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1 S1 SUPPRTIG IFRMATI Discovery of a Selective Aurora A Kinase Inhibitor by Virtual Screening Falco Kilchmann,a) Maria J. Marcaida,a)c) Sachin Kotak,b)d) Thomas Schick,a) Silvan D. Boss,a) Mahendra Awale,a) Pierre Gönczyb)* and Jean-Louis Reymonda)* a) Department of Chemistry and Biochemistry, University of Berne, Freiestrasse 3, 3012 Berne Switzerland; jean-louis.reymond@dcb.unibe.ch; b) Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology (EPFL), CH-1015 Lausanne, Switzerland; pierre.gonczy@epfl.ch c) Present address: Institute of Bioengineering, School of Life Sciences, Swiss Federal Institute of Technology (EPFL), CH-1015 Lausanne, Switzerland d) Present address: Department of Microbiology and Cell Biology (MCB), Indian Institute of Science (IISc), Bangalore, India Table of Contents: SUPPLEMETARY FIGURES AD TABLES... 2 ADDITIAL CHEMISTRY H-MR AD C-MR SPECTRA F FIAL CMPUDS AD SELECTED ITERMEDIATES... 12
2 S2 Supplementary Figures and Tables Supplementary Figure 1. Structures of the 16 kinase inhibitors used as references for xls virtual screening.
3 S3 H H Me S Me Me H H Cl Cl H H H t Bu H1 (5) H2 (7) H3 H4 IC 50 = 6.5 ± 0.8 µm C 50 = 2.0 ± 0.3 µm IC 50 = 5.9 ± 1.3 µm IC 50 = 7.2 ± 1.2 µm Me S Cl H Cl H Cl H H H t Bu H Me H H Cl H t Bu H5 IC 50 = 7.5 ± 2.3 µm H6 IC 50 = 12.9 ± 1.0 µm H7 IC 50 = 12 ± 3 µm H8 IC 50 = 13.2 ± 2.2 µm H H H Me H Me H H S H H Cl Cl S H H S H9 H10 H11 H12 IC 50 = 17 ± 4 µm IC 50 = 23 ± 5 µm IC 50 = 31 ± 9 µm 59 ± 8 % inhib. at 10 µm Me 2 S H H H Me Me F 3 C H Cl H13 53 ± 3 % inhib. at 10 µm H14 52 ± 14 % inhib. at 10 µm H15 52 ± 23 % inhib. at 10 µm Supplementary Figure 2. Structure of the 1 st round screening hits. The activity against Aurora A in the biochemical HTRF assay is indicated, see methods for assay details.
4 S4 Me S H H S Me H H H Me H16 (8) H17 H18 IC 50 = 0.39 ± 0.04 µm IC 50 = 7.2 ± 1.2 µm IC 50 = 7.5 ± 2.3 µm H H H Me S Me Me S Br H Br Me H19 H20 H21 IC 50 = 12.9 ± 1.0 µm IC 50 = 13.2 ± 2.2 µm IC 50 = 17 ± 4 µm H H H H H H Cl H H Me H22 IC 50 = 23 ± 5 µm H23 59 ± 8 % inhib. at 10 µm H24 53 ± 3 % inhib. at 10 µm Supplementary Figure 3. Structure of the 2 nd round screening hits. The activity against Aurora A in the biochemical HTRF assay is indicated, see methods for assay details. Supplementary Figure 4. X-ray crystal structures of phenylimino-thiazolidinones 76 (CCDC ) and 78 (CCDC ) shown as RTEP plots with 50 % probability levels, arbitrary numbering. The configurations of the exocyclic C= as well as the exocyclic C=C double bonds are (Z) for both molecules. Molecule 78 showed severe disorders at the cyclohexyl and the ethyl moieties and was modelled in several orientations (only one orientation is shown for clarity). CCDC nnnnnnn contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via
5 S5 Supplementary Table 1. Crystallographic data collection and refinement statistics Data collection Space group P P P P Cell dimensions a, b, c (Å) 82.88, 82.88, , 83.52, , 83.27, , 82.38, α, β, γ ( ) 90, 90, , 90, , 90, , 90, 120 Resolution (Å)* ( ) ( ) ( ) ( ) R merge * 7.6 (60) 6.2 (69.4) 6.0 (77.1) 7.7 (63.3) I / σi* 18.5 (3.5) 25.6 (3.7) 20.2 (2.7) 13.1 (2.0) Completeness (%)* (100) 99.6 (98.1) 99.9 (100.0) 99.3 (99.1) Redundancy* 8.8 (8.3) 9 (9) 8.2 (8.4) 4.2 (4.4) Refinement Resolution (Å) o. reflections R work / R free 20.2/ / / /24.9 o. atoms Protein Ligand (77) 8 (MPD) (88) 8 (MPD) Water B-factors Protein Ligand Water R.m.s deviations Bond lengths (Å) Bond angles ( ) PDB accession code 4ZS0 4ZTQ 4ZTR 4ZTS *Values for the highest resolution shell are shown in parenthesis. ne crystal was used per data set.
