WO2015025283A2 - Dual action carbonic anhydrase inhibitors - Google Patents

Dual action carbonic anhydrase inhibitors Download PDF

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WO2015025283A2
WO2015025283A2 PCT/IB2014/063989 IB2014063989W WO2015025283A2 WO 2015025283 A2 WO2015025283 A2 WO 2015025283A2 IB 2014063989 W IB2014063989 W IB 2014063989W WO 2015025283 A2 WO2015025283 A2 WO 2015025283A2
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ealkyl
aryl
substituted
alkyl
amino
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PCT/IB2014/063989
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WO2015025283A3 (en
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Philippe Lambin
Jean-Yves Winum
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Stichting Maastricht Radiation Oncology "Maastro-Clinic"
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Publication of WO2015025283A2 publication Critical patent/WO2015025283A2/en
Publication of WO2015025283A3 publication Critical patent/WO2015025283A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/91—Nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/91—Nitro radicals
    • C07D233/92—Nitro radicals attached in position 4 or 5
    • C07D233/95—Nitro radicals attached in position 4 or 5 with hydrocarbon radicals, substituted by nitrogen atoms, attached to other ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503—Five-membered rings
    • C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
    • C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
    • C07F9/65842—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring
    • C07F9/65846—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring the phosphorus atom being part of a six-membered ring which may be condensed with another ring system

Definitions

  • the present invention concerns novel carbonic anhydrase IX inhibitors comprising a nitroimidazole moiety including their use in cancer treatment, especially with radiotherapy and treatment with chemotherapy or targeted agents.
  • Cancer is a leading cause of death and accounts for approximately 13% of all deaths in the world. Most cancers form solid tumors in tissues like head and neck, colon, breast, lung, liver and stomach, and are often characterized by low oxygen concentrations (hypoxia) and acidification of the microenvironment surrounding the tumor cells. Hypoxia and acidification of the extratumoral environment are both associated with aggressive tumor growth, metastasis formation and poor response to radiotherapy, surgery and/or to anticancer chemotherapy. Hypoxia is linked with acidification of extracellular environment that facilitates tumor invasion and CA IX is believed to play a role in this process via its catalytic activity (Svastova et al., 2004).
  • CAs Carbonic anhydrases
  • these enzymes participate in a variety of biological processes, including respiration, calcification, acid-base balance, bone resorption, formation of aqueous humor.
  • 16 isozymes are characterized from which 15 present in humans.
  • CAs in humans are present in several tissues (e.g. Gl tract, reproductive tract, skin, kidneys, lungs, eyes) and some of the CAs are expressed in almost all tissues (e.g. CA II), whereas the expression of others appears to be more restricted (e.g., CA VI and CA VII in salivary glands).
  • CA IX membrane-associated CA isozymes
  • CA IXII membrane-associated CA isozymes
  • CA IX shows restricted expression in normal tissues, but is tightly associated with different types of tumors.
  • CA IX originally detected in human carcinoma HeLa cells as a cell density-regulated antigen (Pastorekova et al, 1992), is strongly induced by tumor hypoxia, through a transcriptional activation by the HlF-1 pathway. Strong association between carbonic anhydrase CA IX expression and intratumoral hypoxia has been demonstrated in carcinomas.
  • CA IX has a very high catalytic activity with the highest proton transfer rate among the known CAs, and has been shown to acidify the extracellular environment and is therefore an interesting target for anticancer therapy, preferably in combination with conventional treatment schedules.
  • CAIs carbonic anhydrase inhibitors
  • CAIs carbonic anhydrase inhibitors
  • the critical problem in designing inhibitors against CAs is the high number of isozymes, the diffuse localization in tissues and the lack of isozyme selectivity of the presently available inhibitors.
  • the ideal characteristics for specific CA IX inhibitors should demonstrate a relatively low inhibition constant (Ki in the nanomolar range) and should be relatively specific over the cytosolic enzymes CA I and CA II, i.e. a strong inhibiting action against CA IX and a relative weak inhibition or no inhibition against CA I and CA II.
  • Ki inhibition constant
  • CA II cytosolic enzymes
  • WO2004048544 that specifically bind to the extracellular components of the in particular CAIX enzyme, which show a higher specificity than those hitherto known in the art.
  • Therapeutic and diagnostic sulfonamide agents are described in WO2006137092.
  • WO2008071421 it was shown that the inhibitory effect of heterocyclic sulfonamides can be further increased by oxidative substituents, in particular nitrosated or nitrosylated substituents, since such groups may increase the acidity of the zinc binding groups and as such being beneficial for the carbonic anhydrase inhibitory properties.
  • Sulfonamide-based metal chelate complexes for imaging are described in WO2009089383.
  • irradiation is used to treat cancer patients as a combined or single treatment.
  • the basic principle of irradiation is to damage the cancer cells to such an extent that they will die. Free radicals are formed and damage the DNA immediately or they react with oxygen, creating reactive oxygen species which damage the cell and more specific the DNA in the cell. However when no or little oxygen is present, what is the case in hypoxic tumors, less reactive oxygen species are formed and the irradiation is not as effective. It has been shown that a 3 fold higher radiation dose is required to kill the same amount of hypoxic cells as compared under normal oxygen concentrations. The concept of radio sensitization of hypoxic cells emerged when certain compounds were able to mimic oxygen and thus enhance radiation damage.
  • the first compounds which demonstrated radio sensitization were nitrobenzenes, followed by nitrofurans and 2-nitroimidazoles, such as misonidazole (see e.g. WO2006102759).
  • misonidazol is neurotoxic and thus the administration thereof is limited.
  • better radio sensitizing drugs such as etanidazole and pimonidazole, were synthesized and tested, but clinical results did not result in a significant therapeutic benefit.
  • WO2012087115 discloses 2- nitroimidazol compounds that show a radio sensitizing effect but are also CA-IX inhibitors.
  • R i is Y, L- Y, or NR (Ci- 6 alkyl-X 2 )), or B-A, or B-L-A;
  • A is an active moiety selected from the group of chelating agent comprising a therapeutically active metal ion, chelating agent comprising a metal ion suitable for imaging, fluorescent moiety, 18 F containing moiety, alkylating moiety, wherein the active moiety comprises at least one hydroxyl;
  • n 1-12;
  • Y may be substituted with halo, hydroxy, amino, nitro, carbonyl, cyano, carboxyamine,
  • Ci- 6 alkylS0 2 NR 7 R 8 , S0 2 NR 7 R 8 , Ci-ealkyl OS0 2 NR 7 R 8 , OS0 2 NR 7 R 8 , Ci- 6 alkylN(R9)S0 2 NR3 ⁇ 4 8 , N(R9)S0 2 NR 7 R 8 , Ci- 6 alkylN(R6)C( 0)N(R6)Ci- 6 alkylaryl, Ci-
  • Ci ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR 12 R 13 , or OP( 0)(OR 14 ) 2 ; wherein the aryl is substituted with a S0 2 NR 7 R 8 , N(R9)S0 2 NR3 ⁇ 4 8 , or OS0 2 NR 7 R 8 ; and wherein the aryl is optionally further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C 2 -6alkenyl, C 2 -6alkynyl, Ci- 6alkyloxy, di(Ci-6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR 4 R 5
  • Y is a saturated, partially unsaturated, or unsaturated heterocycle comprising 5, 6, or 7 atoms, wherein at least one of the atoms is a heteroatom selected from nitrogen, oxygen and sulphur;
  • R 2 is hydrogen, SG, or L-SG, wherein SG is a sulfonamide, sulfamate, or sulfamide group selected from the group consisting of S02NR 7 R 8 ,
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 is each independently hydrogen, halo, hydroxy, or Ci-6alkyl,wherein the Ci ealkyl is optionally substituted with with a substituent selected from the group comprising halo, hydroxy, amino, nitro, Ci- 6alkyloxy, di(Ci-6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, heterocyclic, C3- 7Cycloalkyl, , hydroxyCi-6alkyl or aminoCi-6alkyl , cyano, SiFR 12 R 13 , or a leaving group;
  • R 12 and R 13 is each independently a Ci i2alkyl, or C2-i2alkenyl;
  • R 14 is hydrogen, Ci-2oalkyl, or C2-2oalkenyl, aryl, aminoCi i2alkyl, carbonylCi i2alkyl, hydroxyCi ealkyl, Ci-6alkyloxyCi-6alkyl, or NR 4 R 5 ; wherein at least one of R 1 , R 2 , R 3 is connected to the Nl of the imidazol of formula (I),
  • the compound comprises at least one moiety selected from S0 2 NR 7 R 8 , OS0 2 NR 7 R 8 , NR 9 S0 2 NR 7 R 8 , NR 9 S0 2 .
  • the present invention is directed to compounds according to the invention and/or embodiments thereof for use in the treatment of cancer.
  • the present invention is directed to compounds according to the invention and/or embodiments there of for use in the treatment of infections caused by bacteria, fungi, protozoa, and/or mycoplasma.
  • the present invention is also related to treatment of cancer administering the compound of the present invention and/or embodiments thereof.
  • the present invention is also related to treatment of infections caused by bacteria, fungi, protozoa, and/or mycoplasma administering the compound of the present invention and/or embodiments thereof.
  • the compounds of the present invention have a high specificity for CA IX. It was also found that the compounds of the present invention have a radio- and chemo sensitizing effect. In addition, the compounds of the present invention are less toxic. Furthermore, the compounds of the present invention are more active than the 2-nitroimidazol of the prior art such as disclosed in WO2012087115. Moreover, it has been found that the compounds of the present invention have an improved solubility. What is more, the compounds of the present invention may be administered orally. Oral administration of the compounds of the present invention enables the use for preventing metastasis, as a adjuvant treatment after the main anti-cancer treatment. In addition, inhibition of CA IX decreases the intracellular pH, i.e.
  • the compounds of the present invention have an antimicrobial action and may be used as antimicrobe, such as used as an antibiotic against bacteria, mycoplasma and/or against fungi.
  • the compounds of the invention have a significantly improved overall profile for treating solid tumours, such as tumours of the breast, brain, kidney, colorectal, lung, head and neck, bladder etc. compared to carbonic anhydrase inhibitors known in the art.
  • solid tumours such as tumours of the breast, brain, kidney, colorectal, lung, head and neck, bladder etc.
  • other therapeutic fields such as treating eye disorders in particular, glaucoma, ocular hypertension, age-related macular degeneration, diabetic macular edema, diabetic retinopathy, hypertensive retinopathy and retinal vasculopathies, epilepsy, high-altitude disorders and neuromuscular diseases fall within the range of applications of the compounds of the invention.
  • Extracellular acidosis has been thought to be the result of excess production of lactic acid.
  • glycolytic deficient cells cells in which lactic acid production is hampered
  • extracellular acidosis makes tumours less sensitive to irradiation treatment (Brizel et al, 2001 ; Quennet et al, 2006).
  • the compounds of the present invention are able to reduce the extracellular acidosis in tumors and may improve the sensitivity to irradiation of tumours.
  • the compounds of the present invention are specific for CA IX over other CAs.
  • hypoxic conditions in tumours make them less sensitive to the ionizing radiation commonly used in radiotherapy (Thomlinson & Gray, 1955). Attracting the CA inhibitory compounds towards hypoxic cells, would greatly increase the possible therapeutic effect. This can be done using nitroimidazoles which are trapped in hypoxic cells after a two-fold electron reduction upon low oxygen conditions.
  • there is a need to increase the anti- acidic, antitumor genie effects and specificity of CA IX inhibiting compounds and on the other hand there is a need to target specifically hypoxic cells with compounds that are suitable for radio sensitizing therapy.
  • the compounds of the invention also show a positive effect on chemo sensitivity.
  • Increased intracellular acidosis being the result of CAIX inhibition increase a) the uptake of basic drugs such as doxorubicin or any drug being a base and b) increase the activation of drugs like Temozolomide or any drug being activated intracellularly by low pH.
  • the compounds of the present invention are able to increase the intracellular acidosis in tumors and may improve the sensitivity to drugs of tumours.
  • the compounds of the present invention are specific for CA IX over other CAs and are dual drugs namely have more than one active moieties.
  • compositions containing at least a compound of the present invention of formula (I) together with non toxic adjuvants and/or carriers usually employed in the pharmaceutical field.
  • Figure 1 synthesis route for CAIX inhibitors wherein R 1 is Ci ealkyl substituted with a morpholine,
  • Figure 3 synthesis route for CAIX inhibitors wherein R 1 is Ci ealkyl substituted with a piperazine.
  • Figure 4 alternative synthesis route for CAIX inhibitors wherein R 1 is Ci ealkyl substituted with NR (Ci- 6 alkyl-X 2 )).
  • the nitro group is on the 2, 4 or 5 position of the imidazol of formula (I) see formula (la), formula (lb), and formula (Ic):
  • the nitro group is in the 2 or 5 position of the imidazol, see formula (lb) and (Ic).
  • the nitro group is in the 5 position of the imidazole, see formula (Ic).
  • the nitro group is not in the 4 position. Reduction in hypoxic condition is better for nitro imidazole compound when the nitro is in the 2 or 4 position.
  • R 1 is connected to the Nl of the imidazol, see formula (II):
  • R 2 is connected to the Nl of the imidazole, see formula (III):
  • R 3 is connected to the Nl of the imidazole, see formula (IV):
  • the linker L or Ci ealkyl is further substituted with a substituent selected from the group comprising halo, hydroxy, amino, nitro, Ci- 6alkyl, C 2 -6alkenyl, C 2 -6alkynyl, Ci ealkyloxy, di(Ci-6alkyl)amino, hydroxyamino, bydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci- 6alkylcarbonyl, NR 4 R 5 , heterocyclic, C3-7Cycloalkyl, , hydroxyCi ealkyl, aminoCi- 6alkyl, cyano, SiFR 12 R 13 , or a SG group or an active moiety A.
  • a substituent selected from the group comprising halo, hydroxy, amino, nitro, Ci- 6alkyl, C 2 -6alkenyl, C 2 -6alkynyl, Ci
  • a substituent selected from the group comprising halo, hydroxy, amino, nitro, Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, Ci ealky
  • the alkyl is preferably Ci ealkyl, more preferably Ci-4alkyl, C2-3alkyl, Ci salkyl, Ci-2alkyl, more preferably, C2-3alkyl, or Ci-2alkyl.
  • Ci ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR 12 R 13 , or OP( 0)(OR 14 ) 2 ; wherein the aryl is substituted with a S0 2 NR 7 R 8 , N(R 9 )S0 2 NR 7 R 8 , or OSO2 NR 7 R 8 ; and wherein the aryl is optionally further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci ealkyloxy, di(Ci- 6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi e
  • Y is a saturated, partially unsaturated, or unsaturated heterocycle comprising 5, 6, or 7 atoms, wherein at least one of the atoms is a heteroatom selected from nitrogen, oxygen and sulphur. It is to be understood that also other heteroatoms may be present in Y, such as phosphor.
  • Y is selected from the group comprising pyrrolidine, pyrrole, tetrahydrofuran, furan, thiolane, thiophene, imidazolidine, pyrazolidine, imidazole, pyrazole, oxazolidine, isoxazolidine, oxazole, isoxazole, thiazole, isothiazole, dioxolane, dithiolane, triazole, furazan, oxadiazole, thiazolidine, isothiazolidine, thiadiazole, dithiazole, piperidine, pyridine, oxane, pyran, thiane, thiopyran, piperazine, diazine, morpholine, oxazine, thiomorpholine, thiazine, dioxane, dioxine, dithiane, dithiine, triazine, trio
  • Y is selected from the group comprising Pyrrolidine, Pyrrole, tetrahydrofuran, furan, thiophene, imidazolidine, pyrazolidine, imidazole, pyrazole, oxazolidine, isoxazolidine, oxazole, isoxazole, thiazole, isothiazole, triazole, thiazolidine, isothiazolidine, thiadiazole, dithiazole, piperidine, pyridine, oxane, pyran, piperazine, morpholine, thiomorpholine, and homopiperazine, pyrimidine.
  • Y is selected from the group comprising pyrrolidine, tetrahydrofuran, imidazolidine, imidazole, oxazolidine, isoxazolidine,
  • thiazole triazole, thiadiazole, dithiazole, piperidine, pyridine, piperazine, morpholine, thiomorpholine, and homopiperazine, pyrimidine.
  • Y is selected from the group comprising tetrahydrofuran. imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, triazole, thiazolidine, isothiazolidine, piperazine, morpholine, thiomorpholine, and homopiperazine, pyrimidine.
  • Y is selected from the group comprising tetrahydrofuran, imidazole, triazole, piperazine, morpholine, pyrimidine and thiomorpholine.
  • Y is a saturated heterocycle. In another preferred embodiment of the present invention and/or embodiments thereof, Y is a unsaturated heterocycle.
  • Y is a 5-membered heterocycle. In another preferred embodiment of the present invention and/or embodiments thereof, Y is a 6- membered heterocycle. In another preferred embodiment of the present invention and/or embodiments thereof, Y is a 6- or 7-membered heterocycle. In another preferred embodiment of the present invention and/or embodiments thereof, Y is not a 5-membered heterocycle. In another preferred embodiment of the present invention and/or embodiments thereof, Y is a 7-membered heterocycle.
  • the heteroatom in Y the heteroatom is nitrogen. In another preferred embodiment of the present invention and/or embodiments thereof, in Y the heteroatom is nitrogen and/or sulphur. In another preferred embodiment of the present invention and/or embodiments thereof, in Y the heteroatom is oxygen. In another preferred embodiment of the present invention and/or embodiments thereof, in Y the heteroatom is not oxygen. In another preferred embodiment of the present invention and/or embodiments thereof, in Y the heteroatom is sulfur. In another preferred embodiment of the present invention and/or embodiments thereof, in Y the heteroatom is nitrogen and is attached to the Ci ealkyl via the nitrogen. In another preferred embodiment of the present invention and/or embodiments thereof, Y comprises at least 2 heteroatoms selected from the group of oxygen, nitrogen and sulphur.
  • in Y is not a saturated 5-membered heterocycle comprising a oxygen atom.
  • in Y is not a ribofuranosyl.
  • in Y is not a a-D- Ribofuranosyl.
  • in Y is not a ⁇ -D-Ribofuranosyl.
  • Y in when R 1 is in the 1 position of the imidazol, and R 1 is Y, then Y is not a ⁇ -D-Ribofuranosyl. In another preferred embodiment of the present invention and/or embodiments thereof, when Y is a 6-D-Ribofuranosyl, R 1 is in the 2, 4, or 5 position of the imidazol, preferably in the 4 position.
  • R 1 is Y, NRn(Ci- 6 alkyl-X 2 )), or , L-Y, wherein the L is further substituted with a substituent selected from the group comprising halo, hydroxy, amino, nitro, Ci ealkyl, C 2 -6alkenyl, C 2 -6alkynyl, Ci- 6alkyloxy, di(Ci-6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl,
  • R 1 is Y, Ci-ealkyl substituted
  • R 1 is Y, Ci-ealkyl substituted
  • R 1 is Y, L-Y or
  • R 1 isY or L-Y or NR n (Ci- ealkyl- ⁇ 2 )), wherein L is further substituted with a substituent selected from the group comprising halo, hydroxy, amino, nitro, Ci ealkyl, C 2 -6alkenyl, SiFR 12 R 13 , or a SG group or an active moiety A, and/ or wherein Y may be optionally substituted with halo, hydroxy, amino, nitro, carbonyl, cyano,
  • Ci ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR 12 R!3, or OP( 0)(OR 14 ) 2 ; wherein the aryl is substituted with a S0 2 NR 7 R 8 , N(R 9 )S0 2 NR 7 R 8 , or OS0 2 NR 7 R 8 ; and wherein the aryl is optionally further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C 2 -6alkenyl, C 2 -6alkynyl, Ci ealkyloxy, di(Ci- 6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR 4 R 5 ,
  • R 1 is Y or Ci ealkyl substituted with Y, or Ci ealkyl substituted with wherein the Ci- 6alkyl is further substituted with a substituent selected from the group comprising halo, hydroxy, amino, nitro, SiFR 12 R 13 , and/ or wherein Y may be optionally substituted with halo, hydroxy, amino, nitro, carbonyl, cyano,
  • Ci ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR 12 R 13 , or OP( 0)(OR 14 ) 2 ; wherein the aryl is substituted with a S0 2 NR 7 R 8 , N(R 9 )S0 2 NR 7 R 8 , or OS0 2 NR 7 R 8 ; and wherein the aryl is optionally further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C 2 -6alkenyl, C 2 -6alkynyl, Ci ealkyloxy, di(Ci- 6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR 4 R 5
  • R 1 is Y or L-Y, or NR (Ci- ealkyl- ⁇ 2 )), wherein Y and/or the linker L is not further substituted.
  • R 1 is Y or Ci ealkyl substituted with Y, or Ci ealkyl substituted with wherein Y and/or the Ci ealkyl is not further substituted.
  • Y is further substituted with a substituent selected from the group comprising halo, hydroxy, amino, nitro, SiFR 12 R 13 , or Ci- 6alkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR 12 R 13 , or
  • Y is not further substituted.
  • the linker L is Ci ealkyl, preferably Ci-4alkyl, C2-3alkyl, Ci salkyl, Ci-2alkyl, more preferably, C2-3alkyl, Ci-2alkyl.
  • R 1 is Ci-4alkyl substituted with Y or Ci-4alkyl substituted with NRn(Ci- 6 alkyl-X 2 )).
  • R 1 is Ci salkyl substituted Y or Ci salkyl substituted with - NR ii (Ci- 6 alkyl-X 2 )).
  • R 1 is Ci-2alkyl substituted Y or Ci-2alkyl substituted with - NR ii (Ci- 6 alkyl-X 2 )).
  • R 1 is Ci alkyl substituted with Y or Ci-alkyl substituted with NR 11 (Ci- 6 alkyl-X 2 )).
  • R 1 may be substituted with the substituents as indicated for the L and Ci ealkyl in any embodiment above, where possible. A skilled person will know when such substitution is possible or not.
  • a substituent selected from the group comprising halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci- 6alky
  • a substituent selected from the group comprising halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci- 6alkyloxy, di(Ci-6alkyl)amin
  • Y comprises 5, or 6 atoms, preferably 6 atoms.
  • Y comprises nitrogen and one or two further heteroatoms selected from nitrogen, oxygen and sulphur, preferably oxygen or nitrogen and most preferred nitrogen.
  • Y comprises nitrogen and one further heteroatom selected from nitrogen, oxygen and sulphur, preferably oxygen or nitrogen and most preferred nitrogen.
  • the heteroatom in Y is oxygen or nitrogen and preferably nitrogen.
  • Y is selected from the group comprising imidazolidine, pyrazolidine, tetrahydrofuran, triazole, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperazine, morpholine, thiomorpholine, pyrimidine, and
  • Y is selected from the group comprising imidazolidine, pyrazolidine, tetrahydrofuran, oxazolidine, isoxazolidine, thiazolidine,
  • Y is selected from the group comprising imidazolidine, oxazolidine, tetrahydromran, triazole, thiazolidine, isothiazolidine, piperazine, morpholine, pyrimidine, and thiomorpholine.
  • Y is selected from the group comprising imidazolidine, thiazolidine, tetrahydrofuran, triazole, piperazine, morpholine, pyrimidine, and thiomorpholine .
  • Y is selected from the group comprising imidazolidine, tetrahydrofuran, triazole, piperazine, pyrimidine, and morpholine.
  • Y is selected from the group comprising piperazine, tetrahydrofuran, triazole, pyrimidine, and morpholine.
  • Y is piperazine
  • Y is morpholine
  • Y is imidazolidine
  • Y is thiomorpholine.
  • Y is triazole
  • Y is tetrahydrofuran.
  • Y is pyrimidine
  • Y comprises at least 2 nitrogen atoms.
  • Y comprises at least 2 nitrogen atoms and is substituted with halo, amine, nitro, or cyano.
  • Y comprises at least 2 nitrogen atoms and is substituted with halo. In a more preferred embodiment of the present invention and/or embodiments thereof, Y comprises at least 2 nitrogen atoms and is substituted with amine or nitro.
  • Y comprises at least 2 nitrogen atoms and is further not substituted.
  • Y is substituted with an aryl which aryl is further
  • Y is substituted with an aryl which aryl is further
  • Y is substituted with a aryl which aryl is further substituted with a SO 2 NFOT or OSO 2 NFOT.
  • Y is substituted with a aryl which aryl is further substituted with a S0 2 NR 7 R 8 .
  • Y is substituted with a aryl which aryl is further substituted with a N(R 9 )S0 2 NR 7 R 8 or OS0 2 NR 7 R 8 .
  • Y is substituted with a aryl which aryl is further substituted with a S0 2 NR 7 R 8 or N(R 9 )S0 2 NR 7 R 8 .
  • Y is substituted with a aryl which aryl is further substituted
  • Y is substituted with a aryl which aryl is further substituted with a OS0 2 NR 7 R 8 .
  • Y is substituted with Ci-6alkyl
  • Y is substituted with Ci-6alkylS0 2 NR 7 R 8 , S0 2 NR 7 R 8 , Ci- 6 alkylOS0 2 NR 7 R 8 , OSO2 NR 7 R 8 , Ci-6alkylN(R 9 )S0 2 NR 7 R 8 , or N(R 9 )S0 2 NR 7 R 8 .
  • Y is substituted with Ci-6alkylS02NR 7 R 8 , or S02NR 7 R 8 .
  • Y is substituted with Ci-2alkylS02NR 7 R 8 , or S02NR 7 R 8 .
  • Y is substituted with CialkylS0 2 NR 7 R 8 , or S0 2 NR 7 R 8 .
  • Y is substituted with Ci-6alkylOS0 2 NR 7 R 8 , or OS0 2 NR 7 R 8 .
  • Y is substituted with Ci-3alkylOS0 2 NR 7 R 8 , or OS0 2 NR 7 R 8 .
  • Y is substituted with Ci-2alkylOS0 2 NR 7 R 8 , or OS0 2 NR 7 R 8 .
  • Y is substituted with CialkylOS0 2 NR 7 R 8 , or OS0 2 NR 7 R 8 .
  • Y is substituted with Ci-6alkylN(R 9 )S02NR 7 R 8 , or
  • N(R9)S0 2 NR 7 R 8 is substituted with Ci-3alkylN(R 9 )S02NR 7 R 8 , or
  • Y is substituted with Ci-2alkylN(R 9 )S02NR 7 R 8 , or
  • Y is substituted with CialkylN(R 9 )S02NR 7 R 8 , or
  • Y comprises at least 2 nitrogen atoms and is substituted on the nitrogen atom. In a more preferred embodiment of the present invention and/or embodiments thereof, Y comprises at least 2 nitrogen atoms and is attached to the Ci ealkyl at the terminal C atom of the Ci-ealkyl.
  • X 1 , X 2 is each independently halo or cyano.
  • X 1 , X 2 is each independently halo.
  • a substituent selected from
  • a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci ealkyloxy, carbonyl, Ci- 6alkylcarbonyl, NR 4 R 5 , heterocyclic, C3-7Cycloalkyl,
  • a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci ealkyloxy, carbonyl, Ci- 6alkylcarbonyl, NR 4 R 5 , heterocyclic, C3-7Cycloal
  • X 1 , X 2 is each independently SG, or L-SG.
  • the aryl in X 1 , X 2 is each independently substituted with a
  • the aryl in X 1 , X 2 is each independently substituted with a S0 2 NR3 ⁇ 4 8 .
  • the aryl in X 1 , X 2 is each independently substituted with a N(R9)S0 2 NR3 ⁇ 48 or OSO2 NR3 ⁇ 4 8 .
  • the aryl in X 1 , X 2 is each independently substituted with a S0 2 NR 7 R 8 or N(R 9 )S0 2 NR 7 R 8 .
  • the aryl in X 1 , X 2 is each independently substituted with a N(R 9 )S0 2 NR 7 R 8 .
  • the aryl in X 1 , X 2 is each independently substituted with a OSO2 NR 7 R 8 .
  • X 1 , X 2 is each independently
  • X 1 , X 2 is each independently SG, or L-SG ,Ci-
  • X 1 , X 2 is each independently
  • X 1 , X 2 is each independentl
  • X 1 , X 2 is each independently SG, L-SG, Ci-
  • X 1 , X 2 is each independently Ci-
  • X 1 , X 2 is each independently SG, L-SG, Ci-
  • X 1 , X 2 is each independently Ci-6alkyl
  • X 1 , X 2 is each independently
  • X 1 , X 2 is each independently
  • X 1 , X 2 is each independently
  • X 1 , X 2 is each independently
  • X 1 , X 2 is each independently
  • X 1 , X 2 is each independently
  • X 1 , X 2 is each independently Ci-6alkylS02NR 7 R 8 , S02NR 7 R 8 , Ci- 6 alkylOS02 NR 7 R 8 , OSO2 NR3 ⁇ 4s, Ci-6alkylN(R 9 )S0 2 NR3 ⁇ 48, or N(R 9 )S0 2 NR3 ⁇ 48.
  • X 1 , X 2 is each independently Ci-6alkylS02NR 7 R 8 , or
  • X 1 , X 2 is each independently Ci-3alkylS02NR 7 R 8 , or
  • X 1 , X 2 is each independently Ci-2alkylS02NR 7 R 8 , or
  • X 1 , X 2 is each independently CialkylS02NR7R8, or
  • X 1 , X 2 is each independently Ci-6alkylOS0 2 NR 7 R 8 , or OSO2 NR 7 R 8 .
  • X 1 , X 2 is each independently Ci-3alkylOS02 NR 7 R 8 , or OSO2 NR 7 R 8 .
  • X 1 , X 2 is each independently Ci-2alkylOS02 NR 7 R 8 , or OSO2 NR 7 R 8 .
  • X 1 , X 2 is each independently CialkylOS02 NR 7 R 8 , or OSO2 NR 7 R 8 .
  • X 1 , X 2 is each independently Ci-6alkylN(R 9 )S02NR 7 R 8 , or N(R 9 )S0 2 NR 7 R 8 .
  • X 1 , X 2 is each independently Ci-3alkylN(R 9 )S02NR 7 R 8 , or N(R 9 )S0 2 NR 7 R 8 .
  • X 1 , X 2 is each independently Ci-2alkylN(R 9 )S02NR 7 R 8 , or N(R 9 )S0 2 NR 7 R 8 .
  • X 1 , X 2 is each independently CialkylN(R 9 )S02NR 7 R 8 , or N(R 9 )S0 2 NR 7 R 8 .
  • the compounds of the present invention comprise at least one SG group wherein SG is a sulfonamide, sulfamate, or sulfamide group selected from the group consisting of S0 2 NR 7 R 8 , OS0 2 NR 7 R 8 , NR 9 S0 2 NR 7 R 8 , NR 9 S0 2 -phenyl, aryl substituted with S02NR 7 R 8 , aryl substituted with OS02NR 7 R 8 , aryl substituted with NR 9 S0 2 NR 7 R 8 , or aryl substituted with NR 9 S0 2 -phenyl.
  • SG is a sulfonamide, sulfamate, or sulfamide group selected from the group consisting of S0 2 NR 7 R 8 , OS0 2 NR 7 R 8 , NR 9 S0 2 NR 7 R 8 , NR 9 S0 2 -phenyl, aryl substituted with S02NR 7 R 8 ,
  • the compounds of the present invention comprise only one SG group. It is to be understood that the SG group may be present in R 1 and R 3 , as substituent of L, A, B, Y, X 1 , X 2 , or in R 2 .
  • R 1 when R 1 comprises a SG group then R 2 does not comprise a SG group. In a more preferred embodiment of the present invention and/or embodiments thereof, when R 1 comprises a S02NR 7 R 8 , OS02NR 7 R 8 , or a
  • R 1 comprises a S02NR 7 R 8 , OS02NR 7 R 8 , or a
  • R 2 does not comprise a SG group.
