WO2010028862A1 - Pyrrolidin-2-ones as hdm2 ligands - Google Patents

Pyrrolidin-2-ones as hdm2 ligands Download PDF

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Publication number
WO2010028862A1
WO2010028862A1 PCT/EP2009/006670 EP2009006670W WO2010028862A1 WO 2010028862 A1 WO2010028862 A1 WO 2010028862A1 EP 2009006670 W EP2009006670 W EP 2009006670W WO 2010028862 A1 WO2010028862 A1 WO 2010028862A1
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yield
alkyl
hplc
aralkyl
formula
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PCT/EP2009/006670
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French (fr)
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Christoph Burdack
Cédric KALINSKI
Guenther Ross
Lutz Weber
Vladimir Khazak
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Priaxon Ag
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Priority to EA201100483A priority Critical patent/EA201100483A1/en
Priority to EP09778533.1A priority patent/EP2346852B1/en
Priority to NZ591073A priority patent/NZ591073A/en
Priority to CA2736295A priority patent/CA2736295A1/en
Priority to MX2011002676A priority patent/MX2011002676A/en
Priority to CN200980135970XA priority patent/CN102149708A/en
Priority to BRPI0918603A priority patent/BRPI0918603A2/en
Priority to JP2011526418A priority patent/JP5701758B2/en
Application filed by Priaxon Ag filed Critical Priaxon Ag
Priority to AU2009291155A priority patent/AU2009291155A1/en
Publication of WO2010028862A1 publication Critical patent/WO2010028862A1/en
Priority to TN2011000051A priority patent/TN2011000051A1/en
Priority to ZA2011/00789A priority patent/ZA201100789B/en
Priority to IL211756A priority patent/IL211756A0/en
Priority to MA33757A priority patent/MA32702B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Definitions

  • MDM2 (also known as HDM2) plays a central role in regulating and influencing important cell-signalling pathways.
  • HDM2 is known to interact with a range of different proteins that control cell cycle progression, cellular apoptosis, proliferation and survival.
  • HDM2 binds to the tumor suppressor protein p53 and targets this protein for ubiquitination and degradation; facilitate translocation of p53 from the nucleus to cytosole and further translocation to the proteosomes.
  • HDM2 prevents transactivation of p53 target genes that are implicated in the regulation of cell cycle and apoptosis.
  • the p53 protein is a potent cell cycle inhibitor that prevents propagation of permanently damaged cell clones by the induction of growth arrest or apoptosis, resulting in the protection against development of cancer by guarding cellular and genomic integrity.
  • Both p53 as well as HDM2 can be associated with cancer: about 50% of all human tumors harbor a mutation or deletion in the p53 gene that impairs normal p53 function. In many cancers with wild-type p53, HDM2 is overexpressed, disabling the normal p53 function (Momand et al. Nucleic Acids Res. 1998, 26, 3453-3459).
  • the HDM2 gene has a p53 -responsive promoter element and elevated levels of p53 that translocate to the nucleus induce expression of HDM2.
  • Induction of HDM2 by p53 forms an autoregulatory feedback loop, ensuring low levels of both HDM2 and p53 in normally proliferating cells (Vousden and Lu Nature Reviews Cancer 2002, 2, 594- 604).
  • this normal ratio of HDM2 to p53 is changed and misregulated.
  • Inhibiting the interaction of HDM2 with p53 in cells with wild-type p53 should lead to an increase of p53 levels in the nucleus, facilitating cell cycle arrest and/or apoptosis and restoring the tumor suppressor role of p53.
  • the feasibility of this strategy has been shown by the use of different macromolecular tools for inhibition of HDM2-p53 interaction (e.g. antibodies, antisense oligonucleotides, peptides).
  • HDM2 Besides p53, a number of proteins have been found to interact with HDM2, performing either affectors (regulating HDM2 functions) or effectors (regulated by HDM2). Totally about 20 interacting with HDM2 proteins have been described (Ganguli and Wasylyk, MoI. Cancer Research, 2003, v.l, 1027-1035), Zhu et al. MoI. Cell, 2009, 35, 316-326). Among them, HDM2 binds to the tumor suppressor pRB, as well as E2F-1 (Yang et al. Clinical Cancer Research 1999, 5, 2242-2250).
  • E2F-1 is a transcription factor that regulates S phase entry and has been shown to cause apoptosis in some cell types when overexpressed.
  • HDM2 binds to E2F through a conserved binding region at p53, activating E2F-dependent transcription of cyclin A, and suggesting that HDM2 small molecule ligands or antagonists might have also antitumor effects in cells independent of their role of restoring p53 function.
  • HDM2 can associate in vitro and in vivo with the mammalian Numb protein. The association occurs through the N-terminal domain of HDM2, which is the region also involved in p53 binding. The Numb protein is involved in the regulation of cell fate and in a variety of developmental processes, most notably in the nervous system. Through its interaction with Numb, HDM2 may influence processes such as differentiation and survival. This could also contribute to the altered properties of tumor cells, which overexpress HDM2 (Juven-Gershon et al. MoI. Cell. Biol. 1998, 18, 3974-3982).
  • HDM2 small molecules that block the HDM2 interaction with p53 also block the interaction of HDM2 with hypoxia inducible factor l ⁇ (HIF- l ⁇ ), a protein that induces vascular endothelial growth factor (VEGF) under normoxic or hypoxic conditions.
  • HIF- l ⁇ hypoxia inducible factor l ⁇
  • VEGF vascular endothelial growth factor
  • HDM2 has a direct role in the regulation of p21, a cyclin- dependent kinase inhibitor.
  • the inhibition of HDM2 with anti-HDM2 antisense oligonucleotide or Short Interference RNA targeting HDM2 significantly elevates p21 protein levels in p53 null PC3 cells.
  • overexpression of HDM2 diminishes p21 levels by shortening the p21 half-life, an effect reversed by HDM2 antisense inhibition.
  • HDM2 facilitates p21 degradation independent of ubiquitination and the E3 ligase function of HDM2.
  • HDM2 promotes p21 degradation by facilitating binding of p21 with the proteasomal C8 subunit.
  • the p21 and HDM2 bind through 180-the 298 amino acids region of the HDM2 protein (Zhang et al. J. Biol. Chem. 2004, 279, 16000-16006).
  • HDM2 Small molecule antagonists of the HDM2 protein interactions may therefore offer a viable approach towards cancer therapy, either as single agents or in combination with a broad variety of other anti-tumour therapies.
  • HDM2 plays an important role in viral infections.
  • viruses rely on changing normal p53 signalling (O'shea and Fried M. Cell Cycle 2005; Machida et al. Proc. Natl. Acad. Sci. U.S.A. 2004, 25, 101, 4262- 7).
  • HDM2 directly interacts with viral proteins, for example HDM2 is a target of simian virus 40 in cellular transformation and during lytic infection (Henning et al. J. Virol. 1997, 71, 7609-7618). Furthermore, the HDM2 protein, like p53, becomes metabolically stabilized in SV40-transformed cells. This suggests the possibility that the specific targeting of HDM2 by SV40 is aimed at preventing HDM2-directed proteasomal degradation of p53 in SV40-infected and -transformed cells, thereby leading to metabolic stabilization of p53 in these cells.
  • a trimeric LT-p53-HDM2 complex is formed with simian virus 40 large tumour antigen (LT) in SV40-transformed cells.
  • the human immunodeficiency virus type 1 encodes a potent transactivator, Tat.
  • HDM2 has been shown to interact with Tat and mediating its ubiquitination in vitro and in vivo.
  • HDM2 is a positive regulator of Tat-mediated transactivation, indicating that the transcriptional properties of Tat are stimulated by ubiquitination (Bres et al. Nat Cell Biol. 2003, 5, 754-61).
  • HDM2 inhibitors have been reported as small molecule HDM2 inhibitors. It has also been reported that HDM2 ligands have a cytoprotective effect. Thus, HDM2 inhibitors can be employed in methods of inducing cytoprotection and are useful to protect non-target cells against the harmful effects of chemotherapeutic agents.
  • the amount of HDM2 inhibitor that provides such an effect can be about 5 to about 10 fold lower than the amount needed to induce apoptosis (Koblish et al. WO03095625,
  • Pyrrolidin-2-ones are scaffolds for established therapeutic compounds such as rolipram, an antidepressant agent and oxiracetam, piracetam or nebracetam, being nootropic drugs for the Alzheimer's disease. These compounds have low toxicity, good pharmaco-kinetic properties and render the chemical class of pyrrolidin-2-ones an interesting scaffold for new drug candidates.
  • MDMX (also known as MDM4 or HDMX) is a relative of MDM2 that was identified on the basis of its ability to physically interact with p53. An increasing body of evidence, including recent genetic studies, suggests that MDMX also acts as a key negative, independent regulator of p53. Aberrant expression of MDMX may contribute to tumor formation and is observed for example in gliomas, breast cancers, retinoblastomas and in a large subset of cervical and ovarian cancer cell lines.
  • Specific MDMX antagonists should therefore be developed as a pharmaceutical product to ensure activation of 'dormant' p53 activity in tumors that retain wild-type p53.
  • MDMX is highly homologous to MDM2, it does not possess ubiquitin ligase capability and its expression level is not p53 dependent. It was shown that MDMX could inhibit p53 transcriptional activity even stronger than MDM2 and both proteins cooperate in the inactivation of p53. Therefore, to achieve full activation of p53 in tumor cells, compounds that exhibit dual specificity for MDMX and MDM2 may be superior over MDM2 or MDMX specific binders alone.
  • the structures of p53/MDMX and p53/MDM2 complexes show that both MDMX and MDM2 utilize the same p53-binding motif and many of the same residues for binding to p53.
  • the overall shape of the binding sites is similar in terms of general shape and orientation of hydrophobic binding pockets, but the exact sizes respectively depths of these pockets are somewhat different.
  • the hydrophobic cleft on which the p53 peptide binds appears slightly more flexible than in MDM2.
  • novel small molecules are described that bind to HDM2 and/or MDMX, are inhibitors of HDM2 and/or MDMX mediated biology and can be used as novel therapeutic agents, especially for the treatment of cancer and/or viral infections.
  • the present invention provides at least one compound selected from formula (I), (Ia), (Ic), (Id), (Ie) or (If) and pharmaceutically acceptable salts and esters thereof.
  • Such a compound preferably is a ligand binding to HDM2 and/or MDMX protein, inducing apoptosis and inhibiting proliferation, and having therapeutic utility in cancer therapy and prevention.
  • This therapeutic effect can be achieved by using one or more compounds of formula (I), (Ia), (Ic), (Id), (Ie) or (If) alone or in combination with other agents that are used to treat or prevent cancer.
  • One or more compounds of formula (I), (Ia), (Ic), (Id), (Ie) or (If) can also be used to treat or prevent cancer e.g. by protecting non-cancer cells from the deleterious effects of cytotoxic cancer treating drugs or radiotherapy.
  • a combination of either an antineoplastic agent or radiotherapy and a cytoprotective amount of at least one compound of formula (I), (Ia), (Ic), (Id), (Ie) or (If), and preferably one or more pharmaceutically acceptable excipients are used.
  • the compound of formula (I), (Ia), (Ic), (Id), (Ie) or (If) (also called HDM2 and/or MDMX ligand herein) is administered prior to, concurrently or after administration of the antineoplastic agent.
  • the HDM2 and/or MDMX inhibitor can be administered continuously or at repeated regular intervals.
  • a compound selected from compounds of formula (I), (Ia), (Ic), (Id), (Ie) or (If) can e.g. be used as a therapeutic agent in methods of treating stroke, myocardial infarction, ischemia, multi-organ failure, spinal cord injury, Alzheimer's Disease, injury from ischemic events, heart valvular degenerative disease or decreasing the side effects from cytotoxic agents, such as hair loss or cardio toxicity induced by doxorubicin or paclitaxel.
  • a compound selected from compounds of formula (I), (Ia), (Ic), (Id), (Ie) or (If) of the present invention can further be used to treat viral infections, especially in a pharmaceutical combination comprising a known antiviral compound.
  • the present invention is directed to a pharmaceutical composition comprising a cytoprotective amount of a compound of formula (I), (Ia), (Ic), (Id), (Ie) or (If), and one or more pharmaceutically acceptable excipients that is applied before, concomitantly and or subsequent to the treatment of a patient with a cytotoxic cancer treatment such as radiation or a cytotoxic antineoplastic agent.
  • the present invention provides one or more compounds of formula (I), (Ia), (Ic), (Id), (Ie) or (If) that are preferably small molecule ligands of the HDM2 and/or MDMX protein and prevent or reduce binding of other proteins to HDM2 and/or MDMX.
  • one or more compounds of the present invention inhibit the interaction of the HDM2 and/or MDMX protein with the p53 protein.
  • such compounds demonstrate mechanistic activity such as induction of apoptosis and inhibition of proliferation.
  • Incubation of cancer cells with one or more compounds of formula (I), (Ia), (Ic), (Id), (Ie) or (If) leads to an accumulation of p53 protein, induction of p53-regulated p21 gene, and cell cycle arrest in Gl and G2 phase, resulting in potent antiproliferative activity against wild-type p53 cells in vitro.
  • these activities were not observed in cancer cells with missing p53 at comparable compound concentrations. Therefore, the activity of HDM2 and/or MDMX antagonists is likely linked to its mechanism of action.
  • the present invention provides one or more compounds of formula (I)
  • X is sulphur, oxygen or a group of formula CH 2 , CR 4b R 4c , NH, NR 4b , SO or SO 2 or a bond;
  • Y is a group of formula CONR 6 , CH 2 NR 6 , CO, COO, CH 2 O, SO 2 NR 6 , NR 6 CO, NR 6 SO 2 , NR 53 CONR 6 , NR 6 COO, OCONR 6 , CONR 53 NR 6 , CONR 53 OR 6 , CH 2 CO CH 2 CONR 6 , CH 2 COO, COCR 53 R 6 or a bond;
  • n 1, 2, 3 or O
  • R 1 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or hetero- aralkyl radical;
  • R 2 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or hetero- aralkyl radical;
  • R 3 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or hetero- aralkyl radical;
  • R 4 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or hetero- aralkyl radical;
  • R 4b is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or hetero- aralkyl radical;
  • R 4c is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or hetero- aralkyl radical;
  • R 5 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
  • R 5a is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
  • R 6 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
  • the residues R 7 are independently from each other a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
  • the residues R 8 are independently from each other a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
  • R 1 , R 2 , R 3 , R 4 , R 4b , R 4c , R 5 , R 5a , R 6 , R 7 and R 8 together are part of an optionally substituted cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heteroaryl, aralkyl or heteroarylalkyl ring system;
  • alkyl refers to a saturated, straight-chain or branched hydrocarbon group that contains from 1 to 20 carbon atoms, preferably from 1 to 12 carbon atoms, especially from 1 to 6 (e.g. 1, 2, 3 or 4) carbon atoms, for example a methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl, 2,2-dimethylbutyl or n-octyl group.
  • alkenyl and alkynyl refer to at least partially unsaturated, straight-chain or branched hydrocarbon groups that contain from 2 to 20 carbon atoms, preferably from 2 to 12 carbon atoms, especially from 2 to 6 (e.g. 2, 3 or 4) carbon atoms, for example an ethenyl (vinyl), propenyl (allyl), iso-propenyl, butenyl, ethinyl, propinyl, butinyl, acetylenyl, propargyl, isoprenyl or hex-2-enyl group.
  • alkenyl groups have one or two (especially preferably one) double bond(s)
  • alkynyl groups have one or two (especially preferably one) triple bond(s).
  • alkyl, alkenyl and alkynyl refer to groups in which one or more hydrogen atoms have been replaced by a halogen atom (preferably F or Cl) such as, for example, a 2,2,2-trichloroethyl or a trifiuoromethyl group.
  • a halogen atom preferably F or Cl
  • heteroalkyl refers to an alkyl, alkenyl or alkynyl group in which one or more (preferably 1, 2 or 3) carbon atoms have been replaced by an oxygen, nitrogen, phosphorus, boron, selenium, silicon or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom).
  • the expression heteroalkyl furthermore refers to a carboxylic acid or to a group derived from a carboxylic acid, such as, for example, acyl, acylalkyl, alkoxy- carbonyl, acyloxy, acyloxyalkyl, carboxyalkylamide or alkoxycarbonyloxy.
  • a heteroalkyl group contains from 1 to 12 carbon atoms and from 1 to 4 hetero atoms selected from oxygen, nitrogen and sulphur (especially oxygen and nitrogen).
  • a heteroalkyl group contains from 1 to 6 (e.g. 1, 2, 3 or 4) carbon atoms and 1, 2 or 3 (especially 1 or 2) hetero atoms selected from oxygen, nitrogen and sulphur (especially oxygen and nitrogen).
  • Ci-C 6 heteroalkyl refers to a heteroalkyl group containing from 1 to 6 carbon atoms and 1, 2 or 3 heteroatoms selected from O, S and/or N (especially O and/or N).
  • Ci-C 4 heteroalkyl refers to a heteroalkyl group containing from 1 to 4 carbon atoms and 1, 2 or 3 heteroatoms selected from O, S and/or N (especially O and/or N). Furthermore, the term heteroalkyl refers to groups in which one or more hydrogen atoms have been replaced by a halogen atom (preferably F or Cl).
  • heteroalkyl groups are groups of formulae: R a -0-Y a -, R a -S-Y a -, R a -N(R b )-Y a -, R a -C0-Y a -, R a -O-CO-Y a -, R a -C0-0-Y a -, R a -CO-N(R b )-Y a -, R a -N(R b )-CO-Y a -, R a -O-CO-N(R b )-Y a -, R a -N(R b )-CO-O-Y a -, R a -N(R b )-CO-O-Y a -, R a -N(R b )-CO-N(R c )-Y a -, R a -O-CO-O-Y a -,
  • heteroalkyl groups are methoxy, trifluoromethoxy, ethoxy, n-pro- pyloxy, isopropyloxy, butoxy, tert-butyloxy, methoxymethyl, ethoxymethyl, -CH 2 CH 2 OH, -CH 2 OH, methoxyethyl, 1-methoxyethyl, 1-ethoxyethyl, 2-methoxyethyl or 2-ethoxyethyl, methylamino, ethylamino, propylamino, isopropylamino, dimethyl- amino, diethylamino, isopropylethylamino, methylamino methyl, ethylamino methyl, diisopropylamino ethyl, methylthio, ethylthio, isopropylthio, enol ether, dimethylamino methyl, dimethylamino ethyl,
  • cycloalkyl refers to a saturated or partially unsaturated (for example, a cycloalkenyl group) cyclic group that contains one or more rings (preferably 1 or 2), and contains from 3 to 14 ring carbon atoms, preferably from 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbon atoms.
  • cycloalkyl groups are a cyclopropyl, cyclobutyl, cyclopentyl, spiro[4,5]decanyl, norbornyl, cyclohexyl, cyclopentenyl, cyclohexadienyl, decalinyl, bicyclo[4.3.0]nonyl, tetraline, cyclopentylcyclohexyl, fluorocyclohexyl or cyclohex-2-enyl group.
  • heterocycloalkyl refers to a cycloalkyl group as defined above in which one or more (preferably 1, 2 or 3) ring carbon atoms have been replaced by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom).
  • a heterocycloalkyl group has preferably 1 or 2 ring(s) containing from 3 to 10 (especially 3, 4, 5, 6 or 7) ring atoms (preferably secected from C, O, N and S).
  • Examples are a piperidyl, prolinyl, imidazolidinyl, piperazinyl, morpholinyl, urotropinyl, pyrrolidinyl, tetrahydro- thiophenyl, tetrahydropyranyl, tetrahydrofuryl or 2-pyrazolinyl group and also lactames, lactones, cyclic imides and cyclic anhydrides.
  • alkylcycloalkyl refers to groups that contain both cycloalkyl and also alkyl, alkenyl or alkynyl groups in accordance with the above definitions, for example alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkenyl, alkenylcycloalkyl and alkynyl- cycloalkyl groups.
  • An alkylcycloalkyl group preferably contains a cycloalkyl group that contains one or two ring systems having from 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbon atoms, and one or two alkyl, alkenyl or alkynyl groups having 1 or 2 to 6 carbon atoms.
  • heteroalkylcycloalkyl refers to alkylcyclo alkyl groups as defined above in which one or more (preferably 1, 2 or 3) carbon atoms have been replaced by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom).
  • a heteroalkylcycloalkyl group preferably contains 1 or 2 ring systems having from 3 to 10 (especially 3, 4, 5, 6 or 7) ring atoms, and one or two alkyl, alkenyl, alkynyl or heteroalkyl groups having from 1 or 2 to 6 carbon atoms.
  • Examples of such groups are alkylheterocycloalkyl, alkylheterocycloalkenyl, alkenyl- heterocycloalkyl, alkynylheterocycloalkyl, heteroalkylcycloalkyl, heteroalkylhetero- cycloalkyl and heteroalkylheterocycloalkenyl, the cyclic groups being saturated or mono-, di- or tri-unsaturated.
  • aryl refers to an aromatic group that contains one or more rings containing from 6 to 14 ring carbon atoms, preferably from 6 to 10 (especially 6) ring carbon atoms.
  • the expression aryl refers furthermore to groups in which one or more hydrogen atoms have been replaced by fluorine, chlorine, bromine or iodine atoms or by OH, SH, NH 2 , N 3 or NO 2 groups. Examples are the phenyl, naphthyl, biphenyl, 2-fluorophenyl, anilinyl, 3-nitrophenyl or 4-hydroxyphenyl group.
  • heteroaryl refers to an aromatic group that contains one or more rings containing from 5 to 14 ring atoms, preferably from 5 to 10 (especially 5 or 6) ring atoms, and contains one or more (preferably 1, 2, 3 or 4) oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably O, S or N).
  • heteroaryl refers furthermore to groups in which one or more hydrogen atoms have been replaced by fluorine, chlorine, bromine or iodine atoms or by OH, SH, N 3 , NH 2 or NO 2 groups. Examples are pyridyl (e.g. 4-pyridyl), imidazolyl (e.g. 2-imidazolyl), phenylpyrrolyl (e.g.
  • thiazolyl isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl,thiadiazolyl, indolyl, indazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, pyridazinyl, quinolinyl, isoquinolinyl, pyrrolyl, purinyl, carbazolyl, acridinyl, pyrimidyl, 2,3 '-bifuryl, pyrazolyl (e.g. 3-pyrazolyl)
  • aralkyl refers to groups containing both aryl and also alkyl, alkenyl, alkynyl and/or cycloalkyl groups in accordance with the above definitions, such as, for example, arylalkyl, arylalkenyl, arylalkynyl, arylcycloalkyl, arylcycloalkenyl, alkylaryl- cycloalkyl and alkylarylcycloalkenyl groups.
  • aralkyls are toluene, xylene, mesitylene, styrene, benzyl chloride, o-fluoro toluene, lH-indene, tetraline, dihydronaphthalene, indanone, phenylcyclopentyl, cumene, cyclohexylphenyl, fluorene and indane.
  • An aralkyl group preferably contains one or two aromatic ring systems (1 or 2 rings) containing from 6 to 10 carbon atoms and one or two alkyl, alkenyl and/or alkynyl groups containing from 1 or 2 to 6 carbon atoms and/or a cycloalkyl group containing 5 or 6 ring carbon atoms.
  • heteroaralkyl refers to an aralkyl group as defined above in which one or more (preferably 1, 2, 3 or 4) carbon atoms have been replaced by an oxygen, nitrogen, silicon, selenium, phosphorus, boron or sulfur atom (preferably oxygen, sulfur or nitrogen), that is to say to groups containing both aryl or heteroaryl, respectively, and also alkyl, alkenyl, alkynyl and/or heteroalkyl and/or cycloalkyl and/or heterocycloalkyl groups in accordance with the above definitions.
  • a heteroaralkyl group preferably contains one or two aromatic ring systems (1 or 2 rings) containing from 5 or 6 to 10 ring carbon atoms and one or two alkyl, alkenyl and/or alkynyl groups containing 1 or 2 to 6 carbon atoms and/or a cycloalkyl group containing 5 or 6 ring carbon atoms, wherein 1, 2, 3 or 4 of these carbon atoms have been replaced by oxygen, sulfur or nitrogen atoms.
  • Examples are arylheteroalkyl, arylheterocycloalkyl, arylheterocycloalkenyl, arylalkyl- heterocycloalkyl, arylalkenylheterocycloalkyl, arylalkynylheterocycloalkyl, arylalkyl- heterocycloalkenyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroaryl- heteroalkyl, heteroarylcycloalkyl, heteroarylcycloalkenyl, hetero arylheterocycloalkyl, heteroarylheterocycloalkenyl, heteroarylalkylcycloalkyl, heteroarylheterocycloalkenyl, heteroarylalkylcycloalkyl, heteroarylalkylheterocyclo- alkenyl, heteroarylheteroalkylcycloalkyl, heteroarylheteroalky
  • This expression refers furthermore to groups that are substituted by one, two, three or more unsubstituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, C 2 -Cg heterocycloalkyl, C 6 -C 10 aryl, C 1 -Cg heteroaryl, C 7 -C 12 aralkyl or C 2 -C 11 heteroaralkyl groups.
  • Preferred substituents are F, Cl, Br, Me, OMe, CN or CF 3 .
  • all alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl and heteroaralkyl groups described herein may optionally be substituted.
  • n is 0 or 1, especially 1.
  • R 1 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or hetero- aralkyl radical;
  • R 2 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or hetero- aralkyl radical;
  • R 3 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or hetero- aralkyl radical;
  • R 4 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or hetero- aralkyl radical;
  • R 5 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
  • R 6 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or hetero- aralkyl radical;
  • R 5 and R 6 together are part of an optionally substituted heterocycloalkyl, heteroalkylcycloalkyl, heteroaryl or heteroarylalkyl ring system, and/or R and R together are part of an optionally substituted cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkylcycloalkyl, aralkyl or heteroaralkyl ring system;
  • R 1 is a cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl radical.
  • R 1 is an aryl, heteroaryl, aralkyl or heteroaralkyl radical.
  • R 1 is a group of formula -A-Ar or -A-Cy (especially -A-Ar) wherein A is a bond, Ci-C 4 alkyl (especially a bond, CH 2 or CH(CH 3 )) or C 1 -C 6 heteroalkyl (e.g.
  • A is a group of formula -CHR 1 a - wherein R la is a Ci-C 6 heteroalkyl group, Cy is an optionally substituted C 3 -C 7 cycloalkyl group or an optionally substituted heterocycloalkyl group containing from 3 to 7 ring atoms and Ar is an optionally substituted (e.g. by 1, 2 or 3 substituents) phenyl ring or an optionally substituted (e.g.
  • heteroaryl ring containing 5 or 6 ring atoms especially including from 1 to 3 heteroatoms selected from O, S and N
  • Ar is an optionally substituted phenyl or an optionally substituted pyridyl residue (e.g. a 4-bromobenzyl residue).
  • Preferred substituents are F, Cl, Br, CN, CH 3 , OCH 3 and CF 3 .
  • R 1 is a group of formula -A-Ar wherein A is a bond or Ci-C 4 alkyl (especially a bond, CH 2 or CHCH 3 ) and Ar is an optionally substituted (e.g. by 1 , 2 or 3 substituents) phenyl ring or an optionally substituted (e.g. by 1, 2 or 3 substituents) heteroaryl ring containing 5 or 6 ring atoms (especially containing from 1 to 3 heteroatoms selected from O, S and N), especially preferably Ar is an optionally substituted phenyl or an optionally substituted pyridyl residue (e.g. a 4-bromobenzyl residue).
  • R 1 is a group of formula -A-phenyl (especially -CH 2 -phenyl) which is optionally substituted, preferably by one or two halogen atoms selected from F, Cl and Br and wherein A is preferrably a group of formula -CHR 1 a - wherein R a is a C 1 - C 6 heteroalkyl group (e.g. COOH, CH 2 COOH)
  • R 1 is cyclopropylmethyl, picolyl, phenylbenzyl or phenoxybenzyl, all of which may optionally be substituted.
  • R 3 is Ci-C 6 alkyl, an aryl (especially phenyl), heteroaryl, aralkyl or heteroaralkyl residue, all of which may be substituted (e.g. by 1, 2 or 3 substituents).
  • R 3 is an optionally substituted phenyl group, an optionally substituted benzyl group or an optionally substituted heteroaryl residue having 1 or 2 rings and from 5 to 10 ring atoms (especially 2 rings and a total of 9 ring atoms) including 1, 2, 3 or 4 heteroatoms selected from O, S and N (especially N).