6 S6 Supplementary Figure 5. Intrinsic tryptophan fluorescence intensity change upon complex formation. In Aurora A, the DFG motif is followed by W277. Crystallographic studies show that binding of compounds 7, 9, and 88 (blue curves) changes the conformation of this region of the activation loop. This structural change affects the environment of W277 resulting in a change of its intrinsic fluorescence when the complex is formed. The graphs show the change in this intrinsic tryptophan fluorescence intensity as a function of ligand concentration, which saturates when all the protein is bound. This indicates that the DFG motif rearrangement also occurs in solution. n the other hand, 6 binding (red curve) does not create any fluorescence change as expected from its type I inhibitor-like binding mode. Methods: Binding experiments were performed by mixing Aurora A (500 nm, 375 nm, and 150 nm for 77, 6 and 9, and 88, respectively) with varying concentrations (0-100 µm) of the different compounds in buffer (final DMS concentration 1 %), followed by incubation for 15 min at room temperature. Tryptophan fluorescence spectra were recorded at room temperature using an Infinite M1000 Pro plate reader (Tecan) and Corning 96 well half area, flat bottom, non-binding surface, black polystyrene plates. Excitation occurred at 284 nm (bandwidth ± 5 nm) and emission at 340 nm (bandwidth ± 10 nm). The gain was calculated from the well with the highest protein concentration. Each measurement was done in triplicate. Supplementary Figure 6. Aurora A adopts an inactive conformation upon binding to the phenyliminothiazolidinone compounds. Top: schematic representation of each structure. Bottom: Conformations of DFG motif (pink), HRD motif (yellow), Lys162 and Glu181 (blue), Gln185 (cyan) and αc-helix (blue cylinder). (a) Aurora A bound to TPX2 and ADP (PDB code 1L5). (b) Aurora-A bound to 77. (c) Aurora-A bound to 9. (d) Aurora A bound to 88.
7 S7 Supplementary Table 2. Purity of final compounds. Compound HPLC method * Retention Time [min] Purity [%] 1 a (6-H) b a c a (4 -CH 3 ) b (5 -CH 3 ) b (5 -Br) b (5 -CF 3 ) b (5,6 -Cl) b (4-H) b (5-Cl) b (5-H) b (6-Cl) b (7-H) b (5-CH) b (6-CH) b (5-CHCH 3 ) b (6-CHCH 3 ) b (-CH 3 left) b (-CH 3 right) b a a a a a a a a a a a a a a a a c c a a a c a (±)-89 a (±)-90 a (±)-91 a (±)-92 a * method a: From A/D (7:3) to 100 % D (2.2 min) followed by 100 % D (1 min); detection at 254 nm; method b: From 100 % A to 100 % D (2.2 min) followed by 100 % D (1 min); detection at 254 nm; method c: From A/D (7:3) to 100 % D (2.2 min) followed by 100 % D (1 min); detection at 310 nm.
