METHOD FOR SYNTHESIZING NOVEL CHIRAL LIGAND, METAL CHELATE, A VARIETY OF NON-NATURAL AMINO ACIDS, MARAVIROC AND KEY INTERMEDIATE THEREOF

Abstract

Disclosed is a method for synthesizing a novel chiral ligand, a metal chelate, a variety of non-natural amino acids, Maraviroc and a key intermediate thereof. In the invention, (R)-2-methyl proline is selected and used as a starting raw material, (S)-.sup.3-amino acid is obtained by asymmetric resolution induced by using a nickel chelate, and Maraviroc is synthesized by using (S)-3-amino-3-phenylpropionic acid as a key intermediate with a high yield and the ee value reaching 98.2% or more. The method of the present invention has widely available materials, mild synthetic process conditions, is easy to control, and produces a product of a high optical purity.

Claims

1. A synthesis method for a novel quaternary carbon chiral ligand, wherein the synthesis method comprises the step of synthesizing a compound of formula VI, ##STR00062## wherein n is an integer from 1 to 4; R is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl and unsubstituted or substituted phenyl, wherein the substituted phenyl means that the phenyl has 1-5 substituents, and each substituent is independently selected from the group consisting of amino, halogen, hydroxyl, C1-C4 alkyl and C1-C4 haloalkyl; R.sub.1 is selected from the group consisting of H, C1-C4 alkyl, C1-C4 haloalkyl and unsubstituted or substituted phenyl, wherein the substituted phenyl means that the phenyl has 1-5 substituents, and each substituent is independently selected from the group consisting of amino, halogen, hydroxyl, C1-C4 alkyl and C1-C4 haloalkyl; R.sub.2 is selected from the group consisting of H, halogen, amino, hydroxyl, C1-C4 alkyl and C1-C4 haloalkyl; R.sub.3 is selected from the group consisting of H, C1-C4 alkyl, C1-C4 haloalkyl, unsubstituted or substituted phenyl and (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 the group consisting of amino, halogen, hydroxyl, C1-C4 alkyl and C1-C4 haloalkyl.

2. A novel resolution method for an alpha amino acid, an alpha substituted beta amino acid and a beta substituted beta amino acid comprising the step of hydrolyzing a compound of formula VI to obtain the alpha amino acid, the alpha substituted beta amino acid and the beta substituted beta amino acid of formula VII, ##STR00063## wherein n is an integer from 1 to 4, m is an integer from 0 to 1; R is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl and unsubstituted or substituted phenyl, wherein the substituted phenyl means that the phenyl has 1-5 substituents, and each substituent is independently selected from the group consisting of amino, halogen, hydroxyl, C1-C4 alkyl and C1-C4 haloalkyl; R.sub.1 is selected from the group consisting of H, C1-C4 alkyl, C1-C4 haloalkyl and unsubstituted or substituted phenyl, wherein the substituted phenyl means that the phenyl has 1-5 substituents, and each substituent is independently selected from the group consisting of amino, halogen, hydroxyl, C1-C4 alkyl and C1-C4 haloalkyl; R.sub.2 is selected from the group consisting of H, halogen, amino, hydroxyl, C1-C4 alkyl and C1-C4 haloalkyl; R.sub.3 is selected from the group consisting of H, C1-C4 alkyl, C1-C4 haloalkyl, unsubstituted or substituted phenyl and (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 the group consisting of amino, halogen, hydroxyl, C1-C4 alkyl and C1-C4 haloalkyl; R.sub.4 is selected from the group consisting of H, unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted C3-C6 heteroaryl and unsubstituted or substituted C3-C6 cycloalkyl, wherein the substituted means that there are 1-5 substituents, and each substituent is independently selected from the group consisting of amino, halogen, hydroxyl, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy and C1-C4 haloalkyl; R.sub.5 is selected from the group consisting of H, unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted C3-C6 heteroaryl and unsubstituted or substituted C3-C6 cycloalkyl, wherein the substituted means that there are 1-5 substituents, and each substituent is independently selected from the group consisting of amino, halogen, hydroxyl, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy and C1-C4 haloalkyl.

3. The resolution method of claim 2, wherein the compound of VI is synthesized by the following step: reacting a compound of formula IV with an unnatural amino acid of formula V under the action of a nickel salt to form the compound of formula VI, ##STR00064## wherein n, m, R, R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are as defined in claim 2.

4. A Maravino intermediate having a structure of formula VI: ##STR00065## wherein n, m, R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are as defined in claim 2.

5. A novel chiral ligand having a structure of formula Y: ##STR00066## wherein n, R, R.sub.1, R.sub.2 and R.sub.3 are as defined in claim 2.

6. A method for synthesizing Maraviro comprising the step of synthesizing a Maraviro intermediate, wherein the Maraviro intermediate is: ##STR00067## the step of synthesizing the Maraviro intermediate is as defined in claim 2, wherein n, R.sub.1, R.sub.2 and R.sub.3 are as defined in claim 2 and R.sub.4 is phenyl.

7. A method for synthesizing an unnatural amino acid comprising the following steps: ##STR00068## (i) reacting (R)-2-substituted proline with di-tert-butyl dicarbonate to form (R)-1-(tert-butoxycarbonyl)-2-methylproline; (ii) subjecting (R)-1-(tert-butoxycarbonyl)-2-substituted proline to a condensation reaction with a compound of formula I to obtain a compound of formula II; (iii) removing tert-butoxycarbonyl from the compound of formula II to obtain a compound of formula III; (iv) subjecting the compound of formula III to a reductive amination reaction with R.sub.3CHO or R.sub.3CH.sub.2Cl to obtain a compound of formula IV; (v) reacting the compound of formula IV with various unnatural amino acids of formula V under the action of a nickel salt to form a compound of VI; (vi) hydrolyzing the compound of VI to form a compound of VII, wherein n, m, R, R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are as defined in claim 2.

8. A method for synthesizing a key intermediate of Maraviro, wherein the key intermediate of Maraviro is: ##STR00069## the synthesis method includes the following steps: ##STR00070## (i) reacting the compound IV with 3-amino-3-phenylpropionic acid under the action of a nickel salt to obtain a compound of formula VI; (ii) hydrolyzing the compound of formula VI to obtain a compound of formula VII, wherein n, R, R.sub.1, R.sub.2 and R.sub.3 are as defined in claim 1.

9. A method for synthesizing Maraviro comprising the step of synthesizing a key intermediate of Maraviro, wherein the key intermediate of Maraviro is: ##STR00071## the step of synthesizing the key intermediate of Maraviro is as defined in claim 8.

10. A method for synthesizing Maraviro, wherein the method further comprises the following steps: ##STR00072## (i) reacting (S)-.sup.3-phenylalanine with di-tert-butyl dicarbonate to obtain a compound of formula VIII; (ii) subjecting the compound of formula VIII to a reduction reaction to obtain a compound of formula IX; (iii) subjecting the compound of formula IX to an oxidation reaction to obtain a compound of formula X; (iv) subjecting the compound of formula X to a reductive amination reaction with a compound of formula XI to obtain a compound of formula XII; (v) removing tert-butoxycarbonyl from the compound of formula XII to obtain a compound of formula XIII; (vi) subjecting the compound of formula XIII to a condensation reaction with a compound of formula XIV to obtain Maravino having formula XV.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0074] Based on the extensive and intensive studies, the inventors have developed for the first time a novel synthesis method for (S)-3-amino acid, Maraviro and key intermediates thereof. The invention adopts (R)-2-methylproline as a starting material, uses a nickel chelate to induce asymmetric resolution to obtain (S)-.sup.3-amino acid, and uses (S)-3-amino-3-phenylpropionic acid as a key intermediate and raw material to synthesize Maraviro, and the yield is high, and the ee value is above 98.2%. On the basis of this, the present invention has been completed.

[0075] Intermediate

[0076] An intermediate is a product formed during the production of a desired product. In the present invention, a plurality of intermediates are obtained, and the structures are respectively shown in formula VI and formula Y:

##STR00017##

[0077] wherein n is an integer from 1 to 4, m is an integer from 0 to 1;

[0078] R is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl and unsubstituted or substituted phenyl, wherein the substituted phenyl means that the phenyl has 1-5 substituents, and each substituent is independently selected from the group consisting of amino, halogen, hydroxyl, C1-C4 alkyl and C1-C4 haloalkyl;

[0079] R.sub.1 is selected from the group consisting of H, C1-C4 alkyl, C1-C4 haloalkyl and unsubstituted or substituted phenyl, wherein the substituted phenyl means that the phenyl has 1-5 substituents, and each substituent is independently selected from the group consisting of amino, halogen, hydroxyl, C1-C4 alkyl and C1-C4 haloalkyl;

[0080] R.sub.2 is selected from the group consisting of H, halogen, amino, hydroxyl, C1-C4 alkyl and C1-C4 haloalkyl;

[0081] R.sub.3 is selected from the group consisting of H, C1-C4 alkyl, C1-C4 haloalkyl, unsubstituted or substituted phenyl and (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 the group consisting of amino, halogen, hydroxyl, C1-C4 alkyl and C1-C4 haloalkyl;

[0082] R.sub.4 is selected from the group consisting of H, unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted C3-C6 heteroaryl and unsubstituted or substituted C3-C6 cycloalkyl, wherein the substituted means that there are 1-5 substituents, and each substituent is independently selected from the group consisting of amino, halogen, hydroxyl, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy and C1-C4 haloalkyl.

[0083] R.sub.5 is selected from the group consisting of H, unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted C3-C6 heteroaryl and unsubstituted or substituted C3-C6 cycloalkyl, wherein the substituted means that there are 1-5 substituents, and each substituent is independently selected from the group consisting of amino, halogen, hydroxyl, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy and C1-C4 haloalkyl.

[0084] In another preferred embodiment, n is 1, 2 or 3.

[0085] In another preferred embodiment, R is selected from the group consisting of methyl, trifluoromethyl, ethyl, propyl, difluoromethyl, dichloromethyl, trichloromethyl, benzyl, cyano, F, Cl, Br and I.

[0086] In another preferred embodiment, R.sub.1 is selected from the group consisting of methyl, trifluoromethyl, ethyl, propyl, difluoromethyl, dichloromethyl and trichloromethyl.

[0087] In another preferred embodiment, R.sub.2 is selected from the group consisting of H, F, Cl, Br, I, trifluoromethyl, methyl, ethyl, propyl, difluoromethyl, dichloromethyl and trichloromethyl.

[0088] In another preferred embodiment, R.sub.3 is methyl, ethyl, phenyl, C.sub.6H.sub.5CH.sub.2, C.sub.6H.sub.5CH.sub.2CH.sub.2, C.sub.6H.sub.3Cl.sub.2CH.sub.2, or C.sub.6H.sub.3Cl.sub.2CH.sub.2CH.sub.2.

[0089] In another preferred embodiment, R.sub.4 is phenyl, pyridyl, naphthyl, thienyl, methoxy phenyl or halophenyl.

[0090] 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:

##STR00018##

[0091] wherein n, R.sub.1, R.sub.2 and R.sub.3 are as defined above.

[0092] Synthesis Method

[0093] In the present invention, the compound of formula II is synthesized by the following steps:

##STR00019##

[0094] (i) (R)-2-substituted proline is reacted with di-tert-butyl dicarbonate to form (R)-1-(tert-butoxycarbonyl)-2-methylproline;

[0095] (ii) (R)-1-(tert-butoxycarbonyl)-2-substituted proline and a compound of formula I are subjected to a condensation reaction to obtain a compound of formula II;

[0096] wherein n, R.sub.1 and R.sub.2 are as defined above.

[0097] In another preferred embodiment, the compound of formula I is selected from the group consisting of 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, and 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone.

[0098] 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 one or a mixed solvent of two or more selected from the group consisting of dichloromethane, methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, 1,4-dioxane, DMSO and DMF. In another preferred embodiment, the base is one or a combination of two or more of potassium hydroxide, sodium hydroxide, lithium hydroxide, cesium carbonate, potassium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, DBU, DIPEA, triethylamine and tetramethyl hydroxylamine.

[0099] 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 one or a mixed solvent of two or more selected from the group consisting of dichloromethane, tetrahydrofuran, 1,4-dioxane, DMSO and DMF. In another preferred embodiment, the acyl chloride reagent is one or a combination of two or more selected from the group consisting of methanesulfonyl chloride, dichlorosulfoxide and oxalyl chloride. In another preferred embodiment, the base is one or a combination of two or more selected from the group consisting of N-methylimidazole, imidazole, potassium hydroxide, sodium hydroxide, lithium hydroxide, cesium carbonate, potassium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, DBU, DIPEA, triethylamine and tetramethylhydroxylamine.

##STR00020##

[0100] As shown in the above reaction formula, tert-butoxycarbonyl is removed from a compound of formula II to afford a compound of formula III.

[0101] In another preferred embodiment, the removal of the tert-butoxycarbonyl group is carried out in an organic solvent in the presence of an acid. In another preferred embodiment, the organic solvent is one or a mixed solvent of two or more selected from the group consisting of dichloromethane, 1,2-dichlorohexane, tetrahydrofuran, methanol, ethanol, 1,4-dioxane, DMSO and DMF. In another preferred embodiment, the acid is one or a combination of two or more selected from the group consisting of trifluoroacetic acid, hydrochloric acid, sulfuric acid and nitric acid.

[0102] In the present invention, the compound of formula IV is synthesized by the following step:

##STR00021##

[0103] a compound of formula III is subjected to a reductive amination reaction with R.sub.3CHO to form the compound of formula IV,

[0104] wherein n, R, R.sub.1, R.sub.2 and R.sub.3 are as defined above.

[0105] In another preferred embodiment, R.sub.3CHO is acetaldehyde, propionaldehyde, benzaldehyde, phenylacetaldehyde, phenylpropanal, 3,4-dichlorophenylacetaldehyde or 3,4-dichlorophenylpropanal.

[0106] In another preferred embodiment, R.sub.3CHO is acetaldehyde, propionaldehyde, benzaldehyde, phenylacetaldehyde, phenylpropanal or 3,4-dichlorophenylacetaldehyde.

[0107] 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 reagent.

[0108] In another preferred embodiment, the organic solvent is one or a mixed solvent of two or more selected from the group consisting of dichloromethane, 1,2-dichlorohexane and tetrahydrofuran. In another preferred embodiment, the acid is one or a combination of two or more selected from the group consisting of formic acid, acetic acid, propionic acid and butyric acid. In another preferred embodiment, the reducing agent is one or a combination of two or more selected from the group consisting of sodium borohydride, sodium triacetoxyborohydride and sodium cyanoborohydride.

[0109] In the present invention, the compound of formula IV is synthesized by the following step:

##STR00022##

[0110] a compound of formula III is subjected to a substitution reaction with R.sub.3CH.sub.2Cl to afford the compound of formula IV,

[0111] wherein n, R, R.sub.1, R.sub.2 and R.sub.3 are as defined above.

[0112] In another preferred embodiment, R.sub.3CH.sub.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 or 1-chloropropane.

[0113] In another preferred embodiment, R.sub.3CH.sub.2Cl 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 or 1-chloropropane.

[0114] In another preferred embodiment, the substitution reaction is carried out in the presence of a base in an organic solvent. In another preferred embodiment, the organic solvent is one or a mixed solvent of two or more selected from the group consisting of dichloromethane, 1,2-dichlorohexane and tetrahydrofuran. In another preferred embodiment, the base is one or a mixture of two or more selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate and cesium carbonate.

[0115] The structure of novel quaternary carbon ligand is as follows.

##STR00023## ##STR00024## ##STR00025## ##STR00026## ##STR00027## ##STR00028## ##STR00029## ##STR00030## ##STR00031## ##STR00032## ##STR00033## ##STR00034##

[0116] In the present invention, the compound of formula VI is synthesized by the following step:

##STR00035##

[0117] a compound of formula IV is reacted with a non-natural amino acid of formula V under the action of a nickel salt to form the compound of formula VI,

[0118] wherein n, m, R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are as defined above.

[0119] In another preferred embodiment, the compound of formula V is a variety of non-natural alpha amino acids, alpha substituted beta amino acids, and beta substituted beta amino acids, such as alanine, phenylalanine, phenylalanine, 3-methoxyphenylalanine, 3-methy 1phenylalanine, 4-fluorophenylalanine, 3-methoxyphenylglycine, 3-bromophenylglycine, 2-amino-3-(3,5-diiodo-4-hydroxyphenyl)propionic acid, 2-amino-3-(naphth-1-yl)propionic acid, 2-amino-3-(benzothiophen-3-yl)propionic acid, 2-amino-3-(thiophen-3-yl)propionic acid, 2-amino-2-cyclobutylacetic acid, 2-amino-4,4,4-trifluorobutyric acid, 2-aminovaleric acid, 2-amino-3-methylbutyric acid, 2-amino-4-methylthiobutyric acid, 2-amino-3-(1H-indenyl)propionic acid, 2-amino-5-methyl-4-hexenoic acid, 2-aminoglutaric acid, 2,5-diamino-5-pentanone 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-(naphth-1-yl)propionic acid 3-amino-propionic acid, 3-amino-3-phenylpropionic acid, 3-amino-3-(4-methyl)phenylpropionic acid, 3-amino-3-(3-methyl)phenylpropionic acid, 3-amino-3-(2-methyl)phenylpropionic acid, 3-amino-3-(2-fluoro)phenylpropionic acid, 3-amino-3-(4-chloro)phenylpropionic acid, 3-amino-3-(3,4-dimethoxy)phenylpropionic acid, 3-amino-3-(4-methoxy)phenylpropionic acid, 3-amino-3-(3-methoxy)phenylpropionic acid, 3-amino-3-(pyridin-4-yl)propionic acid, 3-amino-3-(thiophen-2-yl)propionic acid, 3-amino-3-cyclohexylpropionic acid, 3-amino-3-(naphth-2-yl)propionic acid or 3-amino-3-(2,4,5-trifluoro)phenylpropionic acid.

[0120] In another preferred embodiment, a compound of formula IV is reacted with a compound of formula V in an organic solvent in the presence of a base. In another preferred embodiment, the organic solvent is one or a mixed solvents of two or more selected from the group consisting of dichloromethane, 1,2-dichlorohexane, tetrahydrofuran, methanol, ethanol, 1,4-dioxane, DMSO and DMF. In another preferred embodiment, the base is one or a combination of two or more selected from the group consisting of potassium hydroxide, sodium hydroxide, lithium hydroxide, cesium carbonate, potassium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, DBU, DIPEA, triethylamine and tetramethyl hydroxylamine.

[0121] The structure of the novel alpha amino acid nickel chelate is as follows:

##STR00036## ##STR00037## ##STR00038## ##STR00039## ##STR00040## ##STR00041## ##STR00042##

[0122] The structure of the novel -substituted amino acid nickel chelate is as follows:

##STR00043## ##STR00044## ##STR00045## ##STR00046##

[0123] The structure of the novel -substituted amino acid nickel chelate is as follows:

##STR00047## ##STR00048## ##STR00049## ##STR00050## ##STR00051## ##STR00052## ##STR00053##

[0124] The method for synthesizing the (S)-.sup.3-amino acid of the present invention, comprises the step of hydrolyzing a compound of the formula VI to obtain the (S)-.sup.3-amino acid represented by formula VII,

##STR00054##

[0125] wherein n, m, R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are as defined above.

[0126] In another preferred embodiment, the hydrolysis is carried out in an organic solvent in the presence of a base, wherein the organic solvent is one or a mixture of two or more selected from the group consisting of methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, 1,4-dioxane, DMSO and DMF. In another preferred embodiment, the base is one or a composition of two or more selected from the group consisting of DBU, potassium t-butoxide, sodium t-butoxide, sodium hydrogen, potassium hydroxide, sodium hydroxide, cesium carbonate, potassium carbonate, potassium hydrogencarbonate and lithium hydroxide.

