Imidazopyrazine derivatives, methods for producing the same, and their use as luciferin

Abstract

To provide a luminescent substrate useful as an in vitro, ex vivo, or in vivo diagnostic tool, which offers enhanced luminescent signal intensity, signal-to-noise ratio, and luminescent duration compared to luciferin, which is a commonly used luminescent substrate in the field of bioluminescence.SOLUTION: The present invention provides an imidazo[1,2-a]pyrazine derivative represented by the formula (III). (R1 is H or the like; R2 is a substitutable phenyl group or the like; R3 is a substitutable aralkyl group; R4 is H or the like; Z is a substitutable phenyl group, a substitutable furanyl group or the like).SELECTED DRAWING: None

Description

[Technical Field]

[0001] This invention relates to the field of bioluminescence in biology and / or pharmaceuticals. Specifically, the invention provides imidazopyrazine derivatives, methods for producing the same, and their use as luciferins. [Background technology]

[0002] Recently, bioluminescent reporting systems composed of expressed luciferase / luminescent proteins and luciferins have become important tools in many research areas such as biological and biochemical studies, whole-cell or animal imaging, diagnostics, and many types of screening for the potential bioactivity of small molecules. A small number of luciferase types are used as bioluminescent reporters for such assays. Luciferins, relatively large firefly luciferases (i.e., 65 kDa) that require oxygen and ATP were initially adapted, but subsequently, smaller (i.e., 19-35 kDa) luciferases of marine origin have been found to be more suitable in many cases because they are ATP-independent and smaller. Many types of calcium-binding luminescent proteins and luciferases found in the highly diverse assortment of marine organisms actually utilize luciferins characterized by an imidazo[1,2-a]pyrazine-3(7H)-one ring system. Coelenterazine (1) is a natural substrate for the bioluminescent proteins of the cnidarian jellyfish Aequorea, Mitrocoma, Oberia, and Periphylla, or the hydroid Clytia. Furthermore, it is also a natural substrate for the luciferases of the sea pansy Renilla, the shrimp Oplophorus, and the plankton copepods Gaussia and Metridia. Finally, vargula luciferin (2) is a substrate for the luciferases of the ostracod Conchoecia and vargula, or the fish Porichthys.

[0003] [ka]

[0004] A vast amount of research has focused on improving such bioluminescent systems. The use of luciferin analogs such as compounds 4-9 in combination with various forms of sea lichen luciferase has led to violet shift signals and / or stronger signals.

[0005] [ka]

[0006] Another achievement came from the use of artificial luciferase made from improved catalytic fragments of the shrimp *Oxylostoma rhodopolium* in combination with various non-natural substrates. Thus, a strongly improved signal was obtained using furimazine (12).

[0007] [ka]

[0008] Compared to the use of corresponding wild-type luciferases and their natural substrates, coelenterazine (1), many of these synthetic luciferin / luciferase systems showed improvements in the intensity and duration of the bioluminescent signal.

[0009] However, there is a need for bioluminescent systems that provide stronger signals (with a higher signal-to-noise ratio) for longer periods. In fact, the use of such systems as reporters in high-throughput screening requires a strong bioluminescent signal for at least 30 minutes, taking into account the delays inherent in robot-based methods. Furthermore, the stronger the signal of a given assay, the more miniaturization of that assay becomes possible, which is desirable when considering the costs involved when conducting numerous high-throughput screening campaigns. In whole-cell imaging, high initial bioluminescent intensity, as well as a high ratio of "bioluminescent signal" to "chemiluminescent noise," is also often desirable. For example, such signal intensity allows for the design of a wide variety of biological tools based on the use of small luciferases (so far, the smallest being 19 kDa), luciferin, and ordinary microscopes, instead of many tools based on monitoring fluorescence signals that require the use of microscopes featuring larger fluorescent dye molecules such as green fluorescent protein (27 kDa) and devices that highlight this fluorescent dye molecule at a given wavelength to detect the signal at the emission wavelength of the fluorescent dye molecule.

[0010] Furthermore, the recommended storage conditions for these luciferins (in solution or as a dry powder) require use at very low temperatures (-80°C), as solutions of such compounds have been reported to be highly unstable at room temperature overnight (US 20140302539). [Overview of the Initiative] [Problems that the invention aims to solve]

[0011] Therefore, the object of the present invention is to provide an alternative to conventional luciferin that yields a substantially better bioluminescent signal in terms of intensity, signal-to-noise ratio, and / or duration. Another object of the present invention is to provide a stable precursor of luciferin that can be stored under simple conditions before use.

[0012] Another object of the present invention is to provide an easy, versatile, and reliable method for deprotecting a stable precursor of luciferin. In particular, such an easy deprotection method would not need to be carried out under an inert gas. Another object of the present invention is to provide a versatile and reliable method for producing luciferin and luciferin precursors, which provides access to the untapped chemical space surrounding these compounds and / or enables production and purification on a kiloscale.

[0013] The inventors were the first to demonstrate that compounds of formula (I) can be easily deprotected by contacting them with a strong acid. Furthermore, the inventors were the first to demonstrate that the selection of imidazopyrazine derivatives produces superior bioluminescent signals.

[0014] In particular, the inventors found that the compound of formula (III) provides a bioluminescent signal that is significantly improved in terms of intensity, signal-to-noise ratio, and / or duration compared to previously reported substrates such as furimazine (12). [Means for solving the problem]

[0015] Therefore, in one respect, the present invention relates to the use of a compound of the following formula (I) in the presence of a solution containing a strong acid for the detection of luminescent proteins in vitro, in cellulo, or ex vivo, and / or for the measurement of the enzymatic activity of luminescent proteins;

[0016] [ka]

[0017] (In the formula, R1 is H or C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 10 Aryl, Aralkyl and C5-C 10represents a group selected from a C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, aralkyl and C5-C 10 -member heteroaryl group is optionally substituted with at least one Y1 group (Even if it's been replaced) ; R2 represents a group selected from a C6-C 10 aryl and C5-C 10 -member heteroaryl group, and the C6-C 10 aryl and C5-C 10 -member heteroaryl group is optionally substituted with at least one Y2 group; or

[0018] R1 and R2 together form, with the two carbon atoms to which they are respectively attached, a C5-C7 cycloalkene group, a C4-C7 heterocycloalkene group or a C6-C 10 arene, and the C5-C7 cyclo Alken group and the C4-C7 heterocyclo Alken group are condensed with a C6-C 10 arene and condensed death with, the C5-C7 cycloalkene group, the C4-C7 heterocycloalkene group and C6-C 10 arene n is optionally substituted with at least one Y 12 group; R3 represents H, a C1-C6 alkyl, an aralkyl group, a hetaralkyl group or a heterocycloalkyl-CH2- group, and the C1-C6 alkyl, aralkyl group, hetaralkyl group and heterocycloalkyl-CH2- group are optionally substituted with at least one Y3 group;

[0019] R4 represents a group selected from H or a C1-C6 alkyl and a C3-C7 cycloalkyl group, and the C1-C6 alkyl and C3-C7 cycloalkyl group are optionally substituted with at least one Y4 group; R5 represents a -C(=O)R a group or a -C(=O)OR a group, and the C(=O)R a group and -C(=O)ORa The group is optionally replaced by at least one Y5 group; R a H, C1-C6 alkyl groups, C3-C7 cycloalkyl groups, C6-C 10 Representing an aryl or aralkyl group, the C1-C6 alkyl group, C3-C7 cycloalkyl group, C6-C 10 Aryl and aralkyl groups are at least one Y a It can be arbitrarily substituted in the base;

[0020] Z is C6-C 10 Aryl, C5-C 10 - Represents a member heteroaryl group, C1-C6 alkyl, C3-C7 cycloalkyl, or C4-C7 heterocycloalkyl, in particular Z is selected from phenyl, furanyl, thiophenyl, pyridinyl, imidazolyl, oxazolyl, oxadiazolyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, and dioxolanil, and the C6-C 10 Aryl, C5-C 10 - Member heteroaryl group, C1-C6 alkyl, C3-C7 cycloalkyl and C4-C7 heterocycloalkyl are at least one Y Z It can be arbitrarily substituted by the base;

[0021] The aforementioned Y1, Y2, Y 12 Y3, Y4, Y5, Y a and Y Z Each base is independently selected from the following: - C1-C6 alkyl; - C3-C7 cycloalkyl; - C6-C 10 Ariel; - C5-C 10 -Member heteroaryl group; - Halogens, especially -F; - -CF3 group; - -CN group; - -OR i base; - -OSO3H group; - -NR i R ii base; - Guanidinyl group; - -C(=O)OR a Group, R a The above is true;

[0022] R i and R ii These are, independently, H, C1-C6 alkyl, and C3-C 10 Represents a cycloalkyl group, an aralkyl group, or an ad hoc protecting group; or together they form a C4-C7 heterocycloalkyl group with the nitrogen atom to which they are bonded.

[0023] The presence of a strong acid allows for the acquisition of the corresponding deprotected compound (after removal of the R5 moiety) in the imidazopyrazinon state of the skeleton of the present invention, which can emit photons under basic conditions and / or in the presence of a suitable enzyme called luciferase.

[0024] The luciferin, which may exist in the presence of a strong acid, is used diluted in a buffer medium, preferably between 6 and 9, more preferably between 7 and 8, which includes, for example, 2-(N-morpholino)ethanesulfonic acid (MES), tris(hydroxymethyl)aminomethane (TRIS), 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), and / or phosphate-buffered saline (PBS), for the detection of luminogenetic proteins in vitro, in cellulose, or ex vivo, and / or for the measurement of the enzymatic activity of luminogenetic proteins.

[0025] In certain embodiments, the strong acid is hydrochloric acid. In certain embodiments, the solution containing the strong acid is an ethanol-based hydrochloric acid solution. In a particular embodiment, the volume fraction of hydrochloric acid (37% in water) in the solution is 0.1 to 10%, particularly about 1%.

[0026] Immediately after deprotection is performed, the corresponding deprotected compound in the presence of a strong acid solution can be used directly in a buffer medium well known to those skilled in the art, without the need for neutralization before use in the buffer medium. Therefore, the compounds of formula (I) below are brought into contact with a strong acid before being used in a buffer medium, particularly for the detection of luminogenetic proteins in vitro, in cellulose, or ex vivo, and / or for the measurement of the enzymatic activity of luminogenetic proteins.

[0027] In other words, the compounds of formula (I) below are used for the detection of luminescent proteins in vitro, in cellulose, or ex vivo, and / or for the measurement of the enzymatic activity of luminescent proteins, after dilution of the deprotected compounds in a buffer medium (e.g., MES, TRIS, HEPES, PBS) that yields a pH preferably between 6 and 9, more preferably between 7 and 8, in the presence of a solution containing a strong acid (which enables the deprotection of the compounds of formula (I) below).

[0028] In this particular embodiment, R1 represents H. In this particular embodiment, R4 represents H. In a particular embodiment, R5 represents (C=O)Me. In certain embodiments, R3 represents an aralkyl or heteroalkyl group, optionally substituted as defined above.

[0029] In a particular embodiment, R3 represents benzyl optionally substituted with at least one halogen, more specifically with F, as defined above. In a further specific embodiment, R3 represents benzyl substituted with at least one halogen, more specifically with F. In this case, R3 represents benzyl substituted with one halogen, more specifically with F, or benzyl substituted with the same or different halogens, more specifically with F and / or Cl, where the substitution is, for example, 2,3;2,5;2,6 or 3,5.

[0030] For example, R3 is selected from the following group: [ka]

[0031] In certain embodiments, R2 represents a phenyl molecule optionally substituted as defined above, R2, in particular, is as follows: - C1-C6 alkyl groups, especially methyl; - Halogens, especially F; - -OR i base Represents phenyl optionally substituted with at least one Y2 selected from; R i H, C1-C6 alkyl, C3-C 10 Represents a cycloalkyl group, an aralkyl group, or an ad hoc protecting group, in particular, R i represents H, Me, or Bn, and more specifically, R i represents H;

[0032] R2 is, more specifically, the following: [ka] It is selected from the group consisting of the following.

[0033] In certain embodiments, Z is selected from phenyl, furanyl, and thiophenyl and is optionally substituted as defined above. Z is, in particular, the following: - C1-C6 alkyl; - C3-C7 cycloalkyl; - Halogens, especially F or Cl; - -CF3 group; - -OR i Base, especially -OMe base Represents a phenyl, furanyl, or thiophenyl group optionally substituted with at least one Y2 group selected from;

[0034] More specifically, Z is: [ka] It is selected from the group consisting of the following.

[0035] It should be noted that the present invention includes combinations of all embodiments described above for R1, R2, R3, R4 and / or Z. In particular, R3 represents at least one halogen, more specifically, benzyl optionally substituted with F, and Z represents furanyl or thiophenyl optionally substituted with at least one Y2 as defined above.

[0036] In a particular embodiment, the present invention relates to the above-defined use of a compound of the following formula (Ia): [ka]

[0037] (In the formula, R2 is as follows: [ka] Selected from the group consisting of; R3 represents, as defined above, at least one halogen, more specifically benzyl or heteroalkyl optionally substituted with F; R5 is as defined above;

[0038] Z is the following: [ka] (Selected from the group consisting of...)

[0039] In a particular embodiment, the bioluminescent protein is a luciferase derived from the luciferase of the shrimp *Okihimehiodoshi*, more specifically, nanoKAZ luciferase. In certain embodiments, the present invention relates to the above-defined use of a compound of formula (IV) as defined below.

[0040] The present invention also relates to a compound of formula (I) defined above for use after contact with a solution containing a strong acid in an in vivo method for detecting a luminescent protozoan and / or measuring the enzymatic activity of a luminescent protozoan. The present invention also relates to the use of the compound of formula (I) as defined above for the realization of a kit comprising the compound of formula (I) and a solution containing a strong acid.

[0041] The present invention also, i) Compounds of formula (I) as defined above; and ii) Solutions containing strong acids Regarding the kit that includes this.

[0042] In a particular embodiment, the solution containing the compound of formula (I) and a strong acid are present in separate containers. In certain embodiments, the kit defined above further comprises a formulation selected from the group consisting of a luminescent protoprotein, a polynucleotide encoding the luminescent protoprotein, a recombinant vector containing the polynucleotide, and a transformant containing the nucleotide.

[0043] In a more specific embodiment of the present invention, the luminescent protoprotein is - Luciferases and bioluminescent proteins found in marine organisms such as the cnidarian jellyfish Aequorea, Mitrocoma, Oberia, and Periphylla; the hydroid Clytia; the sea pansy Renilla; the shrimp Oplophorus; the plankton copepods Gaussia and Metridia; the ostracod Conchoecia and Vargula; and the fish Porichthys; in particular, these luciferases and bioluminescent proteins are either extracted from natural sources or manufactured by genetic engineering.

[0044] - Any mutant whose amino acid sequence has been mutated from the native sequences of the luciferase and luminescent proteins as defined above by genetic engineering; - The luminescence-catalyzing domains of the natural luciferase and luminescent proteins or their mutant proteins as defined above, particularly the 19 kDa protein or mutant proteins of the luciferase of the Japanese angelfish (GenBank acceptance number BAB 13776, 196 amino acids) Selected from.

[0045] These luminescent protoproteins and their mutant proteins can be produced by methods well known to those skilled in the art. Alternatively, some of these can be commercially purchased from companies such as JNC Corporation (Cosmo Bio), Wako Pure Chemicals Industries, Promega Corporation, and Prolume.

[0046] In particular, the bioluminescent protein corresponds to an optimized luciferase catalytic domain (nanoKAZ, 19kDa) derived from luciferase from the shrimp *Oxylostoma rhodopolium* (in terms of sequence, production, stability, and bioluminescence). This optimization can be carried out by methods well known to those skilled in the art. In a more specific embodiment, the bioluminescent protein is the luciferase of the shrimp *Oxytropis obliqua*, particularly nanoKAZ luciferase (NCBI GenBank reference number: AB823628.1).

[0047] In particular, the present invention is i) Compounds of formula (I) as defined above; ii) Solutions containing strong acids; and iii) buffering medium; Regarding the kit that includes this. The present invention also relates to the kit defined above as an in vitro or ex vivo diagnostic tool. The present invention also relates to the kit defined above for use as an in vivo diagnostic tool.

[0048] The present invention also, - To obtain a deprotected compound, contact the compound of formula (I) with a solution containing a strong acid; - Contact the deprotective compound with a bioluminescent protein, particularly the luciferase of the pygmy shrimp, more specifically, nanoKAZ luciferase. This concerns methods for causing light emission, including those mentioned above.

[0049] The present invention also, - To obtain a concentrated solution containing the deprotection compound, contact the compound of formula (I) with a solution containing a strong acid; - To obtain a diluted solution containing the deprotection compound, the concentrated solution containing the deprotection compound is diluted in a buffer medium; - Contact the diluted solution containing the aforementioned deprotection compound with a luminescent protoprotein, particularly the luciferase of the pygmy shrimp, and more specifically, the nanoKAZ luciferase. This concerns methods for causing light emission, including those mentioned above. The concentrated solution contains a deprotection compound and, in particular, the strong acid.

[0050] The present invention also, - To obtain a deprotected compound, contact the compound of formula (I) with a solution containing a strong acid; - Contacting the sample with the deprotection compound; - If not present in the sample, optionally bring the sample into contact with a bioluminescent protoprotein, particularly the luciferase of the pygmy shrimp, more specifically nanoKAZ luciferase; and - Detecting light emission This relates to a method for detecting luminescence in a sample, including [specific details omitted].

[0051] The present invention also, - To obtain a concentrated solution containing the deprotection compound, contact the compound of formula (I) with a solution containing a strong acid; - To obtain a diluted solution containing the deprotection compound, the concentrated solution containing the deprotection compound is diluted in a buffer medium; - Contact the sample with a diluted solution containing the aforementioned deprotection compound; - If not present in the sample, optionally bring the sample into contact with a bioluminescent protoprotein, particularly the luciferase of the pygmy shrimp, more specifically nanoKAZ luciferase; and - Detecting light emission This relates to a method for detecting luminescence in a sample, including [specific details omitted].

[0052] In a particular embodiment, the sample contains living cells. In another specific embodiment, the sample comprises a bioluminescent protein, in particular the luciferase of the pygmy shrimp, more specifically nanoKAZ luciferase.

[0053] The present invention also, - To obtain a deprotected compound, contact the compound of formula (I) with a solution containing a strong acid; - Administering the deprotective compound to the animals described below; and - Detecting light emission This invention relates to a method for detecting luminescence in genetically modified animals that express luminescent progenitor proteins, including [specific protein name].

[0054] The present invention also, - To obtain a concentrated solution containing the deprotection compound, contact the compound of formula (I) with a solution containing a strong acid; - To obtain a diluted solution containing the deprotection compound, the concentrated solution containing the deprotection compound is diluted in a buffer medium; - Administering the animals described below a diluted solution containing the aforementioned deprotective compound; and - Detecting light emission The present invention relates to a method for detecting luminescence in genetically modified animals that express luminescent proteins or in animals that harbor genetically modified organs that express luminescent proteins.

[0055] The present invention also, - To obtain a deprotected compound, contact the compound of formula (I) with a solution containing a strong acid; - A polynucleotide encoding a luminogen protein is used as the reporter gene, and the deprotected compound defined above is used as the luminescent substrate. This invention relates to a method for assaying the activity of sequences involved in promoter regulation, including [specific sequence name].

[0056] The present invention also, - To obtain a concentrated solution containing the deprotection compound, contact the compound of formula (I) with a solution containing a strong acid; - To obtain a diluted solution containing the deprotection compound, the concentrated solution containing the deprotection compound is diluted in a buffer medium; - In the diluted solution defined above, use a polynucleotide encoding a luminescent protoprotein as the reporter gene and the deprotected compound defined above as the luminescent substrate. The present invention relates to a method for assaying the activity of sequences involved in promoter regulation, including the above. In the foregoing, the compound of formula (I) is in particular the compound of formula (IV) or formula (II) as defined below.

[0057] In the method defined above, the compound of formula (I) is present in the kit defined above, in particular, before use. Therefore, the method defined above, which lists the compound of formula (I), a strong acid, and optionally a buffer medium, can be understood as a method in which different parts of the aforementioned kit are used.

[0058] The present invention also relates to a compound of the following formula (II): [ka]

[0059] R1 is H or C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 10 Aryl, Aralkyl and C5-C 10 - Represents a group selected from member heteroaryl groups, such as C1-C6 alkyl, C3-C7 cycloalkyl, and C6-C 10 Aryl, Aralkyl and C5-C 10 - The member heteroaryl group is optionally substituted with at least one Y1 group; R2 is C6-C 10 Aryl and C5-C 10 - Represents a group selected from member heteroaryl groups, and the C6-C 10 Aryl and C5-C 10 - The member heteroaryl group is optionally substituted with at least one Y2 group; or

[0060] R1 and R2 together form a C5-C7 cycloalkene group, a C4-C7 heterocycloalkene group, or a C6-C2 group, with the two carbon atoms they are bonded to. 10 Forming arenes, the C5-C7 cyclo Alken The group and C4-C7 heterocyclo Alken The base is C6-C 10 Alain and condensation death , the C5-C7 cycloalkene group, C4-C7 heterocycloalkene group and C6-C 10 Alley n at least one Y 12It can be arbitrarily substituted in the base; R3 represents H, a C1-C6 alkyl group, an aralkyl group, a heteroalkyl group, or a heterocycloalkyl-CH2- group, wherein the C1-C6 alkyl group, aralkyl group, heteroalkyl group, and heterocycloalkyl-CH2- group are optionally substituted with at least one Y3 group;

[0061] R4 represents H or a group selected from C1-C6 alkyl and C3-C7 cycloalkyl groups, wherein the C1-C6 alkyl and C3-C7 cycloalkyl groups are optionally substituted with at least one Y4 group; R5 is -C(=O)R a Base or -C(=O)OR a Represents the base, and the C(=O)R a Base and -C(=O)OR a The group is optionally replaced by at least one Y5 group; R a H, C1-C6 alkyl groups, C3-C7 cycloalkyl groups, C6-C 10 Representing an aryl or aralkyl group, the C1-C6 alkyl group, C3-C7 cycloalkyl group, C6-C 10 Aryl and aralkyl groups are at least one Y a It can be arbitrarily substituted in the base;

[0062] Z is C6-C 10 Aryl, C5-C 10 - Represents a member heteroaryl group, C1-C6 alkyl, C3-C7 cycloalkyl, or C4-C7 heterocycloalkyl, in particular Z is selected from phenyl, furanyl, thiophenyl, pyridinyl, imidazolyl, oxazolyl, oxadiazolyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, and dioxolanil, and the C6-C 10 Aryl, C5-C 10 - Member heteroaryl group, C1-C6 alkyl, C3-C7 cycloalkyl and C4-C7 heterocycloalkyl are at least one Y Z It can be arbitrarily substituted by the base;

[0063] Y1, Y2, Y 12Y3, Y4, Y5, Y a and Y Z Each base is independently selected from the following: - C1-C6 alkyl; - C3-C7 cycloalkyl; - C6-C 10 Ariel; - C5-C 10 -Member heteroaryl group; - Halogens, especially -F; - -CF3 group; - -CN group; - -OR i base; - -OSO3H group; - -NR i R ii base; - Guanidinyl group; - -C(=O)OR a Group, R a The above is true;

[0064] R i and R ii These are, independently, H, C1-C6 alkyl, and C3-C 10 Represents a cycloalkyl group, aralkyl group, or ad hoc protecting group; or together they form a C4-C7 heterocycloalkyl group with the nitrogen atom to which they are bonded; However, when R1 and R4 represent H: - R2 is different from unsubstituted phenyl and 4-hydroxyphenyl optionally protected by an ad hoc protecting group, or - R3 is unsubstituted benzyl base Different from, or - Z is different from unsubstituted phenyl, 4-hydroxyphenyl optionally protected by an ad hoc protecting group, and unsubstituted furan.

[0065] In a particular embodiment, the present invention relates to a compound having the following name in general formula II: 8-Benzyl-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 2,8-Dibenzyl-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-((5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-(furan-3-ylmethyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 2-((1,3-dioxolan-2-yl)methyl)-8-benzyl-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate

[0066] 8-Benzyl-2-(4-(benzyloxy)benzyl)-6-(4-(benzyloxy)phenyl)imidazo[1,2-a]pyrazine-3-yl acetate 2-benzyl-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 2-Benzyl-8-methyl-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-(furan-2-ylmethyl)-6-(2-methoxyphenyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-(furan-3-ylmethyl)-6-(2-methoxyphenyl)imidazo[1,2-a]pyrazine-3-yl acetate

[0067] 2,8-Dibenzyl-6-(2-methoxyphenyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-((5-ethylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-6-phenyl-2-(thiophen-2-ylmethyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-(3-methylbenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-(4-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate

[0068] 8-Benzyl-2-((4,5-dimethylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-6-phenyl-2-(pyridine-2-ylmethyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-(3-methoxybenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-6-phenyl-2-((tetrahydrofuran-2-yl)methyl)imidazo[1,2-a]pyrazine-3-yl acetate 2,8-Dibenzyl-6-(2-fluorophenyl)imidazo[1,2-a]pyrazine-3-yl acetate

[0069] 8-Benzyl-6-(2-fluorophenyl)-2-(furan-2-ylmethyl)imidazo[1,2-a]pyrazine-3-yl acetate 2-Benzyl-6-phenyl-8-((tetrahydrofuran-2-yl)methyl)imidazo[1,2-a]pyrazine-3-yl acetate 2-(furan-2-ylmethyl)-6-phenyl-8-((tetrahydrofuran-2-yl)methyl)imidazo[1,2-a]pyrazine-3-yl acetate 4-(3-acetoxy-2-(4-acetoxybenzyl)-8-benzylimidazo[1,2-a]pyrazine-6-yl)phenyl acetate 2,12-Dibenzyl-5H-chromeno[4,3-e]imidazo[1,2-a]pyrazine-3-yl acetate

[0070] 8-Benzyl-6-(2,6-difluorophenyl)-2-(furan-2-ylmethyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-6-phenyl-2-((5-(trifluoromethyl)furan-2-yl)methyl)imidazo[1,2-a]pyrazine-3-yl acetate 2,8-Dibenzyl-6-(2,6-difluorophenyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-6-phenyl-2-(2-(trifluoromethyl)benzyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-6-phenyl-2-(3-(trifluoromethyl)benzyl)imidazo[1,2-a]pyrazine-3-yl acetate

[0071] 8-Benzyl-6-phenyl-2-(4-(trifluoromethyl)benzyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-6-(2-fluorophenyl)-2-((5-methylfuran-2-yl)methyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-6-(4-fluorophenyl)-2-((5-methylfuran-2-yl)methyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-((5-cyclopropylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-6-(4-methoxyphenyl)-2-((5-methylfuran-2-yl)methyl)imidazo[1,2-a]pyrazine-3-yl acetate

[0072] 8-Benzyl-2-(4-isopropylbenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-6-phenyl-2-(3-propylbenzyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-(3-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-(4-methoxybenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 2-Benzyl-6-phenyl-8-(pyridine-3-ylmethyl)imidazo[1,2-a]pyrazine-3-yl acetate

[0073] 8-Benzyl-6-phenyl-2-(4-propylbenzyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-((5-methylfuran-2-yl)methyl)-6-(p-tolyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-(4-bromobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-(4-chlorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-((5-methylfuran-2-yl)methyl)-6-(m-tolyl)imidazo[1,2-a]pyrazine-3-yl acetate

[0074] 8-Benzyl-2-(4-cyclopropylbenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-(3-cyclopropylbenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-((5-ethylfuran-2-yl)methyl)-6-(2-fluorophenyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-6-(3-methoxyphenyl)-2-((5-methylfuran-2-yl)methyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-(4-fluorobenzyl)-6-(2-fluorophenyl)imidazo[1,2-a]pyrazine-3-yl acetate

[0075] 8-Benzyl-6-(3-fluorophenyl)-2-((5-methylfuran-2-yl)methyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-(4-methylbenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-(2-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-(2-methoxybenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-((5-ethylthiophen-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate

[0076] 8-Benzyl-2-(sec-butyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-((3-methylthiophen-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-((4,5-dimethylfuran-2-yl)methyl)-6-(2-fluorophenyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-(2-methylbenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 2-benzylimidazo[1,2-a]quinoxaline-1-yl acetate

[0077] 2,4-Dibenzylimidazo[1,2-a]quinoxaline-1-yl acetate 8-Benzyl-6-phenyl-2-(1-phenylethyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-((4,5-dimethyloxazole-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-(2,4-difluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-(cyclohexylmethyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate

[0078] 8-Benzyl-2-(cyclopentylmethyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-((4,5-dimethylthiophen-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-(bicyclo[2.2.1]heptan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 2-benzyl-8-(2-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 2-Benzyl-8-(3-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate

[0079] 2-Benzyl-8-(4-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 2,8-Dibenzyl-6-(4-hydroxyphenyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-6-(4-hydroxyphenyl)-2-(3-propylbenzyl)imidazo[1,2-a]pyrazine-3-yl acetate 2,8-Dibenzyl-5-methyl-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-((5-ethylfuran-2-yl)methyl)-6-(4-hydroxyphenyl)imidazo[1,2-a]pyrazine-3-yl acetate

[0080] 8-Benzyl-2-((4,5-dimethylfuran-2-yl)methyl)-6-(4-hydroxyphenyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-(furan-2-ylmethyl)-6-(4-hydroxyphenyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-(3-fluorobenzyl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(2-fluorobenzyl)-2-(3-methylbenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(2-fluorobenzyl)-2-(3-methoxybenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate

[0081] 8-(2-fluorobenzyl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(2-fluorobenzyl)-2-((5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-(4-hydroxybenzyl)-6-(4-hydroxyphenyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-(2-chlorobenzyl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 2-Benzyl-8-(2-chlorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate

[0082] 2,8-Dibenzyl-6-(3-fluoro-4-hydroxyphenyl)imidazo[1,2-a]pyrazine-3-yl acetate 2-Benzyl-8-(2-methoxybenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-phenethyl-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 2-Benzyl-8-(2-methylbenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 2-(furan-2-ylmethyl)-8-(2-methylbenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate

[0083] 2-Benzyl-8-(3-methylbenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 2-(furan-2-ylmethyl)-8-(3-methylbenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 2-((5-ethylfuran-2-yl)methyl)-8-(2-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(3-fluorobenzyl)-2-((5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(2-chlorobenzyl)-2-((5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate

[0084] 2-((5-ethylfuran-2-yl)methyl)-8-(3-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(3-fluorobenzyl)-2-(3-methylbenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(3-fluorobenzyl)-2-(3-methoxybenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(2,6-difluorobenzyl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(3,5-difluorobenzyl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate

[0085] 8-(3-chlorobenzyl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(3-fluorobenzyl)-6-(2-fluorophenyl)-2-((5-methylfuran-2-yl)methyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-(3-fluorobenzyl)-2-(4-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(2,3-difluorobenzyl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(2,3-difluorobenzyl)-2-((5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate

[0086] 8-(2,5-difluorobenzyl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(2,5-difluorobenzyl)-2-((5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 2,12-Dibenzyl-6-fluorobenzo[f]imidazo[1,2-a]quinoxaline-3-yl acetate 12-benzyl-6-fluoro-2-(furan-2-ylmethyl)benzo[f]imidazo[1,2-a]quinoxaline-3-yl acetate 8-(3,5-difluorobenzyl)-2-((5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate

[0087] 8-Benzyl-2-((3-methylisoxazole-5-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-((3-ethylisoxazole-5-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 2-Benzyl-8-(2,3-difluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 2-Benzyl-6-phenyl-8-(2-(trifluoromethyl)benzyl)imidazo[1,2-a]pyrazine-3-yl acetate 2-Benzyl-6-phenyl-8-(3-(trifluoromethyl)benzyl)imidazo[1,2-a]pyrazine-3-yl acetate

[0088] 2-Benzyl-6-phenyl-8-(2,3,5-trifluorobenzyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-(2,6-difluorobenzyl)-2-((5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(2,5-difluorobenzyl)-2-((4,5-dimethylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(2,5-difluorobenzyl)-2-((5-ethylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(2,3-difluorobenzyl)-2-((4,5-dimethylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate

[0089] 8-(3,5-difluorobenzyl)-2-((4,5-dimethylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 2-(furan-2-ylmethyl)-6-phenyl-8-(2,3,5-trifluorobenzyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-(2,3-difluorobenzyl)-2-((5-ethylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(3,5-difluorobenzyl)-2-((5-ethylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(2,6-difluorobenzyl)-2-((5-ethylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate

[0090] 8-(2,6-difluorobenzyl)-2-((4,5-dimethylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 2-((4,5-dimethylfuran-2-yl)methyl)-8-(2-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 2-((4,5-dimethylfuran-2-yl)methyl)-8-(3-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-6-phenyl-2-((5-propylfuran-2-yl)methyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-6-phenyl-2-((4,5,6,7-tetrahydrobenzofuran-2-yl)methyl)imidazo[1,2-a]pyrazine-3-yl acetate

[0091] 8-(2,3-difluorobenzyl)-2-((4-ethyl-5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-((4-ethyl-5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(2,3-difluorobenzyl)-6-phenyl-2-((4,5,6,7-tetrahydrobenzofuran-2-yl)methyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-((5-isopropyl-4-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-((5-ethyl-4-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate

[0092] 8-(2,3-difluorobenzyl)-2-((5-ethyl-4-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-benzyl-2-(1-(furan-2-yl)ethyl)-6-phenylimidazo[1,2-a]pyrazine-3-ylacetate 8-(3-fluorobenzyl)-2-(4-hydroxybenzyl)-6-(4-hydroxyphenyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-(2-fluorobenzyl)-2-(4-hydroxybenzyl)-6-(4-hydroxyphenyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-(2,3-difluorobenzyl)-2-((5-isopropyl-4-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate

[0093] 8-Benzyl-2-(furan-2-ylmethyl)-6-(3-hydroxyphenyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-(4-hydroxybenzyl)-6-(3-hydroxyphenyl)imidazo[1,2-a]pyrazine-3-yl acetate.

[0094] The present invention also relates to a compound of the following formula (III): [ka]

[0095] (wherein, R1 represents a group selected from H or a C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, aralkyl and C5-C 10 -member heteroaryl group, and the C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, aralkyl and C5-C 10 -member heteroaryl group is optionally substituted with at least one Y1 group; R2 represents a group selected from C6-C 10 aryl and C5-C 10 -member heteroaryl group, and the C6-C 10 aryl and C5-C 10 -member heteroaryl group is optionally substituted with at least one Y2 group; R3 represents an aralkyl group, and the aralkyl group is optionally substituted with at least one Y3 group; R4 represents a group selected from H or a C1-C6 alkyl and C3-C7 cycloalkyl group, and the C1-C6 alkyl and C3-C7 cycloalkyl group is optionally substituted with at least one Y4 group;

[0096] Z is the following formula: [Chemical formula] group; or represents oxazolyl, or oxadiazolyl;

[0097] R, R’, R’’ and R’’’ are each independently H or the following: - a C1-C6 alkyl group; - a C3-C7 cycloalkyl group; - halogen; - -OR i group; - -CF3 group and represents a group selected from; X represents O or S;

[0098] The Y1, Y2, Y3 and Y4 groups are each independently one of the following: - C1-C6 alkyl group; - C3-C7 cycloalkyl group; - halogen; - -OR ii group and are selected from; R i and R ii each independently represent H, a C1-C6 alkyl group, a C3-C 10 cycloalkyl group or an aralkyl group;

[0099] However, - when Z = Z1: 〇 at least one of R, R’ and R’’ does not represent H; or 〇 when R, R’ and R’’ represent H, R2 is a C6-C 10 aryl and a C5-C 10 -member heteroaryl group selected from groups substituted by at least one halogen group, particularly -F, and R2 particularly represents a 2-F-phenyl, 3-F-phenyl or 2,6-diF-phenyl group; or R3 represents a group selected from at least one halogen group, particularly C6-C 10 aralkyl substituted by -F; or

[0100] - when Z = Z2: 〇 at least one of R, R’, R’’ and R’’’ does not represent H; or 〇 when R, R’, R’’ and R’’’ represent H; R2 is a C6-C 10 aryl and a C5-C 10 -member heteroaryl group selected from groups substituted by at least one halogen group, particularly -F, and R2 particularly represents a 2-F-phenyl, 3-F-phenyl or 2,6-diF-phenyl group; or R3 represents a group selected from at least one halogen group, particularly C6-C 10 aralkyl substituted by -F; or

[0101] 〇 R, R', and R''' represent H, and R'' is a C1-C6 alkyl group or -OR i When representing a group; R2 does not represent a 4-HO-Ph- group, but rather R2 is a C6-C group substituted with a phenyl group or at least one halogen, in particular with -F. 10 Aryl and C5-C 10 - Represents a member heteroaryl group, more specifically, R2 represents a 2-F-phenyl, 3-F-phenyl or 2,6-diF-phenyl group, or R3 represents at least one halogen group, in particular a C6-C substituted with -F. 10 (Represents a group selected from the aralkyl group.)

[0102] In a particular embodiment, the present invention relates to a compound of formula (III) as defined above, wherein, * Z represents the group Z2, R3 represents an aralkyl group, and the aralkyl group is substituted by at least one Y3 group, however, ○ At least one of R, R', R'' and R''' does not represent H; or When R, R', R'' and R'''' represent H, R2 is a C6-C substituted with at least one halogen group, particularly -F. 10 Aryl and C5-C 10 - Represents a group selected from member heteroaryl groups, where R2 specifically represents a 2-F-phenyl, 3-F-phenyl, or 2,6-diF-phenyl group; or R3 represents a C6-C group substituted with at least one -F group. 10 Represents a group selected from the aralkyl; or

[0103] 〇 R, R', and R''' represent H, and R'' is a C1-C6 alkyl group or -OR i When representing a group, R2 does not represent a 4-HO-Ph- group, but rather R2 is a C6-C group substituted with a phenyl group or at least one halogen group, in particular a C6-C group substituted with -F. 10 Aryl and C5-C 10- Represents a group selected from member heteroaryl groups, more specifically, R2 represents a 2-F-phenyl, 3-F-phenyl or 2,6-diF-phenyl group, or R3 represents at least one halogen group, in particular a C6-C substituted with -F. 10 Represents a group selected from aralkyl groups; or

[0104] * Z represents the base of the following equation: [ka] R and R' are distinct from H in particular.

[0105] In a more specific embodiment, the present invention relates to a compound of formula (III) as defined above, Here, * Z represents the group Z2, R3 represents the aralkyl group, and the aralkyl group is substituted with at least one -F group, or * Z represents the base Z1, and R and R' are distinct from H in particular.

[0106] In a particular embodiment, the present invention relates to a compound of formula (III) as defined above, wherein, * R3 represents an aralkyl group, which is substituted by at least one Y3 group, provided that Z=Z2: ○ At least one of R, R', R'' and R''' does not represent H; or ○ When R, R', R'' and R'''' represent H; R2 is C6-C substituted with at least one halogen group, in particular -F. 10 Aryl and C5-C 10 - Represents a group selected from member heteroaryl groups, where R2 specifically represents a 2-F-phenyl, 3-F-phenyl, or 2,6-diF-phenyl group; or R3 represents a C6-C group substituted with at least one -F group. 10 Represents a group selected from aralkyl groups; or 〇 R, R', and R''' represent H, and R'' is a C1-C6 alkyl group or -OR iWhen representing a group, R2 does not represent a 4-HO-Ph- group, but rather R2 is a C6-C group substituted with a phenyl group or at least one halogen group, in particular a C6-C group substituted with -F. 10 Aryl and C5-C 10 - Represents a group selected from member heteroaryl groups, more specifically, R2 represents a 2-F-phenyl, 3-F-phenyl or 2,6-diF-phenyl group; or R3 represents at least one halogen group, in particular a C6-C substituted with -F. 10 Represents a group selected from aralkyl groups; or

[0107] * R2 is C6-C 10 Aryl and C5-C 10 - Represents a group selected from member heteroaryl groups, and the C6-C 10 Aryl and C5-C 10 - The member heteroaryl group is optionally substituted with at least one Y2 group; or * Z represents the base Z1, and R and R' are distinct from H in particular.

[0108] In this particular embodiment, R1 represents H. In this particular embodiment, R4 represents H. In certain embodiments, R3 represents a benzyl group optionally substituted with at least one halogen, more specifically with F, as defined above. In more specific embodiments, R3 represents a benzyl group substituted with at least one halogen, more specifically with F. In this case, R3 may represent a benzyl group substituted with one halogen, more specifically with F, or a benzyl group substituted with the same or different halogens, more specifically with F and / or Cl, where the substitutions are, for example, 2,3;2,5;2,6 or 3,5.

[0109] For example, R3 is: [ka] It is selected from the group consisting of the following.

[0110] In certain embodiments, R2 represents a phenyl molecule optionally substituted as defined above; In particular, R2 represents phenyl optionally substituted with at least one halogen, especially F; More specifically, R2 is: [ka] It is selected from the group consisting of the following.

[0111] In a particular embodiment, Z is selected from Z1 and Z2; R, R', R'', and R'''' are each independent of H or the following: - C1-C6 alkyl groups; - C3-C7 cycloalkyl groups; - Halogen; - -OR i base; - -3 CFs Represents a base selected from,

[0112] More specifically, Z is: [ka] It is selected from the group consisting of the following.

[0113] It should be noted that the present invention includes combinations of all embodiments described above for R1, R2, R3, R4 and / or Z. In particular, R3 represents at least one halogen, more specifically benzyl optionally substituted with F, and Z represents at least one Y as defined above. Z This represents a furanyl or thiophenyl that has been optionally substituted by [the specified character].

[0114] In a particular embodiment, the compound of formula (III) is the compound of formula (IIIa): [ka]

[0115] (In the formula, R2, in particular, is as follows: [ka] Selected from the group consisting of;

[0116] R3 specifically includes the following: [ka] Selected from the group consisting of;

[0117] Z is the following: [ka] (Selected from the group consisting of...)

[0118] In a particular embodiment, the present invention relates to a compound having the following name in general formula IIIa: 8-benzyl-2-((5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-benzyl-2-((5-ethylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-benzyl-2-((4,5-dimethylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-benzyl-6-(2-fluorophenyl)-2-(furan-2-ylmethyl)imidazo[1,2-a]pyrazine-3(7H)-one 8-benzyl-2-(3-methylbenzyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one

[0119] 8-Benzyl-2-(3-methoxybenzyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 2,8-Dibenzyl-6-(2-fluorophenyl)imidazo[1,2-a]pyrazine-3(7H)-one 8-Benzyl-6-(2,6-difluorophenyl)-2-(furan-2-ylmethyl)imidazo[1,2-a]pyrazine-3(7H)-one 8-benzyl-6-phenyl-2-((5-(trifluoromethyl)furan-2-yl)methyl)imidazo[1,2-a]pyrazine-3(7H)-one 2,8-Dibenzyl-6-(2,6-difluorophenyl)imidazo[1,2-a]pyrazine-3(7H)-one

[0120] 8-benzyl-6-(2-fluorophenyl)-2-((5-methylfuran-2-yl)methyl)imidazo[1,2-a]pyrazine-3(7H)-one 8-benzyl-2-((5-cyclopropylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-benzyl-2-(3-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-Benzyl-2-((5-ethylfuran-2-yl)methyl)-6-(2-fluorophenyl)imidazo[1,2-a]pyrazine-3(7H)-one 8-benzyl-6-(3-fluorophenyl)-2-((5-methylfuran-2-yl)methyl)imidazo[1,2-a]pyrazine-3(7H)-one

[0121] 8-benzyl-2-(2-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-benzyl-2-((5-ethylthiophen-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-benzyl-2-((4,5-dimethylfuran-2-yl)methyl)-6-(2-fluorophenyl)imidazo[1,2-a]pyrazine-3(7H)-one 2-benzyl-8-(2-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 2-benzyl-8-(3-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one

[0122] 8-(3-fluorobenzyl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-(2-fluorobenzyl)-2-(3-methylbenzyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-(2-fluorobenzyl)-2-(3-methoxybenzyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-(2-fluorobenzyl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-(2-fluorobenzyl)-2-((5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one

[0123] 8-(3-fluorobenzyl)-2-(3-methoxybenzyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-(3-fluorobenzyl)-2-(3-methylbenzyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 2-((5-ethylfuran-2-yl)methyl)-8-(3-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-(2-chlorobenzyl)-2-((5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-(3-fluorobenzyl)-2-((5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one

[0124] 2-((5-ethylfuran-2-yl)methyl)-8-(2-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-(3-fluorobenzyl)-6-(2-fluorophenyl)-2-((5-methylfuran-2-yl)methyl)imidazo[1,2-a]pyrazine-3(7H)-one 8-(2,3-difluorobenzyl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-(2,3-difluorobenzyl)-2-((5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 2-benzyl-8-(2,3-difluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one

[0125] 8-(2,6-difluorobenzyl)-2-((5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-(2,3-difluorobenzyl)-2-((4,5-dimethylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-(2,3-difluorobenzyl)-2-((5-ethylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-(2,6-difluorobenzyl)-2-((5-ethylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 2-((4,5-dimethylfuran-2-yl)methyl)-8-(2-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one

[0126] 2-((4,5-dimethylfuran-2-yl)methyl)-8-(3-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-(2,3-difluorobenzyl)-2-((4-ethyl-5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-(2,3-difluorobenzyl)-2-((5-ethyl-4-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-benzyl-2-(furan-2-ylmethyl)-6-(3-hydroxyphenyl)imidazo[1,2-a]pyrazine-3(7H)-one.

[0127] The present invention also relates to the use of compounds of formula (III) or (IIIa) as defined above as in vitro or ex vivo diagnostic tools. The present invention also relates to the use of compounds of formula (III) or (IIIa) as defined above as in vivo diagnostic tools. The present invention also relates to a method for inducing luminescence, comprising contacting a compound of formula (III) or (IIIa) as defined above with a luminescent progenitor protein, particularly the luciferase of the pygmy shrimp, more specifically nanoKAZ luciferase.

[0128] The present invention also, - Contacting the sample with a compound of formula (III) or (IIIa) as defined above; - If not present in the sample, optionally bring the sample into contact with a bioluminescent protoprotein, particularly the luciferase of the pygmy shrimp, more specifically nanoKAZ luciferase; and - Detecting light emission This relates to a method for detecting luminescence in a sample, including [specific details omitted].

[0129] In a particular embodiment, the sample contains living cells. In another specific embodiment, the sample comprises a bioluminescent protein, in particular the luciferase of the pygmy shrimp, more specifically nanoKAZ luciferase.

[0130] The present invention also, - Administering the compound of formula (III) or (IIIa) as defined above to the animals described below; and - Detecting light emission This invention relates to a method for detecting luminescence in genetically modified animals that express luminescent progenitor proteins, including [specific protein name]. The present invention also relates to a method for assaying the activity of a sequence related to promoter regulation, comprising using a polynucleotide encoding a luminescent protoprotein as a reporter gene and a compound of formula (III) or (IIIa) as defined above as a luminescent substrate.

[0131] In another respect, the present invention relates to the following formula (IV): [ka]

[0132] (In the formula, R1, R2, R3, R4, and Z are defined for equation (III) or (IIIa); R5 is as defined above.) Regarding the compounds. It should be noted that the present invention includes combinations of all embodiments described above for formula (III) and / or (IIIa).

[0133] In another respect, the present invention relates to the following formula (V): [ka]

[0134] (In the formula, R1, R2, R3, R4, and Z are as defined for formula (III) or (IIIa).) Regarding the compounds. It should be noted that the present invention includes combinations of all embodiments described above for formula (III) and / or (IIIa).

[0135] In another respect, the present invention relates to the following formula (VI): [ka]

[0136] (In the formula, R1, R2, R3, R4, and Z are defined for equation (III) or (IIIa); R d (where represents a group selected from C1-C6 alkyl, C3-C7 cycloalkyl, and aralkyl groups, particularly methyl, ethyl, or benzyl.) Regarding the compounds. It should be noted that the present invention includes combinations of all embodiments described above for formula (III) and / or (IIIa).

