AU2002337151A1 - Substituted benzimidazole compounds and their use for the treatment of cancer - Google Patents

Substituted benzimidazole compounds and their use for the treatment of cancer

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AU2002337151A1
AU2002337151A1 AU2002337151A AU2002337151A AU2002337151A1 AU 2002337151 A1 AU2002337151 A1 AU 2002337151A1 AU 2002337151 A AU2002337151 A AU 2002337151A AU 2002337151 A AU2002337151 A AU 2002337151A AU 2002337151 A1 AU2002337151 A1 AU 2002337151A1
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ester
benzoimidazol
amino
benzenesulfonic acid
acid
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AU2002337151A
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AU2002337151B2 (en
Inventor
Odile Angouillant-Boniface
Chantal Carrez
Francois Clerc
Isabelle Depaty
Stephanie Deprets
Francois Hamy
Manfred Roesner
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Aventis Pharma SA
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Aventis Pharma SA
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Priority claimed from EP01402460A external-priority patent/EP1298125A1/en
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Description

SUBSTITUTED BENZIMIDAZOLE COMPOUNDS AND THEIR
USE FOR THE TREATMENT OF CANCER
Technical Field
The present invention relates to compounds useful for treating pathological states, which arise from or are exacerbated by cell proliferation, to pharmaceutical compositions comprising these compounds, and to methods of inhibiting cell proliferation in a mammal.
Background of the Invention
Neoplastic diseases, characterized by the proliferation of cells, which are not subject to normal cell proliferating controls, are a major cause of death in humans and other mammals. Cancer chemotherapy has provided new and more effective drugs to treat these diseases and has also demonstrated that drugs, which are inhibitors of cyclin-dependent kinases are effective in inhibiting the proliferation of neoplastic cells. Regulators at cell cycle checkpoints determine the decision for a cell to proceed through the cell cycle. Progression of the cell cycle is driven by cyclin- dependent kinases (CDKs) which are activated by oscillating members of the cyclin family, resulting in substrats phosphorylation and ultimately cell division. In addition, endogenous inhibitors of CDKs (TNK4 family and KIP/CIP family) negatively regulate the activity of CDKs. Normal cell growth is due to a balance between activators of CDKs (cyclins) and endogenous inhibitors of CDKS. In several types of cancer, aberrant expression or activity of several components of the cell cycle has been described.
Cdk4 fonctions in Gl phase of the cell cycle and is activated by D-rype cyclins, which results in substrate phosphorylation and progression to S phase. The only known substrate for cdk4 is the retinoblastoma gene product (pRb), a major tumor suppressor gene product, which fonctions as a major checkpoint control in regulation of the Gl/S phase transition. Hyperphosphorylation of pRb by CDKs causes the release of E2F (a family of transcription factors) bound to pRb which then activate genes necessary for cell cycle progression, e.g. thymidine kinase, thymidylate synthase, cyclin E and cyclin A. Cyclin DI is amplified or overexpressed in many types of cancer (breast, ovarian, bladder, esophogeal, lung, lymphoma), while the gene for pl6, the endogenous inhibitor of cdk4, is deleted, mutated, or aberrantly methylated in many tumor types. A point mutation in cdk4 was reported in a melanoma tumor that rendered the enzyme unable to bind pi 6 resulting in a constitutively active enzyme. All of the conditions described above lead to activation of cdk4 and cell cycle progression and tumor cell growth. Arguments to designate CDK2 as an anticancer agent can be found in the litterature « Cyclin E activates Cdk2 which acts to phosphorylate pRb resulting in an ireversible commitment to cell division and transition into S-phase » (PL Toogood, Medicinal Research Reviews (2001), 21(6) ; 487-498. and « CDK2 (and possibly CDK3) is required for Gl progression and entry into S phase. In complex with cyclin E, it sustains pRb hyperphosphrylation to support progression through Gl and into S phase. In addition many other cellular targets of CDK2-CyclinE have been identified.... In complex with cyclinA, CDK2 plays a role in inactivating E2F and is required for completion of S phase. » TD. Davies et al. (2001) Structure 9, 389-397.
An added level of regulation of CDK activity exists. Cyclin-dependent kinase activating kinase (CAK) is a positive regulator of CDKs. CAK phosphorylates the catalytic CDKs on a conserved threonine residue to render the target enzyme completely active.
Because the defects in cell cycle molecules lead to CDK activation and subsequently cell cycle progression, it is logical that inhibition of CDK enzyme activity should block cell cycle progression and tumor cell growth.
The first CDK inhibitor to enter clinical trials is the compound known as Flavopiridol. This compound is currently in Phase II clinical trials and is the only molecule in its class in the clinic at the present time. The aim of this invention is to produce molecules more active that Flavopiridol. It is known following publication of WOOO/41669 that benzimidazole carbamate derivatives are vascular damaging agents that can be used for treating cancer, the sulfonoester derivatives claimed in this patent application are not at all exemplified and their anticancerous way of action is not described. Our invention relates speciffically to sulfonesters derivatives of those carbamates. Summary of the Invention
In one embodiment of the present invention are disclosed compounds of formula (I)
• wherein A is an aryl or heteroaryl entity
• wherein Ri is selected from the group consisting of
- alkyl, eventually substituted by an alkoxy, heteroalkyl, aryl, acyl, acyl derivatives, halogen
-alkoxy eventually substituted by an alkyl, heteroalkyl, aryl, heteroaryl, alkoxyalkyl, hydroxyalkyl amide or a perfluoroalkoxy group or an alkylthio eventually substituted by an amide or a perfluoroalkylthio - aryl or heteroaryl eventually substituted by one or more alkyl group, alkoxy group, nitro group, cyano group, acyl derivative, perfluoroalkoxy group, perfluoroalkyl group, heteroaryl group, aryloxy group
- halogen -4 NH2
- 4 NH alkyl or cycloalkyl eventually substituted with an an acyl, an acylderivative, an hydroxy, an amino, alkoxy, heterocyclyl or aryl group
- 4 N imidazolyl - 3 SO2 Me when A is phenyl
■ wherein R2 is selected from the group consisting of
- CO-alkyl eventually substituted by amino, acid, acid derivative, alkoxy, aryl or OH groups
- CO-aralkyl eventually substituted by alkoxy, halogeno, amino, acid or acid derivatives
- CO-aryl eventually substituted
- CO-alkoxy eventually substituted by aryl - CO-amino, CO-NHR3, CO-NR3R4 wherein R3 and R4 are selected independently from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, fluoroalkyl, alcynyl, heteroalkyl, alkylheteroalkyl, aryl, aralkyl or together form an alkylen chain including eventually one to 4 more heteroatoms
- aryl or aralkyl eventually substituted by heterocycloalkyl, alkyl, aryl, alkoxy, amino, fluoroalkyl, acyl derivatives, halogen or a pharmaceutically acceptable salt.
Among the compounds of formula (I) are preferred those where A represents a phenyl, thiophen, isoxazole, oxazole, pyrazole, furane, pyridine. groups and more preferably those where A is a phenyl group.
Among the compounds of formula (I) are preferred those wherein the aryl, aralkyl, heteroaryl or heteroarylalkyl are eventually substituted with one or more similar or different groups selected from halogen, alkoxy, alkyl, hydroxyalkyl, alkylthio, amino, mono or dialkylamino, heterocyclylamino, arylamino, heteroarylarriino, heteroaryl, nitro, heterocycloalkyl, perfluoroalkyl, perfiuroroalkoxy, perfluoroalkylthio, acyl derivatives.
Among the compounds of fomula (I) are preferred those wherein R is an aminocarbonyl group substituted by a substituent choosen among a monoalkylamino or a monoarylamino substituent In the compounds of formula (I) are preferred those containing for R2 an amino substituent and preferably a monoalkylamino or a monoarylamino substituent and still more preferably those containing a monoalkylamino substituent with an acyl derivative.
Among the alkyl or alkylene substituents which are substituted are included those substituted with one or more amino, aminoalkyl, aminoalkylamino, hydroxy, alkoxy, hydroxyalkoxy, acyl, acyl derivatives, alkyl, heteroalkyl, arylalkyl, arylamino, aryloxy, or aryl groups.
Among the alkoxy or alkythio substituents are included the alkoxy or alkylthio groups substituted with one or more amino, acyl, acyl derivatives, alkyl, arylalkyl or aryl groups. Among the acyl groups or acyl derivatives groups are included the carboxylic acids and the sulfonic acids, the derivatives of which being mainly ester or carbamoyl esters.
The alkyl chain of the present invention includes linear, ramified or cyclic chain containing 1 to 10 carbon atoms. The alkoxy chain of the present invention includes linear, ramified or cyclic chain containing 1 to 4 carbon atoms. The aryl groups includes phenyl or naphtyl groups, heteroaryl groups containing one to four heteroatoms choosen from S, N or O such as furyl, thiophen, isoxazole, oxazole, pyrazole, furane, pyridine. The heterocyclyl group contains one to four heteroatoms choosen from N, O, S and 2 to 6 carbon atoms.
Among those compounds are preferred those containing in the alkyl chain 1 to 10 carbon atoms and those containing in the cycloalkyl chain 3 to 5 carbon atoms. When the alkyl chain is substituted by an alkoxy group this last group has preferably one carbon atom. Among the compounds of formula (I) the following compounds are much more preferred :
Memyl-5-(4-[2-hydroxyemyl]ammophenylsulfonyloxy) benzimidazole-2-carbamate Memyl-5-(4-[4-hydroxbu1yl]ammophenylsulfonyloxy) benzimidazole-2-carbamate Memyl-5-(4-[2-memoxye yl]ammophenylsulfonyloxy) benzimidazole-2-carbamate Methyl-5-(4-[ 1 -imidazolylj-phenylsulfonyloxy) benzimidazole-2-carbamate
Memyl-5-(4-[2-pyridylmemyl]ammophenylsulfonyloxy) benzimidazole-2-carbamate
Methyl-5-(4-ethylaminophenylsulfonyloxy) benzimidazole-2-carbamateMethyl-5-(4-
[N-Glycinyl]-phenylsulfonyloxy) benzimidazole-2-carbamate
Methyl-5-(4-[l -methyl,2-hydroxyethyl] aminophenylsulfonyloxy) benzimidazole-2- carbamate
Methyl-5-(4-[2-methyl,2-hydroxyethyl] aminophenylsulfonyloxy) benzimidazole-2- carbamate
Memyl-5-(4-isoρropylam ophenylsulfonyloxy) ber^rmidazole-2-carbamate Methyl-5-(4-[l -ethyl 2-hydroxyethyl]aminophenyl sulfonyloxy) benzimidazole-2- carbamate
Methyl-5-(4-butylaminophenylsulfonyloxy) benzimidazole-2-carbamate Methyl-5-(4-[3-methoxyρropyl]aminophenylsulfonyloxy) benzimidazole-2- carbamate Memyl-5-(4-memylam ophenylsulfonyloxy) benzimidazole-2-carbamate Memyl-5-(4-[2-sulfonylethyl]aminophenylsulfonyloxy) benzimidazole-2-carbamate
Me yl-5-(4-ammophenylsulfonyloxy) benzimidazole-2-carbamate
Methyl-5-(4-[2-diethylammoethyl] aminophenylsulfonyloxy) benzimidazole-2- carbamate Memyl-5-(4-[l-tetrathydrofurylmethyl] aminophenylsulfonyloxy) benzimidazole-2 - carbamate
Methyl-5-(4-cyclopentylaminophenylsulfonyloxy) benzimidazole-2 -carbamate
Meώyl-5-(4-[2-phenylemyl]anι ophenylsulfonyloxy) benzimidazole-2-carbamate
N- [5-(4- [imidazolylj-phenylsulfonyloxy)- 1 H-benzimidazole-2-yl] -methylurea N-[5-(4-cyclopentylammophenylsulfonyloxy)-lH-benzimidazole-2-yl]-methylurea
N-[5-(4-cyclopentylamώophenylsulfonyloxy)-lH-benzimidazole-2-yl]-dimethylurea
4-Imidazol-l-yl-benzenesulfonic acid 2-benzoylamino-lH-benzoimidazol-5-yl ester
4-Imidazol-l-yl-benzenesulfonic acid 2-phenylacetylamino-lH-benzoimidazol-5-yl ester 4-Imidazol-l-yl-benzenesulfonic acid 2-(2-tert-butoxycarbonylamino-acetylamino)- lH-benzoimidazol-5-yl ester
N-[5-(4-Imidazol-l-yl-benzenesulfonyloxy)-lH-benzoimidazol-2-yl]-succinamic acid methyl ester
4-[5-(4-Imidazol-l-yl-benzenesulfonyloxy)-lH-benzoimidazol-2-ylcarbamoyl]- butyric acid methyl ester
4-[5-(4-Imidazol- 1 -yl-benzenesulfonyloxy)- lH-benzoimidazol-2-ylcarbamoyl]- butyric acid methyl ester
4-Imidazol- 1 -yl-benzenesulfonic acid 2-(cyclohexanecarbonyl-amino)- 1 H- benzoimidazol-5-yl ester 4-Imidazol- 1 -yl-benzenesulfonic acid 2-[(pyridine-2-carbonyl)-amino]- 1H- benzoimidazol-5-yl ester
4-Imidazol- 1 -yl-benzenesulfonic acid 2-[(pyridine-3-carbonyl)-amino]-lH- benzoimidazol-5-yl ester
4-Imidazol-l -yl-benzenesulfonic aci 2-[(pyridinε-4-carbonyl)-amino]-lH- benzoimidazol-5-yl ester
4-Imidazol- 1 -yl-benzenesulfonic acid 2-pentanoylamino-lH-benzoimidazol-5-yl ester
4-Imidazol- 1 -yl-benzenesulfonic acid 2-hexanoylamino-lH-benzoimidazol-5-yl ester
4-Ixnidazol-l-yl-benzenesulfonic acid 2-(2-cyclopropyl-acetylamino)-lH- benzoimidazol-5-yl ester 4-Imidazol-l -yl-benzenesulfonic acid 2-(2-cyclohexyl-acetylamino)-lH- benzoimidazol-5-yl ester
4-Imidazol- 1 -yl-benzenesulfonic acid 2-(2-methoxy-acetylamino)-lH-benzoimidazoI-
5-yl ester 4-Imidazol- 1 -yl-benzenesulfonic acid 2-(2-dimethylamino-acetylamino)-lH- benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-benzoylamino-lH-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-phenylacetylamino- lH-benzoimidazol- 5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(2-tert-butoxycarbonylamino- acetylamino)- lH-benzoimidazol-5-yl ester
N-[5-(4-Cyclopentylamino-benzenesulfonyloxy)-lH-benzoimidazol-2-yl]-succinamic acid methyl ester 4-[5-(4-Cyclopentylamino-benzenesulfonyloxy)-lH-benzoimidazol-2-ylcarbamoyl]- butyric acid methyl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)- 1H- benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(cyclohexanecarbonyl-amino)-lH- benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2- [(pyridine-2-carbonyl)-amino]- 1H- benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[(pyridine-4-carbonyl)-amino]-lH- benzoimidazol-5-yl ester 4-Cyclopentylamino-benzenesulfonic acid 2-[(pyridine-4-carbonyl)-amino]-lH- benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-pentanoylamino- 1 H-benzoimidazol-5-yl ester
4-Cyclopentylammo-benzenesulfonic acid 2-hexanoylamino-lH-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(2-cyclopropyl-acetylamino)- 1 H- benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(2-cyclohexyl-acetylamino)- 1H- benzoimidazol-5-yl ester 4-Cyclopentylamino-benzenesulfonic acid 2-(2-methoxy-acetylamino)-lH- benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(2-dimethylamino-acetylamino)- 1H- benzoimidazol-5-yl ester 4-Imidazol-l -yl-benzenesulfonic acid 2-(3-cyclopropyl-ureido)-lH-benzoimidazol-5- yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(3-cyclopropyl-ureido)-lH- benzoimidazol-5-yl ester
4-Imidazol- 1 -yl-benzenesulfonic acid 2-(3 -isopropyl-ureido)- lH-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(3-isopropyl-ureido)- lH-benzoimidazol-
5-yl ester
4-Imidazol-l -yl-benzenesulfonic acid 2-(3-butyl-ureido)-lH-benzoimidazol-5-yl ester
4-Cyclopentylammo-benzenesulfonic acid 2-(3-butyl-ureido)-lH-benzoimidazol-5-yl ester
4-Imidazol-l-yl-benzenesulfonic acid 2-[3-(2-fluoro-phenyl)-ureido]-lH- benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(2-fluoro-phenyl)-ureido]- 1H- benzoimidazol-5-yl ester 4-Imidazol-l -yl-benzenesulfonic acid 2-[3-(2-methoxy-phenyl)-ureido]-lH- benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2- [3 -(2-methoxy-phenyl)-ureido] - 1 H- benzoimidazol-5-yl ester
4-Imidazol-l -yl-benzenesulfonic acid 2-[3-(3-methoxy-phenyl)-ureido]-lH- benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(3-methoxy-phenyl)-ureido]-lH- benzoimidazol-5-yl ester
4-Imidazol-l-yl-benzenesuIfonic acid 2-[3-(4-methoxy-phenyl)-ureido]-lH- benzoimidazol-5-yl ester 4-Cyclopentylamino-benzenesulfonic acid 2-[3-(4-methoxy-phenyl)-ureido]-lH- benzoimidazol-5-yl ester
4-Imidazol-l-yl-benzenesulfonic acid 2-[3-(2-chloro-phenyl)-ureido]-lH- benzoimidazol-5-yl ester 4-Cyclopentylamino-benzenesulfonic acid 2-[3-(2-chloro-phenyl)-ureido]-lH- benzoimidazol-5-yl ester
4-Imidazol- 1 -yl-benzenesulfonic acid 2- [3 -(4-chloro-phenyl)-ureido]- 1H- benzoimidazol-5-yl ester 4-Cyclopentylamino-benzenesulfonic acid 2-[3-(4-chloro-phenyl)-ureido]-lH- benzoimidazol-5-yl ester
4-Imidazol- 1 -yl-benzenesulfonic acid 2- [3 -(2-methoxy-benzyl)-ureido] - 1 H- benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid2-[3-(2-methoxy-benzyl)-ureido]-lH- benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(3-fluoro-benzyl)-ureido]-lH- benzoimidazol-5-yl ester
4-Imidazol-l-yl-benzenesulfonic acid 2-[3-(3-chloro-phenyl)-ureido]-lH- benzoimidazol-5-yl ester 4-Cyclopentylamino-benzenesulfonic acid 2-[3-(3-chloro-phenyl)-ureido]-lH- benzoimidazol-5-yl ester
4-lmidazol-l-yl-benzenesulfonic acid 2-(3-isobutyl-ureido)-lH-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(3-isobutyl-ureido)-lH-benzoimidazol- 5-yI ester
4-Imidazol- 1 -yl-benzenesulfonic acid 2-[3 -(2-dimethylamino-ethyI)-ureido]- 1H- benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(2-dimethylamino-ethyl)-ureido]-lH- benzoimidazol-5-yl ester 4-Imidazol- 1 -yl-benzenesulfonic acid 2-(3-ethyl-ureido)- lH-benzoimidazol-5-yl ester
