Synthesis and molecular docking of novel indazole derivatives with DFT studies

Synthesis and molecular docking of novel indazole derivatives with DFT studies | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Synthesis and molecular docking of novel indazole derivatives with DFT studies Bandaru Gopi, Vijayaparthasarathi Vijayakumar This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4006780/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract A series of 3-carboxamide indazoles (8a-8z) has been synthesized using an amide coupling technique. The derivatives were described using various spectroscopic methods such as 1 H NMR, 13 C NMR, IR, MASS spectral data. Density function theory (DFT) calculations revealed that compounds 8a , 8c , and 8s had the largest energy gaps among all the compounds. The study also included testing of AutoDock4 and the graphical user interface of Auto-Dock Tools, which identified three derivatives— 8v, 8w , and 8y —with the maximum binding energy. Indazole derivatives DFT studies Molecular Docking Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Indazole is a significant heterocycle in medicinal chemistry. It has been used in the development of numerous commercially successful medications and potential drug prospects for indazole core[ 1 ]. Its pharmacological and biological characteristics make it a valuable compound in drug discovery. It has proven antitumor, antibacterial, anti-inflammatory, and anti-cancer properties. HIV protease inhibitor, antiplatelet, and antidepressant, chemical synthesis, and medicinal chemistry both heavily rely on fused heterocycles containing two or more pharmacophores [ 2 – 4 ]. Indazole is the main structural component in pharmaceutical compounds like bendazac and MK-4827[ 5 ]. Benzylated indazoles I-VIII are important molecules for the pharmaceutical industry and have potential therapeutic uses for the treatment of several illnesses. These molecules act as anticancer agents (I, pazopanib, MK-4827, lonidamine VI), neuroprotective sodium channel modulators (II), antichagasic agents (III), antihypertensive agents (recoguat IV), antibacterial (V), non-steroid anti-inflammatory drugs (bendazac VII) (Fig. 1 )[ 6 ]. Many synthetic methods have been reported due to their biological relevance. It is difficult to directly N-alkylate or arylate indazole because these reactions preferentially result in the thermodynamically more stable indazole. It takes a lot of work to separate N1- and N2-alkylated combinations[ 7 ]. Two nitrogen atoms and the planarity of the indazole ring give it a unique structure that allows for many modification sites to develop several biological and therapeutic variants[ 8 ]. Cancer is a leading cause of death and endangers public health. The International Agency for Research on Cancer reported 19.3 million new cancer cases globally in 2020, with colorectal, lung, and female breast cancer accounting for 10% of all new cancer cases. Indazole compounds are anti-cancer. The anti-cancer potential of indazole compounds has been reported with remarkable results. These compounds were tested as potential cancer therapeutics, and novel compounds with indazole scaffolds were synthesized to expand the chemical library for anti-cancer therapeutic screening [ 9 , 10 ]. The successful application of advanced tools and techniques in the field of chemistry can lead to groundbreaking discoveries. A recent study that utilized GAUSSIAN 09, Gaussian View 6.1, and Auto Dock4 has yielded some promising findings[ 11 – 13 ]. The compounds studied exhibit potential anticancer activity, particularly against kidney cancer. Based on these findings, the synthesis of novel derivatives of indazole molecules is being explored. Experimental Instruments and reagents All the reactions were carried out in round bottom flasks. All the solvents and chemical materials were purchased from commercial sources. The 1-butyl-1H-indazole-3-carboxamide was prepared according to the reported protocols. 1 H and 13 C NMR spectra were recorded on Bruker Avance400 spectrometer and are referred to the residual solvent signal CDCl 3 : (7.26) for 1 H and (77.16) for 13 C NMR: dimethyl sulfoxide-d 6 (2.50) for 1 H and (39.50) for 13 C NMR: chemical shift (δ) is given in ppm and coupling constant (J) were measured in Hz. The following abbreviations are used: s- singlet, d-doublet, dd-doublet of doublet, t-triplet, td-triplet of doublet, dt- doublet of triplet, q-quartet, qd- quartet of doublet, qn-quintet, br-broad, m-multiplet. HRMS ESI-MS was recorded using Xeo G2 XS OT of (water) and values are given m/z. Colum chromatography was carried out using silica gel (100–200 mesh) packed in a glass column. Analytical TLC was carried out on Macherey-Nagel 60 F245 aluminium-backed silica gel plates. General Procedure for the Synthesis 8a-8z A stirred solution of 1-butyl-1 H -indazol-3-carboxylic acid (250 mg, 1.146 mmol) was dissolved in DMF (10 mL), HATU (2 equivalents), and DIPEA (3 equivalents) were added to the reaction mixture, then commercial amines (2 equivalents) were added. The reaction mixture was stirred at room temperature for 8-16h. After completion of the reaction, the resultant reaction mixture was poured into water; the solution was extracted with water and ethyl acetate (4 x 20 mL). The organic layer was dried with anhydrous sodium sulfate and the solvent was removed under reduced pressure to afford crude product. The crude was purified by silica gel chromatography to obtain pure products 8a-8z . Characterization of indazole carboxamide derivatives from 8a-8z. 1-Butyl-1 H -indazol-3-carboxamide (8a). Appearance : Off-white solid (yield = 93.9%, 140 mg). 1 H NMR [400 MHz, DMSO-d 6 ] : δ 8.11 (d, J = 8.00 Hz, 1H), 7.69 (d, J = 8.80 Hz, 1H), 7.56 (s, 1H), 7.37 (t, J = 8.00 Hz, 1H), 7.28 (s, 1H), 7.19 (t, J = 7.60 Hz, 1H), 4.40 (t, J = 6.80 Hz, 2H), 1.79 (q, J = 6.80 Hz, 2H), 1.15–1.17 (m, 2H), 0.82 (t, J = 7.60 Hz, 3H). 13 C NMR [100 MHz, DMSO-d 6 ] : d ppm 141.04, 137.5, 126.84, 122.68, 122.64, 122.41, 110.71, 48.80, 31.88, 19.87, 13.96. IR STRECHING : (N-H) = 3306 Cm − 1 , (C = O) = 1664 Cm − 1 . HRMS (ESI) m/z: [M + H] calculated C 12 H 15 N 3 O 217.1215 + found 240.111[M + Na]. 1-Butyl-N-phenyl-1 H -indazol-3-carboxamide (8b). Appearance : Pale brown solid (yield = 96.7%, 195 mg). 1 H NMR [400 MHz, DMSO-d 6 ] : δ 10.19 (s, 1H), 8.24 (d, J = 8.00 Hz, 1H), 7.89 (d, J = 8.00 Hz, 2H), 7.82 (d, J = 8.80 Hz, 1H), 7.49 (t, J = 7.20 Hz, 1H), 7.38–7.36 (m, 3H), 7.10 (q, J = 6.80 Hz, 1H), 4.56 (t, J = 6.80 Hz, 2H), 1.91 (q, J = 6.80 Hz, 2H), 1.34–1.32 (m, 2H), 0.92 (t, J = 7.20 Hz, 3H) . 13 C NMR [100 MHz, DMSO-d 6 ] : d ppm 161.04, 141.17, 139.21, 137.46, 129.01, 127.17, 123.92, 123.05, 122.25, 120.78, 110.96, 49.08, 32.0, 19.94, 14.02. IR STRECHING : (N-H) = 3306 Cm − 1 , (C = O) = 1664 Cm − 1 . HRMS (ESI) m/z: [M + H] calculated C 18 H 19 N 3 O 293.1528 + found 294.1596 [M + H]. N-Benzyl-1-butyl-1 H -indazol-3-carboxamide (8c). Appearance : Pale yellow solid (yield = 90%, 190 mg). 1 H NMR [400 MHz, DMSO-d 6 ] : δ 8.81 (t, J = 6.40 Hz, 1H), 8.11 (d, J = 8.40 Hz, 1H), 7.70 (d, J = 8.80 Hz, 1H), 7.38 (t, J = 0.80 Hz, 1H), 7.19–7.21 (m, 4H), 7.15–7.16 (m, 2H), 4.40–4.41 (m, 4H), 1.79 (q, J = 7.20 Hz, 2H), 1.16–1.16 (m, 2H), 0.82 (t, J = 7.60 Hz, 3H). 13 C NMR [100 MHz, DMSO-d 6 ] : d ppm 162.4, 141,140,42,137.36, 128.69, 127.89, 127.15, 126.97, 122.74, 122.63, 122.27, 110.8, 48.88, 42.39, 31.93, 19.91, 14. IR STRECHING : (N-H) = 3381 Cm − 1 , (C = O) = 1639 Cm − 1 . HRMS (ESI) m/z: [M + H] calculated C 19 H 21 N 3 O 307.17 + found 308.1760 [M + H]. N-(3-Bromophenyl)-1-butyl-1 H -indazol-3-carboxamide (8d). Appearance : Brown solid (yield = 78.4%, 200 mg). 1 H NMR [400 MHz, CDCl 3 ] : δ 8.78 (s, 1H), 8.32 (d, J = 8.40 Hz, 1H), 7.95 (d, J = 1.60 Hz, 1H), 7.60–7.59 (m, 1H), 7.37–7.36 (m, 2H), 7.16 (t, J = 7.20 Hz, 2H), 4.34 (t, J = 7.20 Hz, 2H), 1.87 (q, J = 7.60 Hz, 2H), 1.34–1.32 (m, 2H), 0.89 (t, J = 7.20 Hz, 3H). 13 C NMR [100 MHz, CDCl 3 ] : 160.51, 141.11, 139.38, 136.73, 126.99, 126.83, 123.03, 122.94, 122.73, 122.44, 118.03, 109.48, 49.38, 31.38, 20.07, 13.66. IR STRECHING : (N-H) = 3272 Cm − 1 , (C = O) = 1655 Cm − 1 . HRMS (ESI) m/z: [M + H] calculated C 18 H 18 BrN 3 O 371.2660 + found 372.0707[M + H]. 2-(1-Butyl-1 H -indazol-3-carboxamido)-5-iodobenzoic acid (8e). Appearance : Yellow solid (yield = 47%, 150 mg). 1 H NMR [400 MHz, DMSO-d 6 ] : δ 8.46 (d, J = 8.00 Hz, 1H), 8.38 (s, 1H), 8.24 (d, J = 8.40 Hz, 1H), 7.88 (d, J = 8.40 Hz, 1H), 1887.17 (q, J = 8.40 Hz, 2H), 7.41 (t, J = 7.60 Hz, 1H), 4.58 (t, J = 6.40 Hz, 2H), 1.90 (t, J = 6.80 Hz, 2H), 1.29 (q, J = 6.80 Hz, 2H), 0.91 (t, J = 7.20 Hz, 3H). 13 C NMR [100 MHz, DMSO-d 6 ] : d ppm 157.97, 153.64, 146.45, 145.49, 141.21, 136.41, 134.02, 129.31, 127.51, 123.75, 122.91, 122.50, 119.65, 111.33, 93.54, 49.40, 31.93, 19.88, 13.98. IR STRECHING : (O-H) = 2947 Cm − 1 , (N-H) = 2860 Cm − 1 , (C = O) = 1740 Cm − 1 . HRMS (ESI) m/z: [M + H] calculated C 19 H 16 IN 3 O 2 445.0287 + found 446.0365[M + H]. 1-Butyl-N-(4-(phenylamino)phenyl)-1 H -indazol-3-carboxamide (8f). Appearance : Grey solid (yield = 87%, 230 mg). 1 H NMR [400 MHz, DMSO-d 6 ] : δ 10.06 (s, 1H), 8.26 (d, J = 8.00 Hz, 1H), 8.08 (s, 1H), 7.78 (t, J = 7.20 Hz, 3H), 7.48 (t, J = 7.20 Hz, 1H), 7.31 (t, J = 7.60 Hz, 1H), 7.22 (t, J = 7.20 Hz, 2H), 7.08 (q, J = 8.40 Hz, 4H), 6.79 (t, J = 7.20 Hz, 1H), 4.53 (t, J = 6.80 Hz, 2H), 1.90 (t, J = 6.80 Hz, 2H), 1.30 (q, J = 7.20 Hz, 2H), 0.90 (t, J = 7.20 Hz, 3H). 13 C NMR [100 MHz, DMSO-d 6 ] : d ppm 160.64, 144.51, 141.16, 139.64, 137.71, 131.98, 129.62, 127.12, 122.91, 122.88, 122.33, 122.15, 119.55, 118.03, 116.43, 110.89, 49.02, 31.98, 19.93, 14. IR STRECHING : (N-H) = 3342 Cm − 1 , (C = O) = 1635 Cm − 1 . HRMS (ESI) m/z: [M + H] calculated C 24 H 24 N 4 O 384.4830 + found 384.1970[M + H]. Ethyl 4-(1-butyl-1 H -indazol-3-carboxamido)benzoate (8g). Appearance : Off white solid (yield = 75.6%, 190 mg). 1 H NMR [400 MHz, DMSO-d 6 ] : δ 10.58 (s, 1H), 8.24 (d, J = 8.00 Hz, 1H), 8.08 (d, J = 8.80 Hz, 2H), 7.96 (d, J = 8.40 Hz, 2H), 7.84 (d, J = 8.40 Hz, 1H), 7.51 (t, J = 8.00 Hz, 1H), 7.34 (t, J = 7.20 Hz, 2H), 4.57 (t, J = 6.80 Hz, 2H), 4.31 (q, J = 6.80 Hz, 2H), 1.91 (q, J = 7.20 Hz, 2H), 1.26–1.27 (m, 2H), 0.00 (t, J = 7.20 Hz, 3H). 13 C NMR [100 MHz, DMSO-d 6 ] : d ppm 165.86, 161.38, 143.72, 141.22, 137.08, 130.47, 127.30, 124.86, 123.32, 122.96, 122.12, 120.06, 111.12, 60.90, 49.16, 31.97, 19.92, 14.70, 14.01. IR STRECHING : (N-H) = 3383 Cm − 1 , (C = O) = 1712 Cm − 1 . HRMS (ESI) m/z: [M + H] calculated C 21 H 23 N 3 O 3 365.4330 + found 366.1817[M + H]. 1-butyl-N-(4-nitrophenyl)-1 H -indazole-3-carbohydrazide (8h). Appearance : Pale brown solid (yield = 57.8%, 140.5 mg). 1 H NMR [400 MHz, DMSO-d 6 ] : δ 10.60 (s, 1H), 9.22 (s, 1H), 8.11 (q, J = 9.20 Hz, 3H), 7.83 (d, J = 8.40 Hz, 1H), 7.49 (t, J = 7.60 Hz, 1H), 7.30 (t, J = 7.20 Hz, 1H), 6.83 (d, J = 9.20 Hz, 1H), 4.54 (t, J = 6.80 Hz, 2H), 1.91 (q, J = 7.20 Hz, 2H), 1.27–1.29 (m, 2H), 0.92 (t, J = 7.20 Hz, 3H). 13 C NMR [100 MHz, DMSO-d 6 ] : d ppm 162.31, 155, 67, 140.87, 138.40, 135.72, 127.21, 126.41, 123.15, 122.96, 121.89, 111.11, 111.02, 49.08, 31.91, 19.92, 14.02. IR STRECHING : (N-H) = 3355 Cm − 1 , (C = O) = 1658 Cm − 1 , (NO 2 ) = 1595 Cm − 1 . HRMS (ESI) m/z: [M + H] calculated C 18 H 19 N 5 O 3 353.3820 + found 354.1569[M + H]. N-(4-Bromophenyl)-1-butyl-1 H -indazol-3-carboxamide (8i). Appearance : Brown solid (yield = 82.5%, 210.6 mg). 1 H NMR [400 MHz, DMSO-d 6 ] : δ 10.41 (s, 1H), 8.23 (d, J = 8.40 Hz, 1H), 7.90 (d, J = 8.80 Hz, 2H), 7.83 (d, J = 8.40 Hz, 1H), 7.55–7.52 (m, 3H), 7.32 (t, J = 7.60 Hz, 1H), 4.55 (t, J = 7.20 Hz, 2H), 1.90 (q, J = 7.20 Hz, 2H), 1.34–1.32 (m, 2H), 0.91 (t, J = 7.20 Hz, 3H). 13 C NMR [100 MHz, DMSO-d 6 ] : d ppm 161.16, 141.18, 138.68, 137.23, 131.82, 127.24, 123.18, 122.74, 122.18, 111.04, 55.37, 31.99, 19.92, 14.01. IR STRECHING : (N-H) = 3272 Cm − 1 , (C = O) = 1655 Cm − 1 . HRMS (ESI) m/z: [M + H] calculated C 18 H 18 BrN 3 O 371.2660 + found 372.0707[M + H]. 1-Butyl-N-(4-hydroxyphenyl)- 1H -indazol-3-carboxamide (8j). Appearance : Off white solid (yield = 72.2%, 153 mg). 1 H NMR [400 MHz, DMSO-d 6 ] : δ 9.97 (s, 1H), 9.24 (s, 1H), 8.22 (d, J = 8.00 Hz, 1H), 7.80 (d, J = 8.40 Hz, 1H), 7.64 (dd, J = 1.60, 8.60 Hz, 2H), 7.48 (t, J = 7.60 Hz, 1H), 7.30 (t, J = 8.00 Hz, 1H), 6.75 (d, J = 8.40 Hz, 2H), 4.53 (t, J = 6.80 Hz, 2H), 1.90 (q, J = 6.80 Hz, 2H), 1.28 (q, J = 7.60 Hz, 2H), 0.91 (t, J = 7.20 Hz, 3H). 13 C NMR [100 MHz, DMSO-d 6 ] : d ppm 160.58, 15.06,141.13, 137.71, 130.75, 127.09, 122.86, 122.61, 122.31, 115.42. 110.88, 48.98, 31.98, 19.92, 14.01. IR STRECHING : (N-H) = 3323 Cm − 1 , (C = O) = 1651 Cm − 1 . HRMS (ESI) m/z: [M + H] calculated C 18 H 19 N 3 O 2 309.3690 + found 310.1553[M + H]. 1-Butyl-N-(2-hydroxy-6methylphenyl)-1 H -indazol-3-carboxamide (8k). Appearance : Pale brown solid (yield = 13.5%, 30 mg). 1 H NMR [400 MHz, DMSO-d 6 ] : δ 9.34 (s, 1H), 9.22 (s, 1H), 8.18 (d, J = 8.00 Hz, 1H), 7.81 (d, J = 8.40 Hz, 1H), 7.48 (t, J = 8.00 Hz, 1H), 7.29 (t, J = 7.20 Hz, 1H), 7.02 (t, J = 8.00 Hz, 1H), 6.75 (q, J = 7.20 Hz, 2H), 4.54 (t, J = 7.20 Hz, 2H), 2.20 (s, 3H), 1.91 (q, J = 7.20 Hz, 2H), 1.28–1.30 (m, 2H), 0.94 (t, J = 5.60 Hz, 3H). 13 C NMR [100 MHz, DMSO-d 6 ] : d ppm 161.17, 153.47 141.08, 137.35, 137.17, 127.37, 127.05, 124.00, 122.87, 122.79, 122.28, 121.00, 113.95, 110.88, 48.98, 31.42, 22.53, 14.42, 14.01. IR STRECHING : (N-H) = 3355 Cm − 1 , (OH) = 3104 Cm − 1 , (C = O) = 1643 Cm − 1 . HRMS (ESI) m/z: [M + H] calculated C 19 H 21 N 3 O 2 323.3960 + found 324.1711[M + H]. 1-Butyl-N-(m-tolyl)-1 H -indazol-3-carboxamide (8l). Appearance : Off white solid (yield = 90.2%, 190 mg). 1 H NMR [400 MHz, DMSO-d 6 ] : δ 10.07 (s, 1H), 8.23 (d, J = 8.00 Hz, 1H), 7.81 (d, J = 8.40 Hz, 1H), 7.76 (s, 1H), 7.67 (d, J = 8.00 Hz, 1H), 7.49 (t, J = 8.00 Hz, 1H), 7.32 (t, J = 7.60 Hz, 1H), 7.23 (t, J = 8.00 Hz, 1H), 6.92 (d, J = 7.60 Hz, 1H), 4.54 (t, J = 7.20 Hz, 2H), 2.33 (s, 3H), 1.91 (q, J = 7.20 Hz, 2H), 1.30 (q, J = 7.60 Hz, 2H), 0.91 (t, J = 7.20 Hz, 3H). 13 C NMR [100 MHz, DMSO-d 6 ] : d ppm 160.97,141.18, 139.11, 138.19, 137.47, 128.87, 127.16, 124.64, 123.04, 122.22, 121.26, 117.91, 110.95, 49.05, 31.96, 21.70, 19.93, 14. IR STRECHING : (N-H) = 3316 Cm − 1 , (C = O) = 1659 Cm − 1 . HRMS (ESI) m/z: [M + H] calculated C 19 H 21 N 3 O 307.3970 + found 308.1765[M + H]. 1-Butyl-N-(o-tolyl)-1 H -indazol-3-carboxamide (8m). Appearance : Off white solid (yield = 90.2%, 190.5 mg). 1 H NMR [400 MHz, DMSO-d 6 ] : δ 9.61 (s, 1H), 8.24–8.22 (m, 3H), 7.83 (d, J = 8.40 Hz, 1H), 7.69 (dd, J = 2.40, -8.40 Hz, 1H), 7.50 (td, J = 0.80, -7.00 Hz, 1H), 7.34 (td, J = 0.40, -11.20 Hz, 1H), 4.53 (t, J = 6.80 Hz, 2H), 2.28 (s, 3H), 1.89 (q, J = 7.20 Hz, 2H), 1.28 (q, J = 7.60 Hz, 2H), 0.89 (t, J = 7.60 Hz, 3H). 