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AU2024215777A1 - Novel compounds that can be used as therapeutic agents - Google Patents

Novel compounds that can be used as therapeutic agents

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Publication number
AU2024215777A1
AU2024215777A1 AU2024215777A AU2024215777A AU2024215777A1 AU 2024215777 A1 AU2024215777 A1 AU 2024215777A1 AU 2024215777 A AU2024215777 A AU 2024215777A AU 2024215777 A AU2024215777 A AU 2024215777A AU 2024215777 A1 AU2024215777 A1 AU 2024215777A1
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branched
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cycloalkyl
cell
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AU2024215777A
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Madeline FELLNER
Jean-Baptiste GUALTIEROTTI
Roman Marty
Matthias OSTERMAIER
Viktoria REINMÜLLER
Olivier WAGNIÈRES
Johann Zimmermann
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Xeniom GmbH
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Xeniom GmbH
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Publication of AU2024215777A1 publication Critical patent/AU2024215777A1/en
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Abstract

The present invention relates to novel compounds and their use as therapeutic agents in human and veterinary medicine. The compounds of the present invention can be applied in the treatment and prevention of hyperproliferative disorders including cancer.

Description

Novel compounds that can be used as therapeutic agents
The present invention relates to novel compounds and their use as therapeutic agents in human and veterinary medicine. The compounds of the present invention can be applied in the treatment and prevention of hyperprolife rative disorders including cancer.
Background
Cellular metabolism denotes the vital network of intracellular processes that balance the supply and consumption of biomolecules and energy. Catabolic processes designate the break-down of biomolecules that are received from the environment or recycled from intracellular storage for extraction of energy and precursor molecules for biosynthesis. Anabolic metabolism describes biosynthetic processes yielding new biomolecules under consumption of energy.
Mitochondria are cell organelles that participate in catabolic and anabolic processes, and contribute substantially to the energy supply of the cells. The said organelles host the infrastructure for extracting and transferring energy to generic molecular energy storage by means of highly efficient generation of adenosine triphosphate (ATP). ATP stores chemical energy and can be used as an energy source at mitochondria distal sites. Moreover, mitochondria play an important role in other cellular processes such as maintaining cellular redox homeostasis, epigenetic regulations, and signaling mechanisms that relate to cell growth, cell proliferation, cell differentiation, cell death and cell survival, respectively.
ATP generation in mitochondria is accomplished by oxidative nutrient break-down via different routes that funnel into the tricarboxylic acid (TCA) cycle and ultimately feed the electron transport chain (ETC) with electrons and protons for cellular respiration. The electrons that are collected upon oxidation of according metabolites are intermediately stored by universal electron acceptor molecules from the nicotinamide nucleotide or flavin nucleotide family. Such molecules serve to enter the electrons into the ETC and are hereafter available again for the next load of electrons. The transport of released electrons through the protein complexes of the ETC is driven by the reduction of elemental oxygen at the end of the ETC. During this process, the energy released from according redox-reactions is converted by proton pumps into an electrochemical potential in the form of a proton gradient across the inner mitochondrial membrane. This transmembrane potential ΔΨm serves as a transient storage and dynamic source of energy for various mitochondria-related functions. Finally, also ATP-synthase consumes ΔΨm derived energy to phosphorylate adenosine diphosphate (ADP) to ATP. This process chain linking the TCA cycle via ETC to the production of ATP is referred to as oxidative phosphorylation (OXPHOS).
Due to their central role in cellular regulations and homeostasis, mitochondria are heavily involved in diseases. In that respect, these organelles play a key role in cancer by contributing to both carcinogenesis and tumor progression. In addition, mitochondrial dynamics provide tumor cells metabolic plasticity for adaptation to harsh conditions and stress stimuli allowing metastatic spread and contributing to drug resistance.
Deregulation of cellular energy metabolism is widely accepted now as being one of the hallmarks of cancer. Specifically, cancer cells exhibit metabolic changes that also enable them to meet the increased demand of biosynthetic processes and the required energy for cell growth and proliferation.
Cancer cells can switch their metabolism towards enhanced rates of glycolysis. This catabolic path of glucose also yields ATP but to substantially lower amount per glucose molecule as compared to OXPHOS. Importantly, glycolysis is a major source of intermediate metabolites that serve as precursors for various anabolic pathways, such as the biosynthesis of amino acids or nucleosides. Alternatively, glycolysis may provide the further downstream metabolite pyruvate that can either be consumed in mitochondria to fuel OXPHOS or converted into lactate in order to maintain high glycolytic rates and biosynthetic precursor generation. Apparently, cancer cells employ pyruvate in adequate balance to both pathways, as highly proliferative cells often rely on both 1) enhanced glycolysis for precursor generation and 2) basic levels of OXPHOS for sufficient ATP generation to power the intensified synthesis of biomolecules.
Pharmaceutical intervention targeting mitochondrial activity can be used to regulate abnormal cell growth and proliferation. In particular, the development of OXPHOS inhibitors for the treatment of hyperproliferative disorders and cancer is highly desirable for several reasons. Firstly, cancer cells including invasive and metastasizing cancer cells, may not meet their increased demand of energy and biomolecules to support an increased proliferation rate and an invasive or metastatic phenotype when OXPHOS is inhibited. As such, inhibition of OXPHOS may stunt extensive growth, proliferation, and colonialization of distant tissues (Wheaton et al., eLife 2014, 3; Andrzejewski et al., Cell Metab 2017, 26). Secondly, the microenvironment in poorly vascularized solid tumors can lack sufficient oxygen and nutrients, such as glucose. The induced metabolic stress may drive the cellular composition of the tumor tissue towards cancer cells that have a slower cell cycle or enter quiescence exhibiting a concomitant dependency on OXPHOS (Zhang et al., Nat Commun 2014, 5). Thirdly, cancer cells may intrinsically have lost some of their metabolic plasticity and therefore exhibit a stronger dependency on OXPHOS. Corresponding observations have been reported for example for cancer cells that are glycolysis-deficient or harbor mutations in corresponding genes such as EN01, GAPDH, GPI, HK1, PKM, SLC2A1, SLC2A3, TPI1, PGD, PHGDH (Birsoy et al., Nature 2014, 508; Molina et al., Nat Med 2018, 24), lack functional PTEN (Naguib et al., Cell Rep 2018, 23), or harbor mutations in LKB1 (Shackelford et al., Cancer Cell 2013, 23), IDH1 (Grassian et al., Cancer Res 2014, 74), or components of the SWI/SNF complex such as SMARCA4 or ARID1A (Lissanu Deribe et al., Nat Med 2018, 24). Notably, OXPHOS is used by cancer cells to survive chemotherapy (Lee et al., Cell Metab 2017, 26; Ippolito et al., Oncotarget 2016, 7) or other treatments including targeted therapy such as inhibition of kinases like B-Raf (Roesch etal., Cancer Cell 2013, 23; Baenke etal., Mol Oncol 2016, 10) and BTK (Zhang et al., Sci Transl Med 2019, 11), or inhibition of antiapoptotic proteins such as Bcl-2 (Xu et al., Exp Hematol Oncol 2022, 11), or inhibition of tumor angiogenesis (Navarro et al., Cell Rep 2016, 15), or radiation therapy (Lu et al., PLoS One 2015, 10) or cancer immunotherapy such as inhibition of checkpoint proteins like PD-1 (Chen et al., / ImmunoTher Cancer 2020, 8). Such chemo- or treatment-resistance of cancer cells, including cancer stem cells (CSCs), is often linked to OXPHOS dependency (Sancho et al., Br J Cancer 2016, 114; Kuntz et al., Nat Med 2017, 23).
Accordingly, inhibition of OXPHOS has been proven to be a promising anti-cancer treatment strategy, particularly, by rendering cancer cells less tumorigenic or highly susceptible to other cancer therapies, by restoring sensitivity towards other cancer therapies upon acquired resistance, by strongly affecting OXPHOS dependent cancer cells including cancer stem cells, and by reducing or inhibiting cancer metastases, as well as cancer recurrence.
Several OXPHOS inhibitors are currently in experimental and clinical development for cancer treatment. Examples are Metformin, Phenformin, IM156, IACS-010759, Lonidamine, Atovaquone, Neoantimycin F, or Oligomycin A. However, to date there is no molecule of this class yet approved for cancer treatment. Many OXPHOS inhibitors exhibit very low potency or show poor selectivity leading to compound related adverse events. Hence, there is a strong need for novel OXPHOS inhibitors with strong potency and high selectivity for the treatment of cancer. Description of the Invention
The present invention comprises novel molecules that inhibit OXPHOS and show remarkable anti-cancer activity. According compounds were found to impact the proliferation and survival of cancer cells with strong potency and high selectivity with respect to primary non-cancer cells.
Thus, the present invention relates to compounds as defined herein that feature antiproliferative activity, which can be used in the treatment and prevention of benign and malignant hyperproliferative disorders including hyperplasia, neoplasia, cancer, precancerous lesions, and metastasis in human and veterinary medicine. The invention also includes pharmaceutical methods and compositions for the medical use of the disclosed molecules.
In particular, the present invention relates to compounds as defined herein for the treatment of cancer, wherein the cancer or cancer cells exhibit one or more of the following properties: The cancer or cancer cells have a high proliferation rate; grow fast and aggressively; grow invasively; metastasize; have a partial or complete dependence on OXPHOS in terms of growth, proliferation, survival, invasiveness, or formation of metastases; are glycolysis-deficient; harbor mutations in glycolytic or glycolysis-relevant genes particularly in ENO1, GAPDH, GPI, HK1, PKM, SLC2A1, SLC2A3, and TPI1 but also in ALDOA, ALDOB, ALDOC, BPGM, ENO2, ENO3, GAPDHS, GCK, HK2, HK3, PFKL, PFKM, PFKP, PGAM2, PGAM5, PGK1, PGK2, PKLR, SLC2A2, SLC2A4, SLC2A5, SLC2A6, SLC2A8, SLC2A9, SLC2A10, SLC2A11, SLC2A12, SLC2A13; harbor mutations in PGD, PHGDH, LKB1, IDH1 or a gene of the SWI/SNF complex such as SMARCA4 or ARID1A; lack functional PTEN; are resistant to chemo- or radiation- or targeted therapies including but not limited to inhibitors of kinases such as B-Raf and BTK, inhibitors of antiapoptotic proteins such as Bcl-2, inhibitors of tumor angiogenesis, or cancer immunotherapies such as inhibitors of immune checkpoint proteins like PD-1; survive and optionally grow under nutrient-poor and particularly glucose-deficient conditions, e.g. in a tight tumor-bulk or in a poorly vascularized microenvironment; or are cancer stem cells or cancer cells with a partial degree of cancer sternness.
Moreover, the compounds disclosed herein can be used to sensitize cancer cells towards other cancer treatments including but not limited to chemo-, radio-, cancer immuno-, or targeted therapies.
The present invention also relates to combination treatments of the compounds as defined herein with one or more other therapeutics or interventions particularly selected from anticancer therapeutics, chemotherapeutics, targeted therapeutics, cancer immunotherapeutics, radiation therapy, surgery and other invasive procedures, therapeutics to reduce treatment related adverse events, other OXPHOS or mitochondrial inhibitors, glycolysis inhibitors, angiogenesis inhibitors, inhibitors of antiapoptotic proteins including Bcl-2, Bcl-xL and Mcl-1 such as BH3 mimetics, and checkpoint inhibitors including monoclonal antibodies against PD1, PD-L1, and CTLA-4, and therapeutics or treatments that lead to a synthetic lethal effect in the target cells when combined with any compound of the invention.
The biological activity, i.e. the antiproliferative activity of the claimed compounds can be attributed to but may not be limited to OXPHOS inhibiting activity.
The compounds of the present invention relate to structures that are composed of two sixmembered aromatic cycles which are bridged by a heteroatom being optionally substituted with a small alkyl group. Both of said aromatic cycles constitute independently from each other either an aryl ring or any nitrogen containing heteroaromatic moiety. One of these six-membered rings is substituted with at least one but preferably two additional substituents different from H, wherein the obligatory one of the two substituents is embodied by an aliphatic group in paraposition relative to the heteroatom bridge bond. The second aromatic ring is substituted with at least one additional substituent different from H, wherein said substituent is linked by the carbonyl group of an amide moiety in para-position relative to the heteroatom bridge bond. The nitrogen atom of said amide is part of a cyclic structure which can be monocyclic or polycyclic in the form of fused, bridged and spiro systems, and which incorporates at least a second substituted nitrogen atom. The substituent of the additional nitrogen atom is either chosen from a monocyclic aliphatic, polycyclic aliphatic and aromatic moiety, or from an aliphatic residue that in turn is optionally substituted with a monocyclic aliphatic, polycyclic aliphatic or aromatic moiety. In both cases, this nitrogen substituent can contain one or more heteroatoms and is either unsubstituted or further substituted with small terminal aliphatic or heteroatom containing groups.
A first aspect of the present invention relates to compounds of general formula (I) and salts and solvates thereof: wherein
R1 = -CR2R3R4, C3-C16 preferably C3-C8 cycloalkyl, C5-C16 preferably C5-C8 cycloalkenyl, C9-C16 preferably C9-C11 cycloalkynyl, C5-C16 preferably C5-C11 bicycloalkyl, C7-C16 preferably C7-C11 bicycloalkenyl, C8-Cig preferably C8-Ci2 tricycloalkyl or C8-Cig preferably C8-Ci2 tricycloalkenyl; wherein R2, R3, and R4 are independently from each other selected from H, F, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C3-C15 cycloalkyl, C5-C15 cycloalkenyl, C9-C15 cycloalkynyl, C5-C15 bicycloalkyl, C7-C15 bicycloalkenyl, C8-Ci7 tricycloalkyl, C8-Ci7 tricycloalkenyl; wherein at least one of the residues selected from R2, R3, and R4 is different from H and F; wherein all alkyl, alkenyl and alkynyl residues contained in the definitions of R2, R3, and R4 are linear or branched, and are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, =O, -CF3, -CHF2, linear or branched C1-C8 preferably C1-C3 alkyl such as -CH3, linear or branched C2-C6 preferably C2-C3 alkenyl, linear or branched C2-C6 preferably C2-C3 alkynyl, C3 cycloalkyl, C3 cycloalkenyl, -OCF3, -OC1-C2 alkyl such as -OCH3, -NHCH3, and -N(CH3)2; wherein all cyclic structures, bicyclic structures and tricyclic structures including cycloalkyl, cycloalkenyl, cycloalkynyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl and tricycloalkenyl residues contained in the definitions of R1 or R2, R3, and R4 are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, =O, -CF3, -CHF2, linear or branched C1-C8 preferably C1-C3 alkyl such as -CH3, linear or branched C2-C6 preferably C2-C3 alkenyl, linear or branched C2-C6 preferably C2-C3 alkynyl, C3 cycloalkyl, C3 cycloalkenyl, -OCF3, -OC1-C2 alkyl such as -OCH3, -NHCH3, and -N(CH3)2 wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl and tricycloalkenyl residues contained in the definitions of R1 or R2, R3, and R4 can contain one or more heteroatoms, or groups composed of heteroatoms, independently selected from O, S, SO, SO2 and N in replacement of a carbon atom; with the proviso that the carbon atom of R1 that is directly bound to the aromatic ring cannot be replaced by a heteroatom, and that such replacement cannot result in a substituent R1 comprising a group C=O or C=N directly bound to the aromatic ring; wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl and tricycloalkenyl residues contained in the definitions of R1 or R2, R3, and R4 can be partially or fully halogenated, particularly fluorinated, more particularly perfluorinated; and wherein bicyclic and tricyclic residues contained in R1 or R2, R3, and R4 include fused, bridged, and spiro systems; and wherein the carbon atom of R1 that is bound to the aromatic ring as defined in general formula (I) is a secondary, tertiary or quaternary carbon atom and sp3 hybridized; and wherein R1 is preferably selected from
X1, X2, X3, and X4 are independently from each other selected from N, CR5, CR6, CR7, CR8 and wherein at least one of X1, X2, X3, and X4 is CR8; wherein R5, R6, and R7 are independently from each other selected from -H, -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -C(O)H, -CH2OH, -NH2, -CH2NH2, -N02, -CF3, -CHF2, -OCF3, linear or branched C1- C5 alkyl, linear or branched C2-C5 alkenyl, linear or branched C2-C5 alkynyl, C3-C5 cycloalkyl, C3- C5 cycloalkenyl, -CH2(C3-C5 cycloalkyl), linear or branched -OC1-C4 alkyl such as -OCH3, -OC3-C5 cycloalkyl, linear or branched -NH(C1-C4 alkyl), linear or branched -N(C1-C4 alkyl)(C1-C4 alkyl), -NH(C3-C5 cycloalkyl), -N(C3-C5 cycloalkyl)(C3-C5 cycloalkyl), and linear or branched -N(C1-C4 alkyl) (C3-C5 cycloalkyl); wherein R5, R6, and R7 are preferably independently from each other selected from -H, -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, -CF3, -CHF2, linear or branched C1-C5 alkyl, C3-C5 cycloalkyl, -OCF3, linear or branched -OC1-C4 alkyl, linear or branched -NH(C1-C4 alkyl), linear or branched -N(C1-C4 alkyl)(C1-C4 alkyl); wherein R8 is selected from -H, -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -C(O)H, -CH2OH, -O(CH2)2OH, -NH2, -CH2NH2, -NO2, -CF3, -CHF2, -OCF3, linear or branched C1-C5 alkyl, linear or branched C2-Cs alkenyl, linear or branched C2-C5 alkynyl, C3-C5 cycloalkyl, C3-C5 cycloalkenyl, -CH2(C3-Cs cycloalkyl), linear or branched -OC1-C4 alkyl such as -OCH3, -OC3-C5 cycloalkyl, linear or branched -NH(C1-C4 alkyl), linear or branched -N(C1-C4 alkyl) (C1-C4 alkyl), -NH(C3-C5 cycloalkyl), -N(C3-C5 cycloalkyl) (C3-C5 cycloalkyl), and linear or branched -N(C1-C4alkyl)(C3-C5 cycloalkyl); wherein R8 is preferably selected from -H, -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -C(O)H, -OCH3, -OCF3, -CH2OH, -O(CH2)2OH, -NH2, -N02, -CF3, -CHF2, linear or branched C1-C5 alkyl, linear or branched C2-C5 alkenyl, C3-C5 cycloalkyl, linear or branched -OC1-C4 alkyl, linear or branched -NH(C1-C4 alkyl), linear or branched -N(C1-C4 alkyl)(C1-C4 alkyl); wherein all alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl residues contained in the definitions and preferred definitions of R5, R6, R7, and R8 can contain one or more heteroatoms, or groups composed of heteroatoms, independently selected from O, S, SO, S02 and N in replacement of a carbon atom; wherein all alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl residues contained in the definitions and preferred definitions of R5, R6, R7, and R8 are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CH3, -CF3, -CHF2, -OH and -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2; and wherein the six-membered aromatic ring containing X1, X2, X3, and X4 as defined in general formula (I) is preferably selected from
A = O, S, SO, SO2, NR9; wherein R9 is selected from -H, -CH3, and -COCH3; and wherein A is preferably 0;
X5, X6, X7, and X8 are independently from each other selected from N, CR10, CR11, CR12, CR13;
Wherein R10, R11, R12, and R13 are independently from each other selected from -H, -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, -CF3, -CHF2, linear or branched C1-C5 alkyl, linear or branched C2-C5 alkenyl, linear or branched C2-C5 alkynyl, C3-C5 cycloalkyl, C3-C5 cycloalkenyl, -CH2(C3-C5 cycloalkyl), -OCF3, linear or branched -OC1-C4 alkyl, -OC3-C5 cycloalkyl, linear or branched -NH(C1-C4 alkyl), linear or branched -N(C1-C4 alkyl) (C1-C4 alkyl), -NH(C3-C5 cycloalkyl), -N(C3-C5 cycloalkyl) (C3-C5 cycloalkyl), and linear or branched -N(C1-C4alkyl)(C3-C5 cycloalkyl); wherein R10, R11, R12, and R13 are preferably independently from each other selected from -H, -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, -CF3, -CHF2, linear or branched C1-C5 alkyl, linear or branched C2-C5 alkenyl, C3-C5 cycloalkyl, -OCF3, linear or branched -OC1-C4 alkyl, linear or branched -NH(C1-C4 alkyl), linear or branched -N(C1-C4alkyl)(C1-C4 alkyl); wherein all alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl residues contained in the definitions and preferred definitions of R10, R11, R12, and R13 can contain one or more heteroatoms, or groups composed of heteroatoms, independently selected from O, S, SO, SO2 and N in replacement of a carbon atom; wherein all alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl residues contained in the definitions and preferred definitions of R10, R11, R12, and R13 are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CH3, -CF3, -CHF2, -OH and -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2; and wherein the six-membered aromatic ring containing X5, X6, X7, and X8 as defined in general formula (I) is preferably selected from
Z1 and Z2 are independently from each other selected from linear or branched C1-C6 alkylene and C2-C6 alkenylene; wherein one or more carbon atoms of Z1 and Z2 can additionally be linked to or shared with each other to form a bicyclic or tricyclic structure including both nitrogen atoms which they are bound to as defined in general formula (I); wherein the bicyclic and tricyclic structures formed with Z1, Z2 and both nitrogen atoms to which they are bound to as defined in general formula (I) include fused, bridged, and spiro systems; wherein Z1 and Z2 can independently from each other be unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, linear or branched -OC1-C6 alkyl such as -OCH3, -OCF3, -OC3-C5 cycloalkyl, -NH2, linear or branched -NH(C1- C6 alkyl) such as -NHCH3, linear or branched -N(C1-C6 alkylJ(C1-C6 alkyl) such as -N(CH3)2, linear or branched -NH(C3-C5 cycloalkyl), linear or branched -N(C1-C6alkyl)(C3-C5 cycloalkyl), -N(C3-C5 cycloalkyl) (C3-C5 cycloalkyl), NO2, =O, -CF3, -CHF2, linear or branched C1-C8 alkyl such as -CH3, linear or branched C2-C8 alkenyl, linear or branched C2-C8 alkynyl, C3-C5 cycloalkyl, C3-C5 cycloalkenyl, -CH2(C8-C5 cycloalkyl); wherein Z1 and Z2 are preferably unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, linear or branched -OC1-C3 alkyl such as -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, N02, =O, -CF3, -CHF2, linear or branched C1-C3 alkyl such as -CH3, linear or branched C2-C3 alkenyl, linear or branched C2-C3 alkynyl, C3-C5 cycloalkyl, C3-C5 cycloalkenyl; wherein all alkyl, alkenyl, and alkynyl substituents of Z1 and Z2 can independently from each other be linked additionally to one or more carbon atoms of Z1 and Z2 independently from which they are bound to; wherein all alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl residues contained in the definitions of Z1 and Z2 or in any of their substituents, and all bicyclic and tricyclic structures formed with Z1, Z2 and both nitrogen atoms which they are bound to as defined in general formula (I) can contain one or more heteroatoms, or groups composed of heteroatoms, independently selected from O, S, SO, SO2 and N in replacement of a carbon atom; wherein all alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl residues contained in the definitions of Z1 and Z2 or in any of their substituents, and all bicyclic and tricyclic structures formed with Z1, Z2 and both nitrogen atoms which they are bound to as defined in general formula (I) can be partially or fully halogenated, particularly fluorinated, more particularly perfluorinated; wherein the structures formed with Z1, Z2 and both nitrogen atoms to which they are bound to are preferably selected from the following residues which can be unsubstituted or substituted as defined above:
Y = linear or branched C1-C5 alkyl, linear or branched C2-C5 alkenyl, linear or branched C2-C5 alkynyl, C3-C5 cycloalkyl, C3-C5 cycloalkenyl; wherein all alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl residues contained in the definitions of Y can contain one or more heteroatoms, or groups composed of heteroatoms, independently selected from O, S, SO, SO2 and N in replacement of a carbon atom; wherein all alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl residues contained in the definitions of Y can be unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -OC1-C3 alkyl such as -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, NO2, =O, -CF3, -CHF2, linear or branched C1-C3 alkyl such as -CH3, linear or branched C2-C3 alkenyl, C2-C3 alkynyl, C3 cycloalkyl, C3 cycloalkenyl; wherein Y is preferably -CH2-, -C(O)-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH(0H)- , -CH2CH2O-, -CH2C(O)-, -CH2-C=C-, -CH2CH(CH3)-, -CH2C(O)CH2CH2-, -C(O)OCH2CH2- and -S(O)2-; wherein for non-symmetrical residues of Y, the residue can be oriented in both directions with regard to the basic structure; wherein Y is even more preferably selected from:
W = H, F, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, C5-C12 bicycloalkyl, C7-C12 bicycloalkenyl, C8-C14 tricycloalkyl, C8-C14 tricycloalkenyl, as well as C6-C14 aromatic and C5-C14 heteroaromatic residues; wherein all aromatic and heteroaromatic residues contained in the definitions of W include monoaromatic, monoheteroaromatic, fused or bridged polyaromatic, fused or bridged polyheteroaromatic systems, as well as bicyclic and tricyclic systems of which at least one cycle is aromatic or heteroaromatic; and wherein all bicyclic and tricyclic residues contained in the definitions of W include fused, bridged, and spiro systems; wherein all cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl and tricycloalkenyl residues, as well as all aromatic and heteroaromatic moieties contained in the definitions of W are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -CF3, -CHF2, -CF2CF3, -CH2CF3, -OH, -OCH3, -OCF3, -OCH2CF3, -NH2, -NHCH3, -N(CH3)2, -NO2, linear or branched C1-C8 alkyl, linear or branched C2-C8 alkenyl, linear or branched C2-C8 alkynyl, C3-C8 cycloalkyl, and C3-C8 cycloalkenyl; wherein all alkyl, alkenyl, and alkynyl substituents of W can independently from each other be linked additionally to more than one carbon atom of W; wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl and tricycloalkenyl residues, as well as all aromatic and heteroaromatic moieties contained in the definitions of W or in any of its substituents, can contain one or more heteroatoms, or groups composed of heteroatoms, independently selected from O, S, SO, SO2 and N in replacement of a carbon atom; wherein all alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl residues contained in the definitions of the substituents of W can be partially or fully halogenated, particularly fluorinated, more particularly perfluorinated; wherein W is preferably selected from -H, -F, and unsubstituted or substituted residues from cyclopentyl, cyclohexyl, benzyl, pyridine, indole, pyrimidine, pyridazine, pyrazine, naphthyl, quinoline, coumarin, isocoumarin, phthalazine, quinoxaline, cinnoline, quinazoline, 1,8- diazanapthtalene, 1,7-diazanapthtalene, 2,7-diazanapthtalene, 1,6-diazanapthtalene, 1,5- diazanapthtalene, 2,6-diazanapthtalene, furan, pyrrole, thiophene, thiazole, benzopyran and benzofuran; wherein if substituted, one or more substituents of said residues are independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -CF3, -CHF2, -CF2CF3, -CH2CF3, -OH, -OCH3, -OCF3, -OCH2CF3, -NH2, -NHCH3, -N(CH3)2, -NO2, linear or branched C1-C8 alkyl such as -CH3, linear or branched C2-C8 alkenyl, linear or branched C2-C8 alkynyl, C3-C8 cycloalkyl, and C3-C8 cycloalkenyl; and wherein all said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl substituents can contain one or more heteroatoms, or groups composed of heteroatoms, independently selected from O, S, SO, SO2 and N in replacement of a carbon atom; and wherein W is even more preferably selected from
and wherein the substituents of W are preferably selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, n = 0 or 1; wherein n is preferably 1; optionally with the proviso that the grouping -(Y)n-W as defined in general formula (I) is different from -H, -F, -CN, -NCO, -NCS, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, =O, -CH3, -CF3 and morpholinyl.
The following preferred definitions of R'-R13, X'-X8, A, Z1, Z2, Y, n, and W may be applied on all aspects including preferred and certain aspects, on all embodiments including preferred and certain embodiments, and on all subgenera as defined in the present invention:
1) R1 contains two or more, preferably three or more, more preferably four or more, even more preferably five or more, and still even more preferably six or more, and most preferably seven or more carbon atoms;
2) R1 contains two or more, preferably three or more, more preferably four or more, even more preferably five or more, and still even more preferably six or more, and most preferably seven or more atoms independently selected from C, O, S and N;
3) R1 contains one or more, two or more, three or more, or four or more heteroatoms independently selected from O, S and N in replacement of a carbon atom contained in R1;
4) R1 contains one or more heteroatoms independently selected from O, S and N in replacement of a carbon atom contained in R1, wherein such a replacement results in residues that contain at least the same number or more than the same number of C atoms than heteroatoms independently selected from O, S and N;
5) R1 contains one or more heteroatoms independently selected from O, S and N in replacement of a carbon atom contained in R1, wherein such a replacement results in residues that contain at least twice the number or more than twice the number of C atoms than heteroatoms independently selected from O, S and N;
6) R1 contains one or more heteroatoms independently selected from O, S and N in replacement of a carbon atom contained in R1, wherein such a replacement results in residues that contain at least three times the number or more than three times the number of C atoms than heteroatoms independently selected from O, S and N;
7) R1 contains no heteroatom;
8) When R1 is C3-C16 cycloalkyl then the cycloalkyl residue is preferably C8-C8 cycloalkyl and even more preferably C4-C8 cycloalkyl and most preferably C5-C8 cycloalkyl;
9) R1 is selected from cyclic structures and/or bicyclic structures and/or tricyclic structures including cycloalkyl, cycloalkenyl, cycloalkynyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl and tricycloalkenyl, and/or from residues that contain such a cyclic and/or bicyclic and/or tricyclic structure;
10) When R1 is selected from cyclic structures and/or bicyclic structures and/or tricyclic structures including cycloalkyl, cycloalkenyl, cycloalkynyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl and tricycloalkenyl, and/or from residues that contain such a cyclic and/or bicyclic and/or tricyclic structure, then the said cyclic, bicyclic or tricyclic structure contains no heteroatom; ) When R1 is selected from cyclic structures and/or bicyclic structures and/or tricyclic structures including cycloalkyl, cycloalkenyl, cycloalkynyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl and tricycloalkenyl, and/or from residues that contain such a cyclic and/or bicyclic and/or tricyclic structure, then the said cyclic, bicyclic or tricyclic structure contains one or more, two or more, or three or more heteroatoms, or groups composed of heteroatoms, independently selected from O, S, SO, SO2 and N in replacement of a carbon atom. ) R1 is different from one or more of the residues selected from -CH2CH3, -CH2NH2, -CH2OH, -CH2OS(O)2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -C(CH3)2CH2CH3, unsubstituted cyclopropyl; ) R1 is different from unsubstituted cyclohexyl; ) R1 is different from one or more of the residues selected from -CH2CH3, -CH2NH2, -CH2OH, -CH2OS(O)2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -C(CH3)2CH2CH3, unsubstituted cyclopropyl, and optionally unsubstituted cyclohexyl when n=0; ) R1 is different from one or more of the residues selected from -CH2CH3, -CH2NH2, -CH2OH, -CH2OS(O)2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -C(CH3)2CH2CH3, unsubstituted cyclopropyl, and optionally unsubstituted cyclohexyl when X8 or X5 are CCN or C Cl;) R1 is different from one or more of the residues selected from -CH2CH3, -CH2NH2, -CH2OH, -CH2OS(O)2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -C(CH3)2CH2CH3, unsubstituted cyclopropyl, and optionally unsubstituted cyclohexyl when X8 or X5 are N; ) R1 is different from one or more of the residues selected from -CH2CH3, -CH2NH2, -CH2OH, -CH2OS(O)2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -C(CH3)2CH2CH3, unsubstituted cyclopropyl, and optionally unsubstituted cyclohexyl when W is phenyl; ) R1 is different from one or more of the residues selected from -CH2CH3, -CH2NH2, -CH2OH, -CH2OS(O)2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -C(CH3)2CH2CH3, unsubstituted cyclopropyl, and optionally unsubstituted cyclohexyl when Wis a heteroaromatic residue selected from pyridine, pyrimidine, pyridazine, oxadiazole, thiazole, triazole, phenyl - pyrazole, phenyl-pyridine, phenyl-oxadiazole and phenyl-triazole; ) R1 is different from one or more of the residues selected from -CH2CH3, -CH2NH2, -CH2OH, -CH2OS(O)2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -C(CH3)2CH2CH3, unsubstituted cyclopropyl, and optionally unsubstituted cyclohexyl when X1, X2, X3, X4 are all CH; ) W is different from residues selected from pyridine, pyrimidine, pyridazine, oxadiazole, thiazole, triazole, phenyl, phenyl-pyrazole, phenyl-pyridine, phenyl-oxadiazole and phenyl-triazole when X8 or X5 are N; ) W is different from residues selected from pyridine, pyrimidine, pyridazine, oxadiazole, thiazole, triazole, phenyl, phenyl-pyrazole, phenyl-pyridine, phenyl-oxadiazole and phenyl-triazole when X8 or X5 are CCN or CC1; ) W is different from residues selected from pyridine, pyrimidine, pyridazine, oxadiazole, thiazole, triazole, phenyl, phenyl-pyrazole, phenyl-pyridine, phenyl-oxadiazole and phenyl-triazole when n=0; ) W is different from one or more of the residues selected from pyridine, pyrimidine, pyridazine, oxadiazole, thiazole, triazole, phenyl, phenyl-pyrazole, phenyl-pyridine, phenyl-oxadiazole and phenyl-triazole, wherein said residues can be unsubstituted or substituted as defined in general formula (I); ) Z1 and Z2 cannot form an unsubstituted and/or substituted piperazinyl together with the nitrogen atoms to which they are bound to as defined in general formula (I); ) Z1 and Z2 cannotform an unsubstituted and/or substituted 3,8-diazabicyclo[3.2.1]octanyl together with the nitrogen atoms to which they are bound to as defined in general formula (i); ) If one or more carbon atoms of Z1 and Z2 are additionally linked to or shared with each other to form a bicyclic or tricyclic structure including both nitrogen atoms which they are bound to as defined in general formula (I), then at least one of the carbon atoms of Z1 and Z2 next to the nitrogen atom bearing the group -(Y)n-W as defined in general formula (I) is a linker atom or shared atom to form said bicyclic or tricyclic structures; ) At least one of Z1 and Z2 is substituted; ) If Z1 and/or Z2 are substituted, the substituent is different from =0; ) If Z1 and/or Z2 are substituted, the substituent is different from =0 at the carbon atom next to the nitrogen atom bearing the group -(Y)n-W as defined in general formula (I);) Z1 and Z2 are independently from each other selected from linear or branched C1- C6 alkylene and C2-C6 alkenylene, wherein one or more carbon atoms of Z1 and Z2 are additionally linked to or shared with each other to form a bicyclic or tricyclic structure including both nitrogen atoms which they are bound to as defined in general formula (I), wherein said bicyclic and tricyclic structures formed with Z1, Z2 and both nitrogen atoms to which they are bound to include fused and/or bridged and/or spiro systems; ) X1 and X4 are CH, X2 is CH or CR7 and X2 is CR8 ; ) R7 is -CH3, -OCH3, -CF3, -CHF2 or -OCF3 and R8 is preferably -OH, -C(O)H, -CH20H, -OCF3, -0CH3, -CH2CH2OH, -CH(0H)CH3, -CH(OH)CF3, -C(CH3)2OH, -NHCH3, -N(CH3)2, -CH2NH2, -CH2CH2NH2, -CH(NH2)CH3; ) R8 is selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -C(O)H, -CH20H, -O(CH2)2OH, -NH2, -CH2NH2, -N02, -CF3, -CHF2, -OCF3, linear or branched C1-C5 alkyl, linear or branched C2- C5 alkenyl, linear or branched C2-C5 alkynyl, C3-C5 cycloalkyl, C3-C5 cycloalkenyl, -CH2(C3- C5 cycloalkyl), linear or branched -OC1-C4 alkyl such as -0CH3, -OC3-C5 cycloalkyl, linear or branched -NH(C1-C4 alkyl), linear or branched -N(C1-C4 alkyl)(C1-C4 alkyl), -NH(C3-Cs cycloalkyl), -N(C3-C5 cycloalkyl)(C3-C5 cycloalkyl), and linear or branched -N(C1-C4 alkyl) (C3- C5 cycloalkyl); ) R8 is selected from -H and/or -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -C(O)H, -0CH3, -OCF3, -CH20H, -O(CH2)2OH, -NH2, -N02, -CF3, -CHF2, linear or branched C1-C5 alkyl, linear or branched C2-C5 alkenyl, C3-C5 cycloalkyl, linear or branched -OC1-C4 alkyl, linear or branched -NH(C1-C4 alkyl), linear or branched -N(C1-C4 alkyl)(C1-C4 alkyl); ) R8 is selected from -H and/or -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -C(O)H, -CH20H, -O(CH2)2OH, -NH2, -NO2, -CF3, -CHF2, -OCF3, -OCH3, -CH2NH2, -NHCH3, -N(CH3)2, cyclopropyl; ) X5, X6, X7 and X8 are selected from CH, N or CR10, wherein R10 is selected from -CH3, -OCH3, -CF3 and -OCF3; ) X8 is CH, X6 and X7 are CH or N, and X8 is CH or N or CCH3; ) When all of X5, X6, X7 and X8 are different from N then X5 and X8 are different from CF and/or COCH3; ) When all of X1, X2, X3, X4, X5, X6, X7 and X8 are different from N then X5 and X8 are different from CF and/or COCH3; ) When all of X1, X2, X3, X4, X5, X6, X7 and X8 are different from N, and when X2 or X3 are COH and/or COCH3 then X5 and X8 are different from CF and/or COCH3; ) When A is -NH- then R1 is different from -CH2CH3, -CH(CH3)2, and/or -C(CH3)3; ) When A is -NH- then Z1 and Z2 cannot form an unsubstituted piperazinyl together with the nitrogen atoms to which they are bound to as defined in general formula (I); ) When A is -NH- then at least one of X1, X2, X3, X4 is different from CH; ) When A is -NH- then at least one of X1, X2, X3, X4 is different from CH, and wherein X2 and/or X3 are different from CC(O)NH2 when R1 is -CH2CH3; ) When Z1 and Z2 form an unsubstituted piperazinyl together with the nitrogen atoms to which they are bound to as defined in general formula (I), then R1 is different from -CH2CH3, -CH(CH3)2, -C(CH3)3, unsubstituted cyclopropyl, -CH2OH, -CH2OSO2CH3, and/or -CH2NH2; ) When Z1 and Z2 form a substituted piperazinyl together with the nitrogen atoms to which they are bound to as defined in general formula (I) and wherein the substituents are bound to Z1 and/or Z2 and are independently selected from one ore two =O, -CH3, or -CH2NH2, then R1 is different from -CH2CH3, -CH(CH3)2, -C(CH3)3, unsubstituted cyclopropyl, -CH20H, -CH2OSO2CH3, and/or -CH2NH2; ) When Z1 and Z2 form an unsubstituted and/or substituted piperazinyl together with the nitrogen atoms to which they are bound to as defined in general formula (I) and wherein the substituents are bound to Z1 and/or Z2 and are independently selected from one or two =O, -CH3, or -CH2NH2, and two of X1, X2, X3, X4 are CH and the other two are selected from CH, CCH3, COH, COCH3, CC(O)NH2 and CF, then R1 is different from -CH2CH3, -CH(CH3)2, -C(CH3)3, unsubstituted cyclopropyl, -CH2OH, -CH2OSO2CH3, and/or -CH2NH2;) When W is pyridine or pyridazine, then W is different from substituted with -NH2; ) Y is -CH2- and n is 1; ) When one ofX1 or X4 is CCH3 and the other is CH, X2 andX3 are CH, one ofX5 or X8 is N and the other is CH, X6 and X7 are CH, and A = O, and Z1 and Z2 form a piperazinyl together with the nitrogen atoms to which they are bound to as defined in general formula (I), wherein the piperazinyl is substituted with one -CH2NH2 substituent that is bound to Z1 or Z2 at the carbon atom next to the nitrogen atom that is bound to the carbonyl group connected to the aromatic ring containing X5-X8 as defined in general formula (I), and the grouping -(Y)n-W as defined in general formula (I) is -CH3, then R1 is different from -CH(CH3)2; 51) If Z1 and/or Z2 are substituted, the substituent is different from -CH3;
52) When R1 is -CH2NH2, and the grouping -(Y)n-W as defined in general formula (I) is -CH3, then Z1 and Z2 cannot form an unsubstituted diazepanyl together with the nitrogen atoms to which they are bound to as defined in general formula (I);
53) A = 0
54) W is selected from C6-C14 aromatic and C5-C14 heteroaromatic residues as defined in general formula (I), preferably unsubstituted or substituted residues selected from benzyl, pyridine, indole, pyrimidine, pyridazine, pyrazine, naphthyl, quinoline, coumarin, isocoumarin, phthalazine, quinoxaline, cinnoline, quinazoline, 1,8-diazanapthtalene, 1,7- diazanapthtalene, 2,7-diazanapthtalene, 1,6-diazanapthtalene, 1,5-diazanapthtalene, 2,6- diazanapthtalene, furan, pyrrole, thiophene, thiazole, benzopyran and benzofuran;
55) The grouping -(Y)n-W as defined in general formula (I) is different from one or more of the groups -CH2CH3, -CH2CH2CH3, -CH2C(O)NH2, -CH2C(O)NHCH2CH3, -CH2-(N- morpholinyl), and/or the following moieties:
In certain embodiments, the compounds may have features (12+13), (17+18), (a combination of any of the features independently selected from 14, 15, 16, 17, 18 and optionally 19), (31+32), (31+32+33 or 34 or 35), (31+33 or 34 or 35), (45+46), (28+51), (1+49), (1+49+53), (1+49+53+2 or 3 or 4 or 5 or 6 or 7), (1+49+54), (1+49+53+54), (1+49+53+54+2 or 3 or 4 or 5 or 6 or 7), (49+55), (1+49+55), (1+49+55+53), (1+49+55+53+2 or 3 or 4 or 5 or 6 or 7), (1+49+55+54), (1+49+55+53+54), (1+49+55+53+54+2 or 3 or 4 or 5 or 6 or 7) as described above.
