CN109748884B - Iron death inhibitor and preparation method and application thereof - Google Patents
Iron death inhibitor and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides an iron death inhibitor, which is a biological pharmaceutically acceptable salt, crystal form and solvate taking a small molecular compound as a main active ingredient, wherein the small molecular compound has the following general formula:
the invention synthesizes a novel micromolecular compound capable of inhibiting iron death, and researches on structure optimization and structure-activity relationship prove that in some embodiments of the micromolecular compound, the micromolecular compound can generate better inhibition effect on body death and can be used as a main active ingredient for preparing a body death inhibitor, and the compound and the inhibitor prepared by the compound have good medicinal potential; meanwhile, the preparation method of the novel compound provided by the invention is simple and convenient, the reaction condition is mild, the operation and control are convenient, the energy consumption is low, the yield is high, the cost is low, the preparation method is suitable for industrial production, and the prepared compound has the advantages of high bioactivity, strong selectivity, remarkable drug-like property and wide market prospect.
Description
Technical Field
The invention relates to the technical field of chemical synthetic drugs, in particular to an iron death inhibitor and a preparation method and application thereof.
Background
Iron death (Ferroptosis) is a new pattern of cell death caused by iron-dependent oxidative damage that has only recently been discovered, and is typically characterized by increased cytoplasmic and lipid reactive oxygen radicals, smaller mitochondria, and increased density of mitochondrial bilayer membranes, unlike traditional apoptotic, necrotic, and autophagic death patterns. Given that this mode of cell death is dependent on the presence of iron, Dixon et al named it as "Ferroptosis" in 2012, i.e. iron death. The cell iron death is closely related to the occurrence and development of diseases such as neurodegeneration, tissue ischemia-reperfusion injury, cerebral apoplexy, cardiovascular diseases, renal failure, diabetic complications and the like, and an iron death inhibitor is considered to be a potential drug for treating the diseases.
Currently, the major small molecule inhibitors of Ferroptosis are antioxidants or iron chelators. Generally, the iron death inhibitor has strong pertinence, low activity or over-strong activity, and is difficult to prepare into a pharmaceutical preparation for stable existence, so how to prepare the iron death inhibitor which has high activity and can be prepared into the pharmaceutical preparation for stable existence is an urgent problem to be solved.
Disclosure of Invention
The purpose of the present invention is to provide an iron death inhibitor.
It is still another object of the present invention to provide a method for preparing an iron death inhibitor.
It is also an object of the present invention to provide a specific use of an iron death inhibitor.
The invention provides an iron death inhibitor, which is a biological pharmaceutically acceptable salt, crystal form and solvate taking a small molecular compound as a main active ingredient, wherein the small molecular compound has the following general formula:
wherein the content of the first and second substances,
a is a five-membered heterocyclic ring containing one N atom or a six-membered heterocyclic ring containing at most two N atoms, one O atom and one S atom or a seven-membered heterocyclic ring containing at least one N atom or a six-membered bicyclic ring containing at least one N atom;
R1independently is H, methyl, ethyl, hydroxyl, carbonyl, an aromatic ring, a six-membered heterocyclic ring,
One of (1);
R2independently hydrogen or hydroxy;
R3independently is H, methyl, ethyl, isopropyl, n-butyl, sulfenyl, carbonyl, phenyl, aromatic heterocycle,
One of (a) and (b);
R4independently is H or methyl;
R5independently methyl, nitro, cyano, ether linkage, halogen atom, -CF3One kind of (1).
The synthesis route is as follows:
the preparation method comprises the steps of firstly, condensing 2-acetylphenothiazine and 4-methylbenzene sulfonyl hydrazide to obtain an intermediate I, and then coupling various secondary amines serving as raw materials with the intermediate I to obtain the target compound.
By this preparation method, the following structural formula is obtained:
the prepared small molecular compound has the effect of inhibiting the iron death, and the iron death is related to various diseases such as cerebral apoplexy, Parkinson's disease, pancreatic cancer and the like, and the development of the diseases can be intervened by activating or inhibiting the iron death.
Compared with the prior art, the invention has the following advantages and beneficial effects:
the invention synthesizes a novel compound capable of inhibiting iron death, and researches on structure optimization and structure-activity relationship prove that the compound can generate better inhibition effect on body death in some embodiments, can be used as a main active ingredient for preparing a body death inhibitor, and has good medicinal potential; meanwhile, the preparation method of the novel compound provided by the invention is simple and convenient, the reaction condition is mild, the operation and control are convenient, the energy consumption is low, the yield is high, the cost is low, the preparation method is suitable for industrial production, and the prepared compound has the advantages of high bioactivity, strong selectivity, remarkable drug-like property and wide market prospect.
Drawings
Other features, objects and advantages of the invention will become more apparent upon reading of the detailed description of non-limiting embodiments with reference to the following drawings:
FIG. 1 is a drawing ofEC of Compounds 3, 10, 17 of the invention with Positive control Fer-150The line graphs are compared.
Detailed Description
The present invention will be described in further detail with reference to examples, but the embodiments of the present invention are not limited thereto, and various substitutions and alterations can be made without departing from the technical idea of the present invention as described above, according to the common technical knowledge and the conventional means in the field.
The present invention will be described in further detail with reference to the following examples for the purpose of making clear the objects, process conditions and advantages of the present invention, which are given by way of illustration only and are not intended to be limiting of the present invention.
The specific synthetic route of the compound contained in the general formula provided by the invention is as follows:
example 1:
compound 1: 4- ((1- (10H-phenothiazin-2-yl) ethyl) sulfonyl) morpholine
First, intermediate I (E) -N' - (1- (10H-phenothiazin-2-yl) ethylidene) -4-methylbenzenesulfonyl hydrazide (2) is prepared, and the synthetic route is as follows:
the specific synthetic process comprises the following steps: 2-acetylphenothiazine (10.0g, 41.44mmol, 1.0eq) and 4-methylbenzenesulfonylhydrazide (7.72g, 41.44mmol, 1.0eq) were dissolved in 100mL of MeOH, 1mL of LOAC was added, the reaction was moved to 60 ℃ for reaction, and the reaction was monitored by TLC, and after about 4 hours, the reaction was complete. After cooling to room temperature, a yellow solid appeared which was filtered off under reduced pressure, washed with MeOH and ether until the filtrate was colourless and dried in vacuo to give intermediate I (15g) in 88.4% yield. Of intermediate I1H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),8.70(s,1H),7.82(d,J＝8.3Hz,2H),7.40(d,J＝8.1Hz,2H),7.06(d,J＝1.7Hz,1H),6.98(dd,J＝8.0,1.7Hz,2H),6.89(dd,J＝7.2,3.0Hz,2H),6.75(dd,J＝7.5,0.9Hz,1H),6.72–6.62(m,1H),2.37(s,3H),2.08(s,3H)。
MS m/z(ESI)：410.1[M+H]+。
then, using secondary amine as a raw material to synthesize a compound 1:
the synthetic route is as follows:
intermediate I (100mg, mmol, 1.0eq), morpholine (mg, mmol, 2.0eq) and DABSO (mg, mmol, 0.55eq) were dissolved in 10mL DMSO, argon replaced 3 times, moved to 100 ℃ for reaction, monitored by TLC, and after about 12h the reaction was complete. Cooling to room temperature, directly extracting with saturated aqueous solution/EA, concentrating the organic layer, and separating by column chromatography to obtain target product 1(47mg) with yield of 76.8%.
The 1H NMR and HRMS data for compound 1 are as follows:
1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),6.98(t,J＝7.6Hz,1H),6.91(t,J＝8.1Hz,2H),6.86–6.81(m,1H),6.78(s,1H),6.74(dd,J＝11.5,7.6Hz,1H),6.68(d,J＝7.9Hz,1H),4.46(d,J＝7.1Hz,1H),3.60–3.42(m,4H),3.09(ddd,J＝12.0,5.7,3.2Hz,2H),3.02–2.87(m,2H),1.54(d,J＝7.0Hz,3H)。
HRMS m/z(ESI)calcd for C18H20N2O3S2[M+H]+377.0994found:377.0998。
example 2:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 2: 2- (1- ((4-methylpiperazin-1-yl) sulfonyl) ethyl) -10H-phenothiazine
The synthesis route is as follows:
process for preparation of Compound 21H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.71(s,1H),6.98(td,J＝7.8,1.4Hz,1H),6.95–6.87(m,2H),6.82(dd,J＝8.0,1.6Hz,1H),6.79–6.72(m,2H),6.68(dd,J＝7.9,1.0Hz,1H),4.42(q,J＝7.0Hz,1H),3.18–3.00(m,2H),3.00–2.86(m,2H),2.22(d,J＝2.9Hz,4H),2.12(s,3H),1.53(d,J＝7.0Hz,3H)。
HRMS m/z(ESI)calcd for C19H23N3O2S2[M+H]+390.1310found:390.1312。
the preparation method is the same as that of the compound 1, and the yield is 74.1%.
