Isoxazolidine RIPK1 inhibitor and application thereof

Abstract

The invention discloses an inhibitor targeting RIPK1 kinase and application of the inhibitor. The inhibitor targeting RIPK1 kinase is selected from a compound with a structure shown in a general formula (I) or pharmaceutically acceptable salt of the compound. The invention provides a series of novel kinase targeted inhibitors, and the compound disclosed by the invention can effectively target RIPK1 kinase and can be used as an effective therapeutic agent for inflammation-related diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry and relates to a class of inhibitors targeting RIPK1 kinase and applications thereof. Background Art

[0002] Programmed necrosis is a new form of cell death that occurs when apoptosis is inhibited. The occurrence of programmed necrosis is accompanied by cell swelling, plasma membrane rupture, and outflow of cell contents, leading to a variety of diseases, including systemic inflammation, neurodegenerative diseases, autoimmune diseases, and cancer. Tumor necrosis factor-induced cell necrosis is the most commonly studied model. The inhibition of RIPK1 or RIPK3 will inhibit the occurrence and development of the disease. These kinase inhibitors have potential therapeutic effects, so targeting programmed necrosis to treat inflammatory diseases is an important strategy.

[0003] Receptor interacting protein kinase 1 (RIPK1) is a serine / threonine family kinase that is essential in cell death and inflammatory signaling pathways. Studies have shown that programmed necrosis and the inflammatory diseases it causes can be improved by chemical inhibitors or gene knockout. Therefore, the development of highly potent RIPK1 kinase inhibitors has far-reaching significance and potential value. Summary of the invention

[0004] The purpose of the present invention is to provide a class of inhibitors targeting RIPK1 kinase in view of the above-mentioned deficiencies in the prior art.

[0005] Another object of the present invention is to provide the use of the inhibitor targeting RIPK1 kinase.

[0006] The purpose of the present invention can be achieved through the following technical solutions:

[0007] A class of inhibitors targeting RIPK1 kinase, selected from compounds represented by the general formula (I) or pharmaceutically acceptable salts thereof,

[0008]

[0009] Wherein R1 is selected from R2 is a substituted or unsubstituted aliphatic hydrocarbon, a substituted or unsubstituted phenyl group; the substitution is selected from halogen, methyl, methoxy, ester, trifluoromethyl, trifluoromethoxy, phenyl or heterocycle, and n is 0, 1, 2, 3 or 4.

[0010] As a preferred embodiment of the present invention, R2 is selected from C1-6 mono-substituted or poly-substituted straight-chain fatty alkyl, C1-6 mono-substituted or poly-substituted branched fatty alkyl, C1-6 alkenyl or mono-substituted phenyl, and the substituent is selected from halogen, methyl, methoxy, ester, trifluoromethyl, trifluoromethoxy, phenyl, heterocycle.

[0011] As a further preferred embodiment of the present invention, n is 0, 1, or 2, and when n is 0, R2 cannot be selected from alkenyl or phenyl; when n is 1, R2 cannot be selected from isopropyl; when n is 2, R2 cannot be selected from phenyl.

[0012] In some preferred embodiments of the present invention, when n is 0, R2 is selected from isopropyl; when n is 1, R2 is selected from C1-3 alkyl, alkenyl, ester, substituted or unsubstituted phenyl, and the substituent is selected from fluorine, chlorine, methyl, trifluoromethoxy.

[0013] In some preferred embodiments of the present invention, n is 1, and R2 is selected from propyl, phenyl or fluorine-substituted phenyl.

[0014] The compound of the present invention is selected from any one of the following:

[0015]

[0016]

[0017] As a preferred embodiment of the present invention, the pharmaceutically acceptable salt of the compound represented by general formula (I) or (II) is selected from the acid addition salt formed by the compound of general formula (I) or (II) and an acid, and the acid is selected from: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid.