13 C NMR [100 MHz, DMSO-d 6 ] : d ppm 160.42, 149.27, 148.46, 141.42, 139.25, 136.37, 129.24, 127.37, 123.49, 122.55, 121.91, 113.34, 111.20, 49.31, 31.77, 19.86, 17.76, 13.93. IR STRECHING : (N-H) = 3391 Cm − 1 , (C = O) = 1679 Cm − 1 . HRMS (ESI) m/z: [M + H] calculated C 19 H 21 N 3 O 307.3970 + found 308.1721[M + H]. 1-Butyl-N-(5-methylpyridin-2-yl)-1 H -indazol-3-carboxamide (8n). Appearance : Off white solid (yield = 87.5%, 185.5 mg). 1 H NMR [400 MHz, DMSO-d 6 ] : δ 9.65 (s, 1H), 8.23 (d, J = 8.00 Hz, 1H), 7.81 (d, J = 8.40 Hz, 1H), 7.69 (d, J = 7.60 Hz, 1H), 7.49 (t, J = 7.20 Hz, 1H), 7.33–7.31 (m, 3H), 7.13 (t, J = 7.60 Hz, 1H), 4.53 (t, J = 6.80 Hz, 2H), 2.31 (s, 3H), 1.90 (q, J = 7.20 Hz, 2H), 1.35–1.34 (m, 2H), 0.91 (t, J = 7.20 Hz, 3H). 13 C NMR [100 MHz, DMSO-d 6 ] : d ppm 160.80, 141.21, 137.26, 136.54, 132.05, 127.16, 125.62, 125.13, 123.05, 122.76, 122.19, 110.96, 48.98, 31.88, 19.9, 18.16, 13.95. IR STRECHING : (N-H) = 3387 Cm − 1 , (C = O) = 1675 Cm − 1 . HRMS (ESI) m/z: [M + H] calculated C 19 H 20 N 4 O 308.3850 + found 309.1719[M + H]. 1-Butyl-N-(5-methylpyridin-2-yl)-1 H -indazol-3-carboxamide (8o). Appearance : off white solid (yield = 89.1%, 198 mg). 1 H NMR [400 MHz, DMSO-d 6 ] : δ 10.11 (s, 1H), 8.24 (d, J = 8.00 Hz, 1H), 7.80 (d, J = 8.80 Hz, 3H), 7.48 (t, J = 7.60 Hz, 1H), 7.30 (t, J = 7.60 Hz, 1H), 6.94 (d, J = 8.80 Hz, 2H), 4.53 (t, J = 7.20 Hz, 2H), 3.76 (s, 3H), 1.90 (q, J = 7.20 Hz, 2H), 1.34–1.30 (m, 2H), 0.90 (t, J = 7.60 Hz, 3H). 13 C NMR [100 MHz, DMSO-d 6 ] : d ppm 160.73, 155.9, 141.14, 137.61, 132.31, 127.12, 122.93, 122.86, 122.37, 122.30, 114.17, 110.91, 55.63, 49.02, 31.99, 19.93, 14. IR STRECHING : (N-H) = 3279 Cm − 1 , (C = O) = 1651 Cm − 1 . HRMS (ESI) m/z: [M + H] calculated C 19 H 21 N 3 O 2 323.3960 + found 324.1711[M + H]. 1-Butyl-N-(4-fluorophenyl)-1 H -indazol-3-carboxamide (8p). Appearance : Pale brown solid (yield = 84.3%, 180.5 mg). 1 H NMR [400 MHz, DMSO-d 6 ] : δ 10.34 (s, 1H), 8.25 (d, J = 8.00 Hz, 1H), 7.96–7.95 (m, 2H), 7.79 (d, J = 8.40 Hz, 1H), 7.48 (t, J = 7.20 Hz, 1H), 7.31 (t, J = 7.60 Hz, 1H), 7.20 (t, J = 9.20 Hz, 2H), 4.53 (t, J = 7.20 Hz, 2H), 1.89 (q, J = 7.20 Hz, 2H), 1.33–1.31 (m, 2H), 0.89 (t, J = 7.60 Hz, 3H). 13 C NMR [100 MHz, DMSO-d 6 ] : d ppm 161.04, 159.9, 141.16, 137.36, 127.16, 123.05, 122.93, 122.7, 122.62, 122.24, 115.65, 115.43, 110.93, 49.07, 31.98, 19.91, 13.96. IR STRECHING : (N-H) = 3307 Cm − 1 , (C = O) = 1663 Cm − 1 . HRMS (ESI) m/z: [M + H] calculated C 18 H 18 FN 3 O 311.3604 + found 312.1508[M + H]. 1-Butyl-N-(2-methoxyphenyl)-1 H -indazol-3-carboxamide (8q). Appearance : Off white solid (yield = 79.8%, 177.5 mg). 1 H NMR [400 MHz, DMSO-d 6 ] : δ 9.44 (s, 1H), 8.40 (dd, J = 7.60, Hz, 1H), 8.26 (d, J = 8.00 Hz, 1H), 7.83 (d, J = 8.80 Hz, 1H), 7.52–7.52 (m, 1H), 7.34 (t, J = 7.60 Hz, 1H), 7.15–7.14 (m, 2H), 4.54 (t, J = 6.80 Hz, 2H), 3.94 (s, 3H), 1.88 (q, J = 7.20 Hz, 2H), 1.34–1.32 (m, 2H), 0.91 (t, J = 7.20 Hz, 3H). 13 C NMR [100 MHz, DMSO-d 6 ] : d ppm 160.06, 148.68, 141.39, 136.9, 127.55, 127.37, 124.35, 123.41, 122.47, 122.07, 121.13, 119.71, 111.41, 111.17, 56.53, 48.99. 31.8,19.84, 13.88. IR STRECHING : (N-H) = 3307 Cm − 1 , (C = O) = 1663 Cm − 1 . HRMS (ESI) m/z: [M + H] calculated C 19 H 21 N 3 O 2 323.3960 + found 324.1713[M + H]. 1-Butyl-N-(3-hydroxyphenyl)-1 H -indazol-3-carboxamide (8r). Appearance : Pale brown solid (yield = 66%, 140 mg). 1 H NMR [400 MHz, DMSO-d 6 ] : δ 10.05 (s, 1H), 9.43 (s, 1H), 8.23 (d, J = 8.40 Hz, 1H), 7.80 (d, J = 8.40 Hz, 1H), 7.50–7.50 (m, 2H), 7.31 (t, J = 7.60 Hz, 1H), 7.26 (d, J = 8.40 Hz, 1H), 7.13 (t, J = 8.40 Hz, 1H), 6.52 (dd, J = 1.60, 8.00 Hz, 1H), 4.53 (t, J = 6.80 Hz, 2H), 1.89 (q, J = 2.80 Hz, 2H), 1.33–1.31 (m, 2H), 0.90 (t, J = 7.20 Hz, 3H). 13 C NMR [100 MHz, DMSO-d 6 ] : d ppm 160.95, 157.99, 141.16, 140.2, 137.53, 129.67, 127.18, 123.04, 122.86, 122.23, 111.56, 111.12, 110.95, 107.88, 49.04, 31.96, 19.91, 13.99. IR STRECHING : (N-H) = 3347 Cm − 1 , (OH) = 3200 Cm − 1, (C = O) = 1703 Cm − 1 . HRMS (ESI) m/z: [M + H] calculated C 18 H 19 N 3 O 2 309.3690 + found 310.1554[M + H]. 1-Butyl-N-(4H-1,2,4-triazol-4yl)-1 H -indazol-3-carboxamide (8s). Appearance : Off white solid (yield = 89%, 174 mg). 1 H NMR [400 MHz, DMSO-d 6 ] : δ 12.12 (s, 1H), 8.80 (s, 2H), 8.14 (d, J = 8.00 Hz, 1H), 7.87 (d, J = 8.40 Hz, 1H), 7.52 (t, J = 7.20 Hz, 1H), 7.35 (t, J = 7.60 Hz, 1H), 4.57 (t, J = 7.20 Hz, 2H), 1.91 (q, J = 6.80 Hz, 2H), 1.32–1.31 (m, 2H), 0.91 (t, J = 7.20 Hz, 3H). 13 C NMR [100 MHz, DMSO-d 6 ] : d ppm 161.53, 144.49, 140.98, 134.46, 127.48, 123.73, 123.01, 121.58, 111.27, 49.26, 31.89, 19.87, 13.99. IR STRECHING : (N-H) = 3112 Cm − 1 , Cm − 1 (C = O) = 1695 Cm − 1 . HRMS (ESI) m/z: [M + H] calculated C 14 H 16 N 6 O 284.3230 + found 285.1460[M + H]. N-(2-amino-4-nitrophenyl)-1butyl-1 H -indazol-3-carbohydrazide (8t). Appearance : Brown solid (yield = 84.4%, 205 mg). 1 H NMR [400 MHz, DMSO-d 6 ] : δ 9.75 (s, 1H), 8.25 (s, 1H), 8.20 (d, J = 8.40 Hz, 1H), 7.93 (dd, J = 2.80, 9.00 Hz, 1H), 7.83 (d, J = 8.80 Hz, 1H), 7.49 (t, J = 8.00 Hz, 1H), 7.32 (t, J = 7.20 Hz, 1H), 6.85 (t, J = 8.80 Hz, 1H), 6.56 (s, 2H), 4.55 (t, J = 7.20 Hz, 2H), 1.92 (q, J = 7.20 Hz, 2H), 1.28–1.30 (m, 2H), 0.92 (t, J = 7.60 Hz, 3H). 13 C NMR [100 MHz, DMSO-d 6 ] : d 161.70, 150.93, 141.11, 137.06, 136.05, 127.15, 123.77, 123.56, 123.07, 122.94, 121.19, 121.73, 114.58, 110.95, 49.07, 32.00, 19.95, 14.03. IR STRECHING : (N-H) = 3459 Cm − 1 , (N-H) = 3327 Cm − 1 , (C = O) = 1669 Cm − 1 . (NO 2 ) = 1623 Cm − 1 . HRMS (ESI) m/z: [M + H] calculated C 18 H 19 N 5 O 3 353.3820 + found 354.1563[M + H]. 1-Butyl-N-phenyl-1 H -indazol-3-carbohydrazide (8u). Appearance : Off white solid (yield = 99%, 140 mg). 1 H NMR [400 MHz, DMSO-d 6 ] : δ 10.14 (d, J = 2.40 Hz, 1H), 8.05 (d, J = 8.00 Hz, 1H), 7.82 (d, J = 2.80 Hz, 1H), 7.73 (d, J = 8.40 Hz, 1H), 7.40 (dt, J = 0.80, 10.80 Hz, 1H), 7.21 (t, J = 7.60 Hz, 1H), 7.08 (t, J = 8.00 Hz, 2H), 6.73 (d, J = 7.60 Hz, 2H), 6.64 (t, J = 7.20 Hz, 1H), 4.46 (t, J = 9.20 Hz, 2H), 1.83 (q, J = 7.20 Hz, 2H), 1.28–1.26 (m, 2H), 0.84 (t, J = 7.20 Hz, 3H). 13 C NMR [100 MHz, DMSO-d 6 ] : d ppm 162.52, 150.06, 140.81, 136.30, 129.14, 127.07, 122.88, 122.86, 121.97, 118.88, 112.71, 110.89, 48.95, 31.90, 19.92, 14.02. IR STRECHING : (N-H) = 3233Cm − 1 , (C = O) = 1645 Cm − 1 . HRMS (ESI) m/z: [M + H] calculated C 18 H 20 N 4 O 308.3850 + found 331.1558[M + Na]. 1-Butyl-N-(2,4-dinitrophenyl)-1 H -indazol-3-carbohydrazide (8v). Appearance : Pale brown solid (yield = 18.3%, 50 mg). 1 H NMR [400 MHz, DMSO-d 6 ] : δ 11.03 (s, 1H), 10.30 (s, 1H), 8.91 (s, 1H), 8.34 (d, J = 8.40 Hz, 1H), 8.14 (d, J = 7.20 Hz, 1H), 7.86 (d, J = 7.60 Hz, 1H), 7.51 (s, 1H), 7.32 (s, 2H), 4.56 (s, 2H), 1.92 (s, 2H), 1.32 (d, J = 6.00 Hz, 2H), 0.926 (s, 3H). 13 C NMR [100 MHz, DMSO-d 6 ] : d 161.89, 149.34, 140.91, 137.14, 135.37, 130.64, 127.31, 123.64, 123.36, 123.02, 121.82, 116.22, 111.10, 49.14, 31.93, 19.91, 14.02. IR STRECHING : (N-H) = 3363 Cm − 1 , (N-H) = 3331 Cm − 1 , (C = O) = 1691 Cm − 1 . HRMS (ESI) m/z: [M + H] calculated C 18 H 18 N 6 O 5 398.3790 + found 399.1414[M + H]. 1-Butyl-N-(4-cyanophenyl)-1 H -indazol-3-carbohydrazide (8w). Appearance : Brown solid (yield = 87.3%, 200 mg). 1 H NMR [400 MHz, DMSO-d 6 ] : δ 10.46 (s, 1H), 8.79 (s, 1H), 8.12 (d, J = 8.00 Hz, 1H), 7.82 (d, J = 8.40 Hz, 1H), 7.56 (d, J = 8.40 Hz, 2H), 7.48 (t, J = 7.60 Hz, 1H), 7.29 (t, J = 7.60 Hz, 1H), 6.83 (d, J = 8.40 Hz, 2H), 4.53 (t, J = 7.20 Hz, 2H), 1.90 (q, J = 7.20 Hz, 2H), 1.26–1.28 (m, 2H), 0.00 (t, J = 7.60 Hz, 3H). 13 C NMR [100 MHz, DMSO-d 6 ] : d 162.39, 153.62, 140.84, 135.87, 133.85, 127.16, 123.07, 122.93, 121.9, 120.58, 112.19, 99.15, 49.04, 31.90, 19.92, 14.01. IR STRECHING : (N-H) = 3343 Cm − 1 , (N-H) = 3235 Cm − 1 , (CN) = 2220 Cm − 1 , (C = O) = 1679 Cm − 1 . HRMS (ESI) m/z: [M + H] calculated C 19 H 19 N 5 O 333.3950 + found 334.1668[M + H]. 1-Butyl-N-(4-hydroxyphenyl)-1 H -indazol-3-carbohydrazide (8x). Appearance : Pale brown solid (yield = 60.5%, 135 mg). 1 H NMR [400 MHz, DMSO-d 6 ] : δ 10.19 (d, J = 9.60 Hz, 2H), 10.09 (s, 1H), 8.14 (d, J = 8.40 Hz, 3H), 7.82 (d, J = 8.40 Hz, 1H), 7.47 (t, J = 0.40 Hz, 1H), 7.30 (t, J = 7.20 Hz, 1H), 6.86 (d, J = 8.40 Hz, 2H), 4.52 (t, J = 7.20 Hz, 2H), 1.90 (q, J = 6.80 Hz, 2H), 1.26–1.26 (m, 2H), 0.91 (t, J = 7.20 Hz, 3H). 13 C NMR [100 MHz, DMSO-d 6 ] : d 165.93, 161.90, 161.07, 140.84, 136.07, 129.98, 1247.09, 123.78, 122.99, 122.93, 121.96, 115.44, 110.93, 48.96, 31.89, 19.90, 14.00. IR STRECHING : (N-H) = 3359 Cm − 1 , (OH) = 3204 Cm − 1 , (C = O) = 1679 Cm − 1 . HRMS (ESI) m/z: [M + H] calculated C 19 H 20 N 4 O 3 352.3940 + found 353.1595[M + H]. N-(4-Bromophenyl)-1butyl-1 H -indazol-3-carbohydrazide (8y). Appearance : Brown solid (yield = 75.3%, 200 mg). 1 H NMR [400 MHz, DMSO-d 6 ] : 10.28 (s, 1H), 8.12 (s, 2H), 7.81 (d, J = 8.40 Hz, 1H), 7.47 (t, J = 8.00 Hz, 1H), 7.29 (t, J = 11.60 Hz, 3H), 6.74 (d, J = 8.40 Hz, 2H), 4.52 (t, J = 6.80 Hz, 2H), 1.90 (q, J = 6.80 Hz, 2H), 1.24–1.26 (m, 2H), 0.91 (t, J = 7.20 Hz, 3H). 13 C NMR [100 MHz, DMSO-d 6 ] : d 162.48, 149.45, 140.81, 136.12, 131.77, 127.10, 122.95, 121.93, 114.69, 110.91, 109.60, 48.98, 31.89, 19.91, 14.01. IR STRECHING : : (N-H) = 3343, 3231 Cm − 1 , (C = O) = 1658 Cm − 1 HRMS (ESI) m/z: [M + H] calculated C 18 H 19 BrN 4 O 2 386.2810 + found 409.0665[M + Na]. 1-Butyl-N-(4-nitrophenyl)-1 H -indazol-3-carboxamide (8z). Appearance : Yellow solid (yield = 25.7%, 40 mg). 1 H NMR [400 MHz, DMSO-d 6 ] : δ 10.88 (s, 1H), 8.26 (q, J = 9.20 Hz, 5H), 7.86 (d, J = 8.40 Hz, 1H), 7.52 (t, J = 7.60 Hz, 1H), 7.36 (t, J = 7.20 Hz, 1H), 4.58 (t, J = 6.80 Hz, 2H), 1.92 (q, J = 7.60 Hz, 2H), 1.27–1.28 (m, 2H), 0.92 (t, J = 7.20 Hz, 3H), (t, J = Hz, 3H). 13 C NMR [100 MHz, DMSO-d 6 ] : d ppm 161.60, 145.67, 142.80, 141.25, 136.80, 127.39, 125.17, 123.04, 122.06, 120.39, 111.21, 49.25, 31.99, 19.92, 14.01. IR STRECHING : (N-H) = 3383 Cm − 1 , (C = O) = 1712 Cm − 1 . HRMS (ESI) m/z: [M + H] calculated C 18 H 18 N 4 O 3 338.14 + found 361.1274[M + Na]. Results and discussion A solution of phenylhydrazine 1 in water was treated with benzaldehyde 2 (1eq) at room temperature. The addition was gradual, and the mixture was stirred for 8 hours to yield benzylidene-1-phenylhydrazine 3 . This compound was then subjected to a reaction with oxalyl chloride in the presence of AlCl 3 (1.5eq) for two hours at 40°C to 45°C, affording 1-(benzylidine amino)indolin-2,3-dione 4 . This compound was further converted to indazole-3-carboxylic acid 5 , which underwent an alkylation reaction with bromobutane using NaH as a base to produce 1-butyl-1 H -indazole-3-carboxylic acid 6 . A simple synthetic approach was employed to obtain a series of 3-carboxamide indazole derivatives 8a-8z . The reaction was performed at room temperature using HATU (2 equiv) as an amide coupling reagent and DIPEA (3 equiv) as a base in DMF (10 vol) solvent ( 8a-8b , Scheme 1 , Fig. 2 ), All derivatives, with the exception of 8e, 8k, 8vand 8z, have yields between 55 and 80%. The progress of the reaction and the purity of the target molecules were determined using TLC. All the derivatives were purified by column chromatography (Ethyl acetate/Hexane 1:3) and characterized by IR, 1 H and 13 C NMR, and HRMS spectral data. Further details on the synthesis and characterization of the derivatives are available in the supplementary information. DFT STUDY Based on Koopman's relation, the LUMO–HOMO energy gap (ΔE = E LUMO – E HOMO ) and other frontier orbital energy characteristics, including the chemical potential of the molecules under test can be calculated. The molecules with highest HOMO values can act as electron donors and the molecules with lowest LUMO can be the electron acceptors[ 14 – 18 ] The HOMO and LUMO energies and global reactivity parameters have been calculated for all the molecules 8a-8z using GAUSSIAN 09 for DFT calculation 6–31 + G (d,p) basis set and the obtained data has been given as Table.1 in the supportive information. Out of all the compounds evaluated, compounds 8a , 8c , and 8s had the biggest energy gap (Table 1 ) The energy gap was computed using the ΔE = (E LUMO – E HOMO )[ 19 ] formula, and Fig. 3 displays the FMO representation. It is discovered that compounds 8a , 8c , and 8q are good electron acceptors whereas compounds 8u , 8x , and 8z are good electron donors. The indazole molecule's HOMO and LUMO distributions span practically the entire molecule. (See the supporting information (SI)). These descriptors provide insight into molecular behavior, facilitating our understanding of chemical reactivity. The HOMO-LUMO energy gap makes it simple to calculate a molecule's chemical hardness, which is a good indicator of its reactivity. A higher degree of molecular softness is indicated by a smaller gap value, whereas a bigger HOMO-LUMO energy gap is indicative of higher molecular hardness. Figure 3 displays the electron distribution of 8a , 8c and 8s under HOMO-LUMO. The red and green colors represent the positive (nucleophile) and negative (electrophilic) lobes respectively. The molecular electrostatic potential (MEP) is an essential tool that assists in predicting the reactivity sites of a molecule for nucleophilic and electrophilic attacks. Understanding hydrogen bonding and the relationship between a molecule's electrical characteristics, such as dipole moment, electronegativity, atomic charges, and so on, is also crucial for comprehending electrophilic and nucleophilic reactions. To compute the MEP surface analysis of a compound, Density Functional Theory (DFT) calculations are employed using the optimized structure and the B3LYP/6-31G(d,p) basis set. The MEP surface analysis provides extensive insights into a compound's properties and behaviour that are critical for scientific research and development. MEP analysis clarifies the electron distribution pattern of compound 8a and its electron density (positive site: +7.281e, negative site: -7.281e), are displayed in Fig. 4, which represents the compounds' mapped electrostatic potential surface. Electrostatic potential levels and zones of positive, negative, and neutral electrostatic potential are represented by different colours. Electrophilic sites are shown in red colour, whereas nucleophilic sites are represented in blue colour. An area with a neutral electrostatic potential is shown by the colour green. The oxygen and nitrogen atoms have electrophilic sites, while the hydrogen atoms have nucleophilic sites. Therefore, nucleophilic and electrophilic molecules are drawn to places with higher negative electronegative potential and positive electrostatic potential[ 20 – 22 ]. Table 1 DFT calculated values of 8u, 8v, 8z. S. No: COMPOUND HOMO LUMO ΔE = E LUMO -E HOMO 1 8a -6.0453 -0.86238 5.18292 2 8b -5.51394 -1.07163 4.44231 3 8c -5.88654 -0.81999 5.06655 4 8d -6.12522 -2.65032 3.4749 5 