8 S8 Additional Chemistry Tert-butyl (2-aminophenyl)carbamate (95). A solution of 1,2-diaminobenzene (300 mg, 27.8 mmol) in EtH (28 ml) at 0 C was treated with guanidine hydrochloride (400 mg, 4.19 mmol) and Boc 2 (6.68 g, 30.6 mmol). The ice-cold solution was stirred for 30 min and then allowed to warm to room temperature. After stirring for 2.5 h, EtH was removed in vacuo. Flash chromatography (Si 2 ; 3:1 hexane/etac) gave the title compound (4.15 g, 72 %) as a white solid. m.p C; 1 H MR (DMS-d 6, 300 MHz): δ 8.26 (s, 1H), 7.17 (d, J = 7.4 Hz, 1H), 6.81 (m, 1H), 6.67 (dd, J = 8.0, 1.5 Hz, 1H), 6.51 (td, J = 7.7, 1.5 Hz, 1H), 4.80 (s, 2H), 1.45 (s, 9H); 13 C MR (DMS-d 6, 75 MHz): δ , , , , , , , 78.60, 28.16; HR-ESI-MS (m/z): calculated for [M + H] + C 11 H , found Tert-butyl 2-amino-5-chlorophenylcarbamate (96). A solution of ah (0.563 g, 23.3 mmol) in DMF (11.5 ml) at 0 C was slowly treated with a solution of 5-chloro-2-nitroaniline (1.00 g, 5.81 mmol) in DMF (11.5 ml) and stirred for 10 min, and then at room temperature for 30 min. A solution of Boc 2 (1.39 g, 6.39 mmol) in DMF (1.5 ml) was added to the red reaction mixture, which was then stirred at room temperature for 15 h. The reaction mixture was poured into ice-cold H 2 (100 ml) and extracted with EtAc (3 x 50 ml). The combined organic phases were dried over MgS 4 and concentrated to give a yellow solid. Purification by flash chromatography (Si 2 ; 0-10 % EtAc/hexane) gave tert-butyl 5-chloro-2-nitrophenylcarbamate (1.28 g, 4.69 mmol, 81 %) as a yellow solid. m.p C; 1 H MR (DMS-d 6, 300 MHz): δ 9.74 (s, 1H), 8.04 (d, J = 8.9 Hz, 1H), 7.85 (d, J = 2.3 Hz, 1H), 7.37 (dd, J = 8.9, 2.3 Hz, 1H), 1.47 (s, 9H); 13 C MR (DMS-d 6, 75 MHz): δ , , , , , , , 81.15, 27.81; HR- ESI-MS (m/z): calculated for [M + H] + C 11 H Cl , found This intermediate (1.00 g, 3.68 mmol) in dioxane/h 2 (5:1, 31 ml) was treated with a 2 S 2 4 (2.56 g, 14.7 mmol) and ahc 3 (3.10 g, 36.8 mmol) and refluxed at 100 C for 40 min. After addition of H 2 (70 ml), the reaction mixture was extracted with EtAc (3 x 50 ml) and the combined organic phases were dried over MgS 4 and concentrated to give 96 as brownish solid (900 mg, 3.70 mmol, 99 %). 1 H MR (DMS-d 6, 300 MHz): δ 8.36 (s, 1H), 7.22 (d, J = 8.5 Hz, 1H), 6.75 (d, J = 2.3 Hz, 1H), 6.57 (dd, J = 8.5, 1.7 Hz, 1H), 5.41 (s, 2H), 1.45 (s, 9H); 13 C MR (DMS-d 6, 75 MHz): δ , , , , , , , 79.02, 28.10; HR-ESI-MS (m/z): calculated for [M + H] + C 11 H Cl , found Tert-butyl 2-amino-4-chlorophenylcarbamate (97). Following the procedure above, conversion of 4-chloro-2-nitroaniline (1.50 g, 8.72 mmol) gave tert-butyl 4-chloro-2-nitrophenylcarbamate as yellow solid (1.23 g, 4.51 mmol, 52 %) after purification by flash chromatography (Si 2 ; 0-10 %
