The present application relates to a novel and improved process for preparing 5- (hydroxyalkyl)-, 5 -(alkoxy carbonyl)- and 5 -(carboxamide)- 1 -aryl- 1,2, 4-triazole derivatives of the general formulas (XXI), (III) and (IV) in which Ar ¹ represents a phenyl group, which is optionally substituted with one or more halogen atoms, R ¹ represents a (Ci-Cz -alkyl group, which is optionally substituted with one or more substituents selected from a fluorine atom, hydroxy and oxo, R ² represents a (Ci-C -alkoxycarbonyl group, and Ar ² represents a phenyl group or a 5- or 6-membered heteroaryl group attached via a ring carbon atom having one or two ring heteroatoms selected from a nitrogen atom and a sulfur atom, wherein any phenyl group and any 5- or 6- membered heteroaryl group are each optionally substituted, identically or differently, with one or two groups selected from a halogen atom, nitro, cyano, (Ci-Cz -alkyl, (Ci-C- -alkoxy, (Ci-C -alkylsulfanyl, (Ci-C- -alkoxycarbonyl, aminocarbonyl, -C(=0)N(H)CH _3, -

S(=0) ₂ CH ₃ , and -S(=0) ₂ NH ₂ , wherein said (Ci-Cz -alkyl group, said (Ci-C- -alkoxy group and said (Ci-C- -alkylsulfanyl group are each optionally substituted with up to three fluorine atoms, and to novel precursors for preparation thereof. Compounds of the formula (IV) as disclosed in WO 2017/191102-A1 and WO 2017/191107- Al, are highly potent and selective antagonists of the Via receptor and can be used as agents for prophylaxis and/or treatment of cardiovascular disorders and renal disorders, for example acute and chronic kidney diseases including diabetic nephropathy, acute and chronic heart failure, preeclampsia, peripheral arterial disease (PAD), coronary microvascular dysfunction (CMD), Raynaud’s syndrome and dysmenorrhea.

3-[[3-(4-Chlorophenyl)-5-oxo-4-((2S)-3,3,3-trifluoro-2-hy droxypropyl)-4,5-dihydro-lH- 1 ,2,4-triazol- 1 -yl]methyl] - 1 -[3 -(trifluoromethyl)pyridin-2-yl] - 1H- 1 ,2,4-triazole-5 - carboxamide, which is example 2 of WO 2017/191102-A1, corresponds to the compound of formula (IV-l-S): (IV-l-S).

3-[[3-(4-Chlorophenyl)-5-oxo-4-((2S)-3,3,3-trifluoro-2-hy droxypropyl)-4,5-dihydro-lH- 1 ,2,4-triazol- 1 -yl]methyl] - 1 -[3 -(trifluoromethyl)pyridin-2-yl] - 1H- 1 ,2,4-triazole-5 - carboxamide (IV-l-S) is known to be a highly potent and selective antagonist of the Vasopressin Via receptor.

Further compounds of the formula (XXI), (III) and (IV) and structurally similar compounds which act as potent selective or dual Vla/V2 receptor antagonists are disclosed in WO 2016/071212, WO 2017/191105, WO 2017/191112, WO 2017/191114, WO 2017/191115, WO 2018/073144, WO 2019/081292, WO 2019/081291, WO 2019/081299, WO 2019/081302, WO 2019/081303, WO 2019/081306, WO 2019/081307.

A general process for the preparation of substituted 1,2,4-triazole derivatives is described in WO 2011/104322 (see page 20-30 and claim 5, examples 17-20, 73,74, 77-83, 89-96, 110, 111, 127, 128, 139, 140, 146 therein; scheme 1 below). However 5 -aryl-substituted 1,2,4- triazole derivatives (Q = 1,2,4-triazolyl) were there prepared by a different synthetic route via a hydrazide intermediate (see page 32, scheme 8, cf. examples 62-29 therein; scheme 2 below).

Scheme 1 and 2 below show the process for preparing the substituted 1,2,4-triazole derivatives according to WO 2011/104322.

Scheme 1: General synthesis of substituted 1,2,4-triazole derivatives according to WO

2011/104322.

Scheme 2: Synthesis of 5 -aryl-substituted 1,2,4-triazole derivatives according to WO 2011/104322. Compounds of the formula (IV) and the preparation thereof are described in WO 2017/191102, WO 2017/191105 and WO 2017/191107. The research synthesis described therein is regarded as the closest prior art. Proceeding from 5-(4-chlorophenyl)-4-|(2.Y)-3.3.3-trifluoro-2-hydroxypropyl |-2.4-dihydro- 3H-l,2,4-triazol-3-one (II-l-S) or 5-(4-chlorophcnyl)-4-|(2//)-3.3.3-trifluoro-2-hydroxy- propyl]-2,4-dihydro-3H-l,2,4-triazol-3-one (II-l-R), the target compounds of the formula (I) are prepared in the gram range in 4 stages using a linear synthesis with an overall yield of 3- 48% of theory. Scheme 3 below shows the process for preparing the compounds of the formula (IV) according to WO 2017/191102, WO 2017/191105 and WO 2017/191107 (see WO 2017/191102, page 13-23, claim 4, examples therein; WO 2017/191105, page 17-30, claim 5, examples therein; WO 2017/191107, page 14-24, claim 4, examples therein) .

Scheme 3: Synthesis of compounds of the formula (IV) according to WO 2017/191102, WO 2017/191105 and WO 2017/191107.

For preparation of 5 -(carboxamide)- 1-pyridinyl- 1,2, 4-triazole derivatives (IV), 5-(4- chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydr o-3H-l,2,4-triazol-3-one (II-l- R/S) is converted to {3-(4-chlorophenyl)-5-oxo-4-[3,3,3-trifluoro-2-hydroxypropyl ]-4,5- dihydro- 177-1, 2, 4-triazol-l-yl} acetonitrile (X-R/S). Subsequently, the nitrile compound (X-

R/S) is converted by reaction with sodium methoxide to methyl 2-{3-(4-chlorophenyl)-5-oxo- 4-[3 ,3 ,3 -trifluoro-2-hydroxypropyl] -4,5 -dihydro- 177- 1 ,2,4-triazol- 1 -yl } ethanimidate (XI- R/S). The 1,2,4-triazole ring is then formed via a one-pot three-component cyclization reaction, wherein the imino ester compound (XI-R/S) reacts with methyl chlorooxoacetate (XII) and a substituted arylhydrazine compound (XIII), and the methyl 3-({3-(4- chlorophenyl)-5 -oxo-4-[3 ,3 ,3 -trifluoro-2-hydroxypropyl] -4,5 -dihydro- 1H- 1 ,2,4-triazol- 1 - yl}methyl)-l-(aryl)-lH-l,2,4-triazole-5-carboxylate (III-A) is obtained. The subsequent aminolysis of the methyl ester group affords the target compounds of the formula (IV-A).

However, this process which is known from WO 2017/191102, WO 2017/191105 and WO 2017/191107 has some disadvantages in the reaction regime which have an unfavourable effect in the preparation of the compounds of the formula (IV) on the industrial scale. It has been found by the inventors in internal experiments to optimize and upscale the known process for a production on an industrial scale, that the reaction outcome was not always reproducible with regard to selectivity in the cyclization step (XI-R S) to (III-A). Thus in some batches an unwanted cyclization on the second carbonyl function led to the formation of a 6,5-fused heterocycle byproduct in a significant amount. Therefore yields for the end product were lower and the undesired byproducts had to be separated via chromatography. For an industrial process it is desirable to have a reliable process in terms of yield and selectivity and thus tolerant to small deviations in process parameters or use of different batches of reagents. Any time-consuming and cost-intensive purification steps shall be avoided. It has been found that either copper sulfate or zinc sulfate could promote best the desired cyclization. However, this is also not favourable for an industrial process in the pharmaceutical industry since the remaining metal salts have to be depleted down to below the maximum limit permissible in the product for regulatory reasons, which implies additional cost and inconvenience.

Another disadvantageous aspect of the synthesis according to WO 2017/191102, WO 2017/191105 and WO 2017/191107 is the linear synthetic route starting from a precious chiral precursor (II-l-R S). This linear sequence is unoptimal in this case since the yield of the step prior to the last step is the lowest of the whole synthesis. That means that all intermediates and reagents used thoughout the synthesis are mostly wasted and do not contribute to make the active ingredient. Overall this linear process is less economical and is therefore disadvantageous for a synthesis on industrial scale. There was therefore a need for a synthetic route practicable on industrial scale that can afford the compounds of the formula (III) and (IV) reproducibly in a high overall yield, with lower production costs and high purity.

