Thiophene[3,2-d]pyrimidine derivatives, processes for their preparation and uses thereof

Abstract

The application belongs to the field of organic chemistry medicine, and particularly relates to a kind of thieno [3, 2-d] pyrimidine derivatives and preparation method and application thereof.The specific technical scheme is: a kind of thieno [3, 2-d] pyrimidine derivatives with specific structure is provided, and 43 new thieno [3, 2-d] pyrimidine derivatives are specifically provided.The thieno [3, 2-d] pyrimidine derivatives provided by the application have great pharmaceutical potential, can be used to prepare powerful, selective small molecule RIPK2 kinase activity inhibitors for specifically blocking RIPK2 dependent pro-inflammatory signaling, provide new optional, researchable drugs for treating bacterial infection, self-inflammatory disease, autoimmune disease, allergic condition and inhibiting tumor metastasis.

Description

Technical Field

[0001] This invention belongs to the field of organic chemistry and medicine, specifically relating to a class of thiophene[3,2-d]pyrimidine derivatives, their preparation methods, and applications. Background Technology

[0002] RIPK2 (RIP2, RICK, CARDIAK, CARD3) is a bispecific serine / threonine and tyrosine kinase that regulates NOD1 and NOD2-mediated pro-inflammatory signaling. The nucleotide-binding oligomerization domain (NOD) protein family is an important intracellular pattern recognition receptor, with NOD1 and NOD2 being two representative receptors. Upon activation, RIPK2 binds to either NOD1 or NOD2, primarily functioning as a molecular scaffold, activating the NF-κB and MAPK signaling pathways, and subsequently recruiting downstream kinases such as TAK1, IKKα, IKKβ, and IKKξ, leading to an increase in immune-related signaling factors such as IL-β, IL-6, IL-12, and TNFα. RIPK2-dependent signaling dysregulation has been confirmed to be associated with autoimmune diseases. Patients with NOD2 gene mutations are prone to Crohn's disease, Blau syndrome, early-onset sarcoidosis, dermatitis, and arthritis; while NOD1 mutations are closely related to asthma and extraintestinal inflammatory diseases.

[0003] Meanwhile, the study found that the amplification of the RIPK2 protein increased with the development of cancer, suggesting that this protein may play a very important role in cancer development.

[0004] Therefore, if new drugs can be provided that can directly inhibit the kinase activity of RIPK2, thereby weakening the pro-inflammatory signals of the bacterial sensing pathway induced by NOD1 and NOD2 stimulation, reducing the inflammatory response and damage caused by inflammation, it is expected to treat bacterial infections, autoinflammatory diseases, autoimmune diseases and inhibit tumor metastasis. Summary of the Invention

[0005] The purpose of this invention is to provide a class of thiophene[3,2-d]pyrimidine derivatives, their preparation methods, and applications.

[0006] To achieve the above-mentioned objectives, the technical solution adopted by this invention is: a thiophene[3,2-d]pyrimidine derivative, the general structural formula of which is as follows:

[0007]

[0008] Where R is selected from Any one of them;

[0009] R1 to R3 are independently selected from H or n = 0 to 1;

[0010] R4 is selected from any one of substituted or unsubstituted C1-C8 alkyl groups, substituted or unsubstituted 3-6 membered cycloalkyl groups, and substituted or unsubstituted C3 alkenyl groups.

[0011] Preferably, R is selected from any one of the following structural formulas:

[0012]

[0013] Preferably, the derivative is any one of the structural formulas in Table 1.

[0014] Accordingly, the preparation method of the thiophene[3,2-d]pyrimidine derivative includes the following steps:

[0015] a. Preparation of M1: Mix with p-toluenesulfonic acid, add isopropanol, and after the reaction is complete, filter, wash the filter cake, and obtain M1;

[0016] b. Preparation of M2: M1, (4-(Boc-amino)cyclohexyl-1-en-1-yl)pinacol ester or N-Boc-1,2,5,6-tetrahydropyridine-4-boranool ester or N-BOC-1,2,5,6-tetrahydropyridine-3-boranool ester, potassium carbonate and PdCl2 are mixed, and dioxane / ethanol / water is added as a solvent. The reaction is carried out in an oil bath under inert gas protection until the reaction is complete. The reaction solution is concentrated, extracted, the organic phases are combined, concentrated again, and the concentrated crude product is dispersed in diethyl ether and filtered to obtain M2.