9 S9 EtAc/hexane). m.p C; 1 H MR (DMS-d 6, 300 MHz): δ 9.74 (s, 1H), 8.04 (d, J = 8.9 Hz, 1H), 7.85 (d, J = 2.3 Hz, 1H), 7.37 (dd, J = 8.9, 2.3 Hz, 1H), 1.47 (s, 9H); 13 C MR (DMS-d 6, 75 MHz): δ , , , , , , , 81.15, 27.81; HR-ESI-MS (m/z): calculated for [M + H] + C 11 H Cl , found This intermediate (1.00 g, 3.68 mmol) in dioxane/h 2 (5:1, 31 ml) was treated with a 2 S 2 4 (2.56 g, 14.7 mmol) and ahc 3 (3.10 g, 36.8 mmol) and refluxed at 100 C for 40 min. After addition of H 2 (70 ml), the reaction mixture was extracted with EtAc (3 x 50 ml) and the combined organic phases were dried over MgS 4 and concentrated to give 97 (0.900 g, 99 %) as a brownish solid. m.p C; 1 H MR (DMS-d 6, 300 MHz): δ 8.36 (s, 1H), 7.22 (d, J = 8.5 Hz, 1H), 6.75 (d, J = 2.3 Hz, 1H), 6.57 (dd, J = 8.5, 1.7 Hz, 1H), 5.41 (s, 2H), 1.45 (s, 9H); 13 C MR (DMS-d 6, 75 MHz): δ , , , , , , , 79.02, 28.10; HR- ESI-MS (m/z): calculated for [M + H] + C 11 H Cl , found Tert-butyldimethylsiloxy-1,2-diaminobenzene (98). A solution of 2-hydroxy-6-nitro-aniline (3.00 g, 19.5 mmol) in DMF (6 ml) was treated with imidazole (3.32 g, 48.7 mmol) and TBSCl (3.52 g, 23.4 mmol) and stirred at room temperature for 1.5 h. After addition of H 2 (80 ml), the reaction mixture was extracted with EtAc (3 x 40 ml) and the combined organic phases were dried over MgS 4 and concentrated to give 3-tert-butyldimethylsiloxy-2-amino-nitrobenzene (3.36 g, 12.5 mmol, 64 %) as an orange solid. m.p C; 1 H MR (DMS-d 6, 300 MHz): δ 7.63 (dd, J = 8.9, 1.2 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), (m, 3H), 0.98 (s, 9H), 0.27 (s, 6H); 13 C MR (DMS-d 6, 75 MHz): δ , , , , , , 25.66, 18.04, ; HR-ESI-MS (m/z): calculated for [M + H] + C 12 H Si , found This intermediate (4.50 g, 16.8 mmol) in dioxane/h 2 (5:1, 84 ml) was treated with a 2 S 2 4 (11.7 g, 67.1 mmol) and ahc 3 (14.1 g, 167 mmol) and refluxed at 100 C for 1 h. After addition of H 2 (60 ml), the reaction mixture was extracted with EtAc (3 x 50 ml) and the combined organic phases were dried over MgS 4 and concentrated to give a crude product. Purification by flash chromatography (Si 2 ; % EtAc/hexane) gave 98 (1.18 g, 4.96 mmol, 30 %) as a dark brown solid. m.p C; 1 H MR (DMS-d 6, 300 MHz): δ 6.35 (d, J = 8.2 Hz, 1H), 6.10 (d, J = 2.6 Hz, 1H), 5.87 (dd, J = 8.2, 2.7 Hz, 1H), 4.44 (s, 2H), 4.00 (s, 2H), 0.92 (s, 9H), 0.10 (s, 6H); 13 C MR (DMS-d 6, 75 MHz): δ , , , , , , 25.64, 17.84, -4.49; HR-ESI-MS (m/z): calculated for [M + H] + C 12 H 23 2 Si , found Tert-butyldimethylsiloxy-1,2-diaminobenzene (99). A solution of 4-hydroxy-2-nitro-aniline (3.00 g, 19.5 mmol) in DMF (6 ml) was treated with imidazole (3.32 g, 48.7 mmol) and TBSCl
10 S10 (3.52 g, 23.4 mmol) and stirred at room temperature for 18 h. After addition of H 2 (100 ml), the reaction mixture was extracted with EtAc (3 x 50 ml) and the combined organic phases were dried over MgS 4 and concentrated to give 4-tert-butyldimethylsiloxy-2-nitroaniline (5.21 g, 19.4 mmol, quant.) as a red solid. m.p C; 1 H MR (CDCl 3, 300 MHz): δ 7.56 (s, 1H), 6.97 (d, J = 4.5 Hz, 1H), 6.71 (m, 1H), 5.83 (s, 2H), 0.98 (s, 9H), (m, 6H); 13 