CN111574474B - Micromolecular compound for inhibiting iron death and preparation method and application thereof - Google Patents

Micromolecular compound for inhibiting iron death and preparation method and application thereof Download PDF

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CN111574474B
CN111574474B CN202010099258.7A CN202010099258A CN111574474B CN 111574474 B CN111574474 B CN 111574474B CN 202010099258 A CN202010099258 A CN 202010099258A CN 111574474 B CN111574474 B CN 111574474B
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CN111574474A (en
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杨胜勇
李琳丽
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Chengdu Henghao Innovation Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/18—[b, e]-condensed with two six-membered rings
    • C07D279/20—[b, e]-condensed with two six-membered rings with hydrogen atoms directly attached to the ring nitrogen atom
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention provides a micromolecule compound for inhibiting iron death and a preparation method and application thereof, belonging to the technical field of chemical synthetic drugs. The small molecule compound is a compound shown in a formula I, or a salt or hydrate thereof, or a pharmaceutical composition thereof. The compound of the present invention has a good inhibitory effect on iron death, and at the same time, the compound of the present invention has a good inhibitory effect on cerebral infarction, and particularly compound 49 has a significant effect on the inhibition of cerebral infarction. The compound can be used as a main active ingredient for preparing iron death inhibitors, medicaments for treating diseases related to iron death and medicaments for preventing and treating cerebral infarction, 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.
Figure DDA0002386332080000011

Description

Micromolecular compound for inhibiting iron death and preparation method and application thereof
Technical Field
The invention relates to the technical field of chemical synthetic drugs, in particular to a micromolecule compound for inhibiting iron death 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. Here, three compounds with specific anti-iron death activity are mainly described:
ferrostatin: the first generation of Ferrostatin, called Ferrostatin-1, acts to inhibit Erastin-and RSL 3-induced iron ion formation in HT1080 cells. The activity of ferrostein-1 is mainly determined by aromatic amines, which specifically inhibit the accumulation of ROS due to lipid oxidation. Compared with Ferrostatin-1, the second generation (named as SRS 11-92) and the third generation Ferrostatin (named as SRS 16-86) have better plasma stability and metabolic stability, and can significantly prevent tissue injury (such as acute kidney injury and ischemia-reperfusion injury) in vivo.
Liproxstatin-1: liproxstatin-1 can prevent ROS accumulation and cell death in GPX4 cells. In addition, liproxstatin-1 inhibits iron death induced by FINs (e.g., erastin, RSL3, and BSO). In the induced GPX4 mice, the survival rate of the animals to the kidney injury can be prolonged by intraperitoneal administration of Liproxstatin-1 (10 mg/kg). Liproxstatin-1 also protected mice from liver damage caused by ischemia-reperfusion.
Zileuton: zileuton is an orally active specific inhibitor of 5-LOX, but not an inhibitor of 12/15-LOX. Zileuton provides significant protection against glutamate and ergomycin-induced iron ion increase in HT22 cells (hippocampal cell line in mice) by inhibiting the production of cytosolic ROS.
Figure BDA0002386332060000021
/>
The existing iron death inhibitor has stronger activity pertinence but not high activity, and has no application to stroke diseases, so how to prepare the iron death inhibitor which has higher activity and can be used as a medicine for treating stroke is an urgent problem to be solved.
Disclosure of Invention
In order to solve the problems, the invention provides a small molecular compound for inhibiting iron death and a preparation method and application thereof.
The invention provides a compound shown as a formula I, or a salt, a hydrate, a solvate or a pharmaceutical composition thereof:
Figure BDA0002386332060000022
wherein the content of the first and second substances,
R 1 independently hydrogen, ester group, -CF 3 Ethyl, -OCF 3 Methyl, n-butyl, isopropyl, peptide bond,
Figure BDA0002386332060000023
Six-membered ring, isobutyl, carbonyl and/or a sugar moiety>
Figure BDA0002386332060000024
Cyano, nitro, ether linkage, amino,
Figure BDA0002386332060000025
Figure BDA0002386332060000026
R 2 Independently hydrogen, amino or methyl;
R 3 independently hydrogen, amino, hydroxyl, nitro,
Figure BDA0002386332060000031
Ether linkage, -OCF 3 、/>
Figure BDA0002386332060000032
Methyl, neobutyl, tert-butyl,
Figure BDA0002386332060000033
Isopropyl and/or liver/kidney>
Figure BDA0002386332060000034
Phenyl, -CF 3 Ester group, cyano group and/or are present in the animal or human>
Figure BDA0002386332060000035
Fluorine and/or oxygen>
Figure BDA0002386332060000036
R 4 Independently hydrogen, amino, hydroxyl, nitro,
Figure BDA0002386332060000037
Ether linkage, -OCF 3 、/>
Figure BDA0002386332060000038
Methyl, new butyl,
Figure BDA0002386332060000039
Isopropyl group or in the combination of isopropyl group and isopropyl group>
Figure BDA00023863320600000310
Phenyl, -CF 3 Ester group, cyano group and/or are present in the animal or human>
Figure BDA00023863320600000311
Figure BDA00023863320600000312
Fluorine or on or in the blood>
Figure BDA00023863320600000313
Further, the air conditioner is characterized in that,
when R is 2 When it is amino, R 1 、R 3 、R 4 Are all hydrogen;
or, when R 2 When it is methyl, R 1 Is composed of
Figure BDA00023863320600000314
R 3 、R 4 Are all hydrogen;
or, when R 2 、R 3 、R 4 When both are hydrogen, R 1 Optionally selected from hydrogen, ester group, -CF 3 Ethyl, -OCF 3 Methyl, n-butyl, isopropyl, peptide bond,
Figure BDA00023863320600000315
Six-membered ring, isobutyl, carbonyl>
Figure BDA00023863320600000316
Figure BDA00023863320600000317
Or, when R is 2 、R 3 、R 4 When both are hydrogen, R 1 Is selected from
Figure BDA0002386332060000041
Wherein R is x Optionally selected from hydrogen and C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, C 2 -C 6 Alkylene radical, C 2 -C 6 Alkynyl, amino-C 1-3 Alkyl, -N- (C) 1- C 3 Alkyl radical) 2 Hydroxy, hydroxy-C 1- C 3 Alkyl or hydroxy-C 3 -C 6 A cycloalkyl group; r is y Optionally selected from hydrogen and C 2 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, C 1 -C 6 Alkylene or C 1 -C 6 An alkynyl group;
or, when R is 1 、R 2 、R 3 When both are hydrogen, R 4 Optionally selected from amino, hydroxy, nitro,
Figure BDA0002386332060000042
Ether linkage, -OCF 3 、
Figure BDA0002386332060000043
Methyl, new butyl and/or methyl>
Figure BDA0002386332060000044
Isopropyl and/or liver/kidney>
Figure BDA0002386332060000045
Phenyl, -CF 3 Ester group, cyano group and/or are present in the animal or human>
Figure BDA0002386332060000046
Figure BDA0002386332060000047
Or, when R is 2 When it is hydrogen, R 1 Optionally selected from hydrogen, cyano, nitro, ether linkages, R 3 Optionally selected from hydrogen, methyl, ether linkage, fluoro, neo-butyl, R 4 Optionally selected from hydrogen, methyl, ether linkage, fluoro, and neo-butyl;
or, when R is 1 And R 2 When both are hydrogen, R 3 And R 4 Are all new butyl;
or, when R is 2 Is hydrogen, R 1 In the case of a cyano group, the compound is,R 3 is hydrogen, R 4 Is a methyl group or a fluorine atom;
or, when R 2 Is hydrogen, R 1 When it is nitro, R 3 Is hydrogen, R 4 Is methyl;
or, when R is 2 Is hydrogen, R 1 When it is an ether bond, R 3 Is hydrogen or an ether bond, R 4 Is an ether bond.
Further, the structure of the compound is one of the following compounds:
Figure BDA0002386332060000048
/>
Figure BDA0002386332060000051
/>
Figure BDA0002386332060000061
the invention also provides a compound shown as a formula II, or a salt, a hydrate, a solvate or a pharmaceutical composition thereof:
Figure BDA0002386332060000071
wherein the content of the first and second substances,
R 5 is selected from
Figure BDA0002386332060000072
Or R 5 Is selected from
Figure BDA0002386332060000073
R y Optionally selected from hydrogen and C 2 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl radical, C 1 -C 6 Alkylene radical, C 1 -C 6 An alkynyl group.
Further, the structure of the compound is one of the following compounds:
Figure BDA0002386332060000074
the invention also provides a compound shown as a formula III, or a salt, a hydrate, a solvate or a pharmaceutical composition thereof:
Figure BDA0002386332060000075
wherein the content of the first and second substances,
R 6 optionally selected from peptide bonds, amino groups or
Figure BDA0002386332060000076
Or R 6 Is composed of
Figure BDA0002386332060000077
R x Is optionally selected from hydrogen, C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl radical, C 2 -C 6 Alkylene radical, C 2 -C 6 Alkynyl, amino-C 1-3 Alkyl, -N- (C) 1- C 3 Alkyl radical) 2 Hydroxy, hydroxy-C 1- C 3 Alkyl or hydroxy-C 3 -C 6 A cycloalkyl group.
Further, the structure of the compound is one of the following compounds:
Figure BDA0002386332060000084
the invention also provides a preparation method of the compound, which comprises the following steps:
step 1:
Figure BDA0002386332060000081
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, carrying out suction filtration under reduced pressure, rinsing until filtrate is colorless, and carrying out vacuum drying to obtain an intermediate I;
step 2:
Figure BDA0002386332060000082
dissolving the intermediate I, the raw material A, tris (dibenzylidene-BASE acetone) dipalladium, 2-dicyclohexyl phosphorus-2, 4, 6-triisopropyl biphenyl and anhydrous t-BuOLi by using 1, 4-dioxane, replacing argon for 3 times, moving to 70 ℃ for reaction, monitoring the reaction process, cooling to room temperature after the reaction is finished, filtering, concentrating under reduced pressure, extracting residues, concentrating an organic layer, and performing column chromatography separation to obtain a target product compound;
wherein R is 1 、R 2 、R 3 、R 4 And the aforementioned R 1 、R 2 、R 3 、R 4 The same;
preferably, in step 2, feed a is a substituted bromide, optionally selected from the group consisting of compounds of the following structures:
Figure BDA0002386332060000083
/>
Figure BDA0002386332060000091
more preferably still, the first and second liquid crystal compositions are,
in the step 1, meOH and ether are used for rinsing in the rinsing process after the reaction is finished;
and/or, in the step 2, saturated NaHCO is used for the extraction process after the reaction is finished 3 Extracting with aqueous solution and DCM;
and/or, the progress of the reaction is monitored by TLC.
