MyD88 inhibitor and application thereof

Abstract

The invention belongs to the technical field of medicines, and provides a MyD88 inhibitor and application thereof. The MyD88 inhibitor comprises one or more of a specific new structure compound, a racemate of the compound, an optical isomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable hydrate, a pharmaceutically acceptable solvate and a pharmaceutically acceptable prodrug. The inhibitor can inhibit the expression and release of inflammatory cytokines exceeding the normal amount, and is used as a pharmacological mechanism to treat diseases related to excessive inflammation. Experiments show that the MyD88 inhibitor provided by the invention has an effective inhibitory effect on inflammatory factors and better in-vivo anti-inflammatory activity.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and in particular to a MyD88 inhibitor and application thereof. Background Art

[0002] Innate immunity is the physiological process by which the human body responds to exogenous or endogenous foreign substances. Under normal circumstances, innate immunity can remove stimulating foreign substances through inflammatory responses and protect human health. However, when certain diseases occur, immune regulation becomes abnormal, causing excessive inflammatory responses in the lesion site, namely inflammatory storms, which further damage human health. According to the duration, inflammation can be divided into acute inflammation and chronic inflammation. Acute inflammation includes acute lung injury, sepsis, etc., while chronic inflammation includes diabetic nephropathy, diabetic cardiomyopathy, hepatitis, fatty liver, etc.

[0003] Taking acute lung injury as an example, acute lung injury (ALI) is caused by various indirect or direct injury factors that damage alveolar epithelial cells and capillary endothelial cells, resulting in diffuse pulmonary interstitial and alveolar edema, leading to acute hypoxic respiratory insufficiency. The mortality rate of this disease can exceed 30%. However, there is currently no effective treatment in clinical practice. The pathogenesis of ALI is very complex, mainly because the body is often invaded by endogenous or exogenous pathogenic microorganisms and their metabolites, and poisoning, shock, acute pancreatitis, etc. can all trigger inflammatory reactions in the body's tissue cells, which in turn cause infection, sepsis, etc., and further induce the body to produce a large number of inflammatory cytokines (mainly interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β) and interleukin-12 (IL-12), etc.). Acute lung injury can activate toll-like receptors (TLRs) to induce inflammatory reactions and release cytokines. Accumulating evidence indicates that cytokine dysregulation plays an important role in mediating, amplifying, and maintaining acute lung injury.

[0004] MyD88 is involved in the signal transduction of all TLRs families except TLR3. It is the central molecule of TLRs / IL-1R (interleukin-1 receptor) signal transduction and a key protein in the regulation of inflammation-related signaling pathways. The activation of MyD88, on the one hand, leads to the activation of the downstream mitogen-activated protein kinase / p38 / c-Jun amino-terminal kinase (MAPKs / p38 / JNK) pathway, thereby activating activator protein-1 (AP-1), and on the other hand, activates the transforming growth factor kinase 1 / TAK1 binding protein (TAK1 / TAB) complex, activates nuclear factor κB (NF-κB), and makes it enter the nucleus, thereby producing pro-inflammatory factors such as TNF-α and IL-6, which leads to the transcription and expression of a large number of inflammation-related factors and chemical factors. Several studies have shown that mice with MyD88 knockout are tolerant to death induced by lipopolysaccharide and staphylococcal enterotoxin. As a key protein target of the TLRs / IL-Rs signaling pathway, MyD88 has the potential to treat inflammation-related diseases and has gradually attracted the attention of more and more researchers. However, the MyD88 inhibitors in the current technology are limited, and there is an urgent need to develop new MyD88 inhibitors. Summary of the invention

[0005] The purpose of the present invention is to provide a MyD88 inhibitor and its application, which can be used as a potential drug for preventing or treating inflammation-related diseases.

[0006] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0007] The present invention provides a MyD88 inhibitor, which includes one or more of a compound having a structure as shown in formula (I), a racemate of the compound having a structure as shown in formula (I), an optical isomer of the compound having a structure as shown in formula (I), a pharmaceutically acceptable salt of the compound having a structure as shown in formula (I), a pharmaceutically acceptable hydrate of the compound having a structure as shown in formula (I), a pharmaceutically acceptable solvate of the compound having a structure as shown in formula (I), and a pharmaceutically acceptable prodrug of the compound having a structure as shown in formula (I);

[0008]

[0009] In formula (I), X is a six-membered aryl group optionally substituted by 1 to 2 identical or different substituents or a five-membered and six-membered heteroaryl group optionally substituted by 1 to 2 identical or different substituents, wherein the substituents are selected from hydrogen, halogen, alkyl, alkoxy, hydroxy, alkylthio, monoalkyl-substituted amino, dialkyl-substituted amino, alkylamido, free carboxyl, salified carboxyl, esterified carboxyl, amidated carboxyl, alkylsulfinyl, sulfonyl, alkylacyl, carbamoyl, monoalkyl-substituted carbamoyl, dialkyl-substituted carbamoyl or alkylenedioxy;

[0010] Y is Z1, Z2, and Z3 are independently a six-membered aromatic group optionally substituted by 1 to 2 identical or different substituents, wherein the substituents are selected from hydrogen, halogen, alkyl, alkoxy, hydroxy, alkylthio, amino, monoalkyl-substituted amino, dialkyl-substituted amino, alkylacylamino, free carboxyl, salified carboxyl, esterified carboxyl, amidated carboxyl, alkylsulfinyl, sulfonyl, alkylacyl, carbamoyl, monoalkyl-substituted carbamoyl, dialkyl-substituted carbamoyl, or alkylenedioxy; m1, m2, and m3 are independently 0 or 1;

[0011] n is 0 or 1.

[0012] Preferably, when n is 0, X is

[0013] When n is 1, X is a six-membered aryl group optionally substituted by 1 to 2 identical or different substituents selected from hydrogen, fluorine, chlorine, bromine, methyl, methoxy, ethoxy, hydroxyl or tert-butyl.

[0014] Preferably, Z1, Z2, and Z3 are independently a six-membered aromatic group optionally substituted by 1 to 2 identical or different substituents, wherein the substituents are selected from hydrogen, fluorine, chlorine, bromine, methyl, methoxy, ethoxy, hydroxyl or tert-butyl.

[0015] Preferably, the MyD88 inhibitor is the following compound, the racemate of the following compound, the optical isomer of the following compound, the pharmaceutically acceptable salt of the following compound, the pharmaceutically acceptable hydrate of the following compound, the pharmaceutically acceptable solvate of the following compound or the pharmaceutically acceptable prodrug of the following compound;

[0016]

[0017]

[0018]

[0019] The present invention also provides a pharmaceutical composition comprising an active ingredient and a pharmaceutically acceptable excipient; the active ingredient is a MyD88 inhibitor.

[0020] The present invention also provides the use of a MyD88 inhibitor or a pharmaceutical composition in the preparation of a drug for preventing or treating inflammation-related diseases.

[0021] Preferably, the inflammation-related diseases include acute lung injury, rheumatoid arthritis, osteoarthritis, spondyloarthropathies, gouty arthritis, rheumatic arthritis, acute attacks of chronic arthritis, persistent joint swelling and pain, non-articular soft tissue rheumatic pain, acute mild to moderate pain, ischemic reperfusion, atherosclerosis, hepatitis, lymphadenitis, pneumonia, dysentery or appendicitis.

