WO2021114691A1 - Nitrogen-containing ring-fused compound, preparation method therefor and use thereof - Google Patents

Abstract

The present invention relates to a nitrogen-containing ring-fused compound, a preparation method therefor and a use thereof. Specifically, the present invention relates to a compound having a structure represented by formula (X), a stereoisomer or a tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, a co-crystal, a polymorph or a solvate of the compound, or a stable isotopic derivative, a metabolite or a prodrug of the compound. The compound of the present invention may have a structure represented by formula (I) or formula (III). The compounds can be used for treating abnormal cell proliferation diseases (such as cancers).

Description

Nitrogen-containing hexacyclic compound, its preparation method and application

Cross-references to related applications

This application claims the priority of the Chinese patent application No. 201911279540.7 filed on December 13, 2019 and titled "Nitrogen-containing hexacyclic compound, its preparation method and use", and the entire content of the patent application is incorporated herein by reference.

Field of invention

The present invention relates to a class of nitrogen-containing hexacyclic compounds, stereoisomers, tautomers or mixtures of said compounds, pharmaceutically acceptable salts, co-crystals, polymorphs or solvates of said compounds Or a stable isotope derivative, metabolite or prodrug of the compound. The compounds of the present invention are used as NLRP3 (NLR family pyrin domain containing 3) modulators (such as agonists or partial agonists) and can be used for the treatment of abnormal cell proliferation diseases (such as cancer).

Background of the invention

NLRP3 belongs to the family of NOD-like receptors. It is one of the most studied intracellular pattern recognition receptors in recent years. It is mainly expressed in macrophages and neutrophils. It participates in the body's innate immunity and resists pathogen infection and stress damage. NLRP3 inflammasome plays a very clear role in inflammatory and metabolic diseases, and its over-activation can lead to type 2 diabetes, immune diseases such as rheumatoid arthritis and atherosclerosis. However, recent studies have shown that NLRP3 has anti-tumor effects that inhibit tumor growth and metastasis.

After NLRP3 protein recognizes pathogen-related molecular patterns (PAMP) or endogenous damage-related molecular patterns (DAMP), its NOD domain oligomerizes and recruits proteins such as ASC and pro-caspase-1 to form functional NLRP3 Inflammatory bodies. After pro-caspase-1 is cleaved and activated to caspase-1, caspase-1 cleaves pro-IL-1β and pro-IL-18 in a large amount to convert them into active forms of IL-1β and IL-18 and release them to Extracellular, amplify the inflammatory response. Agitated NLRP3 inflammasome can significantly increase the levels of immune factors IL-1β and IL-18 in the tumor microenvironment, initiate natural immune killing and subsequent adaptive immune responses to exert its anti-tumor effects. Specifically, IL-1β can induce CD8+ T cells to secrete interferon γ (IFN-γ) and CD4+ cells to secrete IL-17, leading to effective anti-tumor immune effects; while IL-18 can promote the maturation of NK cells Activates the downstream signaling pathway of STAT1 in immune cells and enhances the killing function of immune cells. Clinical studies have shown that the down-regulation of NLRP3 is significantly negatively correlated with the prognosis of liver cancer patients. Preclinical studies have also shown that NLRP3-deficient mice have a higher rate of colorectal tumor formation and worsen liver metastasis of colorectal cancer. It can be seen that NLRP3 plays an important role in the tumor microenvironment and can be used as a key target of tumor immunotherapy, as well as a tumor prognostic marker.

WO2017184746, WO2017184735, WO2018152396 and WO2019014402 disclose NLRP3 modulators. NLRP3 agonists have the potential for tumor immunotherapy, and currently known compound BMS-986299 is in clinical phase I study. Therefore, it is necessary to develop new, high-efficiency and low-toxicity NLRP3 agonists to meet the needs of clinical treatment.

Summary of the invention

Through creative work, the inventors of the present invention have obtained a new type of nitrogen-containing cyclic compounds, which can be used as NLRP3 modulators (such as agonists), directly binding or modifying NLRP3 at the protein level, and by activating, stabilizing, and changing NLRP3 Distribution or other ways to enhance the function of NLRP3 inflammasome, thereby providing the following invention.

Compound

In one aspect, the present invention provides compounds having the structure represented by formula X, stereoisomers, tautomers or mixtures thereof, pharmaceutically acceptable salts, co-crystals, polymorphs of the compounds Forms or solvates, or stable isotope derivatives, metabolites or prodrugs of said compounds:

RLR ³

Formula X

among them:

R ^{3 is} selected from H, halogen, CN, NO ₂ , C _1-8 alkyl, C _3-8 cycloalkyl, 4-10 membered heterocyclic group, C _6-12 aryl, 5-10 membered heteroaryl , 9-12 membered aryl and heterocyclyl, 9-12 membered aryl and heteroaryl, 9-12 membered aryl and cycloalkyl, CO ₂ R ³⁰ , C(O)NR ³¹ R ³² , NR ³³ C(O)R ³⁴ , NR ³¹ R ³² , S(O) ₂ R ³⁵ , OR ³⁷ , SR ³⁷ , C(O)R ³⁰ , OC(O)R ³⁰ , OC(O)NR ³¹ R ³² , NR ³³ C(O)NR ³¹ R ³² , NR ³³ C(O)OR ³⁰ , C(=NR ³⁸ )NR ³¹ R ³² , NR ³³ C(=NR ³⁸ )NR ³¹ R ³² , P(R ³⁹ ) ₂ , P(OR ³⁹ ) ₂ , P(O)R ³⁹ R ⁴⁰ , P(O)OR ³⁹ OR ³⁰ , S(O)R ³⁵ , S(O)NR ³¹ R ³² and S(O) ₂ NR ³¹ R ³² , Wherein the C _1-8 alkyl group, C _3-8 cycloalkyl group, 4-10 membered heterocyclic group, C _6-12 aryl group, 5-10 membered heteroaryl group, 9-12 membered aryl group and hetero Cyclic, 9-12 membered aryl and heteroaryl and 9-12 membered aryl and cycloalkyl are each optionally substituted with one or more of the following substituents: halogen, CN, NO ₂ , C _{1- 4-} alkyl, C _3-8 cycloalkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, 4-10 membered heterocyclic group, C _6-12 aryl, 5-10 membered heteroaryl, 9-12 membered aryl and heterocyclic group, CO ₂ R ³⁰ , C(O)R ³⁰ , C(O)NR ³¹ R ³² , NR ³³ C(O)R ³⁴ , NR ³¹ R ³² , S(O) R ³⁵ , S(O) ₂ R ³⁵ , S(O)NR ³¹ R ³² , S(O) ₂ NR ³¹ R ³² , OR ³⁷ , SR ³⁷ , OC(O)R ³⁰ , OC(O)NR ³¹ R ³² , NR ³³ C(O)NR ³¹ R ³² , NR ³³ C(O)OR ³⁰ , C(=NR ³⁸ )NR ³¹ R ³² , NR ³³ C(=NR ³⁸ )NR ³¹ R ³² , =NNR ³¹ R ³² , P(R ³⁹ ) ₂ , P(OR ³⁹ ) ₂ , P(O)R ³⁹ R ⁴⁰ and P(O)OR ³⁹ OR ³⁰ ;

L is -(L ¹ ) _n -(L ² ) _p -(L ³ ) _q -, wherein L ¹ , L ² and L ^{3 are the} same or different and are each independently selected from C _1-8 alkylene, C _{2 -8} alkenylene, C _2-8 alkynylene, C _1-8 alkyleneoxy, C _3-8 cycloalkylene, 4-10 membered heterocyclylene, C _6-12 arylene, 5 -10 membered heteroarylene, O, S, NR ³³ , S(O), S(O) ₂ , C(O) and C(R ^36a R ^36b ), wherein the C _1-8 alkylene group, C _2-8 alkenylene, C _2-8 alkynylene, C _1-8 alkyleneoxy, C _3-8 cycloalkylene, 4-10 membered heterocyclylene, C _6-12 arylene And 5-10 membered heteroarylene groups are each optionally substituted with one or more of the following substituents: halogen, OH, CN, NO ₂ , C _1-6 alkyl, C _1-4 haloalkyl, C _{1 -4} hydroxyalkyl, C _1-4 alkoxy and NR ³¹ R ³² ;

n, p and q are each independently 0, 1 or 2;

R ³⁰ , R ³⁷ , R ³⁹ and R ⁴⁰ are each independently selected from H, C _1-8 alkyl (e.g. C _1-6 alkyl or C _1-4 alkyl), C _1-8 alkoxy (e.g. C _{1- 6} alkoxy or C _1-4 alkoxy), C _3-8 cycloalkyl, 4-10 membered heterocyclyl, C _6-12 aryl, 5-10 membered heteroaryl, -C _1-8 alkyl-C _6-12 aryl and -C _1-8 alkyl-(5-10 membered heteroaryl), wherein the C _1-8 alkyl, C _1-8 alkoxy, C _3-8 cycloalkyl, 4-10 membered heterocyclic group, C _6-12 aryl, 5-10 membered heteroaryl, -C _1-8 alkyl-C _6-12 aryl and -C _1-8 Alkyl-(5-10 membered heteroaryl) are each optionally substituted with one or more of the following substituents: OH, CN, NO ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, halogen, C _1-4 haloalkoxy, CO ₂ (C _1-6 alkyl), CONR ³¹ R ³² , NR ³¹ R ³² , NR ³³ C(O)R ³⁴ , S(O ) R ³⁵ , S(O) ₂ R ³⁵ , S(O)NR ³¹ R ³² and S(O) ₂ NR ³¹ R ³² ;

R ³¹ , R ³² , R ³³ and R ³⁴ are each independently selected from H, C _1-8 alkyl, C _1-8 alkoxy, C _3-8 cycloalkyl, 4-10 membered heterocyclic group, C _6-12 aryl and 5-10 membered heteroaryl, or R ³¹ and R ³² together with the N atom to which they are attached form a 4-8 membered heterocyclic group, or R ³³ and R ³⁴ and the C to which they are each attached Together with the N atom to form a 4-8 membered heterocyclic group, wherein the C _1-8 alkyl group, C _1-8 alkoxy group, C _3-8 cycloalkyl group, 4-8 membered heterocyclic group, 4-10 Each of the membered heterocyclic group, C _6-12 aryl group and 5-10 membered heteroaryl group is optionally substituted by one or more of the following substituents: OH, CN, halogen, NO ₂ , C _1-4 alkyl , C _1-4 alkoxy, C _1-4 hydroxyalkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, 4-10 membered heterocyclic group, C _6-12 aryl and 5-10 Yuan heteroaryl

R ^{35 is} selected from C _1-8 alkyl, C _1-8 alkoxy, C _3-8 cycloalkyl, 4-10 membered heterocyclic group, C _6-12 aryl, 5-10 membered heteroaryl, -C _1-8 alkyl-C _6-12 aryl and -C _1-8 alkyl-(5-10 membered heteroaryl), wherein the C _1-8 alkyl, C _1-8 alkoxy , C _3-8 cycloalkyl, 4-10 membered heterocyclyl, C _6-12 aryl and 5-10 membered heteroaryl are each optionally substituted by one or more of the following substituents: OH, CN , NO ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, halogen, C _1-4 haloalkoxy, CO ₂ (C _1-6 alkyl), CONR ³¹ R ³² , NR ³¹ R ³² , NR ³³ C(O)R ³⁴ , S(O)Me, S(O) ₂ Me, S(O)NR ³¹ R ³² and S(O) ₂ NR ³¹ R ³² , where R ³¹ , R ³² , R ³³ and R ³⁴ are as defined above;

R ^36a and R ^{36b are the} same or different and are each independently selected from H, C _1-8 alkyl and C _1-8 alkoxy, wherein the C _1-8 alkyl and C _1-8 alkoxy are each independently Optionally substituted by one or more of the following groups: OH, CN, halogen, NH ₂ , NHCH ₃ and N(CH ₃ ) ₂ , or R ^36a and R ^36b together with the C atom to which they are attached form a 3- 7-membered cycloalkyl or heterocyclic group;

R ^{38 is} selected from H, OH, CN, NO ₂ , S(O)R ³⁵ and S(O) ₂ R ³⁵ ;

When multiple R ³⁰ exist at the same time, each R ³⁰ may be the same or different;

When multiple R ³¹ exist at the same time, each R ³¹ may be the same or different;

When multiple R ³² exist at the same time, each R ³² may be the same or different;

When multiple R ³³ exist at the same time, each R ³³ may be the same or different;

When multiple R ³⁴ exist at the same time, each R ³⁴ may be the same or different;

When multiple R ³⁵ exist at the same time, each R ³⁵ may be the same or different;

When multiple R ³⁷ exist at the same time, each R ³⁷ may be the same or different;

When multiple R ³⁸ exist at the same time, each R ³⁸ may be the same or different;

When multiple R ³⁹ exist at the same time, each R ³⁹ may be the same or different;

When multiple R ⁴⁰ exist at the same time, each R ⁴⁰ may be the same or different;

其中： R is selected from

among them:

R ^{1 is} selected from C _1-8 alkyl, C _3-8 cycloalkyl, 4-10 membered heterocyclic group, C _6-12 aryl, 5-10 membered heteroaryl and 9-12 membered aryl and hetero Cyclic group, wherein the C _1-8 alkyl group, C _3-8 cycloalkyl group, 4-10 membered heterocyclic group, C _6-12 aryl group, 5-10 membered heteroaryl group and 9-12 membered aryl group The heterocyclic groups are each optionally substituted by one or more of the following substituents: halogen, CN, NO ₂ , C _1-4 alkyl, C _3-8 cycloalkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, 4-10 membered heterocyclyl, C _6-12 aryl, 5-10 membered heteroaryl, 9-12 membered heterocyclyl, and aryl ^{_{group, CO 2 R 30, C (}} O) R ³⁰ , C(O)NR ³¹ R ³² , NR ³³ C(O)R ³⁴ , NR ³¹ R ³² , OC(O)R ³⁰ , OC(O)NR ³¹ R ³² , NR ³³ C(O)NR ³¹ R ³² , NR ³³ C(O)OR ³⁰ , S(O)NR ³¹ R ³² , S(O) ₂ NR ³¹ R ³² , S(O)R ³⁵ , S(O) ₂ R ³⁵ , OR ³⁷ and SR ³⁷ ;

R ^{2 is} selected from H, NR ^41a R ^41b , C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl and 4-10 membered heterocyclic group, wherein said C _{1- 8} alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl and 4-10 membered heterocyclyl group each optionally substituted with a group of the following or One substitution: halogen, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, 4-7 membered heterocyclic group, CN, NO ₂ , OR ³⁷ , SR ³⁷ , C(O)R ³⁰ , C(O) NR ³¹ R ³² , NR ³³ C(O)R ³⁴ , C(O)OR ³⁰ , OC(O)R ³⁰ , OC(O)NR ³¹ R ³² , NR ³³ C(O)NR ³¹ R ³² and NR ³¹ R ³² ;

R ⁵ is absent or selected from halogen, C _1-6 alkyl, C _1-4 alkoxy, C _3-8 cycloalkyl and 4-10 membered heterocyclic group, wherein the C _1-6 alkyl, C _1-4 alkoxy, C _3-8 cycloalkyl, and 4-10 membered heterocyclic group are each optionally substituted with one or more of the following groups: halogen, OH, CN, C _1-4 alkane Oxy, C _1-4 hydroxyalkyl and NR ³¹ R ³² ;

m is 0, 1 or 2, preferably 0 or 1;

X ^{1 is} selected from CR ⁶ and N;

R ^{4 is} selected from H, NR ^41a R ^41b , C _1-15 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl and 4- 10-membered heterocyclic group, wherein the C _1-15 alkyl group, C _1-8 alkoxy group, C _2-8 alkenyl group, C _2-8 alkynyl group, C _3-8 cycloalkyl group and 4-10 membered The heterocyclic groups are each optionally substituted by one or more of the following substituents: halogen, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, 4-7 membered heterocyclyl, CN, NO ₂ , OR ³⁷ , SR ³⁷ , C(O)R ³⁰ , C(O)NR ³¹ R ³² , NR ³³ C(O)R ³⁴ , C(O)OR ³⁰ , OC(O)R ³⁰ , OC(O)NR ³¹ R ³² , NR ³³ C(O)NR ³¹ R ³² and NR ³¹ R ³² ;

R ^{6 is} selected from H, halogen, C _1-6 alkyl, C _1-4 alkoxy, C _3-8 cycloalkyl and 4-10 membered heterocyclic group, wherein the C _1-6 alkyl, C _1-4 alkoxy, C _3-8 cycloalkyl, and 4-10 membered heterocyclic group are each optionally substituted with one or more of the following groups: halogen, OH, CN, C _1-4 alkoxy Group, C _1-4 hydroxyalkyl group and NR ³¹ R ³² ;

R ^41a and R ^41b are each independently selected from H, C _1-6 alkyl, C _1-6 alkoxy and C _3-8 cycloalkyl, or R ^41a and R ^41b form together with the N atom to which they are attached 4-7 membered heterocyclic group, wherein the C _1-6 alkyl group, C _1-6 alkoxy group, C _3-8 cycloalkyl group and 4-7 membered heterocyclic group are each optionally selected from the following groups One or more of the substitutions: OH, CN and NR ³¹ R ³² .

In some embodiments, the present invention provides a compound having a structure represented by formula I, a stereoisomer, a tautomer or a mixture of the compound, a pharmaceutically acceptable salt, co-crystal, Polymorphs or solvates, or stable isotope derivatives, metabolites or prodrugs of said compounds:

among them:

R ^{1 is} selected from C _1-8 alkyl, C _3-8 cycloalkyl, 4-10 membered heterocyclic group, C _6-12 aryl, 5-10 membered heteroaryl and 9-12 membered aryl and hetero Cyclic group, wherein the C _1-8 alkyl group, C _3-8 cycloalkyl group, 4-10 membered heterocyclic group, C _6-12 aryl group, 5-10 membered heteroaryl group and 9-12 membered aryl group The heterocyclic groups are each optionally substituted by one or more of the following substituents: halogen, CN, NO ₂ , C _1-4 alkyl, C _3-8 cycloalkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, 4-10 membered heterocyclyl, C _6-12 aryl, 5-10 membered heteroaryl, 9-12 membered heterocyclyl, and aryl ^{_{group, CO 2 R 30, C (}} O) R ³⁰ , C(O)NR ³¹ R ³² , NR ³³ C(O)R ³⁴ , NR ³¹ R ³² , OC(O)R ³⁰ , OC(O)NR ³¹ R ³² , NR ³³ C(O)NR ³¹ R ³² , NR ³³ C(O)OR ³⁰ , S(O)NR ³¹ R ³² , S(O) ₂ NR ³¹ R ³² , S(O)R ³⁵ , S(O) ₂ R ³⁵ , OR ³⁷ and SR ³⁷ ;

R ^{2 is} selected from H, NR ^41a R ^41b , C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl and 4-10 membered heterocyclic group, wherein said C _{1- 8} alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl and 4-10 membered heterocyclyl group each optionally substituted with a group of the following or One substitution: halogen, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, 4-7 membered heterocyclic group, CN, NO ₂ , OR ³⁷ , SR ³⁷ , C(O)R ³⁰ , C(O) NR ³¹ R ³² , NR ³³ C(O)R ³⁴ , C(O)OR ³⁰ , OC(O)R ³⁰ , OC(O)NR ³¹ R ³² , NR ³³ C(O)NR ³¹ R ³² and NR ³¹ R ³² ;

R ³ at each occurrence is independently selected from H, halogen, CN, NO ₂ , C _1-8 alkyl, C _3-8 cycloalkyl, 4-10 membered heterocyclic group, C _6-12 aryl, 5-10 membered heteroaryl, 9-12 membered aryl and heterocyclic group, 9-12 membered aryl and heteroaryl, 9-12 membered aryl and cycloalkyl, CO ₂ R ³⁰ , C(O) NR ³¹ R ³² , NR ³³ C(O)R ³⁴ , NR ³¹ R ³² , S(O) ₂ R ³⁵ , OR ³⁷ , SR ³⁷ , C(O)R ³⁰ , OC(O)R ³⁰ , OC(O ) NR ³¹ R ³² , NR ³³ C(O)NR ³¹ R ³² , NR ³³ C(O)OR ³⁰ , C(=NR ³⁸ )NR ³¹ R ³² , NR ³³ C(=NR ³⁸ )NR ³¹ R ³² , P(R ³⁹ ) ₂ , P(OR ³⁹ ) ₂ , P(O)R ³⁹ R ⁴⁰ , P(O)OR ³⁹ OR ³⁰ , S(O)R ³⁵ , S(O)NR ³¹ R ³² and S( O) ₂ NR ³¹ R ³² , wherein the C _1-8 alkyl group, C _3-8 cycloalkyl group, 4-10 membered heterocyclic group, C _6-12 aryl group, 5-10 membered heteroaryl group, 9 The -12-membered aryl and heterocyclyl, 9-12-membered aryl and heteroaryl, and 9-12-membered aryl and cycloalkyl are each optionally substituted with one or more of the following substituents: halogen, CN , NO ₂ , C _1-4 alkyl, C _3-8 cycloalkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, 4-10 membered heterocyclic group, C _6-12 aryl, 5 -10 membered heteroaryl, 9-12 membered aryl and heterocyclic group, CO ₂ R ³⁰ , C(O)R ³⁰ , C(O)NR ³¹ R ³² , NR ³³ C(O)R ³⁴ , NR ³¹ R ³² , S(O)R ³⁵ , S(O) ₂ R ³⁵ , S(O)NR ³¹ R ³² , S(O) ₂ NR ³¹ R ³² , OR ³⁷ , SR ³⁷ , OC(O)R ³⁰ , OC(O)NR ³¹ R ³² , NR ³³ C(O)NR ³¹ R ³² , NR ³³ C(O)OR ³⁰ , C(=NR ³⁸ )NR ³¹ R ³² , NR ³³ C(=NR ³⁸ )NR ³¹ R ³² , = NNR ³¹ R ³² , P(R ³⁹ ) ₂ , P(OR ³⁹ ) ₂ , P(O)R ³⁹ R ⁴⁰ and P(O)OR ³⁹ OR ³⁰ ;

R ⁵ is absent or selected from halogen, C _1-6 alkyl, C _1-4 alkoxy, C _3-8 cycloalkyl and 4-10 membered heterocyclic group, wherein the C _1-6 alkyl, C _1-4 alkoxy, C _3-8 cycloalkyl, and 4-10 membered heterocyclic group are each optionally substituted with one or more of the following groups: halogen, OH, CN, C _1-4 alkane Oxy, C _1-4 hydroxyalkyl and NR ³¹ R ³² ;

m is 0, 1 or 2, preferably 0 or 1;

L is -(L ¹ ) _n -(L ² ) _p -(L ³ ) _q -, wherein L ¹ , L ² and L ^{3 are the} same or different and each is independently selected from C _1-8 sub Alkyl, C _2-8 alkenylene, C _2-8 alkynylene, C _1-8 alkyleneoxy, C _3-8 cycloalkylene, 4-10 membered heterocyclylene, C _6-12 Arylene, 5-10 membered heteroarylene, O, S, NR ³³ , S(O), S(O) ₂ , C(O) and C(R ^36a R ^36b ), wherein the C _{1- 8} alkylene, C _2-8 alkenylene, C _2-8 alkynylene, C _1-8 alkyleneoxy, C _3-8 cycloalkylene, 4-10 membered heterocyclylene, C _{6 The -12} arylene group and the 5-10 membered heteroarylene group are each optionally substituted with one or more of the following substituents: halogen, OH, CN, NO ₂ , C _1-6 alkyl, C _1-4 Haloalkyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy and NR ³¹ R ³² ;

n, p, and q are each independently 0, 1 or 2 each time they appear;

R ³⁰ , R ³⁷ , R ³⁹ and R ⁴⁰ are each independently selected from H, C _1-8 alkyl (e.g. C _1-6 alkyl or C _1-4 alkyl), C _1-8 alkoxy (e.g. C _{1- 6} alkoxy or C _1-4 alkoxy), C _3-8 cycloalkyl, 4-10 membered heterocyclyl, C _6-12 aryl, 5-10 membered heteroaryl, -C _1-8 alkyl-C _6-12 aryl and -C _1-8 alkyl-(5-10 membered heteroaryl), wherein the C _1-8 alkyl, C _1-8 alkoxy, C _3-8 cycloalkyl, 4-10 membered heterocyclic group, C _6-12 aryl, 5-10 membered heteroaryl, -C _1-8 alkyl-C _6-12 aryl and -C _1-8 Alkyl-(5-10 membered heteroaryl) are each optionally substituted with one or more of the following substituents: OH, CN, NO ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, halogen, C _1-4 haloalkoxy, CO ₂ (C _1-6 alkyl), CONR ³¹ R ³² , NR ³¹ R ³² , NR ³³ C(O)R ³⁴ , S(O ) R ³⁵ , S(O) ₂ R ³⁵ , S(O)NR ³¹ R ³² and S(O) ₂ NR ³¹ R ³² ;

R ³¹ , R ³² , R ³³ and R ³⁴ are each independently selected from H, C _1-8 alkyl, C _1-8 alkoxy, C _3-8 cycloalkyl, 4-10 membered heterocyclic group, C _6-12 aryl and 5-10 membered heteroaryl, or R ³¹ and R ³² together with the N atom to which they are attached form a 4-8 membered heterocyclic group, or R ³³ and R ³⁴ and the C to which they are each attached Together with the N atom to form a 4-8 membered heterocyclic group, wherein the C _1-8 alkyl group, C _1-8 alkoxy group, C _3-8 cycloalkyl group, 4-8 membered heterocyclic group, 4-10 Each of the membered heterocyclic group, C _6-12 aryl group and 5-10 membered heteroaryl group is optionally substituted by one or more of the following substituents: OH, CN, halogen, NO ₂ , C _1-4 alkyl , C _1-4 alkoxy, C _1-4 hydroxyalkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, 4-10 membered heterocyclic group, C _6-12 aryl and 5-10 Yuan heteroaryl

R ^{35 is} selected from C _1-8 alkyl, C _1-8 alkoxy, C _3-8 cycloalkyl, 4-10 membered heterocyclic group, C _6-12 aryl, 5-10 membered heteroaryl, -C _1-8 alkyl-C _6-12 aryl and -C _1-8 alkyl-(5-10 membered heteroaryl), wherein the C _1-8 alkyl, C _1-8 alkoxy , C _3-8 cycloalkyl, 4-10 membered heterocyclyl, C _6-12 aryl and 5-10 membered heteroaryl are each optionally substituted by one or more of the following substituents: OH, CN , NO ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, halogen, C _1-4 haloalkoxy, CO ₂ (C _1-6 alkyl), CONR ³¹ R ³² , NR ³¹ R ³² , NR ³³ C(O)R ³⁴ , S(O)Me, S(O) ₂ Me, S(O)NR ³¹ R ³² and S(O) ₂ NR ³¹ R ³² , where R ³¹ , R ³² , R ³³ and R ³⁴ are as defined above;

R ^36a and R ^{36b are the} same or different and are each independently selected from H, C _1-8 alkyl and C _1-8 alkoxy, wherein the C _1-8 alkyl and C _1-8 alkoxy are each independently Optionally substituted by one or more of the following groups: OH, CN, halogen, NH ₂ , NHCH ₃ and N(CH ₃ ) ₂ , or R ^36a and R ^36b together with the C atom to which they are attached form a 3- 7-membered cycloalkyl or heterocyclic group;

R ^{38 is} selected from H, OH, CN, NO ₂ , S(O)R ³⁵ and S(O) ₂ R ³⁵ ;

R ^41a and R ^41b are each independently selected from H, C _1-6 alkyl, C _1-6 alkoxy and C _3-8 cycloalkyl, or R ^41a and R ^41b form together with the N atom to which they are attached 4-7 membered heterocyclic group, wherein the C _1-6 alkyl group, C _1-6 alkoxy group, C _3-8 cycloalkyl group and 4-7 membered heterocyclic group are each optionally selected from the following groups One or more of the substitutions: OH, CN and NR ³¹ R ³² ; and

When multiple R ³⁰ exist at the same time, each R ³⁰ may be the same or different;

When multiple R ³¹ exist at the same time, each R ³¹ may be the same or different;

When multiple R ³² exist at the same time, each R ³² may be the same or different;

When multiple R ³³ exist at the same time, each R ³³ may be the same or different;

When multiple R ³⁴ exist at the same time, each R ³⁴ may be the same or different;

When multiple R ³⁵ exist at the same time, each R ³⁵ may be the same or different;

When multiple R ³⁷ exist at the same time, each R ³⁷ may be the same or different;

When multiple R ³⁸ exist at the same time, each R ³⁸ may be the same or different;

When multiple R ³⁹ exist at the same time, each R ³⁹ may be the same or different;

When multiple R ⁴⁰ exist at the same time, each R ⁴⁰ may be the same or different.

