Convenient Synthesis of N-Heterocycle-Fused Tetrahydro-1,4-diazepinones

Abstract

A general approach towards the synthesis of tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one, tetrahydro[1,4]diazepino[1,2-a]indol-1-one and tetrahydro-1H-benzo[4,5]imidazo[1,2-a][1,4]diazepin-1-one derivatives was introduced. A regioselective strategy was developed for synthesizing ethyl 1-(oxiran-2-ylmethyl)-1H-pyrazole-5-carboxylates from easily accessible 3(5)-aryl- or methyl-1H-pyrazole-5(3)-carboxylates. Obtained intermediates were further treated with amines resulting in oxirane ring-opening and direct cyclisation—yielding target pyrazolo[1,5-a][1,4]diazepin-4-ones. A straightforward two-step synthetic approach was applied to expand the current study and successfully functionalize ethyl 1H-indole- and ethyl 1H-benzo[d]imidazole-2-carboxylates. The structures of fused heterocyclic compounds were confirmed by ¹H, ¹³C, and ¹⁵N-NMR spectroscopy and HRMS investigation.

1. Introduction

Nitrogen-based heterocyclic compounds are integrated into everyday life, including pharmaceuticals [1,2,3], agrochemicals [4,5], various plastics [6,7], dyes [8,9], and other functional materials [10,11,12,13]. When it comes to drug discovery, the development of effective and inexpensive active ingredients is one of the main goals of researchers in the field of medicinal chemistry. Over the years, great attention has been paid to fused heterocyclic derivatives, which are versatile molecules, exhibiting a wide variety of biological properties including antioxidant, antimicrobial, antiproliferative and other activities [14,15,16,17]. For example, fused pyrano[2,3-c]pyrazole derivatives I were designed, synthesized and have been identified as prospective COX-2 inhibitors (Figure 1) [18]. A more recent study by Wang et al. encompasses a discovery of novel pyrrolo[3,4-c]pyrazol-3-carboxamides, where lead compound II exhibited potent inhibition towards H⁺/K⁺-ATPase and in vivo histamine-stimulated gastric acid secretion [19]. In the field of indole-based chemistry, Feng et al. reported 9H-pyrimido[4,5-b]indol-4-amines III as promising non-toxic hematopoietic stem cells ex vivo expansion agents [20]. In the study of Purgatorio and co-workers, azepino[4,3-b]indole IV was found to be a useful and versatile scaffold for developing new small molecules inhibiting BChE, which is a promising drug target in severe Alzheimer’s disease [21]. Fused systems with two 1,4-distanced nitrogen atoms encompass a variety of biological activities. For instance, Conde-Ceide et al. reported series of 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one derivatives, such as V, as mGlu₅ receptor-positive allosteric modulators with efficacy in preclinical models of schizophrenia [22], whereas 2,3-dihydropyrazino[1,2-a]indole-1,4-dione derivatives VI were reported to act as dual EGFR/BRAF^V600E inhibitors [23]. Among a variety of condensed systems, fusion of diazepine with selected heterocycles is important as it represents the most significant class of compounds in terms of clinical use [24]. Another notable example includes 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide VII as a non-nucleoside inhibitor of the respiratory syncytial virus (RSV) polymerase complex [25] (Figure 1).

Combining the azaheterocycle scaffold into one structure with the diazepinone motif has been shown to result in biologically active compounds. However, to date examples of biologically active pyrazole-, pyrrole-, indole- and benzo[d]imidazole-fused diazepinone derivatives are limited. For example, tricyclic indole-diazepinones VIII inhibit induced myeloid leukaemia cell differentiation protein (Mcl-1) [26,27]. Chiral ferrocenylpyrazolo[1,5-a][1,4]diazepin-4-one IX was reported to suppress the growth of A549 lung cancer cells through cell cycle arrest, and H322 together with H1299 lung cancer cells by inducing apoptosis [28]. On the other hand, pyrrole or indole-fused diazepinones X–XII demonstrated inhibitory activity of various kinases, namely, extracellular signal-regulated kinase 2 (ERK2) [29], ribosomal S6 kinase (RSK) [30,31], cyclin-dependent kinase 1 (CDK1), and cyclin-dependent kinase 5 (CDK5) [32]. The abovementioned fused systems are not very widely investigated; therefore, it may be a promising entry in the field of synthetic and medicinal chemistry.

In our previous studies, we investigated the synthesis and biological activity of various annulated pyrazole systems such as substituted 2H-pyrazolo[4,3-c]pyridines [33,34,35], benzopyrano[2,3-c]pyrazol-4(2H)-ones [36], 2H-furo[2,3-c]pyrazole ring systems [37], and others. In continuation of our previous research on fused heterocycles, herein we report an efficient two-step synthesis of tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-ones, tetrahydro[1,4]diazepino[1,2-a]indol-1-ones and tetrahydro-1H-benzo[4,5]imidazo[1,2-a][1,4]-diazepin-1-ones.

2. Results and Discussion

It is known that NH-pyrazoles usually exhibit annular N,N-prototropy [38,39]. N-Alkylation of asymmetrically ring-substituted 1H-pyrazoles generally results in the formation of a mixture of regioisomeric N-substituted products [40,41,42,43] and therefore regioselective N-alkylation requires optimization of reaction conditions [44]. Wright et al. has reported that alkylation of ethyl 1H-pyrazole-3(5)-carboxylate in the presence of K₂CO₃ was found to favor the formation of ethyl 1-substituted pyrazole-3-carboxylates while the formation of 1-substituted-1H-pyrazole-5-carboxylates could be sterically redirected by alkylating ethyl 3-(triphenylsilyl)-1H-pyrazole-5-carboxylate and removing the triphenylsilyl group with Bu₄NF [45]. In another study implemented by Xu et al., regioselective N-alkylation of NH-pyrazoles was accessed by using MgBr₂ and i-Pr₂NEt or K₂CO₃ and leading to the formation of different regioisomers [46,47].

In this work, the formation of the desired 1-(oxiran-2-ylmethyl)-3-aryl-1H-pyrazole-5-carboxylates by alkylation of easily accessible NH-pyrazoles [48] with 2-(chloromethyl)oxirane was optimized using 1a as a model compound. As shown in

Table 1. Optimization of reaction conditions to access 2a.

Entry	2-(Chloromethyl)oxirane	Base	Solvent	Temp.	Time	Yield
						2a	3a
1	15 eq	1.5 eq K2CO3	neat	70 °C	16 h	24%	-
2	10 eq	1.1 eq Cs2CO3	neat	40 °C	5 h	30%	20%
3	10 eq	1.3 eq NaH	neat	40 °C	5 h	-	50%
4 a	11.5 eq	2.0 eq KOH	neat	40 °C	6 h	7%	33%
5	5 eq	3.0 eq Cs2CO3	DMF	50 °C	24 h	49%	6%
6	1.5 eq	1.5 eq NaH	DMF	40 °C	5 h	50%	-
7	2.6 eq	1.4 eq Cs2CO3	ACN	reflux	5 h	45%	-

^a TBAB was used as a phase transfer catalyst.

, reaction outcome is highly dependent on the choice of the base and the solvent. First, application of different bases in solvent-free conditions was investigated. When ethyl 3-phenyl-1H-pyrazole-5-carboxylate 1a was treated with 2-(chloromethyl)oxirane in the presence of K₂CO₃ at 70 °C (Entry 1) [49], a full conversion of 1a was only achieved after 16 h affording regioisomer 2a in 24% yield. Reaction using Cs₂CO₃ as a base at lower temperature (Entry 2) [50] proceeded giving isomers 2a and 3a in 3:2 ratio. Interestingly, when reaction was conducted using NaH (Entry 3), it proved to proceed in high regioselectivity. However, as the major product the undesired 5-phenyl-1H-pyrazole-3-carboxylate 3a was obtained. Reaction with KOH in the presence of a catalytic amount of TBAB [51] also did not provide an increase in the yield of desired regioisomer 2a (Entry 4).

Subsequently, alkylation reaction conditions were investigated in the presence of solvent. To our satisfaction, both Cs₂CO₃ (Entry 5) [52] and NaH (Entry 6) in DMF [53] provided desired isomer 2a as the major product in high regioselectivity. An attempt to perform reaction in refluxing ACN using Cs₂CO₃ as a base [54] gave similar results (Entry 7). Interestingly, we noticed that alkylation using NaH proved to be highly regiospecific as the ratio of obtained products was drastically shifted by changing the reaction media. The use of DMF as a solvent in the presence of NaH was selected as the most suitable approach to synthesize ethyl 1-(oxiran-2-ylmethyl)-3-phenyl-1H-pyrazole-5-carboxylates 2a–h as it required overall reduced reaction time and temperature for full conversion of pyrazoles 1a–h (Scheme 1). Although the reactions exhibit high regioselectivity, obtained yields did not exceed 53–61% due to instability of products 2a–e during the purification process.

Differentiation between major 2a and minor 3a isomers was implemented based on ¹H,¹³C-HSQC, ¹H,¹H-NOESY, ¹H,¹³C- and ¹H,¹⁵N-HMBC experimental data. For example, ¹H,¹³C-HMBC experiment of regioisomer 2a revealed 3-bond correlation between NCH₂ protons at δ 4.83 ppm and C-5 of pyrazole ring at δ 134.3 ppm (Figure 2). In the ¹H,¹⁵N-HMBC spectrum, the same NCH₂ protons exhibited 2-bond correlation with N-1 pyrrole-like (δ −173.3 ppm) and 3-bond correlation with N-2 pyridine-like (δ −64.4 ppm) nitrogen atoms. The ¹H,¹H-NOESY spectrum indicated close-in-space proton interaction between phenyl ring 2′(6′)-protons (δ 7.81 ppm) and pyrazole 4-H proton at δ 7.15 ppm.

The structure of minor regioisomer 3a was elucidated in a similar manner. The ¹H,¹³C-HMBC spectrum indicated that NCH₂ protons correlate with pyrazole C-5 carbon at −146.2 ppm. Unambiguous distinction amongst both regioisomers can be determined using the ¹H,¹H-NOESY experiment. Close-in-space proton interaction was observed between phenyl ring 2′(6′)-H protons and pyrazole 4-H proton at δ 6.84 ppm, whereas regioisomer 3a additionally exhibited NOEs between aromatic phenyl ring 2′(6′)-protons and NCH₂ protons at δ 4.26–4.47 ppm.

According to the synthetic strategy, ethyl 1-(oxiran-2-ylmethyl)-3-aryl-1H-pyrazole-5-carboxylates 2a–h were further used to obtain novel fused pyrazole-diazepinone systems via oxirane ring-opening. Due to high ring-strain, epoxides are prone to undergoing ring-opening reactions upon treatment with various nucleophiles [55] alone, or under the use of transition metal or organocatalysts [56,57,58]. On the other side, small heterocycles are also able to react with diverse electrophiles, affording a variety of functionalized molecules. Unlike the nucleophilic ring-opening reactions, the electrophilic ring-opening of small heterocycles cannot proceed by itself [59]. Methods reported in the literature for the epoxide ring-opening with amines are mainly focused on reactions mediated by a range of catalysts, activators, and promoters, in either solvent or solvent-free media [55,60,61,62,63]. In our study, intermediates 2a–h were treated with various primary amines or ammonia in methanol (Scheme 1). Reaction monitoring indicated that ring closure proceeds rapidly to form a 1,4-diazepinone ring fused to pyrazole as no intermediate or side products have been observed, as opposed to the study reported by Shen et al. [28]. Reactions with primary amines, such as 2-methoxyethyl-, allyl- and benzylamines, afforded pyrazole-diazepinones 4i–x in good to excellent yields (70–98%), while reactions with ammonia gave derivatives 4a–e in substantially lower yields of 34–56%. Interestingly, tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-ones 4g,h bearing a methyl substituent in either 2- or 3-position as well as 2,3-unsubstituted pyrazole 4f were obtained in higher yields (70–91%) compared to their phenyl-substituted counterparts 4a–e.

A possible pyrazole-fused 1,4-diazepinone formation mechanism involves an amine-induced S_N2 ring-opening at the less sterically hindered site of the oxirane ring [64]. Formed primary or secondary amine rapidly reacts with carbonyl carbon of an ester group, resulting in fused intermediate which further undergoes deprotonation and alkoxy group elimination to form final tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-ones 4a–x.

To substantiate the structures of novel compounds, an unambiguous assignment of chemical shifts was carried out by investigating combined NMR spectroscopic data, i.e., ¹H,¹³C-HSQC, ¹H,¹³C-HMBC, ¹H,¹⁵N-HMBC and ¹H,¹H-NOESY. In principle, cyclisation of ethyl 1-(oxiran-2-ylmethyl)-1H-pyrazole-5-carboxylate 2a with ammonia could form two different isomers 4a and 4a′ (Figure 3). The ¹H,¹³C-HMBC experiment revealed a three-bond correlation between NH proton at δ 8.24–8.31 ppm and C-3a carbon at δ 139.4 ppm. Moreover, the same NH proton exhibited strong three-bond connectivity with tertiary C-7 carbon at 69.4 ppm. Interactions between C-4 carbon and 3-H at δ 7.16 ppm as well as 6-H_aH_b protons were observed. Strong three-bond connectivity was observed in the ¹H,¹⁵N-HMBC spectrum between 7-H proton and pyrrole-like nitrogen atom N-9 at δ −175.4 ppm. In case of putative isomer 4a′, the heteronuclear multiple bond correlations between NH proton and secondary aliphatic carbons should be observed. Furthermore, C-4 carbon would not exhibit three-bond correlation with aliphatic protons connected to a secondary carbon atom.

A brief experiment was performed with minor regioisomer 3a in order to investigate if cyclisation reaction is possible when carboxylate and oxirane fragments are distanced via an additional nitrogen atom. Ethyl 1H-pyrazole-3-carboxylate 3a was treated with either ammonia or benzyl amine; however, analysis of LC/MS and NMR data indicated that both reactions resulted in the oxirane ring opening without subsequent cyclisation.

Subsequently, we sought to investigate the reactivity of ethyl 1H-indole-2-carboxylate 5a–e and benzo[d]imidazole-2-carboxylate 5f scaffolds and derive target tetrahydro[1,4]diazepino[1,2-a]indol-1-ones and tetrahydro-1H-benzo[4,5]imidazo[1,2-a][1,4]diazepin-1-one utilizing the same straightforward 2-step approach (Scheme 2). N-Alkylation of 5a with 2-(chloromethyl)oxirane using NaH in DMF at 40 °C provided ethyl 1-(oxiran-2-ylmethyl)-1H-indole-2-carboxylate 6a in 54% yield. To increase the yield of target intermediate, several attempts to optimize reaction conditions were undertaken (

Table 2. Optimization of reaction conditions between 5a and 2-(chloromethyl)oxirane.

Entry	2-(Chloromethyl)oxirane	Base	Solvent	Temp.	Time	Yield
1	1.5 eq	1.0 eq NaH	DMF	40 °C	5 h	54%
2	1.5 eq	1.0 eq NaH	DMF	60 °C	4 h	48%
3	1.2 eq	2.0 eq K2CO3	DMF	90 °C	4 h	40%
4	1.5 eq	2.0 eq K2CO3	DMF	90 °C	4 h	63%
5	1.5 eq	1.0 eq NaH	DMSO	40 °C	6 h	59%
6	1.5 eq	3.0 eq KOH	DMF	40 °C	1 h	73%

). Unfortunately, neither elevation of reaction temperature, nor change of base or solvent have significant impact on the reaction outcome (Entries 2–5). Finally, the use of KOH base in DMF resulted not only in higher reactivity of starting 1H-indole-2-carboxylate 5a (Entry 5) but also suppressed the formation of side products. Conditions utilizing the KOH-DMF system were applied to obtain ethyl 1-(oxiran-2-ylmethyl)-1H-indole-2-carboxylates 6a–e in 39–75% yields (Scheme 2).

Interestingly, in the case benzo[d]imidazole-2-carboxylate 5f, optimized conditions using KOH were not efficient as alkylation product was not obtained, suggesting lower reactivity of the NH group of this compound. Fortunately, N-alkylation of benzo[d]imidazole-2-carboxylate 5f was accomplished under primary optimized conditions utilizing NaH-DMF at 60 °C, giving rise to target intermediate 6f in 33% yield as other alkylation conditions did not provide a better result.

In the next step, applicability of direct ring opening-cyclisation reaction was investigated. Ethyl 1-(oxiran-2-ylmethyl)-1H-indole-2-carboxylates 6a–e and ethyl 1-(oxiran-2-ylmethyl)-1H-benzo[d]imidazole-2-carboxylate (6f) were treated with either ammonia or benzylamine in methanol. Reactions proceeded in the same manner as using pyrazole counterparts and yielded 4-hydroxy-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-ones and 4-hydroxy-2,3,4,5-tetrahydro-1H-benzo[4,5]imidazo[1,2-a][1,4]diazepin-1-one 7a–f in fair to excellent (63–98%) yields, with an exception of 7g which was isolated in a mere 19% yield. In comparison, Putey et al. [32] assessed synthesis of 2,3,4,5-tetrahydro[1,4]diazepino[1,2-a]indol-1-ones in a 4-step procedure.

