TWI541230B - Indoleone derivatives and their pharmaceutical use and methods - Google Patents

Description

Anthrone derivative and its medical use and preparation method

The present invention relates to an anthrone derivative and its medical use and preparation method, in particular to the use of a 3-meridinone acetaminophen compound for cancer treatment, and having 3-meridinone oxime A pharmaceutical composition of an amine compound (3-ylideneoxindole acetamides).

Danggui Longhui Pills is a source of Danxi Xinfa, which is composed of 11 kinds of Chinese herbal medicines such as Angelica, Gentiana, Aloe, Gardenia, Rhizoma Coptidis, Astragalus, Phellodendron, Rhubarb, Woody, Green, and Musk. It is currently known that Angelica Longhui Pill can be used to treat chronic granulocytic leukemia. It has been found that indirubin in Qinglan is the main active ingredient of Danggui Longhui Pill in the treatment of chronic myeloid leukemia, because indirubin can inhibit the activity of cyclin-dependent kinase (CDK). On the other hand, meisoindigo is a derivative of indirubin, which is known to have better anticancer activity and lower toxicity than indirubin.

In order to further improve the above compounds, the present invention proposes a novel anthrone derivative and its use.

The present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof: (I) wherein m is 1, 2, 3 or 4, n is 0, 1, 2 or 3; R ¹ is independently selected from H, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ ) a group consisting of an alkoxy group, a hydroxyl group, a halogen group, a cyano group and a nitro group; R ² is selected from the group consisting of H, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ ) alkoxy , (C ₂ -C ₆ ) alkynyl, (C ₁ -C ₆ ) alkoxycarbonyl (C ₁ -C ₆ )alkyl, (C ₆ -C ₁₈ )aryl and (C ₃ -C ₁₈ ) a group consisting of heteroaryl groups, and R ² is optionally via one or more halo, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ Alkoxycarbonyl, halo(C ₁ -C ₆ )alkyl, cyano, nitro or amine; and R ³ is selected from (C ₆ -C ₁₈ )aryl and (C ₃ - C ₁₈ ) a group consisting of heteroaryl groups, and R ³ is optionally via one or more halo, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, hydroxy or nitro Substituted by the base.

Specifically, the aforementioned compound or a pharmaceutically acceptable salt thereof can be used as an anticancer drug for treating at least one of lung cancer, breast cancer, liver cancer, skin cancer, central nervous system cancer, colon cancer, and gastric cancer.

Specifically, the aforementioned compound or a pharmaceutically acceptable salt thereof can be used as a CDK inhibitor.

The invention also relates to a pharmaceutical composition comprising: a therapeutically effective amount of a compound of formula I above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

The invention also relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cancer.

Furthermore, the present invention also relates to a process for the preparation of a compound of formula I or a pharmaceutically acceptable salt thereof, (I) wherein m is 1, 2, 3 or 4, n is 0, 1, 2 or 3; R ¹ is independently selected from H, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ ) a group consisting of an alkoxy group, a hydroxyl group, a halogen group, a cyano group and a nitro group; R ² is selected from the group consisting of H, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ ) alkoxy , (C ₂ -C ₆ ) alkynyl, (C ₁ -C ₆ ) alkoxycarbonyl (C ₁ -C ₆ )alkyl, (C ₆ -C ₁₈ )aryl and (C ₃ -C ₁₈ ) a group consisting of heteroaryl groups, and R ² is optionally via one or more halo, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ ) alkoxycarbonyl, halo (C ₁ -C ₆₎ substituted alkyl, cyano, nitro or amino; and R ³ is selected from consisting of (C ₆ -C ₁₈₎ aryl and (C ₃ - C ₁₈ ) a group consisting of heteroaryl groups, and R ³ is optionally via one or more halo, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, hydroxy or nitro Substituted; the method comprises the compound of formula II (II) and compounds of formula III (III) The reaction is carried out to obtain a compound of the formula I.

The present invention relates to a compound having the following anthrone structure: .

More specifically, the invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof: (I)

To enable those of ordinary skill in the art to understand the features and functions of the present invention, the general description and definitions of the terms mentioned in the specification and claims are hereby incorporated. Unless otherwise indicated, all technical and scientific terms used herein have the ordinary meaning of those of ordinary skill in the art, and in the case of a conflict, the definition of this specification will control.

In this context, the terms "including", "including", "having", "containing" or any other similar terms are open tones and are intended to cover non-exclusive inclusions. For example, a composition or article containing a plurality of elements is not limited to such elements as listed herein, but may include other elements not specifically listed but which are generally inherent to the composition or article. In addition, the term "or" means an "or" inclusive unless it is specifically stated to the contrary, rather than an exclusive "or". For example, the condition "A or B" is satisfied in any of the following cases: A is true (or exists) and B is pseudo (or non-existent), A is pseudo (or non-existent) and B is true (or exists), A And B are both true (or exist). In addition, in this context, the interpretation of the terms "including", "including", "having" and "including" shall be deemed to have been specifically disclosed and covered by "consisting of" and "consisting essentially of" Or semi-closed tortogether.

As used herein, the term "pharmaceutically acceptable" means a compound, a material, a composition, and/or a dosage form that, within the scope of sound medical judgment, applies to contact with humans and animal tissues without excessive toxicity or irritation. Allergic reactions or other problems. Several pharmaceutically acceptable ingredients are known in the art and can be used to evaluate various pharmaceutically acceptable analytical criteria for various components of interest as mentioned in the official publication of The United States Pharmacopeia.

As used herein, the term "pharmaceutically acceptable salts" refers to an ionic compound wherein the non-toxic pro-compound is modified to form an acid or base salt thereof. Examples of the pharmaceutically acceptable salts include inorganic acid salts or organic acid salts such as amines as basic groups, alkali metal or organic salts such as carboxylic acid as an acidic group, and analogs of the foregoing salts. Pharmaceutically acceptable salts include known non-toxic salts and quaternary ammonium salts of the original compounds formed from non-toxic inorganic or organic acids.

The foregoing salts may include salts derived from inorganic acids of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, nitric acid and similar acids. Among the salts prepared from organic acids, the organic acid may include acetic acid, 2-ethyloxybenzoic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, ethanedisulfonic acid, and formic acid. , fumaric acid, gentisic acid, aldonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxymaleic acid, isethionic acid, isonicotinic acid, lactic acid, maleic acid, malic acid, methanesulfonic acid, Oxalic acid, pantothenic acid, phenylacetic acid, propionic acid, salicylic acid, sulfanilic acid, p-toluenesulfonic acid, stearic acid, succinic acid, tartaric acid, di-tartaric acid and similar acids, specific compounds can also form medicines with various amino acids. Receptive salts.

Pharmaceutically acceptable salts of the compounds described herein can be synthesized from compounds containing basic or acidic groups using known chemical methods. In general, such salts can be prepared by reacting the free acid or base form of the compound with a suitable amount of a suitable base or acid in water or an organic solvent or a mixture of the two, generally a non-aqueous medium can be For example ether, ethyl acetate, ethanol, isopropanol or acetonitrile.

As used herein, the term "anticancer drug" refers to an agent that inhibits the growth of cancer cells or causes cancer cells to die. Known anticancer drugs include, for example, nucleotides and nucleoside analogs, auxiliary anticancer agents, alkylating agents, and the like.

As used herein, the term "CDK inhibitor" refers to a compound that has inhibitory activity against various cyclin-dependent kinases.

The term "pharmaceutical composition" means a composition or composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof, and includes a pharmaceutically acceptable carrier, such as a diluent for co-administration, Agent or excipient. Such carriers can be liquids (such as water and oil), saline or the like. In addition, additives, stabilizers, thickeners, lubricants, and colorants can be used in combination. As used herein, pharmaceutically acceptable carriers or excipients include, but are not limited to, fillers, binders, decomposers, lubricants, and other agents that facilitate administration of a compound of the invention or a pharmaceutically acceptable salt thereof to a recipient Any ingredient.

As used herein, the term "treatment" refers to obtaining the desired pharmacological and/or physiological effect which may be prophylactic, for example, to completely or partially prevent a disease or a symptom thereof; or may be therapeutic, for example, to a disease-to-reach portion Or completely cured; or may have a reverse effect on the disease. As used herein, the term "treatment" encompasses the treatment of any disease in a mammal, especially any disease in humans, and includes: (a) prevention of disease not occurring in a disease-prone subject, even if the subject has not been diagnosed as suffering Have the disease; (b) inhibit the disease, that is, stop its development; and (c) alleviate the disease, that is, let the disease subside. "Therapeutically effective amount" means a dose that treats or prevents a disease or disorder in a subject using a compound or composition described herein. The composition of the compound is preferably a synergistic composition, and the synergistic effect is as known to those skilled in the art, and represents that the effect occurring when the compound is co-administered is greater than the multiplication of the compound when administered alone. In general, synergistic effects are mostly manifested in the suboptimal concentration of the compound. Synergism can reduce cytotoxicity, increase activity, or achieve some other beneficial effect of the composition compared to the effects of the individual ingredients.

The term "alkyl" denotes a saturated hydrocarbon group containing a linear, secondary, tertiary or cyclic carbon atom (cycloalkyl). Examples of "alkyl" include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl (isobutyl, -CH ₂ CH (CH) ₃ ) ₂ ), 2-butyl (t-butyl, -CH(CH ₃ )CH ₂ CH ₃ ), 2-methyl-2-propyl (t-butyl, -C(CH ₃ ) ₃ ) , 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl -1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3- Methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl.

The alkyl group can be a monovalent hydrocarbon group, as described above, or it can be a divalent hydrocarbon group (ie, an alkylene group). As used herein, an alkyl group may be optionally substituted with one or more of the following groups: alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkane Mercapto, alkoxycarbonyl, amine, imine, alkylamino, decylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thione Base, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, etidinyl, ethoxylated, ethoxylated, benzammonium, phenylsulfinyl, benzenesulfonate Amidino, phenylsulfonyl, benzenesulfonylamino, benzhydryl, benzhydrylamine, benzhydryloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzene Methylthio, amine, mercapto, carboxylic acid, isocyanate, amidoxime, amine sulfinyl, sulfinate, sulfonate, sulfonate, thiosulfonate, NR ^x R ^y and/or COOR ^x , wherein each R ^x and R ^{y is} independently H, alkyl, alkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl or hydroxy.

The alkyl group may optionally be one or more of an oxy group (-O-), a thio group (-S-), an amine group (-N(H)-), a methylenedioxy group (-OCH ₂ O-). , carbonyl (-C(=O)-), carboxyl (-C(=O)O-), carbonyldioxy (-OC(=O)O-), carboxy root (-OC(=O)-) The imino group (C=NH), the sulfinyl group (SO) or the sulfonyl group (SO ₂ ) is interrupted. Furthermore, the alkyl group can be optionally at least partially unsaturated, thus providing an alkenyl or alkynyl group.

The term "carbocycle" means a saturated, unsaturated or aromatic ring having, for example, 3 to 8 carbon atoms which are monocyclic, 7 to 12 carbon atoms which are bicyclic, and up to about 30 carbon atoms which are polycyclic. Monocyclic carbocycles typically have from 3 to 6 ring atoms, more typically 5 or 6 ring atoms. Bicyclic carbocycles having from 7 to 12 ring atoms, for example arranged in a bicyclo[4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged in a double ring [5,6] or [6,6] system. Examples of the carbocyclic functional group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a 1-cyclopent-1-enyl group, a 1-cyclopent-2-enyl group, a 1-cyclopent-3-enyl group, and a ring. Hexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl, spiro and naphthyl. The carbocyclic ring may be optionally substituted with a group of the above-mentioned substitutable alkyl group.

The term "cycloalkyl" denotes, for example, a cyclic alkyl group of 3 to 20 carbon atoms which has a monocyclic or polycyclic fused ring. The cycloalkyl group includes, for example, a monocyclic structure such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclooctyl group or the like, or a polycyclic structure such as an adamantyl group or the like.

The term "alkoxy" denotes an alkyl-O- group wherein alkyl is as defined herein. Preferred alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, second butoxy, n-pentyloxy, n-hexyloxy 1,2-dimethylbutoxy and the like. The alkoxy group may be optionally substituted by one or more of the following groups: halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocyclic, cycloalkyl, alkanoyl, alkoxycarbonyl , amine, imido, alkylamino, decylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioketo, alkylthio, alkane A sulfinyl group, an alkylsulfonyl group, a cyano group, an etidinyl group, an ethoxylated group, an ethyl fluorenyl group, a benzamidine group, a sulfinyl group, a benzenesulfonyl group, a benzenesulfonate Base, benzenesulfonylamino, benzhydryl, benzhydrylamino, benzhydryloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio, amine Sulfhydryl, urethane, isocyanate, amidoxime, amine sulfoximine, sulfinate, sulfonate, sulfonate, thiosulfonate, NR ^x R ^y and/or COOR ^x wherein each R ^x and R ^{y is} independently H, alkyl, alkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl or hydroxy.

