MXPA00011849A - Isothiazole derivatives useful as anticancer agents - Google Patents

Abstract

The present invention relates to compounds of formula (1) and to pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein X1, R1, R2 and R3 are as defined herein. The invention also relates to pharmaceutical compositions containing the above compoundsand to methods treating hyperproliferative disorders in mammals by administering the above compounds.

Description

DERIVATIVES OF ISOTIAZOL USEFUL AS ANTICANCER AGENTS BACKGROUND OF THE INVENTION This invention relates to new isothiazole derivatives which are useful in the treatment of hyperproliferative diseases, such as cancers, in mammals. This invention also relates to a method of using such compounds in the treatment of hyperproliferative diseases in mammals, especially humans, and to pharmaceutical compositions containing such compounds. It is known that a cell can become cancerous due to the transformation of a portion of its DNA into an oncogene (that is, a gene that upon its activation leads to the formation of malignant tumor cells). Many oncogenes encode proteins that are aberrant tyrosine kinases capable of causing cell transformation. Alternatively, overexpression of a normal proto-oncogenic tyrosine kinase may also cause proliferative disorders, which are sometimes a cause of a malignant phenotype. It has been shown that certain tyrosine kinases can be mutated or overexpressed in many human cancers such as brain, lung, squamous cell, bladder, gastric, breast, head and neck, esophagus, gynecological and thyroid cancers. In addition, overexpression of a ligand of a receptor tyrosine kinase can cause an increase in the activation state of the receptor, which causes the proliferation of tumor cells or endothelial cells. Thus, it is believed that inhibitors of the tyrosine kinase receptor, such as compounds of the present invention, are useful as selective inhibitors of the growth of mammalian cancer cells. It is known that polypeptide growth factors, such as vascular endothelial growth factor (VEGF) that have a high affinity for the receptor containing the human kinase domain insert (KDR) or the mouse fetal hepatic kinase receptor 1 (FLK-1), have been associated with the proliferation of endothelial cells and more specifically with vasculogenesis and angiogenesis. See PCT international application publication WO 95/21613 (published August 17, 1995). Agents, such as the compounds of the present invention, which are capable of binding or modulating the KDR / FLK-1 receptor can be used to treat disorders related to vasculogenesis or angiogenesis such as diabetes, diabetic retinopathy, hemangioma, glioma, melanoma. , Kaposi's sarcoma and cancer of the ovary, breast, lung, pancreas, prostate, colon and epidermoid. In the patents of E.U.A. 4,059,433 and 4,057,416 both assigned or FMC Corporation are referred to as isothiazole derivatives useful as herbicides.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to compounds of formula I; and pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein: X1 is O or S; R1 is H, C? -C10 alkyl, C2-C? Alkenyl, C2-C10 alkynyl, -C (O) (C1-C10 alkyl), - (Ch C6-C10 aryl), - (CH2) t- ( 4-10 membered heterocycle), -C (O) (CH2) t (C6-C10 aryl) or -C (O) (CH2) t (5-10 membered heterocycle), where t is an integer of 0 to 5; the aforementioned alkyl group optionally includes 1 or 2 heterradicals selected from O, S and -N (R6) - with the proviso that two O atoms, two S atoms or one O and S atom are not bound Directly one to another; the aforementioned aryl and heterocyclic groups R1 are optionally fused with a C 1 -C 4 aryl group, a C 5 -C 8 saturated cyclic group or a 5-10 membered heterocyclic group; 1 or 2 carbon atoms of the preceding cyclic heteroradicals are optionally substituted with an oxo radical (= O); the radicals - (CH2) t- of the preceding R1 groups optionally include a double or triple carbon-carbon bond where t is an integer from 2 to 5; and the preceding R1 groups, except H, are optionally substituted with 1 to 3 R4 groups; R2 is selected from the list of substituents given in the definition of R1, -SO2 (CH2) t (C6-C10 aryl), -SO2 (CH2) t - (5-10 membered heterocycle), and -OR5, t is an integer from 0 to 5, the radicals - (CH2) r of the preceding R2 groups optionally include a double or triple carbon-carbon bond where t is an integer from 2 to 5; and the preceding R2 groups are optionally substituted with 1 to 3 R4 groups; or R1 and R2 can be taken together with the nitrogen to which they are attached to form a saturated monocyclic or polycyclic ring of 4-10 links or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings include optionally 1 or 2 heteroatoms selected from O, S and -N (R6) - in addition to the nitrogen to which R1 and R2 are attached, the -N (R6) -cited is optionally = N- or -N = where R1 and R2 are taken together as the aforementioned heteroaryl group, the aforementioned saturated ring may optionally be partially unsaturated by including 1 or 2 carbon-carbon double bonds, and the saturated and heteroaryl rings mentioned, including the R6 group of -N (R6) - mentioned, they are optionally substituted with 1 to 3 R4 groups. R3 is H, C -C10 alkyl, C2-C10 alkenyl, C2-C- alkynyl-, - (CH2) t (C6-C6O aryl) or - (CH2) t- (5-10 membered heterocycle) , where t is an integer from 0 to 5; the aforementioned alkyl group optionally includes 1 or 2 heteroradioles selected from O, S and -N (R6) - with the proviso that two O atoms, two S atoms or an O and S atom do not they are directly linked to one another; the aforementioned aryl and heterocyclic groups R3 are optionally condensed with a C6-C6 aryl group, a C5-C8 saturated cyclic group > or a 5-10 membered heterocyclic group; 1 or 2 carbon atoms of the preceding cyclic heteroradicals are optionally substituted with oxo radicals (= O); the radicals - (CH2) t- of the preceding R3 groups optionally include a double or triple carbon-carbon bond where t is an integer from 2 to 5; and the foregoing R3 groups are optionally substituted with 1 to 5 R4 groups; each R4 is independently selected from among alkyl C1-C10, C2-C10 alkenyl, C2-C10 alkynyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -OR5, -C (O) R5, -C (O) OR5, -NR6C (O) OR5, -OC (0) R5, -NR6SO2R5, -SO2NR5R6, -NR6C (O) R5, -C (O) NR5R6, -NR5R6, -S (O) jR7 where j is an integer between 0 and 2, -SO3H, -NR5 (CR6R7) tOR6, - (CH2) t (C6-C10 aryl), -SO2 (CH2) t (C6-C? O aryl), -S (CH2) t (C6-C? 0 aryl), - O (CH2) t (C-C10 aryl), - (CH2) t (5-10-membered heterocycle) and - (CR6R7) mOR6, where m is an integer from 1 to 5 and t is an integer from 0 to 5; the aforementioned alkyl group optionally includes 1 or 2 heteroradioles selected from O, S and -N (R6) - with the proviso that two O atoms, two S atoms or an O and S atom do not they are directly linked to one another; the aforementioned aryl and heterocyclic groups R4 are optionally condensed with a C6-C10 aryl group, a C5-C8 saturated cyclic group or a 5-10-membered heterocyclic group; 1 or 2 carbon atoms of the preceding cyclic heteroradicals are optionally substituted with an oxo radical (= O); and the alkyl, aryl and heterocyclic radicals of the preceding R4 groups are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -NR6SO2R5, -S02NR5R6, -C (O) R5, -C (O) OR5, -OC (O) R5, -NR6C (O) R5, -C (O) NR5R6, -NR5R6, - (CR6R7) mOR6, where m is an integer from 1 to 5, -OR5 and the substituents given in the definition of R5; each R5 is independently selected from H, C1-C10 alkyl, - (CH2) t (aryl CT-CIO) and - (5- to 10-membered CHbMheterocycle), where t is an integer from 0 to 5; the aforementioned alkyl group optionally includes 1 or 2 heteroradicals selected from O, S and -N (R6) - with the proviso that two O atoms, two S atoms or one O and S atom are not linked Directly one to another; the aryl and heterocyclic groups R5 mentioned are optionally condensed with a C6-C10 aryl group, a C5-Cs saturated cyclic group or a 5-10-membered heterocyclic group; and the preceding R5 substituents, except H, are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -C (O) R6, -C (O) OR6, - CO (O) R 8, -NR 6 C (O) R 7, -C (O) NR 6 R 7, -NR 6 R 7, hydroxyl, C 6 alkyl, and C 6 C alkoxy; and each R6 and R7 is independently H or alkyl with the proviso that said compound of formula 1 is 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-propioxy-5-isothiazolyl) urea, 1-methyl-3- (4-carbamoyl) 3- (thiomethyl) -5-isothiazolyl) urea, 1-methyl-3- (4-carbamoyl-3- (thioethyl) -5-isothiazolyl) urea, 1,1-dimethyl-3- (4-carbamoyl) 3- (thioethyl) -5-isothiazolyl) urea, 1-methyl-3- (4-carbamoyl-3- (thiopropyl) -5-isothiazolyl) urea, 1,1-dimethyl-3- (4-carbamoyl-3-) (thiopropyl) -5-isothiazolyl) urea or 1-methyl-3- (4-carbamoyl-3- (thioisopropyl) -5-isothiazole) urea. Preferred compounds include those of formula 1 wherein R 2 is H and R 1 is C 1 -C 10 alkyl optionally substituted with 1 or 2 substituents independently selected from -NR 5 R 6, -NR 5 (CR 6 R 7) tOR 6 and - (CH2) r (heterocycle and 5-10 links), where t is an integer from 0 to 5. Preferred concrete R1 groups include propyl, butyl, pentyl and hexyl optionally substituted with dimethylamino, hydroxyl, pyrrolidinyl, morpholino and ethyl- (2-hydroxyethyl) -amino. Other preferred compounds include those of formula 1 wherein R2 is H and R1 is - (CH2) t (5-10 membered heterocycle), where t is an integer from 0 to 5; said heterocyclic group is optionally condensed with a Ce-Cι aryl group, a C5-C8 saturated cyclic group or a 5-10-membered heterocyclic group; and said group R1, including the optionally condensed portions of said group R1, are optionally substituted by 1 or 2 substituents independently selected from C? -C alkyl., hydroxyl and hydroxymethyl. The preferred concrete heterocyclic groups of said group R1 are morpholino, pyrrolidinyl, imidazolyl, piperazinyl, piperidinyl and 2,5-diaza-bicyclo [2.2.1] hept-2-yl, the variable t of said group R1 is between 2 and 5, and the heterocyclic groups mentioned are optionally substituted with hydroxyl, hydroxymethyl and methyl. Other preferred compounds include those of formula 1 in which R 3 is - (CH 2) t (aryl Ce-Cι) where t is an integer between 1 and 3 and said group R 3 is optionally substituted with 1 to 4 R 4 groups. Particular preferred R3 groups include benzyl optionally substituted with 1 to 4 substituents independently selected from halo and CrC alkyl. More preferred preferred R3 groups include benzyl optionally substituted with 1 to 4 substituents independently selected from methyl, fluorine, chlorine and bromine. Specific embodiments of the present invention include the following compounds: 5- acid amide. { 3- [3- (4-Methyl-piperazin-1-yl) -propyl] -uredode} -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- (3- {4- [ethyl- (2-hydroxy-ethyl) -amino] -butyl} -ureide} -isothiazole-4-carboxylic acid 3- (2-fluoro-4-methyl-benzyloxy) -5-. {3- [3- (4-methyl-piperazin-1-yl) -propyl] -amide -ureido.} -isothiazole-4-carboxylic acid 3- (2,5-difluoro-4-methyl-benzyloxy) -5- [3-4- [4- (2-hydroxyethyl) amide ) -piperazin-1-yl] -butyl} -ureido) -isothiazole-4-carboxylic acid; 3- (2,5-difluoro-4-methyl-benzyloxy) -5- [3- (6-dimethylamino-hexyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4-methyl-benzyloxy) -5- [3- (5-isopropylamino-pentyl) -ureido] -isothiazole-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- acid amide. { 3- [3- (4-methyl-piperazin-1-yl) -propyl] -ureido} -isothiazole-4-carboxylic acid; 3- (4-chloro-2) 6-difluoro-benzyloxy) -5- acid amide. { 3 - [(1-methy1-pyrrolidin-2-yl) -ethyl] -ureido} -isothiazole-4-carboxylic acid; 3- (2,6-difluoro-4-methyl-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- [3-. { 4- [4- (2-hydroxy-ethyl) -piperazin-1-yl} -butil} -ureido) -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- [3- (3-hydroxy-5-pyrroidin-1-yl) -pentyl) -ureido acid amide} -isothiazole-4-carboxylic acid; 3- (2,5-difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [4- (3,4-Dihydroxy-pyrrolidin-1-yl) -butyl] -ureido} -isothiazole-4-carboxylic acid; 3- (4-chloro-2,6-difluoro-benzyloxy) -5- acid amide. { 3- [4- (3,4-dihydroxy-pyrrolidin-1-yl) -butyl] -urethane} -isothiazole-4-carboxylic acid; 3- (2,5-difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [4- (2-hydroxymethyl-pyrrolidin-1-yl) -butyl] -uredode} -isothiazole-4-carboxylic acid; 3- (4-chloro-2,6-difluoro-benzyloxy) -5- acid amide. { 3- [4- (2-hydroxymethyl-pyrrolidin-1-yl) -butyl] -ureido} -isothiazole-4-carboxylic acid; 3- (2,5-difiuoro-4-methyl-benzyloxy) -5- acid amide. { 3- [4- (3-hydroxy-pyrrolidin-1-yl) -butyl] -ureido} -isothiazole-4-carboxylic acid; 3- (4-bromo-2,6-difluoro-benzyloxy) -5- [3- (4-pyrrolidol-1-yl-butyl) -ureido acid amide} isothiazole-4-carboxylic acid; 3- (4-bromo-2,6-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido acid amide mesylate salt} -isothiazole-4-carboxylic acid; 3- (2,6-difluoro-4-methyl-benzyloxy) -5- [3- (4-hydroxy-5-piperidin-1-yl-pentyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,5-difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- (4- (3-hydroxy-5-piperidin-1-yl-pentyl) -ureido] -isotrazole-4-carboxylic acid amide of 3- (4-chloro-2,6-difluoro- benzyloxy) -5- { 3- [4- (2-hydroxymethyl-piperidin-1-yl) -butyl] -ureido} -isothiazole-4-carboxylic acid amide of 3- (2, 5-difluoro-4-methyl-benzyloxy) -5- (3- {4- [ethyl- (2-hydroxyethyl) -amino] -butyl} -ureido) -isothiazole-4-carboxylic acid 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- [3- (5-hydroxy-6-p -peridin-1-yl) -hexyl) -ureido acid amide} -isothiazole-4-carboxylic acid; 3- (4-bromo-2,3,6-trifluoro-benzyloxy) -5- acid amide. { 3- [3- (4-methyl-piperazin-1-yl) -propyl] -ureido} -isothiazole-4-carboxylic acid; 3- (2,6-difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [3- (4-methyl-piperazin-1-yl-propyl] -ureido.} - isothiazole-4-carboxylic acid; hydrochloride salt of 3- (4-bromo-2,6-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido acid amide} -isothiazole-4-carboxylic acid; 3- (2,6-difiuoro-4-methyl-benzyloxy) -5- [3- (3-hydroxy-5-pyrrolidin-1-yl-pentyl) -ureido acid amide} -isothiazole-4-carboxylic acid; 5- [3- (4-Pyrrolidin-1-yl-butyl) -uredodo-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-trifluoro-4-methyl-benzyloxy) -isothiazole-4-acid amide -carboxylic; 3- (4-chloro-2,6-difluoro-benzyloxy) -5- acid amide. { 3- [3- (5-methyl-2,5-diaza-bicyclo [2.2.1] hept-2-yl) -propyl] -ureido} -isothiazole-4-carboxylic acid; 3- (4-chloro-2,3,6-trifluoro-benzyloxy) -5- acid amide. { 3- [3- (5-Methyl-2,5-diaza-bicyclo [2.2.1] hept-2-yl) -propyl] -ureido} -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,3,6-trifluoro-benzyloxy) -5- acid amide. { 3- [2- (1-methyl-pyrrolidin-2-yl) -ethyl] -ureido} -isothiazole-4-carboxylic acid; 3- (4-Chloro-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- acid amide. { 3- [4- (2-hydroxymethyl-pyrrolidin-1-yl) -butyl] -ureido} -isothiazole-4-carboxylic acid; 5- acid amide. { 3- [2- (1-methyl-pyrrolidin-2-yl) -ethyl] -uredo} -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -sothiazole-4-carboxylic acid; 5- [3- (4-dimethylamino-butyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; - [3- (3-dimethylamino-propyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (3-hydroxy-5-isopropylamino-pentyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (3-Isopropylamino-propyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- acid amide. { 3- [4- (4-Methyl-piperazin-1-yl) -butyl] -ureido} -3- (213,6-Trifluoro-4-methyl-benzyl) -isothiazole-4-carboxylic acid; 5- (3 { 4- [4- (2-Hydroxy-ethyl) -piperazin-1-yl] -butyl} -ureido) -3- (2) 3,6-trifluoro- acid amide 4-methyl-benzyloxy) -isothiazole-4-carboxylic acid; 5- [3- (3-pyrrolidin-1-yl-propyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (4-Hydroxy-5-piperidin-1-yl-pentyl) -ureido] -3- (2> 3,6-trifluoro-4-methyl-benzyloxy) acid amide Sothiazole-4-carboxylic acid; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- [3- (4-imidazol-1-yl-butyl) -ureido] -sothiazole-4-carboxylic acid amide; 5- (3. {4- [Ethyl- (2-hydroxy-ethyl) -amino] -butyl] -ideido) -3- (2,3,6-trifluoro-4-) acid amide methyloxybenzyloxy) -isothiazole-4-carboxylic acid; 3- (4-chloro-2,3,6-trifluoro-benzyloxy) -5- acid amide. { 3- [4- (2-hydroxymethyl-piperidin-1-yl) -butyl] -ureido} -isothiazole-4-carboxylic acid; 3- (4-Chloro-2I3,6-trifluoro-benzyloxy) -5- [3- (3-hydroxy-5-pyrrolidin-1-yl-pentyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-bromo-2,6-difluoro-benzyloxy) -5- acid amide. { 3- [3- (4-methyl-piperazin-1-yl) -propyl] -ureido} -isothiazole-4-carboxylic acid; 3- (2,6-difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [2- (1-methyl-pyrroidin-2-yl) -ethyl] -ureido} -isothiazole-4-carboxylic acid; 3- (2,6-difluoro-4-methyl-benzyloxy) -5- [3- (4-dimethylamino-butyl] -ureido} -. isothiazole-4-carboxylic acid amide: 3- (2-amide) , 6-difluoro-4-methyl-benzyloxy) -5- [3- (3-dimethylamino-propyl) -ureido] -isot-azole-4-carboxylic acid amide of 3- (4-bromo-2,3, 6-Trifluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido] -isothiazole-4-carboxylic acid amide of 3- (4-chloro-2,3, 6-Trifluoro-benzylloxy) -5- [3- (4-imidazol-1-yl-butyl) -ureido] -isothiazole-4-carboxylic acid amide of 3- (4-chloro-2,3, 6-difluoro-benzyloxy) -5- (3- {3- [ethyl- (2-hydroxy] -ethyl) -amino] -propyl} -ureido) -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,3,6-trifluoro-benzyloxy) -5- (3- {3- [ethyl- (2-hydroxy-ethyl) -amino] -propyl} -ure do) -isothiazole-4-carboxylic acid 5- [3- (3-methylamino-propyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -siazole 4-carboxylic acid 5- [3- (3-amino-propyl) -3-methyl-ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole- acid amide 4-carb oxalic acid 5- [3- (4-diethylamino-butyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (2,6-difluoro-4-methyl-benzyloxy) -5- [3- (3-pyrroiidin-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (3-Chloro-2,6-difluoro-4-methyl-benzyloxy-5- [3- (4-dimethylamino-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- { 4- [bis- (2-hydroxy-ethyl) -amino] -butyl) -ureido) -3- (2,6-difluoro-4-methyl-benzyloxy) -isotrazole-4-carboxylic acid; and the pharmaceutically acceptable hydrate salts of the preceding compounds. The invention also relates to a pharmaceutical composition for the treatment of a hyperproliferative disorder in a mammal which comprises a therapeutically effective amount of a compound of formula 1, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier. In one embodiment, said pharmaceutical composition is for the treatment of cancer such as brain, lung, squamous, bladder, gastric, pancreatic, breast, head, neck, renal, prosthetic, colorectal, esophageal, gynecological cancer (such as of ovary) or thyroid. In another embodiment, said pharmaceutical composition is for the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis) or prostate (e.g., benign prostatic hypertrophy (BPH)). The invention also relates to a pharmaceutical composition for the treatment of pancreatitis or kidney disease (including pro-proliferative glomerulonephritis and diabetes-induced kidney disease) in a mammal comprising a therapeutically effective amount of a compound of formula 1, or a salt or hydrate pharmaceutically acceptable thereof, and a pharmaceutically acceptable carrier. The invention also relates to a pharmaceutical composition for preventing implantation of the blastocyst in a mammal comprising a therapeutically effective amount of a compound of formula 1, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier. The invention also relates to a pharmaceutical composition for treating a disease related to vasculogenesis or angiogenesis in a mammal comprising a therapeutically effective amount of a compound of formula 1, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically carrier acceptable. In one embodiment, said pharmaceutical composition is for treating a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, skin disease such as psoriasis, eczema and scleroderma, diabetes, retinopathy diabetic, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian cancer, breast, lung, pancreas, prostate, colon and epidermoid. The invention also relates to a method for treating a hyperproliferative disorder in a mammal comprising administering to said mammal a therapeutically effective amount of the compound of formula 1, or a pharmaceutically acceptable salt or hydrate thereof. In one embodiment, said method relates to the treatment of cancer such as brain, squamous, bladder, gastric, pancreatic, breast, head, neck, esophagus, prostate, colorectal, lung, renal, gynecological (such as ovary) or thyroid. In another embodiment, said method refers to the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis) or the prostate (e.g., benign prostatic hypertrophy (BPH)). The invention also relates to a method for the treatment of a hyperproliferative disorder in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of formula 1, or a pharmaceutically acceptable salt or hydrate thereof, in combination with an agent antitumor selected from the group consisting of inhibitors of mitosis, alkylating agents, antimetabolites, antibiotics, intercalators, inhibitors of growth factors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones and antiandrogens. The invention also relates to a method of treating pancreatitis or renal disease in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of formula 1, or a pharmaceutically acceptable salt or hydrate thereof.

The invention also relates to a method for preventing implantation of the blastocyst in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of formula 1, or a pharmaceutically acceptable salt or hydrate thereof. The invention also relates to a method for treating diseases related to vasculogenesis or angiogenesis in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of formula 1, or a pharmaceutically acceptable salt or hydrate thereof. In one embodiment, said method is for the treatment of a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, skin diseases such as psoriasis, eczema and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, macular degeneration, hemangioma, glioma, meianoma, Kaposi's sarcoma and ovarian cancer, breast, lung, pancreas, prostate, colon and epidermoid. In addition to the compounds of the present invention, they can be used as contraceptives in mammals. Among the patients that can be treated with the compounds of formula I, and the pharmaceutically acceptable salts and hydrates of said compounds, according to the methods of this invention are included, for example, patients who have been diagnosed with psoriasis, BPH, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer or anal reglon cancer, stomach cancer, colon cancer, breast cancer, gynecological tumors (eg, uterine sarcomas, fallopian tube carcinoma, endometrial carcinoma, carcinoma of the lining of the uterus, carcinoma of the vagina or carcinoma of the vulva), Hodgkin's disease, cancer of the esophagus, small bowel cancer, cancer of the endocrine system (for example, cancer of the thyroid, parathyroid or adrenal glands), soft tissue sarcomas, cancer of the urethra , cancer of the penis, prostate cancer, chronic or acute leukemia, solid infant tumors, lymphocytic lymphomas, bladder cancer, kidney or ureter cancer (eg, renal cell carcinoma, renal pelvis carcinoma), or system neoplasms central nervous system (eg, major CNS lymphoma, spinal cord tumors, brainstem gliomas, or pituitary adenomas). The present invention also relates to intermediates selected from the group consisting of (2,6-difluoro-4-methyl-phenyl) -methanol, (2,3,6-trifluoro-4-methyl-phenyl) -methanol , (4-bromo-2,6-difluoro-phenyl) -methanol, (4-bromo-2,3,6-trifluoro-phenyl) -methanol, (4-chloro-2,6-difluoro-phenyl) -methanol , (3-chloro-2,6-difluoro-phenyl) -methanol and (4-chloro-2,3,6-trifluoro-phenyl) -methanol. The present invention also relates to an intermediate selected from the group consisting of: The present invention also relates to an intermediate selected from the group consisting of: where R3 is such was previously defined. The present invention also relates to a method of preparing a compound of formula 1 comprising (a) treating a compound of formula with a compound of formula R3-X wherein X is a halo group and R3 is as defined above, and treating the resulting compound with a compound of formula R1R2NH wherein R1 are as defined above; or (b) treating a compound of formula 25 wherein R3 is as defined above, with a compound of formula R1R2NH wherein R1 and R2 are as defined above. The term "halo", as used herein, unless otherwise indicated, includes fluorine, chlorine, bromine or iodine. Preferred halo groups are fluorine, chlorine and bromine.

The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, cyclic or branched radicals. It is understood that at least three carbon atoms in said alkyl group are necessary for cyclic radicals. The term "alkenyl", as used herein, unless otherwise indicated, includes monovalent hydrocarbon radicals having at least one carbon-carbon double bond and also having linear, cyclic or branched radicals with the previous conditions of the definition of "alkyl". The term "alkynyl", as used herein, unless otherwise indicated, includes monovalent hydrocarbon radicals having at least one carbon-carbon triple bond and also having linear, cyclic or branched radicals with the previous conditions of the definition of "alkyl". The term "alkoxy", as used herein, unless otherwise indicated, includes O-alkyl groups wherein "alkyl" is tai as defined above. The term "aryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of a hydrogen such as phenyl or naphthyl.

The term "4-10 membered heterocycle", as used herein, unless otherwise indicated, includes aromatic and non-aromatic heterocyclic groups containing one or more heteroatoms each selected from O, S, and N , in which each heterocyclic group has between 4 and 10 atoms in its ring. The non-aromatic heterocyclic groups include groups having only 4 ring atoms, but the aromatic heterocyclic groups must have at least 5 ring atoms. An example of a 4-membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5-membered heterocyclic group is thiazolyl and an example of the 10-membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, tiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1, 2,3,6-terahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0] hexanyl, 3-azabicyclo [4.1.0] heptanil, 3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groups include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzoimidazolyl, benzofuranyl, cinnolinyl, Ndazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridinyl. The foregoing groups, as derivatives of the compounds given above, can be attached to C or attached to N when possible. For example, a group derived from the pyrrole can be pyrrol-1-yl (attached to N) or pyrrole-3-yl (attached to C). The "pharmaceutically acceptable salt (s)" phase, as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of formula 1. Compounds of formula 1 which are basic in nature are capable of forming a wide variety of salts with various organic and inorganic acids. The acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of formula 1 are those which form non-toxic acid addition salts, ie, salts containing pharmacologically acceptable anions, such as the hydrochloride salts, hydrobromide, Ihydrate, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentis? nato, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e. 1, 1'-methylene-bis- (2-hydroxy-3-naphthoate)]. Those compounds of formula 1 which are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline earth metal salts and specifically, the sodium and potassium salts. Certain compounds of formula 1 can have asymmetric centers and therefore exist in different enantiomeric forms. This invention relates to the use of all optical isomers and stereoisomers of the compounds of formula 1 and mixtures thereof. The compounds of formula 1 can also exist as tautomers. This invention relates to the use of all tautomers and mixtures thereof. The present invention also includes isotopically-labeled compounds, and pharmaceutically acceptable salts thereof, which are identical to those described in formula 1, except for the fact that one or more atoms are substituted with an atom having an atomic mass or a mass number different from the atomic mass or the mass number that are normally found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 5N, 8O, 17O, 35S , 18F and 36CI, respectively. The compounds of the present invention, the prodrugs thereof and the pharmaceutically acceptable salts of said compounds or of the aforementioned prodrugs containing the isotopes and / or other isotopes of other atoms are found within the bond of this invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in tissue distribution assays of the drug and / or the substrate. The tritiated isotopes, ie, 3H, and carbon 14, ie 1 C, are especially preferred for their ease of preparation and detection possibilities. Furthermore, replacement with heavier isotopes such as deuterium, ie 2H, can provide certain therapeutic advantages as a consequence of their greater metabolic stability, for example an increase in half-life in vivo or need for lower dosage and, therefore, may prefer in some cases. The isotopically-labeled compounds of formula 1 of this invention and the prodrugs thereof can be prepared in a general manner by carrying out the procedures described in the schemes and / or in the following examples and preparations, substituting an isotopically non-labeled reagent by an isotopically labeled reagent easily obtained. This invention also encompasses pharmaceutical compositions containing them and methods of treating bacterial infections by the administration of prodrugs of compounds of formula 1. Compounds of formula 1 having free amino, amide, hydroxyl or carboxyl groups can be converted to prodrugs. The prodrugs include compounds in which an amino acid radical, or a polypeptide chain of two or more (eg, two, three or four) amino acid radicals is covalently linked by an ester or amide bond to an amino, hydroxyl or acid group free carboxylic acid of the compounds of formula 1. The amino acid radicals include, but are not limited to, the 20 natural amino acids normally designated by the three-letter symbols and also include 4-hydroxyproline, hydroxylysine, desmosine, sodesmosine, 3- methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserin, ornithine and the methionine sulfone. It also comprises additional types of prodrugs. For example, free carboxyl groups can be derivatized as amides or alkyl esters. The amide and ester radicals can incorporate groups including, but not limited to, ether, amine and carboxylic acid functionalities. Free hydroxyl groups can be derivatized using groups including, but not limited to, hemisuccinates, phosphate esters, dimethyl-aminoacetates and phosphoryloxymethyloxycarbonyls, as described in D. Fleisher, R. Bong, BH Stewart, Advanced Drug Delivery Reviews , 19, 115 (1996). Also included are carbamate prodrugs of hydroxyl and amino groups as well as carbonate prodrugs and sulfate esters of hydroxyl groups. Also included is derivatization of hydroxyl groups such as ethers (acyloxy) methyl and (acyloxy) ethyl in which the acyl group may be an alkyl ester, optionally substituted with groups including, but not limited to, ether, amine and carboxylic acid functionalities, or in which the acyl group is an ester of an amino acid as described above. Prodrugs of this type are described in R. P. Robinson et al., J. Medicinal Chemistry 39, 10 (1996).

DETAILED DESCRIPTION OF THE INVENTION The compounds of formula 1 and their pharmaceutically acceptable salts and solvates can be prepared as described below. Unless indicated otherwise, R1, R2 and R3 are as defined above.