  • Preferred substituents are F, Cl, Br, Ci-C 4 alkyl groups (e.g. CH 3 ) and Ci-C 6 heteroalkyl groups (e.g. CH 2 SO 3 " , (CH 2 ) 5 NH 2 ).
  • E is N or CH
  • R 3a is H, Ci-C 6 alkyl or Ci-C 6 heteroalkyl (especially H or CH 3 ),
  • R 3b is H, F, Cl, Br, CH 3 , OCH 3 or CF 3 and R 3c is H, F, Cl, Br, CH 3 , OCH 3 or CF 3 (especially preferably, E is CH, R 3a is H, R 3b is Cl and R 3c is H).
  • R 3 is an aryl (especially phenyl), heteroaryl, aralkyl or heteroaralkyl residue, all of which may be substituted (e.g. by 1, 2 or 3 substituents); especially preferably, R 3 is an optionally substituted heteroaryl residue having 1 or 2 rings and from 5 to 10 ring atoms (especially 2 rings and a total of 9 ring atoms) including 1, 2, 3 or 4 heteroatoms selected from O, S and N (especially N).
  • E is N or CH
  • R 3a is H or CH 3
  • R 3b is F, Cl or Br
  • R 3c is H, F, Cl or Br (especially preferably, E is CH, R 3a is H, R 3b is Cl and R 3c is H).
  • R 2 and R 3 together are part of an optionally substituted heterocycloalkyl or heteroaralkyl ring. Moreover preferred, R 2 and R 3 together are part of a group having the following structure:
  • R 4 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, optionally substituted C 1 -C 4 alkyl-C 3 -C 7 cycloalkyl, an optionally substituted phenyl ring, an optionally substituted benzyl group or an optionally substituted heteroaryl ring having 5 or 6 ring atoms including from 1 to 3 heteroatoms selected from O, S and N (e.g. pyridyl).
  • R 4 is a phenyl ring which is substituted by 1 or 2 substituents, preferably selected from F, Br, Cl, I, NO 2 , methyl or cyanide (e.g. 4-methylphenyl), or an unsubstituted phenyl ring.
  • R 4 is phenyl or 4-methylphenyl.
  • R 4 is C 1 -C 6 alkyl or an optionally substituted phenyl ring or an optionally substituted heteroaryl ring having 5 or 6 ring atoms and containing from 1 to 3 heteroatoms selected from O, S and N.
  • R 4 is a phenyl ring which is substituted by 1 or 2 substituents, preferably selected from F, Br, Cl, I, methyl or cyanide (e.g. 4-methylphenyl).
  • R 5 is an alkyl, hetero- alkyl, heterocycloalkyl, heteroalkylcycloalkyl or heteroaralkyl group, all of which groups may be substituted.
  • R 5 is selected from the following groups: Ci-C 6 alkyl; heteroalkyl containing 1-6 carbon atoms and 1, 2 or 3 heteroatoms selected from O, S and N; heteroalkylcycloalkyl comprising a C 1 -C 4 alkyl group or a Ci-C 4 heteroalkyl group and an optionally substituted heterocycloalkyl group containing 5 or 6 ring atoms and 1 , 2 or 3 heteroatoms selected from O, S and N; heteroaralkyl comprising a C 1 -C 4 alkyl group or a Ci-C 4 heteroalkyl group and an optionally substituted heteroaryl group containing 5 or 6 ring atoms including 1, 2 or 3 heteroatoms selected from O, S and N; optionally substituted heteroaryl containing 5 or 6 ring atoms including 1, 2 or 3 heteroatoms selected from O, S and N; and optionally substituted heterocycloalkyl containing 5 or 6 ring
  • R 5 is Ci-C 6 alkyl; heteroalkyl containing 1-6 carbon atoms and 1, 2 or 3 heteroatoms selected from O, S, N; heteroalkylcycloalkyl comprising a Ci-C 4 alkyl group and an optionally substituted heterocycloalkyl group containing 5 or 6 ring atoms and 1, 2 or 3 heteroatoms selected from O, S and N; heteroaralkyl comprising a Cj-C 4 alkyl group and an optionally substituted heteroaryl group containing 5 or 6 ring atoms and 1 , 2 or 3 heteroatoms selected from O, S and N.
  • heterocycloalkyl ring containing 4, 5, 6 or 7 ring atoms and 1, 2 or 3 heteroatoms selected from O, S and N.
  • R 5 and R 6 together with the nitrogen atom to which they are bound form the following group: — N Q
  • Q is N-CO-R 6a , NR 6b or CHR 6c wherein R 6a is C r C 6 alkyl, C 1 -C 6 0 heteroalkyl, NH 2 , optionally substituted phenyl or hydrogen; R 6b is optionally substituted phenyl or optionally substituted heteroaryl containing 5 or 6 ring atoms including one or two heteroatoms selected from O, S or N; R 6c is Cj-C 6 heteroalkyl, NH 2 or OH.
  • Q is N-CO-NHR 6d , N-COOR 6e , N-SO 2 R 6f , N-SO 2 NHR 6g , N- NHCOR 6h , CH-NH 2 , CH-OH, CH-SH, CH-NH-COR 6i , CO, CONH, NHCONH, SO 2 NH, OCONH, CH-COOH, CH-COOR 6j , CH-COR 6k or CH-SO 2 R 61 , wherein R 6d , R 6e , R 6f , R 6g , R 6h , R 6i , R 6j , R 6k and R 61 independently from each other are a hydrogen atom, OH, NH 2 , SH or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, O cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aral
  • Q is N-CO-R 6a wherein R 6a is preferably NH 2 , Ci-C 6 alkyl, NH-Ci-C 6 alkyl Or N(C 1 -C 6 alkyl) 2 . 5
  • group Q contains a hydrogen bond acceptor (especially an atom or group having a lone electron pair like e.g. an electronegative atom such as fluorine, oxygen, or nitrogen).
  • a hydrogen bond acceptor especially an atom or group having a lone electron pair like e.g. an electronegative atom such as fluorine, oxygen, or nitrogen.
  • o is 1 and m is 1.
  • m is 1
  • Q is N-C0-R 6a .
  • R 6a is preferably Ci-C 4 alkyl or NH-Cj-C 4 alkyl (e.g. CH 3 or NHCH 2 CH 3 ).
  • R 5 and R 6 together are part of an optionally substituted (e.g. by 1, 2 or 3 substituents) heterocycloalkyl ring containing 5 or 6 ring atoms and 1 , 2 or 3 heteroatoms selected from O, S and N
  • W is an optionally substituted phenyl ring or an optionally substituted heteroaryl group having 5 or 6 ring atoms including 1 or 2 heteroatoms selected from O, S and N; and wherein R 1 , R 3a , R 4 , R 5 , R 7 , R 8 , E, X, Y and n are defined as above.
  • W is an optionally substituted phenyl ring (preferably substituted by 1 , 2 or 3 halogen atoms selected from F, Cl and Br);
  • R 1 is an optionally substituted benzyl group (preferably substituted by 1, 2 or 3 halogen atoms selected from F, Cl and Br);
  • X is S;
  • Y is CONR 6 ;
  • n is 1;
  • R 3a is hydrogen;
  • R 4 is an optionally substituted phenyl group (preferably unsubstituted or substituted by a methyl group, especially in the para position);
  • R 7 and R 8 are hydrogen;
  • E is CH; and
  • R 5 and R 6 are defined as above; especially preferably, R 5 and R 6 together are part of an optionally substituted piperazine ring (especially as defined above).
  • R 1 , R 3a , R 3b , R 3c , R 4 , R 5 , R 6 , E and X are defined as above.
  • R 1 is an optionally substituted benzyl group (preferably substituted by 1 , 2 or 3 halogen atoms selected from F, Cl and Br);
  • X is S;
  • R 3a is hydrogen;
  • R 3b is Cl;
  • R 3c is hydrogen,
  • R 4 is an optionally substituted phenyl group (preferably unsubstituted or substituted by a methyl group, especially in the para position);
  • E is CH; and
  • R 5 and R 6 are defined as above; especially preferably, R 5 and R 6 together are part of an optionally substituted piperazine ring (especially as defined above).
  • R 1 is an optionally substituted benzyl group (preferably substituted by 1 , 2 or 3 halogen atoms selected from F, Cl and Br);
  • X is S;
  • R 3a is hydrogen;
  • R 3b is Cl;
  • R 3c is hydrogen,
  • R 4 is an optionally substituted phenyl group (preferably unsubstituted or substituted by a methyl group, especially in the para position);
  • E is CH;
  • Q is N-CO-R 6a wherein R 6a is preferably C 1 -C 6 alkyl, NH-C 1 -C 6 alkyl or N(Ci-C 6 alkyl) 2 ;
  • m is 0, 1 or 2;
  • o is 0, 1 or 2; and the sum of m and o is preferably from 0 to 3.
  • m is 1, o is 1 and Q is N-CO-R 6a , wherein R 6a is preferably Ci-C 4 alkyl or NH-Ci-C 4 alkyl (e.g. CH 3 or NHCH 2 CH 3 ).
  • R 1 is aryl, heteroaryl, arylalkyl or heteroarylalkyl, all of which may be substituted by F, Br, Cl, I, methyl or cyanide, R 2 is hydrogen,
  • R 3 is aryl, heteroaryl, arylalkyl or heteroarylalkyl, all of which may be substituted by F, Br, Cl, I, methyl or cyanide
  • R 4 is aryl, heteroaryl, arylalkyl or heteroarylalkyl
  • R 5 and R 6 are independently selected from hydrogen, alkyl, heteroalkyl, aryl, alkenyl, akinyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, or wherein R 5 and R 6 may be part of one heteroaryl, heterocycloalkyl, heteroalkylcycloalkyl or heteroarylalkyl ring system, and wherein the other residues and groups are defined as above.
  • a further preferred embodiment of the present invention relates to compounds of formula (I) or (Ia), wherein
  • R 1 is aryl, heteroaryl, arylalkyl or heteroarylalkyl, all of which may be substituted by F,
  • R 2 and R 3 together are part of a heteroaryl, heteroaralkyl, heterocycloalkyl or heteroalkylcycloalkyl ring system such as but not restricted to 1 ,3-dihydroindole, 1 ,3- dihydro-indol-2-one, 2,3-dihydro-lH-indazole, tetrahydro-quinoline, tetrahydro- quinoline-2-one, 3,4-dihydro-lH-quinolin-2-one, 3,4-dihydro-lH-quinazolin-2-one, all of which may be substituted by F, Br, Cl, I, methyl or cyanide,
  • R 4 is selected from aryl, heteroaryl, arylalkyl or heteroarylalkyl
  • R 5 and R 6 are independently selected from hydrogen, alkyl, heteroalkyl, aryl, alkenyl, akinyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, or wherein R 5 and R 6 may also be part of one heteroaryl, heterocycloalkyl, heteroalkylcycloalkyl or heteroarylalkyl ring system, and wherein the other residues and groups are defined as above.
  • a further preferred embodiment of the present invention relates to compounds of formula (I), (Ia), (Ic), (Id), (Ie) or (If), wherein R 3 and the sulfanyl group (i.e. the group carrying X) bearing the R 4 group are in cis position (especially when R 2 is H).
  • An especially preferred embodiment are enantiomerically pure compounds of formula (I), (Ia), (Ic), (Id), (Ie) or (If).
  • R 3 is p-C 6 H 5 CH 2 OH (or a derivative thereof which is bound to the solid phase as described in Ng et al. Angew. Chem. Int. Ed. 2007, 46, 5352-5355), R 1 is selected from the following groups:
  • R ,4 is para-C 6 H 5 CH 3 and R is selected from the following groups:
  • the present invention further provides pharmaceutical compositions comprising a compound of formula (I), (Ia), (Ic), (Id), (Ie) or (If) as defined herein or a pharmaceutically acceptable ester, prodrug, hydrate, solvate or salt thereof, optionally in combination with a pharmaceutically acceptable carrier.
  • a further preferred embodiment of the present invention relates to pharmaceutical compositions comprising one or more compounds of formula (I), (Ia), (Ic), (Id), (Ie) or (If) as defined herein or a pharmaceutically acceptable ester, prodrug, hydrate, solvate or salt thereof, optionally in combination with a pharmaceutically acceptable carrier, further comprising one or more other anti-tumor agents, wherein the anti-tumor agent is especially selected from 16-Aza-epothilone B, Aldesleukin, Amifostine, Aranose, Bevacizumab, Bleocin, Bleomycin, BMS- 184476, Bortezomib, Calcitriol, Carmustine, Canertinib, Canfosfamide, Capecitabine, Carboplatin, Carmustine, Cefixime, Ceftriaxone, Celecoxib, Celmoleukin, Cetuximab, Ciclosporin, Cisplatin, Clodronate, Cyclophospham
  • the compounds of the present invention sensibilize cancer cells for radio and/or chemotherapy whereas they display chemoprotective and/or radioprotective activity on healthy cells. Thereby the dosage of these therapies can be better adjusted.
  • a further preferred embodiment of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more compounds of formula (I), (Ia), (Ic), (Id), (Ie) or (If) as defined herein or one or more pharmaceutically acceptable esters, prodrugs, hydrates, solvates or salts thereof, optionally in combination with a pharmaceutically acceptable carrier.
  • the pharmaceutical composition optionally comprises one or more antiviral agents.
  • the antiviral agent is selected from 3TC, Abacavir, Adefovir Dipivoxil, Acyclovir, Amprenavir, Amantadine, Amoxovir, AZT, Clevudine, Delavirdine, d4T, Emtricitabine, Entecavir, Famciclovir, Ganciclovir, Indinavir, Lamivudine, Nelfinavir, Nevirapine, Oseltamavir, Rimantadine, Ritonavir, Saquinavir, Septrin, Telbivudine, Tenofovir, Valacyclovir, Valtorcitabine, Valopicitabine or
  • Zanamivir It is a further object of the present invention to provide a compound of formula (I), (Ia), (Ic), (Id), (Ie) or (If) as defined herein or a pharmaceutical composition as defined herein for the preparation of a medicament for the treatment of cancer and/or viral infections
  • the compounds selected from formula (I), (Ia), (Ic), (Id), (Ie) or (If) of the present invention are e.g. HDM2 and/or MDMX ligands and show binding affinities from about 1 nM to about 100 ⁇ M to HDM2 and/or MDMX, preferably from about 1 nM to about 10 ⁇ M, especially to about 1 ⁇ M, preventing binding of p53 and other proteins, inhibition of proliferation and induction of apoptosis in cell based assays, especially in the assays described herein.
  • HDM2 and/or MDMX ligands show binding affinities from about 1 nM to about 100 ⁇ M to HDM2 and/or MDMX, preferably from about 1 nM to about 10 ⁇ M, especially to about 1 ⁇ M, preventing binding of p53 and other proteins, inhibition of proliferation and induction of apoptosis in cell based assays, especially in the assays described herein.
  • the compounds of the present invention are useful in the treatment or control of cell proliferative disorders, in particular oncological disorders. These compounds and formulations containing said compounds are useful in the treatment or control of solid tumors, such as, for example, breast, colon, lung and prostate tumors, as well as osteosarcoma, acute myeloid leukaemia, sporadic endometrial cancer, melanoma, malignant melanoma, soft tissue Sarcoma, B-cell chronic lymphocytic leukaemia, gastric cancers, cervical cancer, hepatocellular carcinoma, and colorectal cancer.
  • solid tumors such as, for example, breast, colon, lung and prostate tumors, as well as osteosarcoma, acute myeloid leukaemia, sporadic endometrial cancer, melanoma, malignant melanoma, soft tissue Sarcoma, B-cell chronic lymphocytic leukaemia, gastric cancers, cervical cancer, hepatocellular carcinoma, and colorectal cancer.
  • the compounds described herein are especially useful for the treatment and/or prevention of cancers associated with overexpression of HDM2 and/or MDMX.
  • the compounds of the present invention are especially useful for the treatment and/or prevention of the following cancers associated with MDM2 and/or
  • MDM2 is amplified in 7% of all human cancers. Gene amplification was observed in 19 tumor types, with the highest frequency observed in soft tissue tumors (20%), osteosarcomas (16%) and esophageal carcinomas (13%). Tumors which showed a higher incidence of MDM2 amplification than p53 mutation were soft tissue tumors, testicular germ cell cancers and neuro-blastomas (Momand et al, NAR, 1998). Naturally occurring polymorphism (SNP309) occurring within the MDM2 promoter leads to an increase in MDM2 transcription and translation. The overall frequency of MDM2 amplification in these human tumors was 7%. It is a common event in hematological malignancies.
  • a list of cancers with a wild type of p53 gene that is sensitive to MDM2 inhibitors includes: B-cell CLL (chronic lymphocytic leukemia) (Coll-Muler et al, Blood, 2006), AML (Kojima et al, Blood, 2005), multiple myeloma (Shruhmer et al, Blood, 2005), neuroblastoma (Cattelani et al, CCR, 2008), Hodgkin lymphoma (Drakos et al, CCR, 2007), osteosarcoma and prostate cancer (Vassilev et al, Science, 2004), Kaposi's sarcoma (Sarek, J. Clinic.
  • B-cell CLL chronic lymphocytic leukemia
  • AML Kerojima et al, Blood, 2005
  • multiple myeloma Shruhmer et al, Blood, 2005
  • neuroblastoma Cattelani et al, CCR, 2008
  • Total number of tumor samples analyzed was 3889 and the average MDM2 gene amplification frequency was 7.2%. aNumber of samples analyzed. b Sarcomas of soft tissue origin that were not specified. cSoft tissue tumors that did not fall into the listed classes. The number of samples was less than five in any individual class.
  • a therapeutically effective amount of a compound in accordance with this invention means an amount of compound that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is within the skill in the art.
  • the therapeutically effective amount or dosage of a compound according to this invention can vary within wide limits and may be determined in a manner known in the art. Such dosage may be adjusted to the individual requirements in each particular case including the specific compound being administered, the route of administration, the condition being treated, as well as the patient being treated.
  • Examples of pharmacologically acceptable salts of sufficiently basic compounds of formula (I), (Ia), (Ic), (Id), (Ie) or (If) are salts of physiologically acceptable mineral acids like hydrochloric, hydrobromic, sulfuric and phosphoric acid; or salts of organic acids like methanesulfonic, p-toluenesulfonic, lactic, acetic, trifluoroacetic, citric, succinic, fumaric, maleic and salicylic acid.
  • a sufficiently acidic compound of formula (I), (Ia), (Ic), (Id), (Ie) or (If) may form alkali or earth alkali metal salts, for example sodium, potassium, lithium, calcium or magnesium salts; ammonium salts; or organic base salts, for example methylamine, dimethylamine, trimethylamine, triethylamine, ethylenediamine, ethanolamine, choline hydroxide, meglumin, piperidine, morpholine, tris-(2-hydroxyethyl)amine, lysine or arginine salts; all of which are also further examples of salts of formula (I), (Ia), (Ic), (Id), (Ie) or (If).
  • alkali or earth alkali metal salts for example sodium, potassium, lithium, calcium or magnesium salts; ammonium salts; or organic base salts, for example methylamine, dimethylamine, trimethylamine, triethylamine, ethylenediamine, ethanolamine, cho
  • Compounds of formula (I), (Ia), (Ic), (Id), (Ie) or (If) may be solvated, especially hydrated.
  • the hydratization/hydration may occur during the process of production or as a consequence of the hygroscopic nature of the initially water free compounds of formula (I), (Ia), (Ic), (Id), (Ie) or (If).
  • the solvates and/or hydrates may e.g. be present in solid or liquid form.
  • the compounds of formula (I), (Ia), (Ic), (Id), (Ie) or (If) may contain asymmetric C-atoms, they may be present either as achiral compounds, mixtures of diastereomers, mixtures of enantiomers or as optically pure compounds.
  • the present invention comprises both all pure enantiomers and all pure diastereomers, and also the mixtures thereof in any mixing ratio.
  • compositions according to the present invention comprise at least one compound of formula (I), (Ia), (Ic), (Id), (Ie) or (If) as an active ingredient and, optionally, carrier substances and/or adjuvants.
  • the present invention also relates to pro-drugs which are composed of a compound of formula (I), (Ia), (Ic), (Id), (Ie) or (If) and at least one pharmacologically acceptable protective group which will be cleaved off under physiological conditions, such as an alkoxy-, arylalkyloxy-, acyl-, acyloxymethyl group (e.g. pivaloyloxymethyl), an 2- alkyl-, 2-aryl- or 2-arylalkyl-oxycarbonyl-2-alkylidene ethyl group or an acyloxy group as defined herein, e.g.
  • therapeutically useful agents that contain compounds of formula (I), (Ia), (Ic), (Id), (Ie) or (If), their solvates, salts or formulations are also comprised in the scope of the present invention.
  • compounds of formula (I), (Ia), (Ic), (Id), (Ie) or (If) will be administered by using the known and acceptable modes known in the art, either alone or in combination with any other therapeutic agent.
  • oral administration such therapeutically useful agents can be administered by one of the following routes: oral, e.g.
  • TDS transdermal delivery system
  • the therapeutically useful product may be mixed with pharmaceutically inert, inorganic or organic excipients as are e.g. lactose, sucrose, glucose, gelatine, malt, silica gel, starch or derivatives thereof, talc, stearinic acid or their salts, dried skim milk, and the like.
  • pharmaceutically inert, inorganic or organic excipients as are e.g. lactose, sucrose, glucose, gelatine, malt, silica gel, starch or derivatives thereof, talc, stearinic acid or their salts, dried skim milk, and the like.
  • excipients e.g. vegetable, petroleum, animal or synthetic oils, wax, fat, polyols.
  • liquid solutions, emulsions or suspensions or syrups one may use as excipients e.g.
  • excipients e.g. vegetable, petroleum, animal or synthetic oils, wax, fat and polyols.
  • compressed gases suitable for this purpose as are e.g. oxygen, nitrogen and carbon dioxide.
  • the pharmaceutically useful agents may also contain additives for conservation, stabilization, e.g. UV stabilizers, emulsifiers, sweetener, aromatizers, salts to change the osmotic pressure, buffers, coating additives and antioxidants.
  • additives for conservation stabilization, e.g. UV stabilizers, emulsifiers, sweetener, aromatizers, salts to change the osmotic pressure, buffers, coating additives and antioxidants.
  • the daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it may be given as continuous infusion or subcutaneous injection.
  • the compounds of the present invention can be prepared according to the following procedure:
  • the synthesis of the 4-sulfanyl-pyrrolidin-2-one scaffold is based on a four-component reaction (4CR) between a primary amine (II), an aldehyde or ketone (III) with maleic anhydride (IV), and a thiol (V).
  • the reaction is preferably performed in toluene at reflux with a stoichiometric amount of the starting materials, according to J. Wei, J. T. Shaw Org. Lett. 2007, 9, 4077.
  • the resulting 4-sulfanyl-pyrrolidin-2-one (VI) is formed in acceptable to good yields as a diastereoisomeric mixture.
  • reaction procedures described herein may also be carried out in the presence of a chiral catalyst like e.g. proline-derived catalysts (as e.g. described in www.organic-chemistry.org/Highlights/2007/25March.shtm) in order to obtain the corresponding enantiomerically pure compounds.
  • a chiral catalyst like e.g. proline-derived catalysts (as e.g. described in www.organic-chemistry.org/Highlights/2007/25March.shtm) in order to obtain the corresponding enantiomerically pure compounds.
  • the present invention encompasses the following Examples:
  • Preparative separations were usually performed with an acetonitrile-water eluent (+0.1 % formic acid) on a RP Polaris Cl 8 column (length: 250 mm, diameter: 21 mm; particle size: 5 ⁇ m). Generally, good separations were observed (retention times of the two cis/trans diasteroisomers differed by 1 to 2 minutes) by using isocratic systems (70 % acetonitrile: 30 % water).
  • Bodanszky A. Bodanszky, The practice of Peptide Synthesis 2nd Edition, p 102, Springer- Verlag Berlin Heidelberg New York (1994).
  • IR 3397, 3174, 2923, 1674, 1625, 1535, 1487, 1401, 1361, 1241, 1174, 1118, 1002, 794.
  • alpha-benzylsuccinic acid 9 (Ig, 4,8 mmol) was refluxed for Ih in 30 mL trifluoroacetic anhydride. Afterwards, the solvent was removed in vacuo. The crude residue was washed with cold hexane to yield alpha-benzylsuccinic anhydride 10 as a white solid (858.2mg, 93.95 %). Multicomponent reaction
  • l-Phenyl-2,5-dihydro-lH-pyrrole-2,5-dione 19 (5.19 g, 3 mmol), p-cresol 20 (3.24 g, 3 mmol), and triethylamine (3.03 g, 3 mmol) were added in 20 ml toluene extra dry and heated at 100°C for 6h. Afterwards, the mixture was cooled to 0°C. The precipitated solid was filtered and washed with cold toluene and hexane to yield compound 21 as a purple solid (2.895 g, 34.30 %).
  • the obtained alcohol can be oxidized to the corresponding aldehyde (Swern oxidation).
  • this aldehyde can also be obtained by selective reduction of the carboxylic acid.
  • the aldehyde can be converted to numerous further compounds.
  • PXN717-dl has been treated with BMS (dimethylsulfide borane) yielding a mixture of the two compounds PXN723-dl and PXN724-dl.
  • BMS dimethylsulfide borane
  • compounds of formula (I) can be prepared wherein R and/or R are other than hydrogen (see also Org. Lett.2007, 9(20), 4077-4080).
  • PXN736-dl has been treated with 1,1 eq of natrium hydride at room temperature. Thereby, elimination product PXN847-dl has been isolated and characterized by HPLC-MS. This Product can be used for further modifications (for example Michael- addition).
  • compounds of formulas (I), (Ia), (Ic), (Id), (Ie) and (If) may be prepared following the procedures described e.g. in: Synlett, (11), 1883-1885, 2002; Organic Letters, 9(20), 4077-4080, 2007; Organic Letters, 8(18), 3999-4002, 2006; Tetrahedron, 50(36), 10701-8, 1994; Journal of the Chemical Society, Chemical Communications, (5), 386-7, 1987; Journal of the Chemical Society, Chemical Communications, (5), 386-7, 1987; Tetrahedron Letters, 49(35), 5217-5219, 2008 and Journal of Organic Chemistry, 73(14), 5566-5569, 2008.
  • reaction mixture was poured in a mixture of 15g ice in 10 mL water under stirring.
  • 3.4g NaOH in 18 mL were added between in a temperature range between 20 and 30 0 C.
  • the resulting mixture was then refluxed for 5 minutes.
  • the precipitate was filtered off and washed with 10 mL cold water. Crystallization from ethanol yielded ⁇ -chloro-lH-indole-S-carbaldehyde as a white solid (1.04 g, 88%).
  • PA-I or PA-1/E6 cells were plated in each well of 96-well flat bottom plates, and incubated overnight at 37 0 C in 5% CO 2 .
  • the growth of plated cells was measured by adding 7.5 microMol of WST-I reagent (Roche Applied Sciences, Germany) to 3 control wells and measuring the OD 650 and OD 450 absorbances with a SpectraMax250 plate reader. If the OD 650 -OD 45O values were above 0.5, the remainder of the plate was used for incubation with the compounds of formula (I), (Ia), (Ic), (Id), (Ie) or (If), other pharmacological agents or solvent controls for 48 hours.
  • Annexin V and BrdU-incorporation levels were determined with Guava Nexin and Guava Tunel kits using a Guava Personal Cell Analysis System (PCAS, Guava Technologies, Hayward, CA) according to the manufacturer's instruction. 1x10 6 PA-I and PA-1/E6 cells were cultured in BME media supplemented with 10%FBS and various concentrations of the compounds of formula (I) or DMSO for 24 h. Nutlin-3, racemic (Calbiochem, Roche) at 10 ⁇ M was applied as positive control. For the Guava Nexin assay, cells were trypsinized and collected by centrifuging at 1000 rpm for 5 min at 4 °C.
  • Temperature-sensitive H 1299 clones were seeded onto 6-well plates at a density of

Abstract

The present invention provides compounds of formula (I) or (Ia) which are ligands binding to the HDM2 protein, inducing apoptosis and inhibiting proliferation, and having therapeutic utility in cancer therapy and prevention. Compounds of formula (I) or (Ia) can be used as therapeutics for treating stroke, myocardial infarction, ischemia, multi-organ failure, spinal cord injury, Alzheimer's Disease, injury from ischemic events and heart valvular degenerative disease. Moreover, compounds of formula (I) or (Ia) can be used to decrease the side effects from cytotoxic cancer agents, radiation and to treat viral infections.