[0127] In another preferred embodiment, the method for synthesizing the non-natural amino acid comprises the following steps:

[0128] (i) reacting (R)-2-substituted proline with di-tert-butyl dicarbonate to form (R)-1-(tert-butoxycarbonyl)-2-methylproline;

[0129] (ii) subjecting (R)-1-(tert-butoxycarbonyl)-2-substituted proline to a condensation reaction with a compound of formula I to obtain a compound of formula II;

[0130] (iii) removing tert-butoxycarbonyl from the compound of formula II to obtain a compound of formula III;

[0131] (iv) subjecting the compound of formula III to a reductive amination reaction with R.sub.3CHO to obtain a compound of formula IV;

[0132] (v) reacting the compound of formula IV with a .sup.3 amino acid of formula V under the action of nickel acetate to form a compound of VI;

[0133] (vi) hydrolyzing the compound of VI to form a compound of VII,

##STR00055##

wherein n, m, R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are as defined above. The preferred conditions for each step are as indicated above.

[0134] The method for synthesizing Maraviro in the present invention comprises the step of synthesizing a Maraviro intermediate, wherein the Maraviro intermediate is a compound of the formula VI:

##STR00056##

[0135] wherein n, m, R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are as defined above, and R.sub.4 is phenyl.

[0136] In another preferred embodiment, the synthesis step of the Maraviro intermediate, the compound of formula VI is as described above.

[0137] In another preferred embodiment, the method for synthesizing Maraviro also includes the following step:

##STR00057##

[0138] (i) reacting a compound of formula IV with 3-amino-3-phenylpropionic acid under the action of nickel acetate to form a compound of formula VI;

[0139] (ii) hydrolyzing the compound of formula VI to obtain (S)-.sup.3-phenylalanine,

[0140] wherein n, R.sub.1, R.sub.2 and R.sub.3 are as defined above.

[0141] In another preferred embodiment, the method for synthesizing Maraviro further includes the following step:

##STR00058## ##STR00059##

[0142] (a) reacting (S)-.sup.3-phenylalanine with di-tert-butyl dicarbonate to obtain a compound of formula VIII;

[0143] (b) subjecting the compound of formula VIII to a reduction reaction to give a compound of formula IX;

[0144] (c) subjecting the compound of formula IX to an oxidation reaction to give a compound of formula X;

[0145] (d) subjecting the compound of formula X to a reductive amination reaction with a compound of formula XI to give a compound of formula XII;

[0146] (e) removing tert-butoxycarbonyl from the compound of formula XII to give a compound of formula XIII;

[0147] (f) subjecting the compound of formula XIII to a condensation reaction with a compound of formula XIV to obtain Maravino having formula XV.

[0148] In another preferred embodiment, (S)-.sup.3-phenylalanine is reacted with di-tert-butyl dicarbonate in an organic solvent in the presence of a base, wherein the organic solvent is one or a mixed solvent of two or more selected from the group consisting of dichloromethane, methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, 1,4-dioxane, DMSO and DMF; and the base is one or a combination of two or more selected from the group consisting of potassium hydroxide, sodium hydroxide, lithium hydroxide, cesium carbonate, potassium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, DBU, DIPEA and triethylamine.

[0149] 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 one or a mixed solvent of two or more selected from the group consisting of dichloromethane, tetrahydrofuran, 1,4-dioxane, DMSO and DMF; and the reducing agent is one or a combination of two or more selected from the group consisting of sodium borohydride, lithium aluminum hydride and borane.

[0150] 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 one or a mixed solvent of two or more selected from the group consisting of dichloromethane, tetrahydrofuran, 1,4-dioxane, DMSO and DMF; and the oxidizing agent is one or a combination of two or more selected from the group consisting of Collins oxidizing agent, PCC oxidizing agent, PDC oxidizing agent, Swern oxidizing agent, Dess-martin oxidizing agent and IBX oxidizing agent.

[0151] 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 one or a mixed solvent of two or more selected from the group consisting of dichloromethane, 1,2-dichlorohexane and tetrahydrofuran; the acid is one or a combination of two or more selected from the group consisting of formic acid, acetic acid, propionic acid, and butyric acid; and the reducing agent is one or a combination of two or more selected from the group consisting of sodium borohydride, sodium triacetoxyborohydride and sodium cyanoborohydride.

[0152] 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 one or a mixed solvent of two or more selected from the group consisting of dichloromethane, 1,2-dichlorohexane, tetrahydrofuran, methanol, ethanol, 1,4-dioxane, DMSO and DMF; and the acid is one or a combination of two or more selected from the group consisting of trifluoroacetic acid, hydrochloric acid, sulfuric acid and nitric acid.

[0153] 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 one or a mixed solvent of two or more selected from the group consisting of dichloromethane, 1,2-dichlorohexane, tetrahydrofuran, methanol, ethanol, 1,4-dioxane, DMSO and DMF; and the condensation agent is one or a combination of two or more selected from the group consisting of BOP, PyBOP, EDCI, DCC, HOBT, HATU, and HBTU.

[0154] In a preferred embodiment of the invention, the synthesis route for key intermediate of Maraviro, (S)-3-amino-3-phenylpropionic acid is as follows.

##STR00060##

[0155] In a preferred embodiment of the invention, the synthesis route for Maraviro is as follows.

##STR00061##

[0156] The above-mentioned features in the present invention, or the features mentioned in the examples, may be arbitrarily combined. All of the features disclosed in the present specification can be used in combination with any of the compositions, and the various features disclosed in the specification can be substituted with any alternative features that provide the same, equal or similar purpose. Therefore, unless otherwise stated, the disclosed features are only general examples of equal or similar features.

[0157] The beneficial effects of the invention are as follows.

[0158] (1) A cheap 2-methylproline which has a wide range of sources is used as raw material.

[0159] (2) The nickel chelate is used to induce the asymmetric resolution of chiral amino acids to construct a chiral center, which improves the optical purity of the product.

[0160] (3) The present invention optimizes the synthetic route of Malavino, and the synthesis process is mild and easy to be controlled.

[0161] (4) The newly designed proline type chiral ligand is resistant to acid and high temperature and has stable structure. A quantitative recover and recycle can be realized while hydrolyzing the chelate, thereby saving synthesis cost.

[0162] The invention is further illustrated below in conjunction with specific examples. It is to be understood that the examples are used to illuminate the invention and not intended to limit the scope of the invention. The experimental methods in the following examples which do not contain the specific conditions are usually carried out according to conventional conditions or according to the conditions recommended by the manufacturer.

[0163] Unless otherwise defined, all professional and scientific terms used herein have the same meaning known as those skilled in the art. In addition, any methods and materials similar or equivalent to those described may be employed in the methods of the invention. The preferred embodiments and materials described herein are for illustrative purposes only.

Example 1 Preparation of (R)-1-(tert-butoxycarbonyl)-2-methylproline

[0164] 10 g of (R)-2-methylproline (77.42 mmol) and 14.30 g of TMAH (CH.sub.3).sub.4NOH.5H.sub.2O (77.42 mmol) were added into a 250 ml three-necked flask, dissolved in 200 mL of acetonitrile and stirred at 20-40 C. Di-tert-butyl dicarbonate (116.13 mmol) was added and stirred for 3-5 days.

[0165] After completion of the reaction, water and ethyl acetate were added, and the aqueous layer was extracted three times with EtOAc. The combined organic lays were washed with saturated sodium bicarbonate solution and then dried over anhydrous magnesium sulfate. 16.5 g of (R)-1-(tert-butoxycarbonyl)-2-methylproline in a yield of 93% was obtained by removing ethyl acetate under normal pressure.

[0166] .sup.1H NMR (500 MHz, DMSO-d.sub.6) 12.38 (s, 1H), 3.43-3.34 (m, 2H), 2.14-2.00 (m, 1H), 1.93-1.76 (m, 3H), 1.41 (d, J=2.4 Hz, 3H), 1.37 (d, J=19.8 Hz, 9H).

[0167] .sup.13C NMR (125 MHz, DMSO-d.sub.6) 176.4, 153.4, 79.2, 64.7, 48.1, 39.1, 28.4, 23.5, 22.7.

Example 2 Preparation of tert-butyl-(R)-2-((2-benzoyl-4-chlorophenyl)carbamoyl)-2-methylprolinamide

[0168] 10 g of (R)-1-(tert-butoxycarbonyl)-2-methylproline (43.62 mmol), 10.33 mL of 1-methylimidazole (130.85 mmol) and a catalytic amount of DMAP were added into a 250 ml three-necked flask and dissolved in 200 ml of dichloromethane. After 15-45 min, 11.12 g of (2-amino-5-chlorophenyl)benzophenone (47.98 mmol) was added in the reaction mixture system and the reaction temperature was controlled at 0-10 C. The mixture was stirred for 12-36 h and then water and dichloromethane were added. The aqueous phase was extracted three times with dichloromethane. The combined organic lays were washed with saturated sodium bicarbonate solution and then dried over anhydrous magnesium sulfate. 12 g of tert-butyl-(R)-2-((2-benzoyl-4-chlorophenyl)carbamoyl)-2-methylprolinamide (yield 62%) was obtained by removing dichloromethane under normal pressure.

[0169] .sup.1H NMR (500 MHz, DMSO-d.sub.6) 10.39 (s, 1H), 8.02 (d, J=8.9 Hz, 1H), 7.76-7.71 (m, 1H), 7.70-7.63 (m, 3H), 7.54 (t, J=7.7 Hz, 2H), 7.46 (d, J=2.6 Hz, 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=39.3 Hz, 9H).

Example 3 Preparation of (R)-2-((2-benzoyl-4-chlorophenyl)carbamoyl)-2-methylprolinamide

[0170] 8.5 g of tert-butyl (R)-2-((2-benzoyl-4-chlorophenyl)carbamoyl)-2-methylprolinamide (19.19 mmol) was dissolved in 20 ml of dichloromethane and 20 ml of trifluoroacetic acid was added and stirred for 6-8 h at 20-40 C. The mixture was evaporated to obtain 6.5 g of target product, (R)-2-((2-benzoyl-4-chlorophenyl)carbamoyl)-2-methylprolinamide (yield 98%).

[0171] .sup.1H NMR (500 MHz, CDCl.sub.3) 11.95 (s, 1H), 8.63 (d, J=8.9 Hz, 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, 6.4 Hz, 1H), 3.00-2.91 (m, 1H), 2.35-2.24 (m, 1H), 1.82-1.63 (m, 4H), 1.46 (s, 3H).

[0172] .sup.13C NMR (125 MHz, CDCl.sub.3) 196.9, 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.

Example 4 Preparation of (R)N-(2-benzoyl-4-chlorophenyl)-1-ethyl-2-methylpyrrolyl-2-carboxamide

[0173] 5 g of (R)-2-((2-benzoyl-4-chlorophenyl)carbamoyl)-2-methylprolinamide (14.58 mmol) and 16.04 mmol of acetaldehyde were dissolved in dichloromethane. A catalytic amount of acetic acid was added and reacted at 10-30 C. for 15 min-1 h, and then water and dichloromethane were added. The aqueous phase was extracted three times with dichloromethane. Then the combined organic lays were washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated under normal pressure to remove dichloromethane to obtain 10 g of (R)N-(2-benzoyl-4-chlorophenyl)-1-ethyl-2-methylpyrrolyl-2-carboxamide in a yield of 95%.

[0174] mp 87-88 C. [].sub.20.sup.D=+143.5 (c=0.108, CHCl.sub.3).

[0175] .sup.1H NMR (500 MHz, CDCl.sub.3) 11.62 (s, 1H), 8.60 (d, J=9.0 Hz, 1H), 7.75 (d, J=7.2 Hz, 2H), 7.61 (t, J=7.4 Hz, 1H), 7.49 (t, J=7.6 Hz, 3H), 7.42 (d, J=2.5 Hz, 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=7.2 Hz, 3H).

[0176] .sup.13C NMR (125 MHz, CDCl.sub.3) 196.5, 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.

[0177] LRMS (ESI+APCI) m/z: 371.1, HRMS (ESI) m/z: found: 371.1527, calcd 371.1521 for C.sub.21H.sub.23ClN.sub.2O.sub.2.sup.+ [M+H].sup.+.

Example 5 Preparation of (R)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0178] The compound was prepared according to example 4.

[0179] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.04 (s, 1H), 8.60 (d, J=7.5 Hz, 1H), 7.81 (d, J=2.0 Hz, 1H), 7.66-7.43 (m, 8H), 6.98 (ddt, J=7.5, 2.2, 1.1 Hz, 1H), 3.74 (dt, J=12.5, 1.1 Hz, 1H), 3.58 (dt, J=12.4, 1.1 Hz, 1H), 3.21 (ddd, J=9.6, 8.2, 1.4 Hz, 1H), 2.42-2.28 (m, 2H), 2.04-1.82 (m, 2H), 1.75 (dt, J=13.1, 7.0 Hz, 1H), 1.48 (s, 3H).

[0180] LCMS (ESI+APCI) m/z: 501.83

Example 6 Preparation of (R)N-(2-benzoyl-4-chlorophenyl)-1-benzyl-2-methylpyrrolyl-2-carboxamide

[0181] The compound was prepared according to example 4.

[0182] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.04 (s, 1H), 8.62 (d, J=7.5 Hz, 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=12.3 Hz, 1H), 3.57 (d, J=12.4 Hz, 1H), 3.10 (ddd, J=9.6, 6.9, 2.8 Hz, 1H), 2.35-2.21 (m, 2H), 1.89-1.75 (m, 2H), 1.78-1.67 (m, 1H), 1.09 (s, 3H).

[0183] LCMS (ESI+APCI) m/z: 432.95

Example 7 Preparation of (R)N-(2-benzoyl-4-chlorophenyl)-1-phenylethyl-2-methylpyrrolyl-2-carboxamide

[0184] The compound was prepared according to example 4.

[0185] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.04 (s, 1H), 8.48 (d, J=7.5 Hz, 1H), 7.80 (d, J=2.1 Hz, 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, 1.6 Hz, 1H), 2.90 (td, J=12.1, 1.5 Hz, 1H), 2.62 (td, J=12.3, 1.6 Hz, 1H), 2.50-2.34 (m, 2H), 2.18-2.05 (m, 2H), 1.96-1.74 (m, 3H), 1.42 (s, 3H).

[0186] LCMS (ESI+APCI) m/z: 446.98

Example 8 Preparation of (S)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-fluoropyrrolyl-2-carboxamide

[0187] The compound was prepared according to example 4.

[0188] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.04 (s, 1H), 8.61 (d, J=7.5 Hz, 1H), 7.81 (d, J=2.1 Hz, 1H), 7.66-7.55 (m, 4H), 7.55-7.46 (m, 3H), 7.34 (q, J=1.2 Hz, 1H), 7.06-6.98 (m, 1H), 3.80 (d, J=12.6 Hz, 1H), 3.66-3.58 (m, 1H), 2.99 (dd, J=9.1, 6.0 Hz, 1H), 2.56-2.38 (m, 1H), 2.24 (ddd, J=11.6, 9.1, 5.1 Hz, 1H), 2.20-2.07 (m, 1H), 2.12-1.95 (m, 1H), 1.89-1.75 (m, 1H).

[0189] LCMS (ESI+APCI) m/z: 505.80

Example 9 Preparation of (S)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-chloropyrrolyl-2-carboxamide

[0190] The compound was prepared according to example 4.

[0191] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.04 (s, 1H), 8.53 (d, J=7.5 Hz, 1H), 7.80 (d, J=2.1 Hz, 1H), 7.60 (dddd, J=8.4, 7.1, 4.9, 1.9 Hz, 5H), 7.55-7.46 (m, 3H), 7.03-6.95 (m, 1H), 3.78 (d, J=12.3 Hz, 1H), 3.69 (d, J=12.5 Hz, 1H), 3.44 (td, J=9.0, 1.3 Hz, 1H), 2.74-2.62 (m, 1H), 2.37 (q, J=8.6 Hz, 1H), 2.21-2.03 (m, 2H), 2.06-1.91 (m, 1H).

[0192] LCMS (ESI+APCI) m/z: 522.25

Example 10 Preparation of (S)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-bromopyrrolyl-2-carboxamide

[0193] The compound was prepared according to example 4.

[0194] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.04 (s, 1H), 8.61 (d, J=7.5 Hz, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.66-7.55 (m, 4H), 7.55-7.46 (m, 3H), 7.40 (q, J=1.2 Hz, 1H), 6.87-6.79 (m, 1H), 4.55 (d, J=12.4 Hz, 1H), 3.65 (d, J=12.3 Hz, 1H), 3.16 (dt, J=13.7, 7.1 Hz, 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).

[0195] LCMS (ESI+APCI) m/z: 566.70

Example 11 Preparation of (S)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-iodopyrrolyl-2-carboxamide

[0196] The compound was prepared according to example 4.

[0197] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.04 (s, 1H), 8.62 (d, J=7.4 Hz, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.66-7.55 (m, 4H), 7.55-7.46 (m, 3H), 7.40 (q, J=1.2 Hz, 1H), 6.89-6.81 (m, 1H), 4.55 (d, J=12.4 Hz, 1H), 3.74-3.66 (m, 1H), 3.33 (dt, J=13.7, 7.0 Hz, 1H), 3.04-2.95 (m, 1H), 2.40 (dt, J=13.6, 7.1 Hz, 1H), 2.12 (ddd, J=12.1, 9.3, 4.9 Hz, 1H), 2.07-1.91 (m, 1H), 1.34-1.21 (m, 1H).

[0198] LCMS (ESI+APCI) m/z: 613.70

Example 12 Preparation of (S)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-cyanopyrrolylpyrrolyl-2-carboxamide

[0199] The compound was prepared according to example 4.

[0200] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.04 (s, 1H), 8.56 (d, J=7.5 Hz, 1H), 7.82 (d, J=2.0 Hz, 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=12.5 Hz, 1H), 3.35 (ddd, J=9.5, 8.1, 1.4 Hz, 1H), 2.71 (dt, J=13.0, 7.0 Hz, 1H), 2.61-2.49 (m, 1H), 2.33-2.01 (m, 3H).

[0201] LCMS (ESI+APCI) m/z: 512.82

Example 13 Preparation of (R)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-ethylpyrrolyl-2-carboxamide

[0202] The compound was prepared according to example 4.

[0203] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.04 (s, 1H), 8.59 (d, J=7.5 Hz, 1H), 7.81 (d, J=2.0 Hz, 1H), 7.66-7.55 (m, 4H), 7.55-7.44 (m, 4H), 6.99 (dq, J=7.6, 1.3 Hz, 1H), 3.73 (d, J=12.6 Hz, 1H), 3.60 (d, J=12.7 Hz, 1H), 3.21 (ddd, J=10.0, 8.3, 1.9 Hz, 1H), 2.39-2.24 (m, 3H), 2.10 (dq, J=12.5, 7.9 Hz, 1H), 2.03-1.83 (m, 2H), 1.80 (dt, J=13.2, 6.8 Hz, 1H), 0.65 (t, J=7.9 Hz, 3H).

[0204] LCMS (ESI+APCI) m/z: 515.86

Example 14 Preparation of (R)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-trifluoromethylpyrrolyl-2-carboxamide

[0205] The compound was prepared according to example 4.

[0206] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.04 (s, 1H), 8.59 (d, J=7.5 Hz, 1H), 7.80 (d, J=2.0 Hz, 1H), 7.66-7.55 (m, 4H), 7.55-7.46 (m, 4H), 7.02 (dq, J=7.6, 1.1 Hz, 1H), 3.77 (d, J=12.3 Hz, 1H), 3.66 (d, J=12.1 Hz, 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).