SCHEME 1 SCHEME 2 SCHEME 3 H SCHEME 4 SCHEME 5 19 21 20 H 15 23 SCHEME 5 (CONTINUED) The compounds of the present invention are readily prepared following the procedures outlined in the schemes illustrated above and the synthesis procedures familiar to those skilled in the art. Scheme 1 illustrates the condensation of malonitrile with an isocyanate, oxidation with sulfur, alkylation with an R3 containing the compound and hydration of the nitrile to obtain the final compound. In step 1 of scheme 1, the compound of formula 4 can be prepared by treatment of the compound of formula 3 and the compound of formula 2 (R1 and R2 are not H but on the contrary are as defined above) with a base suitable strong, such as, a basic alkoxide, preferably sodium ethoxide, in a protic solvent such as an alcohol, preferably ethanol, at a temperature in the range of -20 ° C to 50 ° C, preferably 0 ° C to 25 ° C, for a period of approximately 12 to 24 hours. In step 2 of scheme 1 the compound of formula 5 can be prepared by treatment of the compound of formula 4 with sulfur (about 1 equivalent to excess) in a polar solvent such as an alcohol solvent, preferably methanol at a temperature in the range of 25 ° C to 80 ° C, preferably at about 65 ° C, for a period of about 12 to 48 hours, preferably about 24 hours. In step 3 of scheme 1 the compound of formula 6 can be prepared by treating the compound of formula 5 with an ether containing an R3 such as halide, preferably a chloride, bromide or iodide of such compound, in a polar solvent, preferably tetrahydrofuran (THF) or N, N-dimethylformamide (DMF), using about 1 to 5 equivalents, preferably a little over 1 equivalent and a base such as a tertiary amine base, preferably diisopropylamine over a period of about 12 to 48 hours, preferably around 24 hours and at a temperature in the range of 0 ° C to 80 ° C, preferably at about 25 ° C. In step 4 of the scheme, the compound of formula 1 (wherein X1 is S) can be prepared by treatment of the compound of formula 6 under strongly acidic conditions such as concentrated sulfuric acid for a period of about 1 to 12 hours, preferably about 1.5 hours, at a temperature in the range of 25 ° C to 100 ° C, preferably at about 25 ° C, or under basic conditions such as an aqueous solution of sodium hydroxide (10%), for a period ranging from 6 to 24 hours at a temperature in the range of 25 ° C to 120 ° C, preferably at about 100 ° C. Scheme 2 illustrates another method for the preparation of a compound of formula 1 wherein X 1 is S. In step 1 of scheme 2, the compound of formula 7 can be prepared by condensation of the compound of formula 3 with alkoxycarbonyl sothiocyanate. , such as ethoxycarbonyl isothiocyanate, in the presence of a strong base, such as an alkoxide base, preferably sodium ethoxide, in a polar solvent, such as an alcohol solvent, preferably ethanol, for a period ranging from 12 to 24 hours at a temperature in the range of about 0 ° C to 30 ° C. In step 2 of scheme 2, the compound of formula 8 can be prepared by cyclizing the compound of formula 7 by treatment of the compound of formula 7 with about one equivalent of sulfur in an alcohol solvent such as methanol at a temperature in the range of approximately 50 ° C to 80 ° C, preferably at about 65 ° C, for a period of about 24 to 48 hours. In step 3 of scheme 2, the compound of formula 9 can be prepared by treating the compound of formula 8 with an electrophile containing an R3 such as a halide, preferably a chloride, bromide or iodide of such compound, in a polar solvent , such as THF, at a temperature in the range of about 25 ° C to 40 ° C for a period ranging from about 12 to 24 hours. In step 4 of scheme 2, the compound of formula 10 can be prepared by hydrolysis of the compound of formula 9 with a suitable strong acid such as concentrated sulfuric acid at a temperature in the range of about 80 ° C to 120 ° C during a period of approximately 6 to 18 hours. In step 5 of scheme 2, the compound of formula 11 (wherein Ph is phenyl) can be prepared by treatment of the compound of formula 10 with an aryl or alkyl chloroformate, such as phenyl chloroformate and a suitable strong base such such as pyridine in a polar aprotic solvent, preferably THF or CH 2 Cl 2 at a temperature in the range of 25 ° C to 40 ° C, for a period of about 12 to 24 hours. In step 6 of scheme 2, the compound of formula 1 (wherein X 1 is S) can be prepared by treating the compound of formula 11 with an excess (about 1.1 to 6 equivalents) of a secondary or primary amine of the formula R1R2NH in an aprotic polar solvent such as THF or a mixture of THF / DMF at a temperature in the range of about 23 ° C to 60 ° C, for a period ranging from 6 to 24 hours. Scheme 3 illustrates a process for the preparation of the compounds of formula 1 in which X1 is O. The starting compound of formula 4 can be prepared as described above in relation to scheme 1. In step 1 of scheme 3 , a solution of the salt of formula 4 in an inert solvent containing water or, preferably, in water alone, is treated with an oxidizing reagent, preferably dihydrogen peroxide. The mixture is maintained at a temperature and time sufficient to effect the dissolution and cyclization, preferably at reflux for about 15 minutes and then cooled to obtain the compound of formula 12. In step 2 of scheme 3, the compound of formula 12 is added to an acid solution, preferably concentrated sulfuric acid, followed by water sufficiently to carry out the hydration, preferably about 10 equivalents, and is stirred at a temperature in the range of -20 ° C to 100 ° C, preferably at room temperature. environment, during a period to carry out hydration, preferably overnight. The mixture is treated with water or preferably with ice to provide the compound of formula 13. In step 3 of scheme 3 the compound of formula 13 is treated with a base, preferably potassium t-butoxide, in an inert solvent, preferably DMF, at a temperature in the range of about -78 ° C to 100 ° C, preferably at room temperature. To this mixture is added an R3 containing an electrophile such as an R3 containing an alkyl halide or sulfonate, preferably an iodide or a bromide of this compound. The mixture is stirred until the reaction is complete which is determined by TLC analysis, to provide the compound of formula 1 (wherein X1 is O). Scheme 4 illustrates another procedure for the preparation of compounds of formula 1 in which X1 is S. In step 1 of scheme 4, the procedure follows the synthetic procedure set forth in M. Yokoyama and K. Sato, Svnthesis. 813 (1988). Accordingly, the compound of formula 3 is treated with an alkyl thiol, such as 4-methoxy benzyl mercaptan, and a strong base, such as sodium hydroxide in a polar solvent such as an alcohol / water mixture, preferably ethanol / water. : 1 at a temperature in the range of -10 ° C to 30 ° C, preferably at about 0 ° C, for a period of 2 to 6 hours, preferably about 3 hours, to obtain the compound of formula 14. In step 2 of scheme 4, the compound of formula 15 (pH is phenyl) can be preparing by treating the compound of formula 14 with an alkoxycarbonyl isothiocyanate, such as phenoxycarbonyl isothiocyanate, in an aprotic solvent, such as ethyl acetate at about 0 ° C, for about 12 to 36 hours. In step 3 of scheme 4, the compound of formula 16 can be prepared by treating the compound of formula 15 with an oxidizing agent, such as bromine or iodine, preferably iodine and a mild base such as pyridine in a polar solvent such as acetonitrile during about 1 hour at about 0 ° C. In the step of scheme 4, the compound of formula 17 can be prepared by deprotection of the 4-methoxy benzyl group by treating the compound of formula 16 with mercuric acetate, about 1 equivalent, in the presence of an acid, preferably trifluoroacetic acid (TFA) ), with an excess of anisole, preferably 10 equivalents at a temperature in the range of 0 ° C to room temperature, for a period in the range of 10 to 24 hours. In the step of scheme 4, the compound of formula 18 can be prepared by hydration of the compound of formula 17 with a suitable strong acid, such as concentrated sulfuric acid, at a temperature in the range of 15 ° C to 80 ° C, preferably at room temperature, for a period in the range of 12 to 24 hours, preferably 18 hours. In step 6 of scheme 4, the compound of formula 1 can be prepared by treating the compound of formula 18 with an electrophile containing an R3 such as halide, preferably a chloride, bromide or iodide of such compound, and a suitable strong base , such as diisopropyl ethyl amine, in a polar solvent, preferably DMF, at a temperature in the range of 0 ° C to 50 ° C, preferably at 25 ° C, for a period in the range of 12 to 24 hours. The resulting compound is then treated with a primary or secondary amine of formula R1R2NH (about 1.1 to 6 equivalents) in a mixture of THF / DMF at a temperature in the range of 25 ° C to 65 ° C, for a period in the range from 18 to 36 hours. In scheme 5, another procedure for the preparation of a compound of formula 1 in which X1 is O is illustrated. In step 1 of scheme 5, the mixture of a thiocyanate salt, preferably potassium thiocyanate, in an inert solvent, preferably ethyl acetate, is stirred, preferably vigorously, under an inert atmosphere overnight to obtain the salt powder. This mixture is then treated with an aryl chloroformate of formula 19 (pH is phenyl) and the resulting mixture is stirred at a temperature in the range of -40 ° C to room temperature, preferably at 5 ° C, for a sufficient period to carrying out the reaction, preferably about 8 hours. The solid by-product is removed by filtration and the product is kept fresh, preferably at a temperature not higher than the ambient temperature. The product is redissolved in a suitable inert solvent, preferably ether and an additional insoluble byproduct is removed. After concentrating, the product is redissolved again in a suitable inert solvent, preferably hexane, and the additional insoluble byproducts are removed. The compound of formula 20 is then isolated. In step 2 of scheme 5, an acidic solution, preferably ethereal HCl, is treated with a compound of formula 3, after dissolution, the solution is cooled, preferably up to 10 ° C and deal with benzyl alcohol. After further stirring, the mixture is maintained at a given temperature, preferably at about 5 ° C for a period sufficient to allow a complete reaction, typically about 4 days, to obtain the compound of formula 21. In step 3 of the scheme 5, a solution of the compound of formula 21 is treated in a suitable inert solvent, preferably acetonitrile, at a temperature in the range of -40 ° C to room temperature, preferably 0 ° C, with a solution of the compound of formula 20 in a solvent suitable inert, preferably acetonitrile. The reaction is maintained at a temperature in the range of 0 ° C to room temperature, preferably at room temperature, to carry out the reaction. The mixture is then maintained at a suitable temperature to increase the solidification of the product, preferably at about 5 ° C, for a period sufficient to maximize the yield, preferably about 2 days. The compound of formula 22 is then isolated (Bn is benzyl). In step 4 of scheme 5, the compound of formula 22 is suspended in a suitable inert solvent, preferably acetonitrile, at a temperature in the range of -40 ° C to 40 ° C, preferably 0 ° C, and treated with a base, preferably pyridine and an oxidant, preferably a solution of bromine or iodine in a suitable solvent, preferably acetonitrile. The mixture is then stirred at a temperature sufficient to carry out the reaction, preferably at 0 ° C, for about 1 hour followed by another hour at room temperature. The mixture is then left to stand at a temperature sufficient to increase solidification, preferably at 5 ° C, for a sufficient period, preferably overnight. The compound of formula 23 is then isolated. In step 5 of scheme 5, hydration and deprotection of the compound of formula 23 are carried out by treatment with an acid, preferably concentrated sulfuric acid. If the compound of formula 23 is sufficiently wet by the water from the previous step, no additional water is added. If the compound of formula 23 is dry, then more water is added, preferably about 10 equivalents. The reaction is carried out at a temperature in the range of -20 ° C to 100 ° C, preferably at room temperature, for a period sufficient to carry out a complete reaction, characteristically marked by the complete solution and preferably about 3 hours. After the reaction has been completed, additional sulfuric acid is added to achieve complete conversion. The mixture is then treated with water or preferably with ice. The compound of formula 24 is isolated. In step 6 of scheme 5, the compound of formula 24 is combined with a trivalent phosphine, preferably triphenyl phosphine and an R3 containing alcohol and treated with an azodicarboxylate derivative, preferably diisopropyl azodicarboxylate. and stirring is continued for a period of at least 1 minute. Then the compound of formula 25 is isolated. In step 7 of scheme 5, a mixture of the compound of formula 25 in a suitable inert solvent, preferably THF, is treated with a desired amine of formula R1R2NH and maintained at a temperature sufficient to carry out the reaction, usually 0 ° C at 100 ° C, preferably 50 ° C to 70 ° C, for a period ranging from 1 hour to 48 hours, preferably overnight. The compound of formula 1 (wherein X 1 is O) is then isolated. The compounds of the present invention have asymmetric carbon atoms. These diastereomeric mixtures can be separated into the individual diastereomers on the basis of their physicochemical differences by methods known to those skilled in the art, for example, chromatography or fractional crystallization. The enantiomers can be separated by conversion of the enantiomeric mixtures in a diastereomeric mixture by reaction with a suitable optically active compound (for example alcohol), separating the diastereomers and converting (for example hydrolyzing) the individual diastereomers into the corresponding pure enantiomers. All these isomers, including mixtures of diastereomers and pure enantiomers are considered as part of the invention. The compounds of formula 1 which are basic in nature are capable of forming a wide variety of different salts with various organic and inorganic acids. Although these salts must be pharmaceutically acceptable for administration to animals, in practice it is often desired to initially isolate the compound of formula 1 from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter to the free base compound by treatment with an alkaline reagent and subsequently converting the last free base into a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention are readily prepared by treating the basic compound with a substantially equivalent amount of the selected organic or mineral acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. After careful evaporation of the solvent, the desired solid is obtained. The desired acid salt can also be precipitated from a solution of free base in an organic solvent by the addition of a suitable mineral organic acid to the solution. Those compounds of formula 1 which are acidic by nature are capable of forming basic salts with various pharmaceutically acceptable cations. Examples of these salts include the alkali metal or alkaline earth salts and in particular, the potassium and sodium salts. These salts are all prepared by conventional techniques. The chemical bases which are used as reagents for preparing the pharmaceutically acceptable basic salts of this invention are those which form non-toxic basic salts with the acidic compounds of formula 1. These non-toxic basic salts include those derived from these pharmacologically acceptable cations such as sodium. , potassium, calcium and magnesium, etc. These salts can be easily prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they can also be prepared by mixing lower alkane solutions of the acidic compounds and the desired alkali metal alkoxide and then evaporating the resulting solution to dryness in the same manner as mentioned above. In any case, it is preferred to employ stoichiometric amounts of reagents in order to ensure the completion of the reaction and obtain maximum yields of the desired final product. In the present invention, compounds identical to the compounds of formula 1 are included but by the fact that one or more hydrogen or carbon atoms are replaced by isotopes thereof. These compounds are useful as research and diagnostic tools in pharmacokinetic studies of metabolism and in binding assays. Specific applications in the research include radioligand binding assays, autoradiography studies, and in vivo binding studies. The radiolabeled forms of the compounds of formula 1 include the isotopes of tritium and C14 thereof. The in vitro activity of the compounds of formula 1 to inhibit KDR? EGF can be determined by the following procedure. The ability of the compounds of the present invention to inhibit tyrosine kinase activity can be determined using a recombinant enzyme in an assay that measures the ability of the compounds to inhibit phosphorylation of the exogenous substrate, polyGluTyr (PGT, Sigma ™, 4). :1). The kinase domain of the human KDR? / EGF receptor (amino acids 805-1350) is expressed in the Sf9 insect cells as a glutathione S-transferase fusion protein (GST) using the baculovirus expression system. The protein is purified from the lysates of these cells using glutathione agarose affinity columns. The enzyme assay is carried out in 96-well plates that are coated with PGT substrate (0.625 μg PGT per well). The test compounds are diluted in dimethylsulfoxide (DMSO) and then added to the PGT plates so that the final concentration of DMSSO in the assay is 1.6% (v / v). The recombinant enzyme is diluted in buffer (50 mM Hepes, pH 7.3, 125 mM, 24 mM MgCl 2). The reaction is initiated by addition of ATP to a final concentration of 10 μM. After a 30 minute incubation at room temperature with stirring, the reaction is aspirated and the plates are washed with buffer (0.1% Tween-20 containing PBS). The amount of phosphorylated PGT is counted by incubation with an anti-PY-54 (Transduction Labs) conjugate with HPP (HRP is horseradish peroxidase), developed with TMB peroxidase (TMB is 3, 3 ', 5, d-tetramethylbenzidine) and the reaction is quantified in a Bioplad ™ Microplate reader at 450 nM. The inhibition of the enzymatic kinase activity by the test compound is detected as a reduced absorbance and the concentration of the compound required to inhibit the 50% signal is recorded with IC50 value for the test compound. To determine the ability of the compounds to inhibit the KDR tyrosine kinase activity of the full length protein that exists in a cellular context, porcine aortic endothelial cells (PAE) transfected with human KDR can be used (Walterberger et al., J. Biol. Chem. 269: 26988, 1994). The cells are plated and allowed to attach 96 well plates in the same medium (Ham F12) with 10% FBS (fetal bovine serum). The cells are then washed, replenished with serum-free medium containing 0.1% (v / v) bovine serum albumin (BSA), and allowed to incubate for 24 hours. Immediately before dosing with the compound, the cells are fed back with serum-free medium (without BSA). The test compounds, dissolved in DMSO, are diluted in the medium (final concentration of DMSO 0.5% (v / v)). After 2 hours of incubation, VEGF165 (50 ng / ml final) is added to the medium for incubation for 8 minutes. The cells are washed and lysed in HNTG buffer (20 mM Hepes, pH 7.5, 150 mM NaCl, 0.2% Triton ™ X-100 10% glycerol, 0.2 mM PMSF (phenylmethylsulfonyl fluoride), 1 μg / ml pepstatin, 1 μg / ml leupeptin, 1 μg / ml aprotonin, 2 mM sodium pyrophosphate, 2 mM sodium orthovanadate). The degree of phosphorylation of KDR is determined using an ELISA assay. The 96-well plates are coated with 1 μg per well of anti-rabbit goat antibody. The unbound antibody is removed from the plate and the remaining sites are blocked with Superblock buffer (Pierce) before the addition of anti-flk-1 antibody C-20 (0.5 μg per plate, Santa Cruz). Any unbound antibody is removed from the plates prior to the addition of the cell lysate. After 2 hours of incubation of the lysates with the flk-1 antibody, the associated phosphotyrosine KDR is accounted for by developing with PY-54 antibodies conjugated with HRP and TMB as described above. The ability of the compounds to inhibit the autophosphorylation reaction stimulated by VEGF by 50% relative to the controls stimulated by VEGF is recorded with the IC50 value for the test compound. The ability of the compounds to inhibit mitogenesis in human endothelial cells is determined by their ability to inhibit 3 H-thymidine incorporation into HUVE cells (endothelial cells of the human umbilical vein, Clonetics ™). This assay is well described in the literature (Waltenberger J et al., J. Biol. Chem. 269: 26988, 1994; Cao Y et al., J. Biol. Chem. 271: 3154, 1996). Briefly, 104 cells are placed in 24-well plates coated with collagen and allowed to bind to the plate. The cells are fed back into serum-free medium and 24 hours later treated with various concentrations of compound (prepared in DMSO, the final concentration of DMSO in the assay is 0.2% v / v) and 2-30 ng / ml VEGF165. During the last 3 hours of 24 hours of compound treatment, 3H thymidine impulses are transmitted to the cells (NEN, 1 μCI per well). The medium is then removed and the cells are washed extensively with Hank's balanced salt solution on ice then 2 times with ice-cold trichloroacetic acid (10% v / v). The cells are used or destroyed by the addition of 0.2 ml of 0.1 N NaOH and the lysates transferred in scintillation vials. The wells are then washed with 0.2 ml of 0.1 N HCl and this wash is transferred to the vials. The degree of 3H thymidine incorporation is determined by scintillation counting. The ability of the compounds to inhibit 50% incorporation relative to the control (VEGF treatment only with DMSO vehicle) is recorded as the IC50 value for the test compound. The activity of the compounds of formula 1, in vivo, can be determined by the amount of inhibition of tumor growth of a test compound relative to a control. The inhibitory effects of tumor growth of several compounds were determined according to the procedures of Corbet TH, et al., "Tumor induction Relationships in Development of Transplantable Cancers of the Colon Mice for Chemotherapy Assays, with a Note on Carcinogen Structure ", Cancer Res., 35. 2434-2439 (1975) and Corbett, TH, et al .." A mouse Colon-tumor Model for Experimental Therapy ", Cancer Chemother. Rep. (Part 2V, 5. 169-186 (1975), with slight modifications.) Tumors are induced on the side by sc injection of 1 x 106 tumor cells grown in logarithmic phase suspended in 0.2 ml of PBS. after sufficient time for the tumors to become palpable (5-6 mm in diameter), the test animals (nude mice) are treated with the active compound (formulated by dissolving in the appropriate diluent, for example water or Gelucire ™). 5% 44/14 rn PBS for intraperitoneal (ip) or oral (po) administration routes once or twice a day for 5-10 consecutive days In order to determine an anti-tumor effect, the tumor is determined in millimeters with VERNIER calibrators along the two diameters and the tumor volume (mm3) is calculated using the formula: Tumor weight = (length x width2) / 2, according to the procedures of Geran, RI, et al. .. "Protocols for Screening Chemical Agents and Nature l Products Against Animal Tumors and Other Biological Systems ", 3rd edition, Cancer Chemother. Reo .. 3, 1-104 (1972). The lateral location of the tumor implantation provides reproducible dose / response effects for a variety of chemotherapeutic agents and the measurement procedure (tumor diameter) is a reliable procedure for the evaluation of tumor growth rates. The administration of the compounds of the present invention (hereinafter the "active compounds") can be carried out by any method that is capable of releasing the compounds at the site of action. These procedures include intraduodenal oral routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical and rectal administration. The amount of active compound administered will depend on the subject being treated, the severity of the disorder or disease, the rate of administration and the discretion of the prescribing physician. However, an effective dose is in the range of about 0.001 to about 100 mg per kg of live weight per day, preferably about 1 to about 35 mg / kg / day in single or divided doses. For a 70 kg human, this amount would be from about 0.05 to about 7 g / day, preferably from about 0.2 to about 2.5 g / day. In some cases the use of lower dosage levels than the lower limit of the aforementioned range may be more appropriate, while in other cases higher doses may be used without causing harmful side effects, provided that these higher doses are first divided into several small doses to be administered throughout the day. The active compound can be applied as a single therapy or it can involve one or more different antitumor substances, for example those selected from, for example, mitotic inhibitors, for example vinblastine; alkylating agents, for example cis-platinum, carboplatin and cyclophosphamide; anti-metabolites, for example 5-fluorouracil, cytosine arabinoside and hydroxyurea or for example one of the preferred anti-metabolites disclosed in European Patent Application No. 239362 such as N- (5-N- (3,4- dihydro-2-methyI-4-oxoqu-nazolin-6-methylmethyl) -N-methylamino) -2-tenoyl) -L-glutamic acid; growth factor inhibitors; cell cycle inhibitors; interpolation antibiotics, for example adriamycin and bleomycin; enzymes, for example interferon; and anti-hormones, for example anti-estrogens such as Nolvadex ™ (tamoxifen) or for example anti-androgens such as Casodex ™ (4'-cyano-3- (4-fluorophenylsulfonyl) -2-hydroxy-2-methyl-3 ' - (trifluoromethyl) propionanilide). This joint treatment can be achieved by the simultaneous, sequential or separate dosing of the individual components of the treatment. The pharmaceutical composition can, for example, be presented as a suitable form for oral administration as tablets, capsules, pills, powder, sustained release formulations, solutions, suspensions, for parenteral administration as sterile solutions, suspensions or emulsions, for administration topical as ointments or creams or for rectal administration as suppositories. The pharmaceutical composition can be presented as unit dosage forms for the single administration of particular doses. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. It can also include other pharmaceutical or medicinal agents, vehicles, adjuvants, etc. Examples of parenteral administration forms include solutions or suspensions of the active compounds in sterile aqueous solutions, for example, aqueous dextrose or propylene glycol solutions. These dosage forms can be suitably buffered, if desired. The pharmaceutically acceptable carriers include diluents or inert fillers, water and various organic solvents. The pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus for the oral administration of tablets citric acid can be used as excipients together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and gum arabic. Also frequently in order to form tablets, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are also used. Solid compositions of a similar type can also be used in hard and soft gelatin capsules. Preferred materials, therefore, include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the active compound may be combined with various sweetening or flavoring agents, colorants and is desired with emulsifying or dispersing agents, together with diluents such as water, ethanol, propylene glycol, glycerin or combinations thereof. the same. The procedures for the preparation of pharmaceutical compositions with a specific amount of active compound are known, or will be apparent to those skilled in the art. For example, see Remington's pharmaceutical Sciences. Mack Publishing Company, Easter, Pa., 15th edition. The examples and preparations provided below illustrate and exemplify the compounds of the present invention and the processes for the preparation of these compounds. It should be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations.

PREPARATION 1 Dimethylcarbamoylisothiocyanate A three-liter three-necked flask equipped with a mechanical stirrer, with dimethylcarbamyl chloride (250 ml, 2.70 mol) in anhydrous acetonitrile (1.5 L) was charged and heated to reflux. Then potassium thiocyanate (270 g, 2.8 moles, pre-dried at 160 ° C under high vacuum for 3 hours) was added, little by little for more than one hour with caution, since the reaction bubbled violently at the beginning of each addition. After the final addition, the mixture was refluxed for an additional hour. The heating jacket was removed and the mixture was stirred at room temperature for an additional 2.5 hours and then stored in the refrigerator overnight. The mixture was filtered to remove solid material that was not wanted and the filtrate was concentrated. The resulting oil was added with ether (1 L) and the solid and the thick material were discarded. The filtrate was concentrated again to provide the desired material as an orange opaque oil (204 g, 1.57 mol, 58%). 1 H NMR (400 MHz, CDCl 3) d 2.90 (s, 3 H), 2.98 (s, 3 H) ppm.

Sodium 2,2-di-cyano-1- (3,3-dimethyl-ureido) -ethenetiolate was added to a solution of 1 M sodium ethoxide in ethanol (prepared by treating 110 ml of anhydrous ethanol with 2.5 g (0.11 moles). sodium) malonitrile (7.2 g, 0.11 mol) at 0 ° C. Dimethylcarbamoylisothiocyanate (14.3 g, 0.110 mol) was added and the resulting mixture was allowed to warm to room temperature. The mixture was concentrated in vacuo. The residue was treated with hexanes and concentrated in vacuo to a solid. The residue was triturated with hexanes, collected by filtration and dried in vacuo to give 20 g (83%) of; 2,2-dicyano-1- (3,3-dimethyl-ureido) -ethenethenolate sodium as a colorless solid. 1 H NMR (400 MHz, DMDO-d 6) d 8.40 (s, 1 H), 2.78 (s, 6 H) ppm; 13 C NMR (100 MHz, DMSO-d 6): d 189.9, 154.3, 121.4, 118.7, 57.9, 36.5 ppm. 3- (4-Cyano-3-mercapto-isothiazol-5-yl) -1,1-dimethyl-urea A mixture of 2,2-dicyano-1- (3,3-dimethylol) was stirred under reflux for 24 hours. sodium l-ureido) -ethenetiolate (5.0 g, 23 mmol), sulfur (0.734 g, 23 mmol) and 46 ml of methanol. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was diluted with water and the resulting mixture was extracted 2 times with ethyl acetate. The aqueous layer was acidified with 1 M HCl (aqueous) and extracted with ethyl acetate. The organic phase was dried with Na 2 SO 4, filtered and concentrated. The solid residue was collected and dried under vacuum to obtain 2 g (40%) of 3- (4-cyano-3-mercapto-isothiazol-5-yl) -1,1-dimethyl-urea as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6) d 2.97 (s, 6 H) ppm; MS (APC I, m / z): 227 (M-H).

General procedure for the alkylation of 3- (4-cyano-3-mercapto-isothiazol-5-yl) -1,1-dimethyl-urea Diisopropylethylamine (0.116 g, 0.90 mmol) was added to a mixture of 3- (4- cyano-3-mercapto-isothiazol-5-yl) -1,1-dimethyl-urea (0.20 g, 0.88 mmol), the appropriate alkyl chloride, bromide or iodide (0.90 mmol) and THF or DMF. The resulting mixture was stirred for 24 hours at room temperature. The mixture was partitioned between 1 M aqueous HCl and ethyl acetate. The organic phase was removed and the aqueous phase was extracted 3 times with ethyl acetate. The combined organic phases were dried with Na 2 SO 4, filtered and concentrated in vacuo. The residue was filtered through a plug bed of silica gel eluting with ethyl acetate / hexanes (1: 1) to provide the alkylated product. 3- (4-Cyano-3-hexylsulfanyl-isothiazol-5-yl) -1,1-dimethyl-urea Following the above general procedure using iodohexane (0.19 g, 0.90 mmol) as the alkyl iodide, 0.14 g was obtained ( 51%) of 3- (4-cyano-3-hexy-iso-phenyl-isothiazol-5-yl) -1,1-dimethyl-urea as a colorless solid: 1 H NMR (400 MHz, acetone-d 6) d 9.82 (br.a, 1 H), 3.20 (t, 2H, J = 7.2 Hz), 3.11 (s, 6H), 1.71 (p, 2H, J = 7.2 Hz), 1.43 (m, 2H), 1.31 (m, 4H), 0.86 ( t, 3H, J = 6.0 Hz) ppm; MS (APCI, m / z): 313 [M + H].

EXAMPLE 1 5- (313-Dimethyl-uredo) -3-hexylsulfanyl-isothiazole-4-carboxylic acid amide A mixture of 3- (4-cyano-3-hexylsulfanyl-isotipazo-5-yl) -1,1-dimethyl-urea (0.09 g, 0.29 mmol) and concentrated sulfuric acid was stirred at room temperature for 1.5 hours. 0.18 mmoles). The mixture was diluted with ice water and extracted 3 times with ethyl acetate. The combined organic phases were dried with Na2SO, filtered and concentrated in vacuo to give 0.076 g (78%) of 5- (3-3-dimethyl-ureido) -3-hexylsulfanyl-isothiazole-4-carboxylic acid amide as a colorless solid. 1 H NMR (300 MHz, acetone-d 6) d 7.08 (br s, 2 H), 3.20 (t, 2 H, J = 7.2 Hz), 3.02 (s, 6 H), 1.63 (p, 2 H, J = 7.2 Hz), 1.35 (m, 2H), 1.23 (m, 4H), 0.78 (t, 3H, J = 6.9 Hz) ppm; MS (APCI, m / z): 331 [M + H].

PREPARATION 2 2.2-Sodium Dicariate-1-ethoxycarbonylamino-ethenetiolate Sodium metal (1.01 g, 44 mmol) was dissolved in 40 ml of ethanol at room temperature. The resulting solution was cooled in an ice bath and malonitrile (2.91 g, 44 mmol) was added. The ice bath and the mixture were removed and the mixture was stirred at room temperature for 30 minutes.

After cooling to 0 ° C, ethoxycarbonylisothiocyanate was added (5.77 g, 44 mmol) and the mixture was allowed to warm to room temperature overnight. The mixture was concentrated in vacuo and the residue solidified after repeated dilutions with hexane and concentration in vacuo. The resulting yellow solid was collected and dried in vacuo, yielding 10.74 g. (100%) of sodium 2,2-dicyano-1-ethoxycarbonylamino-ethenetholate as a light yellow solid containing 0.5 molar equivalents of ethanol as indicated by spectroscopy. 1 H NMR: 1 H NMR (300 MHz, DMSO-d 6) d 4.36 (t, 0.5 H, J = 5.0 Hz (EtOH)), 4.03 (q, 2 H, J = 7.1 Hz), 3.43 (dq, 1 H, J = 5.0 6.7 Hz (EtOH)), 1.26 (t, 3H, J = 7.3 Hz), 1.06 (t, 1.5 H, J = 7.0 Hz (EtOH)) ppm; MS (APCI, m / z): 197 (M-Na).

Sodium 4-cyano-5-ethoxycarbonylamino-isothiazole-3-thiolate A mixture of sodium 2,2-dicyano-1-ethoxycarbonylamino-ethenetiolate (3.3 g, 15 mmol), sulfur (0.48 g, 15 mmol) and methanol (30 ml). The mixture was filtered and concentrated in vacuo and the gummy residue was triturated 2 times with ether-ethyl acetate 10: 1 to give 2.6 g (69%) of sodium 4-cyano-5-ethoxycarbonylamino-isothiazole-3-thiolate as a solid. yellow. 1 H NMR (400 MHz, DMSO-d 6) d 3.99 (q, 2 H, J = 6.8 Hz), 1.16 (t, 3 H, J = 7.2 Hz) ppm; MS (APCI, m / z): 228 (M-Na). (4-Cyano-3-pentylsulfanyl-isothiazol-5-yl) -carbamic acid ethyl ester A mixture of sodium 4-cyano-5-ethoxycarbonylamino-isothiazole-3-thiolate (5.0) was stirred at room temperature for 16 hours. g, 20 mmol), 1-iodopentane (4.0 g, 20 mmol) and THF (20 mL). After concentrating in vacuo, the residue was partitioned between ethyl acetate and brine. The aqueous phase was extracted 3 times with ethyl acetate and the combined organic phases were dried with NaSO, filtered and concentrated in vacuo. The residue was filtered through a short pad of silica gel using 1: 1 ethyl acetate-hexane as eluent. The filtrate was concentrated and the residue was recrystallized from cold aqueous methanol to give 2.5 g (42%) of (4-cyano-3-pentanyl-isothiazol-5-yl) -carbamic acid ethyl ester as a colorless solid. 0.5 g (8.4%) more were obtained by concentrating the mother liquor, purifying it by radial chromatography (4 mm dish, hexane-ethyl acetate 4: 1). 1 H NMR (400 MHz, acetone-d 6) d 11.1 (as, 1H), 4.32 (q, 2H, J = 7.2 Hz), 3.21 (t, 2H, J = 7.2 Hz), 1.73 (p, 2H, J = 6.8 Hz), 1.44-1.28 (m, 7H), 0.90 (t, 3H, J = 7.6 Hz) ppm; MS (APCI, m / z): 312 (M + Na) +.

Amide of 5-amino-3-pentylsulfanyl-isothiazole-4-carboxylic acid A mixture of (4-cyano-3-pentylsulfanyl-isothiazol-5-yl) - ethyl ester was heated to 100 ° C for 6 hours. carbonate (2.7 g, 9.0 mmol) and concentrated sulfuric acid (5 ml). After cooling to room temperature the mixture was diluted with an ice water bath, extracted 3 times with ethyl acetate and the combined organic phases were dried with Na 2 SO 4, filtered and concentrated in vacuo to give 2.2 g (100%). of the 5-amino-3-pentylsulfanyl-isothiazole-4-carboxylic acid amide as a yellow oil. 1 H NMR (400 MHz, CDCl) d 3.26 (t, 2 H, J = 7.2 Hz), 1.71 (m, 2 H), 1.43-1.19 (m, 4 H), 0.88 (t, 3 H, J = 6.8 Hz) ppm.

Phenyl ester of (4-carbamoyl-3-pentylsulfanyl-isothiazol-5-yl) -carbamic acid Pyridine (0.90 g, 11 mmol) and phenyl chloroformate (1.7 g, 11 mmol) were added to a solution of the acid amide 5-amino-3-pentylsulfanyl-isothiazole-4-carboxylic acid 82.2 g, 9.0 mmol) in 36 ml of THF. After stirring for 3 hours, additional pyridine (0.15 g, 1.9 mmol) and phenyl chloroformate (0.29 g, 1.9 mol) were added and the mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo, diluted with water and extracted 2 times with CH2Cl2, and once with ethyl acetate. The combined organic phases were washed with brine, dried with MgSO 4, filtered and concentrated in vacuo. The residue was triturated for 12 hours with ether-hexane and the resulting solids were collected and dried in vacuo to provide 2.6 g (79%) of the phenyl ester of (4-carbamoyl-3-penti-sulphanyl-isothiazol-5-yl) -carbamic acid ester as a colorless solid. 1 H NMR (300 MHz, CDCl 3) d 7.41 (t, 2 H, J = 7.3 Hz), 7.29-7.20 (m, 3H), 3.31 (t, 2H, J = 7.3 Hz), 1.72 (m, 2H), 1.50-1.30 (m, 4H), 0.90 (t, 3H, J = 7.1 Hz) ppm; MS (APCI, m / z): 366 [M + H] +.

EXAMPLE 2 3-Pentylsulfanyl-5-r3- (3-pyrroHdin-1-yl-propyl) -ureidol-isothiazole-4-carboxylic acid amide N-3-aminopropylpyrrolidine (0.175 g, 1.4 moles) was added to a mixture of (4-carbamoyl-3-pentylsulfanyl-isothiazol-5-yl) -carbamic acid phenyl ester (0.10 g, 0.27 mmol) and 1 ml of THF After stirring for 72 hours at room temperature, the mixture was poured into 1 M NaOH, extracted 2 times with ethyl acetate and the organic phases were dried with Na 2 SO 4, filtered and concentrated. The residue was purified by radial chromatography (2 mm dish, ethanol-CH 2 Cl 2 3% -ethanol-CH 2 Cl 2 containing 0.5% NH 4 OH), concentrated and the residue was triturated with ether-hexane and 0.076 g (78%) was obtained. of the 3-pentylsulfanyl-5- [3- (3-pyrrolidin-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide as a colorless solid. 1 H NMR (400 MHz, CDCl 3) d 7.57 (as, 1 H), 7.06 (as, 2H), 3.35 (m, 2H), 3.26 (m, 2H), 2.53 (t, 2H, J = 6.8 Hz), 2.47 (m, 4H), 1.73 (m, 8H), 1.4-1.2 (m, 4H), 0.88 ( t, 3H, J = 7.2 Hz) ppm; MS (APCI, m / z: 400 [M + H] +.

PREPARATION 3 Sodium salt of 3- (4-cyano-3-hydroxy-isothiazol-5-yl) -1,1-dimethyl-urea A solution of 3- (2,2-dicyano-1-mercapto-vinyl) -1,1-dimethylurea (sodium salt) was treated at room temperature with hydrogen peroxide (14 ml of a 10 M solution). (30 g, 137 mmol) in water (300 ml). The reaction was heated and thickened with the formation of a solid and treated with more water (100 ml). The mixture was heated to reflux for 15 minutes, producing a complete solution and then cooling to room temperature. After 1 hour at room temperature, the mixture was concentrated to constant weight (35 g,> 100% due to water content) and used immediately in the next step. - (3,3-Dimethyl-ureido) -3-hydroxy-isothiazole-4-carboxylic acid amide The solid obtained in the previous step (35 g) was added to concentrated sulfuric acid (150 ml) followed by water (5 g). ml) and stirred at room temperature overnight. The mixture was treated with ice (500 g) and stirred 2 hours. The mixture was filtered and the air was extracted from the cake overnight. The solid was crushed with a mortar and pestle and kept under high vacuum until constant weight (21.7 g, 94.2 mmol, 69% after the two steps).

EXAMPLE 3 5- (3,3-Dimethyl-uredo) -3-heptyloxy-isothiazole-4-carboxylic acid amide A suspension of 5- (3,3-dimethyl-ureido) -3-hydroxy-isothiazole-4-carboxylic acid amide was treated with KotBu (107 mg, 0.96 mmol) (200 mg, 87 mmoles) in DMF (5 ml) at room temperature obtaining a complete solution. Then 1-iodoheptane (1 ml) was added and the reaction was stirred at room temperature until complete disappearance of the starting materials determined by TLC using hexane-ethyl acetate-methanol-acetic acid (48-48-2-2) as eluent After the reaction mixture was concentrated by rotary evaporation under high vacuum, the residue was dissolved in ethyl acetate and methanol and then purified by radial chromatography. (2 mm plate) using the same eluent as for the TLC providing the 2 components. The more polar material was identified as the N-alkylated adduct (102 mg, 0.311 mmol, 36%). 1 H NMR (400 MHz, CDCl 3) d 0.86 (t, J = 6.7 Hz, 3H), 1.25-1.31 (m, 8H), 1.64-1.70 (m, 2H), 3.07 (s, 6H), 3.68 (t, J = 7.2 Hz, 2H), 5.40 (s, 1H), 8.86 (s, 1H), 12.1 (s, 1 H) ppm; 13 C NMR (101 MHz, CDCl 3), d 13.94, 22.45, 26.48, 28.74, 29.52, 31.52, 36.11, 42.54, 166.99 ppm; MS (APCI, m / z): 329 [M + H] +. The less polar material was the O-alkylated adduct (134 mg, 0.408 mmol, 48%). 1 H NMR (400 MHz, CDCl 3) d 0.88 (t, J = 6.8 Hz, 3H), 1.24-1.50 (m, 8H), 1.75-1.88 (m, 2H), 3.07 (s, 6H), 4.43 (t, J = 6.7 Hz, 2H), 5.42 (s, 1 H), 7.25 (s, 1H seems to be superimposed on the CDCI3 peak), 11.6 (s, 1 H) ppm; 13 C NMR (101 MHz, CDCl 3), d 13.94, 22.45, 25.86, 28.83, 31.60, 36.11, 68.69, 97.69, 154.15, 162.27, 166.20, 169.45 ppm; MS (APCI, m / z): 329 [M + H] +.

PREPARATION 4 2-Cyano-thioacetimidic acid 4-methoxy benzyl ester To a solution of sodium hydroxide (13 g, 0.32 mmol) in 750 ml of ethanol 1: 1 at 0 ° C, was added 4-methoxybenzyl mercaptan (50 g, 0.324 mmol) and malonitrile (21 g, 0.324 mmol). After stirring for 3 hours at 0 ° C, the mixture was diluted with 500 ml of saturated aqueous NH Cl, diluted with 4 l of water and filtered. The solids were washed with ether and the filtrate was diluted with an equal volume of hexane and filtered. The combined solids were dried in vacuo to provide 43 g (60%) of the 4-methoxy benzyl ester of 2-cyano-thioacetimidic acid as a colorless solid. 1 H NMR (400 MHz, CDCl 3) d 7.22 (d, 2 H, J = 7.6 Hz), 6.84 (d, 2 H, J = 8.8 Hz), 4.74 (as, 1 H), 3.98 (s, 2 H), 3.78 ( s, 3H) ppm; MS (APCI, m / z) 221 [M + H] +. 4-Methoxy-benzylic acid ester of 2-cyano-3-mercapto-3-phenoxycarbonylamino-thioacrylimide To a solution of the 4-methoxy-benzyl ester of 2-cyano-thioacetymidic acid (42 g, 0.19 mole) in 191 ml of acetate of ethyl at 0 ° C was added phenoxycarbonylisothiocyanate (34 g, 0.19 mole) and the mixture was stirred at 0 ° C for 24 hours. The mixture was diluted with ether and filtered. The solids were washed with ether, collected and dried in vacuo to give 56 g (73%) of the 4-methoxy-benzyl ester of 2-cyano-3-mercapto-3-phenoxycarbonylamino-thioacrylimide as a yellow solid. 1 H NMR (400 MHz, CDCl 3) d 12.81 (s, 1 H), 9.01 (s, 1 H), 8.68 (s, 1 H), 7.28-6.99 (m, 7 H), 6.69 (d, 2 H, J = 8.8 Hz), 4.17 (s, 2H), 3.64 (s, 3H) ppm; MS (APCI, m / z) 400 [M + H] +.

Phenyl ester of f4-cyano-3- (4-methoxy-benzylsulfanyl) -sothiazole-5-p-carbamic acid Pyridine (4.4 g, 55 mmol) at 0 ° C was added to a mixture of 4-methoxy-benzyl 2-cyano-3-mercapto-3-phenoxycarbonylamino-thioacrylimide acid ester (11 g, 28 mmol) and ethyl acetate (250 ml). A solution of iodine (7.0 g, 28 mmol) in 350 ml of ethyl acetate was added dropwise over one hour. The resulting suspension was stirred for 1 hour, treated with 200 ml of 1 M HCl and filtered, yielding 7.0 g (64%) of the phenyl ester of [4-cyano-3- (4-methoxy-benzylsulfanyl) -isothiazole) -5-yl] -carbamic acid as a colorless solid. The filtrate was extracted with 1 l of ethyl acetate and the organic phase was washed with aqueous NaHCO 3, dried with Na 2 SO 4, filtered and concentrated obtaining an additional yield of 2.8 g (26%) of the phenyl ester of the acid [4- cyano-3- (4-methoxy-benzylsulfanyl) -isothiazol-5-yl] -carbamic acid. 1 H NMR (400 MHz, CDCl 3) d 11.95 (s, 1 H), 7.35 (t, 2 H, J = 8.4 Hz), 7.20 (m, 3 H), 7.13 (d, 2 H, J = 8.0 Hz), 6.78 ( t, 2H, J = 8.6 Hz), 4.34 (s, 2H), 3.73 (s, 3H) ppm; MS (APCI, m / z 398 [M + H] +.

Phenyl ester of (4-cyano-3-mercapto-isothiazol-5-yl) carbamic acid. Mercuric acetate (0.80 g, 2.5 mmol) was added at 0 ° C to a mixture of the phenyl ester of 4-cyano-3- ( 4-methoxy-benzylsulfanyl-isothiazol-5-yl) -carbamic acid (1.0 g, 2.5 mmol), trifluoroacetic acid (26 ml) and anisole (2.7 g, 25 mmol). The mixture was allowed to warm to room temperature overnight. The mixture was then concentrated in vacuo and diluted with 100 ml of water and 100 ml of ethyl acetate. Hydrogen sulfide was slowly bubbled into the interior until the precipitation of the mercury salts was complete. The mixture was diluted with brineit was extracted 3 times with 200 ml of ethyl acetate and the combined organic phases were filtered through celite, dried over Na 2 SO 4, filtered and concentrated in vacuo to give 0.70 g (100%) of the phenyl ester of the acid (4). -cyano-3-mercapto-isothiazol-5-yl) carbamic acid as a colorless solid. 1 H NMR (400 MHz, acetone-d 6) d 7.47 (t, 2 H, J = 7.6 Hz), 7.35-7.30 (m, 3 H) ppm; MS (APCI, m / z): 276 [M + H] +.

Phenyl ester of (4-carbamoyl-3-mercapto-isothiazol-5-yl) -carbamic acid A mixture of the phenyl ester of (4-cyano-3-mercapto-isothiazol-5-yl) acid was stirred at room temperature for 18 hours. ) carbamic (0.70 g, 2.5 mmol), 2,6-di-t-butyl-4-methylphenol (BHT) (one crystal) and concentrated sulfuric acid (3 ml). The mixture was diluted with ice water, extracted 3 times with ethyl acetate and the combined organic phases were dried with Na 2 SO 4, filtered and concentrated in vacuo. The residue was dissolved in 10 ml of ethanol at 0 ° C and treated with 0.096 (2.5 mmoles) g of NaBH 4. After stirring for 30 minutes, the mixture was acidified with 1M HCl, extracted with ethyl acetate, dried with Na2SO, filtered and concentrated in vacuo to afford 0.60 g (18%) of the phenyl ester of the -carbamoyl-3-mercapto-isothiazol-5-yl) carbamic acid as a yellow solid. 1 H NMR (400 MHz, acetone-d 6) d 13.0 (s, 1 H), 11.0-10.9 (as, 1H), 10.3 (s, 1 H), 7.47 (t, 2H, J = 6.8 Hz), 7.37- 7.30 (m, 4H), ppm; MS (APCI, m / z): 296 [M + H] +.

EXAMPLE 4 5-f3- (3-Chloro-4-fluoro-benzyl) -ureido-3- (4-methyl-benzylsulfani) -isothiazole-4-carboxylic acid amide To a mixture of the phenyl ester of (4-carbamoyl-3-mercapto-isothiazole-5-II) carbamic acid (0.075 g, 0.25 mmol) in 0.5 ml of DMF was added 4-methylbenzylchloride (0.036 g, 0.25 mmol) followed of N, N-diisopropylethylamine (0.33, g 0.25 mmol). After stirring at room temperature for 18 hours THF (1 ml) was added followed by 3-chloro-4-fluorobenzylamine (0.081 g, 0.51 mmol). After stirring 24 hours at 45 ° C, the mixture was diluted with 1 M HCl, extracted 3 times with ethyl acetate and the combined organic phases were dried with Na 2 SO 4, filtered and concentrated in vacuo. The residue was purified by radial chromatography on silica gel eluting with ethyl acetate-hexane to provide 26 mg of the 5-3- (3-chloro-4-phenyl-benzyl) -ureido] -3- (4 -methyl-benzylsulfani) -isothiazo I-4-carboxylic acid as a colorless solid. HPLC retention time: 4.9 minutes. 1 H NMR (400 MHz, acetone-d 6) d 7.95 (ace, 1 H), 7.54 (dd, 1 H, J = 7.2 Hz), 7.39 (m, 1 H), 7.31-7.25 (m, 3H), 7.11 (d, 2H, J = 8.0 Hz), 7.01 (bs, 2H), 4.48 (m, 4H), 2.28 (s, 3H) ppm; MS (APCI, m / z): 456 [M + Hf.

