Synthesis and Photophysical Properties of Novel 1H-Indazole-3-carbohydrazides: Computational and Crystallographic Insights

Abstract

A diverse series of novel indazole derivatives were successfully synthesized via acid–amine coupling reactions with various carboxylic acids. Their chemical structures were comprehensively validated using advanced spectroscopic techniques, including ¹H, ¹³C, and DEPT-135 NMR, FT-IR, and HRMS analyses. Single-crystal X-ray diffraction data for representative compounds, combined with detailed Hirshfeld surface analysis, effectively mapped critical intermolecular interactions within crystal packing. Additionally, density functional theory (DFT) calculations elucidated the theoretical spectral profiles, frontier molecular orbital energy gaps, and electron density distributions. This integrated experimental and computational dataset establishes a highly robust foundation for future advanced structural and functional investigations of these systems.

Introduction

Nitrogen-bearing heterocyclic compounds are widely utilized in pharmaceutical chemistry due to their flexible structures and extensive pharmacological relevance. − Among these, indazole, initially synthesized by Emil Fischercomprises a fused benzene–pyrazole framework. Its planar and conjugated nature, coupled with multiple modifiable sites, enables targeted interactions with biological receptors. Indazole derivatives are recognized for forming strong hydrogen bonds through both nitrogen atoms, typically within hydrophobic protein regions, which underscores their utility as indole bioisosteres. − Although natural indazole-based compounds exhibit noteworthy pharmacological properties, their occurrence remains limited, with only a few examples reported from Nigella species. Furthermore, the biomedical applications of synthetic indazole derivatives have not been comprehensively investigated, particularly regarding their potential utility in oncological research.

This represents a significant gap in current research, particularly given that indazole-derived pharmacophores have been shown to exhibit a broad spectrum of biological activities. Reported properties include antiviral activity against HIV, anti-inflammatory and antimycobacterial effects, as well as antipyretic, antitumor, antidepressant actions, reversible male contraceptive potential, , and targeted enzyme inhibition. In addition, indazole frameworks have demonstrated utility as dopamine antagonists, antiemetic agents, and analgesics, underscoring their versatility as scaffolds in drug discovery. The diversity of these pharmacological attributes highlights the untapped potential of indazole-based compounds, particularly in therapeutic areas, where systematic exploration remains limited.

The clinical significance of indazole motifs is further demonstrated by a number of FDA-approved drugs containing them. Axitinib (renal cancer), bindarit (cardiovascular inflammation), benzydamine (anti-inflammatory), and niraparib (ovarian cancer) − are important examples depicted in Figure .

1.

Commercially available drugs containing the indazole scaffold.

A wide spectrum of carbohydrazide derivativesincluding aliphatic, alicyclic, aromatic, and heterocyclic frameworks, together with structurally related compoundshas been reported to exhibit diverse biological activities. − Density functional theory (DFT) is employed to examine the synthesized compounds. So in this work, we’ve combined both indazole and carbohydrazide and synthesized derivatives based on them to study their properties, such as electronic behavior, orbital energy gap, molecular arrangement, and photophysical properties. , Through this computational method, researchers can uncover a wide spectrum of molecular traits, including molecular mass, absorption patterns across spectra, electron distribution within the structures, and numerous other chemical properties. −

Results and Discussion

The target 1-butyl-indazole-3-carboxamide derivatives were successfully synthesized via a multistep pathway (Figure ). The synthesis commenced with the stirring of phenylhydrazine and benzaldehyde (1 equiv) at room temperature for 8 h to yield the benzylidene-1-phenylhydrazine intermediate. This intermediate was subsequently reacted with oxalyl chloride (1 equiv) in the presence of AlCl₃ (1.5 equiv) at 40–45 °C for 2 h to effect cyclization, affording 1-(benzylideneamino)­indolin-2,3-dione.

2.

Schematic representation of the synthesis route.

Further oxidation and structural transformation delivered the core indazole-3-carboxylic acid, which was then regioselectively alkylated with 1-bromobutane using NaH as a base to yield 1-butyl-1H-indazole-3-carboxylic acid. Conversion of this acid to its ethyl ester, followed by hydrazinolysis with hydrazine hydrate in ethanol under reflux conditions, provided the key precursor, 1-butyl-indazole-3-carbohydrazide.

Final diversification into the corresponding amides was achieved by dissolving the carbohydrazide in N,N-dimethylformamide (DMF), using hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU) as the coupling agent and N,N-diisopropylethylamine (DIPEA) as the base. The crude products were purified via column chromatography using an ethyl acetate/hexane (1:3) eluent system. The chemical structures and purity of all synthesized compounds were thoroughly confirmed by using tandem spectroscopic analyses, including HRMS, ¹H NMR, ¹³C NMR, and IR spectroscopy, which verified the expected functional group conversions and substitution patterns.

The structural integrity of the newly synthesized 1-butyl-indazole-3-carboxamide derivatives was strongly supported by a comprehensive analysis of their spectroscopic data, which aligned well with literature precedents for similar indazole systems. In the infrared (IR) spectra, the successful formation of the carboxamide linkage was verified by the appearance of a characteristic stretching band around 3250–3300 cm^–1 corresponding to the N–H group, alongside a strong carbonyl (C = O) stretching band near 1640–1680 cm^–1.

In the ¹H NMR spectra, the introduction of the butyl chain was unequivocally confirmed by the presence of a triplet for the terminal methyl protons around 0.9–1.0 ppm, multiplets for the internal methylene groups, and a characteristic downfield triplet around 4.3–4.5 ppm corresponding to the N-1 methylene protons attached to the indazole ring, reflecting the electron-withdrawing influence of the heterocyclic nitrogen. The aromatic protons of the indazole core and substituted amides resonated within the expected 7.0–8.5 ppm region, displaying coupling patterns consistent with ortho- and para-substitution. Furthermore, ¹³C NMR spectra displayed the expected diagnostic signals, notably the amide carbonyl carbon appearing around 160–165 ppm, while high-resolution mass spectrometry (HRMS) data provided molecular ion peaks corresponding precisely to the calculated theoretical masses, thereby confirming the proposed empirical formulas and electronic structures.

