Indian Patents
Title of Invention

NOVEL AMIDO-SUBSTITUTED HYDROXY-6- PHENYLPHENANTHRIDINES
Abstract Compounds of a certain formula I, in which R1, R2, R3, R4, R5, R6 and R7 have the meanings indicated in the description, are novel effective HDAC inhibitors.
Full Text FORM 2
THE PATENT ACT 1970 (39 of 1970)
&
The Patents Rules, 2003 COMPLETE SPECIFICATION
(See Section 10, and rule 13)
1. TITLE OF INVENTION : NOVEL AH1IDO-SUBSTITUTED HYDROXY-6-
PHENYLPHENANTHRIDINES
2. APPLICANT(S)
a) NAh1e : ALTANA PHARMA AG
b) Nationality : GERMAN Company
c) Address : BYK-GULDEN-STRASSE 2,
D-78467 KONSTANZ, GERMANY
3. PREAH1BLE TO THE DESCRIPTION
The following specification pAr1icularly describes the invention and the manner in which it is to be performed : -

The invention relates to novel N-sulphonylpyrrole derivatives, which are used in the pharmaceutical industry for the production of pharmaceutical compositions.
Known technical background
Transcriptional regulation in cells is a complex biological process. One basic principle is regulation by posttranslational
modification of histone proteins, nAh1ely histone proteins H2A/B, H3 and H4 forming the octAh1eric histone core complex.
These complex N-terminal modifications at lysine residues by acetylation or methylation and at serine residues by
phosphorylation constitute pAr1 of the so called "histone code" (Strahl & Ellis, Nature 403,41-45, 2000). In a simple model,
acetylation of positively charged lysine residues decreases affinity to negatively charged DNA, which now becomes
accessible for the entry of transcription factors.Histone acetylation and deacetylation is catalysed by histone
acetyltransferases (HATs) and histone deacetylases (HDACs). HDACs are associated with transcriptional repressor
complexes, switching chromatin to a transcriptionally inactive, silent structure (Marks et al. Nature Cancer Rev 1,194-202,
2001). The opposite holds true for HATs which are associated with transcriptional activator complexes. Three different
classes of HDACs have been described so far, nAh1ely class I (HDAC 1-3, 8) with Mr = 42-55 kDa primarily located in the
nucleus and sensitive towards inhibition by Trichostatin A (TSA), class II (HDAC 4-7,9,10) with Mr = 120-130kDa and TSA
sensitivity and class III (Sir2 homologues) which are quite distinct by their NAD* dependency and TSA insensitivity (Ruijter et
al. Biochem.J. 370,737-749,2003; Khochbin et al. Curr Opin Gen Dev 11,162-166,2001; Verdin et al. Trends Gen 19,286-
293, 2003). HDAC 11 with Mr = 39kDa was cloned recently and displayed homology to class I and II fAh1ily members (Gao
et al. J Biol Chem 277,25748-25755,2002). HATs and HDACs exist in large complexes together with transcription factor and
platform proteins in cells (Fischle et al. Mol Cell 9, 45-47, 2002). Surprisingly, only about 2% of all genes are regulated by
histone acetylation (von Lint et al. Gene Expression 5, 245-253, 1996). New studies with SAHA in multiple myeloma cells
showed that these transcriptional changes can be grouped into distinct functional gene classes important for eg regulation of
apoptosis or proliferation (Mitsiades et al. Proc Natl Acad Sci 101, pp540, 2004).Substrates different to histone proteins
exist. For HDACs these include transcription factors like p53 and TFII E / or chaperones like Hsp90 (Johnstone & Licht,
Cancer Cell 4, 13-18, 2003). Therefore the correct nAh1e for HDACs would be lysine-specific protein deacetylases. As a
consequence of these findings, inhibitors of HDACs effect not only chromatin structure and gene transcription but also
protein function and stability by regulating protein acetylation in general. This function of HDACs in protein acetylation might
also be important for understanding of immediate gene repression by treatment with HDIs (von Lint et al. Gene Expression
5, 245-253, 1996). In this regard, proteins involved in oncogenic transformation and malignant cell growth are of pAr1icular
importance.Different publications highlight the importance of histone acetylation for cancer development (reviewed by
KrAh1er et al. Trends Endocrin Maetabol 12, 294-300, 2001; Marks et al. Nature Cancer Rev 1, 194-202, 2001). These
diseases include
(i) mutations of the HAT cAH1P response element binding protein (CBP) associated with Rubinstein-Taybi
syndrome, a cancer predisposition (Murata et al. Hum Mol Genet 10,1071-1076,2001),
(ii) aberrant recruitment of HDAC1 activity by transcription factors in acute promyelocytic leukemia (APL) by the
PML-retinoic acid receptor a fusion gene (He et al. Nat genet 18,126-135,1998)
(iii) aberrant recruitment of HDAC activity by the overexpressed BCL6 protein in non-Hodagkins lymphoma (Dhoradain
et al. Nuceic Acid Res 26,4645-4651,1998) and finally (iv) aberrant recruitment of HDAC activity by the AH1L-ETO fusion protein in acute myelogenous leukemia (AH1L M2
subtype; Wang et al. Proc Natl Acad Sci USA 95,10860-10865,1998). In this AH1L subtype, the recruitment of
HDAC1 activity causally leads to gene silencing, a differentiation block and oncogenic transformation,
(v) HDAC1 gene knock-out in mice showed that HDAC1 has a profound function in embryonal stem cell proliferation
by repressing cyclin-dependent kinase inhibitors p21waf1 and p27kip (Lagger et al. Embo J. 21, 2672-2681,2002).
Since p21"af1 is induced by HDIs in many cancer cell lines, HDAC1 might be a crucial component in cancer cell
proliferation as well. Initial siRNA based gene-knock down experiments in HeLa cells support this hypothesis
(Glaser et al. 310,529-536,2003)
(vi) HDAC2 is overexpressed in colon carcinoma upon constitutive activation of the wnt /U-catenin/TCF signalling
pathay by loss of functional adenomatosis polyposis coli (APC) protein as reported by Zhu et al. recently (Cancer
Cell 5,455-463, 2004)
On the molecular level, a pleithora of published data with various HDAC inhibitors like Trichostatin A (TSA) showed that many cancer relevant genes are up- or down regulated. These include p21cip1, Cyclin E, transforming growth factor ft (TGFft), p53 or the von Hippel-Lindau (VHL) tumor suppressor genes, which are upregulated, whereas Bcl-XL, bcl2, hypoxia inducible factor (HIF)1cc, vascular endothelial growth factor (VEGF) and cyclin A/D are down-regulated by HDAC inhibition (reviewed by KrAh1er et al. Trends Endocrin Metabol 12,294-300, 2001). HDAC inhibitors arrest cells at G1 and G2/M within the cell cycle and deplete S-phase cells, as shown for Depsipeptide as an exAh1ple (Sandor et al., British J Cancer 83,817-825, 2000). HDAC inhibitory compounds induce p53 and caspase3/8 independent apoptosis and have broad anti-tumor activity. Anti-angiogenic activity was described also, which might be related to down-regulation of VEGF and HIF1a. In summary, HDAC inhibition effects tumor cells at different molecular levels and multiple cellular proteins are targetedilnterestingly, HDAC inhibitors were found to induce cellular differentiation and this pharmacological activity might
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contribute to their anti-cancer activity as well. For exAh1ple it was shown recently that suberoylanilide hydroxAh1ic acid (SAHA) induces differentiation of breast cancer cell lines, exemplified by resynthesis of milk fat membrane globule protein (MFMG), milk fat globule protein and lipid (Munster et al. Cancer Res. 61, 8492, 2001).There is growing rational for synergism of HDAC inhibitors with chemotherapeutic as well as target specific cancer drugs. For exAh1ple, synergism was shown for SAHA with the kinase / cdk inhibitor flavopiridol (Alemenara et al. Leukemia 16,1331-1343, 2002), for LAQ-824 with the bcr-abl kinase inhibitor Glivec in CML cells (Nimmanapalli et al. Cancer Res. 63, 5126-5135, 2003) and for SAHA and Trichostatin A (TSA) with etoposide (VP16), cisplatin and doxorubicin (Kim et al. Cancer Res. 63,7291-7300,2003) and LBH589 with the hsp90 inhibitor 17-allyl-Ah1ino-demethoxy-geldanAh1ycin (17-AAG; George et al. Blood online, Oct.28, 2004). Also it was shown that HDAC inhibition causes reexpression of estrogen or androgen receptors in breast and prostate cancer cells with the potential to resensitize these tumors to anti-hormone therapy (Yang et al. Cancer Res. 60, 6890-6894, 2000; NakayAh1a et al. Lab Invest 80,1789-1796, 2000).HDAC inhibitors from various chemical classes were described in the literature with four most important classes, nAh1ely (i) hydroxAh1ic acid analogs, (ii) benzAh1ide analogs, (iii) cyclic peptides / peptolides and (iv) fatty acid analogs. A comprehensive summary of known HDAC inhibitors was published recently (Miller et al. J Med Chem 46, 5097-5116, 2003). There is only limited data published regarding specificity of these histone deacetylase inhibitiors. In general most hydroxAh1ate based HDI are not specific regarding class I and II HDAC enzymes. For exAh1ple. TSA inhibits HDACs 1, 3,4, 6 and 10 with IC50 values around 20nM, whereas HDAC8 was inhibited with IC50 = 0.49 u.M (TatAh1iya et al, AACR Annual Meeting 2004, Abstract #2451). But there are exceptions like the experimental HDI Tubacin, selective for the class II enzyme HDAC 6 (HaggAr1y et al. Proc natl Acad Sci USA 100,4389-4394, 2003). In addition, data on class I selectivity of benzAh1id HDIs are emerging. MS-275 inhibited class I HDAC1 and 3 with IC50 = 0.51 nM and 1.7nM, respectively. In contrast class II HDACs 4, 6, 8 and 10 were inhibited with IC50 values of >100u.M, >100nM, 82.5|xM and 94.7uJvl, respectively (TatAh1iya et al, AACR Annual Meeting 2004, Abstract #2451). So far it is not clear if specificity towards HDAC class I or II enzymes or a defined single isoenzyme should be superior regarding therapeutic efficacy and index.Clinical studies in cancer with HDAC inhibitors are on-going, nAh1ely with SAHA (Merck Inc.), Valproic acid, FK228 / Depsipeptide (Gloucester Pharmaceuticals / NCI), MS275 (Berlex-Schering), NVP LBH-589 (NovAr1is), PXD-101 (Topotarget / Curagen), MGCD0103 (methylene Inc.) and Pivaloyloxymethylbutyrate / Pivanex (Titan Pharmaceuticals). These studies showed first evidence of clinical efficacy, highlighted recently by pAr1ial and complete responses with FK228 / Depsipeptide in patients with peripheral T-cell lymphoma (Plekarz et al. Blood, 98, 2865-2868, 2001).Recent publications also showed possible medical use of HDAC inhibitors in disease different to cancer. These diseases include systemic lupus erythematosus (Mishra et a. J Clin Invest 111,539-552,2003; Reilly et al. J. Immunol. 173, 4171-4178,2004), rheumatoid Ar1hritis (Chung et al. Mol Therapy 8,707-717, 2003; Nishida et al. Ar1hritis & Rheumatology 50, 3365-3376, 2004), inflAh1matory diseases (Leoni et al. Proc Natl Acad Sci USA 99, 2995-3000, 2002) and neurodegenerative diseases like Huntington's disease (Steffan et al. Nature 413, 739-743, 2001, Hockly et al. Proc Natl Acad Sci: USA 100(4):2041-6, 2003).Cancer chemotherapy was established based on the concept that cancer cells with uncontrolled proliferation and a high proportion of cells in mitosis are killed preferentially. Standard cancer chemotherapeutic drugs finally kill cancer cells upon induction of progrAh1med cell death ("apoptosis") by targeting basic cellular processes and molecules, nAh1ely RNA/DNA (alkylating and carbAh1ylating agents, platin analogs and topoisomerase inhibitors), metabolism (drugs of this class are nAh1ed anti-metabolites) as well as the mitotic spindle apparatus (stabilizing and destabilizing tubulin inhibitors). Inhibitors of histone deacetylases (HDIs) constitute a new class of anti cancer drugs with differentiation and apoptosis inducing activity. By targeting histone deacetylases, HDIs effect histone (protein) acetylation and chromatin structure, inducing a complex transcriptional reprogrAh1ming, exemplified by reactivation of tumor suppressor genes and repression of oncogenes. Beside effecting acetylation of N-terminal lysine residues in core histone proteins, nonhistone targets important for cancer cell biology like heat-shock-protein 90 (Hsp90) or the p53 tumor suppressor protein exist. The medical use of HDIs might not be restricted to cancer therapy, since efficacy in models for inflAh1matory diseases, rheumatoid Ar1hritis and neurodegeneration was shown.
Prior Ar1
Benzoyl or acetyl substituted pyrrolyl propenAh1ides are described in the public literature as HDAC-inhibitors, whereas the connectivity of the acyl-group is at position 2 or 3 of the pyrrole scaffold. (Mai et.al., Journal Med.Chem. 2004, Vol. 47, No. 5, 1098-1109). Further pyrrolyl substituted hydroxAh1ic acid derivatives are described in US4960787 as lipoxygenase inhibitors or in US6432999 as cyclooxygenase inhibitors.Various compounds, which are said to be HDAC inhibitors, are reported in WO 01/38322; Journal Med. Chem. 2003, Vol. 46, No. 24, 5097-5116; Journal Med. Chem. 2003, Vol. 46, No. 4, 512-524; Journal Med. Chem. 2003, Vol. 46, No. 5, 820-830; and in Current Opinion Drug Discovery 2002, Vol. 5, 487-499.There remains a need in the Ar1 for new, well tolerated and more efficacious inhibitors of HDACs.
Description of the invention
It has now been found that the N-sulphonylpyrrole derivatives, which are described in greater details below, differ profoundly from prior Ar1 compounds and are effective inhibitors of histone deacetylases and have surprising and pAr1icularly advantageous properties.The invention thus relates, in a first aspect (aspect 1), to compounds of formula I
3



in which
R1 is hydrogen, 1-4C-alkyl, halogen, or 1-4C-alkoxy,
R2 is hydrogen or 1-4C-alkyl, R3 is hydrogen or 1-4C-alkyl,
R4 is hydrogen, 1-4C-alkyl, halogen, or 1-4C-alkoxy,
R5 is hydrogen, 1-4C-alkyl, halogen, or 1-4C-alkoxy,
R6 is-T1-Q1, in which
T1 is a bond, or 1-4C-alkylene,
Q1 is Ar1, Aa1, Hh1, or Ah1, in which
Ar1 is phenyl, or R61- and/or R62-substituted phenyl, in which
R61 is 1-4C-alkyl, or-T2-N(R611)R612, in which either
T2 is a bond, and
R611 is hydrogen, 1-4C-alkyl, hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl, phenyl-1-4C-alkyl, or Har1-1-4C-alkyl, in
which
Har1 is optionally substituted by R6111 and/or R6112, and is a monocyclic or fused bicyclic 5- to 10-membered
unsaturated heteroaromatic ring comprising one to three heteroatoms, each of which is selected from the group
consisting of nitrogen, oxygen and sulfur, in which R6111 is halogen, or 1 -4C-alkyl, R6112 is 1-4C-alkyl, and R612 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl or hydroxy-2-4C-alkyl,or R611 and R612 together and with
inclusion of the nitrogen atom, to which they are bonded, form a heterocyclic ring Het1, in which
Het1 is morpholino, thiomorpholino, S-oxo-thiomorpholino, S.S-dioxo-thiomorpholino, piperidino, pyrrolidino,
piperazino, or 4N-(1 -4C-alkyl)-piperazino,or
T2 is 1-4C-alkylene, or 2-4C-alkylene interrupted by oxygen, and
R611 is hydrogen, 1-4C-alkyl, hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl, phenyl-1-4C-alkyl, or Har1-1-4C-alkyl, in
which
Har1 is optionally substituted by R6111 and/or R6112, and is a monocyclic or fused bicyclic 5- to 10-membered
unsaturated heteroaromatic ring comprising one to three heteroatoms, each of which is selected from the group
consisting of nitrogen, oxygen and sulfur, in which R6111 is halogen, or 1 -4C-alkyl, R6112 is 1-4C-alkyl, and R612 is hydrogen, 1-4C-alkyl, 1 -4C-alkoxy-2-4C-alkyl or hydroxy-2-4C-alkyl,or R611 and R612 together and with
inclusion of the nitrogen atom, to which they are bonded, form a heterocyclic ring Het1, in which
Het1 is morpholino, thiomorpholino, S-oxo-thiomorpholino, S,S-dioxo-thiomorpholino, piperidino, pyrrolidino,
piperazino, 4N-(1-4C-alkyl)-piperazino, imidazolo, pyrrolo or pyrazolo,
R62 is 1-4C-alkyl, 1-4C-alkoxy, halogen, cyano, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkylcarbonylAh1ino, or 1-4C-
alkylsulphonylAh1ino,
Aa1 is a bisaryl radical made up of two aryl groups,
which are selected independently from a group consisting of phenyl and naphthyl, and
which are linked together via a single bond,
Hh1 is a bisheteroaryl radical made up of two heteroaryl groups,
which are selected independently from a group consisting of monocyclic 5- or 6-membered heteroaryl radicals
comprising one or two heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and
sulfur.and which are linked together via a single bond,
Ah1 is a heteroaryl-aryl radical or an aryl-heteroaryl radical made up of a heteroaryl group selected from a group
consisting of monocyclic 5- or 6-membered heteroaryl radicals comprising one or two heteroatoms, each of
which is selected from the group consisting of nitrogen, oxygen and sulfur, and an aryl group selected from a
group consisting of phenyl and naphthyl, whereby said heteroaryl and aryl groups are linked together via a single
bond,
R7 is hydroxyl, or Cyc, in which
Cyc1 is a ring system of formula la
inwhich.A is C (carbon), B is C (carbon),
R71 is hydrogen, halogen, 1-4C-alkyl, or 1-4C-alkoxy,

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R72 is hydrogen, halogen, 1-4C-alkyl, or 1-4C-alkoxy,
M with inclusion of A and B is either a ring Ar2 or a ring Har2, in which
Ar2 is a benzene ring,
Har2 is a monocyclic 5- or 6-membered unsaturated heteroaromatic ring comprising one to three heteroatoms, each of
which is selected from the group consisting of nitrogen, oxygen and sulfur.and the salts of these compounds.The invention
relates, in a second aspect (aspect 2), to compounds of formula I in which
R1 is hydrogen, 1-4C-alkyl, halogen, or 1-4C-alkoxy,
R2 is hydrogen or 1-4C-alkyl, R3 is hydrogen or 1-4C-alkyl,
R4 is hydrogen, 1-4C-alkyl, halogen, or 1-4C-alkoxy,
R5 is hydrogen, 1-4C-alkyl, halogen, or 1-4C-alkoxy,
R6 is-T1-Q1, in which
T1 is a bond, or1-4C-alkylene,
Q1 is Ar1, Aa1, Hh1, or Ah1, in which
Ar1 is phenyl, or R61- and/or R62-substituted phenyl, in which
R61 is 1-4C-alkyl, or -T2-N(R611)R612, in which
T2 is a bond, 1-4C-alkylene, or 2-4C-alkylene interrupted by oxygen,
R611 is hydrogen, 1-4C-alkyl, hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl, phenyl-1-4C-alkyl, or Har1-1-4C-alkyl, in
which
Har1 is optionally substituted by R6111 and/or R6112, and is a monocyclic or fused bicyclic 5- to 10-membered
unsaturated heteroaromatic ring comprising one to three heteroatoms, each of which is selected from the group
consisting of nitrogen, oxygen and sulfur, in which
R6111 is halogen, or 1-4C-alkyl, R6112is1-4C-alkyl,
R612 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl or hydroxy-2-4C-alkyl,
R62 is 1-4C-alkyl, 1-4C-alkoxy, halogen, cyano, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkylcarbonylAh1ino, or 1-4C-
alkylsulphonylAh1ino,
Aa1 is a bisaryl radical made up of two aryl groups,
which are selected independently from a group consisting of phenyl and naphthyl, and
which are linked together via a single bond,
Hh1 is a bisheteroaryl radical made up of two heteroaryl groups,
which are selected independently from a group consisting of monocyclic 5- or 6-membered heteroaryl radicals
comprising one or two heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and
sulfur.and which are linked together via a single bond,
AH1 is a heteroaryl-aryl radical or an aryl-heteroaryl radical made up of a heteroaryl group selected from a group
consisting of monocyclic 5- or 6-membered heteroaryl radicals comprising one or two heteroatoms, each of
which is selected from the group consisting of nitrogen, oxygen and sulfur, and an aryl group selected from a
group consisting of phenyl and naphthyl, whereby said heteroaryl and aryl groups are linked together via a single
bond,
R7 is hydroxyl, or Cyc, in which
Cyc1 is a ring system of formula la


inwhich
A is C (carbon), B is C (carbon),
R71 is hydrogen, halogen, 1-4C-alkyl, or 1-4C-alkoxy,
R72 is hydrogen, halogen, 1-4C-alkyl, or 1-4C-alkoxy,
M with inclusion of A and B is either a ring Ar2 or a ring Har2, in which
Ar2 is a benzene ring,
Har2 is a monocyclic 5- or 6-membered unsaturated heteroaromatic ring comprising one to three heteroatoms, each
of which is selected from the group consisting of nitrogen, oxygen and sulfur.and the salts of these compounds. 1-4C-Alkyl represents a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. ExAh1ples which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl and preferably the ethyl and methyl radicals. 2-4C-Alkyl represents a straight-chain or branched alkyl radical having 2 to 4 carbon atoms. ExAh1ples which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl and preferably the ethyl and propyl radicals. 1-4C-Alkylene is a branched or, pAr1icularly, straight chain alkylene radical having 1 to 4 carbon atoms. ExAh1ples which may be mentioned are the methylene (-CH2-), ethylene (-CH2-CH2-), trimethylene (-CH2-CH2-CH2-) and the tetrAh1ethylene (-CH2-CH2-CH2-CH2-) radical. 2-4C-Alkylene interrupted by oxygen stands for a straight chain alkylene radical having 1 to 4 carbon atoms which is suitably interrupted by an oxygen atom such as, for exAh1ple, the [-CH2-CH2-O-CH2-CH2-] radical.
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1-4C-Alkoxy represents radicals which, in addition to the oxygen atom, contain a straight-chain or branched alkyl radical
having 1 to 4 carbon atoms. ExAh1ples which may be mentioned are the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy,
isopropoxy and preferably the ethoxy and methoxy radicals. 1 -4C-Alkoxy-1 -4C-alkyl represents one of the abovementioned
1-4C-alkyl radicals, which is substituted by one of the abovementioned 1-4C-alkoxy radicals. ExAh1ples which may be
mentioned are the methoxymethyl, the methoxyethyl and the isopropoxyethyl radicals, pAr1icularly the 2-methoxyethyl and
the 2-isopropoxyethyl radicals.1-4C-Alkoxy-2-4C-alkyl represents one of the abovementioned 2-4C-alkyl radicals, which is
substituted by one of the abovementioned 1-4C-alkoxy radicals. ExAh1ples which may be mentioned are the methoxyethyl,
ethoxyethyl and the isopropoxyethyl radicals, pAr1icularly the 2-methoxyethyl, the 2-ethoxyethyl and the 2-isopropoxyethyl
radicals.Hydroxy-2-4C-alkyl represents one of the abovementioned 2-4C-alkyl radicals, which is substituted by a hydroxy
radical. An exAh1ple which may be mentioned is the 2-hydroxyethyl or the 3-hydroxypropyl radical.Phenyl-1 -4C-a!kyl stands
for one of the abovementioned 1-4C-alkyl radicals, which is substituted by a phenyl radical. ExAh1ples which may be
mentioned are the benzyl and the phenethyl radicals.Halogen within the meaning of the invention is bromine or, in pAr1icular,
chlorine or fluorine. 1-4C-Alkylcarbonyl represents a radical which, in addition to the carbonyl group, contains one of the
abovementioned 1-4C-alkyl radicals. An exAh1ple which may be mentioned is the acetyl radical. 1 -4C-AlkylcarbonylAh1ino
represents an Ah1ino radical which is substituted by one of the abovementioned 1-4C-alkylcarbonyl radicals. An exAh1ple
which may be mentioned is the acetAh1ido radical [CH3C(0)-NH-].1-4C-AlkylsulphonylAh1ino is, for exAh1ple, the
propylsulfonylAh1ino [C3H7S(0)2NH-], the ethylsulfonylAh1ino [CaHsSfCtyNH-] and the methylsulfonylAh1ino [ChbSfCtyNH-]
radical.Aal is a bisaryl radical made up of two aryl groups,
which are selected independently from a group consisting of phenyl and naphthyl, and
which are linked together via a single bond.
Aa1 may include, without being restricted thereto, the biphenyl radical, e.g. the 1,1'-biphen-4-yl or 1,1'-biphen-3-yl radical.Hh1 is a bisheteroaryl radical made up of two heteroaryl groups, which are selected independently from a group consisting of monocyclic 5- or 6-membered heteroaryl radicals comprising one or two heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur, and which are linked together via a single bond.Hhl may include, without being restricted thereto, the bithiophenyl, bipyridyl, pyrazolyl-pyridinyl (pAr1icularly pyrazol-1 -yl-pyridinyl), imidazolyl-pyridinyl (pAr1icularly imidazol-1-yl-pyridinyl) or the pyridinyl-thiophenyl radical, e.g. the 5-(pyridin-2-yl)-thiophen-2-yl radical.in a special detail, exemplary Hh1 radicals may include pyridinylTthiophenyl, e.g. 5-(pyridin-2-yl)-thiophen-2-yl.Ah1 is a heteroarylaryl radical or an arylheteroaryl radical made up of a heteroaryl group selected from a group consisting of monocyclic 5- or 6-membered heteroaryl radicals comprising one or two heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur, and an aryl group selected from a group consisting of phenyl and naphthyl, whereby said heteroaryl and aryl groups are linked together via a single bond.The Ah1 radical can be bonded either via said heteroaryl or via said aryl moiety to the parent molecular group. A pAr1icular embodiment of said AH1 radicals refers to heteroaryl-phenyl radicals, e.g. 3-(heteroaryl)-phenyl or 4-(heteroaryl)-phenyl radicals.Ahl may include, without being restricted thereto, the phenyl-thiophenyl or phenyl-pyridyl radicals.Alternatively, AH1 may include, without being restricted thereto the furanyl-phenyl, pyrazolyl-phenyl (e.g. pyrazol-1-yl-phenyl or 1 H-pyrazol-4-yl-phenyl), imidazolyl-phenyl (e.g. imidazol-1 -yl-phenyl) or pyridinyl-phenyl radicals.ln a special detail, exemplary AH1 radicals may include 3-(pyrazolyl)-phenyl, 4-(pyrazolyl)-phenyl, 4-(pyridinyl)-phenyl or 3-(pyridinyl)-phenyl.ln a further special detail, exemplary AH1 radicals may include 3-(pyrazol-1-yl)-phenyl, 4-(pyrazol-1-yl)-phenyl, 4-(pyridin-4-yl)-phenyl, 3-(pyridin-4-yl)-phenyl, 4-(pyridin-3-yl)-phenyl, 3-(pyridin-3-yl)-phenyl, 3-(1H-pyrazol-4-yl)-phenyl or4-(1H-pyrazol-4-yl)-phenyl.lt is to be stated, that each of the radicals Hh1 and Ah1 is bonded preferably via a ring carbon atom to the moiety T1.Har1 is optionally substituted by R6111 and/or R6112, and is a monocyclic or fused bicyclic 5- to 10-membered unsaturated (heteroaromatic) heteroaryl radical comprising one to three heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur. In one detail, fused, in pAr1icular benzo-fused, bicyclic 9- or 10-membered heteroaryl radicals comprising one to three, in pAr1icular one or two, heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur, are to be mentioned. ExAh1ples of Har1 include, withouit being restricted thereto, thiophenyl, furanyl, pyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; and, in pAr1icular, the stable benzo-fused derivatives thereof, such as e.g. benzothiophenyl, benzofuranyl, indolyl, benzoxazolyl, benzothiazolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzofurazanyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl or cinnolinyl; and purinyl, indolizinyl, naphthyridinyl or pteridinyl.ln a special detail, exemplary Har1 radicals may include pyridinyl, benzimidazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl and indolyl, such as e.g. pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, benzimidazol-2-yl, benzoxazol-2-yl, benzofuran-2-yl, benzofuran-3-yl, benzothiophen-2-yl, benzothiophen-3-yl, indol-2-yl, indol-3-yl or indol-5-yl.ln a further special detail, an exemplary Har1 radical may be indolyl, such as e.g. indol-2-yl, indol-3-yl or indol-5-yl.Yet in a further special detail, an exemplary Har1 radical may be pyridinyl, such as e.g. pyridin-2-yl, pyridin-3-yl or pyridin-4-yl.As further exAh1ples of Har1, the R6111 - and/or R6112-substituted derivatives of the abovementioned exemplary Har1 radicals may be mentioned.Har1-1-4C-alkyl stands for one of the abovementioned 1-4C-alkyl radicals, such as e.g. methyl, ethyl or propyl, substituted by one of the abovementioned HAr1 radicals, such as e.g. imidazolyl, benzimidazolyl, indolyl or pyrrolyl and the like or the substituted derivatives thereof. As exAh1ples may be mentioned, without being restricted thereto,
6