Surprisingly, a very efficient process for the preparation of the compounds of the formula (III) and (IV), which meets the demands mentioned above, has now been found. The novel process described herein enables an efficient synthesis of 5 -(alkoxy carbonyl)- and 5-(carboxamide)- 1 -aryl- 1,2, 4-triazole derivatives as well as structurally related compounds. An important advantage of the novel process according to the invention is the modularity of the process. The new route is convergent and allows for a late-stage coupling of the chiral precursors of formula (II-l-R/S).

Favorably, the new inventive process may further be applied to 5 -(hydroxyethyl)-l -aryl- 1,2,4- triazole derivatives of the general formula (XXI)

Pecavaptan, which is 5-(4-chlorophenyl)-2-({l-(3-chlorophenyl)-5-[(lS)-l-hydroxye thyl]- lH-l,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydr oxypropyl]-2,4-dihydro-3H- l,2,4-triazol-3-one and is disclosed as example 79 of WO 2016/071212-A1, corresponds to the compound of formula (XXI-l-S-S) and is a highly potent dual vasopressin receptor antagonist (Via and V2). The synthesis of pecavaptan and congeners thereof (XXI) is described in WO 2016/071212 and WO 2017/191104. Proceeding from 5-(4-chlorophenyl)-4-|(2,Y)-3,3,3-trifluoro-2- hydroxypropyl]-2,4-dihydro-3H-l,2,4-triazol-3-one (II-l-S), the target compounds of the formula (XXI) are prepared in 4 stages with an overall yield of not more than -12% of theory (WO 2016/071212) and between -24-63% of theory (WO 2017/191104). Schemes 4 and 5 below show the process for preparing the compounds of the formula (XXI) according to WO 2016/071212 and WO 2017/191104.

Scheme 4: Synthesis of compounds of the formula (XXI) according to WO 2016/071212.

[R ^1A , R ^1B = hydrogen, fluorine, chlorine, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, ethyl, methoxy, difluoromethoxy and trifluoromethoxy. Compound numbering according to WO 2016/071212] Scheme 5: Synthesis of compounds of the formula (XXI) according to WO 2017/191104.

[R ^1A , R ^1B = hydrogen, fluorine, chlorine, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, ethyl, methoxy, difluoromethoxy and trifluoromethoxy; a) Na2C03, methyl isobutyl ketone; b) sodium methoxide, MeOH, c) 1. (XII- A), DIPEA, toluene/THF, 2. (XIII), DIPEA, THF; d) NaOH, MeOH; Compound numbering according to WO 2017/191104]

Similar as discussed above for the synthesis of 5 -(alkoxy carbonyl)- and 5 -(carboxamide)- 1- aryl- 1,2, 4-triazole derivatives (III) and (IV), is a linear synthetic route as described in WO 2016/071212 and WO 2017/191104 less economical and may therefore be disadvantageous for a synthesis on industrial scale. The novel process described herein enables an efficient synthesis of 5 -(hydroxyethyl)-l -aryl- 1, 2, 4-triazole derivatives. An important advantage of the novel process according to the invention is the modularity of the process. The new route is convergent and allows for a late- stage coupling of the chiral precursors of formula (II-l-R S).

The schemes and process steps which are described hereinafter are synthetic routes to the inventive compounds of the general formula (XXI), (III) and (IV) and should not be regarded as a restriction. The person skilled in the art will be aware that the sequence of transformations as shown by way of example in Schemes 6 to 10 can be modified in various ways, and the sequence presented should therefore not be regarded as a restriction. In addition, it is possible to convert functional groups of individual radicals and substituents, especially those listed under R ¹ , R ² and Ar ² , before and/or after the transformations described by way of example, proceeding from other compounds of the formula (I) and (II) or precursors thereof obtained by the above processes. These transformations are conducted by customary methods familiar to the person skilled in the art and include, for example, reactions such as nucleophilic or electrophilic substitution reactions, transition metal-mediated coupling reactions, preparation and addition reactions of metal organyls (e.g. Grignard compounds or lithium organyls), oxidation and reduction reactions, hydrogenation, halogenation (e.g. fluorination, bromination), dehalogenation, animation, alkylation and acylation, the formation of carboxylic esters, carboxamides and sulphonamides, ester cleavage and hydrolysis, and the introduction and removal of temporary protecting groups or other reactions known to those skilled in the art. These conversions also include those wherein a functionality is introduced, which enables further conversion of substituents. Suitable protecting groups and reagents and reaction conditions for the introduction and detachment thereof are known to those skilled in the art (see, for example, T.W. Greene and P.G.M. Wuts; "Protective Groups in Organic Synthesis 3rd Edition, Wiley 1999). Specific examples are cited in the text passages which follow.

Scheme 6 below illustrates the novel process according to the invention for preparing the compounds of the formula (III-l-S) and (IV-l-S).

Scheme 6: Process according to the invention for preparing the compounds of the formula (III-l-S) and (IV-l-S).

(IV-1-S)

[For substituents: see below; reaction conditions: a) K ₂ CO ₃ , TBAI, acetone; b) NH ₃ , MeOH] There follows a discussion of the individual stages of the process according to the invention for preparing the compound of the formula (III-l-S) and (IV-l-S) according to Scheme 6.

For preparation of methyl 3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydro xy- propyl]-4,5-dihydro-lH-l,2,4-triazol-l-yl}methyl)-l-[3-(trif luoromethyl)pyridin-2-yl]-lH- l,2,4-triazole-5-carboxylate (III-l-S), 3-(4-Chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxy- propyl]-lH-l,2,4-triazol-5-one (II-l-S) is reacted with methyl 5-(bromomethyl)-2-[3- (trifluoromethyl)-2-pyridyl]-l,2,4-triazole-3-carboxylate (1-1) in a nucleophilic substitution reaction (Step 1). The methyl ester compound (III-l-S) may then be converted to the free amide (IV-l-S) in an aminolysis reaction (Step 2). Other 5 -(alkoxy carbonyl)- 1 -aryl- 1,2,4- triazole derivatives (III) and their corresponding 5 -(carboxamide) analogues (IV) may be prepared by an analogous procedure.

An advantageous feature is the late-stage coupling of the chiral precursors of formula (II-R/S) in Step 1. This coupling step is high-yielding and affords the compounds of formula (III) in high yield (80% for III-l-S) on a kilogram scale. Scheme 7 below illustrates the novel process according to the invention for preparing the compounds of the formula (XXI-l-S/S).

Scheme 7: Process according to the invention for preparing the compounds of the formula (XXI-l-S/S) . [For substituents: see below; R ⁵ = hydrogen (XXII-l-S) or PG; PG = protecting group; reaction conditions: a) K ₂ CO ₃ , TBAI, acetone; b) optional deprotection step for R ⁵ = PG].

There follows a discussion of the individual stages of the process according to the invention for preparing the compounds of the formula (XXI-l-S-S) according to Scheme 7.

For preparation of (5-(4-chlorophenyl)-2-( { I -(3 -chlorophcny l )-5-[ ( 1 ,S')- 1 -hydroxyethyl \- \H- 1 2.4-triazol-3-yl [mcthyl)-4-|(2.V)-3 3.3-trifluoro-2-hydroxypropyl |-2.4-dihydro-3//- 1.2.4- triazol-3-one (XXI-l-S/S), 3-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxy-propyl] -lH- l,2,4-triazol-5-one (II-l-S) is reacted with ( I.Y)- 1 |5-bromomehtyl)-2-(3-chlorophenyl)- 1.2.4- triazol-3-yl]ethanol (XXII-l-S) in a nucleophilic substitution reaction. In one aspect of the invention, a hydroxy-protected form of (XXII-l-S) may be employed as a coupling partner. After the coupling reaction, the protection group may then be cleaved by reaction with a suitable deprotection reagent. Other 5 -(hydroxyalkyl)-l -aryl- 1,2, 4-triazole derivatives (XXI) may be prepared by an analogous procedure. The starting compound of the formula (II-l-S) described in Synthesis Schemes 6 and 7 as well as the starting compound of the formula (II-2) can be prepared according to Synthesis Scheme 8 below, proceeding from starting compounds that are commercially available or known to the person skilled in the art:

Scheme 8: Process for preparing the compounds of the formula (II-l-S)

[a) THF; b) aq. NaOH, A; c) 1. (CF ₃ C0) ₂ 0/pyridine, 2. aq. HC1, A; d) chiral Ru(II) catalyst, HCOOH/Et ₃ N ]

The starting substances of the formula (II) are described in WO 2010/105770 (see Schemes 4 and 5; Examples 1A, 2A, 3A, 4A and 158A therein) and WO 2011/104322 (see Scheme 1; Examples 1A, 2A, 3 A, 4A and 5 A therein). The compounds of the formula (II) are obtained by reacting 4-chlorobenzohydrazide (XIV) with ethyl 2-isocyanatoacetate (XV) to give ethyl N-({2-[(4-chlorophenyl)carbonyl]hydrazinyl}carbonyl)glycinat e (XVI). The latter is then converted by a base-induced cyclization reaction to [3-(4-chlorophenyl)-5-oxo-l,5-dihydro- 477-1, 2, 4-triazol-4-yl] acetic acid (XVII). 5-(4-Chlorophenyl)-4-(3,3,3-trifluoro-2-oxopropyl)- 2,4-dihydro-3H-l,2,4-triazol-3-one (II-2) is then obtained by reaction with trifluoroacetic anhydride and subsequent treatment with hydrochloric acid. The ketone (II-2) is then converted by an asymmetric transfer hydrogenation by means of an enantioselective ruthenium(II) catalyst to the chiral alcohol (II-l-S).