[0207] LCMS (ESI+APCI) m/z: 555.80

Example 15 Preparation of (S)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-isopropylpyrrolyl-2-carboxamide

[0208] The compound was prepared according to example 4.

[0209] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.04 (s, 1H), 8.70 (d, J=7.5 Hz, 1H), 7.87 (d, J=2.1 Hz, 1H), 7.66-7.58 (m, 2H), 7.62-7.57 (m, 1H), 7.61-7.46 (m, 3H), 7.43 (dd, J=2.1, 1.1 Hz, 1H), 6.81 (ddd, J=7.5, 2.2, 1.2 Hz, 1H), 3.81 (dd, J=12.3, 1.1 Hz, 1H), 3.11 (dt, J=12.3, 1.1 Hz, 1H), 2.93 (ddd, J=11.8, 9.4, 4.9 Hz, 1H), 2.34 (dd, J=9.5, 6.4 Hz, 1H), 2.18-1.97 (m, 3H), 1.86-1.73 (m, 1H), 1.77-1.59 (m, 1H), 0.96 (d, J=6.8 Hz, 6H).

[0210] LCMS (ESI+APCI) m/z: 529.89

Example 16 Preparation of (S)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-tert-butylpyrrolyl-2-carboxamide

[0211] The compound was prepared according to example 4.

[0212] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.04 (s, 1H), 8.47 (d, J=7.5 Hz, 1H), 7.74 (d, J=2.1 Hz, 1H), 7.66-7.46 (m, 8H), 6.97 (ddt, J=7.6, 2.1, 1.2 Hz, 1H), 3.63 (dt, J=12.5, 1.1 Hz, 1H), 3.35 (dt, J=12.5, 1.1 Hz, 1H), 3.16 (td, J=9.2, 1.8 Hz, 1H), 2.22 (td, J=9.3, 6.9 Hz, 1H), 2.20-2.05 (m, 1H), 1.90 (ddq, J=20.5, 9.4, 6.9 Hz, 2H), 1.63 (ddtd, J=14.1, 8.7, 6.7, 2.9 Hz, 1H), 0.92 (s, 9H).

[0213] LCMS (ESI+APCI) m/z: 543.91

Example 17 Preparation of (S)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-benzylpyrrolyl-2-carboxamide

[0214] The compound was prepared according to example 4.

[0215] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.04 (s, 1H), 8.59 (d, J=7.5 Hz, 1H), 7.85 (d, J=2.0 Hz, 1H), 7.66-7.45 (m, 8H), 7.29-7.14 (m, 3H), 7.07 (ddd, J=7.5, 2.4, 1.2 Hz, 2H), 7.03-6.95 (m, 1H), 3.73 (d, J=12.5 Hz, 1H), 3.61 (d, J=12.3 Hz, 1H), 3.43-3.35 (m, 1H), 3.27 (ddd, J=9.4, 8.0, 2.9 Hz, 1H), 3.13 (d, J=12.2 Hz, 1H), 2.42-2.30 (m, 2H), 2.13-1.95 (m, 2H), 1.87 (dt, J=12.9, 7.0 Hz, 1H).

[0216] LCMS (ESI+APCI) m/z: 577.93

Example 18 Preparation of (S)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0217] The compound was prepared according to example 4.

[0218] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.04 (s, 1H), 8.55 (d, J=7.5 Hz, 1H), 7.76 (d, J=2.0 Hz, 1H), 7.66-7.55 (m, 4H), 7.56-7.46 (m, 3H), 7.44 (ddd, J=7.3, 2.1, 1.1 Hz, 1H), 7.34 (dd, J=2.2, 1.3 Hz, 1H), 3.90 (dt, J=12.4, 1.1 Hz, 1H), 3.73 (dt, J=12.4, 1.1 Hz, 1H), 3.10-3.00 (m, 1H), 2.51-2.35 (m, 2H), 1.77-1.63 (m, 3H), 1.19 (s, 3H). LCMS (ESI+APCI) m/z: 501.83

Example 19 Preparation of (S)N-(2-benzoyl-4-chlorophenyl)-1-benzyl-2-methylpyrrolyl-2-carboxamide

[0219] The compound was prepared according to example 4.

[0220] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.04 (s, 1H), 8.62 (d, J=7.4 Hz, 1H), 7.77 (d, J=1.9 Hz, 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=12.3 Hz, 1H), 3.58 (d, J=12.4 Hz, 1H), 2.97-2.86 (m, 1H), 2.47-2.31 (m, 2H), 1.78-1.63 (m, 3H), 1.33 (s, 3H).

[0221] LCMS (ESI+APCI) m/z: 432.95

Example 20 Preparation of (S)N-(2-benzoyl-4-chlorophenyl)-1-phenylethyl-2-methylpyrrolyl-2-carboxamide

[0222] The compound was prepared according to example 4.

[0223] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.04 (s, 1H), 8.63 (d, J=7.5 Hz, 1H), 7.82 (d, J=1.9 Hz, 1H), 7.66-7.58 (m, 2H), 7.62-7.46 (m, 3H), 7.25 (s, 2H), 7.31-7.14 (m, 3H), 3.08 (dt, J=9.5, 7.0 Hz, 1H), 2.85-2.76 (m, 2H), 2.69 (td, J=7.3, 1.3 Hz, 2H), 2.48 (dt, J=9.5, 7.1 Hz, 1H), 2.09 (dt, J=13.2, 7.1 Hz, 1H), 1.83 (ddd, J=13.1, 7.5, 6.6 Hz, 1H), 1.69 (p, J=7.0 Hz, 2H), 1.33 (s, 3H).

[0224] LCMS (ESI+APCI) m/z: 446.98

Example 21 Preparation of (S)N-(2-benzoyl-4-chlorophenyl)-1-ethyl-2-methyl pyrrolyl-2-carboxamide

[0225] The compound was prepared according to example 4.

[0226] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.04 (s, 1H), 8.64 (d, J=7.5 Hz, 1H), 7.78 (d, J=1.9 Hz, 1H), 7.66-7.55 (m, 4H), 7.56-7.46 (m, 2H), 3.03 (dt, J=9.5, 7.0 Hz, 1H), 2.53-2.34 (m, 2H), 2.22-2.05 (m, 2H), 1.81 (ddd, J=13.0, 7.6, 6.5 Hz, 1H), 1.69 (p, J=7.1 Hz, 2H), 1.30 (s, 3H), 1.04 (t, J=8.0 Hz, 3H).

[0227] LCMS (ESI+APCI) m/z: 370.88

Example 22 Preparation of (R)N-(2-benzoyl-4-chlorophenyl)-1-(4-chlorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0228] The compound was prepared according to example 4.

[0229] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.04 (s, 1H), 8.55 (d, J=7.5 Hz, 1H), 7.76 (d, J=1.9 Hz, 1H), 7.66-7.55 (m, 4H), 7.56-7.46 (m, 2H), 7.37 (d, J=1.4 Hz, 4H), 3.86 (d, J=12.3 Hz, 1H), 3.70 (d, J=12.5 Hz, 1H), 3.06 (ddd, J=9.4, 6.2, 3.0 Hz, 1H), 2.50-2.35 (m, 2H), 1.87-1.73 (m, 2H), 1.76-1.64 (m, 1H), 1.20 (s, 3H).

[0230] LCMS (ESI+APCI) m/z: 467.39

Example 23 Preparation of (R)N-(2-benzoyl-4-chlorophenyl)-1-(3-chlorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0231] The compound was prepared according to example 4.

[0232] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.04 (s, 1H), 8.67 (d, J=7.5 Hz, 1H), 7.69 (d, J=2.0 Hz, 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, 1.1 Hz, 1H), 3.67 (dd, J=12.4, 1.1 Hz, 1H), 3.49 (dd, J=12.5, 1.2 Hz, 1H), 3.07 (ddd, J=9.4, 7.5, 1.9 Hz, 1H), 2.39-2.27 (m, 1H), 2.29-2.14 (m, 1H), 1.90-1.71 (m, 3H), 1.13 (s, 3H).

[0233] LCMS (ESI+APCI) m/z: 467.39

Example 24 Preparation of (R)N-(2-benzoyl-4-chlorophenyl)-1-(2-chlorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0234] The compound was prepared according to example 4.

[0235] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.04 (s, 1H), 8.62 (d, J=7.5 Hz, 1H), 7.68-7.55 (m, 5H), 7.56-7.46 (m, 2H), 7.26 (dd, J=4.5, 2.2 Hz, 2H), 7.15-7.05 (m, 2H), 3.98 (d, J=12.4 Hz, 1H), 3.49 (d, J=12.4 Hz, 1H), 3.11 (ddd, J=9.5, 6.4, 3.2 Hz, 1H), 2.36-2.22 (m, 2H), 1.90-1.76 (m, 2H), 1.73 (ddd, J=12.6, 7.5, 6.2 Hz, 1H), 1.08 (s, 3H).

[0236] LCMS (ESI+APCI) m/z: 467.39

Example 25 Preparation of (R)N-(2-benzoyl-4-chlorophenyl)-1-(3-fluorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0237] The compound was prepared according to example 4.

[0238] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.04 (s, 1H), 8.62 (d, J=7.5 Hz, 1H), 7.79 (d, J=2.0 Hz, 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, 2.0 Hz, 2H), 3.74 (dt, J=12.3, 1.0 Hz, 1H), 3.64-3.56 (m, 1H), 3.20 (ddd, J=9.6, 7.8, 1.8 Hz, 1H), 2.41-2.28 (m, 2H), 2.00-1.80 (m, 2H), 1.77 (dt, J=12.8, 7.0 Hz, 1H), 1.49 (s, 3H).

[0239] LCMS (ESI+APCI) m/z: 450.94

Example 26 Preparation of (R)N-(2-benzoyl-4-chlorophenyl)-1-(4-fluorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0240] The compound was prepared according to example 4.

[0241] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.04 (s, 1H), 8.66 (d, J=7.5 Hz, 1H), 7.70 (d, J=2.1 Hz, 1H), 7.66-7.46 (m, 6H), 7.32 (ddd, J=7.6, 4.2, 1.2 Hz, 2H), 7.17-7.07 (m, 2H), 3.84 (dd, J=12.3, 1.1 Hz, 1H), 3.22 (dt, J=12.4, 1.2 Hz, 1H), 2.94 (td, J=9.5, 1.9 Hz, 1H), 2.29 (ddq, J=12.8, 9.6, 7.2 Hz, 1H), 2.21-2.01 (m, 2H), 1.71 (ddtd, J=13.1, 8.8, 6.9, 1.9 Hz, 1H), 1.57 (dt, J=13.1, 7.1 Hz, 1H), 1.01 (s, 3H).

[0242] LCMS (ESI+APCI) m/z: 450.94

Example 27 Preparation of (R)N-(2-benzoyl-4-chlorophenyl)-1-(2-fluorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0243] The compound was prepared according to example 4.

[0244] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.04 (s, 1H), 8.66 (d, J=7.5 Hz, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.66-7.46 (m, 7H), 7.36 (tdd, J=7.4, 5.6, 1.9 Hz, 1H), 7.22 (ddd, J=9.3, 7.5, 2.1 Hz, 1H), 7.02 (td, J=7.5, 2.1 Hz, 1H), 4.39 (dd, J=12.5, 1.0 Hz, 1H), 3.72 (dd, J=12.3, 1.0 Hz, 1H), 2.96 (ddd, J=11.7, 9.5, 5.7 Hz, 1H), 2.53 (dt, J=13.1, 7.0 Hz, 1H), 2.24-2.15 (m, 1H), 1.99-1.85 (m, 1H), 1.62 (dt, J=13.3, 7.0 Hz, 1H), 1.37 (s, 3H), 1.34 (ddt, J=13.4, 11.6, 6.8 Hz, 1H).

[0245] LCMS (ESI+APCI) m/z: 450.94

Example 28 Preparation of (R)N-(2-benzoyl-4-chlorophenyl)-1-(3-methylbenzyl)-2-methylpyrrolyl-2-carboxamide

[0246] The compound was prepared according to example 4.

[0247] .sup.1H NMR (500 MHz, CDCl.sub.3) 9.82 (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=2.9 Hz, 2H), 7.12-7.01 (m, 2H), 4.13 (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).

Example 29 Preparation of (R)N-(2-benzoyl-4-chlorophenyl)-1-(4-methylbenzyl)-2-methylpyrrolyl-2-carboxamide

[0248] The compound was prepared according to example 4.

[0249] .sup.1H NMR (500 MHz, CDCl3) 8.91 (s, 1H), 7.87 (s, 1H), 7.76-7.70 (m, 2H), 7.60 (d, J=14.8 Hz, 2H), 7.50 (s, 1H), 7.45-7.37 (m, 2H), 7.15-7.09 (m, 4H), 4.00 (s, 1H), 2.88 (s, 1H), 2.79 (s, 1H), 2.34-2.29 (m, 3H), 2.24 (d, J=5.4 Hz, 2H), 1.83 (s, 1H), 1.76 (s, 1H), 1.67 (s, 1H), 1.63-1.59 (m, 3H).

Example 30 Preparation of (R)N-(2-benzoyl-4-chlorophenyl)-1-(2-methylbenzyl)-2-methylpyrrolyl-2-carboxamide

[0250] The compound was prepared according to example 4.

[0251] .sup.1H NMR (500 MHz, CDCl3) 7.74 (d, J=8.8 Hz, 2H), 7.69-7.62 (m, 2H), 7.46 (d, J=6.6 Hz, 2H), 7.43-7.37 (m, 2H), 7.27 (s, 1H), 7.17 (t, J=6.3 Hz, 3H), 3.45 (d, J=5.0 Hz, 2H), 2.89 (s, 1H), 2.70 (s, 1H), 2.32-2.23 (m, 3H), 2.09 (s, 1H), 1.79 (d, J=13.1 Hz, 2H), 1.68 (s, 1H), 1.54-1.46 (m, 3H).

Example 31 Preparation of (R)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-difluorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0252] The compound was prepared according to example 4. .sup.1H NMR (500 MHz, CDCl3) 9.50 (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=7.0 Hz, 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).

Example 32 Preparation of (R)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dimethyl benzyl)-2-methylpyrrolyl-2-carboxamide

[0253] The compound was prepared according to example 4.

[0254] .sup.1H NMR (500 MHz, CDCl3) 9.85 (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).

Example 33 Preparation of (R)N-(2-benzoyl-4-chlorophenyl)-1-(2,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0255] The compound was prepared according to example 4.

[0256] .sup.1H NMR (500 MHz, CDCl3) 7.88 (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=10.7 Hz, 2H), 6.09 (s, 1H), 3.40 (s, 1H), 3.25 (s, 1H), 2.81 (s, 1H), 2.23 (d, J=8.9 Hz, 2H), 1.78 (d, J=16.1 Hz, 2H), 1.67 (s, 1H), 1.42-1.36 (m, 3H).

Example 34 Preparation of (R)N-(2-benzoyl-4-chlorophenyl)-1-(3,5-difluorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0257] The compound was prepared according to example 4.

[0258] .sup.1H NMR (500 MHz, CDCl.sub.3) 9.57 (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).

Example 35 Preparation of (R)N-(2-benzoyl-4-chlorophenyl)-1-(2,3-difluorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0259] The compound was prepared according to example 4.

[0260] .sup.1H NMR (500 MHz, CDCl.sub.3) 9.99 (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).

Example 36 Preparation of (R)N-(2-benzoyl-4-chlorophenyl)-1-(2,5-difluorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0261] The compound was prepared according to example 4.

[0262] .sup.1H NMR (500 MHz, CDCl3) 9.94 (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), 1.77 (s, 1H), 1.68-1.66 (m, 3H).

Example 37 Preparation of (R)N-(2-benzoyl-4-chlorophenyl)-1-(2,6-difluorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0263] The compound was prepared according to example 4.

[0264] .sup.1H NMR (500 MHz, CDCl.sub.3) 9.71 (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).

Example 38 Preparation of (R)N-(2-benzoyl-4-chlorophenyl)-1-(2,6-difluoro-4-chlorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0265] The compound was prepared according to example 4.

[0266] .sup.1H NMR (500 MHz, CDCl.sub.3) 9.67 (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).

Example 39 Preparation of (R)N-(2-benzoyl-4-chlorophenyl)-1-(2,6-difluorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0267] The compound was prepared according to example 4.

[0268] .sup.1H NMR (500 MHz, CDCl.sub.3) 9.71 (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).

Example 40 Preparation of (R)N-(2-benzoyl-4-chlorophenyl)-1-(2,4,6-trimethyl benzyl)-2-methylpyrrolyl-2-carboxamide

[0269] The compound was prepared according to example 4.

[0270] .sup.1H NMR (500 MHz, CDCl3) 7.88 (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, 1H), 3.43 (s, 1H), 3.20 (s, 1H), 2.82 (s, 1H), 2.45-2.30 (m, 9H), 2.20 (d, J=22.6 Hz, 2H), 1.78 (d, J=19.9 Hz, 2H), 1.67 (s, 1H), 1.47-1.26 (m, 3H).

Example 41 Preparation of (R)N-(2-benzoyl-4-chlorophenyl)-1-(2-fluoro-6-chloro-benzyl)-2-methylpyrrolyl-2-carboxamide

[0271] The compound was prepared according to example 4.

[0272] .sup.1H NMR (500 MHz, CDCl.sub.3) 9.81 (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).

Example 42 Preparation of (R)N-(2-benzoyl-4-chlorophenyl)-1-(3-cyanobenzyl)-2-methylpyrrolyl-2-carboxamide

[0273] The compound was prepared according to example 4.

[0274] .sup.1H NMR (500 MHz, CDCl.sub.3) 7.81 (s, 1H), 7.74-7.66 (m, 3H), 7.60-7.54 (m, 4H), 7.47 (d, J=15.1 Hz, 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=7.3 Hz, 2H), 1.68 (s, 1H), 1.47-1.38 (m, 3H).

Example 43 Preparation of (R)N-(2-benzoyl-4-chlorophenyl)-1-(4-trifluoromethyl benzyl)-2-methylpyrrolyl-2-carboxamide

[0275] The compound was prepared according to example 4.

[0276] .sup.1H NMR (500 MHz, CDCl.sub.3) 9.74 (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).

Example 44 Preparation of (R)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dioxolobenzyl)-2-methylpyrrolyl-2-carboxamide

[0277] The compound was prepared according to example 4.

[0278] .sup.1H NMR (500 MHz, CDCl.sub.3) 7.75 (d, J=9.3 Hz, 2H), 7.71-7.65 (m, 2H), 7.46 (d, J=5.0 Hz, 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).

Example 45

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

[0279] The compound was prepared according to example 4.

[0280] .sup.1H NMR (500 MHz, CDCl.sub.3) 9.92 (s, 1H), 7.73 (d, J=4.4 Hz, 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, 2.1 Hz, 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).

Example 46 Preparation of (R)N-(2-benzoyl-3-tolyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0281] The compound was prepared according to example 4.

[0282] .sup.1H NMR (500 MHz, CDCl.sub.3) 9.44 (s, 3H), 7.73-7.70 (m, 6H), 7.68 (s, 3H), 7.66 (s, 3H), 7.46 (s, 3H), 7.43-7.37 (m, 6H), 7.33 (s, 3H), 7.17 (s, 3H), 7.07 (d, J=8.1 Hz, 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=45.0 Hz, 5H), 1.60-1.55 (m, 9H).

Example 47 Preparation of (R)N-(2-benzoylphenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0283] The compound was prepared according to example 4.