pyridinylmethyl (e.g. pyridin-3-yl-methyl), imidazolylmethyl, pyrrolylmethyl, 2-imidazolylethyl (e.g. 2-imidazol-5-yl-ethyl), 2-pyridinylethyl, 3-(benzofuran-2-yl)propyl, 3-(benzimidazol-2-yl)propyl, 2-indolylethyl (e.g. 2-indol-2-yl-ethyl or 2-indol-3-yl-ethyl), indolylmethyl (e.g. indol-2-yl-methyl, indol-3-yl-methyl or indol-5-yl-methyl), 2-benzimidazolylethyl (e.g. 2-benzimidazol-2-ylethyl), benzimidazolylmethyl (e.g. benzimidazol-2-yl-methyl), and the like. In a special detail, exemplary Har1-1-4C-alkyl radicals may include pyridinylmethyl (e.g. pyridin-3-yl-methyl, pyridin-4-yl-methyl or pyrjdin-4-yl-methyl), 2-pyridinylethyl (e.g. 2-pyridin-3-yl-ethyl), indolylmethyl (e.g. indol-2-yl-methyl, indol-3-yl-methyl or indol-5-yl-methyl) or 2-indolylethyl (e.g. 2-indolyl-2-yl-ethyl or 2-indolyl-3-yl-ethyl).ln a further special detail, exemplary Har1-1-4C-alkyl radicals may include pyridin-3-yl-methyl, pyridin-4-yI-methyl, 2-pyridin-3-yl-ethyl, indol-2-yl-methyl, indol-3-yl-methyl, indol-5-yl-methyl, 2-indolyl-2-yl-ethyl or 2-indolyl-3-yl-ethyl.ln the context of the radical Har1-1-4C-alkyl, it is to be stated, that the portion Har1 is bonded preferably via a ring carbon atom to the 1-4C-alkyl moiety.One embodiment of those Har1-1-4C-alkyl radicals, in which the Har1 moiety is a fused bicyclic ring containing a benzene ring, refers to those radicals, in which the Har1 moiety is preferably bonded to the 1-4C-alkyl moiety via a carbon ring atom of the ring comprising one or more heteroatoms.Another embodiment of those Har1-1-4C-alkyl radicals, in which the HAr1 moiety is a fused bicyclic ring containing a benzene ring, refers to those radicals, in which the HAr1 moiety is preferably bonded to the 1-4C-alkyl moiety via a carbon ring atom of the benzene ring.Har2 stands for a monocyclic 5- or 6-membered unsaturated heteroaromatic ring comprising one to three heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur.Har2 may include, without being restricted thereto, thiophene, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, triazole, thiadiazole, oxadiazole, pyridine, pyrimidine, pyrazine or pyridazine.ln a special detail, an exemplary Har2 radical may be pyridine.Cyc stands for a ring system of formula la, which is bonded to the nitrogen atom of the carboxAh1ide group via the moiety A. Cyc may include, without being restricted thereto, 2-Ah1inophenyr substituted by R71 and/or R72.Naphthyl, alone or as pAr1 of another group, includes naphthalen-1-yl and naphthalen-2-yl.ln the meaning of the present invention, it is to be understood, that, when two structural portions of the compounds according to this invention are linked via a constituent which has the meaning "bond", then said two portions are directly attached to another via a single bond.ln general, unless otherwise mentioned the heterocyclic groups mentioned herein refer to all of the possible isomeric forms thereof.The heterocyclic groups mentioned herein refer, unless otherwise noted, in pAr1icular to all of the possible positional isomers thereof.Thus, for exAh1ple, the term pyridyl or pyridinyl, alone or as pAr1 of another group, includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl.Constituents which are optionally substituted as stated herein, may be substituted, unless otherwise noted, at any possible position.The carbocyclic groups, alone or as pAr1 of other groups, mentioned herein may be substituted by their given substituents or parent molecular groups, unless otherwise noted, at any substitutable ring carbon atom.The heterocyclic groups, alone or as pAr1 of other groups, mentioned herein may be substituted by their given substituents or parent molecular groups, unless otherwise noted, at any possible position, such as e.g. at any substitutable ring carbon or ring nitrogen atom.Rings containing quatemizable imino-type ring nitrogen atoms (-N=) may be preferably not quaternized on these imino-type ring nitrogen atoms by the mentioned substituents or parent molecular groups.Any heteroatom of a heterocyclic ring with unsatisfied valences mentioned herein is assumed to have the hydrogen atom(s) to satisfy the valences.When any variable occurs more than one time in any constituent, each definition is independent. Suitable salts for compounds of the formula I - depending on substitution - are all acid addition salts or all salts with bases. PAr1icular mention may be made of the pharmacologically tolerable inorganic and organic acids and bases customarily used in pharmacy. Those suitable are, on the one hand, water-insoluble and, pAr1icularly, water-soluble acid addition salts with acids such as, for exAh1ple, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulphuric acid, acetic acid, citric acid, D-glu-conic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulphosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tAr1aric acid, embonic acid, stearic acid, toluenesulphonic acid, methanesulphonic acid or 3-hydroxy-2-naphthoic acid, the acids being employed in salt preparation - depending on whether a mono- or polybasic acid is concerned and depending on which salt is desired - in an equimolar quantitative ratio or one differing therefrom.On the other hand, salts with bases are - depending on substitution - also suitable. As exAh1ples of salts with bases are mentioned the lithium, sodium, potassium, calcium, aluminium, magnesium, titanium, Ah1monium, meglumine or guanidinium salts, here, too, the bases being employed in salt preparation in an equimolar quantitative ratio or one differing therefrom.Pharmacologically intolerable salts, which can be obtained, for exAh1ple, as process products during the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically tolerable salts by processes known to the person skilled in the Ar1.According to expert's knowledge the compounds of the invention as well as their salts may contain, e.g. when isolated in crystalline form, varying Ah1ounts of solvents. Included within the scope of the invention are therefore all solvates and in pAr1icular all hydrates of the compounds of formula I as well as all solvates and in pAr1icular all hydrates of the salts of the compounds of formula I.The substituents R61 and R62 of compounds of formula I can be attached in the ortho, meta or para position with respect to the binding position in which the phenyl ring is bonded to T1, whereby preference is given to the attachement in the meta or, pAr1icularly, in the para position.ln another embodiment, Ar1 is phenyl which is mono-substituted by R61, whereby preference is given to the attachement of R61 in the meta or para position with respect to the binding position in which the phenyl ring is bonded to T1.In yet another embodiment, Ar1 is phenyl which is mono-substituted by R61, whereby preference is given to the attachement of R61 in the para position with respect to the binding position in which the phenyl ring is bonded to T1.ln still
7

yet another embodiment, Ar1 is phenyl which is mono-substituted by R61, whereby preference is given to the attachement of
R61 in the meta position with respect to the binding position in which the phenyl ring is bonded to T1 .Compounds according
to aspect 1 of the present invention more worthy to be mentioned are those compounds of formula I in which
R1 is hydrogen, or 1-4C-alkyl,
R2 is hydrogen, or 1-4C-alkyl,
R3 is hydrogen, or 1-4C-alkyl,
R4 is hydrogen, or 1-4C-alkyl,
R5 is hydrogen, or 1-4C-alkyl,
R6 is-T1-Q1, in which
T1 is a bond, or 1-4C-alkylene,
Q1 is Ar1, Aa1, Hh1, or Ah1, in which
Ar1 is phenyl, or R61-substituted phenyl, in which
R61 is 1-4C-alkyl, or-T2-N(R611)R612, in which either
T2 is a bond,
R611 is hydrogen, 1-4C-alkyl, phenyl-1 -4C-alkyl, or Har1-1-4C-alkyl, in which
Har1 is either a monocyclic 5-membered unsaturated heteroaromatic ring comprising one, two or three heteroatoms,
each of which is selected from the group consisting of nitrogen, oxygen and sulfur, or a monocyclic 6-membered unsaturated heteroaromatic ring comprising one or two nitrogen atoms, or a fused bicyclic 9-membered unsaturated heteroaromatic ring comprising one, two or three heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur, or a fused bicyclic 10-membered unsaturated heteroaromatic ring comprising one or two heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur, and
R612 is hydrogen, 1-4C-alkyl, or hydroxy-2-4C-alkyl,or R611 and R612 together and with inclusion of the nitrogen atom, to which they are bonded, form a heterocyclic ring Het1, in which
Het1 is morpholino.or
T2 is 1-4C-alkylene,
R611 is hydrogen, 1-4C-alkyl, phenyl-1 -4C-alkyl, or Har1-1-4C-alkyl, in which
Har1 is either a monocyclic 5-membered unsaturated heteroaromatic ring comprising one, two or three heteroatoms,
each of which is selected from the group consisting of nitrogen, oxygen and sulfur, or a monocyclic 6-membered unsaturated heteroaromatic ring comprising one or two nitrogen atoms, or a fused bicyclic 9-membered unsaturated heteroaromatic ring comprising one, two or three heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur, or a fused bicyclic 10-membered unsaturated heteroaromatic ring comprising one or two heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur, and
R612 is hydrogen, 1-4C-alkyl, or hydroxy-2-4C-alkyl, or R611 and R612 together and with inclusion of the nitrogen atom, to which they are bonded, form a heterocyclic ring Het1, in which
Het1 is morpholino,
Aa1 is a biphenyl radical,
Hh1 is a bipyridyl, pyrazolyl-pyridinyl, imidazolyl-pyridinyl, or pyridinyl-thiophenyl radical,
Ah1 is a pyridinyl-plienyl, pyrazolyl-phenyl, or imidazolyl-phenyl radical,
R7 is hydroxyl, or 2-Ah1inophenyl,and the salts of these compounds.Compounds according to aspect 2 of the present
invention more worthy to be mentioned are those compounds of formula I in which
R1 is hydrogen, or 1-4C-alkyl, R2 is hydrogen, or 1-4C-alkyl,
R3 is hydrogen, or 1-4C-alkyl, R4 is hydrogen, or 1-4G-alkyl,
R5 is hydrogen, or 1-4C-alkyl,
R6 is-T1-Q1, in which
T1 is a bond, or 1 -4C-alkylene,
Q1 is AH1, or Aa1, in which
Ar1 is phenyl, or R61-substituted phenyl, in which
R61 is 1-4C-alkyl, or -T2-N(R611)R612, in which
T2 is a bond, or 1 -4C-alkylene,
R611 is hydrogen, 1-4C-alkyl, or Har1-1-4C-alkyl, in which
HAr1 is imidazolyl, benzimidazolyl, indolyl or pyrrolyl,
R612 is hydrogen, or 1-4C-alkyl,
Aa1 is a biphenyl radical,
R7 is hydroxyl, or 2-Ah1inophenyl,and the salts of these compounds.Compounds according to aspect 1 of the
present invention in pAr1icular worthy to be mentioned are those compounds of formula I in which
R1 is hydrogen, R2 is hydrogen,


8
R3 is hydrogen, R4 is hydrogen,
R5 is hydrogen,
R6 is -T1-Q1, Aa1, Hh1, or Ah1, in which
T1 is a bond, or 1 -2C-alkylene,
Q1 is AH1, in which
Ar1 is phenyl, or R61-substituted phenyl, in which
R61 is 1-4C-alkyl, or -T2-N(R611)R612, in which either
T2 is a bond,
R611 is hydrogen, 1 -4C-alkyl, phenyl-1 -2C-alkyl, or Har1 -1 -2C-alkyl, in which
Har1 is pyridinyl, benzimidazolyl, benzoxazolyi, benzofuranyl, benzothiophenyl or indolyl, and
R612 is hydrogen, 1-4C-alkyl, or hydroxy-2-3C-alkyl,or R611 and R612 together and with inclusion of the nitrogen
atom, to which they are bonded, form a heterocyclic ring Het1, in which
Het1 is morpholino.or
T2 is 1-2C-alkylene,
R611 is hydrogen, 1-4C-alkyl, phenyl-1-2C-alkyl, or Har1-1-2C-alkyl, in which
Har1 is pyridinyl, benzimidazolyl, benzoxazolyi, benzofuranyl, benzothiophenyl or indolyl, and
R612 is hydrogen, 1-4C-alkyl, or hydroxy-2-3C-alkyl,or R611 and R612 together and with inclusion of the nitrogen
atom, to which they are bonded, form a heterocyclic ring Het1, in which
Het1 is morpholino,
Aa1 is a biphenyl radical,
Hh1 is a bipyridyl, pyrazolyl-pyridinyl, imidazolyl-pyridinyl, or pyridinyl-thiophenyl radical,
Ah1 is a pyridinyl-phenyl, pyrazolyl-phenyl, or imidazolyl-phenyl radical,
R7 is hydroxyl, or 2-Ah1inophenyl,and the salts of these compounds.Compounds according to aspect 2 of the
present invention in pAr1icular worthy to be mentioned are those compounds of formula I in which
R1 is hydrogen, R2 is hydrogen,
R3 is hydrogen, R4 is hydrogen,
R5 is hydrogen,
R6 is -T1-Q1, or biphenyl, in which
T1 is a bond, or 1 -2C-alkylene,
Q1 is AH1, in which
AH1 is phenyl, or R61-substituted phenyl, in which
R61 is 1-4C-alkyl, or -T2-N(R611)R612, in which
T2 is a bond, or 1 -2C-alkylene,
R611 is 1-4C-alkyl, or Har1-1-2C-alkyl, in which
Har1 is benzimidazolyl or indolyl,
R612 is 1-4C-alkyl,
R7 is hydroxyl, or 2-Ah1inophenyl,and the salts of these compounds.Compounds according to aspect 1 of the
present invention in more pAr1icular worthy to be mentioned are those compounds of formula I in which
R1 is hydrogen, R2 is hydrogen,
R3 is hydrogen, R4 is hydrogen,
R5 is hydrogen,
R6 is -T1-Q1, Aa1, Hh1, AH1, or benzyl, in which
T1 is a bond,
Q1 is AH1, in which
AH1 is phenyl, or R61-substituted phenyl, in which
R61 is 1-4C-alkyl, or-T2-N(R611)R612, in which either
T2 is a bond,
R611 is 1-4C-alkyl, and
R612 is 1-4C-alkyl,or
T2 is 1-2C-alkylene,
R611 is hydrogen, 1-4C-alkyl, phenyl-1-2C-alkyl, or HAh1-1-2C-alkyl, in which
Har1 is pyridinyl, or indolyl, and
R612 is hydrogen, 1-4C-alkyl, or hydroxy-2-3C-alkyl,or R611 and R612 together and with inclusion of the nitrogen
atom, to which they are bonded, form a heterocyclic ring Het1, in which
Het1 is morpholino,
Aa1 is 1,1 '-biphen-4-yl or 1,1 '-biphen-3-yl,
Hh1 is a pyridinyl-thiophenyl radical,
Ah1 is a 3-(pyridinyl)-phenyl, 3-(pyrazolyl)-phenyl, 4-(pyridinyl)-phenyl or 4-(pyrazolyl)-phenyl radical,
9

R7 is hydroxyl, or 2-Ah1inophenyl,and the salts of these compounds.Compounds according to aspect 2 of the
present invention in more pAr1icular worthy to be mentioned are those compounds of formula I in which
R1 is hydrogen, R2 is hydrogen,
R3 is hydrogen, R4 is hydrogen,
R5 is hydrogen,
R6 is -T1-Q1, biphenyl, or benzyl, in which
T1 is a bond,
Q1 is AH1, in which
Ar1 is R61-substituted phenyl, in pAr1icular 4-(R61)-phenyl, in which
R61 is methyl, dimethylAh1ino, or -T2-N(R611 )R612, in which
T2 is methylene,
R611 is methyl or 2-(indol-2-yl)ethyl,
R612 is methyl,
R7 is hydroxyl, or 2-Ah1inophenyl,and the salts of these compounds.Compounds according to aspect 1 of the
present invention to be emphasized are those compounds of formula I in which
R1 is hydrogen, R2 is hydrogen,
R3 is hydrogen, R4 is hydrogen,
R5 is hydrogen,
R6 is -T1-Q1, Aa1, Hh1, Ah1, or benzyl, in which
T1 is a bond,
Q1 is Ar1, in which
Ar1 is phenyl, 3-(R61 )-phenyl, or 4-(R61 )-phenyl, in which
R61 is methyl, or-T2-N(R611)R612, in which either
T2 is a bond, R611 is methyl, and
R612 , is methyl.or
T2 is methylene,
R611 is hydrogen, methyl, isobutyl, benzyl, HAr1 -methyl, or 2-(Har1)-ethyl in which
HAr1 is pyridinyl or indolyl, and
R612 is hydrogen, methyl, or 2-hydroxy-ethyl,or R611 and R612 together and with inclusion of the nitrogen atom, to
which they are bonded, form a heterocyclic ring Het1, in which
Het1 is morpholino,
Aa1 is 1,1 '-biphen-4-yl or 1,1 '-biphen-3-yl,
Hh1 is a pyridinyl-thiophenyl radical,
AH1 is a 3-(pyridinyl)-phenyl, 3-(pyrazolyl)-phenyl, 4-(pyridinyl)-phenyl or 4-(pyrazolyl)-phenyl radical,
R7 is hydroxyl, or 2-Ah1inophenyl,and the salts of these compounds.Compounds according to aspect 1 of the
present invention to be more emphasized are those compounds of formula I in which
R1 is hydrogen,
R2 is hydrogen,
R3 is hydrogen,
R4 is hydrogen,
R5 is hydrogen,
R6 is -T1-Q1, Aa1, Hh1, Ah1, or benzyl, in which
T1 is a bond,
Q1 is Ar1, in which
Ar1 is phenyl, 3-(R61 )-phenyl, or 4-(R61 )-phenyl, in which
R61 is methyl, or -T2-N(R611 )R612, in which either
T2 is a bond,
R611 is methyl, and
R612 is methyl.or
T2 is methylene,
R611 is hydrogen, methyl, isobutyl, benzyl, HAr1-methyl, or 2-(Har1)-ethyl in which
HAr1 is pyridin-3-yl, pyridin-4-yl, indol-2-yl, indol-3-yl or indol-5-yl, and
R612 is hydrogen, methyl, or 2-hydroxy-ethyl,or R611 and R612 together and with inclusion of the nitrogen atom, to
which they are bonded, form a heterocyclic ring Het1, in which
Het1 is morpholino,
Aa1 is 1,1'-biphen-4-yl or 1,1 '-biphen-3-yl,
Hh1 is5-(pyridin-2-yl)-thiophen-2-yl,
10

Ah1
R7
R1
R3
R5
R6
T1
Q1
Ar1
R61
T2
R611
R612
T2
R611
Har1
R612
R611
Har1
R612
R611
HAr1
R612
T2
Het1 Aa1 Hh1 Ah1
R7
R1
R3
R5
R6
T1
Ar1
R61
T2
R611
T2
R611
HAr1
R612
T2
R611
HAr1
R612
T2
R611
HAr1
R612
T2
Het1

is 3-(pyridin-3-yl)-phenyl, 3-(pyridin-4-yl)-phenyl, 3-(pyrazol-1-yl)-phenyl, 3-(1H-pyrazol-4-yl)-phenyl, 4-(pyridin-3-
yl)-phenyl, 4-(pyridin-4-yl)-phenyl, 4-(pyrazol-1-yl)-phenyl or4-(1H-pyrazol-4-yl)-phenyl,
is hydroxyl, or 2-Ah1inophenyl,and the salts of these compounds.Compounds according to aspect 1 of the
present invention to be in pAr1icular emphasized are those compounds of formula I in which
is hydrogen, R2 is hydrogen,
is hydrogen, R4 is hydrogen,
is hydrogen,
is -T1-Q1, Aa1, Hh1, Ah1, or benzyl, in which
is a bond,
is Ar1, in which
is phenyl, 3-(R61)-phenyl, or 4-(R61)-phenyl, in which
is methyl, or -T2-N(R611)R612, in which either
is a bond,
is methyl, and
is methyl.or
is methylene,
is hydrogen, isobutyl, benzyl, HAr1-methyl, or 2-(Har1)-ethyl, in which
is pyridin-3-yl, pyridin-4-yl, indol-2-yl, indol-3-yl or indol-5-yl, and
is hydrogen, or T2 is methylene,
is methyl, or 2-(Har1)-ethyl, in which
is indol-2-yl, and
is methyl, or T2 is methylene,
is 2-(Har1)-ethyl, in which
is indol-2-yl, and
is 2-hydroxy-ethyl, or
is methylene, and R611 and R612 together and with inclusion of the nitrogen atom, to which they are bonded,
form a heterocyclic ring Het1, in which
is morpholino,
is 1,1 '-biphen-4-yl or 1,1 '-biphen-3-yl,
is5-(pyridin-2-yl)-thiophen-2-yl,
is 3-(pyridin-3-yl)-phenyl, 3-(pyridin-4-yl)-phenyl, 3-(pyrazol-1-yl)-phenyl, 3-(1H-pyrazol-4-yl)-phenyl, 4-(pyridin-3-
yl)-phenyl, 4-(pyridin-4-yl)-phenyl, 4-(pyrazol-1-yl)-phenyl or 4-(1 H-pyrazol-4-yl)-phenyl,
is hydroxyl.and the salts of these compounds.Yet compounds according to aspect 1 of the present invention to
be in pAr1icular emphasized are those compounds of formula I in which
is hydrogen, R2 is hydrogen,
s hydrogen, R4 is hydrogen,
is hydrogen,
is -T1-Q1, Aa1, Hh1, AH1, or benzyl, in which
is a bond, Q1 is Ar1, in which
is phenyl, 3-(R61)-phenyl, or4-(R61)-phenyl, in which
is methyl, or -T2-N(R611 )R612, in which either
s a bond,
s methyl, and R612 is methyl,or
s methylene,
is hydrogen, isobutyl, benzyl, HAr1-methyl, or 2-(Har1)-ethyl, in which
is pyridin-3-yl, pyridin-4-yl, indol-3-yl, or indol-5-yl, and
s hydrogen.or
is methylene,
is methyl, or 2-(Har1)-ethyl, in which
s indol-2-yl, and
is methyl.or
is methylene,
is 2-(Har1)-ethyl, in which
is indol-2-yl, and
is 2-hydroxy-ethyl,or
s methylene, and R611 and R612 together and with inclusion of the nitrogen atom, to which they are bonded,
form a heterocyclic ring Het1, in which
is morpholino,