Example 3:
in this example, raw material a was replaced with the above compound, specifically as follows:
compound 3: 2- (1- ((4-methyl-1, 4-homopiperazin-1-yl) sulfonyl) ethyl) -10H-phenothiazine
The synthesis route is as follows:
process for preparation of Compound 31H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),6.99(td,J＝7.8,1.3Hz,1H),6.90(d,J＝7.8Hz,2H),6.84–6.71(m,3H),6.68(d,J＝7.9Hz,1H),4.44(q,J＝7.0Hz,1H),3.12(dd,J＝13.6,6.4Hz,2H),2.48–2.40(m,4H),2.21(s,3H),1.75–1.62(m,2H),1.52(d,J＝7.0Hz,3H)。
HRMS m/z(ESI)calcd for C20H25N3O2S2[M+H]+404.1466found:404.1467。
the preparation method is the same as that of the compound 1, and the yield is 80.1%.
Example 4:
in this example, raw material a was replaced with the above compound, specifically as follows:
compound 4: 2- (1- ((4-isopropylpiperazin-1-yl) sulfonyl) ethyl) -10H-phenothiazine
The synthesis route is as follows:
process for preparation of Compound 41H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),6.98(t,J＝7.2Hz,1H),6.95–6.87(m,2H),6.82(d,J＝7.9Hz,1H),6.80–6.71(m,2H),6.67(d,J＝7.7Hz,1H),4.40(dd,J＝13.7,6.7Hz,1H),3.07(s,2H),2.93(s,2H),2.62(s,1H),2.33(s,4H),1.52(d,J＝7.0Hz,3H),0.90(d,J＝3.9Hz,6H)。
HRMS m/z(ESI)calcd for C21H27N3O2S2[M+H]+418.1623found:418.1619。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 67.8%.
Example 5:
in this example, raw material a was replaced with the above compound, specifically as follows:
compound 5: 2- (1- ((4- (benzo [ d ] [1,3] dioxa-5-ylmethyl) piperazin-1-yl) sulfonyl) ethyl) -10H-phenothiazine
The synthesis route is as follows:
process for preparation of Compound 51H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),6.99(t,J＝7.2Hz,1H),6.91(d,J＝7.8Hz,2H),6.86–6.72(m,6H),6.69(d,J＝7.6Hz,2H),5.98(d,J＝6.7Hz,2H),4.39(q,J＝6.7Hz,1H),3.34(d,J＝10.1Hz,2H),3.07(s,2H),2.97(s,2H),2.26(s,4H),1.51(t,J＝11.9Hz,3H)。
HRMS m/z(ESI)calcd for C26H27N3O4S2[M+H]+510.1521found:510.1523。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 59.4%.
Example 6:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 6: 2- (4- ((1- (10H-phenothiazin-2-yl) ethyl) sulfonyl) piperazin-1-yl) -1- (pyrrolin-1-yl) -1-ethanone
The synthesis route is as follows:
process for preparation of Compound 61H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),6.98(t,J＝7.4Hz,1H),6.96–6.86(m,2H),6.83(d,J＝7.9Hz,1H),6.80–6.72(m,2H),6.68(d,J＝7.8Hz,1H),4.41(d,J＝7.0Hz,1H),3.37(t,J＝6.6Hz,2H),3.25(t,J＝6.8Hz,2H),3.09(s,4H),2.94(s,2H),2.42(s,4H),1.87–1.78(m,2H),1.76–1.67(m,2H),1.53(d,J＝6.9Hz,3H)。
HRMS m/z(ESI)calcd for C24H30N4O3S2[M+H]+487.1838found:487.1839。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 73.5%.
Example 7:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 7: 3- (4- ((1- (10H-phenothiazin-2-yl) ethyl) sulfonyl) piperazin-1-yl) -N, N-dimethylpropan-1-amine
The synthesis route is as follows:
process for preparation of Compound 71H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),6.98(td,J＝7.7,1.4Hz,1H),6.90(dd,J＝7.1,4.3Hz,2H),6.82(dd,J＝8.0,1.6Hz,1H),6.80–6.72(m,2H),6.68(d,J＝7.9Hz,1H),4.40(q,J＝7.0Hz,1H),3.12–3.01(m,2H),2.94(d,J＝5.5Hz,2H),2.30–2.17(m,8H),2.11(d,J＝7.2Hz,6H),1.53(d,J＝7.1Hz,3H),1.49(s,2H)。
HRMS m/z(ESI)calcd for C23H32N4O2S2[M+H]+461.2045found:461.2041。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 73.5%.
Example 8:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 8: 8- ((1- (10H-phenothiazin-2-yl) ethyl) sulfonyl) -8-azabicyclo [3.2.1] -3-octanol
The synthesis route is as follows:
process for preparation of Compound 81H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.66(s,1H),6.98(td,J＝7.7,1.4Hz,1H),6.90(dd,J＝10.8,4.5Hz,2H),6.83–6.73(m,3H),6.73–6.63(m,1H),4.29(d,J＝7.1Hz,1H),4.10(s,1H),3.90–3.75(m,2H),2.08(t,J＝6.4Hz,2H),1.94–1.83(m,2H),1.74(d,J＝8.1Hz,2H),1.63(d,J＝10.2Hz,2H),1.53(d,J＝7.0Hz,3H)。
HRMS m/z(ESI)calcd for C21H24N2O3S2[M+H]+417.1307found:417.1309。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 86.2%.
Example 9:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 9: 2- (1- ((4-phenethylpiperazin-1-yl) sulfonyl) ethyl) -10H-phenothiazine
The synthesis route is as follows:
process for preparation of compound 91H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),7.29–7.22(m,2H),7.17(dd,J＝7.6,3.5Hz,3H),6.98(td,J＝7.6,1.4Hz,1H),6.94–6.87(m,2H),6.83(dd,J＝7.9,1.7Hz,1H),6.77(dd,J＝3.3,1.5Hz,1H),6.76–6.72(m,1H),6.68(d,J＝7.9Hz,1H),4.41(q,J＝7.0Hz,1H),3.21–3.02(m,2H),2.92(dd,J＝22.3,15.4Hz,2H),2.77–2.62(m,2H),2.46–2.27(m,4H),1.52(t,J＝10.6Hz,3H)。
HRMS m/z(ESI)calcd for C26H29N3O2S2[M+H]+480.1799found:480.1795。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 62.7%.
Example 10:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 10: 2- (1- ((4-ethylpiperazin-1-yl) sulfonyl) ethyl) -10H-phenothiazine
The synthesis route is as follows:
process for preparation of Compound 101H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),6.98(t,J＝7.1Hz,1H),6.94–6.86(m,2H),6.82(d,J＝7.8Hz,1H),6.76(d,J＝7.9Hz,2H),6.68(d,J＝7.6Hz,1H),4.40(d,J＝6.7Hz,1H),3.07(s,2H),2.94(s,2H),2.29(d,J＝6.9Hz,6H),1.53(d,J＝6.6Hz,3H),0.94(t,J＝6.8Hz,3H)。
HRMS m/z(ESI)calcd for C20H25N3O2S2[M+H]+404.1466found:404.1467。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 76.8%.