The invention provides a preparation method of the compound, which comprises the following steps:
step (1):
Figure BDA0002386332060000101
dissolving 2-acetylphenothiazine and 4-methylbenzene sulfonyl hydrazide 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, carrying out suction filtration under reduced pressure, rinsing until filtrate is colorless, and carrying out vacuum drying to obtain an intermediate I;
step (2):
Figure BDA0002386332060000102
dissolving the intermediate I, the raw material A, tris (dibenzylidene-BASE acetone) dipalladium, 2-dicyclohexyl phosphorus-2, 4, 6-triisopropyl biphenyl and anhydrous t-BuOLi by using 1, 4-dioxane, replacing argon for 3 times, moving to 70 ℃ for reaction, monitoring the reaction process, cooling to room temperature after the reaction is finished, filtering, concentrating under reduced pressure, extracting residues, concentrating an organic layer, and performing column chromatography separation to obtain a target product compound;
wherein R is 5 And the aforementioned R 5 The same;
preferably, in step (2), feed a is a substituted bromide, optionally selected from the group consisting of compounds of the following structures:
Figure BDA0002386332060000103
more preferably still, the first and second liquid crystal compositions are,
in the step (1), during rinsing after the reaction is finished, meOH and diethyl ether are used for rinsing;
and/or, in the step (2), the extraction process after the reaction is finished,with saturated NaHCO 3 Extracting with aqueous solution and DCM;
and/or, the monitoring of the progress of the reaction is monitored by TLC.
The invention also provides a preparation method of the compound, which comprises the following steps:
step A:
Figure BDA0002386332060000111
dissolving 2-acetylphenothiazine and 4-methylbenzene sulfonyl hydrazide 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, carrying out suction filtration under reduced pressure, rinsing until filtrate is colorless, and carrying out vacuum drying to obtain an intermediate I;
and B:
Figure BDA0002386332060000112
dissolving the intermediate I, the raw material A, tris (dibenzylidene-BASE acetone) dipalladium, 2-dicyclohexyl phosphorus-2, 4, 6-triisopropyl biphenyl and anhydrous t-BuOLi by using 1, 4-dioxane, replacing argon for 3 times, moving to 70 ℃ for reaction, monitoring the reaction process, cooling to room temperature after the reaction is finished, filtering, concentrating under reduced pressure, extracting residues, concentrating an organic layer, and performing column chromatography separation to obtain a target product compound;
wherein R is 6 And the aforementioned R 6 The same;
preferably, in said step B, the feedstock a is a substituted bromide, optionally selected from the group consisting of compounds of the following structures:
Figure BDA0002386332060000113
more preferably, the amount of the organic solvent is,
in the step A, meOH and ether are used for rinsing in the rinsing process after the reaction is finished;
and/or, in the step B, saturated NaHCO is used for the extraction process after the reaction is finished 3 Extracting with aqueous solution and DCM;
and/or, the progress of the reaction is monitored by TLC.
The invention also provides the application of the compound or the salt thereof, the hydrate thereof, the solvate thereof or the pharmaceutical composition thereof in preparing targeted drugs for inhibiting cell iron death;
preferably, the medicament is a medicament for treating neurodegenerative diseases, cerebral stroke, cardiovascular diseases, parkinsonism, renal failure, diabetic complications and/or cancer;
more preferably, the cerebral apoplexy is cerebral infarction, hemorrhagic apoplexy, cerebral ischemia-reperfusion injury.
The invention also provides the use of the aforementioned compound, or a salt thereof, or a hydrate thereof, or a solvate thereof, or a pharmaceutical composition thereof, in the preparation of an oral or intravenous formulation comprising at least one of the aforementioned compounds, or a salt thereof, or a hydrate thereof, or a solvate thereof, or a pharmaceutical composition thereof, together with pharmaceutically acceptable excipients and/or adjuvants.
The invention also provides an iron death inhibitor which is prepared by taking the compound, or the salt, the hydrate, the solvate or the pharmaceutical composition thereof as an active ingredient.
The compounds and derivatives provided in the present invention may be named according to the IUPAC (international union of pure and applied chemistry) or CAS (chemical abstracts service, columbus, OH) naming system.
Definitions of terms used in connection with the present invention: the initial definitions provided herein for a group or term apply to that group or term throughout the specification unless otherwise indicated; for terms not specifically defined herein, the meanings that would be given to them by a person skilled in the art are to be given in light of the disclosure and the context.
"substituted" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
The structures of the compounds in the invention are all structures capable of stably existing.
The minimum and maximum carbon atom contents of the hydrocarbon groups in the present invention are indicated by prefixes, e.g. prefix (C) a ～C b ) Alkyl means any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, C 1 ～C 6 Alkyl means a straight or branched chain alkyl group containing 1 to 6 carbon atoms; c 2 ～C 6 Alkenyl means a straight or branched chain alkenyl group containing 2 to 6 carbon atoms; c 2 ～C 6 Alkynyl refers to straight or branched chain alkynyl containing 2 to 6 carbon atoms; c 3 ～C 6 Cycloalkyl means a monocyclic or polycyclic cycloalkyl group consisting of 3 to 6 carbon atoms, wherein the cycloalkyl group has no double bond.
"amino-C" in the present invention 1-3 Alkyl is-NHR z Wherein R is z Is C 1 ～C 3 An alkyl group; "-N- (C) 1 ～C 3 Alkyl radical) 2 "is-NR z1 R z2 Wherein R is z1 And R z2 Are all C 1 ～C 3 An alkyl group; "hydroxy-C 1- C 3 Alkyl group "," hydroxy-C 3 -C 6 Cycloalkyl "is-OR a Wherein R is a Is C 1 ～C 3 Alkyl or C 3 ～C 6 A cycloalkyl group.
"New butyl" as used herein refers to "t-butyl".
The invention synthesizes a new compound capable of inhibiting iron death, and the compound has good inhibition effect on iron death, and especially the inhibition effect of the compounds 9, 43, 49, 50 and 59 on iron death is obvious. Meanwhile, the compound has good inhibitory action on cerebral infarction, and particularly the compound 49 has remarkable effect on inhibiting cerebral infarction. The compound can be used as a main active ingredient for preparing iron death inhibitors, medicaments for treating diseases related to iron death and medicaments for preventing and treating cerebral infarction, 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.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIG. 1 is a graph showing the inhibition of Ferroptosis by compounds 9, 49, 50 and 59 of the present invention and a positive control group.
FIG. 2 is a statistical chart of cerebral infarction ranges of a compound No. 49, a compound No. CN201810393712.2, and a positive drug (Liproxstatin-1 and Butylphthalamide) for treating cerebral apoplexy, which are disclosed by the invention; in the figure, control is a model Control group, no.1 is a positive drug group Liproxstatin-1, no.2 is a positive drug group butyl phthalide, no.3 is a CN201810393712.2 No. 38 compound group, and No.4 is a compound group 49 of the invention.
FIG. 3 is a statistical chart of cerebral infarction inhibition rates of a compound No. 49, a compound No. CN201810393712.2, and a positive drug (Liproxstatin-1 and Butylphthalamide) on cerebral apoplexy treatment according to the invention; in the figure, control is a model Control group, no.1 is a positive drug group Liproxstatin-1, no.2 is a positive drug group butyl phthalide, no.3 is a CN201810393712.2 No. 38 compound group, and No.4 is a compound group 49 of the invention.
Detailed Description
The raw materials and equipment used in the embodiment of the present invention are known products and obtained by purchasing commercially available products.
EXAMPLE 1 Synthesis of (E) -N' - (1- (10H-phenothiazin-2-yl) ethylene) -4-methylbenzenesulfonylhydrazide (intermediate I)
Figure BDA0002386332060000131
2-acetylphenothiazine (10.0g, 41.44mmol, 1.0eq) and 4-methylbenzenesulfonyl hydrazide (7.72g, 41.44mmol, 1.0eq) were dissolved in 100mLMeOH, 1mLHOAc was added, the mixture was moved to 60 ℃ for reaction, and the reaction was monitored by TLC, and after about 4 hours, the reaction was completed. 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 (15 g) in 88.4% yield. Of intermediate I 1 HNMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )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] + 。
example 2 preparation of 2- (1-phenylethyl) -10H-phenothiazine (Compound 1)
The synthetic route is as follows:
Figure BDA0002386332060000141
intermediate I (120mg, 0.293mmol, 1.2eq), bromobenzene (38mg, 0.244mmol, 1.0eq), tris (dibenzylidene-BASE acetone) dipalladium (0) Pd 2 (dpa) 3 (24mg, 0.03mmol, 0.1eq), 2-dicyclohexylphosphonium-2, 4, 6-triisopropylbiphenyl X-phos (25mg, 0.03mmol, 0.2eq) and anhydrous t-BuOLi (43mg, 0.537mmol, 2.2eq) were dissolved in 10mL1, 4-dioxane, argon was replaced 3 times, the reaction was carried out at 70 ℃ and monitored by TLC, and the reaction was completed after about 4 hours. Cooling to room temperature, filtering with celite, concentrating the reaction under reduced pressure, and adding saturated NaHCO to the residue 3 Aqueous solution/DCM extraction (volume ratio 1.
Process for preparation of Compound 1 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.50(s,1H),7.29(t,J＝7.4Hz,2H),7.22(d,J＝7.1Hz,2H),7.18(d,J＝7.1Hz,1H),6.95(dd,J＝10.9,4.4Hz,1H),6.91–6.85(m,1H),6.82(d,J＝7.9Hz,1H),6.73(td,J＝7.6,1.0Hz,1H),6.71–6.62(m,2H),6.54(d,J＝1.4Hz,1H),4.00(q,J＝7.1Hz,1H),1.50(d,J＝7.2Hz,3H)。
HRMS m/z(ESI)calcd for C 20 H 17 NS[M+H] + 303.1082found:403.1085。
example 3 preparation of methyl 4- (1- (10H-phenothiazin-2-yl) vinyl) benzoic acid (Compound 2)
The synthesis route is as follows:
Figure BDA0002386332060000142
process for preparation of Compound 2 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.57(s,1H),7.97(d,＝8.J 0Hz,2H),7.46(d,J＝7.8Hz,2H),7.02–6.95(m,1H),6.93(dd,J＝13.6,6.1Hz,2H),6.75(t,J＝6.6Hz,2H),6.63(d,J＝7.7Hz,1H),6.55(s,1H),5.54(d,J＝14.4Hz,2H),3.87(s,3H)。
HRMS m/z(ESI)calcd for C 22 H 17 NO 2 S[M+H] + 360.1058found:360.1062。
the preparation method is the same as that of the compound 1, and the yield is 84.1%.
Example 4 preparation of 2- (1- (4- (trifluoromethyl) phenyl) vinyl) -10H-phenothiazine (Compound 3)
The synthesis route is as follows:
Figure BDA0002386332060000151
process for preparation of Compound 3 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.57(s,1H),7.75(d,J＝8.2Hz,2H),7.53(d,J＝8.0Hz,2H),7.01–6.88(m,3H),6.81–6.72(m,2H),6.62(dd,J＝7.9,0.9Hz,1H),6.54(d,J＝1.7Hz,1H),5.59(s,1H),5.51(s,1H)。
HRMS m/z(ESI)calcd for C 21 H 14 F 3 NS[M+H] + 370.0877found:370.0875。
the preparation method is the same as that of the compound 1, and the yield is 73.1%.