A preferred aspect of the present invention relates to compounds of general formula (I) and salts and solvates thereof which fall under the scope of the herein defined subgenera:
S.l
(i) R1-R13, X4-X8, A, Z1, Z2, Y, n, and W are defined as in general formula (I) with the proviso that Z1 and/or Z2 cannot be substituted with =0 at the carbon atom next to the nitrogen atom bearing the group -(Y)n-W as defined in general formula (I), particularly if
R1 is selected from -CR2R3R4, together forming the groups R1 = C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl, and X4-X4 are selected from CR5, CR6, CR7 and CR8, wherein R5, R6, and R7 are dependently from each other selected from -H, -F, -Cl, -Br, -I, -CN, -CH3, -OH, linear or branched C3-C5 alkyl, linear or branched C4-C5 alkenyl, linear or branched C5 alkynyl, linear or branched -OC2-C4 alkyl, and wherein R8 is selected from -H, -F, -Cl, -Br, -I, -CN, -CH3, -OH, linear or branched C3-C5 alkyl, linear or branched C4-C5 alkenyl, linear or branched C5 alkynyl, linear or branched -OC2-C4 alkyl, and wherein all alkyl, alkenyl, and alkynyl residues contained in the definitions of R5, R6, R7, and R8 can contain one or more heteroatoms, or groups composed of heteroatoms independently selected from O, S, SO, S02 and N in replacement of a carbon atom, and wherein all alkyl, alkenyl, and alkynyl residues contained in the definitions of R5, R6, R7, and R8 are unsubstituted or substituted with one or more substituents independently selected from -CH3, -OH and -OCH3, -NH2, -NHCH3, -N(CH3)2, together resulting in the combination of X1 = CH, CF, CC1, CBr, CI, CCN, CCH3, X2 = CH, X3 = CR5, CR6, CR7 or CR8, and X4 = CH, or in the combination of X1 = CH, X2 = CR5, CR6, CR7 or CR8, X3 = CH, and X4 = CH, CF, CC1, CBr, CI, CCN, CCH3, and A = O, and X5-X8 are selected from CR10, CR11, CR12 and CR13, wherein R10, R11, R12, and R13 are dependently from each other selected from -H and -F together resulting in the combination of X5 = CF, X6 = CH, X7 = CH, and X8 = CH, or in the combination of X5 = CH, X6 = CH, X7 = CH, and X8 = CF, and Z1 and Z2 form a piperazine together with the nitrogen atoms to which they are bound to as defined in general formula (I), wherein Z1 and Z2 can independently from each other be unsubstituted or substituted with one or more substituents independently selected from -F, =O, linear or branched C1-C8 alkyl such as -CH3, linear or branched C2-C8 alkenyl, linear or branched C2-C8 alkynyl, -CH2(C3-C5 cycloalkyl), and wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definitions of Z1 and Z2 or in any of their substituents can contain one or more heteroatoms, or groups composed of heteroatoms independently selected from O, S, SO, SO2 and N in replacement of a carbon atom, and wherein all alkyl, alkenyl and alkynyl residues contained in the definitions of Z1 and Z2 or in any of their substituents can be partially halogenated, and Y = linear or branched C1-C5 alkyl, linear or branched C2-C5 alkenyl, linear or branched C2-C5 alkynyl, and wherein all alkyl, alkenyl, and alkynyl residues contained in the definitions of Y can contain one or more heteroatoms, or groups composed of heteroatoms independently selected from O, S, SO, SO2 and N in replacement of a carbon atom, wherein all alkyl, alkenyl, and alkynyl residues contained in the definitions of Y can be unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -OC1-C3 alkyl such as -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, NO2, =O, -CF3, linear or branched C1-C3 alkyl such as -CH3, linear or branched C2-C3 alkenyl, C2-C3 alkynyl, C3 cycloalkyl, C3 cycloalkenyl, and W = -H, -F, C3-C7 cycloalkyl, C4-C6 cycloalkenyl, as well as C6 aromatic and C5-C6 heteroaromatic residues, wherein all aromatic and heteroaromatic residues contained in the definitions of W include monoaromatic and monoheteroaromatic systems, wherein all cycloalkyl and cycloalkenyl residues, as well as all aromatic and heteroaromatic moieties contained in the definitions of W are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, linear or branched C1-C8 alkyl, linear or branched C2- C8 alkenyl, linear or branched C2-C8 alkynyl, C3-C7 cycloalkyl, and wherein all alkyl, alkenyl, and alkynyl substituents of W can independently from each other be linked additionally to more than one carbon atom of W, and wherein all alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl residues, as well as all aromatic and heteroaromatic moieties contained in the definitions of W or in any of its substituents, can contain one or more heteroatoms, or groups composed of heteroatoms independently selected from O, S, SO, SO2 and N in replacement of a carbon atom, and wherein all alkyl, alkenyl, alkynyl, and cycloalkyl residues contained in the definitions of the substituents of W can be partially halogenated, and n = 0 or 1.
(ii) R1-R13, X4-X8, A, Z1, Z2, Y, n, and W are defined as in general formula (I) with the proviso that Z1 and/or Z2 cannot be substituted with =0 at the carbon atom next to the nitrogen atom bearing the group -(Y)n-W as defined in general formula (I), particularly if
R1 is selected from -CR2R3R4, together forming the groups R1 = C1-C8 alkyl, C2-C6 alkenyl and C2-C6 alkynyl, and/or X4-X4 are selected from CR5, CR6, CR7 and CR8, wherein R5, R6, and R7 are dependently from each other selected from -H, -F, -Cl, -Br, -I, -CN, -CH3, -OH, linear or branched C3-C5 alkyl, linear or branched C4-C5 alkenyl, linear or branched C5 alkynyl, linear or branched -OC2-C4 alkyl, and wherein R8 is selected from -H, -F, -Cl, -Br, -I, -CN, -CH3, -OH, linear or branched C3-C5 alkyl, linear or branched C4-C5 alkenyl, linear or branched C5 alkynyl, linear or branched -OC2-C4 alkyl, and wherein all alkyl, alkenyl, and alkynyl residues contained in the definitions of R5, R6, R7, and R8 can contain one or more heteroatoms, or groups composed of heteroatoms independently selected from O, S, SO, SO2 and N in replacement of a carbon atom, and wherein all alkyl, alkenyl, and alkynyl residues contained in the definitions of R5, R6, R7, and R8 are unsubstituted or substituted with one or more substituents independently selected from -CH3, -OH and -OCH3, -NH2, -NHCH3, -N(CH3)2, together resulting in the combination of X1 = CH, CF, CC1, CBr, CI, CCN, CCH3, X2 = CH, X3 = CR5, CR6, CR7 or CR8, and X4 = CH, or in the combination of X1 = CH, X2 = CR5, CR6, CR7 or CR8, X3 = CH, and X4 = CH, CF, CC1, CBr, CI, CCN, CCH3, and/or A = O, and/or X5-X8 are selected from CR10, CR11, CR12 and CR13, wherein R10, R11, R12, and R13 are dependently from each other selected from -H and -F together resulting in the combination of X5 = CF, X6 = CH, X7 = CH, and X8 = CH, or in the combination of X5 = CH, X6 = CH, X7 = CH, and X8 = CF, and/or Z1 and Z2 form a piperazine together with the nitrogen atoms to which they are bound to as defined in general formula (I), wherein Z1 and Z2 can independently from each other be unsubstituted or substituted with one or more substituents independently selected from -F, =O, linear or branched C1-C8 alkyl such as -CH3, linear or branched C2- C8 alkenyl, linear or branched C2-C8 alkynyl, -CH2(C:;-C5 cycloalkyl), and wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definitions of Z1 and Z2 or in any of their substituents can contain one or more heteroatoms, or groups composed of heteroatoms independently selected from O, S, SO, SO2 and N in replacement of a carbon atom, and wherein all alkyl, alkenyl and alkynyl residues contained in the definitions of Z1 and Z2 or in any of their substituents can be partially halogenated, and/or Y = linear or branched C1-C5 alkyl, linear or branched C2-C5 alkenyl, linear or branched C2-C5 alkynyl, and wherein all alkyl, alkenyl, and alkynyl residues contained in the definitions of Y can contain one or more heteroatoms, or groups composed of heteroatoms independently selected from O, S, SO, SO2 and N in replacement of a carbon atom, wherein all alkyl, alkenyl, and alkynyl residues contained in the definitions of Y can be unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -OC1-C3 alkyl such as -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, NO2, =O, -CF3, linear or branched C1-C3 alkyl such as -CH3, linear or branched C2-C3 alkenyl, C2-C3 alkynyl, C3 cycloalkyl, C3 cycloalkenyl, and/or W = -H, -F, C3-C7 cycloalkyl, C4-C6 cycloalkenyl, as well as C6 aromatic and Cs-C8 heteroaromatic residues, wherein all aromatic and heteroaromatic residues contained in the definitions of W include monoaromatic and monoheteroaromatic systems, wherein all cycloalkyl and cycloalkenyl residues, as well as all aromatic and heteroaromatic moieties contained in the definitions of W are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, linear or branched C1-C8 alkyl, linear or branched C2- C8 alkenyl, linear or branched C2-C8 alkynyl, C3-C7 cycloalkyl, and wherein all alkyl, alkenyl, and alkynyl substituents of W can independently from each other be linked additionally to more than one carbon atom of W, and wherein all alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl residues, as well as all aromatic and heteroaromatic moieties contained in the definitions of W or in any of its substituents, can contain one or more heteroatoms, or groups composed of heteroatoms independently selected from O, S, SO, SO2 and N in replacement of a carbon atom, and wherein all alkyl, alkenyl, alkynyl, and cycloalkyl residues contained in the definitions of the substituents of W can be partially halogenated, and/or n = 0 or 1.
S.2
R1-R13, X4-X8, A, Z1, Z2, Y, n, and W are defined as in general formula (I) with the proviso that Z1 and/or Z2 cannot be substituted with =0 at the carbon atom next to the nitrogen atom bearing the group -(Y)n-W as defined in formula (I), particularly if
1) R1 is -CH2CH3, and/or X4-X4 are selected from CR5, CR6, CR7 and CR8, wherein R5, R6, and R7 are dependently from each other selected from -H, -F, -OH, -OCH3 and R8 from -F, -OH, and -OCH3 together resulting in the combination of X1 = CH, X2 = COH or COCH3, X3 = CH, and X4 = CF, or in the combination of X1 = CF, X2 = CH, X3 = COH or COCH3, and X4 = CH, and/or A = O, and/or X5-X8 are selected from CR10, CR11, CR12 and CR13, wherein R10, R11, R12, and R13 are dependently from each other selected from -H and -F together resulting in the combination of X5 = CF, X6 = CH, X7 = CH, and X8 = CH, or in the combination of X5 = CH, X6 = CH, X7 = CH, and X8 = CF, and/or Z1 and Z2 form a piperazine together with the nitrogen atoms to which they are bound to as defined in general formula (I), wherein three of the four carbon atoms of said piperazine are unsubstituted and one carbon atom is substituted wherein said substituted carbon atom is next to the nitrogen atom bearing the group -(Y)n-W, and/or the grouping -(Y)n-W as defined in general formula (I) is selected from -CH3, or -CH2-(N-morpholinyl), or -CH2C(O)NH2. and/or
2) the group R1 is selected from -CR2R3R4, wherein R2, R3 and R4 are dependently from each other selected from -H and -CH3 and wherein the carbon atom of the said -CH3, group is replaced by a nitrogen atom and wherein R2, R3 and R4 form together the group R1 = -CH2NH2, and/or X4-X4 are selected from CR5, CR6, CR7 and CR8, wherein R5, R6, and R7 are each -H, and R8 is -OCH3 together resulting in the combination of X1 = CH, X2 = COCH3, X3 = CH, and X4 = CH, or in the combination of X1 = CH, X2 = CH, X3 = COCH3, and X4 = CH, and/or A = O, and/or X5-X8 are selected from CR10, CR11, CR12 and CR13, wherein R10, R11, R12, and R13 are dependently from each other selected from -H and -OCH3 together resulting in the combination of X5 = COCH3, X6 = CH, X7 = CH, and X8 = CH, or in the combination of X5 = CH, X6 = CH, X7 = CH, and X8 = COCH3, and/or Z1 and Z2 form a piperazine together with the nitrogen atoms to which they are bound to as defined in general formula (I), wherein one of Z1 or Z2 is unsubstituted and the other of Z1 or Z2 is substituted on the carbon atom next to the nitrogen atom that is bound to the carbonyl group connected to the aromatic ring containing X5-X8 as defined in general formula (I), wherein the substituent is -CH3, and/or the grouping -(Y)n-W as defined in general formula (I) is selected from -CH3. and/or
3) the group R1 is -C(CH3)3, and/or X4-X4 are selected from CR5, CR6, CR7 and CR8, wherein R5, R6, R7, and R8 are each -H, and/or A = O, and/or X5-X8 are dependently from each other selected from N, CR10, CR11, CR12 and CR13, wherein R10, R11, R12, and R13 are each -H together resulting in the combination of X5 = CH, X6 = CH, X7 = CH, and X8 = N, or in the combination of X5 = N, X6 = CH, X7 = CH, and X8 = CH, and/or Z1 and Z2 form a piperazine together with the nitrogen atoms to which they are bound to as defined in general formula (I), wherein three of the four carbon atoms of said piperazine are unsubstituted and one carbon atom is substituted wherein said substituted carbon atom is next to the nitrogen atom bearing the group -(Y)n-W, and/or the grouping -(Y)n-W as defined in general formula (I) is -CH2-4-(l,2,3-triazolyl)- l-N-(2-fluoro-3-bromophenyl).
S.3 (i) R1-R13, X4-X8, A, Z1, Z2, Y, n, and W are defined as in general formula (I) with the proviso that when W is pyridine or pyridazine then W is not substituted with -NH2 in para position with respect to the bond to the grouping containing Z1 and Z2 as defined in general formula (I), particularly if
R1 is selected from -CR2R3R4, wherein R2, R3 and R4 are dependently from each other selected from -H, -CH3 and -CH2CH3 together forming the group R1 = C2-C3 alkyl which can be substituted with one to three substituents independently selected from -F, -Cl, -Br, -I, -NH2, =O, -NH(C1-C3 alkyl), -N(C1-C3 alkyl) (C1-C3 alkyl), and/or R1 is selected from C3-C6 cycloalkyl, and X4-X4 are selected from CR5, CR6, CR7 and CR8, wherein R5, R6, and R7 are each -H, and wherein R8 is selected from -H, -F, -Cl, -Br, -I, linear or branched C1-C3 alkyl, linear or branched -OC1-C3 alkyl, and wherein all alkyl residues contained in the definitions of R8 contain no heteroatom and are unsubstituted, together resulting in the combination of X1 = CH, X2 = CH, X3 = CH, and X4 = CR8, or in the combination of X4 = CR8, X2 = CH, X3 = CH, and X4 = CH, and A = O, and X5-X8 are selected from CR10, CR11, CR12 and CR13, wherein R10, R11, R12, and R13 are dependently from each other selected from -H, -F, -Cl, -Br, -I, linear or branched C1-C3 alkyl, linear or branched -OC1-C3 alkyl, wherein all alkyl residues contained in the definitions of R10, R11, R12, and R13 contain no heteroatom and are unsubstituted or substituted with one to three substituents independently selected from -F, -Cl, -Br, -I, together resulting in the combination of X5 = CH, CF, CC1, CBr or CI, X6 = CH, X7 = CR10, CR11, CR12 or CR13, and X8 = CH, or in the combination of X5 = CH, X6 = CR10, CR11, CR12 or CR13, X7 = CH, and X8 = CH, CF, CC1, CBr or CI, and Z1 and Z2 form a piperazine together with the nitrogen atoms to which they are bound to as defined in general formula (I), wherein Z1 and Z2 can independently from each other be unsubstituted or substituted with one to three substituents which cannot be bound to the carbon atom of Z1 and/or Z2 next to the nitrogen atom bearing the group -(Y)n-W as defined in general formula (I), and wherein said substituents are independently selected from linear or branched C1-C8 alkyl, C3-C6 cycloalkyl, and wherein said C1-C8 alkyl substituents of Z1 and Z2 can contain one or more heteroatoms which are 0 in replacement of a carbon atom, and wherein Z1, Z2 and both nitrogen atoms to which they are bound to form a bridged bicyclic structure selected from 3,6-diazabicyclo[3.1.0]hexanyl, 3,6- diazabicyclo[3.1.1]heptanyl, 3,8-diazabicyclo[3.2.1]octanyl, and 3,9- diazabicyclo[3.3.1]nonanyl, wherein the bridging carbon atoms of Z1 and Z2 cannot be bound to the nitrogen atom bearing the group -(Y)n-W as defined in general formula (I), and n = O, and W is pyridine or pyridazine, and wherein said pyridine and pyridazine are bound with the carbon atom in position 3 to the nitrogen of the piperazine ring that is formed by Z1, Z2 and both nitrogen atoms to which they are bound to as defined in general formula (I), and wherein said pyridine or pyridazine can be substituted with one or two substituents selected from linear or branched C1-C3 alkyl and linear or branched -OC1-C3 alkyl in position 4 and/or 5. (ii) R1-R13, X4-X8, A, Z1, Z2, Y, n, and W are defined as in general formula (I) with the proviso that when W is pyridine or pyridazine then W is not substituted with -NH2 in para position with respect to the bond to the grouping containing Z1 and Z2 as defined in general formula (I), particularly if
R1 is selected from -CR2R3R4, wherein R2, R3 and R4 are dependently from each other selected from -H, -CH3 and -CH2CH3 together forming the group R1 = C2-C3 alkyl which can be substituted with one to three substituents independently selected from -F, -Cl, -Br, -I, -NH2, =O, -NH(C1-C3 alkyl), -N(C1-C3 alkyl) (C1-C3 alkyl), and/or R1 is selected from C3-C6 cycloalkyl, and/or X4-X4 are selected from CR5, CR6, CR7 and CR8, wherein R5, R6, and R7 are each -H, and wherein R8 is selected from -H, -F, -Cl, -Br, -I, linear or branched C1-C3 alkyl, linear or branched -OC1-C3 alkyl, and wherein all alkyl residues contained in the definitions of R8 contain no heteroatom and are unsubstituted, together resulting in the combination of X1 = CH, X2 = CH, X3 = CH, and X4 = CR8, or in the combination of X4 = CR8, X2 = CH, X3 = CH, and X4 = CH, and/or A = O, and/or X5-X8 are selected from CR10, CR11, CR12 and CR13, wherein R10, R11, R12, and R13 are dependently from each other selected from -H, -F, -Cl, -Br, -I, linear or branched C1-C3 alkyl, linear or branched -OC1-C3 alkyl, wherein all alkyl residues contained in the definitions of R10, R11, R12, and R13 contain no heteroatom and are unsubstituted or substituted with one to three substituents independently selected from -F, -Cl, -Br, -I, together resulting in the combination of X5 = CH, CF, CC1, CBr or CI, X6 = CH, X7 = CR10, CR11, CR12 or CR13, and X8 = CH, or in the combination of X5 = CH, X6 = CR10, CR11, CR12 or CR13, X7 = CH, and X8 = CH, CF, CC1, CBr or CI, and/or Z1 and Z2 form a piperazine together with the nitrogen atoms to which they are bound to as defined in general formula (I), wherein Z1 and Z2 can independently from each other be unsubstituted or substituted with one to three substituents which cannot be bound to the carbon atom of Z1 and/or Z2 next to the nitrogen atom bearing the group -(Y)n-W as defined in general formula (I), and wherein said substituents are independently selected from linear or branched C1-C8 alkyl, C3-C6 cycloalkyl, and wherein said C1-C8 alkyl substituents of Z1 and Z2 can contain one or more heteroatoms which are 0 in replacement of a carbon atom, and/or wherein Z1, Z2 and both nitrogen atoms to which they are bound to form a bridged bicyclic structure selected from 3,6-diazabicyclo[3.1.0]hexanyl, 3,6- diazabicyclo[3.1.1]heptanyl, 3,8-diazabicyclo[3.2.1]octanyl, and 3,9- diazabicyclo[3.3.1]nonanyl, wherein the bridging carbon atoms of Z1 and Z2 cannot be bound to the nitrogen atom bearing the group -(Y)n-W as defined in general formula (I), and/or n = O, and/or W is pyridine or pyridazine, and wherein said pyridine and pyridazine are bound with the carbon atom in position 3 to the nitrogen of the piperazine ring that is formed by Z1, Z2 and both nitrogen atoms to which they are bound to as defined in general formula (I), and wherein said pyridine or pyridazine can be substituted with one or two substituents selected from linear or branched C1-C3 alkyl and linear or branched -OC1-C3 alkyl in position 4 and/or 5. S.4
(i) R1-R13, X4-X8, A, Z1, Z2, Y, n, and W are defined as in general formula (I) with the proviso that X5 and/or X8 are different from N, particularly if
R1 is C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C8 cycloalkyl which all can be substituted with one or more substituents as defined in general formula (I), and wherein
R1 is preferably selected from -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -C(CH3)2CH2CH3, and cyclohexyl, and X4-X4 are selected from CR5, CR6, CR7 and CR8, wherein R5, R6, R7 and R8 are as defined in general formula (I), and A is as defined in general formula (I), and X6-X8 and/or X5-X7, respectively, are independently from each other selected from CR10, CR11, CR12 and CR13, wherein R10, R11, R12, and R13 are as defined in general formula (I), and Z1 and Z2 form a piperazine together with the nitrogen atoms to which they are bound to as defined in general formula (I), wherein Z1 and Z2 can independently from each other be unsubstituted or substituted with one or more substituents as defined in general formula (I), and wherein Z1, Z2 and both nitrogen atoms to which they are bound to form a bridged bicyclic structure selected from 3,6-diazabicyclo[3.1.1]heptanyl, 3,8- diazabicyclo[3.2.1]octanyl, and 3,9-diazabicyclo[3.3.1]nonanyl, wherein the bridging carbon atoms of Z1 and Z2 cannot be bound either to the nitrogen atom bearing the group -(Y)n-W as defined in general formula (I), or to the nitrogen atom that is bound to the carbonyl group connected to the aromatic ring containing X5-X8 as defined in general formula (I), and wherein Z1 and Z2 can independently from each other be unsubstituted or substituted with one or more substituents as defined in general formula (I), and n = O, and W is selected from C6-C14 aromatic and C5-C14 heteroaromatic residues as defined in general formula (I), wherein W is preferably selected from substituted or unsubstituted pyridine, pyrimidine, oxadiazole, thiazole, phenyl pyrazole, phenyl pyridine and phenyl oxadiazole, and wherein W is most preferably selected from substituted or unsubstituted pyridine.
(ii) R4-R13, X4-X8, A, Z1, Z2, Y, n, and W are defined as in general formula (I) with the proviso that X5 and/or X8 are different from N, particularly if
R1 is C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C8 cycloalkyl which all can be substituted with one or more substituents as defined in general formula (I), and wherein
R1 is preferably selected from -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -C(CH3)2CH2CH3, and cyclohexyl, and/or X4-X4 are selected from CR5, CR6, CR7 and CR8, wherein R5, R6, R7 and R8 are as defined in general formula (I), and/or A is as defined in general formula (I), and/or X6-X8 and/or X5-X7, respectively, are independently from each other selected from CR10, CR11, CR12 and CR13, wherein R10, R11, R12, and R13 are as defined in general formula (I), and/or Z1 and Z2 form a piperazine together with the nitrogen atoms to which they are bound to as defined in general formula (I), wherein Z1 and Z2 can independently from each other be unsubstituted or substituted with one or more substituents as defined in general formula (I), and/or wherein Z1, Z2 and both nitrogen atoms to which they are bound to form a bridged bicyclic structure selected from 3,6-diazabicyclo[3.1.1]heptanyl, 3,8- diazabicyclo[3.2.1]octanyl, and 3,9-diazabicyclo[3.3.1]nonanyl, wherein the bridging carbon atoms of Z1 and Z2 cannot be bound either to the nitrogen atom bearing the group -(Y)n-W as defined in general formula (I), or to the nitrogen atom that is bound to the carbonyl group connected to the aromatic ring containing X5-X8 as defined in general formula (I), and wherein Z1 and Z2 can independently from each other be unsubstituted or substituted with one or more substituents as defined in general formula (I), and/or n = O, and/or W is selected from C6-C14 aromatic and C5-C14 heteroaromatic residues as defined in general formula (I), wherein W is preferably selected from substituted or unsubstituted pyridine, pyrimidine, oxadiazole, thiazole, phenyl pyrazole, phenyl pyridine and phenyl oxadiazole, and wherein W is most preferably selected from substituted or unsubstituted pyridine.
S.5
R1_R13, X'-X8, A, Z1, Z2, Y, n, and W are defined as in general formula (I) with the proviso that X5 and/or X8 are different from N, particularly if
1) R1 is C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C8 cycloalkyl which all can be substituted with one or more substituents as defined in general formula (I), and wherein
R1 is preferably selected from -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -C(CH3)2CH2CH3, and cyclohexyl, and/or X'-X4 are selected from CR5, CR6, CR7 and CR8, wherein R5, R6, R7 and R8 are as defined in general formula (I), and/or A is as defined in general formula (I), and/or X5 is different from N when X7 is CH, and X6 and X8 are independently from each other selected from CR10, CR11, CR12 and CR13, or X8 is different from N when X6 is CH, and X5 and X7 are independently from each other selected from CR10, CR11, CR12 and CR13, wherein R10, R11, R12, and R13 are as defined in general formula (I), and wherein X6 and X8, or X5 and X7, respectively, are preferably selected from CC1, CCF3, CCN, CCH3, CCH(CH3)2, CCHF2, CCF3, CC(O)NH2, CC(S)NH2, CC(=NOH)NH2, CCH2NH2, and/or Z1 and Z2 form a six-membered cycle together with the nitrogen atoms to which they are bound to as defined in general formula (I) wherein said cycle is a piperazine, and wherein Z1 and Z2 can independently from each other be unsubstituted or substituted with one or more substituents as defined in general formula (I), and/or wherein Z1, Z2 and both nitrogen atoms to which they are bound to form a bridged bicyclic structure selected from 3,6-diazabicyclo[3.1.1]heptanyl, 3,8- diazabicyclo[3.2.1]octanyl, and 3,9-diazabicyclo[3.3.1]nonanyl, wherein the bridging carbon atoms of Z1 and Z2 cannot be bound either to the nitrogen atom bearing the group -(Y)n-W as defined in general formula (I), or to the nitrogen atom that is bound to the carbonyl group connected to the aromatic ring containing X5-X8 as defined in general formula (I), and wherein Z1 and Z2 can independently from each other be unsubstituted or substituted with one or more substituents as defined in general formula (I), and/or n = O, and/or W is selected from pyridine, wherein said pyridine is bound in position 2 to the nitrogen of the piperazine ring that is formed by Z1, Z2 and both nitrogen atoms to which they are bound to as defined in general formula (I), and wherein said pyridine can be substituted with one or two substituents as defined in general formula (I) in position 3 and/or 5, and wherein said two substituents are as defined herein above or preferably selected from -F, -Cl, -CF3, -CN, -CH3, -S(O)CH2CH3, -SCH2CH3, -NO2 and -NH2; and/or
2) R1 is C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C8 cycloalkyl which all can be substituted with one or more substituents as defined in general formula (I), and wherein
R1 is preferably selected from -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -C(CH3)2CH2CH3, and cyclohexyl, and/or X'-X4 are selected from CR5, CR6, CR7 and CR8, wherein all of R5, R6, R7 and R8 are H, and/or A is as defined in general formula (I), and/or X5 is different from N when X7 is CH, and X6 and X8 are independently from each other selected from CR10, CR11, CR12 and CR13, or X8 is different from N when X6 is CH, and X5 and X7 are independently from each other selected from CR10, CR11, CR12 and CR13, wherein R10, R11, R12, and R13 are as defined in general formula (I), and wherein X6 and X8, or X5 and X7, respectively, are preferably selected from CC1, CCN, CCH3, CCH(CH3)2, CCHF2, CCF3, and/or Z1 and Z2 form an unsubstituted piperazine together with the nitrogen atoms to which they are bound to as defined in general formula (I), and/or n = O, and/or W is selected from pyridine, wherein said pyridine is bound in position 2 to the nitrogen of the piperazine ring that is formed by Z1, Z2 and both nitrogen atoms to which they are bound to as defined in general formula (I), and wherein said pyridine can be substituted with one or two substituents as defined in general formula (I) in position 3 and/or 5, and wherein said two substituents are preferably selected from -F, -Cl, -CF3, -CN, -CH3, -S(O)CH2CH3, -SCH2CH3, -NO2 and -NH2; and/or 3) R1 is C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C8 cycloalkyl which all can be substituted with one or more substituents as defined in general formula (I), and wherein R1 is preferably -C(CHg)3, and/or X4-X4 are selected from CR5, CR6, CR7 and CR8, wherein all of R5, R6, R7 and R8 are H, and/or A = O, and/or X5 is different from N when X7 is CH, and X6 and X8 are independently from each other selected from CR10, CR11, CR12 and CR13, or X8 is different from N when X6 is CH, and X5 and X7 are independently from each other selected from CR10, CR11, CR12 and CR13, wherein R10, R11, R12, and R13 are as defined in general formula (I), and wherein X6 and X8, or X5 and X7, respectively, are preferably selected from CC1, CCF3, CCN, CCH3, and/or wherein Z1, Z2 and both nitrogen atoms to which they are bound to form a bridged bicyclic structure which is unsubstituted 3,8-diazabicyclo[3.2.1]octanyl, wherein the bridging carbon atoms of Z1 and Z2 cannot be bound to the nitrogen atom that is bound to the carbonyl group connected to the aromatic ring containing X5-X8 as defined in general formula (I), and/or n = O, and/or W is selected from pyridine, wherein said pyridine is bound in position 2 to the nitrogen of the piperazine ring that is formed by Z1, Z2 and both nitrogen atoms to which they are bound to as defined in general formula (I), and wherein said pyridine can be substituted with one or two substituents as defined in general formula (I) in position 3 and/or 5, and wherein said two substituents are preferably selected from -F and -Cl. and/or
4) R1 is C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C8 cycloalkyl which all can be substituted with one or more substituents as defined in general formula (I), and wherein R1 is preferably -C(CHg)3, and/or X4-X4 are selected from CR5, CR6, CR7 and CR8, wherein all of R5, R6, R7 and R8 are H, and/or A = O, and/or X5 is different from N when X7 is CH, X8 is CCN and X6 selected from CR10, CR11, CR12 and CR13, or X8 is different from N when X6 is CH, X5 is CCN and X7 is selected from CR10, CR11, CR12 and CR13, wherein R10, R11, R12, and R13 are as defined in general formula (I), and wherein X6 or X7, respectively, are preferably selected from CCH3 and CCF3, and/or wherein Z1, Z2 and both nitrogen atoms to which they are bound to form a bridged bicyclic structure which is unsubstituted 3,8-diazabicyclo[3.2.1]octanyl, wherein the bridging carbon atoms of Z1 and Z2 cannot be bound to the nitrogen atom bearing the group -(Y)n-W as defined in general formula (I), and/or n = O, and/or W is selected from pyridine, wherein said pyridine is bound in position 2 to the nitrogen of the piperazine ring that is formed by Z1, Z2 and both nitrogen atoms to which they are bound to as defined in general formula (I), and wherein said pyridine can be substituted with one or two substituents as defined in general formula (I) in position 3 and/or 5, and wherein said two substituents are preferably selected from -F and -Cl. and/or
5) R1 is C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C8 cycloalkyl which all can be substituted with one or more substituents as defined in general formula (I), and wherein R1 is preferably selected from -CH(CH3)2 and -C(CH3)3, and/or X'-X4 are selected from CR5, CR6, CR7 and CR8, wherein all of R5, R6, R7 and R8 are -H, and/or A = O, and/or X5 is different from N when X7 is CH, and X6 and X8 are independently from each other selected from CR10, CR11, CR12 and CR13, or X8 is different from N when X6 is CH, and X5 and X7 are independently from each other selected from CR10, CR11, CR12 and CR13, wherein R10, R11, R12, and R13 are as defined in general formula (I), and wherein X6 and X8, or X5 and X7, respectively, are preferably selected from CC1, CCF3, CCN, CCH3, CCH(CH3)2, CCHF2, CCF3, CC(O)NH2, CC(S)NH2, CC(=NOH)NH2, CCH2NH2, and/or Z1 and Z2 form a piperazine together with the nitrogen atoms to which they are bound to as defined in general formula (I), wherein Z1 and Z2 can independently from each other be unsubstituted or substituted with one to four substituents as defined in general formula (I), and wherein one of the carbon atoms of Z1 or Z2 next to the nitrogen atom bearing the group -(Y)n-W as defined in general formula (I) is unsubstituted and the other of the carbon atoms of Z1 or Z2 next to the nitrogen atom bearing the group -(Y)n- W as defined in general formula (I) can be substituted with only one substituent, and/or wherein Z1, Z2 and both nitrogen atoms to which they are bound to form a bridged bicyclic structure selected from 3,6-diazabicyclo[3.1.1]heptanyl, 3,8- diazabicyclo[3.2.1]octanyl, and 3,9-diazabicyclo[3.3.1]nonanyl, wherein the bridging carbon atoms of Z1 and Z2 are bound to the nitrogen atom that is bound to the carbonyl group connected to the aromatic ring containing X5-X8 as defined in general formula (I), and wherein one of Z1 and Z2 can additionally be substituted with one or two substituents as defined in general formula (I), wherein the two said substituents are connected to different C-atoms of Z1 or Z2, and/or n = O, and/or W is selected from pyridine, wherein said pyridine is bound in position 2 to the nitrogen of the piperazine ring that is formed by Z1, Z2 and both nitrogen atoms to which they are bound to as defined in general formula (I), and wherein said pyridine can be substituted with one or two substituents as defined in general formula (I) in position 3 and/or 5, and wherein said two substituents are preferably selected from -F, -Cl, -CF3, -NO2 and -NH2. and/or
6) R1 is C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C8 cycloalkyl which all can be substituted with one or more substituents as defined in general formula (I), and wherein R1 is preferably selected from -CH(CH3)3, -C(CH3)3 and -C(CH3)3CH3CH3, and/or X4-X4 are selected from CR5, CR6, CR7 and CR8, wherein all of R5, R6, R7 and R8 are -H, and/or A = O, and/or X5 is different from N when X7 is CH, X8 is CCN and X6 selected from CR10, CR11, CR12 and CR13, or X8 is different from N when X6 is CH, X5 is CCN and X7 is selected from CR10, CR11, CR12 and CR13, wherein R10, R11, R12, and R13 are as defined in general formula (I), and wherein X6 or X7, respectively, are preferably selected from CCH3 and CCHF2, and/or Z1 and Z2 form a piperazine together with the nitrogen atoms to which they are bound to as defined in general formula (I), wherein either Z1 or Z2 can be substituted with one or two substituents as defined in general formula (I), and wherein the two carbon atoms of Z1 or Z2 can only be monosubstituted each, and wherein the said substituents are preferably -CH3, and/or n = O, and/or W is selected from C6-C14 aromatic and C5-C14 heteroaromatic residues as defined in general formula (I), wherein W is preferably selected from substituted or unsubstituted pyridine, pyrimidine, oxadiazole, thiazole, phenyl pyrazole, phenyl pyridine and phenyl oxadiazole, and wherein W is most preferably selected from substituted or unsubstituted pyridine.
In a certain embodiment, the present invention relates to compounds of general formula (I) and salts and solvates thereof, wherein X5 is CR10 and X8 is CR11, and wherein (i) R4-R13, X4-X4, X6, X7, A, Z1, Z2, Y, n and W are as defined in general formula (I) including the substitutions and preferred definitions, or wherein (ii) R4-R13, X4-X4, X6, X7, A, Z1, Z2, Y, n and W are as defined in general formula (I) including the substitutions and preferred definitions, and wherein
R10 and R11 are different from -F, and/or n is 1, and/or
A is O, and/or
X2 is CR8 and R8 is different from -H, and/or
W is selected from -H, -F, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, C5-C12 bicycloalkyl, C7-C12 bicycloalkenyl, C8-C14 tricycloalkyl, C8-C14 tricycloalkenyl, and C6-C14 aromatic and C5-C14 heteroaromatic residues which are different from pyridine, pyrimidine, pyridazine, oxadiazole, thiazole, triazole, phenyl, phenyl -pyrazole, phenyl -pyridine, phenyl-oxadiazole and phenyl-triazole. and wherein the compounds share the following structure (la): and wherein the compounds of structure (la) are preferred for the use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the treatment of hyperproliferative disorders, wherein the hyperproliferative disorders can be benign or malignant including hyperplasia, neoplasia, cancer, pre-cancerous lesions, and metastases, and even more preferably for the treatment of hyperplasia, neoplasia, cancer, pre- cancerous lesions, and metastases of the breast, blood and the hematopoietic system including but not limited to lymphoma and leukemia of T-cells, B-cells and myeloid cells, neuroendocrine system including but not limited to the thyroid neuroendocrine system, cervix, gastrointestinal tract including but not limited to stomach and colon, mucosal epithelium including but not limited to the oral mucosal epithelium, skin, liver, lung, pancreas, brain, melanocytes, chondrocytes including but not limited to bone-derived chondrocytes, muscle, and connective tissue.
Examples are compounds XPM 0001 to XPM-1198.
In a further certain embodiment, the present invention relates to compounds of general formula (I) and salts and solvates thereof, wherein the grouping -N(Z1/Z2)N- is selected from unsubstituted piperazinyl, and wherein (i) R'-R13, X'-X8, A, Y, n and W are as defined in general formula (I) including the substitutions and preferred definitions, or wherein (ii) R'-R13, X'-X8, A, Y, n and W are as defined in general formula (I) including the substitutions and preferred definitions, and wherein n is 1, and/or
A is O, and/or
W is selected from -H, -F, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, C5-C12 bicycloalkyl, C7-C12 bicycloalkenyl, C8-C14 tricycloalkyl, C8-C14 tricycloalkenyl, and C6-C14 aromatic and C5-C14 heteroaromatic residues which are different from pyridine, pyrimidine, pyridazine, oxadiazole, thiazole, triazole, phenyl, phenyl -pyrazole, phenyl -pyridine, phenyl-oxadiazole and phenyl-triazole, and/or
X5 is CR10 and X8 is CR11 and R10 and R11 can additionally be different from -F, and/or X2 is CR8 and R8 is different from -H. and wherein the compounds share the following structure (lb): and wherein the compounds of structure (lb) are preferred for the use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the treatment of hyperproliferative disorders, wherein the hyperproliferative disorders can be benign or malignant including hyperplasia, neoplasia, cancer, pre-cancerous lesions, and metastases, and even more preferably for the treatment of hyperplasia, neoplasia, cancer, pre- cancerous lesions, and metastases of the breast, blood and the hematopoietic system including but not limited to lymphoma and leukemia of T-cells, B-cells and myeloid cells, neuroendocrine system including but not limited to the thyroid neuroendocrine system, cervix, gastrointestinal tract including but not limited to stomach and colon, mucosal epithelium including but not limited to the oral mucosal epithelium, skin, liver, lung, pancreas, brain, melanocytes, chondrocytes including but not limited to bone-derived chondrocytes, muscle, and connective tissue. Examples are compounds XPM-0001 to XPM-0608 and XPM-0759 to XPM-1213.
