-one (Compound 54)

At 0℃, add compound 51 (100 mg, 0.25 mmol) in tetrahydrofuran (10 mL) solution and zinc powder (163 mg, 2.5 mmol) to ammonium chloride (268 mg, 5.0 mmol) water (3 mL) and ethanol ( 3 mL) of the mixed solution. After stirring for 1 hour, it was warmed 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 by silica gel thin layer chromatography (petroleum ether: ethyl acetate) Ester = 2:1) to obtain 54 (22 mg, yield: 21.8%).

LC-MS(ESI): m/z= 403 [M+1] ⁺ .

¹ H NMR (400 MHz, 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-5 H , 6 H , 7 H- Pyrrole[3,4- d ]pyrimidin-5-one (Compound 55)

At 0℃, add compound 50 (100 mg, 0.4 mmol) in tetrahydrofuran (10 mL) and zinc powder (262 mg, 4.0 mmol) to ammonium chloride (428 mg, 8.0 mmol) water (3 mL) and ethanol ( 3 mL) of the mixed solution. After stirring for 1 hour, it was warmed 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 by silica gel thin layer chromatography (petroleum ether: ethyl acetate) Ester = 2:1) to obtain 55 (15mg, 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 =2.8Hz, 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 -5 H ,6 H ,7 H -pyrrole [3,4- d ] pyrimidin-5-one (compound 56)

Synthesis of compound 56-b: Under the protection of nitrogen, a solution of compound 48-c (275mg, 1.0 mmol) in anhydrous tetrahydrofuran (20 mL) was added dropwise to 1 M potassium hexamethyldisilazide at -78℃. 1.5 mL, 1.5 mmol) of tetrahydrofuran solution, stir for 1 hour, then dropwise add 2-trifluoromethoxy-4-fluorobenzaldehyde (384mg, 2.0 mmol) in anhydrous tetrahydrofuran (20 mL) solution, and continue to stir for 1 hour. After slowly rising 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 a yellow solid 56-b (180 mg , Yield: 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 compound 56-b (130 mg, 0.29 mmol) in dichloromethane (30 mL), and stirred at room temperature 1 hour. The reaction was quenched by adding saturated sodium thiosulfate solution (10 mL). Add water (30 mL), extract with dichloromethane (30 mL×2), wash the combined organic phase with water (30 mL) and saturated brine (30 mL), and concentrate under reduced pressure to obtain a yellow solid 56-a (150 mg, Yield: 99%), this product does not require further purification. LC-MS (ESI): m/z = 482 [M+H] ⁺ .

Synthesis of compound 56: Add 7N ammonia in methanol (5 mL, 35 mmol) to compound 56-a (150 mg, 0.31 mmol) in tetrahydrofuran (15 mL). The mixture was stirred at room temperature for 1 hour. Concentrate under reduced pressure, add methanol (6 mL) to the residue to form a solid, filter, wash the filter cake with methanol (6 mL), and dry under vacuum to obtain compound 56 (50 mg, yield: 39%).

LC-MS (ESI): m/z = 419 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.60 (d, J = 3.2 Hz, 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 = 2.4 Hz, 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- 5 H ,6 H ,7 H -pyrrole [3,4- d ] pyrimidin-5-one (compound 57 )

Synthesis of compound 57: At 0℃, add compound 56 (130 mg, 0.31 mmol) in tetrahydrofuran (10 mL) and zinc powder (201.5 mg, 3.1 mmol) to ammonium chloride (331.7 mg, 6.2 mmol) in water (4 mL) and ethanol (4 mL) mixed solution. After stirring for 1 hour, it was warmed 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 carbonic acid) Ammonium hydrogen), acetonitrile; gradient: 45%-75% (the initial mobile phase is 45% water-55% acetonitrile, the mobile phase is 75% water-25% acetonitrile at the end, where% refers to volume percentage), after purification Obtain 57 (13 mg, yield: 11%). LC-MS (ESI): m/z= 421 [M+1] ⁺ .

採用化合物48-c和4-吡啶甲醛作為原料，合成方法同實施例48。Example 58: 4-((2-Amino-6-methyl-4-(5-methylfuran-2-yl)-5-carbonyl-5 H -pyrrole [3,4- d ] pyrimidine-7 (6H)-Subunit)methyl)-N-pyridine oxide (Compound 58)

Using compound 48-c and 4-pyridinecarboxaldehyde 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 (400 MHz, 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- 5 H -pyrrole[3,4- d ]pyrimidine (Compound 59)

Synthesis of compound 59: At 0℃, add compound 58 (70 mg, 0.2 mmol) in tetrahydrofuran (10 mL) solution and zinc powder (131 mg, 2.0 mmol) to ammonium chloride (215 mg, 4.0 mmol) water (2 mL) and ethanol ( 2 mL) of the mixed solution. After stirring for 1 hour, it was warmed 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 by silica gel thin layer chromatography (petroleum ether: ethyl acetate) Ester = 2:1) to obtain 59 (7mg, yield: 10.4%).

LC-MS(ESI): m/z= 336 [M+1] ⁺ .

¹ H NMR (400 MHz, 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(9 H )-carbonyl-7 H -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 mmol) and stirred at 0°C for 1 hour. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a yellow solid product 60-e (470 mg, yield: 73%).

LC-MS(ESI): m/z=367[M+1] ⁺ .

Synthesis of compound 60-d: Combine compound 60-e (500 mg, 1.37 mmol), 2-(tri-n-butyl) tin furan (210 mg, 1.67 mmol), anhydrous potassium phosphate (890 mg, 4.2 mmol) and 1,1'-Bisdiphenylphosphinoferrocene palladium dichloride (160mg, 0.2mmol) 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. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a yellow solid product 60-d (120 mg, yield: 21%).

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) were added to dry tetrahydrofuran (10 mL). After reacting the reaction mixture 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 a yellow solid product 360-c (120 mg, yield: 65%).

LC-MS(ESI): m/z= 634 [M+1] ⁺ .

Synthesis of compound 60-b: Under stirring at 0℃, ammonium chloride (40 mg, 0.75 mmol), zinc powder (50 mg, 0.75 mmol) and ethanol (3 mL) were added to compound 6 0-c ( 120 mg, 0.19 mmol) in water (3 mL) and ethanol (3 mL) solution. The temperature was raised to 80°C, stirred for 1 hour and then cooled to room temperature. The reaction solution was concentrated under reduced pressure, the residue was diluted with water (50 mL), 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 does not require further purification.

LC-MS(ESI): m/z= 630 [M+1] ⁺ .

Synthesis of compound 60-a: At 0°C, add triphosgene (24 mg, 0.08 mmol) to 60-b (98 mg, 0.16 mmol) and triethylamine (50 mg, 0.48 mmol) in dry tetrahydrofuran (5 mL) and stir for 10 After a minute, it was raised to room temperature and stirring continued for 3 hours. The reaction solution was concentrated under reduced pressure, the residue was diluted with water (5 mL), filtered, and the filter cake was dried in vacuum to obtain a light brown solid 60-a (98 mg, yield: 96%), which 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 a silica gel thin layer chromatography preparation plate ( Dichloromethane: methanol = 10:1) to obtain a light yellow solid 60 (15 mg, yield: 25%). LC-MS(ESI): m/z= 390 [M+1] ⁺ .

¹ H-NMR (400MHz, DMSO- d ₆ ) δ: 11.3 (br, 1H), 7.80 (d, J =8Hz, 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(9 H )-carbonyl- 7 H -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 was slowly added dropwise at 0℃ 4-fluorobenzylamine (423 mg, 2.19 mmol), stirred at 0°C for 1 hour. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain a yellow solid product 61-f (470 mg, yield: 58%). 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)stannyl-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) were 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. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=20:1) to obtain 61-e (160mg, 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 reacting the reaction mixture 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 a yellow solid product 61-d (175 mg, yield: 72%).

LC-MS(ESI): m/z= 652 [M+1] ⁺ .

Synthesis of compound 61-c: Dissolve ammonium chloride (268 mg, 5.0 mmol) in water (3 mL), then add zinc powder (171 mg, 2.6 mmol) and ethanol (3 mL) successively, and add 61-d (with stirring at 0℃). 170 mg, 0.26 mmol) in tetrahydrofuran (10 mL). After stirring for 1 hour at 0°C, 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 concentrated under reduced pressure. Purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1), a black oily 61-c (116 mg, yield: 72%) was obtained.

LC-MS(ESI): m/z= 622 [M+1] ⁺ .

Synthesis of compound 61-b: At 0°C, add triphosgene (63 mg, 0.21 mmol) to a solution of 34-b (110 mg, 0.17 mmol) and diisopropylethylamine (0.5 mL, 2.65 mmol) in dry tetrahydrofuran (15 mL), After stirring for 10 minutes, it was raised to room temperature and stirring was continued for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a yellow oil 61-b (137 mg, yield: 61%), which did not require further purification.

LC-MS(ESI): m/z= 648 [M+1] ⁺ .

Synthesis of compound 61-a: Suspend 60% of sodium hydride (8 mg, 0.2 mol) dispersed in mineral oil in dry N,N-dimethylformamide (4 mL), and add 61 drops to the suspension at 0°C under nitrogen protection -b (137 mg, 0.21 mmol) in dry N,N-dimethylformamide (10 mL) solution, and continue to stir at 0°C for 30 minutes. Add methyl iodide (60 mg, 0.42 mmol), warm up to room temperature and continue the reaction for 12 hours. 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 did not require 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 stirring the reaction mixture 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% (initial mobile phase was 30% water-70% acetonitrile, At the end, the mobile phase was 60% water-40% acetonitrile, where% refers to the 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 (400 MHz, 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-fluorophenylmethylenyl)-4-(5-methylfuran-2-yl)-6-ethyl- 5H , 6H , 7 H -pyrrole[3,4- d ]pyrimidin-5-one (Compound 62)

Synthesis of compound 62-f: Add sodium bicarbonate (33.6 g, 400 mmol) to 5-methylfurfural (11.0 g, 100 mmol), S-methylisothiourea sulfate (16.68 g, 60 mmol) and ethyl acetate Ethyl acetate (14.3 g, 110 mmol) in N,N-dimethylformamide (200 mL). After the reaction mixture was stirred at 70 ^o C for 3 hours and cooled to room temperature. Concentrate under reduced pressure, add water (100 mL) to the residue, extract with ethyl acetate (500 mL×2), wash the combined organic phase with water (200 mL) and saturated brine (100 mL), and dry with 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 a pale yellow solid 62-f (10.0 g, yield: 34%). LC-MS (ESI): m/z = 295 [M+H] ⁺ .