Example 5 preparation of 2- (1- (4-ethylphenyl) vinyl) -10H-phenothiazine (Compound 4)
The synthesis route is as follows:
Figure BDA0002386332060000152
process for preparation of Compound 4 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.56(s,1H),7.22(s,4H),6.96(dd,J＝7.6,1.3Hz,1H),6.91(d,J＝7.9Hz,2H),6.75(dd,J＝7.6,1.4Hz,2H),6.63(dd,J＝7.9,1.0Hz,1H),6.58(d,J＝1.8Hz,1H),5.37(dd,J＝11.5,0.9Hz,2H),2.62(q,J＝7.6Hz,2H),1.20(t,J＝7.6Hz,3H)。
HRMS m/z(ESI)calcd for C 22 H 19 NS[M+H] + 330.1316found:330.1318。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 72.8%.
Example 6 preparation of 2- (1- (4-trifluoromethoxyphenyl) vinyl) -10H-phenothiazine (Compound 5)
The synthesis route is as follows:
Figure BDA0002386332060000161
process for preparation of Compound 5 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.57(s,1H),7.44(d,J＝8.8Hz,2H),7.37(d,J＝8.4Hz,2H),6.98(dd,J＝11.3,3.9Hz,1H),6.96–6.88(m,2H),6.81–6.70(m,2H),6.62(d,J＝7.9Hz,1H),6.56(d,J＝1.6Hz,1H),5.47(d,J＝20.6Hz,2H)。
HRMS m/z(ESI)calcd for C 22 H 19 NS[M+H] + 386.4122found:386.4125。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 63.4%.
Example 7 preparation of 2- (1- (p-toluene) vinyl) -10H-phenothiazine (Compound 6)
The synthesis route is as follows:
Figure BDA0002386332060000162
process for preparation of Compound 6 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.55(s,1H),7.19(s,4H),6.97(dd,J＝11.3,3.9Hz,1H),6.95–6.88(m,2H),6.81–6.70(m,2H),6.62(d,J＝7.9Hz,1H),6.57(d,J＝1.6Hz,1H),5.36(d,J＝13.4Hz,2H),2.32(s,3H)。
HRMS m/z(ESI)calcd for C 21 H 17 NS[M+H] + 316.1160found:316.1163。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 83.5%.
Example 8 preparation of 2- (1- (4-butylphenyl) vinyl) -10H-phenothiazine (Compound 7)
The synthesis route is as follows:
Figure BDA0002386332060000163
process for preparation of Compound 7 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.56(s,1H),7.27–7.15(m,4H),7.05–6.94(m,1H),6.91(d,J＝7.9Hz,2H),6.83–6.71(m,2H),6.63(d,J＝7.9Hz,1H),6.58(d,J＝1.6Hz,1H),5.37(d,J＝4.9Hz,2H),2.64–2.55(m,2H),1.56(dd,J＝15.2,7.8Hz,2H),1.33(dd,J＝14.8,7.4Hz,2H),0.91(t,J＝7.3Hz,3H)。
HRMS m/z(ESI)calcd for C 24 H 23 NS[M+H] + 358.1629found:358.1630。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 68.5%.
Example 9 preparation of 2- (1- (4-isopropylphenyl) vinyl) -10H-phenothiazine (Compound 8)
The synthesis route is as follows:
Figure BDA0002386332060000171
process for preparation of Compound 8 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.57(s,1H),7.34–7.16(m,4H),6.97(td,J＝7.9,1.3Hz,1H),6.91(d,J＝7.9Hz,2H),6.75(dd,J＝10.8,4.4Hz,2H),6.63(d,J＝7.9Hz,1H),6.59(d,J＝1.7Hz,1H),5.37(d,J＝8.4Hz,2H),3.00–2.81(m,1H),1.22(d,J＝6.9Hz,6H)。
HRMS m/z(ESI)calcd for C 23 H 21 NS[M+H] + 344.1473found:344.1476。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 76.2%.
Example 10 preparation of N- (4- (1- (10H-phenothiazin-2-yl) vinyl) phenyl) acetamide (Compound 9)
The synthesis route is as follows:
Figure BDA0002386332060000172
process for preparation of compound 9 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ10.00(s,1H),8.56(s,1H),7.58(d,J＝8.5Hz,2H),7.24(d,J＝8.5Hz,2H),7.01–6.94(m,1H),6.91(d,J＝7.9Hz,2H),6.75(dd,J＝7.8,1.9Hz,2H),6.63(d,J＝7.4Hz,1H),6.58(d,J＝1.6Hz,1H),5.35(s,2H),2.05(s,3H)。
HRMS m/z(ESI)calcd for C 22 H 18 N 2 OS[M+H] + 359.1218found:359.1220。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 75.7%.
Example 11 preparation of N- (4- (1- (10H-phenothiazin-2-yl) vinyl) phenyl) urea (Compound 10)
The synthesis route is as follows:
Figure BDA0002386332060000181
process for preparation of Compound 10 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.61(s,1H),8.55(s,1H),7.40(d,J＝8.6Hz,2H),7.17(d,J＝8.6Hz,2H),7.05–6.94(m,1H),6.94–6.87(m,2H),6.78–6.71(m,2H),6.66–6.61(m,1H),6.59(d,J＝1.7Hz,1H),5.85(s,2H),5.31(d,J＝5.7Hz,2H)。
HRMS m/z(ESI)calcd for C 21 H 17 N 3 OS[M+H] + 360.1171found:360.1174。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 84.8%.
Example 12 preparation of 2- (1- (4-cyclohexylphenyl) vinyl) -10H-phenothiazine (Compound 11)
The synthesis route is as follows:
Figure BDA0002386332060000182
process for preparation of Compound 11 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.57(s,1H),7.22(s,4H),6.97(t,J＝7.6Hz,1H),6.91(d,J＝7.9Hz,2H),6.79–6.70(m,2H),6.62(d,J＝7.8Hz,1H),6.58(d,J＝1.6Hz,1H),5.36(d,J＝2.6Hz,2H),1.80(d,J＝9.5Hz,4H),1.70(d,J＝12.7Hz,1H),1.39(d,J＝8.5Hz,4H),1.29–1.18(m,1H)。
HRMS m/z(ESI)calcd for C 26 H 25 NS[M+H] + 384.1786found:384.1788。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 62.8%.
Example 13 preparation of 2- (1- (4-isobutylphenyl) vinyl) -10H-phenothiazine (Compound 12)
The synthesis route is as follows:
Figure BDA0002386332060000183
process for preparation of Compound 12 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.56(s,1H),7.22(d,J＝8.1Hz,2H),7.16(d,J＝8.1Hz,2H),6.96(dd,J＝10.8,4.5Hz,1H),6.91(d,J＝7.9Hz,2H),6.74(dd,J＝12.2,4.2Hz,2H),6.70–6.61(m,1H),6.59(d,J＝1.7Hz,1H),5.37(s,2H),2.46(d,J＝7.1Hz,2H),1.85(dt,J＝13.5,6.8Hz,1H),0.88(d,J＝6.6Hz,6H).
HRMS m/z(ESI)calcd for C 24 H 23 NS[M+H] + 358.1629found:358.1633。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 76.4%.
Example 14 preparation of 4- (1- (10H-phenothiazin-2-yl) vinyl) benzaldehyde (Compound 13)
The synthesis route is as follows:
Figure BDA0002386332060000191
process for preparation of Compound 13 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.56(s,1H),7.22(d,J＝8.1Hz,2H),7.16(d,J＝8.1Hz,2H),6.96(dd,J＝10.8,4.5Hz,1H),6.91(d,J＝7.9Hz,2H),6.74(dd,J＝12.2,4.2Hz,2H),6.70–6.61(m,1H),6.59(d,J＝1.7Hz,1H),5.37(s,2H),2.46(d,J＝7.1Hz,2H),1.85(dt,J＝13.5,6.8Hz,1H),0.88(d,J＝6.6Hz,6H)。
HRMS m/z(ESI)calcd for C 21 H 15 NOS[M+H] + 330.0953found:330.0955。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 79.8%.
Example 15 preparation of 4- (4- (1- (10H-phenothiazin-2-yl) vinyl) phenyl) morpholine (Compound 14)
The synthesis route is as follows:
Figure BDA0002386332060000192
process for preparation of Compound 14 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.55(s,1H),7.17(d,J＝8.7Hz,2H),7.00–6.87(m,5H),6.78–6.71(m,2H),6.63(d,J＝7.1Hz,1H),6.59(d,J＝1.6Hz,1H),5.27(d,J＝18.8Hz,2H),3.80–3.65(m,4H),3.21–3.10(m,4H)。
HRMS m/z(ESI)calcd for C 24 H 22 N 2 OS[M+H] + 387.1531found:387.1533。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 74.2%.
Example 16 preparation of 4- (4- (1- (10H-phenothiazin-2-yl) vinyl) phenyl) morpholine (Compound 15)
The synthesis route is as follows:
Figure BDA0002386332060000201
process for preparation of Compound 15 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.63(s,1H),8.26(d,J＝7.7Hz,2H),7.64(dd,J＝19.7,8.5Hz,4H),7.46(d,J＝3.6Hz,4H),7.31(dt,J＝7.9,4.1Hz,2H),6.98(d,J＝7.9Hz,2H),6.93(d,J＝7.6Hz,1H),6.85(dd,J＝7.9,1.7Hz,1H),6.76(s,1H),6.71(d,J＝1.6Hz,1H),6.66(d,J＝7.9Hz,1H),5.56(d,J＝16.8Hz,2H)。
HRMS m/z(ESI)calcd for C 32 H 22 N 2 S[M+H] + 467.1582found:467.1583。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 79.8%.
Example 17 preparation of 2- (1- (10H-phenothiazin-2-yl) vinyl) aniline (Compound 16)
The synthesis route is as follows:
Figure BDA0002386332060000202
process for preparation of Compound 16 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.56(s,1H),7.09–7.02(m,1H),6.99–6.91(m,2H),6.91–6.85(m,2H),6.81(dd,J＝8.0,1.7Hz,1H),6.73(td,J＝7.6,1.1Hz,1H),6.69(d,J＝8.0Hz,1H),6.66–6.57(m,2H),6.55(d,J＝1.7Hz,1H),5.69(d,J＝1.2Hz,1H),5.17(d,J＝1.1Hz,1H),4.48(s,2H)。
HRMS m/z(ESI)calcd for C 20 H 16 N 2 S[M+H] + 317.1112found:317.1114。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 86.9%.
Example 18 preparation of 3- (1- (10H-phenothiazin-2-yl) vinyl) aniline (Compound 17)
The synthesis route is as follows:
Figure BDA0002386332060000203
process for preparation of compound 17 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.57(s,1H),6.98(dd,J＝18.2,8.0Hz,2H),6.91(d,J＝2.8Hz,1H),6.90(d,J＝3.9Hz,1H),6.79–6.76(m,1H),6.75(d,J＝3.0Hz,1H),6.64(d,J＝7.8Hz,1H),6.59(d,J＝1.4Hz,1H),6.53(d,J＝7.9Hz,1H),6.47(d,J＝1.6Hz,2H),5.30(d,J＝14.9Hz,2H),5.08(s,2H)。
HRMS m/z(ESI)calcd for C 20 H 16 N 2 S[M+H] + 317.1112found:317.1115。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 67.4%.