Description

PYRROLIDIN-2-ONES AS HDM2 LIGANDS
BACKGROUND OF THE INVENTION
MDM2 (also known as HDM2) plays a central role in regulating and influencing important cell-signalling pathways. HDM2 is known to interact with a range of different proteins that control cell cycle progression, cellular apoptosis, proliferation and survival.
Thus, amongst other proteins, HDM2 binds to the tumor suppressor protein p53 and targets this protein for ubiquitination and degradation; facilitate translocation of p53 from the nucleus to cytosole and further translocation to the proteosomes. Thereby, HDM2 prevents transactivation of p53 target genes that are implicated in the regulation of cell cycle and apoptosis. The p53 protein is a potent cell cycle inhibitor that prevents propagation of permanently damaged cell clones by the induction of growth arrest or apoptosis, resulting in the protection against development of cancer by guarding cellular and genomic integrity.
Both p53 as well as HDM2 can be associated with cancer: about 50% of all human tumors harbor a mutation or deletion in the p53 gene that impairs normal p53 function. In many cancers with wild-type p53, HDM2 is overexpressed, disabling the normal p53 function (Momand et al. Nucleic Acids Res. 1998, 26, 3453-3459).
The HDM2 gene has a p53 -responsive promoter element and elevated levels of p53 that translocate to the nucleus induce expression of HDM2. Induction of HDM2 by p53 forms an autoregulatory feedback loop, ensuring low levels of both HDM2 and p53 in normally proliferating cells (Vousden and Lu Nature Reviews Cancer 2002, 2, 594- 604). However, in many cancers this normal ratio of HDM2 to p53 is changed and misregulated.
Inhibiting the interaction of HDM2 with p53 in cells with wild-type p53 should lead to an increase of p53 levels in the nucleus, facilitating cell cycle arrest and/or apoptosis and restoring the tumor suppressor role of p53. The feasibility of this strategy has been shown by the use of different macromolecular tools for inhibition of HDM2-p53 interaction (e.g. antibodies, antisense oligonucleotides, peptides).
Besides p53, a number of proteins have been found to interact with HDM2, performing either affectors (regulating HDM2 functions) or effectors (regulated by HDM2). Totally about 20 interacting with HDM2 proteins have been described (Ganguli and Wasylyk, MoI. Cancer Research, 2003, v.l, 1027-1035), Zhu et al. MoI. Cell, 2009, 35, 316-326). Among them, HDM2 binds to the tumor suppressor pRB, as well as E2F-1 (Yang et al. Clinical Cancer Research 1999, 5, 2242-2250).
E2F-1 is a transcription factor that regulates S phase entry and has been shown to cause apoptosis in some cell types when overexpressed. HDM2 binds to E2F through a conserved binding region at p53, activating E2F-dependent transcription of cyclin A, and suggesting that HDM2 small molecule ligands or antagonists might have also antitumor effects in cells independent of their role of restoring p53 function.
HDM2 can associate in vitro and in vivo with the mammalian Numb protein. The association occurs through the N-terminal domain of HDM2, which is the region also involved in p53 binding. The Numb protein is involved in the regulation of cell fate and in a variety of developmental processes, most notably in the nervous system. Through its interaction with Numb, HDM2 may influence processes such as differentiation and survival. This could also contribute to the altered properties of tumor cells, which overexpress HDM2 (Juven-Gershon et al. MoI. Cell. Biol. 1998, 18, 3974-3982).
Similarly, small molecules that block the HDM2 interaction with p53 also block the interaction of HDM2 with hypoxia inducible factor lα (HIF- lα), a protein that induces vascular endothelial growth factor (VEGF) under normoxic or hypoxic conditions. As VEGF is proangiogenic, inhibition of HDM2 by small molecules will also prevent blood vessel formation to cancer metastases and primary tumors (G. A. LaRusch et al.
Cancer Res. 2007, 67, 450-454). There is also evidence that HDM2 has a direct role in the regulation of p21, a cyclin- dependent kinase inhibitor. The inhibition of HDM2 with anti-HDM2 antisense oligonucleotide or Short Interference RNA targeting HDM2 significantly elevates p21 protein levels in p53 null PC3 cells. In contrast, overexpression of HDM2 diminishes p21 levels by shortening the p21 half-life, an effect reversed by HDM2 antisense inhibition. HDM2 facilitates p21 degradation independent of ubiquitination and the E3 ligase function of HDM2. Instead, HDM2 promotes p21 degradation by facilitating binding of p21 with the proteasomal C8 subunit. The p21 and HDM2 bind through 180-the 298 amino acids region of the HDM2 protein (Zhang et al. J. Biol. Chem. 2004, 279, 16000-16006).
There is also evidence for a malfunctioning HDM2 regulation having effect on a proper p53 function and causing cancer, beyond mutated p53 or overexpression of HDM2. Thus, when E2F signals the growth of a cancer, Pl 4ARF is dispatched to break down HDM2, freeing p53 to kill the cancer cell, hi certain cancers P14ARF is lacking (Moule et al. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 14063-6). P14ARF binds to HDM2 and promotes the rapid degradation of HDM2. ARF-mediated HDM2 degradation is associated with HDM2 modification and concurrent p53 stabilization and accumulation.
Small molecule HDM2 inhibitors also induce senescence dependent on the presence of functional p53, whereas cells lacking p53 were completely insensitive (A. Efeyan, A. Ortega-Molina, S. Velasco-Miguel, D. Herranz, L.T. Vassilev, M. Serrano, Cancer Res. 2007, 67, 7350-7357).
The validity of inhibiting HDM2 as a therapeutic concept has been first demonstrated by antisense HDM2 inhibitors that exhibit significant antitumor activity in multiple human cancer models with various p53 statuses (Zhang et al. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 11636-11641).
Small molecule antagonists of the HDM2 protein interactions may therefore offer a viable approach towards cancer therapy, either as single agents or in combination with a broad variety of other anti-tumour therapies. There is also growing evidence that HDM2 plays an important role in viral infections. First, it is known that viruses rely on changing normal p53 signalling (O'shea and Fried M. Cell Cycle 2005; Machida et al. Proc. Natl. Acad. Sci. U.S.A. 2004, 25, 101, 4262- 7).
Second, HDM2 directly interacts with viral proteins, for example HDM2 is a target of simian virus 40 in cellular transformation and during lytic infection (Henning et al. J. Virol. 1997, 71, 7609-7618). Furthermore, the HDM2 protein, like p53, becomes metabolically stabilized in SV40-transformed cells. This suggests the possibility that the specific targeting of HDM2 by SV40 is aimed at preventing HDM2-directed proteasomal degradation of p53 in SV40-infected and -transformed cells, thereby leading to metabolic stabilization of p53 in these cells. A trimeric LT-p53-HDM2 complex is formed with simian virus 40 large tumour antigen (LT) in SV40-transformed cells.
The human immunodeficiency virus type 1 (HIV-I) encodes a potent transactivator, Tat. HDM2 has been shown to interact with Tat and mediating its ubiquitination in vitro and in vivo. In addition, HDM2 is a positive regulator of Tat-mediated transactivation, indicating that the transcriptional properties of Tat are stimulated by ubiquitination (Bres et al. Nat Cell Biol. 2003, 5, 754-61).
Small molecule inhibitors of the HDM2 interaction have been reported and show pro- apoptotic effects in in vitro models and an antitumor effect in animal models of cancer. Thus, benzodiazepines have been used as a chemical scaffold to achieve HDM2 inhibitory activity (Grasberger et al. J. Med. Chem. 2005, 48, 909-912; Parks et al. Bioorganic & Medicinal Chemistry Letters 2005, 15, 765-770). Similarly, imidazolines (Vassilev et al. Science 2004, 303, 844-848), isoindolones (Hardcastle et al. Bioorganic & Medicinal Chemistry Letters 2005, 15, 1515-1520), norbornanes (Zhao et al. Cancer Letters 2002, 183, 69-77) and sulfonamides (Galatin and Abraham J. Med. Chem. 2004,
47, 4163-4165) have been reported as small molecule HDM2 inhibitors. It has also been reported that HDM2 ligands have a cytoprotective effect. Thus, HDM2 inhibitors can be employed in methods of inducing cytoprotection and are useful to protect non-target cells against the harmful effects of chemotherapeutic agents. The amount of HDM2 inhibitor that provides such an effect can be about 5 to about 10 fold lower than the amount needed to induce apoptosis (Koblish et al. WO03095625,
METHOD FOR CYTOPROTECTION THROUGH HDM2 AND HDM2 INHIBITION, 2003-11-20).
Pyrrolidin-2-ones have already been described as therapeutically useful compounds to treat viral infections (US 6509359, PYRROLIDIN-2-ONE COMPOUNDS AND
THEIR USE AS NEURAMINIDASE INHIBITORS, 1999-03-25), to inhibit factor Xa for the treatment of cardiovascular disorders (US 7226929, Pyrrolidin-2-one derivatives as inhibitors of factor Xa, 2006-03-17; Watson et al., Design and Synthesis of Orally Active Pyrrolidin-2-one-Based Factor Xa Inhibitors, Bioorganic & Medicinal Chemistry Letters 2006, 16, 3784-3788), as inhibitors of 1 lβHSDl for the treatment of diabetes (WO/2005/108360, PYRROLIDΓN-2-ONE AND PIPERTDΓN-2-ONE DERTVATIVES AS 11-BETA HYDROXYSTEROID DEHYDROGENASE INHIBITORS, 2005-04- 29). Pyrrolidin-2-ones are scaffolds for established therapeutic compounds such as rolipram, an antidepressant agent and oxiracetam, piracetam or nebracetam, being nootropic drugs for the Alzheimer's disease. These compounds have low toxicity, good pharmaco-kinetic properties and render the chemical class of pyrrolidin-2-ones an interesting scaffold for new drug candidates.
MDMX (also known as MDM4 or HDMX) is a relative of MDM2 that was identified on the basis of its ability to physically interact with p53. An increasing body of evidence, including recent genetic studies, suggests that MDMX also acts as a key negative, independent regulator of p53. Aberrant expression of MDMX may contribute to tumor formation and is observed for example in gliomas, breast cancers, retinoblastomas and in a large subset of cervical and ovarian cancer cell lines. A systemic analysis of 500 human tumors (Danovi et al, MCB, 2004) of HDMX expression in primary tumors of different origins revealed a broad spectrum of human cancers with HDMX overexpression such as breast cancer, colon cancer, lung cancer, prostate cancer, stomach cancer, testis cancer, larynx cancer, uterus cancer, melanoma, and sarcoma.
Specific MDMX antagonists should therefore be developed as a pharmaceutical product to ensure activation of 'dormant' p53 activity in tumors that retain wild-type p53.
Although MDMX is highly homologous to MDM2, it does not possess ubiquitin ligase capability and its expression level is not p53 dependent. It was shown that MDMX could inhibit p53 transcriptional activity even stronger than MDM2 and both proteins cooperate in the inactivation of p53. Therefore, to achieve full activation of p53 in tumor cells, compounds that exhibit dual specificity for MDMX and MDM2 may be superior over MDM2 or MDMX specific binders alone.
The 3-dimensional structure of human MDMX protein bound to optimized p53 peptides have been solved by Kallen et al., JBC, 2009, 284, 8812-8821. The crystal structure of humanized zebra fish MDMX to p53 peptide by Popowicz et al., Cell Cycle 6:19, 2386- 2392, 1 October 2007 reveals that the principle features of the p53 and MDM2 interaction are preserved in the p53/MDMX complex and that "hybrid" MDM2/MDMX inhibitors could be developed. Thus, the structures of p53/MDMX and p53/MDM2 complexes show that both MDMX and MDM2 utilize the same p53-binding motif and many of the same residues for binding to p53. The overall shape of the binding sites is similar in terms of general shape and orientation of hydrophobic binding pockets, but the exact sizes respectively depths of these pockets are somewhat different. Thus, in MDMX, the hydrophobic cleft on which the p53 peptide binds appears slightly more flexible than in MDM2.
SUMMARY OF THE INVENTION
hi one embodiment of the present invention, novel small molecules are described that bind to HDM2 and/or MDMX, are inhibitors of HDM2 and/or MDMX mediated biology and can be used as novel therapeutic agents, especially for the treatment of cancer and/or viral infections. The present invention provides at least one compound selected from formula (I), (Ia), (Ic), (Id), (Ie) or (If) and pharmaceutically acceptable salts and esters thereof. Such a compound preferably is a ligand binding to HDM2 and/or MDMX protein, inducing apoptosis and inhibiting proliferation, and having therapeutic utility in cancer therapy and prevention. This therapeutic effect can be achieved by using one or more compounds of formula (I), (Ia), (Ic), (Id), (Ie) or (If) alone or in combination with other agents that are used to treat or prevent cancer.
One or more compounds of formula (I), (Ia), (Ic), (Id), (Ie) or (If) can also be used to treat or prevent cancer e.g. by protecting non-cancer cells from the deleterious effects of cytotoxic cancer treating drugs or radiotherapy. In such a treatment, a combination of either an antineoplastic agent or radiotherapy and a cytoprotective amount of at least one compound of formula (I), (Ia), (Ic), (Id), (Ie) or (If), and preferably one or more pharmaceutically acceptable excipients are used. Preferably, the compound of formula (I), (Ia), (Ic), (Id), (Ie) or (If) (also called HDM2 and/or MDMX ligand herein) is administered prior to, concurrently or after administration of the antineoplastic agent. Additionally, the HDM2 and/or MDMX inhibitor can be administered continuously or at repeated regular intervals.
A compound selected from compounds of formula (I), (Ia), (Ic), (Id), (Ie) or (If) can e.g. be used as a therapeutic agent in methods of treating stroke, myocardial infarction, ischemia, multi-organ failure, spinal cord injury, Alzheimer's Disease, injury from ischemic events, heart valvular degenerative disease or decreasing the side effects from cytotoxic agents, such as hair loss or cardio toxicity induced by doxorubicin or paclitaxel.
A compound selected from compounds of formula (I), (Ia), (Ic), (Id), (Ie) or (If) of the present invention can further be used to treat viral infections, especially in a pharmaceutical combination comprising a known antiviral compound. Further, the present invention is directed to a pharmaceutical composition comprising a cytoprotective amount of a compound of formula (I), (Ia), (Ic), (Id), (Ie) or (If), and one or more pharmaceutically acceptable excipients that is applied before, concomitantly and or subsequent to the treatment of a patient with a cytotoxic cancer treatment such as radiation or a cytotoxic antineoplastic agent.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides one or more compounds of formula (I), (Ia), (Ic), (Id), (Ie) or (If) that are preferably small molecule ligands of the HDM2 and/or MDMX protein and prevent or reduce binding of other proteins to HDM2 and/or MDMX.
In in vitro cell-based assays, one or more compounds of the present invention inhibit the interaction of the HDM2 and/or MDMX protein with the p53 protein. In such cell- based assays, such compounds demonstrate mechanistic activity such as induction of apoptosis and inhibition of proliferation. Incubation of cancer cells with one or more compounds of formula (I), (Ia), (Ic), (Id), (Ie) or (If) leads to an accumulation of p53 protein, induction of p53-regulated p21 gene, and cell cycle arrest in Gl and G2 phase, resulting in potent antiproliferative activity against wild-type p53 cells in vitro. In contrast, these activities were not observed in cancer cells with missing p53 at comparable compound concentrations. Therefore, the activity of HDM2 and/or MDMX antagonists is likely linked to its mechanism of action. These compounds are therefore potent and selective anticancer agents.
The present invention provides one or more compounds of formula (I)
Figure imgf000009_0001
(I) wherein
V is C=O, C=S or CH2 (especially C=O);
X is sulphur, oxygen or a group of formula CH2, CR4bR4c, NH, NR4b, SO or SO2 or a bond;
Y is a group of formula CONR6, CH2NR6, CO, COO, CH2O, SO2NR6, NR6CO, NR6SO2, NR53CONR6, NR6COO, OCONR6, CONR53NR6, CONR53OR6, CH2CO CH2CONR6, CH2COO, COCR53R6 or a bond;
n is 1, 2, 3 or O;
R1 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or hetero- aralkyl radical;
R2 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or hetero- aralkyl radical;
R3 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or hetero- aralkyl radical;
R4 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or hetero- aralkyl radical;
R4b is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or hetero- aralkyl radical; R4c is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or hetero- aralkyl radical;
R5 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
R5a is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
R6 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
the residues R7 are independently from each other a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
the residues R8 are independently from each other a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
or two of the radicals R1, R2, R3, R4, R4b, R4c, R5, R5a, R6, R7 and R8 together are part of an optionally substituted cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heteroaryl, aralkyl or heteroarylalkyl ring system;
or a pharmaceutically acceptable salt, ester, solvate or hydrate or a pharmaceutically acceptable formulation thereof. The expression alkyl refers to a saturated, straight-chain or branched hydrocarbon group that contains from 1 to 20 carbon atoms, preferably from 1 to 12 carbon atoms, especially from 1 to 6 (e.g. 1, 2, 3 or 4) carbon atoms, for example a methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl, 2,2-dimethylbutyl or n-octyl group.
The expressions alkenyl and alkynyl refer to at least partially unsaturated, straight-chain or branched hydrocarbon groups that contain from 2 to 20 carbon atoms, preferably from 2 to 12 carbon atoms, especially from 2 to 6 (e.g. 2, 3 or 4) carbon atoms, for example an ethenyl (vinyl), propenyl (allyl), iso-propenyl, butenyl, ethinyl, propinyl, butinyl, acetylenyl, propargyl, isoprenyl or hex-2-enyl group. Preferably, alkenyl groups have one or two (especially preferably one) double bond(s), and alkynyl groups have one or two (especially preferably one) triple bond(s).
Furthermore, the terms alkyl, alkenyl and alkynyl refer to groups in which one or more hydrogen atoms have been replaced by a halogen atom (preferably F or Cl) such as, for example, a 2,2,2-trichloroethyl or a trifiuoromethyl group.
The expression heteroalkyl refers to an alkyl, alkenyl or alkynyl group in which one or more (preferably 1, 2 or 3) carbon atoms have been replaced by an oxygen, nitrogen, phosphorus, boron, selenium, silicon or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom). The expression heteroalkyl furthermore refers to a carboxylic acid or to a group derived from a carboxylic acid, such as, for example, acyl, acylalkyl, alkoxy- carbonyl, acyloxy, acyloxyalkyl, carboxyalkylamide or alkoxycarbonyloxy.
Preferably, a heteroalkyl group contains from 1 to 12 carbon atoms and from 1 to 4 hetero atoms selected from oxygen, nitrogen and sulphur (especially oxygen and nitrogen). Especially preferably, a heteroalkyl group contains from 1 to 6 (e.g. 1, 2, 3 or 4) carbon atoms and 1, 2 or 3 (especially 1 or 2) hetero atoms selected from oxygen, nitrogen and sulphur (especially oxygen and nitrogen). The term Ci-C6 heteroalkyl refers to a heteroalkyl group containing from 1 to 6 carbon atoms and 1, 2 or 3 heteroatoms selected from O, S and/or N (especially O and/or N). The term Ci-C4 heteroalkyl refers to a heteroalkyl group containing from 1 to 4 carbon atoms and 1, 2 or 3 heteroatoms selected from O, S and/or N (especially O and/or N). Furthermore, the term heteroalkyl refers to groups in which one or more hydrogen atoms have been replaced by a halogen atom (preferably F or Cl).
Examples of heteroalkyl groups are groups of formulae: Ra-0-Ya-, Ra-S-Ya-, Ra-N(Rb)-Ya-, Ra-C0-Ya-, Ra-O-CO-Ya-, Ra-C0-0-Ya-, Ra-CO-N(Rb)-Ya-, Ra-N(Rb)-CO-Ya-, Ra-O-CO-N(Rb)-Ya-, Ra-N(Rb)-CO-O-Ya-, Ra-N(Rb)-CO-N(Rc)-Ya-, Ra-O-CO-O-Ya-, Ra-N(Rb)-C(=NRd)-N(Rc)-Ya-, Ra-CS-Ya-, Ra-O-CS-Ya-, Ra-CS-O-Ya-, Ra-CS-N(Rb)-Ya-, Ra-N(Rb)-CS-Ya-, Ra-O-CS-N(Rb)-Ya-,
Ra-N(Rb)-CS-O-Ya-, Ra-N(Rb)-CS-N(Rc)-Ya-, Ra-O-CS-O-Ya-, Ra-S-CO-Ya-, Ra-CO-S-Ya-, Ra-S-CO-N(Rb)-Ya-, Ra-N(Rb)-CO-S-Ya-, Ra-S-CO-O-Ya-, Ra-O-CO-S-Ya-, Ra-S-CO-S-Ya-, Ra-S-CS-Ya-, Ra-CS-S-Ya-, Ra-S-CS-N(Rb)-Ya-, Ra-N(Rb)-CS-S-Ya-, Ra-S-CS-O-Ya-, Ra-O-CS-S-Ya-, wherein Ra being a hydrogen atom, a CpC6 alkyl, a C2-C6 alkenyl or a C2-C6 alkynyl group; Rb being a hydrogen atom, a Ci-C6 alkyl, a C2-C6 alkenyl or a C2-C6 alkynyl group; Rc being a hydrogen atom, a Ci-C6 alkyl, a C2-C6 alkenyl or a C2-C6 alkynyl group; Rd being a hydrogen atom, a Ci-C6 alkyl, a C2-C6 alkenyl or a C2-C6 alkynyl group and Ya being a direct bond, a Ci-C6 alkylene, a C2-C6 alkenylene or a C2-C6 alkynyl ene group, wherein each heteroalkyl group contains at least one carbon atom and one or more hydrogen atoms may be replaced by fluorine or chlorine atoms.
Specific examples of heteroalkyl groups are methoxy, trifluoromethoxy, ethoxy, n-pro- pyloxy, isopropyloxy, butoxy, tert-butyloxy, methoxymethyl, ethoxymethyl, -CH2CH2OH, -CH2OH, methoxyethyl, 1-methoxyethyl, 1-ethoxyethyl, 2-methoxyethyl or 2-ethoxyethyl, methylamino, ethylamino, propylamino, isopropylamino, dimethyl- amino, diethylamino, isopropylethylamino, methylamino methyl, ethylamino methyl, diisopropylamino ethyl, methylthio, ethylthio, isopropylthio, enol ether, dimethylamino methyl, dimethylamino ethyl, acetyl, propionyl, butyryloxy, acetyloxy, methoxycarbonyl, ethoxycarbonyl, propionyloxy, acetylamino or propionylamino, carboxymethyl, carboxyethyl or carboxypropyl, N-ethyl-N-methylcarbamoyl or N- methylcarbamoyl. Further examples of heteroalkyl groups are nitrile, isonitrile, cyanate, thiocyanate, isocyanate, isothiocyanate and alkylnitrile groups.
The expression cycloalkyl refers to a saturated or partially unsaturated (for example, a cycloalkenyl group) cyclic group that contains one or more rings (preferably 1 or 2), and contains from 3 to 14 ring carbon atoms, preferably from 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbon atoms. The expression cycloalkyl refers furthermore to groups in which one or more hydrogen atoms have been replaced by fluorine, chlorine, bromine or iodine atoms or by OH, =0, SH, =S, NH2, =NH, N3 or NO2 groups, thus, for example, cyclic ketones such as, for example, cyclohexanone, 2-cyclohexenone or cyclopentanone. Further specific examples of cycloalkyl groups are a cyclopropyl, cyclobutyl, cyclopentyl, spiro[4,5]decanyl, norbornyl, cyclohexyl, cyclopentenyl, cyclohexadienyl, decalinyl, bicyclo[4.3.0]nonyl, tetraline, cyclopentylcyclohexyl, fluorocyclohexyl or cyclohex-2-enyl group.
The expression heterocycloalkyl refers to a cycloalkyl group as defined above in which one or more (preferably 1, 2 or 3) ring carbon atoms have been replaced by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom). A heterocycloalkyl group has preferably 1 or 2 ring(s) containing from 3 to 10 (especially 3, 4, 5, 6 or 7) ring atoms (preferably secected from C, O, N and S). The expression heterocycloalkyl refers furthermore to groups in which one or more hydrogen atoms have been replaced by fluorine, chlorine, bromine or iodine atoms or by OH, =0, SH, =S, NH2, =NH, N3 or NO2 groups. Examples are a piperidyl, prolinyl, imidazolidinyl, piperazinyl, morpholinyl, urotropinyl, pyrrolidinyl, tetrahydro- thiophenyl, tetrahydropyranyl, tetrahydrofuryl or 2-pyrazolinyl group and also lactames, lactones, cyclic imides and cyclic anhydrides.
The expression alkylcycloalkyl refers to groups that contain both cycloalkyl and also alkyl, alkenyl or alkynyl groups in accordance with the above definitions, for example alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkenyl, alkenylcycloalkyl and alkynyl- cycloalkyl groups. An alkylcycloalkyl group preferably contains a cycloalkyl group that contains one or two ring systems having from 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbon atoms, and one or two alkyl, alkenyl or alkynyl groups having 1 or 2 to 6 carbon atoms.
The expression heteroalkylcycloalkyl refers to alkylcyclo alkyl groups as defined above in which one or more (preferably 1, 2 or 3) carbon atoms have been replaced by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom). A heteroalkylcycloalkyl group preferably contains 1 or 2 ring systems having from 3 to 10 (especially 3, 4, 5, 6 or 7) ring atoms, and one or two alkyl, alkenyl, alkynyl or heteroalkyl groups having from 1 or 2 to 6 carbon atoms. Examples of such groups are alkylheterocycloalkyl, alkylheterocycloalkenyl, alkenyl- heterocycloalkyl, alkynylheterocycloalkyl, heteroalkylcycloalkyl, heteroalkylhetero- cycloalkyl and heteroalkylheterocycloalkenyl, the cyclic groups being saturated or mono-, di- or tri-unsaturated.
The expression aryl refers to an aromatic group that contains one or more rings containing from 6 to 14 ring carbon atoms, preferably from 6 to 10 (especially 6) ring carbon atoms. The expression aryl refers furthermore to groups in which one or more hydrogen atoms have been replaced by fluorine, chlorine, bromine or iodine atoms or by OH, SH, NH2, N3 or NO2 groups. Examples are the phenyl, naphthyl, biphenyl, 2-fluorophenyl, anilinyl, 3-nitrophenyl or 4-hydroxyphenyl group.
The expression heteroaryl refers to an aromatic group that contains one or more rings containing from 5 to 14 ring atoms, preferably from 5 to 10 (especially 5 or 6) ring atoms, and contains one or more (preferably 1, 2, 3 or 4) oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably O, S or N). The expression heteroaryl refers furthermore to groups in which one or more hydrogen atoms have been replaced by fluorine, chlorine, bromine or iodine atoms or by OH, SH, N3, NH2 or NO2 groups. Examples are pyridyl (e.g. 4-pyridyl), imidazolyl (e.g. 2-imidazolyl), phenylpyrrolyl (e.g. 3 -phenylpyrrolyl), thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl,thiadiazolyl, indolyl, indazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, pyridazinyl, quinolinyl, isoquinolinyl, pyrrolyl, purinyl, carbazolyl, acridinyl, pyrimidyl, 2,3 '-bifuryl, pyrazolyl (e.g. 3-pyrazolyl) and isoquinolinyl groups.
The expression aralkyl refers to groups containing both aryl and also alkyl, alkenyl, alkynyl and/or cycloalkyl groups in accordance with the above definitions, such as, for example, arylalkyl, arylalkenyl, arylalkynyl, arylcycloalkyl, arylcycloalkenyl, alkylaryl- cycloalkyl and alkylarylcycloalkenyl groups. Specific examples of aralkyls are toluene, xylene, mesitylene, styrene, benzyl chloride, o-fluoro toluene, lH-indene, tetraline, dihydronaphthalene, indanone, phenylcyclopentyl, cumene, cyclohexylphenyl, fluorene and indane. An aralkyl group preferably contains one or two aromatic ring systems (1 or 2 rings) containing from 6 to 10 carbon atoms and one or two alkyl, alkenyl and/or alkynyl groups containing from 1 or 2 to 6 carbon atoms and/or a cycloalkyl group containing 5 or 6 ring carbon atoms.
