PAGES GILLES (MC)
RONCO CYRIL (FR)
BENHIDA RACHID (FR)
INST NAT SANTE RECH MED (FR)
UNIV COTE D'AZUR (FR)
INST CURIE (FR)
WO2020079184A2 | 2020-04-23 | |||
WO2010024903A1 | 2010-03-04 | |||
WO2020079184A2 | 2020-04-23 |
US20120071475A1 | 2012-03-22 |
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J. PHARM. SCI., vol. 66, 1977, pages 2
"Handbook of Pharmaceutical Salts: Properties, Selection, and Use", 2002
CLAIMS 1. A compound, a pharmaceutically acceptable salt or a tautomer thereof, of formula (I): in which: → Y is -NH-, -S-, or -O-; → R1 is a radical selected in the group consisting of: • a hydrogen atom, • a (C1-C6)alkyloxy group, • a (C1-C6)alkyl group, • a nitro group, • a -NR3R4 group with R3 and R4 are independently a radical selected in the group consisting of: - a hydrogen atom, - a -COR5 with R5 is a (C1-C6)alkyl group, and - a -SO2R6 with R6 is a (C1-C6)alkyl group, • a halogen atom, and • a 3-14 membered ring selected in the group consisting of an aryl, a heteroaryl, a cycloalkyl, and a heterocycloalkyl, said 3-14 membered ring is optionally substituted by a radical selected in the group consisting of a (C1-C6)alkyl group, a (C1-C6)alkyloxy group, a halogen atom, a nitro group, and a carboxyl group; → R2 is a radical selected in the group consisting of: • a hydrogen atom, • a halogen atom, • a (C1-C6)alkyloxy group, and • a (C1-C6)alkyl group; → n is an integer number from 0 to 5; for use for treating uveal melanoma. 2. A compound for use according to claim 1, wherein Y is -S- or -O-, preferably -S-. 3. A compound for use according to claim 1 or 2, wherein R1 is a radical selected in the group consisting of: • a hydrogen atom, • an ethoxy group, • a methyl group, • a nitro group, • a -NR3R4 group with R3 and R4 are independently a radical selected in the group consisting of: - a hydrogen atom, - a -COR5 with R5 is a methyl group, and - a -SO2R6 with R6 is a methyl group, • a halogen atom, preferably a bromine, and • a 3-14 membered ring selected in the group consisting of a thiophenyl, a furanyl, a naphtalenyl, and a pyridinyl , said 3-14 membered ring is optionally substituted by a radical selected in the group consisting of a (C1-C6)alkyl group, a (C1- C6)alkyloxy group, a halogen atom, a nitro group, and a carboxyl group. 4. A compound for use according to any one of claims 1 to 3, wherein R1 is a radical selected in the group consisting of an ethoxy group, a nitro group, and a 3-14 membered ring selected in the group consisting of a thiophenyl, a furanyl, a naphtalenyl, and a pyridinyl, preferably a nitro group, said 3-14 membered ring is optionally substituted by a radical selected in the group consisting of a (C1-C6)alkyl group, a (C1-C6)alkyloxy group, a halogen atom, a nitro group, and a carboxyl group. 5. A compound for use according to any one of claims 1 to 4, wherein n is an integer number from 1 to 3, preferably 1 or 2. 6. A compound for use according to any one of claims 1 to 5, wherein n is 1 or 2, and R2 is in meta position. 7. A compound for use according to any one of claims 1 to 6, wherein R2 is a radical selected in the group consisting of: • a hydrogen atom, • a halogen atom, preferably a chlorine or a bromine, more preferably a chlorine, • a methoxy group, and • a methyl group. 8. A compound for use according to any one of claims 1 to 7, wherein said compound is of formula (IA): in which Y, R1, R2, and n are such as defined in claim 1 to 7. 9. A compound for use according to claim 1, wherein said compound is selected in the group consisting of: 1-(1H-benzo[d]imidazol-2-yl)-3-(3-chlorophenyl)urea (MCK109); 1-(1H-benzo[d]imidazol-2-yl)-3-(2-chlorophenyl)urea (MCK110); 1-(benzo[d]oxazol-2-yl)-3-phenylurea (MCK112); 1-(1H-benzo[d]imidazol-2-yl)-3-phenylurea (MCK113); 1-(1H-benzo[d]imidazol-2-yl)-3-(4-chlorophenyl)urea (MCK115); 1-(benzo[d]thiazol-2-yl)-3-phenylurea (MCK126); 1-(benzo[d]thiazol-2-yl)-3-(2-chlorophenyl)urea (MCK127); 1-(benzo[d]thiazol-2-yl)-3-(3-chlorophenyl)urea (MCK128); 1-(benzo[d]thiazol-2-yl)-3-(4-chlorophenyl)urea (MCK129); 1-(benzo[d]thiazol-2-yl)-3-(4-methoxyphenyl)urea (MCK130); 1-(1H-benzo[d]imidazol-2-yl)-3-(4-methoxyphenyl)urea (MCK131); 1-(6-ethoxybenzo[d]thiazol-2-yl)-3-(p-tolyl)urea (MCK132); 1-(6-ethoxybenzo[d]thiazol-2-yl)-3-(o-tolyl)urea (MCK133); 1-(6-ethoxybenzo[d]thiazol-2-yl)-3-(m-tolyl)urea (MCK134); 1-(6-ethoxybenzo[d]thiazol-2-yl)-3-(4-methoxyphenyl)urea (MCK135); 1-(2-chlorophenyl)-3-(6-methylbenzo[d]thiazol-2-yl)urea (MCK136); 1-(3-chlorophenyl)-3-(6-methylbenzo[d]thiazol-2-yl)urea (MCK137); 1-(6-methylbenzo[d]thiazol-2-yl)-3-(m-tolyl)urea (MCK138); 1-(2-chlorophenyl)-3-(6-nitrobenzo[d]thiazol-2-yl)urea (MCK139); 1-(3-chlorophenyl)-3-(6-nitrobenzo[d]thiazol-2-yl)urea (MCK140); 1-(4-bromophenyl)-3-(6-nitrobenzo[d]thiazol-2-yl)urea (MCK147); 1-(6-aminobenzo[d]thiazol-2-yl)-3-(3-chlorophenyl)urea (MCK148); N-(2-(3-(3-chlorophenyl)ureido)benzo[d]thiazol-6-yl)acetamide (MCK149); N-(2-(3-(3-chlorophenyl)ureido)benzo[d]thiazol-6-yl)methanesulfonamide (MCK150); 1-(3,5-dichlorophenyl)-3-(6-nitrobenzo[d]thiazol-2-yl)urea (MCK151); 1-(4-methoxyphenyl)-3-(6-nitrobenzo[d]thiazol-2-yl)urea (MCK152); 1-(6-nitrobenzo[d]oxazol-2-yl)-3-(m-tolyl)urea (MCK153); 1-(5-nitrobenzo[d]oxazol-2-yl)-3-phenylurea (MCK154); 1-(6-nitro-1H-benzo[d]thiazol-2-yl)-3-phenylurea (MCK155); 1-(3-chlorophenyl)-3-(6-nitro-1H-benzo[d]imidazol-2-yl)urea (MCK156); 1-(6-nitro-1H-benzo[d]imidazol-2-yl)-3-phenylurea (MCK157); 1-(3-chlorophenyl)-3-(5-nitrobenzo[d]oxazol-2-yl)urea (MCK158); 1-(6-bromobenzo[d]thiazol-2-yl)-3-(3-chlorophenyl)urea (MCK159); 1-(3-chlorophenyl)-3-(6-nitrobenzo[d]oxazol-2-yl)urea (MCK160); 11-(3-chlorophenyl)-3-(6-(thiophen-2-yl)benzo[d]thiazol-2-yl)urea (MCK161); 1-(3-chlorophenyl)-3-(6-(furan-2-yl)benzo[d]thiazol-2-yl)urea (MCK162); 1-(3-chlorophenyl)-3-(6-(thiophen-3-yl)benzo[d]thiazol-2-yl)urea (MCK163); 1-(3-chlorophenyl)-3-(6-(naphthalen-1-yl)benzo[d]thiazol-2-yl)urea (MCK164); 1-(2-bromophenyl)-3-(6-nitrobenzo[d]thiazol-2-yl)urea (MCK165); 1-(3-chlorophenyl)-3-(6-ethoxybenzo[d]thiazol-2-yl)urea (MCK166); 1-(3,5-dichlorophenyl)-3-(6-ethoxybenzo[d]thiazol-2-yl)urea (MCK167); 1-(6-nitrobenzo[d]thiazol-2-yl)-3-(p-tolyl)urea (MCK168); 1-(4-chlorophenyl)-3-(6-nitrobenzo[d]thiazol-2-yl)urea (MCK169); 1-(3-chlorophenyl)-3-(6-(pyridin-2-yl)benzo[d]thiazol-2-yl)urea (MCK172); 1-(6-nitrobenzo[d]thiazol-2-yl)-3-(o-tolyl)urea (MCK173). 10. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 9 for use for treating uveal melanoma, wherein said composition is administered by topical, oral, or parenteral route, preferably by topical or oral route. 11. A compound, a pharmaceutically acceptable salt or a tautomer thereof, of formula (I): in which: → Y is -S-, or -O-; → R1 is a radical selected in the group consisting of: • a nitro group, • a -NR3R4 group with one of R3 or R4 is H and the other is a -SO2R6 with R6 is a (C1-C6)alkyl group, and • a 3-14 membered ring selected in the group consisting of a thiophenyl, a furanyl, and a naphtalenyl, said 3-14 membered ring is optionally substituted by a radical selected in the group consisting of a (C1-C6)alkyl group, a (C1-C6)alkyloxy group, a halogen atom, a nitro group, and a carboxyl group; with the proviso that when R1 is a nitro group, then Y is -O-; → R2 is a radical selected in the group consisting of: • a hydrogen atom, • a halogen atom, • a (C1-C6)alkyloxy group, and • a (C1-C6)alkyl group; and → n is an integer number from 0 to 5. 12. A compound according to claim 11, wherein said compound is selected in the group consisting of: N-(2-(3-(3-chlorophenyl)ureido)benzo[d]thiazol-6-yl)methanesulfonamide (MCK150); 1-(5-nitrobenzo[d]oxazol-2-yl)-3-phenylurea (MCK154); 1-(3-chlorophenyl)-3-(5-nitrobenzo[d]oxazol-2-yl)urea (MCK158); 1-(3-chlorophenyl)-3-(6-nitrobenzo[d]oxazol-2-yl)urea (MCK160); 1-(3-chlorophenyl)-3-(6-(thiophen-2-yl)benzo[d]thiazol-2-yl)urea (MCK161); 1-(3-chlorophenyl)-3-(6-(furan-2-yl)benzo[d]thiazol-2-yl)urea (MCK162); 1-(3-chlorophenyl)-3-(6-(thiophen-3-yl)benzo[d]thiazol-2-yl)urea (MCK163); and 1-(3-chlorophenyl)-3-(6-(naphthalen-1-yl)benzo[d]thiazol-2-yl)urea (MCK164). 13. A compound selected in the group consisting of: N-(2-(3-(3-chlorophenyl)ureido)benzo[d]thiazol-6-yl)acetamide (MCK149); N-(2-(3-(3-chlorophenyl)ureido)benzo[d]thiazol-6-yl)methanesulfonamide (MCK150); 1-(5-nitrobenzo[d]oxazol-2-yl)-3-phenylurea (MCK154); 1-(6-nitro-1H-benzo[d]imidazol-2-yl)-3-phenylurea (MCK157); 1-(3-chlorophenyl)-3-(5-nitrobenzo[d]oxazol-2-yl)urea (MCK158); 1-(3-chlorophenyl)-3-(6-nitrobenzo[d]oxazol-2-yl)urea (MCK160); 1-(3-chlorophenyl)-3-(6-(thiophen-2-yl)benzo[d]thiazol-2-yl)urea (MCK161); 1-(3-chlorophenyl)-3-(6-(furan-2-yl)benzo[d]thiazol-2-yl)urea (MCK162); 1-(3-chlorophenyl)-3-(6-(thiophen-3-yl)benzo[d]thiazol-2-yl)urea (MCK163); 1-(3-chlorophenyl)-3-(6-(naphthalen-1-yl)benzo[d]thiazol-2-yl)urea (MCK164); 1-(3,5-dichlorophenyl)-3-(6-ethoxybenzo[d]thiazol-2-yl)urea (MCK167); and 1-(3-chlorophenyl)-3-(6-(pyridin-2-yl)benzo[d]thiazol-2-yl)urea (MCK172). 14. A pharmaceutical composition comprising a compound as defined in any one of claims 11 to 13 and a pharmaceutically acceptable carrier. 15. A compound as defined in any one of claims 11 to 13 for use as a medicine, preferably for use for treating a cancer. |
Chemical synthesis and characterization Methanol, ethyl acetate, diethyl ether and dichloromethane were purchased from Carlo Erba, and use as received. Anhydrous DMF (99.8% stored under septum) was purchased from Sigma Aldrich, and use as received. All chemicals were purchased from Aldrich, Fisher or Alfa Aesar and used without further purification. Thin layer chromatography (TLC) was performed on precoated Merck 60 GF254 silica gel plates and revealed first by visualization under UV light (254 nm and 360 nm) 1 H and 13 C NMR spectra were recorded on a Bruker Advance 200 MHz spectrometer or a Bruker Advance 400 MHz or a Bruker Advance 500 MHz. Mass spectra (ESI- MS) were recorded on a Bruker (Daltonics Esquire 3000+). HRMS spectra were recorded on a ThermoFisher Q Exactive (ESI-MS) at a resolution of 140 000 at m/z 200. The purity of compounds was further assayed by HPLC analysis on a JASCO PU-2089 apparatus with: Method 1: Supelco analytical column Ascentis Express C18, 100mm x 46 mm 5 μm. UV- detection: 214; 254; 280; 320 nm. Eluent A: water with 1‰ formic acid, Eluent B: CH 3 CN with 1‰ formic acid.0-1 min: 30%B; 1-6 min: 30-100%B; 6-8.5 min: 100%B; 8.5-9: 100-30%B; 9-13: 30%B. Method 2: Supelco analytical column Ascentis Express C18, 100mm x 46 mm 5 μm. UV-detection: 214; 254; 280; 320 nm. Eluent A: water with 1‰ formic acid, Eluent B: CH 3 CN with 1‰ formic acid.0-1 min: 30%B; 1-6 min: 30-100%B; 6-8.5 min: 100%B; 8.5-9: 100-30%B; 9-16: 30%B. Method 3: Supelco analytical column Ascentis Express C18, 100mm x 46 mm 5 μm. UV-detection: 214; 254; 280; 320 nm. Eluent A: water with 1‰ formic acid, Eluent B: CH 3 CN with 1‰ formic acid. 0-1 min: 30%B; 1-6 min: 30-100%B; 6-26 min: 100%B; 26-27: 100-30%B; 27-30: 30%B. Method 4: Supelco analytical column Ascentis Express C18, 100mm x 46 mm 5 μm. UV-detection: 214; 254; 280; 320 nm. Eluent A: water with 1‰ formic acid, Eluent B: CH 3 CN with 1‰ formic acid. 0-1 min: 30%B, 1-6 min: 30- 100%B, 6-8.5 min: 100%B, 8.5-9 min: 100-30%B, 9-16: 30%B. Method 5: Waters Alliance 2695, Supelco Ascentis Express C18, 100mm x 46 mm 5 μm. UV-detection: 214; 254; 280; 320 nm. Eluent A: water with 1‰ formic acid, Eluent B: CH 3 CN with 1‰ formic acid.0-10: 10% B; 10-18min: 10-95% B; 18-20 min: 95% B; 20-24 min 95-10% B; 24-25 min: 10% B. Method 6: Ascentis Express C18, 100mm x 46 mm 5 μM. UV-detection: 214; 254; 280; 360 nm.0-1 min: 0%B; 1-10 min: 0-100%B; 10-15 min: 100%B Synthetic procedures and characterizations: General procedure for the formation of ureas (A). To a solution of corresponding amine (1 equiv) in N,N-dimethylformamide (25 mL) was added the corresponding isocyanate (1 eq.) and the mixture was stirred overnight at room temperature. After completion of the reaction, the reaction mixture was poured into water (200 mL). The precipitate formed was collected and washed with methanol (2x25 mL) and diethyl ether (2x25 mL). General procedure for the formation of ureas (B). To a solution of corresponding amine (1 equiv) in 1,4-dioxane (25 mL) was added the corresponding isocyanate (1 eq.) and the mixture was stirred overnight at room temperature. After completion of the reaction, the precipitate formed was collected and washed with methanol (2x25 mL) and diethyl ether (2x25 mL). General procedure for the Suzuki reaction (C) To a solution of 1-(6-bromobenzo[d]thiazol-2- yl)-3-(3-chlorophenyl)urea (1 eq.) in a mixture of dioxane:water (4:1, 50 mL) was added the corresponding boronic acid (1.5 eq.), potassium carbonate (3 eq.), tetrakis triphenylphosphine palladium (0.1 eq.) and the mixture was refluxed overnight. The reaction mixture was concentrated under reduced pressure and the precipitate was extracted several times with hot isopropyl alcohol (10x50 mL). The alcoholic fractions were combined, concentrated under reduced pressure and purified by silica gel column chromatography (cyclohexane : EtOAc, 10:0 to 6:4). General procedure for the formation of ureas (D). To a cooled (0°C) solution of the corresponding aminobenzothiazole (1.1eq.) in dry N,N-dimethylformamide (10-50mL) was added dropwise the corresponding isocyanate (1eq.). After completion of the addition, the ice bath was removed and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the precipitate formed was filtered, washed with water (2x25mL), diethyl ether (2x25 mL), and dried at air (56 °C). 1-(1H-benzo[d]imidazol-2-yl)-3-(3-chlorophenyl)urea (MCK109): Synthesized following the general procedure (A) using benzo[d]thiazol-2-amine (500 mg, 3.33 mmol) and phenyl isocyanate (0.360mL, 3.33 mmol) to afford the title compound as a pink powder (117 mg, 12%); mp > 260 °C; Rf (Cyclohexane/EtOAc, 75/25, v/v) = 0.53; 1 H NMR (DMSO-d 6 , 200 MHz): δ (ppm): 7.35-7.10 (m, 4H, H Ar ), 7.48-7.37 (m, 3H, H Ar ), 7.92 (s, 1H, H Ar ), 9.63 (s, 1H, N-H), 11.49 (br.s, 2H, 2N-H) 13 C NMR (DMSO-d 6 , 50 MHz) δ: (ppm): 112.2 (2C), 116.8 (2C), 117.7 (2C), 121.3, 121.5130.3 (2C), 133.1 (2C), 141.3150.1; ESI (m/z): [M+H] + for C14H12ClN4O + 287.07, found 287.13; HPLC (λ263Purity 83.0 %, ); tR: 10.4 min (method 6). 1-(1H-benzo[d]imidazol-2-yl)-3-(2-chlorophenyl)urea (MCK110): Synthesized following the general procedure (A) using benzo[d]thiazol-2-amine (500 mg, 3.33 mmol) and phenyl isocyanate (0.360mL, 3.33 mmol) to afford the title compound as a grey powder (74.0 mg, 8%); mp > 260 °C; Rf (Cyclohexane/EtOAc, 75/25, v/v) = 0.50; 1 H NMR (DMSO-d 6 , 200 MHz): δ (ppm) : 7.03-7.15 (m, 3H, HAr), 7.29-7.43 (m, 3H, HAr), 7.51 (dd, J = 8 Hz, J = 2 Hz, 1H, HAr), 8.27 (d, J = 8 Hz, 1H, HAr), 10.21 (s, 1H, N-H), 11.28 (s, 2H, N- H). ESI (m/z): [M+H] + , calcd. for C 14 H 12 ClN 4 O + 287.07, found 287.06; HPLC (λ 263 ): Purity 68.2 %; tR: 9.5 min (method 6). 1-(benzo[d]thiazol-2-yl)-3-phenylurea (MCK126): Synthesized following the general procedure (A) using benzo[d]thiazol-2-amine (500 mg, 3.33 mmol) and phenyl isocyanate (0.360mL, 3.33 mmol) to afford the title compound as a white powder (830 mg, 93%). 1 H NMR (200 MHz, DMSO-d 6 ): δ 10.88 (br. s, 1H), 9.19 (s, 1H), 7.91 (d, J = 7.1 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 1.2 Hz, 2H), 7.45 – 7.29 (m, 3H), 7.29 – 7.20 (m, 1H), 7.06 (t, J = 7.3 Hz, 1H). 13 C NMR (50 MHz, DMSO-d 6 ) δ 159.81, 152.29, 147.93, 138.56, 131.17, 128.97 (2C), 125.99, 122.99, 122.94, 121.54, 119.30, 118.89 (2C). HRMS-ESI (m/z): [M+H] + calc. for C 14 H 12 N 3 OS + , 270.06956; Found: 270.06961. HPLC (λ 280 ): Purity 95.4%; tR: 9.708 min (method 6). 1-(1H-benzo[d]imidazol-2-yl)-3-(4-methoxyphenyl)urea (MCK131): Synthesized following the general procedure (A) using 2-aminobenzimidazole (500 mg, 3.76 mmol) and 4-methoxyphenyl isocyanate (0.438 mL, 3.38 mmol) to afford the title compound as a white powder (922 mg, 87%). 1 H NMR (200 MHz, DMSO-d 6 ) δ 10.99 (br. s, 2H), 9.46 (s, 1H), 7.47 (d, J = 8.7 Hz, 2H), 7.37 (dd, J = 5.5, 2.9 Hz, 2H), 7.05 (dd, J = 5.3, 2.9 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 3.73 (s, 3H). 13 C NMR (50 MHz, DMSO-d 6 ) δ 154.97, 153.62, 148.86, 135.58 (2C), 132.24, 120.95 (2C), 120.52 (2C), 114.10 (2C), 113.12 (2C), 55.21. HRMS-ESI (m/z): [M+H] + calc. for C 15 H 15 N 4 O 2 + , 283.11895; Found: 283.11902. HPLC (λ 280 ): Purity 97.9%; t R : 6.433 min (method 6). 1-(6-ethoxybenzo[d]thiazol-2-yl)-3-(p-tolyl)urea (MCK132): Synthesized following the general procedure (A) using 2-amino-6-ethoxybenzothiazole (500 mg, 2.57 mmol) and p-tolyl isocyanate (0.324 mL, 2.57 mmol) to afford the title compound as a white powder (792 mg, 94%). 1 H NMR (200 MHz, DMSO-d 6 ): δ 10.63 (s, 1H), 9.03 (s, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 2.5 Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.3 Hz, 2H), 6.96 (dd, J = 8.8, 2.6 Hz, 1H), 4.05 (q, J = 6.9 Hz, 2H), 2.26 (s, 3H), 1.34 (t, J = 7.0 Hz, 3H). 