Synthesis methods of novel chiral ligands, metal chelates, various unnatural amino acids, maraviroc and key intermediates thereof

Abstract

The present invention discloses a novel chiral ligand, a metal chelate, a plurality of unnatural amino acids, a method for synthesizing maraviroc and a key intermediate thereof. The present invention selects (R)-2-methylproline as a starting material, utilizes nickel chelate to induce asymmetric splitting to obtain (S)-β 3 ‑amino acid, and (S)‑3‑amino‑3‑phenylpropionic acid as a key intermediate to synthesize maraviroc with high yield and ee value of more than 98.2%. The method of the invention has a wide source of raw materials, mild synthesis process conditions, easy control, and high optical purity of the product.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a synthesis method of a novel chiral ligand, a metal chelate, a plurality of unnatural amino acids, maraviroc and key intermediates thereof. Background Art

[0002] 4,4-Difluoro-N-[(1S)-3-[exo-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-phenylpropyl]cyclohexane-1-carboxamide, also known as maraviroc, is a new anti-HIV drug developed by Pfizer, USA. It was approved by the US FDA in August 2007 and is the first CC-chemokine receptor 5 (CCR5) antagonist drug for the treatment of HIV. It is often used as a monomer. Maraviroc can bind to the CCR5 receptor on the cell surface, blocking CCR5-tropic HIV-1 from entering the cell, thereby inhibiting HIV infection. Therefore, it can significantly hinder and delay the occurrence and development of AIDS.

[0003] In the preparation of maraviroc, the construction of chiral amino acids is the key point of the synthetic route.

[0004] The document Organic Process Research & Development 2008, 12, 1094-1103 uses benzaldehyde, ammonium acetate and malonic acid to condense to obtain racemic β-amino acid, and then esterifies to obtain the corresponding amino acid methyl ester, and then resolves it with L-(+)-tartaric acid to obtain the key intermediate (S)-3-amino-3-phenylpropionic acid methyl ester tartrate. The total yield of this reaction route is only 10%, and the ee value of the final product after two recrystallizations is greater than 95%. The chemical reaction route is as follows.

[0005]

[0006] This method uses tartaric acid splitting, which results in a low overall reaction yield, poor optical purity, and a low ee value, which greatly increases the cost. At the same time, the reaction uses concentrated sulfuric acid to produce a large amount of acidic wastewater, which is not conducive to environmental protection and has great operational risks.

[0007] Therefore, there is still a need to develop new methods for synthesizing maraviroc and its key intermediates in this field.

[0008] In addition, nickel chelate-induced asymmetric synthesis of non-natural chiral amino acids has been a hot topic in recent years, but a good synthesis method for the asymmetric splitting of non-natural α-substituted-β amino acids has not yet been developed. The existing chiral ligand uses substituted proline as the chiral control part. Although it can achieve the splitting of non-natural α amino acids and non-natural β-substituted-β amino acids, the chiral center of proline may undergo self-racemization. Therefore, it is urgent to develop a new chiral ligand to solve the problem of self-racemization. At the same time, the new chiral ligand can be applied to the asymmetric splitting of non-natural chiral α-substituted-β amino acids. Summary of the invention

[0009] The purpose of the present invention is to provide a method for synthesizing a novel chiral ligand, a metal chelate, a plurality of unnatural amino acids, maraviroc and key intermediates thereof, so as to improve the optical purity and yield and save the synthesis cost.

[0010] In a first aspect of the present invention, a method for synthesizing a novel quaternary carbon chiral ligand is provided, the method comprising the steps of synthesizing a compound of formula VI,

[0011]

[0012] Wherein, n is an integer from 1 to 4;

[0013] R is selected from C1-C4 alkyl, C1-C4 haloalkyl, unsubstituted or substituted phenyl, wherein the substituted phenyl means that the phenyl has 1-5 substituents, and each substituent is independently selected from: amino, halogen, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl;

[0014] R 1 Selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, unsubstituted or substituted phenyl, wherein the substituted phenyl means that the phenyl has 1-5 substituents, and each substituent is independently selected from: amino, halogen, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl;

[0015] R 2 Selected from hydrogen, halogen, amino, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl;

[0016] R 3 Selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, unsubstituted or substituted phenyl, -(C1-C4 alkylene)-(unsubstituted or substituted phenyl); wherein the substituted phenyl refers to the phenyl having 1-5 substituents, each substituent is independently selected from: amino, halogen, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl.

[0017] In a second aspect of the present invention, a method for separating novel α-amino acids, α-substituted β-amino acids and β-substituted β-amino acids is provided, wherein the synthesis method comprises the steps of hydrolyzing a compound of formula VI to obtain an α-amino acid, an α-substituted β-amino acid and a β-substituted β-amino acid as shown in formula VII,

[0018]

[0019] Wherein, n is an integer from 1 to 4, and m is an integer from 0 to 1;

[0020] R is selected from C1-C4 alkyl, C1-C4 haloalkyl, unsubstituted or substituted phenyl, wherein the substituted phenyl means that the phenyl has 1-5 substituents, and each substituent is independently selected from: amino, halogen, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl;

[0021] R 1 Selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, unsubstituted or substituted phenyl, wherein the substituted phenyl means that the phenyl has 1-5 substituents, and each substituent is independently selected from: amino, halogen, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl;

[0022] R 2 Selected from hydrogen, halogen, amino, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl;

[0023] R 3 Selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, unsubstituted or substituted phenyl, -(C1-C4 alkylene)-(unsubstituted or substituted phenyl); wherein the substituted phenyl means that the phenyl has 1-5 substituents, and each substituent is independently selected from: amino, halogen, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl;

[0024] R 4 Selected from hydrogen, unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted C3-C6 heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, wherein the substitution refers to having 1-5 substituents, each substituent is independently selected from: amino, halogen, hydroxyl, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl.

[0025] R 5Selected from hydrogen, unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted C3-C6 heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, wherein the substitution refers to having 1-5 substituents, each substituent is independently selected from: amino, halogen, hydroxyl, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl.

[0026] * is a chiral center, which includes various configurations, S configuration or R configuration.

[0027] In another preferred embodiment, the compound of formula VI is synthesized by the following steps:

[0028] The compound of formula IV and the non-natural amino acid shown in formula V generate the compound of formula VI under the action of nickel salt,

[0029]

[0030] Among them, n, m, R, R 1 , R 2 , R 3 , R 4 and R 5 The definition of is as mentioned above.

[0031] In another preferred embodiment, the compound of formula V is various non-natural α amino acids, α-substituted β amino acids and β-substituted β amino acids. For example, alanine, phenylalanine, phenylalanine, 3-methoxyphenylalanine, 3-methylphenylalanine, 4-fluorophenylalanine, 3-methoxyphenylglycine, 3-bromophenylglycine, 2-amino-3-(3,5-diiodo-4-hydroxyphenyl)propionic acid, 2-amino-3-(naphthalene-1-yl)propionic acid, 2-amino-3-(benzothiophene-3-yl)propionic acid, 2-amino-3-(thiophene-3-yl)propionic acid, 2-amino-2-cyclobutylacetic acid, 2-amino-4,4,4-trifluorobutyric acid , 2-aminopentanoic acid, 2-amino-3-methylbutyric acid, 2-amino-4-methylthiobutyric acid, 2-amino-3-(1H-indolyl)propionic acid, 2-amino-5-methyl-4-hexenoic acid, 2-aminoglutaric acid, 2,5-diamino-5-pentanoic acid, homocysteine, 3-amino-2-benzylpropionic acid, 3-amino-2-(4-fluorobenzyl)propionic acid, 3-amino-2-(4-methoxybenzyl)propionic acid, 3-amino-2-methylpropionic acid, 2-(aminomethyl)-4-methylpentanoic acid , 3-amino-2-cyclohexylpropionic acid, 3-amino-2-phenylpropionic acid, 3-amino-2-(4-chlorophenyl)propionic acid, 3-amino-2-(4-methoxyphenyl)propionic acid, 3-amino-2-(naphthalen-1-yl)propionic acid, 3-amino-propionic acid, 3-amino-3-phenylpropionic acid, 3-amino-3-(4-methyl substituted)phenylpropionic acid, 3-amino-3-(3-methyl substituted)phenylpropionic acid, 3-amino-3-(2-methyl substituted)phenylpropionic acid, 3-amino-3-(2-fluoro substituted)phenylpropionic acid propionic acid, 3-amino-3-(4-chloro substituted)benzenepropionic acid, 3-amino-3-(3,4-dimethoxy substituted)benzenepropionic acid, 3-amino-3-(4-methoxy substituted)benzenepropionic acid, 3-amino-3-(3-methoxy substituted)benzenepropionic acid, 3-amino-3-(pyridin-4yl)propionic acid, 3-amino-3-(thiophen-2yl)propionic acid, 3-amino-3-cyclohexylpropionic acid, 3-amino-3-(naphthyl-2yl)propionic acid or 3-amino-3-(2,4,5-trifluoro substituted)benzenepropionic acid.

[0032] In another preferred embodiment, the compound of formula IV is synthesized by the following steps:

[0033]

[0034] The compound of formula III and R 3 CHO undergoes a reductive amination reaction to produce a compound of formula IV,

[0035] Among them, n, R, R 1 , R 2 and R 3 The definition of is as mentioned above.

[0036] In another preferred embodiment, the compound of formula IV is synthesized by the following steps:

[0037]

[0038] The compound of formula III and R 3 CH 2 Cl undergoes substitution reaction to generate a compound of formula IV,

[0039] Among them, n, R, R 1 , R 2 and R 3 The definition of is as mentioned above.

[0040] In another preferred embodiment, the compound of formula III is synthesized by the following steps:

[0041]

[0042] (i) (R)-2-substituted proline reacts with di-tert-butyl dicarbonate to produce (R)-1-(tert-butyloxycarbonyl)-2-methylproline;

[0043] (ii) (R)-1-(tert-butyloxycarbonyl)-2-substituted proline undergoes a condensation reaction with the compound of formula I to produce a compound of formula II;

[0044] (iii) removing the tert-butyloxycarbonyl protection from the compound of formula II to generate a compound of formula III,

[0045] Among them, n, R, R 1 and R 2 The definition of is as mentioned above.

[0046] In another preferred embodiment, R 4 It is phenyl.

[0047] The third aspect of the present invention provides a maraviroc intermediate, the structure of the maraviroc intermediate is shown in Formula VI:

[0048]

[0049] Among them, n, m, R 1 , R 2 , R 3 , R 4 and R 5 The definition of is as mentioned above.

[0050] In another preferred embodiment, the synthesis method comprises the following steps:

[0051]

[0052] The compound of formula IV and the non-natural amino acid shown in formula V are reacted with a nickel salt to generate a compound of formula VI,

[0053] Among them, n, m, R 1 , R 2 , R 3 , R 4 and R 5 The definition of is as mentioned above.

[0054] In a fourth aspect of the present invention, a novel chiral ligand is provided, wherein the structure of the chiral ligand is shown in Formula Y:

[0055]

[0056] Among them, n, R, R 1 , R 2 and R 3 The definition of is as mentioned above.

[0057] The fifth aspect of the present invention provides a method for synthesizing maraviroc, the method comprising the step of synthesizing a maraviroc intermediate, wherein the maraviroc intermediate is:

[0058]

[0059] The steps for synthesizing the key intermediate of Maraviroc are as described above.

[0060] Among them, n, R 1 , R 2 and R 3 The definition of R is as mentioned above. 4 It is phenyl.

[0061] In a sixth aspect of the present invention, a method for synthesizing a plurality of non-natural amino acids is provided, wherein the method comprises the following steps:

[0062]

[0063] (i) (R)-2-substituted proline reacts with di-tert-butyl dicarbonate to produce (R)-1-(tert-butyloxycarbonyl)-2-methylproline;

[0064] (ii) (R)-1-(tert-butyloxycarbonyl)-2-substituted proline undergoes a condensation reaction with the compound of formula I to produce a compound of formula II;

[0065] (iii) removing the tert-butyloxycarbonyl protection from the compound of formula II to generate a compound of formula III;

[0066] (iv) a compound of formula III and R 3 CHO or R 3 CH 2Cl undergoes a reductive amination reaction to produce a compound of formula IV;

[0067] (v) reacting the compound of formula IV with various non-natural amino acids of formula V in the presence of nickel salt to generate the compound of formula VI;

[0068] (vi) hydrolyzing the compound of formula VI to obtain the compound of formula VII,

[0069] Among them, n, m, R, R 1 , R 2 , R 3 , R 4 and R 5 The definition of is as mentioned above.

[0070] In another preferred embodiment, R 4 It is phenyl.

[0071] In a seventh aspect of the present invention, a method for synthesizing a key intermediate of Maraviroc is provided, wherein the key intermediate of Maraviroc is:

[0072]

[0073] The synthesis method comprises the following steps:

[0074]

[0075] (i) reacting a compound of formula IV with 3-amino-3-phenylpropionic acid under the action of a nickel salt to generate a compound of formula VI';

[0076] (ii) hydrolyzing the compound of formula VI' to obtain the compound of formula VII,

[0077] Among them, n, R, R 1 , R 2 , R 3 The definition of is as mentioned above.

[0078] In an eighth aspect of the present invention, a method for synthesizing Maraviroc is provided, the method comprising the step of synthesizing a key intermediate of Maraviroc, wherein the key intermediate of Maraviroc is:

[0079]

[0080] The steps for synthesizing the key intermediate of Maraviroc are as described in the fifth aspect.

[0081] The ninth aspect of the present invention provides a method for synthesizing Maraviroc, the method further comprising the following steps:

[0082]

[0083] (i)(S)-β3 -Phenylalanine reacts with di-tert-butyl dicarbonate to obtain a compound of formula VIII;

[0084] (ii) reducing the compound of formula VIII to obtain the compound of formula IX;

[0085] (iii) subjecting the compound of formula IX to oxidation to obtain the compound of formula X;

[0086] (iv) subjecting the compound of formula X to a reductive amination reaction with the compound of formula XI to obtain a compound of formula XII;

[0087] (v) removing the tert-butyloxycarbonyl protection from the compound of formula XII to obtain a compound of formula XIII;

[0088] (vi) The compound of formula XIII is subjected to a condensation reaction with the compound of formula XIV to obtain maraviroc represented by formula XV.

[0089] The present invention adopts the research of metal nickel chelate asymmetric resolution methodology to efficiently, quickly and highly stereoselectively prepare the key intermediate non-natural chiral amino acid of maraviroc, realizes the synthesis of maraviroc and its intermediates, effectively shortens the synthesis route, improves the synthesis efficiency, and ensures the stereoselectivity of the final product maraviroc. It is an efficient and rapid synthesis method of maraviroc and its key intermediates.

[0090] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0091] After extensive and in-depth research, the inventors of this application have developed for the first time a new method for synthesizing (S)-β3-amino acid, maravirin and its key intermediates. The present invention uses (R)-2-methylproline as the starting material and uses nickel chelate to induce asymmetric splitting to obtain (S)-β 3 -amino acid, using (S)-3-amino-3-phenylpropionic acid as a key intermediate as a raw material to synthesize maraviroc with a high yield and an ee value of more than 98.2%. On this basis, the present invention was completed.

[0092] Intermediates

[0093] An intermediate refers to a product formed during the production of a desired product. In the present invention, multiple intermediates are obtained, and their structures are shown in Formula VI and Formula Y, respectively:

[0094]

[0095] Wherein, n is an integer from 1 to 4, and m is an integer from 0 to 1;

[0096] R is selected from C1-C4 alkyl, C1-C4 haloalkyl, unsubstituted or substituted phenyl, wherein the substituted phenyl means that the phenyl has 1-5 substituents, and each substituent is independently selected from: amino, halogen, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl;

[0097] R 1 Selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, unsubstituted or substituted phenyl, wherein the substituted phenyl means that the phenyl has 1-5 substituents, and each substituent is independently selected from: amino, halogen, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl;

[0098] R 2 Selected from hydrogen, halogen, amino, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl;

[0099] R 3 Selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, unsubstituted or substituted phenyl, -(C1-C4 alkylene)-(unsubstituted or substituted phenyl); wherein the substituted phenyl means that the phenyl has 1-5 substituents, and each substituent is independently selected from: amino, halogen, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl;

[0100] R 4 Selected from hydrogen, unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted C3-C6 heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, wherein the substitution refers to having 1-5 substituents, each substituent is independently selected from: amino, halogen, hydroxyl, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl.

[0101] R 5 Selected from hydrogen, unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted C3-C6 heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, wherein the substitution refers to having 1-5 substituents, each substituent is independently selected from: amino, halogen, hydroxyl, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl.

[0102] In another preferred embodiment, n is 1 or 2 or 3.

[0103] In another preferred embodiment, R is selected from methyl, trifluoromethyl, ethyl, propyl, difluoromethyl, dichloromethyl, trichloromethyl, benzyl, cyano, fluorine, chlorine, bromine and iodine.

[0104] In another preferred embodiment, R 1 Selected from methyl, trifluoromethyl, ethyl, propyl, difluoromethyl, dichloromethyl, trichloromethyl.

[0105] In another preferred embodiment, R 2 Selected from hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, methyl, ethyl, propyl, difluoromethyl, dichloromethyl, trichloromethyl.

[0106] In another preferred embodiment, R 3 Methyl, ethyl, phenyl, C 6 H 5 CH 2 -、C 6 H 5 CH 2 CH 2 -、C 6 H 3 Cl 2 CH 2 -, or C 6 H 3 Cl 2 CH 2 CH 2 -.

[0107] In another preferred embodiment, R 4 It is phenyl, pyridine, naphthyl, thienyl, methoxy substituted phenyl, and halogenated phenyl.

[0108] In another preferred embodiment, the compound of formula Y is a compound of formula II, a compound of formula III or a compound of formula IV:

[0109]

[0110] Among them, n, R 1 , R 2 , R 3 The definition of is as mentioned above.

[0111] Synthesis method

[0112] In the present invention, the compound of formula II is synthesized by the following steps:

[0113]

[0114] (i) (R)-2-substituted proline reacts with di-tert-butyl dicarbonate to produce (R)-1-(tert-butyloxycarbonyl)-2-methylproline;

[0115] (ii) (R)-1-(tert-butyloxycarbonyl)-2-substituted proline undergoes a condensation reaction with the compound of formula I to produce a compound of formula II;

[0116] Among them, n, R1 , R 2 The definition of is as mentioned above.

[0117] In another preferred embodiment, the compound of formula I is selected from: 2-amino-benzophenone, (2-amino-5-chlorophenyl) benzophenone, (2-amino-5-fluorophenyl) benzophenone, (2-amino-5-bromophenyl) benzophenone, (2-amino-5-iodophenyl) benzophenone, (2-amino-5-trifluoromethylphenyl) benzophenone, 1-(2-amino-5-phenyl) ethanone, 1-(2-amino-5-chlorophenyl) ethanone, 1-(2-amino-5-phenyl)-2,2,2-trifluoroethanone, 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone.

[0118] In another preferred embodiment, step i) is carried out in an organic solvent in the presence of a base. In another preferred embodiment, the organic solvent is selected from: one or a mixed solvent of dichloromethane, methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, 1,4-dioxane, DMSO, DMF. In another preferred embodiment, the base is selected from: one or a combination of two or more of potassium hydroxide, sodium hydroxide, lithium hydroxide, cesium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate, DBU, DIPEA, triethylamine, tetramethylhydroxylamine.

[0119] In another preferred embodiment, step ii) is carried out in an organic solvent in the presence of a base and an acyl chloride. In another preferred embodiment, the organic solvent is selected from: one or a mixed solvent of dichloromethane, tetrahydrofuran, 1,4-dioxane, DMSO, DMF. In another preferred embodiment, the acyl chloride reagent is selected from: one or a combination of two or more of methanesulfonyl chloride, dichlorothionyl chloride, and oxalyl chloride. In another preferred embodiment, the base is selected from: one or a combination of two or more of N-methylimidazole, imidazole, potassium hydroxide, sodium hydroxide, lithium hydroxide, cesium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate, DBU, DIPEA, triethylamine, and tetramethylhydroxylamine.

[0120]

[0121] As shown in the above reaction formula, the compound of formula II is deprotected by the tert-butyloxycarbonyl group to generate the compound of formula III.

[0122] In another preferred embodiment, the removal of tert-butyloxycarbonyl protection is carried out in an organic solvent in the presence of an acid. In another preferred embodiment, the organic solvent is selected from: one or a mixed solvent of dichloromethane, 1,2-dichlorohexane, tetrahydrofuran, methanol, ethanol, 1,4-dioxane, DMSO, DMF. In another preferred embodiment, the acid is selected from: one or a combination of two or more of trifluoroacetic acid, hydrochloric acid, sulfuric acid, and nitric acid.

[0123] In the present invention, the compound of formula IV is synthesized by the following steps:

[0124]

[0125] The compound of formula III and R 3 CHO undergoes a reductive amination reaction to produce a compound of formula IV,

[0126] Among them, n, R, R 1 , R 2 and R 3 The definition of is as mentioned above.

[0127] In another preferred embodiment, R 3 CHO is acetaldehyde, propionaldehyde, benzaldehyde, phenylacetaldehyde, phenylpropionaldehyde, 3,4-dichlorophenylacetaldehyde or 3,4-dichlorophenylpropionaldehyde.

[0128] In another preferred embodiment, R 3 CHO is acetaldehyde, propionaldehyde, benzaldehyde, phenylacetaldehyde, phenylpropionaldehyde or 3,4-dichlorophenylacetaldehyde.

[0129] In another preferred embodiment, the reductive amination reaction is carried out in an organic solvent in the presence of a catalytic amount of an acid and a reducing agent. In another preferred embodiment, the organic solvent is selected from: one or a mixed solvent of dichloromethane, 1,2-dichlorohexane, tetrahydrofuran. In another preferred embodiment, the acid is selected from: one or a combination of two or more of formic acid, acetic acid, propionic acid, butyric acid. In another preferred embodiment, the reducing agent is selected from: one or a combination of two or more of sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride.

[0130] In the present invention, the compound of formula IV is synthesized by the following steps:

[0131]

[0132] The compound of formula III and R 3 CH 2 Cl undergoes substitution reaction to generate a compound of formula IV,

[0133] Among them, n, R, R 1 , R 2 and R 3 The definition of is as mentioned above.

[0134] In another preferred embodiment, R 3 CH 2Cl is benzyl chloride, 1,2-dichloro-4-(chloromethyl)phenyl, 1-chloro-4-(chloromethyl)phenyl, 1-fluoro-4-(chloromethyl)phenyl, 1-bromo-4-(chloromethyl)phenyl, 1-iodo-4-(chloromethyl)phenyl, 2-chloro-4-(chloromethyl)phenyl, 3-chloro-4-(chloromethyl)phenyl, 2-fluoro-4-(chloromethyl)phenyl, 2-bromo-4-(chloromethyl)phenyl, 3-fluoro-4-(chloromethyl)phenyl, 3-bromo-4-(chloromethyl)phenyl, 1-chloroethane, 1-chloropropane.

[0135] In another preferred embodiment, R 3 CH 2 Cl is benzyl chloride, 1,2-dichloro-4-(chloromethyl)phenyl, 1-chloro-4-(chloromethyl)phenyl, 1-fluoro-4-(chloromethyl)phenyl, 2-chloro-4-(chloromethyl)phenyl, 3-chloro-4-(chloromethyl)phenyl, 2-fluoro-4-(chloromethyl)phenyl, 3-fluoro-4-(chloromethyl)phenyl, 1-chloroethane, 1-chloropropane.

[0136] In another preferred embodiment, the substitution reaction is carried out in the presence of an alkaline reagent in an organic solvent. In another preferred embodiment, the organic solvent is selected from: one or a mixed solvent of dichloromethane, 1,2-dichlorohexane, tetrahydrofuran. In another preferred embodiment, the base is selected from: sodium hydroxide, potassium hydroxide, sodium carbonate, cesium carbonate, one or a mixed base of two or more.

[0137] The structure of the new quaternary carbon ligand is as follows:

[0138]

[0139]

[0140]

[0141]

[0142] In the present invention, the compound of formula VI is synthesized by the following steps:

[0143]

[0144] The compound of formula IV and the non-natural amino acid shown in formula V are reacted with a nickel salt to generate a compound of formula VI,

[0145] Among them, n, m, R 1 , R 2 , R 3 , R 4 and R 5 The definition of is as mentioned above.

[0146] In another preferred embodiment, the compound of formula V is various non-natural α amino acids, α-substituted β amino acids and β-substituted β amino acids. For example, alanine, phenylalanine, phenylalanine, 3-methoxyphenylalanine, 3-methylphenylalanine, 4-fluorophenylalanine, 3-methoxyphenylglycine, 3-bromophenylglycine, 2-amino-3-(3,5-diiodo-4-hydroxyphenyl)propionic acid, 2-amino-3-(naphthalene-1-yl)propionic acid, 2-amino-3-(benzothiophene-3-yl)propionic acid, 2-amino-3-(thiophene-3-yl)propionic acid, 2-amino-2-cyclobutylacetic acid, 2-amino-4,4,4-trifluorobutyric acid , 2-aminopentanoic acid, 2-amino-3-methylbutyric acid, 2-amino-4-methylthiobutyric acid, 2-amino-3-(1H-indolyl)propionic acid, 2-amino-5-methyl-4-hexenoic acid, 2-aminoglutaric acid, 2,5-diamino-5-pentanoic acid, homocysteine, 3-amino-2-benzylpropionic acid, 3-amino-2-(4-fluorobenzyl)propionic acid, 3-amino-2-(4-methoxybenzyl)propionic acid, 3-amino-2-methylpropionic acid, 2-(aminomethyl)-4-methylpentanoic acid , 3-amino-2-cyclohexylpropionic acid, 3-amino-2-phenylpropionic acid, 3-amino-2-(4-chlorophenyl)propionic acid, 3-amino-2-(4-methoxyphenyl)propionic acid, 3-amino-2-(naphthalen-1-yl)propionic acid, 3-amino-propionic acid, 3-amino-3-phenylpropionic acid, 3-amino-3-(4-methyl substituted)phenylpropionic acid, 3-amino-3-(3-methyl substituted)phenylpropionic acid, 3-amino-3-(2-methyl substituted)phenylpropionic acid, 3-amino-3-(2-fluoro substituted)phenylpropionic acid propionic acid, 3-amino-3-(4-chloro substituted)benzenepropionic acid, 3-amino-3-(3,4-dimethoxy substituted)benzenepropionic acid, 3-amino-3-(4-methoxy substituted)benzenepropionic acid, 3-amino-3-(3-methoxy substituted)benzenepropionic acid, 3-amino-3-(pyridin-4yl)propionic acid, 3-amino-3-(thiophen-2yl)propionic acid, 3-amino-3-cyclohexylpropionic acid, 3-amino-3-(naphthyl-2yl)propionic acid or 3-amino-3-(2,4,5-trifluoro substituted)benzenepropionic acid.

