Substituted benzimidazole compounds and their use for the treatment of cancer

BACKGROUND OF THE INVENTION

1. Field of the Invention

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.

2. Description of the Art

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 substrate phosphorylation and ultimately cell division. In addition, endogenous inhibitors of CDKs (INK4 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 functions in G1 phase of the cell cycle and is activated by D-type 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 functions as a major checkpoint control in regulation of the G1/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 p16, 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 p16 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 literature << Cyclin E activates Cdk2 which acts to phosphorylate pRb resulting in an irreversible commitment to cell division and transition into S-phase >> (P. L. Toogood, Medicinal Research Reviews (2001), 21(6); 487-498. and << CDK2 (and possibly CDK3) is required for G1 progression and entry into S phase. In complex with cyclin E, it sustains pRb hyperphosphrylation to support progression through G1 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. >> T. D. 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 than flavopiridol.

It is known following publication of WO00/41669 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 specifically to sulfonesters derivatives of those carbamates.

SUMMARY OF THE INVENTION

In one embodiment of the present invention are disclosed compounds of formula (I)
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- wherein A is an aryl or heteroaryl entity
- wherein R₁is 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 acyl derivative, an hydroxy, an amino, alkoxy, heterocyclyl or aryl group
  - 4 N imidazolyl
  - 3 SO₂Me 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—NR₃R₄wherein R₃and R₄are selected independently from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, fluoroalkyl, alkynyl, 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 preferred compounds of formula (I) are those where A represents a phenyl, thiophene, isoxazole, oxazole, pyrazole, furan, or pyridine, and more preferably those where A is a phenyl group.

Among the preferred compounds of formula (I) are those wherein the aryl, aralkyl, heteroaryl or heteroarylalkyl are optionally substituted with one or more similar or different groups selected from halogen, alkoxy, alkyl, hydroxyalkyl, alkylthio, amino, mono or dialkylamino, heterocyclylamino, arylamino, heteroarylamino, heteroaryl, nitro, heterocycloalkyl, perfluoroalkyl, perfluroroalkoxy, perfluoroalkylthio, acyl derivatives.

Among the preferred compounds of formula (I) are those wherein R₂is an aminocarbonyl group substituted by a substituent selected from monoalkylamino or a monoarylamino substituent In the preferred compounds of formula (I) are those containing for R₂an 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, branched or cyclic chain containing 1 to 10 carbon atoms. The alkoxy chain of the present invention includes linear, branched or cyclic chains containing 1 to 4 carbon atoms. The aryl groups include phenyl or naphthyl groups, heteroaryl groups containing one to four heteroatoms selected 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 the preferred compounds are those containing an alkyl chain 1 to 10 carbon atoms and those containing acycloalkyl 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:

Methyl-5-(4-[2-hydroxyethyl]aminophenylsulfonyloxy)benzimidazole-2-carbamate
Methyl-5-(4-[4-hydroxbutyl]aminophenylsulfonyloxy)benzimidazole-2-carbamate
Methyl-5-(4-[2-methoxyethyl]aminophenylsulfonyloxy)benzimidazole-2-carbamate
Methyl-5-(4-[1-imidazolyl]-phenylsulfonyloxy)benzimidazole-2-carbamate
Methyl-5-(4-[2-pyridylmethyl]aminophenylsulfonyloxy)benzimidazole-2-carbamate
Methyl-5-(4-ethylaminophenylsulfonyloxy)benzimidazole-2-carbamate
Methyl-5-(4-[N-glycinyl]-phenylsulfonyloxy)benzimidazole-2-carbamate
Methyl-5-(4-[1-methyl,2-hydroxyethyl]aminophenylsulfonyloxy)benzimidazole-2-carbamate
Methyl-5-(4-[2-methyl,2-hydroxyethyl]aminophenylsulfonyloxy)benzimidazole-2-carbamate
Methyl-5-(4-isopropylaminophenylsulfonyloxy)benzimidazole-2-carbamate
Methyl-5-(4-[1-ethyl 2-hydroxyethyl]aminophenyl sulfonyloxy)benzimidazole-2-carbamate
Methyl-5-(4-butylaminophenylsulfonyloxy)benzimidazole-2-carbamate
Methyl-5-(4-[3-methoxypropyl]aminophenylsulfonyloxy)benzimidazole-2-carbamate
Methyl-5-(4-methylaminophenylsulfonyloxy)benzimidazole-2-carbamate
Methyl-5-(4-[2-sulfonylethyl]aminophenylsulfonyloxy)benzimidazole-2-carbamate
Methyl-5-(4-aminophenylsulfonyloxy)benzimidazole-2-carbamate
Methyl-5-(4-[2-diethylaminoethyl]aminophenylsulfonyloxy)benzimidazole-2-carbamate
Methyl-5-(4-[1-tetrathydrofurylmethyl]aminophenylsulfonyloxy)benzimidazole-2-carbamate
Methyl-5-(4-cyclopentylaminophenylsulfonyloxy)benzimidazole-2-carbamate
Methyl-5-(4-[2-phenylethyl]aminophenylsulfonyloxy)benzimidazole-2-carbamate
N-[5-(4-[imidazolyl]-phenylsulfonyloxy)-1H-benzimidazole-2-yl]-methylurea
N-[5-(4-cyclopentylaminophenylsulfonyloxy)-1H-benzimidazole-2-yl]-methylurea
N-[5-(4-cyclopentylaminophenylsulfonyloxy)-1H-benzimidazole-2-yl]-dimethylurea
4-Imidazol-1-yl-benzenesulfonic acid 2-benzoylamino-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-phenylacetylamino-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-(2-tert-butoxycarbonylamino-acetylamino)-1H-benzoimidazol-5-yl ester
N-[5-(4-Imidazol-1-yl-benzenesulfonyloxy)-1H-benzoimidazol-2-yl]-succinamic acid methyl ester
4-[5-(4-Imidazol-1-yl-benzenesulfonyloxy)-1H-benzoimidazol-2-ylcarbamoyl]-butyric acid methyl ester
4-[5-(4-Imidazol-1-yl-benzenesulfonyloxy)-1H-benzoimidazol-2-ylcarbamoyl]-butyric acid methyl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-(cyclohexanecarbonyl-amino)-1H-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]-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-[(pyridine-4-carbonyl)-amino]-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-pentanoylamino-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-hexanoylamino-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-(2-cyclopropyl-acetylamino)-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-(2-cyclohexyl-acetylamino)-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-(2-methoxy-acetylamino)-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-(2-dimethylamino-acetylamino)-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-benzoylamino-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-phenylacetylamino-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(2-tert-butoxycarbonylamino-acetylamino)-1H-benzoimidazol-5-yl ester
N-[5-(4-Cyclopentylamino-benzenesulfonyloxy)-1H-benzoimidazol-2-yl]-succinamic acid methyl ester
4-[5-(4-Cyclopentylamino-benzenesulfonyloxy)-1H-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)-1H-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]-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[(pyridine-4-carbonyl)-amino]-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-pentanoylamino-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-hexanoylamino-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(2-cyclopropyl-acetylamino)-1H-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)-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(2-dimethylamino-acetylamino)-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-(3-cyclopropyl-ureido)-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(3-cyclopropyl-ureido)-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-(3-isopropyl-ureido)-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(3-isopropyl-ureido)-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-(3-butyl-ureido)-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(3-butyl-ureido)-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-[3-(2-fluoro-phenyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(2-fluoro-phenyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-[3-(2-methoxy-phenyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(2-methoxy-phenyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-[3-(3-methoxy-phenyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(3-methoxy-phenyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-[3-(4-methoxy-phenyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(4-methoxy-phenyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-[3-(2-chloro-phenyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(2-chloro-phenyl)-ureido]-1H-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]-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-[3-(2-methoxy-benzyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(2-methoxy-benzyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(3-fluoro-benzyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-[3-(3-chloro-phenyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(3-chloro-phenyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-(3-isobutyl-ureido)-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(3-isobutyl-ureido)-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-[3-(2-dimethylamino-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(2-dimethylamino-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-(3-ethyl-ureido)-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(3-ethyl-ureido)-1H-benzoimidazol-5-yl ester
{3-[5-(4-Cyclopentylamino-benzenesulfonyloxy)-1H-benzoimidazol-2-yl]-ureido}-acetic acid
4-Imidazol-1-yl-benzenesulfonic acid 2-[3-(2-sulfo-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-[3-(2-methoxy-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(2-methoxy-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-[3-(4-dimethylamino-phenyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(4-dimethylamino-phenyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-(3-pyridin-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-1-yl-benzenesulfonic acid 2-(3-cyclobutyl-ureido)-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(3-cyclobutyl-ureido)-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-(3-pyridin-4-ylmethyl-ureido)-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(3-pyridin-4-ylmethyl-ureido)-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-(3-tert-butyl-ureido)-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(3-tert-butyl-ureido)-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-(3-phenyl-ureido)-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(3-phenyl-ureido)-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-(3-cyclohexyl-ureido)-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(3-cyclohexyl-ureido)-1H-benzoimidazol-5-yl ester;
4-Imidazol-1-yl-benzenesulfonic acid 2-(3-cyclopentyl-ureido)-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-[3-(3-fluoro-phenyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(3-fluoro-phenyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(2-hydroxy-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-[3-(2-hydroxy-ethyl)-ureido]-1H-benzoimidazol-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]-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-[3-(2-chloro-benzyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(2-chloro-benzyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-[3-(2-fluoro-benzyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(2-fluoro-benzyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-[(azetidine-1-carbonyl)-amino]-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[(azetidine-1-carbonyl)-amino]-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-(3-pyridin-3-ylmethyl-ureido)-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(3-pyridin-3-ylmethyl-ureido)-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-(3-benzyl-ureido)-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(3-benzyl-ureido)-1H-benzoimidazol-5-yl ester
4-{3-[5-(4-Cyclopentylamino-benzenesulfonyloxy)-1H-benzoimidazol-2-yl]-ureido}-butyric acid methyl ester;
4-{3-[5-(4-Cyclopentylamino-benzenesulfonyloxy)-1H-benzoimidazol-2-yl]-ureido}-butyric acid ethyl ester
4-{3-[5-(4-Cyclopentylamino-benzenesulfonyloxy)-1H-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
1-[5-(4-Cyclopentylamino-benzenesulfonyloxy)-1H-benzoimidazol-2S-ylcarbamoyl]-pyrrolidine-2-carboxylic acid
1-[5-(4-Cyclopentylamino-benzenesulfonyloxy)-1H-benzoimidazol-2S-ylcarbamoyl]-pyrrolidine-2-carboxylic acid methyl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(3-carbamoylmethyl-ureido)-1H-benzoimidazol-5-yl ester
1-[5-(4-Cyclopentylamino-benzenesulfonyloxy)-1H-benzoimidazol-2-ylcarbamoyl]-piperidine-4-carboxylic acid ethyl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(3-piperidin-4-ylmethyl-ureido)-1H-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]-1H-benzoimidazol-5-yl ester;
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(4-hydroxy-cyclohexyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(3-hydroxy-propyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(1,1-dimethyl-propyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-{3-[2-(2-hydroxy-ethylamino)-ethyl]-ureido}-1H-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}-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(2-carbamoyl-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[(2S-carbamoyl-pyrrolidine-1-carbonyl)-amino]-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-{3-[2-(2-hydroxy-ethoxy)-ethyl]-ureido}-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(3-pyrrolidin-1-yl-propyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(1-ethyl-pyrrolidin-2-ylmethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(2-pyrrolidin-1-yl-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(2-piperidin-1-yl-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(2-hydroxy-1-methyl-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(2-isopropylamino-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(2-diethylamino-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
2-{3-[5-(4-Cyclopentylamino-benzenesulfonyloxy)-1H-benzoimidazol-2-yl]-ureido}-3S-hydroxy-propionic acid methyl ester
4-{3-[5-(4-Imidazol-1-yl-benzenesulfonyloxy)-1H-benzoimidazol-2-yl]-ureido}-butyric acid methyl ester
4-{3-[5-(4-Imidazol-1-yl-benzenesulfonyloxy)-1H-benzoimidazol-2-yl]-ureido}-butyric acid ethyl ester
{3-[5-(4-Imidazol-1-yl-benzenesulfonyloxy)-1H-benzoimidazol-2-yl]-ureido}-acetic acid methyl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-[3-(3-imidazol-1-yl-propyl)-ureido]-1H-benzoimidazol-5-yl ester
1-[5-(4-Imidazol-1-yl-benzenesulfonyloxy)-1H-benzoimidazol-2-ylcarbamoyl]-pyrrolidine-2-carboxylic acid
1-[5-(4-Imidazol-1-yl-benzenesulfonyloxy)-1H-benzoimidazol-2-ylcarbamoyl]-pyrrolidine-2-carboxylic acid methyl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-(3-carbamoylmethyl-ureido)-1H-benzoimidazol-5-yl ester
1-[5-(4-Imidazol-1-yl-benzenesulfonyloxy)-1H-benzoimidazol-2-ylcarbamoyl]-piperidine-4-carboxylic acid ethyl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-(3-piperidin-4-ylmethyl-ureido)-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)-ureido]-1H-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-1-yl-benzenesulfonic acid 2-[3-(3-hydroxy-propyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-[3-(1,1-dimethyl-propyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-{3-[2-(2-hydroxy-ethylamino)-ethyl]-ureido}-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-[3-(4-hydroxy-butyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-{3-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-ureido}-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-[3-(2-carbamoyl-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-[3-(1,1-dimethyl-propyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-[(2-carbamoyl-pyrrolidine-1-carbonyl)-amino]-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-{3-[2-(2-hydroxy-ethoxy)-ethyl]-ureido}-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-[3-(3-pyrrolidin-1-yl-propyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-[3-(1-ethyl-pyrrolidin-2-ylmethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-[3-(2-pyrrolidin-1-yl-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-[3-(2-piperidin-1-yl-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-[3-(2-hydroxy-1-methyl-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-[3-(2-isopropylamino-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Imidazol-1-yl-benzenesulfonic acid 2-[3-(2-diethylamino-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
2-{3-[5-(4-Imidazol-1-yl-benzenesulfonyloxy)-1H-benzoimidazol-2-yl]-ureido}-3-hydroxy-propionic acid methyl ester
4-[(Tetrahydro-furan-2-ylmethyl)-amino]-benzenesulfonic acid 2-(3-carbamoylmethyl-ureido)-1H-benzoimidazol-5-yl ester
4-[(Tetrahydro-furan-2-ylmethyl)-amino]-benzenesulfonic acid 2-[3-(2-hydroxy-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-[(Tetrahydro-furan-2-ylmethyl)-amino]-benzenesulfonic acid 2-[3-(3-hydroxy-propyl)-ureido]-1H-benzoimidazol-5-yl ester
4-[(Tetrahydro-furan-2-ylmethyl)-amino]-benzenesulfonic acid 2-[3-(4-hydroxy-butyl)-ureido]-1H-benzoimidazol-5-yl ester
4-[(Tetrahydro-furan-2-ylmethyl)-amino]-benzenesulfonic acid 2-[3-(2-methoxy-1-methyl-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-[(Tetrahydro-furan-2-ylmethyl)-amino]-benzenesulfonic acid 2-[3-(1-ethyl-pyrrolidin-2-ylmethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-[(Tetrahydro-furan-2-ylmethyl)-amino]-benzenesulfonic acid 2-[3-(2-pyrrolidin-1-yl-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-[(Tetrahydro-furan-2-ylmethyl)-amino]-benzenesulfonic acid 2-[3-(3-pyrrolidin-1-yl-propyl)-ureido]-1H-benzoimidazol-5-yl ester
4-[(Tetrahydro-furan-2-ylmethyl)-amino]-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-[(Tetrahydro-furan-2-ylmethyl)-amino]-benzenesulfonic acid 2-(3-ethyl-ureido) 1H-benzoimidazol-5-yl ester
4-[(Tetrahydro-furan-2-ylmethyl)-amino]-benzenesulfonic acid 2-(3-methyl-ureido)-1H-benzoimidazol-5-yl ester
4-[(Tetrahydro-furan-2-ylmethyl)-amino]-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl-ureido)-1H-benzoimidazol-5-yl ester
4-[(Tetrahydro-furan-2-ylmethyl)-amino]-benzenesulfonic acid 2-(3-pyridin-3-ylmethyl-ureido)-1H-benzoimidazol-5-yl ester
4-[(Tetrahydro-furan-2-ylmethyl)-amino]-benzenesulfonic acid 2-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-1H-benzoimidazol-5-yl ester
4-[(Tetrahydro-furan-2-ylmethyl)-amino]-benzenesulfonic acid 2-[3-(2-sulfo-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-[(Tetrahydro-furan-2-ylmethyl)-amino]-benzenesulfonic acid 2-(3-cyclobutyl-ureido)-1H-benzoimidazol-5-yl ester
4-[(Tetrahydro-furan-2-ylmethyl)-amino]-benzenesulfonic acid 2-{3-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-ureido}-1H-benzoimidazol-5-yl ester
4-[(Tetrahydro-furan-2-ylmethyl)-amino]-benzenesulfonic acid 2-{3-[2-(2-hydroxy-ethylamino)-ethyl]-ureido}-1H-benzoimidazol-5-yl ester
4-[(Tetrahydro-furan-2-ylmethyl)-amino]-benzenesulfonic acid 2-[3-(2-piperidin-1-yl-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Benzylamino-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-Methylamino-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2-Hydroxy-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(3-Hydroxy-propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(4-Hydroxy-butylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2-Methoxy-1-methyl-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2-Pyrrolidin-1-yl-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(1-Hydroxymethyl-propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2-Hydroxy-1-methyl-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2-Piperidin-1-yl-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(3-Pyrrolidin-1-yl-propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(3-Hydroxy-2,2-dimethyl-propylamino)-benzenesulfonic acid 2-(cyclopropane-carbonyl-amino)-1H-benzoimidazol-5-yl ester
4-[(Pyridin-3-ylmethyl)-amino]-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-[3-(4-Methyl-piperazin-1-yl)-propylamino]-benzenesulfonic acid 2-(cyclopropane-carbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2-Methoxy-benzylamino)benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(4-Hydroxy-cyclohexylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2-Diethylamino-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(1S-Hydroxymethyl-propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2-Ethylamino-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2-Diisopropylamino-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2-Morpholin-4-yl-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(1-Aza-bicyclo[2.2.2]oct-3-ylamino)-benzenesulfonic acid 2-(cyclopropane-carbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2-Phenylamino-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(1-Benzyl-pyrrolidin-3-ylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2R-Carbamoyl-pyrrolidin-1-yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(3-Dimethylamino-propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2-piperazin-1-yl-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2-Carbamoyl-cyclohexylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2-Acetylamino-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-[2-(2-Amino-ethylamino)-ethylamino]-benzenesulfonic acid 2-(cyclopropane-carbonyl-amino)-1H-benzoimidazol-5-yl ester
4-[3-(2-Oxo-pyrrolidin-1-yl)-propylamino]-benzenesulfonic acid 2-(cyclopropane-carbonyl-amino)-1H-benzoimidazol-5-yl ester
4-[2-(1H-Imidazol-4-yl)-ethylamino]-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-[(Pyridin-2-ylmethyl)-amino]-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-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)-1H-benzoimidazol-5-yl ester
4-(2,3-Dihydroxy-propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2-Imidazol-1-yl-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-[2-(2-Hydroxy-ethylamino)-ethylamino]-benzenesulfonic acid 2-(cyclopropane-carbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2-Methoxy-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2-Dimethylamino-1-methyl-ethylamino)-benzenesulfonic acid 2-(cyclopropane-carbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(Pyrrolidin-3-ylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-[2-(1H-Indol-3-yl)-ethylamino]-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2-Dimethylamino-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2-Phenoxy-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(Bicyclo[2.2.1]hept-2-ylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2-Methylamino-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2-Propylamino-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(1-Methyl-2-phenoxy-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-[(Piperidin-4-ylmethyl)-amino]-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(4-Methoxy-benzylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(1H-Benzoimidazol-5-ylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(3-Methoxy-propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2,2-Dimethoxy-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(4-Dimethylamino-phenylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(3-Methoxy-benzylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(4-Pyrrolidin-1-yl-butylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2,3-Dimethoxy-benzylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-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)-1H-benzoimidazol-5-yl ester
4-[(Pyridin-4-ylmethyl)-amino]-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-[2-(Ethyl-m-tolyl-amino)-ethylamino]-benzenesulfonic acid 2-(cyclopropane-carbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2-Hydroxy-cyclohexylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(3-Dimethylamino-2,2-dimethyl-propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-[3-(2-Hydroxy-ethylamino)-propylamino]-benzenesulfonic acid 2-(cyclopropane-carbonyl-amino)-1H-benzoimidazol-5-yl ester
4-[(Tetrahydro-furan-2-ylmethyl)-amino]-benzenesulfonic acid 2-(cyclopropane-carbonyl-amino)-1H-benzoimidazol-5-yl ester
4-[(Tetrahydro-furan-2R-ylmethyl)-amino]-benzenesulfonic acid 2-(cyclopropane-carbonyl-amino)-1H-benzoimidazol-5-yl ester
4-[(Tetrahydro-furan-2S-ylmethyl)-amino]-benzenesulfonic acid 2-(cyclopropane-carbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2-Butylamino-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(3-Methylamino-propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(1S,2-Dicarbamoyl-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
2-{4-[2-(Cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yloxysulfonyl]-phenylamino}-3R-hydroxy-propionic acid methyl ester
4-(2-Carbamoyl-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(3-Methoxy-propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(3,4,5-Trimethoxy-benzylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(Carbamoylmethyl-amino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
1-{4-[2-(Cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yloxysulfonyl]-phenyl}-piperidine-4-carboxylic acid ethyl ester
4-(2-Amino-2-methyl-propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
3-{4-[2-(Cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yloxysulfonyl]-phenylamino}-propionic acid methyl ester
4-(3-Morpholin-4-yl-propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(5-Hydroxy-pentylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-[(5S-Amino-2,2,4S-trimethyl-cyclopentylmethyl)-amino]-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2-Hydroxymethyl-phenylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(4-Ethoxy-phenylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-Ethylamino-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2-Sulfo-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-{4-[2-(Cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yloxysulfonyl]-phenylamino}-piperidine-1-carboxylic acid ethyl ester
4-({4-[2-(Cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yloxysulfonyl]-phenylamino}-methyl)-benzoic acid
4-[(1-Carbamimidoyl-piperidin-4-ylmethyl)-amino]-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-{4-[2-(Cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yloxysulfonyl]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester
3-{4-[2-(Cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yloxysulfonyl]-phenylamino}-3-phenyl-propionic acid
4-Piperidin-1-yl-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(1-Methyl-4-oxo-imidazolidin-2-ylideneamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(4-Methyl-piperazin-1-yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(3-Hydroxy-pyrrolidin-1-yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(Cyclopropylmethyl-amino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-[(2-Dimethylamino-ethyl)-methyl-amino]-benzenesulfonic acid 2-(cyclopropane-carbonyl-amino)-1H-benzoimidazol-5-yl ester
4-Isobutylamino-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-[Ethyl-(2-hydroxy-ethyl)-amino]-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2-Hydroxy-1-hydroxymethyl-ethylamino)-benzenesulfonic acid 2-(cyclopropane-carbonyl-amino)-1H-benzoimidazol-5-yl ester
4-Propylamino-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-Cyclopropylamino-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-Morpholin-4-yl-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-[2-(1-Methyl-pyrrolidin-2-yl)-ethylamino]-benzenesulfonic acid 2-(cyclopropane-carbonyl-amino)-1H-benzoimidazol-5-yl ester
4-[(1,3-Dimethyl-1H-pyrazol-4-ylmethyl)-amino]-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(4-Acetylamino-benzylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(3-Cyclohexylamino-propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(3-Ethoxy-propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-Pyrrolidin-1-yl-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(4-Methyl-benzylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-[1,4′]Bipiperidinyl-1′-yl-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2-Pyridin-3-yl-pyrrolidin-1-yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(4-Hydroxy-piperidin-1-yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-[(2-Hydroxy-ethyl)-methyl-amino]-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-[(1-Ethyl-pyrrolidin-2-ylmethyl)-amino]-benzenesulfonic acid 2-(cyclopropane-carbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(3-Hydroxy-pyridin-2-ylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-[(1-Carbamoyl-piperidin-4-ylmethyl)-amino]-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2-Pyrrol-1-yl-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(4-Cyclopentyl-piperazin-1-yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2-Propoxy-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(3-Cyclohexylamino-propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(1H-Indol-5-ylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(4-Amino-benzylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2S-Methoxymethyl-pyrrolidin-1-yl)-benzenesulfonic acid 2-(cyclopropane-carbonyl-amino)-1H-benzoimidazol-5-yl ester
4-[4-(2-Hydroxy-ethyl)-piperidin-1-yl]-benzenesulfonic acid 2-(cyclopropane-carbonyl-amino)-1H-benzoimidazol-5-yl ester
4-[2-(2-Hydroxy-ethyl)-piperidin-1-yl]-benzenesulfonic acid 2-(cyclopropane-carbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2-Isopropylamino-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
3-{4-[2-(Cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yloxysulfonyl]-phenylamino}-propionic acid
4-[Methyl-(2-methylamino-ethyl)-amino]-benzenesulfonic acid 2-(cyclopropane-carbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(3-Acetylamino-pyrrolidin-1-yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(Carbamoylmethyl-amino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(4-Hydroxy-piperidin-1-yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(4-Dimethylamino-benzylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(3-Imidazol-1-yl-propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(Quinoxalin-5-ylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-benzenesulfonic acid 2-(cyclopropane-carbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2-Hydroxy-1,1-dimethyl-ethylamino)-benzenesulfonic acid 2-(cyclopropane-carbonyl-amino)-1H-benzoimidazol-5-yl ester
1-{4-[2-(Cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yloxysulfonyl]-phenyl}-piperidine-4-carboxylic acid
6-{4-[2-(Cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yloxysulfonyl]-phenylamino}-hexanoic acid methyl ester
4-[4-(4-Methoxy-phenyl)-piperazin-1-yl]-benzenesulfonic acid 2-(cyclopropane-carbonyl-amino)-1H-benzoimidazol-5-yl ester
4-[4-(2-Methoxy-ethyl)-piperazin-1-yl]-benzenesulfonic acid 2-(cyclopropane-carbonyl-amino)-1H-benzoimidazol-5-yl ester
4-[(2-Hydroxy-ethyl)-phenyl-amino]-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-[(Furan-2-ylmethyl)-amino]-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
1-{4-[2-(Cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yloxysulfonyl]-phenyl}-aziridine-2-carboxylic acid methyl ester
4-(4-Carbamoyl-piperidin-1-yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(3-Methyl-piperazin-1-yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2,6-Dimethyl-morpholin-4-yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(4-Phenyl-piperazin-1-yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(4-Pyridin-2-yl-piperazin-1-yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(4-Diethylamino-1-methyl-butylamino)-benzenesulfonic acid 2-(cyclopropane-carbonyl-amino)-1H-benzoimidazol-5-yl ester
4-{4-[2-(Cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yloxysulfonyl]-phenyl}-piperazine-1-carboxylic acid ethyl ester
4-(5-Hydroxy-naphthalen-1-ylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-[2-(4-Hydroxy-3-methoxy-phenyl)-ethylamino]-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(9H-Purin-6-ylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
1-{4-[2-(Cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yloxysulfonyl]-phenyl}-piperidine-3-carboxylic acid
4-(3,3-Dimethyl-piperidin-1-yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(4-Methyl-piperidin-1-yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2-Pyridin-2-yl-ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(3-Hydroxymethyl-phenylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2-Oxo-2,3-dihydro-1H-pyrimidin-4-ylideneamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(3-Piperidin-1-yl-propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-[2-(1H-Indol-3-yl)-ethylamino]-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(5-Carbamoyl-1H-imidazol-4-ylamino)-benzenesulfonic acid 2-(cyclopropane-carbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(1-Hydroxymethyl-butylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(1-Benzyl-piperidin-4-ylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-{4-[2-(2-Hydroxy-ethoxy)-ethyl]-piperazin-1-yl}-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(4-Methyl-[1,4]diazepan-1-yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(3-Azepan-1-yl-propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2,6-cis-Dimethyl-morpholin-4-yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-(2S-Hydroxymethyl-pyrrolidin-1-yl)-benzenesulfonic acid 2-(cyclopropane-carbonyl-amino)-1H-benzoimidazol-5-yl ester
4-[4-(3-Pyrrolidin-1-yl-propyl)-[1,4]diazepan-1-yl]-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester
4-trifluoromethoxy-benzenesulfonic acid 2-methoxycarbonylamino-1H-benzoimidazol-5-yl ester
3,5-Dimethyl-isoxazole-4-sulfonic acid 2-methoxycarbonylamino-1H-benzoimidazol-5-yl ester
Thiophene-2-sulfonic acid 2-methoxycarbonylamino-1H-benzoimidazol-5-yl ester
5-Isoxazol-3-yl-thiophene-2-sulfonic acid 2-methoxycarbonylamino-1H-benzoimidazol-5-yl ester
2-Fluoro-benzenesulfonic acid 2-methoxycarbonylamino-1H-benzoimidazol-5-yl ester
5-(1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-thiophene-2-sulfonic acid 2-methoxycarbonylamino-1H-benzoimidazol-5-yl ester
3-Trifluoromethoxy-benzenesulfonic acid 2-methoxycarbonylamino-1H-benzoimidazol-5-yl ester
2-Trifluoromethoxy-benzenesulfonic acid 2-methoxycarbonylamino-1H-benzo-imidazol-5-yl ester
2,6-Difluoro-benzenesulfonic acid 2-methoxycarbonylamino-1H-benzoimidazol-5-yl ester
3-Methoxy-benzenesulfonic acid 2-methoxycarbonylamino-1H-benzoimidazol-5-yl ester
3-(2-Methoxycarbonylamino-1H-benzoimidazol-5-yloxysulfonyl)-thiophene-2-carboxylic acid methyl ester
3,4-Dimethoxy-benzenesulfonic acid 2-methoxycarbonylamino-1H-benzoimidazol-5-yl ester
3-Nitro-benzenesulfonic acid 2-methoxycarbonylamino-1H-benzoimidazol-5-yl ester
3-Trifluoromethyl-benzenesulfonic acid 2-methoxycarbonylamino-1H-benzo-imidazol-5-yl ester
2-Cyano-benzenesulfonic acid 2-methoxycarbonylamino-1H-benzoimidazol-5-yl ester
2-Trifluoromethyl-benzenesulfonic acid 2-methoxycarbonylamino-1H-benzo-imidazol-5-yl ester
2,4-Difluoro-benzenesulfonic acid 2-methoxycarbonylamino-1H-benzoimidazol-5-yl ester
5-Fluoro-2-methyl-benzenesulfonic acid 2-methoxycarbonylamino-1H-benzo-imidazol-5-yl ester
3-Fluoro-benzenesulfonic acid 2-methoxycarbonylamino-1H-benzoimidazol-5-yl ester
4-Cyano-benzenesulfonic acid 2-methoxycarbonylamino-1H-benzoimidazol-5-yl ester
2-Methoxy-5-(2-methoxycarbonylamino-3H-benzoimidazol-5-yloxysulfonyl)-thiophene-3-carboxylic acid methyl ester
1,3,5-Trimethyl-1H-pyrazole-4-sulfonic acid 2-methoxycarbonylamino-3H-benzoimidazol-5-yl ester
6-Morpholin-4-yl-pyridine-3-sulfonic acid 2-methoxycarbonylamino-3H-benzoimidazol-5-yl ester
2,4,6-Trifluoro-benzenesulfonic acid 2-methoxycarbonylamino-1H-benzoimidazol-5-yl ester
4-benzyloxy-benzenesulfonic acid 2-methoxycarbonylamino-1H-benzoimidazol-5-yl ester
4-Ethoxy-benzenesulfonic acid 2-methoxycarbonylamino-3H-benzoimidazol-5-yl ester
4-(2-Morpholin-4-yl-ethoxy)-benzenesulfonic acid 2-methoxycarbonylamino-3H-benzoimidazol-5-yl ester
4-(2-Methoxy-ethoxy)-benzenesulfonic acid 2-methoxycarbonylamino-3H-benzoimidazol-5-yl ester
4-(2-piperidin-1-yl-ethoxy)-benzenesulfonic 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-1H-benzoimidazol-5-yl-ester
4-[2-(4-Methyl-piperazin-1-yl)-2-oxo-ethoxy]-benzenesulfonic acid 2-methoxy-carbonylamino-1H-benzoimidazol-5-yl ester
4-[(3-diethylamino-propylcarbamoyl)-methoxy]-benzenesulfonic acid 2-methoxy-carbonylamino-1H-benzoimidazol-5-yl ester
4-{[(furan-2-ylmethyl)-carbamoyl]-methoxy}-benzenesulfonic acid 2-methoxy-carbonylamino-1H-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-1H-benzoimidazol-5-yl ester
4-(benzylamino)-benzenesulfonic acid 2-methoxycarbonylamino-1H-benzoimidazol-5-yl ester
4-(2-Morpholin-4-yl-ethylamino)-benzenesulfonic acid 2-methoxycarbonylamino-1H-benzoimidazol-5-yl ester
4-(2-Piperidin-4-yl-ethylamino)-benzenesulfonic acid 2-[3-(2-piperidin-1-yl-ethyl)-ureido]-3H-benzoimidazol-5-yl ester
4-[(1-Ethyl-pyrrolidin-2-ylmethyl)-amino]-benzenesulfonic acid 2-[3-(2-piperidin-1-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-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(4-morpholin-4-yl-phenylamino)-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(3,5-dimethyl-phenylamino)-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(4-methoxy-phenylamino)-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(4-dimethylamino-phenylamino)-1H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(3-methoxy-5-trifluoromethyl-phenylamino)-1H-benzoimidazol-5-yl ester
3-[5-(4-Cyclopentylamino-benzenesulfonyloxy)-1H-benzoimidazol-2-ylamino]-benzoic acid ethyl ester
4-Cyclopentylamino-benzenesulfonic acid 2-[(4-(4-methyl-piperazin-1-yl)-phenylamino)-1H-benzoimidazol-5-yl ester
4-cyclopentylamino-benzenesulfonic acid 2-(3-phenyl-propionylamino)-1H-benzoimidazol-5-yl ester
4-cyclopentylamino-benzenesulfonic acid 2-[2-2-methoxy-ethoxy)-acetylamino]-1H-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-[1,2,4]oxadiazol-5-ylmethyl)-amino]-3H-benzoimidazol-5-yl ester
4-Fluoro-benzenesulfonic acid 2-(3-chloro-benzylamino)-3H-benzoimidazol-5-yl ester
4-Fluoro-benzenesulfonic acid 2-(3-methoxy-benzylamino)-3H-benzoimidazol-5-yl ester
4-Fluoro-benzenesulfonic 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-[1,2,4]oxadiazol-5-ylmethyl)-amino]-3H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(3-methoxy-benzylamino)-3H-benzoimidazol-5-yl ester
4-Cyclopentylamino-benzenesulfonic acid 2-(3-chloro-4-methoxy-benzylamino)-3H-benzoimidazol-5-yl ester
4-(Cyclopropylmethyl-amino)-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-(Cyclopropylmethyl-amino)-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-(Cyclopropylmethyl-amino)-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-(Cyclopropylmethyl-amino)-benzenesulfonic acid 2-[3-(2-methoxy-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-(Cyclopropylmethyl-amino)-benzenesulfonic acid 2-[3-(2-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-(2-Methoxy-ethylamino)-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-(2-Methoxy-ethylamino)-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-(2-Methoxy-ethylamino)-benzenesulfonic acid 2-[3-(2-methoxy-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-(2-Methoxy-ethylamino)-benzenesulfonic acid 2-[3-(2-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-(2-Hydroxy-1-methyl-ethylamino)-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-(2-Hydroxy-1-methyl-ethylamino)-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-(2-Hydroxy-1-methyl-ethylamino)-benzenesulfonic acid 2-[3-(2-methoxy-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-(2-Hydroxy-1-methyl-ethylamino)-benzenesulfonic acid 2-[3-(2-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Benzyloxy-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Benzyloxy-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Benzyloxy-benzenesulfonic acid 2-[3-(2-methoxy-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-benzyloxy-benzenesulfonic acid 2-[3-(2-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-(2-Morpholin-4-yl-ethylamino)-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-(2-Morpholin-4-yl-ethylamino)-benzenesulfonic acid 2-[3-(2-methoxy-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-[(Piperidin-4-ylmethyl)-amino)-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-[(Piperidin-4-ylmethyl)-amino]-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-[(Piperidin-4-ylmethyl)-amino]-benzenesulfonic acid 2-[3-(2-methoxy-ethyl)-ureido]-1H-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]-1H-benzoimidazol-5-yl ester
4-Benzylamino-benzenesulfonic acid 2-[3-(2-methoxy-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-Benzylamino-benzenesulfonic acid 2-[3-(2-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-[(1-ethyl-pyrrolidin-2ylmethyl)-amino]-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-(4-hydroxy-piperidin-1-yl)-benzenesulfonic acid 2-[(4-hydroxy-piperidine-1-carbonyl)-amino]-1H-benzoimidazol-5-yl ester
4-(4-Methyl-piperazin-1-yl)-benzenesulfonic acid 2-[(4-methyl-piperazin-1-carbonyl)-amino]-3H-benzoimidazol-5-yl ester
4-[(tetrahydro-pyran-4-ylmethyl)-amino]-benezenesulfonic acid 2-[3-(tetrahydro-pyran-4-ylmethyl)-ureido]-3H-benzoimidazol-5-yl ester
4-(2-Fluoro-ethylamino)-benzenesulfonic acid 2-[3-(2-fluoro-ethyl)-ureido]-3H-benzoimidazol-5-yl ester
4-(2-piperidin-1-yl-ethylamino)-benzenesulfonic acid 2-[3-(2-piperidin-1-yl-ethyl)-ureido]-3H-benzoimidazol-5-yl ester
4-phenethylamino-benzenesulfonic acid 2-(3-phenethyl-ureido)-3H-benzoimidazol-5-yl ester
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)-ureido]-3H-benzoimidazol-5-yl ester
4-(2-hydroxy-2-methyl-propylamino)-benzenesulfonic acid 2-[3-(2-hydroxy-3-methyl-propyl)-ureido]-3H-benzoimidazol-5-yl ester
4-(3-hydroxy-propylamino)-benzenesulfonic acid 2-[3-(3-hydroxy-propyl)-ureido]-3H-benzoimidazol-5-yl ester
4-(2,2,6,6-tetramethyl-piperidin-4-ylamino)-benzenesulfonic acid 2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)-ureido]-3H-benzoimidazol-5-yl ester
4-(2-dimethylamino-ethylamino)-benzenesulfonic acid 2-[3-(2-dimethylamino-ethyl)-ureido]-3H-benzoimidazol-5-yl ester
4-morpholin-4-yl-benzenesulfonic acid 2-[(morpholine-4-carbonyl)-amino]-3H-benzoimidazol-5-yl ester
4-(2-Hydroxy-3-methoxy-propylamino)-benzenesulfonic acid 2-[3-(2-hydroxy-3-methoxy-propyl)-ureido]-3H-benzoimidazol-5-yl ester
4-[(Pyridin-2-ylmethyl)-amino]-benzenesulfonic acid 2-(3-pyridin-2-yl-ethyl-ureido)-3H-benzoimidazol-5-yl ester
4-(2-hydroxy-propylamino)-benzenesulfonic acid 2-[3-(2-hydroxy-propyl)-ureido]-3H-benzoimidazol-5-yl ester
4-(4-methoxy-benzylamino)-benzenesulfonic acid 2-[3-(4-methoxy-benzyl)-ureido]-3H-benzoimidazol-5-yl ester
4-(2-pyrrolidin-1-yl-ethylamino)-benzenesulfonic acid 2-[3-(2-pyrrolidin-1-yl-ethyl)-ureido]-3H-benzoimidazol-5-yl ester
4-(1-phenyl-ethylamino)-benzenesulfonic acid 2-[3-(1-phenyl-ethyl)-ureido]-3H-benzoimidazol-5-yl ester
4-(2-diethylamino-ethylamino)-benzenesulfonic acid 2-[3-(2-diethylamino-ethyl)-ureido]-3H-benzoimidazol-5-yl ester
4-(1-hydroxymethyl-cyclopentylamino)-benzenesulfonic acid 2-[3-(1-hydroxy-methyl-cyclopentyl)-ureido]-3H-benzoimidazol-5-yl ester
3-(4-{2-[3-(3-Methoxycarbonyl-ethyl)-ureido]-1H-benzoimidazol-5-yloxysulfonyl}-phenylamino)-propionic acid methyl ester
4-(4-Hydroxy-piperidin-1-yl)-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-(4-methyl-piperazin-1-yl)-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)-ureido]-3H-benzimidazol-5-yl ester
4-(4-methyl-piperazin-1-yl)-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl-ureido)-3H-benzimidazol-5-yl ester
4-(4-methyl-piperazin-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-(2-morpholin-4-yl-ethyl)-ureido]-3H-benzimidazol-5-yl ester
4-(4-hydroxy-piperidin-1-yl)-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl-ureido)-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-ethyl-ureido)-3H-benzimidazol-5-yl ester
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-ylmethyl-ureido)-3H-benzimidazol-5-yl ester
4-[(Pyridin-2-ylmethyl)-amino]-benzenesulfonic acid 2-[3-(2-methoxy-ethyl)-ureido]-3H-benzimidazol-5-yl ester
4-[(Pyridin-2-ylmethyl)-amino]-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)-ureido]-3H-benzimidazol-5-yl ester
4-(3-Hydroxy-propylamino)-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl-ureido)-3H-benzimidazol-5-yl ester
4-(3-Hydroxy-propylamino)-benzenesulfonic acid 2-[3-(2-methoxy-ethyl)-ureido]-3H-benzimidazol-5-yl ester
4-(3-Hydroxy-propylamino)-benzenesulfonic acid 2-(3-ethyl-ureido)-3H-benzimidazol-5-yl ester
4-(2,2,6,6-tetramethyl-piperidin-4-ylamino)-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)-ureido]-3H-benzimidazol-5-yl ester
4-(2,2,6,6-tetramethyl-piperidin-4-ylamino)-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl-ureido)-3H-benzimidazol-5-yl ester
4-(2-dimethylamino-ethylamino)-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)-ureido]-3H-benzimidazol-5-yl ester
4-(2-dimethylamino-ethylamino)-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl-ureido)-3H-benzimidazol-5-yl ester
4-morpholin-4-yl-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)-ureido]-3H-benzimidazol-5-yl ester
4-morpholin-4-yl-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl-ureido)-3H-benzimidazol-5-yl ester
4-[3-(2-oxo-pyrrolidin-1-yl)-propylamino)-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)-ureido]-3H-benzimidazol-5-yl ester
4-[3-(2-oxo-pyrrolidin-1-yl)-propylamino]-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl-ureido)-3H-benzimidazol-5-yl ester
4-(3-Hydroxy-propylamino)-benzenesulfonic acid 2-(3-ethyl-ureido)-3H-benzimidazol-5-yl ester
4-(2-Hydroxy-2-methyl-propylamino)-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)-ureido]-3H-benzimidazol-5-yl ester
4-(2-Hydroxy-2-methyl-propylamino)-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl-ureido)-3H-benzimidazol-5-yl ester
4-(2-Hydroxy-2-methyl-propylamino)-benzenesulfonic acid 2-[3-(2-methoxy-ethyl)-ureido]-3H-benzimidazol-5-yl ester
4-(2-Hydroxy-2-methyl-propylamino)-benzenesulfonic acid-2-[3-(3-hydroxy-propyl)-ureido]-3H-benzimidazol-5-yl ester
4-[(Tetrahydro-pyran-4-ylmethyl)-amino]-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)-ureido]-3H-benzimidazol-5-yl ester
4-[(Tetrahydro-pyran-4-ylmethyl)-amino]-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl-ureido)-3H-benzimidazol-5-yl ester
4-[(Tetrahydro-pyran-4-ylmethyl)-amino]-benzenesulfonic acid 2-[3-(2-methoxy-ethyl)-ureido]-3H-benzimidazol-5-yl ester
4-[(Tetrahydro-pyran-4-ylmethyl)-amino]-benzenesulfonic acid 2-[3-(3-hydroxy-propyl)-ureido]-3H-benzimidazol-5-yl ester
4-(2-fluoro-ethylamino)-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)-ureido]-3H-benzimidazol-5-yl ester
4-(2-fluoro-ethylamino)-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl-ureido)-3H-benzimidazol-5-yl ester
4-(2-Piperidin-1-yl-ethylamino)-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)-ureido]-3H-benzimidazol-5-yl ester
4-(2-Piperidin-1-yl-ethylamino)-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl-ureido)-3H-benzimidazol-5-yl ester
4-phenethylamino-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)-ureido]-3H-benzimidazol-5-yl ester
4-phenethylamino-benzenesulfonic acid 2-[3-(2-methoxy-ethyl)-ureido]-3H-benzimidazol-5-yl ester
4-phenethylamino-benzenesulfonic acid 2-(3-ethyl-ureido)-3H-benzimidazol-5-yl ester
4-phenethylamino-benzenesulfonic acid 2-[3-(3-hydroxy-propyl)-ureido]-3H-benzimidazol-5-yl ester
4-(2-hydroxy-propylamino)-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)-ureido]-3H-benzimidazol-5-yl ester
4-(2-hydroxy-propylamino)-benzenesulfonic acid 2-(3-ethyl-ureido)-3H-benzimidazol-5-yl ester
4-(4-methoxy-benzylamino)-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)-ureido]-3H-benzimidazol-5-yl ester
4-(4-methoxy-benzylamino)-benzenesulfonic acid 2-(3-ethyl-ureido)-3H-benzimidazol-5-yl ester
4-(4-methoxy-benzylamino)-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl-ureido)-3H-benzimidazol-5-yl ester
4-(4-methoxy-benzylamino)-benzenesulfonic acid 2-[3-(3-hydroxy-propyl)-ureido]-3H-benzimidazol-5-yl ester
4-(4-methoxy-benzylamino)-benzenesulfonic acid 2-[3-(2-methoxy-ethyl)-ureido]-3H-benzimidazol-5-yl ester
4-(2-pyrrolidin-1-yl-ethylamino)-benzenesulfonic acid 2-(3-ethyl-ureido)-3H-benzimidazol-5-yl ester
4-(2-pyrrolidin-1-yl-ethylamino)-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl-ureido)-3H-benzimidazol-5-yl ester
4-(2-pyrrolidin-1-yl-ethylamino)-benzenesulfonic acid 2-[3-(2-methoxy-ethyl)-ureido]-3H-benzimidazol-5-yl ester
4-(1-phenyl-ethylamino)-benzenesulfonic acid 2-(3-ethyl-ureido)-3H-benzimidazol-5-yl ester
4-(2-diethylamino-ethylamino)-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl-ureido)-3H-benzimidazol-5-yl ester
Thiophene-2-sulfonic acid 2-[3-(2-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
Thiophene-2-sulfonic acid 2-[3-(2-methoxy-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
Thiophene-2-sulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)-ureido]-1H-benzoimidazol-5-yl ester
Thiophene-2-sulfonic acid 2-(3-pyridin-2-ylmethyl)-ureido]-1H-benzoimidazol-5-yl ester
4-{2-[3-(2-methoxy-ethyl)-ureido]-1H-benzoimidazol-5-yloxysulfonyl}-phenyl ester
Benzoic acid 4-{2-[3-(2-morpholin-4-yl-ethyl)-ureido}-1H-benzoimidazol-5-yloxy-sulfonyl}-phenyl ester
Benzoic acid 4-[2-([3-pyridin-2-ylmethyl)-ureido)-1H-benzoimidazol-5-yloxy-sulfonyl]-phenyl ester
2,6-difluoro-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl-ureido)-3H-benzoimidazol-5-yl ester
2,6-difluoro-benzenesulfonic acid 3-(2-methoxy-ethyl)-3H-benzoimidazol-5-yl ester

DETAILED DESCRIPTION OF THE INVENTION

In still yet another embodiment is disclosed use of compounds of formula (I) for treating cancer diseases.