PREPARATION 5 2-Cyano-acetylimic acid benzyl ester To a solution of ethereal HCl (4.00 1.1 M, 4.00 moles) was added heated (liquefied) malonitrile (252 ml, 4.00 moles). After dissolution, the solution was cooled to 10 ° C. Then benzyl alcohol (414 ml, 4.00 moles) was added and the mixture was stirred at 10 ° C for 0.5 hours. The reaction flask was placed in the refrigerator and allowed to stand at 5 ° C for 4 days. The solid obtained was filtered cold, washed with cold ether (1.5 I) and dried in vacuo (40 mm Hg) for 1 hour providing 545 g (2.59 moles, 65%) of the Pinner adduct as a white solid. The neutralization of this HCl salt was carried out as indicated below. A solution of potassium carbonate (359 g, 2.59 moles) in water (700 ml) was prepared and cooled to 5 ° C. The Pinner adduct (545 g, 2.59 moles) was added to the separatory funnel and this was stirred vigorously for 5 minutes. The aqueous layer was discarded and the organic phase was collected followed by filtration of the suspended particles. The organic phase was again placed in the separatory funnel, stirred with brine and allowed to decant completely to allow complete virtual removal of the brine layer. The organic phase was concentrated on a rotary evaporator and the unstable product (327 g, 1.88 mmol, 73%) was used rapidly in the next step.

Phenoxycarbonylisothiocyanate A suspension of KSCN (80 g, 823 mmol, prepared from a new bottle that had not been opened) was stirred vigorously overnight under nitrogen atmosphere in order to obtain the KSCN powder. Then the fine suspension was treated dropwise with phenyl chloroformate (1000 ml, 800 mmoles) for more than 1 hour. The reaction was stirred overnight at room temperature and then stirred at 5 ° C for 8 hours. The KCl produced was removed by filtration and the solvent was removed by rotary evaporation taking care not to heat the product above room temperature. The product was dissolved in ether (2 I), the additional precipitation was removed by filtration and discarded and the hexane solution of the product was again concentrated under reduced pressure being careful not to heat the product above room temperature. The product thus obtained turned out to have a high purity (101 g, 564 mmoles, 68%) and could be stored at -5 ° C for several days or at room temperature for a few hours, although it is normal to use it quickly as in present example. 1 H NMR (400 MHz, CDCl 3) d 7.10-7.21 (m, 2H), 7.21-7.31 (m, 1H), 7.31-7.45 (m, 2H) ppm; 13 C NMR (101 MHz, CDCl 3) d 120.75, 126.77, 129.65, 150.46 ppm; IR (pure) 1190, 1232, 1491, 1590, 1751, 1960 cm-1. 2-Cyano-3-mercapto-3-phenoxycarbonylaminoacrylimide benzyl ester To a stirred solution at 0 ° C of the benzyl ester of 2-cyanoacetymidic acid (327 g, 1.88 mmoles) in acetonitrile (1 I) was added a 0 ° C solution of phenoxycarbonylisothiocyanate (353 g, 1.97 moles) in acetonitrile (1 I). The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was then placed in the refrigerator and left at 5 ° C for 48 hours. The solid obtained was filtered, compressed and washed with acetonitrile at 20 ° C (3 x 200 ml). The air was then extracted from the relatively stable solid, followed by drying under high vacuum to obtain a yellow solid (282 g, 798 mmol, 42%). H NMR (400 MHz, DMSO) d 5.39 (s, 2H), 7.11-7.19 (m, 2H), 7.20-7.24 (m, 1H), 7.36-7.46 (m, 7H), 10.23 (broad s, 1 H ), 10.67 (s, 1 H), 12.19 (broad s, 1 H) ppm; MS (APCI, m / z); 354 [M + H] +.

Phenyl ester of (3-benzyl-4-cyano-isothizazol-5-iP-carbamic acid) Pyridine (129 ml, 1.60 moles) was added to a suspension at 0 ° C of the adduct of the benzyl ester of 2-cyano- 3-mercapto-3-phenoxycarbonylaminoacrylimide (282 g, 798 mmol) in acetonitrile (2 I).

Then a solution of bromine (41.1 ml, 798 mmol) in acetonitrile (200 ml) was added for more than 15 minutes. The reaction was stirred at 0 ° C for a further 1 hour and then at room temperature for 2 hours. The mixture was placed in the refrigerator and left at 5 ° C overnight. The solid was filtered and washed with ether (1 L) at 0 ° C, dried in the same funnel by extracting the air from the solid for 4 hours. The solid was added to water (1 L), stirred vigorously for 1 hour, filtered and dried in the same funnel by extracting the air from the solid overnight to obtain a white solid (320 g pure still containing some water) that was used, as such, in the next step. 1 H NMR (400 MHz, DMSO) d 5.35 (s, 2H), 7.25-7.45 (m, 10H), 13.20 (broad s, 1 H) ppm; Em (APCI, m / z); 350 [M + H] +.

Phenyl ester of (4-carbamoyl-3-hydroxy-isothiazol-5-yl) -carbamic acid The wet solid, (3-benzyloxy-4-cyano-isothiazol-5-yl) -carbamic acid phenyl ester (320 g) it was slowly added to concentrated sulfuric acid (650 ml) for 1.5 hours. Additional concentrated sulfuric acid (100 ml) was added and the mixture was stirred for another 3 hours. The viscous solution was diluted by the addition of ice (2000 g) followed by vigorous stirring for a further 2 hours. The acid was partially removed by dividing the suspension into 8 containers that were placed in a centrifuge, rotating at 3000 rpm for 45 minutes at 21 ° C. The aqueous phase was discarded, more pure water was added, the precipitate was resuspended and the process repeated. After 7 cycles of dilution-centrifugation-redilution; the pH of the aqueous phase had been increased to approximately 4. The solid was collected, dried by extracting the air from the cake in a funnel for 2 days. The less moist solid was ground, placed back on the filter and the air was extracted from the solid again for another day. This process was repeated until the solid was dried to obtain a tan solid (234 g, 105% of the 2 steps, there were less present impurities - did not interfere appreciably with the following steps). 1 H NMR (400 MHz, DMSO) d 7.00 (s, broad, 1 H), 7.27-7.31 (m, 3H), 7.40-7.45 (m, 2H), 7.89 (s, 1 H), 8.08 (s, 1 H), 11.92 (s, 1 H); MS (APCI, m / z); 184 (M- (H and PhOH)) +.

Phenyl ester of f4-carbamoyl-3- (2,6-difluoro-4-methyl-benzyloxy) -isothiazole-5-n-carbamic acid ester To a suspension of the phenyl ester of (4-carbamoyl-3-hydroxy-isothiazole) -5-yl) -carbamic acid (1.77 g, 6.23 mmol), triphenylphosphine (1.99 g, 7.59 mmol), alcohol or, o'-difluoro-p-methylbenzyl ester (1.00 g, 6.32 mmol) in THF (21 ml) was added. added diisopropyl azodicarboxylate (DIAD, 1.49 ml, 7.59 mmol) slightly faster than dropwise. The reaction mixture was ed and became transparent. After stirring for 15 minutes, most of the THF was removed by rotary evaporation and the crude mixture was purified on silica gel using chloroform-acetone-acetic acid (98.5 / 0.75 / 0.75) as eluent to obtain a white solid (802 mg , 1.91 mmoles, 30%).

EXAMPLE 5 3- (2,6-Difluoro--methyl-benzyloxy) -5- (3-r3- (4-methyl-piperazin-1-yl) -propip-ureidoHsothiazole-4-carboxylic acid amide 1- (3-Aminopropyl) -4-methylpiperazine (70 mg, 0.45 mmol) was added to a suspension of the phenyl ester of [4-carbamoyl-3- (2,6-difluoro-4-methylene-benzyloxy)] -isothiol-5-yl] carbamic acid (125 mg, 0.298 mmol) in THF (1 ml). The mixture was stirred at 50 ° C overnight, cooled to room temperature, and loaded directly onto a radial chromatograph followed by elution with chloroform / methanol / concentrated ammonium hydroxide (50/5/1) to give a white solid ( 121 mg, 0.251 mmol, 84%). 1 H NMR (400 MHz, CDCl 3) d 1.72 (t, J = 5.81 Hz, 2H), 2.20-2.85 (m, 10 H), 2.28 (s, 3H superimposed on multiplet of 2.20-2.85), 2.35 (s, 3H superimposed on multiplet of 2.20-2.85), 3.39 (t, J = 5.4 Hz, 2H), 5.51 (s) , 2H), 5.74 (sa 1H), 6.74 (d, J = 8.3 Hz, 2H), 7.05 (s, 1 H), 7.58 (sa, 1 H), 11.01 (s, 1 H) ppm; MS (APCI, m / z): 483 [M + H] +.

Synthesis of representative fluorotoluene derivatives 1. 3-Difluoro-5-methylbenzene (G = H) A mixture of 1-bromomethyl-3,5-difluoro-benzene (75 g, 0.362 mol), Pd / C (5 g) was treated with hydrogen gas (344, 737 kPa). %, 5g), and sodium acetate (280 g, 2.54 moles) in ether (300 ml) on a Parr shaker for 2 days. The mixture was filtered through Celite and the organic solution was washed three times with saturated aqueous sodium bicarbonate solution. The aqueous phases were washed with ether, and the combined organic phases were dried (MgSO 4), filtered and partially concentrated by evaporation using a cold water bath. The volatile product was obtained as a mixture with ether, and the ratio (~ 3: 2, ethacrylate, g: g) was calculated based on 1 H NMR integration, determined the actual yield (45.5 g, 0.355 moles, 98%) of the product for reagents to scale in the consequent reaction. 1 H NMR (400 MHz, CDCl 3) d 2.25 (s, 3 H), 6.51-6.56 (m, 1 H), 6.58-6.60 (m, 2 H) ppm. 1. 2,5-Trifluoro-3-methyl-benzene (G = F) The title compound was prepared from 1-bromomethyl-2,3,5-trifluoro-benzene by a procedure analogous to that of the above 3,5-difluorotoluene . 1 H NMR (400 MHz, CDCl 3) d ppm; MS (APCI, m / z). [M + H] +.

Synthesis of representative benzylic alcohols by conversion to RJ (2,6-Difluoro-4-methyl-phenyl) -methanol (G = H, G '= Me. G "= F) A solution of 1,3-difluoro-5-methyl-benzene (45.5 g, 0.355 moles) , mixed with a small volume of ether) in dry THF (1.77 I) was cooled to -78 ° C under nitrogen and treated dropwise with n-BuLi (142 ml of a 2.5M solution in hexanes, 0.355 moles). The solution was stirred for an additional 25 minutes and then treated with DMF (27.5 ml, 0.355 mole) After stirring for an additional 45 minutes, the solution was treated with acetic acid (40.6 ml, 0.71 mole) and the flask was removed from the solution. The mixture was stirred at room temperature for 2 hours and treated successively with water (300 ml) and MeOH (300 ml), then NaBH4 (26.8 g, 071 mol) was added portionwise. ) followed by stirring for 1 hour The flask was cooled in an ice bath and the mixture was treated with 6 N HCl until pH ~ 5. The mixture was concentrated by rotary evaporation to remove THF and MeOH, and the product It was extracted with ether and washed several times with small volumes of water and once with brine. The ether layer was dried (MgSO), filtered and concentrated to give an oil (45 g, 0.285 mol, 80%) which solidified under refrigeration. 1 H NMR (400 MHz, CDCl 3) d 1.75 (t, J = 6.5 Hz, 1 H), 2.32 (s, 3 H), 4.72 (d, J = 6.4 Hz, 2 H), 6.69 (d, J = 7.9 Hz, 2H) ppm. f2,3,6-Trifluoro-4-methyl-phenol-methanol (G = F. G '= Me. G "= F) The title compound was prepared from 1, 2,5-trifluoro-3 -methylbenzene by a procedure analogous to that of (2,6-difluoro-4-methyl-phenyl) -methanol, above: 1 H NMR (400 MHz, CDCl 3) d 1.87 (sa, 1H), 2.28 (d, J = 1.9 Hz, 3H), 4.74 (s, 2H), 6.68-6.72 (m, 1 H) ppm. f4-Bromo-2,6-difluoro-phenyl) -methanol- (G = H, G '= Br, G "= F) The title compound was prepared from 1-bromo-3,5-difluoro-benzene by a procedure analogous to that of (2,6-difluoro-4-methyl-fenii) -methanol, above, with the following exception: lithium diisopropylamide (LDA) was used instead of n-BuLi, and the deprotonation time was extended to 45 minutes. 1 H NMR (400 MHz, CDCl 3) d 1.91 (t, J = 6.5 Hz, 1 H), 4.71 (d, J = 6.4 Hz, 2 H), 7.06-7.12 (m, 2 H) ppm. f4-Bromo-2.3.6-trifluoro-phenyl] -methanol- (G = F. G '= Br. G "= F) The title compound was prepared from 1-bromo-2,3,5 -trifluoro-benzene by a procedure analogous to that of (2,6-difluoro-4-methyl-phenyl) -methanol, above, with the following exception: lithium diisopropylamide (LDA) was used instead of n-BuLi, and the The deprotonation time was extended to 45 minutes: 1 H NMR (400 MHz, CDCl 3) d 1.89 (t, J = 6.5 Hz, 1 H), 4.75 (d, J = 6.4 Hz, 2 H), 7.11-7.15 (m, 1 H) ppm. (3-Chloro-2,6-difluoro-phenyl) -methanol- (G = CI, G '= H, G "= F) The title compound was prepared from 1-chloro-2,4-difluoro-benzene by a procedure analogous to that of (2,6-difluoro-4-methyl-phenyl) -methanol, above: 1 H NMR (400 MHz, CDCl 3) d 1.90 (t, J = 6.4 Hz, 1 H), 4.78 (d, J = 6.4 Hz, 2H), 6.87 (approximately, dt, J = 1.8, 8.9 Hz, 1 H), 7.32 (approximately, dt, J = 5.8, 2.8 Hz, 1 H) ppm. f2-Fluoro-4,6-dimethyl-phenol-methanol- (G = H, G '= Me, G "= Me) A solution of N, N, N', N'-tetramethylethylenediamine (13.4 ml, 88.6 mmoles) in THF (115 ml) was cooled to -78 ° C and treated with sec-BuLi (68.2 ml of 1.3 M solution in cyclohexane, 88.6 mmole.) The resulting yellow solution was stirred for 20 minutes at -78 ° C. and was subsequently treated with a solution of 1-fluoro-3,5-dimethyl-benzene (10.0 g, 80.5 mmol) in THF (56 ml) The mixture was stirred for 1 hour at -78 ° C and then treated with a Dissolution of DMF (6.86 ml, 88.6 mmol) in THF (26 ml) The reddish-brown mixture was stirred an additional hour and treated with AcOH (10 ml) and water (200 ml) The mixture was warmed to temperature The mixture was extracted with ether (500 ml) and the aqueous phase was extracted with additional ether (2 x 300 ml) The combined organic extracts were combined and washed successively with 0.2 M HCl (2 x 200 ml), water (500 ml). ) and brine (300 ml) The organic phase was dried (Mg SO4) and Ntr, giving the aldehyde as a clear oil (11.9 g, 78.2 mmol, 97%). Subsequently, the aldehyde was dissolved in THF (100 ml), MeOH (100 ml), and water (100 ml), and treated with portions of NaBH 4 (2.96 g, 78.2 mmol). The mixture was stirred at room temperature for 1 hour and then concentrated at low pressure to remove THF and MeOH. The remaining aqueous phase was extracted twice with ether (600 ml and 200 ml) and the combined organic phases were washed successively with 0.1 M HCl (300 ml), water (300 ml) and brine (300 ml). The organic phase was dried (MgSO4), and concentrated to give an oil (10.8 g, 70.4 mmol, 90%). 1 H NMR (400 MHz, CDCl 3) d 2.28 (s, 3 H), 2.38 (s, 3 H), 4.70 (s, 2H), 6.71 (d, J = 10.6, 1 H), 6.79 (s, 1 H) ppm. f2-Fluoro-4-methyl-phenol) -methanol (G = H, G '= Me, G "= H) A solution of 4-bromo-3-fluorotoluene (12.2 g, 64.7 mmol) in THF (170 ml) was cooled to -78 ° C and treated dropwise with n-BuLi (25.9 ml of a solution in 2.5M hexanes, 65 mmol) After stirring for 1 hour, the solution was treated with N, N- dimethylformamide (DMF) (5.5 ml, 71 mmoies) and stirred for an additional 30 minutes, followed by the addition of acetic acid (12 ml) The flask was taken out of the cold bath and allowed to warm to room temperature. Then, water was added and the product was extracted with ether The organic phase was washed successively with dilute HCl and brine, and then dried (MgSO4) and concentrated The procedure was repeated (using 11.8 g of 4-bromo-3 Fluorotoluene) and the combined material was subjected to the following reduction: the aldehyde (17.6 g, 127 mmol) was dissolved in THF (165 ml), MeOH (165 ml), and water (165 ml). in portion is NaBH 4 (5.3 g, 140 mmol) for a few minutes (bubbling, exothermic), and stirring was continued for 2 hours. The reaction was diluted with a large volume of ether and treated with HCl to terminate. The phases were separated and the organic phase was dried (MgSO4) and concentrated to give the product as an oil (17.0 g, 121 mmol, 95%). 1 H NMR (400 MHz, CDCl 3) d 2.33 (s, 3 H), 4.69 (s, 2 H), 6.86 (d, J = 11.2 Hz, 1 H), 6.93 (d, J = 7.9 Hz, 1 H), 7.24 -7.28 (m, 1 H), ppm. f4-Chloro-2,5-difluoro-phenyl) -methanol To a mixture of 4-chloro-2,5-difluoro-benzoic acid (15 g, 78 mmol), tetrahydrofuran (THF) (75 ml) and trimethyl borate (26 ml, 230 mmol) was added the borane-methylsulfide complex (86 ml, 86 mmol, 10 M solution in DMS), and the mixture was stirred for 18 hours at room temperature. Additional borane-methylsulfide complex (2.47 ml, 24.7 mmol) was added to complete the reaction. The mixture was poured into 1 M aqueous NaOH, extracted with 3x ether, and the combined organic phases were dried over anhydrous MgSO, filtered and concentrated in vacuo. Trituration of the solid residue with ether-hexane gave 14 g of (4-chloro-2,5-difluoro-phenyl) -methanol as a colorless solid. 1 H NMR (400 MHz, CDCl 3) d 7.26 (dd, 1 H, J = 6, 8.8 Hz), 7.11 (dd, 1H, J = 6, 9.2 Hz), 4.71 (d, 2H, J = 6.0 Hz), 1.80 (t, 1H, J = 6.0 Hz) ppm.

Tert-Butyl- (2,3-d-fluoro-benzyloxy) -dimethyl-s-lane Tert-butyldimethylchlorosilane (5.4 g, 36 mmol) was added to a solution of (2,3-difluoro-phenyl) -methanol (5.0 g, 35 mmol), imidazole (4.9 g, 72 mmol) and DMF (40 ml). After stirring at room temperature for 24 hours, the mixture was partitioned between 400 ml of ether and 100 ml of water. The organic phase was washed twice with water, dried over MgSO4, filtered and concentrated in vacuo to give 6.8 g of tert-butyl- (2,3-difluoro-benzyloxy) -dimethylsilane as a colorless oil. 1 H NMR (400 MHz, CDCl 3) d 7.22 (m, 1 H), 7.04 (m, 2 H), 4.79 (s, 2 H), 0.91 (s, 9 H), 0.12 (s, 6 H), ppm.

Tert-butyl- (2,3-difluoro-4-methyl-benzyloxy) -dimethylsilane sec. Butyllithium (20 ml, in 1.3 M hexane, 26 mmol) was added to a solution of TMEDA (3.9 ml, 3.0 g, 26 mmol) in THF (33 ml) at -78 ° C. After stirring for 20 minutes, a solution of tert-butyl- (2,3-difluoro-benzyloxy) -dimethyl-silan (6.0 g, 23 mmol) in 17 ml of THF was added dropwise. After stirring for 1 hour, the solution was added dropwise to a solution of methyl iodide (8 ml) in THF (40 ml) at -20 ° C. After stirring for 18 hours, the mixture was terminated with saturated aqueous NH4CI, extracted 3x in ether, and the combined organic phases were dried over MgSO4, filtered and concentrated in vacuo to give 6.6 g of tert-butyl- ( 2,3-difluoro-4-methyl-benzyloxy) -dimethylol as a light yellow oil. 1 H NMR (400 MHz, CDCl 3) d 7.07 (approximately t, 1 H, J = 7.2 Hz), 6.89 (approximately t, 1 H, J = 7.3 Hz), 4.74 (s, 2H), 2.26 (d, 3H, J = 1.9 Hz), 0.87 (s, 9H), 0.07 (s, 6H), ppm. (2,3-Difluoro-4-methy1-phenyl) -methanol Tetrabutylammonium fluoride (24 ml of a solution) was added.

M in THF, 24 mmol) was added to a solution of tert -Butyl- (2,3-d-fluoro-4-methyl-benzyloxy-dimethylsilane (6.5 g, 24 mmol) in THF (24 ml). at room temperature for 1 hour, the mixture was poured into water, acidified with 1 M aqueous HCl, extracted 3 x with ethyl acetate, and the combined organic phases were dried over Na 2 SO 4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (10: 1 to 2: 1 hexane acetate-ethyl acetate) to give (2,3-difluoro-4-methyl-phenylj-methanol as a light yellow oil. 1-Bromo-2,5-difluoro-4-methylene-benzene A mixture of 2,5-difluorotoluene (25 g, 0.20 mole) and iron powder (11 g, 0.2 mole) was cooled to -5 ° C. . Bromine was added dropwise, so that the internal temperature of the reaction did not exceed 0 ° C. After stirring for 3 hours, the mixture was diluted with ether, filtered and washed with aqueous sodium thiosulfate solution. The aqueous phase was extracted with ether, and the combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. Distillation at atmospheric pressure gave 34 g of 1-bromo-2,5-difluoro-4-methyl-benzene as a colorless oil. (p.80 ° C). 1 H NMR (300 MHz, CDCl 3) d 7.20 (dd, 1 H, J = 6.0, 8.5 Hz), 6.93 (m, 1 H), 2.23 (s, 3 H), ppm. (2,5-Difluoro-4-methyl-phenyl) -methanol A mixture of 1-bromo-2,5-difluoro-4-methyl-benzene (3.3 g, 16 mmol) and ether (75 ml) was cooled to -78. ° C, and a solution of n-butylithium in hexane (5.4 ml, 2.5 M, 13.5 mmol) was added dropwise. After stirring for 1 hour, dimethylformamide (1.1 ml, 14 mmol) was added and the mixture was stirred for 1 hour. The mixture was treated with 1 M HCl and water, warmed to room temperature and extracted 3 x with ether. The combined organic phases were dried over MgSO 4, filtered and concentrated in vacuo. The residue was diluted with tetrahydrofuran (50 ml), and the mixture was treated with sodium borohydride (0.50 g, 13.5 mmol) and ethanol (2 ml). After stirring for 30 minutes, the mixture was carefully diluted with 0.5 M aqueous HCl, extracted 3 x with ethyl acetate, and the combined organic phases were dried over Na 2 SO 4, filtered and concentrated in vacuo. Recrystallization of the residue from hexane gave 1.24 g (54%) of (2,5-difluoro-4-methyl-phenyl) -methanol as a colorless solid. H NMR (400 MHz, CDCl 3) d 7.05 (dd, 1 H, J = 6.0, 9.2 Hz), 6.84 (dd, 1H, J = 6.4 10 Hz), 4.68 (d, 2H, J = 6.0 Hz), 2.23 (s, 3H), 1.76 (t, 1 H, J = 6.0 Hz), ppm. f5-Chloro-2-fluoro-4-methyl-phenyl) -methanol (5-Chloro-2-fluoro-4-methyl-phenyl) -methanol was prepared analogously to (2,5-difluoro-4-methyl) phenyl) -methanol using 2-chloro-5-fluorotoluene as the starting material. 1 H NMR (400 MHz, CDCl 3) d 7.38 (d, 1 H, J = 6.8 Hz), 6.92 (d, 1 H, J = 10 Hz), 4.69 (s, 2H), 2.34 (s, 3H) ppm. 4-Chloro-2,6-difluoro-benzaldehyde was added to a solution of n-butyllithium in hexane (12.1 ml, 2.5 M, 30 mmol) to a solution of 3,5-difluoro-1-chlorobenzene (5.0 g, 34 mmol) in tetrahydrofuran (70 ml) at -78 ° C. After stirring for 1 hour, dimethylformamide (5.2 ml, 67 mmol) was added, and the mixture was stirred for 1.5 hours. The mixture was warmed to room temperature, diluted with ether and poured into 150 ml of 0.5 M aqueous HCl. The aqueous phase was extracted 3 x in ether and the combined organic phases were dried over MgSO 4 > they were filtered and concentrated in vacuo to give 5.72 g (96%) of 4-chloro-2,6-difluoro-benzaldehyde as a colorless solid. 1 H NMR (400 MHz, CDCl 3) d 10.27 (s, 1 H), 7.04 (d, 2 H, J = 7.9 Hz) ppm. (4-Chloro-2,6-difluoro-phenyl) -methanol Sodium borohydride (1.2 g, 32 mmol) was added at 0 ° C to a mixture of 4-chloro-2,6-difluoro-benzaldehyde (5.7 g, 32 g). mmoles), tetrahydrofuran (150 ml) and ethanol (20 ml). The mixture was stirred for 30 minutes, warmed to room temperature, and additional sodium borohydride (0.40 g, 11 mmol) was added to get the reaction complete (TLC). The mixture was concentrated in vacuo, diluted with ether and carefully treated with aqueous 1M HCl. The aqueous phase was extracted 3x with ether and the combined organic phases were dried over MgSO, filtered and concentrated. Trituration of the residue with pentane gave 4.8 g (83%) of (4-chloro-2,6-difluoro-phenyl) -methanol with a colorless solid. 1 H NMR (300 MHz, CDCl 3) d 7.04 (d, 2 H, J = 7.1 Hz), 4.73 (s, 2 H) ppm.

General procedure for the preparation of isothiazole phenyl carbamates: [4-carbamoyl-3- (2,5-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl] carbamic acid phenyl ester Diethylazodicarboxylate (1.3 ml, 8.0 mmol) ) to a mixture of the phenyl ester of (4-carbamoyl-3-hydroxy-isothiazol-5-yl) -carbamic acid (2.1 g, 7.6 mmol), (2,5-difluoro-4-methyl-phenyl) -methanol (1.2 g, 7.6 mmol), triphenylphosphine (2.1 g, 8.0 mmol) and tetrahydrofuran (19 ml). After stirring for 16 hours at room temperature, (2,5-difluoro-4-methyl-phenyl) -methanol (0.24 g, 1.5 mmol), triphenylphosphine (0.42 g, 1.6 mmol) and diethylazodicarboxylate (0.30 ml, 1.8) were added. additional mmoles), and the mixture was stirred for 1 hour. After concentrating in vacuo, the mixture was purified by chromatography on silica gel eluting with acetone-acetic acid-methylene chloride (0.5%, 0.5%, 99%), giving, after trituration in ether-hexane, 1.1 g ( 35%) of the phenyl ester of [4-carbamoyl-3- (2,5-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl] -carbamic acid as a colorless solid. HPLC retention time: 4.8 minutes. 1 H NMR (400 MHz, CD 3 OD) d 7.40 (t, 2 H, J = 8.0 Hz), 7.27 (t, 1 H, J = 7.2 Hz), 7.20 (d, 2 H, J = 8.4 Hz), 7.17 (dd, 1 H, J = 6.0, 9.2 Hz), 7.00 (dd, 1 H, J = 6.4, 10 Hz), 5.49 (s, 2H), 2.24 (s, 3H), ppm.

Phenyl ester of f4-carbamoyl-3- (2,3-difluoro-4-methyl-benzyloxy) -sothiazole-5-ip-carbamic acid Preparation of the title compound as described in example 3 using (2, 3-d-fluoro-4-methyl-phenyl) -methanol yielding 1.7 g (57%) of the phenyl ester of [4-carbamoyl-3- (2,3-difluoro-4-methyl-benzyloxy) -isothiazole) -5-i] -carbamic acid as a colorless solid. Retention time HPLC: 4.8 minutes. 1 H NMR (400 MHz, CDCl 3) d 11.38 (s, 1 H), 7.40 (t, 2 H, J = 8.0 Hz), 7.26 (t, 1 H, J = 7.2 Hz), 7.20 (d, 1 H, J = 8.4 Hz), 7.14 (b, 1 H), 7.11 (t, 1 H, J = 7.6 Hz), 6.94 (t, 1 H, J = 7.2 Hz), 5.6 (b, 1 H), 5.52 (s) , 2H), 2.31 (d, 3H, J = 1.7 Hz) ppm.

Phenyl ester of r4-carbamoyl-3- (2,5-d-fluoro-4-chloro-benzyloxy-isot-azole-5-p-carbamic acid The preparation of the title compound as described in Example 3 using (2,5-difluoro-4-methyl-phenyl) -methanol gave 0.86 g (26%) of the phenyl ester of [4-carbamoyl-3- (2,5-difluoro-4-chloro-benzyloxy) -isot! azol-5-yl] -carbamic acid as a colorless solid HPLC retention time: 4.8 minutes 1 H NMR (400 MHz, DMSO-d 6) d 11.73 (s, 1 H), 8.04 (s, 1 H), 7.77 ( m, 2H), 7.51 (m, 2H), 7.36 (m, 3H), 7.23 (s, 1H), 5.51 (s, 2H) ppm. [4-Carbamoyl-3- (2,6-difluoro-4-chloro-benzyloxy-isothiazole-5-ip-carbamic acid phenyl ester The preparation of the title compound as described in Example 3 using (2.6 -difluoro-4-chloro-phenyl) -methanol, giving 0.86 g (26%) of the phenyl ester of [4-carbamoyl-3- (2,6-difluoro-4-chloro-benzyloxy) -isothiazoi-5-yl] ] -carbamic acid as a colorless solid HPLC retention time: 4.6 minutes 1 H NMR (400 MHz, CDCl 3) CD 3 OD) d 7.31 (t, 2 H, J = 8.0 Hz), 7.18 (t, 1 H, J = 7.6 Hz ), 7.10 (d, 2H, J = 7.6 Hz), 6.92 (d, 2H, J = 7.2 Hz) 5.45 (s, 2H) ppm.

General procedure for the synthesis of isothiazole ureas EXAMPLE 6 3- (2,5-Difluoro-4-methyl-benzyloxy) -5-r3- (4-pyrrolidin-1-yl-butyl) -ureido-1-isothiazole-4-carboxylic acid amide A mixture of [4-carbamoyl-3- (2,5-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl] -carbamic acid phenyl ester (0.34 g) was stirred for 24 hours at 45-50 ° C. , 0.81 mmol), 4-pyrrolidinobutylamine (0.12 g, 0.81 mmol) and tetrahydrofuran (2.8 ml). The mixture was concentrated and purified by radial chromatography (4 mm dish, CH 3 OH-CHCl 3 -NH 4 OH (10: 89: 1) to (15: 84: 1)), giving 0.31 g of the title compound as a colorless solid. The material was dissolved in approximately 10 ml of methanol-chloroform 4: 1 at 10 ° C and treated with a solution of methanesulfonic acid (0.043 ml in 0.5 ml of CH3OH). After stirring for 5 minutes, the mixture was concentrated in vacuo and the residue was triturated with methanol-ether, giving 0.35 g of the title compound (82%) as a colorless solid. HPLC retention time: 3.3 minutes. 1 H NMR (400 MHz, D 2 O) d 6.74 (dd, 1 H, J = 6.0, 9.6 Hz), 6.63 (dd, 1H, J = 6.4, 10.4 Hz), 4.61 (s, 2H), 3.44 (m, 2H ), 3.05-2.98 (m, 4H), 2.98-2.81 (m, 2H), 2.62 (s, 3H), 1.95-1.93 (m, 4H), 1.83-1.80 (m, 2H), 1.6-1.5 (m , 2H), 1.4-1.3 (m, 2H), ppm; MS (APCI, m / z): 468 [M + H] +.

EXAMPLE 7 3- (2,5-Difluoro-4-methyl-benzyloxy) -5-r3- (4-hydroxy-5-piperidin-1-yl-pentyl) -ureido-l-isothiazole-4 acid amide -carboxyl The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,5-d-fluoro-4-methyl-benzyloxy) -isothiazol-5-yl] -carbamic acid and from amino-1-piperidin-1-yl-pentan-2-ol by a procedure analogous to that of example 6. HPLC retention time: 3.3 minutes. 1 H NMR (400 MHz, CD 3 OD) d 7.18 (dd, 1 H, J = 6.0, 9.2 Hz), 7.5 (dd, 1H, J = 6.0, 10 Hz), 5.47 (s, 2H), 3.80 (m, 1 H), 3.23 (t, 2H, J = 6.4 Hz), 2.7-2.4 (m, 7H), 2.25 (s, 3H), 1.8-1.4 (m, nH), ppm; MS (APCI, m / z): 512 [M + H] +.

EXAMPLE 8 (R) -3- (2,5-Difluoro-4-methyl-benzyloxy) -5-f3-f4- (3-hydroxy-5-pyrrolidin-1-yl) -butyne-ureido acid acid amide > -isothiazole-4-carboxylic acid The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,5-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl] -carbamic acid and from (R ) -1- (4-amino-butyl) -pyrrolidin-3-ol by a procedure analogous to that of example 6. HPLC retention time: 3.2 minutes. 1 H NMR (400 MHz, CD 3 OD) d 7.19 (dd, 1 H, J = 6.0, 9.2 Hz), 7.04 (dd, 1H, J = 6.0, 10 Hz), 5.45 (s, 2H), 4.34 (m, 1 H), 3.23 (m, 2H), 2.86 (dd, 1 H, J = 6.0, 10.4 Hz), 2.78 (m, 1 H), 2.65-2.54 (m, 4H), 2.25 (s, 3H), 2.14 (m, 1 H), 1.73 (m, 1H), 1.56 (m, 4H) ppm; MS (APCI, m / z): 484 [M + H] +.

EXAMPLE 9 3- (2,5-Difluoro-4-methyl-benzyloxy) -5-r3- (6-dimethylamino-hexyl) -ureido-l-isothiazole-4-carboxylic acid amide The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,5-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl] -carbamic acid and of N1, N1-dimethyl- hexane-1, 6-diamine by a procedure analogous to that of example 6. HPLC retention time: 3.4 minutes. 1 H NMR (400 MHz, CD 3 OD) d 7.18 (dd, 1 H, J = 6.0, 9.2 Hz), 7.03 (dd, 1H, J = 6.4, 10 Hz), 5.45 (s, 2H), 3.19 (t, 2H , J = 7.2 Hz), 2.28 (m, 2H), 2.24 (s, 3H), 2.22 (s, 6H), 1.55-1.45 (m, 4H), 1.35-1.33 (m, 4H), ppm; MS (APCI, m / z): 470 [M + H] +.

EXAMPLE 10 3- (2,5-Difluoro--methyl-benzyloxy) -5'3-r4- (2-hydroxymethyl-pyrrolidin-1-yl) -but-p-ureido acid amide} -isothiazole-4-carboxylic acid The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2, 5-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl] -carbamic acid and (S) - [1- (4-amino-butyl) -pyrrolidin-2-yl] -methanol by a procedure analogous to that of example 6. HPLC retention time: 3.2 minutes. 1 H NMR (400 MHz, CD 3 OD) d 7.18 (dd, 1 H, J = 6.0, 9.2 Hz), 7.04 (dd, 1H, J = 6.4, 10 Hz), 5.45 (s, 2H), 3.62-3.56 (m , 2H), 3.29-3.23 (m, 2H), 3.02 (m, 1H), 2.78 (m, 1 H), 2.83 (m, 1 H), 2.51 (m, 2H), 2.24 (d, 3H, J = 1.6 Hz), 2.02 (m, 1H), 1.88-1.56 (m, 7H) ppm; MS (APCI, m / z): 498 [M + H] +.

EXAMPLE 11 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- 3 -f4- (3-hydroxy-piperidin-1-yl) -butyne-ureide acid amide > -isothiazole-4-carboxylic acid The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,5-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl] -carbamic acid and 1- (4-amin) No-butyl) -piperidin-3-ol by the procedure analogous to that of example 6. HPLC retention time: 3.3 minutes. 1 H NMR (400 MHz, CD 3 OD) d 7.18 (dd, 1 H, J = 6.8, 9.6 Hz), 7.04 (dd, 1 H, J = 5.6, 10 Hz), 5.45 (s, 2 H), 3.64 (m, 1 H ), 3.24-3.22 (m, 2H), 2.90 (m, 1 H), 2.73 (m, 1 H), 2.37 (m, 2H), 2.25 (d, 3H, J = 1.6 Hz), 1.99-1.87 ( m, 3H), 1.74 (m, 1H), 1.74-1.53 (m, 6H), ppm; MS (APCI, m / z): 498 [M + H] +.

EXAMPLE 12 3- (2,5-Difluoro-4-methyl-benzyloxy) -5-r3- (5-isopropylamino-pentyl) -ureido-1-isothiazole-4-carboxylic acid amide The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,5-difiuoro-4-methyl-benzyloxy) -isothiazol-5-yl] -carbamic acid and N1-isopropyl-pentane -1,5-diamine by the procedure analogous to that of Example 6. HPLC retention time: 3.4 minutes. 1 H NMR (300 MHz, CD 3 OD) d 7.20 (dd, 1 H, J = 5.7, 9.0 Hz), 7.06 (dd, 1H, J = 6.3, 10 Hz), 5.47 (s, 2H), 3.23 (t, 2H, J = 6.6 Hz), 2.93 (s, 1 H, J = 6.3 Hz), 2.70 (m, 2H), 2.27 (d, 3H, J = 1.8 Hz), 1.7-1.5 (m, 4H), 1.5-1.3 (m, 2H), 1.11 (d, 6H, J = 6.6 Hz) ppm; MS (APCI, m / z): 470 [M + H] +.

EXAMPLE 13 3- (2,3-Difluoro-4-methyl-benzyloxy) -5-f3-r4- (3,4-dihydroxy-pyrrolidin-1-yl) -butyl-ureido-isothiazole-4-acid amide -carboxylic The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,5-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl] -carbamic acid and 1- (4-amino) -butyl) -pyrrolidin-3,4-diol by the procedure analogous to that of example 6. HPLC retention time: 3.1 minutes. 1 H NMR (400 MHz, CD 3 OD) d 7.17 (t, 1 H, J = 7.3 Hz), 7.03 (t, 1 H, J = 7.3 Hz), 5.49 (s, 2 H), 4.01 (s, 2 H), 3.21 ( s, 2H), 2.93 (m, 2H), 2.48 (m, 4H), 2.29 (s, 3H), 1.54 (ss, 4H) ppm; MS (APCI, m / z): 500 [M + H] +.