Example 11:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 11: (4- ((1- (10H-phenothiazin-2-yl) ethyl) sulfonyl) piperazin-1-yl) (tetrahydrofuran-2-yl) methanone
The synthesis route is as follows:
process for preparation of Compound 111H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),6.98(td,J＝7.7,1.4Hz,1H),6.94–6.87(m,2H),6.82(dd,J＝8.0,1.6Hz,1H),6.79–6.71(m,2H),6.67(dd,J＝7.9,1.0Hz,1H),4.59(dd,J＝7.4,5.7Hz,1H),4.45(dd,J＝7.0,3.0Hz,1H),3.80–3.63(m,2H),3.60–3.35(m,4H),3.18–3.01(m,2H),2.89(dd,J＝48.8,20.8Hz,2H),2.00–1.87(m,2H),1.86–1.71(m,2H),1.54(d,J＝7.0Hz,3H)。
HRMS m/z(ESI)calcd for C23H27N3O4S2[M+H]+474.1521found:474.1523。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 79.8%.
Example 12:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 12: 4- (2- (4- ((1- (10H-phenothiazin-2-yl) ethyl) sulfonyl) piperazin-1-yl) ethyl) morpholine
The synthesis route is as follows:
process for preparation of Compound 121H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),6.97(dd,J＝7.6,1.2Hz,1H),6.94–6.88(m,2H),6.82(dd,J＝8.0,1.6Hz,1H),6.76(dd,J＝7.4,1.1Hz,2H),6.68(dd,J＝7.9,1.0Hz,1H),4.40(q,J＝6.9Hz,1H),3.55–3.49(m,4H),3.15–3.01(m,2H),2.92(d,J＝4.3Hz,2H),2.44–2.23(m,12H),1.52(d,J＝7.0Hz,3H)。
HRMS m/z(ESI)calcd for C24H32N4O3S2[M+H]+489.1994found:489.1996。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 76.4%.
Example 13:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 13: 2- (4- ((1- (10H-phenothiazin-2-yl) ethyl) sulfonyl) piperazin-1-yl) -1-ethanol
The synthesis route is as follows:
process for preparation of Compound 131H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),6.98(td,J＝7.7,1.4Hz,1H),6.95–6.88(m,2H),6.82(dd,J＝7.9,1.7Hz,1H),6.80–6.71(m,2H),6.68(dd,J＝7.9,1.0Hz,1H),4.46–4.33(m,2H),3.54–3.41(m,2H),3.14–3.02(m,2H),3.00–2.88(m,2H),2.42–2.27(m,6H),1.53(d,J＝7.0Hz,3H)。
HRMS m/z(ESI)calcd for C20H25N3O3S2[M+H]+420.1416found:420.1419。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 77.8%.
Example 14:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 14: (3R) -1- ((1- (10H-phenothiazin-2-yl) ethyl) sulfonyl) pyrrolin-3-ol
The synthesis route is as follows:
process for preparation of Compound 141H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.67(s,1H),6.98(td,J＝7.8,1.3Hz,1H),6.90(dd,J＝10.0,3.6Hz,2H),6.82(d,J＝7.9Hz,1H),6.78(s,1H),6.75(td,J＝7.6,1.0Hz,1H),6.68(d,J＝7.9Hz,1H),5.00(d,J＝3.3Hz,1H),4.56–4.41(m,1H),4.20(dd,J＝29.5,2.9Hz,1H),3.32–3.13(m,2H),2.99(dddd,J＝17.2,12.5,9.2,2.8Hz,2H),1.91–1.62(m,2H),1.55(d,J＝7.0Hz,3H)。
HRMS m/z(ESI)calcd for C18H20N2O3S2[M+H]+377.0994found:377.0996。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 80.2%.
Example 15:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 15: 1- (4- ((1- (10H-phenothiazin-2-yl) ethyl) sulfonyl) piperazin-1-yl) -1-ethanone
The synthesis route is as follows:
process for preparation of Compound 151H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.68(s,1H),7.05–6.95(m,1H),6.90(dd,J＝7.7,3.1Hz,2H),6.81(dd,J＝8.0,1.4Hz,1H),6.75(dd,J＝12.0,4.4Hz,2H),6.67(d,J＝7.9Hz,1H),4.44(q,J＝7.0Hz,1H),3.39(d,J＝22.5Hz,4H),3.15–3.02(m,2H),3.02–2.88(m,2H),1.97(d,J＝11.4Hz,3H),1.54(d,J＝7.0Hz,3H)。
HRMS m/z(ESI)calcd for C20H23N3O3S2[M+H]+418.1259found:418.1255。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 57.8%.
Example 16:
in this example, raw material a was replaced with the above compound, specifically as follows:
compound 16: 2- (1- ((4- (methylsulfonyl) piperazin-1-yl) sulfonyl) ethyl) -10H-phenothiazine
The synthesis route is as follows:
process for preparation of Compound 161H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.71(s,1H),6.98(dd,J＝10.8,4.4Hz,1H),6.95–6.87(m,2H),6.84(dd,J＝7.9,1.6Hz,1H),6.80–6.72(m,2H),6.67(d,J＝7.8Hz,1H),4.46(q,J＝7.0Hz,1H),3.21(dd,J＝9.4,6.8Hz,2H),3.06(dt,J＝14.7,6.5Hz,6H),2.84(d,J＝6.5Hz,3H),1.55(d,J＝7.0Hz,3H)。
HRMS m/z(ESI)calcd for C19H23N3O4S3[M+H]+454.0929found:454.0928。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 80.9%.
Example 17:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 17: 2- (1- ((4- (pyridin-4-yl) piperazin-1-yl) sulfonyl) ethyl) -10H-phenothiazine
The synthesis route is as follows:
process for preparation of compound 171H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),8.15(t,J＝6.6Hz,2H),6.98(td,J＝7.8,1.4Hz,1H),6.93–6.87(m,2H),6.83(dd,J＝8.0,1.6Hz,1H),6.79(d,J＝6.0Hz,3H),6.77–6.72(m,1H),6.66(d,J＝7.8Hz,1H),4.49(q,J＝7.0Hz,1H),3.32–3.25(m,4H),3.25–3.17(m,2H),3.06(dd,J＝11.9,6.4Hz,2H),1.56(d,J＝7.0Hz,3H)。
HRMS m/z(ESI)calcd for C23H24N4O2S2[M+H]+453.1419found:453.1423。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 78.4%.
Example 18:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 18: 1- ((1- (10H-phenothiazin-2-yl) ethyl) sulfonyl) -4-piperidinol
The synthesis route is as follows:
process for preparation of Compound 181H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.68(s,1H),6.98(t,J＝7.2Hz,1H),6.89(d,J＝7.8Hz,2H),6.83–6.71(m,3H),6.68(d,J＝7.8Hz,1H),4.68(d,J＝3.9Hz,1H),4.37(d,J＝7.0Hz,1H),3.61–3.48(m,1H),3.34–3.19(m,2H),2.91(t,J＝9.3Hz,1H),2.73(t,J＝9.4Hz,1H),1.63(d,J＝13.0Hz,2H),1.52(d,J＝7.0Hz,3H),1.29(ddd,J＝19.8,14.0,9.7Hz,2H)。
HRMS m/z(ESI)calcd for C19H22N2O3S2[M+H]+391.1150found:391.1152。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 61.4%.
Example 19:
in this example, raw material a was replaced with the above compound, specifically as follows:
compound 19: (4- ((1- (10H-phenothiazin-2-yl) ethyl) sulfonyl) piperazin-1-yl) (2, 3-dihydrobenzo [ b ] [1,4] dioxan-6-yl) methanone
The synthesis route is as follows:
process for preparation of compound 191H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.70(d,J＝7.2Hz,1H),7.02–6.95(m,1H),6.95–6.87(m,3H),6.87–6.81(m,4H),6.81–6.78(m,1H),6.74(dd,J＝10.8,4.1Hz,1H),6.68(d,J＝7.8Hz,1H),5.16(ddd,J＝16.0,6.5,2.5Hz,1H),4.53–4.41(m,1H),4.34(ddd,J＝11.4,8.6,2.5Hz,1H),4.22–4.04(m,2H),3.59(s,2H),3.46(s,2H),3.28–3.02(m,4H),1.55(d,J＝7.0Hz,3H)。
HRMS m/z(ESI)calcd for C27H27N3O5S2[M+H]+538.1470found:538.1473。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 78.1%.