C MR (CDCl 3, 75 MHz): δ , , , , , , 25.77, 18.28, -4.43; HR-ESI-MS (m/z): calculated for [M + H] + C 12 H Si , found A solution of this intermdiate (4.50 g, 16.8 mmol) in dioxane/h 2 (5:1, 84 ml) was treated with a 2 S 2 4 (11.7 g, 67.1 mmol) and ahc 3 (14.1 g, 168 mmol) and refluxed at 100 C for 1 h. After addition of H 2 (70 ml), the reaction mixture was extracted with EtAc (3 x 60 ml) and the combined organic phases were dried over MgS 4 and concentrated to give a crude product. Purification by flash chromatography (Si 2 ; % EtAc/hexane) gave 99 (630 mg, 2.65 mmol, 16 %) as a dark brown solid. m.p C; 1 H MR (DMS-d 6, 300 MHz): δ 6.34 (d, J = 8.2 Hz, 1H), 6.09 (d, J = 2.7 Hz, 1H), 5.87 (dd, J = 8.2, 2.7 Hz, 1H), 4.44 (s, 2H), 3.99 (s, 2H), 0.91 (s, 9H), 0.10 (s, 6H); 13 C MR (DMS-d 6, 75 MHz): δ , , , , , , 25.64, 17.84, -4.49; HR- ESI-MS (m/z): calculated for [M + H] + C 12 H 23 2 Si , found Tert-butyl 2-nitrophenylcarbamate (100). A solution of ah (1.91 g, 79.6 mmol) in THF (50 ml) at 0 C was slowly treated with a solution of 2-nitroaniline (5.00 g, 36.2 mmol) in THF (50 ml). The mixture was stirred for 10 min at 0 C, and then at room temperature for 30 min. A solution of Boc 2 (8.70 g, 39.8 mmol) in THF (10 ml) was added to the reaction mixture and stirred at room temperature for 1 h. Ice-cold H 2 (100 ml) was slowly added and the reaction mixture was extracted with EtAc (3 x 50 ml). The combined organic phases were dried over MgS 4 and concentrated to give 100 (8.62 g, 36.2 mmol, quant.) as a dark brown solid. m.p C; 1 H MR (DMS-d 6, 300 MHz): δ 9.60 (s, 1H), 7.95 (d, J = 8.1 Hz, 1H), (m, 2H), (m, 1H), 1.44 (s, 9H); 13 C MR (DMS-d 6, 75 MHz): δ , , , , , , , 80.43, 27.85; HR-ESI-MS (m/z): calculated for [M + H] + C 11 H , found Tert-butyl methyl 2-nitrophenylcarbamate (101). A solution of 100 (6.00 g, 25.2 mmol) in DMF (40 ml) at 0 C was treated with ah (0.665 mg, 27.7 mmol) and stirred for 30 min. MeI (1.2 ml, 27.7 mmol) was slowly added and the reaction mixture was allowed to warm to room temperature and stirred for 1.5 h. H 2 (30 ml) was slowly added and the reaction mixture was extracted with EtAc (3 x 40 ml). The combined organic phases were dried over MgS 4 and concentrated to give 101 (6.12 g, 24.3 mmol, 96 %) as an orange solid. m.p C; 1 H MR (DMS-d 6, 300 MHz): δ 7.97 (d, J = 7.4 Hz, 1H), 7.73 (td, J = 7.9, 1.5 Hz, 1H), 7.58 (dd, J = 7.9, 1.0 Hz, 1H), 7.52
11 S (m, 1H), 3.21 (s, 3H), 1.31 (d, J = 59.7 Hz, 9H); 13 C-MR (DMS-d 6, 75 MHz): δ , , , , , , , 80.39, 36.95, 27.22; HR-ESI-MS (m/z): calculated for [M + H] + C 12 H , found Methyl 2-((tert-butoxycarbonyl)amino)isonicotinate (102). A solution of methyl 2- (amino)isonicotinate (8.00 g, 52.6 mmol, 1.0 eq.) in tert-butanol (90 ml) was treated with di-tertbutyl dicarbonate (15.3 g, 70.0 mmol, 1.33 eq.). The solution was stirred overnight and then filtered. The filter residue was washed with tert-butanol (2 x 20 ml) and dried on