CN116574053A - RIPK1 kinase target inhibitor and medical application thereof - Google Patents

RIPK1 kinase target inhibitor and medical application thereof Download PDF

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CN116574053A
CN116574053A CN202310501061.5A CN202310501061A CN116574053A CN 116574053 A CN116574053 A CN 116574053A CN 202310501061 A CN202310501061 A CN 202310501061A CN 116574053 A CN116574053 A CN 116574053A
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acid
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ripk1 kinase
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孔令义
王小兵
李尚�
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China Pharmaceutical University
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Abstract

The application discloses an RIPK1 kinase target inhibitor and medical application thereof. R is R 1 Selected from substituted or unsubstituted aromatic rings; r is R 2 Selected from hydroxyl or amino; r is R 3 Selected from substituted or unsubstituted aromatic rings; r is R 4 Selected from C 1‑6 Aliphatic hydrocarbons or hydrogen. The application provides a series of novel kinase targeted inhibitors, the compounds disclosed in the applicationThe compound can effectively target RIPK1 kinase and can be used as an effective therapeutic agent for neurodegenerative diseases and inflammation-related diseases.

Description

RIPK1 kinase target inhibitor and medical application thereof
Description of the division
The application is a divisional application of the following Chinese application patent application:
parent application number: 2022107034376, parent application name: RIPK1 kinase target inhibitor and medical application thereof, and the application date is as follows: 2022, 6 and 22 days.
Technical Field
The application relates to the field of pharmaceutical chemistry, and relates to an RIPK1 kinase target inhibitor and medical application thereof.
Background
Alzheimer's Disease (AD) is a complex neurodegenerative disease that is manifested clinically by hypomnesis, cognitive dysfunction, and behavioral dysfunction. The main pathological features of AD include neuronal loss, β -amyloid (aβ) deposition and hyperphosphorylated Tau protein-induced neurofibrillary tangles (NFT), which have been demonstrated in recent years to be triggered by neuronal death and neuroinflammation.
Receptor interacting protein kinase 1 (RIPK 1) is a serine/threonine family kinase that exists at the intersection of cell death and inflammatory signaling pathways. Important studies have shown that phosphorylated RIPK1 in the brain of AD patients is aberrantly expressed, and when RIPK1 is inhibited, amyloid is reduced, the occurrence and development of neuroinflammation are delayed, and memory loss is alleviated. In addition, microglial nerve cells promote degradation of aβ, and studies have found that RIPK1 promotes inflammation and aβ aggregation in alzheimer's disease, promoting microglial cells in an inflammatory activated state and attenuating degradation of aβ. These indicate that RIPK1 is a very important therapeutic target for the treatment of AD.
The reported RIPK1 inhibitor has very limited skeleton types, and few small molecules related to the AD treatment field are more few, so that the development of a novel skeleton and high kinase selectivity compound targeting RIPK1 is an urgent and important task, and has profound significance and potential value. Here we disclose the development of novel RIPK1 inhibitors with nanomolar potency for the treatment of neurodegenerative diseases such as AD and their use in the field of alzheimer's disease treatment. Animal behavioural experiments show that the novel RIPK1 inhibitor disclosed by the application has good AD resisting efficacy and shows good clinical application prospect.
Disclosure of Invention
The present application aims to address the above-mentioned shortcomings of the prior art and to provide a novel RIPK1 kinase target inhibitor for use as an effective therapeutic agent for neurodegenerative diseases and other inflammation-related diseases.
It is another object of the present application to provide the use of the novel inhibitors of RIPK1 kinase targeting.
The aim of the application can be achieved by the following technical scheme:
a novel inhibitor targeting RIPK1 kinase, which is selected from compounds with a structure shown as a general formula (I) or a general formula (II) or pharmaceutically acceptable salts thereof:
wherein R is 1 Selected from substituted or unsubstituted aromatic rings; r is R 2 Selected from hydroxyl or amino; r is R 3 Selected from substituted or unsubstituted aromatic rings; r is R 4 Selected from C 1-6 Aliphatic hydrocarbons or hydrogen.
