BR112017005880B1 - CHIRAL SYNTHESIS OF N-ACYL-(3-SUBSTITUTED)-(8-SUBSTITUTED)-5,6-DI-HYDRO-[1,2,4] TRIAZOLE[4,3-A]PYRAZINES - Google Patents

Abstract

CHIRAL SYNTHESIS OF N-ACYL-(3-SUBSTITUTED)-(8-SUBSTITUTED)-5,6-DI-HYDRO-[1,2,4]TRIAZOLE[4,3-A]PYRAZINES. The present invention relates to a new chiral synthesis of N-acyl-(3-substituted)-(8-substituted)-5,6-dihydro-[1,2,4]triazol[4,3-a] Formula I pyrazines, avoiding the use of protection/deprotection steps

Description

FIELD OF INVENTION

[001] The present invention relates to a new chiral synthesis of N-acyl-(3-substituted)-(8-substituted)-5,6-dihydro-[1,2,4]triazol[4,3 -a] Formula I pyrazines, avoiding the use of protection/deprotection steps.

BASICS OF THE INVENTION

[002] The synthesis of N-acyl-(3-substituted)-(8-substituted)-5,6-dihydro-[1,2,4]triazol[4,3-a]pyrazines is revealed in the literature , comprising a) the synthesis of (3-substituted)-(8-substituted)-5,6-dihydro-[1,2,4]triazol[4,3-a]pyrazine intermediates, followed by b) a classical N-acylation (Scheme 1):

[003] Scheme 1: General synthetic scheme for the preparation of N-acyl-(3-substituted)-(8-substituted)-5,6-dihydro-[1,2,4]triazol[4,3- a]pyrazines according to the prior art.

[004] Different synthetic approaches that are of general relevance for step a) of the synthesis of chiral intermediates of (3-substituted)-(8-substituted)-5,6-dihydro-[1,2,4]triazol[ 4,3-a]pyrazine are known in the literature. The following examples and experimental conditions of relevant approaches provided are illustrative only.

[005] In Method A(i) (see Scheme 2), the nucleus of [1,2,4]triazolpyrazine IIIa(i) is formed by acetylation of 2-hydrazidopyrazine (step 1) followed by a cyclodehydration reaction (step 2), using procedures familiar to those skilled in the art. This methodology was initially developed by Nelson and Potts (J. Org. Chem. 1962, 27, 3243-3248). Subsequent reduction of the pyrazine ring with H2/Pd makes [1,2,4]triazol[4,3-a]piperazine available (step 3). This method is well described in the literature and was used, for example, in Merck's synthesis of Sitagliptin (Hansen et al., Org. Process Res. Dev. 2005, 9, 634-639 and references therein).

[006] However, i) careful reading of the existing literature indicates that this procedure is generally used with substrates in which R1 = H (i.e., non-chiral analogues, cf. Scheme 2), and ii) that the application of this method to preparing chiral [1,2,4]triazol[4,3-a]piperazine variant of general Formula IVa(i) (in Method A(i)) has not been disclosed. The paucity of examples of pyrazine substrates where R1#H in this methodology can be attributed to the difficulty of the pyrazine reduction step; Notable in this regard is the fact that, in the large-scale procedure of the optimized process reported by Hansen et al., the reduction of pyrazine (R1 = H) (step 3, Scheme 2) occurred in a yield of merely 51%. In addition to the problem of chemical yield, access to chiral substrates through reduction of [1,2,4]triazolpyrazine substrates in which R1#H would require the additional challenge of efficient asymmetric hydrogenation conditions (in terms of both yield and chiral purity). ); This is not currently a known procedure within the applicant's knowledge. Thus, application of Method A(i) for chiral synthesis of the [1,2,4]triazol[4,3-a]piperazine structure is so far unknown.

[007] Method A(ii) (cf. Scheme 3) is a variation on Method A(i) whereby the reduction of substituted [1,2,4]triazolpyrazine R1 # H substrates is avoided.

[008] This method was reported by the Merck group in their studies related to Sitagliptin (see, for example, Kowalchick et al., Bioorg. Med. Chem. Lett. 2007, 17, 5934-5939), in which Boc- protected compounds represented by general Formula IVa(ii) are deprotonated with a strong base, such as n-butyllithium, in the presence of tetramethylethylenediamine (TMEDA), followed by treatment of the anion thus generated with an electrophile such as an alkyl halide (step 4, Scheme 3). The chiral variant of this methodology has not been reported in the literature.

[009] Inspired by previous work by Makino and Kato (JPH06128261(A), 1994), yet another alternative approach for the synthesis of [1,2,4]triazol[4,3-a]piperazines was developed using chloromethyloxadiazoles as a key reagent (Balsells et al., Org. Lett. 2005, 7, 1039-1042). This methodology (Method B) is represented in Scheme 4 below.

[010] As reported by Balsells et al., however, this approach occurs in high yield mainly when the strong electron extraction group R2 = CF3 is present in the chloromethyloxadiazole reagent. Furthermore, the mechanism suggested by the said authors would make the application of this strategy unlikely, if not impossible, for a chiral synthesis of IVb intermediates (cf. Scheme 4). Of course, in the current literature only racemic or achiral products are described using an approach like this. Thus, application of Method B with respect to the preparation of the chiral [1,2,4]triazol[4,3-a]piperazine structure has never been revealed.

[011] Another well-known method for preparing structures containing [1,2,4]triazol[4,3-a]piperazine is shown in Scheme 5 below (Method C). Scheme 5: Method C. The symbol * denotes a well-defined configuration at the carbon center near which said symbol is placed, that is, the carbon atom to which the R1 group is attached in this scheme.

[012] Addition of acetylhydrazide to piperazinoimidate (step 1) is followed by cyclodehydration to form the fused triazole ring (step 2). This method is well documented in the literature, although exemplified only through racemic or achiral structure; for example: McCort and Pascal, Tetrahedron Lett., 1992, 33, 4443-4446; Brockunier et al. WO 03/082817 A2; Chu-Moyer et al. US 6,414,149 B1; Banka et al. WO2009/089462 A1. To the best of his knowledge, the Applicant is not aware of any published report of the application of this method to obtain chiral products from chiral piperazinones (Ic in Scheme 5).

[013] A synthesis of (R)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazine compounds using general Method C was previously described in the international patent application WO2011/121137 which is in the name of the Applicant. The preparation revealed in it is represented in Scheme 6: EtOH, microwave (sealed tube) Scheme 6: Synthesis of (R)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a] intermediates ]pyrazine according to WO2011/121137. Note: Steps 2 and 3 are particularly prone to racemization, despite the graphical description of the chiral products for each of these steps in the previous scheme. Thus, obtaining intermediates/products in high chiral purity (>80% ee) is feasible, but not in a reproducible manner.

