# Functionalized nitrogen- and chalcogen-containing heterocyclic compounds as aromatase inhibitors: Design, synthesis and biological evaluation

Chang Ha Park, Marc Le Borgne, Marouan Rami, Martin Fossart, Patricia Melnyk, Maxime Liberelle, Saïd Yous

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## ► To cite this version:

Chang Ha Park, Marc Le Borgne, Marouan Rami, Martin Fossart, Patricia Melnyk, et al., Functionalized nitrogen- and chalcogen-containing heterocyclic compounds as aromatase inhibitors: Design, synthesis and biological evaluation. European Journal of Medicinal Chemistry, 2026, 302, 10.1016/j.ejmech.2025.118298. hal-05432136

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Submitted on 26 Dec 2025

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Research paper

# Functionalized nitrogen- and chalcogen-containing heterocyclic compounds as aromatase inhibitors: Design, synthesis and biological evaluation

Chang Ha Park<sup>a</sup>, Marc Le Borgne<sup>b</sup>, Marouan Rami<sup>a</sup>, Martin Fossart<sup>a</sup>, Patricia Melnyk<sup>a</sup>, Maxime Liberelle<sup>a,*</sup> (D), Saïd Yous<sup>a,**</sup>

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## ARTICLE INFO

**Keywords:**

Aromatase

Non-steroidal inhibitors

Heterocycles

Chalcogen isostere

In vitro assays

In vivo evaluation. supplementary

Benzoxazolinone

Benzothiazolinone

Benzoselenazolinone

Benzoxazinone and benzothiazinone

## ABSTRACT

Aromatase inhibition remains a key therapeutic strategy for hormone-dependent breast cancer (HDBC). Among non-steroidal aromatase inhibitors (NSAIs), letrozole and anastrozole are well-established treatments. To further probe structure-function relationships within the human aromatase active site, we synthesized a library of 42 novel azole derivatives. Several compounds displayed nanomolar inhibitory activity, with potencies approaching that of letrozole *in vivo*, while maintaining favorable selectivity against other steroidogenic enzymes. Notably, benzoselenazolinone 75 emerged as the most promising candidate, exhibiting potency comparable to letrozole with improved *in vitro* selectivity, thereby justifying further evaluation *in vivo*.

## 1. Introduction

Steroids are biologically essential triterpenoids that exert wide-ranging effects on key physiological and physiopathological functions. Cholesterol, for instance, regulates membrane fluidity, while cortisol plays a crucial role in immune modulation. Reproductive functions are governed by sex steroids, notably estrogens and androgens. Given their fundamental roles, it is unsurprising that steroids dysregulation has long been implicated in cancer development. Notably, estrogens play a particularly prominent role in driving the development of hormone-dependent breast cancer, one of the most prevalent and deadly cancers worldwide. Although breast cancer has been recognized for long time [1], effective therapeutic strategies only emerged in the latter half of the 20th century [2]. While surgery remains the cornerstone of treatment, chemotherapy has proven valuable for its efficacy and breast-conserving potential [3].

At the molecular level, estrogens are biosynthesized via aromatization of the A ring of androgens, a reaction catalyzed by the cytochrome

P450 enzyme aromatase (CYP19). This enzyme, overexpressed in many breast cancer cell lines, is a validated therapeutic target, particularly for postmenopausal women, for whom peripheral tissues become the main source of estrogen production [4,5]. Aromatase, also referred to as estrogen synthetase, belongs to the cytochrome P450 superfamily and features a heme cofactor at the heart of its catalytic mechanism.

Aromatase inhibitors are broadly classified into steroidal or nonsteroidal compounds (Fig. 1). Steroidal inhibitors, such as formestane [6] and exemestane [7,8], closely mimic the steroid scaffold. These inhibitors compete with the natural substrate and then covalently bind to the catalytic site for a prolonged effect, acting as suicide inhibitors. However, their irreversible binding may not always be desirable. Amine-noglutethimide [9], the first nonsteroidal inhibitor and the first to reach clinic use, lacks selectivity and inhibits multiple cytochrome P450 isoforms, resulting in significant off-target effects. More selective and potent non-steroidal inhibitors were lated developed within the “-rozole” family, including fadrozole, vorozole (marketed in Japan [10, 11]), anastrozole, and letrozole (both marketed worldwide). These

<footnote><sup>a</sup> Univ. Lille, Inserm, CHU Lille, U1172 - LilNCog - Lille Neuroscience & Cognition, F-59000, Lille, France</footnote>

<footnote><sup>b</sup> Small Molecules for Biological Targets Team, Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, CNRS 5286, INSERM 1052, Université Claude Bernard Lyon 1, Univ Lyon, Lyon, 69373, France</footnote>

<footnote>* Corresponding author. U1172 - LilNCog - Lille Neuroscience & Cognition, UFR3S-Pharmacie, 3 rue du Professeur Laguesse, F-59000, Lille, France.</footnote>

<footnote>** Corresponding author. U1172 - LilNCog - Lille Neuroscience & Cognition, UFR3S-Pharmacie, 3 rue du Professeur Laguesse, F-59000, Lille, France.
E-mail addresses: maxime.liberelle@univ-lille.fr (M. Liberelle), said.yous@univ-lille.fr (S. Yous).</footnote>
drugs display higher potency and improved selectivity compared to aminoglutethimide. Beyond breast cancer, non-steroidal aromatase inhibitors have also demonstrated therapeutic benefits in endometriosis [12,13], other hormone-dependent cancers such as ovarian cancer [14] and even lung cancer [15].

Nevertheless, these inhibitors are not without limitations. Reported side effects include reduced bone mineral density leading to increased fracture risk [16], joint pain, cardiovascular complications [17], and reproductive impairment during long-term use. Furthermore, incomplete specificity toward other CYP enzymes can cause clinically relevant drug-drug interactions. The balance of clinical efficacy in treating a variety of severe pathologies, based on their sophisticated mechanism of action, alongside side effects ranging from mild to severe, underscores the need for the development of new and improved compounds, as emphasized by numerous recent studies [18–26].

Structural insights into the aromatase active site guided the design of functionalized azole-based heterocycles incorporating nitrogen and chalcogen atoms. First, the compounds were screened for their ability to inhibit aromatase activity *in vitro*, providing an initial measure of potency. The most active candidates were then advanced to *in vivo* assays to confirm their efficacy in a physiological context. Finally, the selectivity of these inhibitors was examined *in vitro* against other steroid-related enzymes, in order to evaluate potential off-target effects and refine their pharmacological profile. This sequential strategy ensured that only the most promising candidates, combining potency, efficacy, and selectivity, were prioritized for further investigation.

In this context, we report the design, synthesis, and pharmacological evaluation of a novel series of 42 aromatase inhibitors, guided by molecular modeling.

## 2. Results and discussion

### 2.1. Rational design

In 2009, the crystal structure of the catalytic domain of human aromatase CYP19 was resolved, providing an invaluable framework for structure-based drug design [27]. This breakthrough enabled detailed analysis of molecular interactions within the active site, greatly improving the accuracy of predictive modeling. The binding site revealed a relatively canonical topology: a narrow corridor ending in a small pocket near the heme iron. Substrate stabilization is primarily

driven by hydrophobic interactions with Phe134 and Trp224, while orientation is governed by a key hydrogen bond with the Met374 backbone. Subsequent structural studies [28] have further demonstrated the utility of this model in guiding the development of novel inhibitors.

The design of new aromatase inhibitors is challenged by the absence of co-crystal structures with non-steroidal compounds. As a result, molecular docking studies [20,21] remain the main approach, with our own results (using gnina software) aligning with the binding mode previously described for letrozole [29], in which the azole ring coordinates the heme iron. Furthermore, most marketed inhibitors symmetrical molecules, which limits the structural diversity and interpretability of docking outputs. To overcome this, we focused on vorozole, an asymmetrically substituted compound whose docking pose recapitulates that of letrozole but provides additional opportunities for rational optimization (Fig. 2A and B). The benzenetriazole moiety occupies a pocket formed by Arg115 and Met374, while superimposition with crystallized androstenedione (Fig. 2A and B) highlighted a potential for further modulation: the carbonyl function of the natural hormone, crucial for non-hydrophobic interactions, lies in close proximity to the central nitrogen of benzenetriazole.

Based on these insights, we designed a new scaffold summarized in Fig. 2C. The benzenetriazole core was replaced by a fused 6 + 5 heteroaromatic system incorporating a carbonyl group. The 5-membered ring was design as an aza-cycle, with the X position modulated by either chalcogen atoms to explore potential hydrogen bonding with Arg115, or a chalcazinone moiety to evaluate steric tolerance. The N-alkyl substituent (R₁) was varied between hydrogen and small hydrophobic groups to assess steric occupancy. Azole rings such as imidazole, triazole, and tetrazole were incorporated to validate heme-binding consistency with known structure-activity relationships (SARs). Finally, the second aromatic ring was functionalized with hydrogen-bond acceptors in the meta or para position, and both connection isomers for the bi-aryl system were considered to compensate the limited power of docking studies.

### 2.2. Chemistry

Scheme 1 illustrates the synthetic route to the key intermediates **1a-24a**. Previously described starting materials were subjected to regioselective Friedel-Crafts acylation at various positions using benzoyl chloride derivatives and aluminum chloride in DMF [30–34]. Specifically, benzoxazolone (**1a-2a**), benzothiazolone (**3a-9a**), benzoselenazolone

<figure><img src="image_5.png" /><figcaption>**Fig. 1.** Steroidal aromatase inhibitors (SAIs, upper molecules) and non-steroidal aromatase inhibitors (NSAI, lower molecules).</figcaption></figure>
<figure><img src="image_6.png" /><figcaption>**Fig. 2.** (A) Docking of vorozole (in blue) in aromatase (PDB Id 3EQM) compared with native ligand androstenedione (in orange). (B) Structure of both androstenedione and vorozole with key element colored according to their position and role in the binding pocket. (C) Rational design and structures of benzazolinonic heterocycles resulting of the merging of all structural determinants.</figcaption></figure>

<figure><img src="image_7.png" /><figcaption>**Scheme 1.** Synthesis of 6 and 7-acyl-benzazolone and 5-acyl-oxindole derivatives (1a-24a).</figcaption></figure>

Reagents and conditions: a) R₂C₆H₄COCl, AlCl₃, DMF; b) (i) NaOH, (ii) HCl, (iii) NaHCO₃; c) EtONa, BrCH₂CO₂Et, DMSO.

(10a-14a), and benzoxazinone (17a-20a) were acylated at the C-6 position, oxindole (15a-16a) at the C-5 position, and benzothiazinone (22a-24a) at the C-7 position. Benzoxazinone 21a was obtained in three steps from the corresponding benzoxazolinone, as reported by Moussavi et al. [30].

**Scheme 2** details the introduction of the acyl substituent at the C-5 position of benzoxazolinone. To synthesize compounds **30a-33a**, commercially available N-acetyl-2-aminophenol was regioselectively acylated at the C-4 position (25–28) using an AlCl₃/DMF complex and

the appropriate acyl chloride. Subsequent intramolecular cyclization produced benzoxazolone derivatives **30a-32a** as previously described [35,36]. Due to the instability of the cyano group in compound **27** under acidic conditions, compound **33a** was prepared by reacting **27** with ethyl chloroformate, followed by alkaline ring closure. Compounds **31a-33a** were then N-methylated by treatment with methyl iodide and potassium carbonate in acetone, yielding analogues **34a-36a**.

The synthesis of 5-Substituted benzothiazolones **41b-44b** is shown in **Scheme 3**. Starting from commercially available methyl-4-chloro-3-
<figure><img src="image_8.png" /><figcaption>**Scheme 2.** Synthesis of 5-acylated benzoxazolones (30a-36a).</figcaption></figure>

**Reagents and conditions:** a) AlCl₃, DMF, R₂C₆H₄COCl; b) AlCl₃, DMF, C₅H₄NCOCl·HCl; c) (i) HCl (cc), reflux, (ii) ClCO₂C₂H₅, pyridine, CH₂Cl₂, d) K₂CO₃, DMF, e) (i) HCl (cc), reflux, (ii) Urea, 140 °C for compounds **31a-32a**; f) (i) ClCO₂C₂H₅, TEA, CH₂Cl₂, (ii) K₂CO₃, DMF for compound **33a**; d) CH₃I, K₂CO₃, acetone.

<figure><img src="image_9.png" /><figcaption>**Scheme 3.** Synthesis of 5-substituted benzothiazolones **41b-44b**.</figcaption></figure>

**Reagents and conditions:** a) Na₂S·9H₂O, EtOH, (ii) SnCl₂, 6 M HCl, iii) Urea, 150 °C; b) (i) SOCl₂, MeOH, (ii) LiAlH₄, THF, (iii) MnO₂, CH₂Cl₂; c) CH₃I or C₂H₅I, K₂CO₃, acetone.

d) i-PrMgBr, p-R2-C6H4-Br, THF.

nitrobenzoate, compound **37** was prepared in two steps: substitution of the aromatic chlorine with a thiol group to form aminothiophenol, followed by nitro group reduction. Heating the aminothiophenol intermediate with urea produced benzothiazolone **37**. The carboxylic acid group of **37** was then reduced into aldehyde **38** via successive esterification, reduction, and alcohol oxidation steps. Subsequent C-alkylation of **38** with methyl or ethyl iodide yielded compounds **39** and **40**, respectively. Finally, compounds **38-40** were transformed into the corresponding final products **41b-44b** through a Grignard reaction.

Compounds **1b-24b** and **30b-36b** were obtained by reducing the corresponding ketones with NaBH₄. These reduced intermediates and compounds **41b-44b** served as starting materials for the synthesis of the imidazole, triazole, and tetrazole series **45-86**, as depicted in **Scheme 4**. Two synthetic strategies were applied. For the imidazole series, the desired hydroxyl compounds were treated with N, N'-carbon-yldiimidazole (CDI) [37]. In contrast, for tetrazole and triazole analogues, such as compound **57**, the alcohol group was first converted to a chloride, which was then condensed with 1,2,4-triazole or 1,2,3,4-tetrazole in acetonitrile.

## 2.3. Biological activity

### 2.3.1. *In vitro* inhibition of CYP19

All compounds were evaluated for their aromatase inhibitory activity using human placental microsomes with [β-³H]androstenedione (A) as the substrate, following the previously described protocol [36]. Letrozole was used as the reference compound. The results are presented in **Table 1a-c**. Most compounds exhibited potent aromatase inhibition in the nanomolar range, comparable to letrozole and vorozole. By contrast, compounds that were extremely polar, lacked appropriately positioned hydrogen-bond acceptors, or did not contain a chalcogen atom showed significant reduced potency, with decreases of 1-2 orders of magnitude (see **Table 1**).

### 2.3.2. *In vivo* inhibition of CYP19

To assess to translation of *in vitro* inhibitory potency to *in vivo* efficacy, a selection of structurally diverse and highly potent compounds from the ones that were available at the start of this step was evaluated for their ability to inhibit androstenedione-induced uterine hypertrophy in mice (Table 2). Interestingly, clear discrepancies emerged between the two models: only three compounds retained efficacy similar to letrozole, underlining the complexity of predicting *in vivo* performance from *in vitro* data alone.
<figure><img src="image_10.png" /><figcaption>**Scheme 4.** Synthesis of target azolyl-based compounds **45–86**.</figcaption></figure>

Reagents and conditions: a) NaBH₄, CH₃OH; b) CDI, CH₃CN; c) (i) SOCl₂, (ii) 1,2,4-triazole, CH₃CN or 1,2,3,4-tetrazole.

### 2.3.3. *In vitro* selectivity toward other steroid-related enzymes

To assess the *in vitro* selectivity, the three most potent *in vivo* compounds were evaluated for their influence on the steroid biosynthesis. Selectivity was assessed through the formation of mineralo- and glucocorticoids (aldosterone and corticosterone) in ACTH-stimulated rat adrenal fragments, as well as estrogen and progesterone production in LH-stimulated hamster ovarian tissue (Tables 3–6).

In adrenal assays, inhibition of aldosterone and corticosterone formation was only observed at the highest concentrations tested. Compounds **53** and **75** were weaker inhibitors of aldosterone production than letrozole, but showed stronger effects on corticosterone biosynthesis. Notably, compound **59** displayed submicromolar inhibition of aldosterone formation (<0.1 µM), making it over 1500-fold more potent as an inhibitor of aldosterone biosynthesis compared to its effect on corticosterone biosynthesis.

In LH-stimulated ovarian fragments, all tested compounds showed lower IC₅₀ values than letrozole for estrogen production, confirming higher potency in this model. The effects on progesterone biosynthesis appears to be more complex. Letrozole strongly inhibited progesterone formation at all tested concentrations, in agreement with the literature data [38], although a stronger effect was observed here, probably due to the use of a different ovine LH batch (o-LH-S26 vs. o-LH-S18).

All tested compounds exhibited biphasic responses (Fig. 3). Compound **53** displayed the highest inhibitory effect on progesterone biosynthesis, suggesting higher affinity for desmolase, a key enzyme in this pathway. Compounds **59** and **75** demonstrated strong inhibitory only at the highest concentrations (100 and 200 µM), but also significant effects at the lowest concentration tested (0.01 µM). In comparison, their effects were not significant compared to the control at 0.1 and 1 µM. This

unexpected behavior suggests potential interference with androgen biosynthesis, likely through inhibition of 17-β-hydroxylase, which would result in progesterone accumulation due to reduced conversion into androgens. Despite this effect, both compounds were at least as selective as letrozole in this model.

### 2.3.4. Structure - activity relationships (SARs)

This study allowed us to outline several structure-activity relationships (SARs), particularly regarding the discrepancies observed between the *in vitro* and *in vivo* models. Notably, only three compounds displayed efficacy similar to letrozole. These findings highlight that SARs established *in vitro* do not perfectly predict *in vivo* performance, underlining the complexity of this series of aromatase inhibitors.

Both SARs are summarized in Fig. 4. The carbonyl group efficiently replaces the nitrile function of letrozole, enabling hydrogen bonding with Arg115 and Met374. Binding affinity to aromatase is largely driven by increased hydrophobicity combined with moderate polarity. This is illustrated by the higher potency of compounds bearing larger chalcogen atoms and of N-alkylated derivatives compared to NH analogues. Conversely, substituting the para-nitrile with a more polar nitro function on the opposite side of the molecule also appears favorable.

Interestingly, the SAR trends based on *in vivo* results tended to precise *in vitro* tendencies. Notably, hydrophobicity emerged as essential, as evidenced by the superior performance of Se- and N-alkylated compounds. Subtle changes sich as ethyl vs. methyl substitution, differences between triazole and imidazole, or the reverse ranking of nitro versus nitrile groups strongly suggest that drug metabolism and pharmacokinetic (DMPK) properties impose additional constraints.

Docking studies were not pursued to rationalize these SARs, since it
<figure><img src="image_11.png" /><figcaption>**Table 1a**

Aromatase inhibitory activity of azolyl compounds 45–64.</figcaption></figure>

<table><thead><tr><th>Compd.</th><th>X</th><th>R<sub>1</sub></th><th>R<sub>2</sub></th><th>Het</th><th>IC<sub>50</sub> (nM)<sup>a</sup></th></tr></thead><tbody><tr><td>Letrozole</td><td>–</td><td>–</td><td>–</td><td>–</td><td>4.23</td></tr><tr><td>45</td><td>O</td><td>H</td><td>p-CN</td><td>Imidazole</td><td>13.2</td></tr><tr><td>46</td><td>O</td><td>CH<sub>3</sub></td><td>m-CN</td><td>Imidazole</td><td>18.6</td></tr><tr><td>47</td><td>S</td><td>H</td><td>H</td><td>Imidazole</td><td>33.6</td></tr><tr><td>48</td><td>S</td><td>CH<sub>3</sub></td><td>H</td><td>Imidazole</td><td>18.5</td></tr><tr><td>49</td><td>S</td><td>H</td><td>p-CN</td><td>Imidazole</td><td>4.04</td></tr><tr><td>(+/-)-50</td><td>S</td><td>CH<sub>3</sub></td><td>p-CN</td><td>Imidazole</td><td>4.54</td></tr><tr><td>(+)-50</td><td>S</td><td>CH<sub>3</sub></td><td>p-CN</td><td>Imidazole</td><td>8.81</td></tr><tr><td>(–)-50</td><td>S</td><td>CH<sub>3</sub></td><td>p-CN</td><td>Imidazole</td><td>4.94</td></tr><tr><td>51</td><td>S</td><td>C<sub>2</sub>H<sub>5</sub></td><td>p-CN</td><td>Imidazole</td><td>4.29</td></tr><tr><td>52</td><td>S</td><td>H</td><td>p-CN</td><td>1,2,4-Triazole</td><td>7.51</td></tr><tr><td>53</td><td>S</td><td>CH<sub>3</sub></td><td>p-CN</td><td>1,2,4-Triazole</td><td>8.71</td></tr><tr><td>54</td><td>S</td><td>C<sub>2</sub>H<sub>5</sub></td><td>p-CN</td><td>1,2,4-Triazole</td><td>4.49</td></tr><tr><td>55</td><td>S</td><td>CH<sub>3</sub></td><td>p-NO<sub>2</sub></td><td>1,2,4-Triazole</td><td>3.05</td></tr><tr><td>56</td><td>S</td><td>CH<sub>3</sub></td><td>m-CN</td><td>1,2,4-Triazole</td><td>31.7</td></tr><tr><td>57</td><td>S</td><td>CH<sub>3</sub></td><td>p-CN</td><td>1,2,3,4-Tetrazole</td><td>11.8</td></tr><tr><td>58</td><td>Se</td><td>H</td><td>p-Cl</td><td>1,2,4-Triazole</td><td>6.53</td></tr><tr><td>59</td><td>Se</td><td>CH<sub>3</sub></td><td>p-CN</td><td>1,2,4-Triazole</td><td>4.64</td></tr><tr><td>60</td><td>Se</td><td>C<sub>2</sub>H<sub>5</sub></td><td>p-CN</td><td>1,2,4-Triazole</td><td>3.99</td></tr><tr><td>61</td><td>Se</td><td>CH<sub>3</sub></td><td>p-NO<sub>2</sub></td><td>1,2,4-Triazole</td><td>3.64</td></tr><tr><td>62</td><td>Se</td><td>C<sub>2</sub>H<sub>5</sub></td><td>p-NO<sub>2</sub></td><td>1,2,4-Triazole</td><td>3.70</td></tr><tr><td>63</td><td>CH<sub>2</sub></td><td>H</td><td>p-CN</td><td>1,2,4-Triazole</td><td>16.2</td></tr><tr><td>64</td><td>CH<sub>2</sub></td><td>CH<sub>3</sub></td><td>p-CN</td><td>1,2,4-Triazole</td><td>12.1</td></tr></tbody></table>

a Mean IC₅₀ values for 2–3 independent experiments are shown with less than 10 % deviation.