As a preferred mode of the application, the novel RIPK1 kinase targeted inhibitor is selected from compounds with a structure shown as a general formula (I), wherein R 3 Is selected from substituted or unsubstituted benzene rings; r is R 4 Is hydrogen.
As a preferred embodiment of the present application, R in the compound represented by the general formula (I) 4 Is hydrogen, R 3 Selected from halogen, cyano, methoxy, trifluoromethylsulfanyl, C1-5 alkyl, C1-3 alkenyl, methylenedioxy, trifluoromethyl, phenoxy mono-or polysubstituted phenyl or 5,6,7, 8-tetrahydro-2-naphthylphenyl, 4- (2-furyl) phenyl, unsubstituted phenyl. 4. The novel class of RIPK1 kinase-targeting inhibitors according to claim 3, wherein R in the compound of formula (I) 4 Is hydrogen, R 3 Selected from phenyl, 3, 4-dimethylphenyl, 4-cyanophenyl, 3,4- (methylenedioxy) -phenyl, 5,6,7, 8-tetrahydro-2-naphtyl-benzenePhenyl, 3, 5-dimethylphenyl, 2, 4-difluorophenyl, 4-methoxyphenyl, 4-trifluoromethylsulfanyl-phenyl, 4-vinylphenyl, 4- (2-furyl) phenyl, 4-tert-butylphenyl, 4-trifluoromethylphenyl, 2-chlorophenyl, 2-methylphenyl, 4-n-propylphenyl, 4-phenoxyphenyl, 4-methoxy-2-methylphenyl, 2-fluoro-4-methoxyphenyl.
As a preferable aspect of the present application, the R 1 Selected from phenyl, halogen or C1-2 mono-or polysubstituted phenyl, R 2 Selected from hydroxyl or amino; preferably when R 2 R is selected from hydroxy 1 Selected from phenyl or chloro substituted phenyl; when R is 2 When selected from amino, R 1 Selected from phenyl or fluoro, chloro, methyl mono-or poly-substituted phenyl.
As a preferred aspect of the present application, when R 2 R is selected from hydroxy 1 Selected from phenyl or 4-chlorophenyl; when R is 2 When selected from amino, R 1 Selected from 3-fluoro-5-methylphenyl, 3-fluoro-4-chlorophenyl, 2-fluoro-3-chlorophenyl.
The compound of the application is selected from any one of the following:
as a preferred aspect of the present application, the pharmaceutically acceptable salts of the compounds of formula I-II are selected from acid addition salts of the compounds of formula I-II with acids selected from the group consisting of: 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.
A pharmaceutical composition, wherein the compound of the general formula I-II or a pharmaceutically acceptable salt thereof according to the application and a pharmaceutically acceptable carrier.
Preferably, the pharmaceutical composition is prepared into any one of a tablet, a capsule, a powder, a syrup, a liquid, a suspension, a freeze-dried powder injection or an injection.
The preparation method of the RIPK1 kinase target inhibitor comprises the following steps:
route 1: synthesis of target Compounds 1-17 a .
a Reagents and reaction conditions (a) substituted aromatic amine, propionic acid, 110 ℃ for 4-6h; (b) thionyl chloride, tetrahydrofuran, and refluxing for 2 hours; (c) Concentrated ammonia water, tetrahydrofuran, 0 ℃ for 30min.
Route 2: synthesis of target Compound 18-37 a .
a Reagent and reaction conditions (a) 3-fluoro-5-methylaniline, propionic acid, 110 ℃ for 4h; (b) Substituted aromatic amine, tris (dibenzylideneacetone) dipalladium, 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl, cesium carbonate, nitrogen protection, toluene and 100 ℃ overnight; (c) Ammonia-methanol solution (7M), magnesium methoxide, methanol, 80℃for 24h.
Route 3: synthesis of target Compound 38-43 a .
a The reagent and the reaction conditions are (a) lithium hydroxide monohydrate, tetrahydrofuran/methanol/water, and the reaction is carried out at room temperature for 2 hours; (b) Fatty amine, 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethyl urea hexafluorophosphate, N, N-diisopropylethylamine and methylene chloride react at room temperature for 4 hours, 42-89%; (c) Potassium hydroxylamine solution, methanol, was reacted at room temperature for 3h,67%.