Synthesis of compound 62-e: Under ice water bath, 2,3-dichloro-5,6-dicyano-p-benzoquinone (9.26 g, 40.8 mmol) was added to compound 62-f (10.0 g, 34 mmol) in batches In dichloromethane (300 mL) solution, 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 a yellow viscous material 62-e (5.10 g, yield: 52%). 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), selenium dioxide (3.7 g, 33.4 mmol) and glacial acetic acid ( 1.5 mL). 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). After 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 a yellow solid 62-d (4.0 g, yield: 58%). LC-MS (ESI): m/z = 307 [M+H] ⁺ .

Synthesis of compound 62-c: Add ethylamine hydrochloride (1.06 g, 13.07 mmol) and sodium acetate (1.18 g, 13.07 mmol) to methanol (30 mL). The mixture was stirred at room temperature for 1 hour and ice-water bath was cooled to 0 ^o C, then compound 62-d (1.0 g, 3.27 mmol) and methylene chloride (10 mL). After stirring for 30 minutes, sodium cyanoborohydride (0.31 g, 4.9 mmol) was added, and the reaction mixture was raised to room temperature and stirring continued for 12 hours. Concentrate under reduced pressure, dilute the residue with water (100 mL), extract with dichloromethane (50 mL×2), and wash the combined organic phase 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 a yellow solid 62-c (350 mg, yield: 37%).

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 compound 62-c (350 mg, 1.21 mmol) and 2-fluorobenzaldehyde (451 mg, 3.63 mmol) in dioxane (15 mL) solution. After the mixture was refluxed for 12 hours under the protection of nitrogen, it was cooled to room temperature. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a yellow solid 62-b (202 mg, yield: 42%). 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 compound 62-b (202 mg, 0.51 mmol) in dichloromethane (10 mL) at room temperature Stir for 1 hour. The reaction was quenched by adding saturated sodium thiosulfate solution (10 mL). Add water (20 mL), extract with dichloromethane (20 mL×3), wash the combined organic phase with water (20 mL) and saturated brine (20 mL), and concentrate under reduced pressure to obtain a yellow solid 62-a (150 mg, Yield: 68%), this product does not require further purification. LC-MS (ESI): m/z = 428 [M+H] ⁺ .

Synthesis of compound 62: Add 7N ammonia in methanol (2 mL, 14 mmol) to compound 62-a (150 mg, 0.35 mmol) in tetrahydrofuran (10 mL). The mixture was stirred at room temperature for 1 hour. Concentrate under reduced pressure, add methanol (10 mL) to the residue to form a solid, filter, wash the filter cake with methanol (3 mL), and dry under vacuum to obtain compound 62 (135 mg, yield: 91%).

LC-MS (ESI): m/z = 365 [M+H] ⁺ .

¹ H-NMR (400 MHz, 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)phenylmethylenyl)-4-(5-methylfuran-2-yl)-6-ethyl-5 H ,6 H ,7 H -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-(trifluoro (Methyl)benzaldehyde (795 mg, 4.56 mmol) in dioxane (15 mL). After the mixture was refluxed for 12 hours under the protection of nitrogen, it was cooled to room temperature. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a yellow solid 63-b (450 mg, yield: 66%). 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 compound 63-b (450 mg, 1.01 mmol) in dichloromethane (10 mL) at room temperature Stir for 1 hour. The reaction was quenched by adding saturated sodium thiosulfate solution (10 mL). Add water (20 mL), extract with dichloromethane (20 mL×3), wash the combined organic phase with water (20 mL) and saturated brine (20 mL), and concentrate under reduced pressure to obtain a yellow solid 63-a (500 mg) , This product does not require further purification. LC-MS (ESI): m/z = 478 [M+H] ⁺ .

Synthesis of compound 63: A methanol solution of 7N ammonia (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 at room temperature for 1 hour. Concentrate under reduced pressure, add methanol (10 mL) to the residue to form a solid, filter, wash the filter cake with methanol (5 mL), and dry under vacuum to obtain compound 63 (207 mg, yield: 49%). LC-MS (ESI): m/z = 415 [M+H] ⁺ .

¹ H-NMR (400 MHz, 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 = 6.4 Hz, 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)phenylmethylenyl)-6,7-dihydro -5 H -pyrrole[3,4- d ]pyrimidin-5-one (compound 64)

Synthesis of compound 64-d: 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) were dissolved in methanol (20 mL) and dichloromethane (50 mL) mixed solvent, slowly add acetic acid (600 mg, 10.0 mmol) 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 12 hours. Concentrate under reduced pressure, dilute the residue with water (50 mL), extract with dichloromethane (50 mL×3), and wash the combined organic phase 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 a yellow solid 64-d (1.2 g, yield: 58%). LC-MS (ESI): m/z = 412 [M+H] ⁺ .

Synthesis of compound 64-c: Add a solution of compound 64-d (206 mg, 0.5 mmol) in anhydrous tetrahydrofuran (10 mL) dropwise to 1.0 M potassium hexamethyldisilazide under a nitrogen atmosphere at -78 ^o C Tetrahydrofuran solution (0.6 mL, 0.6 mmol). After stirring for 1 hour, a solution of 2-(trifluoromethyl)benzaldehyde (87 mg, 0.5 mmol) in dry tetrahydrofuran (5 mL) was added dropwise, and stirring was continued for 1 hour. The reaction solution was slowly raised to room temperature, and saturated ammonium chloride solution (50 mL) was added to quench the reaction, and then extracted with ethyl acetate (50 mL×3). The organic phase was water (50 mL) and saturated brine (50 mL). ) Was washed, dried over anhydrous 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 a pale yellow solid 64-c (120 mg , Yield: 42%). 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), the reaction solution was stirred at 75 ^o C 3 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate (100 mL), and then saturated sodium bicarbonate solution (20 mL), water (20 mL) and saturated brine (20 mL) were used in sequence. ) Wash, the organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow solid 64-b (120 mg), which does not require 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 compound 64-b (120 mg) in dichloromethane (10 mL) and stirred at room temperature for 2 hours . The reaction was quenched by adding saturated sodium thiosulfate solution (10 mL). Add water (20 mL), extract with dichloromethane (20 mL×3), wash the combined organic phase with water (20 mL) and saturated brine (20 mL), dry the organic phase over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1-3:1) to obtain a yellow solid 64-a (36 mg, yield: 40%). LC-MS (ESI): m/z = 450 [M+H] ⁺ .

Synthesis of compound 64: A methanol solution of 7N ammonia (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 at room temperature for 1 hour. Concentrate under reduced pressure, add methanol (3 mL) to the residue to form a solid, filter, wash the filter cake with methanol (1 mL), and dry under vacuum to obtain compound 64 (11 mg, yield: 35%). LC-MS (ESI): m/z = 387 [M+H] ⁺ .

¹ H-NMR (400 MHz, CDCl ₃ ) δ : 10.48 (s, 1H), 8.46 (d, J = 2.4 Hz, 1H), 8.20 (d, J = 6.0 Hz, 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-fluorophenylmethylenyl)-4-(5-methylfuran-2-yl)-6,7-di Hydrogen-5 H -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 cyclopropylamine (950 mg, 16.6 mmol) and compound 62-d (1.7 g, 5.55 mmol) in methanol (10 mL) and dichloride Methane (30 mL) mixed solvent. After the mixture was stirred at room temperature for 2 hours, sodium cyanoborohydride (520 mg, 8.25 mmol) was added in portions, and the reaction mixture was stirred at room temperature for 12 hours. The reaction solution was diluted with water (100 mL), extracted with dichloromethane (50 mL×3), and the combined organic phase was 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 a white solid 65-c (1.5 g, yield: 89%). 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 compound 65-c (500 mg, 1.67 mmol) and 2-fluorobenzaldehyde (310 mg, 2,5 mmol) in dioxane (10 mL) solution. After the mixture was refluxed for 12 hours under the protection of nitrogen, it was cooled to room temperature. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain a yellow solid 65-b (320 mg, yield: 47%). 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 compound 65-b (320 mg, 0.78 mmol) in dichloromethane (10 mL) at room temperature Stir for 1 hour. The reaction was quenched by adding saturated sodium thiosulfate solution (10 mL). Add water (20 mL), extract with dichloromethane (20 mL×3), wash the combined organic phase with water (20 mL) and saturated brine (20 mL), and concentrate under reduced pressure to obtain a yellow solid 65-a (130 mg, Yield: 38%), this product does not require further purification. LC-MS (ESI): m/z = 428 [M+H] ⁺ .

Synthesis of compound 65: Add 7N ammonia in methanol (3 mL, 21 mmol) to compound 65-a (130 mg, 0.29 mmol) in tetrahydrofuran (15 mL). The mixture was stirred at room temperature for 1 hour. Concentrate under reduced pressure. Add methanol (6 mL) to the residue to form a solid. Ultrasound for one minute and filter. The filter cake was washed with methanol (3 mL) and dried under vacuum to obtain compound 65 (84 mg, yield: 75%).

LC-MS (ESI): m/z = 377 [M+H] ⁺ .

¹ H-NMR (500 MHz, CDCl ₃ ) δ : 8.58 (d, J =3Hz, 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)phenylmethylenyl)-4-(5-methylfuran-2-yl)-6, 7-Dihydro-5 H -pyrrole[3,4- d ]pyrimidin-5-one (compound 66)

Synthesis of compound 66-c: Add a solution of compound 64-d (411 mg, 1.0 mmol) in anhydrous tetrahydrofuran (15 mL) dropwise to 1.0 M potassium hexamethyldisilazide under a nitrogen atmosphere at -78 ^o C Tetrahydrofuran solution (1.0 mL, 1.0 mmol). 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 raised to room temperature, and saturated ammonium chloride solution (50 mL) was added to quench the reaction, and then extracted with ethyl acetate (50 mL×3). The organic phase was water (50 mL) and saturated brine (50 mL). ) Was washed, dried over anhydrous 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 a pale yellow solid 66-c (150 mg , Yield: 25%). 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), the reaction solution was stirred at 75 ^o C 3 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate (100 mL), and then saturated sodium bicarbonate solution (20 mL), water (20 mL) and saturated brine (20 mL) were used in sequence. ) Washing, the organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 66-b (100 mg) as a yellow solid, which does not require 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 solution of compound 66-b (100 mg) in dichloromethane (10 mL) and stirred at room temperature for 2 hours . The reaction was quenched by adding saturated sodium thiosulfate solution (10 mL). Add water (20 mL), extract with dichloromethane (20 mL×3), wash the combined organic phase with water (20 mL) and saturated brine (20 mL), dry the organic phase over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1-3:1) to obtain a yellow solid 66-a (50 mg, yield: 50%). LC-MS (ESI): m/z = 468 [M+H] ⁺ .

