Thiadiazole urea compound or pharmaceutically acceptable salt thereof, pharmaceutical composition and application of thiadiazole urea compound or pharmaceutically acceptable salt thereof

Abstract

The invention relates to the technical field of medicinal chemistry, in particular to a thiadiazole urea compound or pharmaceutically acceptable salt thereof, a pharmaceutical composition and application of the thiadiazole urea compound, and discloses a structural formula of the thiadiazole urea compound, the thiadiazole urea compound has a good inhibitory effect on programmed necrosis in an in-vitro experiment, and the application of the thiadiazole urea compound in the in-vitro experiment is promoted. The TNF-induced cell programmed necrosis can be inhibited in a concentration-dependent manner, I / R-induced mouse acute kidney injury and inflammatory response are improved, the serum creatinine and urea nitrogen level in a mouse blood sample is reduced, and kidney function recovery is promoted.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and in particular to a thiadiazole urone compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition and application thereof. Background Art

[0002] Necroptosis is a regulated necrosis-like programmed cell death that is independent of caspases. Unlike apoptosis, necrosis has its own unique morphological characteristics: cell swelling, plasma membrane rupture, and release of cell contents. This process causes damage-associated molecular patterns (DAMPs) to infiltrate surrounding tissues, which in turn causes a large number of inflammatory cell infiltrations, ultimately triggering an inflammatory response in surrounding tissues.

[0003] Receptor-interacting protein kinase (RIPK) is a serine / threonine kinase that plays a crucial role in the pathophysiological process of regulating cell survival and death. The RIPK family consists of seven members (RIPK1-7) containing homologous kinase domains, among which RIPK1 and RIPK3 are closely related to the cell death mechanism of programmed necrosis. During the process of programmed necrosis induced by tumor necrosis factor (TNF), RIPK1 interacts with the respective RIP homotypic interaction sequence (RHIM) domain of RIPK3, causing RIPK3 to be autophosphorylated and activated. Subsequently, activated RIPK3 phosphorylates mixed-lineage kinase domain-like protein (MLKL), and the phosphorylated MLKL oligomerizes and translocates to the plasma membrane, leading to programmed necrosis. RIPK1, RIPK3 and MLKL are considered to be key molecules in the programmed necrosis signaling pathway.

[0004] Programmed necrosis involves a variety of pathophysiological processes, such as the normal development of embryonic tissues, the regulation of immune responses, tumor growth, and inflammatory damage. Acute kidney injury (AKI) refers to a sudden decline in renal function, resulting in an increase in serum creatinine levels or a drop in urine output below a specific threshold. Cell necrosis and inflammation are key features of AKI. RIPK3 plays an important role in kidney injury and inflammation, including programmed necrosis, inflammation, fibrosis, and the transition from AKI to chronic kidney disease (CKD). Therefore, intervention targeting RIPK3 and reducing programmed necrosis of cells can help improve kidney function and reduce inflammatory responses.

[0005] In view of the above-mentioned defects, the inventors of the present invention finally obtained the present invention after a long period of research and practice. Summary of the invention

[0006] The purpose of the present invention is to solve the problem that there is a lack of drugs in the existing market that use RIPK3 as a drug target to inhibit programmed necrosis and thus prevent and treat acute kidney injury, and provide a thiadiazole urone compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition and its use.

[0007] In order to achieve the above object, the present invention discloses a thiadiazole urone compound or a pharmaceutically acceptable salt thereof, the general structural formula of which is as follows:

[0008]

[0009] Among them, R 1 Selected from the following aromatic rings or aromatic ring systems:

[0010] R 2 Selected from the following aromatic rings or aromatic ring systems:

[0011] The thiadiazole urea compound is any one of the following compounds:

[0012]

[0013]

[0014]

[0015]

[0016] The present invention also discloses a pharmaceutical composition, comprising one or more therapeutically effective amounts of the above-mentioned thiadiazole urone compounds or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable adjuvants.

[0017] The present invention also discloses a use of the thiadiazole urone compound or a pharmaceutically acceptable salt thereof in preparing a drug for preventing and / or treating inflammatory diseases associated with programmed cell necrosis.

[0018] The inflammatory diseases include, but are not limited to, any one of inflammatory bowel disease, psoriasis, neuroinflammation, acute kidney injury, acute and chronic inflammation of the kidney, chronic kidney disease, acute renal failure, renal fibrosis, diabetic nephropathy, and rheumatoid arthritis.

[0019] The present invention also discloses the use of the thiadiazole urone compound or a pharmaceutically acceptable salt thereof in preparing a drug for preventing and / or treating inflammatory diseases.

[0020] Compared with the prior art, the beneficial effect of the present invention is that the thiadiazole urea compound or its pharmaceutically acceptable salt in the present invention has a good inhibitory effect on programmed necrosis in in vitro experiments, can inhibit TNF-induced cell programmed necrosis in a concentration-dependent manner, improve I / R-induced acute kidney injury and inflammatory response in mice, reduce serum creatinine and urea nitrogen levels in mouse blood samples, and promote kidney function recovery. Therefore, compound Cpd-17 has broad clinical application prospects as an acute kidney injury therapeutic agent. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 PAS staining of mouse kidney tissue sections;

[0022] Figure 2 To detect the mRNA expression level of kidney injury factor KIM-1 in mouse kidney tissue using q-RT-PCR technology;

[0023] Figure 3 To detect the protein expression level and distribution of kidney injury factor KIM-1 in mouse kidney tissue by immunofluorescence method;

[0024] Figure 4 are the serum creatinine and serum urea nitrogen levels of mice;

[0025] Figure 5 q-RT-PCR technology was used to detect the mRNA expression levels of inflammatory factors TNF-α, IL-1β and IL-6 in mouse kidney tissue. DETAILED DESCRIPTION

[0026] The above and other technical features and advantages of the present invention are described in more detail below in conjunction with the accompanying drawings.