8e -5.7888 -1.17666 4.61214 6 8f -4.44879 -0.98955 3.45924 7 8g -5.89761 -1.40211 4.4955 8 8h -5.65434 -2.31201 3.34233 9 8i -5.62275 -1.21878 4.40397 10 8j -5.14566 -1.04112 4.10454 11 8k -5.23692 -0.92853 4.30839 12 8l -5.44563 -1.05111 4.39452 13 8m -5.41485 -1.07244 4.34241 14 8n -5.67216 -1.00143 4.67073 15 8o -5.11137 -1.0287 4.08267 16 8p -5.5039 -1.15128 4.35262 17 8q -5.21937 -0.92529 4.29408 18 8r -5.47317 -1.14426 4.32891 19 8s -6.34878 -1.4283 4.92048 20 8t -5.27715 -2.60523 2.67192 21 8u -6.8823 -2.45457 4.42773 22 8v -6.36687 -3.59964 2.76723 23 8w -5.08923 -1.32435 3.76488 24 8x -6.67332 -2.42568 4.24764 25 8y -4.24305 -1.00143 3.24162 26 8z -6.4638 -2.77776 3.68604 Molecular Docking The literature has identified ENTRECTINIB, PAZOPANIB, and AXITINIB as the three most commonly available medications with an indazole moiety that exhibit potent anti-renal cancer activity. To further augment the efficacy of these medications, we synthesized novel indazole derivatives and performed comprehensive molecular docking studies to evaluate their effectiveness against renal cancer. Through rigorous experimentation, we identified an enhanced PDB 6FEW[ 23 ] that is directly linked to renal cancer and utilized the Auto Dock 4.2 software to perform molecular docking studies. The crystal structure of DDR1, specifically 2-[8-(1H-indazole-5-carbonyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5] decan-3-yl], demonstrated exceptional efficacy against renal cancer. The binding energy values (in Kcal/mol) of the ligand-receptor complex were utilized to rank the docking outcomes [ 24 ]. The 2D structures of all 26 derivatives were prepared using the ChemOffice tool "Chem Draw 16.0," which was used to show the proper 2D orientation of the chemical structures of the chosen ligands. ChemBio3D was then used to lower the energy of each molecule to improve geometry estimation and ligand-receptor affinity[ 25 ]. To generate the protein, we employed Discovery Studio Visualizer for a better receptor file, and the auto-prepared file was used in an auto docking station to prepare targeted indazole molecules. The Discovery Studio 2021 application LigPlot v.2.2.8 was utilized to meticulously analyze the docking results, and the outcomes are presented in this report. The 2D structures vividly illustrate the interactions between the ligand and amino acid residues, while the 3D structures reveal the precise location of the ligand in the receptor's active site[ 26 ]. We selected the molecules with the least amount of energy for a docking simulation in AutoDock Vina. The docking simulation grid box was given its configuration and the dimensions of x, y, and z is 40. The macromolecule's target area was placed inside the grid in such a way that it covered the whole structure. It was determined that the ligand and protein could be docked most effectively by utilizing the docking technique made accessible by Auto Dock Vina. During the docking approach, a maximum of ten conformations of each ligand were investigated. The use of a flexible sidechain to simulate the covalent ligand produced good results. All ten docking runs produced comparable conformations, all of which were quite similar to the crystallographic conformation. The 3D and 2D ligand-receptor interactions were investigated using the Discovery studio visualizer. We completed docking studies for 26-molecules, among the 26-molecule three compounds showed more active and binding energy those are 8v, 8w, and 8y (Table 2 ). Table 2 Docking results in terms of binding energy (Kcal/mol) Compound ΔG binding energy (Kcal/mol) Ki (micromolar) [Temperature = 298.15 k] H bond energy (Kcal/mol) 8v -11.77 0.0235 -13.47 8w -11.64 0.0294 -13.33 8y -11.52 0.0361 -13.21 Three compounds interact with amino acid residues involved in water hydrogen bonding, and covalent hydrogen bonding, Alkyl 2D interactions graphics using LigPlot (v.2.2.8) visualizer (Fig. 6 ). The compounds: 8v, 8w, and 8y ligand are interactions with ASP784, LYS655, MET699, GLU672, MET676, ILE685, LEU679, ALA783, ILE675, PHE762. Ki values (micromolar) calculated under room temperature (298K) by utilizing auto dock software are 0.0235, 0.0295, and 0.0361, Our research group was finding the H bonding energy of all compounds (see in supporting information (SI)). We evaluated different approaches to docking covalently linked ligands: a grid-based technique and a flexible sidechain approach. Figure 6 shows the docking results. Compounds 8v, 8w, and 8y interacted with amino acids through covalent bonds made up of hydrogen and alkyl, Pi-alkyl interaction with ASP784, LYS655, and ILE675, LEU679, ALA783, ILE685, MET699, HIS764. Water hydrogen bonds with HOH1193. These two derivatives formed Pi-sulfur and Pi-sigma interactions with GLU672 and MET676. Three substances are actively creating a salt bridge and actively interacting with GLU672. Conclusion In conclusion, amide coupling was used to successfully and efficiently synthesize a range of 3-carboxamide indazole derivatives. The comprehensive characterization of the target compounds and the high yields attained provided validation for the used methodologies. Using DFT analysis, we were able to determine the geometrical optimization of all the derivatives and discovered that 8a, 8c, and 8s had high energy gaps. We then used Auto Dock 4.0 to perform auto docking in order to determine the effectiveness of the indazole molecule in renal cancer and discovered that 8v, 8w, and 8y had the highest binding energy. Declarations Supporting Information The Supporting Information is available free of charge on the RSC Publications website. Synthetic procedures; 1 H, 13 C NMR spectra; computational details are in brief description (PDF) Acknowledgment The authors are thankful to the administration, of VIT University. Vellore, India for providing facilities to carry out research work, and also thankful to SIF-Chemistry, VIT University for NMR facilities. Our sincere thanks to Dr. S. Sarveswari for her valuable comments and suggestions, the authors are thankful to Dr. S. Gururaj for his valuable comments and suggestions for docking studies. Thank you, Suryanarayana Murthy Vallabhaneni, from the writers. Thanks to Ms. V Hemalatha for her suggestions to complete DFT studies. 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Jumabaev, U. Holikulov, H. Hushvaktov, N. ISSAOUI, and A. Absanov, J Mol Liq 377 , (2023). S. Y. Ghansenyuy, K. O. Eyong, P. Yemback, L. Mehreen, V. de P. N. Nziko, M. S. Ali, and G. N. Folefoc, European Journal of Medicinal Chemistry Reports 9 , (2023). M. K. Sharma, S. Parashar, D. Sharma, K. Jakhar, K. Lal, N. U. Pandya, and H. Om, Journal of the Indian Chemical Society 100 , (2023). C. Yuan and X. Hao, Heliyon 9 , (2023). E. Zarenezhad, E. Behmard, I. Sadeghian, S. Sadeghian, A. Ghanbariasad, A. Ghasemian, S. Behrouz, A. Zarenezhad, and M. N. S. Rad, J Mol Struct 1284 , (2023). Scheme 1 Scheme 1 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files SupplementarydataGOPIRCI.docx floatimage9.jpeg Graphical Abstract Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4006780","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":276221804,"identity":"9d5922f6-31d6-4d96-9685-e5bdec9a917a","order_by":0,"name":"Bandaru Gopi","email":"","orcid":"","institution":"Vellore Institute of Technology- Vellore","correspondingAuthor":false,"prefix":"","firstName":"Bandaru","middleName":"","lastName":"Gopi","suffix":""},{"id":276221805,"identity":"de787a8e-ef14-4c8e-980a-c8a28fd6ed8b","order_by":1,"name":"Vijayaparthasarathi Vijayakumar","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEklEQVRIiWNgGAWjYBACCTBpwAYk2MBMORBx4AEpWozBWhIIagEDiJbEBhCJT4vkjNzDn3kK+OQNjh9Lk7pRcy99ftjhh0Bb7OR0G7BrkZbIS5PmMWAz3HAm7Zh0zrHi3I230wyAWpKNzQ5g1yLHc8aMcYYBG+OGA+lt0jlsCbkbZyeAtBxI3IZbi/FHoBb7DeefA7X8S0g3nJ3+Aa8WafYeA4kPBmyJG24AHZbblpAgL52D3xbJ9r40kJbkmTeeJVvn9iUYbpDOKTiQYIDbLxKHeQ9/SPhzzLbvfJrh7ZxvCfLys9M3f/hQYSeHSwsDAw+IOMagAFNgAGYY4FIO11LDIN8A5cMZo2AUjIJRMAqgAAD8DmJqbUJwOAAAAABJRU5ErkJggg==","orcid":"","institution":"Vellore Institute of Technology- Vellore","correspondingAuthor":true,"prefix":"","firstName":"Vijayaparthasarathi","middleName":"","lastName":"Vijayakumar","suffix":""}],"badges":[],"createdAt":"2024-03-02 15:45:04","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4006780/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4006780/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":52099604,"identity":"e9592c59-403d-4b26-b7d3-4fcda11d430e","added_by":"auto","created_at":"2024-03-06 17:52:18","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":391620,"visible":true,"origin":"","legend":"\u003cp\u003eSome representative examples of pharmaceutically important benzylated indazoles I-VIII.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4006780/v1/e7caf8bebbbb85fd625eaa7a.png"},{"id":52099423,"identity":"ad08f342-2f7b-4e0b-a36b-6055f52c1765","added_by":"auto","created_at":"2024-03-06 17:44:18","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":288161,"visible":true,"origin":"","legend":"\u003cp\u003eIndazole derivatives from \u003cstrong\u003e8a\u003c/strong\u003e-\u003cstrong\u003e8z.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-4006780/v1/e8a18e3d56f62a36d388f965.png"},{"id":52099603,"identity":"b473f0fd-86d9-419b-a3a0-45e9c0d6664e","added_by":"auto","created_at":"2024-03-06 17:52:18","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":99977,"visible":true,"origin":"","legend":"\u003cp\u003eFMO diagrams of indazole derivatives\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-4006780/v1/30d4254578d39466253835d4.png"},{"id":52099426,"identity":"b542b87a-30b4-4fda-8aa6-3fb0b706e2fa","added_by":"auto","created_at":"2024-03-06 17:44:18","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":73198,"visible":true,"origin":"","legend":"\u003cp\u003eThe molecular electrostatic potential surface of 8a.\u003c/p\u003e","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-4006780/v1/cc034179bab1470bbf33be92.png"},{"id":52099428,"identity":"e1a281ae-9c8d-4537-93e5-3e7d47018a68","added_by":"auto","created_at":"2024-03-06 17:44:18","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":166046,"visible":true,"origin":"","legend":"\u003cp\u003eThe crystal structure of DDR1, 2-[8-(1H-indazole-5-carbonyl)-4-oxo-1-phenyl-1,3,8-triazaspiro [4.5] decan-3-yl] -N-methyl acetamide (6FEW). 3D graphics were generated using Discovery Studio Visualizer 2021.\u003c/p\u003e","description":"","filename":"floatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-4006780/v1/d4ac8dc40501ea4a59822cb4.png"},{"id":52099605,"identity":"50e532c3-c5a9-4014-b1ec-025a0634f0a0","added_by":"auto","created_at":"2024-03-06 17:52:18","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":770091,"visible":true,"origin":"","legend":"\u003cp\u003eThe binding pattern of indazole derivatives with PBD-6FEW. A) represents 3D surface representation, B) represents the active ligand catalytic center of the protein target, and C) 2D-schematic LigPlot interactions shown for the docked pose of indazole derivatives shown by the spokes.\u003c/p\u003e","description":"","filename":"floatimage8.png","url":"https://assets-eu.researchsquare.com/files/rs-4006780/v1/bcadf89d95f25ede2d91e841.png"},{"id":52812047,"identity":"031a1443-632d-45b8-9ec6-121a1e6ac31f","added_by":"auto","created_at":"2024-03-16 10:15:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2604040,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4006780/v1/32c15fc9-111f-42ca-adba-41360c313c9a.pdf"},{"id":52099429,"identity":"51b0c5b8-ed1c-4b27-af59-c07434e9a3a7","added_by":"auto","created_at":"2024-03-06 17:44:21","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":41309192,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementarydataGOPIRCI.docx","url":"https://assets-eu.researchsquare.com/files/rs-4006780/v1/3a6e811ab0face96bd007244.docx"},{"id":52099422,"identity":"a1f370e8-95a3-48ee-a233-4cd96c8a55f9","added_by":"auto","created_at":"2024-03-06 17:44:18","extension":"jpeg","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":377798,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGraphical Abstract\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage9.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4006780/v1/ac97044c7ae59bea40c5ff70.jpeg"}],"financialInterests":"No competing interests reported.","formattedTitle":"Synthesis and molecular docking of novel indazole derivatives with DFT studies","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIndazole is a significant heterocycle in medicinal chemistry. It has been used in the development of numerous commercially successful medications and potential drug prospects for indazole core[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Its pharmacological and biological characteristics make it a valuable compound in drug discovery. It has proven antitumor, antibacterial, anti-inflammatory, and anti-cancer properties. HIV protease inhibitor, antiplatelet, and antidepressant, chemical synthesis, and medicinal chemistry both heavily rely on fused heterocycles containing two or more pharmacophores [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Indazole is the main structural component in pharmaceutical compounds like bendazac and MK-4827[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Benzylated indazoles I-VIII are important molecules for the pharmaceutical industry and have potential therapeutic uses for the treatment of several illnesses. These molecules act as anticancer agents (I, pazopanib, MK-4827, lonidamine VI), neuroprotective sodium channel modulators (II), antichagasic agents (III), antihypertensive agents (recoguat IV), antibacterial (V), non-steroid anti-inflammatory drugs (bendazac VII) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Many synthetic methods have been reported due to their biological relevance. It is difficult to directly N-alkylate or arylate indazole because these reactions preferentially result in the thermodynamically more stable indazole. It takes a lot of work to separate N1- and N2-alkylated combinations[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Two nitrogen atoms and the planarity of the indazole ring give it a unique structure that allows for many modification sites to develop several biological and therapeutic variants[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Cancer is a leading cause of death and endangers public health. The International Agency for Research on Cancer reported 19.3\u0026nbsp;million new cancer cases globally in 2020, with colorectal, lung, and female breast cancer accounting for 10% of all new cancer cases. Indazole compounds are anti-cancer. The anti-cancer potential of indazole compounds has been reported with remarkable results. These compounds were tested as potential cancer therapeutics, and novel compounds with indazole scaffolds were synthesized to expand the chemical library for anti-cancer therapeutic screening [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The successful application of advanced tools and techniques in the field of chemistry can lead to groundbreaking discoveries. A recent study that utilized GAUSSIAN 09, Gaussian View 6.1, and Auto Dock4 has yielded some promising findings[\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The compounds studied exhibit potential anticancer activity, particularly against kidney cancer. Based on these findings, the synthesis of novel derivatives of indazole molecules is being explored.