[0147] In another preferred embodiment, the compound of formula IV reacts with the compound of formula V in an organic solvent in the presence of a base. In another preferred embodiment, the organic solvent is selected from: one or a mixed solvent of dichloromethane, 1,2-dichlorohexane, tetrahydrofuran, methanol, ethanol, 1,4-dioxane, DMSO, DMF. In another preferred embodiment, the base is selected from: one or a combination of two or more of potassium hydroxide, sodium hydroxide, lithium hydroxide, cesium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate, DBU, DIPEA, triethylamine, tetramethylhydroxylamine.

[0148] The structure of the new α-amino acid nickel chelate is as follows:

[0149]

[0150] The structure of the novel α-substituted β-amino acid nickel chelate is as follows:

[0151]

[0152]

[0153] The structure of the novel β-substituted β-amino acid nickel chelate is as follows:

[0154]

[0155]

[0156] (S)-β of the present invention 3 - A method for synthesizing an amino acid, comprising hydrolyzing a compound of formula VI to obtain (S)-β-amino acid of formula VII 3 - Amino acid steps,

[0157]

[0158] Among them, n, m, R 1 , R 2 , R 3 , R 4 and R 5 The definition of is as mentioned above.

[0159] In another preferred embodiment, the hydrolysis is carried out in an organic solvent in the presence of a base, wherein the organic solvent is selected from: one or a mixed solvent of methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, 1,4-dioxane, DMSO, DMF. In another preferred embodiment, the base is selected from one or a combination of two or more of DBU, potassium tert-butoxide, sodium tert-butoxide, sodium hydrogen, potassium hydroxide, sodium hydroxide, cesium carbonate, potassium carbonate, potassium bicarbonate, and lithium hydroxide.

[0160] In another preferred embodiment, the method for synthesizing the non-natural amino acid comprises the following steps:

[0161] (i) (R)-2-substituted proline reacts with di-tert-butyl dicarbonate to produce (R)-1-(tert-butyloxycarbonyl)-2-methylproline;

[0162] (ii) (R)-1-(tert-butyloxycarbonyl)-2-substituted proline undergoes a condensation reaction with the compound of formula I to produce a compound of formula II;

[0163] (iii) removing the tert-butyloxycarbonyl protection from the compound of formula II to generate a compound of formula III;

[0164] (iv) a compound of formula III and R 3 CHO undergoes a reductive amination reaction to produce a compound of formula IV;

[0165] (v) a compound of formula IV and a β- 3 -Amino acid generates compound of formula VI under the action of nickel acetate;

[0166] (vi) hydrolyzing the compound of formula VI to obtain the compound of formula VII,

[0167]

[0168] Among them, n, m, R 1 , R 2 , R 3 , R 4 and R 5 The definition of is as described above. The preferred conditions of each step are as shown above.

[0169] The synthesis method of maraviroc in the present invention comprises the step of synthesizing a maraviroc intermediate, wherein the maraviroc intermediate is a compound of formula VI:

[0170]

[0171] Among them, n, m, R 1 , R 2 , R 3 , R 4 and R 5 The definition of R is as mentioned above. 4 It is phenyl.

[0172] In another preferred embodiment, the synthesis steps of the maraviroc intermediate compound of formula VI are as described above,

[0173] In another preferred embodiment, the synthesis method of Maravino also includes the following steps:

[0174]

[0175] (i) reacting a compound of formula IV with 3-amino-3-phenylpropionic acid under the action of nickel acetate to generate a compound of formula VI';

[0176] (ii) The compound of formula VI' is hydrolyzed to obtain (S)-β 3 - Phenylalanine,

[0177] Among them, n, R 1 , R 2 and R 3 The definition of is as mentioned above.

[0178] In another preferred embodiment, the synthesis method of Maravino also includes the following steps:

[0179]

[0180] (a)(S)-β 3 -Phenylalanine reacts with di-tert-butyl dicarbonate to obtain a compound of formula VIII;

[0181] (b) reducing the compound of formula VIII to obtain the compound of formula IX;

[0182] (c) subjecting the compound of formula IX to oxidation to obtain the compound of formula X;

[0183] (d) performing a reductive amination reaction of the compound of formula X with the compound of formula XI to obtain a compound of formula XII;

[0184] (e) removing the tert-butyloxycarbonyl protection from the compound of formula XII to obtain a compound of formula XIII;

[0185] (f) The compound of formula XIII is subjected to condensation reaction with the compound of formula XIV to obtain maraviroc represented by formula XV.

[0186] In another preferred embodiment, (S)-β 3 -Phenylalanine and di-tert-butyl dicarbonate are reacted in an organic solvent in the presence of a base, wherein the organic solvent is selected from: one or a mixed solvent of dichloromethane, methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, 1,4-dioxane, DMSO, and DMF; and the base is selected from one or a combination of two or more of potassium hydroxide, sodium hydroxide, lithium hydroxide, cesium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate, DBU, DIPEA, and triethylamine.

[0187] In another preferred embodiment, the step (b) is carried out in an organic solvent in the presence of a reducing agent, wherein the organic solvent is selected from: one or a mixed solvent of two or more of dichloromethane, tetrahydrofuran, 1,4-dioxane, DMSO, and DMF; and the reducing agent is selected from one or a combination of two or more of sodium borohydride, lithium aluminum tetrahydride, and borane.

[0188] In another preferred embodiment, the step (c) is carried out in an organic solvent in the presence of an oxidizing agent, wherein the organic solvent is selected from: one or a mixed solvent of two or more of dichloromethane, tetrahydrofuran, 1,4-dioxane, DMSO, and DMF; and the oxidizing agent is selected from one or a combination of two or more of Collins oxidant, PCC oxidant, PDC oxidant, Swern oxidant, Dess-martin oxidant, and IBX oxidant.

[0189] In another preferred embodiment, the step (d) is carried out in an organic solvent in the presence of a catalytic amount of an acid and a reducing agent, wherein the organic solvent is selected from: one or a mixed solvent of dichloromethane, 1,2-dichlorohexane, and tetrahydrofuran; the acid is selected from one or a combination of two or more of formic acid, acetic acid, propionic acid, and butyric acid; and the reducing agent is selected from one or a combination of two or more of sodium borohydride, sodium triacetoxyborohydride, and sodium cyanoborohydride.

[0190] In another preferred embodiment, the step (e) is carried out in an organic solvent in the presence of an acid, wherein the organic solvent is selected from: one or a mixed solvent of dichloromethane, 1,2-dichlorohexane, tetrahydrofuran, methanol, ethanol, 1,4-dioxane, DMSO, DMF; and the acid is selected from one or a combination of two or more of trifluoroacetic acid, hydrochloric acid, sulfuric acid, and nitric acid.

[0191] In another preferred embodiment, the step (f) is carried out in an organic solvent in the presence of a condensation reagent, wherein the organic solvent is selected from: one or a mixed solvent of dichloromethane, 1,2-dichlorohexane, tetrahydrofuran, methanol, ethanol, 1,4-dioxane, DMSO, DMF; and the condensation reagent is selected from one or a combination of two or more of BOP, PyBOP, EDCI, DCC, HOBT, HATU, HBTU.

[0192] In a preferred embodiment of the present invention, the synthesis route of the key intermediate of maraviroc, (S)-3-amino-3-phenylpropionic acid, is as follows.

[0193]

[0194] In a preferred embodiment of the present invention, the synthesis route of Maraviroc is as follows.

[0195]

[0196] The above features mentioned in the present invention or the features mentioned in the embodiments can be combined in any way. All the features disclosed in the specification of this case can be used in any combination form, and each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equal or similar purpose. Therefore, unless otherwise specified, the disclosed features are only general examples of equal or similar features.

[0197] The beneficial effects of the present invention are:

[0198] (1) Using cheap 2-methylproline as the starting material, it has a wide range of sources;

[0199] (2) The characteristic of nickel chelate-induced asymmetric splitting of chiral amino acids is used to construct chiral centers, thereby improving the optical purity of the product;

[0200] (3) Optimize the synthesis route of maraviroc, and the synthesis process conditions are mild and easy to control;

[0201] (4) The newly designed proline-type chiral ligand is acid-resistant and high-temperature-resistant, has a stable structure, and can be quantitatively recovered and recycled while hydrolyzing the chelate, thus saving synthesis costs.

[0202] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer.

[0203] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0204] Example 1

[0205] Preparation of (R)-1-(tert-butyloxycarbonyl)-2-methylproline

[0206] In a 250 ml three-necked flask, 10 g (77.42 mmol) of (R)-2-methylproline and TMAH (CH 3 ) 4 NOH·5H 2 O 14.30 g (77.42 mmol) was dissolved in 500 ml of acetonitrile, stirred at 20-40 degrees, di-tert-butyl dicarbonate (116.13 mmol) was added and stirring was continued for 3-5 days.

[0207] After the reaction was completed, water and ethyl acetate were added, the aqueous phase was extracted three times with ethyl acetate, and the organic layers were combined. The organic layers were washed with saturated sodium bicarbonate solution and then dried over anhydrous magnesium sulfate. The ethyl acetate was evaporated under normal pressure to obtain 16.5 g of (R)-1-(tert-butoxycarbonyl)-2-methylproline with a yield of 93%.

[0208] 1 H NMR (500 MHz, DMSO-d 6 ) δ12.38 (s, 1H), 3.43-3.34 (m, 2H), 2.14-2.00 (m, 1H), 1.93-1.76 (m, 3H), 1.41 (d, J=2.4Hz, 3H), 1.37 (d, J=19.8Hz, 9H).

[0209] 13 C NMR (125 MHz, DMSO-d 6 )δ176.4, 153.4, 79.2, 64.7, 48.1, 39.1, 28.4, 23.5, 22.7.

[0210] Example 2

[0211] Preparation of tert-butyl-(R)-2-((2-benzoyl-4-chlorophenyl)carbamoyl)-2-methylprolinamide

[0212] Add (R)-1-(tert-butyloxycarbonyl)-2-methylproline 10g (43.62mmol), 1-methylimidazole 10.33mL (130.85mmol), and a catalytic amount of DMAP to a 250ml three-necked flask, and dissolve them in 200ml of dichloromethane. After 15-45 minutes, add (2-amino-5-chlorophenyl)benzophenone 11.12g (47.98mmol) to the reaction mixture, control the reaction temperature at 0-10 degrees, stir for 12-36 hours, then add water and dichloromethane, extract the aqueous phase with dichloromethane three times, combine the organic layers, wash the organic layers with saturated sodium bicarbonate solution, and then dry them over anhydrous magnesium sulfate. Dichloromethane is evaporated at normal pressure to obtain tert-butyl-(R)-2-((2-benzoyl-4-chlorophenyl)carbamoyl)-2-methylprolinamide 12g, with a yield of 62%.

[0213] 1 H NMR (500 MHz, DMSO-d 6 )δ10.39 (s, 1H), 8.02 (d, J=8.9Hz, 1H), 7.76-7.71 (m, 1H), 7.70-7.63 (m, 3H), 7.54 (t, J=7.7Hz, 2H), 7.46 (d, J=2.6Hz, 1H), 3.64-3.50 (m, 1H), 3.42-3.38 (m, 1H), 1.79-1.62 (m, 4H), 1.39 (s, 3H), 1.26 (d, J=39.3Hz, 9H).

[0214] Example 3

[0215] Preparation of (R)-2-((2-benzoyl-4-chlorophenyl)carbamoyl)-2-methylprolinamide

[0216] 8.5 g (19.19 mmol) of tert-butyl (R)-2-((2-benzoyl-4-chlorophenyl)carbamoyl)-2-methylprolinamide was dissolved in 20 ml of dichloromethane, 20 ml of trifluoroacetic acid was added, the reaction temperature was 20-40 degrees, stirred for 6-8 hours, and evaporated to dryness to obtain 6.5 g of the target product (R)-2-((2-benzoyl-4-chlorophenyl)carbamoyl)-2-methylprolinamide, with a yield of 98%.

[0217] 1 H NMR (500 MHz, CDCl 3 )δ11.95 (s, 1H), 8.63 (d, J=8.9Hz, 1H), 7.78-7.72 (m, 2H), 7.66-7.56 (m, 1H), 7.54-7.44 (m, 4H), 3 .16(dt, J=10.6, 6.4Hz, 1H), 3.00-2.91(m, 1H), 2.35-2.24(m, 1H), 1.82-1.63(m, 4H), 1.46(s, 3H).

[0218] 13 C NMR (125 MHz, CDCl 3 )δ196.9, 177.4, 137.9, 137.9, 133.2, 132.9, 131.8, 130.1, 128.5, 127.3, 126.7, 122.8, 67.4, 47.2, 38.1, 26.5, 25.8.

[0219] Example 4

[0220] Preparation of (R)-N-(2-benzoyl-4-chlorophenyl)-1-ethyl-2-methylpyrrolyl-2-carboxamide

[0221] 5 g (14.58 mmol) of (R)-2-((2-benzoyl-4-chlorophenyl)carbamoyl)-2-methylprolinamide and 16.04 mmol of acetaldehyde were dissolved in dichloromethane, and a catalytic amount of acetic acid was added. The reaction temperature was 10-30 degrees, and the reaction was carried out for 15 minutes to 1 hour. Then water and dichloromethane were added, and the aqueous phase was extracted three times with dichloromethane, and the organic layers were combined. The organic layers were washed with saturated sodium bicarbonate solution and then dried over anhydrous magnesium sulfate. The dichloromethane was evaporated at normal pressure to obtain 10 g of (R)-N-(2-benzoyl-4-chlorophenyl)-1-ethyl-2-methylpyrrolyl-2-carboxamide, with a yield of 95%.

[0222] mp 87-88℃.

[0223] [α] 20 D= +143.5 (c = 0.108, CHCl 3 ).

[0224] 1 H NMR (500 MHz, CDCl 3 ) δ11.62 (s, 1H), 8.60 (d, J = 9.0Hz, 1H), 7.75 (d, J = 7.2Hz, 2H), 7.61 (t, J = 7.4Hz, 1H), 7.49 (t, J = 7.6Hz, 3H), 7.42 (d, J = 2.5Hz, 1H), 3.39-3.32 (m, 1H), 2.57-2.45 (m, 1H), 2.43-2.32 (m, 2H), 2.14-2.03 (m, 1H), 1.78-1.67 (m, 3H), 1.25 (s, 3H), 1.10 (t, J=7.2Hz, 3H).

[0225] 13 C NMR (125 MHz, CDCl 3 )δ196.5, 177.5, 137.9, 137.9, 133.1, 133.0, 131.5, 130.1, 128.6, 127.2, 127.1, 122.9, 68.4, 51.0, 43.9, 40.5, 22.8, 16.2, 14.5.

[0226] LRMS(ESI+APCI)m / z: 371.1, HRMS(ESI)m / z: found: 371.1527, calcd 371.1521forC 21 H 23 C1N 2 O 2 + [M+H] + .

[0227] Example 5

[0228] Preparation of (R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0229] This compound was prepared according to Example 4.

[0230] 1 H NMR (400 MHz, DMSO-d 6)δ10.04 (s, 1H), 8.60 (d, J = 7.5Hz, 1H), 7.81 (d, J = 2.0Hz, 1H), 7.66-7.43 (m, 8H), 6.98 (ddt, J=7.5, 2.2, 1.1Hz, 1H), 3.74 (dt, J=12.5, 1.1Hz, 1H), 3.58 (dt, J=12.4, 1.1Hz, 1H), 3.21 (ddd, J=9.6, 8.2, 1.4Hz, 1H), 2.42-2. 28(m, 2H), 2.04-1.82(m, 2H), 1.75(dt, J=13.1, 7.0Hz, 1H), 1.48(s, 3H).

[0231] LCMS (ESI+APCI) m / z: 501.83

[0232] Example 6

[0233] Preparation of (R)-N-(2-benzoyl-4-chlorophenyl)-1-benzyl-2-methylpyrrolyl-2-carboxamide

[0234] This compound was prepared according to Example 4.

[0235] 1 H NMR (400 MHz, DMSO-d 6 )δ10.04 (s, 1H), 8.62 (d, J = 7.5Hz, 1H), 7.69-7.56 (m, 5H), 7.60-7.46 (m, 2H), 7.31 (s, 3H), 7.37-7.22 (m, 2H), 3.67 (d, J = 12.3Hz, 1H ), 3.57 (d, J=12.4Hz, 1H), 3.10 (ddd, J=9.6, 6.9, 2.8Hz, 1H), 2.35-2.21 (m, 2H), 1.89-1.75 (m, 2H), 1.78-1.67 (m, 1H), 1.09 (s, 3H).

[0236] LCMS (ESI+APCI) m / z: 432.95

[0237] Example 7

[0238] Preparation of (R)-N-(2-benzoyl-4-chlorophenyl)-1-phenethyl-2-methylpyrrolyl-2-carboxamide

[0239] This compound was prepared according to Example 4.

[0240] 1 H NMR (400 MHz, DMSO-d 6)δ10.04 (s, 1H), 8.48 (d, J = 7.5Hz, 1H), 7.80 (d, J = 2.1Hz, 1H), 7.66-7.55 ( m, 4H), 7.56-7.46 (m, 2H), 7.25 (s, 2H), 7.31-7.14 (m, 3H), 3.09 (ddd, J=10. 3, 8.2, 1.6Hz, 1H), 2.90 (td, J=12.1, 1.5Hz, 1H), 2.62 (td, J=12.3, 1.6Hz, 1H), 2.50-2.34(m, 2H), 2.18-2.05(m, 2H), 1.96-1.74(m, 3H), 1.42(s, 3H).

[0241] LCMS (ESI+APCI) m / z: 446.98

[0242] Example 8

[0243] Preparation of (S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-fluoropyrrolyl-2-carboxamide

[0244] This compound was prepared according to Example 4.

[0245] 1 H NMR (400 MHz, DMSO-d 6 )δ10.04 (s, 1H), 8.61 (d, J = 7.5Hz, 1H), 7.81 (d, J = 2.1Hz, 1H), 7.66-7.55 (m, 4H), 7.55-7.46 (m, 3H), 7.34 (q, J=1.2Hz, 1H), 7.06-6.98 (m, 1H), 3.80 (d, J=12.6Hz, 1 H), 3.66-3.58 (m, 1H), 2.99 (dd, J=9.1, 6.0Hz, 1H), 2.56-2.38 (m, 1H), 2.24 (ddd, J=11.6, 9.1, 5.1Hz, 1H), 2.20-2.07(m, 1H), 2.12-1.95(m, 1H), 1.89-1.75(m, 1H).

[0246] LCMS (ESI+APCI) m / z: 505.80

[0247] Example 9

[0248] Preparation of (S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-chloropyrrolyl-2-carboxamide

[0249] This compound was prepared according to Example 4.

[0250] 1 H NMR (400 MHz, DMSO-d 6 ) δ10.04 (s, 1H), 8.53 (d, J = 7.5Hz, 1H), 7.80 (d, J = 2.1Hz, 1H), 7.60 (dddd, J=8.4, 7.1, 4.9, 1.9Hz, 5H), 7.55-7.46 (m, 3H), 7.03-6.95 (m, 1H), 3.78 (d , J=12.3Hz, 1H), 3.69 (d, J=12.5Hz, 1H), 3.44 (td, J=9.0, 1.3Hz, 1H), 2.74 -2.62(m, 1H), 2.37(q, J=8.6Hz, 1H), 2.21-2.03(m, 2H), 2.06-1.91(m, 1H).

[0251] LCMS (ESI+APCI) m / z: 522.25

[0252] Example 10

[0253] Preparation of (S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-bromopyrrolyl-2-carboxamide

[0254] This compound was prepared according to Example 4.

[0255] 1 H NMR (400 MHz, DMSO-d 6 )δ10.04 (s, 1H), 8.61 (d, J = 7.5Hz, 1H), 7.82 (d, J = 2.0Hz, 1H), 7.66-7.55 ( m, 4H), 7.55-7.46 (m, 3H), 7.40 (q, J=1.2Hz, 1H), 6.87-6.79 (m, 1H), 4.55 ( d, J=12.4Hz, 1H), 3.65 (d, J=12.3Hz, 1H), 3.16 (dt, J=13.7, 7.1Hz, 1H), 3. 04-2.95(m, 1H), 2.28-2.08(m, 2H), 2.09-1.93(m, 1H), 1.41-1.27(m, 1H).

[0256] LCMS (ESI+APCI) m / z: 566.70

[0257] Embodiment 11

[0258] Preparation of (S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-iodopyrrolyl-2-carboxamide

[0259] This compound was prepared according to Example 4.

[0260] 1 H NMR (400 MHz, DMSO-d 6 ) δ10.04 (s, 1H), 8.62 (d, J = 7.4Hz, 1H), 7.82 (d, J = 2.0Hz, 1H), 7.66-7.55 (m, 4H), 7. 55-7.46 (m, 3H), 7.40 (q, J=1.2Hz, 1H), 6.89-6.81 (m, 1H), 4.55 (d, J=12.4Hz, 1H), 3. 74-3.66 (m, 1H), 3.33 (dt, J = 13.7, 7.0Hz, 1H), 3.04-2.95 (m, 1H), 2.40 (dt, J = 13.6, 7 .1Hz, 1H), 2.12 (ddd, J=12.1, 9.3, 4.9Hz, 1H), 2.07-1.91 (m, 1H), 1.34-1.21 (m, 1H).

[0261] LCMS (ESI+APCI) m / z: 613.70

[0262] Example 12

[0263] Preparation of (S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-cyanopyrrolyl-2-carboxamide

[0264] This compound was prepared according to Example 4.

[0265] 1 H NMR (400 MHz, DMSO-d 6 )δ10.04 (s, 1H), 8.56 (d, J=7.5Hz, 1H), 7.82 (d, J=2.0Hz, 1H), 7.66-7.55 (m, 4H), 7.60-7.46 (m, 4H), 7.03-6.95 (m, 1H), 3.79 (d, J=12.3 Hz, 1H), 3.69 (d, J=12.5Hz, 1H), 3.35 (ddd, J=9.5, 8.1, 1.4Hz, 1H), 2.71 (dt, J=13.0, 7.0Hz, 1H), 2.61-2.49 (m, 1H), 2.33-2.01 (m, 3H).

[0266] LCMS (ESI+APCI) m / z: 512.82

[0267] Example 13

[0268] Preparation of (R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-ethylpyrrolyl-2-carboxamide

[0269] This compound was prepared according to Example 4.

[0270] 1 H NMR (400 MHz, DMSO-d 6 )δ10.04 (s, 1H), 8.59 (d, J = 7.5Hz, 1H), 7.81 (d, J = 2.0Hz, 1H), 7.66-7.55 (m, 4H), 7 .55-7.44 (m, 4H), 6.99 (dq, J=7.6, 1.3Hz, 1H), 3.73 (d, J=12.6Hz, 1H), 3.60 (d, J=12 .7Hz, 1H), 3.21 (ddd, J=10.0, 8.3, 1.9Hz, 1H), 2.39-2.24 (m, 3H), 2.10 (dq, J=12.5, 7.9Hz, 1H), 2.03-1.83 (m, 2H), 1.80 (dt, J=13.2, 6.8Hz, 1H), 0.65 (t, J=7.9Hz, 3H).

[0271] LCMS (ESI+APCI) m / z: 515.86

[0272] Embodiment 14

[0273] Preparation of (R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-trifluoromethylpyrrolyl-2-carboxamide

[0274] This compound was prepared according to Example 4.

[0275] 1 H NMR (400 MHz, DMSO-d 6 ) δ10.04 (s, 1H), 8.59 (d, J = 7.5Hz, 1H), 7.80 (d, J = 2.0Hz, 1H), 7.66-7.55 (m, 4H), 7.55-7.46 (m, 4H), 7.02 (dq, J = 7.6, 1.1Hz, 1H ), 3.77 (d, J = 12.3Hz, 1H), 3.66 (d, J = 12.1Hz, 1H), 3.38-3.29 (m, 1H), 2.61-2.42 (m, 2H), 2.19-2.04 (m, 1H), 2.09-1.95 (m, 2H).

[0276] LCMS (ESI+APCI) m / z: 555.80

[0277] Embodiment 15

[0278] Preparation of (S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-isopropylpyrrolyl-2-carboxamide This compound was prepared according to Example 4.

[0279] 1 H NMR (400 MHz, DMSO-d 6 )δ10.04 (s, 1H), 8.70 (d, J = 7.5Hz, 1H), 7.87 (d, J = 2.1Hz, 1H), 7.66-7.58 (m, 2H), 7.62-7.57 (m, 1 H), 7.61-7.46 (m, 3H), 7.43 (dd, J=2.1, 1.1Hz, 1H), 6.81 (ddd, J=7.5, 2.2, 1.2Hz, 1H), 3.81 (dd, J =12.3, 1.1Hz, 1H), 3.11 (dt, J=12.3, 1.1Hz, 1H), 2.93 (ddd, J=11.8, 9.4, 4.9Hz, 1H), 2.34 (dd, J= 9.5, 6.4Hz, 1H), 2.18-1.97 (m, 3H), 1.86-1.73 (m, 1H), 1.77-1.59 (m, 1H), 0.96 (d, J=6.8Hz, 6H).

[0280] LCMS (ESI+APCI) m / z: 529.89

[0281] Example 16

[0282] Preparation of (S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-tert-butylpyrrolyl-2-carboxamide This compound was prepared according to Example 4.