  • R 1 may comprise a S02NR 7 R 8 , OSO2 NR 7 R 8 or NR 9 S02 through the linker containing an aryl, or through B ccomprising a moiety S0 2 NR 7 R 8 , OSO2 NR 7 R 8 or NR 9 S0 2; that Y or A comprises a moiety S0 2 NR 7 R 8 , OSO2 NR 7 R 8 or NR 9 S02. R !
  • the compound of the present invention and/or embodiments thereof comprises at least one moiety selected from S0 2 NR 7 R 8 , OS0 2 NR 7 R 8 , NR 9 S0 2 NR 7 R 8 , NR 9 S0 2 . It is to be understood that S0 2 NR 7 R 8 , N(R 9 )S0 2 NR 7 R 8 , or OS0 2 NR 7 R 8 > NR 9 S0 2 such as the SG group may be present in R 1 and R 3 , as substituent of L, Y, X 1 , X 2 , or A, or may be present in R 2 .
  • R 1 may also be B-L-A or B-A.
  • L is a linker as defined above.
  • the B group comprises sulfonamide groups S0 2 NR 7 R 8 , N(R 9 )S0 2 NR 7 R 8 , or OS0 2 NR 7 R 8 .
  • R 2 may be hydrogen, as long as the compounds comprises as least one sulfonamide group.
  • A is an active moiety selected from the group of chelating agent comprising a therapeutically active metal ion.
  • Therapeutically active metal ions are well known to a skilled person and are often radioactive metal ion emitting ⁇ and/or ⁇ radiations. However a emitters may be also be used. Suitable therapeutically active metal ion may be selected from the group consisting of Bismuth-213, Caesium-137, Cobalt-60 , Dysprosium- 165, Erbium-169 , Holmium-166, Iodine- 125, Iodine-131 , Iridium-192, Lead-212 , Lutetium-177, alladium-103 , Phosphorus-32, Rhenium- 186 , Rhenium- 188, Samarium- 153, Strontium-89 , Yttrium-90.
  • Suitable chelating agents are chelating agents that can complex metal ions. Suitable chelating agents may be selected from DOTA, DTPA, Deferoxamine, DOTA-TATE, DOTATOC, DTPA-BMA, EOB-DTPA, HP-D03A, BOPTA.
  • A is chelating agent comprising a metal ion suitable for imaging.
  • Metal ions suitable for imaging may be metal ions that are used in PET scans, MM and so on.
  • Suitable metal ion for imaging may be selected from the group consisting of Cobalt - 57 , Copper-64, Copper-67 , Gallium-67 , Gallium-68 , Germanium-68 , Indium- 111, Iodine- 123 , Iodine- 124, Krypton-81m, Rubidium-81, Rubidium, Strontium-82, Thallium-201, Iron, Iron oxide, Gadolinium-64, Zirkonium-89.
  • a fluorescent moiety is a fluorescent chemical compound that can re-emit light upon light excitation.
  • Fluorescent moiety typically contain several combined aromatic groups, or plane or cyclic molecules with several n bonds. Fluorescent moieties may be used as a tracer in fluids, as a dye for staining of certain structures, as a substrate of enzymes, or as a probe or indicator.
  • Suitable fluorescent moieties may be selected from the group comprising fluorescent protein such as GFP (green), YFP (yellow) and RFP (red) or Nonprotein organic fluorescent moiety such as Xanthene derivatives e.g. fluorescein, rhodamine, Oregon green, eosin, and Texas red; Cyanine derivatives e.g. cyanine, indocarbocyanine, oxacarbocyanine, thiacarbocyanine, and merocyanine;
  • Naphthalene derivatives (dansyl and prodan derivatives); Coumarin derivatives, , oxadiazole derivatives e.g. pyridyloxazole, nitrobenzoxadiazole and benzoxadiazole; Anthracene derivatives e.g. anthraquinones, including DRAQ5, DRAQ7 and CyTRAK Orange; Pyrene derivatives e.g.cascade blue; Oxazine derivatives e.g.Nile red, Nile blue, cresyl violet, oxazine 170; Acridine derivatives e.g.proflavin, acridine orange, acridine yellow; Arylmethine derivatives e.g. auramine, crystal violet, malachite green; Tetrapyrrole derivatives e.g.porphin, phthalocyanine, bilirubin.
  • oxadiazole derivatives e.g. pyridyloxazole, nitrobenzox
  • A is a 18 F containing moiety.
  • 18 F containing moieties may be used for imaging and therapy.
  • Suitable 18 F containing moieties may be selected from the group consisting of 18 fluorothymidine, 18 F-miso (fluoromisonidazole), 18 F-choline, and 18 fluorodeoxyglucose, florbetapir-fluorine-18, fallypride (18F), 18F-EF5.
  • A is a alkylating moiety. Alkylating agents are used in cancer treatment and attach an alkyl group (CnH2n+l) to DNA.
  • Suitable alkylating agents may be selected from the group consisting of Nitrogen mustards , Cyclophosphamide, Mechlorethamine or mustine (HN2) (trade name Mustargen), Uramustine or uracil mustard, Melphalan, Chlorambucil, Ifosfamide, Bendamustine, Nitrosoureas , Carmustine, Lomustine, Streptozocin, Alkyl sulfonates , Busulfan, Thiotepa, procarbazine, altretamine, tetrazines, dacarbazine, mitozolomide, temozolomide.
  • the active moiety In order for the active moiety to be able to connect to the linker it must contain at least one hydroxyl.
  • the active moiety may be substituted with a sulfonamide, sulfamate, or sulfamide group selected from the group consisting of S0 2 NR 7 R8, OS0 2 NR 7 R8, NR 9 S0 2 NR 7 R8, NR 9 S02-phenyl.
  • the active moiety needs at least NH group and/or a second hydroxyl group.
  • the active moiety contains a sulfonamide group such as of S0 2 NR3 ⁇ 48, OS0 2 NR3 ⁇ 48, NR9S0 2 NR3 ⁇ 48, then R 2 may be hydrogen.
  • R 2 is hydrogen, SG, or L-SG, wherein SG is a sulfonamide, sulfamate, or sulfamide group selected from the group consisting of S02NR 7 R 8 , OS02NR 7 R 8 ,
  • NR 9 S0 2 NR7R8 NR 9 S0 2 -phenyl, aryl substituted with S0 2 NR 7 R 8 , aryl substituted with OS0 2 NR 7 R 8 , aryl substituted with NR 9 S0 2 NR 7 R 8 .
  • L is defined as above and all the embodiments indicated for L above are also envisioned for L-SG.
  • SG is a moiety selected from the group consisting of S0 2 NR 7 R 8 , OS0 2 NR 7 R ⁇ , NR 9 S0 2 NR3 ⁇ 48, NR 9 S0 2 -phenyl, aryl substituted with
  • SG is a moiety selected from the group consisting of S0 2 NR 7 R 8 , OS0 2 NR 7 R 8 , NR 9 S0 2 NR 7 R 8 , aryl substituted with S0 2 NR 7 R ⁇ , aryl
  • SG is a moiety selected from the group consisting of S0 2 NR 7 R 8 , OS0 2 NR 7 R 8 , NR 9 S0 2 NR 7 R 8 .
  • SG is a moiety selected from the group consisting of aryl substituted with S0 2 NR 7 R 8 , aryl substituted with OS0 2 NR 7 R 8 , aryl substituted with NR 9 S0 2 NR 7 R 8 .
  • n is l-12,more preferably n is 1-12, more preferably n is 1-10, more preferably n is 2-8, more preferably n is 3-6.
  • Ci-6alkyl in the definition of R 1 , R 2 , R 3 is preferably Ci.4alkyl, C2- ealkyl, Ci-ealkyl, Ci.2alkyl, more preferably, C2-3alkyl, or Ci.2alkyl.
  • Ci-6alkyl in the definition of R 2 is preferably Ci.4alkyl, C2-3alkyl, Ci- ealkyl, Ci.2alkyl, more preferably, C2-3alkyl, or Ci.2alkyl.
  • N(R 9 )S0 2 NR3 ⁇ 48, Ci- 6 N(R6)C( 0)N(R6)Ci- 6 aryl, Ci- wherein the aryl is substituted with a S0 2 NR3 ⁇ 4 8 , N(R 9 )S0 2 NR3 ⁇ 4 8 , or OS0 2 NR 7 R 8 ; and wherein the aryl is further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C 2 -6alkenyl, C 2 -6alkynyl, Ci ealkyloxy, di(Ci- 6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR 4 R 5 , heterocyclic, C3-7Cycloalkyl, , hydroxyCi-eal
  • R i is Y, L- Y, or
  • the aryl in R 2 is further not substituted.
  • a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, Ci ealkyloxy, carbonyl, Ci ealkylcarbonyl, NR 4 R 5 , heterocyclic, C3-7Cycloalkyl, , hydroxyCi ealky
  • a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, Ci ealkyloxy, carbonyl, Ci ealkylcarbonyl, NR 4 R 5 , heterocyclic, C3-7Cycloalkyl, , hydroxyCi ealky
  • the aryl in R 2 is further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, carbonyl, NR 4 R 5 , cyano, SiFR 12 R 13 , or
  • the aryl in R 2 is substituted with a S02NR 7 R 8 or OSO2 NR 7 R 8 .
  • the aryl in R 2 is substituted with a S02NR 7 R 8 .
  • the aryl in R 2 is substituted with a N(R 9 )S02NR 7 R 8 or OSO2 NR 7 R 8 .
  • the aryl in R 2 is substituted with a S02NR 7 R 8 or
  • the aryl in R 2 is substituted with a N(R 9 )S02NR 7 R 8 .
  • the aryl in R 2 is substituted with a OSO2 NR 7 R 8 .
  • R 2 is Ci-6alkyl
  • R 2 is
  • R 2 is
  • R 2 is Ci-6alkylS0 2 NR3 ⁇ 48, S0 2 NR3 ⁇ 4 8 , Ci-6alkylOS0 2 NR3 ⁇ 4 8 , OSO2 NR 7 R 8 , Ci-6alkylN(R 9 )S0 2 NR 7 R 8 , N(R 9 )S0 2 NR 7 R 8 .
  • R 2 is Ci- 6 alkylS02NR3 ⁇ 4 8 , or S0 2 NR3 ⁇ 4 8 .
  • R 2 is Ci-3alkylS0 2 NR3 ⁇ 48, or S0 2 NR3 ⁇ 4 8 .
  • R 2 is Ci-2alkylS0 2 NR 7 R 8 , or S0 2 NR 7 R 8 .
  • R 2 is CialkylS02NR7R8, or S0 2 NR 7 R 8 . In a more preferred embodiment of the present invention and/or embodiments thereof, R 2 is Ci- 6 alkylOS0 2 NR 7 R 8 , or OSO2 NR 7 R 8 .
  • R 2 is Ci-3alkylOS0 2 NR 7 R 8 , or OSO2 NR 7 R 8 .
  • R 2 is Ci-2alkylOS0 2 NR 7 R 8 , or OSO2 NR 7 R 8 .
  • R 2 is CialkylOS0 2 NR 7 R 8 , or OSO2 NR 7 R 8 .
  • R 2 is Ci- 6 alkylN(R 9 )S0 2 NR 7 R 8 , or N(R 9 )S0 2 NR 7 R 8 .
  • R 2 is Ci-3alkylN(R 9 )S0 2 NR 7 R 8 , or N(R 9 )S0 2 NR 7 R 8 .
  • R 2 is Ci- 2 alkylN(R 9 )S0 2 NR 7 R 8 , or N(R 9 )S0 2 NR 7 R 8 .
  • R 2 is CialkylN(R 9 )S0 2 NR 7 R 8 , or N(R 9 )S0 2 NR 7 R 8 .
  • R 3 is hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2- 6alkenyl, C 2 -6alkynyl, Ci ealkyloxy, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR 4 R 5 , cyano,
  • B, L and A are as defined above including all the preferred embodiments.
  • R 3 is hydrogen, hydroxy, amino, Ci ealkyl, carbonyl,
  • R 3 is hydrogen, hydroxy, Ci ealkyl, SiFR 12 R 13 , or B-L-A, or B-A, more preferably Ci salkyl, more preferably Ci-2alkyl, more preferably Cialkyl.
  • halo is bromine, chlorine, fluorine, iodine, astatine, or ununseptium, more preferably bromine, chlorine, fluorine, or iodine, ,more preferably, bromine, chlorine, or fluorine, more preferably bromine, or chlorine.
  • R 3 is NR 4 R 5 .
  • R 4 and R 5 is -CH2-CH2-Z, wherein Z is a leaving group.
  • Z is halogen, tosylate, mesylate, fluorosulfonates, triflates, nonaflates.
  • Z is iodide, bromide, chloride, mesylate.
  • R 3 is NR 4 R 5 , wherein R 4 , and R 5 are -CH2-CH2-Z, wherein Z is a leaving group selected from the group consisting of halogen, tosylate, mesylate, fluorosulfonates, triflates, nonaflates, preferably Z is a selected from the group consisting of iodide, bromide, chloride, mesylate.
  • Compounds with N-(C2H4-Z)2 groups may function as alkylating agent and may be used in the treatment of cancer.
  • Alkylating agents attach an alkyl group to the DNA.
  • R 3 is SiFR 12 R 13 .
  • R 12 and R 13 is each independently a Ci i2alkyl, or C2- i2alkenyl, being straight or branched, more preferably Ci ealkyl, or C2-6alkenyl, more preferably methyl, ethyl, propyl, or butyl, more preferably, propyl, or butyl, more preferably isopropyl or tertiary butyl.
  • R 12 and R 13 are the same.
  • R 3 is SiFR 12 R 13 , wherein R 12 and R 13 is each independently a Ci ealkyl, tertiary butyl, isopropyl, preferably tertiary butyl, isopropyl,methyl, ethyl.
  • Compounds with SiFR 12 R 13 may be used for PET imaging by exchanging the normal 19 F by the radioactive 18 F.
  • the compound comprises a
  • SiFR 12 R 13 group, and F is 18 F.
  • R 3 is B-L-A, or B-A.
  • R 1 is B-A, or B-L-A
  • R 3 is not B-A, or B-L-A.
  • R 1 is not B-A, or B-L-A.
  • aryl is an aromatic cyclic compound comprising 5- 12 atoms, and may mono-cyclic, bi- or tricyclic.
  • Aryl may contain heteroatoms and is then referred to as heteroaryl.
  • Aryl is phenyl or naphthalenyl, pyridmyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl, oxadiazolyl, tetrazolyl, benzofuranyl or tetrahydrofuranyl; each phenyl or naphthalenyl can optionally be substituted with one, two or three substituents each independently selected from halo, hydroxy, hydroxyCi ealkyl, Ci-ealkyl, amino, polyhaloCi ealkyl and Ci ealkyloxy; and each phenyl or naphthalenyl can optionally be substituted with a bivalent radical selected from methylene dioxy and
  • each pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl, oxadiazolyl, tetrazolyl, benzofuranyl, or tetrahydrofuranyl can optionally be substituted with one, two or three substituents each independently selected from halo, hydroxy, Ci ealkyl, amino, polyhaloCi ealkyl, aryl, arylCi ealkyl or Ci- 6alkyloxy; and each pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl, benzofuranyl, or tetrahydrofuranyl can optionally be substituted with a bivalent radical selected from methylene dioxy or ethylene dioxy.
  • aryl is phenyl or napthyl, more preferably phenyl.
  • heterocyclic is a cyclic compound comprising 4- 12 atoms of which at least one is a heteroatom and may be saturated, or unsaturated. Heteroatoms are ususally nitrogen, oxygen, or sulphur.
  • Heterocyclic is dioxetan, pyrrolidine, pyrrole, furan, tetrahydrofyran, thioane, thiophene, imidazoldine, imidazole, pyrazole, pyrazolidine, oxazolidine, oxazole, isoxazole, thiazolidine, thiazole, isothiazole, piperidine, pyridine, pyran, oxane, thiane, thiopyran, piperazine, diazine, oxazine, morpholine, thiomorpholine, thiazine, dioxane, or triazine.
  • heterocyclic is pyrrolidine, pyrrole, furan, tetrahydrofyran, thiophene, imidazoldine, imidazole, pyrazole, pyrazolidine, thiazolidine, piperidine, pyridine, pyran, or morpholine.
  • heterocyclic is furan, tetrahydrofyran, imidazole, pyrazole, piperidine, pyridine, pyran, or morpholine.
  • a more preferred embodiment of the present invention and/or embodiments thereof heterocyclic is furan, tetrahydrofyran, imidazole, pyrazole, piperidine, pyridine, pyran, or morpholine.
  • heterocyclic is imidazole, pyridine, or morpholine.
  • a leaving group is a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage.
  • Leaving groups can be anions or neutral molecules.
  • Common anionic leaving groups are halides such as CI “ , Br-, and I " , and sulfonate esters, such as para-toluenesulfonate ("tosylate", TsO " ) or diazonium, oxonium.
  • Common neutral molecule leaving groups are water (H2O), and ammonia.
  • a leaving group is halogen, tosylate, mesylate, fluorosulfonates, triflates, nonaflates, Ci i2alkylN2, Ci i2alkylOCi i2alkyl, Ci i2alkylOS02F, Ci- i2alkylOS02perfluoratedCi-6alkyl, nitrate, phosphate, Ci-6alkylSCi-6alkyl, tetraCi- 6alkylammonium, halogenCi ealkyl, Ci ealkylOaryl, Ci ealkylhydroxy, carbonylCi- 6alkyloxyCi-6alkyl .
  • a leaving group is halogen, tosylate, mesylate,
  • a leaving group is halogen, tosylate, mesylate, fluorosulfonates, triflates, nonaflates, or halogenCi- 6alkyl.
  • a leaving group is iodide, bromide, chloride, tosylate, or mesylate.
  • R 4 , R 5 is each independently hydrogen, hydroxy, or Ci-ealkyl, more preferably Ci salkyl, more preferably Ci-2alkyl, more preferably Cialkyl. In a more preferred embodiment of the present invention and/or embodiments thereof, R 4 , R 5 is each independently hydrogen, Ci-ealkyl, more preferably Ci salkyl, more preferably Ci-2alkyl, more preferably Cialkyl.
  • R 4 , R 5 is hydrogen
  • R 6 is hydrogen, hydroxy, or Ci-ealkyl, more preferably Ci- 3alkyl, more preferably Ci-2alkyl, more preferably Cialkyl.
  • R 6 is hydrogen, Ci ealkyl, more preferably Ci salkyl, more preferably Ci-2alkyl, more preferably Cialkyl.
  • R 6 is hydrogen
  • R 7 , R 8 is each independently hydrogen, hydroxy, or Ci-ealkyl, more preferably Ci salkyl, more preferably Ci-2alkyl, more preferably Cialkyl.
  • R 7 , R 8 is each independently hydrogen, Ci-ealkyl, more preferably Ci salkyl, more preferably Ci-2alkyl, more preferably Cialkyl.
  • R 7 , R 8 is hydrogen
  • R 9 , R 10 , R 11 is each independently hydrogen, hydroxy, or Ci-ealkyl, more preferably Ci salkyl, more preferably Ci-2alkyl, more preferably Cialkyl.
  • R 9 , R 10 , R 11 is each independently hydrogen, Ci ealkyl, more preferably Ci salkyl, more preferably Ci-2alkyl, more preferably Cialkyl.
  • R 9 , R 10 , R 11 is hydrogen.
  • R 10 , R 11 are the same.
  • R 14 is hydrogen, Ci-2oalkyl, or C2-2oalkenyl, aryl, aminoCi i2alkyl, carbonylCi i2alkyl, hydroxyCi ealkyl, Ci-6alkyloxyCi-6alkyl, or NR 4 R 5 .
  • R 14 is hydrogen, Ci-iealkyl, C2 i6alkenyl, aryl, aminoCi i2alkyl, carbonylCi i2alkyl, hydroxyCi ealkyl, Ci-6alkyloxyCi-6alkyl, or NR 4 R 5 .
  • R 14 is hydrogen, Ci-ealkyl, C2- 6alkenyl, aryl, aminoCi ealkyl, carbonylCi i2alkyl, hydroxyCi ealkyl, Ci ealkyloxyCi- 6alkyl, or NR 4 R 5 .
  • R 14 is hydrogen, Ci-2oalkyl, C2-2oalkenyl, aryl, aminoCi i2alkyl, carbonylCi i2alkyl, hydroxyCi ealkyl, or NR 4 R 5 .
  • R 14 is hydrogen, Ci-2oalkyl, C2- 2oalkenyl, aryl, aminoCi i2alkyl, or NR 4 R 5 . In a more preferred embodiment of the present invention and/or embodiments thereof, R 14 is hydrogen, Ci-2oalkyl, or C2- 2oalkenyl, or aryl, or NR 4 R 5 . In a more preferred embodiment of the present invention and/or embodiments thereof, R 14 is hydrogen, Ci-iealkyl, C2-i6alkenyl, or aryl, or NR 4 R 5 .
  • R 14 is hydrogen, Ci i2alkyl, C2-i2alkenyl, or aryl, or NR 4 R 5 . In a more preferred embodiment of the present invention and/or embodiments thereof, R 14 is hydrogen, Ci-ealkyl, C2-ealkenyl, or aryl, or NR 4 R 5 . In a more preferred embodiment of the present invention and/or embodiments thereof, R 14 is hydrogen, Ci-2oalkyl, or C2-2oalkenyl, or NR 4 R 5 . In a more preferred embodiment of the present invention and/or embodiments thereof, R 14 is hydrogen, Ci-2oalkyl, or NR 4 R 5 .
  • the compound is selected from the group consisting of
  • the cancer is selected from the group of breast carcinoma, brain carcinoma, kidney carcinoma, colorectal carcinoma, lung carcinoma, head and neck carcinoma, esophageal carcinoma, hepatocellular carcinoma, cholangiocarcinoma, renal cell carcinoma, testis carcinoma, cervix carcinoma, endometrium carcinoma, ovarian carcinoma, Squamous cell carcinoma, Basal cell carcinoma, glioma, ependymoma, mesothelioma, papillary carcinoma, follicular carcinoma, adenocarcinoma, stomach carcinoma, duodenum carcinoma, biliary carcinoma, pancreas carcinoma, , and bladder carcinoma.
  • the cancer is colorectal cancer.
  • the compound of the present invention and/or embodiments thereof are suitable for use as antimicrobial compound.
  • the compound is used to treat infections caused by bacteria, fungi, protozoa, and/or mycoplasma.
  • the present invention is also related to treatment of cancer
  • the present invention is also related to treatment of infections caused by bacteria, fungi, protozoa, and/or mycoplasma administering the compound of the present invention and/or embodiments thereof.
  • the present invention also features methods of using or preparing or formulating such pharmaceutical compositions.
  • the pharmaceutical compositions can be prepared using conventional pharmaceutical excipients and compounding techniques known to those skilled in the art of preparing dosage forms. It is anticipated that the compounds of the invention can be administered by oral, parenteral, rectal, topical, or ocular routes, intravenous or by inhalation or by nasal spray. Preparations may also be designed to give slow release of the active ingredient.
  • the preparation may be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, powders for reconstitution, liquid preparations, or suppositories.
  • compounds may be administered by intravenous infusion or topical administration, but more preferably by oral administration.
  • the compounds of the invention may be provided in the form of tablets or capsules, or as a solution, emulsion, or suspension.
  • Tablets for oral use may include the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservatives.
  • suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like; typical liquid oral excipients include ethanol, glycerol, water and the like.
  • Starch, polyvinyl-pyrrolidone, sodium starch glycolate, microcrystalline cellulose, and alginic acid are suitable
  • Binding agents may include starch and gelatin.
  • the lubricating agent if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.
  • Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid, semi-solid, or liquid diluent, and soft gelatin capsules wherein the active ingredient is mixed with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.
  • Liquids for oral administration may be suspensions, solutions, emulsions or syrups or may be presented as a dry product for reconstitution with water or other suitable vehicles before use. Compositions of such liquid may contain
  • suspending agents for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel and the like
  • non-aqueous vehicles which include oils (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol or water; preservatives (for example, methyl or propyl p- hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if needed, flavoring or coloring agents.
  • the compounds of this invention may also be administered by non-oral routes.
  • Compound 16 may be further purified by silica gel column chromatography. TLC medium: 9: 1 DCM and Methanol.
  • TLC medium 9: 1 DCM:MeOH, Rf: 0.8, % of Yield: Global
  • lodometronidazole (leqv.) and Boc-Piperazine (2eqv.) were dissolved in THF and allowed to stir at reflux. Reaction was followed by TLC.
  • Reaction mixture was filtered and washed with cold diethyl ether to get pure compound as solid.
  • the compounds of the invention are tested for their effects on CA inhibition and the resulting effect on extracellular acidosis using classical chemistry and biology assays.
  • the compounds of the invention are tested on their inhibitory activity on carbonic anhydrase in the following experiment:
  • the inhibition constants for the compounds for four CA isozymes, CA I, II, IX and XII are determined.
  • An Applied Photophysics (Oxford, UK) stopped-flow instrument is used for assaying the CA-catalyzed CO2 hydration activity (Khalifah, 1971). Phenol red (at a concentration of 0.2 mM) is used as indicator, working at the absorbance maximum of 557 nm, with 10 mM Hepes (pH 7.5) as buffer, 0.1 M Na2SO (for maintaining constant the ionic strength), following the CA-catalyzed CO2 hydration reaction for a period of 10- 100 s.
  • the CO2 concentrations ranges from 1.7 to 17 mM for the determination of the kinetic parameters and inhibition constants.
  • For each inhibitor at least six traces of the initial 5- 10% of the reaction are used for determining the initial velocity. The uncatalyzed rates are determined in the same manner and subtracted from the total observed rates.
  • Stock solutions of inhibitor (1 mM) are prepared in distilled-de ionized water with 10-20% (v/v) DMSO (which is not inhibitory at these concentrations) and dilutions up to 0.1 nM are done thereafter with distilled- deionized water.
  • Inhibitor and enzyme solutions are preincubated together for 15 min at room temperature prior to assay, in order to allow for the formation of CA IX - inhibitor complex.
  • the inhibition constants are obtained by non-linear last- squares methods using PRISM 3 and represent the mean from at least three different determinations.
  • Aim of the in vitro experiments is to assess the efficacy of compounds in reducing the extracellular acidification upon hypoxia.
  • HT-29 colorectal (HT-29) and a cervical (HeLa) carcinoma cell line are tested in normoxic (ambient oxygen concentration) and hypoxic (0.2% oxygen) conditions.
  • HT-29 cells are known to be constitutive hypoxia inducible CA IX (CA IX expression under normoxia and increased CA IX expression upon hypoxia) expressing cells.
  • HeLa cells are hypoxia inducible (at lower density) CA IX expressing cells. Therefore, HeLa cells are first incubated for 24h hypoxia to ensure CA IX expression in the first place (time point assessed in time series experiments). Afterwards, compounds are added and cells are incubated for another 24h.
  • Compounds are added (1 h for HT-29 or 24h for HeLa after start hypoxic exposure) to have a final concentration of 1 mM or 0.1 mM, by adding 400 ⁇ 1 to the dishes, starting from a 10 or 1 mM stock (DMSO final concentration 0.1 %). Blanc controls receive DMSO/PBS without compound.
  • pH of the medium is measured after 24h (HT-29) or 48h (HeLa) inside the hypoxic chamber after calibration of the electrode to reduced oxygen
  • the first experiments are carried out on parental HT-29 xenografts.
  • the second are done on HT-29 xenografts harbouring a knock-down for CA IX.
  • a shRNA construct against CA IX is introduced in the HT-2S cells using the p ETRO-super vector. After selection and screening, cells with a 95% efficient knock-down for CA IX are selected.
  • a scrambled shRNA construct is used and those cells. These cells still demonstrate CA IX mRNA and protein expression.
  • Tumor xenografts are produced by injecting the colorectal carcinoma cells (1 ,5 10 6 ) subcutaneously into the lateral flank of NMRI-nw mice (28 - 32 g).
  • Tumor growth is monitored 3x/week by measuring the tumor dimensions in 3 orthogonal directions. Measurements are corrected for skin thickness (-0.5 mm) and tumor volumes are calculated using the formula A x B x C x pi/6, were A, B and C represent the orthogonal diameters. At an average tumor volume of 250 mm 3 , compounds are injected intravenously (5 x 5 mg/kg intravenously) using the lateral tail vein. At day 3 animals are
  • HT-29 (human colorectal adenocarcinoma) cells are transfected with a lentiviral pTRIPZ plasmid (construct 2.1) containing TurboRFP and CAIX shRNA, flanked by a tetracycline response element. Transcription of the shRNA is induced by 1 pg/mL doxycycline (dox) and verified by expression of tRFP.
  • CAIX human colorectal carcinoma
  • HuSH-29 shRNA targeting CAIX TR314250
  • empty vector R20003
  • FuGENE 6 FuGENE 6
  • Cells are grown under selective pressure (300 ng/ml puromycin) until no mock-transfected cells remain. Two individual clones are selected and designated 95/3 (CAIX knockdown) and EV/2 (control).
  • HT-29 2.1, HT-29 2.1 +dox, HCT116 95/3, HCT116 EV/2 cells are cultivated in Dulbecco's Modified Eagle's Medium (Lonza) supplemented with 10% Fetal Bovine Serum (PAA) at 37°C in humidified air with 20% 0 2 and 5% CO2.
  • Cells are seeded in a 96 wells plate at a density of 1000 cells/well. Cells are allowed to attach overnight before exposing them to the experimental conditions: normoxia (N), 0.2% hypoxia (HO.2) or 1.0% hypoxia (H1.0) during 2 hours or 24 hours.
  • hypoxic experiments are performed in a hypoxic workstation, either 0.2% O2, 5% CO2 and residual N2 (Don Whitley Scientific) or 1.0% O2, 5% CO2 and residual N2 (Ruskinn).
  • the medium of the cells is changed to pre-incubated DMEM (Sigma) containing 10 mM sodium bicarbonate and incubated for 22 hours.
  • DMEM standard Eagle's medium
  • Cells are exposed to compounds of the present invention dissolved in 10 mM sodium bicarbonate medium containing 0.5% DMSO. After 2 hours of exposure, the cells are washed with PBS and 10 mM sodium bicarbonate medium is added. 72 hours after exposure, cells are exposed to Alamar Blue reagent (Invitrogen) for 2 hours and cell viability is measured by fluorescence at 570 nm.

Abstract

The present invention is directed to novel carbonic anhydrase IX inhibitors comprising a nitroimidazole moiety substituted with a heterocycle or phosphinate and having sulfonamide, sulfamate or sulfamide groups. The present invention is also related to the use of these novel carbonic anhydrase IX inhibitors in cancer treatment, especially radiotherapy and chemotherapy and the use in treatment of infections.

Description

Title: Dual action carbonic anhydrase inhibitors
Field of the Invention.
The present invention concerns novel carbonic anhydrase IX inhibitors comprising a nitroimidazole moiety including their use in cancer treatment, especially with radiotherapy and treatment with chemotherapy or targeted agents.
Background.
