HK1036982B - Isothiazole derivatives useful as anticancer agents - Google Patents

Isothiazole derivatives useful as anticancer agents Download PDF

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Publication number
HK1036982B
HK1036982B HK01107830.8A HK01107830A HK1036982B HK 1036982 B HK1036982 B HK 1036982B HK 01107830 A HK01107830 A HK 01107830A HK 1036982 B HK1036982 B HK 1036982B
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HK
Hong Kong
Prior art keywords
isothiazole
ureido
carboxylic acid
acid amide
benzyloxy
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HK01107830.8A
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Chinese (zh)
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HK1036982A1 (en
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E‧R‧拉尔森
M‧C‧诺伊
T‧G‧简特
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辉瑞大药厂
Osi制药公司
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Priority claimed from PCT/IB1999/000797 external-priority patent/WO1999062890A1/en
Publication of HK1036982A1 publication Critical patent/HK1036982A1/en
Publication of HK1036982B publication Critical patent/HK1036982B/en

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Description

Isothiazole derivatives as anticancer agents
Background
The present invention relates to novel isothiazole derivatives useful for treating hyperproliferative diseases, such as cancer, in mammals. The invention also relates to methods of using the compounds in the treatment of hyperproliferative diseases in mammals, particularly humans, and to pharmaceutical compositions containing the compounds.
It is known that a cell becomes a cancer cell when a portion of its DNA is converted into an oncogene (i.e., a gene that, upon activation, can lead to the formation of malignant tumor cells). Many oncogenes encode proteins that are aberrant tyrosine kinases capable of causing cell transformation. Alternatively, overexpression of the normal proto-oncogene tyrosine kinase may also cause proliferative diseases, sometimes resulting in a malignant phenotype. It has been demonstrated that certain tyrosine kinases may be mutated or overexpressed in a variety of human cancers such as brain, lung, squamous cell, bladder, gastric, breast, head and neck, esophageal, gynecological, and thyroid cancers. Furthermore, overexpression of ligands for tyrosine kinase receptors also leads to an increase in the activated state of the receptors, leading to the proliferation of tumor cells or endothelial cells. Thus, inhibitors of tyrosine kinase receptors, such as the compounds of the present invention, are believed to be useful as selective inhibitors of mammalian cancer cell growth.
Polypeptide growth factors, such as Vascular Endothelial Growth Factor (VEGF), which has a high affinity for the human domain-containing kinase receptor (KDR) or the murine fetal liver kinase 1(FLK-1) receptor, are known to be involved in the proliferation of endothelial cells, particularly angiogenesis and vasculogenesis. See PCT International application publication No. WO95/21613 (published 8/17 1995). Agents capable of binding or modulating the KDR/FLK-1 receptor, such as the compounds of the invention, may be useful in the treatment of diseases associated with angiogenesis or vasculogenesis, such as diabetes, diabetic retinopathy, hemangioma, glioma, melanoma, kaposi's sarcoma and ovarian cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer and epidermoid tumors.
U.S. Pat. Nos. 4,059,433 and 4,057,416 (both assigned to FMC corporation) mention isothiazole derivatives useful as herbicides.
Summary of The Invention
The invention relates to1And pharmaceutically acceptable salts, prodrugs and solvates thereof,
wherein:
X1is O or S;
R1is H, C1-C10Alkyl radical, C2-C10Alkenyl radical, C2-C10-alkynyl, -C (O) (C)1-C10Alkyl), - (CH)2)t(C6-C10Aryl), - (CH)2)t(4-10 membered heterocycle), -C (O) (CH)2)t(C6-C10Aryl) or-C (O) (CH)2)t(5-10 membered heterocycle), wherein t is an integer of 0 to 5; the alkyl group optionally contains 1 or 2 groups selected from O, S and-N (R) 6) -a heteroatom moiety, with the proviso that two O atoms, two S atoms or O and S atoms are not directly connected; said aryl and heterocyclic ring R1The radicals being optionally substituted with C6-C10Aryl radical, C5-C8A saturated cyclic group or a 5-to 10-membered heterocyclic group is fused; optionally substituted on 1 or 2 carbon atoms of the aforementioned heterocyclic moiety by an oxo (═ O) moiety; r mentioned above1Of a group- (CH)2)t-the moiety optionally contains a carbon-carbon double or triple bond, wherein t is an integer from 2 to 5; and the aforementioned R1The radical, other than H, being optionally substituted by 1 to 3R4Substituted by a group;
R2is selected from R1The substituents, -SO2(CH2)t(C5-C10Aryl), -SO2(CH2)t(5-10 membered heterocycle) and-OR5T is an integer of 0 to 5, the aforementioned R2Of a group- (CH)2)t-the moiety optionally containing a carbon-carbon double or triple bond, wherein t is an integer from 2 to 5, and the aforementioned R2The radicals being optionally substituted by 1 to 3R4Substituted by a group;
or R1And R2May be taken together with the nitrogen to which they are attached to form a 4-10 membered saturated monocyclic or multicyclic ring or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings are other than R1And R2Optionally containing 1 or 2 nitrogen atoms selected from O, S and-N (R)6) When R is a hetero atom of1And R2When combined in the heteroaryl fashion, the-N (R) 6) -may optionally be-N-or-N-and said saturated ring may optionally be partially unsaturated by containing a 1 or 2 carbon-carbon double bond, said saturated and heteroaryl rings including said-N (R)6) R of (A-C)6A group, optionally substituted by 1 to 3R4Substituted by a group;
R3is H, C1-C10Alkyl radical, C2-C10Alkenyl radical, C2-C10Alkynyl, - (CH)2)t(C6-C10Aryl) or- (CH)2)t(5-10 membered heterocycle), wherein t is an integer of 0 to 5; the alkyl group optionally contains 1 or 2 groups selected from O, S and-N (R)6) -a heteroatom moiety, with the proviso that two O atoms, two S atoms or O and S atoms are not directly connected; said aryl and heterocyclic ring R3The radicals being optionally substituted with C6-C10Aryl radical, C5-C8A saturated cyclic group or a 5-to 10-membered heterocyclic group is fused; optionally substituted on 1 or 2 carbon atoms of the aforementioned heterocyclic moiety by an oxo (═ O) moiety; r mentioned above3Of a group- (CH)2)t-the moiety optionally containing a carbon-carbon double or triple bond, wherein t is an integer from 2 to 5, and the aforementioned R3The radicals being optionally substituted by 1 to 5R4Substituted by a group;
each R4Independently of one another, from C1-C10Alkyl radical, C2-C10Alkenyl radical, C2-C10Alkynyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -OR5、-C(O)R5、-C(O)OR5、-NR6C(O)OR5、-OC(O)R5、-NR6SO2R5、-SO2NR5R6、-NR6C(O)R5、-C(O)NR5R6、-NR5R6、-S(O)jR7Wherein j is an integer from 0 to 2, -SO 3H、-NR5(CR6R7)tOR6、-(CH2)t(C6-C10Aryl), -SO2(CH2)t-(C6-C10Aryl), S (CH)2)t(C6-C10Aryl), -O (CH)2)t-(C6-C10Aryl), - (CH)2)t(5-to 10-membered heterocycle) and- (CR6R7)mOR6Wherein m is an integer of 1 to 5, and t is an integer of 0 to 5; the alkyl group optionally contains 1 or 2 groups selected from O, S and-N (R)6) -a heteroatom moiety, with the proviso that two O atoms, two S atoms or O and S atoms are not directly connected; said aryl and heterocyclic ring R4The radicals being optionally substituted with C6-C10Aryl radical, C5-C8A saturated cyclic group or a 5-to 10-membered heterocyclic group is fused; optionally substituted on 1 or 2 carbon atoms of the aforementioned heterocyclic moiety by an oxo (═ O) moiety; r mentioned above4The alkyl, aryl and heterocyclic moieties of the group are optionally substituted with 1-3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -NR6SO2R5、-SO2NR5R6、-C(O)R5、-C(O)OR5、-OC(O)R5、-NR6C(O)R5、-C(O)NR5R6、-NR5R6、-(CR6R7)mOR6Wherein m is an integer of 1 to 5, -OR5And R5The substituents listed in the definition of (1);
each R5Are independently selected from H, C1-C10Alkyl, - (CH)2)t(C6-C10Aryl) and- (CH)2)t(5-10 membered heterocycle), wherein t is an integer of 0 to 5; the alkyl group optionally contains 1 or 2 groups selected from O, S and-N (R)6) -a heteroatom moiety, with the proviso that two O atoms, two S atoms or O and S atoms are not directly connected; said aryl and heterocyclic ring R 5The radicals being optionally substituted with C6-C10Aryl radical, C5-C8A saturated cyclic group or a 5-to 10-membered heterocyclic group is fused; and the aforementioned R5Substituents, other than H, are optionally substituted by 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -C (O) R6、-C(O)OR6、-CO(O)R6、-NR6C(O)R7、-C(O)NR6R7、-NR6R7Hydroxy, C1-C6Alkyl and C1-C6Substituted by a substituent of alkoxy;
each R6And R7Independently of one another, H or C1-C6An alkyl group;
provided that the formula1The compound(s) of (a) is not 1-methyl-3- (4-carbamoyl-3-ethoxy-5-isothiazolyl) urea, 1-dimethyl-3- (4-carbamoyl-3-ethoxy-5-isothiazolyl) urea, 1-methyl-3- (4-carbamoyl-3-propoxy-5-isothiazolyl) urea, 1-methyl-3- (4-carbamoyl-3- (methylthio) -5-isothiazolyl) urea, 1-methyl-3- (4-carbamoyl-3- (ethylthio) -5-isothiazolyl) urea, 1-dimethyl-3- (4-carbamoyl-3- (ethylthio) -5-isothiazolyl) urea 5-isothiazolyl) urea, 1-methyl-3- (4-carbamoyl-3- (propylsulfanyl) -5-isothiazolyl) urea, 1-dimethyl-3- (4-carbamoyl-3- (propylsulfanyl) -5-isothiazolyl) urea or 1-methyl-3- (4-carbamoyl-3- (isopropylsulfanyl) -5-isothiazolyl) urea.
Preferred compounds include those wherein R2Is H and R 1Is optionally selected from-NR by 1 or 2 independently of each other5R6、-NR5(CR6R7)tOR6And- (CH)2)t(5-to 10-membered heterocycle) substituted C1-C10Alkyl of the formula1A compound wherein t is an integer from 0 to 5. Particularly preferred R1Groups include propyl, butyl, pentyl and hexyl, optionally substituted with dimethylamino, hydroxy, pyrrolidinyl, morpholino and ethyl- (2-hydroxy-ethyl) -amino.
Other preferred compounds include those wherein R is2Is H and R1Is- (CH)2)t(5-to 10-membered heterocycle) of the formula1A compound wherein t is an integer from 0 to 5; the heterocyclic group is optionally substituted with C6-C10Aryl radical, C5-C8A saturated cyclic group or a 5-to 10-membered heterocyclic group is fused; said R1Group comprising said R1Optionally fused-on part of a group, optionally substituted by 1 or 2 substituents independently of one another, selected from C1-C4Alkyl, hydroxy and hydroxymethyl. The R is1Particularly preferred heterocyclic groups of the group are morpholino, pyrrolidinyl, imidazolyl, piperazinyl, piperidinyl and 2, 5-diaza-bicyclo [2.2.1]Hept-2-yl, said R1T of the group may be 2 to 5, and the heterocyclic group may be optionally substituted with hydroxyl, hydroxymethyl, and methyl.
Other preferred compounds include those wherein R is3Is- (CH) 2)t(C6-C10Aryl) of the formula1A compound wherein t is an integer of 1 to 3 and said R3The radicals being optionally substituted by 1 to 4R4Substituted by a group. Particularly preferred R3The radicals comprising optionally 1 to 4 substituents independently of one another selected from halogen and C1-C4Benzyl substituted with a substituent of alkyl. More preferred R3The group includes benzyl substituted with 1 to 4 substituents independently selected from methyl, fluoro, chloro and bromo.
Particular embodiments of the present invention include the following compounds:
5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- (3- {4- [ ethyl- (2-hydroxy-ethyl) -amino } -butyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (2-fluoro-4-methyl-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- (3-4- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -butyl } -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-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- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [ - (1-methyl-pyrrolidin-2-yl) -ethyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- [3- {4- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -butyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- [3- (3-hydroxy-5-pyrrolidin-1-yl) -pentyl) -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- {3- [4- (3, 4-dihydroxy-pyrrolidin-1-yl) -butyl ] ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [4- (3, 4-dihydroxy-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- {3- [4- (2-hydroxymethyl-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [4- (2-hydroxymethyl-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- {3- [4- (3-hydroxy-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-bromo-2, 6-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
the mesylate salt of 3- (4-bromo-2, 6-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
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- {3- [4- (3-hydroxy-5-piperidin-1-yl-pentyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [4- (2-hydroxymethyl-piperidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- (3- {4- [ ethyl- (2-hydroxy-ethyl) -amino ] -butyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- [3- (5-hydroxy-6-piperidin-1-yl) -hexyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-bromo-2, 3, 6-trifluoro-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
Hydrochloride salt of 3- (4-bromo-2, 6-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- [3- (3-hydroxy-5-pyrrolidin-1-yl-pentyl) -ureido ] -isothiazole-4-carboxylic acid amide;
5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (3-hydroxy-5-pyrrolidin-1-yl-pentyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [3- (5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- {3- [3- (5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- {3- [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- [3- (4-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 } -isothiazole-4-carboxylic acid amide;
5- {3- [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -ureido } -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (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;
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- {3- [4- (4-methyl-piperazin-1-yl) -butyl ] -ureido } -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- (3- {4- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -butyl } -ureido) -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (3-pyrrolidin-1-yl-propyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (4-hydroxy-5-piperidin-1-yl-pentyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- [3- (4-imidazol-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
5- (3- {4- [ ethyl- (2-hydroxy-ethyl) -amino ] -butyl } -ureido) -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (4-chloro- (2, 3, 6-trifluoro-benzyloxy) -5- {3- [4- (2-hydroxymethyl-piperidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- [3- (3-hydroxy-5-pyrrolidin-1-yl-pentyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-bromo-2, 6-difluoro-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- {3- [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (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- [3- (3-dimethylamino-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-bromo-2, 3, 6-trifluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- [3- (4-imidazol-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-difluoro-benzyloxy) -5- (3- {3- [ ethyl- (2-hydroxy-ethyl) -amino ] -propyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- (3- {3- [ ethyl- (2-hydroxy-ethyl) -amino ] -propyl } -ureido) -isothiazole-4-carboxylic acid amide;
5- [3- (3-methylamino-propyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (3-amino-propyl) -3-methyl-ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
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-pyrrolidin-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;
5- (3- {4- [ bis- (2-hydroxy-ethyl) -amino ] -butyl } -ureido) -3- (2, 6-difluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
and pharmaceutically acceptable salts and hydrates of the above compounds.
The invention also relates to pharmaceutical compositions for treating hyperproliferative disorders in mammals, said compositions comprising a therapeutically effective amount of a compound of formula (I) 1Compound or pharmaceutically acceptable salt or hydrate thereof anda pharmaceutically acceptable carrier. In one embodiment, the pharmaceutical composition is for the treatment of cancer, such as brain cancer, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, pancreatic cancer, breast cancer, cancer of the head, cancer of the neck, renal cancer, prostate cancer, colorectal cancer, esophageal cancer, gynecological cancer (e.g., ovarian cancer), or thyroid cancer. In another embodiment, the pharmaceutical composition is for use in treating a non-cancerous hyperproliferative disease such as benign hyperplasia of the skin (e.g., psoriasis) or prostate (e.g., Benign Prostatic Hyperplasia (BPH)).
The invention also relates to pharmaceutical compositions for treating pancreatitis or kidney diseases in mammals, including proliferative glomerulonephritis and diabetes-induced nephropathy, said compositions comprising a therapeutically effective amount of a compound of formula (I)1A compound or a pharmaceutically acceptable salt or hydrate thereof and a pharmaceutically acceptable carrier.
The invention also relates to a pharmaceutical composition for preventing blast implantation in a mammal, said composition comprising a therapeutically effective amount of a compound of formula (I)1A compound or a pharmaceutically acceptable salt or hydrate thereof and a pharmaceutically acceptable carrier.
The invention also relates to pharmaceutical compositions for treating diseases associated with angiogenesis or vasculogenesis in a mammal, said compositions comprising a therapeutically effective amount of a compound of formula (I) 1A compound or a pharmaceutically acceptable salt or hydrate thereof and a pharmaceutically acceptable carrier. In one embodiment, the disease for which the pharmaceutical composition is useful is selected from tumor angiogenesis, chronic inflammatory diseases such as rheumatoid arthritis, atherosclerosis, skin diseases such as psoriasis, excema and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, kaposi's sarcoma and ovarian cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer and epidermoid cancer.
The invention also relates to a method of treating a hyperproliferative disorder in a mammal comprising administering to said mammal a treatmentAn effective amount of1A compound or a pharmaceutically acceptable salt or hydrate thereof. In one embodiment, the method relates to the treatment of cancer, such as brain, squamous cell, bladder, gastric, pancreatic, breast, head, neck, oesophageal, prostate, colorectal, lung, kidney, gynaecological (e.g. ovarian) or thyroid cancer. In another embodiment, the method relates to the treatment of a non-cancerous hyperproliferative disease such as benign hyperplasia of the skin (e.g., psoriasis) or prostate (e.g., Benign Prostatic Hyperplasia (BPH)).
The invention also relates to a method of treating a hyperproliferative disorder in a mammal comprising co-administering to said mammal a therapeutically effective amount of a compound of formula (I)1A compound or a pharmaceutically acceptable salt or hydrate thereof and an antineoplastic agent selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, and anti-androgens.
The invention also relates to a method of treating pancreatitis or kidney disease in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of formula (la)1A compound or a pharmaceutically acceptable salt or hydrate thereof.
The invention also relates to a method of preventing blast implantation in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of formula (la)1A compound or a pharmaceutically acceptable salt or hydrate thereof.
The invention also relates to a method of treating a disease associated with angiogenesis or vasculogenesis in a mammal, the method comprising administering to said mammal a therapeutically effective amount of a compound of formula (la)1A compound or a pharmaceutically acceptable salt or hydrate thereof. In one embodiment, the disease for which the method is useful is selected from tumor angiogenesis, chronic inflammatory diseases such as rheumatoid arthritis, atherosclerosis, skin diseases such as psoriasis, excema and scleroderma, diabetes mellitus Sexual retinopathy, retinopathy of prematurity, macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer and epidermoid cancer.
In addition, the compounds of the present invention are also useful as contraceptives in mammals.
Can be used in accordance with the method of the invention1Patients treated with the compounds and pharmaceutically acceptable salts and hydrates of the compounds include, 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 cancer of the anal region, stomach cancer, colon cancer, breast cancer, gynecological tumors (e.g., uterine sarcoma, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer or vulvar cancer), hodgkin's disease, esophageal cancer, small bowel cancer, cancer of the endocrine system (e.g., thyroid, parathyroid or adrenal gland), soft tissue sarcoma, cancer of the urinary tract, penile cancer, prostate cancer, chronic or acute leukemia, solid tumors of childhood, lymphocytic lymphomas, bladder cancer, cancer of the kidney or ureter (e.g., renal cell cancer, renal pelvis cancer) or tumors of the central nervous system (e.g., primary CNS lymphoma, renal cell carcinoma, renal pelvis cancer, renal cell carcinoma, Spinal cord axis tumors, brain stem glioma or pituitary adenoma).
The invention also relates to an intermediate 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 invention also relates to intermediates selected from the following compounds:
and
the invention also relates to intermediates selected from the following compounds:
and
wherein R is3As defined above.
The invention also relates to1A process for the preparation of a compound, which process comprises,
(a) general formula18Of (a) a compound
With the formula R3Treatment with a compound of formula (I) X, wherein X is halogen and R is3As defined above, and then subjecting the resulting compound to the reaction of formula R1R2Treatment of compounds of NH, wherein R1And R2As defined above; or
(b) General formula25Of (a) a compound
Wherein R is3As defined above, with the formula R1R2Treatment of compounds of NH, wherein R1And R2As defined above.
The term "halogen" as used herein includes, unless otherwise specified, fluorine, chlorine, bromine or iodine. Preferred halogen groups are fluorine, chlorine and bromine.
The term "alkyl" as used herein includes saturated monovalent hydrocarbon radicals containing straight, cyclic or branched moieties unless otherwise specified. It will be appreciated that for cyclic moieties, at least 3 carbon atoms are required in the alkyl group.
The term "alkenyl", as used herein, unless otherwise specified, includes monovalent hydrocarbon radicals containing at least one carbon-carbon double bond and containing straight, cyclic or branched moieties as described in the definition of "alkyl" above.
The term "alkynyl", as used herein, unless otherwise specified, includes monovalent hydrocarbon radicals containing at least one carbon-carbon triple bond and containing straight, cyclic or branched moieties as set forth in the definition of "alkyl" above.
The term "alkoxy" as used herein, unless otherwise indicated, refers to an O-alkyl group, wherein "alkyl" is as defined above.
The term "aryl" as used herein includes, unless otherwise specified, organic groups derived from aromatic hydrocarbons by removal of one hydrogen, such as phenyl or naphthyl.
The term "4-to 10-membered heterocyclic ring" as used herein refers to aromatic and non-aromatic heterocyclic groups containing one or more heteroatoms selected from O, S and N, wherein each heterocyclic group contains from 4 to 10 atoms in its ring system, unless otherwise specified. Non-aromatic heterocyclic groups include groups containing only 4 atoms in their ring system, whereas aromatic heterocyclic groups necessarily contain at least 5 atoms in their ring system. An example of a 4-membered heterocyclic group is azetidinyl (a group derived from azetidine). An example of a 5-membered heterocyclic group is thiazolyl and an example of a 10-membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thienylalkyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1, 2, 3, 6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1, 3-dioxolanyl, pyrazolinyl, dithianyl, dithialanyl, dihydropyranyl, dihydrothienyl; dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0] hexyl, 3-azabicyclo [4.1.0] heptyl, 3H-indolyl, and quinolizinyl. Examples of aromatic heterocyclic groups are pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, naphthyridinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridyl. The above groups derived from the above listed compounds may be C-linked or N-linked where possible. For example, the group derived from pyrrole may be pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked).
As used herein, the phrase "pharmaceutically acceptable salt" refers to the formula1Salts of acidic or basic groups that may be present in the compound. Basic formula (I)1The compounds can form various salts with a variety of inorganic and organic acids. Useful for preparing the bases of formula (I)1The acid of a pharmaceutically acceptable acid addition salt of a compound is one which forms a non-toxic acid addition salt comprising a pharmaceutically acceptable anionSalts, for example, the hydrochloride, hydrobromide, hydroiodide, nitrate, sulphate, bisulphate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate and pamoate [ i.e. 1, 1' -methylene-bis- (2-hydroxy-3-naphthoate ]]。
Acidic formula1The compounds may form base salts with various pharmaceutically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly sodium and potassium salts.
Certain formulas1The compounds may contain asymmetric centers and therefore exist in different enantiomeric forms. The invention relates to1The use of all optical isomers and stereoisomers of the compounds and mixtures thereof. Formula (II)1The compounds may also exist in tautomeric forms. The invention also relates to the use of all these tautomers and mixtures thereof.
Also included are isotopically-labeled compounds and pharmaceutically acceptable salts thereof, which are related to formula (I)1The compounds described are identical except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example2H、3H、13C、14C、15N、18O、17O、35S、18F and36and (4) Cl. The compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are included within the scope of this invention. Some are the same asThe compounds of the invention being labelled with a radioisotope, e.g. incorporated therein3H and14c, useful in drug and/or substrate tissue distribution assays. Tritium (i.e., tritium) is particularly preferred 3H) And carbon 14 (i.e.14C) Isotopes because they are easy to prepare and detect. In addition, heavier isotopes such as deuterium (i.e. deuterium) are used2H) Certain therapeutic benefits due to greater metabolic stability, such as increased in vivo half-life or a reduction in required dose, may be obtained by substitution and, therefore, may be preferred in certain circumstances. Isotopically labelled formulae of the present invention1The compounds and prodrugs thereof may generally be prepared by substituting a readily available isotopically-labeled reagent for a non-isotopically-labeled reagent according to the procedures disclosed in the schemes and/or in the examples and preparations below.
The invention also includes compounds of the formula1Pharmaceutical compositions of prodrugs of compounds and methods of treatment by administration of the formula1Methods of treating bacterial infections with prodrugs of the compounds. Containing free amino, amido, hydroxy or carboxyl groups1The compounds may be converted into prodrugs. Prodrugs include the attachment of an amino acid residue or a polypeptide chain of two or more (e.g., two, three, or four) amino acid residues via an amide or ester bond to a compound of formula1A compound in which a free amino, hydroxyl or carboxyl group of the compound is covalently linked. Amino acid residues include, but are not limited to, the 20 natural amino acids commonly represented by three letter symbols, as well as 4-hydroxyproline, hydroxylysine, desmosine, isodesmosine, 3-methylhistidine, norvaline, β -alanine, γ -aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone.
Other types of prodrugs are also included. For example, the free carboxyl groups may be derivatized to form amides or alkyl esters. Amide and ester moieties may incorporate groups including, but not limited to, ether, amine and carboxylic acid functional groups. The free hydroxyl group can be derivatized with, but not limited to, hemisuccinate, phosphate, dimethylaminoacetate, and phosphoryloxymethoxycarbonyl groups, as described in d.f. 1eisher, r.bong, b.h. stewart, Advanced Drug Delivery Reviews (Advanced Drug Delivery Reviews) (1996)19, 115. Also included are carbamate prodrugs of hydroxy and amino groups, as well as carbonate prodrugs and sulfate esters of hydroxy groups. Also included are hydroxyl groups derived in the form of (acyloxy) methyl and (acyloxy ethyl) ethers, wherein the acyl group may be an alkyl ester and optionally substituted with groups including, but not limited to, ether, amine, and carboxylic acid functional groups, or wherein the acyl group is an amino acid ester as described above. Prodrugs of this type are described in r.p. robinson et al, journal of medicinal Chemistry (j.medicinal Chemistry) (1996)39, 10.
Detailed Description
Formula (II)1The compounds and their pharmaceutically acceptable salts and solvates may be prepared as follows, unless otherwise stated, R 1、R2And R3As defined above.