[0283] 1 H NMR (400 MHz, DMSO-d 6)δ10.04 (s, 1H), 8.47 (d, J = 7.5Hz, 1H), 7.74 (d, J = 2.1Hz, 1H), 7.66-7.46 (m, 8H), 6.9 7 (ddt, J=7.6, 2.1, 1.2Hz, 1H), 3.63 (dt, J=12.5, 1.1Hz, 1H), 3.35 (dt, J=12.5, 1.1Hz, 1H), 3.16 (td, J=9.2, 1.8Hz, 1H), 2.22 (td, J=9.3, 6.9Hz, 1H), 2.20-2.05 (m, 1H), 1.90 (ddq, J=20.5, 9.4, 6.9Hz, 2H), 1.63 (ddtd, J=14.1, 8.7, 6.7, 2.9Hz, 1H), 0.92 (s, 9H).

[0284] LCMS (ESI+APCI) m / z: 543.91

[0285] Embodiment 17

[0286] Preparation of (S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-benzylpyrrolyl-2-carboxamide

[0287] This compound was prepared according to Example 4.

[0288] 1 H NMR (400 MHz, DMSO-d 6 )δ10.04 (s, 1H), 8.59 (d, J = 7.5Hz, 1H), 7.85 (d, J = 2.0Hz, 1H), 7.66-7.45 (m, 8H), 7.29 -7.14 (m, 3H), 7.07 (ddd, J=7.5, 2.4, 1.2Hz, 2H), 7.03-6.95 (m, 1H), 3.73 (d, J=12.5Hz, 1H), 3.61 (d, J=12.3Hz, 1H), 3.43-3.35 (m, 1H), 3.27 (ddd, J=9.4, 8.0, 2.9Hz, 1H), 3.13 (d, J=12.2Hz, 1H), 2.42-2.30 (m, 2H), 2.13-1.95 (m, 2H), 1.87 (dt, J=12.9, 7.0Hz, 1H).

[0289] LCMS (ESI+APCI) m / z: 577.93

[0290] Embodiment 18

[0291] Preparation of (S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0292] This compound was prepared according to Example 4.

[0293] 1 H NMR (400 MHz, DMSO-d 6 )δ10.04 (s, 1H), 8.55 (d, J = 7.5Hz, 1H), 7.76 (d, J = 2.0Hz, 1H), 7.66-7.55 (m, 4H), 7.56-7.46 (m, 3H), 7.44 (ddd, J=7.3, 2.1, 1.1Hz, 1H), 7.34 (dd, J= 2.2, 1.3Hz, 1H), 3.90 (dt, J=12.4, 1.1Hz, 1H), 3.73 (dt, J=12.4, 1.1Hz, 1 H), 3.10-3.00(m, 1H), 2.51-2.35(m, 2H), 1.77-1.63(m, 3H), 1.19(s, 3H).

[0294] LCMS (ESI+APCI) m / z: 501.83

[0295] Embodiment 19

[0296] Preparation of (S)-N-(2-benzoyl-4-chlorophenyl)-1-benzyl-2-methylpyrrolyl-2-carboxamide

[0297] This compound was prepared according to Example 4.

[0298] 1 H NMR (400 MHz, DMSO-d 6 )δ10.04 (s, 1H), 8.62 (d, J = 7.4Hz, 1H), 7.77 (d, J = 1.9Hz, 1H), 7.66-7.55 (m, 4H), 7.56-7.46 (m, 2H), 7.31 (s, 3H), 7.37-7.22 ( m, 2H), 4.02 (d, J=12.3Hz, 1H), 3.58 (d, J=12.4Hz, 1H), 2.97-2.86 (m, 1H), 2.47-2.31 (m, 2H), 1.78-1.63 (m, 3H), 1.33 (s, 3H).

[0299] LCMS (ESI+APCI) m / z: 432.95

[0300] Embodiment 20

[0301] Preparation of (S)-N-(2-benzoyl-4-chlorophenyl)-1-phenethyl-2-methylpyrrolyl-2-carboxamide

[0302] This compound was prepared according to Example 4.

[0303] 1 H NMR (400 MHz, DMSO-d 6 )δ10.04 (s, 1H), 8.63 (d, J = 7.5Hz, 1H), 7.82 (d, J = 1.9Hz, 1H), 7.66-7.58 (m, 2H), 7.6 2-7.46 (m, 3H), 7.25 (s, 2H), 7.31-7.14 (m, 3H), 3.08 (dt, J=9.5, 7.0Hz, 1H), 2.85-2. 76 (m, 2H), 2.69 (td, J=7.3, 1.3Hz, 2H), 2.48 (dt, J=9.5, 7.1Hz, 1H), 2.09 (dt, J=13.2 , 7.1Hz, 1H), 1.83 (ddd, J=13.1, 7.5, 6.6Hz, 1H), 1.69 (p, J=7.0Hz, 2H), 1.33 (s, 3H).

[0304] LCMS (ESI+APCI) m / z: 446.98

[0305] Embodiment 21

[0306] Preparation of (S)-N-(2-benzoyl-4-chlorophenyl)-1-ethyl-2-methylpyrrolyl-2-carboxamide

[0307] This compound was prepared according to Example 4.

[0308] 1 H NMR (400 MHz, DMSO-d 6 )δ10.04 (s, 1H), 8.64 (d, J = 7.5Hz, 1H), 7.78 (d, J = 1.9Hz, 1H), 7.66-7.55 (m, 4H), 7.56-7.46 (m, 2H), 3.03 (dt, J = 9.5, 7.0Hz, 1H), 2 .53-2.34 (m, 2H), 2.22-2.05 (m, 2H), 1.81 (ddd, J=13.0, 7.6, 6.5Hz, 1H), 1.69 (p, J=7.1Hz, 2H), 1.30 (s, 3H), 1.04 (t, J=8.0Hz, 3H).

[0309] LCMS (ESI+APCI) m / z: 370.88

[0310] Embodiment 22

[0311] Preparation of (R)-N-(2-benzoyl-4-chlorophenyl)-1-(4-chlorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0312] This compound was prepared according to Example 4.

[0313] 1 H NMR (400 MHz, DMSO-d 6 ) δ10.04 (s, 1H), 8.55 (d, J = 7.5Hz, 1H), 7.76 (d, J = 1.9Hz, 1H), 7.66-7.55 (m, 4H), 7.56-7.46 (m, 2H), 7.37 (d, J = 1.4Hz, 4H), 3.86 (d, J = 12. 3Hz, 1H), 3.70 (d, J=12.5Hz, 1H), 3.06 (ddd, J=9.4, 6.2, 3.0Hz, 1H), 2.50-2.35 (m, 2H), 1.87-1.73 (m, 2H), 1.76-1.64 (m, 1H), 1.20 (s, 3H).

[0314] LCMS (ESI+APCI) m / z: 467.39

[0315] Embodiment 23

[0316] Preparation of (R)-N-(2-benzoyl-4-chlorophenyl)-1-(3-chlorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0317] This compound was prepared according to Example 4.

[0318] 1 H NMR (400 MHz, DMSO-d 6 )δ10.04 (s, 1H), 8.67 (d, J = 7.5Hz, 1H), 7.69 (d, J = 2.0Hz, 1H), 7.66-7.55 (m, 4H ), 7.60-7.46 (m, 2H), 7.40-7.30 (m, 3H), 7.00 (tdd, J=4.8, 2.2, 1.1Hz, 1H), 3.67 (dd, J=12.4, 1.1Hz, 1H), 3.49 (dd, J=12.5, 1.2Hz, 1H), 3.07 (ddd, J=9.4, 7.5, 1. 9Hz, 1H), 2.39-2.27(m, 1H), 2.29-2.14(m, 1H), 1.90-1.71(m, 3H), 1.13(s, 3H).

[0319] LCMS (ESI+APCI) m / z: 467.39

[0320] Embodiment 24

[0321] Preparation of (R)-N-(2-benzoyl-4-chlorophenyl)-1-(2-chlorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0322] This compound was prepared according to Example 4.

[0323] 1 H NMR (400 MHz, DMSO-d 6 )δ10.04(s, 1H), 8.62(d, J=7.5Hz, 1H), 7.68-7.55(m, 5H), 7.56-7.46(m, 2H), 7.26 (dd, J=4.5, 2.2Hz, 2H), 7.15-7.05 (m, 2H), 3.98 (d, J=12.4Hz, 1H ), 3.49 (d, J = 12.4Hz, 1H), 3.11 (ddd, J = 9.5, 6.4, 3.2Hz, 1H), 2.36-2.22 (m , 2H), 1.90-1.76 (m, 2H), 1.73 (ddd, J=12.6, 7.5, 6.2Hz, 1H), 1.08 (s, 3H).

[0324] LCMS (ESI+APCI) m / z: 467.39

[0325] Embodiment 25

[0326] Preparation of (R)-N-(2-benzoyl-4-chlorophenyl)-1-(3-fluorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0327] This compound was prepared according to Example 4.

[0328] 1 H NMR (400 MHz, DMSO-d 6 )δ10.04 (s, 1H), 8.62 (d, J = 7.5Hz, 1H), 7.79 (d, J = 2.0Hz, 1H), 7.66-7.55 (m, 4H ), 7.60-7.46 (m, 2H), 7.18-7.06 (m, 2H), 7.02 (ddt, J=9.2, 7.3, 2.0Hz, 2H), 3.74 (dt, J=12.3, 1.0Hz, 1H), 3.64-3.56 (m, 1H), 3.20 (ddd, J=9.6, 7.8, 1.8Hz, 1H), 2 .41-2.28(m, 2H), 2.00-1.80(m, 2H), 1.77(dt, J=12.8, 7.0Hz, 1H), 1.49(s, 3H).

[0329] LCMS (ESI+APCI) m / z: 450.94

[0330] Embodiment 26

[0331] Preparation of (R)-N-(2-benzoyl-4-chlorophenyl)-1-(4-fluorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0332] This compound was prepared according to Example 4.

[0333] 1 H NMR (400 MHz, DMSO-d 6 )δ10.04 (s, 1H), 8.66 (d, J = 7.5Hz, 1H), 7.70 (d, J = 2.1Hz, 1H), 7.66-7.46 (m, 6H), 7.32 (ddd , J=7.6, 4.2, 1.2Hz, 2H), 7.17-7.07 (m, 2H), 3.84 (dd, J=12.3, 1.1Hz, 1H), 3.22 (dt, J=12.4 , 1.2Hz, 1H), 2.94 (td, J=9.5, 1.9Hz, 1H), 2.29 (ddq, J=12.8, 9.6, 7.2Hz, 1H), 2.21-2.01 (m , 2H), 1.71 (ddtd, J=13.1, 8.8, 6.9, 1.9Hz, 1H), 1.57 (dt, J=13.1, 7.1Hz, 1H), 1.01 (s, 3H).

[0334] LCMS (ESI+APCI) m / z: 450.94

[0335] Embodiment 27

[0336] Preparation of (R)-N-(2-benzoyl-4-chlorophenyl)-1-(2-fluorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0337] This compound was prepared according to Example 4.

[0338] 1 H NMR (400 MHz, DMSO-d 6)δ10.04 (s, 1H), 8.66 (d, J=7.5Hz, 1H), 7.82 (d, J=2.0Hz, 1H), 7.66-7.46 (m, 7H), 7.36 (tdd, J=7.4, 5.6, 1 .9Hz, 1H), 7.22 (ddd, J=9.3, 7.5, 2.1Hz, 1H), 7.02 (td, J=7.5, 2.1Hz, 1H), 4.39 (dd, J=12.5, 1.0Hz, 1H), 3. 72 (dd, J=12.3, 1.0Hz, 1H), 2.96 (ddd, J=11.7, 9.5, 5.7Hz, 1H), 2.53 (dt, J=13.1, 7.0Hz, 1H), 2.24-2.15 ( m, 1H), 1.99-1.85 (m, 1H), 1.62 (dt, J=13.3, 7.0Hz, 1H), 1.37 (s, 3H), 1.34 (ddt, J=13.4, 11.6, 6.8Hz, 1H).

[0339] LCMS (ESI+APC) m / z: 450.94

[0340] Embodiment 28

[0341] Preparation of (R)-N-(2-benzoyl-4-chlorophenyl)-1-(3-methylbenzyl)-2-methylpyrrolyl-2-carboxamide

[0342] This compound was prepared according to Example 4.

[0343] 1 H NMR (500 MHz, CDCl 3 )δ9.82 (s, 1H), 7.80 (s, 1H), 7.68-7.59 (m, 3H), 7.56 (s, 1H), 7.46 (s, 1H), 7.42-7.35 (m, 2H), 7.21 (d, J=2.9Hz, 2H), 7.12-7.01 (m, 2H), 4.1 3(s, 1H), 3.07(s, 1H), 2.76(s, 1H), 2.40(s, 1H), 2.37-2.30(m, 3H), 2 .17(s, 1H), 1.83(s, 1H), 1.76(s, 1H), 1.67(s, 1H), 1.66-1.63(m, 3H).

[0344] Embodiment 29

[0345] Preparation of (R)-N-(2-benzoyl-4-chlorophenyl)-1-(4-methylbenzyl)-2-methylpyrrolyl-2-carboxamide

[0346] This compound was prepared according to Example 4.

[0347] 1 H NMR (500MHz, CDCl3) δ8.91 (s, 1H), 7.87 (s, 1H), 7.76-7.70 (m, 2H), 7.60 (d, J=14.8Hz, 2H), 7.50 (s, 1H), 7.45-7.37 (m, 2H), 7.15-709 (m, 4H) , 4.00 (s, 1H), 2.88 (s, 1H), 2.79 (s, 1H), 2.34-2.29 (m, 3H), 2.24 (d, J= 5.4Hz, 2H), 1.83(s, 1H), 1.76(s, 1H), 1.67(s, 1H), 1.63-1.59(m, 3H).

[0348] Embodiment 30

[0349] Preparation of (R)-N-(2-benzoyl-4-chlorophenyl)-1-(2-methylbenzyl)-2-methylpyrrolyl-2-carboxamide This compound was prepared according to Example 4.

[0350] 1 H NMR (500MHz, CDCl3) δ7.74 (d, J=8.8Hz, 2H), 7.69-7.62 (m, 2H), 7.46 (d, J=6.6Hz, 2H), 7.43-7.37 (m, 2H), 7.27 (s, 1H), 7.17 (t, J=6.3Hz, 3H ), 3.45 (d, J = 5.0Hz, 2H), 2.89 (s, 1H), 2.70 (s, 1H), 2.32-2.23 (m, 3H), 2.09 (s, 1H), 1.79 (d, J = 13.1Hz, 2H), 1.68 (s, 1H), 1.54-1.46 (m, 3H).

[0351] Embodiment 31

[0352] Preparation of (R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-difluorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0353] This compound was prepared according to Example 4. 1H NMR (500MHz, CDCl3) δ9.50 (s, 1H), 7.81 (s, 1H), 7.73 (s, 1H), 7.70-7.66 (m, 2H), 7.56 (s, 1H), 7.46 (s, 1H), 7.42-7.37 (m, 2H), 7.02 (d, J=7.0Hz , 2H), 6.88(s, 1H), 3.59(s, 1H), 3.41(s, 1H), 2.94(s, 1H), 2.79(s, 1H), 2.09(s, 1H), 1.82(s, 1H), 1.76(s, 1H), 1.67(s, 1H), 1.58-1.43(m, 3H).

[0354] Embodiment 32

[0355] Preparation of (R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dimethylbenzyl)-2-methylpyrrolyl-2-carboxamide

[0356] This compound was prepared according to Example 4.

[0357] 1 H NMR (500MHz, CDCl3) δ9.85 (s, 1H), 7.80 (s, 1H), 7.67-7.61 (m, 3H), 7.56 (s, 1H) ), 7.46(s, 1H), 7.42-7.36(m, 2H), 7.16(s, 1H), 7.09(s, 1H), 7.03(s, 1H), 4.12 (s, 1H), 3.05 (s, 1H), 2.75 (s, 1H), 2.39 (s, 1H), 2.36-2.34 (m, 3H), 2.33-2.31 ( m, 3H), 2.18 (s, 1H), 1.83 (s, 1H), 1.76 (s, 1H), 1.67 (s, 1H), 1.65-1.64 (m, 3H).

[0358] Embodiment 33

[0359] Preparation of (R)-N-(2-benzoyl-4-chlorophenyl)-1-(2,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0360] This compound was prepared according to Example 4.

[0361] 1H NMR (500MHz, CDCl3) δ7.88 (s, 1H), 7.74-7.67 (m, 2H), 7.56 (s, 1H), 7.47 (s, 1H), 7.44-7.38 (m, 3H), 7.36 (s, 1H), 7.21 (d, J=10.7Hz, 2H ), 6.09 (s, 1H), 3.40 (s, 1H), 3.25 (s, 1H), 2.81 (s, 1H), 2.23 (d, J = 8.9Hz, 2H), 1.78 (d, J = 16.1Hz, 2H), 1.67 (s, 1H), 1.42-1.36 (m, 3H).

[0362] Embodiment 34

[0363] Preparation of (R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,5-difluorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0364] This compound was prepared according to Example 4.

[0365] 1 H NMR (500 MHz, CDCl 3 )δ9.57(s, 1H), 7.81(s, 1H), 7.73(s, 1H), 7.71-7.65(m, 2H), 7.56(s, 1H), 7.46(s, 1H), 7.43-7.37(m, 2H), 6.79-6.71(m, 3H) , 3.63(s, 1H), 3.39(s, 1H), 2.93(s, 1H), 2.86(s, 1H), 2.09(s, 1H), 1.83(s, 1H), 1.76(s, 1H), 1.67(s, 1H), 1.53-1.44(m, 3H).

[0366] Embodiment 35

[0367] Preparation of (R)-N-(2-benzoyl-4-chlorophenyl)-1-(2,3-difluorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0368] This compound was prepared according to Example 4.

[0369] 1 H NMR (500 MHz, CDCl 3)δ9.99(s, 1H), 7.79(s, 1H), 7.71-7.61(m, 3H), 7.56(s, 1H), 7.46(s, 1H), 7.43-7.36(m, 2H), 7.09-7.00(m, 2H), 6.93( s, 1H), 3.89 (s, 1H), 3.26 (s, 1H), 2.80 (s, 1H), 2.69 (s, 1H), 2.09 (s, 1H), 1.81 (s, 1H), 1.77 (s, 1H), 1.68-1.65 (m, 3H).

[0370] Embodiment 36

[0371] Preparation of (R)-N-(2-benzoyl-4-chlorophenyl)-1-(2,5-difluorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0372] This compound was prepared according to Example 4.

[0373] 1 H NMR (500MHz, CDCl3) δ9.94 (s, 1H), 7.79 (s, 1H), 7.72-7.61 (m, 3H), 7.56 (s, 1H), 7.46 (s, 1H), 7.43-7.35 (m, 2H), 7.07 (s, 1H), 7.00 (s, 1H), 6.94 (s, 1H), 3.89 (s, 1H), 3.26 (s, 1H), 2.82 (s, 1H), 2.69 (s, 1H), 2.08 (s, 1H), 1.81 (s, 1H), 177 (s, 1H), 1.68-1.66 (m, 3H).

[0374] Embodiment 37

[0375] Preparation of (R)-N-(2-benzoyl-4-chlorophenyl)-1-(2,6-difluorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0376] This compound was prepared according to Example 4.

[0377] 1 H NMR (500 MHz, CDCl 3)δ9.71 (s, 1H), 7.79 (s, 1H), 7.70-7.60 (m, 3H), 7.56 (s, 1H), 7.45 (s, 1H), 7.42-7.34 (m, 2H), 7.18 (s, 1H), 6.82-6.72 (m, 2H) , 4.13(s, 1H), 3.14(s, 1H), 2.72(s, 1H), 2.46(s, 1H), 2.18(s, 1H), 1.84(s, 1H), 1.76(s, 1H), 1.67(s, 1H), 1.66-1.64(m, 3H).

[0378] Embodiment 38

[0379] Preparation of (R)-N-(2-benzoyl-4-chlorophenyl)-1-(2,6-difluoro-4-chlorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0380] This compound was prepared according to Example 4.

[0381] 1 H NMR (500 MHz, CDCl 3 )δ9.67(s, 1H), 7.79(s, 1H), 7.66-7.61(m, 3H), 7.56(s, 1H), 7.45(s, 1H), 7.42-7.35(m, 2H), 6.96-6.70(m, 2H), 4.12( s, 1H), 3.13 (s, 1H), 2.70 (s, 1H), 2.46 (s, 1H), 2.18 (s, 1H), 1.83 (s, 1H), 1.76 (s, 1H), 1.67 (s, 1H), 1.66-1.64 (m, 3H).

[0382] Embodiment 39

[0383] Preparation of (R)-N-(2-benzoyl-4-chlorophenyl)-1-(2,6-difluorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0384] This compound was prepared according to Example 4.

[0385] 1 H NMR (500 MHz, CDCl 3)δ9.71 (s, 1H), 7.79 (s, 1H), 7.70-7.60 (m, 3H), 7.56 (s, 1H), 7.45 (s, 1H), 7.42-7.34 (m, 2H), 7.18 (s, 1H), 6.82-6.72 (m, 2H) , 4.13(s, 1H), 3.14(s, 1H), 2.72(s, 1H), 2.46(s, 1H), 2.18(s, 1H), 1.84(s, 1H), 1.76(s, 1H), 1.67(s, 1H), 1.66-1.64(m, 3H).

[0386] Embodiment 40

[0387] Preparation of (R)-N-(2-benzoyl-4-chlorophenyl)-1-(2,4,6-trimethylbenzyl)-2-methylpyrrolyl-2-carboxamide

[0388] This compound was prepared according to Example 4.

[0389] 1 H NMR (500MHz, CDCl3) δ7.88 (s, 1H), 7.76-7.65 (m, 2H), 7.56 (s, 1H), 7.47 (s, 1H), 7.43-7.36 (m, 2H), 7.33 (s, 1H), 7.03-6.98 (m, 2H), 5.47 (s, 1 H), 3.43(s, 1H), 3.20(s, 1H), 2.82(s, 1H), 2.45-2.30(m, 9H), 2.20(d, J=22.6Hz, 2H), 1.78(d, J=19.9Hz, 2H), 1.67(s, 1H), 1.47-1.26(m, 3H).

[0390] Embodiment 41

[0391] Preparation of (R)-N-(2-benzoyl-4-chlorophenyl)-1-(2-fluoro-6-chloro-benzyl)-2-methylpyrrolyl-2-carboxamide

[0392] This compound was prepared according to Example 4.

[0393] 1 H NMR (500 MHz, CDCl 3)δ9.81 (s, 1H), 7.80 (s, 1H), 7.69-7.62 (m, 3H), 7.56 (s, 1H), 7.46 (s, 1H), 7.43-7.34 (m, 2H), 7.14 (s, 1H), 7.07 (s, 1H), 6.90 (s, 1H), 4.29(s, 1H), 3.17(s, 1H), 2.72(s, 1H), 2.46(s, 1H), 2.19(s, 1H), 1.84(s, 1H), 1.77(s, 1H), 1.68(s, 1H), 1.67-1.65(m, 3H).

[0394] Embodiment 42

[0395] Preparation of (R)-N-(2-benzoyl-4-chlorophenyl)-1-(3-cyanobenzyl)-2-methylpyrrolyl-2-carboxamide This compound was prepared according to Example 4.

[0396] 1 H NMR (500 MHz, CDCl 3 )δ7.81 (s, 1H), 7.74-7.66 (m, 3H), 7.60-7.54 (m, 4H), 7.47 (d, J = 15.1Hz, 2H), 7.42-7.37 (m, 2H), 3.70 (s, 1H) , 3.19 (s, 1H), 2.90 (s, 1H), 2.70 (s, 1H), 2.09 (s, 1H), 1.78 (d, J=7.3Hz, 2H), 1.68 (s, 1H), 1.47-1.38 (m, 3H).

[0397] Embodiment 43

[0398] Preparation of (R)-N-(2-benzoyl-4-chlorophenyl)-1-(4-trifluoromethylbenzyl)-2-methylpyrrolyl-2-carboxamide

[0399] This compound was prepared according to Example 4.

[0400] 1 H NMR (500 MHz, CDCl 3)δ9.74 (s, 1H), 7.80 (s, 1H), 7.66-7.60 (m, 3H), 7.58-7.51 (m, 3H), 7.46 (s, 1H), 7.42-7.36 (m, 2H), 7.25-7.20 (m, 2H), 4. 14(s, 1H), 3.08(s, 1H), 2.74(s, 1H), 2.41(s, 1H), 2.17(s, 1H), 1.83(s, 1H), 1.77(s, 1H), 1.68(s, 1H), 1.66-1.64(m, 3H).

[0401] Embodiment 44

[0402] Preparation of (R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dioxolane benzyl)-2-methylpyrrolyl-2-carboxamide

[0403] This compound was prepared according to Example 4.

[0404] 1 H NMR (500 MHz, CDCl 3 )δ7.75 (d, J=9.3Hz, 2H), 7.71-7.65 (m, 2H), 7.46 (d, J=5.0Hz, 2H), 7.44-7.36 (m, 2H), 6.89 (s, 1H), 6.77 (s, 1H), 6.73 (s, 1H), 5.93-5. 86 (m, 2H), 3.61 (s, 1H), 3.12 (s, 1H), 2.97 (s, 1H), 2.84 (s, 1H), 2.12 (s, 1H), 1.81 (s, 1H), 1.76 (s, 1H), 1.67 (s, 1H), 1.52-1.43 (m, 3H).

[0405] Embodiment 45

[0406] Preparation of (R)-N-(2-benzoylphenyl)-1-benzyl-2-methylpyrrolyl-2-carboxamide

[0407] This compound was prepared according to Example 4.

[0408] 1 H NMR (500 MHz, CDCl 3)δ9.92 (s, 1H), 7.73 (d, J=4.4Hz, 2H), 7.70-7.64 (m, 2H), 7.54 (s, 1H), 7.46 (s, 1H), 7.43-7.37 (m, 2H), 7.31-7.25 (m, 2H), 7.21 (dd, J=5.5 , 2.1Hz, 4H), 3.57(s, 1H), 3.18(s, 1H), 2.97(s, 1H), 2.84(s, 1H), 2.10(s, 1H), 1.82(s, 1H), 1.76(s, 1H), 1.67(s, 1H), 1.51-1.42(m, 3H).

[0409] Embodiment 46

[0410] Preparation of (R)-N-(2-benzoyl-3-methylphenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide This compound was prepared according to Example 4.