[0284] .sup.1H NMR (500 MHz, CDCl.sub.3) 9.37 (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).

Example 48 Preparation of (R)N-(2-(4-chlorobenzoyl)phenyl)-1-(3,4-dichloro benzyl)-2-methylpyrrolyl-2-carboxamide

[0285] The compound was prepared according to example 4.

[0286] .sup.1H NMR (500 MHz, CDCl.sub.3) 7.80 (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=14.6 Hz, 2H), 7.08 (s, 1H), 6.93 (s, 1H), 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).

Example 49 Preparation of (R)N-(2-(2-chlorobenzoyl)-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0287] The compound was prepared according to example 4.

[0288] .sup.1H NMR (500 MHz, CDCl.sub.3) 8.28 (s, 1H), 7.82 (s, 1H), 7.70 (s, 1H), 7.54 (s, 1H), 7.49 (s, 1H), 7.43 (d, J=15.8 Hz, 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).

Example 50 Preparation of (R)N-(2-(2-chlorobenzoyl)-4-bromophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0289] The compound was prepared according to example 4.

[0290] .sup.1H NMR (500 MHz, CDCl.sub.3) 8.50 (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=7.9 Hz, 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).

Example 51 Preparation of (R)N-(2-acetyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0291] The compound was prepared according to example 4.

[0292] .sup.1H NMR (500 MHz, CDCl.sub.3) 7.92 (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).

Example 52 Preparation of (R)N-(2-propionyl-4-chlorophenyl)-1-(3,4-dichloro benzyl)-2-methylpyrrolyl-2-carboxamide

[0293] The compound was prepared according to example 4.

[0294] .sup.1H NMR (500 MHz, CDCl.sub.3) 7.98 (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).

Example 53 Preparation of (R)N-(2-(2-methylpropionyl)-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0295] The compound was prepared according to example 4.

[0296] .sup.1H NMR (500 MHz, CDCl.sub.3) 7.93 (s, 1H), 7.64 (s, 1H), 7.55 (s, 1H), 7.27 (d, J=0.8 Hz, 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=26.3 Hz, 2H), 1.66 (s, 1H), 1.47-1.39 (m, 3H), 1.37-1.35 (m, 3H), 1.35 (s, 3H).

Example 54 Preparation of (R)N-(2-(2,2-dimethylpropionyl)-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0297] The compound was prepared according to example 4.

[0298] .sup.1H NMR (500 MHz, CDCl.sub.3) 7.81 (s, 1H), 7.52 (s, 1H), 7.46 (d, J=10.3 Hz, 2H), 7.28 (s, 1H), 7.23 (s, 1H), 7.00 (s, 1H), 3.51 (d, J=11.3 Hz, 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).

Example 55 Preparation of (R)N-(2-trifluoromethylformyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0299] The compound was prepared according to example 4.

[0300] .sup.1H NMR (500 MHz, CDCl.sub.3) 8.05 (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).

Example 56 Preparation of (R)N-(2-(2-thienylformyl)-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0301] The compound was prepared according to example 4.

[0302] .sup.1H NMR (500 MHz, CDCl.sub.3) 9.32 (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, 14.1 Hz, 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).

Example 57 Preparation of (R)N-(2-(3-thienylformyl)-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0303] The compound was prepared according to example 4.

[0304] .sup.1H NMR (500 MHz, CDCl.sub.3) 8.74 (s, 1H), 7.95 (s, 1H), 7.67 (d, J=9.2 Hz, 2H), 7.60 (s, 1H), 7.40 (s, 1H), 7.28 (d, J=9.1 Hz, 2H), 7.19 (d, J=5.0 Hz, 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).

Example 58

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

[0305] The compound was prepared according to example 4.

[0306] .sup.1H NMR (500 MHz, CDCl.sub.3) 8.66 (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=2.0 Hz, 2H), 2.21 (d, J=5.3 Hz, 2H), 1.88 (s, 1H), 1.79 (s, 1H), 1.73 (d, J=24.0 Hz, 2H), 1.53-1.43 (m, 3H), 1.11-1.00 (m, 3H).

Example 59

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

[0307] The compound was prepared according to example 4.

[0308] .sup.1H NMR (500 MHz, CDCl.sub.3) 9.05 (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), 2.51 (s, 8H), 2.45 (d, J=9.2 Hz, 13H), 2.14 (s, 7H), 1.77 (d, J=18.6 Hz, 11H), 1.66 (s, 9H), 1.63-1.60 (m, 21H), 1.13-1.01 (m, 21H).

Example 60 Preparation of (S)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide

[0309] 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 and reacted at 10-30 C. for 15 min-1 h. Then water and dichloromethane were added and the aqueous phase was extracted three times with dichloromethane. The combined organic lays were washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated under normal pressure to remove dichloromethane to afford 7 g of (S)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide in a yield of 95%.

[0310] .sup.1H NMR (400 MHz, CDCl.sub.3) 11.76 (s, 1H), 8.65 (d, J=8.7 Hz, 1H), 7.86-7.40 (m, 8H), 7.22-7.13 (m, 2H), 3.79 (d, J=13.5 Hz, 1H), 3.39 (d, J=13.6 Hz, 1H), 3.15 (t, J=7.4 Hz, 1H), 2.39 (dd, J=15.9, 7.9 Hz, 1H), 2.23-2.14 (m, 1H), 1.95-1.75 (m, 3H), 1.39 (s, 3H).

[0311] .sup.13C NMR (125 MHz, CDCl.sub.3) 197.1, 176.5, 139.2, 138.4, 137.9, 133.4, 132.9, 132.3, 132.2, 130.8, 130.6, 130.1, 130.1, 128.5, 127.9, 127.2, 125.9, 122.8, 68.8, 53.5, 51.3, 40.1, 22.7, 16.4.

Example 61 Preparation of (S)N-(2-benzoyl-4-chlorophenyl)-1-benzyl-2-methylpyrrolyl-2-carboxamide

[0312] 3 g of (S)N-(2-benzoyl-4-chlorophenyl)-1-benzyl-2-methylpyrrolyl-2-carboxamide (yield: 96%) was obtained by the substantially same preparation method as example 60.

[0313] .sup.1H NMR (500 MHz, CDCl.sub.3) 11.52 (s, 1H), 8.58 (d, J=8.9 Hz, 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=13.0 Hz, 1H), 3.40 (d, J=13.1 Hz, 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).

[0314] .sup.13C NMR (125 MHz, CDCl.sub.3) 196.7, 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.

Example 62 Preparation of (S)N-(2-benzoyl-4-chlorophenyl)-1-phenylethyl-2-methylpyrrolyl-2-carboxamide

[0315] 4 g of (S)N-(2-benzoyl-4-chlorophenyl)-1-benzyl-2-methylpyrrolyl-2-carboxamide in a yield of 92% was obtained by the substantially same preparation method as example 60.

[0316] .sup.1H NMR (500 MHz, CDCl.sub.3) 11.60 (s, 1H), 8.57 (d, J=9.0 Hz, 1H), 7.73 (d, J=7.6 Hz, 2H), 7.60 (t, J=7.4 Hz, 1H), 7.52-7.40 (m, 4H), 7.17-7.05 (m, 3H), 6.96 (d, J=6.7 Hz, 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).

[0317] .sup.13C NMR (125 MHz, CDCl.sub.3) 196.6, 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.

Example 63 Preparation of (R)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dimethoxy benzyl)-2-methylpyrrolyl-2-carboxamide

[0318] The compound was prepared according to example 4.

[0319] .sup.1H NMR (500 MHz, CDCl.sub.3) 11.64 (s, 1H), 8.56 (d, J=9.0 Hz, 1H), 7.73-7.69 (m, 2H), 7.64-7.59 (m, 1H), 7.52-7.48 (m, 3H), 7.45 (d, J=2.5 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H), 6.83 (dd, J=8.2, 1.9 Hz, 1H), 6.58 (d, J=8.2 Hz, 1H), 3.79 (s, 3H), 3.77 (s, 3H), 3.37 (d, J=13.0 Hz, 1H), 3.14 (td, J=8.1, 7.6, 4.1 Hz, 1H), 2.43-2.36 (m, 1H), 2.18-2.08 (m, 1H), 1.85-1.69 (m, 4H), 1.39 (s, 3H).

[0320] .sup.13C NMR (126 MHz, CDCl.sub.3) 196.8, 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.

Example 64 Preparation of (R)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dibromo benzyl)-2-methylpyrrolyl-2-carboxamide

[0321] The compound was prepared according to example 4.

[0322] .sup.1H NMR (500 MHz, CDCl.sub.3) 11.72 (s, 1H), 8.63 (d, J=8.7 Hz, 1H), 7.83 (d, J=1.9 Hz, 1H), 7.76 (dd, J=8.2, 1.4 Hz, 2H), 7.65-7.62 (m, 1H), 7.55-7.47 (m, 4H), 7.31 (d, J=8.2 Hz, 1H), 7.18 (d, J=8.2 Hz, 1H), 3.77 (d, J=13.5 Hz, 1H), 3.38 (d, J=13.5 Hz, 1H), 3.16 (t, J=8.1 Hz, 1H), 2.40 (q, J=8.1 Hz, 1H), 2.23-2.13 (m, 1H), 1.91-1.75 (m, 3H), 1.39 (s, 3H).

[0323] .sup.13C NMR (126 MHz, CDCl.sub.3) 197.0, 176.5, 140.0, 138.4, 137.9, 133.8, 133.4, 133.3, 133.0, 132.2, 130.1, 128.8, 128.5, 127.2, 125.9, 124.7, 122.9, 122.8, 68.8, 53.4, 51.3, 40.1, 22.6, 16.4.

Example 65

[0324] Preparation of Nickel Chelate

[0325] 5 g of (R)N-(2-benzoyl-4-chlorophenyl)-1-ethyl-2-methylpyrrolyl-2-carboxamide (13.48 mmol), 6.68 g of 3-amino 3-phenylpropionic acid (40.44 mmol) and 4.77 g of nickel acetate (26.96 mmol) were dissolved in 200 ml methanol and 15.13 g of potassium t-butoxide (134.82 mmol) was added. The reaction system was heated to 60-90 C. for 6-12 h, and then water and dichloromethane were added. The aqueous phase was extracted three times with dichloromethane. The combined organic lays were washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated under normal pressure to remove dichloromethane to obtain 6.8 g of nickel chelate in a yield of 87%. mp 174-176 C. [].sub.20.sup.D=2531.8 (c=0.044, CHCl.sub.3).

[0326] .sup.1H NMR (400 MHz, Methanol-d.sub.4) 8.18 (d, J=9.1 Hz, 1H), 7.71-7.46 (m, 9H), 7.31 (dd, J=9.1, 2.6 Hz, 1H), 7.20 (d, J=7.6 Hz, 1H), 6.72 (d, J=2.6 Hz, 1H), 4.60 (d, J=3.7 Hz, 1H), 3.23 (td, J=12.3, 11.3, 7.1 Hz, 1H), 2.93 (dd, J=17.8, 2.8 Hz, 1H), 2.80 (t, J=9.2 Hz, 1H), 2.69 (dd, J=17.8, 4.1 Hz, 1H), 2.40 (dq, J=14.5, 7.3 Hz, 1H), 2.23 (dq, J=13.8, 6.9 Hz, 1H), 2.02-1.91 (m, 1H), 1.87 (t, J=7.3 Hz, 3H), 1.80-1.45 (m, 3H), 1.10 (s, 3H).

[0327] .sup.13C NMR (150 MHz, CDCl.sub.3) 182.1, 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.

[0328] LRMS (ESI+APCI) m/z: 574.1, HRMS (ESI) m/z: found: 574.1405, calcd 574.1402 for C.sub.30H.sub.30ClN.sub.3NiO.sub.3.sup.+ [M+H].sup.+.

Example 66

Preparation of (S)-3-amino-3-phenylpropionic Acid

[0329] Nickel chelate was dissolved in methanol and concentrated hydrochloric acid was added. The reaction system was heated to 60-100 C. for 15 minutes-2 hours, then water and dichloromethane were added to the reaction system. The aqueous phase was extracted three times with dichloromethane. The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated under normal pressure to remove dichloromethane to obtain 800 mg of (S)-3-amino-3-phenylpropionic acid in a yield of 92%.

[0330] mp=223-224 C. [].sub.20.sup.D=12 (c=0.1, H.sub.2O).

[0331] .sup.1H NMR (500 MHz, D.sub.2O) 7.58-7.41 (m, 5H), 4.70 (t, J=7.3 Hz, 1H), 3.11-2.86 (m, 2H).

[0332] .sup.13C NMR (125 MHz, D.sub.2O) 175.93, 135.66, 129.38, 129.27, 126.91, 52.29, 39.48.

[0333] LRMS (ESI+APCI) m/z: 166.1, HRMS (ESI) m/z: found: 166.0858, calcd 166.0863 for C.sub.9H.sub.11NO.sup.2+ [M+H].sup.+

Example 67

Preparation of (S)-3-tert-butoxycarbonylamino3-phenylpropionic Acid

[0334] (S)-3-amino3-phenylpropionic acid (0.33 g, 2 mmol) was dissolved in 3 mL saturated NaHCO.sub.3 and di-t-butyl carbonate (0.52 g, 2.2 mmol) was slowly added and reacted at room temperature for 24 h. Then the mixture was adjusted to pH 2-3 with 1 N aqueous solution of hydrochloric acid. The aqueous phase was extracted three times with ethyl acetate. Then the combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to obtain 0.52 g of (S)-3-tert-butoxycarbonylamino3-phenylpropionic acid (98%).

[0335] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.34-7.24 (m, 5H), 5.48 (s, br, 1H), 5.11-4.93 (m, 1H), 2.84 (s, 2H), 1.41 (s, br, 9H).

Example 68

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

[0336] (S)-3-tert-butoxycarbonylamino3-phenylpropanamide (0.40 g, 1.5 mmol) was dissolved in 5 mL THF under N.sub.2 and BH.sub.3.THF (3 mL, 1 M/mL) was slowly added dropwise and then reacted for 2 h. An appropriate amount of acetone was added to consume excessive BH.sub.3. Then saturated sodium bicarbonate solution was added and the aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to obtain 0.39 g of tert-butyl (S)N-(3-hydroxy-1-phenylpropyl)carbamate (104%).

Example 69

Preparation of tert-butyl (S)N-(3-O-1-phenylpropyl)carbamate

[0337] At 0 C., tert-butyl (S)N-(3-hydroxy-1-phenylpropyl)carbamate (0.39 g, 1.5 mmol) was dissolved in 10 mL dichloromethane and Dess Martin oxidant (0.76 g, 1.8 mmol) was slowly added and reacted at room temperature for 2 h. Then saturated sodium bicarbonate solution was added and the aqueous phase was extracted three times with dichloromethane. The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and evaporated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate=3:1) to obtain 0.34 g of tert-butyl (S)N-(3-O-1-phenylpropyl)carbamate (92%).

Example 70 Preparation of tert-butyl (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]-1phenylpropyl}carbamate

[0338] (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 1,2-dichloroethane at room temperature and tert-butyl (S)N-(3-O-1-phenylpropyl)carbamate (0.25 g, 1 mmol), glacial acetic acid (12 L, 0.2 mmol), and then sodium triacetoxyborohydride (0.32 g, 1.5 mmol) were added and reacted at room temperature for 12 h. The mixture was adjusted to pH 11-12 with 2 M sodium hydroxide solution and the aqueous phase was extracted three times with dichloromethane. The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by column chromatography (dichloromethane:methanol=15:1) to obtain 0.33 g of tert-butyl (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]-1phenylpropyl}carbamate (71%). LRMS (ESI+APCI) m/z: 468.3.

Example 71 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

[0339] Tert-butyl (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]-1phenylpropyl}carbamate (93.4 mg, 0.2 mmol) was dissolved in 5 mL methanol at 0 C. and 4 N dioxane hydrochloride solution (5 ml) was added slowly at room temperature for 3 h. The mixture was evaporated to obtain a corresponding amine intermediate which was then dissolved in 5 mL dichloromethane. Triethylamine (138.7 L, 1 mmol) was added, followed by adding 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). The mixture was reacted at room temperature for 12 h and then adjusted to pH 11-12 with 2M sodium hydroxide solution. The aqueous phase was extracted three times with dichloromethane. The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and evaporated. The crude product was purified by column chromatography (dichloromethane:methanol=10:1) to obtain 76.9 mg 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 (75%, ee>98.2%).

[0340] [].sup.25.sub.D=28.4 (c=0.5, CHCl.sub.3).

[0341] .sup.1H NMR (400 MHz, CDCl.sub.3) [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=8 Hz, 2H), 2.28-1.64 (m, 19H), 1.37 (d, J=4 Hz, 6H).

[0342] .sup.13C NMR (151 MHz, CDCl.sub.3) 173.71, 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 (J .sup.13C-.sup.19F 6 Hz), 32.82, 32.79, 32.63 (J .sup.13C-.sup.19F 4.5 Hz), 26.66, 26.62, 25.98 (J .sup.13C-.sup.19F 9 Hz), 25.89 (J .sup.13C-.sup.19F 9 Hz), 25.80, 21.63, 13.07.

[0343] LRMS (ESI+APCI) m/z [M+H].sup.+: 514.3, HRMS (ESI) m/z: calcd for C.sub.29H.sub.42F.sub.2N.sub.5O.sup.+ [M+H].sup.+: 514.3552, found: 514.3551.

Example 72

Preparation of nickel chelate of 3-amino-3-(2-fluoro)phenylpropionic Acid

[0344] The preparation process was substantially the same as those in example 65. 3-amino-3-phenylpropionic acid was replaced by 3-amino-3-(2-fluoro)phenylpropionic acid to obtain nickel chelate of 3-amino-3-(2-fluoro)phenylpropionic acid in a yield of 92%.

[0345] mp=180-181 C. [].sup.20.sub.D=3281.3 (c=0.048, CHCl.sub.3).

[0346] .sup.1H NMR (400 MHz, Methanol-d.sub.4) 8.21 (d, J=9.1 Hz, 1H), 7.69-7.50 (m, 5H), 7.45-7.35 (m, 3H), 7.30 (dd, J=9.1, 2.6 Hz, 1H), 7.12-7.05 (m, 1H), 6.65 (d, J=2.6 Hz, 1H), 4.71 (t, J=3.3 Hz, 1H), 3.26-3.14 (m, 1H), 2.93-2.82 (m, 2H), 2.73 (dd, J=18.0, 4.4 Hz, 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).

[0347] .sup.13C NMR (150 MHz, CDCl.sub.3) 181.5, 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.

[0348] LRMS (ESI+APCI) m/z: 592.2, HRMS (ESI) m/z: found: 592.1311, calcd 592.1308 for C.sub.30H.sub.29ClFN.sub.3NiO.sub.3.sup.+ [M+H].sup.+.

Example 73

Preparation of nickel chelate of 3-amino-3-(4-chloro)phenylpropionic Acid

[0349] The preparation process was substantially the same as those in example 65. 3-amino-3-phenylpropionic acid was replaced by 3-amino-3-(4-chloro)phenylpropionic acid to obtain nickel chelate of 3-amino-3-(4-chloro)phenylpropionic acid in a yield of 93%.

[0350] mp=180-182 C. [].sup.20.sub.D=3512.5 (c=0.04, CHCl.sub.3).