[0022] The beneficial effects of the present invention are:

[0023] The present invention provides a novel MyD88 inhibitor, which can inhibit the expression and release of inflammatory cytokines beyond normal levels, and use this as a pharmacological mechanism to treat diseases related to excessive inflammation. Experiments show that the MyD88 inhibitor provided by the present invention has an effective inhibitory effect on inflammatory factors and better in vivo anti-inflammatory activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 Schematic diagram of the activity of different MyD88 inhibitors in inhibiting the release of IL-6 from LPS-stimulated macrophages;

[0025] Figure 2 Schematic diagram of the relationship between the binding affinity and concentration of different MyD88 inhibitors to MyD88 protein (Time—time, Binding signal—binding signal intensity); Figure 2 In the figure, A is a schematic diagram showing the relationship between the binding affinity and concentration of the MyD88 inhibitor and the MyD88 protein in Example 4, B is a schematic diagram showing the relationship between the binding affinity and concentration of the MyD88 inhibitor and the MyD88 protein in Example 5, C is a schematic diagram showing the relationship between the binding affinity and concentration of the MyD88 inhibitor and the MyD88 protein in Example 8, and D is a schematic diagram showing the relationship between the binding affinity and concentration of the MyD88 inhibitor and the MyD88 protein in Example 20;

[0026] Figure 3 This is a schematic diagram of the effect of the MyD88 inhibitor in alleviating the physiological changes caused by acute lung injury in Example 11 (Wet / Dryratle—wet weight / dry weight ratio, Protein concentration—protein concentration, Total cells in BALF—total number of cells in bronchoalveolar lavage fluid, Spleen—spleen weight, Concentration—concentration); Figure 3A is a schematic diagram of wet weight / dry weight ratio, B is a schematic diagram of leukocyte protein concentration in alveolar lavage fluid, C is a schematic diagram of leukocyte number in alveolar lavage fluid, D is a schematic diagram of mouse spleen weight, E is a schematic diagram of IL-6 expression in serum, F is a schematic diagram of TNF-α expression in serum, G is a schematic diagram of IL-6 expression in alveolar lavage fluid, and H is a schematic diagram of TNF-α expression in alveolar lavage fluid;

[0027] Figure 4 This is a staining result diagram showing that the MyD88 inhibitor in Example 11 alleviates the pathological changes caused by acute lung injury. DETAILED DESCRIPTION

[0028] In the present invention, the pharmaceutical composition is preferably in the form of an injection, tablet, capsule, aerosol, suppository, film, pellet, ointment, controlled release agent, sustained release agent or nano preparation.

[0029] In the present invention, the non-articular soft tissue rheumatic pain preferably includes shoulder pain, tenosynovitis, bursitis, myalgia or pain caused by sports injury; the acute mild or moderate pain preferably includes postoperative, post-traumatic, post-strain or primary dysmenorrhea, toothache or headache; the ischemic reperfusion preferably includes cerebral ischemia reperfusion or myocardial ischemia reperfusion.

[0030] In the present invention, the MyD88 inhibitor can treat inflammation by inhibiting MyD88 in a targeted manner, thereby releasing macrophages to release inflammatory factors; the inflammatory factors released by the macrophages are preferably TNF-α and / or IL-6.

[0031] The technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0032] Example 1

[0033] The structural formula of the MyD88 inhibitor in this embodiment is The name is 1-[4-(1H-indol-2-ylmethyl)piperazin-1-yl]-3-[(2-methoxyphenyl)oxy]propan-2-ol;

[0034] Under nitrogen protection, 0.01 mol of indole-2-carboxylic acid and 0.009 mol of N, N'-carbonyldiimidazole (CDI) were added to 20 mL of tetrahydrofuran, and the mixture was reacted at room temperature for 10 min. Then, 0.04 mol of piperazine was added and the mixture was reacted at room temperature overnight. After the reaction, the solvent was evaporated under low pressure, and the residue was dissolved in a mixed solution of dichloromethane and methanol (the volume ratio of dichloromethane to methanol was 10:1). The organic layer was washed 3 times with brine and dried over anhydrous magnesium sulfate. After drying, the solvent was evaporated under reduced pressure, and the mixture was separated by column chromatography (dichloromethane (DCM): methanol (MeOH) = 10:1) to obtain a first intermediate.

[0035] 0.01 mol of the first intermediate was dissolved in 20 mL of tetrahydrofuran, and under nitrogen protection, at -78°C, they were added to a mixture of 0.04 mol of lithium aluminum hydride and 10 mL of tetrahydrofuran, and then the reaction system was transferred to 60°C and reacted for 4 hours. After the reaction, the mixture was adjusted to -78°C, 1.5 mL of water, 1.5 mL of a 15% sodium hydroxide solution and 4.5 mL of water were added in sequence, extracted with ethyl acetate, the organic layer was washed with brine 3 times and dried over anhydrous magnesium sulfate, and after drying, the solvent was evaporated under reduced pressure to obtain a second intermediate;

[0036] 0.001 mol of the second intermediate was added to a mixture of 3 mL of trifluoroethanol and 0.001 mol of 2-((2-methoxyphenoxy)methyl)ethylene oxide (CAS No. 2210-74-4), and refluxed at 70°C for 4 h. After the reflux, the solvent was evaporated under low pressure, and the residue was dissolved with dichloromethane. The organic layer was washed 3 times with brine and dried over anhydrous magnesium sulfate. After drying, the solvent was evaporated under reduced pressure, and the MyD88 inhibitor in this example was obtained by separation by column chromatography (dichloromethane (DCM): methanol (MeOH) = 50:1).

[0037] The hydrogen spectrum data of the MyD88 inhibitor in this example are as follows: 1 H NMR (400MHz, CDCl3) δ8.67 (s, 1H), 7.55 (d, J = 7.8Hz, 1H), 7.36-7.32 (m, 1H), 7.18-7.13 (m, 1H), 7.10-7.05 (m, 1H), 6.98-6.92 (m, 2H),6.90(m,2H),6.37(d,J=1.0Hz,1H),4.14(m,1H),4.02(d,J=4.8Hz,2H),3.85(s,3H),3.69(s,2H),2.70(s,2H),2.57(m,8H). 13C NMR (100MHz, CDCl3) δ149.75,148.27,136.35,134.63,128.20,121.92,121.79,120.99,120.25,119.7 0,114.57,111.99,110.90,102.24,72.26,65.97,60.47,55.87,55.65,53.05×4.HRMS(ESI,m / z):calcd forC 23 H 30 N3O3[M+H] + ,396.2287;found,396.2285.

[0038] Example 2

[0039] The structural formula of the MyD88 inhibitor in this embodiment is The name is 1-[4-(1H-indol-2-ylmethyl)piperazin-1-yl]-3-{[4-(2-methylpropan-2-yl)phenyl]oxy}propan-2-ol;

[0040] The other conditions in Example 1 remain unchanged, and 2-((2-methoxyphenoxy)methyl)ethylene oxide is replaced by p-tert-butylphenol glyceryl ether (CAS No. 3101-60-8) to prepare the MyD88 inhibitor in this example.

[0041] The hydrogen spectrum data of the MyD88 inhibitor in this example are as follows: 1 H NMR (400MHz, CDCl3) δ8.64(s,1H),7.56(d,J=7.8Hz,1H),7.35(d,J=8.0Hz,1H),7.30(d,J=8.8Hz,2H),7.16(t,J=7.5Hz,1H),7.08(t,J=7. 4Hz,1H),6.86(d,J=8.8Hz,2H),6.37(s,1H),4.10(m,1H),3.97(d,J=4.9Hz,2H),3.70(s,2H),2.72(s,2H),2.64-2.46(m,8H),1.30(s,9H). 13 C NMR (100MHz, CDCl3) δ156.49,143.82,136.40,135.09,128.29,126.34×2,121.73,120.28,119.69,114.3 8×2,110.94,102.18,70.41,65.84,60.65,55.78,53.55,53.16×4,34.17,31.62×3.HRMS(ESI,m / z):calcd for C26 H 36 N3O2[M+H] + ,422.2807;found422.2800.

[0042] Example 3

[0043] The structural formula of the MyD88 inhibitor in this embodiment is The name is 3-[(4-fluorophenyl)oxy]-1-[4-(1H-indol-2-ylmethyl)piperazin-1-yl]propan-2-ol;

[0044] The other conditions in Example 1 remain unchanged, and 2-((2-methoxyphenoxy)methyl)ethylene oxide is replaced by 2-((4-fluorophenoxy)methyl)ethylene oxide (CAS No. 18123-82-5) to prepare the MyD88 inhibitor in this example.

[0045] The hydrogen spectrum data of the MyD88 inhibitor in this example are as follows: 1 H NMR (400MHz, CDCl3) δ8.60(s,1H),7.56(d,J=7.8Hz,1H),7.34(d,J=8.0Hz,1H),7.17-7.13(m,1H),7.11-7.06(m,1H),6.98-6.94( m,2H),6.88-6.84(m,2H),6.37(d,J=0.8Hz,1H),4.08(m,1H),3.94(dd,J=4.8,2.0Hz,2H),3.69(s,2H),2.72(s,2H),2.56(m,8H). 13 C NMR (100MHz, CDCl3) δ158.63-156.26,154.90,136.38,135.08,128.27,121.73,120.27,119.69,116.01,11 5.78,115.69,115.60,110.91,102.18,71.04,65.73,60.46,55.75,53.54,53.13×4.HRMS(ESI,m / z):calcd for C 22 H 27 FN3O2[M+H] + ,384.2087;found,384.2081.