In still yet another embodiment is disclosed a method of inhibiting CDK4 enzymes 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 acceptable salt”, as used herein, refers to salts, which are suitable for use in contact with the tissues of humans and lower animals. Pharmaceutically acceptable salts are described in detail in J. Pharmaceutical Sciences, 1977, 66:1 et seq. hereby incorporated by reference. Representative acid addition salts include acetate, citrate, aspartate, benzenesulfonate, hydrochloride, lactate, maleate, methanesulfonate, oxalate, and phosphate.

Chemical Synthesis

Compounds of the present invention can be easily prepared starting from 2-amino-5-(−4-fluorophenylsulfonyloxy)nitrobenzene, the process of preparation of which is described in U.S. Pat. No. 3,996,368.

In a first step this starting material is reacted with the amine bearing the R1 radical in a suitable solvent for carrying out the reaction. Among the list of solvents suitable for dissolving 2-amino-5-(4-fluorophenylsulfonyloxy)nitrobenzene and the amine can be cited the glycols such as ethyl glycol, and the aprotic solvents such as dioxane, dimethylformamide, N-methylpyrrolidone. The preferred temperature for this reaction is comprised between room temperature and the reflux temperature. To recover the intermediate product it is preferred to precipitate the intermediate with hydrochloric acid.

In a second step the compound of step 1 is hydrogenated with hydrogen preferably in presence 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 benzimidazole ring is closed by action of 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea on the intermediate obtained in step 2 without intermediate separation. The reaction mixture is heated to reflux with stirring. The final product (methyl-benzimidazole-2-carbamate) is isolated after evaporation of the solvent under reduced pressure and solubilization in ethyl acetate then crystallisation. A final purification is carried out in methanol with a crystallisation in the same solvent.

Methyl-benzimidazole-2-carbamate can be converted to benzimidazole-2-ureas by treatment with an amine in a suitable solvent such as dimethylformamide, tetrahydrofuran or N-methylpyrrolidone in the presence of a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene in a pressure vessel. The preferred temperature for this reaction is comprised between room temperature and 120° C.

tert-Butyl-benzimidazole-2-carbamate can be prepared by performing the third step described above using 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea instead of 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea. These derivatives can be converted to the corresponding 2-aminobenzimidazole derivative using tert-butylcarbamate deprotection methods known by the persons skilled in the art. The 2-aminobenzimidazoles can be converted to the corresponding amides by reaction with carboxylic acid derivatives using methods known by the persons skilled in the art.

Formulations

The present invention also provides pharmaceutical compositions, which comprise compounds of the present invention formulated together 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 “parenteral”, as used herein, refers to modes of administration, which include intravenous, intramuscular, intraperitoneal, subcutaneous and infusion.

Solid dosage 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 be administered alone or mixed with other anticancer agents. Among the possible combinations, there may be mentioned

- alkylating agents and in particular cyclophosphamide, melphalan, ifosfamide, chlorambucil, busulfan, thiotepa, prednimustine, carmustine, lomustine, semustine, streptozotocin, decarbazine, temozolomide, procarbazine and hexamethylmelamine
- platinum derivatives such as in particular cisplatin, carboplatin or oxaliplatin,
- antibiotic agents such as in particular bleomycin, mitomycin, dactinomycin,
- antimicrotubule agents such as in particular vinblastine, vincristine, vindesine, vinorelbine, taxoids (paclitaxel and docetaxel),
- anthracyclines such as in particular doxorubicin, daunorubicin, idarubicin, epirubicin, mitoxantrone, losoxantrone,
- group I and II topoisomerases such as etoposide, teniposide, amsacrine, irinotecan, topotecan and tomudex,
- fluoropyrimidines such as 5-fluorouracil, UFT, floxuridine,
- cytidine analogues such as 5-azacytidine, cytarabine, gemcitabine, 6-mercaptomurine, 6-thioguanine,
- adenosine analogues such as pentostatin, cytarabine or fludarabine phosphate,
- methotrexate and folinic acid,
- various enzymes and compounds such as L-asparaginase, hydroxyurea, trans-retinoic acid, suramine, dexrazoxane, amifostine, herceptin as well as oestrogenic and androgenic hormones.

It is also possible to combine a radiation treatment with the compounds of the present invention. This treatment may be administered simultaneously, separately or sequentially. The treatment will be adapted to the patient to be treated by the practitioner.

The invention will be more fully described by the following examples, which must not be considered as a limitation of the invention.

EXAMPLES

Method for Analytical Determination

Liquid Chromatography Coupled to Mass Spectrometry (LC/MS) Analysis

LC/MS analyses were conducted on a Micromass instrument model LCT linked to an HP 1100 model instrument. Compound abundance was detected using an HP G1315A (model) photodiode array detector in the 200-600 nm wavelength range and a Sedex 65 (model) evaporative light scattering detector. Mass spectra were acquired in the 160 to 2000 amu range. Data were analysed using the Micromass MassLynx software. Separation were carried out on a Hypersil Highpurity C18, 5 μm particle size column (50×4.6 mm) eluted by a linear gradient 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 regeneration pump, a Waters Reagent Manager make-up pump, a Waters model 2700 sample manager autoinjector, two Rheodyne model LabPro switches, a Waters model 996 photodiode array detector, a Waters model ZMD mass spectrometer and a Gilson model 204 fraction collector. The Waters FractionLynx software controlled the instrument. Separation were conducted alternatively on two Waters Symmetry columns (C₁₈, 5 μM, 19×50 mm, catalogue number 186000210), one column was under regeneration by a 95/5 (v/v) water/acetonitrile mixture containing 0.07% TFA (v/v) while the other one is separating. Columns were eluted by a linear gradient of acetonitrile 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% acetonitrile 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 the 1/1000 ratio using a LC Packing AccuRate splitter; 1/1000 of the flow was mixed with methanol (0.5 ml/min. flow rate) and sent to the detectors, this flow was split again ¾ of the flow was sent to the photodiode array detector and ¼ 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 expected 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 intense ion) the FractionLynx software was additionally supplied with calculated half molecular weight (MW/2), in these conditions collection was also triggered when mass signal corresponding to [M+2H]⁺⁺ and [M+Na+H]⁺⁺ 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 determined by weighing of the tubes after solvent evaporation.

Method of Preparation of Compounds of the Invention

2-amino-5-(4-fluorophenylsulfonyloxy)nitrobenzene (melting point 161° C.), the starting material, can be prepared according to U.S. Pat. No. 3,996,368.

Example 1
Preparation of Methyl-5-(4-[2-hydroxyethyl]aminophenylsulfonyloxy) benzimidazole-2-carbamate

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step 1: 15.6 g of 2-amino-5-(4-fluorophenylsulfonyloxy)nitrobenzene were combined with 25 ml ethanolamine in 100 ml ethyl glycol 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 preciptate 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 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 30 ml of glacial acetic acid, 10.3 g of 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea was added and reaction mixture was heated to reflux with stirring for 3 hours. Solvents were then evaporated under reduced pressure, concentrate was then dissolved in hot ethylacetate, crystallized by cooling and washed with ethylacetate. Compound was then solubilized in 250 ml refluxing methanol, crystallized by cooling and washed with methanol and dried yielding 7.4 g of the title compound. (Melting point 170° C., LC/MS analysis: retention time=2.8 min., mass spectrum: 407.24, [M+H]⁺)

Example 2
Preparation of Methyl-5-(4-[4-hydroxbutyl]aminophenylsulfonyloxy) benzimidazole-2-carbamate

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step 1: 19.7 g of 2-amino-5-(4-fluorophenylsulfonyloxy)nitrobenzene were combined with 20 g butanolamine in 200 ml N-methylpyrrolidinone in a round bottom flask. The reaction mixture was heated to reflux for 120 min and then solvent was evaporated under reduced pressure. Concentrate was then solubilized with ethylacetate and extracted with 2N aqueous HCl and water and then dried over sodium sulfate and dried under reduced pressure. The concentrate was recrystallized in isopropanol, filtered under suction, washed with isopropanol and dried, yielding 13.1 g of 2-amino-5-(4-[4-hydroxbuyl]aminophenylsulfonyloxy)nitrobenzene (melting 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 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 100 ml methanol and 20 ml of glacial acetic acid, 8.2 g of 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea was added and reaction mixture was heated to reflux with stirring for 3 hours. Solvents were then evaporated under reduced pressure, concentrate washed with 2N aqueous ammonia, water and dried. Concentrate was then dissolved in hot ethyl acetate, crystallized by cooling and washed with ethyl acetate. Compound was then solubilized in refluxing methanol, crystallized by cooling and washed with methanol and dried yielding 6.3 g of the title compound. (Melting point 180° C., LC/MS analysis: retention time=2.9 min., mass spectrum: 435.29, [M+H]⁺)

Example 3
Preparation of Methyl-5-(4-[2-methoxyethyl]aminophenylsulfonyloxy) benzimidazole-2-carbamate

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step 1: 15.6 g of 2-amino-5-(4-fluorophenylsulfonyloxy)nitrobenzene were combined with 35 ml methoxyethylamine in 100 ml dioxane in a round bottom flask. The reaction mixture was heated to reflux for 8 hours and then cooled to 40° C. and extracted two times with 250 ml water. Concentrate was solubilized with ethyl acetate and extracted with 2N aqueous HCl and water, the 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: 18.2 g of 2-amino-5-(4-[2-methoxyethyl]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 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 acetic acid, 12.3 g of 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea was added and reaction mixture was heated to reflux with stirring for 3 hours. Solvents were then evaporated under reduced pressure, and concentrate 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+H]⁺).

Example 4
Preparation of Methyl-5-(4-[1-imidazolyl]-phenylsulfonyloxy) benzimidazole-2-carbamate

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step 1: 15.6 g of 2-amino-5-(4-fluorophenylsulfonyloxy)nitrobenzene 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 cooled to room temperature. Reaction mixture was then precipitated by addition of water filtered and precipitate was washed with water and dried. Residue was resolubilized in hot ethyl glycol, crystallized by cooling and the crystals were washed with methanol and dried, yielding 10.4 g of 2-amino-5-(4-[1-imidazolyl]-phenylsulfonyloxy)nitro-benzene (melting point 209° C.).

step 2: 10.4 g of 2-amino-5-(4-[1-imidazolyl]-phenylsulfonyloxy)nitrobenzene in 75 ml of methanol and 75 ml of dimethylformamide are hydrogenated under atmospheric pressure with a catalytic amount of Raney Nickel. After hydrogen uptake is complete, the catalyst was filtered off with suction, washed with methanol and the filtrate is concentred under reduced pressure (Method A). Alternatively 5 g of 2-amino-5-(4-[1-imidazolyl]-phenylsulfonyloxy)nitrobenzene in 475 ml of methanol and 25 ml of dimethylformamide are hydrogenated 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: concentrated filtrate of step 2 was taken up in 150 ml methanol and 25 ml of glacial acetic acid, 10.3 g of 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea was added and reaction mixture was heated to reflux with stirring for 3 hours. After cooling to room temperature reaction mixture was precipitated by addition of ethyl acetate, filtered by suction and washed by ethyl acetate. 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, IR).

Example 5
Preparation of Methyl-5-(4-[2-pyridylmethyl]aminophenylsulfonyloxy) benzimidazole-2-carbamate

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In a similar manner to examples 1 to 4, title compound was obtained by reacting 2-aminomethylpyridine 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=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-ethylaminophenylsulfonyloxy) benzimidazole-2-carbamate

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In a similar manner to examples 1 to 4, title compound was obtained by reacting ethylamine 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: 390.98, [M+H]⁺).

Example 7
Preparation of Methyl-5-(4-[N-Glycinyl]-phenylsulfonyloxy) benzimidazole-2-carbamate

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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 described 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-[1-methyl,2-hydroxyethyl]aminophenyl-sulfonyloxy) benzimidazole-2-carbamate

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In a similar manner to examples 1 to 4, title compound was obtained by reacting 2-aminopropanol 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=2.9 min., mass spectrum: 421.27, [M+H]⁺).

Example 9
Preparation of Methyl-5-(4-[2-methyl,2-hydroxyethyl]aminophenyl-sulfonyloxy) benzimidazole-2-carbamate

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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)nitrobenzene 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: 421.27, [M+H]⁺).

Example 10
Preparation of Methyl-5-(4-isopropylaminophenylsulfonyloxy) benzimidazole-2-carbamate

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In a similar manner to examples 1 to 4, title compound was obtained by reacting isopropylamine 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=3.4 min., mass spectrum: 405.27, [M+H]⁺).

Example 11
Preparation of Methyl-5-(4-[1-ethyl, 2-hydroxyethyl]aminophenyl sulfonyloxy)benzimidazole-2-carbamate

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In a similar manner to examples 1 to 4, title compound was obtained by reacting 2-aminobutanol 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=3.0 min., mass spectrum: 435.30, [M+H]⁺).

Example 12
Preparation of Methyl-5-(4-butylaminophenylsulfonyloxy) benzimidazole-2-carbamate

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In a similar manner to examples 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: retention time=3.6 min., mass spectrum: 419.25, [M+H]⁺).

Example 13
Preparation of Methyl-5-(4-[3-methoxypropyl]aminophenyl-sulfonyloxy) benzimidazole-2-carbamate

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In a similar manner to examples 1 to 4, title compound was obtained by reacting 3-methoxypropanolamine 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) benzimidazole-2-carbamate

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In a similar manner to examples 1 to 4, title compound was obtained by reacting methylamine 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=3.0 min., mass spectrum: 377.22, [M+H]⁺).

Example 15
Preparation of Methyl-5-(4-[2-sulfonylethyl]aminophenylsulfonyloxy) benzimidazole-2-carbamate

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In a similar manner to examples 1 to 4, title compound was obtained by reacting 2-aminoethanesulfonic acid 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=2.6 min., mass spectrum: 471.19, [M+H]⁺; 941.41, [2M+H]⁺).

Example 16
Preparation of Methyl-5-(4-aminophenylsulfonyloxy)benzimidazole-2-carbamate

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In a similar manner to examples 1 to 4, title compound was obtained by reacting ammonia 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=2.9 min., mass spectrum: 363.19, [M+H]⁺).

Example 17
Preparation of Methyl-5-(4-[2-diethylaminoethyl]aminophenyl-sulfonyloxy) benzimidazole-2-carbamate

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In a similar manner to examples 1 to 4, title compound was obtained by reacting 2-diethylaminoethylamine 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=2.6 min., mass spectrum: 462.34, [M+H]⁺; 923.65, [2M+H]⁺; 430.30, fragmentation of carbamate: loss of methanol).

Example 18
Preparation of Methyl-5-(4-[1-tetrathydrofurylmethyl]aminophenyl-sulfonyloxy) benzimidazole-2-carbamate

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In a similar manner to examples 1 to 4, title compound was obtained by reacting tetrahydrofurfurylamine 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: 447.24, [M+H]⁺).

Example 19
Preparation of Methyl-5-(4-cyclopentylaminophenylsulfonyloxy) benzimidazole-2-carbamate

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In a similar manner to examples 1 to 4, title compound was obtained by reacting cyclopentylamine 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=3.6 min., mass spectrum: 431.29, [M+H]⁺).

Example 20
Preparation of Methyl-5-(4-[2-phenylethyl]aminophenylsulfonyloxy) benzimidazole-2-carbamate

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In a similar manner to examples 1 to 4, title compound was obtained by reacting phenethylamine 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=3.6 min., mass spectrum: 467.26, [M+H]⁺).

Example 21
Preparation of 5-(4-[1-imidazolyl]-phenylsulfonyloxy)-1H-benzimidazole-2-ylamine: an intermediate for amide product synthesis

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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 heated to reflux and 9.13 g of 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea 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 taken up in 80 ml dichloromethane and 40 ml trifluoroacetic acid. Reaction mixture was stirred for 4 hours at room temperature. Solvents were evaporated under reduced pressure. Concentrated filtrate was taken in 75 ml water and 50 ml of sodium carbonate aqueous solution (10% w/w). Precipitate obtained was washed with dichloromethane and dried on a glass frit yielding 5.3 g title compound.

Example 22
Preparation of 5-(4-cyclopentylaminophenylsulfonyloxy)-1H-benzimidazole-2-ylamine: an intermediate for amide product synthesis

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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-1-yl-benzenesulfonyloxy)-1H-benzoimidazol-2-yl]-succinamic acid methyl ester

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step 1: 8.9 mg of succinamic acid methyl ester, 25 mg of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) and 12 μl diisopropyl-ethylamine were taken up in 0.4 ml dimethylformamide. Reaction mixture was stirred at room temperature for one hour and 5-(4-[1-imidazolyl]-phenylsulfonyloxy)-1H-benzimidazole-2-ylamine 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-[1-imidazolyl]-phenylsulfonyloxy)-1H-benzimidazole-2-yl]-succinamic-acid-methyl ester. (LC/MS analysis: retention time=2.70 min., mass spectrum: 470.34, [M+H]⁺).

Example 24
Preparation of 4-Cyclopentylamino-benzenesulfonic acid 2-(2-tert-butoxycarbonylamino-acetylamino)-1H-benzoimidazol-5-yl ester

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step 1: 11.3 mg of N-(tert-butoxycarbonyl)glycine, 25 mg HBTU and 12 μl diisopropylethylamine were taken up in 0.4 ml dimethylformamide. Reaction mixture was stirred at room temperature for one hour and 5-(4-cyclopentylaminophenylsulfonyloxy)-1H-benzimidazole-2-ylamine 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 2.4 mg of N-[5-(4-cyclopentylaminophenylsulfonyloxy)-1H-benzimidazole-2-yl]-tert-butoxycarbonylglycineamid. (LC/MS analysis: retention time=3.87 min., mass spectrum: 530.38, [M+H]⁺).

Example 25
Preparation of N-[5-(4-Cyclopentylamino-benzenesulfonyloxy)-1H-benzoimidazol-2-yl]-succinamic acid methyl ester

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In a similar manner to example 24, title compound was obtained by reacting succinamic acid methyl ester with N-5-(4-cyclopentylaminophenylsulfonyloxy)-1H-benzimidazole-2-ylamine (LC/MS analysis: retention time=3.72 min., mass spectrum: 487.34, [M+H]⁺).

Example 26
Preparation of 4-[5-(4-Cyclopentylamino-benzenesulfonyloxy)-1H-benzoimidazol-2-ylcarbamoyl]-butyric acid methyl ester

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In a similar manner to example 24, title compound was obtained by reacting butyric acid methylester with N-5-(4-cyclopentylaminophenylsulfonyloxy)-1H-benzimidazole-2-ylamine. (LC/MS analysis: retention time=3.75 min., mass spectrum: 501.36, [M+H]⁺).

Example 27
Preparation of 4-Cyclopentylamino-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester

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In a similar manner to example 24, title compound was obtained by reacting cyclopropane carboxylic acid with 5-(4-cyclopentylaminophenylsulfonyloxy)-1H-benzimidazole-2-ylamine. (LC/MS analysis: retention time=3.76 min., mass spectrum: 441.36, [M+H]⁺).

Example 28
Preparation of 4-Cyclopentylamino-benzenesulfonic acid 2-(2-methoxy-acetylamino)-1H-benzoimidazol-5-yl ester

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In a similar manner to example 24, title compound was obtained by reacting methoxyaceticacid with 5-(4-cyclopentylaminophenylsulfonyloxy)-1H-benzimidazole-2-ylamine. (LC/MS analysis: retention time=3.66 min., mass spectrum: 445.34, [M+H]⁺).

Example 29
Preparation of 4-Cyclopentylamino-benzenesulfonic acid 2-(2-dimethylamino-acetylamino)-1H-benzoimidazol-5-yl ester

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In a similar manner to example 24, title compound was obtained by reacting N,N-dimethylglycine with 5-(4-cyclopentylaminophenylsulfonyloxy)-1H-benzimidazole-2-ylamine. (LC/MS analysis: retention time=3.36 min., mass spectrum: 458.36, [M+H]⁺).

Example 30
N-[5-(4-[imidazolyl]-phenylsulfonyloxy)-1H-benzimidazole-2-yl]-methylurea

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10 mg of methyl-5-(4-[imidazolyl]-phenylsulfoxy)benzimidazole-2-carbamate (example 4) were combined with 50 μl methylamine (2.0 M in tetrahydrofuran) and 5 μl 1,8-Diazabicyclo[5.4.0]undec-7-ene in 2 ml N-methylpyrrolidone/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 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 reduced pressure and compound in N-methylpyrrolidone were directly purified by preparative LCMS under conditions described above. After purification, solution was dry-concentrated in a JOUAN RC1010 evaporator. (LC/MS analysis: retention time=2.23 min., mass spectrum: 413.23, [M+H]⁺).