[0018] A method for preparing the RIPK1 kinase target inhibitor of the present invention:

[0019] Route 1: Synthesis of Intermediate D a

[0020]

[0021] a Reagents and reaction conditions: (a) tert-butyl N-hydroxycarbamate, sodium hydride, N,N-dimethylformamide, 0°C to room temperature, 72h; (b) ethylsulfonyl chloride, triethylamine, dichloromethane, 0°C, 3h; (c) hydrochloric acid-dioxane solution, dichloromethane, room temperature, 2h;

[0022] Route 2: Synthesis of Compound 1-23 a

[0023]

[0024] a Reagents and reaction conditions: (e) corresponding substituted acyl chloride, triethylamine, dichloromethane, room temperature, 6h;

[0025] Table 1: R1 structure

[0026]

[0027]

[0028] A pharmaceutical composition comprising an inhibitor targeting RIPK1 kinase as described in the present invention and a pharmaceutically acceptable carrier.

[0029] As a preferred embodiment of the present invention, the pharmaceutical composition is prepared into any dosage form of tablets, capsules, powders, syrups, solutions, suspensions, and freeze-dried powder injections.

[0030] The class of inhibitors targeting RIPK1 kinase described in the present invention is used to treat inflammatory-related diseases.

[0031] As a preferred embodiment of the present invention, the use of a class of inhibitors targeting RIPK1 kinase described in the present invention in the preparation of drugs for treating or preventing diseases mediated by RIPK1 kinase is preferably used in the preparation of drugs for treating or preventing inflammatory diseases mediated by RIPK1 kinase.

[0032] Beneficial effects:

[0033] The present invention discloses the development of RIPK1 inhibitors with micromolar to nanomolar potency for treating inflammatory diseases and their application in the field of inflammatory disease treatment. Inflammatory animal models show that the RIPK1 inhibitors disclosed by us have good anti-inflammatory effects and show good clinical application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 . Evaluation of the activity of compound 13 on survival rate and body temperature loss in a mouse model of systemic inflammatory response syndrome (SIRS)

[0035] C57BL / 6 mice (n=7) were treated with the indicated doses of compound 13 (1, 5 or 10 mg / kg) before intravenous injection of mTNF-α (250 μg / kg). (A) Body temperature, (B) survival curve, and (C) serum levels of inflammatory factor IL-6. DETAILED DESCRIPTION

[0036] Example 1: Preparation of (S)-2-(ethylsulfonyl)-3-phenylisoxazolidine (1):

[0037] Dissolve ethylsulfonyl chloride (0.114 mL, 1.2 mmol) in dichloromethane, add (S)-3-phenylisoxazolidine (0.15 g, 1 mmol) and triethylamine (0.28 mL, 2 mmol) under ice bath conditions, and after the reaction is completed by TLC detection, concentrate and dry, and purify by preparative column chromatography to obtain a white solid. The yield is 75%. The operation steps are the same as compound 1. 1 H NMR(500MHz,DMSO-d6)δ7.49-7.32(m,4H),7.28(ddd,J=8.5,5.4,2.2Hz,1H),5.29(dd,J=8.3,6.0Hz,1H),4.34-4.1 1(m,2H),3.38(dq,J=10.0,7.3Hz,2H),2.88(dtt,J=12.2,8.3,4.4Hz,1H),2.40-2.20(m,1H),1.28(t,J=7.4Hz,3H). 13 C NMR(150MHz,DMSO-d6)δ141.13,128.50,127.38,126.28,70.33,59.70,43.96,38.02,7.54.HRMS(ESI)calcd for[M+Na] + :264.0665; found:264.0665.

[0038] Example 2: Preparation of (S)-3-phenyl-2-(propanesulfonyl)isoxazolidine (2):

[0039] The operation steps are the same as in Example 1. 1 H NMR (600MHz, DMSO-d6) δ7.42-7.31(m,4H),7.28(tt,J=5.3,2.3Hz,1H),5.28(dd,J=8.3,6.2Hz,1H),4.27-4.09(m,2H),3. 33(d,J=7.3Hz,2H),2.97-2.79(m,1H),2.27(dtd,J=12.7,8.3,6.2Hz,1H),1.84-1.63(m,2H),1.00(td,J=7.5,1.2Hz,3H). 13 C NMR(150MHz,DMSO-d6)δ141.61,128.97,127.85,126.77,70.78,60.24,51.15,38.52,16.96,13.07.HRMS(ESI)calcd for[M+Na] + :278.0822; found:278.0821.