[0137] In certain embodiments, the present invention relates to a compound having the following name in general formula (IV): 8-Benzyl-2-((5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-((5-ethylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-((4,5-dimethylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-6-(2-fluorophenyl)-2-(furan-2-ylmethyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-(3-methylbenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate

[0138] 8-Benzyl-2-(3-methoxybenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 2,8-Dibenzyl-6-(2-fluorophenyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-6-(2,6-difluorophenyl)-2-(furan-2-ylmethyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-6-phenyl-2-((5-(trifluoromethyl)furan-2-yl)methyl)imidazo[1,2-a]pyrazine-3-yl acetate 2,8-Dibenzyl-6-(2,6-difluorophenyl)imidazo[1,2-a]pyrazine-3-yl acetate

[0139] 8-Benzyl-6-(2-fluorophenyl)-2-((5-methylfuran-2-yl)methyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-((5-cyclopropylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-(3-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-((5-ethylfuran-2-yl)methyl)-6-(2-fluorophenyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-6-(3-fluorophenyl)-2-((5-methylfuran-2-yl)methyl)imidazo[1,2-a]pyrazine-3-yl acetate

[0140] 8-Benzyl-2-(2-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-((5-ethylthiophen-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-((4,5-dimethylfuran-2-yl)methyl)-6-(2-fluorophenyl)imidazo[1,2-a]pyrazine-3-yl acetate 2-benzyl-8-(2-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 2-Benzyl-8-(3-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate

[0141] 8-(3-fluorobenzyl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(2-fluorobenzyl)-2-(3-methylbenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(2-fluorobenzyl)-2-(3-methoxybenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(2-fluorobenzyl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(2-fluorobenzyl)-2-((5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate

[0142] 8-(3-fluorobenzyl)-2-(3-methoxybenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(3-fluorobenzyl)-2-(3-methylbenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 2-((5-ethylfuran-2-yl)methyl)-8-(3-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(2-chlorobenzyl)-2-((5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(3-fluorobenzyl)-2-((5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate

[0143] 2-((5-ethylfuran-2-yl)methyl)-8-(2-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(2,6-difluorobenzyl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(3,5-difluorobenzyl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(3-chlorobenzyl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(3-fluorobenzyl)-6-(2-fluorophenyl)-2-((5-methylfuran-2-yl)methyl)imidazo[1,2-a]pyrazine-3-yl acetate

[0144] 8-(2,3-difluorobenzyl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(2,3-difluorobenzyl)-2-((5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(2,5-difluorobenzyl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(2,5-difluorobenzyl)-2-((5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(3,5-difluorobenzyl)-2-((5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate

[0145] 2-Benzyl-8-(2,3-difluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 2-Benzyl-6-phenyl-8-(2-(trifluoromethyl)benzyl)imidazo[1,2-a]pyrazine-3-yl acetate 2-Benzyl-6-phenyl-8-(3-(trifluoromethyl)benzyl)imidazo[1,2-a]pyrazine-3-yl acetate 2-Benzyl-6-phenyl-8-(2,3,5-trifluorobenzyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-(2,6-difluorobenzyl)-2-((5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate

[0146] 8-(2,5-difluorobenzyl)-2-((4,5-dimethylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(2,5-difluorobenzyl)-2-((5-ethylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(2,3-difluorobenzyl)-2-((4,5-dimethylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(3,5-difluorobenzyl)-2-((4,5-dimethylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 2-(furan-2-ylmethyl)-6-phenyl-8-(2,3,5-trifluorobenzyl)imidazo[1,2-a]pyrazine-3-yl acetate

[0147] 8-(2,3-difluorobenzyl)-2-((5-ethylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(3,5-difluorobenzyl)-2-((5-ethylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(2,6-difluorobenzyl)-2-((5-ethylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(2,6-difluorobenzyl)-2-((4,5-dimethylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 2-((4,5-dimethylfuran-2-yl)methyl)-8-(2-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate

[0148] 2-((4,5-dimethylfuran-2-yl)methyl)-8-(3-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-6-phenyl-2-((5-propylfuran-2-yl)methyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-(2,3-difluorobenzyl)-2-((4-ethyl-5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-((4-ethyl-5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-((5-isopropyl-4-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate

[0149] 8-Benzyl-2-((5-ethyl-4-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(2,3-difluorobenzyl)-2-((5-ethyl-4-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-benzyl-2-(1-(furan-2-yl)ethyl)-6-phenylimidazo[1,2-a]pyrazine-3-ylacetate 8-(2,3-difluorobenzyl)-2-((5-isopropyl-4-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-(furan-2-ylmethyl)-6-(3-hydroxyphenyl)imidazo[1,2-a]pyrazine-3-yl acetate;

[0150] Or relating to compounds having the following names in general formula (V): 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(5-methylfuran-2-yl)propanoic acid 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(5-ethylfuran-2-yl)propanoic acid 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(4,5-dimethylfuran-2-yl)propanoic acid 2-((3-benzyl-5-(2-fluorophenyl)pyrazine-2-yl)amino)-3-(furan-2-yl)propanoic acid 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(m-tolyl)propanoic acid

[0151] 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(3-methoxyphenyl)propanoic acid (3-benzyl-5-(2-fluorophenyl)pyrazine-2-yl)phenylalanine 2-((3-benzyl-5-(2,6-difluorophenyl)pyrazine-2-yl)amino)-3-(furan-2-yl)propanoic acid 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(5-(trifluoromethyl)furan-2-yl)propanoic acid (3-benzyl-5-(2,6-difluorophenyl)pyrazine-2-yl)phenylalanine

[0152] 2-((3-benzyl-5-(2-fluorophenyl)pyrazine-2-yl)amino)-3-(5-methylfuran-2-yl)propanoic acid 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(5-cyclopropylfuran-2-yl)propanoic acid 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(3-fluorophenyl)propanoic acid 2-((3-benzyl-5-(2-fluorophenyl)pyrazine-2-yl)amino)-3-(5-ethylfuran-2-yl)propanoic acid 2-((3-benzyl-5-(3-fluorophenyl)pyrazine-2-yl)amino)-3-(5-methylfuran-2-yl)propanoic acid

[0153] 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(2-fluorophenyl)propanoic acid 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(5-ethylthiophen-2-yl)propanoic acid 2-((3-benzyl-5-(2-fluorophenyl)pyrazine-2-yl)amino)-3-(4,5-dimethylfuran-2-yl)propanoic acid (3-(2-fluorobenzyl)-5-phenylpyrazine-2-yl)phenylalanine (3-(3-fluorobenzyl)-5-phenylpyrazine-2-yl)phenylalanine

[0154] 2-((3-(3-fluorobenzyl)-5-phenylpyrazine-2-yl)amino)-3-(furan-2-yl)propanoic acid 2-((3-(2-fluorobenzyl)-5-phenylpyrazine-2-yl)amino)-3-(m-tolyl)propanoic acid 2-((3-(2-fluorobenzyl)-5-phenylpyrazine-2-yl)amino)-3-(3-methoxyphenyl)propanoic acid 2-((3-(2-fluorobenzyl)-5-phenylpyrazine-2-yl)amino)-3-(furan-2-yl)propanoic acid 2-((3-(2-fluorobenzyl)-5-phenylpyrazine-2-yl)amino)-3-(5-methylfuran-2-yl)propanoic acid

[0155] 2-((3-(3-fluorobenzyl)-5-phenylpyrazine-2-yl)amino)-3-(3-methoxyphenyl)propanoic acid 2-((3-(3-fluorobenzyl)-5-phenylpyrazine-2-yl)amino)-3-(m-tolyl)propanoic acid 3-(5-ethylfuran-2-yl)-2-((3-(3-fluorobenzyl)-5-phenylpyrazine-2-yl)amino)propanoic acid 2-((3-(2-chlorobenzyl)-5-phenylpyrazine-2-yl)amino)-3-(5-methylfuran-2-yl)propanoic acid 2-((3-(3-fluorobenzyl)-5-phenylpyrazine-2-yl)amino)-3-(5-methylfuran-2-yl)propanoic acid

[0156] 3-(5-ethylfuran-2-yl)-2-((3-(2-fluorobenzyl)-5-phenylpyrazine-2-yl)amino)propanoic acid 3-(3-(2,6-difluorobenzyl)-5-phenylpyrazine-2-yl)-2-(furan-2-ylmethyl)propanoic acid 3-(3-(3,5-difluorobenzyl)-5-phenylpyrazine-2-yl)-2-(furan-2-ylmethyl)propanoic acid 3-(3-(3-chlorobenzyl)-5-phenylpyrazine-2-yl)-2-(furan-2-ylmethyl)propanoic acid 3-(3-(3-fluorobenzyl)-5-(2-fluorophenyl)pyrazine-2-yl)-2-((5-methylfuran-2-yl)methyl)propanoic acid

[0157] 3-(3-(2,3-difluorobenzyl)-5-phenylpyrazine-2-yl)-2-(furan-2-ylmethyl)propanoic acid 3-(3-(2,3-difluorobenzyl)-5-phenylpyrazine-2-yl)-2-((5-methylfuran-2-yl)methyl)propanoic acid 3-(3-(2,5-difluorobenzyl)-5-phenylpyrazine-2-yl)-2-(furan-2-ylmethyl)propanoic acid 3-(3-(2,5-difluorobenzyl)-5-phenylpyrazine-2-yl)-2-((5-methylfuran-2-yl)methyl)propanoic acid 3-(3-(3,5-difluorobenzyl)-5-phenylpyrazine-2-yl)-2-((5-methylfuran-2-yl)methyl)propanoic acid

[0158] 2-Benzyl-3-(3-(2,3-difluorobenzyl)-5-phenylpyrazine-2-yl)propanoic acid 2-Benzyl-3-(5-phenyl-3-(2-(trifluoromethyl)benzyl)pyrazine-2-yl)propanoic acid 2-Benzyl-3-(5-phenyl-3-(3-(trifluoromethyl)benzyl)pyrazine-2-yl)propanoic acid 2-Benzyl-3-(5-phenyl-3-(2,3,5-trifluorobenzyl)pyrazine-2-yl)propanoic acid 3-(3-(2,6-difluorobenzyl)-5-phenylpyrazine-2-yl)-2-((5-methylfuran-2-yl)methyl)propanoic acid

[0159] 3-(3-(2,5-difluorobenzyl)-5-phenylpyrazine-2-yl)-2-((4,5-dimethylfuran-2-yl)methyl)propanoic acid 3-(3-(2,5-difluorobenzyl)-5-phenylpyrazine-2-yl)-2-((5-ethylfuran-2-yl)methyl)propanoic acid 3-(3-(2,3-difluorobenzyl)-5-phenylpyrazine-2-yl)-2-((4,5-dimethylfuran-2-yl)methyl)propanoic acid 3-(3-(3,5-difluorobenzyl)-5-phenylpyrazine-2-yl)-2-((4,5-dimethylfuran-2-yl)methyl)propanoic acid 3-(furan-2-yl)-2-((5-phenyl-3-(2,3,5-trifluorobenzyl)pyrazine-2-yl)methyl)propanoic acid

[0160] 3-(3-(2,3-difluorobenzyl)-5-phenylpyrazine-2-yl)-2-((5-ethylfuran-2-yl)methyl)propanoic acid 3-(3-(3,5-difluorobenzyl)-5-phenylpyrazine-2-yl)-2-((5-ethylfuran-2-yl)methyl)propanoic acid 3-(3-(2,6-difluorobenzyl)-5-phenylpyrazine-2-yl)-2-((5-ethylfuran-2-yl)methyl)propanoic acid 3-(3-(2,6-difluorobenzyl)-5-phenylpyrazine-2-yl)-2-((4,5-dimethylfuran-2-yl)methyl)propanoic acid 3-(4,5-dimethylfuran-2-yl)-2-((3-(2-fluorobenzyl)-5-phenylpyrazine-2-yl)methyl)propanoic acid

[0161] 3-(4,5-dimethylfuran-2-yl)-2-((3-(3-fluorobenzyl)-5-phenylpyrazine-2-yl)methyl)propanoic acid 2-((3-(2,3-difluorobenzyl)-5-phenylpyrazine-2-yl)amino)-3-(4-ethyl-5-methylfuran-2-yl)propanoic acid 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(4-ethyl-5-methylfuran-2-yl)propanoic acid 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(5-isopropyl-4-methylfuran-2-yl)propanoic acid 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(5-ethyl-4-methylfuran-2-yl)propanoic acid

[0162] 2-((3-(2,3-difluorobenzyl)-5-phenylpyrazine-2-yl)amino)-3-(5-ethyl-4-methylfuran-2-yl)propanoic acid 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(furan-2-yl)butanoic acid (144) 2-((3-(2,3-difluorobenzyl)-5-phenylpyrazine-2-yl)amino)-3-(5-isopropyl-4-methylfuran-2-yl)propanoic acid 2-((3-benzyl-5-(3-(benzyloxy)phenyl)pyrazine-2-yl)amino)-3-(furan-2-yl)propanoic acid 2-((3-benzyl-5-(3-(hydroxy)phenyl)pyrazine-2-yl)amino)-3-(furan-2-yl)propanoic acid.

[0163] In another respect, the present invention relates to a compound of the following formula (VII): [ka]

[0164] (In the formula, R1 is H or C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 10 Aryl, Aralkyl and C5-C 10 - Represents a group selected from member heteroaryl groups, such as C1-C6 alkyl, C3-C7 cycloalkyl, and C6-C 10 Aryl, Aralkyl and C5-C 10 - The member heteroaryl group is optionally substituted with at least one Y1 group; R2 is C6-C 10 Aryl and C5-C 10 - Represents a group selected from member heteroaryl groups, and the C6-C 10 Aryl and C5-C 10 - The member heteroaryl group is optionally substituted with at least one Y2 group; R3 represents an aralkyl group, which is optionally substituted with at least one Y3 group;

[0165] Y is a leaving group, particularly a halogen, more specifically -Cl; The above Y1, Y2, and Y3 are each independent of the following: - C1-C6 alkyl groups; - C3-C7 cycloalkyl groups; - Halogen; - -OR ii base Selected from; Rii H, C1-C6 alkyl, C3-C 10 (Represents a cycloalkyl group or aralkyl group)

[0166] However, the compound has the following formula: [ka] It is not one of them.

[0167] In this particular embodiment, R1 represents H. In certain embodiments, R3 represents a benzyl group optionally substituted with at least one halogen, more specifically with F, as defined above.

[0168] More specifically, R3 is as follows: [ka] It is selected from the group consisting of the following.

[0169] In certain embodiments, R2 represents a phenyl molecule optionally substituted as defined above, In particular, R2 represents phenyl optionally substituted with at least one halogen, especially F. More specifically, R2 is: [ka] It is selected from the group consisting of the following.

[0170] definition The following terms and phrases included in this specification are defined as follows: As used herein, the range of values ​​in the form "xy" or "x~(to) y" or "x through y" includes integers x, y and integers in between. For example, the phrases "1-6" or "1~6" or "1 to 6" are intended to include integers 1, 2, 3, 4, 5, and 6. Preferred embodiments include individual integers within the range as well as any subcombination of integers. For example, preferred integers for "1-6" include 1, 2, 3, 4, 5, 6, 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 2-6, etc.

[0171] As used herein, the term "alkyl" means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, neopentyl, 1-ethylpropyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, hexyl, etc. The alkyl portion of an alkyl-containing group, such as aralkyl or O-alkyl, has the same meaning as alkyl as defined above. Preferred lower alkyl groups are alkyl groups as defined above, containing 1 to 4 carbon atoms. Names such as "C1-C4 alkyl" mean alkyl groups containing 1 to 4 carbon atoms.

[0172] As used herein, the term "cycloalkyl" refers to a saturated or partially saturated monocyclic or bicyclic alkyl ring system containing 3 to 7 carbon atoms. Names such as "C5-C6 cycloalkyl" refer to a cycloalkyl group containing 5 to 6 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pinenyl, and adamantyl. The cycloalkyl portion of a cycloalkyl-containing group, such as O-cycloalkyl, has the same meaning as alkyl as defined above.

[0173] As used herein, the term “aryl” means an aromatic ring system of monocyclic or bicyclic hydrocarbons having 6 to 10 ring carbon atoms, substituted or unsubstituted. Examples include phenyl and naphthyl. Preferred aryl groups include unsubstituted or substituted phenyl and naphthyl groups. Condensed ring systems, including, for example, ring systems in which an aromatic ring is fused to a cycloalkyl ring, are included in the definition of “aryl.” Examples of such fused ring systems include indan, indene, and tetrahydronaphthalene.

[0174] As used herein, the term “aralkyl” means an arylalkyl group of the formula Ar-alkyl-, where “aryl” and “alkyl” are as defined above, in particular Ar being phenyl and in particular alkyl being Me(-CH2-).

[0175] As used herein, the term “heteroaryl” means an aromatic group containing 5 to 10 ring carbon atoms, in which one or more ring carbon atoms are replaced by at least one heteroatom such as -O-, -N-, or -S-. Examples of heteroaryl groups include pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxathiolyl, oxadiazolyl, triazolyl, oxatriazolyl, flazanyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, triazinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, isobenzofuranyl, prinyl, quinazolinyl, quinolyl, isoquinolyl, benzimidazolyl, benzothiazolyl, benzothiophenyl, thianaphthenyl, benzoxazolyl, benzisoxazolyl, synnolinyl, phthalazinyl, naphthilidinyl, and quinoxalinyl. For example, fused ring systems, including those in which an aromatic ring is fused to a heterocycloalkyl ring, are included in the definition of "heteroaryl." Examples of such fused ring systems include phthalamides, phthalic anhydride, indoline, isoindoline, tetrahydroisoquinoline, chroman, isochroman, chromene, and isochromene.

[0176] As used herein, the term “hetallalkyl” means a heteroarylalkyl group of the formula heteroaryl-alkyl-, where “heteroaryl” and “alkyl” are as defined above, and in particular alkyl is Me(-CH2-).

[0177] As used herein, the term “pharmaceutically acceptable” means a compound, material, composition and / or form of medication that is suitable, to the extent of reasonable medical judgment, for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problematic complications commensurate with a reasonable benefit / risk ratio.

[0178] As used herein, the term “luminescent protoprotein” means a luminescent protein that utilizes luciferase and luciferin. A "strong acid" is an acid that becomes completely ionized in an aqueous solution by losing one proton.

[0179] The term "leaving group" refers to a nucleofuge, particularly in nucleophilic substitution reactions, that retains a lone pair of electrons from a previous bond with another species. The leaving group is selected from, for example, halogens, especially -I, -Br, -Cl, and -F, as well as the triflate -OS(O2)CF3. All other terms used in describing this invention have meanings well known in the art.

[0180] In another view, the present invention relates to pharmaceutically acceptable salts of the aforementioned compounds. As used herein, “pharmaceutically acceptable salt” includes salts of such compounds derived from combinations of non-toxic acids with the compounds of the present invention. Acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, as well as organic acids such as acetic acid, citric acid, propionic acid, tartaric acid, glutamic acid, salicylic acid, oxalic acid, methanesulfonic acid, para-toluenesulfonic acid, succinic acid, and benzoic acid, and related inorganic and organic acids.

[0181] In addition to pharmaceutically acceptable salts, other salts are included in the present invention. These can function as intermediates in the purification of compounds, the production of other salts, or in the identification and characterization of compounds or intermediates. pharmaceutically acceptable salts of the compounds of the present invention can also exist as various solvates with, for example, water, methanol, ethanol, dimethylformamide, ethyl acetate, etc. Mixtures of such solvates can also be prepared. The origin of such solvates is from the solvents inherent in the solvent of crystallization, preparation, or crystallization, or from solvents associated with such solvents. Such solvents are within the scope of the present invention.

[0182] It is recognized that the compounds of the present invention can exist in various stereoisomers. Therefore, the compounds of the present invention include both diastereomers and optical isomers. Typically, the compounds are prepared as racemates and can be conveniently used as such, but if desired, the individual stereoisomers can be isolated or synthesized by conventional methods. Such racemates, individual optical isomers, and mixtures thereof form part of the present invention.

[0183] Methods for producing and isolating such optically active forms are well known in the art. Specific stereoisomers can be produced by stereospecific synthesis using optically isomerically pure or optically rich starting materials. Specific stereoisomers of starting materials or products can be separated and recovered by methods known in the art, such as racemic separation, normal-phase, reverse-phase, and chiral chromatography, recrystallization, enzymatic separation, or fractional recrystallization of addition salts formed by reagents used for that purpose. Useful methods for separating and recovering specific stereoisomers are described in Eliel, EL; Wilen, SH. Stereochemistry of Organic Compounds; Wiley: New York, 1994, and Jacques, J, et al. Enantiomers, Racemates, and Resolutions; Wiley: New York, 1981, which are incorporated herein by direct reference, respectively.

[0184] synthesis The compounds of the present invention may be produced by many methods well known to those skilled in the art, including but not limited to those described below, or by modifications of these methods by applying standard methods known to those skilled in the art of organic synthesis. Appropriate modifications and substitutions will be readily apparent and well known to those skilled in the art, or readily available from the chemical literature. Specifically, such methods can be found in RC Larock, Comprehensive Organic Transformations, Wiley-VCH Publishers, 1999.

[0185] All methods disclosed in connection with the present invention are intended to be carried out on any scale, including milligrams, grams, multigrams, kilograms, multikilograms, or commercial industrial scale.

[0186] It will be understood that the compounds of the present invention may contain one or more asymmetrically substituted carbon atoms and may be isolated in optically active or racemic forms. Therefore, unless a specific stereochemistry or isomer is specifically indicated, all forms are intended with respect to structure: chiral, diastereomer, racemic, and isomeric. Methods for producing and isolating such optically active forms are well known in the art. For example, mixtures of stereoisomers may be isolated by standard methods including, but not limited to, racemic resolution, normal-phase, reverse-phase, and chiral chromatography, preferential salt formation, recrystallization, or by chiral synthesis from chiral starting materials or by intentional synthesis of target chiral centers.

[0187] The compounds of the present invention can be prepared by various synthetic routes. Reagents and starting materials are commercially available or readily synthesized by methods well known to those ordinarily skilled in the art. Unless otherwise specified, all substitutions are as previously defined.

[0188] In the reactions described below, it may be necessary to protect reactive functional groups, such as hydroxy, amino, imino, thio, or carboxyl groups desired in the final product, to avoid their undesirable inclusion in the reaction. Conventional protecting groups can be used according to standard techniques, e.g., TW Greene and PGM Wuts in Protective Groups in Organic Chemistry, 3 rd ed., John Wiley and Sons, 1999; see JFW McOmie in Protective Groups in Organic Chemistry, Plenum Press, 1973.

[0189] The present invention also relates to a method for producing a compound of formula (III) as defined above, comprising the step of converting a compound of formula (IV) as defined above to a compound of formula (III). In a particular embodiment, a method for producing the compound of formula (III) as defined above includes the following steps: i) A step of contacting a compound of formula (IV) as defined above with a strong acid in the presence of a solvent for the compound of formula (IV); or ii) A step of contacting the compound of formula (IV) as defined above with ammonia in the presence of a solvent for the compound of formula (IV), and especially under an inert gas when a strong acid or ammonia is used.

[0190] In certain embodiments, the strong acid is hydrochloric acid. In a particular embodiment, the conversion of (IV) to (III) is carried out at a temperature within the range of 40°C to 90°C, for example, 50°C, especially in a sealed tube. In certain embodiments, the strong acid used for the conversion of (IV) to (III) is hydrochloric acid, particularly in solution of ethanol. In a particular embodiment, the conversion of (IV) to (III) is performed at a temperature within the range of 40°C to 90°C, for example, at 50°C.

[0191] In a particular embodiment, the compound of formula (IV) is produced by a method comprising the following steps: i) A step of converting the compound of formula (IV) as defined above to the compound of formula (V), followed by a step of converting the compound of formula (V) to the compound of formula (IV); or ii) A step to convert the compound of formula (VI) to the compound of formula (IV).

[0192] In a particular embodiment, the compound of formula (IV) is produced by a method comprising the following steps: i) A step of hydrolyzing the COO-Ra ester functional group of the compound of formula (VI) as defined above, in particular, by contacting the compound of formula (VI) with a strong base in the presence of the solvent of the compound of formula (VI) to obtain the compound of formula (V), and then contacting the compound of formula (V) with a compound selected from the group consisting of anhydrides, chloroformates, and dicarbonates: or ii) A step of contacting the compound of formula (VI) with a mixture of acetic acid and an anhydride of an aliphatic acid, particularly acetic anhydride.

[0193] In certain embodiments, the strong base used for the conversion of (VI) to (V) is sodium hydroxide, and the hydrolysis is carried out at temperatures particularly within 15–30°C. In certain embodiments, the compound selected from the group consisting of anhydrides, chloroformates, and dicarbonates is an anhydride of acetic acid or pivalic acid, and contact with the compound is carried out at a temperature particularly within 15-30°C. In a particular embodiment, the conversion of (VI) to (IV) is carried out at temperatures within the range of 100°C to 150°C, particularly 140°C, especially under microwave irradiation.

[0194] In a particular embodiment, the compound of formula (VI) is obtained by a method comprising the following steps: i) The following equation (VIII): [ka]

[0195] Replace the hydroxyl group with a leaving group -Y (where Y is a halogen in particular) to obtain the following equation (VII): [ka] The process of obtaining the compound, and

[0196] ii) In the presence of copper or palladium and a ligand selected from BINAP, xanthophos, or dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazole-2-ylidene](3-chloropyridyl) (PEPPSI-IPentCl), the compound of formula (VII) is converted to the following formula (IX): [ka] A step of contacting the compound with the compound of formula (VI) to obtain the compound of formula (VI), Here, R1, R2, R3, R4, Z and R d This is as defined above.

[0197] In a particular embodiment, Y is Cl, and step vi) is the step of contacting the compound of formula (VIII) with phenylphosphonic acid dichloride at a temperature particularly within the range of 60°C to 150°C, more specifically at 100°C.

[0198] In a particular embodiment, Y is Br, and step i) is a step of contacting a compound of formula (VIII) with triflic anhydride, followed by a step of contacting the product obtained in the previous step with sodium bromide, particularly at a temperature within 80°C to 160°C, for example 120°C, especially in a sealed tube.

[0199] In certain embodiments, step ii) is carried out in the presence of a base, particularly cesium carbonate. In a particular embodiment, the catalyst and the ligand for step ii) are palladium acetate and BINAP, respectively, and step ii) is carried out at a temperature within the range of 40°C to 80°C, more specifically at 60°C.

[0200] In a particular embodiment, the compound of formula (VIII) is the following formula (X): [ka] From a method including the steps of dehydrogenation and aromatization of the compound;

[0201] especially, i) A step of contacting the compound of formula (X) with sulfur at a temperature within reflux of 180°C in the presence of a solvent; or ii) A step of contacting the compound of formula (X) with a peroxide-based oxidizing agent such as peracetic acid, followed by heat treatment at a temperature within 150°C to 190°C, particularly in the presence of a solvent. It is obtained by a method that includes [a specific method].

[0202] A general route for manufacturing an example of the present invention is shown in Scheme AC below. The reagents and starting materials are commercially available or readily synthesized by methods known to the ordinary art in question. Unless otherwise specified, all substitutions of compound AQ shown in scheme AC are as previously defined for the corresponding compound (III)-(X).

[0203] [ka]

[0204] With respect to the synthetic route described in Scheme A, step a is the 1,4-addition of amino ester B to nitrovinyl A, which is preferably achieved in the absence of a solvent. Step b is the reduction of the nitro group of compound C, which is preferably achieved in an acidic medium using zinc. Step c involves the heat-induced cyclization of the resulting free diamine D to compound E. Typically, steps a, b, and c have been shortened to minimize potential losses in the process of side reactions and purification steps. Step e is the dehydrogenation / aromatization of compound E to give hydroxypyrazine derivative H, which is preferably achieved using sulfur in a boiling inert solvent. Alternative means have been found by the production of 5-oxo-2,3,4,5-tetrahydropyrazine 1-oxide derivative J using peracetic acid (step f) and its rearrangement to hydroxypyrazine derivative H (step h). 1 When is H, 3-hydroxypyrazine H can also be produced by step g using the reported (J. Am. Chem. Soc., 1949, 78; US 2520088, 1949; J. Am. Chem. Soc., 1952, 1580; US 4046763, 1977) condensation of glyoxal G and aminoamide F (produced by step d from the reaction between aminoester B and ammonia).

[0205] Step j involves the replacement of the hydroxyl group of compound H with a halogen to give compound L. When the X group is a chloride, the preferred reagent used to achieve this conversion is phenylphosphonic acid dichloride. These compounds can also be prepared in two steps (i and l) by a reaction similar to the subsequent aromatic Finkelstein reaction (Heterocycles, 1998, 1255; WO 2012119046, 2012), which involves an ester intermediate with strong leaving ability such as Triflick ester K. Subsequent substitution with an iodide salt to obtain the iodine derivative (X=I) is also possible by known acid-catalyzed reactions (J. Org. Chem., 1961, 1907; Tetrahedron, 1998, 9701; Synlett, 2003, 1801). Furthermore, it was found that the direct conversion of the 5-oxo-2,3,4,5-tetrahydropyrazine 1-oxide derivative J to chloropyrazine L (step k) is also possible, for example, by using phenylphosphonic acid dichloride and heat. Finally, a recent publication (Org. Process. Res. Dev. 2017, 21, 346) suggests the possibility of producing the corresponding aminopyrazine M from these halogen nopyrazines via step m, which is a key intermediate for most previously reported imidazo[1,2-a]pyrazine-3(7H)-one luciferin (Chem. Eur. J. 2015, 21, 17158).

[0206] As shown in scheme B from halogenopyrazine L, the production of O-protected luciferin having general formula P has been found to be possible either in two independent steps via amino acid O or in a one-pot process from their amino ester precursors having general formula N. Among many points of interest, it is important to state that our invention addresses the unmet need for processing fresh solutions of any luciferin having general formula Q and thus for a regenerative potency. Thus, O-protected luciferin having general formula P (pre-luciferin) can yield a ready-to-use solution of the corresponding luciferin Q in a simple and unprecedented process. In fact, these O-protected luciferin P are far more stable and can be conveniently shipped, stored at room temperature for extended periods, and then hydrolyzed to easily produce a solution of luciferin for immediate use. Furthermore, the removal of such groups can be easily achieved in vials without the need for an inert atmosphere using a solution containing a strong acid such as hydrochloric acid. Indeed, since the products resulting from the chemiluminescence process are hardly observed during this deprotection process, the use of this unprecedented acid helps to provide a certain degree of stability to the resulting solution. This is in stark contrast to the use of bases such as ammonia, which have been previously reported (Tetrahedron Lett., 1977, 2685; Chemistry, 2013, 14970), resulting in much more extensive decomposition in the presence of oxygen.

[0207] With respect to the chemistry described in Scheme B, step n is an amination reaction that yields compound N using a wide variety of α-aminoesters B. This can be achieved using copper or palladium catalysts and various ligands described for many halogenated aromatic or heteroaromatic derivatives (Acc. Chem. Res., 1998, 852; J. Organomet. Chem., 1999, 125; Chem. Rev., 2006, 2651; Angew. Chem., Int. Ed., 2008, 6338; Angew. Chem., Int. Ed., 2008, 3096; J. Org. Chem., 2013, 7930; Org. Lett., 2016, 4128; Beilstein J. Org. Chem., 2012, 2004; Tetrahedron, 2011, 9405). In this case, it was found that this step requires a low temperature (60°C) to avoid side reactions. Step o yields acid O by hydrolysis of the ester functional group of N, which is preferably achieved under basic conditions. Step p is O-protection following cyclization, which is preferably achieved by activating the acid functional group of O with various reagents such as anhydride, chloroformate, or dicarbonate. This directly yields a considerably more stable O-protected compound. Furthermore, in many cases, steps o and p can be performed in a one-pot reaction using acetic acid together with acetic anhydride (step q). Finally, the compound N or O can be directly converted to the corresponding luciferin Q using, for example, high-temperature acetic acid and / or hydrochloric acid (step r).

[0208] [ka]

[0209] Considering each of the synthesis steps individually shown in the scheme, step e, dehydrogenation / aromatization of piperazine-2-one to 2-hydroxypyrazine H; step f, production of N-oxide J and step h, rearrangement to 2-hydroxypyrazine H; step k, conversion of N-oxide J to halogenopyrazine L; and step p, isolation of the O-protected derivative P obtained from compound O or step q, from compound N, are the only steps without precedent. Furthermore, before or after each of these steps, the side chain R 1 , R 2 , R 3 and R 4 Furthermore, further chemistry focusing on these various protecting or functional groups may be devised to modify and / or adapt them to the chemistry used in subsequent steps. For example, the final hydrogenation of the benzyl group protecting the OH functional group present in a type N or O compound may be carried out before the conversion to a type P compound by steps o-q.

[0210] The synthetic route for this uses large quantities of many amino esters of type B. Therefore, to produce such intermediates, we used the route shown in scheme C, for example. The first route is based on the reported use of ethyl nitro to produce the corresponding nitroacrylate and then reduce it to the amino ester (Bull. Acad. Sci. USSR Div. Chem. Sci. (Engl. Transl.), 1980, 458; Bull. Acad. Sci. USSR Div. Chem. Sci. (Engl. Transl.), 1981, 466). The simplification of the method led us to shorten the first three steps of this method and simply isolate the intermediate nitroester R before the final reduction to amino ester B. The second route gives a broader range and is based on the use of the Knoevenagel reaction with diethyl malonate, which gives the corresponding substituted malonate after reduction. From these, as reported (Ber. Dtsch. Chem. Ges., 1902, 3772; Org. Process. Res. Dev., 2007, 1069), α-oxime esters can be readily produced and reduced to the corresponding amino esters. Again, shortening the first three steps has repeatedly led us to the proper isolation of only the intermediate oxime S before the final reduction to the amino ester. Less common methods have also been used to produce other types of α-oxime esters, as will be further described in detail below.

[0211] [ka] [Brief explanation of the drawing]

[0212] [Figure 1]Figure 1 shows the time-course HPLC profile of the acetyl hydrolysis of P-21 (M = 451) to the corresponding luciferin Q-12 (M = 409). The results were obtained on an Agilent instrument with a 3.5 μm XDB-C18 column and a water / methanol gradient (containing 5 mM ammonium formate, 95-5 to 5-95 at 3.5 min, 5-95 at 3.5 min, then back to 95-5 at 0.5 min), and a UV monitor set at 254 nM. [Figure 2] Figure 2 shows the bioluminescence emission of furimazine (Q-1) and hydroxyfurimazine (Q-80), as well as imidazo[1,2-a]pyrazine-3(7H)-one Q-84 and Q-85 of the present invention, over a period of 2 hours. [Figure 3] Figure 3 shows the dynamic range (relative units versus serial dilution) of nanoKAZ, plotted using imidaso[1,2-a]pyrazine-3(7H)-one Q-3. [Figure 4] Figure 4 shows a comparative Lineweaver-Burk representation of the bioluminescent activity of nanoKAZ using flimazine (Q-1) and imidazo[1,2-a]pyrazine-3(7H)-one Q-3 as substrates: In both cases, the enzyme concentration was kept constant, and the reciprocal of the reaction rate (relative units (RLU) / sec) was plotted against the reciprocal of the substrate concentration (10⁵M⁻¹). The two dashed lines (linear regressions) converge to the same intercept (-1 / Km) on the x-axis and different intercepts (1 / Vmax) on the y-axis. The equations for the two linear regressions are shown, and the corresponding correlation coefficients (R²) are reported using experimental data. [Figure 5]Figure 5 compares the expression and location of protein chimeras fused with nanoKAZ in transiently transfected HEK and Jurkat cell lines, as well as in primary human T cells: cytokine receptor IL7Rα:nanoKAZ at the membrane (top), microtubule-associated enconsin tubulin-binding protein EMTB:nanoKAZ (middle), and transcription factor STAT5a:nanoKAZ densely clustered across the cytoplasm and faintly in the nucleus (bottom). Images were obtained from live cells in 1 second using Q-1 (top row) and Q-3 (rows 2-4) substrates, showing intracellular resolution and luminescence acquisition at Q-3 under cell culture conditions. [Figure 6] Figure 6 shows a superposition of two 1H NMR spectra of the same batch of compound 8-benzyl-2-((5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate (stored at 4°C) taken on the day of manufacture (A) and 30 months later (B). [Modes for carrying out the invention] [Examples]

[0213] Explanation, Chemistry General experimental procedure For reactions that refer to the heating method, Biotage Initiator 2 Microwave A bread oven was used. 1 The 1H NMR spectra were obtained at 400 MHz and 100 MHz, respectively, using the Bruker NMR spectrum analyzer. The data was recorded using an Avance 400 spectrometer. Shift (δ) is given in ppm relative to the TMS signal, and coupling constant (J) is given in Hertz. Column chromatography was performed using either Merck silica gel 60 (0.035–0.070 mm) or neutral alumina, with an automated collection system driven by a solvent pump and a UV detector set to 254 nm, unless otherwise specified. Sample deposition was performed by absorption of a small amount of the mixture to be purified onto a solid phase, followed by deposition to the top of the column. Low-resolution mass spectra were obtained using an Agilent 1100 series LC / MSD system with electrospray ionization in air, and high-resolution mass spectra (HRMS) were obtained using a Waters Micromass Q-Tof with an electrospray ion source.

[0214] General procedure for the synthesis of α-aminoester B via α-nitroester R, and production of nitroester R. Step 1: Production of Dimethylacetal The corresponding aldehyde (0.044 mol) and trimethyl orthoformate (5.8 mL, 0.053 mol) were dissolved in methanol (7.3 mL, 0.24 mol, dried on a 3A molecular sieve). Add DOWEX 50WX8-100 ion exchange resin (0.2 g) to this, and the solution is treated with calcium chloride- The mixture was stirred overnight under air-protected conditions. The resin was then removed by filtration, the filter was washed with dry methanol, and the filtrate was concentrated to dryness (at 30 mbar) to obtain the corresponding volatile acetal (which is usually not sufficiently stable in CDCl3).

[0215] Step 2: Condensation with ethyl nitroacetate to produce nitroacrylate To remove some final trace amounts of water, a calcium chloride-protective atmosphere is used before this reaction. Below, nitroacetate (5.7 g, 0.042 mol) was dissolved in acetic anhydride (5 mL, 0.053 mol) for 15 minutes. The mixture was stirred. To this solution, the crude acetal dissolved in acetic anhydride (5.1 mL, 0.053 mol) was added, and the solution was heated at the temperatures and times described below, allowing the resulting low-boiling methyl acetate to be removed. The mixture was then concentrated to dryness to obtain crude 3-aryl-2-nitroacrylate.

[0216] Step 3: Reduction with sodium borohydride to produce substituted nitroesters Disperse crude acrylate in isopropanol (100 mL, dried on a 4A molecular sieve). / It was dissolved. Sodium borohydride (2 g, 0.053 mol) was added little by little to this, and The suspension was heated to reflux and then cooled to room temperature. Acetic acid was then carefully added (3.3 mL, 0.053 mol), and the isopropanol was removed under vacuum. The crude residue was dispersed in water (100 mL), and 10% hydrochloric acid (5.7 mL, 0.0057 mol) was added to aid the hydrolysis of the partially reacted boron hydride. The resulting solution was extracted with ethyl acetate, the organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated to dryness. The residue was then purified as described in each of the following cases to obtain the corresponding α-nitroester R.

[0217] Ethyl 3-(4-fluorophenyl)-2-nitropropanoate (R-1): After heating at 190°C for 4 hours, the oil is extracted through a concentration process and chromatography in two silica gels (cyclohexane-ethyl acetate 9 / 1) and (cyclohexane-dichloromethane 2 / 1). It was obtained as a granular substance (2.72 g, 23% from 4-fluorobenzaldehyde).

[0218] 1H NMR (CDCl3): 7.21 (m, 2H), 7.02 (m, 2H), 5.32 (dd, 1H, J = 5.7, 9.4), 4.30 (m, 2H), 3.56 (dd, 1H, J = 9.4, 14.7), 3.47 (dd, 1H, J = 5.7, 14.7), 1.31 (m, 3H). HRMS (m / z): C 11 H 11 [MH] of the calculated value for FNO4 - : 240.0672; measured value, 240.0645.

[0219] Ethyl 3-(2-methoxyphenyl)-2-nitropropanoate (R-2): After heating at 150°C for 9 hours, a concentration process and chromatography with silica gel (cyclohex (6.12 g, 2-methoxyben) obtained as an oily substance in the process of ethyl acetate (95 / 5~9 / 1) 53% from zualdehyde.

[0220] 1 H NMR (CDCl3): 7.28 (m, 1H), 7.14 (m, 1H), 6.91 (m, 2H), 5.57 (dd, 1H, J = 6.2, HRMS: C 12 H 15 Calculated value for NO5Na: 276.0848; Measured value: 276.0831.

[0221] Ethyl 3-(3-methoxyphenyl)-2-nitropropanoate (R-3): After heating at 150°C for 9 hours, a concentration process and chromatography with silica gel (cyclohex (2.34 g, 3-methoxyben) obtained as an oily substance in the process of ethyl acetate (95 / 5~9 / 1) 21% from zualdehyde.

[0222] 1 H NMR (CDCl3): 7.25 (t, 1H, J = 7.9), 6.81 (m, 3H), 5.35 (dd, 1H, J = 5.8, 9.3), 4.31 (q, 2H, J = 7.2), 3.81 (s, 3H), 3.56 (dd, 1H, J = 9.3, 14.7), 3.47 (dd, 1H, J = 5.8, 14.7), 1.31 (t, 3H, J = 7.2). HRMS: C 12 H 15 Calculated value for NO5Na: 276.0848; Measured value: 276.0831.

[0223] Ethyl 3-(4-methoxyphenyl)-2-nitropropanoate (R-4): After heating at 150°C for 9 hours, a concentration process and chromatography with silica gel (cyclohex (6.95 g, 4-methoxyben) obtained as an oily substance in the process of ethyl acetate (95 / 5~9 / 1) 55% from zualdehyde.

[0224] 1 H NMR (CDCl3): 7.15 (m, 2H), 6.86 (m, 2H), 5.31 (dd, 1H, J = 5.9, 9.5), 4.30 (m, 2H), 3.81 (s, 3H), 3.52 (dd, 1H, J = 9.5, 14.6), 3.44 (dd, 1H, J = 5.9, 14.6), 1.31 (t, 3H, J = 7.1). HRMS: C 12 H 15 Calculated value for NO5Na: 276.0848; Measured value: 276.0840.

[0225] Ethyl 3-(4-(benzyloxy)phenyl)-2-nitropropanoate (R-5): After heating at 150°C for 9 hours, a concentration process and chromatography with silica gel (cyclohex San - Ethyl acetate (92 / 8~9 / 1) was obtained as a yellow solid during the process (4.08 g, 4-benzyl ethyl acetate) 51% from xybenzaldehyde.

[0226] 1 H NMR (CDCl3): 7.46-7.33 (m, 5H), 7.15 (m, 2H), 6.94 (m, 2H), 5.31 (dd, 1H, J = HRMS: C 18 H 19 Calculated value for NO5Na: 352.1161; Measured value: 352.1150.

[0227] Ethyl 2-nitro-3-m-tolylpropanoate (R-6): After heating at 180°C for 8 hours, a concentration process and chromatography using two silica gels (silica gels) are performed. It was obtained as an oily substance (1.05 g, 16% from 3-methylbenzaldehyde) in the process of (cyclohexane - dichloromethane 2 / 1~1 / 6) ​​and (cyclohexane - ethyl acetate 97 / 3).

[0228] 1 H NMR (CDCl3): 7.22 (m, 1H), 7.60 (m, 1H), 7.01 (m, 2H), 5.33 (dd, 1H, J = 5.8, HRMS (m / z): C 12 H 14 Calculated value for NO4 [MH] - : 236.0923; Measured value, 236.0983.

[0229] Ethyl 3-(furan-2-yl)-2-nitropropanoate (R-7): In this case, the nitroacrylate was previously described (Org. Biomol. Chem., 2012, 524) It was thus produced directly from furfural. After chromatography on silica gel (dichloromethane-methanol 99 / 1), it was obtained as an oily substance (5.04 g, 39% from furfural).

[0230] 1 H NMR (CDCl3): 7.36 (m, 1H), 6.32 (m, 1H), 6.19 (m, 1H), 5.44 (dd, 1H, J = 5.5, HRMS: C9H 11 Calculated value for NO5Na: 236.0535; Measured value Value: 236.0522.

[0231] Ethyl 3-(5-methylfuran-2-yl)-2-nitropropanoate (R-8): After heating at 140°C for 2 hours, the concentration process and chromatography with silica gel (cyclohexa (3.44 g, 5-methylfurfulr) obtained as an oily substance in the process of n-dichloromethane 3 / 2) 60% of the answer is given after answering the question. 1 H NMR (CDCl3): 6.02 (d, 1H, J = 3.0), 5.86 (dd, 1H, J = 3.0, 0.9), 6.19 (m, 1H), 5.40 (dd, 1H, J = 5.5, 9.3), 4.30 (q, 2H, J = 7.1), 3.58 (dd, 1H, J = 9.3, 15.7), 3.45 (dd, 1H, J = 5.5, 15.7), 2.23 (s, 3H), 1.30 (t, 3H, J = 7.1). HRMS: C 10 H 13 Calculated value for NO5Na: 250.0691; Measured value: 250.0682.

[0232] Ethyl 3-(4,5-dimethylfuran-2-yl)-2-nitropropanoate (R-9): 1 As can be seen from the 1H NMR, this compound was heated at 140 °C for 2 hours, followed by a concentration step and silica gel. During chromatography (cyclohexane-dichloromethane 2 / 1) in a 2 / 1 quartz crystallization process, 50 mol% It was obtained as an oily substance containing ethyl-3-(4,5-dimethylfuran-2-yl)acrylate (1.94 g). This was used in the next step without further purification.

[0233] Ethyl 3-(5-ethylfuran-2-yl)-2-nitropropanoate (R-10): After heating at 140°C for 2 hours, a concentration process and chromatography (cyclo) in two silica gels are performed. It was obtained as an oily substance (3.68 g, 39% from 5-ethylfurfural) in the process of hexane-dichloromethane (2 / 1 to 1 / 6) and (cyclohexane-ethyl acetate 97 / 3).

[0234] 1H NMR (CDCl3): 6.05 (d, 1H, J = 3.0), 5.88 (m, 1H), 6.19 (m, 1H), 5.42 (dd, 1H, J = 5.7, 9.1), 4.31 (q, 2H, J = 7.0), 3.61 (dd, 1H, J = 9.1, 15.7), 3.48 (dd, 1H, J = 5.7, 15.7), 2.60 (q, 2H, J = 7.0), 1.32 (t, 3H, J = 7.0), 1.21 (t, 3H, J = 7.5). HRMS (m / z): C 11 H 14 [MH] of the calculated value for NO5 - : 240.0872; Measured value, 240.0857.

[0235] Ethyl 3-(furan-3-yl)-2-nitropropanoate (R-11): Ethyl (E)-3-( prepared as previously described (Org. Biomol. Chem., 2012, 524) It was obtained from furan-3-yl)-2-nitroacrylate as an oily substance after chromatography on silica gel (cyclohexane-ethyl acetate 95 / 5~9 / 1) (0.74 g, 34% from furan-3-carbaldehyde).

[0236] 1 H NMR (CDCl3): 7.40 (m, 1H), 7.34 (m, 1H), 6.30 (m, 1H), 5.26 (dd, 1H, J= 5.3, 9.4), 4.32 (q, 2H, J = 7.1), 3.39 (dd, 1H, J = 9.4, 15.2), 3.32 (dd, 1H, J = 5.4, 15.2), 1.32 (t, 3H, J = 7.1). HRMS: C9H 11 Calculated value for NO5Na: 236.0559; Measured value: 236.0567.

[0237] Ethyl 2-nitro-3-(thiophene-2-yl)propanoate (R-12): After heating at 140°C for 4 hours, a concentration process and chromatography (cyclo) in two silica gels are performed. It was obtained as an oily substance (3.43 g, 33% from thiophene-2-carbaldehyde) in the processes of hexane-dichloromethane (3 / 2) and cyclohexane-ethyl acetate (97 / 3~95 / 5).

[0238] 1 ¹H NMR (CDCl3): 7.23 (dd, 1H, J = 1.3, 5.1), 6.96 (m, 1H), 6.92 (m, 1H), 5.35 (dd, 1H, J = 5.6, 9.2), 4.32 (q, 2H, J = 7.1), 3.83 (dd, 1H, J = 9.2, 15.4), 3.70 (dd, 1H, J = 5.6, 15.4), 1.32 (t, 3H, J = 7.1). HRMS (m / z): Calculated values ​​for C9H8NO4 [MH] - , 228.0331; measured value, 228.0348.

[0239] General procedure for the reduction of α-nitroester R The α-nitroester under consideration (0.023 mol) was dissolved in ethanol (75 mL) and 37% hydrochloric acid (29 mL, 0.34 mol), and cooled to °C. Zinc powder (9.05 g, 0.13 mol, less than 10 μm) was also used. The (size) was added separately. This was left to stand and stirred overnight, then the ethanol was removed under vacuum, and the remaining The residue was dispersed in water and ethyl acetate, the suspension was made basic with 22% ammonia, extracted with ethyl acetate, the organic layer was washed with water and saline solution, dried over sodium carbonate, concentrated to dryness, and in some cases further purified as described below to obtain the amino ester.

[0240] Ethyl 2-amino-3-(4-fluorophenyl)propanoate (B-1): It was obtained as an oily substance (1.95 g, 94%). 1H NMR (CDCl3): 7.18 (m, 3H), 7.01 (m, 1H), 4.17 (q, 2H, J = 7.1), 3.68 (dd, 1H, J = 5.5, 7.6), 3.04 (dd, 1H, J = 5.5, 13.6), 2.86 (dd, 1H, J = 7.6, 13.6), 1.48 (s, 2H), 1.25 (t, 3H, J = 7.1). HRMS: C 11 H 15 Calculated value for FNO2: 212.1087; Measured value Value: 212.1069.

[0241] Ethyl 2-amino-3-(2-methoxyphenyl)propanoate (B-2): Obtained as an oily substance (5.16 g, 90%). 1 H NMR (CDCl3): 7.23 (m, 1H), 7.14 (m, 1H), 6.86-6.92 (m, 2H), 4.19 (q, 2H, J = 7.2), 3.84 (s, 3H), 3.81 (dd, 1H, J = 5.8, 8.1), 3.10 (dd, 1H, J = 5.8, 13.3), 2.84 (dd, 1H, J = 8.1, 13.3), 1.51 (s, 2H), 1.31 (t, 3H, J = 7.1). HRMS: Calculated value for C 12 H 18 NO3: 224.1287; Measured value, 224.1218.