13 C NMR (50 MHz, DMSO-d 6 ): δ 157.56, 154.94, 151.90, 142.41, 135.98, 132.52, 131.86, 129.34 (2C), 120.07, 118.84 (2C), 114.73, 105.53, 63.57, 20.39, 14.73. HRMS-ESI (m/z): [M+H] + calc. for C 17 H 18 N 3 O 2 S + , 328.11142; Found: 328.11157. HPLC (λ 280 ): Purity 100.0%; tR: 10.608 min (method 6). 1-(6-ethoxybenzo[d]thiazol-2-yl)-3-(m-tolyl)urea (MCK134): Synthesized following the general procedure (A) using 2-amino-6-ethoxybenzothiazole (500 mg, 2.57 mmol) and m-tolyl isocyanate (0.298 mL, 2.32 mmol) to afford the title compound as a white powder (731 mg, 87%). 1 H NMR (200 MHz, DMSO-d 6 ): δ 10.65 (br. s, 1H), 9.05 (s, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.50 (d, J = 2.5 Hz, 1H), 7.38 – 7.15 (m, 3H), 6.96 (dd, J = 8.8, 2.6 Hz, 1H), 6.87 (d, J = 6.9 Hz, 1H), 4.05 (q, J = 6.9 Hz, 2H), 2.30 (s, 3H), 1.34 (t, J = 7.0 Hz, 3H). 13 C NMR (50 MHz, DMSO-d 6 ): δ 157.57, 154.95, 151.86, 142.31, 138.46, 138.24, 132.49, 128.78, 123.65, 120.04, 119.25, 115.91, 114.79, 105.52, 63.59, 21.17, 14.73. HRMS- ESI (m/z): [M+H] + calc. for C 17 H 18 N 3 O 2 S + , 328.11142; Found: 328.11151. HPLC (λ 280 ): Purity 97.5%; t R : 10.617 min (method 6). 1-(6-ethoxybenzo[d]thiazol-2-yl)-3-(4-methoxyphenyl)urea (MCK135): Synthesized following the general procedure (A) using 2-amino-6-ethoxybenzothiazole (500 mg, 2.57 mmol) and 4-methoxyphenylisocyanate (0.333 mL, 2.57 mmol) to afford the title compound as a white powder (775 mg, 88%). 1 H NMR (200 MHz, DMSO-d6): δ 10.61 (br. s, 1H), 8.95 (s, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 2.5 Hz, 1H), 7.46 – 7.33 (m, 2H), 7.01 – 6.85 (m, 3H), 4.04 (q, J = 6.9 Hz, 2H), 3.73 (s, 3H), 1.34 (t, J = 6.9 Hz, 3H). 13 C NMR (50 MHz, DMSO-d6): δ 157.71, 155.25, 154.96, 152.03, 142.51, 132.58, 131.49, 120.72 (2C), 120.12, 114.67, 114.10 (2C), 105.53, 63.60, 55.17, 14.72. HRMS-ESI (m/z): [M+H] + calc. for C 17 H 18 N 3 O 3 S + , 344.10634; Found: 344.10641. HPLC (λ 280 ): Purity 98.2%; tR: 9.950 min (method 6). 1-(3-chlorophenyl)-3-(6-methylbenzo[d]thiazol-2-yl)urea (MCK137): Synthesized following the general procedure (A) using 6-methylbenzo[d]thiazol-2-amine (500 mg, 3.05 mmol) and 3-chlorophenyl isocyanate (0.364 mL, 3.05 mmol) to afford the title compound as a white powder (870 mg, 90%). 1 H NMR (400 MHz, DMSO-d6): δ 11.06 (br. s, 1H), 9.37 (s, 1H), 7.76 (s, 1H), 7.68 (s, 1H), 7.51 (d, J = 7.4 Hz, 1H), 7.42 – 7.30 (m, 2H), 7.20 (d, J = 7.7 Hz, 1H), 7.09 (d, J = 6.9 Hz, 1H), 2.38 (s, 3H). 13 C NMR (50 MHz, DMSO-d6): δ 159.52, 152.91, 144.86, 140.33, 133.42, 132.36, 130.89, 130.39, 127.25, 122.44, 121.29, 118.41, 118.23, 117.23, 20.90. HRMS-ESI (m/z): [M+H] + calc. for C 15 H 13 ClN 3 OS + , 318.04624; Found: 318.04626. HPLC (λ 280 ): Purity 95.5%; tR: 11.325 min (method 6). 1-(6-methylbenzo[d]thiazol-2-yl)-3-(m-tolyl)urea (MCK138): Synthesized following the general procedure (A) using 6-methylbenzo[d]thiazol-2-amine (500 mg, 3.05 mmol) and 3-tolylisocyanate (0.393 mL, 3.05 mmol) to afford the title compound as a white powder (788 mg, 87%). 1 H NMR (200 MHz, DMSO-d6): δ 10.75 (br. s, 1H, H10), 9.08 (s, 1H, H12), 7.70 (s, 1H, H3), 7.53 (d, J = 8.1 Hz, 1H, H6), 7.35 (s, 1H, H19), 7.33 – 7.15 (m, 3H, H1, H15, H19), 6.87 (d, J = 7.2 Hz, 1H, H17), 2.39 (s, 3H, H20), 2.30 (s, 3H, H21). 13 C NMR (50 MHz, DMSO-d6): δ 158.91, 152.09, 146.09, 138.51, 138.24, 132.26, 131.34, 128.77, 127.17, 123.68, 121.19, 119.30, 119.04, 115.97, 21.18, 20.89. HRMS-ESI (m/z): [M+H] + calc. for C 16 H 16 N 3 OS + , 298.10086; Found: 298.10092. HPLC (λ 280 ): Purity 99.6%; tR: 10.808 min (method 6). 1-(4-chlorophenyl)-3-(6-nitrobenzo[d]thiazol-2-yl)urea (MCK169): Synthesized following the general procedure (D) using 6-nitro-2-aminobenzothiazol (2.00 g, 13.30 mmol) in dry DMF and 4-chlorophenylisocyanate (1.85 g, 12.05 mmol) to afford the title compound as a yellow powder ( 2.88g, 68%). 1 H NMR (200 MHz, DMSO-d 6 ) δ 11.43 (s, 1H), 9.37 (s, 1H), 8.95 (s, 1H), 8.23 (d, J = 8.1 Hz, 1H), 7.77 (d, J = 8.9 Hz, 1H), 7.55 (d, J = 8.6 Hz, 2H), 7.38 (d, J = 8.5 Hz, 2H). 13 C NMR (101 MHz, DMSO-d 6 ) δ: 164.8, 142.5, 138.5, 137.2, 133.7, 128.8 (2C), 128.6, 126.9, 121.8, 120.6 (2C), 119.8, 118.9. HRMS-ESI (m/z): [M+H] + calcd for C 14 H 10 ClN 4 O 3 S, 349.0159; Found: 349.0157. HPLC (λ 254 ): Purity > 99.9 %; t R : 12.27 min (method 5). 1-(6-nitrobenzo[d]thiazol-2-yl)-3-phenylurea (MCK155): Synthesized following the general procedure (B) using 2-amino-6-nitrobenzothiazole (500 mg, 2.56 mmol) and phenyl isocyanate (0.28 mL, 2.56 mmol) to afford the title compound as a white powder (596 mg, 74%). 1 H NMR (200 MHz, DMSO-d 6 ): δ 10.8 (br. s, 1H), 9.46 (s, 1H), 8.94 (d, J = 2.3 Hz, 1H), 8.21 (dd, J = 8.9, 2.4 Hz, 1H), 7.74 (d, J = 8.9 Hz, 1H), 7.54 (d, J = 7.8 Hz, 2H), 7.32 (t, J = 7.8 Hz, 2H), 7.06 (t, J = 7.3 Hz, 1H). 13 C NMR (50 MHz, DMSO-d 6 ): δ 164.97, 153.63, 151.98, 142.31, 138.34, 132.15, 128.84, 123.14, 121.62, 119.31, 119.06, 118.47. HRMS-ESI (m/z): [M+H] + calc. for C 14 H 11 N 4 O 3 S + , 315.0746; Found: 315.0745. HPLC (λ 280 ): Purity 99.9%; tR: 19.44 min (method 3). 1-(6-nitrobenzo[d]thiazol-2-ylidene)-3-(o-tolyl)urea (MCK173): Synthesized following the general procedure (D) using of 6-nitro-2-aminobenzothiazol (1.02g, 6.79 mmol) and m-tolylisocyanate (892 mg, 6.70 mmol) to afford the title compound as a white powder (493.8mg, 22%). 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.56 (s, 1H), 9.00 (s, 1H), 8.56 (s, 1H), 8.25 (dd, J = 8.9, 2.0 Hz, 1H), 7.82 (d, J = 7.2 Hz, 2H), 7.23 (dd, J = 15.2, 7.5 Hz, 2H), 7.06 (t, J = 7.3 Hz, 1H), 2.28 (s, 3H). 13 C NMR (101 MHz, DMSO-d 6 ): δ 164.6, 153.9, 151.3, 142.3, 135.6, 132.1, 130.2, 128.4, 126.2, 124.0, 121.5, 121.4, 119.6, 118.5, 17.5. HRMS-ESI (m/z): [M+H] + calc. for C 15 H 13 N 4 O 3 S + , 329.0703; Found: 329.0703, tR: 10.78 min. HPLC (λ254): Purity = 98.59 %; tR: 11.85 min (method 5). 