JP2024508105A - Oxindolene compound with a 7-membered heterocycle condensed at the 3- and 4-positions, and its synthesis method and use - Google Patents

Abstract

Abstract: The present invention discloses an oxindole compound having a 7-membered heterocycle fused to the 3- and 4-positions, and its synthesis method and use. The present invention provides a structure of an oxindole compound having a 7-membered nitrogen heterocycle fused to the 3 and 4 positions. The present invention includes the step of reacting propargyl alcohol containing an isatin skeleton with a nucleophile under certain conditions to produce an oxindole compound having a 7-membered nitrogen heterocycle condensed at the 3 and 4 positions. A method for synthesizing an oxindole compound in which a 7-membered heterocycle is fused to the 3- and 4-positions is provided. The present invention provides pharmaceutical compositions. The present invention further provides the use of an oxindole compound having a 7-membered nitrogen heterocycle fused to the 3,4 position in the manufacture of a medicament for treating cancer. The method of efficiently synthesizing the oxindole compound having a diversified structure and having a 7-membered nitrogen heterocycle condensed at the 3 and 4 positions according to the present invention is based on a hydrogen transfer strategy. For the first time, we achieved the efficient synthesis of a biologically active molecule containing two oxindole structures. [Selection diagram] None

Description

[Cross reference to related applications]
This application was submitted to the Chinese Patent Office on July 13, 2021, with the application number CN202110788322.7 and the title of the invention: claims priority to the Chinese patent application ``Indolene Structure, Method of Synthesis and Use thereof'', the entire contents of which are incorporated herein by reference.

The present invention relates to the technical field of drug intermediates and chemical synthesis, and in particular to an oxindole compound having a 7-membered heterocycle condensed at the 3- and 4-positions, and its synthesis method and use.

Benzazepines are the core backbone of many drugs, for example mianserin and mirtazapine are psychotropic drugs with a dual mechanism of action, and compared to tricyclic inhibitors, mianserin has lower cardiovascular toxicity and It has mild anticholinergic side effects and is one of the eight major types of antidepressants in the world. Therefore, several methods have been developed in recent years to efficiently construct benzazepine structures.

For example, in 2019, Professor Li Shuai's team rapidly and efficiently synthesized benzazepine skeletons using cheap and easily available starting materials via a hydrogen transfer strategy. The team selected indole and o-aminobenzaldehyde as starting materials and used hexafluoroisopropynyl alcohol as a solvent to achieve dearomatization of the indole ring in a one-step reaction, with aromatization as the driving force. Furthermore, we achieved an aromatization-driven ring expansion reaction catalyzed by p-toluenesulfonic acid to efficiently synthesize benzazepine compounds containing an indole structure, which led to the efficient synthesis of such drugs and analogues. A new method for the synthesis was provided (Org. Lett., 2019, 21, 6225-6230).

Furthermore, 3,4-fused indole/oxindole is the core structure of many natural products and drugs, and plays an important role in the structure-activity relationship of drugs. However, the synthesis of such structures has always been difficult in the field of organic synthesis and is currently often achieved with expensive transition metal catalysts.

For example, in 2013, Professor Shokusukehei's research team reported C(sp ² )-H and C(sp ³ )-H activation reactions catalyzed by the transition metal palladium, and reported that [1,4]-palladium transfer Through this process, we achieved efficient synthesis of an oxindole compound with a 6-membered heterocycle fused to the 3 and 4 positions (Angew. Chem. Int. Ed., 2013, 52, 12385-12389).

In 2018, Professor Xu Tao's research team reported a carbon-carbon bond activation reaction based on a tension ring-opening process catalyzed by the transition metal rhodium, resulting in the fusion of a 6-membered heterocycle at the 3 and 4 positions. Oxindole-based compounds were efficiently synthesized in one step (Org. Lett., 2018, 20, 7689-7693).

Currently reported syntheses of 3,4-fused oxindoles often require transition metal catalysts, and many of the constructed structures are limited to 3,4-fused 6-membered rings.

An object of the present invention is to overcome the deficiencies of the prior art and to provide an oxindole compound having a 7-membered heterocycle fused to the 3 and 4 positions, and its synthesis method and use. The novel oxindole compound in which a 7-membered nitrogen heterocycle is fused at the 3 and 4 positions according to the present invention provides a new model molecule for drug development.

The method for synthesizing an oxindole compound having a 7-membered nitrogen heterocycle fused to the 3 and 4 positions according to the present invention efficiently synthesizes the skeleton in one step based on a hydrogen transfer process, and is easy to operate and efficient. Moreover, since the constructed skeleton contains a plurality of functional groups, it is advantageous for late-stage synthetic applications of this skeleton.

The technical solution of the present invention is achieved as follows.

An oxindole compound having a 7-membered nitrogen heterocycle condensed at the 3- and 4-positions and having a structural formula of Formula 1, Formula 2, or Formula 3.
(In formula 1, R ¹ is any one of alkyl, benzyl, allyl, propargyl, cyclopropylmethyl, cyclobutylmethyl, and preferably, when R ¹ in formula 1 is alkyl, the above-mentioned Alkyl is an alkyl having 1 to 5 carbon atoms,

R ² is any one of alkyl and benzyl, preferably when R ² in formula 1 is alkyl, the alkyl is an alkyl having 1 to 10 carbon atoms,

R ³ is any one of alkyl, benzyl, and aryl, and preferably when R ³ in formula 1 is alkyl, the alkyl is an alkyl having 1 to 10 carbon atoms,

R ⁴ is any one of alkyl, phenyl, thienyl, substituted phenyl, and preferably when R ⁴ in formula 1 is alkyl, the alkyl is an alkyl having 1 to 8 carbon atoms. ,

R ⁵ is any one of alkyl, deuterated methyl, propargyl, butynyl, benzyl, aryl, and a hydrogen atom; preferably, when R ⁵ in formula 1 is alkyl, the alkyl is is an alkyl having 1 to 10 carbon atoms,

R ⁶ is any one of methyl, ethyl, halogen atom, and hydrogen atom,

X is an oxygen atom or a sulfur atom,
Preferably, in formula 1, R ¹ is any one of methyl, ethyl, benzyl, allyl, R ² is any one of methyl, ethyl, propyl, and R ³ is , methyl, ethyl, propyl, R ⁴ is phenyl, 2-thienyl, cyclopropyl, R ⁵ is ethyl, deuterated methyl, haloethyl , propargyl, butynyl, benzyl, aryl, and a hydrogen atom, R ⁶ is a hydrogen atom, and X is an oxygen atom. Here, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ may be the same or different, each independently represents a substituent, and the adjacent R ² , R ³ may be connected to each other to form a ring.

In formula 2, R ¹ is any one of alkyl, benzyl, allyl, propargyl, cyclopropylmethyl, and cyclobutylmethyl; preferably, when R ¹ in formula 2 is alkyl, the alkyl is preferably alkyl having 1 to 5 carbon atoms, R ² is any one of alkyl and benzyl, and preferably when R ² in formula 2 is alkyl, the alkyl is , preferably alkyl having 1 to 10 carbon atoms, R ³ is any one of alkyl, benzyl, and aryl, and preferably when R ³ in formula 2 is alkyl, the alkyl is preferably alkyl having 1 to 10 carbon atoms, R ⁴ is any one of alkyl, halogen, alkoxy, thioether, carboxylate group, aryl, and aryl ether, preferably formula 2 When R ⁴ in formula 2 is alkyl, the alkyl is preferably an alkyl having 1 to 8 carbon atoms, preferably R ⁴ in formula 2 is a carboxylate group, and the carboxylate group is Preferably, it is any one of a benzoate group, a furan-2-formate group, a phenylpropiolate group, a salicylate group, a ferrocene carboxylate group, an indole acetate group, a naproxen carboxylate group, and an ibuprofen carboxylate group. , R ⁶ is any one of methyl, ethyl, a halogen atom, or a hydrogen atom, and more preferably, in formula 2, R ¹ is benzyl, and R ² is methyl, ethyl, or propyl. R ³ is any one of methyl, ethyl, propyl, and R ⁴ is a benzoate group, a furan-2-formate group, a phenylpropiolate group, a salicylate group, It is any one of a ferrocene carboxylate group, an indole acetate group, a naproxen carboxylate group, and an ibuprofen carboxylate group, and R ⁶ is a hydrogen atom. Here, R ¹ , R ² , R ³ , R ⁴ , and R ⁶ may be the same or different, and each independently represents a substituent, and adjacent R ² , R ^{The three} carbon atoms may be connected to each other to form a ring.