[0242] Ethyl 2-amino-3-(3-methoxyphenyl)propanoate (B-3): It was obtained as an oily substance (0.81 g, 92%). 1 H NMR (CDCl3): 7.23 (t, 1H, J = 7.9), 6.77-6.82 (m, 3H), 4.19 (q, 2H, J = 7.1), 3.81 (s, 3H), 3.73 (dd, 1H, J = 5.2, 7.9), 3.08 (dd, 1H, J = 5.2, 13.5), 2.84 (dd, 1H, J = 7.9, 13.5), 1.51 (s, 2H), 1.31 (t, 3H, J = 7.1). HRMS: C 12 H 18 Calculated value for NO3: 224.1287; Measured value: 224.1260.

[0243] Ethyl 2-amino-3-(4-methoxyphenyl)propanoate (B-4): It was obtained as an oily substance (4.2 g, 95%). 1 H NMR (CDCl3): 7.15 (m, 2H), 6.88 (m, 2H), 4.19 (q, 2H, J = 7.1), 3.80 (s, 3H), 3.68 (dd, 1H, J = 5.3, 7.7), 3.03 (dd, 1H, J = 5.3, 13.7), 2.83 (dd, 1H, J = 7.7, 13.7), 1.48 (s, 2H), 1.31 (t, 3H, J = 7.1). HRMS: 12 H 18 Calculated value for NO3: 224.1287; Measured value: 224.1238.

[0244] Ethyl 2-amino-3-(4-(benzyloxy)phenyl)propanoate (B-5): After chromatography on silica gel (dichloromethane-ethanol 96 / 4), an oily substance was obtained (2.65 g, 67%). 1H NMR (CDCl3): 7.46-7.33 (m, 5H), 7.13 (m, 2H), 6.93 (m, 2H), 5.06 (s, 2H), 4.18 (q, 2H, J = 7.1), 3.68 (dd, 1H, J = 5.3, 7.8), 3.04 (dd, 1H, J = 5.3, 13.7), 2.84 (dd, 1H, J = 7.8, 13.7), 1.47 (s, 2H), 1.27 (t, 3H, J = 7.1). HRMS: C 18 H 22 Calculated value for NO3: 300.1600; Measured value: 300.1591.

[0245] Ethyl 2-amino-3-(m-tolyl)propanoate (B-6): It was obtained as an oily substance (0.73 g, 80%). 1 H NMR (CDCl3): 7.22 (m, 1H), 7.02 (m, 3H), 4.19 (q, 2H, J = 7.1), 3.72 (dd, 1H, J = 8.0, 5.2), 3.07 (dd, 1H, J = 13.6, 5.2), 2.84 (dd, 1H, J = 13.6, 8.0), 2.34 (s, 3H), 1.50 (s, 2H), 1.27 (t, 3H, J= 7.1). HRMS: C 12 H 18 Calculated values ​​for NO2, 208 .1338; measured value, 208.1334.

[0246] Ethyl 2-amino-3-(furan-2-yl)propanoate (B-7): It was obtained as an oily substance (4.84 g, 94%). 1H NMR (CDCl3): 7.34 (dd, 1H, J = 0.8, 1.9), 6.30 (dd, 1H, J = 1.9, 3.2), 6.12 (m, 1H), 4.20 (m, 2H), 3.80 (dd, 1H, J = 7.3, 5.2), 3.10 (dd, 1H, J = 14.9, 5.2), 2.99 (dd, 1H, J = 14.9, 7.3), 1.59 (s, 2H), 1.28 (t, 3H, J= 7.2). HRMS: C9H 14 Calculated value for NO3: 184.0974; Measured value: 184.0955.

[0247] Ethyl 2-amino-3-(5-methylfuran-2-yl)propanoate (B-8): It was obtained as an oily substance (1.26 g, 75%). 1 H NMR (CDCl3): 5.97 (d, 1H, J= 2.9), 5.85 (dd, 1H, J = 2.9, 0.9), 4.24 - 4.14 (m, 2H), 3.72 (dd, 1H, J= 7.3, 5.0), 3.03 (dd, 1H, J = HRMS: C 10 H 16 Calculated value for NO3: 198.1130; Measured value: 198.1089.

[0248] Ethyl 2-amino-3-(4,5-dimethylfuran-2-yl)propanoate (B-9): It was obtained as an oily substance (7% from 0.6 g of 4,5-dimethylfurfural). 1H NMR (CDCl3): 5.88 (s, 1H), 4.20 (m, 2H), 3.00 (dd, 1H, J = 4.8, 14.9), 2.87 (dd, 1H, J = 7.5, 14.9), 2.15 (s, 3H), 1.89 (s, 3H), 1.64 (s, 2H), 1.29 (t, 3H, J= 7.1). HRMS: C 11 H 18 Calculated value for NO3: 212.1287; Measured value: 212.1246.

[0249] Ethyl 2-amino-3-(5-ethylfuran-2-yl)propanoate (B-10): After chromatography on silica gel (dichloromethane-ethanol 98 / 2~97 / 3), an oily substance was obtained (1.83 g, 56%). 1 H NMR (CDCl3): 6.00 (d, 1H, J= 3.0), 5.87 (d, 1H, J = 3.0), 4.20 (m, 2H), 3.74 (dd, 1H, J = 7.2, 5.1), 3.05 (dd, 1H, J = 14.9, 5.1), 2.94 (dd, 1H, J = 14.9, 7.2), 2.24 (q, 2H, J = 7.5), 1.58 (s, 2H), 1.29 (t, 3H, J= 7.2), 1.21 (t, 3H, J = 7.5). HRMS: C 11 H 18 Calculated value for NO3: 212.1287; Measured value: 212.1261.

[0250] Ethyl 2-amino-3-(furan-3-yl)propanoate (B-11): It was obtained as an oily substance (1.4 g, 88%). 1 H NMR (CDCl3): 7.38 (m, 1H), 7.31 (m, 1H), 6.28 (m, 1H), 4.20 (q, 2H, J = 7.2), 3.65 (dd, 1H, J = 7.0, 5.3), 2.90 (dd, 1H, J = 14.3, 5.3), 2.79 (dd, 1H, J = 14.3, 7.0), 1.57 (s, 2H), 1.29 (t, 3H, J= 7.2). HRMS: C9H 14 Calculated value for NO3: 184.0974; Measured value: 184.0951.

[0251] Ethyl 2-amino-3-(thiophen-2-yl)propanoate (B-12): The oily substance was diluted with ethyl acetate, extracted with 1N hydrochloric acid, and this aqueous solution was basicized with 22% ammonia. After extraction with ethyl acetate, the oily substance was obtained (2.5 g, 58%). The organic layer was then washed with saline solution, dried with sodium carbonate, and concentrated to dryness.

[0252] 1 H NMR (CDCl3): 7.19 (dd, 1H, J = 1.1, 5.1), 6.96 (dd, 1H, J = 3.3, 5.1), 6.88 (m, 1H), 4.21 (q, 2H, J = 7.1), 3.72 (dd, 1H, J = 7.2, 4.8), 3.30 (dd, 1H, J = 14.7, 4.8), 3.17 (dd, 1H, J = 14.7, 7.2), 1.57 (s, 2H), 1.29 (t, 3H, J = 7.1). HRMS: C9H 14 Calculated value for NO2S: 200.0745; Measured value: 200.0726.

[0253] General procedure for the synthesis of α-aminoester B via α-oxime ester S Step 1: Knoeffener gel condensation of diethyl malonate and aldehyde, substituted diethyl Production of Chill 2-methylenemalonate Under an inert atmosphere, the aldehyde (0.048 mol) and diethyl malonate (7.54 g) were investigated. (0.048 mol), acetic acid (0.14 g, 0.002 mol), piperidine (0.2 g, 0.002 mol), and 4A mo Recular sieves (15 g) are heated in dry ethanol (20 mL, 4 angstroms, dried with molecular sieves) at 60°C for 10 hours without stirring, and the crude sample is typically prepared as follows: 1 The 1H NMR spectrum showed the complete disappearance of the aldehyde from the starting material.

[0254] Step 2: Preparation of substituted diethyl 2-methylene malonate The suspension containing the aforementioned 4A molecular sieves was filtered, and the 4A molecular sieves were washed with dry ethanol. 10% palladium-carbon (1.27 g, 0.001 mol) was added to the resulting ethanol solution (total volume 160 mL), and the mixture was stirred overnight under a hydrogen atmosphere (1 atm). The resulting suspension was filtered, and the filtrate was concentrated to dryness to obtain a nearly pure substituted malonate. Alternatively, this hydrogenation was achieved using sodium borohydride (1.1 eq.), as specified in some of the following examples. Two procedures were devised: the first involved adding sodium borohydride in small amounts to the ethanol solution at 0°C, stirring at 0°C for 2 hours, and then proceeding with the treatment; the second involved adding sodium borohydride at 4°C, stirring at this temperature overnight, and then proceeding with the treatment described below. Subsequently, this was acidified with acetic acid (1.2 equivalents), diluted with excess water, and extracted with ethyl acetate. Next, the organic layer was washed with water and saline solution, dried over magnesium sulfate, concentrated to dryness, and substituted crude malonate was obtained.

[0255] Step 3: Production of α-oxime ester from substituted malonate The substituted crude malonate (0.0422 mol) was dissolved in ethanol (60 mL, dried on a 4A molecular sieve) and cooled to 0°C. A 21% sodium ethoxide solution (18.4) was then added to the ethanol. (mL, 0.0493 mol) was added, followed by the slow addition of isoamyl nitride (6.2 mL, 0.046 mol). This mixture was stirred at 0°C for 2 hours, slightly acidified with 1N hydrochloric acid, and diluted with water (200 mL). This solution was extracted with ethyl acetate, the organic layer was washed with water and saline solution, dried over magnesium sulfate, concentrated to dryness, and the crude α-oxime ester was obtained, which was further purified as described below. did.

[0256] Ethyl 3-cyclopentyl-2-(hydroxyimino)propanoate (S-1): After chromatography on silica gel (cyclohexane-ethyl acetate 85 / 15), a white solid was observed. The compound was obtained as a whole (2.50 g, 35% from cyclopentanecarbaldehyde). 1 H NMR (CDCl3): 9.51 (s, 1H), 4.32 (q, 2H, J = 7.0), 2.67 (d, 2H, J = 7.6), 2.20 (m, 1H), 1.70 (m, 4H), 1.53 (m, 2H), 1.36 (t, 3H, J = 7.0), 1.25 (m, 2H). HRMS: C 10 H 17 Calculated value for NO3Na: 222.1106; Measured value: 222.1164.

[0257] Ethyl 3-cyclohexyl-2-(hydroxyimino)propanoate (S-2): After chromatography on silica gel (cyclohexane - ethyl acetate 9 / 1), a white solid is obtained. It was obtained as follows (4.34 g, 50% from cyclohexanecarbaldehyde). 1 H NMR (CDCl3): 9.85 (s, 1H), 4.31 (q, 2H, J = 7.2), 2.55 (d, 2H, J = 7.1), 1.70 (m, 6H), 1.36 (t, 3H, J = 7.0), 1.20 (m, 3H), 1.04 (m, 2H). HRMS: C 11 H 19 Calculated value for NO3Na: 236.1263; Measured value: 236.1291.

[0258] Ethyl 3-(bicyclo[2.2.1]heptan-2-yl)-2-(hydroxyimino)propanoate (S-3): After chromatography on two silica gels (cyclohexane-ethyl acetate 7 / 1~4 / 1) and (dichloromethane-ethanol 99 / 1), an oily mixture of diastereoisomers was obtained (1.39 g, 25% from the two isomers of norbornane-2-carboxaldehyde). 1 H NMR (CDCl3): 4,33 (m, 4H, arbitrary value), 2.66 (m, 3.2H), 2.50 (m, 0.9H), 2.22 (m, 3.3H), 2.08 (m, 1.2H), 1.96 (m, 0.7H), 1.85 (m, 0.8H), 1.73 (m, 2.8H), 1.48 (m, 4.5H), 1.34 (m, 10.8H), 1.15 (m, 4.5H), 0.79 (m, 1.3H). HRMS: C 12 H 19 NO3N Calculated value for a: 248.1263; Measured value: 248.1265.

[0259] Ethyl 2-(hydroxyimino)-3-(tetrahydrofuran-2-yl)propanoate (S-4): This compound was obtained by using 10% Pd / C for the hydrogenation step and running the process for 48 hours. From a 12.8 g batch, only the sample was purified by chromatography (dichloromethane-ethanol 97 / 3) to obtain a white solid. 1H NMR (CDCl3): 9.74 (s, 1H), 4.32 (q, 2H, J = 7.2), 4.28 (m, 1H), 3.90 (m, 1H), 3.74 (m, 1H), 2.96 (dd, 1H, J = 5.5, 12.8), 2.80 (dd, 1H, J = 5.9, 12.8), 1.88 (m, 3H), 1.62 (m, 1H), 1.35 (t, 3H, J = 7.2). HRMS: C9H 15 Calculated value for NO4Na: 224.0899; Measured value: 224.0874.

[0260] Ethyl 2-(hydroxyimino)-3-(3-methylthiophen-2-yl)propanoate (S-5): Chromatography (cyclohe) was performed using sodium borohydride at 0°C with silica gel. Xan - Ethyl acetate 5 / 1) was obtained as a yellow solid (1.38 g, 3-methylthiophene-2- 32% from caraldehyde. 1 H NMR (CDCl3): 9.88 (s, 1H), 7.06 (d, 1H, J = 5.1), 6.77 (d, 1H, J = 5.1), 4.33 (q, 2H, J = 7.2), 4.09 (s, 2H), 2.28 (s, 3H), 1.36 (t, 3H, J = 7.2). HRMS: C 10 H 13 Calculated value for NO3SNa: 250.0514; Measured value: 250.0513.

[0261] Ethyl 3-(5-ethylthiophen-2-yl)-2-(hydroxyimino)propanoate (S-6): Chromatography (cyclohe) was performed using sodium borohydride at 0°C with silica gel. Xan - Ethyl acetate 5 / 1) was used to obtain an oily substance (1.36 g, 5-ethylthiophene-2-k 29% from rubaldehyde. 1 H NMR (CDCl3): 10.06 (s, 1H), 6.75 (m, 1H), 6.59 (m, 1H), 4.34 (q, 2H, J = 7.2), 4.09 (s, 2H), 2.78 (m, 2H), 1.38 (t, 3H, J = 7.2), 1.28 (t, 3H, J = 7.5). HRMS: C 11 H 15 Calculated value for NO3SNa: 264.0670; Measured value: 264.0676.

[0262] Ethyl 3-(4,5-dimethylthiophen-2-yl)-2-(hydroxyimino)propanoate (S-7): Chromatography (cyclohe) was performed using sodium borohydride at 0°C with silica gel. After xane-ethyl acetate 5 / 1), an oily substance was obtained (0.69 g, 31% from 4,5-dimethylthiophene-2-carbaldehyde). 1 H NMR (CDCl3): 9.77 (s, 1H), 6.62 (s, 1H), 4.34 (q, 2H, J = 7.2), 4.(s, 2H), 2.28 (s, 3H), 2.06 (s, 3H), 1.37 (t, 3H, J = 7.2). HRMS: C 11 H 15 Calculation for NSO3Na Value: 264.0670; Measured value: 264.0656.

[0263] Ethyl 2-(hydroxyimino)-3-(5-(trifluoromethyl)furan-2-yl)propanoate To (S-8): Chromatography using sodium borohydride at 0°C with two silica gels (di After mixing chloromethane (ethanol 99 / 1) and (cyclohexane (ethyl acetate 5 / 1)), a white solid is formed. The compound was obtained as a whole (0.62 g, 36% from 5-trifluoromethylfuran-2-carbaldehyde). 1 H NMR (CDCl3): 9.70 (s, 1H), 6.72 - 6.64 (m, 1H), 6.21 - 6.15 (m, 1H), 4.33 (q, 2H, J = 7.1), 4.05 (s, 2H), 1.34 (t, 3H, J = 7.1). HRMS: C 10 H 11 Total for F3NO4 Calculated value: 266.0640; Measured value: 266.0584.

[0264] Ethyl 2-(hydroxyimino)-3-(pyridine-2-yl)propanoate (S-9): After chromatography (dichloromethane-ethanol 97 / 3), it was obtained as a solid (4.94 g, 49% from picoline aldehyde). 1 H NMR (CDCl3): 10.53 (s, 1H), 8.53 (m, 1H), 7.61 (dt, 1H, J = 1.8, 7.5), 7.29 (m, 1H), 7.17 (m, 1H), 4.29 (q, 2H, J = 7.1), 4.23 (s, 2H), 1.30 (t, 3H, J = 7.1). HRMS: C 10 H 13 Calculated value for N2O3: 209.0926; Measured value: 209.0857.

[0265] Ethyl 2-(hydroxyimino)-3-(pyridine-3-yl)propanoate (S-10): After chromatography (dichloromethane - ethanol 97 / 3~96 / 4), it becomes a yellowish-brown solid. (7.19 g, 43% from nicotinaldehyde). 1H NMR (CDCl3): 12.79 (s, 1H), 8.65 (m, 1H), 8.46 (dd, 1H, J = 1.6, 4.9), 7.74 (m, 1H), 7.22 (m, 1H), 4.30 (q, 2H, J = 7.1), 4.01 (s, 2H), 1.32 (t, 3H, J = 7.1). HRMS: C 10 H 13 Calculated value for N2O3: 209.0926; Measured value: 209.0921.

[0266] Ethyl 2-(hydroxyimino)-3-(2-(trifluoromethyl)phenyl)propanoate (S-11): After chromatography on silica gel (cyclohexane - ethyl acetate 4 / 1~3 / 1), white It was obtained as a colored solid (1.05 g, 33% purity from 2-(trifluoromethyl)benzaldehyde, 90% purity). 1 H NMR (CDCl3): 9.66 (s, 1H), 7.68 (d(br), 1H, J = 7.5), 7.45 (m, 1H), 7.34 (m, 1H), 7.16 (d(br), 1H, J = 7.7), 4.29 (q, 2H, J = 7.2), 4.23 (s, 2H), 1.27 (t, 3H, J = 7.2). HRMS: C 12 H 12 Calculated value for F3NO3Na: 298.0667; Measured value: 298.0660.

[0267] Ethyl 2-(hydroxyimino)-3-(3-(trifluoromethyl)phenyl)propanoate (S-12): After chromatography on silica gel (cyclohexane-ethyl acetate 4 / 1~3 / 1), it was obtained as a white solid (1.3 g, 41% from 3-(trifluoromethyl)benzaldehyde). 1H NMR (CDCl3): 9.87 (s, 1H), 7.62 (s(br), 1H), 7.50 (m, 2H), 7.42 (m, 1H), 4.32 (q, 2H, J = 7.0), 4.05 (s, 2H), 1.35 (t, 3H, J = 7.0). HRMS: C 12 H 12 Against F3NO3Na Calculated value: 298.0667; Measured value: 298.0643.

[0268] Ethyl 2-(hydroxyimino)-3-(4-(trifluoromethyl)phenyl)propanoate (S-13): After chromatography on silica gel (dichloromethane-ethanol 99 / 1), a white solid was obtained (4.61 g, 62% from 4-(trifluoromethyl)benzaldehyde). 1 H NMR (CDCl3): 9.76 (s, 1H), 7.55 (m, 2H), 7.45 (m, 2H), 4.32 (q, 2H, J = 7.1), 4.05 (s, 2H), 1.35 (t, 3H, J = 7.1). HRMS: C 12 H 13 Calculated value for F3NO3: 276.0847; Measured value: 276.0834.

[0269] Ethyl-3-(4-chlorophenyl)-2-(hydroxyimino)propanoate (S-14): Chromatography using silica gel with sodium borohydride overnight at 4°C (Syc After hydroxybenzoate-ethyl acetate (4 / 1), it was obtained as a white solid (2.31 g, 37% from 4-chlorobenzaldehyde). 1 H NMR (CDCl3): 9.70 (s, 1H), 7.27 (m, 4H), 4.31 (q, 2H, J = 7.1), 3.96 (s, 2H), 1.35 (t, 3H, J = 7.1). HRMS: C 11 H 14 Calculated value for ClNO2Na: 264.0403; Measured value: 264.0437.

[0270] Ethyl 3-(2-chlorophenyl)-2-(hydroxyimino)propanoate (S-15): Using sodium borohydride at 4°C, only 0.5 g of the sample from a 13.1 g batch was subjected to chromatography on silica gel (cyclohexane-ethyl acetate 4 / 1) and cyclohexane It was purified by recrystallization in the chamber, yielding a white solid (0.36 g). 1 H NMR (CDCl3): 9.47 (s, 1H), 7.38 (m, 1H), 7.18 (m, 3H), 4.30 (q, J = 7.1 Hz, 2H), 4.13 (s, 2H), 1.31 (t, J = 7.1 Hz, 3H). HRMS: C 11 H 12 Calculated value for ClNO3Na: 264.0403; Measured value: 264.0401.

[0271] Ethyl-3-(4-bromophenyl)-2-(hydroxyimino)propanoate (S-16): Chromatography using silica gel with sodium boro at 4°C overnight (cyclohex After ethanol-ethyl acetate (4 / 1), it was obtained as a white solid (1.43 g, 42% from 4-bromobenzaldehyde). 1 H NMR (CDCl3): 9.70 (s, 1H), 7.42 (m, 2H), 7.22 (m, 2H), 4.31 (q, 2H, J = 7.1), 3.96 (s, 2H), 1.32 (t, 3H, J = 7.1). HRMS: C 11 H 13 Calculated value for BrNO3: 286.0079; Measured value: 286.0056.

[0272] Ethyl 3-(2-fluorophenyl)-2-(hydroxyimino)propanoate (S-17): After chromatography on silica gel (cyclohexane-ethyl acetate 4 / 1), a white solid is obtained. This was obtained as (3.11 g, 57% from 2-fluorobenzaldehyde). 1 HRMS: C 11 H 12 Calculated value for FNO3Na: 248.0699; Measured value: 248.0704.

[0273] Ethyl 3-(3-fluorophenyl)-2-(hydroxyimino)propanoate (S-18): After chromatography (cyclohexane-ethyl acetate 5 / 1), it was obtained as a white solid (9.46 g, 65% from 3-fluorobenzaldehyde). 1 H NMR (CDCl3): 10.02 (s, 1H), 7.25 (m, 1H), 7.10 (m, 1H), 7.06 (m, 1H), 6.92 (m, 1H), 4.32 (q, 2H, J = 7.2), 3.99 (s, 2H), 3.74 (m, 1H), 1.35 (t, 3H, J = 7.2). HRMS: C 11 H 12 Calculated value for FNO3Na: 248.0699; Measured value: 248.0699.

[0274] Ethyl 3-(2,4-difluorophenyl)-2-(hydroxyimino)propanoate (S-19): After chromatography (cyclohexane-ethyl acetate 6 / 1), it was obtained as a white solid (2.21 g, 50% from 2,4-difluorobenzaldehyde). 1 1H NMR (CDCl3): 1 H NMR (CDCl3): 9.72 (s, 1H), 7.22 (m, 1H), 6.80 (m, 2H), 4.30 (q, 2H, J = 7.1), 3.98 (s, 2H), 1.33 (t, 3H, J = 7.1). 11 H 11 For F2NO3Na Calculated value: 266.0605; Measured value: 266.0601.

[0275] Ethyl 2-(hydroxyimino)-3-(o-tolyl)propanoate (S-20): After chromatography on silica gel (cyclohexane-ethyl acetate 4 / 1), a white solid is obtained. This was obtained as (3.38 g, 61% from 2-methylbenzaldehyde). 1 HRMS: C 12 H 15 Calculated value for NO3Na: 244.0950; Measured value: 244.0942.

[0276] Ethyl 2-(hydroxyimino)-3-(p-tolyl)propanoate (S-21): After chromatography on silica gel (cyclohexane-ethyl acetate 4 / 1), a white solid is obtained. This was obtained as (3.31 g, 60% from 4-methylbenzaldehyde). 1H NMR (CDCl3): 10.07 (s, 1H), 7.24 (m, 2H), 7.11 (m, 2H), 4.31 (q, 2H, J = 7.1), 3.97 (s, 2H), 2.35 (s, 3H), 1.35 (t, 3H, J = 7.1). HRMS: C 12 H 15 Calculated value for NO3Na: 244.0950; Measured value: 244.0944.

[0277] Ethyl 2-(hydroxyimino)-3-(4-isopropylphenyl)propanoate (S-22): After chromatography on silica gel (cyclohexane-ethyl acetate 5 / 1), the mixture was converted to a solid. (48% obtained from 2.04 g, 4-isopropylbenzaldehyde). 1 H NMR (CDCl3): 9.74 (s, 1H), 7.26 - 7.22 (m, 2H), 7.16 - 7.11 (m, 2H), 4.29 (q, 2H, J = 7.1), 3.95 (s, 2H), 2.87 (hept, 1H, J = 6.9), 1.32 (t, 3H, J = 7.1), 1.23 (d, 6H, J = 6.9). 14 H 19 Calculated value for NO3Na: 272.1263; Measured value: 272.1258.

[0278] Additional synthesis of α-oxime esters via carbon-carbon coupling reaction Manufacturing of ethyl 3-(5-cyclopropylfuran-2-yl)-2-(hydroxyimino)propanoate (S-23) Step 1: Synthesis of diethyl 2-((5-bromofuran-2-yl)methylene)malonate Diethyl 2-(furan-2-ylmethylene)malonate (Coll. Czech. Chem. Commun., 1987) 2534) (2 g, 8.39 mmol) was dispersed in acetic acid (20 mL), and then N-bromosuccinimide (2.98 g, 16.78 mmol) was added. This was stirred overnight at room temperature, diluted with ethyl acetate, washed thoroughly with water and saline solution, dried over magnesium sulfate, and concentrated to dryness. The residue was purified by chromatography on silica gel (cyclohexane-ethyl acetate 9 / 1) and obtained as an orange solid. A brominated derivative was obtained (1.1 g, 41%).

[0279] 1 1H NMR (CDCl3): 1 H NMR (CDCl3): 7.35 (s, 1H), 6.71 (d, 1H, J = 3.5), 6.44 (d, 1H, J = 3.5), 4.41 (q, 2H, J = 7.1), 4.29 (q, 2H, J = 7.1), 1.41 (t, 3H, J = 7.1), 1.33 (t, 3H, J = 7.1). HRMS: C 12 H 13 Calculated value for BrO5Na: 338.9844; Measured value: 338.9868. Alternatively, between 5-bromofurfural and diethyl malonate using the above conditions Kneefenagel condensation also yielded this compound (4.72 g, 87%).

[0280] Step 2: Synthesis of diethyl 2-((5-cyclopropylfuran-2-yl)methylene)malonate: Diethyl 2-((5-bromofuran-2-yl)methylene)malonate (4.7 g, 14.8 mmol), Clopropylboronic acid (1.66 g, 19.3 mol) and cesium carbonate (18.84 g, 57.8 mmol) It was dispersed in a 95 / 5 mixture of toluene and water (120 mL). This was degassed by blowing a gentle stream of argon, and the suspension was mixed with dichloromethane and [1,1'-bi [Diphenylphosphino)ferrocene]dichloropalladium (0.30 g, 0.36 mmol) was added and the mixture was refluxed under argon for 50 minutes. The resulting dark-colored solution was diluted with ethyl acetate, washed with water and saline solution, dried over magnesium sulfate, and concentrated to dryness. The residue was purified by silica gel chromatography (cyclohexane-ethyl acetate 8 / 1) to obtain a cyclopropyl derivative as an oily substance (3.12 g, 75%).

[0281] 1 H NMR (CDCl3): 7.32 (s, 1H), 6.65 (d, 1H, J = 3.4), 6.09 (d, 1H, J = 3.4), 4.37 (q, 2H, J = 7.1), 4.25 (q, 2H, J = 7.1), 1.89 (tt, 1H, J = 8.4, 5.0), 1.37 (t, 3H, J = 7.1), 1.30 (t, 3H, J = 7.1), 1.01 - 0.93 (m, 2H), 0.88 - 0.79 (m, 2H). HRMS: C 15 H 18 Calculated value for O5Na: 301.1052; Measured value: 301.1034.

[0282] Steps 3 and 4: Synthesis of ethyl 3-(5-cyclopropylfuran-2-yl)-2-(hydroxyimino)propanoate (S-23): From the above compound, using the above general method for producing oxime esters, the reduction step is performed. Then, at 4°C overnight, chromatography using sodium borohydride and silica gel (silica After dihexane-ethyl acetate (4 / 1), the compound was obtained as an orange solid (1.09 g, 44% from diethyl 2-((5-cyclopropylfuran-2-yl)methylene)malonate).

[0283] 1 1H NMR (CDCl3): 1H NMR (CDCl3): 9.42 (bs, 1H), 5.97 (m, 1H), 5.84 (d, 1H, J = 8.1), 4.33 (q, 2H, J = 7.1), 3.97 (s, 2H), 1.84 (m, 1H), 1.36 (t, 3H, J = 7.1), 0.84 (m, 2H), 0.73 (m, 2H). HRMS (m / z): HRMS: C 12 H 15 Calculated value for NO4Na: 260.0899; Measured value: 260.0892.

[0284] Manufacturing of ethyl-2-(hydroxyimino)-3-(3-propylphenyl)propanoate (S-24): Step 1: Production of diethyl 2-(4-bromobenzylidene)malonate Using the above conditions, the cuclerosing between 3-bromobenzaldehyde and diethyl malonate By using phenagel condensation, the compound was obtained as an oily substance, which was then used directly in the next step.

[0285] Step 2: Production of diethyl 2-(3-cyclopropylbenzylidene)malonate By using the above procedure for the production of diethyl 2-((5-cyclopropylfuran-2-yl)methylene)malonate, chromatography in silica gel (cyclohexane- After ethyl acetate (95 / 5), the compound was obtained as an oily substance (4.68 g, 3-bromobenzaldehyde) From 60%). 1 H NMR (CDCl3): 7.72 (s, 1H), 7.27 (m, 2H), 7.17 (m, 1H), 7.11 (m, 1H), 4.36 (q, 2H, J = 7.1), 4.32 (q, 2H, J = 7.1), 1.90 (m, 1H), 1.35 (t, 3H, J = 7.1), 1.32 (t, 3H, J = 7.1).

[0286] Step 3: Production of diethyl 2-(3-propylbenzyl)malonate The compound was obtained by the aforementioned 10% palladium-carbon catalytic hydrogenation over a long period of two days, and then... It was used directly in the final stage of the process.

[0287] Process 4 Using the general conditions described above, crude diethyl 2-(3-propylbenzyl)malonate is oxidized. In the reaction, after chromatography on silica gel (cyclohexane-ethyl acetate 5 / 1), S-24 was obtained as a white solid (0.2 g, diethyl 2-((5-cyclopropylfuran-2-yl)methyl Lentil (14%) from malonate. 1 H NMR (CDCl3): 9.74 (bs, 1H), 7.19 (m, 3H), 7.05 (m, 1H), 4.31 (q, 2H, J = 7.2), 3.99 (s, 2H), 2.58 (m, 2H), 1.65 (m, 2H), 1.34 (t, 3H, J = 7.2), 0.96 (t, 3H, J = 7.3). HRMS: C 14 H 19 Calculated value for NO3Na: 272.1263; Measured value: 272.1250.

[0288] Manufacturing of ethyl-2-(hydroxyimino)-3-(4-propylphenyl)propanoate (S-25): Manufacturing of ethyl-2-(hydroxyimino)-3-(3-propylphenyl)propanoate (S-24) By using the same procedure described above, this isomer was obtained as a white solid after chromatography on silica gel (cyclohexane-ethyl acetate 6 / 1) (2.64 g, 56% from 4-bromobenzaldehyde). 1H NMR (CDCl3): 9.64 (s, 1H), 7.26 (m, 2H), 7.11 (m, 2H), 4.31 (q, 2H, J = 7.2), 3.98 (s, 2H), 2.57 (m, 2H), 1.64 (m, 2H), 1.34 (t, 3H, J = 7.2), 0.95 (t, 3H, J =7.3). HRMS: C 14 H 19 Calculated value for NO3Na: 272.1263; Measured value: 272.1276.

[0289] Ethyl 3-(3-cyclopropylphenyl)-2-(hydroxyimino)propanoate (S-26). Using the general method for producing the aforementioned oxime ester, sodium borohydride was used in the reduction step overnight at 4°C. After chromatography on silica gel (cyclohexane-ethyl acetate 6 / 1), the compound was obtained as a colorless oil (1.72 g, diethyl 2-(3-oxime ester). 50% from chloropropyl benzylidene malonate. 1 H NMR (CDCl3): 9.99 (bs, 1H), 7.20 (m, 3H), 6.91 (m, 1H), 4.31 (q, J = 7.2 Hz, 2H), 3.97 (s, 2H), 2.58 (m, 2H), 1.88 (m, 1H), 1.34 (t, 3H, J = 7.2), 0.96 (m, 2H), 0.69 (m, 2H). HRMS: C 14 H 17 Calculated value for NO3Na: 270.1106; Measured value: 270.1112.

[0290] Ethyl 3-(4-cyclopropylphenyl)-2-(hydroxyimino)propanoate (S-27). Using the general method for producing the aforementioned oxime ester, sodium borohydride was used overnight at 4°C for the reduction step. After chromatography on silica gel (cyclohexane-ethyl acetate 6 / 1), the compound was obtained as a yellow solid (1.03 g, 4-bromobenzal). Dehyde (27). 1 H NMR (CDCl3): 9.31 (s, 1H), 7.22 (m, 2H), 6.99 (m, 2H), 4.29 (q, J = 7.2 Hz, 2H), 3.95 (s, 2H), 1.86 (m, 1H), 1.33 (t, J = 7.2 Hz, 3H), 0.93 (m, 2H), 0.67 (m, 2H). HRMS: C 14 H 17 Calculated value for NO3Na: 270.1106; Measured value: 270.1109.

[0291] Additional synthesis of α-oxime esters using other methods [ka]

[0292] Ethyl 3-(4,5-dimethyloxazol-2-yl)-2-(hydroxyimino)propanoate (S-28): Under an inert atmosphere, 2,4,5-trimethyloxazole (1.05 g, 9.44 mmol) was dissolved in dry tetrahydrofuran (10 mL). The solution was cooled to -78 °C in a dry ice bath. 4.7 mL, 9.44 mmol of 2N lithium diisopropylamine was added to trahydrofuran. The mixture was stirred for 5 minutes, and diethyl oxalate (1.28 mL, 9.92 mmol) was added. The solution was allowed to warm to 20 °C and stirred for another 10 minutes. The solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saline solution, dried over magnesium sulfate, and concentrated to dryness. The resulting oily substance was dissolved in ethanol (100 mL), and 2.76 g, 39.7 mmol of hydroxylamine hydrochloride and dried pyridine (3.3 mL, 40.8 mmol) were added. The mixture was heated under reflux for 6 hours. The resulting suspension was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saline solution, dried over magnesium sulfate, and concentrated to dryness. The residue was purified by chromatography using silica gel (cyclohexane - ethyl acetate 1 / 1), the corresponding fraction was suspended in boiling cyclohexane, cooled, and filtered to obtain the target oxime ester as a white powder (0.15 g, 7%).

[0293] 1 H NMR (CDCl3): 11.99 (s, 1H), 4.30 (q, 2H, J = 7.2), 4.08 (s, 2H), 2.20 (d, 3H, J = 0.8), 2.05 (d, 3H, J = 0.8), 1.31 (t, 3H, J = 7.2). The regioselectivity of the reaction was confirmed by long-distance correlation experiments. HRMS: C 10 H 14 Calculated value for N2O4: 227.1032; Measured value: 227.1035.

[0294] Ethyl 2-(hydroxyimino)-3-phenylbutanoate (S-29): Step 1: Production of diethyl 2-(1-phenylethyl)malonate: Under calcium chloride protection, diethyl malonate (5.32 g, 0.033 mol) was dissolved in dry DMF (50 mL, dried on a 4A molecular sieve), and 60% sodium hydride (1.39 g, 0.0348 mol) from mineral oil was gradually added while maintaining the solution temperature at 20 °C in a water bath. This was then used to... The mixture was stirred until the generation was complete, and (1-chloroethyl)benzene (4.8 mL, 0.036 mol) was added. This was stirred for 7 days, diluted with water and ethyl acetate, the organic layer was washed five times with water and saline solution, dried over magnesium sulfate, and concentrated to dryness under high vacuum to remove unreacted diethylmalonate and (1-chloroethyl)benzene, yielding a sufficiently pure oily substance for the next step (6.22 g).

[0295] Step 2: Reaction with isoamyl nitride Under an inert atmosphere, 4.68 g of the obtained oily substance was dissolved in dry ethanol (50 mL, dried with 4A molecular sieves) and cooled to 0 °C using ice. 21% sodium in ethanol Emethanolate solution (7.7 mL, 0.0207 mol) was added, followed by isoamyl nitride (2.6 mL, 0.0194 mol). This was allowed to warm to room temperature and stirred for 16 hours. Then, the resulting The solution was treated as described above for the general preparation of α-oxime esters, and after chromatography on silica gel (cyclohexane-ethyl acetate 5 / 1), it was obtained as an oily substance (1.07 g, 14% from diethyl malonate).

[0296] 1 ¹H NMR (CDCl3, once separated, slowly becomes a mixture of two oxime isomers) Equilibrium is achieved at: 10.69 (s, 0.2H), 9.72 (s, 0.8H), 4.82 (q, 0.8H, J = 7.2), 4.21 (m, 2H), 4.02 (q, 0.2H, J = 7.2), 1.68 (d, 2.4H, J = 7.2), 1.54 (d, 0.6H, J = 7.2), 1.26 (t, 2.4H, J = 7.3), 1.15 (t, 0.6H, J = 7.3). HRMS: C 12 H 15 NO3Na Calculated value: 244.0950; Measured value: 244.0939.

[0297] General method for the reduction of α-oxime ester S to α-amino ester B The substituted α-oxime ester under consideration (0.065 mol) was dissolved in ethanol (70 mL) and 37% hydrochloric acid (49 mL, 0.58 mol), and the solution was cooled to °C. Zinc powder (12.9 g, A fraction of 0.19 mol (less than 10 μm in size) was added. This was left to stand and stirred for 2 hours, then diluted with water. The solution was then made basic with 22% ammonia, extracted with ethyl acetate, washed with water and brine, and concentrated to dryness to obtain pure amino ester. If crude oxime was used, the organic layer was back-extracted with 1N hydrochloric acid, the acidic aqueous phase was again made basic with 22% ammonia, extracted with ethyl acetate, washed with water and brine, dried over sodium carbonate, concentrated to dryness, and in some cases further purified as described below to obtain amino ester.

[0298] Ethyl 2-amino-3-cyclopentylpropanoate (B-13): It was obtained as an oily substance (1.16 g, 85%). 1H NMR (CDCl3): 4.17 (q, 2H, J = 7.2), 3.42 (dd, 1H, J = 5.8, 8.1), 1.93 (m, 1H), 1.80 (m, 2H), 1.75-1.48 (m, 8H), 1.27 (t, 3H, J = 7.2), 1.12 (m, 2H). HRMS: C 10 H 20 Calculated value for NO2: 186.1494; Measured value: 186.1491.

[0299] Ethyl 2-amino-3-cyclohexylpropanoate (B-14): It was obtained as an oily substance (2.35 g, 92%). 1 H NMR (CDCl3): 4.17 (m, 2H), 3.48 (dd, 1H, J = 5.8, 8.7), 1.72 (m, 5H), 1.61-137 (m, 5H), 1.28 (t, 3H, J = 7.3), 1.28-1.10 (m, 3H), 0.92 (m, 2H). HRMS: C 11 H 22 Calculated value for NO2: 200.1651; Measured value: 200.1648.

[0300] Ethyl 2-amino-3-(bicyclo[2.2.1]heptan-2-yl)propanoate (B-15): A mixture of four diastereoisomers (four 13 (This can be determined by the C COOEt signal.) It was obtained as an oily substance (1.21 g, 92%). 1 H NMR (CDCl3): 4.17 (m, 2H), 3.37 (m, 1H), 2.16 (m, 1.6H), 1.91 (m, 1H), 1.75 (m, 1.6H), 1.50 (m, 5H), 1.28 (m, 5.9H), 1.10 (m, 2.4H), 0.64 (m, 0.6H). HRMS: C 12 H 22Calculated value for NO2: 212.1651; Measured value: 212.1650.

[0301] Ethyl 2-amino-3-(tetrahydrofuran-2-yl)propanoate (B-16): The mixture of two diastereoisomers in a 3 / 2 ratio was obtained as an oily substance (5.68 g, 36% from furfural. 1 H NMR (CDCl3): Main isomers: 4.17 (q, 2H, J = 7.3), 4.01 (m, 1H), 3.85 (m, 1H), 3.72 (m, 1H), 3.62 (dd, 1H, J = 8.9, 3.5), 2.03 (m, 1H), 1.89 (m, 2H), 1.68 (ddd, 2H, J = 3.5, 8.9, 13.8), 1.68 (s, 2H), 1.51 (m, 1H), 1.27 (t, 3H, J = 7.3). Fewer isomers: 4.17 (q, 2H, J = 7.2), 4.01 (m, 1H), 3.85 (m, 1H), 3.72 (m, 1H), 3.56 (dd, 1H, J = 7.3, 5.4), 2.03 (m, 1H), 1.89 (m, 2H), 1.80 (m, 2H), 1.61 (s, 2H), 1.49 (m, 1H), 1.27 (t, 3H, J = 7.2). HRMS: C9H 18 Calculated value for NO3: 188.1287; Measured value: 188.1258.

[0302] Ethyl 2-amino-3-(4,5-dimethylthiophen-2-yl)propanoate (B-17): It was obtained as an oily substance (0.46 g, 87%). 1 H NMR (CDCl3): 6.54 (s, 1H), 4.22 (d, 2H, J = 7.1), 3.66 (dd, 1H, J = 4.8, 7.4) , 3.17 (dd, 1H, J = 4.8, 14.5), 3.03 (dd, 1H, J = 7.4, 14.5), 2.29 (s, 3H), 2.07 (s, 3H), 1.59 (s, 2H), 1.30 (t, 3H, J = 7.1). HRMS: C 11 H 18 Calculated value for NO2S: 228.1058; Measured value: 228.1053.

[0303] Ethyl 2-amino-3-(3-methylthiophen-2-yl)propanoate (B-18): It was obtained as an oily substance (1.10 g, 89%). 1 H NMR (CDCl3): 7.08 (d, 1H, J = 5.1), 6.80 (d, 1H, J = 5.1), 4.20 (m, 2H), 3.70 (dd, 1H, J = 5.1, 7.6), 3.23 (dd, 1H, J = 5.1, 14.7), 3.04 (dd, 1H, J = 7.6, 14.7), 2.20 (s, 3H), 1.59 (s, 2H), 1.28 (t, 3H, J = 7.6). HRMS: C 10 H 16 Calculated value for NO2S: 214.0902; Measured value: 214.0901.

[0304] Ethyl 2-amino-3-(5-ethylthiophen-2-yl)propanoate (B-19): It was obtained as an oily substance (1.18 g, 92%). 1H NMR (CDCl3): 6.66 (m, 1H), 6.61 (m, 1H), 4.21 (q, 2H, J = 5.1, 7.2), 3.68 (dd, 1H, J = 4.8, 7.3), 3.21 (dd, 1H, J = 4.8, 14.7), 3.04 (dd, 1H, J = 7.3, 14.7), 2.80 (m, 2H), 1.62 (s, 2H), 1.30 (t, 3H, J = 7.1), 1.29 (t, 3H, J = 7.5). HRMS: C 11 H 18 Calculated value for NO2S: 228.1058; Measured value: 228.1055.

[0305] Ethyl 2-amino-3-(o-tolyl)propanoate (B-20): It was obtained as an oily substance (2.69 g, 85%). 1 H NMR (CDCl3): 7.16 (m, 4H), 4.17 (q, 2H, J = 7.2), 3.71 (dd, 1H, J = 8.7, 5.6), 3.14 (dd, 1H, J = 13.8, 5.6), 2.84 (dd, 1H, J = 13.8, 8.7), 2.82 (s, 3H), 1.24 (t, 3H, J = 7.2). HRMS: C 12 H 18 Calculated value for NO2: 208.1338; Measured value: 208.1332.

[0306] Ethyl 2-amino-3-(p-tolyl)propanoate (B-21): It was obtained as an oily substance (2.70 g, 87%). 1H NMR (CDCl3): 7.11 (m, 4H), 4.19 (q, 2H, J = 7.1), 3.70 (dd, 1H, J = 7.9, 5.3), 3.07 (dd, 1H, J = 13.6, 5.3), 2.84 (dd, 1H, J = 13.6, 7.9), 2.34 (s, 3H), 1.28 (t, 3H, J = 7.1). HRMS: C 12 H 18 NO2: Calculated value for 208.1338; measured value, 208.1333.

[0307] Ethyl 2-amino-3-(pyridine-2-yl)propanoate (B-22): It was obtained as an oily substance (2.21 g, 56%). 1 H NMR (CDCl3): 8.55 (m, 1H), 7.61 (dt, 1H, J = 1.9, 7.6), 7.18 (m, 1H), 7.15 (m, 1H), 4.18 (q, 2H, J = 7.2), 3.98 (dd, 1H, J = 4.8, HRMS: C 10 H 15 Calculated value for N2O2: 195.1134; Measured value: 195.1062.

[0308] Ethyl 2-amino-3-(pyridine-3-yl)propanoate (B-23): It was obtained as an oily substance (4.07 g, 63%). 1H NMR (CDCl3): 8.49 (m, 2H), 7.56 (m, 1H), 7.22 (ddd, 1H, J = 0.8, 4.8, 5.6), 4.16 (q, 2H, J = 7.2), 3.70 (dd, 1H, J = 5.5, 7.5), 3.05 (dd, 1H, J = 5.5, 13.5), 2.88 (dd, 1H, J = 7.5, 13.5), 1.46 (s, 2H), 1.23 (t, 3H, J = 7.2). HRMS: C 10 H 15 Calculated value for N2O2: 195.1134; Measured value: 195.1131.

[0309] Ethyl 2-amino-3-(2-(trifluoromethyl)phenyl)propanoate (B-24): It was obtained as an oily substance (0.72 g, 78%, purity 90%). 1 H NMR (CDCl3): 7.58 (d, 1H, J = 8.1), 7.41 (m, 1H), 7.32 (d, 1H, J = 7.7), 7.26 (m, 1H), 4.07 (m, 2H), 3.66 (dd, 1H, J = 5.7, 8.9), 3.21 (dd, 1H, J = 5.7, 14.3), 2.86 (dd, 1H, J = 8.9, 14.3), 1.45 (s, 2H), 1.13 (t, 3H, J = 7.1). HRMS: C 12 H 15 Calculated value for F3NO2: 262.1055; Measured value: 262.1082.

[0310] Ethyl 2-amino-3-(3-(trifluoromethyl)phenyl)propanoate (B-25): It was obtained as an oily substance (0.75 g, 78%). 1 H NMR (CDCl3): 7.51 (m, 1H), 7.48 (m, 1H), 7.43 (m, 2H), 4.17 (q, 2H, J = 7.3), 3.74 (dd, 1H, J = 5.5, 7.5), 3.13 (dd, 1H, J = 5.5, 13.8), 2.96 (dd, 1H, J = 7.5, 13.8), 1.51 (s, 2H), 1.24 (t, 3H, J = 7.3). 12 H 15 Calculated value for F3NO2: 262.1055; Measured value: 262.1054.

[0311] Ethyl 2-amino-3-(4-(trifluoromethyl)phenyl)propanoate (B-26): It was obtained as an oily substance (1.23 g, 91%). 1 H NMR (CDCl3): 7.58 (d, 2H, J = 8.3), 7.35 (d, 2H, J = 8.3), 4.18 (q, 2H, J = 7.3), 3.74 (dd, 1H, J = 5.8, 7.8), 3.14 (dd, 1H, J = 5.8, 13.4), 2.96 (dd, 1H, J = 7.8, 13.4), 1.50 (s, 2H), 1.25 (t, 3H, J = 7.3). HRMS: C 12 H 15 Calculated value for F3NO2: 262.1055; Measured value: 262.1129.

[0312] Ethyl 2-amino-3-(2-fluorophenyl)propanoate (B-27): It was obtained as an oily substance (2.57 g, 88%). 1 H NMR (CDCl3): 7.23 (m, 2H), 7.06 (m, 2H), 4.17 (q, 2H, J = 7.1), 3.76 (dd, 1H, J = 7.9, 5.9), 3.11 (dd, 1H, J = 13.6, 5.9), 2.93 (dd, 1H, J = 13.6, 7.9), 1.24 (t, 3H, J = 7.1). HRMS: C11 H 15 Calculated value for FNO2: 212.1087; Measured value: 212.1089.

[0313] Ethyl 2-amino-3-(2,4-difluorophenyl)propanoate (B-28): It was obtained as an oily substance (1.11 g, 85%). 1 H NMR (CDCl3): 7.19 (m, 1H), 6.80 (m, 2H), 4.15 (q, 2H, J = 7.1), 3.70 (dd, 1H, J = 7.9, 5.9), 3.04 (dd, 1H, J = 13.7, 5.9), 2.89 (dd, 1H, J = 13.7, 7.9), 1.52 (s, 2H), 1.23 (t, 3H, J = 7.1). HRMS: C 11 H 14 F2NO2, 230.0993; measured value, 230.1006.