The beneficial effects are that:
the application provides a series of novel kinase targeted inhibitors, and the compounds disclosed by the application can effectively target RIPK1 kinase and can be used as effective therapeutic agents for neurodegenerative diseases and inflammation related diseases.
Detailed description of the preferred embodiments and methods
Example 1 preparation of 2- (phenylamino) nicotinic acid (1):
raw material a (1.010g, 5.0 mmol) and aniline (0.558 g,6.0 mmol) were dissolved in propionic acid (5 mL) and reacted at 110℃with stirring for 4-6h. Cooling to room temperature after the reaction is finished, cooling to 0 ℃, precipitating crystals, carrying out suction filtration, washing with propionic acid and water in sequence, and drying to obtain white-like crystals with the yield of 46%. 1 HNMR(600MHz,DMSO-d 6 )δ10.49(s,1H),8.54–8.10(m,2H),7.67(dd,J＝8.5,1.2Hz,2H),7.36(dd,J＝8.5,7.3Hz,2H),7.11–7.05(m,1H),6.91(dd,J＝7.7,5.0Hz,1H),5.09(s,1H). 13 C NMR(151MHz,DMSO)δ168.68,154.90,151.00,141.73,138.88,131.58,129.01,123.22,121.00,113.84,108.51.HRMS(ESI)calcd for C 12 H 10 N 2 O 2 [M+H] + :215.0806；found:215.0807.
Example 2 preparation of 2- ((4-chlorophenyl) amino) nicotinic acid (2):
raw material a (1.010g, 5.0 mmol) and 4-chloroaniline (0.764 g,6.0 mmol) were dissolved in propionic acid (5 mL), and the remaining procedure was the same as in compound 1. 1 H NMR(600MHz,DMSO-d 6 )δ10.51(s,1H),8.38(dd,J＝4.9,2.0Hz,1H),8.29(dd,J＝7.7,2.0Hz,1H),7.75(d,J＝8.9Hz,2H),7.38(d,J＝8.8Hz,2H),6.92(dd,J＝7.7,4.9Hz,1H),5.61(s,1H). 13 C NMR(151MHz,DMSO)δ168.82,154.99,151.82,141.17,138.34,128.69,126.11,121.96,114.29,108.36.HRMS(ESI)calcd for C 12 H 9 ClN 2 O 2 [M+H] + :249.0426；found:249.0426.
Example 3 preparation of 2- ((3-chlorophenyl) amino) nicotinic acid (3):
raw material a (1.010g, 5.0 mmol) and 3-chloroaniline (0.764 g,6.0 mmol) were dissolved in propionic acid (5 mL), the remaining procedure was the same as for compound 1, 1 H NMR(600MHz,DMSO-d 6 )δ10.57(s,1H),8.43(dd,J＝4.9,2.0Hz,1H),8.30(dd,J＝7.7,2.0Hz,1H),8.07(s,1H),7.49(ddd,J＝8.2,2.1,1.0Hz,1H),7.34(t,J＝8.1Hz,1H),7.07(ddd,J＝8.0,2.1,0.9Hz,1H),6.94(dd,J＝7.7,4.8Hz,1H),6.20(s,1H). 13 C NMR(151MHz,DMSO)δ168.85,154.99,152.08,141.01,133.19,130.38,121.97,119.35,118.63,114.61,108.49.HRMS(ESI)calcd for C 12 H 9 ClN 2 O 2 [M+H] + :249.0426；found:249.0425.