[0411] 1 H NMR (500 MHz, CDCl 3 )δ9.44(s, 3H), 7.73-7.70(m, 6H), 7.68(s, 3H), 7.66(s, 3H), 7.46(s, 3 H), 7.43-7.37 (m, 6H), 7.33 (s, 3H), 7.17 (s, 3H), 7.07 (d, J=8.1Hz, 6H) , 3.75(s, 3H), 3.40(s, 3H), 3.15(s, 3H), 2.65(s, 3H), 2.40-2.35(m, 9H ), 2.30 (s, 3H), 1.80 (s, 4H), 1.71 (d, J = 45.0Hz, 5H), 1.60-1.55 (m, 9H).

[0412] Embodiment 47

[0413] Preparation of (R)-N-(2-benzoylphenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0414] This compound was prepared according to Example 4.

[0415] 1 H NMR (500 MHz, CDCl 3)δ9.37(s, 3H), 7.77-7.68(m, 12H), 7.52(s, 3H), 7.46(s, 3H), 7.43-7.37(m, 6H), 7.33(s, 3H), 7.21(s, 3H), 7.17(s, 3H), 7.06(s, 3H), 3.75(s, 3H), 3.40(s, 3H), 3.15(s, 3H), 2.65(s, 3H), 2.30(s, 3H), 1.80(s, 4H), 1.75(s, 2H), 1.66(s, 3H), 1.59-1.54(m, 9H).

[0416] Embodiment 48

[0417] Preparation of (R)-N-(2-(4-chlorobenzoyl)phenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0418] This compound was prepared according to Example 4.

[0419] 1 H NMR (500 MHz, CDCl 3 )δ7.80 (s, 1H), 7.74 (s, 1H), 7.70-7.65 (m, 2H), 7.54 (s, 1H), 7.48-7.41 (m, 2H), 7.23 (d, J=14.6Hz, 2H), 7.08 (s, 1H), 6.93 (s, 1 H), 3.52(s, 1H), 3.47(s, 1H), 3.13(s, 1H), 2.62(s, 1H), 2.08(s, 1H), 1.88(s, 1H), 1.77(s, 1H), 1.68(s, 1H), 1.54-1.48(m, 3H).

[0420] Embodiment 49

[0421] Preparation of (R)-N-(2-(2-chlorobenzoyl)-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0422] This compound was prepared according to Example 4.

[0423] 1 H NMR (500 MHz, CDCl 3)δ8.28 (s, 1H), 7.82 (s, 1H), 7.70 (s, 1H), 7.54 (s, 1H), 7.49 (s, 1H), 7.43 (d, J = 15.8Hz, 2H), 7.30 (s, 1H), 7.24 (s, 1H), 7.11 (d, J = 3.3 Hz, 2H), 3.59 (s, 1H), 3.52 (s, 1H), 2.96 (s, 1H), 2.54 (s, 1H), 2.12 (s, 1H), 1.82 (s, 1H), 1.76 (s, 1H), 1.67 (s, 1H), 1.64-1.60 (m, 3H).

[0424] Embodiment 50

[0425] Preparation of (R)-N-(2-(2-chlorobenzoyl)-4-bromophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0426] This compound was prepared according to Example 4.

[0427] 1 H NMR (500 MHz, CDCl 3 )δ8.50 (s, 3H), 8.04 (s, 3H), 7.73 (s, 3H), 7.62 (s, 3H), 7.55 (s, 3H), 7.45 (s, 3H), 7.31 (s, 3H), 7.23 (d, J=7.9Hz, 6H), 7.14 (d, J=24.6 Hz, 6H), 3.55 (s, 3H), 3.51 (s, 3H), 3.01 (s, 3H), 2.55 (s, 3H), 2.11 (s, 3H), 1.80 (s, 4H), 1.76 (s, 2H), 1.67 (s, 3H), 1.50-1.41 (m, 9H).

[0428] Embodiment 51

[0429] Preparation of (R)-N-(2-acetyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0430] This compound was prepared according to Example 4.

[0431] 1 H NMR (500 MHz, CDCl 3)δ7.92(s, 1H), 7.53(s, 1H), 7.37-7.21(m, 3H), 7.10(s, 1H), 6.44(s, 1H), 3.62(s, 1H), 3.60(s, 1H), 2.90(s, 1H), 2.58(s, 1H), 2.54-2.49(m, 3H), 2.08(s, 1H), 1.84(s, 1H), 1.75(s, 1H), 1.66(s, 1H), 1.54-1.47(m, 3H).

[0432] Embodiment 52

[0433] Preparation of (R)-N-(2-propionyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0434] This compound was prepared according to Example 4.

[0435] 1 H NMR (500 MHz, CDCl 3 )δ7.98 (s, 1H), 7.63 (s, 1H), 7.54 (s, 1H), 7.31-7.25 (m, 3H), 3.55 (s, 1H), 3.47 (s, 1H), 3.13-3.05 (m, 2H), 2.90 (s, 1H), 2.55 (s, 1H), 2.11 (s, 1H), 1.88 (s, 1H), 1.76 (s, 1H), 1.67 (s, 1H), 1.55-1.47 (m, 3H), 1.36-1.20 (m, 3H).

[0436] Embodiment 53

[0437] Preparation of (R)-N-(2-(2-methylpropionyl)-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0438] This compound was prepared according to Example 4.

[0439] 1 H NMR (500 MHz, CDCl 3)δ7.93 (s, 1H), 7.64 (s, 1H), 7.55 (s, 1H), 7.27 (d, J=0.8Hz, 2H), 7.11 (s, 1H), 7.03 (s, 1H), 3.87 (s, 1H), 3.69 (s, 1H), 3.20 (s, 1H) , 3.01 (s, 1H), 2.54 (s, 1H), 2.07 (s, 1H), 1.78 (d, J=26.3Hz, 2H), 1.66 (s, 1H), 1.47-1.39 (m, 3H), 1.37-1.35 (m, 3H), 1.35 (s, 3H).

[0440] Embodiment 54

[0441] Preparation of (R)-N-(2-(2,2-dimethylpropionyl)-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0442] This compound was prepared according to Example 4.

[0443] 1 H NMR (500 MHz, CDCl 3 )δ7.81 (s, 1H), 7.52 (s, 1H), 7.46 (d, J = 10.3Hz, 2H), 7.28 (s, 1H), 7.23 (s, 1H), 7.00 (s, 1H), 3.51 (d, J = 11.3Hz, 2H), 2.81(s, 1H), 2.54(s, 1H), 2.31(s, 1H), 1.83(s, 1H), 1.75(s, 1H), 1.66(s, 1H), 1.62-1.60(m, 3H), 1.38-1.26(m, 9H).

[0444] Embodiment 55

[0445] Preparation of (R)-N-(2-trifluoromethylformyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0446] This compound was prepared according to Example 4.

[0447] 1 H NMR (500 MHz, CDCl 3)δ8.05(s, 1H), 7.79(s, 1H), 7.58(s, 1H), 7.24(s, 1H), 7.21(s, 1H), 7.12(s, 1H), 3.62(s, 1H), 3.41(s, 1H), 3.15(s, 1H), 2.64(s, 1H), 2.27(s, 1H), 1.83(s, 1H), 1.75(s, 1H), 1.66(s, 1H), 1.56-1.43(m, 3H).

[0448] Embodiment 56

[0449] Preparation of (R)-N-(2-(2-thenoyl)-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0450] This compound was prepared according to Example 4.

[0451] 1 H NMR (500 MHz, CDCl 3 )δ9.32 (s, 1H), 8.00 (s, 1H), 7.82 (s, 1H), 7.76 (s, 1H), 7.67 (s, 1H), 7.61 (s, 1H), 7.27 (dd, J=25.9, 14.1Hz, 4H), 3.53 ( s, 1H), 3.44 (s, 1H), 2.92 (s, 1H), 2.54 (s, 1H), 2.12 (s, 1H), 1.88 (s, 1H), 1.76 (s, 1H), 1.67 (s, 1H), 1.55-1.46 (m, 3H).

[0452] Embodiment 57

[0453] Preparation of (R)-N-(2-(3-thenoyl)-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0454] This compound was prepared according to Example 4.

[0455] 1 H NMR (500 MHz, CDCl 3)δ8.74 (s, 1H), 7.95 (s, 1H), 7.67 (d, J = 9.2Hz, 2H), 7.60 (s, 1H), 7.40 (s, 1H), 7.28 (d, J = 9.1Hz, 2H), 7.19 (d, J = 5.0Hz, 2H), 3.54(s, 1H), 3.44(s, 1H), 3.00(s, 1H), 2.56(s, 1H), 2.09(s, 1H), 1.84(s, 1H), 1.76(s, 1H), 1.67(s, 1H), 1.52-1.45(m, 3H).

[0456] Embodiment 58

[0457] Preparation of (S)-N-(2-benzoylphenyl)-1-ethyl-2-methylpyrrolyl-2-carboxamide

[0458] This compound was prepared according to Example 4.

[0459] 1 H NMR (500 MHz, CDCl 3 )δ8.66(s, 1H), 7.76(s, 1H), 7.73-7.69(m, 2H), 7.66(s, 1H), 7.54(s, 1H), 7.47(s, 1H), 7.44-7.34(m, 2H), 7.23(s, 1H), 2.95(d , J=2.0Hz, 2H), 2.21 (d, J=5.3Hz, 2H), 1.88 (s, 1H), 1.79 (s, 1H), 1.73 (d, J=24.0Hz, 2H), 1.53-1.43 (m, 3H), 1.11-1.00 (m, 3H).

[0460] Embodiment 59

[0461] Preparation of (R)-N-(2-benzoylphenyl)-1-ethyl-2-methylpyrrolyl-2-carboxamide

[0462] This compound was prepared according to Example 4.

[0463] 1 H NMR (500 MHz, CDCl 3)δ9.05(s,7H),7.76(s,7H),7.73-7.64(m,21H),7.54(s,7H),7.47(s,7H),7.43-7.36(m,14H),7.23(s,7H),2.96(s,7H),2.5 1 (s, 8H), 2.45 (d, J=9.2Hz, 13H), 2.14 (s, 7H), 1.77 (d, J=18.6Hz, 11H), 1.66 (s, 9H), 1.63-1.60 (m, 21H), 1.13-1.01 (m, 21H).

[0464] Embodiment 60

[0465] Preparation of (S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0466] 5 g (14.58 mmol) of (S)-2-((2-benzoyl-4-chlorophenyl)carbamoyl)-2-methylprolinamide and 2.81 g (16.04 mmol) of 3,4-dichlorobenzyl chloride were dissolved in dichloromethane, and a catalytic amount of potassium hydroxide was added. The reaction temperature was 10-30 degrees, and the reaction was carried out for 15 minutes to 1 hour. Subsequently, water and dichloromethane were added, and the aqueous phase was extracted three times with dichloromethane, and then the organic layers were combined. The organic layers were washed with a saturated sodium bicarbonate solution and then dried over anhydrous magnesium sulfate. The dichloromethane was evaporated at normal pressure to obtain 7 g of (S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide, with a yield of 95%.

[0467] 1 H NMR (400 MHz, CDCl 3 )δ11.76 (s, 1H), 8.65 (d, J=8.7Hz, 1H), 7.86-7.40 (m, 8H), 7.22-7.13 (m, 2H), 3.79 (d, J=13.5Hz, 1H), 3.39 (d, J=13 .6Hz, 1H), 3.15 (t, J=7.4Hz, 1H), 2.39 (dd, J=15.9, 7.9Hz, 1H), 2.23-2.14 (m, 1H), 1.95-1.75 (m, 3H), 1.39 (s, 3H).

[0468] 13 C NMR (125 MHz, CDCl 3)δ197.1, 176.5, 139.2, 138.4, 137.9, 133.4, 132.9, 132.3, 132.2, 130.8, 130.6, 13 0.1, 130.1, 128.5, 127.9, 127.2, 125.9, 122.8, 68.8, 53.5, 51.3, 40.1, 22.7, 16.4.

[0469] Embodiment 61

[0470] Preparation of (S)-N-(2-benzoyl-4-chlorophenyl)-1-benzyl-2-methylpyrrolyl-2-carboxamide

[0471] Basically the same as Example 60, 3 g of (S)-N-(2-benzoyl-4-chlorophenyl)-1-benzyl-2-methylpyrrolyl-2-carboxamide was obtained with a yield of 96%.

[0472] 1 H NMR (500 MHz, CDCl 3 )δ11.52 (s, 1H), 8.58 (d, J=8.9Hz, 1H), 7.78-7.73 (m, 2H), 7.66-7.60 (m, 1H), 7.53-7.43 (m, 4H), 7.35-7.28 (m, 2H), 7.15-7.03 (m, 3H), 3 .79 (d, J=13.0Hz, 1H), 3.40 (d, J=13.1Hz, 1H), 3.18-3.04 (m, 1H), 2.45-2.35 (m, 1H), 2.20-2.10 (m, 1H), 1.86-1.70 (m, 3H), 1.39 (s, 3H).

[0473] 13 C NMR (125 MHz, CDCl 3 )δ196.7, 176.9, 138.9, 138.0, 137.9, 133.1, 133.1, 131.6, 130.2, 128.7 , 128.3, 127.4, 127.0, 127.0, 123.0, 68.7, 54.4, 51.3, 40.4, 22.9, 16.5.

[0474] Embodiment 62

[0475] Preparation of (S)-N-(2-benzoyl-4-chlorophenyl)-1-phenethyl-2-methylpyrrolyl-2-carboxamide

[0476] Basically the same as Example 60, 4 g of (S)-N-(2-benzoyl-4-chlorophenyl)-1-benzyl-2-methylpyrrolyl-2-carboxamide was obtained with a yield of 92%.

[0477] 1 H NMR (500 MHz, CDCl 3 )δ11.60 (s, 1H), 8.57 (d, J = 9.0Hz, 1H), 7.73 (d, J = 7.6Hz, 2H), 7.60 (t, J = 7.4Hz, 1H), 7.52-7.40 (m, 4H), 7.17-7.05 (m, 3H), 6 .96(d, J=6.7Hz, 2H), 3.41-3.31(m, 1H), 2.55-2.33(m, 5H), 2.14-2.06(m, 1H), 1.93(s, 1H), 1.86-1.69(m, 4H), 1.24(s, 3H).

[0478] 13 C NMR (125 MHz, CDCl 3 )δ196.6, 177.4, 142.1, 138.0, 137.9, 133.1, 131.6, 130.2, 128.6, 128.3, 128. 3, 127.3, 127.0, 125.7, 123.1, 68.6, 51.5, 49.9, 40.4, 33.9, 30.9, 22.9, 16.3.

[0479] Embodiment 63

[0480] Preparation of (R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dimethoxybenzyl)-2-methylpyrrolyl-2-carboxamide

[0481] This compound was prepared according to Example 4.

[0482] 1 H NMR (500 MHz, CDCl 3) δ11.64 (s, 1H), 8.56 (d, J=9.0Hz, 1H), 7.73-7.69 (m, 2H), 7.64-7.59 (m, 1H), 7.52-7. 48 (m, 3H), 7.45 (d, J=2.5Hz, 1H), 7.08 (d, J=2.0Hz, 1H), 6.83 (dd, J=8.2, 1.9Hz, 1H), 6. 58 (d, J=8.2Hz, 1H), 3.79 (s, 3H), 3.77 (s, 3H), 3.37 (d, J=13.0Hz, 1H), 3.14 (td, J=8.1, 7.6, 4.1Hz, 1H), 2.43-2.36(m, 1H), 2.18-2.08(m, 1H), 1.85-1.69(m, 4H), 1.39(s, 3H).

[0483] 13 C NMR (126 MHz, CDCl 3 )δ196.8, 176.9, 148.9, 147.9, 138.2, 137.9, 133.2, 132.9, 131.8, 131.5, 130.0, 128. 5, 127.3, 126.6, 123.2, 120.6, 111.8, 110.7, 68.5, 55.8, 54.0, 51.1, 40.2, 22.6, 16.2.

[0484] Embodiment 64

[0485] Preparation of (R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dibromobenzyl)-2-methylpyrrolyl-2-carboxamide

[0486] This compound was prepared according to Example 4.

[0487] 1 H NMR (500 MHz, CDCl 3 ) δ11.72 (s, 1H), 8.63 (d, J = 8.7Hz, 1H), 7.83 (d, J = 1.9Hz, 1H), 7.76 (dd, J = 8.2, 1.4Hz, 2H), 7.65-7.62(m, 1H), 7.55-7.47(m, 4H), 7.31(d, J=8.2Hz, 1H), 7.18(d , J=8.2Hz, 1H), 3.77 (d, J=13.5Hz, 1H), 3.38 (d, J=13.5Hz, 1H), 3.16 (t, J=8.1Hz , 1H), 2.40 (q, J=8.1Hz, 1H), 2.23-2.13 (m, 1H), 1.91-1.75 (m, 3H), 1.39 (s, 3H).

[0488] 13 C NMR (126 MHz, CDCl 3 )δ197.0, 176.5, 140.0, 138.4, 137.9, 133.8, 133.4, 133.3, 133.0, 132.2, 130.1, 12 8.8, 128.5, 127.2, 125.9, 124.7, 122.9, 122.8, 68.8, 53.4, 51.3, 40.1, 22.6, 16.4.

[0489] Embodiment 65

[0490] Preparation of Nickel Chelate

[0491] 5 g (13.48 mmol) of (R)-N-(2-benzoyl-4-chlorophenyl)-1-ethyl-2-methylpyrrolyl-2-carboxamide, 6.68 g (40.44 mmol) of 3-amino-3-phenylpropionic acid and 4.77 g (26.96 mmol) of nickel acetate were dissolved in 200 ml of methanol, 15.13 g (134.82 mmol) of potassium tert-butoxide was added, and the reaction system was heated at 60-90 degrees for 6-12 hours, followed by the addition of water and dichloromethane. The aqueous phase was extracted three times with dichloromethane, and the organic layers were combined. The organic layers were washed with a saturated sodium bicarbonate solution and then dried over anhydrous magnesium sulfate. The dichloromethane was evaporated at normal pressure to obtain 6.8 g of nickel chelate with a yield of 87%.

[0492] mp 174-176℃.[α] 20 D = -2531.8 (c = 0.044, CHCl 3 ).

[0493] 1 H NMR (400 MHz, Methanol-d 4)δ8.18 (d, J=9.1Hz, 1H), 7.71-7.46 (m, 9H), 7.31 (dd, J=9.1, 2.6Hz, 1H), 7.20 (d, J=7.6Hz, 1H), 6. 72 (d, J=2.6Hz, 1H), 4.60 (d, J=3.7Hz, 1H), 3.23 (td, J=12.3, 11.3, 7.1Hz, 1H), 2.93 (dd, J=17.8, 2 .8Hz, 1H), 2.80 (t, J=9.2Hz, 1H), 2.69 (dd, J=17.8, 4.1Hz, 1H), 2.40 (dq, J=14.5, 7.3Hz, 1H), 2.23 (dq, J=13.8, 6.9Hz, 1H), 2.02-1.91 (m, 1H), 1.87 (t, J=7.3Hz, 3H), 1.80-1.45 (m, 3H), 1.10 (s, 3H).

[0494] 13 C NMR (150 MHz, CDCl 3 )δ182.1, 172.8, 171.3, 142.0, 139.8, 134.9, 133.0, 132.9, 130.5, 130.0, 129.9, 129.5, 129.4, 128.5, 127.3, 126.9, 126.6, 125.6, 125.3, 73.3, 63.1, 53.5, 49.1, 40.5, 38.2, 20.3, 17.3, 15.3.

[0495] LRMS(ESI+APCI)m / z: 574.1, HRMS(ESI)m / z: found: 574.1405, calcd 574.1402for C 30 H 30 C1N 3 NiO 3 + [M+H] + .

[0496] Embodiment 66

[0497] Preparation of (S)-3-amino-3-phenylpropionic acid

[0498] The nickel chelate was dissolved in methanol, concentrated hydrochloric acid was added, and the reaction system was heated. The reaction temperature was controlled between 60 and 100 degrees. The reaction was carried out for 15 minutes to 2 hours. Water and dichloromethane were added to the reaction system. The aqueous phase was extracted three times with dichloromethane and then the organic layers were combined. The organic layers were washed with a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The dichloromethane was evaporated at normal pressure to obtain 800 mg of (S)-3-amino-3-phenylpropionic acid with a yield of 92%.

[0499] mp=223-224℃.[α] 20 D =-12(c=0.1, H 2 O).

[0500] 1 H NMR (500 MHz, D 2 O) δ7.58-7.41 (m, 5H), 4.70 (t, J=7.3Hz, 1H), 3.11-2.86 (m, 2H).

[0501] 13 C NMR (125 MHz, D 2 O) δ175.93, 135.66, 129.38, 129.27, 126.91, 52.29, 39.48.

[0502] LRMS(ESI+APCI)m / z: 166.1, HRMS(ESI)m / z: found: 166.0858, calcd 166.0863for C 9 H 11 NO 2+ [M+H] + .

[0503] Embodiment 67

[0504] Preparation of (S)-3-tert-Butyloxycarbonylamino-3-phenylpropionic acid

[0505] (S)-3-Amino-3-phenylpropionic acid (0.33 g, 2 mmol) was dissolved in 3 mL of saturated NaHCO 3 Di-tert-butyl carbonate (0.52 g, 2.2 mmol) was slowly added to the mixture. The mixture was reacted at room temperature for 24 hours. Then, a 1N aqueous hydrochloric acid solution was added to adjust the pH to 2-3. The aqueous phase was extracted three times with ethyl acetate and the organic layers were combined. The organic layers were washed with a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate and evaporated to dryness to obtain 0.52 g (98%) of (S)-3-tert-butoxycarbonylamino-3-phenylpropionic acid.

[0506] 1 H NMR (400 MHz, CDCl 3 )δ7.34-7.24(m, 5H), 5.48(s, br, 1H), 5.11-4.93(m, 1H), 2.84(s, 2H), 1.41(s, br, 9H).

[0507] Embodiment 68

[0508] Preparation of (S)-tert-butyl N-(3-hydroxy-1-phenylpropyl)carbamate

[0509] (S)-3-tert-Butyloxycarbonylamino-3-phenylalanine (0.40 g, 1.5 mmol) was dissolved in 5 mL THF and, under nitrogen protection, BH 3 THF (3 mL, 1 M / mL) was slowly added dropwise, and the reaction was continued for 2 hours. An appropriate amount of acetone was added to consume the excess BH 3 Saturated sodium bicarbonate solution was then added, the aqueous phase was extracted three times with ethyl acetate, and the organic layers were combined, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and evaporated to dryness to obtain 0.39 g (104%) of tert-butyl (S)-N-(3-hydroxy-1-phenylpropyl)carbamate.

[0510] Embodiment 69

[0511] Preparation of tert-butyl (S)-N-(3-oxo-1-phenylpropyl)carbamate

[0512] At 0°C, (S)-tert-butyl N-(3-hydroxy-1-phenylpropyl)carbamate (0.39 g, 1.5 mmol) was dissolved in 10 mL of dichloromethane, and Dess-Martin periodinane (0.76 g, 1.8 mmol) was slowly added. The reaction was carried out at room temperature for 2 hours. Saturated sodium bicarbonate solution was then added, and the aqueous phase was extracted three times with dichloromethane and the organic layers were combined. The organic layers were washed with saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The crude product was evaporated to dryness and purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain 0.34 g (92%) of tert-butyl (S)-N-(3-oxo-1-phenylpropyl)carbamate.

[0513] Embodiment 70

[0514] Preparation of (S)-3-{[(1R, 3R, 5S)-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-phenylpropyl}carbamic acid tert-butyl ester

[0515] At room temperature, (1R, 3R, 5S)-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane (0.28 g, 1.2 mmol) was dissolved in 10 mL of 1,2-dichloroethane, and (S)-tert-butyl N-(3-oxo-1-phenylpropyl)carbamate (0.25 g, 1 mmol), glacial acetic acid (12 μL, 0.2 mmol), and sodium triacetoxyborohydride (0.32 g, 1.5 mmol) were added in sequence. The reaction was carried out at room temperature for 12 hours. Then, 2M sodium hydroxide solution was added to adjust the pH to 11-12. The aqueous phase was extracted three times with dichloromethane and the organic layers were combined. The organic layers were washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The crude product was evaporated to dryness and subjected to column chromatography (dichloromethane: methanol = 15: 1) to obtain (S)-3-{[(1R, 3R, 5S)-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-phenylpropyl}carbamic acid tert-butyl ester 0.33 g (71%). LRMS (ESI+APCI) m / z: 468.3.

[0516] Embodiment 71

[0517] Preparation of 4,4-difluoro-N-[(1S)-3-[exo-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-phenylpropyl]cyclohexane-1-carboxamide

[0518] At 0°C, (S)-3-{[(1R, 3R, 5S)-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-phenylpropyl}carbamic acid tert-butyl ester (93.4 mg, 0.2 mmol) was dissolved in 5 mL methanol, 4N hydrochloric acid dioxane solution (5 ml) was slowly added, and the reaction was carried out at room temperature for 3 hours. The corresponding amine intermediate was evaporated to dryness. It was dissolved in 5 mL dichloromethane, and triethylamine (138.7 μL, 1 mmol) was added, followed by 4,4-difluorocyclohexanecarboxylic acid (39.4 mg, 0.24 mmol), EDCI (46.0 mg, 0.24 mmol) and HOBT (32.4 mg, 0.24 mmol) were added in sequence. The reaction was carried out at room temperature for 12 hours. Subsequently, 2M sodium hydroxide solution was added to adjust the pH to 11-12, the aqueous phase was extracted three times with dichloromethane, and the organic layers were combined. The organic layers were washed with saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The crude product was evaporated to dryness and purified by column chromatography (dichloromethane: methanol = 10: 1) to obtain 4,4-difluoro-N-[(1S)-3-[exo-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane-8-yl]-1-phenylpropyl]cyclohexane-1-carboxamide 76.9 mg (75%, ee>98.2%).

[0519] [α] 25 D = -28.4° (c = 0.5, CHCl 3 ).

[0520] 1 H NMR (400 MHz, CDCl 3 )δ[ppm]7.35-7.31(m, 2H), 7.28-7.26(m, 3H), 6.82-6.66(m, br, 1H), 5.12-5.07(m, 1H), 4.32-4.26(m, 1H), 3 .40 (d, br, 2H), 3.01-2.94 (m, 1H), 2.48 (s, 3H), 2.44 (t, J=8Hz, 2H), 2.28-1.64 (m, 19H), 1.37 (d, J=4Hz, 6H).