To expand the structural diversity and compound library of fused tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-ones and tetrahydro[1,4]diazepino[1,2-a]indol-1-ones, 5-substituted 7-hydroxy-2-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-ones 4i,n,t and 2-benzyl-4-hydroxy-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one 7f were further modified using methyl- and ethyl iodides as O-alkylating agents (Scheme 3). Reactions were carried out involving NaH as a base in DMF, where reaction temperature and time were substituent dependent, i.e., compounds bearing benzyl group at 5-position required longer reaction times and higher temperatures. Compounds 8a–f and 9a,b were obtained in 70–92% yields.

3. Materials and Methods

3.1. General

The reagents and solvents were purchased from commercial suppliers and used without further purification unless otherwise indicated. Reaction progress was monitored by thin-layer chromatography (TLC) on pre-coated ALUGRAM^®Xtra SIL G/UV₂₅₄ plates (Macherey—Nagel™, Düren, Germany). The purification of the reaction mixtures was performed using flash chromatography on a glass column, stationary phase—silica gel (high-purity grade 9385, pore size 60 Å, particle size 230–400 mesh, Merck KGaA, Darmstadt, Germany). The ¹H, ¹³C and ¹⁵N-NMR spectra were recorded in chloroform-D (CDCl₃) or dimethyl sulfoxide-d₆ (DMSO-d₆) at 25 °C on either Jeol ECA-500 (500 MHz—¹H NMR, 126 MHz—¹³C NMR) or Jeol EC2 400R (400 MHz—¹H NMR, 101 MHz—¹³C NMR) spectrometer equipped with a 5 mm Royal probe (JEOL USA, Inc., Peabody, MA, USA), or Bruker Avance III 400 spectrometer (400 MHz—¹H NMR, 101 MHz—¹³C NMR, 40 MHz—¹⁵N NMR) using a 5 mm directly detecting BBO probe (Bruker BioSpin AG, Fallanden, Switzerland). Residual solvent signals were used as internal standards, i.e., for DMSO-d₆ δ¹_H = 2.50 and δ¹³_C = 39.52, for CDCl₃ δ¹_H = 7.26 and δ¹³_C = 77.16. ¹⁵N chemical shifts were recalculated using a reference of neat external nitromethane standard (coaxial capillary). ¹⁹F NMR spectra (376 MHz) were obtained on a Bruker Avance III 400 instrument; here absolute referencing via δ ratio was used. The full and unambiguous assignments of the ¹H, ¹³C, ¹⁵N-NMR resonances were achieved using a combination of standard NMR spectroscopic techniques. The following abbreviations are used in reporting NMR data: Ph, phenyl; Ox, oxirane. Melting points were determined using the apparatus DigiMelt MPA160 (Stanford Research Systems Inc., Sunnyvale, CA, USA) or Büchi B-540 (Büchi Labortechnik AG, Flawil, Switzerland) and are provided uncorrected. The IR spectra were recorded on a Bruker TENSOR 27 (Bruker Optik GmbH, Ettlingen, Germany) or Nicolet Impact 410 (SpectraLab Scientific Inc., Markham, ON, Canada) FTIR spectrometer using pressured KBr pellets. HRMS spectra were recorded on a micrOTOF-Q III Bruker (Bruker Daltonik GmbH, Bremen, Germany) or Agilent 6230 TOF LC/MS (Agilent Technologies Inc., Santa Clara, CA, United States) spectrometer in electrospray ionization (ESI) mode. ¹H, ¹³C, ¹⁹F, and ¹H,¹⁵N-HMBC NMR spectra, as well as HRMS data of new compounds, are provided in Figures S1–S229 of the Supplementary Materials.

3.2. Synthetic Procedures

3.2.1. General Procedure for Synthesis of Starting 3(5)-Aryl-1H-pyrazole-5(3)-carboxylates (1a–h) [48,65]

To a 0.5 M solution of sodium ethoxide (1.1 eq) in ethanol, appropriate acetophenone (1 eq) and diethyl oxalate (1 eq) were added, and the resulting mixture was stirred at room temperature for 16 h in an inert atmosphere. Upon completion, the reaction mixture was quenched with 1 M HCl solution until neutral pH and extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate 15/1, v/v). Obtained ketoester (1 eq) was dissolved in a mixture of ethanol and acetic acid (7/3, v/v, 0.2 M), 55% aqueous hydrazine hydrate solution (1.1 eq) was added, and the reaction mixture was stirred at room temperature for 16 h. Subsequently, solvents were evaporated, and residue was dissolved in ethyl acetate and washed with 10% aqueous NaHCO₃ solution. Organic layer was washed again with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate/methanol gradient from 8/1/0.1 to 1/1/0.1, v/v/v) to give corresponding pyrazoles 1a–h in good yields (75–87%).

3.2.2. Synthesis of Ethyl 1-(oxiran-2-ylmethyl)-1H-pyrazole-3(5)-carboxylates (2a–h and 3a,f–h)

Appropriate pyrazole 1a–h (1 eq) was dissolved in dry dimethyl formamide (0.4 M) and NaH (1.5 eq; 60% dispersion in mineral oil) was added followed by 2-(chloromethyl)oxirane (1.5 eq). The reaction mixture was stirred at 40 °C for 1–5 h. Upon completion, the reaction mixture was concentrated to approximately 1/3 volume, diluted with ethyl acetate, and washed with brine. Organic layer was separated, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography.

Ethyl 1-(oxiran-2-ylmethyl)-3-phenyl-1H-pyrazole-5-carboxylate 2a

Purified by column chromatography on silica gel (n-hexane/ethyl acetate gradient from 10/1 to 8/1, v/v). White solid, mp 53–54 °C, 60% (3.13 g). R_f = 0.72 (n-hexane/ethyl acetate 7/3, v/v). IR (KBr) ν_max, cm⁻¹: 2981, 1721 (C=O), 1261, 1086, 1073, 764, 758, 693, 436. ¹H NMR (400 MHz, CDCl₃) δ_H ppm: 1.41 (t, J = 7.1 Hz, 3H, CH₃), 2.58–2.63 (m, 1H, Ox CH_aH_b), 2.81 (t, J = 4.4 Hz, 1H, CH_aH_b), 3.40–3.47 (m, Ox 1H, CH), 4.38 (q, J = 7.1 Hz, 2H, CH₂CH₃), 4.83 (qd, J = 14.2, 4.6 Hz, 2H, NCH₂), 7.15 (s, 1H, 4-H), 7.29–7.37 (m, 1H, Ph 4-H), 7.38–7.44 (m, 2H, Ph 3,5-H), 7.78–7.84 (m, 2H, Ph 2,6-H). ¹³C NMR (101 MHz, CDCl₃) δ_C ppm: 14.4 (CH₃), 45.8 (Ox CH₂), 50.7 (Ox CH), 53.0 (NCH₂), 61.4 (CH₂CH₃), 108.4 (C-4), 125.8 (Ph C-2,6), 128.3 (Ph C-4), 128.8 (Ph C-3,5), 132.5 (Ph C-1), 134.3 (C-5), 150.7 (C-3), 159.9 (C=O). ¹⁵N NMR (40 MHz, CDCl₃) δ_N ppm: −175.6 (N-1), −66.2 (N-2). HRMS (ESI) for C₁₅H₁₆N₂NaO₃ ([M+Na]⁺): calcd m/z 295.1053, found m/z 295.1053.

Ethyl 3-(4-fluorophenyl)-1-(oxiran-2-ylmethyl)-1H-pyrazole-5-carboxylate 2b

Purified by column chromatography on silica gel (n-hexane/ethyl acetate 8/1, v/v). White solid, mp 98–99 °C, 59% (2.04 g). R_f = 0.56 (n-hexane/ethyl acetate 7/3, v/v). IR (KBr) ν_max, cm⁻¹: 3140, 3061, 2979, 1730 (C=O), 1445, 1263, 1214, 1086, 849, 761. ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 1.33 (t, J = 7.1 Hz, 3H, CH₃), 2.48–2.51 (m, 1H, Ox CH_aH_b), 2.72 (t, J = 4.5 Hz, 1H, Ox CH_aH_b), 3.36–3.42 (m, 1H, Ox CH), 4.33 (q, J = 7.1 Hz, 2H, CH₂CH₃), 4.60 (dd, J = 14.5, 5.5 Hz, 1H, NCH_a), 4.85 (dd, J = 14.5, 3.6 Hz, 1H, NCH_b), 7.21–7.29 (m, 2H, Ph 3,5-H), 7.38 (s, 1H, 4-H), 7.86–7.95 (m, 2H, Ph 2,6-H). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 14.0 (CH₃), 44.8 (Ox CH₂), 50.2 (Ox CH), 52.8 (NCH₂), 61.1 (CH₂CH₃), 108.0 (C-4), 115.65 (d, ²J_CF = 21.6 Hz, Ph C-3,5), 127.35 (d, ³J_CF = 8.3 Hz, Ph C-2,6), 128.54 (d, ⁴J_CF = 3.0 Hz, Ph C-1), 134.1 (C-5), 148.6 (C-3), 159.0 (C=O), 162.07 (d, J_CF = 244.8 Hz, Ph C-4). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: −173.3 (N-1), −65.1 (N-2). ¹⁹F NMR (376 MHz, DMSO-d₆) δ_F ppm: −113.8 (Ph 6-F). HRMS (ESI) for C₁₅H₁₅FN₂NaO₃ ([M+Na]⁺): calcd m/z 313.0959, found m/z 313.0959.

Ethyl 3-(4-chlorophenyl)-1-(oxiran-2-ylmethyl)-1H-pyrazole-5-carboxylate 2c

Purified by column chromatography on silica gel (n-hexane/ethyl acetate gradient from 8/1 to 7/1, v/v). Pale yellow solid, mp 110–111 °C, 53% (551 mg). R_f = 0.57 (n-hexane/ethyl acetate 7/3, v/v). IR (KBr) ν_max, cm⁻¹: 3127, 2982, 2960, 1715 (C=O), 1460, 1266, 1123, 1088, 835, 766. ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 1.34 (t, J = 7.1 Hz, 3H, CH₃), 2.51–2.53 (m, 1H, Ox CH_aCH_b), 2.79 (t, J = 4.5 Hz, 1H, Ox CH_aH_b), 3.37–3.43 (m, 1H, Ox CH), 4.34 (q, J = 7.1 Hz, 2H, CH₂CH₃), 4.61 (dd, J = 14.5, 5.6 Hz, 1H, NCH_a), 4.86 (dd, J = 14.4, 3.6 Hz, 1H, NCH_b), 7.42 (s, 1H, 4-H), 7.45–7.51 (m, 2H, Ph 3,5-H), 7.86–7.93 (m, 2H, Ph 2,6-H). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 14.0 (CH₃), 44.8 (Ox CH₂), 50.1 (Ox CH), 52.9 (NCH₂), 61.1 (CH₂CH₃), 108.3 (C-4), 127.0 (Ph C-2,6), 128.8 (Ph C-3,5), 130.8 (Ph C-1), 132.7 (Ph C-4), 134.2 (C-5), 148.3 (C-3), 159.0 (C=O). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: −172.3 (N-1), −65.2 (N-2). HRMS (ESI) for C₁₅H₁₅ClN₂NaO₃ ([M+Na]⁺): calcd m/z 329.0663, found m/z 329.0663.

Ethyl 3-(4-bromophenyl)-1-(oxiran-2-ylmethyl)-1H-pyrazole-5-carboxylate 2d

Purified by column chromatography on silica gel (n-hexane/ethyl acetate gradient from 10/1 to 8/1, v/v). White solid, mp 120–121 °C, 58% (1.88 g). R_f = 0.60 (n-hexane/ethyl acetate 7/3, v/v). IR (KBr) ν_max, cm⁻¹: 3127, 2979, 1716 (C=O), 1459, 1436, 1267, 1123, 1092, 832, 766. ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 1.33 (t, J = 7.1 Hz, 3H, CH₃), 2.48–2.52 (m, 1H, Ox CH_aH_b), 2.78 (t, J = 4.5 Hz, 1H, Ox CH_aH_b), 3.37–3.42 (m, 1H, Ox CH), 4.33 (q, J = 7.1 Hz, 2H, CH₂CH₃), 4.60 (dd, J = 14.5, 5.6 Hz, 1H, NCH_a), 4.86 (dd, J = 14.5, 3.6 Hz, 1H, NCH_b), 7.43 (s, 1H, 4-H), 7.58–7.64 (m, 2H, Ph 3,5-H), 7.79–7.86 (m, 2H, Ph 2,6-H). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 14.0 (CH₃), 44.8 (Ox CH₂), 50.1 (Ox CH), 52.9 (NCH₂), 61.1 (CH₂CH₃), 108.3 (C-4), 121.3 (Ph C-4), 127.3 (Ph C-2,6), 131.2 (Ph C-3,5), 131.7 (Ph C-1), 134.2 (C-5), 148.4 (C-3), 159.0 (C=O). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: −172.3 (N-1), −64.8 (N-2). HRMS (ESI) for C₁₅H₁₅BrN₂NaO₃ ([M+Na]⁺): calcd m/z 373.0158, found m/z 373.0158 and 375.0136.

Ethyl 3-(4-methoxyphenyl)-1-(oxiran-2-ylmethyl)-1H-pyrazole-5-carboxylate 2e

Purified by column chromatography on silica gel (n-hexane/ethyl acetate 8/1, v/v). White solid, mp 75–76 °C, 61% (1.9 g). R_f = 0.49 (n-hexane/ethyl acetate 7/2 v/v). IR (KBr) ν_max, cm⁻¹: 3139, 2975, 2938, 2836, 1726 (C=O), 1447, 1086, 1029, 846, 758. ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 1.33 (t, J = 7.1 Hz, 3H, CH₃), 2.47–2.50 (m, 1H, Ox CH_aCH_b), 2.78 (t, J = 4.5 Hz, 1H, Ox CH_aH_b), 3.35–3.42 (m, 1H, Ox CH), 3.79 (s, 3H, OCH₃), 4.33 (q, J = 7.1 Hz, 2H, CH₂CH₃), 4.59 (dd, J = 14.5, 5.5 Hz, 1H, NCH_a), 4.84 (dd, J = 14.4, 3.5 Hz, 1H, NCH_b), 6.93–7.02 (m, 2H, Ph 3,5-H), 7.30 (s, 1H, 4-H), 7.75–7.83 (m, 2H, Ph 2,6-H). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 14.1 (CH₃), 44.8 (Ox CH₂), 50.2 (Ox CH), 52.7 (NCH₂), 55.2 (OCH₃), 61.0 (CH₂CH₃), 107.5 (C-4), 114.2 (Ph C-3,5), 124.6 (Ph C-1), 126.6 (Ph C-2,6), 133.9 (C-5), 149.4 (C-3), 159.1 (C=O), 159.3 (Ph C-4). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: −174.5 (N-1) −67.0 (N-2). HRMS (ESI) for C₁₆H₁₈N₂NaO₄ ([M+Na]⁺): calcd m/z 325.1159, found m/z 325.1159.

Ethyl 1-(oxiran-2-ylmethyl)-1H-pyrazole-5-carboxylate 2f

Purified by column chromatography on silica gel (n-hexane/ethyl acetate 4/1, v/v). Colorless liquid, 21% (30 mg). R_f = 0.57 (n-hexane/ethyl acetate 2/1, v/v). IR (KBr) ν_max, cm⁻¹: 2985, 1722 (C=O), 1518, 1312, 1254, 1121, 1105, 1039, 765. ¹H NMR (400 MHz, CDCl₃) δ_H ppm: 1.39 (t, J = 7.1 Hz, 3H, CH₃), 2.54–2.56 (m, 1H, Ox CH_aH_b), 2.80 (t, J = 4.4 Hz, 1H, Ox CH_aH_b), 3.37–3.40 (m, 1H, Ox CH), 4.36 (q, J = 7.1 Hz, 2H, CH₂CH₃), 4,73 (dd, J = 14.2, 5.2 Hz, 1H, NCH_aH_b), 4.86 (dd, J = 14.2, 4.2 Hz, 1H, NCH_aH_b), 6.86 (d, J = 1.5 Hz, 1H, 4-H), 7.53 (d, J = 1.4 Hz, 1H, 3-H). ¹³C NMR (101 MHz, CDCl₃) δ_C ppm: 14.3 (CH₃), 45.8 (Ox CH₂), 50.7 (Ox CH), 53.0 (NCH₂), 61.3 (CH₂CH₃), 111.6 (C-4), 133.0 (C-5), 138.8 (C-3), 159.9 (COO). ¹⁵N NMR (40 MHz, CDCl₃) δ_N ppm: –173.5 (N-1), –60.2 (N-2). HRMS (ESI) for C₉H₁₃N₂O₃ ([M+H]⁺): calcd m/z 197.0921, found m/z 197.0916.

