Design, synthesis, and mechanism study of novel 1-arylisoquinoline derivatives as antifungal agents

Design, synthesis, and mechanism study of novel 1-arylisoquinoline derivatives as antifungal agents | 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 Design, synthesis, and mechanism study of novel 1-arylisoquinoline derivatives as antifungal agents Yang Chen, Yanxi Jin, Luyao Wang, Wanxiang Wang, Haiping Zhou, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4470733/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 11 Oct, 2024 Read the published version in Molecular Diversity → Version 1 posted 13 You are reading this latest preprint version Abstract In screening for natural-based fungicides, a series of 32 novel 1-arylisoquinoline derivatives were designed, synthesized, and evaluated for their antifungal activities. Their structures were verified by 1H NMR, 13C NMR, HRMS and single X-ray crystal diffraction analysis. Most of the target products exhibited medium to excellent antifungal activity against 6 phytopathogenic fungi in vitro at a concentration of 50 mg/L. Interestingly, compounds A13 and A25 with EC50 values of 2.375, 2.251 mg/L s against A. alternate, that were similar to boscalid (EC50 = 1.195 mg/L). The in vivo experiments revealed that A13 presented 51.61% and 70.97% protection activities against A. alternate at the dosage of 50 and 100 mg/L, respectively, which were equal to that of boscalid (64.52% and 77.42%). The SEM analysis indicated that compound A13 could strongly damage the mycelium morphology. Molecular electrostatic potential and molecular docking analysis revealed that A13 was covered by negative potential contour, and strongly interacts with the residues of SDH. These results revealed that compounds A13 and A25 could be as promising antifungal candidates for the development of natural-based fungicides. 1-Arylisoquinoline Biomimetic design Antifungal activity Antifungal mechanism Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Introduction Phytopathogenic fungi are causing substantial harm to grain crops, resulting in diminished yield, compromised quality, and ultimately posing a threat to the worldwide food security [ 1 ]. Although, chemical fungicides remain as the most effective and economical method for the control of fungal diseases at present [ 2 ], with the prolonged and massive irrational of traditiona-chemicals have caused resistance, residual toxicity and even environmental problems [ 3 – 4 ]. Therefore, it was urgent to discover and develop novel biocompatibility antifungal agents to control plant diseases and ensure the agricultural production safety. The natural-based or -derived compounds have attracted increasing attention as potential candidates to develop “green” agrochemicals due to their extensive biological properties, multiple modes of action and environment friendly [ 5 ]. Tetrahydroisoquinoline alkaloids (THIQs) are a kind of natural products with a common tetrahydroisoquinoline motif and widely exist in the Papaveraceae family and some members of the Rutaceae family [ 6 – 7 ]. THIQs and their derivatives exhibit antibacterial, antitumor, antimalarial, anti-inflammatory, and influence on the activities of various important biological enzymes [ 8 – 10 ]. Tiwari et al. synthesised a series of 1-aryl tetrahydroisoquinoline derivatives with antibacterial activity [ 11 ]. Amide is an important classic structural motif in agrochemicals and natural products, often serving as a linking bridge to introduce active pharmacophores for the development of novel pesticides [ 12 ]. Valine carbamate fungicides, categorized as amino acid fungicides, feature a double amide bridge chain in their structure, which provides good environmental compatibility [ 13 ]. Succinate dehydrogenase inhibitors (SDHIs) have become the most rapidly growing type of agrochemical due to their powerful and broad-spectrum antifungal activities, which damaging the citric acid cycle and respiratory chain electron transmission in fungal mitochondria [ 14 – 16 ]. The structure of commercial SDHIs typically consists of three components: a polar segment, a hydrophobic tail, and an amide bridge that binds them together. The pyrazole ring is the most commonly used polar segment, which often beneficial in enhancing the antifungal action of bioactive carboxamide derivatives [ 17 – 19 ]. In our previous work, several isoquinoline compounds were designed and synthesized with antifungal activites [ 20 – 21 ]. In order to further study isoquinoline derivatives and find novel active fungicidal candicates. A series of novel 1-arylisoquinoline derivatives were designed and synthesized, which introduce double amide bridge binds tetrahydroisoquinoline motif and polar core together (Fig. 1 ). Their antifungal activities against six plant pathogenic fungi were studied. Compound A13 with excellent fungicidal activity was further tested in vivo to against A. alternata on fragrant pears. In addition, scanning electron microscopy (SEM) observations, molecular electrostatic potential. and molecular docking analysis were conducted. Results and Discussion Chemistry The synthetic route of the target compounds as shown in Scheme 1 . 2-(3′,4′-Dimethoxypheny1)ethy1amine 1 reacts with appropriate aldehydes 2a-2h in anhydrous toluene to form the schiff bases 3a-3h . The intermediates 4a-4h were obtained by intramolecular cyclization of 3 with trifluoroacetic acid. Then, 4a-4h was condensed with Boc-glycine to obtain intermediates 5a-5h . Under acidic conditions, the Boc protective group was removed to obtain intermediates 6a-6h , and then condensed with heterocyclic aryl chlorides 7a-7d to obtain target compound A1-A32 . The structures of the title compounds were identified by 1 H NMR, 13 C NMR, HRMS and single-crystal Xray diffraction. As in A5 , the 1 H NMR spectrum of compound A5 at room temperature showed that the proton signals of the methylene groups at C3 and C4, the methoxy groups at C6 and C7, and most of the carbon atoms on the aromatic ring were splitted. It indicated this type of compounds exhibit steric isomerism, resulting in the splitting of proton signals at room temperature. The variable temperature nuclear magnetic resonance test results showed that as the temperature increased to 120 o C, the splitted signals gradually converged to a single signal (Fig. 2 ). The structure of A5 was further identified by X-ray diffraction (Fig. 3 ). Based on the above details, the target compounds were confirmed as pure substance. Antifungal activity The in vitro antifungal activities of target compound A1-A32 against six kinds of phytopathogenic fungi at a concentration of 50 mg/L were shown in Table 1 . As the data showed, all the target compounds showed varying degrees of inhibition against the tested fungi. For R. cerealis , compounds A30 , A31 , and A32 exceeded more than 70% antifungal activities, which superior to the positive control boscalid (6.23%). Compound A25 has an inhibitory rate of 67.25% against the P. piricola , it is comparable to the boscalid (66.56%), but lower than chlorothalonil (88.69%). In particular, compounds A5 , A9 , A13 , A21 , A25 , A28 , and A32 all have over 70% inhibitory rates against A. alternata. Among them, A13 (90.81%) and A25 (94.13%) were comparable to boscalid (92.13%), and better than chlorothalonil (37.79%). Furthermore, the EC 50 value of A13 (2.375 mg/L) and A25 (2.251 mg/L) against A. alternate was equivalent to the positive control boscalid (1.195 mg/L) (Table 2 ). In compare with boscalid, compounds A13 and A25 exhibited broader antifungal spectrum. Table 1 In vitro antifungual activity of target compounds A1-A32 (50 mg/L, Inhabition rate ± Standard deviation %) Compd R. cerealis P. piricola F. graminearum C. lagenarium B. Cinerea A. alternata A1 24.20 ± 0.5 26.10 ± 0.0 6.50 ± 1.0 13.50 ± 0.5 10.90 ± 0.6 17.80 ± 0.3 A2 16.40 ± 0.3 20.80 ± 0.5 5.30 ± 0.0 6.00 ± 0.8 17.60 ± 0.3 13.23 ± 0.9 A3 14.50 ± 0.3 22.20 ± 0.6 11.70 ± 0.0 1.20 ± 1.3 5.50 ± 0.5 16.28 ± 1.6 A4 20.00 ± 0.3 16.40 ± 0.0 9.60 ± 0.3 7.62 ± 0.6 13.60 ± 0.3 21.34 ± 1.4 A5 46.94 ± 1.0 32.12 ± 0.3 17.26 ± 0.3 20.68 ± 0.0 23.11 ± 0.3 74.55 ± 1.3 A6 48.19 ± 0.5 33.74 ± 0.3 19.15 ± 0.5 19.41 ± 0.3 21.21 ± 0.0 6.98 ± 0.8 A7 50.56 ± 0.6 37.37 ± 0.5 24.82 ± 0.0 21.10 ± 0.5 27.27 ± 0.3 12.08 ± 0.5 A8 56.32 ± 0.8 30.32 ± 1.6 16.35 ± 1.3 18.69 ± 0.3 19.32 ± 0.7 60.49 ± 1.1 A9 26.45 ± 0.0 33.98 ± 0.5 15.67 ± 0.3 20.00 ± 0.3 11.79 ± 1.1 84.36 ± 0.0 A10 18.49 ± 0.8 1.47 ± 0.7 12.99 ± 0.0 4.80 ± 0.3 3.40 ± 0.5 13.33 ± 0.3 A11 18.49 ± 0.4 12.79 ± 0.3 17.51 ± 0.3 12.31 ± 0.5 1.66 ± 1.1 28.89 ± 0.0 A12 30.36 ± 0.8 26.79 ± 0.6 20.72 ± 1.1 14.68 ± 0.5 6.32 ± 0.7 65.79 ± 1.3 A13 65.57 ± 0.5 39.88 ± 0.0 18.89 ± 0.5 17.91 ± 0.1 3.21 ± 0.2 90.81 ± 1.0 A14 5.60 ± 0.2 21.43 ± 0.7 6.11 ± 0.2 4.48 ± 0.0 13.46 ± 0.2 12.12 ± 0.2 A15 3.24 ± 1.1 24.40 ± 0.3 2.78 ± 0.2 1.99 ± 0.0 19.23 ± 0.2 23.23 ± 0.5 A16 47.49 ± 0.5 30.95 ± 1.1 16.67 ± 0.2 19.90 ± 0.0 24.36 ± 0.2 63.64 ± 0.5 A17 20.63 ± 0.0 3.54 ± 0.5 8.73 ± 0.9 12.95 ± 1.1 5.86 ± 0.3 51.53 ± 0.5 A18 13.75 ± 0.7 6.56 ± 0.0 18.8 ± 0.2 12.46 ± 0.5 19.24 ± 0.7 3.43 ± 1.0 A19 21.9 ± 0.3 20.9 ± 0.3 17.7 ± 0.0 13.7 ± 0.7 31.2 ± 0.2 39.37 ± 0.2 A20 28.6 ± 0.0 8.3 ± 1.1 18.3 ± 0.5 22.4 ± 0.5 34.3 ± 0.5 50.23 ± 0.2 A21 39.00 ± 0.6 37.00 ± 0.2 25.00 ± 0.5 48.00 ± 0.5 29.00 ± 0.0 76.05 ± 0.0 A22 1.47 ± 0.3 28.57 ± 0.0 0.56 ± 0.2 5.97 ± 0.2 0.64 ± 1.0 6.06 ± 0.5 A23 12.68 ± 1.1 1.19 ± 0.5 1.67 ± 0.5 1.00 ± 0.2 10.90 ± 0.3 8.08 ± 0.0 A24 26.34 ± 1.6 13.64 ± 0.3 16.79 ± 1.1 34.16 ± 1.6 26.34 ± 1.9 61.23 ± 0.8 A25 66.77 ± 0.0 67.25 ± 0.2 17.00 ± 0.50 59.82 ± 0.0 51.56 ± 0.2 94.13 ± 0.0 A26 58.68 ± 0.3 33.31 ± 0.5 28.12 ± 0.29 38.00 ± 0.2 42.87 ± 1.2 62.89 ± 0.2 A27 64.35 ± 1.3 39.46 ± 0.5 28.85 ± 0.0 38.93 ± 1.1 51.15 ± 0.5 59.29 ± 1.1 A28 47.49 ± 0.0 13.69 ± 0.3 20.56 ± 0.29 25.87 ± 0.5 37.18 ± 1.0 73.69 ± 0.5 A29 15.69 ± 0.6 10.27 ± 0.2 14.41 ± 0.2 7.81 ± 0.5 14.29 ± 0.5 56.11 ± 0.0 A30 77.78 ± 0.3 47.47 ± 0.3 26.71 ± 0.5 38.40 ± 0.5 48.11 ± 0.0 56.03 ± 0.2 A31 73.61 ± 0.0 41.41 ± 1.1 33.81 ± 0.5 35.02 ± 0.3 50.38 ± 0.5 65.22 ± 0.2 A32 77.22 ± 0.3 47.88 ± 0.7 30.02 ± 0.2 36.71 ± 1.0 40.35 ± 0.2 72.81 ± 0.5 Chlorot- halonil 95.56 ± 0.3 88.69 ± 0.6 82.51 ± 0.2 83.12 ± 0.0 75.2 ± 0.2 37.79 ± 0.2 Boscalid 6.23 ± 1.1 66.56 ± 0.6 13.59 ± 1.2 15.46 ± 0.3 40.49 ± 1.3 92.13 ± 1.6 Table 2 EC 50 of A13 , A25 against A. alternata Comp. 95% confidence EC 50 Toxic regression equation r A13 0.698–4.335 2.375 y = -0.65 + 1.65x 0.985 A25 0.731–3.966 2.251 y = -0.73 + 1.97x 0.989 Boscalid 0.124–2.932 1.195 y = -0.27 + 1.52x 0.949 According to the in vitro results, A13 was selected to evaluate in vivo against A. alternata on fragrant pears. As shown in Fig. 4 and Table 3 , A13 indicated effective protective activity at the concentration of 50 and 100 mg/L (51.613 and 70.968%), which was equal to boscalid (64.516 and 77.419%). Longitudinal section of the pear revealed that the decay caused by A. alternata not only expand on the surface of the pear but also spread into the interior of the pear. Table 3 In vivo antifungal activity of compound A13 against A. alternata Compd. Inhibition % 50 mg•L − 1 100 mg•L − 1 A13 51.613 ± 2.4 70.968 ± 1.9 Boscalid 64.516 ± 1.6 77.419 ± 2.1 Structure-activity relationship The bioassay results of in vitro and in vivo test indicated that the "common" scaffold of 1-aryl-tetrahydroisoquinoline served as a promising antifungal core. The C1 substituents and the heterocyclic acid fragments of the amide bridge were identified as significant factors on modulating antifungal activity. When the heterocyclic acid fragment remains consistent, compounds featuring aromatic ring at the C1 position demonstrated higher antifungal efficacy compared to others ( A1-A4 versus A5-A32 ). Notably, among the aryl-substituents, para-substituted phenyl exhibited higher antifungal inhibition than the meta- and ortho-substituted phenyl, mono-substituted compounds ( A5-A28 ) displayed greater antifungal efficacy than multi-substituted compounds ( A29-A32 ). Compare between A13 - A16 with A25 - A28 , revealed that when the aryl-substituents are identical, the antifungal potency followed as thiophenyl > thiazolyl > pyrazolyl. Compounds containing thiophene heterocyclic fragments displayed pronounced antifungal activities and broad-spectrum for various pathogenic fungi. Molecular properties and drug-likeness evaluation The fungicidal activity and the in silico interaction with the assumed target enzyme were greatly affected by the chemical structure. The physical and chemical properties of highly active compounds A13 and A25 were calculated. As shown in the Table 4 , the chemical structure of A13 and A25 meet the Lipinski rule and demonstrate good drug-likeness. Table 4 Lipinski properties of A13 and A25 Compound A13 A25 MW 454.52 470.89 LogP 3.34 3.83 nOHNH 1 1 nON 6 6 nRotb 6 6 DL 0.252 0.244 MW: molecular weight; LogP: octanol/water partition coefficient; nOHNH: number of hydrogen bond acceptors; nON: number of hydrogen bond donors; nRotb: number of rotatable bonds; DL: drug-likeness evaluation. SEM Analysis SEM analysis of A. alternata was conducted to investigate microstructural variations in the mycelia. The untreated mycelia exhibited a relatively uniform, robust, and smooth appearance (Fig. 5 A). In contrast, mycelia treated with compound A13 at concentrations of 50 mg/L and 100 mg/L significant coarsening were observed, with twisted and broken hyphae and a shriveled surface (Fig. 5 C, 5 D). These findings indicated that compound A13 induces substantial damage to the mycelia of A. alternata . Mechanism Molecular electrostatic potential was an important factor for activity and provide a meaningful reference for uncovering the interaction modes of the drug with the target. As shown in Fig. 6 , the positive region of compound A13 is relatively weak, and the negative region located around the oxygen atoms of the isoquinoline ring at C6, C7 methoxy, and the bridge carboxyl group. This distribution suggests the potential for the formation of hydrogen bonds with the target enyzem. Molecular docking simulations were performed to investigate the binding mechanism of compound A13 with succinate dehydrogenase (SDH, PDB: 2FBW). The CDOCKER Interaction Energy of A13 and boscalid were − 8.4 kcal/mol and − 8.3 kcal/mol, respectively. As illustrated in Fig. 7 (A, B), the isoquinoline ring of A13 engages in a Pi-sigma interaction with Leu A470, while the aromatic ring at the C1 position and the thiophenyl ring form Pi-cation interactions with the Arg A218. Additionally, the fluorine atom on the phenyl ring and the oxygen atom of the amide bond establish hydrogen bonds with the arginine residue (Arg B63). Notably, compared to boscalid, compound A13 exhibits a greater difference in binding sites and interaction modes with SDH. It provided a valuable reference for further modifcation of 1-arylisoquinoline derivatives. Conclusions In summary, a series of 32 novel 1-arylisoquinoline derivatives were designed, synthesized, and evaluated for their antifungal activities. The in vitro bioassay results showed that A13 and A25 exhibited effective antifungal activity against A. alternata as well as boscalid. The in vivo activities of A1 and A25 were investigated on pears and indicated that they can control A. alternate as well as boscalid at the dosage of 50 mg/L and 100 mg/L. The exploration of morphological observations indicated that compound A1 3 could strongly damage the mycelium morphology. Molecular electrostatic potential and molecular docking analysis revealed that A13 was covered by negative potential contour, and strongly interacts with the residues of SDH active pocket. This study showed a new way to optimize the tetrehydroisoquinoline alkaloids and further proved that 1-arylisoquinoline was a promising core for antifungal agents. Experimental Instruments and materials The melting points were determined by RY-1G melting point meter. 1 H NMR spectra and 13 C NMR spectra were recorded on Brucker Avance NEO 400 using CDCl 3 , DMSO- d 6 as solvent and tetramethylsilane as the internal standard, and chemical shift values ( δ ) were given in parts per million (ppm). High-resolution mass spectrometry (HRMS) data were obtained on Xevo G2-S Tof Mass Spectrometer (Waters). The crystal structure was recorded by a Rigaku XtaLAB P200 diffractometer. Column chromatography silica gel H type (Qingdao Ocean Chemical Plant, 200–300 mesh). Commercial reagents were analytically pure and used without further purification. All solvents were dried by standard methods in advance and distilled before use. General synthetic procedure for target compounds A1-32 The synthetic route of the target compound as shown in Scheme 1 . 2-(3′,4′-dimethoxypheny1)ethy1amine 1 reacts with appropriate aldehydes 2a-2h in anhydrous toluene to form the intermediate diazo compound 3a-3h . The intermediate 1-substituted-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline compound 4a-4h is obtained by intramolecular cyclization with trifluoroacetic acid [ 22 ]. Compound 4a-4h was condensed with Boc-glycine to obtain intermediate 5a-5h . Under acidic conditions, the Boc protective group was removed to obtain intermediate 6a-6h , and then condensed with heterocyclic acid 7a-7d amide to obtain target compounds A1-32 [ 23 ]. N-(2-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)thiophene-2-carboxamide (A1) white solid, yield 94%, mp 113–115 o C; 1 H NMR (400 MHz, CDCl 3 ) δ 7.55 (q, J = 2.2 Hz, 1H), 7.42 (d, J = 5.0 Hz, 1H), 7.34–7.30 (m, 1H), 7.02 (t, J = 4.1 Hz, 1H), 6.58 (d, J = 8.0 Hz, 2H), 4.64 (s, 1H), 4.49 (s, 1H), 4.26 (q, J = 3.0, 2.6 Hz, 2H), 3.82 (s, 1H), 3.81 (d, J = 2.7 Hz, 6H), 3.61 (td, J = 6.0, 2.0 Hz, 1H), 2.81 3(t, J = 5.9 Hz, 1H), 2.75 (t, J = 6.0 Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ 166.88, 161.77 (161.74), 148.15 (148.31), 148.05, 138.55, 130.08, 128.40,125.65 (126.52), 124.57 (123.41), 111.52 (111.80), 109.58 (109.21), 56.04, 56.03, 45.77, 44.21, 42.32, 41.93, 41.73, 40.29, 28.63, 27.79. HRMS (ESI) calcd for C 18 H 21 N 2 O 4 S [M + H] ་ 361.1222, found 361.1234. 3-(Difluoromethyl)-N-(2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-1-methyl-1H-pyrazole-4-carboxamide (A2) white solid, yield 96%, mp 78–80 o C; 1 H NMR (400 MHz, CDCl 3 ) δ 7.90 (s, 1H), 7.51 (d, J = 5.3 Hz, 1H), 7.00 (td, 1 J CF = 54.2, 3.9 Hz, 1H), 6.61 (s, 1H), 6.58 (d, J = 5.8 Hz, 1H), 4.64 (s, 1H), 4.50 (s, 1H), 4.25 (t, J = 3.8 Hz, 2H), 3.87 (s, 3H), 3.83 (d, J = 2.2 Hz, 3H), 3.82 (d, J = 1.6 Hz, 3H), 3.80 (s, 1H), 3.81–3.80 (m, 1H), 3.62 (t, J = 5.9 Hz, 1H), 2.82 (t, J = 5.9 Hz, 1H), 2.76 (t, J = 6.0 Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ 166.97, 161.34 (d, 4 J CF = 4.8 Hz), 148.13 (148.30), 148.05 (148.02),144.31 (t, 2 J CF = 26.4 Hz), 133.57 (d, 4 J CF = 10.4 Hz), 125.63 (126.56), 124.59 (123.38), 116.12, 111.79 (111.50), 110.62 (t, 1 J CF = 234.9 Hz), 109.57 (109.19), 56.02, 55.99, 45.77, 44.17, 42.33, 41.77, 41.53, 40.24, 39.40, 28.57, 27.75. HRMS (ESI) calcd for C 19 H 23 F 2 N 4 O 4 [M + H] ་ 408.1609, found 408.1624. N-(2-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide (A3) white solid, yield 95%, mp 90–92 o C; 1 H NMR (400 MHz, CDCl 3 ) δ 7.94 (s, 1H), 7.41 (d, J = 5.4 Hz, 1H), 6.60 (s, 1H), 6.58 (d, J = 6.9 Hz, 1H), 4.63 (s, 1H), 4.49 (s, 1H), 4.24 (t, J = 3.8 Hz, 2H), 3.89 (s, 3H), 3.81 (dd, J = 3.8, 1.7 Hz, 6H), 3.79 (s, 1H), 3.61 (t, J = 6.0 Hz, 1H), 2.82 (t, J = 6.0 Hz, 1H), 2.75 (t, J = 6.0 Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ 166.82, 160.37 (d, 4 J CF = 3.7 Hz), 148.13 (148.31), 148.06 (148.02), 139.21 (dd, 2 J CF = 37.6, 8.0 Hz), 134.58 (d, 4 J CF = 8.6 Hz), 125.61 (126.55), 124.53 (123.34), 120.82 (d, 1 J CF = 269.3 Hz), 116.57, 111.50 (111.79), 109.56 (109.19), 56.01, 55.97, 45.73, 44.16, 42.30, 41.90, 41.66, 40.26, 39.58, 28.54, 27.72. HRMS (ESI) calcd for C 18 H 21 N 2 O 4 S [M + H] ་ 427.1593, found 427.1606. N-(2-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-2-methyl-4-(trifluoromethyl)thiazole-5-carboxamide (A4) white solid, yield 92%, mp 96–98 o C; 1 H NMR (400 MHz, CDCl 3 ) δ 7.50 (d, J = 3.8 Hz, 1H), 6.58 (d, J = 2.4 Hz, 1H), 6.55 (d, J = 8.5 Hz, 1H), 4.60 (s, 1H), 4.46 (s, 1H), 4.24 (t, J = 3.5 Hz, 2H), 3.80 (s, 5H), 3.79 (d, J = 1.5 Hz, 4H), 3.77 (d, J = 6.1 Hz, 1H), 3.58 (t, J = 5.9 Hz, 1H), 2.80 (t, J = 6.0 Hz, 1H), 2.74 (t, J = 6.0 Hz, 1H), 2.66 (s, 3H). 13 C NMR (150 MHz, CDCl 3 ) δ 167.97 (168.01), 165.79 (d, 4 J CF = 6.5 Hz), 158.57 (d, 4 J CF = 7.3 Hz), 148.03 (148.21), 147.94 (147.90), 141.59–139.98 (m), 134.62–134.44 (m), 125.39 (126.41), 124.30 (123.02), 120.16 (q, 1 J CF = 272.0 Hz), 111.25 (111.59), 109.30 (108.89), 55.98, 55.96, 55.94 (55.92), 45.70, 44.16, 42.52, 42.32, 42.25, 40.28, 28.52, 27.69, 19.11. HRMS (ESI) calcd for C 19 H 21 F 3 N 3 O 4 S [M + H] ་ 444.1205, found 444.1230. N-(2-(1-(2-Fluorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)thiophene-2-carboxamide (A5) white solid, yield 89%, mp 126–128 o C; 1 H NMR (400 MHz, CDCl 3 ) δ 7.59 (dd, J = 3.7, 1.2 Hz, 1H), 7.48 (dd, J = 5.0, 1.3 Hz, 1H), 7.32 (t, J = 3.7 Hz, 1H), 7.29–7.23 (m, 1H), 7.15–7.09 (6.86–76.82) (m, 1H), 7.09–7.07 (m, 1H), 7.05 (dd, J = 6.1, 3.4 Hz, 2H), 6.93 (6.69) (s, 1H), 6.68 (6.18) (s, 1H), 6.52 (s, 1H), 4.72–4.19 (m, 3H), 3.90 (d, J = 3.4 Hz, 3H), 3.78 (s, 1H), 3.76 (3.81) (s, 3H), 2.92–2.69 (m, 1H), 3.66–3.07 (m, 1H), 3.01 (dt, J = 10.9, 5.3 Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ 166.53 (167.24), 161.79 (161.97), 160.73 (d, 1 J CF = 249.4 Hz), 148.50 (148.90), 148.10 (147.94), 138.53 (138.64), 130.77 (130.63), 130.06, 129.63 (129.54), 128.87 (128.73), 128.41, 127.58, 126.21 (126.00), 123.86 (124.05), 115.89 (d, 2 J CF = 22.1 Hz), 111.73 (111.39), 110.89 (110.66), 56.00, 55.95, 51.27 (53.26), 41.88, 39.32 (36.76), 28.41 (27.16). HRMS (ESI) calcd for C 24 H 24 FN 2 O 4 S [M + H] ་ 455.1441, found 455.1457. 