The term "halo" means fluoro, chloro, bromo and iodo. The term "halogen" means fluoro, chloro, bromo and iodo. The term "haloalkyl" or "haloalkyl", such as halo(C ₁ -C ₆ )alkyl, denotes an alkyl group, as defined herein, substituted by one to four halo groups, as defined herein, each of which Halogen groups may be the same or different. Representative haloalkyl groups include trifluoromethyl and the like.

The term "alkynyl" means a mono-branched or unbranched hydrocarbon chain having a fully unsaturated moiety (i.e., a carbon-carbon sp-bond). In a particular embodiment, an alkynyl group can have from 2 to 10 carbon atoms, or from 2 to 6 carbon atoms. In another embodiment, an alkynyl group can have from 2 to 4 carbon atoms. This term can be exemplified by ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, 3-butynyl, 1-hexyne Base, 2-hexynyl, 3-hexynyl, 1-octynyl and the like.

The term "amino" means -NH ₂ . The amine group can be optionally substituted as defined herein for the term "substituted". The term "alkylamino" denotes -NR ₂ wherein at least one R is alkyl and the second R is alkyl or hydrogen. The term "mercaptoamine" means N(R)C(=O)R, wherein each R is independently hydrogen, alkyl or aryl.

Unless otherwise specified, all of the functional groups described herein may be substituted or unsubstituted. The term "substituted" means that one or more hydrogens on a particular atom are replaced with a group selected from the group specified, provided that the specified atom does not exceed the normal valence and that the substitution results in a stable compound. Suitable designated groups include, for example, alkyl, alkenyl, alkylene, alkenylene, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle , cycloalkyl, alkyl fluorenyl, decyloxy, alkoxycarbonyl, amine, imine, alkylamino, decylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxyl , carboxyalkyl, keto, thioketo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetylamino, ethoxylated, ethyl, benzamide Base, phenylsulfinyl, benzenesulfonylamino, benzenesulfonyl, benzenesulfonylamino, benzhydryl, benzhydrylamino, benzhydryloxy, benzyl, benzo Oxyl, benzyloxycarbonyl, benzylthio, aminemethionyl, urethane, isocyanate, amidoxime, amine sulfoximine, sulfinate, sulfonate, sulfonate An acid amine group, a thiosulfonic acid group, NR ^x R ^y and/or COOR ^x , wherein each R ^x and R ^{y is} independently H, alkyl, alkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl Or hydroxyl. When the substituent is a keto group (i.e., =0) or a thioketo group (i.e., =S), then two hydrogens on the atom are replaced.

The term "aryl" denotes an unsaturated aromatic carbocyclic group of 6 to 20 carbon atoms having a single ring (e.g., phenyl) or a plurality of condensed (fused) rings, wherein at least one ring is an aromatic ring (e.g., naphthalene). Base, dihydrophenanthrenyl, anthracenyl or fluorenyl). Preferred aryl groups include phenyl, naphthyl and the like. The aryl group may also be a divalent group, thus providing an extended aryl group.

The aryl group may be optionally substituted by one or more of the following groups: alkyl, alkenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocyclic, cycloalkyl , alkanoyl, alkoxycarbonyl, amine, imine, alkylamino, decylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, a thioketo group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, a cyano group, an etidinyl group, an ethoxylated group, an ethyl fluorenyl group, a benzamidine group, a phenyl sulfinyl group, Phenylsulfonylamino, phenylsulfonyl, phenylsulfonylamino, benzhydryl, benzhydrylamino, benzhydryloxy, benzyl, benzyloxy, benzyloxycarbonyl , benzylthio, amine, mercapto, carboxylic acid, isocyanate, amidoxime, amine sulfinyl, sulfinate, sulfonate, sulfonate, thiosulfonic acid Base, NR ^x R ^y and/or COOR ^x , wherein each R ^x and R ^y is as defined above.

The term "heteroaryl" is a monocyclic, bicyclic or tricyclic ring system containing one, two or three aromatic rings and containing at least one nitrogen, oxygen or sulfur atom in the aromatic ring, and which may be unsubstituted or Replaced by. The heteroaryl group may be optionally a divalent group, thus providing a heteroaryl group. Examples of heteroaryl groups include, but are not limited to, 2 H -pyrrolyl, 3 H -indolyl, 4 H -quinoyl, 4 H -carbazolyl, acridinyl, benzo[ b ]thienyl, benzo Thiazolyl, b-carbolinyl, oxazolyl, [mouth + gram] alkenyl, [mouth + octyl] cinnaolinyl, dibenzo [b, d] furanyl, furazyl, furyl, Imidazolyl, carbazolyl, anthracene + indolisinyl, fluorenyl, isobenzofuranyl, isodecyl, isoquinolyl, isothiazolyl, isoxazolyl, [mouth + Naphthyl, naphthalene [2,3- b ], oxazolyl, acridinyl, phenanthryl, morpholinyl, aryl arsenyl, morphyl, morphinyl, morphine, morphine Ester, fluorenyl, acridinyl, fluorenyl, piperidyl, pyridyl, pyrazolyl, indolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quin A oxalinyl group, a thiadiazolyl group, a thiol group, a thiazolyl group, a thienyl group, a triazolyl group, and a [mouth + mountain] group.

The heteroaryl group may be optionally substituted by one or more of the following groups: alkyl, alkenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkane Alkyl, alkoxycarbonyl, alkoxycarbonyl, amine, imido, alkylamino, decylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto , thioketo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, etidinyl, ethoxylated, ethoxylated, benzylamino, phenylsulfinyl , benzenesulfonamide, benzenesulfonyl, benzenesulfonylamino, benzhydryl, benzhydrylamino, benzhydryloxy, benzyl, benzyloxy, benzyloxy Carbonyl, benzylthio, aminemethanyl, urethane, isocyanate, amidoxime, amine sulfinyl, sulfinate, sulfonate, sulfonate, thiosulfonate Acid group, NR ^x R ^y and/or COOR ^x , wherein each R ^x and R ^y is as defined above.

In this context, the concentrations, doses, carbon numbers, quantities, etc. of the various ingredients are usually expressed in terms of ranges, and it should be noted that all features or conditions defined in scope are for convenience and convenience and should not be construed There are unalterable restrictions within the scope of the claimed invention. Accordingly, the description of a range should be considered as covering and specifically recognizing all possible sub-ranges and ranges of individual values, particularly integer values. For example, the description of the range of "1 to 8" should be regarded as having specifically disclosed all sub-ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., in particular The sub-range defined by the integer value, and individual values such as 1, 2, 3, 4, 5, 6, 7, 8, etc. within the range. This explanation applies to all content of the present invention, whether broad or not.

In this context, for the use of the Markush group to describe the features or examples of the present invention, those skilled in the art will appreciate that subgroups or any individual members of members of the Markusi group may also be used to describe the present text. invention. For example, if X is described as "selected from a group consisting of bromine, chlorine and iodine", it also means that the claim that X is bromine and that X is bromine and chlorine have been fully described.

Furthermore, for the use of the Markush group to describe features or examples of the invention, those skilled in the art will appreciate that any combination of subgroups or individual members of members of the Markusi group can also be used to describe the invention. Thus, for example, if X is described as "selected from a group consisting of bromine, chlorine, and iodine," and Y is described as "selected from a group consisting of methyl, ethyl, and propyl groups." , indicating that X is bromine or chlorine or iodine and Y is methyl or ethyl or propyl.

Furthermore, as used herein, the term "compound" shall include all stereochemically isomeric forms of the compound or mixtures thereof (eg, those possessing the ability to kill cancer cells and/or inhibit the growth of cancer cells). The mirror image isomers of the present invention can be resolved by methods well known to those skilled in the art, for example, by the formation of non-Spiegelmer salts which can be crystallized, gas-liquid or liquid chromatography or mirror image isomerized. The mirror image isomer of the specificity reagent is selected for reaction separation. The desired mirror image isomer can be converted to another chemical by separation techniques and then subjected to additional steps to form the mirror image isomer; or asymmetrically synthesized using an optically active reagent, matrix, catalyst or solvent, or a mirror image The isomer is converted to another mirror image isomer by an asymmetric conversion reaction to synthesize a specific mirror image isomer.

EXAMPLES: Synthesis of compounds of formula I

Various compounds of formula I can be prepared by reference to the following synthetic routes. In general, Eosin 1 obtained commercially or by the Sandmeyer method is the main starting material for the reaction. Here, taking the structure having the substituent R ¹ at the position of No. 5 as an example, the para-substituted aniline can be treated under acidic conditions with chloral hydrate and hydroxylamine hydrochloride to obtain Eosin 1. Next, the ruthenium 1 is subjected to a substitution reaction with, for example, an aromatic halide to obtain an N-substituted ruthenium 2 . On the other hand, diethylphosphonium acetic acid and an amine compound are subjected to a coupling reaction to synthesize diethylphosphonium acetamide. The above-mentioned eosin 2 is subjected to a nucleophilic addition reaction with the aforementioned diethylphosphonium oxime 3 and then subjected to a de-reaction (Horner-Wadsworth-Emmons reaction) to obtain various types of 3-meridinone B. Indoleamines (No. 4 to 50).

Synthesis of (E)-2-(1-(4-chlorobenzyl)-2-ketoporphyrin-3-ylidene)-N-(pyridin-4-yl)acetamide (4)

To a solution of ruthenium (300 mg, 2.04 mmol) in DMF (10 mL) was added NaH (60% suspended in mineral oil, 86 mg, 2.14 mmol) at 0 °C. At 0 ^o C the mixture was stirred for 30 minutes before dropwise a solution of 4-chlorotoluene chloride (328 mg, 2.04 mmol). The reaction mixture was stirred at room temperature for 12 h until completion was confirmed by TLC. Water was added to cool the reaction, and extraction was carried out with ethyl acetate. The combined organic layer was washed with a brine solution, dried over MgSO ₄ and evaporated. The residue was purified by flash column chromatography to afford product N </RTI><RTIgt;</RTI><RTIgt;

To a solution of N -4-chlorobenzyl ruthenium (200 mg, 0.74 mmol) in THF/H ₂ O (6/1, 5 mL), diethylphosphoniumamine (200 mg, 0.74 mmol) Potassium carbonate (358 mg, 2.6 mmol). The mixture was stirred at room temperature for 8 hours until completion was confirmed by TLC, and then poured into ice water to form a yellow solid precipitate. Purification of the crude mixture by flash column chromatography afforded the title compound 4 (233 mg, 81%). Mp = 208-210 ^o C. ¹ H NMR (600 MHz, DMSO- d ₆ ) d: 11.19 (s, 1H), 8.62 (d, J = 7.2 Hz, 1H), 8.49 (d, J = 6.0 Hz, 2H), 7.69 (dd, J = 4.8, 1.2 Hz, 1H), 7.40-7.38 (m, 3H), 7.35 (d, J = 9.0 Hz, 2H), 7.19 (s, 1H), 7.07 (dt, J = 7.8, 0.6 Hz, 1H), 6.97 (d, J = 7.8 Hz, 1H), 4.97 (s, 2H). ¹³ C NMR (150 MHz, DMSO- d ₆ ) d: 167.2, 163.6, 150.6, 145.2, 144.5, 135.3, 135.2, 132.5, 132.1, 129.1, 128.7, 128.5, 126.3, 122.6, 119.5, 113.4, 109.5, 42.2. HRMS calculated C ₂₂ H ₁₆ N ₃ O ₂ Cl (M) ⁺ 389.0911, actual value 389.0921.

(E)-2-(1-(4-Chlorobenzyl)-2-ketoporphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide (5)

Yield 75%. Mp = 248-250 ^o C. ¹ H NMR (600 MHz, DMSO- d ₆ ) d: 11.20 (s, 1H), 8.80 (dd, J = 4.2, 1.8 Hz, 1H), 8.74 ( d, J = 2.4, 1H), 8.64 (d, J = 2.4 Hz, 1H), 8.37 (d, J = 7.8 Hz, 1H), 8.02 (d, J = 9.0 Hz, 1H), 7.87 (dd, J = 9.0, 2.4 Hz, 1H), 7.51 (dd, J = 8.4, 4.2 Hz, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.34 (m , 1H), 7.29 (s, 1H), 7.08 (t, J = 7.8 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 4.98 (s, 2H). ¹³ C NMR (150 MHz, DMSO - d ₆ ) d: 167.3, 162.9, 149.4, 145.0, 144.4, 136.6, 135.7, 135.2, 134.7, 132.2, 132.1, 129.8, 129.1, 128.7, 128.6, 128.3, 127.1, 123.2, 122.6, 121.9, 119.7, 115.5, 109.4, 42.2. HRMS calcd for _{C 26 H 18 N 3 O 2} Cl (M) + 439.1078, 439.1083 actual value.