11

Aa1 is1,1'-biphen-4-ylor1,1'-biphen-3-yl,
Hh1 is 5-(pyridin-2-yl)-thiophen-2-yl,
Ah1 is 3-(pyridin-3-yl)-phenyl, 3-(pyridin-4-yl)-phenyl, 3-(pyrazol-1-yl)-phenyl, 3-(1H-pyrazol-4-yl)-phenyl, 4-(pyridin-3-
yl)-phenyl, 4-(pyridin-4-yl)-phenyl, 4-(pyrazol-1-yl)-phenyl or 4-(1 H-pyrazol-4-yl)-phenyl,
R7 is 2-Ah1inophenyl,and the salts of these compounds.A special interest in the compounds according to the present
invention refers to those compounds of this invention which are included -within the scope of this invention- by one or, when
possible, a combination of more of the following embodiments:An embodiment of the compounds according to the present
invention relates to those compounds of formula I, in which R1, R2, R3, R4 and R5 are all hydrogen.A further embodiment of
the compounds according to the present invention relates to those compounds of formula I, in which R7 is hydroxyLA further
embodiment of the compounds according to the present invention relates to those compounds of formula I, in which R7 is
Cyc, whereby in a subembodiment thereof Cyc is 2-phenyl.A further embodiment of the compounds according to the
present invention relates to those compounds of formula I, in which R7 is 2-Ah1inophenyl.A further embodiment of the
compounds according to the present invention relates to those compounds of formula I, in which R6 is Aa1 .A further
embodiment of the compounds according to the present invention relates to those compounds of formula I, in which R6 is
Ar1 or -GH2-Ar1 .A further embodiment of the compounds according to the present invention relates to those compounds of
formula I, in which Ar1 is R61-substituted phenyLA further embodiment of the compounds according to the present invention
relates to those compounds of formula I, in which Ar1 is phenyl monosubstituted by R61 in the meta position with respect to
the binding position in which the phenyl ring is bonded to T1 .A further embodiment of the compounds according to the
present invention relates to those compounds of formula I, in which Ar1 is phenyl monosubstituted by R61 in the para
position with respect to the binding position in which the phenyl ring is bonded to T1 .A further embodiment of the compounds
according to the present invention relates to those compounds of formula I, in which R6 is Hh1 .A further embodiment of the
compounds according to the present invention relates to those compounds of formula I, in which R6 is AH1 .A further
embodiment of the compounds according to the present invention relates to those compounds of formula I, in which T2 is a
bond.A further embodiment of the compounds according to the present invention relates to those compounds of formula I, in
which T2 is 1-4C-alkylene, such as e.g. methylene.A further embodiment of the compounds according to the present
invention relates to those compounds of formula I, in which
R6 is Ar1, in which Ar1 is R61-substituted phenyl, in which
R61 is -T2-N(R611)R612, in which
T2 is a bond.
A further embodiment of the compounds according to the present invention relates to those compounds of formula I, in which
R6 is Ar1, in which
Ar1 is R61-substituted phenyl, in which R61 is -T2-N{R611)R612, in which
T2 is 1-4C-alkylene, such as e.g. methylene.
A further embodiment of the compounds according to the present invention relates to those compounds of formula I, in which
R1, R2, R3, R4 and R5 are all hydrogen, and
R6 is Ar1, in which
Ar1 is any one selected from the group consisting of
3-methyl-phenyl, 4-methyl-phenyl,
3-dimethylAh1ino-phenyl, 4-dimethylAh1ino-phenyl,
3-Ah1inomethyl-phenyl, 4-Ah1inomethyl-phenyl,
3-(morpholin-4-yl-methyl)-phenyl, 4-(morpholin-4-yl-methyl)-phenyl,
3-(N-benzylAh1ino-methyl)-phenyl, 3-(N-isobutylAh1ino-methyl)-phenyl,
4-(N-benzylAh1ino-methyl)-phenyl, 4-(N-isobutylAh1ino-methyl)-phenyl,
3-[N-(pyridinylmethyl)Ah1ino-methyl]-phenyl,
3-[N-(indolylmethyl)Ah1ino-methyl]-phenyl,
4-[N-(pyridinylmethyl)Ah1ino-methyl]-phenyl, 4-[N-(indolylmethyl)Ah1ino-methyl]-phenyl,
3-(N,N-dimethylAh1ino-methyl)-phenyl, 4-(N,N-dimethylAh1ino-methyl)-phenyl,
3-[N,N-(2-indolylethyl)-methyl-Ah1ino-methyl]-phenyl, 4-[N,N-(2-indolylethyl)-methyl-Ah1ino-methyl]-phenyl,
3-[N,N-(2-indolylethyl)-(2-hydroxyethyl)-Ah1ino-methyl]-phenyl, and 4-[N,N-(2-indolylethyl)-(2-hydroxyethyl)-Ah1ino-methyl]-phenyl. A further embodiment of the compounds according to the present invention relates to those compounds of formula I, in which R1, R2, R3, R4 and R5 are all hydrogen, and R6 is Aa1, in which
Aa1 is a biphenyl radical. A further embodiment of the compounds according to the present invention relates to those
compounds of formula I, in which R1, R2, R3, R4 and R5 are all hydrogen, and R6 is Ha1, in which
Ha1 is a pyridinyl-thiophenyl radicaLA further embodiment of the compounds according to the present invention relates
to those compounds of formula I, in which R1, R2, R3, R4 and R5 are all hydrogen, and
R6 is Ah1, in which
12

Ah1 is a 3-(pyrazolyl)-phenyl, 4-(pyrazolyl)-phenyl, 4-(pyridinyl)-phenyl, or 3-(pyridinyl)-phenyl radical.
A further embodiment of the compounds according to the present invention relates to those compounds of formula I, in
which R1, R2, R3, R4 and R5 are all hydrogen, and R7 is hydroxyl.A further embodiment of the compounds according to
the present invention relates to those compounds of formula I, in which R1, R2, R3, R4 and R5 are all hydrogen, and R7 is
Cyc .A further embodiment of the compounds according to the present invention relates to those compounds of formula I,
in which R1, R2, R3, R4 and R5 are all hydrogen, and R7 is 2-Ah1inophenyl.A further embodiment of the compounds
according to the present invention relates to those compounds of formula I, in which R1, R2, R3, R4 and R5 are all
hydrogen, and R7 is Ah1inopyridyLA special embodiment of the compounds according to the present invention relates to
those compounds of formula I, in which R1, R2, R3, R4 and R5 are all hydrogen, and R6 is Ar1, in which Ar1 is any
one selected from the group consisting of
3-methyl-phenyl, 4-methyl-phenyl,
3-dimethylAh1ino-phenyl, 4-dimethylAh1ino-phenyl,
3-Ah1inomethyl-phenyl, 4-Ah1inomethyl-phenyl,
3-(morpholin-4-yl-methyl)-phenyl, 4-(morpholin-4-yl-methyl)-phenyl,
3-(N-benzyiAh1ino-methyl)-phenyl, 3-(N-isobutylAh1ino-methyl)-phenyl,
4-(N-benzylAh1ino-methyl)-phenyl, 4-(N-isobutylAh1ino-methyl)-phenyl,
3-[N-(pyridin-3-yl-methyl)Ah1ino-methyl]-phenyl, 3-[N-(pyridin-4-yl-methyl)Ah1ino-methyl]-phenyl,
3-[N-(indol-5-yl-methyl)Ah1ino-methyl]-phenyl, 3-[N-(indol-3-yl-methyl)Ah1ino-methyl]-phenyl,
4-[N-(pyridin-3-yl-methyl)Ah1ino-methyl]-phenyl, 4-[N-(pyridin-4-yl-methyl)Ah1ino-methyl]-phenyl,
4-[N-(indol-5-yl-methyl)Ah1ino-methyl]-phenyl, 4-[N-(indol-3-yl-methyl)Ah1ino-methyl]-phenyl,
3-(N,N-dimethylAh1ino-methyl)-phenyl, 4-(N,N-dimethylAh1ino-methyl)-phenyl,
3-{N,N-[2-(indol-2-yl)-ethyl]-methyl-Ah1ino-methyl}-phenyl, 4-{N,N-[2-(indol-2-yl)-ethyl]-methyl-Ah1ino-methyl}-phenyl,
3-{N,N-[2-(indol-2-yl)-ethyl]-(2-hydroxyethyl)-Ah1ino-methyl}-phenyl, and 4-{N,N-[2-(indol-2-yl)-ethyl]-(2-hydroxyethyl)-Ah1ino-
methylj-phenyl, and
R7 is hydroxyl.and the salts thereof. Another special embodiment of the compounds according to the present
invention relates to those compounds of formula I, in which
R1, R2, R3, R4 and R5 are all hydrogen, and
R6 is Aa1, in which
Aa1 is 1,1 '-biphen-4-yl or 1,1 '-biphen-3-yl, and
R7 is hydroxyl.and the salts thereof.Another special embodiment of the compounds according to the present invention
relates to those compounds of formula I, in which R1, R2, R3, R4 and R5 are all hydrogen, and
R6 is Ha1, in which
Ha1 is 5-(pyridin-2-yl)-thiophen-3-yl, and
R7 is hydroxyl.and the salts thereof.Another special embodiment of the compounds according to the present invention
relates to those compounds of formula I, in which
R1, R2, R3, R4 and R5 are all hydrogen, and
R6 is Ah1, in which
Ah1 is 3-(pyrazol-1-yl)-phenyl, 4-(pyrazol-1-yl)-phenyl, 4-(pyridin-4-yl)-phenyl, 3-(pyridin-4-yl)-phenyl, 4-(pyridin-3-yl)-
phenyl, 3-(pyridin-3-yl)-phenyl, 3-(1H-pyrazol-4-yl)-phenyl or 4-(1 H-pyrazol-4-yl)-phenyl, R7 is hydroxyl.and the salts thereof.Another special embodiment of the compounds according to the present invention relates to those compounds of formula I, in which R1, R2, R3, R4 and R5 are all hydrogen, and R6 is AH1, in which
Ar1 is any one selected from the group consisting of 3-methyNphenyl, 4-methyl-phenyl, 3-dimethylAh1ino-phenyl, 4-dimethylAh1ino-phenyl, 3-Ah1inomethyl-phenyl, 4-Ah1inomethyl-phenyl, 3-(morpholin-4-yl-methyl)-phenyl, 4-(morpholin-4-yl-methyl)-phenyl, 3-(N-benzylAh1ino-methyl)-phenyl, 3-(N-isobutylAh1ino-methyl)-phenyl, 4-(N-benzylAh1ino-methyl)-phenyl, 4-(N-isobutylAh1ino-methyl)-phenyl, 3-[N-(pyridin-3-yl-methyl)Ah1ino-methyl]-phenyl, 3-[N-(pyridin-4-yl-methyl)Ah1ino-methyl]-phenyl, 3-[N-(indol-5-yl-methyl)Ah1ino-methyl]-phenyl, 3-[N-(indol-3-yl-methyl)arnino-methyl]-phenyl, 4-[N-(pyridin-3-yl-methyl)Ah1ino-methyl]-phenyl, 4-[N-(pyridin-4-yl-methyl)Ah1ino-methyl]-phenyl, 4-[N-(indpl-5-yl-methyl)Ah1ino-methyl]-phenyl, 4-[N-(indol-3-yl-methyl)Ah1ino-methyl]-phenyl, 3-(N,N-dimethylAh1ino-methyl)-phenyl, 4-(N,N-dimethylAh1ino-methyl)-phenyl,
3-{N,N-[2-(indol-2-yl)-ethyl]-methyl-Ah1ino-methyl}-phenyl,4-{N,N-[2-(indol-2-yl)-ethyl]-methyl-Ah1ino-methyl}-phenyl, 3-{N,N-[2-(indol-2-yl)-ethyl]-(2-hydroxyethyl)-Ah1ino-methyl}-phenyl, and 4-{N,N-[2-(indol-2-yl)-ethyl]-(2-hydroxyethyl)-Ah1ino-methyl}-phenyl, and
13

R7 is 2-Ah1inophenyl,and the salts thereof.Another special embodiment of the compounds according to the present
invention relates to those compounds of formula I, in which R1, R2, R3, R4 and R5 are all hydrogen, and R6 is Aa1, in which
Aa1 is 1,1 '-biphen-4-yl or 1,1'-biphen-3-yl, and
R7 is 2-Ah1inophenyl,and the salts thereof.Another special embodiment of the compounds according to the present
invention relates to those compounds of formula I, in which R1, R2, R3, R4 and R5 are all hydrogen, and
R6 is Ha1, in which
Ha1 is 5-(pyridin-2-yl)-thiophen-2-yl, and
R7 is 2-Ah1inophenyl,and the salts thereof.Another special embodiment of the compounds according to the present
invention relates to those compounds of formula I, in which R1, R2, R3, R4 and R5 are all hydrogen, and
R6 is Ah1, in which
Ah1 is 3-(pyrazol-1-yl)-phenyl, 4-(pyrazol-1-yl)-phenyl, 4-(pyridin-4-yl)-phenyl, 3-(pyridin-4-yl)-phenyl, 4-(pyridin-3-yl)-
phenyl, 3-(pyridin-3-yl)-phenyl, 3-(1 H-pyrazol-4-yl)-phenyl or 4-(1 H-pyrazol-4-yl)-phenyl, R7 is 2-Ah1inophenyl,and the salts thereof.Exemplary compounds according to this invention may include any one selected from
1. (E)-N-Hydroxy-3-[1-(toluene-4-sulfonyl)-1-H-pyrrol-3-yl]-acrylAh1ide
2. N-Hydroxy-3-(1 -phenylmethanesulfonyl-1 H-pyrrol-3-yl)-acrylAh1ide
3. (E)-3-[1 -(Biphenyl-4-sulfonyl)-1 H-pyrrol-3-yl]-N-hydroxy-acrylAh1ide
4. (E)-3-[1 -(4-DimethylAh1ino-benzenesulfonyl)-1 H-pyrrol-3-yl]-N-hydroxy-acrylAh1ide
5. (E)-N-(2-Ah1ino-phenyl)-3-[1 -(toluene-4-sulfonyl)-1 H-pyrrol-3-yl]-acrylAh1ide
6. (E)-N-(2-Ah1ino-phenyl)-3-(1 -phenylmethanesulfonyl-1 H-pyrrol-3-yl)-acrylAh1ide
7. (E)-N-(2-Ah1ino-phenyl)-3-[1 -(biphenyl-4-sulfonyl)-1 H-pyrrol-3-yl]-acrylAh1ide
8. (E)-N-(2-Ah1ino-phenyl)-3-[1 -(4-dimethylAh1ino-benzenesulfonyl)-1 H-pyrrol-3-yl]-acrylAh1ide
9. (E)-N-Hydroxy-3-(1 -[4-(([2-(1 H-indol-2-yl)-ethyl]-methyl-Ah1ino)-methyl)-benzene sulfonyl] -1 H-pyrrol-3-yl)-acrylAh1ide
10. (E)-3-[1 -(4-DimetylAh1inomethyl-benzenesulfonyl)-1 H-pyrrol-3-yl]-N-hydroxy-acrylAh1ide
11. (E)-N-Hydroxy-3-[1 -(4-{[(pyridin-3-ylmethyl)-Ah1ino]-methyl}-benzenesulfonyl)-1 H-pyrrol-3-yl]-acrylAh1ide
12. (E)-N-Hydroxy-3-[1 -(4-{[(1 H-indol-3-ylmethyl)-Ah1ino]-methyl}-benzenesulfonyl)-1 H-pyrrol-3-yl]-acrylAh1ide
13. (E)-3-{1 -[4-(BenzylAh1ino-methyl)-benzenesulfonyl]-1 H-pyrrol-3-yl}-N-hydroxy-acrylAh1ide
14. (E)-N-Hydroxy-3-{1-[4-(isobutylAh1ino-methyl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylAh1ide
15. (E)-N-Hydroxy-3-[1 -(4-{[(1 H-indol-5-ylmethyl)-Ah1ino]-methyl}-benzenesulfonyl)-1 H-pyrrol-3-yl]-acrylAh1ide
16. (E)-N-Hydroxy-3-[1 -(4-{[(pyridin-4-ylmethyl)-Ah1ino]-methyl}-benzenesulfonyl)-1 H-pyrrol-3-yl]-acrylAh1ide
17. (E)-3-[1 -(4-Ah1inomethyl-benzenesulfonyl)-1 H-pyrrol-3-ylj-N-hydroxy-acrylAh1ide
18. (E)-N-Hydroxy-3-[1-(4-pyridin-4-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylAh1ide
19. (E)-N-Hydroxy-3-{1-[4-(1H-pyrazol-4-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylAh1ide
20. (E)-N-(2-Ah1ino-phenyl)-3-[1 -(4-pyridin-4-yl-benzenesulfonyl)-1 H-pyrrol-3-yl]-acrylAh1ide
21. (E)-N-(2-Ah1ino-phenyl)-3-[1 -(4-pyridin-3-yl-benzenesulfonyl)-1 H-pyrrol-3-ylj-acrylAh1ide
22. (E)-N-(2-Ah1ino-phenyl)-3-{1 -[4-(1 H-pyrazol-4-yl)-benzenesulfonyl]-1 H-pyrrol-3-yl}-acrylAh1ide
23. (E)-3-[1 -(Biphenyl-3-sulfonyl)-1 H-pyrrol-3-yl]-N-hydroxy-acrylAh1ide
24. (E)-N-Hydroxy-3-[1-(5-pyridin-2-yl-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylAh1ide
25. (E)-N-Hydroxy-3-[1-(4-pyrazol-1-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylAh1ide
26. (E)-N-(2-Ah1ino-phenyl)-3-[1-(5-pyridin-2-yl-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylAh1ide
27. (E)-N-Hydroxy-3-[1-(4-morpholin-4-ylmethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylAh1ide
28. (E)-N-Hydroxy-3-{1-[4-({(2-hydroxy-ethyl)-[2-(1H-indol-2-yl)-ethyl]-Ah1ino}-methyl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylAh1ide
29. (E)-N-Hydroxy-3-[1-(3-pyridin-4-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylAh1ide
30. (E)-N-(2-Ah1ino-phenyl)-3-[1-(3-pyridin-4-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylAh1ide
31. (E)-N-(2-Ah1ino-phenyl)-3-[1 -(3-pyridin-3-yl-benzenesulfonyl)-1 H-pyrrol-3-ylj-acrylAh1ide
32. (E)-N-Hydroxy-3-{1-[3-(1 H-pyrazol-4-yl)-benzenesulfonyl]-1 H-pyrrol-3-yl}-acrylAh1ide and
33. (E)-N-(2-Ah1ino-phenyl)-3-{1 -[3-(1 H-pyrazol-4-yl)-benzenesulfonyl]-1 H-pyrrol-3-yl}-acrylAh1ide,and the salts thereof.
The compounds according to the present invention can be prepared, for exAh1ple, as shown in the reaction schemes below
and according to the reaction steps specified as follows, or, pAr1icularly, in a manner as described by way of exAh1ple in the
following exAh1ples, or analogously or similarly thereto using preparation procedures and synthesis strategies known to the
person skilled in the Ar1.ln reaction scheme 1 the carbon chain of compounds of formula V, in which R1, R2, R4 and R5
have the meanings mentioned above, is lengthened, for exAh1ple, by a condensation reaction (with a malonic acid
derivative) or by a Wittig or Julia reaction or, pAr1icularly in the case when R2 is hydrogen, by a Horner-Wadsworth-
Emmons reaction (with a p-(alkoxycarbonyl)-phosphonic acid dialkyl ester) to obtain compounds of formula IV, in which R1,
R2, R3, R4 and R5 have the meanings mentioned above and PG1 stands for a suitable temporary protective group for the
carboxyl group, for exAh1ple tert-butyl or one of those Ar1-known protective groups mentioned in "Protective Groups in
14

Organic Synthesis" by T. Greene and P. Wuts (John Wiley & Sons, Inc. 1999, 3rd Ed.) or in "Protecting Groups (Thieme Foundations Organic Chemistry Series N Group" by P. Kocienski (Thieme Medical Publishers, 2000).
Reaction scheme 1



Compounds of formula V, in which R1, R2, R4 and R5 have the meanings mentioned above, are known, or can be prepared according to Ar1-known procedures, or can be obtained as described in the following exAh1ples for the case that R2 is hydrogen from compounds of formula Vl.Compounds of formula VI are known or are accessible in a known manner or as described in the following exAh1ples.Compounds of formula IV, in which R1, R2, R3, R4 and R5 have the meanings mentioned above and PG1 stands for a said suitable protective group, can be reacted with compounds of formula R6-SO2-X, in which R6 has the meanings mentioned above and X is a suitable leaving group, such as e.g. chlorine, to give the corresponding compounds of formula 111 .In the next reaction step, the protective group PG1 of compounds of formula III can be removed in a manner as described in the following exAh1ples or according to ah Ar1-known manner to afford compounds of formula ll.Compounds of formula R6-SO2-X are known or can be prepared in a known manner.Compounds of formula II, in which R1, R2, R3, R4, R5 and R6 have the meanings given above, can be coupled with compounds of formulae H2N-O-PG2, in which PG2 is a suitable oxygen protective group such as e.g. a suitable silyl or tetrahydropyran-2-yl protective group, or Ha, in which PG3 stands for a suitable nitrogen protective group such as e.g. the tert-butyloxycarbonyl protective group, by reaction with Ah1ide bond linking reagents optionally in the presence of coupling additives known to the person skilled in the Ar1. Exemplary Ah1ide bond linking reagents known to the person skilled in the Ar1 which may be mentioned are, for exAh1ple, carbodiimides (e.g. dicyclohexylcarbodiimide or, preferably, 1-ethyl-3-(3-dimethylAh1inopropyl)carbodiimide hydrochloride), azodicarboxylic acid derivatives (e.g. diethyl azodicarboxylate), uranium salts [e.g. 0-(benzotriazol-1-yl)-N,N,N',N'-tetrAh1ethyluronium tetrafluoroborate or 0-(benzotriazol-1yl)-N,N,N',N'-tetrAh1thyl-uronium-hexafluorophosphate] and N,N'-carbonyldiimidazole.Alternatively, compounds of formula II can be activated prior to the coupling reaction by forming an acid halide or acid anhydride optionally in an in-situ procedure without isolating the acid halide or acid anhydride.Compounds of formulae H2N-O-PG2 or Ha are known or can be prepared according to Ar1-known processes.Removal of the protective groups PG2 or PG3 can be obtained in a manner known for the person skilled in the Ar1 or as described in the following exAh1ples to give compounds of formula I, in which R1, R2, R3, R4, R5, R6 and R7 have the meanings mentioned above.Compounds of formula I, in which T2 is 1-4C-alkylene, pAr1icularly methylene, can be prepared as outlined in the following reaction schemes 2 to 5, and specified below, or as described by way of exAh1ple in the following exAh1ples, or analogously or similarly thereto.As shown in reaction scheme 2 compounds of formula VII, in which T2 is 1-4C-alkylene, pAr1icularly methylene, and Y1 is a suitable leaving group, such as e.g. iodine, chlorine or, pAr1icularly, bromine, and PG4 stands for a suitable temporary protective group for the carboxyl group, for exAh1ple tert-butyl, can be reacted with compounds of formula HN(R611)R612 to give in an Ar1-known nucleophilic substitution reaction corresponding Ah1ino compounds, which are deprotected by removal of PG4 to give corresponding free acids of formula VIII, which can be coupled with compounds of formulae H2N-O-PG2 or Ha as described above to give, after removal of PG2 and PG3, corresponding compounds of formula la.
Reaction scheme 2:

Alternatively, as shown in reaction scheme 3, compounds of formula VII, in which T2 is 1-4C-alkylene, pAr1icularly methylene, and Y1 is a suitable leaving group, such as e.g. iodine, chlorine or, pAr1icularly, bromine, and PG4 stands for a suitable temporary protective group for the carboxyl group, for exAh1ple tert-butyl, can be reacted with a temporarily protected Ah1ine (a primary or, pAr1icularly, a secondary one), such as e.g. phthalimide, to give in an Ar1-known nucleophilic substitution reaction corresponding Ah1ino compounds, which are deprotected by removal of PG4 to give corresponding free acids of formula IX, which can be coupled with compounds of formulae H2N-O-PG2 or Ha as described above to give corresponding compounds of formula X.
Reaction scheme 3:

The Ah1ino moiety of compounds of formula X can be deprotected in an Ar1-known manner to give corresponding compounds of formula XI, such as e.g. when the phthalimido protective group is used, this can be removed in a manner customary per se to the skilled person, e.g. with the aid of hydrazine.Compounds of formula XI can be deprotected to give
15

corresponding compounds of formula ^.Alternatively, as shown in reaction scheme 4, compounds of formula XI can be reacted with compounds of formula R611-Y1 and/or R612-Y2, in which R611 and R612 have the meanings given above and are different from hydrogen and Y1 and Y2 are suitable leaving groups such as e.g. chlorine, bromine, iodine or a sulfonate (e.g. triflate) leaving group, to give in an Ar1-known nucleophilic substitution reaction corresponding compounds of formula XII or XH'.Compounds of formula XII or XII' can be deprotected to give corresponding compounds of formula Ic or Id, respectively.
Reaction scheme 4:


Yet alternatively, as shown in reaction scheme 5, compounds of formula XI can be reacted with aldehydes or ketones in an reductive Ah1ination reaction, such as e.g. compounds of formula XI can be reacted with benzaldehyde, or compounds of formulae 1-3C-alkyl-CHO or Har1-CHO, in which HAr1 has the meanings given above, to give in an Ar1-known reductive Ah1ination reaction corresponding compounds of formula Xlll.Compounds of formula XIII can be deprotected to give corresponding compounds of formula le.
Reaction scheme 5:


Compounds of formula VII can be obtained according to the synthesis route shown in reaction scheme 1 and described above.The abovementioned compounds of formulae HN(R611)R612, R611-Y1, R612-Y2,1-3C-alkyl-CHO or Har1-CHO are known or can be obtained according to Ar1-known procedures.Compounds of formula I, in which R6 is Aa1 or Ah1, can be prepared as outlined in the following reaction scheme 6, and specified below, or as described by way of exAh1ple in the following exAh1ples, or analogously or similarly thereto.
Reaction scheme 6:



As shown in reaction scheme 6 compounds of formula XIV, in which Y3 is a suitable leaving group, such as e.g. iodine or bromine, and PG5 stands for a suitable temporary protective group for the carboxyl group, for exAh1ple tert-butyl, can be reacted with boronic acids of formula R'-B(OH)2, in which R' is the terminal aryl or heteroaryl moiety of the abovementioned Aa1 or Ha1 radicals, or the boronic acid esters (e.g. the pinacol esters) thereof, to give in an Ar1-known Suzuki reaction the corresponding CC-coupled compounds, which are deprotected by removal of PG5 to give corresponding free acids of formula XV, which can be coupled with compounds of formulae H2N-O-PG2 or Ha as described above to give, after removal of PG2 and PG3, corresponding compounds of formula lf.Alternatively, as shown in reaction scheme 7 compounds of formula XIV, in which Y3 is a suitable leaving group, such as e.g. iodine or bromine, and PG5 stands for a suitable temporary protective group for the carboxyl group, for exAh1ple tert-butyl, can be deprotected by removal of PG5, and the free carboxylic acid can be then coupled with compounds of formulae H2N-O-PG2 or I la as described above to give corresponding compounds of formula XVI. Compounds of formula XVI are reacted with boronic acids of formula R'-B(OH)2, in which R' is the terminal aryl or heteroaryl moiety of the abovementioned Aa1 or Ha1 radicals, or the boronic acid esters (e.g. the pinacol esters) thereof, to give in an Ar1-known Suzuki reaction the corresponding CC-coupled compounds, which are deprotected by removal of PG2 or PG3 to give corresponding compounds of formula If.
Reaction scheme 7:


The Suzuki reaction can be carried out in a manner habitual per se to the skilled person or as described in the following exAh1ples, or analogously or similarly thereto.Compounds of formula XIV can be obtained according to the synthesis route shown in reaction scheme 1 and described above.The abovementioned compounds of formula R'-B(OH)2 are known or can be obtained according to Ar1-known procedures.The reactions mentioned above can be expediently carried out analogously to the methods known to the person skilled in the Ar1 or as described by way of exAh1ple in the following exAh1ples.lt is moreover known to the person skilled in the Ar1 that if there are a number of reactive centers on a Starting or intermediate compound it may be necessary to block one or more reactive centers temporarily by protective groups in order to allow a reaction to proceed specifically at the desired reaction center. A detailed description for the use of a large number of proven protective groups is found, for exAh1ple, in "Protective Groups in Organic Synthesis" by T. Greene and P. Wuts (John Wiley & Sons, Inc. 1999, 3rd Ed.) or in "Protecting Groups (Thieme Foundations Organic Chemistry Series N Group" by P. Kocienski (Thieme Medical Publishers, 2000).The isolation and purification of the substances according to the invention is carried out in a manner known per se, e.g. by distilling off the solvent in vacuo and recrystallizing the resulting residue from a
16

suitable solvent or subjecting it to one of the customary purification methods, such as, for exAh1ple, column chromatography on suitable support material.Optionally, compounds of formula I can be converted into their salts, or, optionally, salts of the compounds of formula I can be converted into the free compounds.Salts are obtained by dissolving the free compound in a suitable solvent (e.g. a ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, an ether, such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol such as ethanol or isopropanol) which contains the desired acid or base, or to which the desired acid or base is then added. The salts are obtained by filtering, reprecipitating, precipitating with a nonsolvent for the addition salt or by evaporating the solvent. Salts obtained can be converted by alkalization or by acidification into the free compounds, which in turn can be converted into salts. In this way, pharmacologically intolerable salts can be converted into pharmacologically tolerable salts.Suitably, the conversions mentioned in this invention can be carried out analogously or similarly to methods which are fAh1iliar per se to the person skilled in the Ar1. The person skilled in the Ar1 knows on the basis of his/her knowledge and on the basis of those synthesis routes, which are shown and described within the description of this invention, how to find other possible synthesis routes for compounds of the formula I. All these other possible synthesis routes are also pAr1 of this invention.Having described the invention in detail, the scope of the present invention is not limited only to those described characteristics or embodiments. As will be apparent to persons skilled in the Ar1, modifications, analogies, variations, derivations, homologisations and adaptations to the described invention can be made on the base of Ar1-known knowledge and/or, pAr1icularly, on the base of the disclosure (e.g. the explicite, implicite or inherent disclosure) of the present invention without depAr1ing from the spirit and scope of this invention as defined by the scope of the appended claims.The following exAh1ples serve to illustrate the invention further without restricting it. Likewise, further compounds of the formula I, whose preparation is not explicitly described, can be prepared in an analogous manner or in a manner fAh1iliar per se to the person skilled in the Ar1 using customary process techniques.Any or all of the compounds which are mentioned as final products in the following exAh1ples as well as their salts are a preferred subject of the present invention.ln the exAh1ples, MS stands for mass spectrum, M for molecular ion, TSP for Thermospray Ionization, ESI for Electrospray Ionization, El for Electron Ionization, h for hours, min for minutes. Other abbreviations used herein have the meanings customary per se to the person skilled in the Ar1. Examples
Final products
1. (E)-N-Hydroxy-3-[1-(toluene-4-sulfonyl)-1-H-pyrrol-3-yl]-acrylAh1ide
0.231 g of (E)-3-[1-(toluene-4-sulfonyl)-1 H-pyrrol-3yl]-acrylic acid (compound A1) are dissolved in 8 ml of dichloromethane at room temperature. Then 50 \J\ of N,N-dimethylformAh1ide (DMF) are added, 0.275 g of oxalic acid chloride dissolved in 2 ml of dichoromethane are added dropwise and stirred for 1.5 hour. To the solution are added 0.439 g of 0-(trimethylsilyl)hydroxylAh1ine and stirred for 15 minutes. Then 20 ml of aqueous hydrochloric acid (1 M strength) are added and extracted with ethyl acetate. The combined organic phase is dried over sodium sulfate. Afterwards it is filtered and evaporated under vacuo. The crude product is purified by silica gel flash chromatography using a gradient of dichloromethane and methanol from 98:2 to 6:4 to yield 0.050 g of the title compound as a white solid. MS (TSP): 307.0 (MHM 00%)
'H-NMR (DMSO-d6): 'H-NMR (DMSO-d6): 2.37 (s, 3H); 6,12 (d, J= 15.9 Hz, 1H); 6.54 (m, 1H); 7.25 (m, J= 16.1 Hz, 2H); 7.42 (d, J = 8.1 Hz, 2H); 7.79 (m, 1H); 7.85 (d, J = 8.2 Hz, 2H); 8.96 (bs, exchangeable, 1H); 10.61 (bs, exchangeable, 1H)
2. N-Hydroxy-3-(1-phenylmethanesulfonyl-1H-pyrrol-3-yl)-acrylAh1ide
0.189 g of (E)-3-(1-phenylmethanesulfonyl-1H-pyrrol-3-yl)-N-(tetrahydropyran-2-yloxy)-acrylAh1ide ( compound A2) are
dissolved in 50 ml of a methanol/water (3/2) solution. Then 0.102 g of the acidic ion exchange resin Ah1berlyst IR15 are
added and the mixture is stirred for 91 hours at Ah1bient temperature. The mixture is filtered. The filtrate is evaporated. The
residue is crystallized from methanol to give 0.144 g of the title compound as white crystals.
MS (TSP): 307.0 (MHM 00%)
'H-NMR (DMSO-d6): 5.00 (s, 2H); 6.11 (d, J= 15.7 Hz, 1H); 6.50 (m, 1H); 6.96 (m, 1H); 7.11 (m, 2H); 7.32 (m, J= 17 Hz,
5H); 8.90 (s, exchangeable, 1H); 10.60 (s, exchangeable, 1H)
3. (E)-3-[1-(Biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylAh1ide
The method used for preparation of this compound is analogous to the method described for compound 2.Starting materials:
(E)-3-(1-(biphenyl-4-sulfonyl)-1H-pyrrol-3-yl)-N-(tetrahydro-pyran-2-yloxy)-acrylAh1ide (compound A3) (0.150 g),
methanol/water 3/2 (50 ml), Ah1berlyst IR15 (0.300 g). Reaction conditions: room temperature, 34 hours.
Yield: 0.041 g, pale grey crystals
MS (ESI): 381.1 (MH+-CH3N02,100%)
'H-NMR (DMSO-d6): 6.14 (d, J= 15.8 Hz, 1H); 6.58 (m, 1H); 7.31 (d, J= 15.7 Hz, 1H); 7.43 (m, J= 6.9 Hz, 4H); 7.70 (m, J
=6.6 Hz, 3H); 7.91 (d, J= 8.0 Hz, 2H); 8.02 (d, J= 8.1 Hz, 2H); 8.92 (s, exchangeable, 1H); 10.60 (s, exchangeable, 1H)
4. (E)-3-[1-(4-DimethylAh1ino-benzenesulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylAh1ide
The method used for preparation of this compound is analogous to the method described for compound 2.Starting materials: (E)-3-[1-(4-dimethylAh1ino-benzene sulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylAh1ide (compound A4) (0.200 g), methanol/water 3/2 (50 ml), Ah1berlyst IR15 (0.402 g). Reaction conditions: room temperature, 34 hours.
17

Yield: 0.098 g, pale red crystals MS (ESI): 336.0 (MH+, 100%)
'H-NMR (DMSO-d6): 6.10 (m, J = 16.5 Hz 1H); 6.49 (m, 1H); 6.75 (d, J = 9.2 Hz, 2H); 7.24 (m, 2H); 7.64 (m, J\ = 8.6 Hz, J2
= 17.7 Hz, 3H); 8.89 (bs, exchangeable, 1H), 10.59 (bs, exchangeable, 1H)
5. (E)-N-(2-Ah1ino-phenyl)-3-[1-(toluene-4-sulfonyl)-1H-pyrrol-3-yl]-acrylAh1ide
0.116 g of (2-{(E)-3-[1-(toluene-4-sulfonyl)-1-H-pyrrol-3-yl]-allanoylAh1ino}-phenyl)-carbAh1ic acid tert-butyl ester (compound A5) are dissolved in 20 ml of dichloromethane at Ah1bient temperature. 2 ml of trifluoroacetic acid (TFA) are added and the solution is stirred for 93 hour. The solvent is evaporated to dryness and to the residue are added 25 ml of water. The water phase is extracted exhaustively with ethyl acetate. Afterwards the combined organic phases are dried over sodium sulfate and filtered. The filtrate is evaporated under vacuo. Then the residue is crystallized from methanol to give 0.050 g of the title compound as white crystals. MS (ESI): 382.0 (MH*, 100%)
'H-NMR (DMSO-d6): 2.38 (s, 3H); 4.48 (s, exchangeable, 2H); 6.55 (m, 3H); 6.71 (m, 1H); 6.90 (m, 1H); 7.40 (m, J = 8.1 Hz, 5H); 7.70 (m, 1H); 7,89 (d, J = 8.3 Hz, 2H); 9.20 (s, exchangeable, 1H)
6. (E)-N-(2-Ah1ino-phenyl)-3-(1-phenylmethanesulfonyl-1H-pyrrol-3-yl)-acrylAh1ide
The method used for preparation of this compound is analogous to the method described for compound 5 with the exception
that the product is purified by silica gel flash chromatography using a gradient of dichloromethane/methanol from 99:1 to
95:5. Starting materials: {2-[(E)-3-[1-(phenylmethanesulfonyl-1-H-pyrrol-3-yl)-allanoylAh1ino]-phenyl}-carbAh1ic acid tert-butyl
ester (compound A6) (0.146 g), CH2CI2 (20 ml), TFA (2 ml). Reaction conditions: room temperature, 65 hours.
Yield: 0.037 g, white crystals MS (ESI): 382.0 (MH*)
'H-NMR (DMSO-d6): 4.90 (s, 2H); 5.01 (s, exchangeable, 1H); 6.58 (m, J = 5.7 Hz, 3H); 6.74 (m, J = 6.7 Hz, 2H); 6.90 (m,
1H); 7.01 (m, 1H); 7.11 (m, J = 5.6,2H); 7.34 (m, Ji = 5.7 Hz, Ji = 6.7 Hz, 5H); 9.25 (s, exchangeable, 1H)
7. (E)-N-(2-Ah1ino-phenyl)-3-[1-(biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-acrylAh1ide
The method used for preparation of this compound is analogous to the method described for compound 5.
Starting materials: (2-{{E)-3-[1-(biphenyl-4-sulfonyl)-1H-pyrro!-3-yl]-allanoylAh1ino}-phenyl)-carbAh1ic acid terf-butyl ester
(compound A7) (0.460 mmol), CH2CI2 (50 ml), TFA (5 ml). Reaction conditions: room temperature, 18 hours.
Yield: 0.061 g, white crystals MS (ESI): 444.0 (MH*)
1 H-NMR (DMSO-d6): 4.90 (bs, exchangeable, 2H); 6.58 (m, Ji = 51.4 Hz, J2 = 7.5 Hz, 3H); 6.71 (m, Ji = 1.4 Hz, Ji = 6.6 Hz,
1H); 6.90 (m, Ji = 1.4 Hz, J2 = 6.6 Hz, 1H); 7.40 (m, J, = 7.5 Hz, J2 = 7.7 Hz, 6H); 7.78 (m, J = 7.7 Hz, 3H); 7.95 (d, J = 8.6
Hz, 2H); 8.08 (d, J = 8.8 Hz, 2H); 9.23 (s, exchangeable, 1H)
8. (E)-N-(2-Ah1ino-phenyl)-3-[1-(4-dimethylAh1ino-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylAh1ide
The method used for preparation of this compound is analogous to the method described for compound 5 with the exception that the product is purified by crystallization from ethyl acetate.
Starting materials: (2-{(E)-3-[1-(4-dimethylAh1ino-benzenesulfonyl)-1H-pyrrol-3-yl]-allanoylAh1ino}-phenyl)-carbAh1ic acid terf-butyl ester (compound A8) (0.141 g), CH2CI2 (10 ml), TFA (1 ml). Reaction conditions: room temperature, 20 hours. Yield: 0.109 g, pale red crystals MS (ESI): 411.0 (MH+, 100%)
'H-NMR (DMSO-d6): 3.00 (s, 6H); 3.97 (s, exchangeable, 2H); 6.79 (m, J= 15.4 Hz, 2H); 6.79 (d, J= 9.2 Hz, 2H); 7.04 (m, J1 = 2.7 Hz, J2 = 8.7 Hz, J3= 15.5 Hz, 3H); 7.40 (m, J1 = 15.6 Hz, J2 = 8.6 Hz, 3H) 7.70 (m, J1 = 2.9 Hz, J2 = 9.2 Hz, 3H) 9.74 (s, exchangeable, 1H)
9. (E)-N-Hydroxy-3-(1-[4-(([2-(1H-indol-2-yl)-ethyl]-methyl-Ah1ino)-methyl)-benzene sulfonyl] -1H-pyrrol-3-yl)-
acrylAh1ide
81 mg of (E)-3-(1 -[4-(([2-(1 H-indol-2-yl)-ethyl]-methyl-Ah1ino)-benzenesulfonyl]-1 H-pyrrol-3-yl)-N-(tetrahydropyran-2-yloxy)-acrylAh1ide (compound A9) are dissolved in 5 ml of methanol. After addition of 15 ml of 0.1 N hydrochloric acid the mixture is stirred for 21 hour. Then the reaction mixture is evaporated. The residue is washed with ethyl acetate and dried under vacuum at -50°C. Yield: 55 mg, pale yellow solid
10. (E)-3-[1-(4-DimetylAh1inomethyl-benzenesulfonyl)-1 H-pyrrol-3-yl]-N-hydroxy-acrylAh1ide
The method used for to preparation of this compound is analogous to the method described for compound 9.
Starting material: (E)-3-[1-(4-DimethylAh1inomethyl-benzenesulfonyl)-1 H-pyrrol-3-yl]-N-tetrahydro-pyran-2-yloxy)-acrylAh1ide (compound A10)
11. (E)-N-Hydroxy-3-[1-(4-{[(pyridin-3-ylmethyl)-Ah1ino]-methyl}-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylAh1ide
Starting from compound A11, the method which can be used for the preparation is analogous to the method described for
compound 9. The crude product is pure enough for biological testing. MH+ = 413.0
12. (E)-N-Hydroxy-3-[1-(4-{[(1H-indol-3-ylmethyl)-Ah1ino]-methyl}-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylAh1ide
Starting from compound A12, the method which can be used for the preparation is analogous to the method described for
compound 9. The crude product is pure enough for biological testing.MH+ = 449.0
13. (E)-3-{1-[4-(BenzylAh1ino-methyl)-benzenesulfonyl]-1H-pyrrol-3-yl}-N-hydroxy-acrylAh1ide
Starting from compound A13, the method which can be used for the preparation is analogous to the method described for compound 9. MH+ = 412.1
14. (E)-N-Hydroxy-3-{1-[4-(isobutylAh1ino-methyl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylAh1ide
18

Starting from compound A14, the method which can be used for the preparation is analogous to the method described for compound 9. MH+ = 378.1
15. (E)-N-Hydroxy-3-[1-(4-{[(1H-indol-5-ylmethyl)-Ah1ino]-methyl}-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylAh1ide Starting from compound A15, the method which can be used for the preparation is analogous to the method described for compound 9.MH= 449.1
16. (E)-N-Hydroxy-3-[1-(4-{[(pyridin-4-ylmethyl)-Ah1ino]-methyl}-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylAh1ide Starting from compound A16, the method which can be used for the preparation is analogous to the method described for compound 9.MH+ = 413.1
17. (E)-3-[1-(4-Ah1inomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylAh1ide
Starting from compound B6, the method which can be used for the preparation is analogous to the method described for compound 9. The crude product is purified by washing with methanol. A solid is obtained in 69% yield.Melting point: 227.0-228.6°C
18. (E)-N-Hydroxy-3-[1-(4-pyridin-4-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylAh1ide
Starting from compound A17, the method which can be used for the preparation is analogous to the method described for compound 9. The reaction mixture is pAr1ly evaporated and the resulting suspension is filtered. The product is isolated as colorless solid. Melting point: 219.3-221.4°C
19. (E)-N-Hydroxy-3-{1-[4-(1H-pyrazol-4-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylAh1ide
Starting from compound A18, the method which can be used for the preparation is analogous to the method described for
compound 9.
Melting point: 203.8-211.9°C
20. (E)-N-(2-Ah1ino-phenyl)-3-[1-(4-pyridin-4-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylAh1ide
Starting from compound A19, the method which can be used for the preparation is analogous to the method described for
compound 21.
Melting point: 244.2-246.5°C
21. (E)-N-(2-Ah1ino-phenyl)-3-[1-(4-pyridin-3-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylAh1ide
The compound is prepared by treatment of (2-{(E)-3-[1-(4-pyridin-3-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-allanoylAh1ino}-phenyl)-carbAh1ic acid terf-butyl ester (compound A20) in dioxane with HCI. After the reaction is finished, the product precipitates from the reaction mixture. Melting point: 199.7-202.3°C
22. (E)-N-(2-Ah1ino-phenyl)-3-{1-[4-(1H-pyrazol-4-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylAh1ide
Starting from compound A21, the method which can be used for the preparation is analogous to the method described for
compound 21.
Melting point: 232.3-240.9 °C
23. (E)-3-[1-(Biphenyl-3-sulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylAh1ide
Starting from compound A22, the method which can be used for the preparation is analogous to the method described for compound 9. Melting point: 114-159.4°C Sinter at 83°C
24. (E)-N-Hydroxy-3-[1-(5-pyridin-2-yl-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylAh1ide
Starting from compound A23, the method which can be used for the preparation is analogous to the method described for compound 9. The product crystallizes from the reaction mixture. Melting point: 181.3-182°C
25. (E)-N-Hydroxy-3-[1-(4-pyrazol-1-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylAh1ide
Starting from compound A24, the method which can be used for the preparation is analogous to the method described for compound 9. The crude product is purified by washing with dichloromethane. Melting point: 160.7-166.6°C
26. (E)-N-(2-Ah1ino-phenyl)-3-[1-(5-pyridin-2-yl-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylAh1ide
Starting from compound A25, the method which can be used for the preparation is analogous to the method described for compound 21. The product is purified by washing the crude product with ethyl acetate. Melting point: 171.3-174.7°C
27. (E)-N-Hydroxy-3-[1-(4-morpholin-4-ylmethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylAh1ide
Starting from compound A26, the method which can be used for the preparation is analogous to the method described for compound 9. The title compound is islolated by freeze-drying methods. Melting point: 168-170°C
28. (E)-N-Hydroxy-3-{1-[4-({(2-hydroxy-ethyl)-[2-(1H-indol-2-yl)-ethyl]-Ah1ino}-methyl)-benzenesulfonyl]-1H-
pyrrol-3-yl}-acrylAh1ide
Starting from compound A 27, the method which can be used for the preparation is analogous to the method described for compound 9. The reaction mixture is evaporated and the title compound is isolated as an oil. MH+ = 509.1 Starting from compound D6, the following compounds may be prepared via synthesis routes which are analogous to the synthesis routes resulting to the ExAh1ples 18 to 22.
29. (E)-N-Hydroxy-3-[1-(3-pyridin-4-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylAh1ide
30. (E)-N-(2-Ah1ino-phenyl)-3-[1-(3-pyridin-4-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylAh1ide
31. (E)-N-(2-Ah1ino-phenyl)-3-[1-(3-pyridin-3-yl-benzenesulfonyl)-1 H-pyrrol-3-ylj-acrylAh1ide
32. (E)-N-Hydroxy-3-{1-[3-(1H-pyrazol-4-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylAh1ide
33. (E)-N-(2-Ah1ino-phenyl)-3-{1-[3-(1H-pyrazol-4-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylAh1ide
19

Starting materials
A1 (E)-3-[1-(Toluene-4-sulfonyl)-1H-pyrrol-3yl]-acrylic acid
1.60 g of (E)-3-[1-(toluene-4-sulfonyl)-1H-pyrrol-3yl]-acrylic acid ferf-butyl ester (compound C1) are dissolved in 70 ml of
dichloromethane at Ah1bient temperature. Then 7 ml of trifluoroacetic acid (TFA) are added and stirred for 4 hours. The
solvent is evaporated to dryness and to the residue are added 30 ml of water. The water phase is extracted exhaustively
with ethyl acetate. Then the organic phase is dried over sodium sulfate. The filtrate is evaporated and dried under vacuo to
give 0.951 g of the title compound as a pale grey solid.MS (TSP): 290.0 (M-H+, 100%)
1H-NMR (DMSO-d6): 2.36 (s, 3H); 6,20 (d, J= 15.9 Hz, 1H); 6.74 (m, J = 3.1 Hz, 1H); 7.41 (m, J\ = 3.1 Hz, J2 = 8.2 Hz, J3 =
16.1 Hz, 4H); 7.78 (m, 1H), 7.87 (d, J = 8.4 Hz, 2H); 11.80 (bs, exchangeable, 1H)
A2 (E)-3-(1-Phenylmethanesulfonyl-1H-pyrrol-3-yl)-N-(tetrahydropyran-2-yloxy)-acrylAh1ide
0.295 g of (E)-3-(1-phenylmethansulfonyl-1H-pyrrol-3-yl)-acrylic acid (compound B1), 0.152 g of N-hydroxybenzotriazole
hydrate (HOBtH20) and 561 pi of triethylAh1ine are dissolved in 20 ml of N,N-dimethylformAh1ide (DMF) at room
temperature. Afterwards it is added 0.601 g of N-(3-dimethylAh1inopropyl)-N'-ethylcarbodiimide hydrochloride (EDCHCI)
and stirred for 1 hour at room temperature. Then is added 0.152 g of 0-(tetrahydro-2H-pyran-2-yl)-hydroxylAh1ine and
stirred for 2 hour. The DMF is evaporated under high vacuo. Water is added and the mixture was extracted with ethyl
acetate. The organic phase is dried over sodium sulfate. Then it is filtered and evaporated under vacuo. The crude product
is purified by silica gel flash chromatography using a gradient of dichloromethane/methanol from 99:1 to 98:2 to give 0.189 g
of the title compound as a pale grey solid.MS (ESI): 390.9 (MH+, 100%)
1H-NMR (DMSO-d6): 1.60 (m, 6H); 3.51 (m, 1H); 3.91 (m, 1H); 4.89 (m, 1H); 5.00 (s, 2H); 6,18 (d, J= 15.3 Hz, 1H); 6.50 (s,
1H); 6.96 (m, J=5.2 Hz, 1H); 7.10 (m, J1 = 7.3 Hz, J1= 7.9 Hz, 2H); 7.30 (m, J1 = 5.1 Hz, J2 = 7.3 Hz, J3= 8.1 Hz, J4= 8.1 Hz,
Js= 15.2 Hz, 5H); 10.60 (s, exchangeable, 1H); 11.08 (bs, exchangeable, 1H)
A3 (E)-3-(1-(Biphenyl-4-sulfonyl)-1H-pyrrol-3-yl)-N-(tetrahydro-pyran-2-yloxy)-acrylAh1ide
The method used for preparation of this compound is analogous to the method described for compound A2 with the
exception that the product is purified by crystallization from water and methanol.
Starting materials: (E)-3-[1-(biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-acrylic acid (compound B2) (0.300 g), HOBtH20 (0.130 g),
triethylAh1ine (668 uJ), DMF (20 ml), EDCHCI (0.508 g), 0-(tetrahydro-2H-pyran-yl)hydroxylAh1ine (0.089 g). Reaction
conditions: room temperature, 1 hour; room temperature, 18 hours.
Yield: 0.345 g, pale grey solid MS (ESI): 452.8 (MH*); 369.0 (MH+-C5H90,100%)
= 6.9 Hz, 5H); 7.72 (m, Ji =7.0 Hz, J2 = 14.7 Hz, 3H); 7.98 (d, J = 8.5 Hz, 2H); 8.06 (d, J = 8.6 Hz, 2H); 11.06 (bs,
exchangeable, 1H)
A4 (E)-3-[1-(4-DimethylAh1ino-benzenesulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylAh1ide
The method used for preparation of this compound is analogous to the method described for compound A2 with the exception
that the product is purified by silica gel flash chromatography using a gradient of dichloromethane and methanol from 99:1 to
98:2. Starting materials: (E)-3-[1-(4-dimethylAh1ino-benzensulfonyl)-1H-pyrrol-3-yl)-acrylic acid (compound B3) (0.150 g),
HOBtH20 (0.072 g), triethylAh1ine (259 |J), DMF (10 ml), EDCHCI (0.269 g), 0-(tetrahydro-2H-pyran-2-yl)hydroxylAh1ine
(0.049 g). Reaction conditions: room temperature, 1 hour; room temperature, 17 hours. Yield: 0.187 g, pale red solid
MS (ESI): 419.2 (MH+); 336.0 (MH* -C5H90,100%)
'H-NMR (DMSO-d6): 1.61 (m, 6);); 3.02 (s, 6H); 3.50 (m, 1H); 3.92 (m, 1H); 4.85 (m, 1H); 6.19 (m, 1H); 6.50 (m, 1H); 6.75
(m, J= 9.2 Hz, 2H); 7.31 (m, 2H); 7.64 (m, J= 9.2 Hz, 3H); 11,01 (bs, exchangeable, 1H)
A5 (2-{(E)-3-[1-(Toluene-4-sulfonyl)-1-H-pyrrol-3-yl]-allanoylAh1ino}-phenyl)-carbAh1ic acid fert-butyl ester
The method used for preparation of this compound is analogous to the method described for compound A2 with the
exception that the product is purified by silica gel flash chromatography using a gradient of dichloromethane and methanol
from 99:1 to 98:1.Starting materials: (E)-3-[1-(toluene-4-sulfonyl)-1H-pyrrol-3yl]-acrylic acid (compound A1) (0.400 g),
HOBtH20 (0.285 g), triethylAh1ine (652 nl), DMF (25 ml), EDCHCI (0.698 g), N-BOC-1,2,-phenylenediAh1ine (0.286 g).
Reaction conditions: room temperature, 1 hour; room temperature, 2 hours. Yield: 0.609 g, pale grey solid
MS (ESI): 481.7 (MHM 00%)
1H-NMR (DMSO-d6): 1.40 (m, 9H); 2.39 (s, 3H); 6.61 (m, Ji = 1.7 Hz, Ji = 2.2 Hz, Ji = 5.0 Hz, 2H); 7.09 (m, Ji = 1.8 Hz, Ji
= 2.3 Hz, 2H); 7.37 (m, Ji = 2.0 Hz, J2 = 5.0 Hz, Jz = 8.0 Hz, 4H); 7.64 (m, 1H); 7.88 (d, J = 8.4 Hz, 2H); 8.41 (s,
exchangeable, 1H); 9.57 (s, exchangeable, 1H)
A6 {2-[(E)-3-[1-(Phenylmethanesulfonyl-1-H-pyrrol-3-yl)-allanoylAh1ino]-phenyl}-carbAh1ic acid fert-butyl ester
The method used for preparation of this compound is analogous to the method described for compound A2 with the
exception that the product is purified by silica gel flash chromatography using a gradient of dichloromethane and methanol
from 99:1 to 95:5.Starting materials: (E)-3-( 1 -phenylmethanesuIfonyl-1 H-pyrrol-3-yl)-acrylic acid (compound B1) (0.180 g),
HOBt-H20 (0.090 g), triethylAh1ine (295 ml), DMF (10 ml), EDCHCI (0.315 g), N-BOC-1,2,-phenylenediAh1ine (0.081.g).
Reaction conditions: room temperature, 1 hour; room temperature, 17 hours. Yield: 0.218 g, pale grey solid
MS (ESI): 504.0 (MNa+, 100%); 481.8 (MH+)
20