EXAMPLE 4 preparation of 2- (phenylamino) nicotinamide (4):
raw material a (1.010g, 5.0 mmol) and aniline (0.558 g,6.0 mmol) were dissolved in propionic acid (5 mL) and reacted at 110℃with stirring for 4-6h. Cooling to room temperature after the reaction is finished, cooling to 0 ℃, precipitating crystals, filtering, and washing the crystals with propionic acid and water in sequence. The corresponding crystals (0.214 g,1.0 mmol) were dissolved in tetrahydrofuran (1 mL) and thionyl chloride (5 mL), reacted under reflux for 2 hours, dried by spin, dissolved in 1mL tetrahydrofuran, slowly added dropwise at a constant rate to 0℃aqueous ammonia, and the reaction was continued for 30 minutes. After completion of the reaction, the system was poured into water, extracted with ethyl acetate (3×5 ml), and the organic layer was separated with Na 2 SO 4 Drying, filtration, concentration and purification by preparative TLC (PE: ea=1:1) gave a yellow powder in 72% yield. 1 HNMR(600MHz,DMSO-d 6 )δ11.17(s,1H),8.30(dd,J＝4.8,1.8Hz,1H),8.28(s,1H),8.14(dd,J＝7.7,1.9Hz,1H),7.70(s,1H),7.68(d,J＝7.4Hz,2H),7.29(dd,J＝8.5,7.2Hz,2H),7.02–6.92(m,1H),6.83(dd,J＝7.7,4.8Hz,1H). 13 C NMR(151MHz,DMSO)δ170.06,154.95,150.89,140.25,137.54,128.74,121.57,119.40,113.34,110.27.HRMS(ESI)calcd for C 12 H 12 N 3 O[M+H] + :214.0975；found:214.0974.
Example 5 preparation of 2- ((4-chlorophenyl) amino) nicotinamide (5):
raw material a (1.010g, 5.0 mmol) and 4-chloroaniline (0.764 g,6.0 mmol) were dissolved in propionic acid (5 mL), the remaining procedure was the same as compound 4, 1 H NMR(600MHz,DMSO-d 6 )δ11.27(s,1H),8.32(dd,J＝4.8,1.8Hz,1H),8.30(s,1H),8.16(dd,J＝7.7,1.9Hz,1H),7.75–7.71(m,3H),7.33(dd,J＝8.9Hz,2H),6.87(dd,J＝7.7,4.8Hz,1H). 13 C NMR(151MHz,DMSO)δ169.93,154.63,150.80,139.20,137.60,128.52,124.84,120.78,113.76,110.52.HRMS(ESI)calcd for C 12 H 11 ClN 3 O[M+H] + :245.0587；found:245.0587.
EXAMPLE 6 preparation of 2- ((3-chlorophenyl) amino) nicotinamide (6):
raw material a (1.010g, 5.0 mmol) and 3-chloroaniline (0.764 g,6.0 mmol) were dissolved in propionic acid (5 mL), the remaining procedure was the same as compound 4, 1 H NMR(600MHz,DMSO-d 6 )δ11.36(s,1H),8.37(dd,J＝4.8,1.8Hz,1H),8.33(s,1H),8.18(dd,J＝7.8,1.9Hz,1H),8.10(t,J＝2.1Hz,1H),7.77(s,1H),7.40(ddd,J＝8.3,2.2,0.9Hz,1H),7.30(t,J＝8.1Hz,1H),7.00(ddd,J＝7.9,2.1,0.9Hz,1H),6.91(dd,J＝7.7,4.8Hz,1H). 13 C NMR(151MHz,DMSO)δ169.88,154.54,150.82,141.73,137.67,133.16,130.29,120.99,118.34,117.72,114.10,110.77.HRMS(ESI)calcd for C 12 H 11 ClN 3 O[M+H] + :247.0586；found:247.0585.
example 7 preparation of 2- ((2, 4-difluorophenyl) amino) nicotinamide (7):
raw material a (1.010g, 5.0 mmol) and 2, 4-difluoroaniline (0.774 g,6.0 mmol) were dissolved in propionic acid (5 mL), the remaining procedure was the same as for compound 4, 1 HNMR(600MHz,DMSO-d 6 )δ11.26(d,J＝2.5Hz,1H),8.50(td,J＝9.3,6.2Hz,1H),8.31(dd,J＝4.8,1.8Hz,2H),8.18(dd,J＝7.8,1.8Hz,1H),7.72(s,1H),7.30(ddd,J＝11.7,8.9,2.9Hz,1H),7.05(ddt,J＝11.1,8.8,2.2Hz,1H),6.89(dd,J＝7.7,4.8Hz,1H). 13 C NMR(151MHz,DMSO)δ169.87,157.17,157.09,155.57,155.49,154.68,153.41,153.33,151.79,151.71,150.83,137.59,125.20,125.18,125.13,125.11,122.24,122.23,122.19,122.17,113.94,110.69,103.78,103.62,103.60,103.44.HRMS(ESI)calcd for C 12 H 11 F 2 N 3 O[M+H] + :250.0786；found:250.0787.