Example 20:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 20: 2- (1- (thiomorpholinesulfonyl) ethyl) -10H-phenothiazine
The synthesis route is as follows:
process for preparation of Compound 201H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),7.02–6.95(m,1H),6.91(t,J＝8.4Hz,2H),6.82(dd,J＝8.0,1.5Hz,1H),6.78–6.72(m,2H),6.68(d,J＝7.9Hz,1H),4.40(q,J＝7.0Hz,1H),3.39–3.31(m,2H),3.26–3.12(m,2H),2.58–2.52(m,2H),2.50–2.44(m,2H),1.52(d,J＝7.0Hz,3H)。
HRMS m/z(ESI)calcd for C18H20N2O2S3[M+H]+393.0765found:393.0767。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 64.5%.
Example 21:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 21: 2- (1- (pyrrolin-1-ylsulfonyl) ethyl) -10H-phenothiazine
The synthesis route is as follows:
process for preparation of Compound 211H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),6.98(td,J＝7.8,1.3Hz,1H),6.90(d,J＝7.8Hz,2H),6.86–6.72(m,3H),6.68(d,J＝7.9Hz,1H),4.49(q,J＝7.0Hz,1H),3.28–3.13(m,2H),3.01–2.84(m,2H),1.72(dd,J＝12.7,6.1Hz,4H),1.54(d,J＝7.1Hz,3H)。
HRMS m/z(ESI)calcd for C18H20N2O2S2[M+H]+361.1004found:361.1007。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 74.8%.
Example 22:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 22: 2- (1- ((4- (2-methoxyphenyl) piperazin-1-yl) sulfonyl) ethyl) -10H-phenothiazine
The synthesis route is as follows:
process for preparation of Compound 221H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),7.41–7.30(m,2H),7.26(t,J＝6.1Hz,3H),6.98(t,J＝7.6Hz,1H),6.91(dd,J＝7.7,2.7Hz,2H),6.82(d,J＝8.0Hz,1H),6.80–6.72(m,2H),6.68(d,J＝7.8Hz,1H),4.40(q,J＝6.9Hz,1H),4.32(dd,J＝7.8,3.7Hz,1H),3.08(s,3H),3.05(d,J＝6.4Hz,2H),2.92(d,J＝5.3Hz,2H),2.61(d,J＝8.0Hz,1H),2.50–2.28(m,6H),1.53(d,J＝7.0Hz,3H)。
HRMS m/z(ESI)calcd for C27H31N3O3S2[M+H]+510.1885found:510.1886。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 68.8%.
Example 23:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 23: ethyl 1- ((1- (10H-phenothiazin-2-yl) ethyl) sulfonyl) piperazine-4-carboxylic acid
The synthesis route is as follows:
process for preparation of compound 231H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.67(s,1H),7.06–6.94(m,1H),6.89(dd,J＝7.3,3.9Hz,2H),6.85–6.70(m,3H),6.68(d,J＝7.9Hz,1H),4.39(q,J＝7.0Hz,1H),4.04(q,J＝7.1Hz,2H),3.38(dd,J＝12.4,4.6Hz,2H),2.88(t,J＝10.6Hz,1H),2.63(t,J＝10.7Hz,1H),2.48–2.36(m,1H),1.77(t,J＝10.7Hz,2H),1.52(d,J＝7.0Hz,3H),1.48–1.32(m,2H),1.16(dd,J＝9.1,5.1Hz,3H)。
HRMS m/z(ESI)calcd for C22H26N2O4S2[M+H]+447.1412found:447.1415。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 79.2%.
Example 24:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 24: 2- (1- ((4-phenylpiperazin-1-yl) sulfonyl) ethyl) -10H-phenothiazine
The synthesis route is as follows:
process for preparation of compound 241H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),7.36–7.27(m,2H),7.27–7.17(m,3H),7.05–6.95(m,1H),6.91(d,J＝7.8Hz,2H),6.82(dd,J＝8.0,1.5Hz,1H),6.80–6.73(m,2H),6.69(d,J＝7.9Hz,1H),4.40(d,J＝7.1Hz,1H),3.44(q,J＝13.2Hz,2H),3.10(dd,J＝8.1,4.5Hz,2H),2.97(d,J＝5.9Hz,2H),2.28(dq,J＝14.5,8.1Hz,4H),1.53(d,J＝7.0Hz,3H)。
HRMS m/z(ESI)calcd for C25H27N3O2S2[M+H]+466.1623found:466.1627。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 69.8%.
Example 25:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 25: 1- (4- ((1- (10H-phenothiazin-2-yl) ethyl) sulfonyl) -1, 4-homopiperazin-1-yl) -1-ethanone
The synthesis route is as follows:
process for preparation of Compound 251H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.66(s,1H),6.98(t,J＝7.6Hz,1H),6.90(d,J＝7.7Hz,2H),6.82–6.71(m,3H),6.67(d,J＝7.9Hz,1H),4.47(dd,J＝7.0,3.7Hz,1H),3.52–3.36(m,4H),3.11(dd,J＝30.1,25.6Hz,4H),1.97(t,J＝11.3Hz,3H),1.73–1.65(m,1H),1.64–1.56(m,1H),1.53(dd,J＝7.0,3.2Hz,3H)。
HRMS m/z(ESI)calcd for C21H25N3O3S2[M+H]+432.1416found:432.1419。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 81.5%.
Example 26:
in this example, raw material a was replaced with the above compound, specifically as follows:
compound 26: 2- (1- ((4-Benzylpiperazin-1-yl) sulfonyl) ethyl) -10H-phenothiazine
The synthesis route is as follows:
process for preparation of compound 261H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.75(s,1H),7.41–7.29(m,4H),7.26(t,J＝7.5Hz,4H),7.16(dd,J＝7.9,6.0Hz,2H),7.01(td,J＝7.8,1.3Hz,1H),6.93(d,J＝7.8Hz,2H),6.83(dd,J＝8.0,1.4Hz,1H),6.82–6.71(m,3H),4.40(q,J＝6.9Hz,1H),4.27(s,1H),3.21–3.07(m,2H),2.99(d,J＝6.8Hz,2H),2.30–2.07(m,4H),1.53(d,J＝7.0Hz,3H)。
HRMS m/z(ESI)calcd for C31H31N3O2S2[M+H]+542.1936found:542.1938。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 81.4%.
Example 27:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 27: tert-butyl 4- ((1- (10H-phenothiazin-2-yl) ethyl) sulfonyl) piperazine-1-carbamate
The synthesis route is as follows:
process for preparation of compound 271H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.68(s,1H),6.98(t,J＝7.6Hz,1H),6.90(d,J＝7.7Hz,2H),6.82(d,J＝8.0Hz,1H),6.79–6.70(m,2H),6.67(d,J＝7.8Hz,1H),4.43(q,J＝6.9Hz,1H),3.25(d,J＝5.6Hz,4H),3.07(dd,J＝12.1,4.9Hz,2H),2.92(s,2H),1.53(d,J＝7.0Hz,3H),1.39(d,J＝16.1Hz,10H)。
HRMS m/z(ESI)calcd for C23H29N3O4S2[M+H]+476.1678found:476.1679。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 71.5%.
Example 28:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 28: 2- (1- ((4-phenylpiperazin-1-yl) sulfonyl) ethyl) -10H-phenothiazine
The synthesis route is as follows:
process for preparation of Compound 281H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),7.20(t,J＝7.9Hz,2H),6.97(dd,J＝10.9,4.3Hz,1H),6.91(d,J＝7.9Hz,4H),6.87–6.71(m,4H),6.67(d,J＝7.6Hz,1H),4.48(q,J＝7.0Hz,1H),3.29–3.18(m,2H),3.08(t,J＝9.6Hz,6H),1.56(d,J＝7.0Hz,3H)。
HRMS m/z(ESI)calcd for C24H25N3O2S2[M+H]+452.1466found:452.1469。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 73.8%.