Example 31
N-[5-(4-cyclopentylaminophenylsulfonyloxy)-1H-benzimidazole-2-yl]-methylurea

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In a similar manner to example 30, title compound was obtained by reacting methyl-5-(4-cyclopentylaminophenylsulfonyloxy)benzimidazole-2-carbamate (example 19) with methylamine (2.0 M in tetrahydrofuran). (LC/MS analysis: retention time=3.30 min., mass spectrum: 430.27, [M+H]⁺).

Example 32
N-[5-(4-cyclopentylaminophenylsulfonyloxy)-1H-benzimidazole-2-yl]-dimethylurea

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Title compound was obtained by reacting 10 mg of methyl-5-(4-cyclopentylaminophenylsulfonyloxy)benzimidazole-2-carbamate (example 19) with 50 μl dimethylamine (2.0 M in tetrahydrofuran) and 5 μl 1,8-diazabicyclo[5.4.0]undec-7-ene in 2 ml dimethylformamide 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 dimethylformamide was evaporated in a JOUAN RC1010 evaporator. Compound was diluted in 0.5 ml dimethylsulfoxide for LC/MS trigged purification yielding 9 mg of the title compound (LC/MS analysis: retention time=3.35 min., mass spectrum: 444.29, [M+H]⁺).

Example 33
4-Cyclopentylamino-benzenesulfonic acid 2-(3-cyclopropyl-ureido)-1H-benzoimidazol-5-yl ester

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10 mg of methyl-5-(4-cyclopentylaminophenylsulfonyloxy)benzimidazole-2-carbamate (example 19) were combined with 25 μl cyclopropylamine and 10 μl 1,8-diazabicyclo[5.4.0]undec-7-ene in 2 ml N-methylpyrrolidone/tetrahydrofuran (0.8/1.2) 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 60° C. for 40 hours, and then cooled to room temperature. Compounds were put in an assay tube, tetrahydrofuran was evaporated under reduced pressure and compound in N-methylpyrrolidone 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+H]⁺).

Example 34
4-Cyclopentylamino-benzenesulfonic acid 2-(3-isopropyl-ureido)-1H-benzoimidazol-5-yl ester

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In a similar manner to example 33, title compound was obtained by reacting methyl-5-(4-cyclopentylaminophenylsulfonyloxy)benzimidazole-2-carbamate (example 19) with isopropylamine. (LC/MS analysis: retention time=3.78 min., mass spectrum: 458.36, [M+H]⁺).

Example 35
4-Cyclopentylamino-benzenesulfonic acid 2-(3-butyl-ureido)-1H-benzoimidazol-5-yl ester

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In a similar manner to example 33, title compound was obtained by reacting methyl-5-(4-cyclopentylaminophenylsulfonyloxy)benzimidazole-2-carbamate (example 19) with butylamine. (LC/MS analysis: retention time=3.90 min., mass spectrum: 472.39, [M+H]⁺).

Example 36
4-Imidazol-1-yl-benzenesulfonic acid 2-[3-(2-fluoro-phenyl)-ureido]-1H-benzoimidazol-5-yl ester

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In a similar manner to example 30, title compound was obtained by reacting methyl-5-(4-[imidazolyl]-phenylsulfoxy)benzimidazole-2-carbamate (example 4) with 2-fluoro-aniline. (LC/MS analysis: retention time=3.03 min., mass spectrum: 493.28, [M+H]⁺).

Example 37
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(2-fluoro-phenyl)-ureido]-1H-benzoimidazol-5-yl ester

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In a similar manner to example 33, title compound was obtained by reacting methyl-5-(4-cyclopentylaminophenylsulfonyloxy)benzimidazole-2-carbamate (example 19) with 2-fluoro-aniline. (LC/MS analysis: retention time=3.99 min., mass spectrum: 510.32, [M+H]⁺).

Example 38
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(3-methoxy-phenyl)-ureido]-1H-benzoimidazol-5-yl ester

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In a similar manner to example 33, title compound was obtained by reacting methyl-5-(4-cyclopentylaminophenylsulfonyloxy)benzimidazole-2-carbamate (example 19) with m-anisidine (LC/MS analysis: retention time=4.02 min., mass spectrum: 522.33, [M+H]⁺).

Example 39
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(4-methoxy-phenyl)-ureido]-1H-benzoimidazol-5-yl ester

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In a similar manner to example 33, title compound was obtained by reacting methyl-5-(4-cyclopentylaminophenylsulfonyloxy)benzimidazole-2-carbamate (example 19) with p-anisidine (LC/MS analysis: retention time=3.97 min., mass spectrum: 522.34, [M+H]⁺).

Example 40
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(4-chloro-phenyl)-ureido]-1H-benzoimidazol-5-yl ester

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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+H]⁺).

Example 41
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(3-fluoro-benzyl)-ureido]-1H-benzoimidazol-5-yl ester

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In a similar manner to example 33, title compound was obtained by reacting methyl-5-(4-cyclopentylaminophenylsulfonyloxy)benzimidazole-2-carbamate (example 19) with 3-fluorobenzylamine. (LC/MS analysis: retention time=3.96 min., mass spectrum: 524.33, [M+H]⁺).

Example 42
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(3-chloro-phenyl)-ureido]-1H-benzoimidazol-5-yl ester

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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 spectrum: 526.28, [M+H]⁺).

Example 43
4-Cyclopentylamino-benzenesulfonic acid 2-(3-isobutyl-ureido)-1H-benzoimidazol-5-yl ester

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In a similar manner to example 33, title compound was obtained by reacting methyl-5-(4-cyclopentylaminophenylsulfonyloxy)benzimidazole-2-carbamate (example 19) with isobutylamine. (LC/MS analysis: retention time=3.88 min., mass spectrum: 472.38, [M+H]⁺).

Example 44
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(2-dimethylamino-ethyl)-ureido]-1H-benzoimidazol-5-yl ester

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In a similar manner to example 33, title compound was obtained by reacting methyl-5-(4-cyclopentylaminophenylsulfonyloxy)benzimidazole-2-carbamate (example 19) with N,N-dimethylethylenediamine. (LC/MS analysis: retention time=3.22 min., mass spectrum: 487.38, [M+H]⁺).

Example 45
4-Cyclopentylamino-benzenesulfonic acid 2-(3-ethyl-ureido)-1H-benzoimidazol-5-yl ester;

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In a similar manner to example 33, title compound was obtained by reacting methyl-5-(4-cyclopentylaminophenylsulfonyloxy)benzimidazole-2-carbamate (example 19) with ethylamine (33% in water). (LC/MS analysis: retention time=3.64 min., mass spectrum: 444.35, [M+H]⁺).

Example 46
{3-[5-(4-Cyclopentylamino-benzenesulfonyloxy)-1H-benzoimidazol-2-yl]-ureido}-acetic acid

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In a similar manner to example 33, title compound was obtained by reacting methyl-5-(4-cyclopentylaminophenylsulfonyloxy)benzimidazole-2-carbamate (example 19) with glycine. (LC/MS analysis: retention time=3.48 min., mass spectrum: 474.31, [M+H]⁺).

Example 47
4-Imidazol-1-yl-benzenesulfonic acid 2-[3-(2-sulfo-ethyl)-ureido]-1H-benzoimidazol-5-yl ester

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In a similar manner to example 30, title compound was obtained by reacting methyl-5-(4-[imidazolyl]-phenylsulfoxy)benzimidazole-2-carbamate (example 4) with 2-aminoethanesulfonic acid. (LC/MS analysis: retention time=2.40 min., mass spectrum: 507.21, [M+H]⁺).

Example 48
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(2-methoxy-ethyl)-ureido]-1H-benzoimidazol-5-yl ester

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In a similar manner to example 33, title compound was obtained by reacting methyl-5-(4-cyclopentylaminophenylsulfonyloxy)benzimidazole-2-carbamate (example 19) with 2-methoxyethylamine. (LC/MS analysis: retention time=3.60 min., mass spectrum: 474.34, [M+H]⁺).

Example 49
4-Cyclopentylamino-benzenesulfonic acid 2-[3-(4-dimethylamino-phenyl)-ureido]-1H-benzoimidazol-5-yl ester

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In a similar manner to example 33, title compound was obtained by reacting methyl-5-(4-cyclopentylaminophenylsulfonyloxy)benzimidazole-2-carbamate (example 19) with N,N-dimethyl-1,4-phenylenediamine. (LC/MS analysis: retention time=3.42 min., mass spectrum: 535.34, [M+H]⁺).

Example 50
4-Cyclopentylamino-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl-ureido)-1H-benzoimidazol-5-yl ester

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In a similar manner to example 33, title compound was obtained by reacting methyl-5-(4-cyclopentylaminophenylsulfonyloxy)benzimidazole-2-carbamate (example 19) with 2-aminomethylpyridine. (LC/MS analysis: retention time=3.30 min., mass spectrum: 507.33, [M+H]⁺).

Example 51
4-Cyclopentylamino-benzenesulfonic acid 2-(3-cyclobutyl-ureido)-1H-benzoimidazol-5-yl ester

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In a similar manner to example 33, title compound was obtained by reacting methyl-5-(4-cyclopentylaminophenylsulfonyloxy)benzimidazole-2-carbamate (example 19) with cyclobutylamine. (LC/MS analysis: retention time=3.84 min., mass spectrum: 470.36, [M+H]⁺).

Example 52
4-Cyclopentylamino-benzenesulfonic acid 2-(3-pyridin-4-ylmethyl-ureido)-1H-benzoimidazol-5-yl ester

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In a similar manner to example 33, title compound was obtained by reacting methyl-5-(4-cyclopentylaminophenylsulfonyloxy)benzimidazole-2-carbamate (example 19) with 4-(aminomethyl)pyridine. (LC/MS analysis: retention time=3.24 min., mass spectrum: 507.33, [M+H]⁺).

Example 53
4-Cyclopentylamino-benzenesulfonic acid 2-(3-tert-butyl-ureido)-1H-benzoimidazol-5-yl ester

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In a similar manner to example 33, title compound was obtained by reacting methyl-5-(4-cyclopentylaminophenylsulfonyloxy)benzimidazole-2-carbamate (example 19) with tert-butylamine. (LC/MS analysis: retention time=3.93 min., mass spectrum: 472.36, [M+H]⁺).

Example 54
4-[(Tetrahydro-furan-2-ylmethyl)-amino]-benzenesulfonic acid 2-(3-methyl-ureido)-1H-benzoimidazol-5-yl ester

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10 mg of methyl-5-(4-[1-tetrathydrofurylmethyl]aminophenyl-sulfonyloxy) benzimidazole-2-carbamate (example 18) were combined with 50 μl methylamine (2.0 M in tetrahydrofuran) and 5 μl 1,8-diazabicyclo[5.4.0]undec-7-ene in 2 ml N-methylpyrrolidone/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 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 pressure and compound in N-methylpyrrolidone were directly purified by preparative LCMS in conditions described above. After purification, solution were dry-concentrated in a JOUAN RC1010 evaporator. (LC/MS analysis: retention time=2.91 min., mass spectrum: 446.07, [M+H]⁺).

Example 55
4-Fluoro-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester

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step 1: 10 g of 4-amino-3-nitrophenol in 180 ml of ethanol were hydrogenated under 40 bars pressure at 23° C. temperature with catalytic amound of palladium on carbon. Reaction was performed in an Inox flask for high pressure. After hydrogen uptake was complete, the catalyst was filtered off with suction, washed with methanol and the filtrate was concentred under reduced pressure yielding 8 g of crude 3,4-diaminophenol.

Step 2: 5.75 g of 3,4-diaminophenol were combined with 15.5 g of 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea in 150 ml methanol and 22 ml acetic acid in a round bottom flask. The reaction mixture was heated to reflux with stirring for 3 hours. Solvents were then evaporated under reduce pressure yielding 7.13 g crude (5-hydroxy-1H-benzoimidazol-2-yl)-carbamic acid tert-butyl ester. Step 3: 5.98 g of (5-hydroxy-1H-benzoimidazol-2-yl)-carbamic acid tert-butyl ester were combinated with 4.67 g of 4-fluorobenzenesulfonyl chloride and 6.75 ml of trietylamine in 100 ml acetone. The reaction mixture was stirred at room temperature for 1 hour. Solvents were evaporated under reduced pressure yielding 6.45 g crude 4-fluoro-benzenesulfonic acid 2-tert-butoxycarbonylamino-1H-benzoimidazol-5-yl ester.

Step 4: 6.45 g of 4-fluoro-benzenesulfonic acid 2-tert-butoxycarbonylamino-1H-benzoimidazol-5-yl ester were combined with 15 ml trifluoroacetic acid in 60 ml dichloromethane. The reaction mixture was stirred overnight at room temperature. Solvents were evaporated under reduced pressure. The residue was washed with ethyl ether and dried on glass frit yielding 6.58 g of 4-fluoro-benzenesulfonic acid 2-amino-1H-benzoimidazol-5-yl ester trifluoroacetic acid salt.

Step 5: 5.53 g of 4-fluoro-benzenesulfonic acid 2-amino-1H-benzoimidazol-5-yl ester trifluoroacetic acid salt were combinated with 1.8 ml of cyclopropanecarbonylchloride and 5 ml triethylamine in 75 ml dichloromethane. Reaction mixture was stirred at room temperature for 1 hour. Solvents were evaporated under reduced pressure. The residue was then taken up in dichloromethane, washed with water and dried with magnesium sulfate. Dichloromethane was evaporated under reduced pressure and precipitate obtained was dried on glass frit yielding 4.88 g of 4-fluoro-benzenesulfonic acid 2-amino-3-cyclopropanecarbonyl-3H-benzoimidazol-5-yl ester.

Step 6: 3.27 g of 4-fluoro-benzenesulfonic acid 2-amino-3-cyclopropanecarbonyl-3H-benzoimidazol-5-yl ester; were combinated with 106 mg of 4-(dimethylamino)pyridine in 80 ml acetonitrile. the reaction mixture was heated at 85° C. temperature for 72 hours with stirring. Yellow solution obtained was diluted in dichloromethane, washed with water and dried under magnesium sulfate. Solvents were evaporated under reduced pressure yielding 3.19 g of the title compound.

Example 56
Preparation of 4-[(1-Ethyl-pyrrolidin-2-ylmethyl)-amino]-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester.

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Title compound was obtained by reacting 12 mg of 4-fluoro-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester (example 55) with 21 mg of 2-(aminomethyl)-1-ethylpyrrolidine and 50 mg cesium carbonate in 600 μl dimethylsulfoxide. Reaction was performed in a 24 well Inox plate for high pressure. The reaction mixture was put under 10 bars argon pressure and then heated to 110° C. for 50 hours. Cesium carbonate was filtered off and compound in DMSO was directly purified by LCMS triggered purification yielding 10.7 mg title compound. (LC/MS analysis: retention time=2.58 min, mass spectrum: 483.99, [M+H]⁺.

Example 57

By using a method similar to that for the preparation of example 30, combining methyl-5-(4-[1-imidazolyl]-phenylsulfonyloxy)benzimidazole-2-carbamate precursor (example 4) with suitable amine were obtained the following compounds that were characterized by analytical LC/MS ([M+H]⁺ and retention time given in the following table.

n^oPrecursorRetentionexampleexampleAminecompound[M + H]⁺time (min)57-a4 embedded image

4-Imidazol-1-yl- benzenesulfonic acid 2-(3- phenyl-ureido)-1H- benzoimidazol-5-yl ester475.232.7557-b4 embedded image

4-Imidazol-1-yl- benzenesulfonic acid 2-(3- cyclohexyl-ureido)-1H- benzoimidazol-5-yl ester481.282.7657-c4 embedded image

4-Imidazol-1-yl- benzenesulfonic acid 2-(3- cyclopentyl-ureido)-1H- benzoimidazol-5-yl ester467.242.6257-d4 embedded image

4-Imidazol-1-yl- benzenesulfonic acid 2-[3- (3-fluoro-phenyl)-ureido]- 1H-benzoimidazol-5-yl ester493.222.8757-e4 embedded image

4-Imidazol-1-yl- benzenesulfonic acid 2-[3- (2-hydroxy-ethyl)- ureido]-1H- benzoimidazol-5-yl ester443.232.3257-f4 embedded image

4-Imidazol-1-yl- benzenesulfonic acid 2-[3- (4-fluoro-phenyl)-ureido]- 1H-benzoimidazol-5-yl ester493.222.8057-g4 embedded image

4-Imidazol-1-yl- benzenesulfonic acid 2-[3- (2-chloro-benzyl)-ureido]- 1H-benzoimidazol-5-yl ester523.253.0857-h4 embedded image

4-Imidazol-1-yl- benzenesulfonic acid 2-[3- (2-fluoro-benzyl)-ureido]- 1H-benzoimidazol-5-yl ester507.283.0057-i4 embedded image

4-Imidazol-1-yl- benzenesulfonic acid 2- [(azetidine-1-carbonyl)- amino]-1H- benzoimidazol-5-yl ester439.312.5557-j4 embedded image

4-Imidazol-1-yl- benzenesulfonic acid 2-(3- pyridin-3-ylmethyl-ureido)- 1H-benzoimidazol-5-yl ester490.312.3957-k4 embedded image

4-Imidazol-1-yl- benzenesulfonic acid 2-{3- [3-(4-methyl-piperazin- 1-yl)-propyl]-ureido}-1H- benzoimidazol-5-yl ester539.362.3457-l4 embedded image

4-Imidazol-1-yl- benzenesulfonic acid 2-(3- benzyl-ureido)-1H- benzoimidazol-5-yl ester489.252.71

Example 58

By using a method similar to that for the preparation of example 33, combining methyl-5-(4-cyclopentylaminophenylsulfonyloxy)benzimidazole-2-carbamate (example 19) with suitable amine were obtained the following compounds that were characterized by analytical LC/MS ([M+H]⁺ and retention time given in the following table).

n^oPrecursorRetentionexampleexampleAminecompound[M + H]⁺time (min)58-a19 embedded image

4-Cyclopentylamino- benzenesulfonic acid 2-(3- phenyl-ureido)-1H- benzoimidazol-5-yl ester492.283.7758-b19 embedded image

4-Cyclopentylamino- benzenesulfonic acid 2-(3- cyclohexyl-ureido)-1H- benzoimidazol-5-yl ester;498.313.7958-c19 embedded image

4-Cyclopentylamino- benzenesulfonic acid 2-(3- cyclopentyl-ureido)-1H- benzoimidazol-5-yl ester484.293.6858-d19 embedded image

4-Cyclopentylamino- benzenesulfonic acid 2-[3- (3-fluoro-phenyl)-ureido]- 1H-benzoimidazol-5-yl ester510.253.8758-e19 embedded image

4-Cyclopentylamino- benzenesulfonic acid 2-[3- (2-hydroxy-ethyl)- ureido]-1H- benzoimidazol-5-yl ester460.283.1758-f19 embedded image

4-Cyclopentylamino- benzenesulfonic acid 2-[3- (4-fluoro-phenyl)-ureido]- 1H-benzoimidazol-5-yl ester510.243.8058-g19 embedded image

4-Cyclopentylamino- benzenesulfonic acid 2-[3- (2-chloro-benzyl)-ureido]- 1H-benzoimidazol-5-yl ester540.284.0558-h19 embedded image

4-Cyclopentylamino- benzenesulfonic acid 2-[3- (2-fluoro-benzyl)-ureido]- 1H-benzoimidazol-5-yl ester524.333.9758-i19 embedded image

4-Cyclopentylamino- benzenesulfonic acid 2- [(azetidine-1-carbonyl)- amino]-1H-benzoimidazol- 5-yl ester456.373.6058-j19 embedded image

4-Cyclopentylamino- benzenesulfonic acid 2-(3- pyridin-3-ylmethyl-ureido)- 1H-benzoimidazol-5-yl ester507.353.2458-k19 embedded image

4-Cyclopentylamino- benzenesulfonic acid 2- {3-[3-(4-methyl-piperazin- 1-yl)-propyl]-ureido}-1H- benzoimidazol-5-yl ester556.393.0958-l19 embedded image

4-Cyclopentylamino- benzenesulfonic acid 2-(3- benzyl-ureido)-1H- benzoimidazol-5-yl ester506.313.7058-m19 embedded image

4-{3-[5-(4-Cyclopentylamino- benzenesulfonyloxy)-1H- benzoimidazol-2-yl]- ureido}-butyric acid methyl ester516.313.7458-n19 embedded image

4-{3-[5-(4-Cyclopentylamino- benzenesulfonyloxy)-1H- benzoimidazol-2-yl]- ureido}-butyric acid ethyl ester530.303.8458-o19 embedded image

4-{3-[5-(4-Cyclopentylamino- benzenesulfonyloxy)-1H- benzoimidazol-2-yl]- ureido}-acetic acid methyl ester488.263.6558-p19 embedded image

4-Cyclopentylamino- benzenesulfonic acid 2-[3- (3-imidazol-1-yl-propyl)- ureido]-1H-benzoimidazol- 5-yl ester524.303.2958-q19 embedded image

1-[5-(4-Cyclopentylamino- benzenesulfonyloxy)-1H- benzoimidazol-2S- ylcarbamoyl]-pyrrolidine- 2-carboxylic acid514.273.5658-r19 embedded image

1-[5-(4-Cyclopentylamino- benzenesulfonyloxy)-1H- benzoimidazol-2S-yl- carbamoyl]-pyrrolidine- 2-carboxylic acid methyl ester528.273.7958-s19 embedded image

4-Cyclopentylamino- benzenesulfonic acid 2-(3- carbamoylmethyl-ureido)- 1H-benzoimidazol-5-yl ester473.283.3858-t19 embedded image

1-[5-(4-Cyclopentylamino- benzenesulfonyloxy)-1H- benzoimidazol-2-yl- carbamoyl]-piperidine-4- carboxylic acid ethyl ester556.293.9358-u19 embedded image

4-Cyclopentylamino- benzenesulfonic acid 2-(3- piperidin-4-ylmethyl- ureido)-1H-benzoimidazol- 5-yl ester513.333.2558-v19 embedded image

4-Cyclopentylamino- benzenesulfonic acid 2-[3- (2-morpholin-4-yl-ethyl)- ureido]-1H-benzoimidazol- 5-yl ester529.313.2758-w19 embedded image

4-Cyclopentylamino- benzenesulfonic acid 2-[3- (2-amino-2-methyl-propyl)- ureido]-1H-benzoimidazol- 5-yl ester487.323.2558-x19 embedded image

4-Cyclopentylamino- benzenesulfonic acid 2-[3- (4trans-hydroxy-cyclohexyl)- ureido]-1H-benzoimidazol- 5-yl ester514.303.5458-y19 embedded image