3-(Difluoromethyl)-N-(2-(1-(2-fluorophenyl)-6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-1-methyl-1H-pyrazole-4-carboxamide (A6) white solid, yield 93%, mp 108–110 o C; 1 H NMR (400 MHz, CDCl 3 ) δ 7.88 (d, J = 5.1 Hz, 1H), 7.51 (d, J = 59.2 Hz, 1H), 7.32–7.21 (m, 1H), 7.18–7.06 (6.85–6.79) (m, 1H), 7.02 (d, J = 130.6 Hz, 1H), 7.02–6.96 (m, 2H), 6.91 (6.66) (d, J = 1.6 Hz, 1H), 6.65 (6.14) (d, J = 3.3 Hz, 1H), 6.48 (d, J = 2.3 Hz, 1H), 4.65–4.10 (m, 2H), 3.88 (s, 3H), 3.87 (3.91) (s, 3H), 3.76 (s, 1H), 3.75 (3.77) (d, J = 18.2 Hz, 3H), 3.61–3.05 (m, 1H), 3.00 (ddd, J = 16.7, 10.7, 5.7 Hz, 1H), 2.90–2.63 (m, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ 167.05 (167.36), 161.60 (162.01), 160.77 (d, 1 J CF = 249.3 Hz), 148.58 (148.94), 148.13 (147.97), 144.74 (d, 2 J CF = 30.0 Hz), 132.94 (133.59), 130.82 (130.65), 129.56 (129.64), 128.87 (128.73), 127.43 (125.05), 126.17 (126.09), 123.86 (124.11), 115.96, 115.74, 111.44 (111.76), 110.94 (110.67), 110.28 (t, 1 J CF = 235.4 Hz), 56.05, 56.00, 51.20 (53.28), 41.41, 39.45, 39.37 (37.76), 28.42 (27.18). HRMS (ESI) calcd for C 25 H 26 F 3 N 4 O 4 [M + H] ་ 503.1906, found 502.3.1921. N-(2-(1-(2-Fluorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide (A7) white solid, yield 91%, mp 124–126 o C; 1 H NMR (400 MHz, CDCl 3 ) δ 7.98 (s, 1H), 7.54 (dt, J = 116.5, 4.3 Hz, 1H), 7.35–7.20 (m, 1H), 7.14–7.04 (6.85–6.81) (m, 1H), 7.02–6.96 (m, 2H), 6.93 (6.68) (s, 1H), 6.68 (6.15) (s, 1H), 6.50 (d, J = 2.4 Hz, 1H), 4.64–4.16 (m, 2H), 3.89 (3.94) (s, 3H), 3.89 (s, 3H), 3.78–3.75 (m, 1H), 3.74 (3.79) (s, 3H), 3.64–3.09 (m, 1H), 3.01 (dq, J = 11.8, 6.1, 5.6 Hz, 1H), 2.80 (dddd, J = 55.5, 16.2, 4.4, 2.7 Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ 166.81 (167.10), 161.79 (161.67), 160.73 (d, 1 J CF = 248.9 Hz), 148.55 (148.91), 148.10 (147.94), 139.71 (d, 2 J CF = 37.4 Hz), 134.72, 134.11, 130.80 (130.61), 129.61 (129.53), 128.76 (128.62), 126.10 (126.02), 124.07, 123.81, 125.34–116.65 (m), 116.42 (116.80), 115.93 (115.71), 111.39 (111.73), 110.90 (110.62), 55.99, 55.94, 51.14 (53.24), 41.57, 39.57, 39.27 (36.70), 28.35 (27.11). HRMS (ESI) calcd for C 25 H 25 F 4 N 4 O 4 [M + H] ་ 521.1812, found 521.1825. N-(2-(1-(2-Fluorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-2-methyl-4-(trifluoromethyl)thiazole-5-carboxamide (A8) white solid, yield 93%, mp 119–121 o C; 1 H NMR (400 MHz, CDCl 3 ) δ 7.46 (d, J = 4.0 Hz, 1H), 7.24 (dddd, J = 13.7, 8.6, 5.7, 1.8 Hz, 1H), 7.08 (6.81–6.77) (dd, J = 10.2, 8.8 Hz, 1H), 7.05–6.93 (m, 2H), 6.86 (6.65) (s, 1H), 6.63 (6.09) (s, 1H), 6.47 (s, 1H), 4.26–4.25 (4.61–4.43) (m, 2H), 3.85 (d, J = 4.7 Hz, 3H), 3.70 (3.75) (s, 2H), 3.67 (dd, J = 5.8, 2.8 Hz, 1H), 3.54 (3.11–3.04) (ddd, J = 13.9, 11.2, 4.5 Hz, 1H), 2.97 (ddd, J = 16.9, 11.5, 5.7 Hz, 1H), 2.83 (2.72–2.71) (ddd, J = 15.8, 4.5, 2.8 Hz, 1H), 2.68 (d, J = 1.5 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 167.86, 166.11, 165.35, 160.67 (dd, 1 J CF = 248.4, 12.7 Hz), 158.57 (158.40), 148.45 (148.88), 148.02 (147.87), 140.95 (dd, 2 J CF = 36.5, 27.4 Hz), 134.32 (134.81), 130.86 (130.72), 130.18 (129.67), 128.38 (127.59), 127.28 (125.95), 125.78 (124.65), 124.11 (123.81), 120.16 (d, 1 J CF = 277.3 Hz), 116.02 (115.97), 115.80 (115.75), 111.21 (111.96), 110.69 (110.38), 55.94, 55.91, 53.17 (51.20), 42.44, 39.15 (36.61), 28.31, 27.09, 19.12. HRMS (ESI) calcd for C 25 H 24 F 4 N 3 O 4 S [M + H] ་ 538.5376, found 538.5394. N-(2-(1-(3-Fluorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)thiophene-2-carboxamide (A9) : white solid, yield 87%, mp 106–108 o C; 1 H NMR (600 MHz, CDCl 3 ) δ 7.58 (dt, J = 4.9, 2.5 Hz, 1H), 7.44 (dd, J = 5.0, 1.2 Hz, 1H), 7.36 (q, J = 4.0 Hz, 1H), 7.22 (td, J = 8.0, 5.9 Hz, 1H), 7.04 (dd, J = 5.0, 3.7 Hz, 1H), 7.01 (d, J = 7.7 Hz, 1H), 6.97–6.92 (m, 1H), 6.91 (dt, J = 9.8, 2.1 Hz, 1H), 6.76 (6.62) (s, 1H), 6.66 (s, 1H), 6.50 (5.88) (s, 1H), 4.33–4.23 (4.52–4.42) (m, 2H), 3.87 (s, 3H), 3.75 (3.82) (s, 3H), 3.70 (ddd, J = 13.8, 6.0, 3.0 Hz, 1H), 3.41 (ddd, J = 13.7, 11.3, 4.4 Hz, 1H), 3.00–2.86 (m, 1H), 2.77 (dt, J = 16.2, 3.9 Hz, 1H). 13 C NMR (150 MHz, CDCl 3 ) δ 166.75, 162.82 (d, 1 J CF = 246.6 Hz), 161.82, 148.54 (148.88), 147.94 (147.75), 144.34 (144.29), 138.44 (138.36), 130.27, 129.95 (130.01), 128.50, 127.72, 126.13, 125.67, 124.29 (124.27), 115.74 (115.59), 114.83 (114.69), 111.20 (111.64), 111.04 (110.79), 56.04, 55.97, 55.13, 41.85, 38.81, 28.25. HRMS (ESI) calcd for C 24 H 24 FN 2 O 4 S [M + H] ་ 455.1441, found 455.1453. HRMS (ESI) calcd for C 17 H 20 NO 2 S ([M + H] + ): 302.1215, Found: 302.1222. 3-(Difluoromethyl)-N-(2-(1-(3-fluorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-1-methyl-1H-pyrazole-4-carboxamide (A10) white solid, yield 93%, mp 110–112 o C; 1 H NMR (600 MHz, CDCl 3 ) δ 7.93 (d, J = 4.1 Hz, 1H), 7.54 (s, 1H), 7.07 (d, J = 47.8 Hz, 1H), 7.02 (s, 1H), 7.00–6.88 (m, 2H), 6.80 (6.62) (s, 1H), 6.69 (s, 1H), 6.52 (5.87) (s, 1H), 4.29 (4.52–4.43) (d, J = 4.2 Hz, 2H), 3.93 (s, 2H), 3.90 (d, J = 1.6 Hz, 2H), 3.78 (3.85) (s, 3H), 3.70 (ddd, J = 13.8, 5.9, 2.9 Hz, 1H), 3.43 (ddd, J = 13.8, 11.2, 4.4 Hz, 1H), 2.98 (ddt, J = 19.5, 13.9, 6.9 Hz, 1H), 2.80 (dt, J = 16.3, 3.7 Hz, 1H). 13 C NMR (150 MHz, CDCl 3 ) δ 166.67, 162.80 (d, 1 J CF = 246.6 Hz), 161.25, 148.54, 147.93, 144.29 (144.25), 133.80 (133.76), 129.94, 129.88, 126.06, 125.70, 124.26, 116.17, 115.65 (d, 2 J CF = 22.1 Hz), 114.71 (d, 2 J CF = 21.2 Hz), 112.50–110.69 (m), 111.18, 111.04, 56.02, 55.95, 55.02, 41.72, 39.54, 38.76, 28.18. HRMS (ESI) calcd for C 25 H 26 F 3 N 4 O 4 [M + H] ་ 503.5022, found 503.5046. N-(2-(1-(3-Fluorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide (A11) white solid, yield 88%, mp 122–124 o C; 1 H NMR (400 MHz, CDCl 3 ) δ 7.94 (d, J = 1.4 Hz, 1H), 7.35 (s, 1H), 7.31–7.20 (m, 1H), 7.02 (d, J = 7.7 Hz, 1H), 6.97 (dd, J = 8.4, 2.5 Hz, 1H), 6.94–6.88 (m, 1H), 6.79 (6.60) (s, 1H), 6.67 (s, 1H), 6.50 (5.84) (s, 1H), 4.27 (4.48–4.44) (d, J = 3.9 Hz, 2H), 3.95 (s, 2H), 3.89 (s, 3H), 3.77 (3.84) (s, 3H), 3.68 (ddd, J = 13.6, 6.1, 2.9 Hz, 1H), 3.41 (ddd, J = 13.7, 11.3, 4.5 Hz, 1H), 2.97 (ddt, J = 17.2, 11.9, 6.0 Hz, 1H), 2.84–2.73 (m, 1H). 13 C NMR (150 MHz, CDCl 3 ) δ 166.62, 162.90 (d, 1 J CF = 246.7 Hz), 160.43, 148.64 (148.98), 148.04 (147.82), 144.33 (144.28), 139.26 (d, 2 J CF = 37.6 Hz), 134.86, 130.03 (130.52), 126.11, 125.74, 124.38 (123.21), 120.91 (q, 1 J CF = 269.5 Hz), 116.74, 115.83 (115.68), 114.91 (114.77), 111.26 (111.74), 111.11 (110.79), 56.11, 56.05, 55.13, 41.95, 39.86, 38.82, 28.26. HRMS (ESI) calcd for C 25 H 25 F 4 N 4 O 4 [M + H] ་ 521.1812, found 521.1836. N-(2-(1-(3-Fluorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-2-methyl-4-(trifluoromethyl)thiazole-5-carboxamide (A12) white solid, yield 92%, mp 116–118 o C; 1 H NMR (600 MHz, CDCl 3 ) δ 7.50 (s, 1H), 7.29–7.23 (m, 1H), 7.05–6.98 (m, 1H), 6.97 (dq, J = 8.3, 4.9, 3.8 Hz, 1H), 6.91 (dq, J = 10.0, 2.3 Hz, 1H), 6.78 (6.62) (d, J = 3.7 Hz, 1H), 6.69 (d, J = 2.1 Hz, 1H), 6.51 (5.82) (d, J = 1.6 Hz, 1H), 4.29 (4.53–4.42) (dd, J = 4.0, 2.0 Hz, 2H), 3.90 (d, J = 3.1 Hz, 3H), 3.78 (3.85) (d, J = 2.6 Hz, 3H), 3.74–3.63 (m, 1H), 3.43 (dddd, J = 13.7, 11.4, 4.5, 2.1 Hz, 1H), 3.04–2.93 (m, 1H), 2.89–2.77 (m, 1H). 13 C NMR (150 MHz, CDCl 3 ) δ 168.17, 165.71, 162.86 (d, 1 J CF = 246.8 Hz), 158.64, 148.64 (149), 148.04 (147.83), 144.17 (144.13), 141.19 (140.05), 134.59, 130.07 (130.02), 125.96, 125.59, 124.37, 123.04–117.21 (m), 115.80 (115.65), 114.94 (114.80), 111.22 (111.71), 110.06 (110.75), 56.07, 56.01, 55.17, 42.47, 38.79, 28.22, 19.28. HRMS (ESI) calcd for C 25 H24F 4 N3O 4 S [M + H] ་ 538.1424, found 538.1426. N-(2-(1-(4-Fluorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)thiophene-2-carboxamide (A13) white solid, yield 91%, mp 144–146 o C; 1 H NMR (400 MHz, CDCl 3 ) δ 7.61 (td, J = 4.0, 2.1 Hz, 1H), 7.50 (dd, J = 5.0, 1.1 Hz, 1H), 7.33–7.28 (m, 2H), 7.27–7.21 (m, 1H), 7.10 (dd, J = 5.0, 3.7 Hz, 1H), 7.07–7.03 (m, 1H), 6.99 (ddd, J = 8.3, 3.5, 1.5 Hz, 2H), 6.97–6.92 (m, 1H), 6.80 (5.90) (s, 1H), 6.69 (d, J = 2.8 Hz, 1H), 6.52 (d, J = 12.1 Hz, 1H), 4.32–4.30 (m, 2H), 3.91 (d, J = 1.4 Hz, 3H), 3.78 (d, J = 6.0 Hz, 3H), 3.75 (t, J = 3.1 Hz, 1H), 3.51–3.36 (m, 1H), 2.98 (dtd, J = 17.4, 11.4, 4.6 Hz, 1H), 2.86–2.77 (m, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ 166.63 (166.46), 162.82 (d, 1 J CF = 246.8 Hz), 161.79, 148.55 (148.45), 147.95, 144.30 (144.23), 138.38, 130.45 (130.37), 130.24, 130.01 (129.93), 128.48, 127.69, 126.06, 125.64 (125.99), 124.28 (128.25), 115.77 (115.56), 115.42 (115.20), 114.87 (114.66), 111.19, 111.04, 56.03, 55.96, 55.12, 41.85, 38.76, 28.28. HRMS (ESI) calcd for C 25 H 24 F 4 N 3 O 4 S [M + H] ་ 4545.1441, found 455.1456. 3-(Difluoromethyl)-N-(2-(1-(4-fluorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-1-methyl-1H-pyrazole-4-carboxamide (A14) white solid, yield 94%, mp 165–166 o C; 1 H NMR (600 MHz, CDCl 3 ) δ 7.93 (d, J = 2.6 Hz, 1H), 7.55 (d, J = 16.4 Hz, 1H), 7.28–7.13 (m, 1H), 7.02 (dd, J = 6.7, 3.1 Hz, 1H), 6.97 (dd, J = 8.6, 2.4 Hz, 1H), 6.93 (ddd, J = 9.8, 4.5, 2.5 Hz, 1H), 6.80 (5.87) (s, 1H), 6.68 (d, J = 4.8 Hz, 1H), 6.50 (6.62–6.57) (d, J = 18.9 Hz, 1H), 4.39–4.23 (m, 2H), 3.93 (d, J = 2.9 Hz, 3H), 3.90 (d, J = 2.0 Hz, 3H), 3.77 (3.84) (d, J = 9.3 Hz, 3H), 3.70 (ddd, J = 13.9, 6.0, 2.9 Hz, 1H), 3.42 (dddd, J = 20.6, 16.2, 11.6, 4.4 Hz, 1H), 3.03–2.90 (m, 1H), 2.80 (dt, J = 16.4, 3.6 Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ 166.84 (166.62), 162.81 (d, 1 J CF = 246.6 Hz), 161.30, 148.68, 148.06, 144.35 (144.29), 133.62, 130.38 (130.30), 129.82 (129.91), 126.15, 125.84, 124.18, 116.19, 115.67 (115.46), 115.30 (115.09),114.73 (114.52), 111.41, 111.30, 109.55 (d, 1 J CF = 234.9 Hz), 56.05, 55.97, 55.09, 41.65, 39.44, 38.85, 28.16, 26.89. HRMS (ESI) calcd for C 25 H 26 F 3 N 4 O 4 [M + H] ་ 503.1906, found 5003.1933. N-(2-(1-(4-Fluorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide (A15) white solid, yield 93%, mp 135–137 o C; 1 H NMR (400 MHz, CDCl 3 ) δ 7.99–7.96 (m, 1H), 7.37 (d, J = 5.3 Hz, 1H), 7.36–7.12 (m, 2H), 7.07–7.02 (m, 1H), 7.02–6.97 (m, 1H), 6.97–6.91 (m, 1H), 6.82 (5.85) (s, 1H), 6.69 (d, J = 2.9 Hz, 1H), 6.51 (6.59) (d, J = 12.5 Hz, 1H), 4.28 (4.48) (dd, J = 5.5, 3.9 Hz, 2H), 3.98 (s, 3H), 3.91 (d, J = 1.6 Hz, 3H), 3.78 (3.85) (d, J = 6.2 Hz, 3H), 3.70 (ddd, J = 13.9, 5.9, 3.2 Hz, 1H), 3.49–3.35 (m, 1H), 2.99 (ddt, J = 17.0, 11.6, 5.8 Hz, 1H), 2.81 (ddd, J = 16.2, 4.4, 2.8 Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ 166.42, 162.79 (d, 1 J CF = 240.38 Hz), 160.32, 148.56, 147.95, 144.24 (144.17), 134.81, 130.40, 129.98 (129.90), 126.00, 125.65, 124.30, 116.71, 115.78 (115.56), 115.38 (115.17), 114.85 (114.64), 111.18, 111.04, 56.02, 55.96, 55.03, 41.91, 39.78, 38.71, 28.17. HRMS (ESI) calcd for C 25 H 25 F 4 N 4 O 4 [M + H] ་ 521.1812, found 521.1826. N-(2-(1-(4-Fluorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-2-methyl-4-(trifluoromethyl)thiazole-5-carboxamide (A16) white solid, yield 88%, mp 144–146 o C; 1 H NMR (400 MHz, CDCl 3 ) δ 7.49 (q, J = 6.7, 4.2 Hz, 1H), 7.36–7.11 (m, 1H), 7.06–7.01 (m, 1H), 7.01–6.94 (m, 1H), 6.92 (dt, J = 9.9, 2.1 Hz, 1H), 6.79 (5.82) (s, 1H), 6.69 (d, J = 2.8 Hz, 1H), 6.50 (d, J = 12.7 Hz, 1H), 4.53–4.25 (m, 2H), 3.90 (d, J = 1.5 Hz, 3H), 3.77 (d, J = 6.3 Hz, 2H), 3.72–3.62 (m, 1H), 3.43 (dddd, J = 14.1, 11.2, 9.5, 4.5 Hz, 1H), 2.97 (tdd, J = 16.8, 10.2, 5.8 Hz, 1H), 2.86–2.77 (m, 1H), 2.77 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 168.11, 165.63, 162.81 (d, 1 J CF = 246.9 Hz), 158.57, 148.59, 147.99, 144.12 (144.05), 141.02 (d, 2 J CF = 36.8 Hz), 130.49 (130.41), 130.02 (129.94), 138.17–117.92 (m), 125.88, 125.53, 124.31 (124.28), 115.78 (115.56), 115.42 (115.21), 114.92(114.71), 111.16, 111.00, 56.01, 55.95, 55.11, 42.41, 38.72, 28.16, 19.22. HRMS (ESI) calcd for C 25 H 24 F 4 N 3 O 4 S [M + H] ་ 538.1424, found 538.1443. N-(2-(1-(2-Chlorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)thiophene-2-carboxamide (A17) white solid, yield 91%, mp 112–114 o C; 1 H NMR (400 MHz, CDCl 3 ) δ 7.55 (d, J = 3.7 Hz, 1H), 7.43 (d, J = 5.5 Hz, 1H), 7.40 (s, 1H), 7.35–7.30 (m, 1H), 7.21 (q, J = 7.4 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 7.05–7.00 (m, 1H), 6.94 (d, J = 1.8 Hz, 1H), 6.92 (6.18) (d, J = 1.7 Hz, 1H), 6.66 (s, 1H), 6.54 (s, 1H), 4.62–4.18 (m, 2H), 3.86 (s, 3H), 3.73 (3.75) (s, 3H), 3.80–3.64 (m, 1H), 3.54 (dt, J = 14.0, 7.0 Hz, 1H), 3.03 (ddd, J = 17.1, 11.4, 5.8 Hz, 1H), 2.90–2.83 (m, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ 166.93, 161.78, 148.56, 148.14, 139.53, 138.54, 134.13, 130.80, 130.06, 128.97, 128.39, 127.57, 127.06, 126.66, 125.91, 111.83 (111.53), 110.89 (111.53), 55.95, 54.00, 41.90, 39.42, 28.45. HRMS (ESI) calcd for C 24 H 24 ClN 2 O 4 S [M + H] ་ 471.1145, found 471.1156. N-(2-(1-(2-Chlorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide (A18) white solid, yield 92%, mp 116–118 o C; 1 H NMR (600 MHz, CDCl 3 ) δ 7.87 (s, 1H), 7.61–7.58 (7.45) (m, 1H), 7.39 (7.44) (dd, J = 7.9, 1.4 Hz, 1H), 7.27–7.18 (m, 1H), 7.18–7.08 (m, 1H), 7.09–6.97 (m, 1H), 6.92 (6.53) (s, 1H), 6.90 (dd, J = 7.9, 1.6 Hz, 1H), 6.67 (d, J = 3.7 Hz, 1H), 6.50 (6.16) (s, 1H), 4.25 (ddd, J = 99.6, 17.3, 4.4 Hz, 1H), 3.88 (d, J = 8.4 Hz, 3H), 3.85 (s, 2H), 3.74 (s, 1H), 3.73 (3.77) (s, 3H), 3.51 (3.19–3.14) (ddd, J = 14.0, 11.5, 4.4 Hz, 1H), 3.04 (ddd, J = 17.0, 11.4, 5.8 Hz, 1H), 2.93–2.65 (m, 1H). 13 C NMR (150 MHz, CDCl 3 ) δ 167.19 (168.39), 161.49 (161.09), 148.45 (148.72), 148.01 (147.84), 144.86 (t, 2 J CF = 25.6 Hz), 139.38 (138.56), 134.14 (133.61), 132.82, 130.97, 130.04 (130.26), 129.01 (129.56), 126.63, 126.49 (127.09), 125.83 (125.70), 115.99, 111.29, 111.95–108.44 (m), 110.65, 55.92 (56.28), 53.88, 41.45 (42.03), 39.50, 39.30 (37.48), 28.41, 26.90 (27.15). HRMS (ESI) calcd for C 25 H 26 ClF 2 N 4 O 4 [M + H] ་ 519.1611, found 519.1642. N-(2-(1-(2-Chlorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide (A19) white solid, yield 91%, mp 118–120 o C; 1 H NMR (400 MHz, CDCl 3 ) δ 7.92 (s, 1H), 7.49–7.38 (m, 2H), 7.22 (td, J = 7.9, 1.9 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 6.94 (6.53) (s, 1H), 6.90 (dd, J = 7.8, 1.7 Hz, 1H), 6.68 (d, J = 3.5 Hz, 1H), 6.52 (6.15) (s, 1H), 4.38–4.16 (4.59–4.40) (m, 2H), 3.96–3.89 (m, 3H), 3.88 (s, 3H), 3.74 (3.78) (s, 3H), 3.73–3.70 (m, 1H), 3.51 (3.20–3.15) (ddd, J = 14.1, 11.6, 4.5 Hz, 1H), 3.05 (ddd, J = 17.2, 11.6, 5.8 Hz, 1H), 2.93–2.66 (m, 1H). 13 C NMR (150 MHz, Chloroform- d ) δ 166.84 (168.16), 160.40 (160.08), 148.51 (148.78), 148.05 (147.88), 139.26, 140.09–138.31 (m), 134.21 (134.84), 134.10 (133.62), 131.04, 130.08 (130.28), 129.04 (129.58), 126.59 (127.07), 125.81 (126.49), 123.89–117.55 (m), 116.54, 111.32 (111.67), 110.73 (110.27), 55.93, 53.87, 41.73 (42.23), 39.68, 39.19 (37.44), 28.38, 27.12. HRMS (ESI) calcd for C 25 H 25 ClF 3 N 4 O 4 [M + H] ་ 537.9442, found 537.9453. N-(2-(1-(2-Chlorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-2-methyl-4-(trifluoromethyl)thiazole-5-carboxamide (A20) white solid, yield 93%, mp 108–120 o C; 1 H NMR (400 MHz, CDCl 3 ) δ 7.40 (t, J = 4.3 Hz, 1H), 7.36 (d, J = 7.9 Hz, 0H), 7.24–7.12 (m, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.88 (6.50) (s, 1H), 6.85 (s, 1H), 6.63 (d, J = 4.4 Hz, 1H), 6.48 (6.09) (s, 1H), 4.25 (4.60–4.30) (t, J = 4.6 Hz, 2H), 3.82 (s, 3H), 3.70 (d, J = 11.2 Hz, 3H), 3.67 (s, 1H), 3.53–3.41 (m, 1H), 2.98 (ddd, J = 17.3, 11.5, 6.1 Hz, 1H), 2.87–2.78 (m, 1H), 2.65 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 167.74, 167.37, 165.79, 158.56, 148.61, 148.14, 141.10 (d, 2 J CF = 35.9 Hz), 139.15, 134.16 (134.25, 130.94, 130.09, 129.60, 129.05, 127.11, 126.58 (126.49), 125.78 (125.61), 120.15 (d, 1 J CF = 272.4 Hz), 111.50 (111.82), 110.89 (110.43), 55.92, 53.95, 42.54 (42.69), 39.20 (37.11), 28.35 (27.11), 19.03. HRMS (ESI) calcd for C 25 H 24 ClF 3 N 3 O 4 S [M + H] ་ 554.1128, found 554.1141. N-(2-(1-(3-Chlorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)thiophene-2-carboxamide (A21) white solid, yield 90%, mp 128–130 o C; 1 H NMR (400 MHz, CDCl 3 ) δ 7.61 (dd, J = 3.8, 1.3 Hz, 1H), 7.48 (tt, J = 3.3, 1.3 Hz, 1H), 7.34 (p, J = 3.9 Hz, 1H), 7.29–7.19 (m, 3H), 7.17–7.10 (m, 1H), 7.07 (dt, J = 4.7, 3.6 Hz, 1H), 6.78 (s, 1H), 6.69 (6.63) (s, 1H), 6.51 (5.89) (s, 1H), 4.31 (4.52–4.48) (t, J = 4.0 Hz, 2H), 3.90 (d, J = 2.1 Hz, 3H), 3.78 (3.85) (d, J = 1.9 Hz, 3H), 3.73 (ddd, J = 14.2, 5.9, 2.9 Hz, 1H), 3.49–3.37 (m, 1H), 2.99 (ddd, J = 16.9, 11.4, 5.8 Hz, 1H), 2.81 (ddd, J = 16.3, 4.5, 2.6 Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ 166.77, 161.84, 148.63, 148.05, 143.86, 138.47, 134.53, 130.27, 129.79, 128.77, 128.53, 128.08, 127.74, 126.91, 126.17, 125.58, 111.30, 111.09, 56.10, 56.01, 55.18, 38.80, 28.30. HRMS (ESI) calcd for C 24 H 24 ClN 2 O 4 S [M + H] ་ 471.1145, found 471.1164. N-(2-(1-(3-Chlorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide (A22) white solid, yield 92%, mp 136–138 o C; 1 H NMR (400 MHz, CDCl 3 ) δ 7.90 (s, 1H), 7.55 (dt, J = 4.8, 2.3 Hz, 1H), 7.25–7.22 (m, 1H), 7.20 (d, J = 2.1 Hz, 1H), 7.19 (d, J = 2.1 Hz, 1H), 7.09 (dq, J = 7.1, 2.1 Hz, 1H), 7.00 (t, J = 54.2 Hz, 1H), 6.75 (6.58) (s, 1H), 6.66 (s, 1H), 6.47 (5.84) (s, 1H), 4.33–4.23 (4.46–4.42) (m, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 3.74 (3.82) (s, 3H), 3.68 (ddd, J = 13.9, 6.0, 2.8 Hz, 1H), 3.40 (ddd, J = 13.8, 11.3, 4.4 Hz, 1H), 2.95 (ddt, J = 16.5, 11.0, 5.5 Hz, 1H), 2.77 (ddd, J = 16.1, 4.3, 2.8 Hz, 1H). 13 C NMR (150 MHz, CDCl 3 ) δ 166.88, 161.33, 148.57, 147.97, 144.53–144.00 (m), 143.79, 134.41, 133.62, 129.70, 128.69, 127.97, 126.84, 126.10, 125.56, 116.09, 111.24, 111.03, 110.68 (t, 1 J CF = 234.7 Hz), 56.03, 55.95, 55.05, 41.62, 39.51, 38.77, 28.17, 26.90. HRMS (ESI) calcd for C 25 H 26 ClF 2 N 2 O 4 [M + H] ་ 519.9358, found 519.9367. N-(2-(1-(3-Chlorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide (A23) white solid, yield 91%, mp 110–112 o C; 1 H NMR (400 MHz, CDCl 3 ) δ 7.94 (s, 1H), 7.35 (s, 1H), 7.25–7.21 (m, 2H), 7.19 (d, J = 2.1 Hz, 1H), 6.78 (6.58) (s, 1H), 6.67 (s, 1H), 6.48 (5.81) (s, 1H), 4.27 (4.48–4.44) (d, J = 3.9 Hz, 2H), 3.89 (s, 3H), 3.76 (3.84) (s, 3H), 3.67 (ddd, J = 13.9, 6.0, 2.8 Hz, 1H), 3.40 (ddd, J = 13.9, 11.4, 4.4 Hz, 1H), 2.97 (d, J = 5.5 Hz, 1H), 2.79 (ddd, J = 16.2, 4.5, 2.7 Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ 166.54, 160.44, 148.69, 148.10, 143.84, 139.43, 134.94, 134.59, 129.86, 128.87, 128.17, 127.03, 126.13, 125.61, 122.28, 116.83, 111.31, 111.10, 56.16, 56.08, 55.14, 42.03, 39.91, 38.77, 28.30. HRMS (ESI) calcd for C 25 H 25 ClF 3 N 4 O 4 [M + H] ་ 537.1516, found 537.1542. N-(2-(1-(3-Chlorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-2-methyl-4-(trifluoromethyl)thiazole-5-carboxamide (A24) white solid, yield 86%, mp 125–127 o C; 1 H NMR (600 MHz, CDCl 3 ) δ 7.48 (s, 1H), 7.27 (7.31–7.30) (d, J = 1.8 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 1.8 Hz, 1H), 7.14 (dt, J = 7.3, 1.7 Hz, 1H), 6.79 (6.60) (s, 1H), 6.70 (s, 1H), 6.50 (5.80) (s, 1H), 4.30 (4.51–1.47) (d, J = 3.8 Hz, 2H), 3.92 (s, 3H), 3.79 (3.87) (s, 3H), 3.67 (ddd, J = 13.9, 6.1, 2.8 Hz, 1H), 3.44 (ddd, J = 13.8, 11.5, 4.4 Hz, 1H), 3.05–2.99 (m, 1H), 2.83 (ddd, J = 16.3, 4.4, 2.7 Hz, 1H), 2.76 (s, 3H). 13 C NMR (150 MHz, CDCl 3 ) δ 168.12, 165.62, 158.57, 148.61, 148.03, 143.59, 141.05 (d, 2 J CF = 36.8 Hz), 134.51, 129.77, 128.75, 128.12, 126.92, 125.87, 125.37, 120.17 (d, 1 J CF = 272.0 Hz), 111.17, 110.95, 56.03, 55.96, 55.11, 42.43, 38.66, 28.18 (26.92), 19.24. HRMS (ESI) calcd for C 25 H 24 ClF 3 N 3 O 4 S [M + H] ་ 554.1128, found 554.1139. N-(2-(1-(4-Chlorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)thiophene-2-carboxamide (A25) white solid, yield 87%, mp 123–125 o C; 1 H NMR (600 MHz, CDCl 3 ) δ 7.61 (dd, J = 3.8, 1.2 Hz, 1H), 7.49 (dd, J = 5.0, 1.2 Hz, 1H), 7.32–7.30 (m, 1H), 7.27–7.25 (m, 2H), 7.21–7.16 (7.13–7.12) (m, 2H), 7.08 (dd, J = 5.0, 3.7 Hz, 1H), 6.78 (6.60) (s, 1H), 6.69 (d, J = 2.8 Hz, 1H), 6.49 (5.89) (s, 1H), 4.34–4.25 (4.51–4.50) (m, 2H), 3.90 (s, 3H), 3.77 (3.84) (s, 3H), 3.72 (ddd, J = 13.9, 5.8, 2.6 Hz, 1H), 3.41 (ddd, J = 13.8, 11.5, 4.4 Hz, 1H), 3.02–2.96 (m, 1H), 2.80 (ddd, J = 16.2, 4.2, 2.6 Hz, 1H). 