Example 29:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 29: tert-butyl ((3S) -1- ((1- (10H-phenothiazin-2-yl) ethyl) sulfonyl) piperidin-3-yl) carbamate
The synthesis route is as follows:
process for preparation of compound 291H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.67(s,1H),6.98(t,J＝7.6Hz,1H),6.89(d,J＝7.5Hz,2H),6.86–6.71(m,4H),6.67(d,J＝7.8Hz,1H),4.46–4.28(m,1H),3.59–3.34(m,2H),3.30–3.15(m,2H),2.71(t,J＝10.9Hz,1H),2.41–2.17(m,1H),1.75–1.57(m,2H),1.51(d,J＝7.0Hz,3H),1.36(d,J＝13.0Hz,9H)。
HRMS m/z(ESI)calcd for C24H31N3O4S2[M+H]+490.1834found:490.1835。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 82.8%.
Example 30:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 30: 1- ((1- (10H-phenothiazin-2-yl) ethyl) sulfonyl) -4- (4-chlorophenyl) -4-piperidinol
The synthesis route is as follows:
process for preparation of Compound 301H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),7.43(d,J＝8.6Hz,2H),7.32(d,J＝8.6Hz,2H),7.04–6.96(m,1H),6.89(dt,J＝9.4,8.0Hz,3H),6.81(s,1H),6.78–6.71(m,1H),6.68(d,J＝7.9Hz,1H),5.13(s,1H),4.44(q,J＝6.9Hz,1H),3.45(d,J＝11.9Hz,1H),3.35(s,1H),3.27–3.13(m,1H),2.88(t,J＝11.4Hz,1H),1.76(td,J＝13.0,4.8Hz,1H),1.66(td,J＝12.7,4.2Hz,1H),1.54(t,J＝12.9Hz,5H)。
HRMS m/z(ESI)calcd for C25H25ClN2O3S2[M+H]+501.1073found:501.1075。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 80.7%.
Example 31:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 31: tert-butyl ((3S) -1- ((1- (10H-phenothiazin-2-yl) ethyl) sulfonyl) pyrrolin-3-yl) carbamate
The synthesis route is as follows:
process for preparation of Compound 311H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.68(s,1H),7.09(s,1H),7.03–6.95(m,1H),6.94–6.85(m,2H),6.82(d,J＝7.9Hz,1H),6.76(dd,J＝14.6,7.1Hz,2H),6.68(d,J＝7.8Hz,1H),4.47(q,J＝7.0Hz,1H),3.90(dd,J＝23.0,5.7Hz,1H),3.48(dd,J＝9.5,6.4Hz,1H),3.31–3.19(m,1H),3.19–3.07(m,1H),3.02(d,J＝5.2Hz,1H),2.88(dd,J＝16.0,9.4Hz,1H),1.93(ddd,J＝27.8,13.0,6.7Hz,1H),1.77–1.62(m,1H),1.53(d,J＝7.0Hz,3H),1.36(d,J＝11.5Hz,9H)。
HRMS m/z(ESI)calcd for C23H29N3O4S2[M+H]+476.1678found:476.1672。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 77.2%.
Example 32:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 32: tert-butyl ((3R) -1- ((1- (10H-phenothiazin-2-yl) ethyl) sulfonyl) piperidin-3-yl) carbamate
The synthesis route is as follows:
process for preparation of compound 321H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.68(s,1H),6.98(t,J＝7.6Hz,1H),6.89(d,J＝7.5Hz,2H),6.86–6.70(m,4H),6.67(d,J＝7.7Hz,1H),4.48–4.29(m,1H),3.39(s,1H),3.27(d,J＝28.6Hz,2H),2.31(dd,J＝39.0,16.7Hz,1H),1.68(s,2H),1.51(d,J＝7.0Hz,3H),1.43–1.16(m,11H)。
HRMS m/z(ESI)calcd for C24H31N3O4S2[M+H]+490.1834found:490.1836。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 66.2%.
Example 33:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 33: tert-butyl (((3R) -1- ((1- (10H-phenothiazin-2-yl) ethyl) sulfonyl) pyrrolin-3-yl) methyl) carbamate
The synthesis route is as follows:
process for preparation of compound 331H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.68(s,1H),6.98(t,J＝7.6Hz,1H),6.89(dd,J＝7.9,3.4Hz,2H),6.78(ddd,J＝16.6,14.6,6.7Hz,4H),6.67(d,J＝7.9Hz,1H),4.53–4.39(m,1H),3.83(s,1H),3.28(s,1H),3.15(s,1H),3.10–3.00(m,1H),2.95–2.73(m,1H),1.77(s,2H),1.62(s,2H),1.54(d,J＝6.9Hz,3H),1.37(t,J＝11.9Hz,9H)。
HRMS m/z(ESI)calcd for C24H31N3O4S2[M+H]+490.1834found:490.1835
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 76.4%.
Example 34:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 34: 2- (1- ((4- (4-fluorophenyl) piperazin-1-yl) sulfonyl) ethyl) -10H-phenothiazine
The synthesis route is as follows:
process for preparation of compound 341H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),7.01(dt,J＝15.4,8.1Hz,3H),6.96–6.88(m,4H),6.85(d,J＝8.1Hz,1H),6.80(s,1H),6.75(t,J＝7.5Hz,1H),6.67(d,J＝7.8Hz,1H),4.48(q,J＝6.9Hz,1H),3.28–3.18(m,2H),3.16–3.06(m,2H),3.05–2.93(m,4H),1.56(d,J＝7.0Hz,3H)。
HRMS m/z(ESI)calcd for C24H24FN3O2S2[M+H]+470.1372found:470.1373。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 77.8%.
Example 35:
in this example, raw material a was replaced with the above compound, specifically as follows:
compound 35: tert-butyl ((1- ((1- (10H-phenothiazin-2-yl) ethyl) sulfonyl) piperidin-3-yl) methyl) carbamate
The synthesis route is as follows:
process for preparation of compound 351H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.67(d,J＝9.4Hz,1H),6.98(t,J＝7.6Hz,1H),6.89(t,J＝6.1Hz,2H),6.86–6.80(m,1H),6.80–6.71(m,3H),6.68(d,J＝7.9Hz,1H),4.34(dd,J＝6.9,4.5Hz,1H),3.49(dd,J＝23.4,11.7Hz,1H),2.99–2.64(m,3H),2.45–2.25(m,1H),1.69–1.47(m,7H),1.37(d,J＝4.8Hz,9H),1.25(dd,J＝17.5,5.2Hz,2H)。
HRMS m/z(ESI)calcd for C25H33N3O4S2[M+H]+504.1991found:504.1995。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 74.9%.
Example 36:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 36: 2- (1- ((4- (4-chlorobenzyl) piperazin-1-yl) sulfonyl) ethyl) -10H-phenothiazine
The synthesis route is as follows:
process for preparation of compound 361H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),7.35(d,J＝8.4Hz,2H),7.26(d,J＝8.4Hz,2H),6.99(td,J＝7.9,1.3Hz,1H),6.91(d,J＝7.9Hz,2H),6.82(dd,J＝8.0,1.5Hz,1H),6.79–6.73(m,2H),6.73–6.64(m,1H),4.40(q,J＝7.0Hz,1H),3.43(q,J＝13.4Hz,2H),3.16–3.04(m,2H),2.97(d,J＝5.1Hz,2H),2.38–2.16(m,4H),1.53(d,J＝7.0Hz,3H)。
HRMS m/z(ESI)calcd for C25H26ClN3O2S2[M+H]+500.1233found:500.1237。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 63.4%.
Example 37:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 37: tert-butyl (1- ((1- (10H-phenothiazin-2-yl) ethyl) sulfonyl) piperidin-4-yl) carbamate
The synthesis route is as follows:
process for preparation of compound 371H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.67(s,1H),6.98(t,J＝7.3Hz,1H),6.90(d,J＝7.7Hz,2H),6.81(t,J＝9.3Hz,2H),6.74(d,J＝9.8Hz,2H),6.68(d,J＝7.8Hz,1H),4.37(q,J＝6.7Hz,1H),3.50(d,J＝12.2Hz,1H),3.38(d,J＝12.6Hz,1H),2.86(t,J＝11.2Hz,1H),1.67(dd,J＝24.3,11.3Hz,2H),1.52(d,J＝6.9Hz,3H),1.38(d,J＝8.6Hz,10H),1.33–1.17(m,3H)。
HRMS m/z(ESI)calcd for C24H31N3O4S2[M+H]+490.1834found:490.1838。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 83.8%.