4-Cyclopenrylamino-benzenesulfonic acid 2-(3-ethyl-ureido)- lH-benzoimidazol-5-yl ester
{3-[5-(4-Cyclopentylamino-benzenesulfonyloxy)- lH-benzoimidazol-2-yl]-ureido } - acetic acid 4-]midazol-l-yl-benzenesulfonic acid 2-[3-(2-sulfo-e yl)-ureido]-lH-benzoimidazol- 5-yl ester
4-hnidazol-l -yl-benzenesulfonic acid 2-[3-(2-methox3'-ethyl)-ureido]-lH- benzoimidazol-5-yl ester 4-Cyclopentylamino-benzenesulfonic acid 2-[3-(2-methoxy-ethyl)-ureido3-lH- benzoimidazol-5-yl ester
4-Imidazol-l-yl-benzenesulfonic acid 2-[3-(4-dimethylamino-phenyl)-ureido]-lH- benzoimidazol-5-yl ester
4-Cyclopentylammo-benzenesulfonic acid 2-[3-(4-dimethylamino-phenyl)-ureido]- lH-benzoimidazol-5-yl ester
4-Imidazol- 1 -yl-benzenesulfonic acid 2-(3-pγridin-2-ylmethyl-ureido)- 1H- benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl-ureido)- 1H- benzoimidazol-5-yl ester 4-Imidazol-l -yl-benzenesulfonic acid 2-(3-cyclobutyl-ureido)-lH-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(3-cyclobutyl-ureido)-lH- benzoimidazol-5-yl ester
4-lmidazol-l-yl-benzenesulfonic acid 2-(3-pyridin-4-ylmethyl-ureido)-lH- benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(3-pyridin-4-ylmethyl-ureido)- 1H- benzoimidazol-5-yl ester
4-Imidazol-l-yl-benzenesulfonic acid 2-(3-tert-butyl-ureido)-lH-benzoimidazol-5-yl ester 4-Cyclopentylamino-benzenesulfonic acid 2-(3-tert-butyl-ureido)-lH-benzoimidazol- 5-yl ester
4-]midazol-l-yl-benzenesulfonic acid 2-(3-phenyl-ureido)-lH-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(3-phenyl-ureido)- lH-benzoimidazol-5- yl ester 4-Imidazol-l-yl-benzenesulfonic acid 2-(3-cyclohexyl-ureido)-lH-benzoimidazol-5- yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(3-cyclohexyl-ureido)-lH- benzoimidazol-5-yl ester; 4-Imidazol- 1 -yl-benzenesulfonic acid 2-(3-cyclopentyl-ureido)- lH-benzoimidazol-5- yl ester
4-Imidazol-l-yl-benzenesulfonic acid 2-[3-(3-fluoro-phenyl)-ureido]-lH- benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(3-fluoro-phenyl)-ureido]-lH- benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(2-hydroxy-ethyl)-ureido]-lH- benzoimidazol-5-yl ester
4-Imidazol- 1 -yl-benzenesulfonic acid 2- [3 -(2-hydroxy-ethyl)-ureido]- 1 H- benz;oirnidazol-5-yl ester 4-Imidazol- 1 -yl-benzenesulfonic acid 2-[3 -(4-fluoro-phenyl)-ureido]- 1H- benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(4-fluoro-phenyl)-ureido]-lH- benzoimidazol-5-yl ester
4-Imidazol-l-yl-benzenesulfonic acid 2-[3-(2-chloro-benzyl)-ureido]-lH- benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(2-chloro-benzyl)-ureido]- 1H- benzoimidazol-5-yl ester
4-Imidazol-l -yl-benzenesulfonic acid 2-[3-(2-fluoro-benzyl)-ureido]-lH- benzoimidazol-5-yl ester 4-Cyclopentylamino-benzenesulfonic acid 2-[3-(2-fluoro-benzyl)-ureido]-lH- benzoimidazol-5-yl ester
4-Imidazol-l-yl-benzenesulfonic acid 2-[(azetidme-l-carbonyl)-amino]-lH- benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[(azetidine-l-carbonyl)-amino]-lH- benzoimidazol-5-yl ester 4-hnidazol-l -yl-benzenesulfonic acid 2-(3-pyridin-3-ylmethyl-ureido)-lH- benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(3-pyridin-3-ylmethyl-ureido)- 1H- benzoimidazol-5-yl ester 4-Imidazol-l -yl-benzenesulfonic acid 2-{3-[3-(4-methyl-piperazin-l-yl)-propyl]- ureido}-lH-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2- {3-[3-(4-methyl-ρiperazin- 1 -yl)-propyl]- ureido}-lH-benzoimidazol-5-yl ester
4-Imidazol-l -yl-benzenesulfonic acid 2-(3-benzyl-ureido)-lH-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(3-benzyl-ureido)- lH-benzoimidazol-5- yl ester
4- {3-[5-(4-Cyclopentylamino-benzenesulfonyloxy)- lH-benzoimidazol-2-yl]-ureido} - butyric acid methyl ester; 4-{3-[5-(4-Cyclopen1ylammo-beιιzenesulfonyloxy)-lH-benzoimidazol-2-yl]-ureido}- butyric acid ethyl ester
4-{3-[5-(4-Cyclopentylammo-benzenesulfonyloxy)-lH-benzoimidazol-2-yl]-ureido}- acetic acid methyl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(3-imidazol- 1 -yl-propyl)-ureido]- 1H- benzoimidazol-5-yl ester l-[5-(4-Cyclopentylamino-benzenesulfonyloxy)-lH-benzoimidazol-2S-ylcarbamoyl]- pyrrolidine-2-carboxylic acid l-[5-(4-Cyclopentylamino-benzenesulfonyloxy)-lH-benzoimidazol-2S-ylcarbamoyl]- pyrrolidine-2-carboxylic acid methyl ester 4-Cyclopentylamino-benzenesulfonic acid 2-(3-carbamoylmethyl-ureido)-lH- benzoimidazol-5-yl ester l-[5-(4-Cyclopentylammo-benzenesulfonyloxy)-lH-benzoimidazol-2-ylcarbamoyl]- piperidine-4-carboxylic acid ethyl" ester
4-Cyclopentylamino-benzenesulfonic acid 2-(3-ρiperidin-4-ylmethyl-ureido)-lH- benzoimidazol-5-yl ester 4-Cyclopentylamino-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)-ureido]- 1H- benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(2-amino-2-methyl-propyl)-ureido]- lH-benzoimidazol-5-yl ester; 4-Cyclopentylamino-benzenesulfonic acid 2-[3-(4-hydroxy-cyclohexyl)-ureido]-lH- berιzoimidazol-5-yl ester
4-Cyclopenrylamino-benzenesulfonic acid 2-[3-(3-hydroxy-propyl)-ureido]- 1H- benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(l,l-dimethyl-ρropyl)-ureido]-lH- benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2- {3-[2-(2-hydroxy-ethylamino)-ethyl]- ureido}-lH-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(4-hydroxy-butyl)-ureido]- 1H- benzoimidazol-5-yl ester 4-Cyclopentylamino-benzenesulfonic acid 2- {3 - [3 -(2-oxo-pyrrolidin- 1 -yl)-propyl] - ureido } - 1 H-benzoimidazol-5 -yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(2-carbamoyl-ethyl)-ureido]-lH- benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[(2S-carbamoyl-pyrrolidine-l-carbonyl)- amino]- lH-benzoimidazol-5-yl ester
4-Cycloρentylamino-benzenesulfonic acid 2- {3-[2-(2-hydroxy-ethoxy)-ethyl]- ureido}-lH-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(3-pyrrolidin- 1 -yl-propyl)-ureido]- lH-benzoimidazol-5-yl ester 4-Cyclopentylamino-benzenesulfonic acid 2-[3-(l-e yl-pyrrolidin-2-ylmethyl)- ureido]-lH-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(2-pyrrolidin-l-yl-ethyl)-ureido]-lH- benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(2-piperidin-l-yl-ethyl)-ureido]-lH- benzoimidazol-5-yl ester 4-Cyclopen1ylamino-benzenesulfonic acid 2-[3-(2-hydroxy-l-methyl-ethyl)-ureido]- lH-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(2-isopropylamino-ethyl)-ureido]-lH- benzoimidazol-5-yl ester 4-Cyclopentylamino-benzenesulfonic acid 2-[3-(2-diethylamino-ethyl)-ureido]-lH- benzoimidazol-5-yl ester
2-{3-[5-(4-Cyclopentylammo-benzenesulfonyloxy)-lH-benzoimidazol-2-yl]-ureido}- 3S-hydroxy-propionic acid methyl ester
4-{3-[5-(4-Imidazol-l-yl-benzenesulfonyloxy)-lH-benzoimidazol-2-yl]-ureido}- butyric acid methyl ester
4-{3-[5-(4-lmidazol-l-yl-benzenesulfonyloxy)-lH-benzoimidazol-2-yl]-ureido}- butyric acid ethyl ester
{3-[5-(4-Imidazol- 1 -yl-benzenesulfonyloxy)- lH-benzoimidazol-2-yl]-ureido} -acetic acid methyl ester 4-Imidazol-l -yl-benzenesulfonic acid 2-[3-(3-imidazol-l-yl-propyl)-ureido]-lH- benzoimidazoi-5-yl ester
1 -[5-(4-Imidazol- 1 -yl-benzenesulfonyloxy)- lH-benzoimidazol-2-ylcarbamoyl]- pyrrolidine-2-carboxylic acid
1 -[5-(4-Imidazol- 1 -yl-benzenesulfonyloxy)- lH-benzoimidazol-2-ylcarbamoyl]- pyrrolidine-2-carboxylic acid methyl ester
4-Imidazol-l -yl-benzenesulfonic acid 2-(3-carbamoylmethyl-ureido)-lH- benzoimidazol-5-yl ester
1 -[5-(4-Imidazol- 1 -yl-benzenesulfonyloxy)- lH-benzoimidazol-2-ylcarbamoyl]- piperidine-4-carboxylic acid ethyl ester 4-Imidazol-l -yl-benzenesulfonic acid 2-(3-piperidin-4-ylmethyl-ureido)-lH- benzoimidazol-5-yl ester
4-Imidazol-l-yl-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)-ureido]-lH- benzoimidazol-5-yl ester
4-Imidazol- 1 -yl-benzenesulfonic acid 2-[3-(2-amino-2-methyl-propyl)-ureido]- 1H- benzoimidazol-5-yl ester 4-Imidazol- 1 -yl-benzenesulfonic acid 2- [3 -(4-hydroxy-cyclohexyl)-ureido] - 1H- benzoimidazol-5-yl ester
4-Imidazol-l-yl-benzenesulfonic acid 2-[3-(3-hydrox3^-propyl)-ureido]-lH- benzoimidazol-5-yl ester 4-Imidazol-l -yl-benzenesulfonic acid 2-[3-(l,l-dimethyl-propyl)-ureido]-lH- benzoimidazol-5-yl ester
4-Imidazol-l -yl-benzenesulfonic acid 2- {3-[2-(2-hydroxy-ethylamino)-ethyl]- ureido}-lH-benzoimidazol-5-yl ester
4-Imidazol-l-yl-benzenesulfonic acid 2-[3-(4-hydroxy-butyl)-ureido]-lH- benzoimidazol-5-yl ester
4-Imidazol-l -yl-benzenesulfonic acid 2- {3-[3-(2-oxo-pyrrolidin-l-yl)-propyl}- ureido}-lH-benzoimidazol-5-yl ester
4-Imidazol- 1 -yl-benzenesulfonic acid 2- [3 -(2-carbamoyl-ethy l)-ureido] - 1 H- benzoimidazol-5-yl ester 4-Imidazol-l -yl-benzenesulfonic acid 2-[3-(l,l-dimethyl-propyl)-ureido]-lH- benzoimidazol-5-yl ester
4-Imidazol-l-yl-berizenesulfonic acid 2-[(2-carbamoyl-pyrrolidine-l-carbonyl)- amino]-lH-benzoimidazol-5-yl ester
4-Imidazol-l-yl-benzenesulfonic acid 2-{3-[2-(2-hydroxy-ethoxy)-ethyl]-ureido}-lH- benzoimidazol-5-yl ester
4-Imidazol- 1 -yl-benzenesulfonic acid 2- [3 -(3 -pyrrolidin- 1 -yl-propyl)-ureido]- 1 H- benzoimidazol-5-yl ester
4-lmidazol-l-yl-benzenesulfonic acid 2-[3-(l-ethyl-pyrrolidin-2-ylmethyl)-ureido]- lH-benzoimidazol-5-yl ester 4-Imidazol-l -yl-benzenesulfonic acid 2-[3-(2-pyrrolidin-l-yl-ethyl)-ureido]-lH- benzoimidazol-5-yl ester
4-Imidazol-l-yl-benzenesulfonic acid 2-[3-(2-piperidin-l-yl-ethyl)-ureido]-lH- benzoimidazol-5-yl ester
4-Imidazol-l-yl-benzenesulfonic acid 2-[3-(2-hydroxy-l-methyl-ethyl)-ureido]-lH- benzoimidazol-5-yl ester 4-Imidazol-l-yl-benzenesulfonic acid 2-[3-(2-isopropylamino-ethyl)-ureido]-lH- benzoimidazol-5-yl ester
4-Imidazol-l -yl-benzenesulfonic acid 2-[3-(2-diethylamino-ethyl)-ureido]- 1H- benzoimidazol-5-yl ester 2-{3-[5-(4-lmidazol-l-yl-benzenesulfonylox3 -lH-benzoimidazol-2-yl3-ureido}-3- hydroxy-propionic acid methyl ester
4-[(Tetrahydro-fUran-2-yjmethyl)-am o]-benzenesulfonic acid 2-(3- carbamoylmethyl-ureido)- lH-benzoimidazol-5-yl ester
4-[(Tetτahydro-furan-2-ylmemyl)-amino]-benzenesulfonic acid 2-[3-(2-hydroxy- ethyl)-ureido]-lH-benzoimidazol-5-yl ester
4-[(Tetrahydro-furan-2-ylmemyl)-amino]-benzenesulfonic acid 2-[3-(3-hydroxy- propyl)-ureido] - 1 H-benzoimidazol-5 -yl ester
4-[(Tetrahydro-furan-2-ylmemyl)-amino]-benzenesulfonic acid 2-[3-(4-hydroxy- butyl)-ureido]-lH-benzoimidazol-5-yl ester 4-[(Tetrahydro-fiιran-2-ylmethyl)-amino]-benzenesulfonic acid 2-[3-(2-methoxy- 1 - methyl-ethyl)-ureido] - 1 H-benzoimidazol-5 -yl ester
4-[(Tetrahydro-flιran-2-ylme yl)-ammo]-benzenesulfonic acid 2-[3-(l-ethyl- pyrrolidin-2-ylmethyl)-ureido]- lH-benzoimidazol-5-yl ester
4-[(Tetrahydro-furan-2-ylmethyl)-amino]-benzenesulfonic acid 2-[3-(2-pyrrolidin- 1 - yl-ethyl)-ureido]-lH-benzoimidazol-5-yl ester
4-[(Tetrahyα^o-foran-2-ylmemyl)-ammo]-benzenesulfonic acid 2-[3-(3-pyrrolidm-l^ yl-propyl)-ureido] - 1 H-benzoimidazol-5 NI ester
4-[(Tetrahyα o-furan-2-yhιιe yl)-amino]-benzenesulfonic acid 2-[3 -(2-morpholin-4- yl-ethyl)-ureido]-lH-benzoimidazol-5-yl ester 4-[(Tetrahydro-furan-2-ylmethyl)-amino]-benzenesulfonic acid 2-(3-ethyl-ureido)- lH-benzoimidazol-5-yl ester
4-[(Tetrahyάro-furan-2-ylme&^ lH-benzoimidazol-5-yl ester
4-[(Tetrahydro-furan-2-ylmethyl)-amino]-benzenesulfonic acid 2-(3 -pyridin-2- yhnethyl-ureido)-lH-benzoimidazol-5-yl ester 4-[(Tetrahydro-furan-2-ylmeώyl)^ ylmethyl-ureido)- lH-benzoimidazol-5-yl ester
4-[(Te1τahydro-turan-2-ylmethyl)-arnino]-benzenesulfonic acid 2- {3-[3-(4-methyl- piperazin- 1 -yl)-propyl]-ureido } - lH-benzoimidazol-5-yl ester 4-[(Tetrahydro-furan-2-ylmethyl)-amino]-benzenesulfonic acid 2-[3-(2-sulfo-ethyl)- ureido]-lH-benzoimidazol-5-yl ester
4-[(Tetrahydro-furan-2-ylmemyl)-amino]-benzenesulfonic acid 2-(3-cyclobutyl- ureido)-lH-benzoimidazol-5-yl ester
4-[(Tetrahydro-mran-2-ylmethyl)-amino]-benzenesulfonic acid 2- {3-[3-(2-oxo- pyrrolidin-l-yl)-propyl]-ureido}-lH-benzoimidazol-5-yl ester
4-[(Tetrahydro-furan-2-ylmethyl)-amino]-benzenesulfonic acid 2- {3-[2-(2-hydroxy- ethylamino)-ethyl] -ureido } - 1 H-benzoimidazol-5-yl ester
4-[(Tetrahydro-furan-2-ylmethyl)-amino]-benzenesulfonic acid 2-[3-(2-piperidin-l- yl-ethyl)-ureido]-lH-benzoimidazol-5-yl ester 4-Benzylamino-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)- 1H- benzoimidazol-5-yl ester
4-Memylamino-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-lH- benzoimidazol-5-yl ester
4-(2-Hydroxy-ethylamino)-benzenesulfonic acid 2-(cycloprop anecarbonyl-amino)- lH-benzoimidazol-5-yl ester
4-(3-Hydroxy-propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)- lH-benzoimidazol-5-yl ester
4-(4-Hy roxy-butylarmno)-benzenesulfo c acid 2-(cyclopropanecarbonyl-amino)- lH-benzoimidazol-5-yl ester 4-(2-Methoxy-l-methyl-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-l H-benzoimidazol-5 -yl ester
4-(2-Pyrrolidin- 1 -yl-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester
4-(l-Hydroxyme yl-propylamino)-benzenesulfonic aci 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester 4-(2-Hydroxy- 1 -methyl-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester
4-(2-Piperidin- 1 -yl-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester 4-(3-Pyrrolidin-l-yl-propylamino)-benzenesulfonic acid 2-(cycloρropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester
4-(3-Hydroxy-2,2-dimethyl-propylamino)-benzenesulfonic acid 2-(cyclopropane- carbonyl-amino)-lH-benzoimidazol-5-yl ester
4-[(Pyridin-3-ylmethyl)-amino]-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)- lH-benzoimidazol-5-yl ester
4-[3-(4-Memyl-piperazin-l-yl)-propylamino]-benzenesulfonic acid 2-(cyclopropane- carbonyl-amino)-lH-benzoimidazol-5-yl ester
4-(2-Memoxy-benzylammo)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)- lH-benzoimidazol-5-yl ester 4-(4-Hydroxy-cyclohexylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester
4-(2-Diethylamino-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester
4-( 1 S-Hydroxymethyl-propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)- lH-benzoirnidazol-5-yl ester
4-(2-Emylam o-e ylammo)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)- lH-benzoimidazol-5-yl ester
4-(2-Diisopropylamino-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester 4-(2-Morpholin-4-yl-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester
4-(l-Aza-bicyclo[2.2.2]oct-3-ylamino)-benzenesulfonic acid 2-(cyclopropane- carbonyl- amino)- 1 H-benzoimidazol-5-yl ester
4-(2-Phenylamino-ethylamino)-benzenesulfonic acid 2-(cycloproρanecarbonyl- amino)-lH-benzoimidazol-5-yl ester 4-(l -Benzyl-pyrrolidm-3-ylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester
4-(2R-Carbamoyl-pyrrolidin- 1 -yl)-benzenesulfonic acid 2-(cycloprop necarbonyl- amino)-lH-benzoimidazol-5-yl ester 4-(3-Dimethylamino-propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester
4-(2-Piperazin- 1 -yl-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- ammo)-lH-benzoimidazol-5-yl ester
4-(2-Carbamoyl-cyclohexylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)- lH-benzoimidazol-5-yl ester
4-(2-Acetylamino-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester
4-[2-(2-Amino-ethylamino)-ethylamino]-benzenesulfonic acid 2-(cyclopropane- carbonyl-amino)- lH-benzoimidazol-5-yl ester 4-[3-(2-Oxo-pyrrolidin-l-yl)-propylamino]-benzenesulfonic acid 2-(cycloproρane- carbonyl-amino)- lH-benzoimidazol-5-yl ester
4-[2-(lH-Imidazol-4-yl)-emylamino]-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester
4-[(Pyridm-2-ylmethyl)-amino]-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester
4-Cyclobutylamino-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)- 1H- benzoimidazol-5-yl ester
4-[2-(2-Hydroxy-ethoxy)-ethylamino]-benzenesulfonic acid 2-(cyclopropane- carbonyl-amino)- lH-benzoimidazol-5-yl ester 4-(2,3-Dihydroxy-propylamino)-benzenesulfomc acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester
4-(2-Imidazol-l -yl-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester
4-[2-(2-Hydroxy-ethylamino)-ethylamino]-benzenesulfonic acid 2-(cyclopropane- carbonyl-amino)- lH-benzoimidazol-5-yi ester 4-(2-Methoxy-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)- lH-benzoimidazol-5-yl ester
4-(2-Dimethylamino- 1 -methyl-ethylamino)-benzenesulfonic acid 2-(cyclopropane- carbonyl-amino)-lH-benzoimidazol-5-yl ester 4-(Pyrrolidin-3-ylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-lH- benzoimidazol-5-yl ester
4-[2-(lH-mdol-3-yl)-ethylamino]-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester
4-(2-Dimemylammo-emylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)- 1 H-benzoimidazol-5 -yl ester
4-(2-Phenoxy-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)- lH-benzoimidazol-5-yl ester
4-(Bicyclo[2.2.1 ]hept-2-ylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester 4-(2-Memylamino-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester
4-(2-Propylamino-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester
4-(l -Methyl-2-phenoxy-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester
4-[(Piperidin-4-ylmethyl)-amino]-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester
4-(4-Methoxy-benzylamino)-benzenesulfonic acid 2-(cycloρropanecarbonyl-amino)- lH-benzoimidazol-5-yl ester 4-(lH-Benzoimidazol-5-ylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-l H-benzoimidazol-5 -yl ester
4-(3-Methox3'-propylammo)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)- lH-benzoimidazol-5-yl ester
4-(2,2-Dimethoxy-ethylamino)-benzenesulfonic acid 2-(cycloproρanecarbonyl- amino)- lH-benzoimidazol-5-yl ester 4-(4-Dimethylamino-phenylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester
4-(3-Methoxy-benzylamino)-benzenesulfonic acid 2-(cycloproρanecarbonyl-amino)- lH-benzoimidazol-5-yl ester 4-(4-Pyιτolidin-l-yl-butylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester
4-(2,3-Dimemoxy-benzylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester
4-Prop-2-ynylamino-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)- 1H- benzoimidazol-5-yl ester
4-[4-(2-Hydroxy-ethyl)-piperazin- 1 -yl]-benzenesulfonic acid 2-(cyclopropane- carbonyl-amino)-lH-benzoimidazol-5-yl ester
4-[(Pyridm-4-ylmethyl)-amino]-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester 4-[2-(Timyl-m-tolyl-am o)-ethylamino]-benzenesulfonic acid 2-(cycloproρane- carbonyl-amino)-lH-benzoimidazol-5-yl ester
4-(2-Hydroxy-cyclohexylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester
4-(3-Dimemylammo-2,2-dimethyl-propylamino)-benzenesulfonic acid 2- (cyclopropanecarbonyl-amino)-lH-benzoimidazol-5-yl ester
4-[3 -(2-Hydroxy-ethylamino)-propylamino]-benzenesulfonic acid 2-(cyclopropane- carbonyl-amino)- lH-benzoimidazol-5-yl ester
4-[(TetrahyQ^o-furan-2-ylmethyl)-amino]-benzenesulfonic acid 2-(cyclopropane- carbonyl-amino)-lH-benzoimidazol-5-yl ester 4-[(Tetrahydro-fiαran-2R-ylme yl)-amino]-benzenesulfonic acid 2-(cyclopropane- carbonyl-amino)-lH-benzoimidazol-5-yl ester
4-[(Tetxahydro-fύran-2S-ylmethyl)-amino]-benzenesulfonic acid 2-(cyclopropane- carbonyl-amino)- lH-benzoimidazol-5-yl ester
4-(2-Butylamino-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)- lH-benzoimidazol-5-} ester 4-(3-Methylamino-propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester
4-(lS,2-Dicarbamoyl-emylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester 2- {4-[2-(Cycloproρanecarbonyl-amino)- lH-benzoimidazol-5-yloxysulfonyl]- phenylamino}-3R-hydroxy-propionic acid methyl ester
4-(2-Carbamoyl-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)- lH-benzoimidazol-5-yl ester
4-(3-Methoxy-propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)- lH-benzoimidazol-5-yl ester
4-(3 ,4,5-Trimethoxy-benzylamino)-benzenesulfonic acid 2-(cyclopropanecarbonγl- amino)-lH-benzoimidazol-5-yl ester
4-(Carbamoylmethyl-amino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)- lH-benzoimidazol-5-yl ester l-{4-[2-(Cyclopropanecarbonyl-amino)-lH-benzoimidazol-5-yloxysulfonyl]- phenyl}-piperidine-4-carboxylic acid ethyl ester
4-(2-Amino-2-methyl-propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester
3-{4-[2-(Cyclopropanecarbonyl-amino)-lH-benzoimidazol-5-yloxysulfonyl]- phenylamino} -propionic acid methyl ester
4-(3-Morpholin-4-yl-propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester
4-(5-Hydroxy-pentylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)- 1 H-benzoimidazol-5 -yl ester 4-[(5S-Ammo-2,2,4S-trimethyl-cycloρentyhτιeώyl)-amino]-benzenesulfonic acid 2- (cycloprop anecarbony l-amino)- 1 H-benzoimidazol-5 -yl ester
4-(2-Hydroxymethyl-phenylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-l H-benzoimidazol-5 -yl ester
4-(4-Ethoxy-phenylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)- 1 H-benzoimidazol-5 -yl ester 4-Ethylamino-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-lH- benzoimidazol-5-yl ester
4-(2-Sulfo-ethylamino)-benzenesulfonic acid 2-(cycloρropanecarbonyl-amino)- 1H- benzoimidazol-5-yl ester 4-{4-[2-(Cyclopropanecarbonyl-amino)-lH-benzoimidazol-5-yloxysulfonyl]- phenylamino} -piperidine- 1 -carboxylic acid ethyl ester
4-({4-[2-(Cyclopropanecarbonyl-amino)-lH-benzoimidazol-5-yloxysulfonyl]- phenylamino}-methyl)-benzoic acid
4-[(l-Carbamimidoyl-piperidm-4-ylmemyl)-amino]-benzenesulfonic acid 2- (cyclopropanecarbonyl-amino)-lH-benzoimidazol-5-yl ester
4-{4-[2-(Cyclopropanecarbonyl-amino)-lH-benzoimidazol-5-yloxysulfonyl]- phenyl} -piperazine- 1 -carboxylic acid tert-butyl ester
3-{4-[2-(Cyclopropanecarbonyl-amino)-lH-benzoimidazol-5-yloxysulfonyl]- phenylamino}-3-phenyl-propionic acid 4-Piρeridin- 1 -yl-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)- 1H- benzoimidazol-5-yl ester
4-(l -Memyl-4-oxo-imidazolidin-2-ylideneamino)-benzenesulfonic acid 2- (cyclopropanecarbonyl-amino)-lH-benzoimidazol-5-yl ester
4-(4-Methyl-piperazin- 1 -yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)- lH-benzoimidazol-5-yl ester
4-(3-Hydroxy-pyrrolidin-l -yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester
4-(Cyclopropylmethyl-amino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester 4-[(2-Dime ylammo-emyl)-methyl-amino]-benzenesulfonic acid 2-(cycloρropane- carbonyl-amino)- 1 H-benzoimidazol-5-yl ester
4-Isobutylamino-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-lH- benzoimidazol-5-yl ester
4-[Ethyl-(2-hydroxy-ethyl)-amino]-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)- lH-benzoimidazol-5-yl ester 4-(2-Hydroxy- 1 -hydroxymethyl-ethylamino)-benzenesulfonic acid 2-(cyclopropane- carbonyl-amino)- lH-benzoimidazol-5-yl ester
4-Propylamino-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)- 1H- benzoimidazol-5-yl ester 4-Cyclopropylamino-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-lH- benzoimidazol-5-yl ester
4-Morpholin-4-yl-benzenεsulfonic acid 2-(cyclopropanecarbonyl-amino)-lH- benzoimidazol-5-yl ester
4-[2-(l -Methyl-pyrrolidin-2-yl)-ethylamino]-benzenesulfonic acid 2-(cyclopropane- carbonyl-amino)- lH-benzoimidazol-5-yl ester
4-[( 1,3 -Dimethyl- lH-pyrazol-4-ylmethyl)-amino]-benzenesulfonic acid 2- (cyclopropanecarbonyl-amino)- lH-benzoimidazol-5-yl ester
4-(4-Acetylammo-benzylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester 4-(3-Cyclohexylamino-propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester
4-(3-Ethoxy-propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)- lH-benzoimidazol-5-yl ester
4-Pyrrolidin-l -yl-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-lH- benzoimidazol-5-yl ester
4-(4-Methyl-benzylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)- lH-benzoimidazol-5-yl ester
4-[ 1 ,4']Bipiperidinyl- 1 '-yl-benzenesulfonic acid 2-(cycloprop anecarbony l-amino)- 1H- benzoimidazol-5-yl ester 4-(2-Pyridin-3-yl-pyrrolidin-l-yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester
4-(4-Hydroxy-piperidin- 1 -yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)- lH-benzoimidazol-5-yl ester
4-[(2-Hydroxy-ethyl)-methyl-amino]-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester 4-[(l -Eώyl-pyrrolidώ-2-ylme yl)-amino]-benzenesulfonic acid 2-(cyclopropane- carbonyl-amino)- lH-benzoimidazol-5-yl ester
4-(3-Hydroxy-pyridin-2-ylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester 4-[(l-Carbamoyl-piperidm-4-ylmethyl)-amino]-benzenesulfonic acid 2- (cyclopropanecarbonyl-amino)- lH-benzoimidazol-5-yl ester
4-(2-Pyrrol-l -yl-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)- lH-benzoimidazol-5-yl ester
4-(4-Cyclopentyl-piperazin- 1 -yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester
4-(2-Propoxy-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)- lH-benzoimidazol-5-yl ester
4-(3 -Cyclohexylamino-propylamino)-benzenesulfonic acid 2-(cycloprop anecarbony 1- amino)-lH-benzoimidazol-5-yl ester 4-(lH-IndoI-5-ylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-lH- benzoimidazol-5-yl ester
4-(4-Amino-benzylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)- lH-benzoimidazol-5-yl ester
4-(2S-Methoxymethyl-pyrrolidin- 1 -yl)-benzenesulfonic acid 2-(cyclopropane- carbonyl-amino)- lH-benzoimidazol-5-yl ester
4-[4-(2-Hydroxy-ethyl)-piperidin- 1 -yl]-benzenesulfonic acid 2-(cyclopropane- carbonyl-amino)-lH-benzoimidazol-5-yl ester
4-[2-(2-Hydroxy-ethyl)-piperidin-l-yl]-benzenesulfonic acid 2-(cyclopropane- carbonyl-amino)- lH-benzoimidazol-5-yl ester 4-(2-Isopropylamino-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester
3-{4-[2-(Cyclopropanecarbonyl-amino)-lH-benzoimidazol-5-yloxysulfonyl]- phenylamino} -propionic acid
4-[Methyl-(2-memylammo-emyl)-amino]-benzenesulfonic acid 2-(cyclopropane- carbonyl-amino)- lH-benzoimidazol-5-yl ester 4-(3-Acetylamino-pyrrolidin- 1 -yl)-benzenesulfonic acid 2-(cyclopropanεcarbonyl- amino)-lH-benzoimidazol-5-yl ester
4-(Carbamoylmethyl-amino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)- lH-benzoimidazol-5-yl ester 4-(4-Hydroxy-piperidin-l-yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)- lH-benzoimidazol-5-yl ester
4-(4-Dimemylammo-benzylamino)-benzenesulfonic acid 2-(cycloprop anecarbony 1- amino)-lH-benzoimidazol-5-yl ester
4-(3-Imidazol- 1 -yl-propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)- lH-benzoimidazol-5-yl ester
4-(Quinoxalin-5-ylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)- lH-benzoimidazol-5-yl ester
4-[4-(2-Hydroxy-ethyl)-piperazin- 1 -ylj-benzenesulfonic acid 2-(cyclopropane- carbonyl-amino)- lH-benzoimidazol-5-yl ester 4-(2-Hydroxy- 1 , 1 -dimethyl-ethylamino)-benzenesulfonic acid 2-(cyclopropane- carbonyl-amino)-lH-benzoimidazol-5-yl ester
1 - {4-[2-(Cyclopropanecarbonyl-amino)- lH-benzoimidazol-5-yloxysulfonyl]- phenyl} -piperidine-4-carboxylic acid
6-{4-[2-(Cyclopropanecarbonyl-amino)-lH-benzoimidazol-5-yloxysulfonyl]- phenylarnino}-hexanoic acid methyl ester
4-[4-(4-Methoxy-phenyl)-piperazin- l-yl]-benzenesulfonic acid 2-(cyclopropane- carbonyl-amino)-lH-benzoimidazol-5-yl ester
4-[4-(2-Memoxy-ethyl)-piperazin-l-yl]-benzenesulfonic acid 2-(cyclopropane- carbonyl- amino)- lH-benzoimidazol-5-yl ester 4-[(2-Hydroxy-ethyl)-ρhenyl-amino]-benzenesulfonic acid 2-(cycloproρanecarbonyl- amino)-lH-benzoimidazol-5-yl ester
4-[(Furan-2-ylmethyl)-amino]-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester
1 - {4-[2-(Cyclopropanecarbonyl-amino)- lH-benzoimidazol-5-yloxysulfonyl]- phenyl} -aziridine-2-carboxylic acid methyl ester 4-(4-Carbamoyl-piperidin- 1 -yl)-benzεnesulfonic acid 2-(cyclopropanεcarbonyl- amino)-lH-benzoimidazol-5-yl ester
4-(3-Methyl-piperazin- 1 -yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)~ lH-benzoimidazol-5-yl ester 4-(2,6-Dimethyl-morpholin-4-yl)-benzenesulfonic acid 2-(cyclopropanεcarbonyl- amino)-lH-benzoimidazol-5-yl ester
4-(4-Phenyl-piperazin- 1 -yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)- lH-benzoimidazol-5-yl ester
4-(4-Pyridin-2-yl-piperazin- l-yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amώo)-lH-benzoimidazol-5-yl ester
4-(4-Diethylamino- 1 -methyl-butylamino)-benzenesulfonic acid 2-(cyclopropane- carbonyl-amino)- lH-benzoimidazol-5-yl ester
4-{4-[2-(Cyclopropanecarbonyl-amino)-lH-benzoimidazol-5-yloxysulfonyl]- phenyl} -piperazine- 1 -carboxylic acid ethyl ester 4-(5-Hydroxy-naphthalen- 1 -ylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester
4- [2-(4-Hydroxy-3 -methoxy-phenyl)-ethylamino] -benzenesulfonic acid 2- (cyclopropanec-rrbonyl-amino)-lH-benzoimidazol-5-yl ester
4-(9H-Purin-6-ylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-lH- benzoimidazol-5-yl ester
1 - {4-[2-(Cyclopropanεcarbonyl-amino)- lH-bεnzoimidazol-5-yloxysulfonyl]- phenyl} -piperidine-3 -carboxylic acid
4-(3 ,3 -Dimethyl-piperidin- 1 -yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester 4-(4-Methyl-piperidin-l-yl)-bertzenesuifonic acid 2-(cyclopropanecarbonyl-amino)- lH-benzoimidazol-5-yl ester
4-(2-Pyridin-2-yl-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester
4-(3-Hydrox3αnemyl-phenylamino)-bεnzεnesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester 4-(2-Oxo-2,3-dmydro-lH-pyrimidm-4-ylidεneamino)-benzenesulfonic acid 2- (cyclopropanεcarbonyl-amino)- lH-bεnzoimidazol-5-yl ester
4-(3-Pi eridin- 1 -yl-propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester 4-[2-(lH-Indol-3-yl)-ethylamino]-benzenesulfonic acid 2-(cyclopropanεcarbonyl- amino)-lH-benzoimidazol-5-yl ester
4-(5-Carbamoyl-lH-imidazol-4-ylamino)-benzenesulfonic acid 2-(cyclopropane- carbonyl-amino)-lH-benzoimidazol-5-yl ester
4-(l -Hydroxymethyl-butylamino)-benzenesulfonic acid 2-(cyclopropanεcarbonyl- amino)- lH-benzoimidazol-5-yl ester
4-(l -Benzyl-piperidin-4-ylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester
4- {4-[2-(2-Hydroxy-ethoxy)-ethyl]-piperazin- 1 -yl} -benzenesulfonic acid 2- (cyclopropanecarbonyl-amino)- lH-benzoimidazol-5-yl ester 4-(4-Methyl- [ 1 ,4]diazepan- 1 -yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimid-ιzol-5-yl ester
4-(3-Azepan-l-yl-propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyT- amino)-lH-benzoimidazol-5-yl ester
4-(2,6-c/5-Dimeώyl-mo holin-4-yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-lH-benzoimidazol-5-yl ester
4-(2S-Hydroxymethyl-pyrrolidin- 1 -yl)-benzεnesulfonic acid 2-(cyclopropane- carbonyl-amino)-lH-benzoimidazol-5-yl ester
4-[4-(3-Pyrrolidin-l -yl-propyl)-[l ,4]diazepan- 1 -yl] -benzenesulfonic acid 2- (cyclopropanecarbonyl-amino)-lH-benzoimidazol-5-yl estεr 4-trifluoromεthoxy-benzenesulfonic acid 2-methoxycarbonylamino- 1H- benzoimidazol-5-yl ester
3 ,5-Dimethyl-isoxazole-4-sulfonic acid 2-methoxycarbonylamino- 1 H-benzoimidazol- 5-yl ester
Thiophene-2-sulfonic acid 2-methoxycarbonylamino- lH-benzoimidazol-5-yl ester 5-Isoxazol-3-yl-thiophene-2-sulfonic acid 2-methoxycarbonylamino- 1H- benzoimidazol-5-yl εster
2-Fluoro-benzenesulfonic acid 2-methoxycarbonylamino- lH-benzoimidazol-5-yl ester 5-(l -Methyl-5-trifluoromethyl- lH-pyrazol-3-yl)-thiophene-2-sulfonic acid 2-methoxycarbonylamino- lH-benzoimidazol-5-yl ester
3-Trifluoromethoxy-benzenesulfonic acid 2-methoxycarbonylamino-lH-benzo- imidazol-5-yl ester
2-Trifluoromethoxy-benzenesulfonic acid 2-memoxycarbonylamino-lH-benzo- imidazol-5-yl ester
2,6-Difluoro-benzenesulfonic acid 2-memoxycarbonylammo-lH-benzoimidazol-5-yl ester
3-Methoxy-benzenesulfonic acid 2-methoxycarbonylamino- lH-benzoimidazol-5-yl ester 3-(2-Memoxycarbonylamino- lH-benzoimidazol-5-yloxysulfonyl)-thiophene-2- carboxylic acid methyl ester
3,4-Dimemoxy-benzenesulfonic acid 2-methoxycarbonylamino-lH-benzoimidazol-5- yl ester
3-Nitro-benzenesulfonic acid 2-methoxycarbonylamino-lH-benzoimidazol-5-yl ester 3-Trifluoromethyl-benzεnesulfonic acid 2-methoxycarbonylamino-lH-benzo- imidazol-5-yl ester
2-Cyano-benzenesulfonic acid 2-met oxycarbonylamino-lH-benzoimidazol-5-yl ester
2-Trifluoromethyl-benzenesulfonic acid 2-methoxycarbonylamino- IH-benzo- imidazol-5-yl ester
2,4-Difluoro-benzenesulfonic acid 2-methoxycarbonylamino-lH-bεnzoimidazol-5-yl ester
5 -Fluoro-2-methyl-benzεnesuIfonic acid 2-methoxycarbonylamino- 1 H-benzo- imidazol-5-yl ester 3-Fluoro-benzenesulfonic acid 2-memoxycarbonylamino-lH-benzoimidazol-5-yl estεr
4-Cyano-benzenesulfonic acid 2-methoxycarbonylamino- lH-benzoimidazol-5-yl ester 2-Me oxy-5-(2-memoxycarbonylammo-3H-bεnzoimidazol-5-yloxysulfonyl)- thiophεnε-3-carboxylic acid mεthyi ester l,3,5-Trimethyl-lH-pyrazole-4-sulfonic acid 2-mεthoxycarbonylamino-3H- bεnzoimidazol-5-yl εster
6-Morpholin-4-yl-pyridine-3 -sulfonic acid 2-methoxycarbonylamino-3H- benzoimidazol-5-yl ester
2,4,6-Trifluoro-benzenesulfonic acid 2-methoxycarbonylamino- lH-benzoimidazol-5- yl ester
4-benzyloxy-benzenεsulfonic acid 2-methoxycarbonylamino- lH-benzoimidazol-5-yl ester 4-Ethoxy-benzenesulfonic acid 2-methoxycarbonylamino-3H-benzoimidazol-5-yl ester
4-(2-Morpholώ-4-yl-emoxy)-berιzenesulfonic acid 2-mεmoxycarbonylamino-3H- benzoimidazol-5-yl ester
4-(2-Methoxy-ethoxy)-benzenesulfonic acid 2-methoxycarbonylamino-3H- benzoimidazol-5-yl ester
4-(2-piperidin- 1 -yl-εthoxy)-bεnzenesulfonic acid 2-methoxycarbonylamino-3H- benzoimidazol-5-yl ester
[4-(2-Methoxycarbonylamino-3H-benzoimidazol-5-yloxysulfonyl)-phenoxy]-acetic acid 4-(2-oxo-2-pyrrolidin- 1 -yl-ethoxy)-benzenesulfonic acid 2-methoxycarbonylamino- lH-benzoimidazol-5-yl-ester
4-[2-(4-Methyl-piperazin- 1 -yl)-2-oxo-ethoxy]-benzenesulfonic acid 2-methoxycarbonylamino- lH-benzoimidazol-5-yl ester
4-[(3-diethylarmno-propylcarbamoyl)-m8thoxy]-benzenesulfonic acid 2-mεthoxy- carbonylamino-lH-benzoimidazol-5-yl ester 4- {[(furan-2-ylmethyl)-carbamoyl]-methoxy} -benzenesulfonic acid 2-methoxycarbonylamino- lH-benzoimidazol-5-yl ester
4-(cyclopropylmethyl-amino)-benzenesulfonic acid 2-methoxycarbonylamino- 1H- benzoimidazol-5-yl ester 4-(2-methoxy-ethylamino)-benzenesulfonic acid 2-methoxycarbonylamino- 1H- benzoimidazol-5-yl ester
4-(2-hydroxy- 1 -methyl-ethylamino)-benzenesulfonic acid 2-methoxycarbonylamino- lH-bεnzoimidazol-5-yl ester
4-(henzylamino)-benzenesulfonic acid 2-methoxycarbonylamino- 1 H-benzoimidazol- 5-yl ester
4-(2-Mθ holm-4-yl-ethylamino)-bεnzenesulfonic acid 2-methoxycarbonylamino- lH-benzoimidazol-5-yl ester
4-(2-Piperidin-4-yl-ethylamino)-benzenesulfonic acid 2-[3-(2-piperidin-l-3d-ethyl)- ureido]-3H- benzoimidazol-5-yl ester 4-[(l-E yl-pyirolidin-2-ylmethyl)-amino]-benzenesulfonic acid 2-[3-(2-piperidin-l- yl-ethyl)-ureido]-3H- benzoimidazol-5-yl ester
4-cyclopentylamino-benzenesulfonic acid 2-(3 ,4-dimethoxy-phenylamino)- 1H- benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-phenylamino- 1 H-benzoimidazol-5 -yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(4-morpholin-4-yl-phenylamino)- 1H- benzoimidazol-5-yl ester
4-Cyclopentylammo-benzenesuIfonic acid 2-(3,5-dimethyl-phenylamino)-lH- benzoimidazol-5-yl ester 4-Cyclopentylamino-benzenesulfonic acid 2-(4-methoxy-phenylamino)-lH- benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(4-dimethylamino-phenylamino)- 1H- benzoimidazol-5-yl ester
4-Cyclopentylamino-benzεnesulfonic acid2-(3-methoxy-5-trifluoromethyl- phεnylamino)-lH-benzoimidazol-5-yl estεr 5Δ