The expression heteroaralkyl refers to an aralkyl group as defined above in which one or more (preferably 1, 2, 3 or 4) carbon atoms have been replaced by an oxygen, nitrogen, silicon, selenium, phosphorus, boron or sulfur atom (preferably oxygen, sulfur or nitrogen), that is to say to groups containing both aryl or heteroaryl, respectively, and also alkyl, alkenyl, alkynyl and/or heteroalkyl and/or cycloalkyl and/or heterocycloalkyl groups in accordance with the above definitions. A heteroaralkyl group preferably contains one or two aromatic ring systems (1 or 2 rings) containing from 5 or 6 to 10 ring carbon atoms and one or two alkyl, alkenyl and/or alkynyl groups containing 1 or 2 to 6 carbon atoms and/or a cycloalkyl group containing 5 or 6 ring carbon atoms, wherein 1, 2, 3 or 4 of these carbon atoms have been replaced by oxygen, sulfur or nitrogen atoms.
Examples are arylheteroalkyl, arylheterocycloalkyl, arylheterocycloalkenyl, arylalkyl- heterocycloalkyl, arylalkenylheterocycloalkyl, arylalkynylheterocycloalkyl, arylalkyl- heterocycloalkenyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroaryl- heteroalkyl, heteroarylcycloalkyl, heteroarylcycloalkenyl, hetero arylheterocycloalkyl, heteroarylheterocycloalkenyl, heteroarylalkylcycloalkyl, heteroarylalkylheterocyclo- alkenyl, heteroarylheteroalkylcycloalkyl, heteroarylheteroalkylcycloalkenyl and hetero- arylheteroalkylheterocycloalkyl groups, the cyclic groups being saturated or mono-, di- or tri-unsaturated. Specific examples are a tetrahydroisoquinolinyl, benzoyl, 2- or 3- ethylindolyl, 4-methylpyridino, 2-, 3- or 4-methoxyphenyl, 4-ethoxyphenyl, 2-, 3- or 4-carboxyphenylalkyl group.
As already stated above, the expressions cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl also refer to groups in which one or more hydrogen atoms of such groups have been replaced by fluorine, chlorine, bromine or iodine atoms or by OH, =0, SH, =S, NH2, =NH, N3 or NO2 groups.
The expression "optionally substituted" especially refers to groups in which one, two, three or more hydrogen atoms have been replaced by fluorine, chlorine, bromine or iodine atoms or by OH, =0, SH, =S, NH2, =NH, N3 or NO2 groups. This expression refers furthermore to groups that are substituted by one, two, three or more unsubstituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C10 cycloalkyl, C2-Cg heterocycloalkyl, C6-C10 aryl, C1-Cg heteroaryl, C7-C12 aralkyl or C2-C11 heteroaralkyl groups.
Preferred substituents are F, Cl, Br, Me, OMe, CN or CF3.
Preferably, all alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl and heteroaralkyl groups described herein may optionally be substituted.
Preferred are compounds of formula (I) wherein the radicals R5 and R6 together are part of an optionally substituted heterocycloalkyl, heteroalkylcycloalkyl, heteroaryl or heteroarylalkyl ring system, and/or wherein R2 and R3 together are part of an optionally substituted cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl ring system. Preferred are compounds of formula (I) wherein X is sulphur, oxygen, NH, CH2, SO, SO2, especially sulphur.
Further preferred are compounds of formula (I) wherein Y is a group of formula CONR6.
Further preferred are compounds of formula (I) wherein n is 0 or 1, especially 1.
Further preferred are compounds of formula (I) wherein R7 is hydrogen.
Moreover preferred are compounds of formula (I) wherein R is hydrogen.
Especially preferred are compounds of formula (Ia)
Figure imgf000018_0001
(Ia) wherein
R1 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or hetero- aralkyl radical;
R2 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or hetero- aralkyl radical; R3 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or hetero- aralkyl radical;
R4 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or hetero- aralkyl radical;
R5 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
R6 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or hetero- aralkyl radical;
or the radicals R5 and R6 together are part of an optionally substituted heterocycloalkyl, heteroalkylcycloalkyl, heteroaryl or heteroarylalkyl ring system, and/or R and R together are part of an optionally substituted cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkylcycloalkyl, aralkyl or heteroaralkyl ring system;
or a pharmaceutically acceptable salt, ester, solvate or hydrate or a pharmaceutically acceptable formulation thereof.
Further preferred are compounds of formula (I) or (Ia), wherein R1 is a cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl radical.
Further preferred are compounds of formula (I) or (Ia), wherein R1 is an aryl, heteroaryl, aralkyl or heteroaralkyl radical. Further preferred are compounds of formula (I) or (Ia), wherein R1 is a group of formula -A-Ar or -A-Cy (especially -A-Ar) wherein A is a bond, Ci-C4 alkyl (especially a bond, CH2 or CH(CH3)) or C1-C6 heteroalkyl (e.g. CH(CH2N(CH3)2)), or wherein A is a group of formula -CHR1 a- wherein Rla is a Ci-C6 heteroalkyl group, Cy is an optionally substituted C3-C7 cycloalkyl group or an optionally substituted heterocycloalkyl group containing from 3 to 7 ring atoms and Ar is an optionally substituted (e.g. by 1, 2 or 3 substituents) phenyl ring or an optionally substituted (e.g. by 1, 2 or 3 substituents) heteroaryl ring containing 5 or 6 ring atoms (especially including from 1 to 3 heteroatoms selected from O, S and N), especially preferably Ar is an optionally substituted phenyl or an optionally substituted pyridyl residue (e.g. a 4-bromobenzyl residue). Preferred substituents are F, Cl, Br, CN, CH3, OCH3 and CF3.
Further preferred are compounds of formula (I) or (Ia), wherein R1 is a group of formula -A-Ar wherein A is a bond or Ci-C4 alkyl (especially a bond, CH2 or CHCH3) and Ar is an optionally substituted (e.g. by 1 , 2 or 3 substituents) phenyl ring or an optionally substituted (e.g. by 1, 2 or 3 substituents) heteroaryl ring containing 5 or 6 ring atoms (especially containing from 1 to 3 heteroatoms selected from O, S and N), especially preferably Ar is an optionally substituted phenyl or an optionally substituted pyridyl residue (e.g. a 4-bromobenzyl residue).
Especially preferably, R1 is a group of formula -A-phenyl (especially -CH2-phenyl) which is optionally substituted, preferably by one or two halogen atoms selected from F, Cl and Br and wherein A is preferrably a group of formula -CHR1 a- wherein R a is a C1- C6 heteroalkyl group (e.g. COOH, CH2COOH)
Further preferred, R1 is cyclopropylmethyl, picolyl, phenylbenzyl or phenoxybenzyl, all of which may optionally be substituted.
Further preferred are compounds of formula (I) or (Ia), wherein R2 is hydrogen.
Further preferred are compounds of formula (I) or (Ia), wherein R3 is Ci-C6 alkyl, an aryl (especially phenyl), heteroaryl, aralkyl or heteroaralkyl residue, all of which may be substituted (e.g. by 1, 2 or 3 substituents). Especially preferably, R3 is an optionally substituted phenyl group, an optionally substituted benzyl group or an optionally substituted heteroaryl residue having 1 or 2 rings and from 5 to 10 ring atoms (especially 2 rings and a total of 9 ring atoms) including 1, 2, 3 or 4 heteroatoms selected from O, S and N (especially N). Preferred substituents are F, Cl, Br, Ci-C4 alkyl groups (e.g. CH3) and Ci-C6 heteroalkyl groups (e.g. CH2SO3 ", (CH2)5NH2).
Further preferred are compounds of formula (I) or (Ia), wherein R3 has the following structure
Figure imgf000021_0001
wherein E is N or CH, R3a is H, Ci-C6 alkyl or Ci-C6 heteroalkyl (especially H or CH3),
R3b is H, F, Cl, Br, CH3, OCH3 or CF3 and R3c is H, F, Cl, Br, CH3, OCH3 or CF3 (especially preferably, E is CH, R3a is H, R3b is Cl and R3c is H).
Further preferred are compounds of formula (I) or (Ia), wherein R3 is an aryl (especially phenyl), heteroaryl, aralkyl or heteroaralkyl residue, all of which may be substituted (e.g. by 1, 2 or 3 substituents); especially preferably, R3 is an optionally substituted heteroaryl residue having 1 or 2 rings and from 5 to 10 ring atoms (especially 2 rings and a total of 9 ring atoms) including 1, 2, 3 or 4 heteroatoms selected from O, S and N (especially N).
Further preferred are compounds of formula (I) or (Ia), wherein R3 has the following structure
Figure imgf000021_0002
wherein E is N or CH, R3a is H or CH3, R3b is F, Cl or Br and R3c is H, F, Cl or Br (especially preferably, E is CH, R3a is H, R3b is Cl and R3c is H).
Further preferred, R2 and R3 together are part of an optionally substituted heterocycloalkyl or heteroaralkyl ring. Moreover preferred, R2 and R3 together are part of a group having the following structure:
Figure imgf000022_0001
Further preferred are compounds of formula (I) or (Ia), wherein R4 is C1-C6 alkyl, C2-C6 alkenyl, optionally substituted C1-C4 alkyl-C3-C7 cycloalkyl, an optionally substituted phenyl ring, an optionally substituted benzyl group or an optionally substituted heteroaryl ring having 5 or 6 ring atoms including from 1 to 3 heteroatoms selected from O, S and N (e.g. pyridyl). Especially preferably, R4 is a phenyl ring which is substituted by 1 or 2 substituents, preferably selected from F, Br, Cl, I, NO2, methyl or cyanide (e.g. 4-methylphenyl), or an unsubstituted phenyl ring. Moreover preferably, R4 is phenyl or 4-methylphenyl.
Further preferred are compounds of formula (I) or (Ia), wherein R4 is C1-C6 alkyl or an optionally substituted phenyl ring or an optionally substituted heteroaryl ring having 5 or 6 ring atoms and containing from 1 to 3 heteroatoms selected from O, S and N. Especially preferably, R4 is a phenyl ring which is substituted by 1 or 2 substituents, preferably selected from F, Br, Cl, I, methyl or cyanide (e.g. 4-methylphenyl).
Further preferred are compounds of formula (I) or (Ia), wherein R5 is an alkyl, hetero- alkyl, heterocycloalkyl, heteroalkylcycloalkyl or heteroaralkyl group, all of which groups may be substituted.
Further preferred are compounds of formula (I) or (Ia), wherein R5 is selected from the following groups: Ci-C6 alkyl; heteroalkyl containing 1-6 carbon atoms and 1, 2 or 3 heteroatoms selected from O, S and N; heteroalkylcycloalkyl comprising a C1-C4 alkyl group or a Ci-C4 heteroalkyl group and an optionally substituted heterocycloalkyl group containing 5 or 6 ring atoms and 1 , 2 or 3 heteroatoms selected from O, S and N; heteroaralkyl comprising a C1-C4 alkyl group or a Ci-C4 heteroalkyl group and an optionally substituted heteroaryl group containing 5 or 6 ring atoms including 1, 2 or 3 heteroatoms selected from O, S and N; optionally substituted heteroaryl containing 5 or 6 ring atoms including 1, 2 or 3 heteroatoms selected from O, S and N; and optionally substituted heterocycloalkyl containing 5 or 6 ring atoms and 1, 2 or 3 heteroatoms selected from O, S and N.
Further preferred are dimers of compounds of formulas (I) and/or (Ia) that are linked via a heteroalkyl, heteroalkylcycloalkyl or a heteroaralkyl group, preferably via R5.
Further preferred are compounds of formula (I) or (Ia), wherein R5 is Ci-C6 alkyl; heteroalkyl containing 1-6 carbon atoms and 1, 2 or 3 heteroatoms selected from O, S, N; heteroalkylcycloalkyl comprising a Ci-C4 alkyl group and an optionally substituted heterocycloalkyl group containing 5 or 6 ring atoms and 1, 2 or 3 heteroatoms selected from O, S and N; heteroaralkyl comprising a Cj-C4 alkyl group and an optionally substituted heteroaryl group containing 5 or 6 ring atoms and 1 , 2 or 3 heteroatoms selected from O, S and N.
Further preferred are compounds of formula (I) or (Ia), wherein R6 is hydrogen or CpC4 alkyl, especially hydrogen.
Further preferred are compounds of formula (I) or (Ia), wherein R5 and R6 together with the nitrogen atom to which they are bound form an optionally substituted (e.g. by 1, 2 or
3 substituents) heterocycloalkyl ring containing 4, 5, 6 or 7 ring atoms and 1, 2 or 3 heteroatoms selected from O, S and N.
Moreover preferred, R5 and R6 together with the nitrogen atom to which they are bound form the following group: — N Q
Therein, m is 0, 1 or 2; o is 0, 1 or 2; the sum of m and o is preferably from 0 to 3; Q is N-R6x, CR6yR6z, C=O, -CO-NR6x-, -NR6x-CO-NR6y-, -SO2-NR6x-, -SO-NR6x- or -O-CO-NR6x-, wherein R6x, R6y and R6z independently from each other are a hydrogen 5 atom, OH, NH2, SH or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or hetero- aralkyl radical.
Preferably, Q is N-CO-R6a, NR6b or CHR6c wherein R6a is CrC6 alkyl, C1-C6 0 heteroalkyl, NH2, optionally substituted phenyl or hydrogen; R6b is optionally substituted phenyl or optionally substituted heteroaryl containing 5 or 6 ring atoms including one or two heteroatoms selected from O, S or N; R6c is Cj-C6 heteroalkyl, NH2 or OH.
5 Further preferred, Q is N-CO-NHR6d, N-COOR6e, N-SO2R6f, N-SO2NHR6g, N- NHCOR6h, CH-NH2, CH-OH, CH-SH, CH-NH-COR6i, CO, CONH, NHCONH, SO2NH, OCONH, CH-COOH, CH-COOR6j, CH-COR6k or CH-SO2R61, wherein R6d, R6e, R6f, R6g, R6h, R6i, R6j, R6k and R61 independently from each other are a hydrogen atom, OH, NH2, SH or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, O cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or hetero- aralkyl radical, especially hydrogen or a C1-C6 alkyl group or a C1-C6 heteroalkyl group.
Preferably, Q is N-CO-R6a wherein R6a is preferably NH2, Ci-C6 alkyl, NH-Ci-C6 alkyl Or N(C1-C6 alkyl)2. 5
Further preferrably, group Q contains a hydrogen bond acceptor (especially an atom or group having a lone electron pair like e.g. an electronegative atom such as fluorine, oxygen, or nitrogen).
O Further preferred, o is 1 and m is 1. Especially preferably, m is 1, o is 1 and Q is N-C0-R6a. Thereby R6a is preferably Ci-C4 alkyl or NH-Cj-C4 alkyl (e.g. CH3 or NHCH2CH3).
Especially preferred are compounds of formula (I) or (Ia), wherein R5 and R6 together are part of an optionally substituted (e.g. by 1, 2 or 3 substituents like e.g. =0) piperazine ring.
Further preferred are compounds of formula (I) or (Ia), wherein R5 and R6 together are part of an optionally substituted (e.g. by 1, 2 or 3 substituents) heterocycloalkyl ring containing 5 or 6 ring atoms and 1 , 2 or 3 heteroatoms selected from O, S and N
Further preferred are compounds of formula (Ic):
Figure imgf000025_0001
wherein W is an optionally substituted phenyl ring or an optionally substituted heteroaryl group having 5 or 6 ring atoms including 1 or 2 heteroatoms selected from O, S and N; and wherein R1, R3a, R4, R5, R7, R8, E, X, Y and n are defined as above.
Especially preferred are compounds of formula (Ic) wherein W is an optionally substituted phenyl ring (preferably substituted by 1 , 2 or 3 halogen atoms selected from F, Cl and Br); R1 is an optionally substituted benzyl group (preferably substituted by 1, 2 or 3 halogen atoms selected from F, Cl and Br); X is S; Y is CONR6; n is 1; R3a is hydrogen; R4 is an optionally substituted phenyl group (preferably unsubstituted or substituted by a methyl group, especially in the para position); R7 and R8 are hydrogen; E is CH; and R5 and R6 are defined as above; especially preferably, R5 and R6 together are part of an optionally substituted piperazine ring (especially as defined above).
Further preferred are compounds of formula (Id):
Figure imgf000026_0001
wherein R1, R3a, R3b, R3c, R4, R5, R6, E and X are defined as above.
Especially preferred are compounds of formula (Id) wherein R1 is an optionally substituted benzyl group (preferably substituted by 1 , 2 or 3 halogen atoms selected from F, Cl and Br); X is S; R3a is hydrogen; R3b is Cl; R3c is hydrogen, R4 is an optionally substituted phenyl group (preferably unsubstituted or substituted by a methyl group, especially in the para position); E is CH; and R5 and R6 are defined as above; especially preferably, R5 and R6 together are part of an optionally substituted piperazine ring (especially as defined above).
Further preferred are compounds of formula (Ie):
Figure imgf000026_0002
(Ie) wherein R1, R3a, R3b, R3c, R4, E, Q, m, o and X are defined as above.
Especially preferred are compounds of formula (Ie) wherein R1 is an optionally substituted benzyl group (preferably substituted by 1 , 2 or 3 halogen atoms selected from F, Cl and Br); X is S; R3a is hydrogen; R3b is Cl; R3c is hydrogen, R4 is an optionally substituted phenyl group (preferably unsubstituted or substituted by a methyl group, especially in the para position); E is CH; Q is N-CO-R6a wherein R6a is preferably C1-C6 alkyl, NH-C1-C6 alkyl or N(Ci-C6 alkyl)2; m is 0, 1 or 2; o is 0, 1 or 2; and the sum of m and o is preferably from 0 to 3. Especially preferably, m is 1, o is 1 and Q is N-CO-R6a, wherein R6a is preferably Ci-C4 alkyl or NH-Ci-C4 alkyl (e.g. CH3 or NHCH2CH3).
Further preferred are compounds of formula (If)
Figure imgf000027_0001
(If)
wherein A, Ar, R > 3a , r R>3b , τ R>3c , E, X, R 44aa and R >6oaa are defined as above.
Especially preferred are compounds of formula (If) wherein X is S; R3a is hydrogen; R3b is Cl; R3c is hydrogen, R4a is hydrogen or a methyl group; E is CH; A is CH2; Ar is phenyl which is substituted by one or two halogen atoms selected from F, Cl and Br; and R6a is CrC4 alkyl or NH-Ci-C4 alkyl (e.g. CH3 or NHCH2CH3). A further preferred embodiment of the present invention relates to compounds of formula (I) or (Ia), wherein
R1 is aryl, heteroaryl, arylalkyl or heteroarylalkyl, all of which may be substituted by F, Br, Cl, I, methyl or cyanide, R2 is hydrogen,
R3 is aryl, heteroaryl, arylalkyl or heteroarylalkyl, all of which may be substituted by F, Br, Cl, I, methyl or cyanide, R4 is aryl, heteroaryl, arylalkyl or heteroarylalkyl,
R5 and R6 are independently selected from hydrogen, alkyl, heteroalkyl, aryl, alkenyl, akinyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, or wherein R5 and R6 may be part of one heteroaryl, heterocycloalkyl, heteroalkylcycloalkyl or heteroarylalkyl ring system, and wherein the other residues and groups are defined as above.
A further preferred embodiment of the present invention relates to compounds of formula (I) or (Ia), wherein
R1 is aryl, heteroaryl, arylalkyl or heteroarylalkyl, all of which may be substituted by F,
Br, Cl, I, methyl or cyanide,
R2 and R3 together are part of a heteroaryl, heteroaralkyl, heterocycloalkyl or heteroalkylcycloalkyl ring system such as but not restricted to 1 ,3-dihydroindole, 1 ,3- dihydro-indol-2-one, 2,3-dihydro-lH-indazole, tetrahydro-quinoline, tetrahydro- quinoline-2-one, 3,4-dihydro-lH-quinolin-2-one, 3,4-dihydro-lH-quinazolin-2-one, all of which may be substituted by F, Br, Cl, I, methyl or cyanide,
R4 is selected from aryl, heteroaryl, arylalkyl or heteroarylalkyl, R5 and R6 are independently selected from hydrogen, alkyl, heteroalkyl, aryl, alkenyl, akinyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, or wherein R5 and R6 may also be part of one heteroaryl, heterocycloalkyl, heteroalkylcycloalkyl or heteroarylalkyl ring system, and wherein the other residues and groups are defined as above. A further preferred embodiment of the present invention relates to compounds of formula (I), (Ia), (Ic), (Id), (Ie) or (If), wherein R3 and the sulfanyl group (i.e. the group carrying X) bearing the R4 group are in cis position (especially when R2 is H).
An especially preferred embodiment are enantiomerically pure compounds of formula (I), (Ia), (Ic), (Id), (Ie) or (If).
Further preferred is the following compound:
Figure imgf000029_0001
i.e. the following diastereomers:
Figure imgf000029_0002
especially the following diastereomer:
Figure imgf000030_0001
Further preferred is the following compound:
Figure imgf000030_0002
i.e. the following diastereomers:
Figure imgf000031_0001
especially the following diastereomer:
Figure imgf000031_0002
Further preferred is the following compound: acιd ethylamide
Figure imgf000032_0001
i.e. the following diastereomers.
Figure imgf000032_0002
especially the following diastereomer:
Figure imgf000032_0003
Preferably, the compounds described in: 1. Ng et al. Angew. Chem. Int. Ed. 2007, 46, 5352-5355 and
2. Ng et al. Organic Letters 2006, Vol. 8, No. 18, 3999-4002 (and supporting information thereof) are excluded from the scope of the present application and/or patent.
Further preferred, one or more of the following compounds are excluded from the present application and/or patent:
Figure imgf000033_0001
Further preferred, also the following compounds are excluded from the present application and/or patent:
Figure imgf000033_0002
wherein R3 is p-C6H5CH2OH (or a derivative thereof which is bound to the solid phase as described in Ng et al. Angew. Chem. Int. Ed. 2007, 46, 5352-5355), R1 is selected from the following groups:
Figure imgf000034_0001
R ,4 is para-C6H5CH3 and R is selected from the following groups:
Figure imgf000034_0002
All those compounds are described in Ng et al. Angew. Chem. Int. Ed. 2007, 46, 5352- 5355. Further preferred, compounds of formula (I) or (Ia) are excluded wherein R3 is is p- C6H5CH2OH (or a derivative thereof which is bound to the solid phase as described in Ng et al. Angew. Chem. Int. Ed. 2007, 46, 5352-5355).
Further preferred, also the following compounds are excluded from the present application and/or patent (X = H, I):
Figure imgf000035_0001
The present invention further provides pharmaceutical compositions comprising a compound of formula (I), (Ia), (Ic), (Id), (Ie) or (If) as defined herein or a pharmaceutically acceptable ester, prodrug, hydrate, solvate or salt thereof, optionally in combination with a pharmaceutically acceptable carrier.
A further preferred embodiment of the present invention relates to pharmaceutical compositions comprising one or more compounds of formula (I), (Ia), (Ic), (Id), (Ie) or (If) as defined herein or a pharmaceutically acceptable ester, prodrug, hydrate, solvate or salt thereof, optionally in combination with a pharmaceutically acceptable carrier, further comprising one or more other anti-tumor agents, wherein the anti-tumor agent is especially selected from 16-Aza-epothilone B, Aldesleukin, Amifostine, Aranose, Bevacizumab, Bleocin, Bleomycin, BMS- 184476, Bortezomib, Calcitriol, Carmustine, Canertinib, Canfosfamide, Capecitabine, Carboplatin, Carmustine, Cefixime, Ceftriaxone, Celecoxib, Celmoleukin, Cetuximab, Ciclosporin, Cisplatin, Clodronate, Cyclophosphamide, Cytarabine, Deoxorubicin, Desoxyepothilone B, Diethylstilbestrol, Diflomotecan, Docetaxel, Doxorubicin, Edatrexate, Efaproxiral, EKB-569, Epirubicin, Epratuzumab, Erlotinib, Etoposide, ET-18-OCH3, Exatecan, Fludarabine, Fluorouracil, Folinic acid, Galarubicin, Gefinitib, Gemcitabine, Gemtuzumab, Gimatecan, Glufosfamide, Granisetron, Homoharringtonine, Hyaluronic acid, Ibandronate, Ibritumomab, Ifosfamide, Imatinib, Interferon alfa, Interferon alfa-2a, Interferon alfa- 2b, Irinotecan, Isoflavone, Isotretinoin, Ixabepilone, Ketoconazole, Lapatinib, Leflunomide, Lenograstim, Leucovorin, Lexidronam, Linezolid, Lometrexol, Lurtotecan, MEN10755, Methotrexate, Mitomycin, Neridronate, Nimesulide,
Nitroglycerin, 06-Benzyl guanine, Omeprazole, Ortataxel, Oxalip latin, Paclitaxel, Patupilone, Pegfilgrastim, PEG-filgrastim, Pelitinib, Pemetrexed, Pentostatin, Perifosine, Plevitrexed, Polyprenoic acid, Quinupristin, Raloxifene, Raltitrexed, Ramosetron, Retinoic acid, Risedroante, Rituximab, Rofecoxib, Rubitecan, S-9788, Sabarubicin, Sargramostim, Satraplatin, SN-38, Sorafenib, Suberanilohydroxamic acid, Sutent, Tamoxifen, Taxotere, Tazarotene, Tegafur, Temozolamide, Tesmilifene, Tetrodotoxin, Thalidomide, Tipifarnib, Topotecan, Trabectedin, Trastuzumab, Traszutumab, Tretinoin, Vatalanib, Vincristine, Vinorelbine, Vinscristine, ZD-6474, Zoledronate or Zosuquidar.
In a preferred embodiment, the compounds of the present invention sensibilize cancer cells for radio and/or chemotherapy whereas they display chemoprotective and/or radioprotective activity on healthy cells. Thereby the dosage of these therapies can be better adjusted.
A further preferred embodiment of the present invention relates to a pharmaceutical composition comprising one or more compounds of formula (I), (Ia), (Ic), (Id), (Ie) or (If) as defined herein or one or more pharmaceutically acceptable esters, prodrugs, hydrates, solvates or salts thereof, optionally in combination with a pharmaceutically acceptable carrier. The pharmaceutical composition optionally comprises one or more antiviral agents. Preferably, the antiviral agent is selected from 3TC, Abacavir, Adefovir Dipivoxil, Acyclovir, Amprenavir, Amantadine, Amoxovir, AZT, Clevudine, Delavirdine, d4T, Emtricitabine, Entecavir, Famciclovir, Ganciclovir, Indinavir, Lamivudine, Nelfinavir, Nevirapine, Oseltamavir, Rimantadine, Ritonavir, Saquinavir, Septrin, Telbivudine, Tenofovir, Valacyclovir, Valtorcitabine, Valopicitabine or
Zanamivir. It is a further object of the present invention to provide a compound of formula (I), (Ia), (Ic), (Id), (Ie) or (If) as defined herein or a pharmaceutical composition as defined herein for the preparation of a medicament for the treatment of cancer and/or viral infections
The compounds selected from formula (I), (Ia), (Ic), (Id), (Ie) or (If) of the present invention are e.g. HDM2 and/or MDMX ligands and show binding affinities from about 1 nM to about 100 μM to HDM2 and/or MDMX, preferably from about 1 nM to about 10 μM, especially to about 1 μM, preventing binding of p53 and other proteins, inhibition of proliferation and induction of apoptosis in cell based assays, especially in the assays described herein.
The compounds of the present invention are useful in the treatment or control of cell proliferative disorders, in particular oncological disorders. These compounds and formulations containing said compounds are useful in the treatment or control of solid tumors, such as, for example, breast, colon, lung and prostate tumors, as well as osteosarcoma, acute myeloid leukaemia, sporadic endometrial cancer, melanoma, malignant melanoma, soft tissue Sarcoma, B-cell chronic lymphocytic leukaemia, gastric cancers, cervical cancer, hepatocellular carcinoma, and colorectal cancer.
The compounds described herein are especially useful for the treatment and/or prevention of cancers associated with overexpression of HDM2 and/or MDMX.