1H-NMR (DMS0-d6): 1.42 (m, 9H); 5.04 (s,2H); 6.56 (m, J1 = 2.2 Hz, J2 = 10.2 Hz, 2H); 7.14 (m, J\ = 2.2 Hz, J2 = 5.5 Hz, J3
= 10.1 Hz, 4H); 7.36 (m, J1 = 5.5 Hz, J2 = 7.2 Hz, 4H); 7.52 (m, J1 = 2.2 Hz, J1 = 7.2 Hz, 2H); 8.49 (s, exchangeable, 1H);
9.67 (s, exchangeable, 1H)
A7 (2-{(E)-3-[1-(Biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-allanoylAh1ino}-phenyl)-carbAh1ic acid tert-butyl ester
The method used for preparation of this compound is analogous to the method described for compound A2 with the
exception that the product is purified by silica gel flash chromatography using a gradient of toluene/ethyl acetate from 99:1
to 9:1.Starting materials: (E)-3-[1-(biphenyl-4-sulfonyl)-1H-pyrrol-3-yl)-acrylic acid (compound B2) (0.300 g), HOBt.H2O
(0.130 g), triethylAh1ine (668|J), DMF (20 ml), EDCHCI (0.508 g), N-BOC-1,2,-phenylenediAh1ine (0.176 g). Reaction
conditions: room temperature, 1 hour; room temperature, 17 hours.Yield: 0.285 g, pale grey solid
MS (ESI): 543:8 (MH+); 487.9 (MH+ -C4H8); 336.1 (MH* -C11H14N2O2,100%)
1H-NMR (DMSO-d6): 1.47 (m, 9H); 6.50 (m, J= 5.4 Hz, 1H); 6.64 (m, J= 7.7 Hz, 2H); 7.10 (m, J1 = 5.4 Hz, J2 = 7.7 Hz, 3H);
7.51 (m, J1 = J2 = J3 = 3.6 Hz, 5H); 7.73 (m, 2H); 7.81 (m, 1H); 7.96 (d, J = 8.6 Hz, 2H); 8.08 (d, J = 8.6 Hz, 2H); 8.41 (s,
exchangeable, 1H); 8.59 (s, exchangeable, 1H)
A8 (2-{(E)-3-[1-(4-DimethylAh1ino-benzenesulfonyl)-1H-pyrrol-3-yl]-allanoylAh1ino}-phenyl)-carbAh1ic acid tert-
butyl ester
The method used for preparation of this compound is analogous to the method described for compound A2 with the
exception that the product is purified by crystallization from ethyl acetate.Starting materials: (E)-3-[1-(4-dimethylAh1ino-
benzenesulfonyl)-1H-pyrrol-3-yl)-acrylic acid (compound B3) (0.150 g), HOBt.H2O (0.072 g), triethylAh1ine (259 (il), DMF
(10 ml), EDCHCI (0.269 g), N-BOC-1,2-phenylenediAh1ine (0.049 g). Reaction conditions: room temperature, 1 hour; room
temperature, 21 hours.Yield: 0.142 g, pale red solid
MS (ESI): 510.9 (MHM 00%)
1H-NMR (DMSO-d6): 1.42 (m, 9H); 3.00 (s, 6H); 6.51 (m, 2H) 6.79 (d, J= 9.2 Hz, 2H); 7.09 (m, J= 5.5 Hz, 2H); 7.36 (m,
2H); 7.50 (m, J = 5.5 Hz, 2H); 7.70 (m, J= 9.2 Hz, 2H); 8.41 (s, exchangeable, 1H); 9.55 (s, exchangeable, 1H)
A9 (E)-3-(1-[4-(([2-(1H-lndol-2-yl)-ethyl]-methyl-Ah1ino)-benzenesulfonyl]-1H-pyrro!-3-yl)-N-(tetrahydropyran-2-
yloxy)-acrylAh1ide
825 mg of (E)-3-(1-[4-(([2-(1H-indol-2-yl)-ethyl]-methyl-Ah1ino)-benzenesulfonyl]-1H-pyrrol-3-yl)-acrylic acid (compound B4),
165 mg of HOBH2O and 1.24 ml of triethylAh1ine are dissolved in 70 ml of DMF at room temperature. Afterwards it is added
726 mg of EDCHCI and stirred for 1 hour. Then 140 mg of 0-(tetrahydro-2H-pyran-2-yl)-hydroxylAh1ine are added and
stirred for 18 hour. The DMF is evaporated under high vacuum. Then water is added to the residue and extracted with ethyl
acetate'. The organic phase is dried over sodium sulfate and evaporated under vacuum. Then the mixture is evaporated and
the crude product is purified by silica gel flash chromatography using a gradient of dichloromethane and methanol 98:2 -
9:1.Yield: 289 mg, pale red solid
A10 (E)-3-[1-(4-DimethylAh1inomethyl-benzenesulfonyl)-1H-pyrrol-3yl]-N-tetrahydro-pyran-2-yloxy)-acrylAh1ide
The method used for to preparation of the title compound is analogous to the method described for compound A9.Starting
materials: (E)-3-[1-(4-DimethylAh1inometyl-benzenesulfonyl)-1H-pyrrol-yl]-acrylic acid (compound B5) (1.78 g), HOBt^O
(366 mg), triethylAh1ine (2.1 ml), DMF (80 ml), EDCHCI (1.54 g), 0-(tetrahydro-2H-pyran-2-yl)-hydroxylAh1ine (306 mg).
Reaction condition: room temperature, 1 hour; room temperature, 48 hours. Yield: 835 mg, pale yellow solid
A11 (E)-3-[1-(4-{[(Pyridin-3-ylmethyl)-Ah1ino]-methyl}-benzenesulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-
yloxy)-acrylAh1ide
A mixture of compound B6, sodium triacetoxyborohydride, methanol and 3-pyridinecarboxaldehyde is stirred at Ah1bient
temperature overnight. The reaction mixture is evaporated and pAr1itioned between dichloromethane and water. The crude
product is purified by silica gel flash chromatography. A nearly colorless oil is obtained.
Starting from compound B6 and the appropriate aldehyde the following compounds A12 to A16 can be obtained according to
compound A11.
A12 (E)-3-[1-(4-{[(1H-lndol-3-ylmethyl)-Ah1ino]-methyl}-benzenesulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-
yloxy)-acrylAh1ide
A13 (E)-3-{1-[4-(BenzylAh1ino-methyl)-benzenesulfonyl]-1H-pyrrol-3-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylAh1ide
A14 (E)-3-{1-[4-(lsobutylAh1ino-methyl)-benzenesulfonyl]-1H-pyrrol-3-yl}-N-(tetrahydro-pyran-2-yloxy)-
acrylAh1ide
A15 (E)-3-[1-(4-{[(1H-lndol-5-ylmethyl)-Ah1ino]-methyl}-benzenesulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-
yloxy)-acrylAh1ide
A16 (E)-3-[1 -(4-{[(Pyridin-4-ylmethyl)-Ah1ino]-methyl}-benzenesulfonyl)-1 H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-yloxy)-
acrylAh1ide
A17 (E)-3-[1-(4-Pyridin-4-ylphenylsulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydropyran-2-yloxy)-acrylAh1ide
Starting from compound B7 the title compound can be obtained according to compound A2.
A18 (E)-3-{1-[4-(1H-Pyrazol-4-yl)-phenylsulfonyl]-1H-pyrrol-3-yl}-N-(tetrahydropyran-2-yloxy)-acrylAh1ide
Starting from compound B8 the title compound can be obtained according to compound A2.
21

A19 [2-((E)-3-{1-[4-Pyridin-4-yl-benzenesulfonyl]-1H-pyrrol-3-yl}-allanoylAh1ino)-phenyl]-carbAh1icacid tert-butyl ester
Starting from compound B7 the title compound can be obtained according to compound A5.
A20 [2-((E)-3-{1-[4-Pyridin-3-yl-benzenesulfonyl]-1H-pyrrol-3-yl}-allanoylAh1ino)-phenyl]-carbAh1ic acid tert-butyl
ester
Starting from compound B9 the title compound can be obtained according to compound A5.
A21 [2-((E)-3-{1-[4-(1H-Pyrazol-4-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}-allanoylAh1ino)-phenyl]-carbAh1ic acid
tert-butyl ester
Starting from compound B8 the title compound can be obtained according to compound A5.
A22 (E)-3-(1-(Biphenyl-3-sulfonyl)-1H-pyrrol-3-yl)-N-(tetrahydro-pyran-2-yloxy)-acrylAh1ide
Starting from compound B10 the title compound can be obtained according to compound A2.
A23 (E)-3-(1-(5-Pyridin-2-yl-thiophene-2-sulfonyl)-1H-pyrrol-3-yl)-N-(tetrahydro-pyran-2-yloxy)-acrylAh1ide
Starting from compound B11 the title compound can be obtained according to compound A2.
A24 (E)-3-(1-(4-Pyrazol-1-yl-benzenesulfonyl)-1H-pyrrol-3-yl)-N-(tetrahydro-pyran-2-yloxy)-acrylAh1ide
Starting from compound B12 the title compound can be obtained according to compound A2.
A25 (2-{(E)-3-[1 -(5-Pyridin-2-yl-thiophene-2-yl-sulfonyl)-1 H-pyrrol-3-yl]-allanoylAh1ino}-phenyl)-carbAh1ic acid
tert-butyl ester
Starting from compound B11 the title compound can be obtained according to compound A5.
A26 (E)-3-{1-[4-(Morpholin-4-yl-methyl)-benzenesulfonyl]-1H-pyrrol-3yl}-N-tetrahydro-pyran-2-yloxy)-acrylAh1ide
Starting from compound B13 the title compound can be obtained according to compound A2.
A27 (E)-3-{1-[4-({[2-hydroxy-ethyl]-[2-(1H-indol-3-yl)-ethyl]-Ah1ino}-methyl)-benzenesulfonyl]-1H-pyrrol-3-yl}-N-
(tetrahydro-pyran-2-yloxy)-acrylAh1ide
(E)-3-{1-[4-({[2-( tert-Butyl-dimethyl-silanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-Ah1ino}-methyl)-benzenesulfonyl]-1H-pyrrol-3-
yl}-N-(tetrahydro-pyran-2-yloxy)-acrylAh1ide (compound B 14) (120 mg, 0.169 mmol) is dissolved in THF (20 ml). Then it is
added tetrabutylAh1monium fluoride (203 uJ, 0.203, 1M in THF) and triethylAh1ine (47 u.l, 0.338 mmol) and the mixture is
stirred for 17 hours. After addition of water (50 ml) and extraction with ethyl acetate the organic phase is dried over sodium
sulfate, filtrated and evaporated. The crude product is purified by a silica gel flash chromatography using dichloromethane-
methanol eluent.
B1 (E)-3-(1-Phenylmethanesulfonyl-1H-pyrrol-3-yl)-acrylic acid
The method used for preparation of this compound is analogous to the method described for compound A1 with the
exception that the product is isolated by crystallization from a mixture of aceton (29.7 g), water (10.8 g) and HCI (C(HCIJ=1
mol/l, 5.3 g).Starting materials: (E)-3-(1-phenylmethanesulfonyl-1H-pyrrol-3-yl)-acrylic acid tert-butylester (compound C2)
(1.45g), CH2CI2 (80 ml), TFA (8 ml). Reaction conditions: room temperature, 2 hours. Yield: 0.660 g, pale grey crystals
MS (TSP): 289.9(M-H*, 100%)
1H-NMR(DMSO-d6): 5.00 (s, 2H); 6,21 (d, J= 15.9 Hz, 1H); 6.72 (m, J1=1.9 Hz, J2 = 3.4 Hz, 1H); 7.01 (m, J = 5.3,1H); 7.10
(m, J= 1.6 Hz, 2H); 7.31 (m, 7.41 (m, J1 = 1.6 Hz, Ja = 1.9 Hz, J3= 3.4 Hz, J1= 5.3 Hz, A = 16.1 Hz, 4H)
B2 (E)-3-[1-(Biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-acrylic acid
The method used for preparation of this compound is analogous to the method described for compound A1.
Starting materials: (E)-3-[1-(biphenyl-4-sulfonyl)-1H-pyrrol-3-yl)-acrylic acid tert-butyl ester (compound C3) (1.05 g), CH2CI2
(100 ml), TFA (10 ml). Reaction conditions: room temperature, 21 hours. Yield: 0.710 g, pale yellow solid
MS (ESI): 728.7 (2MNa+, 100%); 354.1 (MH*)
'H-NMR (DMSO-d6): 6.29 (d, J= 16.0 Hz, 1H); 6.81 (m, J1 1.2 Hz, J1 = 1.8 Hz, J3 = 3.0 Hz, 1H); 7.49 (m, J\ = 3 Hz, J2= 7.7
Hz, Jo = 16,0 Hz, 5H); 7.75 (m, J1 =1.3 Hz, J2 = 1.8 Hz, J3 = 7.7 Hz, 2H); 7.85 (s, 1H); 7.95 (d, J = 8.6 Hz, 2H); 8.09 (d, J =
8.6 Hz, 2H); 12.17 (bs, exchangeable, 1H)
B3 (E)-3-[1-(4-DimethylAh1ino-benzensulfonyl)-1H-pyrrol-3-yl)-acrylic acid
The method used for preparation of this compound is analogous to the method described for compound A1 .Starting
materials: (E)-3-[1-(4-dimethylAh1ino-benzensulfonyl)-1H-pyrrol-3-yl)-acrylic acid tert-butyl ester (compound C4) (0.801 g),
CH2CI2 (100 ml), TFA (10 ml). Reaction conditions: room temperature, 16 hours. Yield: 0.550 g, pale red solid
MS (ESI): 662.7 (2MNa*. 100%); 321.0 (MH*)
'H-NMR (DMSO-d6): 2.98 (s, 6H); 6.16 (d, J = 15.8 Hz, 1H); 6.68 (m, J = 3.2 Hz, 1H); 6.75 (m, J = 9.2 Hz, 2H); 7.29 (m, J =
2.9 Hz, 1H); 7.43 (d, J= 15.9 Hz, 1H); 7.70 (m, J = 9.1 Hz, 3H); 12.11 (bs, exchangeable, 1H)
B4 (E)-3-(1-[4-(([2-(1H-lndol-2-yl)-ethyl]-methyl-Ah1ino)-benzenesulfonyl]-1H-pyrrol-3-yl)-acrylicacid
1.01 g of (E)-3-(1-[4-(([2-(1H-indol-2-yl)-ethyl]-methyl-Ah1ino)-benzenesulfonyl]-1H-pyrrol-3-yl)-acrylic acid tert-butyl ester
(compound C5) are dissolved in 100 ml of dichloromethane and stirred for 5 minutes. It is added 10 ml of TFA and the
mixture stirred for 19 hour. The solution is evaporated under vacuum. Then is added toluene to the residue (small Ah1ount to
purify the TFA salt) and evaporated under vacuum.
Yield: 1.32 g, Pale brown solid
B5 (E)-3-[1-(4-DimethylAh1inometyl-benzenesulfonyl)-1 H-pyrrol-yl]-acrylic acid
22

The method used for to preparation of this compound is analogous to the method described for compound B4.Starting
materials: (E)-3-[1-(4-DimethylAh1inometyl-benzenesulfonyl)-1H-pyrrol-yl]-acrylic acid terf-butyl ester (compound C6) (2.13
g),TFA(10ml);24hour.
Yield: 3.21 g (with 3 TFA salt), pale brown solid
B6 (E)-3-[1-(4-Ah1inomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylAh1ide
To a mixture of 1g of compound C7 and 50 ml ethanol is added 0.57 ml hydrazine hydrate (80%). The mixture is refluxed for
2.5 h. Afterwards, the reaction mixture is cooled to Ah1bient temperature and the resulting white suspension is filtered. The
product in the filtrate is purified by silica gel flash chromatography.
B7 (E)-3-[1-(4-Pyridin-4-ylphenylsulfonyl)-1H-pyrrol-3-yl]-acrylic acid
Starting from compound C8 the title compund can be obtained according to compound A1.
B8 (E}-3-{1-[4-(1H-Pyrazo!-4-yl)-phenylsulfonyl]-1H-pyrrol-3-yl}-acrylic acid
Starting from compound C9 the title compund can be obtained according to compound A1.
B9 (E)-3-[1-(4-Pyridin-3-ylphenylsulfonyl)-1 H-pyrrol-3-yl]-acrylic acid
Starting from compound C10 the title compund can be obtained according to compound A1.
B10 (E)-3-(1-(Biphenyl-3-sulfonyl)-1 H-pyrrol-3-yl)-acrylic acid
Starting from compound C11 the title compound can be obtained according to compound A1.
B11 (E)-3-(1-{5-Pyridin-2-yl-thiophene-2-sulfonyl)-1H-pyrrol-3-yl)-acrylic acid
Starting from compound C12 the title compound can be obtained according to compound A1.
B12 (E)-3-(1-(4-Pyrazol-1-yl-benzenesulfonyl)-1H-pyrrol-3-yl)-acrylicacid
Starting from compound C13 the title compound can be obtained according to compound A1.
B13 (E)-3-{1-[4-(Morpholin-4-yl-methyl)-benzenesulfonyl]-1H-pyrrol-3yl}-acrylicacid
Starting from compound C14 the title compound can be obtained according to compound A1.
B14 (E)-3-{1-[4-({[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-Ah1ino}-methyl)-
benzenesulfonyl]-1H-pyrrol-3-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide
(E)-3-{1-[4-({[2-( tert-Butyl-dimethyl-silanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-Ah1ino}-methyl)-benzenesulfonyl]-1H-pyrrol-3-
yl}-acrylic acid (compound C15) (1.15 g, 1.16 mmol), HOBtH2O (171 mg, 1.16 mmol) and triethylAh1ine (2 ml) is dissolved in
DMF (100 ml) at room temperature. After addition of EDCHCI (786 mg, 3.48 mmol) the mixture is stirred for 1.5 hours. Then
it is added 0-(tetrahydro-2H-pyran-2-yl)-hydroxylAh1ine (136 mg, 1.16 mmol) and stirred for 17 hours. After evaporation and
addition of 200ml water the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate. Then it is
filtrated and evaporated. The crude product is purified by a silica gel flash chromatography using dichloromethane- methanol
eluent.
C1 (E)-3-[1-(Toluene-4-sulfonyl)-1H-pyrrol-3yl]-acrylic acid fert-butyl ester
0.230 g of sodium hydride (60%) is suspended in 6 ml of tetrahydrofurane under nitrogen at -30°C. 1.01 g of (E)-3-(1H-
pyrrol-3-yl)acrylic acid terf-butyl ester (compound D1) are added to the suspension and warmed slowly to room temperature
and stirred for 30 minutes. Afterwards it is recooled to -30°C and 1.19 g of p-toluenesulfonylchloride are added and stirred
for 2.5 hours. The suspension is warmed slowly at room temperature and 40 ml of saturated aqueous sodium chloride
solution are added. The mixture is extracted with ethyl acetate. The combined organic phase is dried over sodium sulfate
(Na2S04). Afterwards it is filtered and evaporated under vacuo. The crude product is purified by silica gel flash
chromatography using a gradient of hexane-ethyl acetate from 9:1 to 1:1 to give 1.60 g of the title compound as a pale
yellow solid.
MS (ESI): 347.6 (MH+); 291.9 (MH*-C4H9,100%)
1H-NMR (DMSO-d6): 1.43 (s, 9H); 2.37 (s, 3H); 6,21 (d, J= 15.9 Hz, 1H); 6.74 (m, J = 3.1 Hz, 1H); 7.40 (m, Ji = 15.9 Hz, Ji
= 12.7 Hz, J3 = 3.2 Hz, 4H); 7.82 (m, J = 12.6 Hz, 3H)
C2 (E)-3-(1-Phenylmethansulfonyl-1H-pyrrol-3-yl)-acrylic acid fert-butylester
The method used for preparation of this compound is analogous to the method described for compound C1 with the
exception that the product is purified by silica gel flash chromatography using gradient of hexane/ethyl acetate from 8:1 to
5:1.Starting materials: sodium hydride 60% (0.240 g), (E)-3-(1H-pyrrol-3-yl)-acrylic acid terf-butyl ester (compound D1 )
(1.01 g), a-toluenesulfonylchloride (1.19 g). Reaction conditions: -30°C, 30 min; -30°C, 2.5 hours.
Yield: 1.45 g, pale yellow solid
MS(TSP):346.3(M-HM00%)
'H-NMR(DMSO-d6): 1.47 (s, 9H); 5.00 (s, 2H); 6,21 (d, J= 15.8 Hz, 1H); 6.72 (m, J1=1.8 Hz, J1= 3.3 Hz, 1H); 6.98 (m, J =
5.3,1H); 7.09 (m, J\ = 2.1 Hz, J2= 7.8 Hz, 2H); 7.31 (m, J1 = 1.9 Hz, J1= 3.5 Hz, J3= 5.4 Hz, Jt= 7.7 Hz, J5= 15.7 Hz, 5H)
C3 (E)-3-[1-(Biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-acrylic acid fert-butyl ester
The method used for preparation of this compound is analogous to the method described for compound C1 with the exception
that the product is purified by silica gel flash chromatography using a gradient of petroleum ether/diethylether from 7:1 to 1:1.
Starting materials: sodium hydride 60% (0.207 g), (E)-3-(1H-pyrrol-3-yl)-acrylic acid terf-butyl ester (compound D1) (0.531
g), 4-biphenylsulphonylchloride (0.834 g). Reaction conditions: -30°C, 10 min; -30°C, 30 min.Yield: 1.05 g, pale yellow
solid
23