example 8 preparation of 2- ((3-fluoro-5-methylphenyl) amino) nicotinamide (8):
raw material a (1.010g, 5.0 mmol) and 3-fluoro-5-methylaniline (0.751 g,6.0 mmol) were dissolved in propionic acid (5 mL), the remaining procedure was the same as compound 4, 1 H NMR(600MHz,DMSO-d 6 )δ11.34(s,1H),8.36(dd,J＝4.8,1.8Hz,1H),8.32(s,1H),8.17(dd,J＝7.7,1.9Hz,1H),7.84–7.71(m,2H),7.00(d,J＝1.4Hz,1H),6.89(dd,J＝7.7,4.8Hz,1H),6.60(ddd,J＝9.6,2.6,1.3Hz,1H),2.29(s,3H). 13 C NMR(151MHz,DMSO)δ169.92,163.21,161.63,154.64,150.84,141.70,141.62,140.11,140.05,137.61,115.38,113.90,110.66,108.42,108.28,103.03,102.85,21.05,21.04.HRMS(ESI)calcd for C 13 H 13 FN 3 O[M+H] + :246.1037；found:246.1038.
EXAMPLE 9 preparation of 2- ((3, 4-dimethylphenyl) amino) nicotinamide (9)
Raw material a (1.010g, 5.0 mmol) and 3, 4-dimethylaniline (0.727 g,6.0 mmol) were dissolved in propionic acid (5 mL), the remaining procedure was the same as for compound 4, 1 H NMR(600MHz,DMSO-d 6 )δ11.02(s,1H),8.28(dd,J＝4.8,1.8Hz,1H),8.24(s,1H),8.11(dd,J＝7.7,1.9Hz,1H),7.66(s,1H),7.48(dd,J＝8.2,2.4Hz,1H),7.35(d,J＝2.4Hz,1H),7.04(d,J＝8.1Hz,1H),6.78(dd,J＝7.7,4.8Hz,1H),2.20(s,3H),2.16(s,3H). 13 C NMR(151MHz,DMSO)δ170.13,155.13,150.98,137.98,137.45,136.27,129.61,129.30,120.81,117.03,112.84,109.94,19.64,18.74.HRMS(ESI)calcd for C 13 H 13 FN 3 O[M+H] + :242.1288；found:242.1288.
EXAMPLE 10 preparation of 2- ((3-bromophenyl) amino) nicotinamide (10)
Raw material a (1.010g, 5.0 mmol) and 3-bromoaniline (1.032 g,6.0 mmol) were dissolved in propionic acid (5 mL), the remaining procedure was as for compound 4, 1 H NMR(600MHz,DMSO-d 6 )δ11.35(s,1H),8.37(dd,J＝4.8,1.8Hz,1H),8.33(s,1H),8.22(t,J＝2.0Hz,1H),8.18(dd,J＝7.8,1.8Hz,1H),7.77(s,1H),7.46(ddd,J＝8.2,2.1,1.0Hz,1H),7.24(t,J＝8.0Hz,1H),7.13(ddd,J＝7.9,2.0,0.9Hz,1H),6.90(dd,J＝7.7,4.8Hz,1H). 13 C NMR(151MHz,DMSO)δ169.88,154.51,150.82,141.87,137.66,130.62,123.90,121.74,121.15,118.11,114.11,110.77.HRMS(ESI)calcd for C 12 H 11 BrN 3 O[M+H] + :292.0080；found:292.0081.