In some embodiments, the present invention provides a compound having a structure represented by Formula II, a stereoisomer, a tautomer or a mixture of the compound, a pharmaceutically acceptable salt, co-crystal, Polymorphs or solvates, or stable isotope derivatives, metabolites or prodrugs of said compounds:

Wherein R ¹ , L ² and R ³ are as defined in formula I.

In some embodiments, the present invention provides a compound having a structure represented by Formula II-A, a stereoisomer, a tautomer or a mixture of the compound, a pharmaceutically acceptable salt, or a mixture of the compound Crystals, polymorphs or solvates, or stable isotope derivatives, metabolites or prodrugs of said compounds:

Where L ² and R ³ are as defined in formula I.

In some embodiments, the present invention provides a compound having a structure represented by formula III, a stereoisomer, a tautomer or a mixture of the compound, a pharmaceutically acceptable salt, co-crystal, Polymorphs or solvates, or stable isotope derivatives, metabolites or prodrugs of said compounds:

among them:

X ^{1 is} selected from CR ⁶ and N,

R ^{1 is} selected from C _1-8 alkyl, C _3-8 cycloalkyl, 4-10 membered heterocyclic group, C _6-12 aryl, 5-10 membered heteroaryl and 9-12 membered aryl and hetero Cyclic group, wherein the C _1-8 alkyl group, C _3-8 cycloalkyl group, 4-10 membered heterocyclic group, C _6-12 aryl group, 5-10 membered heteroaryl group and 9-12 membered aryl group The heterocyclic groups are each optionally substituted by one or more of the following substituents: halogen, CN, NO ₂ , C _1-4 alkyl, C _3-8 cycloalkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, 4-10 membered heterocyclyl, C _6-12 aryl, 5-10 membered heteroaryl, 9-12 membered heterocyclyl, and aryl ^{_{group, CO 2 R 30, C (}} O) R ³⁰ , C(O)NR ³¹ R ³² , NR ³³ C(O)R ³⁴ , NR ³¹ R ³² , OC(O)R ³⁰ , OC(O)NR ³¹ R ³² , NR ³³ C(O)NR ³¹ R ³² , NR ³³ C(O)OR ³⁰ , S(O)NR ³¹ R ³² , S(O) ₂ NR ³¹ R ³² , S(O)R ³⁵ , S(O) ₂ R ³⁵ , OR ³⁷ and SR ³⁷ ;

R ³ at each occurrence is independently selected from H, halogen, CN, NO ₂ , C _1-8 alkyl, C _3-8 cycloalkyl, 4-10 membered heterocyclic group, C _6-12 aryl, 5-10 membered heteroaryl, 9-12 membered aryl and heterocyclic group, 9-12 membered aryl and heteroaryl, 9-12 membered aryl and cycloalkyl, CO ₂ R ³⁰ , C(O) NR ³¹ R ³² , NR ³³ C(O)R ³⁴ , NR ³¹ R ³² , S(O) ₂ R ³⁵ , OR ³⁷ , SR ³⁷ , C(O)R ³⁰ , OC(O)R ³⁰ , OC(O ) NR ³¹ R ³² , NR ³³ C(O)NR ³¹ R ³² , NR ³³ C(O)OR ³⁰ , C(=NR ³⁸ )NR ³¹ R ³² , NR ³³ C(=NR ³⁸ )NR ³¹ R ³² , P(R ³⁹ ) ₂ , P(OR ³⁹ ) ₂ , P(O)R ³⁹ R ⁴⁰ , P(O)OR ³⁹ OR ³⁰ , S(O)R ³⁵ , S(O)NR ³¹ R ³² and S( O) ₂ NR ³¹ R ³² , wherein the C _1-8 alkyl group, C _3-8 cycloalkyl group, 4-10 membered heterocyclic group, C _6-12 aryl group, 5-10 membered heteroaryl group, 9 The -12-membered aryl and heterocyclyl, 9-12-membered aryl and heteroaryl, and 9-12-membered aryl and cycloalkyl are each optionally substituted with one or more of the following substituents: halogen, CN , NO ₂ , C _1-4 alkyl, C _3-8 cycloalkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, 4-10 membered heterocyclic group, C _6-12 aryl, 5 -10 membered heteroaryl, 9-12 membered aryl and heterocyclic group, CO ₂ R ³⁰ , C(O)R ³⁰ , C(O)NR ³¹ R ³² , NR ³³ C(O)R ³⁴ , NR ³¹ R ³² , S(O)R ³⁵ , S(O) ₂ R ³⁵ , S(O)NR ³¹ R ³² , S(O) ₂ NR ³¹ R ³² , OR ³⁷ , SR ³⁷ , OC(O)R ³⁰ , OC(O)NR ³¹ R ³² , NR ³³ C(O)NR ³¹ R ³² , NR ³³ C(O)OR ³⁰ , C(=NR ³⁸ )NR ³¹ R ³² , NR ³³ C(=NR ³⁸ )NR ³¹ R ³² , =NNR ³¹ R ³² , P(R ³⁹ ) ₂ , P(OR ³⁹ ) ₂ , P(O)R ³⁹ R ⁴⁰ and P(O)OR ³⁹ OR ³⁰ ;

R ^{4 is} selected from H, NR ^41a R ^41b , C _1-15 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl and 4- 10-membered heterocyclic group, wherein the C _1-15 alkyl group, C _1-8 alkoxy group, C _2-8 alkenyl group, C _2-8 alkynyl group, C _3-8 cycloalkyl group and 4-10 membered The heterocyclic groups are each optionally substituted by one or more of the following substituents: halogen, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, 4-7 membered heterocyclyl, CN, NO ₂ , OR ³⁷ , SR ³⁷ , C(O)R ³⁰ , C(O)NR ³¹ R ³² , NR ³³ C(O)R ³⁴ , C(O)OR ³⁰ , OC(O)R ³⁰ , OC(O)NR ³¹ R ³² , NR ³³ C(O)NR ³¹ R ³² and NR ³¹ R ³² ;

R ^{6 is} selected from H, halogen, C _1-6 alkyl, C _1-4 alkoxy, C _3-8 cycloalkyl and 4-10 membered heterocyclic group, wherein the C _1-6 alkyl, C _1-4 alkoxy, C _3-8 cycloalkyl, and 4-10 membered heterocyclic group are each optionally substituted with one or more of the following groups: halogen, OH, CN, C _1-4 alkoxy Group, C _1-4 hydroxyalkyl group and NR ³¹ R ³² ;

L is -(L ¹ ) _n -(L ² ) _p -(L ³ ) _q -, wherein L ¹ , L ² and L ^{3 are the} same or different and each is independently selected from C _1-8 sub Alkyl, C _2-8 alkenylene, C _2-8 alkynylene, C _1-8 alkyleneoxy, C _3-8 cycloalkylene, 4-10 membered heterocyclylene, C _6-12 Arylene, 5-10 membered heteroarylene, O, S, NR ³³ , S(O), S(O) ₂ , C(O) and C(R ^36a R ^36b ), wherein the C _{1- 8} alkylene, C _2-8 alkenylene, C _2-8 alkynylene, C _1-8 alkyleneoxy, C _3-8 cycloalkylene, 4-10 membered heterocyclylene, C _{6 The -12} arylene group and the 5-10 membered heteroarylene group are each optionally substituted with one or more of the following substituents: halogen, OH, CN, NO ₂ , C _1-6 alkyl, C _1-4 Haloalkyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy and NR ³¹ R ³² ;

n, p, and q are each independently 0, 1 or 2 each time they appear;

R ³⁰ , R ³⁷ , R ³⁹ and R ⁴⁰ are each independently selected from H, C _1-8 alkyl (e.g. C _1-6 alkyl or C _1-4 alkyl), C _1-8 alkoxy (e.g. C _{1- 6} alkoxy or C _1-4 alkoxy), C _3-8 cycloalkyl, 4-10 membered heterocyclyl, C _6-12 aryl, 5-10 membered heteroaryl, -C _1-8 alkyl-C _6-12 aryl and -C _1-8 alkyl-(5-10 membered heteroaryl), wherein the C _1-8 alkyl, C _1-8 alkoxy, C _3-8 cycloalkyl, 4-10 membered heterocyclic group, C _6-12 aryl, 5-10 membered heteroaryl, -C _1-8 alkyl-C _6-12 aryl and -C _1-8 Alkyl-(5-10 membered heteroaryl) are each optionally substituted with one or more of the following substituents: OH, CN, NO ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, halogen, C _1-4 haloalkoxy, CO ₂ (C _1-6 alkyl), CONR ³¹ R ³² , NR ³¹ R ³² , NR ³³ C(O)R ³⁴ , S(O ) R ³⁵ , S(O) ₂ R ³⁵ , S(O)NR ³¹ R ³² and S(O) ₂ NR ³¹ R ³² ;

R ³¹ , R ³² , R ³³ and R ³⁴ are each independently selected from H, C _1-8 alkyl, C _1-8 alkoxy, C _3-8 cycloalkyl, 4-10 membered heterocyclic group, C _6-12 aryl and 5-10 membered heteroaryl, or R ³¹ and R ³² together with the N atom to which they are attached form a 4-8 membered heterocyclic group, or R ³³ and R ³⁴ and the C to which they are each attached Together with the N atom to form a 4-8 membered heterocyclic group, wherein the C _1-8 alkyl group, C _1-8 alkoxy group, C _3-8 cycloalkyl group, 4-8 membered heterocyclic group, 4-10 Each of the membered heterocyclic group, C _6-12 aryl group and 5-10 membered heteroaryl group is optionally substituted by one or more of the following substituents: OH, CN, halogen, NO ₂ , C _1-4 alkyl , C _1-4 alkoxy, C _1-4 hydroxyalkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, 4-10 membered heterocyclic group, C _6-12 aryl and 5-10 Yuan heteroaryl

R ^{35 is} selected from C _1-8 alkyl, C _1-8 alkoxy, C _3-8 cycloalkyl, 4-10 membered heterocyclic group, C _6-12 aryl, 5-10 membered heteroaryl, -C _1-8 alkyl-C _6-12 aryl and -C _1-8 alkyl-(5-10 membered heteroaryl), wherein the C _1-8 alkyl, C _1-8 alkoxy , C _3-8 cycloalkyl, 4-10 membered heterocyclyl, C _6-12 aryl and 5-10 membered heteroaryl are each optionally substituted by one or more of the following substituents: OH, CN , NO ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, halogen, C _1-4 haloalkoxy, CO ₂ (C _1-6 alkyl), CONR ³¹ R ³² , NR ³¹ R ³² , NR ³³ C(O)R ³⁴ , S(O)Me, S(O) ₂ Me, S(O)NR ³¹ R ³² and S(O) ₂ NR ³¹ R ³² , where R ³¹ , R ³² , R ³³ and R ³⁴ are as defined above;

R ^36a and R ^{36b are the} same or different and are each independently selected from H, C _1-8 alkyl and C _1-8 alkoxy, wherein the C _1-8 alkyl and C _1-8 alkoxy are each independently Optionally substituted by one or more of the following groups: OH, CN, halogen, NH ₂ , NHCH ₃ and N(CH ₃ ) ₂ , or R ^36a and R ^36b together with the C atom to which they are attached form a 3- 7-membered cycloalkyl or heterocyclic group;

R ^{38 is} selected from H, OH, CN, NO ₂ , S(O)R ³⁵ and S(O) ₂ R ³⁵ ;

R ^41a and R ^41b are each independently selected from H, C _1-6 alkyl, C _1-6 alkoxy and C _3-8 cycloalkyl, or R ^41a and R ^41b form together with the N atom to which they are attached 4-7 membered heterocyclic group, wherein the C _1-6 alkyl group, C _1-6 alkoxy group, C _3-8 cycloalkyl group and 4-7 membered heterocyclic group may optionally be selected from the following groups One or more of the substitutions: OH, CN and NR ³¹ R ³² ; and

When multiple R ³⁰ exist at the same time, each R ³⁰ may be the same or different;

When multiple R ³¹ exist at the same time, each R ³¹ may be the same or different;

When multiple R ³² exist at the same time, each R ³² may be the same or different;

When multiple R ³³ exist at the same time, each R ³³ may be the same or different;

When multiple R ³⁴ exist at the same time, each R ³⁴ may be the same or different;

When multiple R ³⁵ exist at the same time, each R ³⁵ may be the same or different;

When multiple R ³⁷ exist at the same time, each R ³⁷ may be the same or different;

When multiple R ³⁸ exist at the same time, each R ³⁸ may be the same or different;

When multiple R ³⁹ exist at the same time, each R ³⁹ may be the same or different;

When multiple R ⁴⁰ exist at the same time, each R ⁴⁰ may be the same or different.

In some embodiments, the present invention provides a compound having a structure represented by formula IV, stereoisomers, tautomers or mixtures thereof, pharmaceutically acceptable salts, co-crystals, Polymorphs or solvates, or stable isotope derivatives, metabolites or prodrugs of said compounds:

Wherein R ¹ , L ² and R ³ are as defined in formula III.

In some embodiments, the present invention provides a compound having a structure represented by formula IV-A, a stereoisomer, a tautomer of the compound, or a mixture thereof, a pharmaceutically acceptable salt, or a mixture of the compound Crystals, polymorphs or solvates, or stable isotope derivatives, metabolites or prodrugs of said compounds:

Where L ² and R ³ are as defined in formula III.

In the above general formulas, R ³ is preferably independently selected from H, halogen, CN, C _1-6 alkyl, C _3-6 cycloalkyl, 4-7 membered heterocyclic group, C _{6 each occurrence -10} aryl, 5-6 membered heteroaryl, CO ₂ R ³⁰ , C(O)NR ³¹ R ³² , NR ³³ C(O)R ³⁴ , NR ³¹ R ³² , S(O) ₂ R ³⁵ , OR ³⁷ , SR ³⁷ , C(O)R ³⁰ , OC(O)R ³⁰ , NR ³³ C(O)NR ³¹ R ³² and S(O) ₂ NR ³¹ R ³² , wherein the C _1-6 alkyl group, C _3-6 cycloalkyl, 4-7 membered heterocyclyl, C _6-10 aryl and 5-6 membered heteroaryl are each optionally substituted with one or more of the following substituents: halogen, CN, C _1-4 alkyl, C _3-6 cycloalkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, 4-7 membered heterocyclic group, C _6-10 aryl, 5-6 membered hetero Aryl, CO ₂ R ³⁰ , C(O)R ³⁰ , C(O)NR ³¹ R ³² , NR ³³ C(O)R ³⁴ , NR ³¹ R ³² , S(O) ₂ R ³⁵ , S(O) ₂ NR ³¹ R ³² , OR ³⁷ , SR ³⁷ and NR ³³ C(O)NR ³¹ R ³² ;

Preferably, ^{each occurrence of R 3} is independently selected from H, CN, C _1-6 alkyl, C _3-6 cycloalkyl, 4-7 membered heterocyclyl, C _6-10 aryl, 5- 6-membered heteroaryl, NR ³³ C(O)R ³⁴ , OR ³⁷ , SR ³⁷ , C(O)R ³⁰ and OC(O)R ³⁰ , wherein the C _1-6 alkyl group, C _3-6 ring The alkyl group, 4-7 membered heterocyclic group, C _6-10 aryl group and 5-6 membered heteroaryl group are each optionally substituted with one or more of the following substituents: CN, C _1-4 alkyl and CO ₂ R ³⁰ , R ³⁰ and R ³⁷ are each independently selected from H, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, 4-10 membered heterocyclic group, C _{6 -12} aryl group and 5-10 membered heteroaryl group, wherein the C _1-6 alkyl group, C _1-6 alkoxy group, C _3-8 cycloalkyl group, 4-10 membered heterocyclic group, C _{6- 12} aryl and 5-10 membered heteroaryl are each optionally substituted by one or more of the following substituents: OH, CN, NO ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, halogen and C _1-4 haloalkoxy, and R ³³ and R ³⁴ are each independently selected from H, C _1-6 alkyl, C _1-6 alkoxy and C _3-6 cycloalkane Group, wherein the C _1-6 alkyl group, C _1-6 alkoxy group and C _3-6 cycloalkyl group are each optionally substituted with one or more of the following substituents: OH, CN, halogen, NO _2. C _1-4 alkyl, C _1-4 alkoxy, C _1-4 hydroxyalkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, 4-10 membered heterocyclic group, C _{6 --12} aryl and 5-10 membered heteroaryl;

More preferably, R ³ is independently selected from H, OH, CN, N(CH ₃ )C(O)CH ₃ , N(CH ₃ )C(O)CH ₂ CH ₃ , N(CH ₃ ) C(O)-cyclopropyl and the following groups each optionally substituted with one or more of hydroxy, methyl and CN: methyl, ethyl, propyl, cyclopropyl, cyclobutyl , Cyclopentyl, tetrahydrofuranyl, morpholino, tetrahydropyranyl, isoxazolyl, pyrazolyl and piperidinyl.

In the above general formulas, preferably, L does not exist or is -L ¹ -L ² -, wherein L ¹ is NH or N(CH ₃ ), and L ² does not exist or is selected from C _1-4 alkylene , C _1-4 alkyleneoxy and C _3-6 cycloalkylene.

In the above general formulas, preferably, L does not exist or is -L ¹ -L ² -, where L ¹ is NH or N(CH ₃ ), and L ² does not exist or is selected from methylene, ethylene , Propylene, butylene, methyleneoxy, ethyleneoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, ring Propyl, cyclobutylene, cyclopentylene and cyclohexylene.

In the above general formulas, -LR ³ or -NH-L ² -R ³ is preferably selected from:

In certain embodiments of the present invention, the compounds of the present invention and pharmaceutically acceptable salts thereof include, but are not limited to:

Composition, preparation and use

In another aspect, the present invention provides a pharmaceutical composition comprising a compound as described above, a stereoisomer, a tautomer of the compound, or a mixture thereof, a pharmaceutically acceptable salt, or a mixture of the compound Crystals, polymorphs or solvates, or stable isotope derivatives, metabolites or prodrugs of said compounds. Optionally, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.

In some embodiments, the pharmaceutical composition is used to prevent and/or treat diseases related to NLRP3 inflammasome activity (e.g., tumor diseases).

In another aspect, the present invention provides a pharmaceutical preparation, which comprises the compound as described above, a stereoisomer, a tautomer of the compound, or a mixture thereof, a pharmaceutically acceptable salt, a co-crystal of the compound , Polymorphs or solvates, or stable isotope derivatives, metabolites or prodrugs of the compound, or comprise the above-mentioned pharmaceutical composition.

In another aspect, the present invention provides a compound as described above, a stereoisomer, a tautomer or a mixture of the compound, a pharmaceutically acceptable salt, co-crystal, and polymorph of the compound Or solvates, stable isotope derivatives, metabolites or prodrugs of the compounds, or the use of the above-mentioned pharmaceutical composition for the preparation of medicines for the prevention and/or treatment of NLRP3 inflammasomes Activity-related diseases (e.g. tumor diseases).

In another aspect, the present invention provides a compound as described above, a stereoisomer, a tautomer or a mixture of the compound, a pharmaceutically acceptable salt, co-crystal, and polymorph of the compound Or solvates, stable isotope derivatives, metabolites or prodrugs of the compounds, or pharmaceutical compositions as described above, which are used to prevent and/or treat diseases related to NLRP3 inflammasome activity (such as tumor diseases) ).

In another aspect, the present invention provides a compound as described above, a stereoisomer, a tautomer or a mixture of the compound, a pharmaceutically acceptable salt, co-crystal, and polymorph of the compound Or solvates, stable isotope derivatives, metabolites or prodrugs of the compounds, or the use of the pharmaceutical composition as described above for the preparation of preparations for regulating (for example, increasing) NLRP3 inflammasome active.

In some embodiments, the formulation is administered to a subject (e.g., a mammal, including, for example, bovine, equine, ovine, swine, canine, feline, rodent, Primates (such as humans) in vivo to increase the NLRP3 inflammasome activity in the cells of the subject. Alternatively, the formulation is administered to cells in vitro (e.g., cell lines or cells from a subject) to increase the activity of NLRP3 inflammasomes in the cells.

In another aspect, the present invention provides a method for modulating (e.g. increasing) the activity of NLRP3 inflammasome in a cell, which comprises administering to the cell an effective amount of a compound as described above, stereoisomers, tautomers of the compound Isomers or mixtures thereof, pharmaceutically acceptable salts, co-crystals, polymorphs or solvates of said compounds, stable isotope derivatives, metabolites or prodrugs of said compounds, drugs as described above Composition, or pharmaceutical formulation as described above.

In another aspect, the present invention provides a kit for modulating (for example, increasing) the activity of NLRP3 inflammasomes, the kit comprising a compound as described above, stereoisomers and tautomers of the compound Or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, a stable isotope derivative, metabolite or prodrug of the compound, the pharmaceutical composition as described above, Or a pharmaceutical formulation as described above.

In another aspect, the present invention provides a method for treating and/or preventing diseases (such as tumor diseases) associated with NLRP3 inflammasome activity, which comprises administering to a subject in need thereof a therapeutically and/or preventively effective amount of the above The compound, the stereoisomer, tautomer or mixture of the compound, the pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, Stable isotope derivatives, metabolites or prodrugs, pharmaceutical compositions as described above, or pharmaceutical formulations as described above.

In the present invention, the tumor diseases include, but are not limited to: brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, intrauterine cancer Membranous cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, female reproductive tract cancer, carcinoma in situ, lymphoma, neurofibroma, thyroid cancer, bone cancer, skin cancer, brain Cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, prostate tumor, mast cell tumor, multiple myeloma, melanoma, glioma or sarcoma.

In some embodiments, the compounds of the invention are NLRP3 full agonists. In some embodiments, the compounds of the invention are NLRP3 partial agonists.

Detailed description of the invention

Definition of Terms

Unless otherwise defined below, the meanings of all technical and scientific terms used herein are intended to be the same as those commonly understood by those skilled in the art. The reference to the technology used herein is intended to refer to the technology generally understood in the art, including those technical changes or equivalent technology substitutions that are obvious to those skilled in the art. Although it is believed that the following terms are well understood by those skilled in the art, the following definitions are still set forth to better explain the present invention.

The term "agonist" refers to a compound that binds to a receptor and activates it to trigger a downstream biological effect or response, including full agonist and partial agonist. Full agonists can activate the receptor and produce the greatest effect (maximal effect or E _max ). A partial agonist can bind to the receptor and activate it, but compared to a full agonist, it only produces a partial effect. When a full agonist and a partial agonist coexist, the partial agonist can sometimes become a partial antagonist by competing with the full agonist for binding sites on the receptor or by other mechanisms. Efficacy (potency, when by EC ₅₀ (producing 50% of the concentration of compound E _max) measure) a possible partial agonist potency higher or lower than a full agonist. The NLRP3 agonists of the present invention include NLRP3 full agonists and NLRP3 partial agonists.

The full name of the term "NLRP3" is NLR family pyrin domain containing 3, which is an inflammasome. In the present invention, when referring to "NLRP3", the meaning includes NLRP3 nucleic acid, polynucleotide, oligonucleotide, sense and antisense polynucleotide chain, complementary sequence, short peptide, polypeptide , Proteins, homologous or heterologous molecules, subtypes, precursors, mutants, variants, derivatives, various splicing bodies, alleles, different species and activation fragments, etc.

The terms "including", "including", "having", "containing" or "involving" and other variants herein are inclusive or open-ended, and do not exclude other unlisted elements Or method steps.

The term "halo" refers to substitution by a halogen atom, and the "halogen" includes F, Cl, Br, or I.

The term "alkyl" refers to a linear or branched saturated aliphatic hydrocarbon group. The terms "C _1-15 alkyl", "C _1-8 alkyl", "C _1-6 alkyl" and "C _1-4 alkyl" respectively refer to having 1 to 15 carbon atoms, 1 to 8 Carbon atoms, linear or branched alkyl groups of 1 to 6 carbon atoms and 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl Group, tert-butyl, n-pentyl or n-hexyl. The alkyl group may be optionally substituted with one or more (such as 1 to 3) substituents which are the same or different.

The term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a linear or branched saturated hydrocarbon group, which contains the specified number of carbon atoms. For example, the term "C _1-8 alkylene" refers to an alkylene group having 1 to 8 carbon atoms, such as methylene (-CH ₂ -), ethylene (-CH ₂ CH ₂ -), isopropylidene Group (-CH(CH ₃ )CH ₂ -) and so on. The alkylene group may be optionally substituted with one or more (such as 1 to 3) substituents which are the same or different.

The term "haloalkyl" refers to an alkyl group substituted with one or more (such as 1 to 3) identical or different halogen atoms. The terms "C _1-8 haloalkyl", "C _1-6 haloalkyl" and "C _1-4 haloalkyl" refer to having 1 to 8 carbon atoms, 1 to 6 carbon atoms and 1-4 carbon atoms, respectively For example, -CF ₃ , -C ₂ F ₅ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ , -CH ₂ Cl, -CH ₂ CH ₂ CF ₃ and the like.