In formula 3, R ¹ is any one of alkyl, benzyl, allyl, propargyl, cyclopropylmethyl, and cyclobutylmethyl; preferably, when R ¹ in formula 3 is alkyl, the alkyl is preferably alkyl having 1 to 5 carbon atoms, R ² is any one of alkyl and benzyl, and preferably when R ² in formula 3 is alkyl, the alkyl is , preferably alkyl having 1 to 10 carbon atoms, R ³ is any one of alkyl, benzyl, and aryl, and preferably when R ³ in formula 3 is alkyl, the alkyl is preferably alkyl having 1 to 10 carbon atoms, and R ⁶ is any one of methyl, ethyl, a halogen atom, and a hydrogen atom. Preferably, in formula 3, R ¹ is any one of benzyl, allyl, R ² is any one of methyl, ethyl, propyl, and R ³ is methyl, ethyl. , propyl, and R ⁶ is a hydrogen atom. Here, R ¹ , R ² , R ³ , and R ⁶ may be the same or different, and each independently represents a substituent, and the carbon atoms of adjacent R ² and R ³ may be connected to each other to form a ring. )

The compounds according to the invention may exist in one or more stereoisomeric forms. Various isomers include tautomers, geometric isomers, enantiomers, diastereomers, and the like. All these isomers and mixtures of these isomers are within the protection scope of the present invention.

Based on the same inventive concept, the present invention also provides a method for synthesizing an oxindole compound having a 7-membered nitrogen heterocycle fused to the 3 and 4 positions, and a schematic diagram of the synthesis process of the present invention is shown in FIG. As shown in

Propargyl alcohol containing an isatin skeleton and a nucleophilic reagent were uniformly mixed in a solvent and reacted in the presence of a catalyst at 25 to 90°C to condense a 7-membered nitrogen heterocycle at the 3 and 4 positions. comprising producing an oxindole compound;

Here, the structural formula of propargyl alcohol containing the isatin skeleton is shown by Formula 4.

(In formula 4, R ¹ is any one of alkyl, benzyl, allyl, propargyl, cyclopropylmethyl, and cyclobutylmethyl, preferably when R ¹ in formula 4 is alkyl, The alkyl is preferably an alkyl having 1 to 5 carbon atoms, R ² is any one of alkyl and benzyl, and preferably when R ² in formula 4 is alkyl, The alkyl is preferably an alkyl having 1 to 10 carbon atoms, R ³ is any one of alkyl, benzyl, and aryl, and preferably R ³ in formula 4 is alkyl. , the alkyl is preferably an alkyl having 1 to 10 carbon atoms, and R ⁴ is any one of alkyl, halogen, alkoxy, thioether, carboxylate group, aryl, arylether, and trimethylsilyl. Yes, and preferably, when R ⁴ in formula 4 is a carboxylate group, the carboxylate group is preferably a benzoate group, a furan-2-formate group, a phenylpropiolate group, a salicylate group, a ferrocenecarboxylate group. , an indole acetate group, a carboxylate group of naproxen, and a carboxylate group of ibuprofen. Preferably, when R ⁴ in formula 4 is an alkyl, the alkyl is preferably a carbon It is an alkyl group of numbers 1 to 8, and R ⁶ is any one of methyl, ethyl, a halogen atom, and a hydrogen atom. Here, R ¹ , R ² , R ³ , R ⁴ , R ⁶ may be the same or different, each independently represents a substituent, and adjacent carbon atoms of R ² and R ³ may be linked to each other to form a ring.)

As a result of detecting the above reaction by thin layer chromatography, when the reaction is completed, purification is performed to obtain a purified product of an oxindole compound having a 7-membered nitrogen heterocycle condensed at the 3 and 4 positions.

Specifically, the above reaction process is as follows.

Propynyl alcohol active molecules generate arene cations with acid catalysts, then nucleophiles in the system attack to generate arene intermediates, and electron-deficient allenes undergo intramolecular hydrogen transfer with acid catalysts. , a zwitterionic intermediate is formed, and further, a benzo 7-membered nitrogen heterocyclic structure is generated by an intramolecular cyclization reaction, and an oxindole compound in which a 7-membered nitrogen heterocycle is condensed at the 3 and 4 positions is obtained. It will be done. Specifically, the route of the synthesis principle is as follows.

Preferably, in the above synthesis method, the reaction is carried out at 60°C.

In the above method, the nucleophile is an alcohol, a mercaptan, or water. Preferably, the nucleophile is alcohol or water. More preferably, the nucleophile is water, since water is free from contamination, is low cost, and provides a high yield of the desired product when used as the nucleophile.

In the above synthesis method, the molar ratio of the isatin skeleton-containing propargyl alcohol and the nucleophilic reagent is 1:(10 to 50). Preferably, the molar ratio of the isatin skeleton-containing propargyl alcohol and the nucleophile is 1:10.

In the above synthesis method, the solvent is toluene or a halogenated hydrocarbon. Preferably, the solvent is toluene or dichloromethane. More preferably, the solvent is dichloromethane.

In the above synthesis method, the amount of the solvent used is 10 to 25 L per mole of propargyl alcohol containing an isatin skeleton. Preferably, the amount of the solvent used is such that 20 L of the solvent is added per mole of propargyl alcohol containing an isatin skeleton.

In the above synthesis method, the catalyst is added before the reaction, and the catalyst is a Brønsted acid or a Lewis acid. Preferably, the catalyst is trifluoromethanesulfonate, diphenyl phosphate, or binaphthol phosphate.

In the above synthesis method, the amount of the catalyst used is 5 to 50 mol%. Preferably, the amount of the catalyst used is 30 mol%.

Based on the same invention concept, the present invention also provides oxindole compounds having a 7-membered nitrogen heterocycle fused to the 3 and 4 positions, and pharmaceutically acceptable salts, solvates, and hydrates thereof. , polycrystals, co-crystals, tautomers, geometric isomers, enantiomers, diastereomers, or mixtures or prodrugs thereof, and pharmaceutically acceptable carriers, diluents, excipients, or combinations thereof. Provided is a pharmaceutical composition comprising: In the present invention, the carriers, diluents, and excipients are not particularly limited, but may be carriers, diluents, and excipients that are well known to those skilled in the art and are applicable to pharmaceutical compositions.

Based on the same inventive concept, the present invention also provides the third and fourth priority in the production of drugs for treating cancer, atherosclerosis, tuberculosis, cardiovascular diseases, epilepsy, psychiatric disorders, Parkinson's disease, Alzheimer's disease. Provided is the use of an oxindole compound fused with a 7-membered nitrogen heterocycle.

The beneficial effects of the present invention are as follows.
1. The present invention efficiently synthesizes an oxindole skeleton in which a 7-membered nitrogen heterocycle is fused to the 3- and 4-positions by a one-step reaction under mild temperature conditions. The technical solution of the present invention provides a convenient and easy method for synthesizing an oxindole skeleton in which a 7-membered nitrogen heterocycle is fused to the 3 and 4 positions, and the 7-membered nitrogen heterocycle is fused to the 3 and 4 positions through a hydrogen transfer process. For the first time, we realized the efficient construction of an oxindole skeleton fused with nitrogen heterocycles.

2. The present invention has developed a method for efficiently synthesizing oxindole compounds in which a 7-membered nitrogen heterocycle is fused to the 3rd and 4th positions, and has a variety of structures including multiple functional groups. We provide a compound library containing an oxindole skeleton with a 7-membered nitrogen heterocycle fused to the 3 and 4 positions, providing new model molecules for drug development.

3. This method requires mild reaction conditions and can be applied to a wide variety of propynyl alcohol raw materials. In addition, such propynyl alcohol raw materials can be produced in-situ using various terminal alkynes and are easily available. . The present invention provides an experimental basis for efficiently constructing an oxindole skeleton in which a 7-membered nitrogen heterocycle is fused to the 3 and 4 positions, which has good biological activity, and has good practical significance. and has application value.

FIG. 2 is a diagram showing the route of the synthesis process of the present invention.

Hereinafter, with reference to the content of the embodiments of the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely explained, but the described embodiments are only some embodiments of the present invention. , obviously not all embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without any creative efforts fall within the protection scope of the present invention.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The terms used in the specification of the invention are used only for the purpose of describing specific embodiments and are not used to limit the invention. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items.