Synthesis of compound 66 A methanol solution of 7N ammonia (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 at room temperature for 1 hour. Concentrate under reduced pressure, add methanol (3 mL) to the residue to form a solid, filter, wash the filter cake with methanol (1 mL), and dry under vacuum to obtain compound 66 (3 mg, yield: 6.9%).

LC-MS (ESI): m/z = 405 [M+H] ⁺ .

¹ H-NMR (400 MHz, CDCl ₃ ) δ : 10.53 (s, 1H), 8.45 (d, J = 3.2 Hz, 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-fluorophenylmethylenyl)-6-methyl-4-(1-methyl-1 H -pyrazol-3-yl)-6 ,7-Dihydro-5 H -pyrrole[3,4- d ]pyrimidin-5-one (Compound 67)

Synthesis of compound 67-f: Add sodium bicarbonate (15.2 g, 181.6 mmol) to 1-methylpyrazole-3-carbaldehyde (5.0 g, 45.4 mmol), S-methylisothiourea sulfate (7.58 g, 27.2 mmol) and ethyl acetate (6.49 g, 49.4 mmol) in N,N-dimethylformamide (100 mL). After the reaction mixture was stirred at 70 ^o C for 3 hours and cooled to room temperature. Concentrate under reduced pressure, add water (100 mL) to the residue, extract with ethyl acetate (500 mL×2), wash the combined organic phase with water (200 mL) and saturated brine (100 mL), and dry with anhydrous sodium sulfate. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1-1:1) to obtain an off-white solid 67-f (3.9 g, yield: 30%). LC-MS (ESI): m/z = 295 [M+H] ⁺ .

Synthesis of compound 67-e: Under ice water bath, add 2,3-dichloro-5,6-dicyanoquinone (4.51 g, 19.8 mmol) to compound 67-f (3.9 g, 13.2 mmol) in batches In dichloromethane (200 mL) solution, 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 white solid 67-e (3.0 g, yield: 77%). 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), selenium dioxide (1.71 g, 15.41 mmol) and glacial acetic acid ( 1.0 mL). 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). Filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1-1:1) to obtain white solid 67-d (1.0 g, yield: 32%). LC-MS (ESI): m/z = 307 [M+H] ⁺ .

Synthesis of compound 67-c: Add methylamine hydrochloride (882 mg, 13.0 mmol) and sodium acetate (1.76 g, 13.0 mmol) to methanol (50 mL). The mixture was stirred at room temperature for 1 hour and ice-water bath was cooled to 0 ^o C, then compound 67-d (1.0 g, 3.26 mmol) and methylene chloride (50 mL). After stirring for 30 minutes, sodium cyanoborohydride (368 mg, 4.89 mmol) was added, and the reaction mixture was raised to room temperature and stirring was continued for 12 hours. Concentrate under reduced pressure, dilute the residue with water (100 mL), extract with dichloromethane (50 mL×3), and wash the combined organic phase 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 a yellow solid 67-c (750 mg, yield: 84%). 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 compound 67-c (275 mg, 1.0 mmol) and 2-fluorobenzaldehyde (500 mg, 2.6 mmol) in dioxane (20 mL) solution. After the mixture was refluxed for 12 hours under the protection of nitrogen, it was 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 a yellow solid 67-b (230 mg, yield: 60%). 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 the dichloromethane (10 mL) solution of compound 67-b (230 mg, 0.6 mmol), and stirred at room temperature for 1 hour. The reaction was quenched by adding saturated sodium thiosulfate solution (10 mL). Add water (20 mL), extract with dichloromethane (20 mL×3), wash the combined organic phase with water (20 mL) and saturated brine (20 mL), and concentrate under reduced pressure to obtain a yellow solid. This solid was added to N,N-dimethylformamide (10 mL), ultrasonicated for 1 minute and filtered, the filter cake was washed with methanol (10 mL), and vacuum dried to obtain the product 67-a (150 mg, Yield: 60%), this product does not require further purification.

LC-MS (ESI): m/z = 414 [M+H] ⁺ .

Synthesis of compound 67: A methanol solution of 7N ammonia (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 at room temperature for 1 hour. Concentrate under reduced pressure. Add methanol (6 mL) to the residue to form a solid. Ultrasound for 1 minute and filter. The filter cake was washed with methanol (3 mL). After vacuum drying, a yellow solid 67 (22 mg, yield: 18%) was obtained. . LC-MS (ESI): m/z = 351 [M+H] ⁺ .

¹ H-NMR (400 MHz, 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)phenylmethylenyl)-4-(5-methylfuran-2-yl)furan [3 ,4- d ] Pyrimidine-5(7 H )-one (Compound 68)

Synthesis of compound 68-d: Dissolve compound 62-d (1.53 g, 5.0 mmol) in a mixed solution of methanol (5 mL) and tetrahydrofuran (30 mL), cool to 0 ^o C in an ice-water bath, and add borohydride in batches Sodium (209 mg, 5.5 mmol). The reaction solution was slowly raised to room temperature, and stirring was continued for 1 hour. The reaction solution was concentrated under reduced pressure, 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 reduced pressure The filtrate was concentrated, and 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 dioxane (20 mL). After the mixture was stirred under nitrogen at 120 ^o C 3 hours, 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 a pink solid 68-c (550 mg, yield: 60%). 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 dry toluene (30 mL), and the reaction solution was stirred at 120 ^o C After 6 hours, cool to room temperature. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 12:1-5:1) to obtain a pale yellow solid 68-b (450 mg, yield: 86%). 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 compound 68-b (450 mg, 1.0 mmol) in dichloromethane (30 mL) at room temperature Stir for 3 hours. The reaction was quenched by adding saturated sodium thiosulfate solution (30 mL). Add water (50 mL), extract with dichloromethane (50 mL×3), wash the combined organic phase with water (30 mL) and saturated brine (30 mL), concentrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum Ether: ethyl acetate = 5:1-1:1) to obtain a yellow solid 68-a (170 mg, yield: 36%). LC-MS (ESI): m/z = 446 [M+H] ⁺ .

Synthesis of compound 68: A methanol solution of 7N ammonia (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 and reacted at room temperature for 2 hours. Concentrate under reduced pressure. Add methanol (6 mL) to the residue to form a solid. After ultrasonic ultrasound for 1 minute, it is filtered. The filter cake is washed with methanol (3 mL). After vacuum drying, a yellow solid 68 (25 mg, yield: 25%) is obtained. . LC-MS (ESI): m/z = 404 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO- d ₆ ) δ : 8.32-8.29 (m, 2H), 8.20 (d, J = 2.4 Hz, 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-fluorophenylmethylenyl)-6-methyl-6,7-dihydro- 5 H -pyrrole[3,4- d ]pyrimidin-5-one (compound 69)

Synthesis of compound 69-f: Add sodium bicarbonate (8.5 g, 80 mmol) to 2-chloro-5-furaldehyde (5.2 g, 40 mmol), S-methylisothiourea sulfate (8.3 g, 60 mmol) ) And ethyl acetate (5.2 g, 40 mmol) in N,N-dimethylformaldehyde (40 mL). The reaction mixture was stirred at 80 ^o C for 6 hours, cooled to room temperature. Concentrate under reduced pressure, add water (100 mL) to the residue, extract with ethyl acetate (40 mL×3), wash the combined organic phase with water (100 mL) and saturated brine (100 mL), and dry with anhydrous sodium sulfate. 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: Under ice-water bath, 2,3-dichloro-5,6-dicyano-p-benzoquinone (3.0 g, 13.2 mmol) was added to compound 69-f (3.14 g, 10 mmol) in batches In dichloromethane (100 mL) solution, the reaction solution was raised to room temperature and stirring was continued 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 a yellow solid 69-e (2.44 g, yield: 78%). 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), selenium dioxide (1.0 g, 9.1 mmol) and glacial acetic acid ( 2.0 mL). 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). After 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 a yellow solid 69-d (1.63 g, yield: 65%). LC-MS (ESI): m/z = 327 [M+H] ⁺ .

Synthesis of compound 69-c: Add methylamine hydrochloride (938 mg, 13.8 mmol) and sodium acetate (1.13 g, 13.8 mmol) to methanol (40 mL). The mixture was stirred at room temperature for 1 hour and ice-water bath was cooled to 0 ^o C, then compound 69-d (1.5 g, 4.6 mmol) and methylene chloride (40 mL). After stirring for 30 minutes, sodium cyanoborohydride (434 mg, 6.9 mmol) was added, and the reaction mixture was raised to room temperature and stirring continued for 16 hours. Concentrate under reduced pressure, dilute the residue with water (100 mL), extract with dichloromethane (60 mL×2), and wash the combined organic phase 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 a yellow solid 69-c (840 mg, yield: 62%). 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 compound 69-c (295 mg, 1.0 mmol) and 2-fluorobenzaldehyde (248 mg, 2.0 mmol) in dioxane (20 mL) solution. After the mixture was refluxed for 12 hours under the protection of nitrogen, it was cooled to room temperature. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1-10:1) to obtain a yellow solid 69-b (250 mg, yield: 62%). 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 compound 69-b (250 mg, 0.62 mmol) in dichloromethane (30 mL) at room temperature Stir for 1 hour. The reaction was quenched by adding saturated sodium thiosulfate solution (10 mL). Add water (20 mL), extract with dichloromethane (20 mL×3), wash the combined organic phase with water (20 mL) and saturated brine (20 mL), and concentrate under reduced pressure to obtain a yellow solid. This solid was added to methanol (10 mL), sonicated for 1 minute and then filtered. The filter cake was washed with methanol (3 mL) and dried under vacuum to obtain the product 69-a (250 mg, yield: 92%). No further purification is required. LC-MS (ESI): m/z = 434 [M+H] ⁺ .

Synthesis of compound 69: Add 7N ammonia in methanol (0.5 mL, 3.5 mmol) to compound 69-a (86.5 mg, 0.2 mmol) in tetrahydrofuran (10 mL). The mixture was stirred at room temperature for 1 hour. Concentrate under reduced pressure. Add methanol (6 mL) to the residue to form a solid. Ultrasound for 1 minute and filter. The filter cake is washed with methanol (3 mL). After vacuum drying, a yellow solid 69 (22 mg, yield: 29%) is obtained. .

LC-MS (ESI): m/z = 371 [M+H] ⁺ .