The term "hydroxyalkyl" refers to a group formed by replacing the hydrogen atom of an alkyl group with one or more hydroxy groups, such as a C _1-4 hydroxyalkyl group or a C _1-3 hydroxyalkyl group, examples of which include but are not limited to hydroxy Methyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, -CH(OH)CH ₃ and so on.

The term "alkenyl" refers to a monovalent linear or branched hydrocarbon group containing one or more carbon-carbon double bonds, such as -CH=CH ₂ , -CH ₂ CH=CH ₂ , -C(CH ₃ )=CH ₂ , -CH ₂ -CH=CH-CH ₃ and so on. The alkenyl group may be optionally substituted with one or more (such as 1 to 3) substituents which are the same or different.

The term "alkenylene" refers to a divalent linear or branched aliphatic hydrocarbon group containing one or more carbon-carbon double bonds, which contains the specified number of carbon atoms, for example, 2 to 8 carbon atoms, such as -CH=CH -, -CH ₂ CH=CH-, -C(CH ₃ )=CH-, etc. The alkenylene group may be optionally substituted with one or more (such as 1 to 3) substituents which are the same or different.

The term "alkynyl" refers to a monovalent linear or branched hydrocarbon group with one or more carbon-carbon triple bonds, including but not limited to ethynyl, 2-propynyl, 2-butynyl and 1,3-butynyl Dialkynyl and so on. The alkynyl group may be optionally substituted with one or more (such as 1 to 3) substituents which are the same or different.

等。所述亚炔基可以任选地被一个或多个(诸如1至3个)相同或不同的取代基取代。 The term "alkynylene" refers to a divalent straight or branched chain hydrocarbon group with one or more carbon-carbon triple bonds, which contains the specified number of carbon atoms, such as 2 to 8 carbon atoms, including but not limited to

Wait. The alkynylene group may be optionally substituted with one or more (such as 1 to 3) substituents which are the same or different.

The term "alkoxy" means a group in which an oxygen atom is inserted at any reasonable position of an alkyl group (as defined above), for example, C _1-8 alkoxy, C _1-6 alkoxy, C _1-4 Alkoxy or C _1-3 alkoxy. Representative examples of C _1-6 alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy Group, hexyloxy group, -CH ₂ -OCH ₃ and so on. The alkoxy group may be optionally substituted with one or more (such as 1 to 3) substituents which are the same or different.

The term "alkyleneoxy" refers to a divalent alkoxy group, such as -OCH ₂ -, -OCH(CH ₃ )CH ₂ -, -OCH ₂ CH ₂ O-, -CH ₂ CH ₂ O-, etc., The alkyleneoxy group may be optionally substituted with one or more (such as 1 to 3) substituents which are the same or different.

The term "condensed ring" or "fused ring" refers to a ring system formed by two or more ring structures sharing two adjacent atoms with each other.

The term "spirocyclic ring" refers to a ring system formed by two or more cyclic structures sharing one ring atom with each other.

The term "bridged ring" refers to a ring system formed by two or more ring structures sharing two atoms that are not directly connected to each other.

The term "cycloalkyl" refers to saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring groups, including but not limited to monocyclic alkyl groups (such as cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl) and bicyclic alkyl groups, including spirocyclic, fused ring (fused ring) or bridged ring systems (ie, spirocyclic alkyl, fused ring (fused ring) alkyl And bridged cycloalkyl groups, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, etc.). In the present invention, the cycloalkyl group may be optionally substituted by one or more (such as 1 to 3) substituents which are the same or different. The carbon atom on the cycloalkyl group is optionally substituted with an oxo group (ie forming C=O).

The term "3-7 membered cycloalkyl" refers to a cycloalkyl group having 3 to 7 ring-forming carbon atoms, which may be a monocyclic alkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclo The heptyl group may also be a bicyclic alkyl group, such as a C _5-7 spirocycloalkyl group, a C _5-7 bridged cycloalkyl group or a C _4-7 condensed cycloalkyl group.

The term "C _3-8 cycloalkyl" refers to a cycloalkyl group having 3 to 8 ring-forming carbon atoms, such as a C _3-6 cycloalkyl group, which may be a monocyclic alkyl group, such as cyclopropyl, cyclobutyl , Cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, it can also be a bicyclic alkyl group, such as C _3-8 spirocycloalkyl, C _3-8 bridged cycloalkyl, C _3-8 condensed cycloalkyl , C _3-6 spirocycloalkyl, C _3-6 bridged cycloalkyl or C _3-6 condensed cycloalkyl.

The term "cycloalkylene" refers to a cycloalkyl group as defined herein, which has two monovalent group centers obtained by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent cycloalkyl group. Typical cycloalkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclooctylene, cyclononylidene, cyclohexenylene, etc. .

The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic group having a conjugated π-electron system. As used herein, the term "C _6-12 aryl group" means an aryl group containing 6 to 12 carbon atoms, such as a C _6-10 aryl group, and specific examples are phenyl or naphthyl. The aryl group is optionally substituted with one or more (such as 1 to 3) identical or different substituents (for example, halogen, OH, CN, NO ₂ , C ₁ -C ₆ alkyl, etc.).

The term "arylene" refers to an aryl group as defined herein, which has two monovalent group centers obtained by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent aryl group. Typical arylene groups include, but are not limited to, phenylene and naphthylene.

The term "aryl and cycloalkyl" refers to a fused ring group formed by aryl and cycloalkyl (such as monocyclic alkyl) sharing two adjacent atoms with each other, wherein the point of attachment to other groups can be at the aromatic On the base or on the cycloalkyl group. The term "9-12 membered aryl and cycloalkyl" refers to an aryl and cycloalkyl group containing 9-12 ring atoms in total, such as phenyl and cyclopentyl, phenyl and cyclohexyl, such as

The term "heterocyclyl" refers to having 2 or more (for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) carbon atoms, and one or more ( For example, 1, 2, 3, or 4) heteroatom monocyclic or polycyclic (for example, fused ring, spiro ring or bridged ring) group, the heteroatom includes but not limited to oxygen atom, nitrogen atom or sulfur Atoms, carbon atoms and heteroatoms on the heterocyclic group are optionally substituted with oxo groups (for example, forming C=O, S(=O) or S(=O) ₂ ).

The term "heterocyclylene" refers to a heterocyclic group as defined herein, which has the same carbon atom or two different carbon atoms, one carbon atom and one heteroatom, or two heteroatoms removed from the parent heterocyclic group. Two monovalent group centers derived from a hydrogen atom.

等。 The term "3-14 membered heterocyclic group" means a heterocyclic group containing 3-14 ring atoms, including but not limited to 4-10 membered heterocyclic group, 4-7 membered heterocyclic group, 5-6 membered heterocyclic group Group, 4-7 membered nitrogen-containing heterocyclic group, 4-7 membered oxygen-containing heterocyclic group, 4-7 membered sulfur-containing heterocyclic group, 5-6 membered nitrogen-containing heterocyclic group, 5-6 membered oxygen-containing heterocyclic group Group, 5-6 membered sulfur-containing heterocyclic group, etc., the "nitrogen-containing heterocyclic group", "oxygen-containing heterocyclic group" and "sulfur-containing heterocyclic group" each optionally further contain one or more Other heteroatoms of oxygen, nitrogen and sulfur. Examples of 3-14 membered heterocyclic groups include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuryl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, Pyrazolyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl,

Wait.

等。 In the present invention, the heterocyclic group also includes a fused ring structure, and the point of connection between the fused ring structure and other groups can be on any ring in the fused ring structure. Therefore, the heterocyclic group of the present invention also includes (but is not limited to) heterocyclic group and heterocyclic group, heterocyclic group and cycloalkyl group, single heterocyclic group and single heterocyclic group, single heterocyclic group and monocyclic alkyl group. , Such as 3-7 membered (mono) heterocyclyl and 3-7 membered (mono) heterocyclyl, 3-7 membered (mono) heterocyclyl and (mono) cycloalkyl, 3-7 membered (mono) hetero Cyclic and C _4-6 (mono)cycloalkyl, etc., examples of which include, but are not limited to, pyrrolidinocyclopropyl, cyclopentylazacyclopropyl, pyrrolidinocyclobutyl, pyrrolidinyl Pyrrolidinyl, pyrrolidinopiperidinyl, pyrrolidinopiperazinyl, piperidinomorpholinyl,

Wait.

In the present invention, heterocyclic groups also include bridged heterocyclic groups and spiro heterocyclic groups.

等。所述“含氮桥杂环基”、“含氧桥杂环基”和“含硫桥杂环基”各自任选地还含有一个或多个选自氧、氮和硫的其他杂原子。 The term "bridged heterocyclyl" refers to two saturated rings that share two ring atoms that are not directly connected and contain one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen atoms, Nitrogen atom or sulfur atom), including but not limited to 7-10 membered heterocyclic group, 8-10 membered heterocyclic group, 7-10 membered nitrogen-containing bridged heterocyclic group, 7-10 membered oxygen-containing Bridged heterocyclic group, 7-10 membered sulfur-containing bridged heterocyclic group, etc., for example

Wait. The "nitrogen-containing bridged heterocyclic group", "oxygen-containing bridged heterocyclic group" and "sulfur-containing bridged heterocyclic group" each optionally further contain one or more other heteroatoms selected from oxygen, nitrogen and sulfur.

等。所述“含氮螺杂环基”、“含氧螺杂环基”和“含硫螺杂环基”各自任选地还含有一个或多个选自氧、氮和硫的其他杂原子。术语“6-10元含氮螺杂环基”是指含有共计6-10个环原子并且其中至少一个环原子为氮原子的螺杂环基。 The term "spiroheterocyclic group" refers to two or more saturated rings that share one ring atom and contain one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen atoms, Nitrogen atom, sulfur atom) ring structure, including but not limited to 5-10 membered spiro heterocyclic group, 6-10 membered spiro heterocyclic group, 6-10 membered nitrogen-containing spiro heterocyclic group, 6-10 membered oxygen-containing Spiro heterocyclic group, 6-10 membered sulfur-containing spiro heterocyclic group, etc., for example

Wait. The "nitrogen-containing spiro heterocyclic group", "oxygen-containing spiro heterocyclic group" and "sulfur-containing spiro heterocyclic group" each optionally further contain one or more other heteroatoms selected from oxygen, nitrogen and sulfur. The term "6-10 membered nitrogen-containing spiroheterocyclic group" refers to a spiroheterocyclic group containing 6-10 ring atoms in total and at least one of which is a nitrogen atom.

The term "aryl and heterocyclic group" refers to a cyclic group formed by an aryl group and a heterocyclic group sharing two adjacent carbon atoms with each other (wherein the aryl group and the heterocyclic group are as defined above), which is combined with other groups. The point of attachment of the group may be on an aryl group or a heterocyclic group. For example, as used herein, the term "9-12 membered aryl and heterocyclyl" means an aryl and heterocyclyl group containing a total of 9-12 ring atoms, including but not limited to 9-10 membered Benzoheterocyclic group, such as benzo 5-8 membered heterocyclic group, such as benzo 5-6 membered heterocyclic group, such as benzo 5-6 membered monoheterocyclic group, benzo 5-6 membered nitrogen-containing monohetero Cyclic group, benzo 5-6 membered oxygen-containing monoheterocyclic group, benzo 5-6 membered sulfur-containing heterocyclic group, etc. Each of the "nitrogen-containing heterocyclic group", "oxygen-containing heterocyclic group" and "sulfur-containing heterocyclic group" optionally further contains one or more other heteroatoms selected from oxygen, nitrogen and sulfur. The carbon atoms and heteroatoms on the heterocyclic group are optionally substituted with oxo groups (for example, forming C=O, S(=O) or S(=O) ₂ ). Examples of aryl and heterocyclic groups include, but are not limited to: indazolyl,

The term "heteroaryl" refers to a monocyclic or polycyclic aromatic group containing one or more identical or different heteroatoms, including monocyclic heteroaryl groups and aromatic groups containing at least one heteroaromatic ring (an aromatic group containing at least one heteroatom Ring system), which may have 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, such as 5, 6, 7, 8, 9 or 10 Ring atom. The heteroatom may be oxygen, nitrogen or sulfur. The carbon atoms and heteroatoms on the heteroaryl group are optionally substituted with oxo groups (for example, forming C=O, S(=O) or S(=O) ₂ ).

The term "heteroarylene" refers to a heteroaryl group as described above, which has two hydrogen atoms removed from the same carbon atom or two different carbon atoms of the parent heteroaryl group or one hydrogen atom removed from the carbon atom And two monovalent group centers are obtained by removing one hydrogen atom from the nitrogen atom.

The term "5-10 membered heteroaryl" means a heteroaryl group containing 5 to 10 ring atoms, including 5-6 membered heteroaryl, 5-6 membered monoheteroaryl, 5-10 membered nitrogen-containing heteroaryl Group, 5-10 member oxygen-containing heteroaryl group, 5-10 member sulfur-containing heteroaryl group, 5-6 member nitrogen-containing heteroaryl group, 5-6 member oxygen-containing heteroaryl group, 5-6 member sulfur-containing heteroaryl group Group, 5-6 membered nitrogen-containing monoheteroaryl group, 5-6 membered oxygen-containing monoheteroaryl group, 5-6 membered sulfur-containing monoheteroaryl group. The "nitrogen-containing heteroaryl group", "oxygen-containing heteroaryl group", "sulfur-containing heteroaryl group", "nitrogen-containing monoheteroaryl group", "oxygen-containing monoheteroaryl group" and "sulfur-containing monoheteroaryl group" Each of the "radicals" optionally further contains one or more other heteroatoms selected from oxygen, nitrogen, and sulfur. Examples of 5-10 membered heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, Azolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and 5-10 membered cyclic groups containing these groups.

等。 In the present invention, the term "heteroaryl" encompasses a bicyclic structure, that is, heteroaryl (e.g., monoheteroaryl) can be combined with aryl (e.g., monocyclic aryl, e.g., phenyl), heterocyclic group (e.g., monoheterocyclic group). Group), cycloalkyl (e.g. monocycloalkyl) or another heteroaryl group (e.g. another monoheteroaryl) sharing two adjacent atoms with each other to form a combined ring structure, which is the point of attachment to other groups It can be on any heteroaromatic ring or other ring, including but not limited to (mono)heteroaryl and (mono)heteroaryl, (mono)heteroaryl and (monocyclic)aryl, (mono)heteroaryl And (mono)heterocyclyl or (mono)heteroaryl and (mono)cycloalkyl, for example 5-6 membered (mono)heteroaryl and 5-6 membered (mono)heteroaryl, 5-6 membered ( Mono) heteroaryl phenyl, 5-6 membered (mono) heteroaryl and 5-6 membered (mono) heterocyclic group or 5-6 membered (mono) heteroaryl and C _4-6 (mono) ring Alkyl groups (e.g. 5-6 membered heteroaryl and cyclobutyl, 5-6 membered heteroaryl and cyclopentyl or 5-6 membered heteroaryl and cyclohexyl), examples of which include but are not limited to indolyl, Isoindolyl, indazolyl, benzimidazole, quinolinyl, isoquinolinyl,

Wait.

The term "heteroaryl" encompasses aryl-containing fused ring structures, which are also referred to as "aryl and heteroaryl", which refers to aryl (e.g., monocyclic aryl, e.g., phenyl) and heteroaryl (e.g., monocyclic aryl) Heteroaryl groups, such as 5-6 membered mono-heteroaryl groups, can be connected to other groups on the aromatic ring or on the heteroaromatic ring. The "aryl and heteroaryl" includes, but is not limited to, monocyclic aryl and monoheteroaryl. The term "9-12 membered aryl and heteroaryl group" refers to an aryl and heteroaryl group containing a total of 9 to 12 ring atoms, such as a benzo 5-6 membered nitrogen-containing monoheteroaryl group.

The term "heteroaryl" includes a cycloalkyl-containing bicyclic structure, which is also referred to as "heteroaryl and cycloalkyl", which refers to a heteroaryl group (such as a monoheteroaryl group, such as a 5-6 membered monoheteroaryl group). Group) and a cycloalkyl group (for example, a C _4-6 cycloalkyl group). The point of connection with other groups can be on the heteroaromatic ring or on the cycloalkyl group. The "heteroaryl and cycloalkyl" includes, but is not limited to, monoheteroaryl and monocycloalkyl. The term "9-10 membered heteroaryl and cycloalkyl" refers to a heteroaryl and cycloalkyl group containing a total of 9-10 ring atoms, such as 4-6 membered nitrogen-containing monoheteroaryl and C _4-6 mono Cycloalkyl.

The term "substitution" means that one or more (for example, 1, 2, 3, or 4) hydrogens on the designated atom are replaced by a selection from the indicated group, provided that no more than the designated atom is The normal valence in the current situation and the substitution forms a stable compound. Combinations of substituents and/or variables are only permissible when such combinations form stable compounds.

If a substituent is described as "optionally substituted by", the substituent can be (1) unsubstituted or (2) substituted. If the carbon of a substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the carbon (to the extent of any hydrogens present) may each be independently selected optionally Substituent replacement. If the nitrogen of a substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be independently selected optionally Substituent replacement.

If substituents are described as being "independently selected from" a group, then each substituent is selected independently of the other. Therefore, each substituent may be the same or different from another (other) substituent.

As used herein, the term "one or more" means one or more than one under reasonable conditions, such as two, three, four, five, six, seven, eight, nine Or 10.

Unless otherwise specified, as used herein, the point of attachment of a substituent can be from any suitable position of the substituent.

The present invention also includes all pharmaceutically acceptable isotopic compounds of the compounds of the present invention, which are the same as the compounds of the present invention, except that one or more atoms have the same atomic number but the atomic mass or mass number is different from the one that is predominant in nature. Atomic substitution of atomic mass or mass number. Examples of isotopes suitable for inclusion in the compounds of the present invention include (but are not limited to) isotopes of hydrogen (e.g. ² H, ³ H); isotopes of carbon (e.g. ¹¹ C, ¹³ C, and ¹⁴ C); isotopes of chlorine (e.g. ³⁶ Cl); fluorine isotopes (such as ¹⁸ F); iodine isotopes (such as ¹²³ I and ¹²⁵ I); nitrogen isotopes (such as ¹³ N and ¹⁵ N); oxygen isotopes (such as ¹⁵ O, ¹⁷ O and ¹⁸ O ); Phosphorus isotopes (for example ³² P); and Sulfur isotopes (for example ³⁵ S). The term "stable isotope derivative" means that one or more atoms in the compound of the present invention are replaced by atoms having the same atomic number but whose atomic mass or mass number is different from the predominant atomic mass or mass number in nature. The stable compound.

而吡唑环可以下 列互变异构形式平衡存在：

The term "stereoisomer" refers to an isomer formed by a compound containing at least one asymmetric center. In compounds with one or more (for example, 1, 2, 3, or 4) asymmetric centers, it can produce racemic mixtures, single enantiomers, diastereomeric mixtures, and Individual diastereomers. Certain individual molecules can also exist as geometric isomers (cis/trans). The compounds of the present invention may exist in a mixture of two or more different structural forms (commonly referred to as tautomers) in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait. For example, nitroso-oximes can exist in equilibrium in the following tautomeric forms in solution:

The pyrazole ring can exist in equilibrium in the following tautomeric forms:

It is to be understood that the scope of the present application covers all such proportions (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%). %) isomers or mixtures thereof.

Unless otherwise specified, the compounds of the present invention are intended to be stereoisomers (including cis and trans isomers), optical isomers (such as R and S enantiomers), and diastereomers. , Geometric isomers, rotamers, conformational isomers, atropisomers or mixtures thereof. The compounds of the present invention can exhibit more than one type of isomerism, and are composed of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

The present invention covers all possible crystalline forms or polymorphs of the compounds of the present invention, which can be a single polymorph or a mixture of more than one polymorph in any ratio. It should also be understood that certain compounds of the present invention may exist in free form for treatment, or, when appropriate, in the form of their pharmaceutically acceptable derivatives. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to: pharmaceutically acceptable salts, solvates, metabolites or prodrugs, which can be directly or indirectly administered to patients in need thereof. The compound of the present invention or its metabolite or residue is provided. Therefore, when the "compound of the present invention" is referred to herein, it is also intended to encompass the above-mentioned various derivative forms of the compound.

The pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof. For example, hexafluorophosphate, meglumine salt and the like. For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002).

In the present invention, "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle administered with the therapeutic agent, and it is suitable for contact with humans and/or within the scope of reasonable medical judgment Tissues of other animals without excessive toxicity, irritation, allergic reactions, or other problems or complications corresponding to a reasonable benefit/risk ratio.

The pharmaceutically acceptable carriers that can be used in the pharmaceutical composition of the present invention include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, and mineral oil. Oil, sesame oil, etc. When the pharmaceutical composition is administered intravenously, water is an exemplary carrier. It is also possible to use physiological saline and aqueous glucose and glycerol solutions as liquid carriers, especially for injections. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene glycol, water, Ethanol, etc. The composition may also contain small amounts of wetting agents, emulsifiers or pH buffering agents as needed. Oral preparations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

The pharmaceutical composition of the present invention can act systemically and/or locally. For this purpose, they can be administered by suitable routes, such as by injection, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal administration; or by oral, buccal, transnasal, transmucosal, topical, It is administered in the form of ophthalmic preparations or by inhalation.

For these administration routes, the pharmaceutical composition of the present invention can be administered in a suitable dosage form.

The dosage form includes but not limited to tablet, capsule, lozenge, hard candy, powder, spray, cream, ointment, suppository, gel, paste, lotion, ointment, aqueous suspension , Injectable solutions, elixirs, syrups.

The term "effective dose" as used herein refers to the amount of a compound that will relieve one or more symptoms of the condition being treated to a certain extent after being administered.

The dosage regimen can be adjusted to provide the best desired response. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgent need of the treatment situation. It should be noted that the dose value may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It should be further understood that for any particular individual, the specific dosing regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering the composition or supervising the administration of the composition.

The amount of the compound of the present invention administered will depend on the individual being treated, the severity of the disorder or condition, the rate of administration, the treatment of the compound, and the judgment of the prescribing physician. In general, the effective dose is about 0.0001 to about 50 mg per kg body weight per day, for example, about 0.01 to about 10 mg/kg/day (single or divided administration). For a 70 kg person, this would add up to about 0.007 mg/day to about 3500 mg/day, for example, about 0.7 mg/day to about 700 mg/day. In some cases, a dose level not higher than the lower limit of the aforementioned range may be sufficient, while in other cases, a larger dose can still be used without causing any harmful side effects, provided that the larger dose is first The dose is divided into several smaller doses to be administered throughout the day.

The content or amount of the compound of the present invention in the pharmaceutical composition may be about 0.01 mg to about 1000 mg.

Unless otherwise specified, as used herein, the term "treating" means reversing, alleviating, or inhibiting the progress of one or more symptoms of the disorder or condition to which such term is applied.

The term "prevention" means being able to avoid the occurrence of the disease or condition to which such a term is applied.

"Individual" as used herein includes human or non-human animals. Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from diseases such as those described herein. In the present invention, "non-human animals" include all vertebrates, such as non-mammals (such as birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (such as sheep, dogs). , Cats, cows, pigs, etc.).

The compound of the present invention may exist in the form of a solvate (preferably a hydrate), wherein the compound of the present invention contains a polar solvent as a structural element of the compound crystal lattice, in particular, for example, water, methanol or ethanol. The amount of polar solvent, especially water, can be present in a stoichiometric or non-stoichiometric ratio.

Also included within the scope of the present invention are metabolites of the compounds of the present invention, that is, substances formed in the body when the compounds of the present invention are administered. Such products can be produced by, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic hydrolysis, etc. of the administered compound. Therefore, the present invention includes metabolites of the compounds of the present invention, including compounds obtained by contacting the compound of the present invention with a mammal for a time sufficient to produce its metabolites.

The present invention further includes within its scope the prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity, when administered to the body or The above can be converted into the compound of the present invention having the desired activity by, for example, hydrolytic cleavage. Usually such prodrugs will be functional group derivatives of the compound, which are easily converted into the desired therapeutically active compound in vivo. For other information about the use of prodrugs, please refer to "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 ( Edited by EBRoche, American Pharmaceutical Association). The prodrugs of the present invention can be used, for example, by using certain parts known to those skilled in the art as "pro-moiety (for example, "Design of Prodrugs", described in H. Bundgaard (Elsevier, 1985))" It can be prepared by substituting appropriate functional groups present in the compounds of the present invention.

The present invention also encompasses compounds of the present invention containing protecting groups. In any process of preparing the compounds of the present invention, protection of sensitive groups or reactive groups on any relevant molecule may be necessary and/or desirable, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved through conventional protective groups, such as those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P. GMWuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 Protective base. These references are incorporated herein by reference. Using methods known in the art, the protecting group can be removed at an appropriate subsequent stage.

Preparation

Synthesis method of compound II

Route 1

Wherein R ¹ , R ³ and L ^{2 are} as defined in the above formula I, and X is selected from chlorine, bromine and iodine.

The first step: compound II-1 and guanidine carbonate undergo ring closure reaction to produce compound II-2.

In certain embodiments, the solvent that can be used is 1,4-dioxane, dimethyl sulfoxide, DMF, N,N-dimethylacetamide, and the like. In certain embodiments, the reaction temperature is 0°C to 200°C.

The second step: Compound II-2 and R ¹ -boronic acid or R ¹ -boronic acid ester or R ¹ -organotin compound (such as R ¹ Sn(n-Bu) ₃ ) undergo a coupling reaction (such as Suzuki reaction or Stille reaction) ) To produce compound II-3.

In certain embodiments, the catalysts that can be used are Pd(PPh ₃ ) ₄ , Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ and the like. In certain embodiments, the bases that can be used are Cs ₂ CO ₃ , K ₃ PO ₄ , Na ₂ CO ₃ , AcOK, NaHCO ₃ , K ₂ CO ₃ and the like. In certain embodiments, the solvents that can be used are 1,4-dioxane/H ₂ O, DMF/H ₂ O, DMSO/H ₂ O, CH ₃ CN/H ₂ O, toluene/H ₂ O Wait. In certain embodiments, the reaction temperature is between 60°C and 180°C.

The third step: Compound II-3 and R ³ -L ² -PG undergo substitution reaction to produce compound II, where PG is a leaving group, which can be halogen (for example, F, Cl, Br or I) or sulfonate.

In some embodiments, the solvent that can be used is DMF, DMSO, THF, CH ₃ CN, DCM, and the like. In certain embodiments, the base that can be used is sodium hydride, triethylamine, N,N-diisopropylethylamine, potassium tert-butoxide, sodium hydroxide, and the like. In certain embodiments, the reaction temperature is -20°C to 180°C.

Route 2

Wherein R ¹ , R ³ and L ^{2 are} as defined in the above formula I, and X is selected from chlorine, bromine and iodine.

The first step: compound II-4 and chloroformamidine hydrochloride undergo ring closure reaction to produce compound II-5.