4-Cyclopentylamino- benzenesulfonic acid 2-[3- (3-hydroxy-propyl)-ureido]- 1H-benzoimidazol-5-yl ester474.283.4658-z19 embedded image

4-Cyclopentylamino- benzenesulfonic acid 2-[3- (1,1-dimethyl-propyl)-ureido]- 1H-benzoimidazol-5-yl ester486.334.0858-aa19 embedded image

4-Cyclopentylamino- benzenesulfonic acid 2-{3-[2- (2-hydroxy-ethylamino)- ethyl]-ureido}-1H- benzoimidazol-5-yl ester503.303.1958-ab19 embedded image

4-Cyclopentylamino- benzenesulfonic acid 2-[3- (4-hydroxy-butyl)-ureido]-1H- benzoimidazol-5-yl ester488.293.4958-ac19 embedded image

4-Cyclopentylamino- benzenesulfonic acid 2- {3-[3-(2-oxo-pyrrolidin-1- yl)-propyl]-ureido}-1H- benzoimidazol-5-yl ester541.293.5458-ad19 embedded image

4-Cyclopentylamino- benzenesulfonic acid 2-[3- (2-carbamoyl-ethyl)-ureido]- 1H-benzoimidazol-5-yl ester487.303.4058-ac19 embedded image

4-Cyclopentylamino- benzenesulfonic acid 2- [(2S-carbamoyl-pyrrolidine- 1-carbonyl)-amino]-1H- benzoimidazol-5-yl ester513.303.4258-af19 embedded image

4-Cyclopentylamino- benzenesulfonic acid 2- {3-[2-(2-hydroxy-ethoxy)- ethyl]-ureido}-1H- benzoimidazol-5-yl ester504.303.4658-ag19 embedded image

4-Cyclopentylamino- benzenesulfonic acid 2-[3- (3-pyrrolidin-1-yl-propyl)- ureido]-1H- benzoimidazol-5-yl ester527.353.3358-ah19 embedded image

4-Cyclopentylamino- benzenesulfonic acid 2-[3- (1-ethyl-pyrrolidin-2- ylmethyl)-ureido]-1H- benzoimidazol-5-yl ester527.353.3058-ai19 embedded image

4-Cyclopentylamino- benzenesulfonic acid 2-[3- (2-pyrrolidin-1-yl-ethyl)- ureido]-1H- benzoimidazol-5-yl ester513.343.2958-aj19 embedded image

4-Cyclopentylamino- benzenesulfonic acid 2-[3- (2-piperidin-1-yl-ethyl)- ureido]-1H- benzoimidazol-5-yl ester527.353.3358-ak19 embedded image

4-Cyclopentylamino- benzenesulfonic acid 2-[3- (2-hydroxy-1-methyl- ethyl)-ureido]-1H- benzoimidazol-5-yl ester474.303.5158-al19 embedded image

4-Cyclopentylamino- benzenesulfonic acid 2-[3- (2-isopropylamino-ethyl)- ureido]-1H- benzoimidazol-5-yl ester501.343.3158-am19 embedded image

4-Cyclopentylamino- benzenesulfonic acid 2-[3- (2-diethylamino-ethyl)- ureido]-1H- benzoimidazol-5-yl ester515.343.3158-an19 embedded image

2-{3-[5-(4-Cyclopentylamino- benzenesulfonyloxy)-1H- benzoimidazol-2-yl]- ureido}-3S-hydroxy- propionic acid methyl ester518.273.55

Example 59

By using a method similar to that for the preparation of example 54, combining methyl-5-(4-[1-tetrathydrofurylmethyl]aminophenyl-sulfonyloxy)benzimidazole-2-carbamate (example 18) with suitable amine were obtained the following compounds that were characterized by analytical LC/MS ([M+H]⁺ and retention time given in the following table).

n^oPrecursorRetentionexampleexampleAminecompound[M + H]⁺time (min)59-a18 embedded image

4-[(Tetrahydro-furan-2- ylmethyl)-amino]- benzenesulfonic acid 2-(3- carbamoylmethyl-ureido)- 1H-benzoimidazol-5-yl ester489.152.7859-b18 embedded image

4-[(Tetrahydro-furan-2- ylmethyl)-amino]- benzenesulfonic acid 2-[3- (2-hydroxy-ethyl)-ureido]-1H- benzoimidazol-5-yl ester476.152.9159-c18 embedded image

4-[(Tetrahydro-furan-2- ylmethyl)-amino]- benzenesulfonic acid 2-[3- (3-hydroxy-propyl)-ureido]-1H- benzoimidazol-5-yl ester490.182.8959-d18 embedded image

4-[(Tetrahydro-furan-2- ylmethyl)-amino]- benzenesulfonic acid 2-[3- (4-hydroxy-butyl)-ureido]-1H- benzoimidazol-5-yl ester504.193.4459-e18 embedded image

4-[(Tetrahydro-furan-2- ylmethyl)-amino]-benzenesulfonic acid 2-[3-(2-methoxy-1- methyl-ethyl)-ureido]-1H- benzoimidazol-5-yl ester504.193.1159-f18 embedded image

4-[(Tetrahydro-furan-2- ylmethyl)-amino]-benzenesulfonic acid 2-[3-(1-ethyl-pyrrolidin- 2-ylmethyl)-ureido]-1H- benzoimidazol-5-yl ester543.242.8959-g18 embedded image

4-[(Tetrahydro-furan-2- ylmethyl)-amino]-benzenesulfonic acid 2-[3-(2-pyrrolidin-1-yl- ethyl)-ureido]-1H- benzoimidazol-5-yl ester529.222.6659-h18 embedded image

4-[(Tetrahydro-furan-2- ylmethyl)-amino]-benzenesulfonic acid 2-[3-(3-pyrrolidin-1-yl- propyl)-ureido]-1H- benzoimidazol-5-yl ester543.252.7359-i18 embedded image

4-[(Tetrahydro-furan-2- ylmethyl)-amino]-benzenesulfonic acid 2-[3-(2-morpholin-4-yl- ethyl)-ureido]-1H- benzoimidazol-5-yl ester545.232.6159-j18 embedded image

4-[(Tetrahydro-furan-2- ylmethyl)-amino]-benzenesulfonic acid 2-(3-ethyl-ureido)-1H- benzoimidazol-5-yl ester460.173.0859-k18 embedded image

4-[(Tetrahydro-furan-2- ylmethyl)-amino]-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl- ureido)-1H-benzoimidazol-5-yl ester523.072.7059-l18 embedded image

4-[(Tetrahydro-furan-2- ylmethyl)-amino]- benzenesulfonic acid 2-(3- pyridin-3-ylmethyl-ureido)-1H- benzoimidazol-5-yl ester523.192.6459-m18 embedded image

4-[(Tetrahydro-furan-2- ylmethyl)-amino]- benzenesulfonic acid 2- {3-[3-(4-methyl-piperazin- 1-yl)-propyl]-ureido}-1H- benzoimidazol-5-yl ester572.272.6059-n18 embedded image

4-[(Tetrahydro-furan-2- ylmethyl)-amino]- benzenesulfonic acid 2-[3- (2-sulfo-ethyl)-ureido]- 1H-benzoimidazol-5-yl ester540.132.8159-o18 embedded image

4-[(Tetrahydro-furan-2- ylmethyl)-amino]- benzenesulfonic acid 2-(3- cyclobutyl-ureido)-1H- benzoimidazol-5-yl ester486.193.2859-p18 embedded image

4-[(Tetrahydro-furan-2- ylmethyl)-amino]- benzenesulfonic acid 2- {3-[3-(2-oxo-pyrrolidin-1- yl)-propyl]-ureido}-1H- benzoimidazol-5-yl ester557.232.9459-q18 embedded image

4-[(Tetrahydro-furan-2- ylmethyl)-amino]-benzenesulfonic acid 2-{3-[2-(2-hydroxy- ethylamino)-ethyl]-ureido}- 1H-benzoimidazol-5-yl ester519.212.6459-r18 embedded image

4-[(Tetrahydro-furan-2- ylmethyl)-amino]-benzenesulfonic acid 2-[3-(2-piperidin-1-yl- ethyl)-ureido]-1H- benzoimidazol-5-yl ester543.242.74

Example 60

By using a method similar to that for the preparation of example 56, combining 4-fluoro-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester (example 55) with suitable amine were obtained the following compounds that were characterized by analytical LC/MS ([M+H]⁺ and retention time given in the following table).

n^oPrecursorRetentionexampleexampleAminecompound[M + H]⁺time (min)60-a 55 embedded image

4-Benzylamino-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester436.33.6860-b 55 embedded image

4-Methylamino-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester387.33.1860-c 55 embedded image

4-(2-Hydroxy-ethylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester417.32.9860-d 55 embedded image

4-(3-Hydroxy-propylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazo1-5-yl ester431.353.0460-e 55 embedded image

4-(4-Hydroxy-butylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester445.353.1060-f 55 embedded image

4-(2-Methoxy-1-methyl- ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester445.353.4160-g 55 embedded image

4-(2-Pyrrolidin-1-yl- ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester470.372.8060-h 55 embedded image

4-(1-Hydroxymethyl- propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester445.343.2160-i 55 embedded image

4-(2-Hydroxy-1-methyl- ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester431.343.0860-j 55 embedded image

4-(2-Piperidin-1-yl- ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester484.382.8560-k 55 embedded image

4-(3-Pyrrolidin-1-yl- propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester484.372.8560-l 55 embedded image

4-(3-Hydroxy-2,2- dimethyl-propylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester459.343.3060-m 55 embedded image

4-[(Pyridin-3-yl- methyl)-amino]-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester464.302.7760-n 55 embedded image

4-[3-(4-Methyl-piperazin- 1-yl)-propylamino]- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester513.382.6660-o 55 embedded image

4-(2-Methoxy-benzylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester493.323.7460-p 55 embedded image

4-(4-Hydroxy-cyclohexylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester471.363.1160-q 55 embedded image

4-(2-Diethylamino-ethylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester472.372.8260-r 55 embedded image

4-(1S-Hydroxymethyl- propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester445.323.1960-s 55 embedded image

4-(2-Ethylamino-ethylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester444.342.7560-t 55 embedded image

4-(2-Diisopropylamino- ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester500.382.9160-u 55 embedded image

4-(2-Morpholin-4-yl- ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester486.342.7660-v 55 embedded image

4-(1-Aza-bicyclo[2.2.2]- oct-3-ylamino)-benzenesulfonic acid 2-(cyclopropane-carbonyl- amino)-1H-benzoimidazol-5-yl ester482.352.8260-w 55 embedded image

4-(2-Phenylamino-ethylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester492.343.3460-x 55 embedded image

4-(1-Benzyl-pyrrolidin-3- acid 2-(cyclopropane- carbonyl-amino)-1H- benzoimidazol-5-yl ester532.353.0560-y 55 embedded image

4-(2R-Carbamoyl-pyrrolidin- 1-yl)-benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester470.323.0060-z 55 embedded image

4-(3-Dimethylamino- propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester458.362.7960-aa55 embedded image

4-(2-Piperazin-1-yl- ethylamino)-benzene-sulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester485.372.6360-ab55 embedded image

4-(2-Carbamoyl-cyclohexylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester498.343.2460-ac55 embedded image

4-(2-Acetylamino-ethylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester458.322.9560-ad55 embedded image

4-[2-(2-Amino-ethylamino)- ethylamino]-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester459.342.6060-ae55 embedded image

4-[3-(2-Oxo-pyrrolidin-1- yl)-propylamino]- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester498.343.1460-af55 embedded image

4-[2-(1H-Imidazol-4-yl)- ethylamino]-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester467.312.7960-ag55 embedded image

4-[(Pyridin-2-ylmethyl)- amino]-benzenesulfonic acid 2-(cyclopropane- carbonyl-amino)-1H- benzoimidazol-5-yl ester464.312.8060-ah55 embedded image

4-Cyclobutylamino- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester427.313.6360-ai55 embedded image

4-[2-(2-Hydroxy-ethoxy)- ethylamino]-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester461.343.0160-aj55 embedded image

4-(2,3-Dihydroxy-propylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester447.312.8460-ak55 embedded image

4-(2-Imidazol-1-yl-ethylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester467.322.7860-al55 embedded image

4-[2-(2-Hydroxy-ethylamino)- ethylamino]-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester460.342.7060-am55 embedded image

4-(2-Methoxy-ethylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester431.323.2760-an55 embedded image

4-(2-Dimethylamino-1- methyl-ethylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester458.362.7960-ao55 embedded image

4-(Pyrrolidin-3-ylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester442.352.7560-ap55 embedded image

4-[2-(1H-Indol-3-yl)- ethylamino]-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester516.323.7560-aq55 embedded image

4-(2-Dimethylamino- ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester444.352.7460-ar55 embedded image

4-(2-Phenoxy-ethylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester493.323.7860-as55 embedded image

4-(Bicyclo[2.2.1]hept-2R- ylamino)-benzenesulfonic acid 2-(cyclopropane- carbonyl-amino)-1H- benzoimidazol-5-yl ester467.353.9560-at55 embedded image

4-(2-Methylamino-ethylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester430.352.7460-au55 embedded image

4-(2-Propylamino-ethylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester458.362.8460-av55 embedded image

4-(1-Methyl-2-phenoxy- ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester507.333.8960-aw55 embedded image

4-[(Piperidin-4-ylmethyl)- amino]-benzenesulfonic acid 2-(cyclopropane- carbonyl-amino)-1H- benzoimidazol-5-yl ester470.362.8460-ax55 embedded image

4-(4-Methoxy-benzylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester493.313.6860-ay55 embedded image

4-(1H-Benzoimidazol-5- ylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester489.292.8060-az55 embedded image

4-(3-Methoxy-propylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester445.103.1760-ba55 embedded image

4-(2,2-Dimethoxy-ethylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester461.113.2060-bb55 embedded image

4-(4-Dimethylamino- phenylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester492.122.8760-bc55 embedded image

4-(3-Methoxy-benzylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester493.103.6960-bd55 embedded image

4-(4-Pyrrolidin-1-yl- butylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester498.162.6460-be55 embedded image

4-(2,3-Dimethoxy-benzylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester523.113.8060-bf55 embedded image

4-Prop-2-ynylamino- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester411.073.1560-bg55 embedded image

4-[4-(2-Hydroxy-ethyl)- piperazin-1-yl]- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester464.092.4860-bh55 embedded image

4-[(Pyridin-4-ylmethyl)- amino]-benzenesulfonic acid 2-(cyclopropane- carbonyl-amino)-1H- benzoimidazol-5-yl ester464.092.4860-bi55 embedded image

4-[2-(Ethyl-m-tolyl- amino)-ethylamino]- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester534.183.1060-bj55 embedded image

4-(2-Hydroxy-cyclohexylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester471.133.2560-bk55 embedded image

4-(3-Dimethylamino-2,2- dimethyl-propylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester486.182.6460-bl55 embedded image

4-[3-(2-Hydroxy-ethylamino)- propylamino]-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester474.142.4560-bm55 embedded image

4-[(Tetrahydro-furan-2RS- ylmethyl)-amino]-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester;474.143.1560-bn55 embedded image

4-[(Tetrahydro-furan-2R- ylmethyl)-amino]-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester;456.873.2360-bo55 embedded image

(Tetrahydro-furan-2S- ylmethyl)-amino]-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester;456.883.4860-bp55 embedded image

4-(2-Butylamino-ethylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester471.922.8060-bq55 embedded image

4-(3-Methylamino-propylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester443.902.5460-br55 embedded image

4-(1S,2-Dicarbamoyl- ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester486.902.6060-bs55 embedded image

2-{4-[2-(Cyclopropanecarbonyl- amino)-1H-benzoimidazol-5- yloxysulfonyl]-phenylamino}-3R- hydroxy-propionic acid methyl ester474.832.8160-bt55 embedded image

4-(2-Carbamoyl-ethylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester443.862.7160-bu55 embedded image

4-(3-Methoxy-propylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester444.893.1560-bv55 embedded image

4-(3,4,5-Trimethoxy-benzylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester552.853.4660-bw55 embedded image

4-(Carbamoylmethyl-amino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester429.882.8560-bx55 embedded image

1-{4-[2-(Cyclopropanecarbonyl- amino)-1H-benzoimidazol-5- yloxysulfonyl]-phenyl}- piperidine-4-carboxylic acid ethyl ester512.873.8160-by55 embedded image

4-(2-Amino-2-methyl- propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester443.922.4860-bz55 embedded image

3-{4-[2-(Cyclopropanecarbonyl- amino)-1H-benzoimidazol-5- yloxysulfonyl]-phenylamino}- propionic acid methyl ester458.883.1360-ca55 embedded image

4-(3-Morpholin-4-yl-propylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester499.912.5660-cb55 embedded image

4-(5-Hydroxy-pentylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester458.933.0860-cc55 embedded image

4-[(5S-Amino-2,2,4S-trimethyl- cyclopentylmethyl)- amino]-benzenesulfonic acid 2-(cyclopropane-carbonyl- amino)-1H-benzoimidazol-5-yl ester511.943.2460-cd55 embedded image

4-(2-Hydroxymethyl- phenylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester2.98430.9160-ce55 embedded image

4-(4-Ethoxy-phenylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester493.173.9760-cf55 embedded image

4-Ethylamino-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester401.233.4260-cg55 embedded image

4-(2-Sulfo-ethylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester481.002.8760-ch55 embedded image

4-{4-[2-(Cyclopropanecarbonyl- amino)-1H-benzoimidazol-5- yloxysulfonyl]-phenylamino}- piperidine-1-carboxylic acid ethyl ester528.063.7760-ci55 embedded image

4-({4-[2-(Cyclopropanecarbonyl- amino)-1H-benzoimidazol-5- yloxysulfonyl]-phenylamino}- methyl)-benzoic acid507.003.3060-cj55 embedded image

4-[(1-Carbamimidoyl-piperidin- 4-ylmethyl)-amino]-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester512.102.7360-ck55 embedded image

4-{4-[2-(Cyclopropanecarbonyl- amino)-1H-benzoimidazol-5- yloxysulfonyl]-phenyl}- piperazine-1-carboxylic acid tert-butyl ester542.073.8560-cl55 embedded image

3-{4-[2-(Cyclopropanecarbonyl- amino)-1H-benzoimidazol-5- yloxysulfonyl]-phenylamino}- 3-phenyl-propionic acid521.033.3860-cm55 embedded image

4-Piperidin-1-yl-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester441.073.7660-cn55 embedded image

4-(1-Methyl-4-oxo-imidazolidin-2- ylideneamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester468.932.4560-co55 embedded image

4-(4-Methyl-piperazin-1- yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester456.212.9460-cp55 embedded image

4-(3-Hydroxy-pyrrolidin- 1-yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester442.953.0560-cq55 embedded image

4-(Cyclopropylmethyl- amino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester426.973.6160-cr55 embedded image

4-[(2-Dimethylamino-ethyl)- methyl-amino]-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester457.982.5160-cs55 embedded image

4-Isobutylamino-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester428.993.9660-ct55 embedded image

4-[Ethyl-(2-hydroxy-ethyl)- amino]-benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester444.972.9660-cu55 embedded image

4-(2-Hydroxy-1-hydroxymethyl- ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester446.932.6160-cv55 embedded image

4-Propylamino-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester414.963.4560-cw55 embedded image

4-Cyclopropylamino- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester412.953.3860-cx55 embedded image

4-Morpholin-4-yl-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester442.953.2460-cy55 embedded image

4-[2-(1-Methyl-pyrrolidin- 2-yl)-ethylamino]-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester483.992.6360-cz55 embedded image

4-[(1,3-Dimethyl-1H-pyrazol- 4-ylmethyl)-amino]-benzenesulfonic acid 2-(cyclopropane-carbonyl- amino)-1H-benzoimidazol-5-yl ester480.962.9960-da55 embedded image

4-(4-Acetylamino-benzylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester519.943.4560-db55 embedded image

4-(3-Cyclohexylamino- propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester512.022.7860-dc55 embedded image

4-(3-Ethoxy-propylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester458.983.4160-dd55 embedded image

4-Pyrrolidin-1-yl- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester426.963.5360-de55 embedded image

4-(4-Methyl-benzylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester476.963.8160-df55 embedded image

4-[1,4′]Bipiperidinyl-1′- yl-benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester524.012.7660-dg55 embedded image

4-(2-Pyridin-3-yl-pyrrolidin- 1-yl)-benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester503.962.7660-dh55 embedded image

4-(4-Hydroxy-piperidin-1- yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester456.972.9060-di55 embedded image

4-[(2-Hydroxy-ethyl)- methyl-amino]-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester430.972.8560-dj55 embedded image

4-(3-Hydroxy-pyridin-2- ylamino)-benzenesulfonic acid 2-(cyclopropane- carbonyl-amino)-1H- benzoimidazol-5-yl ester465.932.8860-dk55 embedded image

4-[(1-Carbamoyl-piperidin-4- ylmethyl)-amino]-benzenesulfonic acid 2-(cyclopropane- carbonyl-amino)-1H- benzoimidazol-5-yl ester513.002.9660-dl55 embedded image

4-(2-Pyrrol-1-yl-ethylamino)- benzenesulfonic acid 2- cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester465.973.4360-dm55 embedded image

4-(4-Cyclopentyl-piperazin-1- yl)-benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester510.012.8860-dn55 embedded image

4-(2-Propoxy-ethylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester458.993.4360-do55 embedded image

4-(3-Cyclohexylamino- propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester512.032.8660-dp55 embedded image

4-(1H-Indol-5-ylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester487.962.7660-dq55 embedded image

4-(4-Amino-benzylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester477.942.8060-dr55 embedded image

4-(2S-Methoxymethyl-pyrrolidin- 1-yl)-benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester470.993.6560-ds55 embedded image

4-[4-(2-Hydroxy-ethyl)- piperidin-1-yl]-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester485.013.2160-dt55 embedded image

4-[2-(2-Hydroxy-ethyl)- piperidin-1-yl]-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester485.023.2360-du55 embedded image

4-(2-Isopropylamino- ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester458.012.7360-dv55 embedded image

3-{4-[2-(Cyclopropanecarbonyl- amino)-1H-benzoimidazol-5- yloxysulfonyl]-phenyl- amino}-propionic acid444.952.8160-dw55 embedded image

4-[Methyl-(2-methylamino-ethyl)- amino]-benzenesulfonic acid 2-(cyclopropane- carbonyl-amino)-1H- benzoimidazol-5-yl ester443.992.4660-dx55 embedded image