In a further certain embodiment, the present invention relates to compounds of general formula (I) and salts and solvates thereof, wherein X2 is CR8 and R8 is different from H, and wherein (i) R'-R7, R9-R13, X1, X3-X8, A, Z1, Z2, Y, n and W are as defined in general formula (I) including the substitutions and preferred definitions, or wherein (ii) R'-R7, R9-R13, X1, X3-X8, A, Z1, Z2, Y, n and W are as defined in general formula (I) including the substitutions and preferred definitions, and wherein n is 1, and/or
A is O, and/or
W is selected from -H, -F, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, C5-C12 bicycloalkyl, C7-C12 bicycloalkenyl, C8-C14 tricycloalkyl, C8-C14 tricycloalkenyl, and C6-C14 aromatic and C5-C14 heteroaromatic residues which are different from pyridine, pyrimidine, pyridazine, oxadiazole, thiazole, triazole, phenyl, phenyl -pyrazole, phenyl -pyridine, phenyl-oxadiazole and phenyl-triazole, and/or
X5 is CR10 and X8 is CR11 and R10 and R11 can additionally be different from -F. and wherein the compounds share the following structure (Ic): and wherein the compounds of structure (Ic) are preferred for the use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the treatment of hyperproliferative disorders, wherein the hyperproliferative disorders can be benign or malignant including hyperplasia, neoplasia, cancer, pre-cancerous lesions, and metastases, and even more preferably for the treatment of hyperplasia, neoplasia, cancer, pre- cancerous lesions, and metastases of the breast, blood and the hematopoietic system including but not limited to lymphoma and leukemia of T-cells, B-cells and myeloid cells, neuroendocrine system including but not limited to the thyroid neuroendocrine system, cervix, gastrointestinal tract including but not limited to stomach and colon, mucosal epithelium including but not limited to the oral mucosal epithelium, skin, liver, lung, pancreas, brain, melanocytes, chondrocytes including but not limited to bone-derived chondrocytes, muscle, and connective tissue.
Examples are compounds XPM-0001 to XPM-53O, XPM-0561 to XPM-1108 and XPM-1154 to XPM-1213.
In a further certain embodiment, the present invention relates to compounds of general formula (I) and salts and solvates thereof, wherein Y is -CH2- and n is 1, and wherein (i) R'-R13, X'-X8, A, Z1, Z2 and W are as defined in general formula (I) including the substitutions and preferred definitions, or wherein (ii) R4-R13, X4-X8, A, Z1, Z2 and W are as defined in general formula (I) including the substitutions and preferred definitions, and wherein
A is O, and/or
W is selected from -H, -F, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, C5-C12 bicycloalkyl, C7-C12 bicycloalkenyl, C8-C14 tricycloalkyl, C8-C14 tricycloalkenyl, and C6-C14 aromatic and C5-C14 heteroaromatic residues which are different from pyridine, pyrimidine, pyridazine, oxadiazole, thiazole, triazole, phenyl, phenyl -pyrazole, phenyl -pyridine, phenyl-oxadiazole and phenyl-triazole, and/or
X5 is CR10 and X8 is CR11 and R10 and R11 can additionally be different from -F, and/or X2 is CR8 and R8 is different from -H. and wherein the compounds share the following structure (Id): and wherein the compounds of structure (Id) are preferred for the use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the treatment of hyperproliferative disorders, wherein the hyperproliferative disorders can be benign or malignant including hyperplasia, neoplasia, cancer, pre-cancerous lesions, and metastases, and even more preferably for the treatment of hyperplasia, neoplasia, cancer, pre- cancerous lesions, and metastases of the breast, blood and the hematopoietic system including but not limited to lymphoma and leukemia of T-cells, B-cells and myeloid cells, neuroendocrine system including but not limited to the thyroid neuroendocrine system, cervix, gastrointestinal tract including but not limited to stomach and colon, mucosal epithelium including but not limited to the oral mucosal epithelium, skin, liver, lung, pancreas, brain, melanocytes, chondrocytes including but not limited to bone-derived chondrocytes, muscle, and connective tissue.
Examples are compounds XPM-0001 to XPM-0560 and XPM-0609 to XPM-1213.
In a further certain embodiment, the present invention relates to compounds of general formula (I) and salts and solvates thereof, wherein n = 1, Y = -CH2- and W is phenyl or pyridine that can be unsubstituted, monosubstituted with R14, or disubstituted with R14 and R15, and wherein (i) R4-R13, X4-X8, A, Z1, Z2 are as defined in general formula (I) including the substitutions and preferred definitions, and wherein X9 is N or CH, and wherein R14 or R15 are independently from each other selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -CF3, -CHF2, -CF2CF3, -CH2CF3, -OH, -OCH3, -OCF3, -OCH2CF3, -NH2, -NHCH3, -N(CH3)2, -N02, linear or branched C1-C8 alkyl, linear or branched C2-C6 alkenyl, linear or branched C2-C6 alkynyl, C3-C6 cycloalkyl, and C3-C6 cycloalkenyl, and wherein all alkyl, alkenyl, and alkynyl substituents of W can independently from each other be linked additionally to more than one carbon atom of W, and wherein all alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl residues contained in the definitions of R14 or R15 can contain one or more heteroatoms, or groups composed of heteroatoms independently selected from O, S, SO, SO2 and N in replacement of a carbon atom, and wherein all alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl residues contained in the definitions of R14 or R15 can be partially or fully halogenated, particularly fluorinated, more particularly perfluorinated, or wherein (ii) R4-R13, X4-X8, A, Z1, Z2 are as defined in general formula (I) including the substitutions and preferred definitions, and W, R14, R15 and X9 are as defined above, and wherein
A is O, and/or
X5 is CR10 and X8 is CR11 and R10 and R11 are different from -F, and/or X2 is CR8 and R8 is different from -H. and wherein the compounds share the following structure (le): and wherein the compounds of structure (le) are preferred for the use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the treatment of hyperproliferative disorders, wherein the hyperproliferative disorders can be benign or malignant including hyperplasia, neoplasia, cancer, pre-cancerous lesions, and metastases, and even more preferably for the treatment of hyperplasia, neoplasia, cancer, pre- cancerous lesions, and metastases of the breast, blood and the hematopoietic system including but not limited to lymphoma and leukemia of T-cells, B-cells and myeloid cells, neuroendocrine system including but not limited to the thyroid neuroendocrine system, cervix, gastrointestinal tract including but not limited to stomach and colon, mucosal epithelium including but not limited to the oral mucosal epithelium, skin, liver, lung, pancreas, brain, melanocytes, chondrocytes including but not limited to bone-derived chondrocytes, muscle, and connective tissue.
Examples are compounds XPM-0001 to XPM-003O, XPM-0036 to XPM-0046, XPM-0056 to XPM- 0085, XPM-0091 to XPM-010O, XPM-0111 to XPM-014O, XPM-0146 to XPM-0155, XPM-0166 to XPM-0185, XPM-0191 to 205, XPM-0251 to XPM-026O, XPM-0266 to XPM-029O, XPM-0296 to XPM-035O, XPM-0356 to XPM-0365, XPM-0376 to XPM-0395, XPM-0401 to XPM-0415, XPM- 0461 to XPM-047O, XPM-0476 to XPM-056O, XPM-0609 to XPM-0614, XPM-0621 to XPM-068O, XPM-0687 to XPM-0692, XPM-0699 to XPM-0758, XPM-0897 to XPM-1213.
In a further certain embodiment, the present invention relates to compounds of general formula (I) and salts and solvates thereof, wherein n = 1, Y = -CH2-, Z1 and Z2 are -CH2CH2-, and W is phenyl or pyridine that can be unsubstituted, monosubstituted with R14, or disubstituted with R14 and R15, and wherein (i) R4-R13, X4-X8 and A are as defined in general formula (I) including the substitutions and preferred definitions, and wherein X9 is N or CH, and wherein R14 or R15 are independently from each other selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -CF3, -CHF2, -CF2CF3, -CH2CF3, -OH, -OCH3, -OCF3, -OCH2CF3, -NH2, -NHCH3, -N(CH3)2, -NO2, linear or branched C1-C6 alkyl, linear or branched C2-C6 alkenyl, linear or branched C2-C6 alkynyl, C3-C6 cycloalkyl, and C3-C6 cycloalkenyl, and wherein all alkyl, alkenyl, and alkynyl substituents of W can independently from each other be linked additionally to more than one carbon atom of W, and wherein all alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl residues contained in the definitions of R14 or R15 can contain one or more heteroatoms, or groups composed of heteroatoms independently selected from O, S, SO, S02 and N in replacement of a carbon atom, and wherein all alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl residues contained in the definitions of R14 or R15 can be partially or fully halogenated, particularly fluorinated, more particularly perfluorinated, or wherein (ii) R4-R13, X4-X8 and A are as defined in general formula (I) including the substitutions and preferred definitions, and W, R14, R15 and X9 are as defined above, and wherein A is O, and/or
X5 is CR10 and X8 is CR11 and R10 and R11 are different from -F, and/or
X2 is CR8 and R8 is different from -H. and wherein the compounds share the following structure (If): and wherein the compounds of structure (If) are preferred for the use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the treatment of hyperproliferative disorders, wherein the hyperproliferative disorders can be benign or malignant including hyperplasia, neoplasia, cancer, pre-cancerous lesions, and metastases, and even more preferably for the treatment of hyperplasia, neoplasia, cancer, pre- cancerous lesions, and metastases of the breast, blood and the hematopoietic system including but not limited to lymphoma and leukemia of T-cells, B-cells and myeloid cells, neuroendocrine system including but not limited to the thyroid neuroendocrine system, cervix, gastrointestinal tract including but not limited to stomach and colon, mucosal epithelium including but not limited to the oral mucosal epithelium, skin, liver, lung, pancreas, brain, melanocytes, chondrocytes including but not limited to bone-derived chondrocytes, muscle, and connective tissue.
Examples are compounds XPM-0001 to XPM-003O, XPM-0036 to XPM-0046, XPM-0056 to XPM- 0085, XPM-0091 to XPM-010O, XPM-0111 to XPM-014O, XPM-0146 to XPM-0155, XPM-0166 to XPM-0185, XPM-0191 to 205, XPM-0251 to XPM-026O, XPM-0266 to XPM-029O, XPM-0296 to XPM-035O, XPM-0356 to XPM-0365, XPM-0376 to XPM-0395, XPM-0401 to XPM-0415, XPM- 0461 to XPM-047O, XPM-0476 to XPM-056O, XPM-0897 to XPM-1213. In a further certain embodiment, the present invention relates to compounds of general formula (I) and salts and solvates thereof, wherein R1 is a cyclohexyl that is 4,4-disubstituted with R16 and R17, and wherein (i) R5-R13, X'-X8, A, Z1, Z2 Y, n and W are as defined in general formula (I) including the substitutions and preferred definitions, and wherein R16 and R17 are independently from each other selected from -H, -F, linear or branched C1-C6 preferably C1-C3 alkyl, linear or branched C2-C6 preferably C2-C3 alkenyl, linear or branched C2-C6 preferably C2-C3 alkynyl, or wherein R16 and R17 are linked together to form with the carbon atom they are bound to a C3-C6 cycloalkyl or a C5-C6 cycloalkenyl residue that is unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -CH3 and wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl residues contained in the definitions of R16 and R17 can contain one or more heteroatoms independently selected from O, S and N in replacement of a carbon atom, or wherein (ii) R5-R13, X'-X8, A, Z1, Z2 Y, n and W are as defined in general formula (I) including the substitutions and preferred definitions, and R16 and R17 are as defined above, and wherein n is 1, and/or A is O, and/or
W is selected from -H, -F, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, C5-C12 bicycloalkyl, C7-C12 bicycloalkenyl, C8-C14 tricycloalkyl, C8-C14 tricycloalkenyl, and C6-C14 aromatic and C5-C14 heteroaromatic residues which are different from pyridine, pyrimidine, pyridazine, oxadiazole, thiazole, triazole, phenyl, phenyl -pyrazole, phenyl -pyridine, phenyl-oxadiazole and phenyl-triazole, and/or
X5 is CR10 and X8 is CR11 and R10 and R11 can additionally be different from -F, and/or X2 is CR8 and R8 is different from -H. and wherein the compounds share the following structure (Ig): and wherein the compounds of structure (I g) are preferred for the use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the treatment of hyperproliferative disorders, wherein the hyperproliferative disorders can be benign or malignant including hyperplasia, neoplasia, cancer, pre-cancerous lesions, and metastases, and even more preferably for the treatment of hyperplasia, neoplasia, cancer, pre- cancerous lesions, and metastases of the breast, blood and the hematopoietic system including but not limited to lymphoma and leukemia of T-cells, B-cells and myeloid cells, neuroendocrine system including but not limited to the thyroid neuroendocrine system, cervix, gastrointestinal tract including but not limited to stomach and colon, mucosal epithelium including but not limited to the oral mucosal epithelium, skin, liver, lung, pancreas, brain, melanocytes, chondrocytes including but not limited to bone-derived chondrocytes, muscle, and connective tissue.
Examples are compounds XPM-0001 to XPM-1213. In a further certain embodiment, the present invention relates to compounds of general formula (I) and salts and solvates thereof, wherein R1 is a cyclohexyl that is 4,4-disubstituted with R16 and R17, n = 1, Y = -CH2-, Z1 and Z2 are -CH2CH2-, and W is phenyl or pyridine that can be unsubstituted, monosubstituted with R14, or disubstituted with R14 and R15, and wherein (i) R5-R13, X4-X8 and A are as defined in general formula (I) including the substitutions and preferred definitions, and wherein X9 is N or CH, and wherein R14 or R15 are independently from each other selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -CF3, -CHF2, -CF2CF3, -CH2CF3, -OH, -OCH3, -OCF3, -OCH2CF3, -NH2, -NHCH3, -N(CH3)2, -NO2, linear or branched C1-C6 alkyl, linear or branched C2-C6 alkenyl, linear or branched C2-C6 alkynyl, C3-C6 cycloalkyl, and C3-C6 cycloalkenyl, and wherein all alkyl, alkenyl, and alkynyl substituents of W can independently from each other be linked additionally to more than one carbon atom of W, and wherein all alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl residues contained in the definitions of R14 or R15 can contain one or more heteroatoms, or groups composed of heteroatoms independently selected from O, S, SO, O2 and N in replacement of a carbon atom, and wherein all alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl residues contained in the definitions of R14 or R15 can be partially or fully halogenated, particularly fluorinated, more particularly perfluorinated, and wherein R16 and R17 are independently from each other selected from -H, -F, linear or branched C1-C6 preferably C1-C3 alkyl, linear or branched C2-C6 preferably C2-C3 alkenyl, linear or branched C2-C6 preferably C2-C3 alkynyl, or wherein R16 and R17 are linked together to form with the carbon atom they are bound to a C3-C6 cycloalkyl or a C5-C6 cycloalkenyl residue that is unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -CH3 and wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl residues contained in the definitions of R16 and R17 can contain one or more heteroatoms independently selected from O, S and N in replacement of a carbon atom, or wherein (ii) R5-R13, X4-X8 and A are as defined in general formula (I) including the substitutions and preferred definitions, and wherein W, R14, R15, X9, R16 and R17 are as defined above, and wherein
A is O, and/or
X5 is CR10 and X8 is CR11 and R10 and R11 are different from -F, and/or
X2 is CR8 and R8 is different from -H. and wherein the compounds share the following structure (Ih): and wherein the compounds of structure (Ih) are preferred for the use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the treatment of hyperproliferative disorders, wherein the hyperproliferative disorders can be benign or malignant including hyperplasia, neoplasia, cancer, pre-cancerous lesions, and metastases, and even more preferably for the treatment of hyperplasia, neoplasia, cancer, pre- cancerous lesions, and metastases of the breast, blood and the hematopoietic system including but not limited to lymphoma and leukemia of T-cells, B-cells and myeloid cells, neuroendocrine system including but not limited to the thyroid neuroendocrine system, cervix, gastrointestinal tract including but not limited to stomach and colon, mucosal epithelium including but not limited to the oral mucosal epithelium, skin, liver, lung, pancreas, brain, melanocytes, chondrocytes including but not limited to bone-derived chondrocytes, muscle, and connective tissue.
Examples are compounds XPM-0001 to XPM-003O, XPM-0036 to XPM-0046, XPM-0056 to XPM- 0085, XPM-0091 to XPM-010O, XPM-0111 to XPM-014O, XPM-0146 to XPM-0155, XPM-0166 to XPM-0185, XPM-0191 to 205, XPM-0251 to XPM-026O, XPM-0266 to XPM-029O, XPM-0296 to XPM-035O, XPM-0356 to XPM-0365, XPM-0376 to XPM-0395, XPM-0401 to XPM-0415, XPM- 0461 to XPM-047O, XPM-0476 to XPM-056O, XPM-0897 to XPM-1213.
Specific examples of compounds falling under the scope of general formula (I) are shown in Tables 1 to 12 and Tables 51 and 52.
Table 1:
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
Table 2:
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates. Table 3:
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
Table 4:
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
Table 5:
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
Table 6:
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
Table 7:
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
Table 8:
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
Table 9:
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
Table 10:
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
Table 11:
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
Table 12:
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
Also included are isomers, e.g. enantiomers or diastereomers or mixtures of isomers, salts, particularly pharmaceutically acceptable salts, and solvates of the compounds listed above.
Further definitions
The term "C1-C15 alkyl” comprises all isomers of the corresponding saturated aliphatic hydrocarbon groups containing one to fifteen carbon atoms, i.e. C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, CH, C12, C13, C14, C15; this includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, sec-pentyl, 3 -pentyl, 2 -methylbutyl, iso-pentyl, 2-methylbut-2-yl, 3- methylbut-2-yl, all hexyl-isomers, all heptyl-isomers, all octyl-isomers, all nonyl-isomers, all decyl-isomers, all undecyl-isomers, all dodecyl-isomers, all tridecyl-isomers, all tetradecyl- isomers and all pentadecyl-isomers. This definition correspondingly applies to all indicated ranges of alkyl chain lengths.
The term "C2-C15 alkenyl” comprises all isomers of the corresponding unsaturated olefinic hydrocarbon groups containing two to fifteen carbon atoms, i.e. C2, C3, C4, C5, C8, C7, C8, C9, C10, C11, C12, C13, C14, C15, linked by (i.e. comprising) one or more double bonds; this includes vinyl, all propenyl-isomers, all butenyl-isomers, all pentenyl-isomers, all hexenyl-isomers, all heptenyl- isomers, all octenyl-isomers, all nonenyl-isomers, all decenyl-isomers, all undecenyl-isomers, all dodecenyl-isomers, all tridecenyl-isomers, all tetradecenyl-isomers and all pentadecenyl- isomers. This definition correspondingly applies to all indicated ranges of alkenyl chain lengths.
The term "C2-C15 alkynyl” comprises all isomers of the corresponding unsaturated acetylenic hydrocarbon groups containing two to fifteen carbon atoms, i.e. C2, C3, C4, C5, C8, C7, C8, C9, C10, C11, C12, C13, C14, C15, linked by (i.e. comprising) one or more triple bonds; this includes ethynyl, all propynyl-isomers, all butynyl-isomers, all pentynyl-isomers, all hexynyl-isomers, all heptynyl- isomers, all octynyl-isomers, all nonynyl-isomers, all decynyl-isomers, all undecynyl-isomers, all dodecynyl-isomers, all tridecynyl-isomers, all tetradecynyl-isomers and all pentadecynyl- isomers. The term "alkynyl” also includes groups having one or more triple bonds in combination with one or more double bonds. This definition correspondingly applies to all indicated ranges of alkynyl chain lengths.
The term "C3-C16 cycloalkyl” comprises the corresponding saturated hydrocarbon groups containing three to sixteen carbon atoms, i.e. C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, arranged in a monocyclic ring structure; this includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cyclotetradecyl, cyclopentadecyl and cyclohexadecyl. This definition correspondingly applies to all indicated ranges of cycloalkyl ring sizes.
The term "C5-C16 cycloalkenyl” comprises the corresponding unsaturated non-aromatic and non- heteroaromatic hydrocarbon groups containing five to sixteen carbon atoms, i.e. C5, C8, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, of which at least one is sp3-hybridized, and which are arranged in a monocyclic ring structure and linked by (i.e. comprising) one or more double bonds; this includes all cyclopentenyl-isomers, all cyclohexenyl-isomers, all cycloheptenyl-isomers, all cyclooctenyl- isomers, all cyclononenyl-isomers, all cyclodecenyl-isomers, all cycloundecenyl-isomers, all cyclododecenyl-isomers, all cyclotridecenyl-isomers, all cyclotetradecenyl-isomers, all cyclopentadecenyl-isomers and all cyclohexadecenyl-isomers. This definition correspondingly applies to all indicated ranges of cycloalkenyl ring sizes.
The term " C9-C16 cycloalkynyl” comprises the corresponding unsaturated hydrocarbon groups containing nine to sixteen carbon atoms, i.e. C9, C10, C11, C12, C13, C14, C15, C16, which are arranged in a monocyclic ring structure and linked by (i.e. comprising) one or more triple bonds; this includes all cyclononynyl-isomers, all cyclodecynyl-isomers, all cycloundecynyl-isomers, all cyclododecynyl-isomers, all cyclotridecynyl-isomers, all cyclotetradecynyl-isomers, all cyclopentadecynyl-isomers and all cyclohexadecynyl-isomers. The term "cycloalkynyl” also includes monocyclic groups having one or more triple bonds in combination with one or more double bonds. This definition correspondingly applies to all indicated ranges of cycloalkynyl ring sizes.
The term "C5-C16 bicycloalkyl” comprises the corresponding saturated hydrocarbon groups containing five to sixteen carbon atoms, i.e. C5, C8, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, arranged in a bicyclic ring structure; wherein these bicyclic ring structures include fused, bridged and spiro systems. The term "C7-C16 bicycloalkenyl” comprises the corresponding unsaturated non-aromatic and non-heteroaromatic hydrocarbon groups containing seven to sixteen carbon atoms, i.e. C7, C8, C9, C10, C1 1, C12, C13, C14, C15, C16, arranged in a bicyclic ring structure and linked by (i.e. comprising) one or more double bonds; wherein these bicyclic ring structures include fused, bridged and spiro systems.
The term "C8-C16 tricycloalkyl” comprises the corresponding saturated hydrocarbon groups containing eight to eighteen carbon atoms, i.e. C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C16, arranged in a tricyclic ring structure; wherein these tricyclic ring structures include fused, bridged and spiro systems.
The term "C8-C16 tricycloalkenyl” comprises the corresponding unsaturated non-aromatic and non-heteroaromatic hydrocarbon groups containing eight to eighteen carbon atoms, i.e. C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C16, arranged in a tricyclic ring structure and linked by (i.e. comprising) one or more double bonds; wherein these tricyclic ring structures include fused, bridged and spiro systems.
The terms "cyclic”, "bicyclic”, "tricyclic”, "cycloalkyl”, "cycloalkenyl”, "bicycloalkyl”, "bicycloalkenyl”, "tricycloalkyl” and "tricycloalkenyl” for R1 mean that such cyclic, bicyclic or tricyclic residue is directly linked by a chemical bond to the aromatic ring to which R1 is bound, and wherein the terms "cyclic”, "bicyclic”, "tricyclic”, "cycloalkyl”, "cycloalkenyl”, "bicycloalkyl”, "bicycloalkenyl”, "tricycloalkyl” and "tricycloalkenyl” for a substituent of R1 mean that such cyclic, bicyclic or tricyclic residue is directly linked by a chemical bond to one of the C-atoms or N-atoms or O-atoms or S-atoms contained in R1.
The terms "monoaromatic systems” and "monoheteroaromatic systems” constitute monocyclic aromatic or monocyclic heteroaromatic residues which optionally can be fused or bridged to one or more non-aromatic cycles.
The terms "fused or bridged polyaromatic systems” and "fused or bridged polyheteroaromatic systems” constitute polycyclic aromatic or polycyclic heteroaromatic residues which are composed of two or more monocyclic aromatic and/or heteroaromatic residues that are fused to each other, wherein the said individual monocyclic residues can independently from each other additionally be fused or bridged to one or more non-aromatic cycles.
In case a carbon atom is replaced by a heteroatom selected from O, N, or S, the number of substituents on the respective heteroatom is adapted accordingly to match the corresponding valency, e.g. a -CRR’- group may be replaced by a -NR-, -N+RR’-, -0-, -S-, -S(=0)- or -S(=0)2- group, and a =CR- group may be replaced by a =N- group.
The term "perhalogenated” relates to the exhaustive halogenation of the carbon scaffold; respective residues comprise the corresponding perfluorinated, perchlorinated, perbrominated and periodinated groups. Preferably, the term "perhalogenated” relates to perfluorinated or perchlorinated groups, more preferably to perfluorinated groups.
The following paragraphs contain definitions of terms used in this specification. The initial definition provided for a group or term herein applies to that group or term throughout the present specification, individually or as part of another group, unless otherwise indicated.
The compounds of the present invention may form salts, which are also within the scope of this invention. Reference to a compound of the invention herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases. Zwitterions (internal or inner salts) are included within the term "salt(s)" as used herein (and may be formed, for example, where the substituents comprise an acid moiety such as a carboxyl group and an amino group). Also included herein are quaternary ammonium salts such as alkylammonium salts. Salts of the compounds may be formed, for example, by reacting a compound with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
Exemplary salts resulting from the addition of an acid (formed, for example, where the substituents comprise a basic moiety such as an amine group) include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, chlorates, bromates, iodates, 2- hydroxyethanesulfonates, lactates, maleates, methanesulfonates, 2 -naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3 -phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like.
Exemplary salts resulting from the addition of a base (formed, for example, where the substituents comprise an acidic moiety such as a carboxyl group) include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines, N-methyl-D-glucamines, N-methyl-D-glucamides, tert-butyl amines, and salts with amino acids such as arginine, lysine and the like. The basic nitrogencontaining groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.
The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science 1977, 66 (2), each of which is incorporated herein by reference in its entirety.
The phrase "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Furthermore, in the case of the compounds of the invention which contain an asymmetric carbon atom or an atropoisomeric bond, the invention relates to the D form, the L form and D,L mixtures and also, where more than one asymmetric carbon atom or atropoisomeric bond is present, to the diastereomeric forms. Those compounds of the invention which contain asymmetric carbon atoms or atropoisomeric bonds, and which as a rule accrue as racemates, can be separated into the optically active isomers in a known manner, for example using an optically active acid. However, it is also possible to use an optically active starting substance from the outset, with a corresponding optically active or diastereomeric compound then being obtained as the end product.
Compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers, as well as meso geometric isomers, i.e. axial and equatorial geometric isomers, of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.
Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.
Also included are solvates and hydrates of the compounds of the invention and solvates and hydrates of their pharmaceutically acceptable salts.
The term "compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, rotamers, and isotopes of the structures depicted, unless otherwise indicated.
In some embodiments, the compound can be provided as a prodrug. The term "prodrug”, as employed herein, denotes a compound, which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the invention, or a salt and/or solvate thereof.
In some embodiments, the compounds of the invention, and salts thereof, are substantially isolated. By "substantially isolated” is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compound of the invention. Substantial separation can include compositions containing at least about 50%, at least about 60%, atleast about70%, atleast about80%, atleastabout90%, atleast about95%, atleast about 97%, or at least about 99% by weight of the compound of the invention, or salt thereof. Pharmaceutical Methods
The compounds according to the invention have been found to have important pharmacological properties, which can be used therapeutically. The compounds of the invention can be used alone, in combination with each other or in combination with other active compounds or non-agent- based therapeutic intervention.
The method of use of the present invention relates to the use in vivo, in vitro, and ex vivo, respectively.
In certain embodiments, compounds of the present invention may exhibit growth inhibiting properties in hyperproliferative processes. These hyperproliferative processes can be benign or malignant and include hyperplasia, neoplasia, cancer and pre-cancerous lesions, and metastases. The antiproliferative activities of compounds falling under general formula (I) were investigated on human primary epidermal keratinocytes (HPEK) and human, murine and canine cell lines derived from hyperproliferative tissue or different cancer types, including MDA-MB-231, ZR-75- 3O, HCC-1395, HCC-1937, and T-47D all originating from cancer of the breast, JURKAT, RPMI- 8402, LOUCY, TANOUE, REC-1, HL-6O, NB-4 all originating from different types of blood cancer including lymphoma and leukemia of T-cells, B-cells and myeloid cells, TT originating from cancer of the neuroendocrine system, HeLa originating from cancer of the cervix, 23132/87, SW-948, and HCT-116 all originating from cancer of the gastrointestinal tract including stomach and colon, BHY originating from cancer of the mucosal epithelium, A-431 originating from cancer of the skin, HEP-G2 originating from cancer of the liver, NCI-H460 and A-549 both originating from cancer of the lung, PANC-1 originating from cancer of the pancreas, U-87MG originating from cancer of the brain, A-375 and RVH-421 both originating from cancer of melanocytes, SW-1353 originating from cancer of bone-derived chondrocytes, C2 C1 2 a mouse cell line originating from hyperproliferative muscle progenitor cells, LL/2 a mouse cell line originating from cancer of the lung, CF2 l.T a dog cell line originating from cancer of the connective tissue. To this end, according cells were seeded into 96-well plates (CORNING #3598) suitable for fluorescence assays at following initial cell numbers: 1000 cells per well for HPEK; 3000 cells per well for MDA-MB-231, 8000 cells per well for ZR-75-3O, 1500 cells per well for HCC-1395, 1500 cells per well for HCC- 1937, 3000 cells per well for T-47D, 1500 cells per well for JURKAT, 5000 cells per well for RPMI- 8402, 9000 cells per well for LOUCY, 1500 cells per well for TANOUE, 9000 cells per well for REC- 1, 1000 cells per well for HL-6O, 1000 cells per well for NB-4, 9000 cells per well for TT, 2000 cells per well for HeLa, 2000 cells per well for 23132/87, 9000 cells per well for SW-948, 700 cells per well for HCT-116, 1500 cells per well for BHY, 700 cells per well for A-431, 1500 cells per well for HEP-G2, 500 cells per well for NCI-H46O, 1000 cells per well for A-549, 1500 cells per well for PANC-1, 2500 cells per well for U-87MG, 700 cells per well for A-375, 1500 cells per well for RVH-421, 2000 cells per well for SW-1353, 500 cells per well for C2 C12, 500 cells per well for LL/2, and 3000 cells per well for CF2 1.T. In a volume of 90 pL per well of culture medium the cells were treated with compounds at indicated final concentrations by adding 10pL per well of 10x compound working solutions from 1:100 pre-diluted 10OOx compound DMSO stock-solutions in H2O (Water For Injection, WFI, Fisher Scientific, Gibco™ #A12873) or with the empty carrier DMSO (AppliChem, #A3672) at 0.1% v/v as control yielding a final volume of 10OpL per well. At day 5 after starting the treatments the cells were subjected to the alamarBlue® Proliferation Assay (Bio-Rad Serotec GmbH, BUF012B) according to the protocol of the manufacturer. The readout was taken with a multi- well plate- reader (Tecan Spark®) in the fluorescence mode with applying a filter for excitation at 560 nm (band width 10 nm) and for emission at 590 nm (band width 10 nm). Treatment for maximum proliferation inhibition with the commercial cytotoxic compound (S)-(+)-camptothecin (Fluorochem #M01564) at a concentration of 10μM was included on each plate for assay quality control. Some of the test compounds of the present invention may have been obtained and applied as their salt forms.
The assays were performed in duplicate or more replicates of independent single experiments each containing a three- to six-fold replicate for every condition. For each individual plate, the measured fluorescence intensity values of the conditions with compound treatment were normalized against the corresponding equally weighted arithmetic mean of the fluorescence intensity values of the three to six DMSO treated control wells in order to obtain the relative values to a reference level of 1.0.
Outlier analysis was performed according to the method by Peirce (Ross, Journal of Engineering Technology 2003, 1-12) for assays with more than three replicates per condition. Confirmed outliers were excluded from the calculations but not more than one value out of the four, five or six values, respectively, per compound within a single experiment The weighted arithmetic mean (here abbreviated as AVEW) for each compound was calculated from the normalized values over all independent replicates of the single experiments comprising the three to six replicates each. The corresponding standard deviation for the weighted arithmetic mean was calculated according to the method described by Bronstein et al. (Bronstein, Semendjajew, Musiol, Miihlig, Taschenbuch der Mathematik, 5th edition 2001 (German), publisher: Verlag Harri Deutsch, Frankfurt am Main and Thun) and was combined with the GauR’ error propagation associated with the performed calculation for the normalization. The resulting standard deviation is herein referred to as "combined standard deviation”.
The half maximal inhibitory concentration (IC50) values of the test compounds were investigated by applying measurements at corresponding serially diluted concentrations in the above described assay setting.
In certain embodiments, the compounds of the present invention may be growth inhibitors in hyperproliferative processes.
In the following embodiments, a compound is considered as an inhibitor of cell growth and proliferation of the individually indicated cell types if theIC50 value is 20 μM or lower, preferably 5 μM or lower, more preferably 1 μM or lower, and even more preferably 0.2 μM or lower as determined with the method described above. For the categorization of the compounds into the different activity levels based on the weighted arithmetic mean of the normalized fluorescence intensity values, the corresponding combined standard deviations were considered in the activity assignment. The combined standard deviation for the DMSO control values based on the weighted arithmetic mean of the normalized DMSO values from all measurements amounts to less than 1-10-2.
The following tested compounds of the invention falling under the scope of the molecules herein defined in formula (I) were found to inhibit the growth of MDA-MB-231 cells (human triplenegative breast adenocarcinoma cells) obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 732. MDA- MB-231 cells were cultivated in Leibovitz’s L-15 (no phenol red) medium (Fisher Scientific, Gibco™ #21083) containing 10% fetal bovine serum (Fisher Scientific, Gibco™ #A31608) at37ºC and 0% CO2. The so far identified MDA-MB-231 growth inhibitors relate to the compounds listed in Table 13.
Table 13: Proliferation assay with MDA-MB-231 cells Activity on MDA-MB-
Compound No. 231
The following tested compounds of the invention falling under the scope of the molecules herein defined in formula (I) were found to inhibit the growth of ZR-75-30 cells (human breast ductal carcinoma cells with HER2 amplification) obtainable from the American Type C11lture Collection (ATCC) under the accession number ATCC-CRL-1504. ZR-75-30 cells were cultivated in RPMI 1640 (no phenol red) medium (Fisher Scientific, Gibco™ #11835) containing 10% fetal bovine serum (Fisher Scientific, Gibco™ #A31608), 10mM HEPES (Sigma Aldrich-Merck, #H0887), additional 2500 mg/L D-Glucose (Fisher Scientific, Gibco™ #A2494001) and ImM sodium pyruvate (Fisher Scientific, Cytiva HyClone™ #SH30239.01) at 37ºC and 5% CO2. The so far identified ZR-75-30 growth inhibitors relate to the compounds listed in Table 14.
Table 14: Proliferation assay with ZR-75-30 cells
The following tested compounds of the invention falling under the scope of the molecules herein defined in formula (I) were found to inhibit the growth of HCC-1395 cells (human breast triple negative ductal carcinoma cells) obtainable from the American Type C11lture Collection (ATCC) under the accession number ATCC-CRL-2324. HCC-1395 cells were cultivated in RPMI 1640 (no phenol red) medium (Fisher Scientific, Gibco™ #11835) containing 10% fetal bovine serum (Fisher Scientific, Gibco™ #A31608), 10mM HEPES (Sigma Aldrich-Merck, #H0887), additional 2500 mg/L D-Glucose (Fisher Scientific, Gibco™ #A2494001) and ImM sodium pyruvate (Fisher Scientific, Cytiva HyClone™ #SH30239.01) at 37ºC and 5% CO2. The so far identified HCC-1395 growth inhibitors relate to the compounds listed in Table 15.
Table 15: Proliferation assay with HCC-1395 cells
The following tested compounds of the invention falling under the scope of the molecules herein defined in formula (I) were found to inhibit the growth of HCC-1937 cells (human breast triple negative ductal carcinoma cells) obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 513. HCC-1937 cells were cultivated in RPMI 1640 (no phenol red) medium (Fisher Scientific, Gibco™ #11835) containing 10% fetal bovine serum (Fisher Scientific, Gibco™ #A31608) at 37ºC and 5% CO2. The so far identified HCC-1937 growth inhibitors relate to the compounds listed in Table 16.
Table 16: Proliferation assay with HCC-1937 cells
Activity on HCC-1937 | Compound No.
IC5 O < 20 pM XPM-0760
The following tested compounds of the invention falling under the scope of the molecules herein defined in formula (I) were found to inhibit the growth of T-47D cells (human breast hormone (ER) receptor positive ductal carcinoma cells) obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 739. T-47D cells were cultivated in RPMI 1640 (no phenol red) medium (Fisher Scientific, Gibco™ #11835) containing 10% fetal bovine serum (Fisher Scientific, Gibco™ #A31608), and 10 ug/mL human insulin (Sigma Aldrich-Merck, #19278) at 37ºC and 5% CO2. The so far identified T-47D growth inhibitors relate to the compounds listed in Table 17.
Table 17: Proliferation assay with T-47D cells
The following tested compounds of the invention falling under the scope of the molecules herein defined in formula (I) were found to inhibit the growth of JURKAT cells (human T-cell acute lymphoblastic leukemia cells) obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 282. JURKAT cells were cultivated in RPMI 1640 medium (Fisher Scientific, Gibco™ #72400) containing 10% fetal bovine serum (Fisher Scientific, Gibco™ #A31608), and 2mM L-Glutamine (Fisher Scientific, Gibco™ #A2916801) at 37ºC and 5% CO2. The so far identified JURKAT growth inhibitors relate to the compounds listed in Table 18.
Table 18: Proliferation assay with IURKAT cells
The following tested compounds of the invention falling under the scope of the molecules herein defined in formula (I) were found to inhibit the growth of RPMI-8402 cells (human T-cell acute lymphoblastic leukemia cells) obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 290. RPMI-8402 cells were cultivated in RPMI 1640 medium (Fisher Scientific, Gibco™ #72400) containing 10% fetal bovine serum (Fisher Scientific, Gibco™ #A31608) at 37ºC and 5% CO2. The so far identified RPMI-8402 growth inhibitors relate to the compounds listed in Table 19.
Table 19: Proliferation assay with RPMI-8402 cells
The following tested compounds of the invention falling under the scope of the molecules herein defined in formula (I) were found to inhibit the growth of LOUCY cells (human T-cell acute lymphoblastic leukemia cells) obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 394. LOUCY cells were cultivated in RPMI 1640 medium (Fisher Scientific, Gibco™ #72400) containing 10% fetal bovine serum (Fisher Scientific, Gibco™ #A31608) at 37ºC and 5% CO2. The so far identified LOUCY growth inhibitors relate to the compounds listed in Table 20.
Table 20: Proliferation assay with LOUCY cells
The following tested compounds of the invention falling under the scope of the molecules herein defined in formula (I) were found to inhibit the growth of TANOUE cells (human B cell leukemia cells) obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 399. TANOUE cells were cultivated in RPMI 1640 medium (Fisher Scientific, Gibco™ #72400) containing 10% fetal bovine serum (Fisher Scientific, Gibco™ #A31608) at 37ºC and 5% CO2. The so far identified TANOUE growth inhibitors relate to the compounds listed in Table 21.
Table 21: Proliferation assay with TANOUE cells
The following tested compounds of the invention falling under the scope of the molecules herein defined in formula (I) were found to inhibit the growth of REC-1 cells (human mantle cell lymphoma cells) obtainable from the American Type C11lture Collection (ATCC) under the accession number ATCC-CRL-3004. REC-1 cells were cultivated in RPMI 1640 medium (Fisher Scientific, Gibco™ #72400) containing 10% fetal bovine serum (Fisher Scientific, Gibco™ #A31608) at 37ºC and 5% CO2. The so far identified REC-1 growth inhibitors relate to the compounds listed in Table 22.
Table 22: Proliferation assay with REC-1 cells
The following tested compounds of the invention falling under the scope of the molecules herein defined in formula (I) were found to inhibit the growth of HL-60 cells (human acute myeloid leukemia (AML) cells) obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 3. HL-60 cells were cultivated in RPMI 1640 medium (Fisher Scientific, Gibco™ #72400) containing 10% fetal bovine serum (Fisher Scientific, Gibco™ #A31608) at 37ºC and 5% CO2. The so far identified HL-60 growth inhibitors relate to the compounds listed in Table 23.
Table 23: Proliferation assay with HL-60 cells The following tested compounds of the invention falling under the scope of the molecules herein defined in formula (I) were found to inhibit the growth of NB-4 cells (human acute promyelocytic leukemia (APL) cells) obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 207. NB-4 cells were cultivated in RPMI 1640 medium (Fisher Scientific, Gibco™ #72400) containing 10% fetal bovine serum (Fisher Scientific, Gibco™ #A31608) at 37ºC and 5% CO2. The so far identified NB-4 growth inhibitors relate to the compounds listed in Table 24.