¹ H-NMR (400 MHz 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)phenylmethylenyl)-6-methyl-6, 7-Dihydro-5 H -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-(trifluoro (Methyl)benzaldehyde (235 mg, 1.35 mmol) in dioxane (20 mL). After the mixture was refluxed for 12 hours under the protection of nitrogen, it was cooled to room temperature. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1-10:1) to obtain a yellow solid 70-b (250 mg, yield: 67%). 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 compound 70-b (250 mg, 0.55 mmol) in dichloromethane (30 mL) at room temperature Stir for 1 hour. The reaction was quenched by adding saturated sodium thiosulfate solution (10 mL). Add water (20 mL), extract with dichloromethane (20 mL×3), wash the combined organic phase with water (20 mL) and saturated brine (20 mL), and concentrate under reduced pressure to obtain a yellow solid. This solid was added to methanol (10 mL), sonicated for 1 minute and then filtered. The filter cake was washed with methanol (3 mL) and dried under vacuum to obtain product 70-a (150 mg, yield: 56%). No further purification is required. LC-MS (ESI): m/z = 484 [M+H] ⁺ .

Synthesis of compound 70: Add 7N ammonia in methanol (1.0 mL, 7 mmol) to compound 70-a (150 mg, 0.32 mmol) in tetrahydrofuran (10 mL). The mixture was stirred at room temperature for 1 hour. Concentrate under reduced pressure. Add methanol (6 mL) to the residue to produce a solid. After ultrasonic ultrasound for 1 minute, it is filtered. The filter cake is washed with methanol (3 mL). After vacuum drying, a yellow solid 70 (100 mg, yield: 76%) is obtained. .

LC-MS (ESI): m/z = 421 [M+H] ⁺ .

¹ H-NMR (400 MHz 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-1 H -pyrazol-3-yl)-7-(2-(trifluoromethoxy)benzene Ylmethylenyl)-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 cyclopropylamine (950 mg, 16.6 mmol) and compound 67-d (1.7 g, 5.55 mmol) in methanol (10 mL) and dichloride Methane (30 mL) mixed solvent. After the mixture was stirred at room temperature for 2 hours, sodium cyanoborohydride (520 mg, 8.25 mmol) was added in portions, and the reaction mixture was stirred at room temperature for 12 hours. The reaction solution was diluted with water (100 mL), extracted with dichloromethane (50 mL×3), and the combined organic phase was 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 a white solid 71-c (1.5 g, yield: 89%). 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-(trifluoro Methoxy) benzaldehyde (380 mg, 2.0 mmol) in dioxane (20 mL). After the mixture was refluxed for 12 hours under the protection of nitrogen, it was cooled to room temperature. Concentrate under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15:1-10:1) to obtain yellow solid 71-b (300 mg, yield: 64%). 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 compound 71-b (300 mg, 0.63 mmol) in dichloromethane (10 mL) at room temperature Stir for 1 hour. The reaction was quenched by adding saturated sodium thiosulfate solution (10 mL). Add water (20 mL), extract with dichloromethane (20 mL×3), wash the combined organic phase with water (20 mL) and saturated brine (20 mL), concentrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum Ether: ethyl acetate = 10:1-2:1) to obtain a yellow solid 71-a (300 mg, yield: 93%). LC-MS (ESI): m/z = 506 [M+H] ⁺ .

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

LC-MS (ESI): m/z = 443 [M+H] ⁺ .

¹ H-NMR: (400 MHz, 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)phenyl (Menyl)-6,7-dihydro- 5H -pyrrole[3,4- d ]pyrimidin-5-one (Compound 72)

Synthesis of compound 72-c: Add ethylamine hydrochloride (972 mg, 12.0 mmol) and sodium acetate (984 mg, 12.0 mmol) to methanol (50 mL). After the mixture was stirred for 0.5 hours at room temperature, ice-water bath to 0 ^o C, then compound 67-d (1.1 g, 3.0 mmol) and methylene chloride (30 mL). After stirring for 30 minutes, sodium cyanoborohydride (283.5 mg, 4.5 mmol) was added, and the reaction mixture was raised to room temperature and stirring was continued for 12 hours. Concentrate under reduced pressure, dilute the residue with water (100 mL), extract with dichloromethane (50 mL×3), and wash the combined organic phase 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 to 1:1) to obtain a yellow solid 72-c (650 mg, yield: 75%). 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-(trifluoro Methoxy) benzaldehyde (190 mg, 1.0 mmol) in absolute ethanol (15 mL). After the mixture was refluxed for 12 hours under the protection of nitrogen, it was 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 a yellow solid 72-b (125 mg, yield: 54%). 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 compound 72-b (125 mg, 0.27 mmol) in dichloromethane (15 mL) at room temperature Stir for 1 hour. The reaction was quenched by adding saturated sodium thiosulfate solution (10 mL). Add water (20 mL), extract with dichloromethane (20 mL×3), wash the combined organic phase with water (20 mL) and saturated brine (20 mL), concentrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum Ether: ethyl acetate = 3:1-1:1) to obtain a yellow solid 72-a (90 mg, yield: 68%). LC-MS (ESI): m/z = 494 [M+H] ⁺ .

Synthesis of compound 72: Add 7N ammonia in methanol (0.5 mL, 3.5 mmol) to compound 72-a (90 mg, 0.18 mmol) in tetrahydrofuran (15 mL). The mixture was stirred at room temperature for 1 hour. Concentrate under reduced pressure. Add methanol (6 mL) to the residue to form a solid. After ultrasonic ultrasound for 1 minute, filter. The filter cake was washed with methanol (3 mL). After vacuum drying, a yellow solid 72 (48 mg, yield: 62%) was obtained. .

LC-MS (ESI): m/z = 431 [M+H] ⁺ .

¹ H-NMR: (400 MHz, DMSO- d ₆ ) δ : 8.38 (s, 1H), 8.33 (d, J = 6.4 Hz, 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, 2H), 1.19 (t, J = 6.4 Hz, 3H) ppm .

Example 73: ( E )-2-amino-6-cyclopropyl-4-(1-methyl- 1H -pyrazol-3-yl)-7-(2-fluorophenylmethylenyl)- 6,7-Dihydro-5 H -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 absolute ethanol (10 mL). After the mixture was refluxed for 12 hours under the protection of nitrogen, it was 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 a yellow solid 73-b (145 mg, yield: 71%). 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 compound 73-b (145 mg, 0.35 mmol) in dichloromethane (15 mL) at room temperature Stir for 1 hour. The reaction was quenched by adding saturated sodium thiosulfate solution (10 mL). Add water (20 mL), extract with dichloromethane (20 mL×3), wash the combined organic phase with water (20 mL) and saturated brine (20 mL), concentrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum Ether: ethyl acetate = 5:1-1:1) to obtain a yellow solid 73-a (150 mg, yield: 96%). LC-MS (ESI): m/z = 440 [M+H] ⁺ .

Synthesis of compound 73: Add 7N ammonia in methanol (0.32 mL, 2.24 mmol) to compound 73-a (100 mg, 0.22 mmol) in tetrahydrofuran (15 mL). The mixture was stirred at room temperature for 1 hour. Concentrate under reduced pressure. Add methanol (6 mL) to the residue to form a solid. After ultrasonic ultrasound for 1 minute, it is filtered. The filter cake is washed with methanol (3 mL). After vacuum drying, a yellow solid 73 (50 mg, yield: 60%) is obtained. .

LC-MS (ESI): m/z = 377 [M+H] ⁺ .

¹ H-NMR: (400 MHz, 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)phenyl (Menyl)-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-(trifluoro (Methyl)benzaldehyde (174 mg, 1.0 mmol) in absolute ethanol (10 mL). After the mixture was refluxed for 4 hours under nitrogen protection, it was cooled to room temperature, a solid was formed, filtered, and the filter cake was vacuum-dried to obtain a yellow solid 74-b (150 mg, yield: 66%). This compound does 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 compound 74-b (150 mg, 0.33 mmol) in dichloromethane (15 mL) at room temperature Stir for 1 hour. The reaction was quenched by adding saturated sodium thiosulfate solution (10 mL). Add water (20 mL), extract with dichloromethane (20 mL×3), wash the combined organic phase with water (20 mL) and saturated brine (20 mL), concentrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum Ether: ethyl acetate = 5:1-1:1) to obtain a yellow solid 74-a (140 mg, yield: 87%). LC-MS (ESI): m/z = 490 [M+H] ⁺ .

Synthesis of compound 74: Add 7N ammonia in methanol (0.4 mL, 2.8 mmol) to compound 74-a (140 mg, 0.28 mmol) in tetrahydrofuran (15 mL). The mixture was stirred at room temperature for 1 hour. Concentrate under reduced pressure. Add methanol (6 mL) to the residue to produce a solid. After ultrasonic ultrasound for 1 minute, it is filtered. The filter cake is washed with methanol (3 mL) and dried under vacuum to obtain a yellow solid 74 (45 mg, yield: 38%) .

LC-MS (ESI): m/z = 427 [M+H] ⁺ .

¹ H-NMR: (400 MHz, DMSO- d ₆ ) δ : 8.95 (s, 1H), 8.33 (s, 1H), 8.05 (d, J = 6.0 Hz, 1H), 7.76 (d, J = 6.4 Hz , 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-fluorophenylmethylenyl)-6 ,7-Dihydro-5 H -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 compound 72-c (289 mg, 1.0 mmol) and 2-fluorobenzaldehyde (248 mg, 2.0 mmol) in absolute ethanol (20 mL). The mixture was refluxed for 5 hours under nitrogen protection, and then cooled to room temperature. A solid was formed. The filter cake was washed with ethanol (5 mL). After vacuum drying, a yellow solid 75-b (268 mg, yield: 67%) was obtained. ), this compound does not require 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 compound 75-b (150 mg, 0.38 mmol) in dichloromethane (20 mL) at room temperature Stir for 1 hour. The reaction was quenched by adding saturated sodium thiosulfate solution (10 mL). Add water (20 mL), extract with dichloromethane (20 mL×3), wash the combined organic phase with water (20 mL) and saturated brine (20 mL), concentrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum Ether: ethyl acetate = 5:1-2:1) to obtain a white solid 75-a (140 mg, yield: 86%). LC-MS (ESI): m/z = 428 [M+H] ⁺ .

Synthesis of compound 75: Add 7N ammonia in methanol (0.5 mL, 3.5 mmol) to compound 75-a (140 mg, 0.32 mmol) in tetrahydrofuran (15 mL). The mixture was stirred at room temperature for 1 hour. Concentrate under reduced pressure. Add methanol (10 mL) to the residue to form a solid. After ultrasonic ultrasound for 1 minute, it is filtered. The filter cake is washed with methanol (3 mL). After vacuum drying, a yellow solid 75 (85 mg, yield: 71%) is obtained. .

LC-MS (ESI): m/z = 365 [M+H] ⁺ .