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Experimental","content":"\u003cp\u003e \u003cb\u003eInstruments and reagents\u003c/b\u003e \u003c/p\u003e \u003cp\u003eAll the reactions were carried out in round bottom flasks. All the solvents and chemical materials were purchased from commercial sources. The 1-butyl-1H-indazole-3-carboxamide was prepared according to the reported protocols. \u003csup\u003e1\u003c/sup\u003eH and \u003csup\u003e13\u003c/sup\u003eC NMR spectra were recorded on Bruker Avance400 spectrometer and are referred to the residual solvent signal CDCl\u003csub\u003e3\u003c/sub\u003e: (7.26) for \u003csup\u003e1\u003c/sup\u003eH and (77.16) for \u003csup\u003e13\u003c/sup\u003eC NMR: dimethyl sulfoxide-d\u003csub\u003e6\u003c/sub\u003e (2.50) for \u003csup\u003e1\u003c/sup\u003eH and (39.50) for \u003csup\u003e13\u003c/sup\u003eC NMR: chemical shift (δ) is given in ppm and coupling constant (J) were measured in Hz. The following abbreviations are used: s- singlet, d-doublet, dd-doublet of doublet, t-triplet, td-triplet of doublet, dt- doublet of triplet, q-quartet, qd- quartet of doublet, qn-quintet, br-broad, m-multiplet. HRMS ESI-MS was recorded using Xeo G2 XS OT of (water) and values are given m/z. Colum chromatography was carried out using silica gel (100\u0026ndash;200 mesh) packed in a glass column. Analytical TLC was carried out on Macherey-Nagel 60 F245 aluminium-backed silica gel plates.\u003c/p\u003e \u003cp\u003e \u003cb\u003eGeneral Procedure for the Synthesis 8a-8z\u003c/b\u003e \u003c/p\u003e \u003cp\u003eA stirred solution of 1-butyl-1\u003cem\u003eH\u003c/em\u003e-indazol-3-carboxylic acid (250 mg, 1.146 mmol) was dissolved in DMF (10 mL), HATU (2 equivalents), and DIPEA (3 equivalents) were added to the reaction mixture, then commercial amines (2 equivalents) were added. The reaction mixture was stirred at room temperature for 8-16h. After completion of the reaction, the resultant reaction mixture was poured into water; the solution was extracted with water and ethyl acetate (4 x 20 mL). The organic layer was dried with anhydrous sodium sulfate and the solvent was removed under reduced pressure to afford crude product. The crude was purified by silica gel chromatography to obtain pure products \u003cb\u003e8a-8z\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003cb\u003eCharacterization of indazole carboxamide derivatives from 8a-8z.\u003c/b\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003e1-Butyl-1\u003c/b\u003e \u003cb\u003eH\u003c/b\u003e \u003cb\u003e-indazol-3-carboxamide (8a). Appearance\u003c/b\u003e: Off-white solid (yield\u0026thinsp;=\u0026thinsp;93.9%, 140 mg). \u003csup\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eH NMR [400 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: δ 8.11 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.00 Hz, 1H), 7.69 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.80 Hz, 1H), 7.56 (s, 1H), 7.37 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.00 Hz, 1H), 7.28 (s, 1H), 7.19 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.60 Hz, 1H), 4.40 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.80 Hz, 2H), 1.79 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.80 Hz, 2H), 1.15\u0026ndash;1.17 (m, 2H), 0.82 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.60 Hz, 3H). \u003csup\u003e\u003cb\u003e13\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eC NMR [100 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: d ppm 141.04, 137.5, 126.84, 122.68, 122.64, 122.41, 110.71, 48.80, 31.88, 19.87, 13.96. \u003cb\u003eIR STRECHING\u003c/b\u003e: (N-H)\u0026thinsp;=\u0026thinsp;3306 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, (C\u0026thinsp;=\u0026thinsp;O)\u0026thinsp;=\u0026thinsp;1664 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. \u003cb\u003eHRMS (ESI) m/z: [M\u0026thinsp;+\u0026thinsp;H]\u003c/b\u003e calculated C\u003csub\u003e12\u003c/sub\u003eH\u003csub\u003e15\u003c/sub\u003eN\u003csub\u003e3\u003c/sub\u003eO 217.1215\u0026thinsp;+\u0026thinsp;found 240.111[M\u0026thinsp;+\u0026thinsp;Na].\u003c/p\u003e \u003cp\u003e \u003cb\u003e1-Butyl-N-phenyl-1\u003c/b\u003e \u003cb\u003eH\u003c/b\u003e \u003cb\u003e-indazol-3-carboxamide (8b). Appearance\u003c/b\u003e: Pale brown solid (yield\u0026thinsp;=\u0026thinsp;96.7%, 195 mg). \u003csup\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eH NMR [400 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: δ 10.19 (s, 1H), 8.24 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.00 Hz, 1H), 7.89 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.00 Hz, 2H), 7.82 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.80 Hz, 1H), 7.49 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 1H), 7.38\u0026ndash;7.36 (m, 3H), 7.10 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.80 Hz, 1H), 4.56 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.80 Hz, 2H), 1.91 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.80 Hz, 2H), 1.34\u0026ndash;1.32 (m, 2H), 0.92 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 3H) .\u003csup\u003e\u003cb\u003e13\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eC NMR [100 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: d ppm 161.04, 141.17, 139.21, 137.46, 129.01, 127.17, 123.92, 123.05, 122.25, 120.78, 110.96, 49.08, 32.0, 19.94, 14.02. \u003cb\u003eIR STRECHING\u003c/b\u003e: (N-H)\u0026thinsp;=\u0026thinsp;3306 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, (C\u0026thinsp;=\u0026thinsp;O)\u0026thinsp;=\u0026thinsp;1664 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. \u003cb\u003eHRMS (ESI) m/z: [M\u0026thinsp;+\u0026thinsp;H]\u003c/b\u003e calculated C\u003csub\u003e18\u003c/sub\u003eH\u003csub\u003e19\u003c/sub\u003eN\u003csub\u003e3\u003c/sub\u003eO 293.1528\u0026thinsp;+\u0026thinsp;found 294.1596 [M\u0026thinsp;+\u0026thinsp;H].\u003c/p\u003e \u003cp\u003e \u003cb\u003eN-Benzyl-1-butyl-1\u003c/b\u003e \u003cb\u003eH\u003c/b\u003e \u003cb\u003e-indazol-3-carboxamide (8c). Appearance\u003c/b\u003e: Pale yellow solid (yield\u0026thinsp;=\u0026thinsp;90%, 190 mg). \u003csup\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eH NMR [400 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: δ 8.81 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.40 Hz, 1H), 8.11 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.40 Hz, 1H), 7.70 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.80 Hz, 1H), 7.38 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.80 Hz, 1H), 7.19\u0026ndash;7.21 (m, 4H), 7.15\u0026ndash;7.16 (m, 2H), 4.40\u0026ndash;4.41 (m, 4H), 1.79 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 2H), 1.16\u0026ndash;1.16 (m, 2H), 0.82 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.60 Hz, 3H). \u003csup\u003e\u003cb\u003e13\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eC NMR [100 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: d ppm 162.4, 141,140,42,137.36, 128.69, 127.89, 127.15, 126.97, 122.74, 122.63, 122.27, 110.8, 48.88, 42.39, 31.93, 19.91, 14. \u003cb\u003eIR STRECHING\u003c/b\u003e: (N-H)\u0026thinsp;=\u0026thinsp;3381 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, (C\u0026thinsp;=\u0026thinsp;O)\u0026thinsp;=\u0026thinsp;1639 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. \u003cb\u003eHRMS (ESI) m/z: [M\u0026thinsp;+\u0026thinsp;H]\u003c/b\u003e calculated C\u003csub\u003e19\u003c/sub\u003eH\u003csub\u003e21\u003c/sub\u003eN\u003csub\u003e3\u003c/sub\u003eO 307.17\u0026thinsp;+\u0026thinsp;found 308.1760 [M\u0026thinsp;+\u0026thinsp;H].\u003c/p\u003e \u003cp\u003e \u003cb\u003eN-(3-Bromophenyl)-1-butyl-1\u003c/b\u003e \u003cb\u003eH\u003c/b\u003e \u003cb\u003e-indazol-3-carboxamide (8d). Appearance\u003c/b\u003e: Brown solid (yield\u0026thinsp;=\u0026thinsp;78.4%, 200 mg). \u003csup\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eH NMR [400 MHz, CDCl\u003c/b\u003e\u003csub\u003e\u003cb\u003e3\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: δ 8.78 (s, 1H), 8.32 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.40 Hz, 1H), 7.95 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.60 Hz, 1H), 7.60\u0026ndash;7.59 (m, 1H), 7.37\u0026ndash;7.36 (m, 2H), 7.16 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 2H), 4.34 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 2H), 1.87 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.60 Hz, 2H), 1.34\u0026ndash;1.32 (m, 2H), 0.89 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 3H). \u003csup\u003e\u003cb\u003e13\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eC NMR [100 MHz, CDCl\u003c/b\u003e\u003csub\u003e\u003cb\u003e3\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: 160.51, 141.11, 139.38, 136.73, 126.99, 126.83, 123.03, 122.94, 122.73, 122.44, 118.03, 109.48, 49.38, 31.38, 20.07, 13.66. \u003cb\u003eIR STRECHING\u003c/b\u003e: (N-H)\u0026thinsp;=\u0026thinsp;3272 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, (C\u0026thinsp;=\u0026thinsp;O)\u0026thinsp;=\u0026thinsp;1655 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. \u003cb\u003eHRMS (ESI) m/z: [M\u0026thinsp;+\u0026thinsp;H]\u003c/b\u003e calculated C\u003csub\u003e18\u003c/sub\u003eH\u003csub\u003e18\u003c/sub\u003eBrN\u003csub\u003e3\u003c/sub\u003eO 371.2660\u0026thinsp;+\u0026thinsp;found 372.0707[M\u0026thinsp;+\u0026thinsp;H].\u003c/p\u003e \u003cp\u003e \u003cb\u003e2-(1-Butyl-1\u003c/b\u003e \u003cb\u003eH\u003c/b\u003e \u003cb\u003e-indazol-3-carboxamido)-5-iodobenzoic acid (8e). Appearance\u003c/b\u003e: Yellow solid (yield\u0026thinsp;=\u0026thinsp;47%, 150 mg). \u003csup\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eH NMR [400 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: δ 8.46 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.00 Hz, 1H), 8.38 (s, 1H), 8.24 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.40 Hz, 1H), 7.88 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.40 Hz, 1H), 1887.17 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.40 Hz, 2H), 7.41 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.60 Hz, 1H), 4.58 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.40 Hz, 2H), 1.90 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.80 Hz, 2H), 1.29 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.80 Hz, 2H), 0.91 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 3H). \u003csup\u003e\u003cb\u003e13\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eC NMR [100 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: d ppm 157.97, 153.64, 146.45, 145.49, 141.21, 136.41, 134.02, 129.31, 127.51, 123.75, 122.91, 122.50, 119.65, 111.33, 93.54, 49.40, 31.93, 19.88, 13.98. \u003cb\u003eIR STRECHING\u003c/b\u003e: (O-H)\u0026thinsp;=\u0026thinsp;2947 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, (N-H)\u0026thinsp;=\u0026thinsp;2860 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, (C\u0026thinsp;=\u0026thinsp;O)\u0026thinsp;=\u0026thinsp;1740 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. \u003cb\u003eHRMS (ESI) m/z: [M\u0026thinsp;+\u0026thinsp;H]\u003c/b\u003e calculated C\u003csub\u003e19\u003c/sub\u003eH\u003csub\u003e16\u003c/sub\u003eIN\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e 445.0287\u0026thinsp;+\u0026thinsp;found 446.0365[M\u0026thinsp;+\u0026thinsp;H].\u003c/p\u003e \u003cp\u003e \u003cb\u003e1-Butyl-N-(4-(phenylamino)phenyl)-1\u003c/b\u003e \u003cb\u003eH\u003c/b\u003e \u003cb\u003e-indazol-3-carboxamide (8f). Appearance\u003c/b\u003e: Grey solid (yield\u0026thinsp;=\u0026thinsp;87%, 230 mg). \u003csup\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eH NMR [400 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: δ 10.06 (s, 1H), 8.26 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.00 Hz, 1H), 8.08 (s, 1H), 7.78 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 3H), 7.48 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 1H), 7.31 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.60 Hz, 1H), 7.22 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 2H), 7.08 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.40 Hz, 4H), 6.79 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 1H), 4.53 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.80 Hz, 2H), 1.90 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.80 Hz, 2H), 1.30 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 2H), 0.90 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 3H).\u003csup\u003e\u003cb\u003e13\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eC NMR [100 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: d ppm 160.64, 144.51, 141.16, 139.64, 137.71, 131.98, 129.62, 127.12, 122.91, 122.88, 122.33, 122.15, 119.55, 118.03, 116.43, 110.89, 49.02, 31.98, 19.93, 14.\u003cb\u003eIR STRECHING\u003c/b\u003e: (N-H)\u0026thinsp;=\u0026thinsp;3342 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, (C\u0026thinsp;=\u0026thinsp;O)\u0026thinsp;=\u0026thinsp;1635 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. \u003cb\u003eHRMS (ESI) m/z: [M\u0026thinsp;+\u0026thinsp;H]\u003c/b\u003e calculated C\u003csub\u003e24\u003c/sub\u003eH\u003csub\u003e24\u003c/sub\u003eN\u003csub\u003e4\u003c/sub\u003eO 384.4830\u0026thinsp;+\u0026thinsp;found 384.1970[M\u0026thinsp;+\u0026thinsp;H].