[0027] Example 1

[0028] Synthesis of 1-(5-(2-butoxyphenyl)-1,3,4-thiadiazol-2-yl)-3-(4-fluorophenyl)urea

[0029] The reaction formula is as follows:

[0030]

[0031] Take the synthetic route of final product 1 as an example:

[0032] Methyl 2-n-butoxybenzoate (194 mg, 0.93 mmol) was dissolved in 2.5 mL of methanol, and 2 mL of 2N·NaOH was added. The mixture was moved to 65°C for reaction for 2 h. Then, 2N·HCl was slowly added dropwise to the reaction solution under ice bath conditions to adjust the pH to about 3. The mixture was then extracted with ethyl acetate (3×10 mL), and the combined organic phase was washed with saturated brine (2×10 mL). The organic phase was dried over anhydrous sodium sulfate for 3-4 h, filtered and dried to obtain a1 (161 mg, 88.9%).

[0033] a1 (161 mg, 0.82 mmol) was mixed with thiosemicarbazide (112 mg, 1.23 mmol) and POCl 3 (449μL, 4.92mmol) was slowly added thereto, and then the temperature was gradually raised to 80℃ and the reaction was continued for 2h. After the reaction was completed, the temperature was allowed to stand and cool to room temperature, and then placed in an ice-water bath and 5mL of water was added. The temperature was then raised to 90℃ and the reaction was continued for 4h. After the reaction was completed, the temperature was allowed to stand and cool, and the pH was adjusted to 8 with 50% KOH solution. The solid was precipitated, filtered while hot, and recrystallized from ethanol to obtain the solid a2 (123mg, 59.7%) after drying.

[0034] a2 (123 mg, 0.49 mmol) was dissolved in 10 mL of anhydrous CH 2 Cl 2 Then p-fluoroisocyanate (62 μL, 0.51 mmol) and DIPEA (163 μL, 0.98 mmol) were added and stirred at room temperature overnight. A white solid was precipitated. After filtration and washing with a small amount of petroleum ether and ethyl acetate, the target compound 1 was obtained as a white solid (109 mg, 56%) after drying.

[0035] 1 H NMR (500 MHz, DMSO-d 6)δ10.87(s,1H),9.05(s,1H),8.23(d,J=7.8Hz,1H),7.52(dd,J=9.0,4.8Hz,2H),7.49–7.44(m,1H),7.23(d,J=8.4Hz,1H),7.17( t,J=8.8Hz,2H),7.10(t,J=7.3Hz,1H),4.22(t,J=6.4Hz,2H),1.85(p,J=6.6Hz,2H),1.56(h,J=7.4Hz,2H),0.98(t,J=7.4Hz,3H). 13 C NMR (126 MHz, DMSO-d 6 )δ158.89,156.99,154.57,134.77,131.41,127.08,120.88,120.78,120.71,119 .07,115.49,115.32,112.88,68.54,30.61,18.86,13.56.HRMS(ESI,m / z):calcd for C 19 H 19 FN 4 O 2 S[M+H] + 387.1291; found, 387.1298.

[0036] Example 2

[0037] Synthesis of 1-(5-(3-butoxyphenyl)-1,3,4-thiadiazol-2-yl)-3-(4-fluorophenyl)urea

[0038] 3-n-butoxybenzoic acid methyl ester was used as the raw material instead of 2-n-butoxybenzoic acid methyl ester, and other embodiments were the same as those in Example 1. The prepared compound was a white solid with a yield of 52%.

[0039] 1 H NMR (500 MHz, DMSO-d 6 )δ11.13(s,1H),9.14(s,1H),7.53(dd,J=8.9,4.9Hz,2H),7.41(t,J=7.7Hz,3H),7.17(t,J=8.8Hz,2H),7 .07(d,J=7.4Hz,1H),4.05(t,J=6.5Hz,2H),1.76–1.68(m,2H),1.50–1.41(m,2H),0.94(t,J=7.4Hz,3H). 13 C NMR (126 MHz, DMSO-d 6)δ158.94,158.77,156.86,134.59,131.33,130.30,120.66,120.60,118.86,116 .73,115.33,115.16,111.55,67.21,30.49,18.49,13.47.HRMS(ESI,m / z):calcd forC 19 H 19 FN 4 O 2 S[M+H] + 387.1291; found, 387.1295.

[0040] Example 3

[0041] Synthesis of 1-(5-(4-butoxyphenyl)-1,3,4-thiadiazol-2-yl)-3-(4-fluorophenyl)urea

[0042] 4-n-butoxybenzoic acid methyl ester was used as the raw material instead of 2-n-butoxybenzoic acid methyl ester, and other embodiments were the same as those in Example 1. The prepared compound was a white solid with a yield of 52%.

[0043] 1 H NMR (500 MHz, DMSO-d 6 )δ11.13(s,1H),9.14(s,1H),7.53(dd,J=8.9,4.9Hz,2H),7.41(t,J=7.7Hz,3H),7.17(t,J=8.8Hz,2H),7 .07(d,J=7.4Hz,1H),4.05(t,J=6.5Hz,2H),1.76–1.68(m,2H),1.50–1.41(m,2H),0.94(t,J=7.4Hz,3H). 13 C NMR (126 MHz, DMSO-d 6 )δ158.94,158.77,156.86,134.59,131.33,130.30,120.66,120.60,118.86,116 .73,115.33,115.16,111.55,67.21,30.49,18.49,13.47.HRMS(ESI,m / z):calcd forC 19 H 19 FN 4 O 2 S[M+H] + 387.1291; found, 387.1295.

[0044] Example 4

[0045] Synthesis of 1-(4-fluorophenyl)-3-(5-(2-methoxyphenyl)-1,3,4-thiadiazol-2-yl)urea

[0046] 2-methoxybenzoic acid methyl ester was used as the raw material instead of 2-n-butoxybenzoic acid methyl ester, and other embodiments were the same as those in Example 1. The prepared compound was a white solid with a yield of 62%.

[0047] 1 H NMR (500 MHz, DMSO-d 6 )δ10.90(s,1H),9.06(s,1H),8.22(d,J=7.7Hz,1H),7.53(dd,J=8.5,4.6Hz,2H),7.49(d,J= 7.8Hz,1H),7.26(d,J=8.4Hz,1H),7.17(t,J=8.6Hz,2H),7.12(t,J=7.6Hz,1H),4.00(s,3H). 13 C NMR (126 MHz, DMSO-d 6 )δ159.45,157.54,155.78,135.28,132.02,127.60,121.62,121.37,121.30,119.54,116.01,115.83,112.92,56.55.HRMS(ESI,m / z):calcd for C 16 H 13 FN 4 O 2 S[M+H] + 345.0821; found, 345.0832.