[0040] Example 3: Preparation of (S)-2-(butylsulfonyl)-3-phenylisoxazolidine (3):

[0041] The operation steps are the same as in Example 1. 1 H NMR(500MHz,DMSO-d6)δ7.39-7.33(m,4H),7.29(qt,J=5.8,2.7Hz,1H),5.28 (dd,J=8.3,6.1Hz,1H),4.21(ddd,J=9.0,5.4,3.6Hz,2H),3.39(d,J=1.4Hz,2 H),2.88(dddd,J=12.4,8.3,6.6,4.2Hz,1H),2.27(dtd,J=12.1,8.4,6.1Hz,1 H), 1.70 (pd, J=7.2, 3.5Hz, 2H), 1.42 (h, J=7.4Hz, 2H), 0.89 (t, J=7.4Hz, 3H). 13 C NMR(125MHz,DMSO-d6)δ141.59,128.97,127.85,126.77,70.79,60.27,49.29,38.52,25.11,21.21,13.89.HRMS(ESI)calcd for[M+Na] + :292.0978; found:292.0978.

[0042] Example 4: Preparation of (S)-3-phenyl-2-(ethylenesulfonyl)isoxazolidine (4):

[0043] The operation steps are the same as in Example 1. 1 H NMR (500MHz, DMSO-d6) δ7.42-7.33(m,4H),7.33-7.26(m,1H),7.11(dd,J=16.5,9.9Hz,1H),6.41(dd,J=13.2,3.3Hz,2H),5.18(dd,J=8.2,6.3Hz, 1H), 4.18(td,J=7.9,3.9Hz,1H), 4.11(td,J=8.3,7.0Hz,1H), 2.85(dddd,J=12.2,8.2,6.9,3.9Hz,1H), 2.28(dddd,J=12.3,8.9,7.8,6.3Hz,1H). 13C NMR(125MHz,DMSO-d6)δ133.39,132.81,128.99,127.96,126.89,70.74,62.60,38.59.HRMS(ESI)calcd for[M+Na] + :262.0508; found:262.05081.

[0044] Example 5: Preparation of (S)-2-(allylsulfonyl)-3-phenylisoxazolidine (5):

[0045] The operation steps are the same as in Example 1. 1 H NMR (500MHz, DMSO-d6) δ7.42-7.32(m,4H),7.29(tt,J=5.8,3.0Hz,1H),5.83(ddt,J=17.2,10.1,7.2Hz,1H),5.55-5.36(m,2H),5.31(dd,J=8.3,6 .0Hz,1H),4.23(td,J=4.4,1.9Hz,2H),4.20(dt,J=7.1,1.5Hz,2H),2.89(dddd,J=12.5,8.2,6.6,4.4Hz,1H),2.30(dtd,J=12.1,8.3,6.0Hz,1H). 13 C NMR(125MHz,DMSO-d6)δ141.48,128.96,127.88,126.78,125.46,124.74,70.86,60.58,53.94,38.48.HRMS(ESI)calcd for[M+Na] + :276.0665; found:276.0665.

[0046] Example 6: Preparation of (S)-2-((3-chloropropyl)sulfonyl)-3-phenylisoxazolidine (6):

[0047] The operation steps are the same as in Example 1. 1 H NMR(500MHz,DMSO-d6)δ7.53-7.06(m,5H),5.30(dd,J=8.2,6.1Hz,1H),4.44-4.08(m,2H),3.76(t,J=6.5Hz,2H ),3.67-3.46(m,2H),2.88(dtd,J=11.9,7.6,3.8Hz,1H),2.29(dtd,J=12.0,8.3,6.1Hz,1H),2.22-2.05(m,2H). 13C NMR(125MHz,DMSO-d6)δ141.42,129.01,127.93,126.75,70.95,60.31,47.31,43.49,38.55,26.88.HRMS(ESI)calcd for[M+Na] + :312.0432; found:312.0432.

[0048] Example 7: Preparation of (S)-2-((4-chlorobutyl)sulfonyl)-3-phenylisoxazolidine (7):

[0049] The operation steps are the same as in Example 1. 1 H NMR (500MHz, DMSO-d6) δ7.42-7.32(m,4H),7.28(ddt,J=8.5,5.7,2.3Hz,1H),5.29(dd,J=8.3,6.1Hz,1H),4.26-4.12(m,2H),3.72-3.60(m ,2H),3.44(dpt,J=11.4,6.8,3.6Hz,2H),2.88(dddd,J=12.4,8.3,6.7,4.2Hz,1H),2.28(dtd,J=12.2,8.3,6.1Hz,1H),1.96-1.78(m,4H). 13 C NMR(150MHz,DMSO-d6)δ141.53,128.97,127.88,126.78,70.83,60.32,48.79,45.11,38.51,30.75,20.73.HRMS(ESI)calcd for[M+H] + :304.0767; found:304.0769.