Density Functional Theory (DFT) and Frontier Molecular Orbital (FMO) Analysis

After structural confirmation and spectroscopic characterization of the synthesized carboxamide derivatives, theoretical calculations were subsequently performed to gain deeper insight into their electronic structures and reactive profiles. Quantum chemical calculations were carried out using the Gaussian 16 software package, and molecular geometries were optimized using density functional theory (DFT) at the B3LYP/6-31G­(d,p) level of theory. Molecular structures and frontier orbitals were visualized using GaussView 6.0.

Frontier molecular orbital (FMO) analysis revealed that the HOMO and LUMO distributions are predominantly localized across the indazole core and the extended carboxamide-conjugated system, reflecting the primary sites of electronic transitions. The highest occupied molecular orbital (E _HOMO) denotes a molecule’s ability to donate electrons, where a higher E _HOMO value indicates greater electron-donating capacity. Conversely, the lowest unoccupied molecular orbital (E _LUMO) refers to a molecule’s ability to accept electrons.

As shown in Table S1 ( Supporting Information), the HOMO–LUMO energy gap was calculated using the formula (ΔE = E _LUMO – E _HOMO). Among all evaluated derivatives, compounds 5f and 5h exhibited the smallest energy gaps (both bearing a nitro substituent on the aryl ring attached to the indazole core), and 5m had the largest energy gap, with their frontier molecular orbitals shown in Figure . In accordance with quantum chemical principles, compounds with smaller HOMO–LUMO gaps are less stable and more reactive, whereas molecules with larger HOMO–LUMO gaps are more stable and less reactive. The complete set of calculated DFT values for the indazole analogues is provided in the Supporting Information.

3.

FMO diagrams for 5f and 5m (highest and lowest energy gap).

Molecular Electrostatic Potential

The molecular electrostatic potential (MEP) is used to predict the reactivity of electrophiles and nucleophiles. For every synthesized molecule, MEP surface analysis was carried out using the DFT calculation with the B3LYP/6-31G′(d,p) base set. The MEP surface exhibits multiple colors on the electrostatic potential surface: green indicates the zero potential (neutral), blue indicates the most positive (electrophile) potential, and red indicates the most negative (nucleophile) potential. , Because of their lone pairs of electrons, oxygen and nitrogen atoms have nucleophilic sites, whereas hydrogen atoms usually behave as electrophilic sites. Two of the synthetic indazole derivatives with the lowest and highest HOMO–LUMO energy gaps (5f and 5m, respectively) were subjected to electrostatic potential surface mapping (Figure ).

4.

MEP surface diagrams of (a) 5f and (b) 5m.

Global Reactivity Parameters

Molecular stability and polarization are heavily influenced by the evaluated energy gap. Utilizing HOMO-LUMO energy levels at the 6-31G+(d,p) level, key electronic properties were calculated, including ionization potential (I), electron affinity (A), and global descriptors like absolute electronegativity (χ), chemical potential (μ), hardness (η), softness (S), and the electrophilicity index (ω) encompassing both electron-donating (ω^–) and electron-accepting (ω⁺) capacities. These global reactivity metrics were derived using standard equations (given below) and are compiled in Table S2. Furthermore, supplementary electrical properties for the indazole derivatives are available in Table S2 of the Supporting Information.

$$E=\mathrm{LUMO}-\mathrm{HOMO}(\mathrm{eV})$$ 1

$$I=-E_{\mathrm{HOMO}}(\mathrm{eV})$$ 2

$$A=-E_{\mathrm{LUMO}}(\mathrm{eV})$$ 3

$$\chi =(I+A)/2(\mathrm{eV})$$ 4

$$\mu =-\chi (\mathrm{eV})$$ 5

$$\eta =(I-A)/2(\mathrm{eV})$$ 6

$$S=1/\eta (\mathrm{eV})$$ 7

$$\omega =\mu 2/2\eta (\mathrm{eV})$$ 8

$$\omega -=(3\mathrm{I}+A)2/16(I-A)(\mathrm{eV})$$ 9

$$\omega +=(I+3A)2/16(I-A)(\mathrm{eV})$$ 10

Time-Dependent-DFT

To further investigate the electronic transitions and optical properties, time-dependent density functional theory (TD-DFT) was employed to extend the calculations to excited states. TD-DFT enables the computation of electronic absorption spectra, providing key insights into the optical characteristics of the molecules. The theoretical calculations were performed using the B3LYP/6-31G+(d,p) basis set. The resulting theoretical UV–Vis absorption spectra for all synthesized derivatives are summarized in Table S3 (available in the Supporting Information), detailing the maximum absorption wavelengths (λ _max), excitation energies, oscillator strengths, and significant orbital contribution values (available in the Supporting Information).

Single-Crystal X-ray Diffraction Analysis

Among the 13 synthesized derivatives, single crystals suitable for analysis were obtained for compounds 5c and 5d. The crystals were characterized using a Bruker D8 Venture single-crystal X-ray diffractometer (SC-XRD) with Mo Kα radiation at room temperature. In both cases, the crystals were colorless, needle-like in morphology, and were grown by slow evaporation from ethanol as the solvent. The crystal structures for 5c and 5d have been deposited in the Cambridge Crystallographic Data Centre (CCDC) with the accession numbers 2526939 and 2526948, respectively. Supporting information includes crystal data and structure refinements for 5c and 5d (Tables S4 and S6), as well as selected bond lengths, bond angles, and torsional angles (Tables S5 and S7).