[014] Boc-protected ketopiperazine 1.2 was prepared and then converted to iminoether 1.3 using the Meerwein reagent (e.g., Et3OBF4). Cyclodehydration reaction between acyl hydrazide 1.4 and the aforementioned iminoether was conducted either under forced thermal reflux conditions or by applying excessive microwave irradiation in a sealed tube typically for very prolonged reaction times (often days). During the use of microwave irradiation, N-Boc deprotection occurred during said cyclodehydration step; thus, a deprotection step was typically not required to conduct (i.e., 1.3 + 1.4^1.6 in Scheme 6). However, when thermal cyclodehydration conditions were applied, Boc-deprotection step was required (i.e., 1.3 + 1.4^1.5^1.6).

[015] As noted in Scheme 6 previously, steps 2 and 3 have drawbacks that significantly limit the application of said procedure to uses in which it is necessary to generate intermediates or chiral products in a reproducible manner, such as with the preparation of pharmaceutically active ingredient , for example. Step 2 is the formation of piperazinoimidate (i.e. 1.2^1.3) and step 3 is the cyclodehydration step between said imidate and acetylhydrazide (i.e. 1.3 + 1.4^1.5).

[016] An important disadvantage of the Scheme 6 procedure is that racemization of the stereogenic carbon center frequently occurred in steps 2-3. Consequently, said procedure provided final products that were only rarely of acceptable chiral purity; in fact, much more frequently, the procedures of Scheme 6 have produced final products represented by general Formula 1.7 which are considered essentially racemic by those skilled in the art. As such, said method cannot be used in practice to prepare a pharmaceutically active ingredient, as this method does not reliably provide chiral intermediates (1.3, 1.5, 1.6; Scheme 6) and thus cannot be reliably used to obtain products chirals represented by general Formula 1.7.

[017] Another disadvantage of the Scheme 6 procedure is the excessively prolonged reaction time required for the cyclodehydration step (Scheme 6, 1.3 + 1.4 ^ 1.5). Up to several days (under forced reaction conditions - see below) it was always required with substrates represented by the general Formula IIc (Scheme 5) in which R # H, i.e. the most sterically congested analogues, unlike the case with achiral substrates represented by general Formula IIc (Scheme 5) where R = H. Such significantly prolonged reaction times (several days) are not practical for such cases as a large-scale synthesis of cGMP required to prepare a pharmaceutically active ingredient for clinical studies.

[018] As outlined in the previous paragraph, in the procedure in Scheme 6, the cyclodehydration step required extremely forced conditions. Thus, the use of elevated temperatures at reflux (for prolonged durations), or additionally with application of essentially maximally viable (within the experimental safety margin) microwave irradiation (sealed vessel) is often required.

[019] Applicant resorted to a racemic synthesis of racemic 5,6,7,(8-methyl)-tetrahydro-[1,2,4]triazol[4,3-a]pyrazine followed by a purification step of Additional chiral preparative HPLC after formation of the final product of interest represented by General Formula 1.7 in Scheme 6. Although small scale feasible for the initial research and development phase, such an approach presents the problems of scalability in terms of time, cost and general applicability to such needs as large-scale cGMP of pharmaceutically active ingredients, for example.

[020] An improved chiral synthesis of 5,6,7,(8-substituted)-tetrahydro-[1,2,4]triazol[4,3-a]pyrazine intermediates was then described in the international patent application WO2013/050424 which is in the name of the Applicant.

[021] This method is a variation on the method represented in Scheme 6: the Boc protecting group of Scheme 6, which is an N-Csp2 protecting group, has been replaced by an N-Csp3 protecting group, preferably a benzyl protecting group such as DMB , PMB or TMB.

[022] The use of an N-Csp3 protecting group like this has been observed to provide chiral intermediates of 5,6,7,(8-substituted)-tetrahydro-[1,2,4]triazol[4,3-a ]pyrazine with a good enantiomeric excess and in a reproducible manner. Retention of stereochemistry was observed with minimal, if any, racemization.

[023] Although the method described in WO2013/050424 allows chiral synthesis of N-acyl-(3-substituted)-(8-substituted)-5,6-dihydro-[1,2,4]triazol[4 ,3- a]pyrazines, the Applicant conducted research to further improve the process, especially its scalability in terms of time, cost, number of steps, while minimizing racemization. This is all the more important as these compounds are useful as selective antagonists for neurokine 3 (NK-3) receptor, thereby making such an improved synthetic procedure of practical utility with regard to the development of such products as active pharmaceutical ingredients.

[024] Unlike all previously described methods, the new chiral synthetic procedure of the present invention first involves an N-acylation step followed by the construction of the [1,2,4]triazol[4,3-a]pyrazine core (Scheme 7): Scheme 7: General synthetic scheme for the preparation of N-acyl-(3-substituted)-(8-substituted)-5,6-dihydro-[1,2,4]triazol[4,3-a]pyrazines of the invention.

[025] This strategy, although described for the synthesis of non-chiral substrates (i.e., R1 = H) by Glaxo Group Limited (WO 2010/125102 A1), has never been applied to the chiral synthesis of N-acyl-(3-substituted )-(8-substituted)-5,6-dihydro-[1,2,4]triazol[4,3-a]pyrazines. As explained previously for the method of Scheme 6, protection of the amine nitrogen atom with Boc N-Csp2 protecting group (such as N-Boc) often resulted in impractically high levels of racemization under previously reported conditions. Despite the recently cited findings, additional efforts have revealed that, with milder, more tightly controlled experimental conditions (lower temperature and shorter reaction time), the presence of specific N-Csp2 groups, such as the N-Boc protecting group or N-Csp2 substitution, benzoyl, can also result in final products with acceptably low racemization (<5%). However, these latter observations were also contingent upon the nature of the 5-membered heterocyclic ring in such a way that it may be of practical value for the target structure of interest to the Applicant as antagonists for the neurokine-3 receptor. Collectively, the aforementioned results are unexpected to those skilled in the art.

[026] Therefore, the new synthetic procedure of the present invention presents the distinct advantage of providing final desired targets with very high chiral purity, while eliminating the need for additional protection/deprotection steps that will advantageously impact production costs. SUMMARY OF THE INVENTION

[027] The invention relates to a process for preparing N-acyl-(3-substituted)-(8-substituted)-5,6-dihydro-[1,2,4]triazol[4,3-a ]chiral pyrazine of general Formula I:

[028] or solvates thereof, where

[029] R1 is alkyl, haloalkyl, hydroxyalkyl or alkoxyalkyl, preferably R1 is methyl, ethyl, n-propyl, hydroxyethyl, methoxyethyl, trifluoromethyl, difluoromethyl or fluoromethyl; more preferably R1 is methyl;

[030] R2 is alkyl, alkoxyalkyl or haloalkyl, preferably R2 is methyl, ethyl, methoxymethyl, trifluoromethyl, difluoromethyl, fluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl or 2,2,2-trifluoroethyl; more preferably R2 is methyl, ethyl, methoxymethyl, trifluoromethyl, difluoromethyl or fluoromethyl; even more preferably R2 is methyl;