Ethyl 4-methyl-1-(oxiran-2-ylmethyl)-1H-pyrazole-5-carboxylate 2g

Purified by column chromatography on silica gel (n-hexane/ethyl acetate 4/1, v/v). Colorless liquid, 26% (36 mg). R_f = 0.47 (n-hexane/ethyl acetate 2/1, v/v). IR (KBr) ν_max, cm⁻¹: 2983, 1716 (C=O), 1449, 1277, 1113, 1042. ¹H NMR (400 MHz, CDCl₃) δ_H ppm: 1.40 (t, J = 7.1 Hz, 3H, CH₂CH₃), 2.26 (s, 3H, 4-CH₃), 2.52–2.54 (m, 1H, Ox CH_aH_b), 2.78 (t, J = 4.4 Hz, 1H, Ox CH_aH_b), 3.34–3.37 (m, 1H, Ox CH), 4.38 (q, J = 7.1 Hz, 2H, CH₂CH₃), 4.68 (dd, J = 14.3, 5.1 Hz, 1H, NCH_aH_b), 4.80 (dd, J = 14.3, 4.1 Hz, 1H, NCH_aH_b), 7.36 (s, 1H, 3-H). ¹³C NMR (101 MHz, CDCl₃) δ_C ppm: 10.9 (4-CH₃), 14.3 (CH₂CH₃), 45.7 (Ox CH₂), 50.8 (Ox CH), 53.5 (NCH₂), 61.0 (CH₂CH₃), 123.1 (C-4), 130.1 (C-5), 140.2 (C-3), 160.7 (COO). ¹⁵N NMR (40 MHz, CDCl₃) δ_N ppm: –174.6 (N-1), –63.9 (N-2). HRMS (ESI) for C₁₀H₁₅N₂O₃ ([M+H]⁺): calcd m/z 211.1077, found m/z 211.1067.

Ethyl 3-methyl-1-(oxiran-2-ylmethyl)-1H-pyrazole-5-carboxylate 2h

Purified by column chromatography on silica gel (n-hexane/ethyl acetate 4/1, v/v). Colorless liquid, 24% (32 mg). R_f = 0.42 (n-hexane/ethyl acetate 2/1, v/v). IR (KBr) ν_max, cm⁻¹: 2962, 2909, 1722 (C=O), 1461, 1262, 1085, 767. ¹H NMR (400 MHz, CDCl₃) δ_H ppm: 1.37 (t, J = 7.1 Hz, 3H, CH₂CH₃), 2.28 (s, 3H, 3-CH₃), 2.55–2.57 (m, 1H, Ox CH_aH_b), 2.79 (t, J = 4.4 Hz, 1H, Ox CH_aH_b), 3.34–3.38 (m, 1H, Ox CH), 4.33 (q, J = 7.1 Hz, 2H, CH₂CH₃), 4.63 (dd, J = 14.3, 5.2 Hz, 1H, NCH_aH_b), 4.78 (dd, J = 14.3, 4.1 Hz, 1H, NCH_aH_b), 6.64 (s, 1H, 4-H). ¹³C NMR (101 MHz, CDCl₃) δ_C ppm: 13.5 (3-CH₃), 14.4 (CH₂CH₃), 45.8 (Ox CH₂), 50.8 (Ox CH), 52.7 (NCH₂), 61.2 (CH₂CH₃), 111.0 (C-4), 133.4 (C-5), 148.0 (C-3), 160.0 (COO). ¹⁵N NMR (40 MHz, CDCl₃) δ_N ppm: –178.6 (N-1), –64.1 (N-2). HRMS (ESI) for C₁₀H₁₅N₂O₃ ([M+H]⁺): calcd m/z 211.1077, found m/z 211.1075.

Ethyl 1-(oxiran-2-ylmethyl)-5-phenyl-1H-pyrazole-3-carboxylate 3a

Purified by column chromatography on silica gel (n-hexane/ethyl acetate gradient from 8/1 to 1/1, v/v). Colorless resin, 56% (20 mg). R_f = 0.37 (n-hexane/ethyl acetate 1/1, v/v). IR (KBr) ν_max, cm⁻¹: 2986, 1729 (C=O), 1214, 765, 701. ¹H NMR (400 MHz, CDCl₃) δ_H ppm: 1.41 (t, J = 7.1 Hz, 3H, CH₃), 2.49–2.53 (m, 1H, Ox CH_aH_b), 2.81 (t, J = 4.3 Hz, 1H, Ox CH_aH_b), 3.40–3.45 (m, 1H, Ox CH), 4.26–4.47 (m, 4H, CH₂CH₃, NCH₂), 6.84 (s, 1H, 4-H), 7.42–7.51 (m, 5H, Ph 2,3,4,5,6-H). ¹³C NMR (101 MHz, CDCl₃) δ_C ppm: 14.6 (CH₃), 46.0 (Ox CH₂), 50.7 (Ox CH), 51.6 (NCH₂), 61.2 (CH₂CH₃), 109.2 (C-4), 129.0 (Ph C-1,2,6), 129.4 (Ph C-4), 129.5 (Ph C-3,5), 143.7 (C-3), 146.2 (C-5), 162.5 (C=O). ¹⁵N NMR (40 MHz, CDCl₃) δ_N ppm: −174.4 (N-1), −70.0 (N-2). HRMS (ESI) for C₁₅H₁₆N₂NaO₃ ([M+Na]⁺): calcd m/z 295.1053, found m/z 295.1051.

Ethyl 1-(oxiran-2-ylmethyl)-1H-pyrazole-3-carboxylate 3f

Purified by column chromatography on silica gel (n-hexane/ethyl acetate gradient from 4/1 to 2/1, v/v). Colorless liquid, 28% (39 mg). R_f = 0.49 (n-hexane/ethyl acetate 1/2, v/v). IR (KBr) ν_max, cm⁻¹: 2986, 1721 (C=O), 1375, 1237, 1173, 1154, 1027, 765. ¹H NMR (400 MHz, CDCl₃) δ_H ppm: 1.40 (t, J = 7.1, 3H, CH₃), 2.49–2.51 (m, 1H, Ox CH_aH_b), 2.87 (t, J = 4.2 Hz, 1H, Ox CH_aH_b), 3.36–3.38 (m, 1H, Ox CH), 4.21 (dd, J = 14.7, 6.0 Hz, 1H, NCH_aH_b), 4.41 (q, J = 7.1 Hz, 2H, CH₂CH₃), 4.62 (dd, J = 14.7, 2.6 Hz, 1H, NCH_aH_b), 6.84 (d, J = 2.1 Hz, 1H, 4-H), 7.53 (d, J = 2.1 Hz, 1H, 5-H). ¹³C NMR (101 MHz, CDCl₃) δ_C ppm: 14.5 (CH₃), 45.5 (Ox CH₂), 50.4 (Ox CH), 54.6 (NCH₂), 61.2 (CH₂CH₃), 109.5 (C-4), 131.7 (C-5), 144.2 (C-3), 162.4 (COO). ¹⁵N NMR (40 MHz, CDCl₃) δ_N ppm: –171.8 (N-1), –68.9 (N-2). HRMS (ESI) for C₉H₁₃N₂O₃ ([M+H]⁺): calcd m/z 197.0921, found m/z 197.0915.

Ethyl 4-methyl-1-(oxiran-2-ylmethyl)-1H-pyrazole-3-carboxylate 3g

Purified by column chromatography on silica gel (n-hexane/ethyl acetate gradient from 4/1 to 2/1, v/v). Colorless liquid, 35% (48 mg). R_f = 0.47 (n-hexane/ethyl acetate 1/2, v/v). IR (KBr) ν_max, cm⁻¹: 2983, 2932, 1716 (C=O), 1448, 1367, 1254, 1108. ¹H NMR (400 MHz, CDCl₃) δ_H ppm: 1.41 (t, J = 7.1 Hz, 3H, CH₂CH₃), 2.29 (s, 3H, 4-CH₃), 2.49–2.51 (m, 1H, Ox CH_aH_b), 2.86 (t, J = 4.2 Hz, 1H, Ox CH_aH_b), 3.33–3.35 (m, 1H, Ox CH), 4.13 (dd, J = 14.7, 6.0 Hz, 1H, NCH_aH_b), 4.41 (q, J = 7.1 Hz, 2H, CH₂CH₃), 4.55 (dd, J = 14.7, 2.5 Hz, 1H, NCH_aH_b), 7.33 (s, 1H, 5-H). ¹³C NMR (101 MHz, CDCl₃) δ_C ppm: 9.9 (4-CH₃), 14.5 (CH₂CH₃), 45.4 (Ox CH₂), 50.5 (Ox CH), 54.5 (NCH₂), 60.8 (CH₂CH₃), 121.5 (C-4), 131.0 (C-5), 141.4 (C-3), 163.0 (COO). ¹⁵N NMR (40 MHz, CDCl₃) δ_N ppm: –175.7 (N-1), –69.2 (N-2). HRMS (ESI) for C₁₀H₁₅N₂O₃ ([M+H]⁺): calcd m/z 211.1077, found m/z 211.1072.

Ethyl 5-methyl-1-(oxiran-2-ylmethyl)-1H-pyrazole-3-carboxylate 3h

Purified by column chromatography on silica gel (n-hexane/ethyl acetate gradient from 4/1 to 2/1, v/v). White solid, mp 31–33 °C, 29% (40 mg). R_f = 0.47 (n-hexane/ethyl acetate 1/2, v/v). IR (KBr) ν_max, cm⁻¹: 2985, 1721 (C=O), 1446, 1386, 1228, 1032, 780. ¹H NMR (400 MHz, CDCl₃) δ_H ppm: 1.39 (t, J = 7.1 Hz, 3H, CH₂CH₃), 2.34 (s, 3H, 5-CH₃), 2.47–2.49 (m, 1H, Ox CH_aH_b), 2.82 (t, J = 4.3 Hz, 1H, Ox CH_aH_b), 3.33–3.37 (m, 1H, Ox CH), 4.21 (dd, J = 15.0, 5.2 Hz, 1H, NCH_aH_b), 4.39 (q, J = 7.1 Hz, 2H, CH₂CH₃) 4.53 (dd, J = 15.0, 2.4 Hz, 1H, NCH_aH_b), 6.57 (s, 1H, 4-H). ¹³C NMR (101 MHz, CDCl₃) δ_C ppm: 11.4 (5-CH₃), 14.5 (CH₂CH₃), 45.3 (Ox CH₂), 50.9 (Ox CH), 51.4 (NCH₂), 61.0 (CH₂CH₃), 108.6 (C-4), 141.3 (C-5), 143.1 (C-3), 162.6 (COO). ¹⁵N NMR (40 MHz, CDCl₃) δ_N ppm: –173.3 (N-1), –70.8 (N-2). HRMS (ESI) for C₁₀H₁₅N₂O₃ ([M+H]⁺): calcd m/z 211.1077, found m/z 211.1070.

3.2.3. Synthesis of 7-Hydroxy-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-ones (4a–x)

Procedure a. Carboxylate 2a–h (1 eq) was dissolved in 2M ammonia (30 eq) solution in methanol, sealed in a pressure tube and stirred at 70 °C for 5–18 h. After completion, excess of ammonia in methanol was evaporated under reduced pressure. The residue was purified by column chromatography.

Procedure b. To a solution of carboxylate 2a–e (1 eq) in methanol (5 M), appropriate primary amine (3 eq) was added, the reaction mixture was sealed in a pressure tube and was stirred at 70 °C for 7 h. After completion, the reaction mixture was poured into water and extracted with ethyl acetate. Combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography.

7-Hydroxy-2-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4a

Purified by column chromatography on silica gel (gradient from n-hexane/ethyl acetate/methanol gradient from 1/9/0 to 1/15/0.5, v/v). White solid, decomp. 246 °C, procedure a −34% (27 mg). R_f = 0.40 (dichloromethane/methanol 100/5, v/v). IR (KBr) ν_max, cm⁻¹: 3270, 3196, 3074, 2925, 1681 (C=O), 1460, 1440, 771, 752, 685. ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 2.85–2.96 (m, 1H, 6-H_a), 3.21–3.30 (m, 1H, 6-H_b), 4.20–4.33 (m, 2H, 7-H, 8-H_a), 4.54 (dd, J = 13.8, 4.8 Hz, 1H, 8-H_b), 5.49 (d, J = 3.8 Hz, 1H, OH), 7.16 (s, 1H, 3-H), 7.28–7.35 (m, 1H, Ph 4-H), 7.36–7.45 (m, 2H, Ph 3,5-H), 7.80–7.88 (m, 2H, Ph 2,6-H), 8.24–8.31 (m, 1H, NH). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 45.5 (C-6), 56.2 (C-8), 69.4 (C-7), 105.8 (C-3), 125.1 (Ph C-2,6), 127.8 (Ph C-4), 128.7 (Ph C-3,5), 132.5 (Ph C-1), 139.4 (C-3a), 149.0 (C-2), 163.2 (C-4). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: −270.4 (N-5), −175.4 (N-9), −73.6 (N-1). HRMS (ESI) for C₁₃H₁₃N₃NaO₂ ([M+Na]⁺): calcd m/z 266.0900, found m/z 266.0900.

2-(4-Fluorophenyl)-7-hydroxy-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4b

Purified by column chromatography on silica gel (n-hexane/ethyl acetate/methanol gradient from 1/9/0 to 1/15/0.5, v/v). Pale yellow solid, decomp. 216 °C, procedure a −56% (86 mg). R_f = 0.38 (dichloromethane/methanol 100/5, v/v). IR (KBr) ν_max, cm⁻¹: 3305, 3206, 3071, 2947, 2923, 1681, 1457, 1442, 841, 809. ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 3.74 (dt, J = 12.2, 5.8 Hz, 1H, 6-H_a), 4.09 (dt, J = 14.5, 5.4 Hz, 1H, 6-H_b), 5.02–5.15 (m, 2H, 7-H, 8-H_a), 5.36 (dd, J = 13.9, 5.0 Hz, 1H, 8-H_b), 8.00 (s, 1H, 3-H), 8.04–8.11 (m, 2H, Ph 3,5-H), 8.67–8.75 (m, 2H, Ph 2,6-H), 9.12–9.18 (m, 1H, NH). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 45.5 (C-6), 56.2 (C-8), 69.3 (C-7), 105.8 (C-3), 115.59 (d, ²J_CF = 21.5 Hz, Ph C-3,5), 127.12 (d, ³J_CF = 8.2 Hz, Ph C-2,6), 129.10 (d, ⁴J_CF = 3.0 Hz, Ph C-1), 139.6 (C-3a), 148.2 (C-2), 161.83 (d, J_CF = 244.3 Hz, Ph C-4), 163.1 (C-4). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: −270.5 (N-5), −175.3 (N-9), −73.8 (N-1). ¹⁹F NMR (376 MHz, DMSO-d₆) δ_F ppm: −114.4 (Ph 6-F). HRMS (ESI) for C₁₃H₁₂FN₃NaO₂ ([M+Na]⁺): calcd m/z 284.0806, found m/z 284.0806.

2-(4-Chlorophenyl)-7-hydroxy-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4c

Purified by column chromatography on silica gel (n-hexane/ethyl acetate/methanol gradient from 1/9/0 to 1/20/0.5, v/v). White solid, decomp. 249 °C, procedure a −48% (59 mg). R_f = 0.38 (dichloromethane/methanol 100/5, v/v). IR (KBr) ν_max, cm⁻¹: 3297, 3210, 3080, 2917, 1683 (C=O), 1451, 1435, 1089, 834, 809. ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 2.86–2.95 (m, 1H, 6-H_a), 3.21–3.30 (m, 1H, 6-H_b), 4.19–4.31 (m, 2H, 7-H, 8-H_a), 4.54 (dd, J = 13.9, 4.9 Hz, 1H, 8-H_b), 5.53 (br s, 1H, OH), 7.20 (s, 1H, 3-H), 7.43–7.50 (m, 2H, Ph 3,5-H), 7.82–7.91 (m, 2H, Ph 2,6-H), 8.28–8.33 (m, 1H, NH). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 45.5 (C-6), 56.3 (C-8), 69.3 (C-7), 106.0 (C-3), 126.8 (Ph C-2,6), 128.8 (Ph C-3,5), 131.4 (Ph C-1), 132.3 (Ph C-4), 139.6 (C-3a), 147.9 (C-2), 163.0 (C-4). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: −270.4 (N-5), −174.0 (N-9), −69.7 (N-1). HRMS (ESI) for C₁₃H₁₂ClN₃NaO₂ ([M+Na]⁺): calcd m/z 300.0510, found m/z 300.0510.