(E)-N-(4-methoxyphenyl)-2-(1-((3-methylisoxazol-5-yl)methyl)-2-one porphyrin-3-ene Acetylamine (6)

Yield 74%. Mp = 208-210 ^o C. ¹ H NMR (600 MHz, DMSO- d ₆ ) d: 10.76 (s, 1H), 8.70 (d, J = 7.8 Hz, 1H), 7.68 (dd, J = 7.2, 2.4 Hz, 2H), 7.41-7.38 (m, 1H), 7.18 (s, 1H), 7.11-7.08 (m, 2H), 6.94 (dd, J = 7.2, 2.4 Hz, 2H), 6.35 (s, 1H), 5.11 (s, 2H), 3.74 (s, 3H), 2.17 (s, 3H). ¹³ C NMR (150 MHz, DMSO- d ₆ ) d: 167.0, 166.5, 161.8, 159.8, 155.8 , 143.7, 133.6, 132.0, 132.0, 128.6, 127.9, 122.7, 120.8, 119.7, 114.0, 109.2, 103.9, 55.2, 35.2, 10.9. HRMS calculated C ₂₂ H ₁₉ N ₃ O ₄ (M) ⁺ 389.1396, actual value 389.1386.

(E)-2-(1-((3-methylisoxazol-5-yl)methyl)-2-one porphyrin-3-ylidene)-N-(pyridin-4-yl) Acetamine (7)

Yield 80%. Mp = 210-214 ^o C. ¹ H NMR (600 MHz, DMSO- d ₆ ) d: 11.18 (s, 1H), 8.64 (d, J = 7.2 Hz, 1H), 8.49 (d, J = 6.0 Hz, 2H), 7.68 (dd, J = 4.8, 1.2 Hz, 2H), 7.43 (dt, J = 7.8, 1.2 Hz, 1H), 7.17 (s, 1H), 7.11 (d, J = 7.8 Hz, 2H), 6.36 (s, 1H), 5.11 (s, 2H), 2.17 (s, 3H). ¹³ C NMR (150 MHz, DMSO- d ₆ ) d: 166.8, 166.4, 163.5, 159.8, 150.6, 145.2, 144.1, 135.0, 132.5, 128.5, 126.4, 122.8, 119.4, 113.4, 109.4, 103.9, 35.2, 10.9. HRMS calculated C ₂₂ H ₁₉ N ₃ O ₄ (M) ⁺ 360.1245, actual value 360.1234.

(E)-2-(1-((3-methylisoxazole-5-yl)methyl)-2-one porphyrin-3-ylidene)-N-(quinolin-6-yl) Ethylamine (8)

Yield 78%. Mp = 250-252 ^o C. ¹ H NMR (600 MHz, DMSO- d ₆ ) d: 11.20 (s, 1H), 8.82-8.80 (m, 1H), 8.75 (dd, J = 8.4 , 1.2 Hz, 1H), 8.63 (d, J = 2.4 Hz, 1H), 8.37 (dd, J = 8.4, 1.2 Hz, 1H), 8.01 (d, J = 9.0 Hz, 1H), 7.86 (dd, J = 9.0, 2.4 Hz, 1H), 7.51 (dd, J = 8.4, 4.2 Hz, 1H), 7.43 (dt, J = 7.8, 1.2 Hz, 1H), 7.27 (s, 1H), 7.13 (t, J = 7.8 Hz, 2H), 6.37 (s, 1H), 5.14 (s, 2H), 2.18 (s, 3H). ¹³ C NMR (150 MHz, DMSO- d ₆ ) d: 167.0, 166.5, 162.8, 159.8, 149.4 , 145.0, 143.9, 136.6, 135.7, 134.4, 132.3, 129.8, 128.6, 128.3, 127.3, 123.2, 122.8, 121.9, 119.6, 115.5, 109.3, 103.9, 35.2, 10.9. HRMS calculated C ₂₄ H ₁₈ N ₄ O ₃ (M) ⁺ 410.1359, actual value 410.1369.

(E)-N-(4-hydroxyphenyl)-2-(1-((3-methylisoxazol-5-yl)methyl)-2-one porphyrin-3-ylidene) Acetamine (9)

Yield 74%. Mp = 255-257 ^o C. ¹ H NMR (600 MHz, DMSO- d ₆ ) d: 10.66 (s, 1H), 9.35 (s, 1H), 8.70 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 9.0 Hz, 2H), 7.39 (t, J = 7.8 Hz, 1H), 7.17 (s, 1H), 7.10-7.07 (m, 2H), 6.75 (d, J = 8.4 Hz, 2H), 6.34 (s, 1H), 5.11 (s, 2H), 2.17 (s, 3H). ¹³ C NMR (150 MHz, DMSO- d ₆ ) d: 167.0, 166.5, 161.6, 159.8, 154.1, 143.7, 133.4, 131.8, 130.5, 128.6, 128.2, 122.6, 121.0, 119.8, 115.3, 109.2, 103.9, 35.2, 10.9. HRMS calculated C ₂₁ H ₁₇ N ₃ O ₄ (M) ⁺ 375.1239, actual value 375.1229.

(E)-2-(5-methoxy-1-((3-methylisoxazol-5-yl)methyl)-2-one porphyrin-3-ylidene)-N-( Quinoline-6-yl)acetamide (10)

Yield 78%. Mp = 192-195 ^o C. ¹ H NMR (600 MHz, DMSO- d ₆ ) d: 11.20 (s, 1H), 8.81 (dd, J = 4.2, 1.8 Hz, 1H), 8.61 ( d, J = 1.8 Hz, 1H), 8.45 (s, 1H), 8.38 (d, J = 7.8 Hz, 1H), 8.01 (d, J = 9.0 Hz, 1H), 7.88 (dd, J = 9.0, 2.4 Hz, 1H), 7.50 (dd, J = 8.4, 4.2 Hz, 1H), 7.26 (s, 1H), 7.03 (s, 1H), 6.35 (s, 1H), 5.10 (s, 2H), 3.77 (s , 3H), 2.17 (s, 3H). ¹³ C NMR (150 MHz, DMSO- d ₆ ) d: 166.8, 166.6, 162.8, 159.8, 155.3, 149.4, 145.1, 137.6, 136.6, 135.8, 134.9, 129.8, 128.3 HRMS calcd. C ₂₅ H ₂₁ N ₄ O ₄ (M+H) ⁺ 441.1563, </ RTI></RTI>^{</ RTI} ></RTI>^{</ RTI} ></RTI>^{</ RTI} ></RTI>^{</ RTI} ></RTI>^{</ RTI} ></RTI>^{</ RTI} ></RTI>^{</ RTI} >

(E)-N-(2-iodophenyl)-2-(1-((3-methylisoxazol-5-yl)methyl)-2-one porphyrin-3-ylidene) Acetamine (11)

Yield 84%. Mp = 206-207 ^o C. ¹ H NMR (600 MHz, DMSO- d ₆ ) d: 10.41 (s, 1H), 8.61 (d, J = 7.8 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7.30 (s, 1H) , 7.10 (d, J = 7.8 Hz, 1H), 7.07-7.03 (m, 2H), 6.36 (s, 1H), 5.12 (s, 2H), 2.17 (s, 3H). ¹³ C NMR (150 MHz, DMSO- d ₆ ) d: 166.9, 166.5, 162.7, 159.8, 143.9, 139.0, 139.0, 134.5, 132.2, 128.7, 128.6, 128.3, 127.6, 127.1, 122.6, 119.6, 109.2, 103.9, 96.7, 35.2, 10.9. Calculated C ₂₁ H ₁₆ IN ₃ O ₃ (M) ⁺ 485.0214, ???

(E)-N-(3-iodophenyl)-2-(1-((3-methylisoxazol-5-yl)methyl)-2-one porphyrin-3-ylidene) Acetamine (12)

Yield 77%. Mp = 187-189 ^o C. ¹ H NMR (600 MHz, DMSO- d ₆ ) d: 10.94 (s, 1H), 8.65 (dd, J = 7.8, 0.6 Hz, 1H), 8.29 ( t, J = 1.8 Hz, 1H), 7.63 (dd, J = 7.8, 1.2 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.42 (dt, J = 7.8, 1.2 Hz, 1H), 7.18-7.15 (m, 3H), 7.12-7.10 (m, 2H), 6.35 (s, 2H), 5.11 (s, 2H), 2.17 (s, 3H). ¹³ C NMR (150 MHz, DMSO- d ₆ ) d: 167.0, 166.5, 162.6, 160.0, 143.9, 140.1, 134.5, 132.7, 132.3, 131.0, 128.6, 127.5, 127.1, 122.8, 119.6, 118.7, 109.3, 103.9, 94.8, 35.2, 10.9. HRMS calculated C ₂₁ H ₁₆ IN ₃ O ₃ (M) ⁺ 485.0243, actual value 485.0240.

(E)-2-(1-((3-methylisoxazol-5-yl)methyl)-2-one porphyrin-3-yl)-N-phenylacetamide (13 )

Yield 84%. Mp = 201-204 ^o C. ¹ H NMR (600 MHz, DMSO- d ₆ ) d: 10.86 (s, 1H), 8.68 (d, J = 7.8 Hz, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.41 (t, J = 7.2 Hz, 1H), 7.36 (t, J = 7.8 Hz, 2H), 7.21 (s, 1H), 7.14-7.08 (m, 3H), 6.35 ( s, 1H), 5.12 (s, 2H), 2.17 (s, 3H). ¹³ C NMR (150 MHz, DMSO- d ₆ ) d: 167.0, 166.5, 162.4, 159.8, 143.8, 138.7, 134.0, 132.1, 128.9 , 128.5, 127.7, 124.2, 122.7, 119.6, 119.4, 109.2, 103.9, 35.2, 10.9. HRMS calculated C ₂₁ H ₁₇ N ₃ O ₃ (M) ⁺ 359.1252, actual value 359.1261.

(E)-2-(1-((3-methylisoxazole-5-yl)methyl)-2-one porphyrin-3-ylidene)-N-(4-nitrophenyl) Ethylamine (14)

Yield 76%. Mp = 210-214 ^o C. ¹ H NMR (600 MHz, DMSO- d ₆ ) d: 11.41 (s, 1H), 8.66 (d, J = 7.8 Hz, 1H), 8.27 (d, J = 9.0 Hz, 1H), 7.99 (d, J = 9.0 Hz, 2H), 7.43 (t, J = 7.8 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.20 (s, 1H) , 7.13-7.10 (m, 2H), 6.86 (d, J = 8.4 Hz, 1H), 6.36 (s, 1H), 5.12 (s, 2H), 2.17 (s, 3H). ¹³ C NMR (150 MHz, DMSO- d ₆ ) d: 166.8, 166.4, 163.2, 159.8, 144.7, 144.1, 142.8, 135.1, 132.6, 128.6, 126.4, 125.1, 122.8, 119.3, 113.7, 109.4, 103.9, 35.2, 10.8. HRMS calculated C ₂₁ H ₁₆ N ₄ O ₅ (M) ⁺ 404.1101, actual value 404.1111.

(E)-4-((2-Sideoxy-3-(2-oxo-2-(quinolin-6-ylamino)ethyl)porphyrin-1-yl)methyl)benzoic acid Methyl ester (15)

Yield 78%. Mp = 147-150 ^o C. ¹ H NMR (600 MHz, CDCl ₃ ) d: 8.56 (dd, J = 4.2, 1.2 Hz, 1H), 8.77 (d, J = 7.8 Hz, 1H) , 8.52 (d, J = 2.4 Hz, 1H), 8.15 (d, J = 7.2 Hz, 2H), 8.06 (d, J = 9.0 Hz, 1H), 7.98 (d, J = 7.8 Hz, 2H), 7.65 (dd, J = 9.0, 2.4 Hz, 1H), 7.40 (dd, J = 8.4, 4.2 Hz, 1H), 7.26 (d, J = 7.2 Hz, 1H), 7.15 (s, 1H), 7.08 (t, J = 7.8 Hz, 1H), 6.63 (d, J = 7.8 Hz, 1H), 5.01 (s, 2H), 3.88 (s, 3H). ¹³ C NMR (150 MHz, CDCl ₃ ) d: 168.1, 166.6, 162.7, 149.8, 145.9, 144.5, 140.4, 136.5, 135.9, 135.4, 132.4, 130.6, 130.2, 129.8, 129.5, 128.8, 127.0, 125.7, 123.4, 123.1, 121.8, 120.2, 116.6, 109.0, 52.2, 43.7. ESMS m /z: 462.4 (M‒1) ⁺ .

(E)-2-(1-(naphthalen-2-ylmethyl)-2-one porphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide (16)

Yield 79%. Mp = 231-233 ^o C. ¹ H NMR (600 MHz, CDCl ₃ ) d: 8.83 (d, J = 3.0 Hz, 1H), 8.78 (d, J = 7.2 Hz, 1H), 8.50 (d, J = 1.8 Hz, 1H), 8.48 (s, 1H), 8.09 (d, J = 7.8 Hz, 1H), 8.02 (d, J = 9.6 Hz, 1H), 7.81-7.52 (m, 3H) , 7.69 (s, 1H), 7.68 (dd, J = 9.6, 2.4 Hz, 1H), 7.46-7.44 (m, 2H), 7.40 (dd, J = 8.4, 1.8 Hz, 1H), 7.36 (dd, J = 8.4, 4.2 Hz, 1H), 7.26-7.21 (m, 2H), 7.06 (t, J = 7.8 Hz, . 1H), 6.72 (d, J = 7.8 Hz, 1H), 5.13 (s, 2H). ¹³ C NMR (150 MHz, CDCl ₃ ) d: 168.4, 162.8, 149.7, 145.8, 144.8, 136.6, 136.0, 135.6, 133.3, 132.9, 132.6, 132.3, 129.4, 128.9, 128.8, 127.7, 126.5, 126.2, 125.9, 125.8, 124.9, 123.3, 123.1, 121.8, 120.2, 116.6, 109.3, 44.2. HRMS calculated for C ₃₀ H ₂₁ N ₃ O ₂ (M+H) ⁺ 456.1718, actual value 456.1720.