Table 24: Proliferation assay with NB-4 cells
The following tested compounds of the invention falling under the scope of the molecules herein defined in formula (I) were found to inhibit the growth of TT cells (human medullary thyroid carcinoma cells) obtainable from the American Type C11lture Collection (ATCC) under the accession number ATCC-CRL-1803. TT cells were cultivated in F-12K medium (Fisher Scientific, Gibco™ #21127) containing 10% fetal bovine serum (Fisher Scientific, Gibco™ #A31608) at37ºC and 5% CO2. The so far identified TT growth inhibitors relate to the compounds listed in Table 25. The following tested compounds of the invention falling under the scope of the molecules herein defined in formula (I) were found to inhibit the growth of HeLa cells (human cervical adenocarcinoma cells) obtainable from the American Type C11lture Collection (ATCC) under the accession number ATCC-CCL-2. HeLa cells were cultivated in DMEM medium (Fisher Scientific, Gibco™ #32430) containing 10% fetal bovine serum (Fisher Scientific, Gibco™ #A31608) at37ºC and 5% CO2. The so far identified HeLa growth inhibitors relate to the compounds listed in Table 26.
Table 26: Proliferation assay with HeLa cells
The following tested compounds of the invention falling under the scope of the molecules herein defined in formula (I) were found to inhibit the growth of 23132/87 cells (human gastric adenocarcinoma cells) obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 201. 23132/87 cells were cultivated in RPMI 1640 medium (Fisher Scientific, Gibco™ #72400) containing 10% fetal bovine serum (Fisher Scientific, Gibco™ #A31608) at 37ºC and 5% CO2. The so far identified 23132/87 growth inhibitors relate to the compounds listed in Table 27.
Table 27: Proliferation assay with 23132/87 cells
The following tested compounds of the invention falling under the scope of the molecules herein defined in formula (I) were found to inhibit the growth of SW-948 cells (human colon adenocarcinoma cells) obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 326. SW-948 cells were cultivated in Leibovitz’s L-15 (no phenol red) medium (Fisher Scientific, Gibco™ #21083) containing 10% fetal bovine serum (Fisher Scientific, Gibco™ #A31608) at 37ºC and 0% CO2. The so far identified SW-948 growth inhibitors relate to the compounds listed in Table 28.
Table 28: Proliferation assay with SW-948 cells
The following tested compounds of the invention falling under the scope of the molecules herein defined in formula (I) were found to inhibit the growth of HCT-116 cells (human colon carcinoma cells) obtainable from the American Type C11lture Collection (ATCC) under the accession number ATCC-CCL-247. HCT-116 cells were cultivated in McCoy’s 5A medium (ATCC, #30-2007) containing 10% fetal bovine serum (Fisher Scientific, Gibco™ #A31608) at 37ºC and 5% CO2. The so far identified HCT-116 growth inhibitors relate to the compounds listed in Table 29.
Table 29: Proliferation assay with HCT-116 cells
The following tested compounds of the invention falling under the scope of the molecules herein defined in formula (I) were found to inhibit the growth of BHY cells (human oral squamous cell carcinoma cells) obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 404. BHY cells were cultivated in DMEM medium (Fisher Scientific, Gibco™ #32430) containing 10% fetal bovine serum (Fisher Scientific, Gibco™ #A31608) at 37ºC and 5% CO2. The so far identified BHY growth inhibitors relate to the compounds listed in Table 30.
Table 30: Proliferation assay with BHY cells
The following tested compounds of the invention falling under the scope of the molecules herein defined in formula (I) were found to inhibit the growth of A-431 cells (human epidermoid squamous cell carcinoma cells) obtainable from the Cell Lines Service GmbH (CLS) under the accession number 300112. A-431 cells were cultivated in DMEM medium (Fisher Scientific, Gibco™ #32430) containing 10% fetal bovine serum (Fisher Scientific, Gibco™ #A31608) at37ºC and 5% CO2. The so far identified A-431 growth inhibitors relate to the compounds listed in Table 31.
Table 31: Proliferation assay with A-431 cells
The following tested compounds of the invention falling under the scope of the molecules herein defined in formula (I) were found to inhibit the growth of HEP-G2 cells (human hepatocellular carcinoma cells) obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 180. HEP-G2 cells were cultivated in RPMI 1640 medium (Fisher Scientific, Gibco™ #72400) containing 10% fetal bovine serum (Fisher Scientific, Gibco™ #A31608) at 37ºC and 5% CO2. The so far identified HEP-G2 growth inhibitors relate to the compounds listed in Table 32.
Table 32: Proliferation assay with HEP-G2 cells
The following tested compounds of the invention falling under the scope of the molecules herein defined in formula (I) were found to inhibit the growth of NCI-H460 cells (human lung carcinoma cells) obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 737. NCI-H460 cells were cultivated in RPMI 1640 medium (Fisher Scientific, Gibco™ #72400) containing 10% fetal bovine serum (Fisher Scientific, Gibco™ #A31608) at 37ºC and 5% CO2. The so far identified NCI-H460 growth inhibitors relate to the compounds listed in Table 33.
Table 33: Proliferation assay with NCI-H460 cells
The following tested compounds of the invention falling under the scope of the molecules herein defined in formula (I) were found to inhibit the growth of A-549 cells (human lung carcinoma cells) obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 107. A-549 cells were cultivated in DMEM medium (Fisher Scientific, Gibco™ #32430) containing 10% fetal bovine serum (Fisher Scientific, Gibco™ #A31608) at 37ºC and 5% CO2. The so far identified A-549 growth inhibitors relate to the compounds listed in Table 34.
Table 34: Proliferation assay with A-549 cells
The following tested compounds of the invention falling under the scope of the molecules herein defined in formula (I) were found to inhibit the growth of PANC-1 cells (human pancreas carcinoma cells) obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 783. PANC-1 cells were cultivated in DMEM medium (Fisher Scientific, Gibco™ #32430) containing 10% fetal bovine serum (Fisher Scientific, Gibco™ #A31608) at 37ºC and 5% CO2. The so far identified PANC-1 growth inhibitors relate to the compounds listed in Table 35.
Table 35: Proliferation assay with PANC-1 cells
The following tested compounds of the invention falling under the scope of the molecules herein defined in formula (I) were found to inhibit the growth of U-87MG cells (human glioma cells) obtainable from the American Type C11lture Collection (ATCC) under the accession number ATCC- HTB-14. U-87MG cells were cultivated in EMEM medium (ATCC, #30-2003) containing 10% fetal bovine serum (Fisher Scientific, Gibco™ #A31608) at 37ºC and 5% CO2. The so far identified U- 87MG growth inhibitors relate to the compounds listed in Table 36.
Table 36: Proliferation assay with U-87MG cells
Activity on U-87MG Compound No.
XPM-0119 XPM-0124 XPM-0169 XPM-0204
XPM-0234 XPM-0254 XPM-0259 XPM-0279
IC50 < 20 pM
XPM-0284 XPM-0606 XPM-0624 XPM-0636
XPM-0642 XPM-0672 XPM-0922
IC50 < 5 pM XPM-0113 XPM-0134 XPM-0660 XPM-0666
The following tested compounds of the invention falling under the scope of the molecules herein defined in formula (I) were found to inhibit the growth of A-375 cells (human melanoma cells) obtainable from the American Type C11lture Collection (ATCC) under the accession number ATCC- CRL-1619. A-375 cells were cultivated in DMEM medium (Fisher Scientific, Gibco™ #32430) containing 10% fetal bovine serum (Fisher Scientific, Gibco™ #A31608) at 37ºC and 5% CO2. The so far identified A-375 growth inhibitors relate to the compounds listed in Table 37.
Table 37: Proliferation assay with A-375 cells
The following tested compounds of the invention falling under the scope of the molecules herein defined in formula (I) were found to inhibit the growth of RVH-421 cells (human melanoma cells) obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 127. RVH-421 cells were cultivated in Leibovitz’s L-15 (no phenol red) medium (Fisher Scientific, Gibco™ #21083) containing 10% fetal bovine serum (Fisher Scientific, Gibco™ #A31608) at 37ºC and 0% CO2. The so far identified RVH-421 growth inhibitors relate to the compounds listed in Table 38.
Table 38: Proliferation assay with RVH-421 cells
The following tested compounds of the invention falling under the scope of the molecules herein defined in formula (I) were found to inhibit the growth of SW- 1353 cells (human chondrosarcoma cells) obtainable from the American Type C11lture Collection (ATCC) under the accession number ATCC-HTB-94. SW-1353 cells were cultivated in Leibovitz’s L-15 (no phenol red) medium (Fisher Scientific, Gibco™ #21083) containing 10% fetal bovine serum (Fisher Scientific, Gibco™ #A31608) at 37ºC and 0% CO2. The so far identified SW-1353 growth inhibitors relate to the compounds listed in Table 39.
Table 39: Proliferation assay with SW-1353 cells
The following tested compounds of the invention falling under the scope of the molecules herein defined in formula (I) were found to inhibit the growth of C2 C12 cells (murine myoblast cells) obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 565. C2 C12 cells were cultivated in RPMI 1640 medium (Fisher Scientific, Gibco™ #72400) containing 10% fetal bovine serum (Fisher Scientific, Gibco™ #A31608) at 37ºC and 5% CO2. The so far identified C2 C12 growth inhibitors relate to the compounds listed in Table 40.
Table 40: Proliferation assay with C2 C12 cells
The following tested compounds of the invention falling under the scope of the molecules herein defined in formula (I) were found to inhibit the growth of LL/2 cells (murine Lewis lung carcinoma cells) obtainable from the American Type C11lture Collection (ATCC) under the accession number ATCC-CRL-1642. LL/2 cells were cultivated in DMEM medium (Fisher Scientific, Gibco™ #32430) containing 10% fetal bovine serum (Fisher Scientific, Gibco™ #A31608) at 37ºC and 5% CO2. The so far identified LL/2 growth inhibitors relate to the compounds listed in Table 41.
Table 41: Proliferation assay with LL/2 cells
The following tested compounds of the invention falling under the scope of the molecules herein defined in formula (I) were found to inhibit the growth of CF2 1.T cells (canine connective tissue cancer cells) obtainable from the American Type C11lture Collection (ATCC) under the accession number ATCC-CRL-6220. CF2 1.T cells were cultivated in DMEM medium (Fisher Scientific, Gibco™ #32430) containing 10% fetal bovine serum (Fisher Scientific, Gibco™ #A31608) at37ºC and 5% CO2. The so far identified CF2 l.T growth inhibitors relate to the compounds listed in Table 42.
Table 42: Proliferation assay with CF2 1.T cells
In one embodiment, the compounds of the invention may be growth inhibitors in hyperproliferative processes, wherein the hyperproliferative processes are malignant and include cancer, pre-cancerous lesions, and metastases. Examples are shown in Tables 13 to 39 and Tables 41 to 42, including the cancer cell lines MDA-MB-231, ZR-75-3O, HCC-1395, HCC-1937, T-47D, JURKAT, RPMI-8402, LOUCY, HH, TANOUE, REC-1, HL-6O, NB-4, TT, HeLa, 23132/87, SW- 948, HCT-116, BHY, A-431, HEP-G2, NCI-H46O, A-549, PANC-1, U-87MG, A-375, RVH-421, SW- 1353, LL/2, and CF2 1.T. Thus, the compounds of the invention can be used as medicament for the prevention and/or treatment of a disorder associated with, accompanied by and/or caused by malignant hyperproliferative processes, including cancer, pre-cancerous lesions, and metastases.
In a further embodiment, the compounds of the present invention may be growth inhibitors in hyperproliferative processes, wherein the hyperproliferative processes are benign. Examples are shown in Table 40 including the hyperproliferative non-cancer cell line C2 C12. Thus, the compounds of the invention can be used as medicament for the prevention and/or treatment of a disorder associated with, accompanied by and/or caused by benign hyperproliferative processes, including hyperplasia and neoplasia,
In a further embodiment, the compounds of the present invention may be growth inhibitors in hyperproliferative processes, wherein the hyperproliferative processes are dependent on functional mitochondria and/or OXPHOS. Thus, they can be used as medicament for the prevention and/or treatment of a disorder associated with, accompanied by and/or caused by hyperproliferative processes that are dependent on functional mitochondria and/or OXPHOS. Dependency of a disorder on functional mitochondria and/or OXPHOS may be determined for example by analysis of the mutation status of certain genes that are involved for example in energy sensing and balancing, encoding for glycolytic enzymes, or components of the SWI/SNF complex. This is exemplified in Table 34 with the strong activities of the compounds of the present invention on the A-549 cell line which is being described in the literature of harbouring a mutation in the gene SMARCA4 thus being considered OXPHOS dependent (Lissanu Deribe et al., Nat Med 2018, 24).
Inhibition of mitochondrial function in glycolysis proficient cells may induce a metabolic switch towards increased glycolysis rates in order to meet the energy demand for proliferation and survival. Concurrent glycolysis inability in addition to inhibited mitochondrial function is deleterious. Accordingly, a synthetic lethality can be induced in cells treated with mitochondrial inhibitors when the cells are cultured in glucose-deprived culture medium (Menendez et al., Cell Cycle 2012, 11). This culture condition mimics cancer cell states like OXPHOS dependency, glycolysis deficiency, glucose-deprivation in the tumor microenvironment, and others. Reduced proliferation upon compound treatment of cells cultured in glucose-free culture medium as compared to glucose-containing culture medium can be used as an indicator for the impact of the compounds on mitochondrial function.
Several compounds of the invention were found to inhibit the growth of MDA-MB-231 cells (human breast carcinoma cells) obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 732 when cultured in the glucose-free Leibovitz’s L-15 (no phenol red) medium (Fisher Scientific, Gibco™ #21083) containing 10% fetal bovine serum (Fisher Scientific, Gibco™ #A31608) at 37ºC and 0% CO2. In contrast, proliferation was not inhibited when the cells were cultivated in the D-glucose- containing RPMI 1640 medium (Fisher Scientific, Gibco™ #72400) supplemented with 10% fetal bovine serum (Fisher Scientific, Gibco™ #A31608) at 37ºC and 5% CO2. Thus, the compounds of the invention can be used as medicament for the prevention and/or treatment of a disorder associated with, accompanied by and/or caused by hyperproliferative processes including hyperplasia, neoplasia, cancer, pre-cancerous lesions, and metastases with glycolysis deficiency, i.e with no or poor ability to perform glycolysis, and/or under conditions of lack of sufficient glucose supply.
A compound is considered as an inhibitor of cell growth and proliferation of MDA-MB-231 cells in glucose-free Leibovitz’s L-15 medium if theIC50 value is 10 μM or lower (+), preferably 5 μM or lower (++), and more preferably 1 μM or lower (+++) as determined with the method described above.
According to this method, several molecules falling under the scope of the compounds herein defined in general formula (I) have been identified as growth inhibitors of MDA-MB-231 cells in the glucose-free Leibovitz’s L-15 medium. The said so far identified growth inhibitors of functional mitochondria-dependent and/or OXPHOS-dependent and/or glucose-deprived cancer cells relate to the compounds listed in Tables 13, 51 and 52. The entries in Tables 13, 51 and 52 are categorized by the corresponding IC50 values, hence falling into the ranges as indicated.
Further examples of cell lines cultured in glucose-free Leibovitz’s L-15 medium are SW-948, RVH- 421, and SW-1353. Several molecules falling under the scope of the compounds herein defined in general formula (I) have been identified as growth inhibitors of said cell lines in the glucose-free Leibovitz’s L-15 medium. The respective so far identified growth inhibitors of functional mitochondria- and/or OXPHOS-dependent cancer cells relate to the compounds listed in Tables 28, 38 and 39.
In a further embodiment, the compounds of the present invention may be growth inhibitors in hyperproliferative processes, wherein the antiproliferative effect of the compounds of the present invention acts synergistically and/or additively and/or induces a synthetic lethality in a combination treatment with one or more further active therapeutic agents, i.e., therapeutic agents different from compounds of the general formula (I), or with any other respective non- agent-based therapeutic intervention as described in the present invention. Further therapeutic agents may include, for example, antiproliferative agents, cytostatic agents, anticancer agents, chemotherapeutic agents, targeted therapy agents, radiopharmaceuticals, radiotherapy, photodynamic therapy, laser therapy, antisense therapy, mRNA-based therapy, vaccine therapy, gene therapy, thermotherapy, dietary therapy, cell therapy, and cancer immunotherapy agents, in particular glycolysis inhibitors, LDH inhibitors, MCT inhibitors, glutaminolysis inhibitors, fatty acid oxidation (FAO) inhibitors, TCA cycle inhibitors, mitophagy inhibitors, inhibitors of mitochondrial dynamics and trafficking, angiogenesis inhibitors, oxidative stress inducers, and other OXPHOS inhibitors. Induction of synthetic lethality, or synergistic or additive effects on growth inhibition through a combination treatment can be assessed by investigating the growth behaviour of cancer cells under the respective treatment conditions.
The synergistic or additive activity of a compound falling under general formula (I) was investigated in a combination treatment with the MCT1/MCT4 inhibitor syrosingopine (TargetMol, #TN2252) in a viability assay on MDA-MB-231 cells cultured in D-Glucose-containing RPMI 1640 medium (Fisher Scientific, Gibco™ #72400) supplemented with 10% fetal bovine serum (Fisher Scientific, Gibco™ #A31608) and on HCT-116 cells cultured as described above. The viability assay was performed according to the protocol as described above using alamarBlue® (Bio-Rad Serotec GmbH, BUF012B). To this end, according cells were seeded into 96-well plates (CORNING, #3598) suitable for fluorescence assays at a cell number of 7’000 cells per well for MDA-MB-231 and 7’000 cells per well for HCT-116, and incubated over night at37ºC and 5% CO2. Then, in a volume of 90pL medium per well the cells were treated with compounds at a final concentration of 10nM for the compound of formula (I) and 10μM for syrosingopine by adding 10μL per well of a 10x compound working solution or the empty carrier DMSO as control. The 10x working solutions were prepared by diluting both compounds from their 2000x DMSO stock-solutions together 1:200 each in H2O (Water For Injection, WFI, Fisher Scientific, Gibco™ #A12873) for the combination treatment, or by diluting their 2000x DMSO stock-solutions individually with the empty carrier DMSO 1:200 in H2O for the corresponding single treatments. Addition of the compound working solutions into the wells yielded a final assay volume of 100pL per well containing 0.1% v/v DMSO. After 2 days incubation at 37ºC and 5% CO2, the cells were subjected to the alamarBlue® Proliferation Assay as described above. Relative viability values were calculated from the fluorescence intensities as described above.
The following tested compounds of the invention falling under the scope of the molecules herein defined in formula (I) were found to enhance the growth inhibiting effect of the MCT1/MCT4 inhibitor syrosingopine in a combination treatment on MDA-MB-231 cells in D-Glucose- containing culture medium. A decrease in relative viability upon single treatment was not observed for the tested compounds of formula (I) and less than 25% for syrosingopine. The activities in enhancing the growth inhibiting effect in the combination treatment are indicated as additional decrease in relative viability as compared to the single treatment with syrosingopine. The so far identified growth inhibitors acting synergistically or additively in combination treatments relate to the compounds listed in Table 43.
Table 43: Combination treatment activity assay on MDA-MB-231 cells
The following tested compound of the invention falling under the scope of the molecules herein defined in formula (I) was found to enhance the growth inhibiting effect of the MCT1/MCT4 inhibitor syrosingopine in a combination treatment on HCT-116 cells. A decrease in relative viability upon single treatment was less than 10% for the tested compounds of formula (I) and less than 5% for syrosingopine. The activity in enhancing the growth inhibiting effect in the combination treatment is indicated as additional decrease in relative viability as compared to the single treatment with syrosingopine. The so far identified growth inhibitor acting synergistically or additively in combination treatments relates to the compound listed in Table 44.
Table 44: Combination treatment activity assay on HCT-116 cells Activity ompound No. as treatment enhancer viability decrease > 25% XPM-0139
In a further embodiment, the compounds of the present invention may be growth inhibitors in hyperproliferative processes, wherein the antiproliferative effect does not necessarily or less strongly impact cells under normal proliferative circumstances.
Cells that exhibit any form and degree of dependency on mitochondrial function may be compromised by inhibiting mitochondrial function. In contrast, cells with normal proliferation without any intrinsic or extrinsic mitochondrial dependency may be not or much less affected by the same extent of mitochondrial inhibition. Accordingly, no or minor alteration in proliferation upon equimolar compound treatment of such cells with normal proliferation can be used as an indicator for the selectivity of the compound-related antiproliferative effect towards cells with abnormal metabolism.
Several compounds of the invention were found to inhibit the growth of MDA-MB-231 cells when cultured in the glucose-free Leibovitz’s L-15 as described above but not of human epidermal keratinocyte progenitors, (HPEKp, pooled), obtainable from CELLnTEC Advanced Cell Systems AG under the accession number HPEKp, when grown in medium for primary cell cultures. HPEKp cells were cultivated in CnT-Prime epithelial culture medium (CELLnTEC, #CnT-PR, a fully defined, low calcium formulation, completely free of animal or human-derived components) without addition of further components at 37ºC and 5% CO2.
A compound is considered as a selective inhibitor of cell growth and proliferation of MDA-MB- 231 cells in glucose-free Leibovitz’s L-15 medium if for HPEKp cells the IC50 value is higher, preferably at least 2 -fold higher, even more preferably at least 5 -fold higher, and most preferably at least 10-fold higher than theIC50 value for MDA-MB-231 cells in glucose-free Leibovitz’s L-15 medium as determined with the method described above.
According to this method, several molecules falling under the scope of the compounds herein defined in general formula (I) have been identified as selective growth inhibitors of MDA-MB-231 cells in the glucose-free Leibovitz’s L-15 medium. The said so far identified selective growth inhibitors relate to the compounds listed in Tables 51 and 52. The selectivities as described above of corresponding entries in Tables 51 and 52 are categorized by theIC50 values for HPEKp cells in comparison to the indicated IC50 values for MDA-MB-231 cells. All IC50 values for HPEKp cells shown in Tables 51 and 52 fall into the ranges as indicated with higher than 10μM (-), 10μM or lower (+), and 5μM or lower (++) but not lμM or lower (+++) as determined with the method described above and are for every entry at least 2 -fold higher than the correspondiInCg50 values for MDA-MB-231 cells.
In a further embodiment, the compounds of the present invention may be growth inhibitors in hyperproliferative processes, wherein said hyperproliferative processes are not or only poorly responsive to other treatments, such as with one or more further active therapeutic agents or with any other non-agent-based therapeutic intervention as described in the present invention including, for example, antiproliferative agents, cytostatic agents, anticancer agents, chemotherapeutic agents, targeted therapy agents such as kinase inhibitors, antiapoptotic protein inhibitors, angiogenesis inhibitors, radiopharmaceuticals, radiotherapy, photodynamic therapy, laser therapy, antisense therapy, mRNA-based therapy, vaccine therapy, gene therapy, thermotherapy, dietary therapy, cell therapy, and cancer immunotherapy agents such as immune checkpoint inhibitors, and wherein the compounds of the present invention may sensitize hyperproliferative cells as for example cancer cells or metastatic cells with no or poor response to said other treatments. Thus, the compounds of the present invention can be used as medicament in a combination treatment to sensitize a disorder associated with, accompanied by and/or caused by hyperproliferative processes including hyperplasia, neoplasia, cancer and pre- cancerous lesions, and metastases for a treatment that otherwise would lead to no or poor response.
Sensitization through a compound to other treatments can be assessed by investigating the growth behaviour of cancer cells being not or only poorly responsive to said other treatments in the presence of the sensitizing compound in a combination treatment. The sensitization activity of a compound falling under general formula (I) was investigated in a combination treatment with the B-Raf-V600E inhibitor PLX-4720 (MedChemExpress, #HY-51424) in a viability assay on PLX- 4720-poorly responsive SK-MEL-5 melanoma cells harbouring a BRAF V600E mutation. SK-MEL- 5 cells, obtainable from the American Type C11lture Collection (ATCC) under the accession number ATCC-HTB-7O, were cultivated in EMEM medium (ATCC, #30-2003) containing 10% fetal bovine serum (Fisher Scientific, Gibco™ #A31608) at 37ºC and 5% CO2. The viability assay was performed according to the protocol as described above using alamarBlue® (Bio-Rad Serotec GmbH, BUF012B). To this end, SK-MEL-5 cells were seeded into 96-well plates (CORNING #3598) suitable for fluorescence assays at a cell number of 4’000 cells per well containing 10pL per well of 10x compound working solutions or the empty carrier DMSO as control. The cells were treated with compounds at final concentrations of lμM for the compound of formula (I) and 10μM for PLX-4720. The 10x working solutions were prepared by diluting both compounds from their 2000x DMSO stock-solutions together 1:200 each in H2O (Water For Injection, WFI, Fisher Scientific, Gibco™ #A12873) for the combination treatment, or by diluting their 2000x DMSO stock-solutions individually with the empty carrier DMSO 1:200 in H2O for the corresponding single treatments. The final assay volume was 100pL per well containing 0.1% v/v DMSO. After 3 days incubation at 37ºC and 5% CO2, the cells were subjected to the alamarBlue® Proliferation Assay as described above. Relative viability values were calculated from the fluorescence intensities as described above.
The following tested compound of the invention falling under the scope of the molecules herein defined in formula (I) was found to enhance the growth inhibiting effect of the BRAF inhibitor PLX-4720 in a combination treatment on PLX-4720 -poorly responsive BRAF V600E mutated SK- MEL-5 melanoma cells. The decrease in relative viability upon single treatments was 30% for the tested compounds of formula (I) and less than 20% for PLX-4720 at a concentration of 10μM. The activity in enhancing the growth inhibiting effect in the combination treatment by sensitization is indicated as additional decrease in relative viability as compared to the single treatment with PLX-4720. The so far identified treatment-sensitizing growth inhibitor relates to the compound listed in Table 45.
Table 45: Treatment-sensitization activity assay
No or poor responsiveness to other treatments of a hyperproliferative process can be linked to intrinsic or acquired resistance to said other treatments. Thus, the compounds of the invention falling under the scope of the molecules herein defined in formula (I) may be used as medicament in a combination therapy with other treatments as defined above for the treatment of a hyperproliferative process, particularly cancer, that shows intrinsic or acquired resistance to said other treatments, and/or for the prevention of acquiring a resistance to said other treatments. In certain embodiments, compounds of the present invention may be regulators of cell metabolism that can be used in the treatment of hyperproliferative processes. These hyperproliferative processes can be benign or malignant and include hyperplasia, neoplasia, cancer and pre-cancerous lesions, and metastases.
In one embodiment, the compounds of the present invention may be regulators of cell metabolism by inhibiting mitochondrial function.
A decrease in mitochondrial function can be assessed by the relative quantification of the mitochondrial transmembrane potential ΔΨm . The ΔΨm -decreasing activities of compounds falling under general formula (I) were investigated with tetramethylrhodamine ethyl ester (TMRE) staining on A-549 cells. Access and cultivation method of A-549 cells are as described above. To this end, according cells were seeded into 96-well plates suitable for fluorescence assays (Greiner Bio-One, #655090) ata cell number of 45’000 cells per well. Cells were incubated over night at 37ºC and 5% CO2. This was followed by a complete medium change with 100pL per well of fresh culture medium pre- warmed to 37ºC. Cells were further incubated at 37ºC and 5% CO2 for three hours. Then the cells were treated with compounds at 10μM final concentration by adding 100pL per well of a 2x compound working solution of 1:50 pre-diluted compound DMSO stock-solutions in Hank's Balanced Salt Solution (HBSS, Fisher Scientific, Gibco™ #14025). Cells were incubated for 2 hours and 40 minutes at 37ºC and 5% CO2. Then cells were treated with TMRE (AAT-Bioquest, #22220) at 300nM final concentration by adding 20pL per well of a 10x TMRE working solution from a 1:5 pre-diluted TMRE DMSO stock-solution in H2O (Water For Injection, WFI, Fisher Scientific, Gibco™ #A12873). Cells were incubated for further 20 minutes at room temperature in the dark, gently shaking on an orbital shaker (IKA, MTS 2/4 Digital Shaker, shaking at 300 rpm). Extracellular TMRE signal was quenched by adding 20pL per well of a 1.6mM solution of Brilliant Black BN (Carl Roth, #7643) in H2O. Cells were further incubated for 60 min at room temperature. Then the readout was taken with a multi-well plate-reader (Tecan Spark®) in the fluorescence mode using a filter for excitation at 535 nm (band width 25 nm) and for emission at 595 nm (band width 35 nm) without plate lid. Treatment for strong decrease in ΔΨm with the commercial mitochondrial uncoupler compound 2,4-dinitrophenol (DNP, Sigma Aldrich-Merck #34334) ata final concentration of 50 μM was included on every plate for assay quality control.
The assays were performed in two independent biological replicates, each containing three technical replicates for every condition. For every individual plate, the measured fluorescence intensity values of the conditions with compound treatment were normalized against the corresponding equally weighted arithmetic mean of the fluorescence intensity values of the th ree DMSO treated control wells in order to obtain the relative values to a reference level of 1.0.
The weighted arithmetic mean and the combined standard deviation as defined in the present invention was calculated for each compound as described above. The DNP control decreased the relative mitochondrial transmembrane potential ΔΨm in A-549 cells to 0.2.
The following tested compounds of the invention falling under the scope of the molecules herein defined in formula (I) were found to decrease the relative mitochondrial transmembrane potential ΔΨm in A-549 cells to 0.7 or lower. The so far identified mitochondrial inhibitors relate to the compounds listed in Table 46.
Table 46: Mitochondrial activity assay Activity Compound No.
XPM-0001 XPM-0004 XPM-0007 XPM-0010
ΔΨm ≤ 0.7
XPM-0015 XPM-0028 XPM-0031 XPM-0041
Several other molecules have not been identified as inhibitors of mitochondrial activity according to the above method.
In some cases, the growth inhibiting properties correlate with OXPHOS inhibiting properties, in other cases the growth inhibiting properties do not correlate with OXPHOS inhibiting properties. Thus, the invention also relates to compounds which have anti -hyperprolife rative activity without OXPHOS inhibition.
The biological activity of the claimed compounds can be attributed to but may not be limited to mitochondrial inhibition or OXPHOS inhibition. The mitochondrial or OXPHOS inhibiting and also metabolism regulating properties of the claimed compounds can be used alternatively or in combination with the mechanism leading to antiproliferative effects in medicinal treatments, preferably in the treatment of hyperproliferative disorders including benign or malignant hyperproliferative disorders such as hyperplasia, neoplasia, cancer and pre-cancerous lesions, and metastases.
In a further embodiment, the compounds of the present invention may be regulators of cell metabolism by activating and/or enhancing AMPK signaling.
AMPK activation can be assessed by the levels of AMPK phosphorylation at Thrl72. The APMK activating activities of compounds falling under general formula (I) were investigated by western blotting on different cancer cell lines. Access and cultivation of the respective cell lines are as described above. To this end, A-549, HEP-G2, and HCT-116 cells were seeded into 6-well culture plates (Cyto-One®, #007682-7506) in a total volume of 2mL at a density to achieve 80% confluency by 48 hours and incubated over night at 37ºC and 5% CO2. Cells were treated at a confluency of around 50% with compounds at indicated final concentration by adding 2pL per well of a 10OOx compound DMSO stock-solution. Cells were incubated for 20 hours at 37ºC and 5% CO2. Then, cells were lysed in RIPA buffer (Pierce™ RIPA Buffer, FisherScientific, #89900) supplemented with lx complete™ Mini Protease Inhibitor Cocktail (Roche, #11836153001) and ImM Sodium Orthovanadate (NasVOs, FisherScientific, #J60191) and lysates were subjected to standard western blotting procedure. Protein concentration of the samples was determined by BCA assay and samples were normalized to achieve equal protein concentration. 4x Laemmli Sample Buffer (Bio-Rad, # 1610747) was supplemented with 200 uM DTT (Sigma Aldrich-Merck, # D9779) and added to the samples to achieve a final concentration of lx Laemmli/50 μM DTT by diluting lysate samples with supplemented Laemmli buffer 1:4. Samples were then incubated at 95ºC for 5 min in a Thermomixer (Eppendorf). SDS-PAGE was performed in lx Tris/Glycine/SDS buffer (TGS, Bio-Rad, #1610772) using 4-15% gradient polyacrylamide gels (4-15% Mini- PROTEAN® TGX Stain-Free™ Gel, Bio-Rad, #456-8084). Proteins were transferred onto 0.2pm PVDF membranes using the semi-dry Trans-Blot® Turbo™ transfer system (Trans-Blot® Turbo™, Bio-Rad, #170-4150) with prepacked Trans-Blot® Turbo™ transfer packs (Bio-Rad, #170-4156). Immunodetection of AMPK, pAMPK (Thrl72), and β-Actin was performed using the following primary antibodies: AMPKα (F6) Mouse mAb (Cell Signaling Technologies, #2793) for AMPK, Phospho-AMPKa (Thrl72) (40H9) Rabbit mAb (Cell Signaling Technologies, #2535) for pAMPK (Thrl72), and Purified anti-β-actin Antibody (Rat monoclonal, W16197A) (Cell Signaling Technologies, #664802) for p-Actin. HRP-linked secondary antibodies in 5% nonfat dried milk (AppliChem, #A0830) in lxTBS containing 0.1% Tween-20 were used for the corresponding species mouse, rabbit and rat (Cell Signaling Technologies, #7076, #7074, #7077), respectively. Signals were developed with chemiluminescence substrate (SuperSignal™ West Pico PLUS, Fisher Scientific, #34577) and detected with the ChemiDoc™ MP imaging system (ChemiDoc™ MP, Bio-Rad, #12003154). Chemiluminescence signals of phosphorylation, total protein and loading control were quantified by densitometry using the image analysis software Image Lab™ (version 6.0.1, Bio-Rad). The corresponding lysates from DMSO treated cells were included on each membrane as the base line control for blot-internal signal normalization. The standard deviation of signal intensities of the loading control p-Actin within each blot was 16% or lower confirming equal loading of protein amounts.
For each condition, the ratio of phosphorylation to corresponding total protein was calculated from the signal intensities. The ratios were then normalized to the corresponding ratio of the DMSO control to yield the fold-change values of phosphorylation.
In the following embodiments, a compound is considered as an AMPK activator if the fold-change value of phosphorylation is 1.5 or higher, preferably 2.0 or higher, and more preferably 2.5 or higher as determined with the method described above.
The following tested compounds of the invention falling under the scope of the molecules herein defined in formula (I) were found to increase the relative Thrl 72 -phosphorylation level of AMPK at 10nM in A-549 cells. The so far identified AMPK activators relate to the compounds listed in Table 47.
Table 47: AMPK activation assay on A-549 cells
The following tested compounds of the invention falling under the scope of the molecules herein defined in formula (I) were found to increase the relative Thrl 72 -phosphorylation level of AMPK at 10nM in HEP-G2 cells. The so far identified AMPK activators relate to the compounds listed in Table 48.
Table 48: AMPK activation assay on HEP-G2 cells The following tested compounds of the invention falling under the scope of the molecules herein defined in formula (I) were found to increase the relative Thrl 72 -phosphorylation level of AMPK at lOnM in HCT-116 cells. The so far identified AMPK activators relate to the compounds listed in Table 49.
Table 49: AMPK activation assay on HCT-116 cells
Thus, the compounds of the invention can be used as medicament for regulating cellular metabolism to prevent and/or treat a disorder associated with, accompanied by and/or caused by hyperproliferative processes, including hyperplasia, neoplasia, cancer, pre-cancerous lesions, and metastases.
In another embodiment, the present invention relates to compounds, compositions and methods for the treatment of diseases. In particular, such disease is related to abnormal cell proliferation, in particular hyperproliferative disorders including hyperplasia, neoplasia, cancer, precancerous lesions and metastasis. Said hyperproliferative disorders can derive from cell types of ectodermal, endodermal or mesodermal origin. Also, said hyperproliferative disorders can derive from epithelial tissue, connective tissue, muscle tissue or nervous tissue or the liquid cell compartment. Cancers or precancerous lesions can be solid tumors or hematologic cancers. Moreover, said hyperproliferative disorders can be de novo or recurrent with local recurrence, regional recurrence or distant recurrence , and/or can be acute or chronic, and/or can be resistant to drugs or other types of treatment, i.e. intrinsic resistance, and/or can be induced by drugs or other types of treatment, i.e. acquired resistance. Said hyperproliferative disorders can be hormone dependent or hormone resistant. And said hyperproliferative disorders can be in situ, invasive or metastatic and of any stage according to the staging systems known to the person skilled in the art. The individuum in need of treatment can be of any gender and any age or developmental stage when experiencing one of the said hyperproliferative disorders i.e. embryonal cancer, childhood cancer, or cancer of adolescents, middle aged, or elderly patients.
The compounds, compositions and methods of the present invention may be used to treat or prevent cancer development, cancer maintenance, cancer progression, cancer invasion, the formation of metastasis, including formation of post-surgical or surgery-induced metastasis, and tumor-related angiogenesis.
In a further embodiment, the present invention relates to the treatment of a benign or malignant hyperproliferative disorder including hyperplasia, neoplasia, cancer, precancerous lesions and metastasis of the skin, skin appendages, mucosa, mucosal appendages, glands, eye, cornea, melanocytes, respiratory tract, lung, head and neck, oral cavity, mouth, tongue, lip, larynx, oropharynx, pharynx, esophagus, breast, mammary gland, genitourinary tract, cervix, uterus, ovaries, endometrium, vulva, vagina, penis, anus, prostate, testis, urinary tract, bladder, kidney, urinary tissues, endocrine glands, thyroid, parathyroid, connective tissue, soft tissue, bone, cartilage, muscle, adipose tissue, spleen, neuroendocrine system, central nervous system, peripheral nervous system, brain, forebrain, pituitary gland, adrenal gland, meninges, spinal cord, pancreas, pancreatic islets of Langerhans, gallbladder, bile duct, gastrointestinal tract, colon, large intestine, small intestine, rectum, stomach, liver, biliary passages, vascular system, blood vessels, lymphatic vessels, peritoneum, pleura, pericardium. In certain embodiments, the disorder is a benign disorder. In further embodiments, the disorder is a malignant disorder. In a further embodiment, the present invention relates to the treatment of a malignant hyperproliferative disorder including cancer, precancerous lesions and metastasis of the blood, white blood cell compartment, red blood cell compartment, hematologic system, hematopoietic system, lymphatic system, lymph nodes, lymphoid organs, lymphoid tissues, bone marrow, myeloid lineage, lymphoid lineage, including acute and chronic forms of leukemia and lymphoma, wherein said leukemias and lymphomas can be lymphocytic, lymphoblastic, large granular lymphocytic, small lymphocytic, T-lymphocytic, B -lymphocytic, plasmacytic, myelocytic, myeloblastic, monocytic, granulocytic, basophilic, neutrophilic, eosinophilic, megakaryocytic, mastocytic, erythrocytic, or dendrocytic.
In a further embodiment, the present invention relates to the treatment of a benign or malignant hyperproliferative disorder including hyperplasia, neoplasia, cancer, precancerous lesions and metastasis selected from epithelial cancers and precancerous lesions, epithelial hyperplasia, epithelial neoplasia, carcinoma, squamous cell carcinoma, basal cell carcinoma, transitional cell carcinoma, verrucous carcinoma, mucinous carcinoma, serous carcinoma, cystic carcinoma, papillary carcinoma, papillary adenocarcinoma, small cell carcinoma, combined small cell carcinoma, large cell carcinoma, carcinoid tumors, stromal tumors, leukemia, lymphoma, myeloma, papilloma, intracanalicular papilloma, intraductal papilloma, inverted papilloma, basal cell papilloma, squamous papilloma, precancerous keratoses, adenoma, cystadenoma, serous cystadenoma, mucinous cystadenoma, adenocarcinoma, cystadenocarcinoma, serous cystadenocarcinoma, mucinous cystadenocarcinoma, ductal adenocarcinoma, adenoid cystic carcinoma, medullary carcinoma, ductal carcinoma, lobular carcinoma, villoglandular carcinoma, sarcoma, polyp, angioma, neuroma, adnexal tumor, oncocytoma, cyst, hyperproliferative nevi, biphasic tumors and mixed tumors. In certain embodiments, the disorder is a benign disorder. In further embodiments, the disorder is a malignant disorder.