Example 38:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 38: (1- ((1- (10H-phenothiazin-2-yl) ethyl) sulfonyl) piperidin-3-yl) methanol
The synthesis route is as follows:
process for preparation of Compound 381H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.67(d,J＝4.7Hz,1H),6.98(t,J＝7.6Hz,1H),6.90(d,J＝7.7Hz,2H),6.84–6.71(m,3H),6.68(d,J＝7.9Hz,1H),4.60–4.45(m,1H),4.43–4.27(m,1H),3.64(d,J＝9.6Hz,1H),3.55(d,J＝9.4Hz,1H),3.41(d,J＝12.1Hz,1H),3.32–3.23(m,2H),3.23–3.06(m,1H),2.74(t,J＝10.8Hz,1H),2.43–2.22(m,1H),1.69–1.56(m,2H),1.50(t,J＝10.8Hz,4H),1.37–1.23(m,1H)。
HRMS m/z(ESI)calcd for C20H24N2O3S2[M+H]+405.1307found:405.1302。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 84.7%.
Example 39:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 39: ethyl (3R) -1- ((1- (10H-phenothiazin-2-yl) ethyl) sulfonyl) piperidine-3-carboxylic acid
The synthesis route is as follows:
process for preparation of Compound 391H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.68(d,J＝2.2Hz,1H),6.98(dd,J＝11.1,4.1Hz,1H),6.91(d,J＝2.6Hz,1H),6.89(s,1H),6.85–6.71(m,3H),6.68(d,J＝7.9Hz,1H),4.41(q,J＝6.9Hz,1H),4.15–3.92(m,2H),3.50(t,J＝9.0Hz,1H),3.02–2.78(m,1H),2.74–2.53(m,1H),2.49–2.26(m,2H),1.83(s,1H),1.61(dd,J＝19.6,9.0Hz,1H),1.52(d,J＝7.0Hz,3H),1.40(dd,J＝23.5,13.1Hz,2H),1.17–1.06(m,3H)。
HRMS m/z(ESI)calcd for C22H26N2O4S2[M+H]+447.1412found:447.1416。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 74.4%.
Example 40:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 40: 1- ((1- (10H-phenothiazin-2-yl) ethyl) sulfonyl) piperidin-3-ol
The synthesis route is as follows:
process for preparation of Compound 401H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.67(s,1H),6.98(t,J＝7.1Hz,1H),6.90(d,J＝7.8Hz,2H),6.81(d,J＝7.7Hz,1H),6.78–6.71(m,2H),6.68(d,J＝7.8Hz,1H),4.91(dd,J＝22.3,4.1Hz,1H),4.37(dd,J＝7.0,2.8Hz,1H),3.40(dd,J＝36.2,10.2Hz,2H),2.80–2.53(m,1H),2.31(dt,J＝23.1,10.6Hz,1H),1.77(d,J＝9.3Hz,1H),1.61(dd,J＝24.0,13.7Hz,1H),1.52(d,J＝7.0Hz,3H),1.28(dd,J＝21.9,11.2Hz,1H),1.16(dd,J＝17.2,9.9Hz,1H)。
HRMS m/z(ESI)calcd for C19H22N2O3S2[M+H]+391.1150found:391.1155。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 82.5%.
Example 41:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 41: (3S) -1- ((1- (10H-phenothiazin-2-yl) ethyl) sulfonyl) pyrrolin-3-ol
The synthesis route is as follows:
process for preparation of Compound 411H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.66(s,1H),6.99(td,J＝7.9,1.2Hz,1H),6.94–6.86(m,2H),6.86–6.72(m,3H),6.68(d,J＝7.9Hz,1H),5.00(d,J＝2.9Hz,1H),4.45(tt,J＝6.9,3.4Hz,1H),4.20(dd,J＝29.5,2.5Hz,1H),3.31–3.14(m,2H),3.11–2.87(m,2H),1.92–1.63(m,2H),1.55(d,J＝7.0Hz,3H)。
HRMS m/z(ESI)calcd for C18H20N2O3S2[M+H]+377.0994found:377.0997。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 75.6%.
Example 42:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 42: 2- (1- (((S) -2-methylpyrrolidin-1-yl) sulfonyl) ethyl) -10H-phenothiazine
The synthesis route is as follows:
of Compound 421H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.69(d,J＝8.2Hz,1H),6.98(t,J＝7.6Hz,1H),6.89(dd,J＝7.7,3.9Hz,2H),6.81(dd,J＝13.7,5.9Hz,2H),6.75(t,J＝7.5Hz,1H),6.68(d,J＝7.9Hz,1H),4.44(dq,J＝20.5,6.9Hz,1H),3.91(dd,J＝10.2,6.9Hz,1H),3.24–2.99(m,1H),2.96–2.76(m,1H),1.96(dd,J＝12.1,8.8Hz,1H),1.90–1.66(m,2H),1.69–1.29(m,5H),1.05(dd,J＝9.1,6.4Hz,3H)。
HRMS m/z(ESI)calcd for C19H22N2O2S2[M+H]+375.1201found:375.1205。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 80.7%.
Example 43:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 43: 2- (1- ([1,4 '-dipiperidin ] -1' -ylsulfonyl) ethyl) -10H-phenothiazine
The synthesis route is as follows:
process for preparation of Compound 431H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.68(s,1H),6.98(td,J＝7.9,1.3Hz,1H),6.89(d,J＝7.9Hz,2H),6.80(dd,J＝8.0,1.5Hz,1H),6.78–6.71(m,2H),6.71–6.62(m,1H),4.37(q,J＝7.0Hz,1H),3.51(dd,J＝33.0,12.5Hz,2H),2.77(t,J＝11.2Hz,1H),2.49–2.18(m,6H),1.63(s,2H),1.52(d,J＝7.0Hz,3H),1.42(d,J＝19.7Hz,4H),1.39–1.22(m,4H)。
HRMS m/z(ESI)calcd for C24H31N3O2S2[M+H]+458.1936found:458.1939。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 74.3%.
Example 44:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 44: (2S,6R) -4- ((1- (10H-phenothiazin-2-yl) ethyl) sulfonyl) -2, 6-dimethylmorpholine
The synthesis route is as follows:
process for preparation of compound 441H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),6.98(dd,J＝11.0,4.2Hz,1H),6.91(t,J＝6.6Hz,2H),6.82(d,J＝7.9Hz,1H),6.79–6.72(m,2H),6.69(d,J＝7.8Hz,1H),4.44(q,J＝6.9Hz,1H),3.54–3.42(m,1H),3.38(d,J＝11.6Hz,2H),3.29(d,J＝15.7Hz,2H),2.24–2.09(m,1H),1.53(d,J＝7.0Hz,3H),1.02(d,J＝6.1Hz,3H),0.98(d,J＝6.2Hz,3H)。
HRMS m/z(ESI)calcd for C20H24N2O3S2[M+H]+405.1307found:405.1303。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 83.9%.
Example 45:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 45: 2- (1- ((4-methylpiperidin-1-yl) sulfonyl) ethyl) -10H-phenothiazine
The synthesis route is as follows:
process for preparation of Compound 451H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),6.94(d,J＝33.6Hz,3H),6.72(d,J＝33.3Hz,4H),4.37(s,1H),3.51(s,1H),3.39(s,1H),2.76(s,1H),2.40(s,1H),1.52(s,4H),1.35(s,1H),1.24(s,1H),0.96(s,2H),0.85(s,3H)。
HRMS m/z(ESI)calcd for C20H24N2O2S2[M+H]+389.1357found:389.1359。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 76.1%.
Example 46:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 46: 2- (1- ((3-methylpiperidin-1-yl) sulfonyl) ethyl) -10H-phenothiazine
The synthesis route is as follows:
process for preparation of compound 461H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),7.12–6.87(m,3H),6.85–6.63(m,4H),4.38(s,1H),3.40(s,1H),2.74(d,J＝9.5Hz,1H),2.41(s,1H),2.30–2.10(m,1H),1.65(s,2H),1.52(s,3H),1.25(s,2H),0.94(s,1H),0.79(d,J＝19.6Hz,3H)。
HRMS m/z(ESI)calcd for C20H24N3O2S2[M+H]+389.1357found:389.1353。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 75.1%.