[0314] Ethyl 2-amino-3-(4-chlorophenyl)propanoate (B-29): It was obtained as an oily substance (1.48 g, 73%). 1 H NMR (CDCl3): 7.29 (m, 2H), 7.16 (m, 2H), 4.18 (q, 2H, J = 7.3), 3.69 (dd, 1H, J = 5.6, 7.5), 3.05 (dd, 1H, J = 5.6, 13.7), 2.84 (dd, 1H, J = 7.5, 13.7), 1.47 (s(l), 2H), 1.26 (t, 3H, J = 7.1). HRMS: C 11 H 15 Calculated value for ClNO2: 228.0791; Measured value: 228.0806.

[0315] Ethyl 2-amino-3-(2-chlorophenyl)propanoate (B-30): It was obtained as an oily substance (3.73 g, 19% from 2-chlorobenzaldehyde). 1 H NMR (CDCl3): 7.38 (m, 1H), 7.22 (m, 3H), 4.16 (m, 2H), 3.84 (dd, J = 8.5, 5.8 Hz, 1H), 3.24 (dd, J = 13.5, 5.8 Hz, 1H), 3.96 (dd, J = 13.5, 8.5 Hz, 1H), 1.23 (t, J = 7.2 Hz, 3H). HRMS: C 11 H 15 Calculated value for ClNO2: 228.0791; Measured value: 228.0791.

[0316] Ethyl 2-amino-3-(4-bromophenyl)propanoate (B-31): It was obtained as an oily substance (0.61 g, 76%). 1 H NMR (CDCl3): 7.44 (m, 2H), 7.10 (m, 2H), 4.18 (q, 2H, J = 7.3), 3.69 (dd, 1H, HRMS: C 11 H 15 Calculated value for BrNO2: 272.0286; Measured value: 272.0296.

[0317] Ethyl 2-amino-3-(3-fluorophenyl)propanoate (B-32): It was obtained as an oily substance (4.89 g, 89%). 1H NMR (CDCl3): 7.27 (m, 1H), 7.01-6.92 (m, 3H), 4.18 (q, 2H, J = 7.0), 3.72 (dd, 1H, J = 5.4, 7.9), 3.08 (dd, 1H, J = 5.4, 13.7), 2.88 (dd, 1H, J = 7.9, 13.7), 1.49 (s, 2H), 1.26 (t, 3H, J = 7.0). HRMS: C 11 H 15 Calculated value for FNO2: 212.1087; Measured value: 212.1088.

[0318] Ethyl 2-amino-3-(4-isopropylphenyl)propanoate hydrochloride (B-33): The oily substance was immediately treated with a solution of hydrogen chloride in dioxane, concentrated to dryness, and obtained the hydrochloride salt as a white powder (1.9 g, purity 91%). 1 H NMR (DMSO-d6): 8.23 ​​(s, 3H), 7.22 - 7.12 (m, 4H), 4.16 - 4.02 (m, 3H), 3.16 (dd, 1H, J = 13.9, 5.8), 3.01 (dd, 1H, J = 13.9, 7.8), 2.86 (hept, 1H, J = 6.9), 1.18 (d, 6H, J = 6.9), 1.06 (t, 3H, J = 7.1). HRMS: C 14 H 22 Calculated value for NO2: 236.1651; Measured value: 236.1651.

[0319] Ethyl 2-amino-3-(4-cyclopropylphenyl)propanoate (B-34): It was obtained as an oily substance (0.71 g, 80%). 1 H NMR (CDCl3): 7.09 (m, 2H), 7.01 (m, 2H), 4.18 (q, 2H, J = 7.0), 3.70 (dd, 1H, J = 5.2, 7.9), 3.06 (dd, 1H, J = 5.2, 13.7), 2.83 (dd, 1H, J = 7.9, 13.7), 1.87 (m, 1H), 1.54 (s, 2H), 1.28 (t, 3H, J = 7.0), 0.95 (m, 2H), 0.68 (m, 2H). HRMS: C 14 H 20 Calculated value for NO2: 234.1494; Measured value: 234.1490.

[0320] Ethyl 2-amino-3-(3-cyclopropylphenyl)propanoate (B-35): It was obtained as an oily substance (1.66 g, 89%). 1 H NMR (CDCl3): 7.19 (m, 1H), 6.95 (m, 3H), 4.19 (q, 2H, J = 7.0), 3.71 (dd, 1H, J = 5.2, 7.9), 3.05 (dd, 1H, J = 5.2, 13.5), 2.83 (dd, 1H, J = 7.9, 13.5), 1.88 (m, 1H), 1.53 (s, 2H), 1.28 (t, 3H, J = 7.0), 0.95 (m, 2H), 0.68 (m, 2H). HRMS: C 14 H 20 Calculated value for NO2: 234.1494; Measured value: 234.1496.

[0321] Ethyl 2-amino-3-(4-propylphenyl)propanoate hydrochloride (B-36): The oily substance was immediately treated with a solution of hydrogen chloride in dioxane, concentrated to dryness, and the hydrochloride salt was obtained as a white powder (2.46 g, 85%). 1H NMR (DMSO-d6): 8.59 (bs, 3H), 7.15 (s, 4H), 4.20 (dd, J = 7.5, 5.9 Hz, 1H), 4.10 (m, 2H), 3.16 (dd, J = 7.9, 5.9 Hz, 1H), 3.02 (dd, J = HRMS: C 14 H 22 Calculated value for NO2: 236.1651; Measured value: 236.1659.

[0322] Ethyl 2-amino-3-(3-propylphenyl)propanoate hydrochloride (B-37): The oily substance obtained was immediately treated with a solution of hydrogen chloride in dioxane, concentrated to dryness, and the hydrochloride salt was obtained as a white powder (1.89 g, 90%). 1 H NMR (DMSO-d6): 8.72 (bs, 3H), 7.24 (m, 1H), 7.08 (m, 3H), 4.18 (dd, J = 7.9, 5.6 Hz, 1H), 4.08 (q, J = 7.2 Hz, 2H), 3.21 (dd, J = 13.9, HRMS: Calculated value for C 14 H 22 NO2: 236.1651; Measured value, 236.1637. Ethyl 2-amino-3-(5-(trifluoromethyl)furan-2-yl)propanoate (B-38): It was obtained as an oily substance with a purity of 95% (0.53 g, 93%). 1H NMR (CDCl3): 6.66 (dd, 1H, J= 3.3, 1.2), 6.20 - 6.15 (m, 1H), 4.20 - 4.10 (m, 2H), 3.79 - 3.73 (m, 1H), 3.08 (dd, 1H, J = 15.0, 5.4), 2.99 (dd, 1H, J = 15.0, 7.1), 1.60 (bs, 2H), 1.22 (t, 3H, J = 7.1). HRMS: C 10 H 13 Calculated value for F3NO3, 252.0847; measured value, 252.0852.

[0323] Ethyl 2-amino-3-(5-cyclopropylfuran-2-yl)propanoate (B-39): It was obtained as an oily substance (0.70 g, 88%). 1 H NMR (CDCl3): 5.99 (d, J = 3.1 Hz, 1H), 5.85 (d, J = 3.1 Hz, 1H), 4.20 (q, 2H, J = 7.2), 3.74 (dd, 1H, J = 7.1, 5.1), 3.03 (dd, 1H, J = 14.8, 5.1), 2.93 (dd, 1H, J = 14.8, 7.1), 1.84 (m, 1H), 1.36 (t, 3H, J = 7.2), 0.84 (m, 2H), 0.73 (m, 2H). HRMS: C 12 H 17 Calculated value for NO3: 224.1287; Measured value: 224.1282.

[0324] Ethyl 2-amino-3-(4,5-dimethyloxazol-2-yl)propanoate (B-40): It was obtained as an oily substance (0.23 g, 74%). 1H NMR (CDCl3): 4.19 (m, 2H), 3.90 (dd, 1H, J = 4.5, 8.1), 3.14 (dd, 1H, J = 4.5, 15.0), 2.96 (dd, 1H, J = 8.1, 15.0), 2.27 (s, 3H), 2.05 (s, 3H), 1.84 (s(l), 2H), 1.26 (t, 3H, J = 7.3). HRMS: C 10 H 17 Calculated value for N2O3: 213.1229; Measured value: 213.1230.

[0325] Ethyl 2-amino-3-phenylbutanoate (B-41): It was obtained as an oily substance containing a 1 / 2 mixture of the two diastereoisomers (0.76 g, 88%). 1 H NMR (CDCl3): 7.39-7.21 (m, 5H), 4.20 (q, 1.3H, J = 7.1), 4.20 (q, 0.7H, J = 7.1), 3.62 (d, 0.3H, J = 6.0), 3.56 (d, 0.7H, J = 7.2), 3.18 (m, 0.3H), 3.12 (m, 0.3H), 1.44 (s, 2H), 1.36 (d, 2H, J = 7.2), 1.34 (d, 1H, J = 6.0), 1.29 (t, 2H, J = 7.1), 1.16 (t, 1H, J = 7.1). HRMS: C 12 H 18 Calculated value for NO2: 208.1338; Measured value: 208.1331.

[0326] Manufacturing of 2-amino-4-phenylbutanoate (B-42): Ethyl 5-phenyl-4,5-dihydroisoxazole-3-carboxylate (WO20100142801, 2010) (0.47 g, 2.14 mmol), ammonium formate (2.7 g, 21.4 mmol), and 10% palladium-carbon (0.11 g, 0.10 mmol) were heated under reflux in ethanol (50 mL) for 1 hour. This was filtered, and the insoluble matter was washed with a small amount of ethanol. 37% hydrochloric acid (1.6 mL, 13.6 mmol) was added, followed by the addition of zinc powder (0.42 g, 6.3 mmol) in portions. This was stirred for 90 minutes, the resulting solution was diluted with water, made basic with 22% ammonia, and extracted with ethyl acetate. The organic layer was washed with water and saline solution, dried over sodium carbonate, and concentrated to dryness to obtain an amino ester as an oily substance (0.32 g, 72%).

[0327] 1 H NMR (CDCl3): 7.31 (m, 2H), 7.22 (m, 3H), 4.19 (m, 2H), 3.46 (dd, 1H, J = 5.3, 7.9), 2.76 (m, 2H), 2.07 (m, 1H), 1.87 (m, 1H), 1.65 (s, 2H), 1.30 (t, 3H, J = 7.1).

[0328] Manufacturing of ethyl 2-amino-3-(1,3-dioxolan-2-yl)propanoate (B-43): Step 1: Diethyl 2-((1,3-dioxolann-2-yl)methyl Dissolve malonate (7.8 g, 0.317 mol) in ethanol (40 mL) and add ethanol (60 Potassium hydroxide (1.78 g, 0.0317 mol) dissolved in (mL) was added dropwise. The solution was then prepared at room temperature. It was stirred overnight, then briefly heated under reflux. This was concentrated and dissolved in water to a 22% concentration. The aqueous phase was made more basic with ammonia. The aqueous phase was washed with dichloromethane, acidified with 37% hydrochloric acid, extracted with ethyl acetate, the organic layer was washed with water and brine, dried over magnesium sulfate, concentrated to dryness, and pure 2-((1,3-dioxolan-2-yl)methyl)-3-ethoxy-3-oxopropyl alcohol was obtained. Panic acid (3.85 g, 55%) was obtained.

[0329] 1 H NMR (CDCl3): 5.05 (t, 1H, J = 3.7), 4.24 (q, 2H, J = 7.1), 3.98 (m, 2H), 3.82 (m, 2H), 3.64 (t, 1H, J = 6.9), 2.40 (m, 2H), 1.30 (t, 3H, J = 7.1).

[0330] Step 2: Under argon, this compound (3.85 g, 0.0176 mol) was dissolved in toluene (50 mL, 4A molecular solution) It was dissolved in (dried) solution. Triethylamine (2.95 mL, 0.021 mol) was added, followed by diphenyl phosphoryl azide (4.18 mL, 0.021 mol). This was stirred at 80 °C for 1 hour and 30 minutes, toluene was removed under vacuum, and the resulting oily substance was repeatedly extracted with cyclohexane. The oily substance was obtained by concentrating and drying this extract, and stirred overnight at room temperature in 4% hydrochloric acid (50 mL). The resulting solution was diluted with more acid, extracted with ethyl acetate, and the aqueous phase was made basic with 22% ammonia, and acetic acid ester was added. The organic layer was extracted by chilling, washed with water and saline solution, dried over sodium carbonate, and concentrated to dryness to obtain an amino ester as an oily substance (0.14 g, 16%).

[0331] 1H NMR (CDCl3): 5.05 (dd, 1H, J = 4.3, 5.0), 4.0 (m, 2H), 3.87 (m, 2H), 3.66 (dd, 1H, J = 4.6, 8.2), 2.15 (ddd, 1H, J = 4.6, 5.0, 14.2), 1.94 (ddd, 1H, J = 4.3, 8.2, 14.2), 1.57 (s, 2H), 1.29 (t, 3H, J = 7.1). HRMS: C8H 16 Calculated value for NO4: 190.1079; Measured value: 190.1061.

[0332] Synthesis of piperazine-2-one E, and typical preparation of (3S,5S) and (3S,5R)-3-benzyl-5-phenylpiperazine-2-one Step a, Production of ethyl (2-nitro-1-phenylethyl)-L-phenylalaninate: 2-nitrovinylbenzene (3.78 g, 0.025 mol) was added to freshly extracted free base L-phenylalanine ethyl ester (4.9 g, 0.025 mol). The suspension was homogenized in approximately 10 minutes by stirring in a rotary evaporator at room temperature, yielding 1,4 adduct C.

[0333] Step b, Production of ethyl (2-amino-1-phenylethyl)phenylalaninate: This oily substance was dispersed in a cold solution of dioxane (100 mL) and 37% hydrochloric acid (38.7 mL, 0.33 mol). Zinc powder (7.45 g, 0.11 g, < 10 μm) was added in portions over 10 minutes. Then the temperature was changed. The suspension was allowed to rise to room temperature and stirred for 2 hours. This was diluted with water, made basic with an excess of 22% ammonia, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium carbonate, and concentrated to dryness to obtain crude compound D as an oily substance.

[0334] Step c, Production of 3-benzyl-5-phenylpiperazine-2-one E: The oily substance was heated at 140°C for 3 hours under an argon atmosphere. Ethanol was removed under vacuum. The resulting solid was subjected to the purification method described below. Note: When separated, the structural assignment of these diastereoisomer pairs can be done by checking for the presence (or absence) of an nOe effect between H-3 and H-5.

[0335] (3S,5R)-3-benzyl-5-phenylpiperazine-2-one (E-1): To remove unreacted L-phenylalanine ester, a crude mixture of diastereoisomers is prepared. Disperse the resulting solid in boiling cyclohexane and chromatograph it using silica gel (DiC The compound was purified using lolomethane / ethanol (96 / 4~95 / 5) to obtain a white solid (2.05 g, 35%).

[0336] 1 H NMR (CDCl3): 7.42 - 7.29 (m, 9H), 7.26 - 7.20 (m, 1H), 6.27 (s, 1H), 4.06 (dd, 1H, J = 9.7, 4.7), 3.84 (dt, 1H, J = 10.1, 3.4), 3.60 (dd, 1H, J = 13.6, 3.1), 3.41 - 3.25 (m, 2H), 2.91 (dd, 1H, J = 13.6, 10.1), 1.78 (s, 1H). HRMS: C 17 H 19 Calculated value for N2O: 267.1497; Measured value: 267.1459.

[0337] (3S,5S)-3-benzyl-5-phenylpiperazine-2-one (E-2): The second chromatographic fraction yielded this isomer as a white solid (1.29 g, 22%). 1H NMR (CDCl3): 7.46 - 7.18 (m, 10H), 6.44 (s, 1H), 4.27 (dd, 1H, J = 9.6, 4.0), 3.89 (dd, 1H, J = 10.7, 3.6), 3.54 - 3.44 (m, 1H), 3.41 (dt, 1H, J = 11.5, 4.0), 3.32 (dd, 1H, J = 13.8, 3.6), 3.18 (dd, 1H, J = 13.8, 10.7), 1.79 (s, 1H). HRMS: C 17 H 19 Calculated value for N2O: 267.1497; Measured value: 267.1435.

[0338] 3-benzyl-5-(p-tril)piperazine-2-one (E-3): The resulting solid is dispersed in boiling cyclohexane and filtered at 20°C to obtain two dihydrogen compounds. The compound (5.40 g) was obtained as a crude mixture of astereoisomers and was used directly in the aromatization step. HRMS: C 18 H 20 Calculated value for N2O: 281.1654; Measured value: 281.1649.

[0339] 3-benzyl-5-(m-tril)piperazine-2-one (E-4): The analytical sample of the mixture of the two diastereoisomers was obtained by recrystallization with cyclohexane, but the majority of the solid and filtrate were used directly in the aromatization process. HRMS: C 18 H 20 Calculated value for N2O: 281.1654; Measured value: 281.1645.

[0340] cis-3-(2-methylbenzyl)-5-phenylpiperazine-2-one (E-5): This compound was obtained as a white powder (4.04 g, 26%) after chromatography on silica gel (dichloromethane / ethanol 98 / 2-95 / 5) and dispersion in boiling cyclohexane. 1 H NMR (CDCl3): 7.40 - 7.27 (m, 6H), 7.14 (m, 3H), 6.58 (s (br), 1H), 4.03 (dd, 1H, J = 4.1, 10.5), 3.82 (d (br), 1H, J = 10.5), 3.68 (dd, HRMS: C 18 H 21 Calculated value for N2O: 281.1654; Measured value: 281.1652.

[0341] trans-3-(2-methylbenzyl)-5-phenylpiperazine-2-one (E-6): This compound was obtained as a white powder (2.77 g, 17%) after chromatography on silica gel (dichloromethane / ethanol 98 / 2-95 / 5) and dispersion in boiling cyclohexane. . 1 H NMR (CDCl3): 7.41 - 7.30 (m, 5H), 7.14 (m, 4H), 6.80 (s (br), 1H), 4.35 (dd, 1H, J = 5.0, 9.8), 3.89 (dd, 1H, J = 3.3, 11.2), 3.43 (m, HRMS: C 18 H 21 Calculated value for N2O: 281.1654; Measured value: 281.1652.

[0342] cis-3-(3-methylbenzyl)-5-phenylpiperazine-2-one (E-7): This compound was obtained as a white powder (3.70 g, 26%) after chromatography on silica gel (dichloromethane / ethanol 98 / 2-95 / 5) and dispersion in boiling cyclohexane. 1 H NMR (CDCl3): 7.40 - 7.28 (m, 5H), 7.20 (m, 1H), 7.13 (m, 2H), 7.04 (m, 1H), 6.72 (s (br), 1H), 4.05 (dd, 1H, J = 5.4, 9.5), 3.83 (d HRMS: C 18 H 21 Calculated value for N2O: 281.1654; Measured value: 281.1649.

[0343] trans-3-(3-methylbenzyl)-5-phenylpiperazine-2-one (E-8): This compound was obtained as a white powder (2.73 g, 19%) after chromatography on silica gel (dichloromethane / ethanol 98 / 2-95 / 5) and recrystallization with cyclohexane. 1 H NMR (CDCl3): 7.39 - 7.30 (m, 5H), 7.19 (m, 1H), 7.05 (m, 3H), 6.81 (s (br), 1H), 4.26 (dd, 1H, J= 4.0, 9.9), 3.87 (dd, 1H, J = 3.8, HRMS: C 18 H 21 Calculated value for N2O: 281.1654; Measured value: 281.1656.

[0344] (3S,5R)-3-benzyl-5-(2-methoxyphenyl)piperazine-2-one (E-9): This isomer was chromatographically analyzed in two silica gels (dichloromethane - ethano After (96 / 4~95 / 5) and (cyclohexane-ethyl acetate 1 / 2~1 / 3), a glassy substance and This was obtained (1.06 g, 25%). 1 H NMR (CDCl3): 7.40-7.22 (m, 7H), 6.98 (m, 1H), 6.84 (m, 1H), 6.69 (s (br), 1H), 4.39 (dd, 1H, J = 3.7, 10.7), 3.74 (s, 3H), 3.85 (dd, 1H, J = 3.2, 9.2), 3.53 (dd, 1H, J = 3.5, 13.7), 3.44 (ddd, 1H, J = 4.0, 8.0, 11.0), 3.28 (t, 1H, J = 11.0), 3.01 (dd, 1H, J = 8.3, 13.7), 1.90 (s (br), 1H). HRMS: C 18 H 21 Calculated value for N2O: 297.1603, Measured value: 297.1591.

[0345] (3S,5S)-3-benzyl-5-(2-methoxyphenyl)piperazine-2-one (E-10): This isomer was chromatographically analyzed in two silica gels (dichloromethane - ethano After dissolving (ethyl acetate - ethanol 1 / 0~99 / 1) and (ethyl acetate - ethanol 1 / 0~99 / 1), a white solid was obtained (0.52 g, 12%). 1H NMR (CDCl3): 7.36-7.20 (m, 7H), 6.94 (m, 1H), 6.88 (m, 1H), 6.65 (s (br), 1H), 4.64 (dd, 1H, J = 4.2, 8.1), 3.77 (s, 3H), 3.71 (dd, 1H, J = 3.3, 10.8), 3.59 (m, 1H), 3.47 (ddd, 1H, J = 1.0, 11.2), 3.36 (dd, 1H, J = 3.3, 13.7), 3.09 (dd, 1H, J = 10.8, 13.7), 2.08 (s (br), 1H). HRMS: C 18 H 21 Calculated value for N2O: 297.1603, Measured value: 297.1589.

[0346] (3S,5R)-3-benzyl-5-(3-methoxyphenyl)piperazine-2-one (E-11): This isomer was chromatographically analyzed in two silica gels (dichloromethane - ethano After mixing (97 / 3~95 / 5) and (cyclohexane - ethyl acetate 1 / 4), a glassy substance was obtained (1.33 g, 30%). 1 H NMR (CDCl3): 7.34-7.20 (m, 6H), 6.94 (m, 2H), 6.83 (m, 1H), 6.72 (s (br), 1H), 4.02 (dd, 1H, J = 6.3, 8.7), 3.83 (m, 1H), 3.81 (s, HRMS: C 18 H 21 Calculated value for N2O: 297.1603, Measured value: 297.1582.

[0347] (3S,5S)-3-benzyl-5-(3-methoxyphenyl)piperazine-2-one (E-12): This isomer was chromatographically analyzed in two silica gels (dichloromethane - ethano After dissolving (ethyl acetate - ethanol 1 / 0~99 / 1) and (ethyl acetate - ethanol 1 / 0~99 / 1), a glassy substance was obtained (0.84 g, 19%). 1 H NMR (CDCl3): 7.33-7.22 (m, 6H), 6.94 (m, 2H), 6.85 (m, 1H), 6.76 (s (br), 1H), 4.22 (dd, 1H, J = 4.1, 9.5), 3.88 (dd, 1H, J = 3.6, HRMS: C 18 H 21 Calculated value for N2O: 297.1603, Measured value: 297.1584.

[0348] (3S,5R)-3-benzyl-5-(4-methoxyphenyl)piperazine-2-one (E-13): This isomer was chromatographically analyzed in two silica gels (dichloromethane - ethano After mixing (97 / 3~95 / 5) and (cyclohexane-ethyl acetate 1 / 4), a glassy substance was obtained (1.37 g, 27%). 1 H NMR (CDCl3): 7.28 (m, 7H), 6.87 (m, 2H), 6.38 (s (br), 1H), 3.99 (dd, 1H, J = 4.3, 10.3), 3.82 (m, 1H), 3.80 (s, 3H), 3.58 (dd, 1H, J = 3.8, 13.6), 3.31 (m, 2H), 2.89 (dd, 1H, J = 10.2, 13.6), 1.90 (s (br), 1H). HRMS: C 18 H 21Calculated value for N2O: 297.1603, Measured value: 297.1585.

[0349] (3S,5S)-3-benzyl-5-(4-methoxyphenyl)piperazine-2-one (E-14): This isomer was chromatographically analyzed in two silica gels (dichloromethane - ethano After dissolving (67 / 3~95 / 5) and (ethyl acetate - ethanol 1 / 0~99 / 1), a white powder was obtained (0.81 g, 16%). 1 H NMR (CDCl3): 7.28 (m, 7H), 6.81 (m, 2H), 6.73 (s (br), 1H), 4.19 (dd, 1H, J = 4.0, 9.8), 3.86 (dd, 1H, J = 3.6, 10.6), 3.80 (s, 3H), 3.44 (m, 1H), 3.31 (m, 2H), 3.36 (td, 1H, J = 3.8, 11.5), 3.30 (dd, 1H, J = 3.8, 13.9), 3.17 (dd, 1H, J = 10.6, 13.9), 1.85 (s (br), 1H). HRMS: C 18 H 21 Calculated value for N2O: 297.1603, measured value Value: 297.1533.

[0350] (3S,5R)-3-benzyl-5-(2-fluorophenyl)piperazine-2-one (E-15): This isomer was chromatographically analyzed in two silica gels (dichloromethane - ethano (96 / 4~94 / 6) and (cyclohexane - ethyl acetate 2 / 3~1 / 3), followed by boiling cyclohexane After dispersion in 39 oz and extensive drying under vacuum at 70 °C, it was obtained as a white powder (4.06 g, 39 %). 1H NMR (CDCl3): 7.49 (m, 1H), 7.31 (m, 4H), 7.26 (m, 2H), 7.16 (m, 1H), 7.02 (m, 1H), 6.65 (s (br), 1H), 4.42 (m, 1H), 3.87 (m, 1H), 3.57 (dd, 1H, J = 3.3, 13.8), 3.29 (t, 1H, J = 10.9), 2.95 (dd, 1H, J = 9.1, 13.8), 1.73 (s (br), 1H). HRMS: C 17 H 18 Calculated value for FN2O: 285.1403, Measured value: 285.1391.

[0351] (3S,5S)-3-benzyl-5-(2-fluorophenyl)piperazine-2-one (E-16): This isomer was obtained as a white powder (2.16 g, 20%) after chromatography on silica gel (dichloromethane-ethanol 96 / 4~94 / 6). 1 H NMR (CDCl3): 7.44 (m, 1H), 7.27 (m, 6H), 7.13 (m, 1H), 7.08 (m, 1H), 6.74 (s (br), 1H), 4.65 (dd, 1H, J = 4.3, 9.1), 3.84 (dd, 1H, J = HRMS: C 17 H 18 Calculated value for FN2O: 285.1403, Measured value: 285.1367.

[0352] 3-Benzyl-5-(2,6-difluorophenyl)piperazine-2-one (E-17): This isomer, after recrystallization in cyclohexane, is obtained as a 1 / 1 mixture of diastereoisomers. The result was (1.97 g, 62%). HRMS: C 17 H 17 Calculated value for F2N2O: 303.1309, Measured value: 303.1323.

[0353] (3S,5R)-3-benzyl-5-(4-fluorophenyl)piperazine-2-one (E-18): This isomer was chromatographically analyzed in two silica gels (dichloromethane - ethano After mixing (97 / 3~95 / 5) and (cyclohexane-ethyl acetate 1 / 2~1 / 3), a white powder is obtained. (1.26 g, 29%). 1 H NMR (CDCl3): 7.28 (m, 7H), 7.01 (m, 2H), 6.61 (s (br), 1H), 4.05 (t, 1H, J = 7.3), 3.82 (d, 1H, J = 9.3), 3.58 (dd, 1H, J = 3.0, 13.6), 3.31 (m, 2H), 2.89 (dd, 1H, J = 9.8, 13.6), 1.72 (s (br), 1H). HRMS: C 17 H 18 Calculated value for FN2O: 285.1403, Measured value: 285.1342.

[0354] (3S,5S)-3-benzyl-5-(4-fluorophenyl)piperazine-2-one (E-19): This isomer was chromatographically analyzed in two silica gels (dichloromethane - ethano After dissolving (97 / 3~95 / 5) and (ethyl acetate - ethanol 99 / 1), a white powder was obtained (1.26 g, 29%). 1 H NMR (CDCl3): 7.29 (m, 7H), 7.05 (m, 2H), 6.79 (s (br), 1H), 4.21 (dd, 1H, J = HRMS: C 17 H 18 Calculated value for FN2O: 285.1403, Measured value: 285.1315.

[0355] 3-Benzyl-5-(3-fluorophenyl)piperazine-2-one (E-20): This mixture of isomers was washed with cyclohexane to remove unreacted ethyl phenylalanine ester, obtained as an oily substance, and used directly in the aromatization process.

[0356] (3S,5R)-3-benzyl-5-(4-(benzyloxy)phenyl)piperazine-2-one (E-21): This isomer was chromatographically analyzed in two silica gels (dichloromethane - ethano After recrystallization with (95 / 5~92 / 8) and (cyclohexane-ethyl acetate 1 / 2) and cyclohexane, a white powder was obtained (0.92 g, 17%). 1 H NMR (CDCl3): 7.45 - 7.21 (m, 12H), 6.94 (m, 2H), 6.47 (s (br), 1H), 5.06 (s, 2H), 4.00 (dd, 1H, J = 4.3, 10.1), 3.83 (dd, 1H, J = 3.0, 10.1), 3.59 (dd, 1H, J = 3.0, 13.6), 3.32 (m, 2H), 2.90 (dd, 1H, J = 10.1, 13.6), 1.73 (s (br), 1H). HRMS: C 25 H 25 Calculated value for N2O3: 373.1916, Measured value: 373.1932.

[0357] (3S,5S)-3-benzyl-5-(4-(benzyloxy)phenyl)piperazine-2-one (E-22): This isomer was chromatographically analyzed in two silica gels (dichloromethane - ethano After dissolving (95 / 5~92 / 8) and (ethyl acetate - ethanol 1 / 0~99 / 1), a white powder was obtained (0.59 g, 11%). 1 H NMR (CDCl3): 7.45 - 7.23 (m, 12H), 6.96 (m, 2H), 6.67 (s (br), 1H), 5.07 (s, 2H), 4.21 (dd, 1H, J = 4.0, 9.6), 3.85 (dd, 1H, J = 3.5, HRMS: C 25 H 25 Calculated value for N2O3: 373.1916, Measured value: 373.1907.

[0358] (3S,5R)-3-benzyl-5-(4-(benzyloxy)-3-fluorophenyl)piperazine-2-one (E-23): This isomer was obtained as a powder after chromatography on silica gel (dichloromethane-ethanol 98 / 2~95 / 5) (2.47 g, 54%, purity 90%). 1 H NMR (CDCl3): 7.44 - 7.21 (m, 10H), 7.15 (m, 1H), 7.01 (m, 1H), 6.95 (m, 1H), 6.19 (s (br), 1H), 5.13 (s, 2H), 3.96 (m, 1H), 3.81 (dd, 1H, J = 3.0, 10.1), 3.58 (dd, 1H, J = 3.0, 13.8), 3.28 (m, 2H), 2.88 (dd, 1H, J = 10.2, 13.8), 1.71 (s (br), 1H). HRMS: C24 H 25 Calculated value for FN2O3: 391.1822, Measured value: 391.1828.

[0359] (3S,5S)-3-benzyl-5-(4-(benzyloxy)-3-fluorophenyl)piperazine-2-one (E-24): This isomer was obtained as a powder (0.5 g, 11%) after chromatography on silica gel (dichloromethane-ethanol 98 / 2~95 / 5). 1 H NMR (CDCl3): 7.45 - 7.22 (m, 10H), 7.13 (m, 1H), 7.02 (m, 1H), 6.96 (m, 1H), 6.19 (s (br), 1H), 5.14 (s, 2H), 4.15 (dd, 1H, J = 4.1, 9.3), 3.86 (dd, 1H, J = 3.6, 10.4), 3.45 - 3.33 (m, 2H), 3.29 (dd, 1H, J = 4.1, 14.4), 3.16 (dd, 1H, J = 10.8, 13.8), 1.71 (s (br), 1H). HRMS: C 24 H 25 Calculated value for FN2O3: 391.1822, Measured value: 391.1828.

[0360] cis-3-(2-fluorobenzyl)-5-phenylpiperazine-2-one (E-25): This racemic isomer can be chromatographed on silica gel (dichloromethane - ethanol After dispersion in 97 / 3~95 / 5 and boiling cyclohexane, a white powder was obtained from B-27 (2.85 g, 31%). 1H NMR (CDCl3): 7.35 (m, 6H), 7.21 (m, 1H), 7.07 (m, 2H), 6.60 (s (br), 1H), 4.08 (dd, 1H, J = 6.4, 8.3), 3.92 (dd, 1H, J = 3.1, 9.6), 3.65 (dd, 1H, J = 3.0, 14.0), 3.34 (m, 2H), 2.97 (dd, 1H, J = 9.6, 14.0), 1.78 (s (br), 1H). HRMS: C 17 H 18 Calculated value for FN2O: 285.1403, Measured value: 285.1412.

[0361] trans-3-(2-fluorobenzyl)-5-phenylpiperazine-2-one (E-26): This racemic isomer was obtained from B-27 by chromatography on silica gel (dichloromethane). - The sample was obtained as a white powder (2.15 g, 23%) after recrystallization with ethanol (97 / 3~95 / 5) and cyclohexane for analytical purposes. 1 H NMR (CDCl3): 7.40-7.26 (m, 6H), 7.21 (m, 1H), 7.09 (m, 1H), 7.03 (m, 1H), 6.92 (s (br), 1H), 4.33 (dd, 1H, J = 3.9, 9.8), 3.92 (dd, 1H, J = 3.9, 10.6), 3.51-3.33 (m, 3H), 3.27 (dd, 1H, J = 4.0, 14.0), 1.72 (s (br), 1H). HRMS: C 17 H 18 Calculated value for FN2O: 285.1403, Measured value: 285.1410.

[0362] 3-(2-chlorobenzyl)-5-phenylpiperazine-2-one (E-27): After recrystallization with cyclohexane, this compound was obtained as a white powder containing a mixture of two diastereoisomers from B-30 (2.21 g, 45%). 1 H NMR (CDCl3): 7.42-7.29 (m, 7H), 7.25-7.14 (m, 2H), 6.85 (bs, 0.4H), 6.69 (bs, 0.6H), 4.37 (dd, J = 9.8, 4.2 Hz, 0.4H), 4.10-3.98 (m, 1.4H), 3.83 (dd, J = 13.8, 3.4 Hz, 0.6H), 3.51-3.30 (m, 3H), 3.02 (dd, J = 13.8, 9.8 Hz, 0.6H). HRMS: C 17 H 18 Calculated value for ClN2O: 301.1108; Measured value: 301.1117.

[0363] cis-3-(2-methoxybenzyl)-5-phenylpiperazine-2-one (E-28): This isomer was obtained as a powder after chromatography on silica gel (dichloromethane-ethanol 97.5 / 2.5) (4.03 g, still containing 5% amino ester). 1 H NMR (CDCl3): 7.39-7.27 (m, 6H), 7.21 (m, 1H), 6.89 (m, 2H), 6.38 (s (br), 1H), 4.05 (dd, 1H, J = 5.3, 9.3), 3.92 (m, 1H), 3.84 (s, HRMS: C 18 H 21 Calculated value for N2O: 297.1603, Measured value: 297.1607.

[0364] Trans-3-(2-methoxybenzyl)-5-phenylpiperazine-2-one (E-29): This isomer was obtained as a powder (2.23 g, 24%) after chromatography on silica gel (dichloromethane-ethanol 97.5 / 2.5). 1 H NMR (CDCl3): 7.39-7.30 (m, 5H), 7.21 (m, 2H), 6.92 (m, 1H), 6.82 (m, 1H), 6.70 (s (br), 1H), 4.36 (dd, 1H, J = 3.9, 9.9), 3.97 (dd, HRMS: C 18 H 21 Calculated value for N2O: 297.1603, Measured value: 297.1604.

[0365] cis-3-(3-fluorobenzyl)-5-phenylpiperazine-2-one (E-30): This isomer was obtained as a powder (2.25 g, 13%) after chromatography on silica gel (dichloromethane-ethanol 97.5 / 2.5) and recrystallization with a mixture of toluene and cyclohexane. 1 H NMR (CDCl3): 7.40-7.24 (m, 6H), 7.10 (m, 1H), 7.05 (m, 1H), 6.92 (m, 1H), 6.62 (s (br), 1H), 4.07 (m, 1H), 3.85 (dd, 1H, J = 2.9, HRMS: C 17 H 19 Calculated value for FN2O: 285.1403, Measured value: 285.1400.

[0366] trans-3-(3-fluorobenzyl)-5-phenylpiperazine-2-one (E-31): This isomer was obtained as a powder (2.49 g, 15%) after chromatography on silica gel (dichloromethane-ethanol 97.5 / 2.5). 1 H NMR (CDCl3): 7.35 (m, 5H), 7.26 (m, 3H), 6.70 (s (br), 1H), 4.21 (dd, 1H, J = 4.2, 9.3 Hz, 1H), 3.87 (dd, 1H, J = 3.8, 10.3), 3.54-3.41 (m, 2H), 3.30 (dd, 1H, J = 3.8, 14.0), 3.30 (dd, 1H, J = 10.3, 14.0), 1.77 (s (br), 1H). HRMS: C 17 H 19 Calculated value for FN2O: 285.1403, Measured value: 285.1409.

[0367] 3-(4-fluorobenzyl)-5-phenylpiperazine-2-one (E-32): This compound was obtained as a mixture of diastereoisomers as a white powder after recrystallization with cyclohexane (0.9 g, 59% from phenylnitrostyrene). HRMS: C 17 H 18 Calculated value for FN2O: 285.1403, Measured value: 285.1408.

[0368] (3S,5S)-3-methyl-5-phenylpiperazine-2-one (E-33): This isomer was obtained as a white powder (0.2 g, 12%) after chromatography on silica gel (dichloromethane-ethanol 97 / 3~9 / 1) and recrystallization in a toluene-cyclohexane mixture. Note: Simple recrystallization of the crude reaction product resulted in 1 / 1 of these isomers in two batches. A fairly good overall yield of the mixture was obtained (7.49 g, 47%). 1 HRMS C 11 H 14 Calculated value for N2O + H: 191.1184; Measured value: 191.1109.

[0369] (3S,5R)-3-methyl-5-phenylpiperazine-2-one (E-34): This isomer was obtained as a white powder (0.19 g, 11%) after chromatography on silica gel (dichloromethane-ethanol 97 / 3~9 / 1) and recrystallization in a toluene-cyclohexane mixture. Note: Simple recrystallization of the crude reaction product yielded a fairly good overall yield of a 1 / 1 mixture of these isomers in two recrystallization batches (7.49 g, 47%). 1 HRMS C 11 H 14 Calculated value for N2O + H: 191.1184; Measured value: 191.1138.

[0370] 3-Benzyl-6-methyl-5-phenylpiperazine-2-one (E-35): A mixture of various diastereoisomers of this compound was obtained after removal of unreacted phenylalanine ethyl ester under high vacuum at 180 °C and chromatography on silica gel (dichloromethane-methanol 98 / 2~95 / 5). One of these fractions could be recrystallized on cyclohexane to give the single diastereoisomer (configuration undetermined) described below (0.8 g, 7%). In all cases, as with the other fractions containing different diastereoisomers, this compound was conveniently used in the next step.

[0371] 1 H NMR (CDCl3): 7.38-7.28 (m, 7H), 7.24-7.20 (m, 3H), 6.62 (s, 1H), 3.90-3.87 (dd, 1H, J = 10.2, 3.8), 3.70-3.63 (m, 2H), 3.30-3.16 (m, 2H), 1.73 (s, 1H), 1.03-0.98 (m, 3H). HRMS: C 18 H 21 Calculated value for N2O: 281.1654, Measured value: 281.1659.

[0372] 2-benzyl-1,4a,5,10b-tetrahydro-2H-chromeno[3,4-b]pyrazine-3(4H)-one (E-36) : This compound was prepared from 3-nitro-2H-chromene (Synthesis, 1984, 348; Bioorg. Med. Chem., 2011, 5420) as described above, but an additional step was performed overnight at 0°C, and the resulting solid was... By refluxing with cyclohexane, an inseparable mixture containing one major diastereoisomer was obtained (4.75 g, 76%).

[0373] 1H NMR (CDCl3): 7.38 - 7.29 (m, 16H), 7.20 (m, 1H), 7.02 (s (br), 1H), 6.97 (m, 1H), 6.85 (m, 1H), 4.31 (dd, 1H, J = 4.3, 10.3), 3.99 (m, 2H), 3.90 (dd, 1H, J = HRMS: C 18 H 19 Calculated value for N2O2: 295.1447, Measured value: 295.1402.

[0374] General procedure for the synthesis of pyrazine-2-ol H using sulfur The piperazine-2-one (0.011 mol) and sulfur (0.72 g, 0.0225 mol) under investigation were heated under reflux in 1,3-dichlorobenzene (40 mL) for 10 hours. The mixture was concentrated to dryness, and the residue was purified as described below.

[0375] 3-Methyl-5-phenylpyrazine-2-ol (H-1): From E-33 and / or E-34, chromatography on silica gel (cyclohexane / It was obtained as a beige powder after ethyl acetate (1:2) (1.33 g, 69%). 1 H NMR (DMSO-d6) 12.31 (s, 1H), 7.83 (m, 3H), 7.39 (m, 2H), 7.28 (m, 1H), 2.36 (s, 3H). HRMS: C 11 H 11 Calculated value for N2O: 187.0871; Measured value: 187.0808.

[0376] 3-(2-fluorobenzyl)-5-phenylpyrazine-2-ol (H-2): Chromatography on silica gel from E-25 and / or E-26 (dichloromethane / It was obtained as a white powder (3.66 g, 88%) after ethanol (97.7:2.5). 1 HRMS: C 17 H 14 Calculated value for FN2O: 281.1090; Measured value: 281.1087.

[0377] 3-(2-chlorobenzyl)-5-phenylpyrazine-2-ol (H-3): From E-27, the powder was obtained after chromatography on silica gel (dichloromethane / ethanol 98:2) and dispersion in a boiling mixture of toluene and cyclohexane (2.06 g, 68%). 1 H NMR (DMSO): 12.47 (bs, 1H), 7.90 (s, 1H), 7.70 (m, 2H), 7.46 (m, 1H), 7.32 (m, 5H), 7.25 (m, 1H), 4.22 (s, 2H). HRMS: C 17 H 14 Calculated value for ClN2O: 297.0795; Measured value: 297.0795.

[0378] 3-(2-methoxybenzyl)-5-phenylpyrazine-2-ol (H-4): From (E-28) and / or (E-29), chromatography on silica gel (dichloromethane / ethanol 98.5:1.5~97.5:2.5) and boiling mixture of cyclohexane and toluene. It was obtained as a white powder after dispersion (1.7 g, 30%). 1 H NMR (DMSO-d6) 12.35 (s (br), 1H), 7.86 (s, 1H), 7.73 (m, 2H), 7.34 (m, 2H), 7.23 (m, 2H), 7.11 (m, 1H), 6.98 (m, 1H), 6.87 (m, 1H), 4.04 (s, 2H), 3.75 (s, 3H). HRMS: C 18 H 17 Calculated value for N2O2: 293.1290; Measured value: 293.1280.

[0379] 3-(3-fluorobenzyl)-5-phenylpyrazine-2-ol (H-5): Chromatography on silica gel from E-30 and / or E-31 (dichloromethane / The sample was obtained as a white powder (3.92 g, 88%) after ethanol (98:2). It was recrystallized with a mixture of cyclohexane and toluene. 1 HRMS: C 17 H 14 Calculated value for FN2O: 281.1090; Measured value: 281.1650.

[0380] 3-(4-fluorobenzyl)-5-phenylpyrazine-2-ol (H-6): This crude mixture was obtained from E-32 after evaporation to dryness and was used directly in the chlorination process without any purification.

[0381] 3-benzyl-5-phenylpyrazine-2-ol (H-7): This compound was obtained as a white powder (2.28 g, 73%) after chromatography on silica gel (dichloromethane-ethanol 98 / 2~97 / 3) from E-1 and / or E-2. 1 H NMR (DMSO-d6) 12.41 (s, 1H), 7.85 (m, 3H), 7.40 (m, 4H), 7.30 (m, 3H), 7.20 ( m, 1H), 4.07 (s, 2H). HRMS: C 17 H 15 Calculated value for N2O: 263.1184; Measured value: 263.1118.

[0382] 3-benzyl-5-(p-tril)pyrazine-2-ol (H-8): A pure sample (1.48 g) of this compound (obtained from E-3) was isolated as a white solid by dispersion of the crude mixture in dichloromethane, and the concentrated filtrate and most of this solid were used directly in the next step. 1 H NMR (DMSO-d6) 12.35 (s, 1H), 7.82 (s, 1H), 7.72 (m, 2H), 7.40-7.17 (m, 7H), 4.06 (s, 2H), 2.30 (s, 3H). HRMS: C 18 H 16 Calculated value for N2ONa: 299.1160; Measured value: 299.1177.

[0383] 3-benzyl-5-(m-tril)pyrazine-2-ol (H-9): Crude fractions are obtained from E-4, and the resulting precipitate is filtered and washed with toluene to obtain a simple solution. They were separated. The analytical sample was obtained from recrystallization of the concentrated filtrate in toluene. 1H NMR (DMSO-d6) 12.35 (s, 1H), 7.85 (s, 1H), 7.66 (m, 1H), 7.62 (m, 2H), 7.33-7.17 (m, 5H), 7.08 (m, 1H), 4.07 (s, 2H), 2.33 (s, 3H). HRMS: C 18 H 16 Calculated value for N2ONa: 299.1160; Measured value: 299.1172.

[0384] 3-(2-methylbenzyl)-5-phenylpyrazine-2-ol (H-10): This compound was obtained from E-5 and / or E-6 as a powder after chromatography on silica gel (dichloromethane-ethanol 99 / 1-98 / 2) (5.65 g, 88%). 1 H NMR (DMSO-d6) 12.40 (s, 1H), 7.87 (s, 1H), 7.77 (m, 1H), 7.37 (m, 2H), 7.24 (m, 2H), 7.16 (m, 1H), 7.10 (m, 1H), 4.08 (s, 2H), 2.37 (s, 3H). HRMS: C 18 H 17 Calculated value for N2ON: 277.1341; Measured value: 277.1392.

[0385] 3-(3-methylbenzyl)-5-phenylpyrazine-2-ol (H-11): This compound was obtained from E-7 and / or E-8 as a powder after chromatography on silica gel (dichloromethane-ethanol 99 / 1-98 / 2) (5.52 g, 88%), and the sample (0.29 g) was recrystallized with a mixture of toluene and cyclohexane (0.27 g). 1H NMR (DMSO-d6) 12.38 (s, 1H), 7.87 (s, 1H), 7.84 (m, 2H), 7.40 (m, 2H), 7.28 (m, 1H), 7.16 (m, 3H), 7.01 (m, 1H), 4.03 (s, 2H), 2.26 (s, 3H). HRMS: C 18 H 17 Calculated value for N2ON: 277.1341; Measured value: 277.1395.

[0386] 3-Benzyl-5-(2-methoxyphenyl)pyrazine-2-ol (H-12): This compound is obtained from E-9 and / or E-10 through chromatography on silica gel ( Chloromethane-ethanol (97 / 3) was used to obtain the product as a powder (0.54 g, 79%). 1 H NMR (CDCl3): 13.33 (s(br), 1H), 8.05 (s, 1H), 8.02 (dd, J = 7.7, 1.7 Hz, 1H), 7.51 - 7.42 (m, 2H), 7.37 - 7.28 (m, 3H), 7.25 - 7.19 (m, 1H), 7.08 (td, J = 7.7, 1.0 Hz, 1H), 7.02 - 6.94 (m, 1H), 4.27 (s, 2H), 3.92 (s, 3H). HRMS: C 18 H 17 Calculated value for N2O2: 293.1290; Measured value: 293.1253.

[0387] 3-Benzyl-5-(4-methoxyphenyl)pyrazine-2-ol (H-13): This compound was obtained from E-13 and / or E-14 as a powder after chromatography on silica gel (dichloromethane-ethanol 98 / 2) (0.9 g, 45%). 1H NMR (DMSO-d6) 12.30 (s, 1H), 7.77 (m, 3H), 7.30 (m, 2H), 7.27 (m, 2H), 7.21 (m, 1H), 6.96 (m, 2H), 4.06 (s, 2H), 3.77 (s, 3H). HRMS: C 18 H 17 Calculated value for N2O2: 293.1290; Measured value: 293.1284.

[0388] 3-Benzyl-5-(3-methoxyphenyl)pyrazine-2-ol (H-14): The analytical sample of this compound was obtained as a white powder after recrystallization of the resulting residue in toluene, and the remainder was used directly in the next step. 1 H NMR (DMSO-d6) 12.41 (s, 1H), 7.90 (s, 1H), 7.41 (m, 8H), 6.85 (m, 1H), 4.07 (s, 2H), 3.77 (s, 3H). HRMS: C 18 H 17 Calculated value for N2O2: 293.1290; Measured value: 293.1279.

[0389] 3-Benzyl-5-(4-(benzyloxy)phenyl)pyrazine-2-ol (H-15): This compound is obtained from (E-21) and / or (E-22) by chromatography on silica gel. (Dichloromethane - Ethanol 98 / 2) was subsequently obtained as a powder (0.8 g, 62%). 1 H NMR (CDCl3) 12.31 (s, 1H), 7.78 (m, 2H), 7.40 (m, 4H), 7.37 (m, 9H), 7.19 (m, 1H), 7.03 (m, 2H), 5.13 (s, 2H), 4.06 (s, 2H). HRMS: C 24 H 22 Calculated value for N2O2: 369.1603; Measured value: 369.1603.