Cancer is a leading cause of death and accounts for approximately 13% of all deaths in the world. Most cancers form solid tumors in tissues like head and neck, colon, breast, lung, liver and stomach, and are often characterized by low oxygen concentrations (hypoxia) and acidification of the microenvironment surrounding the tumor cells. Hypoxia and acidification of the extratumoral environment are both associated with aggressive tumor growth, metastasis formation and poor response to radiotherapy, surgery and/or to anticancer chemotherapy. Hypoxia is linked with acidification of extracellular environment that facilitates tumor invasion and CA IX is believed to play a role in this process via its catalytic activity (Svastova et al., 2004). Carbonic anhydrases (CAs) form a large family of ubiquitous zinc metalloenzymes of great physiological importance. As catalysts of reversible hydration of carbon dioxide to bicarbonate and protons (C02 + H20 H<+> + HC03<">), these enzymes participate in a variety of biological processes, including respiration, calcification, acid-base balance, bone resorption, formation of aqueous humor. To date, 16 isozymes are characterized from which 15 present in humans. CAs in humans are present in several tissues (e.g. Gl tract, reproductive tract, skin, kidneys, lungs, eyes) and some of the CAs are expressed in almost all tissues (e.g. CA II), whereas the expression of others appears to be more restricted (e.g., CA VI and CA VII in salivary glands).
It has been shown that some tumor cells predominantly express only some membrane-associated CA isozymes, such as CA IX and CA XII. One of the CA isozymes, CA IX, shows restricted expression in normal tissues, but is tightly associated with different types of tumors. CA IX, originally detected in human carcinoma HeLa cells as a cell density-regulated antigen (Pastorekova et al, 1992), is strongly induced by tumor hypoxia, through a transcriptional activation by the HlF-1 pathway. Strong association between carbonic anhydrase CA IX expression and intratumoral hypoxia has been demonstrated in carcinomas.
CA IX has a very high catalytic activity with the highest proton transfer rate among the known CAs, and has been shown to acidify the extracellular environment and is therefore an interesting target for anticancer therapy, preferably in combination with conventional treatment schedules. There are 2 main classes of carbonic anhydrase inhibitors (CAIs): the metal complexing anions and the unsubstituted sulfonamides and their derivatives, which bind to the Zinc ion of the enzyme either by substituting the non-protein zinc ligand or add to the metal coordination sphere (Supuran, 2008). However, the critical problem in designing inhibitors against CAs is the high number of isozymes, the diffuse localization in tissues and the lack of isozyme selectivity of the presently available inhibitors. All six classical CAIs (acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, and dichlorophenamide) used in clinical medicine or as diagnostic tools, show some tumor growth inhibitory properties. Most of the clinically used sulfonamides mentioned above are systemically acting inhibitors showing several undesired side effects due to simultaneous inhibition of many of the different CA isozymes present in the target tissue/organ (15 isoforms are presently known in humans).
The ideal characteristics for specific CA IX inhibitors should demonstrate a relatively low inhibition constant (Ki in the nanomolar range) and should be relatively specific over the cytosolic enzymes CA I and CA II, i.e. a strong inhibiting action against CA IX and a relative weak inhibition or no inhibition against CA I and CA II. A number of aromatic sulfonamides has been presented (see e.g.
WO2004048544 ) that specifically bind to the extracellular components of the in particular CAIX enzyme, which show a higher specificity than those hitherto known in the art. Therapeutic and diagnostic sulfonamide agents are described in WO2006137092. In WO2008071421 it was shown that the inhibitory effect of heterocyclic sulfonamides can be further increased by oxidative substituents, in particular nitrosated or nitrosylated substituents, since such groups may increase the acidity of the zinc binding groups and as such being beneficial for the carbonic anhydrase inhibitory properties. Sulfonamide-based metal chelate complexes for imaging are described in WO2009089383. However, a large variation is reported in CA IX inhibitory constants for the sulfonamides as well as variation in the selectivity of the inhibitors. Sulfamate and sulfamide inhibitors have also been proposed as candidates (Winum et al, 2009).
Traditional anticancer therapy like surgery, irradiation and
chemotherapy are used to treat cancer patients as a combined or single treatment. The basic principle of irradiation is to damage the cancer cells to such an extent that they will die. Free radicals are formed and damage the DNA immediately or they react with oxygen, creating reactive oxygen species which damage the cell and more specific the DNA in the cell. However when no or little oxygen is present, what is the case in hypoxic tumors, less reactive oxygen species are formed and the irradiation is not as effective. It has been shown that a 3 fold higher radiation dose is required to kill the same amount of hypoxic cells as compared under normal oxygen concentrations. The concept of radio sensitization of hypoxic cells emerged when certain compounds were able to mimic oxygen and thus enhance radiation damage. The first compounds which demonstrated radio sensitization were nitrobenzenes, followed by nitrofurans and 2-nitroimidazoles, such as misonidazole (see e.g. WO2006102759). However, misonidazol is neurotoxic and thus the administration thereof is limited. Alternative, better radio sensitizing drugs, such as etanidazole and pimonidazole, were synthesized and tested, but clinical results did not result in a significant therapeutic benefit. WO2012087115 discloses 2- nitroimidazol compounds that show a radio sensitizing effect but are also CA-IX inhibitors.
There is however, still a need for dual drugs that are CA-IX inhibitors and radio-chemo sensitizers.
In a first aspect, the present invention is directed to compounds represented by formula (I):
Figure imgf000004_0001
Wherein
Ri is Y, L- Y, or
Figure imgf000005_0001
NR (Ci-6alkyl-X2)), or B-A, or B-L-A;
B is a bond, 0-C(=0)-, L-0-C(=0)-, 0-C(=0)-NR9S02-, 0-C(=0)- NR9S02NR7-, 0-C(=0)-NR9S02-0-, 0-C(=0)-NR9S02aryl-, 0-C(=0)-NR9S02NR?- aryl-, 0-C(=0)-NR9S02-0-aryl, L-0-C(=0)-NR9S02-, L-0-C(=0)-NR9S02NR7-, L-O- C(=0)-NR9S02-0-, L-0-C(=0)-NR9S02aryl-, L-0-C(=0)-NR9S02NR7-aryl-, or L-O- C(=0)-NR9S02-0-aryl;
A is an active moiety selected from the group of chelating agent comprising a therapeutically active metal ion, chelating agent comprising a metal ion suitable for imaging, fluorescent moiety, 18F containing moiety, alkylating moiety, wherein the active moiety comprises at least one hydroxyl;
L is a linker selected from the group consisting ofCi ealkyl, C(=0)N(R6),
Figure imgf000005_0002
N(R6)C(=0)N(R6), Ci-6alkylN(R6)C(=0)N(R6)Ci-6alkyl, Ci-6alkylN(R6)C(=0)N(R6), N(R6)C(=0)N(R6)Ci-6alkyl, N(R6)C(=S)N(R6), Ci-6alkylN(R6)C(=S)N(R6)Ci-6alkyl, Ci-
Figure imgf000005_0003
-0-C(=0)N(R6), Ci-ealkyl-O- C(=0)N(R6)Ci-6alkyl, Ci-6alkyl-0-C(=0)N(R6), -0-C(=0)N(R6)Ci-6alkyl, N(R6)C(=0),
Figure imgf000005_0004
C(=0)N(R6)Ci-6alkylN(R6)C(=S)N(R6), Ci-6alkylC(=0)N(R6)Ci- 6alkylN(R6)C(=S)N(R6)Ci-6alkyl, Ci-6alkylC(=0)N(R6)Ci-6alkylN(R6)C(=S)N(R6), C(=0)N(R6)Ci-6alkylN(R6)C(=S)N(R6)Ci-6alkyl, C(=0)N(R6)Ci-
Figure imgf000005_0005
6alkylN(R6)C(=0)N(R6)Ci-6alkyl, C(=0)N(R6)Ci-6alkyl-OC(=0), Ci- 6alkylC(=0)N(R6)Ci-6alkyl-OC(=0)Ci-6alkyl, Ci-6alkylC(=0)N(R6)Ci-6alkyl-OC(=0), C(=0)N(R6)Ci-6alkyl-OC(=0)Ci-6alkyl, 0-C(=0), Ci-6alkyl-0-C(=0)Ci-6alkyl, Ci- 6alkyl-0-C(=0), 0-C(=0)Ci-6alkyl, 0-C(=0)Ci-6alkylC(=0)N(R6), Ci-ealkyl-O- C(=0)Ci-6alkylC(=0)N(R6)Ci-6alkyl, Ci-6alkyl-0-C(=0)Ci-6alkylC(=0)N(R6), O- C(=0)Ci-6alkylC(=0)N(R6)Ci-6alkyl, 0-C(=0)Ci-6alkylN(R6)C(=0), Ci-ealkyl-O- C(=0)Ci-6alkylN(R6)C(=0)Ci-6alkyl, Ci-6alkyl-0-C(=0)Ci-6alkylN(R6)C(=0), O- C(=0)Ci-6alkylN(R6)C(=0)Ci-6alkyl, (0-CH2CH2)n, Ci-6alkyl(0-CH2CH2)nCi-6alkyl, Ci-6alkyl(0-CH2CH2)n, (0-CH2CH2)nCi-6alkyl, (CH2CH2-0)n, Ci-6alkyl(CH2CH2- 0)nCi-6alkyl, Ci-6alkyl(CH2CH2-0)n, (CH2CH2-0)nCi-6alkyl;
n is 1-12;
optionally the L is further substituted with a substituent selected from the group comprising halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2- 6alkynyl, Ci ealkyloxy, di(Ci-6alkyl) amino, hydroxy amino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, , hydroxyCi ealkyl, aminoCi ealkyl, cyano, SiFR12R13, or OP(=0)(OR14)2;
or optionally Y may be substituted with halo, hydroxy, amino, nitro, carbonyl, cyano, carboxyamine,
Figure imgf000006_0001
ealkylaryl, Ci-6alkylS02NR7R8, S02NR7R8, Ci-ealkyl OS02 NR7R8, OS02 NR7R8, Ci- 6alkylN(R9)S02NR¾8, N(R9)S02NR7R8, Ci-6alkylN(R6)C(=0)N(R6)Ci-6alkylaryl, Ci-
Figure imgf000006_0002
Figure imgf000006_0003
or L or Ci ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR12R13, or OP(=0)(OR14)2; wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR¾8, or OS02 NR7R8; and wherein the aryl is optionally further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci- 6alkyloxy, di(Ci-6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3- 7Cycloalkyl, , hydroxyCi ealkyl, aminoCi ealkyl , cyano, or OP(=0)(OR14)¾
Y is a saturated, partially unsaturated, or unsaturated heterocycle comprising 5, 6, or 7 atoms, wherein at least one of the atoms is a heteroatom selected from nitrogen, oxygen and sulphur;
X1, X2 is each independently halo, hydroxy, amino, nitro, carbonyl, cyano, OP(=0)(OR1 )2, SG, L-SG, Ci-3alkylC(=0)N(R6)Ci-6alkylaryl, Ci- 6alkylS02NR7R8, S02NR7R8, Ci-ealkyl OS02 NR7R8, OS02NR7R8, Ci- 6alkylN(R9)S02NR7R8, N(R9)S02NR7R8, Ci-6alkylN(R6)C(=0)N(R6)Ci-6alkylaryl, Ci- 6alkylN(R6)C(=S)N(R6)Ci-6alkylaryl, Ci-6alkylN(R6)C(=0)N(R6)aryl, Ci- 6alkylN(R6)C(=S)N(R6)aryl; wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OS02 NR7R8; and wherein the aryl is optionally further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci ealkyloxy, di(Ci- 6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, , hydroxyCi ealkyl, aminoCi ealkyl , cyano, or
Figure imgf000007_0001
R2 is hydrogen, SG, or L-SG, wherein SG is a sulfonamide, sulfamate, or sulfamide group selected from the group consisting of S02NR7R8,
OS02NR¾8, NR9S02NR¾8, NR9S02-phenyl, aryl substituted with
S02NR7R8, aryl substituted with OS02NR7R8, aryl substituted with
Figure imgf000007_0002
optionally the aryl is further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci ealkyloxy, di(Ci-6alkyl) amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, , hydroxyCi ealkyl, aminoCi ealkyl , cyano, SiFR12R13, or OP(=0)(OR14)¾
R3 is hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2- 6alkynyl, Ci ealkyloxy, di(Ci-6alkyl) amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, , hydroxyCi ealkyl, aminoCi ealkyl , cyano, SiFR12R13 or OP(=0)(OR14)2, or B-A, B-L-A;
R4, R5, R6, R7, R8, R9, R10, R11 is each independently hydrogen, halo, hydroxy, or Ci-6alkyl,wherein the Ci ealkyl is optionally substituted with with a substituent selected from the group comprising halo, hydroxy, amino, nitro, Ci- 6alkyloxy, di(Ci-6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, heterocyclic, C3- 7Cycloalkyl, , hydroxyCi-6alkyl or aminoCi-6alkyl , cyano,
Figure imgf000007_0003
SiFR12R13, or a leaving group;
R12 and R13 is each independently a Ci i2alkyl, or C2-i2alkenyl; R14 is hydrogen, Ci-2oalkyl, or C2-2oalkenyl, aryl, aminoCi i2alkyl, carbonylCi i2alkyl, hydroxyCi ealkyl, Ci-6alkyloxyCi-6alkyl, or NR4R5; wherein at least one of R1, R2, R3 is connected to the Nl of the imidazol of formula (I),
and wherein the compound comprises at least one moiety selected from S02NR7R8, OS02NR7R8, NR9S02NR7R8, NR9S02.
In a second aspect, the present invention is directed to compounds according to the invention and/or embodiments thereof for use in the treatment of cancer.
In a third aspect, the present invention is directed to compounds according to the invention and/or embodiments there of for use in the treatment of infections caused by bacteria, fungi, protozoa, and/or mycoplasma.
In a further aspect, the present invention is also related to treatment of cancer administering the compound of the present invention and/or embodiments thereof.
In another aspect, the present invention is also related to treatment of infections caused by bacteria, fungi, protozoa, and/or mycoplasma administering the compound of the present invention and/or embodiments thereof.
It is found that the compounds of the present invention have a high specificity for CA IX. It was also found that the compounds of the present invention have a radio- and chemo sensitizing effect. In addition, the compounds of the present invention are less toxic. Furthermore, the compounds of the present invention are more active than the 2-nitroimidazol of the prior art such as disclosed in WO2012087115. Moreover, it has been found that the compounds of the present invention have an improved solubility. What is more, the compounds of the present invention may be administered orally. Oral administration of the compounds of the present invention enables the use for preventing metastasis, as a adjuvant treatment after the main anti-cancer treatment. In addition, inhibition of CA IX decreases the intracellular pH, i.e. making it more acid, and thereby increases the uptake of basic drugs such as doxorubicin and increases the activation of drugs like temozolomide. Moreover, the compounds of the present invention have an antimicrobial action and may be used as antimicrobe, such as used as an antibiotic against bacteria, mycoplasma and/or against fungi.
Therefore, the compounds of the invention have a significantly improved overall profile for treating solid tumours, such as tumours of the breast, brain, kidney, colorectal, lung, head and neck, bladder etc. compared to carbonic anhydrase inhibitors known in the art. Also other therapeutic fields such as treating eye disorders in particular, glaucoma, ocular hypertension, age-related macular degeneration, diabetic macular edema, diabetic retinopathy, hypertensive retinopathy and retinal vasculopathies, epilepsy, high-altitude disorders and neuromuscular diseases fall within the range of applications of the compounds of the invention.
Another finding is that the compounds of the invention also show a positive effect on radio sensitivity. Extracellular acidosis has been thought to be the result of excess production of lactic acid. However, glycolytic deficient cells (cells in which lactic acid production is hampered) result in tumors with a similar extent of extracellular acidosis, indicating other involved players aside lactic acid. Several studies have been shown that extracellular acidosis makes tumours less sensitive to irradiation treatment (Brizel et al, 2001 ; Quennet et al, 2006). The compounds of the present invention are able to reduce the extracellular acidosis in tumors and may improve the sensitivity to irradiation of tumours. In addition, the compounds of the present invention are specific for CA IX over other CAs.
On the other hand, hypoxic conditions in tumours make them less sensitive to the ionizing radiation commonly used in radiotherapy (Thomlinson & Gray, 1955). Attracting the CA inhibitory compounds towards hypoxic cells, would greatly increase the possible therapeutic effect. This can be done using nitroimidazoles which are trapped in hypoxic cells after a two-fold electron reduction upon low oxygen conditions. In other words, on the one hand there is a need to increase the anti- acidic, antitumor genie effects and specificity of CA IX inhibiting compounds and on the other hand there is a need to target specifically hypoxic cells with compounds that are suitable for radio sensitizing therapy. These needs are met by the present invention which provides multifunctional CAIX targeting drug compounds and preparations for the treatment of cancer in a patient in need thereof comprising compounds of formula (I) above.
Another finding is that the compounds of the invention also show a positive effect on chemo sensitivity. Increased intracellular acidosis being the result of CAIX inhibition increase a) the uptake of basic drugs such as doxorubicin or any drug being a base and b) increase the activation of drugs like Temozolomide or any drug being activated intracellularly by low pH. The compounds of the present invention are able to increase the intracellular acidosis in tumors and may improve the sensitivity to drugs of tumours. In addition, the compounds of the present invention are specific for CA IX over other CAs and are dual drugs namely have more than one active moieties.
Further objects of the present invention are also pharmaceutical compositions containing at least a compound of the present invention of formula (I) together with non toxic adjuvants and/or carriers usually employed in the pharmaceutical field. The invention will now be described in more detail below.
Description of figures
Figure 1: synthesis route for CAIX inhibitors wherein R1 is Ci ealkyl substituted with a morpholine,
Figure 2; synthesis route for CAIX inhibitors wherein R1 is Ci ealkyl substituted
Figure imgf000010_0001
Figure 3: synthesis route for CAIX inhibitors wherein R1 is Ci ealkyl substituted with a piperazine.
Figure 4: alternative synthesis route for CAIX inhibitors wherein R1 is Ci ealkyl substituted with
Figure imgf000010_0002
NR (Ci-6alkyl-X2)).
Detailed description
In a preferred embodiment of the present invention and/or embodiments thereof, the nitro group is on the 2, 4 or 5 position of the imidazol of formula (I) see formula (la), formula (lb), and formula (Ic):
-nitro imidazol formula (la)
Figure imgf000010_0003
2-nitro imidazol formula (lb)
Figure imgf000011_0001
-nitro imidazol formula (Ic)
Figure imgf000011_0002
In a more preferred embodiment of the present invention and/or embodiments thereof the nitro group is in the 2 or 5 position of the imidazol, see formula (lb) and (Ic).
In a more preferred embodiment of the present invention and/or embodiments thereof the nitro group is in the 5 position of the imidazole, see formula (Ic).
In a more preferred embodiment of the present invention and/or embodiments thereof the nitro group is not in the 4 position. Reduction in hypoxic condition is better for nitro imidazole compound when the nitro is in the 2 or 4 position.
In another preferred embodiment of the present invention and/or embodiments thereof, R1 is connected to the Nl of the imidazol, see formula (II):
Figure imgf000011_0003
In another preferred embodiment of the present invention and/or embodiments thereof, R2 is connected to the Nl of the imidazole, see formula (III):
Figure imgf000012_0001
In another preferred embodiment of the present invention and/or embodiments thereof, R3 is connected to the Nl of the imidazole, see formula (IV):
Figure imgf000012_0002
In another preferred embodiment of the present invention and/or embodiments thereof, R1 is Y. In another preferred embodiment of the present invention and/or embodiments thereof, R1 is L-Y. In another preferred embodiment of the present invention and/or embodiments thereof, R1 is L-OP(=O)(NR10(Ci- 6alkyl-X1))( NR10(Ci-6alkyl-X2)). L is a linker selected from the group consisting ofCi- ealkyl, C(=0)N(R6), Ci-6alkyl-C(=0)N(R6)Ci-6alkyl, Ci-6alkyl-C(=0)N(R6),
C(=0)N(R6)-Ci-6alkyl, N(R6)C(=0)N(R6), Ci-6alkylN(R6)C(=0)N(R6)Ci-6alkyl, Ci-
Figure imgf000012_0003
6alkylN(R6)C(=S)N(R6)Ci-6alkyl, Ci-6alkylN(R6)C(=S)N(R6), N(R6)C(=S)N(R6)Ci- ealkyl, -0-C(=0)N(R6), Ci-6alkyl-0-C(=0)N(R6)Ci-6alkyl, Ci-6alkyl-0-C(=0)N(R6), -O-
Figure imgf000012_0004
Figure imgf000012_0005
N(R6)C(=0)Ci-6alkyl, N(R6)C(=S),
Figure imgf000012_0006
Figure imgf000012_0007
C(=0)N(R6)Ci-6alkylN(R6)C(=S)N(R6)Ci-6alkyl,
Figure imgf000012_0008
6alkylN(R6)C(=0)N(R6)Ci-6alkyl, Ci-6alkylC(=0)N(R6)Ci-6alkylN(R6)C(=0)N(R6),
Figure imgf000012_0009
6alkylC(=0)N(R6)Ci-6alkyl-OC(=0)Ci-6alkyl, Ci-6alkylC(=0)N(R6)Ci-6alkyl-OC(=0),
Figure imgf000013_0001
6alkyl-0-C(=0), 0-C(=0)Ci-6alkyl, 0-C(=0)Ci-6alkylC(=0)N(R6), Ci-ealkyl-O- C(=0)Ci-6alkylC(=0)N(R6)Ci-6alkyl, Ci-6alkyl-0-C(=0)Ci-6alkylC(=0)N(R6), O-
Figure imgf000013_0002
Ci-ealkyl-O- C(=0)Ci-6alkylN(R6)C(=0)Ci-6alkyl, Ci-6alkyl-0-C(=0)Ci-6alkylN(R6)C(=0), O- C(=0)Ci-6alkylN(R6)C(=0)Ci-6alkyl, (0-CH2CH2)n, Ci-6alkyl(0-CH2CH2)nCi-6alkyl, Ci-6alkyl(0-CH2CH2)n, (0-CH2CH2)nCi-6alkyl, (CH2CH2-0)n, Ci-6alkyl(CH2CH2- 0)nCi-6alkyl, Ci-6alkyl(CH2CH2-0)n, (CH2CH2-0)nCi-6alkyl, wherein n is 1-12. In a preferred embodiment of the present invention and/or embodiments thereof n is, 1- 10, more preferably n is 2-8, more preferably n is 3-6.
In a preferred embodiment of the present invention and/or embodiments thereof L is Ci-ealkyl, C(=0)N(R6), Ci-6alkyl-C(=0)N(R6)Ci-6alkyl, Ci-ealkyl- C(=0)N(R6), N(R6)C(=0)N(R6), Ci-6alkylN(R6)C(=0)N(R6)Ci-6alkyl, Ci-
Figure imgf000013_0003
ealkyl, Ci-6alkylN(R6)C(=S)N(R6), N(R6)C(=S)N(R6)Ci-6alkyl, 0-C(=0), Ci-ealkyl-O- C(=0)Ci-6alkyl, Ci-6alkyl-0-C(=0), 0-C(=0)Ci-6alkyl, -0-C(=0)N(R6), Ci-ealkyl-O-
Figure imgf000013_0004
Ci-6alkyl-0-C(=0)N(R6), (O- CH2CH2)n, Ci-6alkyl(0-CH2CH2)nCi-6alkyl, Ci-6alkyl(0-CH2CH2)n, (0-CH2CH2)nCi- ealkyl,
Figure imgf000013_0005
6alkylN(R6)C(=0)N(R6)Ci-6alkyl, Ci-6alkylC(=0)N(R6)Ci-6alkylN(R6)C(=0)N(R6), C(=0)N(R6)Ci-6alkylN(R6)C(=0)N(R6)Ci-6alkyl, (0-CH2CH2)n, (CH2CH2-0)n, Ci- 6alkyl(CH2CH2-0)nCi-6alkyl, Ci-6alkyl(CH2CH2-0)n, (CH2CH2-0)nCi-6alkyl;
In a preferred embodiment of the present invention and/or embodiments thereof L is Ci-ealkyl, C(=0)N(R6), Ci-6alkyl-C(=0)N(R6)Ci-6alkyl, Ci-ealkyl-
Figure imgf000013_0006
6alkylN(R6)C(=0)N(R6), N(R6)C(=0)N(R6)Ci-6alkyl, Ci-6alkylN(R6)C(=S)N(R6)Ci- ealkyl,
Figure imgf000013_0007
0-C(=0), Ci-6alkyl-0-C(=0)Ci-6alkyl, Ci-ealkyl-O- C(=0), (0-CH2CH2)n, Ci-6alkyl(0-CH2CH2)nCi-6alkyl, Ci-6alkyl(0-CH2CH2)n, (O- CH2CH2)nCi-6alkyl, Ci-6alkylC(=0)N(R6)Ci-6alkylN(R6)C(=0)N(R6)Ci-6alkyl, Ci- 6alkylC(=0)N(R6)Ci-6alkylN(R6)C(=0)N(R6), (CH2CH2-0)n, Ci-6alkyl(CH2CH2-0)nCi- ealkyl, Ci-6alkyl(CH2CH2-0)n, (0-CH2CH2)n, (CH2CH2-0)nCi-6alkyl;
In a preferred embodiment of the present invention and/or embodiments thereof L is Ci-ealkyl, Ci-6alkyl-C(=0)N(R6)Ci-6alkyl, Ci-6alkyl-C(=0)N(R6), Ci-
Figure imgf000014_0001
6alkylN(R6)C(=S)N(R6)Ci-6alkyl,
Figure imgf000014_0002
Ci-6alkyl-0-C(=0)Ci- ealkyl, Ci-6alkyl-0-C(=0), (0-CH2CH2)n, (CH2CH2-0)n, Ci-6alkyl(CH2CH2-0)n;
In a preferred embodiment of the present invention and/or embodiments thereof L is a cleavable linkers selected from the group consisting of C(=0)N(R6), Ci-6alkyl-C(=0)N(R6)Ci-6alkyl, Ci-6alkyl-C(=0)N(R6), N(R6)C(=0)N(R6), Ci-
Figure imgf000014_0003
ealkyl, Ci-6alkylN(R6)C(=S)N(R6)Ci-6alkyl, Ci-6alkylN(R6)C(=S)N(R6), 0-C(=0), Ci- 6alkyl-0-C(=0)Ci-6alkyl, Ci-6alkyl-0-C(=0), (0-CH2CH2)n, Ci-6alkyl(0-CH2CH2)nCi- ealkyl, Ci-6alkyl(0-CH2CH2)n, (0-CH2CH2)nCi-6alkyl, Ci-6alkylC(=0)N(R6)Ci- 6alkylN(R6)C(=0)N(R6)Ci-6alkyl, Ci-6alkylC(=0)N(R6)Ci-6alkylN(R6)C(=0)N(R6), (O- CH2CH2)n, (CH2CH2-0)n, Ci-6alkyl(CH2CH2-0)nCi-6alkyl, Ci-6alkyl(CH2CH2-0)n, (CH2CH2.0)nCi-6alkyl;
In a preferred embodiment of the present invention and/or embodiments thereof L is a cleavable linkers selected from the group consisting of Ci-ealkyl- C(=0)N(R6)Ci-6alkyl, Ci-6alkyl-C(=0)N(R6), Ci-6alkylN(R6)C(=0)N(R6)Ci-6alkyl, Ci-
Figure imgf000014_0004
6alkylN(R6)C(=S)N(R6), Ci-6alkyl-0-C(=0)Ci-6alkyl, Ci-6alkyl-0-C(=0), (0-CH2CH2)n, (CH2CH2-0)n, C i-6alkyl(CH2CH2-0)n;
In a preferred embodiment of the present invention and/or embodiments thereof L is a cleavable linkers selected from the group consisting of Ci-ealkyl-
Figure imgf000014_0005
Ci- 6alkylN(R6)C(=0)N(R6), Ci-6alkylN(R6)C(=S)N(R6)Ci-6alkyl, Ci- 6alkylN(R6)C(=S)N(R6), Ci-6alkyl-0-C(=0)Ci-6alkyl, Ci-6alkyl-0-C(=0), (0-CH2CH2)n, (CH2CH2-0)n, C i-6alkyl(CH2CH2-0)n;
In another preferred embodiment of the present invention and/or embodiments thereof, R1 is Ci ealkyl-Y. In another preferred embodiment of the present invention and/or embodiments thereof, R1 is Ci-6alkyl-OP(=O)(NR10(Ci- 6alkyl-Xi))( NRio(Ci-6alkyl-X2)).
In another preferred embodiment of the present invention and/or embodiments thereof, the linker L or Ci ealkyl is further substituted with a substituent selected from the group comprising halo, hydroxy, amino, nitro, Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, Ci ealkyloxy, di(Ci-6alkyl)amino, hydroxyamino, bydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci- 6alkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, , hydroxyCi ealkyl, aminoCi- 6alkyl, cyano, SiFR12R13, or
Figure imgf000015_0001
a SG group or an active moiety A.
In another preferred embodiment of the present invention and/or embodiments thereof, the linker L or Ci ealkyl is further substituted with a substituent selected from the group comprising halo, hydroxy, amino, nitro, Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, Ci ealkyloxy, di(Ci-6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci- 6alkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, , hydroxyCi ealkyl, aminoCi- ealkyl, cyano, SiFR12R13, or OP(=0)(OR14)2.
In another preferred embodiment of the present invention and/or embodiments thereof, the alkyl is preferably Ci ealkyl, more preferably Ci-4alkyl, C2-3alkyl, Ci salkyl, Ci-2alkyl, more preferably, C2-3alkyl, or Ci-2alkyl.
In another preferred embodiment of the present invention and/or embodiments thereof, Y may be substituted with halo, hydroxy, amino, nitro, carbonyl, cyano, OP(=0)(OR1 )2, carboxyamine,SG, L-SG, Ci-3alkylC(=0)N(R6)Ci- ealkylaryl, Ci-6alkylS02NR7R8, S02NR¾8, Ci-6alkylOS02NR7R8, OS02NR7R8, Ci- 6alkylN(R9)S02NR¾8, N(R9)S02NR¾8, Ci-6alkylN(R6)C(=0)N(R6)Ci-6alkylaryl, Ci-
Figure imgf000015_0002
6alkylN(R6)C(=S)N(R6)aryl or Ci ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR12R13, or OP(=0)(OR14)2; wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OSO2 NR7R8; and wherein the aryl is optionally further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci ealkyloxy, di(Ci- 6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, , hydroxyCi ealkyl, aminoCi ealkyl , cyano, or
Figure imgf000015_0003
Y is a saturated, partially unsaturated, or unsaturated heterocycle comprising 5, 6, or 7 atoms, wherein at least one of the atoms is a heteroatom selected from nitrogen, oxygen and sulphur. It is to be understood that also other heteroatoms may be present in Y, such as phosphor. In another preferred embodiment of the present invention and/or embodiments thereof, Y is selected from the group comprising pyrrolidine, pyrrole, tetrahydrofuran, furan, thiolane, thiophene, imidazolidine, pyrazolidine, imidazole, pyrazole, oxazolidine, isoxazolidine, oxazole, isoxazole, thiazole, isothiazole, dioxolane, dithiolane, triazole, furazan, oxadiazole, thiazolidine, isothiazolidine, thiadiazole, dithiazole, piperidine, pyridine, oxane, pyran, thiane, thiopyran, piperazine, diazine, morpholine, oxazine, thiomorpholine, thiazine, dioxane, dioxine, dithiane, dithiine, triazine, trioxane, azepane, azepine, oxepane, oxepine, thiepane, thiepine, homopiperazine, diazepine, and thiazepine, benzotriazine, pyrimidine, hydropyrimidine.oxopyrimidine, oxodihydropyrimidine,
oxazaphosphinan. triazenoimidazole
In another preferred embodiment of the present invention and/or embodiments thereof, Y is selected from the group comprising Pyrrolidine, Pyrrole, tetrahydrofuran, furan, thiophene, imidazolidine, pyrazolidine, imidazole, pyrazole, oxazolidine, isoxazolidine, oxazole, isoxazole, thiazole, isothiazole, triazole, thiazolidine, isothiazolidine, thiadiazole, dithiazole, piperidine, pyridine, oxane, pyran, piperazine, morpholine, thiomorpholine, and homopiperazine, pyrimidine.