Compound 5c (crystal dimensions 0.258 × 0.178 × 0.066 mm³) crystallizes in the monoclinic centrosymmetric space group P2₁/c with unit cell dimensions of a = 14.9776(13) Å, b = 14.3522(13) Å, c = 8.5017(7) Å, β = 96.938(3)°, volume = 1816.6(3) ų, and Z = 4 (R ₁ = 0.0486). The ORTEP diagram for 5c is shown in Figure . Analysis of its geometry indicates that the indazole core maintains a nearly planar conformation, while the N – 1 butyl chain adopts an extended conformation to minimize steric strain. In the crystal lattice, the molecules are organized into a robust supramolecular network stabilized by classical N–H···O hydrogen bonding and weak π–π stacking interactions.

5.

ORTEP diagram for 5c with an ellipsoidal probability of 40%.

In contrast, compound 5d (crystal dimensions 0.306 × 0.285 × 0.117 mm³), which incorporates an additional oxygen-bearing functional group, crystallizes in the triclinic centrosymmetric space group P – 1 with a significantly larger unit cell volume of 2894.7(5) ų (a = 11.7124(12) Å, b = 15.4096(16) Å, c = 18.1197(19) Å, α = 93.030(4)°, β = 104.658(4)°, γ = 111.47(4)°, Z = 6, R ₁ = 0.0673). A notable structural feature of 5d is the presence of three crystallographically independent molecules in the asymmetric unit, which are intricately linked through an extended network of N–H···O hydrogen bonding (Figure ). Furthermore, the butyl chain in two of these independent molecules is thermally disordered over two positions. An individual unit of 5d drawn using ORTEP software is presented in Figure .

6.

ORTEP diagram for 5d with an ellipsoidal probability of 40%.

7.

Individual unit of 5d drawn using ORTEP with an ellipsoidal probability of 40%.

The molecular overlay of the two crystallographically independent molecules in compound 5d reveals subtle but noteworthy conformational differences. While the overall coordination environment around the central metal atom remains consistent, variations are observed in the orientation of the peripheral substituents and hydrogen-bonding interactions. Specifically, one molecule adopts a slightly twisted conformation in the ligand backbone, leading to an altered positioning of donor atoms relative to the metal center. This deviation results in minor differences in intramolecular hydrogen bonding, as highlighted by the dashed interactions in the overlay (Figure ).

8.

Molecular overlay plot of compound 5d.

Comparative structural evaluation between 5c and 5d demonstrates that while the core indazole planarity is strictly conserved, subtle peripheral oxygen substitution profoundly alters the crystal system symmetryshifting from monoclinic to triclinicand rearranges the asymmetric unit architecture. These solid-state findings provide a comprehensive structural context that nicely bridges the experimental observations with the theoretical DFT and FMO findings. Figure a,b depict the crystal packing diagrams of the compounds 5c and 5d.

9.

Molecular packing diagrams of (a) 5c and (b) 5d.

Hirshfeld Surface Analysis

Hirshfeld surface analysis is a powerful tool for visualizing and quantifying intermolecular interactions in crystalline solids. By partitioning space based on electron density contributions from a molecule and its surrounding neighbors, the Hirshfeld surface provides a three-dimensional “skin” around the molecule that highlights regions of close contact. This method allows researchers to identify not only the presence of hydrogen bonds and van der Waals contacts but also the geometric features of molecular packing, thereby offering both qualitative and quantitative insights into crystal structures.

Several parameters mapped onto the Hirshfeld surface help interpret intermolecular interactions. The internal distance (d _i) reflects proximity to atoms within the molecule, while the external distance (d _e) measures closeness to neighboring atoms. Their combination, the normalized contact distance (d_norm), highlights regions where contacts are shorter, equal to, or longer than expected van der Waals separations. Additional descriptors refine this analysis: curvedness distinguishes flat regions, often linked to π–π stacking, from highly curved ones, while the shape index identifies complementary concave and convex features that reveal stacking motifs. The fragment patch option further isolates specific regions for localized interaction analysis. Figures and illustrate these parameters for compounds 5c and 5d.

10.

Hirshfeld surfaces for the compound 5c.

11.

Hirshfeld surfaces for the compound 5d.

For 5c, the shape-index surfaces display distinct complementary red and blue triangular patches across the indazole and phenyl rings, diagnostic of strong face-to-face π–π stacking. The curvedness plots show extended flat regions, further confirming efficient aromatic overlap. Fingerprint plots highlight a high percentage of C···C contacts, underscoring the dominance of π–π stacking as the primary stabilizing force in the lattice. Secondary contributions from C···H and H···H contacts complement but do not outweigh the aromatic interactions.

In contrast, 5d exhibits weaker stacking features. The shape-index surfaces show less pronounced complementary patches, suggesting reduced face-to-face overlap and a greater role for edge-to-face contacts involving the phenoxy substituent. The curvedness plots reveal fewer flat regions and more curved areas, consistent with steric hindrance introduced by the oxygen atom in the phenoxy group. Fingerprint plots confirm this shift, with C···C contacts contributing less than in 5c, while C···H and H···H contacts become more prominent, indicating stabilization through weaker van der Waals interactions.