4-(3-Acetylamino-pyrrolidin- 1-yl)-benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester483.982.8860-dy55 embedded image

{4-[2-(Cyclopropane-carbonyl- amino)-1H-benzoimidazol-5- yloxy-sulfonyl]-phenylamino}- acetic acid430.942.8860-dz55 embedded image

4-(4-Hydroxy-piperidin-1- yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester456.982.9660-ea55 embedded image

4-(4-Dimethylamino-benzylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester506.022.7860-eb55 embedded image

4-(3-Imidazol-1-yl-propylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester480.982.7860-ec55 embedded image

4-(Quinoxalin-5-ylamino)- benzenesulfonic acid 2- (cyclopropane-carbonyl- amino)-1H-benzoimidazol-5-yl ester500.963.4160-ed55 embedded image

4-[4-(2-Hydroxy-ethyl)- piperazin-1-yl]-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester486.002.4860-ef55 embedded image

4-(2-Hydroxy-1,1-dimethyl- ethylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester444.982.4960-eg55 embedded image

1-{4-[2-(Cyclopropanecarbonyl- amino)-1H-benzoimidazol-5- yloxysulfonyl]-phenyl}- piperidine-4-carboxylic acid484.983.1160-eh55 embedded image

6-{4-[2-(Cyclopropanecarbonyl- amino)-1H-benzoimidazol-5- yloxysulfonyl]-phenylamino}- hexanoic acid methyl ester500.993.7060-ei55 embedded image

4-[4-(4-Methoxy-phenyl)- piperazin-1-yl]-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester547.993.2360-ej55 embedded image

4-[4-(2-Methoxy-ethyl)- piperazin-1-yl]-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester500.012.5160-ek55 embedded image

4-[(2-Hydroxy-ethyl)-phenyl- amino]-benzenesulfonic acid 2- (cyclopropanecarbonyl-amino)-1H- benzoimidazol-5-yl ester492.963.6560-el55 embedded image

4-[(Furan-2-ylmethyl)- amino]-benzenesulfonic acid 2-(cyclopropane-carbonyl-amino)- 1H-benzoimidazol-5-yl ester452.943.3860-em55 embedded image

4-(4-Carbamoyl-piperidin- 1-yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester483.982.9060-en55 embedded image

4-(3-Methyl-piperazin-1- yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester456.002.5460-eo55 embedded image

4-(2,6-Dimethyl-morpholin- 4-yl)-benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester471.013.6160-ep55 embedded image

4-(4-Phenyl-piperazin-1- yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl- benzoimidazol-5-yl ester518.003.7160-eq55 embedded image

4-(4-Pyridin-2-yl-piperazin- 1-yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester519.002.7060-er55 embedded image

4-(4-Diethylamino-1-methyl- butylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester514.062.9860-es55 embedded image

4-{4-[2-(Cyclopropanecarbonyl- amino)-1H-benzoimidazol-5- yloxysulfonyl]-phenyl}- piperazine-1-carboxylic acid ethyl ester513.993.3860-et55 embedded image

4-(5-Hydroxy-naphthalen- 1-ylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl amino)-1H-benzoimidazol-5-yl ester514.953.3560-eu55 embedded image

4-[2-(4-Hydroxy-3-methoxy- phenyl)-ethylamino]- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester52.972.8860-ev55 embedded image

4-(9H-Purin-6-ylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester490.942.7160-ew55 embedded image

1-{4-[2-(Cyclopropanecarbonyl- amino)-1H-benzoimidazol-5- yloxysulfonyl]-phenyl}- piperidine-3-carboxylic acid484.983.1860-ex55 embedded image

4-(3,3-Dimethyl-piperidin- 1-yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester469.034.1860-ey55 embedded image

4-(4-Methyl-piperidin-1- yl)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester455.023.8360-ez55 embedded image

4-(2-Pyridin-2-yl-ethylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester477.982.5860-fa55 embedded image

4-(3-Hydroxymethyl-phenyl- amino)-benzene-sulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester478.982.8060-fb55 embedded image

4-(2-Oxo-2,3-dihydro-1H- pyrimidin-4-ylideneamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester466.942.4660-fc55 embedded image

4-(3-Piperidin-1-yl- propylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester498.052.8560-fd55 embedded image

4-[2-(1H-Indol-3-yl)- ethylamino]-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester515.983.8960-fe55 embedded image

4-(5-Carbamoyl-1H-imidazol- 4-ylamino)-benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester481.962.6860-ff55 embedded image

4-(1-Hydroxymethyl-butylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester459.013.3360-fg55 embedded image

4-(1-Benzyl-piperidin-4- ylamino)-benzenesulfonic acid 2-(cyclopropane-carbonyl- amino)-1H-benzoimidazol-5-yl ester546.042.8160-fh55 embedded image

4-{4-[2-(2-Hydroxy-ethoxy)- ethyl)-ethyl]-piperazin- 1-yl}-benzenesulfonic acid 2-(cyclopropane-carbonyl- amino)-1H-benzoimidazol-5-yl ester530.012.4960-fi55 embedded image

4-(4-Methyl-[1,4]diazepan- 1-yl)-benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester470.032.4860-fj55 embedded image

4-(3-Azepan-1-yl-propylamino)- benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester512.062.7360-fk55 embedded image

4-(2,6-cis-Dimethyl-morpholin- 4-yl)-benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester512.043.7360-fl55 embedded image

4-(2S-Hydroxymethyl-pyrrolidin- 1-yl)-benzenesulfonic acid 2- (cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester457.003.1960-fm55 embedded image

4-[4-(3-Pyrrolidin-1-yl-propyl)- [1,4]diazepan-1-yl]- benzenesulfonic acid 2-(cyclopropanecarbonyl- amino)-1H-benzoimidazol-5-yl ester567.072.39

Example 61
Preparation of 4-trifluoromethoxy-benzenesulfonic acid 2-methoxycarbonylamino-1H-benzoimidazol-5-yl ester

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step 1: 7.82 g of 4-amino-3-nitrophenol in 460 ml of methanol were hydrogenated with catalytic amount of palladium on carbon (800 mg, 10% Pd/C). After hydrogen uptake was complete, the catalyst was filtered off, washed with methanol and the filtrate was concentred under reduced pressure to give 6 g of crude 3,4-diaminophenol.

Step 2: 6 g of 3,4-diaminophenol 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 reaction mixture was refluxed for 4 hours. Solvents were then evaporated under reduce pressure yielding 10.8 g crude (5-hydroxy-1H-benzoimidazol-2-yl)-carbamic acid methyl ester. The residue was subjected to flash chromatography eluting with a mixture of dichloromethane-methanol (9:1; v/v) to give 5.6 g of a beige solid. Mass spectrum: 208 [M+H]⁺, retention time=0.56 minute.

Step 3: A stirred solution of (5-hydroxy-1H-benzoimidazol-2-yl)-carbamic acid methyl ester (100 mg) and 4-trifluoromethoxy-benzenesulfonyl chloride (126 mg) in acetone (3 ml) was treated with triethylamine (130 μl). After stirring at ambient temperature for 4 hours, the reaction mixture was 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-trifluoromethoxy-benzenesulfonic acid 2-methoxycarbonylamino-1H-benzoimidazol-5-yl ester (65 mg) as an off-white solid Mass spectrum: 432 [M+H]⁺; retention time=15.04 minutes.

Example 62

By using a method similar to that for the preparation of example 61, combining (5-hydroxy-1H-benzoimidazol-2-yl)-carbamic acid methyl ester with suitable benzene sulfonyl chloride were obtained the following compounds that were characterized by analytical LC/MS ([M+H]⁺ and retention time given in the following table).

Retention timeExampleBenzene sulfonyl chlorideCompound(minutes)Mass [M + H]⁺62-a embedded image

3,5-Dimethyl-isoxazole-4- sulfonic acid 2- methoxycarbonylamino-1H- benzoimidazol-5-yl ester15.8736762-b embedded image

Thiophene-2-sulfonic acid 2- methoxycarbonylamino-1H- benzoimidazol-5-yl ester14.9535462-c embedded image

5-Isoxazol-3-yl-thiophene-2- sulfonic acid 2- methoxycarbonylamino-1H- benzoimidazol-5-yl ester12.5842162-d embedded image

2-Fluoro-benzenesulfonic acid 2-methoxycarbonylamino-1H- benzoimidazol-5-yl ester10.3736662-e embedded image

5-(1-Methyl-5-trifluoromethyl- 1H-pyrazol-3-yl)-thiophene-2- sulfonic acid 2- methoxycarbonylamino-1H- benzoimidazol-5-yl ester16.5850262-f embedded image

3-Trifluoromethoxy- benzenesulfonic acid 2- methoxycarbonylamino-1H- benzoimidazol-5-yl ester4.0643262-g embedded image

2-Trifluoromethoxy- benzenesulfonic acid 2- methoxycarbonylamino-1H- benzoimidazol-5-yl ester13.0643262-h embedded image

2,6-Difluoro-benzenesulfonic acid 2-methoxycarbonylamino- 1H-benzoimidazol-5-yl ester9.7638462-i embedded image

3-Methoxy-benzenesulfonic acid 2-methoxycarbonylamino- 1H-benzoimidazol-5-yl ester10.1637862-j embedded image

3-(2-Methoxycarbonylamino- 1H-benzoimidazol-5- yloxysulfonyl)-thiophene-2- carboxylic acid methyl ester8.0741262-k embedded image

3,4-Dimethoxy- benzenesulfonic acid 2- methoxycarbonylamino-1H- benzoimidazol-5-yl ester9.3240862-l embedded image

3-Nitro-benzenesulfonic acid 2- methoxycarbonylamino-1H- benzoimidazol-5-yl ester11.5639362-m embedded image

3-Trifluoromethyl- benzenesulfonic acid 2- methoxycarbonylamino-1H- benzoimidazol-5-yl ester14.1941662-n embedded image

2-Cyano-benzenesulfonic acid 2-methoxycarbonylamino-1H- benzoimidazol-5-yl ester9.4337362-o embedded image

2-Trifluoromethyl- benzenesulfonic acid 2- methoxycarbonylamino-1H- benzoimidazol-5-yl ester13.2641662-p embedded image

2,4-Difluoro-benzenesulfonic acid 2-methoxycarbonylamino- 1H-benzoimidazol-5-yl ester11.3538462-q embedded image

5-Fluoro-2-methyl- benzenesulfonic acid 2- methoxycarbonylamino-1H- benzoimidazol-5-yl ester12.9338062-r embedded image

3-Fluoro-benzenesulfonic acid 2-methoxycarbonylamino-1H- benzoimidazol-5-yl ester11.1936662-s embedded image

4-Cyano-benzenesulfonic acid 2-methoxycarbonylamino-1H- benzoimidazol-5-yl ester10.3737362-t embedded image

2-Methoxy-5-(2- methoxycarbonylamino-3H- benzoimidazol-5- yloxysulfonyl)-thiophene-3- carboxylic acid methyl ester8.5244262-u embedded image

1,3,5-Trimethyl-1H-pyrazole-4- sulfonic acid 2- methoxycarbonylamino-3H- benzoimidazal-5-yl ester6.9638062-v embedded image

6-Morpholin-4-yl-pyridine-3- sulfonic acid 2- methoxycarbonylamino-3H- benzoimidazol-5-yl ester7.8243462-w embedded image

2,4,6-Trifluoro-benzenesulfonic acid 2-methoxycarbonylamino- 1H-benzoimidazol-5-yl ester3.34402

Example 63
Preparation of 4-benzyloxy-benzenesulfonic acid 2-methoxycarbonylamino-1H-benzoimidazol-5-yl ester

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Step 1: A stirred solution of 4-amino-3-nitro-phenol (3 g) and benzoic acid 4-chlorosulfonyl-phenyl ester (5.7 g) in acetone (80 ml) was treated with triethylamine (5.4 ml). After stirring at ambient temperature for 14 hours, the reaction mixture was evaporated. The residue 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 ester (5.22 g) as a yellow solid Mass spectrum: 401 [M+H]⁺; retention time=4.59 minutes.

Step 2: A solution benzoic acid 4-amino-3-nitro-phenoxysulfonyl)-phenyl ester (3 g) and 2N aqueous solution of sodium hydroxyde in methanol (55 ml) was reluxed for 2 hours. The reaction mixture was concentrated and water (100 ml) and ethyl acetate (100 ml) were 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-phenyl ester.

Step 3: A solution of cesium carbonate (156 mg) in water (0.3 ml) was added to a solution of 4-hydroxy-benzenesulfonic acid 4-amino-3-nitro-phenyl ester (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 ester.

Step 4: Sodium dithionite (624 mg) was added to a solution of 4-benzyloxy-benzenesulfonic acid 4-amino-3-nitrophenyl ester (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 the filtrate was evaporated. The residue was extracted three times with ethyl acetate (15 ml). The combined extracts were dried over magnesium sulfate then evaporated to 137 mg of crude 4-benzyloxy-benzenesulfonic acid 3,4-diamino-phenyl ester.

Step 5: preparation of 4-Benzyloxy-benzenesulfonic acid 2-methoxycarbonylamino-1H-benzoimidazol-5-yl ester

To a solution of 4-benzyloxy-benzenesulfonic 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-thiopseudourea (89 mg). The reaction mixture was refluxed for 2 hours then allowed to cool to ambient temperature and stirred at this temperature for 14 hours. The resultant precipitate was filtered, washed with diethyl ether and dried under vacuum to afford 4-benzyloxy-benzenesulfonic acid 2-methoxycarbonylamino-1H-benzoimidazol-5-yl ester as a beige 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-benzenesulfonic acid 4-amino-3-nitro-phenyl ester with suitable alkyl halide were obtained the following compounds that were characterized by analytical LC/MS ([M+H]⁺ and retention time given in the following table).

Retention timeExampleAlkyl halideCompound(minutes)Mass [M + H]⁺64-a embedded image

4-Ethoxy-benzenesulfonic acid 2- methoxycarbonylamino-3H- benzoimidazol-5-yl ester12.3439264-d embedded image

4-(2-Morpholin-4-yl-ethoxy)- benzenesulfonic acid 2- methoxycarbonylamino-3H- benzoimidazol-5-yl ester3.2447764-c embedded image

4-(2-Methoxy-ethoxy)- benzenesulfonic acid 2- methoxycarbonylamino-3H- benzoimidazol-5-yl ester9.9742264-d embedded image

4-(2-piperidin-1-yl-ethoxy)- benzenesulfonic acid 2- methoxycarbonylamino-3H- benzoimidazol-5-yl ester3.9447564-e embedded image

[4-(2-Methoxycarbonylamino-3H- benzoimidazol-5-yloxysulfonyl)- phenoxy]-acetic acid7.23422

Example 65
Preparation of 4-(2-oxo-2-pyrrolidin-1-yl-ethoxy)-benzenesulfonic acid 2-methoxycarbonylamino-1H-benzoimidazol-5-yl-ester

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A solution of [4-(2-methoxycarbonylamino-3H-benzoimidazol-5-yloxysulfonyl)-phenoxy]-acetic acid (40 mg, example 64-e) in dry dimethylformamide (3 ml) was treated with N-{(dimethylamino)(1H-1,2,3-triazolo[4,5-b]pyridin-1-yl)methylene}-N-methylmethanaminium hexafluorophosphate N-oxide (39 mg) and diisopropylethylamine (50 μl). After stirring at ambient temperature for 30 minutes, pyrrolidine (21 μl) was added and the mixture stirred at room temperature for a further 3 hours. The solvent was removed in vacuo and the residue was purified by triggered LC/MS to give 4-(2-oxo-2-pyrrolidin-1-yl-ethoxy)-benzenesulfonic acid 2-methoxycarbonylamino-1H-benzoimidazol-5-yl-ester as an off-white solid. Mass spectrum: 475[M+H]⁺; retention time=8.39 minutes.

Example 66

By using a method similar to that for the preparation of example 65, combining [4-(2-methoxycarbonylamino-3H-benzoimidazol-5-yloxysulfonyl)-phenoxy]-acetic acid with suitable amine were obtained the following compounds that were characterized by analytical LC/MS ([M+H]⁺ and retention time given in the following table).

Retention timeExampleAmineCompound(minutes)Mass [M + H]+66-a embedded image

4-[2-(4-Methyl-piperazin-1- yl)-2-oxo-ethoxy]- benzenesulfonic acid 2- methoxycarbonylamino-1H- benzoimidazol-5-yl ester1.9650466-b embedded image

4-[(3-diethylamino- propylcarbamoyl)-methoxy]- benzenesulfonic acid 2- methoxycarbonylamino-1H- benzoimidazol-5-yl ester1.9653466-c embedded image

4-{[(furan-2-ylmethyl)- carbamoyl]-methoxy}- benzenesulfonic acid 2- methoxycarbonylamino-1H- benzoimidazol-5-yl ester10.89501

Example 67
Preparation of 4-(cyclopropylmethyl-amino)-benzene sulfonic acid 2-methoxycarbonylamino-1H-benzoimidazol-5-yl ester

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Step 1: preparation of 4-(cyclopropylmethyl-amino)-benzenesulfonic acid 4-amino-3-nitro-phenyl ester

A solution of 4-fluoro-benzenesulfonic acid 4-amino-3-nitro-phenyl ester (800 mg) and cyclopropylmethylamine (890 μl) in N-methylpyrrolidinone (8 ml) was heated at 110° C. in a sealed tube for 14 hours. The reaction mixture was then poured into water (150 ml) and extracted three times with ethyl 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)-benzenesulfonic acid 4-amino-3-nitro-phenyl ester (786 mg) as a yellow solid.

Step 2: Sodium dithionite (3 g) was added to a solution of 4-(cyclopropylmethyl-amino)-benzenesulfonic acid 4-amino-3-nitro-phenyl ester (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 filtrate 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-phenyl ester.

Step 3: To a solution of 4-(cyclopropylmethyl-amino)-benzenesulfonic acid 3,4-diamino-phenyl ester (648 mg) in acetic acid (4.5 ml) and methanol (40 ml) at 80° C. was added 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (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 ether and dried under vacuum to afford 4-(cyclopropylmethyl-amino)-benzene sulfonic acid 2-methoxycarbonylamino-1H-benzoimidazol-5-yl ester (378 mg) as a beige solid. Mass spectrum: 417 [M+H]⁺; retention time=13.16 minutes.

Example 68

By using a method similar to that for the preparation of example 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+H]⁺ and retention time given in the following table).

Retention timeMassExampleAmineCompound(minutes)[M + H]+68-a embedded image

4-(2-methoxy-ethylamino)- benzenesulfonic acid 2- methoxycarbonylamino-1H- benzoimidazol-5-yl ester8.8942168-b embedded image

4-(2-hydroxy-1-methyl- ethylamino)-benzenesulfonic acid 2-methoxycarbonylamino- 1H-benzoimidazol-5-yl ester6.8442168-c embedded image

4-(benzylamino)- benzenesulfonic acid 2- methoxycarbonylamino-1H- benzoimidazol-5-yl ester4.445368-d embedded image

4-(2-Morpholin-4-yl- ethylamino)-benzenesulfonic acid 2-methoxycarbonylamino- 1H-benzoimidazol-5-yl ester2.4447668-e embedded image

4-(2-Piperidin-4-yl-ethylamino)- benzenesulfonic acid 2-[3-(2- piperidin-1-yl-ethyl)-ureido]- 3H-benzoimidazol-5-yl ester2.7746068-f embedded image

4-[(1-Ethyl-pyrrolidin-2- ylmethyl)-amino]-benzenesulfonic acid 2-[3-(2-piperidin-1-yl-ethyl)- ureido]-3H-benzoimidazol-5-yl ester2.3474

Example 69
Preparation of 4-cyclopentylamino-benzenesulfonic acid 2-(3,4-dimethoxy-phenylamino)-1H-benzoimidazol-5-yl ester

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Step 1: A solution of 1-benzyl-6-methoxy-1H-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 aqueous solution of ammonium chloride (100 ml) and extracted three times with ethyl acetate (65 ml). The combined extracts were dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (1:1, v/v) to 1-benzyl-2-chloro-6-methoxy-1H-benzoimidazole (2.09 g) as a yellow solid. Mass spectrum: 273 [M+H]⁺, retention time=3.93 minutes.

Step 2: A mixture of 1-benzyl-2-chloro-6-methoxy-1H-benzoimidazole (600 mg), hydrobromic acid (48%, 11 ml) and glacial acetic acid (6 ml) was heated under reflux for 1 hour. After cooling the mixture was neutralised by addition of 10% sodium bicarbonate solution then extracted 3 times with dichloromethane (30 ml). The combined extracts were dried over magnesium sulfate and then evaporated to give 3-benzyl-2-chloro-3H-benzoimidazol-5-ol (470 mg) as a yellow solid. Mass spectrum: 259 [M+H]⁺ retention time=3.4 minutes.

Step 3: A mixture of 3-benzyl-2-chloro-3H-benzoimidazol-5-ol (250 mg) and 4-amino veratrole (296 mg) in N-methylpyrrolidinone (3 ml) was heated 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 extracted three times with ethyl acetate (30 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 dichloromethane and methanol (95:5, v/v) to give 3-benzyl-2-(3,4-dimethoxy-phenylamino)-3H-benzoimidazol-5-ol (141 mg) as a yellow solid.

Mass spectrum: 376 [M+H]⁺ retention time: 3.44 minutes.

Step 4: A stirred solution of 3-benzyl-2-(3,4-dimethoxy-phenylamino)-3H-benzoimidazol-5-ol (141 mg) and 4-fluoro-benzenesulfonyl chloride (190 mg) in acetone (8 ml) was treated with triethylamine (258 μl). After stirring at ambient temperature for 4 hours, the reaction mixture was 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-fluoro-benzenesulfonic acid 3-benzyl-2-(3,4-dimethoxy-phenylamino)-3H-benzoimidazol-5-yl ester (157 mg) as a yellow solid. Mass spectrum: 534 [M+H]⁺, retention time: 3.7 minutes.

Step 5: A solution of 4-fluoro-benzenesulfonic acid 3-benzyl-2-(3,4-dimethoxy-phenylamino)-3H-benzoimidazol-5-yl ester (151 mg) and cyclopentylamine (118 μl) in N-methylpyrrolidinone (1.5 ml) was heated at 110° C. in a sealed tube for 3 hours. The reaction mixture was allowed to cool then poured into water (30 ml) and extracted three times with ethyl acetate. The combined extracts 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-benzenesulfonic acid 3-benzyl-2-(3,4-dimethoxy-phenylamino)-3H-benzoimidazol-5-yl ester (122 mg) as a brown solid. Mass spectrum: 599 [M+H]⁺, retention time=4.0 minutes.

Example 70

By using a method similar to that for the preparation of example 69, combining 3-benzyl-2-chloro-3H-benzoimidazol-5-ol with suitable amine in step 3 were obtained the following compounds that were characterized by analytical LC/MS ([M+H]⁺ and retention time given in the following table).