\u003c/p\u003e \u003cp\u003e \u003cb\u003eEthyl 4-(1-butyl-1\u003c/b\u003e \u003cb\u003eH\u003c/b\u003e \u003cb\u003e-indazol-3-carboxamido)benzoate (8g). Appearance\u003c/b\u003e: Off white solid (yield\u0026thinsp;=\u0026thinsp;75.6%, 190 mg). \u003csup\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eH NMR [400 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: δ 10.58 (s, 1H), 8.24 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.00 Hz, 1H), 8.08 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.80 Hz, 2H), 7.96 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.40 Hz, 2H), 7.84 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.40 Hz, 1H), 7.51 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.00 Hz, 1H), 7.34 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 2H), 4.57 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.80 Hz, 2H), 4.31 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.80 Hz, 2H), 1.91 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 2H), 1.26\u0026ndash;1.27 (m, 2H), 0.00 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 3H). \u003csup\u003e\u003cb\u003e13\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eC NMR [100 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: d ppm 165.86, 161.38, 143.72, 141.22, 137.08, 130.47, 127.30, 124.86, 123.32, 122.96, 122.12, 120.06, 111.12, 60.90, 49.16, 31.97, 19.92, 14.70, 14.01. \u003cb\u003eIR STRECHING\u003c/b\u003e: (N-H)\u0026thinsp;=\u0026thinsp;3383 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, (C\u0026thinsp;=\u0026thinsp;O)\u0026thinsp;=\u0026thinsp;1712 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. \u003cb\u003eHRMS (ESI) m/z: [M\u0026thinsp;+\u0026thinsp;H]\u003c/b\u003e calculated C\u003csub\u003e21\u003c/sub\u003eH\u003csub\u003e23\u003c/sub\u003eN\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003e 365.4330\u0026thinsp;+\u0026thinsp;found 366.1817[M\u0026thinsp;+\u0026thinsp;H].\u003c/p\u003e \u003cp\u003e \u003cb\u003e1-butyl-N-(4-nitrophenyl)-1\u003c/b\u003e \u003cb\u003eH\u003c/b\u003e \u003cb\u003e-indazole-3-carbohydrazide (8h). Appearance\u003c/b\u003e: Pale brown solid (yield\u0026thinsp;=\u0026thinsp;57.8%, 140.5 mg). \u003csup\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eH NMR [400 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: δ 10.60 (s, 1H), 9.22 (s, 1H), 8.11 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9.20 Hz, 3H), 7.83 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.40 Hz, 1H), 7.49 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.60 Hz, 1H), 7.30 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 1H), 6.83 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9.20 Hz, 1H), 4.54 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.80 Hz, 2H), 1.91 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 2H), 1.27\u0026ndash;1.29 (m, 2H), 0.92 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 3H). \u003csup\u003e\u003cb\u003e13\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eC NMR [100 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: d ppm 162.31, 155, 67, 140.87, 138.40, 135.72, 127.21, 126.41, 123.15, 122.96, 121.89, 111.11, 111.02, 49.08, 31.91, 19.92, 14.02. \u003cb\u003eIR STRECHING\u003c/b\u003e: (N-H)\u0026thinsp;=\u0026thinsp;3355 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, (C\u0026thinsp;=\u0026thinsp;O)\u0026thinsp;=\u0026thinsp;1658 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, (NO\u003csub\u003e2\u003c/sub\u003e)\u0026thinsp;=\u0026thinsp;1595 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. \u003cb\u003eHRMS (ESI) m/z: [M\u0026thinsp;+\u0026thinsp;H]\u003c/b\u003e calculated C\u003csub\u003e18\u003c/sub\u003eH\u003csub\u003e19\u003c/sub\u003eN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003e 353.3820\u0026thinsp;+\u0026thinsp;found 354.1569[M\u0026thinsp;+\u0026thinsp;H].\u003c/p\u003e \u003cp\u003e \u003cb\u003eN-(4-Bromophenyl)-1-butyl-1\u003c/b\u003e \u003cb\u003eH\u003c/b\u003e \u003cb\u003e-indazol-3-carboxamide (8i). Appearance\u003c/b\u003e: Brown solid (yield\u0026thinsp;=\u0026thinsp;82.5%, 210.6 mg). \u003csup\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eH NMR [400 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: δ 10.41 (s, 1H), 8.23 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.40 Hz, 1H), 7.90 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.80 Hz, 2H), 7.83 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.40 Hz, 1H), 7.55\u0026ndash;7.52 (m, 3H), 7.32 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.60 Hz, 1H), 4.55 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 2H), 1.90 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 2H), 1.34\u0026ndash;1.32 (m, 2H), 0.91 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 3H). \u003csup\u003e\u003cb\u003e13\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eC NMR [100 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: d ppm 161.16, 141.18, 138.68, 137.23, 131.82, 127.24, 123.18, 122.74, 122.18, 111.04, 55.37, 31.99, 19.92, 14.01. \u003cb\u003eIR STRECHING\u003c/b\u003e: (N-H)\u0026thinsp;=\u0026thinsp;3272 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, (C\u0026thinsp;=\u0026thinsp;O)\u0026thinsp;=\u0026thinsp;1655 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. \u003cb\u003eHRMS (ESI) m/z: [M\u0026thinsp;+\u0026thinsp;H]\u003c/b\u003e calculated C\u003csub\u003e18\u003c/sub\u003eH\u003csub\u003e18\u003c/sub\u003eBrN\u003csub\u003e3\u003c/sub\u003eO 371.2660\u0026thinsp;+\u0026thinsp;found 372.0707[M\u0026thinsp;+\u0026thinsp;H].\u003c/p\u003e \u003cp\u003e \u003cb\u003e1-Butyl-N-(4-hydroxyphenyl)-\u003c/b\u003e \u003cb\u003e1H\u003c/b\u003e \u003cb\u003e-indazol-3-carboxamide (8j). Appearance\u003c/b\u003e: Off white solid (yield\u0026thinsp;=\u0026thinsp;72.2%, 153 mg). \u003csup\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eH NMR [400 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: δ 9.97 (s, 1H), 9.24 (s, 1H), 8.22 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.00 Hz, 1H), 7.80 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.40 Hz, 1H), 7.64 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.60, 8.60 Hz, 2H), 7.48 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.60 Hz, 1H), 7.30 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.00 Hz, 1H), 6.75 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.40 Hz, 2H), 4.53 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.80 Hz, 2H), 1.90 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.80 Hz, 2H), 1.28 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.60 Hz, 2H), 0.91 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 3H).\u003csup\u003e\u003cb\u003e13\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eC NMR [100 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: d ppm 160.58, 15.06,141.13, 137.71, 130.75, 127.09, 122.86, 122.61, 122.31, 115.42. 110.88, 48.98, 31.98, 19.92, 14.01. \u003cb\u003eIR STRECHING\u003c/b\u003e: (N-H)\u0026thinsp;=\u0026thinsp;3323 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, (C\u0026thinsp;=\u0026thinsp;O)\u0026thinsp;=\u0026thinsp;1651 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. \u003cb\u003eHRMS (ESI) m/z: [M\u0026thinsp;+\u0026thinsp;H]\u003c/b\u003e calculated C\u003csub\u003e18\u003c/sub\u003eH\u003csub\u003e19\u003c/sub\u003eN\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e 309.3690\u0026thinsp;+\u0026thinsp;found 310.1553[M\u0026thinsp;+\u0026thinsp;H].\u003c/p\u003e \u003cp\u003e \u003cb\u003e1-Butyl-N-(2-hydroxy-6methylphenyl)-1\u003c/b\u003e \u003cb\u003eH\u003c/b\u003e \u003cb\u003e-indazol-3-carboxamide (8k). Appearance\u003c/b\u003e: Pale brown solid (yield\u0026thinsp;=\u0026thinsp;13.5%, 30 mg). \u003csup\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eH NMR [400 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: δ 9.34 (s, 1H), 9.22 (s, 1H), 8.18 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.00 Hz, 1H), 7.81 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.40 Hz, 1H), 7.48 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.00 Hz, 1H), 7.29 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 1H), 7.02 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.00 Hz, 1H), 6.75 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 2H), 4.54 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 2H), 2.20 (s, 3H), 1.91 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 2H), 1.28\u0026ndash;1.30 (m, 2H), 0.94 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.60 Hz, 3H). \u003csup\u003e\u003cb\u003e13\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eC NMR [100 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: d ppm 161.17, 153.47 141.08, 137.35, 137.17, 127.37, 127.05, 124.00, 122.87, 122.79, 122.28, 121.00, 113.95, 110.88, 48.98, 31.42, 22.53, 14.42, 14.01. \u003cb\u003eIR STRECHING\u003c/b\u003e: (N-H)\u0026thinsp;=\u0026thinsp;3355 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, (OH)\u0026thinsp;=\u0026thinsp;3104 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, (C\u0026thinsp;=\u0026thinsp;O)\u0026thinsp;=\u0026thinsp;1643 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. \u003cb\u003eHRMS (ESI) m/z: [M\u0026thinsp;+\u0026thinsp;H]\u003c/b\u003e calculated C\u003csub\u003e19\u003c/sub\u003eH\u003csub\u003e21\u003c/sub\u003eN\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e 323.3960\u0026thinsp;+\u0026thinsp;found 324.1711[M\u0026thinsp;+\u0026thinsp;H].\u003c/p\u003e \u003cp\u003e \u003cb\u003e1-Butyl-N-(m-tolyl)-1\u003c/b\u003e \u003cb\u003eH\u003c/b\u003e \u003cb\u003e-indazol-3-carboxamide (8l). Appearance\u003c/b\u003e: Off white solid (yield\u0026thinsp;=\u0026thinsp;90.2%, 190 mg). \u003csup\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eH NMR [400 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: δ 10.07 (s, 1H), 8.23 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.00 Hz, 1H), 7.81 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.40 Hz, 1H), 7.76 (s, 1H), 7.67 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.00 Hz, 1H), 7.49 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.00 Hz, 1H), 7.32 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.60 Hz, 1H), 7.23 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.00 Hz, 1H), 6.92 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.60 Hz, 1H), 4.54 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 2H), 2.33 (s, 3H), 1.91 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 2H), 1.30 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.60 Hz, 2H), 0.91 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 3H).\u003csup\u003e\u003cb\u003e13\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eC NMR [100 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: d ppm 160.97,141.18, 139.11, 138.19, 137.47, 128.87, 127.16, 124.64, 123.04, 122.22, 121.26, 117.91, 110.95, 49.05, 31.96, 21.70, 19.93, 14. \u003cb\u003eIR STRECHING\u003c/b\u003e: (N-H)\u0026thinsp;=\u0026thinsp;3316 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, (C\u0026thinsp;=\u0026thinsp;O)\u0026thinsp;=\u0026thinsp;1659 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. \u003cb\u003eHRMS (ESI) m/z: [M\u0026thinsp;+\u0026thinsp;H]\u003c/b\u003e calculated C\u003csub\u003e19\u003c/sub\u003eH\u003csub\u003e21\u003c/sub\u003eN\u003csub\u003e3\u003c/sub\u003eO 307.3970\u0026thinsp;+\u0026thinsp;found 308.1765[M\u0026thinsp;+\u0026thinsp;H].\u003c/p\u003e \u003cp\u003e \u003cb\u003e1-Butyl-N-(o-tolyl)-1\u003c/b\u003e \u003cb\u003eH\u003c/b\u003e \u003cb\u003e-indazol-3-carboxamide (8m). Appearance\u003c/b\u003e: Off white solid (yield\u0026thinsp;=\u0026thinsp;90.2%, 190.5 mg). \u003csup\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eH NMR [400 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: δ 9.61 (s, 1H), 8.24\u0026ndash;8.22 (m, 3H), 7.83 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.40 Hz, 1H), 7.69 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.40, -8.40 Hz, 1H), 7.50 (td, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.80, -7.00 Hz, 1H), 7.34 (td, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.40, -11.20 Hz, 1H), 4.53 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.80 Hz, 2H), 2.28 (s, 3H), 1.89 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 2H), 1.28 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.60 Hz, 2H), 0.89 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.60 Hz, 3H).\u003csup\u003e\u003cb\u003e13\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eC NMR [100 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: d ppm 160.42, 149.27, 148.46, 141.42, 139.25, 136.37, 129.24, 127.37, 123.49, 122.55, 121.91, 113.34, 111.20, 49.31, 31.77, 19.86, 17.76, 13.93. \u003cb\u003eIR STRECHING\u003c/b\u003e: (N-H)\u0026thinsp;=\u0026thinsp;3391 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, (C\u0026thinsp;=\u0026thinsp;O)\u0026thinsp;=\u0026thinsp;1679 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. \u003cb\u003eHRMS (ESI) m/z: [M\u0026thinsp;+\u0026thinsp;H]\u003c/b\u003e calculated C\u003csub\u003e19\u003c/sub\u003eH\u003csub\u003e21\u003c/sub\u003eN\u003csub\u003e3\u003c/sub\u003eO 307.3970\u0026thinsp;+\u0026thinsp;found 308.1721[M\u0026thinsp;+\u0026thinsp;H].\u003c/p\u003e \u003cp\u003e \u003cb\u003e1-Butyl-N-(5-methylpyridin-2-yl)-1\u003c/b\u003e \u003cb\u003eH\u003c/b\u003e \u003cb\u003e-indazol-3-carboxamide (8n). Appearance\u003c/b\u003e: Off white solid (yield\u0026thinsp;=\u0026thinsp;87.5%, 185.5 mg). \u003csup\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eH NMR [400 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: δ 9.65 (s, 1H), 8.23 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.00 Hz, 1H), 7.81 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.40 Hz, 1H), 7.69 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.60 Hz, 1H), 7.49 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 1H), 7.33\u0026ndash;7.31 (m, 3H), 7.13 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.60 Hz, 1H), 4.53 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.80 Hz, 2H), 2.31 (s, 3H), 1.90 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 2H), 1.35\u0026ndash;1.34 (m, 2H), 0.91 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 3H). \u003csup\u003e\u003cb\u003e13\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eC NMR [100 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: d ppm 160.80, 141.21, 137.26, 136.54, 132.05, 127.16, 125.62, 125.13, 123.05, 122.76, 122.19, 110.96, 48.98, 31.88, 19.9, 18.16, 13.95. \u003cb\u003eIR STRECHING\u003c/b\u003e: (N-H)\u0026thinsp;=\u0026thinsp;3387 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, (C\u0026thinsp;=\u0026thinsp;O)\u0026thinsp;=\u0026thinsp;1675 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. \u003cb\u003eHRMS (ESI) m/z: [M\u0026thinsp;+\u0026thinsp;H]\u003c/b\u003e calculated C\u003csub\u003e19\u003c/sub\u003eH\u003csub\u003e20\u003c/sub\u003eN\u003csub\u003e4\u003c/sub\u003eO 308.3850\u0026thinsp;+\u0026thinsp;found 309.1719[M\u0026thinsp;+\u0026thinsp;H].