Taken together, these results demonstrate that compound 5c is dominated by strong π–π stacking interactions, facilitated by its planar aromatic cores, whereas compound 5d shows disrupted stacking due to the phenoxy substituent, leading to a packing arrangement stabilized by a mixture of weaker dispersive contacts. This comparative analysis highlights how even minor substituent changes can markedly alter intermolecular interactions, in line with established methodologies for aromatic systems. −

Fingerprint Plots

The Hirshfeld surface analysis of compounds 5c and 5d reveals that crystal packing is dominated by H···H contacts, contributing 56.2% and 53.3%, respectively (Table ), which reflects the prevalence of van der Waals interactions in both structures. In 5c, the higher proportion of H···O (6.4%) and H···N (1.4%) contacts underscores the role of hydrogen bonding between the carbohydrazide moiety and neighboring molecules. By contrast, 5d exhibits a markedly greater contribution from H···O contacts (11.0%), indicating stronger hydrogen-bonding interactions facilitated by the phenoxyacetyl substitution.

1. Contact Type and Their Percentage Contributions for 5c and 5d .

	percentage contribution
contact type	5c	5d
H···H	56.2	53.3
H···O	6.4	11
H···N	1.4	0.7
H···C	9.2	6.9
C···C	1.6	2

The analysis also highlights differences in C···C contacts, with 5c showing 1.6% and 5d slightly higher at 2.0%. Although modest in percentage, these contacts are chemically significant, confirming the presence of π–π stacking between aromatic rings. The shape-index and curvedness surfaces further support this interpretation, showing complementary hollows/bumps and extended flat regions consistent with offset stacking motifs. Together, these quantitative results demonstrate that while van der Waals forces dominate overall packing, hydrogen bonding and π–π interactions provide crucial stabilization, with substitution at the acyl group modulating the balance of noncovalent forces. The fingerprint plots of 5c and 5d are shown in Figure .

12.

Overall two-dimensional fingerprint plots of (a) 5c and (b) 5d.

UV–Visible and Fluorescence Analysis

The UV–vis absorption spectra for all synthesized indazole derivatives (5a–5m) were determined in DMSO at a concentration of 2 × 10^–5 M at room temperature. Overall, the absorption bands of these compounds ranged from 298 to 306 nm. The experimental spectra displayed distinct absorption features, with compound 5f exhibiting an absorbance at 298 nm and compound 5l showing an absorbance band at 306 nm. Figure a shows the normalized absorbance spectrum of all of the synthesized indazole derivatives. The band (short) seen near 270 nm is due to π → π* transitions, and the predominant peak near 300 nm is due to n → π* transition.

13.

(a) Normalized absorbance spectra and (b) fluorescence spectra of synthesized indazole derivatives 5a–5m.

The experimental spectra show a uniform absorption maximum near 299–304 nm for all derivatives. While the TD-DFT calculations capture the general trend, the nitro-functionalized derivatives 5f and 5h exhibit computed low-energy transitions at 350 and 422 nm, respectively. These transitions originate from the strong electron-withdrawing nature of the nitro group, promoting intramolecular charge transfer (ICT). Nevertheless, their exceptionally low oscillator strengths (f = 0.0146 for 5f and f = 0.001 for 5h) indicate that these bands are weak and practically obscured experimentally by the more intense localized transitions occurring near 300 nm. The table S3 (available in supporting information) shows the complete set of selected transitions found theoretically, along with the experimentally observed λ_max .

The photophysical investigation was done by obtaining the absorption spectra using a JASCO V-670 spectrometer and the fluorescence spectra via a Hitachi F-7000 FL spectrofluorophotometer, with the excitation wavelength being set at the absorption maxima of the corresponding compounds. All of the compounds showed a good level of fluorescence emission in the wavelength range of 345–355 nm (Figure b). There were no emission peaks observed for the π → π* transitions, with only n → π* transitions showing an emission peak in the aforementioned range. The solutions were prepared in DMSO with a concentration of 2 × 10^–5 M for the purpose of analyzing the fluorescent activity of the synthesized compounds.

The fluorescence emission spectra of compounds 5a–5m demonstrate clear substituent-dependent behavior. The calculated Stokes shifts (Δν) range from 3.897 × 10⁴ cm^–1 to 5.053 × 10⁴ cm^–1 (Table ). Notably, derivative 5e, bearing the 2,4-dichlorobenzoyl group, exhibits the largest Stokes shift (5.053 × 10⁴ cm^–1). This pronounced shift can be attributed to enhanced structural relaxation and a greater change in the molecular dipole moment between the ground (S ₀) and excited (S ₁) states, driven by the steric and electronic influence of the ortho- and para-chloro substituents. Conversely, the nitro-functionalized derivatives (5f and 5h) show distinct optical quenching behavior, which TD-DFT calculations rationalize through low-lying intramolecular charge transfer (ICT) states that promote nonradiative decay pathways over radiative emission.

2. Photophysical Properties of the Synthesized Indazole Derivatives.

compounds	absorption, λabs (nm)	emission, λemi (nm)	Stoke’s Δ × 104 v (cm–1)
5a	300	350	4.761
5b	299	344	4.375
5c	301	341	3.897
5d	301	347	4.404
5e	301	355	5.053
5f	299	344	4.375
5g	301	349	4.569
5h	301	350	4.651
5i	301	347	4.404
5j	302	343	3.958
5k	304	350	4.323
5l	304	347	4.076
5m	302	350	4.541

Conclusion

In conclusion, a series of indazole derivatives were synthesized via the coupling of indazole carbohydrazide with various aromatic acids, and their structures were comprehensively confirmed through ^1H, ^13C, DEPT-135, FT-IR, and HRMS analyses. Complementary spectroscopic investigations, including UV–Vis absorption and fluorescence measurements, further characterized the electronic properties of the compounds. Density functional theory (DFT) calculations provided optimized geometries and energy parameters, revealing that derivatives 5f and 5m exhibited the lowest and highest HOMO–LUMO energy gaps, respectively. Single-crystal X-ray diffraction of compounds 5c and 5d afforded detailed structural insights, with ORTEP representations validating their molecular conformations. Hirshfeld surface analysis subsequently quantified and visualized the intermolecular interactions within the crystalline lattice. Collectively, these experimental and computational findings highlight the structural diversity, electronic characteristics, and intermolecular behavior of the synthesized indazole derivatives, establishing a robust foundation for their potential exploration in future applications.