[031] Ar is a phenyl group, optionally substituted by one or more substituent(s) selected from H, halo, alkyl, alkoxy, haloalkyl, nitrile and thiophen-2-yl; preferably Ar is a phenyl group, optionally substituted by one or more substituent(s) selected from H, F, Cl, methyl, methoxy, trifluoromethyl, nitrile and thiophen-2-yl; more preferably Ar is a phenyl group substituted by H or F; X1 is N and X2 is S or O; or X1 is S and X2 is N;

[032] — represents a single or double bond depending on X1 and X2;

[033] said process comprising the following steps: a. react a compound of Formula A:

[034] where R1 is as previously defined;

[035] with a compound of Formula B:

[036] where Ar is as previously defined; and Y is hydroxyl or halo, where halo is preferably F or Cl; more preferably Y is hydroxyl or Cl, even more preferably Y is Cl;

[037] to obtain a compound of Formula C:

[038] b) convert the compound of Formula C with a tri(C1-C2 alkyl)oxonium salt, a (C1-C2)alkylsulfate, a (C1-C2)chloroformate or PCl5/POCl3/(C1-C2)hydroxyalkyl , in order to obtain a compound of Formula D:

[039] wherein Ar and R1 are as previously defined, and R3 is C1-C2 alkyl;

[040] in the presence of a base;

[041] c) react the compound of Formula D with a compound of Formula E:

[042] or a salt or solvate thereof, wherein X1, X2 and R2 are as previously defined;

[043] in order to obtain a compound of Formula I or solvate thereof.

[044] According to the present invention, the reaction of each step is carried out under controlled mild experimental conditions. Especially, the reaction is carried out at a temperature equal to or below the boiling point of the organic solvent, preferably at room temperature.

[045] In one embodiment, the process does not use any protecting group.

[046] In one embodiment, the process occurs with the retention of stereochemistry in relation to the starting material.

[047] The process according to the present invention preferably provides the (R)-enantiomer of the compounds of Formula I.

[048] The invention also relates to the synthesis of chiral intermediates.

[049] In one embodiment, the process provides chiral compounds of the Formula

[050] or solvates thereof, where R1 and Ar are as previously defined. In a preferred embodiment, compound C has Formula C-b2:

[051] The invention also relates to compounds of Formula D:

[052] or solvates thereof, where R1, R3 and Ar are as previously defined.

[053] In a preferred embodiment, compound D has Formula D-1:

[054] Preferred compounds of Formula C and Formula D are those in which the stereoisomer obtained is the (R)-enantiomer.

[055] The invention also concerns the use of the compounds provided by the process or solvate thereof, for the manufacture of a medicine, a pharmaceutical composition or a pharmaceutically active ingredient.

DETAILED DESCRIPTION Process

[056] The invention concerns a new chiral synthesis of N-acyl-(3-substituted)-(8-substituted)-5,6-dihydro-[1,2,4]triazol[4, 3-a]pyrazine avoiding the use of protection/deprotection steps and, thus, allowing to obtain high chiral purity while increasing cost effectiveness. Especially, the invention relates to a process for preparing N-acyl-(3-substituted)-(8-substituted)-5,6-dihydro-[1,2,4]triazol[4,3- a]pyrazine of Formula I:

[057] or solvates thereof, in which

[058] R1 is alkyl, haloalkyl, hydroxyalkyl or alkoxyalkyl, preferably R1 is methyl, ethyl, n-propyl, hydroxyethyl, methoxyethyl, trifluoromethyl, difluoromethyl or fluoromethyl; more preferably R1 is methyl;

[059] R2 is alkyl, alkoxyalkyl or haloalkyl, preferably R2 is methyl, ethyl, methoxymethyl, trifluoromethyl, difluoromethyl, fluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl or 2,2,2-trifluoroethyl; more preferably R2 is methyl, ethyl, methoxymethyl, trifluoromethyl, difluoromethyl or fluoromethyl; even more preferably R2 is methyl;

[060] Ar is a phenyl group, optionally substituted by one or more substituent(s) selected from H, halo, alkyl, alkoxy, haloalkyl, nitrile and thiophen-2-yl; preferably Ar is a phenyl group, optionally substituted by one or more substituent(s) selected from H, F, Cl, methyl, methoxy, trifluoromethyl, nitrile and thiophen-2-yl; more preferably Ar is a phenyl group substituted by H or F; X1 is N and X2 is S or O; or X1 is S and X2 is N;

[061] — represents a single or double bond depending on X1 and X2;

[062] said process comprising the following steps: a. react a compound of Formula A:

[063] where R1 is as previously defined;

[064] with a compound of Formula B:

[065] where Ar is as previously defined; and Y is hydroxyl or halo, where halo is preferably F or Cl; more preferably Y is hydroxyl or Cl, even more preferably Y is Cl;

[066] to obtain a compound of Formula C:

[067] b) convert the compound of Formula C with a tri(C1-C2 alkyl)oxonium salt, a (C1-C2)alkylsulfate, a (C1-C2)chloroformate or PCl5/POCl3/(C1-C2)hydroxyalkyl , in order to obtain a compound of Formula D:

[068] wherein Ar and R1 are as previously defined, and R3 is C1-C2 alkyl;

[069] in the presence of a base;

[070] c) react the compound of Formula D with a compound of Formula E:

[071] or a salt or solvate thereof, wherein X1, X2 and R2 are as previously defined;

[072] in order to obtain a compound of Formula I or solvate thereof.

[073] The following description of the process of the invention applies to the process of the invention as previously defined, including all described embodiments.

[074] According to a first modality, the process is carried out under controlled mild experimental conditions.

[075] Step a) of amide coupling of the process as defined above is advantageously carried out in an organic solvent, preferably anhydrous, selected from dichloromethane, acetonitrile preferably in dichloromethane.

[076] The reaction is advantageously carried out at a temperature equal to or below the boiling point of the organic solvent, preferably at room temperature.

[077] The expression “ambient temperature” as used here means a temperature between 10 °C and 30 °C, preferably 20 ± 5 °C.

[078] In the case of compounds of Formula B in which Y is a halo, the reaction is carried out in the presence of a base selected from the group consisting of diisopropylethylamine, N-methylmorpholine, triethylamine, preferably N-methylmorpholine. In the case of compounds of Formula B in which Y is a hydroxyl, the reaction is carried out in an activated anhydride, ester, acylurea derivative of the latter compounds - formed through conventional amide bonding forming reagent(s) involving the use of so called activating groups, such as isobutylchloroformate, DIC, DCC, HOBt, HATU, HBTU, DEPBT under reaction conditions known to those skilled in the art. According to a preferred embodiment, Y is a halo in compounds of Formula B and the reaction is carried out in the presence of a base selected from the group consisting of diiso-propylethylamine, N-methylmorpholine, triethylamine, preferably N-methylmorpholine.

[079] Intermediates of Formula C can be optionally purified by flash chromatography on silica gel or chromatography on silica gel, and/or precipitation, and/or trituration, and/or filtration, and/or recrystallization.

[080] The second step of the process, step b), is the conversion of the ketopiperazine compounds of Formula C into iminoether compounds of Formula D.