[0390] 3-Benzyl-5-(4-(benzyloxy)-3-fluorophenyl)pyrazine-2-ol (H-16): This compound was obtained from E-23 and / or E-24 as a powder (2 g) after chromatography on silica gel (dichloromethane-ethanol 985 / 15). 1 HRMS: C 24 H 20 Calculated value for FN2O2: 387.1509; Measured value: 387.1514.

[0391] 3-Benzyl-5-(2-fluorophenyl)pyrazine-2-ol (H-17): This compound was obtained from E-15 and / or E-16 as a white powder after chromatography on silica gel (dichloromethane-ethanol 975 / 25) (3.38 g, 62%). 1 H NMR (DMSO-d6) 12.38 (s, 1H), 7.88 (m, 1H), 7.68 (s, 1H), 7.28 (m, 8H), 4.06 (s, 2H). HRMS: C 17 H 14 Calculated value for FN2O: 281.1090; Measured value: 281.1050.

[0392] 3-Benzyl-5-(2,6-difluorophenyl)pyrazine-2-ol (H-18): This compound was obtained from E-17 by chromatography on silica gel (dichloromethane - E It was obtained as a white powder after Tanol 99 / 1 (1.45 g, 83%). 12.49 (s, 1H), 7.57 (s, 1H), 7.47 (m, 1H), 7.27 (m, 4H), 7.19 (m, 3H), 4.01 (s, 2H). HRMS: C 17 H 13 Calculated value for F2N2O: 299.0996; Measured value: 299.0994.

[0393] 3-Benzyl-5-(4-fluorophenyl)pyrazine-2-ol (H-19): This compound was obtained from E-18 and / or E-19 as a white powder after chromatography on silica gel (cyclohexane-ethyl acetate 1 / 1) (0.43 g, 72%). 1 H NMR (DMSO-d6) 12.4 (s, 1H), 7.87 (m, 3H), 7.22 (m, 7H), 4.06 (s, 2H). HRMS: C 17 H 14 Calculated value for FN2O: 281.1090; Measured value: 281.1030.

[0394] 3-Benzyl-5-(3-fluorophenyl)pyrazine-2-ol (H-20): This compound was obtained from E-20 by chromatography on silica gel (dichloromethane - E It was obtained as a 90% pure orange powder after Tanol 98 / 2 (1.69 g). 1 LCMS (m / z) = 281.

[0395] Synthesis of pyrazine-2-ol H via step d of 5-oxo-2,3,4,5-tetrahydropyrazine 1-oxide J, and typical production of 3-benzyl-5-phenylpyrazine-2-ol (H-7). Step 1: 6-benzyl-5-oxo-2-phenyl-2,3,4,5-tetrahydropyrazine 1-oxide Manufacturing of (J-1): 3-Benzyl-5-phenylpiperazin-2-one (intermediate E-1 / E2) (0.44 g, 1.65 mmol) was dissolved in acetic acid (5 mL), and a 36% solution of peracetic acid in acetic acid (0.77 g, 3.63 mmol) was added. This was stirred overnight, diluted with ethyl acetate, washed with water and saline solution, and dried on a molecular sieve. The solution was concentrated and dried. Chromatography of the residue was performed on silica gel (cyclohexane-acetic acid). The compound was purified with ethyl 1 / 1 to 1 / 2 to obtain N-oxide as a white powder (0.26 g, 56%). Note: The structure of this compound was confirmed by COSY correlation.

[0396] 1 H NMR (CDCl3): 7.43 (m, 2H), 7.35-7.20(m, 6H), 7.15 (m, 2H), 6.84 (s (br), 1H), 5.12 (t, 1H, J = 4.4), 4.13 (s, 2H), 4.00 (dd, 1H, J = 4.4, 13.3), 3.63 (dt, 1H, J = 4.4, 13.3). HRMS: C 17 H 17 Calculated value for N2O2: 281.1190; Measured value: 281.1234. Step 2: Thermal transition of N-oxide Crude J-1 (0.41 g, 1.46 mmol) was dissolved in chlorobenzene (5 mL) in a microwave-safe vial. This was sealed and heated in a microwave oven at 190 °C for 2 hours. The solvent was removed under vacuum, and the residue was subjected to chromatography on silica gel (cyclohexane- Purification with ethyl acetate (3 / 2) yielded 3-benzyl-5-phenylpyrazine-2-ol (H-7) with analytical data consistent with the above (0.20 g, 52% from intermediate E-1 / E2).

[0397] 3-Benzyl-6-methyl-5-phenylpyrazine-2-ol (H-21): As described above, E-35 or other diastereoisomers were obtained via 6-benzyl-3-methyl-5-oxo-2-phenyl-2,3,4,5-tetrahydropyrazine 1-oxide, followed by chromatography on silica gel (cyclohexane-ethyl acetate 2 / 1) and recrystallization in cyclohexane to obtain an analytically pure sample.

[0398] 1 H NMR (CDCl3) 13.33 (s, 1H), 7.48 (m, 6H), 7.39 (m, 1H), 7.28 (m, 2H), 7.20 (m, 1H), 4.19 (s, 2H), 2.37 (s, 3H). HRMS: C 18 H 17 Calculated value for N2O: 277.1341; measured value Value: 277.1344.

[0399] Synthesis of 2-benzyl-5H-chromeno[3,4-b]pyrazine-3-ol (H-22): Under an inert atmosphere, in a tube fitted with a Teflon cap, (E-36) (0.1 g, 0.34 mmol) and N-iodosuccinimide (0.16 g, 0.69 mmol) were stirred in dry DMF (4 mL) at 60 °C for 90 minutes, then at 20 °C for 24 hours. The resulting solution was diluted with ethyl acetate and water. The solution was washed with saline solution, dried over magnesium sulfate, and concentrated to dryness. The resulting residue was purified by chromatography (cyclohexane-ethyl acetate 3 / 1) using silica gel, and the desired chemical composition was obtained. The mixture was obtained as a powder (0.03 g, 30%).

[0400] 1 H NMR (DMSO-d6): 12.33 (s, 1H), 7.78 (dd, 1H, J =1.6 et 7.6), 7.37-7.25 (m, 4H), 7.23-7.16 (m, 2H), 7.05 (dt, 1H, J = 1.0, 8.5), 6.91 (dd, 1H, J = 0.8, 8.1), 5.13 (s, 2H), 4.07 (s, 2H). HRMS: C 18 H 15 Calculated value for N2O2: 291.1133, Measured value: 291.1066.

[0401] General production of α-aminoamide F from α-amino ester B In a steel reactor, the α-amino ester (0.065 mol, free base or hydrochloric acid) under consideration is tested. (either of the salts) was dispersed in 7 N methanolic ammonia (50 mL). This was then heated at 70 °C. The mixture was heated for 16-19 hours, concentrated to dryness, and the residue was further purified as described below.

[0402] 2-amino-3-phenylpropanamide (F-1) From the hydrochloride salt of phenylalanine ethyl ester, after heating for 19 hours and dispersion of the residue in boiling isopropanol (3 steps), a white solid was obtained (10.29 g, 78%). 1 H NMR (DMSO-d6): 7.71 (s(br), 1H), 7.29 (m, 6H), 6.47 (s(br), 3H), 3.74 (dd, 1H, J = 5.9, 7.6), 3.04 (dd, 1H, J = 5.9, 13.7), 2.87 (dd, 1H, J = 7.6, 13.7), Note The signal shift depends on the sample concentration and water content.

[0403] 2-amino-3-(tetrahydrofuran-2-yl)propanamide (F-2): It was obtained as a solid from B-16 without further purification. 1 H NMR (CDCl3): mixture of isomers: 7.23 (s, 1H), 5.63 (s, 1H), 4.02 (m, 2H), 3.88 (m, 1H), 3.74 (m, 1H), 3.56 (m, 1H), 2.07 (m, 1H), 1.89 (m, 5H), 1.54 (m, 1H). HRMS: C7H 15 Calculated value for N2O: 159.1134; Measured value: 159.1122.

[0404] 2-amino-3-(pyridine-3-yl)propanamide (F-3): It was obtained from B-23 as an orange solid (3.46 g, 99%). 1 H NMR (DMSO-d6): 8.42 (m, 1H), 8.40 (dd, 1H, J = 1.9, 4.6), 7.62 (m, 1H), 7.26 (m, 2H), 6.95 (s (br), 1H), 4.02 (m, 2H), 3.35 (dd, 1H, J = 5.3, 8.0), 2.90 (dd, 1H, J = 5.2, 13.6), 2.64 (dd, 1H, J = 8.0, 13.6), 1.75 (m, 2H). HRMS: C8H 12 N3O Calculated value: 166.0980; Measured value: 166.0984.

[0405] A general procedure for the synthesis of pyrazine-2-ol H via condensation between glyoxal and α-aminoamide F. These compounds were prepared according to previously described protocols (J. Am. Chem. Soc., 1949, 78; US 4046763, 1977).

[0406] 5-Phenylpyrazine-2-ol (H-23): It was obtained from phenylglyoxal and glycineamide hydrochloride as a beige powder (1.69 g, 48%). 1 H NMR (DMSO-d6) 12.43 (s, 1H), 8.12 (d, 1H, J=1.3), 8.06 (s, 1H), 7.85 (m, 2H), 7.42 (m, 2H), 7.30 (m, 1H). HRMS: 10 Calculated value for H9N2O: 173.0715; Measured value: 173.0654.

[0407] 5-Phenyl-3-((tetrahydrofuran-2-yl)methyl)pyrazine-2-ol (H-24): It was obtained from phenylglyoxal and F-2 as a pink solid (1.02 g, 45%). 1 H NMR (CDCl3): 13.22 (s(br), 1H), 7.81 (m, 2H), 7.63 (s (br), 1H), 7.44 (m, 2H), 7.35 (m, 1H), 4.60 (p, 1H, J = 6.6), 3.99 (m, 1H), 3.80 (m, 1H), 3.30 (dd, 1H, J = 7.0, 14.8), 3.05 (dd, 1H, J = 6.1, 14.8), 2.17 (m, 1H), 1.98 (m, 2H), 1.76 (m, 1H). HRMS: C 15 H 17 Calculated value for N2O2: 257.1290; Measured value: 257.1281.

[0408] 5-Phenyl-3-(pyridine-3-ylmethyl)pyrazine-2-ol (H-25): From phenylglyoxal and F-3, the crude ethyl acetate extract was dispersed in dichloromethane and chromatographed on silica gel (dichloromethane - ethanol 95 / 5~9 / 1) followed by white ions. It was obtained as a colored powder (0.57 g, 11%). 1 H NMR (DMSO-d6): 12.47 (s(br), 1H), 8.57 (d, 1H, J = 1.7), 8.43 (dd, 1H, J = 1.7, 4.8), 7.89 (s, 1H), 7.92 (m, 2H), 7.74 (m, 1H), 7.40-7.25 (m, 4H), 4.10 (s, 2H). HRMS: C 16 H 14 Calculated value for N3O: 264.1137; Measured value: 264.1122.

[0409] A general procedure for the synthesis of chloropyrazine L, following step j. Under a calcium-protective atmosphere, the 2-hydroxypyrazine H (0.02 mol) under consideration was dispersed in phenylphosphonic acid dichloride (10 mL), and the suspension was heated at 100 °C for 12 hours unless otherwise specified. The resulting solution was diluted with ethyl acetate, poured over an excess of crushed ice, and stirred for 15 minutes. This was made basic with 22% ammonia and extracted with ethyl acetate. The organic layer was diluted with water and food. The solution was washed with brine, dried over magnesium sulfate, concentrated to dryness, and purified as described below.

[0410] 2-Chloro-5-phenylpyrazine (L-1): From H-23, heating at 100°C for 4 hours and chromatography with silica gel (cyclohex It was obtained as a yellow solid after the addition of san-dichloromethane (1 / 1) (1.42 g, 82%). 1 H NMR (CDCl3): 8.80 (d, 1H, J = 1.5), 8.64 (d, 1H, J = 1.5), 8.00 (m, 2H), 7.51 (m, 3H). HRMS: C 10 Calculated value for H8ClN2: 191.0376; Measured value: 191.0322.

[0411] 2-Chloro-3-methyl-5-phenylpyrazine(L-2): From H-1, a yellow solid was obtained after heating at 80 °C for 12 hours and chromatography on silica gel (cyclohexane-dichloromethane 1 / 1) (1.18 g, 74%). 1 H NMR (CDCl3): 8.63 (s, 1H), 8.01 (m, 2H), 7.50 (m, 3H), 2.75 (s, 3H). HRMS: C 11 H 10 Calculated value for ClN2: 205.0533; Measured value: 205.0464.

[0412] 2-Chloro-3-(2-fluorobenzyl)-5-phenylpyrazine (L-3): From H-2, after chromatography on silica gel (cyclohexane-ethyl acetate 94 / 6) It was obtained as a white powder (3.01 g, 79%). 1 1H NMR (CDCl3): 1 H NMR (CDCl3, 400 MHz): 8.70 (s, 1H), 7.98-7.94 (m, 2H), 7.53-7.45 (m, 3H), 7.31-7.25 (m, 2H), 7.14-7.09 (m, 2H), 4.44 (s, 2H). HRMS: C 17 H 13 Calculated value for ClFN2: 299.0751; Measured value: 299.0749.

[0413] 2-Chloro-3-(2-chlorobenzyl)-5-phenylpyrazine (L-4): It was obtained from H-3 as a white powder after recrystallization with ethanol (1.58 g, 73%). 1 H NMR (CDCl3): 8.70 (s, 1H), 7.93 (m, 2H), 7.46 (m, 4H), 7.22 (m, 3H), 4.52 (s, 2H). HRMS: C 17 H 13Calculated value for Cl2N2: 315.0456; Measured value: 315.0466.

[0414] 2-Chloro-3-(2-methoxybenzyl)-5-phenylpyrazine (L-5): It was obtained from H-4 as a white powder after recrystallization with ethanol (0.73 g, 63%). 1 1H NMR (CDCl3): 1 H NMR (CDCl3, 400 MHz): 8.66 (s, 1H), 7.96 (m, 2H), 7.48 (m, 3H), 7.27 (m, 1H), 7.14 (m, 1H), 6.93 (m, 2H), 4.40 (s, 2H), 3.83 (s, 2H). HRMS: C 18 H 16 Calculated value for ClN2O: 311.0951; Measured value: 311.0949.

[0415] 2-Chloro-3-(3-fluorobenzyl)-5-phenylpyrazine (L-6): From H-5, after chromatography on silica gel (cyclohexane-ethyl acetate 97 / 3) It was obtained as an oily substance (3.19 g, 86%). 1 H NMR (CDCl3): 8.69 (s, 1H), 8.03 (m, 2H), 7.52 (m, 3H), 7.29 (m, 1H), 7.18 (m, 1H), 7.12 (m, 1H), 6.96 (m, 1H), 4.39 (s, 2H). HRMS: C 17 H 13 Calculated values ​​for ClFN2 299.0751; measured value, 299.0749.

[0416] 2-Chloro-3-(4-fluorobenzyl)-5-phenylpyrazine (L-7): From H-6, after chromatography on silica gel (cyclohexane-ethyl acetate 97 / 3) It was obtained as a white powder (0.25 g, 29% from E-32). 1 H NMR (CDCl3): 8.68 (s, 1H), 8.02 (m, 2H), 7.52 (m, 3H), 7.36 (m, 2H), 7.02 (m, 2H), 4.36 (s, 2H). HRMS: C 17 H 13 Calculated value for ClFN2: 299.0751; Measured value: 299.0746.

[0417] 3-Benzyl-2-chloro-5-phenylpyrazine (L-8): From H-7, a yellow solid was obtained after chromatography on silica gel (cyclohexane-dichloromethane 3:2) (1.60 g, 82%). Alternatively, this compound can be reacted under the same reaction conditions but using N-oxide J-1 to obtain a 36% solution. It was obtained in the following yield. 1 H NMR (CDCl3): 8.68 (s, 1H), 8.08 - 8.00 (m, 2H), 7.58 - 7.47 (m, 3H), 7.44 - 7.40 (m, 2H), 7.37 - 7.32 (m, 2H), 7.30 - 7.25 (m, 1H), 4.41 (s, 2H). HRMS: C 17 H 14 Calculated value for ClN2: 281.0846; Measured value: 281.0730.

[0418] 2-benzyl-3-chloro-5-methyl-6-phenylpyrazine (L-9): Chromatography on silica gel from H-21 (cyclohexane-ethyl acetate 97:3) Later, an oily substance was obtained (20% overall from 0.38 g of 6-benzyl-3-methyl-5-oxo-2-phenyl-2,3,4,5-tetrahydropyrazine 1-oxide). 1H NMR (CDCl3, 400 MHz): 7.62-7.59 (m, 2H), 7.53-7.45 (m, 3H), 7.40-7.37 (m, 2H), 7.33-7.22 (m, 4H), 4.36 (s, 2H), 2.61 (s, 3H). HRMS: C 18 H 16 Calculated values ​​for ClN2 295.1002; measured value, 295.1003.

[0419] 3-benzyl-2-chloro-5-(p-tolyl)pyrazine (L-10): From H-8, a yellow solid was obtained after chromatography on silica gel (cyclohexane-dichloromethane 3 / 2) (1.83 g, 22% from 1-methyl-4-(2-nitrovinyl)benzene). 1 H NMR (CDCl3): 8.64 (s, 1H), 7.94 (m, 2H), 7.48 - 7.23 (m, 7H), 4.39 (s, 2H), 2.45 (s, 3H). HRMS: C 18 H 16 Calculated value for ClN2: 295.1002; Measured value: 295.0999.

[0420] 3-benzyl-2-chloro-5-(m-tolyl)pyrazine (L-11): This compound was heated from H-9 for 18 hours and chromatographed in silica gel (silica gel). (665 / 35) was then obtained as a white solid (3.02 g, 33% from 1-methyl-3-(2-nitrovinyl)benzene). 1 H NMR (CDCl3): 8.66 (s, 1H), 7.84 (m, 1H), 7.82 (m, 2H), 7.43 - 7.24 (m, 6H), 4.40 (s, 2H), 2.48 (s, 3H). HRMS: C 18 H 16 Calculated value for ClN2: 295.1002; Measured value: 295.1014.

[0421] 2-Chloro-3-(2-methylbenzyl)-5-phenylpyrazine (L-12): This compound was converted from H-10 to silica gel chromatography (cyclohexane-acetic acid). It was obtained as a solid after ethyl 95 / 5 (5.12 g, 89%). 1 H NMR (CDCl3): 8.69 (s, 1H), 7.98 (m, 2H), 7.50 (m, 3H), 7.20 (m, 4H), 4.39 (s, 2H), 2.46 (s, 3H). HRMS: C 18 H 16 Calculated value for ClN2: 295.1002; Measured value: 295.1009.

[0422] 2-Chloro-3-(3-methylbenzyl)-5-phenylpyrazine (L-13): This compound was converted from H-11 to silica gel chromatography (cyclohexane-acetic acid). It was obtained as a solid after ethyl 96 / 4 (5.03 g, 90%). 1 H NMR (CDCl3): 8.68 (s, 1H), 8.05 (m, 2H), 7.51 (m, 3H), 7.22 (m, 3H), 7.08 (m, 1H), 4.37 (s, 2H), 2.36 (s, 3H). HRMS: C 18 H 16 Calculated value for ClN2: 295.1002; Measured value: 295.0997.

[0423] 3-Benzyl-2-chloro-5-(2-methoxyphenyl)pyrazine (L-14): From H-12, heating for 18 hours and chromatography in silica gel (cyclohexane- Dichloromethane (3 / 2) was used to obtain a yellow solid (1.82 g, 81%). 1H NMR (CDCl3): 8.86 (s, 1H), 7.91 (dd, 1H, J = 7.6, 1.8), 7.48 - 7.36 (m, 3H), 7.34 - 7.28 (m, 2H), 7.26 - 7.18 (m, 1H), 7.11 (td, 1H, J = 7.6, 0.8), 7.03 (d, 1H, J = 8.3), 4.37 (s, 2H), 3.90 (s, 3H). HRMS: C 18 H 16 Calculated value for ClN2O: 311.0951; Measured value: 311.0965.

[0424] 3-Benzyl-2-chloro-5-(2-fluorophenyl)pyrazine (L-15): From H-17, heating for 16 hours and chromatography in silica gel (cyclohexane- Dichloromethane (2 / 1) was used to obtain a yellow solid (3.30 g, 67%). 1 H NMR (CDCl3): 8.78 (d, 1H, J = 2.2), 8.04 (dt, 1H, J= 7.6, 1.8), 7.30 (m, 8H), 4.40 (s, 2H). HRMS: C 17 H 13 Calculated value for ClFN2: 299.0751; Measured value: 299.0818.

[0425] 3-Benzyl-2-chloro-5-(3-fluorophenyl)pyrazine (L-16): From H-20, the powder was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 98 / 2) (0.98 g, 8% from 1-fluoro-3-(2-nitrovinyl)benzene). 1 H NMR (CDCl3): 8.66 (s, 1H), 7.78 (m, 2H), 7.48 (m, 1H), 7.41-7.24 (m, 4H), 7.18 (m, 1H), 4.40 (s, 2H). HRMS: C 17 H13 Calculated value for ClFN2: 299.0751; Measured value: 299.0749.

[0426] 3-Benzyl-2-chloro-5-(2,6-difluorophenyl)pyrazine (L-17): Chromatography of H-18 on silica gel (cyclohexane-dichloromethane 3 / 1) It was later obtained as a white solid (0.75 g, 56%). 1 H NMR (CDCl3): 8.44 (m, 1H), 7.43 (m, 3H), 7.27 (m, 2H), 7.25 (m, 1H), 7.05 (m, 2H), 4.40 (s, 2H). HRMS: C 17 H 11 Calculated value for ClF2N2: 317.0657; Measured value: 317.0648.

[0427] 3-Benzyl-2-chloro-5-(4-fluorophenyl)pyrazine (L-18): From H-19, heating for 14 hours and chromatography in silica gel (cyclohexane- Dichloromethane was obtained as a white solid after 3 / 1) (0.84 g, 52%). 1 H NMR (CDCl3): 8.63 (s, 1H), 8.02 (m, 2H), 7.39 (m, 2H), 7.34 (m, 2H), 7.28 (m, 1H), 7.19 (m, 2H), 4.39 (s, 2H). HRMS: C 17 H 13 Calculated value for ClFN2, 299.0751; Actual value Measured value: 299.0763.

[0428] 3-Benzyl-2-chloro-5-(4-methoxyphenyl)pyrazine (L-19): (H-13) was obtained as a yellow solid (0.33 g, 35%) after chromatography on silica gel (cyclohexane-dichloromethane 3 / 2). 1 H NMR (CDCl3): 8.61 (s, 1H), 7.97 (m, 2H), 7.40 (m, 2H), 7.31 (m, 2H), 7.27 (m, 1H), 7.02 (m, 2H), 4.37 (s, 2H), 3.89 (s, 3H). HRMS: C 18 H 16 Calculated values ​​for ClN2O, 311.0951; measured value, 311.0955.

[0429] 3-Benzyl-2-chloro-5-(3-methoxyphenyl)pyrazine (L-20): This compound was obtained from crude H-14 through chromatography on silica gel (cyclohexane-vinegar). After ethyl ethyl acid (95 / 5), it was obtained as a white powder (0.4 g, 32% from E-11 / E-12). 1 H NMR (CDCl3): 8.66 (s, 1H), 7.97 (m, 2H), 7.58 (m, 2H), 7.41 (m, 3H), 7.33 (m, 2H), 7.25 (m, 1H), 7.03 (m, 1H), 4.39 (s, 2H), 3.90 (s, 3H). HRMS: C 18 H 16 ClN2O Calculated value: 311.0951; Measured value: 311.0962.

[0430] 3-Benzyl-5-(4-(benzyloxy)phenyl)-2-chloropyrazine (L-21): From H-15, heating for 18 hours and chromatography in silica gel (cyclohexane- Dichloromethane (1 / 1) was then obtained as a yellow solid (5.66 g, 62%). 1H NMR (CDCl3): 8.61 (s, 1H), 8.0 (m, 2H), 7.47-7.20 (m, 10H), 7.11 (m, 2H), 5.17 (s, 2H), 4.38 (s, 2H). HRMS: C 24 H 20 Calculated value for ClN2O: 387.1264; Measured value: 387.1266.

[0431] 3-benzyl-5-(4-(benzyloxy)-3-fluorophenyl)-2-chloropyrazine (L-22): From H-16, a yellow solid was obtained after chromatography on silica gel (cyclohexane-dichloromethane 1 / 1) (1.39 g, 29% from nitrovinyl). 1 H NMR (CDCl3): 8.58 (s, 1H), 7.84 (m, 1H), 7.70 (m, 1H), 7.50-7.24 (m, 10H), 7.11 (m, 1H), 5.24 (s, 2H), 4.37 (s, 2H). HRMS: C 24 H 19 Calculated value for ClFN2O: 405.1170; Measured value: 405.1154.

[0432] 2-benzyl-3-chloro-5H-chromeno[4,3-b]pyrazine (L-23): From H-22, a white powder was obtained after chromatography on silica gel (cyclohexane-dichloromethane 3 / 2) (0.01 g, 10%). 1 H NMR (CDCl3): 8.15 (dd, 1H, J = 2.0, 7.8), 7.41-7.31 (m, 5H), 7.28-7.24 (m, 1H ), 7.13 (dt, 1H, J = 1.0, 8.1), 7.00 (dd, 1H, J = 1.0, 8.3), 5.31 (s, 2H), 4.37 (s, 2H). HRMS: C 18 H 14Calculated value for ClN2O: 309.0795; Measured value: 309.0804.

[0433] 2-Chloro-5-phenyl-3-(pyridine-3-ylmethyl)pyrazine (L-24): From H-25, an oily substance was obtained after chromatography on silica gel (dichloromethane-ethanol 98 / 2) (0.42 g, 83%). 1 H NMR (CDCl3): 8.70 (m, 1H), 8.69 (s, 1H), 8.52 (dd, 1H, J = 1.6, 4.9), 7.99 (m, 2H), 7.71 (m, 1H), 7.50 (m, 3H), 7.26 (ddd, 1H, J = 0.8, 4.9, 8.0), 4.38 (s, 2H). HRMS: C 16 H 13 Calculated value for ClN3: 282.0798; Measured value: 282.0795.

[0434] General procedure for the synthesis of bromopyrazine L (X = Br) via steps i and l. Process i: Production of trifluoromethanesulfonate K At room temperature, the hydroxypyrazine under consideration (3 mmol) was dissolved in dry dichloromethane (20 mL, stabilized with amylene, dried on a 4A sieve). Triethylamine (0.142 mL, 3.15 mmol) and then Triflick anhydride (0.51 mL, 3.06 mmol) were added. The resulting solution was stirred for 40 minutes, diluted with ethyl acetate, washed with water and saline solution, dried over magnesium sulfate, and concentrated to dryness. The resulting residue was purified as described below.

[0435] Step 1: Exchange reaction with sodium bromide In a tube fitted with a Teflon-coated screw cap, one of these purified triflate esters (2 mmol) and dried sodium bromide (0.51 g, 5 mmol) are mixed with dried dimethyl The solution was dispersed in formamide (4 mL). Triflick acid (0.16 mL, 1.8 mmol) was added, the tube was closed, and the mixture was heated overnight at 120 °C. The resulting solution was diluted with ethyl acetate, washed with water and saline solution, dried over magnesium sulfate, and concentrated to dryness. The resulting residue was then further purified as described below.

[0436] 3-Benzyl-5-phenylpyrazine-2-yl trifluoromethanesulfonate (K-1): From H-7, a white powder was obtained after chromatography on silica gel (cyclohexane-dichloromethane 4 / 1 to 1 / 1) (0.34 g, 30%). 1 HRMS: C 18 H 14 Calculation for F3N2O3S Value: 395.0677; Measured value: 395.0695.

[0437] 3-Benzyl-2-bromo-5-phenylpyrazine (L-25): From K-1, white crystals were obtained after chromatography on silica gel (cyclohexane-dichloromethane 3:2) (0.02 g, 30%). 1 H NMR (CDCl3): 8.63 (s, 1H), 8.05 - 7.97 (m, 2H), 7.56 - 7.47 (m, 3H), 7.43 - 7.37 (m, 2H), 7.35 - 7.29 (m, 2H), 7.28 - 7.21 (m, 1H), 4.41 (s, 2H). HRMS: C 17 H 14 Calculated value for BrN2: 325.0340; Measured value: 325.0319.

[0438] 5-Phenyl-3-((tetrahydrofuran-2-yl)methyl)pyrazine-2-yl trifluoromethanesulfonate (K-2): From (H-24), an oily substance was obtained after chromatography on silica gel (cyclohexane-dichloromethane 1 / 3) (0.37 g, 43%). 1 H NMR (CDCl3): 8.60 (s, 1H), 8.01 (m, 2H), 7.53 (m, 3H), 4.51 (m, 1H), 3.95 (m, HRMS: C 16 H 16 Calculated value for F3N2O4S: 389.0783; Measured value: 389.0808.

[0439] 2-Bromo-5-phenyl-3-((tetrahydrofuran-2-yl)methyl)pyrazine (L-26): Chromatography using silica gel from K-2 (cyclohexane-dichloromethane 1 / 4~ Dichloromethane - Ethanol (99 / 1) was used to obtain an oily substance (0.19 g, 62%). 1 H NMR (CDCl3): 8.62 (s, 1H), 8.02 (m, 2H), 7.50 (m, 3H), 4.57 (p, 1H, J = 6.7), 3.99 (m, 1H), 3.80 (m, 1H), 3.42 (dd, 1H, J = 6.7, 14.6), 3.14 (dd, 1H, J = 6.7, 14.6), 2.12 (m, 1H), 1.99 (m, 2H), 1.76 (m, 1H). HRMS: C 15 H 16 Calculated value for BrN2O: 319.0446; Measured value: 319.0464.

[0440] 2-benzyl-5H-chromeno[4,3-b]pyrazine-3-yl trifluoromethanesulfonate (K-3): From H-22, an oily substance was obtained, and the sample was purified by chromatography using silica gel (cyclohexane-dichloromethane 2 / 1). 1 H NMR (CDCl3): 8.15 (dd, 1H, J = 1.7, 7.8), 7.44-7.30 (m, 6H), 7.14 (dt, 1H, J = 1.1, 8.0), 7.02 (dd, 1H, J = 0.9, 8.3), 5.31 (s, 2H), 4.30 (s, 2H). HRMS: C 18 H 13 Calculated value for F3N2O4S: 423.0627; Measured value: 423.0638.

[0441] 2-benzyl-3-bromo-5H-chromeno[4,3-b]pyrazine (L-27): From K-3, a white solid was obtained after chromatography (cyclohexane-dichloromethane 2 / 1) on silica gel (0.04 g, 24%). Note: Under the same conditions, an improved yield (0.075 g, 40%) was achieved using 10 equivalents of excess sodium bromide. 1 H NMR (CDCl3): 8.15 (dd, 1H, J = 1.6, 7.8), 7.44-7.23 (m, 6H), 7.12 (dt, 1H, J = 1.0, 8.1), 7.02 (dd, 1H, J = 0.7, 8.1), 5.32 (s, 2H), 4.39 (s, 2H). HRMS: C 18 H 13 Calculated value for BrN2O: 353.0290; Measured value: 353.0295.

[0442] The process involves the formation of an N-aryl α-aminoester from halogenopyrazine L and α-aminoester B via step n. General procedure for the synthesis of ester N In a 20 mL sealable vial, the 2-halogenopyrazine L (0.001 mol) under consideration is placed. The amino ester B under consideration (0.0011 mol, either free base or hydrochloride), cesium carbonate (0.0022 mol or 0.0032 mol, 0.69 g or 1.04 g), and a 1 / 1 mixture of palladium acetate and 2,2'-bis(diphenylphosphanyl)-1,1'-binaphthalene (BINAP) (0.05 mmol) 47 mg was weighed. The air was replaced with argon, and the dry acetonite was dried under an inert atmosphere. Inject 8 mL of Lil (dried dimethylformamide can also be used). Then, To break up the resulting cesium bicarbonate clumps, the mixture was heated at 60°C for 12 hours using either an oil bath with high-speed stirring or an ultrasonic bath with temperature control. The resulting dark red or black suspension was then collected in a diced solution. The mixture was dispersed in lolomethane; filtered, concentrated to dryness, and then further purified as described below.

[0443] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-methylpentanoate (N-1): From L-8 and IleOEt, an oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 95 / 5) (0.25 g, 52%). Note: Racemization (approximately 30%) was observed either during storage of IleOEt as a free base or during the N-arylation reaction. 1H NMR (diastereoisomer mixture, 0.30 / 0.70 ratio, CDCl3): 8.41 (s, 1H), 7.95 (m, 2H), 7.47 (m, 2H), 7.38-7.32 (m, 5H), 7.29-7.26 (m, 1H), 4.84 (m, 0.7H), 4.75 (m, 0.3H), 4.65 (m, 1H), 4.31 (m, 2H), 4.15 (m, 2H), 1.83 (m, 1H), 1.35 (m, 1H), 1.24 (m, 3H), 1.02 (m, 1H), 0.85 (m, 3H), 0.75 (m, 3H). HRMS: C 25 H 30 Calculated value for N3O2: 404.2338; Measured value: 404.2348.

[0444] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-cyclopentylpropanoate (N-2): From L-8 and B-13, chromatography on silica gel (cyclohexane - ethyl acetate) It was obtained as an oily substance after (95 / 5) (0.26 g, 58%). 1 H NMR (CDCl3): 8.42 (s, 1H), 7.95 (m, 2H), 7.47 (m, 2H), 7.38-7.32 (m, 5H), 7.29-7.26 (m, 1H), 4.78 (d, 1H, J = 7.4), 4.60 (m, 2H), 4.30 (d, 1H, J = 15.1), 4.21 (d, 1H, J = 15.1), 4.16 (q, 2H, J = 7.2), 1.83 (m, 1H), 1.70-1.39 (m, 7H), 1.24 (t, 3H, J = 7.2), 1.01 (m, 2H). HRMS: C 27 H 32 Calculated value for N3O2: 430.2495; Measured value: 430.2485.

[0445] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-cyclohexylpropanoate (N-3): From L-8 and B-14, an oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 95 / 5) (0.36 g, 78%). 1 H NMR (CDCl3): 8.41 (s, 1H), 7.95 (m, 2H), 7.47 (m, 2H), 7.38-7.32 (m, 5H), 7.29-7.26 (m, 1H), 4.60 (m, 4H), 4.30 (d, 1H, J = HRMS: C 28 H 34 Calculated value for N3O2: 444.2651; Measured value: 444.2647.

[0446] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(bicyclo[2.2.1]heptan-2-yl)propanoate (N-4): From (L-8) and (B-15), a mixture of four diastereoisomers was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 95 / 5). 13 It was obtained as an oily substance (1.48 g, 82%), as indicated by the number of CO signals in the C spectrum. 1H NMR (CDCl3): 8.41 (s, 1H), 7.95 (m, 2H), 7.46 (m, 2H), 7.38-7.25 (m, 6H), 4.77 (m, 1H), 4.56 (m, 1H), 4.31 - 4.16 (m, 4H), 2.17 (m, 0.4H), 2.10 (m, 0.6H), 2.02 (m, 0.4H), 1.90 - 0.88 (m, 14H), 0.50 (m, 0.6H). HRMS: C 29 H 34 Calculated value for N3O2: 456.2651; Measured value: 456.2661.

[0447] Ethyl (3-benzyl-5-phenylpyrazine-2-yl)phenylalaninate (N-5): After chromatography (dichloromethane) on silica gel from L-8 and PheOEt, HCl It was obtained as an oily substance (1.07 g, 69%). 1 H NMR (CDCl3): 8.43 (s, 1H), 7.96 (m, 2H), 7.53 - 7.43 (m, 1H), 7.41 - 7.34 (m, 1H), 7.33 - 7.20 (m, 8H), 7.05 - 6.95 (m, 2H), 4.97 (m, 2H), 4.14 (s, 2H), 4.13 (q, J = 7.1 Hz, 2H), 3.18 (dd, J = 13.8, 5.4 Hz, 1H), 3.09 (dd, J = 13.8, 5.9 Hz, 1H), 1.20 (t, J = 7.1 Hz, 3H). HRMS: C 28 H 28 Calculated value for N3O2: 438.2182; Measured value: 438.2185.

[0448] Ethyl (3-benzyl-6-methyl-5-phenylpyrazine-2-yl)phenylalaninate (N-6): Chromatography on silica gel from L-9 and PheOEt,HCl (cyclohexane- It was obtained as an oily substance after ethyl acetate (94 / 6) (0.4 g, 84%). 1 H NMR (CDCl3, 400 MHz): 7.60-7.57 (m, 2H), 7.48-7.44 (m, 2H), 7.39-7.35 (m, 1H), 7.31-7.20 (m, 8H), 7.03-7.00 (m, 2H), 5.00-4.95 (q, 1H, J = 7.0), 4.80-4.78 (m, 1H), 4.18-4.09 (m, 4H), 3.17-3.12 (m, 1H), 3.08-3.03 (m, 1H), 2.46 (s, 3H), 1.22-1.18 (t, J = 7.9Hz, 3H). HRMS: C 29 H 30 Calculated value for N3O2: 452.2338; Measured value: 452.2347.

[0449] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-phenylbutanoate (N-7): From L-8 and B-41, an oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 96 / 4) (0.3 g, 67%). 1 ¹H NMR (diastereoisomer mixture, 0.6 / 0.4 ratio) (CDCl3): 8.40 (s, 0.6H), 8.34 (s, 0.3H), 7.94 (m, 2H), 7.46 (m, 2H), 7.39-7.19 (m, 7H), 7.21 (m, 1H), 7.16 (m, 1H), 7.05 (m, 2H), 4.95 (m, 1H), 4.89 (d, 0.4H, J = 7.7), 4.69 (d, 0.6H, J = 8.3), 4.20 (m, 0.8H), 4.08 (m, 0.8H), 4.08 (m, 2.6H), 3.37 (m, 0.6H), 3.0 (m, 0.4H), 1.28 (d, 1.8H, J = 7.1), 1.24 (d, 0.8H, J = 7.3), 1.16 (t, 1.8H, J = 7.5), 1.08 (t, 0.8H, J = 7.3). HRMS: C 29 H 30 Calculated value for N3O2: 452.2338; Measured value: 452.2378.

[0450] Methyl 2-((3-benzyl-5-(4-(benzyloxy)phenyl)pyrazine-2-yl)amino)-3-(4-(benzyloxy)phenyl)propanoate (N-8): Obtained from L-21 PheOMe, HCl after chromatography (dichloromethane) on silica gel. (0.53 g, 86%). 1 H NMR (CDCl3): 8.39 (s, 1H), 7.98 - 7.87 (m, 2H), 7.53 - 7.47 (m, 4H), 7.47 - 7.41 (m, 4H), 7.41 - 7.35 (m, 2H), 7.34 - 7.27 (m, 3H), 7.25 - 7.21 (m, 2H), 7.15 - 7.07 (m, 2H), 6.94 - 6.82 (m, 4H), 5.17 (s, 2H), 5.09 (s, 2H), 5.03 - 4.94 (m, 1H), 4.86 (d, 1H, J= 7.4), 4.15 (s, 2H), 3.70 (s, 3H), 3.15 (dd, 1H, J = 13.9, 5.3), 3.05 (dd, 1H, J = 13.9, 6.0). 41 H 38 Calculated value for N3O4: 636.2863; Measured value: 636.2897.

[0451] Ethyl 2-((3-benzyl-5-(4-(benzyloxy)phenyl)pyrazine-2-yl)amino)-3-(4-(benzyloxy)phenyl)propanoate (N-9): From L-21 and B-5, an oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 91 / 9~9 / 1) (1.17 g, 70%). 1 H NMR (CDCl3): 8.34 (s, 1H), 7.92 - 7.83 (m, 2H), 7.49 - 7.43 (m, 4H), 7.43 - 7.37 (m, 4H), 7.37 - 7.31 (m, 2H), 7.30 - 7.22 (m, 3H), 7.22 - 7.17 (m, 2H), 7.11 - 7.02 (m, 2H), 6.91 - 6.77 (m, 4H), 5.13 (s, 2H), 5.05 (s, 2H), 4.95 - 4.87 (m, 1H), 4.86 - 4.79 (m, 1H), 4.15 - 4.09 (m, 4H), 3.10 (dd, 1H, J = 13.9, 5.4), 3.01 (dd, 1H, J = 13.9, 5.9), 1.19 (t, 3H, J = 7.1). HRMS: C 42 H 40 Calculated value for N3O4: 650.3019; Measured value: 650.3049.

[0452] Ethyl (3-benzyl-5-(4-(benzyloxy)-3-fluorophenyl)pyrazine-2-yl)phenylalaninate (N-10): From L-22 and PheOEt,HCl, an oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 96 / 4~93 / 7) (0.66 g, 83%). 1H NMR (CDCl3): 8.33 (s, 1H), 7.75 (m, 1H), 7.60 (m, 1H), 7.49 (m, 2H), 7.41 (m, 2H), 7.37 - 7.18 (m, 9H), 7.07 (m, 1H), 7.98 (m, 2H), 5.21 (s, 2H), 4.12 (m, 4H), 3.16 (dd, 1H, J = 5.4, 14.1), 3.08 (dd, 1H, J = 5.7, 14.1), 1.19 (t, 3H, J = 7.1). HRMS: C 35 H 33 Calculated value for FN3O3: 562.2506; Measured value: 562.2506.

[0453] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(tetrahydrofuran-2-yl)propanoate (N-11): From L-8 and B-16, an oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 9 / 1) (0.50 g, 60%). 1 H NMR (diastereoisomer mixture, 0.53 / 0.47 ratio) (CDCl3): 8.39 (s, 1H), 7.96 (m, 2H), 7.45 (m, 2H), 7.35 (m, 5H), 7.25 (m, 1H), 4.78 (m, 0.6H), 4.59 (m, 0.4H), 4.20 (m, 4H), 3.81 (m, 1.6H), 3.70 (m, 1.4H), 2.1 (m, 1H), 1.88 (m, 4H), 1.46 (m, 1H), 1.25 (t, 1.4H, J = 7.2), 1.18 (t, 1.6H, J = 7.2). HRMS: C 26 H 30 Calculated value for N3O2: 432.2287; Measured value: 432.2253.

[0454] Ethyl 2-(3-benzyl-5-phenylpyrazine-2-ylamino)-3-(1,3-dioxolan-2-yl)propanoate (N-12): From L-8 and B-43, an oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 9 / 1~7 / 3) (0.61 g, 67%). 1 H NMR (CDCl3): 8.41 (s, 1H), 7.94 (m, 2H), 7.46 (m, 2H), 7.37 - 7.31 (m, 5H), 7.25 (m, 1H), 5.66 (m, 1H), 4.85 (t, 2H, J = 4.3), 4.77 (m, 1H), 4.23 (m, 2H), 4.18 (q, 2H, J = 7.1), 3.83 (m, 2H), 3.75 (m, 2H), 2.25 (m, 2H), 1.25 (t, 3H, J = 7.1). HRMS: C 25 H 28 Calculated value for N3O4: 434.2080; Measured value: 434.2117.

[0455] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(2-methoxyphenyl)propanoate (N-13): From L-8 and B-2, chromatography on silica gel (cyclohexane - ethyl acetate) It was obtained as a yellow solid after 95 / 5 (0.32 g, 77%). 1 H NMR (CDCl3): 8.38 (s, 1H), 7.90 (m, 2H), 7.44 (m, 2H), 7.34 (m, 1H), 7.26 (m, 3H), 7.22 (m, 6H), 7.04 (dd, 1H, J = 7.4, 1.7), 6.88 (td, 1H, J = 7.4, 1.0), 6.83 (m, 1H), 5.30 (d, 1H, J = 7.0), 4.85 (m, 1H), 4.11 (m, 4H), 3.75 (s, 3H), 3.20 (dd, 1H, J = 13.6, 5.6), 3.15 (dd, 1H, J = 13.6, 7.6), 1.20 (t, 3H, J = 7.1). HRMS: C 29 H 30 Calculated value for N3O3: 468.2287; Measured value: 468.2281.

[0456] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(3-methoxyphenyl)propanoate (N-14): From L-8 and B-3, chromatography on silica gel (cyclohexane - ethyl acetate) It was obtained as an oily substance after (95 / 5) (0.30 g, 95% pure). 1 H NMR (CDCl3): 8.42 (s, 1H), 7.95 (m, 2H), 7.46 (m, 2H), 7.36 (m, 1H), 7.30 - 7.13 (m, 6H), 6.79 (m, 2H), 6.65 (m, 1H), 6.58 (m, 1H), 4.96 - 4.90 (m, 2H), 4.14 (m, 4H), 3.78 (s, 3H), 3.15 (dd, 1H, J = 5.6, 13.8), 3.07 (dd, 1H, J = 6.0, 13.8), 1.19 (t, 3H, J = 7.1). HRMS: C 29 H 30 Calculated value for N3O3: 468.2287; Measured value: 468.2301.

[0457] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(4-methoxyphenyl)propanoate (N-15): From L-8 and B-4, chromatography on silica gel (cyclohexane-ethyl acetate) (0.16 g, 35%) was obtained as an oily substance after (93 / 7). 1 H NMR (CDCl3): 8.42 (s, 1H), 7.95 (m, 2H), 7.46 (m, 2H), 7.39-7.21 (m, 6H), 6.89 (m, 2H), 6.76 (m, 1H), 4.96 - 4.90 (m, 2H), 4.15 (m, 4H), 3.81 (s, 3H), 3.12 (dd, 1H, J= 4.8, 13.7), 3.03 (dd, 1H, J = 5.2, 13.7), 1.21 (t, 3H, J = 7.1). HRMS: C 29 H 30 Calculated value for N3O3: 468.2287; Measured value: 468.2271.

[0458] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(2-(trifluoromethyl)phenyl)propanoate (N-16): From L-8 and B-24, an oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 95 / 5) (0.08 g, 18%). 1 H NMR (CDCl3): 8.36 (s, 1H), 7.93 (m, 2H), 7.62 (m, 1H), 7.45 (m, 2H), 7.37 - 7.18 (m, 9H), 5.01 - 4.93 (m, 2H), 4.17 (s, 2H), 4.12 (m, 2H), 3.31 (m, 1H), 3.15 (m, 1H), 1.17 (m, 3H). HRMS: C 29 H 27 Calculated value for F3N3O2: 506.2055; Measured value: 506.2053.

[0459] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(3-(trifluoromethyl)phenyl)propanoate (N-17): From L-8 and B-25, an oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 95 / 5) (0.14 g, 31%). 1 H NMR (CDCl3): 8.44 (s, 1H), 7.99 (m, 2H), 7.62 (m, 1H), 7.49 (m, 3H), 7.40 - 7 .26 (m, 8H), 7.10 (m, 1H), 5.02 (m, 2H), 4.17 (s, 2H), 4.13 (m, 2H), 3.25 (m, 1H), 3.14 (m, 1H), 1.19 (m, 3H). HRMS: C 29 H 27 Calculated value for F3N3O2: 506.2055; measured value. Value: 506.2063.

[0460] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(4-(trifluoromethyl)phenyl)propanoate (N-18): From L-8 and B-26, an oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 95 / 5) (0.12 g, 26%). 1 H NMR (CDCl3): 8.44 (s, 1H), 7.98 (m, 2H), 7.48 (m, 2H), 7.40 (m, 3H), 7.29 - 7.26 (m, 5H), 7.03 (m, 2H), 5.02 (m, 2H), 4.19 (m, HRMS: C 29 H 27Calculated value for F3N3O2: 506.2055; Measured value: 506.2002.

[0461] Ethyl (3-benzyl-5-(2-fluorophenyl)pyrazine-2-yl)phenylalaninate (N-19): From L-15 and PheOEt,HCl, an oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 91 / 9) (0.47 g, 81%). 1 H NMR (CDCl3): 8.53 (d, 1H, J = 2.3), 8.04 (dt, 1H, J = 1.9, 7.9), 7.24 (m, 11H), 6.99 (m, 2H), 5.00 (m, 2H), 4.13 (m, 4H), 3.18 (dd, 1H, J = 5.1, 13.7), 3.10 (dd, 1H, J = 5.5, 13.7), 1.20 (t, 3H, J = 7.2). HRMS: C 28 H 27 Calculated value for FN3O2: 456.2087; Measured value: 456.2079.

[0462] Ethyl 2-((3-benzyl-5-(2-fluorophenyl)pyrazine-2-yl)amino)-3-(4-fluorine Lophenyl)propanoate (N-20): From L-15 and B-1, an oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 95 / 5) (0.18 g, purity 90%). 1 H NMR (CDCl3): 8.53 (d, 1H, J = 2.3), 8.05 (dt, 1H, J = 1.9, 7.9), 7.37-7.14 (m, 8H), 6.88 (m, 2H), 6.86 (m, 2H), 4.99 (m, 2H), 4.15 (m, 4H), 3.16 (m, 1H), 3.07 (m, 1H), 1.20 (t, 3H, J = 7.1). HRMS: C 28 H26 Calculated values ​​for F2N3O2, 474.1993; measured values, 474.1991.