Materials and Methods

¹H and ¹³C NMR spectra were obtained using a Bruker 400 MHz spectrometer, with chemical shifts reported in parts per million (δ, ppm) relative to tetramethylsilane (TMS) as the internal standard. High-resolution mass spectrometry (HRMS) data were collected on a Maxis 10138 analyzer. The commercial-grade solvents were purchased from Aldrich and used as such without any purification. Solvents were evaporated under reduced pressure, while the organic phases were dried with anhydrous Na₂SO₄. Thin-layer chromatographic (TLC) analysis was performed on silica gel 60F254 aluminum plates. The purification of compounds was done by column chromatography by using silica gel 60–120 mesh.

General Procedure for Synthesis of Compounds 5a–5m

Phenylhydrazine and benzaldehyde (1 equiv) were stirred in water for 8 h at room temperature to afford benzylidene-1-phenylhydrazine, which was then cyclized with oxalyl chloride and AlCl₃ (1.5 equiv) at 40–45 °C for 2 h to yield 1-(benzylideneamino)­indolin-2,3-dione. This intermediate was converted to indazole-3-carboxylic acid and alkylated with 1-bromobutane and NaH to give 1-butyl-1H-indazole-3-carboxylic acid. The final amides were obtained by coupling the 1-butyl-indazole-3-carbohydrazide obtained after esterification and subsequent hydrazinolysis with hydrazine hydrate in refluxing ethanol with various acids in DMF using HATU and DIPEA. All target compounds were purified by column chromatography with 1:3 ethyl acetate/hexane.

Spectral Characterization Data

1-Butyl-N′-(3-(trifluoromethoxy)­benzoyl)-1H-indazole-3-carbohydrazide (5a)

White solid, yield 67%, m.p: 110 °C; ¹H NMR [400 MHz, DMSO-d ₆]: δ 10.71 (s, 1H), 10.43 (s, 1H), 8.15 (d, J = 8.12 Hz, 1H), 7.99 (d, J = 5.48 Hz, 1H), 7.88 (s, 1H), 7.81 (d, J = −8.56 Hz, 1H), 7.70 (t, J = −8.04 Hz, 1H), 7.63 (d, J = 8.16 Hz, 1H), 7.48 (t, J = 7.36 Hz, 1H), 7.31 (t, J = 7.60 Hz, 1H), 4.52 (t, J = 8.00 Hz, 1H), 1.89 (q, J = 8.00 Hz, 2H), 1.30–1.28 (m, 2H), 0.89 (t, J = 8.00 Hz, 3H). ¹³C NMR [100 MHz, DMSO-d ₆]: δ 164.84, 161.86, 148.83, 140.83, 135.73, 135.20, 127.06, 124.97, 123.16, 122.91, 121.85, 120.39, 119.24, 110.96, 49.01, 31.86, 19.87, 13.95. DEPT-135 NMR [100 MHz, DMSO-d ₆]: δ Positive peaks: 131.36, 127.20, 127.06, 124.16, 123.16, 121.85, 120.39, 110.96, 13.95; Negative peaks: 49.01, 31.87, 19.87. FT-IR (cm^–1): 3229 (N–H), 2964, 2934 (aliphatic C-H), 1649 (CO). HRMS (ESI) m/z: [M + H] calculated for C₂₀H₁₉F₃N₄O₃ = 421.1487 and found = 421.1489.

1-Butyl-N′-(4-(trifluoromethyl)­benzoyl)-1H-indazole-3-carbohydrazide (5b)

White solid, yield 84%, m.p: 136 °C; ¹H NMR [400 MHz, DMSO-d ₆]: δ 10.72 (s, 1H), 10.43 (s, 1H), 8.13 (t, J = 8.00 Hz, 3H), 7.92 (d, J = 8.00 Hz, 2H), 7.82 (d, J = 12.00 Hz, 1H), 7.48 (t, J = 8.00 Hz, 1H), 7.30 (t, J = 8.00 Hz, 1H), 4.52 (t, J = 8.00 Hz, 2H), 1.89 (q, J = 8.00 Hz, 2H), 1.33–1.31 (m, 2H), 0.90 (t, J = 8.00 Hz, 3H). ¹³C NMR [100 MHz, CDCl₃]: δ 163.98, 161.13, 140.68, 134.71, 134.50, 133.48, 127.89, 126.93, 125.54, 124.90, 123.06, 122.17, 109.55, 49.43, 31.69, 20.02, 13.61. DEPT-135 NMR [100 MHz, CDCl₃]: δ Positive peaks: 127.89, 126.93, 125.54, 123.06, 122.17, 109.56, 13.61; Negative peaks: 49.43, 31.69, 20.02. FT-IR (cm^–1): 3222 (N–H), 2965, 2938 (aliphatic C-H), 1644 (CO). HRMS (ESI) m/z: [M + H] calculated for C₂₀H₁₉F₃N₄O₂ = 405.1538 and found = 405.1541.