MS (ESI): 354.0 (MH+-C4Hg, 100%)
1H-NMR (DMSO-d6): 1.45 (s, 9H); 6,26 (d, J= 15.9 Hz, 1H); 6.80 (m, J= 1.7 Hz, 1H); 7.47 (m, J= 15.7 Hz, 5H); 7.72 (m, J =
1.8 Hz, 2H); 7.87 (m, 1H), 7.92 (d, J= 8.7 Hz, 2H); 8.09 (d, J = 8.6 Hz, 2H)
C4 (E)-3-[1-(4-DimethylAh1ino-benzensulfonyl)-1H-pyrrol-3-yl]-acrylic acid tert-butyl ester
The method used for preparation of this compound is analogous to the method described for compound C1 with the
exception that the product is purified by silica gel flash chromatography using a gradient of petroleum ether/diethylether from
7:1 to 1:1.Starting materials: sodium hydride 60% (0.031 g), (E)-3-(1H-pyrrol-3-yl)-acrylic acid tert-butyl ester (compound D1)
(0.100 g), 4-dimethylAh1ino-benzenesulfonyl chloride (0.145 g). Reaction conditions: -30°C, 45 min; -30°C, 2.5 hours.
Yield: 0.160 g, pale red solid
MS (ESI): 376.8 (MH+); 321.0 (MH+-C4Hg, 100%)
'H-NMR (DMSO-d6): 1.42 (s, 9H); 3.00 (s, 6H); 6.19 (d, J= 15.8 Hz, 1H); 6.72 (m, J= 9.2 Hz, 3H); 7.25 (m, 1H); 7.37 (d, J=
15.8Hz,1H);7.69(m,J=9.1Hz,3H)
C5 (E)-3-(1-[4-(([2-(1H-lndol-2-yl)-ethyl]-methyl-Ah1ino)-benzenesulfonyl]-1H-pyrrol-3-yl)-acrylic acid tert-butyl
ester 1.50 g of (E)-3-[1-(4-bromomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylic acid tert-butyl ester (compound D2) are
dissolved in 70 ml of ethanol at room temperature. After addition of 0.486 ml of triethylAh1ine and 696 mg of omega-
methyltryptAh1ine it is stirred for 21 hour. Then the solution is evaporated under vacuum. The crude product is purified by
silica gel flash chromatography using a gradient of hexane and ethyl acetate from 5:1 - 2:1.
Yield: 1.08 g, pale yellow solid
C6 (E)-3-[1-(4-DimethylAh1inometyl-benzenesulfonyl)-1H-pyrrol-yl]-acrylic acid tert-butyl ester
The method used for to preparation of this compound is analogous to the method described for compound C5 with the
exception that the product was crystallized in ethanol.Starting materials: (E)-3-[1-(4-Bromomethyl-benzenesulfonyl)-1H-
pyrrol-3-yl]-acrylic acid tert-butyl ester (compound D2) (3.94g), ethanol (150 ml), dimethylAh1ine (1.89 g) Yield: 2.19 g, pale
yellow solid
C7 (E)-3-{1-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylicacid
Starting from compound D3 the method which can be used for this preparation is analogous to the method described for the
compound B4. The title compound is purified by washing with toluene.Starting from (E)-3-[1-(4-bromo-benzenesulfonyl)-1H-
pyrrol-3-yl]-acrylic acid tert-butyl ester (compound D4) and the appropriate boronic acid derivative the following compounds
C8 and C9 can be obtained according to compound C10.
C8 (E)-3-[1-(4-Pyridin-4-ylphenylsulfonyl)-1 H-pyrrol-3-yl]-acrylic acid tert-butyl ester
C9 (E)-3-{1-[4-(1H-Pyrazol-4-yl)-phenylsulfonyl]-1H-pyrrol-3-yl}-acrylic acid tert-butyl ester
C10 (E)-3-[1-(4-Pyridin-3-ylphenylsulfonyl)-1H-pyrrol-3-yl]-acrylic acid tert-butyl ester 0.18 g (E)-3-[1-(4-bromo-
benzenesulfonyl)-1H-pyrrol-3-yl]-acrylic acid tert-butyl ester (compound D4) and 62 mg 3-pyridylboronic acid are dissolved in
10 ml DME. A catalytic Ah1ount of bis-(triphenylphosphin-palladium (ll)-chloride and 0.6 ml of an aqueous solution of sodium
carbonate are added and the mixture is heated to reflux temperature overnight. The title compound is isolated by means of
chromatography.
C11 (E)-3-[1-(Biphenyl-3-sulfonyl)-1 H-pyrrol-3-yl]-acrylic acid tert-butyl ester
Starting from (E)-3-(1H-pyrrol-3-yl)-acrylic acid tert-butyl ester (compound D1) and Ar1-known 3-biphenylsulphonylchloride
the title compound can be obtained analogously or similarly as described for compound C1.
C12 (E)-3-[1-(5-Pyridin-2-yl-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylic acid tert-butyl ester
Starting from (E)-3-(1H-pyrrol-3-yl)-acrylic acid tert-butyl ester (compound D1) and Ar1-known 5-pyridin-2-yl-thiophene-2-
sulfonylchloride the title compound can be obtained analogously or similarly as described for compound C1.
C13 (E)-3-[1-(4-Pyrazol-1-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylic acid tert-butyl ester
Starting from (E)-3-(1H-pyrrol-3-yl)-acrylic acid tert-butyl ester (compound D1) and Ar1-known 4-pyrazol-1-yl-
benzenesulfonylchloride the title compound can be obtained analogously or similarly as described for compound C1.
C14 (E)-3-{1-[4-(Morpholin-4-yl-methyl)-benzenesulfonyl]-1H-pyrrol-3yl}-acrylic acid tert-butyl ester
Starting from compound D2 and morpholine the title compound can be obtained analogously as described for compound C5.
C15 (E)-3-{1-[4-({[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-Ah1ino}-methyl)-
benzenesulfonyl]-1H-pyrrol-3-yl}-acrylic acid
(E)-3-{3-[4-({[2-( tert-Butyl-dimethyl-silanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-Ah1ino}-methyl)-benzenesulfonyl]-1H-pyrrol-3-
yl}-acrylic acid tert-butyl ester (compound D5) is dissolved in dichloromethane (50 ml). Then it is added TFA and the mixture
is stirred for 26 hours. After evaporation, the residue is washed with toluene.
D1 (E)-3-(1H-Pyrrol-3-yl)-acrylic acid tert-butyl ester
5.29 g of sodium hydride 60% is supended in 100 ml of tetrahydrofurane under nitrogen at -30°C. 27.81 g of tert-butyl
diphosphono acetate are added to the suspension and warmed slowly to room temperature and stirred for 30 minutes.
Afterwards the mixture is recooied at -30°C and it is added 5.24 g of 1 H-pyrrol-3-carbaldehyde (compound E1) and stirred
at -30°C for 30 minutes. The suspension is warmed slowly to room temperature and 200 ml of aqueous Ah1monia solution
are added. Then it is extracted with ethyl acetate. The combined organic phase is dried over Na2S04, filtered and
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evaporated under vacuo. The crude product is purified by silica gel flash chromatography using a gradient of n-hexane-ethyl
acetate from 2:1 to 1:1 to give 9.68 g of the title compound as a pale yellow solid.
MS (El): 193.1 (M+); 137.1 (M+-C4H8,100%)
1H-NMR (DMSO-d6): 1.45 (s, 9H); 5.96 (d, J= 15.7 Hz, 1H); 6.40 (m, 1H); 6.78 (m, 1H); 7.19 (m, 1H); 7.47 (d, J= 15.7 Hz,
1H); 11.11 (bs, exchangeable, 1H)
D2 (E)-3-[1-(4-Bromomethyl-benzenesulfonyl )-1 H-pyrrol-3-yl]-acrylic acid fert-butyl ester
4.25 g of sodium hydride (60% strength) are suspended in 300 ml of THF under nitrogen at -30°C. 9.78 g of (E)-3-(1H-
pyiTOl-3-yl)-acrylic acid terf-butyl ester (compound D1) are added to the suspension and warmed slowly to room temperature
during 55 min. Afterwards it is recooled to -30°C and it is added 13.98 g of 4-(bromomethyl)-benzenesulphonylchloride and
stirred for 45 min. Then it is warmed to room temperature and stirred for 2 hour. After cooling to 0-5°C water is added. Then
the mixture is extracted with ethyl acetate and the organic phase is dried over sodium sulfate. The organic phase is
evaporated under vacuum. The crude product is purified by silica gel flash chromatography using a gradient of hexane and
ethyl acetate from 9:1- 7:1.
Yield: 17.21 g, pale yellow solid
D3 (E)-3-{1-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylic acid tert-
butyl ester
10g (E)-3-[1-(4-bromomethyl-benzenesulfonyl )-1H-pyrrol-3-yl]-acrylic acid ferf-butyl ester (compound D2) is dissolved in
acetone and 6.5 g potassium phthalimide is added and the mixture is stirred for 17.5 h. The suspension is filtered and the
product is purified by crystallization.
D4 (E)-3-[1-(4-Bromo-benzenesulfonyl)-1 H-pyrrol-3-yl]-acrylic acid tert-butyl ester
Starting from compound D1 and 4-bromo-benzenesulfonyl chloride the title compound can be obtained analogously as
described for compound D2.
D5 (E)-3-{1-[4-({[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-Ah1ino}-methyl)-
benzenesulfonyl]-1H-pyrrol-3-yl}-acrylic acid tert-butyl ester
[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-[2-(1H-indol-3yl)-ethyl]-Ah1ine (compound E2) (830 mg, 2.60 mmol) is dissolved in
ethanol (200 ml). (E)-3-[1-(4-bromomethyl-benzenesulfonyl)-1H-pyrrol-3yl]-acrylic acid tert-butyl ester (compound D4) (1.01
g, 2.37 mmol) is added and the mixture is stirred for 43 hours and evaporated. The residue is purified by a silica gel flash
chromatograph using petrol ether- ether eluent.
D6 (E)-3-[1-(3-Bromo-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylic acid tert-butyl ester
Starting from compound D1 and 3-bromo-benzenesulfonyl chloride the title compound can be obtained analogously as
described for compound D4.
E1 1H-Pyrrol-3-carbaldehyde
4.70 g of dimethyl-(1H-pyrrol-3-ylmethylene)-Ah1monium chlorid (compound F1) are dissolved in 500 ml of 5.0% aqueous
sodium hydroxide solution and stirred for 4 hours at Ah1bient temperature. Afterwards the reaction mixture is extracted
exhaustively with CH2CI2. The combined organic phase is dried over Na2S04. Then it is filtered and evaporated under vacuo.
The crude product is purified by a silica gel flash chromatography using petroleum ether/diethylether 1:1 eluent to yield 3,01
g of the title compound as a pale yellow solid.
MS(EI):95.1(MM00%)
1H-NMR (DMSO-d6): 6.42 (dd, J1 = 1.5 Hz, J1= 6.5 Hz, 1H); 6.90 (m, 1H), 7.69 (dd, J1 = 1.5 Hz, J2= 6.4 Hz, 1H); 9.68 (s,
1H); 11.59 (bs, exchangeable, 1H)
E2 [2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-[2-(1H-indol-3yl)-ethyl]-Ah1ine
TryptAh1ine (3.34 g, 20.85 mmol) and t-butyldimethylsilyloxylacetaldehyde (2.44 g, 13.99 mmol) is dissolved in
dichloromethane (200 ml) for 10 minutes. The mixture is cooled to 0 °C and it is added sodium triacetoxyborohydride (5,38
g, 25.38 mmol). The mixture is warmed slowly to room temperature and stirred for 18 hours. Then water is added and the
mixture is extracted with dichloromethane. The organic phase is dried over sodium sulfate, filtered and evaporated. The
crude product is purified by a silica gel flash chromatograph using dichloromethane- methanol eluent.
F1 Dimethyl-(1H-pyrrol-3-ylmethylene)-Ah1monium chlorid
10.60 g of (chloromethylene)dimethylAh1monium chloride and 6.25 g of N-(triisopropylsilyl)-pyrrole are suspended in 200 ml
of CH2CI2 under nitrogen at 0-5°C. The suspension is warmed to 60°C and stirred for 30 minutes. Afterwards the mixture is
cooled to Ah1bient temperature. The suspension is filtered and washed with diethylether to give 5.67 g of the title compound
as grey solid.
MS (ESI): 123.3 (MH*,100%)
1H-NMR (DMSO-d6): 3.55 (s, 3H); 3.63 (s, 3H); 6.82 (m, J1 = 1.4 Hz, J2= 1.5Hz, J3= J* = 4.8 Hz, 1H); 7.22 (dd, J1 = 4.7
Hz, J1= 4.9,1H), 8.00 (dd, J1 = 1.6 Hz, J1= 1.7 Hz, 1H); 8.78 (s, 1H); 12.94 (bs, exchangeable, 1H)
Commercial utility
The N-sulphonylpyrrole derivatives of formula I or the salts of these compounds have valuable pharmacological properties
by inhibiting histone deacetylase activity and function.Histone deacetylase (HDAC) means an enzyme with an activity
towards the e-acetyl group of lysine residues within a substrate protein. HDAC substrates are histone H2A, H2B, H3 or H4
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proteins and isoforms but substrate proteins different to histones like, but not limited to, heat shock protein 90 (Hsp90), tubulin or the tumor suppressor, protein p53 exist. In pAr1icular histone deacetylases catalyse the hydrolysis the e-acetyl group of lysine residues within these substrate proteins, forming the free Ah1ino group of lysine.lnhibition of histone deacetylase by compounds according to this invention means inhibiting the activity and function of one or more HDAC isoenzymes, in pAr1icular isoenzymes selected from the so far known histone deacetylases, nAh1ely HDAC 1, 2, 3 and 8 (class I) and HDAC 4, 5, 6, 7,10 (class II), HDAC 11 as well as the NAD+ dependent class III (Sir2 homologues). In some preferred embodiment this inhibition is at least about 50%, more preferable at least 75% and still more preferable above 90%. Preferably, this inhibition is specific to a specific histone deacetylase class (eg HDAC class I enzymes), a selection of isoenzymes of highest pathophysiological relevance (eg HDAC1, 2, 3 enzymes) or a single isoenzyme (eg the HDAC 1 enzyme). The term histone deacetylase inhibitor is used to identify a compound capable of interacting with a histone deacetylase and inhibiting its activity, in pAr1icular its enzymatic activity. In this context "head group" defines the residues within an histone deacetylase inhibitor responsible for interacting with the active site of the enzyme, eg the Zn 2* ion.The inhibition of histone deacetylases is determined in biochemical assays of various formats and sources of enzymatic activity. HDAC activity is used either derived from nuclear or cellular extracts or by heterologous expression of a defined HDAC isoenzymes in E.coli, insect cells or mAh1malian cells. Since HDAC are active in multiprotein complexes and form homo- and heterodimeres, nuclear extracts derived from human cancer cells, for exAh1ple the human cervical carcinoma cell line HeLa, are preferred. These nuclear extracts contain class I and class II enzymes, but are enriched in class 1 enzymes. For expression of recombinant HDAC isoenzymes, mAh1malian expression systems like HEK293 cells are preferred. The HDAC isoenzyme is expressed as a fusion protein with an affinity tag, like the FLAG epitope. By affinity chromatography, the tagged protein is purified alone or in complex with endogenous proteins (eg other HDAC isoenzmyes and coactivators / platform proteins).The biochemical assays are well described and well known to persons skilled in the Ar1. As substrates, histone proteins, peptides derived from histone proteins or other HDAC substrates as well as acetylated lysine mimetics are used. One preferred promiscous HDAC substrate is the tripeptide Ac-NH-GGK(Ac), coupled with the fluorophore 7-Ah1inomethylcoumarin (AH1C).The invention further relates to the use of the compounds according to this invention for inhibiting histone deacetylase activity in cells and tissues, causing hyperacetylation of substrate proteins and as functional consequence for exAh1ple the induction or repression of gene expression, induction of protein degration, cell cycle arrest, induction of differentiation and/or induction of apoptosis.Cellular activity of a histone deacetylase inhibitor means any cellular effect related to histone deacetylase inhibition, in pAr1icular protein hyperacetylation, transcriptional repression and activation, induction of apoptosis, differentiation and / or cytotoxicity.The term "induction of apoptosis" and analogous terms are used to identify a compound which excecutes progrAh1med cell death in cells contacted with that compound. Apoptosis is defined by complex biochemical events within the contacted cell, such as the activation of cystein specific proteinases ("caspases") and the fragmentation of chromatin. Induction of apoptosis in cells contacted with the compound might not necessarily coupled with inhibition of cell proliferation or cell differentiation. Preferably, the inhibition of proliferation, induction of differentiation and/or induction of apoptosis is specific to cells with aberrant cell growth."Cytotoxicity" in general means arresting proliferation and/or inducing apoptotic cell death in vitro in mAh1malian cells, in pAr1icular human cancer cells/Induction of differentiation" is defined as a process of cellular reprogrAh1ming leading to a reversible or irreversible cell cycle arrest in GO and re-expression of a subset of genes typical for a certain specialized normal cell type or tissue (eg re-expression of milk fat proteins and fat in mAh1mary carcinoma cells).Assays for quantification of cell proliferation, apoptosis or differentiation are well known to experts and state of the Ar1. For exAh1ple, metabolic activity which is linked to cellular proliferation is quantified using the AlAh1ar Blue / Resazurin assay (O'Brian et al. Eur j Biochem 267,5421-5426, 2000) and induction of apoptosis is quantified by measurement of chromatin fragmentation with the cell death detection ELISA commercialized by Roche. ExAh1ples for cellular assays for the determination of hyperacetylation of HDAC substrates are given by measuring core histone acetylation using specific antibodies by Western blotting, reporter gene assays using respective responsive promoters or promoter elements (eg the p21 promoter or the sp1 site as responsive element) or finally by image analysis again using acetylation specific antibodies for core histone. proteins.Compounds according to this invention can be commercially applicable due to their HDAC inhibitory, anti-proliferative and/or apoptosis inducing activity, which may be beneficial in the therapy of diseases responsive thereto, such as e.g. any of those diseases mentioned herein.The invention further relates to a method for inhibiting or treating cellular neoplasia by adminstration of an effective Ah1ount of a compound according to this invention to a mAh1mal, in pAr1icular a human in need of such treatment. A "neoplasia" is defined by cells displaying aberrant cell proliferation and/or survival and/or a block in differentiation. The term neoplasia includes "benign neoplasia" which is described by hyperproliferation of cells, incapable of forming an aggressive, metastasizing tumor in-vivo, and, in contrast, "malignant neoplasia" which is described by cells with multiple cellular and biochemical abnormalities, capable of forming a systemic disease, for exAh1ple forming tumor metastasis in distant organs.The N-sulphonylpyrrole derivatives of the present invention are preferably used for the treatment of malignant neoplasia, also described as cancer, characterized by tumor cells finally metastasizing into distinct organs or tissues. ExAh1ples of malignant neoplasia treated with the N-sulphonylpyrrole derivatives of the present invention include solid and haematological tumors. Solid tumors are exemplified by tumors of the breast, bladder, bone, brain, central and peripheral nervus system, colon, endocrine glands (e.g. thyroid and adrenal cortex), esophagus, endometrium, germ cells, head and
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neck, kidney, liver, lung, larynx and hypopharynx, mesothelioma, ovary, pancreas, prostate, rectum, renal, small intestine, soft tissue, testis, stomach, skin, ureter, vagina and vulva. Malignant neoplasia include inherited cancers exemplified by Retinoblastoma and Wilms tumor. In addition, malignant neoplasia include primary tumors in said organs and corresponding secondary tumors in distant organs ("tumor metastases"). Hematological tumors are exemplified by aggressive and indolent forms of leukemia and lymphoma, nAh1ely non-Hodgkins disease, chronic and acute myeloid leukemia (CML / AH1L), acute lymphoblastic leukemia (ALL), Hodgkins disease, multiple myeloma and T-cell lymphoma. Also included are myelodysplastic syndrome, plasma cell neoplasia, paraneoplastic syndromes, cancers of unknown primary site as well as AIDS related malignancies.Neoplastic cell proliferation might also effect normal cell behaviour and organ function. For exAh1ple the formation of new blood vessels, a process described as neovascularization, is induced by tumors or tumor metastases. N-sulphonylpyrrole derivatives as described herein can be commercially applicable for treatment of pathophysiological relevant processes caused by benign or neoplastic cell proliferation, such as but not limited to neovascularization by unphysiological proliferation of vascular endothelial cells.Drug resistance is of pAr1icular importance for the frequent failure of standard cancer therapeutics. This drug resistance is caused by various cellular and molecular mechanisms like overexpression of drug efflux pumps, mutation within the cellular target protein or fusion proteins formed by chromosomal translocations. The commercial applicability of N-sulphonylpyrrole derivatives according to the present invention is not limited to 1st line treatment of patients. Patients with resistance to cancer chemotherapeutics or target specific anti-cancer drugs can be also Ah1enable for treatment with these compounds for e.g. 2nd or 3ri line treatment cycles. A prominent exAh1ple is given by acute promyelocytic leukemia patients with the PML-RARcc fusion protein, resistant to standard therapy with retinoids. These patients can be resensitized towards retinoids by treatment with HDAC inhibitory drugs like the N-sulphonylpyrrole derivatives according to the present invention.The invention further provides to a method for treating a mAh1mal, in pAr1icular a human, bearing a disease different to cellular neoplasia, sensitive to histone deacetylase inhibitor therapy comprising administering to said mAh1mal a pharmacologically active and therapeutically effective and tolerable Ah1ount of a compound according to this invention. These non malignant diseases include(i) Ar1hropathies and osteopathological conditions such as rheumatoid Ar1hritis, osteoAr1hrtis, gout, polyAr1hritis, and psoriatic Ar1hrtis,(ii) systemic lupus erythematosus,(iii) smooth muscle cell proliferation including vascular proliferative disorders, atherosclerosis and restenosis (iv) inflAh1matory conditions and dermal conditions such as ulcerative colitis, Chrons disease, allergic rhinitis, allergic dermatitis, cystic fibrosis, chronic bronchitis and asthma (v) endometriosis, uterine fibroids, endometrial hyperplasia and benign prostate hyperplasia (vi) cardiac dysfunction (vii) inhibiting immunosuppressive conditions like HIV infections (viii) neuropathological disorders like Parkinson disease, Alzheimer disease or polyglutAh1ine related disorders (ix) pathological conditions Ah1enable to treatment by potentiating of endogenous gene expression as well as enhancing transgene expression in gene therapy.The present invention further includes a method for the treatment of mAh1mals, including humans, which are suffering from one of the abovementioned conditions, illnesses, disorders or diseases. The method is characterized in that a pharmacologically active and therapeutically effective and tolerable Ah1ount of one or more of the N-sulphonylpyrrole derivatives mentioned above, or a salt of said compounds of formula I, which function by inhibiting histone deacetylases and, by modulating protein acetylation, induce various cellular effects, in pAr1icular induction or repression of gene expression, arresting cell proliferation and/or inducing apoptosis, is administered to the subject in need of such treatmentJhe invention further includes a method for treating diseases and/or disorders responsive or sensitive to the inhibition of histone deacetylases, pAr1icularly those diseases mentioned above, such as e.g. cellular neoplasia or diseases different to cellular neoplasia as indicated above, in mAh1mals, including humans, suffering therefrom comprising administering to said mAh1mals in need thereof a pharmacologically active and therapeutically effective and tolerable Ah1ount of one or more of the compounds according to the present invention.The present invention further includes a therapeutic method useful to modulate protein acetylation, gene expression, cell proliferation, cell differentiation and/or apoptosis in vivo in diseases mentioned above, in pAr1icular cancer, comprising administering to a subject in need of such therapy a pharmacologically active and therapeutically effective and tolerable Ah1ount of one or more of the abovementioned N-sulphonylpyrrole derivates, or the salts of said compounds of formula I, which function by inhibiting histone deacetylases.The present invention further provi'des a method for regulating endogenous or heterologous promotor activity by contacting a cell with a compound of formula I as mentioned above.The invention further includes a method for treating diseases, pAr1icularly those diseases mentioned above, in mAh1mals, including humans, suffering therefrom comprising administering to said mAh1mals in need thereof a therapeutically effective and tolerable Ah1ount of one or more of the compounds according to the present invention, optionally, simultaneously, sequentially or separately with one or more further therapeutic agents, such as e.g. those mentioned below. The invention further relates to the use of the compounds according to the present invention for the production of pharmaceutical compositions which are employed for the treatment and/or prophylaxis of the diseases, disorders, illnesses and/or conditions as mentioned herein.The invention further relates to the use of the compounds according to the present invention for the production of pharmaceutical compositions which are employed for the treatment and/or prophylaxis of diseases and/or disorders responsive or sensitive to the inhibition of histone deacetylases, pAr1icularly those diseases mentioned above, such as e.g. cellular neoplasia or diseases different to cellular neoplasia as indicated above.The invention further relates to the use of the compounds according to the present invention for the production of pharmaceutical compositions having histone deacetylases inhibitory activity.The invention further relates to the use of the
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compounds according to the present invention for the production of pharmaceutical compositions for inhibiting or treating cellular neoplasia, such as e.g. benign or malignant neoplasia, e.g: cancer.The invention further relates to the use of the compounds according to the present invention for the production of pharmaceutical compositions for the treatment of a disease different to a cellular neoplasia and sensitive to histone deacetylase inhibitor therapy, such as the non-malignant diseases mentioned before.The invention further relates to the use of the compounds according to the present invention for the production of pharmaceutical compositions for inhibiting histone deacetylase activity in the treatment of diseases responsive to said inhibition or to the functional consequences thereof.The invention further relates to a method for treating, preventing or Ah1eliorating the diseases, disorders, illnesses and/or conditions mentioned herein in a mAh1mal, in pAr1icular a human patient, comprising administering a pharmacologically active and therapeutically effective and tolerable Ah1ount of one or more compounds according to the present invention to said mAh1mal in need thereof.The invention further relates to the compounds according to this invention for use in the treatment and/or prophylaxis of diseases, especially the diseases mentioned.The invention further relates to pharmaceutical compositions comprising one or more of the compounds according to this invention and a pharmaceutically acceptable carrier or diluent.The invention further relates to pharmaceutical compositions according to this invention having histone deacetylases inhibitory activity.The invention further relates to pharmaceutical compositions according to this invention having apoptosis inducing activity.The invention further relates to pharmaceutical compositions according to this invention anti-proliferative activity.The invention further relates to the use of a pharmaceutical composition comprising one or more of the compounds according to this invention and a pharmaceutically acceptable carrier or diluent in the manufacture of a pharmaceutical product, such as e.g. a commercial package, for use in the treatment and/or prophylaxis of the diseases as mentioned.Additionally, the invention relates to an Ar1icle of manufacture, which comprises packaging material and a pharmaceutical agent contained within said packaging material, wherein the pharmaceutical agent is therapeutically effective for inhibiting the effects of histone deacetylases, Ah1eliorating the symptoms of an histone deacetylase mediated disorder, and wherein the packaging material comprises a label or package insert which indicates that the pharmaceutical agent is useful for preventing or treating histone deacetylase mediated disorders, and wherein said pharmaceutical agent comprises one or more compounds of formula I according to the invention. The packaging material, label and package insert otherwise parallel or resemble what is generally regarded as standard packaging material, labels and package inserts for pharmaceuticals having related utilities.The pharmaceutical compositions according to this invention are prepared by processes which are known per se and fAh1iliar to the person skilled in the Ar1. As pharmaceutical compositions, the compounds of the invention (= active compounds) are either employed as such, or preferably in combination with suitable pharmaceutical auxiliaries and/or excipients, e.g. in the form of tablets, coated tablets, capsules, capiets, suppositories, patches (e.g. as TTS), emulsions, suspensions, gels or solutions, the active compound content advantageously being between 0.1 and 95% and where, by the appropriate choice of the auxiliaries and/or excipients, a pharmaceutical administration form (e.g. a delayed release form or an enteric form) exactly suited to the active compound and/or to the desired onset of action can be achieved.The person skilled in the Ar1 is fAh1iliar with auxiliaries, vehicles, excipients, diluents, carriers or adjuvants which are suitable for the desired pharmaceutical formulations, preparations or compositions on account of his/her expert knowledge. In addition to solvents, gel formers, ointment bases and other active compound excipients, for exAh1ple antioxidants, dispersants, emulsifiers, preservatives, solubilizers, colorants, complexing agents or permeation promoters, can be used.Depending upon the pAr1icular disease, to be treated or prevented, additional therapeutic active agents, which are normally administered to treat or prevent that disease, may optionally be coadministered with the compounds according to the present invention. As used herein, additional therapeutic agents that are normally administered to treat or prevent a pAr1icular disease are known as appropriate for the disease being treated.ln a further aspect of the present invention, the N-sulphonylpyrrole derivatives according to this invention or the salts of said compounds of formula I, which function by inhibiting histone deacetylases, may be combined with standard therapeutic agents used for treatment of the deseases as mentioned before. In one pAr1icular embodiment the N-sulphonylpyrrole derivatives may be combinded with one or more Ar1-known anti-cancer agents, such as e.g. Ar1-known chemotherapeutic and/or target specific anti-cancer agents.ExAh1ples of known chemotherapeutic anti-cancer agents used in cancer therapy include, but not are limited to (i) alkylating/carbAh1ylating agents such as CyclophosphAh1id (Endoxan®), IfosfAh1id (Holoxan®), Thiotepa (Thiotehpa Lederle®), Melphalan (Alkeran®), or chloroethylnitrosourea (BCNU); (ii) platinum derivatives like cis-platin (Platinex® BMS), oxaliplatin or carboplatin (Cabroplat® BMS); (iii) antimitotic agents / tubulin inhibitors such as vinca alkaloids (vincristine, vinblastine, vinorelbine), taxanes such as Taxol (Paclitaxel®), Taxotere (Docetaxe!®) and analogs as well as new formulations and conjugates thereof; (iv) topoisomerase inhibitors such as anthracyclines (exemplified by Doxorubicin / Adriblastin®), epipodophyllotoxines (exAh1plified by Etoposide / Etopophos®) and cAh1ptothecin analogs (exemplified by Topotecan / HycAh1tin®); (v) pyrimidine antagonists such as 5-fluorouracil (5-FU), Capecitabine (Xeloda®), Arabinosylcytosine / Cytarabin (Alexan®) or Gemcitabine (Gemzar®); (vi) purin antagonists such as 6-mercaptopurine (Puri-Nethol®), 6-thioguanine or fludarabine (Fludara®) and finally (vii) folic acid antagonists such as methotrexate (Farmitrexat®).ExAh1ples of target specific anti-cancer drug classes used in experimental or standard cancer therapy include but are not limited to (i) kinase inhibitors such as e.g. Glivec (Imatinib®), ZD-1839 / Iressa (Gefitinib®), Bay43-9006 (Sorafenib®), SU11248 (Sutent®) or OSI-774 / Tarceva (Erlotinib®); (ii) proteasome inhibitors such as PS-341 (Velcade®); (iii) heat shock protein
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90 inhibitors like 17-allylAh1inogeldanAh1ycin (17-AAG); (iv) vascular targeting agents (VTAs) and anti-angiogenic drugs like the VEGF antibody Avastin (Bevacizumab®) or the KDR tyrosine kinase inhibitor PTK787 / ZK222584 (Vatalanib®); (v) monoclonal antibodies such as Herceptin (Trastuzumab®) or MabThera / Rituxan (Rituximab®), mutants as well as conjugates of monoclonal antibodies and antibody fragments; (vi) oligonucleotide based therapeutics like G-3139 / Genasense (Oblimersen®); (vii) protease inhibitors (viii) hormonal therapeutics such as anti-estrogens (e.g. TAh1oxifen), anti-androgens (e.g. FlutAh1ide or Casodex), LHRH analogs (e.g. Leuprolide, Goserelin or Triptorelin) and aromatase inhibitors.Other known anti-cancer agents which can be used for combination therapy include bleomycin, retinoids such as all-trans retinoic acid (ATRA), DNA methyltransferase inhibitors such as the 2-deoxycytidine derivative Decitabine (Docagen®), alanosine, cytokines such as interleukin-2, interferons such as interferon a2 or interferon-?, TRAIL, DR4/5 agonistic antibodies, FasL and TNF-R agonists and finally histone deacetylase inhibitors different to sulphonylpyrrole derivatives as described in the present invention such as SAHA, PXD101, MS275, MGCD0103, Depsipeptide / FK228, NVP-LBH589, valproic acid (VPA) and butyrates..As exemplary anti-cancer agents for use in combination with the compounds according to this invention in the cotherapies mentioned herein the following drugs may be mentioned, without being restricted thereto, 5 FU, actinomycin D, ABARELIX, ABCIXIMAB, ACLARUBICIN, ADAPALENE, ALEMTUZUMAB, ALTRETAH1INE, AH1INOGLUTETHIMIDE, AH1IPRILOSE, AH1RUBICIN, ANASTROZOLE, ANCITABINE, AR1EMISININ, AZATHIOPRINE, BASILIXIMAB, BENDAH1USTINE, BICALUTAH1IDE, BLEOMYCIN, BROXURIDINE, BUSULFAN, CAPECITABINE, CARBOPLATIN, CARBOQUONE, CARMUSTINE, CETRORELIX, CHLORAH1BUCIL, CHLORMETHINE, CISPLATIN, CLADRIBINE, CLOMIFENE, CYCLOPHOSPHAH1IDE, DACARBAZINE, DACLIZUMAB, DACTINOMYCIN, DAUNORUBICIN, DESLORELIN, DEXRAZOXANE, DOCETAXEL, DOXIFLURIDINE, DOXORUBICIN, DROLOXIFENE, DROSTANOLONE, EDELFOSINE, EFLORNITHINE, EMITEFUR, EPIRUBICIN, EPITIOSTANOL, EPTAPLATIN, ERBITUX, ESTRAH1USTINE, ETOPOSIDE, EXEMESTANE, FADROZOLE, FINASTERIDE, FLOXURIDINE, FLUCYTOSINE, FLUDARABINE, FLUOROURACIL, FLUTAH1IDE, FORMESTANE, FOSCARNET, FOSFESTROL, FOTEMUSTINE, FULVESTRANT, GEFITINIB, GEMCITABINE, GLIVEC, GOSERELIN, GUSPERIMUS, HERCEPTIN, IDARUBICIN, IDOXURIDINE, IFOSFAH1IDE, IMATINIB, IMPROSULFAN, INFLIXIMAB, IRINOTECAN, LANREOTIDE, LETROZOLE, LEUPRORELIN, LOBAPLATIN, LOMUSTINE, MELPHALAN, MERCAPTOPURINE, METHOTREXATE, METUREDEPA, MIBOPLATIN, MIFEPRISTONE, MILTEFOSINE, MIRIMOSTIM, MITOGUAZONE, MITOLACTOL, MITOMYCIN, MITOXANTRONE, MIZORIBINE, MOTEXAFIN, NAR1OGRASTIM, NEBAZUMAB, NEDAPLATIN, NILUTAH1IDE, NIMUSTINE, OCTREOTIDE, ORMELOXIFENE, OXALIPLATIN, PACLITAXEL, PALIVIZUMAB, PEGASPARGASE, PEGFILGRASTIM, PENTETREOTIDE, PENTOSTATIN, PERFOSFAH1IDE, PIPOSULFAN, PIRARUBICIN, PLICAH1YCIN, PREDNIMUSTINE, PROCARBAZINE, PROPAGERMANIUM, PROSPIDIUM CHLORIDE, RALTITREXED, RANIMUSTINE, RANPIRNASE, RASBURICASE, RAZOXANE, RITUXIMAB, RIFAH1PICIN, RITROSULFAN, ROMURTIDE, RUBOXISTAURIN, SARGRAH1OSTIM, SATRAPLATIN, SIROLIMUS, SOBUZOXANE, SPIROMUSTINE, STREPTOZOCIN, TAH1OXIFEN, TASONERMIN, TEGAFUR, TEMOPORFIN, TEMOZOLOMIDE, TENIPOSIDE, TESTOLACTONE, THIOTEPA, THYMALFASIN, TIAH1IPRINE, TOPOTECAN, TOREMIFENE, TRASTUZUMAB, TREOSULFAN, TRIAZIQUONE, TRIMETREXATE, TRIPTORELIN, TROFOSFAH1IDE, UREDEPA, VALRUBICIN, VERTEPORFIN, VINBLASTINE, VINCRISTINE, VINDESINE, VINORELBINE and VOROZOLE. The person skilled in the Ar1 is aware on the base of his/her expert knowledge of the total daily dosage(s) and administration form(s) of the additional therapeutic agent(s) coadministered. Said total daily dosage(s) can vary within a wide range.ln practicing the present invention and depending on the details, characteristics or purposes of their uses mentioned above, the compounds according to the present invention may be administered in combination therapy separately, sequentially, simultaneously or chronologically staggered (e.g. as combined unit dosage forms, as separate unit dosage forms or a adjacent discrete unit dosage forms, as fixed or non-fixed combinations, as kit-of-pAr1s or as admixtures) with one or more standard therapeutics, in pAr1icular Ar1-known chemotherapeutic or target specific anti-cancer agents, such as those mentioned above.Thus, a further aspect of the present invention is a combination or pharmaceutical composition comprising a first active ingredient, which is a N-sulphonylpyrrole derivative according to this invention or a salt thereof, a second active ingredient, which is an Ar1-known standard therapeutic, in pAr1icular Ar1-known chemotherapeutic or target specific anti-cancer agent, such as one of those mentioned above, and optionally a pharmacologically acceptable carrier, diluent and/or excipient for sequential, separate, simultaneous or chronologically staggered use in therapy in any order, e.g. to treat, prevent or Ah1eliorate in a patient diseases responsive to HDAC inhibitor treatment, such as the diseases, disorders or illnesses mentioned, in pAr1icular cancer.ln this context, the present invention further relates to a combination comprising a first active ingredient, which is at least one compound according to this invention, and a second active ingredient, which is at least one Ar1-known standard therapeutic, for exAh1ple an Ar1-known anti-cancer agent, such as e.g. one or more of those mentioned herein above.for separate, sequential, simultaneous or chronologically staggered use in therapy, such as e.g. in therapy of those diseases mentioned herein.The term "combination" according to this invention may be present as a fixed combination, a non-fixed combination or a kit-of-pAr1s.A "fixed combination" is defined as a combination wherein the said first active ingredient and the said second active ingredient are present together in one unit dosage or in a single entity. One exAh1ple of a "fixed combination" is a pharmaceutical composition wherein the said first active ingredient and the said second active ingredient are present in admixture for simultaneous administration, such as in a formulation. Another exAh1ple of a "fixed combination"
29

