Patent EA-004935-B1 (EA)
Title: Isothiazole derivatives useful as anticancer agents
Inventor: LARSON ERIC ROBERT
IPC: C07C327/38
Filed: 1999-05-03
Abstract: 1. A compound of the formula or a pharmaceutically acceptable sail, prodrug or solvate thereof, wherein X<1> is O or S; R<1> is -(CH2)t(4-5 membered heterocyclic), wherein t is an integer from 0 to 5; said heterocyclic group is optionally fused to a C6-C10aryl group, a C3-C8 saturated cyclic group, or a 5-10 membered heterocyclic group; and said R<1> group, including the optionally fused portions of said R<1> group, is optionally substituted by 1 or 2 substituents independently selected from C1-C4 alkyl, hydroxy and hydroxymethyl; R<2> is H; R<3> is H, C1-C10 alkyl, C2-C10 alkenyl, -(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 include 1 or 2 hetero moieties selected from O, S and -N(R<6>)- 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 R<3> 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 R<3> groups optionally include a carbon-carbon double or triple bond where t is an integer from 2 to 5, and the foregoing R<3> groups are optionally substituted by 1 to 5 R<4> groups; each R<4> is independently selected from C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -OR<5>, -C(O)R<5>, -C(O)OR<5>, -NR<6>C(O)OR<5>, -OC(O)R<5>, -NR<6>SO2R<5>, -SO2NR<5>R<6>, -NR<8>C(O)R<5>, -C(O) NR<5>R<6>, -NR<5>R<6>, -S(O)jR<7> wherein j is an integer ranging from 0 to 2, - SO3H, -NR<5>(CR<6>R<7>)tOR<6>, -(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 -(CR<6>R<7>)m,OR<6>, wherein m is an integer from 1 to 5 and t is an integer from 0 to 5; said alkyl group optionally contains 1 or 2 hetero moieties selected from O, S and -N(R<6>)- 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 R<4> 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 hetero-cyclic moieties of the foregoing R<4> groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -NR<6>SO2R<5>, -SO2NR<5>R<6>, -C(O)R<5>, -C(O)OR<5>, -OC(O)R<3>, -NR<6>C(O)R<5>, -C(O)NR<5>R<6>, -NR<5>R<6>, -(CR<6>R<7>)mOR<6> wherein m is an integer from 1 to 5, -OR<5> and the substituents listed in the definition of R<5>; each R<5> 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(R<6>)- 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 R<5> 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 R<5> substituents, except H, are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -C(O)R<6>, - C(O)OR<6>, -CO(O)R<6>, -NR<6>C(O)R<7>, -C(O)NR<6>R<7>, -NR<6>R<7>, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy; and each R<6> and R<7> is independently H or C1-C6 alkyl. 2. A compound according to claim 1 wherein R<3> is -(CH2)t(6-10-membered aryl) wherein t is an integer from 1 to 3 and said R<3> group is optionally substituted by 1 to 4 R<4> groups. 3. A compound according to claim 2 wherein R<3> is benzyl optionally substituted by 1 to 4 substituents independently selected from halo and C1-C4 alkyl. 4. A compound according to claim 3 wherein R<3> is benzyl substituted by 1 to 4 substituents independently selected from methyl, micro, chloro and bromo. 5. The compound of claim 1, wherein R<1> is -(CH2)t(4-membered heterocyclic). 6. The compound of claim 1, wherein R<1> is -(CH2)t(5-membered heterocyclic). 7. The compound of claim 6, wherein the 5-membered heterocyclic is selected from the group consisting of pyrrolidine, imidazole, furan and tetrazole. 8. The compound of claim 7, wherein the 5-membered heterocyclic is pyrrolidine. 9. A compound according to claim 1 selected from the group consisting of: mesylate salt of 3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid amide; hydrochloride salt of 3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isolhiazole-4-carboxylic acid amide; 3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid amide; 3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[-(1-methyl-pyrrolidin-2-yl)-ethyl]-ureido}-isothiazole-4-carboxylic acid amide: 3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid amide; 3-(4-Chioro-2,6-difluoro-benzyloxy)-5-[3-(3-hydroxy-5-pyrrolidin-1-yl)-pentyl)-ureido]-isothiazole-4-carboxylic acid amide; 3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(3,4-dihydroxy-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylic acid amide; 3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[4-(3,4-dihydroxy-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylic acid amide; 3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylic acid amide; 3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[4-(2-hydroxy methyl-pyrrolidin-1-y l)-butyl]-ureido} isothiazole-4-carboxylic acid amide; 3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(3-hydroxy-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylic acid amide; 3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl]-ureido]-isothiazole-4-carboxylic acid amide; 3-(2,6-Difiuoro-4-methyl-benzyloxy)-5-[3-(3-hydroxy-5-pyrrolidin-1-yl-pentyl)-ureido]-isothiazole-4-carboxylic acid amide; 5-[3-(4-Pyrrolidin-1-yl-butyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylic acid amide: 5-[3-(3-Hydroxy-5-pyrrolidin-1-yl-pentyl)-ureido]-3-(2,3,6-triftuoro-4-methyl-benzyloxy)-isothiazole-4-carboxylic acid amide; 3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-[3-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-ureido}-isothiazole-4-carboxylic acid amide; 3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-[3-(4-pyrroIidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid amide; 3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-{3-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylic acid amide; 5-{3-[2-(1-Methyl-pyrrolidin-2-yl)-ethyl]-ureido}-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylic acid amide; 5-[3-(3-Pyrrolidin-1-yl-propyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylic acid amide; 3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(4-imidazol-1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid amide; 3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-[3-(3-hydroxy-5-pyrrolidin-1-yl-pentyl)-ureido]-isothiazole-4-carboxylic acid amide; 3-(2,6-Difluoro-4-methyl-benzyloxy)-5-{3-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-ureido}-isothiazole-4-carboxylic acid amide; 3-(4-Bromo-2,3,6-trifluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid amide; 3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-[3-(4-imidazol-1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid amide; and 3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(3-pyrrolidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylic acid amide; and the pharmaceutically acceptable salts, prodrugs and solvates of said compounds. 10. 3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid amide, or a pharmaceutically acceptable salt of said compound, or a prodrug of said compound or said pharmaceutically acceptable salt of said compound. 11. The compound of claim 9, wherein said compound is the hydrochloride salt of 3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid amide. 12. The compound of claim 9, wherein said compound is the mesylate salt of 3-(4-Bromo-2,6-difluoro-benzylosy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid amide. 13. A pharmaceutical composition for the treatment of a hyperproliferative disorder in a mammal which comprises a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier. 14. The pharmaceutical composition of claim 13 wherein said hyperproliferative disorder is a cancer selected from brain, lung, squamous cell, bladder, gastric, pancreatic, breast, head, neck, renal, kidney, ovarian, prostate, colorectal, oesophageal, gynecological and thyroid cancer. 15. The pharmaceutical composition of claim 13 wherein said disorder is a non-cancerous hyperproliferative disorder. 16. The pharmaceutical composition of claim 15 wherein said disorder is a benign hyperplasia of the skin or prostate. 17. The pharmaceutical composition of claim 13, wherein said compound is the hydrochloride salt of 3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid amide. 18. The pharmaceutical composition of claim 13, wherein said compound is the mesylate salt of 3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid amide. 19. A method of treating a hyperproliferative disorder in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound according to claim 1. 20. The method of claim 19 wherein said method is for the