[0017] c. Preparation of M3: Dissolve M2 in dichloromethane and add trifluoroacetic acid in batches. The reaction is completed at room temperature. Concentrate the reaction solution and disperse the concentrate in water. Adjust the pH to >9. During this process, a large amount of solid precipitates out. Filter the solution and wash the filter cake with diethyl ether to obtain the thiophene[3,2-d]pyrimidine derivative M3.

[0018] Preferably, step c is followed by step d: dissolving M3 in dichloromethane / methanol, adding acid anhydride or isocyanate, reacting completely at room temperature, concentrating the reaction solution, dispersing the concentrate in diethyl ether, and filtering to obtain the thiophene[3,2-d]pyrimidine derivative.

[0019] Accordingly, the derivative, or the derivative prepared by the preparation method, and / or the pharmaceutically acceptable salts, solvates, hydrates, isomers, and polymorphs of the derivative are used in the preparation of drugs.

[0020] Preferably, the application is in the preparation of RIPK2 inhibitors.

[0021] Preferably, the drug includes: drugs for preventing and treating bacterial infections, drugs for preventing and treating autoinflammatory diseases, drugs for preventing and treating autoimmune diseases, and drugs for inhibiting tumor metastasis.

[0022] Accordingly, a pharmaceutical composition comprising the derivative, or a derivative prepared by the preparation method, and / or a pharmaceutically acceptable salt, solvate, hydrate, isomer, or polymorph of the derivative.

[0023] Preferably, the pharmaceutical composition includes pharmaceutically acceptable excipients.

[0024] The present invention has the following beneficial effects: The present invention provides a new class of thiophene[3,2-d]pyrimidine derivatives with great pharmaceutical potential. They can be used to prepare potent and selective small molecule RIPK2 kinase activity inhibitors that specifically block RIPK2-dependent pro-inflammatory signaling, providing new optional and researchable drugs for the treatment of bacterial infections, autoinflammatory diseases, autoimmune diseases, allergic diseases and the inhibition of tumor metastasis. Detailed Implementation

[0025] I. This invention provides a new class of thiophene[3,2-d]pyrimidine derivatives, the general structural formula of which is as follows:

[0026]

[0027] Where R is selected from Any one of them.

[0028] R1 to R3 are independently selected from H or n = 0 to 1.

[0029] R4 is selected from any one of substituted or unsubstituted C1-C8 alkyl groups, substituted or unsubstituted 3-6 membered cycloalkyl groups, and substituted or unsubstituted C3 alkenyl groups.

[0030] When R4 is selected from any one of substituted C1-C8 alkyl, substituted 3-6 membered cycloalkyl, or substituted C3 alkenyl, the substituent is selected from any one of halogen, 3-6 membered cycloalkyl, halogen-substituted or unsubstituted 6-10 membered aryl.

[0031] A more preferred embodiment is that R is selected from any of the following structural formulas:

[0032]

[0033] A more preferred embodiment is that the structural formula of the derivative of the present invention is any one of the structural formulas in Table 1:

[0034] Table 1. Structural Formula Comparison of Various Thiophene[3,2-d]Pyrimidine Derivatives

[0035]

[0036]

[0037]

[0038] II. This invention also provides a method for preparing the thiophene[3,2-d]pyrimidine derivative. The preparation methods are divided into five categories, as follows:

[0039] (I) The first type of preparation method, the reaction equation is as follows:

[0040]

[0041] Specifically, the steps include the following:

[0042] (a) Preparation of intermediate M1. Raw materials SM1, SM2, and p-toluenesulfonic acid were mixed, and isopropanol was added. The temperature was adjusted to 75–85 °C. After the reaction was complete, a large amount of solid precipitated. The mixture was filtered, and the filter cake was washed with diethyl ether to obtain high-purity intermediate M1.