<figure><img src="image_12.png" /><figcaption>**Table 1b**

Aromatase inhibitory activity of azolyl compounds 65–72.</figcaption></figure>

<table><thead><tr><th>Compd.</th><th>X</th><th>R<sub>1</sub></th><th>R<sub>2</sub></th><th>Het</th><th>IC<sub>50</sub> (nM)<sup>a</sup></th></tr></thead><tbody><tr><td>Letrozole</td><td>–</td><td>–</td><td>–</td><td>–</td><td>4.23</td></tr><tr><td>65</td><td>O</td><td>H</td><td>H</td><td>Imidazole</td><td>14.9</td></tr><tr><td>66</td><td>O</td><td>CH<sub>3</sub></td><td>H</td><td>Imidazole</td><td>46.4</td></tr><tr><td>67</td><td>O</td><td>H</td><td>p-CN</td><td>Imidazole</td><td>5.83</td></tr><tr><td>68</td><td>O</td><td>CH<sub>3</sub></td><td>p-Cl</td><td>1,2,4-Triazole</td><td>18.7</td></tr><tr><td>69</td><td>O</td><td>CH<sub>3</sub></td><td>H</td><td>1,2,4-Triazole</td><td>18.1</td></tr><tr><td>70</td><td>O</td><td>H</td><td>p-CN</td><td>1,2,4-Triazole</td><td>17.1</td></tr><tr><td>71</td><td>O</td><td>CH<sub>3</sub></td><td>p-CN</td><td>1,2,4-Triazole</td><td>24.9</td></tr><tr><td>72</td><td>O</td><td>H</td><td>–</td><td>Imidazole</td><td>26.8</td></tr><tr><td>73</td><td>S</td><td>H</td><td>H</td><td>1,2,4-Triazole</td><td>178</td></tr><tr><td>74</td><td>S</td><td>CH<sub>3</sub></td><td>H</td><td>1,2,4-Triazole</td><td>179</td></tr><tr><td>75</td><td>S</td><td>CH<sub>3</sub></td><td>p-CN</td><td>1,2,4-Triazole</td><td>5.78</td></tr><tr><td>76</td><td>S</td><td>C<sub>2</sub>H<sub>5</sub></td><td>p-CN</td><td>1,2,4-Triazole</td><td>5.51</td></tr></tbody></table>

a Mean IC₅₀ values for 2–3 independent experiments are shown with less than 10 % deviation.

is now clear that the binding of non-steroidal aromatase inhibitors -still unresolved structurally-cannot be reliably modeled. Substantial conformational rearrangements of the enzyme may occur to accommodate certain compounds, and distinct binding modes are plausible depending on substituent. This non linearity is further supported by the separation of both enantiomers of compound 50, which exhibited

<figure><img src="image_13.png" /><figcaption>**Table 1c**

Aromatase inhibitory activity of azolyl compounds 77–85.</figcaption></figure>

<table><thead><tr><th>Compd.</th><th>isomer</th><th>X</th><th>R<sub>1</sub></th><th>R<sub>2</sub></th><th>Het</th><th>IC<sub>50</sub> (nM)<sup>a</sup></th></tr></thead><tbody><tr><td>Letrozole</td><td>–</td><td>–</td><td>–</td><td>–</td><td>–</td><td>4.23</td></tr><tr><td>77</td><td>6</td><td>O</td><td>H</td><td>H</td><td>Imidazole</td><td>65.5</td></tr><tr><td>78</td><td>6</td><td>O</td><td>CH<sub>3</sub></td><td>H</td><td>Imidazole</td><td>5.64</td></tr><tr><td>79</td><td>6</td><td>O</td><td>H</td><td>p-CN</td><td>Imidazole</td><td>9.90</td></tr><tr><td>80</td><td>6</td><td>O</td><td>CH<sub>3</sub></td><td>p-CN</td><td>Imidazole</td><td>3.44</td></tr><tr><td>81</td><td>7</td><td>O</td><td>H</td><td>H</td><td>Imidazole</td><td>74.4</td></tr><tr><td>82</td><td>7</td><td>S</td><td>H</td><td>p-CN</td><td>Imidazole</td><td>13.8</td></tr><tr><td>83</td><td>7</td><td>S</td><td>H</td><td>H</td><td>Imidazole</td><td>55.1</td></tr><tr><td>84</td><td>7</td><td>S</td><td>CH<sub>3</sub></td><td>p-CN</td><td>Imidazole</td><td>5.38</td></tr><tr><td>85</td><td>7</td><td>S</td><td>H</td><td>p-CN</td><td>1,2,4-Triazole</td><td>34.8</td></tr><tr><td>86</td><td>7</td><td>S</td><td>CH<sub>3</sub></td><td>p-CN</td><td>1,2,4-Triazole</td><td>56.6</td></tr></tbody></table>

a Mean IC₅₀ values for 2–3 independent experiments are shown with less than 10 % deviation.

<table><caption>**Table 2**

In vivo aromatase inhibitory activity.</caption><thead><tr><th rowspan="2">Compounds</th><th rowspan="2">In vitro IC<sub>50</sub> (nM)<sup>a</sup></th><th colspan="4">% Inhibition of Aromatase In vivo at Doses (µg/kg)</th><th rowspan="2">ED<sub>50</sub> (µg/kg)<sup>b</sup></th></tr><tr><th>1</th><th>3</th><th>10</th><th>100</th></tr></thead><tbody><tr><td>Letrozole</td><td>4.23</td><td>59</td><td>74</td><td>86</td><td>89</td><td>&lt;1</td></tr><tr><td>45</td><td>13.2</td><td></td><td></td><td>19</td><td>50</td><td>10–100</td></tr><tr><td>46</td><td>18.6</td><td></td><td></td><td>39</td><td>58</td><td>10–100</td></tr><tr><td>49</td><td>4.04</td><td></td><td></td><td>56</td><td>90</td><td>1–10</td></tr><tr><td>50</td><td>4.54</td><td></td><td></td><td>22</td><td>23</td><td>10–100</td></tr><tr><td>51</td><td>4.29</td><td></td><td>37</td><td>16</td><td></td><td>10–100</td></tr><tr><td>52</td><td>7.51</td><td></td><td></td><td>21</td><td>32</td><td>10–100</td></tr><tr><td>53</td><td>8.71</td><td></td><td></td><td>60</td><td>74</td><td>&lt;1</td></tr><tr><td>54</td><td>4.49</td><td></td><td></td><td>32</td><td>50</td><td>10</td></tr><tr><td>55</td><td>3.05</td><td></td><td></td><td>31</td><td>63</td><td>1–10</td></tr><tr><td>58</td><td>6.53</td><td></td><td></td><td>45</td><td>20</td><td>1–100</td></tr><tr><td>59</td><td>4.64</td><td></td><td></td><td>49</td><td>86</td><td>1</td></tr><tr><td>60</td><td>3.99</td><td></td><td></td><td>38</td><td>60</td><td>1–10</td></tr><tr><td>65</td><td>14.9</td><td></td><td></td><td>34</td><td>71</td><td>10–100</td></tr><tr><td>67</td><td>5.83</td><td></td><td></td><td>29</td><td>29</td><td>10–100</td></tr><tr><td>75</td><td>5.78</td><td></td><td></td><td>57</td><td>83</td><td>95</td></tr><tr><td>76</td><td>5.51</td><td></td><td></td><td>22</td><td>45</td><td>10</td></tr><tr><td>78</td><td>5.64</td><td></td><td></td><td>0</td><td>3</td><td>&gt;1000</td></tr><tr><td>80</td><td>3.44</td><td></td><td></td><td>0</td><td>32</td><td>10–100</td></tr></tbody></table>

a Mean IC₅₀ values for 2–3 independent experiments are shown with less than 10 % deviation.

b Mean values for 5 independent rats.

similar strong binding affinity with only a two-fold difference. If both enantiomers shared the same binding mode, one would be in a different pocket. These results suggest that binding modes within this series are flexible and likely non-linear.

### 3. Conclusion

A series of 42 non-steroidal aromatase inhibitor analogues were synthesized and evaluated for their potential in the treatment of hormone-dependent cancers. Six series of compounds were synthesized, exploring both classical structural variations and the less common chalcogen isosteres. The resulting structure-activity relationships (SARs) underscore the need to balance hydrophobic and polar features to achieve optimal *in vivo* efficacy, as enhanced *in vitro* potency does not systematically translate into improved biological activity.

Among the tested compounds, three molecules (53, 59, and 75)
<table><caption>**Table 3**

*In vitro* determination of ACTH-induced aldosterone and corticosterone release from rat adrenal fragments.</caption><thead><tr><th rowspan="2">Compounds</th><th rowspan="2">in vitro<br>IC<sub>50</sub> (nM)</th><th colspan="7">% aldosterone production in vitro at Doses (µM)</th><th rowspan="2">IC<sub>50</sub> of aldosterone production (µM)</th></tr><tr><th>0.1</th><th>1</th><th>10</th><th>100</th><th>200</th><th>350</th><th>Ctrl</th></tr></thead><tbody><tr><td>Letrozole</td><td>4.23</td><td></td><td>75.6 ± 7.5</td><td></td><td>62.7 ± 4.7</td><td></td><td>47.9 ± 0.9</td><td>100.0 ± 7.5</td><td>314</td></tr><tr><td>53</td><td>13.25</td><td>107 ± 10.4</td><td>81.4 ± 2.8</td><td>75.0 ± 2.5</td><td>66.8 ± 9.0</td><td>68.5 ± 4.2</td><td>56.8 ± 4.4</td><td>100.0 ± 1.6</td><td>&gt;350</td></tr><tr><td>75</td><td>18.6</td><td>114 ± 10.7</td><td>101.4 ± 3.7</td><td>77.3 ± 5.0</td><td>71.3 ± 9.9</td><td>56.2 ± 8.5</td><td>53.6 ± 6.6</td><td>100.0 ± 7.4</td><td>&gt;350</td></tr><tr><td>59</td><td>14.95</td><td>39.7 ± 8.0</td><td>44.7 ± 3.9</td><td>24.6 ± 1.5</td><td>12.2 ± 3.1</td><td>12.5 ± 3.7</td><td>11.4 ± 2.7</td><td>100.0 ± 11</td><td>&lt;0.1</td></tr></tbody></table>

<table><caption>**Table 4**

*In vitro* determination of ACTH-induced aldosterone and corticosterone release from rat adrenal fragments.</caption><thead><tr><th rowspan="2">Compounds</th><th rowspan="2">in vitro<br>IC<sub>50</sub> (nM)</th><th colspan="7">% corticosterone production in vitro at Doses (µM)</th><th rowspan="2">IC<sub>50</sub> of corticosterone production (µM)</th></tr><tr><th>0.1</th><th>1</th><th>10</th><th>100</th><th>200</th><th>350</th><th>Ctrl</th></tr></thead><tbody><tr><td>Letrozole</td><td>4.23</td><td></td><td>92.2 ± 3.3</td><td></td><td>71.8 ± 2.6</td><td></td><td>54.2 ± 5.1</td><td>100.0 ± 4.5</td><td>&gt;350</td></tr><tr><td>53</td><td>13.25</td><td>93.7 ± 4.4</td><td>76.0 ± 15.7</td><td>63.6 ± 1.4</td><td>61.8 ± 0.5</td><td>49.6 ± 0.6</td><td>39.6 ± 5.4</td><td>100.0 ± 7.7</td><td>192</td></tr><tr><td>75</td><td>18.6</td><td>122.9 ± 5.7</td><td>83.8 ± 1.2</td><td>76.6 ± 6.8</td><td>62.8 ± 1.2</td><td>42.4 ± 4.8</td><td>37.2 ± 1.4</td><td>100.0 ± 5.0</td><td>163</td></tr><tr><td>59</td><td>14.95</td><td>98.4 ± 3.9</td><td>83.4 ± 8.6</td><td>77.7 ± 3.6</td><td>60.0 ± 3.6</td><td>39.5 ± 0.9</td><td>34.0 ± 5.5</td><td>100.0 ± 5.3</td><td>149</td></tr></tbody></table>

<table><caption>**Table 5**

*In vitro* determination of LH-induced progesterone release from hamster ovarian fragments.</caption><thead><tr><th rowspan="2">Compounds</th><th rowspan="2">in vitro<br>IC<sub>50</sub> (nM)</th><th colspan="7">% progesterone production in vitro at Doses (µM)</th><th rowspan="2">IC<sub>50</sub> of progesterone production (µM)</th></tr><tr><th>0.1</th><th>1</th><th>10</th><th>100</th><th>200</th><th>350</th><th>Ctrl</th></tr></thead><tbody><tr><td>Letrozole</td><td>4.23</td><td></td><td>47.5 ± 2.0</td><td></td><td>47.8 ± 3.9</td><td></td><td>34.8 ± 6.4</td><td>100.0 ± 5.4</td><td>not suitable</td></tr><tr><td>53</td><td>13.25</td><td>81.1 ± 6.2</td><td>42.5 ± 5.5</td><td>57.2 ± 0.8</td><td>72.9 ± 1.0</td><td>17.9 ± 2.0</td><td>13.6 ± 2.8</td><td>100.0 ± 1.6</td><td>not suitable</td></tr><tr><td>75</td><td>18.6</td><td>38.5 ± 10.6</td><td>73.9 ± 5.7</td><td>81.7 ± 8.0</td><td>41.5 ± 3.8</td><td>31.6 ± 5.6</td><td>37.1 ± 7.3</td><td>100.0 ± 7.4</td><td>not suitable</td></tr><tr><td>59</td><td>14.95</td><td>55.3 ± 6.4</td><td>104.0 ± 5.8</td><td>95.9 ± 0.1</td><td>51.3 ± 12.7</td><td>45.4 ± 15.7</td><td>40.9 ± 1.3</td><td>100.0 ± 11</td><td>not suitable</td></tr></tbody></table>

<table><caption>**Table 6**

*In vitro* determination of LH-induced estrogen release from hamster ovarian fragments.</caption><thead><tr><th rowspan="2">Compounds</th><th rowspan="2">in vitro<br>IC<sub>50</sub> (nM)</th><th colspan="7">% estrogene production in vitro at Doses (µM)</th><th rowspan="2">IC<sub>50</sub> of estrogene production (µM)</th></tr><tr><th>0.1</th><th>1</th><th>10</th><th>100</th><th>200</th><th>350</th><th>Ctrl</th></tr></thead><tbody><tr><td>Letrozole</td><td>4.23</td><td></td><td>64.5 ± 0.5</td><td></td><td>37.2 ± 0.9</td><td></td><td>30.7 ± 2.3</td><td>100.0 ± 4.5</td><td>0.161</td></tr><tr><td>53</td><td>13.25</td><td>104.6 ± 1.5</td><td>87.3 ± 0.5</td><td>56.2 ± 3.4</td><td>34.5 ± 1.3</td><td>33.8 ± 2.9</td><td>36.1 ± 0.7</td><td>100.0 ± 7.7</td><td>0.041</td></tr><tr><td>75</td><td>18.6</td><td>93.1 ± 2.4</td><td>88.1 ± 2.8</td><td>53.1 ± 2.1</td><td>29.4 ± 0.9</td><td>28.0 ± 1.6</td><td>29.9 ± 3.1</td><td>100.0 ± 5.0</td><td>0.058</td></tr><tr><td>59</td><td>14.95</td><td>108.9 ± 6.9</td><td>105.2 ± 3.1</td><td>58.5 ± 5.9</td><td>37.4 ± 1.8</td><td>33.7 ± 1.2</td><td>33.6 ± 1.2</td><td>100.0 ± 5.3</td><td>0.078</td></tr></tbody></table>

<figure><img src="image_14.png" /><figcaption>**Fig. 3.** Inhibition of the LH-stimulated production of progesterone in hamster ovaries by compound 53, 59 and 75 **compared to letrozole**, as mean value ± SEM.</figcaption></figure>

displayed efficacy comparable to the reference compound letrozole, although none clearly outperformed it across all evaluation criteria. Compound **53** demonstrated strong inhibition of progesterone formation, while compound **59** showed marked potency in aldosterone biosynthesis inhibition, with a sub-micromolar IC<sub>50</sub>. The most promising inhibitor, compound **75**, combined potent aromatase inhibition *in vitro*

and *in vivo* with a selectivity index equal to or slightly superior to that of letrozole. *In silico* predictions were run on these three compounds with the Deep-PK API [39] and resulted in similar properties compared to letrozole, with the **75** being the most similar, with drug-like properties (Table S1).

These findings support the continued investigation of this chembtype as a basis for the development better-tolerated aromatase inhibitors. Further studies are in progress to explore SARs of compounds diverging from the symmetrical structures of letrozole or anastrozole. In particular, compound **75** is undergoing additional *in vivo* evaluation to further assess its selectivity and safety profile, taking into account the regulatory role of tropic hormones and feedback mechanisms in steroidogenesis.

# 4. Experimental part

## 4.1. Chemistry

Chemicals and solvents were obtained from commercial sources and used without further purification unless otherwise noted. Reactions were monitored by TLC performed on Macherey-Nagel Alugram® Sil 60/UV254 sheets (thickness 0.2 mm, Macherey-Nagel GmbH & Co. KG, Düren, Germany). Purification of products was carried out by recrystallization or column chromatography. Column chromatography was carried out using Macherey-Nagel silica gel (230–400 mesh, Macherey-
<figure><img src="image_15.png" /><figcaption>Fig. 4. (top) Summary of SARs from in vitro assays. (bottom) Resulting SARs after in vivo assays.</figcaption></figure>

Nagel GmbH & Co. KG, Düren, Germany). Melting points were determined on a Büchi SMP-20 capillary apparatus (Büchi SARL, Villebon sur Yvette, France) and are uncorrected. NMR spectra were recorded on a Bruker DRX 300 spectrometer (Division Biospin, Wissembourg, France) operating at 300 MHz for ¹H and 75 MHz for ¹³C). Chemical shifts are expressed in ppm relative to tetramethylsilane (TMS). Chemical shifts are reported as position (δ in ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, dd = double doublet, br = broad, and m = multiplet), coupling constant (J in Hz), relative integral, and assignment. Infrared spectra were obtained on a PerkinElmer FT-IR S1000 on KBr paths. Mass spectra were recorded with decimal precision using a Waters ACQuity UPLC I-Class with UV detection (PDA) and an electrospray mode (ESI) (Waters Corporation, Milford, MA, USA). UPLC-MS Waters system was equipped with a UPLC I SMP MGR-FTN sample manager, an ACQUITY UPLC I-Class eK photodiode array detector (210–400 nm), and an ACQUITY QDa (Performance) detector (scan 50–1250) (Waters Corporation, Milford, MA, USA). Acquity BEH C18 column (50 mm × 2.1 mm, 1.7 µm, Waters) was used. The injection volume was 0.5 µL. A mixture of water and acetonitrile was used as mobile phase in gradient elution. The pH of the mobile phase was adjusted with HCOOH and NH₄OH to form a buffer solution at pH 3.8. The analysis time was 5 min (at a flow rate of 600 µL/min), 10 min (at a flow rate of 600 µL/min), or 30 min (at a flow rate of 600 µL/min). Unless otherwise specified, the purity of evaluated compounds was judged to be >95 % as determined by UPLC-UV-MS system. Elemental analyses for target compounds were performed by CNRS Laboratory (Vernaison, France). Unless otherwise specified, the purity of evaluated compounds was judged to be >95 % as determined by UPLC-UV-MS system.

NMR and LC-MS spectra are provided as supplementary materials (Figure S1).

Some key intermediates were already described in the literature, namely 6-benzoyl-3H-1,3-benzothiazol-2-one (3a) [30], 6-benzoyl-3-methyl-1,3-benzothiazol-2-one (4a) [30], 7-benzoyl-4H-1,4-benzothiazin-3-one (21a) [31], 7-benzoyl-4H-1,4-benzothiazin-3-one (22a)

[32], 5-benzoyl-3H-1,3-benzoxazol-2-one (31a) [35], 5-(4-chlorobenzoyl)-3H-1,3-benzoxazol-2-one (32a) [36], 6-[hydroxy-(phenyl)methyl]-1,3-benzothiazol-2(3H)-one (3b) [42], 6-[hydroxy-(phenyl)methyl]-3-methyl-1,3-benzothiazol-2(3H)-one (4b) [42], and 7-[hydroxy(phenyl)methyl]-2H-1,4-benzoxazin-3(4H)-one (21b) [37]. Only one target compound, 7-[1H-imidazole-1-yl(phenyl)methyl]-2H-1,4-benzoxazin-3(4H)-one (81), was already described [37].

### 4.1.1. General procedure (method general procedure B) for the synthesis of intermediates 1a, 2a, 5a-20a, 23a, 24a, 25-28

Dimethylformamide (5.56 mL, 72 mmol) was slowly added to aluminum chloride (26.7 g, 200 mmol). The mixture was stirred and maintained at 45 °C for 15 min before adding the corresponding heterocyclic derivative or N-(2-hydroxyphenyl)acetamide (20 mmol) and the appropriate benzoyl chloride (24 mmol). The reaction mixture was warmed at 90–100 °C under stirring for 4 h, poured onto crushed ice and the crude product was collected by filtration, washed with water, air-dried and recrystallized to give the title compound.

#### 4.1.1.1. 4-(2-Oxo-3H-1,3-benzoxazol-6-carbonyl)benzonitrile (1a).

Prepared according to the general procedure using benzoxazolone and 4-cyanobenzoyl chloride. Recrystallized from 1,4-dioxane. Yield (60 %); m.p. 260–261 °C. IR (ν cm⁻¹) 3352 (NH), 2227 (CN), 1760 and 1647 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 7.26 (d, 1H, *J* = 8.10 Hz), 7.56 (dd, 1H, *J* = 8.10 Hz, *J* = 1.6 Hz), 7.60 (d, 1H, *J* = 1.6 Hz), 7.82 (d, 2H, *J* = 8.6 Hz), 8.01 (d, 2H, *J* = 8.6 Hz), 12.15 (br s, 1H, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO) δ 193.36, 154.31, 143.30, 141.45, 135.38 (2C), 132.54, 129.89, 129.81 (2C), 127.71, 118.24, 114.24, 110.45, 109.48. LC-MS (ESI) *m/z* found: 265 [M + H]⁺.

#### 4.1.1.2. 3-(3-Methyl-2-oxo-1,3-benzoxazol-6-carbonyl)benzonitrile (2a).

Prepared according to the general procedure using 3-methyl-benzoxazolone and 3-cyanobenzoyl chloride. Recrystallized from ethanol. Yield (53 %); m.p. 200–201 °C. IR (ν cm⁻¹) 2233 (CN), 1791 and 1640 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 3.40 (s, 3H), 7.40 (d, 1H, *J* = 8.1 Hz),
7.67 (dd, 1H, *J* = 8.1 Hz, *J* = 1.65 Hz), 7.71 (d, 1H, *J* = 1.65 Hz), 7.76 (td, 1H, *J* = 7.8, 0.7 Hz), 8.00 (m, 1H), 8.08–8.13 (m, 2H). ¹³C NMR (75 MHz, DMSO) *δ* 192.72, 154.06, 141.88, 138.48, 136.41, 135.53, 133.68, 132.84, 130.16, 129.88, 127.62, 118.15, 111.79, 110.53, 108.80, 28.40. LC-MS (ESI) *m/z* found: 279 [M + H]⁺.