In a further embodiment, the present invention relates to the treatment of a benign or malignant hyperproliferative disorder including hyperplasia, neoplasia, cancer, precancerous lesions and metastasis selected from melanoma, melanoma in situ, cutaneous melanoma, ocular melanoma, uveal melanoma, conjunctival melanoma, mucosal melanoma, amelanotic melanoma, desmoplastic melanoma, nodular melanoma, superficial spreading melanoma, acral -lentiginous melanoma, lentigo maligna melanoma, non-melanoma skin cancer, cutaneous basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (SCC), sebaceous gland carcinoma, salivary gland oncocytoma, acinic cell carcinoma, Warthin tumor, cystadenolymphoma, fibrofolliculomas, epidermoid cyst, Merkel cell carcinoma, dermatofibrosarcoma, actinic keratosis (AK), solar keratosis, seborrheic keratosis (verruca senilis)., chronic scar keratosis, hydrocarbon keratosis, Bowen disease (BD), cutaneous SCC, lung SCC, head and neck SCC, oral SCC, tongue SCC, esophageal SCC, cervical SCC, periocular SCC, SCC of the thyroid, SCC of the penis, SCC of the vagina, SCC of the prostate and SCC of the bladder, Kaposi sarcoma, thymoma, endolymphatic sac tumor, Paget disease of the breast, extramammary Paget disease, medullary breast carcinoma, cystadenocarcinoma of the ovaries, serous ovarian cancer, ovarian serous cystadenoma, Bartholin gland carcinoma, pancreatic serous cystadenoma, uterine serous carcinoma, papillary serous cystadenocarcinoma, cystadenocarcinoma of the liver, cystadenocarcinoma of the pancreas, signet ring cell carcinoma, gastrointestinal stromal tumor, endometrioid tumor, prolactinoma, multiple endocrine neoplasia, adrenocortical adenoma, adrenocortical carcinoma, Hurthle cell carcinoma, Hurthle cell adenoma, neuroendocrine small cell carcinomas, neuroendocrine large cell carcinomas and carcinoid tumors, neuroendocrine tumors, neuroendocrine tumor of the pituitary gland, neuroendocrine tumor of the adrenal gland, pheochromocytoma, paraganglioma, medullary thyroid cancer (MTC), C-cell hyperplasia, anaplastic thyroid cancer (ATC), parathyroid adenoma, intrathyroidal nodules, insular carcinoma, hyalinizing trabecular neoplasm, thyroid oncocytoma, lung carcinoid tumors, gastrointestinal carcinoid, Goblet-cell carcinoid, pancreatic carcinoid, gastrinoma, glucagonoma, somatostatinoma, (vasoactive intestinal peptide-) VIPoma, insulinoma, beta cell tumor, nonfunctional islet cell tumor, multiple endocrine neoplasia type-1, or pulmonary carcinoid, bronchogenic carcinoma, small-cell lung carcinoma (SCLC), combined small cell lung carcinoma, non-small-cell lung cancer (NSCLC), lung adenocarcinoma and lung large cell carcinoma, nephroblastoma, Wilms tumor, medulloblastoma, neuroblastoma, retinoblastoma, glioma, mixed glioma, glioblastoma multiforme, astrocytoma, anaplastic astrocytoma, glioblastoma, blastoglioma, oligodendroglioma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, ependymoma, anaplastic ependymoma, myxopapillary ependymoma, subependymoma, brain stem glioma, chordoma, optic nerve glioma, ganglioglioma, meningioma, adrenocarcinoma, pinealoma, pineocytoma, pineoblastoma, craniopharyngioma, myxosarcoma, myxofibrosarcoma, neurofibrosarcoma, neurosarcoma, malignant schwannoma, malignant peripheral nerve sheath tumor, pancreatic adenocarcinoma, pancreatic ductal adenocarcinoma, pancreatic ductal carcinoma, pancreatic endocrine tumors, pancreatic acinar cell carcinoma, pancreatic pseudopapillary neoplasm, pancreatic intraductal papillary-mucinous neoplasm, pancreatic mucinous cystadenocarcinoma, pancreatoblastoma and pancreatic intraepithelial neoplesia, hepatocellular carcinoma (HCC), fibrolamellar hepatocellular carcinoma, hepatoma, cholangiocarcinoma, Klatskin tumor, bile duct carcinoma, papillary thyroid cancer and follicular thyroid cancer, cervical cancer, cervical mucinous adenocarcinoma, cervical adenoma malignum, hormone receptor-positive breast cancer, hormone receptor-negative breast cancer, hormone receptor-positive breast cancer with HER2 amplification, hormone receptor-negative breast cancer with HER2 amplification, triple negative breast cancer, breast cancer with or without BRCA1 and/or BRCA2 mutation, triple negative breast cancer with or without BRCA1 and/or BRCA2 mutation, breast ductal carcinoma, breast ductal carcinoma in situ, postirradiation breast angiosarcoma, comedocarcinoma, ovarian cancer, Krukenberg tumor, pseudomyxoma peritonei, mucoepidermoid carcinoma, germinoma, intracranial germinoma, dysgerminoma, seminoma, testicular seminoma, nonseminomatous germ cell tumor, ductal adenocarcinoma of the prostate, ductal carcinoma of the prostate, choriocarcinoma, gastric cancer, Brinton disease, endotheliosarcoma, angiosarcoma, cutaneous angiosarcoma, intraoral angiosarcoma, gingival angiosarcoma, breast angiosarcoma, cardiac angiosarcoma, hepatic angiosarcoma, pulmonary angiosarcoma, pleural angiosarcoma, gastrointestinal angiosarcoma, epithelioid angiosarcoma, splenic angiosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma, fibrosarcoma, liposarcoma, rhabdomyosarcoma, leiomyosarcoma, Ewing sarcoma, osteosarcoma, chondrosarcoma, synovial sarcoma, mesothelioma, pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma, renal cell carcinoma (RCC), renal pelvis carcinoma, renal oncocytoma, myeloproliferative disorders, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), erythroid leukemia, acute erythroid leukemia (AEL), erythroblastic leukemia, erythroblastic sarcoma, megakaryoblastic leukemia, acute megakaryoblastic leukemia (AMEL), basophilic leukemia, acute basophilic leukemia (ABL), neutrophilic leukemia, chronic neutrophilic leukemia, eosinophilic leukemia, chronic eosinophilic leukemia, monocytic leukemia, acute monocytic leukemia (AMOL), acute myelomonocytic leukemia (AMML), mast cell leukemia (MCL), acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), pre-T-cell acute lymphoblastic leukemia (pre-T-ALL), B-cell acute lymphoblastic leukemia (B-ALL), pre-B-cell acute lymphoblastic leukemia (pre-B-ALL), chronic lymphocytic leukemia (CLL), T-cell-CLL (T-CLL), B-cell-CLL (B-CLL), prolymphocytic leukemia (PLL), T-cell- PLL (T-PLL), B-cell-PLL (B-PLL), small lymphocytic leukemia, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, marginal zone B-cell lymphoma, diffuse large B-cell lymphoma, lymphomatoid granulomatosis, primary effusion lymphoma, Waldenstrom macroglobulinemia, plasma cell leukemia, primary plasma cell leukemia, secondary plasma cell leukemia, lymphoplasmacytic lymphoma, plasmacytoma, heavy chain disease, Burkitt lymphoma, hairy cell leukemia (HCL), mantle cell lymphoma, myeloma, multiple myeloma, mixed phenotype leukemia, acute mixed phenotype leukemia, mixed-lineage leukemia, acute mixed-lineage leukemia, large granular lymphocytic leukemia (LGLL), T-cell LGLL (T-LGLL), natural killer cell LGLL (NK-LGLL), aggressive natural killer (NK) cell leukemia, aggressive NK cell lymphoma, NK/T-cell lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma, gastric MALT lymphoma, lung MALT lymphoma, dendritic cell leukemia, myeloproliferative neoplasms, myelofibrosis, primary myelofibrosis, secondary myelofibrosis, polycythemia vera (PV), essential thrombocythemia (ET), blastic plasmacytoid dendritic cell neoplasm, lipoma, fibroma, fibromatosis, hepatocellular adenoma, renal tubular adenoma, cystadenoma, colonic polyp, gastric polyp, adenomatous polyp, cholangioma, hemangioma, cardiac myxoma, hemangioblastoma, hydatiform mole, fibroid, uterine fibroid, leiomyoma, rhabdomyoma, ganglioneuroma, acoustic neuroma, vestibular schwannoma, schwannoma, benign synovioma, chondroma, osteoma, osteochondroma, enchondroma, giant cell tumor, giant cell tumor of the bone, tenosynovial giant cell tumor, benign germinoma, lymphangioma squamous cell papilloma, acanthosis, acanthosis nigricans, malignant acanthosis, acanthoma, clear cell acanthoma, Degos acanthoma, pilar sheath acanthoma, keratoacanthoma, subungual keratoacanthoma, clear cell adenocarcinoma, apudoma, cylindroma, cutaneous cylindroma, spiradenoma, papillary hidradenoma, hidrocystoma, syringoma, syringocystadenoma papilliferum, trichoepithelioma, focal epithelial hyperplasia, Heck disease, pseudoepitheliomatous hyperplasia, cervical villoglandular carcinoma, cervical mesonephric carcinoma, endocervical adenocarcinoma, and hamartoma. In certain embodiments, the disorder is a benign disorder. In further embodiments, the disorder is a malignant disorder.
In a further embodiment, the present invention relates to the treatment of a benign or malignant hyperproliferative disorder including hyperplasia, neoplasia, cancer, precancerous lesions and metastasis associated with or derived from a preceding hereditary or non-hereditary disease or syndrome including hereditary cancer syndromes or inherited cancer susceptibility syndromes (ICSS), hereditary breast and ovarian cancer (HBOC) syndrome, breast cancer gene (BRCA) 1 HBOC syndrome, BRCA2 HBOC syndrome, Lynch syndrome, hereditary nonpolyposis colorectal cancer syndrome, familial adenomatous polyposis (FAP), juvenile polyposis syndrome (JPS), multiple endocrine neoplasia (MEN) syndrome, MEN syndrome type 1, MEN syndrome type 2A and 2B, Li-Fraumeni syndrome (LFS), Cowden syndrome, Peutz-Jeghers syndrome, hereditary diffuse gastric cancer, Birt-Hogg-Dube (BHD) syndrome, hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome, hereditary papillary renal cell cancer (PRCC) syndrome, von Hippel-Lindau (VHL) disease, hereditary medullary thyroid carcinoma syndrome, hereditary prostate cancer, hereditary brain cancer, nevoid basal cell carcinoma syndrome, papillar renal cell carcinoma syndrome, von Recklinghausen disease, neurofibromatosis type 1 (NF1), NF2 , schwannomatosis, tuberous sclerosis, hereditary multiple melanoma, neuroblastoma, retinoblastoma, Turcot syndrome, hereditary leukemia syndromes, myoledysplastic syndrome, Stewart-Treves syndrome, Denys-Drash syndrome, Wilms tumor - Aniridia - Genital abnormalities - Retardation (WAGR) syndrome, Beckwith-Wiedemann syndrome, multiple hereditary exostoses (MHE), enchondromatosis, metachondromatosis, Ollier disease, Proteus syndrome, familial multiple lipomatosis, and androgen insensitivity syndrome. In certain embodiments, the disorder is a benign disorder. In further embodiments, the disorder is a malignant disorder.
In a further embodiment, the present invention relates to the treatment of a benign or malignant hyperproliferative disorder including hyperplasia, neoplasia, cancer, precancerous lesions and metastasis associated with, accompanied by and/or caused and/or promoted by viral infections, such as oncoviral infections, including infections with hepatitis virus B (HBV), hepatitis virus C (HCV), human herpes virus (HHV) in particular HHV-4 or Epstein-Barr virus (EBV), HHV-5 or human cytomegalovirus (HCMV), and HHV-8 or Kaposi sarcoma-associated herpesvirus (KSHV), human papilloma virus (HPV), in particular HPV-16, HPV-18, HPV-26, HPV-31, HPV-33, HPV-35, HPV-39, HPV-45, HPV-51, HPV-52, HPV-53, HPV-56, HPV-58, HPV-59, HPV-66, HPV-68, HPV-73, and HPV-82, human T-lymphotrophic virus (HTLV), in particular HTLV-1, and Merkel cell polyomavirus (MCV), simian virus 40 (SV40), Rous sarcoma virus (RSV), Avian sarcoma leukosis virus (ASLV), mouse mammary tumor virus (MMTV), murine leukemia virus (MLV), Friend virus, Shope papilloma virus. In certain embodiments, the disorder is a benign disorder. In further embodiments, the disorder is a malignant disorder. According to the above, the present invention also relates to the treatment of a virus-related hyperproliferative disorder selected from but not limited to liver cancer, Burkitt lymphoma, Hodgkin and non-Hodgkin lymphoma, stomach cancer, nasopharyngeal carcinoma and post- tranplant lymphoproliferative disease, Merkel cell carcinoma, cancer of the urogenital tract including cancer of the cervix, vulva, penis, vagina, and anus, and cancer of the oropharynx, tongue and oral cavity, Kaposi sarcoma, Castleman disease, primary effusion lymphoma, T-cell leukemia and T-cell lymphoma, warts, papillomas, papillomatoses, verruca vulgaris (common wart), verruca plantaris (plantar warts), verruca plana (flat warts), verruca filiformis (filiform warts), recalcitrant plantar (mosaic warts), condyloma acuminatum (genital warts), oral condyloma acuminatum (oral warts), periungual verrucae (periungual warts), subungual warts, fibroepithelial papilloma, intracanalicular papilloma, intraductal papilloma, inverted papilloma, basal cell papilloma, squamous papilloma, cutaneous papilloma, fibrovascular papilloma, plexus papilloma, nasal papilloma, pharyngeal papilloma, papillomatosis cutis, papillomatosis cutis carcinoides, papillomatosis cutis lymphostatica, papillomatosis confluens et reticularis, oropharyngeal papillomatosis, laryngeal papillomatosis, oesophageal papillomatosis, respiratory papillomatosis, recurrent respiratory papillomatosis, vestibular papillomatosis, palatal papillomatosis, florid papillomatosis, oral florid papillomatosis, Buschke-Lowenstein tumor, giant condyloma acuminatum, Gottron carcinoid papillomatosis, lymphoid leucosis. In certain embodiments, the disorder is a benign disorder. In further embodiments, the disorder is a malignant disorder.
In a further embodiment, the present invention relates to the treatment of a benign or malignant hyperproliferative disorder including hyperplasia, neoplasia, cancer, precancerous lesions and metastasis associated with, accompanied by and/or caused and/or promoted by a pathogen- derived infection wherein the pathogen is a non-viral pathogen, e.g. a bacterium, a parasite or a fungus, including infections with oncogenic or carcinogenic bacteria and parasites including Helicobacter (H.j pylori, H. hepaticus, H. bilis, H. felis, H. suis, H. heilmannii, H. bizzozeronii, H. salomonis, Salmonella enterica serovar Typhi, Salmonella enterica serovar Typhimurium, Salmonella enterica serovar Paratyphi, Streptococcus bovis, Chlamydia (C) pneumoniae, C. trachomatis, C. psittaci, Mycoplasma (M.) fermentans, M. penetrans, M. hyorhinis, Campylobacter jejuni, Clostridium, Bacteroides fragilis, Neisseria gonorrhoeae, Cutibacterium acnes, Treponema pallidum, Borrelia burgdorferi, Mycobacterium tuberculosis, Schistosoma haematobium, Schistosoma japonicum, Opisthorchis viverrini, Clonorchis sinensis, Cysticercus fasciolaris, Taenia taeniaformis, Spirocerca lupi, Fasciola hepatica. In certain embodiments, the disorder is a benign disorder. In further embodiments, the disorder is a malignant disorder.
According to the above, the present invention also relates to the treatment of a pathogen-related hyperproliferative disorder selected from but not limited to biliary cancer, gallbladder cancer, bile duct cancer, colorectal cancer, stomach cancer, colon cancer, esophageal cancer, lung cancer, ovarian cancer, cervical cancer, prostate cancer, bladder cancer, eye cancer, mucosa-associated lymphoid tissue (MALT) lymphoma, gastric MALT lymphoma, lung MALT lymphoma, marginal zone B-cell lymphoma, cholangiocarcinoma. In certain embodiments, the disorder is a benign disorder. In further embodiments, the disorder is a malignant disorder.
In a further embodiment, the present invention relates to the treatment of a benign or malignant hyperproliferative disorder including hyperplasia, neoplasia, cancer, precancerous lesions and metastasis associated with and/or caused and/or promoted by carcinogenic drugs, treatments, chemicals, natural substances and materials, including chemotherapies, genotoxic substances, heavy metals, nitrosamines, ethylene oxide, vinyl chloride, alkylating agents, DNA intercalating agents, radiation, radionuclides, dioxins, benzene, formaldehyde, asbestos and microbial carcinogens such as aflatoxins; said benign or malignant hyperproliferative disorders may also be related to smoking tobacco, exposure to UV radiation e.g. derived from sunlight or sunlamps or tanning equipment, obesity, chronic inflammation, diet, or excessive consumption of alcohol. In certain embodiments, the disorder is a benign disorder. In further embodiments, the disorder is a malignant disorder.
As used herein, the term "skin" relates to tissue including epidermis and dermis. The term "mucosa" relates to mucous and submucous tissues including oral mucosa, nasal mucosa, ocular mucosa, mucosa of the ear, respiratory mucosa, genital mucosa, urothelial mucosa, anal mucosa and rectal mucosa. The term "appendages" relates to tissue including hair follicles, hair, fingernails, toenails and glands including sebaceous glands, sweat glands, e.g. apocrine or eccrine sweat glands.
As used herein, the terms "treating”, "to treat” or "treatment” refer to one or more of (1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology); and (2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease. Said terms also encompass post-treatment care.
In some embodiments, administration of a compound of the invention, or a pharmaceutically acceptable salt thereof, is effective in preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.
The compounds of the invention may be used in human and veterinary medicine, which includes the treatment of companion animals, e.g. horses, dogs, cats, rabbits, guinea pigs, fishes e.g. koi, birds e.g. falcon; and livestock, e.g. cattle, poultry, pig, sheep, goat, donkey, yak and camel.
Pharmaceutical Compositions
The present invention further provides pharmaceutical compositions comprising a compound as described herein or a pharmaceutically acceptable salt thereof for use in medicine, e.g. in human or veterinary medicine. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.
An effective dose of the compounds according to the invention, or their salts, solvates or prodrugs thereof is used, in addition to physiologically acceptable carriers, diluents and/or adjuvants for producing a pharmaceutical composition. The dose of the active compounds can vary depending on the route of administration, the age and weight of the patient, the nature and severity of the diseases to be treated, and similar factors. A daily dose can be given as a single dose, which is to be administered once, or be subdivided into two or more daily doses, and is as a rule 0.001- 2000 mg. Preference is given to administering daily doses of 0.01-500 mg, and in particular of 0.01-100 mg. A weekly dose can be given as a single dose, or subdivided into two to seven doses per week, and is as a rule 0.001-2000 mg. Particular preference is given to administering weekly doses of 0.01-500 mg.
Suitable administration forms are topical or systemical including enteral, oral, rectal, intracavitary, and parenteral, as infusion and injection, intravenous, intra-arterial, intraperitoneal, intramuscular, intracardial, intracoronary, intrapericardial, intravascular, intralymphatic, intraventricular epidural, intradural, peridural, perineural, intracerebral, intracerebroventricular, intrameningeal, intraspinal, intraosseous, intramedullary, intraarticular, periarticular, intracartilaginous, intrasynovial, intradiscal, intratendinous, ophthalmic, intraocular, intracorneal, conjunctival, subconjunctival, retrobulbar, intravitreal, intrathecal, intraurethral, intraduodenal, intraileal, intragastric, vaginal, intravaginal, endocervical, intrauterine, transplacental, intra-amniotic, extra-amniotic, intraovarian, intratesticular, intracavernous, intracorporus cavernosum, intraprostatic, intraductal, intraluminal, intratubular, auricular, intratympanic, transtympanic, intravesical, ureteral, urethral, cutaneous, pericutaneous, subcutaneous, hypodermic, intraepidermal, intradermal, transdermal, submucosal, transmucosal, intracoronal, dental, periodontal, respiratory, inhalative, nasal, intranasal, nasogastric, intrasinal, intrabronchial, intrapulmonary, endosinusial, endotracheal, transtracheal, intrapleural, intraesophageal, laryngeal, oropharyngeal, buccal, sublingual, intragingival, interstitial, intra-abdominal, intrathoracic, soft tissue, intrabiliary, intrabursal, intracaudal, subarachnoid, intercisternal, intralesional, intratumor, and other preparations. Particular preference is given to using oral, parenteral, e.g. intravenous or intramuscular, intranasal or inhalative preparations, e.g. dry powder for inhalation or compound solutions for nebulization and inhalation for the delivery into the respiratory tract including the lung, or sublingual, of the compounds according to the invention. The customary galenic preparation forms, such as tablets, sugar-coated tablets, capsules, suppositories, dispersible powders, granulates, aqueous solutions, alcohol-containing or DMSO-containing aqueous solutions, solutions in DMSO, aqueous or oily suspensions, gels, hydrogels, ointments, creams, lotions, shampoos, lip balms, mouthwashes, foams, pastes, tinctures, dermal patches and tapes, forms in occlusion or in combination with time release drug delivery systems, with electrophoretic dermal delivery systems including implants and devices, and with jet injectors, liposome and transfersome vesicles, vapors, sprays, syrups, juices or drops and eye drops, can be used.
Solid medicinal forms can comprise inert components and carrier substances, such as calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginates, gelatine, guar gum, magnesium stearate, aluminium stearate, methyl cellulose, talc, highly dispersed silicic acids, silicone oil, higher molecular weight fatty acids, (such as stearic acid), gelatine, agar-agar or vegetable or animal fats and oils, or solid high molecular weight polymers (such as polyethylene glycol); preparations which are suitable for oral administration can comprise additional flavourings and/or sweetening agents, if desired.
Liquid medicinal forms can be sterilized and/or, where appropriate, comprise auxiliary substances, such as preservatives, stabilizers, wetting agents, penetrating agents, emulsifiers, spreading agents, solubilizers, salts, sugars or sugar alcohols for regulating the osmotic pressure or for buffering, and/or viscosity regulators. Examples of such additives are tartrate and citrate buffers, ethanol and sequestering agents (such as ethylenediaminetetraacetic acid and its non- toxic salts). High molecular weight polymers, such as liquid polyethylene oxides, microcrystalline celluloses, carboxymethyl celluloses, polyvinylpyrrolidones, dextrans or gelatine, are suitable for regulating the viscosity. Examples of solid carrier substances are starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids (such as stearic acid), gelatine, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, and solid high molecular weight polymers, such as polyethylene glycol.
Oily suspensions for parenteral or topical applications can be vegetable, synthetic or semisynthetic oils, such as liquid fatty acid esters having in each case from 8 to 22 C atoms in the fatty acid chains, for example palmitic acid, lauric acid, tridecanoic acid, margaric acid, stearic acid, arachidic acid, myristic acid, behenic acid, pentadecanoic acid, linoleic acid, elaidic acid, brasidic acid, erucic acid or oleic acid, which are esterified with monohydric to trihydric alcohols having from 1 to 6 C atoms, such as methanol, ethanol, propanol, butanol, pentanol or their isomers, glycol or glycerol. Examples of such fatty acid esters are commercially available miglyols, isopropyl myristate, isopropyl palmitate, isopropyl stearate, PEG 6 -capric acid, caprylic/capric acid esters of saturated fatty alcohols, polyoxyethylene glycerol trioleates, ethyl oleate, waxy fatty acid esters, such as artificial ducktail gland fat, coconut fatty acid isopropyl ester, oleyl oleate, decyl oleate, ethyl lactate, dibutyl phthalate, diisopropyl adipate, polyol fatly acid esters, inter alia. Silicone oils of differing viscosity, or fatty alcohols, such as isotridecyl alcohol, 2 -octyldodecanol, cetylstearyl alcohol or oleyl alcohol, or fatty acids, such as oleic acid, are also suitable. It is furthermore possible to use vegetable oils, such as castor oil, almond oil, olive oil, sesame oil, cotton seed oil, groundnut oil or soybean oil.
Suitable solvents, gelatinizing agents and solubilizers are water or water-miscible solvents. Examples of suitable substances are alcohols, such as ethanol or isopropyl alcohol, benzyl alcohol, 2 -octyldodecanol, polyethylene glycols, phthalates, adipates, propylene glycol, glycerol, di- or tripropylene glycol, waxes, methyl cellosolve, cellosolve, esters, morpholines, dioxane, dimethyl sulphoxide, dimethylformamide, tetrahydrofuran, cyclohexanone, etc.
Cellulose ethers which can dissolve or swell both in water or in organic solvents, such as hydroxypropylmethyl cellulose, methyl cellulose or ethyl cellulose, or soluble starches, can be used as film-forming agents.
Mixtures of gelatinizing agents and film-forming agents are also perfectly possible. In this case, use is made, in particular, of ionic macromolecules such as sodium carboxymethyl cellulose, polyacrylic acid, polymethacrylic acid and their salts, sodium amylopectin semiglycolate, alginic acid or propylene glycol alginate as the sodium salt, gum arabic, xanthan gum, guar gum or carrageenan. The following can be used as additional formulation aids: glycerol, paraffin of differing viscosity, triethanolamine, collagen, allantoin and novantisolic acid. Use of surfactants, emulsifiers or wetting agents, for example of sodium lauryl sulphate, fatty alcohol ether sulphates, di-sodium-N-lauryl-p-iminodipropionate, polyethoxylated castor oil or sorbitan monooleate, sorbitan monostearate, polysorbates (e.g. Tween), cetyl alcohol, lecithin, glycerol monostearate, polyoxyethylene stearate, alkylphenol polyglycol ethers, cetyltrimethylammonium chloride or mono-/dialkylpolyglycol ether orthophosphoric acid monoethanolamine salts can also be required for the formulation. Stabilizers, such as montmorillonites or colloidal silicic acids, for stabilizing emulsions or preventing the breakdown of active substances such as antioxidants, for example tocopherols or butylhydroxyanisole, or preservatives, such as p -hydroxybenzoic acid esters, can likewise be used for preparing the desired formulations.
Preparations for parenteral administration can be present in separate dose unit forms, such as ampoules or vials. Use is preferably made of solutions of the active compound, preferably aqueous solutions and, in particular, isotonic solutions and also suspensions. These injection forms can be made available as ready-to-use preparations or only be prepared directly before use, by mixing the active compound, for example the lyophilisate, where appropriate containing other solid carrier substances, with the desired solvent or suspending agent.
Intranasal preparations can be present as aqueous or oily solutions or as aqueous or oily suspensions. They can also be present as lyophilisates which are prepared before use using the suitable solvent or suspending agent.
Inhalable preparations can present as powders, solutions or suspensions. Preferably, inhalable preparations are in the form of powders, e.g. as a mixture of the active ingredient with a suitable formulation aid such as lactose.
The preparations are produced, aliquoted and sealed under the customary antimicrobial and aseptic conditions.
In an embodiment, the compounds of the invention may be administered as a monotherapy, i.e. without further active agents.
In a further embodiment, the compounds of the invention may be administered as a combination therapy with one or more additional pharmacologically active agent including small molecules, peptides, proteins, monoclonal antibodies, humanized monoclonal antibodies, antibody-drug conjugates, cytokines, growth factors, nucleic acids, radiopharmaceuticals, and/or non-agent- based therapeutic intervention including surgery, cryotherapy, electrodessication, radiotherapy, photodynamic therapy, laser therapy, chemotherapy, targeted therapy, cancer immunotherapy, gene therapy, antisense therapy, mRNA-based therapy, vaccine therapy, cell-based transplantation therapy, stem cell therapy, physical therapy, supportive therapy including hemodialysis, and occupational therapy. The combination can be administered separately, sequentially, i.e. in a sequential combination therapy regimen, or simultaneously, i.e. in a simultaneous combination therapy regimen, or in a mixed form of both sequential and simultaneous administration regimen. The combined agents including the compounds of the invention can act independently, additively and/or synergistically. The compounds of the invention can also be used as adjuvant therapy or neoadjuvant therapy.
A compound of the invention may be combined with one or more further suitable agents and/or mentioned non-agent-based therapeutic interventions for example in a combined symptomatic treatment to control and/or reduce therapy-related undesirable side effects or treatment emergent adverse events (TEAE). Said side-effects or TEAE can be mechanism-based i.e. on- target effects, or mechanism-independent i.e. off-target effects, including pain, nausea, emesis, diarrhea, allergic reactions, fever, tissue swelling, mood alteration, depression, sleeping disturbance, skin conditions like dermatitis and rash, anemia, neutropenia, pathogen-related infections like bacterial and fungal infections, acidosis, elevated blood lactate levels, lactic acidosis, neurotoxicity, peripheral neuropathy, visual impairment, myalgia, axonal and demyelinating neuropathy.
A compound of the invention may also be combined with one or more further suitable agents and/or non-agent-based therapeutic interventions as mentioned in the present invention for example in a combined treatment with an adjuvant or with an intervention with adjuvant implication to enhance therapeutic benefit or efficacy of the primary therapeutic agent or intervention. Said therapeutic benefit or efficacy can be enhanced by means of reaching and/or maintaining suitable bioavailability of the primary therapeutic agent, beneficially impacting absorption or distribution or metabolism or excretion of the primary therapeutic agent, overcoming acquired or intrinsic resistance towards the primary therapeutic agent or intervention, sensitizing towards the primary therapeutic agent or intervention, increasing the therapeutic index or the therapeutic window of the primary therapeutic agent or intervention, allowing lower dosage and/or less frequent dosages and/or shorter treatment duration of the primary therapeutic agent or intervention, decreasing toxicity and overcoming dose-limiting toxicity of the primary therapeutic agent or intervention.
A compound of the invention may also be combined with one or more further suitable agents and/or non-agent-based therapeutic interventions as mentioned in the present invention for example in a combined treatment with one or more additional primary therapeutic agent or intervention with additive or synergistic effect to enhance therapeutic benefit or efficacy of one or multiple of the primary therapeutic agents or interventions. Said therapeutic benefit or efficacy can be enhanced by means of overcoming acquired or intrinsic resistance towards any of the primary therapeutic agents or interventions, sensitizing towards any of the primary therapeutic agents or interventions, increasing the therapeutic index or the therapeutic window of any of the primary therapeutic agents or interventions, allowing lower dosage and/or less frequent dosages and/or shorter treatment duration of any of the primary therapeutic agents or interventions, and overcoming dose-limiting toxicity of any of the primary therapeutic agents or interventions.
Pharmacologically or therapeutically active agents that can be used for a combination therapy together with one or more compounds of the invention in a combined symptomatic treatment to control and/or reduce therapy-related undesirable side effects or treatment emergent adverse events (TEAE) include but are not limited to 1) Antiemetics such as neurokinin receptor 1 antagonists (e.g. aprepitant, rolapitant), serotonin 5-HT3 receptor modulators, in particular 5-HT33 antagonists (e.g. dolasetron, granisetron, ondansetron, palonosetron), dopamine modulators, in particular DI, D2, D3 and D4 receptor antagonists (e.g. prochlorperazine, domperidone, olanzapine), corticosteroids (e.g. dexamethasone), and cannabinoids acting on cannabinoid receptors, in particular agonists of CB1 and CB2 (e.g. dronabinol, cannabis).
2) Treatments against acidosis such as pH buffer solutions including tris(hydroxymethyl)aminomethane (e.g. tromethamine) or bicarbonate solutions (e.g. sodium bicarbonate) for injection, device-related treatments including hemodialysis, and treatments against cellular lactate release and/or uptake such as inhibitors of monocarboxylate transporters (MCTs, also called SLC16 family of solute carriers) (e.g. AZD3965, AZD0095, BAY-8002, VB124, Syrosingopine, AR-C155858, MSC-4381).
3) Anti-inflammatory agents such as steroidal anti-inflammatory agents or glucocorticoids (e.g. hydrocortisone, dexamethasone, betamethasone, prednisone, prednisolone, methylprednisolone, triamcinolone, triamcinolone acetonide, triamcinolone hexacetonide, mometasone furoate, clobetasol propionate, deflazacort, budesonide), and non-steroidal antiinflammatory drugs (NSAIDs) (e.g. acetylsalicylic acid, salicylic acid and other salicylates, diflunisal, ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, loxoprofen, flurbiprofen, oxaprozin, indomethacin, ketorolac, tolmetin, diclofenac, etodolac, aceclofenac, nabumetone, sulindac, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, meloxicam, piroxicam, celecoxib, parecoxib, etoricoxib and firocoxib). Treatment with NSAIDs can additionally be combined with treatments reducing stomach acid including proton pump inhibitors (e.g. esomeprazole, lansoprazole), prostaglandins and synthetic prostaglandins (e.g. misoprostol), or H2 receptor antagonists (e.g. famotidine) to improve tolerability if needed; examples for combinations include naproxen/esomeprazole, naproxen/lansoprazole, diclofenac/misoprostol, and ibuprofen/famotidine.
4) Treatments against neuropathy, in particular peripheral neuropathy, such as cyclooxygenase modulators and other NSAIDs, in particular inhibitors of COX-1 and COX-2 (e.g. paracetamol, aspirin, ibuprofen), inhibitors of norepinephrine and/or serotonin transporters (e.g. amitriptyline, nortriptyline), serotonin-norepinephrine reuptake inhibitors (e.g. venlafaxine, desvenlafaxine, doxepine, duloxetine), calcium channel modulators, in particular inhibitors of voltage-dependent calcium channels (e.g. pregabalin, gabapentin), catechol-O-methyltransferase inhibitors (e.g. entacapone, opicapone), opioid receptor modulators, in particular p-opioid receptor agonists (MOR) (e.g. oxycodone, tramadol), HDAC modulators, in particular HDAC6 inhibitors (e.g. ricolinostat), and vanilloid receptor subtype 1 ion channel binding drugs (e.g. capsaicin, for example as cream formulation).
5) Treatments against diarrhea such as opioid receptor modulators, in particular p-opioid receptor agonists (MOR) in the myenteric plexus (e.g. loperamide), combinations of opioids with muscarinic acetylcholine receptor modulators (e.g. diphenoxylate-atropine), glucocorticoid receptor modulators (e.g. budesonide) and somatostatin receptor modulators SSTR, in particular antagonists of SSTR2 and SSTR5 (e.g. octreotide).
6) Treatments against allergic reactions such as anti-histamines of the Hl and/or H2 and/or H3 and/or H4 receptor types, in particular Hl antagonists or inverse agonists (e.g. azelastine, alimemazine, acrivastine, buclizine, brompheniramine, bromazine, cinnarizine, chlorphenamine, cetrizine, carbinoxamine, clemastine, cyclizine, cyproheptadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, dimenhyrinate, dimetindene, diphenhydramine, ebastine, embramine, doxylamine, fexofenadine, hydroxyzine, ketotifen, levocabastine, levocetrizine, levomepromazine, loratadine, maprotiline, meclizine, olopatadine, orphenadrine, phenindamine, pheniramine, phenyltoloxamine, promethazine, mepyramine, rupatadine, tripelenamine, triprolidine) or H2 antagonists or inverse agonists (cimetidine, famotidine, lafutidine, nizatidine, ranitidine, roxatidine, tiotidine), and histidine decarboxylase inhibitors (e.g. tritoqualine, catechin).
7) Treatments against sleeping disturbance such as melatonin receptor modulators, in particular melatonin receptors 1 and 2 agonists (e.g. melatonin), GABA receptor modulators, in particular GABAA receptor agonists (e.g. benzodiazepine), Hl receptor modulators in particular Hl antagonists or inverse agonists (e.g. diphenhydramine), and orexin antagonists, in particular antagonists of orexin receptors 1 and/or 2 (e.g. daridorexant, lemborexant, suvorexant, seltorexant, vornorexant).
8) Treatments against mood alteration or depression such as reuptake inhibitors of serotonin (SRIs) or norepinephrine (NRIs) or dopamine (DRIs) (e.g. desvenlafaxine, duloxetine, levomilnacipran, milnacipran, sibutramine, tramadol, velafaxine), monoamine oxidase inhibitors (MAO), in particular inhibitors of MAO-A and/or MAO-B (e.g. iproniazid, isocarboxazid, hydracarbazine, phenelzine, tranylcypromine, bifemelane, methylthioninium chloride, moclobemide, prilindole, rasagiline, selegiline, safinamide), and N-methyl-D-aspartate (NMDA) receptor antagonists (e.g. phencyclidine, ketamine, dextromethorphan).
9) Treatments against rash and other skin conditions such as glucocorticoids (e.g. hydrocortisone, dexamethasone, betamethasone, prednisone, prednisolone, methylprednisolone, triamcinolone, triamcinolone acetonide, triamcinolone hexacetonide, mometasone furoate, clobetasol propionate, deflazacort, budesonide), cyclooxygenase modulators and other NSAIDs, in particular inhibitors of COX-1 and COX-2 (e.g. paracetamol, aspirin, ibuprofen), and topical application of derivatives of vitamin B5 (e.g. panthenol).
10) Treatments against anemia such as erythropoiesis-stimulating agents (e.g. erythropoietin), iron preparations as infusion or food additive, and blood transfusion.
11) Treatments against thrombocytopenia such as blood or platelet transfusion, glucocorticoids (e.g. prednisone, dexamethasone), and thrombopoietin receptor agonists (e.g. avatrombopaq, eltrombopaq).
12) Treatments against neutropenia such as with granulocyte -colony stimulating factor (e.g. filgrastim), CXCR4 antagonists (e.g. plerixafor, mavorixafor, motixafortide), administration of intravenous immunoglobulins, and febrile neutropenia such as with antibiotics.
13) Treatments against pathogen-related infections such as antibiotics, in particular compounds targeting the bacterial cell wall (e.g. penicillins, cephalosporins), the cell wall (e.g. polymyxins), bacterial enzymes (e.g. rifamycins, quinolones, sulfonamides), bacterial protein biosynthesis (e.g. macrolides, lincosamides, tetracyclines, aminoglycosides), and anti-fungal drugs, in particular antimycotics of the polyene (e.g. natamycin), azole (e.g. clotrimazole, itraconazole), allylamines (e.g. terbinafine), and echinocandins (e.g. caspofungin) classes.
14) Treatments against fever such as antipyretics including cyclooxygenase modulators and other NSAIDs, in particular inhibitors of COX-1 and COX-2 (e.g. paracetamol, aspirin, ibuprofen).
15) Treatments against hypertension such as diuretics (e.g. amiloride, triamterene, spironolactone, eplerenone, indapamide, chlortalidone, metolazone, xipamide, dopamine, epitizide, chlorothiazide, hydrochlorothiazide, bendroflumethiazide, methylclothiazide, polythiazide, torasemide, furosemide, bumetanide, etacrynic acid), calcium channel blockers (e.g. amlodipine, nitrendipine, nisoldipine, barnidipine, cilnidipine, clevidipine, felodipine, isradipine, lercanidipine, levamlodipine, nicardipine, nifedipine, nimodipine, verapamil, diltiazem), inhibitors of the angiotensin-converting enzyme (e.g. benazepril, ramipril, trandolapril, quinapril, perindopril, moexipril, lisinopril, fosinopril, enalapril, captopril), renin inhibitors (e.g. remikiren, aliskiren), vasodilators (e.g. sodium nitroprusside, hydralazine), aldosterone receptor antagonists (e.g. spironolactone, eplerenone); alpha-2 adrenergic receptor agonists (e.g. clonidine), endothelium receptor blockers (e.g. bosentan), adrenergic receptor antagonists, in particular beta blockers (e.g. atenolol, metoprolol, acebutolol, bisoprolol, nadolol, propranolol), alpha blockers (e.g. prazosin, terazosin) and mixed alpha and beta blockers (e.g. carvedilol), and angiotensin II receptor antagonists (e.g. azilsartan, candesartan, eprosartan, ibesartan, fimasartan, valsartan, olmesartan, telmisartan).
16) Treatments against arrhytmia such as nondihydropyridine calcium channel blockers (e.g. verapamil, diltiazem), sodium channel blockers (e.g. disopyramide, flecainide, mexiletine, propafenone, quinidine), potassium channel blockers (e.g. amiodarone, bretylium, dofetilide, dronedarone, ibutilide, sotalol), adrenergic receptor antagonists, in particular beta blockers (e.g. atenolol, metoprolol, acebutolol, bisoprolol, nadolol, propranolol), and other antiarrhytmetics such as adenosine and digoxin.