The starting compound of the formula (1-1) described in Synthesis Scheme 6 can be prepared according to Synthesis Scheme 9 below, proceeding from starting compounds that are commercially available or known to the person skilled in the art: Scheme 9: Process for preparing the compounds of the formula (1-1)

(1-1) (IX-1)

[a) 18-crown-6, KHCO ₃ , K ₂ CO ₃ , D; b) NaBTb; c) PBr3; d) lithium hexamethyldisilane] .

The compound of formula (1-1) is obtained by reacting ethyl lH-l,2,4-triazole-3-carboxylate (V-l) with 2-bromo-3-(trifluoromethyl)pyridine (VI-1) under basic conditions in an aromatic nucleophilic substitution reaction. The resulting ethyl l-[3-(trifluoromethyl)-2-pyridyl]-l,2,4- triazole-3-carboxylate (VII-1) is then reduced to the corresponding [l-[3-(trifluoromethyl)-2- pyridyl]-l,2,4-triazol-3-yl]methanol (VIII-1) before being converted to 2-[3-(bromomethyl)- l,2,4-triazol-l-yl]-3-(trifluoromethyl)pyridine (IX-1) using phosphorus tribromide. The triazole core of (IX-1) is then deprotonated and reacted with an excess of methyl chloroformate to afford methyl 5-(bromomethyl)-2-[3-(trifluoromethyl)-2-pyridyl]-l,2,4-tria zole-3- carboxylate (1-1).

In an advantageous process variant the synthesis of (IX-1) can be conducted as a one-pot method wherein process steps a), b) and c) in Scheme 9 are conducted without isolation of every intermediate.

A way to prepare the starting compounds of the formula (XXII) is described in the Synthesis Scheme 10 below, proceeding from starting compounds that are commercially available or known to the person skilled in the art:

Scheme 10: Process for preparing the compounds of the formula (XXII) (XXII-1-S)

[R ⁵ = hydrogen or PG ² ; PG ² = protecting group, preferably acetyl; a) [Cu], evtl. base, temperature; b) L1AIH ₄ , THF or DIBAL-H, THF; c) PG'-Cl (PG = protecting group, e.g. TBDPS, SEM, MOM); d) LDA, THF; e) [Ru]L*, H ₂ or CBS catalyst, B¾ ; f) acetyl chloride (for PG ² = acetyl); then H ⁺ , then PBr ₃ · alternatively: e): NaBFE; followed by enzymatic resolution] .

The compound of formula (XXII-l-S) may be obtained by reacting ethyl lH-l,2,4-triazole-3- carboxylate (V-l) with (3-chlorophenyl)boronic acid (XXIII-1) in the presence of a copper source under Chan-Lam reaction conditions. The resulting ethyl l-(3-chlorophenyl)-l,2,4- triazole-3-carboxylate (XXIV-1) can then be reduced to the corresponding [l-(3- chlorophenyl)-l,2,4-triazol-3-yl]methanol (XXV-1) and the alcohol funtionality can be protected with s suitable protecting group (e.g. / -butyldiphenylsilyl (TBDPS), methoxymethyl ether (MOM), [2-(trimethylsilyl)ethoxy]methyl acetal (SEM)). The triazole core of (XXVI-1) is then deprotonated and reacted with an excess of N-methoxy-N-methyl- acetamide to afford l-[2-(3-chlorophenyl)-5-(hydroxymethyl)-l,2,4-triazol-3-yl]e thanone (XXVII-1). The methyl ketone is then reduced to the ( l.Y)- 1 -hydroxyethyl group in a ruthenium -catalyzed asymmetric reduction reaction or via reduction with sodium borohydride followed by enzymatic resolution. The hydroxymethyl function of (XXVIII-l-S) may then be converted to the corresponding bromide using phosphorus tribromide analogous to the reaction conditions described above in scheme 9 for the synthesis of (IX-1). It may be beneficial to protect the secondary alcohol of the hydroxyethyl group e.g. by reaction with acetyl chloride before subjecting to the deoxybromination conditions. The acetyl group may thereafter be cleaved under standard deprotection conditions, e.g. by reaction with a suitable base or acid. Other 5-(bromomethyl)-2-(aryl)-l,2,4-triazole-3-carboxylate ester derivatives (I) and their corresponding precursors of formulas (V), (VI), (VII), (VIII) and (IX) as well as other 5-(bromomethyl)-2-(aryl)-l,2,4-triazole-3-ethanol derivatives (XXII) and their corresponding precursors of formulas (XXIV), (XXV), (XXVI), (XXVII) and (XXVIII) may be prepared by an adapted procedure in a way obvious to the person skilled in the art, in analogy to methods published in the literature.

With the novel inventive synthesis, it is possible to prepare the target compounds (XXI), (III) and (IV) in a very efficient manner. The process offers considerable advantages over the prior art with regard to scalability and industrial implementation. By the inventive process presented here, several kg of material of (III) and (IV) for clinical trials have already been successfully produced.

Preferred salts in the context of the present invention are physiologically acceptable salts of the compounds according to the invention (for example, cf. S . M. Berge etai, "Pharmaceutical Salts", J. Pharm. Sci. 1977, 66, 1-19). However, the invention also encompasses salts which themselves are unsuitable for pharmaceutical applications but which can be used, for example, for the isolation or purification of the compounds according to the invention.

Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulphonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid. Physiologically acceptable salts of the inventive compounds also include salts of customary bases, preferred examples being alkali metal salts (e.g. sodium salts and potassium salts), alkaline earth metal salts (e.g. calcium salts and magnesium salts) and ammonium salts, derived from ammonia or organic amines having 1 to 16 carbon atoms, preferred examples being ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine and choline.

Solvates in the context of the invention are described as those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a specific form of the solvates in which the coordination is with water.

In particular, the 3,3,3-trifluoro-2-oxopropyl derivatives (substituent definition in R ¹ ) according to the invention ( ketone form) may also be present in the 3,3,3-trifluoro-2,2- dihydroxypropyl form ( hydrate form) (see Scheme 11 below); both forms are expressly embraced by the present invention.

Scheme 11

The compounds of the formula (I- A), (III-A), (IV-A), (VII-A) (XXI-A), (XXI-B) and (XXII-A) are each a subset of the compounds of formula (I), (III), (IV), (VII), (XXI) and (XXII) as defined by the respective R group definitions. The compounds of the formula (1-1- S), (II-l-S) and the like are assigned here to an (5) configuration of the stereocentre, and the compounds of the formula (I-l-R), (II-l-R) and the like are each assigned to an (R) configuration of the stereocentre. The definitions of the compounds of the formula (II-l- R/S), (III-l-R/S) as well as (IV-l-R/S) shall encompass both enantiomeric forms. The compound of the formula (XXI-l-S/S) and the like are assigned here to an (.V)/(.V) configuration of the stereocentres. The definition of the compounds of the formula (XXI-1- R/R/S/S) shall encompass all diastereomeric forms.

If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses all the tautomeric forms.

The following three tautomer representations (a), (b) and (c) of a triazole derivative are equivalent to one another and synonymous and in all cases are descriptive of a 3,5- disubstituted triazole derivative.