[0043] (b) Preparation of intermediate M2. M1, (4-(Boc-amino)cyclohexyl-1-en-1-yl)borane ester, potassium carbonate, and PdCl2 (dppf) were mixed, and dioxane / ethanol / water (preferred ratio: dioxane:ethanol:water = 7:3:4 by volume) was added as a solvent. The mixture was transferred to an oil bath at 75–85°C under inert gas (e.g., nitrogen) protection until the reaction was complete. After the reaction was complete, the reaction solution was concentrated, extracted, and the organic phases were combined and concentrated again. The concentrated crude product was dispersed in diethyl ether and filtered to obtain high-purity intermediate M2.

[0044] (c) Preparation of M3 (thiophene[3,2-d]pyrimidine derivative W1). M2 was dissolved in dichloromethane, and trifluoroacetic acid was added in batches (avoiding boiling caused by adding trifluoroacetic acid too quickly). After the reaction was completed at room temperature, the reaction solution was concentrated. The concentrate was dispersed in water, and the pH was adjusted to >9, during which a large amount of solid precipitated. The mixture was filtered, and the filter cake was washed with diethyl ether to obtain high-purity compound M3 (W1).

[0045] (d) Preparation of other thiophene[3,2-d]pyrimidine derivatives, including W2. M3 was dissolved in dichloromethane / methanol (preferably, dichloromethane:methanol = 4:1 by volume), and different acid anhydrides or isocyanates were added. The reaction was allowed to proceed completely at room temperature, and the reaction solution was concentrated. The concentrated solution was dispersed in diethyl ether, and the filter cake obtained by vacuum filtration was the pure other thiophene[3,2-d]pyrimidine derivatives.

[0046] (II) The second type of preparation method, the reaction equation is as follows:

[0047]

[0048] The specific steps are the same as the first type of preparation method, except that “(4-(Boc-amino)cyclohexyl-1-en-1-yl)boronic acid pinacol ester” in step (b) is replaced with “N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester”.

[0049] (III) The third type of preparation method, the reaction equation is as follows:

[0050]

[0051] The specific steps are the same as the first type of preparation method, except that “(4-(Boc-amino)cyclohexyl-1-en-1-yl)boronic acid pinacol ester” in step (b) is replaced with “N-BOC-1,2,5,6-tetrahydropyridine-3-boronic acid pinacol ester”.

[0052] Third, the present invention also provides the medical and pharmaceutical applications of the thiophene[3,2-d]pyrimidine derivatives.

[0053] The thiophene[3,2-d]pyrimidine derivatives exhibit good RIPK2 inhibitory activity, thus possessing pharmaceutical potential as RIPK2 inhibitors. Furthermore, since RIPK2 is associated with autoimmune diseases, the thiophene[3,2-d]pyrimidine derivatives also have the potential to be used to prepare drugs for treating autoimmune diseases and allergic conditions. These autoimmune diseases and allergic conditions include, for example, inflammatory bowel disease, sepsis, psoriasis, systemic lupus erythematosus, lupus nephritis, scleroderma, asthma, allergic rhinitis, allergic eczema, multiple sclerosis, various types of arthritis, Crohn's disease, ulcerative colitis, and uveitis.

[0054] It should be understood that the pharmaceutical potential of the thiophene[3,2-d]pyrimidine derivatives referred to in this invention refers not only to the pharmaceutical potential of the derivatives themselves, but also to the pharmaceutical potential of pharmaceutically acceptable salts, solvates, hydrates, isomers, and polymorphs of the derivatives. The derivatives or their pharmaceutically acceptable salts, solvates, hydrates, isomers, and polymorphs can be formulated as drugs alone or in combination with other pharmaceutically acceptable substances.