[0046] Example 4

[0047] The structural formula of the MyD88 inhibitor in this embodiment is The name is 3-[(4-chlorophenyl)oxy]-1-[4-(1H-indol-2-ylmethyl)piperazin-1-yl]propan-2-ol;

[0048] The other conditions in Example 1 remain unchanged, and 2-((2-methoxyphenoxy)methyl)ethylene oxide is replaced by 2-((4-chlorophenoxy)methyl)ethylene oxide (CAS No. 2212-05-7) to prepare the MyD88 inhibitor in this example.

[0049] The hydrogen spectrum data of the MyD88 inhibitor in this example are as follows: 1 H NMR (400MHz, CDCl3) δ8.70 (s, 1H), 7.55 (s, 1H), 7.35 (d, J = 8.0Hz, 1H), 7.24-7.21 (m, 2H), 7.18-7.13 (m, 1H), 7.11-7.06 (m, 1H), 6.86 -6.83(m,2H),6.38(d,J=0.9Hz,1H),4.08(td,J=9.4,4.5Hz,1H),3.95(dd,J=4.8,1.7Hz,2H),3.71(s,2H),2.73(s,2H),2.56(m,8H). 13 C NMR (100MHz, CDCl3) δ157.37,136.28,135.14,129.38×2,128.28,125.94,121.72,120.25,11 9.69,115.89×2,110.81,102.04,70.59,65.53,60.34,55.72,53.15×4.HRMS(ESI)m / z:calcd for C 22 H 27 ClN3O2[M+H] + ,400.1792;found,400.1794.

[0050] Example 5

[0051] The structural formula of the MyD88 inhibitor in this embodiment is The name is 3-[(4-bromophenyl)oxy]-1-[4-(1H-indol-2-ylmethyl)piperazin-1-yl]propan-2-ol;

[0052] The other conditions in Example 1 remain unchanged, and 2-((2-methoxyphenoxy)methyl)ethylene oxide is replaced by 2-((4-bromophenoxy)methyl)ethylene oxide (CAS No. 2212-06-8) to prepare the MyD88 inhibitor in this example.

[0053] The hydrogen spectrum data of the MyD88 inhibitor in this example are as follows: 1 H NMR (400MHz, CDCl3) δ8.62(s,1H),7.56(d,J=7.8Hz,1H),7.37(d,J=9.0Hz,2H),7.33(s,1H),7.19-7.13(m,1H),7.09(dd,J=11. 0,3.9Hz,1H),6.83-6.77(m,2H),6.37(s,1H),4.08(m,1H),3.94(dd,J=6.4,4.1Hz,2H),3.70(s,2H),2.73(s,2H),2.55(m,8H). 13 C NMR (100MHz, CDCl3) δ157.88,136.35,135.03,132.34×2,128.26,121.74,120.27,119.70,11 6.45×2,113.26,110.89,102.18,70.59,65.61,60.39,55.73,53.12×4.HRMS(ESI)m / z:calcd for C 22 H 27 BrN3O2[M+H] + ,444.1287;found,444.1281.

[0054] Example 6

[0055] The structural formula of the MyD88 inhibitor in this embodiment is The name is 1-[4-(1H-indol-2-ylmethyl)piperazin-1-yl]-3-(phenyloxy)propan-2-ol;

[0056] The other conditions in Example 1 remain unchanged, and 2-((2-methoxyphenoxy)methyl)ethylene oxide is replaced by 2-(phenoxymethyl)ethylene oxide (CAS No. 122-60-1) to prepare the MyD88 inhibitor in this example.

[0057] The hydrogen spectrum data of the MyD88 inhibitor in this example are as follows: 1H NMR (400MHz, CDCl3) δ8.66 (s, 1H), 7.56 (d, J = 7.8Hz, 1H), 7.35 (d, J = 8.0Hz, 1H), 7.29 (d, J = 8.2Hz, 2H), 7.16 (t, J = 7.2Hz, 1H), 7.08 (t, J = 7.2Hz, 1H),6.97(d,J=7.3Hz,1H),6.92(d,J=8.1Hz,2H),6.37(s,1H),4.10(m, 1H),3.99(d,J=4.9Hz,2H),3.70(s,2H),2.73(s,2H),2.63-2.48(m,8H). 13 C NMR (100MHz, CDCl3) δ158.72,136.39,134.93,129.56×2,128.25,121.75,121.12,120.27,11 9.69,114.62×2,110.92,102.23,70.26,65.76,60.54,55.72,53.11×4.HRMS(ESI,m / z):calcd for C 22 H 28 N3O2[M+H] + ,366.2182;found,366.2188.

[0058] Example 7

[0059] The structural formula of the MyD88 inhibitor in this embodiment is The name is 3-(benzyloxy)-1-[4-(1H-indol-2-ylmethyl)piperazin-1-yl]propan-2-ol;

[0060] The other conditions in Example 1 remain unchanged, and 2-((2-methoxyphenoxy)methyl)ethylene oxide is replaced by 2-(benzyloxymethyl)ethylene oxide (CAS No. 2930-05-4) to prepare the MyD88 inhibitor in this example.

[0061] The hydrogen spectrum data of the MyD88 inhibitor in this example are as follows: 1 H NMR (400MHz, CDCl3) δ8.71(s,1H),7.56(d,J=7.6Hz,1H),7.34(s,6H),7.15(t,J=6.9Hz,1H),7.08(t,J=7.3Hz,1H),6.3 7(s,1H),4.57(s,2H),3.92(d,J=4.0Hz,1H),3.68(s,2H),3.49(dd,J=9.4,4.8Hz,2H),2.68(s,2H),2.59-2.38(m,8H).13 C NMR (100MHz, CDCl3) δ138.12,136.45,135.05,128.52×2,128.28,127.88×2,127.83,121.71,120 .27,119.66,110.98,102.23,73.58,72.77,66.42,60.74,55.76,53.10×4.HRMS(ESI,m / z):calcd for C 23 H 30 N3O2[M+H] + ,380.2338;found,380.2332.

[0062] Example 8

[0063] The structural formula of the MyD88 inhibitor in this embodiment is The name is 1-[4-(1H-indol-2-ylmethyl)piperazin-1-yl]-3-[(2-methylphenyl)oxy]propan-2-ol;

[0064] The other conditions in Example 1 remain unchanged, and 2-((2-methoxyphenoxy)methyl)ethylene oxide is replaced by 2-((2-methylphenoxy)methyl)ethylene oxide (CAS No. 2210-79-9) to prepare the MyD88 inhibitor in this example.

[0065] The hydrogen spectrum data of the MyD88 inhibitor in this example are as follows: 1 H NMR (400MHz, CDCl3) δ8.68(s,1H),7.56(d,J=6.7Hz,1H),7.35(d,J=6.9Hz,1H),7.15(s,3H),7.09(d,J=7.2Hz,1H),6.8 5(m,2H),6.38(s,1H),4.13(d,J=3.9Hz,1H),3.99(m,2H),3.71(s,2H),2.75(s,2H),2.59(m,8H),2.24(d,J=1.9Hz,3H). 13 C NMR (100MHz, CDCl3) δ156.77,136.32,134.98,130.76,128.25,126.87×2,121.74,120.78,120.25,1 19.69,111.20,110.85,102.11,70.34,65.85,60.74,55.71,53.14×4,16.29.HRMS(ESI,m / z):calcd for C 23 H 30 N3O2[M+H]+ ,380.2338;found,380.2353.

[0066] Example 9

[0067] The structural formula of the MyD88 inhibitor in this embodiment is The name is 1-[4-(1H-indol-2-ylmethyl)piperazin-1-yl]-3-[(4-methoxyphenyl)oxy]propan-2-ol;

[0068] The other conditions in Example 1 remain unchanged, and 2-((2-methoxyphenoxy)methyl)ethylene oxide is replaced by 2-((4-methoxyphenoxy)methyl)ethylene oxide (CAS No. 2211-94-1) to prepare the MyD88 inhibitor in this example.

[0069] The hydrogen spectrum data of the MyD88 inhibitor in this example are as follows: 1 H NMR (400MHz, CDCl3) δppm 8.69(s,1H),7.56(d,J=7.5Hz,1H),7.35(d,J=7.7Hz,1H),7.16(t,J=7.1Hz,1H),7.08(t,J=6.9Hz,1H),6.89-6.81(m,4H) ,6.38(s,1H),4.08(d,J=4.2Hz,1H),3.94(d,J=2.8Hz,2H),3.77(d,J=1.9Hz,3H),3.70(s,2H),2.73(s,2H),2.59(m,8H). 13 C NMR (100MHz, CDCl3) δ154.07,152.90,136.35,134.93,128.24,121.74,120.25,119.68,115.59× 2,114.69×2,110.88,102.17,71.03,65.78,60.50,55.77,55.70,53.10×4.HRMS(ESI,m / z):calcd forC 23 H 30 N3O3[M+H] + ,396.2287;found,396.2283.