3-[5-(4-Cyclopεntylammo-benzenesulfonyloxy)-lH-benzoimidazol-2-ylamino]- benzoic acid ethyl ester
4-Cyclopentylamino-bεnzεnesulfonic acid 2-[(4-(4-methyI-piperazin- 1 -yl)- phenylamino)- lH-benzoimidazol-5-yl ester 4-cyclopentylamino-benzεnesulfonic acid 2-(3-phenyl-propionylarnino)-lH- benzoimidazol-5-yl ester
4-cyclopentylamino-benzenesulfonic acid 2-[2-2-methoxy-ethoxy)-acetylamino]-lH- benzoimidazol-5-yl ester
4-fluoro-benzenesulfonic acid 2-(3(chloro-4-methoxy-benzylamino)-3H- benzoimidazol-5-yl ester
4-Fluoro-benzenesulfonic acid 2-[(3-phenyl-[l ,2,4]oxadiazol-5-ylmεthyl)-amino]- 3H-bεnzoimidazol-5-yl ester
4-Fluoro-benzεnεsulfonic acid 2-(3-chloro-bεnzylamino)-3H-benzoimidazol-5-yl ester 4-Fluoro-benzenεsulfonic acid 2-(3-methoxy-benzylamino)-3H-benzoimidazol-5-yl ester
4-Fluoro-benzenεsulfonic acid 2-benzylamino-3H-benzoimidazol-5-yl ester
4-cyclopentylamino-benzenesulfonic acid 2-benzylamino-3H-benzoimidazol-5-yl ester 4-Cyclopentylamino-benzenesulfonic acid 2-[(3-phenyl-[l,2,4]oxadiazol-5- ylmemyl)--ιmino]-3H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(3-methoxy-benzylamino)-3H- benzoimidazol-5-yl estεr
4-Cyclopεntylamino-bεnzenesulfonic acid 2-(3-chloro-4-methoxy-benzylamino)-3H- benzoimidazol-5-yl ester
4-(Cyclopropylmemyl-ammo)-bεnzεnesulfonic acid 2-[3-(2-moφholin-4-yl-ethyl)- ureido]-lH-benzoimidazol-5-yl estεr
4-(Cyclopropylmemyl-amino)-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)- ureido]-lH-benzoimidazol-5-yl estεr 4-(Cyclopropylmemyl-ammo)-benzenesulfonic acid 2-(3-pyτidin-2-3rlmethyl)- ureido]-lH-benzoimidazol-5-yl ester
4-(Cycloprop3λlmemyl-amino)-bεnzenεsulfonic acid 2-[3-(2-mεthoxy-ethyl)-urεido]- lH-bεnzoimidazol-5-yl ester 4-(Cyclopropylmethyl-amino)-benzenεsulfonic acid 2-[3-(2-ethyl)-ureido]-lH- benzoimidazol-5-yl ester
4-(2-Methoxy-ethylamino)-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)- ureido]-lH-benzoimidazol-5-yl ester
4-(2-Memoxy-emylam o)-benzenεsulfonic acid 2-(3-pyridin-2-ylmethyl)-ureido]- lH-benzoimidazol-5-yl ester
4-(2-Methoxy-ethylamino)-benzenesulfonic acid 2-[3-(2-methoxy-ethyl)-ureido]-lH- benzoimidazol-5-yl ester
4-(2-Methoxy-ethylamino)-benzenesulfonic acid 2-[3-(2-ethyl)-ureido]-lH- benzoimidazol-5-yl ester 4-(2-Hydroxy-l-methyl-ethylamino)-benzenesulfonic acid 2-[3-(2-morpholin-4-yl- ethyl)-ureido]-lH-benzoimidazol-5-yl ester
4-(2-Hydroxy- 1 -methyl-ethylamino)-benzenesulfonic acid 2-(3 -pyridin-2-ylmethyl)- ureido]-lH-benzoimidazol-5-yl ester
4-(2-Hydroxy- l-methyl-ethylamino)-benzεnesulfonic acid 2-[3-(2-methoxy-ethyl)- ureido]-lH-benzoimidazol-5-yl εster
4-(2-Hydroxy-l-methyl-ethylamino)-benzenesulfonic acid 2-[3-(2-ethyl)-ureido]-lH- bεnzoimidazol-5-yl εster
4-Benzyloxy-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)-ureido]-lH- benzoimidazol-5-yl ester 4-Benzyloxy-bεnzenesulfonic acid 2-(3-pyridin-2-ylmethyl)-ureido]-lH- bεnzoimidazol-5-yl εster
4-Benzyloxy-benzenεsulfonic acid 2-[3-(2-methoxy-ethyl)-ureido]-lH- bεnzoimidazol-5-yl εster
4-benzyloxy-benzenesulfonic acid 2-[3-(2-emyl)-ureido]-lH-benzoimidazol-5-yl εster 4-(2-Morpholm-4-yl-emylammo)-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl)- urεido]-lH-benzoimidazol-5-yl ester
4-(2-Morpholin-4-yl-ethylamino)-benzenesulfonic acid 2-[3-(2-methoxy-ethyl)- ureido]-lH-benzoimidazol-5-yl estεr 4-[(Piperidm-4-ylmemyl)-amino)-benzenesulfonic acid 2-[3-(2-morpholin-4-yl- εthyl)-urεido]-lH-benzoimidazol-5-yl ester
4-[(Piperidm-4-ylmethyl)-amino]-benzenεsulfonic acid 2-(3-pyridin-2-ylmethyl)- ureido]-lH-benzoimidazol-5-yl ester
4-[(Piperidm-4-ylmemyl)-amino]-benzenesulfonic acid 2-[3-(2-methoxy-ethyl)- ureido]-l H-benzoimidazol-5 -yl ester
4-Benzylamino-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)-ureido]- 1H- benzoimidazol-5-yl ester
4-Benzylamino-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl)-ureido]-lH- benzoimidazol-5-yl ester 4-Benzylamino-bεnzεnesulfonic acid 2-[3-(2-methoxy-ethyl)-ureido]- 1H- benzoimidazol-5-yl ester
4-Benzylammo-bεnzεnεsulfonic acid 2-[3-(2-emyl)-ureido]-lH-bεnzoimidazol-5-yl εster
4-[(l -emyl-pyrrolidin-2ylmethyl)-amino]-benzenesulfonic acid 2-(3-pyridin-2- ylmethyl)-ureido]-lH-bεnzoimidazol-5-yl ester
4-(4-hydroxy-piperidin-l-yI)-benzenesulfonic acid 2-[(4-hydroxy-piperidine-l- c-ιrbonyl)--mιino]-lH-benzoimidazol-5-yl ester
4-(4-Methyl-piperazin-l -yl)-benzenesulfonic acid 2-[(4-mεthyl-pipεrazin- 1 - carbonyl)-amino]-3H-benzoimidazol-5-yl ester 4-[(tetrahydro-pyran-4-ylmethyl)-amino]-benezεnesulfonic acid 2-[3-(tetrahydro- P3τan-4-ylmemyl)-ιιrεido]-3H-bεnzoimidazol-5-yl ester
4-(2-Fluoro-ethylamino)-benzenεsulfonic acid 2-[3-(2-fluoro-ethyl)-ureido]-3H- bεnzoimidazol-5-yl ester
4-(2-piperidin- 1 -yl-εthylamino)-benzenesulfonic acid 2-[3-(2-piperidin-l -yl-ethyl)- ureido]-3H-benzoimidazol-5-yl ester 4-phenethylammo-benzεnesulfonic acid 2-(3-phenemyl-ureido)-3H-benzoimidazol-5- yl estεr
4-[3-(2-oxo-pyrrolidin- 1 -yl)-propylamino]-benzenesulfonic acid 2- {3-[3-(2-oxo- pyrrolidin- 1 -yl)-propyl]-ureido } -3H-benzoimidazol-5-yl ester 4-(4-fluoro-benzylamino)-benzenesulfonic acid 2-[3-(4-fluoro-benzyl)-urεido]-3H- benzoimidazol-5-yl estεr
4-(2-hydroxy-2-mεthyl-propylamino)-benzenesulfonic acid 2-[3-(2-hydroxy-3- methyl-propyl)-urεido]-3H-benzoimidazol-5-yl ester
4-(3-hydroxy-propylamino)-benzεnesulfonic acid 2-[3-(3-hydroxy-propyl)-ureido]- 3H-bεnzoimidazol-5-yl ester
4-(2,2,6,6-tetram8thyl-pipεridin-4-ylamino)-bεnzεnεsulfonic acid 2-[3-(2,2,6,6- tεtramεtiιyl-piperidm-4-yl)-ureido]-3H-benzoimidazol-5-yl εstεr
4-(2-dimεmylamino-ethylamino)-benzεnεsulfonic acid 2-[3-(2-dimethylamino-ethyl)- urεido]-3H-bεnzoimidazol-5-yl εster 4-morpholin-4-yl-bεnzεnεsulfonic acid 2-[(morpholine-4-carbonyl)-amino]-3H- bεnzoimidazol-5-yl εster
4-(2-Hydroxy-3-methoxy-propylamino)-benzenesulfonic acid 2-[3-(2-hydroxy-3- methoxy-propyl)-ureido]-3H-benzoimidazol-5-yl εster
4-[(Pyridin-2-ylmethyl)-amino]-benzenesulfonic acid 2-(3-pyridin-2-yl- ethyl-ureido)-3H-benzoimidazol-5-yl ester
4-(2-hydroxy-propylamino)-benzεnesulfonic acid 2-[3-(2-hydroxy-proρyl)-ureido]- 3H-benzoimidazol-5-yl ester
4-(4-methoxy-benzylamino)-benzεnesulfonic acid 2-[3-(4-methoxy-benzyl)-urεido]- 3H-bεnzoimidazol-5-yl εster 4-(2-pyrroIidin-l-yl-εthylamino)-benzεnεsulfonic acid 2-[3-(2-pyrrolidin-l-yl-ethyl)- ureido]-3H-benzoimidazol-5-yl estεr
4-(l-phenyl-ethylamino)-bεnzεnεsulfonic acid 2-[3-(l-phenyl-ethyl)-ureido]-3H- benzoimidazol-5-yl ester
4-(2-diethylamino-εthylamino)-bεnz8nesulfonic acid 2-[3 -(2-diethylamino-ethyl)- ureido]-3H-benzoimidazol-5-yl ester 4-(l-hydroxymethyl-cyclopεntylamino)-b8nzenesulfonic acid 2-[3-(l-hydroxy- methyl-cyclopentyl)-urεido]-3H-benzoimidazol-5-yl ester
3-(4-{2-[3-(3-Methoxycarbonyl-eth3 )-ureido]-lH-benzoimidazol-5-yloxysulfonyl}- phenylamino)-propionic acid methyl ester 4-(4-Hydroxy-piperidin-l-yl)-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)- ureido]-lH-benzoimidazol-5-yl ester
4-(4-methyl-piperazin- 1 -yl)-benzenεsulfonic acid 2-[3-(2-moφholin-4-yl-ethyl)- ureido]-3H-benzimidazol-5-yl estεr
4-(4-methyl-piperazin- 1 -yl)-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl-urεido)- 3H-bεnzimidazol-5-yl ester
4-(4-methyl-pipεrazin-l-yl)-benzenesulfonic acid 2-[3-(2-methoxy-ethyl)-urεido]- 3H-benzimidazol-5-yl estεr
4-(4-hydroxy-piperidin- 1 -yl)-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)- ureido]-3H-benzimidazol-5-yl εster 4-(4-hydroxy-piperidin-l-yl)-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl-urεido)- 3H-benzimidazol-5-yl ester
4-(4-hydroxy-piperidin- 1 -yl)-benzenesulfonic acid 2-[3-(2-methoxy-ethyl)-ureido]- 3H-benzimidazol-5-yl ester
4-(4-hydroxy-piperidin- 1 -yl)-benzenesulfonic acid 2-(3-εthyl-ureido)-3H- benzimidazol-5-yl estεr
4-[(Pyridin-2-ylmethyl)-amino]-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)- ureido]-3H-benzimidazol-5-yl ester
4-[(Pyridin-2-ylmethyl)-amino]-benzenesulfonic acid 2-(3-pyridin-2-yhnethyl- ureido)-3H-benzimidazol-5-yl estεr 4-[(Pyridin-2-ylmemyl)-amino]-benzenesulfonic acid 2-[3-(2-methoxy-eth3rl)- urεido]-3H-bεnzimidazol-5-yl ester
4-[(Pyridm-2-ylmemyl)-ammo]-benzenesulfonic acid 2-[3-(2-methoxy-ethyl)- ureido]-3H-benzimidazol-5-yl ester
4-(3-Hydroxy-propylamino)-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)- urεido]-3H-benzimidazol-5-yl ester 4-(3-Hydroxy-propylamino)-benzenesulfonic acid 2-(3 -pyridin-2-ylmethyl-urεido)- 3H-bεnzimidazol-5-yl εstεr
4-(3-Hydrox3'-propylamino)-b8nzenesulfonic acid 2-[3-(2-mεthox3'-ethyl)-ureido]- 3H-benzimidazol-5-yl estεr 4-(3-Hydroxy-propylamino)-benzenesulfonic acid 2-(3-ethyl-urεido)-3H- bεnzimidazol-5-yl εster
4-(2,2,6,6-tεtramεthyl-piperidin-4-ylamino)-bεnzenesulfonic acid 2-[3-(2-moφholin- 4-yl-ethyl)-ureido]-3H-benzimidazol-5-yl εstεr
4-(2,2,6,6-tetramethyl-piperidin-4-ylamino)-bεnzεnεsulfonic acid 2-(3-pyridin-2- ylmethyl-ureido)-3H-bεnzimidazol-5-yl ester
4-(2-dimemylammo-ethylamino)-benzenesulfonic acid 2-[3-(2-moφholin-4-yl-εthyl)- ureido]-3H-benzimidazol-5-yl ester
4-(2-dimethylamino-ethylamino)-benzεnεsulfonic acid 2-(3-pyridin-2-ylmethyl- ureido)-3H-benzimidazol-5-yl ester 4-mθφholin-4-yl-benzεnεsulfonic acid 2-[3-(2-moφholin-4-yl-8thyl)-ureido]-3H- benzimidazol-5-yl estεr
4-mθφholin-4-yl-bεnzεnεsulfonic acid 2-(3-pyridin-2-ylm8thyl-urεido)-3H- bεnzimidazol-5-yl εstεr
4-[3-(2-oxo-pyrrolidm-l-yl)-propylamino]-benzenesulfonic acid 2-[3-(2-moφholin- 4-yl-ethyl)-ureido]-3H-benzimidazol-5-yl ester
4-[3-(2-oxo-pyrrolidin-l-yl)-propylamino]-benzenesulfonic acid 2-(3-pyridin-2- ylmethyl-ureido)-3H-benzimidazol-5-yl ester
4-(3-Hydroxy-propylamino)-benzenεsulfonic acid 2-(3-ethyl-urεido)-3H- benzimidazol-5-yl εster 4-(2-Hydroxy-2-methyl-propylamino)-benzεnesulfonic acid 2-[3-(2-moφholin-4-yl- eth)?l)-urεido]-3H-benzimidazol-5-yl ester
4-(2-Hydroxy-2-methyl-propylamino)-benzenεsulfonic acid 2-(3-pyridin-2-ylmethyl- ureido)-3H-benzimidazol-5-}rl ester
4-(2-Hydroxy-2-methyl-propylamino)-benzenesulfonic acid 2-[3-(2-methoxy-ethyl)- ureido]-3H-benzimidazol-5-yl εster 4-(2-Hydroxy-2-methyl-propylamino)-benzenεsulfonic acid-2-[3-(3-hydroxy-propyl)- ureido]-3H-benzimidazol-5-yl ester
4-[(Tetrahydro-p3τran-4-ylmethyl)-ammo]-benzenesulfonic acid 2-[3-(2-moφholin-4- yl-ethyl)-ureido]-3H-benzimidazol-5-yl ester 4-[(Tetrahydro-p3^an-4-ylmethyl)-amino]-benzenesulfonic acid 2-(3-pyridin-2- ylmethyl-ureido)-3H-benzimidazol-5-yl estεr
4-[(Tetrahydro-pyran-4-ylmεthyl)-amino]-benzenesulfonic acid 2-[3-(2-methoxy- εthyl)-urεido]-3H-bεnzimidazol-5-yl εstεr
4-[(Tetrahyo^o-pyran-4-ylm8myl)-amino]-bεnzenesulfonic acid 2-[3-(3-hydroxy- propyl)-urεido]-3H-benzimidazol-5-yl ester
4-(2-fluoro-emylammo)-berizenesulfonic acid 2-[3-(2-moφholin-4-yl-ethyl)-ureido]- 3H-benzimidazol-5-yl estεr
4-(2-fluoro-ethylamino)-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl-ureido)-3H- benzimidazol-5-yl ester 4-(2-Piperidin-l-yl-ethylamino)-benzenesulfonic acid 2-[3-(2-moφholin-4-yl-ethyl)- urεido]-3H-benzimidazol-5-yl εster
4-(2-Piρεridin- 1 -yl-εthylamino)-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl- ureido)-3H-bεnzimidazol-5-yl εster
4-phene ylammo-benzenesulfonic acid 2-[3-(2-moφholin-4-yl-ethyl)-ureido]-3H- benzimidazol-5-yl ester
4-phenethylamino-benzenesulfonic acid 2-[3-(2-methoxy-ethyl)-ureido]-3H- benzimidazol-5-yl estεr
4-phεnethylamino-benzenesulfonic acid 2-(3-ethyl-ureido)-3H-benzimidazol-5-yl ester 4-phenethylamino-benzεnesulfonic acid 2-[3-(3-hydroxy-propyl)-ureido]-3H- benzimidazol-5-yl estεr
4-(2-hydroxy-propylamino)-benzenesulfonic acid 2-[3-(2-moφholin-4-yl-ethyl)- urεido]-3H-bεnzimidazol-5-yl ester
4-(2-hydroxy-propylamino)-benzenesulfonic acid 2-(3-ethyl-urεido)-3H- benzimidazol-5-yl εstεr 4-(4-me oxy-benzylamino)-benzenesulfonic acid 2-[3-(2-moφholin-4-yl-ethyl)- ureido]-3H-benzimidazol-5-yl ester
4-(4-methoxy-benzylamino)-benzenesulfonic acid 2-(3-εthyl-ureido)-3H- benzimidazol-5-yl ester 4-(4-methoxy-benzylamino)-benzenesulfonic acid 2-(3-pyridin-2-ylm8thyl-ureido)- 3H-benzimidazol-5-yl ester
4-(4-methoxy-benzylamino)-benzenesulfonic acid 2-[3-(3-hydroxy-propyl)-ureido]- 3H-benzimidazol-5-yl εstεr
4-(4-methoxy-benzylamino)-benzenesulfonic acid 2-[3-(2-methoxy-ethyl)-ureido]- 3H-benzimidazol-5-yl ester
4-(2-pyrrolidin- 1 -yl-ethy lamino)-benzenesulfonic acid 2-(3 -ethy l-ureido)-3H- bεnzimidazol-5-yl εstεr
4-(2-pyrrolidin- 1 -yl-ethylamino)-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl- ureido)-3H-benzimidazol-5-yl ester 4-(2-pyrrolidin-l-yl-ethylamino)-bεnzenesulfonic acid 2-[3-(2-methoxy-ethyl)- ureido]-3H-benzimidazol-5-yl εster
4-( 1 -phenyl-ethylamino)-benzenesulfonic acid 2-(3-ethyl-ureido)-3H-benzimidazol- 5-yl ester
4-(2-diemylam o-emylammo)-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl- ureido)-3H-benzimidazol-5-yl ester
Thiophene-2-sulfonic acid 2-[3-(2-ethyl)-ureido]-lH-benzoimidazol-5-yl ester
Thiophene-2-sulfonic acid 2-[3-(2-methoxy-ethyl)-ureido]- lH-benzoimidazol-5-yI ester
Thiophene-2-sulfonic acid 2-[3-(2-moφholin-4-yl-ethyl)-ureido]-lH-benzoimidazol- 5-yl ester
Thiophene-2-sulfonic acid 2-(3-pyridin-2-ylmethyl)-ureido]- lH-benzoimidazol-5-yl ester
4-{2-[3-(2-methoxy-ethyl)-ureido]-lH-benzoimidazol-5-yloxysulfonyl}-phenyl ester
Benzoic acid 4- {2-[3-(2-moφholin-4-yl-ethyl)-ureido}-lH-benzoimidazol-5-3^1oxy- sulfonyl} -phenyl estεr Benzoic acid 4-[2-([3-pyridin-2-ylmethyl)-ureido)- lH-bεnzoimidazol-5-yloxy- sulfonyl] -phenyl ester
2,6-difluoro-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl-ureido)-3H- benzoimidazol-5-yl ester 2,6-difluoro-benzenεsulfonic acid 3-(2-mεthoxy-εthyl)-3H-benzoimidazol-5-yl ester
In still yet another embodimεnt is disclosed use of compounds of formula (I) for treating cancer diseases.
In still yet another embodiment is disclosed a mεthod of inhibiting CDK4 εnzymes in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically effective amount of compounds of formula (I).
In still yet another embodiment is disclosed a pharmaceutical composition which comprises a therapeutically effective amount of a compound of formula (I) in combination with a pharmaceutically acceptable carrier.
The term "pharmaceutically acceptablε salt", as usεd hεrein, rεfers to salts, which are suitable for use in contact with thε tissues of humans and lower animals. Pharmaceutically acceptable salts are dεscribεd in detail in J. Pharmaceutical Sciences, 1977, 66:1 et seq. hereby incoφorated by reference. Reprεsεntative acid addition salts includε acetate, citrate, aspartatε, benzenesulfonate, hydrochloride, lactate, maleate, methanesulfonate, oxalatε, and phosphatε.
Mεthods of Synthesis
Compounds of the presεnt invention can be εasily prepared starting from 2-amino-5-(-4-fluorophenylsulfon3rloxy)nitrobenzene the process of preparation of which is describεd in US 3,996,368.
In a first stεp this starting matεrial is rεacted with the amine bearing the RI radical in a suitable solvent for carrying out the reaction. Among the list of solvents suitable for dissolving 2-amino-5-(-4-fluorophenylsulfonyloxy)nitrobenzen8 and thε aminε can be cited the glycols such as ethylglycol, thε aprotic solvents such as dioxane, dimεthylformamide, N-methylpyrrolidone. The preferred temperature for this reaction is comprised betweεn room tεmperaturε and thε rεflux temperature. To recover the intermediatε product it is preferrεd to prεcipitate the intermεdiatε with chlorhydric acid. In a sεcond step the compound of step 1 is hydrogenatεd with hydrogεn prefεrably in prεsence of Raney nickel (nitro group reduction method A) or palladium on carbon (nitro group reduction method B) in a suitable solvent choosen among the same list as for step 1 in mixture with an alcohol such as methanol. After reaction the catalyst is taken off by filtration.
In a third step the bεnzimidazole ring is closed by action of l,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourεa on the intermediatε obtainεd in step 2 without intermediate separation. The reaction mixture is heatεd to rεflux with stirring. Thε final product (memyl-bεnzimidazole-2-carbamatε) is isolatεd aftεr εvaporation of the solvent under reduced pressure and solubilization in ethylacetate then crystallisation. A final purification is carried out in mεthanol with a crystallisation in the same solvent.
Methyl-bεnzimidazole-2-carbamate can be converted to bεnzimidazole-2- urεas by treatment with an aminε in a suitable solvent such as dimethylformamide, tεtrahydrofuran or N-methylpyrrolidonε in thε prεsence of a base such as l,8-Diazabicyclo[5.4.0]undec-7-ene in a pressure vessel. The preferred temperature for this reaction is comprised between room tempεraturε and 120 °C. tg7-t-butyl-bεnzimidazolε-2-carbamatε can be prepared by performing the third step described above using l,3-bis(tert-butoxycarbonyl)-2-methyl-2- thiopsεudourea instead of l,3-bis(memoxycarbonyl)-2-memyl-2-thiopseudourea. Thεse derivatives can be converted to the corresponding 2-aminobenzimidazole derivative using tert-butylcarbamate deprotεction methods known by the persons skilled in the art. The 2-aminobenzimidazolεs can bε converted to the corresponding amidεs by rεaction with carboxylic acid derivatives using known by the persons skilled in the art.
Methods of Treatment
The present invention also provides pharmaceutical compositions, which comprise compounds of the presεnt invention formulated togethεr with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form or for parenteral injection.