13 C NMR (150 MHz, CDCl 3 ) δ 166.66, 161.82, 148.52, 147.99, 140.35, 138.44, 133.75, 130.30, 130.12, 129.03 (128.89), 128.67, 128.52, 127.75, 126.11, 125.80, 111.20, 110.99, 56.05, 56.00, 55.00, 41.90 (42.15), 38.67 (37.64), 28.34 (27.12). HRMS (ESI) calcd for C 24 H 24 ClN 2 O 4 S [M + H] ་ 471.1145, found 471.1167. N-(2-(1-(4-Chlorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide (A26) white solid, yield 88%, mp 117–119 o C; 1 H NMR (400 MHz, CDCl 3 ) δ 7.90 (s, 1H), 7.50 (tt, J = 4.2, 2.1 Hz, 1H), 7.28–7.22 (m, 1H), 7.21 (d, J = 2.1 Hz, 1H), 7.12 (d, J = 4.9 Hz, 1H), 7.11–6.81 (m, 1H), 6.75 (s, 1H), 6.65 (s, 1H), 6.45 (s, 1H), 4.39–4.16 (m, 2H), 3.89 (s, 3H), 3.86 (s, 3H), 3.73 (s, 3H), 3.71–3.62 (m, 1H), 3.37 (ddd, J = 13.8, 11.4, 4.4 Hz, 1H), 3.06–2.86 (m, 1H), 2.76 (ddd, J = 16.2, 4.3, 2.6 Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ 166.66, 161.26, 148.48, 147.94, 144.13 (t, 2 J CF = 27.1 Hz), 140.30, 133.78, 133.64, 130.05, 128.97 (128.91), 128.56, 126.04, 125.81, 116.12, 111.17, 110.87 (110.68), 113.56–108.20 (m), 110.68, 55.99, 55.94, 54.86, 41.70 (42.03), 39.52, 38.63 (37.52), 28.22 (27.05). HRMS (ESI) calcd for C 25 H 26 ClF 2 N 4 O 4 [M + H] ་ 519.1611, found 519.1633. N-(2-(1-(4-Chlorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide (A27) white solid, yield 93%, mp 114–116 o C; 1 H NMR (600 MHz, CDCl 3 ) δ 7.96 (7.53) (s, 1H), 7.37 (s, 1H), 7.32–7.24 (m, 2H), 7.21–7.05 (m, 2H), 6.79 (6.57) (s, 1H), 6.69 (d, J = 3.9 Hz, 1H), 6.48 (5.84) (s, 1H), 4.27 (4.53–4.42) (dd, J = 4.0, 2.2 Hz, 2H), 3.97 (d, J = 3.4 Hz, 4H), 3.90 (s, 3H), 3.77 (s, 3H), 3.68 (ddd, J = 13.8, 6.0, 2.7 Hz, 1H), 3.40 (ddd, J = 13.8, 11.5, 4.4 Hz, 1H), 2.99 (ddt, J = 19.1, 13.1, 7.0 Hz, 1H), 2.80 (ddd, J = 16.2, 4.3, 2.6 Hz, 1H). 13 C NMR (150 MHz, CDCl 3 ) δ 166.42, 160.31, 148.49, 147.95, 140.23,139.10 (q, 2 J CF = 37.7 Hz), 134.79, 133.69, 130.71, 130.07, 128.97 (128.95), 128.59, 125.99, 125.75, 120.82 (d, 1 J CF = 269.3 Hz), 116.64, 111.14, 110.92, 55.99, 55.94, 54.86, 41.87, 39.76, 38.57, 28.22. HRMS (ESI) calcd for C 25 H 25 ClF 3 N 4 O 4 [M + H] ་ 537.1516, found 537.1528. N-(2-(1-(4-Chlorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-2-methyl-4-(trifluoromethyl)thiazole-5-carboxamide (A28) white solid, yield 85%, mp 129–131 o C; 1 H NMR (400 MHz, CDCl 3 ) δ 7.47–7.43 (m, 1H), 7.33–7.22 (m, 2H), 7.17 (s, 1H), 7.16–7.06 (m, 1H), 6.76 (6.55) (s, 1H), 6.67 (s, 1H), 6.46 (5.78) (s, 1H), 4.26 (4.50–4.43) (d, J = 3.9 Hz, 2H), 3.88 (s, 3H), 3.75 (3.82) (s, 3H), 3.72–3.60 (m, 1H), 3.39 (ddd, J = 13.8, 11.6, 4.4 Hz, 1H), 2.98 (ddd, J = 16.8, 11.4, 5.7 Hz, 1H), 2.79 (ddd, J = 16.2, 4.4, 2.6 Hz, 1H), 2.74 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 168.25, 165.66, 158.67, 148.66, 148.14, 141.12 (d, 2 J CF = 36.9 Hz), 140.21, 134.69, 133.92, 130.21, 129.14, 129.03, 128.76, 125.95, 125.75, 120.28 (d, 1 J CF = 272.1 Hz), 111.25, 111.04, 56.11, 56.06, 55.06, 42.54, 38.66, 28.34, 19.34. HRMS (ESI) calcd for C 25 H 24 ClF 3 N 3 O 4 S [M + H] ་ 554.1128 found 554.1154. N-(2-(1-(2,4-Dichlorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)thiophene-2-carboxamide (A29) white solid, yield 92%, mp 111–113 o C; 1 H NMR (600 MHz, DMSO- d 6 ) δ 8.69 (t, J = 5.9 Hz, 1H), 7.82–7.79 (m, 1H), 7.77–7.72 (m, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.33 (dd, J = 8.4, 2.2 Hz, 1H), 7.17–7.13 (m, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.85 (s, 1H), 6.68 (s, 1H), 6.63 (s, 1H), 4.32 (dd, J = 16.9, 6.2 Hz, 1H), 4.12 (dd, J = 16.8, 5.6 Hz, 1H), 3.90 (dd, J = 11.3, 7.0 Hz, 1H), 3.76 (s, 3H), 3.60 (s, 2H), 3.41 (ddd, J = 14.4, 10.7, 4.5 Hz, 1H), 2.98 (ddd, J = 16.4, 10.6, 5.7 Hz, 1H), 2.86 (dt, J = 16.6, 4.0 Hz, 1H). 13 C NMR (100 MHz, DMSO- d 6 ) δ 168.30, 161.81, 148.59, 147.94, 140.06, 139.99, 134.46, 133.11, 132.31, 131.35, 129.48, 128.83, 128.41, 127.64, 127.22, 126.56, 112.48, 111.25, 56.01, 55.95, 53.27, 41.40, 28.35. HRMS (ESI) calcd for C 24 H 23 Cl 2 N 2 O 4 S [M + H] ་ 505.0756, found 505.0783. N-(2-(1-(2,4-Dichlorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide (A30) white solid, yield 89%, mp 133–135 o C; 1 H NMR (400 MHz, CDCl 3 ) δ 7.85 (d, J = 4.5 Hz, 1H), 7.45 (d, J = 6.1 Hz, 1H), 7.41 (d, J = 2.1 Hz, 1H), 7.11 (ddd, 1 J CF = 17.2, 8.4, 2.2 Hz, 1H), 7.02 (t, J = 54.2 Hz, 1H), 6.86 (6.65) (s, 1H), 6.80 (d, J = 8.4 Hz, 1H), 6.65 (6.46) (s, 1H), 6.45 (6.07) (s, 1H), 4.36–4.12 (4.57) (m, 2H), 3.87 (s, 3H), 3.86 (s, 3H), 3.76 (s, 1H), 3.73 (s, 3H), 3.02 (ddd, J = 17.0, 7.7, 4.0 Hz, 1H), 2.84 (ddd, J = 16.3, 4.5, 2.3 Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ 167.23, 161.41, 148.72, 148.24, 144.68, 138.24, 134.87, 134.19, 132.98, 131.71, 129.81, 126.91, 126.08, 125.86, 116.06, 111.54, 110.69, 110.35, 55.97, 55.95, 53.49, 41.55, 39.42, 28.38, 26.89. HRMS (ESI) calcd for C 25 H 25 Cl 2 F 2 N 4 O 4 [M + H] ་ 553.1221, found 553.1243. N-(2-(1-(2,4-Dichlorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide (A31) white solid, yield 93%, mp 120–122 o C; 1 H NMR (400 MHz, CDCl 3 ) δ 7.92 (s, 1H), 7.46 (dd, J = 19.5, 2.1 Hz, 1H), 7.38 (d, J = 4.2 Hz, 1H), 7.14 (ddd, J = 16.4, 8.4, 2.2 Hz, 1H), 6.89 (6.08) (s, 1H), 6.83 (d, J = 8.5 Hz, 1H), 6.68 (d, J = 4.3 Hz, 1H), 6.48 (s, 1H), 4.46–4.17 (m, 2H), 3.94 (d, J = 9.8 Hz, 4H), 3.89 (s, 3H), 3.75 (3.79) (s, 3H), 3.74–3.71 (m, 1H), 3.46 (ddd, J = 14.1, 11.6, 4.5 Hz, 1H), 3.05 (ddt, J = 17.4, 11.5, 6.7 Hz, 1H), 2.86 (ddd, J = 16.4, 4.5, 2.2 Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ 167.01, 160.39, 148.74, 148.25, 138.14, 134.89, 134.24, 134.12, 131.76, 129.84, 126.90, 126.05, 125.83, 120.75 (d, 1 J CF = 269.6 Hz), 116.54, 111.54, 110.70, 55.97, 55.95, 53.48, 41.74, 39.61, 39.31, 28.36, 26.89. HRMS (ESI) calcd for C 25 H 24 Cl 2 F 3 N 4 O 4 [M + H] ་ 571.1127, found 571.1141. N-(2-(1-(2,4-Dichlorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-2-methyl-4-(trifluoromethyl)thiazole-5-carboxamide (A32) white solid, yield 88%, mp 115–117 o C; 1 H NMR (600 MHz, CDCl 3 ) δ 7.48 (d, J = 27.3 Hz, 1H), 7.41 (d, J = 21.8 Hz, 1H), 7.16 (dd, J = 23.2, 8.5 Hz, 1H), 6.91 (6.69) (s, 1H), 6.83 (d, J = 8.3 Hz, 1H), 6.68 (s, 1H), 6.48 (6.06) (s, 1H), 4.32 (4.70–4.37) (d, J = 3.9 Hz, 2H), 3.90 (s, 3H), 3.76 (3.80) (s, 3H), 3.75–3.69 (m, 1H), 3.47 (td, J = 14.4, 13.1, 4.5 Hz, 1H), 3.13–3.00 (m, 1H), 2.90–2.85 (m, 1H), 2.75 (s, 3H). 13 C NMR (150 MHz, CDCl 3 ) δ 167.96, 165.77, 158.63, 148.68, 148.18, 137.70, 134.99, 134.44, 134.24, 131.95 (132.07), 129.97 (130.11), 127.43, 126.90, 125.85, 125.60, 120.12 (d, 1 J CF = 270.8 Hz), 111.33 (111.74), 110.49 (109.98), 55.95, 53.46, 42.46 (42.75), 39.10 (37.35), 28.32 (26.91), 19.22. HRMS (ESI) calcd for C 25 H 23 Cl 2 F 3 N 3 O 4 S [M + H] ་ 588.0738, found 588.0743. X-ray Diffraction Compound A5 was recrystallized by slow evaporation from a solution of tetrahydrofuran to afford a single crystal suitable for X-ray crystallography for structure validation. A crystal structure was performed on a Rigaku XtaLAB P200 diffractometer. The crystal was kept at 138.15 K during data collection. Using Olex2 [ 24 ], the structure was solved with the SHELXT [ 25 ] structure solution program using Intrinsic Phasing and refined with the SHELXL [ 26 ] refinement package using Least Squares minimisation. Optimization of thermal ellipsoid diagram of crystal by ORTEP-3 [ 27 ]. The crystallographic data of A5 can be download from the CCDC and the Supporting Information. Antifungal activity assay The in vitro activity of the target compounds A1-32 against Rhizotonia cerealis , Physalospora piricola , Fusarium graminearum , Colletotrichum lagenarium Botrytis Cinerea and Alternaria alternata were tested at 50 mg/L by mycelial growth rate method [ 28 – 29 ]. Chlorothalonil and boscalid were used as positive controls. The in vivo fungicidal activity against Alternaria alternata was evaluated at 50 mg/L and 100 mg/L on fragrant Pear. Boscalid as positive controls. Calculation of molecular properties and drug-likeness evaluation Molinspiration was used to calculate the main physical and chemical properties of the target compounds, such as the relative molecular weight, LogP (octanol/water partition coefficient), number of hydrogen bond donors and acceptors, and number of rotatable bonds [ 30 ]. ADMET lap was used to calculate the drug-likeness of the target compounds [ 31 ]. Molecular electrostatic potential analysis Compound A13 were selected for the molecular electrostatic potential analysis by density functional theory (DFT) method via Gaussian 09. The optimization of molecular conformation were carried out by the B3LYP method at 6-31G(d,p) level, and electrostatic potential calculation was based on the optimized structure [ 32 ]. Molecular docking Molecular docking simulation was performed by the CDOCKER module on AutoDock Vina1.1.2. The structures of the chose molecular was optimized and manually docked into the active site in porcine heart mitochondrial SDH from the RCSB Protein Data Bank (PDB ID: 2FBW). The crystal structure of SDH, compound A13 and positive control boscalid were treated according to standard procedures. The molecular docking results were analyzed and displayed by PyMol 2.5 [ 33 ]. SEM Analysis Mycelial morphology were made using scanning electron microscopy (SEM) technology according to previously reported methods [ 34 ]. The A. alternata mycelial cakes were cut from a PDA medium containing compound A13 (including 0.1% DMSO) at a 25 mg/L concentration. The mycelial cakes containing the same amount of DMSO were used as blank controls. Following the treatment according to the literature procedure, the mycelial morphology was observed under the scanning electron microscope. Declarations Supporting Information The supporting information for this article is available at https://doi.orgxxxxx . The authors declare that they have no confict of interest. Author Contribution W. Chen, and Y. Chen conceived and designed the study; Y. Chen, Y.X. Jin, L.Y. Wang, W.X. Wang and H.P. Zhou performed the experiments, analyzed the data for all compounds; W. Chen and Y. Chen co-wrote the paper. Acknowledgement This work was supported by Natural Science Foundation of Sichuan (Nos. 2021YJ0481, 24NSFSC2305) and Fundamental Research Funds for the Central Universities (No. 2682023ZTPY077). We would like to thank Analysis and Testing Center of Southwest Jiaotong University for structural identification and SEM test. References Ghorbanpour M, Omidvari M, Abbaszadeh-Dahaji et al (2018) Mechanisms underlying the protective effects of beneficial fungi against plant diseases. 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Supplementary Files 0522MDGraphicAbstract.docx 0522SI.doc scheme1.png Scheme 1 Synthetic route of title compounds A1-A32 Cite Share Download PDF Status: Published Journal Publication published 11 Oct, 2024 Read the published version in Molecular Diversity → Version 1 posted Editorial decision: Revision requested 05 Sep, 2024 Reviews received at journal 04 Sep, 2024 Reviews received at journal 26 Aug, 2024 Reviews received at journal 24 Aug, 2024 Reviewers agreed at journal 24 Aug, 2024 Reviewers agreed at journal 24 Aug, 2024 Reviewers agreed at journal 22 Aug, 2024 Reviews received at journal 12 Aug, 2024 Reviewers agreed at journal 12 Aug, 2024 Reviewers invited by journal 03 Jun, 2024 Editor assigned by journal 25 May, 2024 Submission checks completed at journal 25 May, 2024 First submitted to journal 24 May, 2024 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. 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20:08:45","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":88035,"visible":true,"origin":"","legend":"\u003cp\u003e\u003csup\u003e1\u003c/sup\u003eH NMR spectrum of \u003cstrong\u003eA5\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4470733/v1/c8ceed80cb17ab7a22f032ed.png"},{"id":58150808,"identity":"b707443a-a5c9-4546-9da9-20290b0cb918","added_by":"auto","created_at":"2024-06-11 20:08:45","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":35382,"visible":true,"origin":"","legend":"\u003cp\u003eX-ray crystal structure of compound \u003cstrong\u003eA5\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4470733/v1/ec6c08ae88f21b8a70786237.png"},{"id":58150806,"identity":"f03c3ce3-108b-4ad8-9c7a-381a36cf2bb6","added_by":"auto","created_at":"2024-06-11 20:08:45","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":447373,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eIn vivo\u003c/em\u003eantifungal activity of compound \u003cstrong\u003eA13\u003c/strong\u003e against \u003cem\u003eA. alternata\u003c/em\u003e.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4470733/v1/6278429c55640006ab5c0c15.png"},{"id":58152253,"identity":"3747c02a-d144-4d8c-865a-fc226a685c20","added_by":"auto","created_at":"2024-06-11 20:16:45","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":269590,"visible":true,"origin":"","legend":"\u003cp\u003eSEM of the hyphae of \u003cem\u003eA. alternata\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e(A) negative control, (B) Boscalid with a concentration of 25 mg/L, (C) compound \u003cstrong\u003eA13\u003c/strong\u003ewith a concentration of 25 mg/L, (D) compound \u003cstrong\u003eA13\u003c/strong\u003e with a concentration of 50 mg/L\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-4470733/v1/0b00ff3e3b8745ff2f003a67.png"},{"id":58150809,"identity":"6e1ac4af-ca44-4d4d-98b8-1d4d72e71f06","added_by":"auto","created_at":"2024-06-11 20:08:45","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":150869,"visible":true,"origin":"","legend":"\u003cp\u003eThe molecular electrostatic potential of compound \u003cstrong\u003eA13\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-4470733/v1/dcdcd7cae6bcb3e4bcec43bc.png"},{"id":58152252,"identity":"1541fb8c-3aab-4405-8581-3bde19358a64","added_by":"auto","created_at":"2024-06-11 20:16:45","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":276666,"visible":true,"origin":"","legend":"\u003cp\u003eDocking modes of compound \u003cstrong\u003eA13\u003c/strong\u003e and boscalid with SDH (2FBW)\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-4470733/v1/51a4a5104367f95332fdd709.png"},{"id":66597262,"identity":"c6b93cf1-7220-435a-afa5-64d7122a233b","added_by":"auto","created_at":"2024-10-14 16:09:05","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3317254,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4470733/v1/429281e9-f180-44ec-ac85-360c21ec1d5a.pdf"},{"id":58150804,"identity":"34192b64-9cbd-46bf-a839-25ab1d71ea96","added_by":"auto","created_at":"2024-06-11 20:08:45","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":7028415,"visible":true,"origin":"","legend":"","description":"","filename":"0522MDGraphicAbstract.docx","url":"https://assets-eu.researchsquare.com/files/rs-4470733/v1/a33030ff8dafd5459a4e3d23.docx"},{"id":58150805,"identity":"6caed070-5a0c-455e-aba1-69647660f602","added_by":"auto","created_at":"2024-06-11 20:08:45","extension":"doc","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":9296384,"visible":true,"origin":"","legend":"","description":"","filename":"0522SI.doc","url":"https://assets-eu.researchsquare.com/files/rs-4470733/v1/25d1c294768c42a9abe8659c.doc"},{"id":58150802,"identity":"0c6e1f99-718c-427f-b4e6-3e32fb55f5ef","added_by":"auto","created_at":"2024-06-11 20:08:45","extension":"png","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":92265,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 1 \u003c/strong\u003e\u0026nbsp;Synthetic route of title compounds \u003cstrong\u003eA1-A32\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"scheme1.png","url":"https://assets-eu.researchsquare.com/files/rs-4470733/v1/cb4baf6f335e7cb42670675f.png"}],"financialInterests":"No competing interests reported.","formattedTitle":"Design, synthesis, and mechanism study of novel 1-arylisoquinoline derivatives as antifungal agents","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePhytopathogenic fungi are causing substantial harm to grain crops, resulting in diminished yield, compromised quality, and ultimately posing a threat to the worldwide food security [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Although, chemical fungicides remain as the most effective and economical method for the control of fungal diseases at present [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], with the prolonged and massive irrational of traditiona-chemicals have caused resistance, residual toxicity and even environmental problems [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Therefore, it was urgent to discover and develop novel biocompatibility antifungal agents to control plant diseases and ensure the agricultural production safety.\u003c/p\u003e \u003cp\u003eThe natural-based or -derived compounds have attracted increasing attention as potential candidates to develop \u0026ldquo;green\u0026rdquo; agrochemicals due to their extensive biological properties, multiple modes of action and environment friendly [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Tetrahydroisoquinoline alkaloids (THIQs) are a kind of natural products with a common tetrahydroisoquinoline motif and widely exist in the Papaveraceae family and some members of the Rutaceae family [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. THIQs and their derivatives exhibit antibacterial, antitumor, antimalarial, anti-inflammatory, and influence on the activities of various important biological enzymes [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Tiwari et al. synthesised a series of 1-aryl tetrahydroisoquinoline derivatives with antibacterial activity [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAmide is an important classic structural motif in agrochemicals and natural products, often serving as a linking bridge to introduce active pharmacophores for the development of novel pesticides [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Valine carbamate fungicides, categorized as amino acid fungicides, feature a double amide bridge chain in their structure, which provides good environmental compatibility [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Succinate dehydrogenase inhibitors (SDHIs) have become the most rapidly growing type of agrochemical due to their powerful and broad-spectrum antifungal activities, which damaging the citric acid cycle and respiratory chain electron transmission in fungal mitochondria [\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The structure of commercial SDHIs typically consists of three components: a polar segment, a hydrophobic tail, and an amide bridge that binds them together. The pyrazole ring is the most commonly used polar segment, which often beneficial in enhancing the antifungal action of bioactive carboxamide derivatives [\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn our previous work, several isoquinoline compounds were designed and synthesized with antifungal activites [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In order to further study isoquinoline derivatives and find novel active fungicidal candicates. A series of novel 1-arylisoquinoline derivatives were designed and synthesized, which introduce double amide bridge binds tetrahydroisoquinoline motif and polar core together (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Their antifungal activities against six plant pathogenic fungi were studied. Compound \u003cb\u003eA13\u003c/b\u003e with excellent fungicidal activity was further tested \u003cem\u003ein vivo\u003c/em\u003e to against \u003cem\u003eA. alternata\u003c/em\u003e on fragrant pears. In addition, scanning electron microscopy (SEM) observations, molecular electrostatic potential. and molecular docking analysis were conducted.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Results and Discussion","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eChemistry\u003c/h2\u003e \u003cp\u003eThe synthetic route of the target compounds as shown in Scheme \u003cspan refid=\"Sch1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. 2-(3\u0026prime;,4\u0026prime;-Dimethoxypheny1)ethy1amine \u003cb\u003e1\u003c/b\u003e reacts with appropriate aldehydes \u003cb\u003e2a-2h\u003c/b\u003e in anhydrous toluene to form the schiff bases \u003cb\u003e3a-3h\u003c/b\u003e. The intermediates \u003cb\u003e4a-4h\u003c/b\u003e were obtained by intramolecular cyclization of \u003cb\u003e3\u003c/b\u003e with trifluoroacetic acid. Then, \u003cb\u003e4a-4h\u003c/b\u003e was condensed with Boc-glycine to obtain intermediates \u003cb\u003e5a-5h\u003c/b\u003e. Under acidic conditions, the Boc protective group was removed to obtain intermediates \u003cb\u003e6a-6h\u003c/b\u003e, and then condensed with heterocyclic aryl chlorides \u003cb\u003e7a-7d\u003c/b\u003e to obtain target compound \u003cb\u003eA1-A32\u003c/b\u003e.\u003c/p\u003e \u003cp\u003eThe structures of the title compounds were identified by \u003csup\u003e1\u003c/sup\u003eH NMR, \u003csup\u003e13\u003c/sup\u003eC NMR, HRMS and single-crystal Xray diffraction. As in \u003cb\u003eA5\u003c/b\u003e, the \u003csup\u003e1\u003c/sup\u003eH NMR spectrum of compound \u003cb\u003eA5\u003c/b\u003e at room temperature showed that the proton signals of the methylene groups at C3 and C4, the methoxy groups at C6 and C7, and most of the carbon atoms on the aromatic ring were splitted. It indicated this type of compounds exhibit steric isomerism, resulting in the splitting of proton signals at room temperature. The variable temperature nuclear magnetic resonance test results showed that as the temperature increased to 120\u003csup\u003eo\u003c/sup\u003eC, the splitted signals gradually converged to a single signal (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The structure of \u003cb\u003eA5\u003c/b\u003e was further identified by X-ray diffraction (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Based on the above details, the target compounds were confirmed as pure substance.