(a) (b) (C) This applies especially to the following structural elements: \H- 1 2.4-triazol-3-yl. \H- 1.2.4- triazol-5-yl, 4H- 1 2.4-triazol-3-yl and 4H- 1 2.4-triazol-5-yl. Y ¹ and Y ² here are different substituents. The present invention provides a method of preparing a compound of general formula (III), or the salts thereof, the solvates thereof or the solvates of the salts thereof, said method comprising the step [A] of allowing an intermediate compound of general formula (II) : in which Ar ¹ represents a phenyl group, which is optionally substituted with one or more halogen atoms, in particular a chlorine atom, and in which R ¹ represents a (Ci-Cz -alkyl group, which is optionally substituted with one or more substituents selected from a fluorine atom, hydroxy and oxo, in particular R ¹ represents a group of the formula in which #' represents the point of attachment to the nitrogen atom, to react in the presence of a suitable solvent and a base with an intermediate compound of general formula (I): in which X is a leaving group, preferably chloride, bromide or iodide, R ² represents a (C1-C4)- alkoxycarbonyl group, in particular a methoxycarbonyl group, and Ar ² represents a phenyl group or a 5- or 6-membered heteroaryl group attached via a ring carbon atom having one or two ring heteroatoms selected from a nitrogen atom and a sulfur atom, wherein any phenyl group and any 5- or 6-membered heteroaryl group are each optionally substituted, identically or differently, with one or two groups selected from a halogen atom, nitro, cyano, (Ci-Cz -alkyl, (Ci-C -alkoxy, (Ci-C- -alkylsulfanyl, (Ci-C -alkoxycarbonyl, amino- carbonyl, -C(=0)N(H)CH _3, -S(=0) ₂ CH ₃ , and -S(=0) ₂ NH ₂ , wherein said (Ci-Cz -alkyl group, said (Ci-C -alkoxy group and said (Ci-C- -alkylsulfanyl group are each optionally substituted with up to three fluorine atoms, in particular Ar ² represents a group of the formula in which # ² represents the point of attachment to the nitrogen atom, R ^3A represents a group selected from a chlorine atom, a bromine atom, trifluoromethyl, trifluoromethoxy, ethoxycarbonyl and -C(=0)NH ₂ , R ^3B represents a group selected from a chlorine atom, trifluoromethyl, and ethoxycarbonyl, thereby giving a compound of general formula (III): (HI), in which R ¹ , R ² , Ar ¹ and Ar ² have the definitions given above, optionally followed by a step [B] of allowing the compound of formula (III-A) in which R ¹ , Ar ¹ and Ar ² have the definitions given above, to react with ammonia thereby giving a compound of general formula (IV): in which R ¹ , Ar ¹ and Ar ² have the definitions given above.

Preference is given to a method for preparing compounds of the formula (III-A), characterized in that said method comprises the step [A] of allowing an intermediate compound of general formula (II-l-R/S) :

(II-l-R/S), to react with an intermediate compound of general formula (I- A): in which X is a leaving group, preferably chloride or bromide, and Ar ² represents a group of the formula - 3B

R ^' in which # ² represents the point of attachment to the nitrogen atom, R ^3A represents a group selected from a chlorine atom, a bromine atom, trifluoromethyl, trifluoromethoxy, ethoxycarbonyl and -C(=0)NH ₂ , R ^3B represents a group selected from a chlorine atom, trifluoromethyl, and ethoxycarbonyl, thereby giving a compound of general formula (III-A) :

(III-A), in which Ar ² has the definitions given above.

Particular preference is given to a process for preparing compounds of the formula (III-l- R/S), characterized in that Ar ² represents a group of the formula

2

#

// W CF ₃ in which # ² represents the point of attachment to the nitrogen atom, thereby giving methyl 3-({3-(4-chlorophenyl)-5-oxo-4-[3,3,3-trifluoro-2-hydroxypro pyl]-4,5- dihydro- 1H- 1 ,2,4-triazol- 1 -yl (methyl)- 1 -[3 -(trifluoromethyl)pyridin-2-yl] - 1H- 1 ,2,4-triazole- 5-carboxylate of general formula (III-l-R/S) : (III-l-R/S).

Very particular preference is given to a method for preparing compounds of the formula (IV- 1-R/S), wherein the compound of general formula (III-l-R/S) is allowed to react with ammonia thereby giving 3-({3-(4-Chlorophenyl)-5-oxo-4-[3,3,3-trifluoro-2-hydroxypro pyl]- 4,5-dihydro-lH-l,2,4-triazol-l-yl}methyl)-l-[3-(trifluoromet hyl)pyridin-2-yl]-lH-l,2,4- triazole-5 -carboxamide of general formula (IV-l-R/S):

(IV-l-R/S).

Very particular preference is given to a process for preparing compounds of the formula (IV- 1-S), wherein intermediate compound 3-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxy- propyl]-lH-l,2,4-triazol-5-one of formula (II-l-S):

(II-l-S), is allowed to react with intermediate compound methyl 5-(bromomethyl)-2-[3- (trifluoromethyl)-2-pyridyl]-l,2,4-triazole-3-carboxylate of formula (1-1):

(1-1), thereby giving methyl 3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydro xy- propyl]-4,5-dihydro-lH-l,2,4-triazol-l-yl}methyl)-l-[3-(trif luoromethyl)pyridin-2-yl]-lH- l,2,4-triazole-5-carboxylate of formula (III-l-S):

(III-l-S), followed by a step [B] of allowing methyl 3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3- trifluoro-2-hydroxypropyl] -4,5 -dihydro- 1H- 1 ,2,4-triazol- 1 -yl }methyl)- 1 -[3 - (trifluoromethyl)pyridin-2-yl]-lH-l,2,4-triazole-5-carboxyla te of formula (III-l-S) to react with ammonia thereby giving 3-({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2- hydroxypropyl] -4,5 -dihydro- 1H- 1 ,2,4-triazol- 1 -yl (methyl)- 1 -[3 -(trifluoromethyl)pyridin-2- yl]-lH-l,2,4-triazole-5-carboxamide of formula (IV-l-S):

(IV-l-S).

The present invention provides a method of preparing a compound of general formula (III) or (XXI), or the salts thereof, the solvates thereof or the solvates of the salts thereof, said method comprising the step [A] of allowing an intermediate compound of general formula (II) : (P), in which Ar ¹ represents a phenyl group, which is optionally substituted with one or more halogen atoms, in particular a chlorine atom, and in which R ¹ represents a (Ci-Cz -alkyl group, which is optionally substituted with one or more substituents selected from a fluorine atom, hydroxy and oxo, in particular R ¹ represents a group of the formula in which #' represents the point of attachment to the nitrogen atom, to react in the presence of a suitable solvent and a base with an intermediate compound of general formula (I) or (XXII): in which X is a leaving group, preferably chloride, bromide or iodide, R ² represents a (C ₁ -C ₄ )- alkoxycarbonyl group, in particular a methoxycarbonyl group, R ⁵ represents hydrogen or a protecting group (PG), preferably acetyl, R ⁶ represents hydrogen or a (Ci-Cz -alkyl group, in particular a methyl group, and Ar ² and Ar ³ each represent a phenyl group or a 5 - or 6-membered heteroaryl group attached via a ring carbon atom having one or two ring heteroatoms selected from a nitrogen atom and a sulfur atom, wherein any phenyl group and any 5- or 6-membered heteroaryl group are each optionally substituted, identically or differently, with one or two groups selected from a halogen atom, nitro, cyano, (Ci-Cz -alkyl, (Ci-C- -alkoxy, (C ₁ -C ₄ )- alkylsulfanyl, (Ci-C4)-alkoxycarbonyl, aminocarbonyl, -C(=0)N(H)CH _3, -S(=0) ₂ CH ₃ , and - S(=0) ₂ NH ₂ , wherein said (Ci-Cz -alkyl group, said (Ci-C- -alkoxy group and said (C ₁ -C ₄ )- alkylsulfanyl group are each optionally substituted with up to three fluorine atoms, in particular Ar ² represents a group of the formula - 3B

R ^’ in which # ² represents the point of attachment to the nitrogen atom, R ^3A represents a group selected from a chlorine atom, a bromine atom, trifluoromethyl, trifluoromethoxy, ethoxycarbonyl and -C(=0)NH ₂ , R ^3B represents a group selected from a chlorine atom, trifluoromethyl, and ethoxycarbonyl, and in particular Ar ³ represents a group of the formula in which # ³ represents the point of attachment to the nitrogen atom, thereby giving a compound of general formula (III) or (XXI): in which R ¹ , R ² , R ⁵ , R ⁶ , Ar ¹ , Ar ² and Ar ³ have the definitions given above, optionally followed by a step [B] of allowing the compound of formula (III-A) in which R ¹ , Ar ¹ and Ar ² have the definitions given above, to react with ammonia thereby giving a compound of general formula (IV): in which R ¹ , Ar ¹ and Ar ² have the definitions given above, or optionally followed by a deprotection step of allowing the compound of formula (XXI-A) (XXI-A), in which R ¹ , R ⁶ , Ar ¹ and Ar ³ have the definitions given above, and PG represents a protecting group, preferably acetyl, to react with a suitable deprotection agentthereby giving a compound of general formula (XXI-

B): (XXI-B), in which R ¹ , R ⁶ , Ar ¹ and Ar ³ have the definitions given above. Preference is given to a method for preparing compounds of the formula (XXI-C), characterized in that said method comprises the step [A] of allowing an intermediate compound of general formula (II-l-R/S) :

(II-l-R/S), to react with an intermediate compound of general formula (XXII-B):

(XXII-B), in which X is a leaving group, preferably chloride or bromide, and R ⁵ represents hydrogen or a protecting group (PG), preferably acetyl, thereby giving a compound of general formula (XXI-C) : in which R ⁵ has the definition given above.