In certain embodiments, the solvent that can be used is 1,4-dioxane, dimethyl sulfone, and the like. In certain embodiments, the reaction temperature is 0°C to 200°C.

The second step: Compound II-5 and R ³ -L ² -NH ₂ undergo condensation reaction to produce compound II-6.

In certain embodiments, condensing agents that can be used are BOP, pyBOP, HOBT, HATU, HBTU, TBTU, and the like. In certain embodiments, the bases that can be used are DBU, DIPEA, K ₃ PO ₄ , Na ₂ CO ₃ , AcOK, NaHCO ₃ and the like. In certain embodiments, the reaction temperature is 0°C to 180°C.

The third step: Compound II-6 and R ¹ -boronic acid or R ¹ -boronic acid ester or R ¹ -organotin compound (such as R ¹ Sn(n-Bu) ₃ ) undergo a coupling reaction (such as Suzuki reaction or Stille reaction) ), to produce compound II.

In certain embodiments, the catalysts that can be used are Pd(PPh ₃ ) ₄ , Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ and the like. In certain embodiments, the bases that can be used are Cs ₂ CO ₃ , K ₃ PO ₄ , Na ₂ CO ₃ , AcOK, NaHCO ₃ , K ₂ CO ₃ and the like. In some embodiments, the solvents that can be used are 1,4-dioxane/H ₂ O, DMF/H ₂ O, DMSO/H ₂ O, CH ₃ CN/H ₂ O, toluene/H ₂ O Wait. In certain embodiments, the reaction temperature is 60°C to 180°C.

Synthesis method of compound IV

Route 3

Wherein R ¹ , R ³ and L ^{2 are} as defined in the above formula III, and X is selected from chlorine, bromine and iodine.

The first step: compound IV-1 and chloroformamidine hydrochloride undergo ring closure reaction to produce compound IV-2.

In certain embodiments, the solvent that can be used is 1,4-dioxane, dimethyl sulfone, and the like. In certain embodiments, the reaction temperature is 0°C to 200°C.

The second step: Compound IV-2 and R ³ -L ² -NH ₂ undergo condensation reaction to produce compound IV-3.

In certain embodiments, condensing agents that can be used are BOP, pyBOP, HOBT, HATU, HBTU, TBTU, and the like. In certain embodiments, the bases that can be used are DBU, DIPEA, K ₃ PO ₄ , Na ₂ CO ₃ , AcOK, NaHCO ₃ and the like. In certain embodiments, the reaction temperature is 0°C to 180°C.

The third step: Compound IV-3 and R ¹ -boronic acid or R ¹ -boronic acid ester or R ¹ -organotin compound (such as R ¹ Sn(n-Bu) ₃ ) undergo coupling reaction (such as Suzuki reaction or Stille reaction ) To generate compound IV.

In certain embodiments, the catalysts that can be used are Pd(PPh ₃ ) ₄ , Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ and the like. In certain embodiments, the bases that can be used are Cs ₂ CO ₃ , K ₃ PO ₄ , Na ₂ CO ₃ , AcOK, NaHCO ₃ , K ₂ CO ₃ and the like. In certain embodiments, the solvents that can be used are 1,4-dioxane/H ₂ O, DMF/H ₂ O, DMSO/H ₂ O, CH ₃ CN/H ₂ O, toluene/H ₂ O Wait. In certain embodiments, the reaction temperature is between 60°C and 180°C.

Beneficial effect

The compound of the present invention has obvious agonistic activity on NLRP3 and its signal pathway, without obvious toxic side effects, and can be used for the treatment of diseases related to NLRP3 inflammatory body activity, such as abnormal cell proliferation diseases (e.g. cancer).

Example

The present invention is further described below in conjunction with examples, but the provision of these examples is not intended to limit the scope of the present invention.

The abbreviations in the present invention have the following meanings:

The structure of the compound was identified by nuclear magnetic resonance spectroscopy ( ¹ H NMR) and/or mass spectrometry (MS).

¹ H NMR chemical shifts (δ) are reported in parts per million (ppm). ¹ H NMR was measured by Bruker superconducting nuclear magnetic resonance spectrometer (model AVACE III HD 400MHz), the solvent was CD ₃ OD, CDCl ₃ or DMSO-d ₆ , and the internal standard was TMS. s: singlet, d: doublet, t: triplet, q: quartet, dd: doublet, qd: quartet, m: multiplet, br: broad, J : Coupling constant, Hz: Hertz.

The monitoring of the reaction is carried out by TLC or LC-MS.

TLC uses silica gel GF 254 as the stationary phase.

LC-MS uses Aglient 1260 Infinity/Aglient 6120 Quadrupole mass spectrometer to record.

The compound can be separated and purified by preparative TLC, silica gel column chromatography, Prep-HPLC and/or flash column chromatography (Flash column chromatography).

Prep-HPLC uses Agilent 1260 preparative liquid chromatograph, the detection wavelength is 214nm or 254nm; the chromatographic column is Waters SunFire Prep C18 OBD (19mm×150mm×5.0μm); the column temperature is 25℃, and the elution conditions are as follows:

Condition 1: 10%-90% acetonitrile and 90%-10% ammonium formate aqueous solution (0.05%), 0-16min; flow rate: 24mL/min;

Condition 2: 10%-46% acetonitrile and 90%-54% ammonium bicarbonate aqueous solution (0.05%), 0-7.2min; flow rate: 24mL/min;

Condition 3: 10%-90% acetonitrile and 90%-10% formic acid aqueous solution (0.05%), 0-16min; flow rate: 28mL/min;

Condition 4: 10%-90% acetonitrile and 90%-10% ammonium bicarbonate aqueous solution (0.05%), 0-16min; flow rate: 28mL/min;

Condition 5: 10%-60% acetonitrile and 90%-40% formic acid aqueous solution (0.05%), 0-16min; flow rate: 28mL/min;

Condition 6: 5%-95% acetonitrile and 95%-5% formic acid aqueous solution (0.05%), 0-20min; flow rate: 28mL/min.

Condition 7: 0%-50% acetonitrile and 100%-50% ammonium bicarbonate aqueous solution (0.05%), 0-20min; flow rate: 28mL/min.

Silica gel column chromatography generally uses 200-300 mesh silica gel (Qingdao Ocean) as the stationary phase. Eluent system A: dichloromethane and methanol; eluent system B: petroleum ether and ethyl acetate; the volume ratio of the solvent is adjusted according to the polarity of the compound.

The flash column chromatography uses the Biotage flash column chromatograph.

The microwave reaction was carried out using BiotageInitiator+microwave reactor.

In the following examples, unless otherwise specified, the reaction temperature is room temperature (15°C to 30°C).

The reagents used in this application are purchased from companies such as Acros Organics, Aldrich Chemical Company, or Terb Chemical.

Example 1: 3-((2-Amino-7-(1H-pyrazol-5-yl)quinazolin-4-yl)amino)-1-propanol formate (Compound 1s)

The first step: 7-bromoquinazoline-2,4-diamine (compound 1b)

Compound 1a (2g), guanidine carbonate (4.68 g) was added DMA (20mL), the under N ₂ the reaction was heated to 150 deg.] C 8h. Water and ethyl acetate were added for extraction, and the organic phase was concentrated. Add appropriate amount of dichloromethane, stir for several minutes, and filter. The filter cake was dried to obtain compound 1b (1.5 g).

MS(ESI,m/z):241.2[M+H] ⁺ .

Step 2: 7-(1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinazoline-2,4-diamine (Compound 1c)

Compound 1b (500mg), potassium phosphate (1.11g), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (0.19g), 1-(2-tetrahydropyranyl)-1H-pyrazole-5-boronic acid Pinacolate (0.87g) was added to the mixed solvent of DMF and water (5mL), heated to 100°C and stirred for 3h. Water and ethyl acetate were added for extraction, the organic phase was concentrated to dryness, and then separated and purified by flash column chromatography (eluent system A) to obtain compound 1c (300 mg).

MS(ESI,m/z):311.2[M+H] ⁺ .

The third step: 3-((2-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinazolin-4-yl)amino) -1-propanol (Compound 1d)

Compound 1c (100 mg) was added to DMSO (2 mL), and the temperature was lowered to 0°C. Slowly add NaH (6.17mg), then add 3-bromo-1-propanol (88.96mg), and react at 0°C for 16h. The reaction was quenched by adding water, and the reaction solution was separated and purified by Prep-HPLC (elution condition 3), and lyophilized to obtain compound 1d (30 mg).

MS(ESI,m/z): 369.1[M+H] ⁺ .

The fourth step: 3-((2-amino-7-(1H-pyrazol-5-yl)quinazolin-4-yl)amino)-1-propanol formate (compound 1s)

Compound 1d (30mg) was added to TFA (2mL), and the reaction was stirred at room temperature for 2h. Concentrated under reduced pressure to obtain crude compound 1, which was separated and purified by Prep-HPLC (elution condition 3), and lyophilized to obtain compound 1s (20 mg).

MS(ESI,m/z):285.1[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400MHz) δ 13.21 (s, 1H), 9.02 (s, 1H), 8.22 (d, J = 8.4 Hz, 1H), 7.85-7.76 (m, 5H), 6.86 ( d, 1H), 4.59 (s, 1H), 3.64-3.59 (m, 2H), 3.53-3.50 (m, 2H), 1.85-1.79 (m, 2H).

Example 2: N ⁴ -(2-methoxyethyl)-7-(1H-pyrazol-5-yl)quinazoline-2,4-diamine (Compound 2)

The first step: 2-amino-7-bromoquinazolin-4-ol (compound 2b)

Compound 2a (5.00 g), chloroformamidine hydrochloride (3.90 g), and dimethyl sulfone (12.75 g) were sequentially added to a single-neck flask, and heated to 155° C. for reaction for 2 hours. The reaction solution was suction filtered, the filter cake was transferred to water (0.5L) and smashed and beaten at room temperature for 0.5h. Suction filtration was performed again, the filter cake was washed with water, and dried to obtain compound 2b (4.70 g).

MS(ESI,m/z): 240.0[M+H] ⁺ .

The second step: 7-bromo-N ⁴ -(2-methoxyethyl)quinazoline-2,4-diamine (compound 2c)

At room temperature, compound 2b (55 mg) was added to DMF (3 mL), DBU (104.64 mg) and BOP (121.60 mg) were added successively, and the mixture was stirred for 5 min. Add 2-methoxyethylamine (127mg) and react for 16h. The reaction solution was suction filtered, and the filtrate was separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 2c (8 mg).

MS(ESI,m/z): 296.9[M+H] ⁺ .

The third step: N ⁴ -(2-methoxyethyl)-7-(1H-pyrazol-5-yl)quinazoline-2,4-diamine (compound 2)

Compound 2c (8mg), 1H-pyrazole-5-boronic acid pinacolate (10.45mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (2.20mg) and potassium carbonate (11.16mg) were added to DMF (3mL) In water (0.5mL), heated to 100°C under the protection of _{N 2 to react for 4h.} The reaction solution was filtered through Celite, and the filtrate was separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 2 (4 mg).

MS(ESI,m/z):285.1[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400MHz) δ 12.96 (s, 1H), 8.00 (d, J = 8.5 Hz, 1H), 7.89 (s, 1H), 7.79 (s, 1H), 7.60 (s, 1H),7.49(s,1H),6.80(d,J=2.1Hz,1H),6.10(s,2H),3.69–3.60(m,2H),3.59–3.52(m,2H), 3.29(s ,3H).

Example 3: (1S,2R)-2-((2-amino-7-(1H-pyrazol-5-yl)quinazolin-4-yl)amino)cyclopentanol (compound 3)

The first step: (1S,2R)-2-((2-amino-7-bromoquinazolin-4-yl)amino)cyclopentanol (compound 3a)

At room temperature, compound 2b (50 mg) was added to DMF (3 mL), DIPEA (134.60 mg) and BOP (110.54 mg) were added successively, and stirred for 5 min. (1S, 2R)-2-aminocyclopentanol hydrochloride (86 mg) was added and reacted for 16 h to obtain crude compound 3a, which was directly used in the next reaction.

MS(ESI,m/z):323.0[M+H] ⁺ .

The second step: (1S,2R)-2-((2-amino-7-(1H-pyrazol-5-yl)quinazolin-4-yl)amino)cyclopentanol (compound 3)

To the reaction solution of compound 3a obtained in the first step, 1H-pyrazole-5-boronic acid pinacolate (80.82mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (17mg), K ₂ CO were sequentially added ₃ (86.35mg) and water (0.5mL), heated to 100℃ under the protection of _{N 2 to react for 4h.} The reaction solution was filtered through Celite, and the filtrate was separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 3 (15 mg).

MS(ESI,m/z):311.0[M+H] ⁺ .

¹ H NMR(DMSO-d ₆ ,400MHz)δ12.97(s,1H), 8.14-8.00(m,1H), 7.81(s,1H), 7.61(s,1H), 7.58-7.50(m,1H) ), 7.21 (s, 1H), 6.80 (s, 1H), 6.05 (s, 2H), 4.77 (d, J = 3.6 Hz, 1H), 4.38-4.28 (m, 1H), 4.22-4.15 (m, 1H), 2.00-1.87(m, 1H), 1.84--1.78(m, 2H), 1.70-1.60(m, 1H), 1.58-1.44(m, 1H), 1.27-1.12(m, 1H).

Example 4: (1R,3R)-3-((2-amino-7-(1H-pyrazol-5-yl)quinazolin-4-yl)amino)cyclopentanol formate (compound 4s)

The first step: (1R,3R)-3-((2-amino-7-bromoquinazolin-4-yl)amino)cyclopentanol (compound 4a)

At room temperature, compound 2b (50 mg) was added to DMF (3 mL), DIPEA (134.60 mg) and BOP (110.54 mg) were added successively, and the mixture was stirred for 5 min. (1R, 3R)-3-aminocyclopentanol hydrochloride (86 mg) was added and reacted for 16 h to obtain crude compound 4a, which was directly used in the next reaction.

MS(ESI,m/z):323.0[M+H] ⁺ .

The second step: (1R,3R)-3-((2-amino-7-(1H-pyrazol-5-yl)quinazolin-4-yl)amino)cyclopentanol formate (compound 4s)

To the reaction solution of compound 4a obtained in the first step, 1H-pyrazole-5-boronic acid pinacolate (80.82mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (17mg), K ₂ CO were sequentially added ₃ (86.35mg) and water (0.5mL), heated to 100℃ under the protection of _{N 2 to react for 4h.} The reaction solution was filtered through Celite, and the filtrate containing compound 4 was separated and purified by Prep-HPLC (elution condition 3), and lyophilized to obtain compound 4s (16 mg).

MS(ESI,m/z):311.0[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400MHz) δ 13.12 (s, 1H), 8.30 (s, 1H), 8.15 (d, J = 8.5 Hz, 1H), 8.07 (s, 1H), 7.79 (s, 1H), 7.68 (s, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.10 (s, 2H), 6.82 (d, J = 1.9 Hz, 1H), 4.90-4.77 (m, 1H), 4.32–4.25(m,1H), 2.24–2.10(m,1H), 2.05–1.88(m,2H), 1.88–1.74(m,1H), 1.63–1.43(m,2H).

Example 5: (1S,3S)-3-((2-amino-7-(1H-pyrazol-5-yl)quinazolin-4-yl)amino)cyclopentanol formate (compound 5s)

The first step: (1S,3S)-3-((2-amino-7-bromoquinazolin-4-yl)amino)cyclopentanol (compound 5a)

At room temperature, compound 2b (50 mg) was added to DMF (3 mL), DIPEA (134.60 mg) and BOP (110.54 mg) were added successively, and the mixture was stirred for 5 min. (1S,3S)-3-aminocyclopentanol hydrochloride (86 mg) was added and reacted for 16 h to obtain crude compound 5a, which was directly used in the next reaction.

MS(ESI,m/z):323.0[M+H] ⁺ .

Step 2: (1S,3S)-3-((2-amino-7-(1H-pyrazol-5-yl)quinazolin-4-yl)amino)cyclopentanol formate (compound 5s)

To the reaction solution of compound 5a obtained in the first step, 1H-pyrazole-5-boronic acid pinacolate (80.82mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (17mg), K ₂ CO were sequentially added ₃ (86.35mg) and water (0.5mL), heated to 100℃ under the protection of _{N 2 to react for 4h.} The reaction solution was filtered through Celite, and the filtrate containing compound 5 was separated and purified by Prep-HPLC (elution condition 3), and lyophilized to obtain compound 5s (2 mg).

MS(ESI,m/z):311.0[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400MHz) δ 13.12 (s, 1H), 8.27 (s, 1H), 8.14 (d, J = 8.5 Hz, 1H), 8.00 (s, 1H), 7.78 (s, 1H), 7.67(s,1H), 7.58(d,J=7.8Hz,1H), 7.25–6.70(m,3H), 4.90–4.74(m,1H), 4.34–4.23(m,1H), 2.24 --2.11(m,1H), 2.04–1.88(m,2H), 1.86–1.74(m,1H), 1.62–1.43(m,2H).

Example 6: (R)-1-((2-amino-7-(1H-pyrazol-5-yl)quinazolin-4-yl)amino)-2-propanol formate (compound 6s)

The first step: (R)-1-((2-amino-7-bromoquinazolin-4-yl)amino)-2-propanol (Compound 6a)

At room temperature, compound 2b (200mg), (R)-(-)-1-amino-2-propanol (187.73mg), BOP (442.18mg) and DIPEA (538.37mg) were added to DMF (5mL) to react At 16h, the crude compound 6a was obtained, which was directly used in the next reaction.

MS(ESI,m/z): 298.1[M+H] ⁺ .

The second step: (R)-1-((2-amino-7-(1H-pyrazol-5-yl)quinazolin-4-yl)amino)-2-propanol formate (compound 6s)

To the reaction solution of compound 6a obtained in the first step, potassium carbonate (111.62 mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (21.99 mg) and 1H-pyrazole-5-boronic acid pinacolate were sequentially added (104.48mg), _{heated to 100°C under N 2} protection, and reacted for 3h. The reaction solution was filtered through Celite, and the filtrate containing compound 6 was separated and purified by Prep-HPLC (elution condition 6), and lyophilized to obtain compound 6s (20 mg).

MS(ESI,m/z):285.1[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400MHz) δ 12.93 (s, 1H), 8.46 (s, 1H), 8.35 (s, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.80 (s, 1H), 7.72 (s, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.51-7.08 (m, 2H), 6.84 (d, J = 1.7 Hz, 1H), 3.98 (dq, J = 12.4 ,6.1Hz,1H),3.51(dt,J=10.1,5.1Hz,1H),3.45-3.36(m,1H),1.12(d,J=6.1Hz,3H).

Example 7: 7-(1H-pyrazol-5-yl)-N ⁴ -(tetrahydrofuran-3-yl)quinazoline-2,4-diamine formate (Compound 7s)

The first step: 7-bromo-N ⁴ -(tetrahydrofuran-3-yl)quinazoline-2,4-diamine (compound 7a)

At room temperature, compound 2b (200mg), 3-aminotetrahydrofuran (217.75mg), BOP (442.18mg) and DIPEA (538.37mg) were added to DMF (5mL) and reacted for 16h to obtain crude compound 7a, which was used directly in the next step reaction.

MS(ESI,m/z): 310.1[M+H] ⁺ .

The second step: 7-(1H-pyrazol-5-yl)-N ⁴ -(tetrahydrofuran-3-yl)quinazoline-2,4-diamine formate (7s)

To the reaction solution of compound 7a obtained in the first step, potassium carbonate (107.29mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (21.13mg) and 1H-pyrazole-5-boronic acid pinacolate were sequentially added (100.42mg), heated to 100°C under the protection of _{N 2 and reacted for 3h.} The reaction solution was filtered through Celite, and the filtrate containing compound 7 was separated and purified by Prep-HPLC (elution condition 6), and lyophilized to obtain compound 7s (35 mg).

MS(ESI,m/z): 297.1[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400MHz) δ 13.08 (s, 1H), 8.33 (s, 2H), 8.24 (d, J = 8.5 Hz, 1H), 7.80 (s, 1H), 7.72 (s, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.42-7.12 (m, 2H), 6.83 (t, J = 4.1 Hz, 1H), 4.74 (td, J = 11.6, 5.8 Hz, 1H), 4.02–3.95(m,1H), 3.95–3.89(m,1H), 3.76(dd,J＝14.4,7.9Hz,1H), 3.68(dd,J＝9.0,4.5Hz,1H), 2.26(td, J = 14.3, 7.7 Hz, 1H), 2.07 (td, J = 12.5, 6.5 Hz, 1H).

Example 8: N-(2-((2-amino-7-(1H-pyrazol-5-yl)quinazolin-4-yl)amino)ethyl)-N-methylpropionamide (Compound 8 )

The first step: tert-butyl (2-((2-amino-7-bromoquinazolin-4-yl)amino)ethyl)(methyl)carbamate (compound 8a)

At room temperature, compound 2b (0.50 g) was added to DMF (20 mL), DIPEA (1.88 g) and BOP (1.11 g) were added successively, and the mixture was stirred for 5 min. Continue to add N-Boc-N-methylethylenediamine (1.09g) and react for 16h to obtain the crude compound 8a, which is directly used in the next reaction.

MS(ESI,m/z): 396.1[M+H] ⁺ .

The second step: tert-butyl (2-((2-amino-7-(1H-pyrazol-5-yl)quinazolin-4-yl)amino)ethyl)(methyl)carbamate( Compound 8b)

To the reaction solution of compound 8a obtained in the first step, 1H-pyrazole-5-boronic acid pinacolate (807.20mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (170mg), K ₂ CO were added sequentially. ₃ (862.41mg) and water (3.5mL), heated to 100℃ under the protection of _{N 2 to react for 4h.} The reaction solution was filtered through Celite, the filtrate was separated and purified by Prep-HPLC (elution condition 7), and compound 8b (525 mg) was obtained after concentration.

MS(ESI,m/z): 384.2[M+H] ⁺ .

The third step: N ⁴ -(2-(methylamino)ethyl)-7-(1H-pyrazol-5-yl)quinazoline-2,4-diamine (Compound 8c)

At room temperature, compound 8b (525 mg) was added to DCM (6 mL), and TFA (2 mL) was continuously added, and reacted for 1 h. After concentration, the crude compound 8c (560 mg) was obtained.

MS(ESI,m/z):284.2[M+H] ⁺ .

The fourth step: N-(2-((2-amino-7-(1H-pyrazol-5-yl)quinazolin-4-yl)amino)ethyl)-N-methylpropionamide (Compound 8 )

Compound 8c (100 mg), propionic acid (28.76 mg), HBTU (134.40 mg) and DIPEA (228.07 mg) were added to DMF (2 mL) and reacted for 4 hours. The reaction solution was filtered through Celite, and the filtrate was separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 8 (3 mg).

MS(ESI,m/z): 340.1[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400MHz) δ 13.02 (s, 1H), 8.06-8.04 (m, 1H), 7.93-7.91 (m, 1H), 7.75 (s, 1H), 7.62 (s, 1H) ),7.52-7.50(m,1H),6.81-6.80(m,1H),6.30-6.20(m,2H),3.64-3.45(m,4H),3.01-2.88(m,3H),2.31-2.25 (m,4H),0.97-0.87(m,3H).

Example 9: N-(2-((2-amino-7-(1H-pyrazol-5-yl)quinazolin-4-yl)amino)ethyl)-N-methylacetamide (Compound 9 )

Compound 8c (100 mg), acetic acid (23.31 mg), HBTU (134.40 mg) and DIPEA (228.07 mg) were added to DMF (2 mL) and reacted for 4 hours. The reaction solution was filtered through Celite, and the filtrate was separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 9 (3 mg).

MS(ESI,m/z): 326.1[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400MHz) δ 13.02 (s, 1H), 8.04-7.91 (m, 2H), 7.75 (s, 1H), 7.62 (s, 1H), 7.52-7.50 (m, 1H) ), 6.81-6.80 (m, 1H), 6.20-6.16 (m, 2H), 3.66-3.45 (m, 4H), 3.02-2.87 (m, 3H), 1.97-1.95 (m, 3H).

Example 10: 3-((2-Amino-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidin-4-yl)amino)-1-propanol (Compound 10)

The first step: 2-amino-6-iodothieno[3,2-d]pyrimidin-4-ol (compound 10b)

Compound 10a (1.00 g), chloroformamidine hydrochloride (415.96 mg), and dimethyl sulfone (997.54 mg) were added to the reaction flask and heated to 150° C. for reaction for 4 hours. Add water (6 mL), add ammonia water to adjust pH=9, and continue stirring for 0.5 h. After beating and filtering, the filter cake was dried to obtain compound 10b (0.98 g).

MS(ESI,m/z):294[M+H] ⁺ .

The second step: 3-((2-amino-6-iodothieno[3,2-d]pyrimidin-4-yl)amino)-1-propanol (compound 10c)

Compound 10b (80.00 mg), 3-amino-1-propanol (61.51 mg), PyBOP (184.66 mg), DIPEA (176.39 mg) and DMF (5.0 mL) were added to the reaction flask and stirred at room temperature for 16 h. It was extracted three times with ethyl acetate, dried and concentrated, separated and purified by Prep-HPLC (elution condition 1), and lyophilized to obtain compound 10c (25.0 mg).

MS(ESI,m/z):351.1[M+H] ⁺ .

The third step: 3-((2-amino-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidin-4-yl)amino)-1-propanol (Compound 10)

Compound 10c (20.00mg), 1H-pyrazole-5-boronic acid pinacle ester (14.41mg), Pd(dppf)Cl _{2 .CH 2} Cl ₂ (9.33mg), K ₃ PO ₄ (24.25mg), water (1.0 mL) and 1,4-dioxane (2.5 mL) were added to the reaction flask, _{replaced with N 2 for} 10 minutes, and heated to 100°C for 5 hours. It was extracted with ethyl acetate, dried and concentrated, separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 10 (14.0 mg).

MS(ESI,m/z):291[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400MHz) δ 13.06 (s, 1H), 7.84 (s, 1H), 7.24 (s, 1H), 7.18 (s, 1H), 6.78 (s, 1H), 5.85 ( s,2H),4.51(s,1H),3.54-3.42(m,4H),1.74(p,J=6.6Hz,2H).

Example 11: N-(2-((2-amino-7-(1H-pyrazol-5-yl)quinazolin-4-yl)amino)ethyl)-N-methylcyclopropanamide (compound 11)

At room temperature, compound 8c (53 mg), cyclopropanoic acid (12.63 mg) and HBTU (60.70 mg) were added to DMF (2 mL), DIPEA (86.19 mg) was added continuously, and the reaction was continued for 2 h. The reaction solution was filtered through Celite, and the filtrate was separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 11 (10 mg).

MS(ESI,m/z):351.9[M+H] ⁺ .