[0521] 13 C NMR (151 MHz, CDCl 3 )δ173.71, 159.23, 150.70, 141.97, 128.77, 127.49, 126.49, 58.99, 58.37, 51.94, 47.99, 47.30, 42.74, 35.40, 35.28, 34.66, 32.95 (J13 C- 19 F6Hz), 32.82, 32.79, 32.63(J 13 C- 19 F 4.5Hz), 26.66, 26.62, 25.98(J 13 C- 19 F 9Hz), 25.89(J 13 C- 19 F 9Hz), 25.80, 21.63, 13.07.

[0522] LRMS (ESI+APCI) m / z [M+H] + :514.3, HRMS(ESI)m / z: calcd for C 29 H 42 F 2 N 5 O + [M+H] + :514.3552, found:514.3551.

[0523] Embodiment 72

[0524] Preparation of Nickel Chelate of 3-Amino-3-(2-Fluoro-Substituted)Benzenepropionic Acid

[0525] Basically the same as Example 65, 3-amino-3-phenylpropionic acid was replaced with 3-amino-3-(2-fluoro-substituted)phenylpropionic acid to obtain the nickel chelate of 3-amino-3-(2-fluoro-substituted)phenylpropionic acid in a yield of 92%.

[0526] mp=180-181℃.[α] 20 D = -3281.3 (c = 0.048, CHCl 3 ).

[0527] 1 H NMR (400 MHz, Methanol-d 4)δ8.21 (d, J=9.1Hz, 1H), 7.69-7.50 (m, 5H), 7.45-7.35 (m, 3H), 7.30 (dd, J=9.1, 2. 6Hz, 1H), 7.12-7.05 (m, 1H), 6.65 (d, J=2.6Hz, 1H), 4.71 (t, J=3.3Hz, 1H), 3.26-3.1 4(m, 1H), 2.93-2.82(m, 2H), 2.73(dd, J=18.0, 4.4Hz, 1H), 2.44-2.33(m, 1H), 2.30- 2.18(m, 1H), 2.04-1.92(m, 1H), 1.90-1.78(m, 4H), 1.75-1.55(m, 2H), 1.09(s, 3H).

[0528] 13 C NMR (150 MHz, CDCl 3 )δ181.5, 171.7, 162.0, 142.1, 135.1, 133.1, 132.9, 131.0, 130.5, 130.2, 129.6, 128.8, 128.7, 128.6, 127 .3, 127.3, 126.5, 125.4, 125.1, 124.8, 116.7, 116.5, 73.7, 60.0, 53.2, 49.2, 40.6, 38.9, 20.7, 16.7, 15.2.

[0529] LRMS(ESI+APCI)m / z: 592.2, HRMS(ESI)m / z: found: 592.1311, calcd 592.1308for C 30 H 29 CIF 3 NiO 3 + [M+H] + .

[0530] Embodiment 73

[0531] Preparation of Nickel Chelate of 3-Amino-3-(4-chloro-substituted)phenylpropionic Acid

[0532] Basically the same as Example 65, 3-amino-3-phenylpropionic acid was replaced with 3-amino-3-(4-chloro-substituted)phenylpropionic acid to obtain the nickel chelate of 3-amino-3-(4-chloro-substituted)phenylpropionic acid in a yield of 93%.

[0533] mp=180-182℃.[α] 20 D = -3512.5 (c = 0.04, CHCl 3 ).

[0534] 1 H NMR (500 MHz, Methanol-d 4 )δ8.19 (d, J=9.1Hz, 1H), 7.68-7.47 (m, 8H), 7.31 (dd, J=9.1, 2.6Hz, 1H), 7.21 (dt, J=7.6, 1.5Hz, 1 H), 6.71 (d, J=2.6Hz, 1H), 4.57 (t, J=3.3Hz, 1H), 3.30-3.21 (m, 1H), 2.90 (dd, J=17.9, 2.8Hz, 1H), 2 .86-2.79(m, 1H), 2.70(dd, J=17.9, 4.1Hz, 1H), 2.46-2.37(m, 1H), 2.28-2.19(m, 1H), 2.07-1.99(m , 1H), 1.88 (t, J=7.3Hz, 3H), 1.85-1.77 (m, 1H), 1.75-1.63 (m, 1H), 1.61-1.52 (m, 1H), 1.12 (s, 3H).

[0535] 13 C NMR (125 MHz, Methanol-d 4 )δ183.6, 176.7, 173.8, 142.6, 139.8, 136.1, 135.6, 134.1, 133.5, 131.6, 131.2, 130.8, 130.6, 130.4, 129.6, 128.4, 128.3, 126.9 , 126.6, 75.0, 63.5, 53.7, 50.2, 41.3, 38.3, 21.4, 17.7, 15.5.LRMS(ESI+APCI)m / z: 608.1, HRMS(ESI)m / z: found: 608.1027, calcd 608.1012 for C 30 H 29 Cl 2 N 3 NiO 3 + [M+H] + .

[0536] Embodiment 74

[0537] Preparation of Nickel Chelate of 3-Amino-3-(3,4-Dimethoxy Substituted)Benzenepropionic Acid

[0538] Basically the same as Example 65, 3-amino-3-phenylpropionic acid was replaced with 3-amino-3-(3,4-dimethoxy-substituted)phenylpropionic acid to obtain the nickel chelate of 3-amino-3-(3,4-dimethoxy-substituted)phenylpropionic acid in a yield of 93%.

[0539] mp=160-162℃.[α] 20 D = -2768.3 (c = 0.06, CHCl 3 ).

[0540] 1 H NMR (400 MHz, Methanol-d 4 )δ8.16 (d, J=9.1Hz, 1H), 7.67-7.50 (m, 4H), 7.32 (dd, J=9.1, 2.6Hz, 1H), 7.24 (d, J=8.4Hz, 1H), 7.20-7.13 (m, 1H), 7.09-7.03 (m, 1H), 6.89 (d, J=2.2Hz, 1H), 6.71 (d, J=2.6Hz, 1H), 4.56 (t, J=3. 4Hz, 1H), 3.93 (s, 3H), 3.82 (s, 3H), 3.27-3.16 (m, 1H), 2.94-2.79 (m, 2H), 2.67 (dd, J=17.8, 4.1H z, 1H), 2.46-2.35 (m, 1H), 2.31-2.21 (m, 1H), 2.04-1.81 (m, 5H), 1.72-1.50 (m, 2H), 1.12 (s, 3H).

[0541] 13 C NMR (125 MHz, CDCl 3 )δ182.0, 172.9, 171.0, 149.7, 149.4, 142.0, 135.0, 133.0, 132.9, 132.5, 130.5, 130.0, 129.9, 129.4, 127.2 , 126.7, 125.7, 125.3, 119.6, 112.0, 110.0, 73.4, 62.9, 56.4, 56.3, 53.4, 49.1, 40.4, 38.4, 20.5, 17.3, 15.3.

[0542] LRMS(ESI+APCI)m / z: 634.2, HRMS(ESI)m / z: found: 634.1627, calcd 634.1613for C 32 H 34 C1N 3 NiO 5 +[M+H] + .

[0543] Embodiment 75

[0544] Preparation of Nickel Chelate of 3-Amino-3-(4-isopropyl Substituted) Phenylpropionic Acid

[0545] Basically the same as Example 65, 3-amino-3-phenylpropionic acid was replaced with 3-amino-3-(4-isopropyl substituted)phenylpropionic acid to obtain the nickel chelate of 3-amino-3-(4-isopropyl substituted)phenylpropionic acid in a yield of 92%.

[0546] mp=120-122℃.[α] 20 D = -2287.5 (c = 0.048, CHCl 3 ).

[0547] 1 H NMR (400 MHz, Methanol-d 4 )δ8.17 (d, J=9.2Hz, 1H), 7.66-7.47 (m, 6H), 7.39 (d, J=8.0Hz, 2H), 7.31 (dd, J=9.1, 2.6Hz, 1H), 7. 22-7.16 (m, 1H), 6.72 (d, J = 2.6Hz, 1H), 4.56 (d, J = 3.5Hz, 1H), 3.27-3.17 (m, 1H), 3.10-2.98 (m, 1H ), 2.90 (dd, J=17.8, 2.8Hz, 1H), 2.79 (t, J=9.1Hz, 1H), 2.67 (dd, J=17.8, 4.2Hz, 1H), 2.45-2.34 (m , 1H), 2.28-2.17(m, 1H), 1.97-1.82(m, 4H), 1.77-1.45(m, 3H), 1.34(d, J=6.9Hz, 6H), 1.10(s, 3H).

[0548] 13 C NMR (125 MHz, CDCl 3 )δ182.0, 172.9, 171.1, 149.6, 142.0, 137.3, 135.0, 133.0, 132.9, 130.5, 130.0, 130.0, 129.4, 127.6, 12 7.4, 127.0, 126.7, 125.6, 125.3, 73.4, 62.9, 53.3, 49.1, 40.3, 38.1, 34.1, 24.3, 24.2, 20.4, 17.2, 15.3.

[0549] LRMS(ESI+APCI)m / z: 616.2, HRMS(ESI)m / z: found: 616.1886, calcd 616.1871for C 33 H 36 C1N 3 NiO 3 + [M+H] + .

[0550] Embodiment 76

[0551] Preparation of Nickel Chelate of 3-Amino-3-(4-Methoxy Substituted) Phenylpropionic Acid

[0552] Basically the same as Example 65, 3-amino-3-phenylpropionic acid was replaced with 3-amino-3-(4-methoxy-substituted)phenylpropionic acid to obtain the nickel chelate of 3-amino-3-(4-methoxy-substituted)phenylpropionic acid in a yield of 93%.

[0553] mp=172-173℃.[α] 20 D = -3139.6 (c = 0.048, CHCl 3 ).

[0554] 1 H NMR (500 MHz, Methanol-d 4 )δ8.18 (d, J=9.1Hz, 1H), 7.65-7.49 (m, 4H), 7.40-7.36 (m, 2H), 7.30 (dd, J=9.1, 2 .6Hz, 1H), 7.23-7.16 (m, 3H), 6.70 (d, J=2.6Hz, 1H), 4.53 (t, J=3.5Hz, 2H), 3.89 (s , 3H), 3.30-3.19 (m, 1H), 2.90-2.79 (m, 2H), 2.65 (dd, J=17.8, 4.2Hz, 1H), 2.47-2 .35(m, 1H), 2.27-2.16(m, 1H), 2.01-1.82(m, 5H), 1.69-1.50(m, 2H), 1.11(s, 3H).

[0555] 13 C NMR (125 MHz, Methanol-d 4)δ183.6, 177.0, 173.0, 161.6, 142.6, 136.2, 134.0, 133.4, 132.9, 131.6, 131.5, 130.8, 130.3, 129 .1, 128.5, 128.4, 126.9, 126.5, 115.9, 75.0, 63.6, 56.1, 53.8, 50.1, 41.3, 38.4, 21.3, 17.6, 15.5.

[0556] LRMS(ESI+APCI)m / z: 604.1, HRMS(ESI)m / z: found: 604.1518, calcd 604.1508for C 31 H 32 C1N 3 NiO 4 + [M+H] + .

[0557] Embodiment 77

[0558] Preparation of Nickel Chelate of 3-Amino-3-(3-Methoxy Substituted) Phenylpropionic Acid

[0559] Basically the same as Example 65, 3-amino-3-phenylpropionic acid was replaced with 3-amino-3-(3-methoxy-substituted)phenylpropionic acid to obtain the nickel chelate of 3-amino-3-(3-methoxy-substituted)phenylpropionic acid in a yield of 90%.

[0560] mp=165-167℃.[α] 20 D = -2850.0 (c = 0.048, CHCl 3 ).

[0561] 1 H NMR (500 MHz, Methanol-d 4 )δ8.17 (d, J=9.1Hz, 1H), 7.70-7.47 (m, 5H), 7.31 (dd, J=9.1, 2.6Hz, 1H), 7.2 0-6.95 (m, 4H), 6.71 (d, J=2.6Hz, 1H), 4.56 (t, J=3.4Hz, 1H), 3.85 (s, 3H), 3.3 1-3.25(m, 1H), 2.97-2.77(m, 2H), 2.67(dd, J=17.8, 4.1Hz, 1H), 2.47-2.34( m, 1H), 2.30-2.21 (m, 1H), 2.03-1.76 (m, 5H), 1.68-1.47 (m, 2H), 1.12 (s, 3H).

[0562] 13 C NMR (125 MHz, Methanol-d 4 )δ183.δ, 177.0, 173.4, 162.1, 142.6, 142.4, 136.1, 134.1, 133.5, 131.9, 131.6, 131.4, 130.8, 130.4, 128 .4, 128.4, 126.9, 126.6, 119.9, 114.4, 114.1, 75.1, 64.0, 55.9, 53.6, 50.2, 41.0, 38.4, 21.4, 17.7, 15.5.

[0563] LRMS(ESI+APCI)m / z: 604.1, HRMS(ESI)m / z: found: 604.1518, calcd 604.1508for C 31 H 32 C1N 3 NiO 4 + [M+H] + .

[0564] Embodiment 78

[0565] Preparation of Nickel Chelate of 3-Amino-3-(3-Trifluoromethyl Substituted) Phenylpropionic Acid

[0566] Basically the same as Example 65, 3-amino-3-phenylpropionic acid was replaced with 3-amino-3-(3-trifluoromethyl-substituted)phenylpropionic acid to obtain the nickel chelate of 3-amino-3-(3-trifluoromethyl-substituted)phenylpropionic acid in a yield of 50%.

[0567] mp=158-160℃.[α] 20 D = -3280.6 (c = 0.036, CHCl 3 ).

[0568] 1 H NMR (500 MHz, Methanol-d 4)δ8.19 (d, J=9.2Hz, 1H), 7.86 (dd, J=28.1, 4.2Hz, 3H), 7.69-7.50 (m, 5H), 7.33 (dd , J=9.1, 2.7Hz, 1H), 7.18 (d, J=7.7Hz, 1H), 6.73 (d, J=2.6Hz, 1H), 4.68 (t, J=3.3Hz, 1H), 3.24-3.12 (m, 1H), 2.98 (dd, J=18.0, 2.9Hz, 1H), 2.87-2.73 (m, 2H), 2.45-2.1 9(m, 2H), 2.06-1.94(m, 1H), 1.88(t, J=7.3Hz, 3H), 1.72-1.48(m, 3H), 1.12(s, 3H).

[0569] 13 C NMR (125 MHz, Methanol-d 4 )δ183.6, 176.6, 174.2, 142.7, 142.4, 136.0, 134.2, 133.7, 132.8, 132.6, 132.2, 131.7, 131.7, 131.2, 130 .9, 130.5, 128.4, 128.2, 127.0, 126.6, 126.5, 123.9, 75.0, 63.6, 53.5, 50.2, 41.1, 38.3, 21.4, 17.7, 15.5.

[0570] LRMS(ESI+APCI)m / z: 642.1, HRMS(ESI)m / z: found: 642.1268, calcd 642.1276for C 31 H 29 CIF 3 N 3 NiO 3 + [M+H] + .

[0571] Embodiment 79

[0572] Preparation of Nickel Chelate of 3-Amino-3-(3-pyridine substituted)propionic acid

[0573] Basically the same as Example 65, 3-amino-3-phenylpropionic acid was replaced with 3-amino-3-(3-pyridine substituted) propionic acid to obtain the nickel chelate of 3-amino-3-(3-pyridine substituted) propionic acid with a yield of 80%.

[0574] mp=138-140℃.[α] 20 D= -2835.4 (c = 0.048, CHCl 3 ).

[0575] 1 H NMR (400 MHz, Methanol-d 4 )δ8.78 (d, J=2.5Hz, 1H), 8.76 (dd, J=4.6, 1.4Hz, 1H), 8.19 (d, J=9.2Hz, 1H), 8.00-7.92 (m, 1H ), 7.75-7.51 (m, 5H), 7.33 (dd, J=9.2, 2.6Hz, 1H), 7.24 (d, J=7.7Hz, 1H), 6.72 (d, J=2.6Hz, 1H ), 4.70 (t, J=3.6Hz, 1H), 3.29-3.18 (m, 1H), 2.99 (dd, J=17.9, 2.9Hz, 1H), 2.87-2.73 (m, 2H), 2.44-2.25(m, 2H), 2.09-1.98(m, 1H), 1.88(t, J=7.3Hz, 3H), 1.74-1.50(m, 3H), 1.13(s, 3H).

[0576] 13 C NMR (125 MHz, Methanol-d 4 )δ183.4, 176.4, 174.4, 150.1, 148.6, 142.7, 137.7, 136.5, 136.0, 134.1, 133.7, 131.7, 131.1, 130 .9, 130.5, 128.3, 128.3, 126.9, 126.6, 125.9, 75.1, 62.4, 53.4, 50.3, 41.1, 38.1, 21.4, 17.7, 15.5.

[0577] LRMS(ESI+APCI)m / z: 575.1, HRMS(ESI)m / z: found: 575.1347, calcd 575.1354forC 29 H 29 C1N 4 NiO 3 + [M+H] + .

[0578] Embodiment 80

[0579] Preparation of Nickel Chelate of 3-Amino-3-(2-Thiophene Substituted) Propionic Acid

[0580] Basically the same as Example 65, 3-amino-3-phenylpropionic acid was replaced with 3-amino-3-(2-thiophene substituted)propionic acid to obtain the nickel chelate of 3-amino-3-(2-thiophene substituted)propionic acid in a yield of 95%.

[0581] mp=145-146℃.[α] 20 D = -2775.0 (c = 0.048, CHCl 3 ).

[0582] 1 H NMR (500 MHz, Methanol-d 4 )δ8.16 (d, J=9.1Hz, 1H), 7.72 (d, J=5.1Hz, 1H), 7.68-7.48 (m, 4H), 7.35-7.25 (m, 2H), 7.19-7 .11 (m, 2H), 6.70 (d, J=2.6Hz, 1H), 4.72 (t, J=4.1Hz, 1H), 3.39 (ddd, J=13.2, 11.5, 5.4Hz, 1H), 2.97-2.91(m, 1H), 2.86-2.68(m, 2H), 2.50-2.40(m, 1H), 2.33-2.23(m, 1H), 2.22-2.12(m, 1H) , 2.08-2.00 (m, 1H), 1.92 (t, J=7.3Hz, 3H), 1.83-1.71 (m, 1H), 1.64-1.55 (m, 1H), 1.15 (s, 3H).

[0583] 13 C NMR (125 MHz, Methanol-d 4 )δ183.6, 176.3, 173.3, 145.2, 142.7, 135.8, 134.1, 133.6, 131.7, 131.2, 130.7, 130.4, 129.2, 128.4, 128.4, 127.9, 126.9, 126.7, 126.4, 75.1, 61.9, 53.8, 50.3, 41.3, 39.4, 21.8, 17.8, 15.6.

[0584] LRMS(ESI+APCI)m / z: 580.1, HRMS(ESI)m / z: found: 580.0976, calcd 580.0966for C 28 H 28 C1N 3 NiO 3 S + [M+H] + .

[0585] Embodiment 81

[0586] Preparation of Nickel Chelate of 3-Amino-3-(1-Naphthyl Substituted) Propionic Acid

[0587] Basically the same as Example 65, 3-amino-3-phenylpropionic acid was replaced with 3-amino-3-(1-naphthalene substituted)propionic acid to obtain the nickel chelate of 3-amino-3-(1-naphthalene substituted)propionic acid in a yield of 91%.

[0588] mp=145-147℃.[α] 20 D = -2292.0 (c = 0.05, CHCl 3 ).

[0589] 1 H NMR (400 MHz, Methanol-d 4 )δ8.19 (d, J=9.2Hz, 1H), 8.14 (d, J=8.6Hz, 1H), 8.02-7.94 (m, 3H), 7.68-7.51 (m, 7H), 7.33 (dd, J=9. 1, 2.6Hz, 1H), 7.31-7.26 (m, 1H), 6.75 (d, J=2.5Hz, 1H), 4.75 (t, J=3.5Hz, 1H), 3.10-3.03 (m, 1H), 3. 03-2.93 (m, 1H), 2.78 (dd, J=17.9, 4.1Hz, 1H), 2.72-2.64 (m, 1H), 2.43-2.30 (m, 1H), 2.22-2.11 (m, 1 H), 1.86 (t, J=7.3Hz, 3H), 1.71-1.59 (m, 1H), 1.39 (q, J=9.9Hz, 1H), 1.22-1.05 (m, 2H), 1.01 (s, 3H).

[0590] 13 C NMR (150 MHz, Methanol-d 4 )δ182.1, 172.8, 171.3, 142.1, 137.0, 135.0, 133.6, 133.1, 133.0, 130.6, 130.1, 130.0, 129.5, 129.3, 128.5, 1 27.8, 127.3, 127.1, 127.0, 126.7, 125.7, 125.5, 125.3, 124.9, 63.3, 53.5, 49.0, 40.2, 38.4, 19.9, 17.1, 15.3.

[0591] LRMS(ESI+APCI)m / z: 624.2, HRMS(ESI)m / z: found: 624.1576, calcd 624.1558for C 34 H 32 C1N 3 NiO 3 + [M+H] + .

[0592] Embodiment 82

[0593] Preparation of Nickel Chelate of 3-Aminobutyric Acid

[0594] Basically the same as Example 65, 3-amino-3-phenylpropionic acid was replaced with 3-aminobutyric acid to obtain nickel chelate of 3-aminobutyric acid with a yield of 87%.

[0595] mp=240-242℃.[α] 20 D = -4309.5 (c = 0.042, CHCl 3 ).

[0596] 1 H NMR (500 MHz, Methanol-d 4 )δ8.14 (d, J=9.1Hz, 1H), 7.64-7.43 (m, 4H), 7.27 (dd, J=9.1, 2.6Hz, 1H), 6.98 (d , J=7.6Hz, 1H), 6.65 (d, J=2.6Hz, 1H), 4.34-4.23 (m, 1H), 3.62-3.52 (m, 1H), 3.4 4-3.35 (m, 1H), 3.29-3.16 (m, 1H), 2.50-2.28 (m, 5H), 2.21 (d, J=6.6Hz, 3H), 2.1 1 (dd, J=17.5, 2.5Hz, 1H), 1.94 (t, J=7.3Hz, 3H), 1.87-1.78 (m, 1H), 1.27 (s, 3H).

[0597] 13 C NMR (125 MHz, Methanol-d 4 )δ183.1, 176.7, 172.1, 141.9, 136.7, 133.8, 133.1, 131.5, 131.3, 130.8, 130.3, 127 .9, 127.9, 126.9, 126.5, 75.9, 58.9, 53.2, 50.7, 41.7, 41.0, 22.4, 22.2, 17.1, 15.5.

[0598] LRMS(ESI+APCI)m / z: 512.1, HRMS(ESI)m / z: found: 512.1259, calcd 512.1245for C 25 H 28 C1N 3 NiO 3 + [M+H] + .

[0599] Embodiment 83

[0600] Preparation of Nickel Chelate of 3-Aminovaleric Acid

[0601] Basically the same as Example 65, 3-amino-3-phenylpropionic acid was replaced with 3-aminovaleric acid to obtain nickel chelate of 3-aminovaleric acid with a yield of 94%.

[0602] mp=248-250℃.[α] 20 D = -4370.5 (c = 0.044, CHCl 3 ).

[0603] 1 H NMR (600 MHz, Methanol-d 4 )δ8.18 (d, J=9.1Hz, 1H), 7.59 (tdd, J=9.0, 5.2, 1.6Hz, 2H), 7.55-7.50 (m, 1H), 7.46 (dt, J =7.0, 1.9Hz, 1H), 7.28 (dd, J=9.1, 2.6Hz, 1H), 6.92 (dd, J=7.6, 1.5Hz, 1H), 6.62 (d, J=2.5H z, 1H), 4.22-4.10 (m, 1H), 3.61-3.52 (m, 1H), 3.37-3.32 (m, 2H), 3.26-3.12 (m, 1H), 2.52- 2.14 (m, 7H), 1.93 (t, J=7.3Hz, 3H), 1.87-1.77 (m, 1H), 1.27 (s, 3H), 1.19 (t, J=7.4Hz, 3H).

[0604] 13 C NMR (150 MHz, Methanol-d 4)δ183.2, 176.8, 173.1, 142.2, 136.9, 134.0, 133.2, 131.7, 131.3, 130.6, 130.3, 128.8 , 128.1, 126.8, 126.3, 75.8, 64.9, 53.3, 50.6, 41.6, 40.2, 30.6, 22.2, 17.2, 15.5, 11.9.

[0605] LRMS(ESI+APCI)m / z: 526.1, HRMS(ESI)m / z: found: 526.1408, calcd 526.1402for C 26 H 30 C1N 3 NiO 3 + [M+H] + .

[0606] Embodiment 84

[0607] Preparation of Nickel Chelate of 3-Aminoheptanoic Acid

[0608] Basically the same as Example 65, 3-amino-3-phenylpropionic acid was replaced with 3-aminoheptanoic acid to obtain nickel chelate of 3-aminoheptanoic acid with a yield of 97%.

[0609] mp=110-112℃.[α] 20 D = -3400.0 (c = 0.046, CHCl 3 ).

[0610] 1 H NMR (400 MHz, Methanol-d 4 )δ8.17 (d, J=9.1Hz, 1H), 7.65-7.42 (m, 4H), 7.29 (dd, J=9.1, 2.6Hz, 1H), 6.96- 6.86 (m, 1H), 6.61 (d, J = 2.5Hz, 1H), 4.18 (td, J = 12.3, 6.7Hz, 1H), 3.60-3.33 (m, 3H), 3.26-3.10(m, 1H), 2.51-2.11(m, 7H), 1.93(t, J=7.3Hz, 3H), 1.88-1.74(m , 2H), 1.60-1.36 (m, 2H), 1.27 (s, 3H), 1.24-1.12 (m, 1H), 0.98 (t, J=7.4Hz, 3H).

[0611] 13 C NMR (125 MHz, Methanol-d 4)δ181.5, 172.7, 170.7, 141.4, 135.6, 132.9, 132.6, 130.2, 129.7, 129.2, 127.6, 126.3, 1 25.5, 125.0, 74.1, 62.7, 52.9, 49.5, 40.8, 40.4, 36.8, 29.1, 22.9, 21.5, 16.8, 15.3, 14.1.