[0351] .sup.1H NMR (500 MHz, Methanol-d.sub.4) 8.19 (d, J=9.1 Hz, 1H), 7.68-7.47 (m, 8H), 7.31 (dd, J=9.1, 2.6 Hz, 1H), 7.21 (dt, J=7.6, 1.5 Hz, 1H), 6.71 (d, J=2.6 Hz, 1H), 4.57 (t, J=3.3 Hz, 1H), 3.30-3.21 (m, 1H), 2.90 (dd, J=17.9, 2.8 Hz, 1H), 2.86-2.79 (m, 1H), 2.70 (dd, J=17.9, 4.1 Hz, 1H), 2.46-2.37 (m, 1H), 2.28-2.19 (m, 1H), 2.07-1.99 (m, 1H), 1.88 (t, J=7.3 Hz, 3H), 1.85-1.77 (m, 1H), 1.75-1.63 (m, 1H), 1.61-1.52 (m, 1H), 1.12 (s, 3H).

[0352] .sup.13C NMR (125 MHz, Methanol-d.sub.4) 183.6, 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.sub.30H.sub.29Cl.sub.2N.sub.3NiO.sub.3.sup.+ [M+H].sup.+.

Example 74

Preparation of nickel chelate of 3-amino-3-(3,4-dimethoxy)phenylpropionic Acid

[0353] The preparation process was substantially the same as those in example 65. 3-amino-3 phenylpropionic acid was replaced by 3-amino-3-(3,4-dimethoxy)phenylpropionic acid to obtain nickel chelate of 3-amino-3-(3,4dimethoxy)phenylpropionic acid in a yield of 93%.

[0354] mp=160-162 C. [].sup.20.sub.D=2768.3 (c=0.06, CHCl.sub.3).

[0355] .sup.1H NMR (400 MHz, Methanol-d.sub.4) 8.16 (d, J=9.1 Hz, 1H), 7.67-7.50 (m, 4H), 7.32 (dd, J=9.1, 2.6 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 7.20-7.13 (m, 1H), 7.09-7.03 (m, 1H), 6.89 (d, J=2.2 Hz, 1H), 6.71 (d, J=2.6 Hz, 1H), 4.56 (t, J=3.4 Hz, 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, 4.1 Hz, 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).

[0356] .sup.13C NMR (125 MHz, CDCl.sub.3) 182.0, 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.

[0357] LRMS (ESI+APCI) m/z: 634.2, HRMS (ESI) m/z: found: 634.1627, calcd 634.1613 for C.sub.32H.sub.34ClN.sub.3NiO.sub.5.sup.+ [M+H].sup.+.

Example 75

Preparation of nickel chelate of 3-amino-3-(4-isopropyl)phenylpropionic Acid

[0358] The preparation process was substantially the same as those in example 65. 3-amino-3-phenylpropionic acid was replaced by 3-amino-3-(4-isopropyl)phenylpropionic acid to obtain nickel chelate of 3-amino-3-(4-isopropyl)phenylpropionic acid in a yield of 92%.

[0359] mp=120-122 C. [].sup.20.sub.D=2287.5 (c=0.048, CHCl.sub.3).

[0360] .sup.1H NMR (400 MHz, Methanol-d.sub.4) 8.17 (d, J=9.2 Hz, 1H), 7.66-7.47 (m, 6H), 7.39 (d, J=8.0 Hz, 2H), 7.31 (dd, J=9.1, 2.6 Hz, 1H), 7.22-7.16 (m, 1H), 6.72 (d, J=2.6 Hz, 1H), 4.56 (d, J=3.5 Hz, 1H), 3.27-3.17 (m, 1H), 3.10-2.98 (m, 1H), 2.90 (dd, J=17.8, 2.8 Hz, 1H), 2.79 (t, J=9.1 Hz, 1H), 2.67 (dd, J=17.8, 4.2 Hz, 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=6.9 Hz, 6H), 1.10 (s, 3H).

[0361] .sup.13C NMR (125 MHz, CDCl.sub.3) 182.0, 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, 127.4, 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.

[0362] LRMS (ESI+APCI) m/z: 616.2, HRMS (ESI) m/z: found: 616.1886, calcd 616.1871 for C.sub.33H.sub.36ClN.sub.3NiO.sub.3.sup.+ [M+H].sup.+.

Example 76

Preparation of nickel chelate of 3-amino-3-(4-methoxy)phenylpropionic Acid

[0363] The preparation process was substantially the same as those in example 65. 3-amino-3-phenylpropionic acid was replaced by 3-amino-3-(4-methoxy)phenylpropionic acid to obtain nickel chelate of 3-amino-3-(4-methoxy)phenylpropionic acid in a yield of 93%.

[0364] mp=172-173 C. [].sup.20.sub.D=3139.6 (c=0.048, CHCl.sub.3).

[0365] .sup.1H NMR (500 MHz, Methanol-d.sub.4) 8.18 (d, J=9.1 Hz, 1H), 7.65-7.49 (m, 4H), 7.40-7.36 (m, 2H), 7.30 (dd, J=9.1, 2.6 Hz, 1H), 7.23-7.16 (m, 3H), 6.70 (d, J=2.6 Hz, 1H), 4.53 (t, J=3.5 Hz, 2H), 3.89 (s, 3H), 3.30-3.19 (m, 1H), 2.90-2.79 (m, 2H), 2.65 (dd, J=17.8, 4.2 Hz, 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).

[0366] .sup.13C NMR (125 MHz, Methanol-d.sub.4) 183.6, 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.

[0367] LRMS (ESI+APCI) m/z: 604.1, HRMS (ESI) m/z: found: 604.1518, calcd 604.1508 for C.sub.31H.sub.32ClN.sub.3NiO.sub.4.sup.+ [M+H].sup.+.

Example 77

Preparation of nickel chelate of 3-amino-3-(3-methoxy)phenylpropionic Acid

[0368] The preparation process was substantially the same as those in example 65. 3-amino-3-phenylpropionic acid was replaced by 3-amino-3-(3-methoxy)phenylpropionic acid to obtain nickel chelate of 3-amino-3-(3-methoxy)phenylpropionic acid in a yield of 90%.

[0369] mp=165-167 C. [].sup.20.sub.D=2850.0 (c=0.048, CHCl.sub.3).

[0370] .sup.1H NMR (500 MHz, Methanol-d.sub.4) 8.17 (d, J=9.1 Hz, 1H), 7.70-7.47 (m, 5H), 7.31 (dd, J=9.1, 2.6 Hz, 1H), 7.20-6.95 (m, 4H), 6.71 (d, J=2.6 Hz, 1H), 4.56 (t, J=3.4 Hz, 1H), 3.85 (s, 3H), 3.31-3.25 (m, 1H), 2.97-2.77 (m, 2H), 2.67 (dd, J=17.8, 4.1 Hz, 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).

[0371] .sup.13C NMR (125 MHz, Methanol-d.sub.4) 183.6, 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.

[0372] LRMS (ESI+APCI) m/z: 604.1, HRMS (ESI) m/z: found: 604.1518, calcd 604.1508 for C.sub.31H.sub.32ClN.sub.3NiO.sub.4.sup.+ [M+H].sup.+.

Example 78

Preparation of nickel chelate of 3-amino-3-(3-trifluoromethyl)phenylpropionic Acid

[0373] The preparation process was substantially the same as those in example 65. 3-amino-3-phenylpropionic acid was replaced by 3-amino-3-(3-trifluoromethyl) phenylpropionic acid to obtain nickel chelate of 3-amino-3-(3-trifluoromethyl)phenylpropionic acid in a yield of 50%.

[0374] mp=158-160 C. [].sup.20.sub.D=3280.6 (c=0.036, CHCl.sub.3).

[0375] .sup.1H NMR (500 MHz, Methanol-d.sub.4) 8.19 (d, J=9.2 Hz, 1H), 7.86 (dd, J=28.1, 4.2 Hz, 3H), 7.69-7.50 (m, 5H), 7.33 (dd, J=9.1, 2.7 Hz, 1H), 7.18 (d, J=7.7 Hz, 1H), 6.73 (d, J=2.6 Hz, 1H), 4.68 (t, J=3.3 Hz, 1H), 3.24-3.12 (m, 1H), 2.98 (dd, J=18.0, 2.9 Hz, 1H), 2.87-2.73 (m, 2H), 2.45-2.19 (m, 2H), 2.06-1.94 (m, 1H), 1.88 (t, J=7.3 Hz, 3H), 1.72-1.48 (m, 3H), 1.12 (s, 3H).

[0376] .sup.13C NMR (125 MHz, Methanol-d.sub.4) 183.6, 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.

[0377] LRMS (ESI+APCI) m/z: 642.1, HRMS (ESI) m/z: found: 642.1268, calcd 642.1276 for C.sub.31H.sub.29ClF.sub.3N.sub.3NiO.sub.3.sup.+ [M+H].sup.+.

Example 79

Preparation of nickel chelate of 3-amino-3-(3-pyridyl)propionic Acid

[0378] The preparation process was substantially the same as those in example 65. 3-amino-3-phenylpropionic acid was replaced by 3-amino-3-(3-pyridyl)propionic acid to obtain nickel chelate of 3-amino-3-(3-pyridyl)propionic acid in a yield of 80%.

[0379] mp=138-140 C. [].sup.20.sub.D=2835.4 (c=0.048, CHCl.sub.3).

[0380] .sup.1H NMR (400 MHz, Methanol-d.sub.4) 8.78 (d, J=2.5 Hz, 1H), 8.76 (dd, J=4.6, 1.4 Hz, 1H), 8.19 (d, J=9.2 Hz, 1H), 8.00-7.92 (m, 1H), 7.75-7.51 (m, 5H), 7.33 (dd, J=9.2, 2.6 Hz, 1H), 7.24 (d, J=7.7 Hz, 1H), 6.72 (d, J=2.6 Hz, 1H), 4.70 (t, J=3.6 Hz, 1H), 3.29-3.18 (m, 1H), 2.99 (dd, J=17.9, 2.9 Hz, 1H), 2.87-2.73 (m, 2H), 2.44-2.25 (m, 2H), 2.09-1.98 (m, 1H), 1.88 (t, J=7.3 Hz, 3H), 1.74-1.50 (m, 3H), 1.13 (s, 3H).

[0381] .sup.13C NMR (125 MHz, Methanol-d.sub.4) 183.4, 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.

[0382] LRMS (ESI+APCI) m/z: 575.1, HRMS (ESI) m/z: found: 575.1347, calcd 575.1354 for C.sub.29H.sub.29ClN.sub.4NiO.sub.3.sup.+ [M+H].sup.+.

Example 80

Preparation of nickel chelate of 3-amino-3-(2-thienyl)propionic Acid

[0383] The preparation process was substantially the same as those in example 65. 3-amino-3-phenylpropionic acid was replaced by 3-amino-3-(2-thienyl)propionic acid to obtain nickel chelate of 3-amino-3-(2-thienyl)propionic acid in a yield of 95%.

[0384] mp=145-146 C. [].sup.20.sub.D=2775.0 (c=0.048, CHCl.sub.3).

[0385] .sup.1H NMR (500 MHz, Methanol-d.sub.4) 8.16 (d, J=9.1 Hz, 1H), 7.72 (d, J=5.1 Hz, 1H), 7.68-7.48 (m, 4H), 7.35-7.25 (m, 2H), 7.19-7.11 (m, 2H), 6.70 (d, J=2.6 Hz, 1H), 4.72 (t, J=4.1 Hz, 1H), 3.39 (ddd, J=13.2, 11.5, 5.4 Hz, 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=7.3 Hz, 3H), 1.83-1.71 (m, 1H), 1.64-1.55 (m, 1H), 1.15 (s, 3H).

[0386] .sup.13C NMR (125 MHz, Methanol-d.sub.4) 183.6, 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.

[0387] LRMS (ESI+APCI) m/z: 580.1, HRMS (ESI) m/z: found: 580.0976, calcd 580.0966 for C.sub.28H.sub.28ClN.sub.3NiO.sub.3S.sup.+ [M+H].sup.+.

Example 81

Preparation of nickel chelate of 3-amino-3-(1-naphthyl)propionic Acid

[0388] The preparation process was substantially the same as those in example 65. 3-amino-3-phenylpropionic acid was replaced by 3-amino-3-(1-naphthyl)propionic acid to obtain nickel chelate of 3-amino-3-(1-naphthyl)propionic acid in a yield of 91%.

[0389] mp=145-147 C. [].sup.20.sub.D=2292.0 (c=0.05, CHCl.sub.3).

[0390] .sup.1H NMR (400 MHz, Methanol-d.sub.4) 8.19 (d, J=9.2 Hz, 1H), 8.14 (d, J=8.6 Hz, 1H), 8.02-7.94 (m, 3H), 7.68-7.51 (m, 7H), 7.33 (dd, J=9.1, 2.6 Hz, 1H), 7.31-7.26 (m, 1H), 6.75 (d, J=2.5 Hz, 1H), 4.75 (t, J=3.5 Hz, 1H), 3.10-3.03 (m, 1H), 3.03-2.93 (m, 1H), 2.78 (dd, J=17.9, 4.1 Hz, 1H), 2.72-2.64 (m, 1H), 2.43-2.30 (m, 1H), 2.22-2.11 (m, 1H), 1.86 (t, J=7.3 Hz, 3H), 1.71-1.59 (m, 1H), 1.39 (q, J=9.9 Hz, 1H), 1.22-1.05 (m, 2H), 1.01 (s, 3H).

[0391] .sup.13C NMR (150 MHz, Methanol-d.sub.4) 182.1, 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, 127.8, 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.

[0392] LRMS (ESI+APCI) m/z: 624.2, HRMS (ESI) m/z: found: 624.1576, calcd 624.1558 for C.sub.34H.sub.32ClN.sub.3NiO.sub.3.sup.+ [M+H].sup.+.

Example 82

Preparation of nickel chelate of nickel chelate of 3-aminobutyric Acid

[0393] The preparation process was substantially the same as those in example 65. 3-amino-3-phenylpropionic acid was replaced by 3-aminobutyric acid to obtain nickel chelate of 3-aminobutyric acid in a yield of 87%.

[0394] mp=240-242 C. [].sup.20.sub.D=4309.5 (c=0.042, CHCl.sub.3).

[0395] .sup.1H NMR (500 MHz, Methanol-d.sub.4) 8.14 (d, J=9.1 Hz, 1H), 7.64-7.43 (m, 4H), 7.27 (dd, J=9.1, 2.6 Hz, 1H), 6.98 (d, J=7.6 Hz, 1H), 6.65 (d, J=2.6 Hz, 1H), 4.34-4.23 (m, 1H), 3.62-3.52 (m, 1H), 3.44-3.35 (m, 1H), 3.29-3.16 (m, 1H), 2.50-2.28 (m, 5H), 2.21 (d, J=6.6 Hz, 3H), 2.11 (dd, J=17.5, 2.5 Hz, 1H), 1.94 (t, J=7.3 Hz, 3H), 1.87-1.78 (m, 1H), 1.27 (s, 3H).

[0396] .sup.13C NMR (125 MHz, Methanol-d.sub.4) 183.1, 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.

[0397] LRMS (ESI+APCI) m/z: 512.1, HRMS (ESI) m/z: found: 512.1259, calcd 512.1245 for C.sub.25H.sub.28ClN.sub.3NiO.sub.3.sup.+ [M+H].sup.+.

Example 83

Preparation of nickel chelate of 3-aminopentanoic Acid

[0398] The preparation process was substantially the same as those in example 65. 3-amino-3-phenylpropionic acid was replaced by 3-aminopentanoic acid to obtain nickel chelate of 3-aminopentanoic acid in a yield of 94%.

[0399] mp=248-250 C. [].sup.20.sub.D=4370.5 (c=0.044, CHCl.sub.3).

[0400] .sup.1H NMR (600 MHz, Methanol-d.sub.4) 8.18 (d, J=9.1 Hz, 1H), 7.59 (tdd, J=9.0, 5.2, 1.6 Hz, 2H), 7.55-7.50 (m, 1H), 7.46 (dt, J=7.0, 1.9 Hz, 1H), 7.28 (dd, J=9.1, 2.6 Hz, 1H), 6.92 (dd, J=7.6, 1.5 Hz, 1H), 6.62 (d, J=2.5 Hz, 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=7.3 Hz, 3H), 1.87-1.77 (m, 1H), 1.27 (s, 3H), 1.19 (t, J=7.4 Hz, 3H).

[0401] .sup.13C NMR (150 MHz, Methanol-d.sub.4) 183.2, 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.

[0402] LRMS (ESI+APCI) m/z: 526.1, HRMS (ESI) m/z: found: 526.1408, calcd 526.1402 for C.sub.26H.sub.30ClN.sub.3NiO.sub.3.sup.+ [M+H].sup.+.

Example 84

Preparation of nickel chelate of 3-aminoheptanoic Acid

[0403] The preparation process was substantially the same as those in example 65. 3-amino-3-phenylpropionic acid was replaced by 3-aminoheptanoic acid to obtain nickel chelate of 3-aminoheptanoic acid in a yield of 97%.

[0404] mp=110-112 C. [].sup.20.sub.D=3400.0 (c=0.046, CHCl.sub.3).

[0405] .sup.1H NMR (400 MHz, Methanol-d.sub.4) 8.17 (d, J=9.1 Hz, 1H), 7.65-7.42 (m, 4H), 7.29 (dd, J=9.1, 2.6 Hz, 1H), 6.96-6.86 (m, 1H), 6.61 (d, J=2.5 Hz, 1H), 4.18 (td, J=12.3, 6.7 Hz, 1H), 3.60-3.33 (m, 3H), 3.26-3.10 (m, 1H), 2.51-2.11 (m, 7H), 1.93 (t, J=7.3 Hz, 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=7.4 Hz, 3H).

[0406] .sup.13C NMR (125 MHz, Methanol-d.sub.4) 181.5, 172.7, 170.7, 141.4, 135.6, 132.9, 132.6, 130.2, 129.7, 129.2, 127.6, 126.3, 125.5, 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.

[0407] LRMS (ESI+APCI) m/z: 554.2, HRMS (ESI) m/z: found: 554.1720, calcd 554.1715 for C.sub.28H.sub.34ClN.sub.3NiO.sub.3.sup.+ [M+H].sup.+.

Example 85

Preparation of nickel chelate of 3-amino-5-methylhexanoic Acid

[0408] The preparation process was substantially the same as those in example 65. 3-amino-3-phenylpropionic acid was replaced by 3-amino-5-methylhexanoic acid to obtain nickel chelate of 3-amino-5-methylhexanoic acid in a yield of 91%.

[0409] mp=248-251 C. [].sup.20.sub.D=3029.5 (c=0.044, CHCl.sub.3).

[0410] .sup.1H NMR (400 MHz, Methanol-d.sub.4) 8.16 (d, J=9.1 Hz, 1H), 7.66-7.46 (m, 4H), 7.28 (dd, J=9.1, 2.6 Hz, 1H), 6.96 (dt, J=8.3, 1.4 Hz, 1H), 6.62 (d, J=2.6 Hz, 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, 2.5 Hz, 1H), 1.92 (t, J=7.3 Hz, 3H), 1.86-1.68 (m, 2H), 1.27 (s, 3H), 0.96 (d, J=6.6 Hz, 3H), 0.73 (d, J=6.5 Hz, 3H).

[0411] .sup.13C NMR (125 MHz, CDCl.sub.3) 181.5, 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.

[0412] LRMS (ESI+APCI) m/z: 554.2, HRMS (ESI) m/z: found: 554.1728, calcd 554.1715 for C.sub.28H.sub.34ClN.sub.3NiO.sub.3.sup.+ [M+H].sup.+.

Example 86

Preparation of nickel chelate of 3-amino-4-methylpentanoic Acid

[0413] The preparation process was substantially the same as those in example 65.

[0414] 3-amino-3-phenylpropionic acid was replaced by 3-amino-4-methylpentanoic acid to obtain nickel chelate of 3-amino-4-methylpentanoic acid in a yield of 76%.