[0048] Example 5

[0049] Synthesis of 1-(4-fluorophenyl)-3-(5-(3-methoxyphenyl)-1,3,4-thiadiazol-2-yl)urea

[0050] 3-methoxybenzoic acid methyl ester was used as the raw material instead of 2-n-butoxybenzoic acid methyl ester, and other embodiments were the same as those in Example 1. The prepared compound was a white solid with a yield of 65%.

[0051] 1 H NMR (500 MHz, DMSO-d 6)δ11.12(s,1H),9.11(s,1H),7.53(dd,J=8.9,4.9Hz,2H),7.44(d,J=7.6Hz,3H),7.17(t,J=8.8Hz,2H),7.08(d,J=7.3Hz,1H),3.84(s,3H). 13 CNMR (126MHz, DMSO-d 6 )δ159.66,158.94,157.03,134.73,131.51,130.47,120.84,120.78,119.15,116.39,115.49,115.31,111.21,55.27.HRMS(ESI,m / z):calcd for C 16 H 13 FN 4 O 2 S[M+H] + 345.0821; found, 345.0829.

[0052] Example 6

[0053] Synthesis of 1-(2-fluorophenyl)-3-(5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-yl)urea

[0054] The reaction formula is as follows:

[0055]

[0056] Taking the synthetic route of final product 6 as an example, a5 (104 mg, 0.5 mmol) and p-nitrophenyl chloroformate (111 mg, 0.55 mol) were dissolved in 10 mL CH 2 Cl 2 Pyridine (40 μL, 0.5 mmol) was added to the reaction mixture and the reaction was continued for 10 min. Then 2-fluoroaniline (56 mg, 0.5 mmol) and DIPEA (54 μL, 0.55 mmol) were added to the reaction mixture and the reaction was continued at room temperature overnight. A white solid was precipitated. The solid was filtered and washed with a small amount of petroleum ether and ethyl acetate. The target compound 6 was obtained after drying as a white solid (112 mg, 65%).

[0057] 1 H NMR (500 MHz, DMSO-d 6)δ11.19(s,1H),8.96(s,1H),8.10(q,J=8.1Hz,1H),7.85(d,J=8.3Hz,2H),7.32–7.25 (m,1H),7.19(t,J=7.8Hz,1H),7.14–7.09(m,1H),7.07(d,J=8.5Hz,2H),3.82(s,3H). 13 C NMR (126 MHz, DMSO-d 6 )δ164.37,161.46,153.88,151.95,128.75,126.63,125.17,124.53,123.30,116.26,115.80,115.64,115.20,55.87.HRMS(ESI,m / z):calcd for C 16 H 13 FN 4 O 2 S[M+H] + 345.0821; found, 345.0834.

[0058] Example 7

[0059] Synthesis of 1-(3-fluorophenyl)-3-(5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-yl)urea

[0060] 3-fluoroaniline was used as the raw material instead of 2-fluoroaniline, and other embodiments were the same as those in Example 6. The prepared compound was a white solid with a yield of 59%.

[0061] 1 H NMR (500 MHz, DMSO-d 6 )δ11.21(s,1H),9.34(s,1H),7.84(d,J=8.4Hz,2H),7.52(d,J=11.6Hz,1H),7.34(q,J=7. 7Hz,1H),7.25(d,J=8.4Hz,1H),7.07(d,J=8.4Hz,2H),6.86(t,J=7.2Hz,1H),3.82(s,3H). 13 C NMR (126MHz, DMSO) δ163.09,161.17,160.81,140.32,130.28,127.97,122.60, 114.52,114.38,109.14,108.97,105.44,105.23,55.19.HRMS(ESI,m / z):calcd for C 16 H 13 FN 4O 2 S[M+H] + 345.0821; found, 345.0831.

[0062] Example 8

[0063] Synthesis of 1-(2-methoxyphenyl)-3-(5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-yl)urea

[0064] 2-Methoxyaniline was used as the raw material instead of 2-fluoroaniline, and other embodiments were the same as those in Example 6. The prepared compound was a white solid with a yield of 59%.

[0065] 1 H NMR (500 MHz, DMSO-d 6 )δ11.45(s,1H),8.75(s,1H),8.11(d,J=8.0Hz,1H),7.84(d,J=8.8Hz,2H),7.09–7.01(m,4H),6.94(t,J=6.6Hz,1H),3.89(s,3H),3.82(s,3H). 13 CNMR(126MHz,DMSO)δ161.01,160.88,158.99,150.90,148.00,128.20,127.38,123 .15,122.90,120.61,118.58,114.67,111.00,55.89,55.34.HRMS(ESI,m / z):calcd forC 17 H 16 N 4 O 3 S[M+H] + 357.1021; found, 357.1030.

[0066] Example 9

[0067] Synthesis of 1-(3-methoxyphenyl)-3-(5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-yl)urea

[0068] 3-methoxyaniline was used as the raw material instead of 2-fluoroaniline, and other embodiments were the same as those in Example 6. The prepared compound was a white solid with a yield of 59%.

[0069] 1 H NMR (500 MHz, DMSO-d 6)δ10.97(s,1H),9.07(s,1H),7.87–7.82(m,2H),7.25–7.19(m,2H),7.10–7.04( m,2H),7.04–6.99(m,1H),6.63(dd,J=8.2,2.7Hz,1H),3.82(s,3H),3.75(s,3H). 13 C NMR(126MHz, DMSO)δ160.93,159.72,139.70,129.69,128.17,122.85,114.68,111.04,108.47,104.48,55.35,55.01.HRMS(ESI,m / z):calcd for C 17 H 16 N 4 O 3 S[M+H] + 357.1021; found, 357.1031.