[081] Step b) takes place without significant loss of chirality resulting in the corresponding products of good enantiomeric purity as defined here.

[082] The procedure involves a tri(C1-C2 alkyl)oxonium salt (Meerwein type reagents), or (C1-C2)alkylsulfate, or (C1-C2)chloroformate, or use of PCl5/POCl3/(C1-C2 )hydroxyalkyl, preferably tri(C1-C2 alkyl)oxonium salt (Meerwein type reagents), or (C1-C2)alkyl sulfate, more preferably tri(C1-C2 alkyl)oxonium salt, and even more preferably a tri( C2 alkyl)oxonium, such as Et3OBF4.

[083] as presented previously, step b) is carried out in the presence of a base.

[084] Use of at least 2 equivalents of tri(C1-C2 alkyl)oxonium salt with respect to the 3-substituted-piperazin-2-one of Formula C was required to assist with a more complete conversion when step b) was performed without a mild base additive, such as Na2CO3, as discussed further below.

[085] Without wishing to be bound by any theory, the Applicant believes that the formation of an acid such as HBF4 may be a side product with the use of moisture-sensitive tri(C1-C2 alkyl)oxonium salt (Meerwein type reagents). Interestingly, there are two references to the literature (See (a) Sánchez et al., J. Org. Chem. 2001, 66, 5731-5735; (b) Kende et al., Org. Lett. 2003, 5, 3205-3208 ) who cite the use of mild bases such as Na2CO3 along with the use of Meerwein reagent although i) without offering any explicit rationale or detailed experimental conditions. After extensive reaction optimization experiments, the Applicant observed that addition of a base, especially Na2CO3, to the Meerwein reagent helped to minimize racemization. The Applicant further noted that the use of a mild base additive, especially Na2CO3, also appears to help accelerate the reaction to completion which in turn may help to minimize racemization in such reactions.

[086] The base is advantageously selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate or cesium carbonate, preferably the base is sodium carbonate.

[087] In a preferred embodiment, between 1 and 5, preferably about 1.8 mol equivalents with respect to base tri(C1-C2 alkyl)oxonium salt is used.

[088] The tri(C1-C2 alkyl)oxonium salt is advantageously selected from the group consisting of trimethyloxonium tetrafluoroborate, triethyloxonium tetrafluoroborate, preferably the tri(C1-C2 alkyl)oxonium salt is triethyloxonium tetrafluoroborate. In an advantageous embodiment, between 1 and 2, preferably about 1.25, mol equivalents of tri(C1-C2 alkyl)oxonium salt is used, with respect to 3-substituted-piperazin-2-one.

[089] Step b) of the iminoether synthesis is advantageously carried out in an organic solvent, preferably anhydrous, preferably dichloromethane.

[090] The reaction is advantageously carried out at a temperature equal to or below the boiling point of the organic solvent; preferably the reaction is carried out at room temperature.

[091] Formula D intermediates can optionally be purified by flash or silica gel column chromatography.

[092] The third step of the process, step c), is the preparation of triazolpiperazine compounds of Formula I by condensation between an iminoether of Formula D and an acylhydrazide of Formula E or a salt or solvate thereof.

[093] Step c) is generally carried out at a temperature between 50°C and 135°C, preferably between 50°C and 90°C; more preferably the temperature is about 70°C.

[094] Compounds of Formula I can optionally be purified by flash chromatography on silica gel or chromatography on silica gel, and/or precipitation, and/or trituration, and/or filtration, and/or recrystallization.

[095] The process of the invention provides compounds of Formula I or solvate thereof having good enantiomeric excess of up to 97% and possibly in a more reproducible manner.

[096] The process of the invention occurs with the retention of stereochemistry with respect to the starting material, except to the point where racemization occurs as a secondary side reaction; thus the configuration at position 8 of the ring is defined by the configuration of the aforementioned chiral starting material.

[097] According to an advantageous embodiment, through the use of chiral 3-substituted-piperazin-2-one starting material, the process of the invention provides access to N-acyl-(3-substituted)-(8-substituted )-5,6-dihydro-[1,2,4]triazol[4,3-a]pyrazines, minimizing any racemization during the process.

[098] Compounds of Formula I

[099] The inventive process provides compounds of Formula I; preferably said compounds are the (R)-enantiomer.

[0100] According to the present invention, preferred compounds of Formula I are those of Formula I':

[0101] and pharmaceutically acceptable solvates thereof, wherein

[0102] R1 is alkyl, haloalkyl, hydroxyalkyl or alkoxyalkyl, preferably R1 is methyl, ethyl, n-propyl, hydroxyethyl, methoxyethyl, trifluoromethyl, difluoromethyl or fluoromethyl; more preferably R1 is methyl;

[0103] R2 is alkyl, alkoxyalkyl or haloalkyl, preferably R2 is methyl, ethyl, methoxymethyl, trifluoromethyl, difluoromethyl, fluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl or 2,2,2-trifluoroethyl; more preferably R2 is methyl, ethyl, methoxymethyl, trifluoromethyl, difluoromethyl or fluoromethyl; even more preferably R2 is methyl;

[0104] Ra Ra’, Rb, Rb’ and Rc independently represent H, halo, alkyl, alkoxy, haloalkyl, nitrile or thiophen-2-yl; preferably H, F, Cl, methyl, methoxy, trifluoromethyl, nitrile or thiophen-2-yl; more preferably H or F;

[0105] X1 is N and X2 is S or O; or X1 is S and X2 is N.

[0106] In one embodiment, preferred compounds of Formula I are those of Formula Ia:

[0107] and pharmaceutically acceptable solvates thereof, wherein R1, R2, Ra, Ra', Rb, Rb' and Rc are as previously defined.

[0108] In one embodiment, preferred compounds of Formula Ia are those of Formula Ia':

[0109] and pharmaceutically acceptable solvates thereof, wherein

[0110] R1 is alkyl, haloalkyl, hydroxyalkyl or alkoxyalkyl, preferably R1 is methyl, ethyl, n-propyl, hydroxyethyl, methoxyethyl, trifluoromethyl, difluoromethyl or fluoromethyl; more preferably R1 is methyl;

[0111] R2 is alkyl, alkoxyalkyl or haloalkyl, preferably R2 is methyl, ethyl, methoxymethyl, trifluoromethyl, difluoromethyl, fluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl or 2,2,2-trifluoroethyl; more preferably R2 is methyl, ethyl, methoxymethyl, trifluoromethyl, difluoromethyl or fluoromethyl; even more preferably R2 is methyl;

[0112] Ra Ra’, Rb, Rb’ and Rc independently represent H, halo, alkyl, alkoxy, haloalkyl, nitrile or thiophen-2-yl; preferably H, F, Cl, methyl, methoxy, trifluoromethyl, nitrile or thiophen-2-yl; more preferably H or F.