(E)-2-(2-Sideoxy-1-(4-(trifluoromethyl)benzyl)porphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide ( 17)

Yield 83%. Mp = 231-233 ^o C. ¹ H NMR (600 MHz, DMSO- d ₆ ) d: 11.21 (s, 1H), 8.81 (dd, J = 4.2, 1.8 Hz, 1H), 8.76 ( d, J = 7.2 Hz, 1H), 8.65 (d, J = 1.8 Hz, 1H), 8.37 (d, J = 7.8 Hz, 1H), 8.02 (d, J = 9.0 Hz, 1H), 7.87 (dd, J = 9.0, 2.4 Hz, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.51 (dd, J = 8.4, 4.2 Hz, 1H), 7.36 ( Dt, J = 7.8, 1.2 Hz, 1H), 7.30 (s, 1H), 7.10 (s, 1H), 6.97 (d, J = 7.8 Hz, 1H), 5.10 (s, 2H). ¹³ C NMR (150 MHz, DMSO- d ₆ ) d: 167.4, 162.9, 149.4, 145.0, 144.3, 141.1, 136.6, 135.7, 134.7, 132.2, 129.8, 128.7, 128.3, 128.0, 127.2, 125.6 (t, J = 3.46 Hz), 125.0 , 123.2, 122.6, 121.9, 119.7 , 115.5, 109.4, 42.4. HRMS calcd for _{C 27 H 19 N 3 O 2} F 3 (M + H) + 474.1409, 474.1405 actual value.

(E)-2-(1-(4-Bromobenzyl)-2-ketoporphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide (18)

Yield 78%. Mp = 228-232 ^o C. ¹ H NMR (600 MHz, CDCl ₃ ) d: 8.84 (dd, J = 3.6, 1.2 Hz, 1H), 8.79 (d, J = 7.8 Hz, 1H) , 8.63 (s, 1H), 8.51 (d, J = 1.8 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 9.6 Hz, 1H), 7.66 (dd, J = 2.4, 1.8 Hz, 1H), 7.42 (d, J = 7.8 Hz, 2H), 7.39 (dd, J = 8.4, 4.2 Hz, 1H), 7.26 (t, J = 7.8 Hz, 1H), 7.24 (s, 1H), 7.14 (d, J = 8.4 Hz, 2H), 7.08 (t, J = 7.8 Hz, 1H), 6.64 (d, J = 7.8 Hz, 1H), 4.91 (s, 2H). ¹³ C NMR ( 150 MHz, CDCl ₃ ) d: 168.3, 162.8, 149.7, 145.8, 144.4, 136.3, 136.0, 135.6, 134.2, 132.3, 132.1, 130.4, 129.6, 128.8, 128.7, 126.2, 123.4, 123.2, 121.8, 120.2, 116.6, 109.0, 43.4. HRMS calcd for _{C 26 H 19 N 3 O 2} Br (M + H) + 484.0660, 484.0657 actual value.

(E)-2-(1-(3-Cyanobenzyl)-2-ketoporphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide (19)

Yield 77%. Mp = 192-194 ^o C. ¹ H NMR (600 MHz, DMSO- d ₆ ) d: 11.20 (s, 1H), 8.80 (d, J = 3.0 Hz, 1H), 8.76 (d, J = 7.8 Hz, 1H), 8.64 (s, 1H), 8.36 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 9.0 Hz, 1H), 7.88-7.86 (m, 2H), 7.75 ( d, J = 7.5 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.50 (dd, J = 8.4, 4.2 Hz, 1H), 7.36 ( t, J = 7.8 Hz, 1H), 7.29 (s, 1H), 7.10 (t, J = 7.8 Hz, 1H), 6.99 (d, J = 7.8 Hz, 1H), 5.04 (s, 2H). ¹³ C NMR (150 MHz, DMSO- d ₆ ) d: 167.5, 162.9, 149.4, 145.0, 144.3, 138.0, 136.7, 135.7, 134.8, 132.2, 132.0, 131.4, 130.9, 130.0, 129.8, 128.7, 128.3, 127.1, 123.3, 122.6, 121.9, 119.8, 118.6, 115.5, 111.6, 109.3, 42.2. HRMS calcd for C ₂₇ H ₁₉ N ₄ O ₂ (M+H) ⁺ 431.1508, actual value 431.1513.

(E)-2-(5-Bromo-1-(4-chlorobenzyl)-2-one porphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide (20 )

Yield 79%. Mp = 256-258 ^o C. ¹ H NMR (600 MHz, DMSO- d ₆ ) d: 11.28 (s, 1H), 8.98 (d, J = 2.4 Hz, 1H), 8.82 (dd, J = 4.2, 1.2 Hz, 1H), 8.63 (d, J = 1.8 Hz, 1H), 8.44 (d, J = 9.0 Hz, 1H), 8.02 (d, J = 9.0 Hz, 1H), 7.87 (dd, J = 9.0, 2.4 Hz, 1H), 7.57 (dd, J = 7.8, 2.4 Hz, 1H), 7.51 (dd, J = 7.8, 4.2 Hz, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 7.8 Hz, 1H), 4.99 (s, 2H). ¹³ C NMR (150 MHz, DMSO- d ₆ ) d: 166.9, 162.6, 149.5 , 145.1, 143.6, 136.5, 135.9, 134.9, 134.4, 133.8, 132.2, 130.9, 129.8, 129.1, 128.8, 128.7, 128.3, 123.3, 121.9, 121.7, 115.7, 114.3, 111.4, 42.3. HRMS calculated C ₂₆ H ₁₈ N ₃ O ₂ ClBr (M+H) ⁺ 518.0270, mp.

(E)-2-(1-(4-Cyanobenzyl)-2-ketoporphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide (21)

Yield 78%. Mp = 237-240 ^o C. ¹ H NMR (600 MHz, DMSO- d ₆ ) d: 11.21 (s, 1H), 8.81 (dd, J = 3.6, 1.2 Hz, 1H), 8.76 ( d, J = 7.8 Hz, 1H), 8.64 (d, J = 1.8 Hz, 1H), 8.38 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 9.0 Hz, 1H), 7.88-7.86 ( m, 2H), 7.76 (d, J = 7.2 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.51 (dd, J = 8.4, 3.6 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.29 (s, 1H), 7.10 (t, J = 7.8 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 5.05 ( s, 2H). ¹³ C NMR (150 MHz, DMSO- d ₆ ) d: 167.9, 163.4, 149.8, 145.5, 144.7, 138.4, 137.1, 136.2, 135.2, 132.6, 132.5, 131.8, 130.5, 130.2, 129.1, 128.8 , 127.6, 123.7, 123.1, 122.4 , 120.3, 119.0, 115.9, 112.1, 109.8, 42.6. HRMS calcd for _{C 27 H 19 N 4 O 2} (M + H) + 431.1508, 431.1504 actual value.

(E)-2-(1-(4-nitrobenzyl)-2-ketoporphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide (22)

Yield 76%. Mp = 272-275 ^o C. ¹ H NMR (600 MHz, DMSO- d ₆ ) d: 11.22 (s, 1H), 8.81 (dd, J = 4.2, 1.8 Hz, 1H), 8.77 ( d, J = 7.8 Hz, 1H), 8.65 (d, J = 1.8 Hz, 1H), 8.38 (dd, J = 7.8, 1.2 Hz, 1H), 8.21 (dt, J = 9.0, 1.8 Hz, 2H), 8.02 (d, J = 9.6 Hz, 1H), 7.87 (dd, J = 9.0, 1.8 Hz, 1H), 7.60 (d, J = 9.0 Hz, 2H), 7.51 (dd, J = 8.4, 4.2 Hz, 1H ), 7.37 (dt, J = 7.2, 1.2 Hz, 1H), 7.31 (s, 1H), 7.11 (dt, J = 7.8, 1.2 Hz, 1H), 6.97 (d, J = 7.8 Hz, 1H), 5.15 (s, 2H). ¹³ C NMR (150 MHz, DMSO- d ₆ ) d: 167.4, 162.8, 149.4, 146.9, 145.0, 144.2, 144.1, 136.6, 135.8, 134.6, 132.2, 129.8, 128.7, 128.3, 128.3, 127.3, 123.9, 123.2, 122.7, 121.9, 119.8, 115.5, 109.4, 42.4. HRMS calcd for C ₂₆ H ₁₉ N ₄ O ₄ (M+H) ⁺ 451.1396, actual value 451.1393.

(E)-2-(1-(3-chlorobenzyl)-2-ketoporphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide (23)

Yield 78%. Mp = 242-245 ^o C. ¹ H NMR (600 MHz, CDCl ₃ ) d: 11.20 (s, 1H), 8.81 (dd, J = 4.2, 1.8 Hz, 1H), 8.75 (d, J = 7.8 Hz, 1H), 8.64 (d, J = 2.4 Hz, 1H), 8.38 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.87 (dd, J = 9.0, 2.4 Hz, 1H), 7.50 (dd, J = 8.4, 4.2 Hz, 1H), 7.43 (s, 1H), 7.38-7.33 (m, 3H), 7.29-7.28 (m, 2H), 7.10 (t , J = 7.8 Hz, 1H), 7.00 (d, J = 7.8 Hz, 1H), 5.00 (s, 2H). ¹³ C NMR (150 MHz, CDCl ₃ ) d: 167.4, 162.9, 149.4, 145.0, 144.3, 138.8, 136.6, 135.8, 134.7, 133.3, 132.2, 130.7, 129.8, 128.6, 128.3, 127.5, 127.2, 127.1, 125.8, 123.3, 122.6, 121.9, 119.7, 115.5, 109.4, 42.3. HRMS calcd for C ₂₆ H ₁₉ N ₃ O ₂ Cl(M+H) ⁺ 440.1166, actual value 440.1173.

(E)-2-(1-(4-chlorobenzyl)-5-methyl-2-ketoporphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide ( twenty four)

Yield 81%. Amorphous powder. ¹ H NMR (600 MHz, DMSO- d ₆ ) d: 11.18 (s, 1H), 8.80 (dd, J = 4.2, 1.8 Hz, 1H), 8.61 (d, J = 2.4 Hz, 1H), 8.58 (s, 1H), 8.39 (d, J = 7.8 Hz, 1H), 8.01 (d, J = 9.0 Hz, 1H), 7.88 (dd, J = 9.0, 2.4 Hz, 1H) , 7.51 (dd, J = 8.4, 4.2 Hz, 1H), 7.39 (dd, J = 6.6, 1.8 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.26 (s, 1H), 7.16 ( d, J = 7.2 Hz, 1H), 7.08 (d, J = 9.0 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 9.0 Hz, 1H), 4.95 (s, 2H), 2.30 (s, 3H). ¹³ C NMR (150 MHz, DMSO- d ₆ ) d: 167.4, 162.9, 149.4, 145.0, 142.2, 136.6, 135.8, 135.3, 135.0, 132.5, 132.1, 131.5, 129.8, 129.1, 129.1, 128.7, 128.3, 127.4, 127.0, 123.3, 122.0, 119.8, 115.5, 113.9, 109.2, 68.8, 42.2. HRMS calculated C ₂₇ H ₂₁ N ₃ O ₂ Cl(M+H) ⁺ 454.1322, actual value 454.1321.

(E)-2-(1-(4-fluorobenzyl)-2-one porphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide (25)

Yield 74%. Mp = 221-225 ^o C. ¹ H NMR (600 MHz, DMSO- d ₆ ) d: 11.20 (s, 1H), 8.81 (dd, J = 4.2, 1.8 Hz, 1H), 8.74 ( d, J = 7.2 Hz, 1H), 8.64 (d, J = 1.8 Hz, 1H), 8.37 (d, J = 7.8 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.87 (dd, J = 9.6, 3.0 Hz, 1H), 7.51 (dd, J = 7.8, 3.6 Hz, 1H), 7.40 (dd, J = 7.8, 1.2 Hz, 1H), 7.36 (dt, J = 7.8, 1.2 Hz, 1H ), 7.29 (s, 1H), 7.17 (dt, J = 6.6, 1.8 Hz, 2H), 7.10 (dt, J = 7.8, 1.2 Hz, 1H), 7.00 (d, J = 7.8 Hz, 1H), 4.97 (s, 2H). ¹³ C NMR (150 MHz, DMSO- d ₆ ) d: 167.3, 162.9, 162.3, 160.7, 149.4, 145.0, 144.4, 136.6, 135.7, 134.8, 132.4, 132.4, 132.2, 129.8, 129.4, 129.3, 128.6, 128.3, 127.1, 123.2, 122.5, 121.9, 119.7, 115.6, 115.5, 115.4, 109.5, 42.1. HRMS calculated C ₂₆ H ₁₉ N ₃ O ₂ F(M+H) ⁺ 424.1461, actual value 424.1460.