1-(6-nitrobenzo[d]thiazol-2-yl)-3-(p-tolyl)urea (MCK168): Synthesized following the general procedure (D) using of 6-nitro-2-aminobenzothiazol (2.03 g, 13.51 mmol) and p-tolylisocyanate (1.58 g, 11.87 mmol) to afford the title compound as a beige powder (2.21 g, 56%). 1 H NMR (200 MHz, DMSO-d 6 ) δ 11.21 (s, 1H), 9.10 (s, 1H), 8.94 (s, 1H), 8.22 (dd, J = 8.9, 1.9 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.39 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 8.1 Hz, 2H), 2.26 (s, 3H). 13 C NMR (400 MHz, DMSO-d 6 ) δ 165.07, 154.17, 151.76, 142.69, 135.70, 132.64, 132.38, 129.62 (2C), 122.02, 119.69, 119.36 (2C), 118.88, 20.64. HRMS-ESI (m/z): [M+H] + calcd for C 15 H 13 N 4 O 3 S, 329.0705; Found: 329.0703. HPLC (λ 254 ): Purity > 99.9%; tR: 11.86 min (method 5). 1-(4-methoxyphenyl)-3-(6-nitrobenzo[d]thiazol-2-yl)urea (MCK152): Synthesized following the general procedure (D) using 6-nitro-2-aminobenzothiazol (2.06g, 13.72 mmol) and 4-methoxyphenylisocyanate (1.50 mL, 12.09 mmol) to afford the title compound as a white powder (2.66g, 64%). 1 H NMR (200 MHz, DMSO-d 6 ) δ 11.21 (br. s, 1H), 8.96 (d, J = 19.6 Hz, 2H), 8.19 (d, J = 6.5 Hz, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.40 (d, J = 6.3 Hz, 2H), 6.92 (br. s, 2H), 3.72 (s, 3H). 13 C NMR (50 MHz, DMSO-d 6 ) δ 164.81, 155.43, 153.59, 151.60, 142.33, 132.08, 130.86, 121.67, 120.90 (2C), 119.36, 118.51, 114.05 (2C), 55.15. HRMS-ESI (m/z): [M+H] + calcd for C 15 H 13 N 4 O 4 S, 345.0654; Found: 345.0652 HPLC (λ 254 ): Purity > 99.9%; tR: 10.71 min (method 5). 1-(3-chlorophenyl)-3-(6-ethoxybenzo[d]thiazol-2-yl)urea (MCK166): To a cooled (0°C) solution of 2-amino-6ethoxybenzothiazole (1.00 g, 5.15 mmol, 1.1eq.) in dry DMF (5.00 mL) was added dropwise 3-chloroisocyanate (623.1 mg, 4.68 mmol, 1eq.). After completion of the addition, the ice bath was removed, and the reaction mixture was stirred at room temperature overnight.1 more equivalent of 3-chloroisocyanate was added and after the reaction completion, Et 2 O (10 mL) was added to the reaction mixture, followed by water (a white precipitate appeared). The white precipitate was washed with water (100 mL), then Et 2 O (50 mL) to afford the title compound (1.68 g, quant.). 1 H NMR (200 MHz, DMSO-d 6 ) δ 10.86 (br.s, 1H), 9.34 (s, 1H), 7.74 (s, 1H), 7.52 (t, J = 6.0 Hz, 2H), 7.39 – 7.32 (m, 2H), 7.15 – 7.03 (m, 1H), 6.97 (dd, J = 8.8, 2.6 Hz, 1H), 4.05 (q, J = 6.9 Hz, 2H), 1.34 (t, J = 6.9 Hz, 3H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 158.81, 155.45, 152.94, 141.45, 140.69, 133.73, 132.57, 130.97, 122.92, 120.22, 118.60, 117.72, 115.31, 106.15, 64.06, 15.17. HRMS-ESI (m/z): [M+H] + calcd for C 16 H 15 ClN 3 O 2 S, 348.0570; Found: 348.0568. HPLC (λ 254 ): Purity = 98.0 %; t R : 12.76 min (method 5). 1-(3,5-dichlorophenyl)-3-(6-ethoxybenzo[d]thiazol-2-yl)urea (MCK167): Synthesized following the general procedure (D) using 2-amino-6ethoxybenzothiazole (227.3 mg, 1.17 mmol) in dry DMF and 3,5-dichloroisocyanate (200.0 mg, 1.06 mmol) to afford the title compound as a white powder (1.68 g, quant.). 1 H NMR (200 MHz, DMSO-d 6 ) δ 11.26 (br. s, 1H), 9.52 (s, 1H), 7.63 (d, J = 1.7 Hz, 2H), 7.50 (d, J = 9.2 Hz, 2H), 7.22 (s, 1H), 6.97 (dd, J = 8.7, 2.5 Hz, 1H), 4.04 (q, J = 6.8 Hz, 2H), 1.34 (t, J = 6.9 Hz, 3H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 159.8, 155.5, 154.2, 141.9, 134.6 (3C), 132.1, 122.2, 119.4, 117.3 (2C), 115.4, 106.3, 64.1, 15.2. HRMS-ESI (m/z): [M+H] + calcd for C 16 H 14 Cl 2 N 3 O 2 S, 382.0185; Found: 382.0178. HPLC (λ254): Purity > 99.9 %; tR: 14.66 min (method 5). 1-(3-chlorophenyl)-3-(6-nitrobenzo[d]oxazol-2-yl)urea (MCK160): Synthesized following the general procedure (B) using 6-nitrobenzo[d]oxazol-2-amine (500 mg, 2.80 mmol) and 3-chlorophenyl isocyanate (0.34 mL, 2.80 mmol) to afford the title compound as a white powder (492 mg, 53%). 1 H NMR (200 MHz, DMSO-d 6 ): δ 12.19 (br. s, 1H), 10.28 (s, 1H), 8.46 (d, J = 1.9 Hz, 1H), 8.24 (dd, J = 8.7, 2.2 Hz, 1H), 7.81 (s, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.54 – 7.41 (m, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.11 (d, J = 7.9 Hz, 1H). 13 C NMR (50 MHz, DMSO-d 6 ): δ 160.02, 145.52 (2C), 142.72, 139.86 (2C), 133.30, 130.27, 122.87, 121.18, 118.45, 117.42, 115.66, 106.08. HRMS-ESI (m/z): [M+H] + calc. for C 14 H 10 ClN 4 O 4 + , 333.03851; Found: 333.03864. HPLC (λ 280 ): Purity 99.5%; t R : 19.93 min (method 3). 1-(6-nitrobenzo[d]oxazol-2-yl)-3-(m-tolyl)urea (MCK153): Synthesized following the general procedure (B) using 6-nitrobenzo[d]oxazol-2-amine (500 mg, 2.80 mmol) and p-tolyl isocyanate (0.35 mL, 2.80 mmol) to afford the title compound as a white powder (419 mg, 48%). 1 H NMR (200 MHz, DMSO-d 6 ) δ 11.95 (br. s, 1H), 10.20 (s, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.26 (dd, J = 8.7, 2.2 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.41 (d, J = 6.6 Hz, 2H), 7.24 (t, J = 8.1 Hz, 1H), 6.92 (d, J = 7.3 Hz, 1H), 2.31 (s, 3H). 13 C NMR (50 MHz, DMSO-d 6 ): δ 160.26, 150.12 (2C), 145.91, 142.77, 138.22, 138.01, 128.75, 124.22, 121.27, 119.77, 116.46, 116.12, 106.32, 21.12. HRMS-ESI (m/z): [M+H] + calc. for C 15 H 13 N 4 O 4 + , 313.09313; Found: 313.09320. HPLC (λ254): Purity 95.3%; tR: 21.09 min (method 3). 1-(3-chlorophenyl)-3-(5-nitrobenzo[d]oxazol-2-yl)urea (MCK158): Synthesized following the general procedure (B) using 5-nitrobenzo[d]oxazol-2-amine (500 mg, 2.80 mmol) and 3-chlorophenyl isocyanate (0.34 mL, 2.80 mmol) to afford the title compound as a white powder (633 mg, 68%). 1 H NMR (200 MHz, DMSO-d 6 ): δ 11.91 (s, 1H), 10.47 (s, 1H), 8.36 (s, 1H), 8.16 (dd, J = 8.9, 2.4 Hz, 1H), 7.82 (d, J = 5.1 Hz, 2H), 7.50 (d, J = 8.8 Hz, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H). 