Retention timeMassExampleAmineCompound(minute)[M + H]⁺70-a embedded image

4-Cyclopentylamino- benzenesulfonic acid 2- phenylamino-1H- benzoimidazol-5-yl ester12.3144970-b embedded image

4-Cyclopentylamino- benzenesulfonic acid 2- (4-morpholin-4-yl-phenylamino)- 1H-benzoimidazol-5-yl ester11.5853470-c embedded image

4-Cyclopentylamino- benzenesulfonic acid 2- (3,5-dimethyl-phenylamino)-1H- benzoimidazol-5-yl ester9.5547770-d embedded image

4-Cyclopentylamino- benzenesulfonic acid 2- (4-methoxy-phenylamino)-1H- benzoimidazol-5-yl ester8.6947970-e embedded image

4-Cyclopentylamino- benzenesulfonic acid 2- (4-dimethylamino- phenylamino)-1H- benzoimidazol-5-yl ester8.5949270-f embedded image

4-Cyclopentylamino- benzenesulfonic acid 2- (3-methoxy-5-trifluoromethyl- phenylamino)-1H- benzoimidazol-5-yl ester11.9454770-g embedded image

3-[5-(4-Cyclopentylamino- benzenesulfonyloxy)-1H- benzoimidazol-2-ylamino]- benzoic acid ethyl ester10.1352170-h embedded image

4-Cyclopentylamino- benzenesulfonic acid 2- [(4-(4-methyl-piperazin-1- yl)-phenylamino)-1H- benzoimidazol-5-yl ester6.64547

Example 71
Preparation of 4-cyclopentylamino-benzenesulfonic acid 2-(3-phenyl-propionylamino)-1H-benzoimidazol-5-yl ester

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A solution of 3-phenyl propionic acid (9.7 mg) in dry dimethylformamide (0.6 ml) was treated with N-{(dimethylamino)(1H-1,2,3-triazolo[4,5-b]pyridin-1-yl) methylene}-N-methylmethanaminium hexafluorophosphate N-oxide (21 mg) and diisopropylethylamine (12 μl). After stirring at ambient temperature for 30 minutes, 4-cyclopentylamino-benzenesulfonic acid 2-amino-3H-benzoimidazol-5-yl ester (20 mg) was added and the mixture stirred at room temperature for a further 3 hours. The solvent was removed under vacuo and the residue was purified by triggered LC/MS to give 4-cyclopentylamino-benzenesulfonic acid 2-(3-phenyl-propionylamino)-1H-benzoimidazol-5-yl ester as an off-white solid (11 mg). Mass spectrum: 505 [M+H]⁺; retention time=4.59 minutes.

Example 72
Preparation of 4-cyclopentylamino-benzenesulfonic acid 2-[2-2-methoxy-ethoxy)-acetylamino]-1H-benzoimidazol-5-yl ester

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By proceeding in a manner similar to example 71 above but using (2-methoxy-ethoxy)-acetic acid there was prepared 4-cyclopentylamino-benzenesulfonic acid 2-[2-2-methoxy-ethoxy)-acetylamino]-1H-benzoimidazol-5-yl ester as an off-white solid. Mass spectrum: 489 [M+H]⁺; retention time=4.06 minutes.

Example 73
Preparation of 4-fluoro-benzenesulfonic acid 2-(3(chloro-4-methoxy-benzylamino)-3H-benzoimidazol-5-yl ester

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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 dimethylformamide (3 ml) was treated with sodium hydride (12 mg, 60% dispersion in mineral oil). After stirring for 30 minutes the mixture was treated with a solution of 3-chloro-4-methoxy-benzyl 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 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 (1:2, v/v) to give 4-fluoro-benzenesulfonic acid 2-[tert-butoxycarbonyl-(3-chloro-4-methoxy-benzyl)-amino]-3H-benzoimidazol-5-yl ester (70 mg) as a beige solid.

Step 2: preparation of 4-fluoro-benzenesulfonic acid 2-(3-(chloro-4-methoxy-benzylamino)-3H-benzoimidazol-5-yl ester

Trifluoroacetic acid (1 ml) was added to a solution of 4-fluoro-benzenesulfonic acid 2-[tert-butoxycarbonyl-(3-chloro-4-methoxy-benzyl)-amino]-3H-benzoimidazol-5-yl ester (67 mg) in dichloromethane (4 ml). After cooling, the mixture was neutralised by addition of saturated sodium bicarbonate solution. Water (10 ml) was added and the solution extracted three times with dichloromethane (10 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 (1:1, v/v) to give 4-fluoro-benzenesulfonic acid 2-(3-(chloro-4-methoxy-benzylamino)-3H-benzoimidazol-5-yl ester (53 mg) as an off-white solid. Mass spectrum: 462 [M+H]⁺; retention time=7.69 minutes.

Example 74

By using a method similar to that for the preparation of example 73, combining 4-fluoro-benzenesulfonic acid 2-tert-butoxycarbonylamino-3H-benzoimidazol-5-yl ester with suitable benzyl halide were obtained the following compounds that were characterized by analytical LC/MS ([M+H]⁺ and retention time given in the following table).

Retention timeMassExampleBenzyl halideCompound(minute)[M + H]⁺74-a embedded image

4-Fluoro-benzenesulfonic acid 2-[(3-phenyl-[1,2,4]- oxadiazol-5-ylmethyl)-amino]- 3H-benzoimidazol-5-yl ester8.1346674-b embedded image

4-Fluoro-benzenesulfonic acid 2-(3-chloro-benzylamino)- 3H-benzoimidazol-5-yl ester7.7243274-c embedded image

4-Fluoro-benzenesulfonic acid 2-(3-methoxy-benzylamino)- 3H-benzoimidazol-5-yl ester7.3142874-d embedded image

4-Fluoro-benzenesulfonic acid 2-benzylamino-3H- benzoimidazol-5-yl ester7.43398

Example 75
Preparation of 4-cyclopentylamino-benzenesulfonic acid 2-benzylamino-3H-benzoimidazol-5-yl ester

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A solution of 4-fluoro-benzenesulfonic acid 2-benzylamino-3H-benzoimidazol-5-yl ester (20 mg) and cyclopentylamine (21 μl) in N-methylpyrrolidinone (0.5 ml) was heated at 110° C. in a sealed tube for 2 hours. The reaction mixture was then purified by triggered LC/MS to give 4-cyclopentylamino-benzenesulfonic acid 2-benzylamino-3H-benzoimidazol-5-yl ester as an off-white solid (4 mg). Mass spectrum: 463[M+H]⁺; retention time=8.35 minutes.

Example 76

By using a method similar to that for the preparation of example 75, combining cyclopentylamine with suitable 4-fluoro-benzenesulfonic acid 2-benzylamino-3H-benzoimidazol-5-yl ester (example 73, 74a-74c) were obtained the following compounds that were characterized by analytical LC/MS ([M+H]⁺ and retention time given in the following table).

RetentiontimeMassExamplePrecursorCompound(minute)[M + H]⁺76-a74-a4-Cyclopentylamino-3.91531benzenesulfonic acid 2-[(3-phenyl-[1,2,4]oxadiazol-5-ylmethyl)-amino]-3H-benzoimidazol-5-ylester76-b74-c4-Cyclopentylamino-8.41493benzenesulfonic acid 2-(3-methoxy-benzylamino)-3H-benzoimidazol-5-ylester76-c734-Cyclopentylamino-3.58527benzenesulfonic acid 2-(3-chloro-4-methoxy-benzylamino)-3H-benzoimidazol-5-ylester

Example 77
Preparation of 4-(Cyclopropylmethyl-amino)-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)-ureido]-1H-benzoimidazol-5-yl ester

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A solution of 4-(cyclopropylmethyl-amino)-benzenesulfonic acid 2-methoxy-carbonylamino-3H-benzoimidazol-5-yl ester (example 67, 40 mg) and 2-(aminoethyl)-morpholine (125 mg) in tetrahydrofuran (2 ml) and N-methylpyrrolidinone (0.2 ml) was heated at 90° C. for 36 hours. The reaction mixture was then evaporated and purified by triggered LC/MS to give 4-(cyclopropylmethyl-amino)-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)-ureido]-1H-benzoimidazol-5-yl ester as an off-white solid (27 mg). Mass spectrum: 515[M+H]⁺; retention time=5.97 minutes.

Example 78

By using a method similar to that for the preparation of example 77, combining 4-(substituted-amino)-benzenesulfonic acid 2-methoxycarbonylamino-3H-benzo-imidazol-5-yl ester [example 63, 67, 68] with suitable amine were obtained the following compounds that were characterized by analytical LC/MS ([M+H]⁺ and retention time given in the following table).

Retention timeMassExamplePrecursorAmineCompound(minutes)[M + H]⁺78-a67 embedded image

4-(Cyclopropylmethyl-amino)- benzenesulfonic acid 2-[3-(2- morpholin-4-yl-ethyl)-ureido]- 1H-benzoimidazol-5-yl ester5.9751578-b67 embedded image

4-(Cyclopropylmethyl-amino)- benzenesulfonic acid 2-(3- pyridin-2-ylmethyl)-ureido]- 1H-benzoimidazol-5-yl ester8.5549378-c67 embedded image

4-(Cyclopropylmethyl-amino)- benzenesulfonic acid 2-[3-(2- methoxy-ethyl)-ureido]-1H- benzoimidazol-5-yl ester10.6646078-d67 embedded image

4-(Cyclopropylmethyl-amino)- benzenesulfonic acid 2-[3-(2- ethyl)-ureido]-1H- benzoimidazol-5-yl ester11.0743078-e 68-a embedded image

4-(2-Methoxy-ethylamino)- benzenesulfonic acid 2-[3-(2- morpholin-4-yl-ethyl)-ureido]- 1H-benzoimidazol-5-yl ester5.7451978-f 68-a embedded image

4-(2-Methoxy-ethylamino)- benzenesulfonic acid 2-(3- pyridin-2-ylmethyl)-ureido]- 1H-benzoimidazol-5-yl ester6.6249778-g 68-a embedded image

4-(2-Methoxy-ethylamino)- benzenesulfonic acid 2-[3-(2- methoxy-ethyl)-ureido]-1H- benzoimidazol-5-yl ester7.3946478-h 68-a embedded image

4-(2-Methoxy-ethylamino)- benzenesulfonic acid 2-[3-(2- ethyl)-ureido]-1H- benzoimidazol-5-yl ester7.5343478-i 68-b embedded image

4-(2-Hydroxy-1-methyl- ethylamino)-benzenesulfonic acid 2-[3-(2-morpholin-4-yl- ethyl)-ureido]-1H- benzoimidazol-5-yl ester5.3651978-j 68-b embedded image

4-(2-Hydroxy-1-methyl- ethylamino)-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl)- ureido]-1H-benzoimidazol-5- yl ester6.1149778-k 68-b embedded image

4-(2-Hydroxy-1-methyl- ethylamino)-benzenesulfonic acid 2-[3-(2-methoxy-ethyl)- ureido]-1H-benzoimidazol-5- yl ester6.8146478-l 68-b embedded image

4-(2-Hydroxy-1-methyl- ethylamino)-benzenesulfonic acid 2-[3-(2-ethyl)-ureido]- 1H-benzoimidazol-5-yl ester6.9443478-m63 embedded image

4-Benzyloxybenzenesulfonic acid 2-[3-(2-morpholin-4-yl- ethyl)-ureido]-1H- benzoimidazol-5-yl ester7.5555278-n63 embedded image

4-Benzyloxy-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl)- ureido]-1H-benzoimidazol-5- yl ester8.9953078-o63 embedded image

4-Benzyloxy-benzenesulfonic acid 2-[3-(2-methoxy-ethyl)- ureido]-1H-benzoimidazol-5- yl ester13.9749778-p63 embedded image

4-benzyloxy-benzenesulfonic acid 2-[3-(2-ethyl)-ureido]- 1H-benzoimidazol-5-yl ester10.1246778-r 68-d embedded image

4-(2-Morpholin-4-yl- ethylamino)-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl)- ureido]-1H-benzoimidazol-5- yl ester4.6155278-s 68-d embedded image

4-(2-Morpholin-4-yl- ethylamino)-benzenesulfonic acid 2-[3-(2-methoxy-ethyl)- ureido]-1H-benzoimidazol-5- yl ester1.4751978-t 68-e embedded image

4-[(Piperidin-4-ylmethyl)- amino)-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)- ureido]-1H-benzoimidazol-5- yl ester4.4755878-u 68-e embedded image

4-[(Piperidin-4-ylmethyl)- amino]-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl)- ureido]-1H-benzoimidazol-5- yl ester5.1253678-v 68-e embedded image

4-[(Piperidin-4-ylmethyl)- amino]-benzenesulfonic acid 2-[3-(2-methoxy-ethyl)- ureido]-1H-benzoimidazol-5- yl ester1.4750378-w 68-c embedded image

4-Benzylamino- benzenesulfonic acid 2-[3-(2- morpholin-4-yl-ethyl)-ureido]- 1H-benzoimidazol-5-yl ester7.1655178-x 68-c embedded image

4-Benzylamino- benzenesulfonic acid 2-(3- pyridin-2-ylmethyl)-ureido]- 1H-benzoimidazol-5-yl ester8.5252978-y 68-c embedded image

4-Benzylamino- benzenesulfonic acid 2-[3-(2- methoxy-ethyl)-ureido]-1H- benzoimidazol-5-yl ester9.2949678-z 68-c embedded image

4-Benzylamino- benzenesulfonic acid 2-[3-(2- ethyl)-ureido]-1H- benzoimidazol-5-yl ester9.35466 78-aa 68-f embedded image

4-[(1-ethyl-pyrrolidin- 2ylmethyl)-amino]- benzenesulfonic acid 2-(3- pyridin-2-ylmethyl)-ureido]- 1H-benzoimidazol-5-yl ester2.14549

Example 79
Preparation of 4-(4-hydroxy-piperidin-1-yl)-benzenesulfonic acid 2-[(4-hydroxy-piperidine-1-carbonyl)-amino]-1H-benzoimidazol-5-yl ester

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A solution of 4-fluoro-benzenesulfonic acid 2-tert-butoxycarbonylamino-3H-benzoimidazol-5-yl ester (200 mg, example 55 (Step 3) and 4-hydroxypiperidine (554 mg) in N-methylpyrrolidinone (6 ml) was heated at 110° C. for 24 hours. The reaction mixture was then poured into water (120 ml) and extracted three times with ethyl acetate (50 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 dichloromethane and methanol (95 C: 5, v/v) to give (4-hydroxy-piperidin-1-yl)-benzenesulfonic acid 2-[(4-hydroxy-piperidine-1-carbonyl)-amino]-1H-benzoimidazol-5-yl ester (125 mg) as a beige solid. Mass Spectrum: 516 [M+H]⁺, retention time=6.51 minutes.

Example 80

By using a method similar to that for the preparation of example 79, combining 4-fluoro-benzenesulfonic acid 2-tert-butoxycarbonylamino-3H-benzoimidazol-5-yl ester with suitable amine were obtained the following compounds that were characterized by analytical LC/MS ([M+H]⁺ and retention time given in the following table).

Retention timeMassExampleAmineCompound(minutes)[M + H]+80-a embedded image

4-(4-Methyl-piperazin-1-yl)- benzenesulfonic acid 2-[(4-methyl- piperazin-1-carbonyl)-amino]-3H- benzoimidazol-5-yl ester0.5351480-b embedded image

4-[(tetrahydro-pyran-4-ylmethyl)- amino]-benezenesulfonic acid 2-[3- (tetrahydro-pyran-4-ylmethyl)-ureido]- 3H-benzoimidazol-5-yl ester8.1454480-c embedded image

4-(2-Fluoro-ethylamino)- benzenesulfonic acid 2-[3-(2-fluoro- ethyl)-ureido]-3H-benzoimidazol-5-yl ester7.8244080-d embedded image

4-(2-piperidin-1-yl-ethylamino)- benzenesulfonic acid 2-[3-(2-piperidin- 1-yl-ethyl)-ureido]-3H-benzoimidazol- 5-yl ester0.544080-e embedded image

4-phenethylamino-benzenesulfonic acid 2-(3-phenethyl-ureido)-3H- benzoimidazol-5-yl ester4.455680-f embedded image

4-[3-(2-oxo-pyrrolidin-1-yl)- propylamino]-benzenesulfonic acid 2- {3-[3-(2-owo-pyrrolidin-1-yl)-propyl]- ureido}-3H-benzoimidazol-5-yl ester3.0959880-g embedded image

4-(4-fluoro-benzylamino)- benzenesulfonic acid 2-[3-(4-fluoro- benzyl)-ureido]-3H-benzoimidazol-5- yl ester4.2556480-h embedded image

4-(2-hydroxy-2-methyl-propylamino)- benzenesulfonic acid 2-[3-(2-hydroxy- 3-methyl-propyl)-ureido]-3H- benzoimidazol-5-yl ester7.0249280-i embedded image

4-(3-hydroxy-propylamino)- benzenesulfonic acid 2-[3-(3-hydroxy- propyl)-ureido]-3H-benzoimidazol-5-yl ester2.746480-j embedded image

4-(2,2,6,6-tetramethyl-piperidin-4- ylamino)-benzenesulfonic acid 2-[3- (2,2,6,6-tetramethyl-piperidin-4-yl)- ureido]-3H-benzoimidazol-5-yl ester2.4462680-k embedded image

4-(2-dimethylamino-ethylamino)- benzene sulfonic acid 2-[3-(2- dimethylamino-ethyl)-ureido]-3H- benzoimidazol-5-yl ester0.7049080-l embedded image

4-morpholin-4-yl-benzenesulfonic acid 2-[(morpholine-4-carbonyl)-amino]- 3H-benzoimidazol-5-yl ester3.1648880-m embedded image

4-(2-Hydroxy-3-methoxy- propylamino)-benzenesulfonic acid 2- [3-(2-hydroxy-3-methoxy-propyl)- ureido]-3H-benzoimidazol-5-yl ester4.7152480-n embedded image

4-[(Pyridin-2-ylmethyl)-amino]- benzenesulfonic acid 2-(3-pyridin-2- ylmethyl-ureido)-3H-benzoimidazol-5- yl ester5.5353080-o embedded image

4-(2-hydroxy-propylamino)- benzenesulfonic acid 2-[3-(2-hydroxy- propyl)-ureido]-3H-benzoimidazol-5-yl ester2.746380-p embedded image

4-(4-methoxy-benzylamino)- benzenesulfonic acid 2-[3-(4-methoxy- benzyl)-ureido]-3H-benzoimidazol-5-yl ester4.4358880-q embedded image

4-(2-pyrrolidin-1-yl-ethylamino)- benzenesulfonic acid 2-[3-(2- pyrrolidin-1-yl-ethyl)-ureido]-3H- benzoimidazol-5-yl ester2.1954280-r embedded image

4-(1-phenyl-ethylamino)- benzenesulfonic acid 2-[3-(1-phenyl- ethyl)-ureido]-3H-benzoimidazol-5-yl ester4.6355680-s embedded image

4-(2-diethylamino-ethylamino)- benzene sulfonic acid 2-[3-(2- diethylamino-ethyl)-ureido]-3H- benzoimidazol-5-yl ester2.7554680-t embedded image

4-(1-hydroxymethyl- acid 2-[3-(1-hydroxymethyl- cyclopentyl)-ureido]-3H- benzoimidazol-5-yl ester3.4554480-u embedded image

3-(4-{2-[3-(3-Methoxycarbonyl- ethyl)-ureido]-1H-benzoimidazol-5- yloxysulfonyl}-phenylamino)- propionic acid methyl ester3.26520

Example 81
Preparation of 4-(4-Hydroxy-piperidin-1-yl)-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)-ureido]-1H-benzoimidazol-5-yl ester

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A solution of 4-(4-hydroxy-piperidin-1-yl)-benzenesulfonic acid 2-[(4-hydroxy-piperidine-1-carbonyl)-amino]-1H-benzoimidazol-5-yl ester (example 79, 20 mg) and 2-(aminomethyl)-morpholine (50 mg) in tetrahydrofuran (1 ml) and N-methylpyrrolidinone (0.2 ml) was heated at 95° C. for 22 hours. The reaction mixture was then evaporated and purified by triggered LC/MS to give 4-(4-hydroxy-piperidin-1-yl)-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)-ureido]-1H-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 [example 80a-u] with suitable amine was obtained the following compounds that were characterized by analytical LC/MS ([M+H]⁺ and retention time given in the following table).