The term "parentεral", as usεd hεrεin, rεfεrs to modεs of administration, which include intravenous, intramuscular, intraperitoneal, subcutaneous and infusion. Solid dosagε forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules.
The compounds of the present invention may bε administεred alonε or mixεd with other anticancer agents. Among the possible combinations, there may be mentionεd
• alkylating agεnts and in particular cyclophosphamidε, melphalan, ifosfamide, chlorambucil, busulfan, thiotepa, prednimustinε, carmustinε, lomustinε, sεmustinε, strεptozotocin, decarb azine, temozolomide, procarbazine and hexamεthylmεlaminε
• platinum dεrivatives such as in particular cisplatin, carboplatin or oxaliplatin, • antibiotic agents such as in particular bleomycin, mitomycin, dactinomycin,
• antimicrotubule agεnts such as in particular vinblastinε, vincristine, vindesine, vinorelbine, taxoids (paclitaxel and docetaxel),
• anthracyclines such as in particular doxorubicin, daunorubicin, idarubicin, epirubicin, mitoxantrone, losoxantrone,
• group I and II topoisomεrasεs such as etoposide, teniposidε, amsacrinε, irinotecan, topotecan and tomudex,
• fluoropyrimidines such as 5-fluorouracil, UFT, floxuridine,
• cytidine analoguεs such as 5-azacytidinε, cytarabinε, gemcitabine, 6-mercaptomurine, 6-thioguaninε,
• adεnosinε analoguεs such as pentostatin, cytarabine or fiudarabinε phosphate,
• methotrexate and folinic acid,
• various enzymes and compounds such as L-asparaginasε, hydroxyurea, trans-retinoic acid, suramine, dexrazoxane, amifostine, herceptin as well as oestrogenic and androgεnic hormones.
It is also possible to combine a radiation treatmεnt with thε compounds of the present invention. This treatmεnt may be administered simultaneously, separatεly or sequentially. The treatmεnt will bε adaptεd to the patient to be treatεd by the practitioner.
The invention will bε more fully described by the following examplεs, which must not be considered as a limitation of the invention.
Method for analytical determination
Liquid chromatography coupled to Mass spεctrometry (LC/MS) analysis
LC/MS analyses were conducted on a Micromass instrument model LCT linked to an HP 1100 model instrument. Compound abundance were detεcted using an HP G1315A (model) photodiode array detεctor in thε 200-600 nm wavεlεngth range and a Sedex 65 (model) εvaporativε light scattering detector. Mass spectra were acquired in the 160 to 2000 amu range. Data werε analysεd using thε Micromass MassLynx software. Separation werε carried out on a Hypersil Highpurity C18, 5 μm particle size column (50 x 4.6 mm) eluted by a linεar gradiεnt of 10 to 90 % acetonitrile containing 0.05 % (v/v) trifluoroacetic acid (TFA) in water containing 0.05 % (v/v) TFA in 6.50 min at a flow rate of 1 ml/min.
Method for Purification
LC/MS triggered purification
Compounds were purified by LC/MS using a Waters FractionLynx system composed of a Waters model 600 gradient pump, a Waters model 515 rεgεnεration pump, a Waters Reagεnt Managεr make-up pump, a Waters model 2700 sample manager autoinjector, two Rheodyne model LabPro switches, a Waters model 996 photodiode array detεctor, a Waters model ZMD mass spectrometer and a Gilson model 204 fraction collector. The Waters FractionLynx software controlled the instrument. Separation werε conducted alternatively on two Waters Symmetry columns (Cι8, 5 μM, 19 x 50 mm, catalogue number 186000210), onε column was under regenεration by a 95/5 (v/v) watεr/acεtonitrile mixture containing 0.07 % TFA (v/v) while the other one is sεparating. Columns were eluted by a linear gradient of acetonitrilε containing 0.07 % (v/v) TFA in water containing 0.07 % (v/v) TFA, from 5 to 95 % (v/v) in 8 min and 2 min at 95 % acetonitrilε containing 0.07 % (v/v) TFA, at a flow rate of 10 ml/min. At the output of the separating column the flow was split to thε 1/1000 ratio using a LC Packing AccuRatε splitter; 1/1000 of the flow was mixed with methanol (0.5 ml/min. flow rate) and sent to the detεctors, this flow was split again % of the flow was sent to the photodiode array detector and lA to the mass spectrometer; the rest of the output of the column (999/1000) was sent to the fraction collector were flow was directed normally to waste unless expεctεd mass signal was detected by the FractionLynx software. The FractionLynx software was supplied with molecular formulas of expected compounds and triggered the collection of compounds when mass signal corresponding to [M+H]÷ and [M+Na]+ are detected. In certain cases (depending on analytical LC/MS result, when [M+2H]÷÷ was detected as an intensε ion) the FractionLynx software was additionally supplied with calculated half molecular weight (MW/2), in these conditions collection was also triggered when mass signal corrεsponding to [M+2H]÷+ and [M+Na- H]"^1" are detected. Compounds were collected in tarred glass tubes. After collection, solvent was evaporated in a Jouan model RC 10.10 centrifuge evaporator or a Genevac model HT8 centrifuge evaporator and the amount of compound was detεrmined by weighing of the tubεs aftεr solvεnt evaporation.
Method of prepartion of compounds of the invεntion
2-amino-5-(4-fluorophenylsulfonyloxy)nitrobεnzεne (melting point 161 °C), the starting material, can be prepared according to U.S. patent N° 3,996,368.
Example 1 : Preparation of Methyl-5-(4-[2-hydroxyethyl]aminophenylsulfonyloxy) benzimidazole-2-carbamatε
step 1 : 15.6 g of 2-amino-5-(4-fluorophεnylsulfonyloxy)nitrobεnzene were combined with 25 ml ethanolaminε in 100 ml ethylglycol in a round bottom flask. The reaction mixture was heated to reflux for 90 min and then cooled on ice. Reaction mixture was then diluted with 250 ml of 2N aqueous HCl, the compound precipitated and was filtered off with suction. The preciptatε was the washed with water and dried, yielding 15.5 g of 2-amino-5-(4-[2-hydroxyethyl] aminophenylsulfonyloxy)nitro benzene (melting point 180°C). step 2 : 15.5 g of 2-amino-5-(4-[2-hydroxyethyl] aminophenylsulfonyloxy)nitro- benzene in 75 ml of methanol and 75 ml of dimethylformamide are hydrogenated under atmospheric pressure with a catalytic amount of Raney Nickel (method A). After hydrogen uptakε is complεtε, the catalyst was filtered off with suction, washed with methanol and the filtrate is concentred under reduced pressure step 3 : concentrated filtrate of step 2 was takεn up in 150 ml mεthanol and 30 ml of glacial acεtic acid, 10.3 g of l,3-bis(memoxycarbonyl)-2-mεmyl-2-thiopseudourea was added and reaction mixture was heated to reflux with stirring for 3 hours. Solvents were then evaporated under reduced pressurε, concentrate was then dissolved in hot ethylacetate, crystallized by cooling and washed with ethylacetate. Compound was then solubilized in 250 ml refluxing mεthanol, crystallizεd by cooling and washed with methanol and dried yielding 7.4 g of thε titlε compound. (Melting point 170°C, LC/MS analysis: retεntion timε = 2.8 min., mass spεctrum: 407.24, [M+H]+)
Example 2 : Preparation of Methyl-5-(4-[4-hydroxbutyl]aminophenylsulfonyloxy) benzimidazolε-2-carbamate
step 1 : 19.7 g of 2-amino-5-(4-fluorophεnylsulfonyloxy)nitrobenzεne were combined with 20 g butanolamine in 200 ml N-methylpyrrolidinonε in a round bottom flask. Thε reaction mixture was heated to reflux for 120 min and then solvent was evaporatεd under reduced pressure. Concentratε was then solubilized with ethylacεtatε and εxtractεd with 2N aqueous HCl and water and then dried over sodium sulfate and dried under reduced pressurε. The concentrate was recrystallizεd in isopropanol, filtεrεd undεr suction, washed with isopropanol and dried, yielding 13.1 g of 2-amino-5-(4-[4-hydroxbuyl] aminophenylsulfonyloxy) nitrobenzεnε (mεlting point 105°C). step 2 : 13.1 g of 2-amino-5-(4-[4-hydroxbutyl] aminophenylsulfonyloxy)nitro- benzene in 75 ml of methanol and 75 ml of dimethylformamide are hydrogenated under atmosphεric pressure with a catalytic amount of Raney Nickel (Method A). After hydrogen uptake is complete, the catalyst was filtered off with suction, washed with methanol and thε filtrate is concentred under reduced pressure. step 3 : concentrated filtrate of step 2 was taken up in 100 ml mεthanol and 20 ml of glacial acetic acid, 8.2 g of l,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea was added and reaction mixture was heated to rεflux with stirring for 3 hours. Solvεnts were then εvaporated undεr rεducεd pressure, concentrate washed with 2N aquεous ammonia, water and dried. Concentrate was then dissolved in hot ethylacetate, crystallized by cooling and washed with ethylacεtatε. Compound was then solubilized in rεfluxing mεthanol, crystallized by cooling and washed with methanol and dried yielding 6.3 g of thε titlε compound. (Melting point 180°C, LC/MS analysis: retεntion time = 2.9 min., mass spectrum: 435.29, [M÷H]+)
Example 3 : Preparation of Methyl-5-(4-[2-methoxyethyl]aminophenylsulfonyloxy) benzimidazole-2-carbamate
step 1 : 15.6 g of 2-amino-5-(4-fluoroph8nylsulfonyloxy)nitrobenzene were combined with 35 ml methoxyethylamine in 100ml dioxane in a round bottom flask. The reaction mixture was hεated to reflux for 8 hours and then cooled to 40°C and extracted two times with 250 ml water. Concentrate was solubilized with ethylacetatε and extracted with 2N aqueous HCl and water, thε organic phase was then dried under reduced pressure, yielding 19.2 g of 2-amino-5-(4-[2-methoxyethyl] aminophenylsulfonyloxy)nitrobenzene (melting point 105°C). step 2 : \ .2 g of 2-amino-5-(4-[2-methoxyethyl] aminophεnylsulfonyloxy)nitro- benzεne in 75 ml of mεthanol and 75 ml of dimethylformamide are hydrogenated under atmospheric pressure with a catalytic amount of Raney Nickel (Method A). After hydrogen uptake is complete, the catalyst was filtered off with suction, washed with methanol and the filtrate is concentred under reduced pressure. step 3 : concentrated filtrate of step 2 was taken up in 150 ml methanol and 25 ml of glacial acεtic acid, 12.3 g of l,3-bis(mεthoxycarbonyl)-2-methyl-2-thiopseudourea was added and reaction mixturε was hεatεd to rεflux with stirring for 3 hours. Solvεnts wεre then evaporated under reduced pressure, and concentratε was crystallized with methanol saturated with ammonia, washed with water, methanol and dried, yielding 12 g of the title compound. (Melting point 155°C, LC/MS analysis: retention time = 3.1 min., mass spectrum: 421.25, [M+Hf). Example 4 : Preparation of Methyl-5-(4-[l-imidazol3rl]-phenylsulfonylox\r) benzimidazole-2 -carbamate
step 1 : 15.6 g of 2-amino-5-(4-were combined with 20.7 g imidazole in 100 ml dimethylformamide in a round bottom flask. The reaction mixture was heated to reflux for 3 hours and then coolεd to room temperature. Reaction mixture was then precipitated by addition of water filtεrεd and precipitate was washed with water and dried. Residue was resolubilized in hot methylglycol, crystallized by cooling and the crystals were washed with methanol and dried, yielding 10.4 g of 2-amino-5-(4-[l- imidazolyl]-phenylsulfonyloxy)nitro-benzene (melting point 209°C). step 2 : 10.4 g of 2-amino-5-(4-[l-imidazolyl]-phenylsulfonyloxy)nitrobεnzene in 75 ml of methanol and 75 ml of dimethylformamidε are hydrogenated under atmospheric pressure with a catalytic amount of Ranεy Nickel. After hydrogen uptake is complete, the catalyst was filtered off with suction, washed with methanol and the filtrate is concentred under reduced pressurε ( Method A).
Alternativεly 5 g of 2-ammo-5-(4-[l-imidazolyl]-phεnylsulfonyloxy)nitrob8nzene in 475 ml of mεthanol and 25 ml of dimethylformamide are hydrogenatεd under 5 bars pressure with 10 % (w/w) of palladium on carbon at 30°C during 6 hours (Method B) yielding 4.18 g (91 %) of expected product. step 3: concentratεd filtratε of stεp 2 was takεn up in 150 ml mεthanol and 25 ml of glacial acεtic acid, 10.3 g of l,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourεa was added and reaction mixture was heatεd to reflux with stirring for 3 hours. After cooling to room temperature reaction mixture was precipitatεd by addition of ethylacetate, filtered by suction and washed by ethylacetate. Filtrate was then resolubilized with 50 ml dimethylformamide and 250 ml of methanol was added. Mixture crystallised upon cooling and crystals were washed with methanol and dried under reduced pressure, yielding 9,4 g of the title compound. (Melting point 258°C, LC/MS analysis: retention time = 2.5 min., mass spectrum: 414.23, [M+H]+; 382.19 fragmentation of carbamate: loss of methanol, NMR, JR). Example 5 : Preparation of Memyl-5-(4-[2-p3τidylmethyl]aminophenylsulfonyloxy) benzimidazole-2 -carbamate
In a similar manner to examples 1 to 4, title compound was obtained by reacting 2-ammomethylpyridine with 2-amino-5-(4-fluorophenylsulfonyloxy)nitrobenzene at step 1 of the procedure describεd abovε and using nitro group reduction method A. (LC/MS analysis: retention time = 2.6 min., mass spectrum : 454.28, [M+H]+ ; 907.53, [2M+H]+ ; 422.24, fragmentation of carbamate : loss of methanol).
Example 6 : Preparation of Methyl-5-(4-ethylaminophεnylsulfonyloxy) benzimidazole-2-carbamate
In a similar manner to examplεs 1 to 4, title compound was obtained by reacting ethylamine with 2-amino-5-(4-fluorophenylsulfonyloxy)nitrobεnzene at step 1 of the procedure described above and using nitro group reduction method A. (LC/MS analysis: retention time = 3.2 min., mass spectrum: 390.98, [M+H]4").
Example 7 : Preparation of Methyl-5-(4-[N-Glycinyl]-phenylsulfonyloxy) benzimidazole-2-carbamatε
In a similar manner to examples 1 to 4, title compound was obtained by reacting glycine with 2-amino-5-(4-fluorophenylsulfonyloxy)nitrobenzene at step 1 of the procedure describεd above and using nitro group reduction method A. (LC/MS analysis: retention time = 2.8 min., mass spectrum: 421.21, [M+H]+). Example 8 : Preparation of Methyl-5-(4-[l-methyl,2-hydroxyethyl] aminophenylsulfonyloxy) benzimidazole-2-carbamatε
In a similar manner to examples 1 to 4, title compound was obtained by reacting 2-aminopropanol with 2-amino-5-(4-fluorophenylsulfonyloxy)nitrobεnzεnε at stεp 1 of the procedure described above and using nitro group reduction method A. (LC/MS analysis: retεntion time = 2.9 min., mass spectrum: 421.27, [M+H]+).
Example 9 : Preparation of Methyl-5-(4-[2-methyl,2-hydroxyethyl] aminophenylsulfonyloxy) benzimidazole-2-carbamatε
In a similar manner to examples 1 to 4, title compound was obtained by reacting 1 -methyl, 2-aminoethanol with 2-amino-5-(4-fluorophenylsulfonyloxy)nitrobεnzεnε at stεp 1 of the procedure described above and using nitro group reduction method A. (LC/MS analysis: retention time = 2.9 min., mass spectrum : 421.27, [M+H]÷).
Example 10 : Preparation of Mεthyl-5-(4-isopropylaminophenylsulfonyloxy) benzimidazole-2-carbamate
In a similar manner to examples 1 to 4, title compound was obtained by reacting isopropylamine with 2-amino-5-(4-fluorophεnylsulfonyloxy)nitrobenzenε at stεp 1 of thε procedure described above and using nitro group reduction method A. (LC/MS analysis: retεntion time = 3.4 min., mass spectrum: 405.27, [M+Hf ).
Example 11 : Preparation of Methyl-5-(4-[l -ethyl, 2-hydroxyethyl]aminophεnyl sulfonyloxy) benzimidazolε-2-carbamate
In a similar manner to examplεs 1 to 4, titlε compound was obtained by reacting 2-aminobutanol with 2-ammo-5-(4-fluorophenylsulfonyloxy)nitrobenzεne at step 1 of the procedure describεd abovε and using nitro group reduction method A. (LC/MS analysis: retεntion time = 3.0 min., mass spectrum: 435.30, [M+H]+).
Example 12 : Preparation of Methyl-5-(4-butylaminophenylsulfonyloxy) benzimidazole-2 -carbamate
In a similar manner to εxamplεs 1 to 4, title compound was obtained by reacting butylamine with 2-amino-5-(4-fluorophenylsulfonyloxy)nitrobenzene at step 1 of the procedure described above and using nitro group reduction method A. (LC/MS analysis: retεntion timε = 3.6 min., mass spectrum: 419.25, [M+H]+).
Example 13 : Preparation of Mεthyl-5-(4-[3-mεthoxypropyl]aminophεnyl- sulfonyloxy) bεnzimidazolε-2-carbamatε
In a similar mannεr to εxamplεs 1 to 4, titlε compound was obtained by reacting 3-mεmoxypropanolaminε with 2-amino-5-(4-fluorophenylsulfonyloxy)nitrobenzene at step 1 of the procedure described above and using nitro group reduction method A. (LC/MS analysis: retention time = 3.2 min., mass spectrum: 435.27, [M+H]+).
Example 14 : Preparation of Methyl-5-(4-methylaminophenylsulfonyloxy) bεnzimidazolε-2-carbamate
In a similar mannεr to examples 1 to 4, title compound was obtained by reacting methylarninε with 2-amino-5-(4-fiuorophεnylsulfon3doxy)nitrobenzenε at step 1 of the procedure described above and using nitro group reduction method A. (LC/MS analysis: retention time = 3.0 min., mass spectrum: 377.22, [M÷H]").
Example 15 : Preparation of Methyl-5-(4-[2-sulfonylethyl] aminophenylsulfonyloxy) bεnzimidazole-2-carbamate
In a similar mannεr to examples 1 to 4, title compound was obtained by reacting 2-aminoethanesulfonic acid with 2-ammo-5-(4-fluorophεnylsulfonyloxy)nitrobεnzene at step 1 of the procedure described above and using nitro group reduction method A. (LC/MS analysis: retεntion time = 2.6 min., mass spectrum: 471.19, [M÷Hf ; 941.41, [2M+H]+).
Example 16 : Preparation of Methyl-5-(4-aminophεnylsulfonyloxy) bεnzimidazolε- 2-carbamatε
In a similar manner to examples 1 to 4, title compound was obtained by reacting ammonia with 2-amino-5-(4-fluorophenylsulfonyloxy)nitrob8nzene at step 1 of the procedure described above and using nitro group reduction method A. (LC/MS analysis: retention time = 2.9 min., mass spectrum: 363.19, [M÷H]T).
Example 17 : Preparation of Methyl-5-(4-[2-diεthylaminoethyl] aminophenylsulfonyloxy) benzimidazole-2 -carbamate
In a similar manner to examplεs 1 to 4, title compound was obtained by reacting
2-diethylaminoethylamine with 2-amino-5-(4-fluorophεnylsulfonyloxy)nitrobenzene at stεp 1 of thε procedure describεd abovε and using nitro group reduction method A. (LC/MS analysis: retention time = 2.6 min., mass spectrum: 462.34, [M- H]-; 923.65, [2M+H]"1"; 430.30, fragmentation of carbamatε: loss of methanol).
Example 18 : Preparation of Memyl-5-(4-[l-te1ramyc ofurylm8thyl] aminophenylsulfonyloxy) benzimidazolε-2-carbamatε
In a similar manner to examplεs 1 to 4, title compound was obtained by reacting tetrahydromrfurylaminε with 2-amino-5-(4-fluorophεnylsulfonyloxy)nitrobenzen8 at stεp 1 of thε procedure described above and using nitro group reduction method A. (LC/MS analysis: retention time = 3.2 min., mass spectrum: 447.24, [M+H]+).
Example 19 : Preparation of Methyl-5-(4-cyclopεntylaminophenylsulfonyloxy) benzimidazolε-2-carbamatε
In a similar mannεr to εxamples 1 to 4, title compound was obtained by reacting cyclopentylamine with 2-amino-5-(4-fluorophenylsulfonyloxy)nitrobenzene at step 1 of the procedure describεd above and using nitro group reduction method A. (LC/MS analysis: retention time = 3.6 min., mass spectrum: 431.29, [M+H]+).
Example 20 : Preparation of Mεthyl-5-(4-[2-phεnylεthyl] aminophenylsulfonyloxy) benzimidazole-2-carbamate
In a similar manner to examplεs 1 to 4, titlε compound was obtained by reacting phenethylamine with 2-amino-5-(4-fluorophεnylsulfonyloxy)nitrobenzεne at step 1 of the procedure describεd abovε and using nitro group reduction method A. (LC/MS analysis: retεntion timε = 3.6 min., mass spεctrum: 467.26, [M÷H]+). Examplε 21 : Preparation of N-5-(4-[l-imidazolyl]-phenylsulfonyloxy)-lH- benzimidazole-2-yl : an intermediate for amide product synthesis
For step 1 and 2, intermediate of title compound is obtained in similar manner to step 1 end 2 of example 4. step 3 : 8 g of step 2 compound were taken up in 128 ml methanol and 21.6 ml acetic acid in a 250 ml round bottom flask. Mixture was heatεd to reflux and 9.13 g of l,3-bis(tert-butoxycarbonyl)-2-methyl-2-thioρseudourεa was added. Reaction mixture was heated to reflux- with stirring for 4 hours. Solid was obtained by cooling to 0°C for one hour and washed with ethyl acetate, triturated and dried on a glass frit yielding 7.55 g compound. step 4 : Compound of step 3 was takεn up in 80 ml dichloromethane and 40 ml trifluoroacetic acid. Reaction mixturε was stirring for 4 hours at room tεmperature. Solvents were evaporated under reduced pressurε. Concentrated filtrate was taken in 75 ml water. 50 ml of sodium carbonate aqueous solution (10 % w/w). Precipitate obtainεd was washεd with dichloromεthane and dried on a glass frit yielding 5.3 g title compound.