#### 4.1.1.3. 4-(2-Oxo-3H-1,3-benzothiazol-6-carbonyl)benzonitrile (5a).

Prepared according to the general procedure using benzothiazolone and 4-cyanobenzoyl chloride. Recrystallized from ethanol. Yield (56 %); m. p. 227–228 °C. IR (ν, cm⁻¹) 3197 (NH), 2229 (CN), 1698 and 1661 (CO). ¹H NMR (300 MHz, DMSO-d₆) *δ* 7.24 (d, 1H, *J* = 8.4 Hz), 7.70 (dd, 1H, *J* = 8.4 Hz, *J* = 1.8 Hz), 7.84 (d, 2H, *J* = 8.6 Hz), 8.02 (d, 2H, *J* = 8.6 Hz), 8.05 (d, 1H, *J* = 1.8 Hz), 12.34 (br s, 1H, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO) *δ* 193.27, 170.56, 141.44, 140.78, 132.52 (2C), 130.34, 129.82 (2C), 129.15, 125.21, 124.01, 118.23, 114.20, 111.33. LC-MS (ESI) *m/z* found: 279 [M – H]⁺.

#### 4.1.1.4. 4-(3-Methyl-2-oxo-1,3-benzothiazol-6-carbonyl)benzonitrile

(6a). Prepared according to the general procedure using 3-methyl-benzothiazolone and 4-cyanobenzoyl chloride. Recrystallized from ethanol. Yield (60 %); m.p. 196–199 °C. IR (ν, cm⁻¹) 2233 (CN) 1683 and 1656 (CO). ¹H NMR (300 MHz, DMSO-d₆) *δ* 3.46 (s, 3H), 7.45 (d, 1H, *J* = 8.4 Hz), 7.78 (dd, 1H, *J* = 8.4 Hz, *J* = 1.7 Hz), 7.83 (d, 2H, *J* = 8.0 Hz), 8.02 (d, 2H, *J* = 8.0 Hz), 8.15 (d, 1H, *J* = 1.7 Hz). ¹³C NMR (75 MHz, DMSO) *δ* 193.27, 170.56, 141.44, 140.78, 132.52 (2C), 130.34, 129.82 (2C), 129.15, 125.21, 124.01, 118.23, 114.20, 111.33, 33.8. LC-MS (ESI) *m/z* found: 295 [M + H]⁺.

#### 4.1.1.5. 4-(3-Ethyl-2-oxo-1,3-benzothiazol-6-carbonyl)benzonitrile (7a).

Prepared according to the general procedure using 3-ethyl-benzothiazolone and 4-cyanobenzoyl chloride. Recrystallized from ethanol. Yield (65 %); m.p. 136–138 °C. IR (ν, cm⁻¹) 2229 (CN) 1678 and 1655 (CO). ¹H NMR (300 MHz, DMSO-d₆) *δ* 1.21 (t, 3H, *J* = 7.2 Hz), 4.01 (q, 2H, *J* = 7.2 Hz), 7.53 (d, 1H, *J* = 9.0 Hz), 7.77 (dd, 1H, *J* = 9.0 Hz, *J* = 1.5 Hz), 7.85 (d, 2H, *J* = 8.7 Hz), 8.03 (d, 2H, *J* = 8.7 Hz), 8.16 (d, 1H, *J* = 1.5 Hz). ¹³C NMR (75 MHz, DMSO) *δ* 193.27, 170.56, 141.44, 140.78, 132.52 (2C), 130.34, 129.82 (2C), 129.15, 125.21, 124.01, 118.23, 114.20, 111.33, 47.2, 13.8. LC-MS (ESI) *m/z* found: 309 [M + H]⁺.

#### 4.1.1.6. 3-(3-Methyl-2-oxo-1,3-benzothiazol-6-carbonyl)benzonitrile

(8a). Prepared according to the general procedure using 3-methyl-benzothiazolone and 3-cyanobenzoyl chloride. Recrystallized from 1,4-dioxane. Yield (59 %); m.p. 247–251 °C. IR (ν, cm⁻¹) 2226 (CN), 1684 and 1651 (CO). ¹H NMR (300 MHz, DMSO-d₆) *δ* 3.47 (s, 3H), 7.46 (d, 1H, *J* = 8.7 Hz), 7.35–7.83 (m, 2H), 8.01 (d, 1H, *J* = 7.80 Hz), 8.12–8.18 (m, 3H). ¹³C NMR (75 MHz, DMSO) *δ* 193.72, 151.16, 141.48, 137.41, 136.41, 135.53, 133.58, 132.24, 130.12, 128.84, 127.32, 118.25, 111.79, 111.53, 108.60, 29.40. LC-MS (ESI) *m/z* found: 295 [M + H]⁺.

#### 4.1.1.7. 3-Methyl-6-(4-nitrobenzoyl)-1,3-benzothiazol-2-one (9a).
Prepared according to the general procedure using 3-methyl-benzothiazolone and 4-nitrobenzoyl chloride. Recrystallized from 1,4-dioxane. Yield (62 %); m.p. 172–175 °C. IR (ν, cm⁻¹) 1685 and 1658 (CO). ¹H NMR (300 MHz, DMSO-d₆) *δ* 3.46 (s, 3H), 7.44 (d, 1H, *J* = 8.7 Hz), 7.78 (m, 1H), 7.85 (d, 2H, *J* = 7.2 Hz), 8.14 (m, 1H), 8.35 (d, 2H, *J* = 7.2 Hz). ¹³C NMR (75 MHz, DMSO) *δ* 194.27, 168.56, 141.44, 140.78, 129.52 (2C), 130.34, 128.82 (2C), 126.15, 125.20, 124.0, 120.20, 119.33, 33.7. LC-MS (ESI) *m/z* found: 315 [M + H]⁺.

#### 4.1.1.8. 6-(4-Chlorobenzoyl)benzo[d][1,3]selenazol-2(3H)-one (10a).

Prepared according to the general procedure using benzoselenazolone and 4-chlorobenzoyl chloride. Recrystallized from acetonitrile. Yield (50 %); m.p. 230–232 °C. IR (ν, cm⁻¹) 3248 (NH), 2229 (CN), 1701 and 1678 (CO). ¹H NMR (300 MHz, DMSO-d₆) *δ* 7.25 (d, 1H, *J* = 8.3 Hz),

7.63 (d, 2H, *J* = 8.6 Hz), 7.69 (dd, 1H, *J* = 8.3, 1.8 Hz), 7.74 (d, 2H, *J* = 8.6 Hz), 8.16 (d, *J* = 1.8 Hz, 1H), 12.18 (br s, 1H, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO) *δ* 193.28, 171.32, 141.66, 137.17, 136.20, 131.33, 131.05 (2C), 129.08, 128.89, 128.65 (2C), 124.03, 112.05. LC-MS (ESI) *m/z* found: 328 [M + H]⁺.

#### 4.1.1.9. 4-[3-Methyl-2-oxo-1,3-benzoselenazol-6-carbonyl]benzonitrile

(11a). Prepared according to the general procedure using 3-methyl-benzoselenazolone and 4-cyanobenzoyl chloride. Recrystallized from acetonitrile. Yield (68 %); m.p. 205–210 °C. IR (ν, cm⁻¹) 2231 (CN) 1699 and 1658 (CO). ¹H NMR (300 MHz, DMSO-d₆) *δ* 3.45 (s, 3H), 7.45 (d, 1H, *J* = 8.8 Hz), 7.77 (m, 1H), 7.83 (d, 2H, *J* = 8.2 Hz), 8.02 (d, 2H, *J* = 8.2 Hz), 8.25 (m, 1H). ¹³C NMR (75 MHz, DMSO) *δ* 194.27, 160.56, 145.44, 142.78, 137.44, 132.72, 131.52 (2C), 129.20, 128.32, 128.82 (2C), 124.20, 121.23, 117.32, 34.4. LC-MS (ESI) *m/z* found: 342 [M + H]⁺.

#### 4.1.1.10. 4-[3-Ethyl-2-oxo-1,3-benzoselenazol-6-carbonyl]benzonitrile

(12a). Prepared according to the general procedure using 3-ethyl-benzoselenazolone and 4-cyanobenzoyl chloride. Recrystallized from ethanol. Yield (62 %); m.p. 130–135 °C. IR (ν, cm⁻¹) 2231 (CN) 1697 and 1670 (CO). ¹H NMR (300 MHz, DMSO-d₆) *δ* 1.19 (t, 3H, *J* = 7.2 Hz), 4.00 (q, 2H, *J* = 7.2 Hz), 7.50 (d, 1H, *J* = 8.7 Hz), 7.76 (dd, 1H, *J* = 8.7 Hz, *J* = 1.8 Hz), 7.85 (d, 2H, *J* = 8.4 Hz), 8.02 (d, 2H, *J* = 8.4 Hz), 8.27 (d, 1H, *J* = 1.8 Hz). ¹³C NMR (75 MHz, DMSO) *δ* 194.27, 171.56, 141.44, 140.48, 131.52 (2C), 130.74, 129.42 (2C), 128.15, 125.21, 125.0, 118.43, 114.20, 113.33, 47.3, 13.4. LC-MS (ESI) *m/z* found: *m/z* (%): 356 [M + H]⁺.

#### 4.1.1.11. 3-Methyl-6-(4-nitrobenzoyl)-1,3-benzoselenazol-2-one (13a).

Prepared according to the general procedure using 3-methyl-benzoselenazolone and 4-nitrobenzoyl chloride. Recrystallized from acetonitrile. Yield (62 %) m.p. 151–155 °C. IR (ν, cm⁻¹) 1680 and 1655 (CO) 1520 (NO₂). ¹H NMR (300 MHz, DMSO-d₆) *δ* 3.45 (s, 3H), 7.44 (d, 1H, *J* = 8.7 Hz), 7.78 (dd, 1H, *J* = 8.7 Hz, *J* = 1.8 Hz), 7.92 (d, 2H, *J* = 8.4 Hz), 8.28 (d, 1H, *J* = 1.8 Hz), 8.36 (d, 2H, *J* = 8.4 Hz). ¹³C NMR (75 MHz, DMSO) *δ* 194.27, 160.56, 145.44, 142.78, 137.44, 132.72, 131.52 (2C), 129.20, 128.32, 128.82 (2C), 124.20, 121.23, 117.32, 34.4. LC-MS (ESI) *m/z* found: *m/z* (%) 362 [M + H]⁺.

#### 4.1.1.12. 3-Ethyl-6-(4-nitrobenzoyl)-1,3-benzoselenazol-2-one (14a).

Prepared according to the general procedure using 3-ethyl-benzoselenazolone and 4-nitrobenzoyl chloride. Recrystallized from ethanol. Yield (60 %); m.p. 99–102 °C. IR (ν, cm⁻¹) 1678 and 1657 (CO), 1520 (NO₂). ¹H NMR (300 MHz, DMSO-d₆) *δ* 1.20 (t, 3H, *J* = 7.2 Hz), 4.01 (q, 2H, *J* = 7.2 Hz), 7.51 (d, 1H, *J* = 8.4 Hz), 7.78 (dd, 1H, *J* = 8.4 Hz, *J* = 1.5 Hz), 7.94 (d, 2H, *J* = 8.7 Hz), 8.30 (d, 1H, *J* = 1.5 Hz), 8.37 (d, 2H, *J* = 8.7 Hz). ¹³C NMR (75 MHz, DMSO) *δ* 194.27, 159.56, 151.2, 145.44, 144.48, 135.30, 130.52, 130.42, 129.0 (2C), 124.43, 123.20 (2C), 121.33, 47.3, 13.4. LC-MS (ESI) *m/z* found: *m/z* (%): 376 [M + H]⁺.

#### 4.1.1.13. 4-(2-Oxindoline-5-carbonyl)benzonitrile (15a).
Prepared according to the general procedure using oxindole and 4-cyanobenzoyl chloride. Recrystallized from ethanol. Yield (60 %); m.p. 250–253 °C. IR (ν, cm⁻¹) 3545 (NH) 2231 (CN) 1720 and 1649 (CO). ¹H NMR (300 MHz, DMSO-d₆) *δ* 3.59 (s, 2H), 6.94 (d, 1H, *J* = 8.6 Hz), 7.63–7.65 (m, 2H), 7.79 (d, 2H, *J* = 8.2 Hz), 8.00 (d, 2H, *J* = 8.2 Hz), 10.88 (br s, 1H, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO) *δ* 193.60, 176.71, 148.98, 142.11, 132.47, 131.62, 129.54, 129.08, 126.43, 126.05, 118.26, 113.87, 108.89, 35.49. LC-MS (ESI) *m/z* found: 261 [M – H]⁺.

#### 4.1.1.14. 4-(1-Methyl-2-oxindoline-5-carbonyl)benzonitrile (16a).
Prepared according to the general procedure using 1-methylindolinone and 4-cyanobenzoyl chloride. Recrystallized from ethanol. Yield (65 %); m. p. 159–164 °C. IR (ν, cm⁻¹) 2227 (CN) 1714 and 1645 (CO). ¹H NMR
(300 MHz, DMSO-d6) δ 3.17 (s, 3H), 3.64 (s, 2H), 7.46 (d, 1H, J = 8.7 Hz), 7.35–7.83 (m, 2H), 7.79 (d, 2H, J = 8.4 Hz), 8.01 (d, 2H, J = 8.4 Hz). ¹³C NMR (75 MHz, DMSO) δ 194.60, 175.71, 148.98, 142.11, 135.47, 131.62 (2C), 131.54, 131.08 (2C), 132.43, 126.05, 118.26, 116.87, 116.89, 35.8, 35.49. LC-MS (ESI) *m/z* found: 277 [*M* + *H*]⁺.

4.1.1.15. **6-Benzoyl-4H-1,4-benzoxazin-3-one (17a).** Prepared according to the general procedure using 1,4-benzoxazinone and benzoyl chloride. Recrystallized from ethanol. Yield (76 %); m.p. 182–185 °C. IR (ν, cm⁻¹) 3192 (NH), 1695 and 1653 (CO). ¹H NMR (300 MHz, DMSO-d6) δ 4.71 (s, 2H), 7.07 (d, 1H, J = 8.4 Hz), 7.33 (dd, 1H, J = 8.4 Hz, J = 2.4 Hz), 7.37 (d, 1H, J = 2.4 Hz), 7.53–7.58 (m, 2H), 7.64–7.71 (m, 3H), 10.85 (br s, 1H, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO) δ 194.20, 168.56, 151.2, 138.74, 138.4, 132.72, 130.52 (2C), 128.52 (2C), 126.8, 126.20, 120.23, 114.32, 68.2. LC-MS (ESI) *m/z* found: 254 [*M* + *H*]⁺.

4.1.1.16. **6-Benzoyl-4-methyl-1,4-benzoxazin-3-one (18a).** Prepared according to the general procedure using 4-methyl-benzoxazinone and benzoyl chloride. Recrystallized from acetonitrile. Yield (65 %); m.p. 173–176 °C. IR (ν, cm⁻¹) 1699 and 1654 (CO). ¹H NMR (300 MHz, DMSO-d6) δ 3.31 (s, 3H), 4.79 (s, 2H), 7.12 (d, 1H, J = 8.1 Hz), 7.37 (dd, 1H, J = 8.1 Hz, J = 1.5 Hz), 7.51 (d, 1H, J = 1.5 Hz), 7.56–7.58 (m, 2H), 7.65–7.74 (m, 3H). ¹³C NMR (75 MHz, DMSO) δ 194.40, 168.26, 151.3, 138.24, 137.4, 132.52, 131.52 (2C), 128.82 (2C), 126.80, 125.30, 121.23, 114.22, 67.2, 36.5. LC-MS (ESI) *m/z* found: 268 [*M* + *H*]⁺.

4.1.1.17. **4-(3-Oxo-4H-1,4-benzoxazin-6-carbonyl)benzonitrile (19a).** Prepared according to the general procedure using 1,4-benzoxazinone and 4-cyanobenzoyl chloride. Recrystallized from acetonitrile; Yield (58 %); m.p. 280–283 °C. IR (ν, cm⁻¹) 3119 (NH), 2227 (CN), 1691 and 1656 (CO). ¹H NMR (300 MHz, DMSO-d6) δ 4.71 (s, 2H), 7.07 (d, 1H, J = 8.4 Hz), 7.32 (dd, 1H, dd, J = 8.4, 2.0 Hz), 7.37 (d, 1H, J = 2.0 Hz), 7.81 (d, 2H, J = 8.3 Hz), 8.02 (d, 2H, J = 8.3 Hz), 10.88 (br s, 1H, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO) δ 193.16, 164.06, 147.63, 141.50, 132.53, 129.97, 129.71, 127.42, 126.33, 118.24, 117.24, 116.19, 114.19, 66.79. LC-MS (ESI) *m/z* found: 277 [*M* − *H*]⁺.

4.1.1.18. **4-(4-Methyl-3-oxo-1,4-benzoxazin-6-carbonyl)benzonitrile (20a).** Prepared according to the general procedure using 4-methyl-benzoxazinone and 4-cyanobenzoyl chloride. Recrystallized from 1,4-dioxane. Yield (56 %); m.p. 208–211 °C. IR (ν, cm⁻¹) 2231 (CN), 1697 and 1643 (CO). ¹H NMR (300 MHz, DMSO-d6) δ 3.31 (s, 3H), 4.81 (s, 2H), 7.13 (d, 1H, J = 8.1 Hz), 7.37 (dd, 1H, J = 8.1 Hz, J = 2.1 Hz), 7.53 (d, 1H, J = 2.1 Hz), 7.85 (d, 2H, J = 7.8 Hz), 8.03 (d, 2H, J = 7.8 Hz). ¹³C NMR (75 MHz, DMSO) δ 194.12, 162.06, 146.43, 141.20, 132.13, 129.57, 128.71, 127.42, 126.33, 118.44, 117.24, 115.19, 114.20, 66.72, 36.2. LC-MS (ESI) *m/z* found: 293 [*M* + *H*]⁺.

4.1.1.19. **4-[(3-Oxo-4H-1,4-benzothiazin-7-carbonyl)benzonitrile (23a).** Prepared according to the general procedure using 1,4-benzothiazinone and 4-cyanobenzoyl chloride. Recrystallized from ethanol. Yield (58 %); m.p. 261–263 °C. IR (ν, cm⁻¹) 3094 (NH), 2233 (CN), 1697 and 1664 (CO). ¹H NMR (300 MHz, DMSO-d6) δ 3.58 (s, 2H), 7.31 (dd, J = 8.1, 1.7 Hz, 1H), 7.40 (d, J = 1.6 Hz, 1H), 7.50 (d, 1H, J = 8.1 Hz), 7.83 (d, 2H, J = 8.3 Hz), 8.03 (d, 2H, J = 8.3 Hz), 10.75 (br s, 1H, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO) δ 193.66, 164.78, 141.01, 137.57, 134.18, 132.59 (2C), 129.89 (2C), 127.46, 126.23, 124.31, 118.21, 117.89, 114.43, 28.39. LC-MS (ESI) *m/z* found: 293 [*M* − *H*]⁺.

4.1.1.20. **4-[(4-Methyl-3-oxo-1,4-benzothiazin-7-carbonyl)benzonitrile (24a).** Prepared according to the general procedure using 4-methyl-benzothiazinone and 4-cyanobenzoyl chloride. Recrystallized from ethanol. Yield (68 %); m.p. 179–180 °C. IR (ν, cm⁻¹) 2227 (CN), 1683 and 1666 (CO). ¹H NMR (300 MHz, DMSO-d6) δ 3.37 (s, 3H), 3.63 (s, 2H), 7.35 (d, 1H, J = 8.1 Hz), 7.56 (m, 1H), 7.59 (d, 1H, J = 8.1 Hz), 7.88 (d, 2H, J = 8.7 Hz), 8.03 (d, 2H, J = 8.7 Hz). ¹³C NMR (75 MHz, DMSO) δ 193.56, 164.28, 141.51, 137.47, 133.28, 131.59 (2C), 129.23 (2C), 127.26, 125.23, 124.31, 118.31, 117.12, 114.23, 35.39, 29.24. LC-MS (ESI) *m/z* found: 309 [*M* + *H*]⁺.

4.1.1.21. **N-(5-benzoyl-2-hydroxyphenyl)acetamide (25).** Prepared according to the general procedure using N-(2-hydroxyphenyl)acetamide and benzoyl chloride. Recrystallized from acetonitrile. Yield (60 %); m.p. 179–180 °C. IR (ν, cm⁻¹) 3349 (OH), 3065 (NH), 1666 (CO). ¹H NMR (300 MHz, DMSO-d6) δ 2.10 (s, 3H), 7.00 (d, 1H, J = 8.1 Hz), 7.39 (dd, 1H, J = 8.1 Hz, J = 1.2 Hz), 7.49–7.55 (m, 5H), 8.35 (d, 1H, J = 1.2 Hz), 9.39 (br s, 1H, exchangeable with D₂O), 10.9 (br s, 1H, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO) δ 194.56, 168.28, 152.23, 138.51, 136.47, 132.28, 130.59 (2C), 128.92, 128.23 (2C), 127.23, 121.31, 115.2, 24.24. LC-MS (ESI) *m/z* found: 256 [*M* + *H*]⁺.

4.1.1.22. **N-[5-(4-chlorobenzoyl)-2-hydroxyphenyl]acetamide (26).** Prepared according to the general procedure using N-(2-hydroxyphenyl) acetamide and 4-chlorobenzoyl chloride. Recrystallized from ethanol. Yield (84 %); m.p. 256–258 °C. IR (ν, cm⁻¹) 3393(OH), 3060 (NH), 1662 (CO). ¹H NMR (300 MHz, DMSO-d6) δ 2.10 (s, 3H), 6.98 (d, 1H, J = 8.4 Hz), 7.39 (dd, 1H, J = 8.4 Hz, J = 2.4 Hz), 7.62 (d, 2H, J = 8.2 Hz), 7.67–7.70 (d, 2H, J = 8.2 Hz), 8.34 (d, 1H, J = 2.4 Hz), 9.38 (br s, 1H, exchangeable with D₂O), 10.97 (br s, 1H, NH, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO) δ 194.26, 167.24, 152.43, 137.51, 135.24, 132.48, 130.79 (2C), 128.13 (2C), 127.43, 121.41, 115.2, 24.24. LC-MS (ESI) *m/z* found: 290 [*M* + *H*]⁺.