Example 47:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 47: 1- ((1- (10H-phenothiazin-2-yl) ethyl) sulfonyl) piperidine-4-carboxamide
The synthesis route is as follows:
process for preparation of Compound 471H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),7.23(s,1H),6.94(d,J＝37.3Hz,3H),6.76(t,J＝25.7Hz,5H),4.40(s,1H),3.55(s,1H),3.42(d,J＝10.5Hz,1H),2.78(s,1H),2.41(s,2H),1.65(d,J＝15.4Hz,2H),1.53(s,3H),1.40(s,2H)。
HRMS m/z(ESI)calcd for C20H23N3O3S2[M+H]+418.1259found:418.1254。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 63.8%.
Example 48:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 48: 2- (1- ((3, 5-dimethylpiperazin-1-yl) sulfonyl) ethyl) -10H-phenothiazine
The synthesis route is as follows:
process for preparation of Compound 481H NMR and HRMS data are as follows:
H NMR(400MHz,DMSO-d6)δ8.67(s,1H),7.05–6.94(m,1H),6.90(d,J＝7.8Hz,2H),6.77(dt,J＝11.3,4.6Hz,3H),6.68(d,J＝7.8Hz,1H),4.38(q,J＝6.9Hz,1H),3.37(d,J＝11.1Hz,1H),3.24(d,J＝11.0Hz,1H),2.69–2.51(m,2H),2.29(t,J＝11.0Hz,1H),2.07–1.90(m,1H),1.51(d,J＝7.0Hz,3H),0.90(d,J＝6.2Hz,3H),0.84(d,J＝6.2Hz,4H)。
HRMS m/z(ESI)calcd for C20H25N3O2S2[M+H]+404.1466found:404.1469。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 68.9%.
Example 49:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 49: 2- (1- ((4- (2-methoxyphenyl) piperazin-1-yl) sulfonyl) ethyl) -10H-phenothiazine
The synthesis route is as follows:
process for preparation of compound 491H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.71(s,1H),7.03–6.80(m,9H),6.75(t,J＝7.3Hz,1H),6.69(d,J＝7.7Hz,1H),4.46(d,J＝6.9Hz,1H),3.74(s,3H),3.22(s,2H),3.12(s,2H),2.87(s,4H),1.57(d,J＝6.8Hz,3H)。
HRMS m/z(ESI)calcd for C25H27N3O3S2[M+H]+482.1572found:482.1576。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 80.8%.
Example 50:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 50: 2- (1- (2- (4-methyl-1, 4-homopiperazin-1-yl) pyrimidin-5-yl) vinyl) -10H-phenothiazine
The synthesis route is as follows:
process for preparation of Compound 501H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.77(s,1H),7.33(s,4H),7.19–6.47(m,11H),4.38(d,J＝26.0Hz,2H),3.11(s,2H),2.97(s,2H),2.17(d,J＝26.3Hz,4H),1.52(s,3H)。
HRMS m/z(ESI)calcd for C31H29F2N3O2S2[M+H]+578.1748found:578.1745。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 82.8%.
Example 51:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 51: 4- (5- (1- (10H-phenothiazin-2-yl) vinyl) pyrimidin-2-yl) morpholine
The synthesis route is as follows:
process for preparation of Compound 511H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),8.09(s,1H),7.52(s,1H),6.73(d,J＝53.8Hz,9H),4.47(s,1H),3.43(s,4H),3.18(s,2H),3.04(s,2H),1.55(s,3H)。
HRMS m/z(ESI)calcd for C23H24N4O2S2[M+H]+453.1419found:453.1415。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 74.8%.
Example 52:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 52: 2- (1- ((4- (pyrimidin-2-yl) piperazin-1-yl) sulfonyl) ethyl) -10H-phenothiazine
The synthesis route is as follows:
process for preparation of Compound 521H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.68(s,1H),8.36(s,2H),6.82(dd,J＝85.3,42.4Hz,8H),4.47(s,1H),3.69(s,4H),3.11(d,J＝52.2Hz,4H),1.55(s,3H)。
HRMS m/z(ESI)calcd for C22H23N5O2S2[M+H]+454.1371found:454.1375。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 64.1%.
Example 53:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 53: 4- (4- ((1- (10H-phenothiazin-2-yl) ethyl) sulfonyl) piperazin-1-yl) benzonitrile
The synthesis route is as follows:
process for preparation of compound 531H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),7.58(s,2H),6.99(d,J＝5.4Hz,3H),6.89(s,2H),6.82(d,J＝16.9Hz,2H),6.75(s,1H),6.67(s,1H),4.49(s,1H),3.30(s,4H),3.26–2.99(m,4H),1.56(s,3H)。
HRMS m/z(ESI)calcd for C25H24N4O2S2[M+H]+477.1419found:477.1412。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 81.2%.
Example 54:
in this example, raw material a was replaced with the above compound, specifically as follows:
compound 54: 2- (1- ((4- (3-methoxyphenyl) piperazin-1-yl) sulfonyl) ethyl) -10H-phenothiazine
The synthesis route is as follows:
process for preparation of compound 541H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.71(s,1H),7.23–6.60(m,8H),6.45(d,J＝21.4Hz,3H),4.47(s,1H),3.69(s,3H),3.26(d,J＝42.1Hz,4H),1.55(s,3H),1.29(d,J＝46.2Hz,4H)。
HRMS m/z(ESI)calcd for C25H27N3O3S2[M+H]+482.1572found:4482.1565。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 86.4%.
Example 55:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 55: 2- (1- ((4- (4-nitrophenyl) piperazin-1-yl) sulfonyl) ethyl) -10H-phenothiazine
The synthesis route is as follows:
process for preparation of Compound 551H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),8.03(s,2H),6.99(s,3H),6.86(d,J＝15.1Hz,3H),6.80–6.69(m,2H),6.65(d,J＝7.1Hz,1H),4.50(s,1H),3.42(s,4H),3.22(s,2H),3.09(s,2H),1.55(s,3H)。
HRMS m/z(ESI)calcd for C24H24N4O4S2[M+H]+497.1317found:497.1313。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 74.6%.
Example 56:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 56: 2- (1- ((4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) sulfonyl) ethyl) -10H-phenothiazine
The synthesis route is as follows:
process for preparation of compound 561H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),7.50(d,J＝8.7Hz,2H),7.04(d,J＝8.6Hz,2H),7.02–6.94(m,1H),6.89(d,J＝8.0Hz,2H),6.86–6.79(m,2H),6.74(dd,J＝10.8,4.2Hz,1H),6.66(d,J＝7.9Hz,1H),4.49(q,J＝6.9Hz,1H),3.22(d,J＝5.6Hz,6H),3.11(d,J＝8.3Hz,2H),1.56(d,J＝7.0Hz,3H)。
HRMS m/z(ESI)calcd for C25H24F3N3O2S2[M+H]+520.1340found:520.1342。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 79.9%.
Example 57:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 57: 2- (1- ((4- (pyrazin-2-yl) piperazin-1-yl) sulfonyl) ethyl) -10H-phenothiazine
The synthesis route is as follows:
process for preparation of compound 571H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)1H NMR(400MHz,DMSO)δ8.70(s,1H),8.30(s,1H),8.07(s,1H),7.86(s,1H),7.20–6.38(m,7H),4.49(s,1H),3.52(s,4H),3.13(d,J＝51.3Hz,4H),1.55(s,3H)。
HRMS m/z(ESI)calcd for C22H23N5O2S2[M+H]+454.1371found:454.1375。
HRMS m/z(ESI)calcd for C24H22N2O2S2[M+H]+435.1201found:435.1203。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 67.4%.
Example 58:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 58: 2- (1- ((4-butylpiperazin-1-yl) sulfonyl) ethyl) -10H-phenothiazine
The synthesis route is as follows:
process for preparation of compound 581H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),6.83(d,J＝45.7Hz,7H),4.39(s,1H),2.99(d,J＝55.5Hz,4H),2.23(s,6H),1.51(s,3H),1.27(d,J＝38.9Hz,4H),0.82(s,3H).
HRMS m/z(ESI)calcd for C22H29N3O2S2[M+H]+432.1779found:432.1775。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 73.4%.