[0070] Example 10

[0071] The structural formula of the MyD88 inhibitor in this embodiment is The name is (2R)-3-[(4-bromophenyl)oxy]-1-[4-(1H-indol-2-ylmethyl)piperazin-1-yl]propan-2-ol;

[0072] The other conditions in Example 1 remain unchanged, and 2-((2-methoxyphenoxy)methyl)ethylene oxide is replaced by (R)-2-((4-bromophenoxy)methyl)ethylene oxide (CAS No. 51594-55-9) to prepare the MyD88 inhibitor in this example.

[0073] The hydrogen spectrum data of the MyD88 inhibitor in this example are as follows: 1 H NMR (400MHz, CDCl3) δ8.83(s,1H),7.58(d,J=7.8Hz,1H),7.35(m,3H),7.17(t,J=7.5Hz,1H),7.10(t,J=7.4Hz,1H),6 .80(d,J=8.9Hz,2H),6.38(s,1H),4.14-4.03(m,1H),3.99-3.91(m,2H),3.67(s,2H),2.71(s,2H),2.64-2.44(m,8H). 13 C NMR (100MHz, CDCl3) δ157.93,136.49,135.00,132.39×2,128.29,121.76,120.33,119.71,11 6.53×2,113.28,111.03,102.36,70.74,65.80,60.54,55.78,53.11×4.HRMS(ESI,m / z):calcd for C 22 H 27 BrN3O2[M+H] + ,444.1287;found,444.1279.

[0074] Embodiment 11

[0075] The structural formula of the MyD88 inhibitor in this embodiment is The name is (2S)-3-[(4-bromophenyl)oxy]-1-[4-(1H-indol-2-ylmethyl)piperazin-1-yl]propan-2-ol;

[0076] The other conditions in Example 1 remain unchanged, and 2-((2-methoxyphenoxy)methyl)ethylene oxide is replaced by (S)-2-((4-bromophenoxy)methyl)ethylene oxide (CAS No. 67843-74-7) to prepare the MyD88 inhibitor in this example.

[0077] The hydrogen spectrum data of the MyD88 inhibitor in this example are as follows: 1H NMR (400MHz, CDCl3) δ8.85(s,1H),7.58(d,J=7.8Hz,1H),7.35(m,3H),7.17(t,J=7.5Hz,1H),7.10(t,J=7.4Hz,1H),6 .80(d,J=8.9Hz,2H),6.38(s,1H),4.14-4.03(m,1H),3.99–3.91(m,2H),3.67(s,2H),2.71(s,2H),2.63–2.42(m,8H). 13 C NMR (100MHz, CDCl3) δ157.94,136.49,135.03,132.39×2,128.30,121.76,120.34,119.71,11 6.54×2,113.28,111.04,102.36,70.76,65.81,60.55,55.79,53.11×4.HRMS(ESI,m / z):calcd for C 22 H 27 BrN3O2[M+H] + ,444.1287;found,444.1293.

[0078] Example 12

[0079] The structural formula of the MyD88 inhibitor in this embodiment is The name is 1-(4-{2-hydroxy-3-[(2-methoxyphenyl)oxy]propyl}piperazin-1-yl)-3-phenylbutan-2-ol;

[0080] 0.01 mol of acetophenone is added to 10 mL of tetrahydrofuran, and then 1.20 g of sodium hydride is added at 0° C. (sodium hydride is added in the form of a “mineral oil solution containing sodium hydride”, and the mass fraction of sodium hydride in the mineral oil solution of sodium hydride is 60%), and finally 0.02 mol of ethyl 2-acetoxy-2-(dioxyphosphoryl)acetate is added, and the reaction is carried out at room temperature overnight under nitrogen protection. After the reaction is completed, water is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with brine for 3 times, and then dried with anhydrous magnesium sulfate. After drying, the solvent is evaporated under vacuum, and the residue is purified by column chromatography (petroleum ether (PE): ethyl acetate (EA) = 4:1) to obtain a first intermediate;

[0081] 0.01 mol of the first intermediate was dissolved in 10 mL of methanol (MeOH), 1 g of sodium hydroxide was added, and the mixture was stirred at 60 ° C for 2 h. The pH was adjusted to 7.0 using a 3.65% hydrochloric acid solution, and the second intermediate was obtained by suction filtration. 0.01 mol of the second intermediate and 0.03 mol of N-Boc piperazine were dissolved in 20 mL of N,N-dimethylformamide (DMF) at room temperature, and then 0.01 mol of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and 0.005 mol of 4-dimethylaminopyridine (DMAP) to obtain a third intermediate; 0.01 mol of the third intermediate is added to 20 mL of trifluoroacetic acid (TFA) in dichloromethane (DCM) solution, the mass fraction of trifluoroacetic acid in the dichloromethane solution of trifluoroacetic acid is 20%, the Boc group of the third intermediate is removed at room temperature, and the fourth intermediate is obtained after evaporation under reduced pressure; 0.01 mol of the fourth intermediate is dissolved in 20 mL of tetrahydrofuran, and under nitrogen protection, at -78°C, they are added to a mixture of 0.04 mol of lithium aluminum hydride and 10 mL of tetrahydrofuran, and then the reaction system is transferred to 60°C and reacted for 4 hours. After the reaction is completed, the mixture is adjusted to -78°C, 1.5 mL of water, 1.5 mL of a 15% sodium hydroxide aqueous solution and 4.5 mL of water are added in sequence, extracted with ethyl acetate, the organic layer is washed 3 times with brine and dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure after drying to obtain a fifth intermediate;

[0082] 0.001 mol of the fifth intermediate was added to a mixture of 3 mL of trifluoroethanol and 0.001 mol of 2-((2-methoxyphenoxy)methyl)ethylene oxide, and refluxed at 70° C. for 4 h. After the reflux, the solvent was evaporated under low pressure, and the residue was dissolved with dichloromethane. The organic layer was washed 3 times with brine and dried over anhydrous magnesium sulfate. After drying, the solvent was evaporated under reduced pressure, and the MyD88 inhibitor in this example was obtained by separation by column chromatography (dichloromethane: methanol = 50:1).

[0083] The hydrogen spectrum data of the MyD88 inhibitor in this example are as follows: 1H NMR (400MHz, CDCl3) δ7.33-7.26(m,3H),7.29-7.23(m,2H),6.99-6.95(m,2H),6.95-6.90(m,2H),4.18(m,1H),4.05(d,J=4.9Hz,2H), 3.93–3.85(m,4H),2.86-2.68(m,5H),2.62-2.47(m,5H),2.46(dd,J=12.2,2.3Hz,2H),2.32(t,J=11.4Hz,1H),1.34(d,J=7.2Hz,3H). 13 C NMR (100MHz, CDCl3) δ149.76,148.26,143.52,128.29×2,128.18×2,126.49,121.91,120.98,114.59, 112.02,72.19,70.20,65.86,61.79,60.51,55.88,53.25×4,44.00,17.30.HRMS(ESI,m / z):calcdfor C 24 H 35 N2O4[M+H] + ,415.2597;found,415.2542.

[0084] According to the method of Example 12, the piperazine-containing MyD88 of Examples 13 to 29 were prepared respectively.

[0085] Embodiment 13

[0086] The structural formula of the MyD88 inhibitor in this embodiment is The name is 1-[4-(2-hydroxy-3-{[4-(2-methylpropan-2-yl)phenyl]oxy}propyl)piperazin-1-yl]-3-phenylbutan-2-ol;

[0087] The other conditions in Example 12 remain unchanged, and 2-((2-methoxyphenoxy)methyl)ethylene oxide is replaced by p-tert-butylphenol glyceryl ether (CAS No. 3101-60-8) to prepare the MyD88 inhibitor in this example.

[0088] The hydrogen spectrum data of the MyD88 inhibitor in this example are as follows: 1H NMR (400MHz, CDCl3) δ7.36-7.27(m,6H),7.24(m,1H),6.85(d,J=8.8Hz,2H),4.08(m,1H),4.02-3.90(m,2H), 3.89-3.80(m,1H),2.80-2.62(br,5H),2.58-2.51(m,5H),2.31-2.25,2.28(t,J=11.4Hz,1H),1.29(s,12H). 13 C NMR (100MHz, CDCl3) δ156.32, 143.87, 143.25, 128.34×2, 128.17×2, 126.58, 126.29×2, 114.01×2, 70. 16,70.02,65.57,65.14,61.85,60.61,53.01×4,43.96,34.11,31.53×3,17.21.HRMS(ESI,m / z):calcd for C 27 H 41 N2O3[M+H] + ,441.3117;found,441.3062.