[0612] LRMS(ESI+APCI)m / z: 554.2, HRMS(ESI)m / z: found: 554.1720, calcd 554.1715for C 28 H 34 C1N 3 NiO 3 + [M+H] + .

[0613] Embodiment 85

[0614] Preparation of Nickel Chelate of 3-Amino-5-Methylhexanoic Acid

[0615] Basically the same as Example 65, 3-amino-3-phenylpropionic acid was replaced with 3-amino-5-methylhexanoic acid to obtain the nickel chelate of 3-amino-5-methylhexanoic acid with a yield of 91%.

[0616] mp=248-251℃.[α] 20 D = -3029.5 (c = 0.044, CHCl 3 ).

[0617] 1 H NMR (400 MHz, Methanol-d 4 )δ8.16 (d, J=9.1Hz, 1H), 7.66-7.46 (m, 4H), 7.28 (dd, J=9.1, 2.6Hz, 1H), 6.96 (dt, J=8. 3, 1.4Hz, 1H), 6.62 (d, J=2.6Hz, 1H), 4.32-4.18 (m, 1H), 3.58-3.49 (m, 1H), 3.41-3.33 ( m, 2H), 3.26-3.10 (m, 1H), 2.56-2.27 (m, 6H), 2.17 (dd, J=17.5, 2.5Hz, 1H), 1.92 (t, J=7 .3Hz, 3H), 1.86-1.68 (m, 2H), 1.27 (s, 3H), 0.96 (d, J=6.6Hz, 3H), 0.73 (d, J=6.5Hz, 3H).

[0618] 13 C NMR (125 MHz, CDCl 3 )δ181.5, 172.7, 170.5, 141.4, 135.5, 133.0, 132.6, 130.3, 130.2, 129.6, 129.2, 127.8, 126. 4, 125.5, 125.0, 74.1, 60.6, 52.8, 49.6, 46.4, 40.8, 40.3, 25.1, 22.8, 22.8, 21.4, 16.8, 15.3.

[0619] LRMS(ESI+APCI)m / z: 554.2, HRMS(ESI)m / z: found: 554.1728, calcd 554.1715for C 28 H 34 C1N 3 NiO 3 + [M+H] + .

[0620] Embodiment 86

[0621] Preparation of Nickel Chelate of 3-Amino-4-Methylpentanoic Acid

[0622] Basically the same as Example 65, 3-amino-3-phenylpropionic acid was replaced with 3-amino-4-methylpentanoic acid to obtain the nickel chelate of 3-amino-4-methylpentanoic acid in a yield of 76%.

[0623] mp=150-152℃.[α] 20 D = -3242.9 (c = 0.042, CHCl 3 ).

[0624] 1 H NMR (400 MHz, Methanol-d 4)δ8.18 (d, J=9.1Hz, 1H), 7.66-7.42 (m, 4H), 7.29 (dd, J=9.1, 2.6Hz, 1H), 6.90 (dt, J=7.6, 1.0Hz, 1H), 6.60 (d, J=2.6Hz, 1H), 4.27-4.03 (m, 2H), 3.37-3.32 (m, 1H), 3. 23-3.09 (m, 1H), 2.99 (dt, J=10.3, 3.3Hz, 1H), 2.51-2.24 (m, 6H), 1.93 (t, J=7.3Hz , 3H), 1.88-1.76 (m, 1H), 1.35 (d, J=6.7Hz, 3H), 1.27 (s, 3H), 0.91 (d, J=6.6Hz, 3H).

[0625] 13 C NMR (125 MHz, CDCl 3 )δ181.5, 173.0, 170.7, 141.5, 135.8, 133.0, 132.6, 130.2, 129.6, 129.3, 127.8, 126.3 , 125.6, 125.0, 74.0, 69.3, 53.1, 49.5, 40.6, 38.4, 34.0, 21.6, 21.3, 19.9, 17.0.15.3.

[0626] LRMS(ESI+APCI)m / z: 540.1, HRMS(ESI)m / z: found: 540.1556, calcd 540.1558for C 27 H 32 C1N 3 NiO 3 + [M+H] + .

[0627] Embodiment 87

[0628] Preparation of Nickel Chelate of 3-Amino-3-Cyclopropylpropionic Acid

[0629] Basically the same as Example 65, 3-amino-3-phenylpropionic acid was replaced with 3-amino-3-cyclopropylpropionic acid to obtain the nickel chelate of 3-amino-3-cyclopropylpropionic acid in a yield of 93%.

[0630] mp=150-151℃.[α] 20 D = -3892.1 (c = 0.038, CHCl 3 ).

[0631] 1H NMR (600 MHz, Methanol-d 4 )δ8.18 (dd, J=9.3, 2.9Hz, 1H), 7.61-7.24 (m, 5H), 6.92 (d, J=7.7Hz, 1H), 6.58 (d , J=2.6Hz, 1H), 4.42-4.29(m, 1H), 4.18-4.02(m, 1H), 3.42-3.33(m, 1H), 3.18-3 .06(m, 1H), 2.97-2.85(m, 1H), 2.56-2.25(m, 6H), 2.02-1.82(m, 4H), 1.26(s, 3H ), 1.20-1.12(m, 1H), 0.85-0.73(m, 1H), 0.24-0.14(m, 1H), 0.08--0.03(m, 1H).

[0632] 13 C NMR (150 MHz, Methanol-d 4 )δ183.2, 177.1, 171.8, 142.1, 136.5, 133.9, 133.2, 131.7, 131.4, 130.6, 130.3, 128.8, 1 28.1, 126.9, 126.4, 75.9, 69.0, 53.4, 50.6, 41.9, 40.3, 22.2, 18.2, 16.9, 15.5, 6.2, 5.4.

[0633] LRMS(ESI+APCI)m / z: 538.1, HRMS(ESI)m / z: found: 538.1413, calcd 538.1402for C 27 H 30 C1N 3 NiO 3 + [M+H] + .

[0634] Embodiment 88

[0635] Preparation of Nickel Chelate of 3-Amino-3-Cyclohexylpropionic Acid

[0636] Basically the same as Example 65, 3-amino-3-phenylpropionic acid was replaced with 3-amino-3-cyclohexylpropionic acid to obtain the nickel chelate of 3-amino-3-cyclohexylpropionic acid with a yield of 85%.

[0637] mp=155-157℃.[α] 20 D = -2770.0 (c = 0.04, CHCl 3 ).

[0638] 1 H NMR (400 MHz, Methanol-d 4 )δ8.17 (d, J=9.1Hz, 1H), 7.63-7.42 (m, 4H), 7.28 (dd, J=9.1, 2.6Hz, 1H), 6.95-6.86 (m, 1H) , 6.58 (d, J=2.6Hz, 1H), 4.27-4.13 (m, 1H), 4.04-3.88 (m, 1H), 3.39-3.33 (m, 1H), 3.24-3.13 (m, 1H), 3.09-3.00 (m, 1H), 2.64-2.25 (m, 7H), 1.99 (d, J=13.1Hz, 1H), 1.91 (t, J=7.3Hz, 3H ), 1.86-1.70(m, 5H), 1.52-1.38(m, 1H), 1.27(s, 3H), 1.17-1.09(m, 1H), 0.81-0.59(m, 2H).

[0639] 13 C NMR (125 MHz, CDCl 3 )δ181.4, 173.3, 170.7, 141.5, 135.7, 133.0, 132.6, 130.3, 130.2, 129.6, 129.2, 128.0, 126.3, 125 .6, 124.9, 74.2, 68.1, 52.8, 49.6, 43.1, 40.6, 37.7, 31.3, 29.8, 26.4, 26.3, 26.0, 21.5, 16.7, 15.3.

[0640] LRMS(ESI+APCI)m / z: 580.2, HRMS(ESI)m / z: found: 580.1876, calcd 580.1871for C 30 H 36 C1N 3 NiO 3 + [M+H] + .

[0641] Embodiment 89

[0642] Preparation of Nickel Chelate of 3-Amino-4-(2,4,5-trifluorophenyl)butyric Acid

[0643] Basically the same as Example 65, 3-amino-3-phenylpropionic acid was replaced with 3-amino-4-(2,4,5-trifluorophenyl)butyric acid to obtain nickel chelate of 3-amino-4-(2,4,5-trifluorophenyl)butyric acid with a yield of 87%.

[0644] mp=140-141℃.[α] 20 D =-2814.0(c=0.05,CHCl 3 ).

[0645] 1 H NMR(500MHz,Methanol-d 4 )δ8.15(d,J=9.1Hz,1H),7.62-7.48(m,2H),7.46-7.34(m,2H),7.28(dd,J=9.1,2.5Hz,1H),7.12(td,J=9.9,6.6Hz,1H),7.03(ddd,J=10.7,8.7,6.7Hz,1H),6.59(d,J=2.6Hz,1H),6.49-6.38(m,1H),4.38(dd,J=13.8,6.9Hz,1H),4.20(ddd,J=13.4,11.4,5.7Hz,1H),4.01-3.91(m,1H),3.62(tdd,J=6.9,4.3,2.5Hz,1H),3.51-3.33(m,2H),2.58-2.28(m,5H),2.09(dd,J=17.6,2.6Hz,1H),2.01(t,J=7.3Hz,3H),1.89-1.78(m,1H),1.31(s,3H).

[0646] 13 C NMR(125MHz,Methanol-d 4 )δ183.4,176.4,173.6,157.6(ddd,J=245.1,9.5,2.2Hz),150.6(dt,J=250.2,13.8Hz),148.07(ddd,J=244.1,12.5,3.1Hz),142.2,136.5,134.0,133.4,131.3,131.0,130.4,130.2,128.0,127.8,126.8,126.6,122.1(dt,J=18.6,5.0Hz),120.0(dd,J=19.3,5.9Hz),106.9(dd,J=28.9,21.2Hz),75.7,6.4.0,53.2,50.9,41.4,39.2,35.9,22.6,18.0,15.6.

[0647] LRMS(ESI+APCI)m / z: 642.1, HRMS(ESI)m / z: found: 642.1287, calcd 642.1276for C 31 H 29 CIF 3 N 3 NiO 3 + [M+H] + .

[0648] Embodiment 90

[0649] Nickel(II)-(S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrole-2-carboxamide / (S)-2-amino-2-benzylacetic acid Schiff base complex

[0650] Synthesis method: The ligand (S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide (100.3 mg, 0.2 mmol), DL-phenylalanine (33 mg, 0.2 mmol), and anhydrous nickel acetate (35.3 mg, 0.2 mmol) were dissolved in 4 mL of methanol, and DBU (149.4 μL, 1.0 mmol) was added. The reaction was carried out at 60° C. for 72 hours, and 5% glacial acetic acid was added to quench the reaction. The reaction was extracted with dichloromethane three times, the organic layers were combined, dried, and the solvent was evaporated under reduced pressure. The red solid (136 mg, yield 98%) was purified by column chromatography (dichloromethane: methanol = 20: 1).

[0651] mp:116.3-117.5℃.[α] 20 D =2502(c=1, CHCl 3 ).

[0652] 1 H NMR (400 MHz, CDCl 3)δ9.08 (d, J=2.1Hz, 1H), 8.32 (d, J=9.3Hz, 1H), 7.61-7.49 (m, 3H), 7.42-7.27 (m, 6H), 7.15-7.0 2 (m, 3H), 6.65 (d, J = 7.7Hz, 1H), 6.61 (d, J = 2.6Hz, 1H), 4.22 (t, J = 5.2Hz, 1H), 3.54 (dd, J = 59.9, 13.0Hz, 2H), 3.36-3.24 (m, 1H), 3.14 (dt, J=17.6, 6.8Hz, 2H), 2.78 (dd, J=13.8, 5.4Hz, 1H), 2.4 2-2.23 (m, 1H), 2.14-2.03 (m, 1H), 1.98 (dd, J=19.7, 9.7Hz, 1H), 1.87-1.73 (m, 1H), 1.33 (s, 3H).

[0653] 13 C NMR (125 MHz, CDCl 3 )δ180.5, 178.1, 170.8, 141.5, 135.8, 134.0, 133.4, 133.1, 133.0, 132.7, 132.6, 131.1, 130.5, 130.3, 129. 8, 129.5, 129.3, 129.1, 127.9, 127.7, 127.5, 125.8, 124.3, 74.3, 71.8, 57.3, 54.7, 41.4, 39.8, 20.7, 17.8.

[0654] MS (ESI, m / z): 704.0 [MH] - .

[0655] Embodiment 91

[0656] Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrole-2-carboxamide / (R)-2-amino-2-(3-methoxybenzyl)acetic acid Schiff base complex

[0657] Synthesis method: The ligand (R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide (100.3 mg, 0.2 mmol), DL-3-methoxyphenylalanine 2-23 (39 mg, 0.2 mmol), and anhydrous nickel acetate (35.3 mg, 0.2 mmol) were dissolved in 4 mL of methanol, and K 2 CO 3(138.1 mg, 1.0 mmol), react at 60 ° C for 24 hours, add 5% glacial acetic acid to quench the reaction, extract with dichloromethane three times, combine the organic layers, dry, evaporate the solvent under reduced pressure, and purify by column chromatography (dichloromethane: methanol = 20: 1) to obtain a red solid (132 mg, yield 90%).

[0658] mp:104.2-106.1℃.[α] 20 D =-2923(c=1, CHCl 3 ).

[0659] 1 H NMR (400 MHz, CDCl 3 )δ9.08 (d, J=2.0Hz, 1H), 8.33 (d, J=9.3Hz, 1H), 7.62-7.47 (m, 3H), 7.40-7.28 (m, 3H), 7.26-7.18 (m, 1H), 7.12 (dd, J =9.3, 2.6Hz, 1H), 6.88 (dd, J=8.3, 2.3Hz, 1H), 6.67 (d, J=7.5Hz, 1H), 6.60 (d, J=2.6Hz, 2H), 6.55 (d, J=7.9Hz, 1H), 4. 21 (t, J=5.3Hz, 1H), 3.65 (s, 3H), 3.55 (dd, J=59.3, 13.1Hz, 2H), 3.45-3.31 (m, 1H), 3.26-3.03 (m, 2H), 2.81 (dd, J=1 3.8, 5.1Hz, 1H), 2.46 (dq, J=14.1, 7.2Hz, 1H), 2.25-2.11 (m, 1H), 2.07-1.96 (m, 1H), 1.95-1.78 (m, 1H), 1.35 (s, 3H).

[0660] 13 C NMR (125 MHz, CDCl 3 )δ180.6, 178.3, 170.9, 141.5, 135.8, 135.7, 134.0, 133.4, 133.1, 133.0, 132.7, 132.6, 131.1, 130.3, 129.8, 1 29.6, 129.5, 129.3, 127.7, 127.4, 126.4, 125.8, 124.3, 124.3, 74.4, 71.3, 57.4, 54.8, 41.5, 34.1, 20.9, 17.9.

[0661] MS (ESI, m / z): 734.0 [MH] - .

[0662] Embodiment 92

[0663] Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrole-2-carboxamide / (R)-2-amino-2-(3-methylbenzyl)acetic acid Schiff base complex

[0664] According to a synthetic method similar to Example 91, DL-3-methoxyphenylalanine was replaced with DL-3-methylphenylalanine, and a red solid was obtained by column chromatography (dichloromethane:methanol=20:1) with a yield of 88%.

[0665] mp:105.3-106.8℃.[α] 20 D =-1898(c=1, CHCl 3 ).

[0666] 1 H NMR (400 MHz, CDCl 3 )δ9.06 (d, J=1.5Hz, 1H), 8.34 (d, J=9.3Hz, 1H), 7.55 (dt, J=17.5, 7.4Hz, 3H), 7.38 (t, J=7.5Hz, 1H), 7.31 (t, J=6.7Hz, 2H ), 7.23 (t, J=7.5Hz, 1H), 7.17-7.09 (m, 2H), 6.87 (d, J=7.8Hz, 2H), 6.63 (dd, J=12.2, 5.1Hz, 2H), 4.21 (t, J=5.1Hz, 1H), 3. 53 (dd, J=47.7, 13.1Hz, 2H), 3.31 (td, J=12.6, 5.8Hz, 1H), 3.11 (dd, J=13.7, 4.7Hz, 2H), 2.75 (dd, J=13.7, 5.4Hz, 1H), 2. 47-2.31 (m, 1H), 2.27 (s, 3H), 2.13-2.06 (m, 1H), 1.99 (dd, J=19.4, 9.7Hz, 1H), 1.84 (dt, J=14.9, 6.7Hz, 1H), 1.33 (s, 3H).

[0667] 13 C NMR (125 MHz, CDCl 3)δ180.4, 178.2, 170.7, 141.5, 138.7, 135.8, 135.6, 134.0, 133.3, 133.1, 133.0, 132.6, 132.6, 131.3, 131.1, 130.2, 129.8, 129.5, 129.2, 128.9, 128.4, 127.9, 127.7, 127.5, 127.5, 125.7, 124.2, 74.3, 71.8, 57.3, 54.7, 41.2, 39.8, 21.6, 20.6, 17.8.

[0668] MS (ESI, m / z): 718.0 [MH] - .

[0669] Embodiment 93

[0670] Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrole-2-carboxamide / (R)-2-amino-2-(4-fluorobenzyl)acetic acid Schiff base complex C4

[0671] According to a synthetic method similar to Example 91, DL-3-methoxyphenylalanine was replaced with DL-4-fluorophenylalanine and a red solid was obtained by column chromatography (dichloromethane:methanol=20:1) with a yield of 76%.

[0672] mp:235-236.8℃.[α] 20 D =-2300(c=1, CHCl 3 ).

[0673] 1 H NMR (400 MHz, CDCl 3)δ9.06 (d, J=1.5Hz, 1H), 8.32 (d, J=9.3Hz, 1H), 7.56 (p, J=7.5Hz, 3H), 7.43 (t, J=7.3Hz, 1H), 7.37-7.28 (m, 2H ), 7.13 (dd, J=9.3, 2.5Hz, 1H), 7.05 (d, J=7.0Hz, 4H), 6.73 (d, J=7.5Hz, 1H), 6.62 (d, J=2.5Hz, 1H), 4.21 (t, J=5 .0Hz, 1H), 3.54 (dd, J=47.7, 13.0Hz, 2H), 3.34 (td, J=12.6, 6.0Hz, 1H), 3.20-3.01 (m, 2H), 2.74 (dd, J=14.0, 5 .4Hz, 1H), 2.45-2.26(m, 1H), 2.26-2.12(m, 1H), 2.00(dd, J=19.3, 9.6Hz, 1H), 1.90-1.83(m, 1H), 1.35(s, 3H).

[0674] 13 C NMR (125 MHz, CDCl 3 )δ180.5, 177.9, 170.9, 163.4, 161.8, 141.5, 135.7, 133.9, 133.3, 133.1, 133.0, 132.7, 132.6, 131.9, 131.9, 131.5, 131.5, 131. 1, 130.4, 129.8, 129.6, 129.3, 127.7, 127.6, 127.4, 125.9, 124.3, 116.0, 115.8, 74.3, 71.6, 57.4, 54.6, 41.2, 38.8, 20.7, 17.8.

[0675] MS (ESI, m / z): 722.0 [MH] - .

[0676] Embodiment 94

[0677] Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrole-2-carboxamide / (R)-2-amino-2-(3-methoxyphenyl)acetic acid Schiff base complex

[0678] According to a synthetic method similar to Example 91, DL-3-methoxyphenylalanine was replaced with DL-3-methoxyphenylglycine and a red solid was obtained by column chromatography (dichloromethane:methanol=20:1) with a yield of 70%.

[0679] mp: 134.8 - 136.6 °C. [α] 20 D = -2183 (c = 1, CHCl 3 ).

[0680] 1 H NMR (400 MHz, CDCl 3 ) δ 9.18 (d, J = 1.6 Hz, 1H), 8.23 (d, J = 9.3 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.39 (dd, J = 15.2, 7.2 Hz, 3H), 7.29 (d, J = 7.5 Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 7.16 (dd, J = 9.3, 2.5 Hz, 1H), 7.11 - 7.02 (m, 2H), 6.80 (dd, J = 8.2, 2.3 Hz, 1H), 6.66 (d, J = 2.5 Hz, 1H), 6.14 (d, J = 7.9 Hz, 1H), 4.71 (s, 1H), 4.08 - 3.95 (m, 1H), 3.80 (d, J = 13.0 Hz, 1H), 3.71 (s, 3H), 3.61 (d, J = 13.0 Hz, 1H), 3.34 (t, J = 8.9 Hz, 1H), 3.14 (dd, J = 18.8, 9.9 Hz, 1H), 2.46 (dd, J = 14.1, 9.9 Hz, 1H), 2.19 (dd, J = 17.6, 7.9 Hz, 2H), 1.76 (s, 1H), 1.49 (s, 3H).

[0681] 13 C NMR (125 MHz, CDCl 3 ) δ 180.8, 177.4, 171.7, 159.8, 141.3, 139.2, 135.8, 134.0, 133.3, 133.3, 133.1, 132.6, 132.4, 131.2, 130.0, 129.9, 129.7, 129.0, 128.9, 127.7, 127.1, 126.7, 126.0, 124.9, 118.4, 113.8, 112.6, 74.7, 74.4, 57.3, 55.4, 55.3, 41.7, 21.2, 18.3.

[0682] MS (ESI, m / z): 720.0 [M - H] - .

[0683] Example 95

[0684] Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrole-2-carboxamide / (R)-2-amino-2-(3-bromophenyl)acetic acid Schiff base complex

[0685] According to a synthetic method similar to Example 91, DL-3-methoxyphenylalanine was replaced with DL-3-bromophenylglycine and a red solid was obtained by column chromatography (dichloromethane:methanol=20:1) with a yield of 85%.

[0686] mp:102.5-104.4℃.[α] 20 D =-2069(c=1, CHCl 3 ).

[0687] 1 H NMR (400 MHz, CDCl 3 )δ9.18 (d, J=2.1Hz, 1H), 8.22 (d, J=9.3Hz, 1H), 8.15 (s, 1H), 7.80 (dd, J=8.2, 2.2Hz, 1H), 7.57 (t, J=7.6Hz, 1H), 7.50-7.38 (m, 3H), 7.32 (dd, J=18.2, 7.8Hz, 2H), 7.15 (ddd, J=24.1, 12.7, 5.5Hz, 3H), 6.67 (d, J=2.5Hz, 1H), 6.13 (d, J=7.8Hz, 1H), 4.71 (s, 1H), 4.04 (t, J=10.9Hz, 1H), 3.72 (dd, J=78.9, 13.1Hz, 2H), 3.41-3.29 (m, 1H), 3.14 (d d, J=21.0, 13.1Hz, 1H), 2.50 (dd, J=13.7, 10.0Hz, 1H), 2.30-2.04 (m, 2H), 1.58 (s, 1H), 1.50 (s, 3H), 1.25 (s, 1H).

[0688] 13 C NMR (125 MHz, CDCl 3 )δ180.8, 176.8, 172.1, 141.4, 139.9, 135.8, 134.0, 133.4, 132.9, 132.9, 132.4, 131.6, 131.3, 130.3, 130.2, 130. 0, 129.3, 129.3, 129.1, 127.6, 127.0, 126.7, 126.1, 125.3, 125.0, 122.9, 74.5, 74.1, 57.3, 55.3, 41.8, 21.2, 18.3.

[0689] MS (ESI, m / z): 769.7 [MH] - .

[0690] Embodiment 96

[0691] Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrole-2-carboxamide / (R)-2-amino-3-(3,5-diiodo-4-hydroxyphenyl)propionic acid Schiff base complex

[0692] According to a synthetic method similar to Example 91, DL-3-methoxyphenylalanine was replaced with DL-2-amino-3-(3,5-diiodo-4-hydroxyphenyl)propionic acid, and a red solid was obtained by column chromatography (dichloromethane:methanol=20:1) with a yield of 90%.

[0693] mp:286.5-287.9℃.[α] 20 D =2038(c=1, CHCl 3 ).

[0694] 1H NMR (400MHz, CDCl3) δ9.05 (d, J=2.0Hz, 1H), 8.43 (d, J=9.3Hz, 1H), 7.66-7.53 (m, 3H), 7.47 (dd, J=10.8, 5.7Hz, 1H), 7.33 (t, J=7.2Hz, 2H), 7.27 (s, 2H), 7.16 (dd, J=9.3, 2.6Hz, 1H), 6.78 (d, J=7.4Hz, 1H), 6.66 (d, J=2.5Hz, 1H), 5.82 (s, 1H), 4. 14-4.07 (m, 1H), 3.56 (dd, J=29.2, 13.0Hz, 2H), 3.46-3.34 (m, 1H), 3.17 (t, J=8.8Hz, 1H), 2.89 (dd, J=14.1, 4.4Hz, 1H), 2 .67 (dd, J=13.9, 6.2Hz, 1H), 2.54-2.39 (m, 1H), 2.24 (dd, J=13.8, 9.8Hz, 1H), 2.02 (td, J=18.7, 9.4Hz, 2H), 1.37 (s, 3H).

[0695] 13 C NMR (125 MHz, CDCl 3)δ180.4, 177.6, 171.0, 153.4, 141.8, 140.6, 135.7, 134.0, 133.2, 133.1, 133.0, 132.6, 131.8, 131.2, 130.6, 129.8, 129.7, 129.4, 127.6, 127.5, 127.4, 125.8, 124.4, 82.8, 74.5, 71.2, 57.5, 54.7, 41.0, 38.0, 21.0, 17.9.

[0696] MS (ESI, m / z): 971.8 [MH] - .

[0697] Embodiment 97

[0698] Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrole-2-carboxamide / (R)-2-amino-3-(naphthalen-1-yl)propionic acid Schiff base complex

[0699] According to a synthetic method similar to Example 91, DL-3-methoxyphenylalanine was replaced with DL-2-amino-3-(naphthalen-1-yl)propionic acid, and a red solid was obtained by column chromatography (dichloromethane:methanol=20:1) with a yield of 92%.

[0700] mp:114.5-116.1℃.[α] 20 D =-1812(c=1, CHCl 3 ).