[0113] According to one embodiment, preferred compounds of Formula Ia and Ia' and pharmaceutically acceptable solvates thereof are those in which:

[0114] R1 is methyl, ethyl, n-propyl, hydroxyethyl, methoxyethyl, trifluoromethyl, difluoromethyl or fluoromethyl; preferably R1 is methyl;

[0115] R2 is methyl, ethyl, methoxymethyl, trifluoromethyl, difluoromethyl, fluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl or 2,2,2-trifluoroethyl; preferably R2 is methyl, ethyl, methoxymethyl, trifluoromethyl, difluoromethyl or fluoromethyl; more preferably R2 is methyl;

[0116] Ra is H, F or methyl;

[0117] Ra’ is H;

[0118] Rb is H, F, Cl or methoxy;

[0119] Rb’ is H or F; It is

[0120] Rc is H, F, Cl, methyl, trifluoromethyl or nitrile.

[0121] In one embodiment, preferred compounds of Formula I are those of Formula Ia-1:

[0122] and pharmaceutically acceptable solvates thereof, wherein:

[0123] Rc is H, F, Cl, methyl, trifluoromethyl or nitrile; preferably Rc is H, F or Cl;

[0124] R1 is alkyl, haloalkyl, hydroxyalkyl or alkoxyalkyl, preferably R1 is methyl, ethyl, n-propyl, hydroxyethyl, methoxyethyl, trifluoromethyl, difluoromethyl or fluoromethyl; more preferably R1 is methyl; It is

[0125] R2 is alkyl, alkoxyalkyl or haloalkyl, preferably R2 is methyl, ethyl, methoxymethyl, trifluoromethyl, difluoromethyl, fluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl or 2,2,2-trifluoroethyl; more preferably R2 is methyl, ethyl, methoxymethyl, trifluoromethyl, difluoromethyl or fluoromethyl; even more preferably R2 is methyl.

[0126] In one embodiment, preferred compounds of Formula Ia-1 are those of Formula Ia-1':

[0127] and pharmaceutically acceptable solvates thereof, wherein:

[0128] R1, R2 and Rc are as defined in Formula Ia-1.

[0129] In one embodiment, preferred compounds of Formula Ia are those of Formula Ia-2:

[0130] and pharmaceutically acceptable solvates thereof, wherein Ra, Ra', Rb, Rb', Rc and R2 are as defined in Formula I'.

[0131] In one embodiment, preferred compounds of Formula Ia-2 are those of Formula Ia-2':

[0132] and pharmaceutically acceptable solvates thereof, wherein Ra, Ra', Rb, Rb', Rc and R2 are as defined in Formula I'.

[0133] According to one embodiment, preferred compounds of Formula Ia-2 and Ia-2' and pharmaceutically acceptable solvates thereof are those in which:

[0134] R2 is methyl, ethyl, methoxymethyl, trifluoromethyl, difluoromethyl, fluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl or 2,2,2-trifluoroethyl; more preferably R2 is methyl, ethyl, methoxymethyl, trifluoromethyl, difluoromethyl or fluoromethyl; even more preferably R2 is methyl;

[0135] Ra is H;

[0136] Ra’ is H;

[0137] Rb is H;

[0138] Rb’ is H; It is

[0139] Rc is F.

[0140] In one embodiment, preferred compounds of Formula Ia are those of Formula Ia-3:

[0141] and pharmaceutically acceptable solvates thereof, wherein Ra, Ra', Rb, Rb', Rc and R1 are as defined in Formula I'.

[0142] In one embodiment, preferred compounds of Formula Ia-3 are those of Formula Ia-3':

[0143] and pharmaceutically acceptable solvates thereof, wherein Ra, Ra', Rb, Rb', Rc and R1 are as defined in Formula I'.

[0144] In one embodiment, preferred compounds of Formula I are those of Formula Ib:

[0145] and pharmaceutically acceptable solvates thereof, wherein

[0146] Rc is F or thiophen-2-yl; preferably Rc is F.

[0147] R2 is methyl, ethyl, methoxymethyl, trifluoromethyl, difluoromethyl, fluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl or 2,2,2-trifluoroethyl, preferably R2 is methyl, ethyl, trifluoromethyl, difluoromethyl or fluoromethyl, preferably R2 is methyl, ethyl, 1-fluoroethyl, 1,1-difluoroethyl or 2,2,2-trifluoroethyl, preferably R2 is methyl or ethyl, preferably R2 is methyl.

[0148] According to one embodiment, compounds of Formula Ib do not comprise a compound in which Rc is thiophen-2-yl when R2 is methyl.

[0149] In one embodiment, preferred compounds of Formula Ib are those of Formula Ib':

[0150] and pharmaceutically acceptable solvates thereof, wherein Rc and R2 are as defined in Formula Ib.

[0151] In one embodiment, preferred compounds of Formula Ib' are those in which Rc is F when R2 is methyl.

[0152] In one embodiment, preferred compounds of Formula Ib' are those of Formula Ib-1:

[0153] and pharmaceutically acceptable solvates thereof, wherein R2 are as defined in Formula Ib.

[0154] In one embodiment, preferred compounds of Formula I are those of Formula Ic:

[0155] and pharmaceutically acceptable solvates thereof, wherein Ra, Ra', Rb, Rb', Rc, R1 and R2 are as defined in Formula I'.

[0156] In one embodiment, preferred compounds of Formula Ic are those of Formula Ic':

[0157] and pharmaceutically acceptable solvates thereof, wherein Ra, Ra', Rb, Rb', Rc, R1 and R2 are as defined in Formula Ic.

[0158] Preferred compounds of Formula Ic and Ic' and pharmaceutically acceptable solvates thereof are those in which:

[0159] Ra is H, F or methyl;

[0160] Ra’ is H;

[0161] Rb is H, F, Cl or methoxy;

[0162] Rb’ is H or F;

[0163] Rc is H, F, Cl, methyl, trifluoromethyl or nitrile;

[0164] R1 is methyl, ethyl, n-propyl or hydroxyethyl;

[0165] R2 is methyl, ethyl or trifluoromethyl.

[0166] Particularly preferred compounds of Formula I of the invention are those listed in table 1 below.

[0167] In table 1, the term “Cpd” means compound.

[0168] The compounds in Table 1 are named using ChemBioDraw® Ultra version 12.0 (PerkinElmer).

[0169] Synthesis Intermediates

[0170] In another aspect, the invention provides intermediates for the synthesis of compounds of Formula I, in particular according to the process of the invention.

[0171] Especially, the process of the invention provides compounds of general Formula C:

[0172] and pharmaceutically acceptable solvates thereof, wherein Ar and R1 are as defined in Formula I.

[0173] In one embodiment, preferred compounds of Formula C or solvates thereof are those of Formula Ca:

[0174] and pharmaceutically acceptable solvates thereof, wherein

[0175] R1 is alkyl, haloalkyl, hydroxyalkyl or alkoxyalkyl, preferably R1 is methyl, ethyl, n-propyl, hydroxyethyl, methoxyethyl, trifluoromethyl, difluoromethyl or fluoromethyl; more preferably R1 is methyl;

[0176] Ra Ra’, Rb, Rb’ and Rc independently represent H, halo, alkyl, alkoxy, haloalkyl, nitrile or thiophen-2-yl; preferably H, F, Cl, methyl, methoxy, trifluoromethyl, nitrile or thiophen-2-yl; more preferably H or F.