[0089] Embodiment 14

[0090] The structural formula of the MyD88 inhibitor in this embodiment is The name is 1-(4-{3-[(4-fluorophenyl)oxy]-2-hydroxypropyl}piperazin-1-yl)-3-phenylbutan-2-ol;

[0091] The other conditions in Example 12 remain unchanged, and 2-((2-methoxyphenoxy)methyl)ethylene oxide is replaced by 2-((4-fluorophenoxy)methyl)ethylene oxide to prepare the MyD88 inhibitor in this example.

[0092] The hydrogen spectrum data of the MyD88 inhibitor in this example are as follows: 1 H NMR (400MHz, CDCl3) δ7.35-7.26(m,3H),7.26-7.18(m,2H),6.96(t,J=12.0Hz,2H),6.91-6.81(m,2H),4.06(dd,J=9.5,4.4Hz, 1H),3.93(d,J=4.1Hz,2H),3.87-3.79(m,1H),2.85-2.62(br,5H),2.59-2.38(m,7H),2.31-2.17(m,1H),1.25(d,J=6.4Hz,3H). 13C NMR (100MHz, CDCl3) δ154.74,143.17,132.82,128.36×2,128.17×2,126.60,116.00,115.77,11 5.63,115.55,70.72,70.18,65.50,61.84,60.44,52.86×4,43.96,17.20.HRMS(ESI,m / z):calcd for C 23 H 32 FN2O3[M+H] + ,403.2397;found,403.2386.

[0093] Embodiment 15

[0094] The structural formula of the MyD88 inhibitor in this embodiment is The name is 1-(4-{3-[(4-chlorophenyl)oxy]-2-hydroxypropyl}piperazin-1-yl)-3-phenylbutan-2-ol;

[0095] The other conditions in Example 12 remain unchanged, and 2-((2-methoxyphenoxy)methyl)ethylene oxide is replaced by 2-((4-chlorophenoxy)methyl)ethylene oxide to prepare the MyD88 inhibitor in this example.

[0096] The hydrogen spectrum data of the MyD88 inhibitor in this example are as follows: 1 H NMR (400MHz, CDCl3) δppm 7.28-7.24(m,2H),7.23-7.19(m,2H),7.18-7.14(m,3H),6.78(d,J=6.1Hz,2H),4.01(m,4.3Hz,1H),3.93-3.84 (m,2H),3.82-3.73(m,1H),2.77-2.55(m,5H),2.52-2.35(m,7H),2.21(t,J=16.7Hz,1H),1.24(d,J=6.9Hz,3H). 13 C NMR (100MHz, CDCl3) δ157.36,143.57,129.36×2,128.28×2,128.18×2,126.47,125.94,11 5.88×2,70.55,70.21,65.46,61.77,60.31,53.28×4,43.98,17.31.HRMS(ESI,m / z):calcd for C 23 H 32 ClN2O3[M+H] +,419.2101;found,419.2091.

[0097] Example 16

[0098] The structural formula of the MyD88 inhibitor in this embodiment is The name is 1-(4-{3-[(4-bromophenyl)oxy]-2-hydroxypropyl}piperazin-1-yl)-3-phenylbutan-2-ol;

[0099] The other conditions in Example 12 remain unchanged, and 2-((2-methoxyphenoxy)methyl)ethylene oxide is replaced by 2-((4-bromophenoxy)methyl)ethylene oxide to prepare the MyD88 inhibitor in this example.

[0100] The hydrogen spectrum data of the MyD88 inhibitor in this example are as follows: 1 H NMR(400MHz, CDCl3) δ7.36(d,J=8.7Hz,2H),7.34-7.27(m,2H),7.26-7.21(m,3H),6.79(d,J=8.7Hz,2H),4.07(dd,J=9.0,4.4Hz,1 H),3.93(d,J=4.7Hz,2H),3.89-3.80(m,1H),2.83-2.63(m,5H),2.58-2.35(m,7H),2.28(t,J=11.1Hz,1H),1.30(d,J=6.4Hz,3H). 13 C NMR(100MHz, CDCl3)δ157.86,143.57,132.30×2,128.28×2,128.18×2,126.47,116.41×2, 113.24,70.48,70.22,65.46,61.77,60.30,53.25×4,43.98,17.32.HRMS(ESI,m / z):calcd for C 23 H 32 BrN2O3[M+H] + ,463.1596;found,463.1591.

[0101] Embodiment 17

[0102] The structural formula of the MyD88 inhibitor in this embodiment is The name is 1-{4-[2-hydroxy-3-(phenyloxy)propyl]piperazin-1-yl}-3-phenylbutan-2-ol;

[0103] The other conditions in Example 12 remain unchanged, and 2-((2-methoxyphenoxy)methyl)ethylene oxide is replaced by 2-(phenoxymethyl)ethylene oxide to prepare the MyD88 inhibitor in this example.

[0104] The hydrogen spectrum data of the MyD88 inhibitor in this example are as follows: 1 H NMR (400MHz, CDCl3) δppm 7.29(d,J=8.4Hz,1H),7.05-7.00(m,1H),6.98(t,J=4.6Hz,1H),6.94(d,J=7.5 Hz,1H),6.91(d,J=7.9Hz,3H),4.10(dt,J=9.0,4.6Hz,1H),3.98(d,J=4.9Hz,2 H),3.83(ddd,J=9.4,6.1,3.0Hz,1H),3.17(d,J=9.3Hz,1H),2.75(dt,J=13.0, 6.5Hz,4H),2.64-2.49(m,4H),2.49-2.35(m,3H),2.25(dd,J=19.2,8.6Hz,1H). 13 C NMR (100MHz, CDCl3) δ164.04,161.61,158.69,146.39,129.62,129.51,123.99,123.97,121.08,115.15,114.94 ,114.59,113.40,113.19,70.17,69.96,65.66,61.80,61.76,60.49,53.29,43.83,17.46.HRMS(ESI,m / z):calcd for C 23 H 33 N2O3[M+H] + ,385.2491;found,385.2486.

[0105] Embodiment 18

[0106] The structural formula of the MyD88 inhibitor in this embodiment is The name is 1-{4-[3-(benzyloxy)-2-hydroxypropyl]piperazin-1-yl}-3-phenylbutan-2-ol;

[0107] The other conditions in Example 12 remain unchanged, and 2-((2-methoxyphenoxy)methyl)ethylene oxide is replaced by 2-(benzyloxymethyl)ethylene oxide to prepare the MyD88 inhibitor in this example.

[0108] The hydrogen spectrum data of the MyD88 inhibitor in this example are as follows: 1H NMR (400MHz, CDCl3) δ7.54(d,J=6.5Hz,1H),7.46(d,J=7.8Hz,1H),7.33(m,7H),7.07(t,J=7.6Hz,1H),4.53(s,2H),4. 01(br,2H),3.48(d,J=4.4Hz,2H),3.46-3.31(m,1H),2.85(br,5H),2.67-2.51(m,7H),2.38-2.30(m,1H),1.25(s,3H). 13 C NMR (100MHz, CDCl3) δ164.04,161.61,146.34,146.27,138.04,129.63,129.54,128.45,127.78,123.96, 115.13,114.92,113.42,113.21,73.54,72.47,69.91,66.16,66.13,61.78,60.62,53.20,43.84,17.43.

[0109] Embodiment 19

[0110] The structural formula of the MyD88 inhibitor in this embodiment is The name is 1-(4-{2-hydroxy-3-[(2-methylphenyl)oxy]propyl}piperazin-1-yl)-3-phenylbutan-2-ol;

[0111] The other conditions in Example 12 remain unchanged, and 2-((2-methoxyphenoxy)methyl)ethylene oxide is replaced by 2-((2-methylphenoxy)methyl)ethylene oxide to prepare the MyD88 inhibitor in this example.

[0112] The hydrogen spectrum data of the MyD88 inhibitor in this example are as follows: 1 H NMR (400MHz, CDCl3) δ7.35-7.29(m,2H),7.27(s,2H),7.23(t,J=11.3,1H),7.14(t,J=7.4Hz,2H),6.87(t,J=7.4Hz,1H),6.82(d,J=8.0Hz,1H), 4.16-4.06(m,1H),3.98(m,2H),3.91-3.79(m,1H),2.85-2.64(m,5H),2 .59-2.33(m,7H),2.33-2.25(m,1H),2.23(s,3H),1.31(d,J=7.2Hz,3H). 13C NMR (100MHz, CDCl3) δ156.76,143.57,130.75,128.29×2,128.19×2,126.85×2,126.48,120.77,1 11.19,70.31,70.23,65.77,61.80,60.73,53.34×4,44.01,17.33,16.27.HRMS(ESI,m / z):calcd for C 24 H 35 N2O3[M+H] + ,399.2647;found,399.2648.