HV to afford the product as off-white solid (11.6 g, 45.9 mmol, 87.2 %). m.p C. 1 H MR (300 MHz, CDCl 3 ) δ 8.96 (s, 1H), 8.48 (t, J = 1.1 Hz, 1H), 8.37 (dd, J = 5.3, 0.9 Hz, 1H), 7.46 (dd, J = 5.2, 1.4 Hz, 1H), 3.88 (s, 3H), 1.49 (s, 9H); 13 C MR (75 MHz, CDCl 3 ) δ , , , , , , , 81.52, 52.75, 28.34; HR-ESI-MS (m/z): , calcd for [M + a] + C 12 H a: Tert-Butyl(4-(hydroxymethyl)pyridin-2-yl)carbamate (103). A solution of 102 (10.0 g, 39.6 mmol, 1.0 eq.) and CaCl 2 (6.59 g, 59.4 mmol, 1.5 eq.) in EtH (130 ml) was treated with abh 4 (6.00 g, 159 mmol, 4.0 eq.) at 0 C. The solution was warmed to RT, stirred for 18 h, and filtered. The solid on the filter was washed with 2-butanone (2 x 75 ml). The filtrate was washed with brine (150 ml) and H 2 (150 ml), evaporated in vacuo, and dried on HV for one day to afford the product as white solid (8.00 g, 35.7 mmol, 90.1 %). 1 H MR (300 MHz, DMS-d 6 ) δ 9.69 (s, 1H), 8.16 (dd, J = 5.1, 0.8 Hz, 1H), 7.82 (t, J = 1.2 Hz, 1H), 6.96 (dd, J = 5.2, 1.4 Hz, 1H), 5.41 (t, J = 5.8 Hz, 1H), 4.52 (d, J = 5.7 Hz, 2H), 1.49 (s, 9H); 13 C MR (75 MHz, DMS-d 6 ) δ , , , , , , 79.45, 61.72, 28.01; HR-ESI-MS (m/z): , calcd for [M + H] + C 11 H : Tert-Butyl(4-formylpyridin-2-yl)carbamate (104). A solution of 103 (7.71 g, 34.4 mmol, 1.0 eq.), ahc 3 (3.47 g, 41.3 mmol, 1.2 eq.), abr (178 mg, 1.72 mmol, 0.05 eq.) in CH 2 Cl 2 (30 ml) at 0 C was treated with bleach (5.0 ml, 5.7 % aqueous solution) and TEMP (53 mg, 0.34 mmol, 0.01 eq.). After 75 min, the reaction was quenched by adding 100 ml sat. aq. a 2 S 2 4 and 100 ml CH 2 Cl 2. The organic layer was separated and washed with H 2 (3 x 50 ml), dried over MgS 4 2H 2, and evaporated in vacuo to afford the product as pale brown solid (5.68 g, 25.6 mmol, 75.0 %). 1 H MR (300 MHz, DMS-d 6 ) δ (s, 1H), (s, 1H), 8.52 (d, J = 4.9 Hz, 1H), 8.28 (s, 1H), 7.44 (dd, J = 5.0, 1.4 Hz, 1H), 1.51 (s, 9H); 13 C MR (75 MHz, DMS-d 6 ) δ , , , , , , , 80.02, 27.95; HR-ESI-MS (m/z): , calcd for [M+a] + C 11 H a:
12 S12 1H-MR and 13 C-MR spectra of final compounds and selected intermediates 1'H-[1,2'-bibenzo[d]imidazol]-2(3H)-one (5):
13 S13 1-(1H-Benzo[d]imidazol-2-yl)-5-hydroxy-1H-benzo[d]imidazol-2(3H)-one (6): 1 H-MR (DMS-d 6, 300 MHz) 13 C-MR (DMS-d 6, 75 MHz)
14 (2Z,5Z)-2-((3,4-dimethylphenyl)imino)-3-methyl-5-(pyridin-4-ylmethylene)thiazolidin-4- one (7): S14
15 (2Z,5Z)-2-((4-ethylphenyl)imino)-3-methyl-5-(pyridin-4-ylmethylene)thiazolidin-4-one (8) S15
16 S16 6-((4-((Z)-((Z)-2-((4-ethylphenyl)imino)-3-methyl-4-oxothiazolidin-5- ylidene)methyl)pyridin-2-yl)amino)nicotinic acid (9):
17 S17 1-(4-Methyl-1H-benzo[d]imidazol-2-yl)-1H-benzo[d]imidazol-2(3H)-one (33): 1 H-MR (DMS-d 6, 300 MHz) 13 C-MR (DMS-d 6, 75 MHz)
18 S18 1-(5-Methyl-1H-benzo[d]imidazol-2-yl)-1H-benzo[d]imidazol-2(3H)-one (34): 1 H-MR (DMS-d 6, 300 MHz) 13 C-MR (DMS-d 6, 75 MHz)
19 S19 1-(5-Bromo-1H-benzo[d]imidazol-2-yl)-1H-benzo[d]imidazol-2(3H)-one (35): 1 H-MR (DMS-d 6, 300 MHz) 13 C-MR (DMS-d 6, 75 MHz)