¹ H-NMR (400 MHz, 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)phenylmethyl (Alkenyl)-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-(trifluoro (Methyl)benzaldehyde (174 mg, 1.0 mmol) in absolute ethanol (20 mL). The mixture was refluxed under nitrogen protection for 5 hours, and then cooled to room temperature. A solid was formed. The filter cake was washed with ethanol (5 mL). After vacuum drying, a yellow solid 76-b (90 mg, yield: 40%) ), this compound does not require 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 compound 76-b (90 mg, 0.2 mmol) in dichloromethane (15 mL) at room temperature Stir for 1 hour. The reaction was quenched by adding saturated sodium thiosulfate solution (10 mL). Add water (20 mL), extract with dichloromethane (20 mL×3), wash the combined organic phase with water (20 mL) and saturated brine (20 mL), concentrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum Ether: ethyl acetate = 5:1-2:1) to obtain white solid 76-a (90 mg, yield: 95%). LC-MS (ESI): m/z = 478 [M+H] ⁺ .

Synthesis of compound 76: Add 7N ammonia in methanol (0.3 mL, 2.1 mmol) to compound 76-a (90 mg, 0.19 mmol) in tetrahydrofuran (15 mL). The mixture was stirred at room temperature for 1 hour. Concentrate under reduced pressure. Add methanol (6 mL) to the residue to form a solid. Ultrasound for 1 minute and filter. The filter cake is washed with methanol (3 mL). After vacuum drying, a yellow solid 76 (55 mg, yield: 70%) is obtained. .

LC-MS (ESI): m/z = 415 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO- d ₆ ) δ : 8.96 (s, 1H), 8.36 (s, 1H), 7.93 (d, J = 1.6 Hz, 1H), 7.76 (d, J = 1.6 Hz, 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 = 6.4 Hz, 2H) , 1.20 (t, J = 6.4 Hz, 3H) ppm.

Example 77: ( E )-2-amino-6-cyclopropyl-4-(1-methyl-1 H -pyrazol-3-yl)-7-(2,4-difluorophenylmethylene) Yl)-6,7-dihydro-5 H -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-bis Fluorobenzaldehyde (142 mg, 1.0 mmol) in absolute ethanol (15 mL). After the mixture was refluxed for 4 hours under nitrogen protection, it was cooled to room temperature, a solid was formed, filtered, and the filter cake was vacuum-dried to obtain a yellow solid 77-b (180 mg, yield: 85%). This compound does 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 compound 77-b (180 mg, 0.42 mmol) in dichloromethane (20 mL) at room temperature Stir for 3 hours. The reaction was quenched by adding saturated sodium thiosulfate solution (10 mL). Add water (20 mL), extract with dichloromethane (20 mL×3), wash the combined organic phase with water (20 mL) and saturated brine (20 mL), concentrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum Ether: ethyl acetate = 5:1-1:1) to obtain a yellow solid 77-a (140 mg, yield: 73%). LC-MS (ESI): m/z = 458 [M+H] ⁺ .

Synthesis of Compound 77: Add 7N ammonia in methanol (0.4 mL, 2.8 mmol) to compound 77-a (140 mg, 0.3 mmol) in tetrahydrofuran (15 mL). The mixture was stirred at room temperature for 1 hour. Concentrate under reduced pressure. Add methanol (6 mL) to the residue to form a solid. After ultrasonic ultrasound for 1 minute, it is filtered. The filter cake is washed with methanol (3 mL). After vacuum drying, a yellow solid 77 (45 mg, yield: 38%) is obtained. .

LC-MS (ESI): m/z = 395 [M+H] ⁺ .

¹ H-NMR (400 MHz, 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) Yl)phenylmethylenyl)-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 absolute ethanol (30 mL). After the mixture was refluxed for 4 hours under nitrogen protection, it was cooled to room temperature, a solid was formed, filtered, and the filter cake was vacuum-dried to obtain a yellow solid 78-b (175 mg, yield: 73%). This compound does 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 compound 78-b (200 mg, 0.42 mmol) in dichloromethane (30 mL) at room temperature Stir for 3 hours. The reaction was quenched by adding saturated sodium thiosulfate solution (10 mL). Add water (20 mL), extract with dichloromethane (20 mL×3), wash the combined organic phase with water (20 mL) and saturated brine (20 mL), concentrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum Ether: ethyl acetate = 5:1-1:1) to obtain a yellow solid 78-a (150 mg, yield: 70%). LC-MS (ESI): m/z = 508 [M+H] ⁺ .

Synthesis of compound 78: Add 7N ammonia in methanol (0.4 mL, 2.8 mmol) to compound 78-a (150 mg, 0.3 mmol) in tetrahydrofuran (15 mL). The mixture was stirred at room temperature for 1 hour. Concentrate under reduced pressure. Add methanol (6 mL) to the residue to form a solid. After ultrasonic ultrasound for 1 minute, it is filtered. The filter cake is washed with methanol (3 mL). After vacuum drying, a yellow solid 78 (95 mg, yield: 72%) is obtained. .

LC-MS (ESI): m/z = 445 [M+H] ⁺ .

¹ H-NMR (400 MHz, 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-1 H -pyrazol-3-yl)-7-phenylmethylenyl-6,7-dihydro -5 H -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 compound 67-c (210 mg, 0.76 mmol) and benzaldehyde (161 mg , 1.52 mmol) in 1,4-dioxane (20 mL) solution. The mixture was refluxed under nitrogen protection for 12 hours, cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15:1-5:1) to obtain a yellow solid 79-b ( 80 mg, yield: 29%), this compound does not require 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 compound 79-b (80 mg, 0.22 mmol) in dichloromethane (20 mL) at room temperature Stir for 3 hours. The reaction was quenched by adding saturated sodium thiosulfate solution (10 mL). Add water (20 mL), extract with dichloromethane (20 mL×3), wash the combined organic phase with water (20 mL) and saturated brine (20 mL), concentrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum Ether: ethyl acetate = 10:1-2:1) to obtain a yellow solid 79-a (70 mg, yield: 80%). LC-MS (ESI): m/z = 396 [M+H] ⁺ .

Synthesis of compound 79: Add 7N ammonia in methanol (0.2 mL, 1.4 mmol) to compound 79-a (70 mg, 0.17 mmol) in tetrahydrofuran (20 mL). The mixture was stirred at room temperature for 1 hour. Concentrate under reduced pressure. Add methanol (6 mL) to the residue to form a solid. After ultrasonic ultrasound for 1 minute, it is filtered. The filter cake is washed with methanol (3 mL). After vacuum drying, a yellow solid 79 (16 mg, yield: 27%) is obtained. .

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-phenylmethylenyl-6,7-di Hydrogen-5 H -pyrrole [3,4- d ] pyrimidin-5-one (compound 80); ( Z )-2-amino-6-cyclopropyl-4-(1-methyl-1 H -pyridine (Azol-3-yl)-7-phenylmethylenyl-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 anhydrous ethanol (10 mL) solution. After the mixture was refluxed for 4 hours under nitrogen protection, it was cooled to room temperature, a solid was formed, filtered, and the filter cake was vacuum-dried to obtain a yellow solid 80-b (110 mg, yield: 56%). This compound does 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 compound 80-b (110 mg, 0.28 mmol) in dichloromethane (20 mL) at room temperature Stir for 3 hours. The reaction was quenched by adding saturated sodium thiosulfate solution (10 mL). Add water (20 mL), extract with dichloromethane (20 mL×3), wash the combined organic phase with water (20 mL) and saturated brine (20 mL), concentrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum Ether: ethyl acetate = 5:1-1:1) to obtain a yellow solid 80-a (110 mg, yield: 94%). LC-MS (ESI): m/z = 422 [M+H] ⁺ .

Synthesis of compounds 80 and 81: A methanol solution of 7N ammonia (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% (initial mobile phase was 35% water-65% acetonitrile) , At the end of the mobile phase is 45% water-55% acetonitrile, where% refers to the volume percentage), yellow solid 80 (26 mg, yield: 28%) and yellow solid 81 (25 mg, yield: 27%) ). LC-MS (ESI): m/z = 359 [M+H] ⁺ .

Compound 80: ¹ H-NMR (400 MHz, 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: (400 MHz DMSO- d ₆ ) δ : 8.98(s, 1H), 8.37(s, 1H), 7.52 (d, J = 6.0 Hz, 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-fluorophenylmethylenyl)-6,7-dihydro -5 H -pyrrole[3,4- d ]pyrimidin-5-one (Compound 82)

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

Synthesis of compound 82-e: Under ice-water bath, 2,3-dichloro-5,6-dicyanoquinone (3.4 g, 14.86 mmol) was added to compound 82-f (3.5 g, 11.25 mmol) in batches In dichloromethane (200 mL) solution, 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 = 5:1) to obtain a yellow viscous 82-e (2.6 g, yield: 74%). 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), selenium dioxide (3.7 g, 33.4 mmol) and glacial acetic acid ( 3 mL). 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). After 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 a pale yellow solid 82-d (1.2 g, yield: 44%). LC-MS (ESI): m/z = 399 [M+H] ⁺ .

Synthesis of compound 82-c: Add methylamine hydrochloride (1.1 g, 14.86 mmol) and sodium acetate (1.22 g, 14.86 mmol) to methanol (20 mL). The mixture was stirred at room temperature for 30 minutes and ice-water bath to 0 ^o C, then compound 82-d (1.2 g, 3.72 mmol) and methylene chloride (20 mL). After stirring for 30 minutes, sodium cyanoborohydride (360 mg, 5.58 mmol) was added, and the reaction mixture was raised to room temperature and stirring continued for 12 hours. Concentrate under reduced pressure, dilute the residue with water (50 mL), extract with dichloromethane (50 mL×2), and wash the combined organic phase 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 a yellow solid 82-c (556 mg, yield: 51.4%). 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 compound 82-c (200 mg, 0.68 mmol) and 2-fluorobenzaldehyde (127 mg, 1.03 mmol) in absolute ethanol (5 mL). After the mixture was refluxed for 12 hours under nitrogen protection, it was cooled to room temperature and stirred for 3 hours. A solid was formed. The filter cake was vacuum dried to obtain a yellow solid 82-b (173 mg, yield: 64%). 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 compound 82-b (210 mg, 0.53 mmol) in dichloromethane (50 mL) at room temperature Stir for 1 hour. The reaction was quenched by adding saturated sodium thiosulfate solution (20 mL). Add water (50 mL), extract with dichloromethane (50 mL×3), wash the combined organic phase with water (50 mL) and saturated brine (50 mL), concentrate under reduced pressure, and use ethyl acetate (10 mL) for the remainder After washing, the solid was dried under vacuum to obtain the yellow compound 82-a (210 mg, yield: 93%), which did not require further purification. LC-MS (ESI): m/z = 431 [M+H] ⁺ .

Synthesis of compound 82: Add 7N ammonia in methanol (3 mL, 21 mmol) to compound 82-a (210 mg, 0.49 mmol) in tetrahydrofuran (15 mL). The mixture was stirred at room temperature for 1 hour. Concentrate under reduced pressure, add methanol (6 mL) to the residue to form a solid, filter, wash the filter cake with methanol (3 mL), and dry under vacuum to obtain compound 82 (28 mg, yield: 16%).