(E)-2-(1-(2,6-Dichlorobenzyl)-2-ketoporphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide (26)

Yield 77%. Mp = 279-281 ^o C. ¹ H NMR (600 MHz, DMSO- d ₆ ) d: 11.17 (s, 1H), 8.81 (d, J = 3.0 Hz, 1H), 8.72 (d, J = 7.8 Hz, 1H), 8.62 (s, 1H), 8.37 (d, J = 9.0 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 9.0 Hz, 1H) , 7.53-7.50 (m, 2H), 7.40 (t, J = 8.4 Hz, 1H), 7.32 (t, J = 8.4 Hz, 1H), 7.23 (s, 1H), 7.06 (t, J = 7.8 Hz, 1H), 6.73 (d, J = 7.8 Hz, 1H), 5.22 (s, 2H). ¹³ C NMR (150 MHz, DMSO- d ₆ ) d: 166.9, 162.9, 149.4, 145.0, 144.4, 136.6, 135.7, 135.3, 134.4, 132.1, 130.7, 130.2, 129.8, 129.2, 128.5, 128.3, 127.0, 123.3, 122.3, 121.9, 119.7, 115.5, 109.0, 40.0. HRMS calculated C ₂₆ H ₁₈ N ₃ O ₂ Cl ₂ (M+ H) ⁺ 474.0776, actual value 474.0778.

(E)-2-(1-(4-chlorobenzyl)-5-methoxy-2-ketoporphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide (27)

Yield 81%. Mp = 239-241 ^o C. ¹ H NMR (600 MHz, CDCl ₃ ) d: 8.85 (dd, J = 4.2, 1.8 Hz, 1H), 8.51 (dd, J = 4.8, 2.4 Hz, 1H), 8.40 (s, 1H), 8.12 (d, J = 9.0 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.67 (dd, J = 9.0, 2.4 Hz, 1H), 7.40 ( Dd, J = 7.8, 2.4 Hz, 1H), 7.28 (d, J = 6.6 Hz, 2H), 7.22 (d, J = 6.6 Hz, 2H), 7.20 (s, 1H), 6.82 (dd, J = 8.4 , 2.4 Hz, 1H), 6.53 (d, J = 8.4 Hz, 1H), 4.90 (s, 2H), 3.82 (s, 3H). ¹³ C NMR (150 MHz, CDCl ₃ ) d: 168.1, 162.6, 156.2 , 149.8, 145.9, 138.2, 136.9, 136.0, 135.5, 133.8, 133.7, 130.5, 129.2, 129.1, 128.8, 128.7, 128.4, 126.2, 123.1, 121.8, 120.9, 118.0, 116.6, 115.5, 109.5, 56.0, 43.4. calculated for _{C 27 H 21 N 3 O 3} Cl (M + H) + 470.1271, 470.1276 actual value.

(E)-2-(1-(4-Methoxybenzyl)-2-ketoporphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide (28)

Yield 76%. Mp = 216-218 ^o C. ¹ H NMR (600 MHz, CDCl ₃ ) d: 8.83 (dd, J = 4.2, 1.2 Hz, 1H), 8.69 (s, 1H), 8.51 (d, J = 2.4 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 9.0 Hz, 1H), 7.68 (dd, J = 9.0, 2.4 Hz, 1H), 7.38 (dd, J = 8.4, 4.8 Hz, 1H), 7.28-7.21 (m, 5H), 7.06 (t, J = 7.8 Hz, 1H), 6.83 (d, J = 6.6 Hz, 2H), 6.71 (d, J = 7.8 Hz, 1H), 4.91 (s, 2H), 3.76 (s, 3H). ¹³ C NMR (150 MHz, CDCl ₃ ) d: 168.3, 162.9, 159.2, 149.7, 145.8, 144.7, 136.6, 135.9, 135.7, 132.2 , 130.4, 129.4, 128.8, 128.4, 127.1, 126.0, 123.2, 121.7, 120.2, 116.6, 114.3, 109.3, 55.3, 43.5. HRMS calculated C ₂₇ H ₂₂ N ₃ O ₃ (M+H) ⁺ 436.1661, actual value 436.1661.

(E)-N-(3-methylisoxazol-5-yl)-2-(1-((3-methylisoxazol-5-yl)methyl)-2-one porphyrin -3-subunit) acetamidine (29)

Yield 81%. Mp = 253-255 ^o C. ¹ H NMR (600 MHz, DMSO- d ₆ ) d: 12.35 (s, 1H), 8.64 (d, J = 7.8 Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.14 (s, 1H), 7.11 (t, J = 8.4, 2H), 6.38 (s, 1H), 6.36 (s, 1H), 5.10 (s, 2H), 2.21 (s , 3H), 2.17 (s, 3H). ¹³ C NMR (150 MHz, DMSO- d ₆ ) d: 166.6, 166.4, 160.9, 160.6, 160.6, 160.0, 144.2, 136.0, 132.8, 128.5, 124.6, 122.8, 119.4 , 109.4, 103.9, 89.8, 35.2, 11.4, 10.9. HRMS calculated C ₁₉ H ₁₆ N ₄ O ₄ (M) ⁺ 364.1171, actual value 364.1179.

(E)-2-(1-((3-methylisoxazole-5-yl)methyl)-2-one porphyrin-3-ylidene)-N-(pyridin-3-yl) Acetamine (30)

Yield 83%. Mp = 195-197 ^o C. ¹ H NMR (600 MHz, DMSO- d ₆ ) d: 11.07 (s, 1H), 8.86 (d, J = 2.4 Hz, 1H), 8.66 (d, J = 7.8 Hz, 1H), 8.33 (dd, J = 4.2, 1.2 Hz, 1H), 8.21-8.18 (m, 1H), 7.43-7.40 (m, 1H), 7.19 (s, 1H), 7.13-7.09 (m, 3H), 6.36 (s, 1H), 5.12 (s, 2H), 2.17 (s, 3H). ¹³ C NMR (150 MHz, DMSO- d ₆ ) d: 166.9, 166.4, 162.9, 159.8, 145.0 , 144.0, 140.9, 135.4, 134.5, 132.3, 128.5, 126.8, 126.3, 123.8, 122.8, 119.5, 109.3, 103.9, 35.2, 10.9. HRMS calculated C ₂₀ H ₁₇ N ₄ O ₃ (M+H) ⁺ 361.1300, The actual value is 361.1295.

(E)-2-(5-Methoxy-1-(4-nitrobenzyl)-2-ketoporphyrin-3-ylidene)-N-(quinolin-6-yl)acetamidine Amines (31)

Yield 79%. Mp = 230-232 ^o C. ¹ H NMR (600 MHz, DMSO- d ₆ ) d: 11.22 (s, 1H), 8.81 (dd, J = 4.2, 1.8 Hz, 1H), 8.61 ( d, J = 2.4 Hz, 1H), 8.40 (d, J = 3.0 Hz, 1H), 8.38 (dd, J = 8.4, 0.6 Hz, 1H), 8.20 (dt, J = 9.6, 2.4 Hz, 2H), 8.01 (d, J = 9.0 Hz, 1H), 7.88 (dd, J = 9.0, 2.4 Hz, 1H), 7.58 (d, J = 9.6 Hz, 2H), 7.50 (dd, J = 8.4, 4.2 Hz, 1H ), 7.31 (s, 1H), 6.96 (dd, J = 8.4, 2.4 Hz, 1H), 6.87 (d, J = 9.0 Hz, 1H), 5.11 (s, 2H), 3.74 (s, 3H). ¹³ C NMR (150 MHz, DMSO- d ₆ ) d: 167.2, 162.8, 155.3, 149.4, 146.9, 145.1, 144.2, 137.9, 136.6, 135.8, 135.1, 129.8, 128.3, 127.6, 123.9, 123.3, 121.9, 120.6, 116.6 , 115.8, 115.6, 109.7, 55.7 , 42.4. HRMS calcd for _{C 27 H 21 N 4 O 5} (M + H) + 481.1512, 481.1527 actual value.

(E)-2-(1-(4-Aminobenzyl)-5-methoxy-2-ketoporphyrin-3-ylidene)-N-(quinolin-6-yl)acetamidine Amines (32)

Yield 78%. Amorphous powder. ¹ H NMR (600 MHz, DMSO- d ₆ ) d: 11.19 (s, 1H), 8.81 (dd, J = 4.2, 1.8 Hz, 1H), 8.61 (d, J = 2.4 Hz, 1H), 8.40 (d, J = 3.0 Hz, 1H), 8.39 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 9.0 Hz, 1H), 7.88 (dd, J = 9.0, 2.4 Hz, 1H), 7.50 (dd, J = 8.4, 4.2 Hz, 1H), 7.26 (s, 1H), 7.00 (d, J = 8.4 Hz, 2H), 6.95 (dd, J = 8.4, 3.0 Hz, 1H), 6.87 (d, J = 8.4 Hz, 2H), 6.49 (d, J = 8.4 Hz, 2H), 5.03 (br, 2H), 4.73 (s, 2H), 3.73 (s, 3H). ¹³ C NMR (150 MHz, DMSO- d ₆ ) d: 166.9, 162.9, 155.0, 149.4, 148.1, 145.0, 138.5, 136.6, 135.8, 135.5, 129.8, 128.4, 128.3, 127.1, 123.3, 122.8, 121.9, 120.5, 116.5, 115.6, 115.5, 113.9, 110.0, 55.7, 42.7. HRMS calcd for C ₂₇ H ₂₃ N ₄ O ₃ (M+H) ⁺ 451.1770, actual value 451.1777.

(E)-2-(1-(4-bromobenzyl)-5-methoxy-2-ketoporphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide (33)

Yield 78%. Mp = 201-203 ^o C. ¹ H NMR (600 MHz, DMSO- d ₆ ) d: 11.21 (s, 1H), 8.81 (dd, J = 4.2, 1.2 Hz, 1H), 8.61 ( d, J = 2.4 Hz, 1H), 8.44 (d, J = 3.0 Hz, 1H), 8.39 (d, J = 7.8 Hz, 1H), 8.01 (d, J = 9.0 Hz, 1H), 7.88 (dd, J = 9.0, 1.8 Hz, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.51 (dd, J = 4.2, 2.4 Hz, 1H), 7.28 (d, J = 8.4 Hz, 2H), 7.28 ( s, 1H), 6.96 (dd, J = 8.4, 2.4 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 4.93 (s, 2H), 3.73 (s, 3H). ¹³ C NMR (150 MHz, DMSO- d ₆ ) d: 167.1, 162.8, 155.2, 149.4, 145.0, 138.0, 136.6, 135.8, 135.7, 135.2, 131.6, 129.8, 129.4, 128.3, 127.4, 123.3, 121.9, 120.6, 120.5, 116.6, 115.7 , 115.6, 109.8, 55.7, 42.3 . HRMS calcd for _{C 27 H 21 N 3 O 3} Br (M + H) + 514.0766, 514.0778 actual value.

(E)-2-(1-(4-Bromobenzyl)-5-hydroxy-2-ketoporphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide (34) )

Yield 78%. Mp = 221-223 ^o C. ¹ H NMR (600 MHz, DMSO- d ₆ ) d: 11.54 (s, 1H), 9.51 (s, 1H), 8.81 (dd, J = 4.2, 1.8 Hz, 1H), 8.48 (d, J = 2.4 Hz, 1H), 8.38 (d, J = 7.8 Hz, 1H), 8.01 (d, J = 9.0 Hz, 1H), 7.86 (dd, J = 9.0, 2.4 Hz, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.53-7.51 (m, 1H), 7.32 (s, 1H), 7.29 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 2.4 Hz, 1H), 6.77-6.73 (m, 1H), 4.87 (s, 2H). ¹³ C NMR (150 MHz, DMSO- d ₆ ) d: 165.2, 163.4, 153.5, 148.9, 144.4, 136.8, 136.1 , 135.7, 134.6, 131.6, 131.5, 131.2, 129.7, 129.6, 129.5, 129.3, 129.2, 128.4, 123.7, 122.5, 121.9, 120.6, 117.4, 115.4, 110.2, 109.1, 42.1. HRMS calculated C ₂₆ H ₁₉ N ₃ O ₃ Br(M+H) ⁺ 500.0609, actual value 500.0603.

(E)-2-(1-methyl-2-ketoporphyrin-3-ylidene)-N-phenylacetamide (35)

Yield 78%. Mp = 236-238 ^o C. ¹ H NMR (600 MHz, DMSO- d ₆ ) d: 10.83 (s, 1H), 8.65 (d, J = 7.8 Hz, 1H), 7.75 (d, J = 7.8 Hz, 2H), 7.41 (dt, J = 7.8, 0.6 Hz, 1H), 7.36 (t, J = 7.8 Hz, 2H), 7.15 (s, 1H), 7.11 (t, J = 7.8 Hz, 1H), 7.07 (t, J = 7.8 Hz, 1H), 7.03 (d, J = 7.8 Hz, 1H), 3.18 (s, 3H). ¹³ C NMR (150 MHz, DMSO- d ₆ ) d: 167.2, 162.6, 145.6, 138.8, 134.8, 132.1, 128.9, 128.4, 126.9, 124.1, 122.3, 119.6, 119.4, 108.8, 26.1.