Example 59:
in this example, raw material a was replaced on the basis of the above compound, specifically as follows:
compound 59: 2- (1- ((4- (p-toluene) piperazin-1-yl) sulfonyl) ethyl) -10H-phenothiazine
The synthesis route is as follows:
process for preparation of compound 591H NMR and HRMS data are as follows:
1H NMR(400MHz,DMSO-d6)δ8.71(s,1H),6.84(dd,J＝83.0,44.9Hz,11H),4.48(s,1H),3.29–2.83(m,8H),2.19(s,3H),1.56(s,3H)。
HRMS m/z(ESI)calcd for C25H27N3O2S2[M+H]+466.1623found:466.1625。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 63.8%.
Example 60:
in this example, to study the inhibitor of iron death, a screening model of iron death was autonomously constructed, as follows:
the Ferroptosis screening model mainly adopts an MTT cell viability detection method. Firstly culturing fibroma cell strain in a dish, inoculating cells in logarithmic phase into a 96-well plate (3000 plus 10000 cells/well) according to a specific quantity, wherein each well has 100 mu L, then placing the 96-well plate into a culture medium, and placing the culture medium at 37 ℃ and 5% CO2Culturing in an environment incubator to allow the cells to adhere to the wall. After 24h, 100 μ L of compound and Ferroptosis inducer Erastin (final concentration 10 μ M) with certain concentration prepared by using a specified culture medium are added, each compound is provided with 3 multiple holes to ensure the accuracy of the result, and a negative control group, a positive control group (Fer-15 μ M), a blank control group and a solvent control group are arranged. Adding the medicines, putting the medicines into an incubator, and culturing for 72 h. And preparing an MTT test solution (5 mg/mLMTT solution dissolved in physiological saline and stored in dark at 4 ℃) in advance on the day of an MTT experiment, adding 20 mu of LMTT solution into each hole, putting the MTT solution into an incubator for continuous culture for 2-4h, then adding 50 mu of 20% SDS solution (dissolved in MiliQ water and added with 1% concentrated hydrochloric acid) into each hole, putting the mixture into the incubator overnight, and detecting the absorbance value at 570nm by using a microplate reader on the next day to calculate the inhibition rate of the drug on Ferroptosis. The absorbance value of the general control group should be between 0.8 and 1.2 as a normal value. After the absorbance data was obtained, the average of 3 replicate wells was calculated and the inhibition was calculated using the following formula:
inhibition Ratio (IR) ═ 1- (a)Experimental group-ABlank space)/(ASolvent(s)-ABlank space)]*100％
Inhibition change curves were fitted and EC calculated using GraphPadprism5 software50。
EC was performed on 59 compounds described above50Test (EC)50The test of (1) was taken as an average of three tests, and Fer-1 was a positive control group), the results are shown in the following table:
EC of a surface Compound50Value of
Preferred compounds 3, 10, 17 are compared to the active positive control, Fer-1, shown in FIG. 1, and the EC for compound 3500.009 μ M, about 6.7 times higher than the active positive control Fer-1, EC of compound 10500.017. mu.M, about 3.5 times higher than the active positive control Fer-1, EC of Compound 1750The activity was about 12 times that of the active positive control Fer-1 at 0.005 μ M. Its EC50The smaller the value, the better the activity, and it can be seen from the above table that the activity of most compounds is better than that of the positive control Fer-1.
While embodiments of the invention have been shown and described, it will be understood by those of ordinary skill in the art that: various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the claims and their equivalents.
Claims (14)
1. A compound, or a salt thereof, as an inhibitor of iron death, wherein the compound has the formula:
R1independently is H, hydroxyl,
One of (1);
R2independently is H;
R3independently is H or methyl;
R4independently is H.
2. A compound, or a salt thereof, as an inhibitor of iron death, wherein the compound has the formula:
R1independently is a hydroxyl group;
R2independently is H;
R3independently is H;
R4independently is H.
3. A compound, or a salt thereof, as an inhibitor of iron death, wherein the compound has the formula:
R1independently is H;
R2independently is H;
R3independently methyl or acetyl;
R4independently is H.
4. A compound, or a salt thereof, as an inhibitor of iron death, wherein the compound has the formula:
R1independently is H;
R2independently is H;
R3independently is H;
R4independently is H.
5. A compound, or a salt thereof, as an inhibitor of iron death, wherein the compound has the formula:
R1independently is H or methyl;
R2independently is H;
R3independently is H or methyl;
R4independently is H.
6. A compound, or a salt thereof, as an inhibitor of iron death, wherein the compound has the formula:
R1independently is H or methyl;
R2independently is H;
R3independently H, methyl, ethyl, isopropyl, n-butyl, methylsulfonyl, acetyl, phenyl,
、
、
、
、
One of (1);
R4independently is H or methyl;
R5independently is methyl, nitro, cyano, methoxy, a halogen atom, -CF3One kind of (1).
7. A compound, or a salt thereof, as an inhibitor of iron death, wherein the compound has the formula:
R1independently is H, methyl, hydroxyl,
、
、
、
One of (1);
R2independently is H or hydroxy;
R3independently are hydrogen, methyl, hydroxy,
One of (1);
R4independently is methyl or fluorine atom;
R5independently is halogen.
8. The process for producing a compound as an iron death inhibitor according to any one of claims 1 to 7, or a salt thereof, comprising the steps of:
(1) dissolving 2-acetylphenothiazine and 4-methylbenzene sulfonyl hydrazine serving as raw materials in MeOH, adding a catalyst HOAc, moving to 60 ℃ for reaction, monitoring the reaction process, cooling to room temperature after the reaction is finished, performing suction filtration under reduced pressure, rinsing filtrate to be colorless, and performing vacuum drying to obtain an intermediate I;
(2) dissolving the intermediate I and the raw material A, DABSO in DMSO, replacing argon for 3 times, moving to 100 ℃ for reaction, monitoring the reaction, cooling to room temperature after about 12 hours later, filtering, concentrating under reduced pressure, extracting residues, concentrating an organic layer, and separating by column chromatography to obtain a target product compound.
9. The method according to claim 8, wherein the starting material A in the step (2) comprises a compound of the following structure:
10. the method according to claim 8 or 9, wherein in the step (1), the rinsing process after the reaction is completed comprises rinsing with MeOH and ether.
11. The method according to claim 8 or 9, wherein in the step (2), the extraction process after the reaction is completed uses saturated NaHCO3Extraction by EA.
12. The method according to claim 8 or 9, wherein the progress of the detection reaction is detected by TLC.
13. Use of the compound as an iron death inhibitor according to any one of claims 1 to 7, or a salt thereof, or a pharmaceutical composition thereof for the preparation of a targeted drug for inhibiting cell iron death.
14. Use of a compound as an iron death inhibitor according to any one of claims 1 to 7, or a salt thereof, or a pharmaceutical composition thereof, for the preparation of an oral or intravenous formulation comprising at least one compound as an iron death inhibitor according to any one of claims 1 to 7, or a salt thereof, or a pharmaceutical composition thereof, and any excipients and/or adjuvants.
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| CN201910124457.6A CN109748884B (en) | 2019-02-19 | 2019-02-19 | Iron death inhibitor and preparation method and application thereof |
| EP19793210.6A EP3786156A4 (en) | 2018-04-27 | 2019-03-25 | 10h-phenothiazine ferroptosis inhibitor and preparation method therefor and application thereof |
| AU2019258078A AU2019258078B2 (en) | 2018-04-27 | 2019-03-25 | 10H-phenothiazine ferroptosis inhibitor and preparation method therefor and application thereof |
| PCT/CN2019/079421 WO2019205854A1 (en) | 2018-04-27 | 2019-03-25 | 10h-phenothiazine ferroptosis inhibitor and preparation method therefor and application thereof |
| JP2021508045A JP7433292B2 (en) | 2018-04-27 | 2019-03-25 | 10H-phenothiazine ferroptosis inhibitor, its production method, and use |
| CA3098219A CA3098219A1 (en) | 2018-04-27 | 2019-03-25 | A 10h-phenothiazine ferroptosis inhibitor as well as the preparative method and the use thereof |
| US17/078,802 US11440909B2 (en) | 2018-04-27 | 2020-10-23 | 10H-phenothiazine ferroptosis inhibitor as well as the preparative method and the use thereof |
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