EXAMPLE 14 Methanesulfonate salt of 3- (4-chloro-2,6-d, fluorobenzylloxy) -5-r3- (3-hydroxy-5-pyrrolidin-1-yl-pentyl) amide ureido1-isothiazole-4-carboxylic acid The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,5-difluoro-4-methyl-benzyloxy) -sothiazol-5-yl] -carbamic acid and of 1-amino- 5-pyrrolidin-1-yl-pentan-3-ol by the procedure analogous to that of example 6. HPLC retention time: 3.1 minutes. 1 H NMR (400 MHz, D 2 O) d 6.81 (d, 2 H, J = 7.2 Hz), 5.17 (s, 2 H), 3.61 (bm, 1 H), 3.47 (bm, 2 H), 3.2-3.0 (m, 4 H) ), 2.89 (m, 2H), 2.62 (s, 3H), 1.94 (m, 2H), 1.85-1.2 (m, 6H) ppm; MS (APCI, m / z): 518 [M + H] +.

EXAMPLE 15 Methanesulfonate salt of 3- (4-chloro-2,6-difluoro-benzyloxy) -5-r3- (3-hydroxy-5-pyrrolidin-1-yl-pentyl) -ureido-isothiazole-4 acid amide - carboxylic The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,5-difluoro-4-methyl-benzyloxy) -isot-azazol-5-yl] -carbamic acid and of 1-amino -5-pyrrolidin-1-yl-pentan-3-oI by the procedure analogous to that of example 6. HPLC retention time: 3.3 minutes. 1 H NMR (400 MHz, CD 3 OD) d 7.17 (d, 2 H, J = 6.4 Hz), 5.51 (s, 2 H), 3.64 (bm, 1 H), 3.24 (t, 2 H, J = 6.0 Hz), 2.92 ( m, 1 H), 2.72 (m, 1 H), 2.39 (m, 2H), 1.98 (m, 1 H), 1.87 (m, 2H), 1.75 (m, 1 H), 1.54 (m, 4H) , 1.22 (m, 2H) ppm; MS (APCI, m / z): 517 [M + H] +.

EXAMPLE 16 Methanesulfonate salt of 3- (4-chloro-2,6-difluoro-benzyloxy) -5-r3- (3-hydroxy-5-pyrroidin-1-yl-pentyl) -ureido-isothiazole acid amide -4- carboxylic The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,5-difiuoro-4-methyl-benzyloxy) -sothiazol-5-yl] -carbamic acid and of 1-amino-5 pyrrolidin-1-yl-pentan-3-ol by the procedure analogous to that of example 6. HPLC retention time: 3.3 minutes. 1 H NMR (400 MHz, CD 3 OD) d 7.17 (d, 2 H, J = 6.4 Hz), 5.51 (s, 2 H), 3.64 (bm, 1 H), 3.24 (t, 2 H, J = 6.0 Hz), 2.92 ( m, 1 H), 2.72 (m, 1 H), 2.39 (m, 2H), 1.98 (m, 1H), 1.87 (m, 2H), 1.75 (m, 1H), 1.54 (m, 4H), 1.22 (m, 2H) ppm; MS (APCI, m / z): 517 [M + H] +.

EXAMPLE 17 S-O - ^ - rbis ^ -hydroxy-etiD-aminol-butyl-ureido) ^^^ - difluoro-4-methyl-benzyloxy) -isotrazole-4-carboxylic acid amide The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,5-difluoro-4-methyl-benzyl-oxy) -isothiazol-5-yl] -carbamic acid and 2 - [( 4-amino-butyl) - (2-hydroxy-ethyl) -amino] -ethanol by the procedure analogous to Example 6. HPLC retention time: 3.1 minutes. 1 H NMR (400 MHz, CD 3 OD) d 7.20 (dd, 1 H, J = 6.0, 9.2 Hz), 7.04 (dd, 1H, J = 6.8, 9.6 Hz), 5.45 (s, 2H), 3.63 (t, 4H , J = 5.6 Hz), 3.28 (m), 2.74 (m, 4H), 2.68 (m, 2H), 2.25 (d, 3H, J = 2.0 Hz), 1.56 (m, 4H), ppm; MS (APCI, m / z): 502 [M + H] +.

EXAMPLE 18 3- (2,5-Difluoro-4-methyl-benzyloxy) -5-f3-f4- (3,4-dihydroxy-pyrrolidin-1-yl) -butyl-ureido-isothiazole-4-carboxylic acid amide The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,5-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl] -carbamic acid and 1- (4-amino) -butyl) -pyrrolidin-3,4-diol by the procedure analogous to example 8. HPLC retention time: minutes. 1 H NMR (400 MHz, CD 3 OD) d 7.20 (dd, 1 H, J = 6.0, 9.2 Hz), 7.04 (dd, 1 H, J = 6.8, 9.6 Hz), 5.45 (s, 2H), 3.63 (t, 4H, J = 5.6 Hz), 3.28 (m), 2.74 (m, 4H), 2.68 (m, 2H), 2.25 (d, 3H, J = 2.0 Hz), 1.56 (m, 4H), ppm.

EXAMPLE 19 5-R3- (4-tert-Butylamino-3-hydroxy-butyl) -ureido-3- (2,5-difluoro-4-methyl-benzyloxy) -isotrazole-4-carboxylic acid amide co The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,5-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl] -carbamic acid and 4-amino-1- tert-butylamino-butan-2-oI by the procedure analogous to Example 6. HPLC retention time: 3.3 minutes. 1 H NMR (400 MHz, CD 3 OD) d 7.18 (dd, 1 H, J = 6.8, 9.6 Hz), 7.04 (dd, 1 H, J = 6.4, 10 Hz), 5.45 (s, 2 H), 3.66 (m, 1 H), 3.34 (t, 2H, J = 7.6 Hz), 2.58 (m, 2H), 2.25 (s, 3H), 1.69-1.60 (m, 2H), 1.12 (s, 9H), ppm; MS (APCI, m / z): 486 [M + Hf.

EXAMPLE 20 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- f3-r3- (4-methyl-piperazin-1-yl) propin-ureidoHsothiazole-carboxylic acid amide hydrochloride salt The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,6-difluoro-4-chloro-benzyloxy) -isothiazol-5-yl] -carbamic acid and 3- (4-methyl) -piperazin-1-yl) -propyllamine by the procedure analogous to Example 6. 1 H NMR (400 MHz, D 2 O) d 6.86 (m a, 2 H), 5.20 (s, 2 H), 3.4-2.6 (ma, 8H), 3.10 (b, 2H), 2.63 (b, 5H), 1.67 (m, 2H) ppm; MS (APCI, m / z): 503 [M + H] +.

EXAMPLE 21 3- (4-Chloro-2,6-difluoro-benzyloxy> -5-r3- (3-hydroxy-5-lsopropylamino-pentyl) -ureido-1-isothiazole-4-carboxylic acid amide The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,6-difluoro-4-chloro-benzyloxy) -isothiazol-5-yl] -carbamic acid and of 1-amino-5- isopropylamino-pentan-3-ol by the procedure analogous to example 6. HPLC retention time: 3.2 minutes. 1 H NMR (400 MHz, CD 3 OD) d 7.17 (d, 1 H, J = 7.6 Hz), 5.52 (s, 2 H), 3.69 (m, 1 H), 3.34 (t, 2 H, J = 6.4 Hz), 2.80 ( s, 1 H, J = 6.0 Hz), 2.73 (m, 2H), 1.68-1.58 (m, 4H), 1.06 (d, 6H, J = 6.0 Hz) ppm; MS (APCI, m / z): 506 [M + H] +.

EXAMPLE 22 3- (4-Chloro-2,6-difluoro-benzyloxy) -5-r3- (3-hydroxy-5-isopropylamino-p-ethyl) -ureido] -isothiazole-4-carboxylic acid amide The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,6-difluoro-4-chloro-benzyloxy) -isothiazol-5-yl] -carbamic acid and of 1-amino-5- isopropylamino-pentan-3-ol by the procedure analogous to example 6. HPLC retention time: 3.2 minutes. 1 H NMR (400 MHz, CD 3 OD) d 7.17 (d, 1 H, J = 7.6 Hz), 5.52 (s, 2 H), 3.69 (m, 1 H), 3.34 (t, 2 H, J = 6.4 Hz), 2.80 (s, 1H, J = 6.0 Hz), 2.73 (m, 2H), 1.68-1.58 (m, 4H), 1.06 (d, 6H, J = 6.0 Hz) ppm; MS (APCI, m / z): 506 [M + H] +.

EXAMPLE 23 3- (2,5-difluoro-benzyloxy> -5- (3-l6-r4- (2-hydroxy-ethyl) -piperazin-1-ip-hexyl) -ureido) -isot-azole-4 acid amide -carboxylic The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,5-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl] -carbamic acid and 2- [4 - (6-amino-hexyl) -piperazin-1-yl] -ethanol by the procedure analogous to Example 6. HPLC retention time: 3.0 minutes. 1 H NMR (400 MHz, CD 3 OD) d 7.17 (d, 1 H, J = 6.4, 9.6 Hz), 7.01 (m, 1 H), 5.44 (s, 2 H), 3.64 (t, 2 H, J = 5.6 Hz), 3.18 (t, 2H, J = 6.8 Hz), 2.7-2.4 (ma, 8H), 2.50 (t, 2H, J = 6.0 Hz), 2.33 (m, 2H), 2.23 (s, 3H), 1.50 (m , 4H), 1.35 (m, 4H) ppm; MS (APCI, m / z): 555 [M + H] +.

EXAMPLE 24 3- (4-Chloro-2,5-difluoro-benzyloxy) -5- [3- (6-dimethylamino-hexyl) -ureido] -isothiazole-4-carboxylic acid amide The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,5-d-fluoro-4-methyl-benzyl) -sot-azole-5-yl] -carbamic and 2- [4- (6-amino-hexyl) -piperazin-1-yl] -ethanol by the procedure analogous to Example 6. HPLC retention time: 3.0 minutes. 1 H NMR (400 MHz, CD 3 OD) d 7.17 (d, 1 H, J = 6.4, 9.6 Hz), 7.01 (m, 1 H), 5.44 (s, 2 H), 3.64 (t, 2 H, J = 5.6 Hz), 3.18 (t, 2H, J = 6.8 Hz), 2.7-2.4 (ma, 8H), 2.50 (t, 2H, J = 6.0 Hz), 2.33 (m, 2H), 2.23 (s, 3H), 1.50 (m, 4H), 1.35 (m, 4H) ppm; MS (APCI, m / z): 555 [M + Hf.

EXAMPLE 25 Amide of the acid 5-. { 3-r3- (4-methyl-piperaz8n-1-yl) -propin-ureido > -3- 2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazol-5-yl] -carbamic acid and 3- (4 -methyl-piperazin-1-yl) -propyl amine by the procedure analogous to Example 1. MS (APCI, m / z): 501 [M + H] +.

EXAMPLE 26 3- (2-Fluoro-4-methyl-benzyloxy) -5- (3-r3- (4-methyl-piperazin-1-yl) -propyl-1-ureido} -isothiazole-4-carboxylic acid amide The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2-fluoro-4-methyl-benzyloxy) -isothiazol-5-yl] -carbamic acid and 3- (4-methyl) piperazin-1-yl) -propylamine by the procedure analogous to Example 1. MS (APCI, m / z): 465 [M + H] +.

EXAMPLE 27 3- (2-Fluoro-4-methyl-benzyloxy) -5-r3- (5-isopropylamino-pentyl) -ureido-1-isothiazole-4-carboxylic acid amide The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2-fluoro-4-methyl-benzyloxy) -isothiazol-5-yl] -carbamic acid and of N-isopropyl-pentane- 1,5-diamine by the procedure analogous to Example 1. MS (APCI, m / z): 452 [M + H] +.

EXAMPLE 28 3- (2,6-Difluoro-4-methyl-benzyloxy) -5-r3- (4-pyrrolidin-1-yl-butyl) -ureidol-isothiazon-4-carboxylic acid amide The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,6-d-fluoro-4-methyl-benzyloxy) -isothiazol-5-yl] -carbamic acid and 4- pyrrolidin-1-yl-butylamine by the analogous procedure to Example 1. 1 H NMR (400 MHz, CDCl 3) d 1.63 (br s, 4 H), 1.83 (br s, 4 H), 2.34 (s, 3 H), 2.46-2.52 (m , 6H), 3.28 (s, 2H), 5.40 (s, 1 H), 5.50 (s, 2H), 6.74 (d, J = 8.3 Hz, 2H), 6.98 (s, 1 H), 7.94 (sa, 1H), 10.3 (br s, 1H), ppm; MS (APCI, m / z): 468 [M + Hf.

EXAMPLE 29 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- (3-f4-r4- (2-hydroxy-ethyl) -piperazin-1-yn-butyl) acid amide. .-solid) -isothiazole-4-carboxylic acid The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,6-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl] -carbamic acid and 2- [4 - (4-amino-butyl) -piperazin-1-yl] -ethanol by the procedure analogous to example 1. MS (APCI, m / z): 527 [M + H] +.

EXAMPLE 30 3- (4-Bromo-2,6-difluoro-benzyloxy) -5-r3- (4-pyrrolidin-1-yl-buty-O-ureido-isothiazole-4-carboxylic acid amide The title compound was prepared from the phenyl ester of [3- (4-bromo-2,6-difluoro-benzyloxy) -4-carbamoyl-isothiazol-5-yl] -carbamic acid and 4-pyrrolidine -1-yl-butamine by the procedure analogous to example 1. MS (APCI, m / z): 532 and 534 [M + H] +.

EXAMPLE 31 3- (2,6-trifluoro ^ -methyl encyloxy? 5-r3- (4-hydroxy-5-piperidin-1-yl-pentyl) -ureidol-isothiazole-4-carboxylic acid amide The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,6-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl] -carbamic acid and 5-amino-1- piperidin-1-yl-pentan-2-ol by the procedure analogous to example 1. MS (APCI, m / z): 512 [M + H] +.

EXAMPLE 32 3- (4-Bromo-2,3,6-trifluoro-benzyloxy) -5-l3"r3- (4-methyl-piperazin-1-di-propyl) -reidol-isothiazole-4-carboxylic acid amide The title compound was prepared from the phenyl ester of [3- (4-bromo-2,3,6-trifluoro-benzyloxy) -4-carbamoyl-isothiazol-5-yl] -carbamic acid and 3- (4 methyl-piperazin-1-yl) -propylamine by the procedure analogous to Example 1. MS (APCI, m / z): 565 and 567 [M + H] +.

EXAMPLE 33 3- (2,6-Difluoro-4-methyl-benzyloxy) -5-l3-f3- (4-methyl-piperazin-1-yl) -prop-H-ureidoHsothiazole-carboxylic acid amide The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,6-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl] -carbamic acid and 3- (4-methyl) -piperazin-1-yl) -propyl amine by the procedure analogous to Example 1. MS (APCI, m / z): 483 [M + H] +.

EXAMPLE 34 3- (2,6-Difluoro-4-methyl-benzyloxy) -5-r3- (3-hydroxy-5-pyrolidin-1-yl-pentyl) -ureido-1-isothiazole-4-carboxylic acid amide The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,6-difluoro-4-methy-benzyloxy) -isothiazol-5-yl] -carbamic acid and of 1-amino-5- pyrrolidin-1-yl-pentan-3-ol by the procedure analogous to example 1. MS (APCl, m / z): 498 [M + H] +.

EXAMPLE 35 5-R3- (4-pyrroHdin-1-yl-butyl) -ureido-3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2I3,6-trifluoro-4-methyl-benzyloxy) -isothiazol-5-yl] -carbamic acid and 4-pyrrolidin-1- 1-butylamine by the procedure analogous to Example 1. MS (APCI, m / z): 486 [M + H] +.

EXAMPLE 36 5- [3- (3-Hydroxy-5-pyrrolidin-1-yl-pentyl) -ureido-3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole acid amide -4-carboxylic The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazol-5-yl] -carbamic acid and of 1-amino- 5-pyrrolidin-1-yl-pentan-3-ol by the procedure analogous to example 1. MS (APCI, m / z): 516 [M + H] +.

EXAMPLE 37 Amide of 5-l3-r2- (1-methyl-pyrrolidin-2-yl) -etip-ureido acid > -3- (2.3.6- trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,3,6-trifluoro-4-methyl-benzyloxy) -sothiazol-5-yl] -carbamic acid and 2- ( 1-methyl-pyrrolidin-2-yl) -ethylamine by the procedure analogous to Example 1. MS (APCI, m / z): 472 [M + H] +.

EXAMPLE 38 5-f3- (4-Dimethylamino-butyl) -urethane-3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,3,6-trifluoro-4-methyl-benzyl) -isothiazol-5-yl] -carbamic acid and N, N-dimethyl-butane-1,4-diamine by the procedure analogous to Example 1. MS (APCI, m / z): 460 [M + H] +.

EXAMPLE 39 5-R3- (3-D-methylamino-propyl) -ureidoT-3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazol-5-yl] -carbamic acid and of N, N- dimethyl-propane-1,3-diamine by the procedure analogous to example 1. MS (APCI, m / z): 446 [M + H] +.

EXAMPLE 40 5-R3- (3-Hydroxy-5-isopropylamine-pentyl) -ureido-3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazol-5-yl] -carbamic acid and of 1-amino- 5-isopropylamino-pentan-3-ol by the procedure analogous to example 1. MS (APCI, m / z): 504 [M + H] +.

EXAMPLE 41 5-f3- (3-isopropylamino-propyl) -ureido-3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,3,6-trifluoro-4-methyl-benzyloxy) -sothiazole-5-yl] -carbamic acid and N -isopropyl-propane-1,3-diamine by the procedure analogous to example 1. MS (APCI, m / z): 460 [M + H] +.

EXAMPLE 42 5- (4- (4-Methyl-piperazin-1-yl) -butyne-ureido> -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole acid amide -4-carboxylic The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,3,6-trifluoro-4-methyl-benzyloxy) -sothiazol-5-yl] -carbamic acid and 4- ( 4-methyl-piperazin-1-yl) -butylamine by the procedure analogous to Example 1. MS (APCI, m / z): 515 [M + H] +.

EXAMPLE 43 5- (3-l4-R4- (2-Hydroxy-ethyl) -piperazin-1-yn-butyl> -3-trifluoro-4-methyl-benzyloxy acid acid amide -isothiazole-4-carboxylic acid The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazol-5-yl] -carbamic acid and from - [4- (4-amino-butyl) -piperazin-1-yl] -ethane I by the procedure analogous to Example 1. MS (APCI, m / z): 545 [M + H] +.

EXAMPLE 44 5-R3- (3-pyrrolidin-1-yl-propH) -ureido-3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazol-5-yl] -carbamic acid and 3-pyrroidin- 1-α-propylamine by the procedure analogous to Example 1. MS (APCI, m / z): 472 [M + H] +.

EXAMPLE 45 5-R3- (4-Hydroxy-5-piperidin-1-yl-pentip-ureido1-3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,3) 6-trifluoro-4-methyl-benzyloxy) -isothiazol-5-yl] -carbamic acid and 5-amino- 1-piperidin-1-yl-pentan-2-ol by the procedure analogous to example 1. MS (APCI, m / z): 530 [M + H] +.

EXAMPLE 46 5- (3- (4-Retyl- (2-hydroxy-ethyp-aminol-butyl-ureido) -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole acid amide -4-carboxylic The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazol-5-yl] -carbamic acid and 2 - [( 4-amino-butyl) -ethyl-amino] -ethanol by the procedure analogous to Example 1. MS (APCI, m / z): 504 [M + H] +.

EXAMPLE 47 3- (4-Bromo-2,6-difluoro-benzyloxy) -5-f3-y3- (4-methyl-p¡perazin-1-yl) -propyl-ureido acid amide} -isothiazole-4-carboxylic acid The title compound was prepared from the phenyl ester of [3- (4-bromo-2,6-difluoro-benzyloxy) -4-carbamoyl-isothiazol-5-yl] -carbamic acid and from 3- (4-methyl-piperazin-1-yl) -propylamine by the procedure analogous to Example 1. MS (APCI, m / z): 547 and 549 [M + H] +.

EXAMPLE 48 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3-r2- (1-methyl-pyrrolidin-2-yl) -etip-ureido} -isothiazoic-4-carboxylic acid The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,6-difluoro-4-methyl-benzyloxy) -isotirazole-5-yl] -carbamic acid and 2- (1 -methyl-pyrrolidin-2-yl) -ethylamine by the procedure analogous to example 1. MS (APCI, m / z): 454 [M + H] +.

EXAMPLE 49 3- (2,6-Difluoro-4-methyl-benzyloxy) -5-r3- (4-dimethylamino-butyl) -urethane] -isothiazole-4-carboxylic acid amide The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,6-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl] -carbamic acid and of N, N-dimethyl- butane-1,4-diamine by a procedure analogous to example 1. MS (APCI, m / z): 442 [M + H] +.

EXAMPLE 50 3- (2,6-Difluoro-4-methyl-benzyloxy) -5-r3- (3-dimethylaminopropyl) -ureidol-isothiazole-4-carboxylic acid amide The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,6-difluoro-4-methyl-benzyloxy) -isothiazoI-5-yl] -carbamic acid and N, N-dimethyl-propane -1, 3-diamine by the procedure analogous to example 1. MS (APCI, m / z): 428 [M + H] +.

EXAMPLE 51 3- (4-Bromo-2,3,6-trifluorobenzyloxy) -5-r3- (4-pyrrolidin-1-yl-buty-O-ureido-isothiazole-4-carboxylic acid amide The title compound was prepared from the phenyl ester of [3- (4-bromo-2,3,6-trifluoro-benzyloxy) -4-carbamoyl-isothiazol-5-yl] -carbamic acid and 4-pyrrolidin- 1-butylamine by the procedure analogous to example 1. MS (APCI, m / z): 550 and 552 [M + H] +.

EXAMPLE 52 5- (3-Methylamino-propyl) -ureidol-3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazol-5-yl] -carbamic acid and from N-methyl-propane-1,3-diamine by the procedure analogous to Example 1. MS (APCI, m / z): 432 [M + H] +.

EXAMPLE 53 5-R3- (3-Amino-propyl) -3-methyl-ureido-3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazol-5-yl] -carbamic acid and from N- methy1-propane-1,3-diamine by the procedure analogous to Example 1. MS (APCI, m / z): 432 [M + H] +.

EXAMPLE 54 5-f3- (4-Dethylamino-butyl) -ureidol-3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazol-5-yl] -carbamic acid and N, N-diethyl -butane-1,4-diamine by the procedure analogous to example 1. MS (APCI, m / z): 488 [M + H] +.

EXAMPLE 55 3- (2,6-Difluoro-4-methyl-benzyloxy) -3- (3-pyrrolidin-1-yl-propyl) -ureido-isothiazole-4-carboxylic acid amide The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,6-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl] -carbamic acid and 3-pyrrolidin- 1-yl-propylamine by the procedure analogous to Example 1. MS (APCI, m / z): 454 [M + H] +.

EXAMPLE 56 3- (3-Chloro-2,6-d.fluoro-4-methyl-benzyloxy) -5-F3- (4-dimethyl-butyl) -ureido-1-isothiazole-4 acid amide -carboxylic The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (3-chloro-2,6-d-fluoro-4-methyl-benzyloxy) -isothiazol-5-yl] -carbamic acid. and of N, N-diethyl-butane-1,4-diamine by the procedure analogous to Example 1. MS (APCI, m / z): 476 [M + H] +.