\u003c/p\u003e \u003cp\u003e \u003cb\u003e1-Butyl-N-(5-methylpyridin-2-yl)-1\u003c/b\u003e \u003cb\u003eH\u003c/b\u003e \u003cb\u003e-indazol-3-carboxamide (8o). Appearance\u003c/b\u003e: off white solid (yield\u0026thinsp;=\u0026thinsp;89.1%, 198 mg). \u003csup\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eH NMR [400 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: δ 10.11 (s, 1H), 8.24 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.00 Hz, 1H), 7.80 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.80 Hz, 3H), 7.48 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.60 Hz, 1H), 7.30 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.60 Hz, 1H), 6.94 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.80 Hz, 2H), 4.53 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 2H), 3.76 (s, 3H), 1.90 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 2H), 1.34\u0026ndash;1.30 (m, 2H), 0.90 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.60 Hz, 3H). \u003csup\u003e\u003cb\u003e13\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eC NMR [100 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: d ppm 160.73, 155.9, 141.14, 137.61, 132.31, 127.12, 122.93, 122.86, 122.37, 122.30, 114.17, 110.91, 55.63, 49.02, 31.99, 19.93, 14. \u003cb\u003eIR STRECHING\u003c/b\u003e: (N-H)\u0026thinsp;=\u0026thinsp;3279 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, (C\u0026thinsp;=\u0026thinsp;O)\u0026thinsp;=\u0026thinsp;1651 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. \u003cb\u003eHRMS (ESI) m/z: [M\u0026thinsp;+\u0026thinsp;H]\u003c/b\u003e calculated C\u003csub\u003e19\u003c/sub\u003eH\u003csub\u003e21\u003c/sub\u003eN\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e 323.3960\u0026thinsp;+\u0026thinsp;found 324.1711[M\u0026thinsp;+\u0026thinsp;H].\u003c/p\u003e \u003cp\u003e \u003cb\u003e1-Butyl-N-(4-fluorophenyl)-1\u003c/b\u003e \u003cb\u003eH\u003c/b\u003e \u003cb\u003e-indazol-3-carboxamide (8p). Appearance\u003c/b\u003e: Pale brown solid (yield\u0026thinsp;=\u0026thinsp;84.3%, 180.5 mg). \u003csup\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eH NMR [400 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: δ 10.34 (s, 1H), 8.25 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.00 Hz, 1H), 7.96\u0026ndash;7.95 (m, 2H), 7.79 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.40 Hz, 1H), 7.48 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 1H), 7.31 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.60 Hz, 1H), 7.20 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9.20 Hz, 2H), 4.53 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 2H), 1.89 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 2H), 1.33\u0026ndash;1.31 (m, 2H), 0.89 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.60 Hz, 3H). \u003csup\u003e\u003cb\u003e13\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eC NMR [100 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: d ppm 161.04, 159.9, 141.16, 137.36, 127.16, 123.05, 122.93, 122.7, 122.62, 122.24, 115.65, 115.43, 110.93, 49.07, 31.98, 19.91, 13.96. \u003cb\u003eIR STRECHING\u003c/b\u003e: (N-H)\u0026thinsp;=\u0026thinsp;3307 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, (C\u0026thinsp;=\u0026thinsp;O)\u0026thinsp;=\u0026thinsp;1663 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. \u003cb\u003eHRMS (ESI) m/z: [M\u0026thinsp;+\u0026thinsp;H]\u003c/b\u003e calculated C\u003csub\u003e18\u003c/sub\u003eH\u003csub\u003e18\u003c/sub\u003eFN\u003csub\u003e3\u003c/sub\u003eO 311.3604\u0026thinsp;+\u0026thinsp;found 312.1508[M\u0026thinsp;+\u0026thinsp;H].\u003c/p\u003e \u003cp\u003e \u003cb\u003e1-Butyl-N-(2-methoxyphenyl)-1\u003c/b\u003e \u003cb\u003eH\u003c/b\u003e \u003cb\u003e-indazol-3-carboxamide (8q). Appearance\u003c/b\u003e: Off white solid (yield\u0026thinsp;=\u0026thinsp;79.8%, 177.5 mg). \u003csup\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eH NMR [400 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: δ 9.44 (s, 1H), 8.40 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.60, Hz, 1H), 8.26 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.00 Hz, 1H), 7.83 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.80 Hz, 1H), 7.52\u0026ndash;7.52 (m, 1H), 7.34 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.60 Hz, 1H), 7.15\u0026ndash;7.14 (m, 2H), 4.54 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.80 Hz, 2H), 3.94 (s, 3H), 1.88 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 2H), 1.34\u0026ndash;1.32 (m, 2H), 0.91 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 3H).\u003csup\u003e\u003cb\u003e13\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eC NMR [100 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: d ppm 160.06, 148.68, 141.39, 136.9, 127.55, 127.37, 124.35, 123.41, 122.47, 122.07, 121.13, 119.71, 111.41, 111.17, 56.53, 48.99. 31.8,19.84, 13.88. \u003cb\u003eIR STRECHING\u003c/b\u003e: (N-H)\u0026thinsp;=\u0026thinsp;3307 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, (C\u0026thinsp;=\u0026thinsp;O)\u0026thinsp;=\u0026thinsp;1663 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. \u003cb\u003eHRMS (ESI) m/z: [M\u0026thinsp;+\u0026thinsp;H]\u003c/b\u003e calculated C\u003csub\u003e19\u003c/sub\u003eH\u003csub\u003e21\u003c/sub\u003eN\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e 323.3960\u0026thinsp;+\u0026thinsp;found 324.1713[M\u0026thinsp;+\u0026thinsp;H].\u003c/p\u003e \u003cp\u003e \u003cb\u003e1-Butyl-N-(3-hydroxyphenyl)-1\u003c/b\u003e \u003cb\u003eH\u003c/b\u003e \u003cb\u003e-indazol-3-carboxamide (8r). Appearance\u003c/b\u003e: Pale brown solid (yield\u0026thinsp;=\u0026thinsp;66%, 140 mg). \u003csup\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eH NMR [400 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: δ 10.05 (s, 1H), 9.43 (s, 1H), 8.23 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.40 Hz, 1H), 7.80 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.40 Hz, 1H), 7.50\u0026ndash;7.50 (m, 2H), 7.31 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.60 Hz, 1H), 7.26 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.40 Hz, 1H), 7.13 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.40 Hz, 1H), 6.52 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.60, 8.00 Hz, 1H), 4.53 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.80 Hz, 2H), 1.89 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.80 Hz, 2H), 1.33\u0026ndash;1.31 (m, 2H), 0.90 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 3H).\u003csup\u003e\u003cb\u003e13\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eC NMR [100 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: d ppm 160.95, 157.99, 141.16, 140.2, 137.53, 129.67, 127.18, 123.04, 122.86, 122.23, 111.56, 111.12, 110.95, 107.88, 49.04, 31.96, 19.91, 13.99. \u003cb\u003eIR STRECHING\u003c/b\u003e: (N-H)\u0026thinsp;=\u0026thinsp;3347 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, (OH)\u0026thinsp;=\u0026thinsp;3200 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1,\u003c/sup\u003e (C\u0026thinsp;=\u0026thinsp;O)\u0026thinsp;=\u0026thinsp;1703 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. \u003cb\u003eHRMS (ESI) m/z: [M\u0026thinsp;+\u0026thinsp;H]\u003c/b\u003e calculated C\u003csub\u003e18\u003c/sub\u003eH\u003csub\u003e19\u003c/sub\u003eN\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e 309.3690\u0026thinsp;+\u0026thinsp;found 310.1554[M\u0026thinsp;+\u0026thinsp;H].\u003c/p\u003e \u003cp\u003e \u003cb\u003e1-Butyl-N-(4H-1,2,4-triazol-4yl)-1\u003c/b\u003e \u003cb\u003eH\u003c/b\u003e \u003cb\u003e-indazol-3-carboxamide (8s). Appearance\u003c/b\u003e: Off white solid (yield\u0026thinsp;=\u0026thinsp;89%, 174 mg). \u003csup\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eH NMR [400 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: δ 12.12 (s, 1H), 8.80 (s, 2H), 8.14 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.00 Hz, 1H), 7.87 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.40 Hz, 1H), 7.52 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 1H), 7.35 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.60 Hz, 1H), 4.57 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 2H), 1.91 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.80 Hz, 2H), 1.32\u0026ndash;1.31 (m, 2H), 0.91 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 3H). \u003csup\u003e\u003cb\u003e13\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eC NMR [100 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: d ppm 161.53, 144.49, 140.98, 134.46, 127.48, 123.73, 123.01, 121.58, 111.27, 49.26, 31.89, 19.87, 13.99. \u003cb\u003eIR STRECHING\u003c/b\u003e: (N-H)\u0026thinsp;=\u0026thinsp;3112 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (C\u0026thinsp;=\u0026thinsp;O)\u0026thinsp;=\u0026thinsp;1695 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. \u003cb\u003eHRMS (ESI) m/z: [M\u0026thinsp;+\u0026thinsp;H]\u003c/b\u003e calculated C\u003csub\u003e14\u003c/sub\u003eH\u003csub\u003e16\u003c/sub\u003eN\u003csub\u003e6\u003c/sub\u003eO 284.3230\u0026thinsp;+\u0026thinsp;found 285.1460[M\u0026thinsp;+\u0026thinsp;H].\u003c/p\u003e \u003cp\u003e \u003cb\u003eN-(2-amino-4-nitrophenyl)-1butyl-1\u003c/b\u003e \u003cb\u003eH\u003c/b\u003e \u003cb\u003e-indazol-3-carbohydrazide (8t). Appearance\u003c/b\u003e: Brown solid (yield\u0026thinsp;=\u0026thinsp;84.4%, 205 mg). \u003csup\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eH NMR [400 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: δ 9.75 (s, 1H), 8.25 (s, 1H), 8.20 (d, J\u0026thinsp;=\u0026thinsp;8.40 Hz, 1H), 7.93 (dd, J\u0026thinsp;=\u0026thinsp;2.80, 9.00 Hz, 1H), 7.83 (d, J\u0026thinsp;=\u0026thinsp;8.80 Hz, 1H), 7.49 (t, J\u0026thinsp;=\u0026thinsp;8.00 Hz, 1H), 7.32 (t, J\u0026thinsp;=\u0026thinsp;7.20 Hz, 1H), 6.85 (t, J\u0026thinsp;=\u0026thinsp;8.80 Hz, 1H), 6.56 (s, 2H), 4.55 (t, J\u0026thinsp;=\u0026thinsp;7.20 Hz, 2H), 1.92 (q, J\u0026thinsp;=\u0026thinsp;7.20 Hz, 2H), 1.28\u0026ndash;1.30 (m, 2H), 0.92 (t, J\u0026thinsp;=\u0026thinsp;7.60 Hz, 3H). \u003csup\u003e\u003cb\u003e13\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eC NMR [100 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: d 161.70, 150.93, 141.11, 137.06, 136.05, 127.15, 123.77, 123.56, 123.07, 122.94, 121.19, 121.73, 114.58, 110.95, 49.07, 32.00, 19.95, 14.03. \u003cb\u003eIR STRECHING\u003c/b\u003e: (N-H)\u0026thinsp;=\u0026thinsp;3459 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, (N-H)\u0026thinsp;=\u0026thinsp;3327 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, (C\u0026thinsp;=\u0026thinsp;O)\u0026thinsp;=\u0026thinsp;1669 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. (NO\u003csub\u003e2\u003c/sub\u003e)\u0026thinsp;=\u0026thinsp;1623 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. \u003cb\u003eHRMS (ESI) m/z: [M\u0026thinsp;+\u0026thinsp;H]\u003c/b\u003e calculated C\u003csub\u003e18\u003c/sub\u003eH\u003csub\u003e19\u003c/sub\u003eN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003e 353.3820\u0026thinsp;+\u0026thinsp;found 354.1563[M\u0026thinsp;+\u0026thinsp;H].\u003c/p\u003e \u003cp\u003e \u003cb\u003e1-Butyl-N-phenyl-1\u003c/b\u003e \u003cb\u003eH\u003c/b\u003e \u003cb\u003e-indazol-3-carbohydrazide (8u). Appearance\u003c/b\u003e: Off white solid (yield\u0026thinsp;=\u0026thinsp;99%, 140 mg). \u003csup\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eH NMR [400 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: δ 10.14 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.40 Hz, 1H), 8.05 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.00 Hz, 1H), 7.82 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.80 Hz, 1H), 7.73 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.40 Hz, 1H), 7.40 (dt, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.80, 10.80 Hz, 1H), 7.21 (t, J\u0026thinsp;=\u0026thinsp;7.60 Hz, 1H), 7.08 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.00 Hz, 2H), 6.73 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.60 Hz, 2H), 6.64 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 1H), 4.46 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9.20 Hz, 2H), 1.83 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 2H), 1.28\u0026ndash;1.26 (m, 2H), 0.84 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 3H). \u003csup\u003e\u003cb\u003e13\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eC NMR [100 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: d ppm 162.52, 150.06, 140.81, 136.30, 129.14, 127.07, 122.88, 122.86, 121.97, 118.88, 112.71, 110.89, 48.95, 31.90, 19.92, 14.02. \u003cb\u003eIR STRECHING\u003c/b\u003e: (N-H)\u0026thinsp;=\u0026thinsp;3233Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, (C\u0026thinsp;=\u0026thinsp;O)\u0026thinsp;=\u0026thinsp;1645 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. \u003cb\u003eHRMS (ESI) m/z: [M\u0026thinsp;+\u0026thinsp;H]\u003c/b\u003e calculated C\u003csub\u003e18\u003c/sub\u003eH\u003csub\u003e20\u003c/sub\u003eN\u003csub\u003e4\u003c/sub\u003eO 308.3850\u0026thinsp;+\u0026thinsp;found 331.1558[M\u0026thinsp;+\u0026thinsp;Na].\u003c/p\u003e \u003cp\u003e \u003cb\u003e1-Butyl-N-(2,4-dinitrophenyl)-1\u003c/b\u003e \u003cb\u003eH\u003c/b\u003e \u003cb\u003e-indazol-3-carbohydrazide (8v). Appearance\u003c/b\u003e: Pale brown solid (yield\u0026thinsp;=\u0026thinsp;18.3%, 50 mg). \u003csup\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eH NMR [400 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: δ 11.03 (s, 1H), 10.30 (s, 1H), 8.91 (s, 1H), 8.34 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.40 Hz, 1H), 8.14 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 1H), 7.86 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.60 Hz, 1H), 7.51 (s, 1H), 7.32 (s, 2H), 4.56 (s, 2H), 1.92 (s, 2H), 1.32 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.00 Hz, 2H), 0.926 (s, 3H). \u003csup\u003e\u003cb\u003e13\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eC NMR [100 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: d 161.89, 149.34, 140.91, 137.14, 135.37, 130.64, 127.31, 123.64, 123.36, 123.02, 121.82, 116.22, 111.10, 49.14, 31.93, 19.91, 14.02. \u003cb\u003eIR STRECHING\u003c/b\u003e: (N-H)\u0026thinsp;=\u0026thinsp;3363 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, (N-H)\u0026thinsp;=\u0026thinsp;3331 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, (C\u0026thinsp;=\u0026thinsp;O)\u0026thinsp;=\u0026thinsp;1691 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. \u003cb\u003eHRMS (ESI) m/z: [M\u0026thinsp;+\u0026thinsp;H]\u003c/b\u003e calculated C\u003csub\u003e18\u003c/sub\u003eH\u003csub\u003e18\u003c/sub\u003eN\u003csub\u003e6\u003c/sub\u003eO\u003csub\u003e5\u003c/sub\u003e 398.3790\u0026thinsp;+\u0026thinsp;found 399.1414[M\u0026thinsp;+\u0026thinsp;H].