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eAntifungal activity\u003c/h2\u003e \u003cp\u003eThe \u003cem\u003ein vitro\u003c/em\u003e antifungal activities of target compound \u003cb\u003eA1-A32\u003c/b\u003e against six kinds of phytopathogenic fungi at a concentration of 50 mg/L were shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. As the data showed, all the target compounds showed varying degrees of inhibition against the tested fungi. For \u003cem\u003eR. cerealis\u003c/em\u003e, compounds \u003cb\u003eA30\u003c/b\u003e, \u003cb\u003eA31\u003c/b\u003e, and \u003cb\u003eA32\u003c/b\u003e exceeded more than 70% antifungal activities, which superior to the positive control boscalid (6.23%). Compound \u003cb\u003eA25\u003c/b\u003e has an inhibitory rate of 67.25% against the \u003cem\u003eP. piricola\u003c/em\u003e, it is comparable to the boscalid (66.56%), but lower than chlorothalonil (88.69%). In particular, compounds \u003cb\u003eA5\u003c/b\u003e, \u003cb\u003eA9\u003c/b\u003e, \u003cb\u003eA13\u003c/b\u003e, \u003cb\u003eA21\u003c/b\u003e, \u003cb\u003eA25\u003c/b\u003e, \u003cb\u003eA28\u003c/b\u003e, and \u003cb\u003eA32\u003c/b\u003e all have over 70% inhibitory rates against \u003cem\u003eA. alternata.\u003c/em\u003e Among them, \u003cb\u003eA13\u003c/b\u003e (90.81%) and \u003cb\u003eA25\u003c/b\u003e (94.13%) were comparable to boscalid (92.13%), and better than chlorothalonil (37.79%). Furthermore, the EC\u003csub\u003e50\u003c/sub\u003e value of \u003cb\u003eA13\u003c/b\u003e (2.375 mg/L) and \u003cb\u003eA25\u003c/b\u003e (2.251 mg/L) against \u003cem\u003eA. alternate\u003c/em\u003e was equivalent to the positive control boscalid (1.195 mg/L) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In compare with boscalid, compounds \u003cb\u003eA13\u003c/b\u003e and \u003cb\u003eA25\u003c/b\u003e exhibited broader antifungal spectrum.\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\u003e\u003cem\u003eIn vitro\u003c/em\u003e antifungual activity of target compounds \u003cb\u003eA1-A32\u003c/b\u003e (50 mg/L, Inhabition rate\u0026thinsp;\u0026plusmn;\u0026thinsp;Standard deviation %)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCompd\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eR. cerealis\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eP. piricola\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eF. graminearum\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eC. lagenarium\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003eB. Cinerea\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cem\u003eA. alternata\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eA1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e24.20\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e26.10\u0026thinsp;\u0026plusmn;\u0026thinsp;0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e6.50\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e13.50\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e10.90\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e17.80\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eA2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e16.40\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e20.80\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e5.30\u0026thinsp;\u0026plusmn;\u0026thinsp;0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e6.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e17.60\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e13.23\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eA3\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e14.50\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e22.20\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e11.70\u0026thinsp;\u0026plusmn;\u0026thinsp;0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e1.20\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e5.50\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e16.28\u0026thinsp;\u0026plusmn;\u0026thinsp;1.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eA4\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e20.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e16.40\u0026thinsp;\u0026plusmn;\u0026thinsp;0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e9.60\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e7.62\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e13.60\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e21.34\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eA5\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e46.94\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e32.12\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e17.26\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e20.68\u0026thinsp;\u0026plusmn;\u0026thinsp;0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e23.11\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e74.55\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eA6\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e48.19\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e33.74\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e19.15\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e19.41\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e21.21\u0026thinsp;\u0026plusmn;\u0026thinsp;0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e6.98\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eA7\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e50.56\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e37.37\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e24.82\u0026thinsp;\u0026plusmn;\u0026thinsp;0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e21.10\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e27.27\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e12.08\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eA8\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e56.32\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e30.32\u0026thinsp;\u0026plusmn;\u0026thinsp;1.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e16.35\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e18.69\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e19.32\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e60.49\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eA9\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e26.45\u0026thinsp;\u0026plusmn;\u0026thinsp;0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e33.98\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e15.67\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e20.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e11.79\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e84.36\u0026thinsp;\u0026plusmn;\u0026thinsp;0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eA10\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e18.49\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e1.47\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e12.99\u0026thinsp;\u0026plusmn;\u0026thinsp;0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e4.80\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e3.40\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e13.33\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eA11\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e18.49\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e12.79\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e17.51\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e12.31\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e1.66\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e28.89\u0026thinsp;\u0026plusmn;\u0026thinsp;0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eA12\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e30.36\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e26.79\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e20.72\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e14.68\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e6.32\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e65.79\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eA13\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e65.57\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e39.88\u0026thinsp;\u0026plusmn;\u0026thinsp;0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e18.89\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e17.91\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e3.21\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e90.81\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eA14\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e5.60\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e21.43\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e6.11\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e4.48\u0026thinsp;\u0026plusmn;\u0026thinsp;0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e13.46\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e12.12\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eA15\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e3.24\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e24.40\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e2.78\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e1.99\u0026thinsp;\u0026plusmn;\u0026thinsp;0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e19.23\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e23.23\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eA16\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e47.49\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e30.95\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e16.67\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e19.90\u0026thinsp;\u0026plusmn;\u0026thinsp;0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e24.36\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e63.64\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eA17\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e20.63\u0026thinsp;\u0026plusmn;\u0026thinsp;0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e3.54\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e8.73\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e12.95\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e5.86\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e51.53\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eA18\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e13.75\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e6.56\u0026thinsp;\u0026plusmn;\u0026thinsp;0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e18.8\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e12.46\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e19.24\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e3.43\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eA19\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e21.9\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e20.9\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e17.7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e13.7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e31.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e39.37\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eA20\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e28.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e8.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e18.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e22.4\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e34.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e50.23\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eA21\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e39.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e37.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e25.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e48.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e29.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e76.05\u0026thinsp;\u0026plusmn;\u0026thinsp;0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eA22\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e1.47\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e28.57\u0026thinsp;\u0026plusmn;\u0026thinsp;0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e0.56\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e5.97\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e0.64\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e6.06\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eA23\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e12.68\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e1.19\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e1.67\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e1.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e10.90\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e8.08\u0026thinsp;\u0026plusmn;\u0026thinsp;0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eA24\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e26.34\u0026thinsp;\u0026plusmn;\u0026thinsp;1.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e13.64\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e16.79\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e34.16\u0026thinsp;\u0026plusmn;\u0026thinsp;1.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e26.34\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e61.23\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eA25\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e66.77\u0026thinsp;\u0026plusmn;\u0026thinsp;0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e67.25\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e17.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e59.82\u0026thinsp;\u0026plusmn;\u0026thinsp;0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e51.56\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e94.13\u0026thinsp;\u0026plusmn;\u0026thinsp;0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eA26\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e58.68\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e33.31\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e28.12\u0026thinsp;\u0026plusmn;\u0026thinsp;0.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e38.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e42.87\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e62.89\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eA27\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e64.35\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e39.46\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e28.85\u0026thinsp;\u0026plusmn;\u0026thinsp;0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e38.93\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e51.15\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e59.29\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eA28\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e47.49\u0026thinsp;\u0026plusmn;\u0026thinsp;0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e13.69\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e20.56\u0026thinsp;\u0026plusmn;\u0026thinsp;0.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e25.87\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e37.18\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e73.69\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eA29\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e15.69\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e10.27\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e14.41\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e7.81\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e14.29\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e56.11\u0026thinsp;\u0026plusmn;\u0026thinsp;0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eA30\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e77.78\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e47.47\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e26.71\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e38.40\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e48.11\u0026thinsp;\u0026plusmn;\u0026thinsp;0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e56.03\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eA31\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e73.61\u0026thinsp;\u0026plusmn;\u0026thinsp;0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e41.41\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e33.81\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e35.02\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e50.38\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e65.22\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eA32\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e77.22\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e47.88\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e30.02\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e36.71\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e40.35\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e72.81\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eChlorot-\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003ehalonil\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e95.56\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e88.69\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e82.51\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e83.12\u0026thinsp;\u0026plusmn;\u0026thinsp;0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e75.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e37.79\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBoscalid\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e6.23\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e66.56\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e13.59\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e15.46\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e40.49\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e92.13\u0026thinsp;\u0026plusmn;\u0026thinsp;1.6\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\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\u003eEC\u003csub\u003e50\u003c/sub\u003e of \u003cb\u003eA13\u003c/b\u003e, \u003cb\u003eA25\u003c/b\u003e against \u003cem\u003eA. alternata\u003c/em\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\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=\"left\" 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\u003eComp.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e95% confidence\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEC\u003csub\u003e50\u003c/sub\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eToxic regression equation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003er\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eA13\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.698\u0026ndash;4.335\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.375\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ey = -0.65\u0026thinsp;+\u0026thinsp;1.65x\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.985\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eA25\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.731\u0026ndash;3.966\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.251\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ey = -0.73\u0026thinsp;+\u0026thinsp;1.97x\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.989\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBoscalid\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.124\u0026ndash;2.932\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.195\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ey = -0.27\u0026thinsp;+\u0026thinsp;1.52x\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.949\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\u003eAccording to the \u003cem\u003ein vitro\u003c/em\u003e results, \u003cb\u003eA13\u003c/b\u003e was selected to evaluate \u003cem\u003ein vivo\u003c/em\u003e against \u003cem\u003eA. alternata\u003c/em\u003e on fragrant pears. As shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e and Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, A13 indicated effective protective activity at the concentration of 50 and 100 mg/L (51.613 and 70.968%), which was equal to boscalid (64.516 and 77.419%). Longitudinal section of the pear revealed that the decay caused by \u003cem\u003eA. alternata\u003c/em\u003e not only expand on the surface of the pear but also spread into the interior of the pear.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cem\u003eIn vivo\u003c/em\u003e antifungal activity of compound \u003cb\u003eA13\u003c/b\u003e against \u003cem\u003eA. alternata\u003c/em\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCompd.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eInhibition %\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50 mg\u0026bull;L\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100 mg\u0026bull;L\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eA13\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e51.613\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e70.968\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBoscalid\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e64.516\u0026thinsp;\u0026plusmn;\u0026thinsp;1.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e77.419\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1\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\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStructure-activity relationship\u003c/h2\u003e \u003cp\u003eThe bioassay results of \u003cem\u003ein vitro\u003c/em\u003e and \u003cem\u003ein vivo\u003c/em\u003e test indicated that the \"common\" scaffold of 1-aryl-tetrahydroisoquinoline served as a promising antifungal core. The C1 substituents and the heterocyclic acid fragments of the amide bridge were identified as significant factors on modulating antifungal activity. When the heterocyclic acid fragment remains consistent, compounds featuring aromatic ring at the C1 position demonstrated higher antifungal efficacy compared to others (\u003cb\u003eA1-A4\u003c/b\u003e versus \u003cb\u003eA5-A32\u003c/b\u003e). Notably, among the aryl-substituents, para-substituted phenyl exhibited higher antifungal inhibition than the meta- and ortho-substituted phenyl, mono-substituted compounds (\u003cb\u003eA5-A28\u003c/b\u003e) displayed greater antifungal efficacy than multi-substituted compounds (\u003cb\u003eA29-A32\u003c/b\u003e). Compare between \u003cb\u003eA13\u003c/b\u003e-\u003cb\u003eA16\u003c/b\u003e with \u003cb\u003eA25\u003c/b\u003e-\u003cb\u003eA28\u003c/b\u003e, revealed that when the aryl-substituents are identical, the antifungal potency followed as thiophenyl\u0026thinsp;\u0026gt;\u0026thinsp;thiazolyl\u0026thinsp;\u0026gt;\u0026thinsp;pyrazolyl. Compounds containing thiophene heterocyclic fragments displayed pronounced antifungal activities and broad-spectrum for various pathogenic fungi.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eMolecular properties and drug-likeness evaluation\u003c/h2\u003e \u003cp\u003eThe fungicidal activity and the \u003cem\u003ein silico\u003c/em\u003e interaction with the assumed target enzyme were greatly affected by the chemical structure. The physical and chemical properties of highly active compounds \u003cb\u003eA13\u003c/b\u003e and \u003cb\u003eA25\u003c/b\u003e were calculated. As shown in the Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, the chemical structure of \u003cb\u003eA13\u003c/b\u003e and \u003cb\u003eA25\u003c/b\u003e meet the Lipinski rule and demonstrate good drug-likeness.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eLipinski properties of \u003cb\u003eA13\u003c/b\u003e and \u003cb\u003eA25\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\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=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\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\u003eA13\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eA25\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e454.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e470.89\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLogP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.83\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003enOHNH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003enON\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003enRotb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.252\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.244\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\u003eMW: molecular weight; LogP: octanol/water partition coefficient; nOHNH: number of hydrogen bond acceptors; nON: number of hydrogen bond donors; nRotb: number of rotatable bonds; DL: drug-likeness evaluation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eSEM Analysis\u003c/h2\u003e \u003cp\u003eSEM analysis of \u003cem\u003eA. alternata\u003c/em\u003e was conducted to investigate microstructural variations in the mycelia. The untreated mycelia exhibited a relatively uniform, robust, and smooth appearance (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eA). In contrast, mycelia treated with compound \u003cb\u003eA13\u003c/b\u003e at concentrations of 50 mg/L and 100 mg/L significant coarsening were observed, with twisted and broken hyphae and a shriveled surface (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eC, \u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eD). These findings indicated that compound \u003cb\u003eA13\u003c/b\u003e induces substantial damage to the mycelia of \u003cem\u003eA. alternata\u003c/em\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eMechanism\u003c/h2\u003e \u003cp\u003eMolecular electrostatic potential was an important factor for activity and provide a meaningful reference for uncovering the interaction modes of the drug with the target. As shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e, the positive region of compound \u003cb\u003eA13\u003c/b\u003e is relatively weak, and the negative region located around the oxygen atoms of the isoquinoline ring at C6, C7 methoxy, and the bridge carboxyl group. This distribution suggests the potential for the formation of hydrogen bonds with the target enyzem.\u003c/p\u003e \u003cp\u003eMolecular docking simulations were performed to investigate the binding mechanism of compound \u003cb\u003eA13\u003c/b\u003e with succinate dehydrogenase (SDH, PDB: 2FBW). The CDOCKER Interaction Energy of \u003cb\u003eA13\u003c/b\u003e and boscalid were \u0026minus;\u0026thinsp;8.4 kcal/mol and \u0026minus;\u0026thinsp;8.3 kcal/mol, respectively. As illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e (A, B), the isoquinoline ring of \u003cb\u003eA13\u003c/b\u003e engages in a Pi-sigma interaction with Leu A470, while the aromatic ring at the C1 position and the thiophenyl ring form Pi-cation interactions with the Arg A218. Additionally, the fluorine atom on the phenyl ring and the oxygen atom of the amide bond establish hydrogen bonds with the arginine residue (Arg B63). Notably, compared to boscalid, compound \u003cb\u003eA13\u003c/b\u003e exhibits a greater difference in binding sites and interaction modes with SDH. It provided a valuable reference for further modifcation of 1-arylisoquinoline derivatives.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn summary, a series of 32 novel 1-arylisoquinoline derivatives were designed, synthesized, and evaluated for their antifungal activities. The \u003cem\u003ein vitro\u003c/em\u003e bioassay results showed that \u003cb\u003eA13\u003c/b\u003e and \u003cb\u003eA25\u003c/b\u003e exhibited effective antifungal activity against \u003cem\u003eA. alternata\u003c/em\u003e as well as boscalid. The \u003cem\u003ein vivo\u003c/em\u003e activities of \u003cb\u003eA1\u003c/b\u003e and \u003cb\u003eA25\u003c/b\u003e were investigated on pears and indicated that they can control \u003cem\u003eA. alternate\u003c/em\u003e as well as boscalid at the dosage of 50 mg/L and 100 mg/L. The exploration of morphological observations indicated that compound \u003cb\u003eA1\u003c/b\u003e3 could strongly damage the mycelium morphology. Molecular electrostatic potential and molecular docking analysis revealed that \u003cb\u003eA13\u003c/b\u003e was covered by negative potential contour, and strongly interacts with the residues of SDH active pocket. This study showed a new way to optimize the tetrehydroisoquinoline alkaloids and further proved that 1-arylisoquinoline was a promising core for antifungal agents.\u003c/p\u003e"},{"header":"Experimental","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eInstruments and materials\u003c/h2\u003e \u003cp\u003eThe melting points were determined by RY-1G melting point meter. \u003csup\u003e1\u003c/sup\u003eH NMR spectra and \u003csup\u003e13\u003c/sup\u003eC NMR spectra were recorded on Brucker Avance NEO 400 using CDCl\u003csub\u003e3\u003c/sub\u003e, DMSO-\u003cem\u003ed\u003c/em\u003e\u003csub\u003e6\u003c/sub\u003e as solvent and tetramethylsilane as the internal standard, and chemical shift values (\u003cem\u003eδ\u003c/em\u003e) were given in parts per million (ppm). High-resolution mass spectrometry (HRMS) data were obtained on Xevo G2-S Tof Mass Spectrometer (Waters). The crystal structure was recorded by a Rigaku XtaLAB P200 diffractometer. Column chromatography silica gel H type (Qingdao Ocean Chemical Plant, 200\u0026ndash;300 mesh). Commercial reagents were analytically pure and used without further purification. All solvents were dried by standard methods in advance and distilled before use.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eGeneral synthetic procedure for target compounds A1-32\u003c/h2\u003e \u003cp\u003eThe synthetic route of the target compound as shown in Scheme \u003cspan refid=\"Sch1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. 2-(3\u0026prime;,4\u0026prime;-dimethoxypheny1)ethy1amine \u003cb\u003e1\u003c/b\u003e reacts with appropriate aldehydes \u003cb\u003e2a-2h\u003c/b\u003e in anhydrous toluene to form the intermediate diazo compound \u003cb\u003e3a-3h\u003c/b\u003e. The intermediate 1-substituted-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline compound \u003cb\u003e4a-4h\u003c/b\u003e is obtained by intramolecular cyclization with trifluoroacetic acid [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Compound \u003cb\u003e4a-4h\u003c/b\u003e was condensed with Boc-glycine to obtain intermediate \u003cb\u003e5a-5h\u003c/b\u003e. Under acidic conditions, the Boc protective group was removed to obtain intermediate \u003cb\u003e6a-6h\u003c/b\u003e, and then condensed with heterocyclic acid \u003cb\u003e7a-7d\u003c/b\u003e amide to obtain target compounds \u003cb\u003eA1-32\u003c/b\u003e [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eN-(2-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)thiophene-2-carboxamide (A1)\u003c/strong\u003e \u003cp\u003ewhite solid, yield 94%, mp 113\u0026ndash;115\u003csup\u003eo\u003c/sup\u003eC; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 7.55 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.2 Hz, 1H), 7.42 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.0 Hz, 1H), 7.34\u0026ndash;7.30 (m, 1H), 7.02 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.1 Hz, 1H), 6.58 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.0 Hz, 2H), 4.64 (s, 1H), 4.49 (s, 1H), 4.26 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.0, 2.6 Hz, 2H), 3.82 (s, 1H), 3.81 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.7 Hz, 6H), 3.61 (td, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.0, 2.0 Hz, 1H), 2.81 3(t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.9 Hz, 1H), 2.75 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.0 Hz, 1H). \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 166.88, 161.77 (161.74), 148.15 (148.31), 148.05, 138.55, 130.08, 128.40,125.65 (126.52), 124.57 (123.41), 111.52 (111.80), 109.58 (109.21), 56.04, 56.03, 45.77, 44.21, 42.32, 41.93, 41.73, 40.29, 28.63, 27.79. HRMS (ESI) calcd for C\u003csub\u003e18\u003c/sub\u003eH\u003csub\u003e21\u003c/sub\u003eN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003eS [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e་\u003c/sup\u003e 361.1222, found 361.1234.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003e3-(Difluoromethyl)-N-(2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-1-methyl-1H-pyrazole-4-carboxamide (A2)\u003c/strong\u003e \u003cp\u003ewhite solid, yield 96%, mp 78\u0026ndash;80\u003csup\u003eo\u003c/sup\u003eC; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 7.90 (s, 1H), 7.51 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.3 Hz, 1H), 7.00 (td, \u003csup\u003e1\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 54.2, 3.9 Hz, 1H), 6.61 (s, 1H), 6.58 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.8 Hz, 1H), 4.64 (s, 1H), 4.50 (s, 1H), 4.25 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.8 Hz, 2H), 3.87 (s, 3H), 3.83 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.2 Hz, 3H), 3.82 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.6 Hz, 3H), 3.80 (s, 1H), 3.81\u0026ndash;3.80 (m, 1H), 3.62 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.9 Hz, 1H), 2.82 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.9 Hz, 1H), 2.76 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.0 Hz, 1H). \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 166.97, 161.34 (d, \u003csup\u003e4\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 4.8 Hz), 148.13 (148.30), 148.05 (148.02),144.31 (t, \u003csup\u003e2\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 26.4 Hz), 133.57 (d, \u003csup\u003e4\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 10.4 Hz), 125.63 (126.56), 124.59 (123.38), 116.12, 111.79 (111.50), 110.62 (t, \u003csup\u003e1\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 234.9 Hz), 109.57 (109.19), 56.02, 55.99, 45.77, 44.17, 42.33, 41.77, 41.53, 40.24, 39.40, 28.57, 27.75. HRMS (ESI) calcd for C\u003csub\u003e19\u003c/sub\u003eH\u003csub\u003e23\u003c/sub\u003eF\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e4\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e་\u003c/sup\u003e 408.1609, found 408.1624.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eN-(2-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide (A3)\u003c/strong\u003e \u003cp\u003ewhite solid, yield 95%, mp 90\u0026ndash;92\u003csup\u003eo\u003c/sup\u003eC; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 7.94 (s, 1H), 7.41 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.4 Hz, 1H), 6.60 (s, 1H), 6.58 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.9 Hz, 1H), 4.63 (s, 1H), 4.49 (s, 1H), 4.24 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.8 Hz, 2H), 3.89 (s, 3H), 3.81 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.8, 1.7 Hz, 6H), 3.79 (s, 1H), 3.61 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.0 Hz, 1H), 2.82 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.0 Hz, 1H), 2.75 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.0 Hz, 1H). \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 166.82, 160.37 (d, \u003csup\u003e4\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 3.7 Hz), 148.13 (148.31), 148.06 (148.02), 139.21 (dd, \u003csup\u003e2\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 37.6, 8.0 Hz), 134.58 (d, \u003csup\u003e4\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 8.6 Hz), 125.61 (126.55), 124.53 (123.34), 120.82 (d, \u003csup\u003e1\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 269.3 Hz), 116.57, 111.50 (111.79), 109.56 (109.19), 56.01, 55.97, 45.73, 44.16, 42.30, 41.90, 41.66, 40.26, 39.58, 28.54, 27.72. HRMS (ESI) calcd for C\u003csub\u003e18\u003c/sub\u003eH\u003csub\u003e21\u003c/sub\u003eN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003eS [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e་\u003c/sup\u003e 427.1593, found 427.1606.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eN-(2-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-2-methyl-4-(trifluoromethyl)thiazole-5-carboxamide (A4)\u003c/strong\u003e \u003cp\u003ewhite solid, yield 92%, mp 96\u0026ndash;98\u003csup\u003eo\u003c/sup\u003eC; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 7.50 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.8 Hz, 1H), 6.58 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.4 Hz, 1H), 6.55 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.5 Hz, 1H), 4.60 (s, 1H), 4.46 (s, 1H), 4.24 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.5 Hz, 2H), 3.80 (s, 5H), 3.79 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.5 Hz, 4H), 3.77 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.1 Hz, 1H), 3.58 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.9 Hz, 1H), 2.80 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.0 Hz, 1H), 2.74 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.0 Hz, 1H), 2.66 (s, 3H). \u003csup\u003e13\u003c/sup\u003eC NMR (150 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 167.97 (168.01), 165.79 (d, \u003csup\u003e4\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 6.5 Hz), 158.57 (d, \u003csup\u003e4\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 7.3 Hz), 148.03 (148.21), 147.94 (147.90), 141.59\u0026ndash;139.98 (m), 134.62\u0026ndash;134.44 (m), 125.39 (126.41), 124.30 (123.02), 120.16 (q, \u003csup\u003e1\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 272.0 Hz), 111.25 (111.59), 109.30 (108.89), 55.98, 55.96, 55.94 (55.92), 45.70, 44.16, 42.52, 42.32, 42.25, 40.28, 28.52, 27.69, 19.11. HRMS (ESI) calcd for C\u003csub\u003e19\u003c/sub\u003eH\u003csub\u003e21\u003c/sub\u003eF\u003csub\u003e3\u003c/sub\u003eN\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003eS [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e་\u003c/sup\u003e 444.1205, found 444.1230.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eN-(2-(1-(2-Fluorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)thiophene-2-carboxamide (A5)\u003c/strong\u003e \u003cp\u003ewhite solid, yield 89%, mp 126\u0026ndash;128\u003csup\u003eo\u003c/sup\u003eC; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 7.59 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.7, 1.2 Hz, 1H), 7.48 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.0, 1.3 Hz, 1H), 7.32 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.7 Hz, 1H), 7.29\u0026ndash;7.23 (m, 1H), 7.15\u0026ndash;7.09 (6.86\u0026ndash;76.82) (m, 1H), 7.09\u0026ndash;7.07 (m, 1H), 7.05 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.1, 3.4 Hz, 2H), 6.93 (6.69) (s, 1H), 6.68 (6.18) (s, 1H), 6.52 (s, 1H), 4.72\u0026ndash;4.19 (m, 3H), 3.90 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.4 Hz, 3H), 3.78 (s, 1H), 3.76 (3.81) (s, 3H), 2.92\u0026ndash;2.69 (m, 1H), 3.66\u0026ndash;3.07 (m, 1H), 3.01 (dt, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;10.9, 5.3 Hz, 1H). \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 166.53 (167.24), 161.79 (161.97), 160.73 (d, \u003csup\u003e1\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 249.4 Hz), 148.50 (148.90), 148.10 (147.94), 138.53 (138.64), 130.77 (130.63), 130.06, 129.63 (129.54), 128.87 (128.73), 128.41, 127.58, 126.21 (126.00), 123.86 (124.05), 115.89 (d, \u003csup\u003e2\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 22.1 Hz), 111.73 (111.39), 110.89 (110.66), 56.00, 55.95, 51.27 (53.26), 41.88, 39.32 (36.76), 28.41 (27.16). HRMS (ESI) calcd for C\u003csub\u003e24\u003c/sub\u003eH\u003csub\u003e24\u003c/sub\u003eFN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003eS [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e་\u003c/sup\u003e 455.1441, found 455.1457.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003e3-(Difluoromethyl)-N-(2-(1-(2-fluorophenyl)-6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-1-methyl-1H-pyrazole-4-carboxamide (A6)\u003c/strong\u003e \u003cp\u003ewhite solid, yield 93%, mp 108\u0026ndash;110\u003csup\u003eo\u003c/sup\u003eC; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 7.88 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.1 Hz, 1H), 7.51 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;59.2 Hz, 1H), 7.32\u0026ndash;7.21 (m, 1H), 7.18\u0026ndash;7.06 (6.85\u0026ndash;6.79) (m, 1H), 7.02 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;130.6 Hz, 1H), 7.02\u0026ndash;6.96 (m, 2H), 6.91 (6.66) (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.6 Hz, 1H), 6.65 (6.14) (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.3 Hz, 1H), 6.48 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.3 Hz, 1H), 4.65\u0026ndash;4.10 (m, 2H), 3.88 (s, 3H), 3.87 (3.91) (s, 3H), 3.76 (s, 1H), 3.75 (3.77) (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;18.2 Hz, 3H), 3.61\u0026ndash;3.05 (m, 1H), 3.00 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16.7, 10.7, 5.7 Hz, 1H), 2.90\u0026ndash;2.63 (m, 1H). \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 167.05 (167.36), 161.60 (162.01), 160.77 (d, \u003csup\u003e1\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 249.3 Hz), 148.58 (148.94), 148.13 (147.97), 144.74 (d, \u003csup\u003e2\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 30.0 Hz), 132.94 (133.59), 130.82 (130.65), 129.56 (129.64), 128.87 (128.73), 127.43 (125.05), 126.17 (126.09), 123.86 (124.11), 115.96, 115.74, 111.44 (111.76), 110.94 (110.67), 110.28 (t, \u003csup\u003e1\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 235.4 Hz), 56.05, 56.00, 51.20 (53.28), 41.41, 39.45, 39.37 (37.76), 28.42 (27.18). HRMS (ESI) calcd for C\u003csub\u003e25\u003c/sub\u003eH\u003csub\u003e26\u003c/sub\u003eF\u003csub\u003e3\u003c/sub\u003eN\u003csub\u003e4\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e་\u003c/sup\u003e 503.1906, found 502.3.1921.