1-Butyl-N′-(2-phenylacetyl)-1H-indazole-3-carbohydrazide (5c)

White solid, yield 86%, m.p: 108 °C; ¹H NMR [400 MHz, DMSO-d ₆]: δ 10.17 (d, J = 8.00 Hz, 2H), 8.13 (s, 1H), 7.80 (d, J = −4.00 Hz, 1H), 7.47 (t, J = 8.00 Hz, 1H), 7.38–7.36 (m, 4H), 7.29-7.27 (m, 3H), 4.50 (t, J = 4.00 Hz, 2H), 3.55 (s, 2H), 1.88 (q, J = 4.00 Hz, 2H), 1.32–1.30 (m, 2H), 0.89 (t, J = 4.00 Hz, 3H). ¹³C NMR [100 MHz, CDCl₃]: δ 168.48, 160.03, 140.64, 134.63, 134.02, 129.39, 128.92, 127.40, 126.81, 123.03, 122.90, 122.24, 109.48, 49.33, 41.45, 31.66, 19.99, 13.59. DEPT-135 NMR [100 MHz, CDCl₃]: δ Positive peaks: 129.40, 128.95, 127.45, 126.82, 122.92, 122.24, 109.49, 13.61; Negative peaks: 49.34, 41.49, 31.67, 20.00.FT-IR (cm^–1): 3244 (N–H), 2958, 2927 (aliphatic C-H), 1639 (CO).HRMS (ESI) m/z: [M + H] calculated for C₂₀H₂₀N₄O₂ = 351.1821 and found = 351.1823.

1-Butyl-N′-(2-phenoxyacetyl)-1H-indazole-3-carbohydrazide (5d)

White solid, yield 86%, m.p: 118 °C; ¹H NMR [400 MHz, DMSO-d ₆]: δ 10.22 (d, J = 16.00 Hz, 2H), 8.14 (d, J = 8.00 Hz, 1H), 7.82 (d, J = 8.00 Hz, 1H), 7.48 (t, J = 8.00 Hz, 1H), 7.36–7.34 (m, 3H), 7.06-7.04 (m, 2H), 6.99 (s, 1H), 4.56 (t, J = 8.00 Hz, 2H), 2.41 (q, J = 8.00 Hz, 2H), 0.92–1.31 (m, 2H), (t, J = 8.00 Hz, 3H). ¹³C NMR [100 MHz, CDCl₃]: δ 167.55, 161.53, 158.24, 140.83, 135.83, 129.95, 127.12, 123.06, 122.89, 121.90, 121.71, 115.25, 110.97, 66.58, 31.88, 19.89, 14.00. DEPT-135 NMR [100 MHz, CDCl₃]: δ Positive peaks: 129.96, 127.13, 123.06, 121.90, 121.71, 115.25, 110.97, 14.00; Negative peaks: 66.58, 48.96, 31.89, 19.89. FT-IR (cm^–1): 3213 (N–H), 2962, 2931 (aliphatic C-H), 1701, 1658 (CO). HRMS (ESI) m/z: [M + H] calculated for C₂₀H₂₂N₄O₃ = 405.1538 and found = 405.1541.

1-Butyl-N′-(2,4-dichlorobenzoyl)-1H-indazole-3-carbohydrazide (5e)

White solid, yield 80%, m.p: 114 °C; ¹H NMR [400 MHz, DMSO-d6]: δ 10.44 (d, J = 10.80 Hz, 2H), 8.17 (d, J = 8.40 Hz, 1H), 7.82 (t, J = 8.80 Hz, 1H), 7.77 (s, 1H), 7.60-7.60 (m, 2H), 7.49 (t, J = 7.20 Hz, 1H), 7.32 (t, J = 7.60 Hz, 1H), 4.53 (t, J = 6.80 Hz, 2H), 1.95–1.93 (m, 2H), 1.32–1.30 (m, 2H), 0.91 (t, J = 7.20 Hz, 3H).¹³C NMR [100 MHz, DMSO-d ₆]: δ 165.33, 161.55, 140.86, 136.49, 135.74, 131.30, 130.08, 129.98, 127.86, 127.14, 123.10, 121.89, 121.53, 110.98, 48.98, 31.85, 19.90, 14.00. DEPT-135 NMR [100 MHz, DMSO-d ₆]: δ Positive peaks: 130.31, 130.09, 129.98, 127.45, 127.14, 123.11, 121.89, 110.99, 14.01; Negative peaks: 48.98, 31.86, 19.90. FT-IR (cm^–1): 3210 (N–H), 2954, 2933 (C–H stretching)­1696, 1640 (CO). HRMS (ESI) m/z: [M + H] calculated for C₁₉H₁₈Cl₂N₄O₂ = 405.0885 and found = 405.0886.

1-Butyl-N′-(4-nitrobenzoyl)-1H-indazole-3-carbohydrazide (5f)

White solid, yield 85%, m.p: 140 °C; ¹H NMR [400 MHz, DMSO-d ₆]: δ 10.83 (s, 1H), 10.47 (s, 1H), 8.40 (d, J = 8.00 Hz, 2H), 8.14-8.16 (m, 3H), 7.84 (d, J = 8.00 Hz, 1H), 7.51 (d, J = 8.00 Hz, 1H), 7.32 (t, J = 8.00 Hz, 1H), 4.54 (t, J = 8.00 Hz, 2H), 1.90 (q, J = 4.00 Hz, 2H), 1.26–1.27 (m, 2H), 0.92 (t, J = 8.00 Hz, 3H). ¹³C NMR [100 MHz, DMSO-d ₆]: δ 164.77, 161.74, 149.86, 140.86, 138.77, 135.76, 129.49, 127.18, 124.25, 123.15, 122.93, 121.88, 111.02, 49.02, 31.91, 19.91, 14.02. DEPT-135 NMR [100 MHz, DMSO-d ₆]: δ Positive peaks: 129.50, 127.18, 124.25, 123.16, 121.88, 111.02, 14.02; Negative peaks: 49.02, 31.91, 19.91. FT-IR (cm^–1): 3217 (N–H), 1646 (CO), 1530, 1341 (N–O asymmetric and symmetric stretching). HRMS (ESI) m/z: [M + H] calculated for C₁₉H₁₉N₅O₄ = 382.1515 and found = 382.1516.