\u003c/p\u003e \u003cp\u003e \u003cb\u003e1-Butyl-N-(4-cyanophenyl)-1\u003c/b\u003e \u003cb\u003eH\u003c/b\u003e \u003cb\u003e-indazol-3-carbohydrazide (8w). Appearance\u003c/b\u003e: Brown solid (yield\u0026thinsp;=\u0026thinsp;87.3%, 200 mg). \u003csup\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eH NMR [400 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: δ 10.46 (s, 1H), 8.79 (s, 1H), 8.12 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.00 Hz, 1H), 7.82 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.40 Hz, 1H), 7.56 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.40 Hz, 2H), 7.48 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.60 Hz, 1H), 7.29 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.60 Hz, 1H), 6.83 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.40 Hz, 2H), 4.53 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 2H), 1.90 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 2H), 1.26\u0026ndash;1.28 (m, 2H), 0.00 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.60 Hz, 3H). \u003csup\u003e\u003cb\u003e13\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eC NMR [100 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: d 162.39, 153.62, 140.84, 135.87, 133.85, 127.16, 123.07, 122.93, 121.9, 120.58, 112.19, 99.15, 49.04, 31.90, 19.92, 14.01. \u003cb\u003eIR STRECHING\u003c/b\u003e: (N-H)\u0026thinsp;=\u0026thinsp;3343 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, (N-H)\u0026thinsp;=\u0026thinsp;3235 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, (CN)\u0026thinsp;=\u0026thinsp;2220 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, (C\u0026thinsp;=\u0026thinsp;O)\u0026thinsp;=\u0026thinsp;1679 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. \u003cb\u003eHRMS (ESI) m/z: [M\u0026thinsp;+\u0026thinsp;H]\u003c/b\u003e calculated C\u003csub\u003e19\u003c/sub\u003eH\u003csub\u003e19\u003c/sub\u003eN\u003csub\u003e5\u003c/sub\u003eO 333.3950\u0026thinsp;+\u0026thinsp;found 334.1668[M\u0026thinsp;+\u0026thinsp;H].\u003c/p\u003e \u003cp\u003e \u003cb\u003e1-Butyl-N-(4-hydroxyphenyl)-1\u003c/b\u003e \u003cb\u003eH\u003c/b\u003e \u003cb\u003e-indazol-3-carbohydrazide (8x). Appearance\u003c/b\u003e: Pale brown solid (yield\u0026thinsp;=\u0026thinsp;60.5%, 135 mg). \u003csup\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eH NMR [400 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: δ 10.19 (d, J\u0026thinsp;=\u0026thinsp;9.60 Hz, 2H), 10.09 (s, 1H), 8.14 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.40 Hz, 3H), 7.82 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.40 Hz, 1H), 7.47 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.40 Hz, 1H), 7.30 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 1H), 6.86 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.40 Hz, 2H), 4.52 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 2H), 1.90 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.80 Hz, 2H), 1.26\u0026ndash;1.26 (m, 2H), 0.91 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 3H). \u003csup\u003e\u003cb\u003e13\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eC NMR [100 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: d 165.93, 161.90, 161.07, 140.84, 136.07, 129.98, 1247.09, 123.78, 122.99, 122.93, 121.96, 115.44, 110.93, 48.96, 31.89, 19.90, 14.00. \u003cb\u003eIR STRECHING\u003c/b\u003e: (N-H)\u0026thinsp;=\u0026thinsp;3359 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, (OH)\u0026thinsp;=\u0026thinsp;3204 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, (C\u0026thinsp;=\u0026thinsp;O)\u0026thinsp;=\u0026thinsp;1679 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e.\u003cb\u003eHRMS (ESI) m/z: [M\u0026thinsp;+\u0026thinsp;H]\u003c/b\u003e calculated C\u003csub\u003e19\u003c/sub\u003eH\u003csub\u003e20\u003c/sub\u003eN\u003csub\u003e4\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003e 352.3940\u0026thinsp;+\u0026thinsp;found 353.1595[M\u0026thinsp;+\u0026thinsp;H].\u003c/p\u003e \u003cp\u003e \u003cb\u003eN-(4-Bromophenyl)-1butyl-1\u003c/b\u003e \u003cb\u003eH\u003c/b\u003e \u003cb\u003e-indazol-3-carbohydrazide (8y). Appearance\u003c/b\u003e: Brown solid (yield\u0026thinsp;=\u0026thinsp;75.3%, 200 mg). \u003csup\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eH NMR [400 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: 10.28 (s, 1H), 8.12 (s, 2H), 7.81 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.40 Hz, 1H), 7.47 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.00 Hz, 1H), 7.29 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11.60 Hz, 3H), 6.74 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.40 Hz, 2H), 4.52 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.80 Hz, 2H), 1.90 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.80 Hz, 2H), 1.24\u0026ndash;1.26 (m, 2H), 0.91 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 3H). \u003csup\u003e\u003cb\u003e13\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eC NMR [100 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: d 162.48, 149.45, 140.81, 136.12, 131.77, 127.10, 122.95, 121.93, 114.69, 110.91, 109.60, 48.98, 31.89, 19.91, 14.01. \u003cb\u003eIR STRECHING\u003c/b\u003e: : (N-H)\u0026thinsp;=\u0026thinsp;3343, 3231 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, (C\u0026thinsp;=\u0026thinsp;O)\u0026thinsp;=\u0026thinsp;1658 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e \u003cb\u003eHRMS (ESI) m/z: [M\u0026thinsp;+\u0026thinsp;H]\u003c/b\u003e calculated C\u003csub\u003e18\u003c/sub\u003eH\u003csub\u003e19\u003c/sub\u003eBrN\u003csub\u003e4\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e 386.2810\u0026thinsp;+\u0026thinsp;found 409.0665[M\u0026thinsp;+\u0026thinsp;Na].\u003c/p\u003e \u003cp\u003e \u003cb\u003e1-Butyl-N-(4-nitrophenyl)-1\u003c/b\u003e \u003cb\u003eH\u003c/b\u003e \u003cb\u003e-indazol-3-carboxamide (8z). Appearance\u003c/b\u003e: Yellow solid (yield\u0026thinsp;=\u0026thinsp;25.7%, 40 mg). \u003csup\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eH NMR [400 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: δ 10.88 (s, 1H), 8.26 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9.20 Hz, 5H), 7.86 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.40 Hz, 1H), 7.52 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.60 Hz, 1H), 7.36 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 1H), 4.58 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.80 Hz, 2H), 1.92 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.60 Hz, 2H), 1.27\u0026ndash;1.28 (m, 2H), 0.92 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.20 Hz, 3H), (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;Hz, 3H). \u003csup\u003e\u003cb\u003e13\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eC NMR [100 MHz, DMSO-d\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e]\u003c/b\u003e: d ppm 161.60, 145.67, 142.80, 141.25, 136.80, 127.39, 125.17, 123.04, 122.06, 120.39, 111.21, 49.25, 31.99, 19.92, 14.01. \u003cb\u003eIR STRECHING\u003c/b\u003e: (N-H)\u0026thinsp;=\u0026thinsp;3383 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, (C\u0026thinsp;=\u0026thinsp;O)\u0026thinsp;=\u0026thinsp;1712 Cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. \u003cb\u003eHRMS (ESI) m/z: [M\u0026thinsp;+\u0026thinsp;H]\u003c/b\u003e calculated C\u003csub\u003e18\u003c/sub\u003eH\u003csub\u003e18\u003c/sub\u003eN\u003csub\u003e4\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003e 338.14\u0026thinsp;+\u0026thinsp;found 361.1274[M\u0026thinsp;+\u0026thinsp;Na].\u003c/p\u003e"},{"header":"Results and discussion","content":"\u003cp\u003eA solution of phenylhydrazine \u003cb\u003e1\u003c/b\u003e in water was treated with benzaldehyde \u003cb\u003e2\u003c/b\u003e (1eq) at room temperature. The addition was gradual, and the mixture was stirred for 8 hours to yield benzylidene-1-phenylhydrazine \u003cb\u003e3\u003c/b\u003e. This compound was then subjected to a reaction with oxalyl chloride in the presence of AlCl\u003csub\u003e3\u003c/sub\u003e (1.5eq) for two hours at 40\u0026deg;C to 45\u0026deg;C, affording 1-(benzylidine amino)indolin-2,3-dione \u003cb\u003e4\u003c/b\u003e. This compound was further converted to indazole-3-carboxylic acid \u003cb\u003e5\u003c/b\u003e, which underwent an alkylation reaction with bromobutane using NaH as a base to produce 1-butyl-1\u003cem\u003eH\u003c/em\u003e-indazole-3-carboxylic acid \u003cb\u003e6\u003c/b\u003e. A simple synthetic approach was employed to obtain a series of 3-carboxamide indazole derivatives \u003cb\u003e8a-8z\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe reaction was performed at room temperature using HATU (2 equiv) as an amide coupling reagent and DIPEA (3 equiv) as a base in DMF (10 vol) solvent (\u003cb\u003e8a-8b\u003c/b\u003e, Scheme \u003cspan refid=\"Sch1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), All derivatives, with the exception of 8e, 8k, 8vand 8z, have yields between 55 and 80%. The progress of the reaction and the purity of the target molecules were determined using TLC. All the derivatives were purified by column chromatography (Ethyl acetate/Hexane 1:3) and characterized by IR, \u003csup\u003e1\u003c/sup\u003eH and \u003csup\u003e13\u003c/sup\u003eC NMR, and HRMS spectral data. Further details on the synthesis and characterization of the derivatives are available in the supplementary information.\u003c/p\u003e \u003cp\u003e \u003cb\u003eDFT STUDY\u003c/b\u003e \u003c/p\u003e \u003cp\u003eBased on Koopman's relation, the LUMO\u0026ndash;HOMO energy gap (ΔE\u0026thinsp;=\u0026thinsp;E\u003csub\u003eLUMO\u003c/sub\u003e \u0026ndash; E\u003csub\u003eHOMO\u003c/sub\u003e) and other frontier orbital energy characteristics, including the chemical potential of the molecules under test can be calculated. The molecules with highest HOMO values can act as electron donors and the molecules with lowest LUMO can be the electron acceptors[\u003cspan additionalcitationids=\"CR15 CR16 CR17\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] The HOMO and LUMO energies and global reactivity parameters have been calculated for all the molecules \u003cb\u003e8a-8z\u003c/b\u003e using GAUSSIAN 09 for DFT calculation 6\u0026ndash;31\u0026thinsp;+\u0026thinsp;G (d,p) basis set and the obtained data has been given as Table.1 in the supportive information. Out of all the compounds evaluated, compounds \u003cb\u003e8a\u003c/b\u003e, \u003cb\u003e8c\u003c/b\u003e, and \u003cb\u003e8s\u003c/b\u003e had the biggest energy gap (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) The energy gap was computed using the ΔE = (E\u003csub\u003eLUMO\u003c/sub\u003e \u0026ndash; E\u003csub\u003eHOMO\u003c/sub\u003e)[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] formula, and Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e displays the FMO representation. It is discovered that compounds \u003cb\u003e8a\u003c/b\u003e, \u003cb\u003e8c\u003c/b\u003e, and \u003cb\u003e8q\u003c/b\u003e are good electron acceptors whereas compounds \u003cb\u003e8u\u003c/b\u003e, \u003cb\u003e8x\u003c/b\u003e, and \u003cb\u003e8z\u003c/b\u003e are good electron donors. The indazole molecule's HOMO and LUMO distributions span practically the entire molecule. (See the supporting information (SI)). These descriptors provide insight into molecular behavior, facilitating our understanding of chemical reactivity. The HOMO-LUMO energy gap makes it simple to calculate a molecule's chemical hardness, which is a good indicator of its reactivity. A higher degree of molecular softness is indicated by a smaller gap value, whereas a bigger HOMO-LUMO energy gap is indicative of higher molecular hardness. Figure\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e displays the electron distribution of \u003cb\u003e8a\u003c/b\u003e, \u003cb\u003e8c\u003c/b\u003e and \u003cb\u003e8s\u003c/b\u003e under HOMO-LUMO. The red and green colors represent the positive (nucleophile) and negative (electrophilic) lobes respectively. The molecular electrostatic potential (MEP) is an essential tool that assists in predicting the reactivity sites of a molecule for nucleophilic and electrophilic attacks. Understanding hydrogen bonding and the relationship between a molecule's electrical characteristics, such as dipole moment, electronegativity, atomic charges, and so on, is also crucial for comprehending electrophilic and nucleophilic reactions.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTo compute the MEP surface analysis of a compound, Density Functional Theory (DFT) calculations are employed using the optimized structure and the B3LYP/6-31G(d,p) basis set. The MEP surface analysis provides extensive insights into a compound's properties and behaviour that are critical for scientific research and development. MEP analysis clarifies the electron distribution pattern of compound \u003cb\u003e8a\u003c/b\u003e and its electron density (positive site: +7.281e, negative site: -7.281e), are displayed in Fig.\u0026nbsp;4, which represents the compounds' mapped electrostatic potential surface. Electrostatic potential levels and zones of positive, negative, and neutral electrostatic potential are represented by different colours. Electrophilic sites are shown in red colour, whereas nucleophilic sites are represented in blue colour. An area with a neutral electrostatic potential is shown by the colour green. The oxygen and nitrogen atoms have electrophilic sites, while the hydrogen atoms have nucleophilic sites. Therefore, nucleophilic and electrophilic molecules are drawn to places with higher negative electronegative potential and positive electrostatic potential[\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDFT calculated values of \u003cb\u003e8u, 8v, 8z.