EXAMPLE 57 5- (3-f4-fbis- (2-Hydroxy-ethyl) -aminol-butyl > -ureido) -3- 2,6-difluoro-4-methyl-benzyloxy) -isothiazole-4- acid amide carboxylic The title compound was prepared from the phenyl ester of [4-carbamoyl-3- (2,6, -difluoro-4-methyl-benzyloxy) -isothiazol-5-yl] -carbamic acid and 2 - [( 4-amino-butyl) - (2-hydroxy-ethyl) -amino] -ethanol by a procedure analogous to example 1. MS (APCI, m / z): 502 [M + H] +. The following specific compounds were prepared using the general synthetic procedures described above with reference to Schemes 1-5, and to the specific synthetic procedures described in the above preparations and examples. (3-tert-ButyI-isothiazol-5-yl) - (6,7-dimethoxy-quinolin-4-yl) -amine; 3-Ethyl-isanyl-5- (3-hexyl-ureido) -isothiazole-4-carboxylic acid amide; 5- (3-Benzyl-uredo) -3-ethylsulfanyl-isothiazole-4-carboxylic acid amide; 3-Ethylsulfanyl-5- (3-ethyl-ureido) -isothiazole-4-carboxylic acid amide; 3-Ethylsulfanyl-5 - [(pyrrolidin-1-carbonyl) -amino] -isothiazo I-4-carboxylic acid amide; - (3-Butyl-ureido) -3-ethylsulfanyl-isothiazole-4-carboxylic acid amide; 5- (3,3-Dimethyl-ureido) -3-propylsulfanyl-isothiazole-4-carboxylic acid amide; 5- (3-Methyl-ureido) -3-propylsulfanyl-isothiazole-4-carboxylic acid amide; 5- (3-Butyl-ureido) -3-propylsulfanyl-isothiazole-4-carboxylic acid amide; 5- (3-Methyl-ureido) -3-pentylsulfanyl-isothiazole-4-carboxylic acid amide; 5- (3,3-Dimethyl-ureido) -3-pentylsulfanyl-isothiazole-4-carboxylic acid amide; 5- (3,3-Dimethyl-ureido) -3-isopropylsulfanyl-isothiazole-4-carboxylic acid amide, 3-Pentylsulfanyl-5-ureido-isothiazole-4-carboxylic acid amide; 5-Benzylsulfanyl-5- (3,3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide; 5- (3,3-Dimethyl-ureido) -3-propoxy-isothiazole-4-carboxylic acid amide; Ethyl (3-butoxy-4-carbamoyl-isothiazol-5-yl) -carbamic acid ester; 5- (3,3-Dimethyl-ureido) -3-phenethylsulfanyl-isothiazole-4-carboxylic acid amide; - (3,3-Dimethyl-ureido) -3-hexylsulfanyl-isothiazole-4-carboxylic acid amide; 3- (4-Chloro-butylsulfanyl) -5- (3,3-dimethyl-ureido) -isothiazo I-4-carboxylic acid amide; 3-Butoxy-5- (3,3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide; 3-Butylsulfanyl-5- (3,3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide; 3-Cyclohexysulfanyl-5- (3-methyl-ureido) -isothiazole-4-carboxylic acid amide; 5- (3,3-Dimethyl-uredo) -3- (3-methyl-butylsulfanyl) -isothiazole-4-carboxylic acid amide; 5- (3,3-Dimethyl-ureido) -3-pentyloxy-isothiazole-4-carboxylic acid amide; 5- (3,3-Dimethyl-uredo) -3-prop-2-ynylsulfanyl-isothiazole-4-carboxylic acid amide, 5- (3,3-dimethyl-ureido) -3-heptylsulfanyl- acid amide isothiazole-4-carboxylic acid; 5- (3,3-Dimethyl-ureido) -3-isobutylsulfanyl-isothiazole-4-carboxylic acid amide 5- (3-dimethyl-ureido) -3-phenylsulfanyl-isothiazole-4-carboxylic acid amide; - (3,3-Dimethyl-ureido) -3- (3-hydroxy-butylsulphanii) -isothiazole-4-carboxylic acid amide; 5-amino-3-propoxy-isothiazole-4-carboxylic acid amide, 3-propoxy-5- (3-propyl-ureido) -isothiazole-4-carboxylic acid amide; 5- (3-Butyl-ureido) -3-propoxy-isothiazole-4-carboxylic acid amide; 5- (3-Ethyl-ureido) -3-propoxy-isothiazole-4-carboxylic acid amide; 5- (3-Pentyl-ureido) -3-propoxy-isothiazole-4-carboxylic acid amide; 5- (3-hexyl-ureido) -3-propoxy-isothiazole-4-carboxylic acid amide; 5 - [(Azetidin-1-carbonyl) -amino] -3-propoxy-isothiazole-4-carboxylic acid amide; 4-Carbamoyl-3-propoxy-isothiazol-5-yl) -amide of piperidin-1-carboxylic acid, 5- (3-phenethyl-ureido-3-propoxy-isothiazole-4-carboxylic acid amide; 3-propoxy-5 - [(pyrrolidin-1-carbonyl) -amino] -isothiazoI-4-carboxylic acid 5- (3,3-d-methyl-ureido) -3-methylsulfanyl-isothiazole-4-carboxylic acid amide; 3-Cyclopentylsulfanyl-5- (3,3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide; 5- (3-Benzyl-ureido) -3-propoxy-isothiazole-4-carboxylic acid amide; 5- (3,3-Dimethyl-ureido) -3- (naphthalen-1-ylmethylisulfanyl) -isothiazole-4-carboxylic acid amide; 3- [4-Carbamoyl-5- (3,3-dimethyl-ureido) -isothiazol-3-Hsulfanyl] -propionic acid amide, 3-propoxy-5-ureido-isothiazole-4-carboxylic acid amide; 3-Propoxy-5- (3-pyrridin-3-yl-ureido) -isothiazole-4-carboxylic acid amide; 5- (3,3-Dimethyl-ureido) -3- (4-methyl-benzylsulfanyl) -isothiazole-4-carboxylic acid amide; 5- (3,3-Dimethyl-ureido) -3- (4-methoxy-benzylsulfanyl) -isothiazole-4-carboxylic acid amide; 5- (3,3-Dimethyl-ureido) -3- (4-methyl-pentylsulfanyl) -isothiazo I-4-carboxylic acid amide; 5- (3-Butyl-ureido) -3-pentylsulfanyl-isothiazole-4-carboxylic acid amide; 5-Acetylamino-3-pentylsulfanyl-isothiazole-4-carboxylic acid amide; 5-Benzoylamino-3-penti-sulphanyl-isothiazole-4-carboxylic acid amide; -decyloxy-5- (3,3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide; (4-Carbamoyl-3-pentylsulfanyl-isothiazol-5-yl) -amide of morfoin-4-carboxylic acid; 5- [3- (2-Hydroxy-ethyl) -ureido] -3-pentylsulfanyl-isothiazo I-4-carboxylic acid amide; 5 - [(3-Hydroxy-acetidin-1-carbonyl) -amino] -3-pentylsulfanyl-isothiazole-4-carboxylic acid amide; 5- [3- (3-Hydroxy-propyl) -ureido] -3-pentylsulfanyl-isothiazole-4-carboxylic acid amide; 5-Pentylsulfanyl-5- (3-propyl-ureido) -isothiazole-4-carboxylic acid amide; 5- (3,3-Dimethyl-ureido) -3-hexyloxy-isothiazole-4-carboxylic acid amide; 5- (3,3-Dimethyl-uredo) -3-heptyloxy-isothiazole-4-carboxylic acid amide; 5- (3-Isobutyl-ureido) -3-pentylsulfanyl-isothiazole-4-carboxylic acid amide; 5- (3-furan-2-ylmethyl-ureido) -3-pentylsulphanyl-isothiazoI-4-carboxylic acid amide; 5- (3,3-Dimethyl-uredo) -3-octyloxy-isothiazole-4-carboxylic acid amide; - (3,3-Dimethyl-ureido) -3- (3-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3-Alloxy-5- (3,3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide; 5- (3,3-dimethyl-ureido) -3-nonyloxy-isothiazole-4-carboxylic acid amide, 5- (3,3-dimethyl-ureido) -3- (naphthalen-2-ylmethylsulfanyl) -amide isothiazole-4-carboxylic acid; 5- (3,3-Dimethyl-ureido) -3- (3-methyl-but-2-enyloxy) -isothiazole-4-carboxylic acid amide; 5- (3,3-Dimethyl-ureido) -3- (3-phenyl-allyloxy) -isothiazole-4-carboxylic acid amide, 5- (3,3-dimethyl-ureido) -3-pent- 2-enyloxy-isothiazole-4-carboxylic acid; 5- (3,3-Dimethyl-uredo) -3- (2-methyl-allyloxy) -isotrazole-4-carboxylic acid amide; 3-Benzyloxy-5- (3,3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide; 5- (3,3-Dimethyl-ureido) -3-phenethyloxy-isothiazole-4-carboxylic acid amide; 3- (2-Cyclohexyl-ethoxy) -5- (3,3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide; - (3-Ethyl-ureido) -3-pentylsulphanyl-isothiazole-4-carboxylic acid amide; 5- [3- (3-Dimethylamino-propyl) -ureido] -3-pent-lysulfanyl-isothiazole-4-carboxylic acid amide, 5- (3,3-dimethyl-ureido) -3- acid amide (2-fluoro-3-methyl-benzyloxy) -isothiazole-4-carboxylic acid; 5- (3,3-Dimethyl-ureido) -3- (3-methoxy-benzyloxy) -isothiazo I-4-carboxylic acid amide; 3-Pentylsulfanyl-5- (3-thiophen-2-ylmethyl-ureido) -isothiazo I-4-carboxylic acid amide; 5- [3- (3-Methyl-butyl) -ureido] -3-pentylsulfanyl-isothiazole-4-carboxylic acid amide; 5- [3- (4-Hydroxy-butyl) -ureido] -3-pentylsulfanyl-isothiazoI-4-carboxylic acid amide; 5- [3- (3-Methoxy-propyl) -ureido] -3-pentylsulfanyl-isothiazole-4-carboxylic acid amide, (4-carbamoyl-3-pentylsulfonyl-isothiazol-5-yl) -amide of the acid 4-hydroxy-piperidine-1-carboxylic acid, 5- (3,3-dimethyl-ureido) -3- (3-trifluoromethyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- (3,3-dimethyI-ureido) -3- (4-methyl-benzyloxy) -isothiazo I-4-carboxylic acid amide; - (3,3-Dimethyl-uredo) -3- (naphthalen-2-ylmethoxy) -isothiazo I-4-carboxylic acid amide; 3-Heptyloxy-5- (3-methyl-ureido) -isothiazole-4-carboxylic acid amide; 3- (3,5-Dimethyl-benzyloxy) -5- (3,3-dimethyl-ureido) -isothiazo I-4-carboxylic acid amide; 5- (3,3-Dimethyl-ureido) -3- (2-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; [3- (4-Carbamoyl-3-pentylsulfanyl-isothiazol-5-yl) -ureido] -acetic acid methyl ester; 5- [3- (5-Methyl-furan-2-ylmethyl) -ureido] -3-pentyl-isopylamino-4-carboxylic acid amide; 5- [3- (2-Hydroxy-propyl) -ureido] -3-pentaksulfanyl-isothiazole-4-carboxylic acid amide; 5 - [(2,5-Dihydro-pyrrol-1-carbonyl) -amino] -3-pentylsulfanyl-isothiazole-4-carboxylic acid amide; Amide of acid 5-. { 3- [2- (1 H-imidazol-4-yl) -ethyl] -ureido] -3-penti-sulphanyl-isothiazole-4-carboxylic acid, 3-pentylsulfanyl-5- [3- (tetrahydro-furan-2-acid -ylmethyl) -ureido] -isothiazole-4-carboxylic acid; 5- (3- (2-Cyano-ethyl) -ureido] -3-pentylsulfanyl-isothiazole-4-carboxylic acid amide 5- (3-Cyclopropylmethyl-ureido) -3-pentylsulfanyl-isothiazole-4 -carboxylic acid 5- (3-allyl-uredo) -3-pentylsulfanyl-isothiazole-4-carboxylic acid amide 5- [3- (2-dimethylamino-ethyl] -uretinate] -3-Pentylsulfanyl-isothiazole-4-carboxylic acid 3-Hexylsulfanyl-5- (3-isobutyl-ureido) -isothiazole-4-carboxylic acid amide 3-Hexylsulfanyl-5- (3-propyl-ureido) -isothiazole-4-carboxylic acid 5- (3,3-dimethyl-ureido) -3- (3-fluoro-benzyloxy) -isothiazole-4-carboxylic acid amide, 3- (3,5-acid amide -dilufuoro-benzyloxy) -5- (3,3-dimethyl-ureido) -isothiazole-4-carboxylic acid 5- (3-butyl-ureido) -3-heptyloxy-isothiazole-4-carboxylic acid amide, 3- (3-Chloro-benzyloxy) -5- (3,3-dimethyl-ureido) -isothiazoI-4-carboxylic acid; 5- (3,3-dimethyl-ureido) -3- (3-iodo) acid -benzyloxy) -sothiazole-4-carboxylic acid, 5- (3,3, -dimethyl-ureido) acid amide -3- (3-phenoxy-propoxy) -isothiazo I-4-carboxylic acid; - (3,3-Dimethyl-ureido) -3- (4-phenoxy-butoxy) -isothiazo I-4-carboxylic acid amide; 5- (3,3-dimethyl-ureido) -3- (3-m-tolyl-propoxy) -isothiazoI-4-carboxylic acid amide, 3- (5-cyano-pentyloxy) -5- acid amide - (3,3-dimethyl-ureido) -isothiazole-4-carboxylic acid; 5- (3,3-dimethyI-ureido) -3-methoxy-isot-azole-4-carboxylic acid amide; 3- (5-Chloro-pentyloxy) -5- (3,3-dimethyl-ureido) -isothiazo I-4-carboxylic acid amide; 3- (4-Cyanobutoxy) -5- (3,3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide; 5- (3-Furan-2-ylmethyl-ureido) -3-hexylsulfanyl-isothiazole-4-carboxylic acid amide; 5- (3-Butyl-uredo) -3-hexyl-sulfonyl-isothiazole-4-carboxylic acid amide; 3-Hexy-sulphanyl-5- [3- (3-hydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid amide, 3-pentylsulfanyl-5- [3- (3-pyrrolidin-1-yl- propyl) -ureido] -isothiazole-4-carboxylic acid; 3-Hexylsulfanyl-5- [3- (2-hydroxy-ethyl) -ureido] -isothiazole-4-carboxylic acid amide, 3-benzylsulfanyl-5- (3-methyl-ureido) -isothiazole-4-acid -carboxylic; Amide of acid 5-. { 3- [2- (1-methyl-1 H-pyrrol-2-yl) -ethyl] -ureido} -3-pentylsulfanyl-isothiazole-4-carboxylic acid; 3-Benzylsulfanyl-5- (3-butyl-ureido) -isothiazole-4-carboxylic acid amide; Ester 2- [4-carbamoyl-5- (3,3-d, methyl-ureido) -isothiazol-3-yloxy] -ethyl benzoic acid; 5- (3,3-Dimethyl-ureido) -3- (2-phenoxy-ethoxy) -isothiazole-4-carboxylic acid amide, 3- (3-benzyloxy-propoxy) -5- (3,3) acid amide -dimethyl-ureido) -isothiazole-4-carboxylic acid; 5- (3,3-dimethyI-ureido) -3- (3,3-diphenyl-propoxy) -isothiazole-4-carboxylic acid amide; 3- (6-Chlorohexyloxy) -5- (3,3-dimethyl-uredium-isothiazoI-4-carboxylic acid amide, 5- (3,3-dimethyl-ureido) -3- ( 2-ethoxy-ethoxy) -sothiazole-4-carboxylic acid 5- (3,3-D-methyl-ureido) -3- (4-vinyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3-Cylcohexylmethoxy-5- (3,3-dimethyl-uredo) -isothiazole-4-carboxylic acid, 5- (3,3-dimethyl-ureido) -3- (4-phenylbutoxy) -isothiazole-4-amide -carboxylic acid 5- (3,3-dimethyl-ureido) -3- [3- (3-methoxy-phenyl) -propoxy-O-isothiazole-4-carboxylic acid amide, 3- (2,5-d) acid amide Methyl-benzyloxy) -5- (3,3-dimethyl-ureido) -isothiazo I-4-carboxylic acid; 3-Hexylsulfanyl-5- Acid Amide. { 3- [2- (1 H-imidazol-4-yl) -ethyl] -ureido} -isothiazole-4-carboxylic acid; 3-Hexylsulfanyl-5- [3- (4-hydroxy-butyl) -ureido acid amide} -isothiazole-4-carboxylic acid; 3-Hexylsulfanyl-5- [3- (2-hydroxy-propyl) -ureido acid amide} -isothiazole-4-carboxylic acid; 3-Benzylsulfanyl-5- [3- (2-hydroxypropyl) -urethane acid amide} -isothiazo I-4-carboxylic acid; 3-Benzylsulfanyl-5- (3-benzyl-ureido) -sothiazole-4-carboxylic acid amide; 3-Benzylsulfanyl-5- (3-furan-2-ylmethyl-ureido) -isothiazo I-4-carboxylic acid amide; 3-Benzylsulfanyl-5- (3-isobutyl-ureido) -sothiazole-4-carboxylic acid amide; 3-Hexylsulfanyl-5- (3-pentyl-ureido) -isothiazole-4-carboxylic acid amide; 3-Hexylsulfanyl-5- (3-methyl-ureido) -isothiazole-4-carboxylic acid amide; 3-Hexylsulfanyl-5- [3- (3-methyl-butyl-ureido] -isothiazole-4-carboxylic acid amide 5- (3-ethyl-ureido) -3-hexylsulfanyl-isothiazole-4-carboxylic acid amide; 5- [3- (2-morpholin-4-yl-ethyl) -ureido] -3-pentylsulfanyl-isothiazole-4-carboxylic acid amide; 5- [3- (2,3-dihydroxy-propyl) amide ) -ureido] -3-heptyloxy-isothiazoI-4-carboxylic acid; 3-heptyloxy-5- [3- (2-hydroxy-pentyl) -uretho]] -isothiazole-4-carboxylic acid amide; -heptyloxy-5- [3- (2-hydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid amide of 3-heptyloxy-5- [3- (5-hydroxy-propyl) -ureido] -isothiazole- 4-carboxylic acid 3-heptyloxy-5- [3- (3-hydroxy-2,2-dimethyl-propyl) -ureido] -isothiazole-4-carboxylic acid amide 3-heptyloxy-5-acid amide [3- (2-hydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid, 3-heptyloxy-5- [3- (3-hydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3-Heptyloxy-5- [3- (2-hydroxy-ethyl) -ureido] -isothiazole-4-carboxylic acid amide; 3-Heptyloxy-5- [3- (4-hydroxy-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 5- (3,3-Dimethyl-uredo) -3- (5-methylene-hexyloxy) -isothiazo I-4-carboxylic acid amide; 5- (3,3-Dimethyl-ureido) -3- (naphthalen-1-ylmethoxy) -isothiazoI-4-carboxylic acid amide, 5- (3,3-dimethyl-ureido) -3- (3 phenyl-propoxy) -isothiazo I-4-carboxylic acid; 5- (3,3-Diemti? -ureido) -3- (4-methyl-pentyloxy) -α-thiazoi-4-carboxylic acid amide; 3- (3-Bromo-benzyloxy) -5- (3,3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide; 3- (3,4-Dimethyl-benzyloxy) -5- (3,3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide; 3- (2,4-Dimethyl-benzyloxy) -5- (3,3-dimethyl-ureido) -isothiazo I-4-carboxylic acid amide; 3- (3,5-Bis-trifluoromethyl-benzyl) -5- (3,3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-benzylsulfanyl) -5- [3- (3-hydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3-Benzylsulfanyl-5- [3- (3-hydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-benzylsulfanyl) -5- (3-furan-2-ylmethyl-uido) -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-benzylsulfanyl) -5- [3- (2-hydroxypropyl) -ureido] -isothiazole-4-carboxylic acid amide; 3-Hexylsulfanyl-5- [3- (2-morpholin-4-yl-ethyl] -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-benzyl-sulfanyl) -5- (3-butyl-ureido) -isothiazole-4-carboxylic acid amide; 5- (3-Benzyl-ureido) -3- (4-chloro-benzylsulfanyl) -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-benzylsulfanyl) -5- (3-methyl-ureido) -isothiazo I-4-carboxylic acid amide; 5- (3-Butyl-ureido) -3- (4-cyano-benzylsulfanyl) -isothiazole-4-carboxylic acid amide; 5- [3- (2-Dimethylamino-ethyl) -ureido] -3-hexylsulfanyl-isothiazole-4-carboxylic acid amide; 3-Hexylsulfanyl-5- [3- (3-pyrrolidin-1-yl) -propyl) -ureido] -isothiazole-4-carboxylic acid amide; 5- [3- (3-Dimethylamino-propyl) -ureido] -3-hexy-sulphanyl-isothiazole-4-carboxylic acid amide; 3-Hexylsulfanyl-5- Acid Amide. { 3- [3- (2-Oxo-pyrrolidin-1-yl) -propyl] -uredo} isothiazole-4-carboxylic acid; 3- (4-Chloro-benzylsulfanyl) -5- [3- (2,3-dihydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-benzylsulfanyl) -5- [3- (5-hydroxy-pentyl) -uret] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-benzylsulfanyl) -5- [3- (4-hydroxy-butyl) -ureido] -isothiazo I-4-carboxylic acid amide; 3- (4-Chloro-benzylsulfanyl) -5- [3- (2-hydroxy-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 5- [3- (2,3-Dihydroxy-propyl) -ureido] -3-hexylsulfanyl-isothiazole-4-carboxylic acid amide; 3-Hexylsulfanyl-5- [3- (2-hydroxy-butyl) -ureido] -isothiazo I-4-carboxylic acid amide; 3-Benzylsulfanyl-5- [3- (2,3-dihydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3-Hexylsulfanyl-5- [3- (5-hydroxy-pentyl) -ureido] -isothiazole-4-carboxylic acid amide; 3-Benzylsulfanyl-5- [3- (2-hydroxy-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-benzylsulfanyl) -5- [3- (2-hydroxy-ethyl) -uredio] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-benzylsulfanyl) -5- (3I3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide; 3-Benzylsulfanyl-5- [3- (5-hydroxy-pentyl) -ureido] -isothiazole-4-carboxylic acid amide; 1- (4-cyano-3-pentylsulfanyl-isothiazol-5-yl) -3-methyl-urea; 5- (3,3-Dimethyl-ureido) -3- (2,4,6-trimethyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- (3,3-Dimethyl-ureido) -3- (2-trifluoromethyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- (3,3-Dimethyl-ureido) -3- (4-trifluoromethyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (2,4-Dimethyl-benzyl-sulfanyl) -5- (3,3-dimethyl-uido) -isothiazole-4-carboxylic acid amide; 5- (3,3-Dimethyl-ureido) -3- (2-fluorobenzylsulfonyl) -isothiazole-4-carboxylic acid amide; 5- (3,3-Dimethyl-ureido) -3- (3-methy-benzylsulfanyl) -isothiazole-4-carboxylic acid amide; 5- (3,3-Dimethyl-ureido) -3- (2-fluoro-3-methyl-benzyl-sulfanyl) -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-benzyloxy) -5- (3,3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide; 3- (2-Chloro-benzylsulfanyl) -5- (3,3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide; 1-Methyl-3- [3-pentylsulfanyl-4- (1 H -tetrazol-5-yl) -isothiazol-5-yl] -urea; 5- (3,3-Dimethyl-ureido) -3- (4-fluoro-benzylsulfanyl) -isothiazo I-4-carboxylic acid amide; 3- (3-Chloro-benzylsulfanyl) -5- (3,3-dimethyl-uredo) -isothiazole-4-carboxylic acid amide; 3- (2,5-Dimethyl-benzylsulfanyl) -5- (3,3-dimethyl-ureido-J-isothiazole-^ -carboxylic acid amide; 3- (1-bromo-naphthalen-2-ylmethylsulfanii) -5- acid amide - (3,3-dimethyl-ureido) -isothiazole-4-carboxylic acid: 3- (3,4-dimethyl-benzylsulfanyl) -5- (3,3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide; 3- (Biphenyl-4-ylmethoxy) -5- (3,3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide 5- (3,3-dimethyl-ureido) -3- (2) acid amide -fluoro-benzyloxy) -sothiazole-4-carboxylic acid 3- (2-chloro-benzyloxy) -5- (3,3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide; 3,3-dimethyl-ureido) -3- (4-isopropyI-benzyloxy) -isothiazoI-4-carboxylic acid amide of 5- (3,3-dimethyl-ureido) -3- (2,3,4, 5,6-pentamethyl-benzyloxy) -isothiazoI-4-carboxylic acid 3- (4-chloro-benzylsulfanyl) -5- [3- (2-dimethylamino-ethyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Cyano-benzylsulfanyl) -5- [3- (3-dimethylamino-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-benzylsulfanyl) -5- [3- (3-pyrrolidin-1-yl-poryl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-benzylsulfanyl) -5- acid amide. { 3- [2- (1H-imidazol-4-yl) -ethyl] -uredo} -isothiazole-4-carboxylic acid; 3- (4-Chloro-benzylsulfanyl) -5- acid amide. { 3- [2- (1-methyl-1 H -pyrroI-2-yl) -ethyl] -u reid or} -isothiazole-4-carboxylic acid; 3- (4-Chloro-benzylsulfanyl) -5- [3- (2-morpholin-4-yl-etl) -ureido acid amide} -isothiazole-4-carboxylic acid; 3- (4-Chloro-benzyl-sulphanii) -5- acid amide. { 3- [3- (2-Oxo-pyrrolidin-1-yl) -propl] -ureido} -isothiazole-4-carboxylic acid; 3-But-2-enyloxy-5- (3,3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide; 5- (3,3-Dimethyl-ureido) -3- (4-methoxy-benzyl) -isothiazole-1-carboxylic acid amide; 3- (2,4-Difluoro-benzyloxy) -5- (3,3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide; Amide of the acid 5- (3-sec-butyl-ureido) -3- (4-chloro-benzyl-sulfanyl) -isothiazole-4-carboxylic acid; 3- (4-Chloro-benzylsulfanyl) -5- [3- (2,2-dimethyl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-benzylsulfanyl) -5- [3- (1-ethyl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-benzylsulfanyl) -5- [3-cyclopropylmethyl-ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-benzylsulfanyl) -5- [3- (1-methyl-1-phenyl-ethyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-benzylsulfanyl) -5- [3- (3,4-difluoro-benzyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- (3,3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide; 3- (4-tert-Butyl-benzyloxy) -5- (3,3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide; 5- (3-Isobutyl-ureido) -3- (4-methyl-benzylsulfanyl) -isothiazo I-4-carboxylic acid amide; 5- (3-Butyl-ureido) -3- (4-methyl-benzyl-sulfanyl) -isothiazo I-4-carboxylic acid amide; 5- [3- (3-Hydroxy-propyl) -ureido] -3- (4-methyl-benzylsulfanyl) -isotriazole-4-carboxylic acid amide; Phenyl ester of (4-carbamoyl-3-mercapto-isothiazol-5-yl) -carbamic acid; 5- (3-Butyl-ureido) -3- (3,4-dichloro-benzylsulfanyl) -isothiazole-4-carboxylic acid amide; 3- (3,4-Dichloro-benzyl-sulphanyl) -5- (3-isobutyl-ureido) -isothiazole-4-carboxylic acid amide; 3- (3,4-Dichloro-benzylsulfanyl) -5- [3- (3-hydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 4- [4-Carbamoyl-5- (3-isobutyl-ureido) -isothiazol-3-sulfosylmethyl] -benzoic acid methyl ester; 4- [5- (3-Butyl-ureido) -4-carbamoyl-isothiazol-3-ylsulfanylmethyl] -benzoic acid methyl ester; Methyl ester of 4- acid. { 4-carbamoyl-5- [3- (3-hydroxy-propyI) -ureido] -isothiazol-3-ylsulfanylmethyl} -benzoic; 3- (3,3-Diphenyl-propylsu! Fanyl) -5- [3- (3-hydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (3,3-Diphenyl-propylsulfanyl) -5- (3-isobutyl-ureido) -isothiazole-4-carboxylic acid amide; 5- (3-Butyl-ureido) -3- (3,3-diphenyl-propylsulfanyl) -isothiazo I-4-carboxylic acid amide; 5- [3- (2-Dimethylamino-ethyl) -ureido] -3- (3,3-diphenyl-propylsulfanyl) -isothiazole-4-carboxylic acid amide; 3-Hexylsulfanyl-5- [3- (2-methoxy-ethyl) -ureido] -isothiazo I-4-carboxylic acid amide; 3-Hexylsulfanyl-5- [3- (2-pyridin-2-yl-ethyl) -uret] -isothiazo I-4-carboxylic acid amide; 3-Hexylsulfani-5- [3- (2-pyrrolidin-1-yl-ethyl) -ureido] -isothiazole-4-carboxylic acid amide; 5- (3,3-Dimethyl-ureido) -3- (2-methoxy-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (2,3-Dichloro-benzyloxy) -5- (3,3-dimethyl-ureido) -isothiazo I-4-carboxylic acid amide; 3-Benzylsulfanyl-5- [3- (2-dimethylamino-ethyl) -ureido] -isothiazole-4-carboxylic acid amide; 5- [3- (2-Dimethylamino-ethyl) -ureido] -3- (4-methyl-benzyl-sulphanyl) -isot-azole-4-carboxylic acid amide; 5- [3- (2-Dimethylamino-ethyl) -ureido] -3- (4-methoxy-benzylsulfanyl) -isothiazole-4-carboxylic acid amide; 5- [3- (2-Dimethylamino-ethyl) -urethane] -3- (3-methoxy-benzylsulphanyl) -isothiazole-4-carboxylic acid amide; 5- [3- (2-Dimethylamino-ethyl) -ureido] -3- (2-methyl-benzylsulfanyl) -isothiazole-4-carboxylic acid amide; 5- [3- (2-Dimethylamino-ethyl) -ureido] -3- (2-methoxy-benzylsulfanyl) -isothiazole-4-carboxylic acid amide; Acid methyl ester 3-. { 4-carbamoyl-5- [3- (2-dimethylamino-ethyl) -ureido] -isothiazol-3-ylsulfanylmethyl} -benzoic; 3-Benzylsulfanyl-5- [3- (3-pyrrolidin-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Methyl-benzylsulfanyl) -5- [3- (3-pyrrolidin-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Methoxy-benzylsulfanyl) -5- [3- (3-pyrrolidin-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (3-Methoxy-benzylsulfanyl) -5- [3- (3-pyrroidin-1-yl-propyl) -ureido] -isotrazole-4-carboxylic acid amide; 3- (3-Methoxy-benzylsulfanyl) -5- [3- (3-pyrrolidin-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; Methyl ester of 4- acid. { 4-carbamoyl-5- [3- (3-pyrrolidin-1-yl-propyl) -ureido] -isothiazol-3-ylsulfanylmethyl} -benzoic; 3- (2-Chloro-benzylsulfanyl) -5- [3- (3-pyrrolidin-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-benzylsulfanyl) -5- [3- (3-pyrrolidin-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 5- (3-Isobutyl-ureido) -3- (2-methyl-benzylsulfanyl) -isothiazole-4-carboxylic acid amide; 5- (3-Isobutyl-ureido) -3- (3-methoxy-benzylsulfanyl) -isothiazo I-4-carboxylic acid amide; 5- (3-Isobutyl-ureido) -3- (4-methoxy-benzylsulfanyl) -isothiazo I-4-carboxylic acid amide; 5- (3-Isobutyl-ureido) -3- (3-methyl-benzylsulfanyl) -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-benzylsulfanyl) -5- (3-isobutyl-ureido) -isothiazo I-4-carboxylic acid amide; 3- (4-Fluoro-benzylsulfanyl) -5- (3-isobutyl-ureido) -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-3-methyl-benzylsulfanyl) -5- (3-isobutyl-uredo) -isothiazole-4-carboxylic acid amide; 3- (2,4-Difluoro-benzylsulfanyl) -5- (3-isobutyl-ureido) -isothiazole-4-carboxylic acid amide; 3- (5-Chloro-thiophen-2-ylmethylsulfanyl) -5- (3-isobutyl-ureido) -isothiazole-4-carboxylic acid amide; 3- (Benzo [1, 3] dioxol-5-ylmethylsulfanyl) -5- (3-isobutyl-ureido) -isothiazole-4-carboxylic acid amide; 5- (3-Cyclopropylmethyl-ureido) -3- (3,4-dimethyl-benzyl-isofl) -isothiazole-4-carboxylic acid amide; 3- (3,4-Dimethyl-benzylsulfanyl) -5- (3-isobutyl-ureido) -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzylsulfanyl) -5- (3-isobutyl-ureido) -isothiazole-4-carboxylic acid amide; 3- (2,4-Dimethyl-benzisulfanyl) -5- (3-isobutyl-uredo) -isothiazole-4-carboxylic acid amide; 3- (3,4-Dimethyl-benzylsulfanyl) -5- [3- (3-pyrrolidin-1-yl-propyI-ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzylsulfanyl) -5- [3- (3-pyrrolidin-1-yl-propyl-ureido) -isothiazole-4-carboxylic acid amide; 5- (3-Cyclopropylmethyl) -ureido) -3- (4-methyl-benzyl-sulfanyl) -isothiazole-4-carboxylic acid amide; 3- (3,4-Dimethyl-benzylsulfanyl) -5- [3- (2-morpholin-4-yl-etiI) -ureido] -isothiazole-4-carboxylic acid amide; 5- [3- (2,2-Dimethyl-propyl) -ureido] -3- (4-methyl-benzylsulfanyl) -isothiazole-4-carboxylic acid amide; 5- (3-Cyclopropylmethyl-ureido) -3- (3,4-dichloro-benzylsulfanyl) -isothiazole-4-carboxylic acid amide; 5- (3-Dichlopropylmethyl-ureido) -3- (3-methoxy-benzyl-isofl) -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2-phenyl-benzylsulfanyl) -5- [3- (3,4-difluoro-benzyl) -ureido] -isothiazole-4-carboxylic acid amide; 5- [3- (3,4-Difluoro-benzyl) -ureido] -3- (3,3-diphenyl-propylsulfanyl) -isothiazole-4-carboxylic acid amide, 5- Acid Amide [3- (3,4-difluoro-benzyl) -ureido] -3- (4-methoxy-benzyl-sulphanyl) -isothiazole-4-carboxylic acid; 5- [3- (3,4-Difluoro-benzyl) -ureido] -3- (3,4-dimethyl-benzylsulfanyl) -isothiazole-4-carboxylic acid amide, 3- (3-methyl-benzylsulfanyl) acid amide ) -5- [3- (3-pyrrolidin-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid; - [3- (2-Dimethylamino-ethyl) -ureido] -3- (3-methy1-benzylsulfanyl) -isothiazole-4-carboxylic acid amide; 5- [3- (2-Dimethylamino-ethyl) -ureido] -3- (3,4-dimethyl-benzylsulfanyl) -sothiazole-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzylsulfanyl) -5- [3- (3-hydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid amide; Acid methyl ester 3-. { 4-carbamoyl-5- [3- (3,4-difluoro-benzyl) -ure? Do] -isot-azole-3-ylsulfanylmethi} -benzoic; Acid methyl ester 3-. { 4-carbamoyl-5- [3- (3-hydroxy-propyl) -ureido] -isothiazol-3-ylsulfanylmethyl} -benzoic; 5- [3- (3,4-Difluoro-benzyl) -urethane] -3-phenethylsulfanyl-isothiazoI-4-carboxylic acid amide; 5- [3- (3,4-Difluoro-benzyl) -ureido] -3- (4-methyl-benzylsu-phenyl) -isothiazole-4-carboxylic acid amide; 5- [3- (3,4-Difluoro-benzyl) -ureido] -3- (2,4-dimethyl-benzylsulfanyl) -isothiazole-4-carboxylic acid amide; 3- (4-tert-Butyl-benzylsulfanii) -5- (3,3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide; 3- (4-Methyl-benzylsulfanyl) -5- [3- (2-phenyl-propyl) -u-3-isothiazoi-4-carboxylic acid amide; 5- [3- (1, 2-Dimethyl-propyl) -ureido] -3- (4-methyl-benzyl-sulphanyl) -isothiazole-4-carboxylic acid amide; - [3- (3,5-Difluoro-benzyl) -ureido] -3- (4-methyl-benzylsu-phenyl) -isothiazole-4-carboxylic acid amide; Amide of acid 5-. { 3- [1- (4-fluoro-phenyl) -ethyl] -ureido} -3- (4-methyl-benzylsulfanyl) -isothiazole-4-carboxylic acid; 5- [3- (3-Fluoro-benzyl) -ureido] -3- (4-methyl-benzylsulfanyl) -isothiazoi-4-carboxylic acid amide; 5- [3- (4-Fluoro-2-trifluoromethyl-benzyl) -ureido] -3- (methyl-benzylsulfanyl) -isothiazole-4-carboxylic acid amide; 5- [3- (3-Chloro-4-fluoro-benzyl) -ureido] -3- (4-methyl-benzylsulfanyl) -isothiazole-4-carboxylic acid amide, 3- (4-bromo-2) -amide -fluoro-benzyloxy) -5- (3-isobutyl-ureido) -isothiazole-4-carboxylic acid; 3- (4-Bromo-2-fluoro-benzyloxy) -5- (3-butyl-ureido) -isothiazo I-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- [3- (2,2-dimethyl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- (3-furan-2-ylmethyl) -isothiazole-4-carboxylic acid amide; 5- (3-Allyl-ureido) -3- (4-bromo-2-fluoro-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- (3-cyclobutyl-ureido) -isothiazole-4-carboxylic acid amide, 3- (4-bromo-2-fluoro-benzyloxy) acid amide ) -5- [3- (3,3-dimethyl-butyl) -ureido] -isothiazole-4-carboxylic acid; 3- (4-Bromo-2-fluoro-benzyloxy) -5- (3-cyclopropylmethyl-ureido) -isothiazo I-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- [3- (3-phenyl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 5- [3- (2-isopropylamino-ethyl) -ureido] -3- (4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- (3-Cylcohexylmethyl-ureido) -3- (4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- (3-Isobutyl-uredo) -3- (4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (3-Dimethylamino-propyl) -ureido] -3- (4-methyl-benzyloxy) -isothiazo I-4-carboxylic acid amide; 3- (5-Chloro-thiophen-2-ylmethylsulfanyl) -5- [3- (3,4-difluoro-benzyl) -ureido] -isothiazo I-4-carboxylic acid amide; 3- (5-Chloro-thiophen-2-ylmethylsulfanyl) -5- (3-cyclopropylmethyl-ureido) -isothiazole-4-carboxylic acid amide; 3- (5-Chloro-thiophen-2-ylmethylsulfanyl) -5- [3- (2-morpholin-4-yl-etyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (5-Chloro-thiophen-2-ylmethylsulfanyl) -5- [3- (3-pyrrolidin-1-yl-propyl) -uret] -isothiazole-4-carboxylic acid amide; - [3- (3,4-Difluoro-benzyl) -ureido] -3- (5-methyl-thiophen-2-ylmethylsulfanyl) -isothiazole-4-carboxylic acid amide; 3- (5-Chloro-thiophen-2-ylmethoxy) -5- (3-cyclopropylmethyl-ureido) -isothiazole-4-carboxylic acid amide; 5- (3-Isobutyl-ureido) -3- (5-methyl-thiophen-2-ylmethyl-sulphanyl) -isothiazole-4-carboxylic acid amide; 3- (5-Chloro-thiophen-2-ylmethoxy) -5- [3- (3,4-difluoro-benzyl) -ureido] -isothiazole-4-carboxylic acid amide; 5- (3-Cyclopropylmethyl-ureido) -3- (5-methyl-thiophen-2-ylmethylsulfanyl) -isothiazole-4-carboxylic acid amide; 3- (5-Methyl-thiophen-2-ylmethylsulfanyl) -5- [3- (2-morfoin-4-yl-ethyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (5-Methyl-thiophen-2-ylmethylsulfanyl) -5- [3- (3-pyrrolidin-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide, 3- (3-Amide 4-chloro-benzyloxy) -5- [3- (3-hydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid, 3- (4-bromo-2-phenyl-benzyloxy) -5- [3 - (3,4-difluoro-benzyl) -ureido] -isothiazole-4-carboxylic acid; 3- (4-Bromo-2-fluoro-benzyloxy) -5- [3- (2-dimethylamine-ethylal) -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- [3- (3-dimethylamino-propyl) -ureido] -isothiazole-4-carboxylic acid amide; M- Amide of 3- (4-chloro) acid -2-fIuoro-benzyloxy) -5- (3-furan-2-ylmethyl-ureido) -sothiazole-4-carboxylic acid; 3- (4-Chloro-2-fluoro-benzyloxy) -5- [3- (2-morofolin-4-ethyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,3-Dichloro-benzyloxy) -5- [3- (2-morfoin-4-yl-ethyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,3-Dichloro-benzyloxy) -5- [3- (3-morpholin-4-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,3-Dichloro-benzyloxy) -5- [3- (3-hydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,3-Dichloro-benzyloxy) -5- [3- (2-pyrrolidin-1-yl-etiI) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,3-Dichloro-benzyloxy) -5- [3- (3-pyrrolidin-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,3-Dichloro-benzyloxy) -5- acid amide. { 3- [2- (1 H-imidazol-4-yl) -ethyl] -u} -isothiazole-4-carboxylic acid; 3- (2,3-Dichloro-benzyloxy) -5- [3- (1-ethyl-pyrrolidin-2-ylmethyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,3-Dichloro-benzyloxy) -5- [3- (2-isopropylammono-et? L) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,3-Dichloro-benzyloxy) -5- [3- (3-diethylamino-2-hydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2-fluoro-benzyloxy) -5- [3- (3-morpholin-4-yl-propyl) -ureido] -isothiazo I-4-carboxylic acid amide; 3- (4-Chloro-2-fluoro-benzyloxy) -5- [3- (2-pyrrolidin-1-yl-ethyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2-fluoro-benzyloxy) -5- [3- (3-pyrrolidin-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2-fluoro-benzyloxy) -5- [3- (3-imidazol-1-y-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2-fluoro-benzyloxy) -5- [3- (3-hydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2-fluoro-benzyloxy) -5- [3- (3,4-difluoro-benzyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2-fluoro-benzyloxy) -5- [3- (2-hydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 5- (3-Cyclopropylmethyl-uredo) -3- (2,3-dichloro-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- [3- (3-isopropylamino-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- [3- (2-sec-butylamino-ethyl) -uredo] -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- [3- (2-hydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- [3- (2-hydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,3-Difluoro-benzyloxy) -5- [3- (2-morpholin-4-yl-etiI) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,3-Difluoro-benzyloxy) -5- [3- (3-morpholin-4-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,3-Difluoro-benzyloxy) -5- (3-isobutyl-ureido) -isothiazo I-4-carboxylic acid amide; 3- (2,3-Difluoro-benzyloxy) -5- [3- (2-pyrrolidin-1-yl-ethyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,3-Difluoro-benzyloxy) -5- [3- (3-pyrrolidin-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-3-methyl-benzyloxy) -5- [3- (2-morpholin-4-yl-ethyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-3-methyl-benzyloxy) -5- (3-isobutyl-ureido) -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-benzyloxy) -5- [3- (2-hydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-benzyloxy) -5- [3- (2-hydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 5- [3- (2-Dimethylamino-propyl) -urethane] -3- (2-fluoro-3-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-3-methyl-benzyloxy) -5- [3- (2-pyrrolidin-1-yl-etiI) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-3-methyl-benzyloxy) -5- [3- (3-pyrrolidin-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,3-Difluoro-benzyloxy) -5- [3- (2-dimethylamino-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-3-methyl-benzyloxy) -5- [3- (3-morpholin-4-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- [3- (5-methyl-furan-2-ylmethyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (3-Fluoro-2,4-dimethyl-benzyloxy) -5- (3-isobutyl-ureido) -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2-fluoro-benzyloxy) -5- [3- (3-hydroxy-2-methyl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2-fluoro-benzyloxy) -5- [3- (2-methyl-3-morpholin-4-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,3-Dichloro-benzyloxy) -5- [3- (3-hydroxy-2-methyl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,3-Dichloro-benzyloxy) -5- [3- (2-methyl-3-morpholin-4-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (3-Fluoro-4-methyl-benzyloxy) -5- [3- (3-hydroxy-2-methyl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (3-Fluoro-4-methyl-benzyloxy) -5- [3- (2-methyl-3-morfoin-4-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (3,4-Dichloro-benzyloxy) -5- [3- (3-hydroxy-2-methyl-propyl) -ureido] -isotrazole-4-carboxylic acid amide; 3- (3,4-Dichloro-benzyloxy) -5- [3- (2-methyl-3-morpholin-4-yl-propyl) -ureido] -isotrazole-4-carboxylic acid amide; 3- (2,3-Dichloro-benzyloxy) -5- [3- (3-imidazol-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,3-Difluoro-benzyloxy) -5- [3- (3-imidazol-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (3-Fluoro-4-methyl-benzyloxy) -5- [3- (3-imidazol-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-benzyloxy) -5- [3- (2-morpholin-4-yl-ethyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-benzyloxy) -5- [3- (3-morpholin-4-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-benzyloxy) -5- [3- (3-imidazol-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-benzyloxy) -5- [3- (3-hydroxy-2-methyl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2) 5-Difluoro-benzyloxy) -5- [3- (2-morpholin-4-yl-etiI) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-benzyloxy) -5- [3- (3-imidazol-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-benzyloxy) -5- [3- (2-methyl-3-morpholin-4-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- [3- (2-isopropylamino-ethyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (3-fIuoro-2,4-d.methyl-benzyloxy) -5- [3- (2-isopropylamino-ethyl) -ureido] -sothiazole-4-carboxylic acid amide; 3- (3-Fluoro-2,4-dimethyl-benzyloxy) -5- [3- (3-isopropylamino-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 5- [3- (2-sec-Butylamino-ethyl) -ureido] -3- (3-fluoro-2,4-dimethyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (3-Fluoro-2,4-dimethyl-benzyloxy) -5- [3- (2-hydroxy-propyl) -ureido] -isothiazo I-4-carboxylic acid amide; 3- (3-Fluoro-2,4-dimethyl-benzyloxy) -5- [3- (2-hydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 5- [3- (2-sec-Butylamino-ethyl) -ureido] -3- (2-fluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4-methyl-benzyloxy) -5- [3- (3-isopropylamino-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4-methyl-benzyloxy) -5- [3- (2-isopropylamino-ethyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4-methyl-benzyloxy) -5- [3- (2-hydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4-methyl-benzyloxy) -5- [3- (3-imidazol-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,4-Dimethyl-benzyloxy) -5- [3- (3-imidazol-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 5- [3- (3-Midazol-1-yl-propyl) -urethane] -3- (4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-benzyloxy) -5- [3- (3-imidazol-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4-methyl-benzyloxy) -5- [3- (2-hydroxy-propyl) -ureido] -isothiazo I-4-carboxylic acid amide; 5- [3- (3,3-Dimethyl-butyl) -urethane] -3- (2-fluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- (3-Cyclopropylmethyl-ureido) -3- (2-fluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (2,2-Dimethyl-propyl) -ureido] -3- (2-fluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (3-Fluoro-2,4-dimethyl-benzyloxy) -5- [3- (3-imidazol-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4,6-dimethyl-benzyloxy) -5- [3- (3-imidazol-1-ii-propyl) -uredo] -sothiazole-4-carboxylic acid amide; 3- (4-Chloro-2-fluoro-benzyloxy) -5- acid amide. { 3- [2- (1 H-imidazol-4-yl) -eti-ureido} -isothiazole-4-carboxylic acid; 3- (2,3-Dichloro-benzyloxy) -5- [3- (3-imidazol-1-yl-2-methyl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,3-Dichloro-benzyloxy) -5- [3- (2-methyl-3-pyrrolidin-1-yl-propyl) -ureido] -isothiazo I-4-carboxylic acid amide; 3- (4-Chloro-2-fluoro-benzyloxy) -5- [3- (2-hydroxy-3-morpholin-4-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2-fluoro-benzyloxy) -5- [3- (3-imidazol-1-yl-2-methyl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,3-Dichloro-benzyloxy) -5- [3- (2-methyl-3-piperidin-1-yl-propyl) -urethane] -isot-azole-4- carboxylic; 3- (2,3-Dichloro-benzyloxy) -5- [3- (2-hydroxy-3-morpholin-4-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (5-Chloro-thiophen-2-ylmethoxy) -5- [3- (3-morpholin-4-yl-propyl) -uretho] -isothiazole-4-carboxylic acid amide; 3- (5-Chloro-thiophen-2-ylmethoxy) -5- [3- (3-imidazol-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (5-Chloro-thiophen-2-ylmethoxy) -5- (3-furan-2-ylmethyl-ureido) -isothiazole-4-carboxylic acid amide; 3- (5-Chloro-thiophen-2-ylmethoxy) -5- [3- (3-hydroxy-2-methyl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- [3- (3-imidazol-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-fIuoro-4-methyl-benzyloxy) -5- [3- (3-morpholin-4-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,4-Dimethyl-benzyloxy) -5- [3- (3-morpholin-4-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Methyl-benzyloxy) -5- [3- (3-morpholin-4-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-benzyloxy) -5- [3- (3-morpholin-4-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,3-Difluoro-4-methyl-benzyloxy) -5- [3- (3-imidazoI-1-yl-propyl) -ureldo] -sothiazole-4-carboxylic acid amide; 3- (2,3-Difluoro-4-methyl-benzyloxy) -5- [3- (3-morpholin-4-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,3-Difluoro-4-methyl-benzyloxy) -5- [3- (2-hydroxy-3-morpholin-4-l-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,3-Difluoro-4-methyl-benzyloxy) -5- [3- (3-imidazol-1-yl-2-methyl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,3-Difluoro-4-methyl-benzyloxy) -5- [3- (2-methyl-3-morpholin-4-yl-propyl) -ureido] -isot-azole-4-acid amide carboxylic; 3- (2,3-Difluoro-4-methyl-benzyloxy) -5- [3- (3-hydroxy-2-methyl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,3-Difluoro-4-methyl-benzyloxy) -5- [3- (2-hydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,3-Difluoro-4-methyl-benzyloxy) -5- (3-furan-2-iimethyl-ureido) -isothiazole-4-carboxylic acid amide; 3- (2,3-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [3- (2,6-dimethyl-morpholin-4-yl) -2-methyl-propyl-ureido} isothiazole-4-carboxylic acid; 3- (2,3-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [2- (3H-imidazol-4-yl) -ethyl-urethane} -sothiazole-4-carboxylic acid; 3- (2,3-Difluoro-4-methyl-benzyloxy) -5- [3- (3-hydroxy-propyl) -ureido] -isothiazo I-4-carboxylic acid amide; 3- (4-Chloro-2-fluoro-benzyloxy) -5- [3- (3-isopropylamino-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,3-Dichloro-benzyloxy) -5- [3- (2-hydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (5-Chloro-thiophen-2-ylmethoxy) -5- [3- (2-hydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4-methyl-benzyloxy) -5- [3- (3-phenyl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 5- (3-Cyclobutyl-ureido) -3- (2-fluoro-4-methyl-benzyl-oxy) -isotriazole-4-carboxylic acid amide; 5- [3- (2,3-Difluoro-benzyl) -ureido] -3- (2-fiuoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4-methyl-benzyloxy) -5- (3-isobutyl-ureido) -isothiazole-4-carboxylic acid amide; 5- (3-Allyl-ureido) -3- (2-fluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- [3- (3-morpholin-4-yl-propyl) -ureido] -sothiazole-4-carboxylic acid amide; 3- (3-Fluoro-2,4-d.methyl-benzyloxy) -5- [3- (3-morpholin-4-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4,6-dimethyl-benzyloxy) -5- [3- (3-morpholin-4-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4,6-dimethyl-benzyloxy) -5- [3- (2-methyl-3-morpholin-4-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; Amide of acid 5-. { 3- [3- (2,6-dimethyl] -morpholin-4-yl) -2-methyl-propyl] -ureido} -3- (2-Fluoro-4,6-d-methyl-benzyloxy) -isothiazole-4-carboxylic acid; 3- (2-Fluoro-4,6-dimethyl-benzyloxy) -5- [3- (2-hydroxy-3-morfoin-4-yl-propyl) -uredo] -isotrazole-4 acid amide -carboxylic; 3- (2-Fluoro-4,6-dimethyl-benzyloxy) -5- [3- (3-imidazol-1-yl-2-methyl-propyl) -ureido] -isothiazole-4-carboxylic acid amide co; 3- (2-Fluoro-4,6-dimethyl-benzyloxy) -5- acid amide. { 3- [2- (1 H-imidazol-4-yl) -etl] -uredo} isothiazole-4-carboxylic acid; 3- (2-Fluoro-4,6-dimethyl-benzyloxy) -5- [3- (3-isopropylamino-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4,6-dimethyl-benzyloxy) -5- [3- (3-hydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- [3- (4-morpholin-4-yl-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2-fluoro-benzyloxy) -5- [3- (4-morpholin-4-yl-butyl) -ureido] -isothiazo I-4-carboxylic acid amide; 3- (4-Chloro-2-fluoro-benzyloxy) -5- (3-morpholin-2-ylmethyl-ureido) -isothiazole-4-carboxylic acid amide; 3- (2,3-Dichloro-benzyloxy) -5- (3-morpholin-2-ylmethyl-ureido) -isothiazole-4-carboxylic acid amide; 2-aminomethyl-morpholine-4-carboxylic acid [4-carbamoyl-3- (2,3-dichloro-benzyloxy) -isothiazoI-5-yl] -amide; 3- (2-Fluoro-4-methyl-benzyloxy) -5- [3- (2-morpholin-4-yl-ethyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4-methyl-benzyloxy) -5- [3- (2-methyl-3-morpholin-4-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; Amide of acid 5-. { 3- [3- (2,6-dimethyl-morfoin-4-yl) -2-methyl-propyl] -ureido} -3- (2-Fluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid; 3- (2-Fluoro-4-methyl-benzyloxy) -5- [3- (2-hydroxy-3-morpholin-4-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4-methyl-benzyloxy) -5- [3- (3-morpholin-4-yl-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,4-Dimethyl-benzyloxy) -5- [3- (2-hydroxy-3-morpholin-4-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,4-Dimethyl-benzyloxy) -5- [3- (2-methyl-3-morpholin-4-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,4-Dimethyl-benzyloxy) -5- [3- (2-morpholin-4-yl-ethyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,4-Dimethyl-benzyloxy) -5- [3- (4-morpholin-4-yl-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- [3- (2-methyl-allyl) -ureido] -isothiazo I-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- [3- (3-cyclohexyamino-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- [3- (4-dimethylamino-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- [3- (3-dimethylamino-2,2-dimethyl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- [3- (3-imidazol-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- [3- (3-morpholin-4-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- [3- (2-hydroxy-3-morpholin-4-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- [3- (3-imidazol-1-yl-2-methyl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- [3- (3-hydroxy-2-methyl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- [3- (2-hydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2) 5-D-Fluoro-4-methyl-benzyloxy) -5- (3-furan-2-ylmethyl) -isotol-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [2- (1 H-imidazoI-4-yl) -ethyl] -durate} -isothiazole-4-carboxylic acid; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- [3- (3-hydroxyl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- [3- (3-isopropylamino-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 5- (3. {3- [bis- (2-hydroxy-ethyl] -amino] -propyl.