[0415] mp=150-152 C. [].sup.20.sub.D=3242.9 (c=0.042, CHCl.sub.3).

[0416] .sup.1H NMR (400 MHz, Methanol-d.sub.4) 8.18 (d, J=9.1 Hz, 1H), 7.66-7.42 (m, 4H), 7.29 (dd, J=9.1, 2.6 Hz, 1H), 6.90 (dt, J=7.6, 1.0 Hz, 1H), 6.60 (d, J=2.6 Hz, 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, 3.3 Hz, 1H), 2.51-2.24 (m, 6H), 1.93 (t, J=7.3 Hz, 3H), 1.88-1.76 (m, 1H), 1.35 (d, J=6.7 Hz, 3H), 1.27 (s, 3H), 0.91 (d, J=6.6 Hz, 3H).

[0417] .sup.13C NMR (125 MHz, CDCl.sub.3) 181.5, 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.

[0418] LRMS (ESI+APCI) m/z: 540.1, HRMS (ESI) m/z: found: 540.1556, calcd 540.1558 for C.sub.27H.sub.32ClN.sub.3NiO.sub.3.sup.+ [M+H].sup.+.

Example 87

Preparation of nickel chelate of 3-amino-3-cyclopropylpropionic Acid

[0419] The preparation process was substantially the same as those in example 65. 3-amino-3-phenylpropionic acid was replaced by 3-amino-3-cyclopropylpropionic acid to obtain nickel chelate of 3-amino-3-cyclopropylpropionic acid in a yield of 93%.

[0420] mp=150-151 C. [].sup.20.sub.D=3892.1 (c=0.038, CHCl.sub.3).

[0421] .sup.1H NMR (600 MHz, Methanol-d.sub.4) 8.18 (dd, J=9.3, 2.9 Hz, 1H), 7.61-7.24 (m, 5H), 6.92 (d, J=7.7 Hz, 1H), 6.58 (d, J=2.6 Hz, 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).

[0422] .sup.13C NMR (150 MHz, Methanol-d.sub.4) 183.2, 177.1, 171.8, 142.1, 136.5, 133.9, 133.2, 131.7, 131.4, 130.6, 130.3, 128.8, 128.1, 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.

[0423] LRMS (ESI+APCI) m/z: 538.1, HRMS (ESI) m/z: found: 538.1413, calcd 538.1402 for C.sub.27H.sub.30ClN.sub.3NiO.sub.3.sup.+ [M+H].sup.+.

Example 88

Preparation of nickel chelate of 3-amino-3-cyclohexylpropionic Acid

[0424] The preparation process was substantially the same as those in example 65. 3-amino-3-phenylpropionic acid was replaced by 3-amino-3-cyclohexylpropionic acid to obtain nickel chelate of 3-amino-3-cyclohexylpropionic acid in a yield of 85%.

[0425] mp=155-157 C. [].sup.20.sub.D=2770.0 (c=0.04, CHCl.sub.3).

[0426] .sup.1H NMR (400 MHz, Methanol-d.sub.4) 8.17 (d, J=9.1 Hz, 1H), 7.63-7.42 (m, 4H), 7.28 (dd, J=9.1, 2.6 Hz, 1H), 6.95-6.86 (m, 1H), 6.58 (d, J=2.6 Hz, 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=13.1 Hz, 1H), 1.91 (t, J=7.3 Hz, 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).

[0427] .sup.13C NMR (125 MHz, CDCl.sub.3) 181.4, 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.

[0428] LRMS (ESI+APCI) m/z: 580.2, HRMS (ESI) m/z: found: 580.1876, calcd 580.1871 for C.sub.30H.sub.36ClN.sub.3NiO.sub.3.sup.+ [M+H].sup.+.

Example 89

Preparation of nickel chelate of 3-amino-4-(2,4,5-trifluorophenyl)butanoic Acid

[0429] The preparation process was substantially the same as those in example 65. 3-amino-3-phenylpropionic acid was replaced by 3-amino-4-(2,4,5-trifluorophenyl)butanoic acid to obtain nickel chelate of 3-amino-4-(2,4,5-trifluorophenyl)butanoic acid in a yield of 87%.

[0430] mp=140-141 C. [].sup.20.sub.D=2814.0 (c=0.05, CHCl.sub.3).

[0431] .sup.1H NMR (500 MHz, Methanol-d.sub.4) 8.15 (d, J=9.1 Hz, 1H), 7.62-7.48 (m, 2H), 7.46-7.34 (m, 2H), 7.28 (dd, J=9.1, 2.5 Hz, 1H), 7.12 (td, J=9.9, 6.6 Hz, 1H), 7.03 (ddd, J=10.7, 8.7, 6.7 Hz, 1H), 6.59 (d, J=2.6 Hz, 1H), 6.49-6.38 (m, 1H), 4.38 (dd, J=13.8, 6.9 Hz, 1H), 4.20 (ddd, J=13.4, 11.4, 5.7 Hz, 1H), 4.01-3.91 (m, 1H), 3.62 (tdd, J=6.9, 4.3, 2.5 Hz, 1H), 3.51-3.33 (m, 2H), 2.58-2.28 (m, 5H), 2.09 (dd, J=17.6, 2.6 Hz, 1H), 2.01 (t, J=7.3 Hz, 3H), 1.89-1.78 (m, 1H), 1.31 (s, 3H).

[0432] .sup.13C NMR (125 MHz, Methanol-d.sub.4) 183.4, 176.4, 173.6, 157.6 (ddd, J=245.1, 9.5, 2.2 Hz), 150.6 (dt, J=250.2, 13.8 Hz), 148.07 (ddd, J=244.1, 12.5, 3.1 Hz), 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, 5.0 Hz), 120.0 (dd, J=19.3, 5.9 Hz), 106.9 (dd, J=28.9, 21.2 Hz), 75.7, 64.0, 53.2, 50.9, 41.4, 39.2, 35.9, 22.6, 18.0, 15.6.

[0433] LRMS (ESI+APCI) m/z: 642.1, HRMS (ESI) m/z: found: 642.1287, calcd 642.1276 for C.sub.31H.sub.29ClF.sub.3N.sub.3NiO.sub.3.sup.+ [M+11].sup.+.

Example 90 Nickel (II)-(S)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide/(S)-2-amino-2-benzylacetic AcidSchiff Base Complex

[0434] Synthesis Method:

[0435] 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 methanol and DBU (149.4 L, 1.0 mmol) was added and reacted at 60 C. for 72 h. 5% of glacial acetic acid was added to quench the reaction. The mixture was extracted three times with dichloromethane and the combined organic lays were dried, evaporated under reduced pressure to remove solvent and purified by column chromatography (dichloromethane:methanol=20:1) to obtain red solids (136 mg in a yield of 98%).

[0436] mp: 116.3-117.5 C. [].sup.20.sub.D=2502 (c=1, CHCl.sub.3).

[0437] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.08 (d, J=2.1 Hz, 1H), 8.32 (d, J=9.3 Hz, 1H), 7.61-7.49 (m, 3H), 7.42-7.27 (m, 6H), 7.15-7.02 (m, 3H), 6.65 (d, J=7.7 Hz, 1H), 6.61 (d, J=2.6 Hz, 1H), 4.22 (t, J=5.2 Hz, 1H), 3.54 (dd, J=59.9, 13.0 Hz, 2H), 3.36-3.24 (m, 1H), 3.14 (dt, J=17.6, 6.8 Hz, 2H), 2.78 (dd, J=13.8, 5.4 Hz, 1H), 2.42-2.23 (m, 1H), 2.14-2.03 (m, 1H), 1.98 (dd, J=19.7, 9.7 Hz, 1H), 1.87-1.73 (m, 1H), 1.33 (s, 3H).

[0438] .sup.13C NMR (125 MHz, CDCl.sub.3) 180.5, 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.

[0439] MS (ESI, m/z): 704.0 [MH].sup..

Example 91 Nickel (II)-(R)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide/(R)-2-amino-2-(3-methoxybenzyl)acetic AcidSchiff Base Complex

[0440] Synthesis Method:

[0441] ligand (R)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichloro benzyl)-2-methylpyrrolyl-2-carboxamide (100.3 mg, 0.2 mmol), DL-3-methoxyphenyl alanine 2-23 (39 mg, 0.2 mmol) and anhydrous nickel acetate (35.3 mg, 0.2 mmol) were dissolved in 4 mL methanol and K.sub.2CO.sub.3 (138.1 mg, 1.0 mmol) was added and reacted at 60 C. for 24 h. 5% of glacial acetic acid was added to quench the reaction. The mixture was extracted three times with dichloromethane. The combined organic lays were dried, evaporated under reduced pressure to remove solvent and purified by column chromatography (dichloromethane:methanol=20:1) to obtain red solids (132 mg in a yield of 90%).

[0442] mp: 104.2-106.1 C. [].sup.20.sub.D=2923 (c=1, CHCl.sub.3).

[0443] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.08 (d, J=2.0 Hz, 1H), 8.33 (d, J=9.3 Hz, 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, 2.6 Hz, 1H), 6.88 (dd, J=8.3, 2.3 Hz, 1H), 6.67 (d, J=7.5 Hz, 1H), 6.60 (d, J=2.6 Hz, 2H), 6.55 (d, J=7.9 Hz, 1H), 4.21 (t, J=5.3 Hz, 1H), 3.65 (s, 3H), 3.55 (dd, J=59.3, 13.1 Hz, 2H), 3.45-3.31 (m, 1H), 3.26-3.03 (m, 2H), 2.81 (dd, J=13.8, 5.1 Hz, 1H), 2.46 (dq, J=14.1, 7.2 Hz, 1H), 2.25-2.11 (m, 1H), 2.07-1.96 (m, 1H), 1.95-1.78 (m, 1H), 1.35 (s, 3H).

[0444] .sup.13C NMR (125 MHz, CDCl.sub.3) 180.6, 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, 129.6, 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.

[0445] MS (ESI, m/z): 734.0 [MH].sup..

Example 92 Nickel (II)-(R)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide/(R)-2-amino-2-(3-methylbenzyl)acetic AcidSchiff Base Complex

[0446] According to a synthesis procedure similar to example 91, DL-3-methoxyphenyl alanine was replaced by DL-3-methylphenylalanine and red solids in a yield of 88% were obtained by column chromatography (dichloromethane:methanol=20:1).

[0447] mp: 105.3-106.8 C. [].sup.20.sub.D=1898 (c=1, CHCl.sub.3).

[0448] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.06 (d, J=1.5 Hz, 1H), 8.34 (d, J=9.3 Hz, 1H), 7.55 (dt, J=17.5, 7.4 Hz, 3H), 7.38 (t, J=7.5 Hz, 1H), 7.31 (t, J=6.7 Hz, 2H), 7.23 (t, J=7.5 Hz, 1H), 7.17-7.09 (m, 2H), 6.87 (d, J=7.8 Hz, 2H), 6.63 (dd, J=12.2, 5.1 Hz, 2H), 4.21 (t, J=5.1 Hz, 1H), 3.53 (dd, J=47.7, 13.1 Hz, 2H), 3.31 (td, J=12.6, 5.8 Hz, 1H), 3.11 (dd, J=13.7, 4.7 Hz, 2H), 2.75 (dd, J=13.7, 5.4 Hz, 1H), 2.47-2.31 (m, 1H), 2.27 (s, 3H), 2.13-2.06 (m, 1H), 1.99 (dd, J=19.4, 9.7 Hz, 1H), 1.84 (dt, J=14.9, 6.7 Hz, 1H), 1.33 (s, 3H).

[0449] .sup.13C NMR (125 MHz, CDCl.sub.3) 180.4, 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.

[0450] MS (ESI, m/z): 718.0 [MH].sup..

Example 93 Nickel (II)-(R)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide/(R)-2-amino-2-(4-fluorobenzyl)acetic AcidSchiff Base Complex C4

[0451] According to a synthesis procedure similar to example 91, DL-3-methoxyphenyl alanine was replaced by DL-4-fluorophenylalanine and red solids in a yield of 76% was obtained by column chromatography (dichloromethane:methanol=20:1).

[0452] mp: 235-236.8 C. [].sup.20.sub.D=2300 (c=1, CHCl.sub.3).

[0453] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.06 (d, J=1.5 Hz, 1H), 8.32 (d, J=9.3 Hz, 1H), 7.56 (p, J=7.5 Hz, 3H), 7.43 (t, J=7.3 Hz, 1H), 7.37-7.28 (m, 2H), 7.13 (dd, J=9.3, 2.5 Hz, 1H), 7.05 (d, J=7.0 Hz, 4H), 6.73 (d, J=7.5 Hz, 1H), 6.62 (d, J=2.5 Hz, 1H), 4.21 (t, J=5.0 Hz, 1H), 3.54 (dd, J=47.7, 13.0 Hz, 2H), 3.34 (td, J=12.6, 6.0 Hz, 1H), 3.20-3.01 (m, 2H), 2.74 (dd, J=14.0, 5.4 Hz, 1H), 2.45-2.26 (m, 1H), 2.26-2.12 (m, 1H), 2.00 (dd, J=19.3, 9.6 Hz, 1H), 1.90-1.83 (m, 1H), 1.35 (s, 3H).

[0454] .sup.13C NMR (125 MHz, CDCl.sub.3) 180.5, 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.

[0455] MS (ESI, m/z): 722.0 [MH].sup..

Example 94 Nickel (II)-(R)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide/(R)-2-amino-2-(3-methoxyphenyl)acetic AcidSchiff Base Complex

[0456] According to a synthesis procedure similar to example 91, DL-3-methoxyphenyl alanine was replaced by DL-3-methoxyphenylglycine and red solids in a yield of 70% were obtained by column chromatography (dichloromethane:methanol=20:1).

[0457] mp: 134.8-136.6 C. [].sup.20.sub.D=2183 (c=1, CHCl.sub.3).

[0458] .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

[0459] .sup.13C NMR (125 MHz, CDCl.sub.3) 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.

[0460] MS (ESI, m/z): 720.0 [MH].sup..

Example 95 Nickel (II)-(R)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolyl-2-carboxamide/(R)-2-amino-2-(3-bromophenyl)acetic AcidSchiff Base Complex

[0461] According to a synthesis procedure similar to example 91, DL-3-methoxyphenyl alanine was replaced by DL-3-bromophenylglycine and red solids in a yield of 85% were obtained by column chromatography (dichloromethane:methanol=20:1).

[0462] mp: 102.5-104.4 C. [].sup.20.sub.D=2069 (c=1, CHCl.sub.3).

[0463] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.18 (d, J=2.1 Hz, 1H), 8.22 (d, J=9.3 Hz, 1H), 8.15 (s, 1H), 7.80 (dd, J=8.2, 2.2 Hz, 1H), 7.57 (t, J=7.6 Hz, 1H), 7.50-7.38 (m, 3H), 7.32 (dd, J=18.2, 7.8 Hz, 2H), 7.15 (ddd, J=24.1, 12.7, 5.5 Hz, 3H), 6.67 (d, J=2.5 Hz, 1H), 6.13 (d, J=7.8 Hz, 1H), 4.71 (s, 1H), 4.04 (t, J=10.9 Hz, 1H), 3.72 (dd, J=78.9, 13.1 Hz, 2H), 3.41-3.29 (m, 1H), 3.14 (dd, J=21.0, 13.1 Hz, 1H), 2.50 (dd, J=13.7, 10.0 Hz, 1H), 2.30-2.04 (m, 2H), 1.58 (s, 1H), 1.50 (s, 3H), 1.25 (s, 1H).

[0464] .sup.13C NMR (125 MHz, CDCl.sub.3) 180.8, 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.

[0465] MS (ESI, m/z): 769.7 [MH].sup..

Example 96 Nickel (II)-(R)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichloro benzyl)-2-methylpyrrolyl-2-carboxamide/(R)-2-amino-3-(3,5-diiodo-4-hydroxyphenyl) propionic AcidSchiff Base Complex

[0466] According to a synthesis procedure similar to example 91, DL-3-methoxyphenylalanine was replaced by DL-2-amino-3-(3,5-diiodo-4-hydroxy phenyl)propionic acid and red solids in a yield of 90% were obtained by column chromatography (dichloromethane:methanol=20:1).

[0467] mp: 286.5-287.9 C. [].sup.20.sub.D=2038 (c=1, CHCl.sub.3).

[0468] 1H NMR (400 MHz, CDCl3) 9.05 (d, J=2.0 Hz, 1H), 8.43 (d, J=9.3 Hz, 1H), 7.66-7.53 (m, 3H), 7.47 (dd, J=10.8, 5.7 Hz, 1H), 7.33 (t, J=7.2 Hz, 2H), 7.27 (s, 2H), 7.16 (dd, J=9.3, 2.6 Hz, 1H), 6.78 (d, J=7.4 Hz, 1H), 6.66 (d, J=2.5 Hz, 1H), 5.82 (s, 1H), 4.14-4.07 (m, 1H), 3.56 (dd, J=29.2, 13.0 Hz, 2H), 3.46-3.34 (m, 1H), 3.17 (t, J=8.8 Hz, 1H), 2.89 (dd, J=14.1, 4.4 Hz, 1H), 2.67 (dd, J=13.9, 6.2 Hz, 1H), 2.54-2.39 (m, 1H), 2.24 (dd, J=13.8, 9.8 Hz, 1H), 2.02 (td, J=18.7, 9.4 Hz, 2H), 1.37 (s, 3H).

[0469] .sup.13C NMR (125 MHz, CDCl.sub.3) 180.4, 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.

[0470] MS (ESI, m/z): 971.8 [MH].sup..

Example 97 Nickel (II)-(R)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichloro benzyl)-2-methylpyrrolyl-2-carboxamide/(R)-2-amino-3-(naphth-1-yl)propionic AcidSchiff Base Complex

[0471] According to a synthesis procedure similar to example 91, DL-3-methoxyphenyl alanine was replaced by DL-2-amino-3-(naphth-1-yl)propionic acid and red solids in a yield of 92% were obtained by column chromatography (dichloromethane:methanol=20:1).

[0472] mp: 114.5-116.1 C. [].sup.20.sub.D=1812 (c=1, CHCl.sub.3).

[0473] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.09 (d, J=2.0 Hz, 1H), 8.30 (d, J=9.3 Hz, 1H), 7.78 (t, J=8.0 Hz, 2H), 7.68 (dd, J=8.2, 2.0 Hz, 1H), 7.57 (d, J=8.6 Hz, 1H), 7.43-7.35 (m, 1H), 7.30 (dd, J=15.6, 7.6 Hz, 4H), 7.23-7.11 (m, 3H), 7.08 (dd, J=9.3, 2.6 Hz, 1H), 6.68 (t, J=7.6 Hz, 1H), 6.44 (d, J=2.6 Hz, 1H), 5.64 (d, J=7.7 Hz, 1H), 4.41 (dd, J=8.3, 4.3 Hz, 1H), 4.07 (dd, J=14.2, 8.5 Hz, 1H), 3.79 (dd, J=14.1, 4.3 Hz, 1H), 3.70 (d, J=13.2 Hz, 1H), 3.61 (td, J=13.1, 5.9 Hz, 1H), 3.46 (d, J=13.2 Hz, 1H), 3.24 (t, J=9.1 Hz, 1H), 2.83-2.53 (m, 1H), 2.39-2.22 (m, 1H), 2.12 (dd, J=19.8, 9.6 Hz, 1H), 2.00 (dt, J=15.0, 8.9 Hz, 1H), 1.40 (s, 3H).

[0474] .sup.13C NMR (125 MHz, CDCl.sub.3) 180.3, 178.3, 170.5, 141.3, 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.