2-(4-Bromophenyl)-7-hydroxy-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4d

Purified by column chromatography on silica gel (n-hexane/ethyl acetate/methanol gradient from 1/9/0 to 1/12/0.5, v/v). White solid, decomp. 230 °C, procedure a −51% (50 mg). R_f = 0.40 (dichloromethane/methanol 100/5, v/v). IR (KBr) ν_max, cm⁻¹: 3292, 3214, 3079, 1680 (C=O), 1455 and 1434 (doublet), 1071, 991, 922, 816 and 807 (doublet). ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 2.90 (dt, J = 12.2, 5.8 Hz, 1H, 6-H_a), 3.26 (dt, J = 14.4, 5.3 Hz, 1H, 6-H_b), 4.19–4.33 (m, 2H, 7-H, 8-H_a), 4.54 (dd, J = 13.9, 4.9 Hz, 1H, 8-H_b), 5.49 (d, J = 41 Hz, 1H, OH), 7.20 (s, 1H, 3-H), 7.57–7.64 (m, 2H, Ph 3,5-H), 7.76–7.84 (m, 2H, Ph 2,6-H), 8.29 (t, J = 5.1 Hz, 1H, NH). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 45.5 (C-6), 56.3 (C-8), 69.3 (C-7), 106.0 (C-3), 120.8 (Ph C-4), 127.1 (Ph C-2,6), 131.7 (Ph C-3,5), 131.8 (Ph C-1), 139.6 (C-3a), 148.0 (C-2), 163.0 (C-4). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: −173.4 (N-9), −72.7 (N-1). HRMS (ESI) for C₁₃H₁₂BrN₃NaO₂ ([M+Na]⁺): calcd m/z 344.0005, found m/z 344.0005 and 345.9983.

7-Hydroxy-2-(4-methoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4e

Purified by column chromatography on silica gel (n-hexane/ethyl acetate/methanol gradient from 1/9/0 to 1/10/0.5, v/v). White solid, decomp. 239 °C, procedure a −40% (38 mg). R_f = 0.41 (dichloromethane/methanol 100/5, v/v). IR (KBr) ν_max, cm⁻¹: 3200, 3078, 2928, 1681 (C=O), 1463, 1447, 1251, 1176, 1027, 821. ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 2.91 (dt, J = 11.9, 5.7 Hz, 1H, 6-H_a), 3.25 (dt, J = 14.6, 5.4 Hz, 1H, 6-H_b), 3.78 (s, 3H, OCH₃), 4.18–4.32 (m, 2H, 7-H, 8-H_a), 4.51 (dd, J = 14.1, 5.1 Hz, 1H, 8-H_b), 5.48 (d, J = 4.2 Hz, 1H, OH), 6.94–7.00 (m, 2H, Ph 3,5-H), 7.07 (s, 1H, 3-H), 7.73–7.79 (m, 2H, Ph 2,6-H), 8.22–8.27 (m, 1H, NH). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 45.6 (C-6), 55.1 (CH₃), 56.1 (C-8), 69.4 (C-7), 105.2 (C-3), 114.1 (Ph C-3,5), 125.2 (Ph C-1), 126.4 (Ph C-2,6), 139.3 (C-3a), 149.0 (C-3), 156.0 (Ph C-4), 163.2 (C-4). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: −270.1 (N-5), −176.5 (N-9), −74.9 (N-1). HRMS (ESI) for C₁₄H₁₅N₃NaO₃ ([M+Na]⁺): calcd m/z 296.1006, found m/z 296.1006.

7-Hydroxy-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4f

Purified by column chromatography on silica gel (dichloromethane/methanol 100/5, v/v). White solid, decomp. 195 °C, procedure a −89% (76 mg). R_f = 0.41 (dichloromethane/methanol 9/1, v/v). IR (KBr) ν_max, cm⁻¹: 3210, 3127, 3081, 2933, 1685 (C=O), 1387, 1351, 1182, 825. ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 2.81–2.87 (m, 1H, 6-H_a), 3.16–3.22 (m, 1H, 6-H_b), 4.18 (dd, J = 14.0, 4.3 Hz, 1H, 8-H_a), 4.21–4.27 (m, 1H, 7-H), 4.48 (dd, J = 14.0, 5.1 Hz, 1H, 8-H_b), 5.44 (d, J = 4.0 Hz, 1H, OH), 6.66 (d, J = 0.7 Hz, 1H, 3-H), 7.47 (d, J = 0.6 Hz, 1H, 2-H), 8.22 (s, 1H, NH). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 45.6 (C-6), 55.9 (C-8), 69.4 (C-7), 108.8 (C-3), 137.79 (C-3a), 137.83 (C-2), 163.4 (C-4). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: –271.1 (N-5), –173.3 (N-9), –66.0 (N-1). HRMS (ESI) for C₇H₁₀N₃O₂ ([M+H]⁺): calcd m/z 168.0768, found m/z 168.0763.

7-Hydroxy-3-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4g

Purified by column chromatography on silica gel (dichloromethane/methanol 100/5, v/v). White solid, decomp. 213 °C, procedure a −77% (67 mg). R_f = 0.45 (dichloromethane/methanol 9/1, v/v). IR (KBr) ν_max, cm⁻¹: 3301, 3203, 3078, 2932, 1678 (C=O), 1382, 1320, 1247, 1099, 922. ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 2.10 (s, 3H, CH₃), 2.77–2.84 (m, 1H, 6-H_a), 3.12–3.19 (m, 1H, 6-H_b), 4.09 (dd, J = 14.2, 4.2 Hz, 1H, 8-H_a), 4.17–4.23 (m, 1H, 7-H), 4.40 (dd, J = 14.1, 5.4 Hz, 1H, 8-H_b), 5.39 (d, J = 4.1 Hz, 1H, OH), 7.29 (s, 1H, 2-H), 8.14 (s, 1H, NH). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 8.7 (CH₃), 45.5 (C-6), 55.7 (C-8), 69.7 (C-7), 119.4 (C-3), 133.8 (C-3a), 138.4 (C-2), 164.0 (COO). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: –270.3 (N-5), –176.2 (N-9), –69.1 (N-1). HRMS (ESI) for C₈H₁₂N₃O₂ ([M+H]⁺): calcd m/z 182.0924, found m/z 182.0923.

7-Hydroxy-2-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4h

Purified by column chromatography on silica gel (dichloromethane/methanol 100/5, v/v). White solid, decomp. 232 °C, procedure a −90% (78 mg). R_f = 0.44 (dichloromethane/methanol 9/1, v/v). IR (KBr) ν_max, cm⁻¹: 3254, 3144, 2936, 1689 (C=O), 1635, 1464, 1453, 1135, 1054, 758. ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 2.16 (s, 1H, CH₃), 2.82–2.89 (m, 1H, 6-H_a), 3.15–3.21 (m, 1H, 6-H_b), 4.08 (dd, J = 14.2, 4.4 Hz, 1H, 8-H_a), 4.17–4.24 (m, 1H, 7-H), 4.38 (dd, J = 14.2, 5.4 Hz, 1H, 8-H_b), 5.40 (d, J = 4.1 Hz, 1H, OH), 6.43 (s, 1H, 3-H), 8.15 (s, 1H, NH). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 13.0 (CH₃), 45.6 (C-6), 55.5 (C-8), 69.5 (C-7), 108.1 (C-3), 138.4 (C-3a), 146.1 (C-2), 163.4 (COO). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: –271.6 (N-5), –178.8 (N-9), –68.9 (N-1). HRMS (ESI) for C₈H₁₂N₃O₂ ([M+H]⁺): calcd m/z 182.0924, found m/z 182.0923.

7-Hydroxy-5-(2-methoxyethyl)-2-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4i

Purified by column chromatography on silica gel (n-hexane/ethyl acetate 1/9, v/v). White solid, mp 134–135 °C, procedure b −81% (99 mg). R_f = 0.40 (ethyl acetate). IR (KBr) ν_max, cm⁻¹: 3274, 3135, 2932, 1651 (C=O), 1435, 1296, 1177, 1113, 764, 691. ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 3.15 (dd, J = 15.0, 7.5 Hz, 1H, 5-CH_a), 3.29 (s, 3H, CH₃), 3.41–3.56 (m, 4H, 5-CH_b, CH₂O, 6-H_a), 3.89 (dt, J = 13.5, 5.2 Hz, 1H, 6-H_b), 4.24 (dd, J = 14.1, 3.2 Hz, 1H, 8-H_a), 4.35–4.42 (m, 1H, 7-H), 4.47 (dd, J = 14.1, 5.1 Hz, 1H, 8-H_b), 5.52 (d, J = 4.3 Hz, 1H, OH), 7.17 (s, 1H, 3-H), 7.28–7.34 (m, 1H, Ph 4-H), 7.37–7.45 (m, 2H, Ph 3,5-H), 7.81–7.86 (m, 2H, Ph 2,6-H). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 46.8 (C-6), 52.8 (5-CH₂), 55.9 (C-8), 58.0 (CH₃), 69.5 (C-7), 69.9 (CH₂O), 105.4 (C-3), 125.1 (Ph C-2,6), 127.8 (Ph C-4), 128.7 (Ph C-3,5), 132.5 (Ph C-1), 139.3 (C-3a), 149.0 (C-2), 161.6 (C-4). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: −264.8 (N-5), −175.6 (N-9), −73.7 (N-1). HRMS (ESI) for C₁₆H₁₉N₃NaO₃ ([M+Na]⁺): calcd m/z 324.1319, found m/z 324.1319.

2-(4-Fluorophenyl)-7-hydroxy-5-(2-methoxyethyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4j

Purified by column chromatography on silica gel (n-hexane/ethyl acetate gradient from 4/1 to 1/5, v/v). White solid, mp 133–134 °C, procedure b −84% (285 mg). R_f = 0.46 (ethyl acetate). IR (KBr) ν_max, cm⁻¹: 3299, 2941, 2903, 2819, 1620, 1471, 1215, 1113, 827, 806. ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 3.14 (dd, J = 15.0, 7.5 Hz, 1H, 6-H_a), 3.28 (s, 3H, CH₃), 3.39–3.57 (m, 4H, 5-CH_a, 6-H_b, CH₂O), 3.89 (dt, J = 10.6, 5.0 Hz, 1H, 5-CH_b), 4.23 (dd, J = 14.1, 2.6 Hz, 1H, 8-H_a), 4.34–4.50 (m, 2H, 7-H, 8-H_b), 5.52 (d, J = 3.9 Hz, 1H, OH), 7.17 (s, 1H, 3-H), 7.20–7.28 (m, 2H, Ph 3,5-H), 7.84–7.92 (m, 5.9 Hz, 2H, Ph 2,6-H). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 46.8 (5-CH₂), 52.8 (C-6), 55.9 (C-8), 58.0 (CH₃), 69.5 (C-7), 69.9 (CH₂O), 105.4 (C-3), 115.59 (d, ²J_CF = 21.5 Hz, Ph C-3,5), 127.09 (d, ³J_CF = 8.2 Hz, Ph C-2,6), 129.1 (d, ⁴J_CF = 3.0 Hz, Ph C-1), 139.4 (C-3a), 148.1 (C-2), 161.5 (C-4), 161.82 (d, J_CF = 244.3 Hz, Ph C-4). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: −264.6 (N-5), −175.6 (N-9), −75.2 (N-1). ¹⁹F NMR (376 MHz, DMSO-d₆) δ_F ppm: −114.4 (1F, m, Ph 6-F). HRMS (ESI) for C₁₆H₁₈FN₃NaO₃ ([M+Na]⁺): calcd m/z 342.1224, found m/z 342.1224.

2-(4-Chlorophenyl)-7-hydroxy-5-(2-methoxyethyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4k

Purified by column chromatography on silica gel (n-hexane/ethyl acetate gradient from 4/1 to 1/9, v/v). Pale pink solid, mp 148–149 °C, procedure b −98% (221 mg). R_f = 0.41 (ethyl acetate). IR (KBr) ν_max, cm⁻¹: 3300, 2941, 2877, 1623 (C=O), 1469, 1400, 1111, 1068, 826, 756. ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 3.14 (dd, J = 14.9, 7.4 Hz, 1H, 6-H_a), 3.29 (s, 3H, CH₃), 3.40–3.58 (m, 4H, 5-CH_a, 6-H_b, CH₂O), 3.84–3.94 (m, 1H, 5-CH_b), 4.24 (dd, J = 14.1, 2.5 Hz, 1H, 8-H_a), 4.35–4.51 (m, 2H, 7-H, 8-H_b), 5.53 (d, J = 3.8 Hz, 1H, OH), 7.21 (s, 1H, 3-H), 7.37–7.54 (m, 2H, Ph 3,5-H), 7.77–7.95 (m, 2H, Ph 2,6-H). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 46.8 (5-CH₂), 52.8 (C-6), 56.0 (C-8), 58.0 (CH₃), 69.5 (C-7), 69.9 (CH₂O), 105.7 (C-3), 126.8 (Ph C-2,6), 128.8 (Ph C-3,5), 131.4 (Ph C-1), 132.3 (Ph C-4), 139.5 (C-3a), 147.9 (C-2), 161.4 (C-4). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: −264.3 (N-5), −174.7 (N-9), −74.3 (N-1). HRMS (ESI) for C₁₆H₁₈ClN₃NaO₃ ([M+Na]⁺): calcd m/z 358.0929, found m/z 358.0929.

2-(4-Bromophenyl)-7-hydroxy-5-(2-methoxyethyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4l

Purified by column chromatography on silica gel (n-hexane/ethyl acetate gradient from 3/1 to 1/9, v/v). White solid, mp 143–144 °C, procedure b −84% (339 mg). R_f = 0.43 (ethyl acetate). IR (KBr) ν_max, cm⁻¹: 3292, 2943, 2876, 1621 (C=O), 1545, 1467, 1107, 1070, 1007, 812. ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 3.14 (dd, J = 15.0, 7.6 Hz, 1H, 6-H_a), 3.28 (s, 3H, CH₃), 3.40–3.57 (m, 4H, 6-H_b, NCH_a, CH₂O), 3.89 (dt, J = 10.6, 5.1 Hz, 1H, NCH_b), 4.23 (dd, J = 14.1, 2.9 Hz, 1H, 8-H_a), 4.35–4.42 (m, 1H, 7-H), 4.47 (dd, J = 14.1, 5.0 Hz, 1H, 8-H_b), 5.53 (d, J = 3.2 Hz, 1H, OH), 7.21 (s, 1H, 3-H), 7.56–7.63 (m, 2H, Ph 3,5-H), 7.76–7.83 (m, 2H, Ph 2,6-H). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 46.8 (NCH₂), 52.8 (C-6), 56.0 (C-8), 58.0 (CH₃), 69.5 (7-H), 69.9 (CH₂O), 105.6 (C-3), 120.8 (Ph C-4), 127.1 (Ph C-2,6), 131.7 (Ph C-3,5), 131.8 (Ph C-1), 139.5 (C-3a), 147.9 (C-2), 161.4 (C-4). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: −264.5 (N-5), –174.5 (N-9), −73.9 (N-1). HRMS (ESI) for C₁₆H₁₈BrN₃NaO₃ ([M+Na]⁺): calcd m/z 402.0424, found m/z 402.0424 and 404.0409.

7-Hydroxy-5-(2-methoxyethyl)-2-(4-methoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4m

Purified by column chromatography on silica gel (n-hexane/ethyl acetate gradient from 3.5/1 to 1/9, v/v). White solid, mp 147–148 °C, procedure b −80% (274 mg). R_f = 0.38 (ethyl acetate). IR (KBr) ν_max, cm⁻¹: 3212, 2982, 2943, 2882, 2838, 1651 (C=O), 1448, 1249, 1020, 834. ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 3.15 (dd, J = 15.0, 7.4 Hz, 1H, 6-H_a), 3.28 (s, 3H, OCH₃), 3.39–3.57 (m, 4H, 5-CH_a, CH₂O, 6-H_b), 3.78 (s, 3H, Ph 4-OCH₃), 3.89 (dt, J = 13.6, 5.2 Hz, 1H, 5-CH_b), 4.21 (dd, J = 14.0, 3.1 Hz, 1H, 8-H_a), 4.34–4.47 (m, 2H, 7-H, 8-H_b), 5.52 (d, J = 4.2 Hz, 1H, OH), 6.93–6.99 (m, 2H, Ph 3,5-H), 7.07 (s, 1H, 3-H), 7.73–7.80 (m, 2H, Ph 2,6-H). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 46.8 (5-CH₂), 52.9 (C-6), 55.1 (CH₃), 55.8 (C-8), 58.1 (OCH₃), 69.6 (C-7), 70.0 (CH₂O), 104.9 (C-3), 114.1 (Ph C-3,5), 125.2 (Ph C-1), 126.4 (Ph C-2,6), 139.2 (C-3a), 148.9 (C-2), 159.0 (Ph C-4), 161.7 (C-4). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: −264.5 (N-5), −176.2 (N-9), −77.0 (N-1). HRMS (ESI) for C₁₇H₂₁N₃NaO₄ ([M+Na]⁺): calcd m/z 354.1424, found m/z 354.1424.