Very particular preference is given to a method for preparing compounds of the formula (XXI- 1-R/R/S/S), wherein the compound of general formula (XXI-D)

(XXI-D), in which R ⁵ represents a protecting group (PG), preferably acetyl, is allowed to react with a suitable deprotection agent, preferably a base, thereby giving a compound of general formula (XXI-l-R/R/S/S):

(XXI-l-R/R/S/S).

The present invention further provides a method of preparing methyl 5-(bromomethyl)-2-[3- (trifluoromethyl)-2-pyridyl]-l,2,4-triazole-3-carboxylate of formula (1-1), or the salts thereof, the solvates thereof or the solvates of the salts thereof, said method comprising the step [C] of allowing a compound of general formula (V):

(V), in which R ⁴ represents (Ci-Cz -alkyl, in particular methyl or ethyl, to react in the presence of a suitable solvent and a base with 2-bromo-3-(trifluoromethyl)pyridine (VI) thereby giving an intermediate compound of general formula (VII-A):

(VII-A), in which Represents (Ci-Cz -alkyl, in particular methyl or ethyl, followed by the reduction step [D] in the presence of a suitable reduction agent, in particular sodium borohydride, thereby giving [l-[3-(trifluoromethyl)-2-pyridyl]-l,2,4-triazol-3-yl]methan ol of formula (VIII-1): followed by the bromination step [E] in the presence of a suitable bromination agent, in particular phosphorus tribromide, thereby giving 2-[3-(bromomethyl)-l,2,4-triazol-l-yl]-3- (trifluoromethyl)pyridine of formula (IX-1): followed by step [F] of allowing 2-[3-(bromomethyl)-l,2,4-triazol-l-yl]-3-(trifluoromethyl)- pyridine (IX-1) to react with methyl chloroformate in the presence of a suitable base thereby giving methyl 5-(bromomethyl)-2-[3-(trifluoromethyl)-2-pyridyl]-l,2,4-tria zole-3- carboxylate of formula (1-1):

In an advantageous embodiment of the present invention the method of preparing methyl 5- (bromomethyl)-2-[3-(trifluoromethyl)-2-pyridyl]-l,2,4-triazo le-3-carboxylate of formula (I- 1) is conducted as a one-pot reaction in the presence of a suitable solvent, wherein the intermediate compounds (VII-A) and (VIII-1) are converted without isolation from the reaction mixture, i.e. in solution.

Such a one-pot method is especially advantageous for an industrial scale synthesis, since it is possible in this way to avoid additional workup steps as (chromatographic) purification of intermediates is not necessary, and a high overall yield for the process is achieved..

The present invention further provides a compound of the general formula (I) in which R ² , Ar ² and X are as defined above.

In a preferred embodiment of the present invention, the compound is methyl 5-(bromomethyl)- 2-[3-(trifhioromethyl)-2-pyridyl]-l,2,4-triazole-3-carboxyla te (1-1)

The present invention further provides the use of a compound of the general formula (I) for preparation of a compound of the general formula (III).

The present invention further provides a compound of the general formula (XXII) in which R ⁵ , R ⁶ , Ar ³ and X are as defined above.

The present invention further provides the use of a compound of the general formula (XXII) for preparation of a compound of the general formula (XXI).

The present invention further provides a compound of the general formula (VII- A):

(VII-A), in which R ⁴ is as defined above.

The present invention further provides [l-[3-(trifhioromethyl)-2-pyridyl]-l,2,4-triazol-3- yl]methanol (VIII-1) of formula

The present invention further provides 2-[3-(Bromomethyl)-l,2,4-triazol-l-yl]-3- (trifluoromethyl)pyridine (IX- 1) of formula Step GA1: Suitable bases for process step [A] : (I) + (II) — » (III) and (XXII) + (II) — » (XXI) are the standard inorganic or organic bases, for example and with preference alkali metal carbonates such as sodium carbonate, potassium carbonate or caesium carbonate, alkali metal alkoxides such as sodium tert-butoxide or potassium tert-butoxide, alkali metal phosphate such as sodium phosphate or potassium phosphate or organic amines such as N,N- diisopropylethylamine (DIPEA), l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5- Diazabicyclo[4.3.0]non-5-ene (DBN) or tetramethylguanidine (TMG). Solvents used may be inert solvents, for example acetonitrile, methyl isobutyl ketone, dioxane, dimethylformamide, dimethylacetamide, isopropyl acetate, N-methylpyrrolidinone, dimethyl sulphoxide or sulpholane. If appropriate, these process steps can advantageously be conducted with addition of alkylation catalysts, for example lithium bromide, sodium iodide, tetra-u-butylammonium iodide, tetra- u-butylam monium bromide, benzyltriethylammonium chloride. Preference is given to using potassium carbonate with tetrabutylammonium iodide in acetone. The reactions are effected generally within a temperature range from +20°C to +100°C, preferably at +30°C to +70°C. The reaction can be performed at standard, elevated or reduced pressure (e.g. from 0.5 to 5 bar); in general, standard pressure is employed.

Step 1B1: The aminolysis reaction [B-l] (III) — » (IV) is usually carried out in a solution of ammonia. Suitable ammonia solutions for this step are saturated ammonia solutions, in particular a solution of ammonia in methanol, ethanol, isopropanol, tetrahydrofuran, dioxane or water or a mixture thereof. Preferably, a methanolic ammonia solution is used. The reaction is preferably performed directly in the ammonia solution in the absence of any further reaction solvent. This step is generally carried out at a temperature in the range of +20°C to +120°C, preferably at room temperature. Concomitant microwave irradiation may have a beneficial effect in this reaction as well at a temperature in the range of +60°C to +150°C, preferably at +120°C. The reaction can be performed at standard, elevated or reduced pressure (e.g. from 0.5 to 5 bar); in general, standard pressure is employed.

The removal of the protective group (PG) in the process step [B-2] (XXI-A) — » (XXI-B) can be carried out by customary methods known from the literature [see, for example, T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, Wiley, New York, 1999] Thus, the acetyl group is preferably removed with the aid of a suitable base or acid. Step [Cl: The aromatic nucleophilic substitution (V) + (VI) — » (VII)

Suitable bases for process step [C]: (V) + (VI) — » (VII) are the standard inorganic or organic bases, for example and with preference alkali metal carbonates such as sodium carbonate, potassium carbonate, caesium carbonate or caesium fluoride, alkali metal alkoxides such as sodium tert-butoxide or potassium tert-butoxide, alkali metal phosphate such as sodium phosphate or potassium phosphate. Solvents used may be inert solvents, for example acetonitrile, methyl isobutyl ketone, dioxane, dimethylformamide, dimethylacetamide, isopropyl acetate, N-methylpyrrolidinone, dimethyl sulphoxide, tetrahydrofiiran or sulpholane.

This process steps can advantageously be conducted with addition of phase-transfer catalysts, for example te t ra-« -b uty 1 am m o n i um iodide, te t ra-« -b uty 1 am m o n i um bromide, benzyltriethylammonium chloride, tetrabutylammonium fluoride or crown ethers such as 18- crown-6. Preference is given to using potassium carbonate as base, 18-crown-6 as phase- transfer catalyst and propionitrile as solvent.The reactions are effected generally within a temperature range from +60°C to +120°C, preferably at +80°C to +110°C. The reaction can be performed at standard, elevated or reduced pressure (e.g. from 0.5 to 5 bar); in general, standard pressure is employed.

Step [Dl: The reduction (VII) — » (VIII)

The reduction can be performed using hydride sources such as sodium borohydride, lithium borohydride, diisobutylaluminium hydride, lithium aluminium hydride, diborane or its complex with inert solvents. The preferred reducing agent is sodium borohydride. As solvent, a series of solvents that are compatible with reducing agents are possible to use. The preferred ones are alcohols like methanol, ethanol, or isopropanol, ethers such as diethyl ether, tetrahydrofiiran or 1,4-dioxane, or other polar solvents such as acetonitrile, propionitrile, dimethylacetamide, dimethylformamide or water. Mixtures of mentioned solvents are also appropriate. The most preferred solvent is methanol, or a combination of methanol and propionitrile.