Reaction scheme 1
Reaction scheme 2
Reaction scheme 3
Reaction scheme 4
Reaction scheme 5
Reaction scheme 5 (sequence)
The compounds of the present invention may be conveniently prepared according to the procedures described in the reaction schemes set forth above, as well as general synthetic procedures well known to those skilled in the art. Reaction scheme 1 describes the condensation of malononitrile with isocyanates, oxidation with sulfur, with a compound containing R3Alkylation of the compound of (a) and hydration of the nitrile to give the final compound. In step 1 of reaction scheme 1, formula4The compound can be prepared by reacting a compound of formula3Compounds and formula2Compound (R)1And R2Other than H, the remainder being as defined above) is treated with a suitable strong base (such as an alkoxide base, preferably sodium ethoxide) in a protic solvent (such as an alcohol, preferably ethanol) at a temperature of from-20 ℃ to 50 ℃, preferably from 0 ℃ to 25 ℃ for a period of from about 12 to 24 hours. In step 2 of reaction scheme 1, formula5The compound can be prepared by reacting a compound of formula4The compounds are prepared by treating with sulfur (about 1 equivalent to excess) in a polar solvent, such as an alcoholic solvent, preferably methanol, at a temperature of 25 ℃ to 80 ℃, preferably 65 ℃, for about 12 to 48 hours, preferably about 24 hours. In step 3 of reaction scheme 1, formula6Can be prepared by reacting a compound of formula (II) 5The compound is used with about 1 to 5 equivalents, preferably slightly more than 1 equivalent, of the compound containing R3And a base (e.g., a tertiary amine base, preferably diisopropylethylamine) in a polar solvent (preferably Tetrahydrofuran (THF) or N, N-Dimethylformamide (DMF)) at a temperature of from 0 ℃ to 80 ℃, preferably about 25 ℃, for about 12 to 48 hours, preferably about 24 hours. In step 4 of reaction scheme 1, formula1Compound (wherein X1Is S) can be prepared by reacting6The compounds are prepared by treating under strongly acidic conditions (e.g., concentrated sulfuric acid) at a temperature of 25 ℃ to 100 ℃, preferably about 25 ℃ for about 1 to 12 hours, preferably about 1.5 hours, or under basic conditions (e.g., aqueous sodium hydroxide (10%)) at a temperature of 25 ℃ to 120 ℃, preferably about 100 ℃ for about 6 to 24 hours.
Reaction scheme 2 describes the preparation of wherein X1Is of the formula S1Another method of preparing the compound. In step 1 of reaction scheme 2, formula7The compound can be prepared by reacting a compound of formula3The compound is condensed with an alkoxycarbonyl isothiocyanate (e.g., ethoxycarbonyl isothiocyanate) in the presence of a strong base (e.g., an alkoxide base, preferably sodium ethoxide) in a polar solvent (e.g., an alcoholic solvent, preferably ethanol) at a temperature of about 0 ℃ to 30 ℃ for 12 to 24 hours. In step 2 of reaction scheme 2, formula 8The compound can be prepared by reacting a compound of formula7The compound is treated with about 1 equivalent of sulfur in an alcoholic solvent (e.g., methanol) at a temperature of about 50 ℃ to 80 ℃, preferably about 65 ℃ for 24 to 48 hours7The compound is prepared by oxidative cyclization. In step 3 of reaction scheme 2, formula9The compound can be prepared by reacting a compound of formula8For compounds containing R3Is prepared by treating an electrophile such as a halide, preferably a chloride, bromide or iodide of these compounds, in a polar solvent such as THF at a temperature of from 25 ℃ to 40 ℃ for about 12 to 24 hours. In step 4 of reaction scheme 2, formula10The compound can be prepared by reacting a compound of formula9The compounds being suitable forStrong acids such as concentrated sulfuric acid are prepared by hydrolysis at a temperature of 80 to 120 c for about 6 to 18 hours. In step 5 of reaction scheme 2, formula11A compound wherein Ph is phenyl can be prepared by reacting a compound of formula10The compounds are prepared by treating aryl chloroformate or alkyl chloroformate (such as phenyl chloroformate) with a strong base (such as pyridine) in an aprotic solvent, preferably THF or dichloromethane, at a temperature of 25 deg.C to 40 deg.C for 12 to 24 hours. In step 6 of reaction scheme 2, formula1Compound (wherein X1Is S) can be prepared by reacting11The compound is used in excess (about 1.1 to 6 equivalents) of the formula R 1R2Primary or secondary amines of NH are prepared by treatment in a polar aprotic solvent (e.g. THF or THF/DMF mixtures) at a temperature of 23 ℃ to 60 ℃ for 6 to 24 hours.
Reaction scheme 3 describes the preparation of wherein X1Is of the formula O1Methods of using the compounds. Formula (II)4The starting compounds of (a) can be prepared as described in reaction scheme 1 above. In step 1 of reaction scheme 3, the compound of formula4Solutions of the salts in aqueous inert solvents or preferably water itself are treated with an oxidizing agent, preferably hydrogen peroxide. The mixture is maintained at a temperature sufficient to complete the dissolution and cyclization for a sufficient time, preferably at reflux for about 15 minutes, and then cooled to provide formula (la)12A compound is provided. In step 2 of reaction scheme 3, the compound of formula12The compound is added to an acid solution, preferably concentrated sulfuric acid, followed by addition of sufficient water to complete hydration, preferably about 10 equivalents, and then stirred at a temperature of-20 ℃ to 100 ℃, preferably room temperature, for a time sufficient to complete hydration, preferably overnight. The mixture is then treated with water or, preferably, ice to give the formula13A compound is provided. In step 3 of reaction scheme 3, the compound of formula13The compound is treated with a base, preferably potassium tert-butoxide, in an inert solvent, preferably DMF, at a temperature of-78 ℃ to 100 ℃, preferably room temperature. Adding a compound containing R to the mixture 3Electrophiles of, e.g. containing R3Alkyl halides or sulfonates of (a), preferably iodides or bromides of these compounds. Mixing the above materialsThe mixture was stirred until the reaction was complete by TLC analysis to give formula1Compound (wherein X1Is O).
Reaction scheme 4 describes the preparation of wherein X1Is of the formula S1Another method of preparing the compound. In step 1 of reaction scheme 4, the Synthesis was performed according to the synthetic methods described in m.yokoyama and k.sato, Synthesis, 813 (1988). According to the method, the formula3Treatment of the compound with an alkyl thiol (e.g. 4-methoxybenzyl thiol) and a suitable strong base (e.g. sodium hydroxide) in a polar solvent (e.g. an alcohol/water mixture, preferably 1: 1 ethanol/water) at a temperature of-10 ℃ to 30 ℃, preferably 0 ℃ for 2 to 6 hours, preferably about 3 hours gives a compound of formula14A compound is provided. In step 2 of reaction scheme 4, formula15A compound wherein Ph is phenyl can be prepared by reacting a compound of formula14The compounds are prepared by treating an alkoxycarbonyl isothiocyanate (e.g., phenoxycarbonyl isothiocyanate) in an aprotic solvent (e.g., ethyl acetate) at about 0 deg.C for about 12 to 36 hours. In step 3 of reaction scheme 4, formula16The compound can be prepared by reacting a compound of formula15The compounds are prepared by treating with an oxidizing agent, such as bromine or iodine, preferably iodine, and a weak base, such as pyridine, in a polar solvent, such as acetonitrile, at about 0 deg.C for about 1 hour. In step 4 of reaction scheme 4, formula 17The compound can be prepared by reacting a compound of formula16The compounds are prepared by deprotecting 4-methoxybenzyl groups by treatment with about 1 equivalent of mercuric acetate in the presence of an acid, preferably trifluoroacetic acid (TFA), with an excess of anisole, preferably 10 equivalents, at a temperature of 0 ℃ to room temperature for 10 to 24 hours. In step 5 of reaction scheme 4, formula18The compound can be prepared by reacting a compound of formula17The compounds are prepared by hydration with a suitable strong acid, for example concentrated sulphuric acid, at a temperature of from 15 ℃ to 80 ℃, preferably room temperature, for 12 to 24 hours, preferably 18 hours. In step 6 of reaction scheme 4, formula1The compound can be prepared by reacting a compound of formula18For compounds containing R3Of an electrophilic reagent (e.g. halides, preferably chlorides, bromides or iodides of these compounds)And a suitable strong base such as diisopropylethylamine in a polar solvent, preferably DMF, at a temperature of from 0 ℃ to 50 ℃, preferably 25 ℃ for 12 to 24 hours. The resulting compound is then reacted with a compound of formula R1R2Primary or secondary amines of NH (about 1.1 to 6 equivalents) are treated in THF/DMF mixtures at temperatures of 25 ℃ to 65 ℃ for 18 to 36 hours.
Reaction scheme 5 describes the preparation of wherein X1Is of the formula O1Another method of preparing the compound. In step 1 of reaction scheme 5, a 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 break up the salt. Then subjecting the mixture to the following reaction scheme 19Aryl chloroformate (Ph is phenyl) and the resulting mixture is stirred at a temperature between-40 ℃ and room temperature, preferably about 5 ℃, for a time sufficient to complete the reaction, preferably about 8 hours. The solid by-products are filtered off and the product is kept cool, preferably not above room temperature. The product is redissolved in a suitable inert solvent, preferably diethyl ether, and the insoluble by-products are filtered off again. After concentration, the product is dissolved again in a suitable inert solvent, preferably hexane, and the insoluble by-products are removed again. Thereby separating to obtain the formula20The compound of (1). In step 2 of reaction scheme 5, an acidic solution, preferably a solution of hydrogen chloride in diethyl ether, is prepared using formula3And (4) treating the compound. After dissolution, the solution is cooled, preferably to 10 ℃, and then treated with an alcohol, preferably benzyl alcohol. After stirring, the mixture is maintained at the indicated temperature, preferably about 5 ℃, for a time sufficient to complete the reaction (usually about 4 days) to give formula (la)21A compound is provided. In step 3 of reaction scheme 5, the compound of formula (I) is reacted at-40 ℃ to room temperature, preferably 0 ℃21A solution of the compound in a suitable inert solvent, preferably acetonitrile, is prepared according to the formula20The compound is treated in solution in a suitable inert solvent, preferably acetonitrile. The reaction is completed by maintaining the reaction solution at 0 ℃ to room temperature, preferably room temperature. The mixture is then maintained at a temperature suitable to increase the curing of the product, preferably at about 5 ℃, for a time sufficient to obtain maximum yield, preferably for about 2 days. Then separated out 22Compound (Bn is benzyl). In step 4 of reaction scheme 5, the compound of formula22The compound is added to a suitable inert solvent, preferably acetonitrile, at a temperature of-40 ℃ to 40 ℃, preferably 0 ℃, and then treated with a base, preferably pyridine, and an oxidizing agent, preferably a solution of bromine or iodine in a suitable inert solvent, preferably acetonitrile. The mixture is then stirred at a temperature sufficient to complete the reaction, preferably 0 ℃, for about 1 hour, and then at room temperature for an additional 1 hour. The mixture is then held at a temperature sufficient to increase the cure, preferably 5 c, for a sufficient period of time, preferably overnight. Then separated out23A compound is provided. In step 5 of reaction scheme 5, treatment with an acid (preferably concentrated sulfuric acid) completes the formula23Hydration and deprotection of the compound. If formula23The compound contains a sufficient amount of water from the previous step, and no additional water is required. If formula23If the compound is dry, additional water, preferably about 10 equivalents, may be added. The reaction is carried out at-20 ℃ to 100 ℃, preferably at room temperature, for a time sufficient for the reaction to proceed to completion, generally indicated by complete dissolution, preferably about 3 hours. After the reaction is finished, the sulfuric acid is supplemented to achieve complete conversion. The mixture is then treated with water or, preferably, ice. Then separated out 24A compound is provided. In step 6 of reaction scheme 5, the compound of formula (II b)24The compounds are reacted with a trivalent phosphine, preferably triphenylphosphine, and a compound containing R3Is mixed and then treated with an azodicarboxylate derivative (preferably diisopropyl azodicarboxylate) and continuously stirred for at least 1 minute. Then separated out25A compound is provided. In step 7 of reaction scheme 5, the compound of formula25Mixtures of the compounds in suitable inert solvents, preferably THF, are prepared with the desired compounds of the formula R1R2Amine treatment of NH and holding at a temperature sufficient to effect the reaction, typically a temperature of 0 ℃ to 100 ℃, preferably 50 ℃ to 70 ℃, for 1 to 48 hours, preferably overnight. Then separated out1A compound (wherein X' is O).
The compounds of the present invention may contain 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. Enantiomers can be separated by converting a mixture of enantiomers to a mixture of diastereomers by reaction with a suitable optically active compound (e.g., an alcohol), separating the diastereomers and then converting (e.g., hydrolyzing) each diastereomer to the corresponding pure enantiomer. All such isomers, including diastereomeric mixtures and pure enantiomers are part of the invention.
Basic formula (I)1The compounds may form a variety of different salts with a variety of inorganic and organic acids. Although these salts must be pharmaceutically acceptable for administration to animals, it is generally necessary in practice to first isolate the formula from the reaction mixture as an pharmaceutically unacceptable salt1The compound is then converted by treatment with a basic agent to the free base compound, which is subsequently converted to a pharmaceutically acceptable acid addition salt. Acid addition salts of the basic compounds of the present invention are readily prepared by treating the basic compound with substantially equal amounts of the selected mineral or organic acid in an aqueous vehicle or in a suitable organic solvent such as methanol or ethanol. After careful evaporation of the solvent, the desired solid salt is readily obtained. The desired acid addition salts may also be precipitated by adding a suitable mineral or organic acid to a solution of the free base in an organic solvent.
Acidic formula1The compounds may form base salts with various pharmaceutically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly sodium and potassium salts. These salts are prepared by conventional methods. Chemical bases useful in preparing the pharmaceutically acceptable base salts of the present invention are those of the formula 1The compounds form the base of a non-toxic base salt. The non-toxic base salts include salts derived from the pharmaceutically acceptable cations such as sodium, potassium, calcium, magnesium, and the like. These salts are readily prepared by treating the corresponding acidic compound with an aqueous solution containing the desired pharmaceutically acceptable cation and then evaporating (preferably under reduced pressure) the resulting solution to dryness. Alternatively, the salts may be prepared by reacting a lower alkanol solution of the acidic compound withThe desired alkali metal alkoxide was mixed and the resulting solution was evaporated to dryness in the same manner as above. In either case, it is preferred to use stoichiometric amounts of the reagents to ensure that the reaction is complete and that the yield of the desired end product is maximized.
The invention also includes1Compounds which are identical but in which one or more hydrogens or carbons have been replaced by their isotopes. These compounds are useful as research and diagnostic tools in metabolic pharmacokinetics and binding assays. Specific applications in the study include radioligand binding assays, autoradiography studies, and in vivo binding studies. In radiolabeled form1The compounds including tritium and C thereof14An isotope.
Formula (II)1The in vitro activity of a compound to inhibit the KDR/VEGF receptor can be determined by the following method.
The ability of the compounds of the invention to inhibit tyrosine kinase activity can be measured by using recombinant enzymes in the determination of the inhibition of exogenous substrate poly GluTyr (PGT, Sigma)TM4: 1) in the test. The kinase domain of the human KDR/VEGF receptor (amino acids 805-1350) was expressed in Sf9 insect cells as a glutathione S-transferase (GST) -fusion protein using a baculovirus expression system. Proteins were purified from lysates of these cells using a glutathione agarose affinity column. Enzyme assays were performed on 96-well plates (0.625 μ g PGT/well) coated with PGT substrate. Test compounds were diluted in dimethyl sulfoxide (DMSO) and then added to the PGT plate to give a final DMSO concentration of 1.6% (v/v) in the assay. The recombinant enzyme was dissolved in phosphorylation buffer (50mM Hepes, pH7.3, 125mM NaCl, 24mM MgCl)2) And (4) diluting. The reaction was initiated by the addition of ATP (final concentration 10. mu.M). After shaking at room temperature for 30 minutes, the reaction solution was aspirated, and the plate was washed with a washing buffer (PBS containing 0.1% Tween-20). Color development with TMB peroxidase (TMB 3, 3 ', 5, 5' -tetramethylbenzidine) by incubation with an HRP-conjugated (HRP is horseradish peroxidase) PY-54 antibody (Transduction Labs) followed by BioRad TMThe amount of phosphorylated PGT was quantified by quantifying the reaction at 450nM on a Microplate reader. The inhibitory effect of a test compound on kinase enzyme activity is determined by the decrease in absorbance and the concentration of compound required to inhibit signal by 50% is reported as the IC of the test compound50。
To determine the ability of a compound to inhibit the activity of KDR tyrosine kinase on the full-length protein present in a cell, Porcine Aortic Endothelial (PAE) cells transfected with human KDR (Waltenberger et al, journal of biochemistry (j.biol. chem.) 269: 26988, 1994) can be used. Cells were plated and adhered to 96-well plates in the same medium (Ham's f12) containing 10% FBS (fetal bovine serum). The cells were then washed, supplemented with serum free medium containing 0.1% (v/v) Bovine Serum Albumin (BSA), and then incubated for 24 hours. Immediately prior to compound administration, cells were supplemented with serum free medium (no BSA). Test compounds dissolved in DMSO were diluted in medium (final DMSO concentration of 0.5% (v/v)). At the end of the 2 hour incubation, VEGF was added to the medium165(50ng/ml final concentration) and then incubated for 8 minutes. Cells were washed and washed in HNTG buffer (20mM Hepes, pH7.5, 150mM NaCl, 0.2% Triton) TMX-100, 10% glycerol, 0.2mM PMSF (phenylmethylsulfonyl fluoride), 1. mu.g/ml pepstatin, 1. mu.g/ml leupeptin, 1. mu.g/ml aprotinin (aprotinin), 2mM sodium pyrophosphate, 2mM sodium orthovanadate). The extent of phosphorylation of KDR was determined by ELISA analysis. 96-well plates were coated with goat anti-rabbit antibody at 1. mu.g/well. Unbound antibody was washed off the plate and the remaining sites were blocked with Superblock buffer (Pierce) before adding anti-flk-1C-20 antibody (0.5. mu.g/plate, Santa Cruz). All unbound antibody was washed away before adding the cell lysate. After incubation of the lysate with flk-1 antibody for 2 hours, KDR-bound phosphotyrosine was quantitated by developing with HRP-bound PY-54 antibody and TMB as described above. The ability of a compound to inhibit VEGF-stimulated autophosphorylation response by 50% relative to VEGF-stimulated control is reported as the IC of the test compound50The value is obtained.
Compounds in human endothelial cellsBy inhibition thereof3Incorporation of H-thymidine into HUVE cells (human umbilical vein endothelial cells, Clonetics)TM) The ability of (c). This assay is described in detail in the literature (Waltenberger J et al, J.Biol.chem.) 269: 26988, 1994; Cao Y et al, J.Biol.chem. 271: 3154, 1996). Briefly, 10 4Individual cells were placed in collagen-coated 24-well plates for adhesion. Cells were supplemented with serum-free medium and 24 hours later, with various concentrations of compound (prepared in DMSO at a final concentration of 0.2% v/v in the assay) and 2-30ng/ml VEGF165And (6) processing. Within the last 3 hours of 24 hours of treatment with the compound, cells were used3H Thymidine (NEN, 1. mu. Ci/well) pulse treatment. Then, the medium was removed and the cells were washed coarsely with ice-cold Hank's balanced salt solution and then twice with ice-cold trichloroacetic acid (10% v/v). Cells were lysed by adding 0.2mL of 0.1N NaOH, and the lysate was transferred to scintillation vials. Wells were washed with 0.2mL 0.1N HCl and the wash was then transferred to a bottle. Determination by scintillation counting3Degree of incorporation of H thymidine. The ability of a compound to inhibit incorporation by 50% relative to a control (VEGF treated with DMSO vehicle only) is reported as the IC of the test compound50。
Formula (II)1The in vivo activity of a compound can be determined by the amount of test compound that inhibits tumor growth relative to a control. The tumor growth inhibition of the various compounds can be determined by Corbett T.H. et al, "tumor-induced relationships in the development of metastatic colon Cancer in mice used for chemotherapy trials," elucidation of carcinogen structures, "Cancer research (Cancer Res.), 35, 2434-2439(1975) and Corbett, T.H. et al," mouse colon tumor model for experimental therapy, "Cancer chemotherapy report (Cancer Chemother. Rep.) (section 2), 5169-186(1975), the determination was carried out with slight modifications. By subcutaneous injection 1X 106Logarithmic phase of cultured tumor cells in 0.1-0.2mLPBS suspension induced flank swellingAnd (4) tumors. After a sufficient period of time to allow palpation of the tumor (5-6 mm in diameter), the experimental animals (athymic mice) are administered the active compound once or twice daily (by dissolving in a suitable diluent such as water or 5% Gelucire) by intraperitoneal (ip) or oral (po) administration routesTM44/14 rn in PBS) for 5-10 consecutive days. To determine the antitumor effect, the tumors were measured in millimeters of two diameters using a vernier caliper and using the following formula: tumor weight (length × [ width ]]2) Per 2 calculate the volume of tumor (mm)3) See, e.g., Geran, R.I., et al, "methods for screening chemicals and natural products against animal tumors and other biological systems," 3 rd edition, Cancer chemotherapy reports (Cancer Chemotherm. Rep.), 3, 1-104 (1972). Tumor transplantation at the flank site provides reproducible dose/response effects for various chemotherapeutic agents, and the method of measurement (tumor diameter) is a reliable method of assessing tumor growth rate.
Administration of the compounds of the present invention (hereinafter "active compounds") can be carried out by any method that is capable of delivering the compound to the site of action. These methods include oral routes, intraduodenal 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 disease or condition, the rate of administration and the judgment of the prescribing physician. However, an effective dose is in the range of about 0.001 to about 100mg/kg body weight per day, preferably about 1 to about 35 mg/kg/day, and may be administered in a single dose or divided into multiple doses. For a human weighing 70kg, the total is from about 0.05 to about 7 g/day, preferably from about 0.2 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more suitable, while in other cases still larger doses may be employed without causing any harmful side effects, but the larger dose must be divided into smaller doses and administered over the course of a day.
The active compounds can be used in therapy alone or in combination with one or more other antitumor substancesThe neoplastic substance is selected, for example, from mitotic inhibitors, such as vinblastine; alkylating agents such as cisplatin, carboplatin, and cyclophosphamide; antimetabolites, such as 5-fluorouracil, cytarabine and hydroxyurea, or, for example, one of the preferred antimetabolites disclosed in European patent application No. 239362, such as N- (5- [ N- (3, 4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl) -N-methylamino ]-2-thenoyl) -L-glutamic acid; a growth factor inhibitor; a cell cycle inhibitor; intercalating antibiotics, such as doxorubicin and bleomycin; enzymes, such as interferon; anti-hormones, e.g. anti-oestrogens such as NolvadexTM(tamoxifen), or antiandrogens, e.g. CasodexTM(4 '-cyano-3- (4-fluorophenylsulfonyl) -2-hydroxy-2-methyl-3' - (trifluoromethyl) propionylaniline). Such combination therapy may be achieved by the simultaneous, sequential or separate administration of the various components of the therapy.
The pharmaceutical composition may be, for example, in a form suitable for oral administration, such as tablets, capsules, pills, powders, sustained release formulations, solutions, suspensions; forms suitable for parenteral injection, such as sterile solutions, suspensions or emulsions; forms suitable for topical administration, such as ointments or creams; suitable for rectal administration, such as suppositories. The pharmaceutical compositions may be in unit dosage form suitable for single administration of precise dosages. The pharmaceutical compositions may contain conventional pharmaceutical carriers or excipients and, as active ingredient, the compounds of the present invention. In addition, other drugs, carriers, adjuvants, etc. may be included.
Examples of parenteral administration forms include solutions or suspensions of the active compounds in sterile aqueous solutions, for example aqueous propylene glycol or glucose solutions. The dosage form may also be suitably buffered, if desired.
Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. The pharmaceutical compositions may contain other ingredients, such as flavoring agents, binders, excipients, and the like, as desired. Thus, for oral administration, tablets containing various excipients such as citric acid may also contain various disintegrants such as starch, alginic acid and certain complex silicates, together with binding agents such as sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are also frequently used in the preparation of tablets. Solid compositions of the same type may also be used in soft and hard gelatin capsules. Thus, preferred materials include lactose and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the active compound therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and diluents such as water, ethanol, propylene glycol, glycerin or mixtures thereof, as desired, and emulsifying or suspending agents may also be added.
Methods for preparing various pharmaceutical compositions containing specific amounts of active compounds are known or will be apparent to those skilled in the art. See, for example, Remington's Pharmaceutical Sciences, Mack publishing company, Easter, Pa., 15 th edition (1975).
The following examples and preparations are presented to further illustrate and explain the compounds of the present invention and the methods of making the compounds. It should be understood that the following examples and preparations are not intended to limit the scope of the present invention in any way.