[0113] Embodiment 20

[0114] The structural formula of the MyD88 inhibitor in this embodiment is The name is 1-(4-{2-hydroxy-3-[(4-methoxyphenyl)oxy]propyl}piperazin-1-yl)-3-phenylbutan-2-ol;

[0115] The other conditions in Example 12 remain unchanged, and 2-((2-methoxyphenoxy)methyl)ethylene oxide is replaced by 2-((4-methoxyphenoxy)methyl)ethylene oxide to prepare the MyD88 inhibitor in this example.

[0116] The hydrogen spectrum data of the MyD88 inhibitor in this example are as follows: 1 H NMR (400MHz, CDCl3) δ7.35-7.27(m,2H),7.23(m,2H),7.24-7.20(m,2H),6.88-6.79(m,4H),4.07(m,1H),3.92(d,J=4.9Hz, 2H),3.88-3.80(m,1H),3.76(s,3H),2.83-2.62(br,5H),2.60-2.32(m,7H),2.27(t,J=10.7Hz,1H),1.36-1.28(d,J=7.2Hz 3H). 13 C NMR (100MHz, CDCl3) δ154.06,152.90,143.59,128.28×2,128.18×2,126.46,115.57×2,114.6 7×2,70.96,70.22,65.64,61.78,60.46,55.75,53.30×4,44.00,17.31.HRMS(ESI,m / z):calcd for C 24 H 35 N2O4[M+H] +,415.2597;found,415.2591.

[0117] Embodiment 21

[0118] The structural formula of the MyD88 inhibitor in this embodiment is The name is 3-(3-fluorophenyl)-1-(4-{2-hydroxy-3-[(2-methoxyphenyl)oxy]propyl}piperazin-1-yl)butan-2-ol;

[0119] The other conditions in Example 12 were kept unchanged, and the initial raw material acetophenone was replaced with 2-fluoroacetophenone to prepare the MyD88 inhibitor in this example.

[0120] The hydrogen spectrum data of the MyD88 inhibitor in this example are as follows: 1 H NMR (400MHz, CDCl3) δ7.28-7.22(m,1H),7.05-6.96(m,2H),6.96-6.86(m,5H),4.19-4.09(m,1H),4.01(d,J=4.7Hz, 2H),3.85(s,3H),3.83-3.77(m,1H),2.79-2.63(m,5H),2.59-2.39(m,7H),2.28-2.19(m,1H),1.28(d,J=6.7Hz,3H). 13 C NMR (100MHz, CDCl3) δ164.01-161.58,149.67,148.28,146.45,129.59,124.00,121.81,121.00,115.15-114.94,114. 40,113.35-113.14,112.01,72.21,69.95,66.00,61.79,60.52,55.85,53.39×4,43.83,17.47.HRMS(ESI,m / z):calcd forC 24 H 34 FN2O4[M+Na] + ,433.2503;found,433.2492.

[0121] Embodiment 22

[0122] The structural formula of the MyD88 inhibitor in this embodiment is The name is 3-(3-fluorophenyl)-1-[4-(2-hydroxy-3-{[4-(2-methylpropan-2-yl)phenyl]oxy}propyl)piperazin-1-yl]butan-2-ol;

[0123] The other conditions in Example 13 were kept unchanged, and the initial raw material acetophenone was replaced with 2-fluoroacetophenone to prepare the MyD88 inhibitor in this example.

[0124] The hydrogen spectrum data of the MyD88 inhibitor in this example are as follows: 1 H NMR(400MHz, CDCl3) δ7.29(d,J=8.7Hz,2H),7.26-7.22(m,1H),7.01(m,2H),6.91(m,1H),6.85(d,J=8.8Hz,2H),4.13-4.0 4(m,1H),3.96(d,J=4.7Hz,2H),3.85-3.77(m,1H),2.81-2.61(m,5H),2.59-2.30(m,7H),2.29-2.17(m,1H),1.29(s,12H). 13 C NMR (100MHz, CDCl3) δ164.05-161.61,156.43,146.36,143.78,129.61,126.27×2,123.96,115.14-114.93,114.03×2 ,113.41-113.20,70.19,69.91,65.62,61.79,60.52,53.22×4,43.83,34.11,31.54×3,17.43.HRMS(ESI,m / z):calcd for C 27 H 40 FN2O3[M+H] + ,459.3023;found,459.3023.

[0125] Embodiment 23

[0126] The structural formula of the MyD88 inhibitor in this embodiment is The name is 3-(3-fluorophenyl)-1-(4-{3-[(4-fluorophenyl)oxy]-2-hydroxypropyl}piperazin-1-yl)butan-2-ol;

[0127] The other conditions in Example 14 were kept unchanged, and the initial raw material acetophenone was replaced with 2-fluoroacetophenone to prepare the MyD88 inhibitor in this example.

[0128] The hydrogen spectrum data of the MyD88 inhibitor in this example are as follows: 1H NMR (400MHz, CDCl3) δ7.28-7.22(m,1H),7.05-6.88(m,5H),6.87-6.82(m,2H),4.07(m,1H),3.93(dd,J=7. 5,3.2Hz,2H),3.84-3.77(m,1H),2.75(br,5H),2.58-30(m,7H),2.29-2.19(m,1H),1.29(d,J=7.1Hz,3H). 13 CNMR (100MHz, CDCl3) δ164.04-161.60,158.55-156.24,154.86,146.35,129.62,123.97,115.96,115.73,115.64,115. 56,115.14-114.93,113.41-113.20,70.90,69.94,65.58,61.78,60.37,53.25×4,43.82,17.43.HRMS(ESI,m / z):calcd for C 23 H 31 F2N2O3[M+H] + ,421.2302;found,421.2290.

[0129] Embodiment 24

[0130] The structural formula of the MyD88 inhibitor in this embodiment is The name is 1-(4-{3-[(4-chlorophenyl)oxy]-2-hydroxypropyl}piperazin-1-yl)-3-(3-fluorophenyl)butan-2-ol;

[0131] The other conditions in Example 15 were kept unchanged, and the initial raw material acetophenone was replaced with 2-fluoroacetophenone to prepare the MyD88 inhibitor in this example.

[0132] The hydrogen spectrum data of the MyD88 inhibitor in this example are as follows: 1 H NMR (400MHz, CDCl3) δ7.29-7.22(m,1H),7.25-7.19(m,2H),7.06-6.95(m,2H),6.91(m,1H),6.87-6.81(m,2H),4.07(m,1H),3 .94(dd,J=7.6,3.6Hz,2H),3.84-3.76(m,1H),2.81-2.61(m,5H),2.60-2.30(m,7H),2.29-2.20(m,1H),1.28(d,J=7.1Hz,3H). 13C NMR (100MHz, CDCl3) δ164.03-161.60,157.35,146.30,129.62-129.53,129.36×2,125.92,123.98,115.89×2,11 5.14-114.93,113.40-113.19,70.56,69.96,65.53,61.78,60.33,53.25×4,43.82,17.45.HRMS(ESI,m / z):calcd for C 23 H 31 ClFN2O3[M+H] + ,437.2007;found,437.2000.

[0133] Embodiment 25

[0134] The structural formula of the MyD88 inhibitor in this embodiment is The name is 1-(4-{3-[(4-bromophenyl)oxy]-2-hydroxypropyl}piperazin-1-yl)-3-(3-fluorophenyl)butan-2-ol;

[0135] The other conditions in Example 16 were kept unchanged, and the initial raw material acetophenone was replaced with 2-fluoroacetophenone to prepare the MyD88 inhibitor in this example.

[0136] The hydrogen spectrum data of the MyD88 inhibitor in this example are as follows: 1 H NMR (400MHz, CDCl3) δ7.36(d,J=8.8Hz,2H),7.29-7.22(m,1H),7.01(dd,J=12.3,9.4Hz,2H),6.95-6.88(m,1H),6.79(d,J=8.9Hz,2H) ,4.07(m,1H),3.94(d,J=4.8Hz,2H),3.82(m,1H),2.81-2.62(m,5H),2.59-2.30(m,7H),2.25(t,J=11.5Hz,1H),1.29(d,J=7.1Hz,2H). 13 C NMR (100MHz, CDCl3) δ164.04-161.60,157.86,146.39-146.32,132.30×2,129.61-129.53,123.97,116.41×2,115.14 -114.93,113.40,113.24-113.19,70.49,69.95,65.49,61.77,60.31,53.29×4,43.82,17.45.HRMS(ESI,m / z):calcd for C23 H 31 BrFN2O3[M+H] + ,481.1502;found,481.1491.