[0050] Example 8: Preparation of (S)-2-(isopropylsulfonyl)-3-phenylisoxazolidine (8):

[0051] The operation steps are the same as in Example 1. 1 H NMR (500MHz, DMSO-d6) δ7.39-7.33(m,4H),7.28(ddd,J=8.6,5.6,2.7Hz,1H),5.31(dd,J=8.3,6.1Hz,1H),4.25-4.11(m,2H),3.69( hept,J=6.9Hz,1H),2.88(dddd,J=12.1,8.4,6.9,3.8Hz,1H),2.25(dddd,J=12.1,9.0,7.9,6.1Hz,1H),1.32(dd,J=6.8,3.9Hz,6H).13 C NMR(125MHz,DMSO-d6)δ141.23,128.52,127.33,126.14,70.42,59.64,50.90,37.93,16.96,14.75.HRMS(ESI)calcd for[M+Na] + :278.0820; found:278.0821.

[0052] Example 9: Preparation of (S)-2-(isobutylsulfonyl)-3-phenylisoxazolidine (9):

[0053] The operation steps are the same as in Example 1. 1 H NMR (500MHz, DMSO-d6) δ7.40-7.32(m,4H),7.28(ddt,J=8.5,5.4,2.6Hz,1H),5.28(dd,J=8.3,6.1Hz,1H),4.24-4.15(m,2H),3.3 0-3.22(m,2H),2.92-2.81(m,1H),2.28(dtd,J=12.2,8.4,6.1Hz,1H),2.19(dq,J=13.4,6.7Hz,1H),1.04(dd,J=6.7,5.1Hz,6H). 13 C NMR(150MHz,DMSO-d6)δ141.61,128.96,127.86,126.80,70.77,60.31,56.73,38.58,24.58,22.52,22.50.HRMS(ESI)[M+H] + :270.1156; found:270.1158.

[0054] Example 10: Preparation of (S)-2-((2-methoxyethyl)sulfonyl)-3-phenylisoxazolidine (10):

[0055] The operation steps are the same as in Example 1. 1 H NMR(500MHz,DMSO-d6)δ7.40-7.32(m,4H),7.28(ddd,J=8.6,5.7,2.3Hz,1H),5.29(dd,J=8.3,6.1Hz,1H),4.24-4.15(m,2H),3 .77-3.70(m,2H),3.67-3.60(m,2H),3.26(s,3H),2.88(dddd,J=12.7,8.2,6.4,4.5Hz,1H),2.28(dtd,J=12.2,8.3,6.1Hz,1H). 13C NMR(150MHz,DMSO-d6)δ141.01,128.51,127.42,126.33,70.37,65.32,59.93,58.00,54.92,49.05,38.07.HRMS(ESI)[M+H] + :272.0953; found:272.0951.

[0056] Example 11: Preparation of (S)-methyl 2-((3-phenylisoxazolidin-2-yl)sulfonyl)acetate (11):

[0057] The operation steps are the same as in Example 1. 1 HNMR(500MHz,DMSO-d6)δ7.36(d,J=5.2Hz,4H),7.32-7.25(m,1H),5.34(dd,J=8.2,6.1Hz,1H),4.67-4.55(m,2H), 4.27-4.15(m,2H),3.71(s,3H),2.89(dddd,J=12.3,8.2,6.8,4.0Hz,1H),2.30(dddd,J=12.2,8.7,7.8,6.1Hz,1H). 13 CNMR(150MHz,DMSO-d6)δ162.66,140.64,128.51,127.50,126.26,70.54,60.63,53.70,52.87,37.99.HRMS(ESI)[M+H] + :286.0745; found:286.0744.