Accordingly the compounds of the present invention are especially useful for the treatment and/or prevention of the following cancers associated with MDM2 and/or
MDMX:
MDM2 is amplified in 7% of all human cancers. Gene amplification was observed in 19 tumor types, with the highest frequency observed in soft tissue tumors (20%), osteosarcomas (16%) and esophageal carcinomas (13%). Tumors which showed a higher incidence of MDM2 amplification than p53 mutation were soft tissue tumors, testicular germ cell cancers and neuro-blastomas (Momand et al, NAR, 1998). Naturally occurring polymorphism (SNP309) occurring within the MDM2 promoter leads to an increase in MDM2 transcription and translation. The overall frequency of MDM2 amplification in these human tumors was 7%. It is a common event in hematological malignancies. A list of cancers with a wild type of p53 gene that is sensitive to MDM2 inhibitors includes: B-cell CLL (chronic lymphocytic leukemia) (Coll-Muler et al, Blood, 2006), AML (Kojima et al, Blood, 2005), multiple myeloma (Shruhmer et al, Blood, 2005), neuroblastoma (Cattelani et al, CCR, 2008), Hodgkin lymphoma (Drakos et al, CCR, 2007), osteosarcoma and prostate cancer (Vassilev et al, Science, 2004), Kaposi's sarcoma (Sarek, J. Clinic. Invest., 2007), rhabdomyosarcoma (Miyachi et al, CCR, 2009), RCC (renal cell carcinoma) (Roberts et al, CR, 2009), squamous cell carcinoma and esophageal cancers (Cescon et al, CCR, 2009), cutaneous melanoma (Firoz et al, CCR, 2009), retinoblastoma (Laurie et al, Nature, 2006). There are evidences that pancreatic cancer with wild type p53 gene could be sensitive to MDM2 inhibitors as well (submitted for publication).
Table 1. Summary of MDM2 gene amplification frequencies from 28 human tumors (Momand et al, NAR, 1998).
Figure imgf000038_0001
Figure imgf000039_0001
Total number of tumor samples analyzed was 3889 and the average MDM2 gene amplification frequency was 7.2%. aNumber of samples analyzed. bSarcomas of soft tissue origin that were not specified. cSoft tissue tumors that did not fall into the listed classes. The number of samples was less than five in any individual class.
Human MDMX gene maps in chromosomal region Iq32, which is frequently amplified in human cancers. It has been documented in 4% of gliomas (Riemenschneider, CR 1999) and 5% breast cancers (Danovi et al, MCB, 2004). Recently, -60% of retinoblastomas (Laurie, Nature 2006) have been found to bear HDMX overexpression. Moreover, HDMX gene was found overexpressed in a large subset of cervical and ovarian cancer cell lines (Ramos, CR 2001). A systemic analysis of HDMX expression in primary tumors of different origins revealed broad spectrum of human cancers with HDMX overexpression
Table 1. Summary of HDMX gene amplification frequencies from 500 human tumors (Danovi et al, MCB, 2004).
Figure imgf000040_0001
A therapeutically effective amount of a compound in accordance with this invention means an amount of compound that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is within the skill in the art.
The therapeutically effective amount or dosage of a compound according to this invention can vary within wide limits and may be determined in a manner known in the art. Such dosage may be adjusted to the individual requirements in each particular case including the specific compound being administered, the route of administration, the condition being treated, as well as the patient being treated.
Examples of pharmacologically acceptable salts of sufficiently basic compounds of formula (I), (Ia), (Ic), (Id), (Ie) or (If) are salts of physiologically acceptable mineral acids like hydrochloric, hydrobromic, sulfuric and phosphoric acid; or salts of organic acids like methanesulfonic, p-toluenesulfonic, lactic, acetic, trifluoroacetic, citric, succinic, fumaric, maleic and salicylic acid. Further, a sufficiently acidic compound of formula (I), (Ia), (Ic), (Id), (Ie) or (If) may form alkali or earth alkali metal salts, for example sodium, potassium, lithium, calcium or magnesium salts; ammonium salts; or organic base salts, for example methylamine, dimethylamine, trimethylamine, triethylamine, ethylenediamine, ethanolamine, choline hydroxide, meglumin, piperidine, morpholine, tris-(2-hydroxyethyl)amine, lysine or arginine salts; all of which are also further examples of salts of formula (I), (Ia), (Ic), (Id), (Ie) or (If). Compounds of formula (I), (Ia), (Ic), (Id), (Ie) or (If) may be solvated, especially hydrated. The hydratization/hydration may occur during the process of production or as a consequence of the hygroscopic nature of the initially water free compounds of formula (I), (Ia), (Ic), (Id), (Ie) or (If). The solvates and/or hydrates may e.g. be present in solid or liquid form.
It should be appreciated that certain compounds of formula (I), (Ia), (Ic), (Id), (Ie) or (If) may have tautomeric forms from which only one might be specifically mentioned or depicted in the following description, different geometrical isomers (which are usually denoted as cis/trans isomers or more generally as (E) and (Z) isomers) or different optical isomers as a result of one or more chiral carbon atoms (which are usually nomenclatured under the Cahn-Ingold-Prelog or R/S system). All these tautomeric forms, geometrical or optical isomers (as well as racemates and diastereomers) and polymorphous forms are included in the invention. Since the compounds of formula (I), (Ia), (Ic), (Id), (Ie) or (If) may contain asymmetric C-atoms, they may be present either as achiral compounds, mixtures of diastereomers, mixtures of enantiomers or as optically pure compounds. The present invention comprises both all pure enantiomers and all pure diastereomers, and also the mixtures thereof in any mixing ratio.
The therapeutic use of compounds according to formula (I), (Ia), (Ic), (Id), (Ie) or (If), their pharmacologically acceptable salts, solvates and hydrates, respectively, as well as formulations and pharmaceutical compositions also lie within the scope of the present invention.
The pharmaceutical compositions according to the present invention comprise at least one compound of formula (I), (Ia), (Ic), (Id), (Ie) or (If) as an active ingredient and, optionally, carrier substances and/or adjuvants.
The present invention also relates to pro-drugs which are composed of a compound of formula (I), (Ia), (Ic), (Id), (Ie) or (If) and at least one pharmacologically acceptable protective group which will be cleaved off under physiological conditions, such as an alkoxy-, arylalkyloxy-, acyl-, acyloxymethyl group (e.g. pivaloyloxymethyl), an 2- alkyl-, 2-aryl- or 2-arylalkyl-oxycarbonyl-2-alkylidene ethyl group or an acyloxy group as defined herein, e.g. ethoxy, benzyloxy, acetyl or acetyloxy or, especially for a compound of formula (I), (Ia), (Ic), (Id), (Ie) or (If), carrying a hydroxy group (-OH): a sulfate, a phosphate (-OPO3 or -OCH2OPO3) or an ester of an amino acid. Especially preferred are pro-drugs of the hydroxy group of a compound of formula (I), (Ia), (Ic), (Id), (Ie) or (If).
As mentioned above, therapeutically useful agents that contain compounds of formula (I), (Ia), (Ic), (Id), (Ie) or (If), their solvates, salts or formulations are also comprised in the scope of the present invention. In general, compounds of formula (I), (Ia), (Ic), (Id), (Ie) or (If) will be administered by using the known and acceptable modes known in the art, either alone or in combination with any other therapeutic agent. For oral administration such therapeutically useful agents can be administered by one of the following routes: oral, e.g. as tablets, dragees, coated tablets, pills, semisolids, soft or hard capsules, for example soft and hard gelatine capsules, aqueous or oily solutions, emulsions, suspensions or syrups, parenteral including intravenous, intramuscular and subcutaneous injection, e.g. as an injectable solution or suspension, rectal as suppositories, by inhalation or insufflation, e.g. as a powder formulation, as microcrystals or as a spray (e.g. liquid aerosol), transdermal, for example via an transdermal delivery system (TDS) such as a plaster containing the active ingredient or intranasal. For the production of such tablets, pills, semisolids, coated tablets, dragees and hard, e.g. gelatine, capsules the therapeutically useful product may be mixed with pharmaceutically inert, inorganic or organic excipients as are e.g. lactose, sucrose, glucose, gelatine, malt, silica gel, starch or derivatives thereof, talc, stearinic acid or their salts, dried skim milk, and the like. For the production of soft capsules one may use excipients as are e.g. vegetable, petroleum, animal or synthetic oils, wax, fat, polyols. For the production of liquid solutions, emulsions or suspensions or syrups one may use as excipients e.g. water, alcohols, aqueous saline, aqueous dextrose, polyols, glycerin, lipids, phospholipids, cyclodextrins, vegetable, petroleum, animal or synthetic oils. Especially preferred are lipids and more preferred are phospholipids (preferred of natural origin; especially preferred with a particle size between 300 to 350 nm) preferred in phosphate buffered saline (pH = 7 to 8, preferred 7.4). For suppositories one may use excipients as are e.g. vegetable, petroleum, animal or synthetic oils, wax, fat and polyols. For aerosol formulations one may use compressed gases suitable for this purpose, as are e.g. oxygen, nitrogen and carbon dioxide. The pharmaceutically useful agents may also contain additives for conservation, stabilization, e.g. UV stabilizers, emulsifiers, sweetener, aromatizers, salts to change the osmotic pressure, buffers, coating additives and antioxidants.
hi general, in the case of oral or parenteral administration to adult humans weighing approximately 80 kg, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 20 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded when indicated. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it may be given as continuous infusion or subcutaneous injection.
The compounds of the present invention can be prepared according to the following procedure:
Figure imgf000044_0001
The synthesis of the 4-sulfanyl-pyrrolidin-2-one scaffold is based on a four-component reaction (4CR) between a primary amine (II), an aldehyde or ketone (III) with maleic anhydride (IV), and a thiol (V). The reaction is preferably performed in toluene at reflux with a stoichiometric amount of the starting materials, according to J. Wei, J. T. Shaw Org. Lett. 2007, 9, 4077. The resulting 4-sulfanyl-pyrrolidin-2-one (VI) is formed in acceptable to good yields as a diastereoisomeric mixture. Generally, the two diastereoisomers are separated and isolated by preparative HPLC-chromatography. The final 4-sulfanyl-pyrrolidin-2-one amide of formula (I), (Ia), (Ic), (Id), (Ie) or (If) was obtained via amino lysis using amine (VIII) of the corresponding pentafluorophenyl esters of formula (VII) that were synthesized according to M. Bodanszky, A. Bodanszky, The practice of Peptide Synthesis 2nd Edition, p 102, Springer- Verlag Berlin Heidelberg New York (1994). These compounds of formula (I), (Ia), (Ic), (Id), (Ie) or (If) can be further modified such as the conversion into esters or salts from acids, salts from amines or by cleaving off protecting groups found in substituents R1 to R6. Further compounds of formula (I) wherein n is 0 can be prepared following the procedures described in:
1) M. R. Linder, J. Podlech, Organic Letters 2001, Vol. 3, No. 12, 1849-1851;
2) J. Podlech, M. R. Linder, J. Org. Chem. 1997, 62, 5873-5883; 3) J. Cesar, M. Sollner Dolenc, Tetrahedron Letters 42 (2001) 7099-7102.
The reaction procedures described herein may also be carried out in the presence of a chiral catalyst like e.g. proline-derived catalysts (as e.g. described in www.organic-chemistry.org/Highlights/2007/25March.shtm) in order to obtain the corresponding enantiomerically pure compounds.
EXAMPLES
The present invention encompasses the following Examples:
Example 1
General procedure for the synthesis of 5-oxo-3-sulfanyl-pyrrolidin-3-carboxamides
(I):
Maleic anhydride (IV, 1 mmol), a thiol (V, 1 mmol), aldehyde or ketone (III, 1 mmol) and amine (II, 1 mmol) in toluene (8 mL) were heated to 150°C in a sealed tube for 24 hours. After cooled to room temperature, the solution was concentrated in vacuo. Purification on silica gel using an eluent (ethyl acetate: methanol = 9:1 to 1 :1) yielded compounds of formula (VI) as a diastereoisomeric mixture. Afterwards, the two diastereoisomers were separated by preparative HPLC chromatography. Preparative separations were usually performed with an acetonitrile-water eluent (+0.1 % formic acid) on a RP Polaris Cl 8 column (length: 250 mm, diameter: 21 mm; particle size: 5 μm). Generally, good separations were observed (retention times of the two cis/trans diasteroisomers differed by 1 to 2 minutes) by using isocratic systems (70 % acetonitrile: 30 % water).
To a suspension of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EDCI (1.5 mmol) in 8 mL ethyl acetate was added pentafluorophenol (3 mmol) at 0°C. After 10 minutes, S-oxo-pyrrolidine-S-carboxylic acid VI (1 mmol) was added at 0°C and the reaction mixture was stirred for 1 hour at room temperature. After evaporation of the solvent, the crude product was purified by chromatography on silica gel (ethyl acetate:hexane = 1:2) to yield the corresponding 5-oxo-pyrrolidine-3-carboxylic acid pentafluorophenyl ester VII as a colourless oil.
To a suspension of 5-oxo-pyrrolidine-3-carboxylic acid pentafluorophenyl ester VII (0.5 mmol) in 2 mL dry THF was added the desired amine VIII (0.5 mmol) at room temperature. The reaction mixture was stirred for 1 hour at room temperature. Afterwards, 20 mL methylene chloride were added. The resulting organic layer was washed with 20 mL of a saturated aqueous solution of sodium hydrogencarbonate, dried over magnesium sulfate and the solvent was removed in vacuo. Finally, the crude product was purified by chromatography on silica gel with a suitable eluent to afford the desired 5-oxo-pyrrolidine-3-carboxamide I as a white solid.
Example 2
According to the general procedure in example 1, the following compounds were prepared:
2.1 cis-2-(6-chloro-l-methyl-lH-indol-3-yl)-l-[(4-chlorophenyl)methyl]-3-[(4- methylphenyl)sulfanyl] -5 -oxo-N-(pyridin-2-ylmethyl)pyrrolidine-3 -carboxamide. Molecular Formula = C34H30C12N4O2S. Molecular Weight = 629.599. [M+H]+ observed = 629.1. Isolated yield 34.08 %.
2.2 trans-2-(6-chloro-l-methyl-lH-indol-3-yl)-l-[(4-chlorophenyl)methyl]-3-[(4- methylphenyl)sulfanyl]-5-oxo-N-(pyridin-2-ylmethyl)pyrrolidine-3-carboxamide. Molecular Formula = C34H30C12N4O2S. Molecular Weight = 629.599. [M+H]+ observed = 629.1. Isolated yield 3.78 %.
2.3 trans-2-(6-chloro-l-methyl-lH-indol-3-yl)-l-[(4-chlorophenyl)methyl]-3-[(4- methylphenyl)sulfanyl]-5-oxo-N-(thiophen-2-ylmethyl)pyrrolidine-3-carboxamide. Molecular Formula = C33H29C12N3O2S2. Molecular Weight = 634.638. [M+H]+ observed = 656.0. Isolated yield 3.04 %.
2.4 cis-2-(6-chloro-l-methyl-lH-indol-3-yl)-l-[(4-chlorophenyl)methyl]-3-[(4- methylphenyl)sulfanyl]-5-oxo-N-(thiophen-2-ylmethyl)pyrrolidine-3-carboxamide. Molecular Formula = C33H29C12N3O2S2. Molecular Weight = 634.638. [M+Na]+ observed = 656.0. Isolated yield 27.34 %.
2.5 trans-2-(6-chloro-l -methyl- lH-indol-3-yl)- l-(4-chlorophenyl)-3-[(4- methylphenyl)sulfanyl]-5-oxo-N-(pyridin-2-ylmethyl)pyrrolidine-3-carboxamide. Molecular Formula = C33H28C12N4O2S. Molecular Weight = 615.572. [M+H]+ observed = 615.1. Isolated yield 2.78 %.
2.6 cis-2-(6-chloro-l-methyl-lH-indol-3-yl)-l-(4-chlorophenyl)-3-[(4- methylphenyl)sulfanyl]-5-oxo-N-(pyridin-2-ylmethyl)pyrrolidine-3-carboxamide. Molecular Formula = C33H28C12N4O2S. Molecular Weight = 615.572. [M+H]+ observed = 615.1. Isolated yield 25.06 %.
2.7 cis-2-(6-chloro-lH-indol-3-yl)-l-[(4-chlorophenyl)methyl]-3-[(4- methylphenyl)sulfanyl]-5-oxo-N-(pyridin-2-ylmethyl)pyrrolidine-3-carboxamide. Molecular Formula = C33H28C12N4O2S. Molecular Weight = 615.572. [M+H]+ observed = 615.2. Isolated yield 12.50 %.
2.8 trans-2-(6-chloro-lH-indol-3-yl)-l-[(4-chlorophenyl)methyl]-3-[(4- methylphenyl)sulfanyl]-5-oxo-N-(pyridin-2-ylmethyl)pyrrolidine-3-carboxamide.
Molecular Formula = C33H28C12N4O2S. Molecular Weight = 615.572. [M+H]+ observed = 615.2. Isolated yield 4.56 %.
2.9 trans-2-(6-chloro-lH-indol-3-yl)-l-[(4-chlorophenyl)methyl]-N-[3-(morpholin-4- yl)propyl]-5-oxo-3-(phenylsulfanyl)pyrrolidine-3-carboxamide. Molecular Formula =
C33H34C12N4O3S. Molecular Weight = 637.619. [M+H]+ observed = 637.2. Isolated yield 7.30 %. 2.10 cis-2-(6-chloro-lH-indol-3-yl)-l-[(4-chlorophenyl)methyl]-N-[3-(morpholin-4- yl)propyl]-5-oxo-3-(phenylsulfanyl)pyrrolidine-3-carboxamide. Molecular Formula = C33H34C12N4O3S. Molecular Weight = 637.619. [M+H]+ observed = 637.2. Isolated yield 7.18 %.
2.11 trans-2-(6-chloro-lH-indol-3-yl)-l-[(4-chloro-2-methylphenyl)methyl]-N-[3- (moφholin-4-yl)propyl]-5-oxo-3-(phenylsulfanyl)pyrrolidine-3-carboxamide. Molecular Formula = C34H36C12N4O3S. Molecular Weight = 651.646. [M+H]+ observed = 651.2. Isolated yield 5.18 %.
2.12 cis-2-(6-chloro-lH-indol-3-yl)-l-[(4-chloro-2-methylphenyl)methyl]-N-[3- (morpholin-4-yl)propyl]-5-oxo-3-(phenylsulfanyl)pyrrolidine-3-carboxamide. Molecular Formula = C34H36C12N4O3S. Molecular Weight = 651.646. [M+H]+ observed = 651.2. Isolated yield 7.74 %.
2.13 trans-2-(6-chloro-lH-indol-3-yl)-l-[(3-chlorophenyl)methyl]-N-[3-(morpholin-4- yl)propyl]-5-oxo-3-(phenylsulfanyl)pyrrolidine-3-carboxamide. Molecular Formula = C33H34C12N4O3S. Molecular Weight - 637.619. [M+H]+ observed = 637.2. Isolated yield 2.82 %.
2.14 cis-2-(6-chloro- 1 H-indol-3-yl)- 1 - [(3 -chlorophenyl)methyl] -N- [3-(morpholin-4- yl)propyl]-5-oxo-3-(phenylsulfanyl)pyrrolidine-3-carboxamide. Molecular Formula = C33H34C12N4O3S. Molecular Weight = 637.619. [M+H]+ observed = 637.2. Isolated yield 3.81 %.
2.15 trans-2-(6-chloro-lH-indol-3-yl)-l-[(lR)-l-(4-chlorophenyl)ethyl]-N-[3- (morpholin-4-yl)propyl]-5-oxo-3-(phenylsulfanyl)pyrrolidine-3-carboxamide. Molecular Formula = C34H36C12N4O3S. Molecular Weight = 651.646. [M+H]+ observed = 651.2. Isolated yield 2.65 %. 2.16 cis-2-(6-chloro-lH-indol-3-yl)-l-[(lR)-l-(4-chlorophenyl)ethyl]-N-[3-(morpholin- 4-yl)propyl]-5-oxo-3-(phenylsulfanyl)pyrrolidine-3-carboxamide. Molecular Formula = C34H36C12N4O3S. Molecular Weight - 651.646. [M+H]+ observed = 651.2. Isolated yield 1.36 %.
2.17 trans-2-(6-chloro-lH-indol-3-yl)-l-[(4-chlorophenyl)methyl]-3-[(4- chlorophenyl)sulfanyl]-N-[3-(moφholin-4-yl)propyl]-5-oxopvrrolidine-3-carboxamide. Molecular Formula = C33H33C13N4O3S. Molecular Weight = 672.064. [M+H]+ observed = 671.1. Isolated yield 6.65 %.
2.18 cis-2-(6-chloro-lH-indol-3-yl)-l-[(4-chlorophenyl)methyl]-3-[(4- chlorophenyl)sulfanyl]-N-[3-(morpholin-4-yl)propyl]-5-oxopyrrolidine-3-carboxamide. Molecular Formula = C33H33C13N4O3S. Molecular Weight = 672.064. [M+H]+ observed = 673.1. Isolated yield 19.04 %.
2.19 trans-l-benzyl-2-(6-chloro-lH-indol-3-yl)-N-[3-(morpholin-4-yl)propyl]-5-oxo-3- (phenylsulfanyl)pyrrolidine-3-carboxamide. Molecular Formula = C33H35C1N4O3S. Molecular Weight = 603.174. [M+H]+ observed = 603.0. Isolated yield 4.31 %.
2.20 cis-l-benzyl-2-(6-chloro-lH-indol-3-yl)-N-[3-(morpholin-4-yl)propyl]-5-oxo-3- (phenylsulfanyl)pyrrolidine-3-carboxamide. Molecular Formula = C33H35C1N4O3S. Molecular Weight = 603.174. [M+H]+ observed = 603.0. Isolated yield 4.59 %.
2.21 trans-2-(6-chloro-lH-indol-3-yl)-l-[(lS)-l-(4-chlorophenyl)ethyl]-N-[3- (moipholin^-y^propy^-S-oxo-S-φhenylsulfanytypyrrolidine-S-carboxamide.
Molecular Formula = C34H36C12N4O3S. Molecular Weight = 651.646. [M+H]+ observed = 650.9. Isolated yield 4.91 %.
2.22 cis-2-(6-chloro-lH-indol-3-yl)-l-[(lS)-l-(4-chlorophenyl)ethyl]-N-[3-(morpholin- 4-yl)propyl]-5-oxo-3-(phenylsulfanyl)pyrrolidine-3-carboxamide. Molecular Formula =
C34H36C12N4O3S. Molecular Weight = 651.646. [M+H]+ observed = 651.0. Isolated yield 4.86 %. 2.23 trans-2-(6-bromo-lH-indol-3-yl)-l-[(4-chlorophenyl)methyl]-3-[(4- methylphenyl)sulfanyl]-N- [3 -(morpholin-4-yl)propyl] -5 -oxopyrrolidine-3 -carboxamide. Molecular Formula = C34H36BrClN4O3S. Molecular Weight = 696.097. [M+H]+ observed = 697.1. Isolated yield 9.27%.
2.24 cis-2-(6-bromo-lH-indol-3-yl)-l-[(4-chlorophenyl)methyl]-3-[(4- methylphenyl)sulfanyl]-N-[3-(moφholin-4-yl)propyl]-5-oxopyrrolidine-3-carboxamide. Molecular Formula = C34H36BrClN4O3S. Molecular Weight = 696.097. [M+H]+ observed = 697.0. Isolated yield 11.14%.
2.25 trans-2-(5 -bromo- 1 H-indol-3 -yl)- 1 -[(4-chlorophenyl)methyl] -N- [3 -(moφholin-4- yl)propyl]-5-oxo-3-(phenylsulfanyl)pyrrolidine-3-carboxamide. Molecular Formula = C33H34BrClN4O3S. Molecular Weight = 682.07. [M+H]+ observed = 682.9. Isolated yield 3.71 %.
2.26 cis-2-(5 -bromo- 1 H-indol-3 -yl)- 1 -[(4-chlorophenyl)methyl] -N- [3 -(morpholin-4- yl)propyl]-5-oxo-3-(phenylsulfanyl)pyrrolidine-3-carboxamide. Molecular Formula = C33H34BrClN4O3S. Molecular Weight = 682.07. [M+H]+ observed = 682.8. Isolated yield 4.65 %.
2.27 cis-2-(6-chloro-lH-indol-3-yl)-l-[(6-chloropyridin-3-yl)methyl]-N-[3-(morpholin- 4-yl)propyl]-5-oxo-3-(phenylsulfanyl)pyrrolidine-3-carboxamide. Molecular Formula = C32H33C12N5O3S. Molecular Weight = 638.607. [M+H]+ observed = 638.0. Isolated yield 3.76 %.
2.28 trans-2-(6-chloro-lH-indol-3-yl)-l-[(6-chloropyridin-3-yl)methyl]-N-[3- (moφholin-4-yl)propyl]-5-oxo-3-(phenylsulfanyl)pyrrolidine-3-carboxamide. Molecular Formula = C32H33C12N5O3S. Molecular Weight = 638.607. Isolated yield 1.46 %. 2.29 trans-4-{[2-(6-chloro-lH-indol-3-yl)-l-[(lS)-l-(4-chlorophenyl)ethyl]-5-oxo-3- (phenylsulfanyl)pyrrolidin-3-yl]carbonyl}piperazin-2-one. Molecular Formula = C31H28C12N4O3S. Molecular Weight = 607.55. [M+H]+ observed = 607.2. Isolated yield 4.44 %.
2.30 cis-4-{[2-(6-chloro-lH-indol-3-yl)-l-[(lS)-l-(4-chlorophenyl)ethyl]-5-oxo-3- (phenylsulfanyl)pyrrolidin-3-yl]carbonyl}piperazin-2-one. Molecular Formula = C31H28C12N4O3S. Molecular Weight = 607.55. [M+H]+ observed = 607.2. Isolated yield 4.09 %.
2.31 trans-4-{[2-(6-chloro-lH-indol-3-yl)-l-[(lR)-l-(4-chlorophenyl)ethyl]-5-oxo-3- (phenylsulfanyl)pyrrolidin-3-yl]carbonyl}piperazin-2-one. Molecular Formula = C31H28C12N4O3S. Molecular Weight = 607.55. [M+H]+ observed = 608.8. Isolated yield 2.62 %.
2.32 cis-4-{[2-(6-chloro-lH-indol-3-yl)-l-[(lR)-l-(4-chlorophenyl)ethyl]-5-oxo-3- (phenylsulfanyl)pyrrolidin-3-yl]carbonyl}piperazin-2-one. Molecular Formula = C31H28C12N4O3S. Molecular Weight = 607.55. [M+H]+ observed = 606.9. Isolated yield 1.89 %.
2.33 trans-l-[(4-chlorophenyl)methyl]-2-(6-fluoro-lH-indol-3-yl)-N-[3-(moφholin-4- yl)propyl]-5-oxo-3-(phenylsulfanyl)pyrrolidine-3-carboxamide. Molecular Formula = C33H34C1FN4O3S. Molecular Weight = 621.164. [M+H]+ observed = 621.0. Isolated yield 2.98 %.
2.34 cis-l-[(4-chlorophenyl)methyl]-2-(6-fluoro-lH-indol-3-yl)-N-[3-(morpholin-4- yl)propyl]-5-oxo-3-(phenylsulfanyl)pyrrolidine-3-carboxamide. Molecular Formula = C33H34C1FN4O3S. Molecular Weight = 621.164. [M+H]+ observed = 621.0. Isolated yield 4.72 %.
2.35 cis-4-{[2-(6-bromo-lH-indol-3-yl)-l-[(4-chlorophenyl)methyl]-3-[(4- methylphenyl)sulfanyl]-5-oxopyrrolidin-3-yl]carbonyl}piperazin-2-one. Molecular Formula = C31H28BrClN4O3S. Molecular Weight = 652.001. [M+H]+ observed = 651.3. Isolated yield 8.00 %.
2.36 cis-l-[(4-bromophenyl)methyl]-2-(6-chloro-lH-indol-3-yl)-3-[(4- methylpheny^sulfany^-N-fS-^orpholin^-y^propylJ-S-oxopyrrolidine-S-carboxamide. Molecular Formula = C34H36BrClN4O3S. Molecular Weight = 696.097. [M+H]+ observed = 697.2. Isolated yield 8.39 %.
2.37 trans-l-[(4-bromophenyl)methyl]-2-(6-chloro-lH-indol-3-yl)-3-[(4- methylphenyljsulfanylJ-N-fS-^orpholm^-y^propyll-S-oxopyrrolidine-S-carboxamide. Molecular Formula = C34H36BrClN4O3S. Molecular Weight = 696.097. [M+H]+ observed = 697.1. Isolated yield 3.45 %.
2.38 cis-2-(6-bromo-lH-indol-3-yl)-l-[(4-bromophenyl)methyl]-3-[(4- methylphenyl)sulfanyl]-N-[3-(morpholin-4-yl)propyl]-5-oxopyrrolidine-3-carboxamide. Molecular Formula = C34H36Br2N4O3S. Molecular Weight = 740.548. [M+H]+ observed = 740.5. Isolated yield 10.00 %.