5-Allyl-7-hydroxy-2-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4n

Purified by column chromatography on silica gel (n-hexane/ethyl acetate 1/9, v/v). White solid, mp 126–127 °C, procedure b −71% (231 mg). R_f = 0.42 (n-hexane/ethyl acetate 3/7, v/v). IR (KBr) ν_max, cm⁻¹: 3346, 2939, 1619 (C=O), 1470, 1431, 1286, 1055, 942, 749, 690. ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 3.09 (dd, J = 15.0, 7.3 Hz, 1H, 6-H_a), 3.38 (dd, J = 15.0, 5.1 Hz, 1H, 6-H_b), 3.94 (dd, J = 15.1, 6.4 Hz, 1H, 5-CH_a), 4.20–4.31 (m, 2H, 5-CH_b, 8-H_a), 4.34–4.42 (m, 1H, 7-H), 4.55 (dd, J = 14.4, 5.4 Hz, 1H, 8-H_b), 5.18–5.29 (m, 2H, CH₂-CH=CH₂), 5.55 (d, J = 4.2 Hz, 1H, OH), 5.87 (ddd, J = 22.5, 10.8, 5.9 Hz, 1H, CH₂-CH=CH₂), 7.19 (s, 1H, 3-H), 7.29–7.35 (m, 1H, Ph 4-H), 7.37–7.44 (m, 2H, Ph 3,5-H), 7.81–7.88 (m, 2H, Ph 2,6-H). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 49.6 (5-CH₂), 51.3 (C-6), 55.9 (C-8), 69.3 (C-7), 105.8 (C-3), 117.8 (CH₂-CH=CH₂), 125.1 (Ph C-2,6), 127.8 (Ph C-4), 128.7 (Ph C-3,5), 132.5 (Ph C-1), 133.5 (CH₂-CH=CH₂), 139.2 (C-3a), 149.0 (C-2), 161.3 (C-4). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: −263.8 (N-5), −175.4 (N-9), −73.8 (N-1). HRMS (ESI) for C₁₆H₁₇N₃NaO₂ ([M+Na]⁺): calcd m/z 306.1213, found m/z 306.1213.

5-Allyl-2-(4-fluorophenyl)-7-hydroxy-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4o

Purified by column chromatography on silica gel (n-hexane/ethyl acetate gradient from 7/2 to 1/9, v/v). White solid, mp 143–144 °C, procedure b −89% (175 mg). R_f = 0.39 (n-hexane/ethyl acetate 3/7, v/v). IR (KBr) ν_max, cm⁻¹: 3230, 2951, 2892, 1651, 1461, 1440, 933, 837, 816, 756. ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 3.08 (dd, J = 15.0, 7.3 Hz, 1H, 6-H_a), 3.38 (dd, J = 15.0, 5.1 Hz, 1H, 6-H_b), 3.94 (dd, J = 15.2, 6.3 Hz, 1H, 5-CH_a), 4.19–4.32 (m, 2H, 5-CH_b, 8-H_a), 4.34–4.42 (m, 1H, 7-H), 4.54 (dd, J = 14.3, 5.3 Hz, 1H, 8-H_b), 5.18–5.28 (m, J = 14.0 Hz, 2H, CH₂-CH=CH₂), 5.55 (d, J = 4.1 Hz, 1H, OH), 5.87 (dq, J = 10.9, 5.8 Hz, 1H, CH₂-CH=CH₂), 7.20 (s, 1H, 3-H), 7.21–7.29 (m, 2H, Ph 3,5-H), 7.84–7.92 (m, 2H, Ph 2,6-H). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 49.6 (5-CH₂), 51.3 (C-6), 55.9 (C-8), 69.3 (C-7), 105.7 (C-3), 115.59 (d, ²J_CF = 21.5 Hz, Ph C-3,5), 117.8 (CH₂-CH=CH₂), 127.10 (d, ³J_CF = 8.2 Hz, Ph C-2,6), 129.07 (d, ⁴J_CF = 3.0 Hz, Ph C-1), 133.5 (CH₂-CH=CH₂), 139.2 (C-3a), 148.1 (C-2), 161.3 (C-4), 161.83 (d, J_CF = 244.3 Hz, Ph C-4). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: −264.0 (N-5), −175.1 (N-9), −74.3 (N-1). ¹⁹F NMR (376 MHz, DMSO-d₆) δ_F ppm: −114.4 (Ph 6-F). HRMS (ESI) for C₁₆H₁₆FN₃NaO₂ ([M+Na]⁺): calcd m/z 324.1119, found m/z 324.1119.

5-Allyl-2-(4-chlorophenyl)-7-hydroxy-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4p

Purified by column chromatography on silica gel (n-hexane/ethyl acetate gradient from 7/2 to 1/9, v/v). White solid, mp 179–180 °C, procedure b −92% (188 mg). R_f = 0.42 (n-hexane/ethyl acetate 3/7, v/v). IR (KBr) ν_max, cm⁻¹: 3363, 2939, 2891, 1620, 1470, 1091, 1053, 939, 812, 753. ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 3.08 (dd, J = 15.0, 7.3 Hz, 1H, 6-H_a), 3.38 (dd, J = 15.0, 5.1 Hz, 1H, 6-H_b), 3.94 (dd, J = 15.1, 6.3 Hz, 1H, 5-H_a), 4.19–4.42 (m, 3H, 5-CH_b, 7-H, 8-H_a), 4.55 (dd, J = 14.4, 5.4 Hz, 1H, 8-H_b), 5.19–5.29 (m, 2H, CH₂-CH=CH₂), 5.55 (d, J = 4.2 Hz, 1H, OH), 5.86 (ddd, J = 22.5, 10.8, 5.9 Hz, 1H, CH₂-CH=CH₂), 7.23 (s, 1H, 3-H), 7.43–7.51 (m, 2H, Ph 3,5-H), 7.83–7.91 (m, 2H, Ph 2,6-H). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 49.6 (5-CH₂), 51.2 (C-6), 56.0 (C-8), 69.3 (C-7), 106.0 (C-3), 117.8 (CH₂-CH=CH₂), 126.8 (Ph C-2,6), 128.8 (Ph C-3,5), 131.4 (Ph C-1), 132.3 (Ph C-4), 133.4 (CH₂-CH=CH₂), 139.3 (C-3a), 147.9 (C-2), 161.2 (C-4). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: −264.1 (N-5), −174.4 (N-9), −73.7 (N-1). HRMS (ESI) for C₁₆H₁₆ClN₃NaO₂ ([M+Na]⁺): calcd m/z 340.0823, found m/z 340.0823.

5-Allyl-2-(4-bromophenyl)-7-hydroxy-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4r

Purified by column chromatography on silica gel (n-hexane/ethyl acetate gradient 1/9, v/v). White solid, mp 186–187 °C, procedure b −76% (277 mg). R_f = 0.43 (n-hexane/ethyl acetate 3/7, v/v). IR (KBr) ν_max, cm⁻¹: 3366, 2938, 1621 (C=O), 1469, 1434, 1052, 1006, 933, 811, 752. ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 3.08 (dd, J = 14.9, 7.3 Hz, 1H, 6-H_a), 3.35–3.42 (m, 1H, 6-H_b), 3.94 (dd, J = 15.1, 6.2 Hz, 1H, 5-CH_a), 4.19–4.32 (m, 2H, 5-CH_b, 8-H_a), 4.34–4.41 (m, 1H, 7-H), 4.55 (dd, J = 14.3, 5.3 Hz, 1H, 8-H_b), 5.18–5.28 (m, 2H, CH₂-CH=CH₂), 5.56 (d, J = 4.0 Hz, 1H, OH), 5.81–5.92 (m, 1H, CH₂-CH=CH₂), 7.23 (s, 1H, 3-H), 7.57–7.63 (m, 2H, Ph 3,5-H), 7.78–7.84 (m, 2H, Ph 2,6-H). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 49.6 (5-CH₂), 51.2 (C-6), 56.0 (C-8), 69.3 (C-7), 106.0 (C-3), 117.8 (CH₂-CH=CH₂), 120.9 (Ph C-4), 127.1 (Ph C-2,6), 131.67 (Ph C-3,5), 131.73 (Ph C-1), 133.4 (CH₂-CH=CH₂), 139.3 (C-3a), 147.9 (C-2), 161.2 (C-4). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: −263.2 (N-5), −173.1 (N-9), −74.0 (N-1). HRMS (ESI) for C₁₆H₁₆BrN₃NaO₂ ([M+Na]⁺): calcd m/z 384.0318, found m/z 384.0318 and 386.0303.

5-Allyl-7-hydroxy-2-(4-methoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4s

Purified by column chromatography on silica gel (n-hexane/ethyl acetate gradient from 4/1 to 1/9, v/v). White solid, mp 134–135 °C, procedure b −85% (301 mg). R_f = 0.35 (n-hexane/ethyl acetate 1.5/3.5, v/v). IR (KBr) ν_max, cm⁻¹: 3284, 2932, 2835, 1624 (C=O), 1467, 1285, 1061, 1026, 935, 828. ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 3.08 (dd, J = 15.0, 7.2 Hz, 1H, 6-H_a), 3.37 (dd, J = 14.8, 4.9 Hz, 1H, 6-H_b), 3.78 (s, 3H, Ph 4-OCH₃), 3.94 (dd, J = 15.1, 6.4 Hz, 1H, 5-CH_a), 4.20 (dd, J = 14.3, 3.8 Hz, 1H, 8-H_a), 4.28 (dd, J = 15.1, 5.3 Hz, 1H, 5-CH_b), 4.33–4.40 (m, 1H, 7-H), 4.51 (dd, J = 14.3, 5.4 Hz, 1H, 8-H_b), 5.17–5.28 (m, 2H, CH₂-CH=CH₂), 5.54 (d, J = 4.2 Hz, 1H, OH), 5.86 (ddd, J = 22.5, 10.3, 5.9 Hz, 1H, CH₂-CH=CH₂), 6.93–7.00 (m, 2H, Ph 3,5-H), 7.10 (s, 1H, 3-H), 7.72–7.80 (m, 2H, Ph 2,6-H). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 49.6 (5-CH₂), 51.3 (C-6), 55.1 (Ph 4-OCH₃), 55.8 (C-8), 69.4 (C-7), 105.2 (C-3), 114.1 (Ph C-3,5), 117.8 (CH₂-CH=CH₂), 125.2 (Ph C-1), 126.4 (Ph C-2,6), 133.5 (CH₂-CH=CH₂), 139.0 (C-3a), 148.9 (C-2), 159.0 (Ph C-4), 161.4 (C-4). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: −176.8 (N-9), −75.9 (N-1). HRMS (ESI) for C₁₇H₁₉N₃NaO₃ ([M+Na]⁺): calcd m/z 336.1319, found m/z 336.1319.

5-Benzyl-7-hydroxy-2-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4t

Purified by column chromatography on silica gel (n-hexane/ethyl acetate 1/9, v/v). Pale yellow solid, mp 167–168 °C, procedure b −87% (138 mg). R_f = 0.55 (n-hexane/ethyl acetate 3/7, v/v). IR (KBr) ν_max, cm⁻¹: 3257, 3143, 2892, 1649 (C=O), 1451, 1235, 765 and 754 (doublet), 705 and 692 (doublet). ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 3.08 (dd, J = 14.9, 7.5 Hz, 1H, 6-H_a), 3.37 (dd, J = 15.0, 5.2 Hz, 1H, 6-H_b), 4.12–4.19 (m, 1H, 7-H), 4.24 (dd, J = 14.4, 3.5 Hz, 1H, 8-H_a), 4.43–4.56 (m, 2H, 5-CH_a, 8-H_b), 4.96 (d, J = 14.7 Hz, 1H, 5-CH_b), 5.51 (d, J = 4.1 Hz, 1H, OH), 7.25 (s, 1H, 3-H), 7.29–7.35 (m, 2H, CPh 4-H, CH₂Ph 4-H), 7.36–7.44 (m, 6H, CPh 3,5-H, CH₂Ph 2,3,5,6-H), 7.82–7.88 (m, 2H, CPh 2,6-H). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 50.3 (5-CH₂), 51.3 (C-6), 55.9 (C-8), 69.3 (C-7), 105.9 (C-3), 125.1 (CPh C-2,6), 127.5 (CH₂Ph C-4), 127.8 (CPh C-4), 128.1 (CH₂Ph C-2,6), 128.6 (CH₂Ph C-3,5), 128.7 (CPh C-3,5), 132.5 (CPh C-1), 137.5 (CH₂Ph C-1), 139.0 (C-3a), 149.0 (C-2), 161.7 (C-4). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: −259.1 (N-5), −176.3 (N-9), −73.3 (N-1). HRMS (ESI) for C₂₀H₁₉N₃NaO₂ ([M+Na]⁺): calcd m/z 356.1369, found m/z 356.1370.

5-Benzyl-2-(4-fluorophenyl)-7-hydroxy-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4u

Purified by column chromatography on silica gel (n-hexane/ethyl acetate gradient from 4/1 to 1/9, v/v). Pale yellow solid, mp 192–193 °C, procedure b −70% (301 mg). R_f = 0.52 (n-hexane/ethyl acetate 1.5/3.5, v/v). IR (KBr) ν_max, cm⁻¹: 3291, 3144, 2945, 1617 (C=O), 1470, 1442, 1230, 839, 701, 639. ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 3.07 (dd, J = 14.9, 7.5 Hz, 1H, 6-H_a), 3.34–3.40 (m, 1H, 6-H_b), 4.11–4.26 (m, 2H, 7-H, 8-Ha), 4.43–4.55 (m, 2H, 5-CH_a, 8-H_b), 4.96 (d, J = 14.7 Hz, 1H, 5-CH_b), 5.50 (d, J = 4.0 Hz, 1H, OH), 7.20–7.41 (m, 8H, 3-H, CPh 3,5-H, CH₂Ph 2,3,4,5,6-H), 7.85–7.93 (m, 2H, CPh 2,6-H). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 50.3 (5-CH₂), 51.3 (C-6), 55.9 (C-8), 69.2 (C-7), 105.9 (C-3), 115.61 (d, ²J_CF = 21.5 Hz, CPh C-3,5), 127.10 (d, ³J_CF = 8.2 Hz, CPh C-2,6), 127.5 (CH₂Ph C-4), 128.1 (CH₂Ph C-2,6), 128.6 (CH₂Ph C-3,5), 129.06 (d, ⁴J_CF = 2.8 Hz, CPh C-1), 137.5 (CH₂Ph C-1), 139.1 (C-3a), 148.2 (C-2), 161.6 (C-4), 161.84 (d, J_CF = 244.3 Hz, CPh C-4). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: −259.9 (N-5), −175.3 (N-9), −74.4 (N-1). ¹⁹F NMR (376 MHz, DMSO-d₆) δ_F ppm: −114.3 (CPh 6-F). HRMS (ESI) for C₂₀H₁₈FN₃NaO₂ ([M+Na]⁺): calcd m/z 374.1275, found m/z 374.1275.

5-Benzyl-2-(4-chlorophenyl)-7-hydroxy-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4v

Purified by column chromatography on silica gel (n-hexane/ethyl acetate gradient from 7/2 to 1/9, v/v). White solid, mp 181–182 °C, procedure b −96% (419 mg). R_f = 0.57 (n-hexane/ethyl acetate 3/7, v/v). IR (KBr) ν_max, cm⁻¹: 3246, 2939, 1619 (C=O), 1455, 1434, 1091, 830 and 819 (doublet), 757, 699. ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 3.08 (dd, J = 14.9, 7.5 Hz, 1H, 6-H_a), 3.37 (dd, J = 15.0, 5.0 Hz, 1H, 6-H_b), 4.11–4.27 (m, 2H, 7-H, 8-H_a), 4.43–4.57 (m, 2H, 5-CH_a, 8-H_b), 4.96 (d, J = 14.7 Hz, 1H, 5-CH_b), 5.51 (d, J = 3.6 Hz, 1H, OH), 7.28–7.41 (m, 6H, 3-H, CH₂Ph 2,3,4,5,6-H), 7.44–7.50 (m, 2H, CPh 3,5-H), 7.84–7.91 (m, 2H, CPh 2,6-H). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 50.3 (5-CH₂), 51.3 (C-6), 56.0 (C-8), 69.2 (C-7), 106.1 (C-3), 126.8 (CPh C-2,6), 127.5 (CH₂Ph C-4), 128.1 (CH₂Ph C-2,6), 128.6 (CH₂Ph C-3,5), 128.8 (CPh C-3,5), 131.4 (CPh C-1), 132.3 (CPh C-4), 137.5 (CH₂Ph C-1), 139.2 (C-3a), 147.9 (C-2), 161.6 (C-4). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: −259.6 (N-5), −174.8 (N-9), −73.4 (N-1). HRMS (ESI) for C₂₀H₁₈ClN₃NaO₂ ([M+Na]⁺): calcd m/z 390.0980, found m/z 390.0980.