In another preferred embodiment of the present invention and/or embodiments thereof, Y is selected from the group comprising pyrrolidine, tetrahydrofuran, imidazolidine, imidazole, oxazolidine, isoxazolidine,
thiazole, triazole, thiadiazole, dithiazole, piperidine, pyridine, piperazine, morpholine, thiomorpholine, and homopiperazine, pyrimidine.
In another preferred embodiment of the present invention and/or embodiments thereof, Y is selected from the group comprising tetrahydrofuran. imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, triazole, thiazolidine, isothiazolidine, piperazine, morpholine, thiomorpholine, and homopiperazine, pyrimidine.
In another preferred embodiment of the present invention and/or embodiments thereof, Y is selected from the group comprising tetrahydrofuran, imidazole, triazole, piperazine, morpholine, pyrimidine and thiomorpholine.
In another preferred embodiment of the present invention and/or embodiments thereof, Y is a saturated heterocycle. In another preferred embodiment of the present invention and/or embodiments thereof, Y is a unsaturated heterocycle.
In another preferred embodiment of the present invention and/or embodiments thereof, Y is a 5-membered heterocycle. In another preferred embodiment of the present invention and/or embodiments thereof, Y is a 6- membered heterocycle. In another preferred embodiment of the present invention and/or embodiments thereof, Y is a 6- or 7-membered heterocycle. In another preferred embodiment of the present invention and/or embodiments thereof, Y is not a 5-membered heterocycle. In another preferred embodiment of the present invention and/or embodiments thereof, Y is a 7-membered heterocycle.
In another preferred embodiment of the present invention and/or embodiments thereof, in Y the heteroatom is nitrogen. In another preferred embodiment of the present invention and/or embodiments thereof, in Y the heteroatom is nitrogen and/or sulphur. In another preferred embodiment of the present invention and/or embodiments thereof, in Y the heteroatom is oxygen. In another preferred embodiment of the present invention and/or embodiments thereof, in Y the heteroatom is not oxygen. In another preferred embodiment of the present invention and/or embodiments thereof, in Y the heteroatom is sulfur. In another preferred embodiment of the present invention and/or embodiments thereof, in Y the heteroatom is nitrogen and is attached to the Ci ealkyl via the nitrogen. In another preferred embodiment of the present invention and/or embodiments thereof, Y comprises at least 2 heteroatoms selected from the group of oxygen, nitrogen and sulphur.
In another preferred embodiment of the present invention and/or embodiments thereof, in Y is not a saturated 5-membered heterocycle comprising a oxygen atom. In another preferred embodiment of the present invention and/or embodiments thereof, in Y is not a ribofuranosyl. In another preferred embodiment of the present invention and/or embodiments thereof, in Y is not a a-D- Ribofuranosyl. In another preferred embodiment of the present invention and/or embodiments thereof, in Y is not a β-D-Ribofuranosyl.
In another preferred embodiment of the present invention and/or embodiments thereof, in when R1 is in the 1 position of the imidazol, and R1 is Y, then Y is not a β-D-Ribofuranosyl. In another preferred embodiment of the present invention and/or embodiments thereof, when Y is a 6-D-Ribofuranosyl, R1 is in the 2, 4, or 5 position of the imidazol, preferably in the 4 position.
In another preferred embodiment of the present invention and/or embodiments thereof, R1 is Y,
Figure imgf000018_0001
NRn(Ci-6alkyl-X2)), or , L-Y, wherein the L is further substituted with a substituent selected from the group comprising halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci- 6alkyloxy, di(Ci-6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl,
carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3- Tcycloalkyl hydroxyCi-ealkyl, aminoCi-ealkyl , cyano, SiFR^R13, OP(=0)(OR14)2, an SG group or an active moiety A, and/ or wherein Y may be optionally substituted with halo, hydroxy, amino, nitro, carbonyl, cyano,
Figure imgf000018_0002
SG, L-SG, Ci- 3alkylC(=0)N(R6)Ci-6alkylaryl, Ci-6alkylS02NR¾8, S02NR¾8, Ci-ealkyl OSO2 NR7R8, OS02NR7R8, Ci-6alkylN(R9)S02NR7R8, N(R9)S02NR7R8, Ci- 6alkylN(R6)C(=0)N(R6)Ci-6alkylaryl, Ci-6alkylN(R6)C(=S)N(R6)Ci-6alkylaryl, Ci- 6alkylN(R6)C(=0)N(R6)aryl, Ci-6alkylN(R6)C(=S)N(R6)aryl or Ci-ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR12R13, or OP(=0)(OR14)2; wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OS02 NR7R8; and wherein the aryl is optionally further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2- 6alkynyl, Ci ealkyloxy, di(Ci-6alkyl) amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, , hydroxyCi ealkyl, aminoCi ealkyl , cyano, or
OP(=0)(OR14)¾
In another preferred embodiment of the present invention and/or embodiments thereof, R1 is Y, Ci-ealkyl substituted
Figure imgf000018_0003
NRn(Ci-6alkyl-X2)), or , Ci ealkyl substituted with Y, wherein the Ci ealkyl is further substituted with a substituent selected from the group comprising halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci ealkyloxy, di(Ci- 6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl hydroxyCi-ealkyl, aminoCi-ealkyl , cyano, SiFR12R13, OP(=0)(OR14)2 ;and/ or wherein Y may be optionally substituted with halo, hydroxy, amino, nitro, carbonyl, cyano, OP(=0)(OR14)2, SG, L-SG, Ci-3alkylC(=0)N(R6)Ci-6alkylaryl, Ci- 6alkylS02NR7R8, S02NR7R8, Ci-ealkyl OSO2 NR7R8, OSO2 NR7R8, Ci- 6alkylN(R9)S02NR7R8, N(R9)S02NR7R8, Ci-6alkylN(R6)C(=0)N(R6)Ci-6alkylaryl, Ci- 6alkylN(R6)C(=S)N(R6)Ci-6alkylaryl, Ci-6alkylN(R6)C(=0)N(R6)aryl, Ci- 6alkylN(R6)C(=S)N(R6)aryl or Ci-ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR12R13, or OP(=0)(OR14)2; wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OS02 NR7R8; and wherein the aryl is optionally further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci ealkyloxy, di(Ci- 6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, , hydroxyCi ealkyl, aminoCi ealkyl , cyano, or OP(=0)(OR14)2;
In another preferred embodiment of the present invention and/or embodiments thereof, R1 is Y, Ci-ealkyl substituted
Figure imgf000019_0001
X1))(NR11(Ci-6alkyl-X2)), or , Ci-ealkyl substituted with Y, wherein the L or Ci-ealkyl is further substituted with a substituent selected from the group comprising halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci ealkyloxy, di(Ci- 6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl hydroxyCi-ealkyl, aminoCi-ealkyl , cyano, SiFR12R13, OP(=0)(OR14)2, an SG group or an active moiety A ,and/ or wherein Y may be optionally substituted with halo, hydroxy, amino, nitro, carbonyl, cyano, OP(=0)(OR14)2, SG, L-SG, Ci- 3alkylC(=0)N(R6)Ci-6alkylaryl, Ci-6alkylS02NR7R8, S02NR7R8, Ci-ealkyl OS02 NR¾8, OS02 NR¾8, Ci-6alkylN(R9)S02NR¾8, N(R9)S02NR¾8, Ci-
Figure imgf000019_0002
6alkylN(R6)C(=0)N(R6)aryl, Ci-6alkylN(R6)C(=S)N(R6)aryl or Ci-ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR12R13, or OP(=0)(OR14)2; wherein the aryl is substituted with a S02NR¾8, N(R9)S02NR¾8, or OS02 NR7R8; and wherein the aryl is optionally further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2- 6alkynyl, Ci ealkyloxy, di(Ci-6alkyl) amino, hydroxy amino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, , hydroxyCi ealkyl, aminoCi ealkyl , cyano, or
OP(=0)(OR14)¾
In a more preferred embodiment of the present invention and/or embodiments thereof, R1 is Y, L-Y or
Figure imgf000020_0001
X2)), wherein the L is further substituted with a substituent selected from the group selected from halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci-ealkyloxy, carbonyl, NR4R5, cyano, SiFR12R13, OP(=0)(OR14)¾ a SG group or an active moiety A, and/ or wherein Y may be optionally substituted with halo, hydroxy, amino, nitro, carbonyl, cyano,
Figure imgf000020_0002
SG, L-SG, Ci- 3alkylC(=0)N(R6)Ci-6alkylaryl, Ci-6alkylS02NR7R8, S02NR¾8, Ci-ealkyl OSO2 NR¾8, OSO2 NR¾8, Ci-6alkylN(R9)S02NR¾8, N(R9)S02NR¾8, Ci-
Figure imgf000020_0003
6alkylN(R6)C(=0)N(R6)aryl, Ci-6alkylN(R6)C(=S)N(R6)aryl or Ci-ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR12R13, or
Figure imgf000020_0004
wherein the aryl is substituted with a S02NR¾8, N(R9)S02NR¾8, or OSO2 NR7R8; and wherein the aryl is optionally further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2- 6alkynyl, Ci ealkyloxy, di(Ci-6alkyl) amino, hydroxy amino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, hydroxyCi ealkyl, aminoCi ealkyl , cyano, or
Figure imgf000020_0005
a more preferred embodiment of the present invention and/or embodiments thereof, R1 is Y, Ci ealkyl substituted with Y or Ci ealkyl substituted with
Figure imgf000020_0006
NR (Ci-6alkyl-X2)), wherein the Ci-ealkyl is further substituted with a substituent selected from the group selected from halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci ealkyloxy, carbonyl, NR R5, cyano, SiFR12R13, OP(=0)(OR1 )¾ and/ or wherein Y may be optionally substituted with halo, hydroxy, amino, nitro, carbonyl, cyano,
Figure imgf000020_0007
SG, L-SG, Ci-3alkylC(=0)N(R6)Ci-6alkylaryl, Ci-6alkylS02NR¾8, S02NR¾8, Ci-ealkyl OSO2 NR¾8, OSO2 NR¾8, Ci-6alkylN(R9)S02NR7R8, N(R9)S02NR7R8, Ci- 6alkylN(R6)C(=0)N(R6)Ci-6alkylaryl, Ci-6alkylN(R6)C(=S)N(R6)Ci-6alkylaryl, Ci-
Figure imgf000021_0001
or Ci-ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR12R13, or
Figure imgf000021_0002
wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OSO2 NR7R8; and wherein the aryl is optionally further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2- 6alkynyl, Ci ealkyloxy, di(Ci-6alkyl) amino, hydroxy amino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, hydroxyCi ealkyl, aminoCi ealkyl , cyano, or
OP(=0)(OR14)2.
In a more preferred embodiment of the present invention and/or embodiments thereof, R1 is Y, Ci ealkyl substituted with Y or Ci ealkyl substituted with
Figure imgf000021_0003
NRn(Ci-6alkyl-X2)), wherein the Ci-ealkyl is further substituted with a substituent selected from the group selected from halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci ealkyloxy, carbonyl, NR4R5, cyano, SiFR12R13, OP(=0)(OR14)¾ a SG group or an active moiety A, and/ or wherein Y may be optionally substituted with halo, hydroxy, amino, nitro, carbonyl, cyano, OP(=0)(OR14)2, SG, L-SG, Ci-3alkylC(=0)N(R6)Ci-6alkylaryl, Ci- 6alkylS02NR7R8, S02NR7R8, Ci-ealkyl OSO2 NR7R8, OSO2 NR7R8, Ci- 6alkylN(R9)S02NR7R8, N(R9)S02NR7R8, Ci-6alkylN(R6)C(=0)N(R6)Ci-6alkylaryl, Ci- 6alkylN(R6)C(=S)N(R6)Ci-6alkylaryl, Ci-6alkylN(R6)C(=0)N(R6)aryl, Ci- 6alkylN(R6)C(=S)N(R6)aryl or Ci ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR12R13, or OP(=0)(OR14)2; wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OSO2 NR7R8; and wherein the aryl is optionally further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci ealkyloxy, di(Ci- 6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, hydroxyCi ealkyl, aminoCi ealkyl , cyano, or
Figure imgf000021_0004
In a more preferred embodiment of the present invention and/or embodiments thereof, R1 isY or L-Y or
Figure imgf000021_0005
NRn(Ci- ealkyl-Χ2)), wherein L is further substituted with a substituent selected from the group comprising halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, SiFR12R13, or
Figure imgf000022_0001
a SG group or an active moiety A, and/ or wherein Y may be optionally substituted with halo, hydroxy, amino, nitro, carbonyl, cyano,
OP(=0)(OR14)2, SG, L-SG, Ci-3alkylC(=0)N(R6)Ci-6alkylaryl, Ci-6alkylS02NR7R8, S02NR7R8, Ci-ealkyl OSO2 NR7R8, OSO2 NR7R8, Ci-6alkylN(R9)S02NR7R8,
Figure imgf000022_0002
Figure imgf000022_0003
or Ci ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR12R!3, or OP(=0)(OR14)2; wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OS02 NR7R8; and wherein the aryl is optionally further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci ealkyloxy, di(Ci- 6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, hydroxyCi ealkyl, aminoCi ealkyl , cyano, or OP(=0)(OR14)¾
In a more preferred embodiment of the present invention and/or embodiments thereof, R1 isY or Ci ealkyl substituted with Y or Ci ealkyl substituted with
Figure imgf000022_0004
wherein the Ci- 6alkyl is further substituted with a substituent selected from the group comprising halo, hydroxy, amino, nitro, Ci-ealkyl, C2-6alkenyl, SiFR12R13, or OP(=0)(OR1 )2, and/ or wherein Y may be optionally substituted with halo, hydroxy, amino, nitro, carbonyl, cyano, OP(=0)(OR1 )2, SG, L-SG, Ci-3alkylC(=0)N(R6)Ci-6alkylaryl, Ci- 6alkylS02NR7R8, S02NR7R8, Ci-ealkyl OS02 NR7R8, OS02 NR7R8, Ci- 6alkylN(R9)S02NR7R8, N(R9)S02NR7R8, Ci-6alkylN(R6)C(=0)N(R6)Ci-6alkylaryl, Ci- 6alkylN(R6)C(=S)N(R6)Ci-6alkylaryl, Ci-6alkylN(R6)C(=0)N(R6)aryl, Ci- 6alkylN(R6)C(=S)N(R6)aryl or Ci ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR12R!3, or OP(=0)(OR1 )2; wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OS02 NR7R8; and wherein the aryl is optionally further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci ealkyloxy, di(Ci- 6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, hydroxyCi ealkyl, aminoCi ealkyl , cyano, or
Figure imgf000023_0001
In a more preferred embodiment of the present invention and/or embodiments thereof, R1 isY or Ci ealkyl substituted with Y or Ci ealkyl substituted with
Figure imgf000023_0002
NRn(Ci-6alkyl-X2)), wherein the Ci- 6alkyl is further substituted with a substituent selected from the group comprising halo, hydroxy, amino, nitro, Ci-ealkyl, C2-6alkenyl, SiFR12R13, or OP(=0)(OR14)2, a SG group or an active moiety A, and/ or wherein Y may be optionally substituted with halo, hydroxy, amino, nitro, carbonyl, cyano,
Figure imgf000023_0003
SG, L-SG, Ci- 3alkylC(=0)N(R6)Ci-6alkylaryl, Ci-6alkylS02NR7R8, S02NR7R8, Ci-ealkyl OSO2 NR7R8, OSO2 NR7R8, Ci-6alkylN(R9)S02NR7R8, N(R9)S02NR7R8, Ci-
Figure imgf000023_0004
6alkylN(R6)C(=0)N(R6)aryl, Ci-6alkylN(R6)C(=S)N(R6)aryl or Ci-ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR12R13, or
Figure imgf000023_0005
wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OS02 NR7R8; and wherein the aryl is optionally further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2- 6alkynyl, Ci ealkyloxy, di(Ci-6alkyl) amino, hydroxy amino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, hydroxyCi ealkyl, aminoCi ealkyl , cyano, or
OP(=0)(OR14)¾
In a more preferred embodiment of the present invention and/or embodiments thereof, R1 is Y or L-Y, or
Figure imgf000023_0006
NRn(Ci- ealkyl-Χ2)), wherein L is further substituted with a substituent selected from the group comprising halo, hydroxy, amino, nitro, SiFR12R13, OP(=0)(OR14)2, SG group or active moiety A, and/ or wherein Y may be optionally substituted with halo, hydroxy, amino, nitro, carbonyl, cyano, OP(=0)(OR14)2, SG, L-SG, Ci- 3alkylC(=0)N(R6)Ci-6alkylaryl, Ci-6alkylS02NR7R8, S02NR7R8, Ci-ealkyl OS02 NR7R8, OS02 NR7R8, Ci-6alkylN(R9)S02NR7R8, N(R9)S02NR7R8, Ci- 6alkylN(R6)C(=0)N(R6)Ci-6alkylaryl, Ci-6alkylN(R6)C(=S)N(R6)Ci-6alkylaryl, Ci-
Figure imgf000023_0007
or Ci-ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR12R13, or
Figure imgf000024_0001
wherein the aryl is substituted with a S02NR¾8, N(R9)S02NR¾8, or OSO2 NR¾8; and wherein the aryl is optionally further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2- 6alkynyl, Ci ealkyloxy, di(Ci-6alkyl) amino, hydroxy amino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, hydroxyCi ealkyl, aminoCi ealkyl , cyano, or
OP(=0)(OR14)¾
In a more preferred embodiment of the present invention and/or embodiments thereof, R1 is Y or Ci ealkyl substituted with Y, or Ci ealkyl substituted with
Figure imgf000024_0002
wherein the Ci- 6alkyl is further substituted with a substituent selected from the group comprising halo, hydroxy, amino, nitro, SiFR12R13,
Figure imgf000024_0003
and/ or wherein Y may be optionally substituted with halo, hydroxy, amino, nitro, carbonyl, cyano,
OP(=0)(OR1 )2, SG, L-SG, Ci-3alkylC(=0)N(R6)Ci-6alkylaryl, Ci-6alkylS02NR¾8, S02NR¾8, Ci-ealkyl OSO2 NR¾8, OSO2 NR¾8, Ci-6alkylN(R9)S02NR¾8,
Figure imgf000024_0004
6alkylN(R6)C(=S)N(R6)Ci-6alkylaryl, Ci-6alkylN(R6)C(=0)N(R6)aryl, Ci- 6alkylN(R6)C(=S)N(R6)aryl or Ci ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR12R!3, or OP(=0)(OR1 )2; wherein the aryl is substituted with a S02NR¾8, N(R9)S02NR7R8, or OSO2 NR7R8; and wherein the aryl is optionally further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci ealkyloxy, di(Ci- 6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, hydroxyCi ealkyl, aminoCi ealkyl , cyano, or
Figure imgf000024_0005
In a more preferred embodiment of the present invention and/or embodiments thereof, R1 is Y or Ci ealkyl substituted with Y, or Ci ealkyl substituted with
Figure imgf000024_0006
wherein the Ci- 6alkyl is further substituted with a substituent selected from the group comprising halo, hydroxy, amino, nitro, SiFR12R13,
Figure imgf000024_0007
SG group or active moiety A, and/ or wherein Y may be optionally substituted with halo, hydroxy, amino, nitro, carbonyl, cyano, OP(=0)(OR14)2, SG, L-SG, Ci-3alkylC(=0)N(R6)Ci-6alkylaryl, Ci-6alkylS02NR¾8, S02NR¾8, Ci-ealkyl OSO2 NR¾8, OSO2 NR¾8, Ci- 6alkylN(R9)S02NR¾8, N(R9)S02NR¾8, Ci-6alkylN(R6)C(=0)N(R6)Ci-6alkylaryl, Ci-
Figure imgf000025_0001
Figure imgf000025_0002
or Ci ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR12R13, or OP(=0)(OR14)2; wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OS02 NR7R8; and wherein the aryl is optionally further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci ealkyloxy, di(Ci- 6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, hydroxyCi ealkyl, aminoCi ealkyl , cyano, or OP(=0)(OR14)¾
In a more preferred embodiment of the present invention and/or embodiments thereof, R1 is Y, or L-Y, or L
Figure imgf000025_0003
NR (Ci- ealkyl-Χ2)), wherein L is further substituted with a substituent selected from the group comprising halo, hydroxy, SiFR12R13, OP(=0)(OR14)2, or a SG group or a active moiety A, more preferably with halo, more preferably with hydroxyl, more preferably with OP(=0)(OR14)2, more preferably with SiFR12R13 more preferably with a SG group, more preferably with an active moiety A.
In a more preferred embodiment of the present invention and/or embodiments thereof, R1 is Y, or Ci ealkyl substituted with Y, or Ci ealkyl substituted with
Figure imgf000025_0004
NR (Ci-6alkyl-X2)), wherein the Ci- 6alkyl is further substituted with a substituent selected from the group comprising halo, hydroxy, SiFR12R13, OP(=0)(OR14)2, more preferably with halo, more preferably with hydroxyl, more preferably with OP(=0)(OR14)2, more preferably with SiFR12R13.
In a more preferred embodiment of the present invention and/or embodiments thereof, R1 is Y, or L-Y, and wherein Y is substituted with halo, hydroxy, amino, nitro, carbonyl, cyano, OP(=0)(OR14)2, SG, L-SG, Ci- 3alkylC(=0)N(R6)Ci-6alkylaryl, Ci-6alkylS02NR¾8, S02NR¾8, Ci-ealkyl OS02 NR¾8, OS02 NR¾8, Ci-6alkylN(R9)S02NR7R8, N(R9)S02NR7R8, Ci- 6alkylN(R6)C(=0)N(R6)Ci-6alkylaryl, Ci-6alkylN(R6)C(=S)N(R6)Ci-6alkylaryl, Ci-
Figure imgf000026_0001
or Ci-ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR12R13, or
Figure imgf000026_0002
wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OSO2 NR7R8; and wherein the aryl is optionally further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2- 6alkynyl, Ci ealkyloxy, di(Ci-6alkyl) amino, hydroxy amino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, hydroxyCi ealkyl, aminoCi ealkyl , cyano, or
OP(=0)(OR14)¾
In a more preferred embodiment of the present invention and/or embodiments thereof, R1 is Y, or Ci ealkyl substituted with Y, and wherein Y is substituted with halo, hydroxy, amino, nitro, carbonyl, cyano,
Figure imgf000026_0003
SG, L-SG, Ci-3alkylC(=0)N(R6)Ci-6alkylaryl, Ci-6alkylS02NR7R8, S02NR7R8, Ci-ealkyl OSO2 NR7R8, OSO2 NR7R8, Ci-6alkylN(R9)S02NR¾8, N(R9)S02NR7R8, Ci- 6alkylN(R6)C(=0)N(R6)Ci-6alkylaryl, Ci-6alkylN(R6)C(=S)N(R6)Ci-6alkylaryl, Ci-
Figure imgf000026_0004
or Ci-ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR12R13, or
Figure imgf000026_0005
wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OSO2 NR7R8; and wherein the aryl is optionally further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2- 6alkynyl, Ci ealkyloxy, di(Ci-6alkyl) amino, hydroxy amino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, hydroxyCi ealkyl, aminoCi ealkyl , cyano, or
OP(=0)(OR1 )¾
In a more preferred embodiment of the present invention and/or embodiments thereof, R1 is Y, or L-Y, and wherein Y is substituted with halo, hydroxy, amino, nitro, carbonyl, cyano,
Figure imgf000026_0006
SG, L-SG, Ci- 6alkylS02NR7R8, S02NR¾8, Ci-ealkyl OSO2 NR7R8, OSO2 NR7R8, Ci- 6alkylN(R9)S02NR7R8, N(R9)S02NR7R8, or Ci-ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR12R13, or OP(=0)(OR14)2. In a more preferred embodiment of the present invention and/or embodiments thereof, R1 is Y, or Ci ealkyl substituted with Y, and wherein Y is substituted with halo, hydroxy, amino, nitro, carbonyl, cyano,
Figure imgf000027_0001
SG, L-SG, Ci-6alkylS02NR7R8, S02NR7R8, Ci-ealkyl OSO2 NR7R8, OSO2 NR7R8, Ci- 6alkylN(R9)S02NR¾8, N(R9)S02NR7R8, or Ci-ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR12R13, or OP(=0)(OR14)2.
In a more preferred embodiment of the present invention and/or embodiments thereof, R1 is Y, or L-Y, and wherein Y is substituted with halo, hydroxy, amino, nitro, carbonyl, cyano, SG, L-SG, Ci-3alkylC(=0)N(R6)Ci-6alkylaryl, Ci-6alkylS02NR7R8, S02NR7R8, Ci-ealkyl OS02 NR7R8, OS02 NR7R8, Ci-
Figure imgf000027_0002
6alkylN(R6)C(=0)N(R6)aryl, Ci-6alkylN(R6)C(=S)N(R6)aryl or Ci-ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR12R13, or OP(=0)(OR14)2; wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OS02 NR7R8; and wherein the aryl is optionally further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2- ealkynyl, Ci ealkyloxy, di(Ci-6alkyl) amino, hydroxy amino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, hydroxyCi ealkyl, aminoCi ealkyl , cyano, or
OP(=0)(OR14)¾
In a more preferred embodiment of the present invention and/or embodiments thereof, R1 is Y, or Ci ealkyl substituted with Y, and wherein Y is substituted with halo, hydroxy, amino, nitro, carbonyl, cyano, Ci- 3alkylC(=0)N(R6)Ci-6alkylaryl, Ci-6alkylS02NR7R8, S02NR7R8, Ci-ealkyl OS02 NR7R8, OS02 NR7R8, SG, L-SG, Ci-6alkylN(R6)C(=0)N(R6)Ci-6alkylaryl, Ci- 6alkylN(R6)C(=S)N(R6)Ci-6alkylaryl, Ci-6alkylN(R6)C(=0)N(R6)aryl, Ci-
Figure imgf000027_0003
or Ci ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR12R!3, or OP(=0)(OR1 )2; wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OS02 NR7R8; and wherein the aryl is optionally further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci ealkyloxy, di(Ci- 6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, hydroxyCi ealkyl, aminoCi ealkyl , cyano, or
Figure imgf000028_0001
In a more preferred embodiment of the present invention and/or embodiments thereof, R1 is Y, or L-Y, and wherein Y is substituted with halo, hydroxy, amino, cyano, or Ci ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR12R13, or OP(=0)(OR14)2.
In a more preferred embodiment of the present invention and/or embodiments thereof, R1 is Y, or Ci ealkyl substituted with Y, and wherein Y is substituted with halo, hydroxy, amino, cyano, or Ci ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR12R13, or OP(=0)(OR14)2.
In a more preferred embodiment of the present invention and/or embodiments thereof, R1 is Y or L-Y, or
Figure imgf000028_0002
NR (Ci- ealkyl-Χ2)), wherein Y and/or the linker L is not further substituted.
In a more preferred embodiment of the present invention and/or embodiments thereof, R1 is Y or Ci ealkyl substituted with Y, or Ci ealkyl substituted with
Figure imgf000028_0003
wherein Y and/or the Ci ealkyl is not further substituted.
In a more preferred embodiment of the present invention, Y is further substituted with a substituent selected from the group selected from halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci ealkyloxy, di(Ci-6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, a further heterocycle, C3-7Cycloalkyl, , hydroxyCi ealkyl, aminoCi-ealkyl , cyano, SiFR12R13, OP(=0)(OR14)2or Ci-ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR12R13, or OP(=0)(OR1 )2.
In a more preferred embodiment of the present invention, Y is further substituted with a substituent selected from the group selected from halo, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci ealkyloxy, di(Ci-6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carboxyamide, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, a further heterocycle, C3- 7Cycloalkyl, , hydroxyCi-6alkyl, aminoCi-6alkyl , cyano, SiFR12R13, OP(=0)(OR14)2 or Ci ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR12R13, or
OP(=0)(OR14)2.
In another preferred embodiment of the present invention and/or embodiments thereof, Y is further substituted with a substituent selected from the group comprising halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci- 6alkyloxy, di(Ci-6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, a further heterocycle, C3-7Cycloalkyl, , hydroxyCi ealkyl or aminoCi ealkyl , cyano, SiFR12R13,
Figure imgf000029_0001
or Ci ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR12R13, or OP(=0)(OR14)2.
In a more preferred embodiment of the present invention and/or embodiments thereof, Y is further substituted with a substituent selected from the group comprising halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci- ealkyloxy, carbonyl, NR4R5, cyano, SiFR12R13, OP(=0)(OR1 )2., or Ci-ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR12R13, or
Figure imgf000029_0002
In a more preferred embodiment of the present invention and/or embodiments thereof, Y is further substituted with a substituent selected from the group comprising halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, SiFR12R13,
Figure imgf000029_0003
or Ci ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR12R13, or OP(=0)(OR1 )2.
In a more preferred embodiment of the present invention and/or embodiments thereof, Y is further substituted with a substituent selected from the group comprising halo, hydroxy, amino, nitro, SiFR12R13,
Figure imgf000029_0004
or Ci- 6alkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR12R13, or
Figure imgf000029_0005
In a more preferred embodiment of the present invention and/or embodiments thereof, Y is further substituted with a substituent selected from the group comprising halo, hydroxy, SiFR12R13,
Figure imgf000030_0001
or Ci ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR12R13, or
Figure imgf000030_0002
more preferably with halo, more preferably with hydroxyl, more preferably with more preferably with SiFR12R13, more preferably with Ci ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR12R13, or OP(=0)(OR14)2.
In a more preferred embodiment of the present invention and/or embodiments thereof, Y is not further substituted.
In suitable embodiments of the present invention and/or embodiments thereof the linker L is Ci ealkyl, preferably Ci-4alkyl, C2-3alkyl, Ci salkyl, Ci-2alkyl, more preferably, C2-3alkyl, Ci-2alkyl.
In a more preferred embodiment of the present invention and/or embodiments thereof, R1 is Ci-4alkyl substituted with Y or Ci-4alkyl substituted with
Figure imgf000030_0004
NRn(Ci-6alkyl-X2)).
In a more preferred embodiment of the present invention and/or embodiments thereof, R1 is Ci salkyl substituted Y or Ci salkyl substituted with -
Figure imgf000030_0005
NRii(Ci-6alkyl-X2)).
In a more preferred embodiment of the present invention and/or embodiments thereof, R1 is Ci-2alkyl substituted Y or Ci-2alkyl substituted with -
Figure imgf000030_0006
NRii(Ci-6alkyl-X2)).
In a more preferred embodiment of the present invention and/or embodiments thereof, R1 is Ci alkyl substituted with Y or Ci-alkyl substituted with
Figure imgf000030_0007
NR11(Ci-6alkyl-X2)).
It is to be understood that also the shorter alkyl groups in R1 may be substituted with the substituents as indicated for the L and Ci ealkyl in any embodiment above, where possible. A skilled person will know when such substitution is possible or not.
In another preferred embodiment of the present invention and/or embodiments thereof, L is further substituted with a substituent selected from the group comprising halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci- 6alkyloxy, di(Ci-6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3- Tcycloalkyl, , hydroxy Ci-ealkyl, aminoCi-ealkyl, cyano, SiFR12R13, or OP(=0)(OR14)2, a SG group or an active moiety A.
In another preferred embodiment of the present invention and/or embodiments thereof, L is further substituted with a substituent selected from the group comprising halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci- 6alkyloxy, di(Ci-6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3- 7Cycloalkyl, , hydroxyCi-6alkyl, aminoCi-6alkyl, cyano, SiFR12R13, or OP(=0)(OR14)2.