[0463] Ethyl 2-((3-benzyl-5-(2-fluorophenyl)pyrazine-2-yl)amino)-3-(furan-2-yl)propanoate (N-21): From L-15 and B-7, an oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 91 / 9) (0.42 g, 72%). 1 H NMR (CDCl3): 8.52 (d, 1H, J = 2.3), 8.03 (dt, 1H, J = 1.9, 7.9), 7.41-7.24 (m, 8H), 7.17 (ddd, 1H, J = 1.3, 8.0, 11.4), 6.22 (dd, 1H, HRMS: C 26 H 25 Calculated value for FN3O3: 446.1880; Measured value: 446.1870.

[0464] Ethyl 2-((3-benzyl-5-(2-fluorophenyl)pyrazine-2-yl)amino)-3-(5-methyl Fran-2-il propanoate (N-22): From L-15 and B-8, an oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 98 / 2~95 / 5) (0.11 g, 30%). 1H NMR (CDCl3): 8.52 (d, 1H, J = 2.3), 8.03 (dt, 1H, J = 1.9, 7.8), 7.35-7.24 (m, 7H), 7.16 (ddd, 1H, J = 1.2, 8.1, 11.1), 5.82 (m, 1H), 5.75 (d, 1H, J = 3.0), 5.19 (d(br), 1H, J = 7.5), 4.95 (m, 1H), 4.18 (m, 4H), 3.16 (d, 2H, J = 5.4), 2.24 (s, 3H), 1.24 (t, 3H, J = 7.2). HRMS: C 27 H 27 Calculated value for FN3O3: 460.2036; Measured value: 460.2039.

[0465] Ethyl 2-((3-benzyl-5-(2-fluorophenyl)pyrazine-2-yl)amino)-3-(5-ethyl Fran-2-il propanoate (N-23): From L-15 and B-10, chromatography on silica gel (cyclohexane-acetic acid) It was obtained as an oily substance after chilling (95 / 5) (0.2 g, 46%). 1 H NMR (CDCl3): 8.51 (d, 1H, J = 2.3), 8.03 (dt, 1H, J = 1.9, 7.8), 7.35-7.23 (m, 7H), 7.16 (ddd, 1H, J = 1.3, 8.1, 9.4), 5.82 (m, 1H), 5.75 (d, 1H, J = 3.0), 5.19 (d(br), 1H, J = 7.5), 4.95 (m, 1H), 4.18 (m, 4H), 3.15 (d, 2H, J = 5.3), 2.58 (q, 2H, J= 7.6), 1.24 (t, 3H, J = 7.2), 1.21 (t, 3H, J = 7.6) HRMS: C 28 H 29 Calculated value for FN3O3: 474.2193; Measured value: 474.2186.

[0466] Ethyl 2-((3-benzyl-5-(2-fluorophenyl)pyrazine-2-yl)amino)-3-(4,5-dimethyl Tilfuran-2-yl)propanoate (N-24): From L-15 and B-9, an oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 95 / 5) (0.48 g, 86%). 1 H NMR (CDCl3): 8.51 (d, 1H, J = 2.4), 8.02 (dt, 1H, J = 1.9, 7.8), 7.35-7.23 (m, 7H), 7.16 (ddd, 1H, J = 1.3, 8.1, 9.4), 5.65 (s, 1H), 5.19 (d(br), 1H, J = 7.5), 4.92 (m, 1H), 4.16 (m, 4H), 3.11 (d, 2H, J = 5.1), 2.13 (s, 3H), 1.88 (s, 3H), 1.25 (t, 3H, J= 7.2). HRMS: C 28 H 29 Calculated value for FN3O3: 474.2193; Measured value: 474.2203.

[0467] Ethyl 2-((3-benzyl-5-(3-fluorophenyl)pyrazine-2-yl)amino)-3-(5-methyl Fran-2-yl)propanoate (N-25): From L-16 and B-8, an oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 95 / 5) (0.14 g, purity 90%). 1H NMR (CDCl3): 8.73 (s, 1H), 7.70 (m, 2H), 7.45-7.23 (m, 6H), 7.02 (m, 1H), 5.82 (m, 1H), 5.74 (d(br), 1H, J = 3.1), 5.18 (d(br), 1H, HRMS: C 27 H 27 Calculated value for FN3O3: 460.2036; Measured value: 460.2040.

[0468] Ethyl 2-((3-benzyl-5-(4-fluorophenyl)pyrazine-2-yl)amino)-3-(5-methyl Fran-2-yl)propanoate (N-26): From L-18 and B-8, an oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 96 / 4) (0.12 g, 21%). 1 H NMR (CDCl3): 8.36 (s, 1H), 7.91 (m, 2H), 7.34-7.23 (m, 5H), 7.15 (m, 2H), 5.82 (m, 1H), 5.75 (d, 1H, J = 3.0), 5.13 (d(br), 1H, J = 7.6), 4.92 (m, 1H), 4.17 (m, 4H), 3.15 (d, 2H, J = 5.3), 2.22 (s, 3H), 1.23 (t, 3H, J = 7.2). HRMS: C 27 H 27 Calculated value for FN3O3: 460.2036; Measured value: 460.2039.

[0469] Ethyl 2-((3-benzyl-5-(4-methoxyphenyl)pyrazine-2-yl)amino)-3-(5-methyl Fran-2-il propanoate (N-27): Using DMF as the reaction solvent, L-19 and B-8 were obtained as an oily substance (0.16 g, 44%) after chromatography on silica gel (cyclohexane-ethyl acetate 95 / 5~94 / 6). 1 H NMR (CDCl3): 8.35 (s, 1H), 7.90 (m, 2H), 7.33-7.23 (m, 5H), 7.01 (m, 2H), 5.82 (m, 1H), 5.75 (d, 1H, J = 2.6), 5.06 (d(br), 1H, J = HRMS: C 28 H 30 Calculated value for N3O4: 472.2236; Measured value: 472.2230.

[0470] 2-((3-benzyl-5-(3-methoxyphenyl)pyrazine-2-yl)amino)-3-(5-methylfuran-2-yl)propanoate (N-28): From L-20 and B-8, chromatography on silica gel (cyclohexane-ethyl acetate) It was obtained as an oily substance (0.07 g, 20%) after the 95 / 5~94 / 6 stage. 1 H NMR (CDCl3): 8.41 (s, 1H), 7.51 (m, 2H), 7.40-7.23 (m, 6H), 6.91 (m, 1H), 5.82 (m, 1H), 5.75 (d, 1H, J = 2.9), 5.06 (d(br), 1H, J = HRMS: C 28 H 30 Calculated value for N3O4: 472.2236; Measured value: 472.2250.

[0471] Ethyl 2-((3-benzyl-5-(4-(benzyloxy)phenyl)pyrazine-2-yl)amino)-3-(5-methylfuran-2-yl)propanoate (N-29): Using DMF as the reaction solvent, L-21 and B-8 were obtained as an oily substance (0.31 g, 50%) after chromatography on silica gel (cyclohexane-ethyl acetate 95 / 5). 1 H NMR (CDCl3): 8.36 (s, 1H), 7.89 (m, 2H), 7.50-7.23 (m, 10H), 7.01 (m, 2H), 5.81 (m, 1H), 5.76 (d, 1H, J = 2.6), 5.15 (s, 2H), 5.07 (d(br), 1H, J = 7.5), 4.91 (m, 1H), 4.19 (m, 4H), 3.15 (d, 2H, J = 5.5), 2.24 (s, 3H), 1.23 (t, 3H, J = 7.2). HRMS: C 34 H 34 Calculated value for N3O4: 548.2549; Measured value: 548.2533.

[0472] Ethyl (3-benzyl-5-(2,6-difluorophenyl)pyrazine-2-yl)phenylalanine T (N-30): From L-17 and PheOEt,HCl, an oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 9 / 1) (0.24 g, 65%). 1 H NMR (CDCl3): 8.14 (s, 1H), 7.30-7.19 (m, 9H), 7.04 - 6.96 (m, 4H), 5.01 (m, 2H), 4.12 (m, 2H), 4.11 (s, 2H), 3.16 (dd, 1H, J = 5.2, 13.8), 3.08 (dd, 1H, J = 5.9, 13.8), 1.18 (t, 3H, J = 7.1). HRMS: C28 H 25 Calculated value for F2N3O2, 474.1993; Actual measurement value, 474.2011.

[0473] Ethyl 2-((3-benzyl-5-(2,6-difluorophenyl)pyrazine-2-yl)amino)-3-(fura N-2-Il)propanoate (N-31): From L-17 and B-7, an oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 9 / 1) (0.19 g, 52%). 1 H NMR (CDCl3): 8.13 (s, 1H), 7.36-7.19 (m, 7H), 7.04 - 6.98 (m, 2H), 6.23 (m, 1H), 5.84 (m, 1H), 5.22 (d, 1H, J = 7.3), 4.96 (m, 1H), 4.16 (s, 2H), 4.15 (m, 2H), 3.20 (d, 2H, J= 5.3), 1.12 (t, 3H, J = 7.0). HRMS: C 26 H 23 Calculated value for F2N3O3: 464.1786; Measured value: 464.1799.

[0474] Isopropyl (5-phenylpyrazine-2-yl)phenylalaninate (N-32): From L-1 and PheOiPr,HCl, dimethylformamide was used as the solvent, and silica gel was used. It was obtained as a solid after chromatography (cyclohexane-ethyl acetate 5 / 1). 1H NMR (CDCl3): 8.48 (m, 1H), 8.01 (m, 1H), 7.89 (m, 2H,), 7.46 (m, 2H), 7.39-7.19 (m, 6H), 5.15 (d(br), 1H, J = 7.7), 5.07 (sept, 1H, J HRMS: C 22 H 24 Calculated value for N3O2: 362.1869; Measured value: 362.1851.

[0475] Isopropyl (3-methyl-5-phenylpyrazine-2-yl)phenylalaninate (N-33): Chromatography was performed on silica gel using dimethylformamide from L-2 and PheOiPr,HCl. It was obtained as a solid after graphing (cyclohexane-ethyl acetate 6 / 1). 1 H NMR (CDCl3): 8.36 (s, 1H), 7.90 (m, 2H), 7.46 (m, 2H), 7.37-7.18 (m, 6H), 5.06 (sept, 1H, J = 6.3), 5.01 (m, 1H), 4.88 (d(br), 1H, J = HRMS: C 23 H 26 Calculated value for N3O2: 376.2025; Measured value: 376.2027.

[0476] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(furan-2-yl)prop Noeto (N-34): From L-8 and B-7, an oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 95:5) (6.31 g, 89%). 1 H NMR (CDCl3): 8.42 (s, 1H), 7.99 - 7.92 (m, 2H), 7.52 - 7.42 (m, 2H), 7.39 - 7.28 (m, 5H), 7.28 - 7.24 (m, 2H), 6.22 (dd, J = 3.2, 1.9 Hz, 1H), 5.85 (dd, J = 3.2, 0.7 Hz, 1H), 5.13 (d, J = 7.5 Hz, 1H), 4.95 (dt, J = 7.5, 5.3 Hz, 1H), 4.23 - 4.11 (m, 4H), 3.24 - 3.18 (m, 2H), 1.22 (t, J= 7.1 Hz, 3H). HRMS: C 26 H 26 N3O3 Calculated value for , 428.1974; Measured value: 428.1965.

[0477] Ethyl 2-(3-benzyl-5-phenylpyrazine-2-ylamino)-3-(furan-3-yl)propano Eto (N-35): From L-8 and B-11, chromatography on silica gel (cyclohexane-ethyl acetate) It was obtained as an oily substance (1.2 g, 89%) after 95 / 5 to 9 / 1. 1H NMR (CDCl3): 8.43 (s, 1H), 7.97 (m, 2H), 7.48 (m, 2H), 7.40 - 7.24 (m, 7H), 6.96 (m, 1H), 5.96 (m, 1H), 5.00 (m, 1H), 4.93 (m, HRMS: C 26 H 26 Calculated values ​​for N3O3 , 428.1974; Measured value: 428.2006.

[0478] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(5-methylfuran-2-yl)propanoate (N-36): From L-8 and B-8, after chromatography on silica gel (dichloromethane), an oily substance was obtained. This was obtained as (0.69 g, 74%). 1 H NMR (CDCl3): 8.38 (s, 1H), 7.96 - 7.89 (m, 2H), 7.48 - 7.40 (m, 2H), 7.38 - 7.26 (m, 5H), 7.25 - 7.19 (m, 1H), 5.83 - 5.77 (m, 1H), 5.72 (d, J = 3.0 Hz, 1H), 5.11 (d, J = 7.5 Hz, 1H), 4.89 (dt, J = 7.5, 5.3 Hz, 1H), 4.21 - 4.08 (m, 4H), 3.12 (d, J = 5.3 Hz, 2H), 2.20 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H). HRMS: C 27 H 28 Calculated value for N3O3: 442.2131; Measured value: 442.2121.

[0479] Ethyl 2-((3-benzyl-5-(p-tolyl)pyrazine-2-yl)amino)-3-(5-methylfuran-2-yl)propanoate (N-37): From L-10 and B-8, chromatography on silica gel (cyclohexane-ethyl acetate) (95:5) Later, it was obtained as an oily substance (0.23 g, 45%). 1 H NMR (CDCl3): 8.38 (s, 1H), 7.83 (m, 2H), 7.28 (m, 2H), 7.26 - 7.17 (m, 7H), 5.81 (m, 1H), 5.74 (d, 1H, J = 3.0), 5.07 (d, 1H, J = 7.9), 4.91 (m, 1H), 4.15 (m, 4H), 3.13 (d, 2H, J = 5.3), 2.41 (s, 3H), 2.22 (s, 3H), 1.24 (t, 3H, J = 7.2); 28 H 30 Calculated value for N3O3: 456.2287; Measured value: 456.2274.

[0480] Ethyl 2-((3-benzyl-5-(m-tolyl)pyrazine-2-yl)amino)-3-(5-methylfuran-2-yl)propanoate (N-38): From L-11 and B-8, chromatography on silica gel (cyclohexane-ethyl acetate) 96:4) Later, it was obtained as an oily substance (0.20 g, 26%). 1H NMR (CDCl3): 8.39 (s, 1H), 7.77 (m, 1H), 7.72 (m, 1H), 7.37 - 7.23 (m, 6H), 7.17 (m, 1H), 5.81 (m, 1H), 5.74 (d, 1H, J = 3.0), HRMS: C 28 H 30 Calculated value for N3O3: 456.2287; Measured value: 456.2253.

[0481] Ethyl (3-benzyl-5-(2-methoxyphenyl)pyrazine-2-yl)phenylalaninate (N-39): Chromatography on silica gel from L-14 and PheOEt,HCl (cyclohexane-vinegar Ethyl acid (90:10) was then used to obtain an oily substance (0.42 g, 72%). 1 H NMR (CDCl3): 8.59 (s, 1H), 7.87 (m, 1H), 7.37 - 7.26 (m, 2H), 7.26 - 7.17 (m, 7H), 7.08 (m, 1H), 7.03 - 6.92 (m, 3H), 5.01 - 4.93 (m, 1H), 4.86 (d, J = 7.5 Hz, 1H), 4.11 (s, 2H), 4.10 (q, J = 7.1 Hz, 2H), 3.89 (s, 3H), 3.15 (dd, J = 13.8, 5.5 Hz, 1H), 3.06 (dd, J = 13.8, 6.0 Hz, 1H), 1.16 (t, J = 7.1 Hz, 3H). HRMS: C 29 H 30 Calculated value for N3O3: 468.2287; Measured value: 468.2282.

[0482] Ethyl 2-((3-benzyl-5-(2-methoxyphenyl)pyrazine-2-yl)amino)-3-(furan-2-yl)propanoate (N-40): From L-14 and B-7, chromatography on silica gel (cyclohexane-ethyl acetate) (90:10) It was later obtained as an oily substance (0.40 g, 64%). 1 H NMR (CDCl3): 8.58 (s, 1H), 7.87 (dd, J = 7.7, 1.8 Hz, 1H), 7.37 - 7.27 (m, 5H), 7.25 - 7.19 (m, 2H), 7.08 (td, J = 7.5, 1.0 Hz, 1H), 7.00 (dd, J = 8.3, 0.6 Hz, 1H), 6.20 (dd, J = 3.1, 1.8 Hz, 1H), 5.82 (dd, J = 3.1, 0.5 Hz, 1H), 5.07 (d, J = 7.6 Hz, 1H), 5.00 - 4.91 (m, 1H), 4.15 (s, 2H), 4.13 (qd, J= 7.1, 1.4 Hz, 2H), 3.89 (s, 3H), 3.19 (d, J = 5.3 Hz, 2H), 1.19 (t, J= 7.1 Hz, 3H). HRMS: C 27 H 28 Calculated value for N3O4: 458.2080; Measured value: 458.2083.

[0483] Ethyl 2-((3-benzyl-5-(2-methoxyphenyl)pyrazine-2-yl)amino)-3-(furan-3-yl)propanoate (N-41): From L-14 and B-11, chromatography on silica gel (cyclohexane-ethyl acetate) (90:10) was subsequently obtained as an oily substance (0.53 g, 84%). 1H NMR (CDCl3): 8.60 (s, 1H), 7.89 (dd, J = 7.6, 1.7 Hz, 1H), 7.38 - 7.19 (m, 7H), 7.13 - 7.04 (m, 1H), 7.00 (d, J = 8.3 Hz, 1H), 6.94 (s, 1H), 5.97 - 5.91 (m, 1H), 5.02 - 4.87 (m, 2H), 4.24 - 4.07 (m, 4H), 3.89 (s, 3H), 2.97 (qd, J = 14.7, 4.8 Hz, 2H), 1.21 (t, J = 7.1 Hz, 3H). HRMS: C 27 H 28 Calculated value for N3O4: 458.2080; Measured value: 458.2095.

[0484] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(pyridine-2-yl)pro Panoate (N-42): From L-8 and B-22, chromatography on silica gel (cyclohexane-ethyl acetate) It was obtained as an oily substance after 95:5~75:25 (0.45 g, 64%). 1H NMR (CDCl3): 8.42 - 8.39 (m, 1H), 8.38 (s, 1H), 7.95 - 7.89 (m, 2H), 7.52 (td, J = 7.6, 1.8 Hz, 1H), 7.47 - 7.39 (m, 2H), 7.36 - 7.29 (m, 3H), 7.29 - 7.23 (m, 2H), 7.23 - 7.18 (m, 1H), 7.11 (ddd, J = 7.6, 4.9, 1.0 Hz, 1H), 7.01 (d, J = 7.8 Hz, 1H), 6.30 (d, J = 7.3 Hz, 1H), 5.03 (dt, J = 7.3, HRMS: C 27 H 27 Calculated value for N4O2: 439.2134; Measured value: 439.2152.

[0485] Ethyl (5-phenyl-3-((tetrahydrofuran-2-yl)methyl)pyrazine-2-yl)phenylalaninate (N-42'): From L-26 and PheOEt,HCl, a mixture of two diastereoisomers was obtained as an oily substance (0.06 g, 21%) after chromatography on silica gel (cyclohexane-ethyl acetate 93:7). 1 H NMR (CDCl3): 8.34 (s, 0.5H), 8.33 (s, 0.5H), 7.89 - 7.84 (m, 2H), 7.45 - 7.40 (m, 2H), 7.35 - 7.21 (m, 6H), 6.62 (d, J = 7.5 Hz, 0.5H), 6.44 (d, J = 7.1 Hz, 0.5H), 4.95 (dd, J = 13.0, 6.8 Hz, 0.5H), 4.86 (td, J = 7.4, 5.9Hz, 0.5H), 4.37 - 4.30 (m, 0.5H), 4.30 - 4.23 (m, 0.5H), 4.22 - 4.13 (m, 2H), 3.89 - 3.79 (m, 0.5H), 3.77 - 3.58 (m, 1.5H), 3.31 - 2.88 (m, HRMS: C2 6H 30 Calculated value for N3O3: 432.2287; Measured value: 432.2273.

[0486] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(4,5-dimethylfuran-2-yl)propanoate (N-43): From L-8 and B-9, an oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 95:5) (0.20 g, 49%). 1 H NMR (CDCl3): 8.39 (s, 1H), 7.97 - 7.90 (m, 2H), 7.50 - 7.40 (m, 2H), 7.39 - 7.19 (m, 6H), 5.65 (s, 1H), 5.11 (d, J = 7.5 Hz, 1H), 4.88 (dt, J = 7.5, 5.4 Hz, 1H), 4.19 - 4.12 (m, 4H), 3.09 (d, J = 5.4 Hz, 2H), 2.12 (s, 3H), 1.87 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H). HRMS: C 28 H 30 Calculated value for N3O3: 456.2287; Measured value: 456.2337.

[0487] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(4,5-dimethylthiophen N-2-Il)propanoate (N-44): From L-8 and B-17, chromatography on silica gel (cyclohexane-ethyl acetate) 96:4) Later, it was obtained as an oily substance (0.24 g, 47%). 1 H NMR (CDCl3): 8.42 (s, 1H), 7.95 (m, 2H), 7.47 (m, 2H), 7.36 (m, 1H), 7.28 (m, 5H), 6.33 (s, 1H), 5.12 (d, J= 7.3 Hz, 1H), 4.92 (dt, 1H, J= 7.2, 5.0), 4.18 (m, 4H), 3.32 (dd, 1H,J = 4.7, 14.8), 3.26 (dd, 1H, J= 5.4, 14.8), 2.28 (s, 3H), 2.06 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H). HRMS: C 28 H 30 Calculated value for N3O2S: 472.2059; Measured value: 472.2054.

[0488] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(4,5-dimethyloxazo (N-45): From L-8 and B-40, chromatography on silica gel (cyclohexane-ethyl acetate) It was obtained as an oily substance after 97:3~3 / 1 (0.20 g, 49%). 1H NMR (CDCl3): 8.39 (s, 1H), 7.93 (m, 2H), 7.46 (m, 2H), 7.37 - 7.21 (m, 6H), 5.75 (d, J = 7.8 Hz, 1H), 5.07 (m, 1H), 4.20 (m, 2H), 4.15 (q, J= 7.1 Hz, 2H), 3.30 (dd, J = 5.6 and 15.3 Hz, 1H), 3.22 (dd, J= 5.4 and 15.3 Hz, 1H), 2.17 (s, 3H), 2.05 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H). HRMS: C 27 H 29 Calculated value for N4O3: 457.2240; Measured value: 457.2234.

[0489] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(4-fluorophenyl)propanoate (N-46): (L-8) and (B-1) chromatography on silica gel (cyclohexane-acetic acid After chilling (95:5), it was obtained as an oily substance (0.45 g, 69%). 1 H NMR (CDCl3): 8.41 (s, 1H), 7.99 - 7.91 (m, 2H), 7.51 - 7.41 (m, 2H), 7.40 - 7.32 (m, 1H), 7.31 - 7.25 (m, 3H), 7.23 - 7.17 (m, 2H), 6.91 - 6.79 (m, 4H), 4.99 - 4.84 (m, 2H), 4.21 - 4.06 (m, 4H), 3.15 (dd, J = 13.9, 5.1 Hz, 1H), 3.03 (dd, J = 13.9, 5.5 Hz, 1H), 1.20 (t, J = 7.1 Hz, 3H). HRMS: C 28 H 27 Calculated value for FN3O2: 456.2087; Measured value: 456.2110.

[0490] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(3-fluorophenyl)propanoate (N-46'): From L-8 and B-32, chromatography on silica gel (cyclohexane-ethyl acetate) (95:5) It was later obtained as an oily substance (0.25 g, 64%). 1 H NMR (CDCl3): 8.44 (s, 1H), 7.97 (m, 2H), 7.48 (m, 2H), 7.38 (m, 1H), 7.32 - 7.23 (m, 5H), 7.17 (m, 1H), 6.92 (m, 1H), 6.73 (m, HRMS: C 28 H 27 Calculated value for FN3O2: 456.2087; Measured value: 456.2065.

[0491] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(2-fluorophenyl)propanoate (N-47): From L-8 and B-27, chromatography on silica gel (cyclohexane-ethyl acetate) (95:5) It was later obtained as an oily substance (0.32 g, 79%). 1 H NMR (CDCl3): 8.42 (s, 1H), 7.96 (m, 2H), 7.47 (m, 2H), 7.37 (m, 1H), 7.27 (m, 6H), 6.98 (m, 3H), 4.99 (m, 2H), 4.15 (m, 4H), 3.22 (dd, 1H, J = 13.9, 5.5), 3.16 (dd, 1H, J = 13.9, 6.3), 1.20 (t, 3H, J = 7.1). HRMS: C 28 H27 Calculated value for FN3O2: 456.2087; Measured value: 456.2084.

[0492] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(2,4-difluorophenyl Propanoate (N-48): From L-8 and B-28, chromatography on silica gel (cyclohexane-ethyl acetate) 96:4) Later, it was obtained as an oily substance (0.27 g, 61%). 1 H NMR (CDCl3): 8.42 (s, 1H), 7.96 (m, 2H), 7.47 (m, 2H), 7.37 (m, 1H), 7.27 (m, 5H), 6.98 (m, 1H), 6.70 (m, 2H), 4.97 (m, 2H), 4.16 (m, 4H), 3.22 (dd, 1H, J = 5.4, 14.3), 3.10 (dd, 1H, J = 6.1, 14.3), 1.22 (t, 3H, J = 7.1). HRMS: C 28 H 26 Calculated values ​​for F2N3O2, 474.1993; measured values, 474.1988.

[0493] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(4-chlorophenyl)propanoate (N-49): From L-8 and B-29, chromatography on silica gel (cyclohexane-ethyl acetate) (97:3~96:4) was obtained as an oily substance (0.38 g, 64%). 1 H NMR (CDCl3): 8.43 (s, 1H), 7.97 (m, 2H), 7.48 (m, 2H), 7.37 (m, 1H), 7.30 (m, 3H) 7.22 (m, 2H), 7.14 (m, 2H) 6.85 (m, 2H), 4.95 (m, 2H), 4.15 (m, 4H), 3.16 (m, 1H), 3.03 (m, 1H), 1.23 (t3H, J = 7.2 Hz,). HRMS: C 28 H 27 Calculated values ​​for ClN3O2 472.1792; measured value, 472.1782.

[0494] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(4-bromophenyl)propanoate (N-50): From L-8 and B-31, chromatography on silica gel (cyclohexane-ethyl acetate) (97:3~96:4) was obtained as an oily substance (0.37 g, 57%). 1 H NMR (CDCl3): 8.43 (s, 1H), 7.97 (m, 2H), 7.48 (m, 2H), 7.37 (m, 1H), 7.29 (m, 5H), 7.22 (m, 2H), 6.79 (m, 2H), 4.95 (m, 2H), 4.15 (m, 4H), 3.16 (m, 1H), 3.03 (m, 1H), 1.23 (t, 3H, J = 7.2). HRMS: C 28 H 27 Calculated value for BrN3O2: 516.1287; Actual value Measured value: 516.1267.

[0495] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(o-tolyl)propanoate (N-51): From L-8 and B-20, chromatography on silica gel (cyclohexane-ethyl acetate) (95:5) It was later obtained as an oily substance (0.48 g, 90%). 1H NMR (CDCl3): 8.40 (s, 1H), 7.94 (m, 2H), 7.48 - 7.42 (m, 2H), 7.38 - 7.24 (m, 6H), 7.15 (m, 2H), 7.06 (m, 1H), 6.93 (m, 1H), 4.92 (m, 2H), 4.16 (m,4H), 3.14 (dd, 1H, J = 6.1, 14.0), 3.02 (dd, 1H, J = 7.1, 14.0), 2.29 (s, 3H), 1.16 (t, 3H, J= 7.1). HRMS: C 29 H 29 Calculated value for N3O2: 452.2338; Measured value: 452.2352.

[0496] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(m-tolyl)propanoate (N-52): From L-8 and B-6, an oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 95:5) (0.28 g, 61%). 1 H NMR (CDCl3): 8.41 (s, 1H), 8.07 - 7.90 (m, 2H), 7.48 - 7.42 (m, 2H), 7.38 - 7.32 (m, 1H), 7.30 - 7.26 (m, 1H), 7.26 - 7.23 (m, 1H), 7.21 - 7.16 (m, 2H), 7.15 - 7.08 (m, 1H), 7.07 - 7.01 (m, 1H), 6.88 (s, 1H), 6.78 (d, 1H, J = 7.5), 4.93 (t, 1H, J = 5.9), 4.92 (t, 1H, J = 6.5), 4.88 - 4.79 (m, 2H), 4.11 (q, 2H, J = 7.1), 4.11 (q, 2H, J = 15.4), 3.11 (dd, 1H, J = 13.8, 5.5), 3.03 (dd, 1H, J = 13.8, 6.1), 2.30 (s, 3H), 1.17 (t, 3H, J = 7.1). HRMS: C29 H 29 Calculated value for N3O2: 452.2338; Measured value: 452.2408.

[0497] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(p-tolyl)propanoate (N-53): From L-8 and B-21, chromatography on silica gel (cyclohexane-ethyl acetate) 94:6) It was later obtained as an oily substance (0.35 g, 87%). 1 H NMR (CDCl3): 8.43 (s, 1H), 7.97 (m, 2H), 7.48 (m, 2H), 7.37 (m, 1H), 7.28 (m, 3H), 7.22 (m, 2H), 7.04 (m, 2H), 6.89 (m, 2H), 4.93 (m, 2H), 4.15 (m, 4H), 3.15 (dd, 1H, J = 13.8, 5.2), 3.06 (dd, 1H, J = 13.8, 5.8), 2.35 (s, 3H), 1.21 (t, 3H, J= 7.2). HRMS: C 29 H 29 Calculated value for N3O2: 452.2338; Measured value: 452.2325.

[0498] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(3-propylphenyl)propanoate (N-54): From L-8 and B-37, chromatography on silica gel (cyclohexane-ethyl acetate) (95:5) It was later obtained as an oily substance (0.27 g, 79%). 1 H NMR (CDCl3): 8.42 (s, 1H), 7.95 (m, 2H), 7.47 (m, 2H), 7.37 (m, 1H), 7.26 (m, 5H), 7.16 (m, 1H), 7.07 (m, 1H), 6.92 (m, 1H), 6.82 (m, 1H), 4.93, (m, 2H), 4.14 (m, 4H), 3.15 (dd, 1H, J = 13.7, 5.6), 3.07 (dd, 1H, J = 13.7, 6.1), 2.56 (m, 2H), 1.63 (m, 2H), 1.18 (t, 3H, J = 7.2), 0.95 (t, 3H, J = 7.3). HRMS: C 31 H 34 Calculated value for N3O2: 480.2651; Measured value: 480.2661.

[0499] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(4-propylphenyl)propanoate (N-55): From L-8 and B-36, chromatography on silica gel (cyclohexane-ethyl acetate) (95:5) It was later obtained as an oily substance (0.25 g, 73%). 1 H NMR (CDCl3): 8.42 (s, 1H), 7.96 (m, 2H), 7.47 (m, 2H), 7.37 (m, 1H), 7.26 (m, 5H), 7.05 (m, 2H), 6.91 (m, 2H), 4.93, (m, 2H), 4.13 (m, 4H), 3.14 (dd, 1H, J = HRMS: C 31 H 34 Calculated value for N3O2: 480.2651; Measured value: 480.2671.

[0500] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(4-isopropylphenyl Propanoate (N-56): From L-8 and B-33, chromatography on silica gel (cyclohexane-ethyl acetate) (95:5) It was later obtained as an oily substance (0.25 g, 73%). 1 H NMR (CDCl3): 8.40 (s, 1H), 7.97 - 7.90 (m, 2H), 7.49 - 7.40 (m, 2H), 7.38 - 7.32 (m, 1H), 7.32 - 7.23 (m, 3H), 7.23 - 7.17 (m, 2H), 7.12 - 7.05 (m, 2H), 6.94 - 6.88 (m, 2H), 4.99 - 4.84 (m, 2H), 4.18 - 4.06 (m, 4H), 3.08 (qd, 2H, J = 13.8, 5.7), 2.96 - 2.84 (m, 1H), 1.25 (d, 6H, J = 6.9), 1.16 (t, 3H, J = 7.1). HRMS: C 31 H 34 Calculated value for N3O2: 480.2683; Measured value: 480.2690.

[0501] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(4-cyclopropyl phenyl Nil-propanoate (N-57): From L-8 and B-34, chromatography on silica gel (cyclohexane-ethyl acetate) (95:5) It was later obtained as an oily substance (0.46 g, 76%). 1H NMR (CDCl3): 8.42 (s, 1H), 7.96 (m, 2H), 7.47 (m, 2H), 7.36 (m, 1H), 7.31-7.23 (m, 3H), 7.20 (m, 2H), 6.94 (m, 2H), 6.86 (m, 2H), 4.93, (m, 2H), 4.13 (m, 4H), 3.13 (dd, 1H, J = 5.3, 13.9), 3.04 (dd, 1H, J = 5.9, 13.9), 1.89 (m, 1H), 1.19 (t, 3H, J = 7.2), 0.98 (m, 2H), 0.69 (m, 2H). HRMS: C 31 H 32 Calculated value for N3O2: 478.2495; Measured value: 478.2487.

[0502] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(3-cyclopropyl phenyl Nil-propanoate (N-58): From L-8 and B-35, chromatography on silica gel (cyclohexane-ethyl acetate) (95:5) It was later obtained as an oily substance (0.46 g, 79%). 1 H NMR (CDCl3): 8.42 (s, 1H), 7.95 (m, 2H), 7.47 (m, 2H), 7.36 (m, 1H), 7.28-7.19 (m, 5H), 7.13 (m, 1H), 6.95 (m, 1H), 6.82 (m, 1H), 6.77 (m, 1H), 4.93, (m, 2H), 4.13 (m, 4H), 3.13 (dd, 1H, J = 5.5, 13.7), 3.05 (dd, J = 6.0, 13.7 Hz, 1H), 1.86 (m, 1H), 1.18 (t, 3H, J = 7.2), 0.96 (m, 2H), 0.67 (m, 2H). HRMS: C 31 H 32 Calculated value for N3O2: 478.2495; Measured value: 478.2480.

[0503] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(thiophen-2-yl) Lopanoate (N-59): From L-8 and B-12, chromatography on silica gel (cyclohexane-ethyl acetate) (95:5) It was later obtained as an oily substance (0.51 g, 80%). 1 H NMR (CDCl3): 8.42 (s, 1H), 8.00 - 7.89 (m, 2H), 7.50 - 7.42 (m, 2H), 7.40 - 7.32 (m, 1H), 7.32 - 7.26 (m, 3H), 7.26 - 7.21 (m, 2H), 7.14 - 7.08 (m, 1H), 6.85 (dd, J = 5.2, 3.4 Hz, 1H), 6.58 - 6.50 (m, 1H), 5.12 (d, J= 7.1 Hz, 1H), 4.99 (dt, J = 7.1, 5.0 Hz, 1H), 4.17 (s, 2H), 4.14 (q, J= 7.1 HRMS: C 26 H 26 Calculated value for N3O2S: 444.1746; Measured value: 444.1766.

[0504] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(3-methylthiophen-2-yl)propanoate (N-60): From L-8 and B-18, chromatography on silica gel (cyclohexane-ethyl acetate) (95:5) It was later obtained as an oily substance (0.41 g, 76%). 1H NMR (CDCl3): 8.44 (s, 1H), 7.97 (m, 2H), 7.47 (m, 2H), 7.37 (m, 1H), 7.33 - 7.23 (m, 5H), 7.05 (d, 1H, J = 4.8), 6.75 (d, 1H, J = 4.8), 5.15 (d, 1H, J = 7.1), 4.96 (m, 1H), 4.15 (m, 4H), 3.41 (dd, 1H, J = 5.1, 15.1), 3.31 (dd, 1H, J = 5.1, 15.1), 2.0 (s, 3H), 1.23 (t, J = 7.3 Hz, 3H). HRMS: C 27 H 28 Calculated value for N3O2S: 458.1902; Measured value: 458.1910.

[0505] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(5-ethylthiophen-2-yl)propanoate (N-61): From L-8 and B-19, chromatography on silica gel (cyclohexane-ethyl acetate) (95:5) It was later obtained as an oily substance (0.47 g, 84%). 1 H NMR (CDCl3): 8.43 (s, 1H), 7.97 (m, 2H), 7.47 (m, 2H), 7.37 (m, 1H), 7.33 - 7.23 (m, 5H), 6.55 (m, 1H), 6.39 (m, 1H), 5.13 (d, 1H, J = 7.1), 4.91 (m, 1H), 4.17 (m, 4H), 3.34 (m, 2H), 2.79 (qd, 2H, J = 0.8, 7.5), 1.30 (t, J = 7.5 Hz, 3H), 1.24 (t, J = 7.3 Hz, 3H). HRMS: C 28 H 30 Calculated value for N3O2S: 472.2059; Measured value: 472.2055.

[0506] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(5-ethylfuran-2-yl)propanoate (N-62): From L-8 and B-10, chromatography on silica gel (cyclohexane-ethyl acetate) (95:5) It was later obtained as a yellow solid (0.48 g, 74%). 1 H NMR (CDCl3): 8.39 (s, 1H), 7.96 - 7.89 (m, 2H), 7.50 - 7.40 (m, 2H), 7.37 - 7.26 (m, 4H), 7.26 - 7.20 (m, 2H), 5.80 (dd, J = 2.0, 1.0 Hz, 1H), 5.74 (d, J = 3.0 Hz, 1H), 5.09 (d, J= 7.5 Hz, 1H), 4.91 (dt, J = 7.5, 5.4 Hz, 1H), 4.22 - 4.08 (m, 4H), 3.14 (d, J = 5.3 Hz, 2H), 2.56 (qd, J = 7.5, 0.6 HRMS: C 28 H 30 Calculated value for N3O3: 457.2319; Measured value: 457.2314.

[0507] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(5-cyclopropyl N-2-Il)propanoate (N-63): From L-8 and B-39, chromatography on silica gel (cyclohexane-ethyl acetate) (95 / 5) was obtained as an oily substance (0.31 g, 67%). 1H NMR (CDCl3): 8.39 (s, 1H), 7.97 - 7.90 (m, 2H), 7.48 - 7.41 (m, 2H), 7.38 - 7.20 (m, 6H), 5.78 (dd, J= 3.1, 0.5 Hz, 1H), 5.72 (d, J= 3.1 Hz, 1H), 5.08 (d, 1H, J = 7.6), 4.90 (dt, 1H, J = 7.6, 5.3), 4.20 - 4.11 (m, 4H), 3.12 (d, 2H, J= 5.3), 1.81 (tt, 1H, J = 8.5, 5.1), 1.22 (t, 3H, J = 7.1), 0.88 - 0.80 (m, 2H), 0.73 - 0.65 (m, 2H). HRMS: C 29 H 30 Calculated value for N3O3: 468.2287; Measured value: 468.2291.

[0508] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(5-(trifluoromethyl)furan-2-yl)propanoate (N-64): From L-8 and B-38, chromatography on silica gel (cyclohexane-ethyl acetate) 93 / 7) It was later obtained as an oily substance (0.17 g, 44%). 1 H NMR (CDCl3): 8.40 (s, 1H), 7.99 - 7.92 (m, 2H), 7.50 - 7.42 (m, 2H), 7.40 - 7.33 (m, 1H), 7.33 - 7.20 (m, 5H), 6.55 (dd, J = 3.3, 1.2 Hz, 1H), 5.74 (dd, J = 3.3, 0.6 Hz, 1H), 5.12 (d, J = 7.1 Hz, 1H), 4.98 (dt, J = 7.1, 5.2 Hz, 1H), 4.26 - 4.09 (m, 4H), 3.29 (dd, J = 15.2, 5.2 Hz, 1H), 3.19 (dd, J = 15.2, 5.2 Hz, 1H), 1.24 (t, J = 7.1 Hz, 3H). HRMS: C 27 H 25 Calculated value for F3N3O3: 496.1848; Measured value: 496.1847.

[0509] Ethyl 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(4-(benzyloxy) Enylpropanoate (N-65): From L-8 and B-5, an oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 95 / 5) (0.68 g, 70%). 1 H NMR (CDCl3): 8.41 (s, 1H), 8.00 - 7.86 (m, 2H), 7.50 - 7.16 (m, 13H), 6.90 - 6.84 (m, 2H), 6.84 - 6.79 (m, 2H), 5.05 (s, 2H), 4.99 - 4.84 (m, 2H), 4.12 (qd, 2H, J = 7.1, 0.6), 4.12 (s, 2H), 3.11 (dd, 1H, J = 13.9, 5.0), 3.01 (dd, 1H, J = 13.9, 5.5), 1.19 (t, 3H, J = 7.1). HRMS: C 35 H 33 Calculated value for N3O3: 544.2600; Measured value: 544.2654.

[0510] Ethyl (3-benzyl-5-(4-(benzyloxy)phenyl)pyrazine-2-yl)phenylalanine Nate (N-66): From L-21 and PheOEt,HCl, a white solid was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 95 / 5~94 / 6) (4.47 g, 87%). 1 H NMR (CDCl3): 8.36 (s, 1H), 7.89 (m, 2H), 7.49 (m, 2H), 7.42 (m, 2H), 7.35 (m, 1H), 7.32-7.20 (m, 8H), 7.08 (m, 2H), 7.00 (m, 2H), 5.15 (s, 2H), 4.97 (m, 1H), 4.86 (d(br), 1H, J = 8.1), 4.14 (m, 4H), 3.17 (dd, 1H, J = 5.5, 13.8), 3.08 (dd, 1H, J = 6.0, 13.8), 1.19 (t, 3H, J = 7.2). HRMS: C 35 H 34 Calculated value for N3O3: 544.2600; Measured value: 544.2609.

[0511] Ethyl 2-((3-benzyl-5-(4-(benzyloxy)phenyl)pyrazine-2-yl)amino)-3-( Fran-2-il propanoate (N-67): From L-21 and B-7, an oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 94 / 6~93 / 7) (0.83 g, 79%). 1 H NMR (CDCl3): 8.35 (s, 1H), 7.89 (m, 2H), 7.48 (m, 2H), 7.42 (m, 2H), 7.36 (m, 1H), 7.32-7.20 (m, 5H), 7.08 (m, 2H), 6.22 (dd, 1H, J = 2.0, 3.0), 5.85 (dd, 1H, J = 0.7, 3.0), 5.15 (s, 2H), 5.07 (d(br), 1H, J = 7.6), 4.94 (m, 1H), 4.16 (m, 4H), 3.20 (d, 2H, J = 5.3), 1.21 (t, 3H, J = 7.2). HRMS: C 33 H 32Calculated value for N3O4: 534.2393; Measured value: 534.2410.

[0512] Ethyl 2-((3-benzyl-5-(4-(benzyloxy)phenyl)pyrazine-2-yl)amino)-3-(5-ethylfuran-2-yl)propanoate (N-68): From L-21 and B-10, chromatography on silica gel (cyclohexane-acetic acid) It was obtained as an oily substance after chilling (94 / 6) (0.65 g, 60%). 1 H NMR (CDCl3): 8.34 (s, 1H), 7.88 (m, 2H), 7.48 (m, 2H), 7.42 (m, 2H), 7.36 (m, 1H), 7.32-7.20 (m, 5H), 7.08 (m, 2H), 5.82 (m, 1H), 5.76 (d, 1H, J = 3), 5.14 (s, 2H), 5.06 (d(br), 1H, J = 7.5), 4.91 (m, 1H), 4.16 (m, 4H), 3.15 (d, 2H, J = 5.4), 2.57 (q, 2H, J = 7.8), 1.23 (t, 3H, J = 7.2), 1.21 (t, 3H, J = 7.8). HRMS: C 35 H 36 Calculated value for N3O4: 562.2706; Measured value: 562.2716.

[0513] Ethyl 2-((3-benzyl-5-(4-(benzyloxy)phenyl)pyrazine-2-yl)amino)-3-(4,5-dimethylfuran-2-yl)propanoate (N-69): From L-21 and B-9, an oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 94 / 6) (0.62 g, 56%). 1H NMR (CDCl3): 8.34 (s, 1H), 7.88 (m, 2H), 7.48 (m, 2H), 7.42 (m, 2H), 7.36 (m, 1H), 7.32-7.20 (m, 5H), 7.07 (m, 2H), 5.66 (s, 1H), 5.14 (s, 2H), 5.06 (d(br), 1H, J = 7.4), 4.88 (m, 1H), 4.17 (m, 4H), 3.10 (d, 2H, J = 5.4), 2.14 (s, 3H), 1.89 (s, 3H), 1.23 (t, 3H, J = 7.8). HRMS: C 35 H 36 Calculated value for N3O4: 562.2706; Measured value: 562.2690.

[0514] Ethyl 2-((3-benzyl-5-(4-(benzyloxy)phenyl)pyrazine-2-yl)amino)-3-(3-propylphenyl)propanoate (N-70): From L-21 and B-37, chromatography on silica gel (cyclohexane-acetic acid) (0.97 g, 85%) obtained after chilling 98 / 2. 1 H NMR (CDCl3): 8.36 (s, 1H), 7.89 (m, 2H), 7.32 (m, 11H), 7.07 (m, 3H), 6.92 (m, 1H), 6.82 (m, 1H), 5.15 (s, 2H), 4.95 (m, 1H), 4.84 (d, 1H, J = 7.5), 4.12 (m, 4H), 3.14 (dd, 1H, J = 13.7, 5.7), 3.07 (dd, 1H, J = 13.7, 6.2), 2.56 (m, 2H), 1.64 (m, 2H), 1.18 (t, 3H, J = 7.1), 0.96 (t, 3H, J = 7.3) HRMS: C 38 H 40 Calculated value for N3O3: 586.3069; Measured value: 586.3096.

[0515] Ethyl 2-(3-benzyl-5-phenylpyrazine-2-ylamino)-4-phenylbutanoate (N-71): From L-8 and B-42, an oily substance was obtained after chromatography on silica gel (cyclohexane / ethyl acetate 95:5) (0.36 g, 80%). 1 H NMR (CDCl3): 8.42 (s, 1H), 7.97 (m, 2H), 7.48 (m, 1H), 7.38 (m, 5H), 7.28 (m, 3H), 7.20 (m, 1H), 7.06 (m, 2H), 4.97 (d (br), 1H, J = 7.0), 4.73 (m, 1H), 4.27 (d, 1H, J = 15.4), 4.21 (d, 1H, J = 15.4), 4.16 (q, 2H, J = 7.1), 2.43 (m, 2H), 2.21 (m, 1H), 1.99 (m, 1H), 1.26 (t, 3H, J = 7.1). HRMS: C 29 H 30 Calculated value for N3O2: 452.2338; Measured value: 452.2335.

[0516] Ethyl (2-benzyl-5H-chromeno[3,4-b]pyrazine-3-yl)phenylalaninate (N-72): From L-27 and PheOEt,HCl, an orange oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 93 / 7) (0.05 g, 33%). 1H NMR (CDCl3): 8.07 (dd, 1H, J = 1.6, 7.7), 7.38-7.18 (m, 9H), 7.12 (dt, 1H, J = 1.0, 7.8), 7.01-6.93 (m, 3H), 5.18 (s, 2H), 5.01-4.91 (m, 2H), 4.20-4.06 (m, 4H), 3.15 (dd, 1H, J = 5.2, 13.9), 3.05 (dd, 1H, J = 5.9, 13.9), 1.22 (t, 3H, J = 7.8). 29 H 28 Calculated value for N3O3: 466.2131; Measured value: 466.2117.

[0517] Ethyl (5-phenyl-3-(pyridine-3-ylmethyl)pyrazine-2-yl)phenylalaninate (N-73): From L-24 and PheOEt,HCl, an oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 2 / 1) (0.28 g, 62%). 1 H NMR (CDCl3): 8.52 (m, 3H), 8.44 (s, 1H), 7.90 (m, 2H), 7.46 (m, 3H), 7.35 (m, 1H), 7.26 (m, 3H), 7.19 (ddd, 1H, J = 0.9, 4.9, 5.6), 7.03 (m, 2H), 5.01 (m, 1H), 4.84 (d(br, 1H, J = 7.4), 4.17 (q, 2H, J = 7.0), 4.08 (s, 2H), 3.24 (dd, 1H, J = 5.9, 13.5), 3.16 (dd, 1H, J = 5.9, 13.6), 1.23 (t, 3H, J = 7.0). HRMS: C 27 H 27 Calculated value for N4O2: 439.2134; Measured value: 439.2137.

[0518] Ethyl (3-(2-methylbenzyl)-5-phenylpyrazine-2-yl)phenylalaninate (N-74): From L-12 and PheOEt,HCl, an oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 95:5) (0.40 g, 86%). 1 H NMR (CDCl3): 8.43 (s, 1H), 7.92 (m, 2H), 7.43 (m, 2H), 7.35 (m, 1H), 7.20 (m, 5H), 7.11 (m, 1H), 6.98 (m, 3H), 5.01 (m, 1H), 4.86 (d (br), 1H, J = 7.1), 4.14 (m, 4H), 3.17 (dd, 1H, J = 5.6, 13.8), 3.07 (dd, 1H, J = 6.0, 13.8), 2.33 (s, 3H), 1.21 (t, 3H, J = 7.1). HRMS: C 29 H 29 Calculated value for N3O2: 452.2338; Measured value: 452.2338.

[0519] Ethyl 3-(furan-2-yl)-2-((3-(2-methylbenzyl)-5-phenylpyrazine-2-yl)amino)propanoate (N-75): From L-12 and B-7, chromatography on silica gel (cyclohexane-ethyl acetate) (95:5) It was later obtained as an oily substance (0.30 g, 71%). 1 H NMR (CDCl3): 8.43 (s, 1H), 7.93 (m, 2H), 7.47 (m, 2H), 7.35 (m, 1H), 7.20 (m, 3H), 7.13 (m, 1H), 7.06 (m, 1H), 6.21 (dd, 1H, J = 1.8, 3.1), 5.85 (m, 1H), 5.09 (d (br), 1H, J = 7.6), 4.98 (m, 1H), 4.18 (m, 4H), 3.20 (m, 2H), 2.39 (s, 3H), 1.23 (t, 3H, J= 7.1). HRMS: C 27 H 28 Calculated for C 27 H 28 N3O3, 442.2131; found, 442.2137.