(E)-2-(2-ketoporphyrin-3-ylidene)-N-phenylacetamide (36)

Yield 74%. Mp = 242-245 ^o C. ¹ H NMR (600 MHz, DMSO- d ₆ ) d: 10.79 (s, 1H), 10.70 (s, 1H), 8.60 (d, J = 7.2 Hz, 1H), 7.74 (dd, J = 8.4, 1.2 Hz, 2H), 7.36 (t, J = 7.8 Hz, 2H), 7.31 (dt, J = 7.8, 1.2 Hz, 1H), 7.10 (t, J = 7.8 Hz, 1H), 7.10 (s, 1H), 6.99 (dt, J = 7.8, 1.2 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H). ¹³ C NMR (150 MHz, DMSO- d ₆ ) d: 168.5, 162.7, 144.5, 138.8, 135.7, 132.1, 128.9, 128.6, 126.3, 124.0, 121.7, 120.2, 119.4, 110.0. HRMS calculated C ₁₆ H ₁₃ N ₂ O ₂ (M+H) ⁺ 265.0977, actual The value is 265.0972.

(E)-2-(2-ketoporphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide (37)

Yield 68%. Mp = 165-168 ^o C. ¹ H NMR (600 MHz, DMSO- d ₆ ) d: 11.14 (s, 1H), 10.75 (s, 1H), 8.79 (dd, J = 4.2, 1.2 Hz, 1H), 8.65 (d, J = 7.2 Hz, 1H), 8.60 (d, J = 2.4 Hz, 1H), 8.34 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.85 (dd, J = 9.0, 2.4 Hz, 1H), 7.49 (dd, J = 8.4, 4.2 Hz, 1H), 7.33 (dt, J = 7.8, 1.2 Hz, 1H), 7.11 (s, 1H) ), 7.01 (dt, J = 7.8, 1.2 Hz, 1H), 6.88 (d, J = 7.8 Hz, 1H). ¹³ C NMR (150 MHz, DMSO- d ₆ ) d: 168.7, 163.3, 149.6, 145.1, 144.7, 136.9, 136.3, 136.0, 132.5, 129.8, 128.9, 128.5, 126.1, 123.5, 122.2, 122.0, 120.4, 115.7, 110.3. HRMS calculated C ₁₉ H ₁₃ N ₃ O ₂ (M) ⁺ 315.1007, actual value 315.1006 .

(E)-2-(1-methyl-2-ketoporphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide (38)

Yield 77%. Mp = 251-256 ^o C. ¹ H NMR (DMSO- d ₆ ) d: 8.94 (br, 1H), 8.83 (s, 1H), 8.54 (s, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.70-7.57 (m, 2H), 7.43-7.24 (m, 2H), 7.13 (t, J = 7.2 Hz, 1H), 6.98-6.95 (m, 2H), 6.64-6.62 ( m, 1H), 3.31 (s, 3H). ¹³ C NMR (DMSO- d ₆ ) d: 172.7, 166.2, 150.6, 145.4, 144.8, 132.3, 131.9, 130.4, 129.9, 129.5, 129.2, 125.1, 123.1, 122.6 , 121.9, 121.1, 120.5, 108.7, 107.8, 26.2. ESMS m/z: 656.5 (2M‒1) ^- .

(E)-2-(2-Sideoxy-1-(prop-2-yn-1-yl)porphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide (39 )

Yield 81%. Mp = 178-181 ^o C. ¹ H NMR (600 MHz, DMSO- d ₆ ) d: 11.20 (s, 1H), 8.80 (dd, J = 4.2, 1.8 Hz, 1H), 8.75 ( d, J = 7.8 Hz, 1H), 8.63 (d, J = 2.4 Hz, 1H), 8.37 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 9.0 Hz, 1H), 7.86 (dd, J = 9.0, 2.4 Hz, 1H), 7.51 (dd, J = 7.8, 3.6 Hz, 1H), 7.47 (dt, J = 7.8, 1.2 Hz, 1H), 7.25 (s, 1H), 7.15 (t, J = 8.4 Hz, 2H), 4.61 (d, J = 2.4 Hz, 2H), 3.29 (t, J = 2.4 Hz, 1H). ¹³ C NMR (150 MHz, DMSO- d ₆ ) d: 166.5, 162.8, 149.5 , 145.1, 143.7, 136.6, 135.8, 134.5, 132.3, 129.8, 128.6, 128.4, 127.3, 123.3, 122.8, 122.0, 119.6, 115.6, 109.6, 77.5, 74.6, 30.7. ESMS m/z: 252.2 (M‒1) ^- .

(E)-2-(1-(4-Chlorobenzyl)-2-ketoporphyrin-3-ylidene)-N-(3-nitrobenzyl)acetamidamine (40)

(E)-N-(3-Methylisothiazol-5-yl)-2-(1-((3-methylisoxazol-5-yl)methyl)-2-one porphyrin- 3-substyl) acetamamine (41)

(E)-2-(2-Sideoxy-3-(2-oxo-oxy-2-(quinolin-6-ylamino)ethylidene) porphyrin-1-yl)acetate (42)

(E)-2-(5-Chloro-1-(4-chlorobenzyl)-2-one porphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide (43 )

(E)-2-(5-Bromo-1-(4-chlorobenzyl)-2-one porphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide (44 )

(E)-2-(1-(4-Chlorobenzyl)-5-hydroxy-2-ketoporphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide (45 )

(E)-2-(2-Sideoxy-1-(thiophen-2-ylmethyl) porphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide (46)

(E)-2-(2-Sideoxy-1-(thiophen-2-ylmethyl)porphyrin-3-ylidene)-N-(pyridin-4-yl)acetamide (47)

(E)-2-(2-Sideoxy-1-(thiophen-3-ylmethyl)porphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide (48)

(E)-2-(1-(furan-2-ylmethyl)-2-one porphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide (49)

(E)-2-(1-(furan-3-ylmethyl)-2-one porphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide (50)

Example: Cancer cell activity inhibition assay

Various cancer cell lines, including lung cancer cell line NCI-H460, breast cancer cell line MCF-7, liver cancer cell line Hep3B, skin cancer cell line KB, central nervous system cancer cell line SF-268, and gastric cancer cell line MKN-45, respectively seeded into 96-well plates, and cultured in CO ₂ incubator for 24 hours at 37 ^o C condition each test compound was dissolved in DMSO and culture containing DMSO was diluted to a final concentration of 0.5% to 5%. The respective cancer cell lines were tested in triplicate or duplicate at a single concentration of test compounds of different, and incubated at 37 ^o C for 72 hours. 10 nM actinomycin D and 0.3% DMSO were used as the positive control group and the vehicle control group, respectively. The cytotoxicity of each test compound was confirmed by colorimetric analysis of the MTS/PMS system. The optical density value at 490 nm was measured, and then the concentration value at which 50% of cancer cell growth activity was inhibited, i.e., IC ₅₀ , was calculated. Table ₅₀ value of a test compound IC of NCI-H460 lung cancer cell lines, and lists the conventional compound Roscovitine and indirubin-3'-oxime as a reference. <TABLE border="1"borderColor="#000000"width="85%"><TBODY><tr><td>compound</td><td>R¹</td><td>R²</td><td>R³</td><td> NCI-H460(μM) </td></tr><Tr><td> 4 </td><td> H </td><td><i>p</i>-Cl-Ph </td><td><i>p</i>-pyridine Base </td><td>4.5±0.6^a</td></tr><tr><td> 5 </td><td> H </td><td><i>p</i>-Cl-Ph</td><td>6-quinolinyl</td><td>4.1±0.6^a</td></tr><Tr><td> 6 </td><td> H </td><td>3-methylisoxazolyl</td><td><i>p</i>-MeO-Ph</Td><td>4.3±0.8^a</td></tr><tr><td> 7 </td><td> H </td><td> 3-methyl Isoxazolyl</td><td><i>p</i>-pyridyl</td><td>4.5±0.6^a</td></tr><tr><td> 8 </td><td> H </td><td>3-methylisoxazolyl</td><td>6-quinolinyl</td><td> 3.3±0.2 ^a</td></tr><tr><td> 9 </td><td> H </td><td>3-methylisoxazolyl</td><td><i>p</i>-HO-Ph</td><td>4.6±0.6^a</td></tr><tr><td> 10 </ Td><td> MeO </td><td>3-methylisoxazolyl</td><td>6-quinolinyl</td><td>2.2±0.6^a</td></tr><tr><td> 11 </td><td> H </td><td>3-methylisoxazolyl</td><td>2-iodophenyl</td><td>9.0±1.4^a</td></tr><tr><td> 12 </td><td> H </td><td>3-methylisoxazolyl</td><td> 3- Iodophenyl</td><td>20.4±1.4^a</td></tr><tr><td> 13 </td><td> H </td><td >3-methylisoxazolyl</td><td>phenyl</td><td>64.9±3.2^a</td></tr><tr><td> 14 </td><td> H </td><td>3-methylisoxazolyl</td><td><i>p</i>-NO₂- Ph </td><td>>100^a</td></tr><tr><td> 15 </td><td> H </td><td><i >p</i>-CO₂Me-Ph </td><td>6-quinolinyl</td><td>1.9±0.3^a</td></tr><tr><td> 16 </td><td> H </td><td>2-naphthyl</td><td>6-quinolinyl</td><Td>1.6±0.2^a</td></tr><tr><td> 17 </td><td> H </td><td><i>p</i >-CF₃-Ph </td><td>6-quinolinyl</td><td>1.5±0.2^a</td></tr><tr><td> 18 </td><td> H </td><td><i>p</i>-Br-Ph </td><td>6-quinolinyl</td><td>1.3±0.1^a</td></tr><tr><td> 19 </td><td> H </td><td><i>m</i>-CN-Ph</td><td>6-quinolinyl</td><td> 59.6± 4.9^a</td></tr><tr><td> 20 </td><td> Br </td><td><i>p</i>-Cl- Ph </td><td>6-quinolinyl</td><td>55.6±3.1^a</td></tr><tr><td> 21 </td><td> H </td><td><i>p</i>-CN-Ph </td><td>6-quinolinyl</td><td>60.7±1.1^a</td></tr><tr><td> 22 </td><td> H </td><td><i>p</i>-NO_{2</sub >-Ph </td><td>6-quinolinyl</td><td>1.4±0.1^a</td></tr><tr><td> 23 </ Td><td> H </td><td><i>m</i>-Cl-Ph </td><td>6-quinolinyl</td><td>38.8±3.5^a</td></tr><tr><td> 24 </td><td> Me </td><td><i>p</i>-Cl-Ph </td ><td>6-quinolinyl</td><td>3.9±0.6^a</td></tr><tr><td> 25 </td><td> H </td><td><i>p</i>-F-Ph </td><td>6-quinolinyl</td><td>54.2±3.4^a</td></tr><tr><td> 26 </td><td> H </td><td>2,6-Cl₂-Ph</td><td>6-quinolinyl</td><td>4.0±0.3^a</td></tr><tr><td> 27 </td><td> MeO </td ><td><i>p</i>-Cl-Ph </td><td>6-quinolinyl</td><td>0.4±0.1^a</td></tr><tr><td> 28 </td><td> H </td><td><i>p</i>-MeO-Ph </td><td> 6-quinolinyl </td><Td>16.0±0.4^a</td></tr><tr><td> 29 </td><td> H </td><td> 3-methylisoxazole Base </td><td>3-methylisoxazolyl</td><td>8.0±0.3^a</td></tr><tr><td> 30 </td><td> H </td><td>3-methylisoxazolyl</td><td><i>m</i>-pyridyl</td><td> 3.7±0.3 ^a</td></tr><tr><td> 31 </td><td> MeO </td><td><i>p</i>-NO<sub >2}-Ph </td><td>6-quinolinyl</td><td>>100^a</td></tr><tr><td> 32 </td><td> MeO </td><td><i>p</i>-NH₂-Ph </td><td>6-quinolinyl</td><td>14.9±1.8^a</td></tr><tr><td> 33 </td><td> MeO </td><td><i>p</i>-Br-Ph</td><td>6-quinolinyl</td><td>3.2±0.2^a</td></tr><tr><td> 34 </td><td> HO </td><td><i>p</i>-Br-Ph </td><td>6-quinolinyl</td><td>3.1±0.1^a</td></tr><tr><td> 35 </td><td> H </td><td> Me </td><td> benzene Base </td><td>32.0±2.4^a</td></tr><tr><td> 36 </td><td> H </td><td> H </td><td>phenyl</td><td>3.8±0.1^a</td></tr><tr><td> 37 </td><td> H </td><td> H </td><td>6-quinolinyl</td><td>32.2±1.4^a</td></tr><tr><td> 38 </td><td> H </td><td> Me </td><td> 6 -quinolinyl</td><td>44.3±8.9^a</td></tr><tr><td> 39 </td><td> H </td><Td> propargyl </td><td>6-quinolinyl</td><td>>100^a</td></tr><tr><td> 40 </td><td> H </td><td><i>p</i>-Cl-Ph </td><td><i>m</i>-NO<sub>2</sub >-Ph </td><td>61.0±1.1^b</td></tr><tr><td> 41 </td><td> H </td><td >3-methylisoxazolyl</td><td>3-methylisothiazolyl</td><td>>100^b</td></tr><tr><td> 42 </td><td> H </td><td>CH₂CO₂CH₃</td><td>6-quinolinyl</td><td>>100^b</td></tr><tr><td> 43 </td><td> Cl </td><td><i>p</i>-Cl-Ph</td><td>6-quinolinyl</td><td>>100^b</td></tr><tr><td> 44 </td><td> Br </td><td><i>p</i>-Cl-Ph </td><td> 6-quinoline Base </td><td>55.6±3.1^b</td></tr><tr><td> 45 </td><td> OH </td><td><i>p</i>-Cl-Ph</td><td>6-quinolinyl</td><td>44.6±5.1^b</td></tr><Tr><td> 46 </td><td> H </td><td>2-thienyl</td><td>6-quinolinyl</td><td> 7.4 ± 0.6^b</td></tr><tr><td> 47 </td><td> H </ Td><td>2-thienyl</td><td><i>p</i>-pyridyl</td><td> 11.4 ± 1.2^b</td></tr><tr><td> 48 </td><td> H </td><td>3-thienyl</td><td>6-quinolinyl</td><td> 9.4 ± 0.7^b</td></tr><tr><td> 49 </td><td> H </td><td> 2-furyl group</td><td>6-quinolinyl</td><td> 3.4 ± 0.5^b</td></tr><tr><td> 50 </td><td> H </td><td>3-furanyl</td><td>6-quinolinyl</td><td> 5.4 ± 0.4^b</td></tr><tr><td >靛玉红-3'-肟</td><td></td><td></td><td></td><td> 32.6±5.1 </td></tr><tr ><td> Roscovitine </td><td></td><td></td><td></td><td> 11.6±1.9 </td></tr></TBODY></ TABLE> ^a IC ₅₀ value is the mean of three replicates ± SD. ^b IC ₅₀ values are single repeat values ± SD. Table I