Example 19 preparation of 3- (1- (10H-phenothiazin-2-yl) vinyl) phenol (Compound 18)
The synthesis route is as follows:
Figure BDA0002386332060000211
process for preparation of Compound 18 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.57(s,1H),7.99(s,1H),7.89(d,J＝8.3Hz,2H),7.37(d,J＝8.3Hz,3H),6.95(ddd,J＝18.4,10.9,3.3Hz,3H),6.84–6.70(m,2H),6.62(d,J＝7.9Hz,1H),6.56(d,J＝1.7Hz,1H),5.49(d,J＝16.9Hz,2H)。
HRMS m/z(ESI)calcd for C 20 H 15 NOS[M+H] + 318.0953found:318.0955。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 83.4%.
Example 20 preparation of 2- (1- (3-Nitrophenyl) vinyl) -10H-phenothiazine (Compound 19)
The synthesis route is as follows:
Figure BDA0002386332060000212
process for preparation of compound 19 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.59(s,1H),8.23(d,J＝7.1Hz,1H),8.07(s,1H),7.78(d,J＝7.7Hz,1H),7.71(d,J＝7.9Hz,1H),7.06–6.87(m,3H),6.76(t,J＝7.0Hz,2H),6.63(d,J＝7.8Hz,1H),6.59(s,1H),5.60(d,J＝11.2Hz,2H)。
HRMS m/z(ESI)calcd for C 20 H 14 N 2 O 2 S[M+H] + 347.0854found:347.0824。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 64.1%.
Example 21 preparation of 3- (1- (10H-phenothiazin-2-yl) vinyl) benzenesulfonamide (Compound 20)
The synthesis route is as follows:
Figure BDA0002386332060000221
process for preparation of Compound 20 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.59(s,1H),7.81(d,J＝7.7Hz,1H),7.74(s,1H),7.64–7.50(m,2H),7.39(s,2H),7.05–6.87(m,3H),6.74(dd,J＝10.9,4.4Hz,2H),6.63(d,J＝7.8Hz,1H),6.56(d,J＝1.6Hz,1H),5.55(s,1H),5.46(s,1H)。
HRMS m/z(ESI)calcd for C 20 H 16 N 2 O 2 S 2 [M+H] + 381.0731found:381.0733。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 87.5%.
Example 22 preparation of 2- (1- (3-methoxyphenyl) vinyl) -10H-phenothiazine (Compound 21)
The synthesis route is as follows:
Figure BDA0002386332060000222
process for preparation of Compound 21 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.56(s,1H),7.30(t,J＝7.9Hz,1H),6.95(dd,J＝7.6,4.5Hz,2H),6.91(d,J＝7.9Hz,2H),6.84(dd,J＝8.3,4.9Hz,2H),6.75(dd,J＝7.8,1.4Hz,2H),6.62(d,J＝7.1Hz,1H),6.58(d,J＝1.7Hz,1H),5.42(d,J＝16.3Hz,2H),3.75(s,3H)。
HRMS m/z(ESI)calcd for C 21 H 17 NOS[M+H] + 332.1109found:332.1105。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 65.8%.
Example 23 preparation of 2- (1- (3-trifluoromethoxyphenyl) vinyl) -10H-phenothiazine (Compound 22)
The synthesis route is as follows:
Figure BDA0002386332060000223
process for preparation of Compound 22 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.59(s,1H),7.53(t,J＝8.0Hz,1H),7.48–7.31(m,2H),7.26(s,1H),6.95(dt,J＝14.3,6.9Hz,3H),6.75(t,J＝7.2Hz,2H),6.64(d,J＝7.8Hz,1H),6.58(s,1H),5.52(d,J＝13.2Hz,2H)。
HRMS m/z(ESI)calcd for C 21 H 14 F 3 NOS[M+H] + 386.0826found:386.0829。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 75.8%.
Example 24 preparation of 2- (1- (3-Isopropoxyphenyl) vinyl) -10H-phenothiazine (Compound 23)
The synthesis route is as follows:
Figure BDA0002386332060000231
process for preparation of compound 23 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.60(s,1H),7.27(t,J＝7.9Hz,1H),6.97(t,J＝7.6Hz,1H),6.90(t,J＝6.6Hz,3H),6.85(d,J＝7.6Hz,1H),6.76(dd,J＝15.9,8.1Hz,3H),6.65(d,J＝7.9Hz,1H),6.62(d,J＝1.1Hz,1H),5.41(d,J＝11.3Hz,2H),4.58(dd,J＝12.0,6.0Hz,1H),1.25(d,J＝6.0Hz,7H)。
HRMS m/z(ESI)calcd for C 23 H 21 NOS[M+H] + 360.1422found:360.1425。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 62.2%.
Example 25 preparation of 2- (1- (m-tolyl) vinyl) -10H-phenothiazine (Compound 24)
The synthesis route is as follows:
Figure BDA0002386332060000232
process for preparation of compound 24 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.57(s,1H),7.27(t,J＝7.6Hz,1H),7.16(d,J＝7.6Hz,1H),7.14–7.03(m,2H),7.01–6.94(m,1H),6.93(dd,J＝16.7,4.6Hz,2H),6.82–6.71(m,2H),6.63(d,J＝7.9Hz,1H),6.57(d,J＝1.6Hz,1H),5.41(s,1H),5.36(s,1H),2.31(s,3H)。
HRMS m/z(ESI)calcd for C 21 H 17 NS[M+H] + 316.1160found:316.1165。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 73.8%.
Example 26 preparation of 2- (1- (3-tert-butylphenyl) vinyl) -10H-phenothiazine (Compound 25)
The synthesis route is as follows:
Figure BDA0002386332060000241
process for preparation of Compound 25 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.58(s,1H),7.39(d,J＝7.9Hz,1H),7.31(dd,J＝13.9,6.2Hz,2H),7.07(d,J＝7.6Hz,1H),6.96(dd,J＝7.6,1.1Hz,1H),6.91(d,J＝7.9Hz,2H),6.75(dd,J＝7.6,1.3Hz,2H),6.62(dd,J＝11.6,4.8Hz,2H),5.44(s,1H),5.38(s,1H),1.28(s,9H)。
HRMS m/z(ESI)calcd for C 24 H 23 NS[M+H] + 358.1629found:358.1625。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 69.5%.
Example 27 preparation of 3- (1- (10H-phenothiazin-2-yl) vinyl) benzamide (Compound 26)
The synthesis route is as follows:
Figure BDA0002386332060000242
process for preparation of compound 26 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.57(s,1H),8.03(s,1H),7.86(d,J＝7.2Hz,1H),7.83(s,1H),7.50–7.41(m,2H),7.38(s,1H),6.95(ddd,J＝18.0,11.0,3.4Hz,3H),6.75(dd,J＝12.2,4.3Hz,2H),6.62(d,J＝7.9Hz,1H),6.56(d,J＝1.6Hz,1H),5.48(d,J＝20.9Hz,2H)。
HRMS m/z(ESI)calcd for C 21 H 16 N 2 OS[M+H] + 345.1062found:345.1064。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 69.5%.
Example 28 preparation of 2- (1- (3-isopropylphenyl) vinyl) -10H-phenothiazine (Compound 27)
The synthesis route is as follows:
Figure BDA0002386332060000243
process for preparation of compound 27 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.57(s,1H),7.29(d,J＝7.5Hz,1H),7.23(d,J＝7.8Hz,1H),7.18(s,1H),7.08(d,J＝7.5Hz,1H),6.96(dd,J＝7.6,1.2Hz,1H),6.95–6.88(m,2H),6.75(dd,J＝7.8,1.8Hz,2H),6.63(dd,J＝7.9,0.9Hz,1H),6.59(d,J＝1.7Hz,1H),5.49–5.31(m,2H),3.01–2.81(m,1H),1.22(dd,J＝16.0,8.7Hz,6H)。
HRMS m/z(ESI)calcd for C 23 H 21 NS[M+H] + 344.1473found:344.1475。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 75.4%.
Example 29 preparation of Ethyl 3- (1- (10H-phenothiazin-2-yl) vinyl) benzoic acid (Compound 28)
The synthesis route is as follows:
Figure BDA0002386332060000251
process for preparation of Compound 28 1 H NMR and HRThe MS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.57(s,1H),7.96(d,J＝7.4Hz,1H),7.84(s,1H),7.57(dt,J＝15.1,7.7Hz,2H),7.01–6.95(m,1H),6.92(t,J＝7.0Hz,2H),6.75(t,J＝7.5Hz,2H),6.63(d,J＝7.8Hz,1H),6.56(d,J＝1.5Hz,1H),5.54(s,1H),5.45(s,1H),4.32(q,J＝7.1Hz,2H),1.28(dt,J＝8.0,6.2Hz,3H)。
HRMS m/z(ESI)calcd for C 23 H 19 NO 2 S[M+H] + 374.1215found:374.1212。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 68.2%.
Example 30 preparation of 2- (1- ([ 1,1' -Diphenyl ] -3-yl) vinyl) -10H-phenothiazine (Compound 29)
The synthesis route is as follows:
Figure BDA0002386332060000252
process for preparation of compound 29 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.58(s,1H),7.65(dd,J＝9.4,2.2Hz,3H),7.55(s,1H),7.48(dd,J＝16.8,7.8Hz,3H),7.38(d,J＝7.3Hz,1H),7.29(d,J＝7.8Hz,1H),6.94(dt,J＝15.3,4.2Hz,3H),6.81(dd,J＝8.0,1.8Hz,1H),6.75(dd,J＝7.5,1.0Hz,1H),6.62(dd,J＝8.6,1.2Hz,2H),5.50(d,J＝3.1Hz,2H)。
HRMS m/z(ESI)calcd for C 26 H 19 NS[M+H] + 378.1316found:378.1318。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 76.8%.
Example 31 preparation of 2- (1- (3- (trifluoromethyl) phenyl) vinyl) -10H-phenothiazine (Compound 30)
The synthesis route is as follows:
Figure BDA0002386332060000261
process for preparation of Compound 30 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.58(s,1H),7.74(d,J＝7.5Hz,1H),7.62(dd,J＝10.9,7.1Hz,3H),7.03–6.87(m,3H),6.82–6.71(m,2H),6.66–6.59(m,1H),6.55(d,J＝1.7Hz,1H),5.54(d,J＝20.9Hz,2H)。
HRMS m/z(ESI)calcd for C 21 H 15 F 3 NS[M+H] + 370.0877found:370.0879。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 67.8%.
Example 32 preparation of methyl 3- (1- (10H-phenothiazin-2-yl) vinyl) benzoic acid (Compound 31)
The synthesis route is as follows:
Figure BDA0002386332060000262
process for preparation of Compound 31 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.56(s,1H),8.01–7.90(m,1H),7.83(d,J＝1.5Hz,1H),7.67–7.60(m,1H),7.56(t,J＝7.7Hz,1H),6.97(td,J＝7.8,1.4Hz,1H),6.92(t,J＝7.3Hz,2H),6.75(td,J＝7.5,1.4Hz,2H),6.62(dd,J＝7.9,0.9Hz,1H),6.56(d,J＝1.8Hz,1H),5.49(d,J＝26.7Hz,2H),3.85(s,3H)。
HRMS m/z(ESI)calcd for C 22 H 17 NO 2 S[M+H] + 360.1058found:360.1055。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 61.9%.