[0058] Example 12: Preparation of (S)-3-phenyl-2-(phenylsulfonyl)isoxazolidine (12):

[0059] The operation steps are the same as in Example 1. 1 H NMR (600MHz, DMSO-d6) δ7.99(dt,J=8.4,1.3Hz,2H),7.83(td,J=7.4,1.3Hz,1H),7.75-7.68(m,2H),7.43-7.34(m,4H),7.33-7.27(m,1H) ),5.24(dd,J=8.1,6.1Hz,1H),4.01(td,J=7.7,4.3Hz,1H),3.61(q,J=7.8Hz,1H),2.49-2.40(m,1H),2.19(dtd,J=12.5,8.0,6.2Hz,1H). 13C NMR(125MHz,DMSO-d6)δ141.19,135.53,135.03,130.15,129.47,129.00,127.99,126.88,70.21,62.84,38.21.HRMS(ESI)calcdfor[M+Na] + :312.0667; found:312.0665.

[0060] Example 13: Preparation of (S)-2-(Benzylsulfonyl)-3-phenylisoxazolidine (13):

[0061] The operation steps are the same as in Example 1. 1 H NMR (500MHz, DMSO-d6) δ7.44(dd,J=6.6,3.0Hz,2H),7.39(dd,J=5.1,2.1Hz,3H),7.29(d,J=7.1Hz,2H),7.27-7.20(m,3 H),5.33-5.26(m,1H),4.79-4.66(m,2H),4.27(dd,J=8.4,5.5Hz,2H),2.91(tt,J=12.6,5.5Hz,1H),2.33-2.22(m,1H). 13 C NMR(125MHz,DMSO-d6)δ141.49,131.73,128.81,127.78,126.67,70.91,60.52,55.18,38.54.HRMS(ESI)calcd for[M+Na] + :326.0824.

[0062] Example 14: Preparation of (S)-2-(phenylethylsulfonyl)-3-phenylisoxazolidine (14):

[0063] The operation steps are the same as in Example 1. 1 H NMR(500MHz,DMSO-d6)δ7.42-7.34(m,4H),7.33-7.27(m,5H),7.26-7.20(m,1H),5.32(dd,J=8.2,6.1Hz,1H),4 .27-4.20(m,2H),3.73-3.64(m,2H),3.09-3.02(m,2H),2.94-2.84(m,1H),2.29(dtd,J=12.2,8.3,6.1Hz,1H). 13C NMR(125MHz,DMSO-d6)δ141.01,137.86,128.50,127.39,126.62,126.33,70.41,59.96,49.96,38.11,28.63.HRMS(ESI)calcd for[M+Na] + :340.0979.

[0064] Example 15: Preparation of (S,E)-3-phenyl-2-(styrenesulfonyl)isoxazolidine (15):

[0065] The operation steps are the same as in Example 1. 1 H NMR(500MHz,DMSO-d6)δ7.89-7.81(m,2H),7.68(d,J=15.5Hz,1H),7.58(d,J=1 5.5Hz,1H),7.54-7.45(m,3H),7.44-7.35(m,4H),7.33-7.28(m,1H),5.23(dd,J =8.1,6.4Hz,1H),4.18(td,J=7.8,3.8Hz,1H),4.09(td,J=8.4,6.9Hz,1H),2.8 3(dddd,J=10.8,8.2,6.9,3.8Hz,1H),2.28(dddd,J=12.3,9.1,7.7,6.3Hz,1H). 13 C NMR(125MHz,DMSO-d6)δ145.87,140.99,132.52,131.43,129.16,128.50,127.45,126.47,121.24,70.36,62.48,38.23.HRMS(ESI)calcd for[M+Na] + :338.0820; found:338.0821.

[0066] Example 16: Preparation of (S)-2-((4-fluorobenzyl)sulfonyl)-3-phenylisoxazolidine (16):

[0067] The operation steps are the same as in Example 1. 1H NMR(500MHz,DMSO-d6)δ7.40-7.33(m,4H),7.33-7.27(m,5H),7.26-7.20(m,1H),5.32(dd,J=8.2,6.1Hz,1H),4 .26-4.18(m,2H),3.71-3.63(m,2H),3.09-3.02(m,2H),2.93-2.84(m,1H),2.29(dtd,J=12.2,8.3,6.1Hz,1H). 13 C NMR (126MHz, DMSO-d6) δ163.71, 161.77, 141.43, 133.81 (d, J = 8.5Hz), 128.85, 127.81, 12 6.65,125.18(d,J=3.1Hz),115.82,115.65,70.95,60.49,54.30,38.54.HRMS(ESI)calcd for[M+Na] + :344.0724; found:344.0727.