[0177] In a preferred embodiment, the compound of Formula C is the (R)-enantiomer.

[0178] In one embodiment, preferred compounds of Formula C or solvates thereof are those of Formula Cb:

[0179] and pharmaceutically acceptable solvates thereof, wherein, Rc and R1 are as defined in Formula C-a.

[0180] In one embodiment, preferred compounds of Formula C and solvates thereof are those of Formula C-b':

[0181] and pharmaceutically acceptable solvates thereof, wherein Rc and R1 are as defined in Formula C-a.

[0182] In one embodiment, preferred compounds of Formula C and solvates thereof are those of Formula Ca-1:

[0183] and pharmaceutically acceptable solvates thereof, wherein Ra, Ra', Rb, Rb' and Rc are as defined in Formula C-a.

[0184] In one embodiment, preferred compounds of Formula C and solvates thereof are those of Formula Ca-1':

[0185] and pharmaceutically acceptable solvates thereof, wherein Ra, Ra', Rb, Rb', and Rc are as defined in Formula C-a.

[0186] In one embodiment, preferred compounds of Formula C and solvates thereof are those of Formula C-b1:

[0187] and pharmaceutically acceptable solvates thereof, wherein Rc is as defined in Formula C-a.

[0188] In one embodiment, preferred compounds of Formula C and solvates thereof are those of Formula C-b1':

[0189] and pharmaceutically acceptable solvates thereof, wherein Rc is as defined in Formula C-a.

[0190] In a preferred embodiment, preferred compounds of Formula C and solvates thereof are compounds of Formula C-b2:

[0191] In one embodiment, preferred compounds of Formula C and solvates thereof are compounds of Formula C-b2':

[0192] and pharmaceutically acceptable solvates thereof.

[0193] The process of the invention also provides compounds of general Formula D:

[0194] and pharmaceutically acceptable solvates thereof, wherein Ar and R1 are as defined above, and R3 is C1-C2 alkyl.

[0195] In a preferred embodiment, a compound of Formula D is a compound of Formula D-1 ((3-ethoxy-2-methyl-5,6-dihydropyrazin-1(2H)-yl)(4-fluorophenyl)methanone ):

[0196] In a preferred embodiment, compound of Formula D is the (R)-enantiomer.

DEFINITIONS

[0197] In the present invention, the following terms have the following meanings:

[0198] The expression “about” that precedes a number means more or less 10% of the value of said number.

[0199] The term “halo” or “halogen” means fluorine, chlorine, bromine, or iodine. Preferred halo groups are fluorine and chlorine.

[0200] The term “alkyl” by itself or as part of another substituent refers to a hydrocarbyl radical of the Formula CnH2n+1 where n is a number greater than or equal to 1. “Cx-Cy alkyl” refers to groups alkyl that comprise from x to y carbon atoms. Generally, alkyl groups of this invention comprise 1 to 4 carbon atoms (C1-C4), preferably 1 to 3 carbon atoms (C1-C3), more preferably 1 to 2 carbon atoms (C1-C2). Alkyl groups can be linear or branched. Suitable alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl.

[0201] The term “haloalkyl” alone or in combination refers to an alkyl radical having the meaning as previously defined, in which one or more hydrogens are replaced with a halogen as previously defined. Non-limiting examples of such haloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and the like.

[0202] The term “alkoxy” refers to any -O-alkyl group, where alkyl is as previously defined. Suitable alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, f-butoxy, sec-butoxy, and n-pentoxy.

[0203] The term “alkoxyalkyl” refers to any -alkyl-O-alkyl group, where alkyl is as previously defined.

[0204] The term “hydroxyalkyl” refers to any -alkyl-OH group, where alkyl is as previously defined. The term “(C1-C2)hydroxyalkyl” refers to any (C1-C2)alkyl-OH.

[0205] The term “(C1-C2)alkylsulfate” refers to any compound of (C1-C2)alkyl-O-SO3-, where alkyl is as previously defined.

[0206] The term “(C1-C2)chloroformate” refers to any compound (C1-C2)alkyl-O-COCl, where alkyl is as previously defined.

[0207] The term “tri(C1-C2 alkyl)oxonium salt” refers to any [C1-C2)alkyl]3-O+ salt, where alkyl is as previously defined.

[0208] The term “thiophen-2-yl” as used here means a group of the Formula

[0209] where the arrow defines the attachment point.

[0210] The term "ester" or "esters" as used herein means a group selected from the group consisting of unsubstituted C1-C4 alkyloxycarbonyl, unsubstituted phenyloxycarbonyl or unsubstituted phenyl(C1-C2 alkyl)oxycarbonyl. Suitable ester groups include methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl, i-propyloxycarbonyl, n-butyloxycarbonyl, i-butyloxycarbonyl, s-butyloxycarbonyl, t-butyloxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl and phenethyloxycarbonyl, among which methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, i-propyloxycarbonyl , phenyloxycarbonyl, and benzyloxycarbonyl are preferred.

[0211] The term “protecting group” refers to a suitable organic moiety used to protect a certain functional group in a chemical synthesis. In the present invention, protecting group refers to an organic moiety selected from 2,4-dimethoxybenzyl (DMB), 4-methoxybenzyl (PMB), tert-butoxycarbonyl (Boc), allyl, diphenyl-phosphiramide (DPP) and/or 2- trimethylsilylethanesulfonyl (SES).

[0212] The numbering scheme for N-acyl-(3-substituted)-(8-substituted)-5,6-dihydro-[1,2,4]triazol[4,3-a]pyrazines of the invention is shown below:

[0213] Compounds of Formula I and subformulas thereof contain a stereogenic carbon center in position 8 and, thus, can exist as (R)- and (S)- enantiomers. The use of a solid line to represent the bond between position 8 of the ring and R1, with a star close to position 8, (i.e., *) indicates that the enantiomers are individual, thus excluding racemic mixtures thereof.

[0214] A full wedge for the bond between position 8 of the ring and R1 is used to represent the (S)-enantiomer and a dotted wedge for the bond between the 8 position of the ring and R1 is used to represent the (R)-enantiomer.

[0215] The term “solvate” is used here to describe a compound in this invention that contains stoichiometric or substoichiometric amounts of one or more pharmaceutically acceptable solvent molecules such as ethanol. The term “hydrate” refers to when said solvent is water.

[0216] All references to compounds of Formula I include references to solvates, multicomponent complexes and liquid crystals thereof.

[0217] The compounds of the invention include compounds of Formula I, Formula C and Formula D as previously defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including tautomeric isomers and isotopically labeled compounds of Formula I.

[0218] Furthermore, with regard to salts of the compounds of the invention, it should be noted that the invention in its broadest sense also included salts, which can, for example, be used in the isolation and/or purification of the compounds of the invention . For example, salts formed with optically active acids or bases can be used to form diastereoisomeric salts that can facilitate the separation of optically active isomers of the compounds of Formula E above. EXAMPLES

[0219] The present invention will now be better understood with reference to the following examples. These examples are intended to be representative of specific embodiments of the invention, and are not considered to limit the scope of the invention. CHEMICAL EXAMPLES

[0220] Reaction schemes as described in the example section illustrate by way of example the different possible approaches.