2.39 cis-2-(6-chloro-lH-indol-3-yl)-l-[(4-chloro-3-fluorophenyl)methyl]-3-[(4- methylphenyl)sulfanyl]-N-[3-(moφholin-4-yl)propyl]-5-oxopyrrolidine-3-carboxamide. Molecular Formula = C34H35C12FN4O3S. Molecular Weight = 669.636. [M+H]+ observed = 669.1. Isolated yield 14.85 %.
2.40 trans-2-(6-chloro-lH-indol-3-yl)-l-[(4-chloro-3-fluorophenyl)methyl]-3-[(4- methylpheny^sulfanylJ-N-fS-^orpholin^-y^propylJ-S-oxopyrrolidine-S-carboxamide.
Molecular Formula = C34H35C12FN4O3S. Molecular Weight = 669.636. [M+H]+ observed = 669.0. Isolated yield 4.48 %.
2.41 cis-2-(6-chloro-5-fluoro-lH-indol-3-yl)-l-[(4-chlorophenyl)methyl]-3-[(4- methylphenyl)sulfanyl]-N-[3-(morpholin-4-yl)propyl]-5-oxopyrrolidine-3-carboxamide.
Molecular Formula = C34H35C12FN4O3S. Molecular Weight = 669.636. [M+H]+ observed = 669.1. Isolated yield 4.88 %. 2.42 trans-2-(6-chloro-5 -fluoro- 1 H-indol-3 -yl)- 1 - [(4-chlorophenyl)methyl] -3-[(4- methylphenyl)sulfanyl]-N-[3-(moφholin-4-yl)propyl]-5-oxopyπOlidine-3-carboxamide. Molecular Formula = C34H35C12FN4O3S. Molecular Weight = 669.636. [M+H]+ observed = 669.1. Isolated yield 1.08 %.
2.43 cis-5-(6-chloro-lH-indol-3-yl)-l-[(4-chlorophenyl)methyl]-4-{[4-(2- hydroxyethyl)piperazin- 1 -yljcarbonyl} -4-[(4-methylphenyl)sulfanyl]pyπOlidin-2-one. Molecular Formula = C33H34C12N4O3S. Molecular Weight = 637.619. [M+H]+ observed = 637.0. Isolated yield 7.67 %.
2.44 cis-2-(6-chloro-lH-indazol-3-yl)-l-[(4-chlorophenyl)methyl]-3-[(4- methylphenyl)sulfanyl]-N-[3-(morpholin-4-yl)propyl]-5-oxopyrrolidine-3-carboxamide. Molecular Formula = C33H35C12N5O3S. Molecular Weight = 652.634. [M+H]+ observed = 652.0. Isolated yield 6.04 %.
2.45 cis-2-(6-chloro-lH-indol-3-yl)-l-[(4-chlorophenyl)methyl]-3-[(4- methylphenyl)sulfanyl]-N-[3-(morpholin-4-yl)propyl]-5-oxopyrrolidine-3-carboxamide. Molecular Formula = C34H36C12N4O3S. Molecular Weight = 651.646. [M+H]+ observed = 651.1. Isolated yield 7.97 %.
2.46 cis-l-[(4-bromophenyl)methyl]-5-(6-chloro-lH-indol-3-yl)-4-{[4-(2- hydroxyethyl)piperazin- 1 -yl]carbonyl} -4-[(4-methylphenyl)sulfanyl]pyrrolidin-2-one. Molecular Formula = C33H34BrClN4O3S. Molecular Weight = 682.07. [M+H]+ observed = 683.0. Isolated yield 5.35 %.
2.47 cis-l-[(4-bromophenyl)methyl]-2-(6-chloro-lH-indol-3-yl)-N-(2,3- dihydroxypropyl)-3-[(4-methylphenyl)sulfanyl]-5-oxopyrrolidine-3-carboxamide. Molecular Formula = C30H29BrClN3O4S. Molecular Weight = 642.991. [M+Na]+ observed = 668.1. Isolated yield 6.92 %. 2.48 cis-4-{[l-[(4-bromophenyl)methyl]-2-(6-chloro-lH-indol-3-yl)-3-[(4- methylphenyl)sulfanyl] -5 -oxopyrrolidin-3 -yl]carbonyl} piperazin-2-one. Molecular Formula = C31H28BrClN4O3S. Molecular Weight = 652.001. [M+H]+ observed = 653.1. [M+Na]+ observed = 675.3. Isolated yield 3.39 %.
2.49 cis-l-[(4-bromophenyl)methyl]-2-(6-chloro-lH-indol-3-yl)-3-[(4- methylphenyl)sulfanyl]-N-[2-(morpholin-4-yl)ethyl]-5-oxopyrrolidine-3-carboxamide. Molecular Formula = C33H34BrClN4O3S. Molecular Weight = 682.07. [M+H]+ observed = 683.1. Isolated yield 7.30 %.
2.50 cis-l-[(4-bromophenyl)methyl]-2-(6-chloro-lH-indol-3-yl)-3-[(4- methylphenyl)sulfanyl]-N-[4-(moφholin-4-yl)butyl]-5-oxopyrrolidine-3-carboxamide. Molecular Formula = C35H38BrClN4O3S. Molecular Weight = 710.123. [M+H]+ observed = 711.0. Isolated yield 7.08 %.
2.50 cis-l-[(4-bromophenyl)methyl]-2-(6-chloro-lH-indol-3-yl)-N-(4-hydroxybutyl)-3- [(4-methylphenyl)sulfanyl]-5-oxopyrrolidine-3-carboxamide. Molecular Formula = C31H31BrClN3O3S. Molecular Weight = 641.018. [M+Na]+ observed = 664.2. Isolated yield 7.32 %.
2.51 cis-l-[(4-bromophenyl)methyl]-2-(6-chloro-lH-indol-3-yl)-3-[(4- methylphenyl)sulfanyl] -N-( 1 -methylpiperidin-4-yl)-5 -oxopyrrolidine-3 -carboxamide. Molecular Formula = C33H34BrClN4O2S. Molecular Weight = 666.071. [M+H]+ observed = 668.2. Isolated yield 7.51 %.
2.52 cis-l-[(4-bromophenyl)methyl]-2-(6-chloro-lH-indol-3-yl)-3-[(4- ethylphenyl)sulfanyl] -N- [3 -(morpholin-4-yl)propyl]-5 -oxopyrrolidine-3 -carboxamide. Molecular Formula = C35H38BrClN4O3S. Molecular Weight = 710.123. [M+H]+ observed = 711.1. Isolated yield 17.16 %.
2.53 cis-l-[(4-bromophenyl)methyl]-2-(6-chloro-lH-indol-3-yl)-3-[(3,4- dimethylphenyl)sulfanyl]-N-[3-(morpholin-4-yl)propyl]-5-oxopyrrolidine-3- carboxamide. Molecular Formula = C35H38BrClN4O3S. Molecular Weight = 710.123. [M+H]+ observed = 711.0. Isolated yield 9.74 %.
2.52 cis-l-[(4-bromophenyl)methyl]-2-(6-chloro-lH-indol-3-yl)-3-[(2,4- dimethylphenyl)sulfanyl]-N-[3-(moφholin-4-yl)propyl]-5-oxopyrrolidine-3- carboxamide. Molecular Formula = C35H38BrClN4O3S. Molecular Weight = 710.123. [M+H]+ observed = 711.0. Isolated yield 6.38 %.
2.53 trans-l-[(4-bromophenyl)methyl]-2-(6-chloro-lH-indol-3-yl)-N-[3-(morpholin-4- yl)propyl]-3-[(4-nitrophenyl)sulfanyl]-5-oxopyrrolidine-3-carboxamide. Molecular
Formula = C33H33BrClN5O5S. Molecular Weight = 727.068. [M+H]+ observed = 726.0. Isolated yield 3.00 %.
2.54 cis- 1 -[(4-bromophenyl)methyl]-2-(6-chloro- lH-indol-3-yl)-N-[3-(morpholin-4- yl)propyl]-3-[(4-nitrophenyl)sulfanyl]-5-oxopyrrolidine-3-carboxamide. Molecular
Formula = C33H33BrClN5O5S. Molecular Weight = 727.068. [M+H]+ observed = 727.9. Isolated yield 0.41 %.
2.55 cis-l-[(4-bromophenyl)methyl]-2-(6-chloro-lH-indol-3-yl)-N-[(2R)-l- hydroxypropan-2-yl]-3-[(4-methylphenyl)sulfanyl]-5-oxopyrrolidine-3-carboxamide. Molecular Formula - C30H29BrClN3O3S. Molecular Weight = 626.992. [M+Na]+ observed = 650.6. Isolated yield 8.24 %.
2.56 cis-l-[(4-bromophenyl)methyl]-2-(6-chloro-lH-indol-3-yl)-N-[(2S)-l- hydroxypropan-2-yl]-3-[(4-methylphenyl)sulfanyl]-5-oxopyrrolidine-3-carboxamide. Molecular Formula = C30H29BrClN3O3S. Molecular Weight = 626.992. [M+Na]+ observed - 650.2. Isolated yield 8.04 %.
Example 3
1) Synthesis of 4-[5-oxo-pyrrolidine-3-carbonvπ-piperazine-l-carboxylic acid ethylamide compounds Synthesis of (cis)-4-[l-(4-Bromo-benzyl)-2-(6-chloro-lH-indol-3-yl)-5- oxo-B-p-tolylsulfanyl-pyrrolidine-S-carbonylJ-piperazine-l-carboxylic acid ethylamide [PXN727-dl]
Figure imgf000056_0001
Multicomponent reaction (step 1):
Maleic anhydride 2 (6 mmol), thiol 4 (6 mmol), aldehyde 3 (6 mmol) and amine 1 (6 mmol) in toluene (50 mL) were heated to 150 °C under Dean- Stark conditions for 24 hours. After being cooled to room temperature, the solution was concentrated in vacuo. Purification on silica gel (ethyl acetate: methanol = 9:1 to 1 :1) yielded 5 as a diastereoisomeric mixture (1.48 g, 46 %). Literature: J. Wei, J. T. Shaw Org. Lett. 2007, P, 4077.
Separation of the diastereoisomeric mixture: The above described reaction sequence yielded two diastereoisomers dl and d2 in a 50:50 ratio. They were separated by preparative HPLC chromatography using the following conditions:
- Column RP Polaris C18 (length: 250 mm, 0: 21 mm; particle size: 5 μm). - Isocratic elution (70 % acetonitrile: 30 % water, 0.1% HCOOH), 21mL/min, Rt=7.62min. The separation can also be performed with methanol/water mixtures.
Concentration of the solution in vacuo yielded the desired pure diastereoisomer 6 (cis, dl) as a light yellow solid (528.9 mg, 33.6 %).
Overall yield for the preparation of 6: 15.47 % (MCR and isolation of the cis- isomer dl)
Pentafluorophenyl ester formation:
To a suspension of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EDCI (267 mg, 1.4 mmol) in 8 mL ethyl acetate was added pentafluorophenol (512 mg, 2.8 mmol) at 0 0C. After 10 minutes, compound 6 (528.9 mg, 0.9 mmol) was added at 0 °C and the reaction mixture was stirred for 1 hour at room temperature. After evaporation of the solvent, the crude product was purified by chromatography on silica gel (ethyl acetate:hexane = 1 :2 -> 1 :1) to yield the corresponding pentafluorophenyl ester 7 as a colourless oil (632.0 mg, 92.5%).
Literature:
M. Bodanszky, A. Bodanszky, The practice of Peptide Synthesis 2nd Edition, p 102, Springer- Verlag Berlin Heidelberg New York (1994).
Amide coupling: To a suspension of pentafluorophenyl ester 7 (1.3 g, 1.8 mmol) in 16 mL dry
THF was added piperazine (7.2 mmol) at room temperature. The reaction mixture was stirred for 20 hours at room temperature. Afterwards, 20 mL methylene chloride were added. The resulting organic layer was washed with 20 mL of a saturated aqueous solution of sodium hydrogenocarbonate, dried over magnesium sulfate and the solvent was removed in vacuo. Finally, the crude product was purified by chromatography on silica gel (ethyl acetate: methanol 9:1 -> 1 :1) to afford the desired piperazine amide 8 as a white solid (977.8 mg, 84.20 %).
Reaction with ethyl isocyanate:
To a solution of compound 8 (848.3 mg, 1.3 mmol) in 15 mL THF extra dry was added ethyl isocyanate (283.6 mg, 4 mmol) at -30°C. After Ih of stirring at -30°C, 20 mL methylene chloride were added. The resulting organic layer was washed with 20 mL of a saturated aqueous solution of sodium hydrogenocarbonate, dried over magnesium sulfate and the solvent was removed in vacuo. Finally, the crude product was purified by chromatography on silica gel with the system ethyl acetate:methanol 19:1 to yield PXN727-dl as a white solid (853.4 mg, 90.5 %).
mp = 263.7-267.2 °C
1H-NMR (400 MHz, DMSO) δ 11.57 (s, IH), 7.57 (s, IH), 7.50 (s, IH), 7.44 (d, 2H, J = 6.70 Hz), 7.25 (d, 1 H, J = 7.39 Hz), 7.09 (m, 5 H), 6.90 (d, 2H, J
= 7.39 Hz), 6.53 (s, 1 H), 4.93 (s, IH), 4.74 (d, IH, J = 15.29 Hz), 3.84 (s, 2 H), 3.60-3.20 (m, 4H), 3.45 (d, IH, J = 15.29), 3.15-2.80 (m, 4H), 3.09-3.06 (m, 2 H), 2.25 (s, 3H), 1.03 (t, 3H, J = 7.05 Hz).
IR: 3397, 3174, 2923, 1674, 1625, 1535, 1487, 1401, 1361, 1241, 1174, 1118, 1002, 794.
MS (+ESI): m/z = 709.9 [M+H], 730.2 [M+Na].
Overall yield (four preparative steps and diastereoisomer separation): 10.91
%
Example 4
2) Replacement of the sulfur S (group X) by methylene CH2 Synthesis of (cis)4-[3-Benzyl-l-(4-chloro-3-fluoro-benzyl)-2-(6-ch!oro- lH-indol-S-y^-S-oxo-pyrrolidine-S-carbonyll-piperazine-l-carboxylic acid ethylamide [PXN790-dl]
Figure imgf000059_0001
Synthesis of alpha-benzylsuccinic anhydride 10
Figure imgf000059_0002
The commercially available alpha-benzylsuccinic acid 9 (Ig, 4,8 mmol) was refluxed for Ih in 30 mL trifluoroacetic anhydride. Afterwards, the solvent was removed in vacuo. The crude residue was washed with cold hexane to yield alpha-benzylsuccinic anhydride 10 as a white solid (858.2mg, 93.95 %). Multicomponent reaction
Alpha-benzylsuccinic anhydride 10 (850 mg, 4.5 mmol) , aldehyde 3 (1 mmol) and amine 11 (1 mmol) in toluene (16 mL) were heated to 150 °C in a sealed tube for 24 hours. After cooled to room temperature, the solution was concentrated in vacuo. Purification on silica gel (ethyl acetate: methanol = 9:1 to 1 :1) yielded MCR-product 12 as a diastereoisomeric mixture (210.3 mg, 9.20 %).
Pentafluorophenyl ester formation
To a suspension of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EDCI (118.2 mg, 0.617 mmol) in 5 mL ethyl acetate was added pentafluorophenol (227.1 mg, 1.23 mmol) at 0 °C. After 10 minutes, 5- oxo-pyrrolidine-3-carboxylic acid 12 (210.3 mg, 0.411 mmol) was added at 0 °C and the reaction mixture was stirred for 1 hour at room temperature. After evaporation of the solvent, the crude product was purified by chromatography on silica gel (ethyl acetate:hexane = 1:2 ->1 :1) to yield the corresponding (cis)-5-oxo-pyrrolidine-3-carboxylic acid pentafluorophenyl ester 13 as a colourless oil (78.2 mg, 28.9 %).
Amide coupling
To a suspension of (cis)-5-oxo-pyrrolidine-3-carboxylic acid pentafluorophenyl ester 13 (78.2 mg, 0.1154 mmol) in 2 mL THF extra dry was added piperazine (39.8 mg, 0.4616 mmol) at room temperature. The reaction mixture was stirred for 10 hours at room temperature. Afterwards,
20 mL methylene chloride were added. The resulting organic layer was washed with 20 mL of a saturated aqueous solution of sodium hydrogenocarbonate, dried over magnesium sulfate and the solvent was removed in vacuo. Finally, the crude product was purified by chromatography on silica gel (ethyl acetate:methanol 9:1 -> 1 :1) to afford the desired (cis)-4-(piperazine-l-carbonyl)-pyrrolidin-2-one 14 as a white solid (38.5 mg, 57.55 %). Reaction with ethyl isocyanate
To a solution of compound 14 (38.5 mg, 0,066 mmol) in 3 mL THF extra dry was added ethyl isocyanate (14.2 mg, 0.199 mmol) at -3O0C. After Ih of stirring at -300C, 20 mL methylene chloride were added. The resulting organic layer was washed with 20 mL of a saturated aqueous solution of sodium hydrogenocarbonate, dried over magnesium sulfate and the solvent was removed in vacuo. Finally, the crude product was crystallized from ethyl acetate:methanol 19:1 to yield PXN790-dl as a white solid (26.9 mg, 62.24 %).
1H-NMR (400 MHz, DMSO) δ 11.57 (s, IH), 7.58-7.43 (m, 3H), 7.28-7.11 (m, 5H), 6.95-6.83 (m, 4H), 6.55 (s, IH), 4.97-4.91 (m, IH), 4.71 (d, IH, J = 15.24 Hz), 3.63-3.57 (m, 5H), 3.10-3.08 (m, 3H), 2.91-2.85 (m, 3H), 2.69- 2.65 (m, IH), 1.03 (t, 3H, J = 7.02 Hz).
IR: 3043, 3165, 3033, 2964, 2930, 1677, 1615, 1538, 1449, 1401, 1262,
1240,1207,1119,796,698.
MS (+ESI): m/z = 650.1 [M+H], 672.1 [M+Na].
Overall yield (four preparative steps): 0.93 %
Example 5
Replacement of the sulfur S (group X) by oxygene O
Synthesis of (ris)-4-[l-(4-Chloro-3-fluoro-benzyl)-2-(6-chloro-lH-indoI-3- yty-S-oxo-S-p-tolyloxy-pyrrolidine-B-carbonyll-piperazine-l-carboxylic acid ethylamide [PXN789-dl ]
Figure imgf000062_0001
Synthesis of the oxo-substituted anhydride The oxo-substituted anhydride was obtained via a three-step synthesis:
Figure imgf000062_0002
l-Phenyl-2,5-dihydro-lH-pyrrole-2,5-dione 19 (5.19 g, 3 mmol), p-cresol 20 (3.24 g, 3 mmol), and triethylamine (3.03 g, 3 mmol) were added in 20 ml toluene extra dry and heated at 100°C for 6h. Afterwards, the mixture was cooled to 0°C. The precipitated solid was filtered and washed with cold toluene and hexane to yield compound 21 as a purple solid (2.895 g, 34.30 %).
Analytic data for Compound 21: 1H NMR (DMSO, 399.83 MHz): 2.26 (s, 3H), 2.89-2.94 (m, IH), 3.31-3.46 (m,lH), 5.44-5.47 (m, IH), 6.97 (d, 2H, J=8,4 Hz), 7.14 (d, 2H, J=7.6 Hz), 7.33 (d, 2H, J=7,2 Hz), 7.44-7.53 (m, 3H). MS (+ESI): m/z= 282 [M+H].
Compound 21 (610.3 mg, 2.17 mmol) was dissolved in 30 ml of a mixture of aqueous HCl 37%:HCOOH 1:1. The mixture was heated for 3h at 1100C. Afterwards, the mixture was cooled to room temperature and the aqueous phase was washed 3 times with DCM and then evaporated. The resulting solid was washed 3 times with cold ether and the resulting ether phase evaporated to yield the succinic acid 22 as a white solid. Finally, the succinic acid 22 was solved in 10ml of trifluoroacetic anhydride (TFAA) and heated for 6h at 100°C. Then TFAA was evaporated and the resulting solid was washed with cold hexane to yield the corresponding succinic anhydride 15 as a white solid (170.4 mg, 95.56 %).
Analytic data for compound 15 :
1H NMR (DMSO, 399.43 MHz): 2.25 (s,3H), 3.21-3.27 (m, IH), 3.52-3.59
(m, IH), 5.57-5.61 (m, IH), 6.92 (d, 2H, J=8.26 Hz), 7.14 (d, 2H, J=8.22
Hz). IR: 3001, 2920, 1865, 1781, 1608, 1508, 1396, 1213, 1178, 1086, 1021, 903, 806.
Figure imgf000063_0001
Multicomponent reaction First, aldehyde 3 (646.6 mg, 3.6 mmol) and amine 11 (478.8 mg, 3 mmol) were condensed in 3 mL trimethylorthoformiate for 10 hours at room temperature. Then, the solvent was removed in vacuo and the residue was solved in 25 mL o-xylene. Afterwards, succinic anhydride 15 (850 mg, 4.5 mmol) was added and the mixture was heated to 150 °C for 24 hours under Dean-Stark conditions. After cooled to room temperature, the solution was concentrated in vacuo. Purification on silica gel (ethyl acetate: methanol = 9:1 -> 1 :1) yielded MCR-product 16 as a diastereoisomeric mixture (33.9 mg, 2.11 %).
Pentafluorophenyl ester formation
To a suspension of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EDCI (18.5 mg, 0.096 mmol) in 2 mL ethyl acetate was added pentafluorophenol (35.6 mg, 0.193 mmol) at 0 °C. After 10 minutes, 5-oxo- pyrrolidine-3-carboxylic acid 16 (33.9 mg, 0.064 mmol) was added at 0 0C and the reaction mixture was stirred for 1 hour at room temperature. After evaporation of the solvent, the crude product was purified by chromatography on silica gel (ethyl acetate:hexane = 1:2) to yield the corresponding 5-oxo-pyrrolidine-3-carboxylic acid pentafluorophenyl ester
17 as a colourless oil (40.1 mg, 89.80 %).
Amide coupling To a suspension of S-oxo-pyrrolidine-S-carboxylic acid pentafluorophenyl ester 17 (40.1 mg, 0.0578 mmol) in 2 mL THF extra dry was added piperazine (19.9 mg, 0.231 mmol) at room temperature. The reaction mixture was stirred for 10 hours at room temperature. Afterwards, 20 mL methylene chloride were added. The resulting organic layer was washed with 20 mL of a saturated aqueous solution of sodium hydrogenocarbonate, dried over magnesium sulfate and the solvent was removed in vacuo. Finally, the crude product was purified by chromatography on silica gel (ethyl acetate:methanol 9:1 -> 1:1) to afford the desired 4-(piperazine-l-carbonyl)-pyrrolidin-2-one
18 as a white solid (12.2 mg, 45.91 %).
Reaction with ethyl isocyanate To a solution of compound 18 (12.2 mg, 0.0204 mmol) in 3 niL THF extra dry was added ethyl isocyanate (4.4 mg, 0.0612 mmol) at -300C. After Ih of stirring at -30°C, 20 mL methylene chloride were added. The resulting organic layer was washed with 20 mL of a saturated aqueous solution of sodium hydrogenocarbonate, dried over magnesium sulfate and the solvent was removed in vacuo. Finally, the crude product was purified by chromatography on silica gel (methylene chloride:methanol 95:5) to yield PXN789-dl as a yellow solid (9.6 mg, 70.60 %).
MS (+ESI): w/z=666.1[M+H].
Overall yield (four preparative steps): 0.61 %
Further examples
Further examples which have been prepared according to one of the procedures described above: All products were obtained and tested as racemates. The cellular activity was measured on p53 wild type ovarian teratocarcinoma cells (PA-I) and measured IC5Q are given in micromolar. CCA is the abbreviation of Cell Cycle Arrest.