[0068] Example 17: Preparation of (S)-2-((3-chlorobenzyl)sulfonyl)-3-phenylisoxazolidine (17):

[0069] The operation steps are the same as in Example 1. 1 HNMR(500MHz,DMSO-d6)δ7.52(q,J=1.3Hz,1H),7.45(ddt,J=7.4,5.1,2.7Hz,1H),7.43-7.39(m,2H),7.33-7.28(m,2H),7.25(dh,J=5.4,2.0,1.5 Hz,3H),5.31(dd,J=8.2,6.1Hz,1H),4.81(s,2H),4.36-4.16(m,2H),2.9 1(dddd,J=12.2,8.3,6.1,4.0Hz,1H),2.28(dtd,J=12.1,8.3,6.1Hz,1H). 13 C NMR(125MHz,DMSO-d6)δ141.40,133.25,131.40,130.65,130.43,128.90,128.87,127.82,126.59,71.01,60.45,54.44,38.56.HRMS(ESI)calcd for[M+Na] + :360.0430; found:360.0432.

[0070] Example 18: Preparation of (S)-2-((4-chlorobenzyl)sulfonyl)-3-phenylisoxazolidine (18):

[0071] The operation steps are the same as in Example 1. 1 HNMR(500MHz,DMSO-d6)δ7.46(s,4H),7.33-7.17(m,5H),5.30(dd,J=8.2,6.2Hz,1H),4.84-4.72(m, 2H), 4.26 (ddd, J=8.8, 5.4, 3.0Hz, 2H), 2.90 (dddd, J=12.4, 8.2, 6.5, 4.2Hz, 1H), 2.33-2.22 (m, 1H). 13 C NMR(125MHz,DMSO-d6)δ140.92,133.39,133.02,128.37,127.55,127.34,126.16,70.49,60.02,53.91,38.06.HRMS(ESI)calcd for[M+Na] + :360.0433; found:360.0432.

[0072] Example 19: Preparation of (S)-2-((3-bromobenzyl)sulfonyl)-3-phenylisoxazolidine (19):

[0073] The operation steps are the same as in Example 1. 1 H NMR(500MHz,DMSO-d6)δ7.66(t,J=1.8Hz,1H),7.58(ddd,J=8.0,2.1,1.1Hz, 1H),7.45(dt,J=7.8,1.4Hz,1H),7.36(t,J=7.8Hz,1H),7.33-7.28(m,2H),7. 28-7.22(m,3H),5.31(dd,J=8.3,6.0Hz,1H),4.79(s,2H),4.42-4.05(m,2H), 2.91(dddd,J=12.6,8.2,6.4,4.4Hz,1H), 2.29(dtd,J=12.2,8.3,6.1Hz,1H). 13 C NMR(151MHz,DMSO-d6)δ141.40,134.27,131.77,131.67,130.92,130.79,128.88,127.81,126.58,121.76,71.00,60.43,54.36,38.58.HRMS(ESI)calcd for[M+Na] + :403.9925; found:403.9926.

[0074] Example 20: Preparation of (S)-2-((4-bromobenzyl)sulfonyl)-3-phenylisoxazolidine (20):

[0075] The operation steps are the same as in Example 1. 1 H NMR (500MHz, DMSO-d6) δ7.62-7.58(m,2H),7.41-7.37(m,2H),7.30(dd,J=8.0,6.3Hz,2H),7.27-7.21(m,3H),5.30(dd,J=8.2,6.1Hz,1 H),4.80-4.72(m,2H),4.25(ddd,J=9.0,5.4,3.6Hz,2H),2.90(dddd,J=12.3,8.2,6.6,4.1Hz,1H),2.27(dtd,J=12.2,8.4,6.1Hz,1H). 13 C NMR(125MHz,DMSO-d6)δ140.92,133.33,131.31,128.37,127.97,127.34,126.16,122.02,70.50,60.03,54.00,38.06.HRMS(ESI)calcd for[M+Na] + :403.9925; found:403.9926.