The reactions are effected generally within a temperature range from -20°C to +70 °C, preferably at -10°C to +20°C. Step 1E1: The deoxybromination (VIII) — » (IX)

The deoxybromination can be performed using typical bromination agents such as phosphorus tribromide, thionyl bromide, or combination of triphenyl phosphine and an electrophilic bromide source such as carbon tetrabromide, hexabromoacetone, N-b ro m os lice i n i m i de or N- bromosaccharin. Typical solvents are, for example, dichloromethane, dichloroethane, dioxane, tetrahydrofuran, toluene, acetonitrile, dimethylformamide, ethyl acetate, acetone, methyl isobutylketone or dimethyl carbonate.

The preferred conditions are using phosphorus tribromide as reagent and dichloromethane as solvent. The reactions are effected generally within a temperature range from -20°C to +50°C, preferably at 0°C to +30°C.

Step 1F1: Process step (IX) — » (I)

Suitable bases for this process step are, for example, lithium hexamethyldisilane, lithium diisopropyl amide, lithium tetramethylpiperidine, tert-butyl lithium, sec-butyl lithium, n-butyl lithium, sodium hemamethyldisilane, potassium hexamethyldisilane, Grignard reagents such as isopropyl magnesium chloride or isopropyl magnesium bromide.

Typical solvents are, for example, dioxane, tetrahydrofuran, 2-methyl-tetrahydrofuran, toluene, acetonitrile, dimethyl carbonate.

Preference is given to using lithium hexamethyldisilane as base and tetrahydrofuran as solvent.

Typical reagents are, for example, dimethyl carbonate, methyl cyanoformate or methyl chloroformate. Preference is given to using methyl chloroformate. The reactions are effected generally within a temperature range from -78°C to +50°C, preferably at -10°C to +30°C.

The compounds of the formula (1-1) may alternatively also be prepared from compounds of the formula (XVIII) and (VI-1) that are known from the literature in 3 steps (Scheme 12):

Scheme 12: (1-1)

[K ₂ CO ₃ = potassium carbonate, LHMDS = Lithium hexamethyldisilane, NBS = N- Bromosuccinimide] .

Analogously to the synthesis described in Scheme 9, 3-methyl-lH-l, 2, 4-triazole (XVIII) can be reacted with 2-bromo-3-(trifluoromethyl)-pyridine (VI-1) and a base to give the compound of formula (XIX). This compound can then be deprotonated and reacted with methyl chloroformate, to afford the compound of formula (XX). The methyl group on (XX) can then be radically brominated using an appropriate bromination reagent such as A'-bromo- succinimide (NBS) and a radical initiator or light to afford the compound of formula (1-1). The compounds of the formula (XXII) can be synthesized according to the route depicted in scheme 10.

The coupling step (V) + (XXIII) (XXIV) is typically carried out under Chan-Lam coupling" conditions; see, for instance, D. M. T. Chan et al., Tetrahedron Lett. 44 (19), 3863- 3865 (2003); J. X. Qiao and P. Y. S. Lam, Synthesis, 829-856 (2011); K. S. Rao and T.-S. Wu, Tetrahedron 68, 7735-7754 (2012); Org. Biomol. Chem., 16 (46), 8984 - 8988 (2018)]. The reduction step (XXIV) (XXV) can be performed under typical conditions as described above for reaction step [D] Preferably diisobutylaluminium hydride or lithium aluminium hydride in tetrahydrofuran will be employed. Introduction of the protective group (PG ¹ ) (XXV) -> (XXVI) can be carried out by customary methods known from the literature [see, for example, T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, Wiley, New York, 1999] Typical reaction conditions for the acylation (XXVI) (XXVII) are e.g. in Hoffmann-La Roche US 5,438,052 A. . The asymmetric reduction of (XXVII) Ά (XXVIII) is typically performed with the aid of an asymmetric transition metal catalys, for example and preferably a ruthenium complex, e.g. Eur. J. Med. Chem, 162, 80-108, (2019). Typical reaction conditions and reagents for the deoxybromination reaction from (XXVIII) -> (XXII) are those listed above for reaction step [E] .

The compounds of the formulae (V), (VI), (XIV), (XV) and (XVIII) as well as their structure analogs are either commercially available or described as such in the literature, or they can be prepared in a way obvious to the person skilled in the art, in analogy to methods published in the literature. Numerous detailed methods and literature information for preparation of the starting materials can also be found in the Experimental.

The compounds according to the invention have valuable pharmacological properties and can be used for prevention and/or treatment of various disorders and disease-related conditions in humans and animals. Possible target indications are listed by way of example and with preference in WO 2017/191102-A1 , pages 24 to 27 for compounds of the formula (IV) as well as in WO 2016/071212-A1, pages 16 to 19 for compounds of the formula (XXI).

Suitable combination active ingredients and dosage forms are listed by way of example and with preference in WO 2017/191102-A1, pages 28 to 39 for compounds of the formula (IV) as well as in WO 2016/071212-A1, pages 19 to 25 for compounds of the formula (XXI)..

The working examples which follow illustrate the invention. The invention is not restricted to the examples.

Unless stated otherwise, the percentages in the tests and examples which follow are percentages by weight; parts are parts by weight. Solvent ratios, dilution ratios and concentration data for liquid/liquid solutions are based in each case on volume.

A. Examples Abbreviations:

DMSO dimethyl sulphoxide eq. equivalent(s)

Et ethyl h hour(s)

HPLC high-pressure, high-performance liquid chromatography

Me methyl min minute (s)

MtBE methyl tert- butyl ether

NMR nuclear magnetic resonance spectrometry

R, retention time (in HPLC)

THF tetrahydrofuran

UV ultraviolet spectrometry v/v volume to volume ratio (of a solution) wt% Weight percent HPLC method:

Method 1 (HPLC)

Instrument: HPLC with thermoregulated column over, UV-Dectector and data analysis system Agilent 1260. Column: Phenomenex Luna Omega Polar 50 mm lenght x 3 mm diameter, 3 pm particle size. Eluent A: ammonium phosphate buffer pH 2.4, 10 mmol/L (1.15 g ammonium dihydrogen phosphate + 0.7 mL phosphoric acid in 1000 mL water). Eluent B: acetonitrile. Gradient: 0.0 0.5 Oven temperature: 45°C. Flow rate: 2.5 mL/min. UV detection: 210 nm.

Method 2 (LC/MS): Instrument: Agilent MS Quad 6150;HPLC: Agilent 1290; Column: Waters Acquity UPLC HSS T3 1.8 m 50 x 2.1 mm; Eluent A: 1 1 Water + 0.25 ml 99% formic acid, Eluent B: 1 1 Acetonitrile + 0.25 ml 99% formic acid; Gradient: 0.0 min 90% A 0.3 min 90% A 1.7 min 5% A 3.0 min 5% A Oven: 50°C; Flow: 1,20 ml/min; UV- Detection: 205 - 305 nm. Further details:

The percentages in the example and test descriptions which follow are, unless indicated otherwise, percentages by weight; parts are parts by weight. Solvent ratios, dilution ratios and concentration data for liquid/liquid solutions are based in each case on volume.

Purity figures are generally based on corresponding peak integrations in the HPLC chromatogram, but may additionally also have been determined with the aid of the 'H NMR spectrum. If no purity is indicated, the purity is generally 100% according to automated peak integration in the LC/MS chromatogram, or the purity has not been determined explicitly.

Stated yields in % of theory are generally not corrected for purity. In solvent-containing or contaminated batches, the formal yield may be ">100%"; in these cases the yield is not corrected for solvent or purity.

The descriptions of the coupling patterns of 'H NMR signals that follow have in some cases been taken directly from the suggestions of the ACD SpecManager (ACD/Labs Release 12.00, Product version 12.5) and have not necessarily been strictly scrutinized. In some cases, the suggestions of the SpecManager were adjusted manually. Manually adjusted or assigned descriptions are generally based on the optical appearance of the signals in question and do not necessarily correspond to a strict, physically correct interpretation. In general, the stated chemical shift refers to the centre of the signal in question. In the case of broad multiplets, an interval is given. Signals obscured by solvent or water were either tentatively assigned or have not been listed. Significantly broadened signals - caused, for example, by rapid rotation of molecular moieties or because of exchanging protons - were likewise assigned tentatively (often referred to as a broad multiplet or broad singlet) or are not listed.

The 'H NMR data of selected examples are stated in the form of 'H NMR peak lists. For each signal peak, first the d value in ppm and then the signal intensity in round brackets are listed. The d value/signal intensity number pairs for different signal peaks are listed with separation from one another by commas. The peak list for an example therefore takes the following form: di (intensityi), 6 ₂ (intensity2), , dί (intensity i), ... , d _h (intensity _n ).