Retention timeMassExamplePrecursorAmineCompound(minutes)[M + H]+82-a80-a embedded image

4-(4-methyl-piperazin-1- yl)-benzene sulfonic acid 2-[3-(2-morpholin-4-yl- ethyl)-ureido]-3H- benzimidazol-5-yl ester5.1254482-b80-a embedded image

4-(4-methyl-piperazin-1- yl)-benzene sulfonic acid 2-(3-pyridin-2-ylmethyl- ureido)-3H-benzimidazol- 5-yl ester4.4652282-c80-a embedded image

4-(4-methyl-piperazin-1- yl)-benzene sulfonic acid 2-[3-(2-methoxy-ethyl)- ureido]-3H-benzimidazol- 5-yl ester5.8648982-d79 embedded image

4-(4-hydroxy-piperidin-1- yl)-benzene sulfonic acid 2-[3-(2-morpholin-4-yl- ethyl)-ureido]-3H- benzimidazol-5-yl ester5.4754582-e79 embedded image

4-(4-hydroxy-piperidin-1- yl)-benzene sulfonic acid 2-(3-pyridin-2-ylmethyl- ureido)-3H-benzimidazol- 5-yl ester6.452382-f79 embedded image

4-(4-hydroxy-piperidin-1- yl)-benzene sulfonic acid 2-[3-(2-methoxy-ethyl)- ureido]-3H-benzimidazol- 5-yl ester7.0649082-g79 embedded image

4-(4-hydroxy-piperidin-1- yl)-benzene sulfonic acid 2-(3-ethyl-ureido)-3H- benzimidazol-5-yl ester3.346082-h80-n embedded image

4-[(Pyridin-2-ylmethyl)- amino]-benzene sulfonic acid 2-[3-(2-morpholin-4- yl-ethyl)-ureido]-3H- benzimidazol-5-yl ester4.8355282-i80-n embedded image

4-[(Pyridin-2-ylmethyl)- amino]-benzene sulfonic acid 2-(3-pyridin-2- ylmethyl-ureido)-3H- benzimidazol-5-yl ester5.5353082-j80-n embedded image

4-[(Pyridin-2-ylmethyl)- amino]-benzene sulfonic acid 2-[3-(2-methoxy- ethyl)-ureido]-3H- benzimidazol-5-yl ester6.649782-k80-n embedded image

4-[(Pyridin-2-ylmethyl)- amino]-benzene sulfonic acid 2-[3-(2-methoxy- ethyl)-ureido]-3H- benzimidazol-5-yl ester6.246782-l80-i embedded image

4-(3-Hydroxy-propylamino)- benzenesulfonic acid 2-[3-(2- morpholin-4-yl-ethyl)- ureido]-3H-benzimidazol-5- yl ester6.249782-m80-i embedded image

4-(3-Hydroxy-propylamino)- benzenesulfonic acid 2-(3- pyridin-2-ylmethyl-ureido)- 3H-benzimidazol-5-yl ester5.4851982-n80-i embedded image

4-(3-Hydroxy-propylamino)- benzenesulfonic acid 2-[3-(2- methoxy-ethyl)-ureido]-3H- benzimidazol-5-yl ester6.8446482-o80-i embedded image

4-(3-Hydroxy-propylamino)- benzenesulfonic acid 2-(3- ethyl-ureido)-3H- benzimidazol-5-yl ester82-p80-j embedded image

4-(2,2,6,6-tetramethyl- piperidin-4-ylamino)- benzenesulfonic acid 2-[3-(2- morpholin-4-yl-ethyl)-ureido]- 3H-benzimidazol-5-yl ester0.4160082-q80-j embedded image

4-(2,2,6,6-tetramethyl- pipendin-4-ylamino)- benzenesulfonic acid 2-(3- pyridin-2-ylmethyl-ureido)-3H- benzimidazol-5-yl ester0.4257682-r80-k embedded image

4-(2-dimethylamino- ethylamino)-benzenesulfonic acid 2-[3-(2-morpholin-4-yl- ethyl)-ureido]-3H- benzimidazol-5-yl ester0.4153282-s80-k embedded image

4-(2-dimethylamino- ethylamino)-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl- ureido)-3H-benzimidazol-5-yl ester0.4151082-t80-l embedded image

4-morpholin-4-yl- benzenesulfonic acid 2-[3-(2- morpholin-4-yl-ethyl)-ureido]- 3H-benzimidazol-5-yl ester0.453182-u80-l embedded image

4-morpholin-4-yl- benzenesulfonic acid 2-(3- pyridin-2-ylmethyl-ureido)-3H- benzimidazol-5-yl ester2.950982-v80-f embedded image

4-[3-(2-oxo-pyrrolidin-1-yl)- propylamino]- benzenesulfonic acid 2-[3-(2- morpholin-4-yl-ethyl)-ureido]- 3H-benzimidazol-5-yl ester2.658682-w80-f embedded image

4-[3-(2-oxo-pyrrolidin-1-yl)- propylamino]- benzenesulfonic acid 2-(3- pyridin-2-ylmethyl-ureido)-3H- benzimidazol-5-yl ester2.4648582-x80-g embedded image

4-(4-fluoro-benzylamino)- benzenesulfonic acid 2-(3- ethyl-ureido)-3H- benzimidazol-5-yl ester9.2951482-y80-h embedded image

4-(2-Hydroxy-2-methyl- propylamino)- benzenesulfonic acid 2-[3-(2- morpholin-4-yl-ethyl)- ureido]-3H-benzimidazol-5- yl ester6.6151182-z80-h embedded image

4-(2-Hydroxy-2-methyl- propylamino)- benzenesulfonic acid 2-(3- pyridin-2-ylmethyl-ureido)- 3H-benzimidazol-5-yl ester6.29533 82-aa80-h embedded image

4-(2-Hydroxy-2-methyl- propylamino)- benzenesulfonic acid 2-[3-(2- methoxy-ethyl)-ureido]-3H- benzimidazol-5-yl ester2.89478 82-ab80-h embedded image

4-(2-Hydroxy-2-methyl- propylamino)- benzenesulfonic acid-2-[3-(3- hydroxy-propyl)-ureido]-3H- benzimidazol-5-yl ester7.33478 82-ac80-b embedded image

4-[(Tetrahydro-pyran-4- ylmethyl)-amino]- benzenesulfonic acid 2-[3-(2- morpholin-4-yl-ethyl)- ureido]-3H-benzimidazol-5- yl ester7.28537 82-ad80-b embedded image

4-[(Tetrahydro-pyran-4- ylmethyl)-amino]- benzenesulfonic acid 2-(3- pyridin-2-ylmethyl-ureido)- 3H-benzimidazol-5-yl ester6.88559 82-ae80-b embedded image

4-[(Tetrahydro-pyran-4- ylmethyl)-amino]- benzenesulfonic acid 2-[3-(2- methoxy-ethyl)-ureido]-3H- benzimidazol-5-yl ester8.67504 82-af80-b embedded image

4-[(Tetrahydro-pyran-4- ylmethyl)-amino]- benzenesulfonic acid 2-[3-(3- hydroxy-propyl)-ureido]-3H- benzimidazol-5-yl ester8.03504 82-ag80-c embedded image

4-(2-fluoro-ethylamino)- benzenesulfonic acid 2-[3-(2- morpholin-4-yl-ethyl)-ureido]- 3H-benzimidazol-5-yl ester2.5507 82-ah80-c embedded image

4-(2-fluoro-ethylamino)- benzenesulfonic acid 2-(3- pyridin-2-ylmethyl-ureido)-3H- benzimidazol-5-yl ester2.46485 82-ai80-d embedded image

4-(2-Piperidin-1-yl- ethylamino)-benzenesulfonic acid 2-[3-(2-morpholin-4-yl- ethyl)-ureido]-3H- benzimidazol-5-yl ester5.47550 82-aj80-d embedded image

4-(2-Piperidin-1-yl- ethylamino)-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl- ureido)-3H-benzimidazol-5- yl ester4.2557282-ak80-e embedded image

4-phenethylamino- benzenesulfonic acid 2-[3-(2- morpholin-4-yl-ethyl)-ureido]- 3H-benzimidazol-5-yl ester3.14565 82-al80-e embedded image

4-phenethylamino- benzenesulfonic acid 2-[3-(2- methoxy-ethyl)-ureido]-3H- benzimidazol-5-yl ester3.78510 82-am80-e embedded image

4-phenethylamino- benzenesulfonic acid 2-(3- ethyl-ureido)-3H- benzimidazol-5-yl ester3.83480 82-an80-e embedded image

4-phenethylamino- benzenesulfonic acid 2-[3-(3- hydroxy-propyl)-ureido]-3H- benzimidazol-5-yl ester3.57510 82-ao80-o embedded image

4-(2-hydroxy-propylamino)- benzenesulfonic acid 2-[3-(2- morpholin-4-yl-ethyl)-ureido]- 3H-benzimidazol-5-yl ester2.36519 82-ap80-o embedded image

4-(2-hydroxy-propylamino)- benzenesulfonic acid 2-(3- ethyl-ureido)-3H- benzimidazol-5-yl ester2.91434 82-aq80-p embedded image

4-(4-methoxy-benzylamino)- benzenesulfonic acid 2-[3-(2- morpholin-4-yl-ethyl)-ureido]- 3H-benzimidazol-5-yl ester3.03581 82-ar80-p embedded image

4-(4-methoxy-benzylamino)- benzenesulfonic acid 2-(3- ethyl-ureido)-3H- benzimidazol-5-yl ester3.67496 82-as80-p embedded image

4-(4-methoxy-benzylamino)- benzenesulfonic acid 2-(3- pyridin-2-ylmethyl-ureido)-3H- benzimidazol-5-yl ester3.41559 82-at80-p embedded image

4-(4-methoxy-benzylamino)- benzenesulfonic acid 2-[3-(3- hydroxy-propyl)-ureido]-3H- benzimidazol-5-yl ester3.41526 82-au80-p embedded image

4-(4-methoxy-benzylamino)- benzenesulfonic acid 2-[3-(2- methoxy-ethyl)-ureido]-3H- benzimidazol-5-yl ester3.61526 82-av80-q embedded image

4-(2-pyrrolidin-1-yl- ethylamino)-benzenesulfonic acid 2-(3-ethyl-ureido)-3H- benzimidazol-5-yl ester2.26473 82-aw80-q embedded image

4-(2-pyrrolidin-1-yl- ethylamino)-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl- ureido)-3H-benzimidazol-5-yl ester2.08536 82-ax80-q embedded image

4-(2-pyrrolidin-1-yl- ethylamino)-benzenesulfonic acid 2-[3-(2-methoxy-ethyl)- ureido]-3H-benzimidazol-5-yl ester2.25503 82-ay80-r embedded image

4-(1-phenyl-ethylamino)- benzenesulfonic acid 2-(3- ethyl-ureido)-3H- benzimidazol-5-yl ester3.76480 82-az80-s embedded image

4-(2-diethylamino- ethylamino)-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl- ureido)-3H-benzimidazol-5-yl ester3.5543

Example 83
Preparation of 1-(6-hydroxy-1H-benzoimidazol-2-yl)-3-(2-methoxy-ethyl)-urea

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A solution of (6-hydroxy-1H-benzoimidazol-2-yl)-carbamic acid methyl ester (300 mg, example 61) and 2-methoxy-ethylamine (630 IA) in N-methylpyrrolidinone (8 ml) was heated at 90° C. in a sealed tube for 20 hours. The reaction mixture was poured into water (160 ml) and extracted three times with ethyl 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 dichloromethane and methanol (95 C:5 C, v/v) to 1-(6-hydroxy-1H-benzoimidazol-2-yl)-3-(2-methoxy-ethyl)-urea as a yellow solid (180 mg). Mass spectrum: 251[M+H]⁺; retention time=0.55 minutes.

Example 84(a)
Preparation of 1-(6-hydroxy-1H-benzoimidazol-2-yl)-3-pyridin-2-ylmethyl-urea

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By proceeding in a manner similar to example 83 above but using 2-(aminomethyl)-pyridine there was prepared 1-(6-hydroxy-1H-benzoimidazol-2-yl)-3pyridin-2-ylmethyl-urea as a beige solid. Mass spectrum: 284 [M+H]⁺; retention time=0.55 minutes.

Example 84(b)
Preparation of 1-(6-hydroxy-1H-benzoimidazol-2-yl)-3-(2-morpholin-4-yl-ethyl)-urea

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By proceeding in a manner similar to example 83 above but using 2-(aminoethyl)-morpholine there was prepared 1-(6-hydroxy-1H-benzoimidazol-2-yl)-3-(2-morpholin-4-yl-ethyl)-urea as a beige solid. Mass spectrum: 306 [M+H]⁺; retention time=1.02 minute.

Example 84(c)
Preparation of 1-(6-hydroxy-1H-benzoimidazol-2-yl)-3-(ethyl)-urea

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By proceeding in a manner similar to example 83 above but using ethylamine there was prepared 1-(6-hydroxy-1H-benzoimidazol-2-yl)-3-(ethyl)-urea as a beige solid. Mass spectrum: 367 [M+H]⁺; retention time=1.36 minute.

Example 85
Preparation of thiophene-2-sulfonic acid 2-[3-(2-ethyl)-ureido]-1H-benzoimidazol-5-yl ester

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A stirred solution of 1-ethyl-3-(6-hydroxy-1H-benzoimidazol-2-yl)-urea (35 mg, example 84-c) and thiophene-2-sulfonyl chloride (18 mg) in acetone (3 ml) was treated with triethylamine (25 el). After stirring at ambient temperature for 4 hours, the reaction mixture was evaporated. The residue was filtered and the filtrate evaporated. The residue was directly purified by LCMS triggered purification to give thiophene-2-sulfonic acid 2-[3-(2-ethyl)-ureido]-1H-benzoimidazol-5-yl ester (14 mg) as a off-white solid Mass spectrum: 367 [M+H]⁺; retention time=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 1-(6-hydroxy-1H-benzoimidazol-2-yl)-urea (example 83, 84) were obtained the following compounds that were characterized by analytical LC/MS ([M+H]⁺ and retention time given in the following table).

Example1-(6-hydroxy-1H-benzoimidazol-2-yl)-ureaCompoundRetention time (minutes)Masse [M + H]+86-a embedded image

Thiophene-2-sulfonic acid 2-[3-(2-methoxy-eth- yl)-ureido]-1H-benzo- imidazol-5-yl ester2.9939786-b embedded image

Thiophene-2-sulfonic acid 2-[3-(2-morpholin-4-yl-eth- yl)-ureido]-1H-benzo- imidazol-5-yl ester2.845286-c embedded image

Thiophene-2-sulfonic acid 2-(3-pyridin-2-ylmeth- yl)-ureido]-1H-benzo- imidazol-5-yl ester6.52430

Example 87
Preparation of benzoic acid 4-{2-[3-(2-methoxy-ethyl)-ureido]-1H-benzoimidazol-5-yloxysulfonyl}-phenyl ester

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A stirred solution of 1-(6-hydroxy-1H-benzoimidazol-2-yl)-3-(2-methoxy-ethyl)-urea (31 mg, example 82) and benzoic acid 4-chlorosulfonyl-phenyl ester (37 mg) in acetone (0.6 ml) was treated with triethylamine (33 μl). After stirring at ambient temperature for 4 hours, the reaction mixture was evaporated. The residue was filtered and the filtrate evaporated. The residue was directly purified by LCMS triggered purification to give benzoic acid 4-{2-[3-(2-methoxy-ethyl)-ureido]-1H-benzoimidazol-5-yloxysulfonyl}-phenyl ester (7.2 mg) as a off-white solid Mass spectrum: 511 [M+H]⁺; 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 1-(6-hydroxy-1H-benzoimidazol-2-yl)-urea (example 83,84) were obtained the following compounds that were characterized by analytical LC/MS ([M+H]⁺ and retention time given in the following table).

Example1-(6-hydroxy-1H-benzoimidazol-2-yl)-ureaCompoundRetention time (minutes)Masse [M + H]+88-a embedded image

Benzoic acid 4-{2-[3-(2-morpho- lin-4-yl-ethyl)-urei- do}-1H-benzoimidazol-5-yl- oxysulfonyl}-phenyl ester7.4456688-b embedded image

Benzoic acid 4-[2-([3-pyri- din-2-ylmethyl)-ureido)-1H-benzo- imidazol-5-yl- oxysulfonyl]-phenyl ester8.91544

Example 89 (a)
Preparation of 2,6-difluoro-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl-ureido)-3H-benzoimidazol-5-yl ester

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A stirred solution of 1-(6-hydroxy-1H-benzoimidazol-2-yl)-3-pyridin-2-ylmethyl-urea (50 mg, example 83-a) and 2,6-difluoro-benzene-sulfonyl chloride (38 mg) in acetone (1 ml) was treated with triethylamine (48 μl). After stirring at ambient temperature for 4 hours, the reaction mixture was evaporated. The residue was filtered and the filtrate evaporated. The residue was directly purified by LC/MS triggered purification to give benzoic acid 2,6-difluoro-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl-ureido)-3H-benzoimidazol-5-yl ester (29.6 mg) as a off-white solid Mass spectrum: 427 [M+H]⁺; retention time=7.86 minutes.

Example 89(b)
Preparation of 2,6-difluoro-benzenesulfonic acid 2-[3-(2-methoxy-ethyl)-ureido]-3H-benzoimidazol-5-yl ester

By proceeding in a manner similar to example 89(a) above but using 1-(6-hydroxy-1H-benzoimidazol-2-yl)-3-(2-methoxy-ethyl)-urea there was prepared 2,6-difluoro-benzenesulfonic acid 2-[3-(2-methoxy-ethyl)-ureido]-3H-benzoimidazol-5-yl ester as an off-white solid. Mass spectrum: 427[M+H]⁺; retention 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 were made in DMSO at 10 mM and stored at −20° C. Subsequent dilutions were made in 28% DMSO and used to add 3 μl of the drugs at varied concentrations to the HeLa cells.

All cell lines were cultured at 37° C. in a humidified atmosphere containing 5% CO₂.

HeLa human epithelial cell line was obtained from the American Type Culture Collection (Rockville, Md., USA). Cells were grown as monolayers in Dubelcco's Modified Eagle Medium containing 2 mM L-glutamine, 200 I.U./ml penicillin, 200 μg/ml streptomycin, and supplemented with 10% (v/v) heat inactivated foetal calf serum. Cells were transferred twice a week at 10⁵cells/ml in 75 cm²flasks after trypsinisation. Different flasks were done to prepare two preparations the day of experiment.

Cell Growth Inhibition

Cells in exponential phase of growth were trypsinised and resuspended in their culture medium at 2.5 10⁴cells/ml, in two independent preparations. Cell suspension was distributed in 96 well Cytostar microplates (Amersham) (0.2 ml/well, 5000 cells). Hela cells were coated for 4 hours at 37° C. [¹⁴C]-thymidine (0.1 μCi/well) and ten final concentrations of molecules (3 μl) ranging from 20 to 0.03 μM were then added. The uptake of [¹⁴C]-thymidine was measured 48 h after the labelling had been started using a Microbeta Trilux counter (Wallac).

Staurosporine, the reference compound, was evaluated 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 the 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 determined by non-linear regression analysis and calculated as a concentration at middle of curve.

IC₅₀values result from 2 independent experiments for all tested molecules.

CDK4/CyclinD1 Flashplate Assay: 96-Well Format

This is a CDK4/CyclinD1 kinase assay in a 96-well Streptavidin-coated Flashplate with a biotinylated-Rb peptide substrate.

Each point is tested in duplicate

Biotinylated-Rb: Biotin-RPPTLSPIPHIPRSPYKFPSSPLR

Kinase Buffer:HEPES, pH 850 mMMgCl₂6H₂O, pH 710 mMDTT 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/CyclinD1 kinase: 70 ng per well, in a volume of 90 μl in kinase buffer (except for “no enzyme” control wells).
- 7. Add 1 μl¹per 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 cold 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.

CDK2/CyclinE Flashplate Assay: 96-Well Format

This is a CDK2/CyclinE kinase assay in a 96-well Streptavidin-coated Flashplate with a biotinylated-Rb peptide substrate.

Each point is tested in duplicate

Biotinylated-Rb: Biotin-SACPLNLPLQNNHTAADMYLSPVRSPKKKGSTTR-OH

Kinase Buffer:HEPES, pH 8.050 mMMgCl₂6H₂O10 mMDTT 1 mM

- 1. Prepare 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. Was 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 (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. 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 cold 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.

IC50 CDK4/cyclinD1IC50 CDK2/cyclinEExample N°(μM)(μM) 11.50.6 220.7 32.40.5 46.31.5 51.122.2 60.840.3 70.472 81.1Nd 92Nd100.70.8110.930.51214% inhibition at 10 μMNd130.42140.30.2150.31.8160.371.8176.32181.30.6192.920.720>3>10221.77Nd233.10.4240.60.4250.130.08260.680.13270.60.042281.030.6291.70.6301.80.9310.50.132>51.1330.640.06341.180.12351.10.12360.770.53370.570.45381.254.3391.620.29403.711.09412.80.064284% inhibition at 10 μM0.91431.90.244O.60.13450.60.06460.0120.06470.80.16480.30.044988% inhibition at 10 μM0.4500.30.04510.80.145210.085383% inhibition at 10 μM0.8540.50.00557-a10.2457-b51% inhibition at 10 μM1.957-c60% inhibition at 10 μM0.657-d70% inhibition at 10 μM0.557-e90% inhibition at 10 μM0.357-f88% inhibition at 10 μM0.557-g52% inhibition at 10 μM0.657-h4.40.157-i27% inhibition at 10 μM5.257-j30.157-k49% inhibition at 10 μM0.657-l10.0758-a96% inhibition at 10 μM0.3858-b70% inhibition at 10 μM0.958-c60% inhibition at 10 μM0.658-d84% inhibition at 10 μM1.658-e0.10.0458-f91% inhibition at 10 μM0.758-g69% inhibition at 10 μM158-h30.158-i81% inhibition at 10 μM0.358-j0.50.00958-k0.50.0458-l10.0358-m0.240.0358-n0.6Nd58-o0.0290.0258-p0.6Nd58-q1Nd58-r80% inhibition at 10 μM0.0258-s0.0120.0258-t9Nd58-u0.290.0158-v0.110.158-w0.190.2558-x0.310.0458-y0.270.0158-z2.23Nd58-aa0.340.158-ab0.220.00258-ac0.170.01358-ad0.130.01658-ae1.49Nd58-af0.210.1858-ag0.390.0458-ah0.330.0358-ai0.330.1558-aj0.380.3758-ak0.180.158-al0.250.1558-am0.240.0858-an0.20.159-a0.10.00859-b0.30.00759-c10.00759-d0.50.01559-e1.60.159-f1.80.0659-g1.80.259-h1.10.259-i1.20.0459-j0.90.00759-k0.30.0259-l0.30.00459-m1.20.0359-n0.130.03659-o0.80.0459-p0.180.01759-q0.750.1159-r1.80.2260-a0.8Nd60-b0.15Nd60-c0.34Nd60-d0.9Nd60-e0.9Nd60-f1Nd60-g1.5Nd60-hNdNd60-i0.3Nd60-jNdNd60-kNdNd60-l0.4Nd60-m0.5Nd60-n2Nd60-o5Nd60-p1.2Nd60-q1.8Nd60-r0.6Nd60-s8Nd60-t2Nd60-uNdNd60-v4.2Nd60-w0.5Nd60-x5Nd60-y2.5Nd60-z3Nd60-aa3.9Nd60-ab4Nd60-ac0.8Nd60-ad1.3Nd60-ae2.2Nd60-afNdNd60-agNdNd60-ah0.55Nd60-ai1.6Nd612.06Nd62-a50% inhibition at 10 μMNd62-b0.440.262-c30.862-d1.3Nd62-e4.6162-f31.562-g3162-h0.80.0762-i1.5162-j31.562-k3Nd62-l2.5Nd62-m1.2Nd62-n1Nd62-o1Nd62-p0.7Nd62-q1.6Nd62-r2.5Nd62-s1.75Nd631.5Nd64-a1Nd64-b50% at 10 μMNd64-c4.37Nd64-d50% at 10 μMNd64-eNdNd65Nd166-a19% inhibition at 10 μMNd66-b3.05Nd66-cNd16791% inhibition at 10 μMNd68-a97% inhibition at 10 μMNd68-b78% inhibition at 10 μMNd690.840.1370-a1.18Nd70-b0.67370-c20.870-d0.650.370-e0.50.870-fNd570-g51.570-h0.140.2578-e0.6Nd78-f0.1Nd78-h90% inhibition at 10 μMNd78-i97% inhibition at 10 μMNd78-k78% inhibition at 10 μMNd78-l100% inhibition at 10 μMNd78-n54% inhibition at 10 μMNd78-o54% inhibition at 10 μMNd78-q94% inhibition at 10 μMNd78-s88% inhibition at 10 μMNd78-t55% inhibition at 10 μMNd78-u93% inhibition at 10 μMNd78-v46% inhibition at 10 μMNd78-w90% inhibition at 10 μMNd80-c100% inhibition at 10 μMNd80-m103% inhibition at 10 μMNd82-h92% inhibition at 10 μMNd

	Number	Date	Country
Parent	PCT/EP02/11353	Sep 2002	US
Child	10808889	Mar 2004	US

Substituted benzimidazole compounds and their use for the treatment of cancer

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