[0137] Embodiment 26

[0138] The structural formula of the MyD88 inhibitor in this embodiment is The name is 3-(3-fluorophenyl)-1-{4-[2-hydroxy-3-(phenyloxy)propyl]piperazin-1-yl}butan-2-ol;

[0139] The other conditions in Example 17 were kept unchanged, and the initial raw material acetophenone was replaced with 2-fluoroacetophenone to prepare the MyD88 inhibitor in this example.

[0140] The hydrogen spectrum data of the MyD88 inhibitor in this example are as follows: 1 H NMR (400MHz, CDCl3) δ7.29-7.22(m,3H),7.05-6.94(m,3H),6.94-6.87(m,3H),4.10(m,1H),3.98(d,J=4.9 Hz,2H),3.83(m,1H),2.84-2.63(m,5H),2.62-2.32(m,7H),2.26(t,J=10.7Hz,1H),1.31(d,J=9.0Hz,3H). 13 C NMR (100MHz, CDCl3) δ164.04-161.61,158.69,146.39-146.32,129.62,129.51×2,123.99-123.97,121.08,115.15-114.9 4,114.59×2,113.40-113.19,70.17,69.96,65.66,61.80,60.49,53.29×4,43.83,17.46.HRMS(ESI,m / z):403.2395[M+H] + .

[0141] Embodiment 27

[0142] The structural formula of the MyD88 inhibitor in this embodiment is The name is 1-{4-[3-(benzyloxy)-2-hydroxypropyl]piperazin-1-yl}-3-(3-fluorophenyl)butan-2-ol;

[0143] The other conditions in Example 18 were kept unchanged, and the initial raw material acetophenone was replaced with 2-fluoroacetophenone to prepare the MyD88 inhibitor in this example.

[0144] The hydrogen spectrum data of the MyD88 inhibitor in this example are as follows: 1 H NMR (400MHz, CDCl3) δ7.39-7.22(m,6H),7.06-6.96(m,2H),6.91(td,J=8.6,2.3Hz,1H),4.56(s,2H),3.93(m,1H),3.8 6-3.78(m,1H),3.54-3.41(m,2H),2.80-2.65(m,5H),2.57-2.31(m,7H),2.25(t,J=14.9Hz,1H),1.29(d,J=7.1Hz,3H). 13 C NMR (100MHz, CDCl3) δ164.04-161.61,146.34-146.27,138.04,129.63-129.54,128.45×2,127.78×3,123.96,115.1 3-114.92,113.42-113.21,73.54,72.47,69.91,66.16,61.78,60.62,53.20×4,43.84,17.43.HRMS(ESI,m / z):calcd forC 24 H 34 FN2O3[M+H] + ,417.2553;found,417.2549.

[0145] Embodiment 28

[0146] The structural formula of the MyD88 inhibitor in this embodiment is The name is 3-(3-fluorophenyl)-1-(4-{2-hydroxy-3-[(2-methylphenyl)oxy]propyl}piperazin-1-yl)butan-2-ol;

[0147] The other conditions in Example 19 were kept unchanged, and the initial raw material acetophenone was replaced with 2-fluoroacetophenone to prepare the MyD88 inhibitor in this example.

[0148] The hydrogen spectrum data of the MyD88 inhibitor in this example are as follows: 1H NMR (400MHz, CDCl3) δ7.29-7.22(m,1H),7.14(t,J=7.4Hz,2H),7.01(dd,J=12.3,9.4Hz,2H),6.95-6.79(m,3H),4.18-4.08(m,1 H),3.98(m,2H),3.87-3.78(m,1H),2.84-2.64(m,5H),2.60-2.30(m,7H),2.30-2.25(m,1H),2.23(s,3H),1.30(d,J=7.1Hz,3H). 13 C NMR (100MHz, CDCl3) δ164.05-161.61,156.77,146.43-146.36,130.76,129.62-129.54,126.86×2,123.99,120.77,115.16 -114.95,113.41-113.20,111.18,70.33,69.95,65.82,61.81,60.74,53.39×4,43.85,17.47,16.29.HRMS(ESI,m / z):calcd for C 24 H 34 FN2O3[M+H] + ,417.2553;found,417.2547.

[0149] Embodiment 29

[0150] The structural formula of the MyD88 inhibitor in this embodiment is The name is 3-(3-fluorophenyl)-1-(4-{2-hydroxy-3-[(4-methoxyphenyl)oxy]propyl}piperazin-1-yl)butan-2-ol;

[0151] The other conditions in Example 20 remain unchanged, and the initial raw material acetophenone is replaced by 2-fluoroacetophenone to prepare the MyD88 inhibitor in this example.

[0152] The hydrogen spectrum data of the MyD88 inhibitor in this example are as follows: 1 H NMR (400MHz, CDCl3) δ7.29-7.22(m,1H),6.96(m,3H),6.87-6.78(m,4H),4.06(m,1H),3.95-3.88(m,2H), 3.86-3.79(m,1H),3.76(s,3H),2.71(m,5H),2.56-2.31(m,7H),2.31-2.19(m,1H),1.29(d,J=7.2Hz,3H). 13CNMR (100MHz, CDCl3) δ164.04-161.60,154.06,152.85,146.34,129.62,123.95,115.56×2,115.13-114.92,1 14.66×2,113.42-113.21,70.91,69.93,65.66,60.45,55.75×2,53.20×4,43.83,17.42.HRMS(ESI,m / z):calcd for C 24 H 34 FN2O4[M+H] + ,433.2502;found,433.2501.

[0153] Performance Testing

[0154] (1) Performance test of inhibiting LPS-stimulated macrophages from releasing inflammatory factors

[0155] The MyD88 inhibitors in Examples 1 to 29 were tested for their ability to inhibit the release of IL-6 from RAW 264.7 macrophages stimulated by LPS. The specific method was as follows: 1.2×10 6 RAW ethyl acetate 264.7 macrophages were cultured in DMEM culture medium at 37°C, and the culture medium was renewed after 24 hours. The test compound - MyD88 inhibitor prepared in Examples 1 to 29 (final concentration of 10 μM) was added for pretreatment for 2 hours, and then 0.5 μg / mL LPS was added for further treatment for 22 hours. The culture medium was collected and the IL-6 content was detected by ELISA. The cells were collected to detect the total protein concentration, and the ELISA results were divided by the corresponding total protein concentration for accuracy. The IL-6 content of the LPS control group was calibrated as 100, and the average value and error value were calculated to obtain a schematic diagram of the activity of different MyD88 inhibitors in inhibiting the release of IL-6 from LPS-stimulated macrophages, as shown in FIG. Figure 1 shown. Figure 1 In the abscissa, con is the blank group, lps is the control group to which only LPS is added, and 1 to 29 correspond to the MyD88 inhibitors prepared in Examples 1 to 29, respectively. Figure 1 It can be seen that most of the example compounds have a good inhibitory effect on LPS-induced IL-6 secretion, indicating that the obtained MyD88 inhibitor has a good anti-inflammatory effect.

[0156] (2) Relationship between the binding affinity of MyD88 inhibitors to MyD88 protein and their concentration

[0157] The relationship between the binding affinity and concentration of the MyD88 inhibitors to the MyD88 protein in Examples 4, 5, 8, and 20 was tested. The specific method is as follows: The binding affinity of Examples 4 (i.e., A4), 5 (i.e., A5), 8 (i.e., A8), and 20 (i.e., B9) to rhMyD88 was determined using the ForteBio OctetRed system (ForteBio, San Francisco, CA, USA). The recombinant protein was immobilized on a SuperStreptavidin biosensor (#18-5057; ForteBio) using the ReadiLink protein biotinylation kit (#AAT-5520; AAT Bioquest, Sunnyvale, CA, USA), and the binding and dissociation of each MyD88 inhibitor were monitored for 100 s, and the blank sensor and blank sample in the duplicate wells were subtracted to obtain the final image. The data was analyzed using ForteBio's data analysis software version 8.1 (ForteBio) to obtain a schematic diagram of the relationship between the binding affinity and concentration of different MyD88 inhibitors to the MyD88 protein, as shown in FIG. Figure 2 As shown; Figure 2 In the figure, A is a schematic diagram showing the relationship between the binding affinity and concentration of the MyD88 inhibitor and the MyD88 protein in Example 4, B is a schematic diagram showing the relationship between the binding affinity and concentration of the MyD88 inhibitor and the MyD88 protein in Example 5, C is a schematic diagram showing the relationship between the binding affinity and concentration of the MyD88 inhibitor and the MyD88 protein in Example 8, and D is a schematic diagram showing the relationship between the binding affinity and concentration of the MyD88 inhibitor and the MyD88 protein in Example 20. Figure 2 It can be seen that the tested MyD88 inhibitors have good binding activity to MyD88 protein, among which the MyD88 inhibitor in Example 5 has the best activity, and its binding affinity Kd value is 8.48×10 -5 M.