13 C NMR (50 MHz, DMSO-d 6 ): δ 158.71, 150.73 (2C), 144.68, 140.91, 139.89, 133.29, 130.45, 122.81, 119.29, 118.27, 117.30, 112.73, 110.37 HRMS-ESI (m/z): [M+H] + calc. for C 14 H 10 ClN 4 O 4 + , 333.03851; Found: 333.03879. HPLC (λ 280 ): Purity 99.6%; tR: 19.97 min (method 3). 1-(5-nitrobenzo[d]oxazol-2-yl)-3-phenylurea (MCK154): Synthesized following the general procedure (B) using 5-nitrobenzo[d]oxazol-2-amine (500 mg, 2.80 mmol) and phenyl isocyanate (0.30 mL, 2.80 mmol) to afford the title compound as a white powder (518 mg, 62%). 1 H NMR (200 MHz, DMSO-d 6 ): δ 11.84 (s, 1H), 10.46 (s, 1H), 8.41 (s, 1H), 8.17 (dd, J = 8.9, 2.3 Hz, 1H), 7.84 (d, J = 8.9 Hz, 1H), 7.58 (d, J = 7.9 Hz, 2H), 7.35 (t, J = 7.8 Hz, 2H), 7.08 (t, J = 7.4 Hz, 1H). 13 C NMR (50 MHz, DMSO-d 6 ): δ 158.68, 151.03, 149.51, 144.75, 141.06, 138.29, 128.94, 123.30, 119.24, 118.95, 112.70, 110.38. HRMS-ESI (m/z): [M+H] + calc. for C 14 H 11 N 4 O 4 + , 299.07748; Found: 299.07748. HPLC (λ 280 ): Purity 96.5%; tR: 10.32 min (method 3). 1-(6-nitro-1H-benzo[d]imidazol-2-yl)-3-phenylurea (MCK157): Synthesized following the general procedure (B) using 6-nitro-1H-benzo[d]imidazol-2-amine (500 mg, 2.80 mmol) and phenyl isocyanate (0.30 mL, 2.80 mmol) to afford the title compound as a white powder (433 mg, 52%). 1 H NMR (200 MHz, DMSO-d 6 ): δ 11.48 (s, 2H), 9.65 (s, 1H), 8.28 (d, J = 2.2 Hz, 1H), 8.02 (dd, J = 8.8, 2.3 Hz, 1H), 7.67 – 7.47 (m, 3H), 7.35 (t, J = 7.9 Hz, 2H), 7.06 (t, J = 7.3 Hz, 1H). 13 C NMR (50 MHz, DMSO-d 6 ): δ 152.01, 151.63, 143.42, 141.49, 138.68, 135.51, 129.01 (2C), 122.98, 118.76 (2C), 117.26, 113.74, 109.23. HRMS-ESI (m/z): [M+H] + calc. for C 14 H 12 N 5 O 3 + , 298.09347; Found: 298.09360. HPLC (λ 280 ): Purity 99.6%; tR: 18.66 min (method 3). 1-(6-aminobenzo[d]thiazol-2-yl)-3-(3-chlorophenyl)urea (MCK148) To a cooled (0°C) solution of 1-(3-chlorophenyl)-3-(6-nitrobenzo[d]thiazol-2-yl)urea (3.0 g, 8.6 mmol) in methanol (50 mL) was added palladium on charcoal (200 mg), then sodium borohydride (2.0 g, 52.8 mmol) portion wise. After the addition, the reaction mixture was allowed to warm to r.t. and stirred at this temperature until completion of the reaction (TLC monitoring, about 2h). The mixture was filtered through celite© and the filtrate was concentrated under reduced pressure, then partitioned between water and EtOAc/MeOH, 9/1, v/v (3 x 80 mL). The combined organic layers were dried with Na2SO4 and evaporated. The solid obtained was triturated in EtOAc/Et2O, 2/1, v/v, filtered and dried at air to afford the title compound as a pale yellow solid (950 mg, 35%). 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.77 (s, 1H), 9.33 (s, 1H), 7.75 (t, J = 1.9 Hz, 1H), 7.42 – 7.25 (m, 3H), 7.07 (dt, J = 7.5, 1.9 Hz, 1H), 6.98 (d, J = 2.1 Hz, 1H), 6.68 (dd, J = 8.6, 2.2 Hz, 1H), 5.11 (s, 2H). 13 C NMR (101 MHz, DMSO-d 6 ): δ 155.71, 152.72, 145.35, 140.43, 138.10, 133.29, 132.09, 130.51, 122.31, 119.37, 118.06, 117.17, 114.11, 104.60. HRMS-ESI (m/z): [M+H] + calc. for C 14 H 12 ClN 4 OS + , 319.04149; Found: 319.04169. HPLC (λ 254 ): Purity 98.3%; tR: 7.26 min (method 4). N-(2-(3-(3-chlorophenyl)ureido)benzo[d]thiazol-6-yl)acetamid e (MCK149): To a cooled (0°C) solution of 1-(6-aminobenzo[d]thiazol-2-yl)-3-(3-chlorophenyl)urea (96 mg, 0.30 mmol) in dichloromethane (2 mL) and DMF (2.5 mL), was added triethylamine (63 µL, 0.45 mmol), then acetic anhydride (34 µL, 0.36 mmol). After the addition, the reaction mixture was allowed to warm to r.t. and stirred at this temperature for 5h. The reaction was quenched at 0°C by addition of water (30 mL), then the mixture was extracted with CHCl3/MeOH, 95/5, v/v. The combined organic layers were dried with Na2SO4 and evaporated. Purification by silica gel flash chromatography (dichloromethane/acetone, 9/1 to 5/5, v/v) afforded the desired compound as a pale yellow solid (79 mg, 74%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.00 (s, 1H), 10.05 (s, 1H), 9.36 (s, 1H), 8.24 (d, J = 1.7 Hz, 1H), 7.74 (t, J = 1.9 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.45 (dd, J = 8.7, 2.1 Hz, 1H), 7.35 (dt, J = 15.9, 8.3 Hz, 2H), 7.09 (dt, J = 7.7, 1.9 Hz, 1H), 2.06 (s, 3H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 168.20, 158.95, 152.63, 143.18, 140.22, 135.00, 133.31, 131.25, 130.53, 122.52, 118.88, 118.30, 118.20, 117.29, 111.53, 23.98. HRMS-ESI (m/z): [M+H] + calc. for C 16 H 14 ClN 4 O 2 S + , 361.05205; Found: 361.05228. HPLC (λ 254 ): Purity 98.3%; t R : 7.26 min (method 4). N-(2-(3-(3-chlorophenyl)ureido)benzo[d]thiazol-6-yl)methanes ulfonamide (MCK150): To a cooled (0°C) solution of 1-(6-aminobenzo[d]thiazol-2-yl)-3-(3-chlorophenyl)urea (96 mg, 0.30 mmol) in dichloromethane (2 mL) and DMF (2.5 mL) was added triethylamine (63 µL, 0.45 mmol), then mesyl chloride (28 µL, 0.36 mmol). The reaction mixture was allowed to warm to r.t. at the end of the addition and stirred at r.t. for 5h. The reaction was quenched at 0°C by addition of water (30 mL), then the mixture was extracted with CHCl 3 /MeOH, 95/5, v/v. The combined organic layers were dried with Na 2 SO 4 and evaporated. The residue was triturated with a little amount of dichloromethane/acetone, 1/1, v/v. The white precipitate was filtered to afford the title compound as a yellow solid (58 mg, 49%). 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.93 (s, 1H), 9.72 (s, 1H), 9.36 (s, 1H), 7.74 (s, 2H), 7.61 (d, J = 8.5 Hz, 1H), 7.41 – 7.32 (m, 2H), 7.25 (dd, J = 8.6, 2.2 Hz, 1H), 7.10 (dd, J = 8.9, 1.8 Hz, 1H), 2.98 (s, 3H). 13 C NMR (50 MHz, DMSO-d 6 ): δ 159.47, 152.48, 144.47, 140.14, 133.59, 133.28, 131.75, 130.55, 122.59, 120.29, 119.53, 118.22, 117.35, 113.85, 39.78. HRMS-ESI (m/z): [M+H] + calc. for C 15 H 14 ClN 4 O 3 S 2 + , 397.01904; Found: 397.01904. HPLC (λ254): Purity 98.5%; tR: 7.46 min (method 4). 