Methyl 2-(2-(1-butyl-1H-indazole-3-carbonyl)­hydrazine-1-carbonyl)­benzoate (5g)

White solid, yield 66%, m.p: 120 °C; ¹H NMR [400 MHz, DMSO-d ₆]: δ 11.14 (s, 1H), 8.09 (d, J = 8.40 Hz, 1H), 8.01–8.02 (m, 2H), 7.77–7.98 (m, 2H), 7.88 (d, J = 8.56 Hz, 1H), 7.52 (t, J = 7.72 Hz, 1H), 7.34 (t, J = 7.40 Hz, 1H), 4.58 (t, J = −6.96 Hz, 2H), 3.83 (s, 1H), 1.93 (q, J = −7.12 Hz, 2H), 1.27–1.29 (m, 2H), 0.92 (t, J = 7.40 Hz, 3H). ¹³C NMR [100 MHz, DMSO-d ₆]: δ 167.85, 165.86, 161.28, 140.95, 135.92, 134.50, 132.13, 131.87, 129.88, 129.16, 127.44, 124.33, 123.68, 122.96, 121.56, 111.27. DEPT-135 NMR [100 MHz, DMSO-d ₆]: δ Positive peaks: 135.93, 132.13, 129.17, 127.44, 124.34, 123.68, 121.56, 111.27, 53.09, 14.02; Negative peaks: 49.26, 31.95, 19.93. FT-IR (cm^–1): 3263 (N–H), 2960 (−OCH3), 1738, 1672 (CO). HRMS (ESI) m/z: [M + H] calculated for C₂₁H₂₂N₄O₄ = 395.1719 and found = 395.1720.

1-Butyl-N′-(3-nitrobenzoyl)-1H-indazole-3-carbohydrazide (5h)

White solid, yield 87%, m.p: 130 °C; ¹H NMR [400 MHz, DMSO-d ₆]: δ 10.73 (s, 1H), 10.43 (s, 1H), 8.14 (t, J = 8.00 Hz, 3H), 7.94 (d, J = 8.00 Hz, 2H), 7.83 (d, J = 8.00 Hz, 1H), 7.49 (t, J = 8.00 Hz, 1H), 7.31 (t, J = 8.00 Hz, 1H), 4.54 (t, J = 8.00 Hz, 2H), 1.91 (q, J = 8.00 Hz, 2H), 1.25–1.27 (m, 2H), 0.91 (t, J = 8.00 Hz, 3H). ¹³C NMR [100 MHz, DMSO-d ₆]: δ 165.22, 161.78, 140.85, 136.94, 135.80, 128.80, 127.17, 126.08, 125.71, 122.93, 121.88, 111.00, 49.00, 31.89, 19.90, 14.00. DEPT-135 NMR [100 MHz, DMSO-d ₆]: δ Positive peaks: 128.90, 127.17, 126.04, 123.13, 121.89, 111.00, 14.01; Negative peaks: 49.00, 31.90, 19.90. FT-IR (cm^–1): 3221 (N–H), 2965, 2938 (aliphatic C-H), 1643 (CO), 1528, 1322 (N–O asymmetric and symmetric stretching). HRMS (ESI) m/z: [M + H] calculated for C₁₉H₁₉N₅O₄ = 382.1515 and found = 382.1516.

1-Butyl-N′-(3-(methylsulfonyl)­benzoyl)-1H-indazole-3-carbohydrazide (5i)

White solid, yield 77%, m.p: 182 °C; ¹H NMR [400 MHz, DMSO-d ₆]: δ 400 MHz, DMSO-d6: δ 10.79 (s, 1H), 10.46 (s, 1H), 8.46 (s, 1H), 8.26 (d, J = 7.80 Hz, 2H), 8.16 (t, J = 8.00 Hz, 1H), 7.49 (t, J = 8.00 Hz, 2H), 7.87–7.85 (m, 2H), 7.50 (t, J = 0.76, Hz, 1H), 7.32 (t, J = 7.64 Hz, 1H), 3.31 (s, 3H), 4.54 (t, J = 8.00 Hz, 2H), 1.91 (q, J = 8.00 Hz, 2H), 0.92 (t, J = 8.00 Hz, 3H). ¹³C NMR [100 MHz, DMSO-d ₆]: δ 164.90, 161.79, 141.69, 140.85, 135.76, 134.14, 132.91, 130.62, 130.51, 127.19, 126.48, 123.16, 122.93, 121.87, 111.02, 49.02, 31.92, 19.91, 14.02. DEPT-135 NMR [100 MHz, DMSO-d ₆]: δ Positive peaks: 132.91, 130.62, 130.51, 127.20, 126.48, 123.16, 121.88, 111.02, 43.93, 14.02; Negative peaks: 49.02, 31.92, 19.91. FT-IR (cm^–1): 3232 (N–H), 2965, 2935 (aliphatic C-H), 1649 (CO). HRMS (ESI) m/z: [M + H] calculated for C₂₀H₂₂N₄O₄S = 415.144 and found = 415.1442.