4.1.1.23. **N-[5-(4-Cyanobezoyl)-2-hydroxyphenyl]acetamide (27).** Prepared according to the general procedure using N-(2-hydroxyphenyl) acetamide and 4-cyanobenzoyl chloride. Recrystallized from 95 % ethanol. Yield (82 %); m.p. 238–243 °C. IR (ν, cm⁻¹) 3317 (OH), 3065 (NH), 2233 (CN), 1695 and 1645 (CO). ¹H NMR (300 MHz, DMSO-d6) δ 2.10 (s, 3H, CH₃), 6.99 (d, 1H, J = 8.4 Hz), 7.39 (d, 1H, J = 8.4 Hz), 7.78 (d, 2H, J = 8.1 Hz), 7.99 (d, 2H, J = 8.1 Hz), 8.38 (s, 1H, H₆), 9.37 (s, 1H, OH, exchangeable with D₂O), 11.06 (br s, 1H, NH, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO) δ 193.46, 164.31, 152.30, 142.45, 136.20, 131.38 (2C), 130.21, 132.81 (2C), 128.71, 127.24, 121.24, 116.45, 115.48, 24.52. LC-MS (ESI) *m/z* found: 281 [*M* + *H*]⁺.

4.1.1.24. **N-[2-hydroxy-5-(pyridine-4-carbonyl)phenyl]acetamide (28).** Prepared according to the general procedure using N-(2-hydroxyphenyl) acetamide and isonicotinoyl chloride hydrochloride. Recrystallized from 95 % ethanol. Yield (43 %); m.p. 228–231 °C. IR (ν, cm⁻¹) 3420 (OH) 3055 (NH) 1693 and 1643 (CO). ¹H NMR (300 MHz, DMSO-d6) δ 2.09 (s, 3H, CH₃), 6.99 (d, 1H, J = 8.4 Hz), 7.41 (d, 1H, J = 8.4 Hz), 7.60 (d, 2H, J = 5.4 Hz), 8.40 (s, 1H), 8.79 (d, 2H, J = 5.4 Hz), 9.38 (s, 1H, OH, exchangeable with D₂O), 11.1 (br s, 1H, NH, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO) δ 193.26, 165.31, 152.20, 150.28 (2C), 145.21, 132.21, 128.20, 123.41, 123.81 (2C), 120.45, 116.48, 24.22. LC-MS (ESI) *m/z* found: 257.24 [*M* + *H*]⁺.

### 4.1.2. Synthesis of ethyl N-[2-[hydroxyl-5-(pyridine-4-carbonyl)phenyl] carbamate (29)

A mixture of compound 28 (9.4 g, 37 mmol) in 37 % solution of HCl (200 mL) was refluxed for 4 h. The solution was concentrated under reduced pressure and the solid was triturated with acetonitrile and filtered. The precipitate was taken in methylene chloride (200 mL) and pyridine (11.0 mL, 140 mmol). The reaction mixture was cooled at 0 °C and ethyl chloroformate (38 mL, 40 mmol) was added dropwise. The reaction was stirred at room temperature for 2 h. Water was added and the organic layer was separated, dried over MgSO₄ and evaporated under reduced pressure. The solid was triturated with diethyl ether and filtered. Yield (80 %); m.p. 134–139 °C. IR (ν, cm⁻¹) 3422 (OH) 3146
(NH), 1770 and 1676 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 2.09 (t, 3H, J = 6.3 Hz), 4.07 (q, 2H, J = 6.3 Hz), 6.96 (d, 1H, J = 8.7 Hz), 7.41 (dd, 1H, J = 8.7 Hz, J = 1.8 Hz), 7.54 (d, 2H, J = 4.8 Hz), 8.16 (d, 1H, J = 1.8 Hz), 8.44 (br s, 1H, OH, exchangeable with D₂O), 8.76 (d, 2H, J = 4.8 Hz), 11.04 (br s, 1H, NH, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO) δ 193.46, 155.31, 152.20, 150.58 (2C), 145.51, 132.71, 126.20, 125.41, 123.41 (2C), 120.25, 116.44, 61.72, 13.8. LC-MS (ESI) *m/z* found: 287 [M + H]⁺.

### 4.1.3. Synthesis of 5-(pyridine-4-carbonyl)-3H-1,3-benzoxazol-2-one (30a)

A mixture of compound 29 (4.3 g, 15 mmol) and potassium carbonate (6.2 g, 45 mmol) in dimethylformamide (50 mL) was heated at 70 °C during 5 h. After cooling, the reaction mixture was hydrolyzed with water and the precipitate was filtered, washed with water, dried and recrystallized from ethanol. Yield (82 %); m.p. 307–310 °C. IR (ν, cm⁻¹) 3352 (NH), 1738 and 1701 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 6.88 (d, 1H, *J* = 8.1 Hz), 7.04 (dd, 1H, *J* = 8.1 Hz, *J* = 1.8 Hz), 7.14 (d, 1H, *J* = 1.8 Hz), 7.53 (d, 2H, *J* = 6.3 Hz), 8.73 (d, 2H, *J* = 6.3 Hz), 11.80 (br s, 1H, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO) δ 193.56, 155.22, 150.58 (2C), 147.21, 145.51, 136.35, 135.71, 125.20, 123.51 (2C), 121.25, 119.24. LC-MS (ESI) *m/z* found: 241 [M + H]⁺.

### 4.1.4. General procedure for the synthesis of intermediates 31a and 32a

Acetamide derivative 25 or 26 (50 mmol) in 37 % solution of HCl (200 mL) was refluxed for 4 h. The reaction mixture was concentrated under reduced pressure and the residue was triturated with acetonitrile and filtered. The obtained aminophenol was heated with urea (18 g, 300 mmol) for 6 h. The reaction mixture was hydrolyzed with water and acidified with 6 M HCl. The precipitate was filtered, washed with water, dried and recrystallized from acetonitrile to give the title compound.

#### 4.1.4.1. 5-Benzoyl-3H-1,3-benzoxazol-2-one (31a)
Prepared according to the general procedure using acetamide 25. Yield (73 %); m.p. 153–160 °C. IR (ν, cm⁻¹) 3188 (NH), 1770 and 1689 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 7.38–7.48 (m, 3H), 7.56–7.74 (m, 5H), 11.70 (br s, 1H, NH, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO) δ 194.26, 155.32, 147.58, 140.51, 138.35, 135.41, 132.21, 130.51 (2C), 128.41 (2C), 126.24, 121.45, 119.74. LC-MS (ESI) *m/z* found: 240 [M + H]⁺.

#### 4.1.4.2. 5-(4-Chlorobenzoyl)-3H-1,3-benzoxazol-2-one (32a)
Prepared according to the general procedure using acetamide 26. Yield (68 %); m.p. 206–210 °C. IR (ν, cm⁻¹) 3155 (NH), 1770 and 1657 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 7.40 (s, 1H), 7.42 (d, 1H, *J* = 7.8 Hz), 7.48 (dd, 1H, *J* = 7.8 Hz, *J* = 1.8 Hz), 7.61 (d, 2H, *J* = 7.5 Hz), 7.73 (d, 2H, *J* = 7.5 Hz), 11.90 (br s, 1H, NH, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO) δ 193.48, 155.32, 147.66, 140.17, 139.20, 132.33, 131.05 (2C), 129.08, 128.89, 128.65 (2C), 121.03, 120.05. LC-MS (ESI) *m/z* found: 274 [M + H]⁺.

### 4.1.5. Synthesis of 4-(2-oxo-3H-1,3-benzoxazol-5-carbonyl)benzonitrile (33a)

To a cooled solution of 27 (6.0 g, 21 mmol) in dichloromethane (300 mL) were added triethylamine (21 mL, 150 mmol) and ethyl chloroformate (2.5 mL, 26 mmol). The mixture was stirred at room temperature for 3 h. Water was added and the solution was acidified with 3 M HCl. The organic layer was separated, dried over MgSO₄ and evaporated under reduced pressure. The solid was dissolved in dimethylformamide, potassium carbonate (6.2 g, 45 mmol) was added and the mixture was heated at 70 °C during 5 h. After cooling, the reaction mixture was hydrolyzed with water and the precipitate was filtered, washed with water, dried and recrystallized from ethanol to give compound 33a. Yield (62 %); m.p. 250–253 °C. IR (ν, cm⁻¹) 3221 (NH), 2224 (CN), 1770 and 1643 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 7.42–7.52 (m, 3H), 7.85

(d, 2H, *J* = 8.1 Hz), 8.03 (d, 2H, *J* = 8.1 Hz), 11.95 (br s, 1H, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO) δ 193.36, 154.31, 146.32, 142.30, 141.45, 135.21, 131.38 (2C), 128.89 (2C), 127.21, 121.24, 120.24, 118.45, 116.48. LC-MS (ESI) *m/z* found: 265 [M + H]⁺.

### 4.1.6. General procedure for the synthesis of intermediates 34a-36a

To a solution of the corresponding benzoxazolone 31a-33a (10 mmol) in acetone (150 mL) was added potassium carbonate (4.15 g, 30 mmol) and the mixture was heated at reflux during 1 h. Iodomethane (0.78 mL, 13 mmol) was added dropwise and the mixture was refluxed for another 3 h. The acetone was removed under reduced pressure and the residual product was taken with water and acidified with 6 M HCl. The precipitate was filtered, washed with water, dried and recrystallized to give the title compound.

#### 4.1.6.1. 5-Benzoyl-3-methyl-1,3-benzoxazol-2-one (34a)
Prepared according to the general procedure using 31a. Recrystallized from acetonitrile. Yield (84 %); m.p. 152–156 °C. IR (ν, cm⁻¹) 1770 and 1649 (CO). ¹H NMR (300 MHz, CDCl₃) δ 3.46 (s, 3H), 7.24 (d, 1H, *J* = 8.1 Hz) 7.48–7.64 (m, 5H), 7.76–7.82 (m, 2H). ¹³C NMR (75 MHz, DMSO) δ 194.42, 155.52, 146.58, 142.51, 139.31, 135.21, 133.21, 130.51 (2C), 130.41 (2C), 126.24, 121.45, 119.74, 29.2. LC-MS (ESI) *m/z* found: 254 [M + H]⁺.

#### 4.1.6.2. 5-(4-Chlorobenzoyl)-3-methyl-1,3-benzoxazol-2(3H)-one (35a)
Prepared according to the general procedure using 32a. Recrystallized from acetonitrile. Yield (88 %); m.p. 163–164 °C. IR (ν, cm⁻¹) 1774 and 1651 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 3.39 (s, 3H) 7.46–7.53 (m, 2H), 7.62–7.65 (m, 3H), 7.74 (d, 2H, *J* = 8.7 Hz). ¹³C NMR (75 MHz, DMSO) δ 193.68, 154.32, 147.36, 141.17, 139.24, 132.43, 131.42 (2C), 129.48, 128.89, 128.25 (2C), 121.33, 120.25, 29.30. LC-MS (ESI) *m/z* found: 288 [M + H]⁺.

#### 4.1.6.3. 4-(3-Methyl-2-oxo-1,3-benzoxazol-5-carbonyl)benzonitrile (36a)
Prepared according to the general procedure using 33a. Recrystallized from ethanol. Yield (92 %); m.p. 182–185 °C. IR (ν, cm⁻¹) 2229 (CN), 1770 and 1649 (CO). ¹H NMR (300 MHz, CDCl₃) δ 3.39 (s, 3H) 7.48–7.54 (m, 2H) 7.69 (m, 1H), 7.86 (d, 2H, *J* = 8.1 Hz), 8.03 (d, 2H, *J* = 8.1 Hz). ¹³C NMR (75 MHz, DMSO) δ 193.36, 154.31, 143.30, 141.45, 140.21, 132.38 (2C), 131.89, 131.21 (2C), 126.71, 121.24, 120.24, 118.45, 115.48, 28.6. LC-MS (ESI) *m/z* found: 279 [M + H]⁺.

### 4.1.7. Synthesis of intermediates 37 and 38

#### 4.1.7.1. 2-Oxo-2,3-dihydrobenzo[d]thiazole-5-carboxylic acid (37)
Stage 1- Sodium sulfide nonahydrate (14.4 g, 60 mmol) was added to the solution of methyl 4-chloro-3-nitrobenzoate (10 g, 46 mmol) in ethanol (250 mL). The mixture was stirred at room temperature 6 h. The mixture was quenched over ice water and acidified with 6 M HCl to pH 2. The precipitate was collected by filtration and air dried to isolate a crude solid (7.8 g). m.p. 98–101 °C. IR (ν, cm⁻¹) 2546 (SH), 1722 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 3.81 (s, 3H), 4.31 (br s, 1H, exchangeable with D₂O), 7.82 (d, 1H, *J* = 8.2 Hz), 8.17 (dd, 1H, *J* = 8.2 Hz, *J* = 1.5 Hz), 8.41 (d, 1H, *J* = 1.5 Hz).

Stage 2- To a solution of methyl 3-nitro-4-sulfanylbenzoate (7.67 g, 36 mmol) in 6 M HCl (150 mL) was added portion wise tin(II) chloride (17 g, 90 mmol) under inert atmosphere. The mixture was stirred under reflux for 4 h and poured on ice water. The crude product was collected by filtration, washed with diethyl ether and dried under inert atmosphere. Then a crude solid was isolated (5.6 g). m.p. 215–217 °C. IR (ν, cm⁻¹) 2511 (SH), 1711 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 4.42 (br s, 1H, exchangeable with D₂O), 4.54 (br s, 3H, exchangeable with D₂O), 7.76 (d, 1H, *J* = 8.2 Hz), 8.31 (dd, 1H, *J* = 8.2 Hz, *J* = 1.5 Hz), 8.44 (d, 1H, *J* = 1.5 Hz), 12.2 (br s, 1H, exchangeable with D₂O).

Stage 3- A finely pulverized mixture of 3-amino-4-sulfanylbenzoic
acid hydrochloride (5.2 g, 25 mmol) and urea (6 g, 100 mmol) was stirred at 150 °C for 4 h. The reaction mixture was quenched over ice water and acidified with 6 M HCl to pH 2. The crude product was collected by filtration, air dried and washed with diethyl ether. Yield (42 %); m.p. 275–277 °C. IR (ν, cm⁻¹) 1718 and 1682 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 7.62 (d, 1H, *J* = 8.4 Hz), 7.82 (dd, 1H, *J* = 8.4 Hz, *J* = 2.4 Hz), 7.95 (d, 1H, *J* = 2.4 Hz), 12.10 (br s, 1H, exchangeable with D₂O), 13.06 (br s, 1H, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO) δ 171.36, 166.31, 134.30, 131.45, 130.21, 127.38, 125.89, 121.21. LC-MS (ESI) *m/z* found: 196 [M + H]⁺.

### 4.1.7.2. 2-Oxo-3H-1,3-benzothiazol-5-carbaldehyde (38).
Stage 1- A solution of compound 37 (3.8 g, 20 mmol) in methanol (150 mL) was cooled at 0 °C and thionyl chloride (4.32 mL, 60 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 h and under reflux during 5 h. Methanol was evaporated under reduced pressure and the residue was dissolved in EtOAc. The organic layer was washed with a 10 % solution of K₂CO₃, dried over anhydrous MgSO₄ and evaporated under reduced pressure to give 2.8 g of methyl 2-oxo-3H-1,3-benzothiazolone-5-carboxylate. m.p. 217–219 °C. IR (ν, cm⁻¹) 1695 and 1684 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 3.85 (s, 3H), 7.60 (d, 1H, *J* = 2.7 Hz), 7.67–7.69 (m, 2H), 12.13 (br s, 1H, exchangeable with D₂O).

Stage 2- To a stirred solution of methyl 2-oxo-3H-1,3-benzothiazolone-5-carboxylate (2 g, 10 mmol) in THF (50 mL) cooled to 0 °C was added portion wise LiAlH₄ (0.76 g, 20 mmol). After 3 h, water was added and the solution was acidified with 1 M HCl to pH 5. The reaction mixture was extracted twice with CH₂Cl₂. The organic layer was dried over anhydrous MgSO₄ and evaporated under reduced pressure. The crude product was triturated with diethyl ether and filtered to give 1.5 g of 5-(hydroxymethyl)-2-oxo-3H-1,3-benzothiazolone. m.p. 178–181 °C. IR (ν, cm⁻¹) 3319 (OH), 1684 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 4.49 (d, 2H, *J* = 5.7 Hz), 5.26 (br t, 1H, exchangeable with D₂O), 7.02 (d, 1H, *J* = 8.1 Hz), 7.09 (s, 1H), 7.45 (d, 1H, *J* = 8.1 Hz), 11.85 (s, 1H, exchangeable with D₂O).

Stage 3- A mixture of 5-(hydroxymethyl)-2-oxo-3H-1,3-benzothiazolone (1 g, 5.5 mmol) and manganese dioxide (4.8 g, 55 mmol) in CH₂Cl₂ was stirred at room temperature for 12 h. The reaction mixture was then filtered, the cake was washed with CH₂Cl₂, and the filtrate was concentrated under reduced pressure. Trituration with diethyl ether gave aldehyde 38. Yield 42 %; m.p. 211–215 °C. IR (ν, cm⁻¹) 1730 and 1691 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 7.53 (d, 1H, *J* = 8.1 Hz), 7.65 (dd, 1H, *J* = 8.1 Hz, *J* = 2.1 Hz), 7.80 (d, 1H, *J* = 2.1 Hz), 9.95 (s, 1H), 12.22 (br s, 1H, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO) δ 191.36, 170.31, 135.30, 134.45, 132.20, 130.21, 125.89, 120.21. LC-MS (ESI) *m/z* found: 180 [M + H]⁺.

### 4.1.8. General procedure for the synthesis of intermediates 39 and 40

A mixture of potassium carbonate (2.3 g, 16.7 mmol) and 38 (1 g, 5.6 mmol) in acetone (50 mL) was stirred under reflux for 1 h and then the corresponding iodoalkane (6.7 mmol) was added. The reaction mixture was refluxed for 2 h, cooled, hydrolyzed with water and extracted with EtOAc. The organic layer was dried over anhydrous MgSO₄ and evaporated under reduced pressure. Trituration with diethyl ether gave the title compound.

#### 4.1.8.1. 3-Methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-5-carbaldehyde (39).
Prepared according to the general procedure using 38 and iodo-methane. Yield (84 %); m.p. 140–142 °C. IR (ν, cm⁻¹) 1682, 1674 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 3.46 (s, 3H), 7.73–7.75 (m, 2H), 7.90 (d, 1H, *J* = 8.1 Hz), 9.99 (s, 1H). ¹³C NMR (75 MHz, DMSO) δ 194.36, 168.31, 135.20, 134.25, 132.40, 130.51, 125.59, 119.21, 33.52. LC-MS (ESI) *m/z* found: 194 [M + H]⁺.

#### 4.1.8.2. 3-Ethyl-2-oxo-2,3-dihydro-1,3-benzothiazol-5-carbaldehyde (40).
Prepared according to the general procedure using 38 and

iodoethane. Yield (87 %); m.p. 155–156 °C. IR (ν, cm⁻¹) 1689, 1664 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 1.23 (t, 3H, *J* = 6.7 Hz), 4.03 (q, 2H, *J* = 6.7 Hz), 7.74 (dd, 1H, *J* = 8.1 Hz, *J* = 2.1 Hz), 7.85 (d, 1H, *J* = 2.1 Hz), 7.91 (d, 1H, *J* = 8.1 Hz), 10.04 (s, 1H). ¹³C NMR (75 MHz, DMSO) δ 195.16, 168.71, 135.25, 134.25, 131.40, 130.51, 124.49, 119.41, 43.52, 13.2. LC-MS (ESI) *m/z* found: 208 [M + H]⁺.

### 4.1.9. General procedure for the synthesis of intermediates 1b–36b

To a solution of the corresponding acyl derivative (5 mmol) in methanol (50 mL) was added slowly sodium borohydride (0.20 g, 5 mmol) at room temperature. The resulting solution was stirred for 2 h at room temperature, acidified with an aqueous solution of 2 M HCl and methanol was evaporated. Water was added and the precipitate was filtered, washed with water, dried and recrystallized or triturated to give the title compound.

#### 4.1.9.1. 4-[Hydroxy-(2-oxo-3H-1,3-benzoxazol-6-yl)methyl]benzonitrile (1b).
Prepared according to the general procedure using 1a. Recrystallized from ethyl acetate. Yield (77 %); m.p. 195–197 °C. IR (ν, cm⁻¹) 3348–3064 (NH, OH), 2230 (CN), 1746 (CO). ¹H NMR (300 MHz, CDCl₃) δ 5.87 (s, 1H), 6.23 (br s, 1H, exchangeable with D₂O), 7.01–7.18 (m, 2H), 7.31 (m, 1H), 7.58 (d, 2H, *J* = 8.30 Hz), 7.76 (d, 2H, *J* = 8.30 Hz), 10.10 (br s, 1H, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO) δ 170.09, 151.12, 139.43, 135.42, 132.74 (2C), 129.69 (2C), 124.69, 123.34, 120.57, 118.65, 112.32, 110.52, 74.30. LC-MS (ESI) *m/z* found: 267 [M + H]⁺.

#### 4.1.9.2. 3-[Hydroxy-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)methyl]benzonitrile (2b).
Prepared according to the general procedure using 2a. Recrystallized from ethyl acetate. Yield (84 %); m.p. 83–85 °C. IR (ν, cm⁻¹) 3498 (OH), 2232 (CN), 1773 (CO). ¹H NMR (300 MHz, CDCl₃) δ ¹H NMR (300 MHz, DMSO-d₆) δ 3.38 (s, 3H), 5.81 (d, 1H, *J* = 3.0 Hz), 6.21 (br d, 1H, exchangeable with D₂O), 7.32 (d, 1H, *J* = 7.8 Hz), 7.32 (m, 1H), 7.54 (m, 1H), 7.60–7.75 (m, 3H), 7.81 (m, 1H). ¹³C NMR (75 MHz, DMSO) δ 155.38, 143.15, 140.32, 138.42, 133.42, 132.25, 129.70, 129.34, 128.35, 120.57, 118.55, 114.32, 113.30, 108.55, 73.30, 30.20. LC-MS (ESI) *m/z* found: 281 [M + H]⁺.

#### 4.1.9.3. 4-[Hydroxy-(2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)methyl]benzonitrile (5b).
Prepared according to the general procedure using 5a. Triturated with diethyl ether. Yield (87 %); m.p. 202–203 °C; IR (ν, cm⁻¹) 3504 (OH), 3148 (NH), 2229 (CN), 1682 (CO); ¹H NMR (300 MHz, DMSO-d₆) δ 5.80 (d, 1H, *J* = 3.65 Hz), 6.19 (br d, 1H, *J* = 3.65 Hz), 7.04 (d, 1H, *J* = 8.30 Hz), 7.26 (dd, 1H, *J* = 8.30 Hz, *J* = 1.90 Hz), 7.57–7.58 (m, 3H), 7.66 (d, 2H, *J* = 8.20 Hz), 11.85 (br s, 1H, exchangeable with D₂O). LC-MS (ESI) *m/z* found: 283 [M + H]⁺. ¹³C NMR (75 MHz, DMSO) δ 170.09, 151.12, 139.43, 135.42, 132.24 (2C), 127.79 (2C), 124.79, 123.38, 120.57, 118.95, 111.32, 109.52, 73.30. LC-MS (ESI) *m/z* found: 383 [M + H]⁺.