[0055] The salts include those formed by reactions with acids, specifically those obtained through the reaction of a free base of a parent compound with an inorganic or organic acid; inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, etc.; organic acids include acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, etc. The solvates refer to the assemblage formed by one or more solvent molecules and the derivative. Solvents include water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, etc. The hydrates refer to compounds formed by the binding of stoichiometric or non-stoichiometric water through non-covalent intermolecular forces. The isomers refer to compounds with the same chemical composition but different spatial arrangements of atoms or groups, including diastereomers, enantiomers, regioisomers, structural isomers, rotational isomers, tautomers, etc. The polymorphs refer to the solid crystalline form of the derivative or its complex.

[0056] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Unless otherwise specified, the technical means used in the embodiments are conventional means well known to those skilled in the art. All obtained data are average values ​​obtained after at least three repetitions, and each repetition yields valid data.

[0057] Example 1: Preparation of thiophene[3,2-d]pyrimidine derivatives

[0058] I. Preparation of compounds W1-W14 (Demonstration of the effects of the first type of preparation method)

[0059] The reaction equation is the same as the first type of preparation method in the specific embodiment, including the following steps:

[0060] Step a: Preparation of intermediate M1. Weigh raw materials SM1 (18.5 g, 110 mmol), SM2 (25.0 g, 100 mmol), and p-toluenesulfonic acid (1.7 g, 10 mmol) and add them to a 500 mL round-bottom flask. Add 250 mL of isopropanol, set the temperature to 80 °C, and react for 2 h. Continue reacting until TLC analysis shows complete reaction and a large amount of solid precipitates. Filter the solid and wash the filter cake with diethyl ether to obtain high-purity intermediate M1. The 1H NMR spectrum of intermediate M1 is as follows:

[0061] 1 H NMR (400MHz, DMSO-d6) δ10.80(s,1H),9.45(s,1H),8.65(s,1H),8.28(s,1H),8.26(d,J=3.6Hz,1H),7.77(s,1H).

[0062] Step b: Preparation of intermediate M2. Intermediate M1 (19.1 g, 50 mmol), (4-(Boc-amino)cyclohexyl-1-en-1-yl)borane ester (17.8 g, 55 mmol), potassium carbonate (13.8 g, 100 mmol), and PdCl2 (dppf) (1.8 g, 2.5 mmol) were added to a 500 mL three-necked flask. Dioxane / ethanol / water (200 mL, volume ratio: dioxane:ethanol:water = 7:3:4, total) was added as a solvent. The mixture was reacted in an oil bath at 80 °C for 2 h under nitrogen protection. After the reaction, the reaction solution was concentrated and extracted twice with 500 mL of ethyl acetate. The combined organic phases were concentrated again. The concentrated crude product was dispersed in 100 mL of diethyl ether and filtered to obtain high-purity intermediate M2. The 1H NMR spectrum of intermediate M2 is as follows:

[0063] 1 H NMR (400MHz, DMSO-d6) δ9.73 (s, 1H), 9.41 (s, 1H), 8.45 (s, 1H), 8.23 ​​(d, J = 6. 9Hz,1H),8.19(d,J=9.8Hz,1H),7.36(s,1H),6.91(d,J=6.5Hz,1H),6.35(s,1 H),3.57(s,1H),2.65(d,J=17.1Hz,1H),2.59–2.53(m,1H),2.47–2.40(m,1H ),2.20–2.08(m,1H),1.94(d,J=10.8Hz,1H),1.67–1.55(m,1H),1.40(s,9H).

[0064] Step c: Preparation of M3(W1). The intermediate M2 (12.4 g, 25 mmol) was dissolved in 100 mL of dichloromethane, and 50 mL of trifluoroacetic acid was added in portions. The reaction was allowed to proceed at room temperature for 0.5 hours until complete, and the reaction solution was concentrated. The concentrated solution was dispersed in water, and potassium hydroxide was added to adjust the pH to >9, resulting in the precipitation of a large amount of solid. The solid was filtered, and the filter cake was washed with diethyl ether to obtain high-purity M3(W1), which required no further purification.