LC-MS (ESI): m/z = 367 [M+H] ⁺ .

¹ H-NMR (500 MHz, 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-fluorophenylmethylenyl)-6,7-dihydro -5 H -pyrrole[3,4- d ]pyrimidin-5-one (Compound 83)

Synthesis of compound 83-c: Add methylamine hydrochloride (1.76 g, 26.0 mmol) and sodium acetate (3.56 g, 26.0 mmol) to methanol (50 mL). The mixture was stirred at room temperature for 30 minutes and ice-water bath to 0 ^o C, then compound 62-d (2.0 g, 6.5 mmol) and methylene chloride (10 mL). After stirring for 1 hour, sodium cyanoborohydride (615 mg, 9.7 mmol) was added, and the reaction mixture was raised to room temperature and stirring continued for 12 hours. Concentrate under reduced pressure, dilute the residue with water (100 mL), extract with dichloromethane (50 mL×2), and wash the combined organic phase 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 a pink solid 83-c (1.5 g, yield: 84%). 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 compound 83-c (275 mg, 1.0 mmol) and 3-fluorobenzaldehyde (248 mg, 2.0 mmol) in anhydrous ethanol (30 mL) solution. The mixture was stirred for 4 hours at 80 ^o C under the protection of nitrogen, and then cooled to room temperature. A solid was formed. The filter cake was washed with water (10 mL) and dried under vacuum to obtain a yellow solid 83-b (300 mg, yield : 78%). 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 compound 83-b (300 mg, 0.78 mmol) in dichloromethane (30 mL) at room temperature Stir for 3 hours. The reaction was quenched by adding saturated sodium thiosulfate solution (10 mL). Add water (20 mL), extract with dichloromethane (20 mL×3), wash the combined organic phase with water (20 mL) and saturated brine (20 mL), and concentrate under reduced pressure to obtain a yellow solid 83-a (290 mg, Yield: 80%), this product does not require further purification. LC-MS (ESI): m/z = 414 [M+H] ⁺ .

Synthesis of compound 83: Add 7N ammonia in methanol (0.5 mL, 3.5 mmol) to compound 83-a (150 mg, 0.36 mmol) in tetrahydrofuran (25 mL). The mixture was stirred at room temperature for 3 hours. Concentrate under reduced pressure, add methanol (10 mL) to the residue to form a solid, filter, wash the filter cake with methanol (3 mL), and dry under vacuum to obtain compound 83 (70 mg, yield: 55%).

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-phenylmethylenyl-6,7-dihydro-5 H -pyrrole [3,4- d ] Pyrimidine-5-one (Compound 84)

Synthesis of compound 84-c: Add n-propylamine (1.76 g, 26.0 mmol), acetic acid (1.66 g, 26.0 mmol) to methanol (10 mL) and dichloromethane (50 mL). The mixture was stirred at room temperature for 30 minutes and ice-water bath to 0 ^o C, then compound 62-d (2.0 g, 6.5 mmol) and methylene chloride (10 mL). After stirring for 1 hour, sodium cyanoborohydride (614 mg, 9.7 mmol) was added, and the reaction mixture was raised to room temperature and stirring continued for 12 hours. Concentrate under reduced pressure, dilute the residue with water (50 mL), extract with dichloromethane (50 mL×3), and wash the combined organic phase 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 a pink solid 84-c (1.5 g, yield: 75%). 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 anhydrous ethanol (30 mL) solution. The mixture was stirred at 80 ^o C for 4 hours under the protection of nitrogen, and then cooled to room temperature. A solid was formed. The filter cake was washed with water (10 mL) and dried under vacuum to obtain a yellow solid 84-b (350 mg, yield : 89%). 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 compound 84-b (350 mg, 0.89 mmol) in dichloromethane (30 mL) at room temperature Stir for 3 hours. The reaction was quenched by adding saturated sodium thiosulfate solution (20 mL). Add water (50 mL), extract with dichloromethane (50 mL×3), wash the combined organic phase with water (20 mL) and saturated brine (20 mL), concentrate the organic phase under reduced pressure, and purify the residue by silica gel column chromatography (Petroleum ether: ethyl acetate = 10:1-3:1) to obtain a yellow solid 84-a (300 mg, yield: 79%). LC-MS (ESI): m/z = 424 [M+H] ⁺ .

Synthesis of compound 84: A methanol solution of 7N ammonia (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. Concentrate under reduced pressure, add methanol (10 mL) to the residue to form a solid, filter, wash the filter cake with methanol (3 mL), and dry under vacuum to obtain compound 84 (70 mg, yield: 65%).

LC-MS (ESI): m/z = 361 [M+H] ⁺ .

¹ H-NMR (400 MHz, 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-phenylmethylenyl-6,7-dihydro-5 H- 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 benzene Formaldehyde (212 mg, 2.0 mmol) in absolute ethanol (30 mL). The mixture was stirred for 4 hours at 80 ^o C under the protection of nitrogen, and then cooled to room temperature. A solid was formed. The filter cake was washed with ethanol (5 mL) and dried under vacuum to obtain a yellow solid 85-b (130 mg, yield). Rate: 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% (initial mobile phase is 85% water-15% Acetonitrile, the mobile phase at the end is 95% water-5% acetonitrile, where% refers to volume percentage), to obtain a yellow solid 86-b (180 mg, yield: 46%). 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 compound 85-b (120 mg, 0.3 mmol) in dichloromethane (20 mL) at room temperature Stir for 3 hours. The reaction was quenched by adding saturated sodium thiosulfate solution (20 mL). Add water (50 mL), extract with dichloromethane (50 mL×3), wash the combined organic phase with water (20 mL) and saturated brine (20 mL), concentrate the organic phase under reduced pressure, and purify the residue by silica gel column chromatography (Petroleum ether: ethyl acetate = 10:1-3:1) to obtain a yellow solid 85-a (85 mg, yield: 65%). LC-MS (ESI): m/z = 422 [M+H] ⁺ .

Synthesis of compound 85: A methanol solution of 7N ammonia (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. Concentrate under reduced pressure, add methanol (5 mL) to the residue to form a solid, filter, wash the filter cake with methanol (2 mL), and dry under vacuum to obtain compound 85 (30 mg, yield: 42%).

LC-MS (ESI): m/z = 359 [M+H] ⁺ .

¹ H-NMR (400 MHz, 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-phenylmethylenyl-6,7-dihydro-5 H- 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 compound 86-b (180 mg, 0.46 mmol) in dichloromethane (20 mL) at room temperature Stir for 3 hours. The reaction was quenched by adding saturated sodium thiosulfate solution (20 mL). Add water (50 mL), extract with dichloromethane (50 mL×3), wash the combined organic phase with water (20 mL) and saturated brine (20 mL), concentrate the organic phase under reduced pressure, and purify the residue by silica gel column chromatography (Petroleum ether: ethyl acetate = 10:1-3:1) to obtain a yellow solid 86-a (50 mg, yield: 25%). LC-MS (ESI): m/z = 422 [M+H] ⁺ .

Synthesis of compound 86: A methanol solution of 7N ammonia (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. Concentrate under reduced pressure, add methanol (5 mL) to the residue to form a solid, filter, wash the filter cake with methanol (2 mL), and dry under vacuum to obtain compound 86 (26 mg, yield: 62%).

LC-MS (ESI): m/z = 359 [M+H] ⁺ .

¹ H-NMR (400 MHz 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-phenylmethylenyl-6-isopropyl-4-(5-methylfuran-2-yl)-6,7-dihydro-5 H- Pyrrole[3,4- d ]pyrimidin-5-one (Compound 87)

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

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-diazepine was added to the solution Dicycloundec-7-ene (702.2 mg, 4.62 mmol). The reaction mixture was stirred for 16 hours at 85 ^o C under nitrogen, was allowed to stand at room temperature. The suspension mixture was filtered to obtain a yellow solid 87-b (510 mg, yield: 56%).

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, saturated sodium sulfite solution was added to quench the reaction, extracted with DCM (100 ml), the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1-1:1) to obtain a yellow solid 87-a (300 mg, yield: 83%).

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), ammonia methanol solution (0.40 ml) was added to the reaction solution at zero degrees, and stirring was continued for 4 hours at room temperature. It was concentrated under reduced pressure, methanol (4 ml) was added to the residue, and treated with ultrasound for one minute. The insoluble matter was filtered and dried to obtain a yellow solid 87 (22 mg, yield: 44%).

LC-MS (ESI): m/z = 361.3[M+H] ⁺ .

¹ H NMR: (400 MHz, 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 = 4.8 Hz, 3H), 1.50 (d, J = 1.2 Hz, 3H) ppm.

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

Synthesis of compound 88-c: Dissolve compound 67-d (1.53 g, 5.0 mmol) and isopropylamine (590 mg, 10.0 mmol) in anhydrous methanol/dichloromethane (10 mL/50 mL), and slowly add acetic acid (600 mg, 10.0 mmol). The reaction mixture was stirred for 2 hours at room temperature under nitrogen protection. Sodium cyanoborohydride (472.5 mg, 7.5 mmol) was added to the reaction solution in batches, and stirred at room temperature overnight. , Water (50 mL) was added to quench the reaction, the target substance was extracted with DCM (150 ml), the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. 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-diazogen was added to the solution Heterobicycloundec-7-ene (456 mg, 3.0 mmol). The reaction mixture was stirred under nitrogen at 80 ^o C 16 h. 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, saturated sodium sulfite solution was added to quench the reaction, extracted with DCM (50 ml), the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1-1:1) to obtain a yellow solid 88-a (80 mg, yield: 46%).

LC-MS (ESI): m/z = 424.2[M+H] ⁺ .

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

LC-MS (ESI): m/z = 361.2[M+H] ⁺ .

¹ H NMR: (400 MHz 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 = 6.4 Hz, 3H), 1.33 (d, J = 5.2 Hz, 3H) ppm.

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

Synthesis of compound 89-b: 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- Diazabicycloundec-7-ene (456 mg, 3.0 mmol). The reaction mixture was stirred under nitrogen at 80 ^o C 24 h. After returning to room temperature, the suspension mixture was filtered to obtain a yellow solid 89-b (250 mg, yield: 61%).

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, saturated sodium sulfite solution was added to quench the reaction, extracted with DCM (50 ml), the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1-1:1) to obtain a yellow solid 89-a (250 mg, yield: 92%).

LC-MS (ESI): m/z =442.1[M+H] ⁺ .