#### 4.1.9.4. 4-[Hydroxy-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)methyl]benzonitrile (6b).
Prepared according to the general procedure using 6a. Recrystallized from acetonitrile. Yield (92 %); m.p. 196–197 °C. IR (ν, cm⁻¹) 3468 (OH), 2226 (CN), 1657 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 3.36 (s, 3H) 5.82 (d, 1H, *J* = 3.6 Hz), 6.25 (br d, 1H, exchangeable with D₂O), 7.22 (d, 1H, *J* = 8.1 Hz), 7.36 (d, 1H, *J* = 8.1 Hz), 7.57 (d, 2H, *J* = 8.3 Hz), 7.65 (s, 1H), 7.75 (d, 2H, *J* = 8.3 Hz). ¹³C NMR (75 MHz, DMSO) δ 165.09, 147.12, 139.43, 135.42, 132.24 (2C), 128.72 (2C), 124.79, 123.38, 120.57, 118.45, 112.32, 110.52, 73.50, 34.26. LC-MS (ESI) *m/z* found: 297 [M + H]⁺.

#### 4.1.9.5. 4-[(3-Ethyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)(hydroxy)methyl]benzonitrile (7b).
Prepared according to the general procedure using 7a. Triturated with diethyl ether. Yield (80 %); m.p. 146–150 °C. IR (ν, cm⁻¹) 3414 (OH), 2227 (CN), 1672 (CO). ¹H NMR (300 MHz,
DMSO-d₆) δ 1.15 (t, 3H, *J* = 7.2 Hz), 3.91 (q, 2H, *J* = 7.2 Hz), 5.82 (d, 1H, *J* = 3.6 Hz), 6.21 (br d, 1H, exchangeable with D₂O), 7.29 (d, 1H, *J* = 8.4 Hz), 7.36 (dd, 1H, *J* = 8.4 Hz, *J* = 1.2 Hz), 7.58 (d, 2H, *J* = 8.7 Hz), 7.67 (m, 1H), 7.76 (d, 2H, *J* = 8.7 Hz). ¹³C NMR (75 MHz, DMSO) δ 162.09, 146.12, 139.44, 135.22, 132.25 (2C), 128.75 (2C), 124.73, 123.35, 120.57, 118.25, 111.32, 110.42, 73.20, 38.25, 14.20. LC-MS (ESI) *m/z* found: 311 [*M* + *H*]⁺.

#### 4.1.9.6. 3-[Hydroxy-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)methyl]benzonitrile (8b).
Prepared according to the general procedure using **8a**. Triturated with diethyl ether. Yield (70 %); m.p. 147–151 °C. IR (ν, cm⁻¹) 3396 (OH), 2227 (CN), 1651 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 3.36 (s, 3H), 5.81 (d, 1H, *J* = 3.0 Hz), 6.21 (br d, 1H, exchangeable with D₂O), 7.22 (d, 1H, *J* = 7.8 Hz), 7.31 (m, 1H), 7.51 (m, 1H), 7.68–7.72 (m, 3H), 7.84 (m, 1H). ¹³C NMR (75 MHz, DMSO) δ 163.38, 140.15, 136.32, 134.32, 132.42, 130.42, 132.25, 129.25, 129.70, 126.34, 125.35, 122.57, 118.45, 113.30, 73.50, 32.20. LC-MS (ESI) *m/z* found: 297 [*M* + *H*]⁺.

#### 4.1.9.7. 3-Methyl-6-[hydroxy(4-nitrophenyl)methyl]-1,3-benzothiazol-2(3H)-one (9b).
Prepared according to the general procedure using **9a**. Recrystallized from acetonitrile. Yield (91 %); m.p. 191–195 °C. IR (ν, cm⁻¹) 3408 (OH), 1647 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 3.36 (s, 3H), 5.89 (s, 1H), 6.31 (br s, 1H, exchangeable with D₂O), 7.22 (d, 1H, *J* = 8.7 Hz), 7.39 (m, 1H), 7.65–7.67 (m, 3H), 8.16 (d, 2H, *J* = 9.0 Hz). ¹³C NMR (75 MHz, DMSO) δ 163.09, 149.12, 145.43, 135.40, 129.24 (2C), 125.72 (2C), 124.79, 123.38, 120.57, 113.32, 110.52, 73.68, 34.25. LC-MS (ESI) *m/z* found: 317 [*M* + *H*]⁺.

#### 4.1.9.8. 6-((4-Chlorophenyl)(hydroxy)methyl)benzo[d][1,3]selenazol-2(3H)-one (10b).
Prepared according to the general procedure using **10a**. Recrystallized from acetonitrile. Yield (70 %); m.p. 209–213 °C. IR (ν, cm⁻¹) 3506 (OH), 3146 (NH), 2227 (CN), 1695 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 5.76 (s, 1H), 6.17 (br s, 1H, exchangeable with D₂O), 7.02 (d, 1H, *J* = 8.1 Hz), 7.25 (dd, 1H, *J* = 8.1 Hz, *J* = 1.5 Hz), 7.50–7.55 (m, 3H), 7.66 (d, 2H, *J* = 8.4 Hz), 11.85 (br s, 1H, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO) δ 170.09, 141.12, 139.43, 135.20, 131.42, 130.25 (2C), 129.70 (2C), 128.38, 124.57, 120.32, 119.52, 74.30. LC-MS (ESI) *m/z* found: 339 [*M* + *H*]⁺.

#### 4.1.9.9. 4-[Hydroxy-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoselenazol-6-yl)methyl]benzonitrile (11b).
Prepared according to the general procedure using **11a**. Recrystallized from ethyl acetate. Yield (92 %); m.p. 205–208 °C. IR (ν, cm⁻¹) 3472 (OH), 2224 (CN), 1651 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 3.30 (s, 3H), 5.80 (s, 1H), 5.82 (br s, 1H, exchangeable with D₂O), 7.19 (d, 1H, *J* = 8.4 Hz), 7.34 (m, 1H), 7.55 (d, 2H, *J* = 7.8 Hz), 7.73–7.77 (m, 3H). ¹³C NMR (75 MHz, DMSO) δ 159.09, 147.22, 139.43, 133.42, 132.24 (2C), 128.62 (2C), 124.49, 122.38, 121.57, 118.35, 111.32, 110.42, 73.40, 33.56. LC-MS (ESI) *m/z* found: 344 [*M* + *H*]⁺.

#### 4.1.9.10. 4-[(3-Ethyl-2-oxo-2,3-dihydro-1,3-benzoselenazol-6-yl)-(hydroxy)methyl]benzonitrile (12b).
Prepared according to the general procedure using **12a**. Recrystallized from acetonitrile. Yield (90 %); m.p. 132–134 °C. IR (ν, cm⁻¹) 3427 (OH), 2227 (CN), 1641 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 1.13 (t, 3H, *J* = 7.1 Hz), 3.89 (q, 2H, *J* = 7.1 Hz), 5.80 (d, 1H, *J* = 3.9 Hz), 6.19 (br d, 1H, exchangeable with D₂O), 7.26 (d, 1H, *J* = 8.1 Hz), 7.34 (dd, 1H, *J* = 8.1 Hz, *J* = 1.8 Hz), 7.57 (d, 2H, *J* = 8.4 Hz), 7.75–7.79 (m, 3H). ¹³C NMR (75 MHz, DMSO) δ 164.09, 146.15, 138.44, 135.48, 132.25 (2C), 128.62 (2C), 124.79, 123.38, 120.57, 118.45, 112.32, 110.42, 73.30, 42.26, 14.25. LC-MS (ESI) *m/z* found: 358 [*M* + *H*]⁺.

#### 4.1.9.11. 3-Methyl-6-[hydroxy(4-nitrophenyl)methyl]-1,3-benzoselenazol-2(3H)-one (13b).
Prepared according to the general procedure using

13a. Recrystallized from acetonitrile. Yield (84 %); m.p. 182–183 °C. IR (ν, cm⁻¹) 3406 (OH), 2224 (CN), 1645 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 3.35 (s, 3H), 5.88 (s, 1H), 6.29 (br s, 1H, exchangeable with D₂O), 7.21 (d, 1H, *J* = 8.1 Hz), 7.37 (dd, 1H, *J* = 8.1 Hz, *J* = 1.8 Hz), 7.64 (d, 2H, *J* = 8.7 Hz), 7.75 (d, 1H, *J* = 1.8 Hz), 8.16 (d, 2H, *J* = 8.7 Hz). ¹³C NMR (75 MHz, DMSO) δ 161.09, 149.15, 145.83, 134.40, 128.24 (2C), 126.72 (2C), 124.79, 123.30, 120.58, 112.32, 110.42, 73.68, 34.35. LC-MS (ESI) *m/z* found: 364 [*M* + *H*]⁺.

#### 4.1.9.12. 3-Ethyl-6-[hydroxy(4-nitrophenyl)methyl]-1,3-benzoselenazol-2(3H)-one (14b).
Prepared according to the general procedure using **14a**. Recrystallized from acetonitrile. Yield (78 %); m.p. 135–137 °C. IR (ν, cm⁻¹) 3420 (OH), 1653 (CO), 1514 (NO₂). ¹H NMR (300 MHz, DMSO-d₆) δ 1.13 (t, 3H, *J* = 7.2 Hz), 3.89 (q, 2H, *J* = 7.2 Hz), 5.87 (s, 1H), 6.28 (s, 1H, exchangeable with D₂O), 7.27 (d, 1H, *J* = 8.4 Hz), 7.36 (dd, 1H, *J* = 8.4 Hz, *J* = 1.8 Hz), 7.65 (d, 2H, *J* = 9.0 Hz), 7.76 (d, 1H, *J* = 1.8 Hz), 8.17–8.20 (m, 2H). ¹³C NMR (75 MHz, DMSO) δ 164.09, 146.18, 138.45, 135.38, 132.45 (2C), 129.42 (2C), 124.54, 123.32, 120.47, 112.34, 110.47, 73.48, 43.24, 14.35. LC-MS (ESI) *m/z* found: 378 [*M* + *H*]⁺.

#### 4.1.9.13. 4-[Hydroxy-(2-oxo-indolin-5-yl)methyl]benzonitrile (15b).
Prepared according to the general procedure using **15a**. Triturated with diethyl ether. Yield (92 %); m.p. 178–180 °C. IR (ν, cm⁻¹) 3412 (OH), 3292 (NH), 2227 (CN), 1691 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 3.42 (s, 2H), 5.72 (d, 1H, *J* = 2.6 Hz), 6.04 (d, 1H, *J* = 3.6 Hz, exchangeable with D₂O), 6.74 (d, 1H, *J* = 8.4 Hz), 7.18 (d, 2H, *J* = 5.5 Hz), 7.56 (d, 2H, *J* = 8.2 Hz), 7.76 (d, 2H, *J* = 8.2 Hz), 10.34 (br s, 1H, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO) δ 176.42, 151.59, 142.77, 137.73, 132.13 (2C), 126.92 (2C), 125.92, 125.70, 122.61, 118.96, 109.30, 108.68, 73.58, 35.76. LC-MS (ESI) *m/z* found: 263 [*M* − *H*]⁺.

#### 4.1.9.14. 4-[Hydroxy-(1-methyl-2-oxo-indolin-5-yl)methyl]benzonitrile (16b).
Prepared according to the general procedure using **16a**. Triturated with diethyl ether. Yield (90 %); m.p. 186–189 °C. IR (ν, cm⁻¹) 3396 (OH), 2226 (CN), 1676 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 3.07 (s, 3H), 3.49 (s, 2H), 5.89 (d, 1H, *J* = 3.3 Hz), 6.09 (br d, 1H, Hz, exchangeable with D₂O), 6.88 (d, 1H, *J* = 8.1 Hz), 7.22 (m, 1H), 7.29 (m, 1H), 7.66 (d, 2H, *J* = 8.1 Hz), 7.75 (d, 2H, *J* = 8.1 Hz). ¹³C NMR (75 MHz, DMSO) δ 175.44, 151.59, 142.77, 137.73, 132.13 (2C), 128.92 (2C), 125.72, 125.70, 122.45, 118.86, 109.40, 108.65, 73.54, 35.56, 35.34. LC-MS (ESI) *m/z* found: 279 [*M* + *H*]⁺.

#### 4.1.9.15. 6-[Hydroxy-(phenyl)methyl]-2H-1,4-benzoxazin-3(4H)-one (17b).
Prepared according to the general procedure using **17a**. Recrystallized from acetonitrile. Yield (72 %); m.p. 180–182 °C. IR (ν, cm⁻¹) 3464 (OH), 3123 (NH), 1684 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 4.50 (s, 2H), 5.60 (d, 1H, *J* = 2.7 Hz), 5.83 (br d, 1H, exchangeable with D₂O) 6.83–6.99 (m, 3H), 7.37 (d, 1H, *J* = 2.4 Hz), 7.53–7.58 (m, 2H), 7.64–7.71 (m, 2H), 10.61 (br s, 1H, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO) δ 167.44, 145.59, 143.77, 132.73, 129.13 (2C), 128.42 (2C), 127.70, 126.45, 124.85, 121.40, 112.65, 74.56, 69.34. LC-MS (ESI) *m/z* found: 256 [*M* + *H*]⁺.

#### 4.1.9.16. 6-[Hydroxy-(phenyl)methyl]-4-methyl-2H-1,4-benzoxazin-3(4H)-one (18b).
Prepared according to the general procedure using **18a**. Recrystallized from acetonitrile. Yield (92 %); m.p. 79–82 °C. IR (ν, cm⁻¹) 3341 (OH), 1682 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 3.25 (s, 3H), 4.59 (s, 2H), 5.70 (s, 1H), 5.93 (br s, 1H, exchangeable with D₂O) 6.90–6.98 (m, 2H), 7.20–7.41 (m, 6H). ¹³C NMR (75 MHz, DMSO) δ 167.44, 146.54, 143.47, 132.63, 129.63 (2C), 128.52 (2C), 127.60, 126.55, 124.35, 121.50, 112.45, 74.46, 69.44, 36.52. LC-MS (ESI) *m/z* found: 270 [*M* + *H*]⁺.
4.1.9.17. **4-[Hydroxy-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) methyl]benzonitrile (19b).** Prepared according to the general procedure using **19a**. Recrystallized from acetonitrile. Yield (92 %); m.p. 156–160 °C. IR (ν, cm⁻¹) 3437 (OH), 3190 (NH), 2227 (CN), 1649 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 4.52 (s, 2H), 5.70 (d, 1H, *J* = 3.0 Hz), 6.11 (br d, 1H, exchangeable with D₂O), 6.85–6.89 (m, 3H), 7.53 (d, 2H, *J* = 7.8 Hz), 7.78 (d, 2H, *J* = 7.8 Hz), 10.65 (br s, 1H, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO) δ 164.91, 151.12, 142.37, 138.99, 132.19 (2C), 127.19 (2C), 127.00, 121.17, 118.94, 115.82, 113.72, 109.49, 72.99, 66.73. LC-MS (ESI) *m/z* found: 279 [M − H]⁺.

4.1.9.18. **4-[Hydroxy-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)methyl]benzonitrile (20b).** Prepared according to the general procedure using **20a**. Recrystallized from acetonitrile. Yield (88 %); m.p. 138–140 °C. IR (ν, cm⁻¹) 3387 (OH), 3072 (NH), 2224 (CN), 1666 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 3.07 (s, 3H), 4.60 (s, 2H), 5.79 (d, 1H, *J* = 4.2 Hz), 6.18 (br d, 1H, Hz, exchangeable with D₂O), 6.91–6.99 (m, 2H), 7.21 (m, 1H), 7.59 (d, 2H, *J* = 8.1 Hz), 7.75 (d, 2H, *J* = 8.1 Hz). ¹³C NMR (75 MHz, DMSO) δ 164.81, 151.15, 142.27, 138.89, 132.18 (2C), 127.15 (2C), 127.10, 121.27, 119.14, 115.87, 113.42, 109.45, 72.99, 67.23, 36.25. LC-MS (ESI) *m/z* found: 295 [M + H]⁺.

4.1.9.19. **7-[Hydroxy-(phenyl)methyl]-2H-1,4-benzothiazin-3(4H)-one (22b).** Prepared according to the general procedure using **22a**. Recrystallized from acetonitrile. Yield (68 %); m.p. 173–179 °C. IR (ν, cm⁻¹) 3468 (OH); 3198 (NH), 1655 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 3.41 (s, 2H), 5.61 (d, 1H, *J* = 3.6 Hz), 5.91 (br d, 1H, exchangeable with D₂O), 6.93 (d, 1H, *J* = 8.4 Hz), 7.04 (m, 1H), 7.20–7.35 (m, 6H), 10.50 (br s, 1H, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO) δ 166.44, 147.54, 143.42, 132.64, 129.67 (2C), 128.58 (2C), 127.64, 126.52, 123.35, 121.40, 111.45, 74.86, 69.52, 36.42. LC-MS (ESI) *m/z* found: 272 [M + H]⁺.

4.1.9.20. **4-[Hydroxy-(3-oxo-3,4-dihydro-2H-1,4-benzothiazin-7-yl) methyl] benzonitrile (23b).** Prepared according to the general procedure using **23a**. Recrystallized from ethyl acetate. Yield (75 %); m.p. 238–240 °C. IR (ν, cm⁻¹) 3454 (OH), 3198 (NH), 2229 (CN), CO 1658 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 3.40 (s, 2H), 5.71 (d, 1H, *J* = 3.6 Hz), 6.18 (br d, 1H, exchangeable with D₂O), 6.97 (dd, 1H, *J* = 8.0 Hz, *J* = 1.4 Hz), 7.00 (d, 1H, *J* = 1.4 Hz), 7.24 (d, 1H, *J* = 8.0 Hz), 7.54 (d, 2H, *J* = 8.3 Hz), 7.78 (d, 2H, *J* = 8.3 Hz), 10.50 (br s, 1H, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO) δ 165.23, 150.78, 143.73, 137.43, 132.24 (2C), 127.15, 127.05 (2C), 121.05, 118.90, 117.72, 114.90, 109.59, 73.01, 28.82. LC-MS (ESI) *m/z* found: 295 [M − H]⁺.

4.1.9.21. **4-[Hydroxy-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-7-yl)methyl]benzonitrile (24b).** Prepared according to the general procedure using **24a**. Recrystallized from ethyl acetate. Yield (78 %); m.p. 115–118 °C. IR (ν, cm⁻¹) 3383 (OH), 2224 (CN), 1641(CO). ¹H NMR (300 MHz, DMSO-d₆) δ 3.33 (s, 3H), 3.48 (s, 2H), 5.82 (s, 1H), 6.26 (br s, 1H, exchangeable with D₂O) 7.02 (d, 1H, *J* = 8.4 Hz), 7.31–7.34 (m, 2H), 7.60 (d, 2H, *J* = 8.4 Hz), 7.76 (d, 2H, *J* = 8.4 Hz). ¹³C NMR (75 MHz, DMSO) δ 165.25, 150.71, 143.75, 137.73, 132.44 (2C), 127.55, 127.15 (2C), 121.42, 118.40, 117.42, 114.95, 109.65, 73.12, 35.24, 28.82. LC-MS (ESI) *m/z* found: 311 [M + H]⁺.

4.1.9.22. **5-[Hydroxy-(4-pyridyl)methyl]-1,3-benzoxazol-2(3H)-one (30b).** Prepared according to the general procedure using **30a**. Recrystallized from acetone. Yield (64 %); m.p. 216–220 °C. IR (ν, cm⁻¹) 3414 (OH), 3090 (NH), 1780 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 5.73 (s, 1H), 6.14 (br s, 1H, exchangeable with D₂O), 7.05–7.09 (m, 2H), 7.18 (d, 1H, *J* = 8.1 Hz), 7.36 (d, 2H, *J* = 5.1 Hz), 8.46 (d, 2H, *J* = 5.1 Hz), 11.10 (br s, 1H, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO) δ 155.20, 150.25 (2C), 145.12, 140.43, 136.20, 135.42, 128.20 (2C), 123.52, 122.32, 120.10, 74.50. LC-MS (ESI) *m/z* found: 243 [M + H]⁺.

4.1.9.23. **5-[Hydroxy-(phenyl)methyl]-1,3-benzoxazol-2(3H)-one (31b).** Prepared according to the general procedure using **31a**. Recrystallized from acetonitrile. Yield (62 %); m.p. 185–187 °C. IR (ν, cm⁻¹) 3447 (NH), 3196 (OH), 1738 (CO). ¹H NMR (300 MHz, DMSO-d₆). δ 5.73 (s, 1H), 5.97 (br s, 1H, exchangeable with D₂O), 7.07–7.40 (m, 3H), 7.27–7.32 (m, 3H), 7.38 (m, 2H), 11.58 (br s, 1H, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO) δ 155.09, 143.12, 140.20, 37.43, 136.42, 130.25 (2C), 129.20 (2C), 126.32, 124.50, 122.32, 120.52, 74.20. LC-MS (ESI) *m/z* found: 242 [M + H]⁺.

4.1.9.24. **4-[Hydroxy-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)methyl] benzonitrile (33b).** Prepared according to the general procedure using **33a**. Recrystallized from acetonitrile. Yield (74 %); m.p. 208–212 °C. IR (ν, cm⁻¹) 3487 (OH), 3331 (NH) 2233 (CN), 1765 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 5.82 (d, 1H, *J* = 3.3 Hz), 6.21 (br d, 1H, exchangeable with D₂O), 7.07–7.11 (m, 2H) 7.20 (d, 1H, *J* = 8.1 Hz), 7.57 (d, 2H, *J* = 8.1 Hz), 7.38 (d, 2H, *J* = 8.1 Hz), 11.59 (br s, 1H, exchangeable with D₂O). *J*⁺. ¹³C NMR (75 MHz, DMSO) δ 155.20, 145.15, 138.43, 135.42, 131.25 (2C), 128.70 (2C), 124.74, 123.35, 121.57, 118.55, 111.32, 110.55, 73.20. LC-MS (ESI) *m/z* found: 267 [M + H]⁺.