The experimental methods used in the following examples are all conventional methods unless otherwise specified. Reagents, materials, equipment, etc. used in the following examples are commercially available, unless otherwise specified. The reaction vessel used in the following examples is a 25 mL thick-walled pressure tube.
Example 1

This example provides a method for synthesizing an oxindole compound having a 7-membered nitrogen heterocycle fused to the 3 and 4 positions, which includes the following steps.
0.1 mmol of propargyl alcohol containing an isatin skeleton was placed in a reaction tube, and 1 mL of toluene and 1 mmol of a nucleophilic reagent were sequentially added. In the examples, H ₂ O is a nucleophilic reagent. Finally, 0.03 mmol of binaphthol phosphate was added as a catalyst. The reaction temperature of the system was controlled at 25° C. with continuous stirring, and the reaction was followed by spotting samples on TLC plates until the raw materials were completely reacted. After the reaction was completed, separation and purification were performed using a silica gel column, and the purified product was rotary evaporated to obtain the desired product, formula 1-1, in a yield of 50%. The reaction formula is as follows.
Example 2

The method of this example was almost the same as Example 1 except that the reaction temperature was 40° C. and the yield was 58%.
Example 3

The method of this example was almost the same as Example 1 except that the reaction temperature was 60° C. and the yield was 70%.
Example 4

The method of this example was almost the same as Example 1 except that the reaction temperature was 80° C. and the yield was 67%.
Example 5

The method of this example was almost the same as Example 1 except that the reaction solvent was 1 mL of dichloromethane, the reaction temperature was 60° C., and the yield was 88%.
Example 6

The method of this example was almost the same as Example 1 except that the reaction solvent was 2 mL of dichloromethane, the reaction temperature was 60° C., and the yield was 90%.
Example 7

The method of this example was almost the same as Example 1, except that 0.03 mmol of scandium trifluoromethanesulfonate was added as a catalyst, the reaction temperature was 60° C., and the yield was 20%.
Example 8

The method of this example was almost the same as Example 1, except that 0.03 mmol of diphenyl phosphate was added as a catalyst, the reaction temperature was 60° C., and the yield was 85%.
Example 9

The method of this example was almost the same as Example 1, except that 0.01 mmol of binaphthol phosphate was added as a catalyst, the reaction temperature was 60° C., and the yield was 29%.
Example 10

The method of this example was almost the same as Example 1, except that 0.02 mmol of binaphthol phosphate was added as a catalyst, the reaction temperature was 60° C., and the yield was 58%.
Example 11

The method of this example was almost the same as Example 1, except that 0.05 mmol of binaphthol phosphate was added as a catalyst, the reaction temperature was 60° C., and the yield was 82%.
Analysis of the results of the above parallel tests revealed that when the synthesis reaction of the present invention was carried out under the conditions of Example 6, the yield of the desired product was highest.

In Examples 12-36 below, reactions were carried out according to the operating steps of Example 6. That is, 0.1 mmol of propargyl alcohol containing an isatin skeleton was placed in a reaction tube, 2 mL of dichloromethane and 1 mmol of a nucleophilic reagent were sequentially added, and finally, 0.03 mmol of binaphthol phosphate was added as a catalyst. The reaction temperature of the system was controlled at 60° C. with continuous stirring, and the reaction was followed by spotting samples on TLC plates until the raw materials were completely reacted. After the reaction was completed, separation and purification were performed using a silica gel column, and the purified products were rotary evaporated to obtain the desired products, respectively.
Example 12

material:
Nucleophile: _H2O
Product: Chemical formula: C ₂₇ H ₂₄ N ₂ O ₂
Molecular weight: 408.1838

Structural formula:

Yield: 90%
^1H NMR (500 MHz, _CDCl3 ) δ 7.29 (d, J = 4.4 Hz, 2H), 7.23 (t, J = 11.6 Hz, 8H), 7.15 (t, J = 8.0 Hz, 1H), 7.08 (dd, J = 7.0, 3.0 Hz, 1H), 6.46 (d, J = 8.4 Hz, 1H), 6.30 (d , J = 7.6 Hz, 1H), 5.08 (d, J = 15.7 Hz, 1H), 4.84 (d, J = 15.7 Hz, 1H), 3.62-3.39 (m, 1H), 3.36-3.23 (m, 2H), 3.09 (t, J = 8.1 Hz, 1H), 2.39 (dd, J = 13.4, 7.4 Hz, 1H), 1.95 (dd, J = 14.5, 6.1 Hz, 1H), 1.53-1.43 (m, 1H), 0.47-0.31 (m, 1H) ．． ^13C NMR (125 MHz, _CDCl3 ) δ 168.4, 143.6, 143.3, 141.6, 138.3, 136.4, 130.2, 128.7, 127.4, 127.3 , 127.3, 127.1, 126.8, 126.1, 108.2, 106.6, 99.0, 76.5, 66.8, 49.7, 43.8, 27.8, 22 .8. HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₂₇ H ₂₅ N ₂ O ₂ 409.1911; found: 409.1922.
Example 13

material:
Nucleophile: _CH3OH
Product: Chemical formula: C ₃₈ H ₂₆ N ₂ O ₂
Molecular weight: 422.1994

Structural formula:

Yield: 70%
^1H NMR (500 MHz, _CDCl3 ) δ 7.38 (d, J = 7.3 Hz, 2H), 7.32 (dd, J = 14.4, 6.7 Hz, 2H), 7.28 (d, J = 4.7 Hz, 1H), 7.23-7.18 (m, 4H), 7.17-7.11 (m, 3H), 6.44 (d, J = 8.4 Hz, 1H), 6.30 (d, J = 7.6 Hz, 1H), 5.12 (d, J = 15.6 Hz, 1H), 4.89 (d, J = 15.6 Hz, 1H), 3.52 (s, 3H), 3.49 (d, J = 8.6 Hz, 1H), 3.33 (m, 1H), 3.05 (t, J = 8.2 Hz, 1H), 2.40 (dd, J = 13.2, 7.5 Hz, 1H), 2.02-1.92 (m, 1H), 1.55-1.46 (m, 1H), 0 .44 (dd, J = 7.5, 4.4 Hz, 1H). ^13C NMR (125 MHz, _CDCl3 ) δ 167.8, 143.6, 143.4, 141.0, 136.6, 136.3, 130.3, 129.1, 128.7, 127.5 , 127.5, 127.2, 127.2, 127.2, 108.1, 106.8, 98.9, 80.5, 63.7, 51.4, 49.8, 43.9, 26 .9, 22.9. HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₂₈ H ₂₇ N ₂ O ₂ 423.2067; found: 423.2074.
Example 14

material:
Nucleophile: CH ₃ CH ₂ OH
Product: Chemical formula: C ₂₉ H ₂₈ N ₂ O ₂
Molecular weight: 436.2151

Structural formula:

Yield: 72%
¹ H NMR (500 MHz, CDCl ₃ ) δ 7.38 (d, J = 7.5 Hz, 2H), 7.31 (t, J = 7.5 Hz, 2H), 7.27 - 7.16 (m, 7H), 7.13 (t, J = 8.0 Hz, 1H), 6.43 (d, J = 8.4 Hz, 1H), 6.29 (d, J = 7.6 Hz) , 1H), 5.11 (d, J = 15.6 Hz, 1H), 4.87 (d, J = 15.6 Hz, 1H), 3.69 (dt, J = 15.5, 8. 5 Hz, 2H), 3.46 (d, J = 9.1 Hz, 1H), 3.32 (m, 1H), 3.05 (t, J = 8.2 Hz, 1H), 2.41 (dd, J = 13.1, 7.5 Hz, 1H), 1.96 (m, 1H), 1.54 - 1.44 (m, 1H), 1.33 (t, J = 6.9 Hz, 3H), 0.42 (m, 1H). ^13C NMR (125 MHz, _CDCl3 ) δ 167.9, 143.6, 143.4, 141.4, 137.2, 136.7, 130.2, 128.7, 128.7, 127.5 , 127.5, 127.2, 127.2, 127.1, 108.1, 106.9, 98.9, 80.4, 64.1, 58.8, 49.9, 43.9, 27 .1, 22.9, 16.4. HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₂₉ H ₂₉ N ₂ O ₂ 437.2224; found: 437.2235.
Example 15

material:
Nucleophile: _{CD3OD
Product : Chemical formula} : _C28H23D3N2O2
Molecular weight: 425.2183

Structural formula:

Yield: 71%
^1H NMR (500 MHz, _CDCl3 ) δ 7.38 (d, J = 7.4 Hz, 2H), 7.32 (t, J = 7.5 Hz, 2H), 7.26 (d, J = 7.3 Hz, 1H), 7.22 - 7.18 (m, 4H), 7.17 - 7.12 (m, 3H), 6.43 (d, J = 8.4 Hz, 1H) , 6.30 (d, J = 7.6 Hz, 1H), 5.11 (d, J = 15.6 Hz, 1H), 4.88 (d, J = 15.6 Hz, 1H), 3 .48 (d, J = 8.9 Hz, 1H), 3.38 - 3.27 (m, 1H), 3.04 (t, J = 8.2 Hz, 1H), 2.40 (dd, J = 13.2, 7.5 Hz, 1H), 2.05 - 1.91 (m, 1H), 1.56 - 1.46 (m, 1H), 0.49 - 0.37 (m, 1H). ^13C NMR (125 MHz, _CDCl3 ) δ 167.8, 143.6, 143.4, 143.4, 141.1, 136.6, 136.4, 130.3, 130.2, 129.1 , 128.7, 127.5, 127.5, 127.2, 127.2, 127.2, 108.1, 106.8, 98.9, 80.4, 63.8, 49.8, 43 .9, 26.8, 22.9. HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₂₈ H ₂₄ D ₃ N ₂ O ₂ 426.2255; found: 426.2263.
Example 16

material:
Nucleophile: CF ₃ CH ₂ OH
_{Product : Chemical formula} : _C29H25F3N2O2
Molecular weight: 490.1868

Structural formula:

Yield: 62%
^1H NMR (500 MHz, _CDCl3 ) δ 7.38 (d, J = 7.5 Hz, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.28 (d, J = 7.2 Hz, 1H), 7.25-7.13 (m, 6H), 7.08 (s, 1H), 6.46 (d, J = 8.4 Hz, 1H), 6.32 (d, J = 7.6 Hz, 1H), 5.12 (d, J = 15.6 Hz, 1H), 4.86 (d, J = 15.6 Hz, 1H), 4.09 (m , 1H), 4.03-3.90 (m, 1H), 3.49-3.31 (m, 2H), 3.09 (t, J = 8.2 Hz, 1H), 2.42 ( dd, J = 13.4, 7.5 Hz, 1H), 2.01 (m, 1H), 1.57-1.49 (m, 1H), 0.51-0.36 (m, 1H) ．． ^13C NMR (125 MHz, _CDCl3 ) δ 167.5, 143.6, 143.4, 139.8, 136.4, 132.9, 130.8, 129.8, 128.7, 127.6 , 127.5, 127.4, 126.9, 124.0 (q, J = 276.3 Hz), 108.3, 106.5, 99.3, 80.5, 63.8, 61.9 (q, J = 34.7 Hz), 49.9, 43.9, 27.1, 22.8. HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₂₉ H ₂₆ F ₃ N ₂ O ₂ 491.1941; found: 491.1950.
Example 17

material:
Nucleophile: 2-bromoethanol Product: Chemical formula: C ₂₉ H ₂₇ BrN ₂ O ₂
Molecular weight: 514.1256

Structural formula:

Yield: 62%
¹ H NMR (500 MHz, CDCl ₃ ) δ 7.37 (t, J = 7.2 Hz, 2H), 7.32 (t, J = 7.5 Hz, 2H), 7.29 - 7.22 (m, 2H), 7.20 (d, J = 7.7 Hz, 4H), 7.15 (dd, J = 10.8, 5.1 Hz, 2H), 6.44 (d, J = 8.4 Hz, 1H), 6.31 (d, J = 7.6 Hz, 1H), 5.11 (d, J = 15.6 Hz, 1H), 4.87 (d, J = 15. 6 Hz, 1H), 4.03 (m, 1H), 3.88 (m, 1H), 3.72 - 3.48 (m, 2H), 3.44 (d, J = 8.8 Hz, 1H), 3.34 (m, 1H), 3.07 (t, J = 8.2 Hz, 1H), 2.46 (dd, J = 13.2, 7.5 Hz, 1H), 1. 99 (m, 1H), 1.60 - 1.46 (m, 1H), 0.42 (m, 1H). ^13C NMR (125 MHz, _CDCl3 ) δ 167.6, 143.6, 143.3, 140.8, 136.5, 135.6, 130.4, 129.1, 128.7, 127.5 , 127.5, 127.3, 127.2, 127.1, 108.1, 106.7, 99.1, 80.1, 63.8, 63.4, 49.9, 43.9, 31 .6, 27.1, 22.8. HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₂₉ H ₂₈ BrN ₂ O ₂ 515.1329; found: 515.1338.
Example 18

material:
Nucleophile: Propynyl Alcohol Product: Chemical Formula: C ₃₀ H ₂₆ N ₂ O ₂
Molecular weight: 446.1994

Structural formula:

Yield: 67%
^1H NMR (500 MHz, _CDCl3 ) δ 7.38 (d, J = 7.4 Hz, 2H), 7.34 (d, J = 7.3 Hz, 2H), 7.32 - 7.26 (m, 2H), 7.21 (dd, J = 7.0, 2.9 Hz, 3H), 7.20 - 7.13 (m, 3H), 6.44 (d, J = 8.4 Hz, 1H), 6.31 (d, J = 7.6 Hz, 1H), 5.11 (d, J = 15.6 Hz, 1H), 4.88 (d, J = 15.6 Hz, 1H), 4.42 (dd, J = 15.5, 2.4 Hz, 1H), 4.34 (dd, J = 15.5, 2.3 Hz, 1H), 3.49 (d, J = 9.1 Hz, 1H), 3.34 (m, 1H), 3.06 (t, J = 8.2 Hz, 1H), 2.49 (t, J = 2.4 Hz, 1H), 2.49 - 2.43 (m, 1H), 2.10 - 1.96 (m, 1H), 1.55 - 1.45 (m, 1H), 0.48 - 0.28 (m, 1H) ). ^13C NMR (125 MHz, _CDCl3 ) δ 167.7, 143.7, 143.5, 140.4, 136.5, 134.6, 130.5, 129.4, 128.8, 127.5 , 127.5, 127.4, 127.3, 127.2, 108.2, 106.7, 99.1, 81.2, 80.6, 74.5, 64.1, 52.4, 49 .9, 43.9, 27.9, 22.9. HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₃₀ H ₂₇ N ₂ O ₂ 447.2067; found: 447.2090.
Example 19

material:
Nucleophile: Butynyl Alcohol Product: Chemical Formula: C ₃₁ H ₂₈ N ₂ O ₂
Molecular weight: 460.2151

Structural formula:

Yield: 68%
^1H NMR (500 MHz, _CDCl3 ) δ 7.38 (d, J = 7.4 Hz, 2H), 7.32 (t, J = 7.5 Hz, 2H), 7.30-7.26 (m, 1H), 7.24 (s, 1H), 7.19 (d, J = 7.3 Hz, 5H), 7.14 (t, J = 8.0 Hz, 1H), 6.44 (d, J = 8.4 Hz, 1H), 6.30 (d, J = 7.6 Hz, 1H), 5.11 (d, J = 15.6 Hz, 1H), 4.87 (d , J = 15.6 Hz, 1H), 3.85-3.78 (m, 1H), 3.73 (dd, J = 15.2, 6.9 Hz, 1H), 3.46 (d, J = 9.1 Hz, 1H), 3.34 (m, 1H), 3.06 (t, J = 8.2 Hz, 1H), 2.60 (m, 2H), 2.44 (dd, J = 13.2, 7.5 Hz, 1H), 2.04 (dd, J = 5.9, 3.4 Hz, 1H), 1.98 (m, 1H), 1.57-1.46 (m, 1H), 0.42 (m, 1H). ^13C NMR (125 MHz, _CDCl3 ) δ 167.7, 143.7, 143.4, 141.0, 136.6, 136.2, 130.3, 129.0, 128.7, 128.6 , 127.5, 127.2, 127.2, 127.2, 126.9, 108.1, 106.8, 99.0, 81.4, 80.3, 69.6, 63.9, 61 .7, 49.9, 43.9, 27.1, 22.8, 20.9. HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₃₁ H ₂₉ N ₂ O ₂ 461.2224; found: 461.2232.
Example 20

material:
Nucleophile: Tryptopol Product: Chemical formula: C ₃₇ H ₃₃ N ₃ O ₂
Molecular weight: 551.2573

Structural formula:

Yield: 77%
^1H NMR (500 MHz, _CDCl3 ) δ 8.10 (s, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.36 (t, J = 7.3 Hz, 2H ), 7.34 - 7.27 (m, 3H), 7.23 (dd, J = 16.4, 7.0 Hz, 3H), 7.16 (t, J = 6.1 Hz, 5H) , 7.14 - 7.08 (m, 2H), 7.07 (t, J = 3.9 Hz, 1H), 6.41 (t, J = 6.8 Hz, 1H), 6.28 ( t, J = 7.3 Hz, 1H), 5.11 (d, J = 15.6 Hz, 1H), 4.85 (d, J = 15.6 Hz, 1H), 3.92 (dd, J = 15.5, 7.2 Hz, 1H), 3.85 (dd, J = 15.6, 7.3 Hz, 1H), 3.42 (d, J = 9.1 Hz, 1H), 3.28 (m, 1H), 3.15 (t, J = 7.0 Hz, 2H), 3.02 (t, J = 8.1 Hz, 1H), 2.32 (dd, J = 13 .1, 7.5 Hz, 1H), 1.83 (m, 1H), 1.52 - 1.35 (m, 1H), 0.36 (m, 1H). ^13C NMR (125 MHz, _CDCl3 ) δ 167.9, 143.6, 143.4, 141.4, 136.9, 136.6, 136.2, 130.2, 128.8, 128.7 , 127.7, 127.5, 127.3, 127.2, 127.1, 126.8, 122.3, 121.9, 119.3, 118.9, 112.9, 111.2, 108 .1, 106.9, 98.9, 80.4, 63.9, 63.8, 49.9, 43.9, 26.9, 26.9, 22.9. HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₃₇ H ₃₄ N ₃ O ₂ 552.2646; found: 552.2655.
Example 21

material:
Nucleophile: Citronellol Product: Chemical formula: C ₃₇ H ₄₂ N ₂ O ₂
Molecular weight: 546.3246

Structural formula:

Yield: 72%
^1H NMR (500 MHz, _CDCl3 ) δ 7.31 (d, J = 7.5 Hz, 2H), 7.25 (t, J = 7.5 Hz, 2H), 7.18 (dd, J = 8.9, 5.5 Hz, 2H), 7.15 - 7.09 (m, 5H), 7.08 - 7.04 (m, 1H), 6.36 (d, J = 8.4 Hz, 1H), 6.23 (d, J = 7.6 Hz, 1H), 5.03 (dd, J = 15.7, 8.4 Hz, 2H), 4.86 - 4.74 (m , 1H), 3.71 - 3.51 (m, 2H), 3.43 (t, J = 11.1 Hz, 1H), 3.32 - 3.19 (m, 1H), 2.99 ( t, J = 8.1 Hz, 1H), 2.32 (dd, J = 13.0, 7.5 Hz, 1H), 2.04 - 1.83 (m, 3H), 1.73 - 1 .64 (m, 2H), 1.62 (s, 3H), 1.55 (s, 3H), 1.53 - 1.46 (m, 2H), 1.46 - 1.37 (m, 2H ), 1.37 - 1.28 (m, 1H), 1.17 - 1.09 (m, 1H), 0.94 - 0.85 (m, 3H), 0.44 - 0.25 (m , 1H). ^13C NMR (125 MHz, _CDCl3 ) δ 167.8, 143.6, 143.3, 141.6, 137.4, 137.4, 136.7, 131.3, 130.2, 128.7 , 128.6, 127.5, 127.5, 127.2, 127.2, 127.1, 124.9, 108.0, 106.9, 98.9, 80.1, 80.0, 63 .9, 61.3, 49.9, 43.9, 37.8, 37.8, 37.5, 37.0, 29.5, 29.4, 27.1, 25.8, 25.5 , 25.5, 22.9, 19.9, 19.6, 17.7, 17.7. HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₃₇ H ₄₃ N ₂ O ₂ 547.3319; found: 547.3330.
Example 22

material:
Nucleophile: _H2O
Product: Chemical formula: C ₂₃ H ₂₀ N ₂ O ₂
Molecular weight: 356.1525

Structural formula:

Yield: 64%
^1H NMR (500 MHz, _CDCl3 ) δ 7.28 (d, J = 7.9 Hz, 1H), 7.24 - 7.17 (m, 5H), 7.01 (s, 1H), 6 .58 (d, J = 7.6 Hz, 1H), 6.51 (d, J = 8.4 Hz, 1H), 4.54 (dt, J = 17.7, 8.9 Hz, 2H) , 3.35 (m, 1H), 3.28 (d, J = 8.7 Hz, 1H), 3.15 (s, 1H), 3.11 (t, J = 8.2 Hz, 1H) , 2.40 (dd, J = 13.4, 7.4 Hz, 1H), 2.23 (t, J = 2.5 Hz, 1H), 2.07 - 1.94 (m, 1H), 1.55 - 1.45 (m, 1H), 0.39 (d, J = 11.9 Hz, 1H). ^13C NMR (125 MHz, _CDCl3 ) δ 167.4, 143.6, 142.3, 141.5, 138.3, 130.3, 127.4, 127.2, 126.7, 125.9 , 108.5, 106.7, 99.0, 76.5, 72.1, 66.8, 49.8, 29.3, 27.9, 22.8. HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₂₃ H ₂₁ N ₂ O ₂ 357.1598; found: 357.1606.
Example 23

material:
Nucleophile: _H2O
Product: Chemical formula: C ₃₁ H ₃₀ N ₂ O ₂
Molecular weight: 462.2307

Structural formula:

Yield: 72%
¹ H NMR (500 MHz, CDCl ₃ ) δ 7.25 - 7.18 (m, 7H), 7.17 - 7.12 (m, 2H), 7.10 (dd, J = 12.8, 4 .7 Hz, 3H), 6.45 (d, J = 8.4 Hz, 1H), 6.27 (d, J = 7.6 Hz, 1H), 5.11 (d, J = 15.8 Hz, 1H), 4.76 (d, J = 15.7 Hz, 1H), 4.17 (d, J = 30.6 Hz, 1H), 3.40 (dd, J = 11.7, 8 .9 Hz, 1H), 2.96 - 2.84 (m, 2H), 2.48 (m, 1H), 1.62 - 1.50 (m, 2H), 1.38 (d, J = 14.2 Hz, 2H), 1.28 - 1.12 (m, 3H), 0.90 (dd, J = 13.8, 9.1 Hz, 2H). ^13C NMR (125 MHz, _CDCl3 ) δ 168.6, 144.1, 143.1, 141.9, 139.3, 136.3, 130.0, 128.7, 127.3, 127.0 , 126.9, 126.6, 125.5, 108.2, 106.6, 98.8, 75.1, 50.4, 43.7, 39.7, 33.3, 29.2, 26 .9, 25.4, 24.0, 21.3. HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₃₁ H ₃₁ N ₂ O ₂ 463.2380; found: 463.2408.
Example 24

material:
Nucleophile: _H2O
Product: Chemical formula: C ₂₂ H ₁₉ BrN ₂ O
Molecular weight: 406.0681

Structural formula:

Yield: 80%
¹ H NMR (500 MHz, CDCl ₃ ) δ 7.56 (s, 1H), 7.25 - 7.20 (m, 4H), 7.19 - 7.14 (m, 1H), 6.97 ( t, J = 8.0 Hz, 1H), 6.57 (s, 1H), 6.24 (d, J = 8.4 Hz, 1H), 6.10 (d, J = 7.6 Hz, 1H), 4.95 (d, J = 15.7 Hz, 1H), 4.80 (d, J = 15.7 Hz, 1H), 3.94 (d, J = 8.5 Hz, 1H) , 3.47 - 3.34 (m, 2H), 2.51 (dd, J = 13.5, 5.9 Hz, 1H), 2.17 - 2.07 (m, 1H), 2.03 (dt, J = 11.5, 5.8 Hz, 1H), 1.90 (td, J = 11.9, 6.0 Hz, 1H). ^13C NMR (125 MHz, _CDCl3 ) δ 168.1, 144.4, 143.5, 140.4, 136.5, 130.9, 130.1, 129.8, 128.7, 127.5 , 127.3, 112.3, 108.3, 107.2, 99.5, 61.3, 49.7, 43.8, 27.9, 24.6. HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₂₂ H ₂₀ BrN ₂ O 407.0754; found: 407.0764.
Example 25

material:
Nucleophile: _H2O
Product: _{Chemical formula : C24H24N2O2}
Molecular weight: 372.1838

Structural formula:

Yield: 72%
^1H NMR (500 MHz, _CDCl3 ) δ 7.21 - 7.10 (m, 5H), 7.00 (t, J = 8.0 Hz, 1H), 6.83 (s, 1H), 6 .34 (d, J = 8.4 Hz, 1H), 6.11 (d, J = 7.6 Hz, 1H), 4.92 (d, J = 15.8 Hz, 1H), 4.75 (d, J = 15.8 Hz, 1H), 3.45 (t, J = 8.2 Hz, 1H), 3.40 - 3.31 (m, 1H), 3.14 (d, J = 8.5 Hz, 1H), 2.80 (dd, J = 48.4, 6.7 Hz, 1H), 2.51 (t, J = 9.7 Hz, 1H), 2.14 - 1. 99 (m, 1H), 1.91 (td, J = 15.3, 8.5 Hz, 2H), 0.79 (m, 1H), 0.73 - 0.63 (m, 1H), 0 .41 - 0.27 (m, 2H), 0.24 (m, 1H). ^13C NMR (125 MHz, _CDCl3 ) δ 168.7, 144.3, 143.6, 140.7, 136.9, 130.6, 129.1, 127.9, 127.7, 126.5 , 108.4, 106.8, 99.3, 74.6, 66.9, 50.4, 44.2, 28.5, 24.5, 17.5, 0.65. HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₂₄ H ₂₅ N ₂ O ₂ 373.1911; found: 373.1922.
Example 26

material:
Nucleophile: _H2O
Product: Chemical formula: C ₂₉ H ₂₄ N ₂ O ₃
Molecular weight: 448.1784

Structural formula:

Yield: 80%
^1H NMR (500 MHz, _CDCl3 ) δ 8.13 (d, J = 7.4 Hz, 2H), 7.83 (s, 1H), 7.77 (s, 1H), 7.57 (t , J = 7.4 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 7.25 - 7.21 (m, 3H), 7.18 (d, J = 8. 4 Hz, 2H), 6.97 (t, J = 8.0 Hz, 1H), 6.28 (d, J = 8.4 Hz, 1H), 6.12 (d, J = 7.6 Hz) , 1H), 4.97 (d, J = 15.8 Hz, 1H), 4.84 (d, J = 15.8 Hz, 1H), 4.03 (d, J = 8.3 Hz, 1H) ), 3.46 (dd, J = 10.2, 5.9 Hz, 2H), 2.61 (d, J = 5.6 Hz, 1H), 2.21 (s, 1H), 2.12 - 1.98 (m, 2H). ^13C NMR (125 MHz, _CDCl3 ) δ 168.2, 163.1, 144.9, 143.3, 136.6, 136.3, 134.0, 130.3, 130.3, 128.8 , 128.7, 128.4, 127.4, 127.3, 126.9, 123.4, 108.6, 107.2, 99.4, 77.3, 77.0, 76.8, 59 .6, 49.8, 43.8, 27.9, 24.8. HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₂₉ H ₂₅ N ₂ O ₃ 449.1860; found: 449.1871.
Example 27

material:
Nucleophile: _H2O
Product : Chemical _{formula : C27H22N2O4}
Molecular weight: 438.1580