[0065] Step d: Preparation of other thiophene [3,2-d]pyrimidine derivatives. Weigh M3 (199 mg, 0.5 mmol) and dissolve it in 10 mL of dichloromethane / methanol (volume ratio: dichloromethane:methanol = 4:1). Add different acid anhydrides or isocyanates (94 μL, 1 mmol). React at room temperature for 0.5 hours until the reaction is complete. Concentrate the reaction solution. Disperse the concentrated solution in diethyl ether, filter, and obtain the filter cake, which is the pure other thiophene [3,2-d]pyrimidine derivatives.

[0066] The structural formulas of the various thiophene[3,2-d]pyrimidine derivatives prepared by this method are shown in Table 1, and the corresponding 1H NMR data of the added acid anhydride or isocyanate and the compound are shown in Table 2.

[0067] Table 2 Compounds W1~W14

[0068]

[0069]

[0070]

[0071] II. Preparation of compounds W15–W29 (Demonstration of the effects of the second type of preparation method)

[0072] Proceed according to Method 1, replacing "(4-(Boc-amino)cyclohexyl-1-en-1-yl)boraneol ester" in step b with "N-Boc-1,2,5,6-tetrahydropyridine-4-boraneol ester". The structural formulas of W15 to W29 are shown in Table 1, and the NMR data and the corresponding added anhydrides or isocyanates are shown in Table 3. The preparation method of W15 is similar to W1, without the need for the addition of anhydrides or isocyanates.

[0073] Table 3 Compounds W15~W29

[0074]

[0075]

[0076] III. Preparation of compounds W30–W43 (Demonstration of the effects of the third type of preparation method)

[0077] Proceed according to Method 1, replacing "(4-(Boc-amino)cyclohexyl-1-en-1-yl)boraneol ester" in step b with "N-BOC-1,2,5,6-tetrahydropyridine-3-boraneol ester". The structural formulas of W30 to W43 are shown in Table 1, and the NMR data and the corresponding added anhydrides or isocyanates are shown in Table 4. The preparation method for W30 is similar to W1, without the need for the addition of anhydrides or isocyanates.

[0078] Table 4 Compounds W30~W43

[0079]

[0080]

[0081] Example 2: Demonstration of the in vitro RIPK2 inhibitory effects of various thiophene[3,2-d]pyrimidine derivatives

[0082] RIPK2 was incubated in buffer (20 mM MOPS, pH 8.5, 0.2 mM EDTA, 10 mM MnCl2), and 0.33 mg / mL myelin basic protein, 10 mM magnesium acetate, and [γ-] were added. 33 [P-ATP], and various thiophene[3,2-d]pyrimidine derivatives synthesized in Example 1 at different concentrations (1000, 300, 100, 30, 10, 3, 1, 0.3, 0.1 nM). Mg / ATP was then added to the reaction to initiate the enzyme reaction process, and the mixture was incubated at room temperature for 120 minutes.

[0083] RIPK1 was incubated in buffer (8 mM MOPS, pH 7.0, 0.2 mM EDTA) and 0.33 mg / mL myelin basic protein, 10 mM magnesium acetate, and [γ-] were added. 33 The reaction mixture contained 1 μM of 1-p-ATP and various thiophene[3,2-d]pyrimidine derivatives synthesized in Example 1. Mg / ATP was then added to the reaction to initiate the enzyme reaction, and the mixture was incubated at room temperature for 120 minutes.