¹ H NMR(DMSO-d ₆ ,400MHz)δ13.7--12.7(m,1H), 8.45-7.97(m,1H), 7.96-7.74(m,2H), 7.61(s,1H), 7.52(s ,1H),6.80(s,1H),6.23--5.90(m,2H),3.79-3.64(m,2H),3.62--3.24(m,2H),3.22-2.86(m,3H),1.96-1.83 (m,1H),0.74-0.47(m,4H).

Example 12: (2S)-1-((2-amino-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidin-4-yl)amino)-2-propanol (Compound 12)

The first step: (2S)-1-[(2-amino-6-iodothieno[3,2-d]pyrimidin-4-yl)amino]-2-propanol (Compound 12a)

Compound 10b (80.00mg), (S)-1-amino-2-propanol (61.51mg), PyBOP (184.66mg), DIPEA (176.39mg) and DMF (5.0mL) were added to the reaction flask at room temperature Stir for 16h. It was extracted three times with ethyl acetate, dried and concentrated, separated and purified by Prep-HPLC (elution condition 1), and lyophilized to obtain compound 12a (25.0 mg).

MS(ESI,m/z):351.1[M+H] ⁺ .

The second step: (2S)-1-((2-amino-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidin-4-yl)amino)-2-propanol (Compound 12)

Compound 12a (20.00mg), 1H-pyrazole-5-boronic acid pinacle ester (14.41mg), Pd(dppf)Cl _{2 .CH 2} Cl ₂ (9.33mg), K ₃ PO ₄ (24.25mg), water (1.0 mL) and 1,4-dioxane (2.5 mL) were added to the reaction flask, _{replaced with N 2 for} 10 minutes, and heated to 100°C for 5 hours. It was extracted with ethyl acetate, dried and concentrated, separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 12 (14.0 mg).

MS(ESI,m/z):291[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400MHz) δ 13.12 (s, 1H), 8.14 (s, 1H), 7.87 (s, 1H), 7.61 (s, 1H), 7.29 (s, 1H), 6.82 ( s, 1H), 6.31 (s, 2H), 3.89 (q, J = 6.2 Hz, 1H), 3.94-3.42 (m, 2H), 1.09 (d, J = 6.2 Hz, 3H).

Example 13: 3-((2-amino-7-(1H-pyrazol-5-yl)quinazolin-4-yl)amino)-2,2-dimethyl-1-propanol (compound 13 )

The first step: 3-((2-amino-7-bromoquinazolin-4-yl)amino)-2,2-dimethyl-1-propanol (compound 13a)

Compound 2b (100mg), 3-amino-2,2-dimethyl-1-propanol (128.92mg), BOP (276.18mg) and DIPEA (269.19mg) were added to DMF (2mL) and reacted for 16h to obtain The crude compound 13a was directly used in the next reaction.

MS(ESI,m/z): 327.1[M+H] ⁺ .

The second step: 3-((2-amino-7-(1H-pyrazol-5-yl)quinazolin-4-yl)amino)-2,2-dimethyl-1-propanol (compound 13 )

To the reaction solution of compound 13a obtained in the first step, potassium carbonate (126.52mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (49.87mg), 1H-pyrazole-5-boronic acid pinacolate were sequentially added (118.60mg) and water (1mL), heated to 100°C under the protection of _{N 2 to react for 3h.} It was separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 13 (5 mg).

MS(ESI,m/z): 313.1[M+H] ⁺ .

¹ H NMR(DMSO-d ₆ ,400MHz)δ13.01(s,1H), 8.03(d,J=8.5Hz,1H),7.81-7.78(m,2H), 7.61(d,J=1.7Hz, 1H), 7.52 (s, 1H), 6.82 (d, J = 2.2 Hz, 1H), 6.13 (s, 2H), 5.01-4.98 (m, 1H), 3.11 (d, J = 6.2 Hz, 2H), 2.51-2.50 (m, 2H), 0.90 (s, 6H).

Example 14: 4-((2-Amino-7-(1H-pyrazol-5-yl)quinazolin-4-yl)amino)cyclohexanol (Compound 14)

The first step: 4-((2-amino-7-bromoquinazolin-4-yl)amino)cyclohexanol (compound 14a)

Compound 2b (100mg), 4-aminocyclohexanol (143.93mg), BOP (276.18mg) and DIPEA (269.19mg) were added to DMF (2mL) and reacted for 16h to obtain crude compound 14a, which was directly used in the next reaction .

MS(ESI,m/z): 338.8[M+H] ⁺ .

The second step: 4-((2-amino-7-(1H-pyrazol-5-yl)quinazolin-4-yl)amino)cyclohexanol (compound 14)

To the reaction solution of compound 14a obtained in the first step, potassium carbonate (122.04mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (48.11mg), 1H-pyrazole-5-boronic acid pinacolate were sequentially added (114.40mg) and water (1mL), heated to 100°C under the protection of _{N 2 to react for 3h.} It was separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 14 (5 mg).

MS(ESI,m/z): 325.1[M+H] ⁺ .

¹ H NMR(DMSO-d ₆ ,400MHz)δ13.02(s,1H), 8.04(d,J=8.5Hz,1H), 7.75(s,1H), 7.59(d,J=1.7Hz,1H) ,7.47(d,J=8.5Hz,1H),7.40(d,J=8.0Hz,1H), 6.80(d,J=2.2Hz,1H), 6.05(s,2H), 4.62(d,J= 4.5Hz,1H),4.14-4.08(m,1H),3.47-3.37(m,1H),1.93-1.88(m,4H),1.49-1.42(m,2H),1.32-1.22(m,2H) .

Example 15: (S)-7-(1H-pyrazol-5-yl)-N ⁴ -((tetrahydrofuran-2-yl)methyl)quinazoline-2,4-diamine formate (compound 15s)

The first step: (S)-7-bromo-N ⁴ -((tetrahydrofuran-2-yl)methyl)quinazolin-2,4-diamine (compound 15a)

At room temperature, compound 2b (50 mg) was added to DMF (2 mL), DIPEA (134.60 mg) and BOP (110.54 mg) were added successively, and the mixture was stirred for 5 min. (S)-(+)-tetrahydrofurfurylamine (63.20mg) was added and reacted for 16h to obtain the crude compound 15a, which was directly used in the next reaction.

MS(ESI,m/z):323.0[M+H] ⁺ .

The second step: (S)-7-(1H-pyrazol-5-yl)-N ⁴ -((tetrahydrofuran-2-yl)methyl)quinazoline-2,4-diamine formate (compound 15s)

To the reaction solution of compound 15a obtained in the first step, 1H-pyrazole-5-boronic acid pinacolate (80.82mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (17mg), K ₂ CO were added sequentially. ₃ (86.35mg) and water (0.5mL), heated to 100℃ under the protection of _{N 2 to react for 4h.} The reaction solution was filtered through Celite, and the filtrate containing compound 15 was separated and purified by Prep-HPLC (elution condition 3), and lyophilized to obtain compound 15s (30 mg).

MS(ESI,m/z):311.0[M+H] ⁺ .

¹ H NMR(DMSO-d ₆ ,400MHz)δ13.04(s,1H), 8.39–8.16(m,2H), 8.09(d,J=8.6Hz,1H), 7.85–7.72(m,1H), 7.66(s,1H),7.57(d,J=7.6Hz,1H), 7.05–6.45(m,3H), 4.20–4.08(m,1H), 3.85–3.78(m,1H), 3.69–3.62( m, 1H), 3.59--3.50 (m, 2H), 2.00--1.77 (m, 3H), 1.68--1.57 (m, 1H).

Example 16: (R)-1-((2-amino-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidin-4-yl)amino)-2-propanol (Compound 16)

The first step: (R)-1-[(2-amino-6-iodothieno[3,2-d]pyrimidin-4-yl)amino]-2-propanol (Compound 16a)

Compound 10b (80mg), (R)-(-)-1-amino-2-propanol (61.51mg), PyBOP (184.66mg, DIPEA (176.39mg) and DMF (5.0mL) were added to the reaction flask, The reaction was carried out at room temperature for 16 hours. It was extracted with ethyl acetate for 3 times, dried and concentrated, separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 16a (21.0 mg).

MS(ESI,m/z):351[M+H] ⁺ .

The second step: (R)-1-((2-amino-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidin-4-yl)amino)-2-propanol (Compound 16)

Compound 16a (29mg), 1H-pyrazole-5-boronic acid pinacolate (20.89mg), Pd(dppf)Cl _{2 .CH 2} Cl ₂ (13.53mg), K ₃ PO ₄ (35.16mg), water ( 1.0 mL) and 1,4-dioxane (2.0 mL) were added to the reaction flask, _{replaced with N 2 for} 10 minutes, and heated to 100°C for 5 hours. It was extracted with ethyl acetate, dried and concentrated, separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 16 (21.0 mg).

MS(ESI,m/z):291[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400MHz) δ 13.07 (s, 1H), 7.84 (s, 1H), 7.25 (s, 1H), 7.14 (s, 1H), 6.78 (s, 1H), 5.86 ( s, 2H), 4.82 (s, 1H), 4.05-3.77 (m, 1H), 3.41-3.35 (m, J = 5.3 Hz, 2H), 1.09 (d, J = 6.2 Hz, 3H).

Example 17: (R)-2-((2-amino-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidin-4-yl)amino)-1-butanol (Compound 17)

The first step: (R)-2-[(2-amino-6-iodothieno[3,2-d]pyrimidin-4-yl)amino]-1-butanol (Compound 17a)

Compound 10b (80mg), (R)-2-amino-1-butanol (72.99mg), PyBOP (184.66mg), DIPEA (176.39mg) and DMF (3.0mL) were added to the reaction flask and left at room temperature Reaction for 16h. It was extracted three times with ethyl acetate, dried and concentrated, separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 17a (29.0 mg).

MS(ESI,m/z):365[M+H] ⁺ .

The second step: (R)-2-((2-amino-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidin-4-yl)amino)-1-butanol (Compound 17)

Compound 17a (29mg), 1H-pyrazole-5-boronic acid pinacolate (20.09mg), Pd(dppf)Cl _{2 .CH 2} Cl ₂ (13.01mg), K ₃ PO ₄ (33.80 mg), water ( 0.5 mL) and 1,4-dioxane (2.0 mL) were added to the reaction flask, _{replaced with N 2 for} 10 minutes, and heated to 100°C for 5 hours. It was extracted with ethyl acetate, dried and concentrated, separated and purified by Prep-HPLC (elution condition 2), and lyophilized to obtain compound 17 (8.0 mg).

MS(ESI,m/z):305[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400MHz) δ 13.09 (s, 1H), 7.86 (s, 1H), 7.26 (s, 1H), 6.82 (d, J = 17.3 Hz, 2H), 5.83 (s, 2H), 4.70 (s, 1H), 4.19 (s, 1H), 3.50 (d, 2H), 1.75 (d, J = 21.2 Hz, 1H), 1.52 (d, J = 7.0 Hz, 1H), 0.90 ( t,J=6.5Hz,3H).

Example 18: (S)-2-((2-amino-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidin-4-yl)amino)-1-propanol (Compound 18)

The first step: (S)-2-[(2-amino-6-iodothieno[3,2-d]pyrimidin-4-yl)amino]-1-propanol (Compound 18a)

Compound 10b (80 mg), L-aminopropanol (61.51 mg), PyBOP (184.66 mg), DIPEA (176.39 mg) and DMF (3.0 mL) were added to the reaction flask and reacted at room temperature for 16 hours. It was extracted three times with ethyl acetate, dried and concentrated, separated and purified by Prep-HPLC (elution condition 2), and lyophilized to obtain compound 18a (28.0 mg).

MS(ESI,m/z):351[M+H] ⁺ .

The second step: (S)-2-((2-amino-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidin-4-yl)amino)-1-propanol (Compound 18)

Compound 18a (28.00mg), 1H-pyrazole-5-boronic acid pinacolate (20.17mg), Pd(dppf)Cl _{2 .CH 2} Cl ₂ (13.06mg), K ₃ PO ₄ (33.94 mg), water (0.5mL) and 1,4-dioxane (2.0mL) were added to the reaction flask, _{replaced with N 2 for} 10 minutes, and heated to 100°C for 5 hours. It was extracted with ethyl acetate, dried and concentrated, separated and purified by Prep-HPLC (elution condition 2), and lyophilized to obtain compound 18 (17.0 mg).

MS(ESI,m/z):291[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400MHz) δ 13.08 (s, 1H), 7.85 (s, 1H), 7.25 (s, 1H), 7.01 (s, 1H), 6.79 (s, 1H), 5.95 ( s, 2H), 4.74 (s, 1H), 4.35-4.29 (m, 1H), 3.51-3.48 (m, 1H), 3.39 (d, 1H), 1.16 (d, J = 6.6 Hz, 3H).

Example 19: N ⁴ -Propyl-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidine-2,4-diamine (Compound 19)

The first step: 6-iodo-N ⁴ -propylthieno[3,2-d]pyrimidine-2,4-diamine (compound 19a)

Compound 10b (80mg), 1-propylamine (48.40mg), PyBOP (184.66mg), DIPEA (176.39mg) and DMF (3.0mL) were added to the reaction flask and reacted at room temperature for 16h. It was extracted three times with ethyl acetate, dried and concentrated, separated and purified by Prep-HPLC (elution condition 2), and lyophilized to obtain compound 19a (45.0 mg).

MS(ESI,m/z):335[M+H] ⁺ .

The second step: N ⁴ -propyl-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidine-2,4-diamine (Compound 19)

Compound 19a (45.00mg), 1H-pyrazole-5-boronic acid pinacolate (33.97mg), Pd(dppf)Cl _{2 .CH 2} Cl ₂ (21.99 mg), K ₃ PO ₄ (57.17 mg), water (0.5mL) and 1,4-dioxane (2.0mL) were added to the reaction flask, _{replaced with N 2 for} 10 minutes, and heated to 100°C for 5 hours. It was extracted with ethyl acetate, dried and concentrated, separated and purified by Prep-HPLC (elution condition 2), and lyophilized to obtain compound 19 (35.0 mg).

MS(ESI,m/z):276[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400MHz) δ 13.06 (s, 1H), 7.84 (s, 1H), 7.24 (s, 2H), 6.78 (s, 1H), 5.85 (s, 2H), 3.38 ( d,J=6.2Hz,2H),1.74-1.46(m,2H),0.91(t,J=7.4Hz,3H).

Example 20: 2-(((2-amino-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidin-4-yl)amino)methyl)cyclopropanol (compound 20)

The first step: 2-(((2-amino-6-iodothieno[3,2-d]pyrimidin-4-yl)amino)methyl)cyclopropanol (Compound 20a)

Compound 10b (80mg), 2-aminomethylcyclopropanol (71.34mg), PyBOP (184.66mg), DIPEA (176.39mg) and DMF (3.0mL) were added to the reaction flask and reacted at room temperature for 16h. It was extracted three times with ethyl acetate, dried and concentrated, and then separated and purified by flash column chromatography (eluent system A) to obtain compound 20a (3.1 mg).

MS(ESI,m/z):362[M+H] ⁺ .

The second step: 2-((2-amino-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidin-4-yl)amino)methyl)cyclopropanol (Compound 20 )

Compound 20a (50.00mg), 1H-pyrazole-5-boronic acid pinacolate (41.71mg), Pd(dppf)Cl _{2 .CH 2} Cl ₂ (21.01mg), K ₃ PO ₄ (70.20mg), water (0.8mL) and 1,4-dioxane (2.3mL) were added to the reaction flask, _{replaced with N 2 for} 10 minutes, and heated to 100°C for 5 hours. It was extracted with ethyl acetate, dried and concentrated, separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 20 (13.0 mg).

MS(ESI,m/z):303[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400MHz) δ 13.10 (s, 1H), 7.84 (s, 1H), 7.23 (d, J = 23.0 Hz, 2H), 6.78 (s, 1H), 5.55 (s, 1H), 3.57 (d, J = 5.1 Hz, 2H), 0.59 (d, J = 7.4 Hz, 4H).

Example 21: N ⁴ -(2-morpholinoethyl)-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidine-2,4-diamine (Compound 21)

The first step: 6-iodo-N ⁴ -(2-morpholinoethyl)thieno[3,2-d]pyrimidine-2,4-diamine (compound 21a)

Compound 10b (50mg), 2-morpholinoethylamine (66.63mg), PyBOP (115.41mg), DIPEA (22.05mg) and DMF (3.0mL) were added to the reaction flask and reacted at room temperature for 16h. It was extracted 3 times with ethyl acetate, dried and concentrated, separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 21a (50.0 mg).

MS(ESI,m/z):406[M+H] ⁺ .

The second step: N ⁴ -(2-morpholinoethyl)-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidine-2,4-diamine (Compound 21)

Compound 21a (80.33mg), 1H-pyrazole-5-boronic acid pinaline (50.00mg), Pd(dppf)Cl _{2 .CH 2} Cl ₂ (32.37 mg), K ₃ PO ₄ (84.15 mg), water (0.8mL) and 1,4-dioxane (2.0mL) were added to the reaction flask and stirred at room temperature for 16h. Replace with N _{2 for} 10 min, and heat to 100° C. to react for 5 h. It was extracted with ethyl acetate, dried and concentrated, separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 21 (17.0 mg).

MS(ESI,m/z):346[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400MHz) δ 13.10 (s, 1H), 7.86 (s, 1H), 7.27 (s, 1H), 7.18 (s, 1H), 6.80 (s, 1H), 5.90 ( s, 2H), 3.69--3.49 (m, 8H), 2.45 (s, 2H).

Example 22: 4-((2R,6R)-2,6-dimethylmorpholino)-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidine-2- Amine (Compound 22)

The first step: 4-((2R,6R)-2,6-dimethylmorpholino)-6-iodothieno[3,2-d]pyrimidin-2-amine (Compound 22a)

At room temperature, compound 10b (100 mg) was added to DMF (4 mL), DIPEA (220.48 mg) and BOP (181.09 mg) were added successively, and stirred for 5 min. Continue to add 2R,6R-dimethylmorpholine (117.89mg) and react for 16h to obtain the crude compound 22a, which was directly used in the next reaction.

MS(ESI,m/z): 391.0[M+H] ⁺ .

The second step: 4-((2R,6R)-2,6-dimethylmorpholino)-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidine-2- Amine (Compound 22)

To the reaction solution of compound 22a obtained in the first step, 1H-pyrazole-5-boronic acid pinacolate (132.41mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (28mg), K ₂ CO were sequentially added ₃ (141.47mg) and water (1mL), heated to 100℃ under the protection of _{N 2 to react for 4h.} The reaction solution was filtered through Celite, and the filtrate was separated and purified by Prep-HPLC (elution condition 2), and lyophilized to obtain compound 22 (11 mg).

MS(ESI,m/z):331.1[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400MHz) δ 13.12 (s, 1H), 7.86 (s, 1H), 7.32 (s, 1H), 6.83 (s, 1H), 6.02 (s, 2H), 4.12-- 4.02(m,2H), 3.98–3.89(m,2H), 3.52–3.44(m,2H), 1.18(d,J=6.4Hz,6H).

Example 23: (1R,3R)-3-((2-amino-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidin-4-yl)amino)cyclopentanol (Compound 23)

The first step: (1R,3R)-3-((2-amino-6-iodothieno[3,2-d]pyrimidin-4-yl)amino)cyclopentanol (compound 23a)

At room temperature, compound 10b (50 mg) was added to DMF (2 mL), DIPEA (110.24 mg) and BOP (90.69 mg) were added successively, and the mixture was stirred for 5 min. (1R,3R)-3-aminocyclopentanol hydrochloride (117.89mg) was added continuously, and reacted for 16h to obtain crude compound 23a, which was directly used in the next reaction.

MS(ESI,m/z): 377.0[M+H] ⁺ .

Step 2: (1R,3R)-3-((2-amino-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidin-4-yl)amino)cyclopentanol (Compound 23)

To the reaction solution of compound 23a obtained in the first step, 1H-pyrazole-5-boronic acid pinacolate (66.20mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (14mg), K ₂ CO were sequentially added ₃ (70.73mg) and water (0.5mL), heated to 100℃ under the protection of _{N 2 to react for 4h.} The reaction solution was filtered through Celite, and the filtrate was separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 23 (12 mg).

MS(ESI,m/z): 317.2[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400MHz) δ 13.07 (s, 1H), 7.85 (s, 1H), 7.34-7.11 (m, 2H), 6.78 (s, 1H), 5.91 (s, 2H), 4.80–4.65(m,1H), 4.52(d,J=3.4Hz,1H), 4.28–4.17(m,1H), 2.18–2.05(m,1H), 2.00–1.84(m,2H), 1.78– 1.66 (m, 1H), 1.54-1.41 (m, 2H).

Example 24: (1S,3S)-3-((2-amino-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidin-4-yl)amino)cyclopentanol (Compound 24)

The first step: (1S,3S)-3-((2-amino-6-iodothieno[3,2-d]pyrimidin-4-yl)amino)cyclopentanol (Compound 24a)

At room temperature, compound 10b (50 mg) was added to DMF (2 mL), DIPEA (110.24 mg) and BOP (90.69 mg) were added successively, and the mixture was stirred for 5 min. (1S,3S)-3-aminocyclopentanol hydrochloride (117.89mg) was continuously added and reacted for 16h to obtain crude compound 24a, which was directly used in the next reaction.

MS(ESI,m/z): 377.0[M+H] ⁺ .

The second step: (1S,3S)-3-((2-amino-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidin-4-yl)amino)cyclopentanol (Compound 24)

To the reaction solution of compound 24a obtained in the first step, 1H-pyrazole-5-boronic acid pinacolate (66.20mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (14mg), K ₂ CO were sequentially added ₃ (70.73mg) and water (0.5mL), heated to 100℃ under the protection of _{N 2 to react for 4h.} The reaction solution was filtered through Celite, and the filtrate was separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 24 (12 mg).

MS(ESI,m/z): 317.2[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400MHz) δ 13.09 (s, 1H), 7.85 (s, 1H), 7.41-7.21 (m, 2H), 6.79 (s, 1H), 6.16-5.97 (m, 2H) ), 4.80–4.68(m,1H), 4.53(d,J=3.4Hz,1H), 4.28–4.18(m,1H), 2.19–2.05(m,1H), 2.01–1.82(m,2H), 1.81-1.66(m,1H), 1.58-1.39(m,2H).

Example 25: (R)-N ⁴ -(1-methoxyprop-2-yl)-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidine-2,4 -Diamine formate (Compound 25s)

The first step: (R)-6-iodo-N ⁴ -(1-methoxyprop-2-yl)thieno[3,2-d]pyrimidine-2,4-diamine (Compound 25a)

At room temperature, compound 10b (50 mg) was added to DMF (2 mL), DIPEA (110.24 mg) and BOP (90.69 mg) were added successively, and the mixture was stirred for 5 min. (R)-1-methoxypropan-2-amine (50.94mg) was continuously added and reacted for 16h to obtain the crude compound 25a, which was directly used in the next reaction.

MS(ESI,m/z): 365.0[M+H] ⁺ .

The second step: (R)-N ⁴ -(1-methoxyprop-2-yl)-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidine-2,4 -Diamine formate (Compound 25s)

To the reaction solution of compound 25a obtained in the first step, 1H-pyrazole-5-boronic acid pinacolate (66.20mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (14mg), K ₂ CO were sequentially added ₃ (70.73mg) and water (0.5mL), heated to 100℃ under the protection of _{N 2 to react for 4h.} The reaction solution was filtered through Celite, and the filtrate containing compound 25 was separated and purified by Prep-HPLC (elution condition 3), and lyophilized to obtain compound 25s (14 mg).

MS(ESI,m/z): 305.1[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400MHz) δ 13.08 (s, 1H), 8.21 (s, 1H), 7.83 (s, 1H), 7.24 (s, 1H), 7.06 (d, J = 8.3 Hz, 1H), 6.77(s, 1H), 5.91(s, 2H), 4.62–4.42(m, 1H), 3.48–3.41(m, 2H), 3.27(s, 3H), 1.16(d,J=6.7Hz ,3H).

Example 26: (R)-N ⁴ -(2-Methoxypropyl)-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidine-2,4-diamine (Compound 26)

The first step: (R)-6-iodo-N ⁴ -(2-methoxypropyl)thieno[3,2-d]pyrimidine-2,4-diamine (compound 26a)

At room temperature, compound 10b (50 mg) was added to DMF (2 mL), DIPEA (110.24 mg) and BOP (90.69 mg) were added successively, and the mixture was stirred for 5 min. (R)-2-Methoxyprop-1-amine hydrochloride (64.28mg) was continuously added and reacted for 16h to obtain crude compound 26a, which was directly used in the next reaction.

MS(ESI,m/z): 365.0[M+H] ⁺ .

The second step: (R)-N ⁴ -(2-methoxypropyl)-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidine-2,4-diamine (Compound 26)

To the reaction solution of compound 26a obtained in the first step, 1H-pyrazole-5-boronic acid pinacolate (66.20mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (14mg), K ₂ CO were sequentially added ₃ (70.73mg) and water (0.5mL), heated to 100℃ under the protection of _{N 2 to react for 4h.} The reaction solution was filtered through Celite, and the filtrate was separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 26 (15 mg).

MS(ESI,m/z): 305.1[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400MHz) δ 13.07 (s, 1H), 7.85 (s, 1H), 7.32-7.21 (m, 2H), 6.78 (s, 1H), 5.86 (s, 2H), 3.62–3.54(m,1H), 3.53–3.45(m,1H), 3.40–3.36(m,1H), 3.29(s,3H), 1.10(d,J=6.1Hz,3H).

Example 27: N ⁴ -((1-methylcyclopropyl)methyl)-7-(1H-pyrazol-5-yl)quinazoline-2,4-diamine (Compound 27)

The first step: 7-bromo-N ⁴ -((1-methylcyclopropyl)methyl)quinazoline-2,4-diamine (compound 27a)

At room temperature, compound 2b (70mg), 1-methylcyclopropylethylamine (70.92mg), BOP (89.28mg) and DIPEA (188.43mg) were added to DMF (2mL) and reacted for 16h to obtain crude compound 27a. Used directly in the next reaction.

MS(ESI,m/z): 309.0[M+H] ⁺ .

The second step: N ⁴ -((1-methylcyclopropyl)methyl)-7-(1H-pyrazol-5-yl)quinazoline-2,4-diamine (Compound 27)

To the reaction solution of compound 27a obtained in the first step, potassium carbonate (93.72 mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (27.71 mg), 1H-pyrazole-5-boronic acid pinacolate were added sequentially (87.86mg) and water (1mL), heated to 100°C under the protection of _{N 2 to react for 3h.} The reaction solution was filtered through Celite, and the filtrate was separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 27 (7 mg).

MS(ESI,m/z): 295.1[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400MHz)) δ 13.10 (s, 1H), 8.37 (s, 1H), 8.20 (d, J = 8.5 Hz, 1H), 7.83 (s, 1H), 7.69-7.64 (m,2H),6.83-6.78(m,3H),3.48(d,J=5.6Hz,2H),1.11(s,3H),0.59-0.58(m,2H),0.30-0.27(m,2H ).