5-Benzyl-2-(4-bromophenyl)-7-hydroxy-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4w

Purified by column chromatography on silica gel (n-hexane/ethyl acetate 1/9, v/v). Pale yellow solid, mp 157–158 °C, procedure b −72% (287 mg). R_f = 0.57 (n-hexane/ethyl acetate 3/7, v/v). IR (KBr) ν_max, cm⁻¹: 3270, 1619 (C=O), 1460, 1429, 1247, 1068, 1009, 816, 756, 701. ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 3.08 (dd, J = 14.9, 7.6 Hz, 1H, 6-H_a), 3.34–3.41 (m, 1H, 6-H_b), 4.12–4.18 (m, 1H, 7-H), 4.20–4.27 (m, 1H, 8-H_a), 4.46 (d, J = 14.7 Hz, 1H, 5-CH_a), 4.52 (dd, J = 14.4, 5.3 Hz, 1H, 8-H_b), 4.96 (d, J = 14.7 Hz, 1H, 5-CH_b), 5.51 (d, J = 4.1 Hz, 1H, OH), 7.28–7.34 (m, 2H, 3-H, CH₂Ph 4-H), 7.35–7.39 (m, 4H, CH₂Ph 2,3,5,6-H), 7.56–7.64 (m, 2H, CPh 3,5-H), 7.78–7.85 (m, 2H, CPh 2,6-H). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 50.4 (5-CH₂), 51.3 (C-6), 56.0 (C-8), 69.2 (C-7), 106.1 (C-3), 120.9 (CPh C-4), 127.1 (CPh C-2,6), 127.5 (CH₂Ph C-4), 128.2 (CH₂Ph C-3,5), 128.6 (CH₂Ph C-2,6), 131.68 (CPh C-3,5), 131.72 (CPh C-1), 137.5 (CH₂Ph C-1), 139.2 (C-3a), 148.0 (C-2), 161.6 (C-4). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: −259.5 (N-5), −174.5 (N-9), −73.7 (N-1). HRMS (ESI) for C₂₀H₁₈BrN₃NaO₂ ([M+Na]⁺): calcd m/z 434.0475, found m/z 434.0475 and 436.0445.

5-Benzyl-7-hydroxy-2-(4-methoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 4x

Purified by column chromatography on silica gel (n-hexane/ethyl acetate gradient from 3.5/1 to 1/9, v/v). White solid, mp 179–180 °C, procedure b −72% (313 mg). R_f = 0.46 (n-hexane/ethyl acetate 1.5/3.5, v/v). IR (KBr) ν_max, cm⁻¹: 3204, 1651 (C=O), 1462, 1436, 1250, 1180, 1029, 833, 753, 705. ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 3.07 (dd, J = 14.9, 7.5 Hz, 1H, 6-H_a), 3.36–3.40 (m, 1H, 6-H_b), 3.78 (s, 3H, -OCH₃), 4.11–4.24 (m, 2H, 7-H, 8-H_a), 4.42–4.53 (m, 2H, 5-CH_a, 8-H_b), 4.96 (d, J = 14.7 Hz, 1H, 5-CH_b), 5.50 (s, 1H, OH), 6.94–7.00 (m, 2H, CPh 3,5-H), 7.15 (s, 1H, 3-H), 7.28–7.34 (m, 1H, CH₂Ph 4-H), 7.35–7.41 (m, 4H, CH₂Ph 2,3,5,6-H), 7.74–7.81 (m, 2H, CPh 2,6-H). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 50.4 (5-CH₂), 51.4 (C-6), 55.1 (OCH₃), 55.8 (C-8), 69.3 (C-7), 105.3 (C-3), 114.1 (CPh C-3,5), 125.1 (CPh C-1), 126.4 (CPh C-2,6), 127.5 (CH₂Ph C-4), 128.1 (CH₂Ph C-2,6), 128.6 (CH₂Ph C-3,5), 137.6 (CH₂Ph C-1), 138.9 (C-3a), 149.0 (C-2), 159.0 (CPh C-4), 161.8 (C-4). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: −258.9 (N-5), −176.9 (N-9), −75.4 (N-1). HRMS (ESI) for C₂₁H₂₁N₃NaO₃ ([M+Na]⁺): calcd m/z 386.1475, found m/z 386.1475.

3.2.4. Synthesis of Ethyl 1-(oxiran-2-ylmethyl)-1H-indole-2-carboxylates (6a–e) and Ethyl 1-(oxiran-2-ylmethyl)-1H-benzo[d]imidazole-2-carboxylate (6f)

Procedure a. Indole-2-carboxylate 5a–e (1 eq) was dissolved in dry dimethyl formamide (0.2 M) and KOH (3 eq; flakes) was added followed by 2-(chloromethyl)oxirane (1.5 eq). The reaction mixture was stirred at 40 °C for 1 h under argon atmosphere. Upon completion, the mixture was concentrated to approximately 1/3 volume, diluted with ethyl acetate, and washed with brine. Organic layer was separated, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography.

Procedure b. Benzimidazole-2-carboxylate 5f (1 eq) was dissolved in dry dimethyl formamide (0.3 M) and NaH (1.5 eq; 60% dispersion in mineral oil) was added followed by 2-(chloromethyl)oxirane (1.5 eq). The reaction mixture was stirred at 60 °C for 4 h. Upon completion, the reaction mixture was cooled to 0 °C, quenched with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography.

Ethyl 1-(oxiran-2-ylmethyl)-1H-indole-2-carboxylate 6a

Purified by column chromatography on silica gel (n-hexane/ethyl acetate 8/1, v/v). White solid, mp 47–49 °C, procedure a −73% (94 mg). R_f = 0.29 (n-hexane/ethyl acetate 6/1, v/v). IR (KBr) ν_max, cm⁻¹: 3064, 2974, 2928, 1713 (C=O), 1408, 1265, 1205, 1140, 1096, 744. ¹H NMR (400 MHz, CDCl₃) δ_H ppm: 1.41 (t, J = 7.1 Hz, 3H, CH₃), 2.49–2.53 (m, 1H, Ox CH_aH_b), 2.77 (t, J = 4.2 Hz, 1H, Ox CH_aH_b), 3.33–3.39 (m, 1H, Ox CH), 4.38 (q, J = 7.1 Hz, 2H, CH₂CH₃), 4.56 (dd, J = 15.1, 5.0 Hz, 1H, NCH_aH_b), 5.03 (dd, J = 15.1, 2.4 Hz, 1H, NCH_aH_b), 7.14–7.18 (m, 1H, 5-H), 7.34–7.37 (m, 2H, 3-H, 6-H), 7.45–7.47 (m, 1H, 7-H), 7.66–7.68 (m, 1H, 4-H). ¹³C NMR (101 MHz, CDCl₃) δ_C ppm: 14.5 (CH₃), 45.5 (Ox CH_aH_b), 46.2 (NCH_aH_b), 51.6 (Ox CH), 60.8 (CH₂CH₃), 110.9 (C-7), 111.1 (C-3), 121.1 (C-5), 122.7 (C-4), 125.5 (C-6), 126.1 (C-3a), 127.7 (C-2), 140.0 (C-7a), 162.3 (COO). ¹⁵N NMR (40 MHz, CDCl₃) δ_N ppm: –250.9 (N). HRMS (ESI) for C₁₄H₁₆NO₃ ([M+H]⁺): calcd m/z 246.1125, found m/z 246.1119.

Ethyl 5-fluoro-1-(oxiran-2-ylmethyl)-1H-indole-2-carboxylate 6b

Purified by column chromatography on silica gel (n-hexane/ethyl acetate 8/1, v/v). White solid, mp 65–66 °C, procedure a −39% (50 mg). R_f = 0.19 (n-hexane/ethyl acetate 6/1, v/v). IR (KBr) ν_max, cm⁻¹: 2974, 2930, 1713 (C=O), 1527, 1266, 1246, 1177, 1091, 756. ¹H NMR (400 MHz, CDCl₃) δ_H ppm: 1.41 (t, J = 7.1 Hz, 3H, CH₃), 2.45–2.53 (m, 1H, Ox CH_aH_b), 2.79 (t, J = 4.2 Hz, 1H, Ox CH_aH_b), 3.32–3.40 (m, 1H, Ox CH), 4.38 (q, J = 7.1 Hz, 2H, CH₂CH₃), 4.47 (dd, J = 15.2, 5.3 Hz, 1H, NCH_aH_b), 5.08 (dd, J = 15.2, 2.4 Hz, 1H, NCH_aH_b), 7.07–7.15 (m, 1H, 6-H), 7.24–7.33 (m, 2H, 3-H, 7-H), 7.38–7.45 (m, 1H, 4-H). ¹³C NMR (101 MHz, CDCl₃) δ_H ppm: 14.5 (CH₃), 45.3 (Ox CH_aH_b), 46.6 (NCH_aH_b), 51.7 (Ox CH), 61.0 (CH₂CH₃), 106.7 (d, J = 23.2 Hz, C-7), 110.7 (d, J = 5.1 Hz, C-3), 112.1 (d, J = 10.1 Hz, C-4), 114.6 (d, J = 27.3 Hz, C-6), 126.1 (d, J = 11.1 Hz, C-3a), 129.0 (C-2), 136.7 (C-7a), 158.4 (d, J = 238.4 Hz, C-5), 162.0 (COO). ¹⁵N NMR (40 MHz, CDCl₃) δ_N ppm: –250.9 (N). ¹⁹F NMR (376 MHz, DMSO-d₆) δ_F ppm: –127.7 (F). HRMS (ESI) for C₁₄H₁₅FNO₃ ([M+H]⁺): calcd m/z 264.1030, found m/z 264.1031.

Ethyl 5-chloro-1-(oxiran-2-ylmethyl)-1H-indole-2-carboxylate 6c

Purified by column chromatography on silica gel (n-hexane/ethyl acetate 8/1, v/v). White solid, mp 79–80 °C, procedure a −69% (72 mg). R_f = 0.23 (n-hexane/ethyl acetate 6/1, v/v). IR (KBr) ν_max, cm⁻¹: 2984, 2928, 1703 (C=O), 1517, 1457, 1252, 1199, 763. ¹H NMR (400 MHz, CDCl₃) δ_H ppm: 1.42 (t, J = 7.1 Hz, 3H, CH₃), 2.48 (dd, J = 4.4, 2.6 Hz, 1H, Ox CH_aH_b), 2.78 (t, J = 4.3 Hz, 1H, Ox CH_aH_b), 3.32–3.38 (m, 1H, Ox CH), 4.38 (q, J = 7.1 Hz, 2H, CH₂CH₃), 4.47 (dd, J = 15.2, 5.4 Hz, 1H, NCH_aH_b), 5.07 (dd, J = 15.2, 2.6 Hz, 1H, NCH_aH_b), 7.25–7.26 (m, 1H, 3-H), 7.28–7.30 (m, 1H, 6-H), 7.39–7.41 (m, 1H, 7-H), 7.62–7.63 (m, 1H, 4-H). ¹³C NMR (101 MHz, CDCl₃) δ_C ppm: 14.5 (CH₃), 45.3 (Ox CH_aH_b), 46.5 (NCH_aH_b), 51.6 (Ox CH), 61.1 (CH₂CH₃), 110.3 (C-3), 112.3 (C-7), 121.7 (C-4), 125.9 (C-6), 126.8 (C-5), 126.9 (C-3a), 128.8 (C-2), 138.3 (C-7a), 162.0 (COO). ¹⁵N NMR (40 MHz, CDCl₃) δ_N ppm: –250.0 (N). HRMS (ESI) for C₁₄H₁₅ClNO₃ ([M+H]⁺): calcd m/z 280.0735, found m/z 280.0733.

Ethyl 5-methyl-1-(oxiran-2-ylmethyl)-1H-indole-2-carboxylate 6d

Purified by column chromatography on silica gel (n-hexane/ethyl acetate 8/1, v/v). White solid, mp 72–74 °C, procedure a −75% (96 mg). R_f = 0.27 (n-hexane/ethyl acetate 6/1, v/v). IR (KBr) ν_max, cm⁻¹: 2976, 1706 (C=O), 1408, 1263, 1211, 1128, 1096, 763. ¹H NMR (400 MHz, CDCl₃) δ_H ppm: 1.41 (t, J = 7.1 Hz, 3H, CH₂CH₃), 2.44 (s, 3H, 5-CH₃), 2.49 (dd, J = 4.4, 2.6 Hz, 1H, Ox CH_aH_b), 2.76 (t, J = 4.4 Hz, 1H, Ox CH_aH_b), 3.32–3.37 (m, 1H, Ox CH), 4.37 (q, J = 7.1 Hz, 2H, CH₂CH₃), 4.55 (dd, J = 15.1, 5.0 Hz, 1H, NCH_aH_b), 4.99 (dd, J = 15.1, 3.2 Hz, 1H, NCH_aH_b), 7.16–7.20 (m, 1H, 6-H), 7.22–7.27 (m, 1H, 3-H), 7.33–7.37 (m, 1H, 7-H), 7.42–7.48 (m, 1H, 4-H). ¹³C NMR (101 MHz, CDCl₃) δ_H ppm: 14.5 (CH₂CH₃), 21.5 (5-CH₃), 45.5 (Ox CH_aH_b), 46.2 (NCH_aH_b), 51.7 (Ox CH), 60.7 (CH₂CH₃), 110.59 (C-7), 110.62 (C-3), 121.9 (C-4), 126.3 (C-3a), 127.5 (C-6), 127.6 (C-2), 130.4 (C-5), 138.5 (C-7a), 162.3 (COO). ¹⁵N NMR (40 MHz, CDCl₃) δ_N ppm: –251.8 (N). HRMS (ESI) for C₁₅H₁₈NO₃ ([M+H]⁺): calcd m/z 260.1281, found m/z 260.1277.

Ethyl 3-methyl-1-(oxiran-2-ylmethyl)-1H-indole-2-carboxylate 6e

Purified by column chromatography on silica gel (petroleum ether/ethyl acetate gradient from 9/1 to 8/1, v/v). Colorless liquid, procedure a −47% (60 mg). R_f = 0.14 (petroleum ether/ethyl acetate 10/1, v/v). IR (KBr) ν_max, cm⁻¹: 1698 (C=O), 1273, 1250, 1208, 1129, 1111, 741. ¹H NMR (500 MHz, CDCl₃) δ_H ppm: 1.44 (t, J = 7.2 Hz, 3H, CH₂CH₃), 2.49 (dd, J = 4.9, 2.8 Hz, 1H, Ox CH_aH_b), 2.59 (s, 3H, 5-CH₃), 2.74–2.77 (m, 1H, OxCH_aH_b), 3.33–3.37 (m, 1H, Ox CH), 4.42 (q, J = 7.1 Hz, 2H, CH₂CH₃), 4.50 (dd, J = 15.3, 5.2 Hz, 1H, NCH_aH_b), 4.94 (dd, J = 15.3, 3.4 Hz, NCH_aH_b), 7.13–7.17 (m, 1H, 5-H), 7.33–7.37 (m, 1H, 6-H), 7.39–7.43 (m, 1H, 7-H), 7.64–7.69 (m, 1H, 4-H). ¹³C NMR (125 MHz, CDCl₃) δ_C ppm: 11.0 (3-CH₃), 14.5 (CH₂CH₃),45.4 (Ox CH_aH_b), 46.4 (NCH_aH_b), 51.8 (Ox CH), 60.6 (CH₂CH₃), 110.6 (C-7), 120.2 (C-5), 120.8 (C-4), 121.5 (C_q), 124.6 (C_q), 125.7 (C-6), 127.4 (C_q), 139.1 (C_q), 163.2 (COO). ¹⁵N NMR (40 MHz, CDCl₃) δ_N ppm: −254.7 (N). HRMS (ESI) for C₁₅H₁₈NO₃ ([M+H]⁺): calcd m/z 260.1281, found m/z 260.1276.