Example 33, preparation of 3- (1- (10H-phenothiazin-2-yl) vinyl) benzonitrile (compound 32) the synthetic route is as follows:
Figure BDA0002386332060000263
process for preparation of compound 32 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.58(s,1H),7.87–7.81(m,1H),7.78(s,1H),7.64–7.58(m,2H),7.03–6.95(m,1H),6.92(t,J＝7.6Hz,2H),6.79–6.70(m,2H),6.67–6.59(m,1H),6.54(d,J＝1.7Hz,1H),5.55(d,J＝17.8Hz,2H)。
HRMS m/z(ESI)calcd for C 21 H 14 N 2 S[M+H] + 327.0956found:327.0959。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 73.2%.
Example 34 preparation of (3- (1- (10H-phenothiazin-2-yl) vinyl) phenyl) benzophenone (Compound 33)
The synthesis route is as follows:
Figure BDA0002386332060000271
process for preparation of compound 33 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.62(s,1H),7.76(t,J＝6.8Hz,3H),7.70–7.64(m,2H),7.62(d,J＝7.7Hz,1H),7.59(s,1H),7.54(t,J＝7.6Hz,2H),6.98(dd,J＝10.8,4.4Hz,1H),6.92(dd,J＝7.3,4.4Hz,2H),6.84–6.72(m,2H),6.65(dd,J＝10.6,4.8Hz,2H),5.52(d,J＝17.4Hz,2H)。
HRMS m/z(ESI)calcd for C 27 H 19 NOS[M+H] + 406.1266found:406.1261。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 76.4%.
Example 35 preparation of 2- (1- (3- (difluoromethyl) phenyl) vinyl) -10H-phenothiazine (Compound 34)
The synthesis route is as follows:
Figure BDA0002386332060000272
process for preparation of compound 34 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.59(s,1H),7.57(s,1H),7.47(d,J＝6.5Hz,3H),6.95(dt,J＝15.3,7.2Hz,3H),6.76(d,J＝5.9Hz,2H),6.63(d,J＝7.8Hz,1H),6.57(s,1H),5.49(d,J＝25.2Hz,2H)。
HRMS m/z(ESI)calcd for C 21 H 15 F 2 NS[M+H] + 352.0972found:352.0975。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 83.8%.
Example 36 preparation of 2- (1- (3- (benzyloxy) phenyl) vinyl) -10H-phenothiazine (Compound 35)
The synthesis route is as follows:
Figure BDA0002386332060000281
process for preparation of compound 35 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.56(s,1H),7.23(t,J＝7.9Hz,1H),7.02–6.87(m,4H),6.83(s,1H),6.80–6.68(m,3H),6.61(dd,J＝14.3,4.7Hz,2H),5.39(d,J＝23.4Hz,2H),3.84–3.63(m,4H),3.18–2.98(m,4H)。
HRMS m/z(ESI)calcd for C 27 H 21 NOS[M+H] + 408.1422found:408.1425。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 68.9%.
EXAMPLE 37 preparation of 4- (3- (1- (10H-phenothiazine example oxazin-2-yl) vinyl) phenyl) morpholine (Compound 36)
The synthesis route is as follows:
Figure BDA0002386332060000282
process for preparation of compound 36 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.56(s,1H),7.23(t,J＝7.9Hz,1H),7.02–6.87(m,4H),6.83(s,1H),6.80–6.68(m,3H),6.61(dd,J＝14.3,4.7Hz,2H),5.39(d,J＝23.4Hz,2H),3.84–3.63(m,4H),3.18–2.98(m,4H)。
HRMS m/z(ESI)calcd for C 24 H 22 N 2 OS[M+H] + 387.1531found:387.1533。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 83.3%.
Example 38 preparation of 4- (1- (10H-phenothiazin-2-yl) vinyl) -2-methylbenzonitrile (Compound 37)
The synthesis route is as follows:
Figure BDA0002386332060000283
process for preparation of compound 37 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.57(s,1H),7.77(d,J＝8.0Hz,1H),7.41(s,1H),7.29(d,J＝8.0Hz,1H),6.97(dd,J＝10.9,4.4Hz,1H),6.92(t,J＝7.1Hz,2H),6.79–6.70(m,2H),6.65–6.59(m,1H),6.53(d,J＝1.7Hz,1H),5.58(s,1H),5.51(s,1H),2.49(s,3H)。
HRMS m/z(ESI)calcd for C 22 H 16 N 2 S[M+H] + 341.1112found:341.1115。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 75.8%.
Example 39 preparation of 2- (1- (3-methyl-4-nitrophenyl) vinyl) -10H-phenothiazine (Compound 38)
The synthesis route is as follows:
Figure BDA0002386332060000291
process for preparation of Compound 38 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.57(s,1H),8.00(d,J＝8.4Hz,1H),7.45(s,1H),7.35(dd,J＝8.4,1.5Hz,1H),6.95(ddd,J＝20.0,13.2,5.4Hz,3H),6.76(d,J＝8.0Hz,2H),6.62(dd,J＝7.9,0.8Hz,1H),6.54(d,J＝1.7Hz,1H),5.61(s,1H),5.54(s,1H),2.54(s,3H)。
HRMS m/z(ESI)calcd for C 21 H 16 N 2 O 2 S[M+H] + 361.1011found:361.1015。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 73.7%.
EXAMPLE 40 preparation of 2- (1- (3, 4-Dimethoxyphenyl) vinyl) -10H-phenothiazine (Compound 39)
The synthesis route is as follows:
Figure BDA0002386332060000292
process for preparation of Compound 39 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.56(s,1H),6.93(ddd,J＝20.3,8.4,3.1Hz,5H),6.78(ddd,J＝13.3,8.1,1.9Hz,3H),6.62(t,J＝5.3Hz,2H),5.35(d,J＝5.9Hz,2H),3.76(d,J＝13.3Hz,6H)。
HRMS m/z(ESI)calcd for C 22 H 19 NO 2 S[M+H] + 362.1215found:361.1218。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 54.4%.
Example 41 preparation of 4- (1- (10H-phenothiazin-2-yl) vinyl) -2-fluorobenzonitrile (Compound 40)
The synthesis route is as follows:
Figure BDA0002386332060000301
process for preparation of Compound 40 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.58(s,1H),7.93(t,J＝7.5Hz,1H),7.49(d,J＝10.6Hz,1H),7.32(d,J＝8.0Hz,1H),6.95(dt,J＝17.1,8.2Hz,3H),6.75(dd,J＝15.3,7.7Hz,2H),6.63(d,J＝7.8Hz,1H),6.55(s,1H),5.65(d,J＝1.9Hz,2H)。
HRMS m/z(ESI)calcd for C 21 H 13 FN 2 S[M+H] + 345.0862found:345.0866。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 76.5%.
Example 42 preparation of 2- (1- (3, 5-di-tert-butylphenyl) vinyl) -10H-phenothiazine (Compound 41)
The synthesis route is as follows:
Figure BDA0002386332060000302
process for preparation of Compound 41 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.58(s,1H),7.40(t,J＝1.7Hz,1H),7.10(d,J＝1.8Hz,2H),6.96(td,J＝7.8,1.4Hz,1H),6.91(d,J＝7.9Hz,2H),6.80–6.70(m,2H),6.62(dd,J＝8.0,1.2Hz,2H),5.47–5.31(m,2H),1.25(d,J＝22.6Hz,18H)。
HRMS m/z(ESI)calcd for C 28 H 31 NS[M+H] + 414.2255found:414.2259。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 75.6%.
Example 43 preparation of 2- (1- (3, 4, 5-trimethoxyphenyl) vinyl) -10H-phenothiazine (Compound 42)
The synthesis route is as follows:
Figure BDA0002386332060000303
of Compound 42 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.57(s,1H),6.97(t,J＝7.6Hz,1H),6.91(d,J＝7.9Hz,2H),6.85–6.71(m,2H),6.63(d,J＝6.1Hz,2H),6.56(s,2H),5.41(d,J＝10.9Hz,2H),3.72(d,J＝21.8Hz,9H)。
HRMS m/z(ESI)calcd for C 23 H 21 NO 3 S[M+H] + 392.1320found:392.1321。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 72.7%.
Example 44 preparation of N- (5- (1- (10H-phenothiazin-2-yl) vinyl) pyridin-2-yl) acetamide (Compound 43)
The synthesis route is as follows:
Figure BDA0002386332060000311
process for preparation of Compound 43 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ10.59(s,1H),8.57(s,1H),8.24(d,J＝2.2Hz,1H),8.08(d,J＝8.6Hz,1H),7.69(dd,J＝8.6,2.4Hz,1H),6.96(d,J＝7.8Hz,1H),6.92(t,J＝6.7Hz,2H),6.82–6.70(m,2H),6.65–6.60(m,1H),6.58(d,J＝1.7Hz,1H),5.46(d,J＝11.9Hz,2H),2.11(s,3H)。
HRMS m/z(ESI)calcd for C 21 H 17 N 3 OS[M+H] + 360.1171found:360.1175。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 76.3%.
Example 45 preparation of 5- (1- (10H-phenothiazin-2-yl) vinyl) pyridin-2-amine (Compound 44)
The synthesis route is as follows:
Figure BDA0002386332060000312
process for preparation of compound 44 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.56(s,1H),7.86(d,J＝2.2Hz,1H),7.30(dd,J＝8.6,2.4Hz,1H),6.96(dd,J＝7.6,1.2Hz,1H),6.94–6.87(m,2H),6.79–6.70(m,2H),6.67–6.58(m,2H),6.44(d,J＝8.6Hz,1H),6.08(s,2H),5.42–5.14(m,2H)。
HRMS m/z(ESI)calcd for C 19 H 15 N 3 S[M+H] + 318.1065found:318.1069。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 68.9%.
Example 46 preparation of 4- (5- (1- (10H-phenothiazin-2-yl) vinyl) pyridin-2-yl) morpholine (Compound 45)
The synthesis route is as follows:
Figure BDA0002386332060000321
process for preparation of Compound 45 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.55(s,1H),8.09(d,J＝2.2Hz,1H),7.46(dd,J＝8.8,2.4Hz,1H),7.03–6.95(m,1H),6.91(d,J＝7.9Hz,2H),6.84(d,J＝8.8Hz,1H),6.75(dd,J＝12.5,4.7Hz,2H),6.62(d,J＝7.9Hz,1H),6.59(d,J＝1.7Hz,1H),5.33(d,J＝5.6Hz,2H),3.81–3.65(m,4H),3.51–3.40(m,4H)。
HRMS m/z(ESI)calcd for C 23 H 21 N 3 OS[M+H] + 388.1484found:388.1487。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 68.1%.