Pharmacologically or therapeutically active agents and/or non-agent-based therapeutic interventions that can be used for a combination therapy as indicated above together with one or more compounds of the invention particularly include said agents and interventions suitable for treatments of the same disorders as mentioned for the compounds of the present invention, in particular agents and interventions suitable for the treatment of benign or malignant hyperproliferative disorders including hyperplasia, neoplasia, cancer, precancerous lesions and metastasis. The respective agents and interventions can be antiproliferative agents, cytostatic agents, anticancer agents, chemotherapeutic agents, targeted therapy agents, cellular signaling pathway modulators, cancer immunotherapy agents, cell therapy, surgery, radiopharmaceutical agents, radiotherapy, thermotherapy, dietary therapy, and others including but not limited to
1) Antimetabolites such as nucleobase analogues, nucleoside analogues, and nucleotide analogues of the purine type analogues (e.g. fludarabine or fludarabine phosphate, cladribine, pentostatin, nelarabine, clofarabine, and thiopurines like mercaptopurine, azathioprine, thioguanine) and the pyrimidine type analogues (e.g. 5 -fluorouracil, tegafur, gemcitabine, cytarabine, liposomal cytarabine, azacitidine, decitabine, carmofur, floxuridine, capecitabine, doxifluridine, floxurinide), hydroxyurea, and antifolates (e.g. methotrexate, pemetrexed, pralatrexate, raltitrexed, aminopterin, trimetrexate). Treatment with antifolates can additionally be combined with treatments of folic acid (e.g. leucovorin) as antidote to rescue overdose or improve tolerability if needed.
2) DNA replication and transcription inhibitors such as topoisomerase I and II inhibitors, and DNA intercalators e.g. irinotecan, topotecan, belotecan, teniposide, etoposide, etoposide phosphate, mitoxantrone, amsacrine, antibody-drug conjugates of govitecan and deruxtecan such as sacituzumab govitecan and trastuzumab deruxtecan, and anthracyclines e.g. doxorubicin, liposomal doxorubicin, epirubicin, valrubicin, idarubicin, daunorubicin, liposomal daunorubicin, sabarubicin, and others e.g. dactinomycin, bleomycin, mitomycin C, plicamycin.
3) DNA crosslinking agents, alkylating agents such as monoalkylating and dialkylating agents, and DNA damage inducers, such as platinum-based drugs e.g. cisplatin, oxaliplatin, carboplatin, nedaplatin, heptaplatin, lobaplatin, satraplatin, and nitrogen mustards and their derivatives e.g. mechlorethamine or chlormethin, cyclophosphamide, melphalan, bendamustine, ifosfamide, chlorambucil, estramustine or estramustine phosphate, uramustine, and nitrosoureas e.g. aranose, carmustine, chlorozotocin, nimustine, lomustine, fotemustine, ranimustine, semustine, streptozotocin, and alkyl sulfonates e.g. busulfan, and others e.g. temozolomide, procarbazine, dacarbazine, altretamine, and thiotepa. 4) Antimitotic agents such as microtubule stabilizers (e.g. ixabepilone) including diterpenoids like taxanes (e.g. docetaxel, paclitaxel, nab-paclitaxel, cabazitaxel), and microtubule inhibitors like vinca alkaloids (e.g. vinblastine, vindesine, vinorelbine, vincristine).
5) Cell cycle inhibitors such as inhibitors of cyclin-dependent kinases (CDKs), in particular inhibitors of CDK4/CDK6 (e.g. ribociclib, trilaciclib, abemaciclib, palbociclib), CDK9 (e.g. zotiraciclib), CDK7 (e.g. SY-5609), and pan-CDK inhibitors (e.g. dinaciclib, seliciclib, alvocidib, riviciclib, roniciclib, voruciclib, purvalanol A and B, olomoucine).
6) Proteasome inhibitors (e.g. bortezomib, ixazomib, carfilzomib, disulfiram, oprozomib, betahydroxy beta-methylbutyric acid) and drugs modulating the ubiquitin system (e.g. thalidomide, lenalidomide, pomalidomide).
7) Hormone signaling modulators, i.e. hormone signaling agonists and antagonists, such as estrogen signaling modulators like antiestrogens, selective estrogen receptor modulators (SERMs) and selective estrogen receptor degrader (SERD) (e.g. raloxifene, tamoxifen, lasofoxifene, toremifene, afimoxifene, anordrin, bazedoxifene, broparestrol, clomifene, cyclofenil, lasofoxifene, ormeloxifene, ospemifene, fulvestrant, brilanestrant, elacestrant), progesterone signaling modulators like antiprogestogens and selective progesterone receptor modulators (SPRMs) (e.g. mifepristone, ulipristal acetate, aglepristone), androgen signaling modulators like antiandrogens, androgen receptor (AR) antagonists, selective androgen receptor degrader (SARD), androgen synthesis inhibitors (e.g. bicalutamide, flutamide, abiraterone acetate, allylestrenol, apalutamide, chlormadinone acetate, cyproterone acetate, delmadinone acetate, enzalutamide, gestonorone caproate, ketokonazole, hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate, nilutamide, osaterone acetate, oxendolone, spironolactone, topilutamide), 5a-reductase inhibitors (e.g. finasteride, dutasteride), aromatase inhibitors (e.g. anastrozole, letrozole, exemestane, aminoglutethimide, testolactone, vorozole, fadrozole, 1, 4, 6-androstatriene-3, 17-dione and 4-androstene-3, 6, 17-trione), and gonatropin- releasing hormone (GnRH) agonists, GnRH antagonists and antigonatropins (e.g. leuprorelin, buserelin, triptorelin, fertirelin, goserelin, peforelin, nafarelin, deslorelin, gonadorelin, histrelin, lecirelin, abarelix, cetrorelix degarelix, ganirelix, elagolix, linzagolix, relugolix, estradiol, estradiol esters, estradiol valerate, estradiol undecylate, polyestradiol phosphate, ethinyl estradiol, stilbestrols like bifluranol).
8) Nuclear receptor signaling modulators i.e. agonists and antagonists, such as retinoic acid receptor (RAR) and retinoid X receptor (RXR) signaling modulators including retinoids (e.g. retinol, tretinoin, isotretinoin, alitretinoin, bexarotene, tazarotene, acitretin, adapalene, etretinate, trifarotene), and Vitamin D receptor (VDR) signaling modulators (e.g. calcitriol, calcipotriol).
9) Angiogenesis inhibitors such as vascular endothelial growth factor (VEGF) binders, in particular therapeutic antibodies binding to VEGF (e.g. bevacizumab, ranibizumab, ziv- aflibercept), VEGF receptor (VEGFR) binders, in particular VEGFR2 binders (e.g. ramucirumab), inhibitors of angiogenesis-related kinases including VEGFR2 and others (e.g. sorafenib, sunitinib, apatinib, nintedanib, regorafenib, cabozantinib, prazopanib, lenvatinib, vandetanib, axitinib, pazopanib, tivozanib), and compounds inhibiting the proliferation or migration of endothelial cells including precursor cells (e.g. thalidomide).
10) Kinase modulators, i.e. inhibitors or activators, such as modulators of one or several of the following kinases, in particular of Src (e.g dasatinib, bosutinib), polo-like kinase 1 (Plk-1) (e.g. volasertib, onvansertib, rigosertib), Fit- 3 (e.g. gilteritinib, quizartinib), Myc (e.g. ML327, MYCi361), c-Met (e.g. cabozantinib), c-Kit (e.g. regorafenib, dovitinib), WEE1 (e.g. adavosertib), FAK (e.g. PF-562271, NVP-TAE226), anaplastic lymphoma kinase (ALK) including ALK inhibitors (e.g. crizotinib, entrectinib), Bruton tyrosin kinase (BTK) including BTK inhibitors (e.g. ibrutinib), Aurora kinase (e.g. tozasertib, ZM447439, hesperadin) and casein kinases (e.g. silmitasertib, DMAT); and cell growth signaling pathway modulators, i.e. inhibitors or activators, such as modulators of the signaling pathways Ras-Raf-MEK-MAPK, K-Ras inhibitors (e.g. adagrasib), B- Raf inhibitors (e.g. vemurafenib, dabrafenib, PLX-4720) and MEK inhibitors (e.g. trametinib, binimetinib, cobimetinib, selumetinib), Wnt/beta catenin/tankyrase (NVP-XAV939, foscenvivint), PI3K/AKT/mT0R including mammalian target of rapamycin (mTOR) inhibitors (e.g. everolimus, temsirolimus, sirolimus, protein-bound sirolimus), PDGFR (e.g. sorafenib, sunitinib, ponatinib, axitinib, foretinib), FGFR1 (e.g pemigatinib), IGF-1R and insulin receptor (e.g. lisitinib, ceritinib, brigatinib), EGFR (e.g. erlotinib, afatinib, osimertinib, gefitinib, mobocertinib, vandetanib, cetuximab, panitumumab, necitumumab), Her2 (e.g. neratinib, tucatinib, dacomitinib, margetuximab, lapatinib, trastuzumab, ado-trastuzumab emtansine, famtrastuzumab deruxtecan, pertuzumab, hyaluronidase/ trastuzumab, hyaluronidase/pertuzumab/trastuzumab), Hedgehog/Smoothened (SMO) including SMO inhibitors (e.g. vismodegib, sonidegib), Notch including Notch inhibitors and enhancers, NK1- receptor (e.g. casopitant, maropitant, rolapitant), spingosine-1 -receptors S1PR (e.g. fingolimod, ozanimod, siponimod, ponesimod), CSF-1R, TGF-beta/Smad, JAK/STAT including JAK inhibitors (e.g. ruxolitinib, oclacitinib, tofacitinib, fedratinib, filgotinib, peficitinib, baricitinib, upadacitinib, pacritinib, abrocitinib) and STAT inhibitors such as STAT3 inhibitors (e.g. OPB-51602, YY201, WB737), and BCR-ABL tyrosine kinase inhibitors (e.g. nilotinib, dasatinib, imatinib, bosutinib, ponatinib, asciminib) and others (e.g. ingenol mebutate).
11) Glycolysis inhibitors such as inhibitors of glycolytic or glycolysis-promoting enzymes including hexokinase inhibitors (e.g. lonidamine, 3 -bromopyruvate) and others (e.g. 3PO, dichloroacetate), antimetabolites (e.g. 2 -deoxy-D-glucose (2-DG), and glucose uptake or transport inhibitors (e.g. WZB117, STF31, quercetin, phloretin, BAY-876).
12) Histone deacetylase (HDAC) inhibitors (e.g. vorinostat, romidepsin, panobinostat, belinostat, chidamide, ricolinostat, valproate).
13) Binders of the bromodomains of bromodomain and extra-terminal motif (BET) proteins, e.g. molibresib, BI894999, or JQ1.
14) Enzymes such as digestive enzymes (e.g. L-asparaginase and modified analogs like pegaspargase).
15) Cancer immunotherapies such as immune checkpoint inhibitors including monoclonal antibodies against PD1, PD-L1, SLAMF7, CD20 and CTLA-4 (e.g., ipilimumab, atezolizumab, ofatumumab, rituximab, elotuzumab, nivolumab and pembrolizumab), immunomodulators (e.g. imiquimod) such as sphingosine- 1 -phosphate receptor modulators and modulators of the calcineurin-phosphatase pathway, and antibody-dependent cell-mediated cytotoxicity (ADCC) inducing antibodies (e.g. alemtuzumab), cancer vaccines (e.g. sipuleucel-T, rocapuldencel-T, CMN-001, Bacillus Calmette-Guerin (BCG vaccine), nadofaragene firadonevec, talimogene laherparepvec), cytokine therapy (e.g. IFN-a, IFN-y, and IL-2), and adoptive cellular therapy, such as chimeric antigen receptor (CAR) T cell therapy (e.g. tisagenlecleucel, axicabtagene ciloleucel, brexucabtagene autoleucel, lisocabtagene maraleucel, idecabtagene vicleucel, ciltacabtagene autoleucel), chimeric antigen receptor (CAR) natural killer cell therapy (e.g. SNK02, CYNK-001), tumor-infiltrating lymphocytes.
16) Inhibitors of antiapoptotic proteins such as BH3 mimetics including inhibitors of Bcl-2, Bcl- xL and Mcl-1 (e.g. navitoclax, venetoclax).
17) Antiviral agents such as reverse transcriptase inhibitors and viral DNA polymerase inhibitors (e.g. zidovudine, lamivudine, emtricitabine, entecavir, aciclovir, ganciclovir). 18) Agents for treating lytic or blastic bone lesions such as bisphosphonates (e.g. zoledronate, alendronate, risedronate, pamidronate).
19) HMG-CoA reductase inhibitors such as statins (e.g. cerivastain, fluvastatin, lovastatin, atorvastatin, mevastatin, pitavastatin, simvastatin, pravastatin, rosuvastatin), farnesyltransferase inhibitors, geranyl geranyl transferase inhibitors, and compounds involved in the regulation of fatty acid and lipid metabolism such as fatty acid synthetase inhibitors.
20) Mitochondrial inhibitors such as OXPHOS inhibitors other than related to the compounds of this invention (e.g. metformin, phenformin, IM156, EVT-701, IACS-010759, lonidamine, atovaquone, Neoantimycin F, Oligomycin A, AG311, ASP4132, BAY87-2243, DX3-213b, EVP4593, EVT-701, FRV-1, HP661, mubritinib, SCAL-255, SCAL-266, SMIP004-7, piericidin A, YK-135, ME- 344), mitochondrial uncouplers (e.g. Baml5, FR58Pla), ClpP agonists (e.g. ONC2 01), and mitochondria-targeting compounds (e.g. Mito-Py, Mito-NPH).
21) Therapeutics or treatments that induce OXPHOS dependency and/or lead to a synthetic lethal effect in the target cells when combined with any compound of the invention such as inhibitors of ENO1, GAPDH, GPI, HK1, PKM, SLC2 A1, SLC2 A3 TPI1, ALDOA, ALDOB, ALDOC, BPGM, ENO2 , ENO3, GAPDHS, GCK, HK2, HK3, PFKL, PFKM, PFKP, PGAM2, PGAM5,PGK1, PGK2, PKLR, SLC2 A2, SLC2 A4, SLC2 A5, SLC2 A6, SLC2 A8, SLC2 A9, SLC2 A1O, SLC2 A11, SLC2 A12, SLC2 A13, PGD, PHGDH, LKB1, IDH1, and components of the SWI/SNF complex including SMARCA4 and ARID1A.
22) Inhibitors of cellular DNA damage repair systems such as poly (ADP-ribose) polymerase (PARP) inhibitors (e.g. olaparib, niraparib, talazoparib, rucaparib).
23) RNA-based therapeutics or treatments such as mRNA vaccines, antisense RNA, RNA interference (e.g. small interfering RNA, micro RNAs), and RNA aptamers (e.g. pegaptanib, NOX- A12).
24) Antibody-drug conjugates (e.g. gemtuzumab ozogamicin, brentuximab vedotin, tisotumab vedotin-tftv, loncastuximab tesirine, moxetumomab pasudotox, belantamab mafodotin, sacituzumab govitecan, trastuzumab deruxtecan, enfortumab vedotin, polatuzumab vedotin, inotuzumab ozogamicin and trastuzumab emtansine).
25) LDH inhibitors (e.g. GSK2837808A, FX-11, CHK-336, GNE-14O, AZ-33)
26) MCT inhibitors (e.g. AZD3965, AZD0095, BAY-8002, VB124, Syrosingopine, AR-C1 55858, MSC-4381)
27) Glutaminolysis inhibitors (e.g. CB-839, BPTES, JHU-083, IPN6009O, L-DON)
28) Fatty acid oxidation (FAO) inhibitors (e.g. etomoxir, teglicar, STI 326)
29) TCA cycle inhibitors including PDH-KGDH inhibitors (e.g. CPI-613), malate dehydrogenase inibitors (e.g. LW1497), and IDH inhibitors (e.g. ivosidenib, enasidenib, vorasidenib, olutasidenib, BAY1436032, IDH3 05, Novartis-53O, AGI-6780)
30) Compounds inducing reactive oxygen species (ROS) or oxidative stress, or targeting cellular antioxidant systems (e.g. ubidecarenone, BPM3151O, PT-112, buthionine sulfoximine, ATN-224)
31) Mitophagy inhibitors (e.g. Mdivi-1, dynasore) and inhibitors of mitochondrial dynamics and trafficking (e.g. Pl 10)
32) NAMPT inhibitors (e.g A4276, FK866, CHS828, OT-82) 33) Dihydroorotate dehydrogenase inhibitors (e.g. BAY2402234, MEDS433)
34) Radiotherapies such as external beam radiation therapy or teletherapy (e.g. X-ray therapy, particle therapy including proton therapy, Auger therapy), brachytherapy, systemic radionuclide therapy, neutron capture therapy (e.g. boron-neutron capture therapy), treatment with radiopharmaceuticals.
Any pharmacologically or therapeutically active agent mentioned in the present invention targeting proteins or protein complexes including enzymes can be directed against the wild type form or any mutated form of the according target protein or target protein complex.
For a combination therapy, the active ingredients may be formulated as compositions containing several active ingredients in a single dose form and/or as kits containing individual active ingredients in separate dose forms. The active ingredients used in combination therapy may be co-administered or administered separately.
The compounds of the invention or any of their combinations with one or more pharmacologically or therapeutically active agent can also or in addition be combined with one or more non-agent-based therapeutic interventions.
The term "non-agent-based therapeutic intervention” as used herein relates to any form of intervention that is not based on a molecular i.e. a chemical or biological agent. This includes surgery, radiotherapy including, external beam radiation therapy or teletherapy (e.g. X-ray therapy, particle therapy including proton therapy, Auger therapy), brachytherapy and systemic radioisotope therapy, neutron capture therapy, thermotherapy such as hyperthermia therapy, cryotherapy, electrodessication, abrasion therapy, photodynamic therapy, laser therapy, physical therapy, medical nutrition therapy or dietary therapy including defined food supplementation, removal of specific nutrients, energy or macronutrient restriction and intermittent fasting, supportive therapy including hemodialysis, and occupational therapy.
The compounds of the invention may be administered as antibody-drug conjugates.
The compounds of the invention may be covalently linked to a mitochondria-targeting moiety such as lipophilic cations (e.g. alkyltriphenylphosphonium cations, rhodamine, cyanine cations, and cationic peptides).
Chemical Synthesis
Abbreviations
Ac Acetyl
ACN Acetonitrile aq Aqueous
Bn Benzyl
Bu Butyl
DCE 1,2-dichloroethane
DCM Dichloromethane
DIBAL-H Diisobutylaluminium hydride DMF N,N-dimethylformamide
DMSO Dimethyl sulfoxide equiv equivalent
ESI Electron Spray Ionization
Et Ethyl
Me Methyl
PE Petroleum Ether
PTSA p-Toluenesulfonic acid sat Saturated
TBAF Tetrabutylammonium Fluoride
TFA Trifluoroacetic acid
THF Tetrahydrofuran
TLC Thin Layer Chromatography
UV Ultraviolet
General considerations
The compounds listed in Table 50 have been identified by TLC using pre-coated silica TLC sheets and common organic solvents such as petroleum ether, ethyl acetate, dichloromethane, methanol, triethylamine or acetic acids as eluent, preferably as binary or tertiary solvent mixtures thereof, UV light at a wavelength of 254 or 366 nm, and/or common staining solutions such as phosphomolybdic acid, potassium permanganate, or ninhydrin.
All solvents used for chemical reactions are used dry.
The compounds listed in Table 50 have furthermore been identified by mass spectrometry using formic acid in the mobile phase for detection of positive ions, while no additive was used for negative ions. Ammonium Carbonate was used for negative ions if the molecule was difficult to ionize. Representative compounds have also been identified by nuclear magnetic resonance spectroscopy. Chemical shifts (δ) were reported in parts per million (ppm) relative to residual solvent peaks rounded to the nearest 0.01 ppm for proton and 0.1 ppm for carbon (ref: CHC] [1H : 7.26 ppm, 13C: 77.2 ppm], DMSO [1H: 2.50 ppm, 13C: 39.5 ppm]). Coupling constants (/) were reported in Hz to the nearest 0.1 Hz. Peak multiplicity was indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), hept (heptet), m (multiplet), and br (broad).
Synthesis of described compounds
The aforementioned compounds of the invention falling under the scope of general formula (I) can be synthesized and purified by those persons skilled in the art and are preferably synthesized according to the general procedures (A to PP), or combinations thereof, mentioned herein as illustrated below. In some cases, often when X = N, the order of steps C, D, E was changed to E, C, D. Minor variations of functional groups that do not impact the general procedures are not explicitly described but can be reached in similar fashions.
A) To the corresponding 2,4-disubstituted phenol (1.0-1.5 equiv) and 4-ethyl ester halo(hetero)aryl (1.0 equiv), dissolved in DMSO (0.5 M) under argon and stirring, was added K2CO3 (1.5 equiv) and the mixture was heated between 80 ºC and 160 ºC until full conversion. The mixture was allowed to return to room temperature and was partitioned between an organic solvent, preferably PE and water. The aqueous layer was extracted twice more and the combined organic phases were then washed with NaOH (aq, 2 M) followed by Brine, dried over Na2SO4 , filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2 , gradient PE/AcOEt or DCM/MeOH) to yield the desired bis(hetero)aryl ether ethyl ester.
B) To the corresponding 2,4-disubstituted phenol (1.0 equiv) and 4-ethyl ester bromo(hetero)aryl (1.0 equiv) dissolved in DMSO (0.2 M) under argon and stirring was added picolinic acid (0.4 equiv), K3PO4 (1.3 equiv) and C11i (0.2 equiv). The mixture was heated between 80 ºC and 120 ºC until full completion of the reaction. The mixture was allowed to return to room temperature and was partitioned between an organic solvent, preferably PE and water. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2 , gradient PE /AcOEtor DCM/MeOH) to yield the desired bis (hetero) aryl ether ethyl ester.
C) To the corresponding ester (1.0 equiv) in THF (0.5M) was added an aqueous solution of NaOH (1-2M, 2 equiv). Ethanol was added until the mixture turned homogeneous. The mixture was then stirred at room temperature or at 60 ºC until full completion. The mixture was partitioned between an organic solvent, preferably AcOEt and aqueous HC1 1 M. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient PE/AcOEt or DCM/MeOH) to yield the desired bis(hetero)aryl ether carboxylic acid.
D) To the corresponding carboxylic acid (1.0 equiv) in a polar aprotic solvent, preferably DCM or DMF (0.2M) was added l-Ethyl-3-(3-dimethylaminopropyl)carbodiimine hydrochloride (1.5 equiv), 1 -hydroxybenzotriazole hydrate (1.5 equiv), triethylamine (10 equiv) and the desired amine (1.5 equiv). The reaction mixture was stirred at room temperature until full completion. The mixture was partitioned between an organic solvent, preferably AcOEt and water. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2SO4 , filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2 , gradient PE/AcOEt or DCM/MeOH; or C18, gradient H2O/ACN) to yield the desired bis (hetero) aryl ether amide.
E) To the corresponding aldehyde (1.0 equiv) in DCM (0.2M) was added NaBEU (2 equiv). Few drops of MeOH were added to activate the reaction and the mixture was stirred at room temperature until full completion. The mixture was partitioned between an organic solvent, preferably AcOEt and water. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient PE/AcOEt or DCM/MeOH; or C18, gradient H2O/ACN) to yield the desired bis (hetero) aryl ether amide.
F) To the corresponding alcohol (1.0 equiv) in a polar aprotic solvent, preferably DCM or DMF (0.2) was added trialkylsilyl chloride, preferably tert-butyl-dimethylsilyl chloride (1.2 equiv), imidazole (1.3 equiv) and 4-dimethylaminopyridine (0.1 equiv). The reaction mixture was stirred at room temperature until full completion. The mixture was partitioned between an organic solvent, preferably AcOEt and water. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient PE/AcOEt or DCM/MeOH) to yield the desired protected benzylic alcohol.
G) To the corresponding silyl-protected benzyl alcohol (1.0 equiv) in THF (0.2M) was added TBAF (1 M in THF, 2 equiv) and the mixture was stirred at room temperature until full completion. The mixture was partitioned between an organic solvent, preferably AcOEt and water. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient PE/AcOEt or DCM/MeOH; or C18, gradient H2O/ACN) to yield the desired free benzylic alcohol.
H) To a solution of 4-(4-hydroxyphenyl)cyclohexanone (1.0 equiv) in toluene (0.2 M) was added ethylene glycol (1.1 equiv) and TsOH hydrate (0.05 equiv). The reaction was refluxed with a Dean-Stark until full completion. The reaction mixture was cooled down to room temperature. Crystals were filtered off and washed with cold toluene. The combined Mother liquors were concentrated under vacuum, recrystallized in toluene and combined with the first crop to yield the desired ketal.
I) To a solution of 4-(4-hydroxyphenyl)cyclohexanone (1.0 equiv) in DCM (0.2 M) was added 1,2-Ethandithiol (1.1 equiv) and Hafnium triflate (0.05 equiv). The reaction was stirred at room temperature until full completion. The reaction mixture was partitioned between an organic solvent, preferably DCM and aqueous saturated NaHCO3. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2SO4 , filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2 , gradient PE/AcOEt) to yield the desired dithioketal.
J) To MgCD (2 equiv) and paraformaldehyde (3 equiv) in dry THF (0.2 M) under argon was added triethylamine (2 equiv). The mixture was stirred at room temperature for 15 minutes. A solution of the corresponding 4-substituted phenol (1.0 equiv) in THF (2.5 M) was then added and the mixture was stirred at reflux until full completion. The mixture was allowed to return to room temperature and was partitioned between an organic solvent, preferably EA and aqueous HC1 IM. The aqueous layer was extracted twice more and the combined organic phases were then washed with water followed by Brine, dried over Na2SO4 , filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2 , gradient PE/AcOEt) to yield the desired o-formyl phenol.
K) To a solution of the desired phenol (1 equiv) in 1,4-Dioxane (0.2 M) at 0 ºC was added NaH (1.3 equiv) portionwise. After 30 min, chloro(methoxy)methane (1.5 equiv) was added and the reaction was stirred at room temperature until full completion. The mixture was partitioned between an organic solvent, preferably EA and aqueous 2 M NaOH. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2SO4 , filtered and concentrated under vacuum. The desired protected phenol was clean enough to be used in the next step without further purifications.
L) To a suspension of 4-[4-(methoxymethoxy)phenyl]cyclohexanone (1.0 equiv) and methoxymethyl(triphenyl)phosphonium bromide (2 equiv) in dry THF (0.2 M) was added dry DMSO dropwise until the suspension fully dissolve. The reaction mixture was cooled down to 0 ºC and LiHMDS (1 M solution in THF, 1.8 equiv) was added dropwise. The reaction mixture was warmed up to room temperature and stirred until full completion. The mixture was partitioned between an organic solvent, preferably PE and water. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2SO4 , filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2 , gradient PE/AcOEt) to yield the desired product.
M) To a solution of l-(methoxymethoxy)-4-[4-(methoxymethylene)cyclohexyl]benzene (1.0 equiv) in 1,4-Dioxane was added concentrated hydrochloric acid (~12 M, 1.1 equiv) and the mixture was stirred for 3 h at room temperature. The reaction was diluted with water and extracted with EtOAc. Tthe combined organic phases were then washed with Brine, dried over Na2SO4 , filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiOs, gradient PE/AcOEt) to yield the desired product.
N) To a solution of the aldehyde (1.0 equiv) in a 1:1 MeOH/THF Mix (0.2 M) was added formalin solution (37 %, 3.0 equiv) followed by aqueous NaOH (5 M, 1.3 equiv) dropwise. The reaction mixture was stirred until full completion. The mixture was partitioned between an organic solvent, preferably AcOEt and water. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2SO4 , filtered and concentrated under vacuum. The crude residue was dissolved in a minimum amount of 2 : 1 MeOH /THF Mix. The solution was added dropwise to a vigorously stirring aqueous NaCl solution (3 M). The suspension was filtered off and the solid was washed with water and PE, dried under vacuum to yield the desired diol.
O) To a solution of the diol (1.0 equiv) in THF (0.2 M) was added NaH (2.2 equiv) and the mixture was stirred 30 min before Mel (2.4 equiv) was added. The reaction mixture was stirred at 60 ºC until full completion. The mixture was partitioned between an organic solvent, preferably AcOEt and aqueous 1 M HC1. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2SO4, filtered and concentrated under vacuum. The desired dimethylated product was clean enough to be used in the next step without further purifications.
P) To a solution of the diol (1.0 equiv) in acetone (0.2 M) was added para-toluenesulfonic acid monohydrate (0.1 equiv) and activated 3 A molecular sieve. The suspention was stirred at 50 ºC until full completion. The mixture was filtered and partitioned between an organic solvent, preferably AcOEt and aqueous saturated NaHCOs. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2SO4, filtered and concentrated under vacuum. The desired acetal product was clean enough to be used in the next step without further purifications.
Q) To a solution of the MOM protected phenol (1.0 equiv) in 1,4-dioxane (0.2 M. In the case of 9-[4-(methoxymethoxy)phenyl]-3,3-dimethyl-2,4-dioxaspiro[5.5]undecane, acetone was used.) was added concentrated HC1 (~37%, 1-10 equiv) or TFA (1-10 equiv) and the mixture was stirred until full completion at room temperature or 50 ºC. The mixture was partitioned between an organic solvent, preferably AcOEt and aqueous saturated NaHCOs. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2SO4, filtered and concentrated under vacuum. The desired phenol product was clean enough to be used in the next step without further purifications.
R) To a solution of the alcohol (1.0 equiv) in acetic anhydride (0.2 M) was added pyridine (2 equiv) and the reaction mixture was stirred until full completion. The volatiles were removed under vacuum and the mixture was partitioned between an organic solvent, preferably AcOEt and aqueous saturated NaHCOs. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2SO4, filtered and concentrated under vacuum. The desired acetylated alcohol was clean enough to be used in the next step without further purifications.
S) To a solution of the alcohol (1.0 equiv) in THF (0.2 M) was added potassium tert-butoxide or NaH (1.2 equiv) and iodomethane (1.1 equiv). The reaction mixture was stirred until full completion. The reaction mixture was partitioned between an organic solvent, preferably EtOAc and water. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient PE/AcOEt) to yield the desired methylated phenol.
T) To a solution of the desired ethyl ester (1.0 equiv) in THF (0.2 M) at 0 ºC was added dropwise a solution of DIBAL-H (2.2 equiv, 1.2 M in Toluene). The reaction mixture was stirred until full completion. The mixture was then partitioned between an organic solvent, preferably EA and aqueous HC1 IM. The aqueous layer was extracted twice more and the combined organic phases were then washed with water followed by Brine, dried over Na2SO4, filtered and concentrated under vacuum. To the crude oil was added HC10.5 M in Methanol (0.2 M compared to starting ester) and the mixture was stirred until full completion. The reaction mixture was partitioned between an organic solvent, preferably EtOAc and aqueous saturated NaHCO3. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient PE/AcOEt) to yield the desired diol.
U) To a solution of the desired hydroxyalkene (1.0 equiv) in toluene (0.2 M) was added para- toluenesulfonic acid (0.05 equiv) and the reaction mixture was stirred at reflux until full completion. The reaction mixture was partitioned between an organic solvent, preferably EtOAc and aqueous saturated NaHCO3. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2SO4 , filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient DCM/MeOH) to yield the cyclic ether.
V) To a solution of the desired aldehyde (1.0 equiv) in THF (0.2 M) was added potassium tert-butoxide (1.2 equiv) and allyl bromide (1.5 equiv). The reaction mixture was stirred until full completion. The reaction mixture was partitioned between an organic solvent, preferably EtOAc and aqueous 1 M HC1. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient PE/AcOEt) to yield the desired allylated product. W) To a solution of the desired diene (1.0 equiv) in DCE (0.2 M) was added Grubbs II Catalyst (0.015 equiv) and the reaction was stirred until full completion. The mixture was concentrated under vacuum before being partitioned between an organic solvent, preferably PE and aqueous 1 M HC1. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2SO4 , filtered and concentrated under vacuum. The desired cycloalkene was clean enough to be used in the next step without further purifications.
X) To a solution of the desired alkene (1.0 equiv) in EtOAc (0.2 M) was added Pd/C (0.1 equiv) and the reaction atmosphere was replaced by H2 (>1 atm). The reaction mixture was vigorously stirred until full completion. The reaction mixture was filtered through celite and the plug was washed with EtOAc. The filtrate was concentrated under vacuum. The desired cycloalkane was clean enough to be used in the next step without further purifications.
Y) To a solution of the desired methylated alcohol (1.0 equiv) in DCM (0.2 M) at 0 ºC was added BBrs (3 equiv) and the mixture was stirred at room temperature until completion. The reaction mixture was partitioned between an organic solvent, preferably EtOAc and aqueous saturated NaHCOs. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient PE/AcOEt) to yield the desired phenol.
Z) To 4-phenylcyclohexanone (1 equiv) was added slowly sulfuric acid 93-98% (9.8 equiv) and the mixture was cooled to 0 ºC under vigorous stirring. Nitric acid (1.8 equiv) was then added dropwise keeping the temperature under 5 ºC and left at 0 ºC for 5 hours. The reaction was then slowly poured into ice-water and extracted thrice with AcOEt. The combined organic phases were concentrated under vacuum to obtain 4-(4- nitrophenyl)cyclohexanone (>90% pure) which was use as such without further purification.
AA) To a solution of 4-(4-nitrophenyl)cyclohexanone (1.0 equiv) in toluene (0.2 M) was added ethylene glycol (1.1 equiv) and TsOH hydrate (0.05 equiv). The reaction was refluxed with a Dean-Stark until full completion. The reaction mixture was cooled down to room temperature and partitioned between AcOEt and aqueous saturated NaHCOs. The aqueous phases were extracted twice more with AcOEt and the combined organic phases were washed with Brine, dried with Na2SO4 and concentrated under vacuum. The residue (8-(4-nitrophenyl)-l,4-dioxaspiro[4.5]decane, >90% pure) was used as such without further purification.
BB) To 8-(4-nitrophenyl)-l,4-dioxaspiro[4.5]decane (1 equiv) in AcOEt (1 M) was added 5% Pd/C (about 5%-10% w/w) before the atmosphere was swapped for H2 (1 atm). The whole was vigorously stirred till completion before being filtered on celite and concentrated in vacuum. The residue was purified by flash chromatography (Si02, gradient PE/AcOEt) to yield 4-(l,4-dioxaspiro[4.5]decan-8-yl)aniline.
CC) 4-(l,4-dioxaspiro[4.5]decan-8-yl)aniline (1 equiv), potassium tert-butoxide (1.1 equiv), X-Phos (0.2 equiv), Pd(OAc2) (0.1 equiv) and Na2SO4 (2 equiv) were combined and flushed with nitrogen before ethyl bromobenzoate (1.1 equiv) in dioxane-(l,4) (0.2 M) were added and the mixture was heated to 60 ºC overnight. The reaction mixture was cooled down to room temperature and partitioned between AcOEtand aqueous saturated NaHCOs. The aqueous phases were extracted twice more with AcOEt and the organic phases were combined, washed with Brine, dried with Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography (SiO2 , gradient PE/AcOEt) to yield ethyl 4-[4-(l,4-dioxaspiro[4.5]decan-8-yl)anilino]benzoate.
DD) To ethyl 4-[4-(l,4-dioxaspiro[4.5]decan-8-yl)anilino]benzoate (1 equiv) in THF (0.2 M) was added NaH (1.1 equiv) and the mixture was stirred 15 minutes before AcCl (1.2 equiv) was added and the whole was stirred to 80 ºC overnight. The reaction mixture was cooled down to room temperature and partitioned between AcOEtand aqueous saturated NaHCO3. The aqueous phases were extracted twice more with AcOEt and the organic phases were combined, washed with Brine, dried with Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography (SiO2, gradient PE/AcOEt) to yield ethyl 4-[N-acetyl-4-(l,4-dioxaspiro[4.5]decan-8-yl)anilino]benzoate
EE) To ethyl 4-[4-(l,4-dioxaspiro[4.5]decan-8-yl)anilino]benzoate (1 equiv) in THF (0.2 M) at-78ºC was added n-BuLi (1.1 equiv) and the mixture was stirred 30 minutes before Mel (1.1 equiv) was added and the whole left to return slowly to room temperature. The reaction was then partitioned between AcOEt and water. The aqueous phases were extracted twice more with AcOEt and the organic phases were combined, washed with Brine, dried with Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography (SiO2, gradient PE/AcOEt) to yield ethyl 4- [4- (1,4- dioxaspiro[4.5]decan-8-yl)-N-methyl-anilino]benzoate.
FF) To the protected phenol (1 equiv) in dry THF (0.2 M) at 0ºC was added n-Butyllithium (2.5 eq, freshly titrated) and the mixture stirred for 2 h. Trimethyl borate (2 equiv) was then added and the mixture stirred for a further 2 h. A 4 M aqueous solution of NaOH (10 equiv) was then added followed by H2O2 (10 equiv, 35% aq) and the mixture was stirred for a further 2 h. The reaction was then partitioned between AcOEt and aqueous saturated NH4CI. The aqueous phases were extracted twice more with AcOEt and the organic phases were combined, washed with Brine, dried with Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography (SiO2, gradient PE/AcOEt) to yield the corresponding alcohol.
GG) To 4-cyclohexyl-2-methoxy-l-(methoxymethoxy)benzene (1.0 eq) in THF (0.1 M) was added TMEDA (1.2 eq) and the solution was cooled down to 0 ºC before n-Butyllithium (2.5 eq, freshly titrated) was added dropwise. The mixture was stirred for 30min more before dry N,N-Dimethylformamide (5.0 eq) was added. The resulting mixture was then stirred 30 min at 0 ºC and another 30 min at room temperature. The reaction was then partitioned between AcOEt and aqueous saturated NH4CI. The aqueous phases were extracted twice more with AcOEt and the organic phases were combined, washed with Brine, dried with Na2SO4 and concentrated under vacuum. The obtained crude alcohol was used as such without further purification
HH) To the methyl ether (1 equiv) in DCM (0.2M) was added AICI3 (10 equiv) and the reaction was stirred for 1.5 h. Ethane- 1,2 -dithiol (10 equiv) was then added the mixure stirred until full conversion. The reaction was then partitioned between DCM and aq. HC1 (IM). The aqueous phases were extracted twice more with DCM and the organic phases were combined, washed with Brine, dried with Na2SO4 and concentrated under vacuum. The obtained crude alcohol was used as such without further purification. In certain cases the dichlorinated alcohol was obtained as side product.
II) To a solution of secondary amine (1.0 equiv) in an organic solvent, preferably DCE (0.2 M) was added the desired aldehyde (1.0 equiv) and sodium triacetoxyborohydride (1.6 equiv). The mixture was stirred at 20-60 ºC until full completion. The reaction mixture was partitioned between an organic solvent, preferably AcOEt and aqueous saturated NaHCOs. The aqueous phases were extracted twice more and the organic phases were combined, washed with Brine, dried with Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography (SiO2, gradient PE/AcOEt) to yield the desired tertiary amine.
JJ) To a solution of secondary amine (1.0 equiv) in DCM (0.2 M) was added K2CO3 (2 equiv) and aryl (or alkyl) bromide. The mixture was stirred until full completion. The reaction mixture was partitioned between an organic solvent, preferably AcOEt and aqueous saturated NaHCOs. The aqueous phases were extracted twice more and the organic phases were combined, washed with Brine, dried with Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography (SiO2 , gradient PE/AcOEt) to yield the desired tertiary amine.
KK) To a solution of Boc-protected amine (1.0 equiv) in methanol (0.2 M) was added concentrated HC1 until pH < 1. The mixture was stirred at 50 ºC until full completion. The volatiles were removed under vacuum and the crude amine used without further purification.
LL) To a solution of Boc-protected piperazine (1.0 equiv) in DCM (0.2 M) was added triethylamine (1.6 equiv) and benzoyl chloride (1.0 equiv) or arylsulfonyl chloride. The mixture was stirred until full completion. The reaction mixture was partitioned between an organic solvent, preferably AcOEt and aqueous 1 M HC1. The aqueous phases were extracted twice more and the organic phases were combined, washed with Brine, dried with Na2SO4 and concentrated under vacuum and the crude amine used without further purification.
MM) To a solution of the diamine (1.0 equiv) in EtOH (0.2 M) was added dimethyl oxalate (1.0 equiv) and the mixture was stirred at reflux until full completion. The mixture was filtered and the filtrate evaporated under vacuum. The obtained crude product was used as such without further purification
NN) To a solution of the desired oxahydroquinoxaline (1.0 equiv) in THF (0.2 M) was added NaH (1.1 equiv) followed by the desired aryl bromide (1.05 equiv). The mixture was stirred until full completion. The reaction mixture was partitioned between an organic solvent, preferably AcOEt and aqueous saturated NaHCO3. The aqueous phases were extracted twice more and the organic phases were combined, washed with Brine, dried with Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography (SiO2 , gradient PE/AcOEt) to yield the desired tertiary amine.