[0701] 1 H NMR (400 MHz, CDCl 3)δ9.09 (d, J=2.0Hz, 1H), 8.30 (d, J=9.3Hz, 1H), 7.78 (t, J=8.0Hz, 2H), 7.68 (dd, J=8.2, 2.0Hz, 1H), 7.57 (d, J=8.6Hz, 1H), 7.43-7.35 (m, 1H), 7.30 (dd, J=15.6, 7.6Hz, 4H), 7.23-7.11 (m, 3H), 7.08 (dd, J=9.3, 2.6Hz, 1H), 6.68 (t, J=7.6Hz, 1H), 6.44 (d, J=2.6Hz, 1H), 5.64 (d, J=7.7Hz, 1H), 4.41 ( dd, J=8.3, 4.3Hz, 1H), 4.07 (dd, J=14.2, 8.5Hz, 1H), 3.79 (dd, J=14.1, 4.3Hz, 1H), 3.70 (d, J=13.2Hz, 1H), 3.61 (td, J=13.1, 5.9Hz, 1H), 3.46 (d, J= 13.2Hz, 1H), 3.24 (t, J=9.1Hz, 1H), 2.83-2.53 (m, 1H), 2.39-2.22 (m, 1H) , 2.12 (dd, J=19.8, 9.6Hz, 1H), 2.00 (dt, J=15.0, 8.9Hz, 1H), 1.40 (s, 3H).

[0702] 13 C NMR (125 MHz, CDCl 3 )δ180.3, 178.3, 170.5, 1412, 135.8, 134.2, 133.8, 133.3, 133.0, 132.8, 132.6, 132.5, 132.3, 131.7, 131.2, 129.8, 129.6, 128.8, 128. 7, 128.6, 128.6, 128.5, 127.7, 127.5, 127.4, 126.5, 126.1, 125.7, 125.6, 124.1, 123.4, 74.4, 71.6, 56.9, 55.1, 41.6, 40.2, 20.9, 17.9.

[0703] MS (ESI, m / z): 75.0 [MH] - .

[0704] Embodiment 98

[0705] Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrole-2-carboxamide / (R)-2-amino-3-(benzothiophen-3-yl)propionic acid Schiff base complex

[0706] According to a synthetic method similar to Example 91, DL-3-methoxyphenylalanine was replaced with DL-2-amino-3-(benzothiophen-3-yl)propionic acid, and a red solid was obtained by column chromatography (dichloromethane:methanol=20:1) with a yield of 94%.

[0707] mp:127.1-128.9℃.[α] 20 D =-1836(c=1, CHCl 3 ).

[0708] 1 H NMR (400 MHz, CDCl 3 )δ9.06 (d, J=2.0Hz, 1H), 8.34 (d, J=9.3Hz, 1H), 7.86 (d, J=8.0Hz, 1H), 7.57 (dd, J=8.2, 2.0Hz, 1H), 7.49 (t, J =7.5Hz, 1H), 7.45-7.34(m, 2H), 7.30(dd, J=11.9, 6.2Hz, 3H), 7.19-7.08(m, 4H), 6.59(d, J=2.6Hz, 1H), 6.48( d, J=7.5Hz, 1H), 4.31 (t, J=5.5Hz, 1H), 3.71-3.59 (m, 1H), 3.51 (dd, J=57.6, 9.8Hz, 2H), 3.18 (dd, J=14.5, 4.7 Hz, 1H), 3.03 (dt, J=19.1, 10.3Hz, 2H), 2.01 (ddd, J=20.7, 18.6, 11.3Hz, 3H), 1.81-1.69 (m, 1H), 1.30 (s, 3H).

[0709] 13 C NMR (125 MHz, CDCl 3 )δ180.3, 178.3, 170.8, 141.5, 140.6, 139.3, 135.7, 133.9, 133.2, 133.0, 132.9, 132.7, 131.1, 130.5, 130.1, 129.8, 129. 3, 129.0, 127.5, 127.5, 125.9, 125.8, 124.8, 124.5, 124.3, 122.9, 122.1, 74.3, 70.9, 57.2, 54.8, 41.0, 34.0, 20.4, 17.8.

[0710] MS (ESI, m / z): 760.0 [MH] - .

[0711] Embodiment 99

[0712] Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrole-2-carboxamide / (R)-2-amino-3-(thiophen-3-yl)propionic acid Schiff base complex

[0713] According to a synthetic method similar to Example 91, DL-3-methoxyphenylalanine was replaced with DL-2-amino-3-(thiophen-3-yl)propionic acid and a red solid was obtained by column chromatography (dichloromethane:methanol=20:1) with a yield of 89%.

[0714] mp:208.5-209.6℃.[α] 20 D =-2419(c=1, CHCl 3 ).

[0715] 1 H NMR (400 MHz, CDCl 3 )δ9.09 (d, J=2.1Hz, 1H), 8.34 (d, J=9.3Hz, 1H), 7.63-7.49 (m, 3H), 7.46-7.39 (m, 1H), 7.38-7.28 (m, 3H), 7.13 ( dd, J=9.3, 2.6Hz, 1H), 7.04 (d, J=1.8Hz, 1H), 6.86 (dd, J=4.9, 1.2Hz, 1H), 6.70 (d, J=7.7Hz, 1H), 6.62 (d, J=2.6 Hz, 1H), 4.18 (t, J=5.1Hz, 1H), 3.63 (d, J=13.1Hz, 1H), 3.50 (dq, J=11.9, 5.9Hz, 2H), 3.25-3.05 (m, 2H), 2.77 (d d, J=14.3, 5.4Hz, 1H), 2.62-2.41(m, 1H), 2.29-2.12(m, 1H), 2.09-1.98(m, 1H), 1.96-1.84(m, 1H), 1.36(s, 3H).

[0716] 13 C NMR (125 MHz, CDCl 3)δ180.6, 178.3, 170.9, 141.5, 135.8, 135.7, 134.0, 133.4, 133.1, 133.0, 132.7, 132.6, 131.1, 130.3, 129.8, 1 29.6, 129.5, 129.3, 127.7, 127.4, 126.4, 125.8, 124.3, 124.3, 74.4, 71.3, 57.4, 54.8, 41.5, 34.1, 20.9, 17.9.

[0717] MS (ESI, m / z): 710.0 [MH] - .

[0718] Embodiment 100

[0719] Nickel(II)-(S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrole-2-carboxamide / (S)-2-amino-2-cyclobutylacetic acid Schiff base complex

[0720] According to a synthetic method similar to Example 91, DL-3-methoxyphenylalanine was replaced with DL-2-amino-2-cyclobutylacetic acid, and a red solid was obtained by column chromatography (dichloromethane:methanol=20:1) with a yield of 85%.

[0721] mp:307.5-308.9℃.[α] 20 D =3252(c=1, CHCl 3 ).

[0722] 1 H NMR (400 MHz, CDCl 3)δ9.12 (s, 1H), 8.23 ​​(d, J = 9.3Hz, 1H), 7.70 (d, J = 8.2Hz, 1H), 7.60-7.38 (m, 3H), 7.29 (t, J = 6.9Hz, 2H), 7.09 (d d, J=9.3, 2.5Hz, 1H), 6.87 (d, J=7.4Hz, 1H), 6.58 (d, J=2.5Hz, 1H), 4.21-3.95 (m, 1H), 3.82-3.69 (m, 2H), 3.51 (d, J=13.0Hz, 1H), 3.40 (t, J=8.7Hz, 1H), 3.17-2.88 (m, 1H), 2.67 (dq, J=17.3, 8.7Hz, 1H), 2.58-2.33 (m, 3H), 2.29-2.12 (m, 2H), 2.09-1.96 (m, 1H), 1.81 (dd, J=18.1, 8.2Hz, 1H), 1.70 (dd, J=18.3, 9.0Hz, 2H), 1.44 (s, 3H).

[0723] 13 C NMR (125 MHz, CDCl 3 )δ180.3, 177.2, 169.6, 140.9, 135.8, 133.9, 133.3, 133.1, 133.0, 132.5, 132.3, 131.1, 130.3, 129.8, 129.4 , 129.1, 128.1, 128.0, 127.8, 125.8, 124.2, 74.5, 74.0, 57.2, 55.0, 41.9, 40.7, 26.0, 25.6, 20.7, 18.1, 17.5.

[0724] MS (ESI, m / z): 668.0 [MH] - .

[0725] Embodiment 101

[0726] Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrole-2-carboxamide / (R)-2-amino-4,4,4-trifluorobutyric acid Schiff base complex

[0727] According to a synthetic method similar to Example 91, DL-3-methoxyphenylalanine was replaced with DL-2-amino-4,4,4-trifluorobutyric acid and a red solid was obtained by column chromatography (dichloromethane:methanol=20:1) with a yield of 80%.

[0728] mp:274.0-276.0℃.[α] 20 D=-3150(c=1, CHCl 3 ).

[0729] 1 H NMR (400 MHz, CDCl 3 )δ9.16 (d, J=1.8Hz, 1H), 8.35 (d, J=9.3Hz, 1H), 7.68-7.47 (m, 4H), 7.36 (d, J=8.1Hz, 1H), 7.30 ( d, J=6.8Hz, 1H), 7.16 (dd, J=9.3, 2.5Hz, 1H), 6.90 (d, J=7.4Hz, 1H), 6.60 (d, J=2.5Hz, 1H), 4.16 (ddd, J=10.3, 9.3, 4.7Hz, 2H), 3.74-3.49 (m, 2H), 3.38 (t, J=8.7Hz, 1H), 3.09-2.80 (m, 1H), 2.6 3-2.46 (m, 1H), 2.42 (dd, J=13.7, 9.8Hz, 1H), 2.23-2.09 (m, 2H), 2.06-1.90 (m, 1H), 1.44 (s, 3H).

[0730] 13 C NMR (125 MHz, CDCl 3 )δ180.5, 177.2, 172.4, 141.9, 135.8, 134.0, 133.2, 133.2, 133.2, 133.1, 132.5, 131.3, 130.8, 129.9, 129.8, 129.7, 127.6, 127.6, 126.8, 125.8, 124.6, 74.9, 64.5, 57.8, 54.8, 41.2, 35.7, 35.5, 20.3, 17.4.

[0731] MS (ESI, m / z): 696.0 [MH] - .

[0732] Embodiment 102

[0733] Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrole-2-carboxamide / (R)-2-aminovaleric acid Schiff base complex

[0734] According to the synthesis method similar to Example 91, DL-3-methoxyphenylalanine was replaced by DL-2-aminopentanoic acid, and a red solid was obtained by column chromatography (dichloromethane:methanol=20:1) with a yield of 90%. mp:277.8-228.9℃.[α] 20 D=-2430(c=1, CHCl 3 ).

[0735] 1 H NMR (400 MHz, CDCl 3 )δ9.11 (d, J=2.0Hz, 1H), 8.21 (d, J=9.3Hz, 1H), 7.73 (dd, J=8.2, 2.0Hz, 1H), 7.61-7.49 (m, 2H), 7.46 (t, J=7.4Hz, 1H), 7.31 (dd, J=15.9, 7.6Hz, 2H), 7.12 (dd, J=9.3, 2.6Hz, 1H), 6.86 (d, J=7.5Hz, 1H), 6.60 (d, J=2.6Hz, 1H), 4.11-3.98 (m, 1H), 3.87 (dd, J=7.6 , 3.6Hz, 1H), 3.65 (dd, J=82.3, 13.0Hz, 2H), 3.38 (t, J=8.8Hz, 1H), 3.25-3.02 (m, 1H), 2.48-2.37 (m, 1H), 2.27-2.14 (m, 2H), 2.13 -1.97 (m, 1H), 1.84 (dt, J=13.1, 8.4Hz, 1H), 1.69 (dd, J=13.1, 6.3Hz, 1H), 1.59-1.49 (m, 1H), 1.45 (s, 3H), 0.79 (t, J=7.2Hz, 3H). 13 C NMR (125 MHz, CDCl 3 )δ180.4, 179.0, 169.8, 140.9, 135.8, 133.9, 133.3, 133.1, 133.1, 132.4, 131.2, 130.3, 129.9, 129.5, 129.3, 128. 1, 127.5, 127.5, 125.9, 124.5, 74.5, 70.5, 57.2, 55.0, 41.6, 37.4, 21.0, 18.4, 17.9, 13.9.MS (ESI, m / z): 656.1[MH] - .

[0736] Embodiment 103

[0737] Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrole-2-carboxamide / (R)-2-amino-3-methylbutyric acid Schiff base complex

[0738] According to a synthetic method similar to Example 91, DL-3-methoxyphenylalanine was replaced with DL-2-amino-3-methylbutyric acid, and a red solid was obtained by column chromatography (dichloromethane:methanol=20:1) with a yield of 93%.

[0739] mp:267.5-269.2℃.[α] 20 D =3016(c=1, CHCl 3 ).

[0740] 1 H NMR (400 MHz, CDCl 3 )δ9.17 (d, J=2.1Hz, 1H), 8.28 (d, J=9.3Hz, 1H), 7.65 (dd, J=8.2, 2.1Hz, 1H), 7.54 (dt, J=16.1, 7.9Hz, 2H), 7.45 (t, J=6.9Hz, 1H), 7.31 (dd, J=7.7, 4.2Hz, 2H), 7.10 (dd, J=9.3, 2.6Hz, 1H), 6.85 (d, J=7.5Hz, 1H), 6.61 (d, J=2.6Hz, 1H) , 4.14-3.97 (m, 1H), 3.83-3.72 (m, 2H), 3.53 (d, J = 13.1Hz, 1H), 3.40 (t, J = 9.0Hz, 1H), 3.00 (td, J = 12.5, 4.0Hz, 1H), 2.53-2.34 (m, 1H), 2.27-2.08 (m, 2H), 1.84 (d, J=6.6Hz, 3H), 1.80-1.67 (m, 1H), 1.45 (s, 3H), 0.73 (d, J=6.8Hz, 3H).

[0741] 13 C NMR (125 MHz, CDCl 3 )δ180.4, 177.4, 170.3, 141.0, 135.9, 134.0, 133.2, 133.2, 133.0, 132.5, 132.4, 131.2, 130.2, 129.8, 129 .5, 129.1, 127.9, 127.9, 127.5, 125.8, 124.2, 75.6, 74.4, 57.3, 54.9, 41.7, 34.4, 20.5, 19.9, 17.8, 17.7.

[0742] MS (ESI, m / z): 656.0 [MH] - .

[0743] Embodiment 104

[0744] Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrole-2-carboxamide / (R)-2-amino-4-methylthiobutyric acid Schiff base complex

[0745] According to a synthetic method similar to Example 91, DL-3-methoxyphenylalanine was replaced with DL-2-amino-4-methylthiobutyric acid, and a red solid was obtained by column chromatography (dichloromethane: methanol = 20: 1) with a yield of 90%.

[0746] mp:123.4-125.8℃.[α] 20 D =-2202(c=1, CHCl 3 ).

[0747] 1 H NMR (400 MHz, CDCl 3 )δ9.11 (d, J=1.5Hz, 1H), 8.21 (d, J=9.3Hz, 1H), 7.72 (d, J=6.7Hz, 1H), 7.60-7.51 (m, 2H), 7.47 (t, J=7.4Hz, 1H), 7.32 (d d, J=14.6, 7.6Hz, 2H), 7.13 (dd, J=9.3, 2.5Hz, 1H), 6.88 (d, J=7.5Hz, 1H), 6.60 (d, J=2.5Hz, 1H), 4.09-3.96 (m, 1H), 3.93 (dd, J=8.3, 3.6Hz, 1H), 3.66 (dd, J=74.8, 13.0Hz, 2H), 3.37 (t, J=8.9Hz, 1H), 3.17 (dd, J=16.5, 10.3Hz, 1H), 3.09-3.01 ( m, 1H), 2.67-2.53 (m, 1H), 2.49-2.37 (m, 1H), 2.19 (dd, J=15.7, 6.7Hz, 3H), 1.97 (s, 3H), 1.91-1.77 (m, 1H), 1.45 (s, 3H).

[0748] 13 C NMR (125 MHz, CDCl 3 )δ180.4, 178.3, 170.3, 141.1, 135.7, 133.9, 133.3, 133.2, 132.9, 132.6, 132.4, 131.2, 130.4, 129.9, 129 .6, 129.4, 127.9, 127.5, 127.4, 125.9, 124.6, 74.5, 69.8, 57.3, 55.0, 41.6, 35.1, 29.8, 21.3, 18.0, 15.8.

[0749] MS (ESI, m / z): 688.0 [MH] - .

[0750] Embodiment 105

[0751] Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrole-2-carboxamide / (R)-2-amino-3-(1H-indolyl)propionic acid Schiff base complex

[0752] According to a synthetic method similar to Example 91, DL-3-methoxyphenylalanine was replaced with DL-2-amino-3-(1H-indolyl)propionic acid and a red solid was obtained by column chromatography (dichloromethane:methanol=20:1) with a yield of 93%.

[0753] 1 H NMR (400 MHz, CDCl 3 )δ8.90 (d, J=1.9Hz, 1H), 8.45 (s, 1H), 8.17 (d, J=9.3Hz, 1H), 7.60-7.55 (m, 2H), 7.52 (t, J=7.5Hz, 1H), 7.44 (d, J=8.2Hz, 1H) , 7.40-7.26 (m, 4H), 7.19 (t, J=7.7Hz, 1H), 7.11 (dd, J=9.3, 2.6Hz, 1H), 7.03 (d, J=2.0Hz, 1H), 6.96 (t, J=7.5Hz, 1H), 6.85 (d, J=7.7Hz, 1H), 6.63 (d, J=2.6Hz, 1H), 4.31 (t, J=4.7Hz, 1H), 4.08 (d, J=12.4Hz, 1H), 3.32 (dd, J=14.7, 4.5Hz, 1H), 3.01 (ddd, J =19.7, 11.9, 6.0Hz, 3H), 2.88-2.82 (m, 1H), 2.13 (tt, J = 13.5, 8.1Hz, 1H), 1.65 (s, 3H), 1.88-1.70 (m, 2H), 1.51-1.42 (m, 1H).

[0754] MS (ESI, m / z): 741.1 [MH] - .

[0755] Embodiment 106

[0756] Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrole-2-carboxamide / (R)-2-amino-5-methyl-4-hexenoic acid Schiff base complex

[0757] According to a synthetic method similar to Example 91, DL-3-methoxyphenylalanine was replaced with DL-2-amino-5-methyl-4-hexenoic acid, and a red solid was obtained by column chromatography (dichloromethane: methanol = 20: 1) with a yield of 90%.

[0758] 1 H NMR (400 MHz, CDCl 3 )δ8.90 (d, J=2.0Hz, 1H), 8.11 (d, J=9.3Hz, 1H), 7.74 (dd, J=8.2, 2.0Hz, 1H), 7.58-7.50 (m, 2H), 7.46 (ddd, J=7.3, 4.5, 1.8Hz, 1H), 7.34 (d, J=8.1Hz, 1H), 7.30-7.27 (m, 1H), 7.10 (dd, J=9.3, 2.6Hz, 1H), 6.89 (d, J=7.5Hz, 1H), 6.57 (d, J=2.5Hz, 1H), 5.66 (t, J=7.6Hz, 1H), 4.30 (d, J=12.6Hz, 1H), 4.01 (dd, J=6.4, 4.6Hz, 1H), 3.67-3.45 (m, 2H), 3.35 (dd, J=10.9, 6.2Hz, 1H), 3.20 ( d, J=12.6Hz, 1H), 2.78-2.52 (m, 3H), 2.43-2.32 (m, 1H), 2.05 (td, J=10.7, 6.3Hz, 1H), 1.86 (s, 3H), 1.70 (s, 3H), 1.54 (s, 3H).

[0759] MS (ESI, m / z): 680.09 [MH] - .

[0760] Embodiment 107

[0761] Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrole-2-carboxamide / (R)-2-aminoglutaric acid Schiff base complex

[0762] According to a synthetic method similar to Example 91, DL-3-methoxyphenylalanine was replaced with DL-2-aminoglutaric acid and a red solid was obtained by column chromatography (dichloromethane:methanol=20:1) with a yield of 89%.

[0763] 1 H NMR (400 MHz, CDCl 3)δ8.90 (s, 1H), 8.02 (d, J = 9.2Hz, 1H), 7.74 (d, J = 7.8Hz, 1H), 7.57-7.50 (m, 2H), 7.47 (t, J = 6.9Hz, 1H), 7.32 (d, J = 8.1Hz, 1H), 7.26-7.23 (m, 1H), 7.11-7.01 (m, 2H), 6.57 (d, J=2.3Hz, 1H), 4.27 (d, J=12.4Hz, 1H), 3.93 (dd, J=8.0, 3.4Hz, 1H), 3.61 (dd, J= 19.2, 9.7Hz, 1H), 3.55-3.48 (m, 1H), 3.40 (dd, J=11.1, 5.4Hz, 1H), 3.20 (d, J=12.4Hz, 1H), 3.06 (dt, J=17.1, 6.9Hz, 1H), 2.71 -2.62 (m, 1H), 2.56-2.44 (m, 2H), 2.35 (dq, J=15.7, 7.8Hz, 1H), 2.22-2.13 (m, 1H), 2.05 (td, J=10.8, 6.0Hz, 1H), 1.90 (s, 3H).

[0764] MS (ESI, m / z): 684.09 [MH] - .

[0765] Embodiment 108

[0766] Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrole-2-carboxamide / (R)-2,5-diamino-5-pentanoic acid Schiff base complex

[0767] According to a synthetic method similar to Example 91, DL-3-methoxyphenylalanine was replaced with DL-2,5-diamino-5-pentanoic acid and a red solid was obtained by column chromatography (dichloromethane:methanol=20:1) with a yield of 88%.

[0768] 1 H NMR (400 MHz, CDCl 3)δ8.88 (d, J=0.9Hz, 1H), 8.05 (d, J=9.2Hz, 1H), 7.75 (dd, J=8.1, 1.2Hz, 1H), 7.58-7.49 (m, 3H), 7.37 (d, J=8.2Hz, 1H), 7.2 2 (s, 1H), 7.12 (dd, J=9.2, 2.3Hz, 1H), 6.94 (d, J=7.0Hz, 1H), 6.59 (d, J=2.4Hz, 1H), 6.00 (s, 1H), 5.21 (s, 1H), 4.30 (d, J=1 2.6Hz, 1H), 3.82 (dd, J=10.9, 4.3Hz, 1H), 3.74-3.59 (m, 1H), 3.52 (dd, J=10.5, 5.6Hz, 1H), 3.38 (dd, J=11.4, 5.4Hz, 1H), 3 .22 (d, J=12.4Hz, 1H), 2.76-2.54 (m, 3H), 2.50-2.42 (m, 1H), 2.31-2.20 (m, 2H), 2.08 (td, J=10.9, 5.6Hz, 1H), 1.98 (s, 3H).

[0769] MS (ESI, m / z): 683.06 [MH] - .

[0770] Embodiment 109

[0771] Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrole-2-carboxamide / (R)-homocystine Schiff base complex

[0772] According to a synthetic method similar to Example 91, DL-3-methoxyphenylalanine was replaced with DL-homocysteine ​​and a red solid was obtained by column chromatography (dichloromethane:methanol=20:1) with a yield of 93%.

[0773] 1 H NMR (400 MHz, CDCl 3)δ8.88 (d, J=1.2Hz, 1H), 8.05 (d, J=9.3Hz, 1H), 7.75 (dd, J=8.0, 1.0Hz, 1H), 7.50 (ddt, J=29.3, 14.8, 7.3Hz, 3H), 7.36 (d, J= 8.1Hz, 1H), 7.24 (s, 1H), 7.11 (dd, J=9.3, 2.4Hz, 1H), 6.89 (d, J=7.4Hz, 1H), 6.57 (d, J=2.4Hz, 1H), 4.30 (d, J=12.5Hz, 1H), 3. 87 (dd, J=8.2, 3.4Hz, 1H), 3.68-3.56 (m, 1H), 3.55-3.49 (m, 1H), 3.37 (dd, J=10.9, 5.8Hz, 1H), 3.21 (d, J=12.6Hz, 1H), 2.95 ( dd, J=17.5, 9.3Hz, 1H), 2.75-2.64 (m, 1H), 2.63-2.45 (m, 3H), 2.29-2.19 (m, 1H), 2.10 (s, 3H), 1.96 (dd, J=24.2, 10.7Hz, 1H).

[0774] MS (ESI, m / z): 672.03 [MH] - .

[0775] Embodiment 110

[0776] Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-ethyl-2-methylpyrrole-2-carboxamide / (S)-3-amino-2-benzylpropionic acid Schiff base complex

[0777] According to the synthesis method similar to Example 65, brown solid (yield 68%).

[0778] mp 128-130℃.[α] 20 D = +2426.5 (c = 0.034, CHCl 3 ).

[0779] 1 H NMR (400 MHz, Methanol-d 4)δ8.91 (d, J=2.1Hz, 1H), 8.32 (dd, J=8.3, 2.1Hz, 1H), 7.74 (d, J=9.2Hz, 1H), 7.48 (d, J=8.2Hz, 1H), 7.3 9-7.25 (m, 2H), 7.23-7.12 (m, 4H), 7.06 (dd, J=9.2, 2.6Hz, 1H), 7.03-6.95 (m, 3H), 6.64 (dt, J=7.6, 1.6 Hz, 1H), 6.42 (d, J=2.6Hz, 1H), 3.98-3.83 (m, 2H), 3.77 (d, J=13.3Hz, 1H), 3.58-3.48 (m, 1H), 3.40 (d, J =13.3Hz, 1H), 3.27-3.18(m, 1H), 3.14-3.02(m, 2H), 2.68-2.62(m, 1H), 2.51-2.10(m, 4H), 1.43(s, 3H).

[0780] 13 C NMR (125 MHz, Methanol-d 4 )δ182.5, 180.4, 173.1, 141.3, 139.8, 138.2, 134.9, 134.6, 133.9, 133.5, 133.1, 132.7, 132.4, 132.2, 131.2, 131.0, 130.3, 130.2, 129.9, 129.6, 128.1, 127.7, 127.6, 126.8, 125.9, 74.9, 56.7, 56.3, 55.3, 49.3, 42.8, 37.2, 22.2, 18.6.

[0781] LRMS(ESI+APCI)m / z: 718.0, HRMS(ESI)m / z: found: 718.0940, calcd 718.0935for C 35 H 32 Cl 3 N 3 NiO 3 + [M+H] + .