EXAMPLE 11 preparation of 2- ((4- (trifluoromethyl) phenyl) amino) nicotinamide (11):
starting material a (1.010g, 5.0 mmol) and 4-trisFluoromethylaniline (0.967 g,6.0 mmol) was dissolved in propionic acid (5 mL) and the remaining steps were identical to compound 4, 1 H NMR(600MHz,DMSO-d 6 )δ11.56(s,1H),8.38(dd,J＝4.8,1.8Hz,1H),8.37(s,1H),8.21(dd,J＝7.8,1.9Hz,1H),7.92(d,J＝8.5Hz,2H),7.82(s,1H),7.63(d,J＝8.5Hz,2H),6.96(dd,J＝7.7,4.8Hz,1H). 13 C NMR(151MHz,DMSO)δ169.84,154.35,150.76,143.81,137.74,126.04,126.02,125.58,123.79,121.21,121.00,118.73,114.61,111.16.HRMS(ESI)calcd for C 13 H 11 F 3 N 3 O[M+H] + :282.0849；found:282.0850.
example 12 preparation of 2- ((4-isopropylphenyl) amino) nicotinamide (12):
raw material a (1.010g, 5.0 mmol) and 4-isopropylaniline (0.611 g,6.0 mmol) were dissolved in propionic acid (5 mL), the remaining steps were identical to compound 4, 1 HNMR(600MHz,DMSO-d 6 )δ11.05(s,1H),8.27(dd,J＝4.8,1.8Hz,1H),8.25(s,1H),8.11(dd,J＝7.7,1.9Hz,1H),7.66(s,1H),7.56(d,J＝8.5Hz,2H),7.16(d,J＝8.5Hz,2H),6.79(dd,J＝7.7,4.8Hz,1H),2.84(p,J＝6.9Hz,1H),1.19(d,J＝6.9Hz,6H). 13 C NMR(151MHz,DMSO)δ170.09,155.08,150.94,141.72,137.94,137.48,126.41,119.74,112.98,109.99,32.82,24.07.HRMS(ESI)calcd for C 15 H 18 N 3 O[M+H] + :256.1444；found:256.1446.
EXAMPLE 13 preparation of 2- ((4-chloro-3-fluorophenyl) amino) nicotinamide (13):
raw material a (1.010g, 5.0 mmol) and 3-fluoro-4-chloroaniline (0.873 g,6.0 mmol) were dissolved in propionic acid (5 mL), the remaining procedure was the same as compound 4, 1 H NMR(600MHz,DMSO-d 6 )δ11.45(s,1H),8.38(dd,J＝4.8,1.8Hz,1H),8.35(s,1H),8.19(dd,J＝7.8,1.8Hz,1H),8.13(dd,J＝12.6,2.5Hz,1H),7.79(s,1H),7.44(t,J＝8.7Hz,1H),7.32(ddd,J＝8.8,2.5,1.0Hz,1H),6.93(dd,J＝7.7,4.8Hz,1H). 13 C NMR(151MHz,DMSO)δ169.76,157.93,156.32,154.29,150.73,140.89,140.82,137.69,130.19,116.13,116.11,114.38,110.95,110.53,110.41,107.03,106.85.HRMS(ESI)calcd for C 12 H 10 ClFN 3 O[M+H] + :266.0491；found:266.0492.
example 14 preparation of 2- ((3-chloro-2-fluorophenyl) amino) nicotinamide (14):
raw material a (1.010g, 5.0 mmol) and 2-fluoro-3-chloroaniline (0.873 g,6.0 mmol) were dissolved in propionic acid (5 mL), the remaining procedure was the same as compound 4, 1 HNMR(600MHz,DMSO-d 6 )δ11.57(d,J＝2.8Hz,1H),8.65–8.50(m,1H),8.37(dd,J＝4.8,1.8Hz,2H),8.22(dd,J＝7.8,1.8Hz,1H),7.80(s,1H),7.17(td,J＝8.2,1.3Hz,1H),7.13(td,J＝8.2,6.7,1.7Hz,1H),6.95(dd,J＝7.8,4.8Hz,1H). 13 C NMR(151MHz,DMSO)δ169.80,154.36,150.81,148.87,147.25,137.67,130.18,130.12,124.97,124.94,121.88,119.56,119.24,119.14,114.58,111.23.HRMS(ESI)calcd for C 12 H 10 ClFN 3 O[M+H] + :266.0491；found:266.0491.