Example 22 : Preparation of N-5-(4-cyelopεntylamώophεnylsulfon3'loxy)-lH- benzimidazole-2-yl : an intermediate for amide product synthesis
For step 1 and 2, intermediate of title compound is obtained in similar manner to step 1 end 2 of example 19.
For step 3 and 4, title compound is obtained in similar manner to example 21.
Example 23 : Preparation of N-[5-(4-Imidazol-l-yl-benzenesulfonyloxy)-lH- benzoimidazol-2-yI]-succinamic acid methyl ester step 1 : 8.9 mg of succinamic acid mεthylεstεr, 25 mg of 2-(lH-Benzotriazolε-l-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) and 12 μl diisopropylethylamine were taken up in 0.4 ml dimethylformamide. Reaction mixture was stirred at room temperature for one hour and N-5-(4-[l-imidazolyl]-phenylsulfon3 oxy)-lH- bεnzimidazolε-2-yl was added in 0.2 ml dimethylformamide. Reaction mixture was then stirred at room temperature for 24 hours. Solvent was evaporated in a Jouan model RC 10.10 centrifuge evaporator and title compound was solubilised in 0.5 ml dimethylsulfoxide for LCMS trigged purification yielding 3.9 mg of N-[5-(4-[l- imidazolyl]-phenylsulfonyloxy)-lH-bεnzimidazolε-2-34]-succinamic-acid- methylester. (LC/MS analysis: retention time = 2.70 min., mass spectrum: 470.34, [M+H ).
Example 24 : Preparation of 4-Cyclopentylamino-benzεnεsulfonic acid 2-(2-tεrt- butoxycarbonylammo-acetylamino)- lH-benzoimidazol-5-yl ester
step 1 : 11.3 mg of N-(tert-butoxycarbonyl)glycine, 25 mg HBTU and 12 μl diisopropylethylamine were taken up in 0.4 ml dimethylformamidε. Reaction mixture was stirred at room temperature for one hour and N-5-(4- cyclopentylaminophenylsulfonyloxy)-lH-benzimidazole-2-yl was addεd in 0.2 ml dimεthylformamide. Reaction mixture was then stirred at room temperature for 24 hours. Solvent was evaporatεd in a Jouan modεl RC 10.10 cεntrifugε εvaporator and title compound was solubilised in 0.5 ml dimethylsulfoxide for LCMS trigged purification yielding 2.4 mg of N-[5-(4-cyclopentylaminophenylsulfonyloxy)-lH- benzimidazole-2-yl]-tert-butoxycarbonylglycineamid. (LC/MS analysis: retention time = 3.87 min., mass spectrum: 530.38, [M+H]+).
Examplε 25 : Preparation of N-[5-(4-Cyclopεntylamino-benzenesulfonyloxy)-lH- benzoimidazol-2-yl]-succinamic acid methyl ester In a similar mannεr to εxamplε 24, titlε compound was obtainεd by rεacting succinamic acid methyl ester with N-5-(4-cyclopentylaminophenylsulfonyloxy)-lH- benzimidazole-2-yl. (LC/MS analysis: retention timε = 3.72 min., mass spectrum:
Example 26 : Preparation of 4-[5-(4-Cyclopentylamino-bεnzenesulfonyloxy)-lH- benzoimidazol-2-yicarbamoyl]-butyric acid methyl estεr
In a similar manner to examplε 24, titlε compound was obtainεd by rεacting butyric acid mεthylεstεr with N-5-(4-cyclopentylaminophεnylsulfonyloxy)-lH- bεnzimidazolε-2-yl. (LC/MS analysis: retεntion timε = 3.75 min., mass spεctrum: 501.36, [M+Hf).
Examplε 27 : Preparation of 4-Cyclopentylamino-benzenesulfonic acid 2- (cyclopropanecarbonyl-amino)- lH-benzoimidazol-5-yl εstεr
In a similar mannεr to example 24, title compound was obtained by reacting cyclopropane carboxylic acid with N-5-(4-cyclopentylaminophεnylsulfonyloxy)-lH- benzimidazole-2-yl. (LC/MS analysis: retention time = 3.76 min., mass spectrum: Example 28 : Preparation of 4-Cyclopεntylamino-bεnzεnεsulfonic acid 2-(2- methoxy-acεtylamino)- 1 H-bεnzoimidazol-5-yl ester
In a similar mannεr to example 24, title compound was obtained by reacting methoxyaceticacid with N-5-(4-cyclopentylaminophenylsulfonyloxy)- 1H- benzimidazole-2-yl. (LC/MS analysis: retεntion timε = 3.66 min., mass spεctrum: 445.34, [M+Hf).
Example 29 : Preparation of 4-Cyclopentylamino-benzenesulfonic acid 2-(2- dimethylamino-acεtylamino)-lH-benzoimidazol-5-yl ester
In a similar manner to εxamplε 24, title compound was obtained by reacting N,N- dimethylglycine with N-5-(4-cyclopentylaminophenylsulfonyloxy)-lH- benzimidazole-2-yl. (LC/MS analysis: retεntion time = 3.36 min., mass spectrum:
Example 30 : N-[5-(4-[imidazolyl]-phenylsulfonyloxy)-lH-bεnzimidazolε-2-yl]- mεthylurεa
lO mg of Mεmyl-5-(4-[imidazolyl]-phεnylsulfoxy)bεnzimidazole-2-carbamate (example 4) were combined with 50 μl mεthylamine (2,0 M in tεtrahydrofuran) and 5 μl l,8-Diazabicyclo[5.4.0]undεc-7-ene in 2 ml N-mεthylpyrrolidonε/ tetrahydrofuran (1/1). In a 24 well inox plate for high pressure reaction. The reaction mixture was put under a 10 Bars argon pressure and then hεated to 80°C for 4 hours, and then cooled at room temperature. Compounds werε put in an assay tube and tetrahydrofuran was evaporated under reduce pressure and compound in N-methylpyrrolidonε wεrε directly purified by preparative LCMS in conditions described above. Aftεr purification, solution was dry-concentrated in a JOUAN RC1010 evaporator. (LC/MS analysis: retention time = 2.23 min., mass spεctrum: 413.23, [M+Hf).
Examplε 31 : N-[5-(4-cyclopεntylaminophεnylsulfonyloxy)-lH-benzimidazole-2- ylj-mεthylurεa
In a similar manner to example 30, title compound was obtained by reacting Methyl- 5-(4-cyclopentylaminophenylsulfonyloxy)bεnzimidazole-2 -carbamate (example 19) with methylaminε (2,0 M in tεtrahydrofuran). (LC/MS analysis: retention time = 3.30 min., mass spectrum: 430.27, [M+Hf).
Example 32 : N-[5-(4-cyclopentylaminophenylsulfonyloxy)-lH-benzimidazole-2- yl]-dimethylurea
Titlε compound was obtained by reacting 10 mg of Methyl-5-(4- cyclopentylammophenylsulfonyloxy)bεnzimidazole-2-carbamatε (εxamplε 19) with 50 μl dimεthylaminε (2,0 M in tεtrahydrofuran) and 5 μl 1,8-Diazabicyclo[5.4.0] undεc-7-εnε in 2 ml dimεthylformamide. In a 24 well inox plate for high pressure reaction. The reaction mixture was put under a 10 Bars argon pressure and then heated to 80°C for 4 hours, and then cooled at room temperature. Compounds were put in an assay tube and dimethylformamidε was dry concεntrate evaporated in a JOUAN RC1010 evaporator. Coumpound was diluted in 0.5 ml dimethylsulfoxidε for LC/MS triggεd purification yielding 9 mg expected (LC/MS analysis: retention time = 3.35 min., mass spectrum: 444.29, [M+Hf).
Example 33 : 4-Cyclopentylamino-bεnzenesulfonic acid 2-(3-cyclopropyl-ureido)- lH-benzoimidazol-5-yl ester
lO g of Memyl-5-(4-cyclopentylaminophεnylsulfonyloxy)benzimidazole-2- carbamate (example 19) were combined with 25 μl cyclopropylamine and 10 μl l,8-Diazabicyclo[5.4.0]undec-7-ene in 2 ml N-me ylpyσolidonε/tetrahydrofuran (0.8/1.2). In a 24 wεll inox platε for high pressure reaction. The reaction mixture was put undεr a 10 Bars argon pressurε and thεn heated to 60°C for 40 hours, and then cooled at room tεmpεrature. Compounds wεrε put in an assay tubε, tetrahydrofuran was evaporated under reduce pressure and compound in N-methylpyrrolidonε was directly purified by LC/MS trigged purification yielding 8.7 mg title compound. (LC/MS analysis: retention time = 3.66 min., mass spectrum: 456.36, [M+Hf).
Example 34 : 4-Cyclopentylamino-bεnzenεsulfonic acid 2-(3-isopropyl-ureido)-lH- benzoimidazol-5-yl ester
In a similar manner to εxample 33, title compound was obtainεd by rεacting Methyl- 5-(4-cyclopentylaminophenylsulfonyloxy)benzimidazole-2-carbamate (εxample 19) with isopropylamine. (LC/MS analysis: retεntion time = 3.78 min., mass spectrum:
Example 35 : 4-Cyclopentylamino-bεnzenesulfonic acid 2-(3-butyl-ureido)-lH- bεnzoimidazol-5-yl ester
In a similar manner to εxample 33, title compound was obtained by rεacting Methyl- 5-(4-cyclopentylaminophεnylsulfonyloxy)bεnzimidazole-2-carbamate (example 19) with butylamine. (LC/MS analysis: retεntion timε = 3.90 min., mass spεctrum: Example 36 : 4-Imidazol- 1-yl-bεnzεnεsulfonic acid 2-[3-(2-fluoro-phenyl)-ureido]- lH-bεnzoimidazol-5-yl ester
In a similar manner to example 30, title compound was obtained by rεacting Methyl- 5-(4-[imidazolyl]-phεnylsulfoxy)benzimidazole-2-carbamatε (εxamplε 4) with 2-fiuoro-aniline. (LC/MS analysis: retention time = 3.03 min., mass spectrum: 493.28, [M+Hf).
Example 37 : 4-Cyclopentylamino-bεnzenesulfonic acid 2-[3-(2-fiuoro-phεnyl)~ ureido]-lH-benzoimidazol-5-yl ester
In a similar manner to example 33, title compound was obtained by reacting Methyl- 5-(4-cyclopεntylaminophenylsulfonyloxy)benzimidazolε-2-carbamatε (εxample 19) with 2-fiuoro-aniline. (LC/MS analysis: retention time = 3.99 min., mass spectrum: 510.32, [M+Hf).
Example 38 : 4-Cyclopentylamino-b8nzεnesulfonic acid 2-[3-(3-methoxy-phenyl)- urεido]-lH-bεnzoimidazol-5-yl ester
In a similar mannεr to example 33, title compound was obtained by reacting Methyl- 5-(4-cyclopentylammophenylsulfonyloxy)berιzirnidazole-2 -carbamate (example 19) with m-anisidine (LC/MS analysis: retεntion timε = 4.02 min., mass spεctrum: 522.33, [M+Hf).
Example 39 : 4-Cyclopεntylamino-benzenesulfonic acid 2-[3-(4-methoxy-phenyl)- ureido]-lH-benzoimidazol-5-yl ester
In a similar manner to example 33, title compound was obtained by reacting Methyl- 5-(4-cyclopentylaminophεnylsulfonyloxy)benzimidazolε-2-carbamate (example 19) with / -anisidine (LC/MS analysis: retention time = 3.97 min., mass spectrum: 522.34, [M+Hf). Examplε 40 : 4-Cyclopentylamino-benzenesulfonic acid 2-[3-(4-chloro-phεnyl)- ureido]-lH-benzoimidazol-5-yl ester
In a similar manner to example 33, title compound was obtained by reacting Methyl- 5-(4-cyclopentylaminophenylsulfonyloxy)benzimidazole-2-carbamate (example 19) with 4-chloroaniline. (LC/MS analysis: retention time = 4.20 min., mass spectrum: 526.28, [M+Hf).
Example 41 : 4-Cyclopentylamino-benzenεsulfonic acid 2-[3-(3-fluoro-bεnzyl)- urεido]-lH-bεnzoimidazol-5-yl ester
In a similar manner to example 33, title compound was obtainεd by reacting Methyl- 5-(4-cyclopentylaminophenylsulfonyloxy)b8nzimidazole-2-carbamate (example 19) with 3-fluoro-aniline. (LC/MS analysis: retention time = 3.96 min., mass spectrum: 524.33, [M+Hf).
Example 42 : 4-Cyclopentylamino-benzεnesulfonic acid 2-[3-(3-chloro-phenyl)- urεido]-lH-bεnzoimidazol-5-yl ester
In a similar manner to example 33, title compound was obtained by reacting Methyl- 5-(4-cyclopentylaminophenylsulfonyloxy)benzimidazole-2-carbamate (example 19) with 3-chloroaniline. (LC/MS analysis: retention time = 4.21 min., mass spεctrum: 526.28, [M+Hf).
Examplε 43 : 4-Cyclopentylamino-benzεnesulfonic acid 2-(3-isobutyl-ureido)-lH- benzoimidazol-5-yl ester
In a similar manner to examplε 33, title compound was obtained by reacting Methyl- 5-(4-cyclopentylammophenylsulfonyloxy)benzimidazole-2-carbamate (example 19) with isobutylamine. (LC/MS analysis: retention time = 3.88 min., mass spectrum: 472.38, [M+Hf).
Example 44 : 4-Cyclopentylamino-benzenesulfonic acid 2-[3-(2-dimethylamino- ethyl)-ureido]- lH-benzoimidazol-5-yl ester
In a similar manner to εxamplε 33, titlε compound was obtained by reacting Methyl- 5-(4-cyclopεntylammophenylsulfonyloxy)benzimidazole-2-carbamate (example 19) with N,N-dimethylethylenediamine. (LCMS analysis: retention time = 3.22 min., mass spectrum: 487.38, [M+Hf).
Examplε 45 : 4-Cyclopentylamino-benzenesulfonic acid 2-(3-ethyl-ureido)-lH- benzoimidazol-5-yl ester;
In a similar manner to example 33, title compound was obtained by reacting Methyl- 5-(4-cyclopentylaminophenylsulfonyloxy)benzimidazole-2-carbamate (example 19) with ethylaminε (33 % in water). (LC/MS analysis: retεntion timε = 3.64 min., mass spectrum: 444.35, [M+Hf).
Example 46 : {3-[5-(4-Cyclopentylamino-benzenesulfonyloxy)-lH-benzoimidazol- 2-yl]-urεido} -acetic acid
In a similar manner to example 33, title compound was obtained by reacting Methyl- 5-(4-cyclopεntylaminophenylsulfonyloxy)benzimidazolε-2-carbamate (example 19) with glycine. (LC/MS analysis: retention time = 3.48 min., mass spectrum: 474.31, [M+Hf).
Example 47 : 4-Imidazol- 1 -yl-benzenesulfonic acid 2-[3-(2-sulfo-εthyl)-urεido]-lH- bεnzoimidazol-5-yl ester
In a similar manner to example 30, title compound was obtained by reacting Mεthyl- 5-(4-[imidazolyl]-phεnylsulfoxy)benzimidazole-2-carbamate (example 4) with 2-aminoeτhanεsulfonic acid. (LC/MS analysis : retention time = 2.40 min., mass spectrum: 507.21, [M+Hf).
Example 48 : 4-Cyclopentylamino-benzenesulfonic acid 2-[3-(2-methoxy-ethyl)- ureido]-lH-bεnzoimidazoI-5-yl estεr
In a similar mannεr to εxample 33, titlε compound was obtained by reacting Methyl- 5-(4-cyclopentylaminophenylsulfonyloxy)benzimidazole-2-carbamate (example 19) with 2-methoxyεthylamine. (LC/MS analysis: retention time = 3.60 min., mass spectrum: 474.34, [M+Hf).
Example 49 : 4-Cyclopentylamino-bεnzεnesulfonic acid 2-[3-(4-dimethylamino- phenyl)-ureido]-lH-benzoimidazol-5-yl ester
In a similar manner to example 33, title compound was obtained by reacting Methyl- 5-(4-cyclopεntylammophεnylsulfonyloxy)bεnzimidazole-2-carbamate (example 19) with N,N-dimethyl-l,4-phεnylεnediamine. (LC/MS analysis: retεntion timε = 3.42 min., mass spεctrum: 535.34, [M+Hf).
Example 50 : 4-Cyclopεntylamino-bεnzεnεsulfonic acid 2-(3-pyridm-2-ylmethyl- urεido)- lH-bεnzoimidazol-5-yl ester
In a similar manner to example 33, title compound was obtained by reacting Methyl- 5-(4-cyclopentylaminoph8nylsulfonyloxy)bεnzimidazolε-2-carbamate (example 19) with 2-aminomethylpyridine. (LC/MS analysis: retention time = 3.30 min., mass spectrum: 507.33, [M+Hf).
Example 51 : 4-Cyclopentylamino-benzenesulfonic acid 2-(3-cyclobutyl-ureido)-lH- benzoimidazol-5-yl ester
In a similar manner to example 33, title compound was obtained by reacting Methyl- 5-(4-cyclopentylaminophεnylsulfonyloxy)bεnzimidazole-2-carbamate (example 19) with cyclobutylamine. (LC/MS analysis: retention time = 3.84 min., mass spectrum: 470.36, [M+Hf).
Example 52 : 4-Cyclopentylamino-bεnzenesulfonic acid 2-(3-pyridin-4-ylmethyl- urεido)-lH-benzoimidazol-5-yl ester
In a similar manner to example 33, title compound was obtained by reacting Methyl- 5-(4-cyclopεntylaminoph8nylsulfonyloxy)benzimidazole-2-carbamate (εxample 19) with 4-(aminomethyl)pyridine. (LC MS analysis: retention time = 3.24 min., mass spectrum: 507.33, [M+Hf). Example 53 : 4-Cyclopentylamino-benzεnesulfonic acid 2-(3-tert-butyl-ureido)-lH- bεnzoimidazol-5-yl ester
In a similar manner to example 33, title compound was obtained by reacting Methyl- 5-(4-cyclopentylaminophεnylsulfonyloxy)bεnzimidazole-2-carbamate (example 19) with tβrt-butylamine. (LC/MS analysis: retention time = 3.93 min., mass spectrum: 472.36, [M+Hf).
Example 54 : 4-[(Tetrahyc o-fiιran-2-ylmemyl)-amino]-bεnzenesulfonic acid 2-(3- mεthyl-urεido)-lH-benzoimidazol-5-yl ester
10 mg of Memyl-5-(4-[l-tetra yατofuryimethyi] aminophenyl-suifonyioxy) benzimidazole-2-carbamate (example 18) were combined with 50 μl methylamine (2,0 M in tetrahydrofuran) and 5 μl l,8-Diazabicyclo[5.4.0]undec-7-ene in 2 ml N-methylpyrrolidone/ tεtrahydrofuran (1/1). In a 24 well inox plate for high pressure reaction. The reaction mixture was put under a 10 Bars argon pressure and then heated to 80°C for 4 hours, and then cooled at room temperature. Compounds were put in an assay tube and tetrahydrofuran was evaporated under reduce pressurε and compound in N-methylpyrrolidone were directly purified by preparative LCMS in conditions described above. After purification, solution were dry-concentrated in a JOUAN RClOlO evaporator. (LC/MS analysis: retention time = 2.91 min., mass spectrum: 446.07, [M+Hf).
Example 55 : 4-Fluoro-benzenesulfonic acid 2-(c3'clopropanecarbonyl-amino)-lH- benzoimidazol-5-yl ester
step 1: 10 g of 4-amino, 3-nitrophέnol in 180 ml of εthanol were hydrogenatεd undεr 40 bars pressure at 23°C temperature with catalytic amoxind of palladium on carbon. Reaction was performed in inox flask for high pressurε. Aftεr hydrogen uptake was complete, thε catalyst was filtered off with suction, washed with methanol and the filtrate was concentred under reduced pressurε yiεlding 8 g of crude 3 ,4-diaminophenol.
Step 2: 5.75 g of 3,4-diaminophεnol were combined with 15.5 g of l,3-bis(tert- butoxycarbonyl)-2-mεthyl-2-thiopseudourea in 150 ml methanol and 22 ml acetic acid in a round bottom flask. The reaction mixture was hεatεd to rεflux with stirring for 3 hours. Solvents were then evaporated under reduce pressure yielding 7.13 g crude (5-Hydroxy-lH-benzoimidazol-2-yl)-carbamic acid tert-butyl ester.
Step3: 5.98g of (5-Hydroxy-lH-benzoimidazol-2-yl)-carbamic acid tert-butyl ester were combinated with 4.67g of 4-fluorobenzεnesulfonyl chloride and 6.75 ml of triεtylaminε in 100 ml acεton. Thε reaction mixture was stirred at room tempεrature for 1 hour. Solvents were evaporated under reduced pressure yiεlding 6.45 g crudε 4- Fluoro-benzεnεsulfonic acid 2-tεrt-butoxycarbonylamino- lH-bεnzoimidazol-5-yl εstεr.
Step 4: 6.45g of 4-Fluoro-bεnzεnεsulfonic acid 2-tert-butoxycarbonylamino-lH- benzoimidazol-5-yl ester were combinated with 15 ml trifluoroacetic acid in 60 ml dichloromethanε. Thε reaction mixture was stirred overnight at room tempεraturε. Solvεnts wεrε εvaporatεd undεr reduced pressure. The residuε was washεd with ethylic εthεr and driεd on glass frit yielding 6.58 g of 4-Fluoro-benzεnesulfonic acid 2-amino-lH-benzoimidazol-5-yl εstεr trifluoroacetic acid salt.
Step 5 : 5.53 g of 4-Fluoro-benzεnesulfonic acid 2-amino-lH-benzoimidazol-5-yl ester trifluoroacetic acid salt were combinated with 1.8 ml of cyclopropanecarbonylchloridε and 5 ml triethylamine in 75 ml dichloromethanε.