4.1.9.25. **5-[Hydroxy-(phenyl)methyl]-3-methyl-1,3-benzoxazol-2(3H)-one (34b).** Prepared according to the general procedure using **34a**. Titrated with diethyl ether. Yield (84 %); m.p. 106–107 °C. IR (ν, cm⁻¹) 3464 (OH), 1741 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 3.31 (s, 3H) 5.74 (d, 1H, *J* = 3.9 Hz), 5.98 (br d, 1H, exchangeable with D₂O), 7.10 (d, 1H, *J* = 8.4 Hz) 7.17–7.24 (m, 2H), 7.27–7.32 (m, 3H), 7.38 (d, 2H, *J* = 7.2 Hz). ¹³C NMR (75 MHz, DMSO) δ 154.28, 143.71, 135.65, 135.73, 132.52, 129.44 (2C), 128.15 (2C), 126.42, 118.40, 123.42, 122.55, 121.65, 74.23, 29.80. LC-MS (ESI) *m/z* found: 256 [M + H]⁺.

4.1.9.26. **5-[(4-Chlorophenyl)-(hydroxymethyl)]-3-methyl-1,3-benzoxazol-2(3H)-one (35b).** Prepared according to the general procedure using **35a**. Titrated with diethyl ether. Yield (86 %); m.p. 129–133 °C. IR (ν, cm⁻¹) 3429 (OH), 1759 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 3.31 (s, 3H) 5.76 (s, 1H), 6.11 (br s, 1H, exchangeable with D₂O), 7.10 (d, 1H, *J* = 8.1 Hz), 7.22–7.26 (m, 2H), 7.35 (d, 2H, *J* = 8.1 Hz), 7.40 (d, 2H, *J* = 8.1 Hz). ¹³C NMR (75 MHz, DMSO) δ 170.23, 142.12, 139.33, 135.24, 131.45, 130.85 (2C), 128.70 (2C), 128.28, 125.57, 120.32, 119.52, 74.30, 30.24. LC-MS (ESI) *m/z* found: 290 [M + H]⁺.

4.1.9.27. **4-[Hydroxy-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) methyl]benzonitrile (36b).** Prepared according to the general procedure using **36a**. Titrated with diethyl ether. Yield (77 %); m.p. 121–127 °C. IR (ν, cm⁻¹) 3441 (OH), 2226 (CN), 1745 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 3.31 (s, 3H), 5.84 (d, 1H, *J* = 3.6 Hz), 6.26 (br d, 1H, exchangeable with D₂O) 7.13 (d, 1H, *J* = 8.1 Hz), 7.24–7.29 (m, 2H), 7.60 (d, 2H, *J* = 7.8 Hz), 7.76 (d, 2H, *J* = 7.8 Hz). ¹³C NMR (75 MHz, DMSO) δ 161.92, 147.53, 137.42, 136.35, 132.70 (2C), 130.25, 128.50 (2C), 127.52, 124.41, 122.20, 118.21, 110.15, 74.25, 30.42. LC-MS (ESI) *m/z* found: 281 [M + H]⁺.

### 4.1.10. General procedure for the synthesis of intermediates 41b–44b

A solution of *i*-propyl magnesium chloride 2 M in THF (5.2 mL, 10.4 mmol) was slowly added to a solution of bromobenzene or 4-bromobenzonitrile (10.4 mmol) in THF (20 mL). The mixture was stirred at room temperature for 2 h and then a solution of **38** (2 g, 10.4 mmol) in THF (20 mL) was added dropwise. The reaction mixture was stirred at room temperature for 12 h and then water was added and the mixture was extracted with EtOAc. The organic layer was dried over anhydrous MgSO₄ and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc/c-hexane 3:7, *v*/*v*).

4.1.10.10. **5-(Hydroxy(phenyl)methyl)benzo[d]thiazol-2(3H)-one (41b).** Prepared according to the general procedure using *i*-propyl magnesium
chloride, bromobenzene and 38. Purified by column chromatography (EtOAc/c-hexane 3:7, v/v). Yield (32 %); m.p. 165–167 °C. IR (ν, cm⁻¹) 3477 (OH), 3325 (NH), 1655 (CO). ¹H NMR (300 MHz, CDCl₃) δ 5.72 (s, 1H), 5.99 (br s, 1H, exchangeable with D₂O), 7.14 (d, 1H, *J* = 2.20 Hz), 7.23 (d, 1H, *J* = 8.0 Hz), 7.33–7.38 (m, 5H), 7.47 (dd, 1H, *J* = 8.0 Hz, *J* = 2.10 Hz), 11.82 (br s, 1H, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO) δ 170.16, 142.71, 134.25, 131.62, 131.25, 130.40 (2C), 129.51 (2C), 126.12, 124.49, 121.41, 120.52, 74.20. LC-MS (ESI) *m/z* found: 258 [M + H]⁺.

4.1.10.2. 5-(Hydroxy(phenyl)methyl)-3-methylbenzo[d]thiazol-2(3H)-one (42b). Prepared according to the general procedure using *i*-propyl magnesium chloride, bromobenzene and compound 39. Purified by column chromatography (EtOAc/c-hexane 3:7, v/v). Yield (32 %); m.p. 191–194 °C. IR (ν, cm⁻¹) 3477 (OH), 1655 (CO). ¹H NMR (300 MHz, CDCl₃) δ 3.45 (s, 3H), 5.79 (s, 1H), 5.97 (br s, 1H, exchangeable with D₂O), 6.99 (s, 1H), 7.63 (d, 1H, *J* = 8.0 Hz), 7.41 (m, 2H), 7.43–7.59 (m, 3H), 7.63 (m, 1H). ¹³C NMR (75 MHz, DMSO) δ 163.15, 147.41, 137.42, 134.35, 132.50 (2C), 130.20, 128.20 (2C), 127.12, 122.49, 120.20, 118.21, 110.12, 74.35, 33.42. LC-MS (ESI) *m/z* found: 272 [M + H]⁺.

4.1.10.3. 4-[Hydroxy-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-5-yl)methyl]benzonitrile (43b). Prepared according to the general procedure using *i*-propyl magnesium chloride, 4-bromobenzonitrile and compound 39. Yield (45 %); m.p. 183–186 °C. IR (ν, cm⁻¹) 3398 (OH), 2224 (CN), 1658 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 3.38 (s, 3H), 5.84 (d, 1H, *J* = 3.9 Hz), 6.28 (br d, 1H, *J* = 3.9 Hz, exchangeable with D₂O), 7.16 (d, 1H, *J* = 8.0 Hz), 7.36 (d, 1H, *J* = 2.10 Hz), 7.54 (dd, 1H, *J* = 8.0 Hz, *J* = 2.10 Hz), 7.60 (d, 2H, *J* = 8.1 Hz), 7.75 (d, 2H, *J* = 8.1 Hz). LC-MS (ESI) *m/z* found: 297 [M + H]⁺. ¹³C NMR (75 MHz, DMSO) δ 162.92, 147.53, 136.42, 135.35, 132.70 (2C), 130.25, 128.30 (2C), 127.52, 122.41, 121.20, 118.21, 110.12, 74.25, 47.42. LC-MS (ESI) *m/z* found: 297 [M + H]⁺.

4.1.10.4. 4-[(3-Ethyl-2-oxo-2,3-dihydrobenzo[d]thiazol-5-yl)(hydroxy)methyl]benzonitrile (44b). Prepared according to the general procedure using *i*-propyl magnesium chloride, 4-bromobenzonitrile and compound 40. Purified by column chromatography (EtOAc/c-hexane 5:5, v/v). Yield (30 %); m.p. 156–158 °C. IR (δ, cm⁻¹) 3441 (OH), 2226 (CN), 1745 (CO). ¹H NMR (300 MHz, DMSO-d₆); δ 1.80 (t, 3H, *J* = 7.2 Hz), 3.93 (q, 2H, *J* = 7.2 Hz), 5.97 (d, 1H, *J* = 3.6 Hz), 6.30 (br d, 1H, D₂O exchangeable), 7.17 (d, 1H, *J* = 8.0 Hz), 7.45 (s, 1H), 7.56 (d, 1H, *J* = 8.0 Hz), 7.62 (d, 2H, *J* = 8.1 Hz), 7.77 (d, 2H, *J* = 8.1 Hz). ¹³C NMR (75 MHz, DMSO) δ 163.20, 147.50, 136.32, 135.32, 132.80 (2C), 130.25, 128.50 (2C), 127.55, 122.53, 121.20, 118.52, 111.12, 74.75, 47.32, 14.5. LC-MS (ESI) *m/z* found: 311 [M + H]⁺.

### 4.1.11. General procedure for the synthesis of target compounds 45–86

**Method A.** A solution of the corresponding hydroxyl derivative (1.5 mmol) and 1,1'-carbonyldiimidazole (0.98 g, 6 mmol) in anhydrous acetonitrile (50 mL) was stirred at room temperature for 1 h and then heated under reflux for 4 h. The solvent was removed, and the residue was triturated with water, acidified with 1 M HCl and extracted with diethyl ether. The aqueous layer was basifed to pH 9 with saturated solution of NaHCO₃ and extracted twice with ethyl acetate. The organic phase was dried over anhydrous MgSO₄ and evaporated. Purification by column chromatography gave the title compound.

**Method B.** Thionyl chloride (0.43 mL, 6.0 mmol) was added to a cooled solution of the corresponding hydroxyl derivative (1.5 mmol) in CH₂Cl₂. After stirring for 3 h at room temperature, the solvent was removed in vacuo and the residue was dissolved in acetonitrile (30 mL). 1,2,4-Triazole (0.2 g, 3 mmol) or tetrazole (0.21 g, 3 mmol), KI as catalyst and K₂CO₃ (0.62 g, 4.5 mmol) were added, and the reaction mixture was stirred at 60 °C overnight. Water (30 mL) was added, and the product was extracted twice with EtOAc. The combined organic

layers were washed with water and 1 M NaOH. The organic layer was dried (MgSO₄), filtered, evaporated under reduced pressure. Purification by column chromatography gave the title compound.

4.1.11.1. 4-[Imidazole-1-yl-(2-oxo-3H-1,3-benzoxazol-6-yl)methyl]benzonitrile (45). Prepared according to the general procedure (Method A) using 1b. Purified by silica gel column chromatography (ethyl acetate/methanol 9:1, v/v). Yield (34 %); m.p. 122–126 °C. IR (ν, cm⁻¹) 3425 (NH), 2229 (CN), 1776 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 7.02–6.98 (m, 3H), 7.12 (d, 1H, *J* = 8.04 Hz), 7.17 (m, 2H), 7.26 (d, 2H, *J* = 8.40 Hz), 7.69 (s, 1H), 7.87 (d, 2H, *J* = 8.40 Hz), 11.78 (br s, 1H, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO-d₆) δ 147.44, 136.82, 136.31, 129.12, 124.54, 124.39 (2C), 122.78, 120.29 (2C), 120.12, 116.12, 111.22, 109.77, 103.83, 101.64, 101.53, 55.75. LC-MS (ESI) *m/z* found: 315 [M – H]⁺. Anal. (C₁₈H₁₂N₄O₂) C, H, N.

4.1.11.2. 3-[Imidazole-1-yl-(2-oxo-1,3-benzoxazol-6-yl)methyl]benzoniitrile (46). Prepared according to the general procedure (Method A) using 2b. Purified by silica gel column chromatography (ethyl acetate/methanol 9:1, v/v). Yield (22 %); m.p. 185–187 °C. IR (ν, cm⁻¹) 2228 (CN), 1776 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 6.99–712 (m, 2H), 7.12 (m, 1H), 7.21–7.23 (m, 2H), 7.27 (d, 1H, *J* = 9.0 Hz), 7.49 (m, 1H), 7.53 (s, 1H), 7.62 (m, 1H), 7.71 (s, 1H), 7.83 (d, 1H, *J* = 7.7 Hz), 11.76 (br s, 1H). ¹³C NMR (75 MHz, DMSO-d₆) δ 154.42, 143.59, 141.68, 137.32, 132.84, 132.56, 131.88, 131.01, 130.45, 130.09, 129.05, 123.89, 119.14, 118.51, 111.79, 109.88, 109.42, 62.39. LC-MS (ESI) *m/z* found: 331 [M + H]⁺. Anal. (C₁₉H₁₄N₄O₂) C, H, N.

4.1.11.3. 6-[(1H-imidazole-1-yl)(phenyl)methyl]benzo[d]thiazol-2(3H)-one (47). Prepared according to the general procedure (Method A) using 3b. Purified by silica gel column chromatography (ethyl acetate/methanol 9:1, v/v). Yield (42 %); m.p. 55–60 °C. IR (ν, cm⁻¹) 3433 (NH), 1678 (CO). ¹H NMR (300 MHz, CDCl₃) δ 6.56 (s, 1H), 6.87–7.01 (m, 2H), 7.08–7.16 (m, 5H), 7.36–7.39 (m, 3H), 7.60 (s, 1H), 11.50 (br s, 1H, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO) δ 168.85, 140.14, 137.67, 137.42, 135.08, 129.70 (2C), 128.46, 128.20, 127.65 (2C), 126.53, 122.60, 122.31, 119.27, 111.42, 62.99. LC-MS (ESI) *m/z* found: 308 [M + H]⁺. Anal. (C₁₇H₁₃N₃OS) C, H, N.

4.1.11.4. 6-[Imidazole-1-yl(phenyl)methyl]-3-methyl-1,3-benzothiazol-2-one (48). Prepared according to the general procedure (Method A) using 4b. Purified by silica gel column chromatography (ethyl acetate/methanol 8:2, v/v). Yield (54 %); m.p. 65–68 °C. IR (ν, cm⁻¹) 1681 (CO). ¹H NMR (300 MHz, DMSO) δ 7.67 (s, 1H), 7.50 (d, *J* = 1.5 Hz, 1H), 7.47–7.34 (m, 3H), 7.32 (d, *J* = 8.4 Hz, 1H), 7.19 (dd, *J* = 8.4, 1.5 Hz, 1H), 7.16–7.07 (m, 3H), 6.97 (s, 1H), 6.91 (s, 1H), 3.39 (s, 3H). ¹³C NMR (75 MHz, DMSO) δ 168.81, 139.94, 137.37, 137.21, 135.08, 128.79 (2C), 128.76, 127.98, 127.63 (2C), 126.53, 122.30, 121.91, 119.17, 111.42, 62.90, 29.08. LC-MS (ESI) *m/z* found: 322 [M + H]⁺. Anal. (C₁₈H₁₅N₃OS) C, H, N.

4.1.11.5. 4-[Imidazole-1-yl-(2-oxo-3H-1,3-benzothiazol-6-yl)methyl]benzonitrile (49). Prepared according to the general procedure (Method A) using 5b. Purified by silica gel column chromatography (ethyl acetate/ethanol 9:1, v/v). Yield (34 %); m.p. 214–216 °C. IR (ν, cm⁻¹) 3115 (NH), 2229 (CN), 1682 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 6.8–7.15 (m, 5H), 7.25 (d, 2H, *J* = 7.8 Hz), 7.44 (s, 1H), 7.68 (s, 1H), 7.85 (d, 2H, *J* = 7.8 Hz), 11.99 (br s, 1H, Exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO-d₆) δ 155.42, 141.26, 140.25, 138.2, 137.25, 133.46, 132.44 (2C), 128.82, 127.86, 127.56 (2C), 123.76, 120.42, 118.57, 116.22, 110.54, 61.18. LC-MS (ESI) *m/z* found: 333 [M + H]⁺. Anal. (C₁₈H₁₂N₄OS).

4.1.11.6. 4-[Imidazole-1-yl-(3-methyl-2-oxo-1,3-benzothiazol-6-yl)methyl]benzonitrile (50). Prepared according to the general procedure
(Method A) using **6b**. Purified by silica gel column chromatography (ethyl acetate/ethanol 9:1, *v/v*). Yield (38 %); m.p. 88–90 °C. IR (ν, cm⁻¹) 2227 (CN), 1680 (CO). **¹H NMR** (300 MHz, DMSO-d₆) δ 3.39 (s, 3H), 6.98 (s, 1H), 7.04 (s, 1H), 7.16 (s, 1H), 7.21–7.28 (m, 3H), 7.32 (d, 1H, *J* = 8.4 Hz), 7.54 (d, 1H, *J* = 1.2 Hz), 7.69 (s, 1H), 7.86 (d, 2H, *J* = 8.4 Hz). **¹³C NMR** (75 MHz, DMSO-d₆) δ 156.32, 142.61, 141.2, 139.4, 137.25, 133.65, 132.62 (2C), 128.32, 127.81, 127.40 (2C), 123.72, 120.35, 118.73, 117.25, 110.50, 64.24. 30.52. LC-MS (ESI) *m/z* found: 347 [M + H]⁺. Anal. (C₁₉H₁₄N₄OS).

4.1.11.7. 4-[[3-Ethyl-2-oxo-1,3-benzothiazol-6-yl]-imidazole-1-yl-methyl]benzonitrile (51). Prepared according to the general procedure (Method A) using **7b**. Purified by silica gel column chromatography (ethyl acetate/ethanol 9:1, *v/v*). Yield (78 %); m.p. 95–98 °C. IR (ν, cm⁻¹) 2226 (CN), 1680 (CO). **¹H NMR** (300 MHz, DMSO-d₆) δ 1.17 (t, 3H, *J* = 7.2 Hz), 3.93 (q, 2H, *J* = 7.2 Hz), 6.98 (s, 1H), 7.03 (s, 1H), 7.17 (s, 1H), 7.20 (dd, 1H, *J* = 8.1 Hz, *J* = 1.8 Hz), 7.26 (d, 2H, *J* = 8.7 Hz), 7.29 (d, 1H, *J* = 8.1 Hz), 7.54 (d, 1H, *J* = 1.8 Hz), 7.70 (s, 1H), 7.85 (d, 2H, *J* = 8.7 Hz). **¹³C NMR** (75 MHz, DMSO-d₆) δ 157.35, 142.84, 142.25, 140.40, 137.22, 133.62, 132.57 (2C), 128.45, 127.52, 127.24 (2C), 123.72, 121.34, 118.42, 116.24, 111.52, 63.41. 30.64, 13.83. LC-MS (ESI) *m/z* found: 361 [M + H]⁺. Anal. (C₂₀H₁₆N₄OS).

4.1.11.8. 4-[(2-Oxo-3H-1,3-benzothiazol-6-yl)-(1,2,4-triazol-1-yl)methyl]benzonitrile (52). Prepared according to the general procedure (Method B) using **5b** and triazole as starting material. Purified by silica gel column chromatography (ethyl acetate). Yield (46 %); m.p. 127–130 °C. IR (ν, cm⁻¹) 3117 (NH), 2229 (CN), 1682 (CO). **¹H NMR** (300 MHz, DMSO-d₆) δ **¹H NMR** (300 MHz, DMSO) δ 12.0 (br s, 1H, exchangeable with D₂O), 8.64 (s, 1H), 8.10 (s, 1H), 7.86 (d, *J* = 8.2 Hz, 2H), 7.51 (s, 1H), 7.36 (d, *J* = 8.2 Hz, 2H), 7.23 (s, 1H), 7.18 (dd, 1H, *J* = 8.3 Hz, *J* = 1.8 Hz), 7.13 (d, *J* = 8.3 Hz, 1H). **¹³C NMR** (75 MHz, DMSO) δ 170.12, 152.24, 144.76, 144.47, 136.45, 132.67 (2C), 132.38, 128.71 (2C), 126.90, 123.93, 122.81, 118.54, 111.66, 110.83, 64.58. LC-MS (ESI) *m/z* found: 332 [M − H]⁺. Anal. (C₁₇H₁₁N₅OS).

4.1.11.9. 4-[(3-Methyl-2-oxo-1,3-benzothiazol-6-yl)-(1,2,4-triazol-1-yl)methyl]benzonitrile (53). Prepared according to the general procedure (Method B) using **6b** and triazole as starting material. Purified by silica gel column chromatography (ethyl acetate/ethanol 9:1, *v/v*). Yield (48 %); m.p. 165–168 °C. IR (ν, cm⁻¹) 3431(NH), 2229 (CN), 1660 (CO). **¹H NMR** (300 MHz, DMSO-d₆) δ 3.38 (s, 3H), 7.27–7.38 (m, 5H), 7.59 (s, 1H), 7.85 (d, 2H, *J* = 8.1 Hz), 8.10 (s, 1H), 8.65 (s, 1H). **¹³C NMR** (75 MHz, DMSO) δ 164.12, 151.25, 144.76, 143.42, 136.47, 132.62 (2C), 132.32, 128.52 (2C), 126.80, 124.43, 122.81, 118.44, 111.86, 111.13, 64.52, 35.58. LC-MS (ESI) *m/z* found: 348 [M + H]⁺. Anal. (C₁₈H₁₃N₅OS).

4.1.11.10. 4-[(3-Ethyl-2-oxo-1,3-benzothiazol-6-yl)-(1,2,4-triazol-1-yl)methyl]benzonitrile (54). Prepared according to the general procedure (Method B) using **7b** and triazole as starting material. Purified by silica gel column chromatography (ethyl acetate/ethanol 9:1, *v/v*). Yield (38 %); m.p. 65–70 °C. IR (ν, cm⁻¹) 3412 (NH), 2229 (CN), 1676 (CO). **¹H NMR** (300 MHz, DMSO-d₆) δ 1.17 (t, 3H, *J* = 7.2 Hz), 3.92 (q, 2H, *J* = 7.2 Hz), 7.27–7.41 (m, 5H), 7.60 (s, 1H), 7.85 (d, 2H, *J* = 8.1 Hz), 8.10 (s, 1H), 8.66 (s, 1H). **¹³C NMR** (75 MHz, DMSO) δ 167.12, 153.21, 144.26, 142.47, 136.45, 132.25 (2C), 131.38, 129.21 (2C), 126.45, 123.81, 122.81, 118.64, 112.66, 110.43, 64.58, 41.25, 13.56. LC-MS (ESI) *m/z* found: 362 [M + H]⁺. Anal. (C₁₉H₁₅N₅OS).

4.1.11.11. 3-Methyl-6-[(4-nitrophenyl)-(1,2,4-triazol-1-yl)methyl]-1,3-benzothiazol-2-one (55). Prepared according to the general procedure (Method B) using **9b** and triazole as starting material. Purified by silica gel column chromatography (ethyl acetate). Yield (48 %); m.p. 156–160 °C. IR (ν, cm⁻¹) 1664 (CO). **¹H NMR** (300 MHz, DMSO-d₆) δ

3.39 (s, 3H), 7.33–7.35 (m, 3H), 7.44 (d, 2H, *J* = 8.7), 7.61 (s, 1H), 8.12 (s, 1H), 8.23 (d, 2H, *J* = 8.7), 8.68 (s, 1H). **¹³C NMR** (75 MHz, DMSO) δ 154.45, 153.16, 143.55, 142.51, 137.15, 133.84, 132.73, 131.41, 129.76 (2C), 128.67 (2C), 124.51, 109.74, 108.51, 64.53, 32.15. LC-MS (ESI) *m/z* found: 368 [M + H]⁺. Anal. (C₁₇H₁₃N₅O₃S).