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eN-(2-(1-(2-Fluorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide (A7)\u003c/strong\u003e \u003cp\u003ewhite solid, yield 91%, mp 124\u0026ndash;126\u003csup\u003eo\u003c/sup\u003eC; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 7.98 (s, 1H), 7.54 (dt, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;116.5, 4.3 Hz, 1H), 7.35\u0026ndash;7.20 (m, 1H), 7.14\u0026ndash;7.04 (6.85\u0026ndash;6.81) (m, 1H), 7.02\u0026ndash;6.96 (m, 2H), 6.93 (6.68) (s, 1H), 6.68 (6.15) (s, 1H), 6.50 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.4 Hz, 1H), 4.64\u0026ndash;4.16 (m, 2H), 3.89 (3.94) (s, 3H), 3.89 (s, 3H), 3.78\u0026ndash;3.75 (m, 1H), 3.74 (3.79) (s, 3H), 3.64\u0026ndash;3.09 (m, 1H), 3.01 (dq, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11.8, 6.1, 5.6 Hz, 1H), 2.80 (dddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;55.5, 16.2, 4.4, 2.7 Hz, 1H). \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 166.81 (167.10), 161.79 (161.67), 160.73 (d, \u003csup\u003e1\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 248.9 Hz), 148.55 (148.91), 148.10 (147.94), 139.71 (d, \u003csup\u003e2\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 37.4 Hz), 134.72, 134.11, 130.80 (130.61), 129.61 (129.53), 128.76 (128.62), 126.10 (126.02), 124.07, 123.81, 125.34\u0026ndash;116.65 (m), 116.42 (116.80), 115.93 (115.71), 111.39 (111.73), 110.90 (110.62), 55.99, 55.94, 51.14 (53.24), 41.57, 39.57, 39.27 (36.70), 28.35 (27.11). HRMS (ESI) calcd for C\u003csub\u003e25\u003c/sub\u003eH\u003csub\u003e25\u003c/sub\u003eF\u003csub\u003e4\u003c/sub\u003eN\u003csub\u003e4\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e་\u003c/sup\u003e 521.1812, found 521.1825.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eN-(2-(1-(2-Fluorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-2-methyl-4-(trifluoromethyl)thiazole-5-carboxamide (A8)\u003c/strong\u003e \u003cp\u003ewhite solid, yield 93%, mp 119\u0026ndash;121\u003csup\u003eo\u003c/sup\u003eC; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 7.46 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.0 Hz, 1H), 7.24 (dddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;13.7, 8.6, 5.7, 1.8 Hz, 1H), 7.08 (6.81\u0026ndash;6.77) (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;10.2, 8.8 Hz, 1H), 7.05\u0026ndash;6.93 (m, 2H), 6.86 (6.65) (s, 1H), 6.63 (6.09) (s, 1H), 6.47 (s, 1H), 4.26\u0026ndash;4.25 (4.61\u0026ndash;4.43) (m, 2H), 3.85 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.7 Hz, 3H), 3.70 (3.75) (s, 2H), 3.67 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.8, 2.8 Hz, 1H), 3.54 (3.11\u0026ndash;3.04) (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;13.9, 11.2, 4.5 Hz, 1H), 2.97 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16.9, 11.5, 5.7 Hz, 1H), 2.83 (2.72\u0026ndash;2.71) (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;15.8, 4.5, 2.8 Hz, 1H), 2.68 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.5 Hz, 3H). \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 167.86, 166.11, 165.35, 160.67 (dd, \u003csup\u003e1\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 248.4, 12.7 Hz), 158.57 (158.40), 148.45 (148.88), 148.02 (147.87), 140.95 (dd, \u003csup\u003e2\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 36.5, 27.4 Hz), 134.32 (134.81), 130.86 (130.72), 130.18 (129.67), 128.38 (127.59), 127.28 (125.95), 125.78 (124.65), 124.11 (123.81), 120.16 (d, \u003csup\u003e1\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 277.3 Hz), 116.02 (115.97), 115.80 (115.75), 111.21 (111.96), 110.69 (110.38), 55.94, 55.91, 53.17 (51.20), 42.44, 39.15 (36.61), 28.31, 27.09, 19.12. HRMS (ESI) calcd for C\u003csub\u003e25\u003c/sub\u003eH\u003csub\u003e24\u003c/sub\u003eF\u003csub\u003e4\u003c/sub\u003eN\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003eS [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e་\u003c/sup\u003e 538.5376, found 538.5394.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eN-(2-(1-(3-Fluorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)thiophene-2-carboxamide (A9)\u003c/b\u003e: white solid, yield 87%, mp 106\u0026ndash;108\u003csup\u003eo\u003c/sup\u003eC; \u003csup\u003e1\u003c/sup\u003eH NMR (600 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 7.58 (dt, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.9, 2.5 Hz, 1H), 7.44 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.0, 1.2 Hz, 1H), 7.36 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.0 Hz, 1H), 7.22 (td, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.0, 5.9 Hz, 1H), 7.04 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.0, 3.7 Hz, 1H), 7.01 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.7 Hz, 1H), 6.97\u0026ndash;6.92 (m, 1H), 6.91 (dt, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9.8, 2.1 Hz, 1H), 6.76 (6.62) (s, 1H), 6.66 (s, 1H), 6.50 (5.88) (s, 1H), 4.33\u0026ndash;4.23 (4.52\u0026ndash;4.42) (m, 2H), 3.87 (s, 3H), 3.75 (3.82) (s, 3H), 3.70 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;13.8, 6.0, 3.0 Hz, 1H), 3.41 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;13.7, 11.3, 4.4 Hz, 1H), 3.00\u0026ndash;2.86 (m, 1H), 2.77 (dt, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16.2, 3.9 Hz, 1H). \u003csup\u003e13\u003c/sup\u003eC NMR (150 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 166.75, 162.82 (d, \u003csup\u003e1\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 246.6 Hz), 161.82, 148.54 (148.88), 147.94 (147.75), 144.34 (144.29), 138.44 (138.36), 130.27, 129.95 (130.01), 128.50, 127.72, 126.13, 125.67, 124.29 (124.27), 115.74 (115.59), 114.83 (114.69), 111.20 (111.64), 111.04 (110.79), 56.04, 55.97, 55.13, 41.85, 38.81, 28.25. HRMS (ESI) calcd for C\u003csub\u003e24\u003c/sub\u003eH\u003csub\u003e24\u003c/sub\u003eFN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003eS [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e་\u003c/sup\u003e 455.1441, found 455.1453. HRMS (ESI) calcd for C\u003csub\u003e17\u003c/sub\u003eH\u003csub\u003e20\u003c/sub\u003eNO\u003csub\u003e2\u003c/sub\u003eS ([M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e): 302.1215, Found: 302.1222.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003e3-(Difluoromethyl)-N-(2-(1-(3-fluorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-1-methyl-1H-pyrazole-4-carboxamide (A10)\u003c/strong\u003e \u003cp\u003ewhite solid, yield 93%, mp 110\u0026ndash;112\u003csup\u003eo\u003c/sup\u003eC; \u003csup\u003e1\u003c/sup\u003eH NMR (600 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 7.93 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.1 Hz, 1H), 7.54 (s, 1H), 7.07 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;47.8 Hz, 1H), 7.02 (s, 1H), 7.00\u0026ndash;6.88 (m, 2H), 6.80 (6.62) (s, 1H), 6.69 (s, 1H), 6.52 (5.87) (s, 1H), 4.29 (4.52\u0026ndash;4.43) (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.2 Hz, 2H), 3.93 (s, 2H), 3.90 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.6 Hz, 2H), 3.78 (3.85) (s, 3H), 3.70 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;13.8, 5.9, 2.9 Hz, 1H), 3.43 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;13.8, 11.2, 4.4 Hz, 1H), 2.98 (ddt, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;19.5, 13.9, 6.9 Hz, 1H), 2.80 (dt, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16.3, 3.7 Hz, 1H). \u003csup\u003e13\u003c/sup\u003eC NMR (150 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 166.67, 162.80 (d, \u003csup\u003e1\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 246.6 Hz), 161.25, 148.54, 147.93, 144.29 (144.25), 133.80 (133.76), 129.94, 129.88, 126.06, 125.70, 124.26, 116.17, 115.65 (d, \u003csup\u003e2\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 22.1 Hz), 114.71 (d, \u003csup\u003e2\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 21.2 Hz), 112.50\u0026ndash;110.69 (m), 111.18, 111.04, 56.02, 55.95, 55.02, 41.72, 39.54, 38.76, 28.18. HRMS (ESI) calcd for C\u003csub\u003e25\u003c/sub\u003eH\u003csub\u003e26\u003c/sub\u003eF\u003csub\u003e3\u003c/sub\u003eN\u003csub\u003e4\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e་\u003c/sup\u003e 503.5022, found 503.5046.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eN-(2-(1-(3-Fluorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide (A11)\u003c/strong\u003e \u003cp\u003ewhite solid, yield 88%, mp 122\u0026ndash;124\u003csup\u003eo\u003c/sup\u003eC; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 7.94 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.4 Hz, 1H), 7.35 (s, 1H), 7.31\u0026ndash;7.20 (m, 1H), 7.02 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.7 Hz, 1H), 6.97 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.4, 2.5 Hz, 1H), 6.94\u0026ndash;6.88 (m, 1H), 6.79 (6.60) (s, 1H), 6.67 (s, 1H), 6.50 (5.84) (s, 1H), 4.27 (4.48\u0026ndash;4.44) (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.9 Hz, 2H), 3.95 (s, 2H), 3.89 (s, 3H), 3.77 (3.84) (s, 3H), 3.68 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;13.6, 6.1, 2.9 Hz, 1H), 3.41 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;13.7, 11.3, 4.5 Hz, 1H), 2.97 (ddt, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;17.2, 11.9, 6.0 Hz, 1H), 2.84\u0026ndash;2.73 (m, 1H). \u003csup\u003e13\u003c/sup\u003eC NMR (150 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 166.62, 162.90 (d, \u003csup\u003e1\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 246.7 Hz), 160.43, 148.64 (148.98), 148.04 (147.82), 144.33 (144.28), 139.26 (d, \u003csup\u003e2\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 37.6 Hz), 134.86, 130.03 (130.52), 126.11, 125.74, 124.38 (123.21), 120.91 (q, \u003csup\u003e1\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 269.5 Hz), 116.74, 115.83 (115.68), 114.91 (114.77), 111.26 (111.74), 111.11 (110.79), 56.11, 56.05, 55.13, 41.95, 39.86, 38.82, 28.26. HRMS (ESI) calcd for C\u003csub\u003e25\u003c/sub\u003eH\u003csub\u003e25\u003c/sub\u003eF\u003csub\u003e4\u003c/sub\u003eN\u003csub\u003e4\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e་\u003c/sup\u003e 521.1812, found 521.1836.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eN-(2-(1-(3-Fluorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-2-methyl-4-(trifluoromethyl)thiazole-5-carboxamide (A12)\u003c/strong\u003e \u003cp\u003ewhite solid, yield 92%, mp 116\u0026ndash;118\u003csup\u003eo\u003c/sup\u003eC; \u003csup\u003e1\u003c/sup\u003eH NMR (600 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 7.50 (s, 1H), 7.29\u0026ndash;7.23 (m, 1H), 7.05\u0026ndash;6.98 (m, 1H), 6.97 (dq, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.3, 4.9, 3.8 Hz, 1H), 6.91 (dq, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;10.0, 2.3 Hz, 1H), 6.78 (6.62) (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.7 Hz, 1H), 6.69 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.1 Hz, 1H), 6.51 (5.82) (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.6 Hz, 1H), 4.29 (4.53\u0026ndash;4.42) (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.0, 2.0 Hz, 2H), 3.90 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.1 Hz, 3H), 3.78 (3.85) (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.6 Hz, 3H), 3.74\u0026ndash;3.63 (m, 1H), 3.43 (dddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;13.7, 11.4, 4.5, 2.1 Hz, 1H), 3.04\u0026ndash;2.93 (m, 1H), 2.89\u0026ndash;2.77 (m, 1H). \u003csup\u003e13\u003c/sup\u003eC NMR (150 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 168.17, 165.71, 162.86 (d, \u003csup\u003e1\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 246.8 Hz), 158.64, 148.64 (149), 148.04 (147.83), 144.17 (144.13), 141.19 (140.05), 134.59, 130.07 (130.02), 125.96, 125.59, 124.37, 123.04\u0026ndash;117.21 (m), 115.80 (115.65), 114.94 (114.80), 111.22 (111.71), 110.06 (110.75), 56.07, 56.01, 55.17, 42.47, 38.79, 28.22, 19.28. HRMS (ESI) calcd for C\u003csub\u003e25\u003c/sub\u003eH24F\u003csub\u003e4\u003c/sub\u003eN3O\u003csub\u003e4\u003c/sub\u003eS [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e་\u003c/sup\u003e 538.1424, found 538.1426.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eN-(2-(1-(4-Fluorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)thiophene-2-carboxamide (A13)\u003c/strong\u003e \u003cp\u003ewhite solid, yield 91%, mp 144\u0026ndash;146\u003csup\u003eo\u003c/sup\u003eC; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 7.61 (td, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.0, 2.1 Hz, 1H), 7.50 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.0, 1.1 Hz, 1H), 7.33\u0026ndash;7.28 (m, 2H), 7.27\u0026ndash;7.21 (m, 1H), 7.10 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.0, 3.7 Hz, 1H), 7.07\u0026ndash;7.03 (m, 1H), 6.99 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.3, 3.5, 1.5 Hz, 2H), 6.97\u0026ndash;6.92 (m, 1H), 6.80 (5.90) (s, 1H), 6.69 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.8 Hz, 1H), 6.52 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;12.1 Hz, 1H), 4.32\u0026ndash;4.30 (m, 2H), 3.91 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.4 Hz, 3H), 3.78 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.0 Hz, 3H), 3.75 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.1 Hz, 1H), 3.51\u0026ndash;3.36 (m, 1H), 2.98 (dtd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;17.4, 11.4, 4.6 Hz, 1H), 2.86\u0026ndash;2.77 (m, 1H). \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 166.63 (166.46), 162.82 (d, \u003csup\u003e1\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e = 246.8 Hz), 161.79, 148.55 (148.45), 147.95, 144.30 (144.23), 138.38, 130.45 (130.37), 130.24, 130.01 (129.93), 128.48, 127.69, 126.06, 125.64 (125.99), 124.28 (128.25), 115.77 (115.56), 115.42 (115.20), 114.87 (114.66), 111.19, 111.04, 56.03, 55.96, 55.12, 41.85, 38.76, 28.28. HRMS (ESI) calcd for C\u003csub\u003e25\u003c/sub\u003eH\u003csub\u003e24\u003c/sub\u003eF\u003csub\u003e4\u003c/sub\u003eN\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003eS [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e་\u003c/sup\u003e 4545.1441, found 455.1456.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003e3-(Difluoromethyl)-N-(2-(1-(4-fluorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-1-methyl-1H-pyrazole-4-carboxamide (A14)\u003c/strong\u003e \u003cp\u003ewhite solid, yield 94%, mp 165\u0026ndash;166\u003csup\u003eo\u003c/sup\u003eC; \u003csup\u003e1\u003c/sup\u003eH NMR (600 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 7.93 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.6 Hz, 1H), 7.55 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16.4 Hz, 1H), 7.28\u0026ndash;7.13 (m, 1H), 7.02 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.7, 3.1 Hz, 1H), 6.97 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.6, 2.4 Hz, 1H), 6.93 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9.8, 4.5, 2.5 Hz, 1H), 6.80 (5.87) (s, 1H), 6.68 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.8 Hz, 1H), 6.50 (6.62\u0026ndash;6.57) (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;18.9 Hz, 1H), 4.39\u0026ndash;4.23 (m, 2H), 3.93 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.9 Hz, 3H), 3.90 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.0 Hz, 3H), 3.77 (3.84) (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9.3 Hz, 3H), 3.70 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;13.9, 6.0, 2.9 Hz, 1H), 3.42 (dddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;20.6, 16.2, 11.6, 4.4 Hz, 1H), 3.03\u0026ndash;2.90 (m, 1H), 2.80 (dt, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16.4, 3.6 Hz, 1H). \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 166.84 (166.62), 162.81 (d, \u003csup\u003e1\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 246.6 Hz), 161.30, 148.68, 148.06, 144.35 (144.29), 133.62, 130.38 (130.30), 129.82 (129.91), 126.15, 125.84, 124.18, 116.19, 115.67 (115.46), 115.30 (115.09),114.73 (114.52), 111.41, 111.30, 109.55 (d, \u003csup\u003e1\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 234.9 Hz), 56.05, 55.97, 55.09, 41.65, 39.44, 38.85, 28.16, 26.89. HRMS (ESI) calcd for C\u003csub\u003e25\u003c/sub\u003eH\u003csub\u003e26\u003c/sub\u003eF\u003csub\u003e3\u003c/sub\u003eN\u003csub\u003e4\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e་\u003c/sup\u003e 503.1906, found 5003.1933.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eN-(2-(1-(4-Fluorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide (A15)\u003c/strong\u003e \u003cp\u003ewhite solid, yield 93%, mp 135\u0026ndash;137\u003csup\u003eo\u003c/sup\u003eC; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 7.99\u0026ndash;7.96 (m, 1H), 7.37 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.3 Hz, 1H), 7.36\u0026ndash;7.12 (m, 2H), 7.07\u0026ndash;7.02 (m, 1H), 7.02\u0026ndash;6.97 (m, 1H), 6.97\u0026ndash;6.91 (m, 1H), 6.82 (5.85) (s, 1H), 6.69 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.9 Hz, 1H), 6.51 (6.59) (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;12.5 Hz, 1H), 4.28 (4.48) (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.5, 3.9 Hz, 2H), 3.98 (s, 3H), 3.91 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.6 Hz, 3H), 3.78 (3.85) (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.2 Hz, 3H), 3.70 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;13.9, 5.9, 3.2 Hz, 1H), 3.49\u0026ndash;3.35 (m, 1H), 2.99 (ddt, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;17.0, 11.6, 5.8 Hz, 1H), 2.81 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16.2, 4.4, 2.8 Hz, 1H). \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 166.42, 162.79 (d, \u003csup\u003e1\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 240.38 Hz), 160.32, 148.56, 147.95, 144.24 (144.17), 134.81, 130.40, 129.98 (129.90), 126.00, 125.65, 124.30, 116.71, 115.78 (115.56), 115.38 (115.17), 114.85 (114.64), 111.18, 111.04, 56.02, 55.96, 55.03, 41.91, 39.78, 38.71, 28.17. HRMS (ESI) calcd for C\u003csub\u003e25\u003c/sub\u003eH\u003csub\u003e25\u003c/sub\u003eF\u003csub\u003e4\u003c/sub\u003eN\u003csub\u003e4\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e་\u003c/sup\u003e 521.1812, found 521.1826.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eN-(2-(1-(4-Fluorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-2-methyl-4-(trifluoromethyl)thiazole-5-carboxamide (A16)\u003c/strong\u003e \u003cp\u003ewhite solid, yield 88%, mp 144\u0026ndash;146\u003csup\u003eo\u003c/sup\u003eC; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 7.49 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.7, 4.2 Hz, 1H), 7.36\u0026ndash;7.11 (m, 1H), 7.06\u0026ndash;7.01 (m, 1H), 7.01\u0026ndash;6.94 (m, 1H), 6.92 (dt, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9.9, 2.1 Hz, 1H), 6.79 (5.82) (s, 1H), 6.69 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.8 Hz, 1H), 6.50 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;12.7 Hz, 1H), 4.53\u0026ndash;4.25 (m, 2H), 3.90 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.5 Hz, 3H), 3.77 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.3 Hz, 2H), 3.72\u0026ndash;3.62 (m, 1H), 3.43 (dddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;14.1, 11.2, 9.5, 4.5 Hz, 1H), 2.97 (tdd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16.8, 10.2, 5.8 Hz, 1H), 2.86\u0026ndash;2.77 (m, 1H), 2.77 (s, 3H). \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 168.11, 165.63, 162.81 (d, \u003csup\u003e1\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 246.9 Hz), 158.57, 148.59, 147.99, 144.12 (144.05), 141.02 (d, \u003csup\u003e2\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 36.8 Hz), 130.49 (130.41), 130.02 (129.94), 138.17\u0026ndash;117.92 (m), 125.88, 125.53, 124.31 (124.28), 115.78 (115.56), 115.42 (115.21), 114.92(114.71), 111.16, 111.00, 56.01, 55.95, 55.11, 42.41, 38.72, 28.16, 19.22. HRMS (ESI) calcd for C\u003csub\u003e25\u003c/sub\u003eH\u003csub\u003e24\u003c/sub\u003eF\u003csub\u003e4\u003c/sub\u003eN\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003eS [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e་\u003c/sup\u003e 538.1424, found 538.1443.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eN-(2-(1-(2-Chlorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)thiophene-2-carboxamide (A17)\u003c/strong\u003e \u003cp\u003ewhite solid, yield 91%, mp 112\u0026ndash;114\u003csup\u003eo\u003c/sup\u003eC; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 7.55 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.7 Hz, 1H), 7.43 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.5 Hz, 1H), 7.40 (s, 1H), 7.35\u0026ndash;7.30 (m, 1H), 7.21 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.4 Hz, 1H), 7.13 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.5 Hz, 1H), 7.05\u0026ndash;7.00 (m, 1H), 6.94 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.8 Hz, 1H), 6.92 (6.18) (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.7 Hz, 1H), 6.66 (s, 1H), 6.54 (s, 1H), 4.62\u0026ndash;4.18 (m, 2H), 3.86 (s, 3H), 3.73 (3.75) (s, 3H), 3.80\u0026ndash;3.64 (m, 1H), 3.54 (dt, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;14.0, 7.0 Hz, 1H), 3.03 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;17.1, 11.4, 5.8 Hz, 1H), 2.90\u0026ndash;2.83 (m, 1H). \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 166.93, 161.78, 148.56, 148.14, 139.53, 138.54, 134.13, 130.80, 130.06, 128.97, 128.39, 127.57, 127.06, 126.66, 125.91, 111.83 (111.53), 110.89 (111.53), 55.95, 54.00, 41.90, 39.42, 28.45. HRMS (ESI) calcd for C\u003csub\u003e24\u003c/sub\u003eH\u003csub\u003e24\u003c/sub\u003eClN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003eS [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e་\u003c/sup\u003e 471.1145, found 471.1156.