20 S20 1-(5-(Trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1H-benzo[d]imidazol-2(3H)-one (36): 1 H-MR (DMS-d 6, 300 MHz) 13 C-MR (DMS-d 6, 75 MHz)
21 S21 1-(5,6-Dichloro-1H-benzo[d]imidazol-2-yl)-1H-benzo[d]imidazol-2(3H)-one (37): 1 H-MR (DMS-d 6, 300 MHz) 13 C-MR (DMS-d 6, 75 MHz)
22 S22 1-(1H-Benzo[d]imidazol-2-yl)-7-hydroxy-1H-benzo[d]imidazol-2(3H)-one (38): 1 H-MR (DMS-d 6, 300 MHz) 13 C-MR (DMS-d 6, 101 MHz)
23 S23 1-(1H-Benzo[d]imidazol-2-yl)-6-chloro-1H-benzo[d]imidazol-2(3H)-one (39): 1 H-MR (DMS-d 6, 300 MHz) 13 C-MR (DMS-d 6, 75 MHz)
24 S24 1-(1H-Benzo[d]imidazol-2-yl)-6-hydroxy-1H-benzo[d]imidazol-2(3H)-one (40): 1 H-MR (DMS-d 6, 300 MHz) 13 C-MR (DMS-d 6, 101 MHz)
25 S25 1-(1H-Benzo[d]imidazol-2-yl)-5-chloro-1H-benzo[d]imidazol-2(3H)-one (41): 1 H-MR (DMS-d 6, 300 MHz) 13 C-MR (DMS-d 6, 75 MHz)
26 S26 1-(1H-Benzo[d]imidazol-2-yl)-4-hydroxy-1H-benzo[d]imidazol-2(3H)-one (42): 1 H-MR (DMS-d 6, 300 MHz) 13 C-MR (DMS-d 6, 101 MHz)
27 S27 3-(1H-Benzo[d]imidazol-2-yl)-2,3-dihydro-2-oxo-1H-benzo[d]imidazole-6-carboxylic acid (45): 1 H-MR (DMS-d 6, 300 MHz) 13 C-MR (DMS-d 6, 101 MHz)
28 S28 1-(1H-Benzo[d]imidazol-2-yl)-2,3-dihydro-2-oxo-1H-benzo[d]imidazole-5-carboxylic acid (46): 1 H-MR (DMS-d 6, 300 MHz) 13 C-MR (DMS-d 6, 101 MHz)
29 S29 3-(1H-Benzo[d]imidazol-2-yl)-2,3-dihydro--methyl-2-oxo-1H-benzo[d]imidazole-6- carboxamide (47): 1 H-MR (DMS-d 6, 300 MHz) 13 C-MR (DMS-d 6, 101 MHz)
30 S30 1-(1H-Benzo[d]imidazol-2-yl)-2,3-dihydro--methyl-2-oxo-1H-benzo[d]imidazole-5- carboxamide (48): 1 H-MR (DMS-d 6, 300 MHz) 13 C-MR (DMS-d 6, 101 MHz)
31 S31 1-(1-Methyl-1H-benzo[d]imidazol-2-yl)-1H-benzo[d]imidazol-2(3H)-one (51): 1 H-MR (DMS-d 6, 300 MHz) 13 C-MR (DMS-d 6, 75 MHz) H
32 S32 1-(1H-Benzo[d]imidazol-2-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one (53): 1 H-MR (DMS-d 6, 300 MHz) 13 C-MR (DMS-d 6, 75 MHz)
33 (Z)-2-((4-ethylphenyl)imino)-3-methylthiazolidin-4-one (54): S33
34 (Z)-2-((3-ethylphenyl)imino)-3-methylthiazolidin-4-one (55) S34
35 (Z)-2-((2-ethylphenyl)imino)-3-methylthiazolidin-4-one (56) S35
36 (Z)-3-methyl-2-((4-propylphenyl)imino)thiazolidin-4-one (57) S36
37 (Z)-2-((4-isopropylphenyl)imino)-3-methylthiazolidin-4-one (58) S37
38 (Z)-2-((4-butylphenyl)imino)-3-methylthiazolidin-4-one (59) S38
39 (Z)-2-((4-(tert-butyl)phenyl)imino)-3-methylthiazolidin-4-one (60) S39
40 (Z)-3-methyl-2-((4-(trifluoromethyl)phenyl)imino)thiazolidin-4-one (61) S40
41 (Z)-2-((4-bromophenyl)imino)-3-methylthiazolidin-4-one (62) S41
42 S42 (2Z,5Z)-2-((3-ethylphenyl)imino)-3-methyl-5-(pyridin-4-ylmethylene)thiazolidin-4-one (63)
43 S43 (2Z,5Z)-2-((2-ethylphenyl)imino)-3-methyl-5-(pyridin-4-ylmethylene)thiazolidin-4-one (64)
44 S44 (2Z,5Z)-3-methyl-2-((4-propylphenyl)imino)-5-(pyridin-4-ylmethylene)thiazolidin-4-one (65)
45 S45 (2Z,5Z)-2-((4-isopropylphenyl)imino)-3-methyl-5-(pyridin-4-ylmethylene)thiazolidin-4- one (66)