Preparation example 1
Dimethylcarbamoyl isothiocyanates
To a 3L three-necked flask equipped with a mechanical stirrer was added a solution of dimethylcarbamoyl chloride (250mL, 2.70mol) in anhydrous acetonitrile (1.5L) and then heated to reflux. Potassium thiocyanate (270g, 2.8mol, previously dried under high vacuum at 160 ℃ for 3 hours) was then added in portions over 1 hour, taking care during the addition, since the reaction solution boils vigorously at the beginning of each addition. After the addition was complete, the mixture was heated to reflux for an additional 1 hour. The heating mantle was removed and the mixture was stirred for an additional 2.5 hours at room temperature and then placed in the refrigerator overnight.The mixture was filtered to remove unwanted solid material and the filtrate was concentrated. To the resulting oil was added diethyl ether (1L) and the solid and viscous material was discarded. The filtrate was again concentrated to give the desired material as a light orange oil (204g, 1.57mol, 58%).1H NMR(400MHz，CDCl3)δ2.90(s，3H)，2.98(s，3H)ppm。
2, 2-dicyano-1- (3, 3-dimethyl-ureido) -ethanethiol sodium salt
To a 1M ethanol solution of sodium ethoxide (prepared by treating 110mL of anhydrous ethanol with 2.5g (0.11 mole) of sodium) was added malononitrile (7.2g, 0.11 mole) at 0 ℃. Dimethylcarbamoyl isothiocyanate (14.3g, 0.110 mole) was added and the resulting mixture was allowed to warm to room temperature overnight. The mixture was concentrated in vacuo. The residue was treated with hexane and then concentrated in vacuo to a solid. The residue was triturated with hexane, collected by filtration and then dried in vacuo to give 20g (83%) of sodium 2, 2-dicyano-1- (3, 3-dimethyl-ureido) -ethanethiol as a colorless solid:1H NMR(400MHz，DMSO-d6)δ8.40(s，1H)，2.78(s，6H)ppm；13C NMR(100MHz，DMSO-d6)δ：189.9，154.3，121.4，118.7，57.9，36.5ppm。
3- (4-cyano-3-mercapto-isothiazol-5-yl) -1, 1-dimethyl-urea
A mixture of sodium 2, 2-dicyano-1- (3, 3-dimethyl-ureido) -ethanethiol (5.0g, 23mmol), sulfur (0.734g, 23mmol) and 46mL of methanol was stirred at reflux for 24 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was diluted with water and the resulting mixture was extracted twice with ethyl acetate. The aqueous layer was acidified with 1M hydrochloric acid (aq) and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid residue was collected and dried in vacuo to give 2.0g (40%) 3- (4-cyano-3-mercapto-isothiazol-5-yl) -1, 1-dimethyl-urea as a yellow solid: 1H NMR(400MHz，DMSO-d6)δ2.97(s，6H)ppm；MS(APCI，m/z)：227[M-H]-。
General procedure for the alkylation of 3- (4-cyano-3-mercapto-isothiazol-5-yl) -1, 1-dimethyl-urea Method of
To a mixture of 3- (4-cyano-3-mercapto-isothiazol-5-yl) -1, 1-dimethyl-urea (0.20g, 0.88mmol), the appropriate alkyl chloride, alkyl bromide or alkyl iodide (0.90mmol) and THF or DMF was added diisopropylethylamine (0.116g, 0.90 mmol). The resulting mixture was stirred at room temperature for 24 hours. The mixture was partitioned between 1M aqueous hydrochloric acid and ethyl acetate. The organic layer was removed and the aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was filtered through a small pad of silica gel eluting with ethyl acetate-hexane (1: 1) to give the alkylated product.
3- (4-cyano-3-hexylsulfanyl-isothiazol-5-yl) -1, 1-dimethyl-urea
Following the general procedure described above, using iodohexane (0.19g, 0.90mmol) as the alkyl iodide gave 0.14g (51%) 3- (4-cyano-3-hexylsulfanyl-isothiazol-5-yl) -1, 1-dimethyl-urea as a colorless solid:1h NMR (400MHz, acetone-d6)δ9.82(bs，1H)，3.20(t，2H，J＝7.2Hz)，3.11(s，6H)，1.71(p，2H，J＝7.2Hz)，1.43(m，2H)，1.31(m，4H)，0.88(t，3H，J＝6.0Hz)ppm；MS(APCI，m/z)：313[M+H]+。
Example 1
5- (3, 3-dimethyl-ureido) -3-hexylthio-isothiazole-4-carboxylic acid amide
A mixture of 3- (4-cyano-3-hexylsulfanyl-isothiazol-5-yl) -1, 1-dimethyl-urea (0.09g, 0.29mmol) and concentrated sulfuric acid (0.18mL) was stirred at room temperature for 1.5 hours. The mixture was diluted with ice water and extracted 3 times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give 0.076g (78%) 5- (3, 3-dimethyl-ureido) -3-hexylthio-isothiazole-4-carboxylic acid amide as a colorless solid:1h NMR (300MHz, acetone-d6)δ7.08(bs，2H)，3.20(t，2H，J＝7.2Hz)，3.02(s，6H)，1.63(p，2H，J＝7.2Hz)，1.35(m，2H)，1.23(m，4H)，0.78(t，3H，J＝6.9Hz)ppm；MS(APCI，m/z)：331[M+H]+。
Preparation example 2
2, 2-dicyano-1-ethoxycarbonylamino-ethanethiol sodium salt
Metallic sodium (1.01g, 44mmol) was dissolved in 40mL of ethanol at room temperature. The resulting solution was cooled in an ice bath, and malononitrile (2.91g, 44mmol) was then added. The ice bath was removed and the mixture was stirred at room temperature for 30 minutes. After cooling to 0 ℃ ethoxycarbonyl isothiocyanate (5.77g, 44mmol) was added and the mixture was allowed to warm to room temperature overnight. The mixture was concentrated in vacuo and the residue solidified after repeated dilution with hexane and concentration in vacuo. The yellow solid formed was collected and dried in vacuo to give 10.74g (100%) of sodium 2, 2-dicyano-1-ethoxycarbonylamino-ethanethiol as a pale yellow solid,1the H NMR spectrum confirmed that 0.5 molar equivalent of ethanol was contained therein.1H NMR(300MHz，DMSO-d6)δ4.36(t，0.5H，J＝5.0Hz(EtOH))，4.03(q，2H，J＝7.1Hz)，3.43(dq，1H J＝5.0，6.7Hz(EtOH))，1.26(t，3H，J＝7.3Hz)，1.06(t，1.5H，J＝7.0Hz(EtOH))ppm；MS(APCI，m/z)：197[M-Na]-。
4-cyano-5-ethoxycarbonylamino-isothiazole-3-thiol sodium salt
A mixture of sodium 2, 2-dicyano-1-ethoxycarbonylamino-ethanethiol (3.3g, 15mmol), sulfur (0.48g, 15mmol) and methanol (30mL) was refluxed for 24 hours. The mixture was filtered and concentrated in vacuo, and the gummy residue was triturated twice with 10: 1 ethyl ether-ethyl acetate to give 2.6g (69%) 4-cyano-5-ethoxycarbonylamino-isothiazol-3-one as a yellow solid Sodium mercaptide.1H NMR(400MHz，DMSO-d6)δ3.99(q，2H，J＝6.8Hz)，1.16(t，3H，J＝7.2Hz)ppm；MS(APCI，m/z)：228[M-Na]-。
(4-cyano-3-pentylthio-isothiazol-5-yl) -carbamic acid ethyl ester
A mixture of sodium 4-cyano-5-ethoxycarbonylamino-isothiazole-3-thiolate (5.0g, 20mmol), 1-iodopentane (4.0g, 20mmol), and tetrahydrofuran (20mL) was stirred at room temperature for 16 hours. After concentration in vacuo, the residue was partitioned between ethyl acetate and brine. The aqueous layer was extracted 3 times with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was filtered through a pad of silica gel eluting with 1: 1 ethyl acetate-hexanes. The filtrate was concentrated and the residue was recrystallized from cold aqueous methanol to give 2.5g (42%) of (4-cyano-3-pentylthio-isothiazol-5-yl) -carbamic acid ethyl ester as a colorless solid. The mother liquor was concentrated and purified by radial chromatography (4mm plate, 4: 1 hexane-ethyl acetate) to give a further 0.5g (8.4%).1H NMR (400MHz, acetone-d6)δ11.1(bs，1H)，4.32(q，2H，J＝7.2Hz)，3.21(t，2H，J＝7.2Hz)，1.73(p，2H.J＝6.8Hz)，1.44-1.28(m，7H)，0.90(t，3H，J＝7.6Hz)ppm；MS(APCI，m/z)：312[M+Na]+。
5-amino-3-pentylthio-isothiazole-4-carboxylic acid amide
A mixture of (4-cyano-3-pentylthio-isothiazol-5-yl) -carbamic acid ethyl ester (2.7g, 9.0mmol) and concentrated sulfuric acid (5mL) was heated at 100 ℃ for 6 hours. After cooling to room temperature, the mixture was diluted with ice water, extracted 3 times with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give 2.2g (100%) of 5-amino-3-pentylthio-isothiazole-4-carboxylic acid amide as a yellow oil. 1H NMR(400MHz，CDCl3)δ3.26(t，2H，J＝7.2Hz)，1.71(m，2H)，1.43-1.19(m，4H)，0.88(t，3H，J＝6.8Hz)ppm。
(4-carbamoyl-3-pentylthio-isothiazol-5-yl) -carbamic acid phenyl ester
To a solution of 5-amino-3-pentylthio-isothiazole-4-carboxylic acid amide (2.2g, 9.0mmol) in 36mL tetrahydrofuran was added pyridine (0.90g, 11mmol) and phenyl chloroformate (1.7g, 11 mmol). After stirring for 3 hours, pyridine (0.15g, 1.9mmol) and phenyl chloroformate (0.29g, 1.9mmol) were added, and the mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo, diluted with water and extracted with dichloromethane (2 times) and ethyl acetate (1 time). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated with ether-hexane for 12 hours, the solid formed was collected and then dried in vacuo to give 2.6g (79%) of phenyl (4-carbamoyl-3-pentylthio-isothiazol-5-yl) -carbamate as a colorless solid.1H NMR(300MHz，CDCl3)δ7.41(t，2H，J＝7.3Hz)，7.29-7.20(m，3H)，3.31(t，2H，J＝7.3Hz)，1.72(m，2H)，1.50-1.30(m，4H)，0.90(t，3H，J＝7.1Hz)ppm；MS(APCI，m/z)：366[M+H]+。
Example 2
3-pentylthio-5- [3- (3-pyrrolidin-1-yl-propyl) -ureido]-isothiazole-4-carboxylic acid
Amides of carboxylic acids
To a mixture of (4-carbamoyl-3-pentylthio-isothiazol-5-yl) -carbamic acid phenyl ester (0.10g, 0.27mmol) and 1mL tetrahydrofuran was added N-3-aminopropylpyrrolidine (0.175g, 1.4 mmol). After stirring at room temperature for 72 hours, the mixture was poured into 1m naoh, extracted twice with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by radial chromatography (2mm plate, 3% ethanol-dichloromethane _ containing 0.5% NH) 4OH in 30% ethanol-dichloromethane), then concentrated and the residue triturated with ether-hexane to give 0.076g (78%)Colorless solid 3-pentylthio-5- [3- (3-pyrrolidin-1-yl-propyl) -ureido]-isothiazole-4-carboxylic acid amide.1HNMR(400MHz，CDCl3)δ7.57(bs，1H)，7.06(bs，2H)，3.35(m，2H)，3.26(m，2H)，2.53(t，2H，J＝6.8Hz)，2.47(m，4H)，1.73(m，8H)，1.4-1.2(m，4H)，0.88(t，3H，J＝7.2Hz)ppm；MS(APCI，m/z)：400[M+H]+。
Preparation example 3
3- (4-cyano-3-hydroxy-isothiazol-5-yl) -1, 1-dimethyl-urea (sodium salt)
A solution of 3- (2, 2-dicyano-1-mercapto-vinyl) -1, 1-dimethyl-urea (sodium salt) (30g, 137mmol) in water (300mL) was treated with hydrogen peroxide (14mL of a solution of 10M) at room temperature. The reaction solution warmed up and thickened by the formation of solids, whereupon water (100mL) was added. The mixture was heated to reflux for 15 minutes, completely dissolved and cooled to room temperature. After 1 hour at room temperature, the mixture was concentrated to constant weight (> 100% due to water) and used immediately in the next step.
5- (3, 3-dimethyl-ureido) -3-hydroxy-isothiazole-4-carboxylic acid amide
The solid obtained in the previous step (35g) was added to concentrated sulfuric acid (150mL), followed by addition of water (5mL) and stirring at room temperature overnight. The mixture was treated with ice (500g) and stirred for 2 hours. The mixture was filtered and air was passed through the filter cake overnight. The solid was crushed with a mortar and pestle and placed under high vacuum until constant weight (21.7g, 94.2mmol, 69% yield in two steps).
Example 3
5- (3, 3-dimethyl-ureido) -3-heptyloxy-isothiazole-4-carboxylic acid amide
5- (3, 3-dimethyl-ureido) -3-hydroxy-isothiazole-4-carboxylic acid amide (200mg, 0.87mmol) in DMF (5mL) suspension was treated with KOtBu (107mg, 0.96mmol) at room temperature to completely dissolve it. 1-iodoheptane (1mL) was then added and the reaction solution was stirred at room temperature until complete disappearance of starting material (TLC detection with hexane/ethyl acetate/methanol/acetic acid (48/48/2/2) as eluent). The reaction mixture was then concentrated by rotary evaporation under high vacuum and the residue was dissolved in ethyl acetate and methanol and then purified by radial chromatography (2mm plates) eluting with the same eluent as TLC to give two components. The more polar species were identified as N-alkylated adducts (102mg, 0.311mmol, 36%).1H NMR(400MHz，CDCl3)δ0.86(t，J＝6.7Hz，3H)，1.25-1.31(m，8H)，1.64-1.70(m，2H)，3.07(s，6H)，3.68(t，J＝7.2Hz，2H)，5.40(s，1H)，8.86(s，1H)，12.1(s，1H)ppm：13C NMR(101MHz，CDCl3)δ13.94，22.45，26.48，28.74，29.52，31.52，36.11，42.54，166.99ppm；MS(APCI，m/z)：329[M+H]+. The less polar material was the O-alkylated adduct (134mg, 0.408mmol, 48%).1H NMR(400MHz，CDCl3) δ 0.88(t, J ═ 6.8Hz, 3H), 1.24-1.50(m, 8H), 1.75-1.88(m, 2H), 3.07(s, 6H), 4.43(t, J ═ 6.7Hz, 2H), 5.42(s, 1H), 7.25(s, 1H, as it appears with CDCl3Peaks overlapped), 11.6(s, 1H) ppm;13C NMR(101MHz，CDCl3)δ13.94，22.45，25.86，28.83，31.60，36.11，68.69，97.69，154.15，162.27，166.20，169.45ppm；MS(APCI，m/z)：329[M+H]+。
preparation example 4
2-cyano-thioiminoacetic acid 4-methoxy-benzyl ester
To 750mL of a 1: 1 ethanol-water solution of sodium hydroxide (13g, 0.32mol) were added 4-methoxybenzylthiol (50g, 0.324mol) and malononitrile (21g, 0.324mol) at 0 ℃. After stirring at 0 ℃ for 3 hours, the mixture was diluted with 500mL of saturated aqueous ammonium chloride, diluted with 4L of water and then filtered. The solid was washed with diethyl ether and the filtrate was taken up in an equal volume of hexaneDiluted and then filtered. The combined solids were dried in vacuo to give 43g (60%) 4-methoxy-benzyl 2-cyano-thioiminoacetate as a colorless solid.1H NMR-(400MHz：CDCl3)δ7.22(d，2H，J＝7.6Hz)，6.84(d，2H，J＝8.8Hz)，4.74(bs，1H)，3.98(s，2H)，3.78(s，3H)ppm；MS(APCI，m/z)：221[M+H]+。
2-cyano-3-mercapto-3-phenoxycarbonylamino-thioiminoacrylic acid 4-methoxy-benzyl ester
To a solution of 4-methoxy-benzyl 2-cyano-thioiminoacetate (42g, 0.19mol) in 191mL of ethyl acetate at 0 deg.C was added phenoxycarbonyl isothiocyanate (34g, 0.19mol), and the mixture was stirred at 0 deg.C for 24 hours. The mixture was diluted with ether and then filtered. The solid was washed with ether, collected and dried in vacuo to give 56g (73%) of 4-methoxy-benzyl 2-cyano-3-mercapto-3-phenoxycarbonylamino-thioiminoacrylate as a yellow solid.1H NMR(400MHz，CDCl3)δ12.81(s，1H)，9.01(s，1H)，8.68(s，1H)，7.28-6.99(m，7H)，6.69(d，2H，J＝8.8Hz)，4.17(s，2H)，3.64(s，3H)ppm；MS(APCI，m/z)：400[M+H]+。
[ 4-cyano-3- (4-methoxy-benzylthio) -isothiazol-5-yl]-carbamic acid phenyl ester
To a mixture of 4-methoxy-benzyl 2-cyano-3-mercapto-3-phenoxycarbonylamino-thioiminoacrylate (11g, 28mmol) and ethyl acetate (250mL) was added pyridine (4.4g, 55mmol) at 0 ℃. A solution of iodine (7.0g, 28mmol) in 350mL ethyl acetate was added dropwise over 1 hour. The resulting suspension is stirred for 1 hour, treated with 200mL of 1M HCl and then filtered to give 7.0g (64%) of [ 4-cyano-3- (4-methoxy-benzylthio) -isothiazol-5-yl as a colorless solid ]-phenyl carbamate. The filtrate is extracted with 1L of ethyl acetate, the organic phase is washed with aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated to yield a further 2.8g (26%) [ 4-cyano-3- (4-methoxy-benzylthio) -isothiazol-5-yl group]-phenyl carbamate.1H NMR(400MHz，CDCl3)δ11.95(s，1H)，7.35(t，2H，J＝8.4Hz)，7.20(m，3H)，7.13(d，2H，J＝8.0Hz)，6.78(t，2H，J＝8.6Hz)，4.34(s，2H)，3.73(s，3H)ppm；MS(APCI，m/z)：398[M+H]+。
(4-cyano-3-mercapto-isothiazol-5-yl) -carbamic acid phenyl ester
To [ 4-cyano-3- (4-methoxy-benzylthio) -isothiazol-5-yl at 0 DEG C]To a mixture of phenyl carbamate (1.0g, 2.5mmol), trifluoroacetic acid (26mL) and anisole (2.7g, 25mmol) was added mercury acetate (0.80g, 2.5 mmol). The mixture was allowed to warm to room temperature overnight. After concentration in vacuo, the mixture was diluted with 100mL of water and 100mL of ethyl acetate. Hydrogen sulfide was slowly added until the mercury salt precipitation was complete. The mixture was diluted with brine, extracted with 3 × 200mL of ethyl acetate, and the combined organic layers were filtered over celite, dried over sodium sulfate, filtered and concentrated in vacuo to give 0.70g (100%) of phenyl (4-cyano-3-mercapto-isothiazol-5-yl) -carbamate as a colorless solid.1H NMR (400MHz, acetone-d6)δ7.47(t，2H，J＝7.6Hz)，7.35-7.30(m，3H)ppm；MS(APCI，m/z)：276[M-H]-。
(4-carbamoyl-3-mercapto-isothiazol-5-yl) -carbamic acid phenyl ester
A mixture of phenyl (4-cyano-3-mercapto-isothiazol-5-yl) -carbamate (0.70g, 2.5mmol), 2, 6-di-tert-butyl-4-methylphenol (BHT) (one crystal), and concentrated sulfuric acid (3mL) was stirred at room temperature for 18 hours. The mixture was diluted with ice water, extracted 3 times with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue is dissolved in 10mL of ethanol at 0 ℃ and washed with 0.096g (2.5mmol) NaBH 4And (6) processing. After stirring for 30 min, the mixture was acidified with 1M HCl, extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated in vacuo to give 0.60g (81%) of phenyl (4-carbamoyl-3-mercapto-isothiazol-5-yl) -carbamate as a yellow solid.1H NMR (400MHz, acetone-d6)δ13.0(s，1H)，11.0-10.9(bs，1H)，10.3(s，1H)，7.47(t，2H，J＝6.8Hz)，7.37-7.30(m，4H)ppm；MS(APCI，m/z)：296[M+H]+。
Example 4
5- [3- (3-chloro-4-fluoro-benzyl) -ureido]-3- (4-methyl-benzylthio) -isothiazole-4-carboxylic acid
Formic acid amides
To a mixture of (4-carbamoyl-3-mercapto-isothiazol-5-yl) -carbamic acid phenyl ester (0.075g, 0.25mmol) in 0.5mL of DMF was added 4-methylbenzyl chloride (0.036g, 0.25mmol) followed by N, N-diisopropylethylamine (0.033g, 0.25 mmol). After stirring at room temperature for 18 hours, tetrahydrofuran (1mL) was added followed by 3-chloro-4-fluorobenzylamine (0.081g, 0.51 mmol). After stirring at 45 ℃ for 24 h, the mixture was diluted with 1M HCl, extracted 3 times with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by radial chromatography on silica gel, eluting with ethyl acetate-hexanes to give 26mg of 5- [3- (3-chloro-4-fluoro-benzyl) -ureido as a colorless solid]-3- (4-methyl-benzylsulfanyl) -isothiazole-4-carboxylic acid amide. HPLC retention time: 4.9 minutes. 1H NMR (400MHz, acetone-d6)δ7.95(bs，1H)，7.54(dd，1H，J＝2，7.2Hz)，7.39(m，1H)，7.31-7.25(m，3H)，7.11(d，2H，J＝8.0Hz)，7.01(bs，2H)，4.48(m，4H)，2.28(s，3H)ppm；MS(APCI，m/z)：465[M+H]+。
Preparation example 5
2-cyano-iminoacetic acid benzyl ester
To a solution of HCl in ether (4.00L, 1M, 4.00mol) was added warm (liquefied) malononitrile (252mL, 4.00 mol). After dissolution, the solution was cooled to 10 ℃. Benzyl alcohol (414mL, 4.00mol) was then added and the mixture was stirred at 10 ℃ for 0.5 h. The reaction flask was placed in a refrigerator and left at 5 ℃ for 4 days. The resulting solid was cold filtered, washed with cold diethyl ether (1.5L) and then dried in vacuo (40mmHg) for 1 hour to give 545g (2.59mol, 65%) of the Pinner adduct as a white solid. The neutralization of the hydrochloride salt was carried out as follows. A solution of potassium carbonate (359g, 2.59mol) in water (700mL) was prepared and cooled to 5 ℃. The solution was added to a separatory funnel along with ether (2L) and THF (500 mL). The entire separatory funnel was placed in an ice bath until the temperature of the extract reached 5 ℃. The Pinner adduct (545g, 2.59mol) was then added to the separatory funnel and the funnel shaken vigorously for 5 minutes. After filtering off the suspended particles, the aqueous layer was discarded and the organic layer was collected. The organic layer was again placed in a separatory funnel, shaken with brine and then allowed to stand to completely remove the brine layer. The organic layer was concentrated on a rotary evaporator and the unstable product (327g, 1.88mmol, 73%) was used immediately in the next step.
Phenoxycarbonyl isothiocyanates
A suspension of KSCN (80g, 823mmol, from a fresh, previously unopened bottle) in ethyl acetate (2L, dry) was stirred vigorously under nitrogen overnight to powder the KSCN. Phenyl chloroformate (100mL, 800mmol) was then added dropwise over 1 hour to the fine suspension. The reaction solution was stirred overnight at room temperature and then at 5 ℃ for 8 hours. The KCl formed was filtered off and the solvent removed by rotary evaporation, taking care not to bring the temperature of the product above room temperature. The product was redissolved in ether (2L), filtered to form a precipitate, and the ether solution of the product was again concentrated under reduced pressure, taking care not to bring the temperature of the product above room temperature. The product was redissolved in hexane (2L), the precipitate formed was filtered off and the hexane solution of the product was again concentrated under reduced pressure, taking care not to bring the temperature of the product above room temperature. The product thus obtained (101g, 564mmol, 68%) has a very high purity and can be stored at-5 ℃ for several days or at room temperature for several hours, but is generally used immediately as in this example.1H NMR(400MHz，CDCl3)δ7.10-7.21(m，2H)，7.21-7.31(m，1H)，7.31-7.45(m，2H)ppm；13C NMR(101MHz，CDCl3) δ 120.75, 126.77, 129.65, 150.46 ppm; IR (pure) 1190, 1232, 1491, 1590, 1751, 1960cm-1。
2-cyano-3-mercapto-3-phenoxycarbonylamino-iminobenzyl acrylate
To a stirred solution of benzyl 2-cyano-iminoacetate (327g, 1.88mol) in acetonitrile (1L) at 0 ℃ was added a solution of phenoxycarbonyl isothiocyanate (353g, 1.97mol) in acetonitrile (1L) at 0 ℃. The reaction was warmed to room temperature and stirred overnight. The mixture was then placed in a refrigerator and left at 5 ℃ for 48 hours. The solid product was filtered off, extruded and washed with acetonitrile (3X 200mL) at 20 ℃. Air was then passed over the relatively stable solid, followed by further drying under high vacuum to give a yellow solid (282g, 798mmol, 42%).1HNMR(400MHz，DMSO)δ5.39(s，2H)，7.11-7.19(m，2H)，7.20-7.24(m，1H)，7.36-7.46(m，7H)，10.23(bs，1H)，10.67(s，1H)，12.19(bs，1H)ppm；MS(APCI，m/z)：354[M+H]+。
(3-benzyloxy-4-cyano-isothiazol-5-yl) -carbamic acid phenyl ester
To a suspension of the adduct at 0 deg.C, benzyl 2-cyano-3-mercapto-3-phenoxycarbonylaminoiminoacrylate (282g, 798mmol) in acetonitrile (2L), was added pyridine (129mL, 1.60 mol). A solution of bromine (41.1mL, 798mmol) in acetonitrile (200mL) was then added over 15 minutes. The reaction was stirred at 0 ℃ for 1 hour and then at room temperature for 2 hours. The mixture was placed in a refrigerator and kept at 5 ℃ overnight. The solid product was filtered off, washed with 0 ℃ diethyl ether (1L) and dried in the same funnel by passing air over the solid for 4 hours. The solid was added to water (1L), stirred vigorously for 1 hour, filtered and then dried in the same funnel by passing air over the solid overnight to give a white solid (320g, pure product, containing a small amount of water) which was used directly in the next step. 1H NMR(400MHz，DMSO)δ5.35(s，2H)，7.25-7.45(m，10H)，13.20(bs，1H)ppm；MS(APCI，m/z)：350[M-H]-。
4- (carbamoyl-3-hydroxy-isothiazol-5-yl) -carbamic acid phenyl ester
The wet solid, (3-benzyloxy-4-cyano-isothiazol-5-yl) -carbamic acid phenyl ester (320g) was added slowly to concentrated sulfuric acid (650mL) over 1.5 hours. Concentrated sulfuric acid (100mL) was added and the mixture was stirred for an additional 3 hours. Ice (2000g) was slowly added to dilute the viscous solution, followed by vigorous stirring for 2 hours. The suspension was divided into 8 containers placed in a centrifuge and spun at 3000rpm at 21 ℃ for 45 minutes to partially remove the acid. The aqueous layer was discarded, purified water was added, the sediment was resuspended and the above procedure was repeated. After 7 dilution/centrifugation/re-dilution cycles, the pH of the aqueous layer increased to-4, the solids were collected and air was passed through the filter cake in the funnel for 2 days to dry. The already drier solid was crushed, placed again in the funnel and air was again passed through the solid for 1 day. This procedure was repeated until the solid was dried to give a tan solid (234g, 105% yield in two steps, with a small amount of impurities present, but without interfering with the subsequent steps).1H NMR (400MHz, DMSO). delta.7.00 (bs, 1H), 7.27-7.31(m, 3H), 7.40-7.45(m, 2H), 7.89(s, 1H), 8.08(s, 1H), 11.92(s, 1H); MS (APCI, m/z): 184[ M- (H and PhOH) ]-。
[ 4-carbamoyl-3- (2, 6-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl]-ammonia Phenyl formate ester
To a suspension of phenyl (4-carbamoyl-3-hydroxy-isothiazol-5-yl) carbamate (1.77g, 6.23mmol), triphenylphosphine (1.99g, 7.59mmol), o, o' -difluoro-p-methylbenzyl alcohol (1.00g, 6.32mmol) in THF (21mL) was added diisopropyl azodicarboxylate (DIAD, 1.49mL, 7.59mmol) at a rate faster than the dropwise addition. The reaction mixture warmed up and became clear. After stirring for 15 min, most of the THF was removed by rotary evaporation and the crude mixture was purified on silica gel eluting with chloroform/acetone/acetic acid (98.5/0.75/0.75) to give a white solid (802mg, 1.91mmol, 30%).