PXN610
Figure imgf000065_0001
C28H28Cl2N2O3S; MW: 543.52; found (HPLC MS): [M+H+] = 543.0; Yield: 47 %; IC50=15
PXN611
Figure imgf000066_0001
C29H31Cl2N3O2S; MW: 556.56; found (HPLC MS): [M+H+] = 556.1; Yield: 28 %; IC50=8.3
PXN612
Figure imgf000066_0002
C27H26Cl2N2O3S; MW: 529.49; found (HPLC MS): [M+H+] = 529.0; Yield: 17 %; IC50=I 0.3
PXN613
Figure imgf000066_0003
C28H29Cl2N3O2S; MW: 542.53; found (HPLC MS): [M+H+] = 542.0; Yield: 13 %; IC50=8
PXN617
Figure imgf000067_0001
C30H29Cl2N3O3S; MW: 582.55; found (HPLC MS): [M+H+]
582.1; [M+Na+] = 604.0; Yield: 32 %; IC50=3.1
PXN618
Figure imgf000067_0002
C31H32Cl2N4O2S; MW: 595.60; found (HPLC MS): [M+H+] 595.1; Yield: 35 %; IC50=4.2
PXN619
Figure imgf000067_0003
C31H3ICl2N3O3S; MW: 596.58; found (HPLC MS): [M+Na+] = 618.1; Yield: 40 %; IC50=28.7
PXN620
Figure imgf000068_0001
C30H29Cl2N3O3S; MW: 582.55; found (HPLC MS): [M+H+] = 581.9; Yield: 15 %; IC5O=15.3
PXN623
Figure imgf000068_0002
C32H36Cl2N4O2S; MW: 611.64; found (HPLC MS): [M+H+] = 611.1; Yield: 49 %; IC50=7.8
PXN624
Figure imgf000068_0003
C3IH27Cl2N3O2S; MW: 576.55; found (HPLC MS): [M+H+] = 576.0; Yield: 41 %; IC50=22.4
PXN625
Figure imgf000069_0001
C30H26Cl2N2O2S2; MW: 581.59; found (HPLC MS): [M+H+] = 581.1; Yield: 37 %; IC50>60
Figure imgf000069_0002
C31H34Cl2N4O2S; MW: 597.61; found (HPLC MS): [M+H+] = 597.1; Yield: 21 %; IC50=7.4
PXN627
Figure imgf000069_0003
C30H25Cl2N3O2S; MW: 562.52; found (HPLC MS): [M+H+] = 562.0; Yield: 17 %; IC50-10.2
PXN628
Figure imgf000070_0001
C29H24Cl2N2O2S2; MW: 567.56; found (HPLC MS): [M+H+] = 567.0; Yield: 20 %; IC50>60
PXN629
Figure imgf000070_0002
C35H39Cl2N5O2S; MW: 664.70; found (HPLC MS): [M+H+] = 664.2; Yield: 40 %; IC50=7.2
PXN630-dl
Figure imgf000070_0003
C34H30Cl2N4O2S; MW: 629.61; found (HPLC MS): [M+H+] = 629.1; Yield: 38 %; IC50>60
PXN631-dl
Figure imgf000071_0001
C33H29Cl2N3O2S2; MW: 634.65; found (HPLC MS): [M+Na+] = 656.0; Yield: 30 %; IC50>60
Figure imgf000071_0002
C34H37Cl2N5O2S; MW: 650.68; found (HPLC MS): [M+H+] = 650.2; Yield: 36 %; IC50=5.2
Figure imgf000071_0003
C33H28Cl2N4O2S; MW: 615.59; found (HPLC MS): [MH-H+] = 615.1; Yield: 17 %; IC50=23.3
PXN633-d2
Figure imgf000072_0001
C33H28Cl2N4O2S; MW: 615.59; found (HPLC MS): [M+H+] = 615.1; Yield: 11 %; IC50=22.2
PXN634
Figure imgf000072_0002
C32H27Cl2N3O2S2; MW: 620.62; found (HPLC MS): [M+H+] = 620.0; Yield: 27 %; IC50>60
PXN635
Figure imgf000072_0003
C23H26Cl2N2O3S; MW: 481.45
PXN636
Figure imgf000073_0001
C27H25Cl3N2O3S; MW: 563.93; found (HPLC MS): [M+H+] 563.0; Yield: 26 %; IC50>60
Figure imgf000073_0002
C30H24Cl3N3O2S; MW: 596.97; found (HPLC MS): [M+H+] 596.0; Yield: 24 %; IC50>60
Figure imgf000073_0003
C30H29Cl2N3O5S; MW: 614.55; found (HPLC MS): [M+H+] = 614.1; Yield: 11 %; IC50=60.4
PXN639
Figure imgf000074_0001
C33H28Cl2N4O4S; MW: 647.59; found (HPLC MS): [M+H+] = 647.1; Yield: 5 %; IC50=65.7
Figure imgf000074_0002
C33H28Cl2N4O2S; MW: 615.59; found (HPLC MS): [M+H+] = 615.2; Yield: 13 %; IC50=I 8.7
Figure imgf000074_0003
C33H28Cl2N4O2S; MW: 615.59; found (HPLC MS): [M+H+] = 615.2; Yield: 5 %; IC50=24.5
PXN641
Figure imgf000075_0001
C34H36Cl2N4O3S; MW: 651.66; found (HPLC MS): [M+H+] = 651.2; Yield: 9 %; IC50=9.4
Figure imgf000075_0002
C29H27Cl2N3O2S; MW: 552.53; found (HPLC MS): [M+H+] 552.1; [M+Na+] = 574.1; Yield: 8 %; IC50=5.7
PXN643
Figure imgf000075_0003
C3IH28Cl2N4O3S; MW: 607.56; found (HPLC MS): [M+H+] = 607.2; Yield: 4 %; IC50=3.9
PXN644
Figure imgf000076_0001
C28H25Cl2N3O3S; MW: 554.50; found (HPLC MS): [M+Na+] - 576.1; Yield: 10 %; IC5o=13.5
PXN645
Figure imgf000076_0002
C27H3ICl2N3O3S; MW: 548.54; found (HPLC MS): [M+Na+] = 570.2; Yield: 1 %
Figure imgf000076_0003
C26H24Cl2N2O3S; MW: 515.46; found (HPLC MS): [M+H+] = 515.0; Yield: 11 %; IC50=14.6
Figure imgf000076_0004
C25H30Cl2N2O3S; MW: 509.50
Figure imgf000077_0001
C26H24C12N2O3S; MW: 515.46
PXN650
Figure imgf000077_0002
C28H25Cl2N3O3S; MW: 554.50; found (HPLC MS): [M+Na+] = 576.1; Yield: 8 %; IC50=I 7.1
Figure imgf000077_0003
C32H32Cl2N4O3S; MW: 623.61; found (HPLC MS): [M+H+] = 623.2; Yield: 9 %; IC50=9.2
PXN652
Figure imgf000078_0001
C30H31Cl2N3O3S; MW: 584.57; found (HPLC MS): [M+H+] = 584.1; Yield: 29 %; IC50=I 7.4
PXN653
Figure imgf000078_0002
C3]H31Cl2N4O4S; MW: 625.58; found (HPLC MS): [M+H+] = 625.1; Yield: 2 %
PXN654
Figure imgf000078_0003
C31H30Cl2N4O4S; MW: 625.58; found (HPLC MS): [M+H+] = 625.1; Yield: 3 %; IC50=29.9
PXN655
Figure imgf000079_0001
C29H34Cl2N4O4S; MW: 605.59
Figure imgf000079_0002
C3IH38Cl2N4O3S; MW: 617.64; found (HPLC MS): [M+H+] = 617.2; Yield: 1 %; IC50=17.8
PXN657
Figure imgf000079_0003
C28H26ClN3O4S; MW: 536.05; found (HPLC MS): [M+H+] = 536.1; Yield: 11 %
PXN658
Figure imgf000080_0001
C32H32Cl2N4O4S; MW: 639.61
PXN659-dl
Figure imgf000080_0002
C33H34Cl2N4O3S; MW: 637.63; found (HPLC MS): [M+H+] = 637.2; Yield: 7 %; IC50=6.8
PXN659-d2
Figure imgf000080_0003
C33H34Cl2N4O3S; MW: 637.63; found (HPLC MS): [M+H+] = 637.2; Yield: 7 %; IC50=12
PXN660-dl
Figure imgf000081_0001
C34H36Cl2N4O3S; MW: 651.66; found (HPLC MS): [M+H+] = 651.2; Yield: 8 %; IC50=I 3
PXN660-d2
Figure imgf000081_0002
C34H36Cl2N4O3S; MW: 651.66; found (HPLC MS): [M+H+] = 651.2; Yield: 5 %; IC50=8.3
PXN661-dl
Figure imgf000081_0003
C33H34Cl2N4O3S; MW: 637.63; found (HPLC MS): [M+H+] = 637.2; Yield: 4 %; IC50=13.8
PXN661-d2
Figure imgf000082_0001
C33H34Cl2N4O3S; MW: 637.63; found (HPLC MS): [M+H+] = 637.2; Yield: 3 %; IC50=10.2
PXN662-dl
Figure imgf000082_0002
C34H36Cl2N4O3S; MW: 651.66; found (HPLC MS): [M+H+] = 651.2; Yield: 1 %; IC50=I 7.2
PXN662-d2
Figure imgf000082_0003
C34H36Cl2N4O3S; MW: 651.66; found (HPLC MS): [M+H+] = 651.2; Yield: 3 %; IC50=I 1.5
PXN663-dl
Figure imgf000083_0001
C33H33Cl3N4O3S; MW: 672.08; found (HPLC MS): [M+H+] = 673.1; Yield: 19 %; IC50=9.2
PXN663-d2
Figure imgf000083_0002
C33H33Cl3N4O3S; MW: 672.08; found (HPLC MS): [M+H+] = 671.1; Yield: 7 %; IC50=I 1.2
PXN666-dl
Figure imgf000083_0003
C30H29Cl2N3O3S; MW: 582.55; PXN617- enantiomerl; IC50=2.9
PXN667-dl
Figure imgf000084_0001
C30H29Cl2N3O3S; MW: 582.55; PXN617-enantiomer2; IC50=39
PXN668-dl
Figure imgf000084_0002
C33H35ClN4O3S; MW: 603.19; found (HPLC MS): [M+H+] = 603.0; Yield: 5 %; IC50=18.3
PXN668-d2
Figure imgf000084_0003
C33H35ClN4O3S; MW: 603.19; found (HPLC MS): [M+H+] = 603.0; Yield: 4 %; IC50=26.9
PXN669-dl
Figure imgf000085_0001
C34H36Cl2N4O3S; MW: 651.66; found (HPLC MS): [M+H+] = 651.0; Yield: 5 %; IC50=I 6.1
PXN669-d2
Figure imgf000085_0002
C34H36Cl2N4O3S; MW: 651.66; found (HPLC MS): [M+H+] = 650.9; Yield: 5 %; IC50=10.6
PXN671-dl
Figure imgf000085_0003
C34H36BrClN4O3S; MW: 696.11; found (HPLC MS): [M+H+] = 697.0; Yield: 11 %; IC50=8.7
PXN671-d2
Figure imgf000086_0001
C34H36BrClN4O3S; MW: 696.11; found (HPLC MS): [M+H+] - 697.1; Yield: 9 %; IC50=8.5
PXN672-dl
Figure imgf000086_0002
C33H34BrClN4O3S; MW: 682.08; found (HPLC MS): [M+H+] = 682.8; Yield: 5 %; IC50=29.5
PXN672-d2
Figure imgf000086_0003
C33H34BrClN4O3S; MW: 682.08; found (HPLC MS): [M+H+] = 682.9; Yield: 4 %; IC50=8.8
PXN673-d2
Figure imgf000087_0001
C32H33Cl2N5O3S; MW: 638.62; found (HPLC MS): [M+H+] = 637.9; Yield: 1 %; IC50=163.4
PXN673-dl
Figure imgf000087_0002
C32H33Cl2N5O3S; MW: 638.62; found (HPLC MS): [M+H+] = 638.0; Yield: 4 %; IC50=9.3
PXN674-dl
Figure imgf000087_0003
MW: 607.56; found (HPLC MS): [M+H+] = 607.2; Yield: 4 %; IC50-17.5
PXN674-d2
Figure imgf000088_0001
C3IH28Cl2N4O3S; MW: 607.56; found (HPLC MS): [M+H+] = 607.2; Yield: 4 %; IC50=28.9
PXN675-dl
Figure imgf000088_0002
C3IH28Cl2N4O3S; MW: 607.56; found (HPLC MS): [M+H+] = 606.9; Yield: 2 %; IC50=25.5
PXN675-d2
Figure imgf000088_0003
C31H28Cl2N4O3S; MW: 607.56; found (HPLC MS): [M+H+] = 608.8; Yield: 3 %; IC50=I 7.8
PXN676-dl
Figure imgf000089_0001
C33H34ClFN4O3S; MW: 621.18; found (HPLC MS): [M+H+] = 621.0; Yield: 5 %; IC50=15.6
PXN676-d2
Figure imgf000089_0002
C33H34ClFN4O3S; MW: 621.18; found (HPLC MS): [M+H+] = 621.0; Yield: 3 %; IC50=I 8.5
PXN677-dl
Figure imgf000089_0003
MW: 652.01; found (HPLC MS): [M+H+] = 651.3; Yield: 8 %; IC50=5.45
PXN678-dl
Figure imgf000090_0001
C33H33Cl3N4O5S; MW: 704.08; found (HPLC MS): [M+H+] = 702.9; Yield: 5 %; IC50=49.3
PXN679-d2
Figure imgf000090_0002
C34H36BrClN4O3S; MW: 696.11; found (HPLC MS): [M+H+] - 697.1; Yield: 3 %; IC50=9.3
PXN679-dl
Figure imgf000090_0003
C34H36BrClN4O3S; MW: 696.11; found (HPLC MS): [M+H+] = 697.2; Yield: 8 %; IC50=7.7
PXN680-dl
Figure imgf000091_0001
MW: 740.56; found (HPLC MS): [M+H+] = 740.5; Yield: 10 %; IC50=8.2
PXN681-d2
Figure imgf000091_0002
MW: 669.65; found (HPLC MS): [M+H+] = 669.0; Yield: 4 %; IC50=I 1.8
PXN681-dl
Figure imgf000091_0003
C34H35Cl2FN4O3S; MW: 669.65; found (HPLC MS): [M+H+] = 669.1; Yield: 15 %; IC50=9.5
PXN682-d2
Figure imgf000092_0001
C34H35Cl2FN4O3S; MW: 669.65; found (HPLC MS): [M+H+] = 669.1; Yield: 1 %; IC50=I 6.2
PXN682-dl
Figure imgf000092_0002
MW: 669.65; found (HPLC MS): [M+H+] = 669.1; Yield: 5 %; IC50=8.6
PXN683-dl
Figure imgf000092_0003
C33H34Cl2N4O3S; MW: 637.63; found (HPLC MS): [M+H+] = 637.0; Yield: 8 %; IC50=6.0
PXN684
Figure imgf000093_0001
MW: 598.55; found (HPLC MS): [M+H+] - 598.2; Yield: 7 %; IC50=5.7
PXN686-dl
Figure imgf000093_0002
MW: 652.65; found (HPLC MS): [M+H+] = 652.0; Yield: 6 %; IC50=6.8
PXN687
Figure imgf000093_0003
C28H24Cl2N2O3S; MW: 539.49; found (HPLC MS): [M+H+] = 539.1
PXN688
Figure imgf000094_0001
C34H36Cl2N4O5S; MW: 683.66; found (HPLC MS): [M+H+] - 683.1; Yield: 5 %; IC50>60
PXN689-dl
Figure imgf000094_0002
C34H36Cl2N4O3S; MW: 651.66; found (HPLC MS): [M+H+] = 651.1; Yield: 8 %; IC50=8.6
PXN690
Figure imgf000094_0003
MW: 686.62; found (HPLC MS): [M+Na+] = 710.1; Yield: 9 %; IC50=33.8
PXN691
Figure imgf000095_0001
C34H37Cl2N3O7S; MW: 702.66; found (HPLC MS): [M+H+] = 702.3; [M+Na+] = 724.1; Yield: 4 %; IC50=I 7.6
PXN693-dl
Figure imgf000095_0002
C34H36BrClN4O5S; MW: 728.11; found (HPLC MS): [M+H+] = 729.1; Yield: 4 %
PXN694-dl
Figure imgf000095_0003
C34H35Cl2FN4O5S; MW: 701.65; found (HPLC MS): [M+H+] = 703.1; Yield: 7 % PXN695-dl
Figure imgf000096_0001
MW: 682.08; found (HPLC MS): [M+H+] = 683.0; Yield: 5 %; IC50=5.4 PXN696-dl
Figure imgf000096_0002
C30H29BrClN3O4S; MW: 643.00; found (HPLC MS): [M+H+] = 668.1; Yield: 7 %; IC50=4.1
PXN697-dl
Figure imgf000096_0003
MW: 652.01; found (HPLC MS): [M+H+] = 653.1; [M+Na+] = 675.3; Yield: 3 %; IC50=3.6 PXN698-dl
Figure imgf000097_0001
MW: 682.08; found (HPLC MS): [M+H+] = 683.1 ; Yield: 7 %; IC50=6.3 PXN699-dl
Figure imgf000097_0002
MW: 710.14; found (HPLC MS): [M+H+] = 711.0; Yield: 7 %; IC50=4.2
PXN700-dl
Figure imgf000097_0003
MW: 641.03; found (HPLC MS): [M+Na+] = 664.2; Yield: 7 %; IC50-4.3 PXN701-dl
Figure imgf000098_0001
C33H34BrClN4O2S; MW: 666.09; found (HPLC MS): [M+H+] = 668.2; Yield: 8 %; IC50=4.1 PXN702-dl
Figure imgf000098_0002
MW: 710.14; found (HPLC MS): [M+H+] = 711.1; Yield: 17 %; IC50=18.6
PXN703-dl
Figure imgf000098_0003
MW: 710.14; found (HPLC MS): [M+H+] = 711.0; Yield: 10 %; IC50=9.5 PXN704-dl
Figure imgf000099_0001
MW: 710.14; found (HPLC MS): [M+H+] = 711.0; Yield: 6 %; IC50=I 1.7 PXN705-dl
Figure imgf000099_0002
C33H33BrClN5O5S; MW: 727.08; found (HPLC MS): [M+H+] = 727.9; Yield: 1 %; IC50=16.4
PXN706-dl
Figure imgf000099_0003
C31H29BrClN3O3S; MW: 639.02; found (HPLC MS): [M+H+] = 640.3; [M+Na+] = 662.3; Yield: 8 %; IC50=4.7 PXN707-dl
Figure imgf000100_0001
C31H29BrClN3O3S; MW: 639.02; found (HPLC MS): [M+H+] = 640.3; [M+Na+] = 662.3; Yield: 11 %; IC50=5.4 PXN708-dl
Figure imgf000100_0002
C30H29BrClN3O3S; MW: 627.00; found (HPLC MS): [M+Na+] = 650.6; Yield: 8 %; IC50=6.1
PXN709-dl
Figure imgf000100_0003
C30H29BrClN3O3S; MW: 627.00; found (HPLC MS): [M+Na+] = 650.2; Yield: 8 %; IC50=7.4 PXN705-d2
Figure imgf000101_0001
MW: 727.08; found (HPLC MS): [M+H+] = 726.0; Yield: 3 %; IC50=9.5
PXN710
Figure imgf000101_0002
C35H40BrClN4O2S; MW: 696.16; found (HPLC MS): [M+H+] = 697.3; Yield: 6 %
PXN711-dl
Figure imgf000101_0003
MW: 700.08; found (HPLC MS): [M+H+] = 701.2; Yield: 3 %; IC50=7.3 PXN712-dl
Figure imgf000102_0001
MW: 682.08; found (HPLC MS): [M+H+] = 683.1; Yield: 6 %
PXN713-dl
Figure imgf000102_0002
C32H40BrClN4O3S; MW: 676.12; found (HPLC MS): [M+H+] = 677.2; Yield: 4 %; IC50=8.1
PXN714-dl
Figure imgf000102_0003
C34H36BrClN4O3S; MW: 696.11; found (HPLC MS): [M+H+] = 697.2; Yield: 2 %; IC50=6.8
PXN715-dl
Figure imgf000103_0001
MW: 718.07; found (HPLC MS): [M+H+] = 719.2; Yield: 4 %; IC50=7.9
PXN716-dl
Figure imgf000103_0002
MW: 652.01; found (HPLC MS): [M+H+] = 653.1; [M+Na+] = 675.3; Yield: 4 %
PXN717-dl
Figure imgf000103_0003
C3IH29BrClN3O3S; MW: 639.02; found (HPLC MS): [M+H+] = 640.2; [M+Na+] = 662.1; Yield: 10 %; IC50=8.9
PXN718-dl
Figure imgf000104_0001
C31H30BrClN4O2S; MW: 638.03; found (HPLC MS): [M+H+] = 639.2; Yield: 9 %; IC50=3.5
PXN719-dl
Figure imgf000104_0002
C33H34BrClN4O2S; MW: 666.09; found (HPLC MS): [M+H+] = 665.4; Yield: 8 %; IC50=8.2
PXN720-dl
Figure imgf000104_0003
C34H36BrClN4O3S; MW: 696.11; found (HPLC MS): [M+H+] = 695.4; Yield: 5 %; IC50=6.6
PXN721-dl
Figure imgf000105_0001
C32H32BrClN4O2S; MW: 652.06; found (HPLC MS): [M+H+] = 651.4; Yield: 5 %; IC50=7.2
PXN722-dl
Figure imgf000105_0002
MW: 668.10; found (HPLC MS): [M+H+] = 667.3; Yield: 2 %; IC50=13.2
PXN725-dl
Figure imgf000105_0003
C32H32BrClN4O4S2; MW: 716.12; found (HPLC MS): [M+Na+] = 737.2; Yield: 5 %; IC50>60
PXN726-dl
Figure imgf000106_0001
MW: 680.07; found (HPLC MS): [M+H+] = 681.1; [M+Na+] = 703.2; Yield: 9 %; IC50=2.1
PXN727-dl
Figure imgf000106_0002
MW: 709.11; found (HPLC MS): [M+H+] = 710.0; [M+Na+] = 732.2; Yield: 11 %; IC50=I.4
PXN728-dl
Figure imgf000106_0003
MW: 656.05; found (HPLC MS): [M+H+] = 657.2; Yield: 4 %
PXN729
Figure imgf000107_0001
C58H52Br2Cl2N6O5S2; MW:
1207.94; found (HPLC MS): [M+Na+] = 1229.5; Yield: 10 %
PXN730-dl
Figure imgf000107_0002
C32H30BrClN4O3S; MW: 666.04; found (HPLC MS): [M+H+] = 666.9; [M+Na+] = 689.0; Yield: 6 %; IC50=4.8
PXN731-dl
Figure imgf000107_0003
C34H34BrClN4O4S; MW: 710.10; found (HPLC MS): [M+H+] = 711.5; [M+Na+] = 733.5; Yield: 4 %; IC50=I 18.7
PXN732-dl
Figure imgf000108_0001
MW: 696.07; found (HPLC MS): [M+H+] = 697.4; [M+Na+] = 719.4; Yield: 4 %; IC50=2.1
PXN733-dl
Figure imgf000108_0002
C36H38BrClN4O4S; MW: 738.15; found (HPLC MS): [M+H+] = 739.1; [M+Na+] = 759.5; Yield: 4 %
PXN734-dl
Figure imgf000108_0003
PXN735-dl
Figure imgf000109_0001
C35H36BrClN4O3S; MW: 708.12; found (HPLC MS): [M+H+] = 711.0; [M+Na+] = 731.0; Yield: 8 %; IC50=3.4
PXN736-dl
Figure imgf000109_0002
C36H38BrClN4O3S; MW: 722.15; found (HPLC MS): [M+H+] = 723.4; [M+Na+] = 745.4; Yield: 7 %; IC50>60
PXN737-dl
Figure imgf000109_0003
C36H38BrClN4O3S; MW: 722.15; found (HPLC MS): [M+H+] = 721.4; [M+Na+] = 743.5; Yield: 7 %; IC5o=15.6
PXN738-dl
Figure imgf000110_0001
C33H33BrClN5O3S; MW: 695.08
PXN739-dl
Figure imgf000110_0002
MW: 709.11; found (HPLC MS): [M+H+] = 710.2; Yield: 2 %; IC50=2.0
PXN740-dl
Figure imgf000110_0003
C35H37BrClN5O3S; MW: 723.14 PXN741-dl
Figure imgf000111_0001
MW: 667.07; found (HPLC MS): [M+H+] - 668.5; [M+Na+] = 690.4; Yield: 5 %; IC50=7.0
PXN742-dl
Figure imgf000111_0002
MW: 664.66; found (HPLC MS): [M+H+] = 664.2; [M+Na+] = 686.1; Yield: 6 %; IC50=Ll
PXN743-dl
Figure imgf000111_0003
MW: 682.65; found (HPLC MS): [M+H+] = 682.7; [M+Na+] = 704.2; Yield: 6 %; IC50=I.5
PXN744-dl - I l l -
Figure imgf000112_0001
C35H38ClN5O3S; MW: 644.24; found (HPLC MS): [M+H+] = 644.4; [M+Na+] = 666.3; Yield: 5 %; IC50=I 07.1
PXN745
Figure imgf000112_0002
C31H32Cl2N4O3S; MW: 611.60; found (HPLC MS): [M+H+] = 611.3; [M+Na+] = 633.2; Yield: 2 %
PXN746
Figure imgf000112_0003
C32H34Cl2N4O3S; MW: 625.62; found (HPLC MS): [M+H+] = 625.3; [M+Na+] = 649.3; Yield: 22 %; IC50=14.7
PXN747
Figure imgf000113_0001
C30H31Cl2N5O3S; MW: 612.58
PXN748-dl
Figure imgf000113_0002
MW: 738.11; found (HPLC MS): [M+H+] = 739.3; [M+Na+] = 762.1; Yield: 5 %; IC50=I 6.6
PXN749-dl
Figure imgf000113_0003
Na C35H33BrClN4NaO5S; MW: 760.09 PXN750-dl
Figure imgf000114_0001
PXN751-dl
Figure imgf000114_0002
MW: 636.61; found (HPLC MS): [M+H+] = 636.3; [M+Na+] = 658.2; Yield: 2 %; IC50=5.8
PXN752-dl
Figure imgf000114_0003
MW: 621.59; found (HPLC MS): [M+H+] = 621.1; Yield: 6 %; IC50=2.0
PXN753-dl
Figure imgf000115_0001
MW: 630.21; found (HPLC MS): [M+H+] = 630.3; [M+Na+] = 652.3; Yield: 5 %; IC50=170.6
PXN754-dl
Figure imgf000115_0002
C3IH36ClN5O3S; MW: 594.18; found (HPLC MS): [M+H+] = 594.3; Yield: 12 %; IC50=I 3.6
PXN755-dl
Figure imgf000115_0003
MW: 650.63; found (HPLC MS): [M+H+] = 650.1; [M+Na+] = 672.3; Yield: 1 %; IC50=3.6
PXN756-dl
Figure imgf000116_0001
MW: 709.11; found (HPLC MS): [M+H+] = 710.0; [M+Na+] = 732.2; Yield: 8 %; IC50=2.6
PXN757-dl
Figure imgf000116_0002
MW: 709.11; found (HPLC MS): [M+Na+] = 730.4; Yield: 12 %; IC50=206.1
PXN758-dl
Figure imgf000116_0003
MW: 709.11; found (HPLC MS): [M+H+] = 710.0; [M+Na+] = 732.2; Yield: 13 %
PXN759-dl
Figure imgf000117_0001
MW: 630.21; found (HPLC MS): [M+H+] = 630.2; [M+Na+] = 652.3; Yield: 6 %; IC50=I 82.6
PXN760-dl
Figure imgf000117_0002
MW: 725.11; found (HPLC MS): [M+H+] = 726.2; [M+Na+] = 748.0; Yield: 4 %; IC50=3.2
PXN761-dl
Figure imgf000117_0003
C34H36BrCl2N5O3S; MW: 745.57; found (HPLC MS): [M+H+] = 708.1; Yield: 10 %; IC50=3.1
PXN762-dl
Figure imgf000118_0001
C33H34Cl3N5O3S; MW: 687.09; found (HPLC MS): [M+H+] = 650.2; Yield: 4 %; IC50=4.5
PXN763-dl
Figure imgf000118_0002
2C35H38Cl2N6O3S; MW: 693.70; found (HPLC MS):
[M+H+] = 693.2; Yield: 2 %
PXN764-dl
Figure imgf000118_0003
C36H39Cl2N5O4S; MW: 708.71; found (HPLC MS): [M+H+] = 708.2; [M+Na+] = 730.2; Yield: 5 %; IC50=3.3
PXN765-dl
Figure imgf000119_0001
H C35H37Cl2N5O4S; MW: 694.69; found (HPLC MS): [M+H+] = 694.2; [M+Na+] = 716.3; Yield: 4 %; IC50=2.6
PXN766-dl
Figure imgf000119_0002
MW: 696.07; found (HPLC MS): [M+Na+] - 717.2; Yield: 6 %; IC50=3.8
PXN767-dl
Figure imgf000119_0003
C36H33Cl2N5O2S; MW: 670.67; found (HPLC MS): [M+H+] = 670.2; Yield: 9 %; IC50>60
PXN768-dl
Figure imgf000120_0001
C35H32Cl2N6O2S; MW: 671.65; found (HPLC MS): [M+H+] = 671.4; Yield: 6 %; IC50=I 18.7
PXN769-dl
Figure imgf000120_0002
C35H32Cl2N6O2S; MW: 671.65; found (HPLC MS): [M+H+] = 671.1; Yield: 8 %; IC50>60
PXN770-dl
Figure imgf000120_0003
C38H35Cl2N5O3S; MW: 712.70; found (HPLC MS): [M+H+] = 712.2; Yield: 5 %; IC50=191.7
PXN771-dl
Figure imgf000121_0001
MW: 709.11; found (HPLC MS): [M+H+] = 710.0; [M+Na+] = 732.2; Yield: 10 %
PXN775-dl
Figure imgf000121_0002
MW: 688.69; found (HPLC MS): [M+H+] = 690.2; Yield: 2 %; CCA
PXN776-dl
Figure imgf000121_0003
MW: 695.08; found (HPLC MS): [M+Na+] = 716.1; Yield: 11 %; IC50=2.1
PXN777-dl
Figure imgf000122_0001
C35H37BrClN5O3S; MW: 723.14; found (HPLC MS): [M+H+] = 722.1; Yield: 10 %; IC50=5.5
PXN779-dl
Figure imgf000122_0002
C33H34BrClN6O3S; MW: 710.10; found (HPLC MS): [M+H+] = 711.2; Yield: 6 %; IC50=5.0
PXN780-dl
Figure imgf000122_0003
C35H35ClF3N5O3S; MW: 698.21; found (HPLC MS): [M+H+] = 698.2; [M+Na+] = 720.2; Yield: 6 %; IC50=5.3
PXN781-dl
Figure imgf000123_0001
PXN782-dl
Figure imgf000123_0002
MW: 768.18; found (HPLC
MS): [M+H+] = 769.2; Yield: 8 %
PXN783-dl
Figure imgf000123_0003
found (HPLC MS): [M+H+] = 753.2; Yield: 9 %
PXN784-dl
Figure imgf000124_0001
MW: 794.26; found (HPLC MS): [M+H+] = 795.3; Yield: 5 %
PXN785-dl
Figure imgf000124_0002
MW: 781.26; found (HPLC MS): [M+H+] = 781.6; [M+Na+] = 803.8; Yield: 10 %
PXN787-dl
Figure imgf000125_0001
C35H39BrClN5O2S; MW: 709.15; found (HPLC MS): [M+H+] = 709.5; Yield: 13 %; IC50=8.3
PXN791-dl
Figure imgf000125_0002
C34H35BrClN5O3S; MW: 709.11; found (HPLC MS): [M+H+] = 710.2; [M+Na+] = 732.0; Yield: 1 %; IC50=6.6
PXN792-dl
Figure imgf000125_0003
C34H35BrClN5O3S; MW: 709.11; found (HPLC MS): [M+H+] = 708.0; [M+Na+] = 730.1; Yield: 8 %; IC5O=5.3
PXN793-dl
Figure imgf000126_0001
C33H32BrClN4O3S; MW: 680.07; found (HPLC MS): [M+Na+] = 703.1; Yield: 6 %; IC50=4.7
PXN794-dl
Figure imgf000126_0002
C33H32BrClN4O3S; MW: 680.07; found (HPLC MS): [M+H*] = 679.0; [M+Na+] = 701.0; Yield: 4 %; IC50=6.0
PXN795-dl
Figure imgf000126_0003
C34H34BrClN4O4S; MW: 710.10; found (HPLC MS): [M+H+] = 711.1; [M+Na+] - 733.1; Yield: 3 %; IC5O=8O.O
PXN796-dl
Figure imgf000127_0001
C34H34BrClN4O4S; MW: 710.10
PXN797-dl
Figure imgf000127_0002
MW: 692.66; found (HPLC MS): [M+H+] = 693.5; [M+Na+] = 716.2; Yield: 11 %; CCA
PXN798-dl
Figure imgf000127_0003
C37H42BrClN6O3S; MW: 766.21 PXN799-dl
Figure imgf000128_0001
MW: 653.04; found (HPLC MS): [M+H+] = 651.8; [M+Na+] = 675.7; Yield: 13 %; IC50=4.1
PXN800-dl
Figure imgf000128_0002
C34H34BrClN4O4S; MW: 710.10; found (HPLC MS): [M+H+] = 711.3; [M+Na+] = 731.2; Yield: 2 %; IC50=I 1.7
PXN801-dl
Figure imgf000128_0003
C35H37BrClN5O3S; MW: 723.14; found
(HPLC MS): [M+H+] = 724.3; [M+Na+] = 746.3; Yield: 5 %; IC50>60
PXN802-dl
Figure imgf000129_0001
C34H34BrClN4O3S; MW: 694.10; found (HPLC MS): [M+H+] = 695.3; Yield: 6 %; IC50=4.5
PXN803-dl
Figure imgf000129_0002
C35H36BrClN4O4S; MW: 724.12
PXN805-dl
Figure imgf000129_0003
C32H32BrClN4O2S; MW: 652.06; found (HPLC MS): [M+H+] = 653.4; [M+Na+] = 675.4; Yield: 7 %; IC50=5.5
PXN806-dl
Figure imgf000130_0001
PXN807-dl
Figure imgf000130_0002
C33H32BrClN4O4S; MW: 696.07
PXN808-dl
Figure imgf000130_0003
MW: 639.58; found (HPLC MS): [M+H+] - 639.2; [M+Na+] = 660.9; Yield: 16 %; IC50=I.3 PXN811-dl
Figure imgf000131_0001
MW: 598.53; found (HPLC MS): [M+H+] = 598.1; [M+Na+] = 620.0; Yield: 7 %; IC50=5.6
PXN813-dl
Figure imgf000131_0002
MW: 624.99; found (HPLC MS): [M+H+] = 624.0; [M+Na+] = 646.0; Yield: 11 %; IC50=5.4
PXN814-dl
Figure imgf000131_0003
C28H25BrClN3O3S; MW: 598.95
PXN815-dl