Structural formula:

Yield: 81%
^1H NMR (500 MHz, _CDCl3 ) δ 7.76 (s, 1H), 7.67 (s, 1H), 7.61 (s, 1H), 7.38 (d, J = 3.3 Hz , 1H), 7.23 (q, J = 7.5 Hz, 4H), 7.18 - 7.14 (m, 1H), 6.96 (t, J = 8.0 Hz, 1H), 6 .51 (dd, J = 3.5, 1.6 Hz, 1H), 6.26 (d, J = 8.4 Hz, 1H), 6.11 (d, J = 7.6 Hz, 1H) , 4.89 (dd, J = 59.0, 15.8 Hz, 2H), 3.99 (d, J = 8.3 Hz, 1H), 3.44 (dd, J = 9.6, 5 .8 Hz, 2H), 2.58 (dd, J = 13.4, 5.8 Hz, 1H), 2.26 - 2.12 (m, 1H), 2.00 (m, 2H). ^13C NMR (125 MHz, _CDCl3 ) δ 168.2, 154.9, 147.9, 144.8, 143.3, 142.9, 136.6, 135.6, 130.4, 128.7 , 128.5, 127.4, 127.3, 126.9, 123.5, 120.4, 112.4, 108.5, 107.2, 99.4, 59.4, 49.8, 43 .7, 27.9, 24.8. HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₂₅ H ₂₃ N ₂ O ₄ 439.1652; found: 439.1659.
Example 28

material:
Nucleophile: _H2O
Product: Chemical formula: C ₃₁ H ₂₄ N ₂ O ₃
Molecular weight: 472.1787

Structural formula:

Yield: 75%
^1H NMR (500 MHz, _CDCl3 ) δ 7.76 (s, 1H), 7.63 - 7.59 (m, 2H), 7.57 (s, 1H), 7.43 - 7.38 ( m, 1H), 7.32 (t, J = 7.6 Hz, 2H), 7.24 - 7.20 (m, 4H), 7.17 - 7.13 (m, 1H), 6.94 (t, J = 8.0 Hz, 1H), 6.24 (d, J = 8.4 Hz, 1H), 6.10 (d, J = 7.6 Hz, 1H), 4.93 (d , J = 15.8 Hz, 1H), 4.82 (d, J = 15.8 Hz, 1H), 3.95 (d, J = 8.3 Hz, 1H), 3.48 - 3.34 (m, 2H), 2.51 (dd, J = 13.4, 5.7 Hz, 1H), 2.14 (m, 1H), 2.05 - 1.86 (m, 2H). ^13C NMR (125 MHz, _CDCl3 ) δ 168.3, 150.3, 144.8, 143.4, 136.6, 135.8, 132.9, 131.2, 130.5, 128.7 , 128.7, 128.7, 127.4, 127.3, 126.9, 123.6, 119.1, 108.5, 107.3, 99.4, 89.6, 79.8, 59 .3, 49.8, 43.8, 27.8, 24.7. HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₃₁ H ₂₅ N ₂ O ₃ 473.1860; found: 473.1870.
Example 29

material:
Nucleophile: _H2O
Product: Chemical formula: C ₂₉ H ₂₄ N ₂ O ₄
Molecular weight: 464.1736

Structural formula:

Yield: 63%
^1H NMR (500 MHz, _CDCl3 ) δ 10.31 (s, 1H), 8.00 (dd, J = 8.0, 1.5 Hz, 1H), 7.77 (s, 1H), 7 .70 (s, 1H), 7.50 - 7.43 (m, 1H), 7.26 - 7.21 (m, 3H), 7.18 (d, J = 6.2 Hz, 1H), 7.02 - 6.85 (m, 3H), 6.28 (d, J = 8.4 Hz, 1H), 6.13 (d, J = 7.6 Hz, 1H), 4.96 (d , J = 15.8 Hz, 1H), 4.84 (d, J = 15.8 Hz, 1H), 4.01 (d, J = 8.2 Hz, 1H), 3.46 (dd, J = 9.5, 5.9 Hz, 2H), 2.59 (dd, J = 13.4, 5.8 Hz, 1H), 2.27 - 2.16 (m, 1H), 2.08 ( dd, J = 11.9, 5.7 Hz, 1H), 2.03 - 1.93 (m, 1H). ^13C NMR (125 MHz, _CDCl3 ) δ 168.2, 166.6, 162.3, 144.8, 143.4, 136.9, 136.5, 135.2, 130.6, 130.4 , 128.9, 128.7, 127.5, 127.3, 126.3, 124.1, 119.9, 117.8, 111.0, 108.5, 107.3, 99.5, 59 .4, 49.9, 43.8, 27.9, 24.8. HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₂₉ H ₂₅ N ₂ O ₄ 465.1809; found: 465.1825.
Example 30

material:
Nucleophile: _H2O
Product: Chemical formula: C ₃₃ H ₂₈ FeN ₂ O ₃
Molecular weight: 556.1449

Structural formula:

Yield: 70%
^1H NMR (500 MHz, _CDCl3 ) δ 7.78 (s, 1H), 7.68 (s, 1H), 7.24 (q, J = 7.5 Hz, 4H), 7.18 (d , J = 7.0 Hz, 1H), 6.97 (t, J = 7.9 Hz, 1H), 6.28 (d, J = 8.3 Hz, 1H), 6.13 (d, J = 7.5 Hz, 1H), 4.99 (d, J = 15.7 Hz, 1H), 4.91 (s, 2H), 4.83 (d, J = 15.8 Hz, 1H), 4.45 (s, 2H), 4.20 (s, 5H), 4.02 (d, J = 8.3 Hz, 1H), 3.51 - 3.40 (m, 2H), 2.59 (d, J = 12.8 Hz, 1H), 2.18 (dd, J = 16.9, 10.1 Hz, 1H), 2.00 (dd, J = 17.6, 11.8 Hz, 2H). ^13C NMR (125 MHz, _CDCl3 ) δ 168.8, 168.3, 144.9, 136.6, 136.4, 130.2, 128.7, 127.9, 127.4, 127.3 , 122.7, 107.2, 99.4, 72.4, 70.8, 70.7, 70.2, 59.6, 49.9, 43.8, 27.8, 24.8. HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₃₃ H ₂₉ FeN ₂ O ₃ 557.1522; found: 557.1533.
Example 31

material:
Nucleophile: _H2O
Product: Chemical formula: C ₃₂ H ₂₇ N ₂ O ₃
Molecular weight: 501.2052

Structural formula:

Yield: 80%
^1H NMR (500 MHz, _CDCl3 ) δ 8.26 (s, 1H), 7.68 (s, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.50 (s , 1H), 7.27 (d, J = 7.4 Hz, 1H), 7.25 - 7.20 (m, 4H), 7.19 - 7.15 (m, 1H), 7.14 - 7.06 (m, 3H), 6.94 (dd, J = 11.7, 4.3 Hz, 1H), 6.23 (d, J = 8.4 Hz, 1H), 6.10 (d , J = 7.6 Hz, 1H), 4.96 (d, J = 15.7 Hz, 1H), 4.82 (d, J = 15.7 Hz, 1H), 3.91 (d, J = 8.5 Hz, 1H), 3.87 (s, 2H), 3.44 - 3.32 (m, 2H), 2.45 (dd, J = 13.1, 5.0 Hz, 1H) , 2.17 - 2.04 (m, 1H), 2.01 - 1.79 (m, 2H). ^13C NMR (125 MHz, _CDCl3 ) δ 168.4, 168.3, 144.8, 143.3, 136.6, 136.4, 136.2, 130.3, 128.7, 128.1 , 127.4, 127.3, 127.2, 127.1, 123.6, 122.9, 122.3, 119.9, 118.8, 111.4, 108.5, 107.2, 107 .1, 99.4, 59.4, 49.8, 43.7, 31.2, 27.8, 24.7. HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₃₂ H ₂₈ N ₃ O ₃ 502.2125; found: 502.2134.
Example 32

material:
Nucleophile: _H2O
Product: Chemical formula: C ₃₆ H ₃₂ N ₂ O ₄
Molecular weight: 556.2362

Structural formula:

Yield: 52%
^1H NMR (500 MHz, _CDCl3 ) δ 7.73 - 7.61 (m, 4H), 7.47 (d, J = 9.6 Hz, 1H), 7.44 - 7.36 (m, 1H), 7.23 - 7.20 (m, 3H), 7.21 - 7.12 (m, 2H), 7.10 - 6.99 (m, 2H), 6.92 (dt, J = 11.4, 8.0 Hz, 1H), 6.20 (dd, J = 14.3, 8.4 Hz, 1H), 6.08 (dd, J = 9.9, 7.7 Hz, 1H) ), 4.95 (d, J = 15.7 Hz, 1H), 4.81 (dd, J = 15.7, 4.6 Hz, 1H), 3.98 (dd, J = 15.1, 7.4 Hz, 1H), 3.92 - 3.85 (m, 1H), 3.82 (d, J = 7.4 Hz, 3H), 3.37 (m, 2H), 2.50 - 2.41 (m, 1H), 2.09 (dt, J = 13.1, 6.2 Hz, 1H), 2.01 - 1.79 (m, 2H), 1.60 (dd, J = 7.1, 3.0 Hz, 3H). ^13C NMR (125 MHz, _CDCl3 ) δ 171.3, 171.3, 168.3, 168.2, 157.8, 157.8, 144.8, 143.3, 143.2, 136.6 , 136.3, 134.2, 133.9, 133.9, 130.3, 130.3, 129.5, 128.9, 128.9, 128.7, 128.2, 128.2, 127 .5, 127.5, 127.4, 127.3, 127.1, 127.1, 126.3, 126.2, 126.2, 123.1, 122.9, 119.2, 119.1 , 108.5, 107.2, 105.6, 105.6, 99.4, 59.4, 55.4, 49.8, 49.8, 45.3, 45.3, 43.7, 27 .8, 27.7, 24.7, 24.7, 18.3, 18.3. HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₃₆ H ₃₃ N ₂ O ₄ 557.2435; found: 557.2445.
Example 33

material:
Nucleophile: _H2O
Product: Chemical formula: C ₃₅ H ₃₆ N ₂ O ₃
Molecular weight: 532.2726

Structural formula:

Yield: 60%
^1H NMR (500 MHz, _CDCl3 ) δ 7.63 (d, J = 13.8 Hz, 1H), 7.48 (d, J = 7.5 Hz, 1H), 7.27 - 7.19 (m, 7H), 7.05 (dd, J = 15.0, 7.9 Hz, 2H), 6.94 (dd, J = 14.2, 7.9 Hz, 1H), 6.23 ( t, J = 7.9 Hz, 1H), 6.10 (dd, J = 7.3, 5.9 Hz, 1H), 4.96 (dd, J = 15.7, 2.3 Hz, 1H) ), 4.81 (dd, J = 15.8, 3.2 Hz, 1H), 3.92 (t, J = 9.2 Hz, 1H), 3.87 - 3.80 (m, 1H) , 3.46 - 3.35 (m, 2H), 2.53 - 2.44 (m, 1H), 2.37 (dd, J = 12.0, 7.1 Hz, 2H), 2.12 (dd, J = 14.0, 5.9 Hz, 1H), 2.03 - 1.88 (m, 2H), 1.77 (m, 1H), 1.52 (dd, J = 7.1 , 4.0 Hz, 3H), 0.82 (dd, J = 9.4, 6.7 Hz, 6H). ^13C NMR (125 MHz, _CDCl3 ) δ 171.4, 168.2, 144.8, 143.3, 141.1, 136.6, 136.3, 130.3, 129.6, 129.6 , 128.7, 127.4, 127.3, 127.3, 123.0, 122.9, 108.5, 107.1, 99.4, 99.3, 59.4, 49.8, 45 .1, 44.9, 43.7, 30.2, 27.8, 24.7, 22.4, 18.3. HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₃₅ H ₃₇ N ₂ O ₃ 533.2799; found: 533.2810.
Example 34

material:
Nucleophile: _H2O
Product: Chemical formula: C ₂₁ H ₁₈ N ₂ O ₂
Molecular weight: 330.1368

Structural formula:

Yield: 70%
^1H NMR (500 MHz, _CDCl3 ) δ 7.36 - 7.27 (m, 5H), 7.22 - 7.15 (m, 2H), 6.52 (d, J = 8.5 Hz, 1H), 6.25 (d, J = 7.5 Hz, 1H), 5.06 (d, J = 15.7 Hz, 1H), 4.84 (d, J = 15.7 Hz, 1H) , 3.70 - 3.58 (m, 2H), 3.56 - 3.48 (m, 1H), 3.02 (d, J = 6.1 Hz, 1H), 2.11 (t, J = 5.3 Hz, 1H), 2.01 - 1.90 (m, 2H); ^13C NMR (125 MHz, _CDCl3 ) δ 186.4, 168.2, 144.9, 144.7, 138 .4, 135.9, 133.6, 128.8, 127.7, 127.4, 126.9, 108.9, 108.3, 99.9, 65.3, 50.1, 43.9 , 25.3, 24.6. HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₂₁ H ₁₉ N ₂ O ₂ 331.1441; found: 331.1430.
Example 35

material:
Nucleophile: _H2O
Product: Chemical formula: C ₁₇ H ₁₆ N ₂ O ₂
Molecular weight: 280.1212

Structural formula:

Yield: 78%
^1H NMR (500 MHz, _CDCl3 ) δ 7.24 (s, 1H), 7.14 (s, 1H), 6.55 (d, J = 8.5 Hz, 1H), 6.34 (d , J = 7.5 Hz, 1H), 5.87 (m, 1H), 5.30 - 5.20 (m, 2H), 4.52 - 4.42 (m, 1H), 4.35 - 4.24 (m, 1H), 3.64 (m, 2H), 3.58 - 3.49 (m, 1H), 3.02 (t, J = 5.1 Hz, 1H), 2.11 (t, J = 5.5 Hz, 1H), 2.04 - 1.90 (m, 2H); ^13C NMR (125 MHz, _CDCl3 ) δ 186.4, 167.8, 144.9, 144 .7, 138.4, 133.6, 131.7, 126.8, 117.6, 108.8, 108.3, 99.7, 65.4, 50.1, 42.5, 25.3 , 24.6. HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₁₇ H ₁₇ N ₂ O ₂ 281.1285; found: 281.1302.
Example 36

material:
Nucleophile: _H2O
Product: Chemical formula: C ₂₅ H ₂₀ N ₂ O ₂
Molecular weight: 380.1525

Structural formula:

Yield: 66%
^1H NMR (500 MHz, _CDCl3 ) δ 7.59 (dd, J = 14.4, 7.4 Hz, 4H), 7.31 - 7.19 (m, 3H), 7.05 (d, J = 20.5 Hz, 1H), 6.96 (t, J = 7.9 Hz, 1H), 6.31 (d, J = 8.5 Hz, 1H), 6.09 (d, J = 7.5 Hz, 1H), 5.03 (d, J = 15.7 Hz, 1H), 4.80 (d, J = 15.7 Hz, 1H), 3.42 (dd, J = 16. 2, 8.9 Hz, 2H), 3.36 - 3.28 (m, 1H), 2.83 (d, J = 5.9 Hz, 1H), 1.89 (dd, J = 17.3 , 12.2 Hz, 1H), 1.80 - 1.70 (m, 2H); ^13C NMR (125 MHz, _CDCl3 ) δ 186.4, 168.3, 144.9, 144.7, 138 .4, 133.6, 133.5, 133.3, 132.9, 128.8, 127.8, 127.7, 126.9, 126.4, 126.2, 126.1, 125.3 , 108.9, 108.4, 100.0, 65.4, 50.1, 44.2, 25.3, 24.6. HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₂₅ H ₂₁ N ₂ O ₂ 381.1598; found: 381.1607.

The foregoing is only a preferred embodiment of the present invention and is not intended to limit the present invention, and all modifications, equivalent substitutions, improvements, etc. that may be made without departing from the spirit and principles of the present invention are applicable to the present invention. shall be included in the scope of protection.

Claims (25)