Ethyl 1-(oxiran-2-ylmethyl)-1H-benzo[d]imidazole-2-carboxylate 6f

Purified by column chromatography on silica gel (petroleum ether/ethyl acetate gradient from 1/1 to 2/3, v/v). White solid, mp 49–52 °C, procedure b −33% (86 mg). R_f = 0.37 (petroleum ether/ethyl acetate 1/1, v/v). IR (KBr) ν_max, cm⁻¹: 2360, 2341, 1709 (C=O), 1494, 1457, 1410, 1338, 1283, 1202, 1138, 743. ¹H NMR (500 MHz, DMSO-d₆) δ_H ppm: 1.34 (t, J = 7.2 Hz, 3H, CH₃), 2.42–2.45 (m, 1H, Ox CH_aH_b), 2.72 (t, J = 4.4 Hz, OxCH_aH_b), 3.33–3.38 m, 1H, Ox CH), 4.37 (q, J = 7.1 Hz, 2H, CH₂CH₃), 4.58 (dd, J = 15.1, 8.7 Hz, 1H, NCH_aH_b), 5.03 (dd, J = 15.3, 3.1 Hz, NCH_aH_b), 7.29–7.34 (m, 1H, 5-H), 7.37–7.42 (m, 1H, 6-H), 7.69–7.72 (m, 1H, 7-H), 7.74–7.78 (m, 1H, 4-H). ¹³C NMR (125 MHz, DMSO-d₆) δ_C ppm: 14.5 (CH₃), 45.2 (Ox CH_aH_b), 46.8 (NCH_aH_b), 50.9 (Ox CH), 62.2 (CH₂CH₃), 112.5 (C-7), 121.4 (C-4), 124.0 (C-5), 125.7 (C-6), 136.8 (C_q), 141.5 (C_q), 141.6 (C_q), 160.1 (COO). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: −229.8 (N). HRMS (ESI) for C₁₃H₁₄N₂O₃ ([M+H]⁺): calcd m/z 247.1077, found m/z 247.1071.

3.2.5. Synthesis of 4-Hydroxy-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-ones (7a–f) and 4-Hydroxy-2,3,4,5-tetrahydro-1H-benzo[4,5]imidazo[1,2-a][1,4]diazepin-1-one (7g)

Procedure a. Ethyl 1-(oxiran-2-ylmethyl)-1H-indole-2-carboxylate 6a–e or ethyl 1-(oxiran-2-ylmethyl)-1H-benzo[d]imidazole-2-carboxylate 6f (1 eq) was dissolved in 7M ammonia (100 eq) solution in methanol, sealed in a pressure tube and stirred at 70 °C for 18 h. After completion, the reaction mixture was cooled to 0 °C, quenched with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography.

Procedure b. To a solution of ethyl 1-(oxiran-2-ylmethyl)-1H-indole-2-carboxylate 7a (1eq) in methanol (5 M) benzylamine (3 eq) was added, the reaction mixture was sealed in a pressure tube and stirred at 70 °C for 18 h. After completion, the reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography.

4-Hydroxy-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one 7a

Purified by column chromatography on silica gel (dichloromethane/methanol 100/5, v/v). White solid, decomp. 216 °C, procedure a −93% (82 mg). R_f = 0.45 (dichloromethane/methanol 9/1, v/v). IR (KBr) ν_max, cm⁻¹: 3318, 3194, 3049, 2895, 1660 (C=O), 1643 (C=O), 1549, 1461, 1407, 740. ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 2.83 (dt, J = 12.0, 5.6 Hz, 1H, 3-H_a), 3.21 (dt, J = 11.3, 5.4 Hz, 1H, 3-H_b), 4.18–4.28 (m, 2H, 5-H_a, 4-H), 4.42 (dd, J = 13.9, 4.1 Hz, 1H, 5-H_b), 5.37 (d, J = 3.8 Hz, 1H, OH), 6.93 (s, 1H, 11-H), 7.06–7.10 (m, 1H, 9-H), 7.25–7.29 (m, 1H, 8-H), 7.55–7.57 (m, 1H, 7-H), 7.62–7.64 (m, 1H, 10-H), 8.08–8.10 (m, 1H, NH). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 45.6 (C-3), 48.2 (C-5), 69.5 (C-4), 105.3 (C-11), 110.5 (C-7), 119.9 (C-9), 121.6 (C-10), 123.5 (C-8), 126.0 (C-10a), 134.7 (C-11a), 137.5 (C-6a), 165.5 (C-1). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: –272.6 (N-2), –249.8 (N-6). HRMS (ESI) for C₁₂H₁₃N₂O₂ ([M+H]⁺): calcd m/z 217.0972, found m/z 217.0969.

9-Fluoro-4-hydroxy-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one 7b

Purified by column chromatography on silica gel (dichloromethane/methanol 100/5, v/v). White solid, decomp. 220 °C, procedure a −63% (56 mg). R_f = 0.55 (dichloromethane/methanol 9/1, v/v). IR (KBr) ν_max, cm⁻¹: 3335, 3283, 3200, 3047, 1647 (C=O), 1548, 1408, 1203, 796. ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 2.78–2.87 (m, 1H, 3-H_a), 3.16–3.26 (m, 1H, 3-H_b), 4.16–4.30 (m, 2H, 5-H_a, 4-H), 4.43 (dd, J = 14.0, 4.2 Hz, 1H, 5-H_b), 5.38 (d, J = 4.0 Hz, 1H, OH), 6.91 (s, 1H, 11-H), 7.08–7.19 (m, 1H, 8-H), 7.36–7.43 (m, 1H, 10-H), 7.56–7.63 (m, 1H, 7-H), 8.12–8.20 (m, 1H, NH). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 45.6 (C-3), 48.5 (C-5), 69.5 (C-4), 105.0 (d, ⁴J_CF = 5.1 Hz, C-11), 105.8 (d, ²J_CF = 23.3 Hz, C-10), 111.9 (d, ³J_CF = 9.8 Hz, C-7), 112.1 (d, ²J_CF = 26.6 Hz, C-8), 126.1 (d, ³J_CF = 10.6 Hz, C-10a), 134.2 (C-6a), 136.3 (C-11a), 157.2 (d, J_CF = 233.1 Hz, C-9), 165.2 (C-1). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: –271.8 (N-2), –250.1 (N-6). HRMS (ESI) for C₁₂H₁₂FN₂O₂ ([M+H]⁺): calcd m/z 235.0877, found m/z 235.0876.

9-Chloro-4-hydroxy-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one 7c

Purified by column chromatography on silica gel (dichloromethane/methanol 100/5, v/v). White solid, decomp. 210 °C, procedure a −84% (75 mg). R_f = 0.52 (dichloromethane/methanol 9/1, v/v). IR (KBr) ν_max, cm⁻¹: 3325, 3275, 3191, 3046, 1660 (C=O), 1643 (C=O), 1545, 1408, 797. ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 2.86–2.75 (m, 1H, 3-H_a), 3.27–3.14 (m, 1H, 3-H_b), 4.29–4.16 (m, 2H, 4-H, 5-H_a), 4.43 (dd, J = 13.8, 3.9 Hz, 1H, 5-H_b), 5.39 (d, J = 3.8 Hz, 1H, OH), 6.91 (s, 1H, 11-H), 7.24–7.31 (m, 1H, 8-H), 7.57–7.65 (m, 1H, 7-H), 7.68–7.73 (m, 1H, 10-H), 8.14–8.22 (m, 1H, NH). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 45.5 (C-3), 48.5 (C-5), 69.4 (C-4), 104.7 (C-11), 112.3 (7-C), 120.6 (C-10), 123.5 (C-8), 124.4 (C-9), 127.0 (C-10a), 135.9 (C-6a), 136.1 (C-11a), 165.1 (C-1). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: –271.5 (N-2), –248.7 (N-6). HRMS (ESI) for C₁₂H₁₂ClN₂O₂ ([M+H]⁺): calcd m/z 251.0582, found m/z 251.0580.

4-Hydroxy-9-methyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one 7d

Purified by column chromatography on silica gel (dichloromethane/methanol 100/5, v/v). White solid, decomp. 225 °C, procedure a −86% (76 mg). R_f = 0.66 (dichloromethane/methanol 9/1, v/v). IR (KBr) ν_max, cm⁻¹: 3319, 3194, 3046, 1659 (C=O), 1640 (C=O), 1552, 1463, 1407, 790. ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 2.38 (s, 3H, CH₃), 2.78–2.87 (m, 1H, 3-H_a), 3.15–3.24 (m, 1H, 3-H_b), 4.16 (dd, J = 14.3, 4.3 Hz, 1H, 5-H_a), 4.20–4.27 (m, 1H, 4-H), 4.38 (dd, J = 14.2, 4.7 Hz, 1H, 5-H_b), 5.35 (d, J = 4.1 Hz, 1H, OH), 6.83 (s, 1H, 11-H), 7.06–7.14 (m, 1H, 8-H), 7.37–7.42 (m, 1H, 10-H), 7.41–7.47 (m, 1H, 7-H), 8.02–8.09 (m, 1H, NH). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 21.0 (CH₃), 45.7 (C-3), 48.3 (C-5), 69.6 (C-4), 104.8 (C-11), 110.2 (C-7), 120.9 (C-10), 125.3 (C-8), 126.2 (C-9), 128.5 (C-10a), 134.6 (C-11a), 136.0 (C-6a), 165.6 (C-1). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: –273.1 (N-2), –250.9 (N-6). ¹⁹F NMR (376 MHz, DMSO-d₆) δ_F ppm: –123.9 (F). HRMS (ESI) for C₁₃H₁₅N₂O₂ ([M+H]⁺): calcd m/z 231.1128, found m/z 231.1124.

4-Hydroxy-11-methyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one 7e

Purified by column chromatography on silica gel (petroleum ether/ethyl acetate/methanol gradient from 1/3/0 to 5/20/1, v/v/v). White solid, decomp. 218 °C, procedure a −66% (66 mg). R_f = 0.42 (ethyl acetate/methanol 10/1, v/v). IR (KBr) ν_max, cm⁻¹: 3308, 1631 (C=O), 1556, 1461, 1418, 1383, 1362, 1341, 1329, 1259, 1066, 733. ¹H NMR (500 MHz, DMSO-d₆) δ_H ppm: 2.36 (s, 3H, CH₃), 2.76 (dt, J = 14.4, 6.0 Hz, 1H, 3-H_a), 3.13 (dt, J = 14.4, 5.8 Hz, 1H, 3-H_b), 4.10 (dd, J = 14.2, 4.4 Hz, 1H, 5-H_a), 4.12–4.19 (m, 1H, 4-H), 4.32 (dd, J = 14.4, 4.9 Hz, 1H, 5-H_b), 5.30 (d, J = 4.0 Hz, 1H, OH), 7.02–7.10 (m, 1H, 9-H), 7.22–7.29 (m, 1H, 8-H), 7.47–7.52 (m, 1H, 7-H), 7.57–7.62 (m, 1H, 10-H), 7.97–8.02 (m, 1H, NH). ¹³C NMR (125 MHz, DMSO-d₆) δ_C ppm: 9.6 (CH₃), 46.1 (C-3), 48.6 (C-5), 69.4 (C-4), 110.6 (C-7), 115.5 (C_q), 119.6 (C-9), 120.3 (C-10), 124.3 (C-8), 127.4 (C_q), 130.3 (C_q), 137.0 (C_q), 166.3 (C-1). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: −271.4 (N-2), −254.4 (N-6). HRMS (ESI) for C₁₃H₁₅N₂O₂ ([M+H]⁺): calcd m/z 231.1128, found m/z 231.1126.

2-Benzyl-4-hydroxy-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one 7f

Purified by column chromatography on silica gel (petroleum ether/ethyl acetate gradient from 7/1 to 1/6, v/v). White solid, mp 183–184 °C, procedure b −87% (142.1 mg). R_f = 0.53 (petroleum ether/ethyl acetate 3/1, v/v). IR (KBr) ν_max, cm⁻¹: 3313 (OH), 2360, 2341, 1610 (C=O), 1541, 1421, 1079, 740. ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 3.01 (dd, J = 14.8, 7.4 Hz, 1H, 3-H_a), 3.31 (dd, J = 14.8, 5.2 Hz, 1H, 3-H_b), 4.06–4.14 (m, 1H, 4-H), 4.23 (dd, J = 14.6, 3.8 Hz, 1H, 5-H_a), 4.38 (dd, J = 14.6, 4.9 Hz, 1H, 5-H_b), 4.46 (d, J = 14.6 Hz, 1H, 2-CH_a), 5.00 (d, J = 14.6 Hz, 1H, 2-CH_b), 5.40 (d, J = 4.0 Hz, 1H, OH), 6.99–7.01 (m, 1H, 11-H), 7.05–7.11 (m, 1H, 9-H), 7.23–7.35 (m, 2H, 8-H, CH₂Ph 4-H), 7.36–7.41 (m, 4H, CH₂Ph 2,3,5,6-H), 7.50–7.57 (m, 1H, 7-H), 7.61–7.67 (m, 1H, 10-H). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 48.1 (C-5), 50.4 (CH₂Ph), 51.4 (C-3), 69.1 (C-4), 105.5 (C-11), 110.4 (C-7), 120.0 (C-9), 121.6 (C-10), 123.6 (C-8), 126.0 (C-10a), 127.4 (CH₂Ph C-4), 128.2 (CH₂Ph C-3,5), 128.7 (CH₂Ph C-2,6), 134.3 (C-11a), 137.3 (C-6a), 137.9 (CH₂Ph C-1), 163.9 (C-1). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: –255.0 (N-6), -265.7 (N-2). HRMS (ESI) for C₁₉H₁₉N₂O₂ ([M+H]⁺): calcd m/z 307.1441, found m/z 307.1388.

4-Hydroxy-2,3,4,5-tetrahydro-1H-benzo[4,5]imidazo[1,2-a][1,4]diazepin-1-one 7g

Purified by column chromatography on silica gel (petroleum ether/ethyl acetate/methanol gradient from 1/5/0 to 1/12/1, v/v/v). White solid, decomp. 190 °C, procedure a −19% (18 mg). R_f = 0.21 (ethyl acetate/methanol 9/1, v/v). IR (KBr) ν_max, cm⁻¹: 3379, 3220, 1676 (C=O), 1522, 1466, 1458, 1418, 1336, 1079, 741. ¹H NMR (500 MHz, DMSO-d₆) δ_H ppm: 2.75 (dt, J = 15.0 Hz, 6.1 Hz, 1H, 3-H_a), 3.21 (dt, J = 14.7 Hz, 5.8 Hz, 1H, 3-H_b), 4.22–4.31 (m, 2H, 5-H_a, 4-H), 4.49 (dd, J = 14.1 Hz, 4.3 Hz, 1H, 5-H_b), 5.35–5.55 (br s, 1H, OH), 7.23–7.28 (m, 1H, 9-H), 7.31–7.37 (m, 1H, 8-H), 7.63–7.73 (m, 2H, 7-H, 10-H), 8.56–8.63 (m, 1H, NH). ¹³C NMR (125 MHz, DMSO-d₆) δ_C ppm: 45.4 (C-3), 48.2 (C-5), 69.9 (C-4), 111.5 (C-7), 120.7 (C-10), 123.1 (C-9), 124.6 (C-8), 135.2 (C_q), 142.0 (C_q), 147.4 (C_q), 163.2 (C-1). HRMS (ESI) for C₁₁H₁₂N₃O₂ ([M+H]⁺): calcd m/z 218.0924, found m/z 218.0918.

3.2.6. Synthesis of O-Alkylated 5-Substituted 7-Hydroxy-2-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-ones (8a–f) and 2-Benzyl-4-hydroxy-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one (9a,b)

Pyrazolo-diazepinone 4i,n,t or indole-diazepinone 7f (1 eq) was dissolved in dimethyl formamide (0.1 M) and NaH (1.5 eq; 60% dispersion in mineral oil) was added followed by appropriate alkylating agent (1.5 eq). The reaction mixture was stirred at 25–50 °C for 5–8 h. Upon completion, the mixture was concentrated to approximately 1/3 volume, diluted with ethyl acetate, and washed with brine. Organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography.