In a more preferred embodiment of the present invention and/or embodiments thereof, Y comprises 5, or 6 atoms, preferably 6 atoms.
In a more preferred embodiment of the present invention and/or embodiments thereof, Y comprises nitrogen and one or two further heteroatoms selected from nitrogen, oxygen and sulphur, preferably oxygen or nitrogen and most preferred nitrogen.
In a more preferred embodiment of the present invention and/or embodiments thereof, Y comprises nitrogen and one further heteroatom selected from nitrogen, oxygen and sulphur, preferably oxygen or nitrogen and most preferred nitrogen.
In a more preferred embodiment of the present invention and/or embodiments thereof, the heteroatom in Y is oxygen or nitrogen and preferably nitrogen.
In another preferred embodiment of the present invention and/or embodiments thereof, Y is selected from the group comprising imidazolidine, pyrazolidine, tetrahydrofuran, triazole, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperazine, morpholine, thiomorpholine, pyrimidine, and
homopiperazine.
In another preferred embodiment of the present invention and/or embodiments thereof, Y is selected from the group comprising imidazolidine, pyrazolidine, tetrahydrofuran, oxazolidine, isoxazolidine, thiazolidine,
isothiazolidine, triazole, piperazine, morpholine, pyrimidine, and thiomorpholine.
In another preferred embodiment of the present invention and/or embodiments thereof, Y is selected from the group comprising imidazolidine, oxazolidine, tetrahydromran, triazole, thiazolidine, isothiazolidine, piperazine, morpholine, pyrimidine, and thiomorpholine.
In another preferred embodiment of the present invention and/or embodiments thereof, Y is selected from the group comprising imidazolidine, thiazolidine, tetrahydrofuran, triazole, piperazine, morpholine, pyrimidine, and thiomorpholine .
In another preferred embodiment of the present invention and/or embodiments thereof, Y is selected from the group comprising imidazolidine, tetrahydrofuran, triazole, piperazine, pyrimidine, and morpholine.
In another preferred embodiment of the present invention and/or embodiments thereof, Y is selected from the group comprising piperazine, tetrahydrofuran, triazole, pyrimidine, and morpholine.
In another preferred embodiment of the present invention and/or embodiments thereof, Y is piperazine.
In another preferred embodiment of the present invention and/or embodiments thereof Y is morpholine.
In another preferred embodiment of the present invention and/or embodiments thereof, Y is imidazolidine.
In another preferred embodiment of the present invention and/or embodiments thereof, Y is thiomorpholine.
In another preferred embodiment of the present invention and/or embodiments thereof, Y is triazole.
In another preferred embodiment of the present invention and/or embodiments thereof, Y is tetrahydrofuran.
In another preferred embodiment of the present invention and/or embodiments thereof, Y is pyrimidine.
In a more preferred embodiment of the present invention and/or embodiments thereof, Y comprises at least 2 nitrogen atoms.
In a more preferred embodiment of the present invention and/or embodiments thereof, Y comprises at least 2 nitrogen atoms and is substituted with halo, nitro, carbonyl, cyano, carboxyamine, SiFR12R13,
Figure imgf000032_0001
Ci- 3alkylC(=0)N(R6)Ci-6alkylaryl, SG, L-SG, Ci-6alkylS02NR7R8, S02NR¾8, Ci-ealkyl OS02 NR7R8, OSO2 NR¾8, Ci-6alkylN(R9)S02NR7R8, N(R9)S02NR7R8, Ci-
Figure imgf000033_0001
6alkylN(R6)C(=0)N(R6)aryl, Ci-6alkylN(R6)C(=S)N(R6)aryl, or Ci-ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR12R13, or
Figure imgf000033_0002
wherein the aryl is substituted with a S02NR¾8, N(R9)S02NR¾8, or OSO2 NR¾8; and wherein the aryl is optionally further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2- 6alkynyl, Ci ealkyloxy, di(Ci-6alkyl) amino, hydroxy amino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, , hydroxyCi ealkyl, aminoCi ealkyl , cyano, SiFR12R13, or OP(=0)(OR14)2.
In a more preferred embodiment of the present invention and/or embodiments thereof, Y comprises at least 2 nitrogen atoms and is substituted with amine, carboxyamine, SG, L-SG, Ci-3alkylC(=0)N(R6)Ci-6alkylaryl, Ci- 6S02NR¾8, S02NR¾8, C1-6OSO2 NR¾8, OSO2 NR¾8, Ci-6N(R9)S02NR¾8,
N(R9)S02NR¾8, Ci-6N(R6)C(=0)N(R6)Ci-6aryl, Ci-6N(R6)C(=S)N(R6)Ci-6aryl, Ci-
Figure imgf000033_0003
or Ci-ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR12R13, or
Figure imgf000033_0004
wherein the aryl is substituted with a S02NR¾8, N(R9)S02NR7R8, or OSO2 NR7R8; and wherein the aryl is further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci- 6alkyloxy, di(Ci-6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3- Tcycloalkyl, , hydroxy Ci-ealkyl, aminoCi-ealkyl , cyano, SiFR12R13, or OP(=0)(OR14)2.
In a more preferred embodiment of the present invention and/or embodiments thereof, Y comprises at least 2 nitrogen atoms and is substituted with halo, amine, nitro, or cyano.
In a more preferred embodiment of the present invention and/or embodiments thereof, Y comprises at least 2 nitrogen atoms and is substituted with halo. In a more preferred embodiment of the present invention and/or embodiments thereof, Y comprises at least 2 nitrogen atoms and is substituted with amine or nitro.
In a more preferred embodiment of the present invention and/or embodiments thereof, Y comprises at least 2 nitrogen atoms and is further not substituted.
In a more preferred embodiment of the present invention and/or embodiments thereof, Y comprises at least 2 nitrogen atoms and is further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, carboxyamine, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci- 6alkyloxy, carbonyl, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, , hydroxyCi-ealkyl, aminoCi-ealkyl , cyano, SiFR12R13, or OP(=0)(OR14)2, or Ci-ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR12R13, or
Figure imgf000034_0001
In a more preferred embodiment of the present invention and/or embodiments thereof, Y comprises at least 2 nitrogen atoms and is further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, carboxyamine, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci- 6alkyloxy, carbonyl, Ci ealkylcarbonyl, NR4R5, a further heterocycle, C3-7Cycloalkyl, , hydroxyCi-ealkyl, aminoCi-ealkyl , cyano, SiFR12R13, or OP(=0)(OR14)2, or Ci-ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR12R13, or
Figure imgf000034_0002
In a more preferred embodiment of the present invention and/or embodiments thereof, Y is substituted with an aryl which aryl is further
substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, carbonyl, NR4R5, cyano, SiFR12R13, or OP(=0)(OR14)2.
In a more preferred embodiment of the present invention and/or embodiments thereof, Y is substituted with an aryl which aryl is further
substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci-ealkyl, SiFR12R13, or OP(=0)(OR1 )2. In a more preferred embodiment of the present invention and/or embodiments thereof, Y is substituted with a aryl which aryl is further substituted with a SO2NFOT or OSO2NFOT.
In a more preferred embodiment of the present invention and/or embodiments thereof, Y is substituted with a aryl which aryl is further substituted with a S02NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, Y is substituted with a aryl which aryl is further substituted with a N(R9)S02NR7R8 or OS02NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, Y is substituted with a aryl which aryl is further substituted with a S02NR7R8 or N(R9)S02NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, Y is substituted with a aryl which aryl is further substituted
Figure imgf000035_0001
In a more preferred embodiment of the present invention and/or embodiments thereof, Y is substituted with a aryl which aryl is further substituted with a OS02 NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, Y is substituted with a aryl which aryl is further substituted with Ci-3C(=0)N(R6)Ci-6alkylaryl, Ci-6alkyl N(R6)C(=0)N(R6)Ci-6alkyl aryl, Ci-
Figure imgf000035_0002
6N(R6)C(=S)N(R6)aryl.
In a more preferred embodiment of the present invention and/or embodiments thereof, Y is substituted with Ci-3alkylC(=0)N(R6)Ci-3alkylaryl, Ci- 6alkylN(R6)C(=0)N(R6)Ci-3alkylaryl, Ci-6alkylN(R6)C(=S)N(R6)Ci-3alkylaryl, Ci-
Figure imgf000035_0003
In a more preferred embodiment of the present invention and/or embodiments thereof, Y is substituted with Ci-3alkylC(=0)N(R6)Ci-2alkylaryl, Ci-
Figure imgf000035_0004
6alkylN(R6)C(=0)N(R6)aryl, Ci-6alkylN(R6)C(=S)N(R6)aryl.
In a more preferred embodiment of the present invention and/or embodiments thereof, Y is substituted with Ci-3alkylC(=0)N(R6)Cialkylaryl, Ci-
Figure imgf000036_0001
6alkylN(R6)C(=0)N(R6)aryl, Ci-6alkylN(R6)C(=S)N(R6)aryl.
In a more preferred embodiment of the present invention and/or embodiments thereof, Y is substituted with
Figure imgf000036_0002
Ci- 6alkylN(R6)C(=S)N(R6)aryl.
In a more preferred embodiment of the present invention and/or embodiments thereof, Y is substituted with Ci-6alkyl
Figure imgf000036_0003
Ci-6alkylN(R6)C(=0)N(R6)aryl, preferably, Ci-3alkyl N(R6)C(=0)N(R6)Ci-6alkylaryl, or
Figure imgf000036_0004
more preferably Ci-2alkyl
6alkylaryl, or
Figure imgf000036_0005
more preferably Cialkyl
Figure imgf000036_0006
In a more preferred embodiment of the present invention and/or embodiments thereof, Y is substituted with Ci-6alkylN(R6)C(=S)N(R6)Ci-6alkylaryl,
Figure imgf000036_0007
In a more preferred embodiment of the present invention and/or embodiments thereof, Y is substituted with Ci-3alkylN(R6)C(=S)N(R6)Ci-6alkylaryl,
Figure imgf000036_0008
In a more preferred embodiment of the present invention and/or embodiments thereof, Y is substituted with Ci-2alkylN(R6)C(=S)N(R6)Ci-6alkylaryl,
Figure imgf000036_0009
In a more preferred embodiment of the present invention and/or embodiments thereof, Y is substituted with CialkylN(R6)C(=S)N(R6)Ci-6alkylaryl, or
Figure imgf000036_0010
more preferably Y is substituted with
Figure imgf000036_0011
more preferably Y is substituted with
Figure imgf000036_0012
and most preferably Y is substituted with CialkylN(R6)C(=S)N(R6)Cialkylaryl, or
Figure imgf000036_0013
In a more preferred embodiment of the present invention and/or embodiments thereof, Y is substituted with Ci-3alkylC(=0)N(R6)Ci-6alkylaryl, more preferably Ci-3alkylC(=0)N(R6)Ci-3alkylaryl, more preferably Ci- 3alkylC(=0)N(R6)Ci-2alkylaryl, and more preferably Ci- 3alkylC(=0)N(R6)Cialkylaryl. In a more preferred embodiment of the present invention and/or embodiments thereof, Y is substituted with Ci-2alkylC(=0)N(R6)Ci-6alkylaryl, more preferably Ci-2alkylC(=0)N(R6)Ci-3alkylaryl, more preferably Ci- 2alkylC(=0)N(R6)Ci-2alkylaryl, and more preferably Ci- 2alkylC(=0)N(R6)Cialkylaryl.
In a more preferred embodiment of the present invention and/or embodiments thereof, Y is substituted with CialkylC(=0)N(R6)Ci-6alkylaryl, more preferably CialkylC(=0)N(R6)Ci-3alkylaryl, more preferably CialkylC(=0)N(R6)Ci- 2alkylaryl, and more preferably CialkylC(=0)N(R6)Cialkylaryl.
In a more preferred embodiment of the present invention and/or embodiments thereof, Y is substituted with Ci-6alkylS02NR7R8, S02NR7R8, Ci- 6alkylOS02 NR7R8, OSO2 NR7R8, Ci-6alkylN(R9)S02NR7R8, or N(R9)S02NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, Y is substituted with Ci-6alkylS02NR7R8, or S02NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, is substituted with Ci-3alkylS02NR7R8, or S02NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, Y is substituted with Ci-2alkylS02NR7R8, or S02NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, Y is substituted with CialkylS02NR7R8, or S02NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, Y is substituted with Ci-6alkylOS02NR7R8, or OS02NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, Y is substituted with Ci-3alkylOS02NR7R8, or OS02NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, Y is substituted with Ci-2alkylOS02NR7R8, or OS02NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, Y is substituted with CialkylOS02NR7R8, or OS02NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, Y is substituted with Ci-6alkylN(R9)S02NR7R8, or
N(R9)S02NR7R8. In a more preferred embodiment of the present invention and/or embodiments thereof, Y is substituted with Ci-3alkylN(R9)S02NR7R8, or
N(R9)S02NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, Y is substituted with Ci-2alkylN(R9)S02NR7R8, or
N(R9)S02NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, Y is substituted with CialkylN(R9)S02NR7R8, or
N(R9)S02NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, in case Y is substituted with Ci-3alkylC(=0)N(R6)Ci- ealkylaryl, Ci-6alkylS02NR7R8, S02NR7R8, Ci-ealkyl OSO2 NR7R8, OSO2 NR7R8, Ci- 6alkylN(R9)S02NR7R8, N(R9)S02NR7R8, Ci-6alkylN(R6)C(=0)N(R6)Ci-6alkylaryl, Ci-
Figure imgf000038_0001
6alkylN(R6)C(=S)N(R6)aryl; and wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OSO2 NR7R8, then R2 is hydrogen.
In a more preferred embodiment of the present invention and/or embodiments thereof, in case Y is substituted with a moiety selected from the group consisting of SG, L-SG, Ci-3alkylC(=0)N(R6)Ci-6alkylaryl, Ci-6alkylS02NR7R8, S02NR7R8, Ci-ealkyl OSO2 NR7R8, OSO2 NR7R8, Ci-6alkylN(R9)S02NR7R8,
N(R9)S02NR7R8, Ci-6alkylN(R6)C(=0)N(R6)Ci-6alkylaryl, Ci-
Figure imgf000038_0002
6alkylN(R6)C(=S)N(R6)aryl; wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OSO2 NR7R8, then R2 is not a moiety selected from the group consisting of Ci-3alkylC(=0)N(R6)Ci-6alkylaryl, Ci-6alkylS02NR7R8, S02NR7R8, Ci- ealkyl OSO2 NR7R8, OSO2 NR7R8, Ci-6alkylN(R9)S02NR7R8, N(R9)S02NR7R8, Ci-
Figure imgf000038_0003
6alkylN(R6)C(=0)N(R6)aryl, Ci-6alkylN(R6)C(=S)N(R6)aryl; wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OS02NR7R8 .
In a more preferred embodiment of the present invention and/or embodiments thereof, Y comprises at least 2 nitrogen atoms and is substituted on the nitrogen atom. In a more preferred embodiment of the present invention and/or embodiments thereof, Y comprises at least 2 nitrogen atoms and is attached to the Ci ealkyl at the terminal C atom of the Ci-ealkyl.
In a more preferred embodiment of the present invention and/or embodiments thereof, X1, X2, is each independently halo, nitro, carbonyl, cyano, SiFR12R13, OP(=0)(OR14)2, SG, L-SG, Ci-3alkylC(=0)N(R6)Ci-6alkylaryl, Ci- 6alkylS02NR7R8, S02NR7R8, Ci-ealkyl OSO2 NR7R8, OSO2 NR7R8, Ci- 6alkylN(R9)S02NR7R8, N(R9)S02NR7R8, Ci-6alkylN(R6)C(=0)N(R6)Ci-6alkylaryl, Ci-
Figure imgf000039_0001
6alkylN(R6)C(=S)N(R6)aryl; wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OS02 NR7R8; and wherein the aryl is optionally further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci ealkyloxy, di(Ci- 6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, , hydroxyCi-ealkyl, aminoCi-ealkyl , cyano, SiFR12R13, or OP(=0)(OR14)2.
In a more preferred embodiment of the present invention and/or embodiments thereof, X1, X2, is each independently halo or cyano.
In a more preferred embodiment of the present invention and/or embodiments thereof, X1, X2, is each independently halo.
In a more preferred embodiment of the present invention and/or embodiments thereof, X1, X2, is each independently SG, L-SG, Ci- 3alkylC(=0)N(R6)Ci-6alkylaryl, Ci-6S02NR7R8, S02NR7R8, Ci-6OS02 NR7R8, OS02 NR7R8, Ci-6N(R9)S02NR7R8, N(R9)S02NR7R8,
Figure imgf000039_0002
Ci-
Figure imgf000039_0003
wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OS02 NR7R8; and wherein the aryl is further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2- 6alkynyl, Ci ealkyloxy, di(Ci-6alkyl) amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, , hydroxyCi ealkyl, aminoCi ealkyl , cyano, SiFR12R13, or OP(=0)(OR14)2. In a more preferred embodiment of the present invention and/or embodiments thereof, the aryl in X1, X2, is each independently further not substituted.
In a more preferred embodiment of the present invention and/or embodiments thereof, the aryl in X1, X2, is each independently further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci ealkyloxy, carbonyl, Ci- 6alkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, , hydroxyCi ealkyl, aminoCi- ealkyl , cyano, SiFR12R13, or OP(=0)(OR14)2.
In a more preferred embodiment of the present invention and/or embodiments thereof, the aryl in X1, X2, is each independently further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci ealkyloxy, carbonyl, Ci- 6alkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, , hydroxyCi ealkyl, aminoCi- ealkyl , cyano, SiFRi2Ri3, or OP(=0)(OR14)2.
In a more preferred embodiment of the present invention and/or embodiments thereof, the aryl in X1, X2, is each independently further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, carbonyl, NR4R5, cyano, SiFR12R13, or OP(=0)(OR14)2.
In a more preferred embodiment of the present invention and/or embodiments thereof, the aryl in X1, X2, is each independently further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci-ealkyl, SiFR12R13, or OP(=0)(OR14)2.
In a more preferred embodiment of the present invention and/or embodiments thereof, X1, X2, is each independently SG, or L-SG.
In a more preferred embodiment of the present invention and/or embodiments thereof, the aryl in X1, X2, is each independently substituted with a
Figure imgf000040_0001
In a more preferred embodiment of the present invention and/or embodiments thereof, the aryl in X1, X2, is each independently substituted with a S02NR¾8. In a more preferred embodiment of the present invention and/or embodiments thereof, the aryl in X1, X2, is each independently substituted with a N(R9)S02NR¾8 or OSO2 NR¾8.
In a more preferred embodiment of the present invention and/or embodiments thereof, the aryl in X1, X2, is each independently substituted with a S02NR7R8 or N(R9)S02NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, the aryl in X1, X2, is each independently substituted with a N(R9)S02NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, the aryl in X1, X2, is each independently substituted with a OSO2 NR7R8.In a more preferred embodiment of the present invention and/or embodiments thereof, X1, X2, is each independently SG, or L-SG,
Figure imgf000041_0001
Ci-ealkyl
Figure imgf000041_0002
Ci- 6alkylN(R6)C(=0)N(R6)aryl, Ci-6N(R6)C(=S)N(R6)aryl.
In a more preferred embodiment of the present invention and/or embodiments thereof, X1, X2, is each independently
Figure imgf000041_0003
Ci-6alkyl N(R6)C(=0)N(R6)Ci-6alkyl aryl, Ci-6alkylN(R6)C(=S)N(R6)Ci-6alkylaryl, Ci-
Figure imgf000041_0004
In a more preferred embodiment of the present invention and/or embodiments thereof, X1, X2, is each independently SG, or L-SG ,Ci-
Figure imgf000041_0005
6alkylN(R6)C(=S)N(R6)Ci-3alkylaryl, Ci-6alkylN(R6)C(=0)N(R6)aryl, Ci- 6alkylN(R6)C(=S)N(R6)aryl.
In a more preferred embodiment of the present invention and/or embodiments thereof, X1, X2, is each independently
Figure imgf000041_0006
salkylaryl,
Figure imgf000041_0007
salkylaryl, Ci-6alkylN(R6)C(=0)N(R6)aryl, Ci-6alkylN(R6)C(=S)N(R6)aryl.
In a more preferred embodiment of the present invention and/or embodiments thereof, X1, X2, is each independently SG, L-SG, Ci- 3alkylC(=0)N(R6)Ci-2alkylaryl, Ci-6alkylN(R6)C(=0)N(R6)Ci-2alkylaryl, Ci-
Figure imgf000041_0008
6alkylN(R6)C(=S)N(R6)aryl. In a more preferred embodiment of the present invention and/or embodiments thereof, X1, X2, is each independentl
2alkylaryl, Ci-6alkylN(R6)C(=0)N(R6)Ci-2alkylaryl,
Figure imgf000042_0001
2alkylaryl,
Figure imgf000042_0002
In a more preferred embodiment of the present invention and/or embodiments thereof, X1, X2, is each independently SG, L-SG, Ci-
Figure imgf000042_0003
6alkylN(R6)C(=S)N(R6)Cialkylaryl, Ci-6alkylN(R6)C(=0)N(R6)aryl, Ci- 6alkylN(R6)C(=S)N(R6)aryl.
In a more preferred embodiment of the present invention and/or embodiments thereof, X1, X2, is each independently Ci-
Figure imgf000042_0004
6alkylN(R6)C(=S)N(R6)Cialkylaryl, Ci-6alkylN(R6)C(=0)N(R6)aryl, Ci- 6alkylN(R6)C(=S)N(R6)aryl.
In a more preferred embodiment of the present invention and/or embodiments thereof, X1, X2, is each independently SG, L-SG, Ci-
Figure imgf000042_0005
In a more preferred embodiment of the present invention and/or embodiments thereof, X1, X2, is each independently Ci-6alkylN(R6)C(=0)N(R6)aryl,
Figure imgf000042_0006
In a more preferred embodiment of the present invention and/or embodiments thereof, X1, X2, is each independently Ci-6alkyl
Figure imgf000042_0007
ealkylaryl, Ci-6alkylN(R6)C(=0)N(R6)aryl, preferably, Ci-3alkyl N(R6)C(=0)N(R6)Ci- 6alkylaryl, or Ci-3alkylN(R6)C(=0)N(R6)aryl, more preferably Ci-2alkyl
Figure imgf000042_0008
more preferably Cialkyl N(R6)C(=0)N(R6)Ci-6alkylaryl, or CialkylN(R6)C(=0)N(R6)aryl.
In a more preferred embodiment of the present invention and/or embodiments thereof, X1, X2, is each independently
Figure imgf000042_0009
ealkylaryl, or Ci-6N(R6)C(=S)N(R6)aryl.
In a more preferred embodiment of the present invention and/or embodiments thereof, X1, X2, is each independently
Figure imgf000042_0010
ealkylaryl, or Ci-3N(R6)C(=S)N(R6)aryl. In a more preferred embodiment of the present invention and/or embodiments thereof, X1, X2, is each independently
Figure imgf000043_0001
ealkylaryl, or
Figure imgf000043_0002
In a more preferred embodiment of the present invention and/or embodiments thereof, X1, X2, is each independently
Figure imgf000043_0003
6alkylaryl, or CiN(R6)C(=S)N(R6)aryl, more preferably X1, X2, is each independently
Figure imgf000043_0004
more preferably X1, X2, is each independently CialkylN(R6)C(=S)N(R6)Ci-2alkylaryl, or
CiN(R6)C(=S)N(R6)aryl, and most preferably X1, X2, is each independently
CialkylN(R6)C(=S)N(R6)Cialkylaryl, or CiN(R6)C(=S)N(R6)aryl.
In a more preferred embodiment of the present invention and/or embodiments thereof, X1, X2, is each independently
Figure imgf000043_0005
6alkylaryl, more preferably Ci-3alkylC(=0)N(R6)Ci-3alkylaryl, more preferably Ci- 3alkylC(=0)N(R6)Ci-2alkylaryl, and more preferably Ci- 3alkylC(=0)N(R6)Cialkylaryl.
In a more preferred embodiment of the present invention and/or embodiments thereof, X1, X2, is each independently
Figure imgf000043_0006
6alkylaryl, more preferably Ci-2alkylC(=0)N(R6)Ci-3alkylaryl, more preferably Ci- 2alkylC(=0)N(R6)Ci-2alkylaryl, and more preferably Ci-
Figure imgf000043_0007
In a more preferred embodiment of the present invention and/or embodiments thereof, X1, X2, is each independently CialkylC(=0)N(R6)Ci- 6alkylaryl, more preferably CialkylC(=0)N(R6)Ci-3alkylaryl, more preferably CialkylC(=0)N(R6)Ci-2alkylaryl, and more preferably
Figure imgf000043_0008
In a more preferred embodiment of the present invention and/or embodiments thereof, X1, X2, is each independently Ci-6alkylS02NR7R8, S02NR7R8, Ci-6alkylOS02 NR7R8, OSO2 NR¾s, Ci-6alkylN(R9)S02NR¾8, or N(R9)S02NR¾8.
In a more preferred embodiment of the present invention and/or embodiments thereof, X1, X2, is each independently Ci-6alkylS02NR7R8, or
S02NR7R8. In a more preferred embodiment of the present invention and/or embodiments thereof, X1, X2, is each independently Ci-3alkylS02NR7R8, or
S02NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, X1, X2, is each independently Ci-2alkylS02NR7R8, or
S02NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, X1, X2, is each independently CialkylS02NR7R8, or
S02NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, X1, X2, is each independently Ci-6alkylOS02 NR7R8, or OSO2 NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, X1, X2, is each independently Ci-3alkylOS02 NR7R8, or OSO2 NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, X1, X2, is each independently Ci-2alkylOS02 NR7R8, or OSO2 NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, X1, X2, is each independently CialkylOS02 NR7R8, or OSO2 NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, X1, X2, is each independently Ci-6alkylN(R9)S02NR7R8, or N(R9)S02NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, X1, X2, is each independently Ci-3alkylN(R9)S02NR7R8, or N(R9)S02NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, X1, X2, is each independently Ci-2alkylN(R9)S02NR7R8, or N(R9)S02NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, X1, X2, is each independently CialkylN(R9)S02NR7R8, or N(R9)S02NR7R8. In a more preferred embodiment of the present invention and/or embodiments thereof, in case X1 and/or X2 is a moiety selected from the group consisting of SG, L-SG, Ci-3alkylC(=0)N(R6)Ci-6alkylaryl, Ci-6alkylS02NR7R8, S02NR7R8, Ci-ealkyl OSO2 NR7R8, OSO2 NR7R8, Ci-6alkylN(R9)S02NR7R8,
N(R9)S02NR7R8, Ci-6alkylN(R6)C(=0)N(R6)Ci-6alkylaryl, Ci-
Figure imgf000045_0001
6alkylN(R6)C(=S)N(R6)aryl; wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OS02 NR7R8, then R2 is hydrogen.
In a more preferred embodiment of the present invention and/or embodiments thereof, in case X1 and/or X2 is a moiety selected from the group consisting of Ci-3alkylC(=0)N(R6)Ci-6alkylaryl, Ci-6alkylS02NR7R8, S02NR7R8, Ci- ealkyl OS02 NR7R8, OS02 NR7R8, Ci-6alkylN(R9)S02NR7R8, N(R9)S02NR7R8, Ci- 6alkylN(R6)C(=0)N(R6)Ci-6alkylaryl, Ci-6alkylN(R6)C(=S)N(R6)Ci-6alkylaryl, Ci-
Figure imgf000045_0002
wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OS02 NR7R8, then R2 is hydrogen.
In a more preferred embodiment of the present invention and/or embodiments thereof, in case X1 and/or X2 is a moiety selected from the group consisting of SG, L-SG, Ci-3alkylC(=0)N(R6)Ci-6alkylaryl, Ci-6alkylS02NR7R8, S02NR7R8, Ci-ealkyl OS02 NR7R8, OS02 NR7R8, Ci-6alkylN(R9)S02NR7R8,
N(R9)S02NR7R8, Ci-6alkylN(R6)C(=0)N(R6)Ci-6alkylaryl, Ci-
Figure imgf000045_0003
6alkylN(R6)C(=S)N(R6)aryl; wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OS02NR7R8, then R2 is not a moiety selected from the group consisting of Ci-3alkylC(=0)N(R6)Ci-6alkylaryl, Ci-6alkylS02NR7R8, S02NR7R8, Ci- ealkyl OS02 NR7R8, OS02 NR7R8, Ci-6alkylN(R9)S02NR7R8, N(R9)S02NR7R8, Ci-
Figure imgf000045_0004
6alkylN(R6)C(=0)N(R6)aryl, Ci-6alkylN(R6)C(=S)N(R6)aryl; wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OS02NR7R8 .
The compounds of the present invention comprise at least one SG group wherein SG is a sulfonamide, sulfamate, or sulfamide group selected from the group consisting of S02NR7R8, OS02NR7R8, NR9S02NR7R8, NR9S02-phenyl, aryl substituted with S02NR7R8, aryl substituted with OS02NR7R8, aryl substituted with NR9S02NR7R8, or aryl substituted with NR9S02-phenyl.
In a more preferred embodiment of the present invention and/or embodiments thereof, the compounds of the present invention comprise only one SG group. It is to be understood that the SG group may be present in R1 and R3 , as substituent of L, A, B, Y, X1, X2, or in R2.
In a more preferred embodiment of the present invention and/or embodiments thereof, when R1 comprises a SG group then R2 does not comprise a SG group. In a more preferred embodiment of the present invention and/or embodiments thereof, when R1 comprises a S02NR7R8, OS02NR7R8, or a
N(R9)S02NR7R8 then R2 is not a moiety selected from the group consisting of Ci- 3alkylC(=0)N(R6)Ci-6alkylaryl, Ci-6alkylS02NR7R8, S02NR7R8, Ci-ealkyl OSO2 NR7R8, OSO2 NR7R8, Ci-6alkylN(R9)S02NR7R8, N(R9)S02NR7R8, Ci-
Figure imgf000046_0001
6alkylN(R6)C(=0)N(R6)aryl, Ci-6alkylN(R6)C(=S)N(R6)aryl; wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OSO2 NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, when R1 comprises a S02NR7R8, OS02NR7R8, or a
N(R9)S02NR7R8 then R2 does not comprise a SG group.
It is to be understood that R1 may comprise a S02NR7R8, OSO2 NR7R8 or NR9S02 through the linker containing an aryl, or through B ccomprising a moiety S02NR7R8, OSO2 NR7R8 or NR9S02; that Y or A comprises a moiety S02NR7R8, OSO2 NR7R8 or NR9S02. R! may be Ci-3alkylC(=0)N(R6)Ci-6alkylaryl, Ci-6S02NR7R8, S02NR7R8, C1-6OSO2 NR7R8, OSO2 NR7R8, Ci-6N(R9)S02NR7R8, N(R9)S02NR7R8, Ci-
Figure imgf000046_0002
Ci-6N(R6)C(=S)N(R6)aryl; wherein the aryl is substituted with a S02NR7R8,
N(R9)S02NR7R8, or OSO2 NR7R8; or R1 is Y, L-Y or Ci-e substituted with Y, or Ci- ealkyl substituted with NR (Ci-6alkyl-X2)) or L-
Figure imgf000046_0004
NRii(Ci-6alkyl-X2)), wherein Y, Ci-6 substituted with Y, L-Y
Figure imgf000046_0005
or Ci-ealkyl substituted with
Figure imgf000046_0006
NRii(Ci-6alkyl-X2)), Y, L or Ci-ealkyl is substituted with a SG group, Ci-3alkylC(=0)N(R6)Ci-6alkylaryl, Ci-6alkylS02NR7R8, S02NR7R8, Ci-ealkyl OSO2 NR7R8, OSO2 NR7R8, Ci-6alkylN(R9)S02NR7R8, N(R9)S02NR7R8, Ci-
Figure imgf000047_0001
6alkylN(R6)C(=0)N(R6)aryl,
Figure imgf000047_0002
wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OSO2 NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, the compounds of the present invention comprises one moiety selected from the group consisting of Ci-3alkylC(=0)N(R6)Ci-6alkylaryl, Ci- 6alkylS02NR7R8, S02NR7R8, Ci-ealkyl OSO2 NR7R8, OSO2 NR7R8, Ci- 6alkylN(R9)S02NR7R8, N(R9)S02NR7R8, Ci-6alkylN(R6)C(=0)N(R6)Ci-6alkylaryl, Ci-
Figure imgf000047_0003
6alkylN(R6)C(=S)N(R6)aryl; wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OS02 NR7R8.