00) To a solution of the benzylated oxahydroquinoxaline (1.0 equiv) and AICI3 (3 equiv) in THF (0.2 M) at 0 ºC was added LiAlH4 (8 equiv). The mixture was stirred at room temperature until full completion. Aluminium species were crashed using Fieser work-up and the mixture filtered over Na2SO4. The filtrate evaporated under vacuum. The obtained crude product was used as such without further purification PP) Ammonia was condensed onto the ketone (1 equiv) cooled to -78 ºC in a sealed tube so as to have a volume approximatively equating to a 0.2 -0.5 M solution. The tube was closed and the mixture was stirred at room temperature for 5 h before being cooled back down to -78 ºC where freshly purified hydroxylamine-O-sulfonic acid (1.2 equiv) was added. After a further 16 h at room temperature, the tube was slightly opened and the ammonia was left to gently evaporate. Methanol (0.2 M) and NEts (2 equiv) was added to the residue followed dropwise by a solution of h in DCM (minimal volume to dissolve the I2) until the colour held for 30 seconds (about 1.05-1.2 equiv). The reaction was then partitioned between AcOEt and aqueous saturated Na2S20s. The aqueous phases were extracted twice more with AcOEt and the organic phases were combined, washed first with NaHCOsthen Brine, dried with Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography (SiO2, gradient DCM/MeOH) to yield the corresponding diazirine. The corresponding hydroxylamine can be isolated as a side product of this reaction.
The following compounds in Table 50 were synthetized according to the aforementioned protocols and characterized via mass spectrometry.
Table 50:
Compound No. Formula Expected m/z Ion Type m/z [ESI+]
XPM-0001 C31H37N3O4 516.2883 (M+H)+ 516.28
XPM-0004 C32H37N3O5 544.2833 (M+H)+ 544.21
XPM-0005 C30H35N3O3 486.2778 (M+H)+ 486.25
XPM-0006 C32H39N3O5 546.2990 (M+H)+ 546.31
XPM-0007 C34H41N3O4S2 620.2638 (M+H)+ 620.34
XPM-0010 C31H37N3O4 516.2883 (M+H)+ 516.28
XPM-0011 C31H36F5N3O4S 642.2419 (M+H)+ 642.24
XPM-0015 C30H34F5N3O3S 612.2314 (M+H)+ 612.23
XPM-0016 C32H36F3N3O5 600.2706 (M+H)+ 600.42
XPM-0020 C31H34F3N3O4 570.2601 (M+H)+ 570.3
XPM-0021 C32H36F3N3O4 584.2731 (M+H)+ 584.27
XPM-0026 C31H36CIN3O4 550.2494 (M+H)+ 550.27
XPM-0027 C33H38CIN3O3S2 624.2142 (M+H)+ 624.24
XPM-0028 C32H36CIN3O3S2 610.1986 (M+H)+ 610.23
XPM-0030 C30H34CIN3O3 520.2388 (M+H)+ 520.29
XPM-0031 C35H39N3O4 566.3013 (M+H)+ 566.3
XPM-0036 C30H35CIN4O4 551.2446 (M+H)+ 551.27
XPM-0041 C30H35CIN4O4 551.2446 (M+H)+ 551.37
XPM-0046 C34H38N4O4 567.2993 (M+H)+ 567.38
XPM-0062 C34H39N3O4S2 618.2482 (M+H)+ 618.33
XPM-0063 C33H37N3O4S2 604.2298 (M+H)+ 604.23
XPM-0082 C33H36CIN3O3S2 622.1986 (M+H)+ 622.24
XPM-0083 C32H34CIN3O3S2 608.1803 (M+H)+ 608.2
XPM-0111 C32H38N2O4 515.2931 (M+H)+ 515.3
XPM-0113 C33H38N2O3S2 575.2423 (M+H)+ 575.33
XPM-0114 C33H38N2O5 543.2880 (M+H)+ 543.34 Compound No. Formula Expected m/z Ion Type m/z [ESI+]
XPM-0115 C31H36N2O3 485.2825 (M+H)+ 485.35
XPM-0116 C33H40N2O5 545.3037 (M+H)+ 545.3
XPM-0117 C35H42N2O4S2 619.2686 (M+H)+ 619.4
XPM-0118 C34H40N2O4S2 605.2502 (M+H)+ 605.25
XPM-0119 C34H40N2O6 573.2986 (M+H)+ 573.33
XPM-0120 C32H38N2O4 515.2931 (M+H)+ 515.3
XPM-0121 C32H37F5N2O4S 641.2494 (M+H)+ 641.36
XPM-0124 C33H37F5N2O5S 669.2443 (M+H)+ 669.4
XPM-0125 C31H35F5N2O3S 611.2388 (M+H)+ 611.33
XPM-0126 C33H37F3N2O5 635.2494 (M+H)+ 599.27
XPM-0129 C34H37F3N2O6 627.2703 (M+H)+ 627.38
XPM-0130 C32H35F3N2O4 569.2648 (M+H)+ 569.29
XPM-0131 C33H37F3N2O4 583.2778 (M+H)+ 583.28
XPM-0134 C34H37F3N2O5 611.2754 (M+H)+ 611.27
XPM-0136 C32H37CIN2O4 549.2542 (M+H)+ 549.5
XPM-0137 C34H39CIN2O3S2 623.2190 (M+H)+ 623.3
XPM-0138 C33H37CIN2O3S2 609.2007 (M+H)+ 609.2
XPM-0139 C33H37CIN2O5 577.2490 (M+H)+ 577.34
XPM-0140 C31H35CIN2O3 519.2436 (M+H)+ 519.3
XPM-0141 C36H40N2O4 565.3061 (M+H)+ 565.3
XPM-0144 C37H40N2O5 593.3037 (M+H)+ 593.45
XPM-0146 C31H36CIN3O4 550.2467 (M+H)+ 550.25
XPM-0149 C32H36CIN3O5 578.2443 (M+H)+ 578.34
XPM-0151 C31H36CIN3O4 550.2467 (M+H)+ 550.25
XPM-0154 C32H36CIN3O5 578.2443 (M+H)+ 578.3
XPM-0156 C35H39N3O4 566.3013 (M+H)+ 566.3
XPM-0159 C36H39N3O5 594.2990 (M+H)+ 594.29
XPM-0164 C36H39N3O5 594.2990 (M+H)+ 594.25
XPM-0169 C34H40N2O6 573.2986 (M+H)+ 573.33
XPM-0174 C33H37CIN2O5 577.2490 (M+H)+ 577.24
XPM-0179 C33H37CIN2O5 577.2490 (M+H)+ 577.34
XPM-0184 C33H39N3O6 574.2938 (M+H)+ 574.33
XPM-0189 C36H41N3O5 596.3146 (M+H)+ 596.35
XPM-0194 C35H40N2O7 601.2935 (M+H)+ 601.36
XPM-0199 C36H43N3O6 614.3251 (M+H)+ 614.37
XPM-0204 C32H37N3O5 544.2833 (M+H)+ 544.41
XPM-0209 C36H39N3O5 594.2990 (M+H)+ 594.45
XPM-0214 C37H40N2O5 593.3037 (M+H)+ 593.4
XPM-0219 C31H36N2O6 533.2673 (M+H)+ 533.4
XPM-0224 C32H39N3O5 546.2990 (M+H)+ 546.31
XPM-0229 C30H35N3O5S 550.2397 (M+H)+ 550.41
XPM-0234 C31H36N2O5S 549.2444 (M+H)+ 549.41
XPM-0239 C31H36N2O5S 549.2444 (M+H)+ 549.31
XPM-0244 C31H37N3O5 532.2833 (M+H)+ 532.31
XPM-0249 C36H38N2O7 611.2778 (M+H)+ 611.3
XPM-0251 C32H36F3N3O4 584.2758 (M+H)+ 584.3 Compound No. Formula Expected m/z Ion Type m/z [ESI+]
XPM-0254 C33H36F3N3O5 612.2706 (M+H)+ 612.37
XPM-0256 C32H36F3N3O4 584.2731 (M+H)+ 584.27
XPM-0259 C33H36F3N3O5 612.2706 (M+H)+ 612.37
XPM-0264 C35H39N3O5 582.2990 (M+H)+ 582.44
XPM-0269 C35H42N2O7 603.3091 (M+H)+ 603.26
XPM-0279 C33H38N2O6 559.2830 (M+H)+ 559.3
XPM-0284 C33H37N3O7 588.2731 (M+H)+ 588.4
XPM-0289 C35H40N2O7 601.2935 (M+H)+ 601.4
XPM-0294 C36H39N3O5 594.2990 (M+H)+ 594.35
XPM-0299 C34H40N2O7S 621.2656 (M+H)+ 621.4
XPM-0304 C33H39N3O7S 622.2608 (M+H)+ 622.27
XPM-0309 C35H43N3O7S 650.2921 (M+H)+ 650.3
XPM-0314 C35H41N3O6 600.3095 (M+H)+ 600.36
XPM-0316 C34H39F3N2O5 613.2911 (M+H)+ 613.29
XPM-0323 C33H36N2O3S2 573.2267 (M+H)+ 573.23
XPM-0324 C33H36N2O5 541.2724 (M+H)+ 541.23
XPM-0325 C31H34N2O3 483.2669 (M+H)+ 483.45
XPM-0328 C34H38N2O4S2 603.2346 (M+H)+ 603.4
XPM-0329 C34H38N2O6 571.2830 (M+H)+ 571.33
XPM-0330 C32H36N2O4 513.2775 (M+H)+ 513.28
XPM-0331 C32H35F5N2O4S 639.2311 (M+H)+ 639.3
XPM-0334 C33H35F5N2O5S 667.2286 (M+H)+ 667.3
XPM-0336 C33H35F3N2O5 597.2571 (M+H)+ 597.4
XPM-0339 C34H35F3N2O6 625.2547 (M+H)+ 625.28
XPM-0340 C32H33F3N2O4 567.2492 (M+H)+ 567.28
XPM-0344 C34H35F3N2O5 609.2598 (M+H)+ 609.36
XPM-0348 C33H35CIN2O3S2 607.1850 (M+H)+ 607.2
XPM-0349 C33H35CIN2O5 575.2334 (M+H)+ 575.33
XPM-0350 C31H33CIN2O3 517.2279 (M+H)+ 517.38
XPM-0354 C37H38N2O5 591.2880 (M+H)+ 591.45
XPM-0356 C31H34CIN3O4 548.2311 (M+H)+ 548.1
XPM-0359 C32H34CIN3O5 576.2286 (M+H)+ 576.34
XPM-0361 C31H34CIN3O4 548.2311 (M+H)+ 548.3
XPM-0364 C32H34CIN3O5 576.2286 (M+H)+ 576.24
XPM-0369 C36H37N3O5 592.2833 (M+H)+ 592.25
XPM-0394 C33H37N3O6 572.2782 (M+H)+ 572.33
XPM-0399 C36H39N3O5 594.2990 (M+H)+ 594.35
XPM-0404 C35H38N2O7 599.2778 (M+H)+ 599.46
XPM-0409 C36H41N3O6 612.3095 (M+H)+ 612.47
XPM-0414 C32H35N3O5 542.2676 (M+H)+ 542.41
XPM-0419 C36H37N3O5 592.2833 (M+H)+ 592.25
XPM-0429 C31H34N2O6 531.2516 (M+H)+ 531.3
XPM-0434 C32H37N3O5 544.2833 (M+H)+ 544.31
XPM-0439 C30H33N3O5S 548.2241 (M+H)+ 548.21
XPM-0444 C31H34N2O5S 547.2288 (M+H)+ 547.21
XPM-0449 C31H34N2O5S 547.2288 (M+H)+ 547.21 113 Compound No. Formula Expected m/z Ion Type m/z [ESI+] XPM-0459 C36H36N2O7 609.2622 (M+H)+ 609.3 XPM-0464 C33H34F3N3O5 610.2550 (M+H)+ 610.26 XPM-0469 C33H34F3N3O5 610.2550 (M+H)+ 610.26 XPM-0479 C35H40N2O7 601.2935 (M+H)+ 601.46 XPM-0484 C34H38N2O6 571.2830 (M+H)+ 571.33 XPM-0489 C33H36N2O6 557.2673 (M+H)+ 557.4 XPM-0494 C33H35N3O7 586.2574 (M+H)+ 586.3 XPM-0499 C35H38N2O7 599.2778 (M+H)+ 599.4 XPM-0504 C33H37N3O5 556.2833 (M+H)+ 556.2 XPM-0509 C34H38N2O7S 619.2499 (M+H)+ 619.4 XPM-0519 C35H41N3O7S 648.2765 (M+H)+ 648.4 XPM-0526 C34H37F3N2O5 611.2754 (M+H)+ 611.33 XPM-0539 C31H37N3O4 516.2883 (M+H)+ 516.33 XPM-0542 C32H38N2O4 515.2931 (M+H)+ 515.33 XPM-0545 C30H34ClN3O3 520.2388 (M+H)+ 520.34 XPM-0548 C31H35ClN2O3 519.2436 (M+H)+ 519.34 XPM-0561 C34H38N2O5 555.2880 (M+H)+ 555.32 XPM-0564 C34H40N2O5 557.3037 (M+H)+ 557.32 XPM-0567 C34H38N2O5 555.2880 (M+H)+ 555.42 XPM-0570 C34H40N2O5 557.3037 (M+H)+ 557.22 XPM-0573 C33H34N2O6 555.2516 (M+H)+ 555.4 XPM-0576 C33H36N2O6 557.2673 (M+H)+ 557.3 XPM-0579 C33H36N2O7S 605.2343 (M+H)+ 605.36 XPM-0582 C33H38N2O7S 607.2499 (M+H)+ 607.36 XPM-0588 C32H35FN2O7S 611.2222 (M+H)+ 611.22 XPM-0591 C32H34N2O5 527.2567 (M+H)+ 527.2 XPM-0594 C32H36N2O5 529.2724 (M+H)+ 529.3 XPM-0597 C32H34N2O6 543.2516 (M+H)+ 543.1 XPM-0600 C32H36N2O6 545.2673 (M+H)+ 545.3 XPM-0603 C32H33ClN2O5 561.2178 (M+H)+ 561.1 XPM-0606 C32H35ClN2O5 563.2334 (M+H)+ 563.1 XPM-0609 C34H36N2O5 553.2724 (M+H)+ 553.47 XPM-0612 C34H38N2O5 555.2880 (M+H)+ 555.32 XPM-0618 C35H40N2O7S 633.2656 (M+H)+ 633.42 XPM-0624 C35H40N2O5 569.3037 (M+H)+ 569.4 XPM-0627 C35H37ClN2O5 601.2490 (M+H)+ 601.36 XPM-0630 C35H39ClN2O5 603.2647 (M+H)+ 603.3 XPM-0633 C34H36N2O5 553.2724 (M+H)+ 553.3 XPM-0634 C32H34N2O3 495.2669 (M+H)+ 495.46 XPM-0636 C34H38N2O5 555.2880 (M+H)+ 555.3 XPM-0637 C32H36N2O3 497.2825 (M+H)+ 497.29 XPM-0638 C33H38N2O4 527.2931 (M+H)+ 527.41 XPM-0639 C34H35ClN2O5 587.2334 (M+H)+ 587.35 XPM-0640 C32H33ClN2O3 529.2279 (M+H)+ 529.29 XPM-0642 C34H37ClN2O5 589.2490 (M+H)+ 589.35 XPM-0643 C32H35ClN2O3 531.2436 (M+H)+ 531.3 Compound No. Formula Expected m/z Ion Type m/z [ESI+]
XPM-0644 C33H37CIN2O4 561.2542 (M+H)+ 561.3
XPM-0645 C35H38N2O6 583.2830 (M+H)+ 583.34
XPM-0648 C35H40N2O6 585.2986 (M+H)+ 585.34
XPM-0649 C33H38N2O4 527.2931 (M+H)+ 527.3
XPM-0650 C34H40N2O5 557.3037 (M+H)+ 557.4
XPM-0651 C34H38N2O5 555.2880 (M+H)+ 555.25
XPM-0654 C34H40N2O5 557.3037 (M+H)+ 557.42
XPM-0657 C35H37F3N2O5 623.2754 (M+H)+ 623.38
XPM-0660 C35H39F3N2O5 625.2911 (M+H)+ 625.38
XPM-0663 C34H37CIN2O5 589.2490 (M+H)+ 589.25
XPM-0666 C34H39CIN2O5 591.2647 (M+H)+ 591.35
XPM-0672 C35H42N2O6 587.3142 (M+H)+ 587.35
XPM-0675 C37H41CIN2O5 629.2777 (M+H)+ 629.4
XPM-0678 C37H43CIN2O5 631.2933 (M+H)+ 631.29
XPM-0681 C30H34N2O8 551.2415 (M+H)+ 551.31
XPM-0715 C31H35N3O3 498.2778 (M+H)+ 498.37
XPM-0721 C31H34CIN3O3 532.2388 (M+H)+ 532.3
XPM-0722 C32H36CIN3O4 562.2494 (M+H)+ 562.32
XPM-0727 C32H37N3O4 528.2883 (M+H)+ 528.39
XPM-0728 C33H39N3O5 558.2990 (M+H)+ 558.42
XPM-0759 C27H30N2O3 431.2356 (M+H)+ 431.28
XPM-0760 C26H30N2O4 435.2305 (M+H)+ 435.26
XPM-0765 C27H32N2O3 433.2513 (M+H)+ 433.3
XPM-0766 C26H32N2O4 437.2462 (M+H)+ 437.31
XPM-0771 C29H32N2O5 489.2411 (M+H)+ 489.26
XPM-0773 C28H34N2O6 495.2516 (M+H)+ 495.26
XPM-0774 C29H36N2O5 493.2724 (M+H)+ 493.36
XPM-0775 C32H40N2O5 533.3037 (M+H)+ 533.4
XPM-0776 C30H38N2O5 507.2880 (M+H)+ 507.27
XPM-0777 C29H34N2O5 491.2567 (M+H)+ 491.27
XPM-0779 C28H36N2O6 497.2673 (M+H)+ 497.39
XPM-0780 C29H38N2O5 495.2880 (M+H)+ 495.39
XPM-0781 C32H42N2O5 535.3193 (M+H)+ 535.4
XPM-0782 C30H40N2O5 509.3037 (M+H)+ 509.4
XPM-0783 C27H30N2O4 447.2305 (M+H)+ 447.29
XPM-0789 C27H31N3O4 462.2414 (M+H)+ 462.33
XPM-0795 C27H30N4O3 459.2417 (M+H)+ 459.33
XPM-0922 C34H36N4O4 565.2836 (M+H)+ 565.43
XPM-0925 C35H40N2O3 537.3138 (M+H)+ 537.4
XPM-0929 C35H42N2O3 539.3295 (M+H)+ 539.4
XPM-0933 C34H38N2O4 539.2931 (M+H)+ 539.3
XPM-0937 C34H40N2O4 541.3088 (M+H)+ 541.3
XPM-0941 C35H40N2O4 553.3088 (M+H)+ 553.32
XPM-0945 C35H42N2O4 555.3244 (M+H)+ 555.32
XPM-0953 C34H40N2O5 557.3037 (M+H)+ 557.32
XPM-0961 C31H34N2O4 499.2618 (M+H)+ 499.17 Compound No. Formula Expected m/z Ion Type m/z [ESI+]
XPM-0963 C31H33CIN2O4 533.2228 (M+H)+ 533.2
XPM-0971 C32H37CIN2O4 549.2542 (M+H)+ 549.27
XPM-0979 C35H43CIN2O5 607.2933 (M+H)+ 607.29
XPM-0980 C36H46N2O6 603.3429 (M+H)+ 603.34
XPM-0983 C36H41CIN2O5 618.2756 (M+H)+ 617.43
XPM-0987 C36H43CIN2O5 619.2933 (M+H)+ 619.29
XPM-0994 C32H36N2O4 513.2775 (M+H)+ 513.38
XPM-1004 C32H38N2O4 515.2931 (M+H)+ 515.38
XPM-1010 C30H34CIN3O4 536.2337 (M+H)+ 536.4
XPM-1011 C31H37N3O5 532.2833 (M+H)+ 532.3
XPM-1015 C31H35CIN2O4 535.2385 (M+H)+ 535.25
XPM-1016 C32H38N2O5 531.2880 (M+H)+ 531.35
XPM-1017 C31H35F5N2O4S 627.2337 (M+H)+ 627.34
XPM-1020 C31H36CIN3O4 550.2494 (M+H)+ 550.3
XPM-1025 C32H37CIN2O4 549.2542 (M+H)+ 549.27
XPM-1030 C30H32CI3N3O4 604.1558 (M+H)+ 604.3
XPM-1031 C31H35CI2N3O5 600.2053 (M+H)+ 600.4
XPM-1080 C34H38N2O5 555.2880 (M+H)+ 555.4
XPM-1095 C34H40N2O5 557.3037 (M+H)+ 557.3
XPM-1110 C32H37N3O3 512.2934 (M+H)+ 512.2
XPM-1125 C33H39N3O3 526.3091 (M+H)+ 526.5
XPM-1140 C34H39N3O4 554.3040 (M+H)+ 554.4
For illustrative purposes the NMR characterisation of the following examples are described in detail.
XPM-0006
1H NMR (400 MHz, Chloroform-d ) δ 8.27 (dd, J = 2.8, 0.7 Hz, 1H), 7.62 (dd, J= 8.6, 0.7 Hz, 1H), 7.36 (d, J = 2.3 Hz, 1H), 7.25 - 7.19 (m, 3H), 7.12 (dd, J = 8.3, 2.3 Hz, 1H), 6.90 - 6.80 (m, 3H), 4.66 (s, 2H), 3.9-3.7 (s, 5H), 3.65 (t, J = 4.9 Hz, 2H), 3.47 (s, 2H), 3.38 (s, 3H), 3.3-3.1 (m, 1H), 2.64 - 2.35 (m, 6H), 2.27 - 2.11 (m, 2H), 1.95 (d, J = 13.1 Hz, 2H), 1.59 - 1.42 (m, 2H), 1.42 - 1.28 (m, 2H).
13C NMR (101 MHz, Chloroform-d ) δ 166.8, 158.8, 154.8, 150.7, 148.O, 143.9, 138.1, 132.3, 130.3, 129.5, 127.7, 127.4, 125.3, 124.4, 119.4, 113.6, 79.O, 62.2, 60.4, 55.7, 55.2, 53.2, 52.5, 47.3, 43.1, 42.5, 32.4, 32.1
XPM-0063
1H NMR (400 MHz, Chloroform-d ) δ 10.28 (s, 1H), 8.26 (dd, J = 2.8, 0.7 Hz, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.60 (dd, J = 8.6, 0.7 Hz, 1H), 7.35 (dd, J = 8.5, 2.4 Hz, 1H), 7 ,27 (dd, J = 8.6, 2.8 Hz, 1H), 7.12 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 8.5 Hz, 1H), 6.75 (d, J = 8.6 Hz, 2H), 3.77 - 3.64 (m, 5H), 3.56 (t, J = 5.2 Hz, 2H), 3.38 (s, 2H), 3.31 - 3.15 (m, 4H), 2.56 - 2.47 (m, 1H), 2.44 (t, J = 5.5 Hz, 2H), 2.34 (t, J = 4.8 Hz, 2H), 2.21 - 2.11 (m, 2H), 1.99 (td, J = 13.2, 3.6 Hz, 2H), 1.88 - 1.79 (m, 2H), 1.77 - 1.61 (m, 2H).
13C NMR (101 MHz, Chloroform-d ) δ 188.6, 166.6, 158.9, 156.2, 154.3, 149.2, 143.5, 139.O, 134.7, 130.4, 129.5, 127.3, 127.2, 125.8, 125.6, 119.6, 113.7, 67.7, 62.3, 55.3, 53.3, 52.6, 47.3, 42.6, 42.6, 42.2, 41.O,38.9, 38.2, 33.5. 1H NMR (400 MHz, Chloroform-d ) δ 7.40 - 7.27 (m, 3H), 7.23 - 7.12 (m, 2H), 7.08 (dd, J = 8.4, 2.3 Hz, 1H), 6.99 - 6.87 (m, 2H), 6.87 - 6.72 (m, 3H), 4.64 (s, 2H), 3.86-3.33 (m, 4H), 3.78 (s, 3H), 3.46 (s, 2H), 3.37 (s, 3H), 3.29 - 3.09 (m, 1H), 2.65 (brs, 1H), 2.57 - 2.29 (m, 5H), 2.28 - 2.09 (m, 2H), 2.04 - 1.86 (m, 2H), 1.61 - 1.42 (m, 2H), 1.42 - 1.20 (m, 2H).
13C NMR (101 MHz, Chloroform-d ) δ 169.7, 158.9, 158.8, 151.2, 143.O, 132.3, 130.2, 129.9, 129.3,
129.1, 127.3, 127.O, 119.5, 117.O, 113.6, 79.O, 62.1, 60.4, 55.6, 55.1, 52.8, 47.8, 43.1, 42.2, 32.4, 32.0.
XPM-0328
1H NMR (400 MHz, Chloroform-d ) δ 10.37 (s, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.39 (d, J = 8.7 Hz, 2H), 7.19 (d, J= 8.6 Hz, 2H), 7.07 - 6.98 (m, 2H), 6.88 (d, J= 8.5 Hz, 1H), 6.85 - 6.77 (m, 3H), 3.86-3.33 (m, 4H), 3.76 (s, 3H), 3.45 (s, 2H), 3.35 - 3.23 (m, 4H), 2.54 (ttj = 12.1, 3.6 Hz, 1H), 2.60-2.32 (m, 4H), 2.33 - 2.19 (m, 2H), 2.06 (m, J = 13.2, 3.6 Hz, 2H), 1.95 - 1.86 (m, 2H), 1.83 - 1.68 (m, 2H).
13C NMR (101 MHz, Chloroform-d ) δ 189.1, 169.5, 158.9, 158.2, 157.2, 142.6, 134.5, 131.3, 130.3, 129.4, 129.4, 127.2, 126.5, 119.7, 118.4, 113.7., 67.6, 62.1, 55.1, 52.7, 47.8, 42.5, 42.2, 42.O, 38.7, 37.9, 33.3.
XPM-0548
1H NMR (400 MHz, Chloroform-d ) δ 7.44 - 7.36 (m, 2H), 7.35-7.25 (m, 4H), 7.24 - 7.17 (m, 2H), 7.03 - 6.93 (m, 4H), 3.95-3.33 (m, 4H), 3.52 (s, 2H), 3.42 (s, 3H), 3.32 - 3.15 (m, 1H), 2.63 - 2.30 (m, 5H), 2.29 - 2.16 (m, 2H), 2.04 - 1.91 (m, 2H), 1.62 - 1.45 (m, 2H), 1.45 - 1.29 (m, 2H).
13C NMR (101 MHz, Chloroform-d ) δ 170.O, 159.1, 154.3, 142.5, 136.2, 133.O, 130.4, 129.9, 129.1, 128.5, 128.1, 119.5, 117.8, 79.1, 62.1, 55.8, 53.O, 47.9,43.1, 42.3 32.6, 32.2.
XPM-0606
1H NMR (400 MHz, Chloroform-d ) δ 7.4 - 7.4 (m, 2H), 7.4 (d, J = 2.3 Hz, 1H), 7.2 - 7.2 (m, 2H), 7.1 (dd, J = 8.3, 2.3 Hz, 1H), 7.0 - 6.9 (m, 2H), 6.9 - 6.8 (m, 3H), 4.7 (s, 2H), 4.0 (s, 4H), 3.9 - 3.6 (m, 4H), 3.1 (s, 4H), 2.6 - 2.5 (m, 1H), 2.0 - 1.6 (m, 8H).
13C NMR (101 MHz, Chloroform-d ) δ 169.9, 159.2, 151.4, 149.5, 143.1, 132.2, 129.5, 129.2, 129.O, 127.7, 127.3, 125.5, 119.6, 117.8, 117.2, 108.3, 64.2, 64.2, 60.8, 49.6, 42.7, 35.O, 31.6.
XPM-0643
1H NMR (400 MHz, Chloroform-d ) δ 7.6 - 7.5 (m, 2H), 7.4 (d, J = 2.3 Hz, 1H), 7.3 - 7.3 (m, 2H), 7.2 - 7.2 (m, 2H), 7.1 (dd, J = 8.3, 2.3 Hz, 1H), 7.0 - 6.9 (m, 2H), 6.9 (d, J = 8.3 Hz, 1H), 4.6 (s, 2H), 4.4 (s, 2H), 4.2 (s, 2H), 3.5 (s, 2H), 3.3 (s, 4H), 2.7 (brs, 1H), 2.6 - 2.4 (m, 1H), 2.0 - 1.7 (m, 5H), 1.5 - 1.1 (m, 5H).
13C NMR (101 MHz, Chloroform-d ) δ 169.5, 160.4, 150.9, 144.9, 136.O, 133.O, 132.5, 130.O, 129.8,
128.6. 127.6. 127.3. 127.1, 119.9, 116.8, 64.1, 63.9, 62.6, 60.6, 58.6, 44.1, 34.6, 34.1, 26.9, 26.1.
XPM-0721
1H NMR (400 MHz, Chloroform-d ) δ 8.2 (d, J = 2.8 Hz, 1H), 7.9 (d, J = 8.7 Hz, 1H), 7.3 (d, J = 2.3 Hz, 1H), 7.2 - 7.2 (m, 2H), 7.2 - 7.1 (m, 3H), 7.1 (dd, J = 8.3, 2.3 Hz, 1H), 6.8 (d, J = 8.3 Hz, 1H), 4.7 (s, 2H), 4.6 (s, 2H), 4.2 (s, 2H), 3.5 (s, 2H), 3.3 (s, 4H), 2.5 - 2.4 (m, 1H), 1.9 - 1.6 (m, 5H), 1.4 - 1.1 (m, 5H). 13C NMR (101 MHz, Chloroform-d ) δ 164.2, 155.8, 150.2, 145.8, 145.4, 138.O, 136.O, 132.9, 132.4, 129.7, 128.5, 127.8, 127.4, 125.O, 123.7, 119.6, 65.O, 64.O, 62.6, 60.3, 58.6, 44.O, 34.5, 30.8, 26.7, 26.0.
XPM-0774
1H NMR (400 MHz, Chloroform-d ) δ 10.40 (s, 1H), 7.82 (d, J = 2.4 Hz, 1H), 7.43 (d, J = 8.7 Hz, 3H), 7.04 (d, J = 8.7 Hz, 2H), 6.89 (d, J = 8.5 Hz, 1H), 3.98 (s, 4H), 3.77 (brs, 2H), 3.50 (brs, 2H), 2.74 (brs, 1H), 2.67 - 2.39 (m, 5H), 1.94 - 1.61 (m, 8H), 1.05 (d, J= 6.5 Hz, 6H).
13C NMR (101 MHz, Chloroform-d ) δ 189.1, 169.4, 158.2, 157.1, 142.8, 134.5, 131.2, 129.3, 127.1, 126.6, 119.6, 118.3, 108.1, 64.3,64.2, 54.6, 48.4, 42.4, 34.9, 31.4, 18.2.
XPM-0979
1H NMR (400 MHz, Chloroform-d ) δ 7.43 - 7.35 (m, 3H), 7.33 - 7.23 (m, 4H), 7.14 (dd, J = 8.3, 2.3 Hz, 1H), 7.00 - 6.93 (m, 2H), 6.87 (d, J = 8.3 Hz, 1H), 4.69 (s, 2H), 3.90-3.33 (m, 4H), 3.51 (s, 2H), 3.45 (s, 2H), 3.39 (s, 3H), 3.38 (s, 3H), 3.21 (s, 2H), 2.64 - 2.35 (m, 5H), 1.88 - 1.71 (m, 4H), 1.61 (qd, J = 13.6, 13.2, 3.7 Hz, 2H), 1.38 (td, J = 14.O, 13.6, 4.2 Hz, 2H).
13C NMR (101 MHz, Chloroform-d ) δ 169.9, 159.1, 151.4, 144.1, 136.2, 133.O, 132.2, 130.4, 130.O, 129.2, 128.5, 127.6, 127.4, 119.7, 117.2, 80.O, 72.6, 62.1, 60.9, 59.5, 59.4, 53.O, 47.9, 43.7, 42.6, 37.9, 30.2, 29.4.
XPM-1004
1H NMR (400 MHz, Chloroform-d ) δ 7.41 - 7.25 (m, 6H), 6.96 (d, J = 2.0 Hz, 1H), 6.93 - 6.66 (m, 3H), 4.59 (s, 2H), 3.93-3.39 (m, 4H) 3.76 (s, 3H), 3.59 (s, 2H), 2.67-2.27 (m, 5H), 2.12 - 1.73 (m, 5H), 1.57 - 1.19 (m, 5H).
13C NMR (101 MHz, Chloroform-d ) δ 170.1, 159.6, 151.8, 146.6, 138.1, 134.6, 129.3, 129.1, 128.4, 127.4, 118.8, 114.7, 110.9, 62.8, 60.8, 56.O, 52.9, 44.7, 34.6, 26.9, 26.1.
XPM-1015
1H NMR (400 MHz, Chloroform-d ) δ 7.48 - 7.34 (m, 2H), 7.34 - 7.21 (m, 4H), 7.07 - 6.94 (m, 2H), 6.90 (d,J = 2.1 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 6.71 (dd, J = 8.3, 2.1 Hz, 1H), 3.88-3.33 (m, 4H), 3.52 (s, 2H), 3.41 (s, 3H), 3.22 (tt,/= 10.5, 4.1 Hz, 1H), 2.60-2.20 (m, 5H), 2.31 - 2.14 (m, 2H), 2.05 - 1.86 (m, 2H), 1.56 - 1.23 (m, 4H).
13C NMR (101 MHz, Chloroform-d ) δ 169.76, 158.6O, 147.58, 144.52, 140.43, 135.94, 133.02, 130.32, 130.07, 129.12, 128.44, 119.8O, 118.91, 116.89, 114.92, 79.06, 62.0O, 55.64, 52.92, 47.7, 43.16, 42.2, 32.37, 32.07.
XPM-1110
1H NMR (400 MHz, Chloroform-d ) δ 7.43 - 7.22 (m, 7H), 7.23 - 7.12 (m, 2H), 7.11 - 7.02 (m, 2H), 7.02 - 6.82 (m, 2H), 6.05 (s, 1H), 4.00 (s, 4H), 3.66 (s, 4H), 3.55 (s, 2H), 2.65-2.40 (m, 5H), 1.98 - 1.54 (m, 8H).
13C NMR (101 MHz, Chloroform-d ) δ 170.4, 145.6, 140.5, 139.5, 137.5, 129.O, 129.O, 128.2, 127.6, 127.1, 126.2, 119.6, 115.O, 108.4, 64.2, 64.1, 62.8, 53.O, 42.5, 35.O, 31.5.
Analytical Data
Table 51: Analytical data and antiproliferative activities on HPEK and MD-MB-231 cells
The above table shows specific examples of compounds falling under the scope of general Formula I. Also included are isomers, salts, particularly pharmaceutical acceptable salts, and solvates thereof. The synthesized compounds were analysed via mass spectrometry. Activity [HPEK] indicates the antiproliferative activities of the compounds on HPEK cells cultivated in CnT-Prime medium as determined with the method described herein. Activity (MDA] indicates the antiproliferative activities of the compounds on MDA-MB-231 cells cultivated in glucose-free Leibovitz’s L-15 medium. The activities are given by IC50 values categorized according to the concentration range they fall into: (-] higher than 10 pM, (+) 10 pM or lower, (++) 5 pM or lower, (+++) 1 pM or lower. In all entries the ICso values for HPEK cells are at least 2-fold higher than for MDA-MB-231 cells. ND: Not yet determined.
Table 52: Analytical data and antiproliferative activities on HPEK and MD-MB-231 cells
The above table is the continuation of Table 51 and shows further specific examples of compounds falling under the scope of general Formula I. Also included are isomers, salts, particularly pharmaceutical acceptable salts, and solvates thereof. The synthesized compounds were analysed as described above.