Example 5
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propane
Base of]-ureido } -isothiazole-4-carboxylic acid amide
To [ 4-carbamoyl-3- (2, 6-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl]Phenyl carbamate (125mg, 0.298mmol) in THF (1mL) was added 1- (3-aminopropyl) -4-methylpiperazine (70mg, 0.45 mmol). The mixture was shaken at 50 ℃ overnight, cooled to room temperature, applied directly to radial chromatography and then eluted with chloroform/methanol/concentrated ammonium hydroxide (50/5/1) to give a white solid (121mg, 0.251mmol, 84%). 1H NMR(400MHz，CDCl3) δ 1.72(t, J ═ 5.81Hz, 2H), 2.20-2.85(m, 10H), 2.28(s, 3H, overlapping multiple peaks from 2.20-2.85), 2.35(s, 3H, overlapping multiple peaks from 2.20-2.85), 3.39(t, J ═ 5.4Hz, 2H), 5.51(s, 2H), 5.74(bs, 1H), 6.74(d, J ═ 8.3Hz, 2H), 7.05(s, 1H), 7.58(bs, 1H), 11.01(bs, 1H) ppm; MS (APCI, m/z): 483[ M + H]+。
Synthesis of representative fluorotoluene derivatives
1, 3-difluoro-5-methyl-benzene (G ═ H)
A mixture of 1-bromomethyl-3, 5-difluoro-benzene (75g, 0.362mol), Pd/C (5%, 5g), and sodium acetate (208g, 2.54mol) in ether (300mL) was treated with hydrogen (50psi) in a Parr shaker for 2 days. The mixture was filtered through celite and the organic solution was washed 3 times with saturated aqueous sodium bicarbonate. The aqueous layer was washed with ether and the combined organic layers were dried (magnesium sulfate), filtered, and partially concentrated by evaporation in a cold water bath. To obtain a mixture with diethyl etherAccording to the formula (I), according to1H NMR integration calculated ratios (-3: 2, ether: product, g: g) to determine the actual yield of product (45.5g, 0.355mol, 98%) in order to determine the ratio of reagents in subsequent reactions.1H NMR(400MHz，CDCl3)δ2.25(s，3H)，6.51-6.56(m，1H)，6.58-6.60(m，2H)ppm。
1, 2, 5-trifluoro-3-methyl-benzene (G ═ F)
The title compound was prepared from 1-bromomethyl-2, 3, 5-trifluoro-benzene in analogy to 3, 5-difluorotoluene above.1H NMR(400MHz，CDCl3)δppm；MS(APCI，m/z)：[M+H]+。
For conversion into R 3 Synthesis of representative benzyl alcohol of
(2, 6-difluoro-4-methylphenyl) -methanol (G ═ H, G ═ Me, G ═ F)
A solution of 1, 3-difluoro-5-methyl-benzene (45.5g, 0.355mol, mixed with a small volume of diethyl ether) in dry THF (1.77L) was cooled to-78 deg.C under a nitrogen atmosphere and n-butyllithium (142mL of a 2.5M solution in hexane, 0.355mol) was added dropwise. The solution was stirred for a further 25 minutes and then treated with DMF (27.5 mL; 0.355 mol). After stirring for an additional 45 minutes, the solution was treated with acetic acid (40.6mL, 0.71mol) and the flask was removed from the-78 deg.C cooling bath. The mixture was stirred at room temperature for 2 hours, then treated with water (300mL) and MeOH (300mL) in that order. Then add NaBH in portions4(26.8g, 0.71mol) and stirred for 1 hour. The flask was cooled in an ice bath and the mixture was treated with 6N HCl until pH-5. The mixture was concentrated by rotary evaporation to remove THF and MeOH, then the product was extracted with ether and washed several times with small volumes of water, then once with brine. The ether layer was dried (sulfur)Magnesium), filtered and concentrated to give an oil (45g, 0.285mol, 80%) which solidifies after refrigeration. 1H NMR(400MHz，CDCl3)δ1.75(t，J＝6.5Hz，1H)，2.32(s，3H)，4.72(d，J＝6.4Hz，2H)，6.69(d，J＝7.9Hz，2H)ppm。
(2, 3, 6-trifluoro-4-methyl-phenyl) -methanol (G ═ F, G' ═ Me, G ═ F)
The title compound was prepared from 1, 2, 5-trifluoro-3-methyl-benzene in analogy to (2, 6-difluoro-4-methyl-phenyl) -methanol above.1H NMR(400MHz，CDCl3)δ1.87(bs，1H)，2.28(d，J＝1.9Hz，3H)，4.74(s，2H)，6.68-6.72(m，1H)ppm。
(4-bromo-2, 6-difluoro-phenyl) -methanol (G ═ H, G ═ Br, G ═ F)
The title compound was prepared from 1-bromo-3, 5-difluoro-benzene following a similar procedure as above for (2, 6-difluoro-4-methyl-phenyl) -methanol, except that Lithium Diisopropylamide (LDA) was used instead of n-butyllithium and the deprotonation time was extended to 45 minutes.1H NMR(400MHz，CDCl3)δ1.91(t，J＝6.5Hz，1H)，4.71(d，J＝6.4Hz，2H)，7.06-7.12(m，2H)ppm。
(4-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 following a similar procedure to (2, 6-difluoro-4-methyl-phenyl) -methanol above, except that Lithium Diisopropylamide (LDA) was used instead of n-butyllithium and the deprotonation time was extended to 45 minutes.1HNMR(400MHz，CDCl3)δ1.89(t，J＝6.5Hz，1H)，4.75(d，J＝6.4Hz，2H)，7.11-7.15(m，1H)ppm。
(3-chloro-2, 6-difluoro-phenyl) -methanol (G ═ Cl, G ═ H, G ═ F)
The title compound was prepared from 1-chloro-2, 4-difluoro-benzene following a procedure analogous to (2, 6-difluoro-4-methyl-phenyl) -methanol above.1H NMR(400MHz，CDCl3) δ 1.90(t, J ═ 6.4Hz, 1H), 4.78(d, J ═ 6.4Hz, 2H), 6.87 (approx. dt, J ═ 1.8, 8.9Hz, 1H), 7.32 (approx. dt, J ═ 5.8, 2.8Hz, 1H) ppm.
(2-fluoro-4, 6-dimethyl-phenyl) -methanol (G ═ H, G' ═ Me, G ═ Me)
A solution of N, N, N ', N' -tetramethylethylenediamine (13.4mL, 88.6mmol) in THF (115mL) was cooled to-78 deg.C and treated with sec-butyllithium (68.2mL of a 1.3M solution in cyclohexane, 88.6 mmol). The resulting yellow solution was stirred at-78 ℃ for 20 minutes and then treated with a solution of 1-fluoro-3, 5-dimethyl-benzene (10.0g, 80.5mmol) in THF (56 mL). The mixture was stirred at-78 ℃ for 1 h, then treated with DMF (6.86mL, 88.6mmol) in THF (26 mL). The reddish brown mixture was stirred for an additional 1 hour and then treated with HOAc (10mL) and water (200 mL). The mixture was warmed to room temperature, extracted with ether (500mL) and the aqueous layer was extracted again with ether (2X 300 mL). The combined organic extracts were washed successively with 0.2M HCl (2X 200mL), water (500mL) and brine (300mL), and the organic layer was dried (magnesium sulfate) and concentrated to give the aldehyde as a clear oil (11.9g, 78.2mmol, 97%). The aldehyde was then dissolved in THF (100mL), MeOH (100mL), and water (100mL) and then portionwise with NaBH4(2.96g, 78.2 mmol). The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to remove THF and MeOH. The remaining aqueous layer was extracted with ether (600mL and 200mL) and the combined organic layers were washed successively with 0.1M HCl (300mL), water (300mL) and brine (300mL), the organic layer was dried (magnesium sulfate) and then concentrated to give an oil (10.8g, 70.4mmol, 90%). 1H NMR(400MHz，CDCl3)δ2.28(s，3H)，2.38(s，3H)，4.70(s，2H)，6.71(d，J＝10.6Hz，1H)，6.79(s，1H)ppm。
(2-fluoro-4-methyl-phenyl) -methanol (G ═ H, G ═ Me, G ═ H)
A solution of 4-bromo-3-fluorotoluene (12.2g, 64.7mmol) in THF (170mL) was cooled to-78 deg.C and n-butyllithium (25.9mL of a 2.5M solution in hexane, 65mmol) was added dropwise. After stirring for 1 hour, the solution was treated with N, N-Dimethylformamide (DMF) (5.5mL, 71mmol) and stirring was continued for 30 minutes,acetic acid (12mL) was then added. The flask was removed from the cooling bath and allowed to warm to room temperature. Then water was added and the product was extracted with ether. The organic layer was washed successively with dilute HCl and brine, then dried (magnesium sulfate) and concentrated. The procedure was repeated (using 11.8g of 4-bromo-3-fluorotoluene) and the combined materials were subjected to the following reduction reaction: the aldehyde (17.6g, 127mmol) was dissolved in THF (165mL), MeOH (165mL), and water (165 mL). NaBH is then added in portions over a period of several minutes4(5.3g, 140mmol) (boiling, exothermic) and stirring was continued for 2 hours. The reaction was quenched by diluting with a large amount of ether and treating with dilute HCl. The organic layer was dried (magnesium sulfate) and concentrated to give an oily product (17.0g, 121mmol, 95%),1H NMR(400MHz，CDCl3)δ2.33(s，3H)，4.69(s，2H)，6.86(d，J＝11.2Hz，1H)，6.93(d，J＝7.9Hz，1H)，7.24-7.28(m，1H)ppm。
(4-chloro-2, 5-difluoro-phenyl) -methanol
To a mixture of 4-chloro-2, 5-difluoro-benzoic acid (15g, 78mmol), Tetrahydrofuran (THF) (75mL), and trimethyl borate (26mL, 230mmol) was added borane-dimethyl sulfide complex (86mL, 86mmol, 10M in DMS) and the mixture was stirred at room temperature for 18 hours. Additional borane-dimethyl sulfide complex (2.47mL, 24.7mmol) was added to complete the reaction. The mixture was poured into 1M aqueous sodium hydroxide solution, extracted 3 times with ether, and the combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The solid residue was triturated with ether-hexane to give 14g (4-chloro-2, 5-difluoro-phenyl) -methanol as a colorless solid. 1HNMR(400MHz，CDCl3)δ7.26(dd，1H，J＝6，8.8Hz)，7.11(dd，1H，J＝6，9.2Hz)，4.71(d，2H，J＝6.0Hz)，1.80(t，1H，J＝6.0Hz)ppm。
Tert-butyl- (2, 3-difluoro-benzyloxy) -dimethyl-silane
To a solution of (2, 3-difluoro-phenyl) -methanol (5.0g, 35mmol), imidazole (4.9g, 72mmol) and DMF (40mL) was added tert-butyldimethylchlorosilane (5.4g, 36 mmol). At room temperatureAfter stirring for 24 hours, the mixture was partitioned between 400mL of diethyl ether and 100mL of water. The organic layer was washed twice with water, dried over magnesium sulfate, filtered and concentrated in vacuo to give 6.8g of tert-butyl- (2, 3-difluoro-benzyloxy) -dimethyl-silane as a colorless oil.1HNMR(400MHz，CDCl3)δ7.22(m，1H)，7.04(m，2H)，4.79(s，2H)，0.91(s，9H)，0.12(s，6H)ppm。
Tert-butyl- (2, 3-difluoro-4-methyl-benzyloxy) -dimethyl-silane
To a solution of TMEDA (3.9mL, 3.0g, 26mmol) in THF (33mL) at-78 deg.C was added sec-butyllithium (20mL, 1.3M in hexane, 26 mmol). After stirring for 20 min, a solution of tert-butyl- (2, 3-difluoro-benzyloxy) -dimethyl-silane (6.0g, 23mmol) in 17mL of THF was added dropwise. After stirring for 1 hour, the solution was added dropwise to a solution of methyl iodide (8mL) in THF (40mL) at-20 ℃. After stirring for 18 h, the reaction was quenched with saturated aqueous ammonium chloride, extracted 3 times with ether, and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give 6.6g of tert-butyl- (2, 3-difluoro-4-methyl-benzyloxy) -dimethyl-silane as a pale yellow oil. 1H NMR(400MHz，CDCl3) δ 7.07 (approx. t, 1H, J ═ 7.2Hz), 6.89 (approx. t, 1H, J ═ 7.3Hz), 4.74(s, 2H), 2.26(d, 3H, J ═ 1.9Hz), 0.87(s, 9H), 0.07(s, 6H) ppm.
(2, 3-difluoro-4-methyl-phenyl) -methanol
To a solution of tert-butyl- (2, 3-difluoro-4-methyl-benzyloxy) -dimethyl-silane (6.5g, 24mmol) in THF (24mL) was added tetrabutylammonium fluoride (24mL of a 1M solution in THF, 24 mmol). After stirring at room temperature for 1 hour, the mixture was poured into water, acidified with 1M hydrochloric acid, extracted 3 times with ethyl acetate, the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (10: 1 to 2: 1 hexane-ethyl acetate) to give (2, 3-difluoro-4-methyl-phenyl) -methanol as a pale yellow oil.
1-bromo-2, 5-difluoro-4-methyl-benzene
A mixture of 2, 5-difluorotoluene (25g, 0.20mol) and iron powder (11g, 0.2mol) was cooled to-5 ℃. Bromine was added dropwise while keeping the internal temperature of the reaction solution at 0 ℃ or lower. After stirring for 3 hours, the mixture was diluted with ether, filtered and washed with aqueous sodium thiosulfate. The aqueous layer was extracted with ether and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Atmospheric distillation gave 34g of 1-bromo-2, 5-difluoro-4-methyl-benzene as a colorless oil (b.p.180 ℃). 1H NMR(300MHz，CDCl3)δ7.20(dd，1H，J＝6.0，8.5Hz)，6.93(m，1H)，2.23(s，3H)ppm。
(2, 5-difluoro-4-methyl-phenyl) -methanol
A mixture of 1-bromo-2, 5-difluoro-4-methyl-benzene (3.3g, 16mmol) and diethyl ether (75mL) was cooled to-78 deg.C, then a solution of n-butyllithium in hexane (5.4mL, 2.5M, 13.5mmol) was added dropwise. After stirring for 1 hour, dimethylformamide (1.1mL, 14mmol) was added and the mixture was stirred for 1 hour. The mixture was treated with 1M HCl and water, warmed to room temperature and extracted 3 times with ether. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was diluted with tetrahydrofuran (50mL) and the mixture was treated with sodium borohydride (0.5g, 13.5mmol) and ethanol (2 mL). After stirring for 30 minutes, the mixture was carefully diluted with 0.5M hydrochloric acid, extracted 3 times with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was recrystallized from hexane to give 1.24g (54%) of (2, 5-difluoro-4-methyl-phenyl) -methanol as a colorless solid.1HNMR(400MHz，CDCl3)δ7.05(dd，1H，J＝6.0，9.2Hz)，6.84(dd，1H，J＝6.4，10Hz)，4.68(d，2H，J＝6.0Hz)，2.23(s，3H)，1.76(t，1H，J＝6.0Hz)ppm。
(5-chloro-2-fluoro-4-methyl-phenyl) -methanol
(5-chloro-2-fluoro-4-methyl-phenyl) -methanol was prepared in a similar manner to (2, 5-difluoro-4-methyl-phenyl) -methanol starting with 2-chloro-5-fluorotoluene.1HNMR(400MHz，CDCl3)δ7.38(d，1H，J＝6.8Hz)，6.92(d，1H，J＝10Hz)，4.69(s，2H)，2.34(s，3H)ppm。
4-chloro-2, 6-difluoro-benzaldehyde
To a solution of 3, 5-difluoro-1-chlorobenzene (5.0g, 34mmol) in tetrahydrofuran (70mL) at-78 deg.C was added a solution of n-butyllithium in hexane (12.1mL, 2.5M, 30 mmol). After stirring for 1 hour, dimethylformamide (5.2mL, 67mmol) was added and the mixture was stirred for 1.5 hours. The mixture was warmed to room temperature, diluted with ether and poured into 150ml0.5m hydrochloric acid. The aqueous phase was extracted 3 times with ether and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give 5.72g (96%) of 4-chloro-2, 6-difluoro-benzaldehyde as a colorless solid. 1H NMR(400MHz，CDCl3)δ10.27(s，1H)，7.04(d，2H，J＝7.9Hz)ppm。
(4-chloro-2, 6-difluoro-phenyl) -methanol
To a mixture of 4-chloro-2, 6-difluoro-benzaldehyde (5.7g, 32mmol), tetrahydrofuran (150mL) and ethanol (20mL) was added sodium borohydride (1.2g, 32mmol) at 0 ℃. The mixture was stirred for 30 min, warmed to room temperature and supplemented with sodium borohydride (0.40g, 11mmol) to complete (TLC). The mixture was concentrated in vacuo, diluted with ether and carefully treated with 1M hydrochloric acid. The aqueous phase was extracted 3 times with diethyl ether, and the combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was triturated with pentane to give 4.8g (83%) of (4-chloro-2, 6-difluoro-phenyl) -methanol as a colorless solid.1H NMR(300MHz，CDCl3)δ7.04(d，2H，J＝7.1Hz)，4.73(s，2H)ppm。
General procedure for the preparation of isothiazolophenylcarbamates:
[ 4-carbamoyl-3- (2, 5-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl]-ammonia Phenyl formate ester
To (4-carbamoyl-3-hydroxy-isothiazole)Diethyl azodicarboxylate (1.3mL, 8.0mmol) was added to a mixture of phenyl (2.1g, 7.6mmol) carbamate (2.1g, 7.6mmol), (2, 5-difluoro-4-methyl-phenyl) -methanol (1.2g, 7.6mmol), triphenylphosphine (2.1g, 8.0mmol) and tetrahydrofuran (19 mL). After stirring at room temperature for 16 h, additional (2, 5-difluoro-4-methyl-phenyl) -methanol (0.24g, 1.5mmol), triphenylphosphine (0.42g, 1.6mmol) and diethyl azodicarboxylate (0.30mL, 1.8mmol) were added and the mixture was stirred for 1 h. After concentration in vacuo, the mixture was purified by silica gel chromatography eluting with acetone-acetic acid-dichloromethane (0.5%, 0.5%, 99%) and triturated with ether-hexane to give 1.1g (35%) of [ 4-carbamoyl-3- (2, 5-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl as a colorless solid ]-phenyl carbamate. HPLC retention time: 4.8 minutes.1HNMR(400MHz，CD3OD)δ7.40(t，2H，J＝8.0Hz)，7.27(t，1H，J＝7.2Hz)，7.20(d，2H，J＝8.4Hz)，7.17(dd，1H，J＝6.0，9.2Hz)，7.00(dd，1H，J＝6.4，10Hz)，5.49(s，2H)，2.24(s，3H)ppm。
[ 4-carbamoyl-3- (2, 3-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl]-ammonia Phenyl formate ester
The title compound was prepared as described in example 3 using (2, 3-difluoro-4-methyl-phenyl) -methanol to give 1.7g (57%) of [ 4-carbamoyl-3- (2, 3-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl as a colorless solid]-phenyl carbamate. HPLC retention time: 4.8 minutes.1H NMR(400MHz，CDCl3)δ11.38(s，1H)，7.40(t，2H，J＝8.0Hz)，7.26(t，1H，J＝7.2Hz)，7.20(d，1H，J＝8.4Hz)，7.14(b，1H)，7.11(t，1H，J＝7.6Hz)，6.94(t，1H，J＝7.2Hz)，5.6(b，1H)，5.52(s，2H)，2.31(d，3H，J＝1.7Hz)ppm。
[ 4-carbamoyl-3- (2, 5-difluoro-4-chloro-benzyloxy) -isothiazol-5-yl]-amino group Benzoic acid phenyl ester
The title compound was prepared as described in example 3 using (2, 5-difluoro-4-chloro-phenyl) -methanol to yield 0.86g (26%) of colorlessSolid [ 4-carbamoyl-3- (2, 5-difluoro-4-chloro-benzyloxy) -isothiazol-5-yl]-phenyl carbamate. HPLC retention time: 4.8 minutes.1H NMR(400MHz，DMSO-d6)δ11.73(s，1H)，8.04(s，1H)，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) -isothiazol-5-yl]-amino group Benzoic acid phenyl ester
The title compound was prepared as described in example 3 using (2, 6-difluoro-4-chloro-phenyl) -methanol to give 0.86g (26%) of [ 4-carbamoyl-3- (2, 6-difluoro-4-chloro-benzyloxy) -isothiazol-5-yl as a colorless solid]-phenyl carbamate. HPLC retention time: 4.5 minutes. 1H NMR(400MHz，CDCl3，CD3OD)δ7.31(t，2H，J＝8.0Hz)，7.18(t，1H，J＝7.6Hz)，7.10(d，2H，J＝7.6Hz)，6.92(d，2H，J＝7.2Hz)，5.45(s，2H)ppm。
General Process for the preparation of isothiazoleureas
Example 6
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- [3- (4-pyrrolidin-1-ylbutyl) -urea Base of]-isothiazole-4-carboxylic acid amide
Reacting [ 4-carbamoyl-3- (2, 5-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl]A mixture of phenyl carbamate (0.34g, 0.81mmol), 4-pyrrolidinylbutylamine (0.12g, 0.81mmol) and tetrahydrofuran (2.8mL) was shaken at 45-50 ℃ for 24 hours. The mixture was concentrated and purified by radial chromatography (4mm plate, CH)3OH-CHCl3-NH4OH (10: 89: 1) to (15: 84: 1)) to give 0.31g of the title compound as a colorless solid. This material was dissolved in about 10mL 4: 1 methanol-chloroform at-10 ℃ and dissolved with methanesulfonic acid solution (0.043mL in 0.5mL CH)3Solution in OH). After stirring for 5 minutes, the mixture is concentrated in vacuo and the residue is triturated with methanol-ether to give 0.35g of a colourless solidTitle compound (82%). HPLC retention time: 3.3 minutes.1H NMR(400MHz，D2O)δ6.74(dd，1H，J＝6.0，9.6Hz)，6.63(dd，1H，J＝6.4，10.4Hz)，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- [3- (4-hydroxy-5-piperidin-1-yl-pentan-e Radical) -ureido radical]-isothiazole-4-carboxylic acid amide
The title compound was synthesized from [ 4-carbamoyl-3- (2, 5-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] following an analogous method to example 6 ]Phenyl carbamate and 5-amino-1-piperidin-1-yl-pent-2-ol. HPLC retention time: 3.3 minutes.1HNMR(400MHz，CD3OD)δ7.18(dd，1H，J＝6.0，9.2Hz)，7.05(dd，1H，J＝6.0，10Hz)，5.47(s，2H)，3.80(m，1H)，3.23(t，2H，J＝6.4Hz)，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- {3- [4- (3-hydroxy-pyrrolidine-1-) Alkyl) -butyl]-ureido } -isothiazole-4-carboxylic acid amide
The title compound was synthesized from [ 4-carbamoyl-3- (2, 5-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] following an analogous method to example 6]Phenyl carbamate and (R) -1- (4-amino-butyl) -pyrrolidin-3-ol. HPLC retention time: 3.2 minutes.1HNMR(400MHz，CD3OD)δ7.19(dd，1H，J＝6.0，9.2Hz)，7.04(dd，1H，J＝6.0，10Hz)，5.45(s，2H)，4.34(m，1H)，3.23(m，2H)，2.86(dd，1H，J＝6.0，10.4Hz)，2.78(m，1H)，2.65-2.54(m，4H)，2.25(s，3H)，2.14(m，1H)，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- [3- (6-dimethylamino-hexyl) -urea Base of]-isothiazole-4-carboxylic acid amide
The title compound was synthesized from [ 4-carbamoyl-3- (2, 5-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] following an analogous method to example 6]Phenyl carbamate and N1, N1-dimethyl-hexane-1, 6-diamine. HPLC retention time: 3.4 minutes.1HNMR(400MHz，CD3OD)δ7.18(dd，1H，J＝6.0，9.2Hz)，7.03(dd，1H，J＝6.4，10Hz)，5.45(s，2H)，3.19(t，2H，J＝7.2Hz)，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-4-methyl-benzyloxy) -5- {3- [4- (2-hydroxymethyl-pyrrolidine-1- Alkyl) -butyl]-ureido } -isothiazole-4-carboxylic acid amide
The title compound was synthesized from [ 4-carbamoyl-3- (2, 5-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] following an analogous method to example 6 ]Phenyl carbamate and (S) - [1- (4-amino-butyl) -pyrrolidin-2-yl]-methanol. HPLC retention time: 3.2 minutes.1H NMR(400MHz，CD3OD)δ7.18(dd，1H，J＝6.0，9.2Hz)，7.04(dd，1H，J＝6，4，10Hz)，5.45(s，2H)，3.62-3.56(m，2H)，3.29-3.23(m，2H)，3.02(m，1H)，2.78(m，1H)，2.83(m，1H)，2.51(m，2H)，2.24(d，3H，J＝1.6Hz)，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- [4- (3-hydroxy-piperidin-1-yl) -butan-e Base of]-ureido } -isothiazole-4-carboxylic acid amide
The title compound was synthesized from [ 4-carbamoyl-3- (2, 5-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] following an analogous method to example 6]Phenyl carbamate and 1- (4-amino-butyl) -piperidin-3-ol. HPLC retention time: 3.3 minutes.1HNMR(400MHz，CD3OD)δ7.18(dd，1H，J＝6.8，9.6Hz)，7.04(dd，1H，J＝5.6，10Hz)，5.45(s，2H)，3.64(m，1H)，3.24-3.22(m，2H)，2.90(m，1H)，2.73(m，1H)，2.37(m，2H)，2.25(d，3H，J＝1.6Hz)，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- [3- (5-isopropylamino-pentyl) -urea Base of]-isothiazole-4-carboxylic acid amide