} -ureido) -3- (4-bromo-2-fluoro-benzyloxy) acid amide -isothiazole-4-carboxylic acid; 3- (4-Bromo-2-fluoro-benzyloxy) -5- [3- (3-diethylamino-2-hydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- [3- (3-hydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- [3- (2-hydroxy-3,3-d-methyl-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- [3- (2,3-dihydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- [3- (3-hydroxy-2-methyl-1-propyl) -ureido] -isothiazo I-4-carboxylic acid amide; 3- (2,3-Difluoro-4-methyl-benzyloxy) -5- [3- (4-morpholin-4-yl-butyl) -u-acid] -isothiazole-4-carboxylic acid amide; 3- (2,3-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- (2- (1-methyl-pyrrolidin-2-yl) -ethyl] -ureido}. Isothiazole-4-carboxylic acid amide of 3- (2,3-difluoro-4-methyl-benzyloxy) -5- { 3- [3- (2-oxo-pyrrolidrn-1-yl) -propyl] -ureido}. Isothiazole-4-carboxylic acid amide of 3- (2,3-difluoro-4-) methyl-benzyloxy) -5- [3- (2-hydroxy-butyl) -ureido] -isothiazole-4-carboxylic acid amide of 5- (3-cyclopropylmethyl-ureido) -3- (2,3-difluoro) 4-methyI-benzyloxy) -isothiazole-4-carboxylic acid 3- (2,3-difluoro-4-methyl-benzyloxy) -5-. {3- [3- (4-methyl-piperazine- 1-yl) -propyrr-ureido.) -sothiazole-4-carboxylic acid; 3- (2,5-difiuoro-4-methyl-benzyloxy) -5- [3- (2 -methyl-3-morfoiin-4-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide of 3- (2,4-dimethyl-benzyloxy) -5-. {3- [3- 3- (2,6-Dimethyl-morfoin-4-yl) -2-methyl-propyl-ureido} -isothiazole-4-carboxylic acid 5- [3- (3-cyclohexylamino-propyl) -ureido acid ] -3- (2-fluoro-4-methyl-1-benzyloxy) -isothiazole-4-carboxylic acid; 3- (2-Fluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [3- (4-methyl-piperazin-1-yl) -propyl] -ureido} isothiazole-4-carboxylic acid; 3- (2-Fluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [2- (1 H-imidazoI-4-yl) -ethyl] -ureido} isothiazole-4-carboxylic acid; 3- (2-Fluoro-4-methyl-benzyloxy) -5- [3- (2-methyl-allyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- [3- (3-imidazol-1-yl-2-methyl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- acid amide. { 3- [3- (2,6-d.methyl-morfoin-4-yl) -2-methyl-propyl] -ureido} -isothiazole-4-carboxylic acid; 5- (3-Allyl-ureido) -3- (2-fluoro-4,6-dimethyl-benzyloxy) -isothiazo I-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- acid amide. { 3- [3- (2-methyl-piperidin-1-yl) -propyl] -ureido} -isothiazole-4-carboxylic acid; 3- (4-Bromo-2-fluoro-benzyloxy) -5- [3- (2-methyl-3-piperidin-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- [3- (2-methyl-3-pyrroidin-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -uredo] -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- [3- (3-pyrrolidin-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- acid amide. { 3- [3- (4-Methyl-piperazin-1-yl) -propyl] -uredode} -isothiazole-4-carboxylic acid; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- [3- (4-morpholin-4-yl-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,3-Difluoro-4-methyl-benzyloxy) -5- [3- (2-morpholin-4-yl-ethyl) -ureido] -isothiazo I-4-carboxylic acid amide; 3- (2,3-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [2- (1-methyl-1 H -pyrroI-2-yl) -ethyl] -ureido} -isothiazole-4-carboxylic acid; 3- (2,3-Difluoro-4-methylene-benzyloxy) -5- [3- (2,3-dihydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,3-Difluoro-4-methyl-benzyloxy) -5- (3-isobutyl-ureido) -isothiazole-4-carboxylic acid amide; 5- (3-Allyl-uredo) -3- (2,3-difluoro-4-methyl-benzyloxy) -isothiazo I-4-carboxylic acid amide; 5- (3-Cyclohexylmethyl-ureido) -3- (2,3-difluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (2,3-Difluoro-4-methyl-benzyloxy) -5- [3- (2-piperidin-1-yl-ethyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,3-Difluoro-4-methyl-benzyloxy) -5- [3- (2-methyl-3-piperidin-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [3- (2,6-dimethyl-morpholin-4-yl) -2-methyl-propyl] -ureido} -isothiazole-4-carboxylic acid; 3- (5-Chloro-thiophen-2-ylmethoxy) -5- [3- (3-isopropylamine-propyl) -ureido] -isothiazoi-4-carboxylic acid amide; 3- (2-Fluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [2- (3-Methyl-3H-imidazol-4-yl) -ethyl] -ureido} isothiazole-4-carboxylic acid; 3- (2-Fluoro-4-methyl-benzyloxy) -5- [3- (2-pyrrolidin-1-I-ethyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4-methyl-benzyloxy) -5- [3- (2-methyl-3-pyrrolidin-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 5- [3- (1-Benzyl-pyrrolidin-3-yl) -ureido] -3- (2-fluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (1-Ethyl-pyrrolidin-2-ylmethyl) -ureido] -3- (2-fluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4-methyl-benzyloxy) -5- [3- (3-hydroxy-propyl) -ureido] -isot-azole-4-carboxylic acid amide; 5- [3- (3-Dimethylamino-2,2-dimethyl-propyl) -ureido] -3- (2-fluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4-methyl-benzyloxy) -5- [3- (2-methyl-3-piperidin-1-yl-propyl) -ureido] -sothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [2- (1-methyl-pyrrolidin-2-yl) -etl] -uredo} -sothiazole-4-carboxylic acid; 3- (2-Fluoro-4-methyl-benzyloxy) -5- [3- (3-pyrrolidin-1-yl-propyl) -ureido] -isotrazole-4-carboxylic acid amide; 3- (2-Fluoro-4-methyl-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4-methyl-benzyloxy) -5- [3- (3-methyl-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2) 3-Difluoro-4-methyl-benzyloxy) -5- (3-morpholin-2-ylmethyl-ureldo) -isothiazole-4-carboxylic acid amide; 2-aminomethyl-morpholine-4-carboxylic acid [4-carbamoyl-3- (2,3-d? -fluoro-4-methyl-benzyloxy) -sothiazol-5-yl] -amide; 3- (2,3-Dichloro-benzyloxy) -5- [3- (3-isopropylamino-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,3-D-Fluoro-4-methyl-benzyloxy) -5- [3- (3-isopropylamino-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 5- [3- (3-Cyclohexylamino-propyl) -ureido] -3- (2,3-difluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (2,3-Difluoro-4-iodo-benzyloxy) -5- [3- (3-imidazoI-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4-methyl-benzyloxy) -5- [3- (3-imidazol-1-yl-2-methyl-propyl) -ureido] -isot-azole-4- carboxylic; 3- (2-Fluoro-4-methyl-benzyloxy) -5- (3-furan-2-ylmethyl-ureido) -isothiazole-4-carboxylic acid amide; 5- (3. {3- [bis- (2-hydroxy-ethyl) -amino] -propyl} -ureido] -3- (2-fluoro-4-methyl-benzyloxy) acid amide Sothiazole-4-carboxylic acid; - [3- (3-Diethylamino-2-hydroxy-propyl) -urethane] -3- (2-fluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- acid amide. { 3- [3- (2-Oxo-pyrrolidin-1-yl) -propyl] -ureido} -isothiazole-4-carboxylic acid; 3- (4-Bromo-2-fluoro-benzyloxy) -5- [3- (2-hydroxy-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- (3-methyl-ureido) -isothiazoi-4-carboxylic acid amide; 5- [3- (2-Dimethylamino-ethyl) -ureido] -3- (2-fluoro-4-methyl-benzyloxy) -sothiazole-4-carboxylic acid amide; 5- [3- (3-Dimethylamino-propyl) -ureido] -3- (2-fluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- (3-ethyl-ureido) -isothiazo I-4-carboxylic acid amide; 3- (2-Fluoro-4-methyl-benzyloxy) -5- (3-methylene-ureido) -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- (3-propyl-ureido) -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4-methyl-benzyloxy) -5- [3- (3-hydroxy-2-methyl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4-methyl-benzyloxy) -5- [3- (2-hydroxy-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [2- (1-methyl-1 H-pyrrole-2-yl) -etii] -ureido} -isothiazole-4-carboxylic acid; 3- (4-Ethyl-2,3-difluoro-benzyloxy) -5- [3- (3-imidazol-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Ethyl-2,3-difluoro-benzyloxy) -5- [3- (3-hydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Ethyl-2,3-difluoro-benzyloxy) -5- [3- (3-hydroxy-2-methyl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Ethyl-2,3-difluoro-benzyloxy) -5- [3- (3-morpholin-4-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Ethyl-2,3-difluoro-benzyloxy) -5- [3- (4-morfoin-4-yl-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Ethyl-2,3-difluoro-benzyloxy) -5- [3- (3-imidazol-1-yl-2-methyl-propyl) -ureido] -isothiazole-4 acid amide -carboxylic; 3- (4-Ethyl-2,3-difluoro-benzyloxy) -5- acid amide. { 3- [2- (1 H-imidazol-4-yl) -ethyl-ureido} -sothiazole-4-carboxylic acid; 3- (4-Ethyl-2,3-difluoro-benzyloxy) -5- acid amide. { 3- [3- (4-methyl-piperazin-1-yl) -propip-ureido} -sothiazole-4-carboxylic acid; 3- (4-Ethyl-2,3-difluoro-benzyloxy) -5- (3-furan-2-ylmethyl-ureido) -isothiazole-4-carboxylic acid amide; 3- (4-Ethyl-2,3-difluoro-benzyloxy) -5- [3- (3-isopropylamino-propyl) -ureido] -isothiazole-4-carboxylic acid amide; Amide of acid 5-. { 3- [3- (2,6-dimethyl-morpholin-4-yl) -2-methyl-propyl-ureido} -3- (4-ethyl-2,3-d-fluoro-benzyloxy) -sothiazole-4-carboxylic acid; Amide of (4-ethyl-2,3-difluoro-benzyloxy) -5- [3- (2-hydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid; 5- [3- (4-Dimethylamino-butyl) -ureido] -3- (2-fluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- [3- (3-dibutylamino-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- [3- (3-diethyl-amino-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- [3- (6-dimethylamino-hexyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [3- (2-methyl-p -perid? N-1-yl) -propyl] -ureido} -isothiazole-4-carboxylic acid; 5- [3- (3-Dibutylamino-propyl) -ureido] -3- (2-fluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- (3-isobutyl-ureido) -isothiazole-4-carboxylic acid amide; 5- (3-Cyclopropylmethyl-ureido) -3- (2,5-difluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [2- (1-methyl-1H-pyrroI-2-yl) -ethyl] -ureido} -isothiazole-4-carboxylic acid; - [3- (3-Cyclohexylamino-propyl) -ureido] -3- (2,5-difluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- [3- (4-pyrroidin-1-yl-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [2- (1-methyl-pyrrolidin-2-yl) -ethyl] -ureido} -isothiazole-4-carboxylic acid; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- [3- (2,3-dihydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- (3-morpholin-2-methyl-ureido) -isothiazole-4-carboxylic acid amide; 2-aminomethyl-morpholine-4-carboxylic acid [4-carbamoyl] -3- (2,5-d.fluoro-4-methyl-benzyloxy) -isothiazol-5-yl-amide; 5- (3-Allyl-ureido) -3- (2,5-difluoro-4-methyl-benzyloxy) -isothiazo I-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- [3- (tetrahydro-furan-2-ylmethyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [3- (4-methyl-piperazin-1-yl) -propyl] -ureido} -isothiazole-4-carboxylic acid; 5- [3- (3-Cyclohexylamino-propyl) -ureido] -3- (4-ethyl-2,3-difluoro-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (4-Ethyl-2,3-difluoro-benzyloxy) -5- (3-isobutyl-ureido) -isothiazole-4-carboxylic acid amide; - (3-Cyclopropylmethyl-ureido) -3- (4-ethyl-2,3-difluoro-benzyloxy) -isothiazo I-4-carboxylic acid amide; 3- (4-Ethyl-2,3-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 5- (3-Allyl-ureido) -3- (4-ethyl-2,3-difluoro-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (3-Diethylamino-propyl) -ureido] -3- (2-fluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (6-Dimethylamino-hexyl) -ureido] -3- (2-fluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- [3- (3-imidazol-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- [3- (2-morpholin-4-yl-ethyl) -ureido] -sothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4-methoxy-benzyloxy) -5- [3- (3-imidazol-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4-methoxy-benzyloxy) -5- [3- (2-morpholin-4-yl-ethyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Furo-4-methoxy-benzyloxy) -5- [3- (3-morpholin-4-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4-methoxy-benzyloxy) -5- [3- (4-morpholin-4-yl-butyl) -ureido] -isothiazole-4-carboxylic acid amide; - (3. {3- (Bis- (2-hydroxy-ethyl) -amino] -propyl} -ureido) -3- (2-fluoro-4-methoxy-benzyloxy) -isothiazole acid amide -4-carboxylic acid; 3- (2-Fluoro-4-methoxy-benzyloxy) -5- acid amide. { 3- [3- (4-methyl-piperazin-1-yl) -propyl] -ureido} isothiazole-4-carboxylic acid; 5- [3- (3-Dimethylamino-propyl) -ureido] -3- (2-fluoro-4-methoxy-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (4-Dimethylamino-butyl) -uredo] -3- (2-fluoro-4-methoxy-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4-methoxy-benzyloxy) -5- [3- (3-isopropylamino-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 5- [3- (3-Cyclohexylamino-propyl) -ureido] -3- (2-fluoro-4-methoxy-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (4-Ethyl-2,5-difluoro-benzyloxy) -5- [3- (3-imidazol-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4-methoxy-benzyloxy) -5- [3- (3-hydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Ethyl-2,5-difluoro-benzyloxy) -5- [3- (4-morpholin-4-yl-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Ethyl-2,5-difluoro-benzyloxy) -5- [3- (3-imidazol-1-I-2-methyl-propyl) -uredo] acid amide] -sothiazole-4 -carboxylic; 3- (4-Ethyl-2,5-difluoro-benzyloxy) -5- [3- (3-hydroxy-2-methyl-propyl) -ureido] -isothiazo I-4-carboxylic acid amide; 3- (4-Ethyl-2,5-difluoro-benzyloxy) -5- [3- (3-morpholin-4-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-ethyl-2,5-difluoro-benzyloxy) -5- [3- (2-hydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-ethyl-2,5-difluoro-benzyloxy) -5- (3-furan-2-ylmethyl-ureido] -isothiazo I-4-carboxylic acid amide; 3- (4-ethyl-2-acid) amide , 5-difluoro-benzyloxy) -5- { 3- [2- (3H-imidazol-4-yl) -ethyl] -ureido] -isothiazole-4-carboxylic acid amide of 3- (4-ethyl- 2,5-difluoro-benzyloxy) -5- [3- (3-hydroxy-propyl) -ureido] -isotol-4-carboxylic acid amide of 3- (4-ethyl-2,5-difluoro) -benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -uredo] -sothiazole-4-carboxylic acid amide of 3- (4-ethyl-2, 5-difluoro-benzyloxy) -5- (3-isobutyl-ureido] -isothiazole-4-carboxylic acid 5- [3- (2,3-dihydroxy-propyl) -ureido] -3- (4-ethyl) amide -2,3-difluoro-benzyloxy) -isothiazole-4-carboxylic acid 3- (2-fluoro-4-methyl-benzyloxy) -5- (3-morpholin-2-ylmethyl-ureido) -isothiazole-4 acid amide -carboxylic acid [4-carbamoyl-3- (2-fluoro-4-methyl-benzyloxy) -isothiazol-5-yl] -amide of 2-aminomethyl-morpholine-4-carboxylic acid; fluoro-4-methyl-benzyloxy) -5- (3- { 3- [4- (2-hydroxy-ethyl) -piperazin-1-yl] - propyl.} - solid) -isothiazole-4-carboxylic acid; 3- (2-Fluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [3- (2-Oxo-pyrrolidin-1-yl) -propyl] -ureido} isothiazole-4-carboxylic acid; 5- [3- (3-Diethylamino-2-hydroxy-propyl) -ureido] -3- (2,5-difluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- [3- (2-morpholin-4-yl-etiI) -ureido] -isothiazole-4-carboxylic acid amide; 5- (3. {3- [bis- (2-hydroxy-ethyl] -amino] -propyl] -ideido) -3- (2,5-d-fluoro-4) acid amide -methyl-benzyloxy) -sothiazole-4-carboxylic acid; 3- (4-Chloro-2,5-difluoro-benzyloxy) -5- [3- (3-imidazol-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2,5-difluoro-benzyloxy) -5- acid amide. { 3- [3- (4-methyl-piperazin-1-yl) -propyl] -ureido} isothiazole-4-carboxylic acid; 3- (4-Chloro-2,5-difluoro-benzyloxy) -5- [3- (2-morpholin-4-yl-ethyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2,5-difluoro-benzyloxy) -5- [3- (4-morfoin-4-yl-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2,5-difluoro-benzyloxy) -5- [3- (4-phenyloidin-1-yl-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2,5-difluoro-benzyloxy) -5- (3-cyclopropylmethyl-ureido) -isotrazole-4-carboxylic acid amide; 3- (4-Chloro-2,5-difluoro-benzyloxy) -5- [3- (3-hydroxy-prop? I) -ureido] -isothiazole-4-carboxylic acid amide; - [3- (6-Dimethylamino-hexyl) -ureido] -3- (2-fluoro-4,6-dimethyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (4-Dimethylamino-butyl) -ureido] -3- (2-fluoro-4,6-dimethyl-benzyloxy) -sothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4,6-dimethyl-benzyloxy) -5- (3. {3- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -propyl] -amide. - solid) -isothiazole-4-carboxylic acid; 5- [3- (3-tert-Butylamino-propyl) -ureido] -3- (2-fluoro-4,6-dimethyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (6-Dimethylamino-hexyl) -ureido] -3- (2,4,6-trifluoro-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (4-ethyl-2,5-difluoro-benzyloxy) -5- [3- (3-isopropylamino-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 5- [3- (3-Cyclohexylamino-propyl) -urethane] -3- (4-ethyl-2,5-difluoro-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (2-Chloro-4-methyl-benzyloxy) -5- [3- (4-morpholin-4-yl-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Chloro-4-methyl-benzyloxy) -5- [3- (6-dimethylamino-hexyl) -uredo] -isot-azole-4-carboxylic acid amide; 3- (2-Chloro-4-methyl-benzyloxy) -5- [3- (3-imidazol-1-y-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Chloro-4-methyl-benzyloxy) -5- [3- (2-morpholin-4-yl-etl) -u-3-methoxy-4-carboxylic acid amide; 3- (2-Chloro-4-methyl-benzyloxy) -5- acid amide. { 3- [3- (4-methyl-piperazin-1-yl) -propyl] -ureido} -sothiazole-4-carboxylic acid; 5- [3- (3-Midazol-1-yl-propyl) -ureido] -3- (2,4,6-trifluoro-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (4-Dimethylamino-butyl) -ureido] -3- (2,4,6-trifluoro-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (4-tert-Butylamino-3-hydroxy-butyl) -ureido] -3- (2-fluoro-4,6-dimethyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- (3- {4- [4; 3- (2,5-difluoro-4-methyl-benzyloxy) -5-) {.3- [4- (4-Methyl-piperazin-1-yl) -butyl] -ureido}. -isothiazole-4-carboxylic acid 3- (2,5-difluoro-4-methyl) amide -benzyloxy) -5- (3- { 4- [4- (3-hydroxy-propyl) -piperazin-1-yl] -butyl} -ureido) -isothiazole-4-carboxylic acid; co-; 3- (2,5-difluoro-4-methyl-benzyloxy) -5- (3- {3 - [4- (2-hydroxyethyl) -p-piperazin-1-) acid amide il] -propyl.} -ureido) -isothiazole-4-carboxylic acid 5- [3- (3-tert-butylamino-propyl) -ureido] -3- (2-fluoro-4-methyl-benzyloxy) acid amide !) -isothiazole-4-carboxylic acid; 3- (2,5-difluoro-4-methyl-benzyloxy) -5- [3- (6-d-methylamino-hexyl) -ureido] -isothiazole- 4-carboxylic acid 3- (2,4-difluoro-benzyloxy) -5- [3- (3-imidazol-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; (2,4-difluoro-benzyloxy) -5-. {3- [3- (4-methyl-piperazin-1-yl) -propyl] -ureido} - -thiazole-4-carboxylic acid; 1? 5 3- (2,4-difluoro-benzyloxy) -5- [3- (3-isopropylamino-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,4-Difluoro-benzyl) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4-trifluoromethyl-benzyloxy) -5- [3- (2-morpholin-4-yl-ethyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,4-Difluoro-benzyloxy) -5- [3- (6-dimethylamino-hexyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,4-Difluoro-benzyloxy) -5- [3- (3-hydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,5-Dichloro-benzyloxy) -5- [3- (3-imidazol-1-ylpropyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,5-Dichloro-benzyloxy) -5- [3- (3-isopropylamino-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,5-Dichloro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,5-Dichloro-benzyloxy) -5- acid amide. { 3- (3- (4-methyl-piperazin-1-yl) -propiI] -ureido}. Isothiazole-4-carboxylic acid amide of 3- (2,5-dichloro-benzyloxy) -5- [3- (6-dimethylamino-hexyI) -ureido] -isothiazole-4-carboxylic acid 3- (2,5-dichloro-benzyloxy) -5- [3- (3-hydroxy-propyl) -ureido acid amide ] -isothiazole-4-carboxylic acid; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- [3- (5-isopropylamino-pentyl) -ureido] -isothiazole-4-carboxylic acid amide; 5- (3. {3- [bis- (2-hydroxy-ethyl) -amino] -propyl} -ureido) -3- (4-chloro-2,5-difluoro-benzyloxy) acid amide -isothiazole-4-carboxylic; 3- (4-Chloro-2,5-difluoro-benzyloxy) -5- acid amide. { 3- [4- (4-methyl-piperazin-1-yl) -butyl] -ureido} -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,5-difluoro-benzyloxy) -5- (3. {3- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -propyl acid amide .) - solid) -isothiazole-4-carboxylic acid; Amide of acid 5-. { 3- [4- (4-Benzyl-piperazin-1-yl) -butyl] -ureido} -3- (4-Chloro-2,5-difluoro-benzyloxy) -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,5-difluoro-benzyloxy) -5- [3- (6-dimethylamino-hexyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2,5-difluoro-benzyloxy) -5- [3- (3-isopropylamino-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 5- [3- (2-azepan-1-yl-ethyl) -ureido] -3- (2,5-difluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (1-Aza-bicyclo [2.2.2] oct-4-ylmethyl) -ureido] -3- (2,5-difluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (4-tert-Butylamino-3-hydroxy-butyl) -ureido] -3- (2,5-difluoro-4-methyl-benzyloxy) -isotrazole-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- [3- (4-hydroxy-1-methyl-pyrroidin-2-ymethyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2,5-difluoro-benzyloxy) -5- [3- (3-diethylamino-2-hydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2,5-difluoro-benzyloxy) -5- [3- (5-isopropylamino-pentyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2,5-difluoro-benzyloxy) -5- (3. {4- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -butyl acid amide .) urethane) -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,5-difluoro-benzyloxy) -5- [3- (3-hydroxy-2-methyl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 2-aminomethyl-morpholine-4-carboxylic acid [4-carbamoyl-3- (4-chloro-2,5-difluoro-benzyloxy) -isothiazol-5-yl] -amide; 3- (4-Chloro-2,5-difluoro-benzyloxy) -5- (3-morpholin-2-ylmethyl-ureido) -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2,5-difluoro-benzyloxy) -5- acid amide. { 3- [2- (1-methyl-pyrrolidin-2-yl) -ethyl] -uredode} -sothiazole-4-carboxylic acid; 3- (4-Chloro-2,5-difluoro-benzyloxy) -5- (3 { 4- [4- (3-hydroxy-propyl) -piperazin-1-yl] -butyl acid amide} - solid) -isothiazole-4-carboxylic acid; 3- (2-Fluoro-4-methyl-benzyloxy) -5- [3- (5-isopropylamino-pentyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (3-Fluoro-2,4-dimethyl-benzyloxy) -5- [3- (2-morpholin-4-yl-ethyl) -ureido] -isothiazole-4-carboxylic acid amide; 5- (3. {4- [bis- (2-hydroxy-ethyl) -amino] -butyl} -ureido) -3- (2,5-difluoro-4-methyl-becyloxy) acid amide isothiazole-4-carboxylic acid; 3- (2,5-D-Fluoro-4-methyl-benzyloxy) -5- [3- (5-morpholin-4-yl-pentyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [5- (4-methyl-piperazin-1-yl) -pentyl] -ureido} -isothiazole-4-carboxylic acid; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- (3. {5- [4- (2-hydroxy-ethyl) -piperazin-1-yl] pentyl] acid amide. .-solid) -isothiazo I-4-carboxylic acid; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [7- (4-methyl-piperazin-1-yl) -heptyl] -ureido} -isothiazole-4-carboxylic acid; 3- (2,5-D-Fluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [6- (4-methyl-piperazin-1-yl) -hexyl] -ureido} -isothiazole-4-carboxylic acid; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- (3- {6- [4- (2-Hydroxy-ethyl) -piperazin-1-yl) acid amide ] -hexyl.} -ureido) -isothiazole-4-carboxylic acid; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- (3. {7-7- [4- (2-hydroxy-etii) -piperazin-1-yl] -heptyl acid amide .}.-solid) -sothiazole-4-carboxylic acid; 3- (2,5-Dichloro-4-methyl-benzyloxy) -5- acid amide. { 3- [4- (4-Methyl-piperazin-1-yl) -butyl] -ureido} -isothiazole-4-carboxylic acid; 3- (2,5-Dichloro-4-methyl-benzyloxy) -5- [3- (6-dimethylamino-hexii) -ureido] -sothiazole-4-carboxylic acid amide; 3- (2,5-Dichloro-4-methyl-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [4- (5-methyl-2,5-diaza-bicyclo [2.2.1] hept-2-yl) -butyl] -uredo} -isothiazole-4-carboxylic acid; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- [3- (octahydro-pyrido [1, 2-a] pyrazin-7-ylmethyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [7- (4-Methyl-piperazn-1-yl) -heptyl] -u} -isothiazole-4-carboxyl; 3- (2-Fluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [6- (4-Methyl-piperazin-1-yl) -hexyl] -ureido} - sodium-4-carboxylic acid; 3- (2-Fluoro-4-methyl-benzyloxy) -5- (3- {7- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -heptyl} acid amide. .-solid) -isothiazo I-4-carboxylic acid; 3- (2-Fluoro-4-methyl-benzyloxy) -5- (3- {6- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -hexyl] -amide} -ureido) -isothiazole-4-carboxylic acid; 3- (2-Fluoro-4-methyl-benzyloxy) -5- (3. {5- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -pentyl] -amide. ureido) -isothiazole-4-carboxylic acid; 3- (2-Fluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [5- (4-methyl-piperazin-1-yl) -pentl] -ureido} -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,5-difluoro-benzyloxy) -5- acid amide. { 3- [5- (4-methyl-piperazin-1-yl) -pentyl] -ureido} -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,5-difluoro-benzyloxy) -5- (3- {5- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -pentyl} -amide. .-solid) -stothiazo I-4-carboxylic acid; 3- (4-Chloro-2,5-difluoro-benzyloxy) -5- acid amide. { 3- [7- (4-Methy-p-piperazin-1-yl) -heptyl] -ureido} Sothiazoi-4-carboxylic acid; 3- (4-Chloro-2,5-difluoro-benzyl) -5- (3- {7- [4- (2-hydroxy-ethyl) -piperazin-1-yl) - acid amide - heptl} -ureido) -sothiazole-4-carboxylic acid; 3- (4-Chloro-2,5-difluoro-benzyloxy) -5- acid amide. { 3- [6- (4-methyl-piperazin-1-yl) -hex] [] -ureido} -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,5-difluoro-benzyloxy) -5- acid amide. { 3- [6- (4-propyI-piperazin-1-yl) -hexyl] -ureido} -isothiazole-4-carboxylic acid; 5- (3 { 5- [4- (2-Hydroxy-ethyl) -piperazin-1-yl] -pentyl} -idethyl) -3- (4-methyl-benzyloxy) acid amide ) -isothiazole-4-carboxylic acid; 5- (3. {6- [4- (2-Hydroxy-ethyl) -piperazin-1-yl] -hexyl} -ureido] -3- (4-methyl-benzyloxy) -isothiazole acid amide -4-carboxylic acid; 3- (2,4-Dimethyl-benzyloxy) -5- acid amide. { 3- [5- (4-methyl-piperazin-1-yl) -pentyl] -ureido} isothiazole-4-carboxylic acid; 3- (2,4-Dimethyl-benzyloxy) -5- acid amide. { 3- [7- (4-methyl-piperazin-1-ii) -heptyl-uredo} isothiazole-4-carboxylic acid; 3- (2,4-Dimethyl-benzyloxy) -5- acid amide. { 3- [6- (4-Methyl-piperazin-1-y!) -hexyl] -ureido} -isothiazole-4-carboxylic acid; 3- (2,4-Dimethyl-benzyloxy) -5- (3- {7- [4- (2-hydroxy-ethy) -piperazin-1-yl] -heptyl} -deide acid amide ) -isothiazole-4-carboxylic acid; 5- (3. {4- [Bis- (2-hydroxy-ethyl) -amino] -butyl} -ureido) -3- (4-chloro-2,5-difluoro-benzyloxy) acid amide ) -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,5-difluoro-benzyloxy) -5- [3- (5-morpholin-4-yl-pentyl) -ureido] -isothiazole-4-carboxylic acid amide; 7- tertiary butyl ester. { 3- [4-carbamoyl-3- (4-chloro-2,5-difluoro-benzyloxy) -isothiazol-5-yl] -ureidomethyl} -octahydro-pyrido [1,2-a] pyrazine-2-carboxylic acid; 3- (4-Chloro-2,5-difluoro-benzyloxy) -5- acid amide. { 3- [4- (5-methyl-2) 5-diaza-bicyclo [2.2.1] hept-2-yl) -butyl] -ureido} -isothiazole-4-carboxylic acid; 5- [3- (4-tert-Butylamino-3-hydroxy-butyl) -ureido] -3- (4-chloro-2,5-difluoro-benzyloxy) -isotrazole-4-carboxylic acid amide; 3- (4-Chloro-2,5-difluoro-benzyloxy) -5- [3- (Octahydro-pyrido [1,2-a] pyrazin-7-ylmethyl) -ureido] -isothiazole-4 acid amide -carboxylic; 5- [3- (5-isopropylamino-penti) -ureido] -3- (2,4,5-trifluoro-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (6-Dimethylamino-hexyl) -ureido] -3- (2,4,5-trifluoro-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (4-Pyrrolidin-1-yl-butyl) -ureido] -3- (2,4,5-trifluoro-benzyloxy) -isotriazole-4-carboxylic acid amide; 5- (3 { 6- [4- (2-Hydroxy-ethyl) -piperazin-1-yl] -hexyl] -idene acid amide) -3- (2,4I5-) trifluorobenzyloxy) -isothiazole-4-carboxylic acid; 5- (3 { 7- [4- (2-Hydroxy-ethyl) -piperazin-1-yl] -heptyl} -ureido) -3- (2,4) 5-trifluoro- acid amide benzyloxy) -sothiazole-4-carboxylic acid; 5- [3- (2-Morpholin-4-yl-ethyl] -ureido] -3- (2,4,5-trifluoro-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- [3- (4-pyrroidin-1-yl-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- acid amide. { 3- [3- (4-Methyl-piperazin-1-yl) -propyl] -uredode} -isothiazole-4-carboxylic acid; - (3. {3- [bis- (2-hydroxy-ethyl) -amino] -propyl} -ureido) -3- (4-chloro-2,6-difluoro-becyloxy) acid amide) -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- acid amide. { 3- [2- (1-methyl-pyrrolidin-2-yl) -ethyl] -ureido} Sothiazole-4-carboxylic acid; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- (3- {4- [4- (2-hydroxy-ethyl) -piperazin-1-yl] acid amide] -butyl) -isole-4-carboxylic acid; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- [3- (6-dimethylamino-hexyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- (3. {4- [4- (3-hydroxy-propyl) p-piperazin-1-yl] -butyl acid amide} -ureido) -isothiazo I-4-carboxylic acid; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- (3 { 5- [4- (2-hydroxy-ethyl) piperazin-1-yl] -pentyl acid amide. -ureido) -isotol-4-carboxylic acid; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- (3. {6- [4- (2-Hydroxy-ethyl) piperazin-1-yl] -hexyl acid amide} - solid) -isotol-4-carboxylic acid; 3- (4-Chloro-2,6-difluoro-becyloxy) -5- [3- (5-isopropylamino-pentyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- acid amide. { 3- [4- (4-methyl-piperazin-1-yl) -butyl] -ureido} -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- acid amide. { 3- [5- (4-methyl-piperazin-1-yl) -pentyl] -ureido} isothiazole-4-carboxylic acid; 5- [3- (4-tert-Butylamino-3-hydroxy-butyl) -ureido] -3- (2-fIuoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [4- (5-methyl-2,5-diaza-bicicon [2.2.1] hept-2-yl) -butyl] -ureido} -isothiazole-4-carboxylic acid; 3- (2-Fluoro-4-methyl-benzyloxy) -5- (3- {4- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -butyl} - acid. ureido) -isothiazole-4-carboxylic acid; 3- (2-Fluoro-4-methyl-benzyloxy) -5- [3- (3-isopropylamino-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- (3- {4- [4- (3-hydroxy-propyl) -piperazine-1-yl) acid amide ] -butyl} -ureido) -isothiazole-4-carboxylic acid; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- [3- (3-isopropylamino-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- [3- (6-dimethylamino-hexyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- [3- (6-dimethylamino-hexyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- [3- (5-isopropylamino-pentyl) -ureido] -isothiazole-4-carboxylic acid amide; 5- (3. {3- [bis- (2-hydroxy-ethyl) -amino] -propyl} -ureido) -3- (2,6-difluoro-4-methyl-benzyloxy) acid amide -isothiazole-4-carboxylic acid; 5- [3- (4-tert-Butylamino-3-hydroxy-butyl) -ureido] -3- (2,6-difluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (2,6-Difluoro-4-methyl-becyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- (3- {4- [4- (2-hydroxy-ethyl) piperazin-1-yl] -butyl} acid amide. .-solid) -isothiazole-4-carboxylic acid; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- (3. {5- [4- (2-hydroxy-etiI) -1-yl] -pentiI} -amide. ureido) -isothiazole-4-carboxylic acid; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- (3- {6- [4- (2-hydroxy-etiI) -1-yl] -hexyl} -amide. uredode) -sothiazole-4-carboxylic acid; Acid 4-. { 3- [4-carbamoyl-3- (2,5-difluoro-4-methyl-benzyloxy) -isothiazoI-5-irj-ureido} -butyric; 5- (3. {3- [bis- (2-hydroxy-ethyl) -amino] -propyl.} -ureido) -3- (2-cyclo-5-fluoro-4-methyl- acid) amide benzyloxy) -isothiazole-4-carboxylic acid; 3- (2-Chloro-5-fIuoro-4-methy-benzyloxy) -5- [3- (5-isopropylamino-pentyl) -uret] -isothiazole-4-carboxylic acid amide; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- [3- (6-dimethylamino-hexyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- [3- (5-isopropylamino-pentyl) -uret] -isothiazole-4-carboxylic acid amide; 5- (3. {3- [bis- (2-hydroxy-ethyl) -amino] -propyl} -ureido) -3- (2,6-difluoro-4-methyl-benzyloxy) acid amide -sothiazole-4-carboxylic acid; 5- [3- (4-tert-Butylamino-3-hydroxy-butyl) -ureido] -3- (2,6-difluoro-4-methyl-benzyloxy) -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- (2,6-Difluoro-4-methyl-benzyloxy) -5- (3- {4- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -butyl acid amide I.) -ureido) -isothiazole-4-carboxylic acid; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- (3. {5- [4- (2-hydroxy-ethyl) -piperazin-1-yl] pentyl] acid amide. -ureido) -isothiazole-4-carboxylic acid; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- (3. {6- [4- (2-hydroxy-ethyl) piperazin-1-yl] hexyl acid amide} - solid) -isotol-4-carboxylic acid; 5- [3- (3-tert-Butylamino-propyl) -ureido] -3- (2-fluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [3-hydroxy-5- (4-methyl-piperazin-1-yl) -pentyl] -ureido} -sothiazole-4-carboxylic acid; 3- (2-Chloro-5-fluoro-4-methyl-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Chloro-5-fluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [3- (4-methyl-piperazin-1-yl) -propyl] -ureido} -isothiazole-4-carboxylic; 3- (4-Chloro-2,5-difluoro-benzyloxy) -5- acid amide. { 3- [3-hydroxy-5- (4-methyl-piperazin-1-yl) -pentyl] -ureido} -sothiazole-4-carboxylic acid; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- [3- (3-hydroxy-5-pyrrolidin-1-yl-pentyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2,5-difluoro-becyloxy) -5- [3- (3-hydroxy-5-pyrroidin-1-yl-pentyl) -ureido] -saltazole-4- carboxylic; 3- (4-Chloro-2,6-difluoro-becyloxy) -5- [3- (3-hydroxy-5-pyrrolidin-1-yl-pentyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Chloro-5-fluoro-4-methyl-becyloxy) -5- [3- (6-dimethylamino-hexyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Chloro-5-fluoro-4-methyl-becyloxy) -5- (3- { 4- [4- (2-hydroxy-ethyl) -piperazin-1-yl) acid amide ] -butyl} -ureido) -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,6-difluoro-becyloxy) -5- acid amide. { 3- [3-hydroxy-5- (4-methylp? Perazin-1-yl) -pentyl] -ureido} -sothiazole-4-carboxylic acid; 3- (5-Chloro-2-fluoro-4-methyl-benzyloxy) -5- [3- (4-pyrroyl-indin-1-yl-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (5-Chloro-2-fluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [3- (4-methyl-piperazin-1-yl) -propyl] -ureido} -isothiazole-4-carboxylic acid; 5- (3. {3- (Bis- (2-hydroxy-ethyl) -amino] -propyl} -ureido) -3- (5-cyclo-2-fluoro-4-methyl- acid) amide benzyloxy) -isothiazole-4-carboxylic acid; 5- [3- (4-tert-Butylamino-3-hydroxy-butyl) -ureido] -3- (2-fluoro-4,6-dimethyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (5-Chloro-2-fluoro-4-methyl-benzyloxy) -5- [3- (6-dimethylamino-hexyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (5-Chloro-2-fluoro-4-methyl-benzyloxy) -5- [3- (5-isopropylamino-pentyl) -ureido] -isothiazole-4-carboxylic acid amide; 5- [3- (6-Dimethylamino-hexyl) -ureido] -3- (2,4,6-trifluoro-benzyloxy) -sothiazo I-4-carboxylic acid amide; 3- (5-Chloro-2-fluoro-4-methyl-benzyloxy) -5- (3. {4- [4- (2-hydroxy-ethyl) -piperazin-1-yl] acid amide] -butyl) -isotol-4-carboxylic acid 3- (5-chloro-2-fluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [4- (4-Methylpiperazin-1-yl) -butyl] -ureido} -isothiazole-4-carboxylic acid; 3- (5-Chloro-2-fluoro-4-methyl-benzyloxy) -5- (3 { 4- [4- (3-hydroxy-propyl) -piperazin-1-yl] -butyl acid amide .).-solid) -sot-azole-4-carboxylic acid; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- [3- (2-morofolin-4-yl-ethyl) -uret] -isothiazole-4-carboxylic acid amide; 5- [3- (4-tert-Butylamine-3-hydroxy-butyl) -urethane] -3- (4-chloro-2,6-diluoro-benzyloxy) -isothiazole-4-carboxylic acid amide 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- acid amide. { 3- [4- (5-methyl-2,5-diaza-bicyclo [2.2.1] hept-2-yl) -butyl] -ureido} -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- [3- (3-hydroxy-5-isopropylamino-pentyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2,5-d-fluoro-benzyloxy) -5- [3- (3-hydroxy-5-isopropylamino-pentyl) -ureido] -isot-azole-4-acid amide -carboxylic acid, 3- (5-chloro-2-fluoro-4-methyl-benzyloxy) -5- (3-. {5- [4- (2-hydroxy-ethyl) piperazin-1-yl] acid amide] -pentyl.} -ureido) -isothiazole-4-carboxylic acid; 3- (5-Chloro-2-fluoro-4-methyl-benzyloxy) -5- (3- {6- [4- (2-hydroxy-ethyl) piperazin-1-yl] -hexamide 1-solid) -isothiazole-4-carboxylic acid; 7- Tertiary butyl ester. { 3- [4-carbamoyl-3- (4-chloro-2,6-d '? FIuoro-benzyloxy) -sothiazol-5-yl] -ureidomethyl} -octah-pyrido [1,2-a] pyrazine-2-carboxylic acid, 3- (4-chloro-2,5-difluoro-benzyloxy) -5- [3- (3-hydroxy-5- isopropylamino-pentyl) -ureido] -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- acid amide. { 3- (Octahydro-pyrido [1,2- a] pyrazin-7-ylmethyl) -ureido] -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,6-difiuoro-benzyloxy) -5- (3-. {3- [4- (2-hydroxy-ethyl) -1-yl] propyl} -ureidoic acid amide ) -isothiazole-4-carboxylic acid; 5- (3. {4- [bis- (2-hydroxy-ethyl) -amino] -butyl} -ureido) -3- (4-chloro-2,6-difluoro-benzyl) acid amide loxi) -sothiazole-4-carboxylic acid; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- (3. {3- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -propyl] -amide. .-solid) -isothiazole-4-carboxylic acid; 5- (3. {3- [bis- (2-hydroxy-ethyl) -amino] -propyl.} -ureido) -3- (2,3-dichloro-4-methyl) acid amide benzyloxy) -isothiazole-4-carboxylic acid; 3- (2,3-Dichloro-4-methyl-benzyloxy) -5- [3- (6-dimethylamino-hexyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,3-Dichloro-4-methyl-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,3-Dichloro-4-methyl-benzyloxy) -5- (3- {4- [4- (3-hydroxy-propyl) -piperazin-1-yl] -butyl} acid amide. - solid) -isothiazole-4-carboxylic acid; 5- (3. {4- [bis- (2-hydroxy-ethyl) -amino] -butyl} -idene) -3- (2,3-dichloro-4-) acid amide methyl-benzyloxy) -isothiazole-4-carboxylic acid, 3- (2,3-dichloro-4-methyl-benzyloxy) -5- (3-. {5- [4- (2-hydroxy-ethyl)) -piperazin-1-yl] -pentyl.} -ureido) -isothiazole-4-carboxylic acid; 3- (2,3-Dichloro-4-methyl-benzyloxy) -5- (3. {6- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -hexyl acid amide .}.-solid) -sothiazole-4-carboxylic acid; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- (3- {5- [4- (2-hydroxy-ethy) -piperazin-1-yl] -pentyl acid amide) .sup.-solid) -isoxy-4-carboxylic acid; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- (3- {6- ({4- (2-hydroxy-ethyl) -piperazin-1-yl] -amide] -hexyl.