[0520] Ethyl (3-(3-methylbenzyl)-5-phenylpyrazin-2-yl)phenylalaninate (N-76): Obtained as an oil (0.41 g, 89%) after chromatography on silica gel (cyclohexane-ethyl acetate 95:5) from L-13 and PheOEt, HCl. 1 H NMR (CDCl3): 8.43 (s, 1H), 7.97 (m, 2H), 7.48 (m, 2H), 7.37 (m, 1H), 7.21 (m, 4H), 7.08-6.96 (m, 4H), 4.97 (m, 2H), 4.14 (m, 4H), 3.17 (dd, 1H, J = 5.0, 13.7), 3.07 (dd, 1H, J = 5.7, 13.7), 2.31 (s, 3H), 1.20 (t, 3H, J = 7.1). HRMS: C 29 H 29 Calculated for C 29 H 29 N3O2, 452.2338; found, 452.2337.

[0521] Ethyl 3-(furan-2-yl)-2-((3-(3-methylbenzyl)-5-phenylpyrazin-2-yl)amino)propanoate (N-77): Obtained as an oil after chromatography on silica gel (cyclohexane-ethyl acetate 95:5) from L-13 and B-7 (0.35 g, 75%). 1 1H NMR (CDCl3): 8.42 (s, 1H), 7.96 (m, 2H), 7.48 (m, 2H), 7.38 (m, 1H), 7.21 (m, 2H), 7.08 (m, 3H), 6.22 (dd, 1H, J = 2.0, 3.3), 5.83 (m, 1H), 5.16 (d (br), 1H, J = 7.6), 4.96 (m, 1H), 4.17 (m, 4H), 3.21 (m, 2H), 2.33 (s, 3H), 1.21 (t, 3H, J = 7.1). HRMS: C 27 H 28 alculated for C21H22N3O3, 442.2131; found, 442.2133.

[0522] Ethyl (3-(2-fluorobenzyl)-5-phenylpyrazin-2-yl)phenylalaninate (N-78): Obtained as an oil (0.19 g, 40%) after chromatography on silica gel (cyclohexane-ethyl acetate 94 / 6) from L-3 and PheOEt, HCl. 1 1H NMR (CDCl3, 400 MHz): 8.44 (s, 1H), 7.94 - 7.91 (m, 2H), 7.48 - 7.44 (m, 2H), 7.38 - 7.34 (m, 1H), 7.28 - 7.22 (m, 5H), 7.11 - 7.05 (m, 4H), 5.10 - 5.08 (m, 1H), 5.04 - 4.99 (m, 1H), 4.20 - 4.09 (m, 4H), 3.28 - 3.23 (m, 1H), 3.18 - 3.13 (m, 1H), 1.23 - 1.20 (t, 3H, J = 7.9). HRMS: C 28 H 27 alculated for C22H23FN3O2, 456.2087; found, 456.2096.

[0523] Ethyl 2-((3-(2-fluorobenzyl)-5-phenylpyrazine-2-yl)amino)-3-(m-tolyl)propanoate (N-79): From L-3 and B-6, an oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 95 / 5) (0.34 g, 69%). 1 H NMR (CDCl3, 400 MHz): 8.42 (s, 1H), 7.91 (m, 2H), 7.45 (m, 2H), 7.36 (m, 1H), 7.23 (m, 2H), 7.16-7.04 (m, 4H), 6.95 (m, 1H), 6.88 (m, 1H), 5.06 (d(br), 1H, J = 7.3), 4.97 (m, 1H), 4.15 (m, 4H), 3.20 (dd, 1H, J = 5.5, 13.7), 3.10 (dd, 1H, J = 6.7, 13.7), 2.31 (s, 3H), 1.21 (t, 3H, J = 7.1). HRMS: C 29 H 29 FN3O2 Calculated value: 470.2244, Measured value: 470.2253.

[0524] Ethyl 2-((3-(2-fluorobenzyl)-5-phenylpyrazine-2-yl)amino)-3-(3-methoxy Siphenyl)propanoate (N-80): From L-3 and B-3, an oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 94 / 6) (0.32 g, 63%). 1 H NMR (CDCl3, 400 MHz): 8.42 (s, 1H), 7.91 (m, 2H), 7.45 (m, 2H), 7.36 (m, 1H), 7.23 (m, 2H), 7.16 (m, 1H), 7.06 (m, 2H), 6.78 (m, 1H), 6.68 (m, 2H), 5.08 (d(br), 1H, J = 7.2), 4.99 (m, 1H), 4.16 (m, 4H), 3.77 (s, 3H), 3.23 (dd, 1H, J = 5.6, 13.9), 3.12 (dd, 1H, J = 6.4, 13.9), 1.22 (t, 3H, J = 7.1). HRMS: C 29 H 29 Calculated value for FN3O3: 486.2193, Measured value: 486.2182.

[0525] Ethyl 2-((3-(2-fluorobenzyl)-5-phenylpyrazine-2-yl)amino)-3-(furan-2-yl)propanoate (N-81): From L-3 and B-7, an oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 95 / 5) (0.29 g, 62%). 1 H NMR (CDCl3, 400 MHz): 8.42 (s, 1H), 7.92 (m, 2H), 7.45 (m, 2H), 7.36 (m, 1H), 7.26 (m, 3H), 7.09 (m, 2H), 6.24 (dd, 1H, J = 1.9, 3.2), 5.95 (d, 1H, J = 3.1), 5.28 (d(br), 1H, J = 7.6), 5.01 (m, 1H), 4.19 (m, 4H), 3.77 (s, 3H), 3.26 (m, 2H), 1.24 (t, 3H, J = 7.1). HRMS: C 26 H 25 Calculated value for FN3O3: 446.1880, Measured value: 446.1873.

[0526] Ethyl 2-((3-(2-fluorobenzyl)-5-phenylpyrazine-2-yl)amino)-3-(5-methyl Fran-2-il propanoate (N-82): From L-3 and B-8, an oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 95 / 5) (0.23 g, 48%). 1 H NMR (CDCl3, 400 MHz): 8.42 (s, 1H), 7.91 (m, 2H), 7.45 (m, 2H), 7.36 (m, 1H), 7.25 (m, 2H), 7.08 (m, 2H), 5.82 (m, 2H), 5.27 (d(br), 1H, J = 7.6), 4.97 (m, 1H), 4.19 (m, 4H), 3.77 (s, 3H), 3.20 (d, 2H, J = 5.8), 2.23 (s, 3H), 1.24 (t, 3H, J = 7.1). HRMS: C 27 H 27 Calculated value for FN3O3: 460.2036, Measured value: 460.2044.

[0527] Ethyl 3-(5-ethylfuran-2-yl)-2-((3-(2-fluorobenzyl)-5-phenylpyrazine-2-yl)amino)propanoate (N-83): L-3 and B-10 were chromatographed on silica gel (cyclohexane-ethyl acetate). (95 / 5) was obtained as an oily substance afterwards (0.19 g, 46%). 1 H NMR (CDCl3, 400 MHz): 8.41 (s, 1H), 7.91 (m, 2H), 7.46 (m, 2H), 7.34 (m, 1H), 7.25 (m, 2H), 7.07 (m, 2H), 5.82 (m, 2H), 5.27 (d(br), 1H, J = 7.3), 4.97 (m, 1H), 4.20 (m, 4H), 3.77 (s, 3H), 3.20 (d, 2H, J = 5.1), 2.57 (q, 2H, J = 7.5), 1.25 (t, 3H, J = 7.1), 1.20 (t, 3H, J = 7.5). HRMS: C 28 H 29 Calculated value for FN3O3: 474.2193, Measured value: 474.2198.

[0528] Ethyl (3-(2-chlorobenzyl)-5-phenylpyrazine-2-yl)phenylalaninate (N-84): Chromatography on silica gel from L-4 and PheOEt,HCl (cyclohexane-vinegar Ethyl acid (96 / 4) was used to obtain an oily substance (0.19 g, 68%). 1 H NMR (CDCl3): 8.44 (s, 1H), 7.91 (m, 2H), 7.44 (m, 3H), 7.35 (m, 1H), 7.26-7.16 (m, 6H), 7.05 (m, 2H), 5.00 (m, 2H), 4.24 (m, HRMS: C 28 H 27 Calculated value for ClN3O2: 472.1792; Measured value: 472.1784.

[0529] Ethyl 2-((3-(2-chlorobenzyl)-5-phenylpyrazine-2-yl)amino)-3-(furan-2-yl)propanoate (N-85): From L-4 and B-7, an oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 96 / 4) (0.44 g, 65%). 1 H NMR (CDCl3): 8.44 (s, 1H), 7.91 (m, 2H), 7.45 (m, 3H), 7.35 (m, 1H), 7.25-7.15 (m, 4H), 6.22 (m, 1H), 5.92 (m, 1H), 5.18 (m, 1H), 5.00 (m, 1H), 4.28 (m, 2H), 4.19 (q, J = 7.1 Hz, 2H), 3.24 (d, J = 5.5 Hz, 2H), 1.24 (t, J = 7.1 Hz, 3H). HRMS: C 26 H 25 Calculated value for ClN3O3: 462.1584; Measured value: 462.1576.

[0530] Ethyl 2-((3-(2-chlorobenzyl)-5-phenylpyrazine-2-yl)amino)-3-(5-methyl Lan-2-yl)propanoate (N-86): From L-4 and B-8, an oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 95 / 5) (0.11 g, 36%). 1 H NMR (CDCl3): 8.43 (s, 1H), 7.91 (m, 2H), 7.43 (m, 3H), 7.35 (m, 1H), 7.20 (m, 3H), 6.22 (m, 1H), 5.80 (m, 2H), 5.19 (d (br), 1H, J = 7.6), 4.98 (m, 1H), 4.28 (m, 2H), 4.20 (m, 2H), 3.19 (m, 2H), 2.21 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H). HRMS: C 27 H 27 Calculated value for ClN3O3: 476.1741; Measured value: 476.1744.

[0531] Ethyl (3-(3-fluorobenzyl)-5-phenylpyrazine-2-yl)phenylalaninate (N-87): Chromatography on silica gel from L-6 and PheOEt,HCl (cyclohexane-vinegar Ethyl acid (94:6) was subsequently obtained as an oily substance (0.40 g, 57%). 1 H NMR (CDCl3): 8.45 (s, 1H), 7.95 (m, 2H), 7.48 (m, 2H), 7.38 (m, 1H), 7.36 - 7.21 (m, 4H), 7.10 - 6.92 (m, 5H), 5.02 (m, 1H), 4.85 (d(br), 1H, J = 7.5), 4.16 (q, 2H, J = 7.2), 4.11 (s, 2H), 3.21 (dd, 1H, J = 5.4, 13.8), 3.13 (dd, 1H, J = 5.9, 13.8), 1.22 (t, J = 7.1 Hz, 3H). HRMS: C 28 H 27 Calculated value for FN3O2: 456.2087; Measured value: 456.2067.

[0532] Ethyl 2-((3-(3-fluorobenzyl)-5-phenylpyrazine-2-yl)amino)-3-(furan-2-yl)propanoate (N-88): From L-6 and B-7, an oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 95:5) (0.22 g, 57%). 1 H NMR (CDCl3): 8.44 (s, 1H), 7.95 (m, 2H), 7.48 (m, 2H), 7.37 (m, 1H), 7.28 (m, 2H), 7.06 (m, 1H), 6.96 (m, 2H), 6.24 (dd, 1H, J = 2.0, 3.2), 5.89 (dd, 1H, J = HRMS: C 26 H 25 Calculated value for FN3O3: 446.1880; Measured value: 446.1883.

[0533] Ethyl 2-((3-(3-fluorobenzyl)-5-phenylpyrazine-2-yl)amino)-3-(5-methyl Fran-2-il propanoate (N-89): From L-6 and B-8, an oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 95:5) (0.24 g, 57%). 1 H NMR (CDCl3): 8.43 (s, 1H), 7.93 (m, 2H), 7.47 (m, 2H), 7.37 (m, 1H), 7.28 (m, 1H), 7.06 (m, 1H), 6.96 (m, 2H), 5.82 (m, 1H), 5.78 (m, 1H), 5.06 (d(br), 1H, J =7.9), 4.93 (m, 1H), 4.18 (m, 4H), 3.20 (d, 2H, J = 5.2), 2.22 (s, 3H), 1.24 (t, 3H, J = 7.1). 27 H 27 Calculated value for FN3O3: 460.2036; Measured value: 460.2039.

[0534] Ethyl 3-(5-ethylfuran-2-yl)-2-((3-(3-fluorobenzyl)-5-phenylpyrazine-2-yl)amino)propanoate (N-90): From L-6 and B-10, chromatography on silica gel (cyclohexane-ethyl acetate) (95:5) It was later obtained as an oily substance (0.20 g, purity 90%). 1 H NMR (CDCl3): 8.43 (s, 1H), 7.94 (m, 2H), 7.47 (m, 2H), 7.37 (m, 1H), 7.27 (m, 1H), 7.06 (m, 1H), 6.96 (m, 2H), 5.82 (m, 1H), 5.78 (m, 1H), 5.06 (d(br), 1H, J HRMS: C 28 H 29 Calculated value for FN3O3: 474.2193; Measured value: 474.2199.

[0535] Ethyl 2-((3-(3-fluorobenzyl)-5-phenylpyrazine-2-yl)amino)-3-(m-tolyl)propanoate (N-91): From L-6 and B-6, an oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 95:5) (0.35 g, 74%). 1 H NMR (CDCl3): 8.45 (s, 1H), 7.94 (m, 2H), 7.47 (m, 2H), 7.37 (m, 1H), 7.23 (m, 1H), 7.14 (m, 1H), 7.07 (m, 1H), 6.93 (m, 3H), 6.81 (m, 1H), 4.96 (m, 1H), 4.82 (d(br), 1H, J = 7.4), 4.18 (m, 4H), 3.17 (dd, 1H, J = 5.5, 13.7), 3.09 (dd, 1H, J = 6.2, 13.7), 2.32 (s, 3H), 1.21 (t, 3H J = 7.1). HRMS: C 29 H 29Calculated value for FN3O2: 470.2244; Measured value: 470.2249.

[0536] Ethyl 2-((3-(3-fluorobenzyl)-5-phenylpyrazine-2-yl)amino)-3-(3-methoxy Cyphenyl)propanoate (N-92): From L-6 and B-3, an oily substance was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 95:5) (0.22 g, 45%). 1 H NMR (CDCl3): 8.44 (s, 1H), 7.94 (m, 2H), 7.47 (m, 2H), 7.36 (m, 1H), 7.19 (m, 2H), 6.93 (m, 3H), 6.79 (m, 1H), 6.60 (m, 2H), 4.97 (m, 1H), 4.81 (d(br), 1H, J = 7.7), 4.18 (m, 4H), 3.77 (s, 3H), 3.19 (dd, 1H, J = 5.7, 13.8), 3.10 (dd, 1H, J = 5.9, 13.8), 1.21 (t, 3H J = 7.1). HRMS: C 29 H 29 Calculated value for FN3O3: 486.2193; Measured value: 486.2209.

[0537] Ethyl (3-(4-fluorobenzyl)-5-phenylpyrazine-2-yl)phenylalaninate (N-93): Chromatography on silica gel from L-7 and PheOEt,HCl (cyclohexane-vinegar Ethyl acid (94:6) was subsequently obtained as an oily substance (0.12 g, purity 80%). 1H NMR (CDCl3): 8.44 (s, 1H), 7.96 (m, 2H), 7.48 (m, 2H), 7.38 (m, 1H), 7.27 - 7.22 (m, 3H), 7.16 (m, 2H), 7.01 - 6.94 (m, 4H), 5.02 (m, 1H), 4.88 (d(br), 1H, J = 7.5), 4.16 (q, 2H, J = 7.0), 4.10 (s, 2H), 3.24 (dd, 1H, J = 5.5, 13.8), 3.14 (dd, 1H, J = 5.9, 13.8), 1.24 (t, J = 7.1 Hz, 3H). HRMS: C 28 H 27 Calculated value for FN3O2: 456.2087; Measured value: 456.2072.

[0538] Ethyl 2-(3-(2-methoxybenzyl)-5-phenylpyrazine-2-ylamino)-3-phenylpropanoate (N-94): Chromatography on silica gel from L-5 and PheOEt,HCl (cyclohexane-vinegar Ethyl acid (96:4) was subsequently obtained as an oily substance (0.1 g, 28%). 1 H NMR (CDCl3): 8.37 (s, 1H), 7.97 (m, 2H), 7.47 (m, 2H), 7.37 (m, 2H), 7.21 (m, 4H), 7.02 (m, 2H), 6.93 (m, 1H), 6.85 (m, 1H), 6.03 (d(br), 1H, J = 7.7), 5.08 (m, 1H), 4.17 (m, 4H), 3.72 (s, 3H), 3.20 (dd, 1H, J = 6.0, 13.9), 3.12 (dd, 1H, J = 6.2, 13.9), 1.21 (t, 3H, J = 7.2). HRMS: C 29 H 29 Calculated value for N3O3: 468.2287; Measured value: 468.2298.

[0539] General procedure for debenzylation of N-aryl α-aminoester N containing O-benzyl The compound under consideration (0.53 mmol), ammonium formate (0.17 g, 2.64 mmol), and 10% palladium-carbon (30 mg, 0.026 mmol) were heated under reflux in ethanol (15 mL) for 2 hours. The suspension was filtered, and the filtrate was concentrated to dryness to obtain a fairly clean deprotected product as described below.

[0540] Ethyl (3-benzyl-5-(4-hydroxyphenyl)pyrazine-2-yl)tyrosinate (N-95): From N-9, after chromatography on silica gel (dichloromethane-ethanol 97 / 3) It was obtained as a white solid (0.18 g, 72%). 1 H NMR (CDCl3): 8.28 (s, 1H), 7.79 - 7.72 (m, 2H), 7.29 - 7.19 (m, 3H), 7.19 - 7.12 (m, 2H), 6.88 - 6.75 (m, 4H), 6.66 - 6.59 (m, 2H), 4.92 - 4.75 (m, 2H), 4.13 (q, J = 7.1 Hz, 2H), 4.09 (s, 2H), 3.06 (dd, J = 14.0, 5.4 Hz, 1H), 2.97 (dd, J= 14.0, 6.0 Hz, 1H), 1.19 (t, J= 7.1 Hz, 3H). HRMS: C 28 H 28 Calculated value for N3O4: 470.2080; Measured value: 470.2104.

[0541] Ethyl 2-((3-benzyl-5-(4-hydroxyphenyl)pyrazine-2-yl)amino)-3-(5-methyl Refrain-2-Il Propanoate (N-96): From N-29, after chromatography on silica gel (cyclohexane-ethyl acetate 3 / 1) It was obtained as a glassy substance (0.21 g, 81%). 1 H NMR (CDCl3): 8.29 (s, 1H), 7.76 (m, 2H), 7.28 (m, 5H), 6.84 (m, 2H), 5.98 (m, 1H), 5.76 (d(br), 1H, J = 3), 5.69 (s (br), 1H), 5.69 (d (br), 1H), 4.88 (m, 1H), 4.17 (m, 2H), 4.14 (s, 2H), 3.13 (dd, 2H, J = 3.0, 5.6), 2.23 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H). HRMS: C 27 H 28 Calculated value for N3O4: 459.2112; Measured value: 459.2108.

[0542] Ethyl (3-benzyl-5-phenylpyrazine-2-yl)tyrosinate (N-97): From N-65, a white solid was obtained after chromatography on silica gel (dichloromethane-ethanol 98.5 / 1.5) (0.24 g, 46%). 1 H NMR (CDCl3): 8.39 (s, 1H), 7.98 - 7.88 (m, 2H), 7.50 - 7.40 (m, 2H), 7.38 - 7.31 (m, 1H), 7.31 - 7.22 (m, 3H), 7.22 - 7.17 (m, 2H), 6.84 - 6.76 (m, 2H), 6.67 - 6.59 (m, 2H), 4.96 (s, 1H), 4.94 - 4.86 (m, 2H), 4.12 (s, 2H), 4.19 - 4.07 (m, 2H), 3.13 - 3.03 (m, 1H), 3.03 - 2.92 (m, 1H), 1.19 (t, 3H, J = 7.1). HRMS: C 28 H 28 Calculated value for N3O3: 454.2131; Measured value: 454.2104.

[0543] General Procedure for the Hydrolysis of the Corresponding N - Aryl α - Amino Acid O from N - Aryl α - Amino Ester N In a round - bottom flask, the ester under investigation (0.0046 mol) and powdered sodium hydroxide (0.54 g, 0.0137 mol) were mixed. The air was replaced with argon and dry tetrahydrofuran (30 mL) was added. This was stirred overnight under an inert atmosphere, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate and concentrated to dryness to obtain the corresponding acid as described below.

[0544] (3 - Benzyl - 5 - phenylpyrazin - 2 - yl)phenylalanine (O - 1): Obtained as a hard foamy substance from N - 5 (1.7 g, 91 %). 1 H NMR (DMSO - d6): 12.61 (s, 1H), 8.44 (s, 1H), 7.90 (m, 2H), 7.40 (m, 2H), 7.32 - 7.15 (m, 11H), 6.84 (m, 1H), 4.66 (m, 1H), 4.30 (d, 1H, J = 14.5), 4.06 (d, 1H, J = 14.5), 3.21 (m, 2H). HRMS: C 26 H 24 Calculated for C₂₄H₂₁N₃O₂, 410.1869; Found, 410.1875.

[0545] 2 - ((3 - Benzyl - 5 - (4 - (benzyloxy)phenyl)pyrazin - 2 - yl)amino) - 3 - (4 - (ben zyloxy)phenyl)propanoic acid (O - 2): Obtained as a hard foamy substance from Intermediate N - 8 or N - 9 (0.42 g, 87 %). 1H NMR (CDCl3): 8.31 (s, 1H), 7.88 - 7.81 (m, 2H), 7.49 - 7.29 (m, 11H), 7.24 - 7.16 (m, 3H), 7.13 - 7.08 (m, 2H), 7.08 - 7.01 (m, 2H), 6.95 - 6.87 (m, 2H), 6.86 - 6.79 (m, 2H), 5.11 (s, 2H), 5.03 (s, 2H), 4.86 - 4.76 (m, 1H), 4.71 (d, 1H, J = 6.3), 4.06 (d, 1H, J = 15.4), 4.00 (d, 1H, J = 15.5), 3.19 (dd, 1H, J = 14.2, 5.2), 3.01 (dd, 1H, J = 14.2, 6.9). 40 H 36 Calculated value for N3O4: 622.2706; Measured value: 622.2763.

[0546] (3-benzyl-5-(4-(benzyloxy)phenyl)pyrazine-2-yl)phenylalanine (O-3): From N-66, a foamy substance containing some ethyl acetate was obtained (3.73 g). 1 H NMR (DMSO-d6): 12.60 (s, 1H), 8.36 (s, 1H), 7.83 (m, 2H), 7.46 (m, 2H), 7.40 (m, 2H), 7.32 (m, 1H), 7.29 - 7.15 (m, 9H), 7.04 (m, 2H), 6.71 (m, 1H), 5.13 (s, HRMS: C 33 H 30 Calculated value for N3O3: 516.2287; Measured value: 516.2273.

[0547] 2-((3-benzyl-5-(4-(benzyloxy)phenyl)pyrazine-2-yl)amino)-3-(3-propylphenyl)propanoic acid (O-4): This compound was obtained from N-70 as a glassy substance still containing some ethyl acetate (0.76 g). 1 H NMR (CDCl3): 8.33 (s, 1H), 7.86 (m, 2H), 7.34 (m, 11H), 7.09 (m, 5H), 6.96 (s, 1H), 6.87 (m, 1H), 4.81 (m, 1H), 4.69 (m, 1H), 4.07 (d, 1H, J = 15.4), 3.93 (d, 1H, J = 15.4), 3.27 (dd, 1H, J = 14.2, 5.2), 3.05 (dd, 1H, J = 14.2, 7.6), 2.56 (m, 2H), 1.62 (m, 2H), 0.93 (t, 3H, J = 7.3). HRMS: C 36 H 36 Calculated value for N3O3: 558.2757; Measured value: 558.2746.

[0548] 2-((3-benzyl-5-(4-(benzyloxy)phenyl)pyrazine-2-yl)amino)-3-(furan-2-yl)propanoic acid (O-5): From N-67, a foamy substance containing some ethyl acetate was obtained (0.8 g). 1 H NMR (CDCl3): 10.29 (s(br), 1H), 8.33 (s, 1H), 7.87 (m, 2H), 7.49 (m, 2H), 7.4 1 (m, 2H), 7.37- 7.23 (m, 7H), 7.08 (m, 2H), 6.25 (dd, 1H, J = 1.9, 3.4), 5.95 (dd, 1H, J = 0.5, 3.4), 5.14 (s, 2H), 5.0 (d(br), 1H, J = 7.4), 4.85 (m, 1H), 4.15 (m, 2H), 3.28 (dd, 1H, J = 5.0, 15.4), 3.20 (dd, 1H, J = 6.5, 15.0). HRMS: C 31 H 28 Calculated value for N3O4: 506.2080; Measured value: 516.2109.

[0549] 2-((3-benzyl-5-(4-(benzyloxy)phenyl)pyrazine-2-yl)amino)-3-(4,5-dimethylfuran-2-yl)propanoic acid (O-6): From N-69, a foamy substance containing some ethyl acetate was obtained (0.61 g). 1 H NMR (CDCl3): 9.16 (s(br), 1H), 8.32 (s, 1H), 7.87 (m, 2H), 7.49- 7.22 (m, 10H), 7.08 (m, 2H), 5.77 (s, 1H), 5.14 (s, 2H), 5.01 (d(br), 1H, J = 6.6), 4.76 (m, 1H), 4.15 (m, 2H), 3.18 (dd, 1H, J = 4.9, 15.3), 3.10 (dd, 1H, J = 7.1, 15.3), 2.14 (s, 3H), 1.89 (s, 3H). HRMS: C 33 H 32 Calculated value for N3O4: 534.2393; Measured value: 534.2410.

[0550] 2-((3-benzyl-5-(4-(benzyloxy)phenyl)pyrazine-2-yl)amino)-3-(5-ethylfuran-2-yl)propanoic acid (O-7): From N-68, a foamy substance containing some ethyl acetate was obtained (0.59 g). 1 H NMR (CDCl3): 9.16 (s(br), 1H), 8.32 (s, 1H), 7.87 (m, 2H), 7.47 (m, 2H), 7.41 (m, 2H), 7.37- 7.22 (m, 9H), 7.08 (m, 2H), 5.89 (m, 2H), 5.14 (s, 2H), 4.96 (d(br), 1H, J = 6.4), 4.80 (m, 1H), 4.12 (m, 2H), 3.23 (dd, 1H, J = 4.9, 15.2), 3.14 (dd, 1H, J = 7.1, 15.2), 2.57 (q, 2H, J = 7.6), 1.19 (t, 3H, J = 7.6). HRMS: C 33 H 32 Calculated value for N3O4: 534.2393; Measured value: 534.2405.

[0551] (3-benzyl-5-(4-(benzyloxy)-3-fluorophenyl)pyrazine-2-yl)phenyl Ranine (O-8): It was obtained from N-10 as a hard, foamy substance (0.56 g, 92%). 1 H NMR (DMSO-d6): 12.61 (s, 1H), 8.42 (s, 1H), 7.73 (m, 1H), 7.67 (m, 1H), 7.47 (m, 2H), 7.40 (m, 2H), 7.34 (m, 1H), 7.29 - 7.16 (m, 11H), 6.82 (d (br), 1H, J = 8.2), 5.20 (s, 2H), 4.66 (m, 1H), 4.27 (d, 1H, J = 15.0), 4.02 (d, 1H, J = 15.0), 3.19 (m, 2H). HRMS: C 33 H 29 Calculated value for FN3O3: 535.2225; Measured value: 535.2239.

[0552] General procedure for debenzylation of N-aryl α-amino acid O containing O-benzyl The O-benzyl derivative under consideration (1.5 mmol) and ammonium formate (2.8 g, 0.044 mol) were dissolved in isopropanol (50 mL). 10% palladium-carbon (0.16 g, 0.15 mmol) was added, and the suspension was heated under reflux for 1 hour. This was cooled, filtered, and concentrated to dryness under high vacuum. This yielded a foamy substance still containing some isopropanol. In some cases, some unreacted compounds were detected, and the crude residue was then subjected to a second hydrogenation. Several attempts were made to further purify the resulting amino acids (with considerable loss), as described below, but it was found that the crude compound was suitable for use in the next step, provided it was completely dried under high vacuum (to remove all ammonium formate).

[0553] (3-benzyl-5-(4-hydroxyphenyl)pyrazine-2-yl)tyrosine (O-9): The residue is obtained from O-2, dispersed in water, filtered, and the resulting solid is dried and treated with 0.5 M hydrochloric acid. The compound was resuspended, filtered, and dried completely again to obtain a pure compound (0.37 g, 45%). 1 H NMR (DMSO-d6): 8.31 (s, 1H), 7.72 (m, 2H), 7.22 (m, 5H), 7.02 (m, 2H), 6.82 (m, 2H), 6.61 (m, 2H), 6.54 (bs, 1H), 4.54 (m, 1H), 4.28 (d, 1H, J = 14.6), 4.02 (d, 1H, J = 14.6), 3.06 (m, 2H). HRMS: C 26 H 24 Calculated value for N3O4: 442.1767; measured value Value: 442.1773.

[0554] (3-benzyl-5-(4-hydroxyphenyl)pyrazine-2-yl)phenylalanine (O-10): The residue is obtained from O-3, dispersed in water, filtered, and the resulting solid is dried and treated with 0.5 M hydrochloric acid. The compound was resuspended, filtered, and dried completely again to obtain a pure compound (2.06 g, corresponding 70% from esters. 1 H NMR (DMSO-d6): 8.34 (s, 1H), 7.72 (m, 2H), 7.20 (m, 5H), 7.08 (m, 5H), 6.82 (m, 2H), 6.34 (bs, 1H), 4.36 (m, 1H), 4.05 (d, 1H, J = HRMS: C 26 H 24 Calculated value for N3O3: 426.1818; Measured value: 426.1806.

[0555] 2-((3-benzyl-5-(4-hydroxyphenyl)pyrazine-2-yl)amino)-3-(3-propylphenyl)propanoic acid (O-11): A residue was obtained from O-4, dispersed in water, made basic with ammonia, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to dryness to obtain the compound as a glassy substance still containing a small amount of ethyl acetate (0.5 g, 71% from the initial ester). 1H NMR (DMSO-d6): 9.56 (s(br), 1H), 8.38 (s, 1H), 7.70 (m, 2H), 7.20 (m, 6H), 7.04 (m, 5H), 6.80 (m, 2H), 6.52 (m, 1H), 4.61 (m, HRMS: C 29 H 30 Calculated value for N3O3: 468.2287; Measured value: 468.2286.

[0556] 2-((3-benzyl-5-(4-hydroxyphenyl)pyrazine-2-yl)amino)-3-(furan-2-yl)propanoic acid (O-12): From O-5, a hard, foamy substance still containing small amounts of isopropanol after extensive drying under high vacuum. This compound was obtained as follows (0.54 g, 85% from the initial ester N-67). 1 H NMR (DMSO-d6): 9.56 (s(br), 1H), 8.34 (s, 1H), 7.73 (m, 2H), 7.46 (dd, 1H, J = 0.7, 1.8), 7.31-7.14 (m, 6H), 6.80 (m, 2H), 6.61 (d, 1H, J = 7.3), 6.30 (dd, 1H, J = 1.8, 3.1), 6.07 (dd, 1H, J = 0.7, 3.1), 4.67 (m, 1H), 4.20 (d, 1H, J = 14.8), 4.04 (d, 1H, J = 14.9), 3.24 (m, 2H). HRMS: C 24 H 22 Calculated value for N3O4: 416.1610; Measured value: 416.1606.

[0557] 2-((3-benzyl-5-(4-hydroxyphenyl)pyrazine-2-yl)amino)-3-(4,5-dimethylfuran-2-yl)propanoic acid (O-13): A residue was obtained from O-6, dispersed in water, made basic with ammonia, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated to dryness, and purified by chromatography on silica gel (cyclohexane-ethyl acetate 1 / 1 to 0 / 1) to obtain the compound as a glassy substance still containing some ethyl acetate (0.21 g, 42% from ester N-69). 1 H NMR (DMSO-d6): 12.4 (s, 1H), 9.49 (s(br), 1H), 8.33 (s, 1H), 7.75 (m, 2H), 7.32-7.16 (m, 6H), 6.80 (m, 2H), 6.54 (d, 1H, J = 8.0), HRMS: C 26 H 26 Calculated value for N3O4: 444.1923; Measured value: 444.1937.

[0558] 2-((3-benzyl-5-(4-hydroxyphenyl)pyrazine-2-yl)amino)-3-(5-ethylfuran-2-yl)propanoic acid (O-14): A residue was obtained from O-7, dispersed in water, made basic with ammonia, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to dryness, yielding the compound with a purity of 80% as a glassy substance still containing some ethyl acetate (0.11 g). 1H NMR (DMSO-d6): 9.54 (s(br), 1H), 8.29 (s, 1H), 7.75 (m, 2H), 7.41-7.16 (m, 6H), 6.80 (m, 2H), 5.79 (s(br), 2H), 4.37 (m, 1H), 4.08 (d, 1H, J = 14.5), 3.98 (d, 1H, J = 14.5), 3.24 (dd, 1H, J = 4.6, 15.2), 3.07 (dd, 1H, J = 6.6, 15.2), 2.45 (q, 2H, J = 7.6), 1.06 (t, 3H, J = 7.6). HRMS: C 26 H 26 Calculated value for N3O4: 444.1923; Measured value: 444.1930.

[0559] (3-benzyl-5-(3-fluoro-4-hydroxyphenyl)pyrazine-2-yl)phenylalanine (O-15): From O-8, using ethanol as the solvent, after extensive drying under high vacuum, a small amount of ethanol The compound was obtained as a hard, foamy substance still containing the ruth (0.43 g, 92%). 1 H NMR (DMSO-d6): 8.37 (s, 1H), 7.64 (m, 1H), 7.54 (m, 1H), 7.26- 7.13 (m, 11H), 6.99 (m, 1H), 6.61 (d (br), 1H, J = 7.4), 4.55 (m, 1H), 4.18 (d, 1H, J = 14.7), 3.98 (d, 1H, J = 14.7), 3.23 (dd, 1H, J = 4.7, 13.6), 3.13 (dd, 1H, J = 8.9, 13.6).HRMS: C 26 H 23 Calculated value for FN3O3: 444.1723; Measured value: 444.1732.

[0560] General procedure for the synthesis of O-protected imidazo[1,2-a]pyrazine P from α-aminoester N via steps o and p. Place the N-pyrazyl α-aminoester (1.0 mmol) and hydroxyl in a sealable container. Sodium phosphate (0.06 g, 1.5 mmol) was weighed. The air was replaced with argon, and anhydrous THF (5 mL) was injected. This was stirred overnight at 20 °C under an inert atmosphere. The corresponding equivalent amounts of acetic anhydride (0.28 mL, 3.0 mmol) or pivalic anhydride were added to provide the required O-protecting groups. After stirring for a further 3 hours at room temperature, this was diluted with ethyl acetate, washed with water and brine, and concentrated to dryness. Traces of acetic acid and acetic anhydride were removed by azeotrope with toluene, then with cyclohexane, and the residue was further purified as described below.

[0561] 8-Benzyl-2-(sec-butyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate (P-1): From N-1, it was obtained as a white solid after recrystallization with n-heptane (0.11 g, 48%). 1 H NMR (CDCl3): 7.92 (m, 2H), 7.79 (s, 1H), 7.66 (m, 2H), 7.47 (m, 2H), 7.39 (m, 1H), 7.32 (m, 2H), 7.23 (m, 1H), 4.63 (s, 2H), 2.89 (six, 1H, J = 7.5), 2.49 (s, 3H), 1.89 (m, 1H), 1.74 (m, 1H), 1.39 (d, 3H, J = 7.5), 0.93 (t, 3H, J = 7.5). HRMS: C 25 H 26 Calculated value for N3O2: 400.2025; Measured value: 400.2024.

[0562] 8-benzyl-2-(cyclopentylmethyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl Ceteate (P-2): From N-2, a powder was obtained after concentration and drying (0.21 g, 88%). 1 H NMR (CDCl3): 7.92 (m, 2H), 7.80 (s, 1H), 7.65 (m, 2H), 7.47 (m, 2H), 7.39 (m, 1H), 7.32 (m, 2H), 7.23 (m, 1H), 4.63 (s, 2H), 2.78 (d, 2H, J = 7.4), 2.50 (s, 3H), 2.38 (m, 1H), 1.80 (m, 2H), 1.64 (m, 4H), 1.29 (m, 2H). HRMS: C 27 H 28 N3O2 The calculated value is 426.2181; the measured value is 426.2180.

[0563] 8-benzyl-2-(cyclohexylmethyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl Ceteate (P-3): From N-3, it was obtained as a powder after recrystallization with n-heptane (0.24 g, 72%). 1 H NMR (CDCl3): 7.92 (m, 2H), 7.80 (s, 1H), 7.65 (m, 2H), 7.47 (m, 2H), 7.39 (m, 1H), 7.32 (m, 2H), 7.23 (m, 1H), 4.63 (s, 2H), 2.78 (d, 2H, J = 7.2), 2.50 (s, 3H), 1.87 (m, 1H), 1.75 (m, 5H), 1.27 (m, 3H), 1.05 (m, 2H). HRMS: C 28 H 30 N3O2 The calculated value is 440.2338; the measured value is 440.2326.

[0564] 8-benzyl-2-(bicyclo[2.2.1]heptan-2-ylmethyl)-6-phenylimidazo[1,2-a]p Radin-3-yl acetate (P-4): From N-4, after recrystallization with n-heptane, a mixture of two diastereoisomers is obtained as a powder and This was obtained (0.58 g, 52%). 1 H NMR (CDCl3): 7.92 (m, 2H), 7.80 (s, 0.4H), 7.79 (s, 0.6H), 7.65 (m, 2H), 7.47 (m, 2H), 7.39 (m, 1H), 7.32 (m, 2H), 7.23 (m, 1H), 4.63 (m, 2H), 2.85 - 2.57 (m , 2H), 2.51 and 2.50 (2s, 3H), 2.42 (m, 0.6H), 2.26 (m, 1H), 2.11 (m, 1H), 2.04 (m, 0.4H), 1.84 (m, 0.6H), 1.73 (m, 0.8H), 1.63 - 1.15 (m, 6H), 0.82 (m, 0.6H). HRMS: C 29 H 30 Calculated value for N3O2: 452.2338; Measured value: 452.2355.

[0565] 2,8-Dibenzyl-5-methyl-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate (P-5): It was obtained from N-6 as a glassy substance (0.3 g, 76%). 1 1H NMR (CDCl3): 1 HRMS: C 29 H 26 Calculated value for N3O2: 448.2025; Measured value: 448.2020.

[0566] 8-Benzyl-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate (P-6): From N-34, a beige solid was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 4:1) (0.10 g, 36%). 1 H NMR (CDCl3): 7.92 (m, 2H), 7.83 (s, 1H), 7.63 (m, 2H), 7.47 (m, 2H), 7.42-7.30 (m, 4H), 7.23 (m, 1H), 6.35 (m, 1H), 6.16 (m, 1H), 4.64 (s, 2H), 4.24 (s, 2H), 2.36 (s, 3H). HRMS: C 26 H 22 Calculated value for N3O3: 424.1661; Measured value: 424.1607.

[0567] 2,8-Dibenzyl-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate (P-7): From N-5, a yellowish solid was obtained after recrystallization from cyclohexane (0.17 g, 50 %). 1 H NMR (CDCl3): 7.92 (m, 2H), 7.80 (s, 1H), 7.64 (m, 2H), 7.47 (m, 2H), 7.40 (m, HRMS: C 28 H 24 Calculated value for N3O2: 434.1869; Measured value: 434.1825.

[0568] 8-Benzyl-6-phenyl-2-(1-phenylethyl)imidazo[1,2-a]pyrazine-3-yl acetate (P-8): From N-7, a white powder was obtained after recrystallization from n-heptane (0.12 g, 44%). 1 H NMR (CDCl3): 7.90 (m, 2H), 7.74 (s, 1H), 7.68 (m, 2H), 7.46 (m, 2H), 7.40 (m, 1H), 7.33 (m, 5H), 7.25 (m, 2H), 4.68 (d, 1H, J = 13.8), 4.63 (d, 1H, J = 13.8), 4.34 (q, 1H, J = 6.7), 2.14 (s, 3H), 1.83 (d, 3H, J = 6.7). HRMS: C 29 H 26 Calculated value for N3O2: 448.2025; Measured value: 448.2031.

[0569] 8-Benzyl-2-phenethyl-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate (P-9): It was obtained from N-71 as a white powder after recrystallization from n-heptane (0.22 g, 67%). 1 H NMR (CDCl3): 7.92 (m, 2H), 7.81 (s, 1H), 7.64 (m, 2H), 7.47 (m, 2H), 7.40 (m, 1H), 7.35-7.21 (m, 8H), 4.65 (s, 2H), 3.12 (m, 4H), 2.42 (s, 3H). HRMS: C 29 H 26 Calculated value for N3O2: 448.2025; Measured value: 448.2026.

[0570] 8-Benzyl-2-((5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate (P-10): From N-36, a white solid was obtained after chromatography on silica gel (cyclohexane-ethyl acetate 5:1) and recrystallization from cyclohexane (0.14 g, 24%). 1 H NMR (CDCl3): 7.93 - 7.86 (m, 2H), 7.82 (s, 1H), 7.64 - 7.57 (m, 2H), 7.49 - 7.41 (m, 2H), 7.41 - 7.35 (m, 1H), 7.35 - 7.27 (m, 2H), 7.25 - 7.16 (m, 1H), 6.03 - 5.97 (m, 1H), 5.93 - 5.86 (m, 1H), 4.62 (s, 2H), 4.17 (s, 2H), 2.34 (s, 3H), 2.26 (s, 3H). HRMS: C 27 H 24 Calculated value for N3O3: 438.1818; Measured value: 438.1828.

[0571] 8-Benzyl-2-((5-methylfuran-2-yl)methyl)-6-(p-tolyl)imidazo[1,2-a]pyrazine-3-yl acetate (P-11): It was obtained from N-37 as a white solid after recrystallization from n-heptane (0.15 g, 70%). 1 H NMR (CDCl3): 7.82 - 7.79 (m, 3H), 7.62 (m, 2H), 7.33 - 7.20 (m, 5H), 6.01 (d, 1H, J = 1), 5.90 (m, 1H), 4.62 (s, 2H), 4.17 (s, 2H), 2.41 (s, 3H), 2.35 (s, 3H), 2.28 (s, 2H). HRMS: C 28 H 26 Calculated value for N3O3: 452.1974; Measured value: 452.1960.

[0572] 8-Benzyl-2-((5-methylfuran-2-yl)methyl)-6-(m-tolyl)imidazo[1,2-a]pyrazine-3-yl acetate (P-12): It was obtained from N-38 as a white solid after (slow) recrystallization from n-heptane (0.1 g, 53%). 1 H NMR (CDCl3): 7.82 (s, 1H), 7.73 (m, 1H), 7.79 (m, 1H), 7.37 - 7.20 (m, 5H), 6.01 (d, 1H, J = 3), 5.91 (m, 1H), 4.62 (s, 2H), 4.18 (s, 2H), 2.45 (s, 3H), 2.36 (s, 3H), 2.28 (s, 2H). HRMS: C 28 H 26 Calculated value for N3O3: 452.1974; Measured value: 452.1981.

[0573] 8-Benzyl-2-(furan-3-ylmethyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate (P-13): It was obtained from N-35 as a beige solid after recrystallization from n-heptane (0.74 g, 67%). 1 H NMR (CDCl3): 7.92 (m, 2H), 7.83 (s, 1H), 7.63 (m, 2H), 7.47 (m, 2H), 7.40 (m, HRMS: C 26 H 22 Calculated value for N3O3: 424.1661; Measured value: 424.1688.

[0574] 2-((1,3-dioxolan-2-yl)methyl)-8-benzyl-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate (P-14): It was obtained from N-12 as a white solid after recrystallization from n-heptane (0.46 g, 76%). 1 H NMR (CDCl3): 7.92 (m, 2H), 7.85 (s, 1H), 7.62 (m, 2H), 7.47 (m, 2H), 7.40 (m, 1H), 7.32 (m, 2H), 7.23 (m, 1H), 5.29 (t, 1H, J = 4.5), 4.64 (s, 2H), 3.97 - 3.86 (m, 4H), 3.22 (d, 2H, J = 4.5), 2.49 (s, 3H). HRMS: C 25 H 24 Calculated value for N3O3: 430.1767; Measured value: 430.1762.

[0575] 8-Benzyl-2-(4-(benzyloxy)benzyl)-6-(4-(benzyloxy)phenyl)imidazo[1,2-a]pyrazine-3-yl acetate (P-15): From N-9, it was obtained as a brown solid after recrystallization from cyclohexane (0.27 g, 66%). 1 H NMR (CDCl3): 7.84 (m, 2H), 7.71 (s, 1H), 7.61 (m, 2H), 7.48 - 7.29 (m, 12H), 7.25 - 7.20 (m, 3H), 7.06 (m, 2H), 6.94 (m, 2H), 5.14 (s, 2H), 5.09 (s, 2H), 4.62 (s, 2H), 2.17 (s, 3H). HRMS: C 42 H 36 Calculated value for N3O4: 646.2706; Measured value: 646.2728.

[0576] [ka]

[0577] 2-benzyl-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate (P-16): It was obtained from N-32 as a yellow solid after recrystallization from n-heptane (0.22 g, 48%). 1H NMR (CDCl3): 9.08 (m, 1H), 7.94 - 7.90 (m, 3H), 7.50 (m, 2H), 7.43 (m, 1H), 7.36 - 7.24 (m, 5H), 4.19 (s, 2H), 2.27 (s, 3H). HRMS: C 21 H 18 Calculated value for N3O2: 344.1399; Measured value: 344.1389.

[0578] 2-Benzyl-8-methyl-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate (P-17): From N-33, it was obtained as a yellow solid after recrystallization from n-heptane (0.59 g, 88%). 1 H NMR (CDCl37.91 (m, 2H), 7.80 (m, 1H), 7.48 (m, 2H), 7.41 (m, 1H), 7.35 - 7.23 (m, 5H), 4.21 (s, 2H), 2.96 (m, 3H), 2.18 (s, 3H). HRMS: C 22 H 20 Calculated value for N3O2: 358.1556; Measured value: 358.1544.

[0579] 8-Benzyl-2-(furan-2-ylmethyl)-6-(2-methoxyphenyl)imidazo[1,2-a]pyrazine-3-yl acetate (P-18): It was obtained from N-40 as a beige solid after recrystallization from n-heptane (0.27 g, 68%). 1 H NMR (CDCl3): 8.21 (s, 1H), 8.05 (dd, J = 7.7, 1.8 Hz, 1H), 7.59 (dd, J = 7.9, 0.9 Hz, 2H), 7.39 - 7.27 (m, 4H), 7.23 - 7.18 (m, 1H), 7.09 (td, J = 7.6, 1.1 Hz, 1H), 6.99 (dd, J = 8.3, 0.9 Hz, 1H), 6.33 (dd, J = HRMS: C 27 H 24 Calculated value for N3O4: 454.1767; Measured value: 454.1785.

[0580] 8-Benzyl-2-(furan-3-ylmethyl)-6-(2-methoxyphenyl)imidazo[1,2-a]pyrazine-3-yl acetate (P-19): It was obtained from N-41 as a beige solid after recrystallization from n-heptane (0.15 g, 29%). 1 H NMR (CDCl3): 8.21 (s, 1H), 8.07 (dd, J = 7.7, 1.8 Hz, 1H), 7.61 (d, J = 7.4 Hz, 2H), 7.41 - 7.27 (m, 5H), 7.22 (d, J = 7.4 Hz, 1H), 7.15 - 7.06 (m, 1H), 6.99 (d, J = 8.2 Hz, 1H), 6.40 - 6.34 (m, 1H), 4.61 (s, 2H), 3.98 (s, 2H), 3.88 (s, 3H), 2.30 (s, 3H). HRMS: C 27 H 24 Calculated value for N3O4: 454.1767; Measured value: 454.1786.

[0581] 2,8-Dibenzyl-6-(2-methoxyphenyl)imidazo[1,2-a]pyrazine-3-yl acetate (P-20): From N-39, it was obtained as a beige solid after recrystallization from n-heptane (0.22 g, 53%). . 1 H NMR (CDCl3): 8.17 (s, 1H), 8.05 (dd, J = 7.7, 1.8 Hz, 1H), 7.65 - 7.58 (m, 2H), 7.38 - 7.27 (m, 7H), 7.26 - 7.16 (m, 2H), 7.09 (td, J= HRMS: C 29 H 26 Calculated value for N3O3: 464.1974; Measured value: 464.1979.