Example 28: N ⁴ -(2-morpholinoethyl)-7-(1H-pyrazol-5-yl)quinazoline-2,4-diamine (Compound 28)

The first step: 7-bromo-N ⁴ -(2-morpholinoethyl)quinazoline-2,4-diamine (compound 28a)

At room temperature, compound 2b (70mg), 2-morpholinoethylamine (75.92mg), BOP (89.28mg) and DIPEA (188.43mg) were added to DMF (2mL) and reacted for 16h to obtain crude compound 28a, which was used directly In the next step.

MS(ESI,m/z):352.1[M+H] ⁺ .

The second step: N ⁴ -(2-morpholinoethyl)-7-(1H-pyrazol-5-yl)quinazoline-2,4-diamine (Compound 28)

To the reaction solution of compound 28a obtained in the first step, potassium carbonate (93.72mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (27.71mg), 1H-pyrazole-5-boronic acid pinacolate were added sequentially (87.86mg) and water (1mL), heated to 100°C under the protection of _{N 2 to react for 3h.} The reaction solution was filtered through Celite, and the filtrate was separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 28 (12 mg).

MS(ESI,m/z): 340.1[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400MHz) δ 13.00 (s, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.78-7.76 (m, 2H), 7.61 (d, J = 1.6 Hz, 1H), 7.57-7.45 (m, 1H), 6.81 (d, J = 2.1Hz, 1H), 6.11 (s, 2H), 3.63-3.57 (m, 6H), 2.58-2.55 (m, 2H), 2.47 –2.44(m,4H).

Example 29: 4-((2R,6R)-2,6-Dimethylmorpholino)-7-(1H-pyrazol-5-yl)quinazolin-2-amine (Compound 29)

The first step: 7-bromo-4-((2R,6R)-2,6-dimethylmorpholino)quinazolin-2-amine (compound 29a)

At room temperature, compound 2b (70mg), (2R,6R)-2,6-dimethylmorpholine (67.17mg), BOP (89.28mg) and DIPEA (188.43mg) were added to DMF (2mL) and reacted for 16h , The crude compound 29a was obtained, which was directly used in the next reaction.

MS(ESI,m/z): 338.1[M+H] ⁺ .

The second step: 4-((2R,6R)-2,6-dimethylmorpholino)-7-(1H-pyrazol-5-yl)quinazolin-2-amine (Compound 29)

To the reaction solution of compound 29a obtained in the first step, potassium carbonate (93.72 mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (27.71 mg), 1H-pyrazole-5-boronic acid pinacolate were sequentially added (87.86mg) and water (1mL), heated to 100°C under the protection of _{N 2 to react for 3h.} The reaction solution was filtered through Celite, and the filtrate was separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 29 (5 mg).

MS(ESI,m/z): 325.1[M+H] ⁺ .

¹ H NMR(DMSO-d ₆ ,400MHz)δ13.03(s,1H),7.77(d,J=8.7Hz,2H),7.71(d,J=1.7Hz,1H),7.56(s,1H) ,6.82(d,J=2.3Hz,1H),6.34(s,2H),4.17-4.13(m,2H),3.63-3.59(m,2H),3.35-3.30(m,2H),1.24(d ,J=6.4Hz,6H).

Example 30: N ⁴ -(Cyclobutylmethyl)-7-(1H-pyrazol-5-yl)quinazoline-2,4-diamine (Compound 30)

The first step: 7-bromo-N ⁴ -(cyclobutylmethyl)quinazoline-2,4-diamine (compound 30a)

At room temperature, compound 2b (70mg), cyclobutylmethylamine (49.66mg), BOP (89.28mg) and DIPEA (188.43mg) were added to DMF (2mL) and reacted for 16h to obtain crude compound 30a, which was directly used in the next reaction .

MS(ESI,m/z): 309.0[M+H] ⁺ .

The second step: N ⁴ -(cyclobutylmethyl)-7-(1H-pyrazol-5-yl)quinazoline-2,4-diamine (compound 30)

To the reaction solution of compound 30a obtained in the first step, potassium carbonate (93.72mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (27.71mg), 1H-pyrazole-5-boronic acid pinacolate were sequentially added (87.86mg) and water (1mL), heated to 100°C under the protection of _{N 2 to react for 3h.} The reaction solution was filtered through Celite, and the filtrate was separated and purified by Prep-HPLC (elution condition 2), and lyophilized to obtain compound 30 (7 mg).

MS(ESI,m/z): 295.1[M+H] ⁺ .

¹ H NMR(DMSO-d ₆ ,400MHz)δ12.98(s,1H), 8.02(d,J=8.5Hz,1H),7.86-7.83(m,1H), 7.60(d,J=1.7Hz, 1H), 7.50 (s, 1H), 6.80 (d, J = 2.2 Hz, 1H), 6.13 (s, 2H), 3.54-3.50 (m, 2H), 2.72-2.65 (m, 1H), 2.08-1.99 (m, 2H), 1.91-1.83 (m, 2H), 1.79-1.73 (m 2H).

Example 31: (R)-N ⁴ -(1-methoxyprop-2-yl)-7-(1H-pyrazol-5-yl)quinazoline-2,4-diamine formate ( Compound 31s)

The first step: (R)-7-bromo-N ⁴ -(1-methoxyprop-2-yl)quinazoline-2,4-diamine (compound 31a)

At room temperature, compound 2b (70 mg), (R)-1-methoxypropan-2-amine hydrochloride (73.25 mg), BOP (89.28 mg) and DIPEA (188.43 mg) were added to DMF (2 mL), After 16 hours of reaction, the crude compound 31a was obtained, which was directly used in the next reaction.

MS(ESI,m/z): 313.1[M+H] ⁺ .

The second step: (R)-N ⁴ -(1-methoxyprop-2-yl)-7-(1H-pyrazol-5-yl)quinazoline-2,4-diamine formate ( Compound 31s)

To the reaction solution of compound 31a obtained in the first step, potassium carbonate (93.72mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (27.71mg), 1H-pyrazole-5-boronic acid pinacolate were sequentially added (87.86mg) and water (1mL), heated to 100°C under the protection of _{N 2 to react for 3h.} The reaction solution was filtered through Celite, and the filtrate containing compound 31 was separated and purified by Prep-HPLC (elution condition 3), and lyophilized to obtain compound 31s (2 mg).

MS(ESI,m/z): 299.1[M+H] ⁺ .

¹ H NMR(DMSO-d ₆ ,400MHz)δ8.32(s,1H), 8.11(d,J=8.6Hz,1H), 7.78(d,J=6.7Hz,2H), 7.64(d,J= 1.7Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 2.2 Hz, 1H), 6.70 (s, 2H), 4.66-4.59 (m, 1H), 3.52-3.46 ( m, 1H), 3.38-3.34 (m, 1H), 3.29 (s, 3H), 1.22 (d, J = 6.7 Hz, 3H).

Example 32: N ⁴ -(pent-3-yl)-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidine-2,4-diamine (Compound 32)

The first step: 6-iodo-N ⁴ -(pent-3-yl)thieno[3,2-d]pyrimidine-2,4-diamine (compound 32a)

At room temperature, compound 10b (50 mg) was added to DMF (2 mL), DIPEA (110.24 mg) and BOP (90.69 mg) were added successively, and the mixture was stirred for 5 min. Continue to add 3-pentylamine (44.61mg) and react for 16h to obtain the crude compound 32a, which was directly used in the next reaction.

MS(ESI,m/z): 363.0[M+H] ⁺ .

The second step: N ⁴ -(pent-3-yl)-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidine-2,4-diamine (Compound 32)

To the reaction solution of compound 32a obtained in the first step, 1H-pyrazole-5-boronic acid pinacolate (66.20mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (14mg), K ₂ CO were sequentially added ₃ (70.73mg) and water (0.5mL), heated to 100℃ under the protection of _{N 2 to react for 4h.} The reaction solution was filtered through Celite, and the filtrate was separated and purified by Prep-HPLC (elution condition 2), and lyophilized to obtain compound 32 (10 mg).

MS(ESI,m/z): 303.2[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400MHz) δ 13.06 (s, 1H), 7.84 (s, 1H), 7.23 (s, 1H), 6.88 (d, J = 8.6 Hz, 1H), 6.77 (s, 1H), 5.77(s, 2H), 4.19–4.04(m,1H), 1.63–1.45(m,4H), 0.87(t,J=7.4Hz,6H).

Example 33: N ⁴ -(Cyclopropylmethyl)-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidine-2,4-diamine (Compound 33)

The first step: N ⁴ -(cyclopropylmethyl)-6-iodothieno[3,2-d]pyrimidine-2,4-diamine (compound 33a)

At room temperature, compound 10b (50 mg) was added to DMF (2 mL), DIPEA (110.24 mg) and BOP (90.69 mg) were added successively, and the mixture was stirred for 5 min. Cyclopropylmethylamine (36.40mg) was continuously added and reacted for 16h to obtain crude compound 33a, which was directly used in the next reaction.

MS(ESI,m/z): 347.0[M+H] ⁺ .

Step 2: N ⁴ -(Cyclopropylmethyl)-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidine-2,4-diamine (Compound 33)

To the reaction solution of compound 33a obtained in the first step, 1H-pyrazole-5-boronic acid pinacolate (66.20mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (14mg), K ₂ CO were sequentially added ₃ (70.73mg) and water (0.5mL), heated to 100℃ under the protection of _{N 2 to react for 4h.} The reaction solution was filtered through Celite, and the filtrate was separated and purified by Prep-HPLC (elution condition 2), and lyophilized to obtain compound 33 (8 mg).

MS(ESI,m/z):287.1[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400MHz) δ 13.08 (s, 1H), 7.85 (s, 1H), 7.49 (s, 1H), 7.25 (s, 1H), 6.79 (s, 1H), 5.97 ( s, 2H), 3.31--3.27 (m, 2H), 1.20-1.05 (m, 1H), 0.48-0.41 (m, 2H), 0.28-0.23 (m, 2H).

Example 34: (1S,2R)-2-((2-amino-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidin-4-yl)amino)cyclopentanol (Compound 34)

The first step: (1S,2R)-2-((2-amino-6-iodothieno[3,2-d]pyrimidin-4-yl)amino)cyclopentanol (Compound 34a)

At room temperature, compound 10b (50 mg) was added to DMF (2 mL), DIPEA (110.24 mg) and BOP (90.69 mg) were added successively, and the mixture was stirred for 5 min. (1S,2R)-2-aminocyclopentanol (51.77mg) was continuously added and reacted for 16h to obtain crude compound 34a, which was directly used in the next reaction.

MS(ESI,m/z): 377.0[M+H] ⁺ .

The second step: (1S,2R)-2-((2-amino-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidin-4-yl)amino)cyclopentanol (Compound 34)

To the reaction solution of compound 34a obtained in the first step, 1H-pyrazole-5-boronic acid pinacolate (66.20mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (14mg), K ₂ CO were sequentially added ₃ (70.73mg) and water (0.5mL), heated to 100℃ under the protection of _{N 2 to react for 4h.} The reaction solution was filtered through Celite, and the filtrate was separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 34 (8 mg).

MS(ESI,m/z): 317.1[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400MHz) δ 13.07 (s, 1H), 7.85 (s, 1H), 7.26 (s, 1H), 6.79 (s, 1H), 6.60 (s, 1H), 5.92 ( s,2H),4.77(d,J=3.9Hz,1H), 4.32–4.20(m,1H), 4.18–4.08(m,1H),1.95–1.86(m,1H),1.83–1.69(m, 3H), 1.66-1.57 (m, 1H), 1.55-1.45 (m, 1H).

Example 35: 6-(1H-pyrazol-5-yl)-N ⁴ -((tetrahydro-2H-pyran-4-yl)methyl)thieno[3,2-d]pyrimidine-2, 4-Diamine (Compound 35)

The first step: 6-iodo-N ⁴ -((tetrahydro-2H-pyran-4-yl)methyl)thieno[3,2-d]pyrimidine-2,4-diamine (compound 35a)

At room temperature, compound 10b (50 mg) was added to DMF (2 mL), DIPEA (110.24 mg) and BOP (90.69 mg) were added successively, and the mixture was stirred for 5 min. Continue to add 4-aminomethyltetrahydropyran (58.95mg) and react for 16h to obtain the crude compound 35a, which was directly used in the next reaction.

MS(ESI,m/z): 391.0[M+H] ⁺ .

The second step: 6-(1H-pyrazol-5-yl)-N ⁴ -((tetrahydro-2H-pyran-4-yl)methyl)thieno[3,2-d]pyrimidine-2, 4-Diamine (Compound 35)

To the reaction solution of compound 35a obtained in the first step, 1H-pyrazole-5-boronic acid pinacolate (66.20mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (14mg), K ₂ CO were sequentially added ₃ (70.73mg) and water (0.5mL), heated to 100℃ under the protection of _{N 2 to react for 4h.} The reaction solution was filtered through Celite, and the filtrate was separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 35 (13 mg).

MS(ESI,m/z):331.1[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400MHz) δ 13.06 (s, 1H), 7.84 (s, 1H), 7.35-7.18 (m, 2H), 6.78 (s, 1H), 5.85 (s, 2H), 3.85(dd,J=11.3,2.5Hz,2H),3.32–3.24(m,4H),1.97–1.82(m,1H),1.62(d,J=11.3Hz,2H),1.27– 1.14(m, 2H).

Example 36: N ⁴ -(2-Methoxyethyl)-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidine-2,4-diamine formate ( Compound 36s)

The first step: 6-iodo-N ⁴ -(2-methoxyethyl)thieno[3,2-d]pyrimidine-2,4-diamine (compound 36a)

Compound 10b (40mg), 2-methoxyethylamine (30.75mg), BOP (27.86mg), DIPEA (17.64mg) and DMF (2.0mL) were added to the reaction flask and reacted at room temperature for 16h to obtain the crude product Compound 36a was directly used in the next reaction.

MS(ESI,m/z): 350[M+H] ⁺ .

The second step: N ⁴ -(2-methoxyethyl)-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidine-2,4-diamine formate ( Compound 36s)

To the reaction solution of compound 36a obtained in the first step, 1H-pyrazole-5-boronic acid pinacolate (67.71 mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (43.84 mg), K _{3 were sequentially added} PO ₄ (113.96 mg) and water (0.5 mL) were stirred at 100°C for 5 h under the protection of _{N 2.} The reaction solution was filtered through Celite, and the filtrate containing compound 36 was separated and purified by Prep-HPLC (elution condition 6), and lyophilized to obtain compound 36s (17.0 mg).

MS(ESI,m/z):337[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400MHz) δ 13.10 (s, 1H), 8.16 (s, 1H), 7.84 (s, 1H), 7.47 (t, J = 5.3 Hz, 1H), 6.79 (d, J = 1.9Hz, 1H), 6.10 (s, 2H), 3.59 (q, J = 5.6 Hz, 2H), 3.51 (dd, J = 6.2, 4.8 Hz, 2H), 3.28 (s, 3H).

Example 37: 2-((2-Amino-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidin-4-yl)(methyl)amino)ethanol (Compound 37)

The first step: 2-((2-amino-6-iodothieno[3,2-d]pyrimidin-4-yl)(methyl)amino)ethanol (compound 37a)

At room temperature, compound 10b (50 mg) was added to DMF (2 mL), DIPEA (110.24 mg) and BOP (90.69 mg) were added successively, and the mixture was stirred for 5 min. Continue to add N-methyl-2-hydroxyethylamine (38.44mg) and react for 16h to obtain the crude compound 37a, which was directly used in the next reaction.

MS(ESI,m/z):351.0[M+H] ⁺ .

Step 2: 2-((2-Amino-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidin-4-yl)(methyl)amino)ethanol (Compound 37)

To the reaction solution of compound 37a obtained in the first step, 1H-pyrazole-5-boronic acid pinacolate (66.20mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (14mg), K ₂ CO were sequentially added ₃ (70.73mg) and water (0.5mL), heated to 100℃ under the protection of _{N 2 to react for 4h.} The reaction solution was filtered through Celite, and the filtrate was separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 37 (22 mg).

MS(ESI,m/z): 291.1[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400MHz) δ 13.10 (s, 1H), 7.83 (s, 1H), 7.27 (s, 1H), 6.79 (d, J = 1.9 Hz, 1H), 5.84 (s, 2H), 4.82(t,J=5.2Hz,1H), 3.80–3.72(m,2H), 3.70–3.62(m,2H), 3.34(s,3H).

Example 38: 4-((2-Amino-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidin-4-yl)amino)cyclohexanol (Compound 38)

The first step: 4-((2-amino-6-iodothieno[3,2-d]pyrimidin-4-yl)amino)cyclohexanol (compound 38a)

At room temperature, compound 10b (50 mg) was added to DMF (2 mL), DIPEA (110.24 mg) and BOP (90.69 mg) were added successively, and the mixture was stirred for 5 min. Continue to add 4-aminocyclohexanol (58.95mg) and react for 16h to obtain crude compound 38a, which was directly used in the next reaction.

MS(ESI,m/z): 391.0[M+H] ⁺ .

Step 2: 4-((2-Amino-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidin-4-yl)amino)cyclohexanol (Compound 38)

To the reaction solution of compound 38a obtained in the first step, 1H-pyrazole-5-boronic acid pinacolate (66.20mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (14mg), K ₂ CO were sequentially added ₃ (70.73mg) and water (0.5mL), heated to 100℃ under the protection of _{N 2 to react for 4h.} The reaction solution was filtered through Celite, and the filtrate was separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 38 (16 mg).

MS(ESI,m/z):331.1[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400MHz) δ 13.07 (s, 1H), 7.82 (s, 1H), 7.22 (s, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.75 (s, 1H),5.81(s,2H),4.56(d,J=4.5Hz,1H),4.09–3.94(m,1H),3.45–3.36(m,1H),1.93-1.80(m,4H),1.46 –1.32(m,2H),1.30–1.16(m,2H).

Example 39: 1-((2-amino-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidin-4-yl)amino)methyl)cyclopropanecarbonitrile (compound 39)

The first step: 1-((2-amino-6-iodothieno[3,2-d]pyrimidin-4-yl)amino)methyl)cyclopropanecarbonitrile (compound 39a)

At room temperature, compound 10b (50 mg) was added to DMF (2 mL), DIPEA (110.24 mg) and BOP (90.69 mg) were added successively, and the mixture was stirred for 5 min. Continue to add 1-(aminomethyl)cyclopropanecarbonitrile hydrochloride (67.86mg) and react for 16h to obtain crude compound 39a, which was directly used in the next reaction.

MS(ESI,m/z): 372.0[M+H] ⁺ .

The second step: 1-((2-amino-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidin-4-yl)amino)methyl)cyclopropanecarbonitrile (compound 39)

To the reaction solution of compound 39a obtained in the first step, 1H-pyrazole-5-boronic acid pinacolate (66.20mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (14mg), K ₂ CO were sequentially added ₃ (70.73mg) and water (0.5mL), heated to 100℃ under the protection of _{N 2 to react for 4h.} The reaction solution was filtered through Celite, and the filtrate was separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 39 (9 mg).

MS(ESI,m/z):312.1[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400MHz) δ 13.08 (s, 1H), 7.85 (s, 1H), 7.73 (s, 1H), 7.28 (s, 1H), 6.81 (s, 1H), 5.99 ( s, 2H), 3.60 (d, J = 5.9 Hz, 2H), 1.21 (s, 4H).

Example 40: N ⁴ -((3,5-dimethylisoxazol-4-yl)methyl)-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidine -2,4-Diamine (Compound 40)

The first step: N ⁴ -((3,5-dimethylisoxazol-4-yl)methyl)-6-iodothieno[3,2-d]pyrimidine-2,4-diamine (compound 40a)

At room temperature, compound 10b (50 mg) was added to DMF (2 mL), DIPEA (110.24 mg) and BOP (90.69 mg) were added successively, and the mixture was stirred for 5 min. Continue to add 3,5-dimethyl-4-aminomethylisoxazole hydrochloride (83.23mg) and react for 16h to obtain the crude compound 40a, which was directly used in the next reaction.

MS(ESI,m/z):402.0[M+H] ⁺ .

The second step: N ⁴ -((3,5-dimethylisoxazol-4-yl)methyl)-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidine -2,4-Diamine (Compound 40)

To the reaction solution of compound 40a obtained in the first step, 1H-pyrazole-5-boronic acid pinacolate (66.20mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (14mg), K ₂ CO were sequentially added ₃ (70.73mg) and water (0.5mL), heated to 100℃ under the protection of _{N 2 to react for 4h.} The reaction solution was filtered through Celite, and the filtrate was separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 40 (11 mg).

MS(ESI,m/z):342.1[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400MHz) δ 13.06 (s, 1H), 7.84 (s, 1H), 7.60 (t, J = 5.3 Hz, 1H), 7.25 (s, 1H), 6.78 (s, 1H), 5.87 (s, 2H), 4.36 (d, J = 5.4 Hz, 2H), 2.43 (s, 3H), 2.23 (s, 3H).

Example 41: cis-3-((2-amino-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidin-4-yl)amino)-1-methyl ring Butanol (Compound 41)

The first step: cis-3-((2-amino-6-iodothieno[3,2-d]pyrimidin-4-yl)amino)-1-methylcyclobutanol (Compound 41a)

At room temperature, compound 10b (50 mg) was added to DMF (2 mL), DIPEA (110.24 mg) and BOP (90.69 mg) were added successively, and the mixture was stirred for 5 min. Continue to add cis-3-amino-1-methylcyclobutanol hydrochloride (51.77 mg) and react for 16 h to obtain the crude compound 41a, which was directly used in the next reaction.

MS(ESI,m/z): 377.0[M+H] ⁺ .

Step 2: cis-3-((2-amino-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidin-4-yl)amino)-1-methyl ring Butanol (Compound 41)

To the reaction solution of compound 41a obtained in the first step, 1H-pyrazole-5-boronic acid pinacolate (66.20mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (14mg), K ₂ CO were sequentially added ₃ (70.73mg) and water (0.5mL), heated to 100℃ under the protection of _{N 2 to react for 4h.} The reaction solution was filtered through Celite, and the filtrate was separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 494 (13 mg).

MS(ESI,m/z): 317.1[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400MHz) δ 13.07 (s, 1H), 7.85 (s, 1H), 7.53 (s, 1H), 7.24 (s, 1H), 6.78 (s, 1H), 5.95 ( s, 2H), 4.96 (s, 1H), 4.20-4.04 (m, 1H), 2.39-2.31 (m, 2H), 2.16-2.05 (m, 2H), 1.27 (s, 3H).

Example 42: N ⁴ -((1-methyl-1H-pyrazol-4-yl)methyl)-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidine- 2,4-Diamine (Compound 42)

The first step: 6-iodo-N ⁴ -((1-methyl-1H-pyrazol-4-yl)methyl)thieno[3,2-d]pyrimidine-2,4-diamine (Compound 42a )

At room temperature, compound 10b (50 mg) was added to DMF (2 mL), DIPEA (110.24 mg) and BOP (90.69 mg) were added successively, and the mixture was stirred for 5 min. Continue to add 4-(aminomethyl)-1-methylpyrazole (56.88mg) and react for 16h to obtain the crude compound 42a, which was directly used in the next reaction.

MS(ESI,m/z): 387.0[M+H] ⁺ .

The second step: N ⁴ -((1-methyl-1H-pyrazol-4-yl)methyl)-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidine- 2,4-Diamine (Compound 42)

To the reaction solution of compound 42a obtained in the first step, 1H-pyrazole-5-boronic acid pinacolate (66.20mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (14mg), K ₂ CO were sequentially added ₃ (70.73mg) and water (0.5mL), heated to 100℃ under the protection of _{N 2 to react for 4h.} The reaction solution was filtered through Celite, and the filtrate was separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 42 (13 mg).

MS(ESI,m/z): 327.1[M+H] ⁺ .

¹ H NMR(DMSO-d ₆ ,400MHz)δ13.06(s,1H),7.84(s,1H),7.71-7.62(m,2H),7.41(s,1H),7.25(s,1H), 6.78 (s, 1H), 6.01 (s, 2H), 4.42 (d, J = 5.6 Hz, 2H), 3.77 (s, 3H).

Example 43: N ⁴ -Cyclopentyl-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidine-2,4-diamine (Compound 43)

The first step: N ⁴ -cyclopentyl-6-iodothieno[3,2-d]pyrimidine-2,4-diamine (compound 43a)

At room temperature, compound 10b (50 mg) was added to DMF (2 mL), DIPEA (110.24 mg) and BOP (90.69 mg) were added successively, and the mixture was stirred for 5 min. Cyclopentylamine (43.58mg) was continuously added and reacted for 16h to obtain crude compound 43a, which was directly used in the next reaction.

MS(ESI,m/z): 361.0[M+H] ⁺ .

The second step: N ⁴ -cyclopentyl-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidine-2,4-diamine (Compound 43)

To the reaction solution of compound 43a obtained in the first step, 1H-pyrazole-5-boronic acid pinacolate (66.20mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (14mg), K ₂ CO were sequentially added ₃ (70.73mg) and water (0.5mL), heated to 100℃ under the protection of _{N 2 to react for 4h.} The reaction solution was filtered through Celite, and the filtrate was separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 43 (7 mg).

MS(ESI,m/z): 301.1[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400MHz) δ 13.06 (s, 1H), 7.84 (s, 1H), 7.23 (s, 1H), 7.15 (d, J = 6.7 Hz, 1H), 6.77 (s, 1H), 5.84 (s, 2H), 4.53--4.40 (m, 1H), 2.01--1.88 (m, 2H), 1.78--1.66 (m, 2H), 1.60--1.47 (m, 4H).

Example 44: N ⁴ -(2-methoxy-2-methylpropyl)-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidine-2,4-di Amine (Compound 44)

The first step: 6-iodo-N ⁴ -(2-methoxy-2-methylpropyl)thieno[3,2-d]pyrimidine-2,4-diamine (compound 44a)

At room temperature, compound 10b (50 mg) was added to DMF (2 mL), DIPEA (110.24 mg) and BOP (90.69 mg) were added successively, and the mixture was stirred for 5 min. 2-Methoxy-2-methylpropylamine hydrochloride (71.46 mg) was continuously added and reacted for 16 h to obtain crude compound 44a, which was directly used in the next reaction.

MS(ESI,m/z): 379.0[M+H] ⁺ .

The second step: N ⁴ -(2-methoxy-2-methylpropyl)-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidine-2,4-di Amine (Compound 44)

To the reaction solution of compound 44a obtained in the first step, 1H-pyrazole-5-boronic acid pinacolate (66.20mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (14mg), K ₂ CO were sequentially added ₃ (70.73mg) and water (0.5mL), heated to 100℃ under the protection of _{N 2 to react for 4h.} The reaction solution was filtered through Celite, and the filtrate was separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 44 (8 mg).