is a pharmaceutical combination wherein the said first active ingredient and the said second active ingredient are present in one unit without being in admixture.A "kit-of-pAr1s" is defined as a combination wherein the said first active ingredient and the said second active ingredient are present in more than one unit. One exAh1ple of a "kit-of-pAr1s" is a combination wherein the said first active ingredient and the said second active ingredient are present separately. The components of the kit-of-pAr1s may be administered separately, sequentially, simultaneously or chronologically staggered.The first and second active ingredient of a combination or kit-of-pAr1s according to this invention may be provided as separate formulations (i.e. independently of one another), which are subsequently brought together for simultaneous, sequential, separate or chronologically staggered use in combination therapy; or packaged and presented together as separate components of a combination pack for simultaneous, sequential, separate or chronologically staggered use in combination therapy.The type of pharmaceutical formulation of the first and second active ingredient of a combination or kit-of-pAr1s according to this invention can be similar, i.e. both ingredients are formulated in separate tablets or capsules, or can be different, i.e. suited for different administration forms, such as e.g. one active ingredient is formulated as tablet or capsule and the other is formulated for e.g. intravenous administration.The Ah1ounts of the first and second active ingredients of the combinations, compositions or kits according to this invention may together comprise a therapeutically effective Ah1ount for the treatment, prophylaxis or Ah1elioration of a disease responsive or sensitive the inhibition of histone deacetylases, pAr1icularly one of those diseases mentioned herein. A further aspect of the present invention is a combination comprising, in non-fixed form, one or more N-sulphonylpyrrole derivatives according to this invention or the salts thereof, and one or more Ar1-known standard therapeutic, in pAr1icular Ar1-known chemotherapeutic or target specific anti-cancer agents, such as those mentioned above, for sequential, separate, simultaneous or chronologically staggered use in therapy in any order, e.g. to treat, prevent or Ah1eliorate in a patient diseases responsive to HDAC inhibitor treatment, such as the diseases, disorders or illnesses mentioned, in pAr1icular cancer. Optionally said combination comprises instructions for its use in therapy.A further aspect of the present invention is a combined preparation, such as e.g. a kit of pAr1s, comprising a preparation of a first active ingredient, which is a compound according to this invention and a pharmaceutical^ acceptable carrier or diluent; a preparation of a second active ingredient, which is an Ar1-known therapeutic agent, in pAr1icular an anti-cancer agent, such as e.g. one of those mentioned above, and a pharmaceutical^ acceptable carrier or diluent; and optionally instructions for simultaneous, sequential, separate or chronologically staggered use in therapy, e.g. to treat benign and malignant neoplasia or diseases different to cellular neoplasia responsive or sensitive to the inhibition of histone deacetylases.A further aspect of the present invention is a kit of pAr1s comprising a dosage unit of a first active ingredient, which is a sulphonylpyrrole derivative mentioned in above or a salt thereof, a dosage unit of a second active ingredient, which is an Ar1-known standard therapeutic, in pAr1icular an anti-cancer agent such as e.g. one of those mentioned above, and optionally instructions for simultaneous, sequential or separate use in therapy, e.g. to treat disorders responsive or sensitive to the inhibition of histone deacetylases, such as, for exAh1ple, benign or malignant neoplasia, e.g. cancerA further aspect of the present invention is a pharmaceutical product comprising one or more compounds according to this invention, or one or more pharmaceutical compositions comprising said compounds; and one or more Ar1-known therapeutic agents, in pAr1icular Ar1-known anticancer agents, or one or more pharmaceutical compositions comprising said therapeutic agents, such as e.g. those mentioned above, for simultaneous, sequential or separate use in therapy, e.g. to treat diseases as mentioned before, in pAr1icular cancer. Optionally this pharmaceutical product comprises instructions for use in said therapy.ln this connection, the present invention further relates to combinations, compositions, formulations, preparations or kits according to the present invention having histone deacetylases inhibitory activity .A further aspect of the present invention is a pharmaceutical composition as unitary dosage form comprising, in admixture, a first active ingredient, which is a N-sulphonylpyrrole derivative according to this invention or a salt thereof, a second active ingredient, which is an Ar1-known standard therapeutic, in pAr1icular Ar1-known chemotherapeutic or target specific anti-cancer agent, such as one of those mentioned above, and optionally a pharmacologically acceptable carrier, diluent or excipientA further aspect of the present invention is a commercial package comprising one or more compounds according to the present invention together with instructions for simultaneous, sequential or separate use with one or more Ar1-known standard therapeutic, in pAr1icular anti-cancer, agents such as those mentioned above.The pharmaceutical compositions, combinations, preparations, formulations, kits, products or packages mentioned above may also include more than one of the compounds according to this invention and/or more than one of the Ar1-known standard therapeutics, in pAr1icular anti-cancer agents as mentioned.Furthermore, also an aspect of the present invention is a method for treating diseases and/or disorders responsive or sensitive to the inhibition of histone deacetylases, such as e.g. cancer, in combination therapy in a patient comprising administering a pharmacologically active and therapeutically effective and tolerable Ah1ount of a pharmaceutical combination, composition, formulation, preparation or kit as described above to said patient in need thereof.A further aspect of the present invention is a method for treating cotherapeutically diseases responsive or sensitive to inhibiting histone deacetylases, such as e.g. those diseases as mentioned before, in a patient in need of such treatment comprising administering separately, sequentially, simultaneously, fixed or non-fixed a pharmacologically active and therapeutically effective and tolerable Ah1ount of one or more of the compounds according to the present invention and a pharmacologically active and therapeutically effective and tolerable Ah1ount of one or more Ar1-known therapeutic agents, in pAr1icular anti-cancer agents, such as those mentioned above, to said patient.ln addition, compounds according to the present invention can be used in the pre- or post-surgical treatment of
30

cancer.ln further addition, compounds according to the present invention can be used in combination with radiation therapy, in pAr1icular in sensitization of cancer patients towards standard radiation therapy.The administration of the compounds according to this invention, the combinations and pharmaceutical compositions according to the invention may be performed in any of the generally accepted modes of administration available in the Ar1. Illustrative exAh1ples of suitable modes of administration include intravenous, oral, nasal, parenteral, topical, transdermal and rectal delivery. Oral and intravenous delivery are preferred.For the treatment of dermatoses, the N-sulphonylpyrrole derivatives of the invention are in pAr1icular administered in the form of those pharmaceutical compositions which are suitable for topical application. For the production of the pharmaceutical compositions, the compounds of the invention (= active compounds) are preferably mixed with suitable pharmaceutical auxiliaries and further processed to give suitable pharmaceutical formulations. Suitable pharmaceutical formulations are, for exAh1ple, powders, emulsions, suspensions, sprays, oils, ointments, fatty ointments, creAh1s, pastes, gels or solutionsJhe pharmaceutical compositions according to the invention are prepared by processes known per se. The dosage of the active compounds is carried out in the order of magnitude customary for histone deacetylases inhibitors. Topical application forms (such as ointments) for the treatment of dermatoses thus contain the active compounds in a concentration of, for exAh1ple, 0.1-99%. The customary dose in the case of systemic therapy (p.o.) is between 0.3 and 30 mg/kg per day, (i. v.) is between 0.3 and 30 mg/kg/h.The choice of the optimal dosage regime and duration of medication, pAr1icularly the optimal dose and manner of administration of the active compounds necessary in each case can be determined by a person skilled in the Ar1 on the basis of his/her expert knowledge.
Biological Investigations
Isolation of HDAC activity from HeLa cell nuclei:HDAC activity was isolated from nuclear HeLa extracts according to a method original described by DignAh1 et al. (Nucl. Acids Res. 11, pp1475,1983). Briefly, nuclei isolated from HeLa cells (CIL SA, Seneffe, Belgium) were resuspended in buffer C (20mM Hepes pH 7.9, 25% v:v glycerol, 0.42M NaCI, 1.5mM MgCfc, 0.2mM EDTA, 0.5mM PefaBloc and 0.5mM DTT) and stirred for 30min on ice. After centrifugation, the supernatant was dialysed against buffer D (40mM Tris HCI pH 7.4,100mM KCI, 0.2mM EDTA, 0.5mM DTT and 25% v:v glycerol) for 5h at 4°C. After dialysis and centrifugation, the supernatant was stored in aliquots at -80°C and used for Western blot analysis as well as the enzymatic assay as described in the following.
Isolation of rHDACI Human HDAC1 fused with the flag epitope is stably expressed in Hek293 cells. After mass cultivation in DMEM with supplements and 2% fetal calf serum, cells are lysed and flag-HDAC1 purified by M2-agarose affinity chromatography as described (Sigma Ar1. No. A-2220). Fractions from the purification are analysed by Western blot as well as for enzymatic activity as described below.
Fluorimetric HDAC activity assay:The HDAC enzyme activity assay was done as described by Wegener et al. (Chem. & Biol. 10, 61-68, 2003). Briefly 40|jl of a 1:100 dilution ( = 0.4uJ) nuclear HeLa extract (mixture of class I and II HDACs), 29 uJ enzyme buffer (15mM Tris HCI pH 8.1,0.25mM EDTA, 250mM NaCI, 10% v:v glycerol) and 1uJ test compound were added to a well of a 96well microtiter plate and reaction stAr1ed by addition of 30|ul substrate (Ac-NH-GGK(Ac)-AH1C; final concentration 25|Jv1 and final volume 100(oJ). After incubation for 90min at 30°C, reaction was terminated by the addition of 25uJ stop solution (50mM Tris HCI pH 8, 100mM NaCI, 0.5mg/ml trypsine and 2yM TSA). After incubation at room temperature for further 40min, fluorescence was measured using a Wallac Victor 1420 multilabel counter (Ex 355nm, Em 460nm) for quantification of AH1C (7-Ah1ino-4-methylcoumarin) generated by trypsine cleavage of the deacetylated peptide. For the calculation of ICso values the fluorescence in wells without test compound (1% DMSO, negative control was set as 100% enzymatic activity and the fluorescence in wells with 2u.M TSA (positive control) were set at 0% enzymatic activity. The corresponding IC50 values of the compounds for HDAC inhibitory activity were determined from the concentration-effect curves by means of non-linear regression.The HDAC inhibitory activity expressed by ICso values for selected compounds according to the present invention is shown in the following table 1, in which the numbers of the compounds correspond to the numbers of the exAh1ples.
Table 1: HDAC inhibitory activity (HDAC activity isolated from HeLa nuclear extract)





31

The HDAC1 enzymatic assay is done with slight modifications with recombinant flag-HDAC1 protein isolated from HEK293 cell lysates. About 14ng/well flag-HDAC1 are incubated with 6^M Ac-NH-GGK(Ac)-AH1C substrate for 3h at 30°C. Termination of the reaction and all further steps are done as described for HeLa cell nuclear extracts as a source for HDAC enzymatic activity.Recombinant human HDAC1 expressed in Hek293 cells is inhibited by ExAh1ples 4,5,8 to 11,25 and 28 with an IC50 > 0.95 nM.
55
Cellular Histone H3 hyperacetylation assay: To assess the cellular efficacy of an histone deacetylase inhibitor in vitro, an assay was set up in black clear-bottom 96-well plates and optimized for use on the Cellomics "ArrayScan II" platform for a quantitative calculation of histone acetylation. The protocol uses a polyclonal rabbit antibody, specifically binding to acetylated lysine 23 of human histone H3 on fixed cells with an Alexa Fluor 488 labeled goat anti rabbit-IgG used for counterstaining (Braunger et al. AACR annual conference 2003, Abstract 4556).5x103 HeLa cervical carcinoma cells/well (ATCC CCL-2) in 200JUI Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal calf serum were seeded at day 1 in Packard view plates and incubated for 24h under standard cell culture conditions. On day 2, 2|jl test compound (100x final concentration) was added and incubation continued for further 24h. On day 3, the culture medium was discarded and attached cells fixed for 15min at room temperature by addition of 100uJ fixation buffer (3.7% v:v formaldehyde in phosphate buffered saline / PBS). After discarding the fixation buffer and one wash with PBS, cells were permeabilized at room temperature by addition of 100uJ/well permeabilization buffer (30,8 mM NaCI, 0,54 mM Na2HP04,0,31 mM KH2PO4,5% v:v Triton X-100) for 15min at room temperature. After discarding the permeabilization buffer and addition of 100uJ/well blocking solution (PBS with 0.05% v:v Tween 20 and 5% w:v milk powder) for 30min at room temperature, the 1st antibody (anti-K23 histone H3 antibody, Cell Signaling No. 9674) in blocking solution (50uJ/well) was added. After incubation for 1h at 37°C, the wells were washed 5 times for 5min at room temperature with wash buffer (PBS with 0.05% v:v Tween 20) before additon of the 2nd antibody (goat-anti-rabbit Alexa Fluor 488; MoBiTec No. A-11008) in blocking solution (50^1/ well). After further incubation for 30min at 37°C, wells were washed 5 times for 5min at RT with 100uJ wash buffer at room temperature. Finally, 100uJ/well PBS were added and image analysis performed on the Cellomics "ArrayScan II" platform. For calculation of EC50 values, the nuclear fluorescence in cells treated with and without a reference HDAC inhibitor like SAHA or NVP-LBH-589 were taken as a positive and negative control, respectively. For EC50 determination, the percentage of positive cells was determined and EC50 calculation done from concentration-effect curves by means of non-linear regression.The histone hyperacetylating cellular potency expressed by EC50 values for selected compounds according to the present invention is shown in the following table 2, in which the numbers of the compounds correspond to the numbers of the exAh1ples.
Table 2: Induction of histone H3K" hyperacetylation in HeLa cervical carcinoma cells





Cellular cytotoxicity assay: The anti-proliferative activity of the histone deacetylase inhibitory compounds as described herein, was evaluated with the HeLa cervical carcinoma cell line (ATCC CCL2) using the AlAh1ar Blue (Resazurin) cell viability assay (O'Brien et al. Eur J Biochem 267, 5421-5426, 2000). Resazurin is reduced to the fluorescent resorufin by cellular dehydrogenase activity, correlating with viable, proliferating cells. Test compounds were dissolved as 10 mM solutions in dimethylsulfoxide (DMSO) and subsequently diluted in semi-logarithmic steps. HeLa cells were seeded into 96 well flat bottom plates at a density of 3000 cells per well in a volume of 200 yl per well. 24 hours after seeding 1 \i\ each of the compound dilutions were added into each well of the 96 Well plate. Each compound dilution was tested as quadruplicates. Wells containing untreated control cells were filled with 200 \J\ DMEM medium containing 0.5% v:v DMSO. The cells were then incubated with the substances for 48 hours at 37°C in a humidified athmosphere containing 5% carbon dioxide. To determine the viability of the cells, 20 pi of an Resazurin solution (Sigma; 90mg /1) were added. After 4 hours incubation at 37°C the fluorescence was measured at an extinction of 544 nm and an emission of 590 nm. For the calculation of the cell viability the emission value from untreated cells was set as 100% viability and the emission rates of treated cells were set in relation to the values of untreated cells. Viabilities were expressed as % values. The corresponding ICso values of the compounds for cytotoxic activity are determined from the concentration-effect curves by means of nonlinear regression.The anti-proliferative / cytotoxic potency expressed by IC50 values for selected compounds according to the present invention is shown in the following table 3, in which the numbers of the compounds correspond to the numbers of the exAh1ples.
32

Table 3: Cytotoxicity in HeLa cervical carcinoma cells





Apoptosis induction
The induction of apoptosis is measured by using the cell death detection ELISA (Ar1. No. 1774425, Roche Biochemicals, Mannheim, Germany). A549 NSCLC cells are seeded into 96 well flat bottom plates at a density of 3x10 E3 cells/well in a total volume of 10Opl/well. 24 hours after seeding, 1 pi each of the compound dilutions in DMEM are added in a total volume of 100|jl into each well Final volume 200|jl/well). Each compound dilution is tested at least as triplicates. Wells containing untreated control cells are filled with 200|jl DMEM containing 0.5 vol% DMSO. The cells are incubated with test compound for 48 hours at 37°C in a humidified athmosphere containing 5% carbon dioxide. As a positive control for the induction of apoptosis, cells are treated with 50(jM Cispiatin (Gry Pharmaceuticals, KirchzAr1en, Germany). Medium is then removed and the cells lysed in 200 \i\ lysis buffer. After centrifugation as described by the manufacturer, 10 pi of cell lysate is processed as described in the protocol. The degree of apoptosis is calculated as follows: The absorbance at 405 nm obtained with lysates from cells treated with 50|jM cispiatin is set as 100 cpu (cispiatin units), while an absorbance at 405 nm of 0.0 is set as 0.0 cpu. The degree of apoptosis is expressed as cpu in relation to the value of 100 cpu reached with the lysates obtained from cells treated with 50pM cisplatin.The compounds according to this invention tested in the assays above are expected to have an apoptosis inducing effect when tested in this assay.
33

WE CLAIM:
Compounds of formula I
in which
R1 is hydrogen, 1-4C-alkyl, halogen, or 1-4C-alkoxy, R2 is hydrogen or 1-4C-alkyl,
R3 is hydrogen or 1-4C-alkyl,
R4 is hydrogen, 1-4C-alkyl, halogen, or 1-4C-alkoxy,
R5 is hydrogen, 1-4C-alkyl, halogen, or 1-4C-alkoxy,
R6 is-T1-Q1, in which
T1 is a bond, or 1 -4C-alkylene,
Q1 isAr1,Aa1, Hh1, or Ah1, in which
Ar1 is phenyl, or R61- and/or R62-substituted phenyl, in which
R61 is 1-4C-alkyl, or -T2-N(R611)R612, in which either
T2 is a bond, and
R611 is hydrogen, 1-4C-alkyl, hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl, phenyl-1-4C-alkyl, or Har1-1-4C-alkyl, in
which
Har1 is optionally substituted by R6111 and/or R6112, and is a monocyclic or fused bicyclic 5- to 10-membered
unsaturated heteroaromatic ring comprising one to three heteroatoms, each of which is selected from the group
consisting of nitrogen, oxygen and sulfur, in which R6111 is halogen, or 1-4C-alkyl, R6112 is 1-4C-alkyl, and R612 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl or hydroxy-2-4C-alkyl,or R611 and R612 together and with
inclusion of the nitrogen atom, to which they are bonded, form a heterocyclic ring Het1, in which
Het1 is morpholino, thiomorpholino, S-oxo-thiomorpholino, S,S-dioxo-thiomorpholino, piperidino, pyrrolidino,
piperazino, or 4N-(1-4C-alkyl)-piperazino,or
T2 is 1-4C-alkylene, or 2-4C-alkylene interrupted by oxygen, and
R6111 is hydrogen, 1-4C-alkyl, hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl, phenyl-1-4C-alkyl, or Har1-1-4C-alkyl, in
which
Har1 is optionally substituted by R6111 and/or R6112, and is a monocyclic or fused bicyclic 5- to 10-membered
unsaturated heteroaromatic ring comprising one to three heteroatoms, each of which is selected from the group
consisting of nitrogen, oxygen and sulfur, in which R6111 is halogen, or 1 -4C-alkyl, R6112 is 1-4C-alkyl, and R612 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl or hydroxy-2-4C-alkyl,or R611 and R612 together and with
inclusion of the nitrogen atom, to which they are bonded, form a heterocyclic ring Het1, in which
Het1 is morpholino, thiomorpholino, S-oxo-thiomorpholino, S,S-dioxo-thiomorpholino, piperidino, pyrrolidino,
piperazino, 4N-(1-4C-alkyi)-piperazino, imidazolo, pyrrolo or pyrazolo,
R62 is 1-4C-alkyl, 1-4C-alkoxy, halogen, cyano, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkylcarbonylAh1ino, or 1-4C-
alkylsulphonylAh1ino,
Aa1 is a bisaryl radical made up of two aryl groups,
which are selected independently from a group consisting of phenyl and naphthyl, and
which are linked together via a single bond,
Hh1 is a bisheteroaryl radical made up of two heteroaryl groups,
which are selected independently from a group consisting of monocyclic 5- or 6-membered heteroaryl radicals
comprising one or two heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and
sulfur.and which are linked together via a single bond,
AH1 is a heteroaryl-aryl radical or an aryl-heteroaryl radical made up of a heteroaryl group selected from a group
consisting of monocyclic 5- or 6-membered heteroaryl radicals comprising one or two heteroatoms, each of
which is selected from the group consisting of nitrogen, oxygen and sulfur, and an aryl group selected from a
group consisting of phenyl and naphthyl, whereby said heteroaryl and aryl groups are linked together via a single
bond,
R7 is hydroxyl, or Cyc, in which
Cyc is a ring system of formula la