4.1.11.12. 3-[(3-Methyl-2-oxo-1,3-benzothiazol-6-yl)-(1,2,4-triazol-1-yl)methyl]benzonitrile (56). Prepared according to the general procedure (Method B) using **8b** and triazole as starting material. Purified by silica gel column chromatography (ethyl acetate). Yield (38 %); m.p. 177–180 °C. IR (ν, cm⁻¹) 2227 (CN), 1655 (CO). **¹H NMR** (300 MHz, DMSO-d₆) δ 3.38 (s, 3H), 7.23 (s, 1H), 7.27–7.34 (m, 2H), 7.59–7.60 (m, 4H), 7.82–7.84 (m, 1H), 8.10 (s, 1H), 8.65 (s, 1H). **¹³C NMR** (75 MHz, DMSO-d₆) δ 154.62, 143.54, 141.68, 137.32, 132.84, 132.56, 131.78, 131.12, 130.42, 130.19, 129.45, 123.89, 119.34, 118.57, 111.79, 109.88, 109.42, 62.39. LC-MS (ESI) *m/z* found: 348 [M + H]⁺. Anal. (C₁₈H₁₃N₅OS).

4.1.11.13. 4-[(3-Methyl-2-oxo-1,3-benzothiazol-6-yl)-(tetrazol-1-yl)methyl]benzonitrile (57). Prepared according to the general procedure (Method B) using **6b** and tetrazole as starting material. Purification by column chromatography using (ethyl acetate) gave **57** in 45 % yield. Mp 80–85 °C; IR (ν, cm⁻¹) 2229 (CN), 1680 (CO); **¹H NMR** (300 MHz, CDCl₃) δ 3.39 (s, 3H), 7.31–7.35 (m, 2H), 7.39 (d, 2H, *J* = 8.1 Hz), 7.60 (s, 1H), 7.64 (s, 1H), 7.84 (d, 2H, *J* = 8.1 Hz), 9.54 (s, 1H). **¹³C NMR** (75 MHz, DMSO-d₆) δ 155.32, 143.58, 138.32, 133.84, 131.56, 130.78, 131.12, 130.42, 130.19, 129.45, 123.89, 119.24, 118.53, 111.71, 109.88, 109.64, 62.25. LC-MS (ESI) *m/z* found: 349 [M + H]⁺. Anal. (C₁₇H₁₂N₆OS).

4.1.11.14. 6-((4-Chlorophenyl)(1H-1,2,4-triazol-1-yl)methyl)benzo[d] [1,3]selenazol-2(3H)-one (58). Prepared according to the general procedure (Method B) using **10b** and triazole as starting material. Purified by silica gel column chromatography (ethyl acetate). Yield (38 %); m.p. 223–226 °C. IR (ν, cm⁻¹) 3435 (NH), 2229 (CN), 1685 (CO). **¹H NMR** (300 MHz, DMSO-d₆) δ 7.10–7.12 (m, 3H), 7.22 (d, 2H, *J* = 8.4 Hz), 7.45 (d, 2H, *J* = 8.4 Hz), 7.55 (s, 1H), 8.08 (s, 1H), 8.61 (s, 1H), 11.84 (br s, 1H, exchangeable with D₂O). **¹³C NMR** (75 MHz, DMSO) δ 170.71, 152.08, 144.52, 138.13, 137.43, 133.19, 132.72, 129.78 (2C), 128.67 (2C), 126.80, 126.21, 124.08, 112.36, 64.40. LC-MS (ESI) *m/z* found: 389, 391 [M − H]⁺. Anal. (C₁₆H₁₁ClN₄OSe).

4.1.11.15. 4-[(3-Methyl-2-oxo-1,3-benzoselenazol-6-yl)-(1,2,4-triazol-1-yl)methyl]benzonitrile (59). Prepared according to the general procedure (Method B) using **11b** and triazole as starting material. Purified by silica gel column chromatography (ethyl acetate). Yield (40 %); m.p. 154–158 °C. IR (ν, cm⁻¹) 2229 (CN), 1657 (CO). **¹H NMR** (300 MHz, DMSO-d₆) δ 3.37 (s, 3H), 7.25–7.30 (m, 3H), 7.34 (d, 2H, *J* = 8.7 Hz), 7.66 (s, 1H), 7.84 (d, 2H, *J* = 8.7 Hz), 8.09 (s, 1H), 8.64 (s, 1H). **¹³C NMR** (75 MHz, DMSO) δ 170.71, 152.08, 144.52, 138.13, 137.73, 133.19, 132.42 (2C), 131.52, 129.74, 128.69 (2C), 126.84, 126.24, 124.18, 118.52, 64.45, 29.42. LC-MS (ESI) *m/z* found: 395 [M + H]⁺. Anal. (C₁₈H₁₃N₅OSe).

4.1.11.16. 4-[(3-Ethyl-2-oxo-1,3-benzoselenazol-6-yl)-(1,2,4-triazol-1-yl)methyl]benzonitrile (60). Prepared according to the general procedure (Method B) using **12b** and triazole as starting material. Purified by silica gel column chromatography (ethyl acetate). Yield (40 %); m.p. 95–98 °C. IR (ν, cm⁻¹) 2229 (CN), 1670 (CO). **¹H NMR** (300 MHz, DMSO-d₆) δ 1.15 (t, 3H, *J* = 7.2 Hz), 3.91 (q, 2H, *J* = 7.2 Hz), 7.26 (m, 2H), 7.35–7.39 (m, 3H), 7.69 (s, 1H), 7.86 (d, 2H, *J* = 8.1 Hz), 8.11 (s, 1H), 8.67 (s, 1H). **¹³C NMR** (75 MHz, DMSO) δ 170.42, 152.48, 144.86, 138.13, 137.45, 133.27, 132.72 (2C), 131.22, 128.54 (2C), 126.44, 126.25, 122.18, 118.53, 113.76, 64.45, 42.42, 17.52. LC-MS (ESI) *m/z* found: 409 [M + H]⁺. Anal. (C₁₉H₁₅N₅OSe).
4.1.11.17. **3-Methyl-6-[(4-nitrophenyl)-(1,2,4-triazol-1-yl)methyl]-1,3-benzoselenazol-2-one** (61). Prepared according to the general procedure (Method B) using **13b** and triazole as starting material. Purified by silica gel column chromatography (ethyl acetate). Yield (30 %); m.p. 190–195 °C. IR (ν, cm⁻¹) 1651 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 3.36 (s, 3H), 7.30–7.35 (m, 3H), 7.44 (d, 2H, *J* = 8.7), 7.69 (s, 1H), 8.12 (s, 1H), 8.24 (d, 2H, *J* = 8.7), 8.68 (s, 1H). ¹³C NMR (75 MHz, DMSO) δ 170.54, 152.18, 143.51, 139.13, 137.53, 133.12, 132.42, 130.48 (2C), 128.35 (2C), 127.80, 126.71, 124.52, 112.76, 64.45, 30.25. LC-MS (ESI) *m/z* found: 415 [M + H]⁺. Anal. (C₁₇H₁₃N₅O₃Se).

4.1.11.18. **3-Ethyl-6-[(4-nitrophenyl)-(1,2,4-triazol-1-yl)methyl]-1,3-benzoselenazol-2-one** (62). Prepared according to the general procedure (Method B) using **14b** and triazole as starting material. Purified by silica gel column chromatography (ethyl acetate). Yield (32 %); m.p. 79–82 °C. IR (ν, cm⁻¹) 1670 (CO). ¹H NMR (300 MHz, CDCl₃) δ 1.13 (t, 3H, *J* = 7.2 Hz), 3.91 (q, 2H, *J* = 7.2 Hz), 7.27–7.39 (m, 3H), 7.45 (d, 2H, *J* = 8.7 Hz), 7.70 (s, 1H), 8.12 (s, 1H), 8.24 (d, 2H, *J* = 8.7 Hz), 8.69 (s, 1H). ¹³C NMR (75 MHz, DMSO) δ 170.84, 152.48, 143.54, 139.53, 137.54, 133.17, 132.72, 131.25 (2C), 128.42 (2C), 127.80, 126.74, 124.72, 111.76, 64.46, 40.25, 18.21. LC-MS (ESI) *m/z* found: 427 [M – H]⁺. Anal. (C₁₈H₁₅N₅O₃Se).

4.1.11.19. **4-[(2-Oxindolin-5-yl)-(1H-1,2,4-triazol-1-yl)methyl]benzoni-trile** (63). Prepared according to the general procedure (Method B) using **15b** and triazole as starting material. Purified by silica gel column chromatography (ethyl acetate). Yield (42 %); m.p. 66–70 °C. IR (ν, cm⁻¹) 3412 (NH), 2229 (CN), 1626 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 3.47 (s, 2H), 6.82 (d, 1H, *J* = 7.9 Hz), 7.10–7.18 (m, 3H), 7.35 (d, 2H, *J* = 8.3 Hz), 7.86 (d, 2H, *J* = 8.3 Hz), 8.09 (s, 1H), 8.61 (s, 1H), 10.47 (br s, 1H, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO) δ 176.42, 152.15, 144.92, 144.58, 143.90, 132.58, 130.67, 128.59, 128.06, 126.50, 124.53, 118.54, 110.65, 109.11, 64.89, 35.74. LC-MS (ESI) *m/z* found: 314 [M – H]⁺.

4.1.11.20. **4-[(1-Methyl-2-oxo-indolin-5-yl)-(1,2,4-triazol-1-yl)methyl]benzonitrile** (64). Prepared according to the general procedure (Method B) using **16b** and triazole as starting material. Purified by silica gel column chromatography (ethyl acetate). Yield (42 %); m.p. 59–62 °C. IR (ν, cm⁻¹) 2227 (CN), 1626 (CO) 1620. ¹H NMR (300 MHz, DMSO-d₆) δ 3.09 (s, 3H), 3.53 (s, 2H), 6.81 (d, 1H, *J* = 8.1 Hz), 7.20–7.24 (m, 3H), 7.34 (d, 2H, *J* = 8.1 Hz), 7.84 (d, 2H, *J* = 8.1 Hz), 8.10 (s, 1H), 8.61 (s, 1H). ¹³C NMR (75 MHz, DMSO) δ 175.42, 151.15, 144.82, 143.58, 143.40, 131.58, 130.67, 128.47, 127.06, 126.40, 125.53, 118.52, 117.75, 110.12, 64.89, 35.64, 30.62. LC-MS (ESI) *m/z* found: 328 [M – H]⁺.

4.1.11.21. **5-[Imidazol-1-yl(phenyl)methyl]-3H-1,3-benzoxazol-2-one** (65). Prepared according to the general procedure (Method A) using **25b**. Purified by silica gel column chromatography (ethyl acetate/ethanol 9:1, v/v). Yield (48 %); m.p. 108–111 °C. IR (ν, cm⁻¹) 3424 (NH), 1776 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 6.50 (s, 1H), 6.56 (s, 1H), 6.85–6.90 (m, 2H), 7.08–7.42 (m, 8H), 11.70 (br s, 1H, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO) δ 168.52, 138.94, 137.37, 137.21, 135.08, 128.6 (2C), 128.76, 127.98, 127.63 (2C), 126.53, 122.30, 121.91, 119.17, 111.42, 62.9. LC-MS (ESI) *m/z* found: 292 [M + H]⁺. Anal. (C₁₇H₁₃N₅O₃).

4.1.11.22. **5-[Imidazol-1-yl(phenyl)methyl]-3-methyl-1,3-benzoxazol-2-one** (66). Prepared according to the general procedure (Method A) using **27b**. Purified by silica gel column chromatography (ethyl acetate/methanol 8:2, v/v). Yield (82 %); m.p. 133–135 °C. IR (ν, cm⁻¹) 1781 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 3.34 (s, 3H), 6.58 (s, 1H), 6.68 (d, 1H, *J* = 1.67), 6.85–6.88 (m, 2H), 7.09–7.41 (m, 8H). ¹³C NMR (75 MHz, DMSO) δ 168.74, 139.42, 137.34, 137.32, 135.52, 128.85 (2C), 128.74, 127.56, 127.65 (2C), 126.57, 122.30, 122.12, 119.25, 110.45, 63.90, 30.05. LC-MS (ESI) *m/z* found: 306 [M + H]⁺. Anal. (C₁₈H₁₅N₃O₂).

4.1.11.23. **4-[Imidazol-1-yl-(2-oxo-3H-1,3-benzoxazol-5-yl)methyl]benzonitrile** (67). Prepared according to the general procedure (Method A) using **34b**. Purified by silica gel column chromatography (ethyl acetate/methanol 8:2, v/v). Yield (42 %); m.p. 125–132 °C. IR (ν, cm⁻¹) 3420 (NH), 2229 (CN), 1778 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 6.85 (s, 1H), 6.87 (d, 1H, *J* = 7.8 Hz), 6.98 (s, 1H), 7.04 (s, 1H), 7.14 (s, 1H), 7.27–7.32 (m, 3H), 7.67 (s, 1H), 7.86 (d, 2H, *J* = 8.1 Hz), 11.65 (br s, 1H, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO-d₆) δ 155.45, 141.62, 141.52, 139.32, 138.22, 133.62, 132.74 (2C), 128.24, 127.82, 127.45 (2C), 122.72, 120.4, 118.25, 116.32, 110.1, 64.25. LC-MS (ESI) *m/z* found: 317 [M + H]⁺. Anal. (C₁₈H₁₂N₄O₂).

4.1.11.24. **5-[(4-Chlorophenyl)-(1,2,4-triazol-1-yl)methyl]-3-methyl-1,3-benzoxazol-2-one** (68). Prepared according to the general procedure (Method B) using **28b** and triazole as starting material. Purified by silica gel column chromatography (ethyl acetate). Yield (32 %); m.p. 70–74 °C. IR (ν, cm⁻¹) 1778 (CO). ¹H NMR (300 MHz, CDCl₃) δ 3.32 (s, 3H), 7.14–7.25 (m, 6H), 7.35 (d, 2H, *J* = 8.5 Hz), 8.09 (s, 1H), 8.62 (s, 1H). ¹³C NMR (75 MHz, DMSO) δ 154.05, 152.10, 144.55, 142.01, 138.15, 132.82, 132.73, 131.81, 129.66 (2C), 128.64 (2C), 124.01, 109.44, 109.01, 64.53, 28.15.

LC-MS (ESI) *m/z* found: 341 [M + H]⁺. Anal. (C₁₇H₁₃ClN₄O₂). LC-MS (ESI) *m/z* found: 328 [M – H]⁺.

4.1.11.25. **3-Methyl-5-[phenyl(1,2,4-triazol-1-yl)methyl]-1,3-benzoxazol-2-one** (69). Prepared according to the general procedure (Method B) using **27b** and triazole as starting material. Purified by silica gel column chromatography (ethyl acetate). Yield (42 %) m.p. 135–138 °C. IR (ν, cm⁻¹) 1780. ¹H NMR (300 MHz, CDCl₃) δ 3.35 (s, 3H), 7.18 (d, 1H, *J* = 1.5 Hz), 6.79 (s, 1H), 6.90 (dd, 1H, *J* = 8.1 Hz, *J* = 1.5 Hz), 7.13–7.16 (m, 2H), 7.21 (d, 1H, *J* = 8.7 Hz), 7.38–7.40 (m, 3H), 7.98 (s, 1H), 8.05 (s, 1H). ¹³C NMR (75 MHz, DMSO-d₆) δ 157.32, 142.61, 141.4, 140.65, 132.64, 129.42 (2C), 128.81 (2C), 127.40, 126.72, 125.35, 123.43, 120.25, 112.50, 65.24, 29.52. LC-MS (ESI) *m/z* found: 305 [M – H]⁺. Anal. (C₁₇H₁₄N₄O₂).

4.1.11.26. **4-[(2-Oxo-3H-1,3-benzoxazol-5-yl)-(1,2,4-triazol-1-yl)methyl]benzonitrile** (70). Prepared according to the general procedure (Method B) using **34b** and triazole as starting material. Purified by silica gel column chromatography (ethyl acetate). Yield (42 %); m.p. 85–90 °C. IR (ν, cm⁻¹) 3342 (NH), 2229 (CN), 1778 (CO). ¹H NMR (300 MHz, CDCl₃) δ 6.98–7.02 (m, 2H), 7.27–7.36 (m, 5H), 7.84 (d, 2H, *J* = 8.1 Hz), 8.11 (s, 1H), 8.65 (s, 1H). ¹³C NMR (75 MHz, DMSO) δ 171.15, 152.24, 144.76, 144.47, 136.45, 132.672 (2C), 132.38, 128.51 (2C), 126.90, 123.93, 125.81, 120.54, 111.86, 110.23, 65.58. LC-MS (ESI) *m/z* found: 316 [M – H]⁺. Anal. (C₁₇H₁₁N₅O₂).

4.1.11.27. **4-[(3-Methyl-2-oxo-1,3-benzoxazol-5-yl)-(1,2,4-triazol-1-yl)methyl]benzonitrile** (71). Prepared according to the general procedure (Method B) using **35b** and triazole as starting material. Purified by silica gel column chromatography (ethyl acetate/cyclohexane 8:2, v/v). Yield (42 %); m.p. 75–77 °C. IR (ν, cm⁻¹) 2229 (CN), 1770 (CO). ¹H NMR (300 MHz, CDCl₃) δ 3.28 (s, 3H), 7.05 (dd, 1H, *J* = 1.5 Hz, *J* = 8.7 Hz), 7.22 (d, 1H, *J* = 1.5 Hz), 7.363–7.38 (m, 4H), 7.84 (d, 2H, *J* = 8.1 Hz), 8.11 (s, 1H), 8.65 (s, 1H). ¹³C NMR (75 MHz, DMSO) δ 170.32, 151.24, 145.74, 144.27, 136.45, 132.77 (2C), 132.38, 128.74 (2C), 126.90, 123.93, 123.81, 118.54, 111.66, 110.85, 64.58, 28.43. LC-MS (ESI) *m/z* found: 330 [M – H]⁺. Anal. (C₁₈H₁₃N₅O₂).

4.1.11.28. **5-[Imidazole-1-yl(4-pyridyl)methyl]-3H-1,3-benzoxazol-2-one** (72). Prepared according to the general procedure (Method A) using **31b**. Purified by silica gel column chromatography (ethyl acetate/
ethanol 9:1, v/v). Yield (56 %); m.p. 70–80 °C. IR (ν, cm⁻¹) 3373 (NH), 1772 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 6.26 (s, 1H), 6.84–6.92 (m, 2H), 7.16–7.25 (m, 4H)), 7.71 (s, 1H), 7.92 (s, 1H), 7.52 (d, 2H, *J* = 5.8 Hz), 11.0 (br s, 1H, Exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO) δ 168.52, 138.94 (2C), 137.37, 137.28, 135.08, 128.65 (2C), 127.78, 127.63, 126.53, 122.30, 121.81, 119.17, 112.42, 62.52. LC-MS (ESI) *m/z* found: 293 [M + H]⁺. Anal. (C₁₆H₁₂N₄O₂).

4.1.11.29. **5-[Phenyl(1,2,4-triazol-1-yl)methyl]-3H-1,3-benzothiazol-2-one** (73). Prepared according to the general procedure (Method B) using **40b** and triazole as starting material. Purified by silica gel column chromatography (ethyl acetate/methanol 9:1, v/v). Yield (52 %); m.p. 124–126 °C. IR (ν, cm⁻¹) 3345 (NH), 1693 (CO). ¹H NMR (300 MHz, CDCl₃) δ 6.25 (s, 1H), 6.82 (d, 1H, *J* = 8.0 Hz), 7.20–7.31 (m, 6H), 7.54 (m, 1H), 8.12 (s, 1H), 8.81 (s, 1H), 11.52 (br s, 1H, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO) δ 168.81, 147.94, 142.37, 135.08, 128.79 (2C), 128.76, 127.98, 127.63 (2C), 126.53, 122.30, 122.12, 119.27, 111.45, 62.95. LC-MS (ESI) *m/z* found: 307 [M – H]⁺. Anal. (C₁₆H₁₂N₄OS).

4.1.11.30. **3-Methyl-5-[phenyl-(1,2,4-triazol-1-yl)methyl]-1,3-benzothiazol-2-one** (74). Prepared according to the general procedure (Method B) using **41b** and triazole as starting material. Purified by silica gel column chromatography (ethyl acetate). Yield (44 %); m.p. 145–147 °C. IR (ν, cm⁻¹) 1680 (CO). ¹H NMR (300 MHz, CDCl₃) δ 3.33 (s, 3H), 7.14–7.15 (m, 2H), 7.21–7.25 (m, 3H), 7.33–7.40 (m, 3H), 7.67 (d, 1H, *J* = 8.1 Hz), 8.09 (s, 1H), 8.62 (s, 1H). ¹³C NMR (75 MHz, DMSO-d₆) δ 157.32, 142.61, 141.4, 140.65, 132.64, 129.42 (2C), 128.81 (2C), 127.40, 125.72, 124.35, 123.73, 117.25, 110.50, 65,24. 29.52. LC-MS (ESI) *m/z* found: 321 [M – H]⁺. Anal. (C₁₇H₁₄N₄OS).

4.1.11.31. **4-[(3-Methyl-2-oxo-1,3-benzothiazol-5-yl)-(1,2,4-triazol-1-yl)methyl]benzonitrile** (75). Prepared according to the general procedure (Method B) using **42b** and triazole as starting material. Purified by silica gel column chromatography (ethyl acetate/methanol 9:1, v/v). Yield (54 %); m.p. 122–125 °C. IR (ν, cm⁻¹) 2229 (CN), 1680 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 3.34 (s, 3H), 7.10 (dd, 1H, *J* = 8.2 Hz, *J* = 1.5 Hz), 7.27–7.28 (m, 2H), 7.35 (d, 2H, *J* = 8.4 Hz), 7.66 (d, 1H, *J* = 8.1 Hz), 7.84 (d, 2H, *J* = 8.4 Hz), 8.11 (s, 1H), 8.66 (s, 1H). ¹³C NMR (75 MHz, DMSO) δ 165.35, 152.35, 144.88, 144.68, 138.64, 136.41, 132.72 (2C), 128.14, 127.77 (2C), 124.48, 119.41, 118.32, 116.46, 111.15, 65.24, 31.55. LC-MS (ESI) *m/z* found: 346 [M – H]⁺. Anal. (C₁₈H₁₃N₅OS).