1-(6-bromobenzo[d]thiazol-2-yl)-3-(3-chlorophenyl)urea (MCK159): Synthesized following the general procedure (B) using 6-bromobenzo[d]thiazol-2-amine (500 mg, 2.18 mmol) and 3-chlorophenyl isocyanate (0.27 mL, 2.18 mmol) to afford the title compound as a white powder (685 mg, 82%). 1 H NMR (200 MHz, DMSO-d 6 ): δ 11.28 (br. s, 1H), 9.45 (s, 1H), 8.18 (s, 1H), 7.74 (s, 1H), 7.66 – 7.45 (m, 2H), 7.46 – 7.26 (m, 2H), 7.10 (d, J = 6.6 Hz, 1H). 13 C NMR (50 MHz, DMSO-d 6 ): δ 160.49, 152.38, 146.83, 140.01, 133.39, 133.31, 130.47, 128.97, 124.04, 122.69, 120.75, 118.33, 117.35, 114.91. HRMS-ESI (m/z): [M+H] + calc. for C 14 H 10 BrClN 3 OS + , 381.94110; Found: 381.94110. HPLC (λ 280 ): Purity 99.9%; t R : 19.44 min (method 3). 1-(3-chlorophenyl)-3-(6-(furan-2-yl)benzo[d]thiazol-2-yl)ure a (MCK162): Synthesized following the general procedure (C) using 1-(6-bromobenzo[d]thiazol-2-yl)-3-(3- chlorophenyl)urea (1.00 g, 2.61 mmol), 2-furanylboronic acid (439 mg, 3.92 mmol), potassium carbonate (1.08 g, 7.83 mmol) and tetrakis triphenylphosphine palladium (300 mg, 0.261 mmol) to afford the title compound as a white powder (473 mg, 49%). 1 H NMR (200 MHz, DMSO-d 6 ) : δ 11.04 (s, 1H), 9.40 (s, 1H), 8.26 (s, 1H), 7.70 (dd, J = 17.4, 6.9 Hz, 4H), 7.52 – 7.26 (m, 2H), 7.11 (d, J = 6.7 Hz, 1H), 6.95 (d, J = 3.1 Hz, 1H), 6.61 (s, 1H). 13 C NMR (50 MHz, DMSO-d 6 ): δ 160.34, 153.00, 152.81, 146.61, 142.66, 140.14, 133.28, 131.71, 130.52, 125.62, 122.58, 122.03, 119.16, 118.23, 117.34, 116.50, 112.15, 105.35. HRMS-ESI (m/z): [M+H] + calc. for C 18 H 13 ClN 3 O 2 S + , 370.04115; Found: 370.04099. HPLC (λ 280 ): Purity 98.8%; t R : 21.00 min (method 3). 1-(3-chlorophenyl)-3-(6-(thiophen-2-yl)benzo[d]thiazol-2-yl) urea (MCK161): Synthesized following the general procedure (C) using 1-(6-bromobenzo[d]thiazol-2-yl)-3-(3- chlorophenyl)urea (1.00 g, 2.61 mmol), 2-thienylboronic acid (502 mg, 3.92 mmol), potassium carbonate (1.08 g, 7.83 mmol) and tetrakis triphenylphosphine palladium (300 mg, 0.261 mmol) to afford the title compound as a white powder (383 mg, 38%). 1 H NMR (200 MHz, DMSO-d 6 ): δ 11.02 (s, 1H), 9.40 (s, 1H), 8.25 (s, 1H), 7.72 (d, J = 17.1 Hz, 3H), 7.53 (d, J = 4.3 Hz, 2H), 7.43 – 7.28 (m, 2H), 7.13 (dd, J = 9.1, 5.3 Hz, 2H). 13 C NMR (101 MHz, DMSO- d6): δ 160.22, 152.59, 145.96, 143.28, 140.33, 133.25, 130.82, 130.55, 128.96, 128.52, 125.34, 124.00, 123.44, 122.61, 122.54, 118.38, 118.22, 117.36. HRMS-ESI (m/z): [M+H] + calc. for C 18 H 13 ClN 3 OS 2 + , 386.01831; Found: 386.01810. HPLC (λ 280 ): Purity 95.1%; t R : 12.48 min (method 3). 1-(3-chlorophenyl)-3-(6-(thiophen-3-yl)benzo[d]thiazol-2-yl) urea (MCK163): Synthesized following the general procedure (C) using 1-(6-bromobenzo[d]thiazol-2-yl)-3-(3- chlorophenyl)urea (1 g, 2.61 mmol), 3-thienylboronic acid (501 mg, 3.92 mmol), potassium carbonate (1.08 g, 7.83 mmol) and tetrakis triphenylphosphine palladium (300 mg, 0.261 mmol) to afford the title compound as a white powder (423 mg, 42%). 1 H NMR (200 MHz, DMSO-d 6 ): δ 11.12 (br. s, 1H), 9.41 (s, 1H), 8.29 (s, 1H), 7.89 (s, 1H), 7.83 – 7.73 (m, 2H), 7.71 – 7.55 (m, 3H), 7.37 (q, J = 8.3 Hz, 2H), 7.11 (d, J = 6.9 Hz, 1H). 13 C NMR (50 MHz, DMSO-d 6 ): δ 160.3, 152.8, 146.1, 141.2, 140.2, 133.3, 131.6, 130.5, 130.4, 127.0, 126.2, 124.5, 122.5, 120.4, 118.9 (2C), 118.2, 117.3. HRMS-ESI (m/z): [M+H] + calc. for C 18 H 13 ClN 3 OS 2 + , 386.01831; Found: 386.01877. HPLC (λ 280 ): Purity 99.8%; tR: 21.15 min (method 3). 1-(3-chlorophenyl)-3-(6-(naphthalen-1-yl)benzo[d]thiazol-2-y l)urea (MCK164): Synthesized following the general procedure (C) using 1-(6-bromobenzo[d]thiazol-2-yl)-3-(3- chlorophenyl)urea (1.00 g, 2.61 mmol), naphthalene-1-boronic acid (674 mg, 3.92 mmol), potassium carbonate (1.08 g, 7.83 mmol) and tetrakis triphenylphosphine palladium (300 mg, 0.261 mmol) to afford the title compound as a white powder (583 mg, 52%). 1 H NMR (200 MHz, DMSO-d 6 ): δ 11.09 (br. s, 1H), 9.45 (s, 1H), 8.13 – 7.92 (m, 3H), 7.83 (dd, J = 10.5, 8.9 Hz, 3H), 7.65 – 7.31 (m, 7H), 7.11 (d, J = 7.2 Hz, 1H). 13 C NMR (50 MHz, DMSO-d 6 ): δ 160.7, 152.8, 146.2, 140.2, 139.3, 134.9, 133.5, 133.3, 131.0 (2C), 130.5, 128.3, 128.1, 127.6, 127.2, 126.4, 125.9, 125.5, 125.4, 122.7, 122.5, 118.4, 118.3, 117.3. HRMS-ESI (m/z): [M+H] + calc. for C 24 H 17 ClN 3 OS + , 430.07754; Found: 430.07764. HPLC (λ 280 ): Purity 97.3%; tR: 22.33 min (method 3). 1-(3-chlorophenyl)-3-(6-(pyridin-2-yl)benzo[d]thiazol-2-yl)u rea (MCK172): To a solution of (Z)-N'-(6-bromobenzo[d]thiazol-2-yl)-N-(3-chlorophenyl)carba mimidic acid (500.00 mg, 1.30 mmol, 1eq) and pyridin-2-ylboronic acid (239.69 mg, 1.95 mmol, 1.5eq) in a mixture of degassed dioxane/water (24 mL/6 mL), was added K 2 CO 3 (719 mg, 5.2 mmol, 4eq) followed by Pd(PPh 3 ) 4 (152 mg, 0.13 mmol, 0.1eq.). The reaction mixture was stirred overnight at reflux temperature, then cooled down to r.t. and partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic layers were dried with Na2SO4 and concentrated under reduced pressure to afford a brown-orange residue. Purification by silica gel flash chromatography (CHCl 3 /MeOH, 100/0 to 95/5, v/v) afforded the title compound as beige solid (494 mg, 22%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.15 (br. s, 1H), 9.43 (s, 1H), 8.96 (s, 1H), 8.56 (d, J = 4.0 Hz, 1H), 8.33 (s, 1H), 8.13 (d, J = 8.1 Hz, 1H), 7.76 (s, 3H), 7.49 (dd, J = 7.8, 4.8 Hz, 1H), 7.38 (dt, J = 15.9, 7.9 Hz, 2H), 7.11 (d, J = 7.2 Hz, 1H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 160.8, 149.2, 148.2, 147.8, 147.7, 140.2, 135.4, 134.5, 134.1, 133.3, 132.0, 130.6, 125.2, 123.9, 122.6, 120.1, 119.4, 118.3, 117.4. HRMS-ESI (m/z): [M+H] + calc. for C 19 H 14 ClN 4 OS + , 381.0571; Found: 381.0574. HPLC (λ 254 ): Purity 96.3 %; tR: 8.02 min (method 5). Example B: Biology Material and Methods: Cell culture: Uveal melanoma cells were derived from the primary tumor (eye tumor, MP38 and MP46) and one is from liver metastasis (MM66) were a kind gift from Dr. Roman Roman (Curie Institute). UM cells were cultured in RPMI medium supplemented with 20% FBS. Cell viability (XTT): Cells (5x10 3 cells/100 μl) were incubated in a 96-well plate with different effectors for the times indicated in the figure legends. 