7-Methoxy-5-(2-methoxyethyl)-2-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 8a

Purified by column chromatography on silica gel (n-hexane/ethyl acetate 1/1, v/v). White solid, mp 88–89 °C, 77% (104 mg). R_f = 0.41 (n-hexane/ethyl acetate 1/4, v/v). IR (KBr) ν_max, cm⁻¹: 3120, 2933, 2890, 2828, 1638 (C=O), 1470, 1354, 1016, 771, 700. ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 3.23 (dd, J = 15.2, 7.6 Hz, 1H, 5-CH_a), 3.29 (s, 3H, CH₂OCH₃), 3.37 (s, 3H, 7-OCH₃), 3.39–3.47 (m, 1H, 6-H_a), 3.51–3.62 (m, 3H, 5-CH_b, CH₂O), 3.90 (dt, J = 13.6, 5.2 Hz, 1H, 6-H_b), 4.05–4.12 (m, 1H, 7-H), 4.46 (qd, J = 14.7, 4.3 Hz, 2H, 8-H_aH_b), 7.18 (s, 1H, 3-H), 7.29–7.35 (m, 1H, Ph 4-H), 7.38–7.45 (m, 2H, Ph 3,5-H), 7.8 –7.87 (m, 2H, Ph 2,6-H). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 46.6 (C-6), 50.0 (5-CH₂), 52.1 (C-8), 56.3 (7-OCH₃), 58.0 (CH₂OCH₃), 69.8 (CH₂O), 79.2 (C-7), 105.5 (C-3), 125.2 (Ph C-2,6), 127.8 (Ph C-4), 128.7 (Ph C-3,5), 132.4 (Ph C-1), 139.3 (C-3a), 149.1 (C-2), 161.6 (C-4). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: −266.0 (N-5), −176.2 (N-9), −74.1 (N-1). HRMS (ESI) for C₁₇H₂₁N₃NaO₃ ([M+Na]⁺): calcd m/z 338.1475, found m/z 338.1475.

5-Allyl-7-methoxy-2-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 8b

Purified by column chromatography on silica gel (n-hexane/ethyl acetate 3.5/1, v/v). White solid, mp 89–90 °C, 84% (78 mg). R_f = 0.47 (n-hexane/ethyl acetate 1/1, v/v). IR (KBr) ν_max, cm⁻¹: 2984, 2929, 2826, 1657 (C=O), 1461, 1243, 1206, 1089, 770, 697. ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 3.19 (dd, J = 15.2, 6.9 Hz, 1H, 6-H_a), 3.36 (s, 3H, CH₃), 3.46 (dd, J = 15.2, 5.0 Hz, 1H, 6-H_b), 3.97 (dd, J = 15.1, 6.2 Hz, 1H, 5-CH_a), 4.09 (dt, J = 10.4, 5.1 Hz, 1H, 7-H), 4.23 (dd, J = 15.1, 5.5 Hz, 1H, 5-CH_b), 4.40 (dd, J = 14.7, 4.0 Hz, 1H, 8-H_a), 4.58 (dd, J = 14.7, 5.4 Hz, 1H, 8-H_b), 5.18–5.31 (m, 2H, CH₂-CH=CH₂), 5.81–5.92 (m, 1H, CH₂-CH=CH₂), 7.20 (s, 1H, 3-H), 7.29–7.36 (m, 1H, Ph 4-H), 7.37–7.45 (m, 2H, Ph 3,5-H), 7.81–7.88 (m, 2H, Ph 2,6-H). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 48.4 (C-6), 49.6 (5-CH₂), 52.3 (C-8), 56.3 (CH₃), 78.9 (C-7), 105.8 (C-3), 117.9 (CH₂-CH=CH₂), 125.1 (Ph C-2,6), 127.9 (Ph C-4), 128.7 (Ph C-3,5), 132.4 (Ph C-1), 133.4 (CH₂-CH=CH₂), 139.1 (C-3a), 149.1 (C-2), 161.3 (C-4). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: −176.0 (N-9), −73.9 (N-1). HRMS (ESI) for C₁₇H₁₉N₃NaO₂ ([M+Na]⁺): calcd m/z 320.1369, found m/z 320.1370.

5-Benzyl-7-methoxy-2-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 8c

Purified by column chromatography on silica gel (n-hexane/ethyl acetate 7/2, v/v). Pale yellow solid, mp 176–177 °C, 70% (57 mg). R_f = 0.41 (n-hexane/ethyl acetate 3/2, v/v). IR (KBr) ν_max, cm⁻¹: 3146, 2988, 2928, 2871, 1651 (C=O), 1449, 1241, 1101, 764, 695. ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 3.19 (dd, J = 15.2, 7.1 Hz, 1H, 6-H_a), 3.28 (s, 3H, CH₃), 3.48 (dd, J = 15.2, 5.0 Hz, 1H, 6-H_b), 3.86–3.93 (m, 1H, 7-H), 4.42 (dd, J = 14.8, 3.8 Hz, 1H, 8-H_a), 4.48–4.59 (m, 2H, 8-H_b, 5-CH_a), 4.88 (d, J = 14.7 Hz, 1H, 5-CH_b), 7.26 (s, 1H, 3-H), 7.30–7.35 (m, 2H, CPh 4-H, CH₂Ph 4-H), 7.36–7.44 (m, 6H, CPh 3,5-H, CH₂Ph 2,3,5,6-H), 7.82–7.87 (m, 2H, CPh 2,6-H). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 48.6 (C-6), 50.4 (5-CH₂), 52.3 (C-8), 56.3 (CH₃), 78.8 (C-7), 106.0 (C-3), 125.1 (CPh C-2,6), 127.5 (CH₂Ph C-4), 127.9 (CPh C-4), 128.1 (CH₂Ph C-2,6), 128.6 (CH₂Ph C-3,5), 128.7 (CPh C-3,5), 132.4 (CPh C-1), 137.4 (CH₂Ph C-1), 139.0 (C-3a), 149.2 (C-2), 161.7 (C-4). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: −261.2 (N-5), −176.7 (N-9), −74.1 (N-1). HRMS (ESI) for C₂₁H₂₁N₃NaO₂ ([M+Na]⁺): calcd m/z 370.1526, found m/z 370.1526.

7-Ethoxy-5-(2-methoxyethyl)-2-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 8d

Purified by column chromatography on silica gel (n-hexane/ethyl acetate/methanol 1/1/0.05, v/v). Yellowish resin, 75% (118 mg). R_f = 0.54 (n-hexane/ethyl acetate 1/4, v/v). IR (KBr) ν_max, cm⁻¹: 2977, 2931, 2893, 1647 (C=O), 1461, 1440, 1104, 1077, 769, 695. ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 1.14 (t, J = 7.0 Hz, 3H, 7-OCH₂CH₃), 3.24 (dd, J = 15.3, 7.4 Hz, 1H, 5-CH_a), 3.29 (s, 3H, CH₂OCH₃), 3.41–3.49 (m, 1H, 6-H_a), 3.51–3.68 (m, 5H, 5-CH_b, CH₂OCH₃, 7-OCH₂), 3.88 (dt, J = 13.5, 5.0 Hz, 1H, 6-H_b), 4.15–4.22 (m, 1H, 7-H), 4.44 (ddd, J = 18.2, 14.6, 4.4 Hz, 2H, 8-H_aH_b), 7.18 (s, 1H, 3-H), 7.29–7.36 (m, 1H, Ph 4-H), 7.38–7.45 (m, 2H, Ph 3,5-H), 7.81–7.87 (m, 2H, Ph 2,6-H). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 15.3 (7-OCH₂CH₃), 46.6 (C-6), 50.4 (5-CH₂), 52.7 (C-8), 58.0 (CH₂OCH₃), 63.9 (7-OCH₂), 69.8 (CH₂OCH₃), 77.4 (C-7), 105.5 (C-3), 125.1 (Ph C-2,6), 127.8 (Ph C-4), 128.7 (Ph C-3,5), 132.4 (Ph C-1), 139.3 (C-3a), 149.1 (C-2), 161.5 (C-4). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: −265.2 (N-5), −175.8 (N-9), −74.2 (N-1). HRMS (ESI) for C₁₈H₂₃N₃NaO₃ ([M+Na]⁺): calcd m/z 352.1632, found m/z 352.1632.

5-Allyl-7-ethoxy-2-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 8e

Purified by column chromatography on silica gel (n-hexane/ethyl acetate 7/2, v/v). Pale yellow solid, mp 113–144 °C, 77% (116 mg). R_f = 0.59 (n-hexane/ethyl acetate 1/1, v/v). IR (KBr) ν_max, cm⁻¹: 3118, 2980, 1645 (C=O), 1460, 1438, 1396, 1248, 1101, 770, 696. ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 1.13 (t, J = 6.9 Hz, 3H, CH₃), 3.20 (dd, J = 15.1, 6.8 Hz, 1H, 6-H_a), 3.44 (dd, J = 15.1, 4.7 Hz, 1H, 6-H_b), 3.50–3.65 (m, 2H, OCH₂), 3.98 (dd, J = 15.1, 6.0 Hz, 1H, 5-CH_a), 4.15–4.27 (m, 2H, 5-CH_b, 7-H), 4.37 (dd, J = 14.6, 3.8 Hz, 1H, 8-H_a), 4.58 (dd, J = 14.6, 5.4 Hz, 1H, 8-H_b), 5.18–5.31 (m, 2H, CH₂-CH=CH₂), 5.81–5.93 (m, 1H, CH₂-CH=CH₂), 7.20 (s, 1H, 3-H), 7.29–7.36 (m, 1H, Ph 4-H), 7.38–7.45 (m, 2H, Ph 3,5-H), 7.81–7.87 (m, 2H, Ph 2,6-H). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 15.3 (CH₃), 48.8 (C-6), 49.6 (5-CH₂), 52.9 (C-8), 63.9 (OCH₂), 77.1 (C-7), 105.8 (C-3), 117.8 (CH₂-CH=CH₂), 125.1 (Ph C-2,6), 127.9 (Ph C-4), 128.7 (Ph C-3,5), 132.4 (Ph C-1), 133.4 (CH₂-CH=CH₂), 139.1 (C-3a), 149.1 (C-2), 161.3 (C-4). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: −265.6 (N-5), −176.4 (N-9), −73.9 (N-1). HRMS (ESI) for C₁₈H₂₁N₃NaO₂ ([M+Na]⁺): calcd m/z 334.1526, found m/z 334.1526.

5-Benzyl-7-ethoxy-2-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 8f

Purified by column chromatography on silica gel (n-hexane/ethyl acetate 3.5/1, v/v). Pale yellow solid, mp 115–116 °C, 72% (92 mg). R_f = 0.55 (n-hexane/ethyl acetate 3/2, v/v). IR (KBr) ν_max, cm⁻¹: 3121, 2982, 2871, 1658 (C=O), 1460 and 1440 (doublet), 1239, 1105, 771, 693. ¹H NMR (400 MHz, DMSO-d₆) δ_H ppm: 1.06 (t, J = 7.0 Hz, 3H, CH₃), 3.20 (dd, J = 15.2, 7.1 Hz, 1H, 6-H_a), 3.39–3.58 (m, 3H, 6-H_b, OCH₂), 3.95–4.02 (m, 1H, 7-H), 4.38 (dd, J = 14.7, 3.8 Hz, 1H, 8-H_a), 4.48–4.59 (m, 2H, 8-H_b, 5-CH_a), 4.88 (d, J = 14.7 Hz, 1H, 5-CH_b), 7.26 (s, 1H, 3-H), 7.29–7.35 (m, 2H, CPh 4-H, CH₂Ph 4-H), 7.36–7.44 (m, 6H, CPh 3,5-H, CH₂Ph 2,3,5,6-H), 7.81–7.88 (m, 2H, CPh 2,6-H). ¹³C NMR (101 MHz, DMSO-d₆) δ_C ppm: 15.2 (CH₃), 49.0 (C-6), 50.4 (5-CH₂), 52.9 (C-8), 63.8 (OCH₂), 77.0 (C-7), 106.0 (C-3), 125.1 (CPh C-2,6), 127.4 (CH₂Ph C-4), 127.9 (CPh C-4), 128.1 (CH₂Ph C-2,6), 128.6 (CH₂Ph C-3,5), 128.7 (CPh C-3,5), 132.4 (CPh C-1), 137.4 (CH₂Ph C-1), 149.2 (C-2), 161.7 (C-4). ¹⁵N NMR (40 MHz, DMSO-d₆) δ_N ppm: −261.6 (N-5), −176.1 (N-9), −73.5 (N-1). HRMS (ESI) for C₂₂H₂₃N₃NaO₂ ([M+Na]⁺): calcd m/z 384.1682, found m/z 384.1682.

2-Benzyl-4-methoxy-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one 9a

Purified by column chromatography on silica gel (petroleum ether/ethyl acetate gradient from 5/1 to 2/1, v/v). White solid, mp 97–98 °C, 92% (50 mg). R_f = 0.63 (petroleum ether/ethyl acetate 2/1, v/v). IR (KBr) ν_max, cm⁻¹: 1642 (C=O), 1541, 1457, 1421, 1099, 741. ¹H NMR (400 MHz, CDCl₃) δ_H ppm: 3.31–3.37 (m, 5H, CH₃, 3-H_aH_b), 3.68 (p, J = 5.2 Hz, 1H, 4-H), 4.27 (dd, J = 14.7, 5.2 Hz, 1H, 5-H_a), 4.33–4.41 (m, 2H, 2-CH_a, 5-H_b), 5.26 (d, J = 14.6 Hz, 1H, 2-CH_b), 7.11–7.16 (m, 1H, 9-H), 7.19 (s, 1H, 11-H), 7.28–7.41 (m, 7H, 7-H, 8-H, CH₂Ph 2,3,4,5,6-H), 7.66–7.71 (m, 1H, 10-H). ¹³C NMR (101 MHz, CDCl₃) δ_C ppm: 45.1 (C-5), 48.5 (C-3), 51.5 (2-CH₂), 57.0 (CH₃), 79.7 (C-4), 107.5 (C-11), 109.4 (C-7), 120.5 (C-9), 122.5 (C-10), 124.4 (C-8), 126.9 (C-10a), 127.9 (CH₂Ph C-4), 128.7 (CH₂Ph C-3,5), 128.9 (CH₂Ph C-2,6), 134.0 (C-11a), 137.4 (C-6a), 137.6 (CH₂Ph C-1), 165.0 (C=O). ¹⁵N NMR (40 MHz, CDCl₃): δ_N ppm: −259.5 (N-6), −267.8 (N-2). HRMS (ESI) for C₂₀H₂₁N₂O₂ ([M+H]⁺): calcd m/z 321.1598, found m/z 321.1596.

2-Benzyl-4-ethoxy-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one 9b

Purified by column chromatography on silica gel (petroleum ether/ethyl acetate gradient from 5/1 to 4/1, v/v). Colorless resin, 73% (45 mg). R_f = 0.57 (petroleum ether/ethyl acetate 2/1, v/v). IR (KBr) ν_max, cm⁻¹: 2360, 2341, 1641 (C=O), 1540, 1417, 1100, 741. ¹H NMR (400 MHz, CDCl₃) δ_H ppm: 1.14–1.20 (m, 3H, CH₃), 3.29–3.35 (m, 2H, 3-H_aH_b), 3.43–3.59 (m, 2H, OCH₂), 3.73– 3.81 (m, 1H, 4-H), 4.23–4.31 (m, 1H, 5-H_a), 4.33–4.42 (m, 2H, 2-CH_a, 5-H_b), 5.22–5.30 (m, 1H, 2-CH_b), 7.10–7.21 (m, 2H, 9-H, 11-H), 7.27–7.41 (m, 7H, 7-H, 8-H, CH₂Ph 2,3,4,5,6-H), 7.66–7.72 (m, 1H, 10-H). ¹³C NMR (101 MHz, CDCl₃) δ_C ppm: 15.5 (CH₃). 45.5 (C-5), 49.0 (C-3), 51.5 (2-CH₂), 64.8 (OCH₂), 77.9 (C-4), 107.4 (C-11), 109.4 (C-7), 120.4 (C-9), 122.5 (C-10), 124.3 (C-8), 126.9 (C-10a), 127.90 (CH₂Ph C-4), 128.7 (CH₂Ph C-3,5), 128.9 (CH₂Ph C-2,6), 134.1 (C-11a), 137.5 (C-6a), 137.6 (CH₂Ph C-1), 165.1 (C-1). ¹⁵N NMR (40 MHz, CDCl₃): δ_N ppm: −259.8 (N-6), −268.6 (N-2). HRMS (ESI) for C₂₁H₂₃N₂O₂ ([M+H]⁺): calcd m/z 335,1781, found m/z 335.1798.

4. Conclusions

To summarize, a regioselective strategy was developed for synthesizing ethyl 1-(oxiran-2-ylmethyl)-3-aryl-1H-pyrazole-5-carboxylates from easily accessible 3(5)-aryl-1H-pyrazole-5(3)-carboxylates. Regioselective alkylation was achieved via optimization using different bases, reaction media and temperatures. Established conditions were applied to the synthesis of novel pyrazolo[1,5-a][1,4]diazepin-4-one compound series via ring-opening of the oxirane with amines, and direct cyclisation sequence. Furthermore, the synthetic strategy was further applied to investigate the reactivity of ethyl 1H-indole-2-carboxylate and ethyl benzo[d]imidazole-2-carboxylate scaffolds which led to the formation of additional fused tetrahydro[1,4]diazepino[1,2-a]indol-1-one and tetrahydro-1H-benzo[4,5]imidazo[1,2-a][1,4]diazepin-1-one derivatives. The structures of all synthesized compounds were confirmed by detailed NMR spectroscopy and HRMS investigations.