Synthesis of compound 89: Dissolve compound 89-a (250 mg, 0.56 mmol) in THF (40 ml), add methanol solution of ammonia (0.80 ml) to the reaction solution at 0 ^o C, continue stirring at room temperature 4 hours. Concentrate under reduced pressure, add methanol (6 ml), sonicate for one minute, filter and dry the insoluble matter to obtain a yellow solid 89 (28 mg, yield: 13%).

LC-MS (ESI): m/z =379.2[M+H] ⁺ .

¹ H NMR: (400 MHz 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-fluorophenylmethylenyl)-6-methyl-4-(1-methyl-1-hydro-pyrazol-3-yl)- 6,7-Dihydro-5 H -pyrrole[3,4- d ]pyrimidin-5-one (Compound 90)

Synthesis of compound 90-b: Dissolve 67-c (275 mg, 1.0 mmol) and m-fluorobenzaldehyde (248 mg, 2.0 mmol) in absolute ethanol (20 mL), and add 1,8-dinitrogen to the solution Heterobicycloundec-7-ene (456 mg, 2.0 mmol). The reaction mixture was stirred under nitrogen at 80 ^o C 24 h. After returning to room temperature, the suspension mixture was filtered to obtain a yellow solid 90-b (260 mg, yield: 68%).

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, saturated sodium sulfite solution was added to quench the reaction, extracted with DCM (50 ml), the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1-1:1) to obtain a yellow solid 90-b (250 mg, yield: 89%).

LC-MS (ESI): m/z =414.2[M+H] ⁺ .

Synthesis of compound 90: Dissolve compound 90-a (250 mg, 0.60 mmol) in THF (30 ml), add ammonia methanol solution (0.86 ml) to the reaction solution at zero degrees, and continue stirring at room temperature for 4 hours . Concentrate under reduced pressure, add methanol (6 ml) to the residue, and ultrasonicate for one minute. The insoluble matter is filtered and dried to obtain a yellow solid 90 (22 mg, yield: 11%).

LC-MS (ESI): m/z =351.2[M+H] ⁺ .

¹ H NMR: (400 MHz 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 = 6.0 Hz, 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 added to the solution Add 1,8-diazabicycloundec-7-ene (152 mg, 1.0 mmol). The reaction mixture was stirred under nitrogen at 80 ^o C 24 h. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1-1:1) to obtain a yellow solid 91-b (150 mg, yield: 70%).

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, saturated sodium sulfite solution was added to quench the reaction, extracted with DCM (100 ml), the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. 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: Dissolve compound 91-a (120 mg, 0.26 mmol) in THF (30 ml), add methanol solution of ammonia (0.37 ml) to the reaction solution at 0 ^o C, continue stirring at room temperature 4 hours. Concentrate under reduced pressure, add methanol (6 ml) to the residue, sonicate for one minute, filter and dry the insoluble matter to obtain 91 as a yellow solid (45 mg, yield: 44%).

LC-MS (ESI): m/z =401.2[M+H] ⁺ .

¹ H NMR: (400 MHz 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 embodiment 1:

Compound 1-61 binding affinity IC ₅₀ test for human adenosine A2A receptor

1. Reagent preparation 1) Detection buffer: 50 mM Tris-HCl pH 7.4, 10 mM MgCl ₂ , 1 mM EDTA, 1 μg/mL Adenosine Deaminase, stored at 4˚C for later use. 2) Washing solution: 50 mM Tris-HCl pH 7.4, 154 mM NaCl, 4˚C stored for later use. 3) 0.5% PEI solution: 0.5 g PEI is dissolved in 100 mL ddH2O and stored at 4˚C for later use.

2. Operation steps 1) Add compound: add 250 nL of compound to Opti-plate with Echo550, and seal with parafilm. 2) Membrane dilution: Add 20 U A2A membrane, 0.75 uCi [3H]-CGS 21680 (final 25 nM) to 1 mL detection buffer, mix well, and add 50 uL to the Opti-plate. 3) Incubation: Incubate the above mixture at 25˚C for 90 minutes. 4) Prepare the pre-filter plate: add 100 uL 0.5% PEI solution to the UNIFILTER-96 GF/B filter plate and soak for 90 minutes at 4˚C. 5) Filter: a. Transfer 500 uL of cleaning solution/empty to Cell Harvester to clean UNIFILTER-96 GF/B filter plate 2 times. b. Suspend the mixed system in the Opti-plate and transfer it to the UNIFILTER-96 GF/B filter plate. c. 500 uL cleaning solution/empty cleaning UNIFILTER-96 GF/B filter plate 9 times. d. Incubate for 10 minutes in a 55˚C incubator.

3. Reading Add 40 uL ULTIMA GOLD scintillation fluid to each well, and read the CPM (count per minute) value on TopCount.

Experimental results: The results of the binding affinity of compound 1-61 to human adenosine A2A receptor according to the above experiment are shown in Table 1: Table 1: The IC ₅₀ value of the binding affinity of compound 1-61 to human adenosine A2A receptor Compound IC ₅₀ (nM) Compound IC ₅₀ (nM) 1 14.7 2 39.3 3 159 4 249 5 40 6 157.3 7 nd 8 10.7 9 nd 10 114.4 11 32.1 12 99.8 13 152 14 218.2 15 274 16 15.7 17 29.2 18 73.7 19 31.1 20 298.9 twenty one 105.8 twenty two 47.3 twenty three 3.9 twenty four 917.8 25 18.6 26 32.1 27 twenty one 28 11.2 29 252.3 30 94 31 38.4 32 19.9 33 274.8 34 39.2 35 30.1 36 28.1 37 67.4 38 6.1 39 127.7 40 106.3 41 43.5 42 87.4 43 992.4 44 64.6 45 11.6 46 8.7 47 16.4 48 13.2 49 32.1 50 7.3 51 4.7 52 3.6 53 56.2 54 34.7 55 29.3 56 3.4 57 152.1 58 twenty one 59 178.7 60 176.9 61 212.8 nd: No test.

Effect Example 2: The IC ₅₀ evaluation experiment of the binding affinity of compound 62-91 to human adenosine A2A receptor

Experimental steps:

1: Prepare the compound to be tested 1) Centrifuge the compound main board (1500 rpm, 1 minute); 2) Use the nano-upgraded sonic pipetting system to transfer 50 nanoliters from the compound main board to the reaction plate; 2: Preparation of membrane in buffer, preparation of dagger suspension 1) Add DMSO to the measurement buffer, 1% of the final concentration of DMSO; 2) The homogenized A2A receptor membrane is connected to a 1ml syringe five times through a 26 gauge needle (to avoid air bubbles); 3) Mix the buffer, A2A receptor membrane and ADA, and leave it at room temperature for 15 minutes; 4) Add SPA dagger and A2A receptor membrane to mix well; 3: Prepare radioisotope buffer 4: Mixed reagents 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 and vigorously mix and shake; 4) Before reading, let the dagger settle for 4-5 minutes; 5) Use Microbeta to read the board; 5: Processing data.

Experimental results: According to the above experiments, the results of the binding affinity of the compound 62-91 to the human adenosine A2A receptor are shown in Table 2: Table 2: The IC ₅₀ value of the binding affinity of the compound 62-91 to the human adenosine A2A receptor Compound IC ₅₀ (nM) Compound IC ₅₀ (nM) 62 15.2 63 8.9 64 13.5 65 5.1 66 22.4 67 8.6 69 13.6 70 14.4 71 34.8 72 71.3 73 13.1 74 103.3 75 99.1 76 239.3 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 .

Although the present invention has been disclosed in the above embodiments, it is not intended to limit the present invention. Those with ordinary knowledge in the technical field to which the present invention belongs can make some changes and modifications without departing from the spirit and scope of the present invention. Therefore, the protection scope of the present invention shall be subject to those defined by the attached patent application scope.

no

no

Claims (15)

A compound represented by formula I, its pharmaceutically acceptable salt, deuterium, tautomer, cis-trans isomer, enantiomer, diastereomer or prodrug;

among them,"

"Represents a single bond or a double bond;"

"Represents a single key; when"

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

When "is a double bond, W is C, and the double bond is Z configuration, E configuration or their mixture; X is O, CO or NR ³ ; Y is CO, CH ₂ or NR ⁴ ; R ¹ is substituted or unsubstituted A substituted 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 substituent The number of is one or more, and each substituent is independently halogen or C ₁ -C ₁₀ alkyl; R ² is substituted or unsubstituted C ₆ -C ₂₀ aryl or substituted or unsubstituted 5-10 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, halo-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 cycloalkane 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; and, as shown in formula I The compound does not have any of the following structures:

. The compound of formula I as described in claim 1, its pharmaceutically acceptable salt, deuterium, tautomer, cis-trans isomer, enantiomer, diastereomer or A prodrug, wherein: 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 _{In the case of 1} -C ₁₀ alkyl, the C ₁ -C ₁₀ alkyl is a C ₁ -C ₄ alkyl; and/or, when R ³ is a 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, said 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 substituted Or an 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 hetero In the case of an aryl 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; and/or, when R ¹ is a substituted or unsubstituted 5- In the case of a 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 substituted 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 Aryl, when 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, When the substituent is a C ₁ -C ₁₀ alkyl group, the C ₁ -C ₁₀ alkyl group is a C ₁ -C ₄ alkyl group; and/or, when R ² is a substituted or unsubstituted C ₆ -C ₂₀ aryl group When R ² is a substituted or unsubstituted 5-10 membered heteroaryl 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 The membered heteroaryl group is a 5-membered heteroaryl group or a 6-membered heteroaryl group, such as a 6-membered heteroaryl group; and/or, when R ² is a substituted or unsubstituted 5-10 membered heteroaryl group, said 5 The number of heteroatoms in the -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, substituted The number of groups 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 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, the substituent is C _{In the case of 1} -C ₁₀ alkyl, the C ₁ -C ₁₀ alkyl is C ₁ -C ₄ alkyl; and/or, when R ² is substituted C ₆ -C ₂₀ aryl or substituted 5-10 When the substituent is a C ₁ -C ₁₀ alkoxy group, the C ₁ -C ₁₀ alkoxy group is a C ₁ -C ₄ alkoxy group; and/or, when R ² is a substituted C _{When a 6-} C ₂₀ aryl group or a substituted 5-10 membered heteroaryl group is a C ₁ -C ₁₀ alkyl mercapto group, the C ₁ -C ₁₀ alkyl mercapto group is a C ₁ -C ₄ alkyl mercapto group; 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 "is C ₁ -C ₁₀ alkyl is C ₁ -C ₄ alkyl; and / or, when R ² is substituted C ₆ -C ₂₀ aryl group or a substituted 5-10 membered heteroaryl When the substituent is a halogen-substituted C ₁ -C ₁₀ alkyl group, the number of halogens in the "halogen-substituted C ₁ -C ₁₀ alkyl group" is 1-5, when the number of halogens is When there are more than one, 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, the substituent is a halogen substituted C ₁ -C _{In the case of 10} alkyl groups, the halogen in the "halogen substituted C ₁ -C ₁₀ alkyl group" is fluorine, chlorine, bromine or iodine; and/or, when R ² is a substituted C ₆ -C ₂₀ aryl group or Substituted 5-10 membered heteroaryl group, the substituent is