50 μl of sodium 3′-[1- phenylaminocarbonyl)-3,4- tetrazolium]-bis(4-methoxy-6-nitro) benzene sulfonic acid hydrate (XTT) reagent was added to each well. The assay is based on the cleavage of the yellow tetrazolium salt XTT to form an orange formazan dye by metabolically active cells. Absorbance of the formazan product, reflecting cell viability, was measured at 490 nm. Each assay was performed in quadruplicate. Immunoblotting: Cells were lysed in SDS 7.5%; glycerol 30%; Tris 0.3 M pH 6.8 lysis buffer. 30 μg of proteins were separated on 10% SDS– polyacrylamide gels and transferred on PVDF membranes. The following primary antibodies were used: SLUG (Cell signaling, ref:9585) and HSP90 (Cell signaling, ref:4877). Analyses by RT-qPCR: RNA from cells were purified with the RNeasy Mini Kit (Quiagen). The “QuantiTect Reverse Transcription Kit” (Qiagen) was used for cDNA obtention. The PCR program was executed on “Professional Basic Thermocycler” (Biometra). SYBR master mix plus (Eurogentec) was used for qPCR. The mRNA levels were normalized to 36B4 mRNA. Migration assays: 50 000 cells were cultured in RPMI 0% FCS and seeded in Boyden chambers. After 24 h, Boyden chambers were washed with PBS. Migrative cells were fixed with paraformaldehyde 3% and colored with crystal violet. ROS assay: Deep Red Reagent was used to assess the level of intracellular ROS. The CellROX /Deep Red reagent (which is initially non-fluorescent) freely enters the cells, where it is cleaved by endogenous esterases. After oxidization by ROS, the reagent becomes highly fluorescent with an absorption/emission maximal of 644/665 nm. Cells were treated 24h and incubated at 37 °C with CellROX Deep Red reagent (0.01 μmol/L) for 2 h. The cells were then washed with PBS and analyzed by cytometry. Tumor xenograft experiments: These studies were carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals. Our experiments were approved by the ''Comité National Institutionnel d'Ethique pour l'Animal de Laboratoire''. Five million MP41 cells were injected subcutaneously into the flank of 5-week-old Nod-SDIC female mice (Janvier). When the tumor reached 100 mm3, mice were treated. The tumor volume was determined with a caliper (v = L*l2*0.5). Results: Results are illustrated by Figures 1-5, Tables 2 and 3 below. In vitro efficacy of MCK compounds in comparison with other CXCR1 or/and CXCR2 inhibitors on uveal melanoma cells. Table 2: MCK140 and MCK151 decreased the viability of cells from the primary tumor (MP38 and MP41) and from liver metastases (MM66). Table 3: MCK compounds of the invention decrease the viability of cells from the primary tumor (MP41) and from liver metastases (MM66). IC50 (µM) at 48h. The efficacy of MCK151 on uveal melanoma cells was compared to other CXCR1 and/or CXCR2 inhibitors (Ladarixin and AZD-5069). The results show that MCK151 strongly inhibits the metabolism of UM cells whereas AZD-5069 and Ladarixin have no effect on UM cells (Figure 2A). Inhibition of ROS production by MCK151 and other CXCR1 or/and CXCR2 inhibitors UM cells. Cancer cells, as a result of hypermetabolism, have higher levels of reactive oxygen species (ROS) as compared to normal cells. ROS are also implicated in tumorigenesis (tumor initiation, tumor progression, and metastasis) and favor the aggressiveness of cancer cells and, more particularly, for UM. The inventors have shown that MCK151 inhibits ROS production by UM cells whereas ladarixin has no effect (Figure 2B). Evaluation of the migration ability of uveal melanoma cells treated with MCK151. Whereas MP41 cells isolated from a primary tumor do not migrate, MM66 cells, isolated from a liver metastasis, have this property. MCK151 inhibits this migration ability with an optimal effect at 0.5µM (Figure 3A). Moreover, MCK151 decreases epithelial-mesenchymal transition (EMT) markers. Indeed, MCK151 decreases MMP9 mRNA levels (Figure 3B) and the expression of SLUG (Figure 3C). Altogether, these results show that MCK compounds, in particular MCK151, are efficient for the treatment of primary and metastatic UM. In vivo efficacy of MCK151 on mice treated by intraperitoneal injection. Inventors have evaluated the efficacy of MCK151 in vivo. The growth of experimental tumors generated with MP41 cells in immunodeficient NOD-SCID mice was inhibited by MCK151. in a dose-dependent manner (inhibition of 73% with the 400µg dose) – Figure 4A. At the end of the experiment, the tumors from mice treated with MCK151 were smaller (Figure 4B). Importantly, MCK151 did not modify the weight of mice whatever the concentration (Figure 4C). In vivo efficacy of MCK151 on mice treated by gavage. An oral formulation (10% ethanol in ultrapure water) was developed and tested in the same in vivo model (Figure 5). MCK151 orally administered at 33mg/kg per day, had a trend to decrease tumor growth. However, a 100mg/kg dose reduced tumor growth (50% reduction, Figure 5A). Tumor weight was also reduced by 50% (Figure 5B). At 33 and 100mg/kg/day, MCK151 did not modify mice weight (Figure 5C). These results show that the MCK compounds of the invention, in particular MCK151 can be used by oral route.