The intensity of sharp signals correlates with the height of the signals in a printed example of an NMR spectrum in cm and shows the true ratios of the signal intensities in comparison with other signals. In the case of broad signals, several peaks or the middle of the signal and the relative intensity thereof may be shown in comparison to the most intense signal in the spectrum. The lists of the 'H NMR peaks are similar to the conventional 'H NMR printouts and thus usually contain all peaks listed in a conventional NMR interpretation. In addition, like conventional 'H NMR printouts, they may show solvent signals, signals of stereoisomers of the target compounds which are likewise provided by the invention, and/or peaks of impurities. The peaks of stereoisomers of the target compounds and/or peaks of impurities usually have a lower intensity on average than the peaks of the target compounds (for example with a purity of > 90%). Such stereoisomers and/or impurities may be typical of the particular preparation process. Their peaks can thus help in identifying reproduction of our preparation process with reference to "by-product fingerprints". An expert calculating the peaks of the target compounds by known methods (MestreC, ACD simulation, or using empirically evaluated expected values) can, if required, isolate the peaks of the target compounds, optionally using additional intensity filters. This isolation would be similar to the peak picking in question in conventional 'H NMR interpretation. A detailed description of the presentation of NMR data in the form of peak lists can be found in the publication "Citation of NMR Peaklist Data within Patent Applications" (cf. Research Disclosure Database Number 605005, 2014, 1 August 2014 or http://www.researchdisclosure.com/searching-disclosures). In the peak picking routine described in Research Disclosure Database Number 605005, the parameter "MinimumHeight" can be set between 1% and 4%. Depending on the type of chemical structure and/or depending on the concentration of the compound to be analysed, it may be advisable to set the parameters "MinimumHeight" to values of < 1%.

Melting points and melting point ranges, if stated, are uncorrected.

All reactants or reagents whose preparation is not described explicitly hereinafter were purchased commercially from generally accessible sources. For all other reactants or reagents whose preparation likewise is not described hereinafter and which were not commercially obtainable or were obtained from sources which are not generally accessible, a reference is given to the published literature in which their preparation is described. Working examples

Example 1

Ethyl l-[3-(trifluoromethyl)-2-pyridyl]-l,2,4-triazole-3-carboxyla te (VI-1) 2-Bromo-3-(trifluoromethyl)pyridine (VI-1) (10.0 g, 44.1 mmol) was suspended in propionitrile (100 mL). Ethyl lH-l,2,4-triazole-3-carboxylate (V-l) (7.49 g, 53.1 mmol, 1.2 eq.), 18-crown-6 (2.81 g, 10.6 mmol, 0.24 eq.), potassium bicarbonate (5.32 g, 53.1 mmol, 1.2 eq.) and potassium carbonate (7.34 g, 53.1 mmol, 1.2 eq.) were sequentially added to the mixture at room temperature. The resulting suspension was then heated at reflux under argon for 46 hours. It was then cooled to room temperature before being added over 15 min to 100 mL of a 1 M aqueous potassium phosphate buffer solution (pH = 7). The phases were then separated and the organic phase was washed with 100 mL of a saturated aqueous potassium dihydrogen phosphate solution. The organic phase was then fdtered over a fritted glass fdter and evaporated under reduced pressure to afford the title compound (10.6 g, 84%). HPLC (method 1): % R _t = 1.86 min.

1H NMR (600 MHz, DMSO-d6): d [ppm] = 9.34 (s, 1 H), 8.98 (d, J=4.7 Hz, 1 H), 8.62 (d, J=8.0 Hz, 1 H), 7.99 (dd, J=7.8, 4.9 Hz, 1 H), 4.43 (q, J=7.0 Hz, 2 H), 1.36 (t, J=7.0 Hz, 3 H).

Example 2

[l-[3-(Trifluoromethyl)-2-pyridyl]-l,2,4-triazol-3-yl]met hanol (VII-1)

Ethyl l-[3-(trifluoromethyl)-2-pyridyl]-l,2,4-triazole-3-carboxyla te (21.9 g, 76.5 mmol) was dissolved in EtOH (130 mL) at room temperature. To this solution was added sodium borohydride (2.89 g, 76.5 mmol, 1.0 eq.) and the mixture was allowed to stir at room temperature for one hour before another portion of sodium borohydride (2.89 g, 76.5 mmol, 1.0 eq.) was added. The reaction mixture was then stirred for 16 hours before being added onto 255 mL of an aqueous solution of dipotassium dihydrogen phosphate (80:20 (v:v) saturated aqueous solution : water). Without performing a phase separation, the organic volatiles were evaporated under reduced pressure. The resulting mixture was then extracted 4 times with 100 mL methyl tert-butyl ether. The combined organic layers were then evaporated under reduced pressure to afford 15.5 g (83%) of the title compound.

HPLC (method 1): % R _t = 1.26 min.

1H NMR (600 MHz, DMSO-d6): d [ppm] = 9.09 (s, 1 H), 8.91 (dd, J=4.69, 0.98 Hz, 1 H), 8.51 - 8.58 (m, 1 H), 7.87 (dd, J=7.92, 4.79 Hz, 1 H), 5.51 (br s, 1 H), 4.60 (s, 2 H). Example 3

2-[3-(Bromomethyl)-l,2,4-triazol-l-yl]-3-(trifluoromethyl )pyridine (VIII-1)

[l-[3-(Trifluoromethyl)-2-pyridyl]-l,2,4-triazol-3-yl]met hanol (VII-1) (22.7 g, 92.8 mmol) was dissolved in 235 g dichloromethane and cooled to 5°C. Phosphorus tribromide (25.1 g, 92.8 mmol, 1.0 eq.) was slowly added to the mixture within 20 min. lh after the addition, the reaction mixture was allowed to reach room temperature and was then stirred for 16 h at room temperature. A saturated aqueous solution of dihydrogen potassium phosphate (135 mL) was slowly added while stirring and the resulting biphasic mixture was filtered over Celite. The phases were separated, and the organic phase was washed with 110 mL of a saturated aqueous dihydrogen potassium phosphate solution. The organic phase was evaporated and the solid residue was taken up in 130 mL of a 1: 1 EtOH: water mixture. The suspension was then heated to 50°C and then slowly cooled to 5°C within 600 min. The crystals obtained were filtered off and washed once with 20 mL cold 1: 1 EtOH: water mixture. 20.7 g (73%) of the title compound were obtained after drying under vacuum for 16 h at 40°C. HPLC (method 1): R _t = 1.90 min, 97.8 area%.

Process variant (one-pot procedure):

In a 2 L reactor, methyl lH-l,2,4-triazole-3-carboxylate (VII-2) (100 g, 787 mmol) was suspended in ethanol (1.5 L) and then sodium ethylate (95%, 56.4 g, 787 mmol) was added in one portion to the mixture. The resulting suspension was then heated under reflux for 7.5 hours (jacket @ 90°C). The jacket temperature was then adjusted to 100 °C and 350g EtOH were distilled off. 1000 mL propionitrile were then added to the reactor and ethanol was distilled off at 175 mbar until constant boiling point. Propionitrile (500 mL) was added each time the mixture reached the limit of stirrability. Once all the ethanol was distilled off, propionitrile was added up to a volume of 1 L. 2-Bromo-3-(trifluoromethyl)pyridine (VI-1) (148 g, 655 mmol) was added followed by 18-crown-6 (41.6 g, 157 mmol), potassium hydrogen carbonate (78.8 g, 787 mmol) and potassium carbonate (108 g, 787 mmol). The mixture was then heated under reflux for 40 hours. The reaction mixture was then cooled down to room temperature and poured onto 1.5 L of 1 M aqueous potassium phosphate buffer solution (pH = 7) in a separate 6 L reactor. The phases were then separated, and the organic phase was washed once with 1.5