Reaction mixture was stirred at room tempεraturε for 1 hour. Solvεnts werε evaporatεd undεr reduced pressurε. The residuε was then takεn up in dichloromethane, washed with water and dried under magnesium sulfate. Dicloromethane was evaporatεd under reduced pressurε and precipitate obtained was dried on glass frit yielding 4.88 g of 4-Fluoro-benzεnesulfonic acid 2-amino-3- cyclopropanεcarbonyl-3H-bεnzoimidazol-5-yl ester.
Step 6 : 3.27 g of 4-Fluoro-benzεnesulfonic acid 2-amino-3-cyclopropanecarbonyl- 3H-bεnzoimidazol-5-yl estεr; wεrε combinated with 106 mg of 4-(dimethylamino)pyridinε in 80 ml acetonitrile. the reaction mixture was hεatεd at 85°C temperature for 72 hours with stirring. Yellow solution obtained was diluted in dichloromethanε, washεd with water and dried under magnesium sulfate. Solvents were evaporated under reduced pressurε yiεlding 3.19 g of thε titlε compound.
Example 56 : Preparation of 4-[(l-Ethyl-pyrrolidin-2-ylmethyl)-amino]- bεnzεnεsulfonic acid 2-(cyclopropanεcarbonyl-amino)-lH- bεnzoimidazol-5-yl εster.
Title compound was obtained by reacting 12 mg of 4-Fluoro-benzenεsulfonic acid 2- (cyclopropanεcarbonyl-amino)-lH-benzoimidazol-5-yl εstεr (example 55) with 21 mg of 2-(aminomethyl)-l-ethylpyrrolidine and 50 mg cesium carbonate in 600 μl dimethylsulfoxide. Reaction was performεd in a 24 well inox plate for high pressure, the reaction mixture was put under 10 bars argon pressure and then heatεd to 110°C for 50 hours. Cesium carbonate was filtered off and compound in DMSO was directfy purified by LCMS triggered purification yielding 10.7 mg title compound. (LC/MS analysis : retention time = 2.58 min, mass spectrum : 483.99, [M+Hf.
Examplε 57 :
By using a mεthod similar to that for thε preparation of example 30, combining Methyl-5-(4-[l-imidazolyl]-phenylsulfon3'loxy) bεnzimidazole-2-carbamate precursor (example 4) with suitable amine were obtained the following compounds that were charactεrizεd by analytical LC/MS ([M+Hf and rεtεntion timε givεn in the following table).
Example 58 :
By using a method similar to that for the preparation of example 33, combining Methyl-5-(4-cyclopεntylaminophεnylsulfonyloxy)benzimidazole-2-carbamate (example 19) with suitable amine wεrε obtainεd thε following compounds that were characterized by analytical LC/MS ([M+Hf and retεntion timε given in the following table).
Example 59 :
By using a method similar to that for the preparation of example 54, combining Methyl-5-(4-[ 1 -teframydrofurylmethyl] aminophenyl-sulfonyloxy) benzimidazole-2- carbamatε (example 18) with suitable amine were obtained the following compounds that werε characterized by analytical LC/MS (|M+H]"r and retention timε givεn in thε following tablε).
Example 60 :
By using a method similar to that for the preparation of εxamplε 56, combining 4- Fluoro-benzenεsulfonic acid 2-(cyclopropanεcarbonyl-amino)- lH-benzoimidazol-5- yl ester (εxample 55) with suitable amine were obtained the following compounds that were characterized by analytical LC/MS ([M+Hf and retention timε given in the following table).
NOT FURNISHED UPON FILING
Example 61 : Preparation of 4-trifluoromethoxy-bεnzεnεsulfonic acid 2- mεmoxycarbonylammo-lH-bεnzoimidazol-5-yl εstεr
step 1 : 7.82 g of 4-amino-3-nitrophεnol in 460 ml of mεthanol wεrε hydrogεnatεd with catalytic amount of palladium on carbon (800 mg, 10 % Pd/C). Aftεr hydrogεn uptake was complete, the catalyst was fϊltεrεd off, washed with methanol and the filtrate was concentred under reduced pressure to give 6 g of crude 3,4- diaminophεnol.
Step 2: 6 g of 3,4-diaminophεnol were combined with 9.8 g of 1,3- bis(methoxycarbonyl)-2-methyl-2-thiopseudourea in 50 ml methanol and 30 ml acetic acid. The rεaction mixture was refluxεd for 4 hours. Solvents were then evaporatεd undεr reduce pressure yielding 10.8 g crude (5-Hydroxy-lH-benzoimidazol-2-yl)- carbamic acid methyl ester. The residuε was subjεctεd to flash chromatography eluting with a mixture of dichloromethanε-mεthanol (9:1 ; v/v) to givε 5.6 g of a bεige solid. Mass spectrum : 208 [M+Hf, retεntion timε = 0.56 minute.
Step 3 : A stirred solution of (5-hydroxy-lH-bεnzoimidazol-2-yI)-carbamic acid methyl εstεr (100 mg) and 4-trifluoromεthox3?-benzenεsulfonyl chloride (126 mg) in acetone (3 ml) was treatεd with triethylaminε (130 μl). After stirring at ambient temperature for 4 hours, the reaction mixture was evaporated. The residuε was subjected to flash chromatography on silica eluting with a mixture of ethyl acetatε and heptane (1 :1, v/v) to give 4-trifluoromethoxy-benzenesulfonic acid 2-memoxycarbonylarrιmo-lH-benzoiπιidazol-5-yl εstεr (65 mg) as an off-white solid Mass spectrum : 432 [M+Hf ; retention time = 15.04 minutes.
Example 62 :
By using a method similar to that for the preparation of examplε 61, combining (5-hydroxy-lH-bεnzoimidazol-2-yl)-carbamic acid methyl εster with suitablε bεnzenε sulfonyl chloride were obtained the following compounds that werε charactεrizεd by analytical LC/MS ({M+Hf and retention time given in thε following
102
Example 63 : Preparation of 4-benzyloxy-bεnzεnesulfonic acid 2- mεthoxycarbonylamino- lH-bεnzoimidazol-5-yl ester
Step 1 : A stirred solution of 4-amino-3-nitro-phenol (3 g) and bεnzoic acid 4-chlorosulfonyl-phenyl ester (5.7 g) in acetone (80 ml) was treated with trie ylvirnine (5.4 ml). After stirring at ambient temperature for 14 hours, the reaction mixture was evaporatεd. Thε rεsiduε was triturated with diisopropylic ether, filtered off and dried under vacuum to give 5.22 g of benzoic acid 4-amino-3-nitro- phenoxysulfonyl)-phenyl estεr (5.22 g) as a yellow solid Mass spectrum : 401 [M+H]+ ; retention time = 4.59 minutes.
Step 2 : A solution bεnzoic acid 4-amino-3-nitro-phεnoxysulfonyl)-phenyl ester (3 g) and 2N aqueous solution of sodium hydroxyde in methanol (55 ml) was reluxed for 2 hours. The reaction mixture was concentratεd and watεr (100ml) and ethyl acetatε (100ml) wεre added. The organic layer was dried over magnesium sulfate then evaporated to give 1.77 g of crude 4-hydroxy-benzenesulfonic acid 4-amino-3-nitro- phεnyl εstεr.
Step 3 : A solution of cesium carbonatε (156 mg) in water (0.3 ml) was added to a solution of 4-hydroxy-benzenesulfonic acid 4-amino-3-nitro-phenyl εster (150 mg) and benzyl bromide (58 μl) in dimethylformamide (3 ml). The reaction mixture was heated at 80°C for 3 hours then allowed to cool to ambient temperature, poured into water (25 ml) and extracted three times with ethyl acetate (30 ml). The combined extracts were dried over magnesium sulfate then evaporated to give 189 mg of crude 4-benzyloxy-benzenesulfonic acid_4-amino-3-nitrophenyl estεr .
Step 4 : Sodium dithionitε (624 mg) was addεd to a solution of 4-benzyloxy- benzεnεsulfonic acid 4-amino-3-nitrophεnyl εstεr (180 mg) and sodium hydroxyde
(0.5 N, 3.1 ml) in ethanol (6 ml) at 80°C. The reaction mixture was stirred at 80°C for 10 minutes then filtered and thε filtrat was evaporated. The residuε was εxtractεd threε timεs with ethyl acetatε (15 ml). Thε combined extracts were dried over magnesium sulfate then evaporated to 137 mg of crude 4-benzylox3r-benzεnεsulfonic acid 3,4-diamino-phenyl estεr .
Step 5 : prεparation of 4-Bεnzyloxy-bεnz8nεsulfonic acid 2-mεmoxycarbonylamino- 1 H-benzoimidazol-5 -yl ester
To a solution of 4-benzyloxy-bεnzεnεsulfonic acid 3,4-diamino-phenyl ester (134 mg) in acetic acid (0.83 ml) and methanol (2.5 ml) at 80°C was added 1.3-bis(methoxycarbonyl)-2-methyl-2-thiops8udourεa (89 mg). Thε reaction mixture was refluxed for 2 hours then allowed to cool to ambient temperature and stirred at this tempεraturε for 14 hours. Thε resultant prεcipitatε was filtered, washed with diethyl ether and dried under vacuum to afford 4-Benzyloxy-bεnz8nεsulfonic acid 2-mεmoxycarbonylammo-lH-benzoimidazol-5-yl ester as a bεige solid. Mass spectrum : 454 [M+H]+ ; retention time = 11.46 minutes.
Example 64 :
By using a method similar to that for the preparation of example 63, combining in step 3 the 4-hydroxy-benzεnεsulfonic acid 4-amino-3-nitro-phεnyl εster with suitable alkyl halide werε obtainεd thε following compounds that wεrε characterized by analytical LC/MS ([M+Hf and retention time given in the following table).
Example 65 Preparation of 4-(2-oxo-2-pyrrolidin- 1 -yl-ethoxy)-benzenεsulfonic acid 2-mεthoxycarbonylamino- 1 H-bεnzoimidazol-5 -yl-εster
A solution of [4-(2-me oxycarbonylanιino-3H-benzoimidazol-5-yloxysulfonyl)- phεnoxy] -acetic acid (40 mg, examplε 64-ε) in dry dimethylformamidε (3ml) was treated wim N-{(dimemylam o)(lH^ memylmεmanaminium hexafluorophosphatε N-oxide (39 mg) and diisopropylεmylainine (50 μl). After stirring at ambient tempεraturε for 30 minutes, pyrrolidine (21 μl) was added and thε mixture stirred at room tempεrature for a further 3 hours. The solvent was removed under vacuo and thε rεsiduε was purified by triggered LC/MS to givε 4-(2-oxo-2-pyrrolidin-l-yl-εthoxy)-bεnzenesulfonic acid 2-m8thoxycarbonylammo-lH-bεnzoimidazol-5-yl-ester as an off-whitε solid. Mass spεctrum : 475[M+Hf ; rεtεntion time = 8.39 minutes.
Example 66 By using a method similar to that for the preparation of example 65, combining [4-(2- methoxycarbonyl-ιmmo-3H-b8nzoimidazol-5-yloxysulfonyl)-phenoxy]-acetic acid with suitable aminε werε obtainεd thε following compounds that wεre characterized by analytical LC/MS ([M+Hf and retεntion time given in the following table).
Example 67 Preparation of 4-(cyclopropylmemyl-amino)-benzenε sulfonic acid 2- methoxycarbonylamino- 1 H-benzoimidazol-5-yl estεr
Step 1 : preparation of 4-(cyclopropylmεthyl-amino)-bεnzεnesulfonic acid 4-amino- 3-nitro-phenyl εster
A solution of 4-fluoro-benzεnesulfonic acid 4-amino-3-nitro-phεnyl estεr (800 mg) and cyclopropylmεmylamine (890 μl) in N-methylpyrrolidinone (8 ml) washεated at 110°C in a sεaled tube for 14 hours. The reaction mixture was then poured into water (150 ml) and extracted three times with eύ l acetate (40 ml). The combined extracts were dried over magnesium sulfate and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and heptane (50 :50, v/v) to give 4-(cyclopropylmethyl-amino)-b8nzenesulfonic acid 4-amino-3- nitro-phenyl ester (786 mg) as a yellow solid. Step 2 : Sodium dithionitε (3 g) was added to a solution of 4-(c3'elopropylmeth3''l- amino)-benzenesulfonic acid 4-amino-3-nitro-phenyl εstεr (783 mg) and sodium hydroxyde (0.5 N, 15 ml) in ethanol (30 ml) at 80°C. The reaction mixture was stirred at 80°C for 10 minutes then filtered then the filtrat was evaporated. The residue was extracted three times with ethyl acetate (30 ml). The combined extracts were dried over magnesium sulfate then evaporated to give 652 mg of 4-(cyclopropylmethyl- amino)-benzenesulfonic acid 3,4-diamino-phεn3rl ester.
Step 3 : To a solution of 4-(cyclopropylmethyl-amino)-bεnzenεsulfonic acid 3,4- diamino-phenyl estεr (648 mg) in acεtic acid (4.5 ml) and methanol (40 ml) at 80°C was added 1.3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourεa (580 mg). The reaction mixture was refluxed for 4 hours then allowed to cool to ambient temperature and stirred at this temperature for 14 hours. The resultant precipitate was filtered, washed with diethyl εthεr and dried under vacuum to afford 4-(cyclopropylmεmyl-amino)-bεnz8nε sulfonic acid 2-mεmoxycarbonylamino-lH- bεnzoimidazol-5-yl estεr (378 mg) as a beige solid. Mass spectrum : 417 [M+Hf ; retεntion timε = 13.16 minutes.
Example 68 :
By using a method similar to that for thε prεparation of εxample 67, combining 4- fluoro-benzenesulfonic acid 4-amino-3-nitro-phenyl ester with suitable amine in step 1 were obtained the following compounds that were characterized by analytical LC/MS ([M+Hf and retention time givεn in the following table).
Example 69 Preparation of 4-cyclopenrylamino-benzεnesulfonic acid 2-(3,4- dimethoxy-phenylamino)-lH-benzoimidazol-5-yl estεr
Step 1 : A solution of l-benzyl-6-mεthoxy-lH-benzoimidazole (3 g) in dry tetrahydrofuran (65 ml), cooled to -78°C, was treated with a solution of n-butyllithium in hexanes (12 ml, 15 %). After stirring for 45 minutes the mixture was treated with N-chlorosuccinimide (2.24 g in 65 ml of tetrahydrofuran) then allowed to warm slowly to ambient temperature. The reaction mixture was allowed to stir at ambient temperature for 2 hours then treated with a saturated aquεous solution of ammonium chloridε (100 ml) and εxtractεd three times with ethyl acetate (65 ml). The combined extracts werε driεd ovεr magnesium sulfate and then εvaporatεd. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexanε (1 :1, v/v) to l-benzyl-2-chloro-6-methoxy-lH- bεnzoimidazolε (2.09 g) as a yεllow solid. Mass spectrum : 273 [M+Hf , retention time = 3.93 minutes.
Step 2 : A mixture of l-benzyl-2-chloro-6-methoxy-lH-bεnzoimidazolε (600 mg), hydrobromic acid (48 %, 11 ml) and glacial acεtic acid (6 ml) was hεatεd under rεflux for 1 hour. Aftεr cooling thε mixture was neutralised by addition of 10 % sodium bicarbonate solution then extracted 3 times with dichloromethanε (30 ml). Thε combinεd extracts were dried over magnesium sulfate and then evaporated to give 3-benzyl-2-chloro-3H-bεnzoimidazol-5-ol (470 mg) as a yellow solid. Mass spectrum : 259 [M+Hf retention time = 3.4 minutes.
Step 3 : A mixture of 3-benzyl-2-chloro-3H-benzoimidazol-5-ol (250 mg) and 4-amino veratrolε (296 mg) in N-mεthyl pyrrolidinonε (3 ml) was hεatεd at 150°C in a sealed tube for 4 hours then allowed to cool. The reaction mixture was then poured into water (30 ml) and extractεd thrεε timεs with ethyl acetate (30 ml). The combined extracts wεrε driεd over magnesium sulfate and then evaporatεd. The residuε was subjεcted to flash chromatography on silica eluting with a mixture of dichloromethane and mεthanol (95 :5, v/v) to givε 3-bεnzyl-2-(3,4-dimεthoxy- phεnylamino)-3H-bεnzoimidazol-5-ol (141 mg) as ayεllow solid. Mass spεctrum : 376 [M+H]+ retεntion timε : 3.44 minutes.
Step 4 : A stirred solution of 3-benzyl-2-(3,4-dimεmoxy-phεnylamino)-3H- bεnzoimidazol-5-ol (141 mg) and 4-fluoro-bεnzenesulfonyl chloridε (190 mg) in acεtone (8 ml) was trεated with triethylamine (258 μl). After stirring at ambient temperature for 4 hours, the reaction mixture was evaporated. The residuε was subjected to flash chromatography on silica eluting with a mixture of ethyl acεtatε and heptane (1 :1, v/v) to give 4-fluoro-benzenesulfonic acid 3-benzyl-2-(3,4- dimethoxy-phenylammo)-3H-bεnzoimidazol-5-yl εstεr (157 mg) as a yεllow solid. Mass spεctrum : 534 [M+Hf , retεntion timε : 3.7 minutεs.
Step 5 : A solution of 4-fluoro-bεnzεnεsulfonic acid 3-benzyl-2-(3,4-dimethoxy- phenylamino)-3H-benzoimidazol-5-yl ester (151 mg) and cyclop entylaminε (118 μl) in N-mεthyl pyrrolidinonε (1.5 ml) was hεatεd at 110°C in a sεalεd tubε for 3 hours. Thε reaction mixture was allowεd to cool then poured into water (30 ml) and extracted three times with ethyl acetatε. Thε combinεd εxtracts were dried over magnesium sulfate then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and heptane (1 :1 , v/v) to give 4-cyclopentylamino-bεnzenesulfonic acid 3-benzyl-2-(3,4-dimethoxy- phenylamino)-3H-benzoimidazol-5-yl ester (122 mg) as a brown solid. Mass spectrum : 599 [M+Hf , retention time = 4.0 minutεs.
Examplε 70 :
By using a method similar to that for the preparation of example 69, combining 3-ben2yl-2-cMoro-3H-berιzoimidazol-5-ol with suitable aminε in step 3 were obtained thε following compounds that were characterizεd by analytical LC/MS (jM+H and retention time given in the following table).
Examplε 71 Preparation of 4-cyclopentylamino-benzεnεsulfonic acid 2-(3-phεnyl- propionylam o)-lH-bεnzoimidazol-5-yl estεr
A solution of 3-phenyl propionic acid (9.7 mg) in dry dimethylformamide (0.6ml) was treated with N-{(dimemylamino)(lH-l,2,3-triazolo[4,5-b]pyridin-l-yl) mεmylene}-N-memylmemanaminium hεxafluorophosphate N-oxide (21 mg) and diisopropylεthylaminε (12 μl). Aftεr stirring at ambient tempεraturε for 30 minutes, 4-cyclopentylamino-bεnzεnεsulfonic acid 2-amino (20mg) was added and the mixture stirred at room tempεraturε for a further 3 hours. Thε solvεnt was rεmovεd undεr vacuo and the residue was purified by triggered LC/MS to give 4-cyclopentylamino- benzenesulfonic acid 2-(3-phenyl-propion3rlamino)-lH-benzoimidazol-5-yl εstεr as an off-white solid (11 mg). Mass spectrum : 505 [M+HT ; rεtεntion timε = 4.59 minutεs.
Example 72 : Preparation of 4-cyclopentylamino-benzenesulfonic acid 2-[2-2-
By proceeding in a mannεr similar to examplε 71 abovε but using (2-mεthoxy- ethoxy)-acεtic acid thεre was prepared 4-cyclopentylamino-benzenεsulfonic acid 2-[2-2-memoxy-ε oxy)-acεtylanιino]-lH-bεnzoimidazol-5-yl εstεr as an off-white solid. Mass spεctrum : 489 [M+BTT ; rεtεntion time = 4.06 minutes. Example 73 : Preparation of 4-fiuoro-benzenεsuIfonic acid 2-(3(chloro-4-methoxy- bεnzylamino)-3K-bεnzoimidazol-5-yl ester
Step 1 : A stirred solution of 4-fluoro-benzenesulfonic acid 2-tert- butoxycarbonylamino-3H-benzoimidazol-5-yl ester (Example 55 (step 3), 200 mg) in dry dimethylformamidε (3 ml) was treatεd with sodium hydride (12 mg, 60 % dispersion in mineral oil). Aftεr stirring for 30 ininutεs the mixture was trεated with a solution of 3-chloro-4-methoxy-bεnzyl bromide (94 mg) in dimethylformamide (1 ml) and stirring was continued for a further 3 hours. The reaction mixture was poured into water (10 ml) and then extracted three times with ethyl acetate (10 ml). The combined extracts werε driεd ovεr magnεsium sulfatε and thεn εvaporatεd. Thε residue was subjected to flash chromatography on silica eluting with a mixture of εthyl acetate and heptanε (1 :2 , v/v) to give 4-fluoro-benzenεsulfonic acid 2-[tert- butoxycarbonyl-(3-chloro-4-memoxy-bεrιzyl)-amino]-3H-b8nzoimidazol-5-yl ester (70 mg) as a beige solid.
Step 2 : preparation of 4-fluoro-benzenesulfonic acid 2-(3(chloro-4-methoxy- bεnzylamino)-3H-benzoimidazol-5-yl ester
Trifluoroacetic acid (1 ml) was added to a solution of 4-fluoro-benzenεsulfonic acid
2-[tert-butoxycarbonyl-(3-cHoro-4-memoxy-bεnzyl)-ammo]-3H-bεnzoimidazol-5-yl εstεr (67 mg) in dichloromethanε (4 ml). Aftεr cooling, thε mixturε was nεutralisεd by addition of saturatεd sodium bicarbonatε solution. Watεr (10 ml) was addεd and thε solution εxtractεd three times with dichloromethane (10 ml). The combined extracts werε driεd over magnesium sulfate and then evaporatεd. The residue was subjectεd to flash chromatography on silica εluting with a mixturε of εthyl acetatε and heptanε (1 :1 , v/v) to givε 4-fluoro-benzεnεsulfonic acid 2-(3(chloro-4-mεthoxy- benzylamino)-3H-benzoimidazol-5-yl ester (53 mg) as an off-white solid. Mass spectrum : 462 [M+Hf ; retention time = 7.69 minutes.