[0076] Example 21: Preparation of (S)-2-((4-methylbenzyl)sulfonyl)-3-phenylisoxazolidine (21):

[0077] The operation steps are the same as in Example 1. 1 H NMR (500MHz, DMSO-d6) δ7.31(t,J=7.5Hz,4H),7.30-7.23(m,3H),7.19(d,J=7.9Hz,2H),5.30(dd,J=8.3,6.0H z,1H),4.78-4.62(m,2H),4.26(dd,J=8.3,5.5Hz,2H),2.90(ddt,J=12.4,8.3,5.5Hz,1H),2.34-2.20(m,4H). 13 C NMR(125MHz,DMSO-d6)δ141.05,137.89,131.13,128.93,128.38,127.31,126.23,125.12,70.41,60.06,54.42,38.07,20.78.HRMS(ESI)calcd for[M+H] +:388.0825; found:388.0825.

[0078] Example 22: Preparation of (S)-3-phenyl-2-((4-(trifluoromethyl)benzyl)sulfonyl)isoxazolidine (22):

[0079] The operation steps are the same as in Example 1. 1 HNMR (500MHz, DMSO-d6) δ7.78(d,J=8.1Hz,2H),7.67(d,J=8.0Hz,2H),7.32-7.21(m,3H),7.21-7.16(m,2H),5.30(dd,J=8.2,6. 3Hz,1H),4.95-4.87(m,2H),4.26(dqd,J=14.6,7.8,2.2Hz,2H),2.91(dddd,J=12.2,8.3,6.7,3.8Hz,1H),2.32-2.21(m,1H).13C NMR(126MHz,DMSO-d6)δ141.33,133.89,132.54,129.53,129.28,128.79,127.81, 126.56,125.66(p,J=3.8Hz),123.56,71.04,60.46,54.68,38.53.HRMS(ESI)calcd for[M+Na] + :394.0694; found:394.0695.

[0080] Example 23: Preparation of (S)-3-phenyl-2-((4-(trifluoromethoxy)benzyl)sulfonyl)isoxazolidine (23):

[0081] The operation steps are the same as in Example 1. 1 H NMR(500MHz,DMSO-d6)δ7.60-7.53(m,2H),7.40(d,J=8.1Hz,2H),7.31-7.16(m,5H),5.30(dd,J=8.2,6.3Hz,1H),4 .89-4.78(m,2H),4.30-4.20(m,2H),2.91(dddd,J=12.3,8.3,6.5,4.0Hz,1H),2.27(dtd,J=12.1,8.5,6.3Hz,1H). 13CNMR(125MHz,DMSO-d6)δ148.92(d,J=1.7Hz),141.36,133.67,128.78,127.79,126.56,121.39,70.99,60.38,54.32,38.53.HRMS(ESI)calcd for[M+H] + :388.0825; found:388.0825.

[0082] Example 24: Detection of inhibitory activity of programmed necrosis in L929 cells

[0083] Mouse fibroblast L929 cells (purchased from Wuhan Punosai Life Science Co., Ltd., China) were grown in a medium containing 4mM L-glutamine, 4500mg / L glucose, 1mM sodium pyruvate (Hyclone), 10% fetal bovine serum, and 1% GlutaMAXTM (Gibco). The culture environment was 37°C, 5% CO2. During the experiment, L929 cells were cultured at 5×10 3 Cells / well were seeded in 96-well plates for 24 h. L929 cells were incubated with the indicated concentrations of compounds or DMSO for 1 h, and then z-VAD-fmk (20 μM) and TNF-α (10 ng / ml) were added and incubated for 24 h. Cell viability was detected by CCK-8 (Adamas).

[0084] EC was calculated using nonlinear regression with normalized dose-response fit using Prism GraphPad 8.0 software. 50 All experiments were performed independently at least 3 times.

[0085] Table 2. Inhibition of programmed necrosis in L929 cells by compounds 1-23 50 value a

[0086]

[0087]

[0088] a EC 50 Values, data are expressed as the mean ± SD of three independent experiments.

[0089] Example 25: Evaluation of the anti-inflammatory activity of the compound in the mouse systemic inflammatory response syndrome model. Necrosis plays an important role in various inflammatory diseases, so we evaluated the anti-inflammatory effect of compound 13 using the TNF-α-induced systemic inflammatory response syndrome (SIRS) model characterized by cryogenic injury.