[0070] Example 10

[0071] Synthesis of 1-(5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-yl)-3-(o-tolyl)urea

[0072] 2-Methylaniline was used as the raw material instead of 2-fluoroaniline, and other embodiments were the same as those in Example 6. The prepared compound was a white solid with a yield of 61%.

[0073] 1 H NMR (500 MHz, DMSO-d 6 )δ11.21(s,1H),8.37(s,1H),8.24(dd,J=7.9,1.8Hz,1H),7.86(d,J=8.1Hz,1H),7.54–7.47(m,1H),7.26(d, J=8.4Hz,1H),7.21(q,J=7.6Hz,2H),7.12(t,J=7.6Hz,1H),7.03(t,J=7.4Hz,1H),4.00(s,3H),2.26(s,3H). 13 C NMR (126 MHz, DMSO-d 6 )δ161.50,155.72,155.18,151.30,136.19,131.47,130.32,128.08,127.04,126. 29,123.75,121.21,121.10,119.03,112.36,56.41,17.62.HRMS(ESI,m / z):calcd for C 17H 16 N 4 O 2 S[M+H] + 341.1072; found, 341.1075.

[0074] Embodiment 11

[0075] Synthesis of 1-(5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-yl)-3-(m-tolyl)urea

[0076] 3-Methylaniline was used as the raw material instead of 2-fluoroaniline, and other embodiments were the same as those in Example 6. The prepared compound was a white solid with a yield of 61%.

[0077] 1 H NMR (500 MHz, DMSO-d 6 )δ10.98(s,1H),8.97(s,1H),7.85(s,2H),7.35(s,1H),7.28(s,1H),7.20(s,1H),7.08(s,2H),6.88(s,1H),3.82(s,3H),2.30(s,3H). 13 C NMR (126 MHz, DMSO-d 6 )δ161.47,138.15,128.69,128.13,123.68,122.85,119.24,115.91,114.67,55.80,21.08.HRMS(ESI,m / z):calcd for C 17 H 16 N 4 O 2 S[M+H] + 341.1072; found, 341.1078.

[0078] Example 12

[0079] Synthesis of 1-(5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-yl)-3-(p-tolyl)urea

[0080] 4-Methylaniline was used as the raw material instead of 2-fluoroaniline, and other embodiments were the same as those in Example 6. The prepared compound was a white solid with a yield of 56%.

[0081] 1 H NMR (500 MHz, DMSO-d 6)δ10.98(s,1H),8.99(s,1H),7.83(s,2H),7.39(d,J=8.1Hz,2H),7.13(d,J=8.1Hz,2H),7.06(s,2H),3.82(s,3H),2.26(s,3H). 13 C NMR (126 MHz, DMSO-d 6 )δ160.73,135.68,131.79,129.11,127.98,122.72,118.70,114.51,55.18,20.16.HRMS(ESI,m / z):calcd for C 17 H 16 N 4 O 2 S[M+H] + 341.1072; found, 341.1082.

[0082] Embodiment 13

[0083] Synthesis of 1-(5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-yl)-3-(2-(trifluoromethoxy)phenyl)urea

[0084] 2-Trifluoromethoxyaniline was used instead of 2-fluoroaniline as the raw material, and other embodiments were the same as those in Example 6. The prepared compound was a white solid with a yield of 49%.

[0085] 1 H NMR (500 MHz, DMSO-d 6 )δ11.55(s,1H),8.88(s,1H),8.24(d,J=8.2Hz,1H),7.86(d,J=8.7Hz,2H),7.43(d,J=8 .1Hz,1H),7.40(t,J=7.9Hz,1H),7.22–7.16(m,1H),7.08(d,J=8.8Hz,2H),3.83(s,3H). 13 C NMR (126 MHz, DMSO-d 6 )δ160.97,151.01,137.61,130.96,128.26,128.01,123.89,122.75,121.33,121.19,121.10,119.14,114.71,55.81.HRMS(ESI,m / z):calcd for C 17 H 13 F 3 N 4 O 3 S[M+H]+ 411.0739; found, 411.0745.

[0086] Embodiment 14

[0087] Synthesis of 1-(5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea

[0088] 4-trifluoromethoxyaniline was used as the raw material instead of 2-fluoroaniline, and other embodiments were the same as those in Example 6. The prepared compound was a white solid with a yield of 52%.

[0089] 1 H NMR (500 MHz, DMSO-d 6 )δ11.17(s,1H),9.35(s,1H),7.83(d,J=8.9Hz,2H),7.63(d,J=8.9Hz,2H),7.32(d,J=8.6Hz,2H),7.07(d,J=8.7Hz,2H),3.82(s,3H). 13 C NMR (126 MHz, DMSO-d 6 )δ161.47,143.86,138.39,128.65,123.68,123.29,122.20,121.65,120.65,119.62,117.59,115.19,55.86.HRMS(ESI,m / z):calcd for C 17 H 13 F 3 N 4 O 3 S[M+H] + 411.0739; found, 411.0742.

[0090] Embodiment 15

[0091] Synthesis of 1-(1H-indol-5-yl)-3-(5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-yl)urea

[0092] 5-aminoindole was used as the raw material instead of 2-fluoroaniline, and other embodiments were the same as those in Example 6. The prepared compound was a white solid with a yield of 62%.

[0093] 1 H NMR (500 MHz, DMSO-d 6)δ11.03(s,2H),8.86(s,1H),7.84(d,J=8.2Hz,2H),7.73(s,1H),7.38–7.31(m ,2H),7.14(d,J=10.7Hz,1H),7.07(d,J=8.5Hz,2H),6.40(s,1H),3.82(s,3H). 13 C NMR (126 MHz, DMSO-d 6 )δ160.89,160.68,159.74,151.70,132.82,130.02,128.18,127.70,126.10,1 23.01,114.92,114.72,111.44,110.76,101.06,55.39.HRMS(ESI,m / z):calcd for C 18 H 15 N 5 O 2 S[M+H] + 366.1025; found, 366.1032.

[0094] Example 16

[0095] Synthesis of 1-(1H-indol-6-yl)-3-(5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-yl)urea

[0096] 6-aminoindole was used as the raw material instead of 2-fluoroaniline, and other embodiments were the same as those in Example 6. The prepared compound was a white solid with a yield of 65%.