The compound of the present invention and/or embodiments thereof comprises at least one moiety selected from S02NR7R8, OS02NR7R8, NR9S02NR7R8, NR9S02. It is to be understood that S02NR7R8, N(R9)S02NR7R8, or OS02 NR7R8> NR9S02 such as the SG group may be present in R1 and R3, as substituent of L, Y, X1, X2, or A, or may be present in R2. Compounds with more than one S02NR7R8, OS02NR7R8, NR9S02NR7R8, NR9S02. Compounds with one S02NR7R8, OS02NR7R8, NR9S02NR7R8, NR9S02 are preferred.
It is to be understood that the moiety selected form the group consisting of SG, Ci-3alkylC(=0)N(R6)Ci-6alkylaryl, Ci-6alkylS02NR7R8, S02NR7R8, Ci-ealkyl OS02 NR7R8, OS02 NR7R8, Ci-6alkylN(R9)S02NR7R8, N(R9)S02NR7R8, Ci-
Figure imgf000047_0004
6alkylN(R6)C(=0)N(R6)aryl, Ci-6alkylN(R6)C(=S)N(R6)aryl; wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OS02 NR7R8 may be present in R1 and R2, as substituent of Y, X1, X2, or L of R1 or in R2.
R1 may also be B-L-A or B-A. L is a linker as defined above.
B is a bond, 0-C(=0)-, L-0-C(=0)-, 0-C(=0)-NR9S02-, 0-C(=0)- NR9S02NR7-, 0-C(=0)-NR9S02-0-, 0-C(=0)-NR9S02aryl-, 0-C(=0)-NR9S02NR7- aryl-, 0-C(=0)-NR9S02-0-aryl, L-0-C(=0)-NR9S02-, L-0-C(=0)-NR9S02NR7-, L-O- C(=0)-NR9S02-0-, L-0-C(=0)-NR9S02aryl-, L-0-C(=0)-NR9S02NR7-aryl-, L-O- C(=0)-NR9S02-0-aryl.
In a preferred embodiment of the invention and/or embodiments thereof B is , 0-C(=0)-, L-0-C(=0)-, 0-C(=0)-NR9S02-, 0-C(=0)-NR9S02NR7-, 0-C(=0)- NR9S02-0-, 0-C(=0)-NR9S02aryl-; 0-C(=0)-NR9S02NR7-aryl-, 0-C(=0)-NR9S02-0- aryl, L-0-C(=0)-NR9S02-, L-0-C(=0)-NR9S02NR7-, L-0-C(=0)-NR9S02-0-, L-O- C(=0)-NR9S02aryl-; L-0-C(=0)-NR9S02NR7-aryl-, L-0-C(=0)-NR9S02-0-aryl.
In a preferred embodiment of the invention and/or embodiments thereof B is O-C(=0)-, L-0-C(=0)-.
Under hypoxic conditions, the nitroimidazol is reduced, and is cleaved at the 0-C(=0).
In a preferred embodiment of the invention and/or embodiments thereof B is, 0-C(=0)-NR9S02-, 0-C(=0)-NR9S02NR7-, 0-C(=0)-NR9S02-0-, 0-C(=0)- NR9S02aryl-, 0-C(=0)-NR9S02NR7-aryl-, 0-C(=0)-NR9S02-0-aryl, L-0-C(=0)- NR9S02-, L-0-C(=0)-NR9S02NR7-, L-0-C(=0)-NR9S02-0-, L-0-C(=0)-NR9S02aryl-, L-0-C(=0)-NR9S02NR7-aryl-, L-0-C(=0)-NR9S02-0-aryl. In suitable embodiments, the B group comprises sulfonamide groups S02NR7R8, N(R9)S02NR7R8, or OS02 NR7R8. When the B group comprises a sulfonamide group comprising S02NR7R8, N(R9)S02NR7R8, or OS02 NR7R8, R2 may be hydrogen, as long as the compounds comprises as least one sulfonamide group.
Under hypoxic conditions, the nitro-imidazol group is reduced and is cleaved at the 0-C(=0), positon. Compounds wherein the sulfonamide group S02NR7R8, N(R9)S02NR7R8, or OS02 NR7R8 is attached to the A-group are then compounds with dual action. They have the activity of the active moiety and have the activity of a carboxyanhydrase inhibitor.
In a preferred embodiment of the invention and/or embodiments thereof A is an active moiety selected from the group of chelating agent comprising a therapeutically active metal ion.
Therapeutically active metal ions are well known to a skilled person and are often radioactive metal ion emitting β and/or γ radiations. However a emitters may be also be used. Suitable therapeutically active metal ion may be selected from the group consisting of Bismuth-213, Caesium-137, Cobalt-60 , Dysprosium- 165, Erbium-169 , Holmium-166, Iodine- 125, Iodine-131 , Iridium-192, Lead-212 , Lutetium-177, alladium-103 , Phosphorus-32, Rhenium- 186 , Rhenium- 188, Samarium- 153, Strontium-89 , Yttrium-90. Suitable chelating agents are chelating agents that can complex metal ions. Suitable chelating agents may be selected from DOTA, DTPA, Deferoxamine, DOTA-TATE, DOTATOC, DTPA-BMA, EOB-DTPA, HP-D03A, BOPTA.
In a preferred embodiment of the invention and/or embodiments thereof A is chelating agent comprising a metal ion suitable for imaging. Metal ions suitable for imaging may be metal ions that are used in PET scans, MM and so on. Suitable metal ion for imaging may be selected from the group consisting of Cobalt - 57 , Copper-64, Copper-67 , Gallium-67 , Gallium-68 , Germanium-68 , Indium- 111, Iodine- 123 , Iodine- 124, Krypton-81m, Rubidium-81, Rubidium, Strontium-82, Thallium-201, Iron, Iron oxide, Gadolinium-64, Zirkonium-89.
In a preferred embodiment of the invention and/or embodiments thereof A is fluorescent moiety., A fluorescent moiety is a fluorescent chemical compound that can re-emit light upon light excitation. Fluorescent moiety typically contain several combined aromatic groups, or plane or cyclic molecules with several n bonds. Fluorescent moieties may be used as a tracer in fluids, as a dye for staining of certain structures, as a substrate of enzymes, or as a probe or indicator.
Suitable fluorescent moieties may be selected from the group comprising fluorescent protein such as GFP (green), YFP (yellow) and RFP (red) or Nonprotein organic fluorescent moiety such as Xanthene derivatives e.g. fluorescein, rhodamine, Oregon green, eosin, and Texas red; Cyanine derivatives e.g. cyanine, indocarbocyanine, oxacarbocyanine, thiacarbocyanine, and merocyanine;
Naphthalene derivatives (dansyl and prodan derivatives); Coumarin derivatives, , oxadiazole derivatives e.g. pyridyloxazole, nitrobenzoxadiazole and benzoxadiazole; Anthracene derivatives e.g. anthraquinones, including DRAQ5, DRAQ7 and CyTRAK Orange; Pyrene derivatives e.g.cascade blue; Oxazine derivatives e.g.Nile red, Nile blue, cresyl violet, oxazine 170; Acridine derivatives e.g.proflavin, acridine orange, acridine yellow; Arylmethine derivatives e.g. auramine, crystal violet, malachite green; Tetrapyrrole derivatives e.g.porphin, phthalocyanine, bilirubin.
In a preferred embodiment of the invention and/or embodiments thereof A is a 18F containing moiety. 18F containing moieties may be used for imaging and therapy. Suitable 18F containing moieties may be selected from the group consisting of 18fluorothymidine, 18F-miso (fluoromisonidazole), 18F-choline, and 18fluorodeoxyglucose, florbetapir-fluorine-18, fallypride (18F), 18F-EF5. In a preferred embodiment of the invention and/or embodiments thereof A is a alkylating moiety. Alkylating agents are used in cancer treatment and attach an alkyl group (CnH2n+l) to DNA. Suitable alkylating agents may be selected from the group consisting of Nitrogen mustards , Cyclophosphamide, Mechlorethamine or mustine (HN2) (trade name Mustargen), Uramustine or uracil mustard, Melphalan, Chlorambucil, Ifosfamide, Bendamustine, Nitrosoureas , Carmustine, Lomustine, Streptozocin, Alkyl sulfonates , Busulfan, Thiotepa, procarbazine, altretamine, tetrazines, dacarbazine, mitozolomide, temozolomide.
In order for the active moiety to be able to connect to the linker it must contain at least one hydroxyl.
In suitable embodiments of the invention and/or embodiments thereof the active moiety may be substituted with a sulfonamide, sulfamate, or sulfamide group selected from the group consisting of S02NR7R8, OS02NR7R8, NR9S02NR7R8, NR9S02-phenyl. In such case the active moiety needs at least NH group and/or a second hydroxyl group. In cases the active moiety contains a sulfonamide group such as of S02NR¾8, OS02NR¾8, NR9S02NR¾8, then R2 may be hydrogen. In a preferred embodiment of the present invention and/or embodiments thereof, R2 is hydrogen, SG, or L-SG, wherein SG is a sulfonamide, sulfamate, or sulfamide group selected from the group consisting of S02NR7R8, OS02NR7R8,
NR9S02NR7R8, NR9S02-phenyl, aryl substituted with S02NR7R8, aryl substituted with OS02NR7R8, aryl substituted with NR9S02NR7R8.
In a more preferred embodiment of the present invention and/or
embodiments thereof, the aryl or L is optionally further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci-ealkyl, C2-6alkenyl, C2-6alkynyl, Ci ealkyloxy, di(Ci-6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, , hydroxyCi ealkyl, aminoCi- ealkyl , cyano, or OP(=0)(OR14)¾
L is defined as above and all the embodiments indicated for L above are also envisioned for L-SG.
In a preferred embodiment of the present invention and/or embodiments thereof SG is a moiety selected from the group consisting of S02NR7R8, OS02NR7R§, NR9S02NR¾8, NR9S02-phenyl, aryl substituted with
S02NR7R8, aryl substituted with OS02NR7R8, aryl substituted with
Figure imgf000051_0001
In a preferred embodiment of the present invention and/or embodiments thereof SG is a moiety selected from the group consisting of S02NR7R8, OS02NR7R8, NR9S02NR7R8, aryl substituted with S02NR7R§, aryl
substituted with OS02NR7R§, aryl substituted with NR9S02NR7R§.
In a preferred embodiment of the present invention and/or embodiments thereof SG is a moiety selected from the group consisting of S02NR7R8, OS02NR7R8, NR9S02NR7R8.
In a preferred embodiment of the present invention and/or embodiments thereof SG is a moiety selected from the group consisting of aryl substituted with S02NR7R8, aryl substituted with OS02NR7R8, aryl substituted with NR9S02NR7R8.
In a preferred embodiment of the present invention and/or
embodiments thereof R2 is hydrogen, C i-ealkyl-SG, C(=0)N(R6)-SG, Ci- 6alkyl-C(=0)N(R6)Ci.6alkyl-SG, Ci-6alkyl-C(=0)N(R6)-SG,
Figure imgf000051_0002
ealkyl-SG, N(R6)C(=0)N(R6)-SG, Ci.6alkylN(R6)C(=0)N(R6)Ci.6alkyl-SG, Ci- 6alkylN(R6)C(=0)N(R6)-SG, N(R6)C(=0)N(R6)C i-6alkyl-SG, N(R6)C(=S)N(R6)- SG, Ci-6alkylN(R6)C(=S)N(R6)Ci.6alkyl-SG, Ci-6alkylN(R6)C(=S)N(R6)-SG, N(R6)C(=S)N(R6)C i-ealkyl-SG, -0-C(=0)N(R6)-SG, C i-6alkyl-0-C(=0)N(R6)C i- ealkyl-SG, Ci-6alkyl-0-C(=0)N(R6)-SG, -0-C(=0)N(R6)Ci-6alkyl-SG,
N(R6)C(=0)-SG, C i.6alkylN(R6)C(=0)C i-ealkyl-SG, C i-6alkylN(R6)C(=0)-SG, N(R6)C(=0)Ci.6alkyl-SG, N(R6)C(=S)-SG, Ci.6alkylN(R6)C(=S)Ci.6alkyl-SG, Ci.6alkylN(R6)C(=S)-SG, N(R6)C(=S)Ci-6alkyl-SG, C(=0)N(R6)Ci- 6alkylN(R6)C(=S)N(R6)-SG, C i-6alkylC(=0)N(R6)C i-6alkylN(R6)C(=S)N(R6)C i- ealkyl-SG, Ci-6alkylC(=0)N(R6)Ci.6alkylN(R6)C(=S)N(R6)-SG, C(=0)N(R6)Ci- 6alkylN(R6)C(=S)N(R6)C i-ealkyl-SG, C(=0)N(R6)C i-6alkylN(R6)C(=0)N(R6)- SG, C i.6alkylC(=0)N(R6)C i-6alkylN(R6)C(=0)N(R6)C i-ealkyl-SG, C i- 6alkylC(=0)N(R6)Ci.6alkylN(R6)C(=0)N(R6)-SG, C(=0)N(R6)Ci- 6alkylN(R6)C(=0)N(R6)C i.6alkyl-SG, C(=0)N(R6)C i.6alkyl-OC(=0)-SG, C i- 6alkylC(=0)N(R6)Ci.6alkyl-OC(=0)Ci.6alkyl-SG, Ci.6alkylC(=0)N(R6)Ci. 6alkyl-OC(=0)-SG, C(=0)N(R6)Ci.6alkyl-OC(=0)Ci.6alkyl-SG, 0-C(=0)-SG, Ci.6alkyl-0-C(=0)Ci.6alkyl-SG, Ci.6alkyl-0-C(=0)-SG, 0-C(=0)Ci-6alkyl-SG, 0-C(=0)Ci.6alkylC(=0)N(R6)-SG, Ci.6alkyl-0-C(=0)Ci.6alkylC(=0)N(R6)Ci. ealkyl-SG, Ci.6alkyl-0-C(=0)Ci.6alkylC(=0)N(R6)-SG, 0-C(=0)Ci.
6alkylC(=0)N(R6)Ci.6alkyl-SG, 0-C(=0)Ci.6alkylN(R6)C(=0)-SG, Ci-ealkyl-O- C(=0)Ci.6alkylN(R6)C(=0)Ci.6alkyl-SG, Ci.6alkyl-0-C(=0)Ci.
6alkylN(R6)C(=0)-SG, 0-C(=0)Ci-6alkylN(R6)C(=0)Ci.6alkyl-SG, (O- CH2CH2)n-SG, Ci.6alkyl(0-CH2CH2)n-Ci.6alkyl-SG, Ci.6alkyl(0-CH2CH2)n- SG, (0-CH2CH2)n-Ci.6alkyl-SG, (CH2CH2-0)n-SG,Ci.6alkyl(CH2CH2.0)n-Ci. ealkyl-SG, Ci.6alkyl(CH2CH2-0)n-SG, (CH2CH2-0)n-Ci.6alkyl-SG. Wherein n is l-12,more preferably n is 1-12, more preferably n is 1-10, more preferably n is 2-8, more preferably n is 3-6.
In a preferred embodiment of the present invention and/or
embodiments thereof R2 is hydrogen, Ci-ealkyl-SG, C(=0)N(R6)-SG, Ci- 6alkyl-C(=0)N(R6)Ci.6alkyl-SG, Ci-6alkyl-C(=0)N(R6), Ci- 6alkylN(R6)C(=0)N(R6)Ci.6alkyl-SG, Ci-6alkylN(R6)C(=0)N(R6)-SG,
N(R6)C(=0)N(R6)Ci.6alkyl-SG, Ci-6alkylN(R6)C(=S)N(R6)Ci.6alkyl-SG, Ci- 6alkylN(R6)C(=S)N(R6)-SG, N(R6)C(=S)N(R6)Ci-6alkyl-SG, 0-C(=0)-SG, Ci- 6alkyl-0-C(=0)Ci.6alkyl-SG, Ci.6alkyl-0-C(=0)-SG, 0-C(=0)Ci.6alkyl-SG, -O- C(=0)N(R6)-SG, Ci.6alkyl-0-C(=0)N(R6)Ci.6alkyl-SG, Ci-ealkyl-O- C(=0)N(R6)-SG, -0-C(=0)N(R6)Ci.6alkyl-SG, (0-CH2CH2)n-SG, Ci-6alkyl(0- CH2CH2)nCi.6alkyl-SG, Ci-6alkyl(0-CH2CH2)n-SG, (0-CH2CH2)nCi.6alkyl-SG, C(=0)N(R6)Ci.6alkylN(R6)C(=0)N(R6)-SG, Ci-6alkylC(=0)N(R6)Ci.
6alkylN(R6)C(=0)N(R6)Ci.6alkyl-SG, Ci-6alkylC(=0)N(R6)Ci.
6alkylN(R6)C(=0)N(R6)-SG, C(=0)N(R6)C i-6alkylN(R6)C(=0)N(R6)C i-6alkyl- SG;
In a preferred embodiment of the present invention and/or
embodiments thereof R2 is hydrogen-SG, Ci-ealkyl-SG, C(=0)N(R6)-SG, Ci- 6alkyl-C(=0)N(R6)Ci.6alkyl-SG, Ci.6alkyl-C(=0)N(R6)-SG, Ci- 6alkylN(R6)C(=0)N(R6)Ci.6alkyl-SG, Ci.6alkylN(R6)C(=0)N(R6)-SG,
N(R6)C(=0)N(R6)Ci.6alkyl-SG, Ci.6alkylN(R6)C(=S)N(R6)Ci.6alkyl-SG, Ci- 6alkylN(R6)C(=S)N(R6)-SG, 0-C(=0)-SG,
Figure imgf000053_0001
Ci- 6alkyl-0-C(=0)-SG, (0-CH2CH2)n-SG, Ci.6alkyl(0-CH2CH2)nCi.6alkyl-SG, Ci- 6alkyl(0-CH2CH2)n-SG,
Figure imgf000053_0002
Ci-6alkylC(=0)N(R6)Ci. 6alkylN(R6)C(=0)N(R6)Ci.6alkyl-SG, Ci-6alkylC(=0)N(R6)Ci.
6alkylN(R6)C(=0)N(R6)-SG;
In a preferred embodiment of the present invention and/or
embodiments thereof R2 is hydrogen-SG, Ci-ealkyl-SG, Ci-ealkyl- C(=0)N(R6)Ci.6alkyl-SG, Ci.6alkyl-C(=0)N(R6)-SG, Ci- 6alkylN(R6)C(=0)N(R6)Ci.6alkyl-SG, Ci.6alkylN(R6)C(=0)N(R6)-SG,
N(R6)C(=0)N(R6)Ci.6alkyl-SG, Ci.6alkylN(R6)C(=S)N(R6)Ci.6alkyl-SG, Ci- 6alkylN(R6)C(=S)N(R6)-SG, C i.6alkyl-0-C(=0)C i.6alkyl-SG, C i-6alkyl-0- C(=0)-SG, (0-CH2CH2)n-SG;
Ci-6alkyl in the definition of R1, R2, R3 is preferably Ci.4alkyl, C2- ealkyl, Ci-ealkyl, Ci.2alkyl, more preferably, C2-3alkyl, or Ci.2alkyl.
Ci-6alkyl in the definition of R2 is preferably Ci.4alkyl, C2-3alkyl, Ci- ealkyl, Ci.2alkyl, more preferably, C2-3alkyl, or Ci.2alkyl.
In a more preferred embodiment of the present invention and/or embodiments thereof, R2 is hydrogen, Ci-3alkylC(=0)N(R6)Ci-6alkylaryl, Ci- 6S02NR¾8, S02NR¾8, C1-6OSO2 NR¾8, OS02NR¾8, Ci-6N(R9)S02NR¾8,
N(R9)S02NR¾8, Ci-6N(R6)C(=0)N(R6)Ci-6aryl,
Figure imgf000053_0003
Ci-
Figure imgf000053_0004
wherein the aryl is substituted with a S02NR¾8, N(R9)S02NR¾8, or OS02 NR7R8; and wherein the aryl is further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci ealkyloxy, di(Ci- 6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, , hydroxyCi-ealkyl, aminoCi-ealkyl , cyano, SiFR1^, or OP(=0)(OR14)2. It is to be understood that the compounds of the present invention comprise at least one SG group, preferably one SG group. Thus R1, R2, or R3 may comprise a SG group.
In a preferred embodiment of the present invention and/or embodiments thereof, the compounds of the present invention comprise at least one moiety selected from the group consisting of Ci-3alkylC(=0)N(R6)Ci-6alkylaryl, Ci- 6S02NR7R8, S02NR7R8, Ci-6OS02 NR7R8, OSO2 NR7R8, Ci-6N(R9)S02NR7R8, N(R9)S02NR¾8, Ci-6N(R6)C(=0)N(R6)Ci-6aryl, Ci-6N(R6)C(=S)N(R6)Ci-6aryl, Ci-
Figure imgf000054_0001
wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OS02 NR7R8. In a preferred embodiment of the present invention and/or embodiments thereof, R2 is a moiety selected from the group consisting of Ci-3alkylC(=0)N(R6)Ci-6alkylaryl, Ci-6S02NR7R8, S02NR7R8, Ci- 6OS02 NR7R8, OS02 NR7R8, Ci-6N(R9)S02NR7R8, N(R9)S02NR7R8, Ci-
Figure imgf000054_0002
Ci-6N(R6)C(=S)N(R6)aryl; wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OS02 NR7R8, or R1 is a moiety selected from the group consisting of Ci-3alkylC(=0)N(R6)Ci-6alkylaryl, Ci-6S02NR7R8, S02NR7R8, Ci-6OS02 NR7R8, OS02 NR7R8, Ci-6N(R9)S02NR7R8, N(R9)S02NR7R8, Ci-6N(R6)C(=0)N(R6)Ci- earyl,
Figure imgf000054_0003
Ci- 6N(R6)C(=S)N(R6)aryl; wherein the aryl is substituted with a S02NR7R8,
N(R9)S02NR7R8, or OS02 NR7R8; or Ri is Y, L- Y, or
Figure imgf000054_0004
Figure imgf000054_0005
wherein Y, L- Y, or NR (Ci- ealkyl-X2)) or the L is substituted with Ci-3alkylC(=0)N(R6)Ci-6alkylaryl, Ci- 6alkylS02NR7R8, S02NR7R8, Ci-ealkyl OS02 NR7R8, OS02 NR7R8, Ci- 6alkylN(R9)S02NR7R8, N(R9)S02NR7R8, Ci-6alkylN(R6)C(=0)N(R6)Ci-6alkylaryl, Ci- 6alkylN(R6)C(=S)N(R6)Ci-6alkylaryl, Ci-6alkylN(R6)C(=0)N(R6)aryl, Ci- 6alkylN(R6)C(=S)N(R6)aryl; wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OS02NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, the aryl in R2 is further not substituted.
In a more preferred embodiment of the present invention and/or embodiments thereof, the aryl in R2 is further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, Ci ealkyloxy, carbonyl, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, , hydroxyCi ealkyl, aminoCi ealkyl , cyano, SiFR12R13, or OP(=0)(OR14)2.
In a more preferred embodiment of the present invention and/or embodiments thereof, the aryl in R2 is further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, Ci ealkyloxy, carbonyl, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, , hydroxyCi ealkyl, aminoCi ealkyl , cyano, SiFR12R13, or OP(=0)(OR14)2.
In a more preferred embodiment of the present invention and/or embodiments thereof, the aryl in R2 is further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, carbonyl, NR4R5, cyano, SiFR12R13, or
OP(=0)(OR14)2.
In a more preferred embodiment of the present invention and/or embodiments thereof, the aryl in R2 is further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci- ealkyl, SiFRi2Ri3, or OP(=0)(OR1 )2.
In a more preferred embodiment of the present invention and/or embodiments thereof, the aryl in R2 is substituted with a S02NR7R8 or OSO2 NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, the aryl in R2 is substituted with a S02NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, the aryl in R2 is substituted with a N(R9)S02NR7R8 or OSO2 NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, the aryl in R2 is substituted with a S02NR7R8 or
Figure imgf000055_0001
In a more preferred embodiment of the present invention and/or embodiments thereof, the aryl in R2 is substituted with a N(R9)S02NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, the aryl in R2 is substituted with a OSO2 NR7R8. In a more preferred embodiment of the present invention and/or embodiments thereof, R2 is
Figure imgf000056_0001
Ci-6alkyl
N(R6)C(=0)N(R6)Ci-6alkyl aryl, Ci-6alkylN(R6)C(=S)N(R6)Ci-6alkylaryl, Ci-
Figure imgf000056_0002
In a more preferred embodiment of the present invention and/or embodiments thereof, R2 is Ci-3alkylC(=0)N(R6)Ci-3alkylaryl, Ci-
Figure imgf000056_0003
6alkylN(R6)C(=0)N(R6)aryl, Ci-6alkylN(R6)C(=S)N(R6)aryl.
In a more preferred embodiment of the present invention and/or embodiments thereof, R2 is Ci-3alkylC(=0)N(R6)Ci-2alkylaryl, Ci-
Figure imgf000056_0004
In a more preferred embodiment of the present invention and/or embodiments thereof, R2 is Ci-3alkylC(=0)N(R6)Cialkylaryl, Ci- 6alkylN(R6)C(=0)N(R6)Cialkylaryl, Ci-6alkylN(R6)C(=S)N(R6)Cialkylaryl, Ci- 6alkylN(R6)C(=0)N(R6)aryl, Ci-6alkylN(R6)C(=S)N(R6)aryl.
In a more preferred embodiment of the present invention and/or embodiments thereof, R2 is Ci-6alkylN(R6)C(=0)N(R6)aryl, Ci- 6alkylN(R6)C(=S)N(R6)aryl.
In a more preferred embodiment of the present invention and/or embodiments thereof, R2 is Ci-6alkyl N(R6)C(=0)N(R6)Ci-6alkylaryl, Ci-
Figure imgf000056_0005
or Ci-3alkylN(R6)C(=0)N(R6)aryl, more preferably Ci-2alkyl N(R6)C(=0)N(R6)Ci- 6alkylaryl, or Ci-2alkylN(R6)C(=0)N(R6)aryl, more preferably Cialkyl
Figure imgf000056_0006
In a more preferred embodiment of the present invention and/or embodiments thereof, R2 is Ci-6alkylN(R6)C(=S)N(R6)Ci-6alkylaryl, or Ci- 6N(R6)C(=S)N(R6)aryl.
In a more preferred embodiment of the present invention and/or embodiments thereof, R2 is Ci-3alkylN(R6)C(=S)N(R6)Ci-6alkylaryl, or Ci- 3N(R6)C(=S)N(R6)aryl. In a more preferred embodiment of the present invention and/or embodiments thereof, R2 is Ci-2alkylN(R6)C(=S)N(R6)Ci-6alkylaryl, or Ci-
Figure imgf000057_0001
In a more preferred embodiment of the present invention and/or embodiments thereof, R2 is CialkylN(R6)C(=S)N(R6)Ci-6alkylaryl, or
Figure imgf000057_0002
or
Figure imgf000057_0003
more preferably R2 is
2alkylaryl, or
Figure imgf000057_0004
and most preferably R2 is
Figure imgf000057_0005
In a more preferred embodiment of the present invention and/or embodiments thereof, R2 is Ci-3alkylC(=0)N(R6)Ci-6alkylaryl, more preferably Ci- 3alkylC(=0)N(R6)Ci-3alkylaryl, more preferably Ci-3alkylC(=0)N(R6)Ci-2alkylaryl, and more preferably Ci-3alkylC(=0)N(R6)Cialkylaryl.
In a more preferred embodiment of the present invention and/or embodiments thereof, R2 is Ci-2alkylC(=0)N(R6)Ci-6alkylaryl, more preferably Ci- 2alkylC(=0)N(R6)Ci-3alkylaryl, more preferably Ci-2alkylC(=0)N(R6)Ci-2alkylaryl, and more preferably Ci-2alkylC(=0)N(R6)Cialkylaryl.
In a more preferred embodiment of the present invention and/or embodiments thereof, R2 is CialkylC(=0)N(R6)Ci-6alkylaryl, more preferably CialkylC(=0)N(R6)Ci-3alkylaryl, more preferably CialkylC(=0)N(R6)Ci-2alkylaryl, and more preferably
Figure imgf000057_0006
In a more preferred embodiment of the present invention and/or embodiments thereof, R2 is Ci-6alkylS02NR¾8, S02NR¾8, Ci-6alkylOS02 NR¾8, OSO2 NR7R8, Ci-6alkylN(R9)S02NR7R8, N(R9)S02NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, R2 is Ci-6alkylS02NR¾8, or S02NR¾8.
In a more preferred embodiment of the present invention and/or embodiments thereof, R2 is Ci-3alkylS02NR¾8, or S02NR¾8.
In a more preferred embodiment of the present invention and/or embodiments thereof, R2 is Ci-2alkylS02NR7R8, or S02NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, R2 is CialkylS02NR7R8, or S02NR7R8. In a more preferred embodiment of the present invention and/or embodiments thereof, R2 is Ci-6alkylOS02 NR7R8, or OSO2 NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, R2 is Ci-3alkylOS02 NR7R8, or OSO2 NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, R2 is Ci-2alkylOS02 NR7R8, or OSO2 NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, R2 is CialkylOS02 NR7R8, or OSO2 NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, R2 is Ci-6alkylN(R9)S02NR7R8, or N(R9)S02NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, R2 is Ci-3alkylN(R9)S02NR7R8, or N(R9)S02NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, R2 is Ci-2alkylN(R9)S02NR7R8, or N(R9)S02NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, R2 is CialkylN(R9)S02NR7R8, or N(R9)S02NR7R8.
In a more preferred embodiment of the present invention and/or embodiments thereof, R3 is hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2- 6alkenyl, C2-6alkynyl, Ci ealkyloxy, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, cyano,
SiFR12R13, or OP(=0)(OR14)2, B-L-A, or B-A, more preferably Ci-3alkyl, more preferably Ci-2alkyl, more preferably Cialkyl. B, L and A are as defined above including all the preferred embodiments.
In a more preferred embodiment of the present invention and/or embodiments thereof, R3 is hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, carbonyl, carbonylCi-ealkyl, cyano, SiFR12R13, B-L-A, or B-A or OP(=0)(OR14)2, more preferably Ci salkyl, more preferably Ci-2alkyl, more preferably Cialkyl.
In a more preferred embodiment of the present invention and/or embodiments thereof, R3 is hydrogen, hydroxy, amino, Ci ealkyl, carbonyl,
SiFR12R13, or OP(=0)(OR14)2> B-L-A, or B-A more preferably Ci-3alkyl, more preferably Ci-2alkyl, more preferably Cialkyl.
In a more preferred embodiment of the present invention and/or embodiments thereof, R3 is hydrogen, hydroxy, Ci ealkyl, SiFR12R13, or
Figure imgf000059_0001
B-L-A, or B-A, more preferably Ci salkyl, more preferably Ci-2alkyl, more preferably Cialkyl.