[0158] (3) Experiment on the effect of MyD88 inhibitor on the physiological changes of mice caused by inflammation

[0159] Taking the alleviation of physiological changes caused by acute lung injury as an example, a suspension was prepared with 0.5% sodium carboxymethyl cellulose and the MyD88 inhibitor in Example 11. The concentration of the MyD88 inhibitor in the suspension was 2 mg / mL, which was used for oral administration (30 minutes before LPS instillation). Each group of mice was anesthetized with ether and the trachea was exposed. Except for the blank group (CON), 20 μL 5 mg / kg LPS was slowly instilled into the trachea of ​​the other groups to cause acute lung injury in mice; the blank group was instilled with an equal amount of saline in the same way, and the wound was sutured to establish an acute lung injury model. After 6 hours of animal modeling, the mice were anesthetized by intraperitoneal injection of 10% chloral hydrate at a dose of 5 mL / kg, the left lung was ligated by thoracotomy, and the right lung was lavaged with 1 mL of saline for bronchoalveolar lavage, and the lavage fluid was collected. The same operation was repeated 3 times.

[0160] After the alveolar lavage fluid is collected, it is centrifuged for 5 minutes at a temperature of 4°C and a rotation speed of 1000 rpm. The supernatant is taken and the protein concentration of the alveolar lavage fluid is measured. After the alveolar lavage fluid is centrifuged, the precipitate is resuspended with 50 μL of normal saline, mixed and 20 μL is taken to count the total number of cells in the alveolar lavage fluid using a Standard cell counter. In addition, the right upper lobe of the lung is taken, the moisture on the tissue is absorbed with filter paper, and the wet weight is weighed, and it is placed in a 60°C oven and baked for more than 48 hours until its weight no longer changes. The dry weight is weighed, and the wet weight / dry weight ratio (W / D) of the lung tissue is calculated to determine the degree of pulmonary edema. A schematic diagram of the effect of the MyD88 inhibitor in alleviating acute lung injury in Example 11 is obtained, as shown in FIG. Figure 3 shown. Figure 3 A is a schematic diagram of the wet weight / dry weight ratio, B is a schematic diagram of the leukocyte protein concentration in the alveolar lavage fluid, C is a schematic diagram of the number of leukocytes in the alveolar lavage fluid, D is a schematic diagram of the mouse spleen weight, E is a schematic diagram of the IL-6 expression level in serum, F is a schematic diagram of the TNF-α expression level in serum, G is a schematic diagram of the IL-6 expression level in the alveolar lavage fluid, and H is a schematic diagram of the TNF-α expression level in the alveolar lavage fluid. In the abscissas of A, B, C, D, E, F, G, and H, CON is the blank group, LPS is the control group injected with only LPS, DXM is the positive control compound dexamethasone (controlling the other aforementioned conditions unchanged, and gavage 30 minutes before LPS established acute lung injury), and A5S represents the MyD88 inhibitor in Example 11. From Figure 3 It can be seen that the MyD88 inhibitor in Example 11 can physiologically effectively alleviate acute lung injury in mice.

[0161] (4) Experiment on the effect of MyD88 inhibitor on the pathological changes of mice caused by inflammation

[0162] Taking the alleviation of pathological changes in mouse lung tissue caused by acute lung injury in (3) as an example, after characterization, the staining result diagram of the pathological changes caused by the MyD88 inhibitor relieving acute lung injury in Example 11 was obtained, as shown in FIG. Figure 4 As shown. Figure 4 It can be seen that the alveolar cavity of the CON group mice was clear, the structure was intact, and the wall was smooth; after tracheal instillation of LPS to cause an acute lung injury model, the alveolar wall was significantly edematous and thickened, and the infiltration of inflammatory cells increased; after treatment with the MyD88 inhibitor in Example 11, the cell edema and thickening were significantly weakened, and the infiltration of inflammatory cells was significantly reduced, which was not much different from that of the normal group, indicating that the MyD88 inhibitor prepared in Example 11 can effectively alleviate lung tissue damage in acute lung injury.

[0163] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A MyD88 inhibitor, characterized in that The MyD88 inhibitor includes one or more of a compound having a structure as shown in formula (I), a racemate of a compound having a structure as shown in formula (I), an optical isomer of a compound having a structure as shown in formula (I), a pharmaceutically acceptable salt of a compound having a structure as shown in formula (I), a pharmaceutically acceptable hydrate of a compound having a structure as shown in formula (I), a pharmaceutically acceptable solvate of a compound having a structure as shown in formula (I), and a pharmaceutically acceptable prodrug of a compound having a structure as shown in formula (I); In formula (I), X is a six-membered aryl group optionally substituted by 1 to 2 identical or different substituents or a five-membered and six-membered heteroaryl group optionally substituted by 1 to 2 identical or different substituents, wherein the substituents are selected from hydrogen, halogen, alkyl, alkoxy, hydroxy, alkylthio, monoalkyl-substituted amino, dialkyl-substituted amino, alkylamido, free carboxyl, salified carboxyl, esterified carboxyl, amidated carboxyl, alkylsulfinyl, sulfonyl, alkylacyl, carbamoyl, monoalkyl-substituted carbamoyl, dialkyl-substituted carbamoyl or alkylenedioxy; Y is Z1, Z2, and Z3 are independently a six-membered aromatic group optionally substituted by 1 to 2 identical or different substituents, wherein the substituents are selected from hydrogen, halogen, alkyl, alkoxy, hydroxy, alkylthio, amino, monoalkyl-substituted amino, dialkyl-substituted amino, alkylacylamino, free carboxyl, salified carboxyl, esterified carboxyl, amidated carboxyl, alkylsulfinyl, sulfonyl, alkylacyl, carbamoyl, monoalkyl-substituted carbamoyl, dialkyl-substituted carbamoyl, or alkylenedioxy; m1, m2, and m3 are independently 0 or 1; n is 0 or 1.

2. The MyD88 inhibitor according to claim 1, characterized in that When n is 0, X is When n is 1, X is a six-membered aryl group optionally substituted by 1 to 2 identical or different substituents selected from hydrogen, fluorine, chlorine, bromine, methyl, methoxy, ethoxy, hydroxyl or tert-butyl.

3. The MyD88 inhibitor according to claim 1 or 2, characterized in that Z1, Z2, and Z3 are independently six-membered aromatic groups optionally substituted by 1 to 2 identical or different substituents, wherein the substituents are selected from hydrogen, fluorine, chlorine, bromine, methyl, methoxy, ethoxy, hydroxyl, or tert-butyl.

4. The MyD88 inhibitor according to claim 1, characterized in that The MyD88 inhibitor is the following compound, the racemate of the following compound, the optical isomer of the following compound, the pharmaceutically acceptable salt of the following compound, the pharmaceutically acceptable hydrate of the following compound, the pharmaceutically acceptable solvate of the following compound, or the pharmaceutically acceptable prodrug of the following compound; 5. A pharmaceutical composition, characterized in that It comprises an active ingredient and a pharmaceutically acceptable excipient; the active ingredient is the MyD88 inhibitor according to any one of claims 1 to 4.

6. Use of the MyD88 inhibitor according to any one of claims 1 to 4 or the pharmaceutical composition according to claim 5 in the preparation of a drug for preventing or treating inflammation-related diseases.

7. The use according to claim 6, characterized in that The inflammation-related diseases include acute lung injury, rheumatoid arthritis, osteoarthritis, spondyloarthropathies, gouty arthritis, rheumatic arthritis, acute attacks of chronic arthritis, persistent joint swelling and pain, non-articular soft tissue rheumatic pain, acute mild to moderate pain, ischemic reperfusion, atherosclerosis, hepatitis, lymphadenitis, pneumonia, dysentery or appendicitis.

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