1-Butyl-N′-(3-fluoro-5-(trifluoromethyl)­benzoyl)-1H-indazole-3-carbohydrazide (5j)

White solid, yield 88%, m.p: 138 °C; ¹H NMR [400 MHz, DMSO-d ₆]: δ 10.86 (s, 1H), 10.51 (s, 1H), 8.15 (d, J = 8.24 Hz, 2H), 8.06 (d, J = 8.96 Hz, 1H), 8.01 (d, J = 8.32 Hz, 1H), 7.83 (d, J = 8.52 Hz, 1H), 7.49 (t, J = 7.48 Hz, 1H), 7.31 (t, J = 7.68 Hz, 1H), 4.54 (t, J = 6.92 Hz, 2H), 1.91 (q, J = 7.08 Hz, 2H), 1.25–1.27 (m, 2H), 0.91 (t, J = 7.36 Hz, 3H). ¹³C NMR [100 MHz, DMSO-d ₆]: δ 163.56, 161.68, 161.23, 140.85, 136.54, 135.70, 127.20, 123.18, 122.92, 121.85, 119.33, 119.10, 111.02, 49.03, 31.90, 19.90, 14.00. DEPT-135 NMR [100 MHz, DMSO-d ₆]: δ Positive peaks: 127.21, 123.18, 121.885, 120.80, 119.11, 111.02, 14.00; Negative peaks: 49.03, 31.91, 19.90. FT-IR (cm^–1): 3232 (N–H), 2965, 2935 (aliphatic C-H), 1649 (CO). HRMS (ESI) m/z: [M + H] calculated for C₂₀H₁₈F₄N₄O₂ = 423.1444 and found = 423.1444.

1-Butyl-N′-(2-(3-chlorophenyl)­acetyl)-1H-indazole-3-carbohydrazide (5k)

Pale yellow solid, yield 69%, m.p: 110 °C; ¹H NMR [400 MHz, CDCl₃]: δ 10.19 (s, 2H), 8.15 (d, J = 8.16 Hz, 1H), 7.79 (d, J = 8.52 Hz, 1H), 7.47 (t, J = 7.32 Hz, 1H), 7.40 (s, 4H), 7.29 (t, J = 7.52 Hz, 1H), 4.49 (t, J = 6.92 Hz, 2H), 1.90–1.89 (m, 2H), 1.31–1.29 (m, 1H), 0.88 (t, J = 7.28 Hz, 3H). ¹³C NMR [100 MHz, CDCl₃]: 169.52, 161.50, 140.82, 135.80, 135.78, 131.72, 131.45, 128.62, 127.09, 123.01, 122.88, 121.91, 110.92, 48.94, 31.86, 19.88, 13.98. DEPT-135 NMR [100 MHz, CDCl₃]: Positive peaks: 131.45, 128.62, 127.09, 123.01, 121.91, 110.92, 13.98; Negative peaks: 48.94, 39.87, 31.86. FT-IR (cm^–1): 3248 (N–H), 2958, 2927 (aliphatic C-H), 1631 (CO). HRMS (ESI) m/z: [M + H] calculated for C₂₀H₂₁ClN₄O₂ = 385.1431 and found = 385.1431.

1-Butyl-N′-isonicotinoyl-1H-indazole-3-carbohydrazide (5l)

Pale yellow solid, yield 46%, m.p: 140 °C; ¹H NMR [400 MHz, DMSO-d ₆]: δ 10.85 (s, 1H), 10.52 (s, 1H), 8.86 (d, J = 8.00 Hz, 2H), 8.20 (d, J = 8.00 Hz, 1H), 7.90-7.90 (m, 3H), 7.54 (t, J = 8.00 Hz, 1H), 7.36 (t, J = 8.00 Hz, 1H), 4.59 (t, J = 8.00 Hz, 2H), 1.96 (q, J = 4.00 Hz, 2H), 1.39–1.38 (m, 2H), 0.96 (t, J = 8.00 Hz, 3H). ¹³C NMR [100 MHz, CDCl₃]: δ 164.75, 161.73, 150.95, 140.86, 140.10, 135.76, 127.18, 123.15, 122.94, 121.88, 121.83, 111.02, 49.01, 31.90, 19.90, 14.01. DEPT-135 NMR [100 MHz, CDCl₃]: δ Positive peaks: 150.95, 127.18, 123.15, 121.88, 121.83, 14.02; Negative peaks: 49.01, 31.91, 19.91. FT-IR (cm^–1): 3260 (N–H), 2962, 2920 (aliphatic C-H), 1697, 1643 (CO). HRMS (ESI) m/z: [M + H] calculated for C₁₈H₁₉N₅O₂ = 338.1617 and found = 338.1618.

1-Butyl-N′-(2-chlorobenzoyl)-1H-indazole-3-carbohydrazide (5m)

White solid, yield 42%, m.p: 128 °C; ¹H NMR [400 MHz, CDCl₃]: δ 9.16 (s, 1H), 8.15 (d, J = 8.00 Hz, 1H), 7.56 (t, J = 8.00 Hz, 1H), 7.33 (s, 2H), 7.25-7.24 (m, 4H), 4.30 (t, J = 4.00 Hz, 2H), 1.83 (q, J = 8.00 Hz, 2H), 1.28-1.26 (m, 2H), 0.88 (t, J = 8.00 Hz, 3H).¹³C NMR [100 MHz, CDCl₃]: δ 167.96, 161.55, 140.59, 134.76, 134.12, 131.40, 129.56, 128.84, 126.93, 126.83, 123.15, 123.09, 122.25, 109.49, 49.41, 31.61, 19.98, 13.62. DEPT-135 NMR [100 MHz, CDCl₃]: δ Positive peaks: 131.40, 129.56, 128.84, 126.93, 126.83, 123.15, 122.25, 109.49, 13.62; Negative peaks: 49.41, 31.61, 19.68. FT-IR (cm^–1): 3375 (N–H), 2962, 2922 (aliphatic C-H), 1693 (CO). HRMS (ESI) m/z: [M + H] calculated for C₂₀H₂₂N₄O₃ = 371.1275 and found = 371.1274.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.6c07492.

• Characterization data such as FT-IR, ¹H NMR, ¹³C NMR, and HRMS data for all of the new compounds and basic crystallographic data of compounds 5c & 5d (PDF)

The authors declare no competing financial interest.