In a more preferred embodiment of the present invention and/or embodiments thereof, halo is bromine, chlorine, fluorine, iodine, astatine, or ununseptium, more preferably bromine, chlorine, fluorine, or iodine, ,more preferably, bromine, chlorine, or fluorine, more preferably bromine, or chlorine.
In a more preferred embodiment of the present invention and/or embodiments thereof, R3 is NR4R5. In a more preferred embodiment of the present invention and/or embodiments thereof, R4 and R5 is -CH2-CH2-Z, wherein Z is a leaving group. In a more preferred embodiment of the present invention and/or embodiments thereof, Z is halogen, tosylate, mesylate, fluorosulfonates, triflates, nonaflates. In a more preferred embodiment of the present invention and/or embodiments thereof, Z is iodide, bromide, chloride, mesylate.
In a more preferred embodiment of the present invention and/or embodiments thereof, R3 is NR4R5, wherein R4, and R5 are -CH2-CH2-Z, wherein Z is a leaving group selected from the group consisting of halogen, tosylate, mesylate, fluorosulfonates, triflates, nonaflates, preferably Z is a selected from the group consisting of iodide, bromide, chloride, mesylate.
Compounds with N-(C2H4-Z)2 groups may function as alkylating agent and may be used in the treatment of cancer. Alkylating agents attach an alkyl group to the DNA.
In a more preferred embodiment of the present invention and/or embodiments thereof, R3 is SiFR12R13.
In a more preferred embodiment of the present invention and/or embodiments thereof, R12 and R13 is each independently a Ci i2alkyl, or C2- i2alkenyl, being straight or branched, more preferably Ci ealkyl, or C2-6alkenyl, more preferably methyl, ethyl, propyl, or butyl, more preferably, propyl, or butyl, more preferably isopropyl or tertiary butyl. In a preferred embodiment of the present invention and/or embodiments thereof, R12 and R13 are the same.
In a more preferred embodiment of the present invention and/or embodiments thereof, R3 is SiFR12R13, wherein R12 and R13 is each independently a Ci ealkyl, tertiary butyl, isopropyl, preferably tertiary butyl, isopropyl,methyl, ethyl. Compounds with SiFR12R13 may be used for PET imaging by exchanging the normal 19F by the radioactive 18F. In a more preferred embodiment of the present invention and/or embodiments thereof, the compound comprises a
SiFR12R13 group, and F is 18F.
In a more preferred embodiment of the present invention and/or embodiments thereof, R3 is B-L-A, or B-A. Preferably when R1 is B-A, or B-L-A, then R3 is not B-A, or B-L-A. . Preferably when R3 is B-A, or B-L-A, then R1 is not B-A, or B-L-A.
For the purpose of the present invention, aryl is an aromatic cyclic compound comprising 5- 12 atoms, and may mono-cyclic, bi- or tricyclic. Aryl may contain heteroatoms and is then referred to as heteroaryl. Aryl is phenyl or naphthalenyl, pyridmyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl, oxadiazolyl, tetrazolyl, benzofuranyl or tetrahydrofuranyl; each phenyl or naphthalenyl can optionally be substituted with one, two or three substituents each independently selected from halo, hydroxy, hydroxyCi ealkyl, Ci-ealkyl, amino, polyhaloCi ealkyl and Ci ealkyloxy; and each phenyl or naphthalenyl can optionally be substituted with a bivalent radical selected from methylene dioxy and
ethylene dioxy; each pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl, oxadiazolyl, tetrazolyl, benzofuranyl, or tetrahydrofuranyl can optionally be substituted with one, two or three substituents each independently selected from halo, hydroxy, Ci ealkyl, amino, polyhaloCi ealkyl, aryl, arylCi ealkyl or Ci- 6alkyloxy; and each pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl, benzofuranyl, or tetrahydrofuranyl can optionally be substituted with a bivalent radical selected from methylene dioxy or ethylene dioxy.
In a preferred embodiment of the present invention and/or embodiments thereof, aryl is phenyl or napthyl, more preferably phenyl.
For the purpose of the present invention, heterocyclic is a cyclic compound comprising 4- 12 atoms of which at least one is a heteroatom and may be saturated, or unsaturated. Heteroatoms are ususally nitrogen, oxygen, or sulphur. Heterocyclic is dioxetan, pyrrolidine, pyrrole, furan, tetrahydrofyran, thioane, thiophene, imidazoldine, imidazole, pyrazole, pyrazolidine, oxazolidine, oxazole, isoxazole, thiazolidine, thiazole, isothiazole, piperidine, pyridine, pyran, oxane, thiane, thiopyran, piperazine, diazine, oxazine, morpholine, thiomorpholine, thiazine, dioxane, or triazine.
In a preferred embodiment of the present invention and/or embodiments thereof, heterocyclic is pyrrolidine, pyrrole, furan, tetrahydrofyran, thiophene, imidazoldine, imidazole, pyrazole, pyrazolidine, thiazolidine, piperidine, pyridine, pyran, or morpholine. In a more preferred embodiment of the present invention and/or embodiments thereof, heterocyclic is furan, tetrahydrofyran, imidazole, pyrazole, piperidine, pyridine, pyran, or morpholine. In a more preferred
embodiment of the present invention and/or embodiments thereof, heterocyclic is imidazole, pyridine, or morpholine.
For the purpose of the present invention, a leaving group is a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage. Leaving groups can be anions or neutral molecules. Common anionic leaving groups are halides such as CI", Br-, and I", and sulfonate esters, such as para-toluenesulfonate ("tosylate", TsO") or diazonium, oxonium. Common neutral molecule leaving groups are water (H2O), and ammonia.
In a preferred embodiment of the present invention and/or embodiments thereof, a leaving group is halogen, tosylate, mesylate, fluorosulfonates, triflates, nonaflates, Ci i2alkylN2, Ci i2alkylOCi i2alkyl, Ci i2alkylOS02F, Ci- i2alkylOS02perfluoratedCi-6alkyl, nitrate, phosphate, Ci-6alkylSCi-6alkyl, tetraCi- 6alkylammonium, halogenCi ealkyl, Ci ealkylOaryl, Ci ealkylhydroxy, carbonylCi- 6alkyloxyCi-6alkyl . In a more preferred embodiment of the present invention and/or embodiments thereof, a leaving group is halogen, tosylate, mesylate,
fluorosulfonates, triflates, nonaflates, Ci i2alkylN2, Ci i2alkylOS02F, Ci- i2alkylOS02perfluoratedCi-6alkyl, halogenCi ealkyl. In a more preferred
embodiment of the present invention and/or embodiments thereof, a leaving group is halogen, tosylate, mesylate, fluorosulfonates, triflates, nonaflates, or halogenCi- 6alkyl. In a more preferred embodiment of the present invention and/or
embodiments thereof, a leaving group is iodide, bromide, chloride, tosylate, or mesylate.
In a more preferred embodiment of the present invention and/or embodiments thereof, R4, R5 is each independently hydrogen, hydroxy, or Ci-ealkyl, more preferably Ci salkyl, more preferably Ci-2alkyl, more preferably Cialkyl. In a more preferred embodiment of the present invention and/or embodiments thereof, R4, R5 is each independently hydrogen, Ci-ealkyl, more preferably Ci salkyl, more preferably Ci-2alkyl, more preferably Cialkyl.
In a more preferred embodiment of the present invention and/or embodiments thereof, R4, R5 is hydrogen.
In a more preferred embodiment of the present invention and/or embodiments thereof, R6is hydrogen, hydroxy, or Ci-ealkyl, more preferably Ci- 3alkyl, more preferably Ci-2alkyl, more preferably Cialkyl.
In a more preferred embodiment of the present invention and/or embodiments thereof, R6 is hydrogen, Ci ealkyl, more preferably Ci salkyl, more preferably Ci-2alkyl, more preferably Cialkyl.
In a more preferred embodiment of the present invention and/or embodiments thereof, R6 is hydrogen.
In a preferred embodiment of the present invention and/or embodiments thereof, R7, R8 is each independently hydrogen, hydroxy, or Ci-ealkyl, more preferably Ci salkyl, more preferably Ci-2alkyl, more preferably Cialkyl.
In a more preferred embodiment of the present invention and/or embodiments thereof, R7, R8 is each independently hydrogen, Ci-ealkyl, more preferably Ci salkyl, more preferably Ci-2alkyl, more preferably Cialkyl.
In a more preferred embodiment of the present invention and/or embodiments thereof, R7, R8 is hydrogen.
In a preferred embodiment of the present invention and/or embodiments thereof, R9, R10, R11 is each independently hydrogen, hydroxy, or Ci-ealkyl, more preferably Ci salkyl, more preferably Ci-2alkyl, more preferably Cialkyl.
In a more preferred embodiment of the present invention and/or embodiments thereof, R9, R10, R11 is each independently hydrogen, Ci ealkyl, more preferably Ci salkyl, more preferably Ci-2alkyl, more preferably Cialkyl.
In a more preferred embodiment of the present invention and/or embodiments thereof, R9, R10, R11, is hydrogen.
In a preferred embodiment of the present invention and/or embodiments thereof, R10, R11 are the same.
In a preferred embodiment of the present invention and/or embodiments thereof, R14 is hydrogen, Ci-2oalkyl, or C2-2oalkenyl, aryl, aminoCi i2alkyl, carbonylCi i2alkyl, hydroxyCi ealkyl, Ci-6alkyloxyCi-6alkyl, or NR4R5. In a more preferred embodiment of the present invention and/or embodiments thereof, R14 is hydrogen, Ci-iealkyl, C2 i6alkenyl, aryl, aminoCi i2alkyl, carbonylCi i2alkyl, hydroxyCi ealkyl, Ci-6alkyloxyCi-6alkyl, or NR4R5. In a more preferred embodiment of the present invention and/or embodiments thereof, R14 is hydrogen, Ci-ealkyl, C2- 6alkenyl, aryl, aminoCi ealkyl, carbonylCi i2alkyl, hydroxyCi ealkyl, Ci ealkyloxyCi- 6alkyl, or NR4R5. In a more preferred embodiment of the present invention and/or embodiments thereof, R14 is hydrogen, Ci-2oalkyl, C2-2oalkenyl, aryl, aminoCi i2alkyl, carbonylCi i2alkyl, hydroxyCi ealkyl, or NR4R5. In a more preferred embodiment of the present invention and/or embodiments thereof, R14 is hydrogen, Ci-2oalkyl, C2- 2oalkenyl, aryl, aminoCi i2alkyl, or NR4R5. In a more preferred embodiment of the present invention and/or embodiments thereof, R14 is hydrogen, Ci-2oalkyl, or C2- 2oalkenyl, or aryl, or NR4R5. In a more preferred embodiment of the present invention and/or embodiments thereof, R14 is hydrogen, Ci-iealkyl, C2-i6alkenyl, or aryl, or NR4R5. In a more preferred embodiment of the present invention and/or embodiments thereof, R14 is hydrogen, Ci i2alkyl, C2-i2alkenyl, or aryl, or NR4R5. In a more preferred embodiment of the present invention and/or embodiments thereof, R14 is hydrogen, Ci-ealkyl, C2-ealkenyl, or aryl, or NR4R5. In a more preferred embodiment of the present invention and/or embodiments thereof, R14 is hydrogen, Ci-2oalkyl, or C2-2oalkenyl, or NR4R5. In a more preferred embodiment of the present invention and/or embodiments thereof, R14 is hydrogen, Ci-2oalkyl, or NR4R5.
In a preferred embodiment of the present invention and/or embodiments thereof, the compound is selected from the group consisting of
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
suitable for use in the treatment of cancer. In a preferred embodiment of the present invention and/or embodiments thereof the cancer is selected from the group of breast carcinoma, brain carcinoma, kidney carcinoma, colorectal carcinoma, lung carcinoma, head and neck carcinoma, esophageal carcinoma, hepatocellular carcinoma, cholangiocarcinoma, renal cell carcinoma, testis carcinoma, cervix carcinoma, endometrium carcinoma, ovarian carcinoma, Squamous cell carcinoma, Basal cell carcinoma, glioma, ependymoma, mesothelioma, papillary carcinoma, follicular carcinoma, adenocarcinoma, stomach carcinoma, duodenum carcinoma, biliary carcinoma, pancreas carcinoma, , and bladder carcinoma. Preferably the cancer is colorectal cancer.
The compound of the present invention and/or embodiments thereof are suitable for use as antimicrobial compound. In a preferred embodiment of the present invention and/or embodiments thereof the compound is used to treat infections caused by bacteria, fungi, protozoa, and/or mycoplasma.
The present invention is also related to treatment of cancer
administering the compound of the present invention and/or embodiments thereof..
The present invention is also related to treatment of infections caused by bacteria, fungi, protozoa, and/or mycoplasma administering the compound of the present invention and/or embodiments thereof.
The present invention also features methods of using or preparing or formulating such pharmaceutical compositions. The pharmaceutical compositions can be prepared using conventional pharmaceutical excipients and compounding techniques known to those skilled in the art of preparing dosage forms. It is anticipated that the compounds of the invention can be administered by oral, parenteral, rectal, topical, or ocular routes, intravenous or by inhalation or by nasal spray. Preparations may also be designed to give slow release of the active ingredient. The preparation may be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, powders for reconstitution, liquid preparations, or suppositories. Preferably, compounds may be administered by intravenous infusion or topical administration, but more preferably by oral administration.
For oral administration, the compounds of the invention may be provided in the form of tablets or capsules, or as a solution, emulsion, or suspension. Tablets for oral use may include the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservatives. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like; typical liquid oral excipients include ethanol, glycerol, water and the like. Starch, polyvinyl-pyrrolidone, sodium starch glycolate, microcrystalline cellulose, and alginic acid are suitable
disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating. Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid, semi-solid, or liquid diluent, and soft gelatin capsules wherein the active ingredient is mixed with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol. Liquids for oral administration may be suspensions, solutions, emulsions or syrups or may be presented as a dry product for reconstitution with water or other suitable vehicles before use. Compositions of such liquid may contain
pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel and the like); non-aqueous vehicles, which include oils (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol or water; preservatives (for example, methyl or propyl p- hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if needed, flavoring or coloring agents. The compounds of this invention may also be administered by non-oral routes.
Examples
Compounds according to the present invention are made according to the synthesis as described in figure 1-3.
Example 1: Making of compound 16
Sulfamoylation of 1-Boc Piperazine:
NH2S02C1
Boc N NH ► Boc N N S02NH2
\^ ^ DMA RT \^ ^
Sulfamoylchloride Preparation:
A round bottom flask is placed in a in acetone-Ice bath (-10°C) and 1 equivalent of chlorosulfonyl isocyanate is added. 1 equivalent of formic acid is added and the mixture is stirred for 1 hour. A high vacuum is applied for 30 min to remove hydrogen chloride. Until further use, the sulfamoylchloride in stored at - 20°C to prevent decomposition.
Procedure for preparation of Sulfamoylation of 1-Boc Piperazine on 500 mg scale:
1 equivalent of 1-Boc protected piperazine is added to round bottom flask. 20 ml of dimethylacetamide (DMA) is added. 2 Equivalents of
Sulfamoylchloride is added and allowed to stir at room temperature for 3 hours. 30 ml of water is added and extracted with ethyl acetate. The ethyl acetate is evaporated to obtain piperazine sulfonamide. The product may be further purified by silica gel column chromatography. TLC medium: 9: 1 dichloromethane (DCM) and methanol. Percentage of yield: 28.5%. Data NMR: Ή NMR (DMSO d6, ppm): 6.83 (s, 2H), 3.40 (t, 4H, J=4Hz), 2.85 (t, 4H, J=4Hz), 1.4 (s, 9H).
Deprotection of Boc (200 mg scale):
Figure imgf000078_0001
A B
1 equivalent of compound A is added to a 100 ml round bottom flask and 10 ml of 20% trifluor acetic acid (TFA) in dichloromethane is added at RT and allowed to stir for 1 hour.
The reaction mixture is evaporated. TLC medium: 9: 1 DCM and Methanol. Percentage of Yield: 100%. Data: mass spectra showed that deprotection was successful.
Tosylation of Metronidazole:
Figure imgf000078_0002
1 equivalent of Metronidazole is added to a to 100 ml round bottom flask and is dissolved in CH2CI2 (DCM) at 0°C via an ice bath. 2.5 equivalents of triethylamine is added. 2 equivalent of Tosylchloride (TsCl) is dissolved in DCM and added to the reaction mixture comprising metronidazole. Follow the reaction by TLC (Reaction time approximately. 5 hrs.; DCM:methanol 9: 1).
Wash reaction mixture with water three times and evaporate organic layer to obtain product. Product may be further purified through silica gel column chromatography. TLC medium: 9: 1 DCM and ethanol. Percentage of Yield: 83%. Data: Ή NMR (DMSO d6, ppm): 7.92 (s, 1H), 7.59 (d, 2H, J=8.5Hz), 7.39 (d, 2H, 8.5Hz), 4.55 (t, 2H, J=4.9Hz), 4.4 (t, 2H, J=4.9Hz), 2.4 (s, 3H), 2.39 (s, 2H).
Coupling:
Figure imgf000079_0001
2
1 equivalent of compound B is added to 100 ml round bottom flask and dissolved in DMA. 2.5 equivalent of Na2C03 is added. The reaction temperature is raised to 80°C. 1 equivalent of compound C is added and the reaction mixture is allowed to stir overnight. The reaction temperature is maintained between 80°C to 100°C.
Water is added to reaction mixture to stop reaction and the reaction mixture is extracted with ethyl acetate. The ethyl acetate layer is evaporated to obtain compound 16. Compound 16 may be further purified by silica gel column chromatography. TLC medium: 9: 1 DCM and Methanol.
Figure imgf000080_0001
Ref: BMCL, 21 (2011) 394-397
Procedure:
Metronidazole (leqv.), Triphenylphosphene (1 eqv.), Imidazole (2.5 eqv.) and Iodine (1 eqv.) were dissolved in Dry DCM allowed to stir at room
temperature. Reaction was followed by TLC.
Work-Up:
Reaction mixture was washed with water and extracted with DCM. Organic layer was dried over sodium sulfate and evaporated to get crude.
Purification:
Crude was dissolved in minimum amount of DCM and precipitated with Diethyl ether.
Data:
TLC medium: 9: 1 DCM:MeOH, Rf: 0.8, % of Yield: Global
Ή NMR (DMSO-d6, 400 MHzj δ 8.05 (s, 1H), 4.61 (t, J = 7.3, 2H), 3.51 (t, J
= 7.3, 2H), 2.50 (s, 3H);
13C NMR (DMSO-d6, 101 MHz) δ 151.08, 138.18, 133.14, 47.09 (s, 1H), 14.09, 2.28.
MS (ESI+/ESI ) m/z 281.97 [M+H]+.
Figure imgf000081_0001
Ref: BMCL, 21 (2011) 394-397
Procedure:
lodometronidazole (leqv.) and Boc-Piperazine (2eqv.) were dissolved in THF and allowed to stir at reflux. Reaction was followed by TLC.
Work-Up:
Reaction mixture was washed with water and extracted with Ethyl acetate. Organic layer was washed with brine and dried over sodium sulfate.
Evaporated to get crude.
Purification:
Crude was purified through column chromatography eluent using gradient
100% DCM, 99: 1 DCM:MeOH to 98:2 DCM:MeOH
Data:
TLC medium: 9: 1 DCM:MeOH, Rf: 0.7, % of Yield:21%
Ή NMR (DMSO-d6, 400 MHz) δ 8.00 (s, 1H), 4.38 (t, J = 6.0, 2H), 3.23 (s,
3H), 2.61 (t, J = 6.0, 2H), 2.46 (s, 3H), 2.39 - 2.32 (m, 4H), 1.38 (s, 9H).
13C NMR (DMSO-d6, 101 MHz) δ 153.59 , 151.10 , 138.42 , 132.54 , 78.62 , 56.84 , 52.54 , 43.06 , 27.83 , 13.71.
MS (ESI+/ESI ) m/z 341.20 [M+H]+. NKP 252
02N
Boc H
Procedure:
Tert-butyl 4-(2-(2-methyl-5-nitro-lH-imidazol-l-yl) ethyl) piperazine-1- carboxylate (1 eqv.) dissolved in 20% TFA and DCM (TFA-16.2 eqv.) and allowed to stir at room temperature.
Work-Up:
Reaction mixture was evaporated, obtained oil crude was dissolved in
Methanol and co-evaporated to remove TFA.
Purification:
Crude was dissolved in minimum amount of Methanol and precipitated with Diethyl ether.
Data:
TLC medium: 9: 1 DCM:MeOH, Rf: 0.08, %of Yield: Quantitative
Ή NMR (DMSO-d6, 400 MHz) δ 8.78 (s, 1H), 8.01 (s, 1H), 4.37 (t, J = 6.1,
2H), 3.06 - 2.98 (m, 4H), 2.67 (t, J = 6.1, 2H), 2.64 - 2.58 (m, 4H), 2.46 (s,
3H).
13C NMR (DMSO-d6, 101 MHz) δ 151.55, 138.82, 133.03 , 56.81 , 49.79 , 43.38 , 43.16, 14.11.
MS (ESI+/ESI ) m/z 241.15 [M+H]
Figure imgf000083_0001
2NHBoc
Procedure:
Dried round bottom flask was charged with Dry DCM (16.3 eqv.) allowed to stir at 0°C (Ice -Acetone bath) to this added chlorosulfonylisocyanate (1.2 eqv.) followed by Tert-Butanol (1.2 eqv.) and allowed to stir at same temperature for 1 hr.
In another round bottom flask l-(2-(2-methyl-5-nitro-lH-imidazol- l- yl)ethyl)piperazine (leqv.) dissolved in dry DCM and added triethylamine (2eqv.) allowed to stir at room temperature for 10- 15 min. after 15 min this reaction mixture was poured into CSI+tBuOH suspension after completion of addition ice bath was removed to raise the reaction temperature to ambient and allowed to stir for overnight at RT.
Work-Up:
Reaction mixture was washed with water and extracted with DCM, organic layer was dried over sodium sulfate and evaporated to get crude.
Purification:
Crude was applied to column chromatography to afford pure compound, eluent 100% Ethyl acetate.
Data:
TLC medium: 9: 1 DCM:MeOH, Rf: 0.7, %of Yield: 32%
Ή NMR (DMSO-d6, 400 MHz) δ 10.97 (s, 1H), 7.97 (s, 1H), 4.38 (t, J = 5.8,
2H), 3.14 - 3.07 (m, 4H), 2.62 (t, J = 5.8, 2H), 2.46 (s, 3H), 2.45 (d, 4H), 1.44
(s, 9H). i3C NMR (DMSO-de, 101 MHz) δ 151.11, 150.54 , 138.78 , 132.52 , 81.67 , 56.73 , 52.22 , 46.31, 43.28, 31.30, 27.66. MS (ESI+/ESI ) m/z 419.17 [M+H]+.
Figure imgf000084_0001
Procedure:
Tert-butyl 4-(2-(2-methyl-5-nitro-lH-imidazol-l-yl) ethyl) piperazin-1- ylsulfonylcarbamate (leqv.) dissolved in 20% TFA and DCM (TFA-16.2 eqv.) and allowed to stir at room temperature.
Work-Up:
Reaction mixture was evaporated, obtained oil crude was dissolved in
Methanol and co-evaporated to remove TFA.
Purification:
Crude was dissolved in minimum amount of Methanol and precipitated with
Diethyl ether.
Data:
TLC medium: 9: 1 DCM:MeOH, Rf: 0.27, %of Yield: Quantitative
Ή NMR (DMSO-d6, 400 MHzJ δ 8.08 (s, 1H), 7.05 (s, 2H), 4.51 (t, J = 6.7,
2H), 3.51 - 2.93 (m, 14H).
13C NMR (DMSO-d6, 101 MHz) δ 151.85, 138.87, 133.45, 65.33, 51.47 , 44.36, 15.58, 14.22.
MS (ESI+/ESI ) m/z 319.12 [M+H] Nn2OU2^l
BocHN^OH DMA, RT ' BocHN^0802 2
Procedure:
N-Boc ethanolamine (leq) was dissolved in DMA and added
Sulfamoylchloride (3eq) and allowed to stir at room temperature. Reaction was followed by TLC.
Work-Up:
Reaction mixture was washed with water and extracted with EtOAc. Organic layer was dried over sodium sulfate and evaporated to get crude. Purification:
Crude was purified through column by using 5:5 EtOAc:EP as eluent. Data:
Ή NMR (400 MHz, DMSO) δ 7.47 (s, 2H), 6.99 (t, J = 5.6, 1H), 3.97 (t, J = 5.6, 2H), 3.20 (q, J = 5.6, 2H), 1.38 (s, 9H).
i3C NMR (101 MHz, DMSO) δ 155.59, 77.97, 67.34, 59.76, 28.19.
TLC Eluent: 5:5 EtOAc:EP, Rf: 0.64, % of Yield:80%.
UM/^OS02NH2 4N HCl in Dioxane, /^OS02NH2
BocHN 2 2 DCM, RT 2
Procedure:
2-(tert-butoxycarbonylamino) ethyl sulfamate (leq) was dissolved in DCM (10 ml/ mmol) and added 4N HCl in 1,4 Dioxane(40eq) allowed to stir at room temperature. Reaction was followed by TLC
Work-Up:
Reaction mixture was filtered and washed with cold diethyl ether to get pure compound as solid.
Data: Mass: MS (ESI+/ESI ) m/z 141.97 [M+H]+.
Ή NMR (400 MHz, DMSO) δ 8.11 (s, 2H), 7.67 (s, 2H), 4.23 - 4.18 (m, 2H), 3.18 - 3.14 (m, 2H).
!3C NMR (101 MHz, DMSO) δ 65.48, 38.11.
TLC Eluent: 9: 1 DCM: MeOH, Rf: 0.66, % of Yield: 88%
Figure imgf000086_0001
Ref:
PCT/US2006/025881; WO 2007/002931
Procedure:
To suspension of 2-aminoethyl sulfamate(2eq) in Dry DCM was added phenyl phosphorodichloridate(leq) at -60°C followed by addition of TEA (4eq)and reaction mixture warmed to room temperature for overnight.
Reaction was followed by TLC.
Work-Up:
Reaction mixture was washed with water and extracted with DCM and organic Iyer was dried over sodium sulfate and evaporated to get crude. Purification:
Crude was purified using column chromatography by applying eluent as
99: 1 to 98:2 DCm:MeOH
Data:
Mass: MS (ESI+/ESI ) m/z 419.05 [M+H]+.
Ή NMR (400 MHz, DMSO) δ 7.48 (s, 4H), 7.34 (dt, J = 9.7, 2.0, 2H), 7.21 - 7.09 (m, 3H), 5.06 (dt, J = 11.1, 7.0, 2H), 4.00 (t, J = 6.3, 4H), 3.18 - 3.06 (m, 4H).
13C NMR (101 MHz, DMSO) δ 151.28, 140.71, 129.44, 123.95, 120.56, 68.90. TLC Eluent: 9: 1 DCM:MeOH, Rf:0.33, % of Yield:23%.
Example 2: In vitro experiments:
The compounds of the invention are tested for their effects on CA inhibition and the resulting effect on extracellular acidosis using classical chemistry and biology assays.
Carbonic Anhydrase inhibiting activity.
The compounds of the invention are tested on their inhibitory activity on carbonic anhydrase in the following experiment:
The inhibition constants for the compounds for four CA isozymes, CA I, II, IX and XII are determined. An Applied Photophysics (Oxford, UK) stopped-flow instrument is used for assaying the CA-catalyzed CO2 hydration activity (Khalifah, 1971). Phenol red (at a concentration of 0.2 mM) is used as indicator, working at the absorbance maximum of 557 nm, with 10 mM Hepes (pH 7.5) as buffer, 0.1 M Na2SO (for maintaining constant the ionic strength), following the CA-catalyzed CO2 hydration reaction for a period of 10- 100 s. The CO2 concentrations ranges from 1.7 to 17 mM for the determination of the kinetic parameters and inhibition constants. For each inhibitor at least six traces of the initial 5- 10% of the reaction are used for determining the initial velocity. The uncatalyzed rates are determined in the same manner and subtracted from the total observed rates. Stock solutions of inhibitor (1 mM) are prepared in distilled-de ionized water with 10-20% (v/v) DMSO (which is not inhibitory at these concentrations) and dilutions up to 0.1 nM are done thereafter with distilled- deionized water. Inhibitor and enzyme solutions are preincubated together for 15 min at room temperature prior to assay, in order to allow for the formation of CA IX - inhibitor complex. The inhibition constants are obtained by non-linear last- squares methods using PRISM 3 and represent the mean from at least three different determinations.
Compound Ki CA-IX (nM)
1 22
16 18 The effects of compounds of the invention on acidosis in tumor cells is measured in the following experiment.
Aim of the in vitro experiments is to assess the efficacy of compounds in reducing the extracellular acidification upon hypoxia.
The experiment is set up as previously described (Dubois et al, 2007). A colorectal (HT-29) and a cervical (HeLa) carcinoma cell line are tested in normoxic (ambient oxygen concentration) and hypoxic (0.2% oxygen) conditions. HT-29 cells are known to be constitutive hypoxia inducible CA IX (CA IX expression under normoxia and increased CA IX expression upon hypoxia) expressing cells.
Therefore, compounds are added after 1 h of hypoxic exposure (to ensure active CA IX) and incubation is done for another 23h (total of 24h hypoxia). HeLa cells are hypoxia inducible (at lower density) CA IX expressing cells. Therefore, HeLa cells are first incubated for 24h hypoxia to ensure CA IX expression in the first place (time point assessed in time series experiments). Afterwards, compounds are added and cells are incubated for another 24h.
Experiments are performed in triplicate for each condition. The described conditions are done both for HT-29 and HeLa under normoxic and hypoxic conditions.
Cells are seeded in 6 cm dishes (HT-29: 106; HeLa: 4xl05: to compensate for cell size) in 5 ml of DMEM supplemented with 10% FCS. The day after, medium is replaced by 3.6 ml of freshly prepared DMEM/FCS 10%, from which the pH is measured = pH at incubation), after which dishes are placed in the hypoxic chamber (normoxic dishes remained at ambient air in the incubator: 37°C, 95% humidity, 5% CO2). Compounds are added (1 h for HT-29 or 24h for HeLa after start hypoxic exposure) to have a final concentration of 1 mM or 0.1 mM, by adding 400μ1 to the dishes, starting from a 10 or 1 mM stock (DMSO final concentration 0.1 %). Blanc controls receive DMSO/PBS without compound.
pH of the medium is measured after 24h (HT-29) or 48h (HeLa) inside the hypoxic chamber after calibration of the electrode to reduced oxygen
concentrations. Delta pH (pH at end hypoxic exposure - pH of replacement medium before incubation) are calculated. Aim of these experiments is to assess the in vivo therapeutic effect of the compounds in combination with conventional treatment modalities such as radiotherapy and chemotherapy. We hypothesize that blocking CA (X may both decrease extracellular acidosis, and thus increase the effect of irradiation, as well as increase the uptake of the weak base doxorubicin, and therefore its therapeutic effect. Furthermore, a clinically approved sulfonamide Acetazoliamide (AZA) - a known general carbonic anhydrase inhibitor (meaning no preference for one CA) is used to prove the CA IX specificity of the investigated compounds.