46 S46 (2Z,5Z)-2-((4-butylphenyl)imino)-3-methyl-5-(pyridin-4-ylmethylene)thiazolidin-4-one (67)
47 S47 (2Z,5Z)-2-((4-(tert-butyl)phenyl)imino)-3-methyl-5-(pyridin-4-ylmethylene)thiazolidin-4- one (68)
48 S48 (2Z,5Z)-3-methyl-5-(pyridin-4-ylmethylene)-2-((4-(trifluoromethyl)phenyl)imino) thiazolidin-4-one (69)
49 S49 (2Z,5Z)-2-((4-bromophenyl)imino)-3-methyl-5-(pyridin-4-ylmethylene)thiazolidin-4-one (70)
50 (Z)-2-((4-ethylphenyl)imino)-3-ethylthiazolidin-4-one (72) S50
51 (Z)-2-((4-ethylphenyl)imino)-3-(2-methoxyethyl)thiazolidin-4-one (73) S51
52 (Z)-3-(cyclohexylmethyl)-2-((4-ethylphenyl)imino)thiazolidin-4-one (74) S52
53 (2Z,5Z)-2-((4-ethylphenyl)imino)-5-(pyridin-4-ylmethylene)thiazolidin-4-one (75) S53
54 (2Z,5Z)-3-ethyl-2-((4-ethylphenyl)imino)-5-(pyridin-4-ylmethylene)thiazolidin-4-one (76) S54
55 S55 (2Z,5Z)-2-((4-ethylphenyl)imino)-3-(2-methoxyethyl)-5-(pyridin-4-ylmethylene) thiazolidin-4-one (77)
56 S56 (2Z,5Z)-3-(cyclohexylmethyl)-2-((4-ethylphenyl)imino)-5-(pyridin-4- ylmethylene)thiazolidin-4-one (78)
57 S57 (2Z,5Z)-5-((2-aminopyridin-4-yl)methylene)-2-((4-ethylphenyl)imino)-3- methylthiazolidin-4-one (79):
58 S58 3-amino--(4-((Z)-((Z)-2-((4-ethylphenyl)imino)-3-methyl-4-oxothiazolidin-5- ylidene)methyl)pyridin-2-yl)propanamide (TFA salt) (80)
59 S59 3-((4-((Z)-((Z)-2-((4-ethylphenyl)imino)-3-methyl-4-oxothiazolidin-5- ylidene)methyl)pyridin-2-yl)amino)-3-oxopropanoic acid (81)
60 S60 3-((4-((Z)-((Z)-2-((4-ethylphenyl)imino)-3-methyl-4-oxothiazolidin-5- ylidene)methyl)pyridin-2-yl)amino)-4-oxobutanoic acid (82)
61 S61 3-((4-((Z)-((Z)-2-((4-ethylphenyl)imino)-3-methyl-4-oxothiazolidin-5- ylidene)methyl)pyridin-2-yl)amino)-5-oxopentanoic acid (83)
62 S62 (2Z,5Z)-2-((4-ethylphenyl)imino)-3-methyl-5-((2-(phenylamino)pyridin-4- yl)methylene)thiazolidin-4-one (84)
63 S63 (2Z,5Z)-2-((4-ethylphenyl)imino)-3-methyl-5-((2-(pyridin-2-ylamino)pyridin-4- yl)methylene)thiazolidin-4-one (85):
64 S64 (2Z,5Z)-2-((4-ethylphenyl)imino)-5-((2-((4-(hydroxymethyl)phenyl)amino)pyridin-4- yl)methylene)-3-methylthiazolidin-4-one (86):
65 S65 4-((4-((Z)-((Z)-2-((4-ethylphenyl)imino)-3-methyl-4-oxothiazolidin-5- ylidene)methyl)pyridin-2-yl)amino)benzoic acid (87):
66 S66 (2Z,5Z)-5-((2-((4-(1H-tetrazol-5-yl)phenyl)amino)pyridin-4-yl)methylene)-2-((4- ethylphenyl)imino)-3-methylthiazolidin-4-one (88):
67 S67 (Z)- and (E)-1-(2-aminopyridin-4-yl)-5-((4-ethylphenyl)imino)-6-methyl-4-thia-6- azaspiro[2.4]heptan-7-one ((±)-89 and (±)-90)Major isomer:
68 Minor isomer: S68
69 S69 (±)-(Z)-5-((2-aminopyridin-4-yl)methyl)-2-((4-ethylphenyl)imino)-3-methylthiazolidin-4- one ((±)-91):
70 S70 (±)-(Z)-6-((4-((2-((4-ethylphenyl)imino)-3-methyl-4-oxothiazolidin-5-yl)methyl)pyridin- 2-yl)amino)nicotinic acid ((±)-92):
71 methyl 2-((tert-butoxycarbonyl)amino)isonicotinate (102) S71
72 tert-butyl (4-(hydroxymethyl)pyridin-2-yl)carbamate (103) S72
73 tert-butyl (4-formylpyridin-2-yl)carbamate (104) S73
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