} -ureido) -isothiazole-4-carboxylic acid; 5- (3. {4- [bis- (2-hydroxy-ethyl) -amino] -butyl} -ureido) -3- (2,5-d.fluoro-4-methyl- acid) amide benzyloxy) -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,5-dilfuoro-benzyloxy) -5- acid amide. { 3- [4- (5-Methyl-2,5-diaza-bicyclo [2.2.1] hept-2-yl) -butyl] -ureido} -isoxy-4-carboxylic acid; 3- (2,4-Dimethyl-benzyloxy) -5- [3- (5-isopropylamino-pentyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Ethyl-benzyloxy) -5- (3- {5- [4- (2-hydroxy-ethyl) piperazin-1-yl] -pentyl} -amide. -isothiazole-4-carboxylic acid; 3- (4-Ethyl-benzyloxy) -5- (3- {6- [4- (2-hydroxy-ethyl) piperazin-1-yl] -hexyl} -ideido) - amide Sothiazole-4-carboxylic acid; 5- [3- (6-Dimethylamino-hexyl) -ureido] -3- (4-etl-benzyl-oxy) -isothiazole-4-carboxylic acid amide; 3- (4-Ethyl-benzyloxy) -5- [3- (5-isopropyl-lane-pentyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4-methyl-benzyloxy) -5- (3. {5- [4- (2-hydroxy-ethyl) piperazin-1-yl] -petyl} -ureamide. Do) -sot-azole-4-carboxylic acid; 3- (2-Fluoro-4-methyl-benzyloxy) -5- (3- {6- [4- (2-hydroxy-ethyl) piperazin-1-yl] -hexyl} -amide. ) -isothiazole-4-carboxylic acid; 5- [3- (6-Dimethylamino-hexyl) -ureido] -3- (2-fluoro-4-methyo-benzyloxy) -sothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4-methyl-benzyloxy) -5- [3- (5-isopropylamino-pentyl) -ureido] -isothiazole-4-carboxylic acid amide; 3-Heptyloxy-5- (3. {5- [4- (2-hydroxy-ethyl) piperazin-1-y-pentiyl} -ureido) -isothiazole-4-carboxylic acid amide; 3-Hepti-Ioxy-5- (3. {6 - [4- (2-hydroxy-ethyl) -piperazin-1-yl] -hexyl} -ideido} -sothiazole-4-carboxylic acid amide; 3- (2,5-Difuoro-4-methyl-benzyloxy) -5- acid amide. { 3- [4- (3,4-Dihydroxy-pyrrolidin-1-yl) -butyl] -ureido} - sodium-4-carboxylic acid; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- acid amide. { 3- [4- (3,4-Dihydroxy-pyrrolidin-1-yl) -butyl] -ureido} -isothiazole-4-carboxylic acid; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- [3- (4-phenyloidin-1-yl-butyl) -ureido] -isothiazole-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- (2,5-Difluoro-4-methyl-benzyloxy) -5- [3- (5-isopropylamino-pentyl) -ureido] -isothiazole-4-carboxylic acid amide; 5- [3- (5-isopropylamino-pentyl) -ureido] -3- (2,4,6-trifluoro-benzyloxy) -isotrazole-4-carboxylic acid amide; - (3. {3- [bis (2-hydroxy-ethyl) -amino] -propyl] -idethyl) -3- (2,4,6-trifluoro-benzyloxy) -isothiazole- acid amide 4-carboxylic; 5- [3- (4-tert-Butylamino-3-hydroxy-butyl) -ureido] -3- (2,4,6-trifluoro-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (4-Pyrrolidin-1-yl-butyl) -ureido] -3- (2,4,6-trifluoro-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- (3 { 4- [4- (2-Hydroxy-ethyl) -1-yl] -butyl} -ureido) -3- (2,4,6-trifluoro-benzyloxy) acid amide isothiazole-4-carboxylic acid; 5- (3 { 5- [4- (2-Hydroxy-ethyl) -piperazin-yl] -pentyl} -ureido] -3- (2,4,6-trylfuorobenzyloxy) -isothiazole acid amide -4-carboxylic acid; 5- (3 { 6- [4- (2-Hydroxy-ethyl) -piperazin-yl] -hexyl} -ureido] -3- (2,4,6-trifluoro-benzyloxy) acid amide -isothiazole-4-carboxylic acid, 3- (4-bromo-2-fluoro-benzyloxy) -5- [3- (5-isopropylamine-pentyl) -ureido] -isot-azole-4-carboxylic acid amide; 3- (4-Bromo-2-fluoro-benzyloxy) -5- [3- (4-tert-butylamino-3-hydroxy-butyl) -ureido] -isot-azole-4-carboxylic acid amide; 3 ~ (4-Bromo-2-fluoro-benzyloxy) -5- (3- {4- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -butyl} -amide. ureido) -isothiazole-4-carboxylic acid; 3- (4-Bromo-2-fluoro-benzyloxy) -5- (3- {5- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -pentyl} -amide. ureido) -isothiazole-4-carboxylic acid; 3- (2-Fluoro-4,6-dimethyl-benzyloxy) -5- [3- (5-isopropylamine-pentyl) -ureido] -isothiazole-4-carboxylic acid amide; - (3. {3- [bis- (2-hydroxy-ethyl) -amino] -propyl} -ureido) -3- (2-fluoro-4,6-dimethyl-benzyloxy) acid amide -isothiazole-4-carboxylic acid; 3- (2-Fluoro-4,6-diethyl-benzyloxy) -5- [3- (4-pyrroidin-1-yl-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4,6-dimethyl-benzyloxy) -5- (3. {4- [4- (2-hydroxy-etii) -piperazin-1-yl] -butyl} acid amide. .-solid) -isothiazole-4-carboxylic acid; 3- (2-Fluoro-4,6-dimethyl-benzyloxy) -5- (3. {5- [4- (2-hydroxy-ethyl) -1-yl] -pentyl acid amide. -ureido) -isothiazole-4-carboxylic acid; 3- (2-Fluoro-4,6-dimethyl-benzyloxy) -5- (3. {6- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -hexyl acid amide. .-solid) -isothiazole-4-carboxylic acid, 3- [1- (4-chloro-2,6-difluoro-phenyl) -ethoxy] -5- [3- (4-pyrrolidin-1-yl) amide -butyl) -ureido] -isothiazole-4-carboxylic acid; 3- [1- (4-Chloro-2,6-difluoro-phenyl) -ethoxy] -5- (3- {5- [4- (2-hydroxy-ethyl) -piperazin-1) acid amide -l] -pentyl.} -ureido) -isothiazole-4-carboxylic acid; 5- [3- (6-Dimethylamino-hexyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (5-isopropylamino-pentyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide, 5- (3-Amide) - { 6- [4- (2-hydroxy-ethyl) -piperazin-yl] -hexyl] -ureido) -3- (2,3,6-trifluoro-4-methyl-benzyl) Loxi) -sothiazole-4-carboxylic acid; 5- [3- (4-tert-Butylamino-3-hydroxy-butyl) -ureido] -3- [1- (4-chloro-2,6-difluoro-phenyl) -ethoxy] -isothiazoI-4 acid amide -carboxylic; - (3. {5- [4- (2-Hydroxy-ethyl) -piperazin-yl] -petyl} -amide) -3- (2,3,6-trifluoro-4-) acid amide methyl-benzyloxy) -isothiazole-4-carboxylic acid, 3- [1- (4-chloro-2,6-difluoro-phenyl) -ethoxy] -5- [3- (5-isopropylamino-pentyl) -ureidoic acid amide ] -isothiazole-4-carboxylic acid; 5- [3- (4-tert-Butylamino-3-hydroxy-butyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -sothiazole-3- (4-aminide) amide -chloro-2,6-difluoro-benzyloxy) -5- [3- (3-hydroxy-5-pyrrolidin-1-yl-pentyl) -ureido] -isothiazole-4-carboxylic acid; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [4- (2-hydroxymethyl-pyrrolidin-1-yl) -butyl] -ureido} -isothiazole-4-carboxylic acid; 5- (3. {5- [4- (2-Hydroxy-ethyl) -piperazin-yl] -petyl} -ureido] -3- (4-methyl-benzyloxy) isothiazole-4-acid amide carboxylic; 5- (3 { 6- [4- (2-Hydroxy-ethyl) -piperazin-1-yl] -hexyl} -ideido) -3- (4-methyl-benzyloxy) -isothiazole acid amide -4-carboxylic acid; 5- [3- (6-Dimethylamino-hexyl) -ureido] -3- (4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (6-Dimethylamino-hexyl) -ureido] -3-heptyloxy-isothiazoI-4-carboxylic acid amide; 3-Hexyloxy-5- [3- (5-isopropylamino-pentyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- acid amide. { 3- [4- (2-hydroxymethyl-pyrrolidin-1-yl) -butyl] -ureido} -isothiazole-4-carboxylic acid; 3- (5-Chloro-2-fluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [4- (2-hydroxymethyl-pyrrolidin-1-yl) -butyl] -ureido} -sothiazole-4-carboxylic acid; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [4- (3-hydroxy-pipOlidin-1-yl) -butyl] -ureido} isothiazole-4-carboxylic acid; 5- [3- (6-Dimethylamino-hexyl) -ureido] -3- (2,3,5,6-tetrafluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- (3 { 6- [4- (2-Hydroxy-ethyl) -piperazin-yl] -hexyl} -ideido) -3- (2,3,5,6-tetrafluoro-) acid amide 4-methyl-benzyloxy) -isothiazole-4-carboxylic acid, 3- (4-chloro-2,5-diluoro-benzyloxy) -5- acid amide. { 3- [4- (2-hydroxymethyl-pyrrolidin-1-yl) -butyl] -uredo} -isothiazole-4-carboxylic acid; 5- [3- (4-Pyrrolidin-1-yl-butyl) -ureido] -3- (2, 3,5,6-tetrafluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2,5-dilfuoro-benzyloxy) -5- acid amide. { 3- [4- (3-hydroxy-pyrrolidin-1-yl) -butyl] -ureido} -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,5-difluoro-benzyloxy) -5- acid amide. { 3- [4- (3,4-dihydroxy-pyrrolidin-1-yl) -butyl] -ureido} -isothiazole-4-carboxylic acid; 5- [3- (4-tert-Butylamino-3-hydroxy-butyl) -ureido] -3- (2,3,5,6-tetrafluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2,6-dif! Uoro-benzyloxy) -5- acid amide. { 3- [4- (3-hydroxy-pyrrolidin-1-yl) -butyl] -ureido} -isothiazole-4-carboxylic acid; 5- [3- (5-isopropylamino-pentyl) -ureido] -3- (2,3,5,6-tetrafluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2,5-dilfuoro-benzyloxy) -5- acid amide. { 3- [2- (Octahydro-pyrido [1,2- a] pyrazin-7-yl) -ethyl] -ureido} -isothiazole-4-carboxylic acid; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [6- (4-methyl-piperazin-1-yl) -hexyl] -ureido} isothiazole-4-carboxylic acid; 3- (2-Fluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [3- (4-methyl-piperazin-1-yl) -propyl] -ureido} -isothiazole-4-carboxylic acid; 3- (2,5-difiuoro-4-methyl-benzyloxy) -5- [3- (4-piperidin-1-yl-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- [3- (4-piperidin-1-yl-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,3-Difluoro-4-methyl-benzyloxy) -5 ~ [3- (4-piperidn-1-yl-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2,5-difluoro-benzyloxy) -5- [3- (4-piperidin-1-yl-butyl) -ureido] -sothiazole-4-carboxylic acid amide; 3- (4-Bromo-2,6-difluoro-benzyloxy) -5- [3- (6-dimethylamino-hexyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2,6-difluoro-benzyloxy) -5- [3- (5-isopropylamino-pentyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Bromo-2,6-difluoro-benzyloxy) -5- (3-. {6- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -hex I.) -ureido) -isothiazole-4-carboxylic acid; 3- (4-Bromo-2,6-difiuoro-benzyloxy) -5- (3-. {5- [4- (2-hydroxy-ethyl) -piperazin-1-yl] acid amide -pentyl.} -ureido) -isothiazole-4-carboxylic acid; 3- (4-Bromo-2,6-difluoro-benzyloxy) -5- [3- (4-tert-butylamino-3-hydroxy-butyl) -ureido] -isotrazole-4-carboxylic acid amide; 3- (4-Bromo-2,6-difluoro-benzyloxy) -5- [3- (4-pyrroidin-1-yl-butyl) -ureido] -isothiazo I-4-carboxylic acid amide; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- (3- {4- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -butyl} acid amide .} ureido) -isothiazole-4-carboxylic acid; 3- (2-Fluoro-4-methyl-benzyloxy) -5- [3- (4-hydroxy-5-piperidin-1-yl-pentyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- [3- (4-hydroxy-5-piperidin-1-yl-pentyl) -uret] -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4-methyl-benzyloxy) -5- [3- (4-hydroxy-5-iso-butylamino-pentyl) -ureido] -isothiazole-4-carboxylic acid amide; 5- [3- (4-tert-Butylamino-3-hydroxy-butyl) -ureido] -3- (2-fluoro-4-methyl-benzyloxy) -isotipazoi-4-carboxylic acid amide; 3- (2,3-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [4- (3,4-Dihydroxy-pyrrolidin-1-yl) -butyl] ureido} isothiazole-4-carboxylic acid; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- acid amide. { 3- [4- (3,4-d.hydroxy-pyrrolidin-1-yl) -butyl] uredo} -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,5-difluoro-benzyloxy) -5- acid amide. { 3- [4- (3,4-Dihydroxy-pyrrolidin-1-yl) -butyl] ureido} isothiazole-4-carboxylic acid; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [4- (3,4-dihydroxy-pyrrolidin-1-yl) -butyl] -ureido} -sothiazole-4-carboxylic acid; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- acid amide. { 3- [3- (4-methyl-piperazin-1-yl) -propyl] -ureido} isothiazole-4-carboxylic acid; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- [3- (4-hydroxy-5-morfoin-4-ii-pentyl) -uretho] -isothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- [3- (5-hydroxy-6-morfoyl-4-yl-hexyl) -ureido] -isothiazole-4-acid amide -carboxylic; 3- (4-Chloro-2,6-diluoro-benzyloxy) -5- [3- (5-hydroxy-6-morfoin-4-yl-hexyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- [3- (4-hydroxy-5-piperidin-1-yl] -pentyl) -urethane] -isothiazole acid amide -4-carboxylic acid; 3- (4-Chloro-2,6-diluoro-benzyloxy) -5- [3- (4-hydroxy-5-piperidin-1-yl-pentyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,3-Difluoro-4-methyl-benzyloxy) -5- [3- (4-hydroxy-5-piperidin-1-yl-pentyl) -ureido] -sothiazole-4-carboxylic acid amide; 3- (2) 5-difiuoro-4-methyl-benzyloxy) -5- acid amide. { 3- [4- (3-hydroxy-piperidin-1-yl) -butyl] -ureido} -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- acid amide. { 3- [4- (3-hydroxy-piperidin-1-yl) -butyl] -ureido} -sothiazole-4-carboxylic acid; 3- (2,3-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [4- (3-hydroxy-p.peridin-1-yl) -butyl] -ureido} isothiazole-4-carboxylic acid; 3- (2,6-Difluoro-benzyloxy) -5- acid amide. { 3- [3- (4-methyl-piperazin-1-yl) -propyl] -ureido} isothiazole-4-carboxylic acid; 3- (2,6-Difluoro-benzyloxy) -5- [3- (6-dimethylamino-hexyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- [3- (5-hydroxy-6-morfoin-4-yl-hexyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4-methyl-benzyloxy) -5- [3- (4-hydroxy-5-morpholin-4-yl-pentyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2-Fluoro-4-methyl-benzyloxy) -5- [3- (5-hydroxy-6-morpholin-4-yl-hexyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- [3- (5-hydroxy-6-isobutylamino-hexyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- [3- (5-hydroxy-6-piperidn-1-yl-hexyl) -ureido] isothiazole-4-acid amide carboxylic; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- [3- (6-hydroxy-7-morpholin-4-yl-heptyl) -ureido] -isothiazo I-4-carboxylic acid amide; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- [3- (4-hydroxy-5-morpholin-4-yl-pentyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- [3- (7-dimethylamino-6-hydroxy-heptyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- [3- (6-hydroxy-7-piperidin-1-yl-heptyl) -ureido] -isothiazole-4-carboxylic acid amide co; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- acid amide. { 3- [4- (2-methoxymethyl-pyrrolidin-1-yl) -butyl] -ureido} -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- acid amide. { 3- [4- (2-hydroxymethyl-p.peridin-1-yl) -butyl] -ureido} isothiazole-4-carboxylic acid; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- (3- {4- [ethyl- (2-hydroxy-ethyl) -amino] -butyl} -ureido} -amide -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- (3- {4- [ethyl- (2-hydroxy-ethyl) -amino] -butyl} -ureido} -amide -isothiazole-4-carboxylic acid; 3- (2,3-Difluoro-4-methyl-benzyloxy) -5- (3- {4- [ethyl- (2-hydroxy-ethyl) -amino] -butyl} -ureido} -amide -isothiazole-4-carboxylic acid; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [4- (2-methoxymethyl-pyrrolidol-1-yl) -butyl] -urethane} isothiazole-4-carboxylic acid; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [4- (2-hydroxymethyl-piperidin-1-yl) -butyl] -ureido} -isothiazole-4-carboxylic acid; 5- [3- (6-Dimethylamino-hexyl) -ureido] -3- (2,3,6-trifluoro-benzyloxy) -isothiazole-4-carboxylic acid amide; Amide of acid 5-. { 3- [3- (4-methyl-piperazin-1-yl) -propyl] -ureido} -3- (2,3,6-trifluoro-benzyloxy) -isothiazole-4-carboxylic acid; 3- (2,3-Difluoro-4-methyl-benzyloxy) -5- [3- (5-hydroxy-6-pyridin-1-yl-hexyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2-fluoro-benzyloxy) -5- [3- (5-hydroxy-6-piperidin-1-yl-hexyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Ethyl-2,3-difluoro-benzyloxy) -5- [3- (5-hydroxy-6-piperidin-1-H-hexyl) -uretinate] -saltazole- 4-carboxylic acid; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- [3- (5-hydroxy-6-p-peridin-1-yl-hexyl) -ureido] -isothiazole acid amide -4-carboxylic acid; 3- (4-Chloro-2-fluoro-benzyloxy) -5- [3- (5-hydroxy-6-morpholin-4-yl-hexyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2-fluoro-benzyloxy) -5- [3- (6-hydroxy-7-morfoin-4-yl-heptyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Cyano-2,6-difluoro-benzyloxy) -5- [3- (6-hydroxy-7-morpho-4-yl-heptyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- [3- (6-hydroxy-7-morpholin-4-yl-heptyl) -ureido] -isotirazole-4 acid amide -carboxylic; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- [3- (5-hydroxy-6-pyridin-1-yl-hexyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- [3- (6-hydroxy-7-piperidin-1-yl-heptyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- [3- (7-dimethylamino-6-hydroxy-heptyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- [3- (6-hydroxy-7-piperidin-1-yl-heptyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- [3- (7-dimethylamino-6-hydroxy-heptyl) -uretho] -isothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- [3- (5-hydroxy-6-isobutylamino-hexyl) -ureido] -sothiazole-4-carboxylic acid amide; 3- (4-Chloro-2,6-difiuoro-benzyloxy) -5- [3- (5-hydroxy-6-isobutylamino-hexyl) -ureido] -isot-azole-4-carboxylic acid amide; 3- (4-Bromo-2,3,6-trifluoro-benzyloxy) -5- acid amide. { 3- [3- (4-methyI-piperazin-1-yl) -propyl] -ureido} -isothiazole-4-carboxylic acid; 3- (4-Bromo-2,3,6-trifluoro-benzyloxy) -5- [3- (6-dimethylamino-hexyl) -ureido] -isothiazo I-4-carboxylic acid amide; 3- (2-Fluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [3- (4-methyl-piperazin-1-yl) -propyl] -ureido} -isothiazole-4-carboxylic acid; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [4- (2-hydroxymethyl-pyrrolidin-1-yl) -butyl] -ureido} -isothiazole-4-carboxylic acid; 3- (3-Chloro-2,6-difluoro-benzyloxy) -5- [3- (6-dimethylamino-hexyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (3-Chloro-2,6-difluoro-benzyloxy) -5- acid amide. { 3- [3- (4-methyl-piperazin-1-yl) -propyl] -ureido} -isothiazole-4-carboxylic acid; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [3- (4-methyl-piperazin-1-yl) -propy] -ureido} -isoxy-4-carboxylic acid; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- [3- (4-pyrroidin-1-yl-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- [3- (3-hydroxy-5-pyrolidin-1-yl-pentyl) -ureido] -saliazole acid amide -4-carboxylic acid; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- [3- (4-hydroxy-5-piperidin-1-yl-pentyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- [3- (4-piperidin-1-yl-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- [3- (3-hydroxy-5-pyrroidin-1-yl-pentyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [4- (3-hydroxy-pyrrolidin-1-yl) -butyl] -ureido} -isothiazole-4-carboxylic acid; 5- [3- (4-Pyrrolidin-1-yl-butyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; Amide of acid 5-. { 3- [3- (4-methyl-piperazin-1-yl) -propyl] -ureido} -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid; 5- [3- (3-Hydroxy-5-pyrrolidin-1-yl-pentyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [3- (4-methyl-p-piperazin-1-yl) -propl] -uret} -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,5-difluoro-benzyloxy) -5- acid amide. { 3- [4- (2-hydroxymethyl-pyrrolidin-1-yl) -butyl] -ureido} -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,5-difluoro-benzyloxy) -5- (3- {4- [ethyl- (2-hydroxy-ethyl) -amino] -butyl} -ureido} -amide -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,5-difluoro-benzyloxy) -5- [3- (4-hydroxy-5-piperidin-1-yl-pentyl) -ureido] -isothiazoi-4- acid amide carboxylic; 3- (4-Chloro-2,5-difluoro-benzyloxy) -5- acid amide. { 3- [4- (3-hydroxy-piperidin-1-yl) -butyl] -uredode} -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- [3- (3-pyrroidin-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- acid amide. { 3- [2- (1-methyl-pyrrolidin-2-yl) -ethyl] -uredode} -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- acid amide. { 3- [4- (2-Hydroxymethyl-p-peridin-1-yl) -butyl] -uredode} - sodium-4-carboxylic acid; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [3- (5-methyl-2,5-diaza-bicyclo [2.2.1] hept-2-yl) -propyl] -ureido} -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- acid amide. { 3- [3- (5-methyl-2,5-diaza-bicyclo [2.2.1] hept-2-yl) -propyl] -ureido} - sodium-4-carboxylic acid; 3- (4-Chloro-2,5-difluoro-benzyloxy) -5- acid amide. { 3- [4- (2-hydroxymethyl-piperidin-1-yl) -butyl] -ureido} -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- [3-ethyl-3- (4-pyrrolidin-1-yl-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- [3-ethyl-3- (4-pyrrolidin-1-yl-butyl) -ureido] -siathiazole- 4-carboxylic; 3- (4-Chloro-2,3,6-trifluoro-benzyloxy) -5- acid amide. { 3- [3- (5-methyI-2,5-diaza-bicyclo [2.2.1] hept-2-yl) -propl] -ureido} -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,3,6-trifluoro-benzyloxy) -5- acid amide. { 3- [2- (1-methyI-pyrrolidin-2-yl) -ethyl] -ureido} -sothiazo I-4-carboxylic acid; 3- (4-Chloro-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- (2-hydroxymethyl-pyrrolidin-1-yl) -butyl] -ureido acid amide. -sothiazole-4-carboxylic acid; 3- (4-Chloro-2,3,6-trifluoro-benzyloxy) -5- acid amide. { 3- [3- (4-methyI-piperazin-1-yl) -propyl] -ureido} -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,3,6-trifluoro-benzyloxy) -5- (3- {4- [ethyl- (2-hydroxy-ethyl) -amino] -butyl} - acid. ureido) -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- acid amide. { 3-Ethyl-3- [3- (4-methyl-piperazin-1-yl) -propyl] -ureido} -isothiazole-4-carboxylic acid; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3-Ethyl-3- [3- (4-methyl-piperazin-1-yl) -propyl] -ureido} -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- [3-ethyl- (4-piperidin-1-yl-butyl) -ureido] -sothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- [3-ethyl-3- (4-piperidin-1-yl-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 5- (3-Methyl-ureido) -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- (3-Ethyl-ureido) -3- (2I3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- (3-Cyclopropylmethyl-ureido) -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazo I-4-carboxylic acid amide; 5- (3-Cyclobutyl-ureido) -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- (3-Allyl-ureido) -3- (2,3,6-trifiuoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; - (3-Butyl-ureido) -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (3-Hydroxy-propyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; Amide of acid 5-. { 3- [2- (1-methyl-pyrrolidin-2-yl) -ethyl] -ureido} -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid; 5- [3- (2-Dimethylamino-ethyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (4-Dimethylamino-butyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (7-Dimethylamino-6-hydroxy-heptyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; Amide of acid 5-. { 3- [4- (5-methyl-2,5-diaza-bicyclo [2.2.1] hept-2-yl) -butyl] -ureido} -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid; 5- [3- (3-Dimethylamino-propyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (3-Hydroxy-5-isopropylamino-pentyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -sothiazole-4-carboxylic acid amide; 5- [3- (3-isopropylamino-propyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; Amide of acid 5-. { 3- [3- (4-methyl-piperazin-1-yl) -propyl] -ureido} -3- (2,3,6-Tr? Fluoro-4-methylbenzyloxy) -isotriazole-4-carboxylic acid; Amide of acid 5-. { 3- [4- (4-Methyl-piperazin-1-yl) -butyl] -ureido} -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid; Amide of acid 5-. { 3- [5- (4-methyl-piperazin-1-yl) -pentyl] -ureido} -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid; Amide of acid 5-. { 3- [6- (4-methyl-piperazin-1-yl) -hexyl] -ureido} -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid; Amide of acid 5-. { 3- [3-hydroxy-5- (4-methyl-p-piperazin-1-yl) -pentyl] -ureido} -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid; 5- (3. {4- [4- (2-Hydroxy-ethyl) -piperazin-1-yl] -butyl} -ureido) -3- (2,3,6-) acid amide trifluoro-4-methylbenzyloxy) -isothiazole-4-carboxylic acid; 5- (3 { 4- [4- (3-Hydroxy-propyl) -piperazin-1-yl] -butyl] -idene acid) -3- (2,3-Amide) , 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid; 5- [3- (3-Pyrrolidin-1-yl-propyl) -ureido] -3- (2,3,6-trifuoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (3-Hydroxy-5-pyrrolidin-1-yl-pentyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isoti acid amide azole-4-carboxylic acid; 3- (4-Chloro-2,6-difiuoro-benzyloxy) -5- [3-methyl-3- (4-piperidin-1-yl-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- [3-methyl-3- (4-piperidin-1-yl-butyl) -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; - [3- (4-Hydroxy-5-piperidin-1-yl-pentyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isot azole-4-carboxylic acid; 5- [3- (5-Hydroxy-6-piperidin-1-yl-hexyl) -urethane] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole acid amide -4-carboxylic acid; 5- [3- (5-Hydroxy-7-piperidin-1-yl-heptyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [3- (4-methyl-piperazin-1-yl) -propl] -ureido} -isothiazole-4-carboxylic acid; 3- (2,6-D-Fluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [3- (4-methyl-piperazin-1-yl) -propyl] -ureido} -isothiazole-4-carboxylic acid; 3- [3- (4-Hydroxy-5-morpholin-4-yl-pentyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole- acid amide 4-carboxylic; 5- [3- (5-Hydroxy-6-morpholin-4-yl-hexyl) -urethane] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole acid amide -4-carboxylic acid; 5- [3- (5-Hydroxy-7-morpholin-4-yl-heptyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -salicylic acid amide azole-4-carboxylic acid; 5- [3- (2-Morpholin-4-yl-ethyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (4-Morpholin-4-yl-butyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- (3. {3- [bis- (2-hydroxy-ethyl) -amino] -propyl] -idene) -3- (2,3,6-trifluoro-4-methyl) acid amide 1-benzyloxy) -sothiazole-4-carboxylic acid; - (3. {4- [bis- (2-hydroxy-ethyl) -amino] -butyl} -ureido) -3- (2,3,6-trifluoro-4-methyl- acid) amide benzyloxy) -isothiazole-4-carboxylic acid; 5- (3. {4- [Ethyl- (2-hydroxy-ethyl) -amino] -butyl} -ureido) -3- (2> 3,6-trifluoro-4-methyl) acid amide -benzyloxy) -isothiazole-4-carboxylic acid; 5- [3- (3-tert-Butylamino-propyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -sothiazole-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- acid amide. { 3- [4- (3-hydroxy-pyrrolidin-1-yl) -butyl] -ureido} -isothiazole-4-carboxylic acid; 3- (2,5-Difluoro-methyl-benzyloxy) -5- [3- (4-imidazol-1-yl-b-yl) -amido] -isothiazole-4-carboxylic acid amide; Amide of acid 5-. { 3- [4- (2-methoxymethyl-pyrrolidin-1-yl) -butyl] -ureido] -3- (2) 3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- acid amide. { 3-Methyl-3- [3- (4-methyl-piperazin-1-yl-propyl] -ureido} -. Isothiazole-4-carboxylic acid amide of 5-. {3- [4- ( 3-hydroxy-pyrrolidin-1-yl) -butyl] -ureido.} - 3 - (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid; , 5-difluoro-4-methyl-benzyloxy) -5-. {3-methyl-3- [3- (4-methyl-piperazin-1-yl) -prop-H-ureido. Sodiazo-4-carboxylic acid: 5-. {3- [4- (3,4-Dihydroxy-pyrrolidin-1-yl) -butyl] -ureido acid} -3- (2,3,6) -trifiuoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid; Amide of acid 5-. { 3- [4- (2-hydroxymethyl-pyrrolidin-1-yl) -butyl] -ureido} -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid; Amide of acid 5-. { 3- [4- (3-hydroxy-p -peridin-1-yl) -butyl] -ureido} -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid; Amide of acid 5-. { 3- [4- (2-hydroxymethyl-piperidn-1-yl) -butyl] -ureido} -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid; 5- [3- (3-Cyclohexylamino-propyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- (3. {4- [bis- (2-hydroxy-propyl) -amino] -butyl} -uretho] -3- (2,3,6-trifluoro-4-) acid amide methyl-benzyloxy) -isothiazole-4-carboxylic acid; 5-. {3- [3- (5-methyl-2,5-diaza-bicicon [2.2.1] hept-2-yl) -propyl] -ureido.}. -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide of 5- [3- (3-imidazol-1-yl-propyl) - ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide of 3- (4-chloro-2,3,6-trifluoro-benzyloxy) - 5- { 3- [4- (2-hydroxymethyl-p.peridin-1-yl) -butyl] -ureido}. -isothiazole-4-carboxylic acid amide of 3- (4-cyoro-2, 3,6-trifluoro-benzyloxy) -5- [3- (3-hydroxy-5-pyrrolidin-1-yl-pentyl) -uredo] -sothiazole-4-carboxylic acid amide 3- (4-Chloro-2,3,6-trifluoro-benzyloxy) -5- { 3- [4- (3-hydroxy-piperidin-1-ii) -butyl] -ureido.} - isothiazole- 4-carboxylic acid 3- (4-chloro-2,3,6-trifluoro-benzyloxy) -5- [3- (4-hydroxy-5-piperidin-1-yl-pentyl) -ureido] - amide isothiazole-4-carboxylic acid; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- (3-methyl-ureido) -isothiazole-4-carboxylic acid amide; 5- (3-Cyclopropylmethyl-ureido) -3- (2,6-difluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- (3-Cyclobutyl-uredo) -3- (2,6-difluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- [3- (3-hydroxy-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 5- (3-Allyl-ureido) -3- (2,6-difluoro-4-methyl-benzyloxy) -isothiazo I-4-carboxylic acid amide; 3- (2,6-D-Fluoro-4-methyl-benzyloxy) -5- (3-isobutyl-ureido) -isothiazole-4-carboxylic acid amide; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [2- (1-methyl-pyrroidin-2-yl) -etl] -ureido} -isothiazole-4-carboxylic acid; 3- (2,6-Difluoro-4-methyl) -benzylsi) -5- [3- (2-dimethylamino-ethyl) -uredo] -isothiazole-4-carboxylic acid amide; 3- (2,6-Difluoro-4-methyl-benzyl) oxy] -5- [3- (4-dimethylamino-butyl) -ureido] -sothiazole-4-carboxylic acid amide; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- [3- (7-dimethyl-6-hydroxy-heptyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [4- (5-methyl-2,5-diaza-bicicon [2.2.1] hept-2-yl-butyl] -ureido.} - isothiazole-4-carboxylic acid; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- [3- (3-dimethylamino-propyl) -uretho] -isothiazole-4-carboxylic acid amide; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- [3- (3-hydroxy-5-isopropylamino-pentyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- [3- (3-isopropylamino-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [4- (4-methyl-piperazin-1-yl) -butyryl-ureido} -isothiazole-4-carboxylic acid; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [5- (4-methyl-piperazin-1-yl) -pentyl] -ureido} -isothiazole-4-carboxylic acid; 3- (2,6-Difluoro-4-methyl-benzyl) -5- acid amide. { 3- [6- (4-Methy1-piperazin-1-yl) -hexyl] -ureido} -isothiazole-4-carboxylic acid; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [3-hydroxy-5- (4-methyl-piperazin-1-yl) -pentyl] -ureido} - sodium-4-carboxylic acid; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- (3. {4- [4- (3-hydroxy-propyl) -piperazin-1-yl) -butyl acid amide } -ureido] -isothiazole-4-carboxylic acid; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- [3- (3-pyrrolidin-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2,2,6-trifluoro-benzyloxy) -5- acid amide. { 3- [4- (3,4-dihydroxy-pyrrolidin-1-yl) -butyl] -ureido} -isothiazole-4-carboxylic acid; Amide of acid 5-. { 3- [4- (4-acetyl-piperazin-1-yl) -butyl] -ureido} -3- (4-chloro-2,6-difluoro-benzyloxy) -isothiazole-4-carboxylic acid; Amide of acid 5-. { 3- [4- (4-acetyl-piperazin-1-yl) -butyl] -ureido} -3- (2,5-difluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid; 3- [2,5-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [4- (3-hydroxy-piperidin-1-yl) -butyl] -3-methyl-ureido} isothiazole-4-carboxylic acid; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- (3. {4- (ethyl- (2-hydroxy-ethyl) -amino] -butyl} -3- acid amide. methyl-ureido) -isothiazole-4-carboxylic acid; 3- (2,3,6-trifluoro-4-methyl-benzyloxy) -5-ureido-isothiazole-4-carboxylic acid amide; bromo-2,6-difluoro-benzyloxy) -5-. {3- [3- (4-methyl-piperazin-1-yl) -propyl] -ureido} -. isothiazole-4-carboxylic acid amide 3- (4-bromo-2,3,6-trifluoro-benzyloxy) -5- [3- (4-pyrrolein-1-yl-butyl) -ureido] -sothiazole-4-carboxylic acid amide 3- (2,5-dichloro-4-methyl-benzyloxy) ~ 5- (3. {4- [ethyl- (2-hydroxy-ethyl] -amino] -butyl}. -3-methyl-ureido) -sothiazole-4-carboxylic acid: 3- (2,6-difluoro-4-methyl-benzyloxy) -5- [3- (3-hydroxy-5-pyrrolidin-1- il-pentyl) -ureido] -isothiazole-4-carboxylic acid; 3- (2,6-d-fluoro-4-methyl-benzyloxy) -5- [3- (4-hydroxy-5-acid -p? peridin-1-yl-pentyl) -ureido] -isothiazole-4-carboxylic acid; 3- (2,6-difiuoro-4-methyl-benzyloxy) -5- [3- (5-hydroxy) acid amide; 6-piperidin-1 -il-he xi I) -ureido] -isothiazole-4-carboxylic acid; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- [3- (6-hydroxy-7-piperidin-1-yl-heptyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- [3- (4-hydroxy-5-morpholin-4-yl-pentyl) -ureido] -isothiazole-4-acid amide carboxylic; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- [3- (5-hydroxy-6-morfoin-4-yl-hexyl) -ureido] -isotrazole-4-carboxylic acid amide; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- [3- (6-hydroxy-7-morpholin-4-yl-heptyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- [3- (4-morpholin-4-yl-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 5- (3. {4- [bis- (2-hydroxy-ethyl) -amino] -butyl} -ureido) -3- (2,6-difluoro-4-methyl-benzyloxy) acid amide ) -isothiazole-4-carboxylic acid; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- (3. {4- [ethyl- (2-hydroxy-ethyl) -amino] -butyl} -ure do) -isothiazole-4-carboxylic acid; 3- [3- (3-tert-Butylamino-propyl) -ureido] -3- (2,6-difluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [4- (2-methoxymethyl-pyrrolidin-1-yl) -butyl] -ureido} -sothiazole-4-carboxylic acid; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [4- (3-Hydroxy-pyrrolidin-1-yl) -butyl] -ureido} -isothiazole-4-carboxylic acid; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [4- (3,4-dihydroxy-pyrrolidn-1-yl) -butyl] -ureido] -isothiazole-4-carboxylic acid; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [4- (2-hydroxymethyl-pyrrolidin-1-yl) -butyl] -uredo} -zoxy-4-carboxylic acid; Amide of 5-Í3- (4-imidazol-1-yl-butyl) -uredo] -3- (2,3,6-trifuoro-4-methyl-benzyloxy) -isothiazoi-4-carboxylic acid; 3- (4-Chloro-2,3,6-trifluoro-benzyloxy) -5- acid amide. { 3- [4- (3,4-Dihydroxy-pyrrolidin-1-yl) -butyl] -ureido} -isothiazole-4-carboxylic acid; 3- (4-Chloro-2) -3,6-trifluoro-benzyloxy) -5- [3- (4-imidazol-1-yl-butyl) -ureido] -sothiazole-4-carboxylic acid amide; 3- (4-Chloro-2,3,6-trifluoro-benzyloxy) -5- acid amide. { 3- [5- (4-Methy-piperazin-1-yl) -pentyl] -ureido} isothiazole-4-carboxylic acid; 3- (4-Chloro-2,3,6-trifluoro-benzyloxy) -5- acid amide. { 3- [3-hydroxy-5- (4-methyl-1-yl) -pentyl] -ureido} -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,3,6-trifluoro-benzyloxy) -5- (3. {4- [4- (2-hydroxy-ethyl) -piperazin-1-yl) -butyl acid amide } -ureido) -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,3,6-trifluoro-benzyloxy) -5- acid amide. { 3- (4- (5-methyl-2,5-diaza-bicyclo [2.2.1] hept-2-yl) -butyl] -ureido}. -isothiazole-4-carboxylic acid; , 6-difluoro-4-methyl-benzyloxy) -5- { 3- [4- (3-Hydroxy-piperidin-1-yl) -butyl] -ureido} -. Isothiazole-4-carboxylic acid; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5-. {3- [4- (2-hydroxymethyl-p-pyridin-1-yl) -butyl] -ureido acid amide. β-α-4-carboxylic acid 5- [3- (3-cyclohexylamino-propyl) -urethane] -3- (2,6-difluoro-4-methyl-benzyloxy) -isothiazole acid amide -4-carboxylic acid; 3- (2,6-difluoro-4-methyl-benzyloxy) -5-. {3- [3- (5-methyl-2,5-diaza-bicyclo [2.2.1} acid amide ] hept-2-yl) -propyl] -ureido.} - isothiazole-4-carboxylic acid; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5-ureido-isothiazole-4-carboxylic acid amide; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- (3-ethyl-uredo) -isothiazo I-4-carboxylic acid amide; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- [3- (3-cyclopropylamino-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 5- [3- (3-Cyclopropylamino-propyl] -ureido] -3- (2,5-difluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (4-chloro) acid amide -2,6-difluoro-benzyloxy) -5- (3. {3- [ethyl- (2-hydroxy-ethyl) -amino] -propyl] -ureido) -isothiazole-4-carboxylic acid co-3- (2,5-difluoro-4-methyl-benzyloxy) -5- (3- {3 - (ethyl- (2-hydroxyethyl) -amino] -propyl} -amide. .-solid) -isothiazole-4-carboxylic acid; 3- (4-chloro-2,3,6-trifluoro-benzyloxy) -5- (3-. {3- [4- (2- hydroxy-ethyl) -piperazin-1-yl] -propyl.} -ureido) -sothiazole-4-carboxylic acid 3- (4-chloro-2,3,6-trifluoro-benzyloxy) - 5- [3- (3-hydroxy-5-isopropylamino-pentyl) -ureido) -isothiazole-4-carboxylic acid amide of 3- (4-chloro-2,6-difluoro-benzyloxy) -5- [3- (3-imidazoI-1-yl-propyl) -ureido] -isothiazoI-4-carboxylic acid amide of 3- (4-chloro-2,3,6-trifluoro-benzyloxy) -5- (3- { 3- [ethyl- (2-hydroxy-ethyl) -amino] -propyl.} -ureido) -isothiazole-4-carboxylic acid; 5- { 3- [2- (1-methyl-pyrrolidin- 2-yl) -ethyl] -ureido. -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid; -Í3- (4-dimethylamino-butyl-ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide: 5- [3- (3-dimethylamino-propyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide of 5- [3- (3-hydroxy-5- isopropylamino-pentyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide of 5- [3- (3-isopropylamino-propyl) -ureido] -3- (2,3,6-Trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide of 5-. {3- [4- (4-methyl-piperazin-1-yl) ) -butyl] -ureido.}. -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide of 5- (3-. {4- (4- (2-hydroxy-ethyl) -piperazin-1-yl] -butyl} -ure? Do) -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole -4-carboxylic acid 5- (3 { 4- [4- (3-hydroxy-propyl) -piperazin-1-yl] -butyl} -ureide) -3- (2,3-Amide) , 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid; 5- [3- (3-pyrrolidin-1-yl-propyl) -ureido] -3- (2,3, 6 -trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid; 5- [3- (4-Hydroxy-5-piperidin-1-yl) -pentyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole- acid amide 4-carboxylic; 5- (3-Ethyl-ureido) -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- (3-Methylene-ureido) -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; - (3. {4- [bis- (2-hydroxy-propyl) -amino] -butyl} -ureido) -3- (2,6-difluoro-4-methyl-benzyloxy) acid amide -isothiazole-4-carboxylic acid; Amide of acid 5-. { 3- [3- (4-acetyl-piperazin-1-yl) -propyl] -ureido} -3- (2,5-difluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid; Amide of acid 5-. { 3- [3- (4-acetyl-piperazin-1-yl) -propyl] -uredode} -3- (4-Chloro-2,3,6-trifluoro-benzyloxy) -isothiazole-4-carboxylic acid; 3- (1,3-d.fluoro-naphthalen-2-ylmethoxy) -5- (3. {4- [ethyl- (2-hydroxy-ethyl) -amino] -butyl} -amide. ureido) -isothiazole-4-carboxylic acid; Amide of acid 5-. { 3- [3- (4-acetyl-piperazin-1-yl) -propyl] -ureido} -3- (4-chloro-2,6-d-fluoro-benzyloxy) -isothiazole-4-carboxylic acid; Amide of acid 5-. { 3- [4- (4-acetyl-piperazin-1-yl) -butyl] -ureido} -3- (4-chloro-2,3,6-trifluoro-benzyloxy) -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,3,6-trifluoro-benzyloxy) -5- [3- (3-imidazol-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 5- [3- (2-Amino-ethyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (4-Amino-butyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (5-Amino-pentyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (6-Amino-hexyl) -uredo] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; - [3- (7-Amino-heptyl) ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (1,3-difluoro-naphthalen-2-ylmethoxy) -5- acid amide. { 3- [2- (1-methyI-pyrrolidin-2-yl) -ethyl] -ureido} -isothiazole-4-carboxylic acid; 3- (1,3-difluoro-naphthalen-2-ylmethoxy) -5- acid amide. { 3- [4- (2-hydroxymethyl-pyrrolidin-1-yl) -butyl] -uredode} -isothiazole-4-carboxylic acid; 3- (1,3-difluoro-naphthalen-2-ylmethoxy) -5- acid amide. { 3- [3- (5-methyI-2,5-diaza-bicyclo [2.2.1] hept-2-yl) -propyl] -ureido} isothiazole-4-carboxylic acid; 3- (1,3-difluoro-naphthalen-2-ylmethoxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (1,3-difluoro-naphthalen-2-ylmethoxy) -5- acid amide. { 3- [3- (4-Methy-piperazin-1-yl) -propyl] -ureido} -isothiazole-4-carboxylic acid; 5- (3. {4- [Ethyl- (2-hydroxy-ethyl) -amino] -butyl} -ureido) -3- (2,3,6-trifluoro-4-methyl- acid) amide benzyloxy) -isothiazo I-4-carboxylic acid; Amide of acid 5-. { 3- [4- (3-hydroxy-piperidin-1-yl) -butyl] -ureido} -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid; 5- [3- (3-tert-Butylamino-propyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; Amide of acid 5-. { 3- [4- (3-hydroxy-pyrrolidin-1-yl) -butyl] -ureido} -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -sothiazole-4-carboxylic acid; Amide of acid 5-. { 3- [4- (3,4-Dihydroxy-pyrrolidin-1-yl) -butyl] -urethane} -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid; Amide of acid 5-. { 3- [4- (2-hydroxymethyl-pyrrolidin-1-yl) -butyl] -uredode} -3- (2,3,6-Trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid; Amide of acid 5-. { 3- [4- (2-hydroxymethyl-p-peridin-1-yl) -butyl] -uredode} -3- (2,3,6-Trifluoro-4-methyl-benzyloxy) -sothiazole-4-carboxylic acid; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- (3-methyl-ureido) -isothiazole-4-carboxylic acid amide; 3- (2,6-DifIuoro-4-methyl-benzyloxy) -5- acid amide. { 3- [2- (1-methyl-pyrrolidin-2-yl) -ethyl] -ureido} -isothiazole-4-carboxylic acid; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- [3- [2-dimethylamino-ethyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- [3- (4-dimethylamino-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [4- (5-methyl-2,5-diaza-bicyclo [2.2.1] hept-2-yl) -butyl] -uredo} -isothiazole-4-carboxylic acid; Amide of 5- (3: 4- {bis- (2-hydroxy-etiI) -amino] -butyl} -ureido) -3- (2,3,6-trifluoro-4-methyl- benzyloxy) -isothiazole-4-carboxylic acid; Amide of acid 5-. { 3- [3- (5-methyl-2,5-diaza-bicyclo [2.2.1] hept-2-yl) -propyl] -ureido} -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isotriazole-4-carboxylic acid; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- [3- (3-dimethylamino-propyl) -ureido] -sothiazo I-4-carboxylic acid amide; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- [3- (3-hydroxy-5-isopropylamine-pentyl) -ureido] -isothiazole-4-carboxylic acid amide; - [3- (3-Cyclohexylamine-propyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- [3- (3-isopropylamino-propyl) -ureido] -isotrazole-4-carboxylic acid amide; 5- [3- (3-Amino-propyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; Amide of acid 5-. { 3- [2- (2-Amino-ethoxy) -ethyl] -ureido} -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid; 5- [3- (4-Pyrrolidin-1-yl-butyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; Amide of acid 5-. { 3- [3- (4-methyl-piperazin-1-yl) -propyl] -ureido} -3- (2,3,6-trifluoro-4-methyl-benzyl) -sothiazo I-4-carboxylic acid; 5- [3- (4-Amino-butyl) -ureido] -3- (4-chloro-2,6-difluoro-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (7-Amino-heptyl) -ureido] -3- (4-chloro-2,6-difiuoro-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (5-Amino-pentyl) -uredo] -3- (4-chloro-2,6-difluoro-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (4-Amino-butyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (3-azepan-1-yl-propyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -sothiazole-4-carboxylic acid amide; - [3- (3-Diethylamino-propyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazo I-4-carboxylic acid amide; 5- [3- (3-Methylamino-propyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; Amide of acid 5-. { 3- [3- (2-methyl-piperidin-1-yl) -propyl] -ureido} -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid; 3- (2,5-Difluoro-4-methyI-benzyloxy) -5- acid amide. { 3- [4- (pyridin-2-ylamino) -butyl] -ureido} -isothiazole-4-carboxylic acid; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [3- (pyridin-2-ylamino) -propyl] -ureido} -isothiazole-4-carboxylic acid; 5- [3- (6-Amino-hexyl) -ureido] -3- (4-chloro-2,6-difluoro-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- acid amide. { 3- [4- (pyridin-2-ylamino) -butyl] -ureido} -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,3,6-trifluoro-benzyloxy) -5- acid amide. { 3- [4- (pyridin-2-ylamino) -butyl] -urethane} -sothiazole-4-carboxylic acid; 3- (4-Chloro-2,3,6-trifluoro-benzyloxy) -5- acid amide. { 3- [3- (pyridin-2-ylamino) -propyl] -uredode} -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- acid amide. { 3- [3- (pyridin-2-ylamino) -propyl] -ureido} -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- [3- (4-cyclopropylamino-butyl) -ureido] -isothiazole-4-carboxylic acid amide; - [3- (3-Amino-propyl) -3-methyl-ureido] -3- (2,3,6-trifluoro-4-methyl-benzyl) -isothiazole-4-carboxylic acid amide; 3- (3-Chloro-2,6-difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [2- (1-methy1-pyrrolidin-2-yl) -ethyl] -ureido} isothiazole-4-carboxylic acid; 3- (3-Chloro-2,6-difluoro-4-methyl-benzyloxy) -5- [3- (3-dimethylamino-propyl) -ureido] -isothiazole-4-carboxylic acid amide; 3- (3-Chloro-2,6-difluoro-4-methyl-benzyloxy) -5- [3- (4-dimethylamino-butyl) -ureido] -isothiazole-4-carboxylic acid amide; 5- [3- (2-Amino-ethyl) -ureido] -3- (4-chloro-2,6-difluoro-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (2-Amino-ethyl) -ureido] -3- (2,5-difluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (7-Amino-heptyl) -ureido] -3- (2,5-difluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (3-Amino-propyl) -ureido] -3- (2,5-difluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [4- (pyridin-4-ylamino) -butiI] -ure} -sothiazole-4-carboxylic acid; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- acid amide. { 3- [4- (pyridin-4-ylamino) -butyl] -ureido} -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,3,6-trifluoro-benzyloxy) -5- acid amide. { 3- [4- (pyridin-4-ylamino) -butyl] -ureido} -isothiazole-4-carboxylic acid;