[0097] 1 H NMR (500 MHz, DMSO-d 6 )δ11.01(s,2H),8.97(s,1H),7.85(d,J=8.8Hz,2H),7.83(s,1H),7.47(d,J=8.4Hz,1H),7.2 8(t,J=2.7Hz,1H),7.07(d,J=8.8Hz,2H),6.95(d,J=10.3Hz,1H),6.38(s,1H),3.82(s,3H). 13 C NMR (126 MHz, DMSO-d 6 )δ160.88,160.44,159.59,151.44,136.05,132.31,128.15,124.97,123.91,1 22.96,120.06,114.68,112.18,101.84,100.95,55.35.HRMS(ESI,m / z):calcd for C18 H 15 N 5 O 2 S[M+H] + 366.1025; found, 366.1033.

[0098] Embodiment 17

[0099] Synthesis of 1-(Benzo[d]thiazol-5-yl)-3-(5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-yl)urea

[0100] 5-aminobenzothiazole was used as the raw material instead of 2-fluoroaniline, and other embodiments were the same as those in Example 6. The prepared compound was a white solid with a yield of 54%.

[0101] 1 H NMR (500 MHz, DMSO-d 6 )δ11.08(s,1H),9.39(s,1H),9.36(s,1H),8.38(s,1H),8.08(d,J=8.6Hz,1 H),7.85(d,J=8.6Hz,2H),7.56(d,J=10.4Hz,1H),7.06(s,2H),3.84(s,3H). 13 C NMR (126 MHz, DMSO-d 6 )δ161.01,157.07,153.78,137.32,128.21,127.75,122.90,122.51,118.00,114.75,112.41,55.42.HRMS(ESI,m / z):calcd for C 17 H 13 N 5 O 2 S 2 [M+H] + 384.0589; found, 384.0591.

[0102] Embodiment 18

[0103] Synthesis of 1-(Benzo[d]oxazol-6-yl)-3-(5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-yl)urea

[0104] 6-aminobenzoxazole was used as the raw material instead of 2-fluoroaniline, and other embodiments were the same as those in Example 6. The prepared compound was a white solid with a yield of 63%.

[0105] 1 H NMR (500 MHz, DMSO-d 6)δ11.14(s,1H),9.38(s,1H),8.65(s,1H),8.10(s,1H),7.83(d,J=8.7Hz,2H),7 .72(d,J=8.6Hz,1H),7.37(d,J=8.5Hz,1H),7.06(d,J=8.9Hz,2H),3.82(s,3H). 13 C NMR (126 MHz, DMSO-d 6 )δ161.23,160.54,153.98,150.00,137.03,135.35,128.42,128.05,123. 09,120.22,116.73,114.96,114.75,101.52,55.63.HRMS(ESI,m / z):calcd for C 17 H 13 N 5 O 3 S[M+H] + 368.0817; found, 368.0822.

[0106] Embodiment 19

[0107] Synthesis of 1-(1H-indol-5-yl)-3-(5-(2-methoxyphenyl)-1,3,4-thiadiazol-2-yl)urea

[0108] The reaction formula is as follows:

[0109]

[0110] Taking the synthetic route of the final product 19 as an example, 5-(2-methoxyphenyl)-1,3,4-thiadiazole-2-amine (104 mg, 0.5 mmol) and p-nitrophenyl chloroformate (111 mg, 0.55 mol) were dissolved in 10 mL of CH 2 Cl 2 Pyridine (40 μL, 0.5 mmol) was added to the reaction mixture and the reaction was continued for 10 min. Then 5-aminoindole (66 mg, 0.5 mmol) and DIPEA (54 μL, 0.55 mmol) were added to the reaction mixture and the reaction was continued at room temperature overnight. A white solid was precipitated. The solid was filtered and washed with a small amount of petroleum ether and ethyl acetate. The target compound 19 was obtained after drying as a white solid (118 mg, 65%).

[0111] 1 H NMR (500 MHz, DMSO-d 6)δ11.08(s,1H),10.79(s,1H),8.80(s,1H),8.24(d,J=7.9Hz,1H),7.76(s,1H),7.52–7.47(m, 1H),7.39–7.32(m,2H),7.25(d,J=8.4Hz,1H),7.12(t,J=7.4Hz,2H),6.41(s,1H),4.01(s,3H). 13 C NMR (126 MHz, DMSO-d 6 )δ161.73,155.57,155.19,151.53,132.77,131.40,130.01,127.69,127.06,126.06,1 21.10,119.14,114.81,112.35,111.40,110.64,101.01,56.00.HRMS(ESI,m / z):calcd for C 18 H 15 N 5 O 2 S[M+H] + 366.1025; found, 366.1033.

[0112] Embodiment 20

[0113] Synthesis of 1-(1H-indol-5-yl)-3-(5-(3-methoxyphenyl)-1,3,4-thiadiazol-2-yl)urea

[0114] 5-(3-methoxyphenyl)-1,3,4-thiadiazole-2-amine was used as the raw material instead of 5-(2-methoxyphenyl)-1,3,4-thiadiazole-2-amine, and other embodiments were the same as those in Example 19. The prepared compound was a white solid with a yield of 62%.

[0115] 1 H NMR (500 MHz, DMSO-d 6 )δ11.03(s,2H),8.85(s,1H),7.75(s,1H),7.66(d,J=7.6Hz,1H),7.40(d,J=6 .9Hz,2H),7.37–7.31(m,3H),7.14(d,J=8.7Hz,1H),6.40(s,1H),2.52(s,3H). 13 C NMR (126 MHz, DMSO-d 6)δ163.86,160.42,151.64,136.21,132.81,131.41,129.84,129.70,129.50,127.67,1 26.35,126.05,115.75,114.85,111.40,110.72,101.01,21.06.HRMS(ESI,m / z):calcd for C 18 H 15 N 5 OS[M+H] + 350.1076; found, 350.1072.

[0116] Embodiment 21

[0117] Synthesis of 1-(1H-indol-5-yl)-3-(5-(o-tolyl)-1,3,4-thiadiazol-2-yl)urea

[0118] 5-(2-methylphenyl)-1,3,4-thiadiazole-2-amine was used as the raw material instead of 5-(2-methoxyphenyl)-1,3,4-thiadiazole-2-amine, and other embodiments were the same as those in Example 19. The prepared compound was a white solid with a yield of 62%.