MS(ESI,m/z):319.1[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400MHz) δ 13.06 (s, 1H), 7.84 (s, 1H), 7.24 (s, 1H), 6.92 (t, J = 5.6 Hz, 1H), 6.78 (s, 1H), 5.84 (s, 2H), 3.53 (d, J = 6.0 Hz, 2H), 3.17 (s, 3H), 1.13 (s, 6H).

Example 45: N ⁴ -(1-methylcyclobutyl)-7-(1H-pyrazol-5-yl)quinazoline-2,4-diamine formate (Compound 45s)

The first step: 7-bromo-N ⁴ -(1-methylcyclobutyl)quinazoline-2,4-diamine (Compound 45a)

At room temperature, compound 2b (70mg), 1-methylcyclobutylamine hydrochloride (70.92mg), BOP (89.28mg) and DIPEA (188.43mg) were added to DMF (2mL) and reacted for 16h to obtain crude compound 45a , Directly used in the next reaction.

MS(ESI,m/z): 309.1[M+H] ⁺ .

The second step: N ⁴ -(1-methylcyclobutyl)-7-(1H-pyrazol-5-yl)quinazoline-2,4-diamine formate (Compound 45s)

To the reaction solution of compound 45a obtained in the first step, potassium carbonate (94.34mgl), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (27.89mg), 1H-pyrazole-5-boronic acid pinacol ester were sequentially added (87.86mg) and water (1mL), heated to 100°C under the protection of _{N 2 to react for 3h.} The reaction solution was filtered through Celite, and the filtrate containing compound 45 was separated and purified by Prep-HPLC (elution condition 3), and lyophilized to obtain compound 45s (2 mg).

MS(ESI,m/z): 295.1[M+H] ⁺ .

¹ H NMR(DMSO-d ₆ ,400MHz)δ8.32(s,1H),8.11(d,J=8.5Hz,1H),7.99(s,1H),7.76(s,1H),7.63(d, J = 1.7Hz, 1H), 7.53 (d, J = 8.4Hz, 1H), 6.81 (d, J = 2.2Hz, 1H), 6.63 (s, 2H), 2.42-2.34 (m, 2H), 2.20- 2.11 (m, 2H), 1.91-1.80 (m, 2H), 1.60 (s, 3H).

Example 46: 1-(2-Amino-7-(1H-pyrazol-5-yl)quinazolin-4-yl)piperidin-4-ol (Compound 46)

The first step: 1-(2-amino-7-bromoquinazolin-4-yl)piperidin-4-ol (compound 46a)

At room temperature, compound 2b (70mg), piperidin-4-ol (58.99mg), BOP (89.28mg) and DIPEA (188.43mg) were added to DMF (2mL) and reacted for 16h to obtain crude compound 46a, which was used directly Next reaction.

MS(ESI,m/z): 325.1[M+H] ⁺ .

Step 2: 1-(2-Amino-7-(1H-pyrazol-5-yl)quinazolin-4-yl)piperidin-4-ol (Compound 46)

To the reaction solution of compound 46a obtained in the first step, potassium carbonate (94.34mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (27.89mg), 1H-pyrazole-5-boronic acid pinacolate were sequentially added (87.86mg) and water (1mL), heated to 100°C under the protection of _{N 2 to react for 3h.} The reaction solution was filtered through Celite, and the filtrate was separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 46 (7 mg).

MS(ESI,m/z):311.1[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400MHz) δ 13.01 (s, 1H), 7.82 (s, 1H), 7.73-7.68 (m, 2H), 7.56 (s, 1H), 6.82 (d, J = 2.2 Hz, 1H), 6.29 (s, 2H), 4.80 (d, J = 4.2 Hz, 1H), 3.92-3.87 (m, 2H), 3.79-3.74 (m, 1H), 3.26-3.19 (m, 2H) ,1.93-1.88m,2H),1.62-1.53(m,2H).

Example 47: cis-3-((2-amino-7-(1H-pyrazol-5-yl)quinazolin-4-yl)amino)-1-methylcyclobutanol (Compound 47)

The first step: cis-3-((2-amino-7-bromoquinazolin-4-yl)amino)-1-methylcyclobutanol (Compound 47a)

At room temperature, compound 2b (70mg), cis-3-amino-1-methylcyclobutanol hydrochloride (58.99mg), BOP (89.28mg) and DIPEA (188.43mg) were added to DMF (2mL), After 16 hours of reaction, the crude compound 47a was obtained, which was directly used in the next reaction.

MS(ESI,m/z): 323.1[M+H] ⁺ .

The second step: cis-3-((2-amino-7-(1H-pyrazol-5-yl)quinazolin-4-yl)amino)-1-methylcyclobutanol (Compound 47)

To the reaction solution of compound 47a obtained in the first step, potassium carbonate (94.34mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (27.89mg), 1H-pyrazole-5-boronic acid pinacolate were sequentially added (87.86mg) and water (1mL), heated to 100°C under the protection of _{N 2 to react for 3h.} The reaction solution was filtered through Celite, and the filtrate was separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 47 (4 mg).

MS(ESI,m/z):311.1[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400MHz) δ 8.09 (d, J = 8.5 Hz, 1H), 7.84 (d, J = 6.4 Hz, 1H), 7.74 (d, J = 2.2 Hz, 1H), 7.58 (d,J=1.7Hz,1H),7.48-7.46(m,1H),6.80(d,J=2.2Hz,1H),6.04(s,2H),5.02(s,1H),4.21-4.15( m, 1H), 2.43-2.37 (m, 2H), 2.20-2.14 (m, 2H), 1.30 (s, 3H).

Example 48: (S)-2-((2-amino-7-(1H-pyrazol-5-yl)quinazolin-4-yl)amino)-1-propanol (Compound 48)

The first step: (S)-2-((2-amino-7-bromoquinazolin-4-yl)amino)-1-propanol (Compound 48a)

At room temperature, compound 2b (70mg), (S)-2-amino-1-propanol (43.80mg), BOP (89.28mg) and DIPEA (188.43mg) were added to DMF (2mL) and reacted for 16h to obtain crude product Compound 48a was directly used in the next reaction.

MS(ESI,m/z): 299.1[M+H] ⁺ .

The second step: (S)-2-((2-amino-7-(1H-pyrazol-5-yl)quinazolin-4-yl)amino)-1-propanol (Compound 48)

To the reaction solution of compound 48a obtained in the first step, potassium carbonate (94.34mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (27.89mg), 1H-pyrazole-5-boronic acid pinacolate were sequentially added (87.86mg) and water (1mL), heated to 100°C under the protection of _{N 2 to react for 3h.} The reaction solution was filtered through Celite, and the filtrate was separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 48 (10 mg)

MS(ESI,m/z):285.1[M+H] ⁺ .

¹ H NMR(DMSO-d ₆ ,400MHz)δ12.99(s,1H), 8.06(d,J=8.5Hz,1H), 7.80(s,1H), 7.60(d,J=1.7Hz,1H) ,7.57-7.44(m,1H),7.38(d,J=8.0Hz,1H), 6.81(d,J=2.2Hz,1H), 6.06(s,2H), 4.79-4.77(m,1H), 4.44-4.37(m,1H), 3.56-3.51(m,1H), 3.50-3.43(m,1H), 1.20(d,J=6.7Hz,3H).

Example 49: (R)-2-((2-amino-7-(1H-pyrazol-5-yl)quinazolin-4-yl)amino)-1-butanol (Compound 49)

The first step: (R)-2-((2-amino-7-bromoquinazolin-4-yl)amino)-1-butanol (Compound 49a)

At room temperature, compound 2b (70mg), (R)-2-amino-1-butanol (51.98mg), BOP (89.28mg) and DIPEA (188.43mg) were added to DMF (2mL) and reacted for 16h to obtain crude product Compound 49a was directly used in the next reaction.

MS(ESI,m/z): 313.1[M+H] ⁺ .

The second step: (R)-2-((2-amino-7-(1H-pyrazol-5-yl)quinazolin-4-yl)amino)-1-butanol (Compound 49)

To the reaction solution of compound 49a obtained in the first step, potassium carbonate (93.72mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (27.71mg), 1H-pyrazole-5-boronic acid pinacolate were sequentially added (87.86mg) and water (1mL), heated to 100°C under the protection of _{N 2 to react for 3h.} The reaction solution was filtered through Celite, and the filtrate was separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 49 (10 mg).

MS(ESI,m/z): 299.1[M+H] ⁺ .

¹ H NMR(DMSO-d ₆ ,400MHz)δ12.98(s,1H), 8.10(d,J=8.4Hz,1H), 7.81(s,1H), 7.59(d,J=1.7Hz,1H) ,7.51(s,1H),7.29(d,J=8.2Hz,1H),6.81(d,J=2.2Hz,1H),6.00(s,2H),4.74-4.71(m,1H),4.32- 4.23 (m, 1H), 3.57-3.43 (m, 2H), 1.82-1.51 (m, 2H), 0.92-0.89 (m, 3H).

Example 50: (S)-N ⁴ -(1-methoxyprop-2-yl)-7-(1H-pyrazol-5-yl)quinazoline-2,4-diamine (Compound 50)

The first step: (S)-7-bromo-N ⁴ -(1-methoxyprop-2-yl)quinazoline-2,4-diamine (compound 50a)

At room temperature, compound 2b (70mg), (S)-1-methoxypropan-2-amine (51.98mg), BOP (89.28mg) and DIPEA (188.43mg) were added to DMF (2mL) and reacted for 16h. The crude compound 50a was obtained, which was directly used in the next reaction.

MS(ESI, m/z): 313.1[M+H]+.

The second step: (S)-N ⁴ -(1-methoxyprop-2-yl)-7-(1H-pyrazol-5-yl)quinazoline-2,4-diamine (Compound 50)

To the reaction solution of compound 50a obtained in the first step, potassium carbonate (93.72 mg), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (27.71 mg), 1H-pyrazole-5-boronic acid pinacolate were sequentially added (87.86mg) and water (1mL), heated to 100°C under the protection of _{N 2 to react for 3h.} The reaction solution was filtered through Celite, and the filtrate was separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 50.

MS(ESI,m/z): 299.1[M+H] ⁺ .

¹ H NMR(DMSO-d ₆ ,400MHz)δ12.98(s,1H), 8.05(d,J=8.6Hz,1H), 7.81(s,1H), 7.59(d,J=1.7Hz,1H) ,7.46(d,J=9.3Hz,2H),6.81(d,J=2.2Hz,1H),6.04(s,2H),4.64-4.57(m,1H),3.51-3.47(m,1H), 3.35-3.32(m,1H), 3.29(s,3H), 1.21(d,J=6.7Hz,3H).

Activity test

Experimental Example 1: The agonistic effect of the compound of the present invention on IL-1β expression in THP-1 cells after PMA-induced differentiation

In this experiment, a homogeneous time-resolved fluorescence (HTRF) detection method was used to test the effect of the compound of the present invention on the level of the downstream cytokine IL-1β of NLRP3 to evaluate the compound's activation of hNLRP3 inflammasome or hNLRP3 inflammasome pathway at the cellular level effect.

Reagents: RPMI 1640 (Hyclone); heat-inactivated FBS (fetal bovine serum) (Gibco); PMA (Biyuntian)

Cell: THP-1 (Nanjing Kebai)

Kit: IL-1βassay kit (CISBIO)

Experimental steps:

1) The THP-1 cells in the logarithmic growth phase ^{were seeded in a T75 culture flask at a density of 5×10 5} cells/well, and then cultured in a 37°C, 5% CO ₂ cell incubator for 24 hours. 1μM PMA induces THP-1 suspension cells to become adherent macrophages. The medium was RPMI 1640 containing 10% heat-inactivated FBS and 0.05 mM β-mercaptoethanol.

2) After the cells are induced and cultured for 24 hours, the adherent cells are trypsinized. Centrifuge at 1000 rpm for 5 min, remove the supernatant, and resuspend the cells in RPMI 1640 medium containing 2% heat-inactivated FBS to a density of 2×10 ⁶ cells/mL. Take 50μL/well of cell resuspension and spread it on a 96-well plate. The number of cells per well is 1×10 ⁵ cells.

3) Take an appropriate amount of 10 mM DMSO solution of the compound to be tested, and use RPMI 1640 medium containing 2% heat-inactivated FBS to prepare a 2× test concentration. Take 50 μL/well of the dilution and add it to the cells in the 96-well plate, mix well, and place the plate in a 37°C, 5% CO ₂ cell incubator for 6 hours. Collect the supernatant, and measure the level of IL-1β in accordance with the IL-1β detection kit instructions.

4) The EC ₅₀ was fitted by the GraphPad software log(agonist) vs.response-Variable slope four-parameter method. The results are shown in Table 1.

Experimental Example 2: The agonistic effect of the compound of the present invention on the expression of IL-1β _{in THP1 cells (THP1-def NLRP3 cells) lacking NLRP3 after PMA-induced differentiation}

In this experiment, the HTRF detection method was used to test the effect of the compound of the present invention on the _{level of IL-1β in THP1-def} NLRP3 cells to evaluate the specificity of the compound on hNLRP3 inflammasome or hNLRP3 inflammasome pathway agonism.

Reagents: as described in Experimental Example 1

Cell: THP1- _def NLRP3 (InvivoGen)

Kit: IL-1βassay kit (CISBIO)

Experimental steps:

_{1) THP1-def} NLRP3 cells in the logarithmic growth phase were seeded in a T75 culture flask at a density of 5×10 ⁵ cells/well, and then cultured in a cell incubator at _{37°C and 5% CO 2 for 24 hours.} 1μM PMA was used to induce THP1- _def NLRP3 suspension cells to become adherent macrophages. The medium was RPMI 1640 containing 10% heat-inactivated FBS and 0.05 mM β-mercaptoethanol.

2) After the cells are induced and cultured for 24 hours, the adherent cells are trypsinized. Centrifuge at 1000 rpm for 5 min, remove the supernatant, and resuspend the cells in RPMI 1640 medium containing 2% heat-inactivated FBS to a density of 2×10 ⁶ cells/mL. Take 50μL/well of cell resuspension and spread it on a 96-well plate. The number of cells per well is 1×10 ⁵ cells.

3) Take an appropriate amount of 10 mM DMSO solution of the compound to be tested, and use RPMI 1640 medium containing 2% heat-inactivated FBS to prepare a 2× test concentration. Take 50 μL/well of the dilution and add it to the cells in the 96-well plate, mix well, and place the plate in a 37°C, 5% CO ₂ cell incubator for 6 hours. Collect the supernatant, and measure the level of IL-1β in accordance with the IL-1β detection kit instructions.

4) The EC ₅₀ was fitted by the GraphPad software log(agonist) vs.response-Variable slope four-parameter method. The results are shown in Table 1.

Experimental Example 3: The agonistic effect of the compound of the present invention on hTLR7

In this experiment, the luciferase in HEK-hTLR7-NF-κB-luciferase reporter gene cells was tested to test the activating effect of the compound of the present invention on the TLR7 signaling pathway, so as to evaluate the specificity of the compound's agonistic effect on the NLRP3 pathway.

Reagents: DMEM (High glucose), FBS (Gibco)

Cells: HEK-hTLR7-NF-κB-Luciferase reporter cells (human TLR7NF-κB-luciferase reporter cells) (Nanjing Kebai)

Kit: Bright-Glo ^TM Luciferase Detection Kit (Promega)

Experimental steps:

1) Trypsinize HEK-hTLR7-NF-κB-Luciferase reporter gene cells in the logarithmic growth phase, and resuspend them to ^{a concentration of 2×10 6} cells/mL in culture medium. Add 50μL/well of cell resuspension to a 96-well plate, the number of cells per well is 1×10 ⁶ cells. Take an appropriate amount of 10 mM DMSO solution of the test compound, and use the culture medium to prepare a 2× test concentration. Add 50 μL/well to the cells in the 96-well plate, and place the 96-well plate in a 37°C, 5% CO ₂ cell incubator for 16 hours. The medium is DMEM (High glucose) containing 10% FBS.

2) After the cell incubation is over, add 100 μL/well of Bright-Glo ^TM Luciferase detection reagent and incubate at room temperature for 5 minutes. The microplate reader reads the relative luciferase activity unit (Relative Luciferase Unit, RLU).

_{3) The EC 50} of the stimulating effect of the tested compound on hTLR7 was fitted by the GraphPad software log(agonist) vs.response--Variable slope four-parameter method. The results are shown in Table 1.

Experimental Example 4: The agonistic effect of the compound of the present invention on hTLR8

In this experiment, the secretion of alkaline phosphatase in the HEK-Blue cell line was tested to test the activating effect of the compound of the present invention on the TLR8 signaling pathway, so as to evaluate the specificity of the compound's agonistic effect on the NLRP3 pathway.

Reagents: DMEM (High glucose), FBS (Gibco), QUANTI-Blue (InvivoGen)

Cells: HEK-Blue ^TM hTLR8 cells (human TLR 8 cells) (InvivoGen)

Experimental steps:

^{1) Trypsinize HEK-Blue™} hTLR8 cells in the logarithmic growth phase, and resuspend them to ^{a concentration of 2×10 6} cells/mL in culture medium. Add 50μL/well of cell suspension to 96-well plate. Take an appropriate amount of 10 mM DMSO solution of the compound to be tested, prepare a 2× test concentration with culture medium, and add 50 μL/well to the cells in a 96-well plate. The plate was placed in a 37°C, 5% CO ₂ cell incubator for 16 hours. The medium is DMEM (High glucose) containing 10% FBS.

2) After the cell incubation is over, take 10 μL of cell culture supernatant and transfer it to a 96-well plate. Add 90μL/well of QUANTI-Blue detection solution and incubate at 37°C for 3 hours. Microplate reader OD ₆₂₀ reading.

3) The compound of hTLR8 EC stimulation test by GraphPad Software ₅₀ log (agonist) vs.response - Variable slope fitting four parameters, the results are shown in Table 1.

Table 1

The results show that the compounds of the present invention represented by the compounds listed in Table 1 have a significant agonistic effect on the expression of IL-1β in THP-1 cells after PMA-induced differentiation, but on IL-1β _{in THP-1 def NLRP3 cells.} The expression has no agonistic effect even at the highest compound tested concentration (30 μM). All the compounds tested had no activating effect on hTLR7 and hTLR8 at 100 μM. In summary, the compounds of the present invention represented by the compounds listed in Table 1 have obvious specific agonistic activity on hNLRP3 and/or its signal pathway.

Experimental example 5: hERG experiment

1. Using Predictor ^TM hERG Fluorescence Polarization Assay Kit (ThermoFisher), test the inhibitory effect of the compound on the hERG potassium ion channel according to the kit instructions. The test concentrations of the compounds were 1 μM and 10 μM, and the results are shown in Table 2.

Table 2

Compound number IC ₅₀ (μM) 1s >10 10 >10 twenty one >10 26 >10 34 >10

2. The manual patch clamp method was used to test the inhibitory effect of the compounds on hERG.

Cell line: over-expressing hERG potassium channel HEK-293 (human embryonic kidney cells) (Creece Bio)

Negative control: extracellular fluid containing 0.1% DMSO (Sigma)

Positive control: Quinidine (aladdin)

Test compound concentration: 10μM

Reaction temperature: 22～24℃

Data collection: PATCHMASTER V2X60 (HEKA Instruments Inc.).

Experimental steps:

1) Dissolve the compound in DMSO and prepare a 10 mM solution. Take 30 μL of this solution and add it to 30 mL of extracellular fluid for electrophysiological testing.

2) Transfer the experimental cells to a cell bath embedded in the platform of the inverted microscope, and perfuse the extracellular fluid. After stabilizing for 5 minutes, the membrane voltage was clamped to -80mV. The cells were stimulated with +20mV voltage for 2s to activate the hERG potassium channel, and then repolarized to -50mV for 5s to generate outward tail current. The stimulation frequency is 15 seconds/time.

3) Perfuse extracellular fluid (2 ml/min) and record continuously. After the current is stable, the extracellular fluid containing the test compound is perfused and the recording is continued until the inhibitory effect of the compound on the hERG current reaches a steady state.

In this experiment, the positive control quinidine inhibited the hERG potassium channel by 90.7% at 30μM, indicating that the test system was normal. The results are shown in Table 3.

table 3

Compound number 10μM average inhibition rate (%) 3 2.53±1.49 4s 3.48±0.75 5s 1.26±0.81 6s 5.28±2.59

The results show that the IC _{50 of the} compounds listed in Table 3> 10 μM, indicating that the compounds of the present invention represented by the compounds listed in Table 3 have no obvious inhibitory effect on hERG, and the possibility of prolonging the cardiac QT interval is small.

Experimental example 6: CYP enzyme inhibition test

CYP2D6Cyan Screening Kit和

CYP3A4 Red Screening Kit，按照试剂盒说明分别测定化合物对CYP1A2、CYP2D6和CYP3A4的抑制活性。结果见表4。 CYP450 is the most important enzyme system in drug metabolism. Enzymes involved in metabolism interact with drugs, and the most important ones are CYP1A2, CYP2D6 and CYP3A4. This experiment uses P450-Glo ^TM CYP1A2 Screening System,

CYP2D6Cyan Screening Kit and

CYP3A4 Red Screening Kit, according to the kit instructions to determine the compound's inhibitory activity on CYP1A2, CYP2D6 and CYP3A4. The results are shown in Table 4.

Table 4

The results show that the compounds of the present invention represented by the compounds listed in Table 4 have no obvious inhibitory effect on CYP1A2, CYP2D6 and CYP3A4 enzymes.

In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books, and any other publications) is incorporated herein by reference in its entirety.

Claims (13)

A compound having the structure shown in Formula I, a stereoisomer, a tautomer of the compound, or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, Or stable isotope derivatives, metabolites or prodrugs of the compound:

among them: R ^{1 is} selected from C _1-8 alkyl, C _3-8 cycloalkyl, 4-10 membered heterocyclic group, C _6-12 aryl, 5-10 membered heteroaryl and 9-12 membered aryl and hetero Cyclic group, wherein the C _1-8 alkyl group, C _3-8 cycloalkyl group, 4-10 membered heterocyclic group, C _6-12 aryl group, 5-10 membered heteroaryl group and 9-12 membered aryl group The heterocyclic groups are each optionally substituted by one or more of the following substituents: halogen, CN, NO ₂ , C _1-4 alkyl, C _3-8 cycloalkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, 4-10 membered heterocyclyl, C _6-12 aryl, 5-10 membered heteroaryl, 9-12 membered heterocyclyl, and aryl ^{_{group, CO 2 R 30, C (}} O) R ³⁰ , C(O)NR ³¹ R ³² , NR ³³ C(O)R ³⁴ , NR ³¹ R ³² , OC(O)R ³⁰ , OC(O)NR ³¹ R ³² , NR ³³ C(O)NR ³¹ R ³² , NR ³³ C(O)OR ³⁰ , S(O)NR ³¹ R ³² , S(O) ₂ NR ³¹ R ³² , S(O)R ³⁵ , S(O) ₂ R ³⁵ , OR ³⁷ and SR ³⁷ ; R ^{2 is} selected from H, NR ^41a R ^41b , C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl and 4-10 membered heterocyclic group, wherein said C _{1- 8} alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl and 4-10 membered heterocyclyl group each optionally substituted with a group of the following or One substitution: halogen, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, 4-7 membered heterocyclic group, CN, NO ₂ , OR ³⁷ , SR ³⁷ , C(O)R ³⁰ , C(O) NR ³¹ R ³² , NR ³³ C(O)R ³⁴ , C(O)OR ³⁰ , OC(O)R ³⁰ , OC(O)NR ³¹ R ³² , NR ³³ C(O)NR ³¹ R ³² and NR ³¹ R ³² ; R ³ at each occurrence is independently selected from H, halogen, CN, NO ₂ , C _1-8 alkyl, C _3-8 cycloalkyl, 4-10 membered heterocyclic group, C _6-12 aryl, 5-10 membered heteroaryl, 9-12 membered aryl and heterocyclic group, 9-12 membered aryl and heteroaryl, 9-12 membered aryl and cycloalkyl, CO ₂ R ³⁰ , C(O) NR ³¹ R ³² , NR ³³ C(O)R ³⁴ , NR ³¹ R ³² , S(O) ₂ R ³⁵ , OR ³⁷ , SR ³⁷ , C(O)R ³⁰ , OC(O)R ³⁰ , OC(O ) NR ³¹ R ³² , NR ³³ C(O)NR ³¹ R ³² , NR ³³ C(O)OR ³⁰ , C(=NR ³⁸ )NR ³¹ R ³² , NR ³³ C(=NR ³⁸ )NR ³¹ R ³² , P(R ³⁹ ) ₂ , P(OR ³⁹ ) ₂ , P(O)R ³⁹ R ⁴⁰ , P(O)OR ³⁹ OR ³⁰ , S(O)R ³⁵ , S(O)NR ³¹ R ³² and S( O) ₂ NR ³¹ R ³² , wherein the C _1-8 alkyl group, C _3-8 cycloalkyl group, 4-10 membered heterocyclic group, C _6-12 aryl group, 5-10 membered heteroaryl group, 9 The -12-membered aryl and heterocyclyl, 9-12-membered aryl and heteroaryl, and 9-12-membered aryl and cycloalkyl are each optionally substituted with one or more of the following substituents: halogen, CN , NO ₂ , C _1-4 alkyl, C _3-8 cycloalkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, 4-10 membered heterocyclic group, C _6-12 aryl, 5 -10 membered heteroaryl, 9-12 membered aryl and heterocyclic group, CO ₂ R ³⁰ , C(O)R ³⁰ , C(O)NR ³¹ R ³² , NR ³³ C(O)R ³⁴ , NR ³¹ R ³² , S(O)R ³⁵ , S(O) ₂ R ³⁵ , S(O)NR ³¹ R ³² , S(O) ₂ NR ³¹ R ³² , OR ³⁷ , SR ³⁷ , OC(O)R ³⁰ , OC(O)NR ³¹ R ³² , NR ³³ C(O)NR ³¹ R ³² , NR ³³ C(O)OR ³⁰ , C(=NR ³⁸ )NR ³¹ R ³² , NR ³³ C(=NR ³⁸ )NR ³¹ R ³² , =NNR ³¹ R ³² , P(R ³⁹ ) ₂ , P(OR ³⁹ ) ₂ , P(O)R ³⁹ R ⁴⁰ and P(O)OR ³⁹ OR ³⁰ ; R ⁵ is absent or selected from halogen, C _1-6 alkyl, C _1-4 alkoxy, C _3-8 cycloalkyl and 4-10 membered heterocyclic group, wherein the C _1-6 alkyl, C _1-4 alkoxy, C _3-8 cycloalkyl, and 4-10 membered heterocyclic group are each optionally substituted with one or more of the following groups: halogen, OH, CN, C _1-4 alkane Oxy, C _1-4 hydroxyalkyl and NR ³¹ R ³² ; m is 0, 1 or 2, preferably 0 or 1; L is -(L ¹ ) _n -(L ² ) _p -(L ³ ) _q -, wherein L ¹ , L ² and L ^{3 are the} same or different and each is independently selected from C _1-8 sub Alkyl, C _2-8 alkenylene, C _2-8 alkynylene, C _1-8 alkyleneoxy, C _3-8 cycloalkylene, 4-10 membered heterocyclylene, C _6-12 Arylene, 5-10 membered heteroarylene, O, S, NR ³³ , S(O), S(O) ₂ , C(O) and C(R ^36a R ^36b ), wherein the C _{1- 8} alkylene, C _2-8 alkenylene, C _2-8 alkynylene, C _1-8 alkyleneoxy, C _3-8 cycloalkylene, 4-10 membered heterocyclylene, C _{6 The -12} arylene group and the 5-10 membered heteroarylene group are each optionally substituted with one or more of the following substituents: halogen, OH, CN, NO ₂ , C _1-6 alkyl, C _1-4 Haloalkyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy and NR ³¹ R ³² ; n, p, and q are each independently 0, 1 or 2 each time they appear; R ³⁰ , R ³⁷ , R ³⁹ and R ⁴⁰ are each independently selected from H, C _1-8 alkyl (e.g. C _1-6 alkyl or C _1-4 alkyl), C _1-8 alkoxy (e.g. C _{1- 6} alkoxy or C _1-4 alkoxy), C _3-8 cycloalkyl, 4-10 membered heterocyclyl, C _6-12 aryl, 5-10 membered heteroaryl, -C _1-8 alkyl-C _6-12 aryl and -C _1-8 alkyl-(5-10 membered heteroaryl), wherein the C _1-8 alkyl, C _1-8 alkoxy, C _3-8 cycloalkyl, 4-10 membered heterocyclic group, C _6-12 aryl, 5-10 membered heteroaryl, -C _1-8 alkyl-C _6-12 aryl and -C _1-8 Alkyl-(5-10 membered heteroaryl) are each optionally substituted with one or more of the following substituents: OH, CN, NO ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, halogen, C _1-4 haloalkoxy, CO ₂ (C _1-6 alkyl), CONR ³¹ R ³² , NR ³¹ R ³² , NR ³³ C(O)R ³⁴ , S(O ) R ³⁵ , S(O) ₂ R ³⁵ , S(O)NR ³¹ R ³² and S(O) ₂ NR ³¹ R ³² ; R ³¹ , R ³² , R ³³ and R ³⁴ are each independently selected from H, C _1-8 alkyl, C _1-8 alkoxy, C _3-8 cycloalkyl, 4-10 membered heterocyclic group, C _6-12 aryl and 5-10 membered heteroaryl, or R ³¹ and R ³² together with the N atom to which they are attached form a 4-8 membered heterocyclic group, or R ³³ and R ³⁴ and the C to which they are each attached Together with the N atom to form a 4-8 membered heterocyclic group, wherein the C _1-8 alkyl group, C _1-8 alkoxy group, C _3-8 cycloalkyl group, 4-8 membered heterocyclic group, 4-10 Each of the membered heterocyclic group, C _6-12 aryl group and 5-10 membered heteroaryl group is optionally substituted by one or more of the following substituents: OH, CN, halogen, NO ₂ , C _1-4 alkyl , C _1-4 alkoxy, C _1-4 hydroxyalkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, 4-10 membered heterocyclic group, C _6-12 aryl and 5-10 Yuan heteroaryl R ^{35 is} selected from C _1-8 alkyl, C _1-8 alkoxy, C _3-8 cycloalkyl, 4-10 membered heterocyclic group, C _6-12 aryl, 5-10 membered heteroaryl, -C _1-8 alkyl-C _6-12 aryl and -C _1-8 alkyl-(5-10 membered heteroaryl), wherein the C _1-8 alkyl, C _1-8 alkoxy , C _3-8 cycloalkyl, 4-10 membered heterocyclyl, C _6-12 aryl and 5-10 membered heteroaryl are each optionally substituted by one or more of the following substituents: OH, CN , NO ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, halogen, C _1-4 haloalkoxy, CO ₂ (C _1-6 alkyl), CONR ³¹ R ³² , NR ³¹ R ³² , NR ³³ C(O)R ³⁴ , S(O)Me, S(O) ₂ Me, S(O)NR ³¹ R ³² and S(O) ₂ NR ³¹ R ³² , where R ³¹ , R ³² , R ³³ and R ³⁴ are as defined above; R ^36a and R ^{36b are the} same or different and are each independently selected from H, C _1-8 alkyl and C _1-8 alkoxy, wherein the C _1-8 alkyl and C _1-8 alkoxy are each independently Optionally substituted by one or more of the following groups: OH, CN, halogen, NH ₂ , NHCH ₃ and N(CH ₃ ) ₂ , or R ^36a and R ^36b together with the C atom to which they are attached form a 3- 7-membered cycloalkyl or heterocyclic group; R ^{38 is} selected from H, OH, CN, NO ₂ , S(O)R ³⁵ and S(O) ₂ R ³⁵ ; R ^41a and R ^41b are each independently selected from H, C _1-6 alkyl, C _1-6 alkoxy and C _3-8 cycloalkyl, or R ^41a and R ^41b form together with the N atom to which they are attached 4-7 membered heterocyclic group, wherein the C _1-6 alkyl group, C _1-6 alkoxy group, C _3-8 cycloalkyl group and 4-7 membered heterocyclic group are each optionally selected from the following groups One or more of the substitutions: OH, CN and NR ³¹ R ³² ; and When multiple R ³⁰ exist at the same time, each R ³⁰ may be the same or different; When multiple R ³¹ exist at the same time, each R ³¹ may be the same or different; When multiple R ³² exist at the same time, each R ³² may be the same or different; When multiple R ³³ exist at the same time, each R ³³ may be the same or different; When multiple R ³⁴ exist at the same time, each R ³⁴ may be the same or different; When multiple R ³⁵ exist at the same time, each R ³⁵ may be the same or different; When multiple R ³⁷ exist at the same time, each R ³⁷ may be the same or different; When multiple R ³⁸ exist at the same time, each R ³⁸ may be the same or different; When multiple R ³⁹ exist at the same time, each R ³⁹ may be the same or different; When multiple R ⁴⁰ exist at the same time, each R ⁴⁰ may be the same or different; Preferably, the compound has the structure shown in Formula II:

More preferably, the compound has a structure represented by formula II-A:

A compound having the structure represented by Formula III, a stereoisomer, tautomer or mixture of the compound, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, Or stable isotope derivatives, metabolites or prodrugs of the compound:

among them: X ^{1 is} selected from CR ⁶ and N, R ^{1 is} selected from C _1-8 alkyl, C _3-8 cycloalkyl, 4-10 membered heterocyclic group, C _6-12 aryl, 5-10 membered heteroaryl and 9-12 membered aryl and hetero Cyclic group, wherein the C _1-8 alkyl group, C _3-8 cycloalkyl group, 4-10 membered heterocyclic group, C _6-12 aryl group, 5-10 membered heteroaryl group and 9-12 membered aryl group The heterocyclic groups are each optionally substituted by one or more of the following substituents: halogen, CN, NO ₂ , C _1-4 alkyl, C _3-8 cycloalkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, 4-10 membered heterocyclyl, C _6-12 aryl, 5-10 membered heteroaryl, 9-12 membered heterocyclyl, and aryl ^{_{group, CO 2 R 30, C (}} O) R ³⁰ , C(O)NR ³¹ R ³² , NR ³³ C(O)R ³⁴ , NR ³¹ R ³² , OC(O)R ³⁰ , OC(O)NR ³¹ R ³² , NR ³³ C(O)NR ³¹ R ³² , NR ³³ C(O)OR ³⁰ , S(O)NR ³¹ R ³² , S(O) ₂ NR ³¹ R ³² , S(O)R ³⁵ , S(O) ₂ R ³⁵ , OR ³⁷ and SR ³⁷ ; R ³ at each occurrence is independently selected from H, halogen, CN, NO ₂ , C _1-8 alkyl, C _3-8 cycloalkyl, 4-10 membered heterocyclic group, C _6-12 aryl, 5-10 membered heteroaryl, 9-12 membered aryl and heterocyclic group, 9-12 membered aryl and heteroaryl, 9-12 membered aryl and cycloalkyl, CO ₂ R ³⁰ , C(O) NR ³¹ R ³² , NR ³³ C(O)R ³⁴ , NR ³¹ R ³² , S(O) ₂ R ³⁵ , OR ³⁷ , SR ³⁷ , C(O)R ³⁰ , OC(O)R ³⁰ , OC(O ) NR ³¹ R ³² , NR ³³ C(O)NR ³¹ R ³² , NR ³³ C(O)OR ³⁰ , C(=NR ³⁸ )NR ³¹ R ³² , NR ³³ C(=NR ³⁸ )NR ³¹ R ³² , P(R ³⁹ ) ₂ , P(OR ³⁹ ) ₂ , P(O)R ³⁹ R ⁴⁰ , P(O)OR ³⁹ OR ³⁰ , S(O)R ³⁵ , S(O)NR ³¹ R ³² and S( O) ₂ NR ³¹ R ³² , wherein the C _1-8 alkyl group, C _3-8 cycloalkyl group, 4-10 membered heterocyclic group, C _6-12 aryl group, 5-10 membered heteroaryl group, 9 The -12-membered aryl and heterocyclyl, 9-12-membered aryl and heteroaryl, and 9-12-membered aryl and cycloalkyl are each optionally substituted with one or more of the following substituents: halogen, CN , NO ₂ , C _1-4 alkyl, C _3-8 cycloalkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, 4-10 membered heterocyclic group, C _6-12 aryl, 5 -10 membered heteroaryl, 9-12 membered aryl and heterocyclic group, CO ₂ R ³⁰ , C(O)R ³⁰ , C(O)NR ³¹ R ³² , NR ³³ C(O)R ³⁴ , NR ³¹ R ³² , S(O)R ³⁵ , S(O) ₂ R ³⁵ , S(O)NR ³¹ R ³² , S(O) ₂ NR ³¹ R ³² , OR ³⁷ , SR ³⁷ , OC(O)R ³⁰ , OC(O)NR ³¹ R ³² , NR ³³ C(O)NR ³¹ R ³² , NR ³³ C(O)OR ³⁰ , C(=NR ³⁸ )NR ³¹ R ³² , NR ³³ C(=NR ³⁸ )NR ³¹ R ³² , =NNR ³¹ R ³² , P(R ³⁹ ) ₂ , P(OR ³⁹ ) ₂ , P(O)R ³⁹ R ⁴⁰ and P(O)OR ³⁹ OR ³⁰ ; R ^{4 is} selected from H, NR ^41a R ^41b , C _1-15 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl and 4- 10-membered heterocyclic group, wherein the C _1-15 alkyl group, C _1-8 alkoxy group, C _2-8 alkenyl group, C _2-8 alkynyl group, C _3-8 cycloalkyl group and 4-10 membered The heterocyclic groups are each optionally substituted by one or more of the following substituents: halogen, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, 4-7 membered heterocyclyl, CN, NO ₂ , OR ³⁷ , SR ³⁷ , C(O)R ³⁰ , C(O)NR ³¹ R ³² , NR ³³ C(O)R ³⁴ , C(O)OR ³⁰ , OC(O)R ³⁰ , OC(O)NR ³¹ R ³² , NR ³³ C(O)NR ³¹ R ³² and NR ³¹ R ³² ; R ^{6 is} selected from H, halogen, C _1-6 alkyl, C _1-4 alkoxy, C _3-8 cycloalkyl and 4-10 membered heterocyclic group, wherein the C _1-6 alkyl, C _1-4 alkoxy, C _3-8 cycloalkyl, and 4-10 membered heterocyclic group are each optionally substituted with one or more of the following groups: halogen, OH, CN, C _1-4 alkoxy Group, C _1-4 hydroxyalkyl group and NR ³¹ R ³² ; L is -(L ¹ ) _n -(L ² ) _p -(L ³ ) _q -, wherein L ¹ , L ² and L ^{3 are the} same or different and each is independently selected from C _1-8 sub Alkyl, C _2-8 alkenylene, C _2-8 alkynylene, C _1-8 alkyleneoxy, C _3-8 cycloalkylene, 4-10 membered heterocyclylene, C _6-12 Arylene, 5-10 membered heteroarylene, O, S, NR ³³ , S(O), S(O) ₂ , C(O) and C(R ^36a R ^36b ), wherein the C _{1- 8} alkylene, C _2-8 alkenylene, C _2-8 alkynylene, C _1-8 alkyleneoxy, C _3-8 cycloalkylene, 4-10 membered heterocyclylene, C _{6 The -12} arylene group and the 5-10 membered heteroarylene group are each optionally substituted with one or more of the following substituents: halogen, OH, CN, NO ₂ , C _1-6 alkyl, C _1-4 Haloalkyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy and NR ³¹ R ³² ; n, p, and q are each independently 0, 1 or 2 each time they appear; R ³⁰ , R ³⁷ , R ³⁹ and R ⁴⁰ are each independently selected from H, C _1-8 alkyl (e.g. C _1-6 alkyl or C _1-4 alkyl), C _1-8 alkoxy (e.g. C _{1- 6} alkoxy or C _1-4 alkoxy), C _3-8 cycloalkyl, 4-10 membered heterocyclyl, C _6-12 aryl, 5-10 membered heteroaryl, -C _1-8 alkyl-C _6-12 aryl and -C _1-8 alkyl-(5-10 membered heteroaryl), wherein the C _1-8 alkyl, C _1-8 alkoxy, C _3-8 cycloalkyl, 4-10 membered heterocyclic group, C _6-12 aryl, 5-10 membered heteroaryl, -C _1-8 alkyl-C _6-12 aryl and -C _1-8 Alkyl-(5-10 membered heteroaryl) are each optionally substituted with one or more of the following substituents: OH, CN, NO ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, halogen, C _1-4 haloalkoxy, CO ₂ (C _1-6 alkyl), CONR ³¹ R ³² , NR ³¹ R ³² , NR ³³ C(O)R ³⁴ , S(O ) R ³⁵ , S(O) ₂ R ³⁵ , S(O)NR ³¹ R ³² and S(O) ₂ NR ³¹ R ³² ; R ³¹ , R ³² , R ³³ and R ³⁴ are each independently selected from H, C _1-8 alkyl, C _1-8 alkoxy, C _3-8 cycloalkyl, 4-10 membered heterocyclic group, C _6-12 aryl and 5-10 membered heteroaryl, or R ³¹ and R ³² together with the N atom to which they are attached form a 4-8 membered heterocyclic group, or R ³³ and R ³⁴ and the C to which they are each attached Together with the N atom to form a 4-8 membered heterocyclic group, wherein the C _1-8 alkyl group, C _1-8 alkoxy group, C _3-8 cycloalkyl group, 4-8 membered heterocyclic group, 4-10 Each of the membered heterocyclic group, C _6-12 aryl group and 5-10 membered heteroaryl group is optionally substituted by one or more of the following substituents: OH, CN, halogen, NO ₂ , C _1-4 alkyl , C _1-4 alkoxy, C _1-4 hydroxyalkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, 4-10 membered heterocyclic group, C _6-12 aryl and 5-10 Yuan heteroaryl R ^{35 is} selected from C _1-8 alkyl, C _1-8 alkoxy, C _3-8 cycloalkyl, 4-10 membered heterocyclic group, C _6-12 aryl, 5-10 membered heteroaryl, -C _1-8 alkyl-C _6-12 aryl and -C _1-8 alkyl-(5-10 membered heteroaryl), wherein the C _1-8 alkyl, C _1-8 alkoxy , C _3-8 cycloalkyl, 4-10 membered heterocyclyl, C _6-12 aryl and 5-10 membered heteroaryl are each optionally substituted by one or more of the following substituents: OH, CN , NO ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, halogen, C _1-4 haloalkoxy, CO ₂ (C _1-6 alkyl), CONR ³¹ R ³² , NR ³¹ R ³² , NR ³³ C(O)R ³⁴ , S(O)Me, S(O) ₂ Me, S(O)NR ³¹ R ³² and S(O) ₂ NR ³¹ R ³² , where R ³¹ , R ³² , R ³³ and R ³⁴ are as defined above; R ^36a and R ^{36b are the} same or different and are each independently selected from H, C _1-8 alkyl and C _1-8 alkoxy, wherein the C _1-8 alkyl and C _1-8 alkoxy are each independently Optionally substituted by one or more of the following groups: OH, CN, halogen, NH ₂ , NHCH ₃ and N(CH ₃ ) ₂ , or R ^36a and R ^36b together with the C atom to which they are attached form a 3- 7-membered cycloalkyl or heterocyclic group; R ^{38 is} selected from H, OH, CN, NO ₂ , S(O)R ³⁵ and S(O) ₂ R ³⁵ ; R ^41a and R ^41b are each independently selected from H, C _1-6 alkyl, C _1-6 alkoxy and C _3-8 cycloalkyl, or R ^41a and R ^41b form together with the N atom to which they are attached 4-7 membered heterocyclic group, wherein the C _1-6 alkyl group, C _1-6 alkoxy group, C _3-8 cycloalkyl group and 4-7 membered heterocyclic group may optionally be selected from the following groups One or more of the substitutions: OH, CN and NR ³¹ R ³² ; and When multiple R ³⁰ exist at the same time, each R ³⁰ may be the same or different; When multiple R ³¹ exist at the same time, each R ³¹ may be the same or different; When multiple R ³² exist at the same time, each R ³² may be the same or different; When multiple R ³³ exist at the same time, each R ³³ may be the same or different; When multiple R ³⁴ exist at the same time, each R ³⁴ may be the same or different; When multiple R ³⁵ exist at the same time, each R ³⁵ may be the same or different; When multiple R ³⁷ exist at the same time, each R ³⁷ may be the same or different; When multiple R ³⁸ exist at the same time, each R ³⁸ may be the same or different; When multiple R ³⁹ exist at the same time, each R ³⁹ may be the same or different; When multiple R ⁴⁰ exist at the same time, each R ⁴⁰ may be the same or different; Preferably, the compound has the structure shown in Formula IV:

More preferably, the compound has a structure represented by formula IV-A:

The compound according to claim 1 or 2, a stereoisomer, tautomer or mixture of the compound, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound Compounds, or stable isotope derivatives, metabolites or prodrugs of said compounds, wherein Each occurrence of R ³ is independently selected from H, halogen, CN, C _1-6 alkyl, C _3-6 cycloalkyl, 4-7 membered heterocyclyl, C _6-10 aryl, 5-6 Yuan heteroaryl, CO ₂ R ³⁰ , C(O)NR ³¹ R ³² , NR ³³ C(O)R ³⁴ , NR ³¹ R ³² , S(O) ₂ R ³⁵ , OR ³⁷ , SR ³⁷ , C(O ) R ³⁰ , OC(O)R ³⁰ , NR ³³ C(O)NR ³¹ R ³² and S(O) ₂ NR ³¹ R ³² , wherein the C _1-6 alkyl group, C _3-6 cycloalkyl group, The 4-7 membered heterocyclic group, the C _6-10 aryl group and the 5-6 membered heteroaryl group are each optionally substituted by one or more of the following substituents: halogen, CN, C _1-4 alkyl, C _3-6 cycloalkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, 4-7 membered heterocyclic group, C _6-10 aryl, 5-6 membered heteroaryl, CO ₂ R ³⁰ , C(O)R ³⁰ , C(O)NR ³¹ R ³² , NR ³³ C(O)R ³⁴ , NR ³¹ R ³² , S(O) ₂ R ³⁵ , S(O) ₂ NR ³¹ R ³² , OR ³⁷ , SR ³⁷ and NR ³³ C(O)NR ³¹ R ³² ; Preferably, ^{each occurrence of R 3} is independently selected from H, CN, C _1-6 alkyl, C _3-6 cycloalkyl, 4-7 membered heterocyclyl, C _6-10 aryl, 5- 6-membered heteroaryl, NR ³³ C(O)R ³⁴ , OR ³⁷ , SR ³⁷ , C(O)R ³⁰ and OC(O)R ³⁰ , wherein the C _1-6 alkyl group, C _3-6 ring The alkyl group, 4-7 membered heterocyclic group, C _6-10 aryl group and 5-6 membered heteroaryl group are each optionally substituted with one or more of the following substituents: CN, C _1-4 alkyl and CO ₂ R ³⁰ , wherein R ³⁰ and R ³⁷ are each independently selected from H, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, 4-10 membered heterocyclyl, C _6-12 aryl and 5-10 membered heteroaryl groups, wherein the C _1-6 alkyl group, C _1-6 alkoxy group, C _3-8 cycloalkyl group, 4-10 membered heterocyclic group, C _{6 -12} aryl and 5-10 membered heteroaryl are each optionally substituted with one or more of the following substituents: OH, CN, NO ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, halogen and C _1-4 haloalkoxy, and R ³³ and R ³⁴ are each independently selected from H, C _1-6 alkyl, C _1-6 alkoxy and C _3-6 ring Alkyl, wherein the C _1-6 alkyl, C _1-6 alkoxy and C _3-6 cycloalkyl are each optionally substituted with one or more of the following substituents: OH, CN, halogen, NO ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _1-4 hydroxyalkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, 4-10 membered heterocyclic group, C _6-12 aryl and 5-10 membered heteroaryl; More preferably, R ³ is independently selected from H, OH, CN, N(CH ₃ )C(O)CH ₃ , N(CH ₃ )C(O)CH ₂ CH ₃ , N(CH ₃ ) C(O)-cyclopropyl and the following groups each optionally substituted with one or more of hydroxy, methyl and CN: methyl, ethyl, propyl, cyclopropyl, cyclobutyl , Cyclopentyl, tetrahydrofuranyl, morpholino, tetrahydropyranyl, isoxazolyl, pyrazolyl and piperidinyl. The compound according to any one of claims 1 to 3, a stereoisomer, a tautomer, or a mixture of the compound, a pharmaceutically acceptable salt, co-crystal, or polymorph of the compound Compounds or solvates, or stable isotope derivatives, metabolites or prodrugs of said compounds, wherein L does not exist or is -L ¹ -L ² -; L ¹ is NH or N(CH ₃ ); and L ² is absent or selected from C _1-4 alkylene, C _1-4 alkyleneoxy and C _3-6 cycloalkylene, for example selected from methylene, ethylene, propylene, butylene , Methyleneoxy, ethyleneoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, cyclopropylene, cyclobutylene , Cyclopentylene and cyclohexylene. The compound according to any one of claims 1 to 4, a stereoisomer, a tautomer or a mixture of the compound, a pharmaceutically acceptable salt, co-crystal, or polymorph of the compound Or a solvate, or a stable isotope derivative, metabolite or prodrug of the compound, wherein -LR ³ or -NH-L ² -R ^{3 is} selected from:

The compound according to any one of claims 1 to 5, a stereoisomer, a tautomer or a mixture of the compound, a pharmaceutically acceptable salt, co-crystal, or polymorph of the compound Or a solvate, or a stable isotope derivative, metabolite or prodrug of the compound, wherein the compound or a pharmaceutically acceptable salt thereof is selected from:

A pharmaceutical composition comprising the compound according to any one of claims 1 to 6, stereoisomers, tautomers or mixtures of the compounds, pharmaceutically acceptable salts, co- Crystals, polymorphs or solvates, or stable isotope derivatives, metabolites or prodrugs of the compound, and optionally contain one or more pharmaceutically acceptable carriers. A pharmaceutical preparation comprising the compound according to any one of claims 1 to 6, stereoisomers, tautomers or mixtures of the compounds, pharmaceutically acceptable salts, co-crystals of the compounds , Polymorphs or solvates, or stable isotope derivatives, metabolites or prodrugs of the compound, or comprise the pharmaceutical composition according to claim 10. The compound of any one of claims 1 to 6, a stereoisomer, a tautomer or a mixture of the compound, a pharmaceutically acceptable salt, co-crystal, or polymorph of the compound Or a solvate, a stable isotope derivative, metabolite or prodrug of the compound, or the use of the pharmaceutical composition according to claim 10 for the preparation of a medicine, which is used for prevention and/or treatment with NLRP3 Diseases related to the activity of inflammasomes such as abnormal cell proliferation (e.g. cancer). The use according to claim 9, wherein the abnormal cell proliferation disease is brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, children Cervical cancer, endometrial cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, female reproductive tract cancer, carcinoma in situ, lymphoma, neurofibroma, thyroid cancer, bone cancer , Skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, prostate tumor, mast cell tumor, multiple myeloma, melanoma, glioma or sarcoma. A method for treating and/or preventing diseases associated with NLRP3 inflammasome activity, which comprises administering to a subject in need thereof a therapeutically and/or preventively effective amount of the compound according to any one of claims 1-6, Stereoisomers, tautomers or mixtures of said compounds, pharmaceutically acceptable salts, co-crystals, polymorphs or solvates of said compounds, stable isotope derivatives of said compounds, Metabolites or prodrugs, the pharmaceutical composition according to claim 7, or the pharmaceutical formulation according to claim 8. A method for synthesizing the compound of claim 1, wherein the compound has the structure shown in Formula II, and the method includes the steps shown in the following Route 1 or Route 2. (1) Route 1

Wherein R ¹ , R ³ and L ^{2 are} as defined in claim 1, and X is selected from chlorine, bromine and iodine; Preferably, the steps are: The first step: compound II-1 and guanidine carbonate undergo ring closure reaction to produce compound II-2; The second step: the compound II-2 is reacted with R ¹ -boronic acid or R ¹ -boronic acid ester or R ¹ -organotin compound through coupling reaction to produce compound II-3; The third step: compound II-3 and R ³ -L ² -PG undergo substitution reaction to produce compound II, where PG is a leaving group, which can be halogen or sulfonate; Or (2) Route 2

Wherein R ¹ , R ³ and L ^{2 are} as defined in claim 1, and X is selected from chlorine, bromine and iodine; Preferably, the steps are: The first step: compound II-4 and chloroformamidine hydrochloride undergo ring closure reaction to produce compound II-5; The second step: compound II-5 and R ³ -L ² -NH ₂ undergo condensation reaction to produce compound II-6; The third step: Compound II-6 is coupled with R ¹ -boronic acid or R ¹ -boronic acid ester or R ¹ -organotin compound to form compound II. A method for synthesizing the compound of claim 2, said compound having the structure shown in formula IV, and said method comprising the steps shown in the following route

Wherein R ¹ , R ³ and L ^{2 are} as defined in claim 2, and X is selected from chlorine, bromine and iodine; Preferably, the steps are: The first step: compound IV-1 and chloroformamidine hydrochloride undergo ring closure reaction to produce compound IV-2; Step 2: Compound IV-2 and R ³ -L ² -NH ₂ undergo condensation reaction to produce compound IV-3; The third step: Compound IV-3 is coupled with R ¹ -boronic acid or R ¹ -boronic acid ester or R ¹ -organotin compound to generate compound IV.