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eN-(2-(1-(2-Chlorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide (A18)\u003c/strong\u003e \u003cp\u003ewhite solid, yield 92%, mp 116\u0026ndash;118\u003csup\u003eo\u003c/sup\u003eC; \u003csup\u003e1\u003c/sup\u003eH NMR (600 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 7.87 (s, 1H), 7.61\u0026ndash;7.58 (7.45) (m, 1H), 7.39 (7.44) (dd, J\u0026thinsp;=\u0026thinsp;7.9, 1.4 Hz, 1H), 7.27\u0026ndash;7.18 (m, 1H), 7.18\u0026ndash;7.08 (m, 1H), 7.09\u0026ndash;6.97 (m, 1H), 6.92 (6.53) (s, 1H), 6.90 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.9, 1.6 Hz, 1H), 6.67 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.7 Hz, 1H), 6.50 (6.16) (s, 1H), 4.25 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;99.6, 17.3, 4.4 Hz, 1H), 3.88 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.4 Hz, 3H), 3.85 (s, 2H), 3.74 (s, 1H), 3.73 (3.77) (s, 3H), 3.51 (3.19\u0026ndash;3.14) (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;14.0, 11.5, 4.4 Hz, 1H), 3.04 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;17.0, 11.4, 5.8 Hz, 1H), 2.93\u0026ndash;2.65 (m, 1H). \u003csup\u003e13\u003c/sup\u003eC NMR (150 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 167.19 (168.39), 161.49 (161.09), 148.45 (148.72), 148.01 (147.84), 144.86 (t, \u003csup\u003e2\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 25.6 Hz), 139.38 (138.56), 134.14 (133.61), 132.82, 130.97, 130.04 (130.26), 129.01 (129.56), 126.63, 126.49 (127.09), 125.83 (125.70), 115.99, 111.29, 111.95\u0026ndash;108.44 (m), 110.65, 55.92 (56.28), 53.88, 41.45 (42.03), 39.50, 39.30 (37.48), 28.41, 26.90 (27.15). HRMS (ESI) calcd for C\u003csub\u003e25\u003c/sub\u003eH\u003csub\u003e26\u003c/sub\u003eClF\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e4\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e་\u003c/sup\u003e 519.1611, found 519.1642.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eN-(2-(1-(2-Chlorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide (A19)\u003c/strong\u003e \u003cp\u003ewhite solid, yield 91%, mp 118\u0026ndash;120\u003csup\u003eo\u003c/sup\u003eC; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 7.92 (s, 1H), 7.49\u0026ndash;7.38 (m, 2H), 7.22 (td, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.9, 1.9 Hz, 1H), 7.13 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.6 Hz, 1H), 6.94 (6.53) (s, 1H), 6.90 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.8, 1.7 Hz, 1H), 6.68 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.5 Hz, 1H), 6.52 (6.15) (s, 1H), 4.38\u0026ndash;4.16 (4.59\u0026ndash;4.40) (m, 2H), 3.96\u0026ndash;3.89 (m, 3H), 3.88 (s, 3H), 3.74 (3.78) (s, 3H), 3.73\u0026ndash;3.70 (m, 1H), 3.51 (3.20\u0026ndash;3.15) (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;14.1, 11.6, 4.5 Hz, 1H), 3.05 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;17.2, 11.6, 5.8 Hz, 1H), 2.93\u0026ndash;2.66 (m, 1H). \u003csup\u003e13\u003c/sup\u003eC NMR (150 MHz, Chloroform-\u003cem\u003ed\u003c/em\u003e) \u003cem\u003eδ\u003c/em\u003e 166.84 (168.16), 160.40 (160.08), 148.51 (148.78), 148.05 (147.88), 139.26, 140.09\u0026ndash;138.31 (m), 134.21 (134.84), 134.10 (133.62), 131.04, 130.08 (130.28), 129.04 (129.58), 126.59 (127.07), 125.81 (126.49), 123.89\u0026ndash;117.55 (m), 116.54, 111.32 (111.67), 110.73 (110.27), 55.93, 53.87, 41.73 (42.23), 39.68, 39.19 (37.44), 28.38, 27.12. HRMS (ESI) calcd for C\u003csub\u003e25\u003c/sub\u003eH\u003csub\u003e25\u003c/sub\u003eClF\u003csub\u003e3\u003c/sub\u003eN\u003csub\u003e4\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e་\u003c/sup\u003e 537.9442, found 537.9453.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eN-(2-(1-(2-Chlorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-2-methyl-4-(trifluoromethyl)thiazole-5-carboxamide (A20)\u003c/strong\u003e \u003cp\u003ewhite solid, yield 93%, mp 108\u0026ndash;120\u003csup\u003eo\u003c/sup\u003eC; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 7.40 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.3 Hz, 1H), 7.36 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.9 Hz, 0H), 7.24\u0026ndash;7.12 (m, 1H), 7.08 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.6 Hz, 1H), 6.88 (6.50) (s, 1H), 6.85 (s, 1H), 6.63 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.4 Hz, 1H), 6.48 (6.09) (s, 1H), 4.25 (4.60\u0026ndash;4.30) (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.6 Hz, 2H), 3.82 (s, 3H), 3.70 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11.2 Hz, 3H), 3.67 (s, 1H), 3.53\u0026ndash;3.41 (m, 1H), 2.98 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;17.3, 11.5, 6.1 Hz, 1H), 2.87\u0026ndash;2.78 (m, 1H), 2.65 (s, 3H). \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 167.74, 167.37, 165.79, 158.56, 148.61, 148.14, 141.10 (d, \u003csup\u003e2\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 35.9 Hz), 139.15, 134.16 (134.25, 130.94, 130.09, 129.60, 129.05, 127.11, 126.58 (126.49), 125.78 (125.61), 120.15 (d, \u003csup\u003e1\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 272.4 Hz), 111.50 (111.82), 110.89 (110.43), 55.92, 53.95, 42.54 (42.69), 39.20 (37.11), 28.35 (27.11), 19.03. HRMS (ESI) calcd for C\u003csub\u003e25\u003c/sub\u003eH\u003csub\u003e24\u003c/sub\u003eClF\u003csub\u003e3\u003c/sub\u003eN\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003eS [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e་\u003c/sup\u003e 554.1128, found 554.1141.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eN-(2-(1-(3-Chlorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)thiophene-2-carboxamide (A21)\u003c/strong\u003e \u003cp\u003ewhite solid, yield 90%, mp 128\u0026ndash;130\u003csup\u003eo\u003c/sup\u003eC; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 7.61 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.8, 1.3 Hz, 1H), 7.48 (tt, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.3, 1.3 Hz, 1H), 7.34 (p, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.9 Hz, 1H), 7.29\u0026ndash;7.19 (m, 3H), 7.17\u0026ndash;7.10 (m, 1H), 7.07 (dt, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.7, 3.6 Hz, 1H), 6.78 (s, 1H), 6.69 (6.63) (s, 1H), 6.51 (5.89) (s, 1H), 4.31 (4.52\u0026ndash;4.48) (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.0 Hz, 2H), 3.90 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.1 Hz, 3H), 3.78 (3.85) (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.9 Hz, 3H), 3.73 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;14.2, 5.9, 2.9 Hz, 1H), 3.49\u0026ndash;3.37 (m, 1H), 2.99 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16.9, 11.4, 5.8 Hz, 1H), 2.81 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16.3, 4.5, 2.6 Hz, 1H). \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 166.77, 161.84, 148.63, 148.05, 143.86, 138.47, 134.53, 130.27, 129.79, 128.77, 128.53, 128.08, 127.74, 126.91, 126.17, 125.58, 111.30, 111.09, 56.10, 56.01, 55.18, 38.80, 28.30. HRMS (ESI) calcd for C\u003csub\u003e24\u003c/sub\u003eH\u003csub\u003e24\u003c/sub\u003eClN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003eS [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e་\u003c/sup\u003e 471.1145, found 471.1164.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eN-(2-(1-(3-Chlorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide (A22)\u003c/strong\u003e \u003cp\u003ewhite solid, yield 92%, mp 136\u0026ndash;138\u003csup\u003eo\u003c/sup\u003eC; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 7.90 (s, 1H), 7.55 (dt, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.8, 2.3 Hz, 1H), 7.25\u0026ndash;7.22 (m, 1H), 7.20 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.1 Hz, 1H), 7.19 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.1 Hz, 1H), 7.09 (dq, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.1, 2.1 Hz, 1H), 7.00 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;54.2 Hz, 1H), 6.75 (6.58) (s, 1H), 6.66 (s, 1H), 6.47 (5.84) (s, 1H), 4.33\u0026ndash;4.23 (4.46\u0026ndash;4.42) (m, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 3.74 (3.82) (s, 3H), 3.68 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;13.9, 6.0, 2.8 Hz, 1H), 3.40 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;13.8, 11.3, 4.4 Hz, 1H), 2.95 (ddt, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16.5, 11.0, 5.5 Hz, 1H), 2.77 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16.1, 4.3, 2.8 Hz, 1H). \u003csup\u003e13\u003c/sup\u003eC NMR (150 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 166.88, 161.33, 148.57, 147.97, 144.53\u0026ndash;144.00 (m), 143.79, 134.41, 133.62, 129.70, 128.69, 127.97, 126.84, 126.10, 125.56, 116.09, 111.24, 111.03, 110.68 (t, \u003csup\u003e1\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 234.7 Hz), 56.03, 55.95, 55.05, 41.62, 39.51, 38.77, 28.17, 26.90. HRMS (ESI) calcd for C\u003csub\u003e25\u003c/sub\u003eH\u003csub\u003e26\u003c/sub\u003eClF\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e་\u003c/sup\u003e 519.9358, found 519.9367.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eN-(2-(1-(3-Chlorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide (A23)\u003c/strong\u003e \u003cp\u003ewhite solid, yield 91%, mp 110\u0026ndash;112\u003csup\u003eo\u003c/sup\u003eC; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 7.94 (s, 1H), 7.35 (s, 1H), 7.25\u0026ndash;7.21 (m, 2H), 7.19 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.1 Hz, 1H), 6.78 (6.58) (s, 1H), 6.67 (s, 1H), 6.48 (5.81) (s, 1H), 4.27 (4.48\u0026ndash;4.44) (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.9 Hz, 2H), 3.89 (s, 3H), 3.76 (3.84) (s, 3H), 3.67 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;13.9, 6.0, 2.8 Hz, 1H), 3.40 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;13.9, 11.4, 4.4 Hz, 1H), 2.97 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.5 Hz, 1H), 2.79 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16.2, 4.5, 2.7 Hz, 1H). \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 166.54, 160.44, 148.69, 148.10, 143.84, 139.43, 134.94, 134.59, 129.86, 128.87, 128.17, 127.03, 126.13, 125.61, 122.28, 116.83, 111.31, 111.10, 56.16, 56.08, 55.14, 42.03, 39.91, 38.77, 28.30. HRMS (ESI) calcd for C\u003csub\u003e25\u003c/sub\u003eH\u003csub\u003e25\u003c/sub\u003eClF\u003csub\u003e3\u003c/sub\u003eN\u003csub\u003e4\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e་\u003c/sup\u003e 537.1516, found 537.1542.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eN-(2-(1-(3-Chlorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-2-methyl-4-(trifluoromethyl)thiazole-5-carboxamide (A24)\u003c/strong\u003e \u003cp\u003ewhite solid, yield 86%, mp 125\u0026ndash;127\u003csup\u003eo\u003c/sup\u003eC; \u003csup\u003e1\u003c/sup\u003eH NMR (600 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 7.48 (s, 1H), 7.27 (7.31\u0026ndash;7.30) (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.8 Hz, 1H), 7.25 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.6 Hz, 1H), 7.21 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.8 Hz, 1H), 7.14 (dt, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.3, 1.7 Hz, 1H), 6.79 (6.60) (s, 1H), 6.70 (s, 1H), 6.50 (5.80) (s, 1H), 4.30 (4.51\u0026ndash;1.47) (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.8 Hz, 2H), 3.92 (s, 3H), 3.79 (3.87) (s, 3H), 3.67 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;13.9, 6.1, 2.8 Hz, 1H), 3.44 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;13.8, 11.5, 4.4 Hz, 1H), 3.05\u0026ndash;2.99 (m, 1H), 2.83 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16.3, 4.4, 2.7 Hz, 1H), 2.76 (s, 3H). \u003csup\u003e13\u003c/sup\u003eC NMR (150 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 168.12, 165.62, 158.57, 148.61, 148.03, 143.59, 141.05 (d, \u003csup\u003e2\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 36.8 Hz), 134.51, 129.77, 128.75, 128.12, 126.92, 125.87, 125.37, 120.17 (d, \u003csup\u003e1\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 272.0 Hz), 111.17, 110.95, 56.03, 55.96, 55.11, 42.43, 38.66, 28.18 (26.92), 19.24. HRMS (ESI) calcd for C\u003csub\u003e25\u003c/sub\u003eH\u003csub\u003e24\u003c/sub\u003eClF\u003csub\u003e3\u003c/sub\u003eN\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003eS [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e་\u003c/sup\u003e 554.1128, found 554.1139.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eN-(2-(1-(4-Chlorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)thiophene-2-carboxamide (A25)\u003c/strong\u003e \u003cp\u003ewhite solid, yield 87%, mp 123\u0026ndash;125\u003csup\u003eo\u003c/sup\u003eC; \u003csup\u003e1\u003c/sup\u003eH NMR (600 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 7.61 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.8, 1.2 Hz, 1H), 7.49 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.0, 1.2 Hz, 1H), 7.32\u0026ndash;7.30 (m, 1H), 7.27\u0026ndash;7.25 (m, 2H), 7.21\u0026ndash;7.16 (7.13\u0026ndash;7.12) (m, 2H), 7.08 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.0, 3.7 Hz, 1H), 6.78 (6.60) (s, 1H), 6.69 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.8 Hz, 1H), 6.49 (5.89) (s, 1H), 4.34\u0026ndash;4.25 (4.51\u0026ndash;4.50) (m, 2H), 3.90 (s, 3H), 3.77 (3.84) (s, 3H), 3.72 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;13.9, 5.8, 2.6 Hz, 1H), 3.41 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;13.8, 11.5, 4.4 Hz, 1H), 3.02\u0026ndash;2.96 (m, 1H), 2.80 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16.2, 4.2, 2.6 Hz, 1H). \u003csup\u003e13\u003c/sup\u003eC NMR (150 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 166.66, 161.82, 148.52, 147.99, 140.35, 138.44, 133.75, 130.30, 130.12, 129.03 (128.89), 128.67, 128.52, 127.75, 126.11, 125.80, 111.20, 110.99, 56.05, 56.00, 55.00, 41.90 (42.15), 38.67 (37.64), 28.34 (27.12). HRMS (ESI) calcd for C\u003csub\u003e24\u003c/sub\u003eH\u003csub\u003e24\u003c/sub\u003eClN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003eS [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e་\u003c/sup\u003e 471.1145, found 471.1167.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eN-(2-(1-(4-Chlorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide (A26)\u003c/strong\u003e \u003cp\u003ewhite solid, yield 88%, mp 117\u0026ndash;119\u003csup\u003eo\u003c/sup\u003eC; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 7.90 (s, 1H), 7.50 (tt, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.2, 2.1 Hz, 1H), 7.28\u0026ndash;7.22 (m, 1H), 7.21 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.1 Hz, 1H), 7.12 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.9 Hz, 1H), 7.11\u0026ndash;6.81 (m, 1H), 6.75 (s, 1H), 6.65 (s, 1H), 6.45 (s, 1H), 4.39\u0026ndash;4.16 (m, 2H), 3.89 (s, 3H), 3.86 (s, 3H), 3.73 (s, 3H), 3.71\u0026ndash;3.62 (m, 1H), 3.37 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;13.8, 11.4, 4.4 Hz, 1H), 3.06\u0026ndash;2.86 (m, 1H), 2.76 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16.2, 4.3, 2.6 Hz, 1H). \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 166.66, 161.26, 148.48, 147.94, 144.13 (t, \u003csup\u003e2\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 27.1 Hz), 140.30, 133.78, 133.64, 130.05, 128.97 (128.91), 128.56, 126.04, 125.81, 116.12, 111.17, 110.87 (110.68), 113.56\u0026ndash;108.20 (m), 110.68, 55.99, 55.94, 54.86, 41.70 (42.03), 39.52, 38.63 (37.52), 28.22 (27.05). HRMS (ESI) calcd for C\u003csub\u003e25\u003c/sub\u003eH\u003csub\u003e26\u003c/sub\u003eClF\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e4\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e་\u003c/sup\u003e 519.1611, found 519.1633.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eN-(2-(1-(4-Chlorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide (A27)\u003c/strong\u003e \u003cp\u003ewhite solid, yield 93%, mp 114\u0026ndash;116\u003csup\u003eo\u003c/sup\u003eC; \u003csup\u003e1\u003c/sup\u003eH NMR (600 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 7.96 (7.53) (s, 1H), 7.37 (s, 1H), 7.32\u0026ndash;7.24 (m, 2H), 7.21\u0026ndash;7.05 (m, 2H), 6.79 (6.57) (s, 1H), 6.69 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.9 Hz, 1H), 6.48 (5.84) (s, 1H), 4.27 (4.53\u0026ndash;4.42) (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.0, 2.2 Hz, 2H), 3.97 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.4 Hz, 4H), 3.90 (s, 3H), 3.77 (s, 3H), 3.68 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;13.8, 6.0, 2.7 Hz, 1H), 3.40 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;13.8, 11.5, 4.4 Hz, 1H), 2.99 (ddt, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;19.1, 13.1, 7.0 Hz, 1H), 2.80 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16.2, 4.3, 2.6 Hz, 1H). \u003csup\u003e13\u003c/sup\u003eC NMR (150 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 166.42, 160.31, 148.49, 147.95, 140.23,139.10 (q, \u003csup\u003e2\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 37.7 Hz), 134.79, 133.69, 130.71, 130.07, 128.97 (128.95), 128.59, 125.99, 125.75, 120.82 (d, \u003csup\u003e1\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 269.3 Hz), 116.64, 111.14, 110.92, 55.99, 55.94, 54.86, 41.87, 39.76, 38.57, 28.22. HRMS (ESI) calcd for C\u003csub\u003e25\u003c/sub\u003eH\u003csub\u003e25\u003c/sub\u003eClF\u003csub\u003e3\u003c/sub\u003eN\u003csub\u003e4\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e་\u003c/sup\u003e 537.1516, found 537.1528.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eN-(2-(1-(4-Chlorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-2-methyl-4-(trifluoromethyl)thiazole-5-carboxamide (A28)\u003c/strong\u003e \u003cp\u003ewhite solid, yield 85%, mp 129\u0026ndash;131\u003csup\u003eo\u003c/sup\u003eC; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 7.47\u0026ndash;7.43 (m, 1H), 7.33\u0026ndash;7.22 (m, 2H), 7.17 (s, 1H), 7.16\u0026ndash;7.06 (m, 1H), 6.76 (6.55) (s, 1H), 6.67 (s, 1H), 6.46 (5.78) (s, 1H), 4.26 (4.50\u0026ndash;4.43) (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.9 Hz, 2H), 3.88 (s, 3H), 3.75 (3.82) (s, 3H), 3.72\u0026ndash;3.60 (m, 1H), 3.39 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;13.8, 11.6, 4.4 Hz, 1H), 2.98 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16.8, 11.4, 5.7 Hz, 1H), 2.79 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16.2, 4.4, 2.6 Hz, 1H), 2.74 (s, 3H). \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 168.25, 165.66, 158.67, 148.66, 148.14, 141.12 (d, \u003csup\u003e2\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 36.9 Hz), 140.21, 134.69, 133.92, 130.21, 129.14, 129.03, 128.76, 125.95, 125.75, 120.28 (d, \u003csup\u003e1\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 272.1 Hz), 111.25, 111.04, 56.11, 56.06, 55.06, 42.54, 38.66, 28.34, 19.34. HRMS (ESI) calcd for C\u003csub\u003e25\u003c/sub\u003eH\u003csub\u003e24\u003c/sub\u003eClF\u003csub\u003e3\u003c/sub\u003eN\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003eS [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e་\u003c/sup\u003e 554.1128 found 554.1154.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eN-(2-(1-(2,4-Dichlorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)thiophene-2-carboxamide (A29)\u003c/strong\u003e \u003cp\u003ewhite solid, yield 92%, mp 111\u0026ndash;113\u003csup\u003eo\u003c/sup\u003eC; \u003csup\u003e1\u003c/sup\u003eH NMR (600 MHz, DMSO-\u003cem\u003ed\u003c/em\u003e\u003csub\u003e6\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 8.69 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.9 Hz, 1H), 7.82\u0026ndash;7.79 (m, 1H), 7.77\u0026ndash;7.72 (m, 1H), 7.62 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.2 Hz, 1H), 7.33 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.4, 2.2 Hz, 1H), 7.17\u0026ndash;7.13 (m, 1H), 6.97 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.4 Hz, 1H), 6.85 (s, 1H), 6.68 (s, 1H), 6.63 (s, 1H), 4.32 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16.9, 6.2 Hz, 1H), 4.12 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16.8, 5.6 Hz, 1H), 3.90 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11.3, 7.0 Hz, 1H), 3.76 (s, 3H), 3.60 (s, 2H), 3.41 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;14.4, 10.7, 4.5 Hz, 1H), 2.98 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16.4, 10.6, 5.7 Hz, 1H), 2.86 (dt, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16.6, 4.0 Hz, 1H). \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, DMSO-\u003cem\u003ed\u003c/em\u003e\u003csub\u003e6\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 168.30, 161.81, 148.59, 147.94, 140.06, 139.99, 134.46, 133.11, 132.31, 131.35, 129.48, 128.83, 128.41, 127.64, 127.22, 126.56, 112.48, 111.25, 56.01, 55.95, 53.27, 41.40, 28.35. HRMS (ESI) calcd for C\u003csub\u003e24\u003c/sub\u003eH\u003csub\u003e23\u003c/sub\u003eCl\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003eS [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e་\u003c/sup\u003e 505.0756, found 505.0783.