[0119] 1 H NMR (500 MHz, DMSO-d 6 )δ11.03(s,2H),8.85(s,1H),7.75(s,1H),7.66(d,J=7.6Hz,1H),7.40(d,J=6 .9Hz,2H),7.37–7.31(m,3H),7.14(d,J=8.7Hz,1H),6.40(s,1H),2.52(s,3H). 13 C NMR (126 MHz, DMSO-d 6 )δ163.86,160.42,151.64,136.21,132.81,131.41,129.84,129.70,129.50,127.67,1 26.35,126.05,115.75,114.85,111.40,110.72,101.01,21.06.HRMS(ESI,m / z):calcd for C 18 H 15 N 5 OS[M+H] + 350.1076; found, 350.1072.

[0120] Embodiment 22

[0121] Synthesis of 1-(1H-indol-5-yl)-3-(5-(m-tolyl)-1,3,4-thiadiazol-2-yl)urea

[0122] 5-(3-methylphenyl)-1,3,4-thiadiazole-2-amine was used as the raw material instead of 5-(2-methoxyphenyl)-1,3,4-thiadiazole-2-amine, and other embodiments were the same as those in Example 19. The prepared compound was a white solid with a yield of 62%.

[0123] 1 H NMR (500 MHz, DMSO-d 6 )δ11.04(s,2H),8.84(s,1H),7.74(s,2H),7.70(d,J=7.7Hz,1H),7.43–7.29(m,4H),7.15(d,J=8.7Hz,1H),6.41(s,1H),2.39(s,3H). 13 C NMR (126 MHz, DMSO-d 6 )δ160.76,159.93,151.44,138.50,132.67,130.78,130.20,129.77,128.98,127.51,1 26.90,125.91,123.62,114.72,111.25,110.60,100.86,20.67.HRMS(ESI,m / z):calcd for C 18 H 15 N 5 OS[M+H] + 350.1076; found, 350.1082.

[0124] Embodiment 23

[0125] Synthesis of 1-(1H-indol-5-yl)-3-(5-(p-tolyl)-1,3,4-thiadiazol-2-yl)urea

[0126] 5-(4-methylphenyl)-1,3,4-thiadiazole-2-amine was used as the raw material instead of 5-(2-methoxyphenyl)-1,3,4-thiadiazole-2-amine, and other embodiments were the same as those in Example 19. The prepared compound was a white solid with a yield of 51%.

[0127] 1 H NMR (500 MHz, DMSO-d 6)δ11.03(s,2H),8.82(s,1H),7.79(d,J=7.9Hz,2H),7.74(s,1H),7.38–7.30(m,4H),7.14(d,J=10.8Hz,1H),6.40(s,1H),2.39(s,3H). 13 C NMR (126 MHz, DMSO-d 6 )δ160.72,159.69,151.93,139.97,132.65,129.77,129.63,127.55,127.50,12 6.35,125.90,114.71,111.24,110.58,100.85,20.73.HRMS(ESI,m / z):calcdfor C 18 H 15 N 5 OS[M+H] + 350.1076; found, 350.1076.

[0128] Embodiment 24

[0129] Synthesis of 1-(1H-indol-5-yl)-3-(5-(2-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)urea

[0130] 5-(2-(trifluoromethoxy)phenyl)-1,3,4-thiadiazole-2-amine was used as the raw material instead of 5-(2-methoxyphenyl)-1,3,4-thiadiazole-2-amine, and other embodiments were the same as those in Example 19. The prepared compound was a white solid with a yield of 65%.

[0131] 1 H NMR (500 MHz, DMSO-d 6 )δ11.05(s,2H),8.87(s,1H),7.94–7.88(m,2H),7.73(s,1H),7.67(t,J=8.0Hz,1 H),7.51(d,J=5.8Hz,1H),7.39–7.32(m,2H),7.14(d,J=8.6Hz,1H),6.40(s,1H). 13 C NMR (126 MHz, DMSO-d 6)δ169.67,164.38,161.32,149.32,133.37,133.04,132.04,130.32,128.17,126.60,1 26.47,123.04,119.52,118.80,115.41,111.92,111.33,101.52.HRMS(ESI,m / z):calcd for C 18 H 12 F 3 N 5 O 2 S[M+H] + 420.0742; found, 420.0736.

[0132] Embodiment 25

[0133] Synthesis of 1-(1H-indol-5-yl)-3-(5-(3-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)urea

[0134] 5-(3-(trifluoromethoxy)phenyl)-1,3,4-thiadiazole-2-amine was used as the raw material instead of 5-(2-methoxyphenyl)-1,3,4-thiadiazole-2-amine, and other embodiments were the same as those in Example 19. The prepared compound was a white solid with a yield of 65%.

[0135] 1 H NMR (500 MHz, DMSO-d 6 )δ11.04(s,2H),8.88(s,1H),8.26(d,J=9.6Hz,1H),7.74(s,1H),7.66(t,J=7.8Hz, 1H),7.58(d,J=10.5Hz,2H),7.39–7.32(m,2H),7.13(d,J=10.8Hz,1H),6.41(s,1H). 13 C NMR (126 MHz, DMSO-d 6 )δ161.74,154.23,151.18,144.43,132.72,131.72,129.25,127.98,127.51,125.95,1 25.92,123.68,121.17,118.84,114.79,111.25,110.73,100.86.HRMS(ESI,m / z):calcd for C 18 H 12 F 3 N 5 O 2 S[M+H] +420.0742; found, 420.0750.

[0136] Embodiment 26

[0137] Synthesis of 1-(1H-indol-5-yl)-3-(5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)urea

[0138] 5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazole-2-amine was used as the raw material instead of 5-(2-methoxyphenyl)-1,3,4-thiadiazole-2-amine, and other embodiments were the same as those in Example 19. The prepared compound was a white solid with a yield of 54%.