example 15 preparation of 2- ((2, 3, 4-trifluorophenyl) amino) nicotinamide (15):
raw material a (1.010g, 5.0 mmol) and 2,3, 4-trifluoroaniline (0.883 g,6.0 mmol) were dissolved in propionic acid (5 mL), the remaining procedure was as for compound 4, 1 H NMR(600MHz,DMSO-d 6 )δ11.41(d,J＝2.1Hz,1H),8.35(s,1H),8.33(dd,J＝4.8,1.8Hz,1H),8.32–8.27(m,1H),8.21(dd,J＝7.8,1.8Hz,1H),7.79(s,1H),7.27(td,J＝10.4,8.6,2.2Hz,1H),6.94(dd,J＝7.7,4.8Hz,1H). 13 C NMR(151MHz,DMSO)δ169.79,154.53,150.82,145.67,145.61,144.08,144.01,142.72,141.16,141.10,139.99,139.88,139.79,138.36,138.26,138.16,137.65,126.56,126.54,126.51,126.49,115.58,115.54,114.51,111.49,111.46,111.37,111.35,110.93.HRMS(ESI)calcd for C 12 H 9 F 3 N 3 O[M+H] + :268.0692；found:268.0691.
example 16 preparation of 2- ((5-chloro-2-fluorophenyl) amino) nicotinamide (16):
raw material a (1.010g, 5.0 mmol) and 5-chloro-2-fluoroaniline (0.873 g,6.0 mmol) were dissolved in propionic acid (5 mL), the remaining procedure was the same as in compound 4, 1 HNMR(600MHz,DMSO-d 6 )δ11.68(d,J＝3.2Hz,1H),8.81(dd,J＝7.3,2.7Hz,1H),8.43(dd,J＝4.8,1.8Hz,1H),8.37(s,1H),8.23(dd,J＝7.8,1.8Hz,1H),7.80(s,1H),7.29(dd,J＝11.3,8.6Hz,1H),7.00(dt,J＝4.6,2.3Hz,1H),6.98(dd,J＝7.8,4.8Hz,1H). 13 C NMR(151MHz,DMSO)δ169.73,154.16,151.59,150.81,149.99,137.74,129.98,129.90,128.14,128.12,120.51,120.46,119.39,119.37,116.08,115.94,114.74,111.37.HRMS(ESI)calcd for C 12 H 11 ClFN 3 O[M+H] + :266.0491；found:266.0491.
EXAMPLE 17 preparation of 2- (p-toluylamino) nicotinamide (17):
raw material a (1.010g, 5.0 mmol) and 4-methylaniline (0.643 g,6.0 mmol) were dissolved in propionic acid (5 mL), the remaining procedure was the same as for compound 4, 1 H NMR(600MHz,DMSO-d 6 )δ11.07(s,1H),8.28(dd,J＝4.8,1.8Hz,1H),8.25(s,1H),8.12(dd,J＝7.7,1.9Hz,1H),7.67(s,1H),7.55(d,J＝8.4Hz,2H),7.10(d,J＝8.4Hz,2H),6.79(dd,J＝7.7,4.8Hz,1H),2.25(s,3H). 13 C NMR(151MHz,DMSO)δ170.11,155.07,150.94,137.72,137.48,130.43,129.13,119.56,112.96,109.99,20.41.HRMS(ESI)calcd for C 13 H 14 N 3 O[M+H] + :228.1131；found:228.1131.
EXAMPLE 18 inhibition Activity assay of RIPK1 fragment Long kinase and BV2 cell apoptosis
The RIPK1 (#VA 7591) fragment of a long human kinase was purchased from Promega. The assay components included 25mM HEPES (pH 7.2), 20mM MgCl2, 12.5mM MnCl2, 5mM EGTA, 2mM EDTA, 12.5mM beta-glycerophosphate and 2mM DTT (added immediately prior to use). 1. Mu.L of LRIPK1 was incubated with 2. Mu.L of compound or DMSO at various concentrations in assay buffer for 15min at 24 ℃. Then a 2. Mu.LATP/MBP mixture (final concentrations of 25. Mu.M and 5. Mu.M, respectively) was added to trigger the kinase reaction and incubated for 90min at 37 ℃. mu.L of kinase reaction solution was added with 5. Mu.LADP-glo TM Quenching the reagent. After a further 60min incubation, 10 μ L Kinase Detection reagent was added and incubated at 24℃for 30min. The inhibition (%) was calculated by reading using Lum module of Molecular Devices multifunctional microplate reader.