[0090] Female C57BL / 66-8-week-old mice were randomly divided into 6 groups (7 mice in each group), namely control group, model group, positive drug Nec-1 group (10 mg / kg), low-dose group of compound 13 (1 mg / kg), medium-dose group of compound 13 (5 mg / kg), and high-dose group of compound 13 (10 mg / kg). The compound was dissolved in 10% DMSO

[0091] , 10% Tween-80 and 80% saline. Each mouse was intraperitoneally injected with the corresponding control saline or different concentrations of the compound 1 hour before the tail vein injection of 0.2 ml TNF-α (250μg / kg). The survival rate and body temperature loss rate of the mice were continuously observed and monitored until 72 hours. In addition, we took blood from each group of mice 4 hours after the tail vein injection of TNF-α to detect the level of inflammatory factor IL-6 in mouse tissues.

[0092] like Figure 1 As shown, compound 13 (1, 5, 10 mg / kg, intraperitoneal injection) significantly reduced the hypothermia injury induced by TNF-α in mice and had a faster body temperature recovery than Nec-1. Compound 13 completely inhibited the death of mice induced by TNF-α at 10 mg / kg, achieving a survival rate of 100%, while the survival rate at 5 mg / kg was 85%, much higher than the survival rate of Nec-1 42%, and the survival rate of mice in the model group after 72 hours was 28%. In addition, the level of IL-6, an inflammatory factor in mouse tissues induced by TNF-α, was significantly reduced in the experimental group pretreated with compound 13.

Claims

1. A class of inhibitors targeting RIPK1 kinase, characterized in that Selected from compounds represented by general formula (I) or pharmaceutically acceptable salts thereof, Wherein R1 is selected from R2 is a substituted or unsubstituted aliphatic hydrocarbon, a substituted or unsubstituted phenyl group; the substitution is selected from halogen, methyl, methoxy, ester, trifluoromethyl, trifluoromethoxy, phenyl or heterocycle, and n is 0, 1, 2, 3 or 4.

2. The inhibitor targeting RIPK1 kinase according to claim 1, characterized in that R2 is selected from C1-6 mono-substituted or poly-substituted straight-chain fatty alkyl, C1-6 mono-substituted or poly-substituted branched fatty alkyl, C1-6 alkenyl or mono-substituted phenyl, and the substituent is selected from halogen, methyl, methoxy, ester, trifluoromethyl, trifluoromethoxy, phenyl, heterocycle.

3. The inhibitor targeting RIPK1 kinase according to claim 1, characterized in that: n is 0, 1, or 2, and when n is 0, R2 cannot be selected from alkenyl or phenyl; when n is 1, R2 cannot be selected from isopropyl; when n is 2, R2 cannot be selected from phenyl.

4. The inhibitor targeting RIPK1 kinase according to claim 3, characterized in that: When n is 0, R2 is selected from isopropyl; when n is 1, R2 is selected from C1-3 alkyl, alkenyl, ester, substituted or unsubstituted phenyl, and the substituent is selected from fluorine, chlorine, methyl, trifluoromethoxy.

5. The inhibitor targeting RIPK1 kinase according to claim 4, characterized in that: n is 1, and R2 is selected from propyl, phenyl or fluorine-substituted phenyl.

6. The inhibitor targeting RIPK1 kinase according to claims 1 to 5, characterized in that: The compound of general formula (I) is selected from any one of the following:

7. The novel kinase target inhibitor according to any one of claims 1 to 5, characterized in that: The pharmaceutically acceptable salt of the compound represented by the general formula (I) is selected from the acid addition salt formed by the compound of the general formula (I) and an acid, wherein the acid is selected from: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid.

8. A pharmaceutical composition, comprising an inhibitor targeting RIPK1 kinase according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier; the pharmaceutical composition is preferably prepared into any one of the dosage forms of tablets, capsules, powders, syrups, solutions, suspensions, and lyophilized powder injections.

9. The inhibitor targeting RIPK1 kinase according to any one of claims 1 to 5 is used for treating inflammatory-related diseases.

10. Use of an inhibitor targeting RIPK1 kinase according to any one of claims 1 to 5 in the preparation of a drug for treating or preventing a disease mediated by RIPK1 kinase, preferably in the preparation of a drug for treating or preventing an inflammatory disease mediated by RIPK1 kinase.

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