It can be observed from the above Table 1 that when R ¹ is H and R ² is 4-chlorophenyl, R ³ is a compound of p -pyridyl and 6-quinolinyl (No. 4, 5) for lung cancer cells. The strain has roughly equivalent activity. Comparing the compounds 4, 5, 7, and 8, it was found that the compound in which R ² is a 4-chlorophenyl group and a 3-methylisoxazolyl group also has substantially equivalent activity. When the R ² position is a 3-methylisoxazolyl group, if the benzene ring at the R ³ position has an electron-withdrawing group such as a methoxy group (compound 6) or a hydroxyl group (compound 9), the compound is for lung cancer. The cell line has significant inhibitory activity. Further, comparing the compounds 6, 7, and 8, it is understood that when R ³ is a p-methoxyphenyl group, a p-pyridyl group, and a 6-quinolyl group, the compound has substantially equivalent activity. Further, if R ³ is a heteroaryl group such as p-pyridyl (compound 7), 6-quinolyl (compound 8), or 3-methylisoxazolyl (compound 29), it can be found that the compounds all show good. The inhibitory activity, the inhibitory ability is roughly: 6-quinolyl>p-pyridyl>3-methylisoxazolyl, wherein the compound having a R ³ position of 6-quinolyl has the strongest inhibitory activity. Taking compounds 15, 17, 18, and 22 as an example, when the R ² position is p-phenyl and the R ³ position is 6-quinolyl, a good inhibitory activity of a lung cancer cell line can be observed, and the IC _{50 is} about 1 μM. Comparing the test compounds in the table, it can be observed that the electron-deficient property caused by the p-phenyl group at the R ² position is important for the cytotoxicity of such compounds.

Table 2 gives the test compounds IC ₅₀ values for the other five kinds of cancer cell lines (in units of [mu] M), a compound of Formula I for different cancer cells have a wide range of inhibitory activity, and its activity is superior to conventional compounds indirubin - 3'-肟 and Roscovitine. <TABLE border="1"borderColor="#000000"width="_0009"><TBODY><tr><td>compound</td><td> MCF-7 </td><td> Hep3B </td ><td> KB </td><td> SF-268 </td><td> MKN-45 </td></tr><tr><td> 4 </td><td> 14.0±1.9 </td><td> 5.1±0.2 </td><td> 2.7±0.2 </td><td> 3.1±0.1 </td><td> 4.9±1.9 </td></tr><tr ><td> 5 </td><td> 3.5±0.1 </td><td> 9.1±2.9 </td><td> 3.7±0.1 </td><td> 3.6±0.2 </td><Td> 4.7±0.4 </td></tr><tr><td> 6 </td><td> 4.0±0.2 </td><td> 8.6±0.1 </td><td> 5.0±0.4 </td><td> 3.3±0.1 </td><td> 7.1±0.6 </td></tr><tr><td> 7 </td><td> 3.6±0.4 </td><Td> 3.2±0.1 </td><td> 3.1±0.4 </td><td> 3.4±0.2 </td><td> 3.3±0.2 </td></tr><tr><td> 8 </td><td> 3.2±0.1 </td><td> 3.5±0.2 </td><td> 3.5±0.2 </td><td> 3.3±0.1 </td><td> 3.8±0.8 </td></tr><tr><td> 10 </td><td> 2.3±1.8 </td><td> 2.7±1.6 </td><td> 2.2±1.9 </td><Td> 3.6±3.5 </td><td> 3.6±0.3 </td></tr><tr><td> 16 </td><td> 4.7±1.6 </td><td> 4.3±1.0 </td><td> 4.2±0.8 </td><td> 8.9±0.6 </td><td> 6.6±0.7 </td></tr><tr><td> 17 </td><td> 1.5±0.3 </td><td> 3.3±0.3 </td><td> 3.5±0.1 </td><td> 3.5±0.2 </td><td> 1.5±0.2 </td></tr><tr><td> 18 </td><td> 2.5±1.3 </td><td> 1.7±0.1 </td><td> 2.9±0.5 </td><td> 3.9± 0.6 </td><td> 2.4±1.1 </td></tr><tr><td> 21 </td><td>> 100 </td><td>> 100 </td><td >> 100 </td><td>> 100 </td><td>> 100 </td></tr><tr><td> 22 </td><td> 2.4±0.7 </td><td> 3.7±0.1 </td><td> 3.6±0.1 </td><td> 5.2±0.4 </td><td> 3.0±0.2 </td></tr><tr><td> 23 </td><td>> 100 </td><td>> 100 </td><td>> 100 </td><td>> 100 </td><td>> 100 </td></tr><tr><td> 24 </td><td> 6.2±2.6 </td><td> 1.5±0.3 </td><td> 1.6±0.2 </td><td> 6.6± 0.4 </td><td> 3.1±0.6 </td></tr><tr><td> 26 </td><td> 4.1±0.3 </td><td> 1.6±0.1 </td><td> 1.6±0.1 </td><td> 1.8±0.4 </td><td> 2.4±1.3 </td></tr><tr><td> 27 </td><td>> 100 </td><td>> 100 </td><td>> 100 </td><td>> 100 </td><td>> 100 </td></tr><tr><td> 28 </td><td>> 100 </td><td>> 100 </td><td> 58.8±10.0 </td><td>> 100 </td><td> 85.8±7.4 </td></tr><tr><td> 29 </td><td> 3.9±0.1 </td><td> 10.1±1.8 </td><td> 3.1±0.1 </ Td><td> 3.7±0.1 </td><td> 12.2±6.5 </td></tr><tr><td> 30 </td><td> 13.4±5.3 </td><td> 4.9±1.6 </td><td> 3.8±0.1 </td><td> 12.3±3.3 </td><td> 3.7±0.4 </td></tr><tr><td> 32 </ Td><td> 27.9±2.8 </td><td> 22.3±8.4 </td><td> 9.7±0.9 </td><td> 17.7±0.9 </td><td> 19.8±2.7 </ Td></tr><tr><td> 33 </td><td> 3.1±0.2 </td><td> 3.5±0.3 </td><td> 3.5±0.4 </td><td> 3.7±0.4 </td><td> 2.8±0.2 </td></tr><tr><td> 34 </td><td> 3.5±0.2 </td><td> 9.9±0.7 </ Td><td> 4.4±0.2 </td><td> 5.2±0.6 </td><td> 3.2±0.1 </td></tr><tr><td> 35 </td><td>> 100 </td><td> 13.9±0.7 </td><td> 40.5±2.7 </td><td> 71.8±1.9 </td><td> 47.9±1.8 </td></tr><tr><td> 36 </td><td> 84.9±18.9 </td><td> 53.0±0.7 </td><td> 55.9±0.5 </td><td>> 100 </td><td> 56.6±4.6 </td></tr><tr><td> 37 </td><td> 44.7±5.0 </td><td> 42.5±3.9 </td><td> 30.4± 7.7 </td><td> 53.6±1.3 </td><td> 15.5±0.7 </td></tr><tr><td> 38 </td><td> 6 4.3±2.4 </td><td> 53.7±4.8 </td><td> 55.0±0.1 </td><td> 62.5±5.2 </td><td> 19.9±5.6 </td></tr ><tr><td>靛玉红-3'-肟</td><td> 25.5±3.2 </td><td> 9.0±2.1 </td><td> 19.2±0.6 </td><Td> 37.0±2.0 </td><td> 36.7±2.0 </td></tr><tr><td> Roscovitine </td><td>19.6±2.2^b</Td><td> 9.0±2.1 </td><td>24.6±1.9^c</td><td> 8.8±1.5 </td><td> 7.6±2.2 </td></tr></TBODY></TABLE> ^a IC ₅₀ value is the mean of three replicates ± SD. ^b Literature reported IC ₅₀ = 14.7 μM. ^c Literature reported IC ₅₀ = 30.1 μM. Table II

Example: Cell cycle regulation analysis

The regulatory mechanisms involved in the compounds of formula I are analyzed according to conventional methods. A549 cells were treated with 0.5 μg/ml of aphidicolin for 24 hours to synchronize them to the G ₁ /S phase, followed by treatment with vehicle (0.1% DMSO) or compound 10, respectively. At a specific time point, the cells were trypsinized and bound to cells of the supernatant. The cells were washed twice with PBS, fixed at 4 ^o C for 30 minutes and rinsed again with PBS. The cells were then incubated with 0.1% Triton X-100/PBS for 10 minutes, centrifuged and resuspended in PI solution containing RNase A (50 μg/ml) and PI (50 μg/ml). DNA content was analyzed by FACScan and CellQuest software. .

As shown in Fig. 1A and Fig. 1B, the results of flow cytometry showed that compound 10 caused the cell division cycle to remain in the G1 phase, and the number of sub-G1 (sub-G1) population was increased by the mechanism of apoptosis. Specifically, the quantitative data of Figure 1C shows that the sub-G1 population increased significantly from 6% in 8 hours to 40% in 24 hours.

In addition, further analysis of the state of cell cycle regulators, including cyclin D1 and CDK4/6 (known to be involved in the early regulation of G1), as well as cyclin E and CDK2 (known to phosphorylate Rb, is the cell from G1 to S Key steps of the period).

Western blot analysis was performed according to conventional methods. The protein lysate was separated by SDS-PAGE and transferred to a nitrocellulose membrane, wherein the membrane was blocked with 5% skim milk in PBS buffer for 1 hour, and then cultured in primary antibody for 1 hour at room temperature. . The membrane was then rinsed well with PBS buffer and incubated in secondary antibody for 1 hour at room temperature. Proteins were visualized by Immobilon Western Chemiluminescent HRP Substrate and the density of each bright band was measured using Gene-Tools version 4.0.

The inventors further found that Compound 10 promotes the positive regulation of cyclin D1 and maintains its high concentration, as shown in FIG. On the other hand, Compound 10 induces a short-term rise in cyclin E content followed by a decrease and a decrease in the phosphorylation state of Rb. Taken together, these observations show that Compound 10 induces apoptosis in the early stage of G1 and stops the cell cycle.

Example: Analysis of Apoptotic Protease Activity

The activation of apoptosis proteases 3, 8, and 9 was evaluated by a panel of apoptosis protease colorimetric assays. A549 cells were treated with compound 10 (20 μM) for 24 hours. The receptors for the apoptosis proteases 3, 8, and 9 were DEVD-AFC, IETD-AFC, and LEHD-AFC, respectively. The absorbance at 400 nm (excitation wavelength) and 505 nm (fluorescence wavelength) was measured by an ELISA reader, respectively. The results showed that apoptotic proteases 3, 8, and 9 all activated after treatment with compound 10 (Fig. 3A), and the PARP fragmentation of apoptosis protease 3 correlated with time (Fig. 3B). From this, it can be seen that Compound 10 inhibits the growth of cancer cells, and this inhibition is involved in the regulation of apoptotic proteases.

Example: CT-26 xenograft mouse model

The colorectal cancer inhibition ability in vivo test of the compound of formula I was carried out using Balb/c mice. Balb/c mice were subcutaneously inoculated with CT-26 cells (1×10 ⁷ cells/mouse), and the tumor size was measured every 2 to 3 days. When the tumor volume reached 100 to 140 mm ³ , the mice were divided into mice. Three groups, six in each group, were tested. The vehicle, cisplatin (2 mg/kg as a positive control) and compound 10 (10 mg/kg) were administered intraperitoneally daily. The length and width of the tumor were measured every 2 to 3 days, and the tumor volume was calculated as the length *width ² /2.