[0139] 1 H NMR (500 MHz, DMSO-d 6 )δ11.04(s,2H),8.91(s,1H),8.04(d,J=8.5Hz,2H),7.74(s,1H),7.51(d,J=8.3Hz,2H),7.39–7.32(m,2H),7.14(d,J=10.7Hz,1H),6.40(s,1H). 13 CNMR (126MHz, DMSO-d 6 )δ161.07,159.92,152.15,149.89,133.35,130.36,130.14,129.10,128.17,126 .59,122.21,119.47,115.39,111.92,111.30,101.52.HRMS(ESI,m / z):calcdfor C 18 H 12 F 3 N 5 O 2 S[M+H] + 420.0742; found, 420.0746.

[0140] Embodiment 27

[0141] Synthesis of 1-(1H-indol-5-yl)-3-(5-(4-morpholinylphenyl)-1,3,4-thiadiazol-2-yl)urea

[0142] 5-(4-morpholinylphenyl)-1,3,4-thiadiazole-2-amine was used as the raw material instead of 5-(2-methoxyphenyl)-1,3,4-thiadiazole-2-amine, and other embodiments were the same as those in Example 19. The prepared compound was a white solid with a yield of 55%.

[0143] 1H NMR (500 MHz, DMSO-d 6 )δ10.99(s,2H),9.24(s,1H),7.79(s,1H),7.74(d,J=8.5Hz,2H),7.37–7.28(m,2H),7.20(d,J =10.6Hz,1H),7.03(d,J=8.6Hz,2H),6.38(s,1H),3.73(t,J=4.8Hz,4H),3.20(t,J=4.9Hz,4H). 13 C NMR (126 MHz, DMSO-d 6 )δ160.61,160.25,152.47,152.19,132.72,130.54,127.74,127.59,125.98,120. 88,114.86,114.72,111.37,110.52,101.04,65.96,47.55.HRMS(ESI,m / z):calcd for C 21 H 20 N 6 O 2 S[M+H] + 421.1447; found, 421.1452.

[0144] Embodiment 28

[0145] Synthesis of 1-(1H-indol-6-yl)-3-(5-(o-tolyl)-1,3,4-thiadiazol-2-yl)urea

[0146] 5-(2-methylphenyl)-1,3,4-thiadiazole-2-amine was used instead of 5-(2-methoxyphenyl)-1,3,4-thiadiazole-2-amine, and 6-aminoindole was used instead of 5-aminoindole as raw materials. Other embodiments were the same as those in Example 19. The prepared compound was a white solid with a yield of 48%.

[0147] 1 H NMR (500 MHz, DMSO-d 6 )δ11.01(s,2H),9.00(s,1H),7.84(s,1H),7.66(d,J=7.5Hz,1H),7.47(d,J=8.4Hz,1H),7.40(d,J=6.1Hz,2H), 7.35(dd,J=7.8,2.7Hz,1H),7.28(t,J=2.8Hz,1H),6.95(dd,J=8.4,1.7Hz,1H),6.40–6.36(m,1H),2.52(s,3H). 13 CNMR (126MHz, DMSO-d6 )δ168.84,163.49,160.10,136.30,136.10,131.50,129.93,129.82,129.51,126. 44,125.05,123.96,120.14,112.19,101.84,101.01,21.16.HRMS(ESI,m / z):calcd for C 18 H 15 N 5 OS[M+H] + 350.1076; found, 350.1068.

[0148] Embodiment 29

[0149] Synthesis of 1-(1H-indol-6-yl)-3-(5-(p-tolyl)-1,3,4-thiadiazol-2-yl)urea

[0150] 5-(4-methylphenyl)-1,3,4-thiadiazole-2-amine was used instead of 5-(2-methoxyphenyl)-1,3,4-thiadiazole-2-amine, and 6-aminoindole was used instead of 5-aminoindole as raw materials. Other embodiments were the same as those in Example 19. The prepared compound was a white solid with a yield of 61%.

[0151] 1 H NMR (500 MHz, DMSO-d 6 )δ11.03(s,2H),9.09(s,1H),7.95–7.61(m,3H),7.44(dd,J=30.4,8.2Hz ,2H),7.37–7.20(m,2H),6.96(d,J=8.1Hz,1H),6.38(s,1H),2.39(s,3H). 13 C NMR (126 MHz, DMSO-d 6 )δ161.49,160.28,152.30,138.68,136.05,130.98,130.34,129.16,127.08,1 24.98,123.79,120.06,112.16,101.82,100.95,20.84.HRMS(ESI,m / z):calcd for C 18 H 15 N 5 OS[M+H] + 350.1076; found, 350.1082.

[0152] Embodiment 30

[0153] Synthesis of 1-(1H-indol-6-yl)-3-(5-(3-methoxyphenyl)-1,3,4-thiadiazol-2-yl)urea

[0154] 5-(3-methoxyphenyl)-1,3,4-thiadiazole-2-amine was used instead of 5-(2-methoxyphenyl)-1,3,4-thiadiazole-2-amine, and 6-aminoindole was used instead of 5-aminoindole as raw materials. Other embodiments were the same as those in Example 19. The prepared compound was a white solid with a yield of 52%.

[0155] 1 H NMR (500 MHz, DMSO-d 6 )δ11.21–10.83(m,2H),8.97(s,1H),7.83(d,J=1.5Hz,1H),7.50–7.41(m,4H),7.31–7.27(m, 1H), 7.08 (ddd, J=8.1, 2.7, 1.4Hz, 1H), 6.97–6.93 (m, 1H), 6.38 (t, J=2.8Hz, 1H), 3.84 (s, 3H). 13 C NMR (126 MHz, DMSO-d 6 )δ168.63,163.93,159.71,136.08,131.67,130.54,125.06,123.98,120.13,1 19.23,116.35,112.22,111.26,101.89,101.01,55.32.HRMS(ESI,m / z):calcd for C 18 H 15 N 5 O 2 S[M+H] + 366.1025; found, 366.1033.

[0156] Embodiment 31

[0157] Synthesis of 1-(1H-indol-6-yl)-3-(5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)urea

[0158] 5-(4-trifluoromethoxyphenyl)-1,3,4-thiadiazole-2-amine was used instead of 5-(2-methoxyphenyl)-1,3,4-thiadiazole-2-amine, and 6-aminoindole was used instead of 5-aminoindole. Other embodiments were the same as those in Example 19. The prepared compound was a white solid with a yield of 44%.