[0221] All reported temperatures are expressed in degrees Celsius (°C); All reactions were performed at room temperature (RT) unless otherwise stated.

[0222] All reactions were followed by thin layer chromatography analysis (TLC plates) (TLC, silica gel 60 F254, Merck) was used to monitor the reactions, establish flash chromatography conditions on silica gel. All other developing agents/TLC visualization techniques, experimental setup or purification procedures that were used in this invention, when not described in specific detail, are considered known to those skilled in the art and are described in such standard reference manuals as: i) Gordon, A. J.; Ford, R. A. “The Chemist’s Companion - A Handbook of Practical Data, Techniques, and References,” Wiley: New York, 1972; ii) Vogel’s Textbook of Practical Organic Chemistry, Pearson Prentice Hall: London, 1989.

[0223] HPLC-MS spectra were typically obtained on an Agilent LCMS using electrospray ionization (ESI). The Agilent instrument includes a 1200 autosampler, a 1100 binary pump, a 1100 multiwavelength ultraviolet detector, and a 6100 single-quad mass spectrometer. The chromatography column used was Sunfire 3.5 μm, C18, 3.0 x 50 mm in dimensions. The eluent typically used was a mixture of solution A (TFA 0.1% in H2O) and solution B (TFA 0.1% in MeCN). Gradient was applied at a flow rate of 1.3 mL per minute as follows: gradient A: held at initial conditions of 5% solution B for 0.2 minute, increased linearly to 95% solution B over 6 minutes, held at 95% for 1.75 minutes, returned to initial conditions in 0.25 minutes and maintained for 2.0 minutes; gradient B: maintained at the initial conditions of 5% solution B for 0.2 minutes, increased linearly to 95% in 2.0 minutes, maintained at 95% for 1.75 minutes, returned to initial conditions in 0.25 minutes and held for 2 minutes.

[0224] Chiral purity determination was made using chiral HPLC which was performed on an Agilent 1100 (binary pump and an ultraviolet multiwavelength detector) with manual or automatic injection capabilities (Autosampler 1100). Column used is CHIRALPAK IA 5 μm, 4.6 x 250 mm in isocratic mode. Choice of eluent was based on the particularities of each separation. Additional details regarding the chiral HPLC methods used are provided below:

[0225] Method A: CHIRALPAK IA 5 μm column, 4.6 x 250 mm, eluent: DCM/EtOH (98:2 v/v) plus 0.1% DEA, flow rate: 1.0 mL per minute; UV detection at 254 nm; column at RT, eluent was used as sample solvent.

[0226] Method B: CHIRALPAK IA 5μm column 4.6 x 250 mm, eluent: MTBE plus 0.1% DEA, flow rate: 1.0 mL per minute; UV detection at 254 nm, column at RT, eluent was used as sample solvent.

[0227] 1H (300 MHz), 19F NMR (282 MHz) and 13C NMR (75 MHz) spectra were recorded on a Bruker Avance ARX 300 instrument. Chemical shifts are expressed in parts per million, (ppm, δ units). Coupling constants are expressed in Hertz (Hz). Abbreviations for multiplicities observed in NMR spectra are as follows: s (singlet), d (doublet), t (triplet), q (quadruplet), m (multiplet), br (broad).

[0228] Solvents, reagents, and starting materials were purchased and used as received from commercial suppliers unless otherwise specified.

[0229] The following abbreviations are used:

[0230] DCM: Dichloromethane,

[0231] DEA: diethylamine,

[0232] ee: Enantiomeric excess,

[0233] EtOAc: Ethyl acetate,

[0234] EtOH: Ethanol,

[0235] L: Liter(s),

[0236] MeOH: Methanol,

[0237] mL: Milliliter(s),

[0238] mmol: Millimol(s),

[0239] min: Minute(s),

[0240] MTBE: methyl tert-butyl ether,

[0241] P: UV purity at 254 nm or 215 nm determined by HPLC-MS,

[0242] RT: Ambient temperature.

[0243] All compounds disclosed in the present application are named using ChemDraw Ultra 12® purchased from CambridgeSoft (Cambridge, MA, USA). Scheme 1: General synthetic scheme.

[0244] General method A: Acylation of ketopiperazine A by B to make C available Scheme 2: Acylation of A.

[0245] General method A is illustrated by the synthesis of the intermediate (R)-4-(4-fluorobenzoyl)-3-methylpiperazin-2-one (i.e., compound C in which Ar is 4-F-Ph and R1 is ( R)-Me).

[0246] To a solution of (R)-3-methylpiperazin-2-one (14 g, 123 mmol) in commercial anhydrous DCM (400 mL) at RT was added 4-methylmorpholine (12.8 mL, 125 mmol) in drops for 1 minute, followed by 4-fluorobenzoyl chloride (14.5 mL, 123 mmol) drops for 5 minutes. The reaction mixture was stirred at RT for 10 minutes and then washed with HCl (1M, 150 mL) and NaOH (1M, 150 mL). The organic layer was dried over MgSO4, filtered and evaporated under low pressure (1-2 mbar). The residue obtained was solubilized in a hot mixture of DCM (140 mL) and MTBE (315 mL). Pentane (350 mL) was then added until a cloudy solution was obtained. After 5 minutes at RT and 14 hours at 4°C (freezer), the white crystals were filtered, washed with pentane (140 mL) and dried under vacuum (1-2 mbar, 40 °C) for 1 hour to provide white needles. . Yield: 27.6 g, 95%. HPLC-MS: P > 99%, tR = 1.8 min, (M+H)+: 237; Chiral HPLC - Method A: %ee > 99.9; 1H NMR (CDCl3): δ 7.4 (m, 2H), 7.1 (m, 2H), 6.4 (bs, 1H), 4.8 (m, 1H), 4.3 (m, 1H ), 3.5 (m, 1H), 3.3 (m, 2H), 1.5 (d, J = 6.9 Hz, 3H); 19F-NMR (CDCl3): δ -97.4 (s, 1F).

[0247] General method B: Formation of iminoether D from acylated ketopiperazine C

[0248] General method B is illustrated by the synthesis of the intermediate (R)-(3-ethoxy-2-methyl-5,6-dihydropyrazin-1(2H)-yl)(4-fluorophenyl)methanone (i.e. compound D in which Ar is 4-F-Ph and R1 is (R)-Me).