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

When R ^c is a C ₁ -C ₄ alkyl group; 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 substituted C ₁ -C ₁₀ an alkoxy group, a "halogen-substituted C ₁ -C ₁₀ alkoxy" are C ₁ -C ₁₀ alkoxy 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 halogen-substituted C ₁ -C ₁₀ alkoxy group, the "halogen-substituted C _1- The number of halogens in "C ₁₀ alkoxy" is 1-5. When the number of halogens is more than one, the halogens are the same or different; and/or, R ² is substituted C ₆ -C ₂₀ When the aryl group or substituted 5-10 membered heteroaryl group is a halogen-substituted C ₁ -C ₁₀ alkoxy group, the halogen in the "halogen-substituted C ₁ -C ₁₀ alkoxy group" 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 halogen substituted C ₁ -C ₁₀ alkyl mercapto group, the "halogen-substituted C ₁ -C ₁₀ alkylmercapto" in the C ₁ -C ₁₀ alkylmercapto group is C ₁ -C ₄ alkylmercapto; and / or, when R ² is substituted C ₆ -C ₂₀ aryl group Or substituted 5-10 membered heteroaryl, when the substituent is a halogen-substituted C ₁ -C ₁₀ alkyl mercapto group, the number of halogens in the "halogen substituted C ₁ -C ₁₀ alkyl mercapto group" is 1 5, when the number of halogens is more than one, 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, substituted When the group is a halogen-substituted C ₁ -C ₁₀ alkyl mercapto group, the halogen in the "halogen substituted C ₁ -C ₁₀ alkyl mercapto group" is fluorine, chlorine, bromine or iodine. The compound of formula I as described in claim 2, its pharmaceutically acceptable salt, deuterium, tautomer, cis-trans isomer, enantiomer, diastereomer or A prodrug, wherein: when R ³ is a C ₁ -C ₄ alkyl group, the C ₁ -C ₄ alkyl group is methyl, ethyl, isopropyl or n-propyl; and/or when R ^{When 3} is C ₃ -C ₆ cycloalkyl, said C ₃ -C ₆ cycloalkyl is cyclopropyl; and/or, when R ⁴ is C ₁ -C ₄ alkyl, said C ₁ -C ₄ alkyl is methyl; and/or, when R ⁴ is C ₃ -C ₆ cycloalkyl, said C ₃ -C ₆ cycloalkyl is cyclopropyl; and/or, when R ¹ When it is a substituted or unsubstituted C ₆ -C ₁₀ aryl group, the C ₆ -C ₁₀ aryl group is a phenyl group; and/or, when R ¹ is a substituted or unsubstituted 5-10 membered heteroaryl group, When the 5-10 membered heteroaryl group is a 5-membered heteroaryl group, the 5-membered heteroaryl group is furyl, thiazolyl or pyrazolyl; and/or, when R ¹ is substituted or unsubstituted 5-10 membered heteroaryl group, when the 5-10 membered heteroaryl group is a 6-membered heteroaryl group, the 6-membered heteroaryl group is pyridyl; and/or, when R ¹ is a substituted C ₆ -C ₂₀ aryl or substituted 5-10 membered heteroaryl, the number of substituents is 1 or 2; and/or, when R ¹ is substituted C ₆ -C ₂₀ aryl or substituted 5 A -10 membered heteroaryl group, when 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, When the substituent is a C ₁ -C ₄ alkyl group, the C ₁ -C ₄ alkyl group is a methyl group; and/or, when R ² is a substituted or unsubstituted C ₆ -C ₁₀ aryl group, the The C ₆ -C ₁₀ aryl group of 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 pyridyl; 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 Or 2; 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, the halogen is fluorine or chlorine; 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 group, the C ₁ -C ₄ alkyl group is a methyl group 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 alkoxy group, the C ₁ -C ₄ The alkoxy group is a methoxy group; 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, said C ₁ -C _{4 The} alkyl mercapto group is methyl 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 ₄ alkyl group, the "halogen-substituted C ₁ -C ₄ alkyl" C ₁ -C ₄ alkyl is methyl; and / or, when R ² is substituted C ₆ -C ₂₀ aryl group or a substituted 5- When a 10-membered heteroaryl group is a halogen-substituted C ₁ -C ₁₀ alkyl group, the number of halogens in the "halogen-substituted 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 group or a substituted 5-10 membered heteroaryl group, the substituent is

When the said

for

; 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

When R ^c is methyl; and/or, when R ² is substituted C ₆ -C ₂₀ aryl or substituted 5-10 membered heteroaryl, the substituent is C ₁ -C ₄ substituted by halogen an alkoxy group, a "halogen-substituted C ₁ -C ₄ alkoxy" is C ₁ -C ₄ alkoxy groups are methoxy; and / or, when R ² is substituted C ₆ -C ₂₀ aryl or substituted 5-10 membered heteroaryl, when the substituent is a halogen-substituted C ₁ -C ₁₀ alkoxy, the halogen in the "halogen substituted C ₁ -C ₁₀ alkoxy" is The number 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, the substituent is a halogen substituted C ₁ -C ₁₀ alkane In the case of an oxy group, the halogen in the "halogen-substituted C ₁ -C ₁₀ alkoxy group" is fluorine; and/or, when R ² is a substituted C ₆ -C ₂₀ aryl group or a substituted 5-10 member heteroaryl substituent is halogen-substituted C ₁ -C ₄ alkylmercapto, the "halogen-substituted C ₁ -C ₄ alkyl mercapto group" in the C ₁ -C ₄ alkylmercapto as 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 ₁₀ alkyl mercapto group, the “halogen-substituted C _1- The number of halogens in C ₁₀ alkyl mercapto 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, the substituent is In the case of a halogen-substituted C ₁ -C ₁₀ alkyl mercapto group, the halogen in the "halogen substituted C ₁ -C ₁₀ alkyl mercapto group" is fluorine. The compound of formula I as described in claim 3, its pharmaceutically acceptable salt, deuterium, tautomer, cis-trans isomer, enantiomer, diastereomer or A prodrug, wherein: R ³ is a methyl 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, When the 5-membered heteroaryl is furanyl, the furanyl is furan-2-yl; and/or, when R ¹ is a substituted or unsubstituted 5-10 membered heteroaryl, the 5 The -10 membered heteroaryl group is a 5-membered heteroaryl group, and when the 5-membered heteroaryl group is thiazolyl, the thiazolyl is thiazol-4-yl; and/or, when R ¹ is substituted or unsubstituted When the 5-10 membered heteroaryl group is a 5-membered heteroaryl group, and the 5-membered heteroaryl group is a pyrazolyl group, the pyrazolyl group is a pyrazole- 3-base; 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 When it is a pyridyl group, the pyridyl group is a pyridin-2-yl 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 substituents The number is 1; 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 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, the Pyridyl is pyridin-4-yl; and/or, when R ² is substituted C ₆ -C ₂₀ aryl or substituted 5-10 membered heteroaryl, 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, the substituent is a halogen substituted C _1- In the case of C ₄ alkoxy, 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 as described in claim 1, its pharmaceutically acceptable salt, deuterium, tautomer, cis-trans isomer, enantiomer, diastereomer or A prodrug, wherein: in the compound shown in I

for

,

,

,

,

,

,

or

And/or, said R ⁴ is H or C ₁ -C ₁₀ alkyl; and/or, when R ² is substituted C ₆ -C ₂₀ aryl or substituted 5-10 membered heteroaryl, Substituents are 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 as described in claim 1, its pharmaceutically acceptable salt, deuterium, tautomer, cis-trans isomer, enantiomer, diastereomer or A prodrug, wherein: in the compound shown in I

for

,

,

,

,

,

,

,

,

,

,

,

,

or

; And/or, R ¹ is

,

,

,

,

,

or

; Preferably

,

,

,

,

or

; And/or, R ² is

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

or

. The compound of formula I as described in claim 1, its pharmaceutically acceptable salt, deuterium, tautomer, cis-trans isomer, enantiomer, diastereomer or Prodrugs, where: "

"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 member Heteroaryl; when R ¹ is a substituted 5-10 membered heteroaryl, 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, halogen-substituted C ₁ -C ₁₀ alkyl or halogen-substituted C ₁ -C ₁₀ alkoxy; in the 5-10 membered heteroaryl group The number of heteroatoms is 1, 2, 3, or 4, and each heteroatom is independently O, N, or S. The compound of formula I as described in claim 1, its pharmaceutically acceptable salt, deuterium, tautomer, cis-trans isomer, enantiomer, diastereomer or A prodrug, wherein: the compound represented by formula I is selected from any of the following structures:

. A method for preparing the compound represented by formula I according to any one of claims 1-8, wherein it comprises the following steps: in an organic solvent, the compound represented by formula IA and an aminating reagent The nucleophilic substitution reaction shown below can be used to prepare the compound shown in formula I;

among them,"

","

", X, Y, W, R ¹ and R ² are as defined in claim 1, and X ¹ is halogen or a C ₁ -C ₄ alkyl substituted alkyl group. A compound represented by formula IA:

among them,"

","

", X, Y, W, R ¹ and R ² are as defined in any one of claims 1-8, X ¹ is halogen or a C ₁ -C ₄ alkyl substituted alkyl group; and, said The compound represented by formula IA does not have any of the following structures:

. The compound of formula IA according to claim 10, wherein it has any of the following structures:

. A pharmaceutical composition comprising the compound of formula I as described in any one of claims 1-8, and a pharmaceutically acceptable salt, deuterated substance, tautomer, cis-trans isomer, Enantiomers, diastereomers or prodrugs, and pharmaceutically acceptable carriers. An adenosine A2A receptor antagonist, which uses the compound represented by formula I as described in any one of claims 1-8, and its pharmaceutically acceptable salt, deuterium, tautomer, cis-trans Isomers, enantiomers, diastereomers or prodrugs are prepared. A medicament for preventing, alleviating and/or treating related diseases caused by adenosine A2A receptor, which utilizes the compound represented by formula I according to any one of claims 1-8, which is pharmaceutically acceptable Accepted salts, deuterated products, tautomers, cis-trans isomers, enantiomers, diastereomers or prodrugs, or prepared from the pharmaceutical composition described in claim 12. The drug according to claim 14, wherein the related diseases caused by adenosine A2A receptor are one or more of central nervous system diseases, immune tolerance diseases and inflammatory diseases.