The title compound was synthesized from [ 4-carbamoyl-3- (2, 5-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] following an analogous method to example 6]Phenyl carbamate and N1-isopropyl-pentane-1, 5-diamine. HPLC retention time: 3.4 minutes.1HNMR(300MHz，CD3OD)δ7.20(dd，1H，J＝5.7，9.0Hz)，7.06(dd，1H，J＝6.3，10Hz)，5.47(s，2H)，3.23(t，2H，J＝6.6Hz)，2.93(s，1H，J＝6.3Hz)，2.70(m，2H)，2.27(d，3H，J＝1.8Hz)，1.7-1.5(m，4H)，1.5-1.3(m，2H)，1.11(d，6H，J＝6.6Hz)ppm；MS(APCI，m/z)：470[M+H]+。
Example 13
3- (2, 3-difluoro-4-methyl-benzyloxy) -5- {3- [4- (3, 4-dihydroxy-pyrrolidine-1- Alkyl) -butyl]-ureido } -isothiazole-4-carboxylic acidAmides of carboxylic acids
The title compound was synthesized from [ 4-carbamoyl-3- (2, 5-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] following an analogous method to example 6 ]Phenyl carbamate and 1- (4-amino-butyl) -pyrrolidine-3, 4-diol. HPLC retention time: 3.1 minutes.1HNMR(400MHz，CD3OD)δ7.17(t，1H，J＝7.6Hz)，7.03(t，1H，J＝7.3Hz)，5.49(s，2H)，4.01(s，2H)，3.21(s，2H)，2.93(m，2H)，2.48(m，4H)，2.29(s，3H)，1.54(bs，4H)ppm；MS(APCI，m/z)：500[M+H]-。
Example 14
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- [3- (3-hydroxy-5-pyrrolidin-1-yl-pentane Radical) -ureido radical]-isothiazole-4-carboxylic acid amide-methanesulfonate
The title compound was synthesized from [ 4-carbamoyl-3- (2, 5-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] following an analogous method to example 6]Phenyl carbamate and 1-amino-5-pyrrolidin-1-yl-pentan-3-ol. HPLC retention time: 3.1 minutes.1HNMR(400MHz，D2O)δ6.81(d，2H，J＝7.2Hz)，5.17(s，2H)，3.61(bm，1H)，3.47(bm，2H)，3.2-3.0(m，4H)，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
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- [3- (3-hydroxy-5-pyrrolidin-1-yl-pentane Radical) -ureido radical]-isothiazole-4-carboxylic acid amide-methanesulfonate
The title compound was synthesized from [ 4-carbamoyl-3- (2, 5-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] following an analogous method to example 6]Phenyl carbamate and 1-amino-5-pyrrolidin-1-yl-pentan-3-ol. HPLC retention time: 3.3 minutes.1HNMR(400MHz，CD3OD)δ7.17(d，2H，J＝6.4Hz)，5.51(s，2H)，3.64(bm，1H)，3.24(t，2H，J＝6.0Hz)，2.92(m，1H)，2.72(m，1H)，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 16
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- [3- (3-hydroxy-5-pyrrolidin-1-yl-pentane Radical) -ureido radical]-isothiazole-4-carboxylic acid amide-methanesulfonate
The title compound was synthesized from [ 4-carbamoyl-3- (2, 5-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] following an analogous method to example 6 ]Phenyl carbamate and 1-amino-5-pyrrolidin-1-yl-pentan-3-ol. HPLC retention time: 3.3 minutes.1HNMR(400MHz，CD3OD)δ7.17(d，2H，J＝6.4Hz)，5.51(s，2H)，3.64(bm，1H)，3.24(t，2H，J＝6.0Hz)，2.92(m，1H)，2.72(m，1H)，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
5- (3- {4- [ bis- (2-hydroxy-ethyl) -amino]-butyl } -ureido) -3- (2, 5-difluoro- 4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide
The title compound was synthesized from [ 4-carbamoyl-3- (2, 5-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] following an analogous method to example 6]Phenyl carbamate and 2- [ (4-amino-butyl) - (2-hydroxy-ethyl) -amino]-ethanol. HPLC retention time: 3.1 minutes.1H NMR(400MHz，CD3OD)δ7.20(dd，1H，J＝6.0，9.2Hz)，7.04(dd，1H，J＝6.8，9.6Hz)，5.45(s，2H)，3.63(t，4H，J＝5.6Hz)，3.28(m)，2.74(m，4H)，2.68(m，2H)，2.25(d，3H，J＝2.0Hz)，1.56(m，4H)ppm；MS(APCI，m/z)：502[M+H]+。
Example 18
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- {3- [4- (3, 4-dihydroxy-pyrrolidine-1- Alkyl) -butyl]-ureido } -isothiazole-4-carboxylic acid amide
The title compound was synthesized from [ 4-carbamoyl-3- (2, 5-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] following an analogous method to example 8]Phenyl carbamate and 1- (4-amino-butyl) -pyrrolidine-3, 4-diol. HPLC retention time: and (3) minutes.1HNMR(400MHz，CD3OD)δ7.20(dd，1H，J＝6.0，9.2Hz)，7.04(dd，1H，J＝6.8，9.6Hz)，5.45(s，2H)，3.63(t，4H，J＝5.6Hz)，3.28(m)，2.74(m，4H)，2.68(m，2H)，2.25(d，3H，J＝2.0Hz)，1.56(m，4H)ppm。
Example 19
5- [3- (4-tert-butylamino-3-hydroxy-butyl) -ureido]-3- (2, 5-difluoro-4-methyl- Benzyloxy) -isothiazole-4-carboxylic acid amide
The title compound was synthesized from [ 4-carbamoyl-3- (2, 5-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] following an analogous method to example 6 ]Phenyl carbamate and 4-amino-1-tert-butylamino-butan-2-ol. HPLC retention time: 3.3 minutes.1HNMR(400MHz，CD3OD)δ7.18(dd，1H，J＝6.8，9.6Hz)，7.04(dd，1H，J＝6.4，10Hz)，5.45(s，2H)，3.66(m，1H)，3.34(t，2H，J＝7.6Hz)，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+H]-。
Example 20
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propane Base of]-ureido } -isothiazole-4-carboxylic acid amide-hydrochloride
The title compound was synthesized from [ 4-carbamoyl-3- (2, 6-difluoro-4) -according to a similar manner to example 6-chloro-benzyloxy) -isothiazol-5-yl]Phenyl carbamate and 3- (4-methyl-piperazin-1-yl) -propylamine.1H NMR(400MHz，D2O)δ6.86(bm，2H)，5.20(s，2H)，3.4-2.6(bm，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- [3- (3-hydroxy-5-isopropylamino-pentyl) -one-step Urea radical]-isothiazole-4-carboxylic acid amide
The title compound was synthesized from [ 4-carbamoyl-3- (2, 6-difluoro-4-chloro-benzyloxy) -isothiazol-5-yl ] -according to an analogous method to example 6]Phenyl carbamate and 1-amino-5-isopropylamino-pentan-3-ol. HPLC retention time: 3.2 minutes.1HNMR(400MHz，CD3OD)δ7.17(d，1H，J＝7.6Hz)，5.52(s，2H)，3.69(m，1H)，3.34(t，2H，J＝6.4Hz)，2.80(s，1H，J＝6.0Hz)，2.73(m，2H)，1.68-1.58(m，4H)，1.06(d，6H，J＝6.0Hz)ppm；MS(APCI，m/z)：506[M+H]+。
Example 22
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- [3- (3-hydroxy-5-isopropylamino-pentyl) -one-step Urea radical]-isothiazole-4-carboxylic acid amide
The title compound was synthesized from [ 4-carbamoyl-3- (2, 6-difluoro-4-chloro-benzyloxy) -isothiazol-5-yl ] -according to an analogous method to example 6]Phenyl carbamate and 1-amino-5-isopropylamino-pentan-3-ol. HPLC retention time: 3.2 minutes. 1HNMR(400MHz，CD3OD)δ7.17(d，1H，J＝7.6Hz)，5.52(s，2H)，3.69(m，1H)，3.34(t，2H，J＝6.4Hz)，2.80(s，1H，J＝6.0Hz)，2.73(m，2H)，1.68-1.58(m，4H)，1.06(d，6H，J＝6.0Hz)ppm；MS(APCI，m/z)：506[M+H]+。
Example 23
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- (3- {6- [4- (2-hydroxy-ethyl) -piperazine- 1-radical]-hexyl } -ureido) -isothiazole-4-carboxylic acid amide
The title compound was synthesized from [ 4-carbamoyl-3- (2, 5-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] following an analogous method to example 6]Phenyl carbamate and 2- [4- (6-amino-hexyl) -piperazin-1-yl]-ethanol. HPLC retention time: 3.0 minutes.1H NMR(400MHz，CD3OD)δ7.17(d，1H，J＝6.4，9.6Hz)，7.01(m，1H)，5.44(s，2H)，3.64(t，2H，J＝5.6Hz)，3.18(t，2H，J＝6.8Hz)，2.7-2.4(bm，8H)，2.50(t，2H，J＝6.0Hz)，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 amides
The title compound was synthesized from [ 4-carbamoyl-3- (2, 5-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] following an analogous method to example 6]Phenyl carbamate and 2- [4- (6-amino-hexyl) -piperazin-1-yl]-ethanol. HPLC retention time: 3.0 minutes.1H NMR(400MHz，CD3OD)δ7.17(d，1H，J＝6.4，9.6Hz)，7.01(m，1H)，5.44(s，2H)，3.64(t，2H，J＝5.6Hz)，3.18(t，2H，J＝6.8Hz)，2.7-2.4(bm，8H)，2.50(t，2H，J＝6.0Hz)，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 25
5- {3- [3- (4-methyl-piperazin-1-yl) -propyl]-ureido } -3- (2, 3, 6-trifluoro-4-methyl) Yl-benzyloxy) -isothiazole-4-carboxylic acid amide
HeadlineingCompound was prepared in analogy to example 1 from [ 4-carbamoyl-3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazol-5-yl]Phenyl carbamate and 3- (4-methyl-piperazin-1-yl) -propylamine. MS (APCI, m/z): 501[ M + H [ ] ]+。
Example 26
3- (2-fluoro-4-methyl-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propyl]- Ureido } -isothiazole-4-carboxylic acid amides
The title compound was synthesized from [ 4-carbamoyl-3- (2-fluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] following an analogous procedure to example 1]Phenyl carbamate and 3- (4-methyl-piperazin-1-yl) -propylamine. MS (APCI, m/z): 465[ M + H]+。
Example 27
3- (2-fluoro-4-methyl-benzyloxy) -5- [3- (5-isopropylamino-pentyl) -ureido]-iso Thiazole-4-carboxylic acid amides
The title compound was synthesized from [ 4-carbamoyl-3- (2-fluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] following an analogous procedure to example 1]Phenyl carbamate and N-isopropyl-pentane-1, 5-diamine. MS (APCI, m/z): 452[ M + H]+。
Example 28
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -urea Base of]-isothiazole-4-carboxylic acid amide
The title compound was synthesized from [ 4-carbamoyl-3- (2, 6-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] -according to an analogous method to example 1]Phenyl carbamate and 4-pyrrolidin-1-yl-butylamine.1H NMR(400MHz，CDCl3)δ1.63(br.s，4H)，1.83(br.s，4H)，2.34(s，3H)，2.46-2.52(m，6H)，3.28(s，2H)，5.40(s，1H)，5.50(s，2H)，6.74(d，J＝8.3Hz，2H)，6.98(s，1H)，7.94(br.s，1H)，10.83(br.s，1H)ppm；MS(APCI，m/z)：468[M+H]+。
Example 29
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- (3- {4- [4- (2-hydroxy-ethyl) -piperazine- 1-radical]-butyl } -ureido) -isothiazole-4-carboxylic acid amide
The title compound was synthesized from [ 4-carbamoyl-3- (2, 6-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] -according to an analogous method to example 1]Phenyl carbamate and 2- [4- (4-amino-butyl) -piperazin-1-yl]-ethanol. MS (APCI, m/z): 527[ M + H]+。
Example 30
3- (4-bromo-2, 6-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido]- Isothiazole-4-carboxylic acid amides
The title compound was synthesized from [3- (4-bromo-2, 6-difluoro-benzyloxy) -4-carbamoyl-isothiazol-5-yl ] -according to an analogous method to example 1]Phenyl carbamate and 4-pyrrolidin-1-yl-butylamine. MS (APCI, m/z): 532 and 534[ M + H]+。
Example 31
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- [3- (4-hydroxy-5-piperidin-1-yl-pentan-e Radical) -ureido radical]-isothiazole-4-carboxylic acid amide
The title compound was synthesized from [ 4-carbamoyl-3- (2, 6-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] -according to an analogous method to example 1]Phenyl carbamate and 5-amino-1-piperidin-1-yl-pent-2-ol. MS (APCI, m/z): 512[ M + H]+。
Example 32
3- (4-bromo-2, 3, 6-trifluoro-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propane Base of]-ureido } -isothiazole-4-carboxylic acid amide
The title compound was synthesized in analogy to example 1 from [3- (4-bromo-2, 3, 6-trifluoro-benzyloxy) -4-carbamoyl-isothiazol-5-yl ]Phenyl carbamate and 3- (4-methyl-piperazin-1-yl) -propylamine. MS (APCI, m/z): 565 and 567[ M + H ]]+。
Example 33
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propane Base of]-ureido } -isothiazole-4-carboxylic acid amide
The title compound was synthesized from [ 4-carbamoyl-3- (2, 6-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] -according to an analogous method to example 1]Phenyl carbamate and 3- (4-methyl-piperazin-1-yl) -propylamine. MS (APCI, m/z): 483[ M + H]+。
Example 34
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- [3- (3-hydroxy-5-pyrrolidin-1-yl-pentane Radical) -ureido radical]-isothiazole-4-carboxylic acid amide
The title compound was synthesized from [ 4-carbamoyl-3- (2, 6-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] -according to an analogous method to example 1]Phenyl carbamate and 1-amino-5-pyrrolidin-1-yl-pentan-3-ol. MS (APCI, m/z): 498[ M + H]+。
Example 35
5- [3- (4-pyrrolidin-1-yl-butyl) -ureido]-3- (2, 3, 6-trifluoro-4-methyl-benzyloxy Yl) -isothiazole-4-carboxylic acid amide
The title compound was synthesized from [ 4-carbamoyl-3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] following an analogous procedure to example 1]-carbamic acid benzene Ester and 4-pyrrolidin-1-yl-butylamine. 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) Yl-benzyloxy) -isothiazole-4-carboxylic acid amide
The title compound was synthesized from [ 4-carbamoyl-3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] following an analogous procedure to example 1]Phenyl carbamate and 1-amino-5-pyrrolidin-1-yl-pentan-3-ol. MS (APCI, m/z): 516[ M + H]+。
Example 37
5- {3- [2- (1-methyl-pyrrolidin-2-yl) -ethyl]-ureido } -3- (2, 3, 6-trifluoro-4- Methyl-benzyloxy) -isothiazole-4-carboxylic acid amide
The title compound was synthesized from [ 4-carbamoyl-3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] following an analogous procedure to example 1]Phenyl carbamate and 2- (1-methyl-pyrrolidin-2-yl) -ethylamine. MS (APCI, m/z): 472[ M + H]+。
Example 38
5- [3- (4-dimethylamino-butyl) -ureido]-3- (2, 3, 6-trifluoro-4-methyl-benzyloxy Yl) -isothiazole-4-carboxylic acid amide
The title compound was synthesized from [ 4-carbamoyl-3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] following an analogous procedure to example 1]Phenyl carbamate and N, N-dimethyl-butane-1, 4-diamine. MS (APCI, m/z): 460[ M + H ] ]+。
Example 39
5- [3- (3-dimethylamino-propyl) -ureido]-3- (2, 3, 6-trifluoro-4-methyl-benzyloxy Yl) -isothiazole-4-carboxylic acid amide
The title compound was synthesized from [ 4-carbamoyl-3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] following an analogous procedure to example 1]Phenyl carbamate and N, N-dimethyl-propane-1, 3-diamine. MS (APCI, m/z): 446[ M + H [ ]]+。
Example 40
5- [3- (3-hydroxy-5-isopropylamino-pentyl) -ureido]-3- (2, 3, 6-trifluoro-4-methyl) Yl-benzyloxy) -isothiazole-4-carboxylic acid amide
The title compound was synthesized from [ 4-carbamoyl-3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] following an analogous procedure to example 1]Phenyl carbamate and 1-amino-5-isopropylamino-pentan-3-ol. MS (APCI, m/z): 504[ M + H]+。
EXAMPLE 41
5- [3- (3-isopropylamino-propyl) -ureido]-3- (2, 3, 6-trifluoro-4-methyl-benzyloxy Yl) -isothiazole-4-carboxylic acid amide
The title compound was synthesized from [ 4-carbamoyl-3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] following an analogous procedure to example 1]Phenyl carbamate and N-isopropyl-propane-1, 3-diamine. MS (APCI, m/z): 460[ M + H ]]+。
Example 42
5- {3- [4- (4-methyl-piperazin-1-yl) -butyl]-ureido } -3- (2, 3, 6-trifluoro-4-methyl) Yl-benzyloxy) -isothiazole-4-carboxylic acid amide
The title compound was synthesized from [ 4-carbamoyl-3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] following an analogous procedure to example 1]-amino groupPhenyl formate and 4- (4-methyl-piperazin-1-yl) -butylamine. MS (APCI, m/z): 515[ M + H]+。
Example 43
5- (3- {4- [4- (2-hydroxy-ethyl) -piperazin-1-yl]-butyl } -ureido) -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide
The title compound was synthesized from [ 4-carbamoyl-3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] following an analogous procedure to example 1]Phenyl carbamate and 2- [4- (4-amino-butyl) -piperazin-1-yl]-ethanol. MS (APCI, m/z): 545[ M + H]+。
Example 44
5- [3- (3-pyrrolidin-1-yl-propyl) -ureido]-3- (2, 3, 6-trifluoro-4-methyl-benzyloxy Yl) -isothiazole-4-carboxylic acid amide
The title compound was synthesized from [ 4-carbamoyl-3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] following an analogous procedure to example 1]Phenyl carbamate and 3-pyrrolidin-1-yl-propylamine. MS (APCI, m/z): 472[ M + H]+。
Example 45
5- [3- (4-hydroxy-5-piperidin-1-yl-pentyl) -ureido]-3- (2, 3, 6-trifluoro-4-methyl) -benzyloxy) -isothiazole-4-carboxylic acid amide
The title compound was synthesized from [ 4-carbamoyl-3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] following an analogous procedure to example 1]Phenyl carbamate and 5-amino-1-piperidin-1-yl-pent-2-ol. MS (APCI, m/z): 530[ M + H]+。
Example 46
5- (3- {4- [ ethyl- (2-hydroxy) ethyl esterYl-ethyl) -amino]Butyl } -ureido) -3- (2, 3, 6-tris Fluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide
The title compound was synthesized from [ 4-carbamoyl-3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] following an analogous procedure to example 1]Phenyl carbamate and 2- [ (4-amino-butyl) -ethyl-amino]-ethanol. MS (APCI, m/z): 504[ M + H]+。
Example 47
3- (4-bromo-2, 6-difluoro-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propane Base of]-ureido } -isothiazole-4-carboxylic acid amide
The title compound was synthesized from [3- (4-bromo-2, 6-difluoro-benzyloxy) -4-carbamoyl-isothiazol-5-yl ] -according to an analogous method to example 1]Phenyl carbamate and 3- (4-methyl-piperazin-1-yl) -propylamine. MS (APCI, m/z): 547 and 549[ M + H]+。
Example 48
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- {3- [2- (1-methyl-pyrrolidin-2-yl) - Ethyl radical]-ureido } -isothiazole-4-carboxylic acid amide
The title compound was synthesized from [ 4-carbamoyl-3- (2, 6-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] -according to an analogous method to example 1]Phenyl carbamate and 2- (1-methyl-pyrrolidin-2-yl) -ethylamine. MS (APCI, m/z): 454[ M + H]+。
Example 49
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- [3- (4-dimethylamino-butyl) -urea Base of]-isothiazole-4-carboxylic acid amide
The title compound was prepared from [ 4-carbamoyl-3- (2, 6-difluoro-4-methyl-benzyloxy) -isothiazole in analogy to example 1Azol-5-yl]Phenyl carbamate and N, N-dimethyl-butane-1, 4-diamine. MS (APCI, m/z): 442[ M + H ]]+。
Example 50
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- [3- (3-dimethylamino-propyl) -urea Base of]-isothiazole-4-carboxylic acid amide
The title compound was synthesized from [ 4-carbamoyl-3- (2, 6-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] -according to an analogous method to example 1]Phenyl carbamate and N, N-dimethyl-propane-1, 3-diamine. MS (APCI, m/z): 428[ M + H]+。
Example 51
3- (4-bromo-2, 3, 6-trifluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -urea Base of]-isothiazole-4-carboxylic acid amide
The title compound was synthesized in analogy to example 1 from [3- (4-bromo-2, 3, 6-trifluoro-benzyloxy) -4-carbamoyl-isothiazol-5-yl]Phenyl carbamate and 4-pyrrolidin-1-yl-butylamine. MS (APCI, m/z): 550 and 552[ M + H ]]+。
Example 52
5- [3- (3-methylamino-propyl) -ureido]-3- (2, 3, 6-trifluoro-4-methyl-benzyloxy Yl) -isothiazole-4-carboxylic acid amide
The title compound was synthesized from [ 4-carbamoyl-3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] following an analogous procedure to example 1]Phenyl carbamate and N-methyl-propane-1, 3-diamine. MS (APCI, m/z): 432[ M + H]+。
Example 53
5- [3- (3-amino-propyl) -3-methyl-ureido]-3-(2，3，6-trifluoro-4-methyl-benzyloxy Yl) -isothiazole-4-carboxylic acid amide
The title compound was synthesized from [ 4-carbamoyl-3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] following an analogous procedure to example 1]Phenyl carbamate and N-methyl-propane-1, 3-diamine. MS (APCI, m/z): 432[ M + H]+。
Example 54
5- [3- (4-diethylamino-butyl) -ureido]-3- (2, 3, 6-trifluoro-4-methyl-benzyloxy Yl) -isothiazole-4-carboxylic acid amide
The title compound was synthesized from [ 4-carbamoyl-3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] following an analogous procedure to example 1 ]Phenyl carbamate and N, N-diethyl-butane-1, 4-diamine. MS (APCI, m/z): 488[ M + H]+。
Example 55
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- [3- (3-pyrrolidin-1-yl-propyl) -urea Base of]-isothiazole-4-carboxylic acid amide
The title compound was synthesized from [ 4-carbamoyl-3- (2, 6-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] -according to an analogous method to example 1]Phenyl carbamate and 3-pyrrolidin-1-yl-propylamine. MS (APCI, m/z): 454[ M + H]+。
Example 56
3- (3-chloro-2, 6-difluoro-4-methyl-benzyloxy) -5- [3- (4-dimethylamino-butyl) - Urea radical]-isothiazole-4-carboxylic acid amide
The title compound was synthesized from [ 4-carbamoyl-3- (3-chloro-2, 6-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl following an analogous procedure to example 1]Phenyl carbamate and N, N-diethyl-butane-1, 4-diamineAnd (4) preparing. MS (APCI, m/z): 476[ M + H ]]+。
Example 57
5- (3- {4- [ bis- (2-hydroxy-ethyl) -amino]-butyl } -ureido) -3- (2, 6-difluoro- 4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide
The title compound was synthesized from [ 4-carbamoyl-3- (2, 6-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] -according to an analogous method to example 1]Phenyl carbamate and 2- [ (4-amino-butyl) - (2-hydroxy-ethyl) -amino ]-ethanol. MS (APCI, m/z): 502[ M + H]+。
The following specific compounds were prepared using the general synthetic methods described above and with reference to reaction schemes 1-5 and the specific synthetic methods described in the preparations and examples above.