Example 47 preparation of 4- (1- (10H-phenothiazin-2-yl) vinyl) -3-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide (Compound 46)
The synthesis route is as follows:
Figure BDA0002386332060000322
process for preparation of compound 46 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ10.45(s,1H),8.55(s,1H),8.20(d,J＝1.9Hz,1H),8.14–8.03(m,1H),7.94(dd,J＝7.9,1.8Hz,1H),7.84(d,J＝1.7Hz,1H),7.70(d,J＝8.5Hz,1H),7.42(d,J＝8.1Hz,1H),6.95(td,J＝7.9,1.3Hz,1H),6.90(t,J＝6.7Hz,2H),6.79(dd,J＝8.0,1.8Hz,1H),6.73(td,J＝7.6,1.1Hz,1H),6.65–6.58(m,1H),6.48(d,J＝1.7Hz,1H),5.84(s,1H),5.21(s,1H),3.56(s,2H),2.41(d,J＝15.1Hz,8H),2.17(s,3H),2.11(s,3H)。
HRMS m/z(ESI)calcd for C 35 H 33 F 3 N 4 OS[M+H] + 615.2405found:615.2407。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 57.1%.
Example 48 preparation of (4- (1- (10H-phenothiazin-2-yl) vinyl) phenyl) (morpholine) methanone (Compound 47)
The synthesis route is as follows:
Figure BDA0002386332060000331
process for preparation of Compound 47 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.58(s,1H),7.40(dd,J＝21.0,8.1Hz,4H),6.94(dt,J＝14.2,6.8Hz,3H),6.76(dd,J＝13.0,4.8Hz,2H),6.62(d,J＝7.8Hz,1H),6.57(d,J＝1.3Hz,1H),5.48(d,J＝14.7Hz,2H),3.61(s,8H)。
HRMS m/z(ESI)calcd for C 25 H 22 N 2 O 2 S[M+H] + 415.1480found:415.1486。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 64.9%.
Example 49 preparation of (4- (1- (10H-phenothiazin-2-yl) vinyl) phenyl) (4-methylpiperazin-1-yl) methanone (Compound 48)
The synthesis route is as follows:
Figure BDA0002386332060000332
process for preparation of Compound 48 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.58(s,1H),7.46–7.31(m,4H),6.96(dd,J＝7.6,1.1Hz,1H),6.92(t,J＝7.1Hz,2H),6.76(ddd,J＝7.4,3.8,1.4Hz,2H),6.68–6.60(m,1H),6.57(d,J＝1.7Hz,1H),5.48(d,J＝13.0Hz,2H),3.48(d,J＝91.0Hz,4H),2.32(s,4H),2.20(s,3H)。
HRMS m/z(ESI)calcd for C 26 H 25 N 3 OS[M+H] + 428.1797found:428.1795。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 76.9%.
Example 50 preparation of 2- (1- (2- (4-Methylpiperazin-1-yl) pyrimidin-5-yl) vinyl) -10H-phenothiazine (Compound 49)
The synthesis route is as follows:
Figure BDA0002386332060000333
process for preparation of compound 49 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.56(s,1H),8.30(s,2H),6.98(td,J＝7.8,1.4Hz,1H),6.94–6.91(m,1H),6.90(d,J＝1.9Hz,1H),6.84–6.70(m,2H),6.62(dd,J＝9.1,1.3Hz,2H),5.38(d,J＝2.8Hz,2H),3.93–3.65(m,4H),2.47–2.30(m,4H),2.22(s,3H)。
HRMS m/z(ESI)calcd for C 23 H 23 N 5 S[M+H] + 402.1752found:402.1756。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 64.9%.
Example 51 preparation of 2- (1- (2- (4-methyl-1, 4-homopiperazin-1-yl) pyrimidin-5-yl) vinyl) -10H-phenothiazine (Compound 50)
The synthesis route is as follows:
Figure BDA0002386332060000341
process for preparation of Compound 50 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.58(s,1H),8.28(s,2H),6.98(t,J＝7.6Hz,1H),6.95–6.88(m,2H),6.82–6.71(m,2H),6.63(d,J＝7.0Hz,2H),5.35(d,J＝6.1Hz,2H),3.97–3.81(m,2H),3.76(t,J＝6.1Hz,2H),2.75–2.57(m,2H),2.28(s,3H),1.97–1.80(m,2H)。
HRMS m/z(ESI)calcd for C 24 H 25 N 5 S[M+H] + 416.1909found:416.1913。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 69.0%.
Example 52 preparation of 4- (5- (1- (10H-phenothiazin-2-yl) vinyl) pyrimidin-2-yl) morpholine (Compound 51)
The synthesis route is as follows:
Figure BDA0002386332060000342
process for preparation of Compound 51 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.56(s,1H),8.33(s,2H),6.98(t,J＝7.6Hz,1H),6.92(dd,J＝7.5,3.2Hz,2H),6.85–6.71(m,2H),6.62(d,J＝8.6Hz,2H),5.39(d,J＝5.6Hz,2H),3.84–3.71(m,4H),3.71–3.60(m,4H)。
HRMS m/z(ESI)calcd for C 22 H 20 N 4 OS[M+H] + 389.1436found:389.14367。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 64.8%.
Example 53 preparation of 4- (1- (10H-phenothiazin-2-yl) vinyl) -N- (tetrahydro-2H-pyran-4-yl) benzenesulfonamide (Compound 52)
The synthesis route is as follows:
Figure BDA0002386332060000351
process for preparation of Compound 52 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.58(s,1H),7.94–7.76(m,3H),7.51(d,J＝8.4Hz,2H),7.03–6.88(m,3H),6.81–6.70(m,2H),6.62(d,J＝7.9Hz,1H),6.55(d,J＝1.6Hz,1H),5.55(d,J＝7.7Hz,2H),3.86–3.62(m,2H),3.24(dd,J＝11.2,9.7Hz,3H),1.53(t,J＝18.7Hz,2H),1.48–1.32(m,2H)。
HRMS m/z(ESI)calcd for C 25 H 24 N 2 O 3 S 2 [M+H] + 465.1307found:465.1309。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 78.8%.
Example 54 preparation of 3- (1- (10H-phenothiazin-2-yl) vinyl) -N- (tert-butyl) benzenesulfonamide (Compound 53)
The synthesis route is as follows:
Figure BDA0002386332060000352
process for preparation of compound 53 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.59(s,1H),7.89–7.77(m,1H),7.70(s,1H),7.58(dd,J＝14.3,8.0Hz,3H),7.06–6.86(m,3H),6.75(t,J＝7.5Hz,1H),6.70(dd,J＝7.9,1.5Hz,1H),6.63(d,J＝7.9Hz,1H),6.58(d,J＝1.4Hz,1H),5.51(d,J＝23.4Hz,2H),1.08(s,9H)。
HRMS m/z(ESI)calcd for C 24 H 24 N 2 O 2 S 2 [M+H] + 437.1357found:437.1356。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 75.3%.
Example 55 preparation of 2- (1- (4- (pyrrolin-1-ylsulfonyl) phenyl) vinyl) -10H-phenothiazine (Compound 54)
The synthesis route is as follows:
Figure BDA0002386332060000353
process for preparation of compound 54 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.58(s,1H),7.81(d,J＝8.4Hz,2H),7.55(d,J＝8.4Hz,2H),7.07–6.88(m,3H),6.83–6.71(m,2H),6.62(d,J＝7.9Hz,1H),6.55(d,J＝1.7Hz,1H),5.57(d,J＝11.8Hz,2H),3.17(s,4H),1.68(d,J＝2.8Hz,4H)。
HRMS m/z(ESI)calcd for C 24 H 22 N 2 O 2 S 2 [M+H] + 435.1201found:435.1205。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 67.2%.
Example 56 preparation of 3- (1- (10H-phenothiazin-2-yl) vinyl) -N- (tetrahydro-2H-pyran-4-yl) benzenesulfonamide (compound 55)
The synthesis route is as follows:
Figure BDA0002386332060000361
process for preparation of Compound 55 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.57(s,1H),7.81(ddd,J＝6.3,5.6,4.5Hz,2H),7.68(s,1H),7.66–7.54(m,2H),6.96(ddd,J＝19.4,11.9,4.1Hz,3H),6.81–6.67(m,2H),6.67–6.60(m,1H),6.56(d,J＝1.7Hz,1H),5.51(d,J＝26.3Hz,2H),3.71(dd,J＝8.3,3.3Hz,2H),3.22(td,J＝11.5,2.2Hz,3H),1.50(d,J＝10.4Hz,2H),1.43–1.27(m,2H)。
HRMS m/z(ESI)calcd for C 25 H 24 N 2 O 3 S 2 [M+H] + 465.1307found:465.1303。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 81.8%.
Example 57 preparation of 4- (1- (10H-phenothiazin-2-yl) vinyl) -N- ((tetrahydro-2H-pyran-4-yl) methyl) benzenesulfonamide (compound 56)
The synthesis route is as follows:
Figure BDA0002386332060000362
process for preparation of compound 56 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.58(s,1H),7.79(d,J＝8.3Hz,2H),7.70(t,J＝6.1Hz,1H),7.52(d,J＝8.3Hz,2H),6.96(ddd,J＝18.9,12.3,4.6Hz,3H),6.75(t,J＝7.3Hz,2H),6.62(d,J＝7.8Hz,1H),6.55(d,J＝1.6Hz,1H),5.54(d,J＝19.5Hz,2H),3.81(dd,J＝11.2,3.1Hz,2H),3.21(t,J＝10.9Hz,2H),2.66(t,J＝6.3Hz,2H),1.55(d,J＝13.3Hz,3H),1.09(dd,J＝11.9,3.7Hz,2H)。
HRMS m/z(ESI)calcd for C 26 H 26 N 2 O 3 S 2 [M+H] + 479.1463found:479.1466。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 79.8%.
Example 58 preparation of 4- ((4- (1- (10H-phenothiazin-2-yl) vinyl) phenyl) sulfonyl) morpholine (Compound 57)
The synthesis route is as follows:
Figure BDA0002386332060000371
process for preparation of compound 57 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.58(s,1H),7.75(d,J＝8.4Hz,2H),7.59(d,J＝8.4Hz,2H),7.09–6.87(m,3H),6.76(d,J＝8.1Hz,2H),6.69–6.60(m,1H),6.55(d,J＝1.7Hz,1H),5.59(d,J＝15.1Hz,2H),3.79–3.54(m,4H),3.03–2.83(m,4H)。
HRMS m/z(ESI)calcd for C 24 H 22 N 2 O 3 S 2 [M+H] + 451.1150found:451.1154。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 69.8%.