Two experimental setups are used. The first experiments are carried out on parental HT-29 xenografts. The second are done on HT-29 xenografts harbouring a knock-down for CA IX. A shRNA construct against CA IX is introduced in the HT-2S cells using the p ETRO-super vector. After selection and screening, cells with a 95% efficient knock-down for CA IX are selected. As a control, a scrambled shRNA construct is used and those cells. These cells still demonstrate CA IX mRNA and protein expression. Tumor xenografts are produced by injecting the colorectal carcinoma cells (1 ,5 106) subcutaneously into the lateral flank of NMRI-nw mice (28 - 32 g). Tumor growth is monitored 3x/week by measuring the tumor dimensions in 3 orthogonal directions. Measurements are corrected for skin thickness (-0.5 mm) and tumor volumes are calculated using the formula A x B x C x pi/6, were A, B and C represent the orthogonal diameters. At an average tumor volume of 250 mm3, compounds are injected intravenously (5 x 5 mg/kg intravenously) using the lateral tail vein. At day 3 animals are
anaesthetized using Sodium Pentobarbital (Nembutal, 0.1 ml/ 00 g body weight) and positioned in the irradiation field using a custom-built jig and subjected to irradiation with a single dose of 10 Gy (15 meV electron beam) using a linear accelerator (Siemens). Another group of animals starts at day 3 with doxorubicin treatment (5 mg/kg i.v. lx/week for 3 weeks). Tumor growth and potential treatment toxicity are monitored (3x/week), by daily evaluation of the body weight. When tumors reaches four times the treatment starting volume, animals are sacrificed and tumors are excised for further histopathological evaluation.
Tumor volumes are normalized to start of the treatment. Cytotoxic experiments under hypoxia and air in CA IX positive or negative cell lines: Material and methods
HT-29 (human colorectal adenocarcinoma) cells are transfected with a lentiviral pTRIPZ plasmid (construct 2.1) containing TurboRFP and CAIX shRNA, flanked by a tetracycline response element. Transcription of the shRNA is induced by 1 pg/mL doxycycline (dox) and verified by expression of tRFP.
To knockdown CAIX in HCT116 (human colorectal carcinoma) cells, the HuSH-29 shRNA targeting CAIX (TR314250) and empty vector (R20003) are purchased form Origene. Cells are transfected using FuGENE 6 (Roche) according the manufacturer's guidelines. Cells are grown under selective pressure (300 ng/ml puromycin) until no mock-transfected cells remain. Two individual clones are selected and designated 95/3 (CAIX knockdown) and EV/2 (control).
HT-29 2.1, HT-29 2.1 +dox, HCT116 95/3, HCT116 EV/2 cells are cultivated in Dulbecco's Modified Eagle's Medium (Lonza) supplemented with 10% Fetal Bovine Serum (PAA) at 37°C in humidified air with 20% 02 and 5% CO2. Cells are seeded in a 96 wells plate at a density of 1000 cells/well. Cells are allowed to attach overnight before exposing them to the experimental conditions: normoxia (N), 0.2% hypoxia (HO.2) or 1.0% hypoxia (H1.0) during 2 hours or 24 hours.
Hypoxic experiments are performed in a hypoxic workstation, either 0.2% O2, 5% CO2 and residual N2 (Don Whitley Scientific) or 1.0% O2, 5% CO2 and residual N2 (Ruskinn).
Directly after exposure to experimental conditions, the medium of the cells is changed to pre-incubated DMEM (Sigma) containing 10 mM sodium bicarbonate and incubated for 22 hours. Cells are exposed to compounds of the present invention dissolved in 10 mM sodium bicarbonate medium containing 0.5% DMSO. After 2 hours of exposure, the cells are washed with PBS and 10 mM sodium bicarbonate medium is added. 72 hours after exposure, cells are exposed to Alamar Blue reagent (Invitrogen) for 2 hours and cell viability is measured by fluorescence at 570 nm.
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Brizel DM, Schroeder T, Scher RL, Walenta S, Clough RW, Dewhirst MW, Mueller-Klieser W (2001 ) Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer. Int J Radiat Oncol Biol Phys SV. 349-53.
Dubois L, Douma K, Supuran CT, Chiu RK, van Zandvoort MA, Pastorekova S, Scozzafava A, Wouters BG, Lambin P (2007) Imaging the hypoxia surrogate marker CA IX requires expression and catalytic activity for binding fluorescent sulfonamide inhibitors. Radiother Oncol 83: 367-73.
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Quennet V, Yaromina A, Zips D, Rosner A, Walenta S, Baumann M, Mueller- Klieser W (2006) Tumor lactate content predicts for response to fractionated irradiation of human squamous cell carcinomas in nude mice.
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Svastova E, Hulikova A, Rafajova M, Zat'ovicova M, Gibadulinova A, Casini A, Cecchi A, Scozzafava A, Supuran CT, Pastorek J, Pastorekova S (2004) Hypoxia activates the capacity of tumor-associated carbonic anhydrase IX to acidify extracellular pH. FEBS Lett 577: 439-45.
Thomlinson RH, Gray LH (1955) The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer 9: 539-49. Winum JY, Scozzafava A, Montero JL, Supuran CT (2009) Inhibition of carbonic anhydrase IX: a new strategy against cancer. Anticancer Agents Med Chem 9: 693-702.

Claims

Claims
Compound represented by formula (I):
Figure imgf000093_0001
wherein
R1 is Y,
Figure imgf000093_0002
NRii(Ci-6alkyl-X2)) or L-Y, B-A, or
B-L-A.
B is a direct bond, 0-C(=0)-, L-0-C(=0)-, 0-C(=0)-NR9S02-, 0-C(=0)- NR9S02NR7-, 0-C(=0)-NR9S02-0-, 0-C(=0)-NR9S02aryl-, 0-C(=0)-NR9S02NR7- aryl-, 0-C(=0)-NR9S02-0-aryl, L-0-C(=0)-NR9S02-, L-0-C(=0)-NR9S02NR7-, L-O- C(=0)-NR9S02-0-, L-0-C(=0)-NR9S02aryl-, L-0-C(=0)-NR9S02NR?-aryl-, or L-O- C(=0)-NR9S02-0-aryl;
A is an active moiety selected from the group of chelating agent comprising a therapeutically active metal ion, chelating agent comprising a metal ion suitable for imaging, fluorescent moiety, 18F containing moiety, alkylating moiety, wherein the active moiety comprises at least one hydroxyl;
L is a linker selected from the group consisting of Ci ealkyl, C(=0)N(R6), Ci ealkyl- C(=0)N(R6)Ci-6alkyl, Ci-6alkyl-C(=0)N(R6), C(=0)N(R6)-Ci-6alkyl, N(R6)C(=0)N(R6), Ci-6alkylN(R6)C(=0)N(R6)Ci-6alkyl, Ci-6alkylN(R6)C(=0)N(R6), N(R6)C(=0)N(R6)Ci- ealkyl, N(R6)C(=S)N(R6), Ci-6alkylN(R6)C(=S)N(R6)Ci-6alkyl, Ci- 6alkylN(R6)C(=S)N(R6), N(R6)C(=S)N(R6)Ci-6alkyl, -0-C(=0)N(R6), Ci-ealkyl-O-
Figure imgf000093_0003
N(R6)C(=S), Ci-6alkylN(R6)C(=S)Ci-6alkyl, Ci-6alkylN(R6)C(=S), N(R6)C(=S)Ci-6alkyl,
Figure imgf000093_0004
6alkylN(R6)C(=S)N(R6)Ci-6alkyl, Ci-6alkylC(=0)N(R6)Ci-6alkylN(R6)C(=S)N(R6),
Figure imgf000094_0001
6alkylN(R6)C(=0)N(R6), Ci-6alkylC(=0)N(R6)Ci-6alkylN(R6)C(=0)N(R6)Ci-6alkyl, Ci- 6alkylC(=0)N(R6)Ci-6alkylN(R6)C(=0)N(R6), C(=0)N(R6)Ci-
Figure imgf000094_0002
6alkylC(=0)N(R6)Ci-6alkyl-OC(=0)Ci-6alkyl, Ci-6alkylC(=0)N(R6)Ci-6alkyl-OC(=0),
Figure imgf000094_0003
6alkyl-0-C(=0), 0-C(=0)Ci-6alkyl, 0-C(=0)Ci-6alkylC(=0)N(R6), Ci-ealkyl-O- C(=0)Ci-6alkylC(=0)N(R6)Ci-6alkyl, Ci-6alkyl-0-C(=0)Ci-6alkylC(=0)N(R6), O-
Figure imgf000094_0004
Ci-ealkyl-O- C(=0)Ci-6alkylN(R6)C(=0)Ci-6alkyl, Ci-6alkyl-0-C(=0)Ci-6alkylN(R6)C(=0), O- C(=0)Ci-6alkylN(R6)C(=0)Ci-6alkyl, (0-CH2CH2)n, Ci-6alkyl(0-CH2CH2)nCi-6alkyl, Ci-6alkyl(0-CH2CH2)n, (0-CH2CH2)nCi-6alkyl, (CH2CH2-0)n, Ci-6alkyl(CH2CH2- 0)nCi-6alkyl, Ci-6alkyl(CH2CH2-0)n, (CH2CH2.0)nCi-6alkyl;optionally the L or Ci- 6alkyl is further substituted with a substituent selected from the group comprising halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci ealkyloxy, di(Ci- 6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, , hydroxyCi ealkyl or aminoCi ealkyl , cyan, OP(=0)(OR14)2;
R2 is hydrogen, SG or L-SG, wherein SG is a sulfonamide, sulfamate, or sulfamide group selected from the group consisting of S02NR7R8, OS02NR7R8, NR9S02NR¾8, NR9S02-phenyl, aryl substituted with S02NR¾s, aryl substituted with OS02NR7R8, aryl substituted with NR9S02NR7R8 ;optionally the aryl is substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, carboxyamine, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci- 6alkyloxy, di(Ci-6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3- 7Cycloalkyl, , hydroxyCi ealkyl, aminoCi ealkyl , cyano, or OP(=0)(OR14)¾
R3 is hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2- 6alkynyl, Ci ealkyloxy, di(Ci-6alkyl) amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, , hydroxyCi ealkyl, aminoCi ealkyl , cyano, SiFRnR12, B- A, B-L-A, or OP(=0)(OR14)¾ X1, X2 is each independently halo, hydroxy, amino, nitro, carbonyl, cyano, OP(=0)(OR14)2, L-SG, SG, Ci-3alkylC(=0)N(R6)Ci-6alkylaryl, Ci-6alkylS02NR7R8, S02NR7R8, Ci-ealkyl OSO2 NR7R8, OSO2 NR7R8, Ci-6alkylN(R9)S02NR7R8,
Figure imgf000095_0001
6alkylN(R6)C(=S)N(R6)Ci-6alkylaryl, Ci-6alkylN(R6)C(=0)N(R6)aryl, Ci- 6alkylN(R6)C(=S)N(R6)aryl; wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OS02 NR7R8; and wherein the aryl is optionally further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci ealkyloxy, di(Ci- 6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, , hydroxyCi ealkyl, aminoCi ealkyl , cyano, or OP(=0)(OR14)¾
Y is a saturated, partially unsaturated, or unsaturated heterocycle comprising 5, 6, or 7 atoms, wherein at least one of the atoms is a heteroatom selected from nitrogen, oxygen and sulphur;
optionally Y may be substituted with halo, hydroxy, amino, nitro, carbonyl, cyano, carboxyamine, OP(=0)(OR14)2, L-SG, SG, Ci-3alkylC(=0)N(R6)Ci-6alkylaryl, Ci- 6alkylS02NR7R8, S02NR7R8, Ci-ealkyl OS02 NR7R8, OS02 NR7R8, Ci- 6alkylN(R9)S02NR7R8, N(R9)S02NR7R8, Ci-6alkylN(R6)C(=0)N(R6)Ci-6alkylaryl, Ci-
Figure imgf000095_0002
Figure imgf000095_0003
or Ci ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR12R!3, or OP(=0)(OR1 )2; wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OS02 NR7R8; and wherein the aryl is optionally further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci ealkyloxy, di(Ci- 6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, , hydroxyCi ealkyl, aminoCi ealkyl , cyano, or OP(=0)(OR14)2;
R4, R5, R6, R7, R8, R9, R10 is each independently hydrogen, halo, hydroxy, or Ci-ealkyl, wherein the Ci ealkyl is optionally substituted with with a substituent selected from the group comprising halo, hydroxy, amino, nitro, Ci ealkyloxy, di(Ci- 6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, , heterocyclic, C3-7Cycloalkyl, , hydroxyCi- 6alkyl or aminoCi ealkyl , cyano, OP(=0)(OR14), or a leaving group;
R11 and R12 is each independently a Ci ealkyl, tertiair butyl, or isopropyl; wherein at least one of R1, R2, R3 is connected to the Nl of the imidazol of formula (I), and wherein the compound comprises at least one moiety selected from
S02NR7R8, OS02NR7R8, NR9S02NR7R8, or NR9S02.
2. Compound according to claim 1 according to formula (la) or formula (lb) or formula Ic):
r
Figure imgf000096_0001
4. Compound according to any one of claims 1-3 wherein Y comprises 5, or 6 atoms, preferably 6 atoms.
5. Compound according to any one of claims 1-4 wherein Y comprises nitrogen and one or two further heteroatoms selected from nitrogen, oxygen and sulphur, preferably oxygen or nitrogen and most preferably nitrogen.
6. Compound according to any one of claims 1-5 wherein Y is selected from the group comprising imidazolidine, pyrazolidine, tetrahydrofuran, triazole, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperazine, morpholine, thiomorpholine, pyrimidine, and homopiperazine.
7. Compound according to any one of claims 1-6 wherein R1 is Y, Ci ealkyl substituted with
Figure imgf000097_0001
NRn(Ci-6alkyl-X2)), L-Y, L-
Figure imgf000097_0002
NR!KCi-ealkyl-X2)) or Ci-ealkyl substituted with Y, wherein the L or Ci ealkyl is further substituted with a substituent selected from the group comprising halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2- 6alkynyl, Ci ealkyloxy, di(Ci-6alkyl) amino, hydroxy amino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, , hydroxyCi ealkyl or aminoCi ealkyl , cyano,
Figure imgf000097_0003
or optionally Y may be substituted with halo, hydroxy, amino, nitro, carbonyl, cyano, OP(=0)(OR14)2, SG or L-SG, Ci-3alkylC(=0)N(R6)Ci- ealkylaryl, Ci-6alkylS02NR7R8, S02NR7R8, Ci-ealkyl OSO2 NR7R8, OSO2 NR7R8, Ci- 6alkylN(R9)S02NR¾8, N(R9)S02NR7R8, Ci-6alkylN(R6)C(=0)N(R6)Ci-6alkylaryl, Ci- 6alkylN(R6)C(=S)N(R6)Ci-6alkylaryl, Ci-6alkylN(R6)C(=0)N(R6)aryl, Ci- 6alkylN(R6)C(=S)N(R6)aryl or Ci ealkyl substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyan, amino, nitro, carbonyl, SiFR12R13, or OP(=0)(OR14)2; wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OS02 NR7R8; and wherein the aryl is optionally further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci ealkyloxy, di(Ci- 6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, , hydroxyCi ealkyl, aminoCi ealkyl , cyano, or OP(=0)(OR14)2.
8. Compound according to any one of claims 1-7 wherein R1 is Y, Ci ealkyl substituted with
Figure imgf000097_0004
NR (Ci-6alkyl-X2)), L-Y, L-
Figure imgf000097_0005
NR (Ci-6alkyl-X2)), or Ci-ealkyl substituted with Y, and wherein the Ci ealkyl is further substituted with a substituent selected from the group comprising halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, and OP(=0)(OR14)2;, and Y is further substituted with halo, hydroxy, amino, nitro, carbonyl, cyano, OP(=0)(OR14)2, SG, L-SG, Ci-3alkylC(=0)N(R6)Ci-6alkylaryl, Ci- 6alkylS02NR7R8, S02NR7R8, Ci-ealkyl OSO2 NR7R8, OSO2 NR7R8, Ci- 6alkylN(R9)S02NR7R8, N(R9)S02NR7R8, Ci-6alkylN(R6)C(=0)N(R6)Ci-6alkylaryl, Ci- 6alkylN(R6)C(=S)N(R6)Ci-6alkylaryl, Ci-6alkylN(R6)C(=0)N(R6)aryl, Ci- 6alkylN(R6)C(=S)N(R6)aryl or Ci ealkyl substituted with one or more substituents selected from the group comprising halo, hydroxyl, cyano, amino, nitro, carbonyl, SiFR12R13, or OP(=0)(OR14)2; wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OSO2 NR7R8; and wherein the aryl is optionally further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci ealkyloxy, di(Ci- 6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, , hydroxyCi ealkyl, aminoCi ealkyl , cyano, or
Figure imgf000098_0001
9. Compound according to any one of claims 1-8 wherein R1 is Y, Ci ealkyl substituted with
Figure imgf000098_0002
NRn(Ci-6alkyl-X2)), L-Y, L-
Figure imgf000098_0003
NRii(Ci-6alkyl-X2)), or Ci-ealkyl substituted with Y, wherein L or Ci ealkyl and/or Y is not further substituted.
10. Compound according to any one of claims 1-9 wherein R1 is Ci-4alkyl substituted with
Figure imgf000098_0004
or Ci-4alkyl substituted with Y; or is Ci-3alkyl substituted with
Figure imgf000098_0005
X1))(R11(Ci-6alkyl-X2)) or Ci salkyl substituted with Y; or is Ci-2alkyl substituted with
Figure imgf000098_0006
NR (Ci-6alkyl-X2)) or Ci-2alkyl substituted with Y,; or is Ci-alkyl substituted with
Figure imgf000098_0007
or Ci alkyl substituted with Y.
11. Compound according to any one of claims 1- 10 wherein R2 is Ci- 3alkylC(=0)N(R6)Ci-6alkylaryl, Ci-6S02NR7R8, S02NR7R8, Ci-6OS02 NR7R8, OSO2 NR7R8, Ci-6N(R9)S02NR7R8, N(R9)S02NR7R8, Ci-6N(R6)C(=0)N(R6)Ci-6aryl, Ci-
Figure imgf000098_0008
wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OS02NR7R8; and wherein the aryl is further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2- 6alkynyl, Ci ealkyloxy, di(Ci-6alkyl) amino, hydroxy amino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, , hydroxyCi ealkyl, aminoCi ealkyl , cyano, or
OP(=0)(OR14)2.
12. Compound according to claim 11 wherein the aryl in R2 and/or the aryl in SG is further not substituted.
13. Compound according to claim 11 wherein the aryl in R2 and/or SG is further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci- 6alkyloxy, carbonyl, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, , hydroxyCi ealkyl, aminoCi ealkyl , cyano, or
Figure imgf000099_0001
14. Compound according to claims 11 or 13 wherein the aryl in R2 and/or SG is further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci- 6alkyloxy, carbonyl, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, , hydroxyCi ealkyl, aminoCi ealkyl , cyano, or
Figure imgf000099_0002
15. Compound according to claims 11, or anyone of 13- 14, wherein the aryl in R2 and/or SG is further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, or
Figure imgf000099_0003
16. Compound according to anyone of claims 1-15 wherein, the aryl in R2 and/or SG is substituted with a S02NR¾8, N(R9)S02NR¾8, or OS02NR¾8.
17. Compound according to anyone of claims 1-16, wherein, R2 is Ci- 3alkylC(=0)N(R6)Ci-6alkylaryl, Ci-6alkyl N(R6)C(=0)N(R6)Ci-6alkyl aryl, Ci-
Figure imgf000099_0004
6alkylN(R6)C(=S)N(R6)aryl.
18. Compound according to anyone of claims 1-17 wherein R2 is Ci- 3alkylC(=0)N(R6)Ci-2alkylaryl, Ci-6alkylN(R6)C(=0)N(R6)Ci-2alkylaryl, Ci- 6alkylN(R6)C(=S)N(R6)Ci-2alkylaryl, Ci-6alkylN(R6)C(=0)N(R6)aryl, or Ci- 6alkylN(R6)C(=S)N(R6)aryl.
19. Compound according to anyone of claims 1-18 wherein, R2 is Ci-
Figure imgf000100_0001
more preferably Ci-3alkylN(R6)C(=S)N(R6)Ci-6alkylaryl, or Ci-3N(R6)C(=S)N(R6)aryl, more preferably
Figure imgf000100_0002
more preferably CialkylN(R6)C(=S)N(R6)Ci-6alkylaryl, or CiN(R6)C(=S)N(R6)aryl, more preferably
Figure imgf000100_0003
preferably R2 is
Figure imgf000100_0004
and most preferably R2 is CialkylN(R6)C(=S)N(R6)Cialkylaryl, or
Figure imgf000100_0005
20. Compound according to anyone of claims 1-19 wherein R2 is Ci- 3alkylC(=0)N(R6)Ci-6alkylaryl, more preferably Ci-3alkylC(=0)N(R6)Ci-3alkylaryl, more preferably Ci-3alkylC(=0)N(R6)Ci-2alkylaryl, and more preferably Ci-
Figure imgf000100_0006
21. Compound according to anyone of claims 1-20 wherein R2 is Ci- 2alkylC(=0)N(R6)Ci-6alkylaryl, more preferably Ci-2alkylC(=0)N(R6)Ci-3alkylaryl, more preferably Ci-2alkylC(=0)N(R6)Ci-2alkylaryl, and more preferably Ci-
Figure imgf000100_0007
more preferably CialkylC(=0)N(R6)Ci-3alkylaryl, more preferably
CialkylC(=0)N(R6)Ci-2alkylaryl, and more preferably
Figure imgf000100_0008
22. Compound according to anyone of claims 1-21 wherein R2 is Ci-
6alkylS02NR7R8, S02NR7R8, Ci-6alkylOS02 NR7R8, OS02 NR7R8, Ci- 6alkylN(R9)S02NR¾8, or N(R9)S02NR¾8.
23. Compound according to anyone of claims 1-22 wherein R2 is Ci- 6alkylS02NR7R8, or S02NR7R8, preferably Ci-3alkylS02NR7R8, or S02NR7R8, preferably Ci-2alkylS02NR7R8, or S02NR7R8, preferably CialkylS02NR7R8, or S02NR7R8.
24. Compound according to anyone of claims 1-23 wherein R2 is Ci- 6alkylOS02 NR7R8, or OS02 NR7R8, Ci-3alkylOS02 NR7R8, or OS02 NR7R8, preferably Ci-2alkylOS02 NR7R8, or OS02 NR7R8, preferably CialkylOS02 NR7R8, or OS02 NR7R8.
25. Compound according to anyone of claims 1-24, wherein R2 is Ci- 6alkylN(R9)S02NR7R8, or N(R9)S02NR7R8, preferably Ci-3alkylN(R9)S02NR7R8, or N(R9)S02NR7R8, preferably Ci-2alkylN(R9)S02NR7R8, or N(R9)S02NR7R8, preferably CialkylN(R9)S02NR7R8, or N(R9)S02NR7R8.
26. Compound according to anyone of claims 1-25 wherein R3 is halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci ealkyloxy,
hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci-ealkylcarbonyl, NR4R5, cyano, B-A, B-L-A, or OP(=0)(OR14)2.
27. Compound according to anyone of claims 1-26 wherein, R3 is halo, hydroxy, amino, nitro, Ci ealkyl, carbonyl, carbonylCi ealkyl, cyano, B-A, B-L-A, or OP(=0)(OR14)2.
28. Compound according to anyone of claims 1-27 wherein R3 is hydroxy, amino, Ci ealkyl, carbonyl, or OP(=0)(OR14)2.
29. Compound according to anyone of claims 1-28 wherein R3 is hydroxy, Ci- ealkyl, or OP(=0)(OR1 )2.
30. Compound according to anyone of claims 1-29 wherein anyone of X1, X2, and/or Y is substituted with L-SG, SG, halo, nitro, carbonyl, cyano, OP(=0)(OR14)2, Ci-3alkylC(=0)N(R6)Ci-6alkylaryl, Ci-6alkylS02NR7R8, S02NR7R8, Ci-ealkyl OS02 NR7R8, OSO2 NR7R8, Ci-6alkylN(R9)S02NR7R8, N(R9)S02NR7R8, Ci- 6alkylN(R6)C(=0)N(R6)Ci-6alkylaryl, Ci-6alkylN(R6)C(=S)N(R6)Ci-6alkylaryl, Ci- 6alkylN(R6)C(=0)N(R6)aryl, or
Figure imgf000102_0001
wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OS02 NR7R8; and wherein the aryl is optionally further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2- 6alkynyl, Ci ealkyloxy, di(Ci-6alkyl) amino, hydroxy amino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, , hydroxyCi ealkyl, aminoCi ealkyl , cyano, or
OP(=0)(OR14)2> more preferably halo or cyano, even more preferably halo.
31. Compound according to anyone of claims 1-30 wherein X1, X2, and/or Y is substituted with SG, L-SG, Ci-3alkylC(=0)N(R6)Ci-6alkylaryl, Ci-6S02NR7R8, S02NR7R8, Ci-6OS02 NR7R8, OS02 NR7R8, Ci-6N(R9)S02NR7R8, N(R9)S02NR7R8, Ci- 6N(R6)C(=0)N(R6)Ci-6aryl,
Figure imgf000102_0002
or Ci-6N(R6)C(=S)N(R6)aryl; wherein the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OS02 NR7R8; and wherein the aryl is further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci ealkyloxy, di(Ci-6alkyl)amino, hydroxyamino, hydroxycarbonyl, carbonyl, carbonylCi ealkyl, carbonylCi ealkyloxy, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, , hydroxyCi ealkyl, aminoCi- ealkyl , cyano, or OP(=0)(OR14)2.
32. Compound according to anyone of claims 1-31 wherein X1, X2, and/or Y is substituted with an aryl comprising moiety and wherein the aryl in X1, X2, or Y is further not substituted.
33. Compound according to anyone of claims 1-31 wherein X1, X2, and/or Y is substituted with an aryl comprising moiety and wherein the aryl in X1, X2, or Y is further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2-6alkynyl, Ci- 6alkyloxy, carbonyl, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3-7Cycloalkyl, , hydroxyCi ealkyl, aminoCi ealkyl , cyano, or OP(=0)(OR14)2> preferably the aryl in X1, X2, and/or Y is further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci ealkyl, C2-6alkenyl, C2- 6alkynyl, Ci ealkyloxy, carbonyl, Ci ealkylcarbonyl, NR4R5, heterocyclic, C3- 7Cycloalkyl, , hydroxyCi ealkyl, aminoCi ealkyl , cyano, or
Figure imgf000103_0001
more preferably, the aryl in X1, X2 and/or Y, is further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, carbonyl, NR4R5, cyano, or
Figure imgf000103_0002
more preferably the aryl in X1, X2, and/or Y is further substituted with a substituent selected from the group comprising hydrogen, halo, hydroxy, amino, nitro, Ci- ealkyl, or OP(=0)(OR1 )2.
34. Compound according to anyone of claims 1-33, wherein X1, X2, and/or Y is substituted with an aryl comprising moiety and wherein the aryl in X1, X2, and/or Y is substituted with a S02NR7R8 or OSO2 NR7R8, or a N(R9)S02NR7R8.
35. Compound according to anyone of claims 1-34, wherein X1, X2, and/or Y is substituted with SG, L-SG, preferably substituted with Ci-3C(=0)N(R6)Ci- ealkylaryl, Ci-6alkyl N(R6)C(=0)N(R6)Ci-6alk
ealkylaryl,
Figure imgf000103_0003
or
36. Compound according to anyone of claims 1-35, wherein X1, X2, and/or Y is substituted with SG, L-SG, preferably substituted with Ci-6alkylS02NR7R8, S02NR7R8, Ci-6alkylOS02 NR7R8, OSO2 NR7R8, Ci-6alkylN(R9)S02NR7R8, or
N(R9)S02NR7R8.
37. Compound according to anyone of claims 1-36, wherein in case X1 and/or X2 and/or Y is substituted with a substituent selected from the group comprising Ci-3alkylC(=0)N(R6)Ci-6alkylaryl, Ci-6alkylS02NR7R8, S02NR7R8, Ci-ealkyl OSO2 NR7R8, OSO2 NR7R8, Ci-6alkylN(R9)S02NR7R8, N(R9)S02NR7R8, Ci-
Figure imgf000103_0004
6alkylN(R6)C(=0)N(R6)aryl, Ci-6alkylN(R6)C(=S)N(R6)aryl; and wherein in the case the aryl is substituted with a S02NR7R8, N(R9)S02NR7R8, or OSO2 NR7R8, then R2 is hydrogen.
38. Compound according to anyone of claims 1-37, wherein R4, R5 is each independently hydrogen, hydroxy, or Ci-ealkyl, more preferably Ci salkyl, more preferably Ci-2alkyl, more preferably Cialkyl.
39. Compound according to anyone of claims 1-38, wherein R4, and/or R5 is hydrogen.
40. Compound according to anyone of claims 1-39, wherein R6 is hydrogen, hydroxy, or Ci ealkyl, more preferably Ci salkyl, more preferably Ci-2alkyl, more preferably Cialkyl.
41. Compound according to anyone of claims 1-40, wherein R6 is hydrogen.
42. Compound according to anyone of claims 1-41, wherein R7, R8 is each independently hydrogen, hydroxy, or Ci ealkyl, more preferably Ci salkyl, more preferably Ci-2alkyl, more preferably Cialkyl.
43. Compound according to anyone of claims 1-42, wherein R7 and/or, R8 is hydrogen.
44. Compound according to anyone of claims 1-43, wherein R9 and/or R10, is each independently hydrogen, hydroxy, or Ci ealkyl, more preferably Ci salkyl, more preferably Ci-2alkyl, more preferably Cialkyl.
45. Compound according to anyone of claims 1-44, wherein R9 and/or R10, is hydrogen.
46. Compound according to anyone of claims 1-45 wherein, R3 is NR4R5, and wherein R4, and R5 are -CH2-CH2-Z, wherein Z is a leaving group selected from the group consisting of halogen, tosylate, mesylate, fluorosulfonates, triflates, nonaflates, preferably Z is a selected from the group consisting of iodide, bromide, chloride, mesylate or tosylate.
47. Compound according to anyone of claims 1-46 selected from the group consisting of
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Compound 71
48. Compound according to anyone of claims 1-47 for use in the treatment of cancer.
49. Compound according to anyone of claims 1-47 for use according to claim 48 wherein the cancer is selected from the group of breast carcinoma, brain carcinoma, kidney carcinoma, colorectal carcinoma, lung carcinoma, head and neck carcinoma, esophageal carcinoma, hepatocellular carcinoma, cholangiocarcinoma, renal eel carcinomal, testis carcinoma, cervix carcinoma, endometrium carcinoma, ovarian carcinoma, Squamous cell carcinoma, Basal cell carcinoma, Glioma, Ependymoma, mesothelioma, papillary thyroid carcinoma, thyroid carcinoma, follicular thyroid carcinoma, follicular lymphoma, non-Hodgkin's lymphoma, adenocarcinoma, stomach carcinoma, duodenum carcinoma, biliary carcinoma, pancreas carcinoma, , and bladder carcinoma.
50. Compound according to anyone of claims 1-47 for use according to claim 48 or 49 wherein the cancer is colorectum cancer.
51. Compound according to anyone of claims 1-47 for use in the treatment of infections caused by bacteria, fungi, protozoa, and/or mycoplasma.
52. Treatment of cancer comprising administering a compound according to anyone of claims 1-47.
53. Treatment of infections caused by bacteria, fungi, protozoa, and/or mycoplasma comprising administering a compound according to anyone of claims 1-47.
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EP3684781A4 (en) * 2017-09-19 2022-06-29 The Governors of the University of Alberta Bioreductively-activated compounds, their prodrugs, radiopharmaceuticals, the compositions, and their applications in multimodal theranostic management of hypoxia diseases including cancer

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