Claims

Claims
1. A compound according to general formula (I) as defined herein or a salt or solvate thereof: wherein
R1 = -CR2R3R4, C3-C16 preferably C3-C8 cycloalkyl, C5-C16 preferably C5-C8 cycloalkenyl, C9- C16 preferably C9-C11 cycloalkynyl, C5-C16 preferably C5-C11 bicycloalkyl, C7-C16 preferably C7-C11 bicycloalkenyl, C8-C16 preferably C8-C12 tricycloalkyl or C8-C16 preferably C8-C12 tricycloalkenyl; wherein R2, R3, and R4 are independently from each other selected from -H, -F, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C3-C15 cycloalkyl, C5-C15 cycloalkenyl, C9-C15 cycloalkynyl, C5-C15 bicycloalkyl, C7-C15 bicycloalkenyl, C8-C17 tricycloalkyl, C8-C17 tricycloalkenyl; wherein at least one of the residues selected from R2, R3, and R4 is different from -H and - F; wherein all alkyl, alkenyl and alkynyl residues contained in the definitions of R2, R3, and R4 are linear or branched, and are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, =O, -CF3, -CHF2, linear or branched C1-C8 preferably C1-C3 alkyl such as -CH3, linear or branched C2-C6 preferably C2-C3 alkenyl, linear or branched C2-C6 preferably C2-C3 alkynyl, C3 cycloalkyl, C3 cycloalkenyl, -OCF3, -OC1-C2 alkyl such as -OCH3, -NHCH3, and -N(CH3)2; wherein all cyclic structures, bicyclic structures and tricyclic structures including cycloalkyl, cycloalkenyl, cycloalkynyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl and tricycloalkenyl residues contained in the definitions of R1 or R2, R3, and R4 are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -N02, =O, -CF3, -CHF2, linear or branched C1-C8 preferably C1-C3 alkyl such as -CH3, linear or branched C2-C6 preferably C2-C3 alkenyl, linear or branched C2-C6 preferably C2-C3 alkynyl, C3 cycloalkyl, C3 cycloalkenyl, -OCF3, -OC1-C2 alkyl such as -OCH3, -NHCH3, and -N(CH3)2; wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl and tricycloalkenyl residues contained in the definitions of R1 or R2, R3, and R4 can contain one or more heteroatoms, or groups composed of heteroatoms, independently selected from O, S, SO, SO2 and N in replacement of a carbon atom; with the proviso that the carbon atom of R1 that is directly bound to the aromatic ring cannot be replaced by a heteroatom, and that such replacement cannot result in a substituent R1 comprising a group C=O or C=N directly bound to the aromatic ring; wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl and tricycloalkenyl residues contained in the definitions of R1 or R2, R3, and R4 can be partially or fully halogenated, particularly fluorinated, more particularly perfluorinated; and wherein bicyclic and tricyclic residues contained in R1 or R2, R3, and R4 include fused, bridged and spiro systems; and wherein the carbon atom of R1 that is bound to the aromatic ring as defined in general formula (I) is a secondary, tertiary or quaternary carbon atom and sp3 hybridized;
X1, X2, X3, and X4 are independently from each other selected from N, CR5, CR6, CR7, CR8 and wherein at least one of X1, X2, X3, and X4 is CR8; wherein R5, R6, and R7 are independently from each other selected from -H, -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -C(O)H, -CH2OH, -NH2, -CH2NH2, -N02, -CF3, -CHF2, -OCF3, linear or branched C1-C5 alkyl, linear or branched C2-C5 alkenyl, linear or branched C2-C5 alkynyl, C3-C5 cycloalkyl, C3-C5 cycloalkenyl, -CH2(C3-C5 cycloalkyl), linear or branched -OC1-C4 alkyl such as -OCH3, -OC3-C5 cycloalkyl, linear or branched -NH(C1-C4 alkyl), linear or branched -N(C1-C4 alkyl)(C1-C4 alkyl), -NH(C3-C5 cycloalkyl), -N(C3-C5 cycloalkyl) (C3-C5 cycloalkyl), and linear or branched -N(C1-C4 alkyl) (C3-C5 cycloalkyl); wherein R5, R6, and R7 are preferably independently from each other selected from -H, -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -N02, -CF3, -CHF2, linear or branched C1-C5 alkyl, C3-C5 cycloalkyl, -OCF3, linear or branched -OC1-C4 alkyl, linear or branched -NH(C1-C4 alkyl), linear or branched -N(C1-C4 alkyl) (C1-C4 alkyl); wherein R8 is selected from -H, -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -C(O)H, -CH2OH, -O(CH2)2OH, -NH2, -CH2NH2, -N02, -CF3, -CHF2, -OCF3, linear or branched C1-C5 alkyl, linear or branched C2-C5 alkenyl, linear or branched C2-C5 alkynyl, C3-C5 cycloalkyl, C3-C5 cycloalkenyl, -CH2(C3-C5 cycloalkyl), linear or branched -OC1-C4 alkyl such as -OCH3, -OC3- C5 cycloalkyl, linear or branched -NH(C1-C4 alkyl), linear or branched -N(C1-C4 alkyl) (C1- C4 alkyl), -NH(C3-C5 cycloalkyl), -N(C3-C5 cycloalkyl) (C3-C5 cycloalkyl), and linear or branched -N(C1-C4 alkyl) (C3-C5 cycloalkyl); wherein R8 is preferably selected from -H, -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -C(O)H, -OCH3, -OCF3, -CH2OH, -O(CH2)2OH, -NH2, -N02, -CF3, -CHF2, linear or branched C1-C5 alkyl, linear or branched C2-C5 alkenyl, C3-C5 cycloalkyl, linear or branched -OC1-C4 alkyl, linear or branched -NH(C1-C4 alkyl), linear or branched -N(C1-C4 alkyl)(C1-C4 alkyl); wherein all alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl residues contained in the definitions and preferred definitions of R5, R6, R7, and R8 can contain one or more heteroatoms, or groups composed of heteroatoms, independently selected from O, S, SO, S02 and N in replacement of a carbon atom; wherein all alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl residues contained in the definitions and preferred definitions of R5, R6, R7, and R8 are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CH3, -CF3, -CHF2, -OH and -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2;
A = O, S, SO, S02, NR9; wherein R9 is selected from -H, -CH3, and -COCH3; X5, X6, X7, and X8 are independently from each other selected from N, CR10, CR11, CR12, CR13; wherein R10, R11, R12, and R13 are independently from each other selected from -H, -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, -CF3, -CHF2, linear or branched C1-C5 alkyl, linear or branched C2-C5 alkenyl, linear or branched C2-C5 alkynyl, C3-C5 cycloalkyl, C3-C5 cycloalkenyl, -CH2(C3-C5 cycloalkyl), -OCF3, linear or branched -OC1-C4 alkyl, -OC3-C5 cycloalkyl, linear or branched -NH(C1-C4 alkyl), linear or branched -N(C1-C4 alkyl) (C1-C4 alkyl), -NH(C8-C5 cycloalkyl), -N(C8-C5 cycloalkyl) (C3-C5 cycloalkyl), and linear or branched -N(C1-C4 alkyl) (C3-C5 cycloalkyl); wherein R10, R11, R12, and R13 are preferably independently from each other selected from -H, -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -N02, -CF3, -CHF2, linear or branched C1-C5 alkyl, linear or branched C2-C5 alkenyl, C3-C5 cycloalkyl, -OCF3, linear or branched -OC1- C4 alkyl, linear or branched -NH(C1-C4 alkyl), linear or branched -N(C1-C4 alkyl)(C1-C4 alkyl); wherein all alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl residues contained in the definitions and preferred definitions of R10, R11, R12, and R13 can contain one or more heteroatoms, or groups composed of heteroatoms, independently selected from O, S, SO, SO2 and N in replacement of a carbon atom; wherein all alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl residues contained in the definitions and preferred definitions of R10, R11, R12, and R13 are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CH3, -CF3, -CHF2, -OH and -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2;
Z1 and Z2 are independently from each other selected from linear or branched C1-C8 alkylene and C2-C8 alkenylene; wherein one or more carbon atoms of Z1 and Z2 can additionally be linked to or shared with each other to form a bicyclic or tricyclic structure including both nitrogen atoms which they are bound to as defined in general formula (I); wherein the bicyclic and tricyclic structures formed with Z1, Z2 and both nitrogen atoms to which they are bound to as defined in general formula (I) include fused, bridged and spiro systems; wherein Z1 and Z2 can independently from each other be unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, linear or branched -OC1-C8 alkyl such as -OCH3, -OCF3, -OC3-C5 cycloalkyl, -NH2, linear or branched -NH(C1-C8 alkyl) such as -NHCH3, linear or branched -N(C1-C8 alkyl) (C1-C8 alkyl) such as -N(CH3)2, linear or branched -NH(C8-C5 cycloalkyl), linear or branched -N(C1-C8 alkyl)(C3-C5 cycloalkyl), -N(C8-C5 cycloalkyl) (C3-C5 cycloalkyl), -NO2, =O, -CF3, -CHF2, linear or branched C1-C8 alkyl such as -CH3, linear or branched C2-C8 alkenyl, linear or branched C2-C8 alkynyl, C3-C5 cycloalkyl, C3-C5 cycloalkenyl, -CH2(C3-C5 cycloalkyl); wherein Z1 and Z2 are preferably unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, linear or branched -OC1-C3 alkyl such as -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, N02, =O, -CF3, -CHF2, linear or branched C1-C3 alkyl such as -CH3, linear or branched C2-C3 alkenyl, linear or branched C2-C3 alkynyl, C3-C5 cycloalkyl, C3-C5 cycloalkenyl; wherein all alkyl, alkenyl, and alkynyl substituents of Z1 and Z2 can independently from each other be linked additionally to one or more carbon atoms of Z1 and Z2 independently from which they are bound to; wherein all alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl residues contained in the definitions of Z1 and Z2 or in any of their substituents, and all bicyclic and tricyclic structures formed with Z1, Z2 and both nitrogen atoms which they are bound to as defined in general formula (I) can contain one or more heteroatoms, or groups composed of heteroatoms, independently selected from O, S, SO, SO2 and N in replacement of a carbon atom; wherein all alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl residues contained in the definitions of Z1 and Z2 or in any of their substituents, and all bicyclic and tricyclic structures formed with Z1, Z2 and both nitrogen atoms which they are bound to as defined in general formula (I) can be partially or fully halogenated, particularly fluorinated, more particularly perfluorinated;
Y = linear or branched C1-C5 alkyl, linear or branched C2-C5 alkenyl, linear or branched C2-C5 alkynyl, C3-C5 cycloalkyl, C3-C5 cycloalkenyl; wherein all alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl residues contained in the definitions of Y can contain one or more heteroatoms, or groups composed of heteroatoms, independently selected from O, S, SO, SO2 and N in replacement of a carbon atom; wherein all alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl residues contained in the definitions of Y can be unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -OC1-C3 alkyl such as -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, -NO2, =O, -CF3, -CHF2, linear or branched C1-C3 alkyl such as -CH3, linear or branched C2-C3 alkenyl, C2-C3 alkynyl, C3 cycloalkyl, C3 cycloalkenyl; wherein Y is preferably -CH2-, -C(O)-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -C(CH3)2- , -CH2CH(OH)-, -CH2CH2O-, -CH2C(O)-, -CH2-C=C-, -CH2CH(CH3)-, -CH2C(O)CH2CH2-, -C(O)OCH2CH2- and -S(O)2-; wherein for non-symmetrical residues of Y, the residue can be oriented in both directions with regard to the basic structure;
W = -H, -F, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, C5-C12 bicycloalkyl, C7-C12 bicycloalkenyl, C8-C14 tricycloalkyl, C8-C14 tricycloalkenyl, as well as C6-C14 aromatic and C5-C14 heteroaromatic residues; wherein all aromatic and heteroaromatic residues contained in the definitions of W include monoaromatic, monoheteroaromatic, fused or bridged polyaromatic, fused or bridged polyheteroaromatic systems, as well as bicyclic and tricyclic systems of which at least one cycle is aromatic or heteroaromatic; and wherein all bicyclic and tricyclic residues contained in the definitions of W include fused, bridged and spiro systems; wherein all cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl and tricycloalkenyl residues, as well as all aromatic and heteroaromatic moieties contained in the definitions of W are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -CF3, -CHF2, -CF2CF3, -CH2CF3, -OH, -OCH3, -OCF3, -OCH2CF3, -NH2, -NHCH3, -N(CH3)2, -NO2, linear or branched C1-C8 alkyl, linear or branched C2-C8 alkenyl, linear or branched C2-C8 alkynyl, C3-C8 cycloalkyl, and C3-C8 cycloalkenyl; wherein all alkyl, alkenyl, and alkynyl substituents of W can independently from each other be linked additionally to more than one carbon atom of W; wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl and tricycloalkenyl residues, as well as all aromatic and heteroaromatic moieties contained in the definitions of W or in any of its substituents, can contain one or more heteroatoms, or groups composed of heteroatoms, independently selected from O, S, SO, SO2 and N in replacement of a carbon atom; wherein all alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl residues contained in the definitions of the substituents of W can be partially or fully halogenated, particularly fluorinated, more particularly perfluorinated; wherein W is preferably selected from -H, -F, and unsubstituted or substituted residues from cyclopentyl, cyclohexyl, benzyl, pyridine, indole, pyrimidine, pyridazine, pyrazine, naphthyl, quinoline, coumarin, isocoumarin, phthalazine, quinoxaline, cinnoline, quinazoline, 1,8-diazanapthtalene, 1,7-diazanapthtalene, 2,7-diazanapthtalene, 1,6- diazanapthtalene, 1,5-diazanapthtalene, 2,6-diazanapthtalene, furan, pyrrole, thiophene, thiazole, benzopyran and benzofuran; wherein if substituted, one or more substituents of said residues are independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -CF3, -CHF2, -CF2CF3, -CH2CF3, -OH, -OCH3, -OCF3, -OCH2CF3, -NH2, -NHCH3, -N(CH3)2, -NO2, linear or branched C1-C8 alkyl such as -CH3, linear or branched C2-C8 alkenyl, linear or branched C2-C8 alkynyl, C3-C8 cycloalkyl, and C3-C8 cycloalkenyl; and wherein all said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl substituents can contain one or more heteroatoms, or groups composed of heteroatoms, independently selected from O, S, SO, SO2 and N in replacement of a carbon atom; and wherein the substituents of W are preferably selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -CH3, -CF3, -CHF2, -CF2CF3, -CH2CF3, -OH, -OCH3, -OCF3, -OCH2CF3, -NH2, -NHCH3, -N(CH3)2, -NO2, -SF6, -OC(O)CH3, -S(O)2N(CH3)2, -S(O)2CH3, -S(O)2NH2, -C(O)N(CH3)2, -C(O)OH, -C(O)OCH3; and n = 0 or 1; wherein n is preferably 1; optionally with the proviso that the grouping -(Y)n-W as defined in general formula (I) is different from -H, -F, -CN, -NCO, -NCS, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, =O, -CH3, -CF3 and morpholinyl.
2. The compound of claim 1 or a salt or solvate thereof, wherein A = 0.
3. The compound of claim 1 or 2 or a salt or solvate thereof, wherein R8 is selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -C(O)H, -CH20H, -O(CH2)2OH, -NH2, -CH2NH2, -NO2, -CF3, -CHF2, -OCF3, linear or branched C1-C5 alkyl, linear or branched C2-C5 alkenyl, linear or branched C2-C5 alkynyl, C3-C5 cycloalkyl, C3-C5 cycloalkenyl, -CH2(C:;-C5 cycloalkyl), linear or branched -OC1-C4 alkyl such as -OCH3, -0C3- C5 cycloalkyl, linear or branched -NH(C1-C4 alkyl), linear or branched -N(C1-C4 alkyl) (C1- C4 alkyl), -NH(C3-C5 cycloalkyl), -N(C3-C5 cycloalkyl) (C3-C5 cycloalkyl), and linear or branched -N(C1-C4 alkyl) (C3-C5 cycloalkyl) .
4. The compound of any one of claims 1-3 or a salt or solvate thereof, wherein R1 is selected from
5. The compound of any one of claims 1-4 or a salt or solvate thereof, wherein the six-membered aromatic ring containing X1, X2, X3, and X4 as defined in general formula (I) is selected from
6. The compound of any one of claims 1-5 or a salt or solvate thereof, wherein the six-membered aromatic ring containing X5, X6, X7, and X8 as defined in general formula [I] is selected from
7. The compound of any one of claims 1-6 or a salt or solvate thereof, wherein the structures formed with Z1, Z2 and both nitrogen atoms to which they are bound to are selected from the following residues which can be unsubstituted or substituted as defined above:
8. The compound of any one of claims 1-7 or a salt or solvate thereof, wherein Y is selected from
9. The compound of any one of claims 1-8 or a salt or solvate thereof, wherein W is selected from
10. The compound of any one of claims 1-9 or a salt or solvate thereof, wherein the compound has the following structure (la): wherein (i) R4-R13, X4-X4, X6, X7, A, Z1, Z2, Y, n and W are as defined in general formula (I) including the substitutions and preferred definitions, or wherein (ii) R4-R13, X4-X4, X6, X7, A, Z1, Z2, Y, n and W are as defined in general formula (I) including the substitutions and preferred definitions, and wherein
R10 and R11 are independently from each other selected from -H, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, -CF3, -CHF2, linear or branched C1-C5 alkyl, linear or branched C2-C5 alkenyl, C3-C5 cycloalkyl, -OCF3, linear or branched -OC1-C4 alkyl, linear or branched -NH(C1-C4 alkyl), linear or branched -N(C1-C4alkyl)(C1-C4 alkyl), and/or n is 1, and/or A is O, and/or
- X2 is CR8 and R8 is selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -C(O)H, -CH2OH, -O(CH2)2OH, -NH2, -CH2NH2, -NO2, -CF3, -CHF2, -OCF3, linear or branched C1-C5 alkyl, linear or branched C2-C5 alkenyl, linear or branched C2-C5 alkynyl, C3-C5 cycloalkyl, C3-C5 cycloalkenyl, -CH2(C3-C5 cycloalkyl), linear or branched -OC1-C4 alkyl such as -OCH3, -OC3-C5 cycloalkyl, linear or branched -NH(C1-C4 alkyl), linear or branched -N(C1-C4 alkyl) (C1-C4 alkyl), -NH(C3-C5 cycloalkyl), -N(C3-C5 cycloalkyl) (C3-C5 cycloalkyl), and linear or branched -N(C1-C4alkyl)(C3-C5 cycloalkyl), and/or W is selected from -H, -F, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, C5-C12 bicycloalkyl, C7-C12 bicycloalkenyl, C8-C14 tricycloalkyl, C8-C14 tricycloalkenyl, and C6-C14 aromatic and C5-C14 heteroaromatic residues which are different from pyridine, pyrimidine, pyridazine, oxadiazole, thiazole, triazole, phenyl, phenyl -pyrazole, phenyl -pyridine, phenyl-oxadiazole and phenyl-triazole.
The compound of any one of claims 1-10 or a salt or solvate thereof, wherein the compound has the following structure (lb): wherein (i) R4-R13, X4-X8, A, Y, n and W are as defined in general formula (I) including the substitutions and preferred definitions, or wherein (ii) R4-R13, X4-X8, A, Y, n and W are as defined in general formula (I) including the substitutions and preferred definitions, and wherein n is 1, and/or
A is O, and/or
W is selected from -H, -F, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, C5-C12 bicycloalkyl, C7-C12 bicycloalkenyl, C8-C14 tricycloalkyl, C8-C14 tricycloalkenyl, and C6-C14 aromatic and C5-C14 heteroaromatic residues which are different from pyridine, pyrimidine, pyridazine, oxadiazole, thiazole, triazole, phenyl, phenyl -pyrazole, phenyl -pyridine, phenyl-oxadiazole and phenyl-triazole, and/or
X5 is CR10 and X8 is CR11 and R10 and R11 can additionally be different from -F, and/or X2 is CR8 and R8 is different from -H.
12. The compound of any one of claims 1-11 or a salt or solvate thereof, wherein the compound has the following structure (Ic): wherein R8 is different from -H, and wherein (i) Rx-R7, R9-R13, X1, X3-X8, A, Z1, Z2, Y, n and W are as defined in general formula (I) including the substitutions and preferred definitions, or wherein (ii) R'-R7, R9-R13, X1, X3-X8, A, Z1, Z2, Y, n and W are as defined in general formula (I) including the substitutions and preferred definitions, and wherein n is 1, and/or
A is O, and/or
W is selected from -H, -F, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, C5-C12 bicycloalkyl, C7-C12 bicycloalkenyl, C8-C14 tricycloalkyl, C8-C14 tricycloalkenyl, and C6-C14 aromatic and C5-C14 heteroaromatic residues which are different from pyridine, pyrimidine, pyridazine, oxadiazole, thiazole, triazole, phenyl, phenyl -pyrazole, phenyl -pyridine, phenyl-oxadiazole and phenyl-triazole, and/or
X5 is CR10 and X8 is CR11 and R10 and R11 can additionally be different from -F.
13. The compound of any one of claims 1-12 or a salt or solvate thereof, wherein the compound has the following structure (Id): wherein (i) R'-R13, X'-X8, A, Z1, Z2 and W are as defined in general formula (I) including the substitutions and preferred definitions, or wherein (ii) R'-R13, X1-X8, A, Z1, Z2 and W are as defined in general formula (I) including the substitutions and preferred definitions, and wherein
A is O, and/or
W is selected from -H, -F, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, C5-C12 bicycloalkyl, C7-C12 bicycloalkenyl, C8-C14 tricycloalkyl, C8-C14 tricycloalkenyl, and C6-C14 aromatic and C5-C14 heteroaromatic residues which are different from pyridine, pyrimidine, pyridazine, oxadiazole, thiazole, triazole, phenyl, phenyl -pyrazole, phenyl -pyridine, phenyl-oxadiazole and phenyl-triazole, and/or
X5 is CR10 and X8 is CR11 and R10 and R11 can additionally be different from -F, and/or X2 is CR8 and R8 is different from -H.
14. The compound of any one of claims 1-13 or a salt or solvate thereof, wherein the compound has the following structure (le): wherein W is phenyl or pyridine that can be unsubstituted, monosubstituted with R14, or disubstituted with R14 and R15, and wherein (i) R4-R13, X4-X8, A, Z1 and Z2 are as defined in general formula (I) including the substitutions and preferred definitions, and wherein X9 is N or CH, and wherein R14 or R15 are independently from each other selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -CF3, -CHF2, -CF2CF3, -CH2CF3, -OH, -OCH3, -OCF3, -OCH2CF3, -NH2, -NHCH3, -N(CH3)2, -N02, linear or branched C1-C6 alkyl, linear or branched C2-C6 alkenyl, linear or branched C2-C6 alkynyl, C3-C6 cycloalkyl, and C3-C6 cycloalkenyl, and wherein all alkyl, alkenyl, and alkynyl substituents of W can independently from each other be linked additionally to more than one carbon atom of W, and wherein all alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl residues contained in the definitions of R14 or R15 can contain one or more heteroatoms, or groups composed of heteroatoms independently selected from O, S, SO, S02 and N in replacement of a carbon atom, and wherein all alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl residues contained in the definitions of R14 or R15 can be partially or fully halogenated, particularly fluorinated, more particularly perfluorinated, or wherein (ii) R4-R13, X4-X8, A, Z1 and Z2 are as defined in general formula (I) including the substitutions and preferred definitions, and R14, R15 and X9 are as defined above, and wherein
A is O, and/or
X5 is CR10 and X8 is CR11 and R10 and R11 are different from -F, and/or
X2 is CR8 and R8 is different from -H.
15. The compound of any one of claims 1-14 or a salt or solvate thereof, wherein the compound has the following structure (If): wherein W is phenyl or pyridine that can be unsubstituted, monosubstituted with R14, or disubstituted with R14 and R15, and wherein (i) R4-R13, X4-X8 and A are as defined in general formula (I) including the substitutions and preferred definitions, and wherein X9 is N or CH, and wherein R14 or R15 are independently from each other selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -CF3, -CHF2, -CF2CF3, -CH2CF3, -OH, -OCH3, -OCF3, -OCH2CF3, -NH2, -NHCH3, -N(CH3)2, -N02, linear or branched C1-C6 alkyl, linear or branched C2-C6 alkenyl, linear or branched C2-C6 alkynyl, C3-C6 cycloalkyl, and C3-C6 cycloalkenyl, and wherein all alkyl, alkenyl, and alkynyl substituents of W can independently from each other be linked additionally to more than one carbon atom of W, and wherein all alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl residues contained in the definitions of R14 or R15 can contain one or more heteroatoms, or groups composed of heteroatoms independently selected from O, S, SO, S02 and N in replacement of a carbon atom, and wherein all alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl residues contained in the definitions of R14 or R15 can be partially or fully halogenated, particularly fluorinated, more particularly perfluorinated, or wherein (ii) R4-R13, X4-X8 and A are as defined in general formula (I) including the substitutions and preferred definitions, and R14, R15 and X9 are as defined above, and wherein
A is O, and/or
X5 is CR10 and X8 is CR11 and R10 and R11 are different from -F, and/or
X2 is CR8 and R8 is different from -H.
16. The compound of any one of claims 1-15 or a salt or solvate thereof, wherein the compound has the following structure (Ig): wherein (i) R5-R13, X4-X8, A, Z1, Z2 Y, n and W are as defined in general formula (I) including the substitutions and preferred definitions, and wherein R16 and R17 are independently from each other selected from -H, -F, linear or branched C1-C8 preferably C1-C3 alkyl, linear or branched C2-C6 preferably C2-C3 alkenyl, linear or branched C2-C6 preferably C2-C3 alkynyl, or wherein R16 and R17 are linked together to form with the carbon atom they are bound to a C3-C6 cycloalkyl or a Cs-C8 cycloalkenyl residue that is unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -CH3 and wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl residues contained in the definitions of R16 and R17 can contain one or more heteroatoms independently selected from O, S and N in replacement of a carbon atom, or wherein (ii) R5-R13, X4-X8, A, Z1, Z2 Y, n and W are as defined in general formula (I) including the substitutions and preferred definitions, and R16 and R17 are as defined above, and wherein n is 1, and/or
A is O, and/or
W is selected from -H, -F, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, C5-C12 bicycloalkyl, C7-C12 bicycloalkenyl, C8-C14 tricycloalkyl, C8-C14 tricycloalkenyl, and C8-C14 aromatic and C5-C14 heteroaromatic residues which are different from pyridine, pyrimidine, pyridazine, oxadiazole, thiazole, triazole, phenyl, phenyl -pyrazole, phenyl -pyridine, phenyl-oxadiazole and phenyl-triazole, and/or
X5 is CR10 and X8 is CR11 and R10 and R11 can additionally be different from -F, and/or X2 is CR8 and R8 is different from -H.
17. The compound of any one of claims 1-16 or a salt or solvate thereof, wherein the compound has the following structure (Ih): wherein W is phenyl or pyridine that can be unsubstituted, monosubstituted with R14, or disubstituted with R14 and R15, and wherein (i) R5-R13, X4-X8 and A are as defined in general formula (I) including the substitutions and preferred definitions, and wherein X9 is N or CH, and wherein R14 or R15 are independently from each other selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -CF3, -CHF2, -CF2CF3, -CH2CF3, -OH, -OCH3, -OCF3, -OCH2CF3, -NH2, -NHCH3, -N(CH3)2, -NO2, linear or branched C1-C8 alkyl, linear or branched C2-C6 alkenyl, linear or branched C2-C6 alkynyl, C3-C6 cycloalkyl, and C3-C6 cycloalkenyl, and wherein all alkyl, alkenyl, and alkynyl substituents of W can independently from each other be linked additionally to more than one carbon atom of W, and wherein all alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl residues contained in the definitions of R14 or R15 can contain one or more heteroatoms, or groups composed of heteroatoms independently selected from O, S, SO, SO2 and N in replacement of a carbon atom, and wherein all alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl residues contained in the definitions of R14 or R15 can be partially or fully halogenated, particularly fluorinated, more particularly perfluorinated, and wherein R16 and R17 are independently from each other selected from -H, -F, linear or branched C1-C6 preferably C1-C3 alkyl, linear or branched C2-C6 preferably C2-C3 alkenyl, linear or branched C2-C6 preferably C2-C3 alkynyl, or wherein R16 and R17 are linked together to form with the carbon atom they are bound to a C3-C6 cycloalkyl or a C5-C6 cycloalkenyl residue that is unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -CH3 and wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl residues contained in the definitions of R16 and R17 can contain one or more heteroatoms independently selected from O, S and N in replacement of a carbon atom, or wherein (ii) R5-R13, X4-X8 and A are as defined in general formula (I) including the substitutions and preferred definitions, and wherein R14, R15, X9, R16 and R17 are as defined above, and wherein
A is O, and/or
X5 is CR10 and X8 is CR11 and R10 and R11 are different from -F, and/or
X2 is CR8 and R8 is different from -H.
18. A compound as shown in any of Tables 1 to 12 and 51 to 52 or a salt or solvate thereof.
19. The compound of any one of claims 1-18 for use in medicine, e.g. in human medicine or veterinary medicine.
20. The compound of any one of claims 1-18 for use in the treatment of a disorder dependent on mitochondrial activity and/or associated with, accompanied by and/or caused by an enhanced mitochondrial activity, and particularly of a disorder wherein the treatment requires inhibition of mitochondrial function.
21. The compound of any one of claims 1-18 for use in the treatment of a disorder dependent on oxidative phosphorylation and/or associated with, accompanied by and/or caused by an enhanced oxidative phosphorylation, and particularly of a disorder wherein the treatment requires inhibition of oxidative phosphorylation.
22. The compound of any one of claims 1-18 for use in the treatment of a hyperprolife rative disorder, including a malignant and non-malignant hyperproliferative disorder.
23. The compound of any one of claims 1-18 for use of claim 22 wherein the hyperproliferative disorder is dependent on oxidative phosphorylation and/or associated with, accompanied by and/or caused by an enhanced mitochondrial activity, and particularly of a hyperproliferative disorder wherein the treatment requires inhibition of mitochondrial function.
24. The compound of any one of claims 1-18 for use of claim 22 or 23 wherein the hyperproliferative disorder is dependent on oxidative phosphorylation and/or associated with, accompanied by and/or caused by an enhanced oxidative phosphorylation, and particularly of a hyperproliferative disorder wherein the treatment requires inhibition of oxidative phosphorylation.
25. The compound of any one of claims 1-18 for use in the treatment of hyperplasia, neoplasia, cancer, cancer metastases, and/or a precancerous lesion.
26. The compound of any one of claims 1-18 for the use according to claims 22 -25 for inhibiting carcinogenesis, tumor progression, and/or metastasis formation.
27. The compound of any one of claims 1-18 for the use according to any one of claims 22 -
26 for targeting cancer stem cells.
28. The compound of any one of claims 1-18 for the use according to any one of claims 22 -
27 for the treatment of treatment-resistant cancer, e.g., cancer resistant to chemotherapy, targeted therapy including kinase inhibitors such as B-Raf inhibitors and BTK inhibitors, antiapoptotic protein inhibitors such as Bcl-2 inhibitors, angiogenesis inhibitors such as VEGFR inhibitors, radiation therapy, or cancer immunotherapy including checkpoint inhibitors such as PD-1 inhibitors.
29. The compound of any one of claims 1-18 for the use according to any one of claims 22 -
28 for the treatment of OXPHOS dependent cancer.
30. The compound of any one of claims 1-18 for the use according to any one of claims 22 -
29 for the treatment of glycolysis deficient cancer.
31. The compound of any one of claims 1-18 for use in the treatmentof a benign or malignant hyperproliferative disorder including hyperplasia, neoplasia, cancer, precancerous lesions and metastasis of the skin, skin appendages, mucosa, mucosal appendages, glands, eye, cornea, melanocytes, respiratory tract, lung, head and neck, oral cavity, mouth, tongue, lip, larynx, oropharynx, pharynx, esophagus, breast, mammary gland, genitourinary tract, cervix, uterus, ovaries, endometrium, vulva, vagina, penis, anus, prostate, testis, urinary tract, bladder, kidney, urinary tissues, endocrine glands, thyroid, parathyroid, connective tissue, soft tissue, bone, cartilage, muscle, adipose tissue, spleen, neuroendocrine system, central nervous system, peripheral nervous system, brain, forebrain, pituitary gland, adrenal gland, meninges, spinal cord, pancreas, pancreatic islets of Langerhans, gallbladder, bile duct, gastrointestinal tract, colon, large intestine, small intestine, rectum, stomach, liver, biliary passages, vascular system, blood vessels, lymphatic vessels, peritoneum, pleura, pericardium.
32. The compound of any one of claims 1-18 for use in the treatment of a malignant hyperproliferative disorder including cancer, precancerous lesions and metastasis of the blood, white blood cell compartment, red blood cell compartment, hematologic system, hematopoietic system, lymphatic system, lymph nodes, lymphoid organs, lymphoid tissues, bone marrow, myeloid lineage, lymphoid lineage, including acute and chronic forms of leukemia and lymphoma, wherein said leukemias and lymphomas can be lymphocytic, lymphoblastic, large granular lymphocytic, small lymphocytic, T- lymphocytic, B-lymphocytic, plasmacytic, myelocytic, myeloblastic, monocytic, granulocytic, basophilic, neutrophilic, eosinophilic, megakaryocytic, mastocytic, erythrocytic, or dendrocytic.
33. The compound of any one of claims 1-18 for use in the treatmentof a benign or malignant hyperproliferative disorder including hyperplasia, neoplasia, cancer, precancerous lesions and metastasis selected from epithelial cancers and precancerous lesions, epithelial hyperplasia, epithelial neoplasia, carcinoma, squamous cell carcinoma, basal cell carcinoma, transitional cell carcinoma, verrucous carcinoma, mucinous carcinoma, serous carcinoma, cystic carcinoma, papillary carcinoma, papillary adenocarcinoma, small cell carcinoma, combined small cell carcinoma, large cell carcinoma, carcinoid tumors, stromal tumors, leukemia, lymphoma, myeloma, papilloma, intracanalicular papilloma, intraductal papilloma, inverted papilloma, basal cell papilloma, squamous papilloma, precancerous keratoses, adenoma, cystadenoma, serous cystadenoma, mucinous cystadenoma, adenocarcinoma, cystadenocarcinoma, serous cystadenocarcinoma, mucinous cystadenocarcinoma, ductal adenocarcinoma, adenoid cystic carcinoma, medullary carcinoma, ductal carcinoma, lobular carcinoma, villoglandular carcinoma, sarcoma, polyp, angioma, neuroma, adnexal tumor, oncocytoma, cyst, hyperproliferative nevi, biphasic tumors and mixed tumors.
34. The compound of any one of claims 1-18 for use in the treatmentof a benign or malignant hyperproliferative disorder including hyperplasia, neoplasia, cancer, precancerous lesions and metastasis selected from melanoma, melanoma in situ, cutaneous melanoma, ocular melanoma, uveal melanoma, conjunctival melanoma, mucosal melanoma, amelanotic melanoma, desmoplastic melanoma, nodular melanoma, superficial spreading melanoma, acral-lentiginous melanoma, lentigo maligna melanoma, non-melanoma skin cancer, cutaneous basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (SCC), sebaceous gland carcinoma, salivary gland oncocytoma, acinic cell carcinoma, Warthin tumor, cystadenolymphoma, fibrofolliculomas, epidermoid cyst, Merkel cell carcinoma, dermatofibrosarcoma, actinic keratosis (AK), solar keratosis, seborrheic keratosis (verruca senilis)., chronic scar keratosis, hydrocarbon keratosis, Bowen disease (BD), cutaneous SCC, lung SCC, head and neck SCC, oral SCC, tongue SCC, esophageal SCC, cervical SCC, periocular SCC, SCC of the thyroid, SCC of the penis, SCC of the vagina, SCC of the prostate and SCC of the bladder, Kaposi sarcoma, thymoma, endolymphatic sac tumor, Paget disease of the breast, extramammary Paget disease, medullary breast carcinoma, cystadenocarcinoma of the ovaries, serous ovarian cancer, ovarian serous cystadenoma, Bartholin gland carcinoma, pancreatic serous cystadenoma, uterine serous carcinoma, papillary serous cystadenocarcinoma, cystadenocarcinoma of the liver, cystadenocarcinoma of the pancreas, signet ring cell carcinoma, gastrointestinal stromal tumor, endometrioid tumor, prolactinoma, multiple endocrine neoplasia, adrenocortical adenoma, adrenocortical carcinoma, Hurthle cell carcinoma, Hurthle cell adenoma, neuroendocrine small cell carcinomas, neuroendocrine large cell carcinomas and carcinoid tumors, neuroendocrine tumors, neuroendocrine tumor of the pituitary gland, neuroendocrine tumor of the adrenal gland, pheochromocytoma, paraganglioma, medullary thyroid cancer (MTC), C-cell hyperplasia, anaplastic thyroid cancer (ATC), parathyroid adenoma, intrathyroidal nodules, insular carcinoma, hyalinizing trabecular neoplasm, thyroid oncocytoma, lung carcinoid tumors, gastrointestinal carcinoid, Gobletcell carcinoid, pancreatic carcinoid, gastrinoma, glucagonoma, somatostatinoma, (vasoactive intestinal peptide-) VIPoma, insulinoma, beta cell tumor, non-functional islet cell tumor, multiple endocrine neoplasia type-1, or pulmonary carcinoid, bronchogenic carcinoma, small-cell lung carcinoma (SCLC), combined small cell lung carcinoma, non- small-cell lung cancer (NSCLC), lung adenocarcinoma and lung large cell carcinoma, nephroblastoma, Wilms tumor, medulloblastoma, neuroblastoma, retinoblastoma, glioma, mixed glioma, glioblastoma multiforme, astrocytoma, anaplastic astrocytoma, glioblastoma, blastoglioma, oligodendroglioma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, ependymoma, anaplastic ependymoma, myxopapillary ependymoma, subependymoma, brain stem glioma, chordoma, optic nerve glioma, ganglioglioma, meningioma, adrenocarcinoma, pinealoma, pineocytoma, pineoblastoma, craniopharyngioma, myxosarcoma, myxofibrosarcoma, neurofibrosarcoma, neurosarcoma, malignant schwannoma, malignant peripheral nerve sheath tumor, pancreatic adenocarcinoma, pancreatic ductal adenocarcinoma, pancreatic ductal carcinoma, pancreatic endocrine tumors, pancreatic acinar cell carcinoma, pancreatic pseudopapillary neoplasm, pancreatic intraductal papillary-mucinous neoplasm, pancreatic mucinous cystadenocarcinoma, pancreatoblastoma and pancreatic intraepithelial neoplesia, hepatocellular carcinoma (HCC), fibrolamellar hepatocellular carcinoma, hepatoma, cholangiocarcinoma, Klatskin tumor, bile duct carcinoma, papillary thyroid cancer and follicular thyroid cancer, cervical cancer, cervical mucinous adenocarcinoma, cervical adenoma malignum, hormone receptor-positive breast cancer, hormone receptor-negative breast cancer, hormone receptor-positive breast cancer with HER2 amplification, hormone receptor-negative breast cancer with HER2 amplification, triple negative breast cancer, breast cancer with or without BRCA1 and/or BRCA2 mutation, triple negative breast cancer with or without BRCA1 and/or BRCA2 mutation, breast ductal carcinoma, breast ductal carcinoma in situ, postirradiation breast angiosarcoma, comedocarcinoma, ovarian cancer, Krukenberg tumor, pseudomyxoma peritonei, mucoepidermoid carcinoma, germinoma, intracranial germinoma, dysgerminoma, seminoma, testicular seminoma, nonseminomatous germ cell tumor, ductal adenocarcinoma of the prostate, ductal carcinoma of the prostate, choriocarcinoma, gastric cancer, Brinton disease, endotheliosarcoma, angiosarcoma, cutaneous angiosarcoma, intraoral angiosarcoma, gingival angiosarcoma, breast angiosarcoma, cardiac angiosarcoma, hepatic angiosarcoma, pulmonary angiosarcoma, pleural angiosarcoma, gastrointestinal angiosarcoma, epithelioid angiosarcoma, splenic angiosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma, fibrosarcoma, liposarcoma, rhabdomyosarcoma, leiomyosarcoma, Ewing sarcoma, osteosarcoma, chondrosarcoma, synovial sarcoma, mesothelioma, pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma, renal cell carcinoma (RCC), renal pelvis carcinoma, renal oncocytoma, myeloproliferative disorders, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), erythroid leukemia, acute erythroid leukemia (AEL), erythroblastic leukemia, erythroblastic sarcoma, megakaryoblastic leukemia, acute megakaryoblastic leukemia (AMEL), basophilic leukemia, acute basophilic leukemia (ABL), neutrophilic leukemia, chronic neutrophilic leukemia, eosinophilic leukemia, chronic eosinophilic leukemia, monocytic leukemia, acute monocytic leukemia (AMOL), acute myelomonocytic leukemia (AMML), mast cell leukemia (MCL), acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), pre-T-cell acute lymphoblastic leukemia (pre-T-ALL), B-cell acute lymphoblastic leukemia (B-ALL), pre-B-cell acute lymphoblastic leukemia (pre-B-ALL), chronic lymphocytic leukemia (CLL), T-cell-CLL (T-CLL), B-cell-CLL (B-CLL), prolymphocytic leukemia (PLL), T-cell-PLL (T-PLL), B-cell-PLL (B-PLL), small lymphocytic leukemia, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, marginal zone B-cell lymphoma, diffuse large B-cell lymphoma, lymphomatoid granulomatosis, primary effusion lymphoma, Waldenstrom macroglobulinemia, plasma cell leukemia, primary plasma cell leukemia, secondary plasma cell leukemia, lymphoplasmacytic lymphoma, plasmacytoma, heavy chain disease, Burkitt lymphoma, hairy cell leukemia (HCL), mantle cell lymphoma, myeloma, multiple myeloma, mixed phenotype leukemia, acute mixed phenotype leukemia, mixed-lineage leukemia, acute mixed-lineage leukemia, large granular lymphocytic leukemia (LGLL), T- cell LGLL (T-LGLL), natural killer cell LGLL (NK-LGLL), aggressive natural killer (NK) cell leukemia, aggressive NK cell lymphoma, NK/T-cell lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma, gastric MALT lymphoma, lung MALT lymphoma, dendritic cell leukemia, myeloproliferative neoplasms, myelofibrosis, primary myelofibrosis, secondary myelofibrosis, polycythemia vera (PV), essential thrombocythemia (ET), blastic plasmacytoid dendritic cell neoplasm, lipoma, fibroma, fibromatosis, hepatocellular adenoma, renal tubular adenoma, cystadenoma, colonic polyp, gastric polyp, adenomatous polyp, cholangioma, hemangioma, cardiac myxoma, hemangioblastoma, hydatiform mole, fibroid, uterine fibroid, leiomyoma, rhabdomyoma, ganglioneuroma, acoustic neuroma, vestibular schwannoma, schwannoma, benign synovioma, chondroma, osteoma, osteochondroma, enchondroma, giant cell tumor, giant cell tumor of the bone, tenosynovial giant cell tumor, benign germinoma, lymphangioma squamous cell papilloma, acanthosis, acanthosis nigricans, malignant acanthosis, acanthoma, clear cell acanthoma, Degos acanthoma, pilar sheath acanthoma, keratoacanthoma, subungual keratoacanthoma, clear cell adenocarcinoma, apudoma, cylindroma, cutaneous cylindroma, spiradenoma, papillary hidradenoma, hidrocystoma, syringoma, syringocystadenoma papilliferum, trichoepithelioma, focal epithelial hyperplasia, Heck disease, pseudoepitheliomatous hyperplasia, cervical villoglandular carcinoma, cervical mesonephric carcinoma, endocervical adenocarcinoma, and hamartoma.
35. The compound of any one of claims 1-18 for the use according to any one of claims 22-34, wherein the malignant or non-malignant hyperproliferative disorder, or cancer or precancerous lesion is associated with, accompanied by and/or caused by a viral infection.
36. The compound of any one of claims 1-18 for the use according to any one of claims 11-35 wherein the compound is administered as a monotherapy.
37. The compound of any one of claims 1-18 for the use according to any one of claims 19-35 or 38 wherein the compound is administered as a combination therapy with at least one further active agent and/or non-agent-based therapeutic intervention.
38. The compound of any one of claims 1-18 for sensitizing a subject suffering from a hyperproliferative disorder, particularly from a malignant or non-malignant hyperproliferative disorder, or hyperplasia, neoplasia, cancer, cancer metastases, or a precancerous lesion to a different treatment.
39. The compound of any one of claims 1-18 for the use of claims 37 or 38, wherein the further active agent, the non-agent-based therapeutic intervention or the different treatment comprises therapy with antiproliferative agents, cytostatic agents, anticancer agents radiotherapy, chemotherapy, targeted therapy, cancer immunotherapy, surgery, cryotherapy, electrodessication, photodynamic therapy, laser therapy, gene therapy, antisense therapy, mRNA-based therapy, vaccine therapy, cell-based transplantation therapy, stem cell therapy, physical therapy, supportive therapy including hemodialysis, and occupational therapy, thermotherapy, dietary therapy, or any combination thereof.
40. A pharmaceutical composition comprising at least one compound of any one of claims 1 - 18 together with a pharmaceutically acceptable carrier and/or excipient.
41. A pharmaceutical combination, e.g., a composition or kit, comprising at least one compound of any one of claims 1-18 and at least one further active agent together with a pharmaceutically acceptable carrier and/or excipient.
42. A method of treating a hyperproliferative disorder comprising administering to a subject in need thereof, particularly a human subject, a therapeutically effective amount of a compound according to any one of claims 1-18.
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