4.1.11.32. **4-[(3-Ethyl-2-oxo-2,3-dihydrobenzo[d]thiazol-5-yl)-(1H-1,2,4-triazol-1-yl)methyl] benzonitrile** (76). Prepared according to the general procedure (Method B) using **43b** and triazole as starting material. Purified by silica gel column chromatography (ethyl acetate/methanol 9:1, v/v). Yield (54 %); m.p. 125–127 °C. IR (ν, cm⁻¹) 2229 (CN), 1674 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 1.12 (t, 3H, *J* = 7.5 Hz), 3.88 (q, 2H, *J* = 7.5 Hz), 7.10 (dd, 1H, *J* = 8.1 Hz, *J* = 1.5 Hz), 7.29 (s, 1H), 7.35 (d, 2H, *J* = 8.1 Hz), 7.40 (s, 1H), 7.68 (d, 1H, *J* = 8.1 Hz), 7.86 (d, 2H, *J* = 8.1 Hz), 8.12 (s, 1H), 8.69 (s, 1H). ¹³C NMR (75 MHz, DMSO) δ 165.55, 151.35, 144.68, 144.28, 138.68, 136.45, 132.23 (2C), 128.74, 127.37 (2C), 124.42, 119.42, 118.22, 116.43, 111.13, 64.25, 31.25, 14.24. LC-MS (ESI) *m/z* found: 360 [M – H]⁺. Anal. (C₁₉H₁₅N₅OS).

4.1.11.33. **6-[Imidazol-1-yl(phenyl)methyl]-4H-1,4-benzoxazin-3-one** (77). Prepared according to the general procedure (Method A) using **17b**. Purified by silica gel column chromatography (ethyl acetate). Yield (70 %); m.p. 139–143 °C. IR (ν, cm⁻¹) 3130 (NH), 1691 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 4.57 (s, 2H), 6.63–6.70 (m, 2H), 6.81 (s, 1H), 6.93–6.95 (m, 2H), 7.05 (s, 1H), 7.10–7.13 (m, 2H), 7.34–7.42 (m, 3H), 7.61 (s, 1H), 10.65 (br s, 1H, exchangeable with D₂O). ¹³C NMR (75

MHz, DMSO) δ 164.74, 143.23, 139.92, 137.19, 134.88, 128.73 (3C), 127.95, 127.63 (2C), 126.95, 122.01, 119.18, 115.94, 115.76, 66.73, 64.77. LC-MS (ESI) *m/z* found: 306 [M + H]⁺. Anal. (C₁₈H₁₅N₃O₂).

4.1.11.34. **6-[1H-imidazol-1-yl(phenyl)methyl]-4-methyl-1,4-benzoxazin-3-one** (78). Prepared according to the general procedure (Method A) using **18b**. Purified by silica gel column chromatography (ethyl acetate). Yield (75 %); m.p. 123–125 °C. IR (ν, cm⁻¹) 3123 (NH), 1682 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 3.18 (s, 3H), 4.66 (s, 2H), 6.77–6.88 (dd, 1H, *J* = 1.5 Hz, *J* = 8.1 Hz), 6.84 (s, 1H), 6.95 (s, 1H), 6.99–7.02 (m, 2H), 7.11–7.13 (m, 2H), 7.31–7.44 (m, 4H), 7.64 (s, 1H). ¹³C NMR (75 MHz, DMSO) δ 164.74, 143.23, 139.92, 137.19, 134.88, 132.20, 128.73 (2C), 127.65, 127.63 (2C), 126.75, 122.41, 119.58, 115.94, 114.76, 65.73, 62.87, 36.24. LC-MS (ESI) *m/z* found: 320 [M + H]⁺. Anal. (C₁₉H₁₇N₃O₂).

4.1.11.35. **4-[(3-Oxo-4H-1,4-benzoxazin-6-yl)-(1,2,4-triazol-1-yl)methyl]benzonitrile** (79). Prepared according to the general procedure (Method B) using **19b**. Purified by silica gel column chromatography (ethyl acetate/methanol 9:1, v/v). Yield (75 %); m.p. 135–140 °C. IR (ν, cm⁻¹) 3117 (NH), 2229 (CN), 1699 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 4.57 (s, 2H), 6.69–6.83 (m, 2H), 6.96 (d, 1H, d, *J* = 8.7 Hz), 7.19 (s, 1H), 7.35 (d, 2H, *J* = 8.3 Hz), 7.87 (d, 2H, *J* = 8.3 Hz), 7.10 (s, 1H), 8.64 (s, 1H), 10.67 (br s, 1H, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO) δ 164.70, 152.23, 144.71, 144.48, 143.23, 132.62 (2C), 132.09, 128.73 (2C), 127.53, 123.10, 118.51, 116.33, 115.80, 110.80, 66.70, 64.16. LC-MS (ESI) *m/z* found: 330 [M – H]⁺. Anal. (C₁₈H₁₃N₅O₂).

4.1.11.36. **4-[Imidazol-1-yl-(4-methyl-3-oxo-1,4-benzoxazin-6-yl)methyl] benzonitrile** (80). Prepared according to the general procedure (Method A) using **20b**. Purified by silica gel column chromatography (ethyl acetate/methanol 9:1, v/v). Yield (55 %); m.p. 80–87 °C. IR (ν, cm⁻¹) 2227 (CN), 1685 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 3.19 (s, 3H), 4.67 (s, 2H), 6.81 (dd, 1H, *J* = 2.1 Hz, *J* = 8.1 Hz), 6.98 (s, 1H), 7.01–7.04 (m, 2H), 7.06 (d, 1H, *J* = 2.1 Hz), 7.21 (m, 1H), 7.25 (d, 1H, *J* = 8.1 Hz), 7.76 (s, 1H), 7.85 (d, 2H, *J* = 8.1 Hz). ¹³C NMR (75 MHz, DMSO) δ 164.78, 143.43, 140.12, 137.25, 134.48, 132.15, 128.78 (2C), 127.65, 127.43 (2C), 126.75, 122.42, 119.58, 118.25, 116.94, 114.36, 65.43, 63.77, 36.14. LC-MS (ESI) *m/z* found: 345 [M + H]⁺. Anal. (C₂₀H₁₆N₄O₂).

4.1.11.37. **4-[Imidazole-1-yl-(3-oxo-4H-1,4-benzothiazin-7-yl)methyl] benzonitrile** (82). Prepared according to the general procedure (Method A) using **23b**. Purified by silica gel column chromatography (ethyl acetate/methanol 9:1, v/v). Yield (64 %); m.p. 150–155 °C. IR (ν, cm⁻¹) 3115 (NH), 2229 (CN), 1676 (CO), 1604. ¹H NMR (300 MHz, DMSO-d₆) δ 3.47 (s, 2H), 6.72–6.78 (m, 2H), 6.99–7.11 (m, 3H), 7.27–7.29 (m, 2H), 7.34–7.37 (m, 1H), 7.67 (s, 1H), 7.77 (m, 2H), 10.55 (br s, 1H, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO) δ 165.15, 152.24, 144.78, 144.41, 137.64, 136.88, 133.52, 132.65 (2C), 128.91, 127.64 (2C), 122.59, 120.44, 118.65, 116.83, 110.43, 64.25, 28.72. LC-MS (ESI) *m/z* found: 347 [M + H]⁺. Anal. (C₁₉H₁₄N₄OS).

4.1.11.38. **7-[1H-imidazole-1-yl-(phenyl)methyl]-4H-1,4-benzothiazin-3-one** (83). Prepared according to the general procedure (Method A) using **22b**. Purified by silica gel column chromatography (ethyl acetate/methanol 9:1, v/v). Yield (60 %); m.p. 187–189 °C. IR (ν, cm⁻¹) 3123 (NH), 1658 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 3.47 (s, 2H), 6.69 (s, 1H), 6.81–6.84 (m, 2H), 6.97 (s, 1H), 7.08 (s, 1H), 7.13–7.15 (m, 2H), 7.32 (s, 1H), 7.34–7.40 (m, 3H), 7.64 (s, 1H), 10.53 (br s, 1H, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO) δ 166.25, 151.25, 144.48, 143.85, 137.62, 136.52, 133.65 (2C), 128.91, 128.62 (2C), 122.59, 119.44, 118.9, 116.83, 110.83, 64.24, 28.53. LC-MS (ESI) *m/z* found: 322 [M + H]⁺. Anal. (C₁₈H₁₅N₃OS).
4.1.11.39. 4-[Imidazole-1-yl-(4-methyl-3-oxo-1,4-benzothiazin-7-yl) methyl]benzonitrile (84). Prepared according to the general procedure (Method A) using 24b. Purified by silica gel column chromatography (ethyl acetate/methanol 9:1, v/v). Yield (30 %); m.p. 74–80 °C. IR (ν, cm⁻¹) 2227 (CN), 1668 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 3.26 (s, 3H), 3.53 (s, 2H), 6.48 (dd, 1H, *J* = 1.2 Hz, *J* = 8.1 Hz), 6.99–7.01 (m, 2H), 7.12 (d, 1H, *J* = 1.2 Hz), 7.20 (s, 1H), 7.28 (d, 2H), 7.42 (d, 1H, *J* = 8.1 Hz), 7.73 (s, 1H), 7.89 (m, 2H). ¹³C NMR (75 MHz, DMSO) δ 166.27, 151.75, 144.42, 143.85, 137.62, 136.52, 132.65 (2C), 128.91, 127.62 (2C), 123.43, 122.52, 119.44, 118.9, 116.83, 110.83, 64.23, 35.34, 28.53. LC-MS (ESI) *m/z* found: 361 [M + H]⁺. Anal. (C₂₀H₁₆N₄OS).

4.1.11.40. 4-[(3-Oxo-4H-1,4-benzothiazin-7-yl)-(1,2,4-triazol-1-yl) methyl]benzonitrile (85). Prepared according to the general procedure (Method B) using 43b and triazole as starting material. Purified by silica gel column chromatography (ethyl acetate/methanol 9:1, v/v). Yield (40 %); m.p. 215–218 °C. IR (ν, cm⁻¹) 3099 (NH), 2227 (CN), 1668 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 3.46 (s, 2H), 6.82–6.86 (m, 2H), 7.21 (s, 1H), 7.34 (d, 1H, *J* = 7.9 Hz), 7.38 (d, 2H, *J* = 8.2 Hz), 7.87 (d, 2H, *J* = 8.2 Hz), 8.11 (s, 1H), 8.66 (s, 1H), 10.53 (br s, 1H, exchangeable with D₂O). ¹³C NMR (75 MHz, DMSO) δ 165.11, 152.25, 144.78, 144.01, 137.68, 136.88, 132.65 (2C), 128.91, 127.64 (2C), 122.59, 119.44, 118.49, 116.83, 110.93, 64.20, 28.61. LC-MS (ESI) *m/z* found: 346 [M − H]⁺. Anal. (C₁₈H₁₃N₅OS).

4.1.11.41. 4-[(4-Methyl-3-oxo-1,4-benzothiazin-7-yl)-(1,2,4-triazol-1-yl) methyl]benzonitrile (86). Prepared according to the general procedure (Method B) using 24b and triazole as starting material. Purified by silica gel column chromatography (ethyl acetate). Yield (45 %); m.p. 95–100 °C. IR (ν, cm⁻¹) 2227 (CN), 1666 (CO). ¹H NMR (300 MHz, DMSO-d₆) δ 3.35 (s, 3H), 3.54 (s, 2H), 6.97 (d, 1H, *J* = 8.1 Hz), 7.25 (s, 1H), 7.39–7.45 (m, 4H), 7.86 (d, 2H, *J* = 8.4 Hz), 7.81 (s, 1H), 7.86 (s, 1H). ¹³C NMR (75 MHz, DMSO) δ 165.51, 152.35, 144.88, 144.21, 137.68, 136.85, 132.68 (2C), 128.71, 127.68 (2C), 123.42, 119.47, 118.42, 116.43, 111.23, 64.25, 35.20, 28.82. LC-MS (ESI) *m/z* found: 360 [M − H]⁺. Anal. (C₁₉H₁₅N₅OS).

### 4.1.12. Chiral HPLC chromatography

The chromatography system consisted of SpectraSystem (Thermo Electron S.A., USA) P1000-010XR2 isocratic pump and a dual wavelength SpectraSystem UV2000 detector. Data acquisition system was performed with an IBM PC/computer using Azur 3.0 (Datalys, France) as chromatography software. Chromatography was performed on the Chiralcel AD-H column (250 mm × 20 mm, Daicel Chemical Industries Ltd, Japan) packed with silica gel coated by cellulose tris (3,5-dimethylphenylcarbamate). A Rheodyne 9125 injector with a 20 µL sample loop was used. The mobile phase used was hexane/ethanol (60:40, v/v). Solvents were of HPLC quality (Carlo Erba, France). The flow-rate was 1.1 mL min⁻¹ and the injection volume was 20 µL. The detection wavelength was 250 nm. The column temperature was at 25–30 °C. The sample concentration was 10 µg/mL in mobile phase. This method was already published [40,41] and used to separate the enantiomers of compound 50.

(+)-50 was obtained following chiral separation of 50 as described above (t₁ = 4.2 min, [α] [20]D +52° (c = 3.6) in EtOH), and then (−)-50 was isolated at t₂ = 6.4 min ([α] [20]D −52° (c = 3.8) in EtOH).

## 4.2. Biology

### 4.2.1. Chemicals

ACTH1-24 was purchased from Sigma Aldrich (Germany), ovine LH-S26 from the National Hormone and Peptid Program (NHPP–NIH, USA), carbogen gas from Linde (Germany) and all other chemicals from Roth (Germany) or VWR Prolabo (Germany). ELISA kits were purchased from ibl-Hamburg (Germany) and DRG (Germany).

### 4.2.2. In vitro inhibition of CYP19

The inhibition of CYP19 was determined *in vitro* using human placental microsomes with [1-β-³H]androstenedione as substrate [43]. Letrozole was used as reference drug.

### 4.2.3. In vivo inhibition of CYP19

The *in vivo* experiments have been performed by Pharmacelius CRO company (Saarbrücken, Germany) using rats. Briefly, immature female rats were treated with androstenedione (A) for 4 successive days with or without varying doses of the test compound. A was converted to estrogens and then induced uterine hypertrophy [44]. Letrozole was included as a quality control in each study. After the last application, the rats were sacrificed and their uteri dissected. The *in vivo* efficacy of the test compounds was then determined by the measurement of the uterine wet and dry weight. The ED₅₀ value is defined by calculating the dose required to inhibit the androstenedione-induced uterine hypertrophy by 50 % [45].

### 4.2.4. In vitro determination of ACTH-induced aldosterone and corticosterone release from rat adrenal fragments

The determination of ACTH-induced release of aldosterone and corticosterone *in vitro* was performed according to Häusler et al. [38]. For each experiment, animals (male Wistar rats, 250–300 g, Janvier, France) were decapitated. Their adrenal glands were removed and freed of adhering fat tissue. Each adrenal was cut into four fragments of approximately equal size on a filter drenched in Krebs-Ringer buffer solution (KRB) with 8.4 mM glucose (pH 7.6). The fragments were randomised and transferred into 5 mL plastic incubation flasks. Each flask finally contained four adrenal fragments in 2 mL of KRB, each one being from a different animal. The flasks were gassed with carbogen (O₂/CO₂ 95:5) for 10 min, tightly closed and incubated in a shaking water bath (120 rpm) at 37 °C for 1 h. After this pre-incubation step, the media were replaced by 2 mL fresh KRB in presence or absence of ACTH and test compounds. The formation of corticosterone was induced by ACTH₁.₂₄ in a final concentration of 0.1 µg/mL, whereas the release of aldosterone was stimulated by the high potassium concentration of KRB (5.9 mM K⁺). Test compounds were dissolved in DMSO. The final concentration of solvent did not exceed 1 %. All experiments were performed in triplicate. At the end of the experiment, supernatants were removed, centrifuged and stored at −20 °C for analysis of hormone levels. The adrenal fragments were blotted dry and weighed.

The quantification of aldosterone and corticosterone was achieved by liquid chromatography-mass spectrometry. The HPLC system consisted of a MS pump (Surveyor) and an auto sampler (Surveyor). Mass spectrometry was performed on a TSQ Quantum triple quadrupole mass spectrometer equipped with an atmospheric pressure chemical ionization (APCI) interface (Thermo-Finnigan, USA) and connected to a PC running the standard software Xcalibur 1.3. The method development was carried out using a starting solution of 1 mg/mL in ACN diluted with a mixture of 10 mM ammonium acetate/0.1 % formic acid (1:1, v:v) to a final concentration of 10 µg/mL.

Full scan mass spectra were acquired in the positive mode using syringe pump infusion to identify the protonated quasimolecular ion [M+H]⁺. Auto-tuning was carried out for maximizing ion abundance followed by the identification of characteristic fragment ions using a generic parameter set: ion source temperature 350 °C, capillary voltage 3.8 kV, collision gas 0.8 mbar argon, spray and sheath gas, 20 and 8 (arbitrary units), respectively. The most intensive product ion was used to quantify the compounds in the selected reaction monitoring mode (SRM).

The HPLC pump flow rate was set to 300 µL/min and the compounds were separated on an Uptisphere MS C18 ODB (Interchim), 3 µm, 50 × 2.0 mm (length, ID) analytical column with a pre-column (Uptisphere MS C18 ODB, 3 µm, 10 × 2.0 mm) using the following gradient: % A (t (min)), 50(0)-97(1.0–2.7)-50(2.9–4.5) [A: MeOH; B: H₂O + 0.1 % formic acid (v:v)].
Calibration standards were prepared by spiking 1900 µL blank KRB with 100 µL of aldosterone or corticosterone working solution to reach final concentrations of 5 and 0.5 µM. The starting solution (10 mM in MeOH) was diluted in KRB to final concentrations of 100 µM and 10 µM (working solutions).

To 2000 µL of incubation supernatant or calibration standard 2000 µL EtOAc containing the internal standard (ISTD 0.1 µM) was added. Samples were vigorously shaken and centrifuged for additional 10 min at 1500 rpm and 20 °C. The organic layers were transferred to fresh vials. The extraction procedure was repeated, the organic layers were pooled and evaporated in an Eppendorf Concentrator 5301 at 30 °C for 30 min. Subsequently the dried residues were re-suspended in 200 µL eluent (ACN:H₂O 1:1), the particle-free supernatant was transferred to 200 µL sampler vials and subjected to LC-MS/MS. For quantification the ISTD method was applied and the system calibrated using quadratic least squares regression as mathematical model. In addition, the levels for calibration were chosen in the range of occurring sample concentrations.

### 4.2.5. *In vitro* determination of LH-induced estrogen and progesterone release from hamster ovarian fragments

The determination of LH-induced release of estrogens and progesterone *in vitro* was performed according to Häusler et al. [46]. Animals (adult female golden hamsters, weighing 75-120 g, Janvier, France) were kept in groups of 4, maintained on a 14 h light/10 h dark schedule (lights on 5.00 a.m., lights of 7.00 p.m.) and were sacrificed after 3-4 consecutive 4-day cycles. Day 1 is defined as the day of ovulation and day 4 corresponds to the proestrus. In all experiments, day 4 animals were used. Animals were killed by decapitation, the ovaries were removed, freed of adhering fat tissue and quartered. The fragments were randomised to 5 mL plastic incubation flasks containing 2 mL KRB glucose. Finally each incubation flask consisted of 4 quarters from different animals. The flasks were gassed with carbogen (O₂/CO₂ 95:5) for 10 min, tightly closed and incubated in a shaking water bath (120 rpm) at 37 °C. After a 1 h pre-incubation, the supernatant was replaced by 2 mL of fresh KRB. The ovarian fragments were further incubated for 4 h in presence or absence of LH and test compounds in various concentrations. For stimulation of steroid hormone release, ovine LH (preparation S-26 from NHPP-NIH, USA) was added in a final concentration of 10 µg/mL. Test compounds were dissolved in DMSO. The final concentration of solvent did not exceed 1 %. All experiments were performed in triplicate.

At the end of the experiment, the supernatants were removed, centrifuged and stored in aliquots for hormone determination by immunoassays. The ovarian fragments were blotted dry and weighed.

The concentrations of estrogens and progesterone were determined in duplicate for the standards and single for the samples using the following kits: "Progesterone ELISA", "17-β-Estradiol ELISA" and "Estrone ELISA" from ibl-Hamburg (Germany). In detail, 50 µL of standards and undiluted sample were added to the wells in the assay plate for the estrone ELISA (25 µL for 17-β-Estradiol- and Progesterone ELISA), which were precoated with the specific antibody by the manufacturer. After dispensing of 100 µL enzyme conjugate (200 µL for 17-β-estradiol- and progesterone ELISA) and thoroughly mixing, the microtiter plate was incubated at room temperature for 120 min (60 min for 17-beta-estradiol- and progesterone ELISA). The wells were then washed 3 times with wash buffer. For the colour reaction, 150 µL of TMB substrate solution (100 µL for 17-β-estradiol ELISA and 200 µL for progesterone ELISA) was added to each well at timed intervals. The reaction was stopped after 15 min by adding 100 µL of 0.5 M sulphuric acid to each well. The plate was read within the next 30 min with a Spectramax plus (Molecular Devices) at 450 nm. The calculation of the results was performed as described above. The concentration of estrogens was calculated according to the following equation:

$$ \text{estrogens [ng/mL]} = \Sigma \text{ estradiol [ng/mL]} + \text{estrone [ng/mL]} $$

### 4.3. Bioinformatics

The aromatase structure was sourced from the Protein Data Bank (PDB ID: 3EQM). Both polar and non-polar hydrogen atoms and assign Gasteiger charges were added to the structure with ChimeraX [47]. The docking was performed with Gnina [48], from the pre build binary. Docking parameter were set with autobox function around the reference steroid recovered from PDB 3EQM, with 3 Å added for each side and exhaustiveness at 64. Initial docking yielded cnn_pose_score and cnn_affinity scores; GNINA's CNN algorithm then prioritized conformations based on cnn_pose_score (ranging from 0 to 1, indicating binding potential), while cnn_affinity provided additional binding potential assessment, with higher values indicating stronger binding.

DMPK predictions were performed with the Deep-PK API (https://biosig.lab.uq.edu.au/deeppk/).

### CRediT authorship contribution statement

Chang Ha Park: Methodology, Investigation. Marc Le Borgne: Conceptualization. Marouan Rami: Investigation. Martin Fossart: Investigation, Data curation. Patricia Melnyk: Writing – review & editing. Maxime Liberelle: Writing – review & editing, Formal analysis, Data curation. Saïd Yous: Writing – review & editing, Writing – original draft, Supervision, Methodology, Investigation, Funding acquisition.

### Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

### Funding

This work was financially supported by grants from le Ministère de l'Education et de la Recherche and the University of Lille (France). This research was also financially supported by Yang Ji Chemical Company of South Korea.

### Declaration of competing interest

The authors alone are responsible for the content and writing of this article.

This work was financially supported by grants from le Ministère de l'Education et de la Recherche and the University of Lille (France). This research was also financially supported by Yang Ji Chemical Company of South Korea.

### Acknowledgements

We express our thanks to the NMR facility (Lille University), the Region Hauts-de-France (France), the Ministère de la Jeunesse, de l'Éducation Nationale et de la Recherche (MJENR) and the Fonds Européens de Développement Régional (FEDER).

### Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.ejmech.2025.118298.

### Data availability

No data was used for the research described in the article.
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