Mouse microglial cells BV2 cells (available from Wuhanplauosai Life technologies Co., ltd., china) were grown in a medium containing 4mM L-glutamine, 4500mg/L glucose, 1mM sodium pyruvate (Hyclone), 10% heat-inactivated fetal bovine serum, and 1% GlutaMAXTM (Gibco). Culture environment 37 ℃, CO 2 The content is 5%. During the experiment, BV2 cells were plated at 4X 10 3 Individual cells/well were seeded in 96-well plates for 24h. Next, the medium was changed to fresh DMEM without FBS, with 200ng/mL LPS, or without addition, and the cells were incubated for an additional 23h. BV2 cells were then incubated with the indicated concentrations of compound or DMSO for 1h, and then incubated with 25. Mu.M zVAD-fmk for 24h. By CellTiterCell viability was measured by Aque No. Radioactive Cell Proliferation (MTS) Assay (Promega).
Calculation of IC using nonlinear regression with normalized dose response fit using Prism GraphPad 8.0 software 50 And EC (EC) 50 Values. All experiments were performed independently at least 3 times.
TABLE 1 BV2 cell apoptosis inhibition EC of Compounds 1-17 50 Value of a
a Enzyme inhibition rate and EC 50 Values, data are expressed as mean ± SD of three independent experiments.
We assessed BV2 necrosis inhibitory activity of the target compounds (Table 1). Table 1 shows that the compounds of formula (II) series have good inhibitory effect on the programmed necrosis of BV2 cells.

Claims (10)

1. A novel inhibitor targeting RIPK1 kinase is characterized in that the structure of the novel inhibitor is a compound shown as a general formula (II):
wherein R is 1 Selected from substituted or unsubstituted aromatic rings; r is R 2 Selected from hydroxyl or amino.
2. The novel class of RIPK1 kinase-targeted inhibitors according to claim 1, characterized in that R 1 Selected from phenyl, halogen or C1-2 mono-or polysubstituted phenyl, R 2 Selected from hydroxyl or amino.
3. A novel class of RIPK1 kinase-targeted inhibitors according to claim 2, characterized in that when R 2 R is selected from hydroxy 1 Selected from phenyl or chloro substituted phenyl; when R is 2 When selected from amino, R 1 Selected from phenyl or fluoro, chloro, methyl mono-or poly-substituted phenyl.
4. A novel class of RIPK1 kinase-targeted inhibitors according to claim 3, characterized in that when R 2 R is selected from hydroxy 1 Selected from phenyl or 4-chlorophenyl; when R is 2 When selected from amino, R 1 Selected from 3-fluoro-5-methylphenyl, 3-fluoro-4-chlorophenyl, 2-fluoro-3-chlorophenyl.
5. The novel inhibitor of claim 1 to 4, wherein the compound of formula (II) has a pharmaceutically acceptable salt selected from acid addition salts of the compound of formula (II) with an acid selected from the group consisting of: 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.
6. A pharmaceutical composition comprising the novel RIPK1 kinase-targeting inhibitor according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier.
7. Use of a novel inhibitor of RIPK1 kinase according to any one of claims 1 to 4 in a medicament for the treatment of neurodegenerative or other inflammatory related diseases.
8. Use of a novel inhibitor of a targeted RIPK1 kinase according to any one of claims 1 to 6 for the manufacture of a medicament for the treatment and/or prophylaxis of a disease mediated by RIPK1 kinase.
9. Use according to claim 8, characterized in that the novel inhibitors of RIPK1 kinase targeted in any of claims 1 to 6 are used in the preparation of a medicament for the treatment of neurodegenerative or inflammatory related diseases mediated by RIPK1 kinase.
10. Use according to claim 9, characterized in that the novel inhibitors of RIPK1 kinase targeted in any of claims 1 to 6 are used for the preparation of a medicament for the treatment of RIPK1 kinase mediated alzheimer's disease.
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