[0249] To a suspension of sodium carbonate (0.3 g, 2.86 mmol) in DCM (1.3 mL) at 0°C was added (R)-4-(4-fluorobenzoyl)-3- methylpiperazin-2-one (0.3g, 1.27 mmol) in one portion, followed by commercial triethyloxonium tetrafluoroborate (0.3g, 1.59 mmol) in one portion. Then, the reaction mixture was further stirred at RT for 45 minutes, after which the reaction mixture was diluted with brine (20 mL). The layers were separated and the aqueous layer was further extracted with DCM (20 ml). The organic layers were combined, dried over MgSO4, filtered and concentrated under low pressure. The crude compound was then purified on silica gel (EtOAc) to provide the desired product as a colorless oil. Yield: 0.16 g, 47%. HPLC-MS: P = 96%, tR = 1.8 min, (M+H2O+H)+: 283; Chiral HPLC - Method B: %ee > 99.9; 1H NMR (CDCl3): δ 7.4 (m, 2H), 7.1 (m, 2H), 4.9 (m, 1H), 4.1 (m, 2H), 3.5 (m, 3H ), 3.1 (m, 1H), 1.4 (m, 3H), 1.2 (m, 3H); 19F NMR (CDCl3): δ -96.7 (s, 1F).

[0250] General method C: Formation of triazolpiperazine I from iminoether D Scheme 4: Formation of triazolpiperazine.

[0251] General method C is illustrated by the synthesis of (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-di -hydro-[1,2,4]triazol[4,3-a]pyrazin-7(8H)-yl)methanone (i.e., compound I in which Ar is 4-F-Ph, R1 is (R)- Me, R2 is Me, X1 = N and X2 = S - Compound 1).

[0252] A (R)-(3-ethoxy-2-methyl-5,6-dihydropyrazin-1(2H)-yl)(4-fluorophenyl) (0.16 g, 0.6 mmol) at RT 3-methyl-1,2,4-thiadiazol-5-carbohydrazide (0.10 g, 0.6 mmol) was added in one portion. The mixture was diluted with commercially anhydrous MeOH (0.6 mL) and the resulting mixture was heated at 70 °C for 5 hours.

[0253] The reaction mixture was then allowed to reach RT after which the solvent was removed under low pressure (1-2 mbar). The crude residue was then dissolved in DCM (25 mL), and the organic phase thus obtained was washed with NaOH (1 M, 25 mL) and HCl (1 M, 25 mL). The organic layer was then dried over MgSO4, filtered and concentrated under low pressure (1-2 mbar) to provide the desired product as a colorless oil. Yield: 0.10 g, 45%.

[0254] Compound 1: HPLC-MS: P = 94%, tR = 2.1 min, (M+H)+: 359; Chiral HPLC: %ee = 96.7; 1H NMR (CDCl3): δ 7.5 (m, 2H), 7.3 (m, 2H), 5.8 (m, 1H), 4.9 (m, 1H), 4.6 (m, 1H ), 4.3 (m, 1H), 3.5 (m, 1H), 2.7 (s, 3H), 1.7 (d, J = 6.9 Hz, 3H); 19F NMR (CDCl3): δ -98.4 (s, 1F).

[0255] The following compound was also prepared by ad hoc reagents using General Method C:

[0256] Compound 2: From 3-methyl-1,2,4-oxadiazol-5-carbohydrazide (48h at 60°C, crude compound purified on silica gel (EtOAc/MeOH 99/1)). Yield: 0.14 g, 53%. HPLC-MS: P > 98%, tR = 2.0 mins, (M+H)+: 343; HPLCchiral: %ee = 92.0; 1H NMR (CDCl3): δ 7.5 (m, 2H), 7.2 (m, 2H), 5.8 (m, 1H), 4.9 (dd, J = 3.3, 13.5 Hz , 1H), 4.6 (m, 1H), 4.3 (td, J = 4.0, 12.8 Hz, 1H), 3.5 (m, 1H), 2.5 (s, 3H) , 1.7 (d, J = 6.9 Hz, 3H); 19F-NMR (CDCl3): δ -98.3 (s, 1F).

Claims (14)

1. Process, characterized by the fact that it is to prepare an N-acyl-(3-substituted)-(8-substituted)-5,6-dihydro-[1,2,4]triazol[4,3- a] chiral pyrazine of general Formula I: or solvates thereof, wherein R1 is alkyl, haloalkyl, hydroxyalkyl or alkoxyalkyl; R2 is alkyl, alkoxyalkyl or haloalkyl; Ar is a phenyl group, optionally substituted by one or more substituent(s) selected from halo, alkyl, alkoxy, haloalkyl, nitrile and thiophen-2-yl; X1 is N and X2 is S or O; or X1 is S and X2 is N; — represents a single or double bond depending on X1 and X2; and the line filled with a star indicates that the enantiomers are individual, excluding racemic mixtures thereof; said process comprising the following steps: a) reacting a compound of Formula A: and R1 is as defined above; and the line filled with a star indicates that the enantiomers are individual, excluding racemic mixtures thereof; with a compound of Formula B: where Ar is as previously defined; and Y is hydroxyl or halo; to obtain a compound of Formula C: wherein the line filled with a star indicates that the enantiomers are individual, excluding racemic mixtures thereof; b) converting the compound of Formula C with a tri(C1-C2 alkyl)oxonium salt, a (C1-C2)alkylsulfate, a (C1-C2)chloroformate or PCl5/POCl3/(C1-C2)hydroxyalkyl, in a manner to obtain a compound of Formula D: wherein Ar and R1 are as defined above, R3 is C1-C2 alkyl; and the line filled with a star indicates that the enantiomers are individual, excluding racemic mixtures thereof; in the presence of a base; c) react the compound of Formula D with a compound of Formula E or a salt or solvate thereof, wherein X1, X2 and R2 are as defined above; in order to obtain a compound of Formula I or solvate thereof. 2. Process according to claim 1, characterized by the fact that it occurs with the retention of stereochemistry in relation to the starting material. 3. Process according to any one of claims 1 and 2, characterized by the fact that the reaction of each step is carried out under controlled mild experimental conditions. 4. Process according to any one of claims 1 to 3, characterized in that the reaction is carried out in an organic solvent at a temperature equal to or below the boiling point of the organic solvent. 5. Process according to any one of claims 1 to 4, characterized in that the process does not use any protecting group. 6. Process according to any one of claims 1 to 5, characterized in that the base in step b) is selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate or cesium carbonate. 7. Process according to any one of claims 1 to 6, characterized by the fact that the compound of Formula I is the (R)-enantiomer. 8. Process according to any one of claims 1 to 7, characterized by the fact that the compound of Formula I is 9. Process according to any one of claims 1 to 7, characterized by the fact that the compound of Formula I is 10. Process according to any one of claims 1 to 9, characterized by the fact that the reaction of step b) is carried out in an organic solvent at a temperature equal to or below the boiling point of the organic solvent. 11. Process according to any one of claims 1 to 10, characterized by the fact that the reactions of steps a) and b) are carried out in dichloromethane. 12. Process according to claim 11, characterized by the fact that the reactions of steps a) and b) are carried out at room temperature. 13. Process according to any one of claims 1 to 12, characterized by the fact that the reaction in step c) is carried out at a temperature between 50oC and 135oC. 14. Process according to claim 13, characterized by the fact that the reaction in step c) is carried out at a temperature between 50oC and 90oC.