(3-tert-butyl-isothiazol-5-yl) - (6, 7-dimethoxy-quinolin-4-yl) -amine;
3-ethylsulfanyl-5- (3-hexyl-ureido) -isothiazole-4-carboxylic acid amide;
5- (3-benzyl-ureido) -3-ethylsulfanyl-isothiazole-4-carboxylic acid amide;
3-ethylsulfanyl-5- (3-ethyl-ureido) -isothiazole-4-carboxylic acid amide;
3-ethylsulfanyl-5- [ (pyrrolidine-1-carbonyl) -amino ] -isothiazole-4-carboxylic acid amide;
5- (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-pentylthio-isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-ureido) -3-pentylthio-isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-ureido) -3-isopropylsulfanyl-isothiazole-4-carboxylic acid amide;
3-pentylthio-5-ureido-isothiazole-4-carboxylic acid amide;
3-benzylsulfanyl-5- (3, 3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-ureido) -3-propoxy-isothiazole-4-carboxylic acid amide;
(3-butoxy-4-carbamoyl-isothiazol-5-yl) -carbamic acid ethyl ester;
5- (3, 3-dimethyl-ureido) -3-phenethylthio-isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-ureido) -3-hexylthio-isothiazole-4-carboxylic acid amide;
3- (4-chloro-butylsulfanyl) -5- (3, 3-dimethyl-ureido) -isothiazole-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-cyclohexylthio-5- (3-methyl-ureido) -isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-ureido) -3- (3-methyl-butylsulfanyl) -isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-ureido) -3-pentoxy-isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-ureido) -3-prop-2-ynylthio-isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-ureido) -3-heptylthio-isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-ureido) -3-isobutylsulfanyl-isothiazole-4-carboxylic acid amide;
5- (3-methyl-ureido) -3-phenylsulfanyl-isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-ureido) -3- (3-hydroxy-butylsulfanyl) -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- [ (azetidine-1-carbonyl) -amino ] -3-propoxy-isothiazole-4-carboxylic acid amide;
piperidine-1-carboxylic acid (4-carbamoyl-3-propoxy-isothiazol-5-yl) -amide;
5- (3-phenethyl-ureido) -3-propoxy-isothiazole-4-carboxylic acid amide;
3-propoxy-5- [ (pyrrolidine-1-carbonyl) -amino ] -isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-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-ylmethylsulfanyl) -isothiazole-4-carboxylic acid amide;
3- [ 4-carbamoyl-5- (3, 3-dimethyl-ureido) -isothiazol-3-ylsulfanyl ] -propionic acid;
3-propoxy-5-ureido-isothiazole-4-carboxylic acid amide;
3-propoxy-5- (3-pyridin-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-pentylthio) -isothiazole-4-carboxylic acid amide;
5- (3-butyl-ureido) -3-pentylthio-isothiazole-4-carboxylic acid amide;
5-acetylamino-3-pentylthio-isothiazole-4-carboxylic acid amide;
5-benzoylamino-3-pentylthio-isothiazole-4-carboxylic acid amide;
3-decyloxy-5- (3, 3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide;
morpholine-4-carboxylic acid (4-carbamoyl-3-pentylthio-isothiazol-5-yl) -amide;
5- [3- (2-hydroxy-ethyl) -ureido ] -3-pentylthio-isothiazole-4-carboxylic acid amide;
5- [ (3-hydroxy-azetidine-1-carbonyl) -amino ] -3-pentylthio-isothiazole-4-carboxylic acid amide;
5- [3- (3-hydroxy-propyl) -ureido ] -3-pentylthio-isothiazole-4-carboxylic acid amide;
3-pentylthio-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-ureido) -3-heptyloxy-isothiazole-4-carboxylic acid amide;
5- (3-isobutyl-ureido) -3-pentylthio-isothiazole-4-carboxylic acid amide;
5- (3-furan-2-ylmethyl-ureido) -3-pentylthio-isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-ureido) -3-octyloxy-isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-ureido) -3- (3-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3-allyloxy-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) -isothiazole-4-carboxylic acid amide;
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 amide;
5- (3, 3-dimethyl-ureido) -3- (2-methyl-allyloxy) -isothiazole-4-carboxylic acid amide;
3-benzyloxy-5- (3, 3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-ureido) -3-phenylethoxy-isothiazole-4-carboxylic acid amide;
3- (2-cyclohexyl-ethoxy) -5- (3, 3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide;
5- (3-ethyl-ureido) -3-pentylthio-isothiazole-4-carboxylic acid amide;
5- [3- (3-dimethylamino-propyl) -ureido ] -3-pentylthio-isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-ureido) -3- (2-fluoro-3-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-ureido) -3- (3-methoxy-benzyloxy) -isothiazole-4-carboxylic acid amide;
3-pentylthio-5- (3-thiophen-2-ylmethyl-ureido) -isothiazole-4-carboxylic acid amide;
5- [3- (3-methyl-butyl) -ureido ] -3-pentylthio-isothiazole-4-carboxylic acid amide;
5- [3- (4-hydroxy-butyl) -ureido ] -3-pentylthio-isothiazole-4-carboxylic acid amide;
5- [3- (3-methoxy-propyl) -ureido ] -3-pentylthio-isothiazole-4-carboxylic acid amide;
4-hydroxy-piperidine-1-carboxylic acid (4-carbamoyl-3-pentylthio-isothiazol-5-yl) -amide;
5- (3, 3-dimethyl-ureido) -3- (3-trifluoromethyl-benzyloxy } -isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-ureido) -3- (4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-ureido) -3- (naphthalen-2-ylmethoxy) -isothiazole-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) -isothiazole-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-pentylthio-isothiazole-4-carboxylic acid amide;
5- [3- (2-hydroxy-propyl) -ureido ] -3-pentylthio-isothiazole-4-carboxylic acid amide;
5- [ (2, 5-dihydro-pyrrole-1-carbonyl) -amino ] -3-pentylthio-isothiazole-4-carboxylic acid amide;
5- {3- [2- (1H-imidazol-4-yl) -ethyl ] -ureido } -3-pentylsulfanyl-isothiazole-4-carboxylic acid amide;
3-pentylthio-5- [3- (tetrahydro-furan-2-ylmethyl) -ureido ] -isothiazole-4-carboxylic acid amide;
5- [3- (2-cyano-ethyl) -ureido ] -3-pentylthio-isothiazole-4-carboxylic acid amide;
5- (3-cyclopropylmethyl-ureido) -3-pentylthio-isothiazole-4-carboxylic acid amide;
5- (3-allyl-ureido) -3-pentylthio-isothiazole-4-carboxylic acid amide;
5- [3- (2-dimethylamino-ethyl) -ureido ] -3-pentylthio-isothiazole-4-carboxylic acid amide;
3-hexylthio-5- (3-isobutyl-ureido) -isothiazole-4-carboxylic acid amide;
3-hexylthio-5- (3-propyl-ureido) -isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-ureido) -3- (3-fluoro-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (3, 5-difluoro-benzyloxy) -5- (3, 3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide;
5- (3-butyl-ureido) -3-heptyloxy-isothiazole-4-carboxylic acid amide;
3- (3-chloro-benzyloxy) -5- (3, 3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-ureido) -3- (3-iodo-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-ureido) -3- (3-phenoxy-propoxy) -isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-ureido) -3- (4-phenoxy-butoxy) -isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-ureido) -3- (3-m-tolyl-propoxy) -isothiazole-4-carboxylic acid amide;
3- (5-cyano-pentyloxy) -5- (3, 3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-ureido) -3-methoxy-isothiazole-4-carboxylic acid amide;
3- (5-chloro-pentyloxy) -5- (3, 3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide;
3- (4-cyano-butoxy) -5- (3, 3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide;
5- (3-furan-2-ylmethyl-ureido) -3-hexylthio-isothiazole-4-carboxylic acid amide;
5- (3-butyl-ureido) -3-hexylthio-isothiazole-4-carboxylic acid amide;
3-hexylthio-5- [3- (3-hydroxy-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3-pentylthio-5- (3- (3-pyrrolidin-1-yl-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3-hexylthio-5- [3- (2-hydroxy-ethyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3-benzylsulfanyl-5- (3-methyl-ureido) -isothiazole-4-carboxylic acid amide;
5- {3- [2- (1-methyl-1H-pyrrol-2-yl) -ethyl ] -ureido } -3-pentylsulfanyl-isothiazole-4-carboxylic acid amine;
3-benzylsulfanyl-5- (3-butyl-ureido) -isothiazole-4-carboxylic acid amide;
benzoic acid 2- [ 4-carbamoyl-5- (3, 3-dimethyl-ureido) -isothiazol-3-yloxy ] -ethyl ester;
5- (3, 3-dimethyl-ureido) -3- (2-phenoxy-ethoxy) -isothiazole-4-carboxylic acid amide;
3- (3-benzyloxy-propoxy) -5- (3, 3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-ureido) -3- (3, 3-diphenyl-propoxy) -isothiazole-carboxylic acid amide;
3- (6-chloro-hexyloxy) -5- (3, 3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-ureido) -3- (2-ethoxy) -isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-ureido) -3- (4-vinyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3-cyclohexylmethoxy-5- (3, 3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-ureido) -3- (4-phenyl-butoxy) -isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-ureido) -3- [3- (3-methoxy-phenyl) -propoxy ] -isothiazole-4-carboxylic acid amide;
3- (2, 5-dimethyl-benzyloxy) -5- (3, 3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide;
3-hexylsulfanyl-5- {3- [2- (1H-imidazol-4-yl) -ethyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3-hexylthio-5- [3- (4-hydroxy-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3-hexylthio-5- [3- (2-hydroxy-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3-benzylsulfanyl-5- [3- (2-hydroxy-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3-benzylsulfanyl-5- (3-benzyl-ureido) -isothiazole-4-carboxylic acid amide;
3-benzylsulfanyl-5- (3-furan-2-ylmethyl-ureido) -isothiazole-4-carboxylic acid amide;
3-benzylsulfanyl-5- (3-isobutyl-ureido) -isothiazole-4-carboxylic acid amide;
3-hexylthio-5- (3-pentyl-ureido) -isothiazole-4-carboxylic acid amide;
3-hexylthio-5- (3-methyl-ureido) -isothiazole-4-carboxylic acid amide;
3-hexylthio-5- [3- (3-methyl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
5- (3-ethyl-ureido) -3-hexylthio-isothiazole-4-carboxylic acid amide;
5- [3- (2-morpholin-4-yl-ethyl) -ureido ] -3-pentylthio-isothiazole-4-carboxylic acid amide;
5- [3- (2, 3-dihydroxy-propyl) -ureido ] -3-heptyloxy-isothiazole-4-carboxylic acid amide;
3-heptyloxy-5- [3- (2-hydroxy-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3-heptyloxy-5- [3- (2-hydroxy-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3-heptyloxy-5- [3- (5-hydroxy-pentyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3-heptyloxy-5- [3- (3-hydroxy-2, 2-dimethyl-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3-heptyloxy-5- [3- (2-hydroxy-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
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-ureido) -3- (5-methyl-hexyloxy) -isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-ureido) -3- (naphthalen-1-ylmethoxy) -isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-ureido) -3- (3-phenyl-propoxy) -isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-ureido) -3- (4-methyl-pentyloxy) -isothiazole-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) -isothiazole-4-carboxylic acid amide;
3- (3, 5-bis-trifluoromethyl-benzyloxy) -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-ureido) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-benzylsulfanyl) -5- [3- (2-hydroxy-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3-hexylsulfanyl-5- [3- (2-morpholin-4-yl-ethyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-benzylsulfanyl) -5- (3-isobutyl-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) -isothiazole-4-carboxylic acid amide;
5- (3-butyl-ureido) -3- (4-chloro-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-hexylsulfanyl-isothiazole-4-carboxylic acid amide;
3-hexylsulfanyl-5- {3- [3- (2-oxo-pyrrolidin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
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) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-benzylsulfanyl) -5- [3- (4-hydroxy-butyl) -ureido ] -isothiazole-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-hexylthio-5- [3- (2-hydroxy-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3-benzylsulfanyl-5- [3- (2, 3-dihydroxy-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3-hexylthio-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) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-benzylthio) -5- (3, 3-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-benzylthio) -5- (3, 3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-ureido) -3- (2-fluoro-benzylsulfanyl) -isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-ureido) -3- (3-methyl-benzyl-sulfanyl) -isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-ureido) -3- (2-fluoro-3-methyl-benzylsulfanyl) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-benzyloxy) -5- (3, 3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide;
3- (2-chloro-benzylthio) -5- (3, 3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide;
1-methyl-3- [ 3-pentylthio-4- (1H-tetrazol-5-yl) -isothiazol-5-yl ] -urea;
5- (3, 3-dimethyl-ureido) -3- (4-fluoro-benzylsulfanyl) -isothiazole-4-carboxylic acid amide;
3- (3-chloro-benzylthio) -5- (3, 3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide;
3- (2, 5-dimethyl-benzylthio) -5- (3, 3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide;
3- (1-bromo-naphthalen-2-ylmethylsulfanyl) -5- (3, 3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide;
3- (3, 4-dimethyl-benzylthio) -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-fluoro-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (2-chloro-benzyloxy) -5- (3, 3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-ureido) -3- (4-isopropyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-ureido) -3- (2, 3, 4, 5, 6-pentamethyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-benzylsulfanyl) -5- [3- (2-dimethylamino-ethyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-benzylsulfanyl) -5- [3- (3-dimethylamino-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-benzylsulfanyl) -5- [3- (3-pyrrolidin-1-yl-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-benzylsulfanyl) -5- {3- [2- (1H-imidazol-4-yl) -ethyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-benzylsulfanyl) -5- {3- [2- (1-methyl-1H-pyrrol-2-yl) -ethyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-benzylsulfanyl) -5- [3- (2-morpholin-4-yl-ethyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-benzylsulfanyl) -5- {3- [3- (2-oxo-pyrrolidin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3-but-2-enyloxy-5- (3, 3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide;
5- (3, 3-dimethyl-ureido) -3- (4-methoxy-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (2, 4-difluoro-benzyloxy) -5- (3, 3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide;
5- (3-sec-butyl-ureido) -3- (4-chloro-benzylsulfanyl) -isothiazole-4-carboxylic acid amide;
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) -isothiazole-4-carboxylic acid amide;
5- (3-butyl-ureido) -3- (4-methyl-benzylsulfanyl) -isothiazole-4-carboxylic acid amide;
5- [3- (3-hydroxy-propyl) -ureido ] -3- (4-methyl-benzylsulfanyl) -isothiazole-4-carboxylic acid amide;
(4-carbamoyl-3-mercapto-isothiazol-5-yl) -carbamic acid phenyl ester;
5- (3-butyl-ureido) -3- (3, 4-dichloro-benzylsulfanyl) -isothiazole-4-carboxylic acid amide;
3- (3, 4-dichloro-benzylsulfanyl) -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-ylsulfanylmethyl ] -benzoic acid methyl ester;
4- [5- (3-butyl-ureido) -4-carbamoyl-isothiazol-3-ylsulfanylmethyl ] -benzoic acid methyl ester;
4- { 4-carbamoyl-5- [3- (3-hydroxy-propyl) -ureido ] -isothiazol-3-ylsulfanylmethyl ] -benzoic acid methyl ester;
3- (3, 3-diphenyl-propylsulfanyl) -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) -isothiazole-4-carboxylic acid amide;
5- [3- (2-dimethylamino-ethyl) -ureido ] -3- (3, 3-diphenyl-propylsulfanyl) -isothiazole-4-carboxylic acid amide;
3-hexylthio-5- [3- (2-methoxy-ethyl) -ureido) -isothiazole-4-carboxylic acid amide;
3-hexylsulfanyl-5- [3- (2-pyridin-2-yl-ethyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3-hexylsulfanyl-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) -isothiazole-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-benzylsulfanyl) -isothiazole-4-carboxylic acid amide;
5- [3- (2-dimethylamino-ethyl) -ureido ] -3- (4-methoxy-benzylsulfanyl) -isothiazole-4-carboxylic acid amide;
5- [3- (2-dimethylamino-ethyl) -ureido ] -3- (3-methoxy-benzylsulfanyl) -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;
3- { 4-carbamoyl-5- [3- (2-dimethylamino-ethyl) -ureido ] -isothiazol-3-ylsulfanylmethyl } -benzoic acid methyl ester;
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-pyrrolidin-1-yl-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (3-methoxy-benzylsulfanyl) -5- [3- (3-pyrrolidin-1-yl-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
4- { 4-carbamoyl-5- [3- (3-pyrrolidin-1-yl-propyl) -ureido ] -isothiazol-3-ylsulfanylmethyl } -benzoic acid methyl ester;
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) -isothiazole-4-carboxylic acid amide;
5- (3-isobutyl-ureido) -3- (4-methoxy-benzylsulfanyl) -isothiazole-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) -isothiazole-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-ureido) -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-benzylsulfanyl) -isothiazole-4-carboxylic acid amide;
3- (3, 4-dimethyl-benzylthio) -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-benzylthio) -5- (3-isobutyl-ureido) -isothiazole-4-carboxylic acid amide;
3- (3, 4-dimethyl-benzylsulfanyl) -5- [3- (3-pyrrolidin-1-yl-propyl) -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-benzylsulfanyl) -isothiazole-4-carboxylic acid amide;
3- (3, 4-dimethyl-benzylsulfanyl) -5- [3- (2-morpholin-4-yl-ethyl) -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-cyclopropylmethyl-ureido) -3- (3-methoxy-benzylsulfanyl) -isothiazole-4-carboxylic acid amide;
3- (4-bromo-2-fluoro-benzylthio) -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- [3- (3, 4-difluoro-benzyl) -ureido ] -3- (4-methoxy-benzylsulfanyl) -isothiazole-4-carboxylic acid amide;
5- [3- (3, 4-difluoro-benzyl) -ureido ] -3- (3, 4-dimethyl-benzylsulfanyl) -isothiazole-4-carboxylic acid amide;
3- (3-methyl-benzylsulfanyl) -5- [3- (3-pyrrolidin-1-yl-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
5- [3- (2-dimethylamino-ethyl) -ureido ] -3- (3-methyl-benzylsulfanyl) -isothiazole-4-carboxylic acid amide;
5- [3- (2-dimethylamino-ethyl) -ureido ] -3- (3, 4-dimethyl-benzylsulfanyl) -isothiazole-4-carboxylic acid amide;
3- (4-bromo-2-fluoro-benzylsulfanyl) -5- [3- (3-hydroxy-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- { 4-carbamoyl-5- [3- (3, 4-difluoro-benzyl) -ureido ] -isothiazol-3-ylsulfanylmethyl } -benzoic acid methyl ester;
3- { 4-carbamoyl-5- [3- (3-hydroxy-propyl) -ureido ] -isothiazol-3-ylsulfanylmethyl } -benzoic acid methyl ester;
5- [3- (3, 4-difluoro-benzyl) -ureido ] -3-phenethylsulfanyl-isothiazole-4-carboxylic acid amide;
5- [3- (3, 4-difluoro-benzyl) -ureido ] -3- (4-methyl-benzylsulfanyl) -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-benzylsulfanyl) -5- (3, 3-dimethyl-ureido) -isothiazole-4-carboxylic acid amide;
3- (4-methyl-benzylsulfanyl) -5- [3- (2-phenyl-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
5- [3- (1, 2-dimethyl-propyl) -ureido ] -3- (4-methyl-benzylsulfanyl) -isothiazole-4-carboxylic acid amide;
5- [3- (3, 5-difluoro-benzyl) -ureido ] -3- (4-methyl-benzylsulfanyl) -isothiazole-4-carboxylic acid amide;
5- {3- [1- (4-fluoro-phenyl) -ethyl ] -ureido } -3- (4-methyl-benzylsulfanyl) -isothiazole-4-carboxylic acid amide;
5- [3- (3-fluoro-benzyl) -ureido ] -3- (4-methyl-benzylsulfanyl) -isothiazole-4-carboxylic acid amide;
5- [3- (4-fluoro-2-trifluoromethyl-benzyl) -ureido ] -3- (4-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-fluoro-benzyloxy) -5- (3-isobutyl-ureido) -isothiazole-4-carboxylic acid amide;
3- (4-bromo-2-fluoro-benzyloxy) -5- (3-butyl-ureido) -isothiazole-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-ureido) -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) -5- [3- (3, 3-dimethyl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-bromo-2-fluoro-benzyloxy) -5- (3-cyclopropylmethyl-ureido) -isothiazole-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-cyclohexylmethyl-ureido) -3- (4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- (3-isobutyl-ureido) -3- (4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- {3- (3-dimethylamino-propyl) -ureido } -3- (4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (5-chloro-thiophen-2-ylmethylsulfanyl) -5- [3- (3, 4-difluoro-benzyl) -ureido ] -isothiazole-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-ethyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (5-chloro-thiophen-2-ylmethylsulfanyl) -5- [3- (3-pyrrolidin-1-yl-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
5- [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-ylmethylsulfanyl) -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-morpholin-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- (4-chloro-benzyloxy) -5- [3- (3-hydroxy-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-bromo-2-fluoro-benzyloxy) -5- [3- (3, 4-difluoro-benzyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-bromo-2-fluoro-benzyloxy) -5- [3- (2-dimethylamino-ethyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-bromo-2-fluoro-benzyloxy) -5- [3- (3-dimethylamino-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2-fluoro-benzyloxy) -5- (3-furan-2-ylmethyl-ureido) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2-fluoro-benzyloxy) -5- [3- (2-morpholin-4-yl-ethyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2, 3-dichloro-benzyloxy) -5- [3- (2-morpholin-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-ethyl) -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- {3- [2- (1H-imidazol-4-yl) -ethyl ] -ureido } -isothiazole-4-carboxylic acid amide;
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-isopropylamino-ethyl) -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 ] -isothiazole-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-yl-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-ureido) -3- (2, 3-dichloro-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (4-bromo-2-fluoro-benzyloxy) -5- [3- (3-isopropylaminopropyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-bromo-2-fluoro-benzyloxy) -5- [3- (2-sec-butylamino-ethyl) -ureido ] -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-ethyl) -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) -isothiazole-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) -ureido ] -3- (2-fluoro-3-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (2-fluoro-3-methyl-benzyloxy) -5- [3- (2-pyrrolidin-1-yl-ethyl) -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-morpholin-4-yl-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (3, 4-dichloro-benzyloxy) -5- [3- (3-hydroxy-2-methyl-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (3, 4-dichloro-benzyloxy) -5- [3- (2-methyl-3-morpholin-4-yl-propyl) -ureido ] -isothiazole-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-ethyl) -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-fluoro-2, 4-dimethyl-benzyloxy) -5- [3- (2-isopropylamino-ethyl) -ureido ] -isothiazole-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 ] -isothiazole-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-imidazol-1-yl-propyl) -ureido ] -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 ] -isothiazole-4-carboxylic acid amide;
5- [3- (3, 3-dimethyl-butyl) -ureido ] -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-yl-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2-fluoro-benzyloxy) -5- {3- [2- (1H-imidazol-4-yl) -ethyl ] -ureido } -isothiazole-4-carboxylic acid amide;
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 ] -isothiazole-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) -ureido ] -isothiazole-4-carboxylic acid amide;
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) -ureido ] -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-fluoro-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-imidazol-1-yl-propyl) -ureido ] -isothiazole-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-yl-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 ] -isothiazole-4-carboxylic acid amide;
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-ylmethyl-ureido) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2, 3-difluoro-4-methyl-benzyloxy) -5- {3- [3- (2, 6-dimethyl-morpholin-4-yl) -2-methyl-propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 3-difluoro-4-methyl-benzyloxy) -5- {3- [2- (3H-imidazol-4-yl) -ethyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 3-difluoro-4-methyl-benzyloxy) -5- [3- (3-hydroxy-propyl) -ureido ] -isothiazole-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-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (2, 3-difluoro-benzyl) -ureido ] -3- (2-fluoro-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 ] -isothiazole-4-carboxylic acid amide;
3- (3-fluoro-2, 4-dimethyl-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;
5- {3- [3- (2, 6-dimethyl-morpholin-4-yl) -2-methyl-propyl ] -ureido } -3- (2-fluoro-4, 6-dimethyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (2-fluoro-4, 6-dimethyl-benzyloxy) -5- [3- (2-hydroxy-3-morpholin-4-yl-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2-fluoro-4, 6-dimethyl-benzyloxy) -5- [3- (3-imidazol-1-yl-2-methyl-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2-fluoro-4, 6-dimethyl-benzyloxy) -5- {3- [2- (1H-imidazol-4-yl) -ethyl ] -ureido } -isothiazole-4-carboxylic acid amide;
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 ] -isothiazole-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) -isothiazol-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;
5- {3- [3- (2, 6-dimethyl-morpholin-4-yl) -2-methyl-propyl ] -ureido } -3- (2-fluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
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- (4-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 ] -isothiazole-4-carboxylic acid amide;
3- (4-bromo-2-fluoro-benzyloxy) -5- [3- (3-cyclohexylamino-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-difluoro-4-methyl-benzyloxy) -5- (3-furan-2-ylmethyl-ureido) -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- {3- [2- (1H-imidazol-4-yl) -ethyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- [3- (3-hydroxy-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) -isothiazole-4-carboxylic acid amide;
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-dimethyl-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-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2, 3-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- (1-methyl-pyrrolidin-2-yl) -ethyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 3-difluoro-4-methyl-benzyloxy) -5- {3- [3- (2-oxo-pyrrolidin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 3-difluoro-4-methyl-benzyloxy) -5- [3- (2-hydroxy-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
5- (3-cyclopropylmethyl-ureido) -3- (2, 3-difluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (2, 3-difluoro-4-methyl-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- [3- (2-methyl-3-morpholin-4-yl-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2, 4-dimethyl-benzyloxy) -5- {3- [3- (2, 6-dimethyl-morpholin-4-yl) -2-methyl-propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
5- [3- (3-cyclohexylamino-propyl) -ureido ] -3- (2-fluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (2-fluoro-4-methyl-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2-fluoro-4-methyl-benzyloxy) -5- {3- [2- (1H-imidazol-4-yl) -ethyl ] -ureido } -isothiazole-4-carboxylic acid amide;
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- {3- [3- (2, 6-dimethyl-morpholin-4-yl) -2-methyl-propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
5- (3-allyl-ureido) -3- (2-fluoro-4, 6-dimethyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (4-bromo-2-fluoro-benzyloxy) -5- {3- [3- (2-methyl-piperidin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
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-pyrrolidin-1-yl-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-bromo-2-fluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -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- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
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 ] -isothiazole-4-carboxylic acid amide;
3- (2, 3-difluoro-4-methyl-benzyloxy) -5- {3- [2- (1-methyl-1H-pyrrol-2-yl) -ethyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 3-difluoro-4-methyl-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-ureido) -3- (2, 3-difluoro-4-methyl-benzyloxy) -isothiazole-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- {3- [3- (2, 6-dimethyl-morpholin-4-yl) -2-methyl-propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (5-chloro-thiophen-2-ylmethoxy) -5- [3- (3-isopropylamino-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2-fluoro-4-methyl-benzyloxy) -5- {3- [2- (3-methyl-3H-imidazol-4-yl) -ethyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2-fluoro-4-methyl-benzyloxy) -5- [3- (2-pyrrolidin-1-yl-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 ] -isothiazole-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 ] -isothiazole-4-carboxylic acid amide;
3- (2-fluoro-4-methyl-benzyloxy) -5- {3- [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -ureido } -isothiazole-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-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-ureido) -isothiazole-4-carboxylic acid amide;
2-aminomethyl-morpholine-4-carboxylic acid [ 4-carbamoyl-3- (2, 3-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] -amide;
3- (2, 3-dichloro-benzyloxy) -5- [3- (3-isopropylamino-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2, 3-difluoro-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-imidazol-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 ] -isothiazole-4-carboxylic acid amide;
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) -isothiazole-4-carboxylic acid amide;
5- [3- (3-dimethylamino-2-hydroxy-propyl) -ureido ] -3- (2-fluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (4-bromo-2-fluoro-benzyloxy) -5- {3- [3- (2-oxo-pyrrolidin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
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) -isothiazole-4-carboxylic acid amide;
5- [3- (2-dimethylamino-ethyl) -ureido ] -3- (2-fluoro-4-methyl-benzyloxy) -isothiazole-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) -isothiazole-4-carboxylic acid amide;
3- (2-fluoro-4-methyl-benzyloxy) -5- (3-methyl-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- {3- [2- (1-methyl-1H-pyrrol-2-yl) -ethyl ] -ureido } -isothiazole-4-carboxylic acid amide;
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-morpholin-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-carboxylic acid amide;
3- (4-ethyl-2, 3-difluoro-benzyloxy) -5- {3- [2- (1H-imidazol-4-yl) -ethyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-ethyl-2, 3-difluoro-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
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;
5- {3- [3- (2, 6-dimethyl-morpholin-4-yl) -2-methyl-propyl ] -ureido } -3- (4-ethyl-2, 3-difluoro-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (4-ethyl-2, 3-difluoro-benzyloxy) -5- [3- (2-hydroxy-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
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-diethylamino-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- {3- [3- (2-methyl-piperidin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
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- {3- [2- (1-methyl-1H-pyrrol-2-yl) -ethyl ] -ureido } -isothiazole-4-carboxylic acid amide;
5- [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-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- {3- [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -ureido } -isothiazole-4-carboxylic acid amide;
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-ylmethyl-ureido) -isothiazole-4-carboxylic acid amide;
2-aminomethyl-morpholine-4-carboxylic acid [ 4-carbamoyl-3- (2, 5-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] -amide;
5- (3-allyl-ureido) -3- (2, 5-difluoro-4-methyl-benzyloxy) -isothiazole-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- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
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;
5- (3-cyclopropylmethyl-ureido) -3- (4-ethyl-2, 3-difluoro-benzyloxy) -isothiazole-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 ] -isothiazole-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-fluoro-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;
5- (3- {3- [ bis- (2-hydroxy-ethyl) -amino ] -propyl } -ureido) -3- (2-fluoro-4-methoxy-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (2-fluoro-4-methoxy-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
5- [3- (3-dimethylamino-propyl) -ureido ] -3- (2-fluoro-4-methoxy-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (4-dimethylamino-butyl) -ureido ] -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-yl-2-methyl-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-ethyl-2, 5-difluoro-benzyloxy) -5- [3- (3-hydroxy-2-methyl-propyl) -ureido ] -isothiazole-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) -isothiazole-4-carboxylic acid amide;
3- (4-ethyl-2, 5-difluoro-benzyloxy) -5- {3- [2- (3H-imidazol-4-yl) -ethyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-ethyl-2, 5-difluoro-benzyloxy) -5- [3- (3-hydroxy-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-ethyl-2, 5-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-ethyl-2, 5-difluoro-benzyloxy) -5- (3-isobutyl-ureido) -isothiazole-4-carboxylic acid amide;
5- [3- (2, 3-dihydroxy-propyl) -ureido ] -3- (4-ethyl-2, 3-difluoro-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (2-fluoro-4-methyl-benzyloxy) -5- (3-morpholin-2-ylmethyl-ureido) -isothiazole-4-carboxylic acid amide;
2-aminomethyl-morpholine-4-carboxylic acid [ 4-carbamoyl-3- (2-fluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] -amide;
3- (2-fluoro-4-methyl-benzyloxy) -5- (3- {3- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -propyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (2-fluoro-4-methyl-benzyloxy) -5- {3- [3- (2-oxo-pyrrolidin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
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-ethyl) -ureido ] -isothiazole-4-carboxylic acid amide;
5- (3- {3- [ bis- (2-hydroxy-ethyl) -amino ] -propyl } -ureido) -3- (2, 5-difluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
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- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
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-morpholin-4-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 5-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 5-difluoro-benzyloxy) -5- (3-cyclopropylmethyl-ureido) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 5-difluoro-benzyloxy) -5- [3- (3-hydroxy-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
5- [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) -isothiazole-4-carboxylic acid amide;
3- (2-fluoro-4, 6-dimethyl-benzyloxy) -5- (3- {3- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -propyl } -ureido) -isothiazole-4-carboxylic acid amide;
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) -ureido ] -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) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2-chloro-4-methyl-benzyloxy) -5- [3- (3-imidazol-1-yl-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2-chloro-4-methyl-benzyloxy) -5- [3- (2-morpholin-4-yl-ethyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2-chloro-4-methyl-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
5- [3- (3-imidazol-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 amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- (3- {4- [4- (3-hydroxy-propyl) -piperazin-1-yl ] -butyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- (3- {3- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -propyl } -ureido) -isothiazole-4-carboxylic acid amide;
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- [3- (6-dimethylamino-hexyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2, 4-difluoro-benzyloxy) -5- [3- (3-imidazol-1-yl-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2, 4-difluoro-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 4-difluoro-benzyloxy) -5- [3- (3-isopropylamino-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2, 4-difluoro-benzyloxy) -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-yl-propyl) -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- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 5-dichloro-benzyloxy) -5- [3- (6-dimethylamino-hexyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2, 5-dichloro-benzyloxy) -5- [3- (3-hydroxy-propyl) -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- {3- [ bis- (2-hydroxy-ethyl) -amino ] -propyl } -ureido) -3- (4-chloro-2, 5-difluoro-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 5-difluoro-benzyloxy) -5- {3- [4- (4-methyl-piperazin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 5-difluoro-benzyloxy) -5- (3- {3- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -propyl } -ureido) -isothiazole-4-carboxylic acid amide;
5- {3- [4- (4-benzyl-piperazin-1-yl) -butyl ] -ureido } -3- (4-chloro-2, 5-difluoro-benzyloxy) -isothiazole-4-carboxylic acid amide;
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-4-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) -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- [3- (4-hydroxy-1-methyl-pyrrolidin-2-ylmethyl) -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 } -ureido) -isothiazole-4-carboxylic acid amide;
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- {3- [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 5-difluoro-benzyloxy) -5- (3- {4- [4- (3-hydroxy-propyl) -piperazin-1-yl ] -butyl } -ureido) -isothiazole-4-carboxylic acid amide;
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-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- [3- (5-morpholin-4-yl-pentyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- {3- [5- (4-methyl-piperazin-1-yl) -pentyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- (3- {5- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -pentyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- {3- [7- (4-methyl-piperazin-1-yl) -heptyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- {3- [6- (4-methyl-piperazin-1-yl) -hexyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- (3- {6- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -hexyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- (3- {7- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -heptyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (2, 5-dichloro-4-methyl-benzyloxy) -5- {3- {4- (4-methyl-piperazin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 5-dichloro-4-methyl-benzyloxy) -5- [3- (6-dimethylamino-hexyl) -ureido ] -isothiazole-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- {3- [4- (5-methyl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