\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eS. No:\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCOMPOUND\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHOMO\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLUMO\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eΔE\u0026thinsp;=\u0026thinsp;E\u003csub\u003eLUMO\u003c/sub\u003e-E\u003csub\u003eHOMO\u003c/sub\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e8a\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-6.0453\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e-0.86238\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e5.18292\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e8b\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-5.51394\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-1.07163\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.44231\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e8c\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-5.88654\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e-0.81999\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e5.06655\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e8d\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-6.12522\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-2.65032\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.4749\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e8e\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-5.7888\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-1.17666\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.61214\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e8f\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-4.44879\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.98955\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.45924\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e8g\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-5.89761\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-1.40211\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.4955\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e8h\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-5.65434\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-2.31201\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.34233\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e8i\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-5.62275\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-1.21878\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.40397\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e8j\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-5.14566\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-1.04112\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.10454\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e8k\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-5.23692\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.92853\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.30839\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e8l\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-5.44563\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-1.05111\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.39452\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e8m\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-5.41485\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-1.07244\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.34241\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e8n\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-5.67216\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-1.00143\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.67073\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e8o\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-5.11137\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-1.0287\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.08267\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e8p\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-5.5039\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-1.15128\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.35262\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e8q\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-5.21937\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e-0.92529\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.29408\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e8r\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-5.47317\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-1.14426\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.32891\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e8s\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-6.34878\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-1.4283\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e4.92048\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e8t\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-5.27715\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-2.60523\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.67192\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e8u\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e-6.8823\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-2.45457\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.42773\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e8v\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-6.36687\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-3.59964\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.76723\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e8w\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-5.08923\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-1.32435\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.76488\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e8x\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e-6.67332\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-2.42568\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.24764\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e8y\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-4.24305\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-1.00143\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.24162\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e8z\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e-6.4638\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-2.77776\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.68604\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Molecular Docking","content":"\u003cp\u003eThe literature has identified ENTRECTINIB, PAZOPANIB, and AXITINIB as the three most commonly available medications with an indazole moiety that exhibit potent anti-renal cancer activity. To further augment the efficacy of these medications, we synthesized novel indazole derivatives and performed comprehensive molecular docking studies to evaluate their effectiveness against renal cancer. Through rigorous experimentation, we identified an enhanced PDB 6FEW[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] that is directly linked to renal cancer and utilized the Auto Dock 4.2 software to perform molecular docking studies. The crystal structure of DDR1, specifically 2-[8-(1H-indazole-5-carbonyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5] decan-3-yl], demonstrated exceptional efficacy against renal cancer. The binding energy values (in Kcal/mol) of the ligand-receptor complex were utilized to rank the docking outcomes [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. The 2D structures of all 26 derivatives were prepared using the ChemOffice tool \"Chem Draw 16.0,\" which was used to show the proper 2D orientation of the chemical structures of the chosen ligands. ChemBio3D was then used to lower the energy of each molecule to improve geometry estimation and ligand-receptor affinity[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. To generate the protein, we employed Discovery Studio Visualizer for a better receptor file, and the auto-prepared file was used in an auto docking station to prepare targeted indazole molecules. The Discovery Studio 2021 application LigPlot v.2.2.8 was utilized to meticulously analyze the docking results, and the outcomes are presented in this report. The 2D structures vividly illustrate the interactions between the ligand and amino acid residues, while the 3D structures reveal the precise location of the ligand in the receptor's active site[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. We selected the molecules with the least amount of energy for a docking simulation in AutoDock Vina. The docking simulation grid box was given its configuration and the dimensions of x, y, and z is 40. The macromolecule's target area was placed inside the grid in such a way that it covered the whole structure. It was determined that the ligand and protein could be docked most effectively by utilizing the docking technique made accessible by Auto Dock Vina. During the docking approach, a maximum of ten conformations of each ligand were investigated. The use of a flexible sidechain to simulate the covalent ligand produced good results. All ten docking runs produced comparable conformations, all of which were quite similar to the crystallographic conformation. The 3D and 2D ligand-receptor interactions were investigated using the Discovery studio visualizer. We completed docking studies for 26-molecules, among the 26-molecule three compounds showed more active and binding energy those are 8v, 8w, and 8y (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDocking results in terms of binding energy (Kcal/mol)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCompound\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eΔG\u003csub\u003ebinding energy\u003c/sub\u003e (Kcal/mol)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eKi (micromolar) [Temperature\u0026thinsp;=\u0026thinsp;298.15 k]\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eH bond energy (Kcal/mol)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8v\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-11.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.0235\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-13.47\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8w\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-11.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.0294\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-13.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-11.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.0361\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-13.21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThree compounds interact with amino acid residues involved in water hydrogen bonding, and covalent hydrogen bonding, Alkyl 2D interactions graphics using LigPlot (v.2.2.8) visualizer (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e6\u003c/span\u003e). The compounds: 8v, 8w, and 8y ligand are interactions with ASP784, LYS655, MET699, GLU672, MET676, ILE685, LEU679, ALA783, ILE675, PHE762. Ki values (micromolar) calculated under room temperature (298K) by utilizing auto dock software are 0.0235, 0.0295, and 0.0361, Our research group was finding the H bonding energy of all compounds (see in supporting information (SI)). We evaluated different approaches to docking covalently linked ligands: a grid-based technique and a flexible sidechain approach. Figure\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e6\u003c/span\u003e shows the docking results. Compounds 8v, 8w, and 8y interacted with amino acids through covalent bonds made up of hydrogen and alkyl, Pi-alkyl interaction with ASP784, LYS655, and ILE675, LEU679, ALA783, ILE685, MET699, HIS764. Water hydrogen bonds with HOH1193. These two derivatives formed Pi-sulfur and Pi-sigma interactions with GLU672 and MET676. Three substances are actively creating a salt bridge and actively interacting with GLU672.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, amide coupling was used to successfully and efficiently synthesize a range of 3-carboxamide indazole derivatives. The comprehensive characterization of the target compounds and the high yields attained provided validation for the used methodologies. Using DFT analysis, we were able to determine the geometrical optimization of all the derivatives and discovered that 8a, 8c, and 8s had high energy gaps. We then used Auto Dock 4.0 to perform auto docking in order to determine the effectiveness of the indazole molecule in renal cancer and discovered that 8v, 8w, and 8y had the highest binding energy.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eSupporting Information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Supporting Information is available free of charge on the RSC Publications website.\u003c/p\u003e\n\u003cp\u003eSynthetic procedures; \u003csup\u003e1\u003c/sup\u003eH, \u003csup\u003e13\u003c/sup\u003eC NMR spectra; computational details are in brief description (PDF)\u003c/p\u003e\n\u003cp\u003eAcknowledgment\u003c/p\u003e\n\u003cp\u003eThe authors are thankful to the administration, of VIT University. Vellore, India for providing facilities to carry out research work, and also thankful to SIF-Chemistry, VIT University for NMR facilities. Our sincere thanks to Dr. S. Sarveswari for her valuable comments and suggestions, the authors are thankful to Dr. S. Gururaj for his valuable comments and suggestions for docking studies. Thank you, Suryanarayana Murthy Vallabhaneni, from the writers. \u0026nbsp;Thanks to Ms. V Hemalatha for her suggestions to complete DFT studies.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Conflicts of interest\u003c/p\u003e\n\u003cp\u003eThere are no conflicts to declare.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eO. S. Kim, J. H. Jang, H. T. Kim, S. J. Han, G. C. Tsui, and J. M. Joo, Org Lett \u003cstrong\u003e19\u003c/strong\u003e, 1450 (2017).\u003c/li\u003e\n\u003cli\u003eN. Lohitha and V. Vijayakumar, Polycycl Aromat Compd \u003cstrong\u003e42\u003c/strong\u003e, 5521 (2022).\u003c/li\u003e\n\u003cli\u003eS. Khaidem, S. Sarveswari, R. Gupta, and V. Vijayakumar, (n.d.).\u003c/li\u003e\n\u003cli\u003eP. Ghosh, S. Mondal, and A. 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Rad, J Mol Struct \u003cstrong\u003e1284\u003c/strong\u003e, (2023).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Scheme 1","content":"\u003cp\u003eScheme 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Indazole derivatives, DFT studies, Molecular Docking","lastPublishedDoi":"10.21203/rs.3.rs-4006780/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4006780/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eA series of 3-carboxamide indazoles (8a-8z) has been synthesized using an amide coupling technique. The derivatives were described using various spectroscopic methods such as \u003csup\u003e1\u003c/sup\u003eH NMR, \u003csup\u003e13\u003c/sup\u003eC NMR, IR, MASS spectral data. Density function theory (DFT) calculations revealed that compounds \u003cb\u003e8a\u003c/b\u003e, \u003cb\u003e8c\u003c/b\u003e, and \u003cb\u003e8s\u003c/b\u003e had the largest energy gaps among all the compounds. The study also included testing of AutoDock4 and the graphical user interface of Auto-Dock Tools, which identified three derivatives\u0026mdash;\u003cb\u003e8v, 8w\u003c/b\u003e, and \u003cb\u003e8y\u003c/b\u003e\u0026mdash;with the maximum binding energy.\u003c/p\u003e","manuscriptTitle":"Synthesis and molecular docking of novel indazole derivatives with DFT studies","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-06 17:44:13","doi":"10.21203/rs.3.rs-4006780/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ce7ca2bb-36af-40c3-a988-391a8d657e50","owner":[],"postedDate":"March 6th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-03-16T10:14:55+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-06 17:44:13","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4006780","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4006780","identity":"rs-4006780","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}