L of a saturated aqueous solution of potassium dihydrogen phosphate. The organic phase was then distilled off at 150 mbar in order to remove the leftover water from the reaction mixture. The volume of the reaction was then adjusted to 1 L by adding propionitrile. 1.5 L of ethanol was then added to the mixture and it was cooled down to 5 °C. At this temperature sodium borohydride (59.5 g, 1573 mmol) was added in 3 portions over 1.5 hours. The mixture was then allowed to stir at 5°C for 3 hours (after which complete conversion was observed). The jacket temperature was reduced to -10 °C and a pre-cooled (5°C) 50 wt% solution of acetaldehyde in ethanol (798 mL, 7.87 mol) was very slowly added while keeping the internal temperature of the reaction mixture under 8°C. [CAUTION! This quench is very exothermic!] The mixture was then taken out of the 6 L reactor and 2L of a 1 M aqueousphosphate buffer solution (pH = 7) was introduced in the reactor. The reaction mixture was then added onto this buffer and the organic solvents were distilled off at a pressure of 175 mbar until constant boiling temperature. Dichloromethane (500 mL) was then added to the resulting mixture and the phases were separated. The aqueous phase was extracted once more with dichloromethane (500 mL) and the combined organic extracts were evaporated under reduced pressure. The residue obtained was taken up in 1.1 L dichloromethane and cooled to 5°C. Phosphorus tribromide (142 g, 524 mmol, 0.8 eq.) was then slowly added to the mixture within 20 min. [The temperature reached a maximum of 11°C upon addition.] 1 h after the addition, the reaction mixture was allowed to reach room temperature and stir for another 16 h. A saturated aqueous solution of potassium dihydrogen phosphate (1 L) was then slowly added while stirring and the resulting biphasic mixture was filtered over Celite. The phases were separated, and the organic phase was washed lx with 500 mL saturated aqueous potassium dihydrogen phosphate solution. The organic phase was evaporated and the solid residue (125 g) was taken up in 590 mL of a 1: 1 (v:v) ethanokwater mixture. The suspension was then heated to 55°C in order to solubilize the material. It was then slowly cooled to 5°C within 600 min. The solid material obtained was filtered off and washed once with cold 1: 1 (v:v) EtOH: water mixture. 87.8 g (286 mmol) of the title compound were obtained after drying under vacuum for 16 h at 40°C. Yield is overall 44% based on the 2-brorno-3-(trifluoromethyl)pyridine (VI-1).

HPLC (method 1): % R _t = 1.86 min.

1H NMR (600 MHz, DMSO-d6) d [ppm] = 9.14 (s, 1 H), 8.91 (dd, J=4.9, 1.4 Hz, 1 H), 8.55 (dd, J=7.9, 1.5 Hz, 1 H), 7.89 (dd, J=7.8, 4.9 Hz, 1 H), 4.71 (s, 2 H).

Example 4

Methyl 5-(bromomethyl)-2-[3-(trifluoromethyl)-2-pyridyl]-l,2,4-tria zole-3-carboxylate (1-1)

2-[3-(Bromomethyl)-l,2,4-triazol-l-yl]-3-(trifluoromethyl )pyridine (VIII-1) (40.0 g, 130 mmol) was dissolved in 2-Methyltetrahydrofuran (400 mL) and the resulting solution was cooled to 0 °C. Methyl chloroformate (50.4 mL, 651 mmol, 5 eq.) was then added to the mixture. A I M solution of lithium hexamethyldisilane in THF (195 mL, 195 mmol, 1.5 eq.) was then added to the mixture over 30 min. The reaction mixture was then quenched with 12 mL of trifluoroacetic acid. It was then placed under reduced pressure (160 mbar)and 200 mL were distilled off to get rid of the excess methyl chloroformate. 200 mL of 2- methyltetrahydrofuran were then added to the mixture followed by 400 mL of an aqueous 0.1 M hydrochloric acid solution. The phases were then separated and the organic phase was washed once more with 400 mL of an aqueous 0.1 M hydrochloric acid solution, followed by 400 mL of a saturated aqueous sodium bicarbonate solution, followed by 400 mL of water and finally 400 mL of a saturated aqueous sodium chloride solution. The organic phase was evaporated under reduced pressure and the residue was taken up in 110 mL ethanol. The heterogeneous mixture was heated at 55 °C to obtain a solution. 110 mL water was then slowly added at this temperature and the solution was cooled to 0°C within 300 minutes. Seeding crystals were added when the temperature reached 51 °C. The resulting suspension was filtered and the solid was dried under vacuum at 40 °C for 16 hours. The title compound was obtained as a solid (35.7 g, 75 % yield).

HPLC (method 1): % R _t = 2.21 min.

1H NMR (600 MHz, DMSO-d6) d [ppm] = 8.96 (d, J=4.30 Hz, 1 H), 8.63 (d, J=7.24 Hz, 1 H), 8.01 (dd, J=7.82, 4.89 Hz, 1 H), 4.80 (s, 2 H), 3.81 (s, 3 H). Example 5

Methyl 3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydro xypropyl]-4,5-dihydro- 1H- 1 ,2,4-triazol- 1 -yl }methyl)- 1 -[3 -(trifluoromethyl)pyridin-2-yl] - 1H- 1 ,2,4-triazole-5 - carboxylate (III-l-S)

3-(4-Chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxy-prop yl]-lH-l,2,4-triazol-5-one (II-l- S) (1.15 kg, 3.74 mol), milled potassium carbonate (0.775 kg, 6.61 mol) and tetrabutylammonium iodide (0.345 kg, 0.935 mol) were placed in a reactor under nitrogen atmosphere. Acetone (11.3 kg) was added and the resulting suspension was stirred and heated up to reflux temperature (58°C) within 45 min. In a separate container, methyl 5- (bromomethyl)-2-[3-(trifluoromethyl)-2-pyridyl]-l,2,4-triazo le-3-carboxylate (1-1) (1.433 kg, 3.93 mol) was dissolved in acetone (2.5 kg) and added within 10 min to the reactor at reflux. The mixture was stirred at reflux for 90 min before being rapidly cooled down to room temperature. MtBE (10.7 kg) and 29.6 kg of a 4 wt.% aqueous sodium bicarbonate solution was added to the mixture. The mixture was stirred for 10 min and the phases were then separated. The organic phase was then washed twice with 14.6 kg of a 2.6 wt.% aqueous sodium chloride solution, once with a 7 wt% hydrochloric acid solution, and once with a 13 wt.% aqueous sodium chloride solution. The resulting organic phase was then filtered over 1- 2 cm layer of diatomaceous earth and washed three times with 2.5 kg MtBE. The resulting product-containing solution (18 L), was evaporated down to 6 L under reduced pressure. The mixture was transferred to a 6 L glass reactor and the solvent was distilled off under atmospheric pressure until the stirring limit. Diisopropyl ether (2 L) was then added and distilled off. This step was repeated until a constant boiling point of 68.5 °C. Diisopropyl ether was then added up to a volume of 6 L and the mixture was heated to 40 °C. Acetone (600 mL) was then added, which resulted in a homogenous red-brown solution. Seeding crystals of the product were then added and the mixture was allowed to stir at 40 °C for 24 hours. The solid product was then collected by filtration and washed with 600 mL of an diisopropyl ether : Acetone 9: 1 (v:v) mixture. The product was dried under vacuum in an oven at 40 °C for 16 hours to afford 1.50 kg (80 %) of the title compound. HPLC (method 1): R, = 2.69 min 1HNMR (400 MHz, DMSO-d6) d [ppm] = 8.93 (dd, J=4.7, 0.9 Hz, 1 H), 8.60 (dd, J=8.0, 1.1 Hz, 1 H), 7.93 - 8.05 (m, 1 H), 7.73 - 7.82 (m, 2 H), 7.58 - 7.68 (m, 2 H), 6.92 (d, J=6.4 Hz, 1 H), 5.22 (s, 2 H), 4.21 - 4.38 (m, 1 H), 3.96 - 4.06 (m, 1 H), 3.86 (dd, J=14.7, 9.5 Hz, 1 H), 3.77 (s, 3 H). (Reference) Example 6-R

3-({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hy droxypropyl]-4,5-dihydro-lH- 1 ,2,4-triazol- 1 -yl (methyl)- 1 -[3 -(trifluoromethyl)pyridin-2-yl] - 1H- 1 ,2,4-triazole-5 - carboxamide (IV-l-S) Procedure according to WO 2017/191102-A1:

1.80 g Methyl 3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydro xypropyl]-4,5- dihydro- 1H- 1 ,2,4-triazol- 1 -yl (methyl)- 1 -[3 -(trifluoromethyl)pyridin-2-yl] - 1H- 1 ,2,4-triazole- 5-carboxylate (as described Example 6, 3.04 mmol) was dissolved in 10.0 mL of an ammonia solution (7N in methanol, 70.0 mmol). The resulting mixture was stirred for 1 h at room temperature. The solvent was removed in vacuo and the crude product was purified by preparative HPLC (Method 5 of WO 2017/191102). Lyophilisation of the product containing fractions afforded 1.49 g (85% of th.) of the title compound as a solid.

LC-MS (Method 2): R, = 1.20 min; MS(ESIpos): m/z = 577 [M+Hf

‘HNMR (DMSO-de, 400 MHz): d =8.87 (d, 1H), 8.51 (d, 1H), 8.39 (s, 1H), 7.99 (s, 1H), 7.90 (dd, 1H), 7.82-7.68 (m, 2H), 7.63 (d, 2H), 6.90 (s, 1H), 5.22-5.07 (m, 2H), 4.39 - 4.20 (br m, 1H), 4.16-3.94 (m, 1H), 3.85 (dd, 1H).