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- {3- [7- (4-methyl-piperazin-1-yl) -heptyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2-fluoro-4-methyl-benzyloxy) -5- {3- [6- (4-methyl-piperazin-1-yl) -hexyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2-fluoro-4-methyl-benzyloxy) -5- (3- {7- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -heptyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (2-fluoro-4-methyl-benzyloxy) -5- (3- {6- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -hexyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (2-fluoro-4-methyl-benzyloxy) -5- (3- {5- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -pentyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (2-fluoro-4-methyl-benzyloxy) -5- {3- [5- (4-methyl-piperazin-1-yl) -pentyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 5-difluoro-benzyloxy) -5- {3- [5- (4-methyl-piperazin-1-yl) -pentyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 5-difluoro-benzyloxy) -5- (3- {5- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -pentyl } -ureido) -isothiazole-4-carboxylic acid amide:
3- (4-chloro-2, 5-difluoro-benzyloxy) -5- {3- [7- (4-methyl-piperazin-1-yl) -heptyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 5-difluoro-benzyloxy) -5- (3- {7- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -heptyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 5-difluoro-benzyloxy) -5- {3- [6- (4-methyl-piperazin-1-yl) -hexyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 5-difluoro-benzyloxy) -5- {3- [6- (4-propyl-piperazin-1-yl) -hexyl ] -ureido } -isothiazole-4-carboxylic acid amide;
5- (3- {5- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -pentyl } -ureido) -3- (4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- (3- {6- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -hexyl } -ureido) -3- (4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (2, 4-dimethyl-benzyloxy) -5- {3- [5- (4-methyl-piperazin-1-yl) -pentyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 4-dimethyl-benzyloxy) -5- {3- [7- (4-methyl-piperazin-1-yl) -heptyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 4-dimethyl-benzyloxy) -5- {3- [6- (4-methyl-piperazin-1-yl) -hexyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 4-dimethyl-benzyloxy) -5- (3- {7- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -heptyl } -ureido) -isothiazole-4-carboxylic acid amide;
5- (3- {4- [ bis- (2-hydroxy-ethyl) -amino ] -butyl } -ureido) -3- (4-chloro-2, 5-difluoro-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 5-difluoro-benzyloxy) -5- [3- (5-morpholin-4-yl-pentyl) -ureido ] -isothiazole-4-carboxylic acid amide;
7- {3- [ 4-carbamoyl-3- (4-chloro-2, 5-difluoro-benzyloxy) -isothiazol-5-yl ] -ureidomethyl } -octahydro-pyrido [1, 2-a ] pyrazine-2-carboxylic acid tert-butyl ester;
3- (4-chloro-2, 5-difluoro-benzyloxy) -5- {3- [4- (5-methyl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
5- [3- (4-tert-butylamino-3-hydroxy-butyl) -ureido ] -3- (4-chloro-2, 5-difluoro-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 5-difluoro-benzyloxy) -5- [3- (octahydro-pyrido [1, 2-a ] pyrazin-7-ylmethyl) -ureido ] -isothiazole-4-carboxylic acid amide;
5- [3- (5-isopropylamino-pentyl) -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) -isothiazole-4-carboxylic acid amide;
5- (3- {6- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -hexyl } -ureido) -3- (2, 4, 5-trifluoro-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- (3- {7- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -heptyl } -ureido) -3- (2, 4, 5-trifluoro-benzyloxy) -isothiazole-4-carboxylic acid amide;
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-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
5- (3- {3- [ bis- (2-hydroxy-ethyl) -amino ] -propyl } -ureido) -3- (4-chloro-2, 6-difluoro-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- (3- {4- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -butyl } -ureido) -isothiazole-4-carboxylic acid amide;
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) -piperazin-1-yl ] -butyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- (3- {5- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -pentyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- (3- {6- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -hexyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- [3- (5-isopropylamino-pentyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [4- (4-methyl-piperazin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [5- (4-methyl-piperazin-1-yl) -pentyl ] -ureido } -isothiazole-4-carboxylic acid amide;
5- [3- (4-tert-butylamino-3-hydroxy-butyl) -ureido ] -3- (2-fluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (2-fluoro-4-methyl-benzyloxy) -5- {3- [4- (5-methyl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2-fluoro-4-methyl-benzyloxy) -5- (3- {4- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -butyl } -ureido) -isothiazole-4-carboxylic acid amide;
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) -piperazin-1-yl ] -butyl } -ureido) -isothiazole-4-carboxylic acid amide;
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) -isothiazole-4-carboxylic acid amide;
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 } -ureido) -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- (3- {5- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -pentyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- (3- {6- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -hexyl } -ureido) -isothiazole-4-carboxylic acid amide;
4- {3- [ 4-carbamoyl-3- (2, 5-difluoro-4-methyl-benzyloxy) -isothiazol-5-yl ] -ureido } -butyric acid;
5- (3- {3- [ bis- (2-hydroxy-ethyl) -amino ] -propyl } -ureido) -3- (2-chloro-5-fluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (2-chloro-5-fluoro-4-methyl-benzyloxy) -5- [3- (5-isopropylamino-pentyl) -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) -isothiazole-4-carboxylic acid amide;
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 } -ureido) -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- (3- {5- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -pentyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- (3- {6- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -hexyl } -ureido) -isothiazole-4-carboxylic acid amide;
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- {3- [ 3-hydroxy-5- (4-methyl-piperazin-1-yl) -pentyl ] -ureido } -isothiazole-4-carboxylic acid amide;
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- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 5-difluoro-benzyloxy) -5- {3- [ 3-hydroxy-5- (4-methyl-piperazin-1-yl) -pentyl ] -ureido } -isothiazole-4-carboxylic acid amide;
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-benzyloxy) -5- [3- (3-hydroxy-5-pyrrolidin-1-yl-pentyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- [3- (3-hydroxy-5-pyrrolidin-1-yl-pentyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2-chloro-5-fluoro-4-methyl-benzyloxy) -5- [3- (6-dimethylamino-hexyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2-chloro-5-fluoro-4-methyl-benzyloxy) -5- (3- {4- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -butyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [ 3-hydroxy-5- (4-methyl-piperazin-1-yl) -pentyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (5-chloro-2-fluoro-4-methyl-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (5-chloro-2-fluoro-4-methyl-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
5- (3- {3- [ bis- (2-hydroxy-ethyl) -amino ] -propyl } -ureido) -3- (5-chloro-2-fluoro-4-methyl-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- (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) -isothiazole-4-carboxylic acid amide;
3- (5-chloro-2-fluoro-4-methyl-benzyloxy) -5- (3- {4- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] butyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (5-chloro-2-fluoro-4-methyl-benzyloxy) -5- {3- [4- (4-methyl-piperazin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (5-chloro-2-fluoro-4-methyl-benzyloxy) -5- (3- {4- [4- (3-hydroxy-propyl) -piperazin-1-yl ] -butyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- [3- (2-morpholin-4-yl-ethyl) -ureido ] -isothiazole-4-carboxylic acid amide;
5- [3- (4-tert-butylamino-3-hydroxy-butyl) -ureido ] -3- (4-chloro-2, 6-difluoro-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [4- (5-methyl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
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-difluoro-benzyloxy) -5- [3- (3-hydroxy-5-isopropylamino-pentyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (5-chloro-2-fluoro-4-methyl-benzyloxy) -5- (3- {5- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -pentyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (5-chloro-2-fluoro-4-methyl-benzyloxy) -5- (3- {6- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -hexyl } -ureido) -isothiazole-4-carboxylic acid amide;
7- {3- [ 4-carbamoyl-3- (4-chloro-2, 6-difluoro-benzyloxy) -isothiazol-5-yl ] -ureidomethyl } -octahydro-pyrido [1, 2-a ] pyrazine-2-carboxylic acid tert-butyl ester;
3- (4-chloro-2, 5-difluoro-benzyloxy) -5- [3- (3-hydroxy-5-isopropylamino-pentyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- [3- (octahydro-pyrido [1, 2-a ] pyrazin-7-ylmethyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- (3- {3- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -propyl } -ureido) -isothiazole-4-carboxylic acid amide;
5- (3- {4- [ bis- (2-hydroxy-ethyl) -amino ] -butyl } -ureido) -3- (4-chloro-2, 6-difluoro-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- (3- {3- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -propyl } -ureido) -isothiazole-4-carboxylic acid amide;
5- (3- {3- [ bis- (2-hydroxy-ethyl) -amino ] -propyl } -ureido) -3- (2, 3-dichloro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
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-methylbenzyloxy) -5- (3- {4- [4- (3-hydroxy-propyl) -piperazin-1-yl ] -butyl } -ureido) -isothiazole-4-carboxylic acid amide;
5- (3- {4- [ bis- (2-hydroxy-ethyl) -amino ] -butyl } -ureido) -3- (2, 3-dichloro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (2, 3-dichloro-4-methylbenzyloxy) -5- (3- {5- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -pentyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (2, 3-dichloro-4-methyl-benzyloxy) -5- (3- {6- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -hexyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methylbenzyloxy) -5- (3- {5- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -pentyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- (3- {6- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -hexyl } -ureido) -isothiazole-4-carboxylic acid amide;
5- (3- {4- [ bis- (2-hydroxy-ethyl) -amino ] -butyl } -ureido) -3- (2, 5-difluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 5-difluoro-benzyloxy) -5- {3- [4- (5-methyl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
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 } -ureido) -isothiazole-4-carboxylic acid amide;
3- (4-ethyl-benzyloxy) -5- (3- {6- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -hexyl } -ureido) -isothiazole-4-carboxylic acid amide;
5- [3- (6-dimethylamino-hexyl) -ureido ] -3- (4-ethyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (4-ethyl-benzyloxy) -5- [3- (5-isopropylamino-pentyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2-fluoro-4-methyl-benzyloxy) -5- (3- {5- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -pentyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (2-fluoro-4-methyl-benzyloxy) -5- (3- {6- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -hexyl } -ureido) -isothiazole-4-carboxylic acid amide;
5- [3- (6-dimethylamino-hexyl) -ureido ] -3- (2-fluoro-4-methyl-benzyloxy) -isothiazole-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-yl ] -pentyl } -ureido) -isothiazole-4-carboxylic acid amide;
3-heptyloxy-5- (3- {6- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -hexyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- {3- [4- (3, 4-dihydroxy-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [4- (3, 4-dihydroxy-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- [3- (4-pyrrolidin-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) -isothiazole-4-carboxylic acid amide;
5- (3- {3- [ bis- (2-hydroxy-ethyl) -amino ] -propyl } -ureido) -3- (2, 4, 6-trifluoro-benzyloxy) -isothiazole-4-carboxylic acid amide;
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) -piperazin-1-yl ] -butyl } -ureido) -3- (2, 4, 6-trifluoro-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- (3- {5- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -pentyl } -ureido) -3- (2, 4, 6-trifluoro-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- (3- {6- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -hexyl } -ureido) -3- (2, 4, 6-trifluoro-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (4-bromo-2-fluoro-benzyloxy) -5- [3- (5-isopropylamino-pentyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-bromo-2-fluoro-benzyloxy) -5- [3- (4-tert-butylamino-3-hydroxy-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-bromo-2-fluoro-benzyloxy) -5- (3- {4- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -butyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (4-bromo-2-fluoro-benzyloxy) -5- (3- {5- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -pentyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (2-fluoro-4, 6-dimethyl-benzyloxy) -5- [3- (5-isopropylamino-pentyl) -ureido ] -isothiazole-4-carboxylic acid amide;
5- (3- {3- [ bis- (2-hydroxy-ethyl) -amino ] -propyl } -ureido) -3- (2-fluoro-4, 6-dimethylbenzyloxy) -isothiazole-4-carboxylic acid amide;
3- (2-fluoro-4, 6-dimethyl-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2-fluoro-4, 6-dimethyl-benzyloxy) -5- (3- {4- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -butyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (2-fluoro-4, 6-dimethyl-benzyloxy) -5- (3- {5- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -pentyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (2-fluoro-4, 6-dimethyl-benzyloxy) -5- (3- {6- [4- (2-hydroxy-ethyl) -piperazin-1-yl- ] -hexyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- [1- (4-chloro-2, 6-difluoro-phenyl) -ethoxy ] -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- [1- (4-chloro-2, 6-difluoro-phenyl) -ethoxy ] -5- (3- {5- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -pentyl } -ureido) -isothiazole-4-carboxylic acid amide;
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- {6- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -hexyl } -ureido) -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (4-tert-butylamino-3-hydroxy-butyl) -ureido ] -3- [1- (4-chloro-2, 6-difluoro-phenyl) -ethoxy ] -isothiazole-4-carboxylic acid amide;
5- (3- {5- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -pentyl } -ureido) -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- [1- (4-chloro-2, 6-difluoro-phenyl) -ethoxy ] -5- [3- (5-isopropylamino-pentyl) -ureido ] -isothiazole-4-carboxylic acid amide;
5- [3- (4-tert-butylamino-3-hydroxy-butyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-3- (4-chloro-2, 6-difluoro-benzyloxy) -5- [3- (3-hydroxy-5-pyrrolidin-1-yl-pentyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- {3- [4- (2-hydroxymethyl-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
5- (3- {5- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -pentyl } -ureido) -3- (4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- (3- {6- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -hexyl } -ureido) -3- (4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (6-dimethylamino-hexyl) -ureido ] -3- (4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (6-dimethylamino-hexyl) -ureido ] -3-heptyloxy-isothiazole-4-carboxylic acid amide;
3-heptyloxy-5- [3- (5-isopropylamino-pentyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [4- (2-hydroxymethyl-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (5-chloro-2-fluoro-4-methyl-benzyloxy) -5- {3- [4- (2-hydroxymethyl-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- {3- [4- (3-hydroxy-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
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-1-yl ] -hexyl } -ureido) -3- (2, 3, 5, 6-tetrafluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 5-difluoro-benzyloxy) -5- {3- [4- (2-hydroxymethyl-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
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-difluoro-benzyloxy) -5- {3- [4- (3-hydroxy-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 5-difluoro-benzyloxy) -5- {3- [4- (3, 4-dihydroxy-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
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-difluoro-benzyloxy) -5- {3- [4- (3-hydroxy-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
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-difluoro-benzyloxy) -5- {3- [2- (octahydro-pyrido [1, 2-a ] pyrazin-7-yl) -ethyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- {3- [6- (4-methyl-piperazin-1-yl) -hexyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2-fluoro-4-methyl-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-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-piperidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 5-difluoro-benzyloxy) -5- [3- (4-piperidin-1-yl-butyl) -ureido ] -isothiazole-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 ] -hexyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (4-bromo-2, 6-difluoro-benzyloxy) -5- (3- {5- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -pentyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (4-bromo-2, 6-difluoro-benzyloxy) -5- [3- (4-tert-butylamino-3-hydroxy-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-bromo-2, 6-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- (3- {4- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -butyl } -ureido) -isothiazole-4-carboxylic acid amide;
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) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2-fluoro-4-methyl-benzyloxy) -5- [3- (4-hydroxy-5-isobutylamino-pentyl) -ureido ] -isothiazole-4-carboxylic acid amide;
5- [3- (4-tert-butylamino-3-hydroxy-butyl) -ureido ] -3- (2-fluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (2, 3-difluoro-4-methyl-benzyloxy) -5- {3- [4- (3, 4-dihydroxy-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [4- (3, 4-dihydroxy-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 5-difluoro-benzyloxy) -5- {3- [4- (3, 4-dihydroxy-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- {3- [4- (3, 4-dihydroxy-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- [3- (4-hydroxy-5-morpholin-4-yl-pentyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- [3- (5-hydroxy-6-morpholin-4-yl-hexyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- [3- (5-hydroxy-6-morpholin-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) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-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 ] -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- {3- [4- (3-hydroxy-piperidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [4- (3-hydroxy-piperidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 3-difluoro-4-methyl-benzyloxy) -5- {3- [4- (3-hydroxy-piperidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
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-morpholin-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-piperidin-1-yl-hexyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- [3- (6-hydroxy-7-piperidin-4-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-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;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [4- (2-methoxymethyl-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [4- (2-hydroxymethyl-piperidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- (3- {4- [ ethyl- (2-hydroxy-ethyl) -amino ] -butyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- (3- {4- [ ethyl- (2-hydroxy-ethyl) -amino ] -butyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (2, 3-difluoro-4-methyl-benzyloxy) -5- (3- {4- [ ethyl- (2-hydroxy-ethyl) -amino ] -butyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- {3- [4- (2-methoxymethyl-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- {3- [4- (2-hydroxymethyl-piperidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
5- [3- (6-dimethylamino-hexyl) -ureido) -3- (2, 3, 6-trifluoro-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- {3- [3- { 4-methyl-piperazin-1-yl) -propyl ] -ureido } -3- (2, 3, 6-trifluoro-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (2, 3-difluoro-4-methyl-benzyloxy) -5- [3- (5-hydroxy-6-piperidin-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-yl-hexyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- [3- (5-hydroxy-6-piperidin-1-yl-hexyl) -ureido ] -isothiazole-4-carboxylic acid amide;
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-morpholin-4-yl-heptyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- [3- (6-hydroxy-7-morpholin-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 ] -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- [3- (5-hydroxy-6-piperidin-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) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- [3- (5-hydroxy-6-isobutylamino-hexyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- [3- (5-hydroxy-6-isobutylamino-hexyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-bromo-2, 3, 6-trifluoro-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- (6-dimethylamino-hexyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2-fluoro-4-methyl-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- {3- [4- (2-hydroxymethyl-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (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- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- [3- (3-hydroxy-5-pyrrolidin-1-yl-pentyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- [3- (4-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-pyrrolidin-1-yl-pentyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- {3- [4- (3-hydroxy-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (3-hydroxy-5-pyrrolidin-1-yl-pentyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 5-difluoro-benzyloxy) -5- {3- [4- (2-hydroxymethyl-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 5-difluoro-benzyloxy) -5- (3- {4- [ ethyl- (2-hydroxy-ethyl) -amino ] -butyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 5-difluoro-benzyloxy) -5- [3- (4-hydroxy-5-piperidin-1-yl-pentyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 5-difluoro-benzyloxy) -5- {3- [4- (3-hydroxy-piperidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- [3- (3-pyrrolidin-1-yl-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [4- (2-hydroxymethyl-piperidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- {3- [3- (5-methyl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [3- (5-methyl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 5-difluoro-benzyloxy) -5- {3- [4- (2-hydroxymethyl-piperidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
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 ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- {3- [3- (5-methyl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- {3- [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- [3- (4-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 } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- (3- {4- [ ethyl- (2-hydroxy-ethyl) -amino ] -butyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- { 3-ethyl-3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- { 3-ethyl-3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- [ 3-ethyl-3- (4-piperidin-1-yl-butyl) -ureido ] -isothiazole-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- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- (3-cyclopropylmethyl-ureido) -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-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-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- (3-isobutyl-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;
5- {3- [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -ureido } -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (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;
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 amide;
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) -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- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- {3- [4- (4-methyl-piperazin-1-yl) -butyl ] -ureido } -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- {3- [5- (4-methyl-piperazin-1-yl) -pentyl ] -ureido } -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- {3- [6- (4-methyl-piperazin-1-yl) -hexyl ] -ureido } -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- {3- [ 3-hydroxy-5- (4-methyl-piperazin-1-yl) -pentyl ] -ureido } -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- (3- {4- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -butyl } -ureido) -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- (3- {4- [4- (3-hydroxy-propyl) -piperazin-1-yl ] -butyl } -ureido) -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (3-pyrrolidin-1-yl-propyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (3-hydroxy-5-pyrrolidin-1-yl-pentyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-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;
5- [3- (4-hydroxy-5-piperidin-1-yl-pentyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (5-hydroxy-6-piperidin-1-yl-hexyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
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- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
5- [3- (4-hydroxy-5-morpholin-4-yl-pentyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (5-hydroxy-6-morpholin-4-yl-hexyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (5-hydroxy-7-morpholin-4-yl-heptyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
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 } -ureido) -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- (3- {4- [ bis- (2-hydroxy-ethyl) -amino ] -propyl } -ureido) -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- (3- {4- [ ethyl- (2-hydroxy-ethyl) -amino ] -butyl } -ureido) -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (3-tert-butylamino-propyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- [3- (4-imidazol-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- {3- [4- (3-hydroxy-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- [3- (4-imidazol-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
5- {3- [4- (2-methoxymethyl-pyrrolidin-1-yl) -butyl ] -ureido } -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- { 3-methyl-3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
5- {3- [4- (3-hydroxy-pyrrolidin-1-yl) -butyl ] -ureido } -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- { 3-methyl-3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
5- {3- [4- (3, 4-dihydroxy-pyrrolidin-1-yl) -butyl ] -ureido } -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- {3- [4- (2-hydroxymethyl-pyrrolidin-1-yl) -butyl ] -ureido } -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- {3- [4- (3-hydroxy-piperidin-1-yl) -butyl ] -ureido } -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- {3- [4- (2-hydroxymethyl-piperidin-1-yl) -butyl ] -ureido } -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
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 } -ureido) -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
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) -isothiazole-4-carboxylic acid amide;
5- [3- (3-imidazol-1-yl-propyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- {3- [4- (2-hydroxymethyl-piperidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- [3- (3-hydroxy-5-pyrrolidin-1-yl-pentyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- {3- [4- (3-hydroxy-piperidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- [3- (4-hydroxy-5-piperidin-1-ylpentyl) -ureido ] -isothiazole-4-carboxylic acid amide;
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-ureido) -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) -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- (3-isobutyl-ureido) -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- {3- [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (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- [3- (7-dimethylamino-6-hydroxy-heptyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- {3- [4- (5-methyl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- [3- (3-dimethylamino-propyl) -ureido ] -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- {3- [4- (4-methyl-piperazin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- {3- [5- (4-methyl-piperazin-1-yl) -pentyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- {3- [6- (4-methyl-piperazin-1-yl) -hexyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- {3- [ 3-hydroxy-5- (4-methyl-piperazin-1-yl) -pentyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- (3- {4- [4- (3-hydroxy-propyl) -piperazin-1-yl ] -butyl } -ureido) -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;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- {3- [4- (3, 4-dihydroxy-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
5- {3- [4- (4-acetyl-piperazin-1-yl) -butyl ] -ureido } -3- (4-chloro-2, 6-difluoro-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- {3- [4- (4-acetyl-piperazin-1-yl) -butyl ] -ureido } -3- (2, 5-difluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- {3- [4- (3-hydroxy-piperidin-1-yl) -butyl ] -3-methyl-ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- (3- {4- [ ethyl- (2-hydroxy-ethyl) -amino ] -butyl } -3-methyl-ureido) -isothiazole-4-carboxylic acid amide;
3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -5-ureido-isothiazole-4-carboxylic acid amide;
3- (4-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-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- (3- {4- [ ethyl- (2-hydroxy-ethyl) -amino } -butyl } -3-methyl-ureido) -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- [3- (3-hydroxy-5-pyrrolidin-1-yl-pentyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- [3- (4-hydroxy-5-piperidin-1-yl-pentyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- [3- (5-hydroxy-6-piperidin-1-yl-hexyl) -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;
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- (5-hydroxy-6-morpholin-4-yl-hexyl) -ureido ] -isothiazole-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) -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- (3- {4- [ ethyl- (2-hydroxy-ethyl) -amino ] -butyl } -ureido) -isothiazole-4-carboxylic acid amide;
5- [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- {3- [4- (2-methoxymethyl-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- {3- [4- (3-hydroxy-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- {3- [4- (3, 4-dihydroxy-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- {3- [4- (2-hydroxymethyl-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
5- [3- (4-imidazol-1-yl-butyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- {3- [4- (3, 4-dihydroxy-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- [3- (4-imidazol-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- {3- [5- (4-methyl-piperazin-1-yl) -pentyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- {3- [ 3-hydroxy-5- (4-methyl-piperazin-1-yl) -pentyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- (3- {4- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -butyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- {3- [4- (5-methyl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- {3- [4- (3-hydroxy-piperidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- {3- [4- (2-hydroxymethyl-piperidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
5- [3- (3-cyclohexylamino-propyl) -ureido ] -3- (2, 6-difluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- {3- [3- (5-methyl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5-ureido-isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- (3-ethyl-ureido) -isothiazole-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-2, 6-difluoro-benzyloxy) -5- (3- {3- [ ethyl- (2-hydroxy-ethyl) -amino ] -propyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- (3- {3- [ ethyl- (2-hydroxy-ethyl) -amino ] -propyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- (3- {3- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -propyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- [3- (3-hydroxy-5-isopropylamino-pentyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- [3- (3-imidazol-1-yl-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- (3- {3- [ ethyl- (2-hydroxy-ethyl) -amino ] -propyl } -ureido) -isothiazole-4-carboxylic acid amide;
5- {3- [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -ureido } -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (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;
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- {3- [4- (4-methyl-piperazin-1-yl) -butyl ] -ureido } -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- (3- {4- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -butyl } -ureido) -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- (3- {4- [4- (3-hydroxy-propyl) -piperazin-1-yl ] -butyl } -ureido) -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (3-pyrrolidin-1-yl-propyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (4-hydroxy-5-piperidin-1-yl-pentyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- (3-ethyl-ureido) -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- (3-methyl-ureido) -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- (3- {4- [ bis- (2-hydroxy-propyl) -amino ] -butyl } -ureido) -3- (2, 6-difluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- {3- [3- (4-acetyl-piperazin-1-yl) -propyl ] -ureido } -3- (2, 5-difluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- {3- [3- (4-acetyl-piperazin-1-yl) -propyl ] -ureido } -3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (1, 3-difluoro-naphthalen-2-ylmethoxy) -5- (3- {4- [ ethyl- (2-hydroxy-ethyl) -amino ] -butyl } -ureido) -isothiazole-4-carboxylic acid amide;
5- {3- [3- (4-acetyl-piperazin-1-yl) -propyl ] -ureido } -3- (4-chloro-2, 6-difluoro-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- {3- [4- (4-acetyl-piperazin-1-yl) -butyl ] -ureido } -3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -isothiazole-4-carboxylic acid amide;
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) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [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- {3- [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (1, 3-difluoro-naphthalen-2-ylmethoxy) -5- {3- [4- (2-hydroxymethyl-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (1, 3-difluoro-naphthalen-2-ylmethoxy) -5- {3- [3- (5-methyl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
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- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
5- (3- {4- [ ethyl- (2-hydroxy-ethyl) -amino ] -butyl } -ureido) -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- {3- [4- (3-hydroxy-piperidin-1-yl) -butyl ] -ureido } -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (3-tert-butylamino-propyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- {3- [4- (3-hydroxy-pyrrolidin-1-yl) -butyl ] -ureido } -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- {3- [4- (3, 4-dihydroxy-pyrrolidin-1-yl) -butyl ] -ureido } -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- {3- [4- (2-hydroxymethyl-pyrrolidin-1-yl) -butyl ] -ureido } -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- {3- [4- (2-hydroxymethyl-piperidin-1-yl) -butyl ] -ureido } -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- (3-methyl-ureido) -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- {3- [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (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- {3- [4- (5-methyl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
5- (3- {4- [ bis- (2-hydroxy-ethyl) -amino ] -butyl } -ureido) - (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- {3- [3- (5-methyl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -propyl ] -ureido } - (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- [3- (3-dimethylamino-propyl) -ureido ] -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;
5- [3- (3-cyclohexylamino-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 ] -isothiazole-4-carboxylic acid amide;
5- [3- (3-amino-propyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- {3- [2- (2-amino-ethoxy) -ethyl ] -ureido } -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
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-difluoro-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (5-amino-pentyl) -ureido ] -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) -isothiazole-4-carboxylic acid amide;
5- [3- (3-diethylamino-propyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (3-methylamino-propyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- {3- [3- (2-methyl-piperidin-1-yl) -propyl ] -ureido } -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- {3- [4- (pyridin-2-ylamino) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- {3- [3- (pyridin-2-ylamino) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
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- {3- [4- (pyridin-2-ylamino) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- {3- [4- (pyridin-2-ylamino) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- {3- [3- (pyridin-2-ylamino) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [3- (pyridin-2-ylamino) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- [3- (4-cyclopropylamino-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
5- [3- (3-amino-propyl) -3-methyl-ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (3-chloro-2, 6-difluoro-4-methyl-benzyloxy) -5- {3- [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -ureido } -isothiazole-4-carboxylic acid amide;
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- {3- [4- (pyridin-4-ylamino) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [4- (pyridin-4-ylamino) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- {3- [4- (pyridin-4-ylamino) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide.