[0084] Each of the above groups was diluted to a concentration of 0.5% with phosphate buffer to terminate the reaction. Ten μL of the terminated reaction solution was then titrated onto a P30 membrane. The membrane was washed four times with 0.425% phosphate solution for 5 minutes each time, followed by one wash with methanol. Finally, the P30 membrane was dried and subjected to scintillation counting. The magnitude of the scintillation count reflects the degree of substrate phosphorylation, thus characterizing the inhibition of kinase activity. The IC50 values ​​were fitted based on the inhibition rates at the nine concentrations. 50 The values ​​were measured in duplicate. Each group was repeated three times, and the average value was taken. A blank control group (using an equal amount of DMSO instead of the thiophene[3,2-d]pyrimidine derivative) and a positive control group (using 7 nM GSK2983559 instead of the thiophene[3,2-d]pyrimidine derivative; GSK2983559 is a known highly active RIRK2 inhibitor) were also included. The results are shown in Table 5. In Table 5, the RIPK2 IC50 values ​​were... 50 The unit of value is nM; "RIPK1 inhibition rate %" refers to the inhibition rate at a concentration of 1 μM.

[0085] Table 5. Comparison of the inhibitory activities of each compound against RIPK kinase.

[0086]

[0087] The results showed that most of the newly synthesized thiophene[3,2-d]pyrimidine derivatives exhibited good in vitro enzymatic inhibitory activity against RIPK2, with IC50 values ​​of [missing information]. 50Within the 50 nM range, it exhibits almost no RIPK1 kinase inhibitory activity against RIPK1 kinase, a member of the same family; demonstrating that the thiophene[3,2-d]pyrimidine derivative of the present invention can selectively inhibit RIPK2 kinase activity.

[0088] Example 3: Demonstration of the metabolic stability of various thiophene[3,2-d]pyrimidine derivatives

[0089] The total volume of the incubation system was 100 μL, including 0.1 M PBS (pH 7.4), and an NADPH generation system (1 mM NADP, 5 mM glucose-6-phosphate, 1 U / mL glucose-6-phosphate dehydrogenase, 3.3 mM MgCl2). 1 μL of each test compound (W1–W43) solution (1 μM / L concentration) was added to an ice bath, and the mixture was pre-incubated at 37°C for 5 min. Then, 2.5 μL of human liver microsome solution was added, and incubation continued for 0, 5, 15, 30, 45, and 60 min. Afterward, 200 μL of ice-cold acetonitrile containing 20 ng / mL of internal standard SAHA was added to terminate the reaction. The mixture was vortexed for 30 s, centrifuged at 13000 rpm for 10 min, and the supernatant was collected for injection. The concentrations of the compounds measured at time points 5, 15, 30, 45, and 60 min were compared with the concentration measured at 0 min to obtain the percentage of unmetabolized compounds. A linear regression curve was plotted using the natural logarithm of the incubation time and the remaining percentage of the compound at each time point to obtain the slope k. The half-life T of the compound was then calculated using the following formula. 1 / 2 The clearance rate (CL) was calculated. The results are shown in Table 6.

[0090] T 1 / 2 (min) = -0.693 / k;

[0091] CL(μL / min / mg)=Ln(2)×1000 / T 1 / 2 / C 肝微粒体

[0092] Table 6 Comparison of liver microsomal stability data for compounds

[0093] serial number <![CDATA[T 1 / 2 ,min]]> Cl, mL / min / g·protein serial number <![CDATA[T 1 / 2 ,min]]> Cl, mL / min / g·protein W1 ＞120 ＜12 W23 ＞120 ＜12 W2 ＞120 ＜12 W24 ＞120 ＜12 W3 ＞120 ＜12 W26 ＞120 ＜12 W4 ＞120 ＜12 W27 ＞120 ＜12 W5 ＞120 ＜12 W28 70.71 19.60 W6 ＞120 ＜12 W30 74.52 18.60 W7 ＞120 ＜12 W31 ＞120 ＜12 W8 ＞120 ＜12 W32 ＞120 ＜12 W9 115.50 12.00 W33 ＞120 ＜12 W10 ＞120 ＜12 W34 ＞120 ＜12 W11 ＞120 ＜12 W35 68.61 20.20 W12 ＞120 ＜12 W36 ＞120 ＜12 W13 ＞120 ＜12 W37 ＞120 ＜12 W14 62.43 22.20 W38 ＞120 ＜12 W15 ＞120 ＜12 W40 ＞120 ＜12 W16 ＞120 ＜12 W41 ＞120 ＜12 W17 ＞120 ＜12 W42 92.40 15.00 W18 ＞120 ＜12 W43 59.74 23.20 W19 ＞120 ＜12 \ \ \ W20 ＞120 ＜12 \ \ \ W21 ＞120 ＜12 \ \ \ W22 ＞120 ＜12 \ \ \