34

inwhich
A is C (carbon),
B is C (carbon),
R71 is hydrogen, halogen, 1-4C-alkyl, or 1-4C-alkoxy,
R72 is hydrogen, halogen, 1-4C-alkyl, or 1-4C-alkoxy,
M with inclusion of A and B is either a ring Ar2 or a ring Har2, in which
Ar2 is a benzene ring,
Har2 is a monocyclic 5- or 6-membered unsaturated heteroaromatic ring comprising one to three heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur.and the salts of these compounds.
2. Compounds of formula I according to claim 1 in which
R1 is hydrogen, 1-4C-alkyl, halogen, or 1-4C-alkoxy,
R2 is hydrogen or 1 -4C-alkyl,
R3 is hydrogen or 1-4C-alkyl,
R4 is hydrogen, 1-4C-alkyl, halogen, or 1-4C-alkoxy,
R5 is hydrogen, 1-4C-alkyl, halogen, or 1-4C-alkoxy,
R6 is-T1-Q1, in which
T1 is a bond, or 1 -4C-alkylene,
Q1 is AH1, Aa1, Hh1, or Ah1, in which
Ar1 is phenyl, or R61- and/or R62-substituted phenyl, in which
R61 is 1-4C-alkyl, or -T2-N(R611)R612, in which
T2 is a bond, 1-4C-alkylene, or 2-4C-alkylene interrupted by oxygen,
R611 is hydrogen, 1-4C-alkyl, hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl, phenyl-1-4C-alkyl, or Har1-1-4C-alkyl, in
which
HAr1 is optionally substituted by R6111 and/or R6112, and is a monocyclic or fused bicyclic 5- to 10-membered
unsaturated heteroaromatic ring comprising one to three heteroatoms, each of which is selected from the group
consisting of nitrogen, oxygen and sulfur, in which R6111 is halogen, or 1-4C-alkyl, R6112 is 1-4C-alkyl,
R612 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl or hydroxy-2-4C-alkyl,
R62 is 1-4C-alkyl, 1-4C-alkoxy, halogen, cyano, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkylcarbonylAh1ino, or 1-4C-
alkylsulphonylAh1ino,
Aa1 is a bisaryl radical made up of two aryl groups,
which are selected independently from a group consisting of phenyl and naphthyl, and
which are linked together via a single bond,
Hh1 is a bisheteroaryl radical made up of two heteroaryl groups,
which are selected independently from a group consisting of monocyclic 5- or 6-membered heteroaryl radicals
comprising one or two heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and
sulfur.and which are linked together via a single bond,
AH1 is a heteroaryl-aryl radical or an aryl-heteroaryl radical made up of a heteroaryl group selected from a group
consisting of monocyclic 5- or 6-membered heteroaryl radicals comprising one or two heteroatoms, each of
which is selected from the group consisting of nitrogen, oxygen and sulfur, and an aryl group selected from a
group consisting of phenyl and naphthyl, whereby said heteroaryl and aryl groups are linked together via a single
bond,
R7 is hydroxyl, or Cyc, in which
Cyc is a ring system of formula la
inwhich
A is C (carbon), B is C (carbon),
R71 is hydrogen, halogen, 1-4C-alkyl, or 1-4C-alkoxy,
R72 is hydrogen, halogen, 1-4C-alkyl, or 1-4C-alkoxy,
M with inclusion of A and B is either a ring Ar2 or a ring Har2, in which
Ar2 is a benzene ring,
Har2 is a monocyclic 5- or 6-membered unsaturated heteroaromatic ring comprising one to three heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur.and the salts of these compounds.
3. Compounds of formula I according to claim 1 in which
R1 is hydrogen, or 1-4C-alkyl, R2 is hydrogen, or 1-4C-alkyl,
R3 is hydrogen, or 1-4C-alkyl,
35

R4 is hydrogen, or 1-4C-alkyl,
R5 is hydrogen, or 1-4C-alkyl,
R6 is-T1-Q1,in which
T1 is a bond, or 1 -4C-alkylene,
Q1 is Ar1, Aa1, Hh1, or AH1, in which
Ar1 is phenyl, or R61-substituted phenyl, in which
R61 is 1-4C-alkyl, or -T2-N(R611)R612, in which either
T2 is a bond,
R611 is hydrogen, 1-4C-alkyl, phenyl-1 -4C-alkyl, or Har1-1-4C-alkyl, in which
Har1 is either a monocyclic 5-membered unsaturated heteroaromatic ring comprising one, two or three heteroatoms, each of
which is selected from the group consisting of nitrogen, oxygen and sulfur, or a monocyclic 6-membered unsaturated
heteroaromatic ring comprising one or two nitrogen atoms, or a fused bicyclic 9-membered unsaturated heteroaromatic ring
comprising one, two or three heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and
sulfur, or a fused bicyclic 10-membered unsaturated heteroaromatic ring comprising one or two heteroatoms, each of which
is selected from the group consisting of nitrogen, oxygen and sulfur, and R612 is hydrogen, 1-4C-alkyl, or hydroxy-2-4C-
alkyl.or R611 and R612 together and with inclusion of the nitrogen atom, to which they are bonded, form a heterocyclic ring
Het1, in which Het1 is morpholino, or
T2 is 1-4C-alkylene,
R611 is hydrogen, 1-4C-alkyl, phenyl-1-4C-alkyl, or Har1-1-4C-alkyl, in which
Har1 is either a monocyclic 5-membered unsaturated heteroaromatic ring comprising one, two or three heteroatoms, each of
which is selected from the group consisting of nitrogen, oxygen and sulfur, or a monocyclic 6-membered unsaturated
heteroaromatic ring comprising one or two nitrogen atoms, or a fused bicyclic 9-membered unsaturated heteroaromatic ring
comprising one, two or three heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and
sulfur, or a fused bicyclic 10-membered unsaturated heteroaromatic ring comprising one or two heteroatoms, each of which
is selected from the group consisting of nitrogen, oxygen and sulfur, and R612 is hydrogen, 1-4C-alkyl, or hydroxy-2-4C-
alkyl, or R611 and R612 together and with inclusion of the nitrogen atom, to which they are bonded, form a heterocyclic ring
Het1, in which
Het1 is morpholino,
Aa1 is a biphenyl radical,
Hh1 is a bipyridyl, pyrazolyl-pyridinyl, imidazolyl-pyridinyl, or pyridinyl-thiophenyl radical,
AH1 is a pyridinyl-phenyl, pyrazolyl-phenyl, or imidazolyl-phenyl radical,
R7 is hydroxyl, or 2-Ah1inophenyl,and the salts of these compounds.
4. Compounds of formula I according to claim 1 in which
R1 is hydrogen, R2 is hydrogen,
R3 is hydrogen, R4 is hydrogen,
R5 is hydrogen,
R6 is -T1-Q1, Aa1, Hh1, or Ah1, in which
T1 is a bond, or 1-2C-alky!ene,
Q1 is Ar1, in which
Ar1 is phenyl, or R61-substituted phenyl, in which
R61 is 1-4C-alkyl, or-T2-N(R611)R612, in which either
T2 is a bond,
R611 is hydrogen, 1-4C-alkyl, phenyl-1-2C-alkyl, or Har1-1-2C-alkyl, in which
Har1 is pyridinyl, benzimidazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl or indolyl, and
R612 is hydrogen, 1-4C-alkyl, or hydroxy-2-3C-alkyl,or R611 and R612 together and with inclusion of the nitrogen
atom, to which they are bonded, form a heterocyclic ring Het1, in which
Het1 is morpholino.or
T2 is 1-2C-alkylene,
R611 is hydrogen, 1-4C-alkyl, phenyl-1-2C-alkyl, or Har1-1-2C-alkyl, in which
Har1 is pyridinyl, benzimidazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl or indolyl, and
R612 is hydrogen, 1-4C-alkyl, or hydroxy-2-3C-alkyl,or R611 and R612 together and with inclusion of the nitrogen
atom, to which they are bonded, form a heterocyclic ring Het1, in which
Het1 is morpholino,
Aa1 is a biphenyl radical,
Hh1 is a bipyridyl, pyrazolyl-pyridinyl, imidazolyl-pyridinyl, or pyridinyl-thiophenyl radical,
AH1 is a pyridinyl-phenyl, pyrazolyl-phenyl, or imidazolyl-phenyl radical,
R7 is hydroxyl, or 2-Ah1inophenyl,and the salts of these compounds.
5. Compounds of formula I according to claim 1 in which
36

R1
R3
R5
R6
T1
Q1
Ar1
R61
T2
R611
R612
T2
R611
Har1
R612
Het1
Aa1
Hh1
Ah1
R7
6.
R1
R3
R5
R6
T1
Q1
Ar1
R61
T2
R611
R612
T2
R611
HAr1
R612






is hydrogen, R2 is hydrogen, is hydrogen, R4 is hydrogen, is hydrogen,
is -T1-Q1, Aa1, Hh1, Ah1, or benzyl, in which is a bond, is Ar1, in which
is phenyl, or R61-substituted phenyl, in which is 1-4C-alkyl, or -T2-N(R611)R612, in which either is a bond, is 1-4C-alkyl, and is 1-4C-alkyl,or is 1-2C-alkylene,
is hydrogen, 1-4C-alkyl, phenyl-1 -2C-alkyl, or Har1-1-2C-alkyl, in which is pyridinyl, or indolyl, and
is hydrogen, 1-4C-alkyl, or hydroxy-2-3C-alkyl,or R611 and R612 together and with inclusion of the nitrogen atom, to which they are bonded, form a heterocyclic ring Het1, in which is morpholino,
is 1,1'-biphen-4-yl or 1,1'-biphen-3-yl, is a pyridinyl-thiophenyl radical,
is a 3-(pyridinyl)-phenyl, 3-(pyrazolyl)-phenyl, 4-(pyridinyl)-phenyl or 4-(pyrazolyl)-phenyl radical, is hydroxyl, or 2-Ah1inophenyl,and the salts of these compounds. Compounds of formula I according to claim 1 in which s hydrogen, R2 is hydrogen, is hydrogen, R4 is hydrogen, s hydrogen,
s-T1-Q1,Aa1, Hh1,Ah1, or benzyl, in which s a bond, is Ar1, in which
s phenyl, 3-(R61)-phenyl, or4-(R61)-phenyl, in which is methyl, or -T2-N(R611)R612, in which either is a bond, is methyl, and s methyl.or s methylene,
s hydrogen, methyl, isobutyl, benzyl, HAr1 -methyl, or 2-(Har1)-ethyl in which s pyridinyl or indolyl, and
s hydrogen, methyl, or 2-hydroxy-ethyl,or R611 and R612 together and with inclusion of the nitrogen atom, to which they are bonded, form a heterocyclic ring Het1, in which is morpholino,
is 1,1'-biphen-4-yl or 1,1'-biphen-3-yl, is a pyridinyl-thiophenyl radical,
is a 3-(pyridinyl)-phenyl, 3-(pyrazolyl)-phenyl, 4-(pyridinyl)-phenyl or 4-(pyrazolyl)-phenyl radical, is hydroxyl, or 2-Ah1inophenyl,and the salts of these compounds. Compounds of formula I according to claim 1 in which is hydrogen, R2 is hydrogen, is hydrogen, R4 is hydrogen, s hydrogen,
is -T1-Q1, Aa1, Hh1, Ah1, or benzyl, in which is a bond, is Ar1, in which
s phenyl, 3-(R61)-phenyl, or4-(R61)-phenyl, in which s methyl, or-T2-N(R611)R612, in which either s a bond, s methyl, and is methyl.or s methylene,







37

R612
Het1 Aa1 Hh1 Ah1
R7
8.
R1
R3
R5
R6
T1
Q1
Ar1
R61
T2
R611
R612
T2
R611
Har1
R612
T2
R611
Har1
R612
T2
R611
HAr1
R612
T2
Het1 Aa1 Hh1 Ah1
R7 9.
R1
R3
R5
R6
T1
Ar1
R61
T2
R611
R612
R611
HAr1
R612
T2
R611
HAr1
R612

is hydrogen, methyl, or 2-hydroxy-ethyl,or R611 and R612 together and with inclusion of the nitrogen atom, to which they are bonded, form a heterocyclic ring Het1, in which is morpholino,
is 1,1'-biphen-4-yl or 1,1'-biphen-3-yl, is5-(pyridin-2-yl)-thiophen-2-yl,
is 3-(pyridin-3-yl)-phenyl, 3-(pyridin-4-yl)-phenyl, 3-(pyrazol-1-yl)-phenyl, 3-(1H-pyrazol-4-yl)-phenyl, 4-(pyridin-3-yl)-phenyl, 4-(pyridin-4-yl)-phenyl, 4-(pyrazol-1-yl)-phenyl or4-(1H-pyrazol-4-yl)-phenyl, is hydroxyl, or 2-Ah1inophenyl,and the salts of these compounds. Compounds of formula I according to claim 1 in which is hydrogen, R2 is hydrogen, is hydrogen, R4 is hydrogen, s hydrogen,
s -T1-Q1, Aa1, Hh1, Ah1, or benzyl, in which s a bond, is Ar1, in which
is phenyl, 3-(R61)-phenyl, or4-(R61)-phenyl, in which is methyl, or-T2-N(R611)R612, in which either s a bond, s methyl, and s methyl.or s methylene,
s hydrogen, isobutyl, benzyl, HAr1-methyl, or 2-(Har1)-ethyl, in which s pyridin-3-yl, pyridin-4-yl, indol-2-yl, indol-3-yl or indol-5-yl, and is hydrogen.or is methylene,
s methyl, or 2-(Har1)-ethyl, in which s indol-2-yl, and is methyl.or is methylene, s 2-(Har1)-ethyl, in which is indol-2-yl, and is 2-hydroxy-ethyl,or
is methylene, and R611 and R612 together and with inclusion of the nitrogen atom, to which they are bonded, form a heterocyclic ring Het1, in which is morpholino,
is 1,1 '-biphen-4-yl or 1,1'-biphen-3-yl, is5-(pyridin-2-yl)-thiophen-2-yl,
is 3-(pyridin-3-yl)-phenyl, 3-(pyridin-4-yl)-phenyl, 3-(pyrazol-1-yl)-phenyl, 3-(1H-pyrazol-4-yl)-phenyl, 4-(pyridin-3-yl)-phenyl, 4-(pyridin-4-yl)-phenyl, 4-(pyrazol-1-yl)-phenyl or 4-(1 H-pyrazol-4-yl)-phenyl, is hydroxyl,and the salts of these compounds. Compounds of formula I according to claim 1 in which is hydrogen, R2 is hydrogen, is hydrogen, R4 is hydrogen, s hydrogen,
s -T1-Q1, Aa1, Hh1, Ah1, or benzyl, in which is a bond, Q1 is Ar1, in which is phenyl, 3-(R61)-phenyl, or4-(R61)-phenyl, in which is methyl, or -T2-N(R611)R612, in which either is a bond, s methyl, and
s methyl.or T2 is methylene,
is hydrogen, isobutyl, benzyl, HAr1-methyl, or 2-(Har1)-ethyl, in which is pyridin-3-yl, pyridin-4-yl, indol-3-yl, or indol-5-yl, and is hydrogen.or s methylene,
s methyl, or 2-(Har1)-ethyl, in which s indol-2-yl, and is methyl.or

38

T2 is methylene,
R611 is 2-(Har1)-ethyl, in which
HAr1 is indol-2-yl, and
R612 is 2-hydroxy-ethyl,or
T2 is methylene, and R611 and R612 together and with inclusion of the nitrogen atom, to which they are bonded
form a heterocyclic ring Het1, in which
Het1 is morpholino,
Aa1 is 1,1'-biphen-4-yl or 1,1'-biphen-3-yl,
Hh1 is 5-(pyridin-2-yl)-thiophen-2-yl,
AH1 is 3-(pyridin-3-yl)-phenyl, 3-(pyridin-4-yl)-phenyl, 3-(pyrazol-1-yl)-phenyl, 3-(1H-pyrazol-4-yl)-phenyl, 4-(pyridin-3-
yl)-phenyl, 4-(pyridin-4-yl)-phenyl, 4-(pyrazol-1-yl)-phenyl or 4-(1H-pyrazol-4-yl)-phenyl,R7 is 2-Ah1inophenyl,anc
the salts of these compounds.
10. Compounds of formula I according to claim 1 in which
R1 is hydrogen, R2 is hydrogen,
R3 is hydrogen, R4 is hydrogen,
R5 is hydrogen,
R6 is -T1-Q1, or biphenyl, in which
T1 is a bond, or 1 -2C-alkylene,
Q1 is Ar1, in which
Ar1 is phenyl, or R61-substituted phenyl, in which
R61 is 1-4C-alkyl, or -T2-N(R611)R612, in which
T2 is a bond, or 1 -2C-alkylene,
R611 is 1-4C-alkyl, or Har1-1-2C-alkyl, in which
HAr1 is benzimidazolyl, or indolyl,
R612 is 1-4C-alkyl,
R7 is hydroxyl, or 2-Ah1inophenyl,and the salts of these compounds.
11. Compounds of formula I according to claim 1 in which
R1 is hydrogen, R2 is hydrogen,
R3 is hydrogen, R4 is hydrogen,
R5 is hydrogen,
R6 is -T1-Q1, biphenyl, or benzyl, in which
T1 is a bond, Q1 is Ar1, in which
Ar1 is R61-substituted phenyl, in which
R61 is methyl, dimethylAh1ino, or -T2-N(R611 )R612, in which
T2 is methylene,
R611 is methyl, or 2-(indol-2-yl)ethyl,
R612 is methyl,
R7 is hydroxyl, or 2-Ah1inophenyl,and the salts of these compounds.
12. A compound of formula I according to claim 1 which is selected from
1. (E)-N-Hydroxy-3-[1 -(toluene-4-sulfonyl)-1 -H-pyrrol-3-yl]-acrylAh1ide
2. N-Hydroxy-3-(1 -phenylmethanesulfonyl-1 H-pyrrol-3-yl)-acrylAh1ide
3. (E)-3-[1-(Biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylAh1ide
4. (E)-3-[1-(4-DimethylAh1ino-benzenesulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylAh1ide
5. (E)-N-(2-Ah1ino-phenyl)-3-[1 -(toluene-4-sulfonyl)-1 H-pyrrol-3-yl]-acrylAh1ide
6. (E)-N-(2-Ah1ino-phenyl)-3-(1 -phenylmethanesulfonyl-1 H-pyrrol-3-yl)-acrylAh1ide
7. (E)-N-(2-Ah1ino-phenyl)-3-[1 -(biphenyl-4-sulfonyl)-1 H-pyrrol-3-yl]-acrylAh1ide
8. (E)-N-(2-Ah1ino-phenyl)-3-[1 -(4-dimethylAh1ino-benzenesulfonyl)-1 H-pyrrol-3-yl]-acrylAh1ide .
9. (E)-N-Hydroxy-3-(1-[4-(([2-(1H-indol-2-yl)-ethyl]-methyl-Ah1ino)-methyl)-benzene sulfonyl] -1 H-pyrrol-3-yl)-acrylamide
10. (E)-3-[1 -(4-DimetylAh1inomethyl-benzenesulfonyl)-1 H-pyrrol-3-yl]-N-hydroxy-acrylAh1ide
11. (E)-N-Hydroxy-3-[1 -(4-{[(pyridin-3-ylmethyl)-Ah1ino]-methyl}-benzenesulfonyl)-1 H-pyrrol-3-yl]-acrylAh1ide
12. (E)-N-Hydroxy-3-[1-(4-{[(1 H-indol-3-ylmethyl)-arnino]-methyl}-benzenesulfonyl)-1 H-pyrrol-3-yl]-acrylAh1ide
13. (E)-3-{1 -[4-(BenzylAh1ino-methyl)-benzenesulfonyl]-1 H-pyrrol-3-yl}-N-hydroxy-acrylAh1ide
14. (E)-N-Hydroxy-3-{1 -[4-(isobutylAh1ino-methyl)-benzenesulfonyl]-1 H-pyrrol-3-yl}-acrylAh1ide
15. (E)-N-Hydroxy-3-[1-(4-{[(1 H-indol-5-ylmethyl)-Ah1ino]-methyl}-benzenesulfonyl)-1 H-pyrrol-3-yl]-acrylAh1ide
16. (E)-N-Hydroxy-3-[1 -(4-{[(pyridin-4-ylmethyl)-Ah1ino]-methyl}-benzenesulfonyl)-1 H-pyrrol-3-yl]-acrylAh1ide
17. (E)-3-[1 -(4-Ah1inomethyl-benzenesulfonyl)-1 H-pyrrol-3-yl]-N-hydroxy-acrylAh1ide
18. (E)-N-Hydroxy-3-[1-(4-pyridin-4-yl-benzenesulfonyl)-1 H-pyrrol-3-yl]-acrylAh1ide
19. (E)-N-Hydroxy-3-{1-[4-(1H-pyrazol-4-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylAh1ide
39

20. (E)-N-(2-Ah1ino-phenyl)-3-[1 -(4-pyridin-4-yl-benzenesulfonyl)-1 H-pyrrol-3-yl]-acrylAh1ide
21. (E)-N-(2-Ah1ino-phenyl)-3-[1 -(4-pyridin-3-yl-benzenesulfonyl)-1 H-pyrrol-3-ylj-acrylAh1ide
22. (E)-N-(2-Ah1ino-phenyl)-3-{1 -[4-(1 H-pyrazol-4-yl)-benzenesulfonyl]-1 H-pyrrol-3-yl}-acrylAh1ide
23. (E)-3-[1-(Biphenyl-3-sulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylAh1ide
24. (E)-N-Hydroxy-3-[1-(5-pyridin-2-yl-thiophene-2-sulfonyl)-1 H-pyrrol-3-yl]-acrylAh1ide
25. (E)-N-Hydroxy-3-[1-(4-pyrazol-1-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylAh1ide
26. (E)-N-(2-Ah1ino-phenyl)-3-[1-(5-pyridin-2-yl-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylAh1ide
27. (E)-N-Hydroxy-3-[1 -(4-morpholin-4-ylmethyl-benzenesulfonyl)-1 H-pyrrol-3-yl]-acrylAh1ide
28. (E)-N-Hydroxy-3-{1-[4-({(2-hydroxy-ethyl)-[2-(1H-indol-2-yl)-ethyl]-Ah1ino}-methyl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylAh1ide
29. (E)-N-Hydroxy-3-[1 -(3-pyridin-4-yl-benzenesulfonyl)-1 H-pyrrol-3-yl]-acrylAh1ide
30. (E)-N-(2-Ah1ino-phenyl)-3-[1-(3-pyridin-4-yl-benzenesulfonyl)-1 H-pyrrol-3-yl]-acrylAh1ide
31. (E)-N-(2-Ah1ino-phenyl)-3-[1-(3-pyridin-3-yl-benzenesulfonyl)-1H-pyrrol-3-ylj-acrylAh1ide
32. (E)-N-Hydroxy-3-{1-[3-(1 H-pyrazol-4-yl)-benzenesulfonyl]-1 H-pyrrol-3-yl}-acrylAh1ide and
33. (E)-N-(2-Ah1ino-phenyl)-3-{1 -[3-(1 H-pyrazol-4-yl)-benzenesulfonyl]-1 H-pyrrol-3-yl}-acrylAh1ide,or a salt thereof.

13. Compounds of formula I as claimed in claim 1 for use in the treatment of diseases.
14. A pharmaceutical composition comprising on or more compounds of formula I as claimed in claim 1 together with customary pharmaceutical excipients and/or vehicles.
15. Use of compounds of formula I as claimed in claim 1 for the manufacture of pharmaceutical compositions for treating diseases responsive or sensitive to inhibition of histone deacetylase activity.
16. Use of compounds of formula I as claimed in claim 1 for the manufacture of pharmaceutical compositions for treating benign and/or malignant neoplasia, such as e.g. cancer.
17. Use of compounds of formula I as claimed in claim 1 for the manufacture of pharmaceutical compositions for treating diseases different to malignant neoplasia, such as e.g. Ar1hropathies and osteopathological conditions, systemic lupus erythematosus, rheumatoid Ar1hritis, smooth muscle cell proliferation including vascular proliferative disorders, atherosclerosis and restenosis, or inflAh1matory conditions.
18. A method for treating diseases in a patient comprising administering to said patient a therapeutically effective and tolerable Ah1ount of a compound of formula I as claimed in claim 1.
19. A method for treating benign and/or malignant neoplasia, such as e.g. cancer, in a patient comprising administering to said patient a therapeutically effective and tolerable Ah1ount of a compound of formula I as claimed in claim 1, optionally, simultaneously, sequentially or separately with one or more further therapeutic agents.
20. A method for treating non-malignant diseases, such as e.g. Ar1hropathies and osteopathological conditions, systemic lupus erythematosus, rheumatoid Ar1hritis, smooth muscle cell proliferation including vascular proliferative disorders, atherosclerosis and restenosis, or inflAh1matory conditions, in a patient comprising administering to said patient a therapeutically effective and tolerable Ah1ount of a compound of formula I as claimed in claim 1, optionally, simultaneously, sequentially or separately with one or more further therapeutic agents.
Dated this 8th day of September, 2006

40

Abstract
Compounds of a certain formula I, in which R1, R2, R3, R4, R5, R6 and R7 have the meanings indicated in the description, are novel effective HDAC inhibitors.
To,
The Controller of Patents
The Patent Office
Mumbai.
41

Documents:

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1187-mumnp-2006-form 13(4-8-2011).pdf

1187-mumnp-2006-form 13(5-11-2008).pdf

1187-MUMNP-2006-FORM 18 3-7-2008.pdf

1187-MUMNP-2006-FORM 18(29-8-2008).pdf

1187-mumnp-2006-form 2(8-4-2009).pdf

1187-MUMNP-2006-FORM 2(GRANTED)-(21-3-2012).pdf

1187-MUMNP-2006-FORM 2(TITLE PAGE) 3-7-2008.pdf

1187-MUMNP-2006-FORM 2(TITLE PAGE)-(29-8-2008).pdf

1187-MUMNP-2006-FORM 2(TITLE PAGE)-(8-4-2009).pdf

1187-MUMNP-2006-FORM 2(TITLE PAGE)-(GRANTED)-(21-3-2012).pdf

1187-MUMNP-2006-FORM 26(22-10-2008).pdf

1187-MUMNP-2006-FORM 3 3-7-2008.pdf

1187-MUMNP-2006-FORM 3(29-8-2008).pdf

1187-MUMNP-2006-FORM 3(4-8-2011).pdf

1187-MUMNP-2006-FORM 3(8-4-2009).pdf

1187-MUMNP-2006-FORM 5 3-7-2008.pdf

1187-MUMNP-2006-FORM 5(29-8-2008).pdf

1187-mumnp-2006-form-1.pdf

1187-mumnp-2006-form-2.pdf

1187-mumnp-2006-form-26.pdf

1187-mumnp-2006-form-3.pdf

1187-mumnp-2006-form-5.pdf

1187-mumnp-2006-form-pct-isa-237.pdf

1187-MUMNP-2006-GENERAL POWER OF ATTORNEY(5-11-2008).pdf

1187-MUMNP-2006-OTHER DOCUMENT 3-7-2008.pdf

1187-MUMNP-2006-OTHER DOCUMENT(8-4-2009).pdf

1187-MUMNP-2006-PCT-IB-373(8-4-2009).pdf

1187-MUMNP-2006-PCT-ISA-237(8-4-2009).pdf

1187-mumnp-2006-pct-request.pdf

1187-mumnp-2006-pct-search report.pdf

1187-MUMNP-2006-PETITION UNDER RULE 137(8-4-2009).pdf

1187-MUMNP-2006-POWER OF ATTORNEY(6-4-2009).pdf

1187-MUMNP-2006-REPLY TO HEARING(4-8-2011).pdf

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Patent Number 251517
Indian Patent Application Number 1187/MUMNP/2006
PG Journal Number 12/2012
Publication Date 23-Mar-2012
Grant Date 21-Mar-2012
Date of Filing 05-Oct-2006
Name of Patentee 4SC AG
Applicant Address AM KLOPFERSPITZ 19A, 82152 PLANEGG- MARTINSRIED, GERMANY
Inventors:
# Inventor's Name Inventor's Address
1 GIMMNICH PETRA SONNENBUHLSTR. 58, 78464 KONSTANZ GERMANY
2 DULLWEBER FRANK MAINAUSER.209B, 78464 KONSTANZ GERMANY
3 VENNEMANN MATTHIAS LEINERSTRASSE 20, 78464 KONSTANZ GERMANY
4 MAIER THOMAS PANORAMAWEG 31, 78333 STOCKACH
5 BECKERS THOMAS AESCHENWEG 12, 78464 KONSTANZ GERMANY
6 BAR THOMAS BERGGASSLE 5, 78479 REICHENAU GERMANY
PCT International Classification Number C07D 207/48
PCT International Application Number PCT/EP05/051086
PCT International Filing date 2005-03-10
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 04101003.4 2004-03-11 EUROPEAN UNION