Example 59 preparation of 4- (1- (10H-phenothiazin-2-yl) vinyl) -N-cyclobutylbenzenesulfonamide (Compound 58)
The synthesis route is as follows:
Figure BDA0002386332060000372
process for preparation of compound 58 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.58(s,1H),8.00(d,J＝8.5Hz,1H),7.78(d,J＝8.4Hz,2H),7.50(d,J＝8.4Hz,2H),7.06–6.86(m,3H),6.74(ddd,J＝9.7,7.8,1.4Hz,2H),6.69–6.57(m,1H),6.55(d,J＝1.7Hz,1H),5.54(d,J＝12.7Hz,2H),3.72–3.53(m,1H),2.02–1.87(m,2H),1.77(dd,J＝15.4,6.3Hz,2H),1.50(td,J＝10.3,5.8Hz,2H)。
HRMS m/z(ESI)calcd for C 24 H 22 N 2 O 2 S 2 [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 60 preparation of 4- (1- (10H-phenothiazin-2-yl) vinyl) -N- (1-methylpiperidin-4-yl) benzenesulfonamide (Compound 59)
The synthesis route is as follows:
Figure BDA0002386332060000381
process for preparation of compound 59 1 H NMR and HRMS data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.58(s,1H),7.81(d,J＝8.4Hz,2H),7.74(d,J＝7.1Hz,1H),7.51(d,J＝8.4Hz,2H),6.96(ddd,J＝18.8,12.4,4.7Hz,3H),6.84–6.70(m,2H),6.62(d,J＝7.9Hz,1H),6.55(d,J＝1.6Hz,1H),5.55(d,J＝7.4Hz,2H),2.94(dd,J＝10.6,4.1Hz,1H),2.61(d,J＝11.7Hz,2H),2.08(s,3H),1.83(t,J＝10.7Hz,2H),1.56(d,J＝10.0Hz,2H),1.42(dd,J＝17.2,6.5Hz,2H)。
HRMS m/z(ESI)calcd for C26H27N3O2S2[M+H]+478.1623found:478.1624。
the specific preparation method is the same as that of the compound 1. The yield thereof was found to be 79.8%.
EXAMPLE 61 study of the inhibitory Rate of the Compound of the present invention on Ferroptosis
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 MTT cell activity detection method. Culturing fibroma cell line in a dish, inoculating a specific number of cells in logarithmic growth phase into a 96-well plate (3000-10000 cells/well) at a volume of 100. Mu.L/well, and adding CO at 37 deg.C and 5% 2 Culturing in an incubator in the environment to allow the cells to adhere to the wall. After 24h, 100. Mu.L of a certain concentration of the compound of the invention prepared using the indicated medium and 10. Mu.L of Ferroptosis inducer Erastin (final concentration 10. Mu.L) were addedM), 3 compound wells are arranged for each compound, and the accuracy of the result is ensured. And a positive control group (compound Ferrostain-1 with a certain concentration and 10 muL Ferroptosis inducer Erastin which are prepared by adding 100 muL of the same culture medium), a blank control group (the specified isovolume culture medium and the DMSO with the same volume of the culture medium are added, and no cells are contained) and a solvent control group (the specified isovolume culture medium and the DMSO with the same volume of the culture medium are added, and cells are contained) are arranged, and 3 multiple wells are also arranged in each group, so that the accuracy of the result is ensured. Adding the medicines, putting the medicines into an incubator, and culturing for 72h. 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 hole into an incubator to continue culturing 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 hole 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 rate% (inhibition, IR) = [1- (a) Experimental group -A Blank space )/(A Solvent(s) -A Blank space )]*100％
Inhibition rate change curves were fitted using GraphPadPrism5 software and EC calculated 50 。
EC was performed on 59 of the above compounds 50 Test (EC) 50 The test of (a) was taken as an average of three tests, and Fer-1 was a positive control group), the results are shown in table 1 below:
TABLE 1 EC of the Compounds of the invention 50 Value of
Compound EC 50 (μM) Compound EC 50 (μM) Compound EC 50 (μM)
Fer-1 0.060 20 0.010 40 0.041
1 0.010 21 0.011 41 0.905
2 0.032 22 0.030 42 0.045
3 0.011 23 0.048 43 0.004
4 0.023 24 0.031 44 0.011
5 0.080 25 0.016 45 0.013
6 0.045 26 0.016 46 0.010
7 0.029 27 0.038 47 0.024
8 0.040 28 0.027 48 0.013
9 0.003 29 0.041 49 0.002
10 0.010 30 0.045 50 0.004
11 0.039 31 0.051 51 0.010
12 0.040 32 0.089 52 0.011
13 0.030 33 0.111 53 0.148
14 0.039 34 0.011 54 0.032
15 0.680 35 0.053 55 0.012
16 0.029 36 0.030 56 0.022
17 0.017 37 0.014 57 0.034
18 0.040 38 0.035 58 0.066
19 0.013 39 0.023 59 0.0002
From the test results shown in table 1, it can be seen that: book (notebook)The compound of the invention has an inhibiting effect on Ferroptosis, wherein the inhibiting activity of the compounds 9, 43, 49, 50 and 59 is obviously better than that of a positive control group. As can be seen from table 1 and fig. 1: EC of Compound 9 50 = 0.003. Mu.M, inhibitory activity about 20 times that of the positive control Fer-1, EC of Compound 49 50 = 0.002. Mu.M, inhibitory activity is about 30 times that of positive control Fer-1, EC of compound 50 50 = 0.004. Mu.M, inhibitory activity about 15 times that of the positive control Fer-1, EC of compound 59 50 =0.0002 μ M, the inhibitory activity was about 300 times that of the positive control Fer-1. The smaller the EC50 value is, the better the activity is, and the results show that the compound of the invention has an inhibition effect on Ferroptosis, while the inhibition activities of the compounds 9, 43, 49, 50 and 59 are obviously better than those of a positive control group, so that the compound has a better Ferroptosis inhibition effect, and the inhibition effect of the compound 59 is optimal. The compounds can be used for preparing iron death inhibitors, and can also be used for preparing medicaments for treating various diseases related to iron death, such as neurodegenerative diseases, parkinson's syndrome, cerebral apoplexy, cardiovascular diseases, renal failure, diabetic complications, cancers and the like.
EXAMPLE 62 therapeutic Effect of Compounds of the present invention on cerebral apoplexy
1. Test method
50 male SD rats were selected, a rat ischemia-reperfusion model was constructed by the wire-plug method, and the experiment was divided into 5 groups (10 SD rats per random division): respectively a model Control group (Control), a compound administration group No. 49 of the invention, a compound administration group No. CN201810393712.2 No. 38, a positive drug group (Liproxstain-1) and a positive drug group (Butylphthalamide).
Animals in each group were reperfused by plugging the middle cerebral artery with a plug for 1.5h and pulling the plug out, and animals were dissected 24h after reperfusion. Each group is respectively administrated by intravenous injection for 1 time within 30min after the middle cerebral artery is blocked by a thread plug and is perfused for 2 hours, and the administration is carried out for 2 times totally; the following doses were administered to each group: the administration dose of the compound No. 49 administration group of the invention is 2.5mg/kg, the administration dose of the compound No. 38 administration group of CN201810393712.2 is 5mg/kg, and the administration doses of the positive drug group and the positive drug group are both 10mg/kg.
The observation indexes in the test comprise: general state observation, body weight, TTC staining after 1 day of postoperative dissection, and cerebral infarction range and cerebral infarction inhibition rate of each group. The cerebral infarction range calculation formula is as follows: cerebral infarction region weight/brain weight × 100%; the cerebral infarction inhibition rate is calculated by the following formula: (administration group cerebral infarction range-model control group cerebral infarction range)/model control group cerebral infarction range x 100%.
The positive drug Liproxstain-1 has the structural formula
Figure BDA0002386332060000401
The positive medicine di-butyl phthalide has the structural formula
Figure BDA0002386332060000402
The structural formula of the No. 38 CN201810393712.2 compound is
Figure BDA0002386332060000411
The structural formula of the compound No. 49 of the invention is
Figure BDA0002386332060000412
2. Test results
(1) General state observation: on the day of operation, abnormal symptoms such as unstable gait, circling, hair uprising and the like appear in each group of animals, symptoms such as emaciation, cachexia, perinasal filthy, perioral filthy and periocular filthy appear in each group 24h after operation, and the severity of the symptoms and the like do not have obvious difference among the groups.
(2) Cerebral infarction Range ratio and cerebral infarction inhibition results
The results of the statistical map of cerebral infarction (fig. 2) show that: when the dosage of the compound No. 49 is 2.5mg/kg, the cerebral infarction range of experimental mice can be obviously reduced, and the cerebral infarction range of the compound No. 49 is obviously smaller than that of the compound No. 38 of CN201810393712.2 with the dosage of 10mg/kg and that of the positive medicaments Liproxstain-1 and Butylphthalamide with the dosage of 5 mg/kg. The effect of the compound No. 49 in reducing the cerebral infarction range is better than that of two positive medicines and the compound No. 38 of CN 201810393712.2.
The results of the cerebral infarction inhibition rate map (fig. 3) show: (1) When the administration dose of the compound No. 49 is 2.5mg/kg, the compound can obviously inhibit cerebral infarction, and the inhibition effect is superior to that of positive medicaments Liproxstatin-1 and Butylphthalamide with the administration dose of 10 mg/kg; (2) The inhibitory effect (inhibition rate of 33%) of the compound No. 49 of the present invention at the administration dose of 2.5mg/kg (low dose) was superior to that of the compound No. 38 of CN201810393712.2 at the administration dose of 5mg/kg (high dose) (inhibition rate of 27%).
The above experimental results show that the 49 th compound of the present invention has significantly better inhibitory effect on cerebral infarction than the positive drugs Liproxstain-1 and butyrthalide at a lower administration dose, and better effect than the high dose administration of CN201810393712.2 compound No. 38. Further, the compound 49 of the present invention has an excellent inhibitory effect on cerebral infarction.
According to the technical standards related to drug development in Stroke of CFDA and Stroke Therapy Industry reversible (STAIR) committees, the most classical line-tying method is selected to establish a middle cerebral artery ischemia-reperfusion Stroke model, indexes such as general state, weight, cerebral infarction area and the like of a model rat are observed and researched, and the treatment effect of the drug on the Stroke can be effectively evaluated. Evaluation experiment results show that the compound No. 49 has the effect of inhibiting cerebral infarction of rats subjected to ischemia reperfusion, the inhibition effect is remarkably superior compared with positive drugs of Liproxstain-1 and Butylphthalamide, and the compound No. 49 can remarkably reduce the cerebral infarction range of rats and increase the inhibition rate of cerebral infarction and is also remarkably superior compared with the compound No. 38 of CN201810393712.2 under lower administration dosage.
In conclusion, the invention synthesizes a new compound capable of inhibiting iron death, the compound has good inhibition effect on iron death, and especially, the compound 9, 43, 49, 50 and 59 have obvious inhibition effect on iron death. Meanwhile, the compound has good inhibitory action on cerebral infarction, and particularly the compound 49 has remarkable effect on inhibiting cerebral infarction. The compound can be used as a main active ingredient for preparing iron death inhibitors, medicaments for treating diseases related to iron death and medicaments for preventing and treating cerebral infarction, 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.