As a result, as shown in Fig. 4A and Fig. 4B, tumor growth inhibition similar to administration of cisplatin was observed in mice administered Compound 10, but the weight loss was less pronounced. From this, it can be inferred that the toxic effect caused by the compound 10 is relatively mild at the aforementioned dose, indicating that the compound 10 has a tumor suppressing ability comparable to that of cisplatin but is less toxic.

Example: Analysis of CDK inhibitory activity

Different compounds of formula I were assayed for CDK inhibitory activity according to conventional methods (see Kim et al, Exp. Mol. Med. 35(5):421-430; Kubo et al, Clin. Cancer Res. 5(12): 4279 -4286), wherein the protein serine/threonine kinase CDK4/CCND1 (cdk4/cyclin D1) was treated with a compound at a concentration of 10 μM, and the results are shown in Table 3 below, showing that the compound of formula I has significant significance for CDK. Inhibition activity.         <TABLE border="1" borderColor="#000000" width="_0011"><TBODY><tr><td> compound</td><td> R¹</td>< Td> R²</td><td> R³</td><td> percent inhibition</td></tr><tr><td> 4 </td><td> H </td><td><i>p</i>-Cl-Ph </td><td><i>p</i>-pyridyl</td> <td> 97 </td></tr><tr><td> 5 </td><td> H </td><td><i>p</i>-Cl-Ph </td> <td> 6-quinolinyl</td><td> 98 </td></tr><tr><td> 8 </td><td> H </td><td> 3-methyl Isoxazolyl</td><td> 6-quinolinyl</td><td> 79 </td></tr><tr><td> 10 </td><td> MeO </td ><td> 3-methylisoxazolyl</td><td> 6-quinolinyl</td><td> 88 </td></tr><tr><td> 15 </td ><td> H </td><td><i>p</i>-CO₂Me-Ph </td><td> 6-quinolinyl</td>< Td> 98 </td></tr><tr><td> 16 </td><td> H </td><td> 2-naphthyl</td><td> 6-quinolinyl< /td><td> 99 </td></tr><tr><td> 17 </td><td> H </td><td><i>p</i>-CF₃-Ph </td><td> 6-quinolinyl</td><td> 99 </td></tr><tr><td> 22 </td><td> H </td><td><i>p</i>-NO₂-Ph </td><td> 6-quinolinyl</td><td> 96 </td ></tr><tr><td> 24 </td><t d> Me </td><td><i>p</i>-Cl-Ph </td><td> 6-quinolinyl</td><td> 99 </td></tr> <tr><td> 25 </td><td> H </td><td><i>p</i>-F-Ph </td><td> 6-quinolinyl</td> <td> 98 </td></tr><tr><td> 27 </td><td> MeO </td><td><i>p</i>-Cl-Ph </td> <td> 6-quinolinyl</td><td> 99 </td></tr><tr><td> 32 </td><td> MeO </td><td><i>p </i>-NH₂-Ph </td><td> 6-quinolinyl</td><td> 93 </td></tr><tr><td> 33 </td><td> MeO </td><td><i>p</i>-Br-Ph </td><td> 6-quinolinyl</td><td> 98 </ Td></tr><tr><td> 34 </td><td> HO </td><td><i>p</i>-Br-Ph </td><td> 6-quine啉基基</td><td> 96 </td></tr></TBODY></TABLE> Table 3       

The above embodiments are merely illustrative in nature and are not intended to limit the application or the application or use of the embodiments. As used herein, the term "exemplary" means "as an example, instance or description." Any of the exemplary embodiments herein is not necessarily to be construed as preferred or advantageous over other embodiments.

In addition, while at least one exemplary embodiment has been presented in the foregoing embodiments, it should be understood that a It should also be understood that the embodiments described herein are not intended to limit the scope, use, or configuration of the claimed application. Conversely, the foregoing embodiments may provide one or more embodiments of the invention in the form of the invention. Furthermore, the scope of the patent application includes the known equivalents and all foreseeable equivalents in the application of the present application.

Figure 1A shows the DNA content at a specific time point after release of Compound 10-treated cells from a synchronized state (X-axis represents fluorescence value; Y-axis represents event); Figure 1B shows distribution of cell cycle at different time points; Figure 1C shows The proportion of cells in the secondary G1 phase.

Figure 2 shows the expression of G1 phase-associated regulatory factor proteins in various cell cycles after treatment with Compound 10.

Figure 3A shows the activity of various apoptotic proteases after treatment with Compound 10; Figure 3B shows that Compound 10 promotes the cleavage of Apoptotic Protease 3 by PARP-1.

4A and 4B show the inhibition of tumor growth and the change in body weight of the compound 10 in the mouse test, respectively.

Claims (13)

A compound of formula I or a pharmaceutically acceptable salt thereof: Wherein m is 1, 2, 3 or 4, n is 0, 1, 2 or 3; R ¹ is independently selected from H, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ ) alkane a group consisting of an oxy group, a hydroxyl group, a halogen group, a cyano group, and a nitro group; and the R ² group is selected from the group consisting of a (C ₆ -C ₁₈ ) aryl group and a (C ₃ -C ₁₈ ) heteroaryl group. And R ² is optionally via one or more halo, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ ) alkoxycarbonyl, halo (C ₁ -C ₆ )alkyl, cyano, nitro or amine; and R ³ is selected from (C ₆ -C ₁₈ )aryl and (C ₃ -C ₁₈ )heteroaryl A group consisting of, and R ³ is optionally substituted with one or more halo, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ ) alkoxy, hydroxy or nitro. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R ¹ is independently selected from the group consisting of H, (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ ) alkoxy, hydroxy And a group consisting of halogen groups. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R ² is selected from the group consisting of phenyl, naphthyl, isoxazolyl, thienyl and furanyl. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R ³ is selected from the group consisting of phenyl, pyridyl, quinolyl, isoxazolyl and isothiazolyl. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 1 and n is 1, and R ¹ is substituted at the position of the carbon atom No. 5 of the indolone structure. The compound of claim 1, wherein R ² is phenyl or isoxazolyl, and R ³ is quinolyl, phenyl or pyridyl, or a pharmaceutically acceptable salt thereof. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: (E)-2-(1-(4-chlorobenzyl)-2-one (Carbinoline-3-ylidene)-N-(pyridin-4-yl)acetamide, (E)-2-(1-(4-chlorobenzyl)-2-ketoporphyrin-3 -ylidene)-N-(quinolin-6-yl)acetamide, (E)-N-(4-methoxyphenyl)-2-(1-((3-methylisoxazole)- 5-yl)methyl)-2-ketoporphyrin-3-ylidene)acetamide, (E)-2-(1-((3-methylisoxazol-5-yl)methyl) )-2-ketoporphyrin-3-ylidene)-N-(pyridin-4-yl)acetamide, (E)-2-(1-((3-methylisoxazole-5-) (meth)-2-ketoporphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide, (E)-N-(4-hydroxyphenyl)-2- (1-((3-Methylisoxazole-5-yl)methyl)-2-one porphyrin-3-ylidene) acetamide, (E)-2-(5-methoxy 1-((3-methylisoxazole-5-yl)methyl)-2-one porphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide, E)-N-(2-iodophenyl)-2-(1-((3-methylisoxazole-5-yl)methyl)-2-one porphyrin-3-ylidene) Indoleamine, (E)-N-(3-iodophenyl)-2-(1-((3-methylisoxazol-5-yl)methyl)-2-one porphyrin-3- Subunit) acetamidine, (E)-2-(1-((3- (iso)oxazol-5-yl)methyl)-2-ketoporphyrin-3-ylidene)-N-phenylacetamide, (E)-2-(1-((3-methyl) Isoxazol-5-yl)methyl)-2-ketoporphyrin-3-ylidene)-N-(4-nitrophenyl)acetamidine, (E)-4-((2- Methyl 3-(2-oxo-2-(quinolin-6-ylamino)ethyl)porphyrin-1-yl)methyl)benzoate, (E)-2-( 1-(naphthalen-2-ylmethyl)-2-ketoporphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide, (E)-2-(2-Sideoxy-1-(4-(trifluoromethyl)benzyl)porphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide, (E)-2-(1-(4-bromobenzyl)-2-ketoporphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide, (E)-2 -(1-(3-Cyanobenzyl)-2-ketoporphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide, (E)-2-(5- Bromo-1-(4-chlorobenzyl)-2-one porphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide, (E)-2-(1-( 4-cyanobenzyl)-2-ketoporphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide, (E)-2-(1-(4-nitro) Benzyl)-2-ketoporphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide, (E)-2-(1-(3-chlorobenzyl)-2 -ketoporphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide, (E)-2-(1-(4-chlorobenzyl)-5-methyl-2 -ketoporphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide, (E)-2-(1-(4-fluorobenzyl)-2-ketooxime Benz-3-yl)-N-(quinolin-6-yl)acetamide, (E)-2-(1-(2,6-dichlorobenzyl)-2-ketoporphyrin- 3-sub))-N-(quinolin-6-yl)acetamide, (E)-2-(1-(4-chlorobenzyl)-5-methoxy-2-ketoporphyrin -3-ylidene)-N-(quinolin-6-yl)acetamide, (E)-2-(1-(4-methoxybenzyl)-2-one porphyrin-3- Subunit)-N-(quinolin-6-yl)acetamidine Amine, (E)-N-(3-methylisoxazol-5-yl)-2-(1-((3-methylisoxazol-5-yl)methyl)-2-one oxime Porphyrin-3-ylideneacetamide, (E)-2-(1-((3-methylisoxazol-5-yl)methyl)-2-ketoporphyrin-3-ylidene -N-(pyridin-3-yl)acetamide, (E)-2-(5-methoxy-1-(4-nitrobenzyl)-2-ketoindolin-3- Subunit)-N-(quinolin-6-yl)acetamide, (E)-2-(1-(4-aminobenzyl)-5-methoxy-2-ketoporphyrin- 3-subsyl)-N-(quinolin-6-yl)acetamide, (E)-2-(1-(4-bromobenzyl)-5-methoxy-2-ketoporphyrin -3-ylidene)-N-(quinolin-6-yl)acetamide, (E)-2-(1-(4-bromobenzyl)-5-hydroxy-2-ketoporphyrin- 3-sub))-N-(quinolin-6-yl)acetamide, (E)-2-(1-(4-chlorobenzyl)-2-one porphyrin-3-ylidene) -N-(3-nitrobenzyl)acetamide, (E)-N-(3-methylisothiazol-5-yl)-2-(1-((3-methylisoxazole-5) -yl)methyl)-2-ketoporphyrin-3-ylidene) (E)-2-(5-chloro-1-(4-chlorobenzyl)-2-one porphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide, E)-2-(5-Bromo-1-(4-chlorobenzyl)-2-one porphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide, (E )-2-(1-(4-chlorobenzyl)-5-hydroxy-2-ketoporphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide, (E) -2-(2-Sideoxy-1-(thiophen-2-ylmethyl)porphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide, (E)-2- (2-Sideoxy-1-(thiophen-2-ylmethyl)porphyrin-3-ylidene)-N-(pyridin-4-yl)acetamide, (E)-2-(2-side Oxy-1-(thiophen-3-ylmethyl)porphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide, (E)-2-(1-(furan-2) -ylmethyl)-2-ketoporphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide, and (E)-2-(1-(furan-3-yl) Methyl)-2-ketoporphyrin-3-ylidene)-N-(quinolin-6-yl)acetamide. The compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, which is an anticancer drug. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein the anticancer drug is for treating at least one of lung cancer, breast cancer, liver cancer, skin cancer, central nervous system cancer, colorectal cancer, and gastric cancer. The compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, which is a CDK inhibitor. A pharmaceutical composition comprising: a therapeutically effective amount of a compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient. A use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer. A process for the preparation of a compound of formula I or a pharmaceutically acceptable salt thereof, Wherein m is 1, 2, 3 or 4, n is 0, 1, 2 or 3; R ¹ is independently selected from H, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ ) alkane a group consisting of an oxy group, a hydroxyl group, a halogen group, a cyano group and a nitro group; R ² is selected from the group consisting of H, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ ) alkoxy, ( C ₂ -C ₆ )alkynyl, (C ₁ -C ₆ )alkoxycarbonyl(C ₁ -C ₆ )alkyl, (C ₆ -C ₁₈ )aryl and (C ₃ -C ₁₈ )heteroaryl a group consisting of, and R ² is optionally via one or more halo, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkoxy a carbonyl group, a halogen (C ₁ -C ₆ )alkyl group, a cyano group, a nitro group or an amine group; and an R ³ group selected from the group consisting of (C ₆ -C ₁₈ ) aryl groups and (C ₃ -C ₁₈ ) a group consisting of heteroaryl groups, and R ³ is optionally substituted by one or more halo, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, hydroxy or nitro The method comprises the compound of formula II And the compound of formula III The reaction is carried out to obtain a compound of the formula I.