[0159] 1 H NMR (500 MHz, DMSO-d 6)δ11.02(s,2H),8.98(s,1H),8.07–8.03(m,2H),7.81(s,1H),7.52(d,J=8.5Hz,2H),7.47( d,J=8.4Hz,1H),7.28(t,J=2.7Hz,1H),6.95(dd,J=8.6,1.9Hz,1H),6.38(t,J=2.7Hz,1H). 13 C NMR (126 MHz, DMSO-d 6 )δ161.30,159.87,149.45,136.05,129.64,128.66,125.08,124.01,121.8 0,121.04,120.12,119.00,112.23,101.93,100.99.HRMS(ESI,m / z):calcd for C 18 H 12 F 3 N 5 O 2 S[M+H] + 420.0742; found, 420.0751.

[0160] The properties of the compounds prepared in Examples 1 to 31 were tested as follows:

[0161] 1. Inhibitory effects of the compounds prepared in Examples 1 to 31 on programmed necrosis

[0162] The experiment used mouse fibroblast L929 cells. After incubating L929 cells with the test compound at 37°C for 1 hour, a combination of TNF-α and Caspase inhibitor z-vad-Fmk (TZ) was added to induce programmed necrosis, and a solvent control group (NC) was set up for reference comparison. Cell viability was measured using the CellTiter-Glo luminescent cell viability assay kit and a multifunctional microplate reader. Finally, the necrosis rate and necrosis inhibition rate were calculated based on the experimental data to evaluate the anti-necrosis effect of the compound.

[0163] Table 1 Inhibition rate of the compounds of Examples 1 to 31 against programmed necrosis at a concentration of 10 μM

[0164] Compound Inhibition rate Compound Inhibition rate Example 1 0.06 Embodiment 17 0.32 Example 2 0.65 Embodiment 18 0.30 Example 3 0.23 Embodiment 19 0.55 Example 4 0.13 Embodiment 20 0.32 Example 5 0.46 Embodiment 21 0.29 Example 6 0.59 Embodiment 22 0.51 Example 7 0.16 Embodiment 23 0.34 Example 8 0.30 Embodiment 24 0.40 Example 9 0.21 Embodiment 25 0.25 Example 10 0.71 Embodiment 26 0.30 Embodiment 11 0.40 Embodiment 27 0.39 Example 12 0.66 Embodiment 28 0.45 Embodiment 13 0.44 Embodiment 29 0.38 Embodiment 14 0.59 Embodiment 30 0.49 Embodiment 15 0.92 Embodiment 31 0.51 Example 16 0.85

[0165] 2. Protective effect of the product prepared in Example 15 on ischemia / reperfusion (I / R)-induced AKI in mice

[0166] A mouse model of acute kidney injury (AKI) induced by renal ischemia-reperfusion (I / R) was established, and the compound prepared in Example 15 or a blank solvent control was administered by gavage. 24 hours after administration, the mice were killed and renal function and pathological examinations were performed to evaluate the preventive effect of the compound prepared in Example 15 on AKI. PAS staining ( Figure 1 ), when different doses of the compound prepared in Example 15 were administered, the above-mentioned renal tubular pathological damage phenomenon was gradually improved, indicating that the compound prepared in Example 15 can inhibit tubular cell necrosis and protect tubular damage.

[0167] The qRT-PCR results showed that the compound prepared in Example 15 could effectively reduce the expression of KIM1 in the I / R-induced AKI mouse model ( Figure 2 ), and immunofluorescence detection of KIM1 further confirmed the above results ( Figure 3 At the same time, the compound prepared in Example 15 also significantly reduced the increase in serum creatinine (Sc) and blood urea nitrogen (BUN) caused by renal ischemia-reperfusion (I / R), and restored the impaired renal function ( Figure 4 ). The qRT-PCR results also showed that compared with the untreated group of mouse kidneys, administration of the compound prepared in Example 15 downregulated the mRNA levels of proinflammatory cytokines (TNF-α, IL-1β and IL-6) ( Figure 5 ). In summary, the research results show that the compound prepared in Example 15 can protect I / R-induced renal injury and inhibit inflammatory response in vivo.

[0168] The above description is only a preferred embodiment of the present invention, which is only illustrative and not restrictive of the present invention. Those skilled in the art understand that many changes, modifications, and even equivalences may be made to the present invention within the spirit and scope defined by the claims of the present invention, but all of them will fall within the scope of protection of the present invention.

Claims

1. A thiadiazole urone compound or a pharmaceutically acceptable salt thereof, characterized in that: The general structural formula is shown below: Among them, R 1 Selected from the following aromatic rings or aromatic ring systems: R 2 Selected from the following aromatic rings or aromatic ring systems:

2. A thiadiazole urone compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The thiadiazole urea compound is any one of the following compounds:

3. A pharmaceutical composition, characterized in that The invention comprises one or more therapeutically effective amounts of the thiadiazole urone compound or a pharmaceutically acceptable salt thereof as claimed in claim 1 or 2, and a pharmaceutically acceptable excipient.

4. Use of the thiadiazole urone compound or a pharmaceutically acceptable salt thereof as claimed in claim 1 or 2 in the preparation of a medicament for preventing and / or treating inflammatory diseases associated with programmed cell necrosis.

5. Use of a thiadiazole urone compound or a pharmaceutically acceptable salt thereof according to claim 4 in the preparation of a medicament for preventing and / or treating inflammatory diseases associated with programmed cell necrosis, characterized in that: The inflammatory diseases include, but are not limited to, any one of inflammatory bowel disease, psoriasis, neuroinflammation, acute kidney injury, acute and chronic inflammation of the kidney, chronic kidney disease, acute renal failure, renal fibrosis, diabetic nephropathy, and rheumatoid arthritis.

6. Use of a thiadiazole urea compound or a pharmaceutically acceptable salt thereof as claimed in claim 1 or 2 in the preparation of a medicament for preventing and / or treating inflammatory diseases.

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