[0582] 8-Benzyl-2-((5-ethylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate (P-21): It was obtained from N-62 as a white solid after recrystallization from n-heptane (0.27 g, 57%). 1 H NMR (CDCl3): 7.93 - 7.86 (m, 2H), 7.81 (s, 1H), 7.64 - 7.57 (m, 2H), 7.49 - 7.41 (m, 2H), 7.41 - 7.35 (m, 1H), 7.33 - 7.27 (m, 2H), 7.24 - 7.18 (m, 1H), 6.01 (d, J = 3.0 Hz, 1H), 5.93 - 5.87 (m, 1H), 4.62 (s, 2H), 4.17 (s, 2H), 2.61 (q, J = 7.5 Hz, 2H), 2.33 (s, 3H), 1.22 (t, J = 7.5 Hz, 3H). HRMS: C 28 H 26 Calculated value for N3O3: 452.1974; Measured value: 452.2014.

[0583] 8-Benzyl-6-phenyl-2-(thiophen-2-ylmethyl)imidazo[1,2-a]pyrazine-3-yl Acetate (P-22): It was obtained from N-59 as a white solid after recrystallization from n-heptane (0.37 g, 73%). 1 H NMR (CDCl3): 7.92 - 7.87 (m, 2H), 7.80 (s, 1H), 7.65 - 7.58 (m, 2H), 7.49 - 7.42 (m, 2H), 7.42 - 7.34 (m, 1H), 7.34 - 7.27 (m, 2H), 7.25 - 7.20 (m, 1H), 7.19 (dd, J = 5.1, 1.3 Hz, 1H), 6.95 (dd, J = 5.1, 3.5 Hz, 1H), 6.93 - 6.88 (m, 1H), 4.62 (s, 2H), 4.38 (d, J = 0.8 Hz, 2H), 2.30 (s, 3H). HRMS: C 26 H 22 Calculated value for N3O2S: 440.1433; Measured value: 440.1486.

[0584] 8-Benzyl-2-((3-methylthiophen-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate (P-23): It was obtained as a solid from N-60 (0.37 g, 95%). 1 H NMR (CDCl3): 7.92 (m, 2H), 7.79 (s, 1H), 7.64 (m, 2H), 7.47 (m, 2H), 7.39 (m, 1H), 7.32 (m, 2H), 7.23 (m, 1H), 7.10 (d, 1H, J = 5.2), 6.83 (d, 1H, J = 5.2), 4.64 (s, 2H), 4.32 (s, 2H), 2.27 (s, 3H), 2.22 (s, 3H). HRMS: C 27 H 24 For N3O2S Calculated value: 454.1589; Measured value: 454.1591.

[0585] 8-Benzyl-2-((5-ethylthiophen-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate (P-24): It was obtained from N-61 as a white solid after recrystallization from n-heptane (0.25 g, 56%). 1 H NMR (CDCl3): 7.93 (m, 2H), 7.83 (s, 1H), 7.65 (m, 2H), 7.47 (m, 2H), 7.40 (m, 1H), 7.32 (m, 2H), 7.24 (m, 1H), 6.72 (m, 1H), 6.63 (m, 1H), 4.64 (s, 2H), 4.32 (s, 2H), 2.82 (q, 2H, J = 7.6), 2.33 (s, 3H), 1.31 (t, 3H, J = 7.6). HRMS: C 28 H 26 Calculated value for N3O2S: 468.1746; Measured value: 468.1757.

[0586] 8-Benzyl-6-phenyl-2-((5-(trifluoromethyl)furan-2-yl)methyl)imidazo[1,2-a]pyrazine-3-yl acetate (P-25): It was obtained from N-64 as a white solid after recrystallization from n-heptane (0.07 g, 43%). 1 H NMR (CDCl3): 7.94 - 7.87 (m, 2H), 7.83 (s, 1H), 7.63 - 7.57 (m, 2H), 7.49 - 7.42 (m, 2H), 7.42 - 7.35 (m, 1H), 7.33 - 7.27 (m, 2H), 7.24 - 7.17 (m, 1H), 6.73 (dd, 1H, J = 3.3, 1.2), 6.21 (dd, 1H, J = 3.4, 0.7), 4.61 (s, 2H), 4.23 (s, 2H), 2.40 (s, 3H). HRMS: C 27 H 21Calculated value for F3N3O3: 492.1535; Measured value: 492.1566.

[0587] 8-Benzyl-2-(2-methylbenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate (P-26): It was obtained as a white solid from N-51 (0.44 g, 96%). 1 H NMR (CDCl3): 7.91 (m, 2H), 7.76 (s, 1H), 7.64 (m, 2H), 7.48 -7.18 (m, 10H), 4.64 (s, 2H), 4.24 (s, 2H), 2.32 (s, 3H), 2.06 (s, 3H). HRMS: C 29 H 26 against N3O2 Calculated value: 448.2025; Measured value: 448.2032.

[0588] 8-Benzyl-2-(3-methylbenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate (P-27): It was obtained from N-52 as a beige solid after recrystallization from n-heptane (0.17 g, 61%). 1 H NMR (CDCl3): 7.92 - 7.85 (m, 2H), 7.77 (s, 1H), 7.66 - 7.58 (m, 2H), 7.49 - 7.35 (m, 3H), 7.35 - 7.27 (m, 2H), 7.24 - 7.16 (m, 2H), 7.15 - 7.01 (m, 3H), 4.62 (s, 2H), 4.16 (s, 2H), 2.33 (s, 3H), 2.17 (s, 3H). HRMS: C 29 H 26 Calculated value for N3O2: 448.2025; Measured value: 448.2053.

[0589] 8-Benzyl-2-(4-methylbenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate (P-28): It was obtained from N-53 as a white solid after recrystallization from n-heptane (0.21 g, 60%). 1 H NMR (CDCl3): 7.91 (m, 2H), 7.80 (s, 1H), 7.64 (m, 2H), 7.49 -7.13 (m, 10H), 4.65 (s, 2H), 4.18 (s, 2H), 2.36 (s, 3H), 2.20 (s, 3H). HRMS: C 29 H 26 against N3O2 Calculated value: 448.2025; Measured value: 448.2034.

[0590] 8-Benzyl-6-phenyl-2-(3-propylbenzyl)imidazo[1,2-a]pyrazine-3-yl acetate Tate (P-29): It was obtained from N-54 as a white solid after recrystallization from n-heptane (0.14 g, 54%). 1 H NMR (CDCl3): 7.91 (m, 2H), 7.80 (s, 1H), 7.64 (m, 2H), 7.47 (m, 2H), 7.40 (m, 1H), 7.33 (m, 2H), 7.24 (m, 2H), 7.10 (m, 3H), 4.65 (s, 2H), 4.20 (s, 2H), 2.59 (m, 2H), 2.17 (s, 3H), 1.66 (m, 2H), 0.97 (t, 3H, J = 7.3). HRMS: C 31 H 30 N3O2 The calculated value is 476.2338; the measured value is 476.2346.

[0591] 8-Benzyl-2-(3-cyclopropylbenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl Acetate (P-30): It was obtained from N-58 as a white solid after recrystallization from n-heptane (0.29 g, 65%). 1 H NMR (CDCl3): 7.91 (m, 2H), 7.79 (s, 1H), 7.64 (m, 2H), 7.46 (m, 2H), 7.39 (m, 1H), 7.33 (m, 2H), 7.23 (m, 2H), 7.06 (m, 2H), 6.96 (m, 1H), 4.64 (s, 2H), 4.18 (s, 2H), 2.18 (s, 3H), 1.89 (m, 1H), 0.95 (m, 2H), 0.70 (m, 2H). HRMS: C 31 H 28 Calculated value for N3O2: 474.2181; Measured value: 474.2189.

[0592] 8-Benzyl-6-phenyl-2-(4-propylbenzyl)imidazo[1,2-a]pyrazine-3-yl acetate Tate (P-31): It was obtained from N-55 as a white solid after recrystallization from n-heptane (0.25 g, 73%). 1 H NMR (CDCl3): 7.91 (m, 2H), 7.80 (s, 1H), 7.64 (m, 2H), 7.47 (m, 2H), 7.40 (m, 1H), 7.33 (m, 2H), 7.24 (m, 3H), 7.15 (m, 2H), 4.65 (s, 2H), 4.20 (s, 2H), 2.60 (m, 2H), 2.18 (s, 3H), 1.66 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H). HRMS: C 31 H 30 Calculated value for N3O2: 476.2338; Measured value: 476.2332.

[0593] 8-Benzyl-2-(4-cyclopropylbenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl Acetate (P-32): It was obtained from N-57 as a white solid after recrystallization from n-heptane (0.29 g, 68%). 1 H NMR (CDCl3): 7.91 (m, 2H), 7.80 (s, 1H), 7.64 (m, 2H), 7.46 (m, 2H), 7.40 (m, 1H), 7.33 (m, 2H), 7.22 (m, 3H), 7.04 (m, 2H), 4.64 (s, 2H), 4.17 (s, 2H), 2.18 (s, 3H), 1.92 (m, 1H), 0.94 (m, 2H), 0.68 (m, 2H). HRMS: C 31 H 28 Calculated value for N3O2: 474.2181; Measured value: 474.2183.

[0594] 8-Benzyl-2-(4-isopropylbenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl Acetate (P-33): It was obtained from N-56 as a white solid after recrystallization from n-heptane (0.16 g, 70%). 1 H NMR (CDCl3): 7.93 - 7.84 (m, 2H), 7.77 (s, 1H), 7.65 - 7.59 (m, 2H), 7.49 - 7.41 (m, 2H), 7.41 - 7.33 (m, 1H), 7.33 - 7.28 (m, 2H), 7.24 - 7.14 (m, 5H), 4.62 (s, 2H), 4.17 (s, 2H), 2.90 (hept, 1H, J = 6.9), 2.13 (s, 3H), 1.25 (d, 6H, J = 6.9). HRMS: C 31 H 30 Calculated value for N3O2: 476.2338; Measured value: 476.2337.

[0595] 8-benzyl-2-(4-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate Tate (P-34): It was obtained from N-46 as a beige solid after recrystallization from n-heptane (0.31 g, 70%). 1 H NMR (CDCl3): 7.94 - 7.86 (m, 2H), 7.79 (s, 1H), 7.65 - 7.58 (m, 2H), 7.50 - 7 .36 (m, 3H), 7.35 - 7.17 (m, 5H), 7.00 (dd, J = 9.8, 7.7 Hz, 2H), 4.62 (s, 2H), 4.15 (s, 2H), 2.25 (s, 3H). HRMS: C 28 H 23 Calculated value for FN3O2: 452.1774; Measured value: 452.1776.

[0596] 8-Benzyl-2-(3-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate Tate (P-35): It was obtained from N-46' as a white solid after recrystallization from n-heptane (0.13 g, 57%). 1 H NMR (CDCl3): 7.92 (m, 2H), 7.81 (s, 1H), 7.63 (m, 2H), 7.47 (m, 2H), 7.40 (m, HRMS: C 28 H 23 Calculated value for FN3O2: 452.1774; Measured value: 452.1778.

[0597] 8-benzyl-2-(2-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate Tate (P-36): It was obtained from N-47 as a white solid after recrystallization from n-heptane (0.22 g, 71%). 1 H NMR (CDCl3): 7.90 (m, 2H), 7.81 (s, 1H), 7.63 (m, 2H), 7.48 - 7.21 (m, 8H), 7.10 (m, 2H), 4.63 (s, 2H), 4.23 (s, 2H), 2.29 (s, 3H). HRMS: C 28 H 23 Calculated value for FN3O2: 452.1774; Measured value: 452.1769.

[0598] 8-Benzyl-2-(2,4-difluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl Acetate (P-37): It was obtained from N-48 as a white solid after recrystallization from n-heptane (0.13 g, 52%). 1 H NMR (CDCl3): 7.90 (m, 2H), 7.81 (s, 1H), 7.63 (m, 2H), 7.47 (m, 2H), 7.40 (m, 1H), 7.32 (m, 2H), 7.23 (m, 1H), 6.84 (m, 2H), 4.62 (s, 2H), 4.16 (s, 2H), 2.36 (s, 3H). HRMS: C 28 H 22 Calculated value for F2N3O2: 470.1680; Measured value: 470.1686.

[0599] 8-Benzyl-2-(4-chlorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate (P-38): It was obtained from N-49 as a white solid after recrystallization from n-heptane (0.23 g, 62%). 1 H NMR (CDCl3): 7.92 (m, 2H), 7.81 (s, 1H), 7.62 (m, 2H), 7.48 (m, 2H), 7.40 (m, 1H), 7.28 (m, 7H), 4.63 (s, 2H), 4.14 (s, 2H), 2.27 (s, 3H). HRMS: C 28 H 23 Calculated value for ClN3O2: 468.1479; Measured value: 468.1485.

[0600] 8-Benzyl-2-(4-bromobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate (P-39): From 50, it was obtained as a white solid after recrystallization from n-heptane (0.18 g, 49%). 1 H NMR (CDCl3): 7.92 (m, 2H), 7.80 (s, 1H), 7.62 (m, 2H), 7.44 (m, 5H), 7.32 (m, HRMS: C 28 H 23 Calculated value for BrN3O2: 512.0974; Measured value: 512.0950.

[0601] 8-Benzyl-2-((4,5-dimethylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate (P-40): It was obtained from N-43 as a beige solid after recrystallization from n-heptane (0.09 g, 45%). 1H NMR (CDCl3): 7.94 - 7.86 (m, 2H), 7.82 (s, 1H), 7.65 - 7.58 (m, 2H), 7.50 - 7.41 (m, 2H), 7.41 - 7.35 (m, 1H), 7.34 - 7.27 (m, 2H), 7.25 - 7.16 (m, 1H), 5.90 (s, 1H), 4.62 (s, 2H), 4.13 (s, 2H), 2.34 (s, 3H), 2.17 (s, 3H), 1.91 (s, 3H). HRMS: C 28 H 26 Calculated value for N3O3: 452.1974; Measured value: 452.1990.

[0602] 8-Benzyl-2-((4,5-dimethylthiophen-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate (P-41): It was obtained from N-44 as a white solid after recrystallization from n-heptane (0.14 g, 59%). 1 H NMR (CDCl3): 7.91 (m, 2H), 7.82 (s, 1H), 7.64 (m, 2H), 7.47 (m, 2H), 7.40 (m, 1H), 7.33 (m, 2H), 7.24 (m, 1H), 6.59 (s, 1H), 4.64 (s, 2H), 4.26 (s, 2H), 2.35 (s, 3H), 2.31 (s, 3H), 2.09 (s, 3H). HRMS: C 28 H 26 Calculated value for N3O2S: 468.1746; Measured value: 468.1758.

[0603] 8-Benzyl-2-((4,5-dimethyloxazole-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate (P-42): From N-45, white crystals were obtained after recrystallization from n-heptane (0.1 g, 34%). 1 H NMR (CDCl3): 7.91 (m, 2H), 7.85 (s, 1H), 7.47 (m, 2H), 7.39 (m, 1H), 7.31 (m, 2H), 7.24 (m, 1H), 4.62 (s, 2H), 4.28 (s, 2H), 2.41 (s, 3H), 2.21 (s, 3H), 2.08 (s, 3H). HRMS: C 27 H 25 Calculated value for N4O3: 453.1927; Measured value: 453.1915.

[0604] 8-Benzyl-2-((4,5-dimethylfuran-2-yl)methyl)-6-(2-fluorophenyl)imidazo[1,2-a]pyrazine-3-yl acetate (P-43): It was obtained from N-24 as a waxy substance (0.44 g, 95%). 1 H NMR (CDCl3): 8.20 (dt, 1H, J = 1.8, 8.0), 8.09 (s, 1H), 7.61 (m, 2H), 7.37 - 7.24 (m, 5H), 7.15 (ddd, 1H, J = 1.8, 8.1, 9.4), 5.91 (s, 1H), 4.63 (s, 2H), 4.41 (s, 2H), 2.35 (s, 3H), 2.19 (s, 3H), 1.92 (s, 3H). HRMS: C 28 H 25 Calculated value for FN3O3: 470.1880; Measured value: 470.1890.

[0605] 8-Benzyl-6-phenyl-2-(pyridine-2-ylmethyl)imidazo[1,2-a]pyrazine-3-yl acetate (P-44): It was obtained as an oily substance from N-42 (0.41 g, 91%). 1H NMR (CDCl3): 8.56 (m, 1H), 7.92 (m, 1H), 7.90 (m, 1H), 7.83 (s, 1H), 7.62 (m, 2H), 7.46 (m, 2H), 7.40 (m, 1H), 7.32 (m, 3H), 7.17 (m, 3H), 4.63 (s, 2H), 4.38 (s, 2H), 2.35 (s, 3H). HRMS: C 27 H 23 Calculated value for N4O2: 435.1821; Measured value: 435.1823.

[0606] 8-Benzyl-2-(2-methoxybenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate Tate (P-45): From N-13, it was obtained as a white solid after recrystallization from n-heptane (0.23 g, 72%). 1 H NMR (CDCl3): 7.90 (m, 2H), 7.78 (s, 1H), 7.64 (m, 2H), 7.46 (m, 2H), 7.39 (m, 1H), 7.32 (m, 2H), 7.24 (m, 3H), 6.92 (m, 2H), 4.63 (s, 2H), 4.22 (s, 2H), 3.82 (s, 3H), 2.16 (s, 3H). HRMS: C 29 H 26 Calculated value for N3O3: 464.1974; Measured value: 464.1978.

[0607] 8-Benzyl-2-(3-methoxybenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate Tate (P-46): It was obtained from N-14 as a white solid after recrystallization from n-heptane (0.20 g, 56%). 1H NMR (CDCl3): 7.92 - 7.86 (m, 2H), 7.78 (s, 1H), 7.65 - 7.58 (m, 2H), 7.49 - 7.41 (m, 2H), 7.41 - 7.34 (m, 1H), 7.33 - 7.27 (m, 2H), 7.25 - 7.18 (m, 2H), 6.91 - 6.86 (m, 1H), 6.86 - 6.83 (m, 1H), 6.81 - 6.75 (m, 1H), 4.63 (s, 2H), 4.17 (s, 2H), 3.77 (s, 3H), 2.21 (s, 3H). HRMS: C 29 H 26 Calculated value for N3O3: 464.1974; Measured value: 464.1982.

[0608] 8-Benzyl-2-(4-methoxybenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate Tate (P-47): It was obtained from N-15 as a white solid after recrystallization from n-heptane (0.04 g, 28%). 1 H NMR (CDCl3): 7.91 (m, 2H), 7.80 (s, 1H), 7.63 (m, 2H), 7.45 (m, 2H), 7.40 (m, 1H), 7.33 (m, 3H), 7.23 (m, 2H), 6.87 (m, 2H), 4.63 (s, 2H), 4.17 (s, 2H), 3.77 (s, 3H), 2.21 (s, 3H). HRMS: C 29 H 26 Calculated value for N3O3: 464.1974; Measured value: 464.1990.

[0609] 8-Benzyl-6-phenyl-2-((tetrahydrofuran-2-yl)methyl)imidazo[1,2-a]pyrazine-3-yl acetate (P-48): It was obtained as an oily substance from N-11 (0.36 g, 81%). 1H NMR (CDCl3): 7.93 - 7.87 (m, 2H), 7.82 (s, 1H), 7.62 - 7.57 (m, 2H), 7.48 - 7.41 (m, 2H), 7.40 - 7.34 (m, 1H), 7.32 - 7.27 (m, 2H), 7.23 - 7.17 (m, 1H), 4.66 - 4.55 (m, 2H), 4.32 - 4.23 (m, 1H), 3.89 - 3.69 (m, 2H), 3.10 - 2.95 (m, 2H), 2.46 (s, 3H), 2.09 - 1.98 (m, 1H), 1.92 - 1.82 (m, 2H), 1.77 - 1.66 (m, 1H). HRMS: C 26 H 26 Calculated value for N3O3: 428.1974; Measured value: 428.1956.

[0610] 2,8-Dibenzyl-6-(2-fluorophenyl)imidazo[1,2-a]pyrazine-3-yl acetate (P-49): From N-19, it was obtained as a solid after recrystallization from n-heptane (0.21 g, 45%). 1 H NMR (CDCl3): 8.20 (m, 1H), 8.05 (s, 1H), 7.62 (m, 2H), 7.32 (m, 10H), 7.15 (m, 1H), 4.63 (s, 2H), 4.22 (s, 2H), 2.18 (s, 3H). HRMS: C 28 H 23 Calculated value for FN3O2: 452.1774; Measured value: 452.1838.

[0611] 8-Benzyl-2-(4-fluorobenzyl)-6-(2-fluorophenyl)imidazo[1,2-a]pyrazine-3-yl acetate (P-50): It was obtained as a solid from N-20 after recrystallization from n-heptane (0.1 g, 63%). 1H NMR (CDCl3): 8.20 (dt, 1H, J = 2.0, 7.9), 8.06 (s, 1H), 7.60 (m, 2H), 7.38-7.21 (m, 7H), 7.15 (m, 1H), 7.01 (m, 2H), 4.62 (s, 2H), 4.16 (s, 2H), 2.26 (s, 3H). HRMS: C 28 H 22 Calculated value for F2N3O2: 470.1680; Measured value: 470.1670.

[0612] 8-Benzyl-6-(2-fluorophenyl)-2-(furan-2-ylmethyl)imidazo[1,2-a]pyrazine-3-yl acetate (P-51): It was obtained as a solid from N-21 after recrystallization from n-heptane (0.15 g, 36%). 1 H NMR (CDCl3): 8.20 (m, 1H), 8.10 (s, 1H), 7.61 (m, 2H), 7.31 (m, 6H), 7.14 (m, HRMS: C 26 H 21 Calculated value for FN3O3: 442.1567; Measured value: 442.1631.

[0613] 8-Benzyl-6-(2-fluorophenyl)-2-((5-methylfuran-2-yl)methyl)imidazo[1,2-a]pyrazine-3-yl acetate (P-52): It was obtained from N-22 as a glassy substance (0.08 g, 72%). 1H NMR (CDCl3): 8.19 (dt, 1H, J = 1.8, 7.8), 8.09 (s, 1H), 7.61 (m, 2H), 7.37-7.21 (m, 5H), 7.15 (ddd, 1H, J = 1.2, 8.1, 12.0), 6.02 (d, 1H, J = 3.0), 5.90 (m, 1H), 4.63 (s, 2H), 4.18 (s, 2H), 2.35 (s, 3H), 2.27 (s, 3H). HRMS: C 27 H 23 Calculated value for FN3O3: 456.1723; Measured value: 456.1734.

[0614] 8-Benzyl-2-((5-ethylfuran-2-yl)methyl)-6-(2-fluorophenyl)imidazo[1,2-a]pyrazine-3-yl acetate (P-53): It was obtained from N-23 as a waxy substance (0.18 g, 95%). 1 H NMR (CDCl3): 8.19 (dt, 1H, J = 1.8, 7.8), 8.10 (s, 1H), 7.62 (m, 2H), 7.39-7.22 (m, 5H), 7.15 (ddd, 1H, J = 1.2, 8.1, 12.0), 6.04 (d, 1H, J = 3.0), 5.93 (m, 1H), 4.64 (s, 2H), 4.21 (s, 2H), 2.65 (q, 2H, J = 7.6), 2.34 (s, 3H), 1.24 (t, 3H, J = 7.6). HRMS: C 28 H 25 Calculated value for FN3O3: 470.1880; Measured value: 470.1884.

[0615] 8-Benzyl-6-(3-fluorophenyl)-2-((5-methylfuran-2-yl)methyl)imidazo[1,2-a]pyrazine-3-yl acetate (P-54): It was obtained from N-25 as a white powder after recrystallization with n-heptane (0.018 g, 14%). 1 H NMR (CDCl3): 7.85 (s, 1H), 7.68 (m, 2H), 7.60 (m, 2H), 7.46-7.37 (m, 2H), 7.34-7.21 (m, 3H), 6.02 (d, 1H, J = 3.1), 5.90 (m, 1H), 4.62 (s, 2H), 4.18 (s, 2H), 2.37 (s, 3H), 2.26 (s, 3H). HRMS: C 27 H 23 Calculated value for FN3O3: 456.1723; Measured value: 456.1732.

[0616] 8-Benzyl-6-(4-fluorophenyl)-2-((5-methylfuran-2-yl)methyl)imidazo[1,2-a]pyrazine-3-yl acetate (P-55): It was obtained from N-26 as a glassy substance (0.1 g, 83%). 1 H NMR (CDCl3): 7.88 (m, 2H), 7.78 (s, 1H), 7.59 (m, 2H), 7.34-7.12 (m, 6H), 6.02 (d, 1H, J = 3.0), 5.90 (m, 1H), 4.61 (s, 2H), 4.18 (s, 2H), 2.36 (s, 3H), 2.27 (s, 3H). HRMS: C 27 H 23 Calculated value for FN3O3: 456.1723; Measured value: 456.1721.

[0617] 2,8-Dibenzyl-6-(2,6-difluorophenyl)imidazo[1,2-a]pyrazine-3-yl acetate (P-56): It was obtained as a solid from N-30 after recrystallization from n-heptane (0.16 g, 61%). 1 H NMR (CDCl3): 7.66 (s, 1H), 7.63 (m, 2H), 7.31 (m, 9H), 7.02 (m, 2H), 4.62 (s, 2H), 4....

Claims

1. The following equation (III): 【Chemistry 1】 (In the formula, R 1 is H or C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, aralkyl and C 5 -C 10 -member heteroaryl group selected from a group, the C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, aralkyl and C 5 -C[[ID=]33] 10 -member heteroaryl group may be substituted with at least one Y 1 group; R 2 The next is: 【Chemistry 2】 Selected from the group consisting of; R 3 The next is: 【Transformation 3】 Selected from the group consisting of; R 4 is H or C 1 -C 6 Alkyl and C 3 -C 7 Represents a group selected from cycloalkyl groups, and the C 1 -C 6 Alkyl and C 3 -C 7 A cycloalkyl group has at least one Y 4 It is also acceptable if it is substituted with the base; Z is the following: 【Chemistry 4】 Selected from the group consisting of; The aforementioned Y 1 , and Y 4 The bases are, independently, the following: - C 1 -C 6 alkyl group; - C 3 -C 7 Cycloalkyl groups; - Halogen; - -OR ii group Selected from; R ii are H and C, respectively, independently. 1 -C 6 Alkyl alkyl group, C 3 -C 10 Represents a cycloalkyl or aralkyl group; however, Z is either (Zc), (Zd), (Ze), (Zi), (Zk), (Zl), or (Zv); or When Z is equation (Za), equation (Zh), equation (Zo), or equation (Zp), R 2 represents a 2-F-phenyl, 3-F-phenyl, or 2,6-difluorophenyl group; or R 3 Compounds represented by formula (3b)-(3i) groups Alternatively, the following formula 【Transformation 5】 One of the compounds.

2. The following equation (IIIa): 【Transformation 6】 (In the formula, R 2 , R 3 (and Z are as defined in claim 1.) The compound according to claim 1.

3. The following equation (IV): 【Transformation 7】 (In the formula, R 1 , R 2 , R 3 , R 4 And Z is as defined in claim 1, R 5 is -C(=O)R a Base or -C(=O)OR a Represents the base, and the C(=O)R a Base and -C(=O)OR a There are few bases. Both are one Y 5 It is also acceptable if it is substituted with the base; R a H, C 1 -C 6 Alkyl alkyl group, C 3 -C 7 Cycloalkyl groups, C 6 -C 10 Aryl or Aralki It represents a group, and the C 1 -C 6 Alkyl alkyl group, C 3 -C 7 Cycloalkyl groups, C 6 -C 10 Aryl and aralkyl groups are at least one Y a It is also acceptable if it is substituted with the base; The aforementioned Y 5 and Y a Each base is independently selected from the following: - C 1 -C 6 Alkyl; - C 3 -C 7 Cycloalkyl; - C 6 -C 10 Ariel; - C 5 -C 10 -Member heteroaryl group; - Halogen; -CF 3 base; - -CN group; - -OR i group; - -OSO 3 H-base; -NR i R ii base; - Guanidinyl group; -C(=O)OR a Group, R a The above is true; R i and R ii are each independently H, C 1 -C 6 alkyl group, C 3 -C 10 cycloalkyl group, Aralkyl group; or together, the nitrogen atom and C to which they are bonded. 4 -C 7 (Forms heterocycloalkyl groups) And, the following equation (V): 【Transformation 8】 (wherein R 1 , R 2 , R 3 , R 4 and Z are as defined in claim 1). And, the following equation (VI): 【Chemistry 9】 (In the formula, R 1 , R 2 , R 3 , R 4 And Z is as defined in claim 1; R d is C 1 -C 6 Alkyl, C 3 -C 7 (Represents a group selected from cycloalkyl and aralkyl groups.) A compound of [this].

4. - R 1 H represents; or - R 4 This represents H; The compound according to claim 1.

5. Next name: 8-benzyl-2-((5-ethylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-benzyl-2-((4,5-dimethylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-benzyl-6-(2-fluorophenyl)-2-(furan-2-ylmethyl)imidazo[1,2-a]pyrazi N-3(7H)-ON 8-benzyl-2-(3-methylbenzyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 2,8-Dibenzyl-6-(2-fluorophenyl)imidazo[1,2-a]pyrazine-3(7H)-one 8-Benzyl-6-(2,6-difluorophenyl)-2-(furan-2-ylmethyl)imidazo[1,2-a]pyrazine-3(7H)-one 2,8-Dibenzyl-6-(2,6-difluorophenyl)imidazo[1,2-a]pyrazine-3(7H)-one 8-benzyl-6-(2-fluorophenyl)-2-((5-methylfuran-2-yl)methyl)imidazo[1,2-a]pyrazine-3(7H)-one 8-benzyl-2-((5-cyclopropylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-benzyl-2-(3-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-Benzyl-2-((5-ethylfuran-2-yl)methyl)-6-(2-fluorophenyl)imidazo[1,2-a]pyrazine-3(7H)-one 8-benzyl-6-(3-fluorophenyl)-2-((5-methylfuran-2-yl)methyl)imidazo[1,2-a]pyrazine-3(7H)-one 8-benzyl-2-(2-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-benzyl-2-((5-ethylthiophen-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-benzyl-2-((4,5-dimethylfuran-2-yl)methyl)-6-(2-fluorophenyl)imida Zo[1,2-a]pyrazine-3(7H)-one 2-benzyl-8-(2-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 2-benzyl-8-(3-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-(3-fluorobenzyl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-(2-fluorobenzyl)-2-(3-methylbenzyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-(2-fluorobenzyl)-2-(3-methoxybenzyl)-6-phenylimidazo[1,2-a]pyrazi N-3(7H)-ON 8-(2-fluorobenzyl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-(2-fluorobenzyl)-2-((5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-(3-fluorobenzyl)-2-(3-methoxybenzyl)-6-phenylimidazo[1,2-a]pyrazi N-3(7H)-ON 8-(3-fluorobenzyl)-2-(3-methylbenzyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 2-((5-ethylfuran-2-yl)methyl)-8-(3-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-(2-chlorobenzyl)-2-((5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-(3-fluorobenzyl)-2-((5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 2-((5-ethylfuran-2-yl)methyl)-8-(2-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-(3-fluorobenzyl)-6-(2-fluorophenyl)-2-((5-methylfuran-2-yl)methyl)imidazo[1,2-a]pyrazine-3(7H)-one 8-(2,3-difluorobenzyl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]p Lazin-3 (7H)-On 8-(2,3-difluorobenzyl)-2-((5-methylfuran-2-yl)methyl)-6-phenylimida Zo[1,2-a]pyrazine-3(7H)-one 2-benzyl-8-(2,3-difluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-(2,6-difluorobenzyl)-2-((5-methylfuran-2-yl)methyl)-6-phenylimida Zo[1,2-a]pyrazine-3(7H)-one 8-(2,3-difluorobenzyl)-2-((4,5-dimethylfuran-2-yl)methyl)-6-phenyl Midazo[1,2-a]pyrazine-3(7H)-one 8-(2,3-difluorobenzyl)-2-((5-ethylfuran-2-yl)methyl)-6-phenylimida Zo[1,2-a]pyrazine-3(7H)-one 8-(2,6-difluorobenzyl)-2-((5-ethylfuran-2-yl)methyl)-6-phenylimida Zo[1,2-a]pyrazine-3(7H)-one 2-((4,5-dimethylfuran-2-yl)methyl)-8-(2-fluorobenzyl)-6-phenylimida Zo[1,2-a]pyrazine-3(7H)-one 2-((4,5-dimethylfuran-2-yl)methyl)-8-(3-fluorobenzyl)-6-phenylimida Zo[1,2-a]pyrazine-3(7H)-one 8-(2,3-difluorobenzyl)-2-((4-ethyl-5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one 8-(2,3-difluorobenzyl)-2-((5-ethyl-4-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3(7H)-one A compound according to claim 1, selected from compounds having the following properties; Next name: 8-Benzyl-2-((5-ethylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-((4,5-dimethylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-6-(2-fluorophenyl)-2-(furan-2-ylmethyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-(3-methylbenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate Tate 2,8-Dibenzyl-6-(2-fluorophenyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-6-(2,6-difluorophenyl)-2-(furan-2-ylmethyl)imidazo[1,2-a]pyrazine-3-yl acetate 2,8-Dibenzyl-6-(2,6-difluorophenyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-6-(2-fluorophenyl)-2-((5-methylfuran-2-yl)methyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-((5-cyclopropylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-benzyl-2-(3-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl Ceteate 8-Benzyl-2-((5-ethylfuran-2-yl)methyl)-6-(2-fluorophenyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-6-(3-fluorophenyl)-2-((5-methylfuran-2-yl)methyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-benzyl-2-(2-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl Ceteate 8-Benzyl-2-((5-ethylthiophen-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-benzyl-2-((4,5-dimethylfuran-2-yl)methyl)-6-(2-fluorophenyl)imida Zo[1,2-a]pyrazine-3-yl acetate 2-benzyl-8-(2-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl Ceteate 2-benzyl-8-(3-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl Ceteate 8-(3-fluorobenzyl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(2-fluorobenzyl)-2-(3-methylbenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(2-fluorobenzyl)-2-(3-methoxybenzyl)-6-phenylimidazo[1,2-a]pyrazi N-3-Il Acetate 8-(2-fluorobenzyl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(2-fluorobenzyl)-2-((5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(3-fluorobenzyl)-2-(3-methoxybenzyl)-6-phenylimidazo[1,2-a]pyrazi N-3-Il Acetate 8-(3-fluorobenzyl)-2-(3-methylbenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 2-((5-ethylfuran-2-yl)methyl)-8-(3-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(2-chlorobenzyl)-2-((5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(3-fluorobenzyl)-2-((5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 2-((5-ethylfuran-2-yl)methyl)-8-(2-fluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(2,6-difluorobenzyl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(3,5-difluorobenzyl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(3-chlorobenzyl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(3-fluorobenzyl)-6-(2-fluorophenyl)-2-((5-methylfuran-2-yl)methyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-(2,3-difluorobenzyl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(2,3-difluorobenzyl)-2-((5-methylfuran-2-yl)methyl)-6-phenylimida Zo[1,2-a]pyrazine-3-yl acetate 8-(2,5-difluorobenzyl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(2,5-difluorobenzyl)-2-((5-methylfuran-2-yl)methyl)-6-phenylimida Zo[1,2-a]pyrazine-3-yl acetate 8-(3,5-difluorobenzyl)-2-((5-methylfuran-2-yl)methyl)-6-phenylimida Zo[1,2-a]pyrazine-3-yl acetate 2-benzyl-8-(2,3-difluorobenzyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 2-benzyl-6-phenyl-8-(2-(trifluoromethyl)benzyl)imidazo[1,2-a]pyrazi N-3-Il Acetate 2-benzyl-6-phenyl-8-(3-(trifluoromethyl)benzyl)imidazo[1,2-a]pyrazi N-3-Il Acetate 2-Benzyl-6-phenyl-8-(2,3,5-trifluorobenzyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-(2,6-difluorobenzyl)-2-((5-methylfuran-2-yl)methyl)-6-phenylimida Zo[1,2-a]pyrazine-3-yl acetate 8-(2,5-difluorobenzyl)-2-((4,5-dimethylfuran-2-yl)methyl)-6-phenyl Midazo[1,2-a]pyrazine-3-yl acetate 8-(2,5-difluorobenzyl)-2-((5-ethylfuran-2-yl)methyl)-6-phenylimida Zo[1,2-a]pyrazine-3-yl acetate 8-(2,3-difluorobenzyl)-2-((4,5-dimethylfuran-2-yl)methyl)-6-phenyl Midazo[1,2-a]pyrazine-3-yl acetate 8-(3,5-difluorobenzyl)-2-((4,5-dimethylfuran-2-yl)methyl)-6-phenyl Midazo[1,2-a]pyrazine-3-yl acetate 2-(furan-2-ylmethyl)-6-phenyl-8-(2,3,5-trifluorobenzyl)imidazo[1,2-a]pyrazine-3-yl acetate 8-(2,3-difluorobenzyl)-2-((5-ethylfuran-2-yl)methyl)-6-phenylimida Zo[1,2-a]pyrazine-3-yl acetate 8-(3,5-difluorobenzyl)-2-((5-ethylfuran-2-yl)methyl)-6-phenylimida Zo[1,2-a]pyrazine-3-yl acetate 8-(2,6-difluorobenzyl)-2-((5-ethylfuran-2-yl)methyl)-6-phenylimida Zo[1,2-a]pyrazine-3-yl acetate 8-(2,6-difluorobenzyl)-2-((4,5-dimethylfuran-2-yl)methyl)-6-phenyl Midazo[1,2-a]pyrazine-3-yl acetate 2-((4,5-dimethylfuran-2-yl)methyl)-8-(2-fluorobenzyl)-6-phenylimida Zo[1,2-a]pyrazine-3-yl acetate 2-((4,5-dimethylfuran-2-yl)methyl)-8-(3-fluorobenzyl)-6-phenylimida Zo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-6-phenyl-2-((5-propylfuran-2-yl)methyl)imidazo[1,2-a]pyrazine-3-yl acetate (133) 8-(2,3-difluorobenzyl)-2-((4-ethyl-5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-((4-ethyl-5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-((5-isopropyl-4-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-Benzyl-2-((5-ethyl-4-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-(2,3-difluorobenzyl)-2-((5-ethyl-4-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate 8-benzyl-2-(1-(furan-2-yl)ethyl)-6-phenylimidazo[1,2-a]pyrazine-3-i Le Acetate 8-(2,3-difluorobenzyl)-2-((5-isopropyl-4-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazine-3-yl acetate A compound according to claim 3, selected from compounds having; or Next name: 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(5-methylfuran-2-yl)propanoic acid 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(5-ethylfuran-2-yl)propanoic acid 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(4,5-dimethylfuran-2-yl)propanoic acid 2-((3-benzyl-5-(2-fluorophenyl)pyrazine-2-yl)amino)-3-(furan-2-yl)propanoic acid 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(m-tolyl)propanoic acid 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(3-methoxyphenyl)prop Acid (3-benzyl-5-(2-fluorophenyl)pyrazine-2-yl)phenylalanine 2-((3-benzyl-5-(2,6-difluorophenyl)pyrazine-2-yl)amino)-3-(furan-2- Iylpropanoic acid 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(5-(trifluoromethyl)furan-2-yl)propanoic acid (3-benzyl-5-(2,6-difluorophenyl)pyrazine-2-yl)phenylalanine 2-((3-benzyl-5-(2-fluorophenyl)pyrazine-2-yl)amino)-3-(5-methylfuran-2-yl)propanoic acid 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(5-cyclopropylfuran-2- Iylpropanoic acid 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(3-fluorophenyl)propane Acid 2-((3-benzyl-5-(2-fluorophenyl)pyrazine-2-yl)amino)-3-(5-ethylfuran-2-yl)propanoic acid 2-((3-benzyl-5-(3-fluorophenyl)pyrazine-2-yl)amino)-3-(5-methylfuran-2-yl)propanoic acid 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(2-fluorophenyl)propane Acid 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(5-ethylthiophen-2-yl)propanoic acid 2-((3-benzyl-5-(2-fluorophenyl)pyrazine-2-yl)amino)-3-(4,5-dimethylfuran-2-yl)propanoic acid (3-(2-fluorobenzyl)-5-phenylpyrazine-2-yl)phenylalanine (3-(3-fluorobenzyl)-5-phenylpyrazine-2-yl)phenylalanine 2-((3-(3-fluorobenzyl)-5-phenylpyrazine-2-yl)amino)-3-(furan-2-yl)propanoic acid 2-((3-(2-fluorobenzyl)-5-phenylpyrazine-2-yl)amino)-3-(m-tolyl)pro Panic acid 2-((3-(2-fluorobenzyl)-5-phenylpyrazine-2-yl)amino)-3-(3-methoxyphenyl)propanoic acid 2-((3-(2-fluorobenzyl)-5-phenylpyrazine-2-yl)amino)-3-(furan-2-yl)propanoic acid 2-((3-(2-fluorobenzyl)-5-phenylpyrazine-2-yl)amino)-3-(5-methylfuran) -2-yl)propanoic acid 2-((3-(3-fluorobenzyl)-5-phenylpyrazine-2-yl)amino)-3-(3-methoxyphenyl)propanoic acid 2-((3-(3-fluorobenzyl)-5-phenylpyrazine-2-yl)amino)-3-(m-tolyl)pro Panic acid 3-(5-ethylfuran-2-yl)-2-((3-(3-fluorobenzyl)-5-phenylpyrazine-2-yl)amino)propanoic acid 2-((3-(2-chlorobenzyl)-5-phenylpyrazine-2-yl)amino)-3-(5-methylfuran-2-yl)propanoic acid 2-((3-(3-fluorobenzyl)-5-phenylpyrazine-2-yl)amino)-3-(5-methylfuran-2-yl)propanoic acid 3-(5-ethylfuran-2-yl)-2-((3-(2-fluorobenzyl)-5-phenylpyrazine-2-yl)amino)propanoic acid 3-(3-(2,6-difluorobenzyl)-5-phenylpyrazine-2-yl)-2-(furan-2-ylmethyl Propanic acid 3-(3-(3,5-difluorobenzyl)-5-phenylpyrazine-2-yl)-2-(furan-2-ylmethyl Propanic acid 3-(3-(3-chlorobenzyl)-5-phenylpyrazine-2-yl)-2-(furan-2-ylmethyl)propanoic acid 3-(3-(3-fluorobenzyl)-5-(2-fluorophenyl)pyrazine-2-yl)-2-((5-methyl furan-2-yl(methyl)propanoic acid 3-(3-(2,3-difluorobenzyl)-5-phenylpyrazine-2-yl)-2-(furan-2-ylmethyl Propanic acid 3-(3-(2,3-difluorobenzyl)-5-phenylpyrazine-2-yl)-2-((5-methylfuran-2-yl)methyl)propanoic acid 3-(3-(2,5-difluorobenzyl)-5-phenylpyrazine-2-yl)-2-(furan-2-ylmethyl Propanic acid 3-(3-(2,5-difluorobenzyl)-5-phenylpyrazine-2-yl)-2-((5-methylfuran-2-yl)methyl)propanoic acid 3-(3-(3,5-difluorobenzyl)-5-phenylpyrazine-2-yl)-2-((5-methylfuran-2-yl)methyl)propanoic acid 2-Benzyl-3-(3-(2,3-difluorobenzyl)-5-phenylpyrazine-2-yl)propanoic acid 2-benzyl-3-(5-phenyl-3-(2-(trifluoromethyl)benzyl)pyrazine-2-yl) Ropanic acid 2-benzyl-3-(5-phenyl-3-(3-(trifluoromethyl)benzyl)pyrazine-2-yl) Ropanic acid 2-benzyl-3-(5-phenyl-3-(2,3,5-trifluorobenzyl)pyrazine-2-yl)prop Acid 3-(3-(2,6-difluorobenzyl)-5-phenylpyrazine-2-yl)-2-((5-methylfuran-2-yl)methyl)propanoic acid 3-(3-(2,5-difluorobenzyl)-5-phenylpyrazine-2-yl)-2-((4,5-dimethylfurethane) 1-2-yl(methyl)propanoic acid 3-(3-(2,5-difluorobenzyl)-5-phenylpyrazine-2-yl)-2-((5-ethylfuran-2-yl)methyl)propanoic acid 3-(3-(2,3-difluorobenzyl)-5-phenylpyrazine-2-yl)-2-((4,5-dimethylfurethane) 1-2-yl(methyl)propanoic acid 3-(3-(3,5-difluorobenzyl)-5-phenylpyrazine-2-yl)-2-((4,5-dimethylfurethane) 1-2-yl(methyl)propanoic acid 3-(furan-2-yl)-2-((5-phenyl-3-(2,3,5-trifluorobenzyl)pyrazine-2-yl)methyl)propanoic acid 3-(3-(2,3-difluorobenzyl)-5-phenylpyrazine-2-yl)-2-((5-ethylfuran-2-yl)methyl)propanoic acid 3-(3-(3,5-difluorobenzyl)-5-phenylpyrazine-2-yl)-2-((5-ethylfuran-2-yl)methyl)propanoic acid 3-(3-(2,6-difluorobenzyl)-5-phenylpyrazine-2-yl)-2-((5-ethylfuran-2-yl)methyl)propanoic acid 3-(3-(2,6-difluorobenzyl)-5-phenylpyrazine-2-yl)-2-((4,5-dimethylfurethane) 1-2-yl(methyl)propanoic acid 3-(4,5-dimethylfuran-2-yl)-2-((3-(2-fluorobenzyl)-5-phenylpyrazine-2-yl)methyl)propanoic acid 3-(4,5-dimethylfuran-2-yl)-2-((3-(3-fluorobenzyl)-5-phenylpyrazine-2-yl)methyl)propanoic acid 2-((3-(2,3-difluorobenzyl)-5-phenylpyrazine-2-yl)amino)-3-(4-ethyl-5-methylfuran-2-yl)propanoic acid 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(4-ethyl-5-methylfuran-2-yl)propanoic acid 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(5-isopropyl-4-methyl Lan-2-yl)propanoic acid 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(5-ethyl-4-methylfuran-2-yl)propanoic acid 2-((3-(2,3-difluorobenzyl)-5-phenylpyrazine-2-yl)amino)-3-(5-ethyl-4-methylfuran-2-yl)propanoic acid 2-((3-benzyl-5-phenylpyrazine-2-yl)amino)-3-(furan-2-yl)butanoic acid 2-((3-(2,3-difluorobenzyl)-5-phenylpyrazine-2-yl)amino)-3-(5-isopropyl-4-methylfuran-2-yl)propanoic acid 2-((3-benzyl-5-(3-(benzyloxy)phenyl)pyrazine-2-yl)amino)-3-(furan-2-yl)propanoic acid 2-((3-benzyl-5-(3-(hydroxy)phenyl)pyrazine-2-yl)amino)-3-(furan-2- Iylpropanoic acid A compound according to claim 3, selected from the compounds.

6. The following equation (VII): 【Chemistry 10】 (In the formula, Y represents a halogen or -OS(O2)CF3; R 1 is H or C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 6 -C 10 Aaryl, Aralkiru Call C 5 -C 10 - Represents a group selected from member heteroaryl groups, and the C 1 -C 6 Alkyl, C 3 -C 7 Shik Roalkyl, C 6 -C 10 Aryl, Aralkyr and C 5 -C 10 - The number of member heteroaryl groups is small Another Y 1 It is also acceptable if it is substituted with the base; R 2 Next: 【Chemistry 11】 Selected from the group consisting of; R 3 Next: 【Chemistry 12】 Selected from the group consisting of; The aforementioned Y 1 Each of these is independent of the following: - C 1 -C 6 alkyl group; - C 3 -C 7 Cycloalkyl groups; - Halogen; - -OR ii group Selected from; R ii H, C 1 -C 6 Alkyl alkyl group, C 3 -C 10 (Represents a cycloalkyl group or aralkyl group) A compound of [this].

7. Use of a compound of formula (III) or (IIIa) as defined in claim 1 or 2 for manufacturing an in vitro or ex vivo diagnostic tool.

8. A compound of formula (III) or (IIIa) as defined in claim 1 or 2 for use as an in vivo diagnostic tool.

9. A method for producing a compound of formula (III) as defined in claim 1, comprising a step of converting a compound of formula (IV) as defined in claim 3 to a compound of formula (III).

10. The method according to claim 9, comprising a step of converting the compound of formula (IV) as defined in claim 3 to the compound of formula (III) by contacting the compound of formula (IV) with a strong acid.

11. The compound of formula (IV) is i) A step of converting a compound of formula (VI) as defined in claim 3 to a compound of formula (V), followed by formula (V) The step of converting the compound of formula (IV) to the compound of formula (IV); or ii) The process of converting the compound of formula (VI) to the compound of formula (IV) The method according to claim 9, manufactured by a method including the following:

12. The compound of formula (VI) is i) The following equation (VIII): 【Chemistry 15】 By replacing the hydroxyl group of the compound with a halogen or another leaving group -Y, we obtain the following formula (VII): 【Chemistry 16】 The process of obtaining the compound, and ii) The compound of formula (VII) is given by the following formula (IX): 【Chemistry 17】 A step of contacting the compound with the compound of formula (VI) to obtain the compound of formula (VI), (Here, R 1 , R 2 , R 3 , R 4 , Z and R d (This is as defined in claim 3.) A manufacturing method according to claim 11, obtained by a method including the following:

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