[0475] MS (ESI, m/z): 75.0 [MH].sup..

Example 98 Nickel (II)-(R)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichloro benzyl)-2-methylpyrrolyl-2-carboxamide/(R)-2-amino-3-(benzothiophen-3-yl)propionic AcidSchiff Base Complex

[0476] According to a synthesis procedure similar to example 91, DL-3-methoxyphenylalanine was replaced by DL-2-amino-3-(benzothiophen-3-yl) propionic acid and red solids in a yield of 94% were obtained by column chromatography (dichloromethane:methanol=20:1).

[0477] mp: 127.1-128.9 C. [].sup.20.sub.D=1836 (c=1, CHCl.sub.3).

[0478] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.06 (d, J=2.0 Hz, 1H), 8.34 (d, J=9.3 Hz, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.57 (dd, J=8.2, 2.0 Hz, 1H), 7.49 (t, J=7.5 Hz, 1H), 7.45-7.34 (m, 2H), 7.30 (dd, J=11.9, 6.2 Hz, 3H), 7.19-7.08 (m, 4H), 6.59 (d, J=2.6 Hz, 1H), 6.48 (d, J=7.5 Hz, 1H), 4.31 (t, J=5.5 Hz, 1H), 3.71-3.59 (m, 1H), 3.51 (dd, J=57.6, 9.8 Hz, 2H), 3.18 (dd, J=14.5, 4.7 Hz, 1H), 3.03 (dt, J=19.1, 10.3 Hz, 2H), 2.01 (ddd, J=20.7, 18.6, 11.3 Hz, 3H), 1.81-1.69 (m, 1H), 1.30 (s, 3H).

[0479] .sup.13C NMR (125 MHz, CDCl.sub.3) 180.3, 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.

[0480] MS (ESI, m/z): 760.0 [MH].sup..

Example 99 Nickel (II)-(R)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichloro benzyl)-2-methylpyrrolyl-2-carboxamide/(R)-2-amino-3-(thiophen-3-yl)propionic AcidSchiff Base Complex

[0481] According to a synthesis procedure similar to example 91, DL-3-methoxyphenylalanine was replaced by DL-2-amino-3-(thiophen-3-yl)propionic acid and red solids in a yield of 89% were obtained by column chromatography (dichloromethane:methanol=20:1).

[0482] mp: 208.5-209.6 C. [].sup.20.sub.D=2419 (c=1, CHCl.sub.3).

[0483] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.09 (d, J=2.1 Hz, 1H), 8.34 (d, J=9.3 Hz, 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, 2.6 Hz, 1H), 7.04 (d, J=1.8 Hz, 1H), 6.86 (dd, J=4.9, 1.2 Hz, 1H), 6.70 (d, J=7.7 Hz, 1H), 6.62 (d, J=2.6 Hz, 1H), 4.18 (t, J=5.1 Hz, 1H), 3.63 (d, J=13.1 Hz, 1H), 3.50 (dq, J=11.9, 5.9 Hz, 2H), 3.25-3.05 (m, 2H), 2.77 (dd, J=14.3, 5.4 Hz, 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).

[0484] .sup.13C NMR (125 MHz, CDCl.sub.3) 180.6, 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, 129.6, 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.

[0485] MS (ESI, m/z): 710.0 [MH].sup..

Example 100 Nickel (II)-(S)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichloro benzyl)-2-methylpyrrolyl-2-carboxamide/(S)-2-amino-2-cyclobutylacetic AcidSchiff Base Complex

[0486] According to a synthesis procedure similar to example 91, DL-3-methoxyphenyl alanine was replaced by DL-2-amino-2-cyclobutylacetic acid and red solids in a yield of 85% were obtained by column chromatography (dichloromethane:methanol=20:1).

[0487] mp: 307.5-308.9 C. [].sup.20.sub.D=3252 (c=1, CHCl.sub.3).

[0488] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.12 (s, 1H), 8.23 (d, J=9.3 Hz, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.60-7.38 (m, 3H), 7.29 (t, J=6.9 Hz, 2H), 7.09 (dd, J=9.3, 2.5 Hz, 1H), 6.87 (d, J=7.4 Hz, 1H), 6.58 (d, J=2.5 Hz, 1H), 4.21-3.95 (m, 1H), 3.82-3.69 (m, 2H), 3.51 (d, J=13.0 Hz, 1H), 3.40 (t, J=8.7 Hz, 1H), 3.17-2.88 (m, 1H), 2.67 (dq, J=17.3, 8.7 Hz, 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, 8.2 Hz, 1H), 1.70 (dd, J=18.3, 9.0 Hz, 2H), 1.44 (s, 3H).

[0489] .sup.13C NMR (125 MHz, CDCl.sub.3) 180.3, 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.

[0490] MS (ESI, m/z): 668.0 [MH].sup..

Example 101 Nickel (II)-(R)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichloro benzyl)-2-methylpyrrolyl-2-carboxamide/(R)-2-amino-4,4,4-trifluorobutanoic AcidSchiff Base Complex

[0491] According to a synthesis procedure similar to example 91, DL-3-methoxyphenylalanine was replaced by DL-2-amino-4,4,4-trifluorobutanoic acid and red solids in a yield of 92% were obtained by column chromatography (dichloromethane:methanol=20:1).

[0492] mp: 274.0-276.0 C. [].sup.20.sub.D=3150 (c=1, CHCl.sub.3).

[0493] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.16 (d, J=1.8 Hz, 1H), 8.35 (d, J=9.3 Hz, 1H), 7.68-7.47 (m, 4H), 7.36 (d, J=8.1 Hz, 1H), 7.30 (d, J=6.8 Hz, 1H), 7.16 (dd, J=9.3, 2.5 Hz, 1H), 6.90 (d, J=7.4 Hz, 1H), 6.60 (d, J=2.5 Hz, 1H), 4.16 (ddd, J=10.3, 9.3, 4.7 Hz, 2H), 3.74-3.49 (m, 2H), 3.38 (t, J=8.7 Hz, 1H), 3.09-2.80 (m, 1H), 2.63-2.46 (m, 1H), 2.42 (dd, J=13.7, 9.8 Hz, 1H), 2.23-2.09 (m, 2H), 2.06-1.90 (m, 1H), 1.44 (s, 3H).

[0494] .sup.13C NMR (125 MHz, CDCl.sub.3) 180.5, 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.

[0495] MS (ESI, m/z): 696.0 [MH].sup..

Example 102 Nickel (II)-(R)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichloro benzyl)-2-methylpyrrolyl-2-carboxamide/(R)-2-aminopentanoic AcidSchiff Base Complex

[0496] According to a synthesis procedure similar to example 91, DL-3-methoxyphenyl alanine was replaced by DL-2-aminopentanoic acid and red solids in a yield of 90% were obtained by column chromatography (dichloromethane:methanol=20:1). mp: 277.8-228.9 C. [].sup.20.sub.D=2430 (c=1, CHCl.sub.3).

[0497] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.11 (d, J=2.0 Hz, 1H), 8.21 (d, J=9.3 Hz, 1H), 7.73 (dd, J=8.2, 2.0 Hz, 1H), 7.61-7.49 (m, 2H), 7.46 (t, J=7.4 Hz, 1H), 7.31 (dd, J=15.9, 7.6 Hz, 2H), 7.12 (dd, J=9.3, 2.6 Hz, 1H), 6.86 (d, J=7.5 Hz, 1H), 6.60 (d, J=2.6 Hz, 1H), 4.11-3.98 (m, 1H), 3.87 (dd, J=7.6, 3.6 Hz, 1H), 3.65 (dd, J=82.3, 13.0 Hz, 2H), 3.38 (t, J=8.8 Hz, 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, 8.4 Hz, 1H), 1.69 (dd, J=13.1, 6.3 Hz, 1H), 1.59-1.49 (m, 1H), 1.45 (s, 3H), 0.79 (t, J=7.2 Hz, 3H). .sup.13C NMR (125 MHz, CDCl.sub.3) 180.4, 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].sup..

Example 103 Nickel (II)-(R)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichloro benzyl)-2-methylpyrrolyl-2-carboxamide/(R)-2-amino-3-methylbutanoic AcidSchiff Base Complex

[0498] According to a synthesis procedure similar to example 91, DL-3-methoxyphenyl alanine was replaced by DL-2-amino-3-methylbutanoic acid and red solids in a yield of 93% were obtained by column chromatography (dichloromethane:methanol=20:1).

[0499] mp: 267.5-269.2 C. [].sup.20.sub.D=3016 (c=1, CHCl.sub.3).

[0500] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.17 (d, J=2.1 Hz, 1H), 8.28 (d, J=9.3 Hz, 1H), 7.65 (dd, J=8.2, 2.1 Hz, 1H), 7.54 (dt, J=16.1, 7.9 Hz, 2H), 7.45 (t, J=6.9 Hz, 1H), 7.31 (dd, J=7.7, 4.2 Hz, 2H), 7.10 (dd, J=9.3, 2.6 Hz, 1H), 6.85 (d, J=7.5 Hz, 1H), 6.61 (d, J=2.6 Hz, 1H), 4.14-3.97 (m, 1H), 3.83-3.72 (m, 2H), 3.53 (d, J=13.1 Hz, 1H), 3.40 (t, J=9.0 Hz, 1H), 3.00 (td, J=12.5, 4.0 Hz, 1H), 2.53-2.34 (m, 1H), 2.27-2.08 (m, 2H), 1.84 (d, J=6.6 Hz, 3H), 1.80-1.67 (m, 1H), 1.45 (s, 3H), 0.73 (d, J=6.8 Hz, 3H).

[0501] .sup.13C NMR (125 MHz, CDCl.sub.3) 180.4, 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.

[0502] MS (ESI, m/z): 656.0 [MH].sup..

Example 104 Nickel (II)-(R)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichloro benzyl)-2-methylpyrrolyl-2-carboxamide/(R)-2-amino-4-methylthiobutanoic AcidSchiff Base Complex

[0503] According to a synthesis procedure similar to example 91, DL-3-methoxyphenyl alanine was replaced by DL-2-amino-4-methylthiobutanoic acid and red solids in a yield of 90% were obtained by column chromatography (dichloromethane:methanol=20:1).

[0504] mp: 123.4-125.8 C. [].sup.20.sub.D=2202 (c=1, CHCl.sub.3).

[0505] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.11 (d, J=1.5 Hz, 1H), 8.21 (d, J=9.3 Hz, 1H), 7.72 (d, J=6.7 Hz, 1H), 7.60-7.51 (m, 2H), 7.47 (t, J=7.4 Hz, 1H), 7.32 (dd, J=14.6, 7.6 Hz, 2H), 7.13 (dd, J=9.3, 2.5 Hz, 1H), 6.88 (d, J=7.5 Hz, 1H), 6.60 (d, J=2.5 Hz, 1H), 4.09-3.96 (m, 1H), 3.93 (dd, J=8.3, 3.6 Hz, 1H), 3.66 (dd, J=74.8, 13.0 Hz, 2H), 3.37 (t, J=8.9 Hz, 1H), 3.17 (dd, J=16.5, 10.3 Hz, 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, 6.7 Hz, 3H), 1.97 (s, 3H), 1.91-1.77 (m, 1H), 1.45 (s, 3H).

[0506] .sup.13C NMR (125 MHz, CDCl.sub.3) 180.4, 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.

[0507] MS (ESI, m/z): 688.0 [MH].sup..

Example 105 Nickel (II)-(R)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichloro benzyl)-2-methylpyrrolyl-2-carboxamide/(R)-2-amino-3-(1H-indol)propionic AcidSchiff Base Complex

[0508] According to a synthesis procedure similar to example 91, DL-3-methoxyphenylalanine was replaced by DL-2-amino-3-(1H-indol)propionic acid and red solids in a yield of 93% were obtained by column chromatography (dichloromethane:methanol=20:1).

[0509] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.90 (d, J=1.9 Hz, 1H), 8.45 (s, 1H), 8.17 (d, J=9.3 Hz, 1H), 7.60-7.55 (m, 2H), 7.52 (t, J=7.5 Hz, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.40-7.26 (m, 4H), 7.19 (t, J=7.7 Hz, 1H), 7.11 (dd, J=9.3, 2.6 Hz, 1H), 7.03 (d, J=2.0 Hz, 1H), 6.96 (t, J=7.5 Hz, 1H), 6.85 (d, J=7.7 Hz, 1H), 6.63 (d, J=2.6 Hz, 1H), 4.31 (t, J=4.7 Hz, 1H), 4.08 (d, J=12.4 Hz, 1H), 3.32 (dd, J=14.7, 4.5 Hz, 1H), 3.01 (ddd, J=19.7, 11.9, 6.0 Hz, 3H), 2.88-2.82 (m, 1H), 2.13 (tt, J=13.5, 8.1 Hz, 1H), 1.65 (s, 3H), 1.88-1.70 (m, 2H), 1.51-1.42 (m, 1H).

[0510] MS (ESI, m/z): 741.1 [MH].sup..

Example 106 Nickel (II)-(R)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichloro benzyl)-2-methylpyrrolyl-2-carboxamide/(R)-2-amino-5-methyl-4-hexenoic AcidSchiff Base Complex

[0511] According to a synthesis procedure similar to example 91, DL-3-methoxyphenylalanine was replaced by DL-2-amino-5-methyl-4-hexenoic acid and red solids in a yield of 90% were obtained by column chromatography (dichloromethane:methanol=20:1).

[0512] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.90 (d, J=2.0 Hz, 1H), 8.11 (d, J=9.3 Hz, 1H), 7.74 (dd, J=8.2, 2.0 Hz, 1H), 7.58-7.50 (m, 2H), 7.46 (ddd, J=7.3, 4.5, 1.8 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.30-7.27 (m, 1H), 7.10 (dd, J=9.3, 2.6 Hz, 1H), 6.89 (d, J=7.5 Hz, 1H), 6.57 (d, J=2.5 Hz, 1H), 5.66 (t, J=7.6 Hz, 1H), 4.30 (d, J=12.6 Hz, 1H), 4.01 (dd, J=6.4, 4.6 Hz, 1H), 3.67-3.45 (m, 2H), 3.35 (dd, J=10.9, 6.2 Hz, 1H), 3.20 (d, J=12.6 Hz, 1H), 2.78-2.52 (m, 3H), 2.43-2.32 (m, 1H), 2.05 (td, J=10.7, 6.3 Hz, 1H), 1.86 (s, 3H), 1.70 (s, 3H), 1.54 (s, 3H).

[0513] MS (ESI, m/z): 680.09 [MH].sup..

Example 107 Nickel (II)-(R)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichloro benzyl)-2-methylpyrrolyl-2-carboxamide/(R)-2-aminoglutaric AcidSchiff Base Complex

[0514] According to a synthesis procedure similar to example 91, DL-3-methoxyphenylalanine was replaced by DL-2-aminoglutaric acid and red solids in a yield of 89% were obtained by column chromatography (dichloromethane:methanol=20:1).

[0515] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.90 (s, 1H), 8.02 (d, J=9.2 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.57-7.50 (m, 2H), 7.47 (t, J=6.9 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.26-7.23 (m, 1H), 7.11-7.01 (m, 2H), 6.57 (d, J=2.3 Hz, 1H), 4.27 (d, J=12.4 Hz, 1H), 3.93 (dd, J=8.0, 3.4 Hz, 1H), 3.61 (dd, J=19.2, 9.7 Hz, 1H), 3.55-3.48 (m, 1H), 3.40 (dd, J=11.1, 5.4 Hz, 1H), 3.20 (d, J=12.4 Hz, 1H), 3.06 (dt, J=17.1, 6.9 Hz, 1H), 2.71-2.62 (m, 1H), 2.56-2.44 (m, 2H), 2.35 (dq, J=15.7, 7.8 Hz, 1H), 2.22-2.13 (m, 1H), 2.05 (td, J=10.8, 6.0 Hz, 1H), 1.90 (s, 3H).

[0516] MS (ESI, m/z): 684.09 [MH].sup..

Example 108 Nickel (II)-(R)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichloro benzyl)-2-methylpyrrolyl-2-carboxamide/(R)-2,5-diamino-5-pentanone AcidSchiff Base Complex

[0517] According to a synthesis procedure similar to example 91, DL-3-methoxyphenylalanine was replaced by DL-2,5-diamino-5-pentanone acid and red solids in a yield of 88% were obtained by column chromatography (dichloromethane:methanol=20:1).

[0518] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.88 (d, J=0.9 Hz, 1H), 8.05 (d, J=9.2 Hz, 1H), 7.75 (dd, J=8.1, 1.2 Hz, 1H), 7.58-7.49 (m, 3H), 7.37 (d, J=8.2 Hz, 1H), 7.22 (s, 1H), 7.12 (dd, J=9.2, 2.3 Hz, 1H), 6.94 (d, J=7.0 Hz, 1H), 6.59 (d, J=2.4 Hz, 1H), 6.00 (s, 1H), 5.21 (s, 1H), 4.30 (d, J=12.6 Hz, 1H), 3.82 (dd, J=10.9, 4.3 Hz, 1H), 3.74-3.59 (m, 1H), 3.52 (dd, J=10.5, 5.6 Hz, 1H), 3.38 (dd, J=11.4, 5.4 Hz, 1H), 3.22 (d, J=12.4 Hz, 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, 5.6 Hz, 1H), 1.98 (s, 3H).

[0519] MS (ESI, m/z): 683.06 [MH].sup..

Example 109 Nickel (II)-(R)N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichloro benzyl)-2-methylpyrrolyl-2-carboxamide/(R)-homocysteineSchiff Base Complex

[0520] According to a synthesis procedure similar to example 91, DL-3-methoxyphenylalanine was replaced by DL-homocysteine and red solids in a yield of 93% were obtained by column chromatography (dichloromethane:methanol=20:1).

[0521] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.88 (d, J=1.2 Hz, 1H), 8.05 (d, J=9.3 Hz, 1H), 7.75 (dd, J=8.0, 1.0 Hz, 1H), 7.50 (ddt, J=29.3, 14.8, 7.3 Hz, 3H), 7.36 (d, J=8.1 Hz, 1H), 7.24 (s, 1H), 7.11 (dd, J=9.3, 2.4 Hz, 1H), 6.89 (d, J=7.4 Hz, 1H), 6.57 (d, J=2.4 Hz, 1H), 4.30 (d, J=12.5 Hz, 1H), 3.87 (dd, J=8.2, 3.4 Hz, 1H), 3.68-3.56 (m, 1H), 3.55-3.49 (m, 1H), 3.37 (dd, J=10.9, 5.8 Hz, 1H), 3.21 (d, J=12.6 Hz, 1H), 2.95 (dd, J=17.5, 9.3 Hz, 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, 10.7 Hz, 1H).

[0522] MS (ESI, m/z): 672.03 [MH].sup..

Example 110 Nickel (II)-(R)N-(2-benzoyl-4-chlorophenyl)-1-ethyl-2-methylpyrrolyl-2-carboxamide/(S)-3-amino-2-benzylpropionic AcidSchiff Base Complex

[0523] According to a synthesis procedure similar to example 65, brown solids (yield 68%) were obtained.

[0524] mp 128-130 C. [].sup.20.sub.D=+2426.5 (c=0.034, CHCl.sub.3).

[0525] .sup.1H NMR (400 MHz, Methanol-d.sub.4) 8.91 (d, J=2.1 Hz, 1H), 8.32 (dd, J=8.3, 2.1 Hz, 1H), 7.74 (d, J=9.2 Hz, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.39-7.25 (m, 2H), 7.23-7.12 (m, 4H), 7.06 (dd, J=9.2, 2.6 Hz, 1H), 7.03-6.95 (m, 3H), 6.64 (dt, J=7.6, 1.6 Hz, 1H), 6.42 (d, J=2.6 Hz, 1H), 3.98-3.83 (m, 2H), 3.77 (d, J=13.3 Hz, 1H), 3.58-3.48 (m, 1H), 3.40 (d, J=13.3 Hz, 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).