[0782] Embodiment 111

[0783] Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-ethyl-2-methylpyrrole-2-carboxamide / (S)-3-amino-2-(4-fluorobenzyl)propionic acid Schiff base complex

[0784] According to the synthesis method similar to Example 65, brown solid (yield 58%).

[0785] mp 123-124℃.[α] 20 D = -3310.5 (c = 0.038, CHCl 3 ).

[0786] 1 H NMR (400 MHz, Methanol-d 4 )δ8.15 (d, J=9.1Hz, 1H), 7.41-7.33 (m, 2H), 7.26 (dd, J=9.1, 2.6Hz, 1H), 7.21-7.13(m, 1H), 7.03-6.94(m, 3H), 6.90-6.82(m, 2H), 6.78(dt, J=6.6, 1.9Hz, 1H), 6.53 (d, J=2.6Hz, 1H), 3.96 (t, J=12.3Hz, 1H), 3.86-3.73 (m, 2 H), 3.22-3.06(m, 3H), 2.62-2.29(m, 6H), 1.94-1.86(m, 4H), 1.24(s, 3H). 13 C NMR (125 MHz, Methanol-d 4 )δ183.7, 180.3, 173.0, 163.9, 162.0, 141.9, 136.1, 136.1, 135.1, 133.4 ,133.0,131.7,131.6,131.6,130.9,130.2,130.2,128.1,127.8,126.9,1 26.6, 116.3, 116.1, 75.0, 56.9, 54.5, 49.7, 49.1, 41.9, 36.3, 23.4, 18.1, 15.5.LRMS(ESI+APCI)m / z: 606.1, HRMS(ESI)m / z: found: 606.1476, calcd 606.1464forC 31 H 31 CIF 3 NiO 3 + [M+H] + .

[0787] Embodiment 112

[0788] Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-ethyl-2-methylpyrrole-2-carboxamide / (S)-3-amino-2-(4-methoxybenzyl)propionic acid Schiff base complex

[0789] According to the synthesis method similar to Example 65, brown solid (yield 62%).

[0790] mp 127-130℃.[α] 20 D = -3618.8 (c = 0.032, CHCl 3 ). 1 H NMR (400 MHz, Methanol-d 4 )δ8.14 (d, J=9.1Hz, 1H), 7.41-7.32 (m, 2H), 7.26 (d, J=9.1Hz, 1H), 7.15 (t, J=8.5Hz, 1 H), 6.99 (d, J=7.6Hz, 1H), 6.91-6.84 (m, 2H), 6.77 (d, J=7.6Hz, 1H), 6.72-6.66 (m, 2H) , 6.53 (d, J=2.6Hz, 1H), 3.94 (t, J=12.4Hz, 1H), 3.79 (s, 3H), 3.78-3.71 (m, 1H), 3.20- 3.02 (m, 3H), 2.64-2.49 (m, 2H), 2.45-2.26 (m, 4H), 1.91 (t, J=7.4Hz, 3H), 1.24 (s, 3H).

[0791] 13 C NMR (125 MHz, Methanol-d 4 )δ183.69, 180.68, 173.00, 159.80, 141.96, 135.13, 133.45, 133.01, 131.93, 131.70, 130.97, 130.94, 130.24, 130.17, 128.13, 127.91, 126.92, 126.55, 115.03, 75.01, 57.02, 55.68, 54.58, 49.69, 49.30, 41.97, 36.33, 23.41, 18.08, 15.50.

[0792] LRMS(ESI+APCI)m / z: 618.1, HRMS(ESI)m / z: found: 618.1667, calcd 618.1664forC 32 H 34 C1N 3 NiO 3 + [M+H] + .

[0793] Embodiment 113

[0794] Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-ethyl-2-methylpyrrole-2-carboxamide / (S)-3-amino-2-methylpropionic acid Schiff base complex

[0795] According to the synthesis method similar to Example 65, brown solid (yield 76%).

[0796] mp 257-259℃.[α] 20 D = -4854.5 (c = 0.044, CHCl 3 ).

[0797] 1 H NMR (400 MHz, Methanol-d 4 )δ8.17 (d, J=9.1Hz, 1H), 7.66-7.49 (m, 3H), 7.45-7.35 (m, 1H), 7.29 (dd, J=9.1, 2.5Hz, 1H), 6.99 (d, J=7.6Hz, 1H), 6.65 (d, J=2.6Hz, 1 H), 4.26-3.53(m, 3H), 3.29-3.18(m, 1H), 3.12-2.90(m, 1H), 2.64-2.18(m, 5H), 2.06-1.76(m, 4H), 1.26(s, 3H), 0.98(d, J=7.3Hz, 3H).

[0798] 13 C NMR (125 MHz, Methanol-d 4 )δ183.7, 182.0, 172.7, 142.0, 135.8, 133.6, 133.1, 131.5, 130.6, 130.1, 128.7, 128.3, 126.9, 126.6, 75.1, 59.8, 54.4, 49.8, 42.1, 41.9, 23.4, 18.1, 15.5, 15.2.

[0799] LRMS(ESI+APCI)m / z: 512.0, HRMS(ESI)m / z: found: 512.1256, calcd 512.1245forC 25 H 28 C1N 3 NiO 3 + [M+H] + .

[0800] Embodiment 114

[0801] Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-ethyl-2-methylpyrrole-2-carboxamide / (S)-2-(aminomethyl)-4-methylpentanoic acid Schiff base complex

[0802] According to the synthesis method similar to Example 65, brown solid (yield 62%).

[0803] mp 120-122℃.[α] 20 D = -4383.3 (c = 0.048, CHCl 3 ).

[0804] 1 H NMR (400 MHz, Methanol-d 4 )δ8.19 (d, J=9.1Hz, 1H), 7.60-7.52 (m, 3H), 7.44-7.42 (m, 1H), 7.29 (dd, J=9.1, 2.6 Hz, 1H), 6.99 (dd, J=7.7, 1.7Hz, 1H), 6.67 (d, J=2.6Hz, 1H), 3.95-3.73 (m, 3H), 3.25- 3.14(m, 2H), 2.62-2.53(m, 1H), 2.41-2.32(m, 3H), 2.24-2.17(m, 1H), 1.94-1.86(m, 4H), 1.74-1.67(m, 1H), 1.26(s, 3H), 1.25-1.05(m, 2H), 0.78(dd, J=6.5, 3.8Hz, 6H).

[0805] 13 C NMR (125 MHz, Methanol-d 4 )δ183.6, 181.9, 172.9, 142.0, 135.9, 133.5, 133.1, 131.4, 131.3, 130.7, 130.2, 128.5, 128. 4, 126.9, 126.6, 75.1, 58.0, 54.3, 49.8, 45.2, 41.9, 40.8, 26.8, 23.6, 23.4, 22.2, 18.1, 15.5.

[0806] LRMS(ESI+APCI)m / z: 554.2, HRMS(ESI)m / z: found: 554.1727, calcd 554.1719forC 28 H 34 C1N 3 NiO 3 + [M+H]+ .

[0807] Embodiment 115

[0808] Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-ethyl-2-methylpyrrole-2-carboxamide / (S)-3-amino-2-cyclohexylpropionic acid Schiff base complex

[0809] According to the synthesis method similar to Example 65, brown solid (yield 87%).

[0810] mp 145-147℃.[α] 20 D =-3161.8 (c = 0.034, CHCl 3 ).

[0811] 1 H NMR (400 MHz, Methanol-d 4 )δ8.18(d, J=9.1Hz, 1H), 7.66-7.51(m, 3H), 7.42-7.37(m, 1H), 7.28(dd, J=9.1, 2.6Hz, 1H), 6.98 (d, J=7.6Hz, 1H), 6.65 (d, J=2.6Hz, 1H), 4.02-3. 69(m, 2H), 3.26-3.03(m, 2H), 2.65-2.50(m, 1H), 2.41-2.32(m, 2H), 2.27 -2.19(m, 1H), 2.14-2.05(m, 1H), 1.96-1.54(m, 8H), 1.46-0.54(m, 11H).

[0812] 13 C NMR (125 MHz, Methanol-d 4 )δ183.6, 180.9, 173.0, 142.0, 135.7, 133.5, 133.0, 131.5, 131.4, 130.6, 130.2, 128.6, 128.4, 126 .9, 126.6, 75.1, 54.8, 54.3, 52.9, 49.9, 41.9, 40.2, 32.5, 29.3, 27.8, 27.6, 27.2, 23.3, 18.0, 15.5.

[0813] LRMS(ESI+APCI)m / z: 580.2, HRMS(ESI)m / z: found: 580.1881, calcd 580.1871forC 30 H 36 C1N 3 NiO3 + [M+H] + .

[0814] Embodiment 116

[0815] Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-ethyl-2-methylpyrrole-2-carboxamide / (S)-3-amino-2-phenylpropionic acid Schiff base complex

[0816] According to the synthesis method similar to Example 65, brown solid (yield 55%, dr 55 / 45).

[0817] mp 150-151℃.[α] 20 D = -3648.0 (c = 0.05, CHCl 3 ).

[0818] 1 H NMR (400 MHz, Methanol-d 4 )δ8.20 (d, J=9.1Hz, 1H), 7.66-7.52 (m, 3H), 7.46 (t, J=7.6Hz, 1H), 7.31 (dd, J=9.1, 2.6Hz, 1 H), 7.28-7.16 (m, 3H), 7.10-7.03 (m, 2H), 6.91 (d, J = 7.7Hz, 1H), 6.69 (d, J = 2.6Hz, 1H), 4.34 ( t, J=13.0Hz, 1H), 3.89-3.86 (m, 2H), 3.53 (dd, J=11.8, 3.5Hz, 1H), 3.29-3.97 (m, 1H), 3.15(d d, J=13.0, 3.6Hz, 1H), 2.65-2.56(m, 1H), 2.46-2.29(m, 3H), 1.99-1.90(m, 4H), 1.27(s, 3H).

[0819] 13 C NMR (125 MHz, Methanol-d 4 )δ183.7, 180.1, 173.3, 142.2, 139.1, 135.8, 133.7, 133.2, 131.6, 131.4, 130.6, 130.1, 129.8, 129.1, 128.5, 128.4, 128.4, 126.9, 126.7, 75.2, 60.1, 54.5, 54.3, 49.9, 41.9, 23.5, 18.1, 15.5.

[0820] LRMS(ESI+APCI)m / z: 574.1, HRMS(ESI)m / z: found: 574.1410, calcd 574.1402forC 30 H 30 C1N 3 NiO 3 + [M+H] + .

[0821] Embodiment 117

[0822] Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-ethyl-2-methylpyrrole-2-carboxamide / (S)-3-amino-2-(4-chlorophenyl)propionic acid Schiff base complex

[0823] According to the synthesis method similar to Example 65, brown solid (yield 59%, dr 59 / 41).

[0824] mp=130-132℃[α] 20 D = -3312.5 (c = 0.048, CHCl 3 ).

[0825] 1 H NMR (400 MHz, Methanol-d 4 )δ8.20 (d, J=9.1Hz, 1H), 7.65-7.44 (m, 4H), 7.31 (dd, J=9.1, 2.6Hz, 1H), 7.28-7.23 (m, 2H), 7.08-7.01 (m, 2H), 6.93 (d, J=7.7Hz, 1H), 6.69 (d, J=2.6Hz, 1H), 4.35 (t, J=12.5Hz , 1H), 3.97-3.81 (m, 2H), 3.54 (dd, J=12.0, 3.4Hz, 1H), 3.29-3.27 (m, 1H), 3.12 (dd, J=1 2.9, 3.5Hz, 1H), 2.63-2.50(m, 1H), 2.46-2.31(m, 3H), 1.98-1.90(m, 4H), 1.27(s, 3H).

[0826] 13 C NMR (125 MHz, Methanol-d 4)δ183.7, 179.6, 173.4, 142.2, 137.8, 135.7, 134.2, 133.7, 133.3, 131.6, 131.4, 130.8, 130. 7, 130.1, 129.8, 128.6, 128.4, 127.0, 126.7, 75.2, 59.8, 54.4, 49.5, 41.9, 23.5, 18.1, 15.5.

[0827] LRMS(ESI+APCI)m / z: 608.0, HRMS(ESI)m / z: found: 608.1026, calcd 608.1012forC 30 H 29 Cl 2 N 3 NiO 3 + [M+H] + .

[0828] Embodiment 118

[0829] Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-ethyl-2-methylpyrrole-2-carboxamide / (S)-3-amino-2-(4-methoxyphenyl)propionic acid Schiff base complex

[0830] According to the synthesis method similar to Example 65, brown solid (yield 65%, dr 50 / 50).

[0831] mp=146-148℃[α] 20 D = -3052.4 (c = 0.042, CHCl 3 ).

[0832] 1 H NMR (400 MHz, Methanol-d 4)δ8.19 (d, J=9.1Hz, 1H), 7.68-7.52 (m, 3H), 7.48 (t, J=7.5Hz, 1H), 7.31 (dd, J=9.1, 2.6Hz, 1H), 7. 01-6.95 (m, 2H), 6.93 (d, J=7.7Hz, 1H), 6.84-6.77 (m, 2H), 6.69 (d, J=2.6Hz, 1H), 4.29 (t, J=12.9Hz , 1H), 3.91-3.78 (m, 2H), 3.73 (s, 3H), 3.48 (dd, J=11.7, 3.6Hz, 1H), 3.29-3.23 (m, 1H), 3.12 (dd, J =13.0, 3.6Hz, 1H), 2.64-2.56(m, 1H), 2.44-2.34(m, 3H), 1.95(q, J=10.3, 8.7Hz, 4H), 1.27(s, 3H).

[0833] 13 C NMR (125 MHz, Methanol-d 4 )δ183.7, 180.6, 173.3, 160.4, 142.2, 135.8, 133.7, 133.2, 131.6, 131.4, 131.0, 130.6, 130.1, 128.5, 128.5, 126.9, 126.6, 115.2, 75.2, 60.2, 55.7, 54.4, 53.5, 49.9, 41.9, 23.5, 18.1, 15.5.

[0834] LRMS(ESI+APCI)m / z: 604.1, HRMS(ESI)m / z: found: 604.1503, calcd 604.1508forC 31 H 32 C1N 3 NiO 3 + [M+H] +

[0835] Embodiment 119

[0836] Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-ethyl-2-methylpyrrole-2-carboxamide / (S)-3-amino-2-(naphthalen-1-yl)propionic acid Schiff base complex

[0837] According to the synthesis method similar to Example 65, brown solid (yield 63%, dr 50 / 50).

[0838] mp=146-147℃.[α] 20D = -3440.0 (c = 0.046, CHCl 3 ).

[0839] 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.21 (d, J = 9.1 Hz, 1H), 7.80 - 7.72 (m, 3H), 7.65 (d, J = 4.6 Hz, 2H), 7.58 - 7.37 (m, 5H), 7.32 (dd, J = 9.1, 2.6 Hz, 1H), 7.18 (dd, J = 8.5, 1.8 Hz, 1H), 6.89 (dd, J = 7.8, 1.4 Hz, 1H), 6.70 (d, J = 2.6 Hz, 1H), 4.45 (t, J = 12.9, 11.8 Hz, 1H), 3.92 - 3.79 (m, 2H), 3.71 (dd, J = 11.7, 3.5 Hz, 1H), 3.38 - 3.32 (m, 1H), 3.22 (dd, J = 13.0, 3.5 Hz, 1H), 2.69 - 2.53 (m, 1H), 2.48 - 2.27 (m, 3H), 2.02 - 1.87 (m, 4H), 1.26 (s, 3H).

[0840] 13 C NMR (125 MHz, Methanol-d 4 ) δ 183.7, 180.1, 173.4, 142.2, 136.4, 135.8, 134.9, 134.0, 133.7, 133.3, 131.6, 131.4, 130.6, 130.1, 129.5, 128.7, 128.6, 128.5, 128.5, 128.2, 127.3, 127.0, 127.0, 126.9, 126.7, 75.2, 60.0, 54.4, 54.4, 49.9, 41.9, 23.5, 18.1, 15.5.

[0841] LRMS (ESI+APCI) m / z: 624.1, HRMS (ESI) m / z: found: 624.1566, calcd 624.1558 for C 34 H 32 ClN 3 NiO 3 + [M + H] + .

[0842] Example 120

[0843] Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-ethyl-2-methylpyrrole-2-carboxamide / (S)-3-amino-2-(4-methylbenzyl) propionic acid Schiff base complex

[0844] According to the synthesis method similar to Example 65, brown solid (yield 70%, dr 84 / 16).

[0845] mp 124-126℃.[α] 20 D = -3277.3 (c = 0.034, CHCl 3 ).

[0846] 1 H NMR (400 MHz, Methanol-d 4 )δ8.13(d, J=9.1Hz, 1H), 7.40-7.32(m, 2H), 7.28-7.21(m, 1H), 7.15-7.09(m, 1H), 6.99- 6.93 (m, 3H), 6.85 (d, J = 8.0Hz, 2H), 6.77 (d, J = 7.2Hz, 1H), 6.53 (d, J = 2.6Hz, 1H), 3.93 (t , J=12.4Hz, 1H), 3.84-3.68(m, 2H), 3.20-3.06(m, 3H), 2.62-2.53(m, 2H), 2.44-2.39(m, 1H), 2.39-2.34(m, 1H), 2.32(s, 3H), 2.31-2.22(m, 2H), 1.92-1.87(m, 4H), 1.24(s, 3H).

[0847] 13 C NMR (125 MHz, Methanol-d 4 )δ183.7, 180.6, 173.0, 142.0, 137.1, 136.9, 135.1, 133.5, 133.0, 131.7, 130.8, 130.3, 130.1, 129.9, 128.1, 127.9, 126.9, 126.6, 75.0, 57.0, 54.7, 49.69, 42.0, 36.8, 23.4, 21.1, 18.1, 15.5.

[0848] LRMS(ESI+APCI)m / z: 601.8, HRMS(ESI)m / z: found: 602.1705, calcd 602.1715forC 32 H 35 C1N 3 NiO 3+ [M+H] + .

[0849] Embodiment 121

[0850] Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-ethyl-2-methylpyrrole-2-carboxamide / (S)-3-amino-2-(4-trifluoromethylbenzyl)propionic acid Schiff base complex

[0851] According to the synthesis method similar to Example 65, brown solid (yield 72%, dr 89 / 11).

[0852] mp 137-139℃.[α] 20 D = -3950.5 (c = 0.046, CHCl 3 ).

[0853] 1 H NMR (400 MHz, Methanol-d 4 )δ8.14 (d, J=9.1Hz, 1H), 7.45 (d, J=8.0Hz, 2H), 7.35-7.25 (m, 3H), 7.17 (d, J=8.1Hz, 2 H), 7.05-6.95 (m, 2H), 6.78 (d, J = 7.6Hz, 1H), 6.52 (d, J = 2.5Hz, 1H), 4.00 (t, J = 12.3Hz, 1H), 3.88-3.78 (m, 2H), 3.30-3.26 (m, 1H), 3.21 (dd, J=11.1, 7.4Hz, 1H), 3.07 (dd, J=1 2.7, 3.4Hz, 1H), 2.61-2.44(m, 3H), 2.39-2.30(m, 3H), 1.94-1.87(m, 4H), 1.25(s, 3H).

[0854] 13 C NMR (125 MHz, Methanol-d 4 )δ183.7, 179.9, 173.1, 145.1, 142.0, 135.1, 133.4, 133.1, 131.4, 131.0, 130.6, 130.1, 130.0, 129.8, 129.5, 128.0, 127.7, 126.9, 126.6, 126.5, 126.5, 75.0, 56.8, 54.5, 49.7, 42.0, 36.9, 23.4, 18.1, 15.5.

[0855] LRMS(ESI+APCI)m / z: 655.8, HRMS(ESI)m / z: found: 656.1431, calcd 656.1432forC 32 H 32 CIF 3 N 3 NiO 3 + [M+H] + .

[0856] Embodiment 122

[0857] Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-ethyl-2-methylpyrrole-2-carboxamide / (S)-3-amino-2-tert-butylpropionic acid Schiff base complex

[0858] mp=136-137℃.[α] 20 D = -3670.0 (c = 0.048, CHCl 3 ).

[0859] 1 H NMR (400 MHz, Methanol-d 4 )δ8.21 (d, J=9.1Hz, 1H), 7.63-7.58 (m, 2H), 7.56-7.52 (m, 1H), 7.42-7.37 (m, 1H), 7.29 (dd, J=9.1, 2.6Hz, 1H), 6.99 (d, J=7.6Hz, 1H), 6.67 (d, J=2.6Hz, 1H), 4.27 (t, J=12.5Hz, 1H), 4.07-3.97 (m, 1H), 3.93-3.84 (m, 1H), 3.33 (d, J=4.7Hz, 1H), 3.13 (dd, J=10.9, 7.8Hz, 1H), 2.66 (dq, J=15.0, 7.5Hz, 1H), 2.44-2.34 (m, 2H), 2.28 (dq, J=14. 1, 7.1Hz, 1H), 2.07 (dd, J=12.5, 4.7Hz, 1H), 2.03-1.95 (m, 1H), 1.89 (t, J=7.3Hz, 3H), 1.24 (s, 3H), 0.84 (s, 9H).

[0860] 13 C NMR (125 MHz, Methanol-d 4)δ183.8, 181.5, 173.1, 142.3, 135.6, 133.5, 133.2, 131.7, 131.7, 130.6, 130.1, 128.8 , 128.6, 126.9, 126.5, 74.9, 57.8, 56.4, 55.0, 49.5, 42.2, 33.9, 28.5, 23.7, 18.1, 15.5.

[0861] LRMS(ESI+APCI)m / z: 655.8, HRMS(ESI)m / z: found: 554.1704, calcd 554.1715forC 28 H 35 C1N 3 NiO 3 + [M+H] + .

[0862] Embodiment 123

[0863] Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-ethyl-2-methylpyrrole-2-carboxamide / (S)-3-amino-2-isopropylpropionic acid Schiff base complex

[0864] mp 130-132℃.[α] 20 D = -3241.0 (c = 0.034, CHCl 3 ).

[0865] 1 H NMR (400 MHz, Methanol-d 4 )δ8.18 (d, J=9.1Hz, 1H), 7.61-7.53 (m, 3H), 7.46-7.39 (m, 1H), 7.29 (dd, J=9.1, 2. 6Hz, 1H), 7.00 (d, J=7.5Hz, 1H), 6.66 (d, J=2.6Hz, 1H), 4.03-3.87 (m, 2H), 3.85-3. 74(m, 1H), 3.24-3.16(m, 2H), 2.60-2.46(m, 2H), 2.41-2.32(m, 3H), 2.14-2.08(m, 1H), 1.95-1.87 (m, 4H), 1.26 (s, 3H), 0.72 (d, J=6.9Hz, 3H), 0.65 (d, J=7.1Hz, 3H).

[0866] 13 C NMR (125 MHz, Methanol-d 4)δ183.6, 181.0, 173.1, 142.1, 135.7, 133.4, 133.1, 131.5, 130.6, 130.2, 128.6, 128.5 , 126.9, 126.6, 75.1, 54.3, 54.0, 53.1, 49.8, 42.0, 29.7, 23.4, 20.9, 18.1, 17.9, 15.5.

[0867] LRMS(ESI+APCI)m / z: 539.9, HRMS(ESI)m / z: found: 540.1543, calcd 540.1558for C 27 H 33 C1N 3 NiO 3 + [M+H] + .

[0868] Embodiment 124

[0869] Basically the same as Example 66, the chelates prepared in Examples 72-89 were hydrolyzed to obtain: (S)-3-amino-3-(2-fluoro substituted)benzenepropanoic acid, (S)-3-amino-3-(4-chloro substituted)benzenepropanoic acid, (S)-3-amino-3-(3,4-dimethoxy substituted)benzenepropanoic acid, (S)-3-amino-3-(4-isopropyl substituted)benzenepropanoic acid, (S)-3-amino-3-(4-methoxy substituted)benzenepropanoic acid, (S)-3-amino-3-(3-methoxy substituted)benzenepropanoic acid, (S)-3-amino-3-(3-trifluoromethyl substituted)benzenepropanoic acid, (S)-3-amino-3-(3-pyridine substituted)propionic acid, (S)-3-amino-3-(2-thiophene substituted)propionic acid, (S)-3-amino-3-(1-naphthalene substituted)propionic acid, (S)-3-aminobutyric acid, (S)-3-aminopentanoic acid, (S)-3-aminoheptanoic acid, (S)-3-amino-5-methylhexanoic acid, (S)-3-amino-4-methylpentanoic acid, (S)-3-amino-3-cyclopropylpropionic acid, (S)-3-amino-3-cyclohexylpropionic acid, (S)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid.

[0870] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A method for synthesizing a key intermediate of Maraviroc, wherein the key intermediate of Maraviroc is: The synthesis method comprises the following steps: (i) reacting a compound of formula IV with 3-amino-3-phenylpropionic acid under the action of nickel acetate to generate a compound of formula VI'; (ii) hydrolyzing the compound of formula VI' to obtain the compound of formula VII', Where n is 1; R is a methyl group; R1 is phenyl; R2 is halogen; R3 is methyl.

2. A method for synthesizing maraviroc, the method comprising the steps of synthesizing a key intermediate of maraviroc, wherein: The key intermediate of Maraviroc is: Key intermediates for the synthesis of Maraviroc The following steps are involved: (i) reacting a compound of formula IV with 3-amino-3-phenylpropionic acid under the action of nickel acetate to generate a compound of formula VI'; (ii) hydrolyzing the compound of formula VI' to obtain the key intermediate of maraviroc represented by formula VII', Wherein, n is 1; R is methyl; R1 is phenyl; R2 is halogen; R3 is methyl, The synthesis method further comprises the following steps: (i)(S)-β 3 -Phenylalanine reacts with di-tert-butyl dicarbonate to obtain a compound of formula VIII; (ii) reducing the compound of formula VIII to obtain the compound of formula IX; (iii) subjecting the compound of formula IX to oxidation to obtain the compound of formula X; (iv) subjecting the compound of formula X to a reductive amination reaction with the compound of formula XI to obtain a compound of formula XII; (v) removing the tert-butyloxycarbonyl protection from the compound of formula XII to obtain a compound of formula XIII; (vi) The compound of formula XIII is subjected to a condensation reaction with the compound of formula XIV to obtain maraviroc represented by formula XV.

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