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eN-(2-(1-(2,4-Dichlorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide (A30)\u003c/strong\u003e \u003cp\u003ewhite solid, yield 89%, mp 133\u0026ndash;135\u003csup\u003eo\u003c/sup\u003eC; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 7.85 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.5 Hz, 1H), 7.45 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.1 Hz, 1H), 7.41 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.1 Hz, 1H), 7.11 (ddd, \u003csup\u003e1\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e = 17.2, 8.4, 2.2 Hz, 1H), 7.02 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;54.2 Hz, 1H), 6.86 (6.65) (s, 1H), 6.80 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.4 Hz, 1H), 6.65 (6.46) (s, 1H), 6.45 (6.07) (s, 1H), 4.36\u0026ndash;4.12 (4.57) (m, 2H), 3.87 (s, 3H), 3.86 (s, 3H), 3.76 (s, 1H), 3.73 (s, 3H), 3.02 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;17.0, 7.7, 4.0 Hz, 1H), 2.84 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16.3, 4.5, 2.3 Hz, 1H). \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 167.23, 161.41, 148.72, 148.24, 144.68, 138.24, 134.87, 134.19, 132.98, 131.71, 129.81, 126.91, 126.08, 125.86, 116.06, 111.54, 110.69, 110.35, 55.97, 55.95, 53.49, 41.55, 39.42, 28.38, 26.89. HRMS (ESI) calcd for C\u003csub\u003e25\u003c/sub\u003eH\u003csub\u003e25\u003c/sub\u003eCl\u003csub\u003e2\u003c/sub\u003eF\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e4\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e་\u003c/sup\u003e 553.1221, found 553.1243.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eN-(2-(1-(2,4-Dichlorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide (A31)\u003c/strong\u003e \u003cp\u003ewhite solid, yield 93%, mp 120\u0026ndash;122\u003csup\u003eo\u003c/sup\u003eC; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 7.92 (s, 1H), 7.46 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;19.5, 2.1 Hz, 1H), 7.38 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.2 Hz, 1H), 7.14 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16.4, 8.4, 2.2 Hz, 1H), 6.89 (6.08) (s, 1H), 6.83 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.5 Hz, 1H), 6.68 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.3 Hz, 1H), 6.48 (s, 1H), 4.46\u0026ndash;4.17 (m, 2H), 3.94 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9.8 Hz, 4H), 3.89 (s, 3H), 3.75 (3.79) (s, 3H), 3.74\u0026ndash;3.71 (m, 1H), 3.46 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;14.1, 11.6, 4.5 Hz, 1H), 3.05 (ddt, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;17.4, 11.5, 6.7 Hz, 1H), 2.86 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16.4, 4.5, 2.2 Hz, 1H). \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 167.01, 160.39, 148.74, 148.25, 138.14, 134.89, 134.24, 134.12, 131.76, 129.84, 126.90, 126.05, 125.83, 120.75 (d, \u003csup\u003e1\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 269.6 Hz), 116.54, 111.54, 110.70, 55.97, 55.95, 53.48, 41.74, 39.61, 39.31, 28.36, 26.89. HRMS (ESI) calcd for C\u003csub\u003e25\u003c/sub\u003eH\u003csub\u003e24\u003c/sub\u003eCl\u003csub\u003e2\u003c/sub\u003eF\u003csub\u003e3\u003c/sub\u003eN\u003csub\u003e4\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e་\u003c/sup\u003e 571.1127, found 571.1141.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eN-(2-(1-(2,4-Dichlorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-2-methyl-4-(trifluoromethyl)thiazole-5-carboxamide (A32)\u003c/strong\u003e \u003cp\u003ewhite solid, yield 88%, mp 115\u0026ndash;117\u003csup\u003eo\u003c/sup\u003eC; \u003csup\u003e1\u003c/sup\u003eH NMR (600 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u003cem\u003eδ\u003c/em\u003e 7.48 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;27.3 Hz, 1H), 7.41 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;21.8 Hz, 1H), 7.16 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;23.2, 8.5 Hz, 1H), 6.91 (6.69) (s, 1H), 6.83 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.3 Hz, 1H), 6.68 (s, 1H), 6.48 (6.06) (s, 1H), 4.32 (4.70\u0026ndash;4.37) (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.9 Hz, 2H), 3.90 (s, 3H), 3.76 (3.80) (s, 3H), 3.75\u0026ndash;3.69 (m, 1H), 3.47 (td, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;14.4, 13.1, 4.5 Hz, 1H), 3.13\u0026ndash;3.00 (m, 1H), 2.90\u0026ndash;2.85 (m, 1H), 2.75 (s, 3H). \u003csup\u003e13\u003c/sup\u003eC NMR (150 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 167.96, 165.77, 158.63, 148.68, 148.18, 137.70, 134.99, 134.44, 134.24, 131.95 (132.07), 129.97 (130.11), 127.43, 126.90, 125.85, 125.60, 120.12 (d, \u003csup\u003e1\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eCF\u003c/sub\u003e = 270.8 Hz), 111.33 (111.74), 110.49 (109.98), 55.95, 53.46, 42.46 (42.75), 39.10 (37.35), 28.32 (26.91), 19.22. HRMS (ESI) calcd for C\u003csub\u003e25\u003c/sub\u003eH\u003csub\u003e23\u003c/sub\u003eCl\u003csub\u003e2\u003c/sub\u003eF\u003csub\u003e3\u003c/sub\u003eN\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003eS [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e་\u003c/sup\u003e 588.0738, found 588.0743.\u003c/p\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eX-ray Diffraction\u003c/h2\u003e \u003cp\u003eCompound \u003cb\u003eA5\u003c/b\u003e was recrystallized by slow evaporation from a solution of tetrahydrofuran to afford a single crystal suitable for X-ray crystallography for structure validation. A crystal structure was performed on a Rigaku XtaLAB P200 diffractometer. The crystal was kept at 138.15 K during data collection. Using Olex2 [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], the structure was solved with the SHELXT [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] structure solution program using Intrinsic Phasing and refined with the SHELXL [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] refinement package using Least Squares minimisation. Optimization of thermal ellipsoid diagram of crystal by ORTEP-3 [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. The crystallographic data of \u003cb\u003eA5\u003c/b\u003e can be download from the CCDC and the Supporting Information.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eAntifungal activity assay\u003c/h2\u003e \u003cp\u003eThe in vitro activity of the target compounds \u003cb\u003eA1-32\u003c/b\u003e against \u003cem\u003eRhizotonia cerealis\u003c/em\u003e, \u003cem\u003ePhysalospora piricola\u003c/em\u003e, \u003cem\u003eFusarium graminearum\u003c/em\u003e, \u003cem\u003eColletotrichum lagenarium Botrytis Cinerea\u003c/em\u003e and \u003cem\u003eAlternaria alternata\u003c/em\u003e were tested at 50 mg/L by mycelial growth rate method [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Chlorothalonil and boscalid were used as positive controls. The \u003cem\u003ein vivo\u003c/em\u003e fungicidal activity against \u003cem\u003eAlternaria alternata\u003c/em\u003e was evaluated at 50 mg/L and 100 mg/L on fragrant Pear. Boscalid as positive controls.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eCalculation of molecular properties and drug-likeness evaluation\u003c/h2\u003e \u003cp\u003eMolinspiration was used to calculate the main physical and chemical properties of the target compounds, such as the relative molecular weight, LogP (octanol/water partition coefficient), number of hydrogen bond donors and acceptors, and number of rotatable bonds [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. ADMET lap was used to calculate the drug-likeness of the target compounds [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eMolecular electrostatic potential analysis\u003c/h2\u003e \u003cp\u003eCompound \u003cb\u003eA13\u003c/b\u003e were selected for the molecular electrostatic potential analysis by density functional theory (DFT) method via Gaussian 09. The optimization of molecular conformation were carried out by the B3LYP method at 6-31G(d,p) level, and electrostatic potential calculation was based on the optimized structure [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eMolecular docking\u003c/h2\u003e \u003cp\u003eMolecular docking simulation was performed by the CDOCKER module on AutoDock Vina1.1.2. The structures of the chose molecular was optimized and manually docked into the active site in porcine heart mitochondrial SDH from the RCSB Protein Data Bank (PDB ID: 2FBW). The crystal structure of SDH, compound \u003cb\u003eA13\u003c/b\u003e and positive control boscalid were treated according to standard procedures. The molecular docking results were analyzed and displayed by PyMol 2.5 [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eSEM Analysis\u003c/h2\u003e \u003cp\u003eMycelial morphology were made using scanning electron microscopy (SEM) technology according to previously reported methods [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. The \u003cem\u003eA. alternata\u003c/em\u003e mycelial cakes were cut from a PDA medium containing compound \u003cb\u003eA13\u003c/b\u003e (including 0.1% DMSO) at a 25 mg/L concentration. The mycelial cakes containing the same amount of DMSO were used as blank controls. Following the treatment according to the literature procedure, the mycelial morphology was observed under the scanning electron microscope.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003ch2\u003eSupporting Information\u003c/h2\u003e \u003cp\u003eThe supporting information for this article is available at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.orgxxxxx\u003c/span\u003e\u003cspan address=\"https://doi.orgxxxxx\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eThe authors declare that they have no confict of interest.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eW. Chen, and Y. Chen conceived and designed the study; Y. Chen, Y.X. Jin, L.Y. Wang, W.X. Wang and H.P. Zhou performed the experiments, analyzed the data for all compounds; W. Chen and Y. Chen co-wrote the paper.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e \u003cp\u003eThis work was supported by Natural Science Foundation of Sichuan (Nos. 2021YJ0481, 24NSFSC2305) and Fundamental Research Funds for the Central Universities (No. 2682023ZTPY077). We would like to thank Analysis and Testing Center of Southwest Jiaotong University for structural identification and SEM test.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGhorbanpour M, Omidvari M, Abbaszadeh-Dahaji et al (2018) Mechanisms underlying the protective effects of beneficial fungi against plant diseases. Biological Control, 117, 147-157. https://doi.org/10.1016/j.biocontrol.2017.11.006\u003c/li\u003e\n\u003cli\u003eUmetsu N, Shirai Y (2020) Development of novel pesticides in the 21st century. J. Pestic. 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Journal of Agricultural and Food Chemistry, 68(40): 11068-11076. https://doi.org/10.1021/acs.jafc.9b06937\u003c/li\u003e\n\u003cli\u003eZhao Y, Zhang A, Wang X, et al (2022) Novel pyrazole carboxamide containing a diarylamine scaffold potentially targeting fungal succinate dehydrogenase: antifungal activity and mechanism of action. Journal of Agricultural and Food Chemistry, 70(42): 13464-13472. https://doi.org/10.1021/acs.jafc.2c00748\u003c/li\u003e\n\u003cli\u003eLuo, X., Chen, Y., Wang, Y, et al (2024) Design, synthesis and antifungal activity of novel amide derivatives containing a pyrrolidine moiety as potential succinate dehydrogenase inhibitors. Molecular diversity, 28, 805\u0026ndash;816. https://doi.org/10.1007/s11030-023-10622-w\u003c/li\u003e\n\u003cli\u003eCheng X, Xu Z, Cui H, et al (2023) Discovery of Pyrazole-5-yl-amide Derivatives Containing Cinnamamide Structural Fragments as Potential Succinate Dehydrogenase Inhibitors. Journal of Agricultural and Food Chemistry, 71(45): 16962-16971. https://doi.org/10.1021/acs.jafc.3c04355\u003c/li\u003e\n\u003cli\u003eZhang Y H, Yang S S, Zhang Q, et al (2023) Discovery of N-phenylpropiolamide as a novel succinate dehydrogenase inhibitor scaffold with broad-spectrum antifungal activity on phytopathogenic fungi. Journal of Agricultural and Food Chemistry, 71(8): 3681-3693. https://doi.org/10.1021/acs.jafc.2c07712\u003c/li\u003e\n\u003cli\u003eLuo B, Zhao Y, Zhang J, et al (2023) Design, synthesis, and antifungal activities of novel pyrazole-4-carboxamide derivatives containing an ether group as potential succinate dehydrogenase inhibitors. Journal of Agricultural and Food Chemistry, 71(24): 9255-9265. https://doi.org/10.1021/acs.jafc.3c00116\u003c/li\u003e\n\u003cli\u003ePatel H A, Patel A (2014) PatelSynthesis and Characterization of N-Substituted Tetrahydroiso-quinoline Derivatives via a Pictet-Spengler Condensation. Journal of Applied Solution Chemistry and Modeling, 3(3): 169. http://dx.doi.org/10.6000/1929-5030.2014.03.03.5\u003c/li\u003e\n\u003cli\u003eWang W, Song L, Wang G, et al (2013) Synthesis and Evaluation of the Antischistosomal Activity against S. japonicum of 1-Methyl-1, 2, 3, 4-tetrahydroisoquinoline Derivatives. Chinese Journal of Organic Chemistry, 33(12): 2588. http://dx.doi.org/10.6023/cjoc201308017\u003c/li\u003e\n\u003cli\u003eChen W, Zhang R, Chen Y, et al (2023) Design, synthesis and mechanism study of novel natural-derived isoquinoline derivatives as antifungal agents. Molecular diversity, 27(3): 1011-1022. https://doi.org/10.1007/s11030-022-10463-z\u003c/li\u003e\n\u003cli\u003eChen W, Lan Y X, Jin Y X, et al (2023) Design， synthesis and antifungal activity of novel spiro-tetrahydroquinoline derivatives. Chemical Journal of Chinese Universities, 44(10): 20230179. https://doi.org/10.7503/cjcu20230179\u003c/li\u003e\n\u003cli\u003eDolomanov O V, Bourhis L J, Gildea R J, et al (2009) OLEX2: a complete structure solution, refinement and analysis program. Journal of applied crystallography, 42(2): 339-341. https://doi.org/10.1107/S0021889808042726\u003c/li\u003e\n\u003cli\u003eSheldrick G M (2015) SHELXT\u0026ndash;Integrated space-group and crystal-structure determination. Acta Crystallographica Section A: Foundations and Advances, 71(1): 3-8. https://doi.org/10.1107/S2053273314026370\u003c/li\u003e\n\u003cli\u003eSheldrick G M (2015) Crystal structure refinement with SHELXL. Acta Crystallographica Section C: Structural Chemistry, 71(1): 3-8. https://doi.org/10.1107/S2053229614024218\u003c/li\u003e\n\u003cli\u003eFarrugia L J (2012) WinGX and ORTEP for Windows: an update. Journal of Applied Crystallography, 45(4): 849-854. https://doi.org/10.1107/S0021889812029111\u003c/li\u003e\n\u003cli\u003eZhou B, Li H, Cui Z, Li D, Geng H, Gao J Zhou L (2020) Simple Analogues of Natural Product Chelerythrine: Discovery of A Novel Anticholinesterase 2-Phenylisoquinolin-2-ium Scaffold with Excellent Potency Against Acetylcholinesterase. Eur J Med Chem 200:112415. https://doi.org/10.1016/j.ejmech.2020.112415\u003c/li\u003e\n\u003cli\u003eChen W, Zuo HL, Li YX, Liu J, Zhou XL Design, Synthesis and Structure-Activity Relationships of Plant-Based 2-Aryl-3,4-dihydroisoquinolin-2-iums as Potential Antifungal Agents. Chin J Org Chem 39:2317-2322. https://doi.org/10.6023/cjoc201905020\u003c/li\u003e\n\u003cli\u003eAyar A, Aksahin M, Mesci S, et al (2022) Antioxidant, cytotoxic activity and pharmacokinetic studies by swiss adme, molinspiration, osiris and DFT of PhTAD-substituted dihydropyrrole derivatives. Current Computer-aided Drug Design, 18(1): 52-63. https://doi.org/10.2174/1573409917666210223105722\u003c/li\u003e\n\u003cli\u003eDong J, Wang N N, Yao Z J, et al (2018) ADMETlab: a platform for systematic ADMET evaluation based on a comprehensively collected ADMET database. Journal of cheminformatics, 10: 1-11. https://doi.org/10.1186/s13321-018-0283-x\u003c/li\u003e\n\u003cli\u003eSun C, Zhang S, Qian P, Li Y, Ren W, Deng H Jiang L (2021) Synthesis and fungicidal activity of novel benzimidazole derivatives bearing pyrimidine-thioether moiety against Botrytis cinerea. Pest Manag Sci 77:5529-5536. https://doi.org/10.1002/ps.6593\u003c/li\u003e\n\u003cli\u003eHua X, Liu W, Chen Y et al (2021) Synthesis, Fungicidal Activity, and Mechanism of Action of Pyrazole Amide and Ester Derivatives Based on Natural Products l-Serine and Waltherione Alkaloids. J Agric Food Chem 69:11470-11484. https://doi.org/10.1021/acs.jafc.1c01346\u003c/li\u003e\n\u003cli\u003eWang W, Zhang S, Wang J, et al (2020) Bioactivity-guided synthesis accelerates the discovery of 3-(iso) quinolinyl-4-chromenones as potent fungicide candidates. Journal of Agricultural and Food Chemistry, 69(1): 491-500. https://doi.org/10.1021/acs.jafc.0c06700\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":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"molecular-diversity","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"modi","sideBox":"Learn more about [Molecular Diversity](http://link.springer.com/journal/11030)","snPcode":"11030","submissionUrl":"https://submission.nature.com/new-submission/11030/3","title":"Molecular Diversity","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"1-Arylisoquinoline, Biomimetic design, Antifungal activity, Antifungal mechanism","lastPublishedDoi":"10.21203/rs.3.rs-4470733/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4470733/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"In screening for natural-based fungicides, a series of 32 novel 1-arylisoquinoline derivatives were designed, synthesized, and evaluated for their antifungal activities. Their structures were verified by 1H NMR, 13C NMR, HRMS and single X-ray crystal diffraction analysis. Most of the target products exhibited medium to excellent antifungal activity against 6 phytopathogenic fungi in vitro at a concentration of 50 mg/L. Interestingly, compounds A13 and A25 with EC50 values of 2.375, 2.251 mg/L s against A. alternate, that were similar to boscalid (EC50 = 1.195 mg/L). The in vivo experiments revealed that A13 presented 51.61% and 70.97% protection activities against A. alternate at the dosage of 50 and 100 mg/L, respectively, which were equal to that of boscalid (64.52% and 77.42%). The SEM analysis indicated that compound A13 could strongly damage the mycelium morphology. Molecular electrostatic potential and molecular docking analysis revealed that A13 was covered by negative potential contour, and strongly interacts with the residues of SDH. These results revealed that compounds A13 and A25 could be as promising antifungal candidates for the development of natural-based fungicides.","manuscriptTitle":"Design, synthesis, and mechanism study of novel 1-arylisoquinoline derivatives as antifungal agents","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-11 20:08:40","doi":"10.21203/rs.3.rs-4470733/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-09-05T04:05:02+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-09-04T12:22:09+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-26T16:05:18+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-24T14:23:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"161916192441168825782516601395661105769","date":"2024-08-24T12:42:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"169895726912045689406958350970057473172","date":"2024-08-24T10:03:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"64240181407595940724691188959988840988","date":"2024-08-22T05:11:24+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-13T02:38:29+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"35562427077939707840915179755867259342","date":"2024-08-13T01:39:36+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-06-04T00:38:16+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-05-25T19:30:45+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-05-25T08:32:59+00:00","index":"","fulltext":""},{"type":"submitted","content":"Molecular Diversity","date":"2024-05-24T07:30:24+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"molecular-diversity","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"modi","sideBox":"Learn more about [Molecular Diversity](http://link.springer.com/journal/11030)","snPcode":"11030","submissionUrl":"https://submission.nature.com/new-submission/11030/3","title":"Molecular Diversity","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"dfd6ff06-94ba-4dd6-9804-45279c9a4e6d","owner":[],"postedDate":"June 11th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-10-14T16:03:12+00:00","versionOfRecord":{"articleIdentity":"rs-4470733","link":"https://doi.org/10.1007/s11030-024-11012-6","journal":{"identity":"molecular-diversity","isVorOnly":false,"title":"Molecular Diversity"},"publishedOn":"2024-10-11 15:57:59","publishedOnDateReadable":"October 11th, 2024"},"versionCreatedAt":"2024-06-11 20:08:40","video":"","vorDoi":"10.1007/s11030-024-11012-6","vorDoiUrl":"https://doi.org/10.1007/s11030-024-11012-6","workflowStages":[]},"version":"v1","identity":"rs-4470733","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4470733","identity":"rs-4470733","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}