Claims (22)

1. A compound, or salt thereof, or pharmaceutical composition thereof, of formula I:
Figure FDA0004093223410000011
wherein the content of the first and second substances,
R 1 independently of one another is hydrogen, -CF 3 Ethyl, -OCF 3 Methyl, n-butyl, isopropyl,
Figure FDA0004093223410000012
Isobutyl, tert-butyl,
Figure FDA0004093223410000013
Cyano, nitro, amino and/or are present in the blood>
Figure FDA0004093223410000014
Figure FDA0004093223410000015
R 2 Independently hydrogen, amino or methyl;
R 3 independently hydrogen, amino, hydroxyl, nitro,
Figure FDA0004093223410000016
-OCF 3 、/>
Figure FDA0004093223410000017
Methyl, neobutyl, tert-butyl,
Figure FDA0004093223410000018
Isopropyl and/or liver/kidney>
Figure FDA0004093223410000019
Phenyl, -CF 3 Cyano, and device for combining or screening>
Figure FDA00040932234100000110
Figure FDA00040932234100000111
Fluorine,
Figure FDA00040932234100000112
R 4 Independently hydrogen, amino, hydroxyl, nitro,
Figure FDA00040932234100000113
-OCF 3 、/>
Figure FDA00040932234100000114
Methyl, new butyl and/or methyl>
Figure FDA0004093223410000021
Isopropyl and/or liver/kidney>
Figure FDA0004093223410000022
Phenyl, -CF 3 Cyano and/or are present in>
Figure FDA0004093223410000023
Figure FDA0004093223410000024
Fluorine,
Figure FDA0004093223410000025
/>
2. The compound, or salt thereof, or pharmaceutical composition thereof, according to claim 1, wherein:
when R is 2 When it is amino, R 1 、R 3 、R 4 Are all hydrogen;
or, when R is 2 When it is methyl, R 1 Is composed of
Figure FDA0004093223410000026
R 3 、R 4 Are all hydrogen;
or, when R is 2 、R 3 、R 4 When both are hydrogen, R 1 Optionally selected from hydrogen, -CF 3 Ethyl, -OCF 3 Methyl, n-butyl, isopropyl,
Figure FDA0004093223410000027
Isobutyl radical and/or a combination thereof>
Figure FDA0004093223410000028
Figure FDA0004093223410000029
Or, when R is 2 、R 3 、R 4 When both are hydrogen, R 1 Is selected from
Figure FDA00040932234100000210
Wherein R is x Optionally selected from hydrogen and C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl radical, C 2 -C 6 Alkylene radical, C 2 -C 6 Alkynyl, amino-C 1-3 Alkyl, -N- (C) 1- C 3 Alkyl radical) 2 Hydroxy, hydroxy-C 1- C 3 Alkyl or hydroxy-C 3 -C 6 A cycloalkyl group; r y Optionally selected from hydrogen,C 2 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl radical, C 1 -C 6 Alkylene or C 1 -C 6 An alkynyl group;
or, when R is 1 、R 2 、R 3 When both are hydrogen, R 4 Optionally selected from amino, hydroxy, nitro,
Figure FDA00040932234100000211
-OCF 3 、/>
Figure FDA00040932234100000212
Methyl, new butyl and/or methyl>
Figure FDA00040932234100000213
Isopropyl and/or liver/kidney>
Figure FDA00040932234100000214
Phenyl, -CF 3 Ester group, cyano group,
Figure FDA0004093223410000031
Or, when R is 2 When it is hydrogen, R 1 Optionally selected from hydrogen, cyano, nitro, R 3 Optionally selected from hydrogen, methyl, fluoro, neo-butyl, R 4 Optionally selected from hydrogen, methyl, fluoro, and neo-butyl;
or, when R is 1 And R 2 When both are hydrogen, R 3 And R 4 Are all new butyl;
or, when R 2 Is hydrogen, R 1 When it is cyano, R 3 Is hydrogen, R 4 Is a methyl group or a fluorine atom;
or, when R 2 Is hydrogen, R 1 When it is nitro, R 3 Is hydrogen, R 4 Is methyl.
3. The compound, or a salt thereof, or a pharmaceutical composition thereof, according to claim 1 or 2, characterized in that: the structure of the compound is one of the following compounds:
Figure FDA0004093223410000032
/>
Figure FDA0004093223410000041
Figure FDA0004093223410000051
4. a compound, or a salt thereof, or a pharmaceutical composition thereof, characterized by: the structure of the compound is one of the following compounds:
Figure FDA0004093223410000052
5. a compound represented by formula II, or a salt thereof, or a pharmaceutical composition thereof:
Figure FDA0004093223410000053
wherein the content of the first and second substances,
R 5 is selected from
Figure FDA0004093223410000054
Or R 5 Is selected from
Figure FDA0004093223410000055
R y Optionally selected from hydrogen and C 2 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl radical, C 1 -C 6 Alkylene radical, C 1 -C 6 An alkynyl group.
6. The compound, or salt thereof, or pharmaceutical composition thereof, according to claim 5, wherein: the structure of the compound is one of the following compounds:
Figure FDA0004093223410000061
7. a compound represented by formula III, or a salt thereof, or a pharmaceutical composition thereof:
Figure FDA0004093223410000062
wherein the content of the first and second substances,
R 6 optionally selected from amino or
Figure FDA0004093223410000063
Or R 6 Is composed of
Figure FDA0004093223410000064
R x Optionally selected from hydrogen and C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, C 2 -C 6 Alkylene radical, C 2 -C 6 Alkynyl, amino-C 1-3 Alkyl, -N- (C) 1- C 3 Alkyl radical) 2 Hydroxy, hydroxy-C 1- C 3 Alkyl or hydroxy-C 3 -C 6 A cycloalkyl group.
8. The compound, or salt thereof, or pharmaceutical composition thereof, according to claim 7, wherein: the structure of the compound is one of the following compounds:
Figure FDA0004093223410000065
9. a process for the preparation of a compound according to any one of claims 1 to 4, characterized in that: the method comprises the following steps:
step 1:
Figure FDA0004093223410000071
dissolving 2-acetylphenothiazine and 4-methylbenzene sulfonyl hydrazide 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, carrying out suction filtration under reduced pressure, rinsing until filtrate is colorless, and carrying out vacuum drying to obtain an intermediate I;
step 2:
Figure FDA0004093223410000072
dissolving the intermediate I, the raw material A, tris (dibenzylidene-BASE acetone) dipalladium, 2-dicyclohexyl phosphorus-2, 4, 6-triisopropyl biphenyl and anhydrous t-BuOLi by using 1, 4-dioxane, replacing argon for 3 times, moving to 70 ℃ for reaction, monitoring the reaction process, cooling to room temperature after the reaction is finished, filtering, decompressing, concentrating, extracting residues, concentrating an organic layer, and separating by column chromatography to obtain a target product compound;
wherein R is 1 、R 2 、R 3 、R 4 And R as claimed in any of claims 1 to 4 1 、R 2 、R 3 、R 4 The same is true.
10. The method of claim 9, wherein: in step 2, the material A is substituted bromide, and is selected from compounds with the following structures:
Figure FDA0004093223410000073
Figure FDA0004093223410000081
/>
Figure FDA0004093223410000091
11. the method of manufacturing according to claim 10, wherein:
in the step 1, meOH and ether are used for rinsing in the rinsing process after the reaction is finished;
and/or, in the step 2, saturated NaHCO is used for the extraction process after the reaction is finished 3 Extracting with aqueous solution and DCM;
and/or, the progress of the reaction is monitored by TLC.
12. A process for the preparation of a compound according to claim 5 or 6, characterized in that: the method comprises the following steps:
step (1):
Figure FDA0004093223410000092
dissolving 2-acetylphenothiazine and 4-methylbenzene sulfonyl hydrazide 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, carrying out suction filtration under reduced pressure, rinsing until filtrate is colorless, and carrying out vacuum drying to obtain an intermediate I;
step (2):
Figure FDA0004093223410000093
dissolving the intermediate I, the raw material A, tris (dibenzylidene-BASE acetone) dipalladium, 2-dicyclohexyl phosphorus-2, 4, 6-triisopropyl biphenyl and anhydrous t-BuOLi by using 1, 4-dioxane, replacing argon for 3 times, moving to 70 ℃ for reaction, monitoring the reaction process, cooling to room temperature after the reaction is finished, filtering, concentrating under reduced pressure, extracting residues, concentrating an organic layer, and performing column chromatography separation to obtain a target product compound;
wherein R is 5 And R as described in claim 5 or 6 5 The same is true.
13. The method for producing as claimed in claim 12, characterized in that: in the step (2), the raw material A is substituted bromide, and is selected from compounds with the following structures:
Figure FDA0004093223410000101
14. the method of manufacturing according to claim 13, wherein:
in the step (1), during rinsing after the reaction is finished, meOH and diethyl ether are used for rinsing;
and/or, in the step (2), the saturated NaHCO is used for the extraction process after the reaction is finished 3 Extracting with aqueous solution and DCM;
and/or, the progress of the reaction is monitored by TLC.
15. A process for the preparation of a compound according to claim 7 or 8, characterized in that: the method comprises the following steps:
step A:
Figure FDA0004093223410000102
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, carrying out suction filtration under reduced pressure, rinsing until filtrate is colorless, and carrying out vacuum drying to obtain an intermediate I;
and B:
Figure FDA0004093223410000111
dissolving the intermediate I, the raw material A, tris (dibenzylidene-BASE acetone) dipalladium, 2-dicyclohexyl phosphorus-2, 4, 6-triisopropyl biphenyl and anhydrous t-BuOLi by using 1, 4-dioxane, replacing argon for 3 times, moving to 70 ℃ for reaction, monitoring the reaction process, cooling to room temperature after the reaction is finished, filtering, concentrating under reduced pressure, extracting residues, concentrating an organic layer, and performing column chromatography separation to obtain a target product compound;
wherein R is 6 And R as described in claim 7 or 8 6 The same is true.
16. The method of claim 15, wherein: in step B, feed a is a substituted bromide, optionally selected from compounds comprising the following structure:
Figure FDA0004093223410000112
17. the method of manufacturing according to claim 16, wherein:
in the step A, meOH and ether are used for rinsing in the rinsing process after the reaction is finished;
and/or, in the step B, saturated NaHCO is used for the extraction process after the reaction is finished 3 Extracting with aqueous solution and DCM;
and/or, the progress of the reaction is monitored by TLC.
18. Use of a compound according to any one of claims 1 to 8, or a salt thereof, or a pharmaceutical composition thereof, for the manufacture of a targeted medicament for inhibiting iron death in a cell.
19. Use according to claim 18, characterized in that: the medicament is a medicament for treating neurodegenerative diseases, cerebral apoplexy, cardiovascular diseases, parkinson's syndrome, renal failure, diabetic complications and/or cancer.
20. Use according to claim 19, characterized in that: the cerebral apoplexy is cerebral infarction, hemorrhagic apoplexy, cerebral ischemia reperfusion injury.
21. Use of a compound according to any one of claims 1 to 8, or a salt thereof, or a pharmaceutical composition thereof, for the preparation of an oral or intravenous formulation comprising at least one compound according to any one of claims 1 to 8, or a salt thereof, or a pharmaceutical composition thereof, and a pharmaceutically acceptable excipient and/or adjuvant.
22. An iron death inhibitor characterized by: it is prepared by using the compound, or the salt thereof, or the pharmaceutical composition thereof according to any one of claims 1 to 8 as an active ingredient.
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