An oxindole compound having a 7-membered nitrogen heterocycle condensed at the 3- and 4-positions, characterized in that the structural formula is represented by Formula 1, Formula 2, or Formula 3.
(In Formula 1, R ¹ is any one of alkyl, benzyl, allyl, propargyl, cyclopropylmethyl, and cyclobutylmethyl, and R ² is any one of alkyl and benzyl. , R ³ is any one of alkyl, benzyl, aryl, R ⁴ is any one of alkyl, phenyl, thienyl, substituted phenyl, R ⁵ is alkyl, deuterium is any one of methyl, propargyl, butynyl, benzyl, aryl, or hydrogen atom, R ⁶ is any one of methyl, ethyl, a halogen atom, or a hydrogen atom, and X is oxygen or a sulfur atom.
In formula 2, R ¹ is any one of alkyl, benzyl, allyl, propargyl, cyclopropylmethyl, and cyclobutylmethyl, and R ² is any one of alkyl and benzyl, R ³ is any one of alkyl, benzyl, aryl, R ⁴ is any one of alkyl, halogen, alkoxy, thioether, carboxylate group, aryl, aryl ether, R ⁶ is any one of methyl, ethyl, a halogen atom, and a hydrogen atom.
In formula 3, R ¹ is any one of alkyl, benzyl, allyl, propargyl, cyclopropylmethyl, and cyclobutylmethyl, and R ² is any one of alkyl and benzyl, R ³ is any one of alkyl, benzyl, and aryl, and R ⁶ is any one of methyl, ethyl, a halogen atom, and a hydrogen atom. ) When R ¹ in formula 1 is alkyl, the alkyl is an alkyl having 1 to 5 carbon atoms,
When R ² in formula 1 is alkyl, the alkyl is an alkyl having 1 to 10 carbon atoms,
When R ³ in formula 1 is alkyl, the alkyl is an alkyl having 1 to 10 carbon atoms,
When R ⁴ in formula 1 is alkyl, the alkyl is an alkyl having 1 to 8 carbon atoms,
When R ⁵ in formula 1 is alkyl, the alkyl is an alkyl having 1 to 10 carbon atoms, and a 7-membered nitrogen heterocycle is fused to the 3rd and 4th positions according to claim 1. Oxindolene compound. In formula 1,
R ¹ is any one of methyl, ethyl, benzyl, allyl,
R ² is any one of methyl, ethyl, propyl,
R ³ is any one of methyl, ethyl, propyl,
R ⁴ is any one of phenyl, 2-thienyl, cyclopropyl,
R ⁵ is any one of ethyl, deuterated methyl, haloethyl, propargyl, butynyl, benzyl, aryl, and hydrogen atom,
R ⁶ is a hydrogen atom,
The oxindole compound having a 7-membered nitrogen heterocycle condensed at the 3rd and 4th positions according to claim 1, wherein X is an oxygen atom. The oxind in which a 7-membered nitrogen heterocycle is fused to the 3rd and 4th positions according to claim 1, wherein in formula 1, adjacent carbon atoms of R ² and R ³ are connected to each other to form a ring. Ren compound. When R ¹ in formula 2 is alkyl, the alkyl is an alkyl having 1 to 5 carbon atoms,
When R ² in formula 2 is alkyl, the alkyl is an alkyl having 1 to 10 carbon atoms,
When R ⁴ in formula 2 is alkyl, the alkyl is preferably an alkyl having 1 to 8 carbon atoms,
R ⁴ in formula 2 is a carboxylate group, and the carboxylate group is preferably a benzoate group, a furan-2-formate group, a phenylpropiolate group, a salicylate group, a ferrocenecarboxylate group, an indole acetate group, The oxindole compound having a 7-membered nitrogen heterocycle condensed at the 3rd and 4th positions according to claim 1, which is any one of the carboxylate group of naproxen and the carboxylate group of ibuprofen. . In formula 2,
R ¹ is benzyl;
R ² is any one of methyl, ethyl, propyl,
R ³ is any one of methyl, ethyl, propyl,
R ⁴ is any one of a benzoate group, a furan-2-formate group, a phenylpropiolate group, a salicylate group, a ferrocene carboxylate group, an indole acetate group, a naproxen carboxylate group, and an ibuprofen carboxylate group. can be,
The oxindole compound having a 7-membered nitrogen heterocycle condensed at the 3rd and 4th positions according to claim 1, wherein R ⁶ is a hydrogen atom. The oxind in which a 7-membered nitrogen heterocycle is fused to the 3rd and 4th positions according to claim 1, wherein in formula 2, adjacent carbon atoms of R ² and R ³ are connected to each other to form a ring. Ren compound. When R ¹ in formula 3 is alkyl, the alkyl is an alkyl having 1 to 5 carbon atoms,
When R ² in formula 3 is alkyl, the alkyl is an alkyl having 1 to 10 carbon atoms, and a 7-membered nitrogen heterocycle is fused to the 3rd and 4th positions according to claim 1. Oxindolene compound. In formula 3,
R ¹ is any one of benzyl and allyl,
R ² is any one of methyl, ethyl, propyl,
R ³ is any one of methyl, ethyl, propyl,
The oxindole compound having a 7-membered nitrogen heterocycle condensed at the 3rd and 4th positions according to claim 1, wherein R ⁶ is a hydrogen atom. The oxind in which a 7-membered nitrogen heterocycle is fused to the 3rd and 4th positions according to claim 1, wherein in formula 3, adjacent carbon atoms of R ² and R ³ are connected to each other to form a ring. Ren compound. 3, 4 according to claim 1, characterized in that the structural formula is represented by any one of formulas 1-1 to 1-14, 2-1 to 2-9, and 3-1 to 3-3. An oxindole compound with a 7-membered nitrogen heterocycle fused to the position.
A 7-membered nitrogen heterocycle is fused to the 3 and 4 positions according to any one of claims 1 to 11, characterized in that it contains tautomers, geometric isomers, enantiomers, or diastereomers. Stereoisomers of oxindole compounds. Propargyl alcohol containing an isatin skeleton and a nucleophilic reagent are uniformly mixed in a solvent and reacted in the presence of a catalyst at 25 to 90°C to condense a 7-membered nitrogen heterocycle at the 3 and 4 positions. the step of producing an oxindole compound;
The structural formula of propargyl alcohol containing the isatin skeleton is shown by formula 4,
The oxindide having a 7-membered nitrogen heterocycle fused to the 3- and 4-positions according to any one of claims 1 to 11, wherein the nucleophile is an alcohol, a mercaptan, or water. A method for synthesizing a stereoisomer of a ren compound or an oxindole compound having a 7-membered nitrogen heterocycle fused to the 3 and 4 positions according to claim 12.
(In formula 4, R ¹ is any one of alkyl, benzyl, allyl, propargyl, cyclopropylmethyl, and cyclobutylmethyl, and R ² is any one of alkyl and benzyl. , R ³ is any one of alkyl, benzyl, aryl, and R ⁴ is any one of alkyl, halogen, alkoxy, thioether, carboxylate group, aryl, arylether, trimethylsilyl. (R ⁶ is any one of methyl, ethyl, halogen atom, and hydrogen atom.) When R ¹ in formula 4 is alkyl, the alkyl is an alkyl having 1 to 5 carbon atoms,
When R ² in formula 4 is alkyl, the alkyl is an alkyl having 1 to 10 carbon atoms,
When R ³ in formula 4 is alkyl, the alkyl is an alkyl having 1 to 10 carbon atoms,
When R ⁴ in formula 4 is a carboxylate group, the carboxylate group is preferably a benzoate group, a furan-2-formate group, a phenylpropiolate group, a salicylate group, a ferrocenecarboxylate group, an indole acetate group, a naproxen group. any one of the carboxylate group of and the carboxylate group of ibuprofen,
The synthesis method according to claim 13, characterized in that when R ⁴ in formula 4 is alkyl, the alkyl is preferably an alkyl having 1 to 8 carbon atoms. 14. The synthesis method according to claim 13, wherein in formula 4, adjacent carbon atoms of ^R2 and ^R3 are connected to each other to form a ring. When the nucleophile is an alcohol, the alcohol includes methanol, ethanol, tritiated methanol, 2,2,2-trifluoroethanol, 2-bromoethanol, propynyl alcohol, butynyl alcohol, tryptopol, or citronellol, the synthesis method according to claim 13. The synthesis method according to claim 13 or 16, wherein the molar ratio of the isatin skeleton-containing propargyl alcohol and the nucleophilic reagent is 1: (10 to 50). 14. The synthesis method according to claim 13, wherein the solvent is toluene or a halogenated hydrocarbon. The synthesis method according to claim 13 or 18, wherein the amount of the solvent used is 10 to 25 L per mole of propargyl alcohol containing an isatin skeleton. The synthesis method according to claim 13, characterized in that the catalyst is added before the reaction, and the catalyst is a Brønsted acid or a Lewis acid. The synthesis method according to claim 13 or 20, characterized in that the amount of the catalyst used is 5 to 50 mol%. The oxindole compound having a 7-membered nitrogen heterocycle fused to the 3- and 4-positions according to any one of claims 1 to 11, and its pharmaceutically acceptable salts, solvates, hydrates, and a crystal, co-crystal, tautomer, geometric isomer, enantiomer, diastereomer, or mixture or prodrug thereof, and a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof; A pharmaceutical composition comprising: 3rd and 4th positions according to any one of claims 1 to 11 in the manufacture of a drug for treating cancer, atherosclerosis, tuberculosis, cardiovascular disease, epilepsy, mental illness, Parkinson's disease, Alzheimer's disease. Use of an oxindole compound having a 7-membered nitrogen heterocycle fused thereto, or a stereoisomer of the oxindole compound having a 7-membered nitrogen heterocycle fused to the 3- and 4-positions according to claim 12. The 7-membered nitrogen complex at the 3- and 4-positions according to any one of claims 1 to 11 in the treatment of cancer, atherosclerosis, tuberculosis, cardiovascular disease, epilepsy, mental illness, Parkinson's disease, Alzheimer's disease. Use of a stereoisomer of an oxindole compound having a condensed ring or a stereoisomer of an oxindole compound having a 7-membered nitrogen heterocycle condensed at the 3 and 4 positions according to claim 12. 23. Use of a pharmaceutical composition according to claim 22 in the treatment of cancer, atherosclerosis, tuberculosis, cardiovascular diseases, epilepsy, psychiatric diseases, Parkinson's disease, Alzheimer's disease.