Isothiazole derivatives useful as anticancer agents

A compound of the formula

• 14
• or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:
• wherein X1 is O or S;
• R1 is H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, —C(O)(C1-C10 alkyl), —(CH2)t(C6-C10 aryl), —(CH2)t(4-10 membered heterocyclic), —C(O)(CH2)t(C6-C10 aryl), or —C(O)(CH2)t(5-10 membered heterocyclic), wherein t is an integer from 0 to 5;
• said alkyl group optionally includes 1or 2 hetero moieties selected from O, S and —N(R6)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other;
• said aryl and heterocyclic R1 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 5-10 membered heterocyclic group;
• 1 or 2 carbon atoms in the foregoing heterocyclic moieties are optionally substituted by an oxo (═O) moiety;
• the —(CH2)t— moieties of the foregoing R1 groups optionally include a carbon-carbon double or triple bond where t is an integer from 2 to 5;
• and the foregoing R1 groups, except H, are optionally substituted by 1 to 3 R4 groups;
• R2 is selected from the list of substituents provided in the definition of R1, —SO2(CH2)t(C6-C10 aryl), —SO2(CH2)t(5-10 membered heterocyclic), and —OR5, t is an integer ranging from 0 to 5, the —(CH2)t— moieties of the foregoing R2 groups optionally include a carbon-carbon double or triple bond where t is an integer from 2 to 5, and the foregoing R2 groups are optionally substituted by 1 to 3 R4 groups;
• or R1 and R2 may be taken together with the nitrogen to which each is attached to form a 4-10 membered saturated monocyclic or polycyclic ring or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings eoptionally include 1or 2 heteroatoms selected from O, S and —N(R6)— in addition to the nitrogen to which R1 and R2 are attached, said —N(R6)— is optionally ═N— or —N═ where R1 and R2 are taken together as said heteroaryl group, said saturated ring optionally may be partially unsaturated by including 1or 2 carbon-carbon double bonds, and said saturated and heteroaryl rings, including the R6 group of said —N(R6)—, are optionally substituted by 1 to 3 R4 groups;
• R3 is H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, —(CH2)t(C6-C10 aryl), or —(CH2)t(5-10 membered heterocyclic), wherein t is an integer from 0 to 5;
• said alkyl group optionally includes 1 or 2 hetero moieties selected from O, S and —N(R6)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other;
• said aryl and heterocyclic R3 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 5-10 membered heterocyclic group;
• 1 or 2 carbon atoms in the foregoing heterocyclic moieties are optionally substituted by an oxo (═O) moiety;
• the —(CH2)t— moieties of the foregoing R3 groups optionally include a carbon-carbon double or triple bond where t is an integer from 2 to 5, and the foregoing R3 groups are optionally substituted by 1 to 5 R4 groups;
• each R4 is independently selected from C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —OR5, —C(O)R5, —C(O)OR5, —NR6C(O)OR5, —OC(O)R5, —NR6SO2R5, —SO2NR5R6, —NR6C(O)R5, —C(O)NR5R6, —NR5R6, —S(O)jR7 wherein j is an integer ranging from 0 to 2, —SO3H, —NR5(CR6R7)tOR6, —(CH2)t(C6-C10 aryl), —SO2(CH2)t(C6-C10 aryl), —S(CH2)t(C6-C10 aryl), —O(CH2) t(C6-C10 aryl), —(CH2)t(5-10 membered heterocyclic), and —(CR6R7)mOR6, wherein m is an integer from 1 to 5 and t is an integer from 0 to 5;
• said alkyl group optionally contains 1or 2 hetero moieties selected from O, S and —N(R6)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other;
• said aryl and heterocyclic R4 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 5-10 membered heterocyclic group;
• 1 or 2 carbon atoms in the foregoing heterocyclic moieties are optionally substituted by an oxo (═O) moiety;
• and the alkyl, aryl and heterocyclic moieties of the foregoing R4 groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —NR6SO2R5, —SO2NR5R6, —C(O)R5, —C(O)OR5, —OC(O)R5, —NR6C(O)R5, —C(O)NR5R6, —NR5R6, —(CR6R7)mOR6 wherein m is an integer from 1 to 5, —OR5 and the substituents listed in the definition of R5;
• each R5 is independently selected from H, C1-C10 alkyl, —(CH2)t(C6-C10 aryl), and —(CH2)t(5-10 membered heterocyclic), wherein t is an integer from 0 to 5;
• said alkyl group optionally includes 1 or 2 hetero moieties selected from O, S and —N(R6)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other;
• said aryl and heterocyclic R5 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 5-10 membered heterocyclic group;
• and the foregoing R5 subsituents, except H, are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —C(O)R6, —C(O)OR6, —CO(O)R6, —NR6C(O)R7, —C(O)NR6R7, —NR6R7, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy;
• and,
• each R6 and R7 is independently H or C1-C6 alkyl;
• with the proviso that said compound of formula 1is not 1-methyl-3-(4-carbamoyl-3-ethoxy-5-isothiazolyl)urea, 1,1-dimethyl-3-(4-carbamoyl-3-ethoxy-5-isothiazolyl)urea, 1-methyl-3-(4-carbamoyl-3-propoxy-5-isothiazolyl)urea, 1-methyl-3-(4-carbamoyl-3-(methylthio)-5-isothiazolyl)urea, 1-methyl-3-(4-carbamoyl-3-(ethylthio)-5-isothiazolyl)urea, 1,1-dimethyl-3-(4-carbamoyl-3-(ethylthio)-5-isothiazolyl)urea, 1-methyl-3-(4-carbamoyl-3-(propylthio)-5-isothiazolyl)urea, 1,1-dimethyl-3-(4-carbamoyl-3-(propylthio)-5-isothiazolyl)urea, or 1-methyl-3-(4-carbamoyl-3-(isopropylthio)-5-isothiazolyl)urea.