Figure imgf000132_0001
C33H32ClF2N5O3S; MW: 652.17; found (HPLC MS): [M+H+] = 652.1; [M+Na+] = 674.2; Yield: 4 %; IC50=5.0
Figure imgf000132_0002
C33H32Cl2FN5O3S; MW: 668.62; found (HPLC MS): [M+H+] = 668.2; Yield: 5 %; IC50=3.2
PXN817-d2
Figure imgf000132_0003
MW: 641.20; found (HPLC MS): [M+H+] = 641.1; [M+Na+] = 663.2; Yield: 1 %; IC50=LO
PXN820-dl
Figure imgf000133_0001
C3IH28Cl2FN3O3S; MW: 612.56; found (HPLC MS): [M+H+] = 612.1; [M+Na+] = 634.1; Yield: 20 %; IC50=3.7
PXN821-dl
Figure imgf000133_0002
MW: 641.60; found (HPLC MS): [M+H+] = 641.2; Yield: 19 %; IC50=8.6
PXN822-dl
Figure imgf000133_0003
C33H32Cl2FN5O3S; MW: 668.62; found (HPLC MS): [M+H+] = 668.2; [M+Na+] = 690.1; Yield: 16 %; IC50=I.2
PXN825-dl
Figure imgf000134_0001
C31H27Cl2FN4O3S; MW: 625.55; found (HPLC MS): [M+H+] - 627.2; [M+Na+] = 647.1; Yield: 23 %; IC50=I.5
PXN826-dl
Figure imgf000134_0002
MW: 626.58; found (HPLC MS): [M+Na+] = 648.1; Yield: 19 %; IC50=3.5
PXN833-dl
Figure imgf000134_0003
C35H37Cl2FN6O4S; MW: 727.69; found (HPLC MS): [M+H+] = 727.2; Yield: 5 %
PXN834-dl
Figure imgf000135_0001
C34H34Cl2FN5O4S; MW: 698.65; found (HPLC MS): [M+H+] = 698.1; Yield: 23 %
PXN835-dl
Figure imgf000135_0002
C34H34Cl2FN5O3S; MW: 682.65; found (HPLC MS): [M+H+] = 684.3; [M+Na+] = 703.9; Yield: 5 %; IC50=3.4
PXN836-d2
Figure imgf000135_0003
C33H30ClN5O3S; MW: 612.16; found (HPLC MS): [M+H+] = 612.5; [M+Na+] = 634.5; Yield: 3 %
PXN849-dl
Figure imgf000136_0001
C33H31Cl2FN4O3S; MW: 653.61; found (HPLC MS): [M+H+] = 653.4; [M+Na+] - 677.4; Yield: 6 %
Figure imgf000136_0002
C34H34Cl2FN5O3S; MW: 682.65; found (HPLC MS): [M+H+] = 682.4; Yield: 11 %
PXN670-dl
Figure imgf000136_0003
C33H34Cl2N4O3; MW: 605.57; found (HPLC MS): [M+H+] = 605.0; Yield: 6 %; IC50=12.5
PXN670-d2
Figure imgf000137_0001
C33H34Cl2N4O3; MW: 605.57; found (HPLC MS): [M+H+] = 605.0; Yield: 7 %; IC50=I 1.2
PXN778-dl
Figure imgf000137_0002
C33H33BrClN5O3; MW: 663.02; found (HPLC MS): [M+H+] = 664.1; Yield: 11 %; IC50=8.1
PXN788-dl
Figure imgf000137_0003
C33H39BrClN5O3; MW: 669.07; found (HPLC MS): [M+H+] = 670.3; [M+Na+] = 692.2; Yield: 1 %; IC50=6.6
PXN790-dl
Figure imgf000138_0001
C34H34Cl2FN5O3; MW: 650.59; found (HPLC MS): [M+H+] = 650.1; [M+Na+] = 672.1; Yield: 1 %; IC50=3.0
PXN804-dl
Figure imgf000138_0002
MW: 626.99; found (HPLC MS): [M+H+] = 628.2; [M+Na+] = 650.2; Yield: 9 %; IC50=9.0
PXN809-dl
Figure imgf000138_0003
C27H26Cl2FN3O3; MW: 530.43
PXN810-dl
Figure imgf000139_0001
C28H28Cl2FN3O3; MW: 544.46
Figure imgf000139_0002
C31H28Cl2FN3O3; MW: 580.49; found (HPLC MS): [M+H+] = 580.1; [M+Na+] = 602.1; Yield: 4 %; IC50=I 1.9
PXN823-dl
Figure imgf000139_0003
C32H30Cl2FN3O3; MW: 594.52 PXN824-dl
Figure imgf000140_0001
C33H31Cl2FN4O3; MW: 621.54
PXN827-dl
Figure imgf000140_0002
C32H29Cl2FN4O3; MW: 607.52
PXN828-dl
Figure imgf000140_0003
PXN829-dl
Figure imgf000141_0001
C33H38Cl2FN5O3; MW: 642.61; found (HPLC MS): [M+H+] = 642.2; [M+Na+] = 664.2; Yield: 1 %; IC50=12.5
PXN830-dl
Figure imgf000141_0002
C31H33Cl2FN4O3; MW: 599.54; found (HPLC MS): [M+H+] = 599.2; [M+Na+] - 621.2; Yield: 1 %; IC50=I 0.2
PXN831-dl
Figure imgf000141_0003
C3IH34Cl2FN5O3; MW: 614.55; found (HPLC MS): [M+H+] = 614.2; [M+Na+] = 636.2; Yield: 1 %; IC50=4.9
PXN832-dl
Figure imgf000142_0001
C3IH36Cl2FN5O3; MW: 616.57; found (HPLC MS): [M+H+] = 616.3; Yield: 1 %; IC50=7.9
PXN789-dl
Figure imgf000142_0002
MW: 666.59; found (HPLC MS): [M+H+] = 666.1; Yield: 1 %; IC50=I 1.7
PXN723-dl
Figure imgf000142_0003
MW: 625.03; found (HPLC MS): [M+H+] = 626.2; Yield: 2 %; IC50=I 5.1
PXN724-dl
Figure imgf000143_0001
MW: 611.05; found (HPLC MS): [M+H+] = 612.3; Yield: 1 %; IC50=20.6
PXN818-dl
Figure imgf000143_0002
MW: 555.93; found (HPLC MS): [M+H+] = 556.9; [M+Na+] = 577.1; Yield: 10 %; IC50=8.4
PXN819-dl
Figure imgf000143_0003
C34H37BrClN5O2S; MW: 695.13
PXN837-dl
Figure imgf000144_0001
= 464.2;
Yield: 5 %
PXN838-dl
Figure imgf000144_0002
MW: 496.43; found (HPLC MS): [M+H+] = 496.9; Yield: 2 %
PXN839-dl
Figure imgf000144_0003
C34H30BrClN4O2S; MW: 674.06; found (HPLC MS): [M+H+] = 675.4; [M+Na+] = 696.9; Yield: 10 %
PXN840-dl
Figure imgf000145_0001
C34H29BrClN3O3S; MW: 675.05; found (HPLC MS): [M+H*] - 676.7; [M+Na+] = 698.3; Yield: 9 %
PXN841-dl
Figure imgf000145_0002
C29H26BrClN2O3S; MW: 597.96; found (HPLC MS):
[M+H+] = 599.3; [M+Na+] = 620.9; Yield: 11 %
PXN842-dl
Figure imgf000145_0003
C34H35BrClN5O2S2; MW: 725.18; found (HPLC MS): [M+H+] = 726.5; [M+Na+] = 749.7; Yield: 9 %
PXN843-dl
Figure imgf000146_0001
C26H22N4O2S; MW: 454.55; found (HPLC MS): [M+H+] 455.3; [M+Na+] = 477.2; Yield: 22 %
PXN844-dl
Figure imgf000146_0002
C27H25N3O4S; MW: 487.58; found (HPLC MS): [M+H+] = 488.2; [M+Na+] = 510.3; Yield: 22 %
PXN845-dl
Figure imgf000146_0003
MW: 583.94; found (HPLC MS): [M+H+] = 585.2; [M+Na+] = 607.4; Yield: 5 %
PXN846-dl
Figure imgf000147_0001
C25H21Cl3N2O3; MW: 503.82; found (HPLC MS): [M+H+]
505.2; Yield: 4 %
PXN847-dl
Figure imgf000147_0002
C29H30BrClN4O3; MW: 597.94; found (HPLC MS): [M+H+] = 597.3; Yield: 7 %
PXN848-dl
Figure imgf000147_0003
C26H21Cl2NO5S; MW: 530.43; found (HPLC MS): [M+H+] 530.2; [M+Na+] = 552.4; Yield: 13 %
PXN 1000
Figure imgf000148_0001
C28H29ClN4O3S; MW: 537.1; found (HPLC MS):
[M+H+] = 537.1; Yield: 9 %
PXN 1001
Figure imgf000148_0002
C28H30ClN3O3S; MW: 524.1; found (HPLC MS): [M+Na+] = 546.2; Yield: 19 %
PXN 1002
Figure imgf000148_0003
C28H30N4O3S; MW: 502.64; found (HPLC MS):
[M+H+] = 503.2, [M+Na+] = 525.2; Yield: 11 %
PXN 1003
Figure imgf000148_0004
C28H3JN3O3S; MW: 489.64; found (HPLC MS):
[M+H+] = 490.5, [M+Na+] = 512.2; Yield: 12 % PXN 1004
Figure imgf000149_0001
C28H29ClN4O3; MW: 505.02; found (HPLC MS): [M+H+] - 505.2; Yield: 11 %
PXN 1005
Figure imgf000149_0002
C28H30ClN3O3; MW: 492.02; found (HPLC MS): [M+H+] = 492.2; Yield: 13 %
PXN 1006
Figure imgf000149_0003
C29H3IClN4O4; MW: 535.05
Figure imgf000149_0004
C26H28ClN3O3S; MW: 498.05; found (HPLC MS):
[M+H+] = 498.3; Yield: 5 %
Figure imgf000150_0001
C26H29N3O3S; MW: 463.60; found (HPLC MS): [M+H+] = 464.3; Yield: 31 %
PXN 1009
Figure imgf000150_0002
C3IH29ClN4O3S; MW: 573.12; found (HPLC MS): [M+H+] = 574.4, [M+Na+] = 595.4; Yield: 1 %
PXN 1010
Figure imgf000150_0003
C3JH30N4O3S; MW: 538.67; found (HPLC MS):
[M+H+] = 539.4; Yield: 3%
PXN lOI l
Figure imgf000151_0001
C29H28ClN3O3S; MW: 534.08; found (HPLC MS):
[M+H+] = 534.3; Yield: 13 %
PXN 1012
Figure imgf000151_0002
C29H29N3O3S; MW: 499.64; found (HPLC MS):
[M+H+] = 500.3; Yield: 31 %
Figure imgf000151_0003
C28H27ClN4O3S; MW: 535.07; found (HPLC MS):
[M+H+] = 535.3; Yield: 2 %
PXN 1014
Figure imgf000152_0001
C30H34ClN5O3S; MW: 580.2; found (HPLC MS): [M+Na+] = 602.4; Yield: 14 %
PXN 1015
Figure imgf000152_0002
C30H29N5O3S; MW: 539.66; found (HPLC MS):
[M+H+] = 540.4; Yield: 1 %
Figure imgf000152_0003
C28H33ClN4O3S; MW: 541.12; found (HPLC MS): [M+H+] = 541.4; Yield: 4 %
PXN 1017
Figure imgf000153_0001
C37H37ClN4O4S; MW: 669.2; found (HPLC MS): [M+H+] = 671.7, [M+Na+] = 691.3; Yield: 3 %
PXN 1018
Figure imgf000153_0002
C30H35N5O3S; MW: 545.7; found (HPLC MS): [M+H+] = 546.3; Yield: 18 %
PXN 1019
Figure imgf000153_0003
C31H35N3O4S; MW: 545.7; found (HPLC MS): [M+H+] = 546.3, [M+Na+] = 568.3; Yield: 27 %
PXN 1020
Figure imgf000154_0001
PXN 1021
Figure imgf000154_0002
C31H34ClN3O4S; MW: 580.15; found (HPLC MS): [M+H+] = 580.3; Yield: 20 %
PXN 1022
Figure imgf000154_0003
C29H30ClN3O4S; MW: 552.1 PXN 1023
Figure imgf000155_0001
C40H40ClN5O4S; MW: 722.3; found (HPLC MS): [M+H+] = 722.6, [M+Na+] = 744.3; Yield: 4 %
PXN 1024
Figure imgf000155_0002
C40H40ClN5O3S; MW: 706.3; found (HPLC MS): [M+H+] = 708.2; Yield: 1 %
Further modifications of the pyrrolidin-2-one scaffold are possible by using the following procedures:
1) Redox variations:
Figure imgf000156_0001
Scheme 1
In the presence of NaBH4, it is possible to reduce the carboxylic acid function of the MCR-product to the corresponding alcohol (see PXN818-dl). The isolated alcohol can be further converted to the corresponding ether (alkylation with various halogens) or to the corresponding ester (acylation with acyl chloride) (Scheme 1).
Furthermore, the obtained alcohol can be oxidized to the corresponding aldehyde (Swern oxidation). Alternatively, this aldehyde can also be obtained by selective reduction of the carboxylic acid. The aldehyde can be converted to numerous further compounds.
Figure imgf000156_0002
Scheme 2
As can be seen from scheme 2, amines are accessible via a reductive animation process. Further, a Knoevenagel condensation is also possible for modification yielding new substituted pyrrolidin-2-ones as shown in Scheme 3.
Figure imgf000157_0001
Scheme 3
2) Amide variations
Different amides have been synthesized by aminolysis of the pentafluorophenyl ester using various amines. Other nucleophilic compounds are also suitable to attack the activated carbone of the pentafluorophenyl ester, leading to new pyrrolidin-2-one derivatives as shown in Scheme 4.
R — NH2 amides (see PXN822-d1)
R 55— N H-NH22 hydrazinamides (see PXN839-d1)
hydroxylamides (see PXN840-d1)
R 7-OH esters (see PXN841-d1)
Figure imgf000157_0002
CH-acids ketones (see PXN843-d1 , PXN844-d1 ) different nucleophiles products
Scheme 4
3) Reduction of amide
Figure imgf000157_0003
PXN724-d1
PXN717-d1
PXN717-dl has been treated with BMS (dimethylsulfide borane) yielding a mixture of the two compounds PXN723-dl and PXN724-dl.
4) Homologation of carboxylic acids (Arndt-Eistert Reaction) 1 example same derivatisation
Figure imgf000158_0002
Figure imgf000158_0001
Under the conditions of the Arndt-Eistert homologation reaction, formation of the desired product has been observed through HPLC-MS analysis (see PXN845-dl). The obtained carboxylic acid can be further modified as described above.
Using a substituted succinic anhydride in the multicomponent reaction, compounds of formula (I) can be prepared wherein R and/or R are other than hydrogen (see also Org. Lett.2007, 9(20), 4077-4080).
PXN687
Figure imgf000158_0003
(as a mixture of diastereoisomers)
5) Elimination
Figure imgf000158_0004
PXN736-dl has been treated with 1,1 eq of natrium hydride at room temperature. Thereby, elimination product PXN847-dl has been isolated and characterized by HPLC-MS. This Product can be used for further modifications (for example Michael- addition).
6) Synthesis of compounds wherein X is N
These compounds may be prepared according to the following scheme:
Figure imgf000159_0001
In addition, compounds of formulas (I), (Ia), (Ic), (Id), (Ie) and (If) may be prepared following the procedures described e.g. in: Synlett, (11), 1883-1885, 2002; Organic Letters, 9(20), 4077-4080, 2007; Organic Letters, 8(18), 3999-4002, 2006; Tetrahedron, 50(36), 10701-8, 1994; Journal of the Chemical Society, Chemical Communications, (5), 386-7, 1987; Journal of the Chemical Society, Chemical Communications, (5), 386-7, 1987; Tetrahedron Letters, 49(35), 5217-5219, 2008 and Journal of Organic Chemistry, 73(14), 5566-5569, 2008.
Synthesis of the starting material ό-chloro-lH-indole-S-carbaldehyde:
This Vilsmeyer reaction was performed according to H. G. O. Becker, Organikum, pp. 364-365, Johann Ambrosius Barth Verlag, Heidelberg-Leipzig (1996). To 5 mL DMF in a three-necked flask equipped with a thermometer, 1.8 mL POCl.; was added dropwise in a temperature range between 15°C and 20°C. Then, a solution of Ig (6.6 mMol) of 6-chloro-lH-indole in 2 mL DMF was added dropwise in a temperature range between 20°C and 30°C. The reaction mixture was stirred for 45 minutes at 37°C. Afterwards, the reaction mixture was poured in a mixture of 15g ice in 10 mL water under stirring. 3.4g NaOH in 18 mL were added between in a temperature range between 20 and 300C. The resulting mixture was then refluxed for 5 minutes. After cooling to room temperature, the precipitate was filtered off and washed with 10 mL cold water. Crystallization from ethanol yielded ό-chloro-lH-indole-S-carbaldehyde as a white solid (1.04 g, 88%).
Proliferation assay:
5000 PA-I or PA-1/E6 cells were plated in each well of 96-well flat bottom plates, and incubated overnight at 370C in 5% CO2. The growth of plated cells was measured by adding 7.5 microMol of WST-I reagent (Roche Applied Sciences, Germany) to 3 control wells and measuring the OD650 and OD450 absorbances with a SpectraMax250 plate reader. If the OD650-OD45O values were above 0.5, the remainder of the plate was used for incubation with the compounds of formula (I), (Ia), (Ic), (Id), (Ie) or (If), other pharmacological agents or solvent controls for 48 hours. After this incubation, the WST-I reagent was added to the wells of the plate and OD650-OD450 values were calculated as before. Triplicate wells were assayed for each conditions and standard deviation was determined: all experiments were performed at least three times independently.
Apoptosis Annexin V and Tunel assay: Annexin V and BrdU-incorporation levels were determined with Guava Nexin and Guava Tunel kits using a Guava Personal Cell Analysis System (PCAS, Guava Technologies, Hayward, CA) according to the manufacturer's instruction. 1x106 PA-I and PA-1/E6 cells were cultured in BME media supplemented with 10%FBS and various concentrations of the compounds of formula (I) or DMSO for 24 h. Nutlin-3, racemic (Calbiochem, Roche) at 10 μM was applied as positive control. For the Guava Nexin assay, cells were trypsinized and collected by centrifuging at 1000 rpm for 5 min at 4 °C. After washing with ice-cold lχ Nexin buffer, cells were resuspended in the same buffer, labeled with Annexin V-PE and 7-aminoactinomycin D in the dark on ice for 20 min, and then analyzed with the PCAS. According to the manufacturer protocol for Guava Tunel assay cells were resuspended in 1% paraformaldehyde, incubated on ice for 60 min, washed in ice-cold PBS buffer. Than cells were fixed in ice-cold 70% ethanol for at least 16h at -2O0C. After incubation, cells were labeled with BrdU DNA labeling mix for 60 min at 370C, collected by centrifugation at 1000 rpm for 5 min. Cells were resuspended in anti-BrdU staining mix and incubated at room temperature for 45 min in the dark, and then analyzed with the PCAS.
Apoptosis Assays
Temperature-sensitive H 1299 clones were seeded onto 6-well plates at a density of
50,000 cells/well. Saos2 cells were plated at 1 x 106 cells/100-mm plate. Cells were shifted to 32 °C and harvested at the times indicated after temperature shift. Control cells were maintained at 39 °C. TUNEL and multi-caspase assays were conducted using the Guava Personal Cytometer (Guava Technologies) using the Guava TUNEL and multi-caspase detection kits, using protocols provided by the manufacturer (Guava Technologies) with the compounds of formula (I), (Ia), (Ic), (Id), (Ie) or (If).

Claims

Claims
1. A compound of formula (I):
Figure imgf000162_0001
(I) wherein
V is C=O, C=S or CH2;
X is sulphur, oxygen or a group of formula CH2, CR4bR4c, NH, NR4b, SO, SO2 or a bond;
Y is a group of formula CONR6, CH2NR6, CO, COO, CH2O, SO2NR6, NR6CO, NR6SO2, NR53CONR6, NR6COO, OCONR6, CONR53NR6, CONR53OR6, CH2CO
CH2CONR6, CH2COO, COCR53R6 or a bond;
n is 1, 2, 3 or O;
R1 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or hetero- aralkyl radical;
R2 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or hetero- aralkyl radical; R3 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or hetero- aralkyl radical;
R4 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or hetero- aralkyl radical;
R4b is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or hetero- aralkyl radical;
R4c is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or hetero- aralkyl radical;
R5 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
R5a is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
R6 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
the residues R7 are independently from each other a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical; the residues R8 are independently from each other a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
or two of the radicals R1, R2, R3, R4, R4b, R4c, R5, R5a, R6, R7 and R8 together are part of an optionally substituted cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heteroaryl, aralkyl or heteroarylalkyl ring system;
or a pharmaceutically acceptable salt, ester, solvate or hydrate or a pharmaceutically acceptable formulation thereof.
2. A compound of formula (Ia)
Figure imgf000164_0001
(Ia) wherein
R1 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
R2 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
R3 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical; R4 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or hetero- aralkyl radical;
R5 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
R6 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
or the radicals R5 and R6 together are part of an optionally substituted heterocycloalkyl, heteroalkylcycloalkyl, heteroaryl or heteroarylalkyl ring system, and/or R2 and R3 together are part of an optionally substituted cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkylcycloalkyl, aralkyl or heteroaralkyl ring system;
or a pharmaceutically acceptable salt, ester, solvate or hydrate or a pharmaceutically acceptable formulation thereof.
3. A compound of formula (I) or (Ia), according to any one of the preceding claims wherein R1 is an aryl, heteroaryl, aralkyl or heteroaralkyl radical.
4. A compound of formula (I) or (Ia), according to any one of the preceding claims wherein R1 is a group of formula -A-Ar or A-Cy wherein A is a bond, Ci-C4 alkyl or
Ci-C6 heteroalkyl or wherein A is a group of formula -CHR1 a- wherein Rla is a Ci-C6 heteroalkyl group, Cy is an optionally substituted C3-C7 cycloalkyl group or an optionally substituted heterocycloalkyl group containing from 3 to 7 ring atoms and Ar is an optionally substituted phenyl ring or an optionally substituted heteroaryl ring containing 5 or 6 ring atoms, especially preferably Ar is an optionally substituted phenyl or an optionally substituted pyridyl residue.
5. A compound of formula (I) or (Ia), according to any one of the preceding claims wherein R2 is hydrogen.
6. A compound of formula (I) or (Ia), according to any one of the preceding claims wherein R3 is an optionally substituted phenyl group, an optionally substituted benzyl group or an optionally substituted heteroaryl residue having 1 or 2 rings and from 5 to 10 ring atoms including 1, 2, 3 or 4 heteroatoms selected from O, S and N.
7. A compound of formula (I) or (Ia), according to any one of the preceding claims wherein R3 has the following structure
Figure imgf000166_0001
wherein E is N or CH, R3a is H, C1-C6 alkyl or C1-C6 heteroalkyl, R3b is H, F, Cl, Br, CH3, OCH3 or CF3 and R3c is H, F, Cl, Br, CH3, OCH3 or CF3.
8. A compound of formula (I) or (Ia), according to any one of the preceding claims wherein R4 is Ci-C6 alkyl, C2-C6 alkenyl, optionally substituted Ci-C4 alkyl-C3-C7 cycloalkyl, an optionally substituted phenyl ring, an optionally substituted benzyl group or an optionally substituted heteroaryl ring having 5 or 6 ring atoms and including from 1 to 3 heteroatoms selected from O, S and N.
9. A compound of formula (I) or (Ia), according to any one of the preceding claims wherein R5 is an alkyl, heteroalkyl, heterocycloalkyl, heteroalkylcycloalkyl or heteroaralkyl group, all of which groups may be substituted.
10. A compound of formula (I) or (Ia), according to any one of the preceding claims wherein R5 is selected from the following groups: Ci-C6 alkyl; heteroalkyl containing 1- 6 carbon atoms and 1, 2 or 3 heteroatoms selected from O, S and N; heteroalkylcycloalkyl comprising a C1-C4 alkyl group or a Ci-C4 heteroalkyl group and an optionally substituted heterocycloalkyl group containing 5 or 6 ring atoms and 1 , 2 or 3 heteroatoms selected from O, S and N; heteroaralkyl comprising a Ci-C4 alkyl group or a Ci-C4 heteroalkyl group and an optionally substituted heteroaryl group containing 5 or 6 ring atoms and 1 , 2 or 3 heteroatoms selected from O, S and N; optionally substituted heteroaryl containing 5 or 6 ring atoms and 1 , 2 or 3 heteroatoms selected from O, S and N; and optionally substituted heterocycloalkyl containing 5 or 6 ring atoms and 1 , 2 or 3 heteroatoms selected from O, S and N.
11. A compound of formula (I) or (Ia), according to any one of the preceding claims wherein R6 is hydrogen or Ci-C4 alkyl.
12. A compound of formula (I) or (Ia), according to any one of claims 1 to 8 wherein R5 and R6 together are part of an optionally substituted heterocycloalkyl ring containing 4, 5, 6 or 7 ring atoms and 1, 2 or 3 heteroatoms selected from O, S and N.
13. A compound of formula (I) or (Ia), according to any one of claims 1 to 8 wherein R5 and R6 together are part of an optionally substituted piperazine or piperidine ring.
14. A pharmaceutical composition comprising a compound according to anyone of the preceding claims or a pharmaceutically acceptable ester, prodrug, hydrate, solvate or salt thereof, optionally in combination with a pharmaceutically acceptable carrier.
15. Use of a compound or a pharmaceutical composition according to anyone of the preceding claims for the preparation of a medicament for the treatment of cancer and/or viral infections.
16. Compound or pharmaceutical composition according to anyone of claims 1 to 14 for use in the treatment of cancer and/or viral infections.
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