Example 74 :
By using a method similar to that for the preparation of example 73, combining 4- fiuoro-benzεnεsulfonic acid 2-tεrt-butoxycarbonylamino-3H-bεnzoimidazol-5-yl εstεr with suitablε benzyl halide were obtained the following compounds that were characterized by analytical LC/MS ([M+H]~ and retention time given in the following tablε).
Examplε 75 Prεparation of 4-cyclopεntylamino-benzenesulfonic acid 2 benzylamino-SH-benzoimidazol-S^l estεr
A solution of 4-fiuoro-bεnzεnesulfonic acid 2-bεnzylamino-3H-bεnzoimidazol-5-yl estεr (20mg) and cyclopentylamine (21 μl) in N-methylpyrrolidinone (0.5 ml) was heatεd at 110°C in a sεaled tube for 2 hours. The reaction mixture was then purified by triggered LC/MS to give 4-cyclopentylamino-benzenεsulfonic acid 2-bεnzylamino-3H-bεnzoimidazol-5-yl ester as an off-white solid (4 mg). Mass spectrum : 463 [M+Hf ; retεntion timε = 8.35 minutεs. Example 76 :
By using a method similar to that for the preparation of examplε 75, combining cyclopentylamine with suitable 4-fluoro-benzenesulfonic acid 2-benzylamino-3H- benzoimidazol-5-yl εstεr (example 73, 74a-74c) werε obtained the following compounds that were characterized by analytical LC/MS ([M÷H]~ and retention time given in the following tablε).
Examplε 77 : Prεparation of 4-(C3^clopropylmethyl-amino)-benzenesulfonic acid 2- [3-(2-morpholin-4-yl-ethyl)-ureido]-lH- benzoimidazol-5-yl εstεr
A solution of 4-(cyclopropylmethyl-amino)-benzεnεsulfonic acid 2-methoxy- carbonylam o-3H-benzoimidazol-5-yl estεr (εxample 67, 40 mg) and 2-(aminomεthyl)-morpholine (125 mg) in tεtrahydrofuran (2 ml) and N-mεthylpyrrolidinonε (0.2 ml) was heated at 90°C for 36 hours. The reaction mixturε was then evaporated and purified by triggered LC/MS to give 4-(cyclopropylmethyl-amino)-benzenεsulfonic acid 2-[3-(2-mo holin-4-yl-εthyl)- ureido]-lH-berizoirrιidazol-5-yl ester as an off-white solid (27 mg). Mass spectrum : 515[M+H]+ ; retεntion timε = 5.97 minutεs.
Example 78 :
By using a method similar to that for thε prεparation of εxample 77, combining 4-(substitated-amino)-bεnzεnesulfonic acid 2-methoxycarbonylarnino-3H-benzo- imidazol-5-yl ester [example 63, 67, 68] with suitable amine were obtained thε following compounds that were characterized by analytical LC/MS ([M+Hf and retention time given in the following table).
Example 79 Preparation of 4-(4-hydroxy-piperidin-l-yl)-bεnzεnesulfonic acid 2- [(4-hydroxy-pipεridinε- 1 -carbonyl)-amino]- IH- bεnzoimidazol-5-3rl εster
A solution of 4-fluoro-benzenesulfonic acid 2-tert-butox37carbon>4amino-3H- bεnzoimidazol-5-yl ester (200 mg, example 55 (Step 3) and 4-hydroxypipεridine (554 mg) in N-methylpyrrohdinone (6 ml) was heatεd at 110°C for 24 hours. The reaction mixture was then poured into watεr (120 ml) and extracted threε timεs with εthyl acεtatε (50 ml). The combined extracts were dried over magnesium sulfate and then evaporatεd. Thε residue was subjected to flash chromatography on silica eluting with a mixture of dichloromεthanε and mεthanol (95 C : 5, v/v) to give (4-hydroxy- pipεridin- 1 -yl)-bεnzenesulfonic acid 2- [(4-hydroxy-piperidinε- 1 -carbonyl)-amino] - lH-benzoimidazol-5-yl εster (125 mg) as a beigε solid. Mass Spεctrum : 516 [M+Hf , retention time = 6.51 minutes.
Example 80 :
By using a method similar to that for thε prεparation of εxamplε 79, combining 4-fluoro-benzenesulfonic acid 2-tert-butoxycarbonylamino-3H-benzoimidazol-5-yl ester with suitable amine wεre obtainεd thε following compounds that werε characterized by analytical LC/MS ([M+Hf and retention time given in the following tablε). 119
28721
120
Example 81 : Preparation of 4-(4-Hydroxy-piperidin-l-yl)-benzenesulfonic acid 2-
A solution of 4-(4-hydroxy-piρeridin-l-yl)-bεnzεnεsulfonic acid 2-[(4-hydroxy- pipεridme-l-carbonyl)-amino]-lH- bεnzoimidazol-5-yl ester (example 79, 20 mg) and 2-(aminometh3rl)-morpholine (50 mg) in tetrahydrofuran (1 ml) and N-methylpyrrolidinone (0.2 ml) was hεated at 95 °C for 22 hours. The reaction mixture was then evaporatεd and purified by triggered LC/MS to give 4-(4-hydroxy- piperidin-l-yl)-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)-ureido]-lH- benzoimidazol-5-yl ester as an off-white solid (7 mg). Mass spectrum : 545 [M+H] : ; retention time = 5.47 minutes.
Example 82 :
By using a method similar to that for the preparation of example 81, combining [examplε 80a-u] with suitablε amine was obtained the following compounds that werε characterized by analytical LC/MS ([M+H]+ and retention time given in the following table).
Retention
Example Precursor Masse
Amine Compound time (minutes) [M+H]+
4-(4-methyl-piperazin-1 - yl)-benzene sulfonic acid
82-a 80-a 2-[3-(2-morphoiin-4-yl- 5,12 544 ethyl)-ureido]-3H- benzimidazol-5-yl ester
4-(4-methyl-piperazin-1 - yl)-benzene sulfonic acid
82-b 80-a 2-(3-pyridin-2-ylmεthyi- 4,46 522 ureido)-3H-benzimidazol- 5-yl ester
4-(4-methyl-piperazin-1 - yl)-benzene sulfonic acid
82-c 80-a 2-[3-(2-methoxy-ethyl)- 5,86 489 ureido]-3H-benzimidazol- 5-yl ester
4-(4-hydroxy-piperidin-1- yl)-beπzene sulfonic acid
82-d 79 2-[3-(2-morpholin-4-yl- 5,47 545 ethyl)-ureidoJ-3H- beπzimidazo!-5-yl ester
4-(4-hydroxy-piperidin-1- yl)-beπzene sulfonic acid
82-e 79 2-(3-pyridin-2-ylmethyl- 6,4 523 ureido)-3H-benzimidazoI-
N 5-yl ester
4-(4-hydroxy-piperidin-1 - yl)-benzene sulfonic acid
82-f 79 2-[3-(2-methoxy-ethyl)- 7,05 490 ureido]-3H-beπzimida∑ol- 5-yl ester
Example 83 : Preparation of l-(6-hydroxy-lH-benzoimidazol-2-yl)-3-(2-methoxy- εthyl)-xιrea
A solution of (6-hydroxy-lH-bεrιzoimidazol-2-yl)-carbamic acid methyl ester (300 mg, example 61) and 2-memoxy-εthylaminε (630 μl) in N-me ylpyrrolidinone (8 ml) was heated at 90°C in a sealεd tube for 20 hours. The reaction mixture was poured into water (160 ml) and εxtractεd thrεε times with εthyl acεtatε (40 ml). The combined extracts were dried over magnesium sulfate and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of dichloromethanε and methanol (95 C:5 C, v/v) to l-(6-hydroxy-lH-bεnzoimidazol-2- yl)-3-(2-mεthoxy-ethyl)-urea as a yellow solid (180 mg). Mass spectrum : 251 [M+Hf ; retention time = 0.55 minutes.
Example 84(a) : Preparation of l-(6-hydroxy-lH-benzoimidazol-2-yl)-3-pyridin-2- ylmεthyl-urεa
By proceεding in a mannεr similar to example 83 above but using 2-(aminomethyl)- pyridine thεrε was prepared l-(6-hydroxy-lH-benzoimidazol-2-yl)-3pyridin-2- ylmεthyl-urεa as a bεigε solid. Mass spεctrum : 284 [M+ETf ; retention time = 0.55 minutes.
Example 84(b) : Preparation of l-(6-hydroxy-lH-benzoimidazol-2-yl)-3-(2- morpholin-4-yl-ethyl)-urεa
By proceeding in a manner similar to example 83 above but using 2-(aminoethyl)- morpholine there was prepared l-(6-hydroxy-lH-benzoimidazol-2-yl)-3-(2- morpholin-4-yl-ethyl)-urea as a beigε solid. Mass spectrum :306 [M+Hf ; rεtention timε = 1.02 minute.
Example 84(c) : Preparation of l-(6-hydroxy-lH-benzoimidazol-2-yl)-3-(εthyl)-urea
By proceεding in a mannεr similar to example 83 above but using 2-(aminoethyl)- morpholine there was preparεd l-(6-hydroxy-lH-bεnzoimidazol-2-yl)-3-(ethyl)-urea as a beigε solid. Mass spectrum : 367 [M+H]+ ; retention time = 1.36 minute.
Example 85 : Preparation of thiophene-2-sulfonic acid 2-[3-(2- ethyl)- ureido]-lH- bεnzoimidazol-5-yl ester
A stirred solution of l-8thyl-3-(6-hydroxy-lH-benzoimidazol-2-yl)-urea (35 mg, εxamplε 84-c) and thiophene-2-sulfonyl chloride (18 mg) in acetonε (3 ml) was treated with triethylamine (25 μl). After stirring at ambient temperature for 4 hours, the reaction mixture was evaporatεd. The residue was filtered and the fiitrat εvaporated. The residue was directly purified by LCMS triggered purification to give thiophene-2-sulfonic acid 2-[3-(2- εthyl)- urεido]-lH- bεnzoimidazol-5-yl εstεr (14 mg) as a off-white solid Mass spectrum : 367 [M+H]~ ; retεntion timε = 7.88 minutes.
Example 86 :
By using a method similar to that for the preparation of example 85, combining thiophene-2-sulfonyl chloride with suitable l-(6-hydroxy-lH-benzoimidazol-2-yl)- urεa (εxample 83, 84) were obtained the following compounds that were characterizεd by analytical LC/MS ([M+H]- and rεtεntion time given in thε following tablε).
Example 87 : Preparation of benzoic acid 4-{2-[3-(2-methoxy-εthyl)- ureido]-lH- benzoimidazol-5-yloxysulfonyl} -phenyl ester
A stirred solution of l-(6-hydroxy-lH-benzoimidazol-2-yl)-3-(2-methoxy-ethyl)-urea (31 mg, examplε 82) and benzoic acid 4-chlorosulfonyl-phenyl estεr (37 mg) in acetone (0.6 ml) was treatεd with triethylamine (33 μl). After stirring at ambient temperature for 4 hours, the reaction mixture was evaporatεd. Thε rεsiduε was filtered and the fϊltrat evaporated. Thε residue was directly purified by LCMS triggered purification to give benzoic acid 4-{2-[3-(2-methoxy-εthyl)- urεido]-lH- benzoimidazol-5-yloxysulfonyl}-phεnyl ester (7.2 mg) as a off-white solid Mass spectrum : 511 [M+Hf ; retention time = 9.90 minutes.
Example 88:
By using a method similar to that for the preparation of example 87, combining benzoic acid 4-chlorosulfonyl-phenyl ester with suitable l-(6-hydroxy-lH- benzoimidazol-2-yl)-urea (examplε 83,84) werε obtained the following compounds that were characterized by analytical LC/MS ([M+Hf and retεntion timε given in the following table).
Example 89 (a) Preparation of 2,6-difluoro-benzenesulfonic acid 2-(3-pyridin-2- ylmεthyl-urεido)-3H- bεnzoimidazol-5-yl εster
A stirred solution of l-(6-hydroxy-lH-benzoimidazol-2-yl)-3pyridin-2-ylmethyl-urea (50 mg, examplε 83-a) and 2,6-difluoro-bεnzene-sulfonyl chloridε (38 mg) in acεtone (1 ml) was treated with triemyla ine (48 μl). After stirring at ambient temperature for 4 hours, thε reaction mixture was evaporatεd. Thε rεsiduε was filtered and the filtrat evaporatεd. Thε rεsiduε was directly purifiεd by LC/MS triggεrεd purification to give benzoic acid 2,6-difluoro-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl- ureido)-3H-benzoimidazol-5-yl εster (mg) as a off-white solid Mass spectrum : 427 [M+Hf ; retention time = 7.86 minutes.
Example 89(b) : Preparation of 2,6-difluoro-benzenesulfonic acid 2-[3-(2-methoxy- ethyl)-ureido]-3H-bεnzoimidazol-5-yl ester
By proceeding in a manner similar to examplε 89(a) abovε but using l-(6-hydroxy- lH-benzoimidazol-2-yl)-3-(2-methoxy-εthyl)-urεa there was prepared 2,6-difluoro- bεnzenesulfonic acid 2-[3-(2-methoxy-ethyl)-ureido]-3H-benzoimidazol-5-yl ester as an off-white solid. Mass spectrum : 427[M+H]+ ; retεntion time = 7.86 minutes.
Biological tests
The experiments described in this report were designed to evaluate the cytotoxicity of "in vitro" Cdk4 inhibitors in comparison with Staurosporine, a non-specific Serine- Threonine kinase inhibitor.
Stock solutions of compounds werε made in DMSO at 10 mM and stored at -20°C. Subsequent dilutions werε made in 28 % DMSO and used to add 3 μl of the drugs at varied concentrations to the HeLa cells.
All cell lines wεrε cultured at 37°C in a humidified atmosphεrε containing 5 % CO2- HεLa human epithelial cell line was obtained from the Amεrican Typε Culturε Collection (Rockville, MD, USA). Cells were grown as monolayers in Dubεlcco's Modified Eagle Medium containing 2 mM L-glutamine, 200 LUJml pεnicillin, 200 μg/ml streptomycin, and supplemεnted with 10 % (v/v) heat inactivated foetal calf serum. Cells were transferred twice a week at 105 cells/ml in 75 cm2 flasks after trypsinisation. Different flasks werε done to prεparε two preparations the day of experiment.
Cell growth inhibition
Cells in exponential phase of growth were trypsinisεd and resuspended in their culturε medium at 2.5 104 cells/ml, in two independεnt preparations. Cell suspension was distributed in 96 well Cytostar microplatεs (Amεrsham) (0.2 ml/wεll,
5000 cells). Hela cells were coated for 4 hours at 37°C. [I4C]-thymidine (O.lμCi/wεll) and ten final concentrations of molecules (3 μl) ranging from 20 to 0.03 μM were then added. The uptake of [KC]-thymidine was measured 48h after the labelling had been started using a Microbeta Trilux counter (Wallac).
Staurosporine, the reference compound, was εvaluatεd using the same procedure. CPM measured 48 hours after the test substance had been added to the media, were compared to those obtained with 0.4 % final DMSO, in thε control wells.
IC50, obtained from a dose response curve of 10 concentrations in duplicate is the concentration of drug wich diminishes half the specific signal. It is detεrmined by non-linear regression analysis and calculated as a concentration at middle of curve. IC5o values result from 2 independent experiments for all tested molecules.
CDK4/CyclinDl Flashplate Assay: 96-well format
This is a CDK4/CyclinDl kinase assay in a 96-well Streptavidin-coatεd Flashplate with a biotinylated-Rb peptide substrate.
Each point is tested in duplicate Biotinylated-Rb: Biotin-RPPTLSPIPHIPRSPYKFPSSPLR
Kinase Buffer:
HEPES, pH 8 50 mM
MgCl2 6H2O, pH 7 10 mM
DTT 1 mM 1. Prepare substrate: 1 mg/ml solution made fresh in PBS.
2. Add 100 μg per well to the Flashplate.
3. Incubate for 2 hours at RT.
4. From 10 mM inhibitor stocks in DMSO, make 1 mM, 300 μM, 100 μM, 30 μM and 10 μM series of dilution in DMSO. 5. Wash the Flashplate 3 times with 300 μl PBS to remove unbound peptide substrate.
6. Add the CDK4/CyclinDl kinase: 70 ng per well, in a volume of 90 μl in kinase buffer (except for "no enzyme" control wells). 7. Add 1 μl per well of inhibitor to test 10 μM, 3 μM. 1 μM, 0.3 μM and 0.1 μM in final concentration per 100 μl in each well.
8. Shakε gεntly thε Flashplate 1 minute.
9. Incubate 30 minutes on wet ice. 10. Initiate the reaction with 10 μl kinase buffer containing 1 μM final cold ATP and 1 μCi final 33P-ATP per well.
11. Shake gεntly thε Flashplatε 1 minute.
12. Incubate 45 minutes at RT (no shaking).
13. Wash the Flashplate 3 timεs with 300 μl PBS 14. Count to dεtect the incorporation of '"P-ATP by the kinase to the Rb phosphorylation site.
CDK2/CyclinE Fias plate Assay: 96-well format
This is a CDK-2/CyclinE kinasε assay in a 96-wεll Strεptavidin-coatεd Flashplate with a biotinylated-Rb pεptidε substratε.
Each point is tested in duplicate
Biotmylated-Rb: Biotin-SACPLNLPLQr HTAADMYLSPVRSPKKKGSTTR-OH Kinasε Buffer:
HEPES, pH 8.0 50 mM
MgCl2 6H2O 10 mM
DTT l mM
1. Prεparε substrate: 1 mg/ml solution made fresh in PBS.
2. Add 4 μg per well to the Flashplate.
3. Incubate for 2 hours at RT.
4. From 10 mM inhibitor stocks in DMSO, make 1 mM, 300 μM, 100 μM, 30 μM and 10 μM series of dilution in DMSO.
5. Wash the Flashplate 3 times with 300 μl PBS to remove unbound peptide substrate.
6. Add the CDK2/CyclinE kinase: 200 ng per well, in a volume of 90 μl in kinase buffer (excεpt for "no enzyme" control wells). 7. Add 1 μl per well of inhibitor to test 10 μM, 3 μM, 1 μM, 0.3 μM and 0.1 μM in final concentration per 100 μl in each well.
8. Shake gently the Flashplate 1 minute.
9. Incubate 30 minutes on wet ice.
10. Initiate the reaction with 10 μl kinase buffer containing 1 μM final coid ATP and 1 μCi final 33P-ATP per well.
11. Shake gently the Flashplate 1 minute.
12. Incubate 45 minutes at RT (no shaking).
13. Wash the Flashplate 3 times with 300 μl PBS
14. Count to detect the incorporation of 33P-ATP by the kinase to the Rb phosphorylation site.
142

Claims (1)

  1. 1 - Compounds of formula (I)
    • wherein A is an aryl or heteroaryl entity • wherein Rj is selected from one or more similar groups selected from:
    - alkyl, εvεntually substituted by an alkoxy, hetεroalkyl, aryl, acyl, acyl derivatives, halogen
    -alkoxy eventually substituted by an alkyl, heteroalkyl, aryl, hetεroaryl, alkoxyalkyl, hydroxyalkyl amidε or a pεrfluoroalkoxy group or an alkylthio eventually substituted by an amide or a perfluoroalkylthio
    - aryl or hetεroaryl εvεntually substituted by onε or more alkyl group, alkoxy group, nitro group, cyano group, acyl derivative, perfluoroalkoxy group, perfluoroalkyl group, hεtεroaryl group, aryloxy group
    - halogεn
    .4 H2
    - 4 H alkyl or cycloalkyl eventually substituted with an an acyl, an acyldεrivativε, an hydroxy, an amino, alkoxy, hεtεrocyclyl or aryl group
    - 4 N imidazolyl
    - 3 SO Mε whεn A is phenyl
    ■ wherein R2 is selected from the group consisting of - CO-alkyl eventually substituted by amino, acid, acid derivative, alkoxy, aryl or OH groups
    - CO-aralkyl εvεntually substituted by alkoxy, halogeno, amino, acid or acid derivatives - CO-aryl εvεntually substituted
    - CO-alkoxy evεntually substitutεd by aryl
    - CO-amino, CO-NHR3, CO-N sR^ whεrεin R3 and R are selεctεd indεpεndtly from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, fluoroalkyl, alcynyl, heteroalkyl, alkylhetero alkyl, aryl, aralkyl or togεthεr form an alkylεn chain including εvεntually onε to 4 heteroatoms
    - aryl or aralkyl evεntually substitutεd by hεterocycloalkyl, alkyl, aryl, alkoxy, amino, fluroroalkyl, acyl derivatives, halogen or a pharmaceutically acceptablε salt or a prodrug.
    2 - Compounds according to claim 1 whεrεin A is sεlεctεd from phεnyl, thiophεn, isoxazolε, oxazolε, pyrazolε, furane, pyridine.
    3 - Compounds according to claim 2 wherein A is phenyl.
    4 - Compounds according to claim 1 wherein the aryl, aralkyl, heteroaryl or heteroarylalkyl groups are eventually substitutεd with one or more similar or different groups sεlectεd from halogεn, alkoxy, alkyl, hydroxyalkyl, allQ thio, amino, mono or dialkylamino, heterocyclylamino, arylamino, hetεroarylamino, hεtεroaryl, nitro, heterocycloalkyl, perfluoroalkyl, perfluroro alkoxy, pεrfluoroalkylthio, acyl derivatives. 5 - Compounds according to claim 1 wherein the alkyl or alkylεnε substituεnts are substituted with one or more amino, aminoalkyl, aminoalkylamino, hydroxy, alkoxy, hydroxyalkoxy, acyl, acyl derivatives, alkyl, heteroalkyl, arylalkyl, arylamino, aryloxy, or aryl groups.
    6 — Compounds according to claim 1 wherein the alkoxy or alkylthio substituents are substituted with one or more amino, acyl, acyl derivatives, alkyl, arylalkyl or aryl groups.
    7 - Compounds according to claim 1 wherein the acyl groups or acyl derivatives groups include carboxylic acids and sulfonic acids or derivativεs.
    8 — Compounds according to claim 5 wherein the acid derivatives include alkyl esters and carbamoyl estεrs
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