[0094] The results showed that most of the newly synthesized compounds in this invention had good in vitro liver microsomal stability and good pharmacokinetic properties.

[0095] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Any modifications, alterations, substitutions, or variations made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention shall fall within the protection scope defined by the claims of the present invention.

Claims

1. A thiophene[3,2-d]pyrimidine derivative, characterized in that: The general structural formula of the derivative is as follows: ， Where R is selected from , and Any one of them; R1 to R3 are independently selected from H or n = 0 to 1; R4 is selected from any one of C1-C8 alkyl, 3-6 membered cycloalkyl, and C3 alkenyl.

2. The derivative according to claim 1, characterized in that: The R is selected from any of the following structural formulas: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

3. The derivative according to claim 1, characterized in that: The derivative is any one of the following structural formulas: 、 。 4. The method for preparing the thiophene[3,2-d]pyrimidine derivative according to any one of claims 1 to 3, characterized in that: The method includes the following steps: a. Preparation of M1: , Mix with p-toluenesulfonic acid, add isopropanol, and after the reaction is complete, filter, wash the filter cake to obtain M1; the structural formula of M1 is: ; b. Preparation of M2: M1, (4-(Boc-amino)cyclohexyl-1-en-1-yl)pinacol ester of borate or N-Boc-1,2,5,6-tetrahydropyridine-4-boranool ester of borate or N-BOC-1,2,5,6-tetrahydropyridine-3-boranool ester of borate, potassium carbonate and PdCl2 are mixed, and dioxane / ethanol / water is added as a solvent. The reaction is carried out in an oil bath under inert gas protection until complete. The reaction solution is concentrated, extracted, and the organic phases are combined and concentrated again. The concentrated crude product is dispersed in diethyl ether and filtered to obtain M2; the structural formula of M2 is: , or , c. Preparation of M3: M2 was dissolved in dichloromethane, and trifluoroacetic acid was added in batches. The reaction was allowed to proceed completely at room temperature. The reaction solution was concentrated, and the concentrate was dispersed in water. The pH was adjusted to >9, during which a large amount of solid precipitated. The mixture was filtered, and the filter cake was washed with diethyl ether to obtain the thiophene[3,2-d]pyrimidine derivative M3. The structural formula of M3 is: , or .

5. The preparation method according to claim 4, characterized in that: Step c is followed by step d: dissolving M3 in dichloromethane / methanol, adding acid anhydride or isocyanate, reacting completely at room temperature, concentrating the reaction solution, dispersing the concentrate in diethyl ether, and filtering to obtain the thiophene[3,2-d]pyrimidine derivative.

6. The use of the derivative according to any one of claims 1 to 3, or the derivative prepared by the preparation method according to claim 4 or 5, in the preparation of a drug, characterized in that: The application is in the preparation of RIPK2 inhibitors.

7. The use of the derivative according to any one of claims 1 to 3, or the derivative prepared by the preparation method according to claim 4 or 5, in the preparation of a drug, characterized in that: The drugs include: drugs for preventing and treating bacterial infections, drugs for preventing and treating autoinflammatory diseases, drugs for preventing and treating autoimmune diseases, and drugs for inhibiting tumor metastasis.

8. A pharmaceutical composition comprising the derivative of any one of claims 1 to 3, or the derivative prepared by the preparation method of claim 4 or 5.

9. The pharmaceutical composition according to claim 8, characterized in that: The pharmaceutical composition includes pharmaceutically acceptable excipients.

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