Claims (21)

1. A compound of the formula or a pharmaceutically acceptable salt, or solvate thereof,
wherein:
X1is O or S;
R1is H, C1-C10Alkyl radical, C2-C10Alkenyl radical, C2-C10-alkynyl, -C (O) (C)1-C10Alkyl), - (CH)2)t(C6-C10Aryl), - (CH)2)t(4-10 membered heterocycle), -C (O) (CH)2)t(C6-C10Aryl) or-C (O) (CH)2)t(5-10 membered heterocycle), wherein t is an integer of 0 to 5; the alkyl group optionally contains 1 or 2 groups selected from O, S and-N (R)6) -a heteroatom moiety, with the proviso that two O atoms, two S atoms or O and S atoms are not directly connected; said aryl and heterocyclic ring R1The radicals being optionally substituted with C6-C10Aryl radical, C5-C8A saturated cyclic group or a 5-to 10-membered heterocyclic group is fused; optionally substituted on 1 or 2 carbon atoms of the aforementioned heterocyclic moiety by an oxo (═ O) moiety; r mentioned above1Of a group- (CH)2)t-the moiety optionally contains a carbon-carbon double or triple bond, wherein t is an integer from 2 to 5; and the aforementioned R1The radical, other than H, being optionally substituted by 1 to 3R4Substituted by a group;
R2is selected from R1The substituents, -SO2(CH2)t(C5-C10Aryl), -SO2(CH2)t(5-10 membered heterocycle) and-OR5T is an integer of 0 to 5, the aforementioned R2Of a group- (CH)2)t-the moiety optionally containing a carbon-carbon double or triple bond, wherein t is an integer from 2 to 5, and the aforementioned R2The radicals being optionally substituted by 1 to 3R 4Substituted by a group;
or R1And R2May be taken together with the nitrogen to which they are attached to form a 4-10 membered saturated monocyclic or multicyclic ring or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings are other than R1And R2Optionally containing 1 or 2 nitrogen atoms selected from O, S and-N (R)6) When R is a hetero atom of1And R2When combined in the heteroaryl fashion, the-N (R)6) -may optionally be-N-or-N-and said saturated ring may optionally be partially unsaturated by containing a 1 or 2 carbon-carbon double bond, said saturated and heteroaryl rings including said-N (R)6) R of (A-C)6A group, optionally substituted by 1 to 3R4Substituted by a group;
R3is H, C1-C10Alkyl radical, C2-C10Alkenyl radical, C2-C10Alkynyl, - (CH)2)t(C6-C10Aryl) or- (CH)2)t(5-10 membered heterocycle), wherein t is an integer of 0 to 5; the alkyl group optionally contains 1 or 2 groups selected from O, S and-N (R)6) -a heteroatom moiety, with the proviso that two O atoms, two S atoms or O and S atoms are not directly connected; said aryl and heterocyclic ring R3The radicals being optionally substituted with C6-C10Aryl radical, C5-C8A saturated cyclic group or a 5-to 10-membered heterocyclic group is fused; optionally substituted on 1 or 2 carbon atoms of the aforementioned heterocyclic moiety by an oxo (═ O) moiety; r mentioned above 3Of a group- (CH)2)t-the moiety optionally containing a carbon-carbon double or triple bond, wherein t is an integer from 2 to 5, and the aforementioned R3The radicals being optionally substituted by 1 to 5R4Substituted by a group;
each R4Independently of one another, from C1-C10Alkyl radical, C2-C10Alkenyl radical, C2-C10Alkynyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -OR5、-C(O)R5、-C(O)OR5、-NR6C(O)OR5、-OC(O)R5、-NR6SO2R5、-SO2NR5R6、-NR6C(O)R5、-C(O)NR5R6、-NR5R6、-S(O)jR7Wherein j is an integer from 0 to 2, -SO3H、-NR5(CR6R7)tOR6、-(CH2)t(C6-C10Aryl), -SO2(CH2)t-(C6-C10Aryl), S (CH)2)t(C6-C10Aryl), -O (CH)2)t-(C6-C10Aryl radicals),-(CH2)t(5-to 10-membered heterocycle) and- (CR6R7)mOR6Wherein m is an integer of 1 to 5, and t is an integer of 0 to 5; the alkyl group optionally contains 1 or 2 groups selected from O, S and-N (R)6) -a heteroatom moiety, with the proviso that two O atoms, two S atoms or O and S atoms are not directly connected; said aryl and heterocyclic ring R4The radicals being optionally substituted with C6-C10Aryl radical, C5-C8A saturated cyclic group or a 5-to 10-membered heterocyclic group is fused; optionally substituted on 1 or 2 carbon atoms of the aforementioned heterocyclic moiety by an oxo (═ O) moiety; r mentioned above4The alkyl, aryl and heterocyclic moieties of the group are optionally substituted with 1-3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -NR6SO2R5、-SO2NR5R6、-C(O)R5、-C(O)OR5、-OC(O)R5、-NR6C(O)R5、-C(O)NR5R6、-NR5R6、-(CR6R7)mOR6Wherein m is an integer of 1 to 5, -OR 5And R5The substituents listed in the definition of (1);
each R5Are independently selected from H, C1-C10Alkyl, - (CH)2)t(C6-C10Aryl) and- (CH)2)t(5-10 membered heterocycle), wherein t is an integer of 0 to 5; the alkyl group optionally contains 1 or 2 groups selected from O, S and-N (R)6) -a heteroatom moiety, with the proviso that two O atoms, two S atoms or O and S atoms are not directly connected; said aryl and heterocyclic ring R5The radicals being optionally substituted with C6-C10Aryl radical, C5-C8A saturated cyclic group or a 5-to 10-membered heterocyclic group is fused; and the aforementioned R5Substituents, other than H, are optionally substituted by 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -C (O) R6、-C(O)OR6、-CO(O)R6、-NR6C(O)R7、-C(O)NR6R7、-NR6R7Hydroxy, C1-C6Alkyl and C1-C6Substituted by a substituent of alkoxy;
each R6And R7Independently of one another, H or C1-C6An alkyl group;
with the proviso that said compound of formula 1 is not 1-methyl-3- (4-carbamoyl-3-ethoxy-5-isothiazolyl) urea, 1-dimethyl-3- (4-carbamoyl-3-ethoxy-5-isothiazolyl) urea, 1-methyl-3- (4-carbamoyl-3-propoxy-5-isothiazolyl) urea, 1-methyl-3- (4-carbamoyl-3- (methylthio) -5-isothiazolyl) urea, 1-methyl-3- (4-carbamoyl-3- (ethylthio) -5-isothiazolyl) urea, 1, 1-dimethyl-3- (4-carbamoyl-3- (ethylthio) -5-isothiazolyl) urea, 1-methyl-3- (4-carbamoyl-3- (propylthio) -5-isothiazolyl) urea, 1-dimethyl-3- (4-carbamoyl-3- (propylthio) -5-isothiazolyl) urea or 1-methyl-3- (4-carbamoyl-3- (isopropylthio) -5-isothiazolyl) urea.
2. The compound of claim 1, wherein R2Is H and R1Is optionally selected from-NR by 1 or 2 independently of each other5R6、-NR5(CR6R7)tOR6And- (CH)2)t(5-to 10-membered heterocycle) substituted C1-C10Alkyl, wherein t is an integer from 0 to 5.
3. The compound of claim 2, wherein R1Selected from propyl, butyl, pentyl and hexyl, and said R1The groups are optionally substituted with dimethylamino, hydroxy, pyrrolidinyl, morpholino, and ethyl- (2-hydroxy-ethyl) -amino.
4. The compound of claim 1, wherein R2Is H and R1Is- (CH)2)t(5-10 membered heterocycle), wherein t is an integer of 0 to 5; the heterocyclic group is optionally substituted with C6-C10Aryl radical, C5-C8A saturated cyclic group or a 5-to 10-membered heterocyclic group is fused; said R1Group comprising said R1Optionally fused-on part of a group, optionally substituted by 1 or 2 substituents independently of one another, selected from C1-C4Alkyl, hydroxy and hydroxymethyl.
5. The compound of claim 4, wherein R is1The heterocyclic part of the group being selected from morpholino, pyrrolidinyl, imidazolyl, piperazinyl, piperidinyl and 2, 5-diaza-bicyclo [2.2.1]Hept-2-yl, said R1T of the group may be 2 to 5, and said R1The groups are optionally substituted with hydroxy, hydroxymethyl and methyl.
6. The compound of claim 1, wherein R3Is- (CH)2)t(C6-C10Aryl) group, wherein t is an integer of 1 to 3 and said R3The radicals being optionally substituted by 1 to 4R4Substituted by a group.
7. The compound of claim 6, wherein R3Is optionally selected from the group consisting of halogen and C independently of one another by 1 to 41-C4Benzyl substituted with a substituent of alkyl.
8. The compound of claim 7, wherein R3Is benzyl substituted with 1 to 4 substituents independently selected from methyl, fluorine, chlorine and bromine.
9. The compound of claim 1 selected from the group consisting of:
the mesylate salt of 3- (4-bromo-2, 6-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -3- {2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- (3- {4- [ ethyl- (2-hydroxy-ethyl) -amino ] -butyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (2-fluoro-4-methyl-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- (3- {4- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -butyl } -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-fluoro-4-methyl-benzyloxy) -5- [3- (5-isopropylamino-pentyl) -ureido ] -isothiazole-4-carboxylic acid amide;
hydrochloride salt of 3- (4-bromo-2, 6-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [ - (1-methyl-pyrrolidin-2-yl) -ethyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- (3- {4- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -butyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- [3- (3-hydroxy-5-pyrrolidin-1-yl) -pentyl) -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- {3- [4- (3, 4-dihydroxy-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [4- (3, 4-dihydroxy-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- {3- [4- (2-hydroxymethyl-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [4- (2-hydroxymethyl-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- {3- [4- (3-hydroxy-pyrrolidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-bromo-2, 6-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (2, 6-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- {3- [4- (3-hydroxy-5-piperidin-1-yl) -pentyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [4- (2-hydroxymethyl-piperidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 5-difluoro-4-methyl-benzyloxy) -5- (3- {4- [ ethyl- (2-hydroxy-ethyl) -amino ] -butyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- [3- (5-hydroxy-6-piperidin-1-yl) -hexyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-bromo-2, 3, 6-trifluoro-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- [3- (3-hydroxy-5-pyrrolidin-1-yl-pentyl) -ureido ] -isothiazole-4-carboxylic acid amide;
5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (3-hydroxy-5-pyrrolidin-1-yl-pentyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- {3- [3- (5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- {3- [3- (5-methyl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- {3- [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- [3- (4-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 } -isothiazole-4-carboxylic acid amide;
5- {3- [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -ureido } -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (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;
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- {3- [4- (4-methyl-piperazin-1-yl) -butyl ] -ureido } -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- (3- {4- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -butyl } -ureido) -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (3-pyrrolidin-1-yl-propyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (4-hydroxy-5-piperidin-1-yl-pentyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 6-difluoro-benzyloxy) -5- [3- (4-imidazol-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
5- (3- {4- [ ethyl- (2-hydroxy-ethyl) -amino ] -butyl } -ureido) -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- {3- [4- (2-hydroxymethyl-piperidin-1-yl) -butyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- [3- (3-hydroxy-5-pyrrolidin-1-yl-pentyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-bromo-2, 6-difluoro-benzyloxy) -5- {3- [3- (4-methyl-piperazin-1-yl) -propyl ] -ureido } -isothiazole-4-carboxylic acid amide;
3- (2, 6-difluoro-4-methyl-benzyloxy) -5- {3- [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] ureido } -isothiazole-4-carboxylic acid amide;
3- (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- [3- (3-dimethylamino-propyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-bromo-2, 3, 6-trifluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-bromo-2, 3, 6-trifluoro-benzyloxy) -5- [3- (4-imidazol-1-yl-butyl) -ureido ] -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-difluoro-benzyloxy) -5- (3- {3- [ ethyl- (2-hydroxy-ethyl) -amino ] -propyl } -ureido) -isothiazole-4-carboxylic acid amide;
3- (4-chloro-2, 3, 6-trifluoro-benzyloxy) -5- (3- {3- [ ethyl- (2-hydroxy-ethyl) -amino ] -propyl } -ureido) -isothiazole-4-carboxylic acid amide;
5- [3- (3-methylamino-propyl) -ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
5- [3- (3-amino-propyl) -3-methyl-ureido ] -3- (2, 3, 6-trifluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
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-pyrrolidin-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;
5- (3- {4- [ bis- (2-hydroxy-ethyl) -amino ] -butyl } -ureido) -3- (2, 6-difluoro-4-methyl-benzyloxy) -isothiazole-4-carboxylic acid amide;
And pharmaceutically acceptable salts, and solvates of said compounds.
10. A pharmaceutical composition for treating a hyperproliferative disorder in a mammal, said composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
11. The pharmaceutical composition of claim 10, wherein the hyperproliferative disease is cancer selected from the group consisting of brain, lung, squamous cell, bladder, gastric, pancreatic, breast, head, neck, kidney, ovarian, prostate, colorectal, esophageal, gynecological and thyroid cancer.
12. The pharmaceutical composition of claim 10, wherein the disease is a non-cancerous hyperproliferative disease.
13. The pharmaceutical composition of claim 12, wherein the disease is benign hyperplasia of the skin or prostate.
14. The use of a compound of claim 1 for the preparation of a medicament for the treatment of a hyperproliferative disorder in a mammal.
15. The use of claim 14, wherein the medicament is for the treatment of cancer selected from the group consisting of brain, squamous cell, bladder, gastric, pancreatic, breast, cancer of the head, cancer of the neck, esophageal, prostate, colorectal, lung, kidney, ovarian, gynecological and thyroid cancer.
16. The use of claim 14, wherein the medicament is for the treatment of a non-cancerous hyperproliferative disease.
17. The use of claim 16, wherein the medicament is for the treatment of benign hyperplasia of the skin or prostate.
18. The use of a compound of claim 1 in combination with an antineoplastic agent selected from the group consisting of: mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, NK1 receptor antagonists, 5-HT3Receptor antagonists, COX-2 inhibitors, EGFR inhibitors, and antiandrogens.
19. A compound which is:
20. a compound which is:
wherein R is3Is H, C1-C10Alkyl radical, C2-C10Alkenyl radical, C2-C10Alkynyl, - (CH)2)t(C6-C10Aryl) or- (CH)2)t(5-10 membered heterocycle), wherein t is an integer of 0 to 5; the alkyl group optionally contains 1 or 2 groups selected from O, S and-N (R)6) -a heteroatom moiety, with the proviso that two O atoms,Two S atoms or O and S atoms are not directly connected; said aryl and heterocyclic ring R3The radicals being optionally substituted with C 6-C10Aryl radical, C5-C8A saturated cyclic group or a 5-to 10-membered heterocyclic group is fused; optionally substituted on 1 or 2 carbon atoms of the aforementioned heterocyclic moiety by an oxo (═ O) moiety; r mentioned above3Of a group- (CH)2)t-the moiety optionally containing a carbon-carbon double or triple bond, wherein t is an integer from 2 to 5, and the aforementioned R3The radicals being optionally substituted by 1 to 5R4Substituted by a group;
each R4Independently of one another, from C1-C10Alkyl radical, C2-C10Alkenyl radical, C2-C10Alkynyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -OR5、-C(O)R5-C(O)OR5、-NR6C(O)OR5、-OC(O)R5、-NR6SO2R5、-SO2NR5R6、-NR6C(O)R5、-C(O)NR5R6、-NR5R6、-S(O)jR7Wherein j is an integer from 0 to 2, -SO3H、-NR5(CR6R7)tOR6、-(CH2)t(C6-C10Aryl), -SO2(CH2)t-(C6-C10Aryl), S (CH)2)t(C6-C10Aryl), -O (CH)2)t-(C6-C10Aryl), - (CH)2)t(5-to 10-membered heterocycle) and- (CR6R7)mOR6Wherein m is an integer of 1 to 5, and t is an integer of 0 to 5; the alkyl group optionally contains 1 or 2 groups selected from O, S and-N (R)6) -a heteroatom moiety, with the proviso that two O atoms, two S atoms or O and S atoms are not directly connected; said aryl and heterocyclic ring R4The radicals being optionally substituted with C6-C10Aryl radical, C5-C8A saturated cyclic group or a 5-to 10-membered heterocyclic group is fused; 1 in the aforementioned heterocyclic moietyOr 2 carbon atoms optionally substituted with an oxo (═ O) moiety; r mentioned above4The alkyl, aryl and heterocyclic moieties of the group are optionally substituted with 1-3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -NR 6SO2R5、-SO2NR5R6、-C(O)R5、-C(O)OR5、-OC(O)R5、-NR6C(O)R5、-C(O)NR5R6、-NR5R6、-(CR6R7)mOR6Wherein m is an integer of 1 to 5, -OR5And R5The substituents listed in the definition of (1);
each R5Are independently selected from H, C1-C10Alkyl, - (CH)2)t(C6-C10Aryl) and- (CH)2)t(5-10 membered heterocycle), wherein t is an integer of 0 to 5; the alkyl group optionally contains 1 or 2 groups selected from O, S and-N (R)6) -a heteroatom moiety, with the proviso that two O atoms, two S atoms or O and S atoms are not directly connected; said aryl and heterocyclic ring R5The radicals being optionally substituted with C6-C10Aryl radical, C5-C8A saturated cyclic group or a 5-to 10-membered heterocyclic group is fused; and the aforementioned R5Substituents, other than H, are optionally substituted by 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -C (O) R6、-C(O)OR6、-CO(O)R6、-NR6C(O)R7、-C(O)NR6R7、-NR6R7Hydroxy, C1-C6Alkyl and C1-C6Substituted by a substituent of alkoxy;
each R6And R7Independently of one another, H or C1-C6An alkyl group.
21. A process for the preparation of a compound according to claim 1, which process comprises,
(a) general formula18Of (a) a compound
With the formula R3Treatment with a compound of formula (I) X, wherein X is halogen and R is3As defined in claim 1, and then subjecting the resulting compound to the reaction of the formula R1R2Treatment of compounds of NH, wherein R1And R2As defined in claim 1; or
(b) General formula25Of (a) a compound
Wherein R is3As defined in claim 1, of the formula R 1R2Treatment of compounds of NH, wherein R1And R2As defined in claim 1.
HK01107830.8A 1998-06-04 1999-05-03 Isothiazole derivatives useful as anticancer agents HK1036982B (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US8796398P 1998-06-04 1998-06-04
US60/087,963 1998-06-04
PCT/IB1999/000797 WO1999062890A1 (en) 1998-06-04 1999-05-03 Isothiazole derivatives useful as anticancer agents

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HK1036982B true HK1036982B (en) 2005-04-01

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