[0526] .sup.13C NMR (125 MHz, Methanol-d.sub.4) 182.5, 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.

[0527] LRMS (ESI+APCI) m/z: 718.0, HRMS (ESI) m/z: found: 718.0940, calcd 718.0935 for C.sub.35H.sub.32Cl.sub.3N.sub.3NiO.sub.3.sup.+ [M+H].sup.+.

Example 111 Nickel (II)-(R)N-(2-benzoyl-4-chlorophenyl)-1-ethyl-2-methylpyrrolyl-2-carboxamide/(S)-3-amino-2-(4-fluorobenzyl)propionic AcidSchiff Base Complex

[0528] According to a synthesis procedure similar to example 65, brown solids (yield 58%) were obtained.

[0529] mp 123-124 C. [].sup.20.sub.D=3310.5 (c=0.038, CHCl.sub.3).

[0530] .sup.1H NMR (400 MHz, Methanol-d.sub.4) 8.15 (d, J=9.1 Hz, 1H), 7.41-7.33 (m, 2H), 7.26 (dd, J=9.1, 2.6 Hz, 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, 1.9 Hz, 1H), 6.53 (d, J=2.6 Hz, 1H), 3.96 (t, J=12.3 Hz, 1H), 3.86-3.73 (m, 2H), 3.22-3.06 (m, 3H), 2.62-2.29 (m, 6H), 1.94-1.86 (m, 4H), 1.24 (s, 3H). .sup.13C NMR (125 MHz, Methanol-d.sub.4) 183.7, 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, 126.6, 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 606.1464 for C.sub.31H.sub.31ClFN.sub.3NiO.sub.3.sup.+ [M+H].sup.+.

Example 112 Nickel (II)-(R)N-(2-benzoyl-4-chlorophenyl)-1-ethyl-2-methylpyrrolyl-2-carboxamide/(S)-3-amino-2-(4-methoxybenzyl)propionic AcidSchiff Base Complex

[0531] According to a synthesis procedure similar to example 65, brown solids (yield 62%) were obtained.

[0532] mp 127-130 C. [].sup.20.sub.D=3618.8 (c=0.032, CHCl.sub.3). .sup.1H NMR (400 MHz, Methanol-d.sub.4) 8.14 (d, J=9.1 Hz, 1H), 7.41-7.32 (m, 2H), 7.26 (d, J=9.1 Hz, 1H), 7.15 (t, J=8.5 Hz, 1H), 6.99 (d, J=7.6 Hz, 1H), 6.91-6.84 (m, 2H), 6.77 (d, J=7.6 Hz, 1H), 6.72-6.66 (m, 2H), 6.53 (d, J=2.6 Hz, 1H), 3.94 (t, J=12.4 Hz, 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=7.4 Hz, 3H), 1.24 (s, 3H).

[0533] .sup.13C NMR (125 MHz, Methanol-d.sub.4) 183.69, 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.

[0534] LRMS (ESI+APCI) m/z: 618.1, HRMS (ESI) m/z: found: 618.1667, calcd 618.1664 for C.sub.32H.sub.34ClN.sub.3NiO.sub.3.sup.+ [M+H].sup.+.

Example 113 Nickel (II)-(R)N-(2-benzoyl-4-chlorophenyl)-1-ethyl-2-methylpyrrolyl-2-carboxamide/(S)-3-amino-2-methylpropionic AcidSchiff Base Complex

[0535] According to a synthesis procedure similar to example 65, brown solids (yield 76%) were obtained.

[0536] mp 257-259 C. [].sup.20.sub.D=4854.5 (c=0.044, CHCl.sub.3).

[0537] .sup.1H NMR (400 MHz, Methanol-d.sub.4) 8.17 (d, J=9.1 Hz, 1H), 7.66-7.49 (m, 3H), 7.45-7.35 (m, 1H), 7.29 (dd, J=9.1, 2.5 Hz, 1H), 6.99 (d, J=7.6 Hz, 1H), 6.65 (d, J=2.6 Hz, 1H), 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=7.3 Hz, 3H).

[0538] .sup.13C NMR (125 MHz, Methanol-d.sub.4) 183.7, 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.

[0539] LRMS (ESI+APCI) m/z: 512.0, HRMS (ESI) m/z: found: 512.1256, calcd 512.1245 for C.sub.25H.sub.28ClN.sub.3NiO.sub.3.sup.+ [M+H].sup.+.

Example 114 Nickel (II)-(R)N-(2-benzoyl-4-chlorophenyl)-1-ethyl-2-methylpyrrolyl-2-carboxamide/(S)-2-(aminomethyl)-4-methylpentanoic AcidSchiff Base Complex

[0540] According to a synthesis procedure similar to example 65, brown solids (yield 62%) were obtained.

[0541] mp 120-122 C. [].sup.20.sub.D=4383.3 (c=0.048, CHCl.sub.3).

[0542] .sup.1H NMR (400 MHz, Methanol-d.sub.4) 8.19 (d, J=9.1 Hz, 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, 1.7 Hz, 1H), 6.67 (d, J=2.6 Hz, 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, 3.8 Hz, 6H).

[0543] .sup.13C NMR (125 MHz, Methanol-d.sub.4) 183.6, 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.

[0544] LRMS (ESI+APCI) m/z: 554.2, HRMS (ESI) m/z: found: 554.1727, calcd 554.1719 for C.sub.28H.sub.34ClN.sub.3NiO.sub.3.sup.+ [M+H].sup.+.

Example 115 Nickel (II)-(R)N-(2-benzoyl-4-chlorophenyl)-1-ethyl-2-methylpyrrolyl-2-carboxamide/(S)-3-amino-2-cyclohexylpropionic AcidSchiff Base Complex

[0545] According to a synthesis procedure similar to example 65, brown solids (yield 87%) were obtained.

[0546] mp 145-147 C. [].sup.20.sub.D=3161.8 (c=0.034, CHCl.sub.3).

[0547] .sup.1H NMR (400 MHz, Methanol-d.sub.4) 8.18 (d, J=9.1 Hz, 1H), 7.66-7.51 (m, 3H), 7.42-7.37 (m, 1H), 7.28 (dd, J=9.1, 2.6 Hz, 1H), 6.98 (d, J=7.6 Hz, 1H), 6.65 (d, J=2.6 Hz, 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).

[0548] .sup.13C NMR (125 MHz, Methanol-d.sub.4) 183.6, 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.

[0549] LRMS (ESI+APCI) m/z: 580.2, HRMS (ESI) m/z: found: 580.1881, calcd 580.1871 for C.sub.30H.sub.36ClN.sub.3NiO.sub.3.sup.+ [M+H].sup.+.

Example 116 Nickel (II)-(R)N-(2-benzoyl-4-chlorophenyl)-1-ethyl-2-methylpyrrolyl-2-carboxamide/(S)-3-amino-2-phenylpropionic AcidSchiff Base Complex

[0550] According to a synthesis procedure similar to example 65, brown solids (yield 55%, dr 55/45) were obtained.

[0551] mp 150-151 C. [].sup.20.sub.D=3648.0 (c=0.05, CHCl.sub.3).

[0552] .sup.1H NMR (400 MHz, Methanol-d.sub.4) 8.20 (d, J=9.1 Hz, 1H), 7.66-7.52 (m, 3H), 7.46 (t, J=7.6 Hz, 1H), 7.31 (dd, J=9.1, 2.6 Hz, 1H), 7.28-7.16 (m, 3H), 7.10-7.03 (m, 2H), 6.91 (d, J=7.7 Hz, 1H), 6.69 (d, J=2.6 Hz, 1H), 4.34 (t, J=13.0 Hz, 1H), 3.89-3.86 (m, 2H), 3.53 (dd, J=11.8, 3.5 Hz, 1H), 3.29-3.97 (m, 1H), 3.15 (dd, J=13.0, 3.6 Hz, 1H), 2.65-2.56 (m, 1H), 2.46-2.29 (m, 3H), 1.99-1.90 (m, 4H), 1.27 (s, 3H).

[0553] .sup.13C NMR (125 MHz, Methanol-d.sub.4) 183.7, 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.

[0554] LRMS (ESI+APCI) m/z: 574.1, HRMS (ESI) m/z: found: 574.1410, calcd 574.1402 for C.sub.30H.sub.30ClN.sub.3NiO.sub.3+[M+H].sup.+.

Example 117 Nickel (II)-(R)N-(2-benzoyl-4-chlorophenyl)-1-ethyl-2-methylpyrrolyl-2-carboxamide/(S)-3-amino-2-(4-chlorophenyl)propionic AcidSchiff Base Complex

[0555] According to a synthesis procedure similar to example 65, brown solids (yield 59%, dr 59/41) were obtained.

[0556] mp=130-132 C. [].sup.20.sub.D=3312.5 (c=0.048, CHCl.sub.3).

[0557] .sup.1H NMR (400 MHz, Methanol-d.sub.4) 8.20 (d, J=9.1 Hz, 1H), 7.65-7.44 (m, 4H), 7.31 (dd, J=9.1, 2.6 Hz, 1H), 7.28-7.23 (m, 2H), 7.08-7.01 (m, 2H), 6.93 (d, J=7.7 Hz, 1H), 6.69 (d, J=2.6 Hz, 1H), 4.35 (t, J=12.5 Hz, 1H), 3.97-3.81 (m, 2H), 3.54 (dd, J=12.0, 3.4 Hz, 1H), 3.29-3.27 (m, 1H), 3.12 (dd, J=12.9, 3.5 Hz, 1H), 2.63-2.50 (m, 1H), 2.46-2.31 (m, 3H), 1.98-1.90 (m, 4H), 1.27 (s, 3H).

[0558] .sup.13C NMR (125 MHz, Methanol-d.sub.4) 183.7, 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.

[0559] LRMS (ESI+APCI) m/z: 608.0, HRMS (ESI) m/z: found: 608.1026, calcd 608.1012 for C.sub.30H.sub.29Cl.sub.2N.sub.3NiO.sub.3.sup.+ [M+H]P.

Example 118 Nickel (II)-(R)N-(2-benzoyl-4-chlorophenyl)-1-ethyl-2-methylpyrrolyl-2-carboxamide/(S)-3-amino-2-(4-methoxyphenyl)propionic AcidSchiff Base Complex

[0560] According to a synthesis procedure similar to example 65, brown solids (yield 65%, dr 50/50) were obtained.

[0561] mp=146-148 C. [].sup.20.sub.D=3052.4 (c=0.042, CHCl.sub.3).

[0562] .sup.1H NMR (400 MHz, Methanol-d.sub.4) 8.19 (d, J=9.1 Hz, 1H), 7.68-7.52 (m, 3H), 7.48 (t, J=7.5 Hz, 1H), 7.31 (dd, J=9.1, 2.6 Hz, 1H), 7.01-6.95 (m, 2H), 6.93 (d, J=7.7 Hz, 1H), 6.84-6.77 (m, 2H), 6.69 (d, J=2.6 Hz, 1H), 4.29 (t, J=12.9 Hz, 1H), 3.91-3.78 (m, 2H), 3.73 (s, 3H), 3.48 (dd, J=11.7, 3.6 Hz, 1H), 3.29-3.23 (m, 1H), 3.12 (dd, J=13.0, 3.6 Hz, 1H), 2.64-2.56 (m, 1H), 2.44-2.34 (m, 3H), 1.95 (q, J=10.3, 8.7 Hz, 4H), 1.27 (s, 3H).

[0563] .sup.13C NMR (125 MHz, Methanol-d.sub.4) 183.7, 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.

[0564] LRMS (ESI+APCI) m/z: 604.1, HRMS (ESI) m/z: found: 604.1503, calcd 604.1508 for C.sub.31H.sub.32ClN.sub.3NiO.sub.3.sup.+ [M+H].sup.+

Example 119 Nickel (II)-(R)N-(2-benzoyl-4-chlorophenyl)-1-ethyl-2-methylpyrrolyl-2-carboxamide/(S)-3-amino-2-(naphth-1-yl)propionic AcidSchiff Base Complex

[0565] According to a synthesis procedure similar to example 65, brown solids (yield 63%, dr 50/50) were obtained.

[0566] mp=146-147 C. [].sup.20.sub.D=3440.0 (c=0.046, CHCl.sub.3).

[0567] .sup.1H NMR (400 MHz, Methanol-d.sub.4) 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).

[0568] .sup.13C NMR (125 MHz, Methanol-d.sub.4) 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.

[0569] LRMS (ESI+APCI) m/z: 624.1, HRMS (ESI) m/z: found: 624.1566, calcd 624.1558 for C.sub.34H.sub.32ClN.sub.3NiO.sub.3.sup.+ [M+H].sup.+.

Example 120 Nickel (II)-(R)N-(2-benzoyl-4-chlorophenyl)-1-ethyl-2-methylpyrrolyl-2-carboxamide/(S)-3-amino-2-(4-methylbenzyl)propionic AcidSchiff Base Complex

[0570] According to a synthesis procedure similar to example 65, brown solids (yield 70%, dr 84/16) were obtained.

[0571] mp 124-126 C. [].sup.20.sub.D=3277.3 (c=0.034, CHCl.sub.3).

[0572] .sup.1H NMR (400 MHz, Methanol-d.sub.4) 8.13 (d, J=9.1 Hz, 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=8.0 Hz, 2H), 6.77 (d, J=7.2 Hz, 1H), 6.53 (d, J=2.6 Hz, 1H), 3.93 (t, J=12.4 Hz, 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).

[0573] .sup.13C NMR (125 MHz, Methanol-d.sub.4) 183.7, 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.

[0574] LRMS (ESI+APCI) m/z: 601.8, HRMS (ESI) m/z: found: 602.1705, calcd 602.1715 for C.sub.32H.sub.35ClN.sub.3NiO.sub.3+[M+H].sup.+.

Example 121 Nickel (II)-(R)N-(2-benzoyl-4-chlorophenyl)-1-ethyl-2-methylpyrrolyl-2-carboxamide/(S)-3-amino-2-(4-trifluoromethylbenzyl)propionic AcidSchiff Base Complex

[0575] According to a synthesis procedure similar to example 65, brown solids (yield 72%, dr 89/11) were obtained.

[0576] mp 137-139 C. [].sup.20.sub.D=3950.5 (c=0.046, CHCl.sub.3).

[0577] .sup.1H NMR (400 MHz, Methanol-d.sub.4) 8.14 (d, J=9.1 Hz, 1H), 7.45 (d, J=8.0 Hz, 2H), 7.35-7.25 (m, 3H), 7.17 (d, J=8.1 Hz, 2H), 7.05-6.95 (m, 2H), 6.78 (d, J=7.6 Hz, 1H), 6.52 (d, J=2.5 Hz, 1H), 4.00 (t, J=12.3 Hz, 1H), 3.88-3.78 (m, 2H), 3.30-3.26 (m, 1H), 3.21 (dd, J=11.1, 7.4 Hz, 1H), 3.07 (dd, J=12.7, 3.4 Hz, 1H), 2.61-2.44 (m, 3H), 2.39-2.30 (m, 3H), 1.94-1.87 (m, 4H), 1.25 (s, 3H).

[0578] .sup.13C NMR (125 MHz, Methanol-d.sub.4) 183.7, 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.

[0579] LRMS (ESI+APCI) m/z: 655.8, HRMS (ESI) m/z: found: 656.1431, calcd 656.1432 for C.sub.32H.sub.32ClF.sub.3N.sub.3NiO.sub.3.sup.+ [M+H].sup.+.

Example 122 Nickel (II)-(R)N-(2-benzoyl-4-chlorophenyl)-1-ethyl-2-methylpyrrolyl-2-carboxamide/(S)-3-amino-2-tert-butyl propionic AcidSchiff Base Complex

[0580] mp=136-137 C. [].sup.20.sub.D=3670.0 (c=0.048, CHCl.sub.3).

[0581] .sup.1H NMR (400 MHz, Methanol-d.sub.4) 8.21 (d, J=9.1 Hz, 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, 2.6 Hz, 1H), 6.99 (d, J=7.6 Hz, 1H), 6.67 (d, J=2.6 Hz, 1H), 4.27 (t, J=12.5 Hz, 1H), 4.07-3.97 (m, 1H), 3.93-3.84 (m, 1H), 3.33 (d, J=4.7 Hz, 1H), 3.13 (dd, J=10.9, 7.8 Hz, 1H), 2.66 (dq, J=15.0, 7.5 Hz, 1H), 2.44-2.34 (m, 2H), 2.28 (dq, J=14.1, 7.1 Hz, 1H), 2.07 (dd, J=12.5, 4.7 Hz, 1H), 2.03-1.95 (m, 1H), 1.89 (t, J=7.3 Hz, 3H), 1.24 (s, 3H), 0.84 (s, 9H).

[0582] .sup.13C NMR (125 MHz, Methanol-d.sub.4) 183.8, 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.

[0583] LRMS (ESI+APCI) m/z: 655.8, HRMS (ESI) m/z: found: 554.1704, calcd 554.1715 for C.sub.28H.sub.35ClN.sub.3NiO.sub.3.sup.+ [M+H].sup.+.

Example 123 Nickel (II)-(R)N-(2-benzoyl-4-chlorophenyl)-1-ethyl-2-methylpyrrolyl-2-carboxamide/(S)-3-amino-2-isopropylpropionic AcidSchiff Base Complex

[0584] mp 130-132 C. [].sup.20.sub.D=3241.0 (c=0.034, CHCl.sub.3).

[0585] .sup.1H NMR (400 MHz, Methanol-d.sub.4) 8.18 (d, J=9.1 Hz, 1H), 7.61-7.53 (m, 3H), 7.46-7.39 (m, 1H), 7.29 (dd, J=9.1, 2.6 Hz, 1H), 7.00 (d, J=7.5 Hz, 1H), 6.66 (d, J=2.6 Hz, 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=6.9 Hz, 3H), 0.65 (d, J=7.1 Hz, 3H).

[0586] .sup.13C NMR (125 MHz, Methanol-d.sub.4) 183.6, 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.

[0587] LRMS (ESI+APCI) m/z: 539.9, HRMS (ESI) m/z: found: 540.1543, calcd 540.1558 for C.sub.27H.sub.33ClN.sub.3NiO.sub.3.sup.+ [M+H].sup.+.

Example 124

[0588] The chelates prepared in examples 72-89 were hydrolyzed in substantially same manner as in example 66 to give: (S)-3-amino-3-(2-fluoro)phenylpropionic acid, (S)-3-amino-3-(4-chloro)phenylpropionic acid, (S)-3-amino-3-(3,4-dimethoxy)phenylpropionic acid, (S)-3-amino-3-(4-isopropyl)phenylpropionic acid, (S)-3-amino-3-(4-methoxy)phenylpropionic acid, (S)-3-amino-3-(3-methoxy)phenylpropionic acid, (S)-3-amino-3-(3-trifluoromethyl)phenylpropionic acid, (S)-3-amino-3-(3-pyridyl)propionic acid, (S)-3-amino-3-(2-thienyl)propionic acid, (S)-3-amino-3-(1-naphthyl)propionic acid, (S)-3-aminobutanoic 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 and (S)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid, respectively.

[0589] All documents mentioned in the present invention are hereby incorporated by reference, just as each document is cited separately as a reference. In addition, it should be understood that various modifications and changes may be made by those skilled in the art after reading the above teachings of the present invention and these equivalent forms also fall within the scope defined by the claims appended hereto.