Claims (17)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A compound of formula 1: R or a pharmaceutically acceptable salt, prodrug or solvate thereof in which: wherein X1 is O or S; R1 is H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, -C (O) (C1-C10 alkyl), - (CH2) -C6-C10aryl), - (CH2) t (heterocycle of 4-10 links), -C (O) (CH2) t (aryl C6-C? 0), or -C (O) (CH2) (heterocycle of 5-10 links), where t is a whole number in the range of 0 to 5; said alkyl group optionally includes 1 or 2 heteroradicals selected from O, S and -N (R6) - with the proviso that two O atoms, two S atoms or one O and S atom are not directly linked to each other; said aryl and heterocyclic groups R1 are optionally fused with a C6-C6 aryl group, a C5-C8 saturated cyclic group, or a heterocyclic group of 5-10 links; 1 or 2 carbon atoms in the above cyclic heteroradicals are optionally substituted with an oxy radical (= 0); the radicals - (CH2) t- of the above groups R1 optionally include a double or triple carbon-carbon bond in which t is an integer from 2 to 5; and the above R1 groups, except H are optionally substituted with 1 to 3 R4 groups; R 2 is selected from the list of substituents provided in the definition of R 1, -SO 2 (CH 2) t (C 6 -C 0 aryl), -SO 2 (CH 2) t (5-10 membered heterocycle), and -OR 5, t is an integer in the range of 0 to 5, the radical (CH2) t- of the above groups R2 optionally include a double or triple carbon-carbon bond in which t is an integer from 2 to 5, and the above Groups R2 are optionally substituted with 1 to 3 R4 groups; or R1 and R2 can be combined with the nitrogen to which they are attached to form a monocyclic or polycyclic 4- to 10-membered saturated ring or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings optionally include 1 or 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 = wherein R and R2 are put together as heteroaryl group, said optionally saturated ring may be partially unsaturated including 1 or 2 double carbon-carbon bonds, and said saturated and heteroaryl rings, which include the group R6 of said -N (R6) - is optionally substituted with 1 to 3 R4 groups; R3 is H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, - (CH2) t (C6-C6 aryl), or - (CH2) t (5-10 membered heterocycle), that t is an integer between 0 and 5; said alkyl group optionally includes 1 or 2 heteroradicals selected from O, S and -N (R6) - with the proviso that two O atoms, two S atoms or one O and S atom, are not directly bound together the other; said aryl and heterocyclic groups R3 are optionally fused to a C 1 -C 10 aryl group, a Cs-Ce saturated cyclic group or a 5-10 membered heterocyclic group; 1 or 2 carbon atoms in the above cyclic heteroradicals are optionally substituted with an oxo radical (= 0); the radicals - (CH2) t of the above groups R3 optionally include a double or triple carbon-carbon bond in which t is an integer from 2 to 5, and the above R3 groups are optionally substituted with 1 to 5 R4 groups; each R 4 is independently selected from C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -OR 5, -C (O) R 5, -C (O) OR 5, -NR6C (O) OR5, -OC (O) R5, -NR6SO2R5, -SO2NR5R6, -NR6C (O) R5, -C (O) NR5R6, -NR5R6, -S (O) jR7 wherein j is a number whole in the range of 0 to 2, -SO3H, -NR5 (CR6R7) jOR6, - (CH2) t (C6-C10 aryl), -SO2 (CH2) t (C6-C? 0 aryl), -S (CH2) t (aryl C6-C? 0), -O (CH2) t (aryl C6-C? 0), - (CH2) t (heterocycle of 5-10 links), and - (CR6R7) mOR6, in wherein m is an integer in the range of 1 to 5 and t is an integer in the range of 0 to 5; said alkyl optionally contains 1 or 2 heterorradicals selected from O, S and -N (R6) - with the proviso that two O atoms, two S atoms or one O and S atom, are not directly attached one another; said aryl and heterocyclic groups R4 are optionally fused to a Ce-Cι aryl group, a C5-Cs saturated cyclic group or a 5-10-membered heterocyclic group; 1 or 2 carbon atoms in the above cyclic heteroradicals are optionally substituted with an oxo radical (= O); and the alkyl, aryl and heterocyclic radicals of the above R groups are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -NR6SO2R5, -SO2NR5R6, -C (O) R5, - C (O) OR 5, -OC (O) R 5, -NR 6 C (O) R 5, -C (O) NR 5 R 6, -NR 5 R 6, - (CR 6 R 7) m OR 6 where m is an integer from 1 to 5, -OR 5 and the substituents listed in the definition of R5; each R5 is independently selected from H, C1-C10 alkyl, - (CH2) t (aryl CT-CIO), and - (CH2) t (5-10 membered heterocycle), wherein t is an integer of 0 to 5; said alkyl group optionally includes 1 or 2 heteroradicals selected from O, S and -N (R6) - with the proviso that two O atoms, two S atoms or one O and S atom, are not directly bound together the other; said aryl and heterocyclic groups R5 are optionally fused to a Ce-Cι aryl group, a Cd-C8 saturated cyclic group or a 5-10-membered heterocyclic group; and the above R5 substituents, except H, are optionally substituted with 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) NR7R7, -NR6R7, hydroxy, C6 alkyl and d6C6 alkoxy; and, each R6 and R7 are independently H or C1-C6 alkyl 'with the proviso that said compound of formula 1 is not 1-methyl-3- (4-carbamoyl-3-ethoxy-5-beta-azoI) urea, 1,1-dimethyl-3- (4-carbamoyl-3-ethoxy-5-isothiazole) urea, 1-methyl-3- (4-carbamoyl-3-propoxy-5-isothiazole) urea, 1-methyl- 3- (4-carbamoyl-3- (methylthio) -5-? Sothiazole) urea, 1-methyl-3- (4-carbamoyl-3- (ethylthio) -5-isotipazole) urea, 1,1-dimethyl -3- (4-carbamoyl-3- (ethylthio) -5-isothiazole) urea, 1-methyl-3- (4-carbamoyl-3- (propylthio) -5-ylthiazole) urea, 1, 1-dimethyl-3- (4-carbamoyl-3- (propylthio) -5-isothiazole) urea or 1-methyl-3- (4-carbamoyl-3- (isopropylthio) -5-isothiazole) urea.
2. 2. The compound according to claim 1 wherein, R2 is H and R1 is C1-C10 alkyl optionally substituted with 1 or 2 substituents independently selected from -NR5R6, -NR5 (CR6R7) tOR6 and - (CH2) t (heterocycle of 5-10 links) where t is an integer from 0 to 5.
3. 3. The compound according to claim 2 wherein, R1 is selected from propyl, butyl, pentyl, and hexyl, and said R1 groups are optionally substituted with dimethylamino, hydroxy, pyrrolidinyl, morpholino, and etiI- (2- hydroxyethyl) amino.
4. 4. The compound according to claim 1 wherein, R2 is H and R1 is - (CH2) t (5-10 membered heterocycle), wherein t is an integer from 0 to 5; said heterocycle group is optionally condensed with a C6-C6 aryl group, a Cs-Cs saturated cyclic group or a 5-10 membered heterocyclic group; and said group R1 including the optionally condensed portions of said group R1, is optionally substituted with 1 or 2 substituents independently selected from C 1 -C 4 alkyl, hydroxy and hydroxymethyl.
5. 5. The compound according to claim 1 wherein, the heterocyclic radical of said group R1 is selected from morpholino, pyrrolidinyl, imidazolyl, piperazinyl, piperidinyl, and 2,5-diazabicyclo [2.2.1] hept- 2- ilo, the variable t of said group R1 is in the range of 2 to 5, and said group R is optionally substituted with hydroxy, hydroxymethyl and methyl.
6. 6. The compound according to claim 1 wherein, R3 is - (CH2) t (C6-C6 aryl) wherein t is an integer from 1 to 3 and said group R3 is optionally substituted with 1 to 4 groups R4.
7. 7. The compound according to claim 6 wherein R3 is benzyl optionally substituted by 1 to 4 substituents independently selected from halo and C -C alkyl.
8. 8. The compound according to claim 7 wherein R3 is benzyl substituted by 1 to 4 substituents independently selected from methyl, fluorine, chlorine and bromine.
9. 9. The compound according to claim 1 selected from the group consisting of: mesylate salt of the acid amide of 3- (4-bromo-2,6-difluoro-benzyloxy) -5- [3- (4-pyrrolidine -1-yl-butyl) -ureido} -isothiazole-4-carboxylic acid; 5. (acid amide. 3- [3- (4-methyl-piperazin-1-yl) -propyl] ureido} -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid; 3- (4-chloro-2,6-difluoro-benzyloxy) -5- [3-. { 4- [ethyl- (2-hydroxy-ethyl) -amino] -butyl) -urethane} -isothiazole-4-carboxylic acid; 3- (2-Fluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [3- (4-methyl-piperazin-1-yl) -propl] -ureido} -isothiazole-4-carboxylic acid; 3- (2,5-difluoro-4-methylene-benzyloxy) -5- (3-4- [4- (2-hydroxy-ethyl) -piperazin-1-yl] acid amide -butyl) -ureido.} - isothiazoI-4-carboxylic acid 3- (2,5-difluoro-4-methyl-benzyloxy) -5- [3- (6-dimethylamine-hexyl) amide -ureido] -isothiazole-4-carboxylic acid 3- (2-fluoro-4-methyl-benzyloxy) -5- [3- (5-isopropylamino-pentyl) -uredo] -saltazole- 4- carboxylic acid 3- (4-bromo-2,6-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido acid amide hydrochloride salt. 4-carboxylic acid amide of 3- (4-chloro-2,6-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido.] Isothiazole- 4-carboxylic acid 3- (4-chloro-2,6-difluoro-benzyloxy) -5-. {3- [3- (4-methyl-piperazin-1-yl) -propyl ester) ] -solid.} -sothiazole-4-carboxylic acid 3- (4-cyclo-2,6-difluoro-benzyloxy) -5- { 3 - [- (1-methyl-pyrrolidine -2-yl) -ethyl] -ureido.} - isothiazole-4-carboxylic acid amide of 3- (2,6-difluoro-4-methyl-benzyloxy) -5- [3- (4- pyrrolidin-1-yl-butyl ) - solid.} isothiazole-4-carboxylic acid; 3- (2,6-d.fluoro-4-methyl-benzyloxy) -5- [3-. { 4- [4- (2-hydroxy-ethyl) -piperazin-1-yl] butyl} -ureido} isothiazole-4-carboxylic acid; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- [3- (3-hydroxy-5-pyrrolidin-1-yl) -pentyl] -ureido acid amide} -sothiazole-4-carboxylic acid; 3- (2,5-difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [4- (3,4-Dihydroxy-pyrrolidin-1-yl] -butyl] -urethane} -isothiazole-4-carboxylic acid amide of 3- (4-chloro-2,6-d) Fluoro-benzyloxy) -5-. {3- [4- (3,4-dihydroxy-pyrrolidin-1-yl) -butyl] -ureido} -. Isothiazole-4-carboxylic acid amide; 2,5-difluoro-4-methyl-benzyloxy) -5-. {3- [4- (2-Hydroxymethyl-pyrrolidin-1-yl) -butyl] -ureido} -isothiazole-4-carboxylic acid 3- (4-Chloro-2,6-difluoro-benzyloxy) -5-. {3- [4- (2-hydroxymethyl-pyrrolidin-1-yl) -butyl] -ureido} -amide. Sothiazole-4-carboxylic acid; 3- (2,5-difluoro-4-methy-benzyloxy) -5- acid amide. { 3- [4- (3-hydroxymethyl-pyrrolidin-1-yl) -butyl] -ureido} -isothiazole-4-carboxylic acid; 3- (4-Bromo-2,6-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl) -butyl] -ureido acid amide} -isothiazole-4-carboxylic acid; 3- (2,6-Difluoro-4-methyl-benzyloxy) -5- [3- (4-hydroxy-5-piperidin-1-yl-pentyl) -ureido acid amide} isothiazole-4-carboxylic acid; 3- (2,5-difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [4- (3-hydroxy-5-piperidin-1-yl-pentyl) -ureido} Sothiazole-4-carboxylic acid; 3- (4-chloro-2 > 6-difiuoro-benzyloxy) -5- acid amide. { 3- [4- (2-hydroxymethyl-piperidin-1-yl) -butyl] -ureido} -isothiazole-4-carboxylic acid; 3- (2,5-Difluoro-4-methyl-benzyloxy) -5- (3- {4- [ethyl- (2-hydroxyethyl) -amino] -butyl} -ureido) -isothiazole acid amide -4-carboxylic acid; 3- (4-Chloro-2,6-difluoro-benzyloxy) -5- [3- (5-hydroxy-6-piperidin-1-yl) -hexyl) -ureido acid amide} -isothiazole-4-carboxylic acid; 3- (4-bromo-2,3,6-trifluoro-benzyloxy) -5- acid amide. { 3- [3- (4-methyl-piperazin-1-yl) -propyl] -ureido} -isothiazo I-4-carboxylic acid; 3- (2,6-difluoro-benzyloxy) -5- acid amide. { 3- [3- (4-methyl-piperazin-1-yl) -propyl] -ureido} -isothiazole-4-carboxylic acid; 3- (2,6-D-Fluoro-4-methyl-benzyl) -5- [3- (3-hydroxy-5-pyrrolidin-1-yl-pentyl) -ureido acid amide ] -isothiazo I-4-carboxylic acid; 5- [3- (4-pyrrolidin-1-yl-butyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isotrazole-4-carboxylic acid amide; 5- [3- (3-Hydroxy-5-pyrrolidin-1-yl-pentyl) -uretinate] -3- (2,3,6-trifluoro-4-methyl- benzyloxy) -isothiazo I-4-carboxylic acid; 3- (4-chloro-2,6-difluoro-benzyloxy) -5- acid amide. { 3- [3- (5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl) -propyl] -ureido} -isothiazole-4-carboxylic acid; 3- (4-chloro-2,3,6-trifluoro-benzyloxy) -5- acid amide. { 3- [3- (5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl) -propyl] -ureido} -isothiazole-4-carboxylic acid; 3- (4-chloro-2,3,6-trifluoro-benzyloxy) -5- acid amide. { 3- [2- (1-methyl-pyrrolidin-2-yl) ethyl] -urethane} -sothiazole-4-carboxylic acid; 3- (4-Chloro-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- acid amide. { 3- [4- (2-hydroxymethyl-1-pyrrolidin-1-yl) -butyl] -ureido} isothiazole-4-carboxylic acid; 5- acid amide. { 3- [2- (1-methyl-pyrrolidin-2-yl) -etiI] ureido} -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid; 5- [3- (4-dimethylamino-butyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (3-dimethylamino-propyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -sothiazole-4-carboxylic acid amide; 5- [3- (3-hydroxy-5-isopropylamino-pentyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (3-isopropylamino-propyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- acid amide. { 3- [4- (4-methyl-piperazin-1-yl) -butyl] ureido} -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid; 5- (3 { 4- [4- (2-Hydroxy-ethyl) -p [perazin-1-yl] -butyl} -ideido} -3- (2,3, 6-Trifluoro-4-methyl-benz [oxy] -isothiazole-4-carboxylic acid 5- [3- (3-pyrrolidin-1-yl-propyl) -ureido] -3- (2,3-amide) , 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid 5- [3- (4-hydroxy-5-piperidin-1-yl-pentyl) -ureido] -3- (2, 3,6-Trifluoro-4-methyl-benzyloxy) -isot-azoI-4-carboxylic acid amide of 3- (4-chloro-2,6-difluoro-benzyloxy) -5- [3- (4-methyl) -1-yl-butyl) -ureido] -isot-azole-4-carboxylic acid amide of 5- (3. {4- [ethyl- (2-hydroxy-etiI) -amino] - butyl) -cyclodo-3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazo I-4-carboxylic acid amide of 3- (4-chloro- (2> 3,6-trifluoro) -benzyloxy) -5- { 3- [4- (2-Hydroxymethyl-piperidin-1-yl) -butyl] -ureido} -isothiazoi-4-carboxylic acid amide; (4-chloro- (2,3,6-trifluoro-benzyloxy) -5- [3- (3-hydroxy-5-pyrrolidin-1-yl-pentyl) -ureido] -isothiazole-4-carboxylic acid 3- (4-bromo-2,6-difluoro-benzyl) amide oxy) -5- { 3- [3- (4-methyl-piperazin-1-yl) -propyl] ureido} -isothiazole-4-carboxylic acid; 3- (2,6-difluoro-4-methyl-benzyloxy) -5- acid amide. { 3- [2- (1-methyl-pyrrolidin-2-yl) -eti0-ureido} -isothiazole-4-carboxylic acid; 3- (2,6-difluoro-4-methyl-benzyloxy) -5- [3- (4-dimethylamino-butyl) -ureido acid amide} -isothiazole-4-carboxylic acid; 3- (2,6-difluoro-4-methyl-benzyloxy) -5- [3- (3-dimethylamino-propyl) -ureido] -isothiazo I-4-carboxylic acid amide; 3- (4-Bromo-2,3,6-trifluoro-benzyloxy) -5- [3- (4-pyrrolidol-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; 3- (4-Chloro-2,3,6-difluoro-benzyloxy) -5- (3. {3- [ethyl- (2-hydroxy-ethyl) -amino] -propyl] -amide. .-solid) -isothiazole-4-carboxylic acid; 3- (4-Chloro-2,3,6-trifluoro-benzyloxy) -5- (3. {3- [ethyl- (2-hydroxy-ethyl) -amino] - amide propyl) -ureido) -isothiazoi-4-carboxylic acid; 5- [3- (3-methylamino-propyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (3-Aminopropyl) -uredo] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 5- [3- (4-Dethoxy-butyl) -ureido] -3- (2,3,6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide; 3- (2,6-difluoro-4-methyl-benzyloxy) -5- [3- (3-pyrrolidin-1-yl-propyl) -ureido] -isothiazole-4-carboxylic acid amide; amide 3- (3-chloro-2,6-difluoro-4-methyl-benzyloxy) -5- [3- (4-dimethylamino-butyl) -ureido] -isothiazole-4-carboxylic acid; 5- (3. {4- [bis- (2-hydroxy-ethyl) -amino] -butyl} -idene) -3- (2,6-d-fluoro-4-) acid amide methyl-benzyloxy) -sothiazole-4-carboxylic acid; and pharmaceutically acceptable salts, prodrugs and solvates of said compounds.
10. 10. A pharmaceutical composition for the treatment of a hyperproliferative disorder in a mammal, comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.
11. 11. The pharmaceutical composition of claim 10 wherein said hyperproliferative disorder is a cancer selected from cancer of the brain, lung, squamous cell, bladder, gastric, pancreatic, breast, head, neck, kidney, kidney, ovaries, colorectal prostate, esophageal, gynecological and thyroid.
12. 12. The pharmaceutical composition of claim 10 wherein said disorder is a non-cancerous hyperproliferative disorder.
13. 13. The pharmaceutical composition of claim 12 wherein said disorder is a benign hyperplasia of the skin or prostate.
14. 14. The use of a compound as claimed in claim 1 for the manufacture of a medicament for treating a hyperproliferative disorder in a mammal.
15. 15. The use as claimed in claim 14, wherein said use is for the treatment of a cancer selected from brain cancer., squamous cells, bladder, gastric, pancreatic, breast, head, neck, esophageal, prostate, colorectal, lung, renal, kidney, ovarian, gynecological and thyroid.
16. 16. The use as claimed in claim 14 in which said use is for the treatment of a non-cancerous hyperproliferative disorder.
17. 17. Use as claimed in claim 16 wherein said use is for the treatment of benign skin or prostate hyperplasia. 18. - The use of a compound as claimed in claim 1 in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors , enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, NK1 receptor antagonists, 5-HT3 receptor antagonists, COX-2 inhibitors, EGFR inhibitors and anti-androgen inhibitors for the manufacture of a medicament for the treatment of a hyperproliferative disorder in a mammal. 19. A compound selected from the group consisting of (2,6-difluoro-4-methyl-phenyl) -methanol, (2,3,6-trifluoro-4-methyl-phenyl) -methanol, (4-bromo- 2,6-difluoro-phenyl) -methanol, (4-bromo-2,3,6-trifluoro-phenyl) -methanol, (4-chloro-2,6-difluoro-phenyl) -methanol, (3-chloro- 2,6-difluoro-phenyl) -methanol and (4-chloro-2,3,6-trifluoro-phenyl) -methanol. 20.- A compound selected from the group consisting of: 21. - A compound selected from the group consisting of: wherein R3 is H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, - (CH2) t (C6-C aryl), or - (CH2) t (5-10 membered heterocycle), where t is an integer between 0 and 5; said alkyl group optionally includes 1 or 2 heteroradioles selected from O, S and -N (R6) - with the proviso that two O atoms, two S atoms or one O and S atom, are not directly linked each other; said aryl and heterocyclic groups R3 are optionally condensed to an aryl group Ce-C or a saturated cyclic group C5-C8 or a heterocyclic group of 5-10 links; 1 or 2 carbon atoms in the above cyclic heteroradicals are optionally substituted with an oxo radical (= O); the radicals - (CH2) t of the above groups R3 optionally include a double or triple carbon-carbon bond in which t is an integer from 2 to 5, and the above R3 groups are optionally substituted with 1 to 5 R4 groups; each R4 is independently selected from C -C0 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, -NR6S02R5, -SO2NR5R6, -NR6C (O) R5, -C (0) NR5R6, -NR5R6, -S (O) jR7 wherein j is a number whole in the range of 0 to 2, -SO3H, NR5 (CR6R7) tOR6, - (CH2) t (C6-C6aryl aryl), -SO2 (CH2) t (C6-C10 aryl), -S (CH2) t (aryl Ce-Cι), -0 (CH 2) t (aryl C6-C? o), - (CH2) t (heterocycle of 5-10 links), and - (CR6R7) mORd, where m is a integer in the range of 1 to 5 and t is an integer in the range of 0 to 5; said alkyl group optionally contains 1 or 2 heteroradicals selected from O, S and -N (R6) - with the proviso that two O atoms, two S atoms or one O and S atom, are not directly bound together. the other; said aryl and heterocyclic groups R4 are optionally fused to a Ce-Cι aryl group, a C5-C8 saturated cyclic group or a 5-10-membered heterocyclic group; 1 or 2 carbon atoms in the above cyclic heteroradicals are optionally substituted with an oxo radical (= O); and the alkyl, aryl and heterocyclic radicals of the above R4 groups are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -NRdSO2R5, -SO2NR5R6, -C (0) R5, - C (0) OR 5, -OC (O) R 5, -NR 6 C (0) R 5, -C (0) NR 5 R 6, -NR 5 R 6, - (CR 6 R 7) m OR 6 where m is an integer from 1 to 5, -OR 5 and the substituents listed in the definition of R5; each R5 is independently selected from H, C? -C10 alkyl, - (CH2) t (C6-C10 aryl), and - (CH2), (5-10 membered heterocycle), wherein t is an integer of 0 to 5; said alkyl group optionally includes 1 or 2 heteroradicals selected from O, S and -N (R6) - with the proviso that two O atoms, two S atoms or one O and S atom, are not directly bound together the other; said aryl and heterocyclic groups R5 are optionally fused to a Ce-Cι aryl group, a Cs-Cβ saturated cyclic group or a 5-10-membered heterocyclic group; and the above R5 substituents, except H, are optionally substituted with 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) NR7R7, -NR6R7, hydroxy, C? -C? Alkyl and C6-C6 alkoxy; and each R6 and R7 are independently H or C? -C6 alkyl. 22. A process for preparing a compound according to claim 1 comprising (a) treating a compound of formula with a compound of formula R3-X wherein X is a halo group and R3 is as defined in claim 1, and treating the resulting compound with a compound of formula R1R2NH wherein R1 and R2 are as have defined in claim 1; or (b) treating a compound of formula 25 wherein R3 is as defined in claim 1, with a compound of formula R1R2NH wherein R1 and R2 are as defined in claim 1.